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* Corresponding authors. Tel.: þ34 93 4039106 (P.R.); tel.: þ34 93 4021247 (F.U.).
E-mail addresses: pedro.romea@ub.edu (P. Romea), felix.urpi@ub.edu (F. Urpı́).
0040-4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.11.092
2684 I. Larrosa et al. / Tetrahedron 64 (2008) 2683e2723
R1
O
O R2
N
O OMe O O O
O
H N OMe O O
O N O
MeO OMe O O
O Br N
O O
OH
OH
Figure 1.
1. Introduction and scope The aim of this report is to highlight Type 1 methodologies
addressed to the stereoselective construction of di- and tetra-
Six-membered oxygenated heterocycles, or pyrans, are prob- hydropyrans and their application to the synthesis of natural
ably one of the most common structural motifs spread across products, with special attention being paid to the most recent
natural products, from simple glucose to structurally complex contributions.
metabolites such as leucascandrolide A (1),1 phorboxazole A
(2a) and B (2b),2e4 and the even more elaborated architectures
present in palytoxin, maitotoxin, and other marine natural prod- 2. SN2-Mediated cyclizations
ucts (Fig. 1).5
Due to the remarkably rich array of functionalities and chiral Transformations based on an SN2-mediated cyclization of
centers that these heterocycles can incorporate, their stereose- a hydroxy precursor represent the simplest strategy leading
lective preparation has become a continuous challenge for to di- and tetrahydropyran. They only require a suitable com-
organic synthesis practitioners.6e10 They can be synthesized bination of base (B: tertiary amine, alkoxide, hydride; see
by means of five-membered ring expansions (e.g., BaeyereVil- Scheme 1) and leaving group (X: sulfonate, halide; see
liger oxidation of cyclopentanones11), cycloaddition processes Scheme 1) to promote a 6-exo-tet process16 with inversion of
(e.g., Hetero-DielseAlder reactions12), or intramolecular cycli- the configuration at the CeX center in accordance with the
zations.13 Classical examples of these cyclizations are the pattern dictated by the Williamson reaction (see path A in
lactonisation of d-hydroxy acids or the thermodynamically Scheme 1). Thus, the stereochemistry of the resulting tetrahy-
favorable conversion of d-hydroxy aldehydes into the corre- dropyran relies exclusively on the configuration of the acyclic
sponding hemiacetals, which, in turn, can be easily modified precursor.
(e.g., C-glycosidation reactions14) to provide other pyran-based
structures. In addition to these processes, there is a set of impor- path A path B
tant methodologies based on the cyclization of an oxygenated B
OH X
precursor that affords pyran structures in a highly efficient
and straightforward manner.
Considering the crucial ring-forming step (or the parallel O X OH
transform in the retrosynthetic sense), the cyclization methodol-
ogies can be classified into three types, represented in Figure 2.
–H
Type 1 gathers those methodologies based on O1eC2 bond
O
formation15 (or disconnection in the retrosynthetic sense),
which encompass SN2- and SN1-mediated cyclizations, metal- Scheme 1.
promoted processes, and Michael-like reactions. Likewise,
Type 2 and 3 methodologies affect C2eC3 and C3eC4 bond With regard to the reactivity of such systems, cyclizations
formation, respectively, which include Prins sequences, Peta- that involve leaving groups placed on a primary position
siseFerrier rearrangements, or ring-closing metathesis take place smoothly,17 whereas those located on a secondary
reactions. position often require a more accurate control of the reaction
conditions.18 Even in such a challenging situation, this strat-
egy enjoys an interesting synthetic potentiality, as has been
4 clearly proved in the successful construction of tetrahydropyr-
3 3 ans embedded in leucascandrolide A (1),1f and phorboxazole
O 2
O 2
O A (2a)2d and B (2b).3b Noteworthy, either 2,6-cis-tetrahydro-
1
pyran (see 4 and 8 in Scheme 2) or 2,6-trans-tetrahydropyran
Type 1 Type 2 Type 3
(see 6 and 10 in Scheme 2) is obtained by simple application
Figure 2. of the same experimental conditions. Thus, both stereochemistries
I. Larrosa et al. / Tetrahedron 64 (2008) 2683e2723 2685
S 7 S 7
NaH
S OH OTs PhH, 90 °C S O
3 3
OPMB 75% OPMB 11 7 OTBDPS
3 4
TBSO OTs OMe O
15 3
11 7 OTBDPS OTBS OPMB
1) HF·pyr, pyr 5
1 O OMe O
15 3 2) NaH, PhH, 60 °C
OH OPMB 73%
6
OH
OTBDPS OTBDPS
15 11 15 11
O O
O 9 NaH O 9
2a N N
O PhH, TsO
5
PMBO PMBO
5 89% HO
PivO 10 9 OPiv
Scheme 2.
O
OTBDPS
N
O
Br
OMe O
OR1 OR2
MeO O OPMB 5
N
O
OMe
OTBDPS OTBDPS Et3N
11 R1: H R2: TES MeCN,
MsCl, Et3N, 99% O
12 R1: Ms R2: TES OTBDPS 86%
PPTS cat., MeOH, 98% N
13 R1: Ms R2: H
O
Br 9
OMe O
2a
O
MeO O OPMB 5
N
O
OMe
OTBDPS 14 OTBDPS
Scheme 3.
2686 I. Larrosa et al. / Tetrahedron 64 (2008) 2683e2723
HO
OTBS 12b OTBS 12b OTBS 12b
O
45%
H H H dr 5:1 H
15 16 17
Scheme 4.
Thereby, cyclization of benzylic allylic alcohol 15 during cyclizations. For instance, treatment of carbonates 22a or
an aqueous work-up is supposed to proceed through cationic b (Scheme 7) with BF3$OEt2 followed by protecting group
intermediate 16, which undergoes ring closure followed by transformations furnishes 2,6-cis-tetrahydropyran 23a or b as
the release of the silicon protecting group (Scheme 4).19d a sole diastereomer through a putative propargylic carboca-
The stereochemistry of the major diastereomer 17 arises tion,24 which has provided a new entry to a formal synthesis
from the preferential attack of the OTBS oxygen from the of (þ)-muconin 24.25
opposite side of C12b methyl.
Better results are typically obtained for 2,6-cis-tetrahydro- 4. Epoxide-mediated cyclizations
pyrans, which are usually the most stable diastereomers. For
instance, construction of the C22eC26 2,6-cis-tetrahydro- Since the seminal studies on the intramolecular epoxide
pyran of phorboxazole A (2a) has been achieved through an opening carried out by Nicolaou et al.26 established the struc-
intramolecular SN1-mediated cyclization of alcohol 18, as tural criteria required for the regio- and stereocontrolled
shown in Scheme 5. Actually, the stereochemical outcome of synthesis of six-membered oxygenated heterocycles overrid-
this transformation is consistent with the internal capture of ing the competitive formation of the corresponding five- or
a transoid allylic cation at C26 by the C22 b-methoxymethyl seven-membered counterparts, acid-catalyzed cyclizations of
ether and dealkylation of the resulting oxonium species.2d,21 hydroxy epoxides have become a common approach to the
Propargylic carbocations can also participate in these stereoselective construction of tetrahydropyrans.27
cyclizations, since they are easily generated by treatment of The regioselectivity of the cyclization for g-hydroxy epox-
Co2(CO)6ealkynol complexes with either Brønsted or Lewis ides greatly depends on the geometry of the epoxide. Indeed,
acid22 and are stable enough to be intramolecularly trapped cis-epoxides reliably afford the 5-exo ring closure probably
by oxygenated nucleophiles. Indeed, ring closure of diol 20 because these systems do not easily assume the planar ar-
affords tetrahydropyrans 21 in excellent overall yield (Scheme rangements necessary for maximum stabilization in the transi-
6).23 Remarkably, the thermodynamically more stable 2,3- tion states leading to six-membered rings (Eq. 1 in Scheme 8).
trans derivative is increasingly obtained with long reaction On the other hand, trans-epoxides enable the desired 6-endo
times or higher temperatures. process provided that a p-orbital adjacent to the epoxide
Furthermore, epoxides can also act as nucleophiles and, in unit activates the CeO bond close to it and stabilizes the
particular, precursors containing a protected epoxy alcohol developing positive charge in the transition state (Eq. 2 in
moiety participate in highly regio- and stereoselective Scheme 8). In both cases, these cyclizations are accompanied
OMOM OPMB
22
OH 22 OPMB O
Tf2O, pyr
N 26 OTES N 26 OTES 2a
R CH2Cl2, –20 °C R
O 55% O
18 19
Scheme 5.
H H
OBn OBn OBn
1) BF3·OEt2, CH2Cl2, T, t
+
Co2(CO)6 2) CAN, acetone, 0 °C
HO HO O O
H H
C5H11 T (°C) t (h) trans-cis Yield (%) C5H11 C5H11
20 21-trans 21-cis
20 0.33 10:1 94
–20 2.5 1.2:1 70
–20 18 9.9:1 87
Scheme 6.
I. Larrosa et al. / Tetrahedron 64 (2008) 2683e2723 2687
TMS Co2(CO)6 OH
O O
OBoc OBoc
22a OH TMS Co2(CO)6 22b
BF3·OEt2, CH2Cl2 BF3·OEt2, CH2Cl2
–20 °C, 4 h rt, 3 h
t-BuO
O O O
TMS
O (CO)6Co2
(CO)6Co2 O
O
TMS Ot-Bu
OH (CO) 6Co2
O OH
(CO)6Co2 OBoc TMS OH
O
1) CAN, acetone, rt, 30 min
TMS
1) Ac2O, CH2Cl2, rt, 30 min 55% 2) K2CO3, MeOH, rt, 6 h
70%
2) CAN, acetone, rt, 10 min 3) CH2(OMe)2, CSA, rt , 3 h
OAc
OBoc
O O O
O
23a 23b
O O
O OH OH
n-C12H25
OH (+)-muconin 24
Scheme 7.
H H
HO HO 7-endo
HO 5-exo 6-endo 6-exo
O O (1) O (3)
H favored favored HO
R R OH R O R HO R O
H OH H
cis epoxide R
cis epoxide
H H
5-exo 6-endo HO HO 6-exo
HO 7-endo
O O (2) O (4)
H favored favored favored favored HO
R R OH R O R H O R O
R: CH2X R: CH=CH2 H R: CH=CH2 OH R: CH2X H
trans epoxide R
trans epoxide
Scheme 8.
Scheme 9.
6-exo
HO OH OH 5-endo
O Ph O
O H3O
O HO
O Ph OTs
OH
HO 26 7-endo 27 OTs
OH
1) 10% HCl, rt, 18 h
62% 2) 10% NaOH, rt OH
3) 10% HCl, rt, 4 h
O O
O O Ph O
(+)-sorangicin A Ph H3O
O HO 5-exo
25
6-endo
O
HOOC 29 OH 28
Scheme 10.
6-exo 22
PMBO OH O
26 Ti(i-PrO)4
HO 22 HO 26 OPMB 2a
O PhH,
OH
76%
30 31
Scheme 11.
As pointed out in Scheme 8, alkenes adjacent to epoxides 8) were highly desirable. In this context, it has been recently
override the common bias favoring the 5-exo ring-closure reported that epoxide openings triggered by bulky silyl triflates
mode. This is the behavior observed in the intramolecular in nitromethane yield the desired tetrahydropyrans regioselec-
cyclization of a,b-unsaturated epoxide 33, which permits the tively.34 In addition to these observations, the regioselective
regio- and stereoselective preparation of a densely substituted tenet summarized in Scheme 8 favoring 5-exo over 6-endo
C8eC12 tetrahydropyran directed toward the synthesis of bre- ring closures of g-hydroxy epoxides has recently been chal-
venal (32 in Scheme 12).31 Indeed, removal of the PMB group lenged in vanadium-catalyzed mediated processes.35 As out-
on 33 triggers a 6-endo cyclization to a tetrahydropyran, which lined in Scheme 14, the asymmetric oxidation of unsaturated
is subsequently converted into TES ether 34.32 a-hydroxy esters followed by an epoxidation/cyclization se-
Occasionally, these methodologies are combined in a syn- quence using the same chiral catalyst provide regio- (6-endo/
thetic sequence. For instance, the tristetrahydropyran substruc- 5-exo ratio ca. 4:1) and stereoselectively (dr>88:12, ee>95%)
ture of diol 35, an advanced intermediate toward the synthesis 2,5-trans-tetrahydropyrans in 20e35% yield (the highest theo-
of thyrsiferol and venustatriol (36a and 36b, respectively, in retical yield is 50%).
Scheme 13), has been regio- and stereoselectively prepared Hence, this process is divided into two steps. The first step
through three intramolecular cyclizations of g- and d-hydroxy involves the oxidative resolution (acetone/O2) of a racemic
epoxides.33 The first acid-catalyzed ring closure of hydroxy mixture of a-hydroxy esters (R1, R2sH) using a vanadium
epoxide 37 proceeds quantitatively to form 38 with complete catalyst prepared from VO(i-PrO)3 and the chiral Schiff base
6-exo regioselectivity,y and no competitive 7-endo cyclization 42. Once the alcohol has been chemo- and stereoselectively
is observed. Next, the construction of tetrahydropyran B takes oxidized, change of solvent and oxidant to CHCl3/t-BuOOH
advantage of the allylic character of a trans-epoxide. Indeed, promotes a stereoselective epoxidation followed by a fast
cyclization of hydroxy diepoxide 39 affords the desired six- cyclization of the resultant hydroxy epoxide. The mechanistic
membered heterocycle 40 under very mild conditions with model that accounts for the stereochemical outcome of the
excellent 6-endo regioselectivity. Eventually, Ti(i-PrO)4 acti- overall process emphasizes the coordination of the ester
vation of hydroxy epoxide 41 produces the third ring in 58% carbonyl to the metal. Such a coordination places the ester
yield. in the pseudoaxial position, which allows an efficient p-facial
In spite of these accomplishments, it was soon realized that discrimination of the carbonecarbon double bond. Finally, the
new methodologies able to switch 5-exo to 6-endo processes resultant short-lived epoxide undergoes a backside attack of
irrespective of the substituent R (see Eqs. 1 and 2 in Scheme the hydroxyl to the corresponding 2,5-trans tetrahydropyran.36
The pursuit for regioselective 6-endo cyclizations has found
its own Holy Grail in the synthesis of fused polycyclic ethers,
a family of marine metabolites with remarkable biological ac-
y tivity.9 As partly suggested by the name, their molecular archi-
Actually ring closure to tetrahydropyran A is carried out on a 1:1 epimeric
mixture of 3-bromo derivatives. Interestingly, the experimental conditions pro-
tectures contain large and highly rigid polycyclic frameworks
vide a highly efficient kinetic resolution and just hydroxy epoxide 37 un- of all fused six- to nine-membered oxygenated rings in a well-
dergoes the desired cyclization. defined stereochemical arrangement, as shown in Figure 3.
I. Larrosa et al. / Tetrahedron 64 (2008) 2683e2723 2689
12 H
1) DDQ, CH2Cl2-H2O, rt OTES
8 O 8 12
TBDPSO 2) TESOTf, 2,6-lut, CH2Cl2, 0 °C TBDPSO
OPMB O
H Me
89%
33 34
6-endo
Me OH
H H H H
8 O O Me
brevenal 32
H O 12 O
Me O H H
OHC H Me
OH
Scheme 12.
The synthesis of these large and complex structures has polyepoxide with the structural elements to allow for the
raised much interest in strategies rooted on biogenetic regio- and stereoselective 6-endo ring closures required for
grounds. Unfortunately, the biosynthesis of these metabolites the fused tetrahydropyran arrays. Otherwise, alternative path-
is not well understood and current working hypotheses are ways based on 5-exo cyclizations leading to tetrahydrofurans
rather speculative. In this context, the CaneeCelmereWestley would predominate (Scheme 15).39
model, originally proposed for the synthesis of polyether anti- In this context, a biomimetic approach takes advantage of
biotics,37 has inspired most of those hypotheses, which envis- endo-selective cyclizations of methoxymethyl epoxy alcohols
age that the fused polycyclic ether frameworks might arise controlled by chelation with a suitable Lewis acid. Indeed,
from the cyclization of a polyepoxide precursor through a the asymmetric epoxidation of polyene 43 leads to 44 in 56%
cascade of SN2 ring openings.38 Therefore, any biomimetic isolated yield, and removal of the silicon protecting group pro-
strategy must be able to provide a synthetic route to a chiral vides quantitatively triepoxide alcohol 45 (Scheme 16). Then,
R
35 R : OH
O OH HO
H
B C thyrsiferol, 36a R: O
O OH
O
A HO
H
Br venustatriol, 36b R: O
OH
O
Br 40 mol% CSA O
OH
HO OAc Et2O,rt, 0.5 h A
OAc
37 Br 38
100%
OH
B 1 equiv PPTS B O
O OTBS O OTBS
O CHCl3, rt, 5 min OH
A O A O
Br 40 70% Br 39 OH
OH O OH
B 0.9 equiv Ti(i-PrO)4 B C
O OH O
O PhMe, 70–80 °C, 3 h O
A O A
Br 41 58% Br 35
Scheme 13.
Scheme 14.
2690 I. Larrosa et al. / Tetrahedron 64 (2008) 2683e2723
O O
O
O O O
MeCN, (MeO)2CH2, 0 °C 1.1 equiv La(OTf)3
OR OR 0.3 equiv La2O3
MeO 56% MeO 5.5 equiv H2O
43 R: TBDPS TBAF, THF 44 R: TBDPS CH2Cl2, rt
100% 45 R: H Me
MeO OMe OMe H OMe O
H H
HO O O O La
R R
O O
R
O O HO O La O O
H H 9% H H
OMe O H
OMe
46 Me
Scheme 16.
I. Larrosa et al. / Tetrahedron 64 (2008) 2683e2723 2691
O O
R O BF3 R O
O O O O BF3
O O O
O O
R O R O R O O
BF3 BF3 BF3
O O O
tertiary carbocation ion pair epoxonium ion
H H
O O
O O
BF3 BF3
R O O R O O
Me Me
cis-fused trans-fused
O
H Me
O OH
Me2N O 0.01 M BF3·OEt2 O
O O O
CH2Cl2, 20 °C O O
O
Me H
31%
47 48
Scheme 17.
H H H H H
HO 1) Cs2CO3, CsF, MeOH, O O
TMS
O O
2) Ac2O, DMAP, pyr, CH2Cl2
O AcO O O
O H H H H H
TMS TMS 20%
49 50
Scheme 18.
6-exo
E
+E –H
E E –E
OH OH O O
6-exo
complex
–H
OH
onium intermediate
Scheme 19.
