Catalytic asymmetric synthesis of anti-1,2-diols [1]

Full text of DOI:10.1021/ja001460v

7386
J. Am. Chem. Soc. 2000, 122, 7386-7387
Communications to the Editor
Scheme 1. Aldol Reaction between Hydroxyacetone and an
Aldehyde
Catalytic Asymmetric Synthesis of anti-1,2-Diols
Wolfgang Notz and Benjamin List*
The Skaggs Institute for Chemical Biology and the Department
of Molecular Biology, The Scripps Research Institute, 10550
North Torrey Pines Road, La Jolla, California 92037
ReceiVed April 26, 2000
the development of aldolase antibody 38C2 has taught us the
power and mildness of catalysis involving enamines. While
aldolases are typically limited to dihydroxyacetone phosphate as
the donor, which usually necessitates an additional enzymatic
dephosphorylation step, aldolase antibody 38C2 is capable of
using R-hydroxylated ketones such as hydroxyacetone as the
donor.6a These reactions are highly regio- and enantioselective
with both 38C2 and the natural fructose-1,6-bisphosphate-aldolase
but selectively provide the syn-diastereomer. Herein we demon-
strate that proline catalyzes the highly regio- and diastereoselective
aldol reaction between hydroxyacetone and various aldehydes to
provide anti-1,2-diols with excellent enantioselectivities.
We have recently shown that proline is a remarkably effective
catalyst for the direct asymmetric aldol reaction of acetone to
various aldehydes with ee’s of the aldol products ranging from
60 to 96%.7 We became interested to determine whether proline
is capable of using unprotected hydroxyacetone as the aldol donor.
This is a challenging task since three different regio- and
diastereomeric products and their enantiomers may be expected
(Scheme 1).
ReVised Manuscript ReceiVed June 16, 2000
The 1,2-diol unit occurs frequently in natural products, such
as carbohydrates, polyketides, and alkaloids, and the development
of enantioselective methodologies for its preparation has been at
the forefront of modern catalytic asymmetric synthesis. While
the syn-1,2-diol unit may be considered a “clearable”1 stereo-
chemical element due to the Sharpless asymmetric dihydroxylation
(AD) of (E)-olefins,2 the diastereomeric anti-1,2-diols are far less
accessible, mainly because the corresponding (Z)-olefins are more
difficult to obtain and show reduced enantioselectivity in the AD.
In this paper we disclose a novel, highly diastereo-, and
enantioselective catalytic synthesis of anti-1,2-diols that is based
on the proline-catalyzed direct asymmetric aldol reaction.
The enantioselective synthesis of 1,2-diols may, in principle,
be achieved either via carbon-oxygen bond-formation (path a,
eq 1, e.g., Sharpless AD) or via carbon-carbon bond-formation
(path b).3 Despite the exceptional usefulness of the catalytic
asymmetric dihydroxylation process, path b provides a potentially
superior strategy because the two adjacent stereocenters are
created simultaneously upon carbon-carbon bond-formation.
We found that L-proline catalyzes the aldol reaction between
cyclohexanecarboxaldehyde and hydroxyacetone to furnish anti-
diol 1 in 60% yield, with a dr >20:1 and an ee >99% (eq 2).
In a manner analogous to path b, the catalytic asymmetric
Mukaiyama reaction of glyoxalate esters with aldehydes has been
used.4 However, this method requires two additional steps to
introduce and remove a hydroxyl protecting group and one
additional step to preform the enolate equivalent. As an alternative,
the direct catalytic asymmetric aldol reaction of R-hydroxylated
ketones with aldehydes has so far only been used with protein-
catalysts such as aldolases and catalytic antibodies.5,6 In particular
Next, a series of anti-diols was prepared in moderate to good
yield, by application of this new methodology (Table 1).8
Regioisomeric products were only found in reactions with an
aromatic aldehyde (∼4%, entry 4) and 3,3-dimethyl butyraldehyde
(14%, entry 5). Diastereoselectivities are very high with R-sub-
stituted aldehydes (>20:1, entries 1-3), whereas low diastereo-
selectivities are obtained in reactions with 2-chlorobenz-
aldehyde (entry 4),9 the R-unsubstituted aldehyde (entry 5) and
with R-oxygenated D-isopropylidene-glyceraldehyde (entry 6). The
reaction with rac-2-phenylpropionaldehyde (entry 3) provided two
readily separable diastereomers (3a and 3b) that both had the
anti-configuration regarding the 1,2-diol subunit while differing
at the benzylic stereocenter. Excellent ee’s were obtained in all
(1) Corey, E. J.; Cheng, X.-M. The Logic of Chemical Synthesis, John Wiley
& Sons: New York, 1989.
