Construction of contiguous tetrasubstituted chiral carbon stereocenters via direct catalytic asymmetric aldol reaction of α-isothiocyanato esters with ketones

Article abstract of DOI:10.1021/ja908571w

(Chemical Equation Presented) Construction of contiguous tetrasubstituted chiral carbon stereocenters via direct catalytic asymmetric aldol reaction of α-substituted α-isothiocyanato esters with unactivated simple ketones is described. A Bu₂Mg/

Full text of DOI:10.1021/ja908571w

Published on Web 11/06/2009
Construction of Contiguous Tetrasubstituted Chiral Carbon Stereocenters
via Direct Catalytic Asymmetric Aldol Reaction of r-Isothiocyanato Esters
with Ketones
Tatsuhiko Yoshino, Hiroyuki Morimoto, Gang Lu, Shigeki Matsunaga,* and Masakatsu Shibasaki*
Graduate School of Pharmaceutical Sciences, The UniVersity of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
Received October 8, 2009; E-mail: smatsuna@mol.f.u-tokyo.ac.jp; mshibasa@mol.f.u-tokyo.ac.jp
The direct catalytic asymmetric aldol reaction is a powerful and
atom-economical method for synthesizing chiral ꢀ-hydroxy carbonyl
compounds. Many metal and organocatalysts for reactions of aldehyde
electrophiles have been developed in the past decade.1 The use of
ketone electrophiles in direct aldol reactions for the construction of a
tetrasubstituted carbon stereocenters,2 however, is limited to either
activated ketones (e.g., R-keto esters, R-keto phosphonates, and isatins)
or intramolecular reactions with organocatalysts.3 Although catalytic
enantioselective intermolecular aldol reactions with simple ketones have
been achieved using either preformed silyl enolates4 or in situ-generated
enolates with stoichiometric reducing reagents (reductive aldol reac-
tions),5 a direct catalytic asymmetric intermolecular aldol reaction with
simple ketones under proton-transfer conditions has not been estab-
lished.6 Furthermore, catalytic asymmetric construction of two contigu-
ous tetrasubstituted chiral carbon stereocenters in C-C bond-forming
reactions is rare,7 possibly because of severe steric hindrance. Herein,
we report our efforts to address these issues. Mg Schiff base catalysts
1 (Figure 1) promoted a direct asymmetric aldol reaction of R-sub-
stituted R-isothiocyanato esters 2 with simple ketones, producing
protected R-amino-ꢀ-hydroxy esters with contiguous tetrasubstituted
chiral carbon stereocenters in up to 98% ee and 98:2 dr.
tert-butyl substituent and 1c without a substituent gave much less
satisfactory enantioselectivities (0-10% ee; entries 2-3). Other metal
sources, such as Et2Zn, Sr(O-iPr)2, Ba(O-iPr)2, and La(O-iPr)3, also
resulted in poor selectivity or reactivity (entries 4-7). The diastereo-
selectivity improved to 97:3 in toluene while a high yield and
enantioselectivity were maintained (97% isolated yield and 97% ee;
entry 8).
Scheme 1. Strategy To Obtain Aldol-Type Adducts from Ketone
Electrophiles
Table 1. Optimization Studies and Control Experiments
entry metal source ligand
solvent
time (h) % yielda
dra
% ee of 4aa
Figure 1. Structures of Schiff bases 1a-d and R-substituted R-isothio-
cyanato esters 2.