2692 I. Larrosa et al. / Tetrahedron 64 (2008) 2683e2723
H HgOAc
OBOM OBOM
3 7 Hg(OAc)2 H NaCl aq. 3 7
OH R CH2Cl2, rt XcCO OH O R
H OBOM
COXc R COXc X
H 99%
52 53 54 X: HgCl
n-Bu3SnH
55 X: H
PhMe
O OH
3 7 94%
HO O O O O O
OH OH OH
OH O
X-206 OH
51
Scheme 20.
attack of the d-OH, which causes an inversion in the configura- the complex and intricate array of sensitive functional groups
tion of the reacting center (Scheme 22). Hence, the stereochem- embedded in their structure and, only in 2004, have Nicolaou
ical outcome of these cyclizations mostly depends upon the et al. reported the correct structure of azaspiracid-1 after con-
configuration of the cyclopropane ring.46 siderable synthetic work. It is, then, not surprising that the
This strategy has been applied to the construction of the C3e endeavors applied to the construction of such challenging
C7 tetrahydropyran of zincophorin (58 in Scheme 23).47 The compounds have spurred the development of new strategies
cyclopropane ring of the advanced intermediate 59 is installed (see also Schemes 57 and 91). As represented in Scheme 24,
at the beginning of the synthesis by means of the catalytic the intramolecular iodoetherification of the structurally com-
asymmetric cyclopropanation of an allylic diazoacetate. plex alcohol 63 affords iodoether 64, which is reduced with
Then, simple treatment of 59 with Hg(OCOCF3)2 followed by an excess of n-Bu3SnH in toluene to remove the superfluous
aqueous work-up cleanly produces 2,6-trans-tetrahydropyran iodine at C29. Thus, the highly advanced intermediate 65 is
60. In turn, this organomercuric bromide is subjected to a reduc- obtained through this two-step sequence in 53% yield.
tive demercuriation, which eventually provides 61 in 85% yield Iodoetherification on substrates containing an allylic alco-
and 93:7 dr. hol turns out to be highly dependent on conformational issues.
Indeed, diol 66a undergoes a facile cyclization to 2,6-cis-tetra-
5.1.2. Halo-mediated cyclizations hydropyran 67a, while the diastereomer 66b fails to give the
Halo-mediated cyclizations are similar to the processes expected bicyclic system 67b (Scheme 25).48e The rationale
based on mercury(II) salts. Most of the intramolecular halo- for such different behavior relies on the conformational anal-
etherification reactions take advantage of the use of iodine ysis of the allylic moiety. Cyclizations in which the nucleo-
or N-iodosuccinimide (NIS),48e50 reagents mild enough to phile is in the R group proceed rapidly (or slowly) through
be used on structurally complex substrates. For instance, the favored p-complex 68a (or the disfavored p-complex
NIS-mediated iodoetherification plays a crucial role in the as- 68b) when CeOH (or CeH) eclipses the carbonecarbon dou-
semblage of the G-ring of azaspiracid-1 (62 in Scheme 24), ble bond. This is the situation for 66a (or 66b). Thus, cycliza-
a prominent member of a family of marine metabolites respon- tion of 66b requires a more reactive iodinating agent such as
sible for human poisoning resulting from the consumption of bis(sym-collidine)2IPF6, prepared in situ from bis(sym-collidi-
tainted shellfish. Initially reported in 1998, azaspiracids were ne)2AgPF6 and iodine in CH2Cl2. This reagent converts 66b
shrouded in structural ambiguity that partially arises from into the desired tetrahydropyran 67b in 80% yield.
I
22 22
OH 1) Hg(OAc)2, PhMe, 0 °C, 8 h O
2b
26 OH 2) I2, rt, 12 h 26 OH
O O
O 71% O
56 57-cis
Scheme 21.
reductive
HgX2 demercuriation
HO OH HO OH –HX O OH O OH
Hg HgX
X X
Scheme 22.
I. Larrosa et al. / Tetrahedron 64 (2008) 2683e2723 2693
CO2Me
H
O O
O
N
O N 0.1% Rh2[5R-MEPY]4
Rh Rh N2
O O
N NOO CH2Cl2,
Rh2[5R-MEPY]4
91% ee > 95%
O 1) Hg(OCOCF3)2, CH2Cl2, rt O
BzO BzO
O OH 2) KBr aq. O OH
H
R 59
60 R: HgBr n-Bu3SnH, PhMe-THF
O OH OH OH
61 R: H –60 °C to rt 3 7
85% dr 93:7 HO O
OH
zincophorin
58
Scheme 23.
H O H H I2
HO I2, NaHCO3 HO O
O H
O R OH O
MeCN H
I R OH
H O 0 °C to rt, 2.5 h I2 H 70% H O
HO HO favored complex
66a 67a 68a
H O H H
HO I2, NaHCO3 HO O
O O R
O R H
MeCN H
I HO H
H O < 5% H O I2
HO I2 OH HO
66b 67b disfavored complex
(collidine)2AgPF6, I2, CH2Cl2, rt, 2.5 h 68b
80%
Scheme 25.
2694 I. Larrosa et al. / Tetrahedron 64 (2008) 2683e2723
OR1
O R E O R O R R1OH O
E E R
E –H
Scheme 26.
O 5 O
NBS Br OMe
MeOH, MeCN TESO 4
TESO
O 59% O AcO O O
70 72 O 5 1 OH
5 O OMe
O N HO
NBS Br H O
MeOH, THF TESO 4 FR-901464
TESO
O 47% O 69
71 73
Scheme 27.
outcome of the selenoetherification reactions mostly relies on of pyrans relies on the intramolecular cyclization of hydroxy
the coordination of electrophiles such as phenylselenyl chlo- alkenes, which implies the suitable activation of the olefin
ride (PhSeCl) or N-phenylselenophthalimide (NPSP) with with a palladium catalyst and the subsequent intramolecular
the olefin, which is then followed by the ring-closure step. attack by the alcohol.
Therefore, the stereoselectivity of these cyclizations reflects Since the reactivity of palladium catalysts is dominated by
the kinetic selectivity for the formation of the onium interme- their oxidation states, Pd(0) and Pd(II) complexes are consid-
diate, which may give access to 2,6-trans-tetrahydropyrans. ered independently. Indeed, Pd(0) complexes are fairly nucleo-
This is the trend observed for hydroxy alkene 74. As shown philic and the cyclizations of d-hydroxy alkenes leading to
in Scheme 28, 2,6-trans-tetrahydropyran 75-trans is only pyrans progress via the p-allylpalladium cations (TsujieTrost
obtained through a selenium-mediated cyclization, whereas reaction). Otherwise, parallel processes involving Pd(II) com-
75-cis results from the other methods.50 plexes take advantage of their electrophilic character and
A more selective reagent has been used for the assemblage of commonly proceed through the fast and reversible formation
the C11eC15 2,6-trans-tetrahydropyran of leucascandrolide A of p-complexes with the carbonecarbon double bond, which
(1) from diol 76 (Scheme 29).1d Unexpectedly, iodine-based next undergo an intramolecular attack by the nucleophile.
electrophiles show little diastereoselectivity, but this is dramat-
ically improved by the use of selenium reagents. Remarkably, 5.2.1.1. Catalysis by Pd(0). Palladium(0) complexes catalyze
the bulky 2,4,6-triisopropylphenylselenyl bromide (TIPPSeBr)z the cyclizations of d-hydroxy alkenes containing allylic leav-
affords 2,6-trans-tetrahydropyran 77 in 74% yield and good ing groups (X: OAc, OCO2R, OPO(OR)2, OAr, Cl, Br). As
diastereomeric ratio (dr 88:12). Eventually, a tin-free radical shown in Scheme 30, the initial p-complex evolves through
reduction of 77 provides the desired advanced intermediate 78 a h3-complex to a p-allyl cation, a highly reactive intermedi-
in 85% yield. ate that undergoes intramolecular attack of the hydroxyl to
provide the corresponding pyran. The regioselectivity of this
5.2. Catalytic cyclizations cyclization is rarely a problem, since 6-exo ring closures are
more favored than their competitive 8-endo counterparts.
5.2.1. Palladium-mediated cyclizations From a stereochemical point of view, substrate-controlled
In spite of the achievements mentioned above, the use and cyclizations usually proceed with retention of configuration
removal of stoichiometric amounts of often toxic elements at the reacting center. Coordination of the palladium to the
have fueled research into alternative activators of olefins that carbonecarbon double bond occurs on the less-hindered face
allow the desired intramolecular cyclizations under mild con- opposite to the leaving group and the nucleophile adds to
ditions and in a catalytic fashion. In this context, catalytic the cationic p-allylpalladium complex on the opposite face
methodologies based on the activation of olefins are domi- to the metal. Thus, a net retention of the stereochemistry is
nated by the palladium chemistry, which has achieved promi- observed.57 Studies on the assemblage of the tetrahydropyran
nent levels of maturity.13e,56 In this arena, the construction of moiety embedded in zampanolide (79 in Scheme 31) have
heterocycles can proceed through carbonecarbon or carbone demonstrated how highly diastereoselective this strategy can
heteroatom bond formation, depending upon the nucleophile be. Indeed, Pd(0)-mediated cyclizations of both 80a and 80b
involved in the ring-closure step. In particular, the synthesis afford, respectively, 2,6-cis- and 2,6-trans-tetrahydropyrans
81 as a single diastereomer in good yields under very mild
conditions.58
Palladium(0) catalysts also offer the opportunity for enan-
z
TIPPSeBr is prepared in situ from (TIPPSe)2 and bromine. tioselective cyclizations. Trost et al. have proved that
I. Larrosa et al. / Tetrahedron 64 (2008) 2683e2723 2695
Scheme 28.
OTBS 11 OTBS
TIPPSeBr, DTBMP
1
OH OH O CH2Cl2, –78 °C, 2 h O OH O
O 15
OH O
CO2Me 74% X CO2Me
dr 88:12 OH
O TBS
O 76 77 X: TIPPSe MeO OMe
, AIBN, hexane,
78 X: H
85%
Scheme 29.
BnO BnO
OCO2Et
OBn OBn
HO 5 mol% Pd(PPh3)4 O
O
THF, rt O HO
O O
80a 71% 81-cis N
H
BnO BnO
OCO2Et O
OBn OBn
HO 5 mol% Pd(PPh3)4 O zampanolide
THF, rt 79
Scheme 31.
2696 I. Larrosa et al. / Tetrahedron 64 (2008) 2683e2723
Scheme 32.
EtO2CO H
OBn OBn
HO Pd(0) O Pd(II) R
HO PdII
THF, rt PdII R O
ligand dr δ 2,6-cis
1,3-axial interactions
PPh3 3:2 R OH H
87 88 PdII
83 1:2
Pd(II) R
ent-83 10:1 HO PdII
R O
1.3 mol% Pd2(dba)3·CHCl3 2,6-trans
Cbz Cbz
5.3 mol% ent-83
N OH OAc N O Scheme 35.
THF, rt
O 96% O
89 90
Scheme 33. unfavorable axial interactions are developed on the way to
2,6-trans isomers.
entry to oxygenated heterocycles. The regioselectivity of such The success of such a strategy is intimately related to the
cyclizations is commonly determined by the ring size, which regioselectivity of the b-hydride elimination step. Studies on
facilitates the acquisition of pyrans from d-hydroxy alkenes this issue have proved that it is highly solvent dependent,
through a 6-exo ring closure (Scheme 34).64e66 The nucleo- DMSO being the best choice,68 but, in spite of these accom-
philic attack of the hydroxyl on the corresponding p-complex plishments, these cyclizations have been scarcely applied to
usually occurs anti to the metal to produce a s-alkylpalladiu- the synthesis of natural products.69 This limitation has been
m(II) intermediate, which next undertakes a b-hydride elimi- overcome through the introduction of a hydroxy group at the
nation. Importantly, Pd(0) is produced in the final step and, allylic position.70 As represented in Scheme 36, the key fea-
consequently, a mild re-oxidant to transform Pd(0) back into ture of this process entails the coordination of the allylic alco-
Pd(II) without affecting the substrates or products is required hol, a0 -OH, to the metal. Then, the initial Pdep-complex is
to obtain a process catalytic in palladium; otherwise, the selectively formed on the same face of the double bond as
process must be carried out using stoichiometric amounts of the a0 -OH. This complex determines the approach of the d-
the Pd(II) complex.67 OH to the reacting center (syn attack) and, consequently, the
The rationale for the stereochemical outcome of these stereochemical outcome of the cyclization. Eventually, the re-
cyclizations usually hinges on the relative steric demands of sultant s-complex undergoes a selective Pd(II) elimination
the reversibly formed palladium intermediates.65 Attention is leading to a new olefinic bond. Hence, the overall sequence
then focused on the steric interactions engaged in the alterna- may be considered as a Pd-mediated SN20 process that can pro-
tive approaches outlined in Scheme 35. Hence, 2,6-cis ceed without any oxidant.
arrangements are often preferred, especially in the case where In this context, a chiral starting material can give access to
all the substituents are placed in equatorial positions or clearly disubstituted tetrahydropyrans stereoselectively (Scheme 37).
Pd(II)LnX2 –Pd(0)Ln
PdIILnX2
–HX PdIILnX –HX
OH OH O O
-complex -alkylpalladium
Scheme 34.
I. Larrosa et al. / Tetrahedron 64 (2008) 2683e2723 2697
α α α
PdCl2 δ
δ δ ClPd
OH OH O –HCl O –Pd(OH)Cl O
α' α' Pd Cl α' Pd H
OH O HO HO
Cl Cl
H Cl
π-complexes σ-complex
Scheme 36.
Indeed, chiral diols 91a,b afford 2,6-cis- or 2,6-trans-tetrahy- alkylpalladium(II) intermediate. This intermediate can then
dropyrans 92 as a single isomer in excellent yields, depending be trapped by CO and the resultant acylpalladium species is
upon the configuration of the allylic stereocenter, a0 , with per- easily converted into the corresponding methyl ester (Scheme
fect 1,3-chirality transfer. According to the mechanistic guide- 39). Thus, the overall process is a 1,2-alkoxycarbonylation that
lines presented in Scheme 37, the p-face selectivity observed avoids any b-elimination. In the case of chiral centers, the in-
in these cyclizations can be rationalized by considering con- sertion of CO into the carbonepalladium bond usually retains
formations on the a0 -stereocenter, so that the most favored the configuration that arises from the cyclization step, and
approaches avoid 1,3-allylic strain.71 so pyran-containing ester groups can be stereoselectively ob-
This strategy has been successfully applied to the construc- tained as a result of these transformations.72,73
tion of pyran rings embedded in the structure of laulimalide This methodology has been applied to the synthesis of leu-
(93 in Scheme 38). Moreover, it has been subjected to the cascandrolide A (1)1a and phorboxazole A (2a).2g As shown in
Pd(0)-mediated methodology described in Section 5.2.1 for Scheme 40, the intramolecular alkoxycarbonylation of diol 98
the synthesis of the C23eC27 dihydropyran 95. Both the Pd in 1:1 MeOHePhCN (the use of benzonitrile facilitates
complexes catalyze the 6-exo-like cyclization of 94 to 95 as a cleaner and more efficient process) provides the desired
a sole isomer in good-to-excellent yields. Furthermore, the 2,6-cis-tetrahydropyran 99 in 75% yield and dr >10:1. Note-
6-endo-trig cyclization of 96 occurs through a syn-SN20 pro- worthy is the fact that the cyclization is highly selective and
cess to give exclusively the desired 2,6-trans-dihydropyran the two alcohols and two alkenes in 98 are completely differ-
97 in 60% yield.70a entiated, which simplifies the protecting-group strategy. Fur-
As shown in Scheme 34, the Pd-mediated intramolecular thermore, the C22eC26 tetrahydropyran (101) of 2a is
addition of a hydroxyl group to an alkene leads to a s- prepared in high yield through the Pd(OAc)2-mediated
S 10 mol% PdCl2(MeCN)2 HO HO
OH THF, 0 °C H
R H H O
HO 72%
91a minimisation of 1,3-allylic strain 92-cis
H
S 10 mol% PdCl2(MeCN)2 OH OH
OH THF, 0 °C
S H H O
HO 79%
91b minimisation of 1,3-allylic strain 92-trans
Scheme 38.
2698 I. Larrosa et al. / Tetrahedron 64 (2008) 2683e2723
CO O MeOH O
with methyl acrylate in the presence of catalytic amounts of
PdIILnX Pd(OCOCF3)2, the chiral ligand 106, and p-benzoquinone
O O PdIILnX –Pd(0)Ln O OMe
–HX affords chroman 107 with 96% ee in 84% yield. This two-
-alkylpalladium step sequence is assumed to proceed via the enantioselective
Scheme 39. oxypalladation of 105. The resultant s-alkylpalladium com-
plex then undergoes a Heck reaction with methyl acrylate
and, finally, a b-hydride elimination delivers the desired
cyclization of hydroxy alkene 100, although 2.5 equiv of the product.
Pd(II) reagent is needed for complete conversion because of A conceptually different strategy to the synthesis of 2,3-di-
its reduction by CO during the course of the reaction (acetoni- hydro-4H-pyranones such as 109aec takes advantage of the
trile is used to minimize such deactivation).74 In turn, the par- reactivity of enones. As represented in Scheme 42, it relies
allel ring closure of 102 has been carried out in the presence of on the oxidative cyclization of b-hydroxy enones 108aec
a large excess of p-benzoquinone to afford 2,6-cis-tetrahydro- with PdCl2. Thus, this methodology represents a new approach
pyran 103 in 58% isolated yield. to the enantioselective assemblage of these useful intermedi-
The s-alkylpalladium(II) intermediates can also be trapped ates, based on a 6-endo ring closure of a Pd(II)ep-complex
through a Heck reaction. This possibility is nicely illustrated followed by a completely regioselective b-hydride elimina-
by a palladium-catalyzed sequence along the synthesis of a-to- tion, without affecting the integrity of the existing
copherol (104 in Scheme 41).75 Indeed, the reaction of 105 stereocenters.76
Scheme 40.
MeO MeO
PdLn(OCOCF3)2
oxypalladation PdLn(OCOCF3)
OH O
105
H2C=CHCO2Me
10 mol% Pd(OCOCF3)2 O
40 mol% 106 84% 96% ee insertion
OMe
p-benzoquinone
CH2Cl2, rt, 3.5 d
MeO MeO
O -HPdLn(OCOCF3) O
-hydride elimination
O OMe O OMe
107 PdLn(OCOCF3)
MeO
O
O N N
-tocopherol O
106
104
Scheme 41.
