Efficient synthesis of (R)-3-amino-1,1,1-trifluoropropan-2-ol via a Dakin-West reaction followed by enantioselective reduction

Article abstract of DOI:10.1016/j.tetasy.2008.12.001

An efficient, chromatography-free asymmetric synthesis of (R)-3-amino-1,1,1-trifluoropropan-2-ol was developed for large scale production of a cholesterol ester transfer protein (CETP) inhibitor. The synthesis features a new efficient route to a β-amino trifluoromethylketone involving a modified Dakin-West reaction followed by an asymmetric hydrogenation or an enzymatic reduction of the resulting ketone to the alcohol.

Full text of DOI:10.1016/j.tetasy.2008.12.001

Tetrahedron: Asymmetry 19 (2008) 2648–2651
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Tetrahedron: Asymmetry
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Efficient synthesis of (R)-3-amino-1,1,1-trifluoropropan-2-ol
via a Dakin–West reaction followed by enantioselective reduction
,
*
*
Lulin Wei, Teresa Makowski, Carlos Martinez , Arun Ghosh
Chemical Research and Development, Pfizer Global Research and Development, Eastern Point Road, PO Box 8013, Groton, CT 06340-8013, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient, chromatography-free asymmetric synthesis of (R)-3-amino-1,1,1-trifluoropropan-2-ol was
developed for large scale production of a cholesterol ester transfer protein (CETP) inhibitor. The synthesis
features a new efficient route to a b-amino trifluoromethylketone involving a modified Dakin–West reac-
tion followed by an asymmetric hydrogenation or an enzymatic reduction of the resulting ketone to the
alcohol.
Received 13 November 2008
Accepted 1 December 2008
Available online 10 January 2009
This paper is respectfully dedicated to
Professor Marvin J. Miller on the occasion of
his 60th birthday
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
2. Results and discussion
The development of asymmetric routes to enantiomerically
pure compounds has become an increasingly important compo-
nent in the synthesis of complex molecules of pharmaceutical
interest. In this context, catalytic asymmetric hydrogenation with
an appropriate chiral catalyst or reduction with a suitable biocata-
lyst has become a valuable tool for more efficient and environmen-
tally friendly industrial processes, and provides the desired
substrates with high chemo-, regio- and stereoselectivities.1,2
Over the last few decades, fluorinated organic molecules have
played a significant role during the development of liquid crystal-
line materials, agrochemicals and pharmaceuticals due to their un-
2.1. Dakin–West approach to the amido-ketone
The existing protocol to access to the alcohol relies on the open-
ing of the chiral, commercially available epoxide (Scheme 1) as the
chiral pool.
H2N
1)
Ar
OH
O
Yb(OTf)3
NH2
F3C
F3C
i-PrOAc
50 oC
2) H2 /Pd
ique physicochemical and biological properties.3
a-Trifluoromethyl
1
2
alcohols, in particular, have served as precursors to a variety of tri-
fluoromethylated chiral frameworks.4 Although a number of re-
ports on the enantioselective reduction of ketones to alcohols
have appeared in the literature, involving stoichiometric chiral hy-
dride sources,5 asymmetric hydrogenation,6 transfer hydrogena-
tion,7 or enzymatic pathways,8 the substrate scope of these
processes are limited. Any alteration of electronic or steric proper-
ties of the molecule often results in a dramatic decline in rate and
enantioselectivity of the reaction. To the best of our knowledge, the
Scheme 1. Epoxide-route to the amino alcohol.
We reasoned that an efficient asymmetric reduction of the pre-
cursor ketone would avoid the limitation of using the volatile
epoxide in a closed reactor that is difficult to monitor (Scheme 2).
asymmetric reduction of
a-amino or a-amido trifluoromethyl
O
OH
ketone has not been reported in the literature to date. Herein, we
report two efficient approaches to (R)-3-amino-1,1,1-trifluoropro-
pan-2-ol involving, (1) asymmetric hydrogenation and (2) biocata-
lytic reduction of the precursor amido-ketone, amenable for large
scale production of this key building block.
NHR
NHR
F3C
F3C
3
4
Scheme 2. Ketone reduction.
Although the requisite ketone can be accessed in a variety of
ways, the classical Dakin–West reaction9 proved most promising
considering the cost efficiency and operational simplicity of the
processes.10 Thus, N-(3,3,3-trifluoro-2-oxopropyl)benzamide could
* Corresponding authors. Tel.: +1 860 715 6080 (A.G.).
E-mail addresses: carlos.martinez6@pfizer.com (C. Martinez), arun.ghosh@
pfizer.com (A. Ghosh).
Biocatalysis.
0957-4166/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2008.12.001

