Application of MerCO as a chiral catalyst in asymmetric synthesis: Asymmetric borane reduction of ketones

Article abstract of DOI:10.1016/S0957-4166(98)00504-7

The borane reduction of aryl methyl ketones catalyzed by MerCO [(1R,2S,3R)-3-mercaptocamphan-2-ol] produced 1-aryl ethyl alcohols in 92% e.e. at 50°C in toluene. Significant temperature and solvent effects were observed in this reaction.

Full text of DOI:10.1016/S0957-4166(98)00504-7

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 10 (1999) 405–409
Application of MerCO as a chiral catalyst in asymmetric
synthesis: asymmetric borane reduction of ketones
Teng-Kuei Yang ∗ and Dong-Sheng Lee
Department of Chemistry, National Chung-Hsing University, Taichung, Taiwan 400
Received 19 November 1998; accepted 15 December 1998
Abstract
The borane reduction of aryl methyl ketones catalyzed by MerCO [(1R,2S,3R)-3-mercaptocamphan-2-ol]
produced 1-aryl ethyl alcohols in 92% e.e. at 50°C in toluene. Significant temperature and solvent effects were
observed in this reaction. © 1999 Elsevier Science Ltd. All rights reserved.
Asymmetric borane reduction has attracted much attention owing to its usefulness in preparing
optically active secondary alcohols.1 Many chiral diols,2 amino alcohols,3 and sulfoximines4 have served
as chiral ligands to accelerate the reaction rate and, more importantly, to provide an asymmetric enviro-
nment for the reacting species. Among these cases, oxygen and nitrogen are used as the coordinating
atoms to boron. In general, the oxygen–nitrogen paired ligands give a better enantioselectivity than the
corresponding oxygen–oxygen paired bidendate ligands. This phenomenon can be rationalized according
to the CBS mechanism proposed by Corey, in which a second molecule of borane coordinates with the
more electron rich nitrogen atom. Thus directing the borohydride to specifically approach one of the
prochiral faces of the carbonyl group.5 However, in the diol ligands, the second borane molecular may
coordinate to either oxygen atom, and scrambled induction may occur if both oxygen atoms have a similar
coordinating capability to the second borane. In principle, the oxygen–sulfur paired bidentate ligands also
have a significant affinity difference to coordinate with borane, possibly offering the second borane a clear
preference among the two coordinating atoms. Consequently, better stereoselectivity could be expected,
but we have found that thiols have rarely been studied for catalytic asymmetric borane reductions.6,7
Herein, we report the use of MerCO 1 and its derivatives 2, 3 as chiral oxygen–sulfur paired bidentate
ligands accompanied with borane to reduce aryl methyl ketones to the corresponding alcohols.
∗
Corresponding author. E-mail: tkyang@mail.nchu.edu.tw
0957-4166/99/$ - see front matter © 1999 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(98)00504-7

