substituted R-amino acid derivatives using catalytic amounts
of L-proline.3a Because of the aldehyde functionality present
in the product, the excellent diastereo- and enantioselectivities
of the reaction, and the mild reaction conditions provided
by L-proline catalysis,4 the products should be useful for the
further transformations such as nucleophilic reactions on the
aldehyde carbonyl to form another carbon-carbon bond
without workup/purification. Here we examine the potential
of this reaction for further one-pot transformations. We chose
a cyanation reaction with Et2AlCN5 for the second step in
the one-pot sequence. Proline-catalyzed Mannich-type reac-
tions followed by cyanation of the first product aldehyde
would provide â-cyanohydroxymethyl R-amino acid deriva-
tives. Cyanohydrins are versatile functional groups in organic
synthesis6 and can be easily transformed to R-hydroxy acid
derivatives,7 R-hydroxy aldehydes,8 â-hydroxy amines,9 and
amino acid derivatives.10 Therefore, the one-pot Mannich-
cyanation reaction products could be transformed into a wide
variety of amino acid derivatives. To the best of our
knowledge, our strategy is the first to provide access to chiral
amino acid derivatives bearing a cyanohydroxymethyl group
at the â position.
product (entry 3) with 2a (<5%). When dioxane was used
as solvent, the reaction also provided 2a as the main product
at rt (entry 4) and a mixture of 1a and 2a at 0 °C (data not
shown). The formation of either 1a or 2a was dependent on
the temperature of the cyanation step and was controlled by
changing the temperature.
To broaden the scope of this methodology, we demon-
strated it efficacy in reactions using a variety of aldehydes
(Tables 2 and 3). The reactions involving cyanation at -78
Table 2. One-Pot Mannich-Cyanation Reactions to Form 1a
entry
R
product
yieldb (%)
eec (%)
1d
2
3
4
5
i-Pr
n-Bu
n-Pent
n-Hex
PhCH2
1b
1c
1d
1e
1f
40
60
68
65
62
94
93
98
98
>99
First, we examined reaction conditions for the cyanation
step in this one-pot sequence (Table 1). When the Mannich-
6
1g
42
>99
7d
1h
40
>99
Table 1. Reaction Conditions Effect One-Pot
Mannich-Cyanation Reactions To Provide Either 1a or 2aa
a A mixture of of N-PMP-protected R-imino ethyl glyoxylate (0.5 mmol),
aldehyde (1.0 mmol), and L-proline (0.15 mmol) in THF (5 mL) was stirred
at room temperature for 16-20 h, and the reaction mixture was cooled to
-78 °C followed by the addition of Et2AlCN (1 M in toluene, 2.0 mmol
except as noted). The mixture was stirred at the same temperature for 3 h.
Typical workup with saturated NaHCO3, extraction with ethyl acetate, and
silica gel column purification afforded 1. b Isolated yield after column
chromatography. c Enantioselectivities were determined by chiral-phase
HPLC analysis. d Et2AlCN (3.0 mmol) was used.
entry solvent
tempb
-78 °C
-78 °C to rt 5 h
timeb product yieldc (%) eed (%)
1
2
3
4
THF
THF
THF
dioxane
3 h
1a
2a
1a
2a
61
60
40
40
93
97
e
°C afforded cyanohydrin 1 (Table 2) and at increased
temperature afforded lactone 2 (Table 3). The yield of either
1 or 2 ranged between 40% and 68%. Excellent enantio-
selectivities were observed in the case of aldehydes with a
longer chain length (R g n-pentyl) for the formation of 1.
High enantioselectivities were also observed in the formation
of lactone 2. A single diastereomer was isolated in all cases,
-40 °C
3 h
rt
18 h
e
a PMP ) p-methoxyphenyl. A mixture of of N-PMP-protected R-imino
ethyl glyoxylate (0.5 mmol), valeraldehyde (1.0 mmol), and L-proline (0.15
mmol) in THF or dioxane (5 mL) as indicated was stirred at room
temperature for 16-20 h, and Et2AlCN (1 M in toluene, 2 mmol) was added
into the reaction mixture at the temperature shown in this table. b Conditions
for the cyanation step. c Isolated yield after column chomatography.
d Enantioselectivities were determined by chiral-phase HPLC analysis. e Not
determined.
(4) Recent studies in proline catalysis: Bui, T.; Barbas, C. F., III.
Tetrahedron Lett. 2000, 41, 6951. List, B.; Lerner, R. A.; Barbas, C. F.,
III. J. Am. Chem. Soc. 2000, 122, 2395. Betancort, J. M.; Sakthivel, K.;
Thayumanavan, R.; Barbas, C. F., III. Tetrahedron Lett. 2001, 42, 4441.
Notz, W.; Sakthivel, K.; Bui, T.; Zhong, G.; Barbas, C. F., III. Tetrahedron
Lett. 2001, 42, 199. Sakthivel, K.; Notz, W.; Bui, T.; Barbas, C. F., III. J.
Am. Chem. Soc. 2001, 123, 5260. Betancort, J. M.; Barbas, C. F., III. Org.
Lett. 2001, 3, 3737. Co´rdova, A.; Notz, W.; Barbas, C. F., III. J. Org. Chem.
2002, 67, 301. Thayumanavan, R.; Dhevalapally, B.; Sakthival, K.; Tanaka,
F.; Barbas, C. F., III. Tetrahedron Lett. 2002, 43, 3817. Ramachary, D. B.;
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T.; Martin, H. J. J. Am. Chem. Soc. 2002, 124, 827. MacMillan, D. W. C.;
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Synlett 2002, 26. Bogevig, A.; Kumaragurubaran, N.; Jorgensen, K. A.
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type reaction was performed using valeraldehyde in THF at
room temperature according to our procedure3a and the
reaction mixture was cooled to -78 °C followed by the
addition of Et2AlCN, â-cyanohydroxymethyl R-amino acid
derivative 1a was obtained as a single diastereomer with good
yield and high enantioselectivity (61% for two steps, 93%
ee) (entry 1) after purification. To complete the reaction, 4
equiv or more of Et2AlCN was required. Increasing the
temperature (-78 °C to rt) of the cyanation step afforded
lactone 2a (60%, 97% ee) (entry 2) with no trace of 1a. The
cyanation at -40 °C also afforded 1a (40%) as the main
4520
Org. Lett., Vol. 4, No. 25, 2002