Catalytic asymmetric synthesis of both syn- and anti-3,5-dihydroxy esters: application to 1,3-polyol/alpha-pyrone natural product synthesis.

Article abstract of DOI:10.1021/ol0273708

[reaction: see text] We describe a catalytic asymmetric synthesis of both syn- and anti-3,5-dihydroxy esters. The method relies upon catalytic asymmetric epoxidation of alpha,beta-unsaturated imidazolides and amides, using lanthanide-BINOL complexes, and

Full text of DOI:10.1021/ol0273708

ORGANIC
LETTERS
2003
Vol. 5, No. 4
495-498
Catalytic Asymmetric Synthesis of Both
syn- and anti-3,5-Dihydroxy Esters:
Application to 1,3-Polyol/r-Pyrone
Natural Product Synthesis
Shin-ya Tosaki, Tetsuhiro Nemoto, Takashi Ohshima, and Masakatsu Shibasaki*
Graduate School of Pharmaceutical Sciences, The UniVersity of Tokyo, Hongo,
Bunkyo-ku, Tokyo 113-0033, Japan
mshibasa@mol.f.u-tokyo.ac.jp
Received November 28, 2002
ABSTRACT
We describe a catalytic asymmetric synthesis of both syn- and anti-3,5-dihydroxy esters. The method relies upon catalytic asymmetric epoxidation
of r,â-unsaturated imidazolides and amides, using lanthanide-BINOL complexes, and diastereoselective reduction of ketones. The method
was applied to the enantioselective syntheses of 1,3-polyol/r-pyrone natural products 9a, 9b, and strictifolione (10). The absolute stereochemistry
of 9a and 9b was also determined.
Optically active syn- and anti-1,3-diol units are ubiquitous
structural motifs in various biologically active compounds.
For example, the polyene class of macrolide antibiotics
contains extended 1,3-polyol chains as the common structural
feature.1 Due to their distribution, as well as their interesting
structure, extensive efforts have focused on the development
of an efficient synthetic method for stereoselective construc-
tion of these core fragments.1,2 Among the many methods
reported to date, Leighton’s tandem reaction strategy is the
state of the art in this field, affording syn,syn-1,3,5-triols
diastereoselectively in a single-pot reaction.3,4 In addition,
efficient approaches to optically active 1,3-diol units have
been achieved by using several catalytic asymmetric
reactions.5-8 We recently developed the catalytic asymmetric
epoxidation of R,â-unsaturated imidazolides9c and R,â-
unsaturated amides9d using a lanthanide-BINOL (Ln-BINOL)
(5) Noyori hydrogenation: (a) Rychnovsky, S. D.; Khire, U. R.; Yang,
G. J. Am. Chem. Soc. 1997, 119, 2058. (b) Sinz, C. J.; Rychnovsky, S. D.
Angew. Chem., Int. Ed. 2001, 40, 3224.
(6) Sharpless asymmetric epoxidation: (a) Ma, P.; Martin, V. S.;
Masamune, S.; Sharpless, K. B.; Vitti, S. M. J. Org. Chem. 1982, 47, 1378.
(b) Miyazawa, M.; Matsuoka, E.; Sasaki, S.; Maruyama, K.; Miyashita, M.
Chem. Lett. 1998, 109.
(7) Sharpless asymmetric dihydroxylation: (a) Hunter, T. J.; O’Doherty,
G. A. Org. Lett. 2001, 3, 1049. (b) Hunter, T. J.; O’Doherty, G. A. Org.
Lett. 2001, 3, 2777.
(8) Biocatalytic reduction: Wolberg, M.; Hummel, W.; Mu¨ller, M. Chem.
Eur. J. 2001, 7, 4562.
(1) Rychnovsky, S. D. Chem. ReV. 1995, 95, 2021.
(2) For a review, see: Schneider, C. Angew. Chem., Int. Ed. 1998, 37,
1375.
(3) (a) Zucuto, M. J.; Leighton, J. L. J. Am. Chem. Soc. 2000, 122, 8587
and references therein. (b) Wang, X.; Meng, Q.; Nation, A. J.; Leighton, J.
L. J. Am. Chem. Soc. 2002, 124, 10672. (c) Zacuto, M. J.; O’Malley, S. J.;
Leighton, J. L. J. Am. Chem. Soc. 2002, 124, 7890.
(4) For the one-pot, five-component linchpin coupling tactic, see: Smith,
A. B., III; Pitram, S. M. Org. Lett. 1999, 1, 2001.
(9) (a) Bougauchi, M.; Watanabe, S.; Arai, T.; Sasai. H.; Shibasaki. M.
J. Am. Chem. Soc. 1997, 119, 2329. (b) Nemoto, T.; Ohshima, T.; Shibasaki,
M. J. Am. Chem. Soc. 2001, 123, 2725 and references therein. (c) Nemoto,
T.; Ohshima, T.; Shibasaki, M. J. Am. Chem. Soc. 2001, 123, 9474. (d)
Nemoto, T.; Kakei, H.; Gnanadesikan, V.; Tosaki, S.; Ohshima, T.;
Shibasaki, M. J. Am. Chem. Soc. 2002, 124, 14544.
10.1021/ol0273708 CCC: $25.00 © 2003 American Chemical Society
Published on Web 01/29/2003

