Asymmetric syntheses of (1r,3R,4S)- and (1s,3R,4S)-(3,4-difluorocyclopentyl)-alanine derivatives

Article abstract of DOI:10.1016/j.tetasy.2009.05.024

By employing a sequence of epoxide opening, asymmetric alkylation, and fluorination, polyfluorinated cyclopentylamino acids with defined stereochemistries were prepared.

Full text of DOI:10.1016/j.tetasy.2009.05.024

Tetrahedron: Asymmetry 20 (2009) 1515–1520
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Tetrahedron: Asymmetry
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Asymmetric syntheses of (1r,3R,4S)- and (1s,3R,4S)-(3,4-difluorocyclopentyl)-
alanine derivatives
*
Robert D. Simpson , Wei Zhao
Department of Chemistry, Vitae Pharmaceuticals, 502 W. Office Center Dr. Fort Washington, PA 19034, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
By employing a sequence of epoxide opening, asymmetric alkylation, and fluorination, polyfluorinated
cyclopentylamino acids with defined stereochemistries were prepared.
Ó 2009 Elsevier Ltd. All rights reserved.
Received 6 May 2009
Accepted 20 May 2009
Available online 24 June 2009
1. Introduction
Unnatural amino acids are readily prepared by the asymmetric
alkylation of a chiral template or by asymmetric hydrogenation of
The synthesis of non-natural amino acids for use in molecular
biology and drug discovery remains an active field of research.
Amino acids containing varying degrees of fluorination are an
important set of these structures.1 Substitution of hydrogen for
fluorine imparts dramatic changes on the physical properties of
compounds; these changes can thus have dramatic effects on drug
distributions and other PK and PD-related effects. The incorpora-
tion of fluorine into drugs may increase lipophilicity and thus pro-
mote passive diffusion across membranes. This is particularly true
for CNS drugs, which are required to traverse the blood–brain bar-
rier. Diminished metabolism by hydroxylation and other oxidative
processes is also commonly observed.2 This increased metabolic
stability often leads to increased duration of action and greater
bioavailability.3
The majority of non-aromatic-fluorinated amino acids reported
in the literature contain trifluoromethyl4 or difluoromethylene5
subunits. There are fewer examples of amino acids containing
intermediate degrees of fluorination in the backbone and only
scant examples of amino acids containing CHF groups.6 Given the
polarity of the C–F bonds and the stereoelectronic effects this im-
parts, we believed that compounds possessing intermediate levels
of fluorination might possess unusual conformations and physico-
chemical properties.7
the enamide. The former proved to be a convenient starting point
for the synthesis. We envisioned that a suitably substituted cyclo-
pentane derivative could be further manipulated to provide the re-
quired amino acid. The relative stereochemistry between the
fluorine atoms and the ring attachment point could be installed
in a predictable manner by oxidation of a cyclopentene carboxylic
acid derivative. The syn-dihydroxylation of cyclopent-3-ene-ala-
nine derivative was an obvious starting point for the synthesis. A
literature search showed that the reaction of vicinal diols with flu-
orinating reagents is often substrate dependent. While acyclic diols
may be converted to vicinal difluorides with traditional SF4-de-
rived reagents, treatment of cyclic diols under similar conditions
gives low yields (<10%) of the desired products.9 Thus, we sought
a more predictable and higher yielding method for this transforma-
tion. We envisioned that the fluorides could be installed stepwise,
via an epoxide opening with an HF reagent, then conversion of the
intermediate fluorohydrin to a vicinal difluoride with a fluorinating
reagent. A similar approach was previously employed by O’Hagan
et al. to prepare a series of 3- and 4-vicinal fluorides with defined
stereochemistry.10
2. Results and discussion
The required trans-epoxide 111 was prepared following the lit-
erature procedures. Using a procedure originally described by
Muelbacher and Poulter,12 the racemic fluorohydrin 2 was pro-
duced in 85% yield by treatment of 1 with NEt3(HF)3 at 115 °C
for 12 h (Scheme 1). A single signal is observed in the 19F NMR
spectrum at ꢀ178.2 ppm.12 The 13C spectrum of this material
was examined rigorously and no evidence for the presence of a dia-
stereomeric fluorohydrin was observed. Protection of the alcohol
as a TBS ether, reduction of the ester, and conversion of the alcohol
to an iodide with I2/PPh3 gave the required racemic iodide 3
in 57% yield for the sequence. Alkylation of the (R)-Schülkopf
reagent13 with 3, followed by cleavage of the pyrazine and
Cyclopentyl alanine has been incorporated in a number of re-
cent drug targets, most prominently inhibitors of HCV protease,8a
DPPIV,8b and cathepsin S.8c Given the propensity for aliphatic ami-
no acids to be metabolized by oxidative processes, we hoped that
modification of this hydrophobic amino acid by incorporation of
fluorine into defined regions may alter the biological activities of
similar compounds. Herein we report efficient stereospecific syn-
theses of (1r,3R,4S)- and (1s,3R,4S)-(3,4-difluorocyclopentyl) (com-
pounds 5 and 10, Schemes 1 and 2) alanine derivatives.
