Novel peptide isosteres that were designed to inhibit the binding of the HIV surface glycoprotein (gp120) to the T cell surface glycoprotein CD4

Article abstract of DOI:10.1039/a800756j

The cis- and trans-isomers of (2S)-2-[3′(RS)-3′-benzyl-3′-benzyloxycarbonylprop-1′- enyl]-N-methoxycarbonylcarbonylpyrrolidines have been prepared from a Wittig reaction between (S)-N-Boc-prolinal and the phosphorus ylide from (2RS)-3-iodo-2-benzyl-1-triisopropylsilyloxypropane. In addition, (2S)-N-methoxycarbonylcarbonyl-2-[(3′RS)-1-oxo-3′-benzyl-3′- benzyloxycarbonylpropyl]pyrrolidine was prepared from the cis-alkene produced in the Wittig reaction. These were intended as peptide isosteres of the known inhibitors of HIV-lymphocyte binding N-methoxycarbonylcarbonylprolylphenylalanyl benzyl esters, but did not possess such activity.

Full text of DOI:10.1039/a800756j

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Novel peptide isosteres that were designed to inhibit the binding of
the HIV surface glycoprotein (gp120) to the T cell surface
glycoprotein CD4
Michael G. B. Drew, Stephen Gorsuch, John Mann* and Shimon Yoshida
Department of Chemistry, Reading University, Whiteknights, Reading, UK RG6 6AD
The cis- and trans-isomers of (2S)-2-[3Ј(RS)-3Ј-benzyl-3Ј-benzyloxycarbonylprop-1Ј-enyl]-N-
methoxycarbonylcarbonylpyrrolidines have been prepared from a Wittig reaction between (S)-N-Boc-
prolinal and the phosphorus ylide from (2RS)-3-iodo-2-benzyl-1-triisopropylsilyloxypropane. In addition,
(2S)-N-methoxycarbonylcarbonyl-2-[(3ЈRS)-1-oxo-3Ј-benzyl-3Ј-benzyloxycarbonylpropyl]pyrrolidine was
prepared from the cis-alkene produced in the Wittig reaction. These were intended as peptide isosteres of
the known inhibitors of HIV-lymphocyte binding N-methoxycarbonylcarbonylprolylphenylalanyl benzyl
esters, but did not possess such activity.
There is now a glimmer of hope that chemotherapy will provide
a means of eradicating the human immunodeficiency virus
(HIV) from infected individuals.1 However, both the reverse
transcriptase inhibitors like AZT, ddC and D4T, and the pro-
tease inhibitors like saquinavir and indinavir, interfere with
viral reproduction after uptake by T-4 lymphocytes. It would be
preferable to have agents that prevented the uptake of the virus
by the lymphocyte. A number of such agents are known and
these include such diverse substances as heparin, various lectins
and derivatives of betulinic acid,2 but these are too non-specific
to consider as drugs.
stability. The synthesis and (preliminary) biological evaluation
of such isosteres are the subject of this paper.
An obvious strategy for construction of these compounds
was to employ a Wittig reaction between an N-protected proli-
nal 3 and a phosphorus ylide formed from 3-iodo-2-benzyl-1-
alkoxypropane 4. (S)-Benzyloxycarbonylproline methyl ester
OR
H
I
O
N
P
H
H
In 1990, Schreiber and co-workers carried out modelling
studies of the interaction between the glycoprotein (so-called
gp120) on the surface of HIV with a key glycoprotein (CD4) on
the cell surface of the T-4 lymphocyte.3 Although a further
interaction with another lymphocyte factor (either CCR5 or
CXCR4)4 is also required, the initial interaction between gp120
and CD4 is crucial for uptake (internalisation) of the virus. The
Schreiber group then synthesised several dipeptides that
prevented such binding and subsequently acted to prevent
infection of the cells by the virus. The N-methoxycarbonyl-
carbonylprolylphenylalanyl benzyl esters 1 were the most
3a P = Cbz
3b P = Boc
4a R = THP
4b R = TIPS
I–
4
3
OTHP
Ph3P+
OTHP
2
H
3′
5
2′
1
H
N
1′
H
Cbz
5
6
was converted into the desired aldehyde 3a via reduction with
LiBH4 followed by Swern oxidation (80% yield overall). The
iodopropane derivative 4a was prepared from diethyl 2-
benzylmalonate via reduction (LiBH4) to 2-benzylpropane-1,3-
diol (55%), followed by formation of the mono-toluene-p-
sulfonate (toluene-p-sulfonyl chloride–pyridine) (55%) and
thence the tetrahydropyranyl (THP) derivative (dihydropyran
in DCM with toluene-p-sulfonic acid as catalyst; essentially
quantitative). Finally, the desired iodide 4a was formed by reac-
tion with sodium iodide in refluxing acetone (95%).
H
H
NH
CO2Bn
CO2Bn
N
N
O
H
H
O
O
O
O
OMe
OMe
1
2 cis - and trans-alkenes
Reaction of this iodide with triphenylphosphine in refluxing
acetonitrile provided the desired phosphonium salt 5 as a light
yellow foam (quantitative). The phosphorus ylide was gener-
ated using butyllithium at Ϫ78 ЊC and the Wittig reaction with
aldehyde 3a proceeded in modest yield (44%) to give what
appeared to be two major products. Although these were just
separable by flash chromatography, the 1H NMR spectra of the
‘discrete’ products were extremely broad, and it seemed likely
that they were mixtures of diastereoisomers (not least due to
the presence of the THP group). Removal of the THP group
from the crude Wittig product mixture (aqueous HCl) pro-
duced one major product (ca. 20% overall) which was identified
as a discrete stereoisomer 6 (but with unknown stereochemistry
at C-3Ј). The other compound appeared to be one of the Wittig
products which had not been changed by exposure to the acid.
H
CO2Bn
N
H
O
O
OMe
potent and were active at concentrations in excess of 600 µg
mlϪ1. However, no further reports have emanated from this
group, though a French group have recently reported similar
results.5 This level of activity is not particularly good and
doubt remains whether such dipeptides would have sufficient
metabolic stability for drug use. We have used Schreiber’s
compounds as models for novel peptide isosteres of general
structure 2, which we hoped would have better activity and
J. Chem. Soc., Perkin Trans. 1, 1998
1627

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Clearly the THP group had been an unwise choice for the syn-
thesis, and in an effort to improve the yields and the ease of
manipulation of the Wittig products, the alternative route
shown in Scheme 1 was investigated.
3b using a Dess–Martin periodinane oxidation7 of the corres-
ponding prolinol. The H NMR spectrum of this sample of
1
aldehyde was identical in all respects with that obtained with
our previous samples, but now the Wittig reaction provided a
good yield of two products 11 (52%) and 12 (18%). We believe
(although we have no experimental proof) that traces of alu-
minium salts contaminated the aldehyde produced from the
Weinreib amide, and that these led to the very poor yields in the
Wittig reaction of aldehyde 3b prepared by this route.
The major product 11 was clearly a mixture of cis-alkenes
(J around 11 Hz), presumably epimeric at C-3Ј. Removal of the
TIPS group (TBAF–THF) produced a separable mixture of
two products 13a and 13b whose stereochemistry was sub-
sequently established by X-ray crystallographic studies
(ORTEP plots are shown in Figs. 1 and 2). The major differences
between 13a and 13b, in the X-ray structures, were the stereo-
chemistry at C-3Ј and the relative positions of the oxygen atoms
of the Boc groups.
O
O
H
EtO
OEt
HO
i, ii
OTIPS
(73%)
7
(80%)
O
iii, iv
H
N
Boc
N
OH
OH
I
OTIPS
Boc
9
The alcohols were then oxidised (Jones’ reagent) to yield the
discrete acids 14a,b (89 and 98% respectively) (Scheme 2), and
vi, vii
(91%)
4b
ix
O
(quant.)
(quant.)
v
OMe
N
Boc
N
OTIPS
N
I–
Ph3P+
H
Me
10
Ph
OTIPS
O
OBut
viii (73%)
11
O
H
i
N
8
Boc
3b
OH
OH
N
N
Ph
Ph
O
OBut
47%
13a
O
OBut
45%
H
x
OTIPS
13b
OTIPS
N
ii
H
N
Boc
Boc
O
O
12 (18%)
O
Ph
iii
OH
N
11 (52%)
N
Ph
Ph
O
OBut
O
OBut
Scheme 1 Reagents and conditions: i, LiAlH4, diethyl ether; ii, NaH,
TIPSCl, DCM; iii, Et3N, MeSO2Cl, DCM; iv, NaI, acetone, reflux; v,
Ph3P, MeCN, reflux, 48 h; vi, carbonyldiimidazole, DCM; vii, MeO-
NHMe; viii, LiAlH4, diethyl ether; ix, Dess–Martin periodinane; x,
BuLi, THF, Ϫ78 ЊC
15a, 15b (51%)
14a, 14b (89%, 98%)
iv, v
O
Diethyl 2-benzylmalonate was converted into 2-benzyl-3-
O
Ph
triisopropylsilyloxypropanol
7 via reduction to the diol
N
(LiAlH4–diethyl ether) then silyl ether formation with sodium
hydride and triisopropylsilyl chloride (73% overall). Conversion
into the methanesulfonate (Et3N–MeSO2Cl–DCM) was fol-
lowed by displacement of the mesylate group by iodide (NaI in
refluxing acetone) (80% overall) to provide the iodide 4b.
Finally, the triphenylphosphonium salt 8 was produced by reac-
tion of the iodide with triphenylphosphine in refluxing
acetonitrile (essentially quantitative). It was quite notable that
the overall yield for this five-stage process was around 58%,
which represented a considerable improvement on the route to
phosphonium salt 5. The compound was a white microcrystal-
line solid. For this second route we employed Boc-prolinal 3b
and this was prepared via the Weinreib amide6 10 formed from
N-Boc-proline 9 (as shown in Scheme 1). Once again, the yields
were very good.
Ph
O
O
OMe
16a, 16b (85%, 80%)
Scheme 2 Reagents and conditions: i, TBAF, THF, 25 ЊC, 60 min; ii,
Jones’ reagent, Me2CO, 0 ЊC, 60 min; iii, CDI, BnOH, DCM, NaOEt,
30 ЊC, 3 days; iv, TFA, DCM, 25 ЊC, 5 min; v, MeO2CCOCl, pyridine,
0 to 25 ЊC, 60 min
these were converted into the corresponding benzyl esters 15a,b
(carbonyldiimidazole then benzyl alcohol and catalytic NaOEt)
(51% in each case). Finally, the Boc groups were removed (TFA–
DCM) and the products reacted with methyl oxyalyl chloride in
pyridine–DCM to provide the desired peptide isosteres 16a and
16b (85 and 80% respectively). A problem now arose since the
1H NMR spectra showed a partial doubling for many of the
signals, and it was not initially clear whether we were dealing
with rotamers or whether racemisation had occurred during
the reaction sequence. Eventually, it was possible to prove
To our dismay, the subsequent Wittig reaction between the
phosphorus ylide from 8 and aldehyde 3b proceeded in at best
7% yield! After numerous attempts to improve upon this by
changing the nature of the alcohol protecting group or the con-
ditions of the Wittig reaction, we decided to prepare aldehyde
1628
J. Chem. Soc., Perkin Trans. 1, 1998

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Fig. 1 ORTEP plot of 13a
definitively by variable temperature NMR studies (at up to
90 ЊC) that both 16a and 16b existed in the form of slowly
interconverting rotamers. Their stereochemical homogeneity
was evidenced by the fact that the optical rotations of the com-
pounds did not vary between the various preparations that we
employed.