L. Wei et al. / Tetrahedron: Asymmetry 19 (2008) 2648–2651
2649
Table 1
be prepared in two steps (Scheme 3) as a crystalline solid from
Screening results for asymmetric hydrogenation of ketonea
readily available and inexpensive (<$20/kg) N-benzoyl glycine
(hippuric acid) as shown in Scheme 3, by using a modified Da-
kin–West reaction.11,12 To this end, treatment of 5 with trfluoro-
acetic anhydride gave trifluoroacylated oxazolone 9 in one step.
Subsequent hydrolysis and decarboxylation in refluxing water fur-
nished the hydrated trifluoromethyl ketone 6 in good yield.13 The
titled amino alcohol 10 was produced following a reductive deben-
zoylation protocol. The product amino alcohol showed identical
spectroscopic characteristics to that described in the literature.14,15
Catalyst
Additive
% ee
%
(pdt
configuration)
Conversion
Diacetato[(R)-(+)-BINAP]ruthenium(II)
Diacetato{(S)-(ꢂ)-dm-
88 (R)
78 (S)
92
73
segphos}ruthenium(II)
Dichloro{(R)-(+)-dm-Segphos[(1R,2R)-(+)-
1,2-diphenylethylenediamine]
ruthenium(II)
66 (R)
84 (S)
78 (R)
80 (R)
18
96
35
65
Dimethylammonium dichlorotri
(mu-chloro)bis[(S)-(ꢂ)-
2.2. Asymmetric hydrogenation for the reduction of the ketone
Segphos]diruthenate(II)
Dichloro{(R)-(+)-xylBINAP}[(2R)-(ꢂ)-1,
1-bis(4-methoxyphenyl)-3-methyl-1,
2-butanediamine]ruthenium(II)
Dichloro{(R)-(+)-2xylyl-BINAP}[(1R,2R)-
(+)-1,2-diphenylethylenediamine]
ruthenium(II)
We first investigated asymmetric hydrogenation as the trifluo-
romethyl group is known to play a significant role in enantiotopic
face selection during hydrogenation. A broad screening was per-
formed using the appropriate library of catalysts for ketone reduc-
tion. A representative list of catalysts, not all inclusive, has been
shown in Table 1. As shown in Table 1, several viable options were
apparent after the initial screening. Further optimization of the ini-
tial combination of hits was examined using diacetato((R)-BINAP)
ruthenium (II) as the catalyst. Solvent screening indicated that
both toluene and ethyl acetate would serve equally well as solvent,
with no differences in either the selectivity or rate of reaction. Fur-
thermore, the enantioselectivity could be enhanced with the addi-
tion of 1 M equiv of acid such as trifluoroacetic acid or acetic acid
(98% ee, ꢀ99%). The configuration of the products was determined
by comparison with authentic samples prepared via the original
epoxide route.
SK-J014-1a
6 (S)
33
Diacetato[(S)-(+)-BINAP]ruthenium(II)
Diacetato[(R)-(+)-BINAP]ruthenium(II)
Dimethylammonium
dichlorotri(
Segphos]diruthenate(II)
90 (S)
90 (R)b
86 (R)
100
100
100
l-chloro)bis[(R)-(ꢂ)-
Diacetato[(R)-(+)-BINAP]ruthenium(II)
Diacetato[(R)-(+)-BINAP]ruthenium(II)
Acetic acid 98 (R)
100
100
Trifluoro
98 (R)
acetic acid
Methane
Diacetato[(R)-(+)-BINAP]ruthenium(II)
98 (R)
100
sulfonic acid
a
All reductions run in toluene unless otherwise stated. Reactions were run at
50 °C, 150 psig for 24–36 h.
b
Reaction run in EtOAc.
The product from the reaction precipitate from toluene and can
be purified, if needed, to attain enantiomeric purity. The hydroge-
nation on a 2 g scale gave a 93% yield of an off-white solid with an
enantiomeric purity of 99% ee after a single recrystallization with
an initial selectivity of 97% ee.
Column: Chiralpak OD, 4.6 mm ꢁ 250 mm, mobile phase heptane
(A): isopropanol + 0.1% DEA (B), A: B (83%:17%), flow rate: 1 mL/
min, detection: 220 nm, temp: 25 °C, run time 15 min. Samples
were dissolved in heptane/IPA (50/50).
2.2.1. Representative procedure for hydrogenation
N-(3,3,3-Trifluoro-2-oxo-propyl)-benzamide and diacetato[(R)-
(+)-2,20-bis(diphenylphosphino)-1,10-binaphthyl]ruthenium(II)
(0.015 M equiv) were added to a clean dry reactor and purged five
times with nitrogen. Next, 10 volumes of nitrogen-sparged toluene
were added to the above followed by 1 equiv of either acetic acid or
trifluoroacetic acid. The reaction mixture was heated to 50 °C, after
which the temperature was allowed to equilibrate, and maintained
at 150 psig under hydrogen for 36 h. The usual work-up after cool-
ing to 30 °C and purging with nitrogen provided a sample for GC–
MS and chiral HPLC analysis.
2.3. Biocatalytic reduction of the ketone
The use of enzymes that reduce ketones (ketone reductases or
KREDs) is widely accepted in organic chemistry and is rapidly
emerging as a useful tool in industry.16 The following section de-
scribes our investigation with regard to the enzymatic reduction
of 6 to the corresponding amino alcohol using an enzyme, thus
introducing an alternative way to prepare 7. The enzyme was iden-
tified after a screening of several hundred commercial and in-
house biocatalysts. Six enzymes showed reasonable to excellent
enantioselectivity for the production of the desired (R)-enantio-
mer. The commercially available KRED102 and Saccharomyces
2.2.2. Chiral assay
For the analysis of the benzoyl-(R)-3-amino-1,1,1-trifluoropro-
pan-2-ol, the following HPLC method was used (Figs. 1 and 2):
O
O
OH
H
H
N
H
N
Dakin-West
Reduction
Ph
Ph
N
Ph
HO
F3C
F3C
O
O
O
7
6
5, hippuric acid
deprotection
NH2
(CF3CO)2O
O
O-
O
OH
F3C
O
O
N
N
F3C
Ph
9
Ph
10
8
Scheme 3. Dakin–West approach to the amido-ketone.