* Corresponding author. Tel.: +1 215 461 2044.
E-mail address: rsimpson@vitaerx.com (R.D. Simpson).
0957-4166/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2009.05.024

1516
R. D. Simpson, W. Zhao / Tetrahedron: Asymmetry 20 (2009) 1515–1520
1. TBSCl
2. LiAlH4
F
F
NEt3(HF)3
3. PPh3/I2
CO2Et
O
CO2Et
OMe
TBSO
I
HO
1
3
2
1. nBuLi
2.
O
3
O
H
C4F4SO2F
NEt3(HF)3
NEt3/THF
H
N
H
N
(S)
3. HCl
(S)
MeO
CBz
MeO
HO
CBz
4. CBzOSu
H
(R)
N
F
N
F
MeO
F
5
4
Scheme 1.
proteo-desilylation with HCl and protection of the amine with
CBzOSu gave the amino acid methyl ester 4 as a mixture of pseud-
oenantiomers about the cyclopentane ring in 88% yield after flash
chromatography.
during its reaction with NEt3(HF)3, however only a small amount
of impure fluorohydrin was produced. Examination of the crude
reaction mixture by NMR spectroscopy showed the loss of the
ethyl group. This may arise from lactonization of the intermediate
alcohol during the epoxide-opening reaction. Using this observa-
tion as a guide we envisioned that reduction of the exocyclic car-
bonyl would eliminate this side reaction. The requisite substrate
was prepared as follows: directed epoxidation of 3-cyclopentenyl-
methanol with VO(acac)2/tBuOOH gives the previously described
cis-epoxide 6,18 which was then protected as the pivalate ester.
This compound underwent smooth fluorohydrin formation using
the previously described conditions. Iodide 8 and amino acid 10
were prepared using the chemistry described above.
The spectroscopy associated with the protected amino acid 10
is similar to that of 5. The methine protons are shifted downfield
by 0.15 ppm relative to 5, yet bear identical H–F couplings while
the 19F NMR signal occurs at ꢀ201.2 ppm. The 19F NMR chemical
shifts are useful in establishing the stereochemistry of the interme-
diates and final amino acids. In all cases, the fluorine cis- to the
1-substituent resonates ca 2 ppm downfield relative to the trans-
isomer. The trend is even more pronounced in the final vicinal
difluorides (ꢀ201.2 for the trans vs ꢀ196.9 ppm for the cis-isomer).
A variety of fluorinating agents were investigated for the con-
version of 4 to the final difluoride. Employing SF4-derived fluori-
nating agents (Deoxo-Fluor or DAST) gave very low yields of
impure difluoride.14,15 The highest yields and chemical purity were
achieved using the C4F9SO2F/NEt3(HF)3 system recently reported
by the Merck Process group.16 Employment of this set of reagents
afforded the required difluoride 5 in 40–60% yield. Examination of
the crude reaction mixture by LC/MS showed varying amounts of a
side product, whose mass is consistent with a cyclopentanone as
the major impurity.9,15 The crude amino acid was purified by con-
ventional flash chromatography on silica.
The NMR spectra of this compound are consistent with a sym-
metrical cyclopentyl group. The methine protons bearing the fluo-
rine substituent are observed as a doublet of multiplets, at
4.82 ppm in the 1H NMR spectra with an averaged H–F coupling
constant of 47.3 Hz. The three cyclopentyl signals in the 13C NMR
spectra display coupling to two magnetically inequivalent fluorine
atoms. The vicinal fluorine atoms display a complex multiplet at
ꢀ196.9 ppm in the ambient temperature 19F NMR spectrum, which
sharpens to a more symmetrical signal as the sample temperature
is increased. This behavior may be indicative of hindered confor-
mational mobility about the cyclopentane ring but a full conforma-
tional analysis was not carried out.
3. Conclusion
In conclusion, the stereoselective syntheses of the epimeric
(1r,3R,4S)- and (1s,3R,4S)-(3,4-difluorocyclopentyl) alanine deriva-
tives 5 and 10 were carried out using epoxidation to establish the
stereochemistry of the alkyl fluorides, then use of standard chiral
This approach required modification to prepare the (1s,3R,4S)-
epimer (Scheme 2). The cis-isomer of epoxide 117 was consumed
1. TBSCl
2. LiAlH4
3. PPh3/I2
t
1. BuCOCl
OPiv
F
F
OH 2. NEt3(HF)3
O
TBSO
HO
I
6
8
7
1. nBuLi
O
2.
