Syn-selective kobayashi aldol reaction using the E,E-vinylketene silyl N,O -acetal

Article abstract of DOI:10.1021/ol3024677

The Kobayashi aldol reaction is one of the most powerful methods to synthesize the polyketide skeleton and has been applied to the total synthesis of natural products. This methodology has been used to construct anti-aldol products, and only a few precedents on the syn-selective Kobayashi aldol reaction are known. A syn-selective Kobayashi aldol reaction by using the E,E-vinylketene silyl N,O-acetal and an excess amount of Lewis acid is presented.

Full text of DOI:10.1021/ol3024677

ORGANIC
LETTERS
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Vol. XX, No. XX
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Syn-Selective Kobayashi Aldol Reaction
Using the E,E-Vinylketene Silyl N,O-Acetal
Yuki Mukaeda, Takuya Kato, and Seijiro Hosokawa*
Department of Applied Chemistry, Faculty of Advanced Science and Engineering,
Waseda University, 3-4-1 Ohkubo, Shinjuku-ku, Tokyo 169-8555, Japan
seijiro@waseda.jp
Received September 6, 2012
ABSTRACT
The Kobayashi aldol reaction is one of the most powerful methods to synthesize the polyketide skeleton and has been applied to the total
synthesis of natural products. This methodology has been used to construct anti-aldol products, and only a few precedents on the syn-selective
Kobayashi aldol reaction are known. A syn-selective Kobayashi aldol reaction by using the E,E-vinylketene silyl N,O-acetal and an excess amount
of Lewis acid is presented.
The vinylogous Mukaiyama aldol reaction (VMAR) is
one of the most useful methods to synthesize polyketide
compounds.1 Recently, theasymmetricVMARshave been
developed and applied to synthesize natural products.2
Among these methodologies, the Kobayashi aldol reaction
is successful and has been widely applied to the synthesis of
natural products (Scheme 1).3 The E,E-vinylketene silyl
N,O-acetal 1reacts with aldehyde in the presence of 1 equiv of
Lewis acid to give the anti adduct 2 in high stereoselectivity.
Kobayashi aldol reaction are known. Kobayashi’s group
found that R-heteroatom substituted aldehyde a provided
syn adducts selectively by switching the facial selectivity of
the aldehyde (Scheme 2, eq 1).4 Chen’s group reported that
syn adducts were obtained by aldehydes capable of chela-
tion in Kobayashi aldol reactions (eq 2).5 More recently,
Kalesse published that the 1-E, 3-Z-vinylketene silyl N,O-
acetal 4 gave syn adducts 5 in a highly stereoselective
manner (eq 3).6 Herein, we present a syn-selective Kobaya-
shi reaction with 1-E,3-E-vinylketene silyl N,O-acetal 1 by
using an excess amount of Lewis acid (eq 4). The stereo-
chemistry of the adduct 3 possesses stereogenic centers
different from Kalesse’s adduct.
Scheme 1. Kobayashi Aldol Reaction
The relationship between the amount of Lewis acid and
the stereochemistry of the adduct is shown in Table 1.
Equal equivalents of the aldehyde c and the E,E-vinylk-
etene silyl N,O-acetal 1 reacted with 1 equiv of TiCl4 to
afford the anti adduct 2c predominantly (Table 1, entry 1),
while in the case of the 1:2 equiv amounts of the alde-
hyde and Lewis acid, the syn adduct was obtained as a
major product while other diastereomers were observed
This methodology has been used to construct anti-aldol
products, and only a few precedents on the syn-selective
(1) (a) Casiraghi, G.; Zanardi, F.; Appendino, G.; Rassu, G. Chem.
Rev. 2000, 100, 1929–1972. (b) Soriente, A.; De, R. M.; Villano, R.;
Scettri, A. Curr. Org. Chem. 2004, 8, 993–1007. (c) Kalesse, M. Top.
Curr. Chem. 2005, 244, 43–76. (d) Denmark, S. E.; Heemstra, J. R., Jr.;
Beutner, G. L. Angew. Chem., Int.Ed. 2005, 44, 4682–4698. (e)Brodmann,
T.; Lorenz, M.; Schackel, R.; Simsek, S.; Kalesse, M. Synlett 2009,
174–192. (f) Casiraghi, G.; Battistini, L.; Curti, C.; Rassu, G.; Zanardi,
F. Chem. Rev. 2011, 111, 3076–3154.
(2) (a) Singer, R. A.; Carreira, E. M. J. Am. Chem. Soc. 1995, 117,
12360. (b) Evans, D. A.; Hu, E.; Burch, J. D.; Jaeschke, G. J. J. Am.
