Iterative approach to enantiopure synlanti-1,3-polyols via proline-catalyzed sequential a-aminoxylation and horner-wadsworth-emmons olefination of aldehvdes

Article abstract of DOI:10.1021/ol900868v

Iterative use of proline-catalyzed tandem α-aminoxylation and HWE olefination of aldehydes provided a simple access to 1,3-polyols. The feasibility of this approach is initially studied to synthesize syn- and anti-1,3-diols and is further extended to a syn/syn-1,3,5-triol at a useful level of asymmetric induction and yield. Its usage is illustrated by the short synthesis of a hydroxylactone pheromone component, (2S,3S)-2- hydroxyhexylcyclopentanone.

Full text of DOI:10.1021/ol900868v

ORGANIC
LETTERS
2009
Vol. 11, No. 12
2611-2614
Iterative Approach to Enantiopure
syn/anti-1,3-Polyols via
Proline-Catalyzed Sequential
r-Aminoxylation and
Horner-Wadsworth-Emmons
Olefination of Aldehydes
Nagendra B. Kondekar and Pradeep Kumar*
DiVision of Organic Chemistry, National Chemical Laboratory, Pune 411 008, India
pk.tripathi@ncl.res.in
Received April 21, 2009
ABSTRACT
Iterative use of proline-catalyzed tandem r-aminoxylation and HWE olefination of aldehydes provided a simple access to 1,3-polyols. The
feasibility of this approach is initially studied to synthesize syn- and anti-1,3-diols and is further extended to a syn/syn-1,3,5-triol at a useful
level of asymmetric induction and yield. Its usage is illustrated by the short synthesis of a hydroxylactone pheromone component,
(2S,3S)-2-hydroxyhexylcyclopentanone.
The 1,3-skipped polyol systems with anti- or syn-config-
uration are structural units of several natural products
including clinically valuable polyene macrolide antibiotics.
This has aroused great interest among synthetic organic
chemists, resulting in an onslaught of activity directed at
the development of efficient, stereoselective approaches
to the assembly of 1,3-diols.1 Despite the numerous
strategies to synthesize polyols through substrate-con-
trolled asymmetric induction, the interest in the new
methods of its synthesis continues unabated.2 We have
recently developed a diastereoselective and iterative
approach for the synthesis of 1,3-polyols using Jacobsen’s
hydrolytic kinetic resolution of racemic epoxide by which
(1) For reviews on this subject, see: (a) Bode, S. E.; Wolberg, M.; Mu¨ller,
M. Synthesis 2006, 557. (b) Schneider, C. Angew. Chem., Int. Ed. 1998,
37, 1375. (c) Rychnovsky, S. D. Chem. ReV. 1995, 95, 2021. (d) Norcross,
R. D.; Paterson, I. Chem. ReV. 1995, 95, 2041. (e) Hoveyda, A. M.; Evans,
D. A.; Fu, G. C. Chem. ReV. 1993, 93, 1307. (f) Oishi, T.; Nakata, T.
Synthesis 1990, 635. (g) Reetz, M. T. Angew. Chem., Int. Ed. 1984, 23,
556.
(2) (a) Chen, K.; Richter, J. M.; Baran, P. S. J. Am. Chem. Soc. 2008,
130, 7247. (b) Kumar, P.; Gupta, P.; Naidu, S. V. Chem.sEur. J. 2006,
12, 1397. (c) Chen, C.; Luo, S.; Jordan, R. F. J. Am. Chem. Soc. 2008,
130, 12892.
10.1021/ol900868v CCC: $40.75
Published on Web 05/18/2009
 2009 American Chemical Society

in principle one can prepare all the stereoisomers from
easily available epoxides.2b However, the sequence of
reaction suffers from a disadvantage due to the loss of
50% of starting compound as diol in each resolution step.
Within the context of this work, the most widely used
method to prepare 1,3-polyols in an iterative fashion are
by allyl addition sequence utilizing stoichiometric amounts
of chiral borons3 and titanium.4 Recently, Kirsch and co-
workers have developed an efficient catalytic, iterative
synthetic route to 1,3-polyols using Overmann esteri-
fication,5a while chromium-mediated asymmetric allylation
has been reported by Kishi et al.5b However, the method
involves a greater number of steps for each iteration5a
(Kirsch et al.) or requires stringent reaction conditions5b
(Kishi et al.) and uses an expensive catalyst.