8
O
H
C4F4SO2F
NEt3(HF)3
NEt3/THF
H
N
H
N
(
)
S
3. HCl
4. CBzOSu
(S)
MeO
F
CBz
MeO
HO
CBz
OMe
H
(R)
N
F
N
F
MeO
Scheme 2.

R. D. Simpson, W. Zhao / Tetrahedron: Asymmetry 20 (2009) 1515–1520
1517
template chemistry to form the amino acid. The fluorine atoms were
installed sequentially by epoxide opening, then SN2 displacement of
the alcohol at a later stage. This allowed for the use of the high-yield-
ing epoxide opening with HF to install the first fluorine substituent.
The absolute stereochemistry of these intermediates19 do not need
to be addressed since the final vicinal difluorides are more symmet-
rical structures than the fluorohydrin intermediates 4 and 9. This
produced the desired products with complete control of stereo-
chemistry about the ring systems and avoided the use of more haz-
ardous fluorinating reagents. The biological behavior of derivatives
of these compounds will be reported in subsequent publications.
4.4. 3-(tert-Butyldimethylsilyloxy)-4-fluorocyclopentyl)methanol
A slurry of LiAlH4 (2.99 g, 78.5 mmol, 2.0 equiv) in THF (100 mL)
was cooled to ꢀ78 °C. A solution of the above ester in THF (50 mL)
was added over a 20-min period, and the mixture stirred at ꢀ78 °C
for 0.5 h. Analysis by TLC showed consumption of the ester. The
mixture was allowed to warm to 0 °C, then 10 mL of brine was
added dropwise over a 15-min period, followed by ꢂ20 g of Celite.
The thick slurry was diluted with EtOAc and allowed to stir for
0.5 h. After this time, the mixture was filtered through a pad of Cel-
ite. The filter cake was washed with additional EtOAc. The resulting
clear solution was dried over Na2SO4, filtered, and evaporated. This
afforded 7.24 g (76% yield) of the primary alcohol. 1H NMR (CDCl3,
400 MHz): d 4.69 (d of m, JHF = 52.3 Hz, 1H), 4.18 (d of m,
JHF = 7.8 Hz, 1H), 3.48 (d, J = 6.6 Hz, 2H), 2.37 (m, 1H), 2.15 (m,
1H), 2.0 (m, 2H), 1.70–1.40 (m, 3H), 0.81 (s, 9H), 0.02 (s, 6H). 13C
NMR (CDCl3, 100 MHz): 99.5 (d, JCF = 177.0 Hz), 76.4 (d,
JCF = 27.4 Hz), 67.0, 37.7, 35.3, 33.0 (d, JCF = 20.2 Hz), 25.6, 17.9,
ꢀ4.9. 19F NMR (CDCl3, 376 MHz): d ꢀ176.0.
4. Experimental
4.1. General
1H NMR, 13C NMR spectra were acquired on Bruker AM-400.
Chemical shifts were given on the delta scale as parts per million
(ppm) with tetramethylsilane and referenced to the signal of the
solvent. 19F NMR spectra were obtained at 376 MHz and referenced
to external trifluoroacetic acid. Optical rotations were measured on
a Perkins-Elmer Polarimeter 341 with a sodium lamp and are re-
4.5. tert-Butyl-2-fluoro-4-(iodomethyl)cyclopentyloxy)-
dimethylsilane 3
ported as follows ½a D23
ꢁ
(c g/100 mL, CH2Cl2). Flash chromatography
The above alcohol (7.24 g, 29.1 mmol, 1.0 equiv), triphenyl-
phosphine (9.2 g (35 mmol, 1.2 equiv), and imidazole (4.0 g,
58.3 mmol, 2.0 equiv) were dissolved in 100 mL of THF and cooled
to 0 °C. Iodine (8.15 g, 32.4 mmol, 1.1 equiv) was added in 3 equal
portions over a 20-min period. The mixture was stirred for 1 h at
0 °C. After this time an additional 0.125 equiv of triphenylphos-
phine was added, followed by an additional 0.125 equiv of iodine.
