Asymmetric organozincate additions to ethyl 2,2,2-trifluoropyruvate

Article abstract of DOI:10.1055/s-2007-984911

A chromatography-free synthesis of enantiomerically enriched chiral α-trifluoromethyl α-hydroxy acids prepared via an asymmetric (R)-BINOL-mediated organozincate addition to ethyl 2,2,2-trifluoropyruvate (1) is reported. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2007-984911

LETTER
2193
Asymmetric Organozincate Additions to Ethyl 2,2,2-Trifluoropyruvate
Asymmetric
O
r
rganozin
a
c
ate
A
ddit
n
2
c
,2,2-Triflu
i
oropyr
s
a
Department of Process Research, Merck Frosst Centre for Therapeutic Research, 16711 Route Transcanadienne, Kirkland, Québec,
H9H 3L1, Canada
Fax +1(514)4284936; E-mail: francis_gosselin@merck.com
b
Department of Process Research, Merck Research Laboratories, P.O. Box 2000, Rahway, NJ 07065, USA
Received 2 April 2007
reacts rapidly with Et2Zn at –78 °C to afford a solvent-de-
pendent mixture of ethyl addition product 2b and reduc-
tion product 3, which results from b-hydride transfer from
Et2Zn (Scheme 2). For example, in toluene, the reaction of
1 with Et2Zn afforded a-hydroxy-ester 3 in yields of up to
95%, while reactions carried out in THF provided the
ethyl adduct 2b in ca. 70% yield. Based on these results,
we evaluated various methodologies for catalyzing the
asymmetric addition of either Et2Zn or Et3Al to ethyl
2,2,2-trifluoropyruvate (1). In general, these reactions
were often complicated by a fast background reaction of 1
with the organometallic reagent and rapid formation of
stable hemiketals (e.g. 4a) with a variety of chiral alcohol
catalysts (e.g., BINOL) or Lewis acid additives such as
Ti(Oi-Pr)4.8
Abstract: A chromatography-free synthesis of enantiomerically
enriched chiral a-trifluoromethyl a-hydroxy acids prepared via an
asymmetric (R)-BINOL-mediated organozincate addition to ethyl
2,2,2-trifluoropyruvate (1) is reported.
Key words: zincate, BINOL, a-keto ester, asymmetric organome-
tallic addition, trifluoropyruvate
The preparation of chiral secondary alcohols by enantio-
selective addition of organometallics to aldehydes has
received considerable attention.1 A plethora of methods
exist to catalyze the addition of organometallics to alde-
hydes. In contrast, there are relatively few reports on the
synthesis of chiral tertiary alcohols by catalytic asym-
metric organometallic additions to ketones2 and a-keto
esters.3 This may be attributed, respectively, to poorly de-
fined catalyst–substrate interaction and the increased
electrophilic character of the carbonyl group that renders
catalyzed additions more difficult. Introduction of an elec-
tron-withdrawing group such as a trifluoromethyl group is
likely to worsen the situation. Recent examples from the
literature confirm the increased difficulty faced in prepar-
ing chiral trifluoromethyl-substituted tertiary alcohol ste-
reogenic centers.4 As part of an on-going drug discovery
program we required large quantities of enantiomerically
enriched chiral a-trifluoromethyl a-hydroxy-acids 6a–i
(Scheme 1).5,6 We report herein a novel procedure for the
introduction of the chiral center found in 2a–i from com-
mercially available ethyl 2,2,2-trifluoropyruvate (1).
O
O
O
F3C
F3C
HO
+
+
1
OEt
Me
OEt
CF3
OEt
HO
OR
OH
4a R = alkyl
4b R = H
rac-2b
3
Scheme 2
Interestingly, while we were unsuccessful in our attempts
to effect a catalytic enantioselective addition of Et2Zn to
1, we found that the addition of Et3Al to trifluoropyruvate
could be catalyzed by chiral ligands (e.g. N-methylephe-
drine) affording high conversion into the ethyl adduct 2b,
albeit with only moderate levels of asymmetric induction
(Table 1).
