A Variant of the Takai - Utimoto Reaction of Acrolein Acetals with Aldehydes Catalytic in Chromium: A Highly Stereoselective Route to Anti Diol Derivatives

Full text of DOI:10.1021/jo980160h

3524
J . Org. Chem. 1998, 63, 3524-3525
the use of excess chiral ligand to observe useful levels of de
owing to the facility of ligand exchange in chromium(II)
species.3,4 In this connection, we have exploited the recent
observations of Fu¨rstner, who developed a redox couple
between chromium(II) and manganese(0) permitting the use
of catalytic amounts of chromium(II) to generate vinyl- and
allylchromium species in situ.6 The results of our studies
are detailed below.
Our preliminary noncatalytic experiments, intended to
determine whether the Cr(II)-Mn(0) redox couple would be
effective in this system, employed conditions that were
related to those employed by Fu¨rstner.6 A mixture of 1.5
equiv of chromium(II) chloride (CrCl2) and 2 equiv of Mn
powder in anhyd THF initially at -30 °C was combined
sequentially with acrolein dimethyl acetal (2) (∼4 equiv),
benzaldehyde (3) (1 equiv), and TMSI (3 equiv), followed by
warming slowly to room temperature, which afforded the
expected mixture of syn and anti alcohols 4 and 5 (∼2-3:1
anti/syn) in excellent yield (eq 2). Repetition of this reaction
A Va r ia n t of th e Ta k a i-Utim oto Rea ction of
Acr olein Aceta ls w ith Ald eh yd es Ca ta lytic in
Ch r om iu m : A High ly Ster eoselective Rou te
to An ti Diol Der iva tives
Robert K. Boeckman, J r.,* and Raymond A. Hudack, J r.
Department of Chemistry, University of Rochester,
Rochester, New York 14627-0216
Received J anuary 30, 1998
The multitude of variants of the aldol reaction and the
reactions of allylmetal derivatives with aldehydes have
provided a potent arsenal of methods useful for the stereo-
selective construction of arrays of acyclic stereogenic cen-
ters.1,2 However, certain stereochemical relationships among
vicinal stereogenic centers are much more difficult to access
with high levels of diastereoselectivity, limited in some cases
by the lack of practical access to the necessary precursors.1,2
Among these are anti relationships in stereo duads and anti/
syn relationships in stereo triads as exemplified by the
general structure 1, in which the nucleophilic component
bears a protected heteroatom and the anti relationship is
created during the C-C bond-forming step.1,2 The Takai-
Utimoto reaction of acrolein acetals with aldehydes mediated
by TMSI and Cr(II)Cl2 is effective for the generation of 1,2-
anti diol derivatives (eq 1).3 However, we have observed that
substrate-based control over diastereofacial selectivity is
problematic during generation of anti/syn triol derivatives
(vide infra).
at -30 °C with quenching at that temperature afforded 4
and 5 in 92% yield but with a disappointing selectivity (4.1:1
anti/syn). By comparison, the optimal stoichiometric reac-
tion afforded 4 and 5 in a 7.3:1 ratio (anti/syn).3a Neverthe-
less, it appeared that the Cr(II)-Mn(0) couple could function
effectively to produce the required (γ-alkoxyallyl) chromium
intermediate(s) 6.
Of greater concern was the observation that use of less
than stoichiometric amounts of CrCl2 (0.5 equiv), while
holding the relative stoichiometry of the remainder of the
components and the reaction conditions including the tem-
perature (-30 °C) constant, led to only 20-40% conversion
to 4 and 5 with considerable amounts of byproduct formation
and substantial amounts of benzaldehyde (3) remaining.
During the latter experiment, a significant exothermic
reaction was noted upon addition of the TMSI. Repetition
of this experiment with addition of the TMSI slowly over 1
h, however, did not significantly alter the composition of the
product mixture. We speculated that the difficulty lay in
the instability of the presumed intermediate R- and/or
γ-methoxyallyl iodides 7 and 8, generated from the reaction
of 2 with TMSI, under the reaction conditions. Given the
expected sensitivity of 7 and 8 to acid and reduction, it
seemed plausible that the lower concentration of CrCl2 would
be insufficient to permit consumption of 7 and 8 rapidly
enough to avoid decomposition or side reactions assuming
7 and 8 are formed rapidly. As a test of this hypothesis, a
control experiment determined that, at -30 °C, the con-
sumption of 2 upon reaction with TMSI was virtually
complete within 3 min (GC analysis). Thus, use of CrCl2 in
truly catalytic quantities required the development of condi-
tions to generate the iodide(s) 7 and 8 sufficiently slowly to
permit efficient conversion to the γ-alkoxyallyl chromium
intermediate(s) 6.
