Studies on the synthesis of cis-4-hydroxy-L-proline

Article abstract of DOI:10.1071/CH11204

A high yielding practical three-step procedure, which relies on an extractive work-up procedure, has been developed to convert N-phenylsulfonyl- trans-4-hydroxy-l-proline to N-phenylsulfonyl-cis-4-hydroxy-l-proline methyl ester in 82% yield over three steps.

Full text of DOI:10.1071/CH11204

CSIRO PUBLISHING
Aust. J. Chem. 2011, 64, 1509–1514
Full Paper
http://dx.doi.org/10.1071/CH11204
Studies on the Synthesis of cis-4-Hydroxy-L-proline
A
A
A B
,
Jessica A. Smith, G. Paul Savage, and Oliver E. Hutt
A
Ian Wark Laboratory, CSIRO Materials Science and Engineering, Bag 10,
Clayton South MDC, Vic. 3169, Australia.
B
Corresponding author. Email: oliver.hutt@csiro.au
A high yielding practical three-step procedure, which relies on an extractive work-up procedure, has been developed to
convert N-phenylsulfonyl-trans-4-hydroxy-L-proline to N-phenylsulfonyl-cis-4-hydroxy-L-proline methyl ester in 82 %
yield over three steps.
Manuscript received: 20 May 2011.
Manuscript accepted: 28 July 2011.
Published onilne: 16 November 2011.
Trans-4-hydroxy-L-proline is a naturally occurring, non-
proteinogenic amino acid. The synthesis of hydroxyproline
derivatives is important because these compounds have proven
to be useful building blocks in medicinal chemistry. For exam-
ple, MK-1220 1 is a highly active hepatitis C virus NS3/4A
protease inhibitor,[1] while GAP-134 2 is small molecule gap-
junction modifier for the treatment of atrial fibrillation (Fig. 1).[2]
These compounds possess a trans-4-hydroxyproline and a trans-
4-aminoproline core, respectively, as key structural templates
upon which are tethered functional and structural motifs. Access
to trans-4-hydroxyproline derivatives often proceeds via an
initial stereoinversion at the hydroxy group of readily available
trans-4-hydroxy-L-proline to cis-4-hydroxy-L-proline, followed
by an SN2 reaction at that centre to install desired functionality
and re-establish the trans configuration.
Simpson also evoked the formation of a bicyclic species to
explain the formation of cis-4-hydroxy amide derived from the
trans-4-bromo-L-proline (Eqn 2).[8] Employing the Mitsunobu
reaction, Joullie´ and coworkers were successful in shortening
the sequence to directly convert a variety of N-functionalized
trans-4-hydroxy-L-proline derivatives to the bicyclic lactones
(Eqn 3).[9] In a related manner, La Rosa and coworkers have
demonstrated the formation of the enantiomeric lactone.[10]
Direct intermolecular SN2 inversion of C4 through the Mitsu-
nobu reaction, or conversion to the mesylate, and subsequent
displacement with oxygen and nitrogen nucleophiles has also
been reported.[3,11,12] More recently, Silverman and coworkers
demonstrated that the bicyclic lactone could be efficiently
opened with MeOH in the presence of catalytic NaN3
(Eqn 4).[13]
The N-phenylsulfonyl group is an excellent functional group
for the construction of small-molecule libraries.[3] As such, we
sought a practical conversion of the N-phenylsulfonyl-trans-4-
hydroxyproline acid 3 to the corresponding N-phenylsulfonyl-
cis-4-hydroxyproline methyl ester 4 (Fig. 2).
Early synthetic studies on this conversion were reported by
Patchett and Witkop, who demonstrated inversion of the C4
alcohol through activation of the trans-hydroxyl as the tosylate
and subsequent internal displacement by the carboxylic acid to
form the corresponding lactone (Eqn 1, Fig. 3).[4–6] Portoghese
and coworkers reported a similar activation step enroute to
the 2,5-diazabicyclo[2.2.1]heptanes,[7] while Robertson and
Despite these advances, the conversion of 3 to 4 via Joullie´’s
route is laborious owing to the well established[14,15] difficulties
in removing the Mitsunobu by-products: triphenyl phosphine
oxide and the dialkyl hydrazine carboxylate. Purification
required several chromatography operations. To overcome
these difficulties, an efficient extractive procedure has been
developed that greatly simplifies the purification process and is
now reported.
