Diastereoselective and enantioselective Mukaiyama aldol reactions of α-ketoesters using hydrogen bond catalysis

Article abstract of DOI:10.1039/b919929b

Hydrogen bond catalyzed Mukaiyama aldol reactions of α-ketoesters proceed in high diastereo- and enantioselectivities, giving products possessing two chiral centers, of which one is a tertiary alcohol. The Royal Society of Chemistry 2010.

Full text of DOI:10.1039/b919929b

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Diastereoselective and enantioselective Mukaiyama aldol reactions
of a-ketoesters using hydrogen bond catalysiswz
Vijaya Bhasker Gondi, Koji Hagihara and Viresh H. Rawal*
Received (in College Park, MD, USA) 24th September 2009, Accepted 17th December 2009
First published as an Advance Article on the web 11th January 2010
DOI: 10.1039/b919929b
Hydrogen bond catalyzed Mukaiyama aldol reactions of
a-ketoesters proceed in high diastereo- and enantioselectivities,
giving products possessing two chiral centers, of which one is a
tertiary alcohol.
Based on the considerations stated above, we focused our
efforts on the hydrogen bond promoted Mukaiyama aldol
reaction of pyruvate esters. In initial studies, the N,O-ketene
acetal 1 was reacted with methyl pyruvate at ꢀ78 1C in the
presence of the commercially available naphthyl-taddol, 4.
Under these conditions, a smooth reaction took place to
produce the expected aldol product 3a in good yield, as a
15 : 1 mixture of diastereomers, with the major isomer having
been formed in 80% ee (Table 1, entry 1). An examination of
several related pyruvates showed the tert-butyl ester to
provide optimal results in this reaction (entry 4): 22 : 1 diastereo-
selectivity and 93% ee for the major diastereomer.
The Mukaiyama aldol is one of the work-horse reactions in
organic synthesis. A fundamental C–C bond-forming process,
it gives b-hydroxy carbonyl compounds, often as their O-silyl
ether derivatives, with up to two chiral centers. Given the
prevalence of the aldol motif in natural products, much effort
has been devoted to the development of catalytic enantio-
selective versions of this reaction, and numerous successes
have been recorded, primarily with metal based catalysts.1
While the catalytic, enantioselective Mukaiyama aldol
reaction of aldehydes has been developed extensively, the
corresponding reaction of ketones has proven more
challenging, with only a handful of reports on this front.2,3
The difficulty in developing the enantioselective ketone
Mukaiyama aldol reaction can be attributed to the lower
intrinsic electrophilicity of ketones over aldehydes, combined
with the smaller steric difference between the two groups
flanking the carbonyl moiety. An effective solution to this
problem is provided by pyruvate esters, in which the
ketone carbonyl is rendered more electron-deficient by the
neighboring carboxylate group.4,5 Moreover, the aldol
products of pyruvates are of special interest, since the resulting
chiral tertiary alcohols2 adjacent to the versatile carboxylate
functionality are found in natural products and other
compounds of biomedical relevance.6 When this reaction is
performed using a-substituted nucleophiles, aldol products
possessing two chiral centers are produced. To our knowledge,
the seminal work of Evans, using metal-based complexes,
provides the only reports of diastereo- and enantioselective
Mukaiyama aldol reactions using substoichiometric amounts
of a catalyst.7 We report here the first hydrogen-bond
promoted diastereo- and enantioselective Mukaiyama aldol
reactions of ketones.8–10
The effectiveness of the above hydrogen bond promoted
enantioselective reaction combined with the usefulness of the
aldol products prompted us to investigate the capability of this
transformation (Table 2). Several ketene acetal nucleophiles
were selected for the study to not only assess the scope of the
reaction but also the ability of the methodology to produce
aldol adducts substituted with commonly encountered groups.