Fig. 2 ORTEP plot of 13b
the single S,S-stereoisomer) was prepared by the route shown in
Scheme 5.
Preliminary biological evaluation was carried out8 according
to the method of Weiss and Schreiber.9 This uses gp120, teth-
ered to an inert support via a monoclonal antibody attached to
its C-terminal region, and this is then monitored for its ability
to bind a CD4–IgG conjugate. The monitoring involves the use
of an anti-human IgG-horseradish peroxidase conjugate whose
presence is visualised following reaction with 3,3Ј,5,5Ј-
tetramethylbenzidine (TMB).10 Our compounds were tested for
the ability to prevent the association between gp120 and CD4,
but were inactive at concentrations up to 1 mg mlϪ1. Further
biological evaluation is being conducted with other systems and
full details will be provided in due course.
The mixture of trans-alkenes 12 (J = 15 Hz) was converted
via a similar sequence of reactions (Scheme 3) into the peptide
Ph
H
Ph
H
i
N
N
70%
OTIPS
OTIPS
O
OBut
O
OBut
12
17
ii
Experimental
Ph
Ph
H
O
H
O
IR spectra were recorded using a Perkin-Elmer 881 series
double beam spectrophotometer, and samples were run as thin
films or in solution using NaCl plates. Low resolution and
accurate mass data were recorded on a VG Autospec (Reading)
or VG7070F (Swansea: EPSRC facility) spectrometers. Elem-
ental analyses were carried out by Medac Ltd., Brunel Uni-
versity. Optical rotations were measured at room temperature
on a Perkin-Elmer 341 polarimeter. NMR spectra were
recorded using a JEOL EX400, Bruker DPX 250 or Bruker
WM250 spectrometers. Solvents were dried by distillation from
calcium hydride (DCM, toluene, benzene, acetonitrile) or from
sodium–benzophenone (THF and diethyl ether). Petrol refers
to petroleum spirit boiling range 40–60 ЊC; ether refers to
diethyl ether. Most of the compounds were very hygroscopic
and it proved difficult to obtain reproducible microanalytical
data. However, all pure compounds were homogeneous on TLC
in at least three solvent systems and exhibited no spurious
signals in their 1H NMR spectra at 400 MHz.
iii
N
N
35%
86%
O
OH
O
OBut
O
OBut
Ph
19
18
iv, v
Ph
H
O
N
87%
O
O
O
Ph
OMe
20
Scheme 3 Reagents and conditions: i, TBAF, THF, 25 ЊC, 2 h; ii, Jones’
reagent, Me2CO, 0 ЊC, 60 min; iii, CDI, BnOH, DCM, NaOEt, 30 ЊC, 3
days; iv, TFA, DCM, 25 ЊC, 15 min; v, MeO2CCOCl, pyridine, 0 to
25 ЊC, 60 min
Data for both crystals were collected with Mo-Kα radiation
using the MARresearch Image Plate System. The crystals were
positioned at 75 mm from the Image Plate and 95 frames were
measured at 2Њ intervals with a counting time of 2 minutes.
Data analysis was carried out with the XDS programme.11 Both
structures were solved using direct methods with the SHELX86
programme.12 In 13a two positions were refined for C(3) with
50% occupancy. In both structures the non-hydrogen atoms
were defined with anisotropic thermal parameters. The hydro-
gen atoms were included in geometric positions. Both structures
were then refined on F2 using SHELX1.13 All calculations were
carried out on a Silicon Graphics R4000 Workstation at the
University of Reading. Full crystallographic details, excluding
structure factor tables, have been deposited at the Cambridge
Crystallographic Data Centre (CCDC). For details of the
isosteres 20, though in this series it did not prove possible to
separate (at least by flash chromatography) the various stereo-
isomers. Preliminary biological evaluation (vide infra) showed
that compounds 16a, 16b and 20 did not inhibit binding of
gp120 to CD4 at concentrations up to 1 mg mlϪ1, so the
ketomethylene isostere 25 (as a pair of diastereoisomers) was
prepared via the route shown in Scheme 4, in the hope that this
would possess better activity. Of particular note was the regio-
selectivity of the hydroboration of cis-alkene 11 to provide the
alcohols 21a and 21b in the ratio of around 5:1. The remainder
of the synthesis was routine. Finally, in order to have a realistic
comparison of the biological activities of our peptide isosteres
with the dipeptides produced by Schreiber, the dipeptide 1 (as
J. Chem. Soc., Perkin Trans. 1, 1998
1629

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H
H
N
O
H
N
O
OTIPS
O
O
OH
O
N
i
Ph
O
O
O
OBut
11
99%
26
i, ii
O
OH
Ph
H
Ph
H
CDI, DCM
N
OH
A
ii
OTIPS
OTIPS
O
O
N
N
OH
O
+
O
OBut
O
OBut
H3N
O
21a
64%
21b
13%
iii
H
O
iii
N
O
N
Ph
H
Ph
O
O
H
O
O
OTIPS
OTIPS
N
N
O
66%
27
O
OBut
O
OBut
22a
22b
iv
87%
60%
iv
H
N
O
Ph
H
Ph
H
O
O
O
+
N
OH
v, vi
O
H
Ph
O
H
N
N
O
O
OBut
O
OBut
23
80%
24
38%
v
H
N
O
vii, viii
O
N
O
OMe
Ph
H
O
O
O
O
Ph
90%
11
N
O
O
O
Scheme 5 Reagents and conditions: i, Carbonyldiimidazole, BnOH,
DCM, NaOEt (cat.), 25 ЊC, 18 h; ii, TFA, DCM, 25 ЊC, 5 min; iii, A,
Et3N, DCM, 25 ЊC, 18 h; iv, TFA, DCM, 25 ЊC, 5 min; v, pyridine,
MeO2CCOCl, DCM, 0 ЊC, 18 h
OMe
25
80%
Scheme 4 Reagents and conditions: i, BH3ؒDMS, THF, 0 to 40 ЊC, 18
h; ii, 3  NaOH, 30% H2O2; iii, Dess–Martin periodinane, DCM, 25 ЊC,
1 h; iv, TBAF, THF, 25 ЊC, 1 h; v, Jones’ reagent, Me2CO, 0 ЊC, 1 h; vi,
CDI, BnOH, DCM, NaOEt, 40 ЊC, 3 h; vii, TFA, DCM, 25 ЊC, 5 min;
viii, MeO2CCOCl, pyridine, 0 to 25 ЊC, 1 h
water was added and the organic layer separated. The aqueous
layer was saturated with sodium chloride and extracted three
times with ethyl acetate. The combined organic extracts were
washed with 1% hydrochloric acid, water and then dried with
magnesium sulfate and concentrated to dryness. A yellow oil
remained containing some white precipitate. The oil was redis-
solved in ethyl acetate and the precipitate was filtered off. After
rotary evaporating to dryness the crude compound was azeo-
tropically distilled with benzene three times to remove traces of
water yielding the desired compound as a light orange oil (1.76
g, 89%) which could not be purified further. Spectroscopic
details were consistent with the literature.14 Rf 0.18 (diethyl
ether–light petroleum, 1:1); νmax(thin film)/cmϪ1 3150–2800s
deposition scheme, see ‘Instructions for Authors’, J. Chem.
Soc., Perkin Trans. 1, available via RSC Web page (http://
www.rsc.org/authors). Any request to the CCDC for this
material should quote the full literature citation and the
reference number 207/210.
(S)-N-Benzyloxycarbonyl-2-formylpyrrolidine 3a
To a stirred solution of dry dimethyl sulfoxide (1.81 ml, 25.5
mmol) in dry DCM (35 ml) in a flame-dried flask at Ϫ78 ЊC
under N2 was added oxalyl chloride (8.5 ml, 17.6 mmol) drop-
wise. The mixture was left stirring for 10 min before a solution
of N-Cbz-pyrrolidinemethanol (2.0 g, 8.51 mmol) in dry DCM
was added dropwise. The mixture was stirred for a further 20
min before triethylamine (4.73 ml, 34 mmol) was added, form-
ing a white precipitate. After warming to room temperature,
(CH), 2700s, 1736s (aldehyde C᎐O), 1700s (amide C᎐O); δ (400
᎐
᎐
H
MHz; CDCl3; Me4Si) 1.9 (2H, m, 4-H), 2.1 (2H, m, 3-H),
3.5 (2H, m, 5-H), 4.2–4.3 (1H, m, 2-H), 5.1 (2H, m, 6-H), 7.3
(5H, m, Ph), 9.6 (1H, s, COH); m/z (CI) 253 (3), 252 (20), 251
(100), 234 (42), 204 (8), 190 (13), 178 (2), 160 (5), 145 (2), 125 (5),
108 (20) (Found: MHϩ, 234.1130. C13H15NO3 requires M,
233.1052).