To explore a reagent-based strategy for stereocontrol in
the generation of anti/syn triol derivatives utilizing the
Takai-Utimoto reaction, a chiral ligand system for chro-
mium must be developed to permit the generation of the
required chiral γ-alkoxyallylchromium species.4,5 Prior to
undertaking such an effort, we felt it necessary and useful
to investigate methods to obtain such species under condi-
tions catalytic in chromium since use of more than stoichio-
metric quantities of chromium, as previously described by
Takai and Utimoto, would be impractical.3 Our experience
with reactions employing stoichiometric γ-alkoxyallyl chro-
mium reagents suggested that these species had limited
stability under the reaction conditions and would require
(1) (a) Franklin, A. S.; Paterson, I. Contemp. Org. Synth. 1994, 1, 317-
338. (b) Braun, M. Angew. Chem., Int. Ed. Engl. 1987, 26, 24. (c) Boeckman,
R. K., J r.; Connell, B. T. J . Am. Chem. Soc. 1995, 117, 12368-9 and
references therein.
(2) (a) Hoppe, D.; Roush, W. R.; Thomas, E. J . Houben-Weyl, Methods of
Organic Chemistry “Stereoselective Synthesis”; Thieme: Stuttgart, 1995; Vol.
E21b, pp 1357-1602. (b) Roush, W. R. In Comprehensive Organic Synthesis;
Trost, B., Fleming, I., Eds.; Pergamon: Oxford, 1991; Vol. 2, pp 1-73.
(3) (a) Takai, K.; Nitta, K.; Utimoto, K. Tetrahedron Lett. 1988, 29, 5263.
(b) Fujimura, O.; Takai, K.; Utimoto, K. J . Org. Chem. 1990, 55, 1705. (c)
Takai, K.; Kataoka, Y.; Utimoto, K. Tetrahedron Lett. 1989, 30, 4389.
(4) For studies of asymmetric allylation using organochromium reagents
see: (a) Sugimoto, K.; Aoyagi, S.; Kibayashi, C. J . Org. Chem. 1997, 62,
2322-2323. (b) Chen, C.; Tagami, K.; Kishi, Y. J . Org. Chem. 1995, 60,
5386. (c) Cazes, B.; Verniere, C.; Gore´, J . Synth. Commun. 1983, 13, 73.
(5) Masamune, S.; Choy, W.; Petersen, J . S.; Sita, L. Angew. Chem., Int.
Ed. Engl. 1985, 24, 1.
(6) Fu¨rstner, A.; Shi, N. J . Am. Chem. Soc., 1996, 118, 12349-57.
S0022-3263(98)00160-1 CCC: $15.00 © 1998 American Chemical Society
Published on Web 05/12/1998

Communications
J . Org. Chem., Vol. 63, No. 11, 1998 3525
Prior work by Sakurai and Olah on the in situ generation
of TMSI suggested that this reagent could be generated
slowly by use of TMSCl and NaI.7,8 Control experiments
established that TMSCl alone did not function effectively
to generate the (γ-alkoxyallyl)chromium intermediate(s) 6.
To establish the validity of the idea, a mixture of CrCl2 (0.5
equiv), Mn powder (2.5 equiv), and NaI (1.5 equiv) in anhyd
THF at -30 °C was treated sequentially with 2 (4 equiv), 3
(1 equiv), and TMSCl (3 equiv). Upon addition of the
TMSCl, a thick, difficultly stirrable slurry of NaCl was
formed after a short time. Analysis of the resulting products
indicated essentially complete conversion of 3 to a 7.4:1 (anti/
syn) mixture of 4 and 5, equivalent to that reported previ-
ously.3 However, the level of diastereoselectivity observed
using 0.5 equiv of CrCl2 was variable owing to the difficulties
with efficient mixing of the thick slurry of NaCl. Ultimately,
it was found that these difficulties could be avoided by use
of catalytic quantities of both NaI and CrCl2 in an ∼2.5:1
ratio.
F igu r e 1.
