Syn -selective vinylogous Kobayashi aldol reaction

Article abstract of DOI:10.1021/ol300353w

The Kobayashi aldol reaction has become a prominent transformation in polyketide syntheses. This methodology takes advantage of the directing effects of the Evans auxiliary and allows the stereoselective incorporation of a four carbon segment with two additional methyl branches establishing an anti-relationship between the two newly formed chiral centers. So far this transformation was restricted to anti-aldol products. We present here a modified protocol that provides the corresponding aldol product with high syn-selectivity.

Full text of DOI:10.1021/ol300353w

ORGANIC
LETTERS
2012
Vol. 14, No. 6
1608–1611
Syn-Selective Vinylogous Kobayashi
Aldol Reaction
Gerrit Symkenberg and Markus Kalesse*
Institut fu€r Organische Chemie and Centre of Biomolecular Drug Research (BMWZ),
€
Leibniz Universitat Hannover, Schneiderberg 1B, 30167 Hannover, Germany
markus.kalesse@oci.uni-hannover.de
Received February 13, 2012
ABSTRACT
The Kobayashi aldol reaction has become a prominent transformation in polyketide syntheses. This methodology takes advantage of the directing
effects of the Evans auxiliary and allows the stereoselective incorporation of a four carbon segment with two additional methyl branches
establishing an anti-relationship between the two newly formed chiral centers. So far this transformation was restricted to anti-aldol products. We
present here a modified protocol that provides the corresponding aldol product with high syn-selectivity.
Vinylogous Mukaiyama aldol reactions are among the
most efficient transformations in polyketide chemistry.1
They serve in establishing carbonÀcarbon bonds and
chiral centers at the same time. A variety of strategies
to utilize these reactions in an enantioselective fashion
were put forward and exhibit chiral Lewis acids,2 Lewis
acidÀbasepairs, or organocatalysts4 for activation. A very
prominent and widely used example of a chiral auxiliary-
based approach was put forward by Kobayashi et al. in
2004.5 Their highly stereoselective vinylogous Mukaiyama
aldol reaction using Evans’ auxiliary based vinylketene
silyl N,O-acetals provides an efficient and hitherto unpre-
cedented high degree of remote (1,7- and 1,6,7-) asym-
metric induction (Scheme 1). It was found that chiral
vinylketene silyl N,O-acetals 1 and 2 underwent a highly
regio- and diastereoselective vinylogous Mukaiyama aldol
reaction. Kobayashi and co-workers could also show
that the R-methyl group of these amide-derived silyl
dienol ethers is important for achieving the high level of
diastereoselectivity.
(1) (a) Casiraghi, G.; Zanardi, F.; Appendino, G.; Rassu, G. Chem.
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Rev. 2000, 100, 1929. (b) Brodmann, T.; Lorenz, M.; Schackel, R.; Simsek,
S.; Kalesse, M. Synthesis 2009, 174. (c) Soriente, A.; De, R. M.; Villano, R.;
Scettri, A. Curr. Org. Chem. 2004, 8, 993. (d) Kalesse, M. Top. Curr.Chem.
2005, 244, 43. (e) Denmark, S. E.; Heemstra, J. R., Jr.; Beutner, G. L.
Angew. Chem., Int. Ed. 2005, 44, 4682. (f) Casiraghi, G.; Battistini, L.; Curti,
C.; Rassu, G.; Zanardi, F. Chem. Rev. 2011, 111, 3076.
(2) (a) Evans, D. A.; Kozlowski, M. C.; Murry, J. A.; Burgey, C. S.;
Campos, K. R.; Connell, B. T.; Staples, R. J. J. Am. Chem. Soc. 1999, 121,
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(c) Szlosek, M.; Figadere, B. Angew. Chem., Int. Ed. 2000, 39, 1799. (d)
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S.; Horzella, M.; Kalesse, M. Org. Lett. 2007, 9, 5637. (g) Simsek, S.;
Kalesse, M. Tetrahedron Lett. 2009, 50, 3485. (h) Evans, D. A.; Dunn,
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Scheme 1. Kobayashi’s Vinylogous Mukaiyama Aldol Reaction
(3) (a) Denmark, S. E.; Beutner, G. L.; Wynn, T.; Eastgate, M. D. J. Am.
Chem. Soc. 2005, 127, 3774. (b) Palombi, L.; Acocella, M. R.; Celenta, N.;
Massa, A.; Villano, R.; Scettri, A. Tetrahedron: Asymmetry 2006, 17, 3300.
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r
10.1021/ol300353w
Published on Web 03/08/2012
2012 American Chemical Society