O
O
O
F3C
R
Although generally not perceived as competitive with cat-
alytic methods, the use of a cheap and readily available
stoichiometric chiral modifier for asymmetric reactions
can provide a viable and practical option.9 For example,
the asymmetric acetylide addition to trifluoromethyl
ketones, using a stoichiometric amount of chiral amino
alcohol modifier, has been reported by others in our labo-
ratories.9a Inspired by this finding we evaluated a number
of stoichiometric chiral modifiers for the addition of orga-
nometallic reagents to ethyl 2,2,2-trifluoropyruvate (1).
As illustrated in Table 2, use of the zincate reagent
derived from either N-methylephedrine6 or TADDOL9b
afforded 2b in low yield and enantioselectivity (entries 1
and 2). In contrast, commercially available and inexpen-
sive (R)-(+)-1,1¢-bi(2-naphthol) (BINOL)10 emerged as a
unique chiral modifier, and provided the R-a-hydroxy-
R
OEt
OH
CF3
OEt
CF3
HO
HO
O
6a–i
2a–i
1
Scheme 1
Although asymmetric additions of organometallic re-
agents to pyruvate derivatives have been reported for the
synthesis of chiral a-hydroxy acids, we found no exam-
ples of catalytic asymmetric organometallic additions to
ethyl 2,2,2-trifluoropyruvate (1).7 Perhaps not surprising-
ly, we found that 1 is a highly electrophilic species that
SYNLETT 2007, No. 14, pp 2193–2196
Advanced online publication: 20.07.2007
DOI: 10.1055/s-2007-984911; Art ID: S01907ST
© Georg Thieme Verlag Stuttgart · New York
0
3
.0
9
.2
0
0
7

2194
F. Gosselin et al.
LETTER
Employing the optimized conditions discussed above, we
evaluated the use of other organometallic nucleophiles in
this methodology. The basic protocol for generating the
chiral BINOL–organozincate reagent involved addition of
a solution of Et2Zn to a suspension of BINOL in 1,2-
DCE–THF (4:1). This exothermic reaction proceeded
with evolution of two equivalents of ethane to afford a
BINOL–zinc complex. Subsequent addition of a suitable
organomagnesium reagent led to the formation of a
BINOL–organozincate reagent (Scheme 3). Importantly,
while the use of THF as a co-solvent was essential for
maintaining a homogeneous reaction, increasing the
amount of THF above 25% by volume led to significant
erosion in the enantioselectivity for this process.
Table 1 Enantioselective Addition of Et3Al to Ethyl 2,2,2-Tri-
fluoropyruvatea
O
Et3Al
ligand (5 mol%)
Me
OEt
CF3
1
HO
Et2O, –78 °C
2b
Entry
Ligand
ee (%)b
35
1
2
3
N-Methylephedrine
N-Methylpseudoephedrine
55
(2S)-(–)-3-exo-(Dimethylamino)isoborneol
14
(DAIB)
4
(S)-(–)-2,2¢-Isopropylidene-bis(4-phenyl-2-
20
Et2Zn
RMgX
O
oxazoline)
–
+
R
+ 3 + 4
(RO)2ZnRMgX
(R)-BINOL
a Et3Al (1 M in hexanes).
OEt
b Determined by chiral GC analysis of the crude reaction mixture.
HO
CF3
R = (R)-BINOL-ate
2a–i
Scheme 3 BINOL–zincate formation and addition to pyruvate 1
ester 2b in 50% conversion and 70–78% ee as determined
by chiral GC analysis (entry 3). A subsequent solvent
screen identified 1,2-dichloroethane (DCE) as the optimal
solvent for this process, providing 2b in high conversion
(>95%) and acceptable enantioselectivity (entry 4). Opti-
mal yields were obtained when ethyl 2,2,2-trifluoropyru-
vate (1) was added dropwise to the chiral (R)-BINOL–
zincate reagent11 over a period of 4–6 hours. This
modified process minimized the competing reaction of 1
with the metal alkoxide from (R)-BINOL, which produces
the hemiketal 4a [R = (R)-BINOL], a stable species under
the reaction conditions. Notably, the reagent obtained
from a stoichiometric mixture of ethyllithium, Et2Zn and
(R)-BINOL gave 2b with the opposite sense of stereo-
selectivity (entry 5).