1630
J. Chem. Soc., Perkin Trans. 1, 1998

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1-Iodo-2-benzyl-3-(tetrahydro-2H-pyran-2-yloxy)propane 4a
To a stirred solution of the toluene-p-sulfonate (0.903 g, 2.23
mmol) in anhydrous acetone (50 ml) in a foil-wrapped flask
under N2 was added sodium iodide (502 mg, 3.36 mmol) all at
once. After refluxing for 9 h the mixture was poured into water
and extracted with 3 × 30 ml of diethyl ether. The organic
extracts were washed with saturated sodium thiosulfate solu-
tion, water and then dried with magnesium sulfate. Flash col-
umn chromatography (diethyl ether–light petroleum, 1:1)
yielded the title compound as a yellow oil (762 mg, 95%); Rf
0.70 (diethyl ether–light petroleum, 1:1) νmax(thin film)/cmϪ1
3200–3000m (CH), 3000–2800s (CH), 1945w, 1882w, 1806w,
was added, dropwise, diethyl 2-benzylmalonate (15.08 g, 59.9
mmol) in diethyl ether (150 ml). After stirring for 24 hours
water (4.5 ml), 15% NaOH (4.5 ml) and water 13.5 ml) were
added successively. The resulting white precipitate was removed
by filtration and washed with copious amounts of ether. Evap-
oration under reduced pressure yielded a pink solid. Trituration
with hexane to remove starting diester and dibenzyl impurities
afforded the title compound as a lustrous white solid. (8.37 g,
50.4 mmol, 84%). Spectroscopic details were consistent with the
literature.15 νmax(film)/cmϪ1 3200s (OH), 3000–2800s (CH),
1460s, 1380m, 1040m; δH(400 MHz; CDCl3; Me4Si) 2.05 (1H,
m, 2-H), 2.5 (2H, br, 2 × OH), 2.6 (2H, d, J4,2 7.7, 4-H), 3.6 (2H,
dd, J1a,1b 10.6 J1a,2 7.0, 1a-H), 3.8 (2H, dd, J1b,1a 10.6 J1b,2 7.0,
1b-H), 7.2 (5H, m, Ph); δC(100 MHz; CDCl3; Me4Si) 33.1 (4-C),
43.8 (2-C), 67.3 (1-C, 3-C), 125.1–139.0 (Ph) (Found: Mϩ,
166.0999. C10H14O2 requires M, 166.0994).
1737w (C᎐O), 1604m, 1500s, 1460s, 1390m, 1360s, 1300m,
᎐
1280m, 1200s; δH(400 MHz; CDCl3; Me4Si) 1.5–1.6 (4H, m, 4Ј-
H and 5Ј-H), 1.7 (1H, m, 2-H), 1.8 (2H, m, 3Ј-H), 2.6–2.7 (2H,
m, 4-H), 3.2–3.4 (2H, m, 1-H and 3-H isomer) 3.5 (1H, m, 6Јa-
H), 3.6–3.7 (2H, m, 3-H), 3.8 (1H, m, 6Јb-H), 4.6 (1H, m, 2Ј-H),
7.1–7.3 (5H, m, Ph); δC(200 MHz, 0.03% CDCl3) 12 (1-C),
19 (4Ј-C), 25 (5Ј-C), 30 (3Ј-C), 37 (4-C), 41 (2-C), 62 (6Ј-C), 69
(3-C), 98 and 99 (2Ј-C diastereomers), 125–130 (Ar-C); m/z 360
(1), 347 (1), 288 (1), 260 (1), 233 (1), 217 (1), 205 (1), 192 (1), 177
(1), 131 (80), 129 (9), 117 (18), 103 (20), 91 (73), 85 (100), 67 (15)
(Found: Mϩ, 360.0586. C15H21O2I requires M, 360.0586).
2-Benzyl-3-triisopropylsilyloxypropanol 7
To a flask containing a slurry of hexane-washed sodium
hydride (60% dispersion, 4.62 g, 115 mmol) in THF (300 ml)
fitted with an overhead stirrer, was added 2-benzylpropane-
1,3-diol (18.2 g, 109 mmol). After 90 minutes a voluminous
precipitate had formed. With vigorous stirring, chlorotriiso-
propylsilane (25.8 ml, 120 mmol) was then added. Once com-
plete dissolution was achieved (2 hours) the solvent was
removed and the residue poured on to ether (200 ml). The solu-
tion was washed with 10% K2CO3 (200 ml) and extracted with
ether (2 × 150 ml). The combined organic extracts were dried
over MgSO4 and evaporated under reduced pressure. The resi-
due was purified by flash column chromatography (using 1:1
ether–petrol as eluent) to yield the title compound as a pale
yellow oil (29.2 g, 90 mmol, 83%); νmax(film)/cmϪ1 3700–3300m
(OH), 3000–2800s (CH), 1494w, 1462m, 1382w, 1109s, 1053s,
882s; δH(400 MHz; CDCl3; Me4Si) 1.05 (18H, d, J1Ј2Ј 4.03,
6 × Me), 1.05–1.2 (3H, m, 3 × 2Ј-H), 2.0–2.13 (1H, m, 2-H),
2.57–2.67 (2H, m, 4-H), 2.9–2.00 (1H, br, OH), 3.6–3.8 (2H, m,
3-H), 3.83–3.90 (2H, m, 1-H), 7.14–7.32 (5H, m, Ph); δC(100
MHz; CDCl3; Me4Si), 11.7 (2Ј-C), 17.9 (1Ј-C), 34.1 (4-C), 44.1
(2-C), 65.7 (3-C), 66.8 (1-C), 125.9–128.9, 140.0 (Ph) (Found:
MHϩ, 323.2411. C19H35O2Si requires MH, 323.2406).
Synthesis of the phosphonium salt of 1-iodo-2-benzyl-3-(tetra-
hydro-2H-pyran-2-yloxy)propane 5
To a stirred solution of the iodide 4a (1.0 g, 2.78 mmol) in dry
acetonitrile (20 ml) under N2 was added triphenylphosphine
(0.72 g, 2.78 mmol). The yellow solution was heated under
reflux for 48 h at which point thin layer chromatography (eluent
light petroleum–diethyl ether, 1:1) showed the formation of a
baseline spot at the expense of starting material. The com-
pound was rotary evaporated to dryness and dried under high
vacuum for 1 day, yielding a light yellow, hygroscopic foam
(100%) (1.73 g, 2.78 mmol); Rf 0.00 (diethyl ether–light petrol-
eum, 1:1); δH(400 MHz, 0.03% CDCl3) 1.4–1.8 (6H, m, 3Ј-H,
4Ј-H and 5Ј-H), 2.3 (1H, m, 2-H), 2.6–2.9 (2H, m, 4-H), 3.2–4.2
(6H, m, 3-H, 6Ј-H and 1-H), 4.3–4.5 (1H, m, 2Ј-H), 7.1–7.4
(5H, m, Ph), 7.6–7.8 (15H, m, 3Ph).
(2S)-1-Benzyloxycarbonyl-2-[(Z)-3-benzyl-4-(tetrahydro-
2H-pyran-2-yloxy)but-1-enyl]pyrrolidine 6
1-Methylsulfonyloxy-2-benzyl-3-triisopropylsilyloxypropane
To a stirred solution of alcohol 7 (35 g, 108.5 mmol), dry DCM
(300 ml) and triethylamine (12.34 ml, 119 mmol) at 0 ЊC was
added dropwise methanesulfonyl chloride (9.24 ml, 130 mmol).
After 18 hours the mixture was washed with water (200 ml) and
the organic phase separated. The aqueous phase was further
extracted with ether (2 × 100 ml). The combined organic phases
were dried with brine and MgSO4 and evaporated under
reduced pressure to yield the title compound as a light yellow
oil (42 g, 107 mmol, 99%); νmax(film)/cmϪ1 3000–2800s (CH),
1500m, 1465s, 1360s and 1178s (SO2᎐O᎐), 960s, 885s, 745m;
δH(250 MHz; CDCl3; Me4Si) 0.95–1.15 (21H, m, isopropyl-H),
2.2 (1H, m, 2-H), 2.7 (2H, m, 4-H), 2.95 (3H, s, Me), 3.7 (2H, m,
3-H), 4.25 (2H, m, 1-H), 7.15–7.35 (5H, m, Ph); δC(100 MHz;
CDCl3; Me4Si) 11.8 (2Ј-C), 17.9 (1Ј-C), 33.6 (4-C), 36.9 (MeS),
43.1 (2-C), 61.8 (3-C), 69.4 (1-C), 126.3–129.0, 138.9 (Ph)
(Found: MHϩ, 401.2208. C20H37O4SiS requires MH, 401.2181).
To a flame-dried three necked flask under N2 at Ϫ78 ЊC was
added the phosphonium salt 5 (4 g, 6.43 mmol) in dry THF
(100 ml). A solution of butyllithium (2.5 ; 2.83 ml, 7.73 mmol)
was added dropwise with stirring over 15 min—the solution
turned from a pale yellow colour to a deep red. After stirring
for a further 30 min a solution of N-Cbz-prolinal (2.99 g, 12.8
mmol) in dry THF (150 ml) was added dropwise, the mixture
was left to stir at Ϫ78 ЊC for 15 min and then warmed to room
temperature and left overnight. The deep yellow solution was
then poured into water and extracted three times with ethyl
acetate, washed with brine and dried with magnesium sulfate
before evaporating to dryness. Flash column chromatography
(light petroleum–diethyl ether, 3:1) gave a separable mixture of
2 compounds (Rf = 0.61 and 0.54) as pale yellow oils (41%, 1.18
g) indistinguishable by 1H NMR spectroscopy; Rf 0.61 and 0.54
(light petroleum–diethyl ether, 1:1); δH(400 MHz, 0.03%
CDCl3) 1.5–1.8 (10H, m, 3Љ-H, 4Љ-C and 5Љ-CH, 3Ј-H and 4Ј-
H), 2.05 (1H, m, 2-H), 3.0–3.2 (2H, m, CH2Ph), 3.3 and 3.6
(6Љ-H), 3.4 (2H, m, 5Ј-H), 3.7–3.9 (2H, m, 1-H), 4.4–4.5 (1H, m,
2Ј-H), 4.6 (1H, m, 2Љ-H), 5.1 (2H, m, OCH2Ph), 5.2 (1H, m,
3-H), 5.4 (1H, m, 4-H), 7.0–7.2 (10H, m, 2Ph); δC(200 MHz,
0.03% CDCl3) 23 (4Ј-C), 38 (2-C), 39 (CH2Ph), 40 (3Ј-C), 47
(5Ј-C), 54 (2Ј-C), 67 (1-C), 125–132 (Ar-C), 135 (3-C), 140
1-Iodo-2-benzyl-3-triisopropylsilyloxypropane 4b
To a solution of 1-methylsulfonyloxy-2-benzyl-3-triisopropyl-
silyloxypropane (3.42 g, 8.5 mmol) in freshly distilled AR
acetone (50 ml) under argon was added sodium iodide (3.9 g,
25.6 mmol). The flask was wrapped in aluminium foil and the
mixture stirred at reflux for 16 hours. The reaction mixture was
evaporated under reduced pressure and washed with ether (100
ml) and water (50 ml). The aqueous phase was extracted with
ether (3 × 50 ml) and the combined organic extracts dried over
anhydrous MgSO4. Evaporation under reduced pressure and
purification of the residue by flash column chromatography
(4-C), 170 (C᎐O).