After stirring for 20 min, TLC analysis showed no remaining alco-
hol. The mixture was filtered through a pad of silica. The silica
was washed with ether and the filtrate evaporated. The iodide
was isolated by flash chromatography on silica, eluting with 0–
9% EtOAc in hexanes. 1H NMR (CDCl3, 400 MHz): d 4.72 (d of m,
JHF = 51.9 Hz, 1H), 4.22 (d of m, JHF = 10.1 Hz, 1H), 3.12 (d,
J = 6.6 Hz, 2H), 2.51 (m, 1H), 2.26 (m, 1H), 1.82 (m, 1H), 1.58–
1.40 (m, 2H), 0.81 (s, 9H), 0.02 (s, 6H). 13C NMR (CDCl3,
100 MHz): 99.2 (d, JCF = 177.9 Hz), 76.6 (d, JCF = 10.1 Hz), 40.2,
38.7, 37.4 (d, JCF = 20.7 Hz), 25.7, 17.9, 13.3, ꢀ4.9. 19F NMR (CDCl3,
376 MHz): d ꢀ174.7.
was performed with the aid of an Isco CombiFlash system. LC/MS
were obtained on a Waters system. All starting materials, reagents,
and solvents were obtained from conventional suppliers and used
as received.
4.2. Ethyl-3-fluoro-4-hydroxycyclopentanecarboxylate19
2
A 100 mL flask was charged with 7.2 g (50.7 mol) of the trans-
epoxide 111 and 12.3 (76 mmol, 1.5 equiv) of NEt3(HF)3 (CAU-
TION).20 The mixture was heated to 120 °C for 16 h. After this time
TLC analysis showed consumption of the starting epoxide. The
mixture was cooled to 0 °C and quenched by addition of saturated
NaHCO3. The mixture was allowed to stir for 1 h, and diluted with
EtOAc. The layers were separated and the aqueous layer was ex-
tracted with additional EtOAc. The combined organic extracts were
washed with brine, dried over Na2SO4, filtered, and evaporated.
The fluorohydrin was purified by flash chromatography on silica,
eluting with 0–47% EtOAc in hexanes. This afforded 6.73 g (75%
yield) of the fluorohydrin. 1H NMR (CDCl3, 400 MHz): d 4.70 (d of
3
4.6. (S)-Methyl 2-(benzyloxycarbonylamino)-3-(3-fluoro-4-
hydroxycyclopentyl)propanoate 4
m, JHF = 51.9 Hz, 1H), 4.32 (d of m, JHF = 9.2 Hz, 1H), 4.11 (q,
J = 7.0 Hz, 2H), 3.02 (quin, J = 8.2 Hz, 1H), 2.34 (m, 1H), 2.15–2.0
(m, 2H), 1.88 (m, 1H), 1.22 (t, J = 7.0 Hz, 3H), 0.83 (s, 9H), 0.04 (s,
1
6H). 13C NMR (CDCl3, 100 MHz): 175.1, 98.4 (d, JCF = 179.4 Hz),
An oven-dried 250 mL flask was charged with 75 mL of dry THF
and 4.02 g (21.8 mmol, 1.5 equiv) of (R)-2,5-dihydro-3,6-dimeth-
oxyl-2-isopropylpyrazine. The mixture was cooled to ꢀ78 °C (dry
ice/IPA) and nBuLi (2.5 M, 8.72 mL, 21.8 mmol, 1.5 equiv) added
dropwise over a 20-min period. After addition was complete the
flask was maintained at ꢀ78 °C for 1 h. After this time a solution
of the iodide 3, (5.2 g, 14.5 mmol, 1.0 equiv) in 25 mL of THF was
added over a 10-min period. The mixture was stirred at ꢀ78 °C
for 2 h, then tightly stoppered and the dry ice/IPA bath placed in
a ꢀ15 C freezer for 19 h. After this time LC/MS analysis showed
consumption of the iodide and formation of the desired product.
The reaction was quenched by addition of 10 mL of saturated
NH4Cl and THF removed in vacuo. The residue was partitioned be-
tween EtOAc/H2O. The water layer was extracted with additional
EtOAc and the combined organic layers were washed with brine,
dried over Na2SO4, filtered, and evaporated. The disubstituted pyr-
azine, contaminated with the starting pyrazine, was used directly
in the next step.
2
2
76.3 (d, JCF = 27.6 Hz), 60.5, 39.9, 35.4, 33.4 (d, JCF = 21.5 Hz),
25.6, 17.8, 14.0, ꢀ5.04. 19F NMR (CDCl3, 376 MHz): d ꢀ178.4.
4.3. Ethyl 3-(tert-butyldimethylsilyloxy)-4-fluorocyclopentane-
carboxylate
A
solution of the above fluorohydrin (6.73 g, 38.2 mmol,
1.0 equiv), TBSCl (11.5 g, 76.4 mmol, 2.0 equiv) and imidazole
(12 g, 0.17 mol, 4.0 equiv) in DMF (10 mL) was stirred at ambient
temperature for 4 h. After this time the free alcohol was consumed
by TLC analysis. The DMF was removed in vacuo and the residue
was partitioned between ether/water. The layers were separated
and the organic layer washed with brine, dried over Na2SO4, fil-
tered, and evaporated. The silyl ether was isolated in >99% yield.
