Increased Felkin-Anh Selectivity Using AlMe3 in the Addition of Vinyllithiums to α-Chiral Aldehydes: Do "Ate" Complexes Play Any Role?

Article abstract of DOI:10.1021/ol027236n

(Matrix Presented) AlMe₃ dramatically increases the diastereoselectivity of addition of vinyllithiums to α-chiral aldehydes but decreases that of methyllithium. Our results are explained in terms of an addition of the free vinyllithium on the M

Full text of DOI:10.1021/ol027236n

ORGANIC
LETTERS
2002
Vol. 4, No. 26
4735-4737
Increased Felkin−Anh Selectivity Using
AlMe3 in the Addition of Vinyllithiums to
r-Chiral Aldehydes: Do “Ate”
Complexes Play Any Role?
Claude Spino,* Marie-Claude Granger, and Marie-Claude Tremblay
UniVersite´ de Sherbrooke, De´partement de Chimie, Sherbrooke, Qc, Canada, J1K 2R1
Claude.Spino@USherbrooke.ca
Received November 5, 2002
ABSTRACT
AlMe3 dramatically increases the diastereoselectivity of addition of vinyllithiums to r-chiral aldehydes but decreases that of methyllithium.
Our results are explained in terms of an addition of the free vinyllithium on the Me3Al−aldehyde complex.
The addition of alkyl and alkenyl organometallics to R-chiral
aldehydes bearing no chelating group generally proceeds with
modest stereodifferentiation of the two faces of the carbonyl
function (the Cram/anti-Cram problem).1,2 The result is of
course very dependent on the nature of the group R to the
aldehyde, and in that respect, 2-phenylpropanal has served
as a reference aldehyde against which selectivities are
compared.1a The selectivity is also dependent on the nature
and size of the alkyl portion of the nucleophile, the metallic
counterion, and the solvent.1a Reports of the use of Lewis
acids to enhance Cram diastereoselectivity with hard nu-
cleophiles are scarce in the literature.3-5 We wish to disclose
a phenomenal increase in stereoselectivity in the addition of
vinyllithiums to R-chiral aldehydes using AlMe3 and discuss
the reactivity of aluminum “ate” complexes in such additions.
We recently reported that vinylalanes could add to R-chiral
aldehydes with stereoselectivities higher than that of the
corresponding vinyllithium.6 The vinylalanes in that study
were all prepared by zirconium-catalyzed carboalumination
of the corresponding alkyne, which involves 3 equiv of
AlMe3 in CH2Cl2. The aldehyde was then directly added to
this mixture as a THF solution.
When we carried out experiments where the CH2Cl2 was
evaporated from the vinylalane mixture and replaced by THF
prior to adding the aldehyde (Scheme 1), we noticed a
(1) (a) For a recent review, see: Mengel, A.; Reiser, O. Chem. ReV.
1999, 99, 1191-1223. (b) See also: Yamaguchi, M. ComprehensiVe
Organic Synthesis; Trost, B. M., Fleming, I. Eds.; Pergamon: New York,
1991; Vol. 1, pp 325-353.
(2) (a) Barlett, P. A. Tetrahedron 1980, 36, 3-72. (b) Cram, D. J.; Abd
Elhafez, F. A. J. Am. Chem. Soc. 1952, 74, 5828-5835.
(3) (a) Boucley, C.; Cahiez, G.; Carini, S.; Cere`, V.; Comes-Franchini,
Knochel, P.; Pollicino, S.; Ricci, A. J. Organomet. Chem 2001, 624, 223-
238. (b) Reetz, M. T.; Kyung, S. H.; Hu¨llmann, M. Tetrahedron 1986, 42,
2931-2935. (c) Lipshutz, B. H.; Ellsworth, E. L.; Siahaan, T. J. J. Am.
Chem. Soc. 1988, 110, 4834-4835.
Scheme 1. Additions of Vinylalanes to Aldehydes
(4) For anti-Cram selectivity using bulky Al reagents, see: (a) Maruoka,
K.; Itoh, T.; Yamamoto, H. J. Am. Chem. Soc. 1985, 107, 4573-4576. (b)
Maruoka, K.; Itoh, T.; Sakurai, M.; Nonoshita, K.; Yamamoto, H. J. Am.
Chem. Soc. 1988, 110, 3588-3597.
(5) Yamamoto, Y.; Yamada, J.-i. J. Am. Chem. Soc. 1987, 109, 4395-
4396.
10.1021/ol027236n CCC: $22.00 © 2002 American Chemical Society
Published on Web 11/22/2002