᎐
2-Benzylpropane-1,3-diol
To a slurry of lithium aluminium hydride (4.45 g, 113.9 mmol)
in freshly distilled diethyl ether (200 ml) under argon at 0 ЊC
J. Chem. Soc., Perkin Trans. 1, 1998
1631

View Article Online
(9:1 petrol–ether) afforded iodide 4b as a colourless oil (2.96 g,
6.85 mmol, 80%); νmax(film)/cmϪ1 3000–2800s (CH), 1462m,
1248w, 1213w, 1178w, 1107s, 1067m, 882s, 699s; δH(250 MHz;
CDCl3; Me4Si) 1.06–1.07 (18H, d, J 4.8, isopropyl-CH3), 1.07–
1.09 (3H, m, isopropyl-H), 1.73 (1H, m, 2-H), 2.56–2.62 (1H,
dd, J4a,4b 13.5 J4a,2 8.1, 4a-H), 2.7–2.76 (1H, dd, J4b,4a 13.5 J4b,2
6.2, 4b-H), 3.19–3.22 (1H, dd, J1a,1b 9.5 J1a,2 5.8, 1a-H), 3.35–
3.38 (1H, dd, J1b,1a 9.8 J1b,2 4.3, 1b-H), 3.57–3.61 (1H, dd, J3a,3b
9.8 J3a,2 6.2, 3a-H), 3.68–3.70 (1H, dd, J3b,3a 9.5 J3b,2 4.7, 3b-H),
7.2–7.3 (5H, m, Ph); δC(100 MHz; CDCl3; Me4Si) 11.8 (1-C),
11.9 (2Ј-C), 18.0 (1Ј-C), 37.0 (4-C), 44.5 (2-C), 65.2 (3-C), 126–
129.1 and 139.4 (Ph) (Found: MHϩ, 433.1449. C19H34IOSi
requires MH, 433.1433).
(Z)- and (E)-(2S)-N-Boc-2-(3Ј-Benzyl-4Ј-triisopropylsilyloxy-
but-1Ј-enyl)pyrrolidine 11 and 12
To a flame dried flask under argon was added phosphonium
salt 8 (5.4 g, 7.76 mmol) and freshly distilled THF (60 ml). After
cooling to Ϫ78 ЊC (acetone–CO2) BuLi (3.1 ml, 2.5  solution
in hexanes, 7.7 mmol) was added dropwise. After 30 minutes
and the observance of a deep yellow colour a solution of the
aldehyde 3b (1.7 g, 8.5 mmol) in THF (10 ml) was added by
cannula over 40 minutes. The reaction mixture was stirred for 3
hours and gradually allowed to warm to room temperature.
Water (30 ml) was added and the mixture extracted with ether
(3 × 50 ml). The combined organic extracts were washed with
brine, dried over MgSO4 and evaporated under reduced
pressure. Flash column chromatography of the residue (9:1
petrol–ether as eluent) afforded the two alkenes as colourless
oils: cis isomer 11 as a mixture of two diastereoisomers, (1.98 g,
4.1 mmol, 52%); νmax(film)/cmϪ1 3000–2800s (CH), 1699s
(NCO), 1456m, 1390s, 1365m, 1254w, 1170s, 1106s; δH(400
MHz; CDCl3; Me4Si) 0.94 (0.5H, m, 0.5 3a-H), 1.03–1.09 (21H,
m, isopropyl-H), 1.41–1.43 [9.5H, m, C(CH3)3 and 0.5 3a-H],
1.5–2.15 (3H, m, 4-H and 3b-H), 2.37–2.46 (0.5H, dd, J5Јa,5Јb
12.9 J5Јa,3Ј 9.3, 5Јa-H), 2.8 (1H, m, 5Јb-H), 2.82–2.93 (1H, m,
3Ј-H), 3.1–3.17 (0.5H, dd, J5Јa,5Јb 12.9 J5Јa,3Ј 4.5, 5Јa-H), 3.22–
3.57 (3.5H, m, 5-H, 4Јa-H and 0.5 4Јb-H), 3.78–3.82 (0.5H, m,
4Јb-H), 4.13–4.2 (0.5H, m, 2-H), 4.5–4.58 (0.5H, m, 2-H), 5.2–
5.45 (2H, overlapping dd, J2Ј,1Ј 11.0, 1Ј-H and 2Ј-H), 7.15–7.3
(5H, m, Ph); δC(100 MHz; CDCl3; Me4Si) 11.9 and 12.0 (2Љ-C),
18.0 (1Љ-C), 23.5 and 23.7 (4-C), 28.5 [C(CH3)3], 32.6 and 33.9
(3-C), 37.1 and 38.2 (5Ј-C), 41.5 and 43.0 (3Ј-C), 46.3 and 46.4
(5-C), 54.5 and 54.7 (2-C), 65.0 and 65.8 (4Ј-C), 78.8 and 79.0
[C(CH3)3], 125.6, 128.0, 129.5, 140.0 and 140.9 (Ph), 128.9 and
130.8 (2Ј-C), 132.9 (1Ј-C), 154.3 and 154.5 (NCO) (Found:
MHϩ, 488.3533. C29H49NO3Si requires MH, 488.3559); trans
isomer 12 (0.65 g, 1.33 mmol, 18%); νmax(film)/cmϪ1 3000–2800s
(CH), 1699s (NCO), 1456w, 1394s, 1364m, 1256w, 1170s, 1106s,
882m; δH(400 MHz; CDCl3; Me4Si) 0.8–0.99 (1H, m, 3a-H),
1.06–1.1 (21H, m, 6 × isopropyl-H), 1.44 [9H, 2 × s, diastereo-
isomers, C(CH3)3], 1.5–1.97 (3H, m, 3b-H and 4-H), 2.4–2.59
(2H, m, 5Јa-H and 3Ј-H), 2.95–3.02 (1H, dd, J5Јb,5Јa 12.1 J5Јb,3Ј
4.2, 5Јb-H), 3.25–3.38 (2H, m, 5-H), 3.45–3.69 (2H, m, 4Ј-H),
4.2 (1H, m, 2-H), 5.18–5.47 (2H, overlapping dd, J1Ј,2Ј 15.9
J2Ј,1Ј15.9, 1Ј-H and 2Ј-H), 7.13–7.3 (5H, m, Ph); δC(100 MHz;
CDCl3; Me4Si) 11.9 (2Љ-C), 18.0 (1Љ-C), 23.2 and 23.5 (4-C),
28.5 [C(CH3)3], 29.7 and 30.3 (3-C), 37.6 and 37.7 (5Ј-C), 41.2
and 43.1 (3Ј-C), 46.0 and 46.9 (5-C), 58.2 (2-C), 66.2 (4Ј-C),
78.8 [C(CH3)3], 125.6–132.3 (Ph and 1Ј-C and 2Ј-C), 140.6
(quat-C), 154.1 (NCO) (Found: MHϩ, 488.3555. C29H49NO3Si
requires MH, 488.3559).
(2-Benzyl-3-triisopropylsilyloxypropyl)triphenylphosphonium
iodide 8
Triphenylphosphine (4.53 g, 17.3 mmol), iodide 4b (7.37 g,
17.04 mmol) and anhydrous acetonitrile (10 ml) were heated at
reflux for 72 hours. The solvent was removed under vacuum
and the residue subjected to high vacuum. The resultant foam
was then twice triturated with a 9:1 petrol–ether mix (30 ml).
This afforded 8 as a microcrystalline solid (11.4 g, 16.4 mmol,
96%); νmax(CH2Cl2 solution)/cmϪ1 3000–2800s (CH), 1605m,
1440s (P᎐Ph), 1273s, 1112s, 909s; δH(250 MHz; CDCl3; Me4Si)
0.90–1.0 (21H, m, isopropyl-H), 2.2–2.42 (1H, m, 2-H), 2.53–
2.65 (1H, m, 4a-H), 2.95–3.10 (1H, m, 4b-H), 3.46–3.95 (4H, m,
3-H and 1-H), 7.0–7.4 (20H, m, 4 × Ph).
N-Boc-Prolinol
To a stirred solution of (S)-prolinol (3.02 g, 29.8 mmol) and dry
THF (60 ml) at 0 ЊC was added triethylamine (4.37 ml, 31.36
mmol). After 15 minutes (Boc)2O (6.39 g, 29.3 mmol) was
added as a solution in THF (20 ml). The reaction mixture was
concentrated to 20 ml and the residue partitioned between ether
(40 ml) and 1  HCl (60 ml). The aqueous phase was extracted
further with ether (2 × 50 ml). The combined organic extracts
were washed with NaHCO3 (30 ml), dried with MgSO4 and
evaporated under reduced pressure. This yielded a colourless oil
which crystallised on cooling (5.96 g, 29.6 mmol, 99%); mp
57 ЊC (lit.,16 57–58 ЊC); [α]D25 Ϫ48.1 (c 1.0 in CHCl3) (lit.,16
Ϫ47.3); νmax(film)/cmϪ1 3400s (OH), 3000–2800s (CH), 1690s
(NCO), 1400s, 1260m, 1170s, 1050s, 905m, 780m; δH(400 MHz;
CDCl3; Me4Si) 1.47 [9H, s, C(CH3)3], 1.54–1.56 (1H, m, 3a-H),
1.74–1.87 (2H, m, 4-H), 1.96–2.01 (1H, m, 3b-H), 3.28–3.3 (1H,
m, 5a-H), 3.42–3.50 (1H, m, 5b-H), 3.58–3.65 (2H, m, 6-H),
3.9–3.96 (1H, m, 2-H), 4.8 (1H, br, OH); δC(100 MHz; CDCl3;
