reactions of these aldehyde donors provide â-hydroxy-R-
amino aldehydes that can be easily transformed into â-hy-
droxy-R-amino acids.
Scheme 1. Direct Asymmetric Aldol Reactions of 1 to Afford
â-Hydroxy-R-amino Aldehydes 2 and the Conversion of 2 to
â-Hydroxy-R-amino Acid Esters 3
Although glycinate Schiff bases have been used as donors
in asymmetric aldol reactions for the synthesis of â-hydroxy-
R-amino acid ester derivatives,3c-e,h glycine aldehyde deriva-
tives have not been examined as donors in direct asymmetric
aldol reactions previously. Asymmetric organocatalysis with
L-proline and other small molecules has received renewed
attention because of its broad applicability, simplicity, and
efficiency.5-10 Reactions involved in organocatalysis are also
environmentally benign. We previously reported the use of
naked aldehyde donors in organocatalytic aldol,8a-d Man-
nich,9 and Michael10 reactions. Thus, the use of R-amino
aldehydes in these reactions should provide the corresponding
reaction products. Here we report simple and efficient, direct
asymmetric aldol reactions of the glycine aldehyde derivative
1 (Scheme 1).
First, we examined the aldol reaction of 1 with isobu-
tyraldehyde under various conditions (Table 1). A mixture
of aldehyde 1 (2 mmol), isobutyraldehyde (5 equiv with
respect to 1), and L-proline (30 mol % with respect to 1) in
DMSO (4 mL) was stirred at room temperature (rt) for 16 h
(entry 1). The desired aldol product 2a was obtained in 62%
yield with high diastereoselectivity (dr ) 10:1) and enantio-
selectivity (95% ee); side products were the dehydration
product of 2a and the self-aldol product of aldehyde 1. We
previously demonstrated that R,R-disubstituted aldehydes
were less reactive than R-monosubstituted aldehydes as
donors in the L-proline-catalyzed aldol reactions.8b In the
reaction of 1 and isobutyraldehyde, only 1 acted as the donor.
No formation of self-aldol product of isobutyraldehyde and
of R,R-dimethyl-â-hydroxy-γ-amino aldehyde was observed.
The reactions in DMF and in N-methylpyrrolidone (NMP)
also gave good results in terms of yield, dr, and ee (entries
2 and 3). The same reaction in NMP afforded a higher yield
(86%) of 2a than the reaction in DMSO primarily as a
consequence of suppression of side products formation.
Although a longer reaction time was required, the reaction
performed in NMP at 4 °C provided excellent diasterose-
lectivity (dr ) >100:1) and enantioselectivity (>99.5% ee)
(entry 4). When higher concentrations were used, a shorter
reaction time afforded the same yield with excellent diastero-
and enantioselectivities (entries 5 and 6). Aldehyde 2a could
be used without purification in additional transformations.
Oxidation of the crude aldol product 2a with NaClO2 and
then esterification afforded 3a (Scheme 1) in good yield with
high diastereo- and enantioselectivities (73% from 1, dr >
100:1, >99.5% ee) (entry 7). The reaction in the presence
of (S)-5-pyrrolidine-2-yl-1H-tetrazole6b,c,i,j (4) also afforded
2a in excellent yield with excellent diastereo- and enantio-
selectivities (entry 8), whereas reaction with another aldol
catalyst, (S)-(+)-1-(2-pyrrolidinylmethyl)pyrrolidine/(S)-(+)-
camphorsulfonic acid,8b,e gave 2a in low yield when the same
reaction time was used, albeit with >99% ee for anti-2a.
Slow addition of the donor aldehyde was not required to
obtain 2a in good yield when 5-10 equiv of the acceptor
aldehyde with respect to the donor aldehyde 1 was used in
the reaction with L-proline or 4; the formation of the self-
aldol product of aldehyde 1 was minimized. This result stands
in contrast to the aldol reactions of R-oxyaldehydes: aldol
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