(2) (a) Jacobsen, E. N.; Marko, I.; Mungall, W. S.; Schro¨der, G.; Sharpless,
K. B. J. Am. Chem. Soc. 1995, 34, 1059. (b) Review: Kolb, H. C.;
VanNieuwenhze, M. S.; Sharpless, K. B. Chem. ReV. 1994, 94, 3-2547.
(3) For alternative, indirect, and noncatalytic methods, see for example:
(a) Enzymatic desymmetrization of 2,3-protected meso-butane-1,2,3,4-tetrol
derivatives: Schoffers, E.; Golebiowski, A.; Johnson, C. R. Tetrahedron 1996,
52, 3769. (b) Enantioselective hydroxyallylation of aldehydes: Roush, W.
R.; Grover, P. T.; Lin, X. Tetrahedron Lett. 1990, 31, 7563-7566. (c)
Asymmetric epoxidation/Payne-rearrangement/epoxide-opening: i. Ko, S. Y.;
Lee, A. W. M.; Masamune, S.; Reed, L. A., III; Sharpless, K. B.; Walker, F.
J. Tetrahedron 1990, 46, 245-264. (d) Enantioselective enzymatic hydrolysis
of a racemic trans-epoxide: Weijers, C. A. G. M. Tetrahedron: Asymmetry
1997, 8, 639-647.
(7) List, B.; Lerner, R. A.; Barbas, C. F., III. J. Am. Chem. Soc. 2000,
122, 2395-2396.
(4) Mukaiyama, T.; Shiina, I.; Uchiro, H.; Kobayashi, S. Bull. Chem. Soc.
Jpn. 1994, 67, 1708-1716.
(8) Diastereoselectivities and enantioselectivities were determined by
comparison with the syn-enantiomers obtained from the aldehydes via Horner-
Wadsworth-Emmons-reaction followed by Sharpless asymmetric dihydroxy-
lations using either AD-mix-R or AD-mix-â (Walsh, P. J.; Sharpless, K. B.
Synlett 1993, 605-606). The proline catalyzed reactions were performed with
both D- and L-proline so that all four stereoisomers were available. Finally,
conditions for the separation of all four stereoisomers were established by
using chiral-phase HPLC techniques.
(5) For excellent reviews on aldolases and the catalytic asymmetric aldol
reaction in general, see: (a) Gijsen, H. J. M.; Qiao, L.; Fitz, W.; Wong, C.-
H. Chem. ReV. 1996, 96, 443-473. (b) Machajewski, T. D.; Wong, C.-H.
Angew. Chem., Int. Ed. 2000, 39, 1352-1374.
(6) (a) List, B.; Shabat, D. Barbas, C. F., III; Lerner, R. A. Chem. Eur. J.
1998, 881-885. (b) Hoffmann, T.; Zhong, G.; List, B.; Shabat, D.; Anderson,
J.; Gramatikova, S.; Lerner, R. A.; Barbas, C. F., III. J. Am. Chem. Soc. 1998,
120, 2768-2779.
(9) Benzaldehyde gave similar results (dr ) 1.3:1, ee ) 80%).
10.1021/ja001460v CCC: $19.00 © 2000 American Chemical Society
Published on Web 07/14/2000

Communications to the Editor
J. Am. Chem. Soc., Vol. 122, No. 30, 2000 7387
Table 1. anti-Diols Synthesized Using the Proline-Catalyzed Aldol
Reaction with Hydroxyacetone and Various Aldehydes
Figure 1. X-ray structure of diol 1.
Figure 2. Potential transition states of the proline-catalyzed aldol reaction
between hydroxyacetone and aldehydes.
