A switch of facial selectivities using a-heteroatom-substituted aldehydes in the vinylogous Mukaiyama aldol reaction

Article abstract of DOI:10.1021/ol9000312

The vinylogous Mukaiyama aldol reaction (VMAR) of chiral nonracemic ketene silyl N,O-acetal with various aldehydes is demonstrated. VMAR with a-heteroatom-unsubstituted aldehydes proceeded with a high degree of anti-selectivity. In sharp contrast, moderat

Full text of DOI:10.1021/ol9000312

ORGANIC
LETTERS
2009
Vol. 11, No. 6
1277-1280
A Switch of Facial Selectivities Using
r-Heteroatom-Substituted Aldehydes in
the Vinylogous Mukaiyama Aldol
Reaction
Mariko Shinoyama, Shin-ichi Shirokawa, Atsuo Nakazaki, and
Susumu Kobayashi*
Faculty of Pharmaceutical Sciences, Tokyo UniVersity of Science (RIKADAI),
2641 Yamazaki, Noda-shi, Chiba 278-8510, Japan
kobayash@rs.noda.tus.ac.jp
Received January 7, 2009
ABSTRACT
The vinylogous Mukaiyama aldol reaction (VMAR) of chiral nonracemic ketene silyl N,O-acetal with various aldehydes is demonstrated. VMAR
with r-heteroatom-unsubstituted aldehydes proceeded with a high degree of anti-selectivity. In sharp contrast, moderate to high syn-selectivity
was observed when r-heteroatom-substituted aldehydes were used.
We have developed the vinylogous Mukaiyama aldol reaction
(VMAR) of chiral ketene silyl N,O-acetal 1 with a variety
of aldehydes affording anti-aldol adducts (Scheme 1),1,2
which have been used toward the total synthesis of naturally
occurring products.3 During the course of our investigation
of the VMAR, we have observed a remarkable switch to
syn-stereoselectivity using R-heteroatom-substituted alde-
hydes. Herein, we report the scope and limitation of the
VMAR and the detail of a stereochemical switch when
R-heteroatom-substituted aldehydes were used.
Initially, we examined VMAR of 1 (dr ) >20:1) with a
variety of achiral aldehydes (Table 1). Compound 1 used in
this study was prepared from commercially available trans-2-
methyl-2-pentenoic acid and Evans chiral auxiliary derived from
Scheme 1
(1) Shirokawa, S.-i.; Kamiyama, M.; Nakamura, T.; Okada, M.; Naka-
zaki, A.; Hosokawa, S.; Kobayashi, S. J. Am. Chem. Soc. 2004, 126, 13604–
13605
.
(2) For reviews of the vinylogous aldol reaction, see: (a) Casiraghi, G.;
Zanardi, F.; Appendino, G.; Rassu, G. Chem. ReV. 2000, 100, 1929–1972.
(b) Soriente, A.; De Rosa, M.; Villano, R.; Scettri, A. Curr. Org. Chem.
2004, 8, 993–1007. (c) Denmark, S. E.; Heemstra, J. R., Jr.; Beutner, G. L.
Angew. Chem., Int. Ed. 2005, 44, 4682–4698. (d) Kalesse, M. Top. Curr.
Chem. 2005, 244, 43–76. (e) Brodmann, T.; Lorenz, M.; Scha¨ckel, R.;
Simsek, S.; Kalesse, M. Synthesis 2009, 174–192
.
10.1021/ol9000312 CCC: $40.75
Published on Web 02/17/2009
2009 American Chemical Society