1H NMR (CDCl3, 400 MHz): d 4.81 (d of m, JHF = 51.5 Hz, 1H), 4.32
(m, 1H), 4.11 (q, J = 7.0 Hz, 2H), 3.05 (ms, 1H), 2.7 (br s, 1H), 2.39
(m, 1H), 2.25–2.1 (m, 2H), 1.92 (m, 1H), 1.22 (t, J = 7.0 Hz, 3H).
13C NMR (CDCl3, 100 MHz): 175.4, 98.0 (d, JCF = 177.9 Hz), 75.3
(d, JCH = 27.6 Hz), 60.6, 39.6, 34.7, 33.2 (d, J = 22.2 Hz), 13.8. 19F
NMR (CDCl3, 376 MHz): d ꢀ178.3.
The above residue was dissolved in 200 mL of 1:1 acetonitrile/
1.0 M aqueous HCl. The mixture was stirred for 7 h at ambient
temperature. After this time, the volatile components were

1518
R. D. Simpson, W. Zhao / Tetrahedron: Asymmetry 20 (2009) 1515–1520
removed in vacuo. The residue was dissolved in 100 mL of 1:1 ace-
tonitrile/water. To this solution were added K2CO3 (15.2 g,
0.110 mol, 5.0 equiv) and CBzOSu (10.9 g, 43.6 mmol, 3.0 equiv)
and the resulting mixture was allowed to stir for 17 h. After this
time, the volatile materials were removed and the residue was par-
titioned between EtOAc/water. The layers were separated and the
organic layer was washed with saturated NaHCO3, brine, then
dried over Na2SO4, filtered, and evaporated. The desired amino acid
derivative was purified by flash chromatography, on silica, eluting
with 0 to 47% EtOAc in hexanes. This afforded 4.4 g (89% yield) of
the desired protected amino acid as a mixture of pseudoenantio-
mers about the cyclopentyl ring. 1H NMR (CDCl3, 400 MHz): d
7.27 (m, 5H), 5.54 (t, J = 9.0 Hz, 1H), 5.08 (s, 2H), 4.79 (d of m,
JHF = 51.5 Hz, 1H), 4.34 (m, 1H), 4.25 (d of m, JHF = 18.3 Hz, 1H),
3.71 (s, 3H), 2.74 (br s, 1H), 2.32–2.20 (m, 2H), 1.90–1.25 (m,
1H). 19F NMR (CDCl3, 376 MHz): d ꢀ175.6.
with additional EtOAc. The combined organic extracts were
washed with brine, dried over Na2SO4, filtered, and evaporated.
The fluorohydrin was purified by flash chromatography on silica,
eluting with 0–27% EtOAc in hexanes. This afforded 1.88 g (61%
yield) of the fluorohydrin. 1H NMR (CDCl3, 400 MHz): d 4.82 (d of
m, JHF = 52.3 Hz, 1H), 4.25 (d of m, JHF = 15.6 Hz, 1H), 3.99 (t,
J = 7.0 Hz, 2H), 3.0 (br s, 1H), 2.49 (m, 1H), 2.20 (m, 1H), 1.99 (m,
1H), 1.73 (m, 1H), 1.36 (m, 1H), 1.16 (s, 9H). 13C NMR (CDCl3,
100 MHz): 178.7. 99.4 (d, JCF = 175.6 Hz), 76.2, 67.7, 38.7, 35.1,
34.6, 33.6, 33.4. 19F NMR (CDCl3, 376 MHz): d m, ꢀ181.2.
4.10. (3-(tert-Butyldimethylsilyloxy)-4-fluorocyclopentyl)-
methyl pivalate
The above fluorohydrin (3.99 g, 18.3 mmol), TBSCl (5.52 g,
36.6 mmol, 2.0 equiv) and imidazole (4.99 g, 73.2 mmol, 4.0 equiv)
were dissolved in 10 mL of DMF. The mixture was stirred for 4 h at
ambient temperature; after this time TLC analysis showed con-
sumption of the starting fluorohydrin. The volatile materials were
removed in vacuo and the residue was portioned between hexanes
and 1.0 M HCl. The layers were separated and the hexane layers
were washed with brine, dried over Na2SO4, filtered, and evapo-
rated. The resulting TBS ether (6.1 g, >99% yield) was of sufficient
purity to carry on to subsequent transformations. 1H NMR (CDCl3,
400 MHz): d 4.76 (d of m, JHF = 51.9 Hz, 1H), 4.21 (d of m,
JHF = 14.8 Hz, 1H), 3.99 (d, J = 7.0 Hz, 2H), 2.47 (sept, J = 7.8 Hz,
1H), 2.12 (m, 1H), 1.99 m, 1H), 1.72 (m, 1H), 1.37 (m, 1H), 1.19
(s, 9H), 0.83 (s, 9H), 0.08 (s, 6). 13C NMR (CDCl3, 100 MHz):
178.3. 99.8 (d, JCF = 176.4 Hz), 76.7, 68.0, 38.7, 34.8 33.9, 33.7,
27.1, 25.7, 17.9, ꢀ4.9. 19F NMR (CDCl3, 376 MHz): d ꢀ179.7.