1
2
3
4
5
6
7
8
Bu2Mg
Bu2Mg
Bu2Mg
Et2Zn
Sr(O-iPr)2
Ba(O-iPr)2 1a
1a
THF
43
43
43
43
43
43
43
36
>95
13
>95
0
93:7
95
0
1b THF
52:48
68:32
-
30:70
38:62
75:25
1c
1a
1a
THF
THF
THF
THF
THF
toluene
10c
-
The direct catalytic intermolecular aldol reaction of ketone elec-
trophiles is difficult because of the small equilibrium constants for
ketone electrophiles compared with those of aldehyde electrophiles (a
vs b in Scheme 1).8 Aldol adducts of ketone electrophiles are unstable
under basic reaction conditions.8c To overcome the inherent instability
of the aldol adducts formed using ketones, we assumed that irreversibly
trapping the unstable tertiary aldols might be key to kinetically
producing more stable adducts. We selected R-isothiocyanato esters 2
as nucleophiles to produce protected R-amino-ꢀ-hydroxy esters
(Scheme 1c).9,10 For the challenging catalytic asymmetric construction
of two contiguous tetrasubstituted chiral carbon stereocenters, we
optimized the reaction conditions using R-substituted R-isothiocyanato
ester 2a and ketone 3a (Table 1). Screening chiral ligands and metal
sources gave promising results for Schiff base 1a derived from vanillin
and binaphthyldiamine. A 1:1 Bu2Mg/1a complex11 effectively
promoted the reaction in THF at room temperature, giving product
4aa in >95% yield, 93:7 dr, and 95% ee (entry 1). Ligands 1b with a
93
13
21c
14c
97
>95
La(O-iPr)3
Bu2Mg
1a
1a
90
97b 97:3
a Determined by 1H NMR analysis of the crude mixture. b Isolated
yield. c ent-4aa was obtained as the major product.
The substrate scope of the reaction is summarized in Table 2.12
The Bu2Mg/Schiff base 1a complex promoted the addition of
R-isothiocyanato ester 2a to aryl and heteroaryl methyl ketones (entries
1-10). The reaction proceeded even with 2.5 mol % catalyst loading
and on an 8.0 mmol scale (1.16 g of 2a) while maintaining a high
yield, dr, and enantioselectivity (entry 2). A longer reaction time (69
h), however, was required because of the modest catalyst turnover
frequency. Various acetophenone derivatives with either an electron-
donating or electron-withdrawing substituent at the para or meta
9
17082 J. AM. CHEM. SOC. 2009, 131, 17082–17083
10.1021/ja908571w CCC: $40.75  2009 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Direct Catalytic Asymmetric Aldol Reactions of
R-Substituted R-Isothiocyanato Esters 2 with Ketones 3a-ma
In summary, we have developed a direct catalytic asymmetric aldol
reaction of R-substituted R-isothiocyanato esters with aryl, heteroaryl,
alkyl, and alkenyl methyl ketones and a cyclic ketone. Mg Schiff base
complexes catalyzed the direct aldol reaction/cyclization sequence at
room temperature, giving protected R-amino-ꢀ-hydroxy esters with
contiguous tetrasubstituted chiral carbon stereocenters in 99 to 68%
yield, 98:2 to 74:26 dr, and 98 to 82% ee. Further studies to improve
the reaction rate through catalyst modification, including the use of
bimetallic Schiff base catalysts, are ongoing.14
Acknowledgment. S.M. is thankful for support by a Grant-in-
Aid for Young Scientists (A). H.M. and G.L. thank JSPS for fel-
lowships.
Supporting Information Available: Experimental details, charac-
terization data for new compounds, and a CIF. This material is available
free of charge via the Internet at http://pubs.acs.org.
References
(1) Reviews of direct aldol reactions: Modern Aldol Reactions; Mahrwald, R.,
Ed.; Wiley-VCH: Weinheim, Germany, 2004.
(2) Reviews of catalytic enantioselective addition to ketones: (a) Adachi, S.;
Harada, T. Eur. J. Org. Chem. 2009, 3661. (b) Riant, O.; Hannedouche, J.
Org. Biomol. Chem. 2007, 5, 873. (c) Hatano, M.; Ishihara, K. Synthesis
2008, 1647. (d) Shibasaki, M.; Kanai, M. Chem. ReV 2008, 108, 2853.
Review of chiral quaternary carbon synthesis: (e) Trost, B. M.; Jiang, C.