Recently, Zhong et al. have reported an R-aminoxylation-
directed tandem reaction catalyzed by proline which involves
a sequential R-aminoxylation, HWE-olefination reaction at
ambient temperature furnishing O-amino-substituted allylic
alcohol from readily available achiral aldehydes.14a We
envisioned that this reaction could give us stereocontrolled
synthetic access to 1,3-polyol motifs. However, it may be
pertinent to mention here that the chirality of the already
established 1,3-polyol chain makes the stereoselective chain
elongation a challenging process.17 Our iterative strategy for
the synthesis of polyols is outlined in Figure 1.
In view of the above considerations, there is still need for a
versatile synthetic method that addresses the following issues:
mild reaction conditions, minimum steps for each iteration,
cheap and readily available catalysts, and flexible construction
of possible isomers. In recent years, there has been growing
interest in the use of small organic molecules to catalyze
reactions in organic synthesis.6 As a result, the area of
organocatalysis has now emerged as a promising strategy and
as an alternative to expensive protein catalysis and toxic metal
catalysis,7 thus becoming a fundamental tool in the catalysis
toolbox available for asymmetric synthesis.8 Proline is among
the most successful secondary amine based organocatalysts
which have been widely employed in the asymmetric aldol,9
Mannich,10 Michael addition,11 and R-functionalization,12 viz.
R-aminoxylation-,12c R-amination-,13 and R-aminoxylation-
directed tandem reactions,14 among many others,15 providing
rapid, catalytic, and atom-economical access to enantiomerically
pure products. Similarly, organocatalytic tandem processes are
emerging as powerful methods for the rapid synthesis and
construction of complex target molecules from simple and readily
available precursors while minimizing yield, time, and energy
losses.16
Figure 1. Iterative strategy for polyol synthesis.
Toward the synthesis of 1,3-polyols, our first goal was to
synthesize γ-hydroxy ester 2 in a tandem fashion (Scheme
1). Thus, when the commercially available phenyl propanal
Scheme 1. Synthesis of γ-Hydroxy Ester
(3) (a) Garcia, A. B.; Leꢀmann, T.; Umarye, J. D.; Mamane, V.;
Sommer, S.; Waldmann, H. Chem. Commun. 2006, 3868. (b) Dreher, S. D.;
Leighton, J. L. J. Am. Chem. Soc. 2001, 123, 341. (c) Barrett, A. G. M.;
Braddock, D. C.; de Koning, P. D.; White, A. J. P.; Williams, D. J. J. Org.
Chem. 2000, 65, 375. (d) Schneider, C.; Rehfeuter, M. Chem.sEur. J. 1999,
5, 2850. (e) Paterson, I.; Wallace, D. J.; Gibson, K. R. Tetrahedron Lett.
1997, 38, 8911. (f) Hoffmann, R. W.; Stu¨rmer, R. Synlett 1990, 759. (g)
Schreiber, S. L.; Goulet, M. T. J. Am. Chem. Soc. 1987, 109, 8120.
(4) (a) BouzBouz, S.; Cossy, J. Org. Lett. 2000, 2, 501. (b) Knochel,
P.; Brieden, W.; Rozema, M. J.; Eisenberg, C. Tetrahedron Lett. 1993, 34,
5881.
(5) (a) Binder, J. T.; Kirsch, S. F. Chem. Commun. 2007, 4164. (b)
Zhang, Z.; Aubry, S.; Kishi, Y. Org. Lett. 2008, 10, 3044.
(6) (a) Dalko, P. L.; Moisan, L. Angew. Chem., Int. Ed. 2004, 43, 5138.
(b) Berkessel, A.; Gro¨ger, H. Asymmetric Organocatalysis: From Biomimetic
Concepts to Applications in Asymmetric Synthesis; Wiley VCH: Weinheim,
2005. (c) Seayed, J.; List, B. Org. Biomol. Chem. 2005, 3, 719.
(7) Dalko, P. I. EnantioselectiVe Organocatalysis: Reactions and
Experimental Procedures; Wiley-VCH: Weinheim, 2007.