4.7. (S)-Methyl 2-(benzyloxycarbonylamino)-3-((1r,3R,4S)-3,4-
difluorocyclopentyl)propanoate 5
The above protected amino acid (4.4 g, 12.9 mmol, 1.0 equiv)
was dissolved in 50 mL of THF and cooled to 0 °C. To this solution
was added C4F9SO2F (7.86 g, 25.93 mmol, 2.0 equiv), NEt3(HF)3
(4.18 g, 25.93 mmol, 2.0 equiv), and NEt3 (7.84 g, 77.8 mmol,
6.0 equiv). The resulting mixture was allowed to stir for 72 h.
After this time, the solution was filtered through a pad of silica.
The silica was washed with additional THF and the filtrate trans-
ferred to a separatory funnel. The solution was washed with sat-
urated NaHCO3 and brine and evaporated. The desired vicinal
difluoride was purified by flash chromatography on silica. This
afforded 3.0 g (68% yield) of the difluoride. An additional
818 mg of the starting alcohol was recovered. 1H NMR (CDCl3,
400 MHz): d 7.38 (m, 5H), 5.29 (db, J = 8.6 Hz, 1H), 5.11 (s, 2H),
4.11. (3-(tert-Butyldimethylsilyloxy)-4-fluorocyclopentyl)-
methanol
1
4.82 (d of m, JHF = 47.3 Hz, 2H), 4.37 (m, 1H), 3.73 (s, 3H),
2.32–2.07 (m, 2H), 2.05–1.90 (m, 2H), 1.80–1.60 (m,3H). 13C
NMR (CDCl3, 100 MHz): 172.8, 155.9, 136.1, 128.5. 128.2, 128.1,
The above TBS ether (6.1 g, 18.3 mmol, 1.0 equiv) was dis-
solved in 50 mL of THF and the solution cooled to 0 °C under
nitrogen. A solution of LiAlH4 (1.0 M in THF, 9.2 mL, 9.2 mmol,
1.5 equiv) was added via syringe over a 15-min period, then the
solution was stirred for 0.5 h. TLC analysis showed consumption
of the pivalate ester. The excess LiAlH4 was quenched by the
dropwise addition of ꢂ7 mL of brine, followed by ꢂ10 g of Celite.
The resulting suspension was filtered through a pad of Celite and
the filter cake washed with EtOAc. The solution was evaporated
and the desired alcohol purified by flash chromatography, eluting
with 0–27% EtOAc in hexanes. This afforded 3.0 g (66% yield) of
the free alcohol. 1H NMR (CDCl3, 400 MHz): d 4.69 (d of m,
JHF = 53.1 Hz, 1H), 4.11 (d of m, JHF = 11.7 Hz, 1H), 3.47 (m, 2H),
2.37 (m, 1H), 2.11 (m, 1H), 1.84 (m, 2H), 1.35 (d of m,
JHF = 14.1 Hz, 1H), 0.78 (s, 9H), 0.01 (s, 6). 13C NMR (CDCl3,
100 MHz): 99.8 (d, JCF = 175.6 Hz), 76.4 (d, JCF = 27.6 Hz), 66.1,
37.8, 36.2, 32.6 (d, JCF = 21.4 Hz), 25.7, 17.9, ꢀ4.9. 19F NMR (CDCl3,
376 MHz): d ꢀ178.4.
1
2
92.1 (d of q, JCF = 187.9 Hz, JCF = 10.0 Hz), 67.1, 34.1 (d of d,
3
3
2JCF = 19.9 Hz, JCF = 3.2 Hz), 28.7 (t, JCF = 2.2 Hz. 19F NMR (CDCl3,
376 MHz):
(M+23) 364.1336. Found: 364.1323.