Chem. Soc. 2002, 124, 5654–5655. (c) Denmark, S. E.; Heemstra, J. R.,
Jr. J. Am. Chem. Soc. 2006, 128, 1038–1039. (d) Nagao, H.; Yamane, Y.;
Mukaiyama, T. Chem. Lett. 2007, 36, 8–9. (e) Simsek, S.; Kalesse, M.
Tetrahedron Lett. 2009, 50, 3485–3488. (f) Singh, R. P.; Foxman, B. M.;
Deng, L. J. Am. Chem. Soc. 2010, 132, 9558–9560.
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10.1021/ol3024677
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unambiguously (Table 1, entry 3). Treatment with 3 equiv
of TiCl4 promoted the reaction to afford syn adduct 3c
predominantly (Table 1, entry 4). When the conditions
Table 1. Relationship between Amount of Reactants and the
Stereochemistry of the Adduct
Scheme 2. Syn-Selective Kobayashi Aldol Reactions
1
Lewis acid
(equiv)
yield
(%)b
entry
(equiv)
2c:3ca
1c
2
3
4
5
6
7
1.0
1.0
1.0
1.0
1.0
1.5
1.5
1.0
1.5
2.0
3.0
4.0
4.0
9.0
72
75
77
67
74
94
92
44:1b
32:1c
1:27d
>1:50c
>1:50c
>1:50c
>1:50c
a Determined by 1H NMR. b Reference 3a. c Trace amounts of
diastereomers were observed. d Other isomers were observed in the ratio
of 2/3/diastereomers = 1:27:1.6:16.
included 1:1.5:4 equiv amounts of the aldehyde, the E,E-
vinylketene silyl N,O-acetal 1, and TiCl4, excellent yield
and selectivity were observed (Table 1, entry 6). More
Lewis acid did not affect bothyield and selectivity (Table 1,
entry 7). The stereochemistry of the syn adduct 3c was
confirmed by esterification which afforded the ester 6
derived by the Mitsunobu reaction from the known anti
adduct 2c3a (Scheme 3).
(3) (a) Shirokawa, S.; Kamiyama, M.; Nakamura, T.; Okada, M.;
Nakazaki, A.; Hosokawa, S.; Kobayashi, S. J. Am. Chem. Soc. 2004,
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Scheme 3. Determination of the Stereochemistry of the Syn
Adduct
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B
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using 1.5 equiv of the E,E-ketene N,O-acetal 1 and 4 equiv
of TiCl4 in dichloromethane (Table 2). The initial color of
the reaction mixture was dark blue while Kobayashi’s
conditions exhibited a dark red color. As the reaction
proceeded, the color of the mixture became yellow. In all
cases, including aromatic aldehydes and saturated alde-
hydes, the reactions proceeded in good to high yield with
excellent stereoselectivity to give syn adducts.7 In the case
of γ-oxygenated aldehydes i and j (Table 2, entries 6 and 7),
the reaction proceeded slowly, and the syn adducts were
obtained as in other cases by increasing the amount of the
dienol silyl ether (3 equiv) and TiCl4 (7 equiv). However, in
the case of crotonaldehyde o and cinnamaldehyde p, the
reaction gave multiple products including 2:1 adducts of
the E,E-ketene N,O-acetal and the aldehyde (Scheme 4).
Since a trace amount of the 1:1 adduct was observed in
each reaction, the 1:1 adduct might easily receive the
second nucleophilic addition of the N,O-acetal or other
reactions. The 2:1 adducts 7o and 7p were obtained as a
mixture of stereoisomers in a moderate ratio, of which
stereochemistry of the major isomer was not determined.
