Facile and stereoselective synthesis of non-racemic 3,3,3-trifluoroalanine

Article abstract of DOI:10.3390/51201251

A highly stereoselective enantiodivergent synthesis of non-racemic 3,3,3-trifluoroalanine 7 is reported. The methodology is based on the reduction, by 9-BBN or DIBAH, of the chiral sulfinimine 3 derived from ethyl trifluoropyruvate, followed by acidic hydrolysis of the resulting diastereomeric sulfinamides 4 and 5.

Full text of DOI:10.3390/51201251

Molecules 2000, 5, 1251-1258
molecules
ISSN 1420-3049
http://www.mdpi.org
Facile and Stereoselective Synthesis of Non-Racemic 3,3,3-
Trifluoroalanine†
Marcello Crucianelli,1,* Natalia Battista,1 Pierfrancesco Bravo,2,3 Alessandro Volonterio2 and Matteo
Zanda2,*
1 Dipartimento di Chimica, Ingegneria Chimica e Materiali, Università di L'Aquila, Via Vetoio,
I-67010 Coppito, Italy
2 Dipartimento di Chimica del Politecnico, via Mancinelli 7, I-20131 Milano, Italy
3 C.N.R. - Centro di Studio sulle Sostanze Organiche Naturali, via Mancinelli 7, I-20131 Milano, Italy
† Presented as Poster A0035 at the 4th Electronic Conference on Synthetic Organic Chemistry
(ECSOC-4), September 1-30, 2000, paper A0035.
* Authors to whom correspondence should be addressed. E-mail: zanda@dept.chem.polimi.it
Received: 6 October 2000 / Accepted: 6 November 2000 / Published: 18 December 2000
Abstract: A highly stereoselective enantiodivergent synthesis of non-racemic 3,3,3-
trifluoroalanine 7 is reported. The methodology is based on the reduction, by 9-BBN or
DIBAH, of the chiral sulfinimine 3 derived from ethyl trifluoropyruvate, followed by acidic
hydrolysis of the resulting diastereomeric sulfinamides 4 and 5.
Keywords: Fluorine, Amino acids, Sulfinimines, Asymmetric synthesis
Introduction
The rapidly expanding interest in the field of peptidomimetics is prompting organic chemists to
develop novel and efficient stereocontrolled approaches to rare and unnatural amino acids. An
extremely intriguing class of unnatural amino acids is represented by those incorporating one or more
fluorine atoms [1]. This interest stems from the peculiar biomedicinal and pharmaceutical properties of
fluorinated substrates [2], as well as from the considerable synthetic challenges connected with the
preparation of these molecules in stereodefined, non-racemic form [3]. 3,3,3-Trifluoroalanine (7)
© 2000 MDPI. All rights reserved.

Molecules 2000, 5
1252
(Scheme 2) and its derivatives have attracted a remarkable deal of interest as suicide inhibitors of a
number of pyridoxal-phosphate dependent enzymes [4]. Incorporation of 7 into small peptides has been
achieved, and some of the resulting oligomers have been found to possess interesting biological
activity [5]. Although several preparations of racemic 7 have been described following the seminal
work of Steglich [6], a very few syntheses of non-racemic 7 are available [7], and only recently its
absolute configuration has been clarified [8]. To date, a straightforward method for the synthesis of
non-racemic 7 from readily available or commercial starting materials, such as trifluoropyruvic esters,
is lacking [9]. In this paper we describe the successful accomplishment of this goal.
Results and Discussion
The chiral Staudinger reagent (S)-2 (e.e. > 95%) [10a-d] (Scheme 1) was synthesized by reaction of
the Davis sulfinamide (S)-1 [11] with DEAD/PPh3 (92%) [12]. Next, a high yielding Staudinger (aza-
Wittig) reaction of (S)-2 with ethyl trifluoropyruvate was performed in benzene freshly distilled from
Na (ca. 90 min. at 40 °C), providing (S)-3 [10f]. After evaporation of the solvent, the crude reaction
mixture containing the highly electrophilic sulfinimine (S)-3 was treated with a variety of reducing
agents (Table 1).
COOEt
O
O
O
ii
i
PPh3
S
S
S
p-Tol
NH2
p-Tol
N
p-Tol
N
CF3
2
1
3
OMe
COOEt
CF3
O
S
p-Tol
N
H
H
O
O
[H]
H
COOEt
CF3
(2S,SS)-5
COOEt
CF3
(2R,SS)-4
+
S
S
6
p-Tol
N
p-Tol
N
H
H
Scheme 1. Key: i) PPh3, DEAD (92%); ii) CF3COCO2Et, C6H6 freshly distilled from Na, 40 °C
(−Ph3PO).
Table 1. Reduction of sulfinimine (S)-3.
Entry
[H]
DIBAH
Conditions
THF, −70 °C
Yield (%)a
D.r. 4/5
4:1
1
2
3
4
52
78
58
9-BBN
THF, 0 °C
1:20
2:1
DIBAH/ZnBr2
THF, r.t. to –70 °C
b,c
b,c
NaBH4
Methanol, −70 °C
/
/
a Yields from (S)-2. b We recovered 66% of 6 with 33% d.e. c Very low yields in THF, 0 °C to r.t.