To avoid the Mitsunobu reagents entirely, Patchett’s approach
was initially investigated (Scheme 1). Readily available trans-
hydroxy-L-proline 5 was converted to the N-phenylsulfonyl
derivative3in89%yield.[16] Arecentmodificationofthisproced-
ure using microwave conditions is a convenient alternative for
moderate scale preparations.[17] The N-phenylsulfonyl derivative
3was subsequentlyconverted tothecorrespondingO-tosylate 6in
N
H3CO
O
OH
HO
O
HO
O
O
O
H
O
N
OH
Steps
N
S
OMe
N
N
N
N
O
HN
H
H
O
O
SO2
O
N
O
SO2
H2N
O
O
1
2
3
4
Fig. 1. Exploitation of hydroxyproline building blocks.
Journal compilation Ó CSIRO 2011
Fig. 2. Desired conversion.
www.publish.csiro.au/journals/ajc

1510
J. A. Smith, G. P. Savage, and O. E. Hutt
Patchett & Witkop (1957)
HO
HO
PhSO2Cl
OH
TsO
OH
O
O
NaOH, H2O
N
N
H
K2CO3, EtCOMe
(1)
O
SO2
O
89 %
CO2H
N
Ac
Reflux
41 %
N
Ac
5
3
Robertson (1967)
TsCl, NaOH
Et2O, H2O
Br
38 % (73 % brsm)
O
O
Conc. NH4OH
1 week
TsO
K2CO3
2-butanone,
O
O
N
H
CO2H
N
H
OH
reflux
56 %
N
N
SO2
SO2 O
NH3
(2)
PhO2SO
7
6
HO
NH2
PhSO2Cl, Et2O
N
10 % Bu4NϩBrϪ, K2CO3,
DCM:H2O
NH2
O
MeOH, Na2CO3
75 %
SO2
1M NaOH
79 %
N
H
O
91 %
HO
HO
Joullié (1983)
OMe
OH
N
N
SO2
O
SO2
O
HO
O
O
DEAD, PPh3
56–93 %
(3)
CO2H
4
8
N
R
N
R
Scheme 1. Initial tosylate-displacement approach.
5 examples
Silverman (2001)
HO
HO
O
O
NaN3, MeOH
100 %
H
7
COtBu
N
(4)
t
OMe
CO2 Bu
HCl⋅NH2
N
N
Boc
K2CO3, 80°C, 2h
Toluene:H2O
N
Boc
O
SO2
O
Fig. 3. Synthesis of cis-4-hydroxy proline derivatives.
74 %
10
9
38% yield.[7] The conversion of O-tosylate 6 to the lactone 7 on
treatmentwithK2CO3 in2-butanoneatrefluxproceededsmoothly
in56 %yield. Althoughthissequenceproceededinmodestoverall
yield, the lactone 7 was obtained in essentially pure form and
required little additional purification. Recent reports employing
the corresponding mesylate derivative provide an alternative
method for exploiting this strategy.[5,6] The lactone 7 is a versatile
intermediatethatcouldbeconvertedtothecis-4-hydroxyester4in
75% yield by treatment with Na2CO3 in methanol.[18] Alterna-
tively, treatment of the lactone 7 with 10% tetrabutyl ammonium
bromide (TBAB) and K2CO3, in a biphasic dichloromethane
(DCM)/water system, delivered the cis-4-hydroxy acid 8 in
91% yield.
HO
7
H
HCl⋅NH2
CO2Me
N
CO2Me
N
NaHCO3, 80°C, 6h
Toluene:H2O
O
SO2
69 %
12
11
HO
7
H
N
HCl⋅NH2
CO2Bn
CO2Bn
N
NaHCO3, 80°C, 12h
O
SO2
Toluene:H2O
92 %
14
13
Lactones that are structurally related to compound 7 have
been used as activated esters in peptide synthesis and we found
that biphasic conditions were excellent conditions for this
reaction.[12,19,20] For example, treatment of b-alanine tert-butyl
ester 9 with lactone 7, in the presence of one equivalent of
K2CO3 gave the amide 10 in 74 % yield. Employing K2CO3 with
more hindered amines such as L-leucine 11 and D-phenylalanine
13 led predominantly to the acid 8 demonstrating the suscepti-
bility of lactone 7 to hydrolysis. However, employing a stoi-
chiometric equivalent of NaHCO3 delivered amides 12 and 14 in
69 and 92 % yield, respectively (Scheme 2).
Scheme 2. Amide bond formation under biphasic conditions.
HO
O
O
DEAD, PPh3
OH
N
N
THF
O
SO2
SO2
77 %
3
7
Although the O-tosylate approach was a feasible method for
synthesizing the desired cis-4-hydroxy-L-proline methyl ester 4,
Scheme 3. The Mitsunobu approach.