Synthesis 2006, 369.
(3) Review: Mukherjee, S.; Yang, J. W.; Hoffmann, S.; List, B. Chem. ReV.
2007, 107, 5471 and references therein.
a Reaction was performed using 0.20 mmol of 2, 2.0 equiv of 3, and
5 Å molecular sieves (40 mg) in toluene (1.0 M), unless otherwise
noted. b Isolated yield based on the amount of 2 used. c Determined by
1H NMR analysis of the crude mixture. d Reaction was performed using
8.0 mmol of 2a, 2.0 equiv of 3a, and 5 Å molecular sieves (800 mg) in
toluene (2.0 M).
(4) Catalytic asymmetric intermolecular aldol reactions with simple ketone
electrophiles using silyl enolates: (a) Denmark, S. E.; Fan, Y. J. Am. Chem.
Soc. 2002, 124, 4233. (b) Oisaki, K.; Suto, Y.; Kanai, M.; Shibasaki, M.
J. Am. Chem. Soc. 2003, 125, 5644. (c) Denmark, S. E.; Fan, Y.; Eastgate,
M. D. J. Org. Chem. 2005, 70, 5235. (d) Oisaki, K.; Zhao, D.; Kanai, M.;
Shibasaki, M. J. Am. Chem. Soc. 2006, 128, 7164. Also see ref 2a.
(5) Catalytic asymmetric reductive aldol reactions with simple ketones: (a)
Deschamp, J.; Chuzel, O.; Hannedouche, J.; Riant, O. Angew. Chem., Int.
Ed. 2006, 45, 1292. (b) Zhao, D.; Oisaki, K.; Kanai, M.; Shibasaki, M.
J. Am. Chem. Soc. 2006, 128, 14440. For an intramolecular variant, see:
(c) Lam, H. W.; Joensuu, P. M. Org. Lett. 2005, 7, 4225. Also see ref 2a.
(6) γ-Additionofallylcyanidetoketonesunderproton-transferconditions:Yazaki,
R.; Kumagai, N.; Shibasaki, M. J. Am. Chem. Soc. 2009, 131, 3195.
(7) Review: (a) Peterson, E. A.; Overman, L. E. Proc. Natl. Acad. Sci. U.S.A.
2004, 101, 11943. Selected recent examples: Direct aldol reaction of
oxindoles with ethyl trifluoropyruvate: (b) Ogawa, S.; Shibata, N.; Inagaki,
J.; Nakamura, S.; Toru, T.; Shiro, M. Angew. Chem., Int. Ed. 2007, 46,
8666. Cyclopropanation: (c) Moreau, B.; Charette, A. B. J. Am. Chem.
Soc. 2005, 127, 18014. Addition to isatins: (d) Shintani, R.; Hayashi, S.;
Murakami, M.; Takeda, M.; Hayashi, T. Org. Lett. 2009, 11, 3754. Addition
to trifluoromethyl ketones: (e) Wang, X.-N.; Shao, P.-L.; Lv, H.; Ye, S.
Org. Lett. 2009, 11, 4029.
Scheme 2. Transformation of Product 4aaa
a Reagents and conditions: (a) LiAlH4, -78 °C to rt, 1 h, 84% yield; (b)
Boc2O, cat. DMAP, CH2Cl2, rt, 40 min, then H2O2, HCO2H, rt, 24 h; (c)
LiOH(aq), 1,4-dioxane/H2O, reflux, 24 h, 92% yield (from 5aa).
(8) For example, the equilibrium constant for the aldol reaction of benzaldehyde
and acetone is 11.7 M-1, while that of acetophenone and acetone is
1.89 × 10-3 M-1 [see: (a) Guthrie, J. P. J. Am. Chem. Soc. 1991, 113,
7249. (b) Guthrie, J. P.; Wang, X.-P. Can. J. Chem. 1992, 70, 1055 and
references therein]. Rapid retroaldol reaction of tertiary aldols was observed
under basic conditions even at -78 °C [see: (c) Hatano, M.; Takagi, E.;
Ishihara, K. Org. Lett. 2007, 9, 4527].
