Practical asymmetric synthesis of a novel γ-secretase inhibitor

Article abstract of DOI:10.1016/j.tet.2008.04.072

An efficient route to γ-secretase inhibitor hydroxyl thiophene sulfonamide 1 is described. The approach contains nine steps with an overall yield of 8%. The synthesis highlights a diastereoselective methylation using Evans' oxazolidinone method and a chiral Strecker reaction via Davis' sulfonimine protocol.

Full text of DOI:10.1016/j.tet.2008.04.072

Tetrahedron 64 (2008) 6440–6443
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Practical asymmetric synthesis of a novel g-secretase inhibitor
*
*
Zheng Wang , Lynn Resnick
Wyeth Research, Chemical and Screening Sciences, PO Box CN 8000, Princeton, NJ 08543, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient route to g-secretase inhibitor hydroxyl thiophene sulfonamide 1 is described. The approach
Received 21 February 2008
Received in revised form 16 April 2008
Accepted 17 April 2008
contains nine steps with an overall yield of 8%. The synthesis highlights a diastereoselective methylation
using Evans’ oxazolidinone method and a chiral Strecker reaction via Davis’ sulfonimine protocol.
Ó 2008 Elsevier Ltd. All rights reserved.
Available online 24 April 2008
Keywords:
g-Secretase inhibitor
Evans’ oxazolidinone
Chiral Strecker
Davis’ sulfonimine
1. Introduction
report a scalable asymmetric synthesis of
(Fig. 1).4
g-secretase inhibitor 1
Alzheimer’s disease (AD) is the ost common cause of dementia
in the elderly. AD affects millions of people worldwide and its di-
rect and indirect costs are at least $100 billion annually. Common
clinical symptoms of AD include cognitive decline, irreversible
memory loss, disorientation, and language impairment.1 One of the
main pathological characteristics of AD is the accumulation and
2. Results and discussion
The original approach to prepare compound 1 involved an
achiral synthesis,4 which started from the commercially available
carboxylic acid 2. The desired compound 3 was obtained as a mix-
ture of four stereoisomers via a six-step synthesis. The isolation of
(1S,2R)-stereoisomer required two stages: (1) reverse phase HPLC
to separate the diastereomers; (2) chiral HPLC to separate the
enantiomers (Scheme 1).
aggregation of
cious plaques.2 Formation of A
amino acids, requires proteolytic cleavage of
protein (APP). Our project involves reduction of A
inhibition of
-secretase, a protease that cleaves APP to form Ab 3
Among our compounds of interest, compound 1 was shown to be
a potent and selective -secretase inhibitor. Therefore, multi-gram
b
-amyloid protein (A
, which is composed of 40–42
-amyloid precursor
levels through
b) into extracellular pertina-
b
b
b
g
.
O
HO
g
O
O
preparation of compound 1 for further pre-clinical evaluations
such as oral efficacy required a practical synthesis. Herein, we
F3C
OH
S
S
F3C
N
Cl
H
2
3
HO
1. Reverse phase HPLC
2. Chiral HPLC
O
O
S
S
F3C
N
Cl
H
1
Scheme 1.
1
Figure 1.
Due to the inefficiency of this method to provide large-scale
quantities of compound 1, we embarked on a chiral synthetic route.
Retrosynthetic analysis for the preparation of target compound 1
via a chiral route entails utilization of chiral amino acid 4 as a key
intermediate (Scheme 2). We envisioned that the C-1 chiral center
would be formed through a chiral Strecker reaction from chiral
aldehyde 5, an intermediate, which could be prepared from
* Corresponding authors. Tel.: þ1 732 274 4793; fax: þ1732 274 4505 (Z.W.); tel.:
þ1 732 274 4780; fax: þ1 732 274 4505 (L.R.).
E-mail addresses: wangz@wyeth.com (Z. Wang), resnicl@wyeth.com (L.
Resnick).
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.04.072

Z. Wang, L. Resnick / Tetrahedron 64 (2008) 6440–6443
6441
carboxylic acid 6 via Evans’ methodology5 by formation of chiral
oxazolidinone followed by diasteroselective methylation and
reduction.
avoid loss of product due to co-evaporation with solvent. Therefore,
the product was used in the next step without removal of work-up
solvent.
