Desymmetrization of meso 1,3- and 1,4-diols with a dinuclear zinc asymmetric catalyst

Article abstract of DOI:10.1021/ja029708z

A dinuclear asymmetric zinc catalyst generated by mixing a 2:1 ratio of diethylzinc and 2,6-bis[5-2-diarylhydroxy methyl-1-pyrrolidinyl]-4-methylphenol has been contrasted with enzymes for the desymmetrization of some meso diols. The best ligand has a p-b

Full text of DOI:10.1021/ja029708z

Published on Web 02/11/2003
Desymmetrization of Meso 1,3- and 1,4-Diols with a Dinuclear Zinc
Asymmetric Catalyst
Barry M. Trost* and Takashi Mino
Department of Chemistry, Stanford UniVersity, Stanford, California 94305-5080
Received December 12, 2002 ; E-mail: bmtrost@stanford.edu
Table 1. Enantioselective Acylation of 1,3-Propanediol 4a
The use of nonenzymatic catalysts for asymmetric acylations of
racemic alcohols, that is, kinetic resolutions, using chiral nucleo-
philic catalysis has recently proved to be quite interesting.1-4 On
the other hand, use of these methods for desymmetrizing meso diols
has been much less examined. An excellent result occurred in one
case with meso-1,3-bis(1′-hydroxyethyl)benzene using planar chiral
catalysts.2b With a chiral diamine as an acyl transfer catalyst, meso-
1,2-diols have been desymmetrized with good yields and selectivi-
ties; however, 2-substituted-1,3-propanediols constitute a greater
challenge because of the remoteness of the prostereogenic center
to the hydroxyl groups and led to high ee’s only if the monoacylated
product was subjected to further kinetic resolution to form the meso
diester thereby limiting the efficiency.3 While enzymatic methods
are highly successful in desymmetrizing meso diols,5,6 mixed results
are reported for the case of 2-substituted-1,3-propanediols.6,7
The nonenzymatic reactions have the advantage that either
enantiomer of the catalyst normally would be equally accessible,
thereby allowing access to both enantiomers of the product in the
same process by simply switching the chirality of the catalyst. Our
development of a novel dinuclear zinc complex formed from phenol
1 and diethylzinc (3) for asymmetric aldol reactions8 raised the
question of how “enzyme-like” this catalyst might behave. Zinc as
a cofactor in enzymatic reactions is well known. Its ability to
function as both a base and an acid suggested that it might catalyze
asymmetric acylations by a different type of mechanism than the
previously reported chiral transacylation catalysts.
c
entry
ligandb
temp
time
yield 5
ee 5
1
2
3
4
5
6
7
1a
1b
1b
1b
1b
1b
1b
rt
rt
rt
20 h
20 h
5 h
20 h
24 h
24 h
120 h
85%
98%
88%
99%
94%
77%
trace
74%
83%
84%
87%
91%
95%
n.d.
-10 °C
-15 °C
-20 °C
-40 °C
a All reactions were performed using 5 mol % 1, 10 mol % 2, and 5
equiv of 3 in toluene at 0.1 M except as indicated elsewhere. b Ligand 1a,
Ar ) Ph; ligand 1b, Ar ) -C6H4-Ph-p. c Isolated yield of monobenzoate.
Dibenzoate was formed in <1% yield (entries 1 and 4), 1% yield (entry 2),
5% yield (entry 3), or not detected (entries 5-7). d Reaction run with 10
mol % 1, 20 mol % 2, and 10 equiv of 3.
Increasing the size of the chiral pocket by switching from 1a, Ar
) phenyl, to 1b, Ar ) 4-biphenylyl,9 increased both yield and ee
(entry 1 vs 2). On the other hand, doubling the amount of catalyst
and vinyl benzoate was somewhat deleterious to yield because small
amounts of dibenzoate were now isolated (entry 2 vs 3). Lowering
the temperature increased the ee to a maximum of 95% (entries
4-6). Attempts to lower the temperature further led to too slow of
a reaction. These results compare favorably with the best ee of
92% reported for an enzymatic desymmetrization.7b The absolute
configuration was assigned by comparison to a known sample.10
With these results in hand, we examined a range of 2-arylpro-
pane-1,3-diols as summarized in eq 2 and Table 2.11
Initial work examined the desymmetrization of cis-cyclohexane-