Me4Si) 24.0 (4-C), 28.4 [C(CH3)3], 28.9 (3-C), 47.5 (5-C), 60.1
(2-C), 67.5 (6-C), 80.1 [C(CH3)3], 157.0 (NCO) (Found: MHϩ,
202.1432. C10H20NO3 requires MH, 202.1443).
(Z)-N-Boc-(2S)-2-[(3ЈR and 3ЈS)-3Ј-benzyl-4Ј-hydroxybut-1Ј-
enyl]pyrrolidines 13a and 13b
N-Boc-Prolinal 3b
To a solution of alkene 11 (2.28 g, 4.68 mmol) in dry THF (35
ml) at room temperature was added tetrabutylammonium fluor-
ide (5.15 ml, 1  solution in THF, 5.15 mmol). After 2 hours
solvent was removed under vacuum and the residue purified
by flash column chromatography (6:4 ether–petrol as eluent)
to yield the two isomers as colourless oils. The oils crystallised
on prolonged standing. 13a (0.73 g, 2.2 mmol, 47%); [α]D25 ϩ54.9
(c 6.9 in CHCl3); mp 65–66 ЊC; νmax(film)/cmϪ1 3450s (OH),
3000–2800s (CH), 1676s (NCO), 1400s, 1167s; δH(400 MHz;
CDCl3; Me4Si) 1.05 (1H, m, 3a-H), 1.4 [9H, s, C(CH3)3], 1.43–
1.55 (1H, m, 3b-H), 1.6–1.7 (1H, m, 4a-H), 1.7–1.8 (1H, m,
4b-H), 2.30–2.36 (1H, dd, J5Јa,5Јb 13.2 J5Јa,3Ј 10.3, 5Јa-H), 2.69–
2.73 (1H, dd, J5Јb,5Јa 13.2 J5Јb,3Ј 4.03, 5Јb-H), 3.19 (1H, m, 3Ј-H),
3.24–3.27 (2H, m, 5-H), 3.38–3.43 (1H, m, 4Јa-H), 3.8–3.83
(1H, m, 4Јb-H), 4.13–4.19 (1H, br, OH), 4.2–4.22 (1H, m, 2-H),
5.19–5.31 (2H, m, 2Ј-H and 1Ј-H), 7.11–7.26 (5H, m, Ph); δC100
MHz; CDCl3; Me4Si) 23.9 (4-C), 28.5 [C(CH3)3], 31.5 (3-C),
38.0 (5Ј-C), 43.0 (3Ј-C), 46.5 (5-C), 54.0 (2-C), 66.6 (4Ј-C), 79.7
[C(CH3)3], 125.8–129.1 (Ph), 132.2 and 132.4 (1Ј-C and 2Ј-C),
To a stirred solution of Dess–Martin periodinane (27.9 g, 65.8
mmol) in DCM (150 ml) at room temperature was added
N-Boc-prolinol (12.1 g, 59.8 mmol) as a solution in DCM
(50 ml). After 2 hours stirring, the reaction was diluted with
ether (200 ml) and washed with 1.3  NaOH (1 × 200 ml,
1 × 100 ml). The organic layer was washed with brine, dried
over MgSO4 and evaporated under reduced pressure to yield a
light yellow oil (10.94 g, 54.9 mmol, 92%). Spectroscopic details
were consistent with the literature.17 νmax(film)/cmϪ1 3000–
2800s (CH), 1715s (CHO), 1695s (NCO), 1680m, 1600m,
1520w, 1440m, 1390s, 1160s, 1120m; δH(400 MHz; CDCl3;
Me4Si) 1.4–1.5 [9H, 2 × s, C(CH3)3], 1.8–2.2 (4H, m, 3-H and
4-H), 3.4–3.6 (2H, m, 5-H), 4.0–4.3 (1H, 2 × m, 2-H), 9.45–
9.55 (1H, 2 × d, J6,2 2.93, 6-H); δC(100 MHz; CDCl3; Me4Si)
23.9 and 24.6 (4-C), 26.7 (3-C), 28.4 [C(CH3)3], 46.7 and 46.8
(5-C), 64.8 and 65.0 (2-C), 80.2 [C(CH3)3], 153.9 (7-C, NCO),
200.4 and 200.6 (6-C, CHO) (Found: MHϩ, 200.1288.
C10H18NO3 requires MH, 200.1286).
1632
J. Chem. Soc., Perkin Trans. 1, 1998

View Article Online
155.0 (NCO) (Found: MHϩ, 322.2210. C19H30NO3 requires
MH, 332.2225). 13b (0.697 g, 2.10 mmol, 45%); [α]D25 ϩ31.7 (c 2.0
in CHCl3); mp 82 ЊC; νmax(film)/cmϪ1 3430s (OH), 3000–2800s
(CH), 1693s (NCO), 1495w, 1477m, 1454m, 1365s, 1167s, 1110;
δH(400 MHz; CDCl3; Me4Si) 1.45 [9H, s, C(CH3)3], 1.58–2.10
(4H, m, 4-H and 3-H), 2.11 (1H, m, 3Ј-H), 2.6–2.7 (1H, dd,
J5Јa,5Јb 13.6 J5Јa,3Ј 8.5, 5Јa-H), 2.77–2.85 (1H, dd, J5Јb,5Јa 13.6 J5b,3Ј
5.4, 5Јb-H), 2.9–3.1 (1H, br s, OH), 3.2–3.5 (3H, m, 5-H and
4Јb-H), 3.51–3.57 (1H, dd, Jgem 10.6 J4Јa,3Ј 4.9, 4Јa-H), 4.5–4.62
(1H, m, 2-H), 5.23 (1H, dd, J2Ј,1Ј 11.0 J2Ј,3Ј 9.9, 2Ј-H), 5.45–5.5
(1H, dd, J1Ј,2Ј 11.0 J1Ј,2 8.2, 1Ј-H), 7.15–7.35 (5H, m, Ph); δC(100
MHz; CDCl3; Me4Si) 23.7 (4-C), 28.4 [C(CH3)3], 28.6 (3-C),
38.0 (5Ј-C), 42.0 (3Ј-C), 46.5 (5-C), 55.0 (2-C), 64.9 (4Ј-C), 79.2
[C(CH3)3], 126.0–129.1 (Ph), 131.1 (2Ј-C), 136.5 (1Ј-C), 154.6
(NCO) (Found: MHϩ, 332.2234. C20H30NO3 requires MH,
332.2225).
Jgem 13.6 J5Јb,3Ј 10.1, 5Јb-H), 3.3–3.5 (2H, m, 5-H), 3.9 (1H, br s,
3Ј-H), 4.6 (1H, br, 2-H), 4.98 (1H, d, Jgem 12.3, 6Јa-H), 5.01 (1H,
d, Jgem 12.3, 6Јb-H), 5.4–5.5 (2H, pseudo quintet, J1Ј,2Ј 10.3 J2Ј,1Ј
10.3, 1Ј-H, 2Ј-H), 7.13–7.36 (10H, m, 2 × Ph); δC(100 MHz;
CDCl3; Me4Si) 24.2 (3-C), 24.3 (4-C), 28.9 [C(CH3)3], 39.2
(5Ј-C), 46.7 (5-C), 46.9 (3Ј-C), 54.9 (2-C), 66.6 (6Ј-C), 79.6
[C(CH3)3], 126.8–128.8 and 139.1 (Ph), 129.4 (2Ј-C), 136.1 (1Ј-
C), 154.8 (NCO), 173.6 (4Ј-C, CO2Bn) (Found: MHϩ, 436.2492.
C27H34NO4 requires MH, 436.2487).
(Z)-(2S)-N-Boc-2-[(3ЈR)-3Ј-benzyl-3Ј-benzyloxycarbonylprop-
1Ј-enyl]pyrrolidine 15a
To a flask under argon at room temperature containing carbon-
yldiimidazole (0.35 g, 2.15 mmol) was added a solution of acid
14a (0.675 g, 1.95 mmol) in DCM (5 ml). After 5 minutes,
benzyl alcohol (0.32 g, 2.96 mmol) was added. Sodium ethoxide
(5 mg, catalytic) was added and the reaction stirred for 72
hours. The solvent was removed under vacuum and the residue
purified by flash chromatography (2:1 petrol–ether as eluent).
This yielded 15a as a viscous colourless oil (0.44 g, 1.00 mmol,
51%); [α]D25 ϩ30.9 (c 1.3 in CHCl3); νmax(film)/cmϪ1 3200–2800
(CH), 1732s (CO2Bn), 1694s (NCO), 1496w, 1455m, 1392s,
1365m, 1105w; δH(400 MHz; CDCl3; Me4Si) 0.9–1.05 (1H, m,
3a-H), 1.35 [9H, s, C(CH3)3], 1.4–1.6 (1H, m, 3b-H), 1.6–1.8
(2H, m, 4-H), 2.67–2.8 (1H, dd, Jgem 13.3, J5Јa,3Ј 8.5, 5Јa-H),
3.05–3.15 (1H, dd, Jgem 13.3 J5Јb,3Ј 6.35, 5Јb-H), 3.23 (2H, m, 5-
H), 3.65–3.85 (1H, br s, 3Ј-H), 4.15–4.25 (1H, m, 2-H), 5.05
(1H, d, Jgem 12.3, 6Јa-H), 5.12 (1H, d, Jgem 12.3, 6Јb-H), 5.35–
5.45 (1H, dd, J1Ј,2 8.7 J1Ј,2Ј 10.9, 1Ј-H), 5.5–5.6 (1H, dd, J2Ј,3Ј 10.8
J2Ј,1Ј 10.8, 2Ј-H), 7.1–7.4 (10H, m, 2 × Ph); δC(100 MHz; CDCl3;
Me4Si) 23.6 (3-C), 28.4 [C(CH3)3], 32.7 (4-C), 39.8 (5Ј-C), 46.3
(5-C), 46.4 (3Ј-C), 54.3 (2-C), 66.4 (6Ј-C), 79.1 [C(CH3)3],
126.5–128.3 and 129.3 (Ph), 128.1 (2Ј-C), 128.4 (1Ј-C), 154.3
(NCO), 173.5 (CO2Bn) (Found: MHϩ, 436.2496. C27H34NO4
requires MH, 436.2487).
(Z)-(2S)-N-Boc-2-[(3ЈR)-3Ј-benzyl-3Ј-carboxyprop-1Ј-enyl]-
pyrrolidine 14a
To a solution of alcohol 13a (0.75 g, 2.26 mmol) in acetone (25
ml) at 0 ЊC was slowly added a solution of Jones’ reagent (2 ml,
2.76  CrO3 in H2SO4). After 1 hour the supernatant liquor was
decanted, washed with water (10 ml) and extracted with ether
(3 × 15 ml). The combined organic extracts were dried with
MgSO4 and filtered through a short pad of silica. Evaporation
in vacuo yielded 14a as a light yellow oil (0.698, 2.02 mmol,
89%); νmax(film)/cmϪ1 3400–2700s (CH and H-bonded OH of
CO2H), 1730s (CO2H), 1690s, 1477w, 1420s, 1367m, 1165s,
750w; δH(400 MHz; CDCl3; Me4Si) 0.95–1.02 (1H, m, 3a-H),
1.4 [9H, s, C(CH3)3], 1.40–1.85 (3H, m, 3b-H and 4-H), 2.68–
2.74 (1H, dd, Jgem 13.6 J5Јa,3Ј 10.6, 5Јa-H), 3.3 (3H, m, 5-H and
5Јb-H), 3.9–4.03 (2H, m, 3Ј-H and 2-H), 5.25–5.3 (1H, dd,
J1Ј,2Ј10.6 J1Ј,2 9.9, 1Ј-H), 5.3–5.4 (1H, overlapping dd, J2Ј,1Ј 10.6
J2Ј,3Ј 10.6, 2Ј-H), 7.1–7.3 (5H, m, Ph) (Found: MHϩ, 346.2035.
C20H28NO4 requires MH, 346.2018).
