aldehyde. The synthetic utility of this method is demonstrated
by extension to a two-step synthesis of carbohydrates,
directly subjecting the resulting chiral â-hydroxy aldehyde
to a second diastereoselective aldol reaction. Second, Evans
reported a Ni(II)-bis(oxazoline)-catalyzed enantioselective
syn aldol reaction using N-propionylthiazolidinethiones as
the donor.6 Chemoselective deprotonation of the donor is
possible through chelate coordination to the cationic Ni.
Although the reaction proceeds via in situ-generated nickel
enolate, stoichiometric amounts of TMSOTf and 2,6-lutidine
are necessary for dissociation of the intermediate aldolate
from the catalyst. Third, Shair reported a Cu(II)-bis-
(oxazoline)-catalyzed enantioselective syn aldol reaction
using a malonic acid half ester as the donor.7 Higher acidity
of the donor than the acceptor aldehydes and irreversible
CO2 emission after aldol-type addition are key to the success
of the cross-aldol reaction under mild conditions. Indeed,
protic functional groups are tolerated in Shair’s reaction.
Although excellent enantioselectivity and chemical yields are
obtained in these three reactions, even from enolizable
aldehydes, all of these examples utilize R-substituted car-
bonyl compounds (such as propionaldehyde or propionate
derivatives) as donors. In contrast, there is no catalytic
enantioselective direct aldol-type reaction of simple acetate
analogues that is applicable to enolizable aldehydes.
a possible complex 2. Once the nitrile aldol reaction proceeds
(from 3 to 1), the intermediate soft metal aldolate 1 again
works as a chiral Bro¨nsted base catalyst for the second cycle.
On the basis of these considerations, we reported preliminary
examples of the catalytic enantioselective direct nitrile aldol
reaction; using CuOtBu10-DTBM-SEGPHOS complex as
a catalyst, nitrile aldol product was produced with up to 53%
ee from aldehydes without enolizable protons. When easily
enolizable linear aldehydes were used, however, chemo-
selective deprotonation of alkylnitriles was difficult and
aldehyde self-condensation was a serious side reaction. In
this communication, we report improved reaction conditions
applicable to linear aldehydes, giving products with up to
77% ee. Specifically, this is the first catalytic enantioselective
direct aldol-type reaction of an acetic acid surrogate that
demonstrates significant enantioselectivity from easily eno-
lizable linear aldehydes.
Basic reaction conditions were first optimized using
heptanal (4a) as an acceptor, acetonitrile as a donor, and
CuOtBu-achiral phosphine ligand complex as a catalyst
(Table 1, entries 1-5). When previously optimized reaction
Table 1. Optimization of Direct Catalytic Nitrile Aldol
Reaction to Linear Aldehyde
Our approach for developing a direct catalytic enantio-
selective aldol-type reaction of carboxylic acid analogues is
to use a chiral soft metal alkoxide as a catalytic Bro¨nsted
base and alkylnitriles as the donor (Scheme 1).8,9 Due to the
entry
ligand
solvent
yield % (ee %)
1b
2
3
4
5
6
7
8
9
dppe
dppe
dppe
Ph3P
(Me2N)3P
(S)-tol-BINAP
(R,R)-Ph-BPE
(R,S)-Josiphos
(R)-SEGPHOS
DMSO
DMSO
HMPA
HMPA
HMPA
HMPA
HMPA
HMPA
HMPA
HMPA
HMPA
DMPU
12 (-)
33 (-)
79 (-)
23 (-)
9 (-)
21 (16)
32 (0)
18 (6)
18 (8)
84 (58)
72 (74)
60 (71)
Scheme 1. General Concept of Direct Enantioselective Nitrile
Aldol Reaction Catalyzed by Soft Metal Alkoxide
10
11c
12c
(R)-DTBM-SEGPHOS
(R)-DTBM-SEGPHOS
(R)-DTBM-SEGPHOS
a Aldehyde was added slowly over 2.5 h using a syringe pump unless
otherwise noted. Reaction time ) 2.7 h (including the slow addition time).
b Aldehyde was added in one portion. Reaction time ) 30 min. c Reaction
was conducted at room temperature. The aldehyde was added slowly over
5 h with a syringe pump. Reaction time ) 5.2 h.
strong coordination ability of nitriles to soft metals, alkyl-
nitriles are selectively activated and deprotonated by a soft
metal alkoxide to generate the active nucleophile 3 through
conditions8 were applied to 4a at 50 °C (entry 1), the nitrile
aldol product was obtained in only 12% yield. The main
reaction pathway was self-condensation of the aldehyde.
Even with slow addition of 4a to a mixture of the catalyst
(4) (a) Northrup, A. B.; MacMillan, D. W. C. J. Am. Chem. Soc. 2002,
124, 6798-6799. (b) Northrup, A. B.; Mangion, I. K.; Hettche, F.;
MacMillan, D. W. C. Angew. Chem., Int. Ed. 2004, 43, 2152-2154. (c)
Northrup, A. B.; MacMillan, D. W. C. Science 2004, 305, 1752-1755.
(5) For other examples of direct catalytic enantioselective aldol reactions
using aldehydes as donors, see: (a) Bøgevig, A.; Kumaragurubaran, N.;
Jørgensen, K. A. Chem. Commun. 2002, 620-621. (b) Mase, N.; Tanaka,
F.; Barbas, C. F., III. Angew. Chem., Int. Ed. 2004, 43, 2420-2423. (c)
Alcaide, B.; Almendros, P. Angew. Chem., Int. Ed. 2003, 42, 858-860.
(6) Enans, D. A.; Downey, C. W.; Hubbs, J. L. J. Am. Chem. Soc. 2003,
125, 8706-8707.
(7) Magdziak, D.; Lalic, G.; Lee, H. M.; Fortner, K. C.; Aloise, A. D.;
Shair, M. D. J. Am. Chem. Soc. 2005, 127, 7284-7285.
(8) Suto, Y.; Kumagai, N.; Matsunaga, S.; Kanai, M.; Shibasaki, M. Org.
Lett. 2003, 5, 3147-3150.
(9) For catalytic nitrile aldol reaction without enantiocontrol, see: (a)
Kisanga, P.; McLeod, D.; D’Sa, B.; Verkade, J. J. Org. Chem. 1999, 64,
3090-3094. (b) Kumagai, N.; Matsunaga, S.; Shibasaki, M. J. Am. Chem.
Soc. 2004, 126, 13632-13633. (c) Kumagai, N.; Matsunaga, S.; Shibasaki,
M. Chem. Commun. 2005, 3600-3602.
3758
Org. Lett., Vol. 7, No. 17, 2005