Asymmetric synthesis of novel α-amino acids with β-branched side chains

Article abstract of DOI:10.1016/j.bmcl.2007.02.041

An asymmetric synthesis of α-amino acids with novel β-branched side chains has been implemented. The syntheses feature a p-toluenesulfinylimine induced chiral Strecker approach and were found to be applicable to the introduction of both aliphatic and aromatic β-branched sidechains for preparation of previously unknown α-amino acids.

Full text of DOI:10.1016/j.bmcl.2007.02.041

Bioorganic & Medicinal Chemistry Letters 17 (2007) 2401–2403
Asymmetric synthesis of novel a-amino acids with
b-branched side chains
Minsheng Zhang,* Alex Porte, George Diamantidis, Kimberly Sogi, Dennis Kubrak,
Lynn Resnick, Scott C. Mayer, Zheng Wang, Anthony F. Kreft and Boyd L. Harrison
Wyeth Research, CN 8000, Princeton, NJ 08543, USA
Received 19 January 2007; revised 12 February 2007; accepted 15 February 2007
Available online 17 February 2007
Abstract—An asymmetric synthesis of a-amino acids with novel b-branched side chains has been implemented. The syntheses fea-
ture a p-toluenesulfinylimine induced chiral Strecker approach and were found to be applicable to the introduction of both aliphatic
and aromatic b-branched sidechains for preparation of previously unknown a-amino acids.
ꢀ 2007 Elsevier Ltd. All rights reserved.
In an effort to discover metabolically more stable and
biologically interesting pharmacophore components
for our current medicinal chemistry programs, we have
implemented an asymmetric synthesis of a-amino acids
with novel b-branched side chains.1 The syntheses fea-
ture a p-toluenesulfinylimine induced chiral Strecker ap-
proach and were found to be applicable to the
introduction of both aliphatic and aromatic b-branched
sidechains for the preparation of previously unknown
a-amino acids.2 Herein, we wish to report three exam-
ples of such a-amino acid syntheses shown in Figure 1.
nium salt 5 is easily accomplished, preparation of 6 via
nucleophilic addition of 5 to ethyl chloroformate using
two equivalents of potassium hexamethyldisilazide was
problematic, affording only 30–40% yield of 6 under
the optimum carefully controlled conditions. A simple
change of the base from potassium to lithium hexameth-
yldisilazide improves the yield dramatically. As illus-
trated in Scheme 1, the proposed side reaction is
largely due to the nucleophilicity of the potassium base
toward ethyl chloroformate and leads to undesired car-
Bis-(trifluoromethyl)-valine 1 is believed to be metabol-
ically more stable due to its fluorine cap. It, therefore, is
a much desired building block for drug design; however,
its synthesis had proved much more difficult than ini-
tially thought. The presence of polyfluoro groups has a
major impact on the reactivity and stability of the syn-
thetic intermediates, therefore, reaction conditions
applicable to normal nucleophilic or electrophilic reac-
tions cannot be applied directly to these cases. Shown
in Schemes 1 and 2 are synthetic routes that helped re-
solve these issues and led to the successful preparation
of this fluorine-capped a-amino acid.
CF3
CF3
CF3
CF3
H2N
1
HO
OH
O
or
or
Chiral Strecker
Retro-synthesis
R
O
R
2
H2N
HO
OH
or
or
Pivotal to the success for the synthesis of 1 was the prep-
aration of the key Horner–Emmons precursor 6. While
conversion of trifluoropropyl iodide 4 to its phospho-
R
R
3
H2N
OH
HO
O
Keywords: Asymmetric synthesis; a-Amino acids.
Corresponding author. E-mail: zhangm8@wyeth.com
*
Figure 1. Retrosynthesis of b-branched a-amino acids 1, 2, and 3.
0960-894X/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2007.02.041