complex.9 The present catalytic asymmetric synthesis of syn-
and anti-1,3-diol units is an extension of these catalytic
asymmetric reactions. Herein, we report an efficient enan-
tioselective synthesis of both syn- and anti-3,5-dihydroxy
ester units using catalytic asymmetric epoxidation. We also
describe the enantioselective syntheses of 1,3-polyol/R-
pyrone natural products using this method.
85% ee. Moreover, there was a slight improvement in the
enantioselectivity when using the (S)-Pr-BINOL-Ph3Pd
O (1:1:3) complex (82%, 86% ee).11 Due to the difficulty of
enantioenrichment by recrystallization, an alternative method
was explored. Very recently, a highly enantioselective
epoxidation of R,â-unsaturated amides with Sm-BINOL-
Ph3AsdO (1:1:1) complex was achieved.9d To apply this
catalytic asymmetric reaction, we focused on the develop-
ment of an efficient conversion of R,â-epoxy amide 6 to 4
(Scheme 2: Path B). With 5 mol % of (S)-Sm-BINOL-
Ph3AsdO (1:1:1) complex, epoxidation of R,â-unsaturated
amide 7 proceeded smoothly to provide optically pure 6 in
94% yield. After several attempts, treatment of 6 with Martin
sulfurane,12 followed by the addition of sodium methoxide
afforded 4 (65%, conv. 98%) without any noticeable loss of
optical purity.
Scheme 1
Having obtained nearly optically pure 4, further transfor-
mations were examined (Scheme 3). The lithium enolate of
Scheme 3 a
Our initial strategy is outlined in Scheme 1. Both syn- and
anti-3,5-dihydroxy esters 1 and 2 were expected to be
obtained by reductive epoxide opening of γ,δ-epoxy â-keto
ester 3, followed by diastereoselective reduction. The com-
mon intermediate 3 should be synthesized from the corre-
sponding R,â-epoxy ester 4, which is produced by the
catalytic asymmetric epoxidation of R,â-unsaturated imida-
zolide 5.
Synthetic studies began with a detailed optimization of a
catalytic asymmetric epoxidation of 5 (Scheme 2, Path A).10
a Conditions: (a) ethyl acetate, LHMDS, THF, -78 to -20 °C,
87%. (b) PhSeSePh, NaBH4, EtOH, rt, 85%; (c) BEt2(OMe),
NaBH4, THF-MeOH, -78 °C, 79%; (d) NMe4BH(OAc)3, CH3CN-
AcOH, 0 °C, 80%.
Scheme 2
ethyl acetate was reacted with 4 at low temperature, giving
γ,δ-epoxy â-keto ester 3 in 87% yield. Extensive investiga-
tion10 of the reductive epoxide opening reaction indicated
that a selenium reagent, prepared from PhSeSePh and NaBH4
in EtOH, was very effective in the reaction, affording
δ-hydroxy â-keto ester 8 in 85% yield.13 Finally, both syn-
selective14 and anti-selective15 reductions of 8 were per-
formed, using the known methods. The corresponding syn-
3,5-dihydroxy ester 1 and anti-3,5-dihydroxy ester 2 were
obtained in 79% isolated yield (syn:anti >20:1) and in 80%
isolated yield (syn:anti 1:9), respectively. The enantiomeric
excesses of both diastereomers were determined after
conversion of the diols into acetonides, and no racemization
occurred during the process.16 Enantiomers of both 1 and 2
(11) Daikai, K.; Kamaura, M.; Inanaga, J. Tetrahedron Lett. 1998, 39,
7321.
(12) Martin, J. C.; Franz, J. A. J. Am. Chem. Soc. 1975, 97, 6137.
(13) Miyashita, M.; Hoshino, M.; Suzuki, T.; Yoshikoshi, A. Chem. Lett.
1988, 507.
(14) (a) Narasaka, K.; Pai, F.-C. Tetrahedron 1984, 40, 2233. (b) Chen,
K.-M.; Hardtmann, G. E.; Prasad, K.; Repic, O.; Shapiro, M. J. Tetrahedron
Lett. 1987, 28, 155.
First, the effect of the central metal was investigated by using
10 mol % of (S)-Ln-BINOL-Ph3AsdO complex, generated
from Ln(O-i-Pr)3, (S)-BINOL, and Ph3AsdO in a ratio of
1:1:1. The (S)-Pr-BINOL-Ph3AsdO (1:1:1) complex func-
tioned best for this reaction, affording 4 in 87% yield and in
(15) Evans, D. A.; Chapman, K. T.; Carreira, E. M. J. Am. Chem. Soc.
1988, 110, 3560.
(10) For detailed data, see the Supporting Information.
496
Org. Lett., Vol. 5, No. 4, 2003