Ketene acetals with alkyl substituents larger than methyl
reacted well under the standard reaction protocol, giving aldol
products in high diastereoselectivities (15 : 1 to 99 : 1) and
useful enantioselectivities. In general, higher selectivities were
observed with tert-butyl pyruvate than methyl pyruvate
(entries 1–5). In contrast to the useful results obtained with
the isobutyl-substituted N,O-ketene acetal, the isopropyl-
substituted ketene acetal (not shown) was essentially
Table 1 Hydrogen bond promoted diastereo- and enantioselective
Mukaiyama aldol reactions of representative esters of pyruvic acid
Entry
R1
Yield (%)
dr
ee (%) anti/syn
Product
1
2
3
4
5
6
Me
Et
iPr
tBu
Bn
Ph
80
72
67
80
60
40
15
17
14
22
15
17
85/60
80/70
89
93
78
3a
3b
3c
3d
3e
3f
59
Department of Chemistry, The University of Chicago,
5735 South Ellis Avenue, Chicago, Illinois 60637, USA.
E-mail: vrawal@uchicago.edu; Fax: +1-773-702-0805;
Tel: +1-773-702-2194
a
All reactions were performed at 0.3 M concentration with 1.5 equiv.
of the N,O-ketene acetal.
w This article is part of a ChemComm ‘Catalysis in Organic Synthesis’
web-theme issue showcasing high quality research in organic chemistry.
Please see our website (http://www.rsc.org/chemcomm/organic
webtheme2009) to access the other papers in this issue.
z Electronic supplementary information (ESI) available: Full
experimental and characterization data, as well as NMR spectra of
all intermediates. See DOI: 10.1039/b919929b
ꢁc
This journal is The Royal Society of Chemistry 2010
904 | Chem. Commun., 2010, 46, 904–906

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Table 2 H-bond promoted diastereo- and enantioselective Mukaiyama
aldol reactions of representative substituted N,O-ketene acetals
Entry
R
R1
Product
Yield (%)
dr
ee (%)
1
2
3
4
5
6
7
8
Et
Et
Bn
iBu
Me
tBu
Me
Me
tBu
Me
tBu
Me
tBu
Me
tBu
Me
Me
6a
6b
6c
6d
6e
6f
6g
6h
6i
85
44
73
74
48
78
63
84
61
76
80
51
84
19 : 1
15 : 1
24 : 1
75 : 1
99 : 1
99 : 1
99 : 1
99 : 1
99 : 1
72 : 1
77 : 1
33 : 1
99 : 1
78
84
88
90
93
88
92
97
95
89
95
91
88
iBu
OMe
OMe
OPh
OPh
OPMP
OPMP
SMe
Cl
Scheme 1 Determination of relative and absolute configuration.
The correlation confirmed the major product of the hydrogen
bond catalyzed Mukaiyama aldol to be the anti, as shown.
The other products shown in Table 2 are expected to possess
congruent stereochemistry. The absolute stereochemistry of
the products was also established through chemical correlation
to the known compound, ester-thioester 12. The structure of
12 was unambiguously assigned based on comparison of its
1H NMR, 13C NMR and optical rotation with that reported in
the literature (Scheme 1).7
9
10
11
12
13
6j
6k
6l
6m
a
All the reactions were performed at 0.3 M concentration with 1.5
equiv. of the N,O-ketene acetal.
unreactive under the standard reaction conditions, presumably
due to steric hindrance.
The high enantioselectivity observed in the above reactions
can be understood by considering a transition state in which
the ketone carbonyl group is activated by the taddol catalyst
through a single-point hydrogen bond. The enantioselectivities
observed for the taddol catalyzed Mukaiyama aldol reactions
of aldehydes were rationalized through such a model,10b
further support for which was provided by a crystal structure
of a complex between a taddol and an aldehyde.10e
Several hetero-atom substituted ketene acetals were
examined in the taddol catalyzed pyruvate aldol reaction
and all worked well (entries 6–13). The high diastereo- and
enantioselectivities observed for these substrates are of
particular interest, since the Lewis basic functionalities in the
reactants, some of which are capable of forming hydrogen
bonds, could have altered the pyruvate-catalyst interactions
required for good selectivities. Alkoxy substituted reactants
gave the aldol products as essentially single diastereomers,
formed in high enantioselectivities (entries 6–11). The
para-methoxy phenyl (PMP) substituted ketene acetal was
examined, as it would provide an orthogonally protected diol
product prior to removal of the TBS group. The aldol adducts
of the PMP substrates were obtained in high diastereo-
selectivities and excellent enantioselectivities. Sulfur and chlorine
substituted ketene acetals were also effectively used in this
reaction and provided the expected products in excellent
selectivities (entries 12, 13).