Table 1. VMAR of 1 with Achiral Aldehydes
Scheme 2. Determination of the C4-C5 Relationships of 3a-c
sequence, rather than the direct VMAR with 2a, is the most
effective method of obtaining aldol adduct 3a with high
diastereoselectivity. Unfortunately, pivalaldehyde 2e, one of the
bulky aldehydes, was not a suitable substrate for the VMAR
(entry 5). Stereochemical determination (vide infra) revealed
that the observed facial selectivities were consistent with similar
previously reported reactions.1 Intriguingly, however, the
VMAR with R-heteroatom-substituted aldehydes was found to
proceed with 4,5-syn-diastereoselectivity (entries 6-8). Thus,
similar reaction of 1 with siloxyacetaldehyde 2f resulted in the
formation of the syn-aldol adduct 3f in 84% yield in a
diastereomeric ratio of 1:4.5 (entry 6). In addition, the VMAR
of monochlorinated aldehyde 2g was found to afford syn adduct
3g as a predominant diastereomer (entry 7). Rather hindered
R-heteroatom-substituted aldehyde 2h also underwent the
VMAR with 1 to afford the aldol adduct 3h with high syn
selectivity, although the yield was only moderate (entry 8).
Several trends became obvious: (1) The C4 chiral center of the
aldol adduct 3 is controlled as an S configuration independent
of the substituent of the aldehyde. (2) syn or anti selectivity is
generally enhanced when hindered aldehydes are used. (3)
Facial selectivity of the aldehyde changes depending on the
substituents on the aldehydes used, although the exact origin
of this stereo changeover remains obscure.
Stereochemical determinations of the aldol adducts 3 were
performed as follows. The C4-C5 relationships of the aldol
adducts 3a-c were determined by the coupling constants of
the corresponding 1,3-dioxane derivatives 4a-c (Scheme 2).
The absolute stereochemistry of the aldol adduct 3a was
confirmed by the modified Mosher method,4 and the absolute
configuration of 3b and 3c was tentatively assigned by assuming
an analogous diastereoselection. The spectroscopic data of the
aldol adducts 3f and 3g,h matched those of the known
compounds 65 and 7,6 respectively (Schemes 3 and 4).
a Diastereomeric ratio was determined by 1H NMR analysis. b Demetallated
aldol adduct 3a was obtained in 13% yield with high anti selectivity (dr )
>20:1).
L-valine.1 Treatment of 2 equiv of ynal 2a with 1 equiv of TiCl4
in CH2Cl2 at -78 °C and careful addition of chiral nonracemic
ketene silyl N,O-acetal 1, followed by warming of the reaction
mixture to -40 °C, led to the aldol adduct 3a in 80% yield,
albeit with moderate 4,5-anti-diastereoselectivity (dr ) 7.7:1,
entry 1). However, the related reaction using 2b-d was found
to afford the corresponding adducts 3b-d in good-to-excellent
yield with high anti diastereoselectivity (entries 2-4). Demeta-
lation of the aldol adduct 3d was easily achieved using a
conventional method (NMO) to afford 3a in good yield without
loss of stereochemical integrity. Thus, the VMAR-demetalation
(3) (a) Hosokawa, S.; Ogura, T.; Togashi, H.; Tatsuta, K. Tetrahedron
Lett. 2005, 46, 333–337. (b) Nakamura, T.; Shirokawa, S.-i.; Hosokawa,
S.; Nakazaki, A.; Kobayashi, S. Org. Lett. 2006, 8, 677–679. (c) Hosokawa,
S.; Yokota, K.; Imamura, K.; Suzuki, Y.; Kawarasaki, M.; Tatsuta, K.
Tetrahedron Lett. 2006, 47, 5415–5418. (d) Hosokawa, S; Kuroda, S;
Imamura, K.; Tatsuta, K. Tetrahedron Lett. 2006, 47, 6183–6186. (e) Xin
Jiang, X.; Liu, B.; Lebreton, S.; De Brabander, J. K. J. Am. Chem. Soc.
2007, 129, 6386–6387. (f) Nicolaou, K. C.; Guduru, R.; Sun, Y.-P.; Banerji,
B.; Chen, D. Y.-K. Angew. Chem., Int. Ed. 2007, 46, 5896–5900. (g)
Shirokawa, S.-i.; Shinoyama, M.; Ooi, I.; Hosokawa, S.; Nakazaki, A.;
Kobayashi, S. Org. Lett. 2007, 9, 849–852. (h) Nicolaou, K. C.; Sun, Y.-
P.; Guduru, R.; Banerji, B.; Chen, D. Y.-K. J. Am. Chem. Soc. 2008, 130,
3633–3644. (i) Schmauder, A.; Mu¨ller, S.; Maier, M. E. Tetrahedron 2008,
64, 6263–6269. (j) Hosokawa, S.; Yokota, K.; Imamura, K.; Suzuki, Y.;
Kawarasaki, M.; Tatsuta, K. Chem. Asian J. 2008, 3, 1415–1421. For
reviews, see: (k) Tatsuta, K.; Hosokawa, S. Chem. ReV. 2005, 105, 4707–
4729. (l) Tatsuta, K.; Hosokawa, S. Chem. Rec. 2006, 6, 217–233. (m)
Hosokawa, S.; Tatsuta, K. Mini-ReV. Org. Chem. 2008, 5, 1–18.
Scheme 3. Determination of the Stereochemistry of 3f
With these observations in hand, our attention was turned
to the VMAR of 1 with chiral nonracemic aldehydes (Table
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Org. Lett., Vol. 11, No. 6, 2009