Synthesis of cis-4-Hydroxy-L-proline
1511
Table 1. Optimization of the process for synthesis of cis-4-hydroxy-L-proline methyl ester 4
Step A
Step B
Step C
HO
HO
HO
O
N
O
OH
OMe
PPh3/DEAD
K2CO3, TBAB
Solvent:H2O
K2CO3, MeI
CO2H
N
N
N
Solvent
Solvent
O
SO2Ph
SO2Ph
PhO2S
PhO2S
O
3
7
8
4
Entry
Solvent
Operation
Solvent
Operation
Conditions
Yield
cis:trans
1
2
3
4
THF
THF
THF
DCM
Remove THF
Remove THF
Remove THF
Add H2O
Toluene
Toluene
Toluene
DCM
Discard toluene. Add DCM
Discard toluene. Add DCM
Acidify aqueous, extract
Acidify aqueous, extract
DCM:H2O 18 h
DCM:H2O 72 h
Acetone
37
65
75
82
1:0
1:1
1:0
1:0
Acetone
HO
ϪOH
HO
HO
path b
O
O
1. DEAD/PPh3
OH
ϪOH
OH
N
N
OH
2. NaHCO3/
Aliquat 336
path a
SO2
O
O
SO2
N
N
(path a)
SO2
O
SO2
3
8
NaHCO3
Aliquat 336
MeI, 96h
8
7
slow
(path b)
HO
HO
HO
HO
OH
OMe
OMe
OH
N
N
ϩ
MeI
N
N
O
O
SO2
SO2
O
O
SO2
SO2
3
15
13 %
15
3
64 %
Fig. 4. Reaction mechanism for the stereo-reversion of 8.
Scheme 4. Complete stereo-reversion of 8.
the low yields and long reactions times of the tosylate formation
and subsequent cyclization were discouraging. Despite the
aforementioned difficulties, the Mitsunobu reaction applied to
this system gave excellent conversion and treatment of 3 with
DEAD/PPh3 delivered the lactone 7 in 77 % yield (Scheme 3).
Unsurprisingly, the remainder of the material could be
accounted for as impure lactone 7 contaminated with triphenyl
phosphine oxide and dialkyl hydrazine carboxylate by-products.
However, the efficient conversion of the lactone 7 to the cis-
4-hydroxy acid 8 (Scheme 1) suggested that the crude Mitsu-
nobu product could be subjected to similar biphasic conditions.
This process would selectively extract the cis-4-hydroxy acid 8
into the water phase. Further, it seemed reasonable that removal
of the organic layer and recharging with fresh solvent, MeI, and
phase-transfer catalyst (PTC) would lead to the formation of the
desired ester 4.[21] Initial attempts to employ a similar strategy
through methanolysis of lactone 7 did not lead to a significant
difference in polarity and was therefore not useful for enhancing
separation from the by-products by chromatography.
the unwanted Mitsunobu adducts was discarded and replaced
with fresh DCM and MeI to give the desired ester 4 in 37 % yield
(Entry 1). No alkylation was observed in the absence of TBAB.
Prolonging the final methylation step (Entry 2) resulted in an
increase of the ester 4 to 65 % yield, but as a 1:1 mixture of the
desired cis-hydroxy-L-proline methyl ester 4 and curiously
the diastereomer, trans-4-hydroxy-L-proline methyl ester 15.
The formation of trans-4-hydroxy-L-proline 3 in this reaction
suggests a mechanism whereby the cis-4-hydroxy-L-proline 8 is
in equilibrium with the lactone 7, which can be ring-opened via
attack on the carbonyl carbon (path a) or the less favoured, but
irreversible, attack on the g-carbon (path b) to give trans-4-
hydroxy-L-proline 3, and then subsequent alkylation leading to
the corresponding ester 15 (Fig. 4).
Even in the presence of 0.5 equivalents of K2CO3 (data not
shown), significant stereoinversion was observed. In fact, com-
plete stereoinversion of C4 could be affected in the presence of
Aliquat 336 (a tetraalkylammonium PTC with C-8 and C-10
alkyl chains) [19] over 96 h, delivering trans-hydroxy-L-proline
methyl ester 15 and the trans-hydroxy-L-proline acid 3 ([a]2D5
ꢀ100.7 (c 1.4 in EtOH); lit. [a]2D5 ꢀ96.2 (2.5 in EtOH))[8] in 13
and 64 % yield, respectively (Scheme 4).