are available, using the catalyst with the opposite enantiomer
of BINOL.
Scheme 5 a
Having established efficient routes to both syn- and anti-
3,5-dihydroxy esters, we applied the developed methods to
the enantioselective syntheses of 1,3-polyol/R-pyrone natural
products 9a, 9b, and strictifolione (10) (Figure 1).
a Conditions: (a) catalytic asymmetric epoxidation; (b) Martin
sulfurane, THF, rt, then NaOMe, 71% (conv. 97%); (c) MeCON-
(OMe)Me, LHMDS, THF, -78 to -50 °C, 60% (conv. 85%); (d)
MeCON(OMe)Me, LHMDS, THF, -78 to -30 °C, 89%; (e)
PhSeSePh, NaBH4, EtOH, rt, 84%; (f) BEt2(OMe), NaBH4, THF-
MeOH, -78 °C; (g) dimethoxypropane, TsOH (cat.), DMF, rt, 76%
(2 steps); (h) PhCH(OMe)2, PPTS (cat.), toluene, reflux, 74% (2
steps); (i) AllylMgBr, THF, 0 °C, 11a 84%, 11b 87%
Figure 1. 1,3-Polyol/R-pyrone natural products 9a, 9b, and
strictifolione (10).
Compounds 9a and 9b, isolated from the leaves and bark
extract of RaVensara anisata, exhibit antifungal activity.17
Structural analysis of 9 revealed that the three oxygenated
chiral centers have syn,syn relative stereochemical relation-
ships. The retrosynthetic analysis of 9 is shown in Scheme
4. We planned to introduce the C(6) stereocenter of 9 using
10 mol % of the (R)-Sm catalyst (92%, >99% ee), followed
by treatment with the corresponding lithium enolate, gave
16 in one fewer step (60%, conv. 85%).19 After a reductive
epoxide opening reaction of 16 (84%), syn-selective reduc-
tion was performed to give the desired syn-3,5-dihydroxy
amide 12 exclusively. The diol moiety was then converted
into an acetonide or benzylidene acetal, affording the
protected amides 17a (76% for 2 steps) and 17b16 (74% for
2 steps), respectively. Treatment of 17a and 17b with
allylmagnesium bromide resulted in successful conversion
into the corresponding â,γ-unsaturated ketone 11a (84%) and
11b (87%), without double bond isomerization.
Scheme 4
The key diastereoselective reduction was then studied
(Scheme 6).10 Although various studies with 11a were
a diastereoselective reduction of ketone 11, which was
expected to be obtained from syn-3,5-dihydroxy amide 12.
12 should be synthesized from R,â-epoxy amide 13, using
the method described above.
Scheme 6
The initial stage of the synthesis is shown in Scheme 5.
Catalytic asymmetric epoxidation of 14a with 10 mol % of
the (R)-Sm catalyst proceeded smoothly, yielding R,â-epoxy
amide 13a in 87% yield and in 99% ee.18 After conversion
of 13a into the corresponding methyl ester 15 (71%, conv.
97%), 15 was then treated with the lithium enolate prepared
from N-methoxy N-methyl acetoamide. As a result, the
desired γ,δ-epoxy â-keto amide 16 was obtained in 89%
yield. Furthermore, we were pleased to find that catalytic
asymmetric epoxidation of morpholinyl amide 14b, using
performed, the desired alcohol 18a was obtained with modest
selectivity (up to 3:1 ratio). Diastereoselective reduction,
however, with 11b proceeded with higher selectivity. After
several attempts, the desired alcohol 18b was obtained in
(16) Enantiomeric excesses were determined by HPLC analysis.
(17) Andrianaivoravelona, J. O.; Sahpaz, S.; Terreaux, C.; Hostettmann,
K.; Stoecki-Evans, H.; Rasolondramanitra, J. Phytochemistry 1999, 52, 265.
(18) The absolute configuration was determined by Mosher’s method
after conversion to the corresponding â-hydroxy methyl ester.
(19) Mart´ın, R.; Romea, P.; Urp´ı, T. F.; Vilarrasa, J. Synlett 1997, 1414.
Org. Lett., Vol. 5, No. 4, 2003
497

