1,3-Rearrangement of ketene-N,O-acetals

Article abstract of DOI:10.1016/S0040-4039(03)00610-5

Ketene N,O-acetals were prepared stereoselectively and submitted to a Lewis acid-mediated 1,3-rearrangement to afford C-alkylated products. The reactions proceeded in a stereoselective manner to construct a chiral quaternary carbon in high selectivity. The stereochemistry of the quaternary center was found to be opposite to that obtained by an anionic direct dienolate alkylation.

Full text of DOI:10.1016/S0040-4039(03)00610-5

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 3713–3716
1,3-Rearrangement of ketene-N,O-acetals
Tatsuo Suzuki,a Masaharu Inui,a Seijiro Hosokawaa and Susumu Kobayashia,b,
*
aFaculty of Pharmaceutical Sciences, Tokyo University of Science, Ichigaya-Funagawara-machi, Shinjuku-ku, Tokyo 162-0826,
Japan
bFrontier Research Center for Genomic Drug Discovery, Tokyo University of Science, Noda, Chiba 278-8510, Japan
Received 5 February 2003; revised 28 February 2003; accepted 28 February 2003
Abstract—Ketene N,O-acetals were prepared stereoselectively and submitted to a Lewis acid-mediated 1,3-rearrangement to
afford C-alkylated products. The reactions proceeded in a stereoselective manner to construct a chiral quaternary carbon in high
selectivity. The stereochemistry of the quaternary center was found to be opposite to that obtained by an anionic direct dienolate
alkylation. © 2003 Elsevier Science Ltd. All rights reserved.
Evans alkylation is an excellent method to construct a
chiral tertiary carbon and has been widely utilized in
the synthesis of a number of natural products.1,2 How-
ever, there had been no example of stereochemical
control of a chiral quaternary carbon by Evans alkyla-
tion using Li- or NaHMDS and alkyl halide. During
the course of our total synthesis of madindoline A, we
developed a novel method for the stereoselective con-
struction of a chiral quaternary carbon via a chiral
dienolate 2 (Eq. (1)).3 Thus, the g-proton of a,b-unsatu-
rated imide 1 was deprotonated with NaHMDS, and
the resulting dienolate anion 2 was reacted with benzyl-
oxymethyl chloride at the a-position with high regio-
and stereoselectivities.
In this reaction, one of the by-products proved to be a
ketene-N,O-acetal 4 which was isolated in 30% yield as
a single isomer by O-alkylation of the dienolate anion
2. The same ketene-N,O-acetal 4 was exclusively
obtained in 92% yield by addition of HMPA (Table 1).
The competing O-alkylation in Evans’ chiral auxiliary
methodology had seldom been observed,4 and there has
been no report concerning such a highly stereoselective
and high-yielding O-alkylation.
With ketene N,O-acetal 4 in quantity, we became inter-
ested in the possibility of a rearrangement of ketene-
N,O-acetal 4 to a-alkylated imide 3 (Scheme 1). We
expected that a Lewis acid might coordinate to the
Table 1. Construction of ketene-N,O-acetal
(1)
Entry
Additive
Yield of 3 (dr)a
Yield of 4 (%)
1
2
–
65% (11:1)
Trace
30
92
HMPA
a dr=diastereomeric ratio. The ratio was determined by NMR.
* Corresponding author.
0040-4039/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)00610-5