(8) MacMillian, D. W. C. Nature 2008, 455, 304.
1 was subjected to sequential R-aminoxylation (L-proline as
a catalyst) followed by HWE-olefination reaction, it furnished
O-amino-substituted allylic alcohol. In an effort to minimize
handling of intermediates and its time-consuming purifica-
tion, the crude product obtained after workup was directly
subjected to hydrogenation conditions using catalytic amounts
of Pd/C to furnish the γ-hydroxy ester 2 in good yield.
Thus, in two steps and one column purification, γ-hydroxy
ester 2 was obtained in 71% yield and 98% ee.18 The free
hydroxy group of γ-hydroxy ester 2 was protected as TBS
(9) (a) Casas, J.; Engqvist, M.; Ibrahem, I.; Kaynak, B.; Cordova, A.
Angew. Chem., Int. Ed. 2005, 44, 1343. (b) List, B.; Lerner, R. A.; Barbas,
C. F. III. J. Am. Chem. Soc. 2000, 122, 2395.
(10) (a) Sabitha, G.; Fatima, N.; Reddy, E. V.; Yadav, J. S. AdV. Synth.
Catal. 2005, 347, 1353. (b) Ramachary, D. B.; Chowdari, N. S.; Barbas,
C. F. III. Synlett 2003, 1910.
(11) Hechavarria Fonseca, M. T.; List, B. Angew. Chem., Int. Ed. 2004,
43, 3958.
2612
Org. Lett., Vol. 11, No. 12, 2009

ether using TBSOTf to furnish compound 3. With a
substantial amount of the TBS ether 3 in hand, we then
proceeded toward the first cycle of iteration (Scheme 2).
D-proline as a catalyst followed by HWE olefination and
subsequent Pd/C reduction gave the anti-diol 4 in 65% yield.
The 1H NMR analysis revealed the diastereomeric purity (de)
of the reaction to be >95%. Further TBS protection of free
hydroxy group afforded TBS ether 5 in 95% yield. Following
similar iteration with L-proline-catalyzed sequence of reac-
tions provided the syn-diol 6 as a 10:1 unseparable mixture
of diastereomers in 63% yield. Nevertheless, after protection
of the hydroxyl group of 6 with TBS, we were able to
separate the major diastereomer 7 in 89% yield in diaste-
reomerically pure form as determined from 1H NMR. These
findings could probably be attributed to match/mismatch
effect of the TBS group, without any appreciable change in
yield of the reaction19 (Scheme 2).
Scheme 2.
First Iteration for Synthesis of Diola
The relative stereochemistry of 1,3-diols 4 and 6 was
determined by using Rychnovsky’s acetonide method20
(Scheme 3). Thus, DIBAL-H reduction of esters 5 and 7
Scheme 3. Relative Stereochemistry Determination
a One cycle of iteration is composed of a four-step sequence: (1) DIBAL-
H, reduction of ester; (2) nitrosobenzene, D/L-proline, DMSO, HWE salt,
DBU, LiCl, CH3CN; (3) H2/Pd-C, EtOAc; (4) TBSOTf, 2,6-lutidine, DCM.
Each cycle of iteration consists of four steps, viz.
DIBAL-H reduction of ester to aldehyde, sequential R-ami-
noxylation, HWE olefination, and H2-Pd/C reduction, fol-
lowed by TBS protection of the hydroxy group to eventually
furnish the TBS protected γ-hydroxy ester. As illustrated in
Scheme 2, the DIBAL-H reduction of ester 3 furnished the
corresponding aldehyde which on R-aminoxylation using
(12) For R-functionalization reviews, see: (a) Franzen, J.; Marigo, M.;
Fielenbach, D.; Wabnitz, T. C.; Kjærsgaard, A.; Jørgensen, K. A. J. Am.