dependence of the selectivity on the time of evaporation:
longer evaporation times led to lower selectivities. Suspecting
that varying quantities of AlMe3 were being stripped from
the solution in those experiments, we wondered if the excess
AlMe3 was in fact the cause of the higher selectivity observed
in vinylalane additions. If so, could AlMe3 be used to increase
the stereoselectivity of addition of vinyllithiums to alde-
hydes?
Indeed, when varying quantities of AlMe3 were added to
an ethereal7 solution of the vinyllithium derived from
vinyliodides 7-98 prior to the addition of the aldehyde
(Figure 1), selectivities soared to levels even higher than that
using 2.5 equiv of AlMe3. However, catalytic amounts of
AlMe3 also increased the selectivity (entry 2).
Paradoxically, the addition of alkyllithiums to aldehyde 4
is less stereoselective in the presence of excess AlMe3 than
in the absence of AlMe3. Indeed, the stereoselectivity of
addition of methyllithium to aldehyde 4 fell from 7:1 with 0
equiv of AlMe3 to 3:1 with 2 equiv of AlMe3. Moreover,
the addition of only 1 equiv of AlMe3 affords no product.
This observation was also noted in the addition of 1 equiv
of vinyllithium 7 on all aldehydes with 1 equiv of AlMe3
(Table 1, entries 3, 6, and 9).
In 1967, Zweifel and co-workers made ate complexes
between vinylalanes (prepared by hydroalumination of
terminal alkynes) and methyllithium and obtained 68% yield
of alcohol upon reaction with acetaldehyde.9 In contrast,
tetralkylalanates were unreactive. They suggested that ate
complexes were in fact unreactive and that the reactive
species in the trialkylvinylalanate reaction may not be the
ate complex 11 but the free vinyllithium upon dispropor-
tionation (Scheme 2). They also suggested that the unfavor-
Scheme 2. Disproportionation of Ate Complexes 11 and 13
Figure 1. Aldehydes and vinyliodides of Table 1.
obtained from vinylalane additions (Table 1). The phenom-
enon seems to be general, and to the best of our knowledge,
this is the first example where selectivities of addition of
vinyllithiums to R-chiral aldehydes are dramatically increased
by the use of a Lewis acid. Two aldehydes afforded >30:1
ratios of diastereomeric alcohols (entries 4 and 7). Aldehyde
6 gave ratios from 3:1 to 5:1, depending on the vinyllithium
used (entry 10). This is substantially higher than the
corresponding ratios obtained without AlMe3 (entry 8). Three
different di- or trisubstituted vinyllithiums gave similarly
satisfying results (entry 4). The best results were obtained
able dissociation of tetraalkyl ate complex 13 prevented its
reaction.
Many years ago, Heathcock proposed that a Lewis acid
coordinated syn to the aldehydic hydrogen atom10 forced a
silyl enol ether to attack the carbonyl at an angle nearer to
90°, thus pushing it closer to the chiral center (Figure 2).11
Table 1. Stereoselectivities of Addition of Vinyllithiums to
Three Aldehydes in the Presence or Absence of AlMe3
Cram/anti Cram ratiosa of 10 (% yield)b
AlMe3
entry ald (equiv)
from 7
from 8
from 9
Figure 2. Effect of the Lewis acid on the angle of attack on the
carbonyl.
1
2
3
4
5
6
7
8
9
4
4
4
4
5
5
5
6
6
6
0
12:1 (52)
16:1 (57)
- (traces)
40:1 (65)
7:1 (75)
- (traces)
80:1 (60)
1.4:1 (59)
- (traces)
3:1 (47)
10:1 (62)
10:1 (44)
0.1
1.0
2.5
0
1.0
2.5
0
- (traces)
99:1 (56)
5:1 (76)
- (traces)
41:1 (73)
In our case, it could be that the free vinylithium (from the
dissociation of 11)9 reacts with the reactive Me3Al-aldehyde
complex when there is excess AlMe3, giving high diaster-
eomeric ratios of 10 in accordance with Heathcock’s
hypothesis.10
34:1 (50)
1.4:1 (55)
1.0
2.5
10
5:1 (60)
(6) (a) Spino, C.; Granger, M.-C.; Boisvert, L.; Beaulieu, C. Tetrahedron
Lett. 2002, 43, 4183-4185. (b) Spino, C.; Beaulieu, C. Angew. Chem., Int.
Ed. 2000, 39, 1930-1932.
a Determined by GC. b Isolated yield.
4736
Org. Lett., Vol. 4, No. 26, 2002

