C O M M U N I C A T I O N S
Table 3. Chiral Proton-Catalyzed Additions of R-Alkyl R-Nitroesters
to Azomethines: Reaction Scopea
system, and hindered aryl esters 6d-g work synergistically with
the catalyst to provide high diastereoselection; achiral catalysis
(Hu¨nig’s base) of the same addition proceeds with low diastereo-
selection (<2:1 dr). The diamine functionality is readily unmasked
as in eq 1. Further investigations of reaction scope and the reason
for the syn-diastereoselection here that is complementary to the
Shibasaki bis(nickel) catalyzed anti-additions are underway.15
Acknowledgment. We are grateful to Dr. Maren Pink (Indiana
University) for X-ray structure determination of 7d. This work was
supported through the generosity of the Eli Lilly Grantee program
and the Astellas USA Foundation. Exploratory studies were
completed through funds provided by the NSF (Grant CHE-
0415811).
a All reactions are 1 M in imine and use 1.1 equiv of the nitro ester
unless otherwise noted. Conversions of 82% and 71% for entries 1-2,
respectively, at 24 h (approximated by 1H NMR). b Diastereomer ratios
measured using 1H NMR. Enantiomer ratios measured using HPLC and a
chiral stationary phase. Yields are for isolated, analytically pure product.
c Reaction was 0.3 M in imine and was performed at -20 °C for entries 5,
12; -78 °C, 3.5 days reaction time for entry 7.
representative pronucleophile, a range of aromatic aldimines were
used to target ꢀ-amino phenyl alanine derivatives 7d/8. At the
higher concentration and lower temperature used in this series,
higher diastereoselection (20:1) and excellent enantioselection (98%
ee) were observed for 7d (83% yield, entry 1). This crystalline
product was used to assign relative and absolute stereochemistry
via single crystal X-ray diffraction. Interestingly, the syn-diaste-
reomer is favored in these additions, opposite to that normally
observed when using these catalysts with simple nitroalkanes13 or
R-nitro tert-butyl esters.10 A survey of additional electronically
neutral (entries 2, 6, 7) and rich aromatic aldimines (entries 3-9)
revealed generally high diastereoselection (8f20:1) and enanti-
oselection (94-98% ee). In one case, a sluggish reaction at -78
°C (entry 4) could be rectified by raising the reaction temperature
to -20 °C, resulting in a slight drop in diastereoselection (10:1f8:1
dr, entry 5). In another case (entry 6), extension of the reaction
time provided complete conversion and higher isolated yield (entry
7). The lowest diastereoselection (5:1 dr) was observed for the furyl
aldimine, but enantioselection remained high (94% ee, entry 9).
The catalyst tolerance to the nature of the R-alkyl group of the
nitroester is also good. The behavior of chlorophenyl imine 3d in
the series 6e, 6d, 6f, 6g (entries 10, 1, 11, 12) led to the derived
R,ꢀ-diamino esters with generally high diastereoselection (12-20:1
dr), enantioselection (97-99% ee), and isolated yield (>82%). The
reaction for hexanoate 6g was noticeably slower but could be
carried out at -20 °C (entry 12) to deliver the desired product
(16:1 dr, 97% ee) in good isolated yield (88%). We investigated
two N-Boc imines derived from aliphatic aldehydes, but these
imines decomposed under our standard reaction conditions.
The nitroester products could be easily reduced to the protected
syn-R,ꢀ-diamines by zinc reduction in aq HCl-EtOH at room
temperature (eq 1).7 The diastereo- and enantiomeric excess were
unchanged in the diamine products. The aryl ester could also be
saponified to provide the free R-amino acid in 77% yield (eq 2).14
In summary, a direct synthesis of R-substituted syn-R,ꢀ-diamino
acid derivatives of phenyl alanine has been developed. This required
the development of catalyzed additions of substituted R-nitroesters,
providing R-nitro-ꢀ-amino esters with high diastereo- and enan-
tioselection. Key to this development is the finding that methoxy
substitution in the catalyst leads to a more active bifunctional
Supporting Information Available: Experimental and charac-
terization data. This information is available free of charge via the
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