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Table 1
Solvent effect on the asymmetric borane reduction of aryl methyl ketones catalyzed by MerCO 1
Chiral compounds 1–3 were easily prepared in satisfactory yields from camphor, according to our
previous report.8 In order to find optimal conditions for using these newly developed ligands, we
examined the influence of solvent, temperature, and stoichiometry in the borane reduction. Table 1
clearly indicates that a non-polar solvent such as toluene is the best solvent to achieve the highest
enantioselectivity for MerCO 1, which compares with most of the existing ligands (entries 1, 4, and
7). Coordination of THF with boron may compete with the coordination of boron to the chiral ligand,
and poor enantioselectivity was observed herein (entries 3, 6, 8). Meanwhile, our results indicate that
such a solvent effect is independent of the reaction temperature9 (entries 7, 8).
The transition states proposed in Scheme 1 reveal that the S configuration of the alcohol should
be obtained from MerCO 1 catalyzed borane reduction. The fact that boron is a hard acid, which
would prefer to coordinate with oxygen as a relatively harder base than sulfur atom, accounts for why
transition states B and D are more favorable than A and C. On the other hand, the bulky camphor
backbone is oriented at the axial position of the six-membered ring ligand–borane–ketone complex in
transition state B whereas the 2-hydroxyl group of the camphor skeleton is set at the equatorial position
in the ligand–borane–ketone complex shown in D. The preference of the aryl group to remain in the
equatorial position would cause the borohydride to approach the Re-face of the ketone, thereby leading
to the S-alcohol according to the spatial arrangement of transition state D. Furthermore, the bulkier 2-
naphthylketone ensures that the aryl group is set at the equatorial position, accounting for the observation
of a higher enantioselectivity (entry 4 vs 10). Closely examining the electronic effect of the substituents
on the aryl group of the ketones did not reveal an obvious trend (entries 20–25; Table 2).
Comparing the e.e. values of the 1-phenylethanol listed in Table 1 reveals that higher enantioselectivi-
ties are achieved at higher reaction temperatures when other factors are kept the same.9,10 More detailed
temperature studies in Table 2 suggest that the maximum e.e. values of the alcohols are always obtained
when reaction temperature is kept at around 50°C (entries 4 and 10). The above results imply that a
chiral ligand–borane–ketone complex is formed at around 50°C, thereby making it the effective chiral

T.-K. Yang, D.-S. Lee / Tetrahedron: Asymmetry 10 (1999) 405–409
407
Scheme 1.
reducing agent. At a lower reaction temperature the chiral borane complex is not formed completely.11
Therefore, a portion of the ketone is reduced by free borane, without the chiral ligands to yield the racemic
alcohols. When the reaction temperature markedly exceeds 50°C, the reaction between the ketone and
free borane becomes fast enough to compete with the chiral ligand associated borane. Therefore, the
enantioselectivity falls to 6% e.e. when the reaction temperature is maintained at 110°C (entry 8). This
hypothesis is further supported by a two stage temperature study, in which the chiral ligand and borane are
initially mixed at a higher temperature to accelerate the formation of the chiral ligand–borane complex;
ketone is then added at a lower temperature. Our results show a better enantioselectivity when the ketone
is added at lower temperature than that of the constant high temperature process (entry 7 vs 15 and 8 vs
16). On the other hand, alkylation of either 2-hydroxyl or 3-mercapto group of MerCO 1 significantly
weakens their coordination with boron, possibly destroying the chiral ligand–borane–ketone complex and
diminishing the enantioselectivities. Nevertheless, the low e.e. of the alcohols produced using catalysts
2 and 3 indirectly confirms the chelation of borane to both 2-hydroxyl and 3-mercapto groups as well as
their importance in the enantioselectivity of the reduction process.
In summary, this study has successfully demonstrated a novel thiol type chiral catalyst, MerCO 1,
for the asymmetric borane reduction. The optimum conditions to use this catalyst in borane reduction
is 50°C in toluene, which also implies that the formation of chiral ligand–borane–ketone complex is
essential for stereoselective reduction. Currently, we are investigating the novel thiol catalyst with even
stronger chelating capability and its application to aliphatic ketone systems.

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T.-K. Yang, D.-S. Lee / Tetrahedron: Asymmetry 10 (1999) 405–409
Table 2
Temperature effect on asymmetric borane reduction of aryl methyl ketones catalyzed by MerCO 1
Acknowledgements
The authors would like to thank the National Science Council of the Republic of China for financially
supporting this research under grant No. NSC-87-2113-M005-006, and Professor Carsten Bolm is also
appreciated for his helpful discussion.
References
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T.-K. Yang, D.-S. Lee / Tetrahedron: Asymmetry 10 (1999) 405–409
409
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11. General procedure: to a solution of chiral ligand in toluene was added BH3·SMe2 at specified temperature and stirred for
60 min. The ketone was added slowly over a period of 60 min then stirred at specified temperature for another 30 min. The
reaction mixture was quenched with 3N NaOH (aq.) and extracted with ethyl acetate. The organic layer was concentrated
in vacuum and passed through a short silica column, then subjected to HPLC analysis.