Reduction;
Sulfonamide
formation
oxidation
see table 1
HO
O
F3C
OH
F3C
O
10
5
1
F3C
NH2
Scheme 4.
4
Addition of chiral
Table 1
Optimization of reaction conditions to convert alcohol 10 to aldehyde 5
Chiral Strecker
reaction;
Hydrolysis
auxiliary;
Methylation;
Reduction
O
Entry
Oxidations
Results (yield)
Cost (supplier)
F3C
F3C
OH
1
2
3
4
5
Swern7
Low conversiona
No reaction
d
O
CYC/TEMPO8
NaOCl/TEMPO9
PhI(OAc)2/TEMP10
Dess–Martin6
d
5
6
No reaction
d
Product 90%b
Product 80%b
$0.89/g (Sigma–Aldrich)
$5.5/g (OmegaChem)
Scheme 2.
The planned strategy was carried out initially on a small scale
to verify the synthetic route and supply small quantities of ma-
terial. As larger batches of the material were required, optimized
scale-up efforts were essential, as will be described. In the first
step, commercially available 4,4,4-trifluorobutyric acid 6 was
converted into a mixed anhydride, and then reacted with lithiated
oxazolidinone 7 to afford carboximide 8 (Scheme 3). The pro-
cedure entails formation of the mixed anhydride by addition of
triethylamine and trimethylacetyl chloride to 4,4,4-trifluorobutyric
acid 6 in THF.
a
Conversion: 20–30%.
Yield estimated by NMR.
b
With chiral aldehyde 5 in hand, we embarked on the asym-
metric synthesis of amino acid 4. Many methods for the asym-
metric synthesis of amino acids have been developed.11,12 It was of
interest to select a method that is amenable to large-scale appli-
cation. We reasoned that the sulfinimine-mediated asymmetric
Strecker method that was developed in the Davis group13–15 would
be appropriate due to the commercial availability and reasonable
price of the sulfinamide chiral auxiliary (Scheme 5). Thus, con-
densation of (S)-(þ)-toluenesulfinamide 11 with aldehyde 5 in the
presence of Ti(OEt)4 in dichloromethane provided sulfinimine 12.
The reaction of Et(i-OPr)AlCN with 12 afforded amino nitrile 13
with a diastereomeric ratio of 7:1. Crystallization of the crude
product with ether/hexane (1:1) provided the product with an
enhanced diastereomeric ratio of >100:1 as judged by 1H NMR and
HPLC. (The other diastereomer was not detected.) In the final step
to form amino acid 4, nitrile 13 was hydrolyzed with concentrated
hydrochloric acid.
O
1. trimethylacetyl chloride,
Et3N, THF
O
2.
O
O
F3C
OH
F3C
N
O
6
8
Bn
LiN
O
7
NaHMDS,
64% MeI, THF,
-40 to -30 °C
Bn
80%
O
O
LiBH4,
ethyl ether
F3C
OH
F3C
N
O
86%
O
S
10
9
Bn
H2N
O
S
Scheme 3.
11
F3C
O
O
F3C
N
12
Ti(OEt)4, CH2CH2
65%
5
The resulting slurry is then added to a solution of lithiated
oxazolidinone salt 7. To ensure maximal transfer of the slurry to the
oxazolidinone salt solution, we found that the concentration of
mixed anhydride should be ꢀ0.93 M. The purification of carbox-
imide 8 originally included tedious silica gel column chromatog-
raphy. Alternatively, we found that 8 can be purified efficiently by
crystallization with hexane/ethyl acetate.
Subsequent asymmetric methylation was carried out by anion
formation with sodium bis(trimethylsilyl)amide in THF at ꢁ40 ꢂC,
followed by addition of iodomethane. The reaction temperature
was then increased to ꢁ30 ꢂC and stirred for 5 h. In this manner, 9
was obtained as a single diastereomer in 64% yield. Treatment of 9
with LiBH4 gave chiral alcohol 10 in 86% yield.