Scheme 4
.
Determination of the Stereochemistry of 3g and 3h
Scheme 5. Determination of the Stereochemistry of 3j
syn-selective VMAR affording 3l was achieved using TIPS
surrogate 2l as a hindered substrate (entry 4), and its
enantiomer 2m led us to the corresponding syn-aldol adducts
3m in good yield (entry 5).
Stereochemical determination of the aldol adducts was
performed by comparison of the 1H NMR spectra with those
of known compounds (Schemes 5 and 6).8,9
2). It is anticipated that matched or mismatched cases of 1
should be observed. However, the VMAR of 1 with each
enantiomer of aldehydes provided a high level of diastereo-
selectivity (entries 1 vs 2 and entries 4 vs 5); thus, the VMAR
of these aldehydes resulted in the exclusive formation of the
corresponding 4S-aldol adducts independent of the config-
uration at the R-chiral center of aldehydes in each case. It
suggested that highly reagent-controlled diastereoselective
VMAR was established. The VMAR of 1 with (S)-aldehyde
2i, a previously reported system toward the synthesis of
khafurefungin,3g afforded the corresponding anti-adduct in
excellent yield with high diastereoselectivity (entry 1). In
addition, the related reaction with (R)-aldehyde 2j provided
the same level of yield and anti-selectivity (entry 2). The
stereochemical changeover was observed in the VMAR with
R-oxygenated aldehydes (entries 3-5). We examined the
reaction with benzyl-protected lactaldehyde 2k, which
unfortunately resulted in poor stereoselectivity, but the syn
product was predominant (entry 3).7 The low level of
diastereoselectivity using an aldehyde containing a chelatable
heteroatom suggests that the highly stereocontrolled VMAR
is not mediated through chelation. In contrast, high level of
Scheme 6. Determination of the Stereochemistry of 3l and 3m
We next demonstrated the VMAR of 1 with racemic
R-monochlorinated aldehyde 2n to investigate the possibility
of kinetic resolution (Scheme 7). Exposure of 2 equiv of
Scheme 7
.
Demonstrated VMAR of 1 with Racemic Chlorinated
Aldehyde 2n
Table 2. VMAR of 1 with Chiral Nonracemic Aldehydes
racemic 2n to 1 equiv of TiCl4 and 1 gave the corresponding
aldol adduct 3n in 76% yield as a mixture of epimers at C5
(anti:syn ) 1:6.8). Our result suggested that the syn-aldol
adduct was mainly obtained through the VMAR, as previ-
ously observed, and that perfect kinetic resolution was
achieved.
(4) Ohtani, I.; Kusumi, T.; Kashman, Y.; Kakisawa, H. J. Am. Chem.
Soc. 1991, 113, 4092–4096
.
(5) (a) Mori, K.; Nomi, H.; Chuman, T.; Kohno, M.; Kato, K.; Noguchi,
M. Tetrahedron 1982, 38, 3705–3711. (b) Nicolaou, K. C.; Papahatjis, D. P.;
Claremon, D. A.; Magolda, R. L.; Dolle, R. E. J. Org. Chem. 1985, 50,
1440–1456
.
(6) Dandapani, S.; Jeske, M.; Curran, D. P. J. Org. Chem. 2005, 70,
9447–9462
.
(7) The VMAR of ent-1 with 2k was found to provide the corresponding
aldol adduct in 81% yield with moderate diastereoselectivity (anti:syn )
1:4.2).
a Diastereomeric ratio was determined by 1H NMR analysis. b Reaction
was performed at -78 to -30 °C.
(8) Wakabayashi, T.; Mori, K.; Kobayashi, S. J. Am. Chem. Soc. 2001,
123, 1372–1375
.
(9) Terada, M. Ph.D. Thesis, Tokyo Institute of Technology, 1993
.
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Scheme 8
.
Structural Determination of the C4-C5 Relationship
of the Aldol Adduct 3n
Scheme 9
.
Structural Determination of the C5-C6 Relationship
of the Aldol Adduct 3n
In summary, we have demonstrated the VMAR of chiral
ketene silyl N,O-acetal 1 with a variety of aldehydes. The
most striking feature is a remarkable switch to syn-stereo-
selectivity using R-heteroatom-substituted aldehyde. To the
best of our knowledge, there has been no precedent for this
kind of stereochemical switch. Further investigation of the
details of the switch as well as extension of this finding is
in progress.
The stereochemical assignment is shown in Schemes 8
and 9. Thus, the inseparable mixture (anti:syn ) 1:6.8) was
first reduced with DIBAL to obtain the syn-9 and anti-9 in
87% and 10% yields, respectively. The C4-C5 relationships
of each isomer were established by correlating to the
corresponding 1,3-dioxane derivative, syn-10 or anti-10
(Scheme 8). The C5-C6 relationship of 3n was established
by converting the mixture (anti:syn ) 1:1.5) into the
corresponding epoxides cis-11 and trans-11 (Scheme 9).
These results imply that only (S)-aldehyde 2n underwent
VMAR with 1. The relatively low level of facial selection
might be attributed to the comparatively weak electronegative
character of monochlorinated aldehyde 2n.
Acknowledgment. This research was supported in part
by a Grant-in-Aid for Scientific Research (B) (KAKENHI
No.18390010) from the Japan Society for the Promotion of
Science. We are grateful to Kureha Corporation for the gift
of chloroacetaldehyde trimer.
Supporting Information Available: Detailed experimen-
tal procedure and characterization data for compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
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