The scope of the BINOL–organozincate asymmetric addi-
tion to ethyl 2,2,2-trifluoropyruvate (1) is summarized in
Table 3. Although not optimized, these additions provid-
ed synthetically useful levels of asymmetric induction for
the preparation of a-alkyl (entries 2–5) and a-phenyl a-tri-
fluoromethyl a-hydroxy acids (entry 8). Unfortunately, in
most cases the reaction was accompanied by competing
hydride transfer and moderate levels of conversion, likely
due to addition of BINOL alkoxides to 1. In all cases, the
reduction product 3 was found to be racemic as deter-
mined by chiral GC analysis. Residual alcohol 3, (R)-
BINOL and other byproducts were readily removed in the
aqueous workup and concentration and the crude esters
Table 2 Chiral Modifiers for Organozincate Addition to Ethyl 2,2,2-Trifluoropyruvatea
O
O
O
F3C
F3C
HO
+
+
1
OEt
Me
OEt
CF3
OEt
HO
OR
OH
4a R = alkyl
4b R = H
2b
3
Entry
Ligand
Ethyl source
Solvent
Toluene
Toluene
Toluene
DCE
Temp (°C)
r.t.
Conv. (%),b ee (%)c
20 (10)
1
2
3
4
5
N-Methylephedrine
TADDOL
Et2Zn, EtMgCl
Et2Zn, EtMgCl
Et2Zn, EtMgCl
Et2Zn, EtMgCl
Et2Zn, EtLi
r.t.
30 (<5)
(R)-BINOL
–40
50d (70–78)
>95e (64–72)
90 (–52)
(R)-BINOL
–20
(R)-BINOL
DCE
–20
a In all cases 1.0 equiv of Et2Zn, chiral modifier, and a second ethyl source were employed.
b Determined by 19F NMR spectroscopic analysis.
c Determined by chiral GC analysis.
d Pyruvate added over 30 min.
e Pyruvate added over 6 h.
Synlett 2007, No. 14, 2193–2196 © Thieme Stuttgart · New York

LETTER
Asymmetric Organozincate Addition to Ethyl 2,2,2-Trifluoropyruvate
2195
Table 3 Asymmetric BINOL–Zincate Addition to Ethyl 2,2,2-Trifluoropyruvatea
O
O
O
(a)
(b)
R
R
F3C
OEt
OH
OEt
HO
CF3
HO
CF3
O
1
2a–i
6a–i
Entry
R = (2a–i)
Me (2a)
Et (2b)
Conv. (%)b
ee (%)c
53
3 (%)b
4a (%)b
53
Yield 6a–i (%), ee (%)d
1
2
3
4
5
6
7
8
9
44
90
48
49
39
76
76
75
79
0
1
29 (50) 6a
74 (74) 6b
34 (76) 6c
35 (83) 6d
25 (83) 6e
29 (13) 6f
37 (4) 6g
70
8
n-Pr (2c)
n-Bu (2d)
76
16
15
14
1
24
84
22
n-C5H11 (2e)
Vinyl (2f)
81
36
13e
4e
18
Allyl (2g)
0
19
Phenyl (2h)
Benzyl (2i)
69f
<5g
0
16
38 (69) 6h
36 (<5) 6i
0
7
a Conditions: (a) (R)-BINOL, Et2Zn, RMgCl, DCE–THF (4:1), –40 °C; (b) KOH, H2O.
b Determined by 19F NMR spectroscopic analysis.
c Determined by chiral GC analysis of the crude reaction mixture.
d Determined by chiral GC analysis of the corresponding methyl ester.
e Determined after catalytic hydrogenation of the corresponding a-hydroxy acid and chiral GC analysis of the corresponding methyl ester.
f Determined by chiral SFC analysis.
g Determined by HPLC analysis after conversion into the corresponding (S)-a-methylbenzylamide.