d
ꢀ196.9. HRMS (EI) calcd. for C17H21F2NO4Na
4.8. (1R,3r,5S)-6-Oxabicyclo[3.1.0]hexan-3-ylmethyl pivalate
The previously reported cis-epoxide 614 (3.95 g, 26.3 mmol,
1.0 equiv) was dissolved in 50 mL of THF. The solution was cooled
to 0 °C and NEt3 (6.64 g, 9.2 mL, 65.7 mmol, 2.5 equiv) was added,
followed by pivaloyl chloride (4.76 g, 4.85 mL, 39.5 mmol,
1.5 equiv). The solution was stirred at 0 °C until the starting alcohol
was consumed by TLC analysis. The mixture was allowed to warm
to ambient temperature, added to a separatory funnel, washed
with 1.0 M HCl, brine, then dried over Na2SO4, filtered, and evapo-
rated. The required ester was purified by flash chromatography,
eluting with 0–19% EtOAc in hexanes. This afforded 2.78 g (53%
yield) of the pivalate ester. 1H NMR (CDCl3, 400 MHz): d 3.84 (d
of m, J = 3.9 Hz, 2H), 3.44 (br s, 2H), 2.33 (m, 1H), 1.82 (m, 4H),
1.14 (s, 9H). 13C NMR (CDCl3, 100 MHz): 178.1, 69.7, 58.2. 38.6.
34.0, 30.0, 27.0.
4.12. tert-Butyl(2-fluoro-4-(iodomethyl)cyclopentyloxy)-
dimethylsilane 8
The aforementioned alcohol (3.02 g, 12.2 mmol, 1.0 equiv),
PPh3 (4.0 g, 15.2 mmol, 1.25 equiv) and imidazole (2.1 g,
30.4 mmol, 2.5 equiv) were dissolved in THF (50 mL) and the
solution was cooled to 0 °C. Iodine (4.6 g, 18.3 mmol, 1.5 equiv)
was added in ꢂ0.5 g portions over 0.5 h. After the addition was
completed the solution was warmed to ambient temperature
for 1 h, during which time the starting alcohol was consumed.
Hexanes (ꢂ50 mL) were added and the mixture was filtered
through a pad of silica gel. The silica was washed with additional
hexanes and the pale yellow filtrate was evaporated. The residue
4.9. (3-Fluoro-4-hydroxycyclopentyl)methyl pivalate 7
The above ester (2.78 g, 14.03 mmol, 1.0 equiv) was dissolved in
3.4 mL of NEt3(HF)3 (21.0 mmol, ꢂ1.5 equiv) and the mixture was
heated to 119 °C for 17 h. After this time the dark solution was
cooled to 0 °C and quenched by the addition of saturated NaHCO3.
The mixture was allowed to stir for 1 h, and diluted with EtOAc.
The layers were separated and the aqueous layer was extracted

R. D. Simpson, W. Zhao / Tetrahedron: Asymmetry 20 (2009) 1515–1520
1519
was dissolved in hexanes and filtered through a fresh pad of sil-
ica. The silica was washed with additional hexanes. The filtrate
was evaporated to yield the iodide as a pale pink liquid (3.63 g,
was washed with saturated NaHCO3 and brine and evaporated. The
desired vicinal difluoride was purified by flash chromatography on
silica, eluting with 0–41% EtOAc in hexanes. This afforded 1.27 g,
54% yield, of the required difluoride as colorless syrup. 1H NMR
(CDCl3, 400 MHz): d 7.35 (m, 5H), 5.29 (db, J = 7.8 Hz, 1H), 5.11
84% yield). 1H NMR (CDCl3, 400 MHz):
d 4.76 (d of m,
JHF = 52.3 Hz, 1H), 4.19 (d of m, JHF = 15.0 Hz, 1H), 3.16 (m, 2H),
2.43 (m, 1H), 2.14 (m, 1H), 2.04 (m, 1H), 1.64 (m, 1H), 1.32 (m,
1H), 0.80 (s, 9H), 0.01 (s, 6). 13C NMR (CDCl3, 100 MHz): 100.1
(d, JCF = 177.1 Hz), 77.1 (d, JCF = 27.6 Hz), 40.2, 38.2, 37.9 (d,
JCF = 21.5 Hz), 25.7 (d, JHF = 2.3 Hz), 25.7, 17.9, ꢀ4.9. 19F NMR
(CDCl3, 376 MHz): d ꢀ177.8.
1
(s, 2H), 4.97 (d of m, JHF = 47.3 Hz, 1H), 4.35 (m, 1H), 3.75 (s,
3H), 2.52 (m, 1H), 2.22 (m, 2H), 1.82–1.45 (m, 5H). 13C NMR (CDCl3,
100 MHz): 172.6, 155.7, 136.0, 128.5. 128.2, 128.1, 92.5 (d of q,
2
2
1JCF = 187.9 Hz, JCF = 15.3 Hz), 39.7, 34.5 (d of d, JCF = 22.2 Hz,
3JCF = 5.4 Hz), 30.5 (t, JCF = 2.3 Hz. 19F NMR (CDCl3, 376 MHz): d
3
ꢀ201.2. HRMS (EI) calcd for C17H21F2NO4Na (M+23) 364.1336.