Remarkably, reagents lacking this methyl substituent
not only exhibit lower selectivities but also provide the
opposite chiral induction (Scheme 2).
the facial selectivity of this vinylogous Mukaiyama aldol
reaction (Scheme 3). Yang9 and Chen9 reported on the syn-
selective Kobayashi aldol reaction when aldehydescapable
of chelation were employed.
The rationale for the observed selectivities in the
Kobayashi aldol reaction discriminates between the favored
and the unfavored transition state based on the steric
interaction as indicated in Figure 1.
Scheme 2. Kobayashi’s Vinylogous Mukaiyama Aldol Reaction
of Unsubstituted Vinylketene Silyl N,O-Acetals
However, the use of 3-Z-vinylketene silyl N,O-acetal 16
would lead to steric interaction between the Lewis acid and
either the terminal methyl group of the vinylketene acetal
or the alkyl chain of the aldeyhde. Even with this aspect of
ambiguity the generation of the N,O-ketene acetal of
Z-configuration at position 3 (16) would be a prerequisite
for the successful implementation of this transformation as
a general method.
This new methodology using Evans’ auxiliary-derived
vinylketene silyl N,O-acetals was further put to use in
several total syntheses of complex natural products. One
of its early applications is the total synthesis of palmerolide A.
Nicolaou6 and De Brabander7 independently demon-
strated the extreme viability and sustainability of this process.
Scheme 3. Kobayashi’s Vinylogous Aldol Reaction with Che-
lating Aldehydes
However, for palmerolide A as for other natural products8
the syn-aldol product was required and consequently the
configuration at the newly established secondary alcohol
had to be inverted later in the synthesis. Nevertheless, these
examples clearly have shown the important status of this
variation of Mukaiyama’s aldol reaction.
Naturally, the syn-variation of Kobayashi’s protocol
would add to the impact of this reaction on natural prod-
ucts syntheses.
Figure 1. Proposed transition state for Kobayashi’s syn-selective
aldol reaction.
However, deprotonation of the corresponding un-
saturated imide generates the ketene N,O-acetal with an
E-configuration at position 3. Additionally, due to unfa-
vorable 1,3-allylic strain interactions of the two methyl
groups it was questionable if the two double bonds would
be in conjugation in order to affect nucleophilicity at the
γ-position (Scheme 4).
So far, only a limited number of reports on the syn-
Kobayashi aldol reaction were reported. Kobayashi9a
found that R-heteroatom substituted aldehydes switch
(5) Shirokawa, S.-i.; Kamiyama, M.; Nakamura, T.; Okada, M.;
Nakazaki, A.; Hosokawa, S.; Kobayashi, S. J. Am. Chem. Soc. 2004,
126, 13604.
(6) (a) Nicolaou, K.; Guduru, R.; Sun, Y. P.; Banerji, B.; Chen, D. K.
Angew. Chem., Int. Ed. 2007, 46, 5896. (b) Nicolaou, K. C.; Sun, Y. P.;
Guduru, R.; Banerji, B.; Chen, D. Y. K. J. Am. Chem. Soc. 2008, 130,
3633.
Scheme 4. Syn-Selective Vinylogous Aldol Reaction Using
Z-Configured Ketene N,O-Acetals
(7) Jiang, X.; Liu, B.; Lebreton, S.; De Brabander, J. K. J. Am. Chem.
Soc. 2007, 129, 6386.
€
(8) Schmauder, A.; Muller, S.; Maier, M. E. Tetrahedron 2008, 64,
6263.
(9) (a) Shinoyama, M.; Shirokawa, S.; Nakazaki, A.; Kobayashi, S.
Org. Lett. 2009, 11, 1277. (b) Wang, L.; Gong, J.; Deng, L.; Xiang, Z.;
Chen, Z.; Wang, Y.; Chen, J.; Yang, Z. Org. Lett. 2009, 11, 1809. (c)
Wang, L.; Xi, Y.; Yang, S.; Zhu, R.; Liang, Y.; Chen, J.; Yang, Z. Org.
Lett. 2011, 13, 74.
Our strategy to generate the 1-E,3-Z-ketene N,O-acetal
takes advantage of the deprotonation of unsaturated ester
12 with concomitant methylation of the so-generated
Org. Lett., Vol. 14, No. 6, 2012
1609