Oxidation of alcohol 10 to aldehyde 5 was initially performed
with Dess–Martin reagent 6 (Scheme 4). We found that the yield of
the oxidation was variable upon scale-up. Therefore, we screened
other oxidation conditions including Swern oxidation,7 tri-
chloroisocyanuric acid/TEMPO,8 NaOBr2/TEMPO,9 and PhI(OAc)2/
TEMPO.10 The optimal conditions for oxidation were found to be
PhI(OAc)2/TEMPO, which was more reproducible than the Dess–
Martin conditions and decreased the cost substantially (see Table
1). Due to the high volatility of aldehyde 5, it was imperative to
Et(iPrO)AlCN,
THF, 63%
HO
CN
O
S
conc. HCl
F3C
N
F3C
NH2
H
13
4
Scheme 5.
Completion of the synthesis involved reduction of amino acid 4
with LiBH4/TMSCl to afford amino alcohol 14, and then treatment of
this compound with 5-chlorothiophene-2-sulfonyl chloride 15 in
the presence of triethylamine to give target compound 1 (Scheme
6). Crystallization with ethyl acetate/heptane (1:4) gave target 1 as
a single crystal form in 86% yield.
HO
15, Et3N, CH2Cl2
NH2
50% from 13
LiBH4, TMSCl, THF
4
1
F3C
14
Scheme 6.

6442
Z. Wang, L. Resnick / Tetrahedron 64 (2008) 6440–6443
3. Conclusion
the solution was added saturated aqueous NH4Cl (3 L). The organic
layer was separated, dried over anhydrous sodium sulfate, filtered,
and concentrated to afford a yellow oil. The crude product was
passed through a short silica gel column (hexane/ethyl acetate, 8:1)
to afford 189 g (estimated yield 64%) of 9 as a light yellow oil, which
was used directly in the next step. 1H NMR (400 MHz, DMSO-d6)
In conclusion an efficient and practical asymmetric synthesis of
biologically active hydroxyl thiophene sulfonamide 1 was de-
veloped. The challenge of the synthesis of this compound involved
formation of two chiral centers. Asymmetric methylation via Evan’s
oxazolidinone method provided the R-configuration of the C-2
chiral center and a sulfinimine-mediated asymmetric Strecker
reaction was used to install the S-configuration of the C-1 chiral
center. Target compound 1 was ultimately prepared in 9 steps with
an overall yield of 8%. Crystallization gave the target molecule as
single crystal form with 99% chemical purity and 98.5% ee.
d
8.40 (s, 1H), 7.30 (t, J¼4 Hz, 2H), 7.25 (t, J¼4 Hz, 1H), 7.19 (d,
J¼4 Hz, 2H), 4.66–4.70 (m, 1H), 4.37 (t, J¼4 Hz, 1H), 4.25 (dd, J¼8,
4 Hz, 1H), 3.89–3.96 (m, 1H), 2.93–3.00 (m, 1H), 2.69–2.80 (m, 1H),
2.35–2.51 (m, 1H), 1.22 (d, J¼8 Hz, 3H). 13C NMR
d 178.0, 153.6,136.1,
130.2, 129.2, 127.7 (q, CF3), 127.6, 67.0, 55.0, 37.2, 35.8 (q), 32.4, 18.3.
MS [M]þ m/z 315. HRMS (ESI) [MþH] calcd for C15H16F3NO3
316.1159; found 316.1155.
4. Experimental
4.1. General
4.4. (2R)-4,4,4-Trifluoro-2-methyl-butan-1-ol (10)
To a solution of 9 (189 g, 600 mmol) and water (10.8 mL,
600 mmol) in ethyl ether (2.5 L) at 0 ꢂC was added a solution of
lithium borohydride (2 M in THF, 300 mL, 600 mmol). After 30 min,
the reaction mixture was warmed to room temperature and stirred
for 3 days. The mixture was quenched with methanol (500 mL) and
then sodium hydroxide (1 N, 4 L) was added. The mixture was
extracted with ethyl ether (3ꢃ500 mL) and the combined organic
extracts were washed with water and brine, then dried over
anhydrous sodium sulfate, filtered, and concentrated to 500 mL.
