Scheme 2. Acetate Aldol and Epoxide Synthesis
Table 2. Aldol Reactions with Representative Aldehydes
major
entry
aldehyde
iBuCHO
iBuCHO
BuCHO
BuCHO
PrCHO
PrCHO
PhCHO
product yielda anti (6):syn (7)b
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
6b
6b
6c
6c
6d
6d
6e
6e
7e
7f
88c
90d
68c
70d
79c
60d
62c
47d
64
99:1
99:1
96:4
96:4
96:4
97:3
96:4
96:4
10:90
1:99
4:96
26:74
1:99
99:1
5:95
PhCHO
PhCHO
BnOCH2CHO
BnO(CH2)2CHO
BnO(CH2)3CHO
(R)-BnOCH-(Me)CHO
(S)-BnOCH-(Me)CHO
(()-BnOCH-(Me)CHO
86
7g
7h
7i
79
82e
94
6j
7i
82
95e
a Isolated yield of pure diastereomer. b Ratio determined by 1H NMR
before chromatography. c CH3CN (2.2 equiv) was used as an additive.
d NMP (2.2 equiv) was used as an additive. e Isolated yield of diastereomeric
mixtures.
excellent anti diastereoselectivities, reaction yields are far
from satisfactory. Also, systematic attempts to improve
reaction yields have been unsuccessful thus far.
The scope and utility of chloroacetate aldol reactions in
the presence of CH3CN or NMP as additive were then
investigated with a range of representative monodentate and
bidentate aldehydes. The results are shown in Table 2. As it
turned out, the chloroacetate aldol reactions with monodenate
aliphatic aldehydes proceeded with excellent anti selectivities
and good to excellent yields (entries 1-6). Interestingly,
reaction with benzaldehyde, in the presence of either CH3-
CN or NMP as an additive showed good anti diastereo-
selectivity (entries 7 and 8). However, the corresponding
reaction in the absence of additive displayed syn diastereo-
facial selectivity (entry 9). Consistent with our previous
observation with propionate aldol reactions, bidentate oxy-
aldehydes such as benzyloxy acetaldehyde and benzyloxy-
propionaldehyde exhibited excellent syn diastereoselectivities
and yields (entries 10 and 11) without any additive. Reaction
of benzyloxyacetaldehyde in the presence of 2 equiv of CH3-
CN as an additive provided no change in syn diastereo-
selectivity, but the aldol product was obtained in only 37%
yield.
14). On the basis of these results, we performed kinetic
resolution experiments with racemic 2-benzyloxypropion-
aldehyde. The aldol reaction was carried out with 2 equiv
of racemic aldehyde for 30 min to provide a 95:5 syn
diastereomeric ratio in 95% yield (entry 15). Formation of
major syn diastereomer 7i resulted from preferential reaction
with matched 2(R)-benzyloxypropionaldehyde. Recovered
2(S)-benzyloxypropionaldehyde showed 98.7% enantiomeric
excess and 40% recovered yield.8
The relative stereochemistry of aldol products was assigned
on the basis of comparison of observed vicinal coupling
constants of the major aldol products (J2,3 ) 6-10 Hz for
anti-aldols and J2,3 ) 3-4 Hz for syn-aldols) with the
corresponding propionate aldol products.10 Further confirma-
tion of the relative stereochemistry of anti-aldols 6b-j and
syn-aldols 7e-i was established by their conversion to the
corresponding isopropylidene derivatives (9 and 11) and
comparison of coupling constants with the literature values
as described by us previously.6 For synthesis of isopropyli-
dene derivatives, aldolates were treated with LiBH4 in a
mixture of THF and methanol at 23 °C to provide chloro-
hydrins 8 and 10. Exposure of chlorohydrins 8 and 10 to
Furthermore, we have investigated double asymmetric
induction employing 2(R)- and 2(S)-benzyloxypropionalde-
hyde. In the matched case, aldol reaction with 2(R)-
benyloxypropionaldehyde provided only a single syn dia-
stereomer 7i in excellent yield (entry 13). However, for the
mismatched case, aldol reaction with 2(S)-benzyloxypropion-
aldehyde exclusively afforded an anti-aldol adduct 6j (entry
(8) Enantiomeric excess was calculated from comparison of the observed
optical rotation value with the reported value ([R]D20 -51.5 (c 0.89, CHCl3);
20
(7) For previous investigations with PPh3, NMP, and THF as additives,
see: (a) Gennari, C.; Colombo, L.; Bertolini, G.; Schimperna G. J. Org.
Chem. 1987, 52, 2754. (b) Palazzi, C.; Colombo, L.; Gennari, C.
Tetrahedron Lett. 1986, 27, 1735. (c) Crimmins, M. T.; King, B. W.; Tabet,
E. A.; Chaudhary, K. J. Org. Chem. 2001, 66, 894. (d) Shirokar, S.; Nerz-
Stormes, M.; Thorntorn, E. R. Tetrahedron Lett. 1990, 31, 4699.
lit.9 [R]D -52.2 (c 6.5, CHCl3)).
(9) Takai, K.; Heathcock, C. H. J. Org. Chem. 1985, 50, 3247.
(10) (a) Yan, T.-H.; Tan, C.-W.; Lee, H.-C.; Lo, H.-C.; Huang, T.-Y. J.
Am. Chem. Soc. 1993, 115, 2613. (b) Heathcock, C. H.; Buse, C. T.;
Kleschick, W. A.; Pirrung, M. C.; John, J. E.; Lampe, J. J. Org. Chem.
1980, 45, 1066.
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