enolate.10 Ester 13 was subsequently hydrolyzed and
transformed to the corresponding imide 15.11 Addi-
tional deprotonation and treatment with TBSCl pro-
vided the desired ketene N,O-acetal 16 for the syn-
selective Kobayashi aldol reaction. Treatment of this
acetal under Kobayashi’s conditions provided the syn-
aldol product 17 in 84% yield and with >20:1 selectivity
(Scheme 5).
Scheme 6. Configurational Assignment of the Syn-Selective
Aldol Reaction
Scheme 5. Synthesis of Z-Configured Ketene N,O-Acetal (16)
and Its Application in the Syn-Selective Aldol Reaction
Table 1. Conversion of Aldehydes to Syn-Aldol Products
The configuration was assigned with the aid of Mosher
ester formation and observed identity of the reduced
VMAR product 19 to known 20.8 Additional reassurance
was obtained by comparison of the anti-products anti-17
and 21 to their syn-isomers 17 and 2212 and by judgment of
the NOE contacts and couplings constants of the corre-
sponding acetonide 24 (Scheme 6).
In order to demonstrate the general applicability of this
procedure we performed vinylogous aldol reactions on
different aldehydes. Table 1 shows that aliphatic, unsatu-
rated, and aromatic aldehydes can be converted to their
corresponding syn-aldol products.
However, taking into consideration the proposed
transition state that leads to syn-aldol products when
conditions for the Kobayashi aldol reaction were
employed (Figure 1) we hypothesized that using ketene
acetals of Z-configurations at position 3 in combina-
tion with aldehydes that are capable of chelation would
in our case lead to anti-aldol products instead. Indeed,
the transformation of 2-methoxybenzaldehyde (25)
with 3-Z-ketene N,O-acetal 16 leads to anti-aldol prod-
uct 26 in 72% yield and dr > 20:1 (Scheme 7).
entry
aldehyde
acetaldehyde
yield (%)a
drb
1
2
3
4
5
6c
75
84
74
73
71
64
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
isovaleraldehyde
cyclohexanecarbaldehyde
hexanal
E-crotonaldehyde
benzaldehyde
a Isolated yield after chromatography. b Determined by 1H NMR.
À78 °C to rt.
c
Scheme 7. Kobayashi’s Vinylogous Mukaiyama Aldol Reaction
on a Chelating Aldehyde
(10) (a) Johnson, W. S.; Lyle, T. A.; Daub, G. W. J. Org. Chem. 1982,
€
47, 163. (b) Adam, W.; Saha-Moller, C. R.; Weichold, O. Monatsh.
Chem. 2000, 131, 697.
(11) Kleber, C.; Andrade, Z.; Rocha, R. O.; Vercillo, O. E.; Silva,
W. A.; Matos, R. A. F. Synlett 2003, 15, 2351.
(12) For comparison of the spectra, see Supporting Information.
1610
Org. Lett., Vol. 14, No. 6, 2012

In summary, we introduced a general applicable syn-
selective vinylogous Kobayashi aldol reaction using 1-E,
3-Z-ketene N,O-acetal 16. This protocol provides the syn-
aldol product in yields ranging from 62 to 84% and
selectivities higher than 20:1 and can be applied to
aliphatic, unsaturated, and aromatic aldehydes as well.
As a complement, this protocol provides the anti-isomers
when aldehydes with substituents capable of chelation are
used.
Acknowledgment. We thank Dr. Hai-Hua Lu for help-
ful discussions.
Supporting Information Available. Spectroscopic data
and experimental procedures for compounds 12À34. This
material is available free of charge via the Internet at
http://pubs.acs.org.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 6, 2012
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