The development of this extractive approach is outlined in
Table 1. Thus, treatment of trans-4-hydroxy-L-proline 3 under
the Mitsunobu conditions outlined above lead to the formation
of the lactone 7. The THF was removed and toluene, water,
K2CO3, and TBAB added to give the acid 8. The toluene/
water mixture was partitioned and the organic layer containing
Although the PTC alkylation approach was initially attrac-
tive owing to its simplicity, the potential for stereochemical
leakage in this step made it untenable. Therefore the acid 8 was

1512
J. A. Smith, G. P. Savage, and O. E. Hutt
isolated after Step B and methylated in the standard fashion
(K2CO3, MeI, acetone), which delivered the desired ester
product 4 in 75 % yield over the three steps (Entry 3). Finally,
by substituting DCM for THF in Step A, removal of the solvent
after the Mitsunobu reaction was not required and this resulted
in an increased overall yield (82 %) over the three steps
(Entry 4).
N-phenylsulfonyl-trans-4-hydroxy proline 3 (700 mg, 35 %).
[a]2D5 ꢀ58.4 (c 2.5 in EtOH). dH (400 MHz, d4-MeOH) 2.16 (m,
1H), 2.34 (m, 1H), 2.44 (s, 3H), 3.54 (d, J 12.9, 1H), 3.63 (dd, J
12.8, 3.6, 1H), 4.16 (dd, J 9.1, 7.6, 1H), 5.00 (br s, 1H), 7.39 (d, J
8.0, 2H), 7.52 (m, 5H), 7.82 (d, J 7.5, 2H). dC (100 MHz, d4-
MeOH) 20.2, 37.1, 54.1, 59.4, 79.3, 127.5, 127.3, 128.9, 129.8,
133.1, 133.2, 137.1, 145.5, 173.4. nmax(film)/cmꢀ1 1734. m/z
(HR-EIþ) found 448.0480; C18H19NO7NaS2 requires
448.0501.
Conclusion
A high yielding practical procedure has been successfully de-
veloped to convert the trans-4-hydroxy-L-proline derivative 3 to
the cis-hydroxy-L-proline derivative 4 in 82 % over three steps.
For comparison, the traditional stepwise route of 3 to 4, through
methanolysis of lactone 7 (Scheme 1), proceeds in 58 % over
two steps. Moreover, this sequence requires an intermediate
chromatography operation that is technically difficult on a larger
scale. Although PTC alkylation of cis-hydroxy-L-proline 8
could be achieved in modest yield, these reaction conditions
lead to significant stereo-reversion to the trans-hydroxy-L-pro-
line derivative 3 through nucleophilic attack on the g-carbon of
lactone 7. Finally, simple biphasic conditions have been de-
veloped for employing lactone 7 as an active ester for use in
amide bond formation.
Lactone 7
Method A: A mixture of N-phenylsulfonyl-trans-4-tosyloxy-
proline methyl ester 6 (200 mg, 0.47 mmol), K2CO3 (64 mg,
0.47 mmol), and 2-butanone (10 mL) was heated at reflux for 2 h
over which time a white precipitate formed. The reaction was
allowed to cool and was diluted with DCM (20 mL) and H2O
(20 mL). The organic layer was washed with brine and the
aqueous layer re-extracted with DCM (20 mL). The combined
organic layers were dried over MgSO4, filtered, and the solvent
removed under reduced pressure. The residue was chromato-
graphed over silica gel eluting with petroleum spirits/EtOAc
(1:1) to give lactone 7 as a white solid (67 mg, 56 %).
Method B: N-Phenylsulfonyl-trans-4-hydroxy proline 3
(2.16 g, 7.96 mmol) was dissolved in anhydrous THF
(140 mL) under a nitrogen atmosphere and triphenylphoshine
(2.19 g, 8.36 mmol) was added. The reaction mixture was cooled
to 08C and diethyl azodicarboxylate (1.32 mL, 8.36 mmol)
added dropwise over 1 h. After complete addition, the resulting
mixture was allowed to warm to room temperature and stirred
for 4 h. The solvent was removed under reduced pressure
affording a sticky residue, which was purified by chromatogra-
phy over silica gel eluting with DCM/EtOAc (4:1). The lactone
7 was isolated as a white powder, mp 118.7–119.58C (1.55 g,
77 %). [a]2D5 þ33.4 (c 1.0 in CHCl3). dH (200 MHz, CDCl3) 2.03
(dd, J 1.9, 10.9, 1H), 2.23 (dq, J 1.3, 10.9, 1H), 3.27 (br d, J 10.0,
1H), 3.68 (dd, J 2.0, 10.0, 1H), 4.52 (q, J 1.3, 1H), 5.03 (br t, J
0.8, 1H), 7.49–7.68 (m, 3H), 7.83–7.90 (m, 2H). dC (100 MHz,
CDCl3) 39.4, 51.1, 59.5, 78.6, 128.0, 129.3, 133.7, 136.5, 169.4.