I. Larrosa et al. / Tetrahedron 64 (2008) 2683e2723 2699
Ph O Ph O Ph O Scheme 44.
109a 109b 109c
61% 74% 50%
118 with Ph3PAuCleAgSbF6 in wet CH2Cl2 gives the enone
Scheme 42.
intermediate 119 that cyclizes to 2,6-cis-tetrahydropyran 120 in
excellent yield (Scheme 45).
A related cyclization involving a 6-endo ring closure of an
a,b-unsaturated ketone has been used to build the dihydropyr-
anyl enone unit of several Alstonia alkaloids, such as alsto- OMe
5 mol% Ph3PAuCl
phylline (110 in Scheme 43).77 Although the detailed 5 mol% AgSbF6 O
mechanism is not clear, the process is believed to involve
HO OH wet CH2Cl2, 35 °C, 2 d O OH
the formation of a Pdep-complex on 111, removal of the
118 O 97% 120
silyl group, and nucleophilic attack of the deprotected alcohol
on the palladium complex. Finally, b-hydride elimination
provides 110, while the Pd(0) is re-oxidized to Pd(II) by 119 HO OH
t-BuOOH.
Scheme 45.
H H
MeO H MeO H
8 mol% Na2PdCl4
Me OTIPS NaOAc, t-BuOOH Me O
N N
N N
1:3:3 AcOH-H2O-dioxane
Me H H Me H H
80 °C, 6 h alstophylline
111 O O
55% 110
Scheme 43.
2700 I. Larrosa et al. / Tetrahedron 64 (2008) 2683e2723
O O 6. Allene-mediated cyclizations
TFA-CH2Cl2 2:1
H
0 °C, 1.5 h Allenes containing a nucleophile can undergo intramolecu-
OH O
lar cyclizations on treatment with transition metal catalysts.89
87%
122a 123 In particular, gold-catalyzed cycloisomerization of b- or d-hy-
O droxyallene gives access to six-membered oxygenated hetero-
HO OH cycles in a straightforward manner. As occurs for alkenes (see
O
H O Scheme 19), the initial coordination of the gold catalyst to one
HOOC N of the terminal double bonds of a b-hydroxyallene such as 132
122b OH H
O
gives rise to the formation of an intermediate, which, upon
platensimycin nucleophilic attack of the oxygen, is converted into a s-gold
121
complex through a 6-endo-trig ring closure (Scheme 49).
Scheme 46.
Subsequent protodemetallation of this complex furnishes the
corresponding dihydropyran 133.90 Likewise, d-hydroxyallene
(Scheme 47). A plausible mechanism for this cyclization in- 134 undergoes a 6-exo-trig hydroalkoxylation to form the cor-
volves the formation of a b-silylcarbenium ion intermediate responding 2-alkenyl tetrahydropyran derivative 135 in excel-
by protonation of the sp2-carbon a to the silyl group and the lent yield.91 Remarkably, gold-mediated hydroalkoxylation of
subsequent intramolecular attack of the hydroxy oxygen on 134 in the presence of the chiral diphosphine 136 affords 135
the cationic center.86 in 96% yield and 88% ee.92
7. Alkyne-mediated cyclizations
OH O
DMPS 5 mol% TsOH DMPS
CHCl3, 60 °C, 4 d A conceptually related set of approaches based on the elec-
124 86% 125 trophilic activation of carbonecarbon triple bonds have also
Scheme 47. proved to be a highly efficient entry into the synthesis of
six-membered oxygenated heterocycles.93 Indeed, the cata-
lytic metal-mediated intramolecular cyclizations of precursors
Eventually, Lewis acids can also be involved in the intra- containing alkynes and different oxygenated nucleophiles can
molecular hydroxyalkoxylation of unactivated olefins, leading be exploited for the construction of a wide array of oxygen-
to tetrahydropyrans. These processes presumably proceed containing heterocycles.
through the formation of a Lewis acideOH complex that Surprisingly, the simplest strategy based on the use of hy-
enhances the acidity of the hydroxyl proton.86,87 Furthermore, droxy alkynes had been scarcely applied to date, but recent
polycyclic compounds such as ()-caparrapi oxide and (þ)-8- reports on the cyclization of 4- and 5-alkynol have established
epicaparrapi oxide (126 and 127, respectively, in Scheme 48) the synthetic potential of such an approach. In this context,
have been obtained from hydroxy alkene 128 in the presence palladium94,95 and iridium96 complexes catalyze the 6-endo-
of stoichiometric amounts of chiral LBA (Lewis acid-assisted dig ring closure of 2-alkynylbenzyl alcohols with internal
chiral Brønsted Acid) complexes 129 and ent-129. Indeed, the triple bonds to the corresponding isochromenes in good yields.
asymmetric ring closure of 128 induced by 129 gives an 81:19 The mechanism for this transformation is outlined in Scheme
mixture of 130 (>99% ee) and 131 (21% ee), whereas the par- 50. As for alkenes or allenes, initial coordination of the metal
allel cyclization induced by ent-129 provides a 14:86 mixture to the carbonecarbon triple bond enhances its electrophilicity
of 130 (27% ee) and 131 (98% ee). Eventually, optically pure and facilitates the attack of the hydroxyl. Then, a protodeme-
130 and 131 are isolated in 74 and 73% yield by column tallation step renders the cyclic enol ether and regenerates the
chromatography.88 catalytic species.
OCOBn
OCOBn O O
2 equiv 129
CH2Cl2-PrCl 1:1
OH –80 °C, 2 d H H
128
74% dr 81:19 > 99% ee 130 (–)-Caparrapi oxide
Ar 126
OCOBn
O
SnCl4 O O
2 equiv ent-129
OH
CH2Cl2-PrCl 1:1
–80 °C, 2 d H H
OMe
Ar: 2-FPh 129
73% dr 86:14 98% ee 131 (+)-8-Epicaparrapi oxide
127
Scheme 48.
I. Larrosa et al. / Tetrahedron 64 (2008) 2683e2723 2701
5 mol% Au[P(t-Bu)2(o-biphenyl)]Cl Ph
5 mol% AgOTs LnAu Ph
PhMe, rt, 5 min
Ph HO
Ph 98%
6-exo-trig
δ
HO O
2.5 mol% Au2[136]Cl2, 5 mol% AgOTs
134 135
PhMe, –20 °C, 18 h
136
MeO PAr2
96% 88% ee
MeO PAr2
Ar: 3,5-(t-Bu)2-4-MeOPh
Scheme 49.
6-endo-dig H
O O
–MLn
R R
OH MLn OH LnM H
R LnM R
O H O
5-exo-dig –MLn
R R
LnM H
Scheme 50.
As shown in Scheme 50, an alternative pathway involving ynoate initially affords a conjugated adduct, which undergoes
a 5-exo-dig ring closure threatens the success of such method- a 6-endo-dig cyclization. Remarkably, the resultant dihydro-
ology. A comprehensive analysis of the regioselectivity of this pyran contains an exocyclic carbonecarbon double bond
cyclization for palladium catalysts has revealed that the with a well-defined geometry (for an outstanding application
6-endo-dig is favored over the 5-exo-dig mode by alkyl, rather of this palladium-based tandem synthesis and a related ruthe-
than aryl, substitution on the triple bond, low solvent polarity nium process, see Scheme 89).
(dioxane), high temperatures (80e100 C), and dilute condi- Furthermore, a palladium(II)-catalyzed 6-endo-dig cycliza-
tions.94,97 Keeping these limitations in mind, both palladiu- tion of b-hydroxy ynones, similar to that outlined in Scheme
m(II) and iridium(III) catalysts provide a good entry into 42, has recently been disclosed.99 Differently, the s-alkenylpal-
isochromenes 138a,b from 2-alkynylbenzyl alcohols 137a,b ladium intermediate obtained in this reaction undergoes inser-
(Scheme 51). tion of ethyl acrylate to form trisubstituted dihydropyranones
Working in the 4-alkynol arena, a tandem palladium(II)- featuring an alkenyl substituent a to the carbonyl (Scheme
catalyzed reaction offers an appealing entry into the synthesis 53). Thus, the overall process entails a cascade Wackere
of dihydropyrans.98 As represented in Scheme 52, the palla- Heck reaction that involves the chemoselective coupling of
dium-catalyzed addition of a terminal alkyne to a hydroxy two electron-deficient reactants. This WackereHeck sequence
does not affect the stereochemical integrity of the starting b-hy-
droxy ynones 139a,b and affords the corresponding dihydro-
OH 2 mol% PdI2, 4 mol% KI O
pyranones 140a,b in good yields.
dioxane, 80 °C, 3 h Bu Otherwise, 5-alkynols with a terminal triple bond undergo
Bu 63%
137a 138a completely regioselective 6-exo-dig ring closures to exocyclic
PPh3
enol ethers in the presence of palladium,100 iridium,101 plati-
4 mol% Ir
H num,102 or gold102,103 catalysts (Scheme 54). Their mechanism
O
OH
O
PPh3 O is also based on the electrophilic activation of the alkyne ac-
CHCl3, 80 °C, 2 h cording to the guidelines previously described, but, differently,
Pr
Pr
the competitive 7-endo-dig pathway is never observed.
77%
137b 138b Interestingly, the resultant cyclic enol ethers can be the start-
Scheme 51. ing point for further transformations. For instance, treatment of
2702 I. Larrosa et al. / Tetrahedron 64 (2008) 2683e2723
CO2R1
CO2R1 CO2R1
H 10 mol% Pd(OAc)2
4 mol% TDMPP
+
R2 PhH, rt, 2–3.5 d
R
R
OH HO R2 50–60% R O R2
R: alkyl, Ph
R1: Me, Et R2: alkyl
Scheme 52.
O O
O
OH O R2 2
PdLnX2 R 2 PdLnX2 PdLnX CO2Et R CO2Et
R1 –HX
R3 R1 O R3 R1 O R3
R2 R3 R1 OH
Wacker Heck
O
OH O CO2Et
Ph
Ph 20 equiv H2C=CHCO2Et, O2 Ph O Ph
139a 140a 47%
10 mol% [PdCl2(CH3CN)2]
Cu(OAc)2·H2O, PPh3, 20 mol% LiBr O
OH O DME, 20 h, 65 °C CO2Et
Ph
139b Ph O 140b 47% de > 99%
Scheme 53.
H H RO HO
H H H MLn
O O MLn O O
MLn 6-exo-dig 143a R: THP 144a R: THP
–MLn 143b R: TBS 144b R: TBS
OH OR
Scheme 54. 1) 1 mol% [PtCl2(CH2=CH2)], Et2O, rt, 30 min
2) 5 mol% CSA, MeCN-H2O, rt, 4 h Alkynol145:146Yield (%)
3) MgSO4, rt, 5 h 143a 30:1 75
alkynols 141 (Scheme 55) with platinum or gold catalysts leads 143b 20:1 83
O
to the enol ethers, which undergo a Prins-type cyclization + O 144a 9:1 60
O
through an oxocarbenium intermediate that eventually affords O 144b 3.7:1 58
H
H OR1
O O O
2 mol% MLn H R1OH
R R R R O R O
88–96%
141 142
Scheme 55.
I. Larrosa et al. / Tetrahedron 64 (2008) 2683e2723 2703
OH
PMBO 6
10 MeO H MeO H
O O
OTBDPS OTBDPS
11 Au
O O
147 O H
PMBO
8 mol% AuCl, PPTS +H –Au
MeOH, rt, 20 min
75% PMBO
A –H , –Me2O O O
B O O OTBDPS
O OTBDPS Me
O D
OPMB C O
O
O
148 Me H
62
Scheme 57.
R SnBu3
5 mol% Pd(OAc)2,
R Ph
2 equiv R1OH, benzoquinone BF3·OEt2
O dioxane, rt, 0.5–1 h O 79% O
74–90% OR1
149 H 150 151
1
R: alkyl, aryl R : Me, Et, i-Pr OTMS
AcOH
Pd(OAc)2 –Pd(OAc)2 Ph
Ph
R (AcO)2Pd R PdOAc BF3·OEt2
R 85% O
R1OH
O OH –AcOH O Ph
Pd(OAc)2
1
152
H OR OR1 O
Scheme 58.
a carbonecarbon triple bond by palladium(II) catalysts allows 2-alkynylbenzaldehydes and related systems. Now, the nucle-
the construction of cyclic alkenyl ethers from acetylenic alde- ophilic attack of the carbonyl oxygen on the electronically
hydes. Indeed, cyclization of 2-alkynylbenzaldehydes 149 pro- deficient alkyne produces a 2-benzopyrylium-like intermedi-
ceeds smoothly in the presence of Pd(OAc)2 to provide acetals ate, which can undergo further transformations that ultimately
150 in high yields (Scheme 58).108 The authors propose offer a rich assortment of structures.111e114
a mechanism in which the palladium catalyst initially acts as This methodology has been applied to the synthesis of ()-
a Lewis acid, promoting the formation of the corresponding S-15183a (153 in Scheme 59), a member of the azaphilones,
hemiacetal. Then, coordination of the metal to the alkyne fa- a family of natural products containing a highly oxygenated
cilitates the anti attack of the hydroxyl from the side opposite bicyclic core and a quaternary stereocenter.115 The reported
to the metal via a 6-endo-dig pathway.x The resultant vinylpal- synthesis takes advantage of a gold-mediated cycloisomeriza-
ladium intermediate is subsequently protonated to afford the tion of 2-alkynylbenzaldehyde 154 followed by oxidation of
final alkenyl acetal with complete regioselectivity. Noteworthy the resultant 2-benzopyrylium salt. As outlined in Scheme
is the fact that the high reactivity of the benzylic acetal in 150 59, a plausible mechanism for this transformation entails the
(R: Ph, R1: Me) makes possible the introduction of carbon coordination of the gold catalyst to the triple bond followed
nucleophiles via HosomieSakurai allylation and Mukaiyama by cyclization and protodemetallation to furnish the 2-benzo-
aldol reactions to afford 151 and 152 in high yields.109 pyrylium salt. Eventually, oxidation of this salt affords in 84%
Other oxygenated nucleophiles such as carboxylic acid overall yield the desired oxygenated heterocycle 155 as a race-
derivatives and carbonyls have also been utilized in this type mic mixture.
of cyclization.93a,110 A step forward in this area relies on the Having developed a straightforward route to the bicyclic
electrophilic activation of the carbonecarbon triple bond of core, attention was focused on the asymmetric oxidation of
the benzopyrylium salt. However, all attempts were unsuccess-
ful and a new strategy, based on the initial oxidation of the
aromatic ring, was disclosed. Remarkably, the Cu2[()-spar-
x teine]2O2-mediated enantioselective oxidative dearomatization
It is worth pointing out that the aromatic ring is crucial to the observed re-
gioselectivity. The reaction of the equivalent carbon-tethered acetylenic alde- of 154 provides a hydroxy derivative, which undergoes the de-
hydes, 4-alkynals, mainly yields the corresponding five-membered acetals sired cycloisomerization under very mild conditions to afford
through 5-exo-dig cyclizations. ()-155 in 98% ee and 84% overall yield (Scheme 60). It is
2704 I. Larrosa et al. / Tetrahedron 64 (2008) 2683e2723
R RCOCl
1) 5 mol% Au(OAc)3
HO O R O R
ClCH2CH2Cl–TFA 10:1, rt i-Pr2NEt, DMAP
O 2) IBX, 5 mol% TBAI, rt O CH2Cl2, rt O
HO RCOO
OH H 84% O 61% O
154 R: –(CH2)6Me (±)-155 (±)-S-15183a
(±)-153
AuLn
oxidation
LnAu R LnAu H
HO HO R HO R
TFA
O O –AuLn O
OH H OH OH CF3COO
Scheme 59.
Scheme 60.
worth emphasizing that the 6-endo-dig ring closure is carried heterocycles120,121 and other carbocycles.122 For instance,
out without any metal at pH 7.2.116,117 addition of the iodonium ion generated from Ipyr2BF4/HBF4
Other systems available for this chemistry are 4-propargyl- to the triple bond of 2-alkynylbenzaldehydes 149 leads to an
1,3-cyclopentanediones 156 represented in Scheme 61. Metal- iodobenzopyrylium salt, which, in turn, reacts with nucleo-
mediated cyclization of these 1,3-diketones admits catalysts philes and offers a straight and useful access to highly elabo-
based on palladium,118 platinum, tungsten, and mercury.119 rated oxygenated heterocycles 158e161 (Scheme 62).120
Noteworthy is the fact that the platinum-mediated catalysis Importantly, most of these transformations can be carried out
of terminal and substituted alkynes affords exclusively the following a procedure based on the use of iodine.121
bicycles 157 in high yields at room temperature. These
6-endo-dig cyclizations are supposed to proceed under kinetic 8. Other metal-promoted cyclizations
control by coordination of the catalyst to the triple bond. Then,
the alkyneemetal complex undergoes anti attack of the car- In addition to the methodologies just described, metals can
bonyl oxygen and the resultant vinylplatinum intermediate is also catalyze other cyclizations that require the in situ gener-
protonated to afford the oxabicycle 157. Since related 1,3-cy- ation of transition metalecarbenoid species. Such transforma-
clohexadienones are prone to 5-exo-dig ring closures, the ex- tions encompass the cycloisomerization of 4-alkynols via
cellent regioselectivity observed for 156 is presumably due metal vinylidene complexes and the intramolecular addition
to subtle intrinsic strain on the way to the exo- or endo-bicyclic of oxygenated nucleophiles to metal carbenes obtained from
systems. diazo precursors.
As well as these catalytic processes, there are some stoi- This chapter also takes into account a less studied transfor-
chiometric metal-free methodologies based on the iodine- mation: the intramolecular etherification of aryl and vinyl
mediated electrophilic activation of the substituted carbone halides catalyzed by palladium and copper.
carbon triple bond of 2-alkynylbenzaldehydes that allow for
the highly efficient construction of six-membered oxygenated 8.1. Cyclizations of 4-alkynols
O
R 10 mol% PtCl2
O R The transition metal-mediated isomerization of hydroxy
O
THF–dioxane 2:1
O alkynes containing a terminal carbonecarbon triple bond rep-
rt, 24–72 h resents a highly valuable route for preparing 3,4-dihydro-2H-
156 157
R: H, Me pyrans (see Eq. 5 in Scheme 63).123 Unlike the methodologies
PtCl2 76–85%
–PtCl2 previously discussed, these processes proceed through a metal
O O R vinylidene intermediate that undergoes intramolecular attack
R 6-endo-dig
HO HO by an alcohol. Thus, the key element of such cyclizations relies
PtCl2 PtCl2 on providing metal vinylidene intermediates reactive enough to
Scheme 61. sustain a catalytic process. These species arise from the initial
I. Larrosa et al. / Tetrahedron 64 (2008) 2683e2723 2705
I
158
Ph O OMe
MeOH
63% I
TMS
Ph O
Ipyr2BF4, HBF4 I 42%
OTMS 159
CH2Cl2, 0 °C to rt
R O H Ph
R I
O H 55% O
Ph O
161 NMe2
Scheme 62.