2402
M. Zhang et al. / Bioorg. Med. Chem. Lett. 17 (2007) 2401–2403
Cl
Proposed transition states
for diastereoselectivity
H
H
O
O
:
:
O
Ph3P
O
CF3
CF3
S
S
I-
Ph3+P
CF3
OEt
1.0x
Ar
O
N
R
Ar
N
R
(S)
PPh3,
PhCH3,
reflux,
(R)
I
11
LiN(SiMe3)2, 2x
THF/PhCH3, -78oC-
OEt
Et2AlCN, i-PrOH
Et2AlCN, i-PrOH
4
6
5
Ar
H
AlCN(Et,OPr-i)
Et
N
S
N
C
S
Transylidation
KHMDS
KHMDS
i-PrO
R
Ar
R
N
Al
Et
Al
O
i-PrO
C
N
H
AlCN(Et,OPr-i)
Cl-
Ph3+P
O
CF3
Ph3P
CF3
Cl
OEt
O
Ar
H
"
S
OEt
O
NH
S
NC
R
Ar
R
N
H
O
NC
"
H
12
Si
N
Si
HCl/H2O
HCl/H2O
Si
N
K
Si
O
OEt
H
R
R
H
Proposed side reaction => Low yield
(S)-sulfinylimine leads
to (S)-amino acid
H2N
COOH
H2N
COOH
(R)
Scheme 1. Conditions and side reactions for the preparation of 6.
(S)
Figure 2. Proposed transition states for the asymmetric induction.
CF3
CF3
OEt
F3CCHO
H2O
Ph3P
O
CF3
CF3
H2, (1 atm) Pd/C, THF
CF3
LAH, Et2O
Franklin Davis and coworkers.2 As illustrated in Figure 2,
the sulfinylimine 11 is believed to form an aluminum com-
plex with the cyanide source and isopropanol in a least
crowded chair-like transition state to deliver diastereose-
lectivity. Consequently, use of (S)-p-toluenesulfinamide
leads to (S)-12.
O
O
OEt
THF, reflux
OEt
6
7
8
NH2
S+
CF3
-O
CF3
CF3
CF3
O
Dess-Martin
CH2Cl2
CF3
CF3
H
Due to the volatility of the aldehyde, crude 10 was used
in the preparation of 11, resulting in an overall yield of
23% for the two steps (un-optimized). The diastereose-
lectivity from 11 to 12 is over 90% on repeated trials
and can be further enriched in subsequent purifications
by re-crystallization. The sulfinylimine 12 is converted
to the desired methyl ester of bis-(trifluoromethyl)-va-
N
S+
Ti(OEt)4
CH2Cl2
H
-O
OH
10
9
11
CF3
CF3
CF3
Et2AlCN,
i-PrOH
MeOH,
H2SO4
CF3
NC
O
O
NH
S+
-O
NH2
12
13
LAH
R
R
Scheme 2. Conditions for the preparation of 13 from 6.
Et2O, RT,
O
LDA(2.2x)
RI (1.2x),
THF, -78oC
O
OH
OH
OH
bamate by-product. The lithium counter ion is probably
modulating the nucleophilicity of the base and suppress-
ing the side product formation.
Ti(OEt)4
R
reflux, CH2Cl2
Dess-Martin
0oC, CH2Cl2
R
H
N
S+
NH2
S+
H
O
-O
Scheme 2 illustrates the synthetic route from intermediate
6 to the desired methyl ester of bis-(trifluoromethyl)-va-
line 13. The key precursor to the asymmetric Strecker
reaction is the aldehyde 10. The precursor 6 is converted
to 8 via the proposed Horner–Emmons reaction of 6 with
excess trifluoroacetaldehyde at reflux conditions in THF
followed by hydrogenation of the olefin 7. LAH reduction
of the ester 8 and oxidation of the resulting alcohol 9 with
Dess–Martin periodinane at 0–25 ꢁC in CH2Cl2 provided
the aldehyde 10. The asymmetric induction of the desired
amino ester 13 was accomplished by using p-toluenesulfi-
nylimine as a chiral auxilliary originally introduced by
-O
Et2AlCN,
i-PrOH
-78oC
R
MeOH,
H2SO4
R
O
O
NC
NH
S+
NH2
R = Me or Et
-O
14
Scheme 3. Preparation of b-methyl or b-ethyl homophenyl-alanine.