(Z)-(2S)-N-Boc-2-[(3ЈS)-3Ј-benzyl-3Ј-carboxyprop-1Ј-enyl]-
pyrrolidine 14b
(2S)-N-Methoxycarbonylcarbonyl-2-[(3ЈR)-3Ј-benzyl-3Ј-
benzyloxycarbonylprop-1Ј-enyl]pyrrolidine 16a
To a solution of alcohol 13b (0.60 g, 1.83 mmol) in acetone (25
ml) at 0 ЊC was slowly added a solution of Jones’ reagent (2 ml,
2.76  CrO3 in H2SO4). After 1 hour the supernatant liquor was
decanted, washed with water (10 ml) and extracted with ether
(3 × 15 ml). The combined organic extracts were dried with
MgSO4 and filtered through a short pad of silica. Evaporation
in vacuo yielded 14b as a light yellow oil (0.62, 1.72 mmol, 98%);
νmax(film)/cmϪ1 3400–2700s (CH and H-bonded OH of CO2H),
1730s (CO2H), 1694s (NCO), 1392s, 1366s, 1163s, 749w; δH(400
MHz; CDCl3; Me4Si) 1.46 [9H, s, C(CH3)3], 1.55–2.15 (4H, m,
3-H and 4-H), 2.85–2.95 (1H, dd unresolved, 5Јa-H), 3.05–3.15
(1H, dd, Jgem 10.7 J5Јb,3Ј 9.5, 5Јb-H), 3.28–3.4 (2H, m, 5-H), 3.7–
3.8 (1H, m, 3Ј-H), 4.55–4.65 (1H, m, 2-H), 5.36–5.44 (1H, over-
lapping dd, J1Ј,2Ј 10.2, J1Ј,2 10.2, 1Ј-H), 5.5–5.59 (1H, dd
unresolved, 2Ј-H), 7.18–7.3 (5H, m, Ph) (Found: MHϩ,
346.2031. C20H28NO4 requires MH, 346.2018).
To a stirred solution of 15a (396 mg, 0.91 mmol) in DCM (2
ml) at room temperature was added trifluoroacetic acid (1
ml). After 20 minutes, solvent and TFA were removed under
vacuum and the residue dissolved in DCM (4 ml). The reac-
tion was cooled to 0 ЊC (ice bath) and pyridine (0.22 ml, 2.73
mmol) and methyl oxalyl chloride (0.09 ml, 1.00 mmol) were
added. The reaction was stirred for 1 hour at 0 ЊC, poured
into 1  HCl (5 ml) and extracted with ether (3 × 10 ml). The
combined organic extracts were dried with MgSO4 and evap-
orated under reduced pressure. Flash column chromatography
of the residue (ether as eluent) afforded 16a as a light orange
oil (0.32 g, 0.77 mmol, 85%) (Found: C, 70.5; H, 6.4; N, 3.3;
C25H27NO5 requires C, 71.2; H, 6.5; N, 3.3%); [α]D23 ϩ20.3
(c 1.8 in CHCl3); νmax(film)/cmϪ1 3200–2800s (CH), 1734s
(CO2Me and CO2Bn), 1655s (NCO), 1497m, 1455s, 1378w,
1161s, 917w; δH(400 MHz; CDCl3; Me4Si) (as a mixture of
rotamers) 0.9–1.17 (2H, m, 4-H), 1.19–1.75 (2H, m, 3-H),
2.65–2.68 (1H, dd, Jgem 13.2 J5Јa,3Ј 10.3, 5Јa-H), 3.13–3.17 (1H,
dd, Jgem 13.2 J5Јb,3Ј 5.13, 5Јb-H), 3.39–3.58 (2H, m, 5-H), 3.5
(2.25H, s, OMe), 3.58–3.7 (0.75H, m, 3Ј-H), 3.8 (0.75H, s,
OMe), 3.98–4.06 (0.25H, m, 3Ј-H), 4.3–4.39 (0.25H, m, 2-H),
4.39–4.45 (0.75H, m, 2-H), 5.07–5.21 (2H, d, Jgem 12.1, 6Ј-H),
5.21–5.28 (1H, m, 1Ј-H), 5.66–5.71 (1H, dd, J2Ј,1Ј 10.62 J2Ј,3Ј
10.63, 2Ј-H), 7.11–7.37 (10H, m, 2 × Ph); δC(100 MHz;
CDCl3; Me4Si) 22.6 and 24.4 (3-C), 30.5 and 33.0 (4-C), 39.3
and 39.5 (5Ј-C), 46.1 and 46.2 (5-C), 46.6 and 47.5 (3Ј-C),
52.3 and 52.5 (OMe), 54.8 and 55.4 (2-C), 66.5 and 66.7 (6Ј-
C), 126.4 and 126.7 (Ph), 127.9 and 128.0 (2Ј-C), 128.2–129.5
(Ph), 130.5 and 131.5 (1Ј-C), 135.7 and 135.9 (quat-C), 138.1
and 138.4 (quat-C), 159.6 (NCO), 162.5 (CO2Me), 173.1 and
173.2 (CO2Bn) (Found: MHϩ, 422.1986. C25H28NO5 requires
MH, 422.1967).
(Z)-(2S)-N-Boc-2-[(3ЈS)-3Ј-benzyl-3Ј-benzyloxycarbonylprop-
1Ј-enyl]pyrrolidine 15b
To a flask under argon at room temperature containing carbon-
yldiimidazole (0.32 g, 1.98 mmol) was added a solution of acid
14b (0.62 g, 1.8 mmol) in DCM (5 ml). After 5 minutes, benzyl
alcohol (0.30 g, 2.7 mmol) was added. Sodium ethoxide (5 mg,
catalytic) was added and the reaction stirred for 72 hours. The
solvent was removed under vacuum and the residue purified by
flash chromatography (7:3 petrol–ether as eluent). This
afforded 15b as a viscous colourless oil (0.40 g, 0.92 mmol,
51%); [α]D22 ϩ134.6 (c 1.8 in CHCl3); νmax(film)/cmϪ1 3200–2800s
(CH), 1733s (CO2Bn), 1695s (NCO), 1456m, 1390s, 1256m,
1162s, 698m; δH(250 MHz; CDCl3; Me4Si) 1.45 [9H, s,
C(CH3)3], 1.45–1.55 (1H, m, 3a-H), 1.64–1.9 (2H, m, 4-H), 1.9–
2.05 (1H, m, 3b-H), 2.9–3.05 (1H, m, 5Јa-H), 3.05–3.2 (1H, dd,
J. Chem. Soc., Perkin Trans. 1, 1998
1633

View Article Online
(2S)-N-Methoxycarbonylcarbonyl-2-[(3ЈS)-3Ј-benzyl-3Ј-
benzyloxycarbonylprop-1Ј-enyl]pyrrolidine 16b
(0.20 g, 1.22 mmol) and DCM (10 ml). After 5 minutes, benzyl
alcohol (0.14 ml, 1.4 mmol) was added. Sodium ethoxide (10
mg, catalytic) was added and the reaction stirred for 72 hours.
The solvent was removed under vacuum and the residue puri-
fied by flash chromatography (3:2 petrol–ether as eluent). This
yielded 19 as a colourless oil (0.18 g, 0.4 mmol, 35%); νmax(film)/
cmϪ1 3200–2800s (CH), 1735s (CO2Bn), 1694s (NCO), 1497w,
1393s, 1364m, 1269m, 1159s, 746m, 699m; δH(400 MHz;
CDCl3; Me4Si) 1.39 [9H, 2 × s, diastereoisomers, C(CH3)3],
1.39–1.9 (4H, m, 4-H and 3-H), 2.78–2.9 (1H, m, 5Јa-H), 3.04–
3.15 (1H, m, 5Јb-H), 3.27–3.43 (3H, m, 5-H and 3Ј-H), 4.15–
4.35 (1H, br m, 2-H), 5.04 (2H, s, 6Ј-H), 5.36–5.41 (1H, dd, J1Ј,2Ј
15.4 J1Ј,2 5.5, 1Ј-H), 5.51–5.57 (1H, dd, J2Ј,1Ј 15.7 J2Ј,3Ј 8.5, 2Ј-H),
7.1–7.4 (10H, m, 2 × Ph); δC(100 MHz; CDCl3; Me4Si) 22.9
(3-C), 28.5 [C(CH3)3], 34.0 (4-C), 38.9 (5Ј-C), 46.1 (5-C), 50.6
(3Ј-C), 57.9 (2-C), 66.3 (6Ј-C), 79.1 [C(CH3)3], 126.4–129.1
(2 × Ph and 1Ј-C, 2Ј-C), 135.8 and 138.6 (quat-C), 154.5
(NCO), 173.3 (CO2Bn) (Found: MHϩ, 436.2472. C27H34NO4
requires MH, 436.2487).
To a stirred solution of 15b (332 mg, 0.76 mmol) in DCM (2 ml)
at room temperature was added trifluoroacetic acid (1 ml).
After 20 minutes the solvent and TFA were removed under
vacuum and the residue dissolved in DCM (4 ml). The reaction
was cooled to 0 ЊC (ice bath) and pyridine (0.185 ml, 2.29
mmol) and methyl oxalyl chloride (0.077 ml, 0.84 mmol) were
added. The reaction was stirred for 1 hour at 0 ЊC, poured into 1
 HCl (5 ml) and extracted with diethyl ether (3 × 10 ml). The
combined organic extracts were dried with MgSO4 and evapor-
ated under reduced pressure. Flash column chromatography of
the residue (diethyl ether as eluent) afforded 16b as a light
orange oil (0.257 g, 0.61 mmol, 80%) (Found: C, 71.1; H, 6.5; N,
3.5; C25H27NO5 requires C, 71.2; H, 6.5; N, 3.3%); [α]D26 ϩ166.7
(c 0.8 in CHCl3); νmax(film)/cmϪ1 3200–2800 (CH), 1733s
(CO2Me and CO2Bn), 1635s (NCO), 1515m, 1418m, 1242s,
1139s; δH(400 MHz; CDCl3; Me4Si) (as a mixture of rotamers)
1.5–2.0 (4H, m, 3-H and 4-H), 2.84–2.88 (0.5H, dd, Jgem 13.9
J5Јa,3Ј 4.7, 5Јa-H), 3.05–3.11 (1.5H, m, 0.5 5Јa-H and 5Јb-H),
3.47–3.54 (1H, m, 5a-H), 3.63–3.75 (1.5H, m, 5b-H and 0.5
3Ј-H), 3.69 (1.5H, s, 1.5 O-Me), 3.85 (1.5H, s, 1.5 O-Me), 4.03–
4.1 (0.5H, m, 3Ј-H), 4.86–4.92 (0.5H, m, 2-H), 4.92–5.02 (2.5H,
m, 0.5 2-H and 6Ј-H), 5.34–5.4 (1H, overlapping dd, J1Ј,2Ј 10.3
J1Ј,2 10.3, 1Ј-H), 5.5–5.6 (1H, overlapping dd, J2Ј,1Ј 10.3 J2Ј,3Ј
10.3, 2Ј-H), 7.11–7.3 (10H, m, 2 × Ph); δC(100 MHz; CDCl3;
Me4Si) 22.8 and 24.7 (3-C), 31.2 and 33.8 (4-C), 38.4 and 38.5
(5Ј-C), 46.5 and 46.6 (5-C), 46.8 and 47.7 (3Ј-C), 52.4 and
52.7 (OMe), 54.9 and 55.8 (2-C), 66.2 and 66.5 (6Ј-C), 126.3–
129.2, 135.5 and 138.3 (Ph), 130.6 (2Ј-C), 132.8 (1Ј-C), 158.3
and 159.3 (NCO), 162.5 and 162.7 (CO2Me), 172.4 and 173.1
(CO2Bn) (Found: MHϩ, 422.1959. C25H28NO5 requires MH,
422.1967).