Chem. Soc. 2005, 127, 18296. (b) Guillena, G.; Ramon, D. J. Tetrahedron:
Asymmetry 2006, 17, 1465. (c) For a comprehensive review on R-ami-
noxylation, see: Merino, P.; Tejero, T. Angew. Chem., Int. Ed 2004, 43,
2995, and references cited therein.
afforded alcohols 8 and 12, respectively, which on benzyl
protection gave compounds 9 and 13. Subsequent TBS
deprotection furnished the diols 10 and 14, which on
treatment with 2,2-DMP gave the anti-acetonide 11 and syn-
acetonide 15, respectively. The appearance of methyl reso-
nance peaks at δ 19.8 and 30.2 ppm and acetal carbon
resonating at δ 98.5 ppm confirmed the presence of syn-
acetonide 15. Similarly, anti-acetonide 11 was confirmed by
the appearance of the methyl carbons resonance at δ 24.8
ppm and the acetal carbon at δ 100.3 ppm (Scheme 3).
This iterative sequence is particularly attractive because
of mild reaction conditions, use of proline as a cheap and
commercially available catalyst,21 and the overall short
reaction sequence involving four steps and two column
purifications per iteration. Since the stereochemical outcome
of the reaction can be predicted on the basis of the catalyst
used, this method gives an easy access to 1,3 syn/anti-diols
with predictable and useful stereocontrol in good yield.
(13) (a) List, B. J. Am. Chem. Soc. 2002, 124, 5656. (b) Bogevig, A.;
Juhl, K.; Kumaragurubaran, N.; Zhuang, W.; Jorgensen, K. A. Angew.
Chem., Int. Ed. 2002, 41, 1790. (c) Kumaragurubaran, N.; Juhl, K.; Zhuang,
W.; Bogevig, A.; Jorgensen, K. A. J. Am. Chem. Soc. 2002, 124, 6254. (d)
Vogt, H.; Vanderheiden, S.; Brase, S. Chem. Commun. 2003, 2448.
(14) (a) Zhong, G.; Yu, Y. Org. Lett. 2004, 6, 1637. (b) Lu, M.; Zhu,
D.; Lu, Y.; Hou, Y.; Tan, B.; Zhong, G. Angew. Chem., Int. Ed. 2008, 47,
10187.
(15) (a) Pidathala, C.; Hoang, L.; Vignola, N.; List, B. Angew. Chem.,
Int. Ed. 2003, 42, 2785. (b) Fonseca, M. T. H.; List, B. Angew. Chem., Int.
Ed. 2004, 43, 3958. (c) For a review of proline-catalyzed asymmetric
reactions, see: List, B. Tetrahedron 2002, 58, 5573. (d) Dalko, P. I.; Moisan,
L. Angew. Chem., Int. Ed. 2004, 43, 5138.
(16) For reviews on organocatalytic tandem reactions, see: (a) Enders,
D.; Grondal, C.; Hu¨ttl, M. R. M. Angew. Chem., Int. Ed. 2007, 46, 1570.
(b) Yu, X.; Wang, W. Org. Biomol. Chem. 2008, 6, 2037. (c) Walji, A. M.;
MacMillan, D. W. C. Synlett 2007, 1477.
(17) Masamune, S.; Choy, W.; Peterson, J. S.; Sita, L. S. Angew. Chem.,
Int. Ed. 1985, 24, 1.
(18) In order to determine the chiral purity of (S)-ethyl 4-hydroxy-5-
phenylpentanoate 2 formed, it was converted into known lactone by
treatment with p-TSA in methanol.
HPLC: Chiracel OD-H column (2-propanol/petroleum ether ) 10:90, flow
rate 1.0 mL/min, λ ) 214 nm). Retention time (min): 17.17 (major) and
20.67 (minor). The racemic standard was prepared in the same way with
racemic γ-hydroxy ester, ee 98%.
(19) Overall yield per iteration cycle can be slightly improved by
following the two-step process for aldehyde formation that is reduction of
ester to alcohol followed by IBX oxidation.
Org. Lett., Vol. 11, No. 12, 2009
2613

To illustrate the feasibility of this approach for preparing
1,3,5-polyols, we further attempted the synthesis of a syn/
syn-1,3,5-triol as a representative example (Scheme 4).
available hexanal 18 was subjected to sequential R-ami-
noxylation (D-proline as a catalyst), HWE olefination, and
reductive hydrogenation to furnish the γ-hydroxy ester 19
in 65% yield and 94% ee.23 This on TBS protection (19 f
20) followed by a first cycle of iteration using L-proline-
catalyzed reaction conditions afforded the anti-diol 21, with
Scheme 4.