The scope of this hydrogen bonding mediated reaction was
expanded further to include benzoyl formates (phenylglyox-
ylates) as electrophiles. A search of the literature revealed no
reports on catalytic diastereoselective and enantioselective
Mukaiyama aldol reactions of these electrophiles. When
N,O-ketene acetal 1 was reacted with methyl benzoyl formate
using taddol catalysis, the aldol product was obtained as a 3 : 1
ratio of diastereomers, with each isomer being formed in
comparable ee (Table 3, entry 1). As with pyruvates, the
tert-butyl ester of benzoyl formate provided higher diastereo-
selectivity (entry 2). The ethyl substituted ketene acetal
was more selective in terms of dr and ee than the parent
nucleophile (entry 4). Alkoxy substituted ketene acetals
afforded modest to very good diastereoselectivity, with both
diastereomers being formed in high ee (entries 5–7).
The absolute and the relative configuration of the aldol
products derived from this methodology were determined
through correlation with known compounds. The aldol
products possess an amide and an ester, two carboxyl groups
known to have dramatically different reactivity. Most nucleo-
philic reagents are known to react preferentially with an ester
carbonyl over an amide. A notable exception is the Schwartz
reagent, which has been shown to selectively reduce a wide
range of simple, tertiary amides to aldehydes.11 In a recent
report we showed not only that Schwartz’s reagent reduces
a-substituted tertiary amides to the corresponding aldehydes,
but that it does so without epimerizing the a-position.10e Thus,
treatment of aldol product 7, a 15 : 1 mixture of diastereomers,
with the Schwartz reagent afforded aldehyde 8 in essentially
the same ratio of diastereomers. Further transformations
converted 8 into the known g-lactone 10, which was used
to confirm the relative configuration of the product.7c
The results above provide the first examples of hydrogen
bond promoted diastereo- and enantioselective Mukaiyama
aldol reactions of activated ketones with various N,O-ketene
acetals. The reactions are catalyzed by the commercially
available chiral hydrogen bond donor molecule, naphthyl
taddol 4. Pyruvates and benzoyl formates function well as
electrophiles in these reactions, giving aldol products
possessing two chiral centers in good to excellent diastereo-
and enantioselectivities. This simple method produces richly
functionalized subunits and should prove useful for natural
product synthesis.
Financial support of this work by the U.S. National
Institutes of Health (#R01GM069990) is gratefully
ꢁc
This journal is The Royal Society of Chemistry 2010
Chem. Commun., 2010, 46, 904–906 | 905

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Table 3 Diastereo- and enantioselective Mukaiyama aldol reactions
with methyl benzoyl formatea
5 After this work had been accepted for publication, an additional
example of Lewis acid catalyzed enantioselective Mukaiyama aldol
reaction of a-ketoesters appeared in press: J. Le Engers and
B. L. Pagenkopf, Eur. J. Org. Chem., 2009, 6109–6111.
6 For representative examples of natural products containing this
motif, see: (a) footnote 5 in reference 7(c) Kinamycins: (b) X. Lei
and J. A. Porco, Jr., J. Am. Chem. Soc., 2006, 128, 14790–14791;
(c) K. C. Nicolaou, H. Li, A. L. Nold, D. Pappo and A. Lenzen,
J. Am. Chem. Soc., 2007, 129, 10356–10357; callipeltosides:
(d) B. M. Trost, O. Dirat and J. L. Gunzner, Angew. Chem., Int.