However, we cannot rule out the possibility that the ate
complex adds to the activated aldehyde in this case. When
we used a catalytic amount of AlMe3 (Table 1, entry 2), most
of the AlMe3 is likely to be tied up as the ate complex 11.
It is possible in this case that the free vinyllithium adds
mainly to unactivated aldehyde because of the low concen-
tration of AlMe3 available for coordination, resulting in a
smaller increase in selectivity. However, if the dispropor-
tionation of 11 did not occur at all to release some AlMe3
for coordination, we would expect no increase at all in the
selectivity. Finally, if exactly 1 equiv of AlMe3 is used, the
concentrations of both the free vinyllithium and free AlMe3
are low, resulting in a sluggish reaction.
How can we explain the fact that methyllithium does not
add to R-chiral aldehydes with increased selectivity when
in the presence of AlMe3? If the disproportionation of the
tetralkylalanate into alkyllithium and AlMe3 is not favorable,
as Zweifel suggested,9 then the reactive species is likely to
be the excess AlMe3 itself. This is supported by the fact that
a 1:1 mixture of RLi and AlR3 is unreactive as well as by
the fact that 1 equiv of MeLi in the presence of 3 equiv of
AlEt3 led exclusively to the ethylation of 4.
force the nucleophile away from perpendicularity and partly
cancel the effect shown in Figure 2.
In conclusion, we have shown that the addition of
vinyllithiums to R-chiral aldehydes is markedly more selec-
tive when AlMe3 is added to the mixture. Our results open
interesting questions about the mechanism of addition of
organoaluminum to aldehydes and the role played, if any,
by the ate complex. Further exploration of these issues is
ongoing in our laboratory.
Acknowledgment. We are grateful to Merck-Frosst
Center for Therapeutic Research, the donors of the Petroleum
Research Fund, administered by the American Chemical
Society, and the Natural Sciences and Engineering Council
of Canada for financial support of this research.
Supporting Information Available: Experimental and
NMR spectra for each compound. This material is available
free of charge via the Internet at http://pubs.acs.org.
OL027236N
(7) THF is decomposed rapidly by t-BuLi in the presence of trimethyl-
aluminum even at -78 °C.
We tested the stereoselectivity of addition of Me3Al alone
to support this hypothesis and found that its addition to
aldehyde 4 is only modestly stereoselective (3:1). This result
may be explained by an intramolecular six-membered
transition state (TS) (Scheme 3).12,13 This particularity could
(8) Negishi, E.-i.; Van Horn, D. E.; Yoshida, T. J. Am. Chem. Soc. 1985,
107, 6639-6647.
(9) Zweifel, G.; Steele, R. B. J. Am. Chem. Soc. 1976, 89, 2754-2755.
(10) Reetz, M. T.; Hu¨llmann, M.; Massa, W.; Berger, S.; Rademacher,
P.; Heymanns, P. J. Am. Chem. Soc. 1986, 108, 2405-2408.
(11) Heathcock, C. H.; Flippin, L. A. J. Am. Chem. Soc. 1983, 105,
1667-1668.
(12) Addition of AlR3 onto carbonyls has been extensively studied, and
the 6-centered transition state is thought to be favored when more than 1
equiv of AlR3 is involved. See: Evans, D. A. Science 1988, 240, 420-
426.
Scheme 3. Six-Centered TS in the Addition of AlR3
(13) (a) Ashby, E. C.; Smith, R. S. J. Organomet. Chem. 1982, 225,
71-85. (b) Ashby, E. C.; Smith, R. S. J. Org. Chem. 1977, 42, 425-427.
(c) Neumann, H. M.; Laemmle, J.; Ashby, E. C. J. Am. Chem. Soc. 1973,
95, 2597-2603. (d) Ashby, E. C.; Laemmle, J.; Neumann, H. M. J. Am.
Chem. Soc. 1968, 90, 5179-5188.
Org. Lett., Vol. 4, No. 26, 2002
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