Molecules 2000, 5
1253
The most interesting results were achieved with DIBAH (entry 1) and 9-BBN [13] (entry 2) which
produced with stereodivergent outcomes the diastereomeric sulfinamides 4 and 5, respectively. In the
latter case (9-BBN), the reduction occurred with excellent stereoselectivity (20:1) and overall yield
(78%). Although DIBAH provided lower stereocontrol (4:1) and yield (52%), the fact that both
diastereomers 4 and 5 are readily accessible from the same enantiomeric sulfinimine (S)-3 makes this
method remarkably attractive. DIBAH reduction occurred with lower stereocontrol in favour of 4 (2:1)
upon pre-complexation of (S)-3 with ZnBr2. Complex mixtures were obtained with K- and L-
Selectride® and LiAlH4 in THF as reducing agents. An undesired side-reaction took place upon
treatment of (S)-3 with NaBH4 in methanol (entry 4), namely the addition of methanol across the C=N
bond. Thus, a diastereomeric mixture of adducts 6 (Scheme 1) was obtained, whereas the reduction
products 4,5 could be neither isolated nor detected [14].
A reasonable transition state (TS) 8 (Scheme 2) accounting for the high stereoselectivity observed
with 9-BBN is based on the hypothesis that the sulfinimine (S)-3 is geometrically homogeneous and
thermodynamically stable with the sulfinyl and the bulky trifluoromethyl group in trans position with
respect to the C=N bond, as strongly suggested by theoretical ab initio calculations supported by NMR
spectroscopy [15]. In line with the previously proposed TS for highly stereoselective 9-BBN reductions
of ketone derived sulfinimines [16], the boron atom should coordinate the sulfinyl oxygen giving rise
to a chair-like TS. As a consequence, the hydride predominantly attacks the Re face of the C=N bond
producing the diastereomeric sulfinamide 5 with overwhelming preference.
H
H
O
O
B
H2N H
HO2C CF3
(R)-7
i, ii
COOEt
CF3
(2R,SS)-4
F3C
S
N
p-Tol
p-Tol
N
S
H
8
COOEt
Scheme 2. Key: i) HCl conc., reflux, overnight. ii) Dowex 50W-X8.
With the diastereomeric sulfinamides 4 and 5 in hand, both enantiomers of 3,3,3-trifluoroalanine (7)
are easily accessible, as demonstrated in the preparation of (R)-7 from 4 (obtained by reduction of 3
with DIBAH), which was treated with 10% HCl (reflux, overnight) [6d] followed by ion exchange
chromatography with DOWEX-50W. We were also able to prepare (R)-7 one-pot in 38% overall yield
from (2R,RS)-5 (obtained from the enantiomeric iminophosphorane (R)-2), by submitting the crude 9-
BBN reduction mixture to hydrolysis with 10% HCl, followed by the usual ion-exchange purification.
The stereochemistry of (R)-7 was assessed by comparison of its optical power with the literature values
for non-racemic 3,3,3-trifluoroalanine [7,8]. Although we could not measure directly the e.e. of (R)-7,
its [α]20D + 7.5 (c 0.18, MeOH) suggests a value higher than 70% [17].