1,2-diol with various acylating agents including isopropenyl acetate,
vinyl acetate, acetic anhydride, acetyl chloride, vinyl benzoate, and
benzoic anhydride. Modest yields of the monoesters were obtained.
Only in the case of acetyl chloride was an appreciable amount of
diacetate formed. However, in all cases, the product was racemic.
Indeed, the enantiomerically enriched monoester of this diol is
rapidly racemized under the reaction conditions.
Substrates bearing election-rich benzenoid rings in entries 1-3
react readily under the standard conditions to give excellent yields
and ee’s. Typically, dibenzoates were not detected. On the other
hand, introduction of an electron-withdrawing group as in entries
4 and 5 led to slower reactions as reflected in the lower isolated
yields which reflects lower conversions using 5 mol % catalyst.
The lower ee’s in this case may arise from some racemization of
the product. Increasing the catalyst loading to 10 mol % restores
the yield and ee. The naphthalene examples (entries 6 and 7)
illustrate the impact of molecular shape on chiral recognition. The
2-naphthyl substrate gives excellent yield and ee. On the other hand,
the placement of the benzo ring close to the two hydroxymethyl
groups in the case of the 1-naphthyl substrate obviously disrupts
the chiral recognition, although the reactivity is quite good. The
sterically smaller thiophene leads to lower chiral recognition as
compared to the benzenoid aromatics.
Switching to a conformationally flexible 1,3-diol should help
minimize product racemization by intramolecular acyl transfer. We,
therefore, turned to the difficult case of 2-substituted-propane-1,3-
diols. Using vinyl acetate as the acyl transfer agent led to significant
diacetylation (58%). On the other hand, vinyl benzoate reacted
smoothly as shown in eq 1 using the complex derived from 1a (Ar
) Ph) to give the monobenzoate3a,7c as summarized in Table 1.
Dibenzoate typically formed in e1% yield. Thus, the ee’s are not
the result of a kinetic resolution of the initial monobenzoate.
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J. AM. CHEM. SOC. 2003, 125, 2410-2411
10.1021/ja029708z CCC: $25.00 © 2003 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Enantioselective Acylation of 2-Arylpropane-1,3-diolsa
SAM II gave 44% yield of monoacetate with only 7% ee.15 This
compound proved useful in the syntheses of antiviral agents.13
Figure 1 depicts a proposed catalytic cycle. Coordination of the
vinyl benzoate away from the diarylcarbinol unit of the prolinol
followed by aryl shift to the alkoxide oxygen then accounts for the
enantioselectivity. Thus, the two diarylcarbinol moieties define the
chiral space responsible for the molecular recognition. It is
noteworthy that this simple catalyst performs comparable to if not
better than the corresponding enzymatic catalyst for similar
substrates. The reactions typically require quite reasonable reaction
conditions of 18-24 h at -15 to -20 °C. This catalyst represents
a very promising design for desymmetrizing meso diols.
Acknowledgment. We thank the National Science Foundation
and the National Institutes of Health, GM-33049, for their generous
support of our work. We thank the Japanese Ministry of Education,
Culture, Sports, Science and Technology for a fellowship for T.M.
Mass spectra were provided by the Mass Spectrometry Regional
Center of the University of California - San Francisco supported
by the NIH Division of Research Resources.
a All reactions run at 0.1 M in toluene at -15 °C. b Isolated yields. c All
ee’s were determined by chiral HPLC typically on a Chiralcel OJ column
using heptane-2-propanol mixtures. d Reference 11.
Supporting Information Available: Experimental procedures and
characterization data for monobenzoates of Table 2, eq 3, and eq 4
(PDF). This material is available free of charge via the Internet at http://
pubs.acs.org.
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