2650
L. Wei et al. / Tetrahedron: Asymmetry 19 (2008) 2648–2651
Figure 1. Chiral assay from the asymmetric ketone reduction without any acid additive: 90% ee using Ru(BINAP)diacetate catalyst.
Figure 2. Chiral assay from the asymmetric ketone reduction with 1 equiv of trifluoroacetic acid present: 99% ee.
2.3.1. General description of the process
Table 2
Enzyme hits identified from screeninga
Ketone 6 is reduced to the (R)-alcohol 7 using KRED102 and
NADPH as the hydride source.17 A glucose dehydrogenase (GDH-
CDX901) is used to convert/recycle NADP+ to NADPH. The glucose
is converted to gluconic acid, which is in turn converted to its so-
dium salt with the addition of 4 M sodium hydroxide. A pH stat is
used to maintain the pH of the reaction mixture at about 6.5. The
reaction takes place as a slurry mixture. This reaction was per-
formed in a high concentration of 6 (ꢀ100 g/L) and 0.1 g KRED
102 and 0.02 g GDH-CDX901 per gram of starting material. The
work-up of the reaction and product isolation consists of extrac-
tion, phase separation and concentration. The product is obtained
as a solid, in good chemical (>95.0%) and very high enantiomeric
(>99% ee) purity.
Hit
Selectivity
% ee
Biocatalytics KRED102
(R)
(R)
(R)
(R)
(R)
(R)
(R)
(S)
(S)
>99
>99
95
95
95
80
80
>99
>99
Recombinant in E. coli S. cerevisiae aldehyde reductase GCY1
Recombinant in E. coli K. lactis aldehyde reductase 2
Biocatalytics KRED131
Diacel ADH E094
Diacel ADH E031
IEP-OX 5
Recombinant in E. coli S. salmonicolor reductase 2
Multiple commercial KREDs
a
Commercial enzymes were purchased from Biocatalytics Inc. (now part of
Codexis Inc.), IEP GmbH and Diacel LTD. Cloned enzymes were produced in house
recombinant in E. coli and used in a crude form as cell lysates. Biocatalytics KREDs
106, 107, 111–115, 118–121, 123, 124, 128–130 and EXPA1-E, F, I, K, L, N, O, Q, S, T,
S, Y, EXPB1-A, E, H, I, K, M, S as well as IEP-OX 25, 28, 56, 58, 59, 66, 76 and Diacel
ADH E0-04, 07, 08, 52, 87, 94 all primarily produced the (S)-enantiomer in high ee’s.
3. Conclusion
Two processes for the asymmetric reduction of
a-trifluoro-
methyl ketoamide using either an efficient asymmetric hydrogena-
tion or using a readily available enzyme are reported. Both
processes provide the desired alcohol in high yield and enantiose-
lectivity and give access to the large-scale synthesis of a pharma-
ceutical intermediate.
cerevisiae aldehyde reductase GCY1 can be used to produce the (R)-
enantiomer in >99% ee. More than three dozen commercial en-
zymes (Table 2) and the Sporobolomyces Salmonicolor Aldehyde
reductase 2 can be used to produce the (S)-enantiomer in >99% ee.