MLn MLn
OH HO O OH OH HO
H MLn H MLn H •
(5)
H MLn H
alkynol metal vinylidene 3,4-dihydro-2H-pyran -complex vinylidene intermediate
R R
O N2 MLn O MLn O
(6) O O MLn O MLn
–N2
MLn or
diazo precursor metal carbene tetrahydropyran
–MLn –MLn
Scheme 63.
O O
1,2-hydride shift
MLn MLn R
R H R H MLn
H H
-complex R MLn
oxidative addition 1,3-hydride shift
Scheme 64.
2706 I. Larrosa et al. / Tetrahedron 64 (2008) 2683e2723
10 mol% CpRuCl[P(4-MeOPh)3]3
40 mol% P(4-MeOPh)3, 30 mol% Bu4NPF6
OH
N H H
6 equiv O O , 2 equiv NaHCO3 O
BnO
DMF, 85 °C, 20 h
BnO O O
60% H
O 163
BnO
H 5 mol% CpRuCl[P(4-FPh)3]3
BnO OH 20 mol% P(4-FPh)3, 15 mol% Bu4NPF6
ONa
162 N H H
0.5 equiv O O O
BnO
DMF, 85 °C, 26 h BnO O
70% H
164
H H H H H H
O O O OH
BnO as previously BnO H
BnO O BnO O
H H H H
65%
166 165
Scheme 66.
with 5e25 mol % W(CO)6 and an excess of a tertiary amine results are obtained with 25 mol % of oxacarbene 172 in the
(DABCO often gives better results than Et3N) in THF or tolu- presence of 10 equiv of Et3N by simple warming to 40 C in
ene under constant irradiation at 350 nm. Remarkably, these THF. This experimental procedure has been successfully
tungsten-based catalysts tolerate substituents at the propargylic applied to the synthesis of the altromycin disaccharide 173
position and are compatible with a wide variety of functional via 174 and 175.
groups such as alcohols, ethers, amides, and carbamates.131
This methodology has been successfully applied to the con- 8.2. Cyclizations of diazo compounds
struction of the trisaccharide component of digitoxin (167 in
Scheme 67). Thereby, iterative alkynol cycloisomerization Metal carbenes are easily obtained from diazo compounds
based on W(CO)6 constitutes the most important feature of in the presence of copper and rhodium complexes. The
the synthetic sequence that provides glycal 171 and eventually accepted mechanism for this transformation combines the
allows for the total synthesis of digitoxin.132 Lewis acid character of the metal complex and the basic
In addition to W(CO)6, a preformed THF$W(CO)5 complex properties of the carbon center of the diazo precursor. Hence,
has been employed.133,134 Moreover, a recent communication formation of an acidebase adduct is followed by back dona-
has disclosed a new catalytic system that does not require pho- tion of electron density from the metal with concomitant loss
tochemical activation, based on (methoxymethylcarbene)pen- of nitrogen, thus producing the metal carbene (Scheme
tacarbonyl tungsten (172 in Scheme 68).135 The optimal 69).136,137
H H 25 mol% W(CO)6 H H
O O O O
OH DABCO O
THF, h , 65 °C
TBSO O TBSO O
TBSO TBS H 96% TBSO TBS
168 169
HO O H OH digitoxin
O O O
O O 167
HO H
HO HO
Scheme 67.
I. Larrosa et al. / Tetrahedron 64 (2008) 2683e2723 2707
OMe CO
MeO
Et3N + W(CO)5 (Et3N)W(CO)5 Et3N + W(CO)6
h
172
HO O O
H 25 mol% 172
10 equiv Et3N
O O O O O O
CbzHN THF, 40 °C, 12 h CbzHN Me2N
OMOM 83% OMOM OMOM
174 OTIPS 175 OTIPS 173 OMe
Scheme 68.
O OH
O N2 CO2Et O HO
O Rh2(OAc)4 O RhLn
CO2Et PhH, rt OH
R 96% R O CO2Et HO O CO2H
15 min O H H H H
R OH HO
177 178a 179a
2-deoxy- -KDO
O
O RhLn O 176
R:
O O CO2Et
OH
R R O CO2Et
O H H
178b 179b
Scheme 71.
R R R
O MLn O MLn O [1,2]–shift O R deals with an intramolecular version of such a cascade se-
quence from a-diazo ketone 190, in which a simple olefin
acts as dipolarophile to obtain diastereoselectively the tricyclic
adduct 191 in 73% yield.148 Surprisingly, the synthetic mate-
O MLn O MLn O O rial shows a higher specific rotation than the samples obtained
[2,3]–shift
from natural sources, which suggests that polygalolide A
might be biosynthesized through a poorly stereoselective
pathway.150
Scheme 72.
H H H
O N2 O O
5 mol% Cu(tfacac)2 1) DBU
CH2Cl2, reflux 2) LiAlH4
O O O O O OH
H H H
80% dr 30:1 86%
180 181 182
H H H H H H
O OH O O O O
1) DBU 5 mol% Cu(tfacac)2
O O 2) LiAlH4 O O CH2Cl2, reflux
O O N2
H H H H H H
86% 80%
185 184 183
Scheme 73.
R O MLn R O MLn R O A B Since the cycloaddition step can be faster than metal
A B R
O decomplexation from the carbonyl ylide, enantioselective tan-
dem sequences can also be achieved by positioning chiral
cyclization carbonyl ylide 1,3-dipolar cycloaddition ligands on the rhodium catalyst.151 This approach has been
applied to the synthesis of pseudolaric acid A (192 in Scheme
Scheme 74.
76).152 Indeed, a substrate-controlled cascade from the a-diazo
ketone 193 in the presence of achiral rhodium catalysts is
found to favor the formation of the oxatricycle 194a, whereas
methodologies that take advantage of the carbonyl ylide reac- a chiral Rh2[(S)-bptv]4 catalyst smoothly delivers a mixture
tivity currently employ rhodium(II) catalysts.144e146 containing the desired diastereomer 194b as the major compo-
The power of the carbonyl ylide cycloaddition methodol- nent in 82% overall yield.
ogy for the rapid assemblage of bicyclic systems has been Moreover, the stereochemical outcome of these transforma-
proved in the stereoselective synthesis of structurally complex tions can also rely on chiral Lewis acids affecting the cycload-
natural products such as zaragozic acid C147 and polygalolide dition step. Although the scope of these transformations is
A148 (186 and 187, respectively, in Fig. 4).149 sometimes narrow, significant levels of enantioselectivity
The first example entails the intermolecular trapping of the have been reported for the reaction of carbonyl ylides arising
carbonyl ylide intermediate from a-diazo ester 188 with 3-bu- from a-diazo ketones 195 with substrates able to form chelates
tyn-2-one to construct the cycloadduct 189 as a single diaste- with chiral Pyboxelanthanide triflate catalysts (Scheme
reomer in 72% yield (Scheme 75).147 The second example 77).153
I. Larrosa et al. / Tetrahedron 64 (2008) 2683e2723 2709
O O
MeO
Ph O OH
OAc H
O
HOOC HO O
O Ph
HOOC O
zaragozic acid C polygalolide A O
HO COOH
186 187 O
Figure 4.
O COMe
5 mol% Rh2(OAc)4 COMe
N2 O OMOM 3 equiv HC CCOMe R1 O
R1 R2 R1 1
R
O R2 186
OTBDPS PhH, reflux, 1 h O O
t-BuO2C
TMSO CO2t-Bu TMSO OTBDPS 72% TMSO
OTBDPS
188 R1: CO2t-Bu R2: (CH2)2OMOM 189
PMBO
OPMB
N2 O
OTBDPS 5 mol% Rh2(OAc)4
O 187
PhCF3, 100 °C, 5 min O
O O O O
OTBDPS
OPMB O 73% O
OTBDPS
190 191
Scheme 75.
OPMB
O
Rh2(OAc)4 iPr N
O O H O
CH2Cl2, 0 °C
N2 H O O
Rh2[(S)-bptv]4
PMBO O 61% dr 3:1 O Rh Rh
O
O
OPMB 194a
O
O
3 mol% Rh2[(S)-bptv]4 O O O
O
PhCF3, –40 °C H
HOOC
193 O OAc
82% dr 1.6:1
O
194b pseudolaric acid A 192
Scheme 76.
8.3. Intramolecular etherification of aryl and vinyl halides can be cyclized in the presence of bulky dialkylphosphino-
biaryl ligands such as 203a and 203b (Scheme 79). Moreover,
Although the coupling of oxygenated nucleophiles with aryl bromides in which the hydroxyl-bearing chain contains
aryl halides is a long-established method for the preparation stereocenters and additional functional groups such as amines,
of aryl ethers, the harsh reaction conditions commonly re- amides, or esters also afford the corresponding heterocycles in
quired to effect this transformation have restricted its synthetic high yields without erosion of the optical purity.
scope. Indeed, there are relatively few examples for the The potential of this transformation has been proved in the
construction of oxygen heterocycles through the intramolecu- synthesis of several heterocyclic compounds with different
lar etherification of aryl halides. biological activities.154a,155 For instance, the intramolecular
This lack of synthetic methodologies was covered a few palladium-mediated etherification of the aryl bromide 204
years ago by a procedure based on intramolecular palladium- generates the chroman ring 205, which is easily transformed
catalyzed carboneoxygen bond formation.154 The reaction into (S)-equol (206), a metabolite with a high estrogenic activ-
proceeds under mild conditions using bulky and electron-rich ity (Scheme 80).155d
o-biarylphosphines in the presence of weak bases. Remarkably, In spite of the success of this palladium-catalyzed cycliza-
the choice of the phosphine turns out to be crucial, since its steric tion, the pursuit of easy-to-handle reagents and easier proce-
bulk accelerates the reductive elimination step and minimizes dures is fueling the development of new methodologies. A
the competitive b-hydride elimination pathway (Scheme 78). recent report on a copper-catalyzed intramolecular coupling
Aryl chlorides and bromides are suitable substrates for this of vinyl bromides is a good example of this emerging chemis-
transformation. Then, primary as well as secondary substrates try.156 As illustrated in Scheme 81, the vinyl bromide 207 is
2710 I. Larrosa et al. / Tetrahedron 64 (2008) 2683e2723
MeO
BnOCH2CHO
10 mol% 196-Sc(OTf)3 O OBn
O
CH2Cl2, –10 °C
O 199 * 96%
exo/endo 12:88
MeO ee (endo) 91%
MeCOCO2Bn, 10 mol% TFA
10 mol% 196-Sc(OTf)3 O
O
CH2Cl2, –25 °C CO2Bn
OR OR
2 mol% O 200 * 98%
O Rh2(OAc)4 O exo/endo 93:7
CH2Cl2 O O O ee (exo) 94%
N2 O O
N O MeO
O O N
195 10 mol% 197-Yb(OTf)3
O
CH2Cl2, –10 °C
O 201 * 94%
exo/endo 82:18
O N O O O O ee (exo) 96%
R2 R2 O
N N O
N O p-BrPhCH2O
R1 R1 N
196 R1: i-Pr R2: H 20 mol% 198-Yb(OTf)3
197 R1: Ph R2: H
O
CH2Cl2, rt
198 R1: Ph R2: Ph
60%
O 202 *exo/endo > 1:99
ee (endo) 96%
Scheme 77.
reductive
O
elimination
OH OH
O
X PdXLn PdLn O
Pd(0)Ln base
H
X: Cl, Br
-hydride elimination
and
reductive elimination
Scheme 78.
easily transformed into the tetrahydropyran 208 in the pres- in Scheme 82). These transformations are usually carried out in
ence of a copper(I) salt and 1,10-phenanthroline. the presence of stoichiometric, or even catalytic, amounts of
base under thermodynamic control, which implies that the con-
9. Intramolecular conjugate additions figuration of the new stereocenter can be predicted from confor-
mational analysis of the resultant heterocycle. Therefore,
The venerable Michael reaction has found a fertile field of considering that the most stable conformer of saturated six-
application in the synthesis of six-membered oxygenated membered heterocycles adopts the chair form as a rule, it is
heterocycles. As outlined in Scheme 82, intramolecular nucleo- in general anticipated that these cyclizations mainly pro-
philic attack of an alcohol on the electronically deficient vide 2,6-cis-disubstituted tetrahydropyrans.157 As represented
C(sp2) or C(sp) center of a,b-unsaturated systems proceeds in Scheme 83, this methodology has been largely applied
smoothly through exo and endo ring-closure modes to provide to the synthesis of leucascandrolide A (1),1d,g,j phorboxazole
the corresponding pyrans. A (2a),2c spongistatin 1 (209), and other natural products.158,159
However, careful optimization of the experimental condi-
9.1. 6-exo Ring closures tions enables the acquisition of the kinetically favored 2,6-
trans diastereomers.160,161 Thereby, cyclization of hydroxy
The most common procedure for the synthesis of tetrahydro- ester 210 affords either 211-cis or 211-trans tetrahydropyran
pyrans based on the Michael reaction involves 6-exo-trig cycli- under basic conditions (Scheme 84).160b The all-equatorial
zations of a,b-unsaturated hydroxy ketones or esters (see Eq. 7 211-cis diastereomer is assumed to be the most stable isomer
I. Larrosa et al. / Tetrahedron 64 (2008) 2683e2723 2711
OTBS OTBS
10 mol% t-BuOK
1
O OH OH THF, 0 °C, 10 min O OH O
Scheme 83.
OH OH OH
Scheme 84.
CO2H
OH
O
O O OH O
O OH O O
O
HO
NaO2C (+)-SCH-351448, 212
Scheme 85.
for the total synthesis of 232, a ring-expanded analogue of this sort of reaction has been applied to 6-exo-trig cyclizations
bryostatin 1. on a,b-unsaturated ketones for the synthesis of complex natu-
Ring closure of the putative intermediate represented in ral products. For instance, deprotection of 1,3-diol in 233 in
Scheme 89 is believed to be catalyzed by the ruthenium Lewis acetic acid triggers the formation of 2,6-trans-tetrahydropyran
acid. Indeed, Michael-mediated cyclizations can also proceed 234 in excellent yield and moderate diastereoselectivity
under Brønsted acid conditions.174 Although poorly exploited, (Scheme 90);175 reaction of lactol 235 with a stabilized
I. Larrosa et al. / Tetrahedron 64 (2008) 2683e2723 2713
H H
OBz OBz OBz OBz
+
CO2Me CO2Me CO2Me
OH O O OH
H H
CO2Me
217-E 218-cis 218-trans 217-Z
2,3-cis-tetrahydropyran 2,3-trans-tetrahydropyran
Scheme 86.
CO2R1
OH 6 O 2
PGO t-BuOK PGO CO2R1
THF, 0 °C
OPG 3 OPG
R1: O R2: O
PG: TBDPS 100% dr > 95:5 2,3-cis-2,6-cis
Ph Ph
219 220
OH 6 O 2 6 O 2
PGO CO2R2 t-BuOK PGO CO2R2 t-BuOK PGO CO2R2
PhMe-t-BuOH, rt PhMe, 0 °C
OPG 3 OPG 3 OPG
PG: TBDPS 76% dr > 98:2 2,3-trans-2,6-trans 100% dr 95:5 2,3-cis-2,6-cis
221 222a 222b
Scheme 87.
phosphorane provides enone 236, which is cyclized by treat- Intramolecular Hetero Michael Addition (DIHMA) based on
ment with CSA to furnish 2,6-cis-tetrahydropyran 237 as the a 6-exo-dig cyclization followed by a stereoselective 6-exo-
sole diastereomer in 73% yield over two steps176 and, eventu- trig ring closure.179 In this manner, the acid-mediated double
ally, removal of isopropylidene acetal and silicon protecting intramolecular oxa-Michael addition on dihydroxy ynone
groups in the advanced intermediate 238 en route to bryosta- 240 gives the bicyclic ketal 241 as a single diastereomer in
tins with HF leads to the C1eC16 fragment 239 containing excellent yield (Scheme 91).180 Similarly, treatment of ynone
two 2,6-cis-tetrahydropyrans.177,178 242 with TBAF promotes silyl ether cleavage and addition of
As well as all of these cyclizations, a 6-exo-dig ring-closure the corresponding oxygen atoms upon C28 to provide in high
mode based on a Michael reaction is, in fact, possible. How- yield the targeted FG-ring system 243 present in
ever, there is no clear example in the literature, because the azaspiracids.181
enone generated in this cyclization process usually undergoes
a second Michael addition, as can be appreciated in the syn- 9.2. 6-endo Ring closures
thesis of azaspiracids (62 in Scheme 24, see also Scheme
57). In this case, the retrosynthetic analysis of the C27eC40 Contrary to the Michael-mediated 6-exo-dig cyclizations,
domain followed by Forsyth et al. relies on a formal Double parallel 6-endo-dig processes have been identified as a useful
EtO2C
HO O
MeO2C OMe
224
Scheme 88.
2714 I. Larrosa et al. / Tetrahedron 64 (2008) 2683e2723
TBDPSO O
O
TBDPSO O
TMS 10 mol% R
TMS
O [CpRu(MeCN)3]PF6 TMS 11
+ OH O
O O OPMB
acetone, rt, 40 h
15
OH 56% 228
PMBO
O OPMB PMBO
dr 9:1
PMBO 227
226 MeO
OAc
1) 4 mol% Pd(OAc)2 OTBS MeO2C 11
OTBS
4 mol% TDMPP O O
OH O 19 O 23 O 15
O Ph, rt, 1 d OH
+
2) 8 mol% Pd(OCOCF3)2 O (H2C)3
O
2d
H CO2Me OH H
55% O O
CO2Me
229 230 231 19 23
Scheme 89.