The crude product was passed through a short silica gel column
(petroleum ether/ethyl ether, 1:1), and concentrated to afford 107 g
of a solution of 10 in petroleum ether/ethyl ether (69% by NMR,
estimated yield: 86% yield). The petroleum ether/ethyl ether
solution of 10 was used directly in the next step. 1H NMR (400 MHz,
All reagents and solvents were purchased from commercial
sources and used without further purification. 1H NMR spectra
were recorded on a Varian Unity Plus 40 spectrometer. The
chemical shifts are reported in parts per million downfield from
zero, and coupling constants are reported in hertz (Hz). Mass
spectra were recorded on either a Hewlett-Packard 5995A, a Fin-
nigan Trace MS or a Micromass LCT spectrometer. C, H, N com-
bustion analyses were determined on either a Perkin–Elmer 2400
analyzer or were performed by Robertson Microlit (Madison, NJ).
HPLC was performed on Agilent systems with solvents indicated.
Enantiomeric excess (ee) was determined by chiral HPLC of two
enantiomers.
4.2. (4R)-4-Benzyl-3-(4,4,4-trifluorobutanoyl)-1,3-oxazolidin-
DMSO-d6) d 4.49 (br s, 1H), 3.21–3.26 (m, 1H), 3.14–3.18 (m, 1H),
2-one (8)
2.58–2.62 (m, 1H), 2.29–2.40 (m, 1H), 1.97–2.04 (m, 1H), 4.36–4.39
(t, J¼4 Hz, 1H), 4.25 (dd, J¼8, 4 Hz, 1H), 3.89–3.96 (m, 1H),
2.93–3.00 (m, 1H), 2.69–2.80 (m, 1H), 2.35–2.51 (m, 1H), 0.82 (d,
Reaction mixture 1: to a solution of 4,4,4-trifluorobutyric acid
(6, 199 g, 1.40 mol), triethylamine (205 mL, 1.47 mol), and THF
(1.5 L) at 0 ꢂC was added trimethylacetyl chloride (177 g, 1.47 mol)
and the resulting slurry was stirred at 0 ꢂC for 1 h. Reaction mixture
2: to a solution of (R)-4-benzyl-oxazolidin-2-one (272 g, 1.53 mol)
in THF (2 L) at ꢁ78 ꢂC was added a solution of n-butyllithium (2.5 N
in hexane, 614 mL, 1.53 mol). The mixture was stirred at ꢁ78 ꢂC for
1 h and then the slurry from reaction mixture 1 was carefully
added. The mixture was then stirred for 3 days at room tempera-
ture, diluted with ethyl acetate (4.3 L), and washed sequentially
with 2 N HCl (1 L) and saturated aqueous NaHCO3 (4 L). The organic
layer was dried over anhydrous sodium sulfate, filtered, and con-
centrated to afford a yellow oil. The crude product was passed
through a short silica gel pad, washed with hexane/ethyl acetate,
10:1, and concentrated to give a light yellow oil. Crystallization with
hexane/ethyl acetate, 10:1 (500 mL) provided 336 g (80%) of 8 as
a white solid. HPLC purity: 97.6% (254 nm, area %). 1H NMR
J¼8 Hz, 3H). 13C NMR
d 127.9 (q, CF3), 65.1, 35.7 (q), 30.4, 16.3. MS
[M]þ m/z 142.