L. Wei et al. / Tetrahedron: Asymmetry 19 (2008) 2648–2651
2651
de Paule, S. D.; Ratovelomanana-Vidal, V.; Gênet, J.-P.; Champion, N.; Dellis, P.
Angew. Chem., Int. Ed. 2004, 43, 320.
Acknowledgements
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The authors thank Drs. Timothy J.N. Watson and Juan Colberg
for helpful discussions and Ms. Sadia Abid and Mr. Adam Smog-
owicz for valuable assistance in the development of chiral assays.
References
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17. Representative procedure:
A
jacketed 0.15 L reactor equipped with
a
a
temperature probe, pH probe (connected to an autotitrator) and
a
mechanical stirrer was charged with a solution of 9 ml of 0.1 M phosphate
buffer, pH 6.5, followed by glucose (794.9 mg 1.02 equiv, 4.4 mmol) and
compound 6 (1.0 g, 1.00 equiv; 4.3 mmol). KRED102 (100 mg), GDH-CDX901
(20 mg) and NADP+ (20 mg) were then charged as solids and the jacket
temperature is maintained at 35 °C. The titrator (Metrohm Titrando pH
autotitrator) is turned on and the reaction mixture is maintained at 6.5 by
the addition of 4 M NaOH using the autotitrator. After reaction completion
(ꢀ18 h), solid KCl (2.0 g) and Celite 545 (1 g) were added to the solution
followed by ethyl acetate (11 mL) and the mixture was extracted for 10 min
keeping the temperature at 35 °C. The extraction was repeated two more
times, and the organic layers were separated and concentrated to a pale yellow
solid. The crude material was obtained in high yield (95–98% yield, based on
the potency of 6) and purity (Chiral HPLC).
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13529; (b) Kuroki, Y.; Sakamaki, Y.; Iseki, K. Org. Lett. 2001, 3, 457; (c) Jeulin, S.;