(2S)-N-Methoxycarbonylcarbonyl-2-[(3ЈRS)-3Ј-benzyl-3Ј-
benzyloxycarbonylprop-1Ј-enyl]pyrrolidine 20
To a stirred solution of 19 (175 mg, 0.4 mmol) in DCM (3 ml) at
room temperature was added trifluoroacetic acid (1 ml). After
15 minutes the solvent and TFA were removed under vacuum
and the residue dissolved in DCM (4 ml). After cooling the
reaction to 0 ЊC (ice bath) pyridine (0.1 ml, 1.21 mmol) and
methyl oxalyl chloride (0.041 ml, 0.44 mmol) were added. The
reaction was stirred for 1 hour at 0 ЊC, poured into 1  HCl (5
ml) and extracted with diethyl ether (3 × 15 ml). The combined
organic extracts were dried with MgSO4 and evaporated under
reduced pressure. Flash column chromatography of the residue
(diethyl ether as eluent) afforded 20 as a colourless oil which
crystallised as a mixture of isomers on standing (0.15 g, 0.35
mmol, 87%) (Found: C, 70.8; H, 6.45; N, 3.3; C25H27NO5
requires C, 71.2; H, 6.5; N, 3.3%); mp 69 ЊC; νmax(film)/cmϪ1
3200–2900s (CH), 1734s (CO2Me and CO2Bn), 1652s (NCO),
1495w, 1456m, 1423m, 1252s, 1150s, 1029w, 747m, 699m;
δH(400 MHz; CDCl3; Me4Si) 1.55–2.11 (4H, m, 3-H and 4-H),
2.75–2.9 (1H, m, 5Јa-H), 3.05 (1H, m, 5Јb-H), 3.3–3.4 (1H, m,
3Ј-H), 3.48–3.6 (2-H, m, 5-H), 3.67 and 3.71 and 3.86 and 3.87
(3H, 4 × s, rotamers and diastereoisomers, OMe), 4.6–4.73 (1H,
m, 2-H), 5.05 (2H, m, 6Ј-H), 5.26–5.41 (1H, m, 1Ј-H), 5.5–5.6
(1H, overlapping dd, J2Ј,1Ј 15.4 J2Ј,3Ј 8.4, 2Ј-H, 7.1–7.3 (10H, m,
2 × Ph); δC(100 MHz; CDCl3; Me4Si) 21.5, 21.8, 23.5 and 23.6
(3-C), 30.1, 30.2, 32.6 and 32.8 (4-C), 38.5 and 38.6 (5Ј-C), 46.2,
46.3 and 47.3 (5-C), 50.2, 50.4 and 50.6 (3Ј-C), 52.4 and 52.6
(OMe), 58.1, 58.3, 59.1 and 59.3 (2-C), 66.3, 66.5 and 66.6
(6Ј-C), 126.3–132.8 and 141.1 (Ph), 135.4, 135.5 and 135.7
(2Ј-C), 138.0, 138.1 and 138.3 (1Ј-C), 158.0 and 159.5 (NCO),
162.5 (CO2Me), 172.5, 172.7 and 173.0 (CO2Bn) (Found: MHϩ,
422.1977. C25H28NO5 requires MH, 422.1967).
(E)-(2S)-N-Boc-2-[(3ЈRS)-3Ј-benzyl-4Ј-hydroxybut-1Ј-enyl]-
pyrrolidine 17
To a solution of alkene 12 (0.67 g, 1.38 mmol) in dry THF (15
ml) at room temperature was added tetrabutylammonium fluor-
ide (1.6 ml, 1  solution in THF, 1.6 mmol). After 2 hours the
solvent was removed under vacuum and the residue purified by
flash column chromatography (2:1 ether–petrol as eluent) to
yield the two inseparable diastereoisomers 17 as a colourless oil
(0.32 g, 0.96 mmol, 70%); νmax(film)/cmϪ1 3400bs (OH), 3000–
2800s (CH), 1691 (NCO), 1401s, 1365, 1254w, 1170s, 1119m,
966m, 744m, 700s; δH(400 MHz; CDCl3; Me4Si) 0.8–0.9 (1H, m,
3a-H), 1.42 [9H, 2 × s, diastereoisomers, C(CH3)3], 1.45–1.62
(1H, m, 3b-H), 1.67–1.8 (2H, m, 4-H), 1.99 (1H, br s, OH),
2.49–2.68 (2H, m, 3Ј-H and 5Јa-H), 2.71–2.76 (1H, dd, Jgem 13.2
J5Јb,3Ј 6.6, 5Јb-H), 3.3–3.41 (3H, m, 5-H and 4Јa-H), 3.55–3.6
(1H, m, 4Јb-H), 4.1–4.15 (0.5H, m, 2-H), 4.2–4.24 (0.5H, m,
2-H), 5.27–5.36 (1H, m, 2Ј-H), 5.38–5.4 (1H, dd, J1Ј,2Ј 15.4 J1Ј,2
5.5, 1Ј-H), 7.13–7.27 (5H, m, Ph); δC(100 MHz; CDCl3; Me4Si)
22.8 and 23.3 (4-C), 28.4 [C(CH3)3], 31.8 and 32.2 (3-C), 37.4
(5Ј-C), 46.3 (3Ј-C), 46.5 (5-C), 58.2 (2-C), 64.7 (4Ј-C), 79.2
[C(CH3)3], 125.8–130.2 and 140.0 (Ph), 133.7 (2Ј-C), 139.7
(1Ј-C), 154.3 and 154.6 (NCO) (Found: MHϩ, 332.2240.
C20H30NO3 requires MH, 332.2225).
(2S)-N-Boc-2-[(3ЈR and 3ЈS)-1-Oxo-3Ј-benzyl-4Ј-triisopropyl-
silyloxybutyl]pyrrolidine 22a
To a stirred solution of alkene 11 (0.51 g, 1.05 mmol) in THF
(10 ml) at 0 ЊC was added BH3ؒDMF (0.50 ml, 1  in THF, 0.50
mmol) dropwise. The reaction was warmed to 40 ЊC and stirred
for 18 hours. 3  NaOH (3 ml) was added followed by H2O2
(30%, 2 ml) and the mixture stirred for 3 hours. The aqueous
mixture was treated with brine (20 ml) and extracted with
diethyl ether (3 × 50 ml). The combined organic extracts were
washed with brine, dried with MgSO4 and evaporated to dry-
ness. Flash column chromatography (1:1 diethyl ether–petrol
as eluent) of the residue afforded the intermediate 1Ј-hydroxy
(21a) (0.34 g, 0.67 mmol, 64%) and the 2Ј-hydroxy (21b) (0.069
g, 0.136 mmol, 13%) regioisomers as colourless oils. To a stirred
solution of Dess–Martin periodinane (0.220 g, 0.52 mmol) in
DCM (2 ml) at room temperature was added the 1Ј-hydroxy
regioisomer (21a) (0.24 g, 0.47 mmol). After 1 hour, diethyl
(E)-(2S)-N-Boc-2-[(3ЈRS)-3Ј-benzyl-3Ј-benzyloxycarbonylprop-
1Ј-enyl]pyrrolidine 19
To a solution of alcohol 17 (1.37 g, 4.1 mmol) in acetone (65
ml) at 0 ЊC was slowly added a solution of Jones’ reagent (3 ml,
2.76  CrO3 in H2SO4). After 1 hour the supernatant liquor was
decanted, washed with water (30 ml) and extracted with ether
(3 × 45 ml). The combined organic extracts were dried with
MgSO4 and filtered through a short pad of silica. Evaporation
in vacuo yielded the acid 18 as a light yellow oil (1.22 g, 3.54
mmol, 86%). Without further purification 18 (0.40 g, 1.16
mmol) as a solution in DCM (5 ml), was added to a flask under
argon at room temperature containing carbonyldiimidazole
1634
J. Chem. Soc., Perkin Trans. 1, 1998

View Article Online
ether (15 ml) was added and the suspension treated with 1.3 
NaOH (4 ml). After 10 minutes stirring the mixture was
washed further with NaOH (2 × 4 ml) and water (1 × 5 ml).
The organic phase was dried (MgSO4) and evaporated. Flash
column chromatography of the residue (8:2 petrol–ether as
eluent) afforded 22a as an inseparable diastereomeric mixture
(210 mg, 0.41 mmol, 87%); νmax(film)/cmϪ1 3000–2800s (CH),
MgSO4 and evaporated under reduced pressure. Flash column
chromatography of the residue (diethyl ether as eluent) afforded
the desired oxalate 25 as a light yellow oil (45 mg, 0.103 mmol,
80%); [α]D23 Ϫ35.1 (c 1.8 in CHCl3); νmax(film)/cmϪ1 3000–2800s
(CH), 1740s (CO2Bn and CO2Me), 1661s (NCO), 1456s,
1423m, 1251s, 1097w, 744m; δH(400 MHz; CDCl3; Me4Si) 2.01–
2.1 (0.5H, m, 3b-H), 2.18–2.3 (0.5H, m, 3a-H), 2.59–2.7 (1H, m,
5Јa-H), 2.77–3.09 (3H, m, 5Јb-H and 2Ј-H), 3.25 (0.5H, m,
3Ј-H), 3.35 (0.5H, m, 3Ј-H), 3.85 (1H, m, 5a-H), 3.75 (1H, m,
5b-H), 3.69, 3.73, 4.84 and 3.87 (3H, 4 × s, diastereomeric and
rotameric mixture, OMe), 4.5 (0.5H, m, 2-H), 4.95 (0.5H, m,
2-H), 5.0–5.12 (2H, m, 6Ј-H), 7.1–7.3 (10H, m, 2 × Ph); δC(100
MHz; CDCl3; Me4Si) 21.8, 21.9, 24.6 and 24.7 (3-C), 27.2, 27.5,
30.2 and 30.3 (4-C), 37.3, 37.5, 37.6 and 37.7 (2Ј-C), 39.5, 39.9
and 40.0 (5Ј-C), 41.1, 41.2, 41.5 and 41.6 (5-C), 47.9, 48.2, 48.3
and 48.4 (3Ј-C), 52.7 and 52.9 (OMe), 64.5 and 64.8 (2-C), 66.4
(6Ј-C), 126.5–129.0 and 135.6–138.2 (Ph), 156.8, 157.4 and
157.5 (NCO), 161.6 (CO2Me), 173.9, 174.0, 174.2 and 174.3
(CO2Bn), 204.9 and 205.4 (1Ј-C) (Found: MHϩ, 438.1910.