SEM OSEM
O
O SEMO O O O OH
AcOH
THF– H2O, rt, 19 h O
SEMO OBn OBn
233 95% dr: 2.5:1 234
O
H
O OH OH O O
10 mol% CSA
CH2Cl2, rt, 1 h
BnO OBn BnO OBn BnO OBn
235 236 73% 237
TMS
MeO
OBn OBn
1) 56% HF, MeCN, rt, 24 h O O
O OBn O O
TBSO
2) HC(OMe)3, MeOH, cat PPTS, rt, 3 h
OTBS
34% OH
238 239 OH OBn
Scheme 90.
tool to gain access to pyranones (see Eq. 8 in Scheme 82). In selectivity of these reactions turns out to be highly dependent
particular, 6-endo-dig cyclizations of o-alkynoylphenols upon the experimental conditions. Indeed, base-catalyzed
provide an appealing entry into the synthesis of the heterocy- cyclization of o-alkynoylphenols can proceed through a
clic structures present in many natural products. The 5-exo-dig or 6-endo-dig pathway to afford, respectively,
O 1) 10 mol% CSA
OTBDPS
O O CH2Cl2-MeOH 5:1,
rt, 3.5 h O O
TBDPSO 2) 10 mol% TsOH
240 O 2 41
PhH, rt, 4 h
90%
6-exo-dig 6-exo-trig OTBDPS
O
OH OH O HO
TBDPSO O
Boc OTBS
Boc H
N O
OTBS TBAF N
O O
THF, rt O
O
H
242 85% 243
O
Scheme 91.
I. Larrosa et al. / Tetrahedron 64 (2008) 2683e2723 2715
benzofuranones or benzopyranones. According to the experi- DielseAlder reaction. Initial reports on 6-endo-trig cycliza-
mental results, theoretical calculations on a model ketone tions of a,b-unsaturated ketones are due to Paterson and Os-
shown in Scheme 92 have revealed that the transition states borne.186 In particular, the aldol adducts obtained through
for both processes are very close in energy. Nevertheless, stereoselective reactions from b-chloro vinyl ketones undergo
the 6-endo-dig product is thermodynamically favored and Lewis acid-mediated cyclizations that eventually give dihydro-
can be obtained under equilibrating conditions in the absence pyranones.187 Application of this methodology to methyl ke-
of proton donors.182 tone 247 and 3-benzoyloxypropanal supplies aldol 248,
This approach has been successfully applied to the synthe- which is easily converted into the desired dihydropyranone
sis of several members of a family of antibiotics containing an 249 (Scheme 94). Further recrystallization provides an enan-
anthrapyran core.183,184 As represented in Scheme 93, basic tiomerically pure material that has been employed for the total
treatment of ynone 244 under aprotic conditions promotes synthesis of swinholide A,188a scytophycin C,188b and, more
a highly selective 6-endo-dig cyclization to the tetracyclic recently, laulimalide (93 in Scheme 38).188c
compound 245 that is further elaborated into the antibiotic Aldol adducts lacking the b-chlorine atom can also take
AH-1763 IIa (246).184a Alternatively, this type of cyclization part in these cyclizations to afford the tetrahydropyranones.
can also be carried out under acidic conditions, but the mech- A comprehensive survey of the ability of Brønsted and Lewis
anism is still unclear.185 acids as well as palladium(II) complexes to enhance the elec-
Overshadowed by 6-exo-trig cyclizations, the related 6- trophilicity of enones 250 has identified Amberlyst-15, Al-
endo-trig ring-closure mode (see Eq. 9 in Scheme 82) had (ClO4)3$9H2O, and [Pd(MeCN)4](BF4)2 as suitable catalysts
traditionally attracted not much attention. However, the in- to carry out the desired 6-endo-trig cyclization (250a,b to
creasing interest in the asymmetric synthesis of di- and tetra- 251a,b) under mild conditions (Scheme 95).76b,189 As antici-
hydropyranones has modified this situation, since this type of pated for a thermodynamically controlled reaction, Amber-
cyclization emerges as an appealing alternative to the hetero- lyst-15 affords the all-equatorial products after extended
reaction times. Interestingly, the palladium-mediated cycliza-
tions are irreversible and give access to the other isomers in
excellent diastereomeric ratios.
O OH O
Another aldol reaction is at the center of a different method-
O ology. Aldol compounds arising from b-keto esters can partic-
5-exo-dig O 6-endo-dig O
ipate in an acid-mediated Knoevenagel condensation that
generates a highly reactive a,b-unsaturated keto ester, which
H B H undergoes a 6-endo-trig cyclization based on a reversible
oxa-Michael addition. Finally, decarboxylation of the resultant
O O O system provides the 2,6-cis-disubstituted tetrahydropyra-
O
O O nones.190,191 This methodology has been applied to the prepa-
ration of ()-centrolobine (252 in Scheme 96). The reported
Scheme 92. sequence takes advantage of a Mukaiyama aldol reaction to
OBn
OBn OH
O O OH O O O OH O O
O Cs2CO3 O O
acetone, rt, 30 min
Scheme 93.
(+)-Ipc2BCl BIpc2
O O O OH
i-Pr2NEt OHC(CH2)2OBz
Cl Et2O, 0 °C Cl –78 to –20 °C Cl OBz
247 1h 20 h 248
56% 80% ee
BzO O TMSOTf, i-Pr2NEt
laulimalide
CH2Cl2, –78 °C to rt, 1.5 h
93
249 O 61% (upgrade to >98% ee by recrystallization)
Scheme 94.
2716 I. Larrosa et al. / Tetrahedron 64 (2008) 2683e2723
OH O 8 mol% HO Ph
[Pd(MeCN)4](BF4)2 M O H O
Ph Ph
CH2Cl2, rt, 3 h H 78%
O
H dr 96:4
250a 251a
M
OH O 8 mol% OH
[Pd(MeCN)4](BF4)2 O
Ph H Ph
CH2Cl2, rt, 3 h 75%
HO Ph O
dr 97:3
250b H 251b
Scheme 95.
OMe OTMS O
1) 1 equiv Yb(OTf)3 MeO2C
TMSO
CH2Cl2, –78 °C, 3 h
+
2) 2 equiv TFA HO
OHC
4-MeOPhCHO
MeO OH 60%
rt, 5 h
OTBS
O
MeO2C
O
O
MeO OH
MeO OH
(±)-centrolobine 252 253
Scheme 96.
OH O O O
1) 10 mol% 254a N
S
Ot-Bu PhMe, –25 °C, 24–38 h
Ar
N N
2) 50 mol% TsOH H H
Ar 255 O Ar H
80 °C, 10–50 h BnO
256a 254a
65–94% 88–94% ee N
N
OH O O 1) 20 mol% 254b O
5 mol% piperidinium acetate S OMe
Ot-Bu PhMe, 4 Å MS, rt, 2 d Ar H
N N
2) 30 mol% TsOH H H N 254b
O 257 O Ph
PhMe, 80 °C, 9 h
H Ph 77% 80% ee flindersiachromanone 256b
Scheme 97.
install the first appendage of the tetrahydropyran. Then, addi- structure can alter this situation. For instance, thermodynami-
tion of anisaldehyde and TFA to the reaction mixture affords cally controlled transannular conjugate addition on
the tetrahydropyranone 253 and further functional-group a,b-unsaturated ketone 258 affords 2,6-trans-disubstituted tet-
manipulations deliver ()-centrolobine.192 rahydropyranone 259, used as an advanced intermediate in
Closely connected to this methodology, it has recently a formal total synthesis of ()-apicularen A (260 in Scheme
been discovered that the chiral thiourea-based catalysts 254, 98). Interestingly, exposure of epimer 258-epi to identical con-
shown in Scheme 97, activate a-alkylidene-b-keto esters ditions yields the same tetrahydropyranone 259.195
255 and trigger intramolecular conjugate additions of phenol In contrast to the above examples, some 6-endo-trig cycli-
to the corresponding flavanones 256. Remarkably, a one-pot zations match the model reaction represented by Eq. 10 in
reaction involving the simple b-keto ester 257, hydrocinna- Scheme 82.196 For instance, chiral dienyl sulfoxides 261
maldehyde, piperidinium acetate, and chiral thiourea 254b have been identified as suitable precursors of dihydropyrans.
in the presence of molecular sieves in toluene at room tem- This process is based on a highly stereoselective conjugated
perature followed by decarboxylation affords the natural addition (the examples shown in Scheme 99 afford a single
product, flindersiachromanone 256b, in 80% ee and 77% diastereomer) followed by subsequent transformations of the
overall yield.193,194 resultant allylic sulfoxides 262.197 Interestingly, this methodo-
Although 2,6-cis-disubstituted tetrahydropyranones are usu- logy accepts additional stereocenters and other substituents on
ally the most stable diastereomers, other elements in the the double bond of the dienyl sulfoxide.
I. Larrosa et al. / Tetrahedron 64 (2008) 2683e2723 2717
(–)- apicularen A
OH 260
Scheme 98.
O O
H
S S HO
p-Tol LDA p-Tol 10 equiv P(OMe)3
THF, –78 °C to rt MeOH, 50 °C
OH R O R O Ph
3–4 h H 4d
261a R: Ph 262a 84% 263a
261b R: Bu 262b 94% 50%
Scheme 99.
10. Conclusions 12895; (b) Kopecky, D. J.; Rychnovsky, S. D. J. Am. Chem. Soc. 2001,
123, 8420e8421; (c) Wipf, P.; Reeves, J. T. Chem. Commun. 2002,
2066e2067; (d) Fettes, A.; Carreira, E. M. J. Org. Chem. 2003, 68,
As this report proves, the apparently simple construction of 9274e9283; (e) Paterson, I.; Tudge, M. Angew. Chem., Int. Ed. 2003,
pyrans through CeO bond formation is surprising, with an ex- 42, 343e347; (f) Williams, D. R.; Plummer, S. V.; Patnaik, S. Angew.
tremely varied array of methodologies ranging from the vener- Chem., Int. Ed. 2003, 42, 3934e3938; (g) Crimmins, M. T.; Siliphaivanh,
able SN2- or Michael-based cyclizations to the more recent P. Org. Lett. 2003, 5, 4641e4644; (h) Wang, Y.; Janjic, J.; Kozmin, S. A.
transition metal-catalyzed reactions. The scope and synthetic Pure Appl. Chem. 2005, 77, 1161e1169; (i) Su, Q.; Dakin, L. A.; Panek,
J. S. J. Org. Chem. 2007, 72, 2e24; (j) Ferrié, L.; Reymond, S.;
efficiency of such ring-forming methodologies have already Capdevielle, P.; Cossy, J. Org. Lett. 2007, 9, 2461e2464; (k) Van Orden,
been established along with the total synthesis of a large num- L. J.; Patterson, B. D.; Rychnovsky, S. D. J. Org. Chem. 2007, 72, 5784e
ber of structurally complex natural products, but, in spite of 5793.
these outstanding achievements, the increasing demand for 2. For total syntheses of phorboxazole A, see: (a) Forsyth, C. J.; Ahmed, F.;
more selective processes to gain access in a straightforward Cink, R. D.; Lee, C. S. J. Am. Chem. Soc. 1998, 120, 5597e5598; (b)
Smith, A. B., III; Minbiole, K. P.; Verhoest, P. R.; Schelhaas, M.
manner to six-membered oxygenated heterocycles is fueling J. Am. Chem. Soc. 2001, 123, 10942e10953; (c) Pattenden, G.; González,
the development of new concepts and methodologies. Remark- M. A.; Little, P. B.; Millan, D. S.; Plowright, A. T.; Tornos, J. A.; Ye, T.
able examples are the recent developments in epoxide-medi- Org. Biomol. Chem. 2003, 1, 4173e4208; (d) Williams, D. R.; Kiryanov,
ated cyclizations that allow selective formation of the pyrans A. A.; Emde, U.; Clark, M. P.; Berliner, M. A.; Reeves, J. T. Proc. Natl.
over the more favored furans or the spectacular simultaneous Acad. Sci. U.S.A. 2004, 101, 12058e12063; (e) Smith, A. B., III; Razler,
T. M.; Ciavarri, J. P.; Hirose, T.; Ishikawa, T. Org. Lett. 2005, 7, 4399e
construction of up to three fused tetrahydropyran units in a 4402; (f) Wang, B.; Forsyth, C. J. Org. Lett. 2006, 8, 5223e5226; (g)
cascade sequence. Moreover, emerging methodologies such White, J. D.; Kuntiyong, P.; Lee, T. H. Org. Lett. 2006, 8, 6029e6042;
as platinum- or gold-catalyzed cyclizations of hydroxy al- (h) White, J. D.; Lee, T. H.; Kuntiyong, P. Org. Lett. 2006, 8, 6043e
kenes, allenes, and alkynes will undoubtedly play a major 6046.
role in further developments in this field. 3. For total syntheses of phorboxazole B, see: (a) Evans, D. A.; Fitch,
D. M.; Smith, T. E.; Cee, V. J. J. Am. Chem. Soc. 2000, 122, 10033e
10046; (b) Li, D.-R.; Zhang, D.-H.; Sun, C.-Y.; Zhang, J.-W.; Yang,
Acknowledgements L.; Chen, J.; Liu, B.; Su, C.; Zhou, W.-S.; Lin, G.-Q. Chem.dEur. J.
2006, 12, 1185e1204; (c) Lucas, B. S.; Gopalsamuthiram, V.; Burke,
S. D. Angew. Chem., Int. Ed. 2007, 46, 769e772.
We are grateful for the financial support from the Spanish
4. For a review on the synthesis of phorboxazoles, see: Haustedt, L. O.;
Ministerio de Ciencia y Tecnologı́a (Grant CTQ2006-13249/ Hartung, I. V.; Hoffmann, H. M. R. Angew. Chem., Int. Ed. 2003, 42,
BQU), the Generalitat de Catalunya (2005SGR00584), and 2711e2716.
the Universitat de Barcelona (ACES-UB2006). 5. (a) Kishi, Y. Pure Appl. Chem. 1998, 70, 339e344; (b) Faulkner, D. J.
Nat. Prod. Rep. 2002, 19, 1e48 and references therein.
6. For reviews on the synthesis of tetrahydropyrans, see: (a) Boivin, T. L. B.
References and notes Tetrahedron 1987, 43, 3309e3362; (b) Elliott, M. C. J. Chem. Soc., Per-
kin Trans. 1 2002, 2301e2323; (c) Clarke, P. A.; Santos, S. Eur. J. Org.
1. For total syntheses of leucascandrolide A, see: (a) Hornberger, K. R.; Chem. 2006, 2045e2053; (d) Tang, Y.; Oppenheimer, J.; Song, Z.; You,
Hamblett, C. L.; Leighton, J. L. J. Am. Chem. Soc. 2000, 122, 12894e L.; Zhang, X.; Hsung, R. P. Tetrahedron 2006, 62, 10785e10813.
2718 I. Larrosa et al. / Tetrahedron 64 (2008) 2683e2723
7. For the stereoselective preparation of pyrans in the context of the synthe- 28. Conformational restrictions on the substrate may alter the model
sis of polyether ionophore antibiotics, see: Faul, M. M.; Huff, B. E. reactions described in Schemes 7 and 8. For an example, see: Nicolaou,
Chem. Rev. 2000, 100, 2407e2473. K. C.; Harrison, S. T. J. Am. Chem. Soc. 2007, 129, 429e440 and refer-
8. For the stereoselective preparation of pyrans in the context of the synthe- ences therein.
sis of marine macrolides, see: Yeung, K.-S.; Paterson, I. Chem. Rev. 29. Crimmins, M. T.; Haley, M. W. Org. Lett. 2006, 8, 4223e4225.
2005, 105, 4237e4313. 30. For other 6-exo cyclizations, see: (a) Bhatt, U.; Christmann, M.;
9. For the stereoselective preparation of pyrans in the context of the synthe- Quitschalle, M.; Claus, E.; Kalesse, M. J. Org. Chem. 2001, 66,
sis of polycyclic ethers, see: (a) Nakata, T. Chem. Rev. 2005, 105, 4314e 1885e1893; (b) Williams, D. R.; Ihle, D. C.; Plummer, S. V. Org.
4347; (b) Inoue, M. Chem. Rev. 2005, 105, 4379e4405. Lett. 2001, 3, 1383e1386; (c) Yoshimitsu, T.; Makino, T.; Nagaoka, H.
10. For the stereoselective preparation of spirans, see: Aho, J. E.; Pihko, J. Org. Chem. 2004, 69, 1993e1998; (d) Chang, S.-K.; Paquette, L. A.
P. M.; Rissa, T. K. Chem. Rev. 2005, 105, 4406e4440. Synlett 2005, 2915e2918; (e) Kadota, I.; Abe, T.; Sato, Y.; Kabuto, C.;
11. For a BaeyereVilliger oxidation of a cyclopentanone en route to phor- Yamamoto, Y. Tetrahedron Lett. 2006, 47, 6545e6548; (f) Takahashi,
boxazoles, see: Misske, A. M.; Hoffmann, H. M. R. Tetrahedron 1999, S.; Hongo, Y.; Ogawa, N.; Koshino, H.; Nakata, T. J. Org. Chem.
55, 4315e4324. 2006, 71, 6305e6308; (g) Takizawa, A.; Fujiwara, K.; Doi, E.; Murai,
12. For HDA cycloadditions en route to 1 and 2, see Refs. 1e,2a,b. A.; Kawai, H.; Suzuki, T. Tetrahedron 2006, 62, 7408e7435; (h) Bedore,
13. For the synthesis of pyrans in the context of comprehensive reactivity M. W.; Chang, S.-K.; Paquette, L. A. Org. Lett. 2007, 9, 513e516.
reviews, see: (a) Nakamura, I.; Yamamoto, Y. Chem. Rev. 2004, 104, 31. Fuwa, H.; Ebine, M.; Bourdelais, A. J.; Baden, D. G.; Sasaki, M. J. Am.
2127e2198; (b) Deiters, A.; Martin, S. F. Chem. Rev. 2004, 104, Chem. Soc. 2006, 128, 16989e16999.
2199e2238; (c) Barluenga, J.; Santamarı́a, J.; Tomás, M. Chem. Rev. 32. For other 6-endo cyclizations, see: (a) Mukai, C.; Sugimoto, Y.-i.; Ikeda,
2004, 104, 2259e2283; (d) Zeni, G.; Larock, R. C. Chem. Rev. 2004, Y.; Hanaoka, M. Tetrahedron 1998, 54, 823e850; (b) Uehara, H.; Oishi,
104, 2285e2309; (e) Muzart, J. Tetrahedron 2005, 61, 5955e6008. T.; Inoue, M.; Shoji, M.; Nagumo, Y.; Kosaka, M.; Le Brazidec, J.-Y.;
14. For C-glycosidation transformations en route to 1 and 2, see Refs. Hirama, M. Tetrahedron 2002, 58, 6493e6512; (c) Sato, K.; Sasaki,
1a,e,3a. M. Angew. Chem., Int. Ed. 2007, 46, 2518e2522; (d) Shangguan, N.;
15. We have systematically adopted along the review the heterocyclic Kiren, S.; Williams, L. J. Org. Lett. 2007, 9, 1093e1096.
nomenclature (and not the carbohydrate-like one), which assigns number 33. McDonald, F. E.; Wei, X. Org. Lett. 2002, 4, 593e595.