Molecules 2000, 5
1254
In summary, we have developed an extremely facile, straightforward, stereoselective and
enantiodivergent approach to non-racemic 3,3,3-trifluoroalanine, which is now readily available for
further biochemical studies and incorporation into peptidomimetics.
Experimental
General
Chemical shifts (δ) are reported in parts per million (ppm) of the applied field. Coupling constants
(J) are reported in Hertz. Me4Si was used as internal standard ( δH and δC = 0.00) for 1H and 13C nuclei,
while C6F6 was used as external standard (δF = −162.90) for 19F nuclei. Peak multiplicities are
abbreviated: singlet, s; doublet, d; triplet, t; quartet, q; multiplet, m; etc. Anhydrous solvents were
obtained by distillation from sodium (THF, benzene) or from calcium hydride (dichloromethane,
diisopropylamine). In all other cases commercially available reagent-grade solvents were employed
without purification. Grignard reagents were purchased from Sigma/Aldrich/Fluka Company.
Reactions performed in dry solvents were carried out under nitrogen atmosphere. Melting points are
uncorrected and were obtained on a capillary apparatus. Analytical thin-layer chromatography (TLC)
was routinely used to monitor reactions. Plates precoated with E. Merck silica gel 60 F254 of 0.25 mm
thickness were used. Merck silica gel 60 (230-400 ASTM mesh) was employed for flash
chromatography (FC).
Synthesis of N-p-Tolylsulfinyl-Imino-Triphenylphosphorane (S)-2
To a solution of (S)-1 (1.93 g, 12.35 mmol) and PPh3 (3.24 g, 12.35 mmol) in dry THF (50 mL) at
0 °C, neat DEAD (1.95 mL, 12.35 mmol) was added dropwise with stirring. The resulting dark-red
mixture was allowed to warm to r.t. in 40 min., then the solvent was removed in vacuo. The
iminophosphorane (S)-2 was obtained in pure form by FC (n-Hex/AcOEt 3:7) as a yellowish sticky oil
1
(4.75g, 92%): [α]20 + 7.6 (c 0.83, CHCl3); H-NMR (CDCl3, 400 MHz): δ 7.8-7.71 (m, 6H), 7.67-
D
13
7.64 (m, 2H), 7.58-7.53 (m, 3H), 7.49-7.43 (m, 6H), 7.2 (d, J = 8.3, 2H), 2.34 (s, 3H). C-NMR
(CDCl3, 62.86 MHz): δ 149.8 (d, J = 24), 139.3, 133.0 (d, J = 10.2), 132.4 (d, J = 2.8), 129.0, 128.7 (d,
31
J = 12), 128.6 (d, J = 99.8), 125.0, 21.3. P-NMR (CDCl3, 162 MHz) δ 27.8 (s) (H3PO4 as external
standard). Anal. Calcd for: C25H22NOPS: C, 72.27; H, 5.34; N, 3.37. Found: C, 72.59; H, 4.99; N,
3.60. Enantiomeric iminophosphorane (R)-2, analogously obtained from (R)-1, had [α]20D − 8.1 (c
0.95, CHCl3).
Reduction with DIBAH: synthesis of 3,3,3-trifluoro-2-(toluene-4-sulfinyl)amino-propionic acid ethyl
esters 4,5
To a solution of iminophosphorane (S)-2 (0.2 g, 0.48 mmol) dissolved in freshly distilled benzene

Molecules 2000, 5
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(1 mL),neat ethyl trifluoropyruvate (82 mg, 0.48 mmol) was added dropwise. The mixture was warmed
to 40 °C for ca. 2 hours. After a rapid evaporation of the solvent, the crude containing the sulfinimine
(S)-3 was redissolved in 1 mL of freshly distilled THF and the resulting yellow solution cooled down
to − 70 °C. A 1.0 M n-hexane solution of DIBAH (0.58 mL, 0.58 mmol) was added dropwise while
stirring. After 15 min. the reaction was quenched at − 70 °C with a saturated solution of ammonium
chloride, filtered over a Celite pad, then extracted with ethyl acetate and the collected organic layers
dried over anhydrous sodium sulfate. Purification by FC (n-hexane/ethyl acetate from 80:20 to 70:30)
afforded a 80:20 mixture of two diastereomers 4,5 with an overall yield of 52%.
1
5: (Rf >): m.p. (isopropyl ether) 116-118 °C (dec.); [α]20 + 252.5° (c 0.56, CHCl3). H-NMR
D
(CDCl3, 250 MHz) δ 7.58 (d, J = 8.3, 2H), 7.34 (d, J = 8.3, 2H), 5.48 (br d, J = 10, 1H), 4.39-4.25 (m,
2H), 4.14-4.01 (m, 1H), 2.43 (s, 3H), 1.32 (t, J = 7, 3H). 19F-NMR (CDCl3, 235.19 MHz) δ − 73.2 (d, J
= 7.4). 13C-NMR (CDCl3, 62.86 MHz) δ 165.08, 141.26, 137.99, 128.72, 125.32, 121.49 (q, J =
281.7), 62.30, 52.42 (q, J = 32), 20.35, 12.76. Anal Calcd. for: C12H14F3NO3S: C, 46.60; H, 4.56; N,
4.53. Found: C, 46.70; H, 4.45; N, 4.78.
4: (Rf <): oil; [α]20 + 119.7° (c 0.33, CHCl3). 1H-NMR (CDCl3, 250 MHz) δ 7.61 (d, J = 8.1,
D
2H), 7.34 (d, J = 8.1, 2H), 5.07 (br d, J = 8.5, 1H), 4.60-4.48 (m, 1H), 4.34-4.22 (m, 2H), 2.43 (s, 3H),
1.29 (t, J = 7.3, 3H). 19F-NMR (CDCl3, 235.19 MHz) δ − 74.14 (d, J = 7.4, 3F).
Reduction with DIBAH and ZnBr2
A solution containing the sulfinimine (S)-3 dissolved in anhydrous THF (1.5 mL), obtained as
described above from the same amount of reagents, was treated with zinc bromide (108 mg, 0.48
mmol) and stirred at r.t. for 30 min. The mixture was cooled to − 70 °C, then a 1.0 M n-hexane
solution of DIBAH (0.58 mL, 0.58 mmol) was added dropwise while stirring. After 15 min. the
reaction was quenched and worked-up as described above. Purification by FC afforded a 2:1 mixture of
the two diastereomers 4,5 with an overall yield of 58 %.
Reduction with NaBH4
A solution containing the sulfinimine (S)-3 dissolved in distilled methanol (1.5 mL), obtained as
described above, was cooled to − 70 °C, then NaBH4 (22 mg, 0.58 mmol) was added in one portion.
After 10 min. the reaction was quenched with saturated aqueous NH4Cl and extracted with ethyl
acetate. The collected organic layers were dried over anhydrous sodium sulfate and the resulting crude
mixture purified by FC (n-hexane/ethyl acetate from 80:20 to 70:30) affording a 2:1 mixture of two
diastereomers 6 (overall yield 66%) resulting from addition of methanol across the C=N bond of (S)-3.