4.13. (S)-Methyl 2-(benzyloxycarbonylamino)-3-(3-fluoro-4-
Found: 364.1340.
hydroxycyclopentyl)propanoate 9
Acknowledgments
An oven-dried 250 mL flask was charged with 75 mL of dry
THF and 2.33 g (21.8 mmol, 1.25 equiv) of (R)-2,5-dihydro-3,6-
dimethoxyl-2-isopropylpyrazine. The mixture was cooled to
ꢀ78 °C (dry ice/IPA) and nBuLi (2.5 M, 4.4 mL, 11.2 mmol,
The authors wish to thank Dr. Marisa Kozlowski and Elizabeth
Linton of the University of Pennsylvania for the use of their
polarimeter.
1.1 equiv) was added dropwise over
a 20-min period. After
the addition was complete the flask was maintained at
ꢀ78 °C for 1 h. After this time a solution of the above iodide,
(3.63 g, 10.13 mmol, 1.0 equiv) in 25 mL of THF was added over
a 10-min period. The mixture was stirred at ꢀ78 C for 2 h,
then tightly stoppered and the dry ice/IPA bath was placed
in a ꢀ15 °C freezer for 19 h. After this time LC/MC analysis
showed consumption of the iodide and formation of the de-
sired product (M+H+). The reaction was quenched by addition
of 10 mL of saturated NH4Cl and THF removed in vacuo. The
residue was partitioned between EtOAc/H2O. The water layer
was extracted with additional EtOAc and the combined organic
layers were washed with brine, dried over dried over Na2SO4,
filtered, and evaporated. The disubstituted pyrazine, contami-
nated with the starting pyrazine, was used directly in the next
step.
The above residue was dissolved in 200 mL of 1:1 acetonitrile/
1.0 M aqueous HCl. The mixture was stirred for 7 h at ambient
temperature. After this time the volatile components were re-
moved in vacuo. The residue was dissolved in 100 mL of 1:1 ace-
tonitrile/water. To this solution were added K2CO3 (50 mL of a
15% solution), acetonitrile (50 mL), and CBzOSu (6.31 g,
25.3 mmol, 2.5 equiv), and the resulting mixture was stirred for
17 h. After this time the volatile materials were removed and
the residue was partitioned between EtOAc/water. The layers
were separated and the organic layer was washed with saturated
NaHCO3, brine, then dried over Na2SO4, filtered, and evaporated.
The desired amino acid derivative was purified by flash chroma-
tography, on silica, eluting with 0–61% EtOAc in hexanes. The fifth
set of UV active fractions were collected and evaporated to yield
2.33 g (68% yield) of the desired protected amino acid as a mix-
ture of pseudoenantiomers about the cyclopentyl ring. 1H NMR
(CDCl3, 400 MHz): d 7.27 (m, 5H), 5.50 (b, 1H), 5.08 (s, 2H),
4.81 (d of m, JHF = 52.3 Hz, 1H), 4.33 (m, 1H), 4.24 (d of m,
JHF = 18.3.0 Hz, 1H), 3.71 (s, 3H), 2.38–1.45 (m, 6H), 1.24 (m,
1H). 19F NMR (CDCl3, 376 MHz): d ꢀ180.3.
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4.14. (S)-Methyl 2-(benzyloxycarbonylamino)-3-((1s,3R,4S)-3,4-
difluorocyclopentyl)propanoate 10
The above fluorohydrin (2.33 g, 6.87 mmol, 1.0 equiv) was dis-
solved in 30 mL of THF and the solution cooled to 0 °C. To this solu-
tion were added C4F9SO2F (4.15 g, 2.5 mL, 13.7 mmol, 2.0 equiv),
NEt3(HF)3 (2.21 g, 2.23 mL, 13.7 mmol, 2.0 equiv), and NEt3
(4.17 g, 5.8 mL, 41.2 mmol, 6.0 equiv). The resulting mixture was
allowed to stir for 72 h. After this time the solution was filtered
through a pad of silica. The silica was washed with additional
THF and the filtrate transferred to a separatory funnel. The solution

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R. D. Simpson, W. Zhao / Tetrahedron: Asymmetry 20 (2009) 1515–1520
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glassware was observed during these transformations. Nevertheless all
precautions for handling HF were followed.
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of ethyl cyclopent-3-ene carboxylate.11
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