4.5. (2R)-4,4,4-Trifluoro-2-methyl-butanal (5)
4.5.1. Method 1 (Dess–Martin)
To
a solution of 10 (107 g, 520 mmol, 69% by NMR) in
dichloromethane (1 L) at 0 ꢂC was added Dess–Martin reagent
(263 g, 621 mmol) in portions over 30 min. The reaction mixture
was warmed to room temperature and stirred for 5 h. To the
solution were added saturated Na2S2O3 (3 L) and saturated NaHCO3
(3 L) and the mixture was stirred for 30 min. The organic layer was
separated and the aqueous layer was extracted with dichloro-
methane (2ꢃ300 mL). The organic extracts were dried over anhy-
drous sodium sulfate, filtered, and concentrated to a 1.5 L solution
of 5 in dichloromethane (0.28 M by NMR, estimated yield 80%). The
solution of 5 was used directly in the next step. 1H NMR (400 MHz,
(400 MHz, DMSO-d6)
d
8.40 (s, 1H), 7.33 (t, J¼4 Hz, 2H), 7.27 (t,
J¼4 Hz, 1H), 7.23 (t, J¼4 Hz, 2H), 4.65–4.69 (m, 1H), 4.33(t, J¼8 Hz,
2H), 4.22 (dd, J¼8, 4 Hz, 1H), 3.08–3.18 (m, 1H), 3.03 (dd, J¼8, 4 Hz,
CDCl3) d 9.61 (s, 1H), 2.66–2.70 (m, 2H), 2.00–2.10 (m, 1H), 1.25 (d,
J¼8 Hz, 3H). MS [M]þ m/z 140.
1H), 2.93 (dd, J¼8, 4 Hz, 1H). 13C NMR
d 170.5, 154.1, 136.1, 130.1,
129.2, 127.9 (q, CF3), 127.5, 67.0, 55.0, 37.3, 28.8, 28.3 (q). MS
[MꢁH]ꢁ m/z 300. Anal. Calcd for C14H14F3NO3: C, 55.82; H, 4.68; N,
4.65. Found: C, 56.03; H, 4.67; N, 4.62.
4.5.2. Method 2 (TEMPO/(PhI(OAc)2))
To a solution of 10 (65 g, 457 mmol) in dichloromethane (1 L) at
0 ꢂC was added TEMPO (10.7 g, 68 mmol) and iodobenzene diac-
etate (177 g, 548 mmol) in small portions. The reaction mixture was
warmed to room temperature and stirred for 6 h. To the solution
was added saturated Na2S2O3 (1.5 L) and saturated NaHCO3 (1.5 L)
and it was stirred for 30 min. The organic layer was separated and
the aqueous layer was extracted with dichloromethane
(2ꢃ300 mL). The combined organic extracts were dried over
anhydrous sodium sulfate, filtered, and concentrated to a 1.2 L
solution of 5 in dichloromethane (0.28 M by NMR, estimated yield
90%), which was used directly in the next step.
4.3. (4R)-4-Benzyl-3-[(2R)-4,4,4-trifluoro-2 methylbutanoyl]-
1,3-oxazolidin-2-one (9)
To a solution of sodium bis(trimethylsilyl)amide (1 M in THF,
1.03 L, 1.03 mol) in THF (3 L) at ꢁ40 ꢂC was added a precooled so-
lution of 8 (282 g, 936 mmol) in THF (3.5 L) dropwise over 1.5 h.
Then iodomethane (87.5 mL, 1.40 mol) was added slowly at ꢁ50 ꢂC.
The reaction mixture was warmed to ꢁ30 ꢂC and stirred for 5 h. To

Z. Wang, L. Resnick / Tetrahedron 64 (2008) 6440–6443
6443
4.6. (S)-N-[(3R)-Methyl-4,4,4-trifluorobutylidene]-p-
toluenesulfinamide (12)
was added. The mixture was extracted with chloroform (3ꢃ500 mL)
and the combined organic extracts were washed with water and
brine, dried over anhydrous sodium sulfate, filtered, and concen-
trated to afford 28 g of 14 (estimated yield 96%) as a colorless oil,
which was used directly in the next step.1H NMR (400 MHz, DMSO-
To a solution of 5 (27.6% in dichloromethane, 1.5 L, 414 mmol) at
room temperature were added titanium(IV) ethoxide (286 mL,
1366 mmol) and (S)-(þ)-toluenesulfinamide (11, 64 g, 414 mmol)
slowly. The reaction mixture was heated to reflux for 5 h. Then the
mixture was poured into ice water (3 L) and filtered through Celite.