good conversion (60%, conv. 97%) and with reasonable
selectivity (7:1 ratio) when L-Selectride was used at -100
°C.20
Having succeeded in the synthesis of 18b, the stage was
set for the completion of the total synthesis (Scheme 7). After
from 9a and 9b. Spectral data of 9a, 9b, and 21 were
identical with those reported in the literature (1H and 13C
NMR spectra).17 The optical rotation of synthetic 9a and 9b
([R]D26 -29.7 (c 0.60, MeOH)) was opposite to the reported
one ([R]D +35 (c 0.05, MeOH)).10 These results indicated
that the absolute stereochemistry of natural products was
6S,4′S,2′R.
In addition, anti-3,5-dihydroxy ester 2 was easily converted
into the intermediate for use in Aimi’s total synthesis of 10
(Scheme 8).22 Transformation of the diol into an acetonide
Scheme 7 a
Scheme 8
followed by reduction of the ester afforded the known
intermediate 22 (92% for 2 steps). This can be utilized for
catalytic asymmetric synthesis of 10.
In conclusion, we developed an efficient enantioselective
synthesis of both syn- and anti-3,5-dihydroxy ester units
using catalytic asymmetric epoxidation. In addition, the
developed method was applied to the enantioselective total
syntheses of 1,3-polyol/R-pyrone natural products 9a, 9b,
and strictifolione (10). Further applications are under inves-
tigation in our group.
a Conditions: (a) acryloyl chloride, i-Pr2NEt, CH2Cl2, rt, 91%;
(b) (Cy3P)2Cl2RudCHPh (4 mol %), CH2Cl2, reflux, 84%; (c) 80%
aq. AcOH, 60 °C; (d) MeC(OEt)3, PPTS (cat.), CH2Cl2, rt; then
H2O, 76% (2 steps); (e) Ac2O, DMAP (cat.), pyridine, rt, 89%.
the formation of acryloyl ester 19 (91%), the 5,6-dihydro-
R-pyrone ring was constructed by ring-closing metathesis.21
In the presence of 4 mol % of Grubbs’s catalyst, lactone 20
was obtained in 84% yield. In this stage, two diastereomers
of 20 were separated, and the major isomer was utilized for
the final conversion. Finally, removal of the benzylidene
group, followed by monoacetylation of the resulting crude
diol via cyclic ortho ester formation yielded 9a and 9b in
good yield (76% for 2 steps). Diacetate 21 was also obtained
Acknowledgment. Financial support was provided by
RFTF. T.N. thanks a JSPS Research Fellowship for young
scientists.
Supporting Information Available: Experimental pro-
cedures and characterization of the products; other detailed
results. This material is available free of charge via the
Internet at http://pubs.acs.org.
(20) Stereoselective reduction of â-alkoxy ketones, see: ref 7b and: Mori,
Y.; Takeuchi, A.; Kageyama, H.; Suzuki, M. Tetrahedron Lett. 1988, 29,
5423.
OL0273708
(21) For representative reviews on ring-closing methathesis, see: (a)
Fu¨rstner, A. Angew. Chem., Int. Ed. 2000, 39, 3012. (b) Grubbs, R. H.;
Chang, S. Tetrahedron 1998, 54, 4413.
(22) Juliawaty, L. D.; Watanabe, Y.; Kitajima, M.; Achmad, S. A.;
Takayama, H.; Aimi, N. Tetrahedron Lett. 2002, 43, 8657 and references
therein.
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Org. Lett., Vol. 5, No. 4, 2003