Second Iteration for Synthesis of Triola
1
de >95% as determined from H NMR. Subsequent acid
treatment with p-TSA in methanol resulted in deprotection
of TBS group and concomitant lactonization to furnish the
required lactone 22.
In conclusion, a practical and efficient iterative approach
to the stereocontrolled synthesis of 1,3-polyols from com-
mercially available and inexpensive starting materials has
been developed. The advantages of using this process are as
follows: (a) the reaction uses mild reaction conditions (at
room temperature, air and moisture are tolerated), (b) the
O-amino-substituted allylic alcohol that is formed after
sequential R- aminoxylation and HWE olefination can be
isolated in good yield and is converted to γ-hydroxy ester
without requiring a separate column purification step, and
(c) both enantiopure forms of proline are commercially
available, and thus, in principle, all possible combinations
of 1,3,5-polyols can be accessed. The synthetic utility of this
protocol was further demonstrated by the asymmetric
synthesis of a pheromone component, (2S,3S)-2-hydroxy-
hexylcyclopentanone. This synthetic strategy, which is
amenable to both syn- and anti-1,3-polyols, has significant
potential for its further extension to the synthesis of variety
of biologically important natural products. Currently, studies
are in progress toward this goal.
a One cycle of iteration is composed of a four-step sequence: (1) DIBAL-
H, reduction of ester; (2) nitrosobenzene, L-proline, DMSO, HWE salt, DBU,
LiCl, CH3CN; (3) H2/Pd-C, EtOAc; (4) TBSOTf, 2,6-lutidine, DCM.
Thus, by subjecting syn-diol 7 to a second cycle of iteration
using the L-proline-catalyzed sequence of reactions, triol 16
was obtained as a 10:1 unseparable mixture of diastereomers
1
in 61% yield as determined from H NMR. However, the
diastereomerically pure triol was obtained as the TBS ether
17 in 88% yield after TBS protection of the hydroxyl group
of 16 and separation by flash chromatography.
As an outgrowth from these efforts, we became interested
in the application of this approach for the expedient total
synthesis of (2S,3S)-2-hydroxyhexylcyclopentanone 22, rep-
resentative of 6-hydroxyalkan-4-olides, hydroxy lactones
with chain lengths between 10 and 13 carbon atoms, which
are part of the complex mixture of compounds that giant
white butterfly Idea leuconoe hairpencils release as a
pheromone (Scheme 5). They seem to act synergistically with
Acknowledgment. N.B.K. thanks CSIR, New Delhi, for
the award of research fellowship. Financial support from
NCL, Pune (Project No. MLP015826), is gratefully acknowl-
edged.
Supporting Information Available: Experimental details
and NMR spectroscopic data for the new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
Scheme 5. Synthesis of (2S,5S)-2-Hydroxyhexylcyclopentanone
OL900868V
(20) Rychnovsky, S. D.; Skalitzky, D. J. Tetrahedron Lett. 1990, 31,
945.
(21) Cost of L-proline in Aldrich catalogue 2009-2010 for 100 g is
INR 4404 (USD $60.40).
(22) Nishida, R.; Schulz, S.; Kim, C. H.; Fukami, H.; Kuwahara, Y.;
Honda, K.; Hayashi, N. J. Chem. Ecol. 1996, 22, 949.
(23) In order to determine the chiral purity of (S)-ethyl 4-hydroxyoc-
tanoate 19 formed it was converted into known lactone on treatment with
p-TSA in methnol.
a One cycle of iteration here is composed of a three-step sequence: (1)
DIBAL-H, reduction of ester; (2) nitrosobenzene, L-proline, DMSO, HWE
salt, DBU, LiCl, CH3CN; (3) H2/Pd-C, EtOAc.
Chiral GC using cyclodextrin TA column (70 kPa pressure, 140 °C isotherm
for 30 min, minor enantiomer 17 min, major enantiomer 15 min). The
racemic standard was prepared in the same way with racemic γ-hydroxy
ester, ee 94%.
the other pheromone components and are probably involved
in male-male interactions.22 To this end, commercially
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Org. Lett., Vol. 11, No. 12, 2009