Efficient conjugate reduction of α,β-unsaturated carbonyl compounds by complexation with aluminum tris(2,6-diphenylphenoxide)

Full text of DOI:10.1021/jo960161e

2928
J . Org. Chem. 1996, 61, 2928-2929
Ta ble 1. Red u ction w ith Va r iou s Kin d s of Red u cin g
Efficien t Con ju ga te Red u ction of
r,â-Un sa tu r a ted Ca r bon yl Com p ou n d s by
Com p lexa tion w ith Alu m in u m
Agen tsa
Tr is(2,6-d ip h en ylp h en oxid e)
Susumu Saito and Hisashi Yamamoto*
School of Engineering, Nagoya University, Chikusa,
Nagoya 464-01, J apan
Received J anuary 25, 1996
The conjugate reduction of R,â-unsaturated carbonyl
compounds remains an active area of organic synthesis.1
To attain chemoselective reduction2-5 (1,2 vs 1,4) of these
compounds, several methods have been thoroughly in-
vestigated, and each method has characteristic advan-
tages. Unfortunately, however, these existing methods
also have some disadvantages: strict reaction conditions
and the structure of the reaction substrate affect the
chemoselectivitiy and yield of the products. Thus, there
still seems to be a need for a new, simple, and practical
reagent for highly selective 1,4-reduction of various kinds
of R,â-unsaturated carbonyl compounds.
We recently showed that Michael addition of alkyl-
lithium toward a host of R,â-unsaturated carbonyl com-
pounds could be achieved by the complete blocking of
carbonyl functions in these substrates with aluminum
tris(2,6-diphenylphenoxide) (ATPH).6 In these reactions,
ATPH acted as a receptor to bind carbonyls, inhibiting
the attack of nucleophiles in a 1,2-manner with the
cooperation of ATPH ligands. These excellent results
prompted us to further survey whether this methodology
could be extended to the highly selective 1,4-reduction
of R,â-unsaturated compounds. We report here that the
selective 1,4-reduction of various kinds of R,â-unsatur-
ated compounds was achieved by complexation with
ATPH using diisobutylaluminum hydride-butyllithium5a
(DIBAL-n-BuLi) as a reducing agent.
We first evaluated a compatible hydride reducing agent
with ATPH in order to obtain the desirable 1,4-reduction
of R,â-unsaturated carbonyl compounds. Using isophor-
one (1) as a model substrate, 1 was reduced with various
kinds of hydride reagents in the presence of ATPH: the
results are presented in Table 1, which shows that
tetracoordinated aluminum “ate” complexes were crucial
for effective 1,4-reduction. ATPH/DIBAL-n-BuLi com-
plex is not the reactive reducing agent, which was
demonstrated by the following experiment: after treat-
ment of ATPH with DIBAL-n-BuLi at -78 °C, ketone 1
was added and was recovered unchanged (>95%).
A typical procedure is as follows: ATPH was easily
prepared from 2,6-diphenylphenol (3.6 equiv) and Me3-
Al (1.2 equiv, hexane solution) in toluene at ambient
temperature. Treatment of 1 with ATPH (1.2 equiv) in
dry toluene at -78 °C under argon, followed by the
subsequent addition of DIBAL-n-BuLi complex (1.2
equiv) in toluene-THF-hexane solution at -78 °C gave,
after 15 min, the desired 1,4-reductant 2 in 90% isolated
yield, along with a trace amount of 1,2-reductant 3. The
present reaction was conducted at 0 °C to provide 2 in
88% yield, as well. Using 1.2 equiv of ATPH and 1.2
equiv of the reducing agent was sufficient to complete
the reduction within 5 min. The procedure is very simple
and could be applied to all of the substrates tested
regardless of their substituents (Table 2). In addition,
the reaction tolerated only one of the double bonds of the
doubly conjugated ketone, and no further reduction was
observed (entry 11, Table 2). The generated enolate was
reacted with an electrophile: the reduction of ketone 4,
followed by the addition of MeOTf (3.5 equiv) at -78 °C
gave, after chromatography on silica gel, R-methylated
ketone 5 in 85% yield (eq 1).
(1) Keinan, E.; Greenspoon, N. In Comprehensive Organic Synthesis;
Trost, B. M., Ed.; Pergamon Press: Oxford, 1991; Vol. 8, Chapter 3.5
and references cited therein.
(2) Cu reagents: (a) Semmelhalck, M. F.; Staffur, R. D. J . Org.
Chem. 1975, 40, 3619. (b) Semmelhalck, M. F.; Staffur, R. D.;
Yamashita, A. Ibid. 1977, 42, 3180. (c) Osborn, M. E.; Pegues, J . F.;
Paquette, L. A. Ibid. 1980, 25, 167. (d) Saegusa, T.; Kawasaki, K.; Fujii,
T.; Tsuda, T. J . Chem. Soc., Chem. Commun. 1980, 1013. (e) Tsuda,
T.; Hayashi, T.; Satomi, H.; Kawamoto, T.; Saegusa, T. J . Org. Chem.
1986, 51, 537. (f) Boeckman, R. K., J r.; Michalak, R. J . Am. Chem.
Soc. 1974, 96, 1623. (g) Masamune, S.; Bates, G. S.; Georghiou, P. E.
Ibid. 1974, 96, 3686. (h) Ashby, E. C.; Lin, J . J .; Goel, A. B. J . Org.
Chem. 1978, 43183. (i) Mahoney, W. S.; Brestensky, D. M.; Stryker, J .
M. J . Am. Chem. Soc. 1988, 110, 291.
(3) Ru reagents: (a) Ohkubo, K.; Terada, I.; Yoshinaga, K. Inorg.
Nucl. Chem. Lett. 1979, 15, 421. (b) Ohkubo, K.; Hirata, K.; Yoshinaga,
K.; Okada, M. Chem. Lett. 1976, 183. (c) Ohkubo, K.; Hirata, K.;
Yoshinaga, K. Ibid. 1976, 577. (d) Ohkubo, K.; Shoji, T.; Terada, I.;
Yoshinaga, K. Inorg. Nucl. Chem. Lett. 1976, 13, 443. (e) Descotes, G.;
Sinou, D. Tetrahedron Lett. 1976, 4083. (f) Descotes, G.; Praly, J . P.;
Sinou, D. J . Mol. Catal. 1979, 6, 421. (g) Beaupe´re, D.; Bauer, P.; Uzan,
R. Can. J . Chem. 1979, 57, 218. (h) Beaupe´re, D.; Bauer, P.; Nadjo,
L.; Uzan, R. J . Organomet. Chem. 1982, 231, C49. (i) Beaupe´re, D.;
Bauer, P.; Nadjo, L.; Uzan, R. J . Mol. Catal. 1983, 20, 185, 195; 1983,
18, 73.
(4) Fe reagents: (a) Collman, J . P.; Finke, R. G.; Matlock, P. L.;
Wahren, R.; Braumann, J . I. J . Am. Chem. Soc. 1976, 98, 4685. (b)
Collman, J . P.; Finke, R. G.; Matlock, P. L.; Wahren, R.; Komoto, J . I.;
Brauman, R. G. Ibid. 1978, 99, 1119.
(5) Selective 1,2-reducing agents for R,â-unsaturated carbonyl com-
pounds: (a) Kim, S.; Moon, Y. C.; Ahn, K. H. J . Org. Chem. 1982, 47,
3311. (b) Kim, S.; Ahn, K. H. Ibid. 1984, 49, 1717. (c) Fuller, J . C.;
Stangeland, E.; Goraski, C. T.; Singaram, B. Tetrahedron Lett. 1992,
34, 257. (d) Bazant, V.; Capka, M.; Cerny, M.; Chvalovsky, V.;
Kochloefl, K.; Kraus, M.; Ma´lek, J . Tetrahedron Lett. 1968, 3303. (e)
Capka, M.; Chvalovsky, V.; Kochloefl, K.; Kraus, M. Collect. Czech.
Chem. Commun. 1969, 34, 118.
(6) (a) Maruoka, K.; Imoto, H.; Saito, S.; Yamamoto, H. J . Am. Chem.
Soc. 1994, 116, 4131. (b) Maruoka, K.; Shimada, I.; Imoto, H.;
Yamamoto, H. Synlett 1994, 519. (c) Maruoka, K.; Shimada, I.;
Yamamoto, H. Ibid. 1994, 847. (d) Maruoka, K.; Ito, M.; Yamamoto,
H. J . Am. Chem. Soc. 1995, 117, 9091.
S0022-3263(96)00161-2 CCC: $12.00 © 1996 American Chemical Society