Experimental
Reaction flasks were oven-dried and solvents employed were
HPLC grade. NMR spectra were recorded on either a 400 or
200 MHz spectrometer. Spectra were recorded as solutions in
CDCl3 [dH ¼ 7.26, dC ¼ 77.26 as internal standards], d6-DMSO
[dH ¼ 2.50, dC ¼ 39.5 as internal standards], or d6-acetone
[dH ¼ 2.05, dC ¼ 29.9 as internal standards]. The data are
reported as integration, s ¼ singlet, d ¼ doublet, t ¼ triplet, q ¼
quartet, quin ¼ quintet, m ¼ multiplet or unresolved, br ¼ broad,
obs ¼ obscured, coupling constant(s) in Hz. Mass spectra were
recorded using electrospray ionization (ESI) employing 35 eV
cone voltage, employing lock spray and sodium iodide as a
reference sample. Specific rotations were determined at the
sodium D line at 258C using a 10-cm length tube. Melting points
were determined using a variable heater apparatus and values
are uncorrected. FTIR spectra were obtained using a Thermo
Nicolet 6700 spectrometer using a SmartATR (attenuated total
reflectance) attachment fitted with a diamond window.
n
max(film)/cmꢀ1 1787, 1586. m/z (ESI) 286 (MþNa, 100%), 254
(MþH, 50), 226 (30). m/z (HR-EIþ) found: 276.0303;
C11H11NO4SþNa requires 276.0306.
N-Phenylsulfonyl-cis-4-hydroxy Proline 8
Lactone 7 (475 mg, 1.88 mmol), K2CO3 (428 mg, 3.09 mmol),
and Bu4NþBrꢀ (61 mg, 0.19 mmol) were dissolved in DCM
(10 mL) and water (10 mL) and the biphasic reaction mixture
stirred for 16 h at room temperature. The reaction mixture was
acidified with 1M HCl and extracted with DCM:iPrOH (4:1).
The combined organic extracts were washed with water, dried
over MgSO4, and the solvent removed under reduced pressure.
The crude material was purified over silica gel eluting with
CH3CN:H2O (1:1) to give the title acid 8 as a white solid, mp
113.1–114.38C (lit.[7] 113.5–114.58C), (472 mg, 91 %). [a]2D5
ꢀ84.9 (c 1.5 in EtOH) (lit.[7] [a]D25 ꢀ72.4 (2.5 EtOH)). dH
(400 MHz, d6-DMSO) 1.87 (dt, J 4.0, 12.8, 1H), 2.00 (m, 1H),
3.11 (dd, J 4.0, 10.5, 1H), 3.28 (dt, J 5.0, 10.5, 1H), 3.95 (quin, J
5.0, 1H), 4.23 (dd, J 4.6, 9.1, 1H), 4.34 (br s, 1H), 7.59–7.64 (m,
2H), 7.67–7.72 (m, 1H), 7.83–7.87 (m, 2H). dC (50 MHz, d6-
DMSO) 38.3, 55.4, 59.5, 68.5, 127.2, 129.4, 133.1, 137.6, 172.8.
N-Phenylsulfonyl-trans-4-tosyloxy-proline Methyl Ester 6
N-Phenylsulfonyl-trans-4-hydroxy proline 3 (2 g, 7.38 mmol)
was dissolved in 2 M NaOH (10 mL, 20 mmol) and a solution of
TsCl (5.7 g, 29.5 mmol) in Et2O (10 mL) added. The mixture
was stirred at room temperature for 4 days over which time the
precipitate completely dissolved. The Et2O layer was then
extracted with 1 M NaOH (2 ꢁ 10 mL). The aqueous layers were
then combined and the water removed under reduced pressure.
The resulting residue was then taken up in EtOH, filtered, and
the solvent again removed under reduced pressure. The residue
was then dissolved in 10 % butan-2-ol/ethyl acetate (20 mL) and
washed with H2O and brine. The organic layer was then
dried over MgSO4, filtered, and the solvent removed under re-
duced pressure to give an oil which was chromatographed
on silica gel (5 % MeOH/DCM with 0.5 % AcOH) to give
the N-phenylsulfonyl-trans-4-tosyloxy-proline methyl ester 6
(1.2 g, 38 %) as a white solid (mp 120.9–121.08C) and
n
max(film)/cmꢀ1 3241, 1691. m/z (ESI) 272 (MþH, 100 %),
226 (30). m/z (HR-EIþ) found: 294.0398; C11H13NO5SþNa
requires 294.0412.