1 to the oxygen atom. 34. (a) Morimoto, Y.; Nishikawa, Y.; Ueba, C.; Tanaka, T. Angew. Chem.,
16. Baldwin, J. E. J. Chem. Soc., Chem. Commun. 1976, 734e736. Int. Ed. 2006, 45, 810e812; (b) Morimoto, Y.; Yata, H.; Nishikawa, Y.
17. (a) Smith, A. B., III; Zhu, W.; Shirakami, S.; Sfouggatakis, C.; Doughty, Angew. Chem., Int. Ed. 2007, 46, 6481e6484.
V. A.; Bennett, C. S.; Sakamoto, Y. Org. Lett. 2003, 5, 761e764; (b) 35. Blanc, A.; Toste, F. D. Angew. Chem., Int. Ed. 2006, 45, 2096e2099.
Brenner, E.; Baldwin, R. M.; Tamagnan, G. Org. Lett. 2005, 7, 937e 36. For a comprehensive analysis of such processes in the context of func-
939. tionalized tetrahydrofurans, see: Hartung, J.; Drees, S.; Greb, M.;
18. (a) Cink, R. D.; Forsyth, C. J. J. Org. Chem. 1997, 62, 5672e5673; (b) Schimdt, P.; Svoboda, I.; Fuess, H.; Murso, A.; Stalke, D. Eur. J. Org.
Chakraborty, T. K.; Reddy, V. R.; Reddy, T. J. Tetrahedron 2003, 59, Chem. 2003, 2388e2408.
8613e8622; (d) Hicks, J. D.; Flamme, E. M.; Roush, W. R. Org. Lett. 37. Cane, D. E.; Celmer, W. D.; Westley, J. W. J. Am. Chem. Soc. 1983, 105,
2005, 7, 5509e5512; (e) Chakraborty, T. K.; Reddy, V. R. Tetrahedron 3594e3600.
Lett. 2006, 47, 2099e2102. 38. (a) Fujiwara, K.; Murai, A. Bull. Chem. Soc. Jpn. 2004, 77, 2129e2146;
19. (a) Bolster, M. G.; Jansen, B. J. M.; de Groot, A. Tetrahedron 2002, 58, (b) Valentine, J. C.; McDonald, F. E. Synlett 2006, 1816e1828; (c)
5275e5285; (b) Smith, A. B., III; Kanoh, N.; Ishiyama, H.; Minakawa, Gallimore, A. R.; Spencer, J. B. Angew. Chem., Int. Ed. 2006, 45,
N.; Rainier, J. D.; Hartz, R. A.; Cho, Y. S.; Cui, H.; Moser, W. H. J. Am. 4406e4413.
Chem. Soc. 2003, 125, 8228e8237; (c) Pichlmair, S.; Marques, 39. The efficiency of such strategy has been proved in the synthesis of a
M. M. B.; Green, M. P.; Martin, H. J.; Mulzer, J. Org. Lett. 2003, 5, Cs-symmetric diastereomer of glabrescol, a polyether containing five
4657e4659; (d) Hua, D. H.; Huang, X.; Chen, Y.; Battina, S. K.; Tamura, contiguous tetrahydrofuran rings, see: Xiong, Z.; Corey, E. J. J. Am.
M.; Noh, S. K.; Koo, S. I.; Namatame, I.; Tomoda, H.; Perchellet, E. M.; Chem. Soc. 2000, 122, 4831e4832.
Perchellet, J.-M. J. Org. Chem. 2004, 69, 6065e6078; (e) Prasad, K.; 40. Tokiwano, T.; Fujiwara, K.; Murai, A. Synlett 2000, 335e338.
Anbarasan, P. Tetrahedron 2007, 63, 1089e1092; (f) Zhou, J.; Snider, 41. Bravo, F.; McDonald, F. E.; Neiwert, W. A.; Do, B.; Hardcastle, K. I.
B. B. Org. Lett. 2007, 9, 2071e2074. Org. Lett. 2003, 5, 2123e2126.
20. Occasionally, an SN20 mechanism can also be proposed to rationalize this 42. Simpson, G. L.; Heffron, T. P.; Merino, E.; Jamison, T. F. J. Am. Chem.
type of cyclizations, see: (a) Ravn, M. M.; Peters, R. J.; Coates, R. M.; Soc. 2006, 128, 1056e1057.
Croteau, R. J. Am. Chem. Soc. 2002, 124, 6998e7006; (b) Kang, Y.; Mei, 43. Chamberlin, A. R.; Mulholland, R. L.; Kahn, S. D.; Hehre, W. J. J. Am.
Y.; Du, Y.; Jin, Z. Org. Lett. 2003, 5, 4481e4484. Chem. Soc. 1987, 109, 672e677.
21. Williams, D. R.; Kiryanov, A. A.; Emde, U.; Clark, M. P.; Berliner, 44. For mercury(II)-mediated cyclizations, see: (a) Evans, D. A.; Bender,
M. A.; Reeves, J. T. Angew. Chem., Int. Ed. 2003, 42, 1258e1262. S. L.; Morris, J. J. Am. Chem. Soc. 1988, 110, 2506e2526; (b) de Kon-
22. For a recent account on the Nicholas reaction, see: Dı́az, D. D.; ing, C. B.; Green, I. R.; Michael, J. P.; Oliveira, J. R. Tetrahedron 2001,
Betancort, J. M.; Martı́n, V. S. Synlett 2007, 343e359. 57, 9623e9634; (c) Liu, B.; Zhou, W.-S. Tetrahedron Lett. 2003, 44,
23. Betancort, J. M.; Martı́n, T.; Palazón, J. M.; Martı́n, V. S. J. Org. Chem. 4933e4935; (d) Takao, H.; Wakabayashi, A.; Takahashi, K.; Imagawa,
2003, 68, 3216e3224; See also: Dı́az, D.; Martı́n, T.; Martı́n, V. S. Org. H.; Sugihara, T.; Nishizawa, M. Tetrahedron Lett. 2004, 45, 1079e
Lett. 2001, 3, 3289e3291. 1082; (e) Petri, A. F.; Bayer, A.; Maier, M. E. Angew. Chem., Int. Ed.
24. Crisóstomo, F. R. P.; Martı́n, T.; Martı́n, V. S. Org. Lett. 2004, 6, 565e 2004, 43, 5821e5823; (f) Nicolaou, K. C.; Pihko, P. M.; Bernal, F.;
568. Frederick, M. O.; Qian, W.; Uesaka, N.; Diedrichs, N.; Hinrichs, J.;
25. Crisóstomo, F. R. P.; Carrillo, R.; León, L. G.; Martı́n, T.; Padrón, J. M.; Koftis, T. V.; Loizidou, E.; Petrovic, G.; Rodriquez, M.; Sarlah, D.;
Martı́n, V. S. J. Org. Chem. 2006, 71, 2339e2345. Zou, N. J. Am. Chem. Soc. 2006, 128, 2244e2257.
26. (a) Nicolaou, K. C.; Prasad, C. V. C.; Somers, P. K.; Hwang, C.-K. J. Am. 45. The cyclization of g-hydroxy-cis-alkenes promoted by mercury(II) salts
Chem. Soc. 1989, 111, 5330e5334; (b) Nicolaou, K. C.; Prasad, C. V. C.; and chiral bisoxazolines as ligands affords 2-substituted tetrahydro-
Somers, P. K.; Hwang, C.-K. J. Am. Chem. Soc. 1989, 111, 5335e5340. furans. Application of this methodology to just a d-hydroxy-cis-alkene
27. For theoretical studies on the acid-mediated epoxy alcohol cyclizations, provides the corresponding tetrahydropyran in excellent ee, see:
see: (a) Na, J.; Houk, K. N.; Shevlin, C. G.; Janda, K. D.; Lerner, R. A. Kang, S. H.; Kim, M. J. Am. Chem. Soc. 2003, 125, 4684e4685.
J. Am. Chem. Soc. 1993, 115, 8453e8454; (b) Na, J.; Houk, K. N. J. Am. 46. Meyer, C.; Blanchard, N.; Defosseux, M.; Cossy, J. Acc. Chem. Res.
Chem. Soc. 1996, 118, 9204e9205. 2003, 36, 766e772.
I. Larrosa et al. / Tetrahedron 64 (2008) 2683e2723 2719
47. Defosseux, M.; Blanchard, N.; Meyer, C.; Cossy, J. J. Org. Chem. 2004, the five-membered counterparts are preferred with Pd(OAc)2. See:
69, 4626e4647. Hosokawa, T.; Murahashi, S.-I. Acc. Chem. Res. 1990, 23, 49e54.
48. (a) Schultz, A. G.; Guzi, T. J.; Larsson, E.; Rahm, R.; Thakkar, K.; 67. Hegedus, S. L. Organometallic in Synthesis: A Manual; Schlosser, M.,
Bidlack, J. M. J. Org. Chem. 1998, 63, 7795e7804; (b) Bernard, N.; Ed.; John Wiley and Sons: Chichester, UK, 2002; Chapter 10,
Chemla, F.; Ferreira, F.; Mostefai, N.; Normant, J.-F. Chem.dEur. J. pp 1123e1217.
2002, 8, 3139e3147; (c) Van der Weghe, P.; Aoun, D.; Boiteau, J.-G.; 68. Semmelhack, M. F.; Kim, C. R. K.; Dobler, W.; Meier, M. Tetrahedron
Eustache, J. Org. Lett. 2002, 4, 4105e4108; (d) Kang, S. H.; Kang, Lett. 1989, 30, 4925e4928.
S. Y.; Kim, C. M.; Choi, H.-w.; Jun, H.-S.; Lee, B. M.; Park, C. M.; 69. For other Pd(II)-mediated cyclizations, see: (a) Semmelhack, M. F.; Epa,
Jeong, J. W. Angew. Chem., Int. Ed. 2003, 42, 4779e4782; (e) Gao, W. R.; Cheung, A. W.-H.; Gu, Y.; Kim, C.; Zhang, N.; Lew, W. J. Am.
X.; Snider, B. B. J. Org. Chem. 2004, 69, 5517e5527; (f) Dı́ez, D.; Chem. Soc. 1994, 116, 7455e7456; (b) Arai, M. A.; Kuraishi, M.;
Nú~
nez, M. G.; Moro, R. F.; Lumeras, W.; Marcos, I. S.; Basabe, P.; Arai, T.; Sasai, H. J. Am. Chem. Soc. 2001, 123, 2907e2908; (c) Trend,
Urones, J. G. Synlett 2006, 939e941; (g) Nicolaou, K. C.; Koftis, T. V.; R. M.; Ramtohul, Y. K.; Ferreira, E. M.; Stoltz, B. M. Angew. Chem., Int.
Vyskocil, S.; Petrovic, G.; Tang, W.; Frederick, M. O.; Chen, D. Y.-K.; Ed. 2003, 42, 2892e2895; (d) Koh, J. H.; Mascarenhas, C.; Gagné, M. R.
Li, Y.; Ling, T.; Yamada, Y. M. A. J. Am. Chem. Soc. 2006, 128, 2859e2872. Tetrahedron 2004, 60, 7405e7410.
49. For a recent example on the classical iodolactonization process leading 70. (a) Uenishi, J.; Ohmi, M. Angew. Chem., Int. Ed. 2005, 44, 2756e2760;
to a six-membered lactone, see: Zakarian, A.; Batch, A.; Holton, R. A. (b) Kawai, N.; Lagrange, J.-M.; Ohmi, M.; Uenishi, J. J. Org. Chem.
J. Am. Chem. Soc. 2003, 125, 7822e7824. 2006, 71, 4530e4537; See also: (c) Miyazawa, M.; Hirose, Y.; Narant-
50. For other halo-mediated cyclizations, see: Zhong, H. M.; Sohn, J.-H.; setseg, M.; Yokoyama, H.; Yamaguchi, S.; Hirai, Y. Tetrahedron Lett.
Rawal, V. H. J. Org. Chem. 2007, 72, 386e397. 2004, 45, 2883e2886.
51. (a) Albert, B. J.; Koide, K. Org. Lett. 2004, 6, 3655e3658; (b) Albert, 71. This analysis has been expanded to the corresponding Z isomers. Under
B. J.; Sivaramakrishnan, A.; Naka, T.; Koide, K. J. Am. Chem. Soc. the same conditions, (2S,3Z,8S) isomer also affords 92-cis as a single
2006, 128, 2792e2793. product in 76% yield. However, cyclization of (2R,3Z,8S) isomer turns
52. For a related iodoetherification involving a ketone, see: Clarke, P. A.; out to be less stereoselective and more stringent conditions are required.
Grist, M.; Ebden, M.; Wilson, C.; Blake, A. J. Tetrahedron 2005, 61, 72. Semmelhack, M. F.; Kim, C.; Zhang, N.; Bodurow, C.; Sanner, M.;
353e363. Dobler, W.; Meier, M. Pure Appl. Chem. 1990, 62, 2035e2040.
53. For other cyclizations involving oxygenated nucleophiles different than 73. For an analysis on the influence of stereochemistry on the intramolecular
alcohols or carboxylic acids, see: (a) Liu, K.; Taylor, R. E.; Kartika, Pd(II)-mediated alkoxycarbonylation, see: Blakemore, P. R.; Browder,
R. Org. Lett. 2006, 8, 5393e5395; (b) Braddock, D. C. Org. Lett. C. C.; Hong, J.; Lincoln, C. M.; Nagornyy, P. A.; Robarge, L. A.; War-
2006, 8, 6055e6058. drop, D. J.; White, J. D. J. Org. Chem. 2005, 70, 5449e5460.
54. For a review on selenocyclizations, see: Petragnani, N.; Stefani, H. A.; 74. White, J. D.; Kranemann, C. L.; Kuntiyong, P. Org. Lett. 2001, 3, 4003e
Valduga, C. J. Tetrahedron 2001, 57, 1411e1448. 4006.
55. (a) See Refs. 1d, 19d, 50, 51; (b) Iwasaki, K.; Nakatani, M.; Inoue, M.; 75. Tietze, L. F.; Sommer, K. M.; Zinngrebe, J.; Stecker, F. Angew. Chem.,
Katoh, T. Tetrahedron 2003, 59, 8763e8773. Int. Ed. 2005, 44, 257e259.
56. For a comprehensive overview, see: Tsuji, J. Palladium Reagents and 76. (a) Reiter, M.; Ropp, S.; Gouverneur, V. Org. Lett. 2004, 6, 91e94; (b)
Catalysts. New Perspectives for the 21st Century; John Wiley and Baker-Glenn, C.; Hodnett, N.; Reiter, M.; Ropp, S.; Ancliff, R.; Gouver-
Sons: Chichester, UK, 2004. neur, V. J. Am. Chem. Soc. 2005, 127, 1481e1486; (c) Reiter, M.; Turner,
57. The stereoselectivity of the process can be eroded if p-facial selectiv- H.; Mills-Webb, R.; Gouverneur, V. J. Org. Chem. 2005, 70, 8478e8485;
ity is not enough effective or the equilibration of diastereomeric com- (d) Han, S. B.; Krische, M. J. Org. Lett. 2006, 8, 5657e5660.
plexes via pesep mechanism is faster than the nucleophilic 77. Liao, X.; Zhou, H.; Wearing, X. Z.; Ma, J.; Cook, J. M. Org. Lett. 2005,
addition. 7, 3501e3504.
58. Hansen, E. C.; Lee, D. Tetrahedron Lett. 2004, 45, 7151e7155. 78. Qian, H.; Han, X.; Widenhoefer, R. A. J. Am. Chem. Soc. 2004, 126,
59. For reviews on stereoselective allylic alkylations, see: (a) Trost, B. M.; 9536e9537.
Van Vranken, D. L. Chem. Rev. 1996, 96, 395e422; (b) Trost, B. M. 79. Coulombel, L.; Favier, I.; Du~nach, E. Chem. Commun. 2005, 2286e
Acc. Chem. Res. 1996, 29, 355e364; (c) Trost, B. M.; Crawley, M. L. 2288.
Chem. Rev. 2003, 103, 2921e2943. 80. Yang, C.-G.; Reich, N. W.; Shi, Z.; He, C. Org. Lett. 2005, 7, 4553e
60. Trost, B. M.; Machacek, M. R.; Faulk, B. D. J. Am. Chem. Soc. 2006, 4556.
128, 6745e6754. 81. Marotta, E.; Foresti, E.; Marcelli, T.; Peri, F.; Righi, P.; Scardovi, N.;
61. For further applications of this methodology, see: Trost, B. M.; Rosini, G. Org. Lett. 2002, 4, 4451e4453.
Machacek, M. R.; Tsui, H. C. J. Am. Chem. Soc. 2005, 127, 7014e7024. 82. Jung, H. H.; Floreancig, P. E. Org. Lett. 2006, 8, 1949e1951.
62. Campbell, J. E.; Englund, E. E.; Burke, S. D. Org. Lett. 2002, 4, 2273e 83. (a) Nicolaou, K. C.; Li, A.; Edmonds, D. J. Angew. Chem., Int. Ed. 2006,
2275. 45, 7086e7090; (b) Zou, Y.; Chen, C.-H.; Taylor, C. D.; Foxman, B. M.;
63. For other Pd(0)-mediated cyclizations, see: (a) Lucas, B. S.; Burke, S. D. Snider, B. B. Org. Lett. 2007, 9, 1825e1828; (c) Kaliappan, K. P.;
Org. Lett. 2003, 5, 3915e3918; (b) Zacuto, M. J.; Leighton, J. L. Org. Ravikumar, V. Org. Lett. 2007, 9, 2417e2419; (d) Nicolaou, K. C.;
Lett. 2005, 7, 5525e5527. Edmonds, D. J.; Li, A.; Tria, G. S. Angew. Chem., Int. Ed. 2007, 46,
64. The alternative 7-endo ring closures leading to oxepanes have never been 1e5; (e) Nicolaou, K. C.; Tang, Y.; Wang, J. Chem. Commun. 2007,
observed. 1922e1923.