Molecules 2000, 5
1256
Reduction with 9-BBN
A solution containing the sulfinimine (S)-3 dissolved in freshly distilled THF (1.5 mL), obtained as
described above starting from 0.58 mmol of iminophosphorane (S)-2 and 0.58 mmol of ethyl
trifluoropyruvate, was cooled to 0 °C, then a 0.5 M THF solution of 9-BBN (1.27 mL, 0.63 mmol) was
added dropwise. The reaction mixture was stirred under nitrogen at the same temperature for ca. 2
hours, then worked-up by adding 5 µL of methanol in order to destroy the excess of 9-BBN [13], then
the solvent was removed in vacuo. The crude was redissolved in 1.5 mL of diisopropyl ether, filtered
and the resulting solution purified by FC, affording the two diastereomers 4, 5 in 1:20 ratio with an
overall yield of 78 %.
Direct synthesis of (R)-(+)-3,3,3-trifluoro-alanine 7
The first part of the synthetic procedure was performed using the same conditions described above
for the preparation of the sulfinimine (S)-3, the only exception being the use of 1.13 mmol of the (R)-
enantiomer of iminophosphorane 2. After addition of 9-BBN (1.24 mmol), the reaction mixture was
stirred under nitrogen (0 °C) for ca. 2 hours, then the solvent evaporated in vacuo. The crude was re-
dissolved in 5 mL of conc. HCl and stirred overnight at reflux [6d]. The reaction mixture was diluted
with water and, after addition of diethyl ether (2 mL), vigorously stirred for 1 hour. The two layers
were then separated, the organic phase washed with two portions of a 10% solution of HCl, and the
collected aqueous phases concentrated in vacuo and loaded in a Dowex 50W-X8 column. Elution with
7.5% aqueous ammonia afforded 61 mg (38% overall yield) of free (R)-3,3,3-trifluoro-alanine 7.
(R)-7: [α]20D +7.5 (c 0.18, MeOH), (lit.[7a] value for (c 0.76, MeOH) of enantio-enriched (R)-7 (e.e.
62%) has been reported = +6.8); mp 205-207 °C (sublimate: lit.[6d] sublimation T > 205 °C) (EtOH);
13
1H-NMR (D O) δ 4.32 (1H, q, J = 9.0 Hz); C-NMR (D2O) δ 164.69, 122.11 (q, J = 280 Hz), 54.89
2
(q, J = 30 Hz); 19F-NMR (D2O) δ −69.1 (d, J = 9.0 Hz).
Acknowledgments
We thank M.U.R.S.T. COFIN 1998 (Nuove metodologie e strategie di sintesi di composti di interesse
biologico) and C.N.R. - C.S.S.O.N. for financial support.
References and Notes
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eds.; Wiley: Chichester, 1995.

Molecules 2000, 5
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important for minimizing the racemization of the sulfinimine 3 upon reaction with a variety of
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work.
11. (a) Davis, F. A.; Reddy, R. E.; Szewczyk, J. M.; Reddy, G. V.; Portonovo, P. S.; Zhang, H.;
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27, 13-18.

Molecules 2000, 5
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of solid samples of 7, purified by ion-exchange chromatography, after one week at 4 °C. Racemic 7
is known to undergo progressive elimination of HF at pH > 6: Weygand, F.; Steglich, W.;
Oettmeier, W. Chem. Ber. 1970, 103, 1655-1663. Therefore, we cannot rule out that a partial
racemization of free 7 might take place during the purification or storage, even if short.
Sample Availability: Samples of iminophosphoranes (R)- and (S)-2 are available from the authors.
© 2000 by MDPI (http://www.mdpi.org).