The organic layer was separated, dried over anhydrous sodium
sulfate, filtered, and concentrated. The crude product was purified
by silica gel chromatography (hexane/ethyl ether, 6:1–4:1) to afford
75 g (65% yield) of 12 as a colorless oil. 1H NMR (400 MHz, DMSO-
d6)
d 4.50 (br, 1H), 3.20–3.31 (m, 1H), 3.11–3.18 (m, 1H), 2.56–2.62
(m,1H), 2.30–2.46 (m,1H),1.94–2.04 (m,1H),1.84–1.93 (m,1H),1.50
(br s, 2H), 0.82 (d, J¼8 Hz, 3H). 13C NMR
d, 126.6 (q, CF3), 63.1, 58.9,
29.8, 27.4 (q),15.9. MS [MꢁH]ꢁ m/z 170. HRMS (ESI) [MþH] calcd for
C6H12F3NO 172.0944; found 172.0945.
4.10. 5-Chloro-N-[(1S,2R)-4,4,4-trifluoro-1-(hydroxymethyl)-
2-methylbutyl]thiophene-2-sulfonamide (1)
d6)
d
8.14 (d, J¼8 Hz,1H), 7.52 (d, J¼12 Hz, 2H), 7.36 (d, J¼12 Hz, 2H),
2.87–2.98 (m, 1H), 2.68–2.84 (m, 1H), 2.37–2.56 (m, 1H), 2.35 (s,
3H), 1.16 (d, J¼12 Hz, 3H). 13C NMR
d 195.5, 165.4, 141.6, 129.8, 126.9
To a mixture of 14 (28 g, 164 mmol), triethylamine (23 mL,
164 mmol) in dichloromethane (280 mL) at 0 ꢂC was added a solu-
tion of 5-chlorothiophene sulfonyl chloride (15, 35.5 g, 164 mmol)
in dichloromethane (280 mL). The reaction mixture was warmed to
room temperature and stirred for 2 days. To the solution was added
aqueous HCl (0.1 N, 1.5 L). The aqueous layer was extracted with
dichloromethane (2ꢃ500 mL). The combined organic extracts were
dried over anhydrous sodium sulfate, filtered, and concentrated.
The product was purified by silica gel column chromatography
(hexane/ethyl acetate, 8:1–4:1) to afford 30 g of 1 as a white solid
(50% yield from 13). Recrystallization: to a mixture of heptane and
ethyl acetate (4:1) was added 1 (30 g) in small portions. The mix-
ture was heated to reflux (about w104 ꢂC) until a clear solution was
obtained. Then the resulting solution was heated for 1 h. The
solution was seeded with a good crystal and then the solution was
allowed to cool to room temperature and stirred for 12 h. The
crystals were filtered and dried to afford 25.7 g (86%) of 1 as a white
crystal. HPLC purity: 99.6% (254 nm, area %); ee: 99% (ee was
determined by comparison to chirally pure samples of SR and RR).
(q, CF3), 124.4, 35.4 (q), 33.8, 20.8, 16.4. MS [MþH]þ m/z 278. Anal.
Calcd for C12H14F3NOS: C, 51.97; H, 5.09; N, 5.05. Found: C, 52.16; H,
4.88; N, 5.23.
4.7. N-[(1S,2R)-1-Cyano-4,4,4-trifluoro-2-methylbutyl]-4-
methylbenzenesulfinamide (13)
To a solution of Et2AlCN (1 M in toluene, 810 mL, 810 mmol) in
THF (800 mL) at 0 ꢂC was added isopropyl alcohol (66 mL,
810 mmol) and the mixture was stirred for 20 min. The resultant
solutionof Et(i-OPr)AlCNwasthen cooled toꢁ38 ꢂC anda solutionof
12 (75 g, 270 mmol) in THF (1.2 L) was added over 30 min. Then the
reaction mixture was warmed to 0 ꢂC and stirred for 15 min. The
reaction was quenched with saturated NH4Cl (3 L) at ꢁ30 ꢂC. Then
the mixture was stirred for 1.5 h and allowed to warm to 8–10 ꢂC.