65. The intramolecular cyclization of g-hydroxy alkenes could afford 84. For other examples on the Brønsted acid-mediated cyclization of
the corresponding six-membered oxygenated heterocycles through a hydroxy alkenes, see: (a) Nicolaides, D. N.; Gautam, D. R.; Litinas,
6-endo ring closure. However, the five-membered oxygenated counter- K. E.; Papamehael, T. J. Chem. Soc., Perkin Trans. 1 2002, 1455e
parts are usually obtained, with the exception of those substrates contain- 1460; (b) Linares-Palomino, P. J.; Salido, S.; Altarejos, J.; Sánchez, A.
ing E-disubstituted olefins. See: (a) Semmelhack, M. F.; Bodurow, C. Tetrahedron Lett. 2003, 44, 6651e6655; (c) Neighbors, J. D.; Beutler,
J. Am. Chem. Soc. 1984, 106, 1496e1498; (b) Semmelhack, M. F.; J. A.; Wiemer, D. F. J. Org. Chem. 2005, 70, 925e931; (d)
Zhang, N. J. Org. Chem. 1989, 54, 4483e4485; (c) McCormick, M.; Alvarez-Manzaneda, E. J.; Chahboun, R.; Pérez, I. B.; Cabrera, E.;
Monahan, R., III; Soria, J.; Goldsmith, D.; Liotta, D. J. Org. Chem. Alvarez, E.; Alvarez-Manzaneda, R. Org. Lett. 2005, 7, 1477e1480;
1989, 54, 4485e4487. (e) Grütter, C.; Alonso, E.; Chougnet, A.; Woggon, W.-D. Angew.
66. The regioselectivity of Pd(II)-mediated intramolecular cyclizations of Chem., Int. Ed. 2006, 45, 1126e1130.
o-allylic phenols seems to be largely dependent of palladium(II) salts. 85. Rosenfeld, D. C.; Shekhar, S.; Takemiya, A.; Utsunomiya, M.; Hartwig,
The use of PdCl2 appears to afford six-membered heterocycles, whereas J. F. Org. Lett. 2006, 8, 4179e4182.
2720 I. Larrosa et al. / Tetrahedron 64 (2008) 2683e2723
86. For a recent account on these cyclizations, see: Miura, K.; Hosomi, A. 2006, 47, 6273e6276; (c) For related mercury-catalyzed 6-exo-dig cycli-
Synlett 2003, 143e155. zations, see: Imagawa, H.; Fujikawa, Y.; Tsuchihiro, A.; Kinoshita, A.;
87. (a) Tsujimori, H.; Bando, M.; Mori, K. Eur. J. Org. Chem. 2000, 297e Yoshinaga, T.; Takao, H.; Nishizawa, M. Synlett 2006, 639e641.
302; (b) Coulombel, L.; Rajzmann, M.; Pons, J.-M.; Olivero, S.; Du~nach, 111. For a silver catalyzed cyclization on 2-alkynylketones, see: Patil, N. T.;
E. Chem.dEur. J. 2006, 12, 6356e6365. Pahadi, N. K.; Yamamoto, Y. J. Org. Chem. 2005, 70, 10096e10098.
88. (a) Uyanik, M.; Ishihara, K.; Yamamoto, H. Bioorg. Med. Chem. 2005, 112. For a rhodium-mediated cyclizationecycloaddition on 2-alkynylbenz-
13, 5055e5065 and references therein; (b) See also Ref. 84e. aldehydes, see: Shin, S.; Gupta, A. K.; Rhim, C. Y.; Oh, C. H. Chem.
89. For reviews on the chemistry of allenes, see: (a) Zimmer, R.; Dinesh, Commun. 2005, 4429e4431.
C. U.; Nandanan, E.; Khan, F. A. Chem. Rev. 2000, 100, 3067e3125; 113. For a tungsten-mediated cyclizationecycloaddition on 2-alkynylphenyl-
(b) Bates, R. W.; Satcharoen, V. Chem. Soc. Rev. 2002, 31, 12e21. carbonyl derivatives, see: Kusama, H.; Funami, H.; Shido, M.; Hara, Y.;
90. (a) Gockel, B.; Krause, N. Org. Lett. 2006, 8, 4485e4488; (b) For a Takaya, J.; Iwasawa, N. J. Am. Chem. Soc. 2005, 127, 2709e2716.
related process involving a gold-catalyzed cyclization of a b-allene ester, 114. 2-Benzopyrylium salts can undergo formal [4þ2] benzannulation cyclo-
see: Piera, J.; Krumlinde, P.; Strübing, D.; Bäckvall, J.-E. Org. Lett. additions to polysubstituted aromatic compounds without any oxygen-
2007, 9, 2235e2237. ated heterocycle. For representative examples, see: (a) Asao, N.;
91. Zhang, Z.; Liu, C.; Kinder, R. E.; Han, X.; Qian, H.; Widenhoefer, R. A. Takahashi, K.; Lee, S.; Kasahara, T.; Yamamoto, Y. J. Am. Chem. Soc.
J. Am. Chem. Soc. 2006, 128, 9066e9073. 2002, 124, 12650e12651; (b) Asao, N.; Nogami, T.; Lee, S.; Yamamoto,
92. Zhang, Z.; Widenhoefer, R. A. Angew. Chem., Int. Ed. 2007, 46, 283e Y. J. Am. Chem. Soc. 2003, 125, 10921e10925; (c) Asao, N.; Kasahara,
285. T.; Yamamoto, Y. Angew. Chem., Int. Ed. 2003, 42, 3504e3506; (d)
93. For reviews on the electrophilic activation of alkynes, see: (a) Alonso, F.; Straub, B. F. Chem. Commun. 2004, 1726e1728; (e) Asao, N.; Sato,
Beletskaya, I. P.; Yus, M. Chem. Rev. 2004, 104, 3079e3159; (b) Beller, K.; Menggenbateer; Yamamoto, Y. J. Org. Chem. 2005, 70, 3682e
M.; Seayad, J.; Tillack, A.; Jiao, H. Angew. Chem., Int. Ed. 2004, 43, 3685; (f) Dyker, G.; Hildebrandt, D. J. Org. Chem. 2005, 70, 6093e
3368e3398. 6096; (g) Sato, K.; Asao, N.; Yamamoto, Y. J. Org. Chem. 2005, 70,
94. Gabriele, B.; Salerno, G.; Fazio, A.; Pitelli, R. Tetrahedron 2003, 59, 8977e8981; (h) Asao, N.; Sato, K. Org. Lett. 2006, 8, 5361e5363; (i)
6251e6259. Asao, N.; Aikawa, H. J. Org. Chem. 2006, 71, 5249e5253; (j) Hilde-
95. For a Pd(II)eCu(II) bimetallic catalytic system, see: Asao, N.; Chan, brandt, D.; Dyker, G. J. Org. Chem. 2006, 71, 6728e6733.
C. S.; Takahashi, K.; Yamamoto, Y. Tetrahedron 2005, 61, 11322e 115. Zhu, J.; Germain, A. R.; Porco, J. A., Jr. Angew. Chem., Int. Ed. 2004, 43,
11326. 1239e1243.
96. Li, X.; Chianese, A. R.; Vogel, T.; Crabtree, R. H. Org. Lett. 2005, 7, 116. Zhu, J.; Grigoriadis, N. P.; Lee, J. P.; Porco, J. A., Jr. J. Am. Chem. Soc.
5437e5440. 2005, 127, 9342e9343.
97. Nakamura, H.; Ohtaka, M.; Yamamoto, Y. Tetrahedron Lett. 2002, 43, 117. A similar strategy has been followed for the enantioselective synthesis of
7631e7633. ()-mitorubrin, see: Zhu, J.; Porco, J. A., Jr. Org. Lett. 2006, 8, 5169e
98. Trost, B. M.; Frontier, A. J. J. Am. Chem. Soc. 2000, 122, 11727e11728. 5171.
99. Silva, F.; Reiter, M.; Mills-Webb, R.; Sawicki, M.; Klär, D.; Bensel, N.; 118. Gulı́as, M.; Rodrı́guez, J. R.; Castedo, L.; Mascare~nas, J. L. Org. Lett.
Wagner, A.; Gouverneur, V. J. Org. Chem. 2006, 71, 8390e8394. 2003, 5, 1975e1977.
100. For an alkoxycarbonylation process in which the s-alkenylpalladium 119. Imagawa, H.; Kotani, S.; Nishizawa, M. Synlett 2006, 642e644.
complex is trapped with CO, see: Marshall, J. A.; Yanik, M. M. Tetra- 120. For the use of Ipyr2BF4, see: Barluenga, J.; Vázquez-Villa, H.; Merino,
hedron Lett. 2000, 41, 4717e4721. I.; Ballesteros, A.; González, J. M. Chem.dEur. J. 2006, 12, 5790e
101. Genin, E.; Antoniotti, S.; Michelet, V.; Genêt, J.-P. Angew. Chem., Int. 5805.
Ed. 2005, 44, 4949e4953. 121. For the use of iodine, NBS, and ICl, see: (a) Zhou, C.; Dubrovsky, A. V.;
102. Barluenga, J.; Diéguez, A.; Fernández, A.; Rodrı́guez, F.; Fa~nanás, F. J. Larock, R. C. J. Org. Chem. 2006, 71, 1626e1632; (b) Yue, D.; Della
Angew. Chem., Int. Ed. 2006, 45, 2091e2093. Cà, N.; Larock, R. C. J. Org. Chem. 2006, 71, 3381e3388.
103. (a) Antoniotti, S.; Genin, E.; Michelet, V.; Genêt, J.-P. J. Am. Chem. Soc. 122. (a) Barluenga, J.; Vázquez-Villa, H.; Ballesteros, A.; González, J. M.
2005, 127, 9976e9977; (b) For a related transformation involving Org. Lett. 2003, 5, 4121e4123; (b) Barluenga, J.; Vázquez-Villa, H.;
epoxy-alkynes, see: Dai, L.-Z.; Qi, M.-J.; Shi, Y.-L.; Liu, X.-G.; Shi, Ballesteros, A.; González, J. M. Adv. Synth. Catal. 2005, 347, 526e530.
M. Org. Lett. 2007, 9, 3191e3194. 123. (a) McDonald, F. E. Chem.dEur. J. 1999, 5, 3103e3106; (b) Miki, K.;
104. Liu, B.; DeBrabander, J. K. Org. Lett. 2006, 8, 4907e4910. Uemura, S.; Ohe, K. Chem. Lett. 2005, 34, 1068e1073.
105. For a related cycloisomerization using a palladium(II) catalyst, see: 124. For reviews on the preparation and reactivity of vinylidene complexes,
Trost, B. M.; Horne, D. B.; Woltering, M. J. Angew. Chem., Int. Ed. see: (a) Ref. 93a; (b) Trost, B. M.; Frederiksen, M. U.; Rudd, M. T.
2003, 42, 5987e5990. Angew. Chem., Int. Ed. 2005, 44, 6630e6666; (c) Bruneau, C.; Dixneuf,
106. For iridium- and rhodium-mediated synthesis of acetals from alkyne P. H. Angew. Chem., Int. Ed. 2006, 45, 2176e2203.
diols, see: (a) Messerle, B. A.; Vuong, K. Q. Pure Appl. Chem. 2006, 125. For a recent contribution to this mechanism, see: Grotjahn, D. B.; Zeng,
78, 385e390; (b) Messerle, B. A.; Vuong, K. Q. Organometallics X.; Cooksy, A. L. J. Am. Chem. Soc. 2006, 128, 2798e2799 and refer-
2007, 26, 3031e3040. ences therein.
107. Li, Y.; Zhou, F.; Forsyth, C. J. Angew. Chem., Int. Ed. 2007, 46, 279e 126. Trost, B. M.; Rhee, Y. H. J. Am. Chem. Soc. 2003, 125, 7482e7483.
282. 127. (a) Trost, B. M.; Rhee, Y. H. J. Am. Chem. Soc. 2002, 124, 2528e2533;
108. (a) Asao, N.; Nogami, T.; Takahashi, K.; Yamamoto, Y. J. Am. Chem. (b) Trost, B. M.; Rhee, Y. H. Org. Lett. 2004, 6, 4311e4313.
Soc. 2002, 124, 764e765; (b) Mondal, S.; Nogami, T.; Asao, N.; 128. Molybdenum catalysts have been used exceptionally. See: McDonald,
Yamamoto, Y. J. Org. Chem. 2003, 68, 9496e9498. F. E.; Zhu, H. Y. H. Tetrahedron 1997, 53, 11061e11068.
109. For related transformations, see: (a) Patil, N. T.; Yamamoto, Y. J. Org. 129. McDonald, F. E.; Reddy, K. S.; Dı́az, Y. J. Am. Chem. Soc. 2000, 122,
Chem. 2004, 69, 5139e5142; (b) Yao, X.; Li, C.-J. Org. Lett. 2006, 8, 4304e4309.
1953e1955; (c) Obika, S.; Kono, H.; Yasui, Y.; Yanada, R.; Takemoto, 130. For a theoretical study on the activation of W(CO)6 and the mechanism
Y. J. Org. Chem. 2007, 72, 4462e4468. of the process, see: Sheng, Y.; Musaev, D. G.; Reddy, K. S.; McDonald,
110. (a) For the synthesis of fused a-pyrones through palladium-catalyzed F. E.; Morokuma, K. J. Am. Chem. Soc. 2002, 124, 4149e4157.
6-endo-dig cyclizations, see: Raju, S.; Batchu, V. R.; Swamy, N. K.; Dev, 131. (a) Cutchins, W. W.; McDonald, F. E. Org. Lett. 2002, 4, 749e752; (b)
R. V.; Sreekanth, B. R.; Babu, J. M.; Vyas, K.; Kumar, P. R.; Mukkanti, Parker, K. A.; Chang, W. Org. Lett. 2003, 5, 3891e3893; (c) Wipf, P.;
K.; Annamalai, P.; Pal, M. Tetrahedron 2006, 62, 9554e9570; (b) For Graham, T. H. J. Org. Chem. 2003, 68, 8798e8807; (d) Davidson,
the synthesis of d-alkylidene lactones through gold-catalyzed 6-exo-dig M. H.; McDonald, F. E. Org. Lett. 2004, 6, 1601e1603; (e) Alcázar,
cyclizations, see: Harkat, H.; Weibel, J.-M.; Pale, P. Tetrahedron Lett. E.; Pletcher, J. M.; McDonald, F. E. Org. Lett. 2004, 6, 3877e3880;
I. Larrosa et al. / Tetrahedron 64 (2008) 2683e2723 2721
(f) Moilanen, S. B.; Tan, D. S. Org. Biomol. Chem. 2005, 3, 798e803; 152. Geng, Z.; Chen, B.; Chiu, P. Angew. Chem., Int. Ed. 2006, 45, 6197e
(g) Koo, B.; McDonald, F. E. Org. Lett. 2005, 7, 3621e3624. 6201.
132. McDonald, F. E.; Reddy, K. S. Angew. Chem., Int. Ed. 2001, 40, 3653e 153. (a) Inoue, K.; Suga, H.; Inoue, S.; Sato, H.; Kakehi, A. Synthesis 2003,
3655; See also McDonald, F. E.; Wu, M. Org. Lett. 2002, 4, 3979e 1413e1418; (b) Suga, H.; Inoue, K.; Inoue, S.; Kakehi, A.; Shiro, M.
3981. J. Org. Chem. 2005, 70, 47e56; (c) Suga, H.; Suzuki, T.; Inoue, K.;
133. For comprehensive experimental and theoretical studies on the Kakehi, A. Tetrahedron 2006, 62, 9218e9225.
THF$W(CO)5 and W(CO)6-mediated cyclizations, see: (a) Barluenga, 154. (a) Kuwabe, S.-i.; Torraca, K. E.; Buchwald, S. L. J. Am. Chem. Soc.
J.; Diéguez, A.; Rodrı́guez, F.; Fa~nanás, F. J. Angew. Chem., Int. Ed. 2001, 123, 12202e12206; (b) Arcadi, A.; Cacchi, S.; Fabrizi, G.;
2005, 44, 126e128; (b) Sordo, T.; Campomanes, P.; Diéguez, A.; Marinelli, F.; Verdecchia, M. Synlett 2006, 909e915.
Rodrı́guez, F.; Fa~nanás, F. J. J. Am. Chem. Soc. 2005, 127, 944e952; 155. (a) Chae, J.; Buchwald, S. L. J. Org. Chem. 2004, 69, 3336e3339; (b)
(c) Barluenga, J.; Diéguez, A.; Rodrı́guez, F.; Fa~nanás, F. J.; Sordo, T.; Palucki, M.; Yasuda, N. Tetrahedron Lett. 2005, 46, 987e990; (c) Fürst-
Campomanes, P. Chem.dEur. J. 2005, 11, 5735e5741. ner, A.; Davies, P. W. J. Am. Chem. Soc. 2005, 127, 15024e15025; (d)
134. For the THF$W(CO)5-mediated cyclizations of 2-ethynylphenyl ketones, Heemstra, J. M.; Kerrigan, S. A.; Doerge, D. R.; Helferich, W. G.;
see: (a) Iwasawa, N.; Shido, M.; Maeyama, K.; Kusama, H. J. Am. Chem. Boulanger, W. A. Org. Lett. 2006, 8, 5441e5443.
Soc. 2000, 122, 10226e10227; (b) Kusama, H.; Sawada, T.; Okita, A.; 156. Fang, Y.; Li, C. J. Am. Chem. Soc. 2007, 129, 8092e8093.
Shiozawa, F.; Iwasawa, N. Org. Lett. 2006, 8, 1077e1079. 157. For equilibration of the initially formed 2,6-trans to the desired 2,6-cis-
135. Koo, B.; McDonald, F. E. Org. Lett. 2007, 9, 1737e1740. tetrahydropyran, see: (a) Evans, D. A.; Ripin, D. H. B.; Halstead, D. P.;
136. Doyle, M. P.; McKervey, M. A.; Ye, T. Modern Catalytic Methods for Campos, K. R. J. Am. Chem. Soc. 1999, 121, 6816e6826; (b) Micalizio,
Organic Synthesis with Diazo Compounds. From Cyclopropanes to G. C.; Pinchuk, A. N.; Roush, W. R. J. Org. Chem. 2000, 65, 8730e
Ylides; John Wiley and Sons: New York, NY, 1998. 8736; (c) Ball, M.; Baron, A.; Bradshaw, B.; Omori, H.; MacCormick,
137. For reviews on the synthesis and reactivity of metal carbenes, see: (a) S.; Thomas, E. J. Tetrahedron Lett. 2004, 45, 8737e8740; (d) Strand,
Hodgson, D. M.; Pierard, F. Y. T. M.; Stupple, P. A. Chem. Soc. Rev. D.; Rein, T. Org. Lett. 2005, 7, 199e202.