Synthesis of cis-4-Hydroxy-L-proline
1513
N-Phenylsulfonyl-cis-4-hydroxy Proline Methyl Ester 4
Benzyl-(R)-2-((2S,4S)-4-hydroxy-1-(phenylsulfonyl)
pyrrolidine-2-carboxamido)-3-phenylpropanoate 14
Lactone 7 (1.0 g, 3.95 mmol) and Na2CO3 (2.09 g, 19.8 mmol)
were combined in MeOH (25 mL) and stirred for 8 h at room
temperature. The MeOH was removed under reduced pressure,
the residue taken up in EtOAc and filtered through a small plug
of silica gel. The title compound 4 was obtained as a white
powder, mp 104.4–104.78C (lit.[7] 104–1058C), (852 mg, 75 %).
[a]2D5 ꢀ65.2 (c 1.5 in CHCl3) (lit.[7] [a]2D5 ꢀ70.3 (2.5 CHCl3)). dH
(400 MHz, CDCl3) 2.10 (dt, J 1.6, 14.1, 1H), 2.17 (m, 1H), 3.40
(dd, J 4.2, 10.3, 1H), 3.55 (dt, J 1.3, 10.3, 1H), 3.77 (s, 3H), 4.34
(m, 1H), 4.38 (dd, J 2.0, 9.7, 1H), 7.42–7.56 (m, 2H), 7.56–7.69
(m, 1H), 7.85–7.90 (m, 2H). dC (100 MHz, CDCl3) 38.7, 53.0,
56.9, 59.1, 70.9, 127.8, 129.2, 133.2, 137.6, 174.1. nmax(film)/
cmꢀ1 3523, 1726. m/z (ESI): 286 (MþH, 100%), 226 (20). m/z
(HR-EIþ) found: 308.0577; C12H15NO5SþNa requires
308.0569.
To a solution of lactone 7 (100 mg, 0.4 mmol) in toluene (1 mL)
was added D-phenylalanine benzyl ester ꢂ HCl (429 mg,
0.24 mmol) and NaHCO3 (33 mg, 0.4 mmol) in H2O (0.2 mL).
The biphasic mixture was heated to 808C for 12 h. The reaction
was then cooled and EtOAc (10 mL) added. The organic layer
was washed with 2 % w/v citric acid (ꢁ2) and brine. The
aqueous layer was re-extracted with EtOAc and the combined
organic extracts dried over MgSO4, filtered, and the solvent
removed under reduced pressure. The residue was chromato-
graphed over silica gel eluting with DCM:MeOH (initial eluent
1 % MeOH increasing to 5 % MeOH) to give the title compound
14 as a white clear oil (186 mg, 91 %). [a]2D5 –38.8 (c 1.0 in
CHCl3). dH (400 MHz, CDCl3) 1.69 (m, 1H), 2.16 (d, J 14.0,
1H), 3.12 (m, 2H), 3.22 (dd, J 10.7, 4.1, 1H), 3.90 (br s, 1H), 4.23
(m, 1H), 4.25 (d, J 8.9, 1H), 4.86 (dd, J 13.8, 6.1, 1H), 5.13
(ABd, J 12.0, 2H), 7.12 - 7.34 (m, 11H), 7.50 (t, J 7.3, 2H), 7.60
(t, J 7.4, 1H), 7.78 (m, 2H). dC (100 MHz, CDCl3) 37.6, 37.9,
53.8, 57.7, 61.3, 67.2, 70.5, 127.1, 127.6, 128.5, 128.5, 128.6,
128.6, 129.4, 129.6, 133.4, 135.1, 135.6, 136.3, 170.7, 171.9.
tButyl-3-((2S,4S)-4-hydroxy-1-(phenylsulfonyl)pyrrolidine-
2-carboxamido)-propanoate 10
To a solution of lactone 7 (500 mg, 1.9 mmol) in toluene (5 mL)
was added b-alanine tert-butyl ester ꢂ HCl (429 mg, 2.4 mmol)
and K2CO3 (325 mg, 2.4 mmol) in H2O (1 mL). The biphasic
mixture was heated to 808C for 2 h. The reaction was then
cooled and toluene (5 mL) added. The organic layer was washed
with H2O and brine. The aqueous layer was re-extracted with
EtOAc and the combined organic extracts dried over MgSO4,
filtered, and the solvent removed under reduced pressure. The
residue was chromatographed over silica gel eluting with DCM/
MeOH(initial eluent 1 % MeOHincreasing to5 % MeOH) togive
the title compound 9 as a white solid, mp 131.9–132.08C (560 mg,
74 %). [a]2D5 ꢀ81.1 (c 2.5 in CHCl3). dH (400 MHz, CDCl3) 1.44
(s, 9H), 1.79 (m, 1H), 2.20 (d, J 14.0, 1H), 2.43 (m, 2H), 3.59–3.39
(m, 3H), 4.18 (d, J 8.9, 1H), 4.28 (m, 2H), 7.20 (t, J 5.7, 1H), 7.52
(m, 2H), 7.60 (m, 1H), 7.80 (m, 2H). dC (100 MHz, CDCl3) 28.1,
34.9, 35.5, 37.8, 57.9, 61.5, 70.6, 81.3, 127.6, 129.3, 133.3, 136.4,
171.5, 172.1. nmax(film)/cmꢀ1 1722, 1654. m/z (HR-EIþ) found
421.1367; C18H26N2O6NaS requires 421.1409.