3714
T. Suzuki et al. / Tetrahedron Letters 44 (2003) 3713–3716
Scheme 1. Expected 1,3-rearrangement of ketene N,O-acetal.
selectivity. Relatively low to moderate yields were due
acetal oxygen close to the oxazolidone because the
carbonyl oxygen would initially coordinate to the Lewis
acid, and that cleavage of the CꢀO bond might occur to
generate a metal enolate and an oxonium cation spe-
cies. The resulting ion pair 5 might undergo a recombi-
nation at the a-position to afford the alkylated imide 3.
Since such a metal enolate would form a tight six-mem-
bered chelation structure, diastereoselectivity of a rear-
rangement was expected to be higher than that of a
direct alkylation of Na dienolate 2. To our knowledge,
such a Lewis acid-promoted 1,3-rearrangement of
ketene N,O-acetal is not yet known.5
to the formation of g-alkylated products (18ꢀ37%).8
On the basis of these results, various ketene N,O-
acetals were prepared and were treated with methylalu-
minum dichloride in toluene at −78°C. As shown in
Table 4, yields of rearranged products were higher with
alkyl substituted dienolate 4 and 7 than that of exo-
dienolate 8. The oxazolidine-2-ones derived from
isoleucine gave comparable to better results than
-valine derivatives.
L-
L
It is quite interesting to find that the opposite stereo-
chemical course was observed by carrying out the reac-
tion under acidic or basic conditions. Although we do
not have any supporting evidence at present, we would
like to propose the following mechanism (Scheme 2).
Stereoselective formation of 6 might be explained by
considering the intermediate ion pair 12 where the
oxazolidone carbonyl oxygen coordinates to the other
molecule of methylaluminum dichloride as depicted in
Figure 1. The oxonium cation might recombine from
When 4 was treated with methylaluminum dichloride6
in CH2Cl2 at −78°C, rearrangement product 6 was
isolated in 28% with diastereoselectivity of 14:1 (Table
1
2). Surprisingly, the H NMR spectrum of the major
isomer was found to be identical to that of the minor
isomer obtained by the anionic dienolate reaction
(Table 3).7 Table 2 summarizes a solvent effect of the
MeAlCl2-mediated rearrangement, and toluene was
found to be the most effective in terms of yield and
Table 2. 1,3-Arrangement of ketene N,O-acetal
Table 4. 1,3-Rearrangement of ketene N,O-acetal
Entry
Solvent
Yield (dr)a
1
2
3
4
Hexane
CH2Cl2
ClCH2CH2Cl
Toluene
27% (3:1)
28% (14:1)
37% (13:1)
54% (\99:1)
a dr=diastereomeric ratio. The diastereo ratio was determined by 1H
NMR.6
Table 3. Comparison of 3 and 6
3
6
Optical rotation [h]2D6 +43.7
[h]2D3 +72.9
Entry
Substrate
Product
Yield (dr)
(c 1.03, CHCl3)
(c 1.03, CHCl3)
1
2
3
4
5
6
8V
8I
7V
7I
4V
4I
10
9
32% (20:1)
36% (20:1)
67% (33:1)
57% (42:1)
54% (\99:1)
55% (\99:1)
1H NMR (l)
Me 1.49 (s, 3H)
BnOCH2 3.46 (d,
1H, J=8.8 Hz)
4.29 (d, 1H, J=8.8
Hz)
Me 1.54 (s, 3H)
BnOCH2 3.44 (d, 1H,
J=8.8 Hz)
6
4.07 (d, 1H, J=8.8 Hz)

T. Suzuki et al. / Tetrahedron Letters 44 (2003) 3713–3716
3715
center by the choice of direct a-alkylation or stepwise
alkylation via ketene N,O-acetal.
In a similar manner, the alkylation of a,a-disubstituted
imide 14 was also examined. Under Evans alkylation
conditions, the C-alkylation product 15 was obtained in
very low yield (Table 5, entry 1). Addition of HMPA
afforded O-alkylation product 16 exclusively (entry 2),
and the resulting ketene N,O-acetal was submitted to
1,3-rearrangement to provide C-alkylation product 15
in good yield (Eq. (2)). Although the quaternary center
of 15 is not chiral, Eq. (2) suggests the utility of the
two-step transformation for construction of a quater-
nary carbon.
Scheme 2. Proposed mechanism.
The reaction conditions presented here were not yet
fully optimized, and studies on the scope and limitation
of the rearrangement are now in progress.
The general experimental procedure (Table 4, entry 5)
is as follows: To a solution of ketene-N,O-acetal 4V
(114 mg, 0.29 mmol) in toluene was dropwise added a
solution of MeAlCl2 in hexane (1.0 M, 0.59 ml, 0.59
mmol) at −78°C under an Ar atmosphere. After stirring
for 1 day at the same temperature, the reaction mixture
was quenched by addition of pyridine and then satu-
rated NaHCO3 aq. The resulting mixture was extracted
with chloroform, and the organic layer was washed
with brine and dried over Na2SO4. Evaporation and
concentration gave a crude oil which was purified by
silica gel column chromatography (hexane–AcOEt=
10:1) to afford colorless oil 6 (61.6 mg, 54%).
Figure 1.
the upper face (opposite to the isopropyl group) afford-
ing 6. The transition state 13 of the direct alkylation of
sodium dienolate 2 is also shown in Figure 1. These
transition states, 12 and 13, would explain the opposite
stereochemical course of the reactions.
Acknowledgements
This work was supported in part by the Fujisawa
Foundation (S.H.) and Grant-in-Aids for Scientific
Research from the Ministry of Education, Culture,
Sports, and, Science and Technology, Japan.
Although the present methodology is limited to the
rearrangement of an alkoxymethyl group, we were able
to control the stereochemistry of a chiral quaternary
Table 5. Alkylation of a,a-disubstituted imide
Entry
Additive
Temperature (°C)
15 (%)
16 (%)
1
2
–
−78ꢀ0
−78
9
43
70
HMPA
Trace
(2)