2001, 30, 50e61; (b) Doyle, M. P. Top. Organomet. Chem. 2004, 13, 158. For the synthesis of spongistatin 1, see: Paterson, I.; Chen, D. Y.-K.;
203e222; (c) Doyle, M. P. J. Org. Chem. 2006, 71, 9253e9260; (d) Coster, M. J.; Ace~na, J. L.; Bach, J.; Gibson, K. R.; Keown, L. E.; Oballa,
For a recent report on the mechanism of Rh-catalyzed carbene formation R. M.; Trieselmann, T.; Wallace, D. J.; Hodgson, A. P.; Norcross, R. D.
from diazo compounds, see: Wong, F. M.; Wang, J.; Hengge, A. C.; Wu, Angew. Chem., Int. Ed. 2001, 40, 4055e4060.
W. Org. Lett. 2007, 9, 1663e1665. 159. For other examples, see: (a) Paterson, I.; Arnott, E. A. Tetrahedron Lett.
138. Qu, Z.; Shi, W.; Wang, J. J. Org. Chem. 2004, 69, 217e219. 1998, 39, 7185e7188; (b) Yadav, J. S.; Bandyopadhyay, A.; Kunwar,
139. Lu, C.-D.; Liu, H.; Chen, Z.-Y.; Hu, W.-H.; Mi, A.-Q. Org. Lett. 2005, 7, A. C. Tetrahedron Lett. 2001, 42, 4907e4911; (c) Robertson, J.; Meo,
83e86. P.; Dallimore, J. W. P.; Doyle, B. M.; Hoarau, C. Org. Lett. 2004, 6,
140. López-Herrera, F. J.; Sarabia-Garcı́a, F. Tetrahedron 1997, 53, 3325e 3861e3863; (d) Alonso, D.; Pérez, M.; Gómez, G.; Covelo, B.; Fall,
3346. Y. Tetrahedron 2005, 61, 2021e2026; (e) Yadav, J. S.; Prakash, S. J.;
141. For a similar transformation, see: Sarabia, F.; Chammaa, S.; López Gangadhar, Y. Tetrahedron: Asymmetry 2005, 16, 2722e2728; (f)
Herrera, F. J. Tetrahedron 2001, 57, 10271e10279. Lambert, W. T.; Hanson, G. H.; Benayoud, F.; Burke, S. D. J. Org.
142. (a) Marmsäter, F. P.; West, F. G. J. Am. Chem. Soc. 2001, 123, 5144e Chem. 2005, 70, 9382e9398; (g) Paterson, I.; Anderson, E. A.; Dalby,
5145; (b) Marmsäter, F. P.; Vanecko, J. A.; West, F. G. Tetrahedron S. M.; Loiseleur, O. Org. Lett. 2005, 7, 4125e4128; (h) Chandrasekhar,
2002, 58, 2027e2040. S.; Prakash, S. J.; Shyamsunder, T. Tetrahedron Lett. 2005, 46, 6651e
143. (a) Clark, J. S.; Whitlock, G.; Jiang, S.; Onyia, N. Chem. Commun. 2003, 6653; (i) Son, J. B.; Kim, S. N.; Kim, N. Y.; Lee, D. H. Org. Lett.
2578e2579; (b) Clark, J. S.; Fessard, T. G.; Whitlock, G. A. Tetrahedron 2006, 8, 661e664; (j) Nonoyama, A.; Hamajima, A.; Isobe, M. Tetrahe-
2006, 62, 73e78. dron 2007, 63, 5886e5894.
144. For reviews on the reactivity of carbonyl ylides, see: (a) Mehta, G.; 160. (a) Schneider, C.; Schuffenhauer, A. Eur. J. Org. Chem. 2000, 73e82;
Muthusamy, S. Tetrahedron 2002, 58, 9477e9504; (b) Padwa, A. (b) Vakalopoulos, A.; Hoffmann, H. M. R. Org. Lett. 2001, 3, 177e
Helv. Chim. Acta 2005, 88, 1357e1374. 180; (c) Oishi, T.; Suzuki, M.; Watanabe, K.; Murata, M. Tetrahedron
145. For the use of allenes as dipolarophiles, see: (a) Hodgson, D. M.; Le Lett. 2006, 47, 3975e3978.
Strat, F. Chem. Commun. 2004, 822e823; (b) Zhang, X.; Ko, R. Y. Y.; 161. Occasionally, 2,6-trans-tetrahydropyrans can be more stable than the
Li, S.; Miao, R.; Chiu, P. Synlett 2006, 1197e1200. 2,3-cis counterparts, being obtained in high diastereoselectivity. For
146. For a combined application of ruthenium metathesis and rhodiume instance, see: Li, M.; O’Doherty, G. A. Org. Lett. 2006, 8, 6087e6090.
carbonyl ylide formation/1,3-dipolar cycloaddition, see: Hodgson, 162. (a) Bhattacharjee, A.; Soltani, O.; De Brabander, J. K. Org. Lett. 2002, 4,
D. M.; Angrish, D. Adv. Synth. Catal. 2006, 348, 2509e2514. 481e484; (b) Soltani, O.; De Brabander, J. K. Org. Lett. 2005, 7, 2791e
147. Nakamura, S.; Hirata, Y.; Kurosaki, T.; Anada, M.; Kataoka, O.; 2793; (c) Pan, Y.; De Brabander, J. K. Synlett 2006, 853e856.
Kitagaki, S.; Hashimoto, S. Angew. Chem., Int. Ed. 2003, 42, 5351e5355. 163. For preliminar analyses on the influence of the protecting group and the
148. Nakamura, S.; Sugano, Y.; Kikuchi, F.; Hashimoto, S. Angew. Chem., Int. alkene geometry, see: (a) Martı́n, V. S.; Nú~nez, M. T.; Ramı́rez, M. A.;
Ed. 2006, 45, 6532e6535. Soler, M. A. Tetrahedron Lett. 1990, 31, 763e766; (b) Gung, B. W.;
149. For other applications to the synthesis of natural products, see: (a) Dau- Francis, M. B. J. Org. Chem. 1993, 58, 6177e6179; (c) Martı́n, V. S.;
ben, W. G.; Dinges, J.; Smith, T. C. J. Org. Chem. 1993, 58, 7635e7637; Palazón, J. M. Tetrahedron Lett. 1992, 33, 2399e2402.
(b) Graening, T.; Friedrichsen, W.; Lex, J.; Schmalz, H.-G. Angew. 164. (a) Betancort, J. M.; Martı́n, V. S.; Padrón, J. M.; Palazón, J. M.;
Chem., Int. Ed. 2002, 41, 1524e1526; (c) Hodgson, D. M.; Le Strat, Ramı́rez, M. A.; Soler, M. A. J. Org. Chem. 1997, 62, 4570e4583; (b)
F.; Avery, T. D.; Donohue, A. C.; Brückl, T. J. Org. Chem. 2004, 69, Ramı́rez, M. A.; Padrón, J. M.; Palazón, J. M.; Martı́n, V. S. J. Org.
8796e8803; (d) Graening, T.; Bette, V.; Neudörfl, J.; Lex, J.; Schmalz, Chem. 1997, 62, 4584e4590; (c) Banwell, M. G.; Bissett, B. D.; Bui,
H.-G. Org. Lett. 2005, 7, 4317e4320. C. T.; Pham, H. T. T.; Simpson, G. W. Aust. J. Chem. 1998, 51, 9e18;
150. Snider, B. B.; Wu, X.; Nakamura, S.; Hashimoto, S. Org. Lett. 2007, 9, (d) Vares, L.; Rein, T. J. Org. Chem. 2002, 67, 7226e7237.
873e874. 165. For a parallel analysis on a,b-unsaturated ketones, see: Avery, T. D.;
151. (a) Kitagaki, S.; Anada, M.; Kataoka, O.; Matsuno, K.; Umeda, C.; Caiazza, D.; Culbert, J. A.; Taylor, D. K.; Tiekink, E. R. T. J. Org.
Watanabe, N.; Hashimoto, S.-i. J. Am. Chem. Soc. 1999, 121, 1417e Chem. 2005, 70, 8344e8351.
1418; (b) Hodgson, D. M.; Stupple, P. A.; Pierard, F. Y. T. M.; Labande, 166. This rule of thumb could be applied to the cyclization (K2CO3 in meth-
A. H.; Johnstone, C. Chem.dEur. J. 2001, 7, 4465e4476; (c) Hodgson, anol) of a (Z)-unsaturated ester containing a methyl group at the allylic
D. M.; Labande, A. H.; Pierard, F. Y. T. M.; Expósito Castro, M. A. position, which furnishes the corresponding 2,3-trans-2,6-cis-tetrahydro-
J. Org. Chem. 2003, 68, 6153e6159. pyran, see Ref. 73.
2722 I. Larrosa et al. / Tetrahedron 64 (2008) 2683e2723
167. Strand, D.; Norrby, P.-O.; Rein, T. J. Org. Chem. 2006, 71, 1879e1891. 182. Nakatani, K.; Okamoto, A.; Yamanuki, M.; Saito, I. J. Org. Chem. 1994,
168. The opposite bias has been observed for the cyclization of hydroxy esters 59, 4360e4361.
containing an epoxide at the allylic position. see: Harvey, J. E.; Raw, 183. Nakatani, K.; Okamoto, A.; Matsuno, T.; Saito, I. J. Am. Chem. Soc.
S. A.; Taylor, R. J. K. Org. Lett. 2004, 6, 2611e2614. 1998, 120, 11219e11225.
169. The thermodynamically controlled addition of benzaldehyde to 184. (a) Tietze, L. F.; Gericke, K. M.; Singidi, R. R. Angew. Chem., Int. Ed.
5-hydroxy-2,3-unsaturated esters or amides in the presence of catalytic 2006, 45, 6990e6993; (b) Tietze, L. F.; Singidi, R. R.; Gericke, K. M.
amounts of base might be mentioned as a good example of this concept. Org. Lett. 2006, 8, 5873e5876.
Indeed, it relies on the initial formation of a metal hemiacetal that sub- 185. (a) Sakamoto, K.; Honda, E.; Ono, N.; Uno, H. Tetrahedron Lett. 2000,
sequently undergoes an intramolecular nucleophilic attack to the conju- 41, 1819e1823; (b) Uno, H.; Sakamoto, K.; Honda, E.; Fukuhara, K.;
gated position to provide benzylidene protected 1,3-syn diols. Thus, Ono, N.; Tanaka, J.; Sakanaka, M. J. Chem. Soc., Perkin Trans. 1
although the target of such process is not the assemblage of a pyran- 2001, 229e238.
like heterocycles, it illustrates the potential of oxa-Michael addition in 186. Paterson, I.; Osborne, S. Tetrahedron Lett. 1990, 31, 2213e2216.
cascade sequences. see: (a) Evans, D. A.; Gauchet-Prunet, J. A. 187. For other intramolecular conjugate addition/elimination processes, see:
J. Org. Chem. 1993, 58, 2446e2453; (b) Ahmed, Md. M.; Mortensen, (a) Miao, H.; Yang, Z. Org. Lett. 2000, 2, 1765e1768; (b) Nicolaou,
M. S.; O’Doherty, G. A. J. Org. Chem. 2006, 71, 7741e7746; (c) Evans, K. C.; Xu, H.; Wartmann, M. Angew. Chem., Int. Ed. 2005, 44, 756e
D. A.; Nagorny, P.; Reynolds, D. J.; McRae, K. J. Angew. Chem., Int. Ed. 761; (c) Gao, B.; Yu, Z.; Fu, Z.; Feng, X. Tetrahedron Lett. 2006, 47,
2007, 46, 541e544. 1537e1539; (d) Hjelmgaard, T.; Søtofte, I.; Tanner, D. J. Org. Chem.
170. Nicolaou, K. C.; Lim, Y. H.; Papageorgiou, C. D.; Piper, J. L. Angew. 2005, 70, 5688e5697; (e) See also Ref. 32c.
Chem., Int. Ed. 2005, 44, 7917e7921. 188. (a) Paterson, I.; Smith, J. D.; Ward, R. A. Tetrahedron 1995, 51, 9413e
171. Ley, S. V.; Brown, D. S.; Clase, J. A.; Fairbanks, A. J.; Lennon, I. C.; 9436; (b) Paterson, I.; Watson, C.; Yeung, K.-S.; Wallace, P. A.; Ward,
Osborn, H. M. I.; Stokes, E. S. E.; Wadsworth, D. J. J. Chem. Soc., R. A. J. Org. Chem. 1997, 62, 452e453; (c) Paterson, I.; De Savi, C.;
Perkin Trans. 1 1998, 2259e2276. Tudge, M. Org. Lett. 2001, 3, 3149e3152.
172. Trost, B. M.; Yang, H.; Wuitschik, G. Org. Lett. 2005, 7, 4761e4764. 189. Reiter, M.; Turner, H.; Gouverneur, V. Chem.dEur. J. 2006, 12, 7190e
173. Trost, B. M.; Yang, H.; Thiel, O. R.; Frontier, A. J.; Brindle, C. S. J. Am. 7203.
Chem. Soc. 2007, 129, 2206e2207. 190. (a) Clarke, P. A.; Martin, W. H. C. Org. Lett. 2002, 4, 4527e4529; (b)
174. Most of these cyclizations involve protic acids. For a Lewis acid-medi- Sabitha, G.; Reddy, G. S. K. K.; Rajkumar, M.; Yadav, J. S.;
ated 6-exo-trig assemblage of 2,6-cis-tetrahydropyran from silyloxy Ramakrishna, K. V. S.; Kunwar, A. C. Tetrahedron Lett. 2003, 44,
enones, see: Evans, P. A.; Andrews, W. J. Tetrahedron Lett. 2005, 46, 7455e7457; (c) Clarke, P. A.; Martin, W. H. C.; Hargreaves, J. M.;
5625e5627. Wilson, C.; Blake, A. J. Chem. Commun. 2005, 1061e1063; (d) Clarke,
175. Paterson, I.; Keown, L. E. Tetrahedron Lett. 1997, 38, 5727e5730. P. A.; Martin, W. H. C.; Hargreaves, J. M.; Wilson, C.; Blake, A. J. Org.
176. Nicolaou, K. C.; Bunnage, M. E.; McGarry, D. G.; Shi, S.; Somers, P. K.; Biomol. Chem. 2005, 3, 3551e3563.
Wallace, P. A.; Chu, X.-J.; Agrios, K. A.; Gunzner, J. L.; Yang, Z. 191. For a similar procedure, see: DiVirgilio, E. S.; Dugan, E. C.; Mulrooney,
Chem.dEur. J. 1999, 5, 599e617. C. A.; Kozlowski, M. C. Org. Lett. 2007, 9, 385e388.
177. O’Brien, M.; Taylor, N. H.; Thomas, E. J. Tetrahedron Lett. 2002, 43, 192. Clarke, P. A.; Martin, W. H. C. Tetrahedron 2005, 61, 5433e5438.
5491e5494. 193. Biddle, M. M.; Lin, M.; Scheidt, K. A. J. Am. Chem. Soc. 2007, 129,
178. For other examples, see: (a) Paterson, I.; Luckhurst, C. A. Tetrahedron 3830e3831.
Lett. 2003, 44, 3749e3754; (b) Chandrasekhar, S.; Shyamsunder, T.; 194. For a related process, see: Chemler, J. A.; Yan, Y.; Leonard, E.; Koffas,
Prakash, S. J.; Prabhakar, A.; Jagadeesh, B. Tetrahedron Lett. 2006, M. A. G. Org. Lett. 2007, 9, 1855e1858.
47, 47e49; (c) Liu, J.; Yang, J. H.; Ko, C.; Hsung, R. P. Tetrahedron 195. Hilli, F.; White, J. M.; Rizzacasa, M. A. Org. Lett. 2004, 6,
Lett. 2006, 47, 6121e6123; (d) See Refs. 157c and 160c. 1289e1292.
179. Nguyen, S.; Xu, J.; Forsyth, C. J. Tetrahedron 2006, 62, 5338e5346. 196. (a) Jones, D. N.; Khan, M. A.; Mirza, S. M. Tetrahedron 1999, 55,
180. Aiguade, J.; Hao, J.; Forsyth, C. J. Org. Lett. 2001, 3, 979e982. 9933e9946; (b) Mukai, C.; Yamashita, H.; Hanaoka, M. Org. Lett.
181. (a) Forsyth, C. J.; Hao, J.; Aiguade, J. Angew. Chem., Int. Ed. 2001, 40, 2001, 3, 3385e3387; (c) Kaye, P. T.; Nocanda, X. W. J. Chem. Soc., Per-
3663e3667; (b) Forsyth, C. J.; Xu, J.; Nguyen, S. T.; Samdal, I. A.; kin Trans. 1 2002, 1318e1323; (d) Kaye, P. T.; Musa, M. A.; Nocanda,
Briggs, L. R.; Rundberget, T.; Sandvik, M.; Miles, C. O. J. Am. Chem. X. W.; Robinson, R. S. Org. Biomol. Chem. 2003, 1, 1133e1138.
Soc. 2006, 128, 15114e15116. 197. Fernández de la Pradilla, R.; Tortosa, M. Org. Lett. 2004, 6, 2157e2160.
I. Larrosa et al. / Tetrahedron 64 (2008) 2683e2723 2723
Biographical sketch
Igor Larrosa graduated from the University of Barcelona in 1999. In 2004, he Pedro Romea completed his B.Sc. in Chemistry in 1984 at the University of
completed his Ph.D. under the supervision of Dr. Fèlix Urpı́ and Dr. Pedro Barcelona. That year, he joined the group of Professor Jaume Vilarrasa, at the
Romea in the area of asymmetric C-glycosidation reactions and natural University of Barcelona and received his Master’s Degree in 1985, and he fol-
product synthesis. Subsequently, he became a postdoctoral research associate lowed Ph.D. studies in the same group from 1987 to 1991. Then, he joined the
in Professor Anthony G. M. Barrett’s group at Imperial College London, where group of Professor Ian Paterson at the University of Cambridge (UK), where
he carried out research on methodology development and its applications to he participated in the total synthesis of oleandolide. Back to the University
natural product synthesis. In 2007, he was appointed as a lecturer at Queen of Barcelona, he became Associate Professor in 1993. His research interests
Mary, University of London. have focused on the development of new synthetic methodologies and their
application to the stereoselective synthesis of naturally occurring molecular
structures.
Fèlix Urpı́ received his B.Sc. in Chemistry in 1980 at the University of Bar-
celona. In 1981, he joined the group of Professor Jaume Vilarrasa, at the
University of Barcelona and received his Master’s Degree in 1981 and
Ph.D. in 1988, where he was an Assistant Professor. He then worked as an
NATO postdoctoral research associate in titanium enolate chemistry with
Professor David A. Evans, at Harvard University at Boston. He moved back
to the University of Barcelona and became Associate Professor in 1991. His
research interests have focused on the development of new synthetic methodo-
logies and their application to the stereoselective synthesis of naturally occur-
ring molecular structures.