(5) Shaw, N. M.; Naughton, A.; Robins, K.; Tinschbert, A.;
Schmid, E.; Hischier, M.-L.; Venetz, V.; Werlen, J.;
Zimmermann, T.; Brieden, W.; de Riedmatten, P.; Roduit,
J.-P.; Zimmermann, B.; Neumüller, R. Org. Process Res.
Dev. 2002, 6, 497.
2a–i were directly hydrolyzed with aqueous KOH to af-
ford the enantiomerically enriched a-hydroxy acids 6a–i
in up to 74% yield over 2 steps and up to 83% ee, without
chromatographic purification.12
(6) Coppola, G. M.; Schuster, H. F. a-Hydroxy Acids in
Enantioselective Synthesis; VCH: Weinheim, 1997.
(7) Enantioselective Friedel–Crafts reaction with ethyl 2,2,2-
trifluoropyruvate: (a) Zhuang, W.; Gatherwood, N.; Hazell,
R. G.; Jørgensen, K. A. J. Org. Chem. 2001, 66, 1009.
(b) Török, B.; Abid, M.; London, G.; Esquibel, J.; Török,
M.; Mhadgut, S. C.; Yan, P.; Surya Prakash, G. K. Angew.
Chem. Int. Ed. 2005, 44, 3086. (c) Lyle, M. P. A.; Draper,
N. D.; Wilson, P. D. Org. Lett. 2005, 7, 901.
In summary, we have developed a novel and preparatively
useful asymmetric synthesis of enantiomerically enriched
a-trifluoromethyl a-hydroxy acids based on the addition
of (R)-BINOL–organozincates to ethyl 2,2,2-trifluoro-
pyruvate.
References and Notes
(d) Enantioselective carbonyl–ene reaction: Aikawa, K.;
Kainuma, S.; Manabu, H.; Mikami, K. Tetrahedron Lett.
2004, 45, 183.
(1) (a) Soai, K.; Niwa, S. Chem. Rev. 1992, 92, 833. (b) Pu, L.;
Yu, H.-B. Chem. Rev. 2001, 101, 757.
(2) (a) Dosa, P. I.; Fu, G. C. J. Am. Chem. Soc. 1998, 120, 445.
(b) García, C.; LaRochelle, L. K.; Walsh, P. J. J. Am. Chem.
Soc. 2002, 124, 10970. (c) García, C.; Walsh, P. J. Org. Lett.
2003, 5, 3641. (d) Jeon, S.-J.; Li, H.; García, C.;
LaRochelle, L. K.; Walsh, P. J. J. Org. Chem. 2005, 70, 448.
(3) (a) DiMauro, E. F.; Kozlowski, M. C. J. Am. Chem. Soc.
2002, 124, 12668. (b) DiMauro, E. F.; Kozlowski, M. C.
Org. Lett. 2002, 4, 3781. (c) Huddleston, R. R.; Jang, H.-Y.;
Krische, M. J. J. Am. Chem. Soc. 2003, 125, 11488.
(d) Kong, J.-R.; Ngai, M.-Y.; Krische, M. J. J. Am. Chem.
Soc. 2006, 128, 718.
(4) (a) Song, J. J.; Tan, Z.; Xu, J.; Reeves, J. T.; Yee, N. K.;
Ramdas, R.; Gallou, F.; Kuzmich, K.; DeLattre, L.; Lee, H.;
Feng, X.; Senanayake, C. H. J. Org. Chem. 2007, 72, 292.
(b) Caron, S.; Do, N. M.; Arpin, P.; Larivée, A. Synthesis
2003, 1693.