Communications
J . Org. Chem., Vol. 61, No. 9, 1996 2929
Ta ble 2. Selective 1,4-Red u ction of Va r iou s Kin d s of
Ta ble 3. Selective 1,4-Red u ction of r,â-Un sa tu r a ted
r,â-Un sa tu r a ted Keton esa
Ald eh yd esa
of enolate/ATPH complex with TfOH (15 equiv) at -78
°C gave low diastereoselectivity (entries 6 and 7, Table
2). The design of a more efficient aluminum reagent for
remote stereocontrol is now under investigation.
Reduction of R,â-unsaturated aldehydes with alumi-
num hydrides is known to give unsaturated and/or
saturated primary alcohols.5d,e The 1,4-reduction of these
substrates also proceeded smoothly to give the corre-
sponding aldehydes in high yields (Table 3). It should
be noted that slightly better yields were achieved with
diisobutylaluminum hydride-tert-butyllithium (DIBAL-
t-BuLi) than with DIBAL-n-BuLi system. Application
of this method to trans-retinal gave the highly selective
delivery of hydride at C-11 to afford the expected 1,6-
reduction product7,8 6 in 87% isolated yield (entry 4, Table
3).
In summary, a strong preference for the 1,4-reduction
of a variety of R,â-unsaturated carbonyl compounds was
realized by the combined use of ATPH and tetradentate
aluminum hydrides. This method is simple, practical,
and general and, thus, has broad applicability in organic
synthesis.
Ack n ow led gm en t. Financial support from the Min-
istry of Education, Science, and Culture of the J apanese
Government is gratefully acknowledged.
Su p p or tin g In for m a tion Ava ila ble: Experimental de-
tails and spectroscopic and analytical data for the reductants
(5 pages).
J O960161E
(7) The structure assigned to the compound is in accord with its
infrared, 300 MHz 1H NMR, 1H-1H COSY, and 75 MHz 13C NMR, as
well as elemental analysis. The stereochemical outcome at position
C-13 was confirmed to be E by NOE experiment as delineated below.
Hydride delivery to the less-hindered face of the
substrate was observed (entries 4 and 8, Table 2) to give
high diastereoselectivites in both cases. These selectivi-
ties are quite similar to that of (PPh3CuH)62i- mediated
reduction and thus suggest that coordination of ATPH
with the carbonyl has little influence on the attacking
site of the reducing agent and that it is instead due to
the steric requirements of the reducing agent. However,
it seems to be interesting to know that the present
stereoselectivity is slightly greater than that in the
reduction by Cu(I)H2g “ate” complexes. The quenching
(8) Selective 1,6-addition of alkyllithiums to R,â,γ,δ-unsaturated
carbonyl compounds, such as benzophenone or benzaldehyde, was also
observed in the presence of ATPH; see ref 6d.