The organic layer was separated, dried over anhydrous sodium
sulfate, filtered, and concentrated to afford the crude product (78 g),
which was purified by recrystallization (hexane/ethyl ether, 1:1) to
afford 52 g (63% yield) of 13 as a white crystal. HPLC purity: 98.9%
(254 nm, area %); ee: 99% (ee was determined by chirally pure
1H NMR (400 MHz, DMSO-d6)
d
7.66 (d, J¼8 Hz, 1H), 7.56 (d, J¼8 Hz,
2H), 7.42 (d, J¼8 Hz, 2H), 4.35 (m, 1H), 2.40–2.54 (m, 2H), 2.40 (s,
samples of (1S,2R) and (1R,2R)).1H NMR (400 MHz, DMSO-d6)
d 7.66
3H), 2.17–2.38 (m, 1H). 1.11 (d, J¼4 Hz, 3H). 13C NMR
d 141.5, 134.9,
(d, J¼8 Hz,1H), 7.56 (d, J¼8 Hz, 2H), 7.42 (d, J¼8 Hz, 2H), 4.35 (m,1H),
132.1, 128.5, 128.3 (q, CF3), 60.5, 59.4, 36.8 (q), 28.2, 14.3. MS
[MꢁH]ꢁ m/z 350. Anal. Calcd for C10H13ClF3NO3S2: C, 34.14; H, 3.72;
N, 3.98. Found: C, 34.13; H, 3.5; N, 3.89.
2.4–2.54 (m, 2H), 2.40 (s, 3H), 2.17–2.38 (m,1H).1.11 (d, J¼4 Hz, 3H).
13C NMR
d 141.9,141.4,130.3,126.3 (q, CF3),126.2,119.1, 48.1, 35.8 (q),
32.5, 21.5,15.9. MS [MþH]þ m/z 305. Anal. Calcd for C13H15F3N2OS: C,
51.31; H, 4.97; N, 9.20. Found: C, 52.07; H, 4.94; N, 9.08.
Acknowledgements
4.8. (2S,3R)-2-Amino-5,5,5-trifluoro-3-methylpentanoic acid
hydrochloride (4)
The authors would like to thank colleagues in Discovery Syn-
thetic Chemistry, Discovery Medicinal Chemistry, and Discovery
Analytical Chemistry Departments at Wyeth Research for their
generous help and assistance, especially Anthony Kreft, Donna
Huryn, Christina Kraml, Madelene Antane, Sherry Pan, Uresh Shah,
Boyd Harrison, John Butera, and John Potoski.
To a round bottom flask charged with concentrated HCl
(750 mL) was added 13 (52 g, 171 mmol) in small portions and the
reaction mixture was heated to reflux for 3 days. The mixture was
cooled to room temperature and washed with ethyl ether (3ꢃ1 L).
The aqueous layer was concentrated to afford 50 g (estimated yield
99%) of 4 as a yellow solid, which was used directly in the next step.
References and notes
HPLC purity: 98.9% (254 nm, area %). 1H NMR (400 MHz, D2O)
d 3.96
1. Citron, M. Nat. Rev. Neurosci. 2004, 5, 677–685.
(d, J¼4 Hz, 1H), 2.52–2.62 (m, 1H), 2.29–2.43 (m, 1H), 2.12–2.26 (m,
2. Tanzi, R.; Bertram, L. Cell 2005, 120, 545–555.
1H), 1.01 (d, J¼4 Hz, 3H). 13C NMR
d 171.0, 126.7 (q, CF3), 57.0, 36.6,
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4.9. (2S,3R)-2-Amino-5,5,5-trifluoro-3-methylpentan-1-ol
(14)
To a mixture of lithium borohydride (2 M in THF, 270 mL,
540 mmol) and chlorotrimethylsilane (137 mL, 1080 mmol) in THF
(2.7 L) at 0 ꢂC was added 4 (50 g, 170 mmol) in small portions. Then
the reaction mixture was allowed to warm to room temperature and
stirred for 3 days. The reaction was quenched with methanol
(500 mL) at 0 ꢂC and then aqueous sodium hydroxide (1 N, 1.5 L)
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´
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