Ta ble 1
Further experimentation led to the following optimized
conditions: a mixture of CrCl2 (0.07 equiv), Mn(0) powder
(2.5 equiv), and NaI (0.2 equiv) in anhyd THF at room
temperature is stirred for 20 min under argon, followed by
cooling to -30 °C and sequential addition of 2 (2.3 equiv)
and 3 (1 equiv) in single portions. Finally, TMSCl (3.2 equiv)
is freed of acid by passage neat through a plug of basic
alumina with washing by a small amount of anhyd THF,
and the resulting solution is added to the reaction mixture
in one portion. The resulting reaction mixture is stirred at
-30 °C for 20 h, followed by quenching with 1 M aqueous
HCl, warming to room temperature, and product isolation
by ether extraction. Under these conditions, 4 and 5 were
obtained in 77-88% yield having diastereomeric ratios of
10.9-11.5:1 (anti/syn), consistently higher than previously
reported.3a The higher selectivity may arise from better
control of the exotherm resulting from the reaction of 2 and
TMSI, since Takai and Utimoto had observed a significant
temperature dependence on selectivity in the stoichiometric
reaction.3a As previously observed, for preparative purposes
it is impractical to conduct the reaction much below -30
°C, even though higher diastereoselectivities might possibly
be obtained.3,4
A plausible sequence of events for coupling the catalytic
cycles is outlined in Figure 1. The iodide necessary to carry
on the catalytic cycle by conversion of TMSCl to TMSI would
appear insufficient unless any MnICl or MnI2 produced
during the reduction of Cr(III)X3 reacts readily with TMSCl
(or less likely with TMSOCH3) to regenerate TMSI.
This procedure has been found to be quite generally
applicable. A variety of structural types of aldehydes have
been employed including aromatic, aliphatic, and R,â-
unsaturated systems as shown in Table 1. One limitation
encountered, thus far, is the somewhat diminished yields
and diastereoselectivities observed for R,â-unsaturated al-
dehydes. Also, preliminary studies of aldehydes bearing R
stereogenic centers, including cases bearing an R heteroatom
(Table 1), show only modest diastereofacial selectivity in
addition to the aldehyde (yields unoptimized), suggesting the
absence of metal coordination between the reagent and the
a
The stereochemistry in this case is 3,4-anti-4,5-syn:anti-anti:
3,4-syn-4,5-anti:syn-syn.
R heteroatom substituent.9 Efforts are underway to remove
these limitations, the former resulting, in part, from pinacol
coupling in the cases involving R,â-unsaturated aldehydes,
as shown by appropriate controls. The reaction is applicable
to R-substituted acrolein acetals as has been previously
observed (Table 1). We are continuing our studies aimed
at the expansion of the scope of this catalytic variant of the
Takai-Utimoto reaction, including investigation of the
utility of ketones as acceptors and the development of chiral
ligand systems for chromium to mediate a catalytic asym-
metric variant of this process and to provide means to secure
reagent-based control over facial selectivity in addition to
aldehydes bearing R stereogenic centers.4,5
Ack n ow led gm en t. We are grateful to the National
Institute of General Medical Sciences (NIGMS) and the
National Cancer Institute (NCI) of the National Institutes
of Health for research grants (GM-29290, GM-30345, and
CA-29108) in support of these studies.
Su p p or tin g In for m a tion Ava ila ble: A detailed general
experimental procedure is provided along with characterization
data and 1H NMR spectra for the new compounds in the Table 1
(17 pages).
(7) (a) Morita, T.; Okamoto, Y.; Sakurai, H. J . Chem. Soc., Chem.
Commun. 1978, 874. (b) Morita, T.; Okamoto, Y.; Sakurai, H. Tetrahedron
Lett. 1978, 2523. (c) Morita, T.; Yoshida, S.; Okamoto, Y.; Sakurai, H.
Synthesis 1979, 379.
J O980160H
(8) (a) Olah, G. A.; Narang, S. C.; Gupta, B. G. B.; Malhotra, R. Synthesis
1979, 61. (b) Olah, G. A.; Narang, S. C.; Gupta, B. G. B.; Malhotra, R. J .
Org. Chem. 1979, 44, 1247.
(9) (a) Mulzer, J .; Schulze, T.; Strecker, A.; Denzer, W. J . Org. Chem.
1988, 53, 4098-103. (b) Martin, S. F.; Li, W. J . Org. Chem. 1989, 54, 6129-
33.