(9) For the utility of R-isothiocyanato imides, see: (a) Evans, D. A.; Weber,
A. E. J. Am. Chem. Soc. 1987, 109, 7151 and references therein. For the
use of R-isothiocyanato imides in direct catalytic asymmetric aldol and
Mannich-type reactions with aldehydes and aldimines, see: (b) Willis, M. C.;
Cutting, G. A.; Piccio, V. J.-D.; Durbin, M. J.; John, M. P. Angew. Chem.,
Int. Ed. 2005, 44, 1543. (c) Cutting, G. A.; Stainforth, N. E.; John, M. P.;
Kociok-Ko¨hn, G.; Willis, M. C. J. Am. Chem. Soc. 2007, 129, 10632. (d)
Li, L.; Klauber, E. G.; Seidel, D. J. Am. Chem. Soc. 2008, 130, 12248. (e)
Li, L.; Ganesh, M.; Seidel, D. J. Am. Chem. Soc. 2009, 131, 11648.
(10) For the addition of isothiocyanatoacetate to simple ketones using a
stoichiometric amount of strong base, see: Hoppe, D.; Follmann, R. Chem.
Ber. 1976, 109, 3047.
(11) For other Bu2Mg/chiral ligand catalysts for direct aldol reactions, see: Trost,
B. M.; Malhotra, S.; Fried, B. A. J. Am. Chem. Soc. 2009, 131, 1674.
(12) The absolute and relative configurations of 4aa were determined by single-
crystal X-ray analysis. Those of others were tentatively assigned by analogy.
(13) Because ligand 1d with additional MeO substituents showed better reactivity
than 1a for ketone 3k, we assume that the nucleophilicity of the Mg enolates
generated from the Bu2Mg/1 catalysts would be important in promoting the
reaction. Mechanistic studies will be reported in due course as a full article.
(14) For the utility of a bimetallic system with Schiff bases derived from vanillin,
see: Mihara, H.; Xu, Y.; Shepherd, N. E.; Matsunaga, S.; Shibasaki, M.
J. Am. Chem. Soc. 2009, 131, 8384 and references therein.
position of the aromatic ring gave products in good yield and dr with
high enantioselectivity (95-98% ee; entries 3-6). 3f with a 4-MeO
substituent, however, resulted in somewhat lower stereoselectivity and
yield (89% ee; entry 7). Heteroaryl ketones 3g-i were also applicable,
giving products in 95-98% ee (entries 8-10). Ketones 3j-m showed
lower reactivity than aryl methyl ketones, and 20 mol % catalyst was
required to obtain the products in good yield (entries 11-14). Cyclic
ketone 3j gave 4ja in 75% yield and 94% ee (entry 11). For alkyl
methyl ketone 3k, the Bu2Mg/1a catalyst resulted in poor yield (<30%).
Modification of the ligand was effective in improving the yield, and
the Bu2Mg/1d complex gave 4ka in 81% yield and 97% ee (entry
12).13 Bu2Mg/1d was also applicable to ketone 3l and alkenyl ketone
3m, giving products in 93 and 96% ee, respectively (entries 13 and
14). The reaction with R-ethyl isothiocyanato ester 2b proceeded
smoothly to afford products in good yields and diastereoselectivities
(76-94%, 92:8-96:4 dr), but the enantioselectivity somewhat de-
creased to 82-95% ee (entries 15-17). The transformation of
oxazolidinethione 4aa into amino alcohol 6aa was performed (Scheme
2). After reduction of 4aa into 5aa, the oxazolidinethione moiety was
converted into an oxazolidinone using a reported procedure.9a Treat-
ment with LiOH gave unprotected 6aa in 92% yield (two steps from
5aa).
JA908571W
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