Ed., 2002, 41, 841–843; (e) J. Carpenter, A. B. Northrup,
D. Chung, J. J. M. Wiener, S. Kim and D. W. C. MacMillan,
Angew. Chem., Int. Ed., 2008, 47, 3568–3572; fostriecin:
(f) K. Maki, R. Motoki, K. Fujii, M. Kanai, T. Kobayashi,
S. Tamura and M. Shibasaki, J. Am. Chem. Soc., 2005, 127,
17111–17117; SM-130686: (g) D. Tomita, K. Yamatsugu,
M. Kanai and M. Shibasaki, J. Am. Chem. Soc., 2009, 131,
6946–6948. For examples of chiral tertiary alcohol containing
compounds of biomedical interest, see: (h) D. E. Levy,
F. Lapierre, W. Liang, W. Ye, C. W. Lange, X. Li, D. Grobelny,
M. Casabonne, D. Tyrell, K. Holme, A. Nadzan and
R. E. Galardy, J. Med. Chem., 1998, 41, 199–223. See also: (i)
a-Hydroxy acids in Enantioselective Syntheses, ed. G. M. Copolla
and H. F. Schuster, Wiley-VCH, Weinheim, Germany, 1997.
7 (a) D. A. Evans, M. C. Kozlowski, C. S. Burgey and D. W.
C. MacMillan, J. Am. Chem. Soc., 1997, 119, 7893–7894;
(b) D. A. Evans, D. W. C. MacMillan and K. R. Campos,
J. Am. Chem. Soc., 1997, 119, 10859–10860; (c) D. A. Evans,
C. S. Burgey and M. C. Kozlowski, J. Am. Chem. Soc., 1999, 121,
686–687.
Entry
R
R1 Product Yield (%) dr
ee (%) anti/syn
1
2
3
4
5
6
Me
Me
Et
OMe
OPh
Me 13a
tBu 13b
Me 13c
Me 13d
Me 13e
81
75
90
76
76
87
3 : 1
5 : 1
10 : 1 87, —
2 : 1
9 : 1
9 : 1
76, 71
73, 86
83, 88
86, 92
88, 87
OPMP Me 13f
a
All reactions were performed at 0.3 M concentration using 1.5 equiv.
of N,O-ketene. The stereochemistry assigned to the products is
tentative.
acknowledged. We thank Kyowa Hakko Kogyo Co. Ltd.,
Japan, for a sabbatical fellowship to KH.
Notes and references
1 E. M. Carriera, in Comprehensive Asymmetric Catalysis,
ed. E. N. Jacobsen, A. Pfaltz and H. Yamamoto, Springer, New York,
New York, 1999, vol. 1–3.
2 For reviews of recent developments on the creation of chiral
tertiary alcohols by nucleophilic additions to ketone carbonyls,
see: (a) Quaternary Stereocenters: Challenges and Solutions for
Organic Synthesis, ed. J. Christoffers and A. Baro, Wiley-VCH,
Weinheim, Germany, 2005; (b) O. Riant and J. Hannedouche,
Org. Biomol. Chem., 2007, 5, 873–888.
8 Recent reviews on enantioselective reactions catalyzed by chiral
hydrogen bond donors: (a) J. D. McGilvra, V. B. Gondi and
V. H. Rawal, in Enantioselective organocatalysis, ed. P. I. Dalko,
Wiley-VCH, Weinheim, 2007, pp. 189–254; (b) A. G. Doyle and
E. N. Jacobsen, Chem. Rev., 2007, 107, 5713–5743; (c) X. Yu and
W. Wang, Chem.–Asian J., 2008, 3, 516–532; (d) Y. Takemoto,
Org. Biomol. Chem., 2005, 3, 4299–4306.