3716
T. Suzuki et al. / Tetrahedron Letters 44 (2003) 3713–3716
N,O-acetal: (a) Huche, M. Tetrahedron Lett. 1976, 17,
References
2607–2610; (b) Corbier, J.; Cresson, P.; Jelenc, P. C. R.
Acad. Sci., Ser. C 1970, 270, 1890–1893.
6. Other Lewis acids such as BF3·OEt2, Et2AlCl, TiCl4, or
AlCl3 were not successful.
1. Evans, D. A.; Ennis, M. D.; Mathre, D. J. J. Am. Chem.
Soc. 1982, 104, 1737–1738.
2. For examples: (a) Evans, D. A.; Bebder, S. L.; Morris, J.
J. Am. Chem. Soc. 1988, 110, 2506–2526; (b) Jones, T. K.;
Reamer, R. A.; Desmond, R.; Mills, S. G. J. Am. Chem.
Soc. 1990, 112, 2998–3017; (c) Evans, D. A.; Bebder, S. L.;
Polniaszek, R. P.; DeVries, K. M.; Guinn, D. E.; Mathre,
D. J. J. Am. Chem. Soc. 1991, 113, 7613–7630; (d)
Yokoshima, S.; Ueda, T.; Kobayashi, S.; Sato, A.;
Kuboyama, T.; Tokuyama, H.; Fukuyama, T. J. Am.
Chem. Soc. 2002, 124, 2137–2139; (e) Paquett, L. A.;
Duan, M.; Konetzki, I.; Kempmann, C. J. Am. Chem. Soc.
2002, 124, 4257–4270.
3. (a) Hosokawa, S.; Sekiguchi, K.; Enemoto, M.;
Kobayashi, S. Tetrahedron Lett. 2000, 41, 6429–6433; (b)
Hosokawa, S.; Sekiguchi, K.; Hayase, K.; Hirukawa, Y.;
Kobayashi, S. Tetrahedron Lett. 2000, 41, 6435–6439; (c)
Hosokawa, S.; Kobayashi, S. J. Synth. Org. Chem. Jpn.
2001, 59, 1103–1108.
7. 3: [h]2D6 +43.7° (c 1.03, CHCl3); 1H NMR (400 MHz,
CDCl3) l 0.80 (d, 3H, J=7.1 Hz), 0.86 (t, 3H, J=7.1 Hz),
0.87 (d, 3H, J=7.1 Hz), 1.24–1.34 (m, 4H), 1.49 (s, 3H),
1.99 (q, 2H, J=6.8 Hz), 2.32 (m, 1H), 3.46 (d, 1H, J=8.8
Hz), 4.15 (dd, 1H, J=2.9, 9.0 Hz), 4.21 (t, 1H, J=9.0 Hz),
4.29 (d, 1H, J=8.8 Hz), 4.47 (d, 1H, J=12.2 Hz), 4.50
(dd, 1H, J=2.9, 3.7 Hz), 4.58 (d, 1H, J=12.2 Hz), 5.37
(td, 1H, J=6.8, 16.1 Hz), 5.75 (td, 1H, J=1.5, 16.1 Hz),
7.28–7.34 (m, 5H). 6: [h]2D3 +72.9° (c 1.03, CHCl3); 1H
NMR (400 MHz, CDCl3) l 0.84 (d, 3H, J=7.0 Hz), 0.86
(t, 3H, J=7.0 Hz), 0.88 (d, 3H, J=7.0 Hz), 1.22–1.32 (m,
4H), 1.54 (s, 3H), 2.00 (q, 2H, J=6.7 Hz), 2.28–2.38 (m,
1H), 3.44 (d, 1H, J=8.8 Hz), 4.07 (d, 1H, J=8.8 Hz), 4.13
(dd, 1H, J=3.4, 8.9 Hz), 4.16 (t, 1H, J=8.9 Hz), 4.45–4.49
(m, 1H), 4.52 (s, 2H), 5.38 (td, 1H, J=6.7, 15.9 Hz), 5.75
(d, 1H, J=15.9 Hz), 7.26–7.32 (m, 5H).
4. Braddock, D. C.; Brown, J. M. Tetrahedron: Asymmetry
2000, 11, 3591–3607.
5. For [3,3]-sigmatropic rearrangement of N-allyl-ketene-
8. Results concerning a g-alkylation will be reported in due
course.