Refined enantioselective methylation catalysts: Improved routes to bifunctional C5 synthons

Article abstract of DOI:10.1016/S0957-4166(98)00076-7

Catalytic enantioselective routes to bifunctional C5 synthons, including those of the macrolide (S)-(-)-zearalenone have been achieved. Stereochemistry was introduced using a mixed ligand arene chromium tricarbonyl catalyst to mediate the enantioselective

Full text of DOI:10.1016/S0957-4166(98)00076-7

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 9 (1998) 901–905
Refined enantioselective methylation catalysts: improved routes
to bifunctional C5 synthons
Graham B. Jones,∗ Mustafa Guzel and Brant J. Chapman
Laboratory of Medicinal Chemistry, Department of Chemistry, Clemson University, Clemson, SC 29634-1905, USA
Received 19 December 1997; accepted 4 February 1998
Abstract
Catalytic enantioselective routes to bifunctional C5 synthons, including those of the macrolide (S)-(−)-
zearalenone have been achieved. Stereochemistry was introduced using a mixed ligand arene chromium tricarbonyl
catalyst to mediate the enantioselective addition of dimethyl zinc to a functionalized aldehyde. Comparison with
alternate reduction strategies is presented. © 1998 Elsevier Science Ltd. All rights reserved.
Synthesis of bifunctional (S)-2-pentanol synthons represents an important endeavor due to the range of
natural products accessible using these building blocks, including the estrogenic mycotoxin zearalenone
2 and the secretory product of Viverra civetta 3 (Scheme 1).1,2 Traditional routes involving commercially
available (S)-propylene oxide, while often expeditious, suffer from the prohibitive cost of this reagent in
optically pure form.3
Scheme 1. Complimentary strategies for enantioselective formation of S-carbinols
∗
Corresponding author. E-mail: graham@clemson.edu
0957-4166/98/$19.00 © 1998 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(98)00076-7

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Based on earlier studies in the synthesis of macrolides,4–6 we sought to demonstrate an effective
catalytic route to synthons 1 (R=functional group). We reasoned that enantioselective re face methylation
of the appropriate aldehyde 4 would prove effective, a consequence of appendage RL presenting a local
steric volume significantly different from RS in a chiral Lewis acid complex (Scheme 1). By analogy,
the alternative approach to product 1, a Lewis acid catalyzed reduction onto the re face of 5 using the
now popular chiral oxazaborolidine reagents, would be expected to afford inferior control, due to poor
(coordinative) discrimination of RL and RS.7
Our most effective alkylation catalysts to date have been zinc alkoxides derived from chromium
tricarbonyl complexed chiral amino alcohols, e.g. the (1S,2R)-dialkylnorephedrine 6, which can mediate
the addition of dialkyl zincs to aldehydes giving S carbinols in up to 99% e.e.8,9 The beneficial
stereodirective capacity of the arene chromium tricarbonyl group is easily demonstrated by comparison
with uncomplexed analogs, e.g. 9.10,11 In the addition of dimethylzinc however, inferior e.e.s are often
observed, particularly with alkyl aldehyde substrates or when (masked) functional groups are present in
the substrate.9 Based on our transition state model for these catalysts,9 we reasoned that increasing the
steric bulk on the metal carbonyl appendage would further increase coordinative discrimination of alkyl
aldehydes to the catalyst–substrate complex, and prepared a series of mixed ligand complexes 8a–d from
6, via photolytic substitution,12 best achieved via intermediate O-protection (Scheme 2).13a
Scheme 2. Preparation of mixed ligand arene chromium carbonyl catalysts
Zinc alkoxides 8 were prescreened in the enantioselective methylation of benzaldehyde using 10 mol%
catalyst.9 Gratifyingly, the system responded favorably to further increase in steric bulk, a trend that
had failed to materialize in other classes of catalysts.14 The most effective of these, 8d, gave among
the highest selectivity ever reported for aldehyde methylation, and is clearly superior to the lesser
encumbered alkoxides 8a–c and 9. Selectivity did not suffer even when using 5 mol% catalyst, although
98% e.e. was still the maximum attainable using 20 mol% catalyst (Table 1).
With a more efficient catalyst for the production of S-carbinols secured, we turned our attention
toward functionalized substrates. Accordingly, butane-1,4-diol was converted into a variety of masked
hydroxyaldehydes 4 (Scheme 1).13b Asymmetric methylation was then conducted using the catalysts 8,
which gave the expected S enantiomeric alcohols 1 with good enantioselectivity (Table 2).9 Remote
ether substituents are known to play a detrimental role in the coordination process, and the highest
selectivity was obtained using the trityloxy protecting group (4, R=OTr).6 As previously observed the
order of selectivity for the catalysts was 8d>8c>8b>8aꢀ9. We were also interested in direct comparison
of this approach with alternative methods, including chemical and enzymatic ketone reduction. Thus,

G. B. Jones et al. / Tetrahedron: Asymmetry 9 (1998) 901–905
903
Table 1
Enantioselective methylation of benzaldehyde using catalysts 8a
Table 2
Complimentary enantioselective routes to 1
derivitization of 3-acetyl-1-propanol gave keto substrates 5.13c A variety of oxazaborolidine catalysts
were surveyed for the reduction of 5 including those derived from (R)-proline 10,15 (+)-pseudoephedrine
11,16 and (1R,2S)-cis-aminoindanol 12.17 In each case examined, inferior selectivity was observed,
attributable to the lack of stereodifferentiation about the re/si faces of the keto group (Scheme 1).
Enzymatic reduction using alcohol dehydrogenase, either from Thermoanaerobium brockii (TBADH)18
or Thermoanaerobacter ethanolicus (SADH)19 was also examined in the case of the more (aqueous)
soluble substrate 5 (R=OTBS). Though selectivity was high, chemical yields were low even under
optimized conditions.
Since product 1 (R=Cl) has been used directly in the synthesis of 3,17 we sought to demonstrate
application of 1 (R=OTr) in the preparation of key synthons for zearalenone 2. In the syntheses of
(S)-(−)-2 reported by Hegedus, the source of chirality was bromopentanol 13 obtained from chiral
pool reagents.20 Alcohol 1 (R=OTr) was effortlessly transformed into this synthon using conventional
methods (Scheme 3).21 Other variants are easily prepared via standard methods, including the robust
iodopentanol 14. In the Pattenden synthesis of 2, which utilized alcohol 15,22 the source of this synthon

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G. B. Jones et al. / Tetrahedron: Asymmetry 9 (1998) 901–905
was naturally derived parasorbic acid, requiring five steps, and effectively restricting studies to the S
enantiomer. Accordingly, 14 was coupled to 1,3-dithiane, and subjected to selective deprotection to give
15 (Scheme 3).21
Scheme 3. Application of 1 in the preparation of (S)-(−)-zearalenone synthons20
In summary, a new family of enantioselective catalysts has been prepared, and employed to optimize
synthesis of important (S)-2-pentanol derivatives 1 via catalytic enantioselective methylation of function-
alized aldehydes. The merits of the alkylation approach are clear when compared to alternative catalytic
methods involving ketone reduction.23 Catalyst 8d affords among the highest selectivity ever reported for
aldehyde methylation, making application in synthesis a viable prospect. The synthesis and biological
evaluation of analogs of 2 will be reported in due course.
Acknowledgements
We thank the Donors of the Petroleum Research Fund (Administered by the American Chemical
Society) for financial support of this work (25958-G1, 28706-AC1), Professor Robert S. Phillips and
Christian Heiss (University of Georgia) for useful discussions and a gift of SADH, and George R. Martin
and John H. Kodjak for some preliminary experiments.
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