M. Zhang et al. / Bioorg. Med. Chem. Lett. 17 (2007) 2401–2403
2403
NH2
S+
2. Davis, F. A.; Portonovo, P. S.; Reddy, R. E.; Chiu, Y.
J. Org. Chem. 1996, 61, 440.
-O
3. To a solution of the primary alcohol (5.8 mmol) in
methylene chloride (17 mL) at 0 ꢁC was added Dess–Martin
periodinane (2.5. g, 5.9 mmol) slowly. The reaction mixture
was left to stir and warm to room temperature overnight.
The solution was diluted with diethylether (15 mL) and a
solution of Na2S2O4 (3.2 g) in a saturated aqueous solution
of NaHCO3 (30 mL). The liquid layers were extracted with
ethyl acetate. The organic layer was separated and concen-
trated to afford the crude aldehyde. The crude aldehyde in
methylene chloride was then treated with titanium (iv)
ethoxide (4 mL, 20 mmol) followed by (S)-toluenesulfini-
mide (0.85 g, 5.5 mmol). The solution was refluxed for
approximately 5 h. Water (18 mL) was added dropwise to
precipitate titanium salts. The suspension was filtered
though Celite and the filter cake was washed with CH2Cl2.
The layers of filtrate were separated and the aqueous layer
was extracted with CH2Cl2. The combined organic extracts
were dried (Na2SO4) and concentrated. Column chroma-
tography affords the purified sulfinylimine. To diethylalu-
minum cyanide (5 mL, 1.0 M in toluene, 5.2 mmol) in THF
(12 mL) at 0 ꢁC was added i-PrOH (267 lL, 3.5 mmol).
After 15 min, this solution was added to a À78 ꢁC solution
of the sulfinylimine (3.5 mmol) in THF (19 mL). After 1 h,
an additional solution of diethylaluminum cyanide and i-
PrOH (in the same amounts) was added to the reaction.
After another 2 h, the reaction mixture was quenched into
saturated aqueous solution of ammonium chloride and
extracted 2· with ethyl acetate. Column chromatography
with ethyl acetate–hexane (0–50% gradient) affords the
Dess-Martin
CH2Cl2
H
N
S+
0oC - rt
Ti(OEt)4
CH2Cl2
reflux
H
OH
-O
O
MeOH,
H2SO4
reflux
Et2AlCN,
i-PrOH
O
O
NC
NH
S+
THF,
-78oC-rt,
NH2
-O
15
Scheme 4. Preparation of the methyl ester of b-ethyl phenylalanine.
line 13 by refluxing in methanol in presence of catalytic
sulfuric acid, or to 1 in presence of sulfuric acid and
water.3,4
The asymmetric Strecker synthesis of novel a-amino
acids demonstrated above were also applied to the syn-
theses of the previously unknown a-amino acids 14 and
15 as shown in Schemes 3 and 43–6
A typical procedure for the asymmetric synthesis of a
b-branched a-amino acid from a b-branched primary
alcohol outlined above is given in the references and
notes section.3
chiral Strecker product.
A solution of this product
(3.5 mmol) in MeOH (8 mL) was treated with H2SO4
(2 mL) dropwise and refluxed for 5 h and then left to stir at
room temperature overnight. Extraction with 1 N NaOH
and EtOAc affords the methyl ester of the desired a-amino
acids.4–6
Applications of these novel a-amino acids as new build-
ing blocks and key pharmacophore components for
drug design in our medicinal chemistry programs will
be reported in future publications.
4. For 13: mass spectrum (+ESI): 268.1 (M+H)+. 1H NMR
(DMSO-d6) d: 2.3 (4H, m, 2CH2), 2.7 (1H,m, CH), 2.9 (2H,
d, NH2), 3.6 (1H, 2t, CHN).
5. For 14: mass spectrum (+ESI): 222.7 (M+H)+. 1H NMR
(CDCl3) d:1.0 (3H, m, CH3), 1.2 (2H, m, CH2CH3), 1.3
(1H, m, CH2CH ), 2.0 (1H, m, CHN), 2.2 (2H, m, NH2), 2.7
(2H, m, ArCH2), 3.7 (3H, s, OCH3), 7.0–7.4 (5H, m, ArH).
6. For 15: mass spectrum (+ESI): 208.3 (M+H)+. 1H NMR
(CDCl3) d: 0.5 (3H, m, CH3), 1.7 (2H, m, CH2), 1.9 (2H, m,
NH2), 2.8 (1H, m, CH), 3.5 (3H, s, OCH3), 3.6 (1H, 2t,
CHN), 7.0–7.4 (5H, m, ArH).
References and notes
1. (a) Kreft, A.F.; Resnick, L.; Mayer, S.C.; Diamantidis, G.;
Cole, D.C.; Harrison, B.L.; Zhang, M.; Hoke, M.; Ting,
W.; Galante, R.C.U.S. Patent 20040198778, 2004; (b).
Chem. Abstr. 2004, 141, 314147.