n
531.1523; C27H28N2O6NaS requires 531.1566.
max(film)/cmꢀ1 3373, 1740 1657, 1524. m/z (HR-EIþ) found
Preferred Three-step One-pot Procedure for Conversion of
N-phenylsulfonyl-trans-hydroxy-L-proline 3 to
N-phenylsulfonyl-cis-hydroxy-L-proline Methyl Ester 4
N-Phenylsulfonyl-trans-4-hydroxy proline
1.85 mmol) was dissolved in anhydrous DCM (20 mL) under
nitrogen atmosphere and triphenylphoshine (678 mg,
3
(500 mg,
a
2.58 mmol) was added. The reaction mixture was cooled to 08C
and diethyl azodicarboxylate (407 mL, 2.58 mmol) added drop-
wise over 20 min. After complete addition, the resultant mixture
was allowed to warm to room temperature and stirred for 4 h.
Water (20 mL), K2CO3 (280 mg, 2.03 mmol) and Bu4NþBrꢀ
(59 mg, 0.19 mmol) were added to the reaction mixture and the
biphasic solution stirred for 16 h at room temperature. The DCM
layer was discarded and the aqueous layer washed with
DCM/iPrOH (4:1) (20 mL ꢁ 3) to remove the diethyl hydrazine
dicarboxylate by-product. The aqueous layer was acidified with
1M HCl and extracted with DCM/iPrOH (4:1). The combined
organic extracts were washed with water, dried over MgSO4,
and the solvent removed under reduced pressure. Acetone
(20 mL) was added to the residue along with K2CO3 (255 mg,
1.85 mmol), methyl iodide (234 mL, 3.69 mmol), and the mix-
ture heated at reflux for 6 h. The reaction was cooled to room
temperature and the acetone removed under reduced pressure.
DCM was added to the residue and the organic layer was washed
with water, dried over MgSO4, and the solvent removed under
reduced pressure. The crude material was purified over C-18
silica gel eluting with water/acetonitrile (7:3) affording the title
ester 4 as white crystals (430 mg, 82 %).
Methyl-(S)-2-((2S,4S)-4-hydroxy-1-(phenylsulfonyl)
pyrrolidine-2-carboxamido)-4-methylpentanoate 12
To a solution of lactone 7 (50 mg, 0.19 mmol) in toluene
(0.5 mL) was added L-leucine methyl ester ꢂ HCl (35 mg,
0.2 mmol) and NaHCO3 (16 mg, 0.2 mmol) in H2O (0.1 mL).
The biphasic mixture was heated to 808C for 6 h. The reaction
was then cooled and EtOAc (10 mL) added. The organic
layer was washed with 2 % w/v citric acid (ꢁ2) and brine. The
aqueous layer was re-extracted with EtOAc and the combined
organic extracts dried over MgSO4, filtered, and the solvent
removed under reduced pressure. The residue was chromato-
graphed over silica gel eluting with DCM/MeOH (initial eleunt
1 % MeOH increasing to 5 % MeOH) to give the title compound
12 as a white solid, mp 142.48C (54 mg, 69%). [a]2D2 –75.5 (c 1.0
in CHCl3). dH (400 MHz, d6-Acetone/0.3 % D2O) 0.89 (d, J 6.6,
6H), 1.60 (m, 2H), 1.80 (m, 1H), 1.94 (m, 2H), 3.26 (dd, J 9.9,
4.3, 1H), 3.40 (d, J 10.3, 1H), 3.66 (s, 3H), 4.14 (br s, 1H), 4.27
(dd, J 7.4, 4.3, 1H), 4.49 (dd, J 9.3, 5.6, 1H), 7.61 (t, J 7.7, 2H),
7.69 (t, J 7.3, 1H), 7.88 (d, J ¼ 7.7, 2H). dC (100 MHz, d6-
Acetone/0.3 % D2O) 21.0, 22.3, 24.2, 37.9, 40.6, 50.7, 51.5,
57.6, 60.9, 69.8, 127.6, 129.3, 133.2, 136.9, 172.4, 172.5.