Next we examined the same reaction with chloral q
and o-methoxybenzaldehyde r (Scheme 5). Kobayashi
reported that the reaction with chloral q by using 1.0 equiv
of TiCl4 provided the syn adduct predominantly.4 Treat-
ment of chloral q with 1.5 equiv of the E,E-vinylketene
N,O-acetal 1 and 4 equiv of TiCl4 allowed the reaction to
proceed and to give the syn adduct 3q predominantly. On
the other hand, Chen’s group found that the reaction with
o-methoxybenzaldehyde r under the original Kobayashi’s
conditions gave the syn adduct predominantly. Kalesse’s
E,Z-vinylketene N,O-acetal 4 afforded the anti adduct
via the same transition state as in Chen’s report.6 The
E,E-vinylketene N,O-acetal 1, however, yielded the syn
adduct 3r as a single isomer. It is interesting that chloral
q and o-methoxybenzaldehyde r did not turn the stereo-
selectivity in VMAR, and both Kobayashi’s original con-
ditions and our conditions gave the syn adduct in high
stereoselectivity.
Table 2. Syn-Selective Kobayashi Aldol Reactions
Scheme 4. Reactions with Crotonaldehyde and
Cinnamaldehyde
a All reactions were performed in the ratio of aldehyde/dienol ether/
TiCl4 = 1:1.5:4. b The diastereomeric ratio was determined by 400 MHz
1H NMR. c Performed in the ratio of aldehyde/dienol ether/TiCl4 = 1:3:7.
According to the stereochemical divergency dependent
on the amount of the Lewis acid in the reaction of the E,E-
vinylketene silylN,O-acetal1withhexanalc, weperformed
theKobayashialdolreaction with a variety of aldehydesby
Although it is clear that the stereoselectivity of the
Kobayashi aldol reaction is dependent on the amount of
Org. Lett., Vol. XX, No. XX, XXXX
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from Kobayashi’s anti aldol reaction reveal the differences
in the structure of the initial titanium complexes. Studies
including calculations to identify the transition state are in
progress.
Scheme 5. Reactions with Chloral and o-Methoxybenzaldehyde
In conclusion, we succeeded in utilizing the syn selective
Kobayashi aldol reaction by using an excess amount
of TiCl4. It is useful that the same starting materials
and reactants give each stereochemistry in high selec-
tivity.8 Stereochemical switching is an advantage of the
Kobayashi reaction in coping with polypropionate skele-
tons having a variety of configurations.9 Application of
this reaction to the total synthesis of natural products is in
progress.
Acknowledgment. Authors are grateful for financial
support from the GCOE program “Center for Practical
Chemical Wisdom” and Grant-in-Aid for Challenging
Exploratory Research from The Ministry of Education,
Culture, Sports, Science and Technology (MEXT). This
research was also supported by the Supporting Strategic
Research Platform for Fusion Biotechnology based on
Biology, Chemistry, and Informatics Project to Form the
Strategic Research Platforms for Private University and a
Matching Fund Subsidy from MEXT, Japan.
Lewis acid, the transition state of the syn selective reaction
remains obscure. Differences in the initial reaction color
(7) Absolute configurations of products were determined as shown in
Scheme 3. Configurations of 3e and 3g were determined by X-ray crystal-
lography. The Kobayashi aldol adducts 3d and 3m were derived into the
crystalline 3d methyl ether and 3m 3,5-dinitrobenzoate, respectively, to
perform X-ray crystallography. Crystallographic data (excluding structure
factors) for the structures of 3d methyl ether, 3e, 3g, and 3m 3,5-dinitro-
benzoate are shown in the Supporting Information.
(8) Danda, H.; Hansen, M. M.; Heathcock, C. H. J. Org. Chem. 1990,
55, 173–181.
(9) The De Brabander and Nicolaou groups have achieved the total
synthesis of palmerolide A independently, in which both groups made
the γ,δ-syn adduct by using Kobayashi aldol reaction followed by
inversion of the configuration of the δ-hydroxy group: (a) Jiang, X.;
Liu, B.; Lebreton, S.; De Brabander, J. K. J. Am. Chem. Soc. 2007, 129,
6386–6387. (b) Nicolaou, K. C.; Guduru, R.; Sun, Y.-P.; Banerji, B.;
Chen, D. Y.-K. Angew. Chem., Int. Ed. 2007, 46, 5896–5900. (c)
Nicolaou, K. C.; Sun, Y.-P.; Guduru, R.; Banerji, B.; Chen, D. Y.-K.
J. Am. Chem. Soc. 2008, 130, 3633–3644.
Supporting Information Available. The experimental
procedure and physical property of new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
The authors declare no competing financial interest.
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