3 Enantioselective Mukaiyama aldol reactions of ketones:
(a) S. E. Denmark and Y. Fan, J. Am. Chem. Soc., 2002, 124,
4233–4234; (b) K. Oisaki, M. Kanai and M. Shibasaki, J. Am.
Chem. Soc., 2003, 125, 5644–5645; (c) X. Moreau, B. Tejada and
J.-M. Champagne, J. Am. Chem. Soc., 2005, 127, 7288–7289.
4 For examples of diastereoselective pyruvate aldol reactions, see:
(a) I. C. Jacobson and G. P. Reddy, Tetrahedron Lett., 1996, 37,
8263–8266; (b) T. Akiyama, K. Ishikawa and S. Ozaki, Synlett,
1994, 275–276; (c) M.-Y. Chen and J.-M. Fang, J. Chem. Soc.,
Perkin Trans. 1, 1993, 1737–1741; (d) I. Ojima, K. Yoshida and
S. Inaba, Chem. Lett., 1977, 429–432; (e) Enantioselective pyruvate
aldol reactions promoted by stoichiometric chiral metal complexes:
S. Kobayashi and I. Hachiya, J. Org. Chem., 1992, 57, 1324–1328;
(f) S. Kobayashi, M. Horibe and Y. Saito, Tetrahedron Lett., 1994,
50, 9629–9642; (g) Enantioselective pyruvate Mukaiyama aldol
reactions promoted by substoichiometric metal complexes:
M. Langner and C. Bolm, Angew. Chem., Int. Ed., 2004, 43,
5984–5987; L. C. Akullian, M. L. Snapper and A. H. Hoveyda,
J. Am. Chem. Soc., 2006, 128, 6532–6533; see also: (h) H. Audrain
and K. A. Jørgensen, J. Am. Chem. Soc., 2000, 122, 11543–11544;
(i) K. Juhl, N. Gathergood and K. A. Jørgensen, Chem. Commun.,
2000, 2211–2212.
9 For selected examples of hydrogen bond catalyzed asymmetric
reactions of ketones from other labs, see: (a) T. Schuster,
M. Bauch, G. Duerner and M. W. Goebel, Org. Lett., 2000, 2,
179–181; (b) D. E. Fuerst and E. N. Jacobsen, J. Am. Chem. Soc.,
2005, 127, 8964–8965; (c) H. Li, B. Wang and L. Deng, J. Am.
Chem. Soc., 2006, 128, 732–733; (d) D. Nakashima and
H. Yamamoto, J. Am. Chem. Soc., 2006, 128, 9626–9627.
10 Prior work from this lab on hydrogen bond catalyzed asymmetric
reactions of carbonyl electrophiles: (a) Y. Huang, A. K. Unni,
A. N. Thadani and V. H. Rawal, Nature, 2003, 424, 146–146;
(b) A. N. Thadani, A. R. Stankovic and V. H. Rawal, Proc. Natl.
Acad. Sci. U. S. A., 2004, 101, 5846–5850; (c) A. K. Unni,
N. Takenaka, H. Yamamoto and V. H. Rawal, J. Am. Chem.
Soc., 2005, 127, 1336–1337; (d) V. B. Gondi, M. Gravel and
V. H. Rawal, Org. Lett., 2005, 7, 5657–5660; (e) J. D. McGilvra,
A. K. Unni, K. Modi and V. H. Rawal, Angew. Chem., Int. Ed.,
2006, 45, 6130–6133; (f) V. B. Gondi, K. Hagihara and
V. H. Rawal, Angew. Chem., Int. Ed., 2009, 48, 776–779.
11 (a) J. M. White, A. R. Tunoori and G. I. Georg, J. Am. Chem. Soc.,
2000, 122, 11995–11996; (b) J. T. Spletstoser, J. M. White,
A. R. Tunoori and G. I. Georg, J. Am. Chem. Soc., 2007, 129,
3408–3419.
ꢁc
This journal is The Royal Society of Chemistry 2010
906 | Chem. Commun., 2010, 46, 904–906