Complete Stereo-reversion of N-phenylsulfonyl-cis-
hydroxy-L-proline 8 to N-phenylsulfonyl-trans-hydroxy-L-
proline 3
N-Phenylsulfonyl-trans-4-hydroxy proline
3
(250 mg,
0.92 mmol) was dissolved in anhydrous DCM (10 mL) under a
nitrogen atmosphere and triphenylphosphine (338 mg,
1.29 mmol) was added. The reaction mixture was cooled to
08C and diethyl azodicarboxylate (175 mL, 1.29 mmol) added
dropwise over 20 min. After complete addition, the resultant
n
421.1396; C18H26N2O6NaS requires 421.1409.
max(film)/cmꢀ1 3355, 1743, 1655, 1534. m/z (HR-EIþ) found

1514
J. A. Smith, G. P. Savage, and O. E. Hutt
mixture was allowed to warm to room temperature and stirred
for 6 h. Water (10 mL), NaHCO3 (78 mg, 0.92 mmol), and
Aliquat 336 (420 mL, 0.92 mmol) were added to the reaction
mixture and the biphasic mixture stirred for 16 mLh at room
temperature. The DCM layer was discarded and the aqueous
layer washed with DCM (2 ꢁ 20 mL). DCM (40 mL) and methyl
iodide (118 mL, 1.85 mmol) were added to the aqueous layer and
the biphasic mixture stirred for 16 h at room temperature. After
this time additional NaHCO3 (78 mg, 0.92 mmol), Aliquat 336
(420 mL, 0.92 mmol), and methyl iodide (586 mL, 9.22 mmol)
were added and the mixture stirred at room temperature for a
further 96 h. At this point LCMS indicated only a small amount
of a methyl ester had been formed and the reaction was termi-
nated. The aqueous layer was acidified with 1M HCl and
extracted with DCM/iPrOH (4:1). The combined organic
extracts were washed with water, dried over MgSO4 and the
solvent removed under reduced pressure. The crude material
was purified by flash chromatography over C-18 silica gel
eluting with water/acetonitrile (8:2). Methyl ester 10 was iso-
lated as a white solid, mp 114.8–116.18C (lit.[22] 121–1228C)
(34 mg, 13 %). [a]2D5 ꢀ98.2 (c 0.7 in CHCl3). dH (400 MHz,
CDCl3) 2.08–2.16 (m, 1H), 2.19–2.17 (m, 1H), 3.42 (d, J 11.3,
1H), 3.61 (dd, J 3.6, 11.3, 1H), 3.74 (s, 3H), 4.45 (t, J 8.3, 1H),
4.43–4.48 (m, 1H), 7.53 (t, J 7.6, 2H), 7.60 (t, J 7.6, 1H), 7.90 (d,
J 7.6, 2H). dC (100 MHz, CDCl3) 39.8, 52.8, 56.6, 59.6, 70.4,
127.9, 129.3, 133.3, 138.1, 172.6. nmax(film)/cmꢀ1 3468, 1712.
m/z (ESI) 286 (MþH, 100 %), 226 (30). m/z (HR-EIþ) found:
308.0576; C12H15NO5SþNa requires 308.0569.
S. W. Ludmerer, M. W. Stahlhut, C. M. Fandozzi, N. Trainor, D. B.
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N-Phenylsulfonyl-trans-4-hydroxy proline 3 was also isolat-
ed as a white glass, mp 152.7–152.88C (lit.[7] 150–1518C)
(160 mg, 64 %). [a]D25 ꢀ100.7 (c 1.4 in EtOH) (lit.[7] [a]2D5
ꢀ96.2 (2.5 EtOH)). dH (400 MHz, d6-DMSO) 2.05–2.09 (m,
2H), 3.24 (ddd, J 0.9, 2.7, 10.5, 1H), 3.54 (dd, J 4.4, 10.5, 1H),
4.22 (t, J 7.7, 1H), 4.33 (quin, J 3.8, 1H), 4.34 (br s, 1H), 7.41–
7.45 (m, 2H), 7.48–7.52 (m, 1H), 7.82–7.84 (m, 2H). dC
(100 MHz, d6-DMSO) 39.5, 56.4, 59.8, 69.5, 127.8, 128.9,
132.7, 138.0, 174.1. nmax(film)/cmꢀ1 3394, 1709. m/z (ESI)
272 (MþH, 100 %), 226 (30). m/z (HR-EIþ) found: 294.0388;
C11H13NO5SþNa requires 294.0412.
Accessory Publication
1H NMR and 13C NMR spectra for compounds 4, 6, 7, 10, 12, 14,
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Acknowledgements
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11451
Jessica Smith gratefully acknowledges the receipt of a CSIRO OCE Post
Doctoral Fellowship. Oliver Hutt thanks Jack Ryan for discussions about
phase-transfer catalysis.
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doi:10.1002/HLCA.200690178
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