(8) Hemiketals prepared by reaction of the metal alkoxides of
MeOH, 2-PrOH, phenol and BINOL consistently exhibited
a singlet with a chemical shift between d = –85.4 and –85.8
ppm by 19F NMR spectroscopic analysis with
benzotrifluoride as internal standard (d = –61.5 ppm).
(9) For a practical example, see: (a) Tan, L.; Chen, C.-y.;
Tillyer, R. D.; Grabowski, E. J. J.; Reider, P. J. Angew.
Chem. Int. Ed. 1999, 38, 711. Other examples include:
(b) Weber, B.; Seebach, D. Tetrahedron 1994, 50, 6117.
(c) Noyori, R.; Suga, S.; Kawai, K.; Okada, S.; Kitamura, M.
Pure Appl. Chem. 1988, 60, 1597. (d) Abenhaim, D.;
Boireau, G.; Sabourault, B. Tetrahedron Lett. 1980, 21,
3043.
(10) For reviews on the use of BINOL in asymmetric synthesis,
see: (a) Brunel, J. M. Chem. Rev. 2005, 105, 857. (b) Chen,
Y.; Yekta, S.; Yudin, A. K. Chem. Rev. 2003, 103, 3155.
Synlett 2007, No. 14, 2193–2196 © Thieme Stuttgart · New York

2196
F. Gosselin et al.
LETTER
(11) A similar BINOL-derived zincate species has been reported
as a Lewis acid catalyst for enantioselective Diels–Alder
cycloadditions: Ward, D. E.; Souweha, M. S. Org. Lett.
2005, 7, 3533.
mL). The organic layer was then treated with 8 N KOH (200
mol%) at reflux for 2 h. The solution was cooled to r.t. and
the layers were separated. The aqueous layer was washed
with MTBE (20 mL) and then acidified to pH 1 with 6 N
HCl. The aqueous layer was extracted with MTBE (20 mL),
dried with MgSO4, and concentrated under vacuum to afford
(2R)-2-hydroxy-2-(trifluoromethyl)butanoic acid (2b) as a
white solid in 74% yield and 74% ee; mp 120–122 °C. 1H
NMR (500 MHz, acetone-d6): d = 1.96 (m, 1 H), 1.81 (m, 1
H), 0.88 (t, 3 H, J = 7.5 Hz). 13C NMR (125 MHz, acetone-
d6): d = 170.4, 123.6 (q, J = 284 Hz), 77.6 (q, J = 28.5 Hz),
24.7, 6.4. 19F NMR (470 MHz, CDCl3, internal standard
PhCF3 at –61.5 ppm): d = –77.3. Chiral GC analysis (methyl
ester): Cyclodex-B column, 50 °C for 1 min, 5 °C/min to 95
°C, hold at 95 °C for 1 min, 20 °C/min to 200 °C, injector
180 °C, detector 250 °C, split 10:1, 13.5 psi He, S-enantio-
mer at 6.10 min, R-enantiomer at 6.83 min.
(12) Experimental Procedure
(R)-(+)-1,1¢-Bi(2-naphthol) (5.1 g, 17.6 mmol, 120 mol%)
was dissolved in anhyd 1,2-dichloroethane (35 mL) and THF
(8.75 mL) and the solution was cooled to –40 °C. A solution
of Et2Zn (13.4 mL, 14.7 mmol, 100 mol%, 1.1 M in toluene)
was added over 30 min. Caution: gas evolution! Proper
venting required! The mixture was stirred at r.t. for 1 h,
cooled to –40 °C and a solution of EtMgCl (8.8 mL, 17.6
mmol, 120 mol%, 2 M in THF) was added over 15 min. The
solution was warmed to r.t. for 1 h and then cooled to –40 °C.
Ethyl 2,2,2-trifluoropyruvate (1.95 mL, 2.50 g, 14.7 mmol)
was added dropwise via syringe pump over 6 h. The mixture
was let stir 18 h and then quenched with 2 N aq HCl (25 mL).
The organic layer was washed with 1 N aq NaOH (3 × 20
Synlett 2007, No. 14, 2193–2196 © Thieme Stuttgart · New York

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