1). The enantiofacial selectivity (re) of the aldehyde in these
reactions is identical to that obtained using acetone as the aldol
donor. Accordingly, the si-face of the hydroxyacetone enamine
attacks the re-face of the aldehyde (unlike-topicity) to give the
anti-product. This selectivity is consistent with chairlike transition
state A and our originally proposed mechanism (Figure 2).7,12
Transition state B leading to the syn-product (like-topicity)
possesses a boat conformation and may become increasingly
important with sterically less hindered (reduced eclipsed interac-
tions) or R-oxygenated aldehydes (hydrogen-bonding). Interest-
ingly, transition state B resembles C, which has been proposed
for the Corey-Bakshi-Shibata (CBS) reduction.13
In summary we have shown that proline catalyzes the direct
aldol reaction between hydroxyacetone and various aldehydes to
give anti-diols 1-6 in excellent diastereo- and enantioselectivities.
Important features of this reaction are the following: (1) This
method is the first small-molecule catalyzed asymmetric synthesis
of anti-diols and complements the Sharpless-AD. (2) For the first
time, unprotected hydroxyacetone has been used as a donor in
nonenzymatic aldol reactions. (3) The reactions are typically
highly regioselective, diastereoselective, and enantioselective, and
(4) do not require protecting groups, metals, preformed enolate
equivalents, inert atmosphere, or temperature manipulations.
Future studies will focus on mechanistic aspects and on further
applications of proline and other chiral amines in important
carbon-carbon bond-forming reactions. The results of which will
be reported in due course.
a The syn:anti-ratio was determined by weighing the separated
1
isomers and/or H NMR-spectroscopy, respectively. b ee of the anti-
isomer; determined by chiral HPLC analysis. c Combined yield of
separated diastereomers. d Identical ee and dr values for 3a and 3b.
e Diastereomers could not be separated. f From optical rotation. In a
typical experiment, cyclohexanecarboxaldehyde (60 µL, 0.5 mmol),
hydroxyacetone (1 mL), DMSO (4 mL), and L-proline (14 mg, 25 mol
%) were stirred at room temperature for 60 h. Aqueous work up and
purification by flash chromatography (50% ethyl acetate/hexanes)
afforded pure diol anti-1 (56 mg, 60%) as a solid.
Acknowledgment. Generous financial support, encouragement, and
critical manuscript reading by Richard A. Lerner and Carlos F. Barbas,
III, is most gratefully acknowledged. W.N. is a research associate in the
laboratories of CFB. We kindly thank Raj K. Chadha, The Scripps
Research Institute, for the X-ray-structural analysis of diol 1.
cases except in the reaction with 2-chlorobenzaldehyde (entry 4).
In the reaction with 3,3-dimethyl-butyraldehyde, the diastereo-
meric syn side-product was obtained in 84% ee but with the
opposite absolute configuration at the â-position (Sharpless AD-
â-product). Similarly, the reaction with the protected gly-
ceraldehyde gave known D-tagatose derivative 610 ([R]D ) + 69°,
lit.10 [R]D ) + 71°) together with the syn byproduct 1-deoxy-
5,6-O-isopropylidene-D-fructose having the opposite configuration
at the â-position.11 These hexoses are readily converted into the
natural sugars 1-deoxy-D-tagatose and 1-deoxy-D-fructose.10,11
Absolute configurations of diols 2-5 have been assigned based
on the crystal structure of diol 1 (Figure 1) and on the absolute
configuration of the known products of the reaction with the
enantiomerically pure glyceraldehyde-substrate (entry 6, Table
Supporting Information Available: (1) General experimental pro-
cedure and characterizations of anti-diols 1-6 and their syn-isomers, (2)
X-ray data for diol 1 (PDF). This material is available free of charge via
the Internet at http://pubs.acs.org.
JA001460V
(12) Regio- and presumed (E)-stereoselectivity of the enamine formation
may result from (a) conjugation (Lin, J.-F.; Wu, C.-C.; Lien, M.-H. J. Phys.
Chem. 1995, 99, 16903-16908) and (b) minimization of 1,3-allylic strain
(Hoffmann, R. W. Chem. ReV. 1989, 89, 1841-1860). However, the enamine
geometry may not necessarily be reflected in product diastereoselectivity, as
in the case of kinetically controlled aldol reactions of preformed enolates;
related transition states involving a (Z)-enamine can be constructed.
(13) Corey, E. J.; Helal, C. J. Angew. Chem., Int. Ed. 1998, 37, 1986-
2012.
(10) Izquierdo Cubero, I.; Garcia Poza, D. Carbohydr. Res. 1985, 138, 139-
42.
(11) Lopez Aparicio, F. J.; Gomez Guillen, M.; Izquierdo Cubero, I. Ann.
Quim. 1976, 72, 938-945.