C25H28NO6 requires MH, 438.1916).
1702s (NCO and C᎐O), 1463m, 1393s, 1366s, 1166s, 995w,
᎐
882m, 700m; δH(400 MHz; CDCl3; Me4Si) 1.05 (21H, m, iso-
propyl), 1.30 and 1.45 [9H, 2 × s, 1.5:1 rotameric mixture,
C(CH3)3], 1.7–1.88 (3H, m, 4-H and 3a-H), 2.1 (1H, m, 3b-H),
2.3–2.8 (5H, m, 2Ј-H, 5Ј-H and 3Ј-H), 3.4–3.65 (4H, m, 5-H and
4Ј-H), 4.15 and 4.3 (1H, 2 × m, 1.5:1 rotameric mixture, 2-H),
7.13–7.3 (5H, m, Ph) (Found: MHϩ, 504.3490. C29H50NO4Si
requires MH, 504.3409).
(2S)-N-Boc-2-[(3ЈRS)-1-Oxo-3-benzyl-4Ј-hydroxybutyl]-
pyrrolidine 23
To a solution of 22a (1.6 g, 3.17 mmol) in THF (35 ml) at room
temperature was added TBAF (3.35 ml, 1  in THF, 3.35
mmol). After 1 hour the mixture was rotary evaporated to dry-
ness and the residue purified by flash column chromatography
(9:1 diethyl ether–petrol as eluent). This afforded 23 as a col-
ourless oil (0.873 g, 2.52 mmol, 80%); νmax(film)/cmϪ1 3445s
N-(tert-Butoxycarbonyl)-L-phenylalanine benzyl ester 26
To a flask containing N-(tert-butoxycarbonyl)phenylalanine
(1.02 g, 3.84 mmol) and carbonyldiimidazole (0.66 g, 4.07 mmol)
under an atmosphere of argon was added DCM (2 ml). After 5
minutes benzyl alcohol (0.45 g, 4.2 mmol) and sodium ethoxide
(2 mg, catalytic) were added. After 18 hours the mixture was
evaporated in vacuo and the residue purified by flash column
chromatography (3:7 diethyl ether–petrol as eluent). This
afforded the benzyl ester 26 as white crystalline solid (1.3 g, 3.8
mmol, 99%); mp 62 ЊC (lit.,18 62–63 ЊC), [α]D26 Ϫ10.0 (c 1.3 in
EtOH) (lit.,18 [α]D25 Ϫ10.0); νmax(film)/cmϪ1 3370s (NH), 3000–
2800s (CH), 1700–1750s (CO2Bn and NCO), 1500s, 1455s,
1167s, 1055m, 1020m, 751s; δH(400 MHz; CDCl3; Me4Si) 1.4
[9H, s, C(CH3)3], 3.05 (2H, br, CH2Ph), 4.6 (1H, m, CHN), 4.95
(1H, d, JNH,CH 7.7, NH), 5.09 (1H, d, Jgem 12.2, OCH2Ph), 7.0–
7.38 (10H, m, 2 × Ph); δC(100 MHz; CDCl3; Me4Si) 28.3
[C(CH3)3], 38.3 (CCH2Ph), 54.5 (CCH2Ph), 67.0 (OCH2Ph),
79.8 [C(CH3)3], 126.9–129.3 (Ph), 135.2 and 135.9 (quat-C),
155.0 (NCO), 171.6 (CO2Bn) (Found: [M Ϫ Boc]Hϩ 256.1340.
C16H18NO2 requires MH, 256.1337).
(OH), 3000–2800s (CH), 1700s (C᎐O), 1690s (NCO), 1455m,
᎐
1403s, 1255w, 1166s, 1030m; δH(400 MHz; CDCl3; Me4Si) 1.42
[9H, 4 × s, diastereomeric and rotameric mixture, C(CH3)3],
1.7–2.1 (5H, m, 4-H, 3-H and 3Ј-H), 2.3–3.0 (5H, m, 2Ј-H, 6Ј-H
and OH), 3.2–3.8 (4H, m, 5-H and 4Ј-H), 4.1–4.4 (1H, m, 2-H),
7.1–7.3 (5H, m, Ph) (Found: MHϩ, 348.2170. C20H30NO4
requires MH, 348.2174).
(2S)-N-Boc-2-[(3ЈRS)-1-Oxo-3-benzyl-3Ј-benzyloxycarbonyl-
propyl]pyrrolidine 24
To a solution of alcohol 23 (0.19 g, 0.55 mmol) in acetone (10
ml) at 0 ЊC was added dropwise a solution of Jones’ reagent (0.5
ml, 2.76  CrO3 in H2SO4). After 1 hour, the supernatant liquor
was decanted, washed with water (3 ml) and extracted with
ether (3 × 15 ml). The combined organic extracts were dried
(MgSO4) and filtered through a short pad of silica. Evaporation
in vacuo afforded the intermediate acid as a light yellow oil
(0.174 g, 0.48 mmol, 87%). Without further purification the
acid (0.150 g, 0.44 mmol), as a solution in DCM (2 ml), was
added to a flask under argon at room temperature containing
carbonyldiimidazole (77 mg, 0.46 mmol) and DCM (3 ml).
After 5 minutes benzyl alcohol (0.05 ml, 0.5 mmol) and sodium
ethoxide (1 mg, catalytic) were added. After stirring for 72
hours the solvent was removed under vacuum and the residue
purified by flash chromatography (1:1 petrol–ether as eluent).
This afforded the benzyl ester 24 as a colourless oil (74 mg, 0.16
mmol, 38%); νmax(film)/cmϪ1 3000–2800s (CH), 1730s (CO2Bn),
1700s (CO), 1690s (NCO), 1455m, 1400s, 1165s, 1118m, 699m;
δH(400 MHz; CDCl3; Me4Si) 1.25 and 1.45 [9H, 4 × s, diastere-
omeric and rotameric mixture, C(CH3)3], 1.63–2.15 (4H, m, 3-H
and 4-H), 2.32–3.17 (5H, m, 2Ј-H, 3Ј-H and 5Ј-H), 3.17–3.6
(2H, m, 5-H), 4.05–4.35 (1H, m, 2-H), 4.95–5.15 (2H, m, 6Ј-H),
7.1–7.3 (10H, m, 2 × Ph) (Found: MHϩ, 452.2428. C27H34NO5
requires MH, 452.2437).
N-[NЈ-(tert-Butoxycarbonyl)-L-prolyl]-L-phenylalanine benzyl
ester 27
To a dry flask containing N-(tert-butoxycarbonyl)proline (0.35
g, 1.61 mmol) and carbonyldiimidazole (0.27 g, 1.69 mmol) was
added dry DCM (5 ml). Evolution of CO2 confirmed the
formation of the imidazolide A. To a second flask containing
Boc-phenylalanine benzyl ester 26 (0.55 g, 1.61 mmol) was
added DCM (3 ml) and TFA (1 ml). The solution was stirred
for 10 minutes at room temperature and then evaporated to
total dryness in vacuo. The residue was redissolved in DCM (5
ml) and treated with Et3N (0.24 ml, 1.69 mmol). This solution
was added dropwise to the imidazolide A. After 18 hours the
mixture was evaporated and the residue purified by flash
column chromatography (8:2 diethyl ether–petrol as eluent).
This afforded the coupled adduct 27 (0.48 g, 1.06 mmol, 66%)
and
a
highly viscous oil; νmax(film)/cmϪ1 3320m (NH),
3000–2800s (CH), 1746s (CO2Bn), 1630s (2 × NCO), 1455m,
1398s, 1167s, 1123m, 1088w; δH(400 MHz; CDCl3; Me4Si)
1.40 [9H, s, C(CH3)3], 1.6–2.3 (4H, m, 3-H and 4-H), 2.98 (1H,
dd, J3Јa,3Јb 13.8 J3Јa,2Ј 6.6, 3Јa-H), 3.14 (1H, dd, J3Јb,3Јa 13.8 J3Јb,2Ј
5.8, 3Јb-H), 3.3 (2H, m, 5-H), 4.2 (1H, m, 2-H), 5.4 (1H, m,
2Ј-H), 5.13 (2H, s, 4Ј-H), 6.5 (1H, br, NH), 6.95–7.4 (10H,
m, 2 × Ph) (Found: MHϩ, 453.2402. C26H32N2O5 requires
MH, 453.2389).
(2S)-N-Methoxycarbonylcarbonyl-2-[(3ЈRS)-1-oxo-3Ј-benzyl-
oxycarbonylpropyl]pyrrolidine 25
To a stirred solution of benzyl ester 24 (58 mg, 0.128 mmol) in
DCM (2 ml) at room temperature was added trifluoroacetic
acid (0.5 ml). After 25 minutes the solvent and TFA were
removed under vacuum and the residue dissolved in DCM (2
ml). The reaction mixture was cooled to 0 ЊC (ice bath) where
pyridine (31 µl, 0.38 mmol) and methyl oxalyl chloride (13 µl,
0.14 mmol) were added. The reaction was stirred for 1 hour at
0 ЊC, poured onto 1  HCl (5 ml) and extracted with ether
(3 × 10 ml). The combined organic extracts were dried with
N-[NЈ-(Methoxycarbonylcarbonyl)-L-prolyl]-L-phenylalanine
benzyl ester 1
To a solution of dipeptide 27 (0.43 g, 0.96 mmol) in DCM
J. Chem. Soc., Perkin Trans. 1, 1998
1635

View Article Online
(3 ml) at room temperature was added trifluoroacetic acid
(1 ml). After 10 minutes the solution was evaporated in vacuo to
total dryness. The residue was redissolved in DCM (10 ml),
cooled to 0 ЊC and successively treated with pyridine (0.23 ml,
2.87 mmol) and methyl oxalyl chloride (97 µl, 1.06 mmol). After
18 hours the mixture was poured onto 1  HCl (10 ml) and
extracted with diethyl ether (3 × 15 ml). The combined organic
phases were dried with MgSO4 and evaporated. Flash column
chromatography of the residue (7:3 diethyl ether–ethyl acetate
as eluent) afforded the desired oxalate 1 as a white crystalline
solid (0.38 g, 0.86 mmol, 90%); mp 127–129 ЊC (lit.,5 127 ЊC);
[α]D25 Ϫ50.9 (c 1.17 in CHCl3); νmax(film)/cmϪ1 3306s (NH), 3000–
2800 (CH), 1738s (CO2Bn and CO2Me), 1660s (2 × NCO),
1538s, 1455s, 1426m, 1344w, 1238s, 1177s; δH(400 MHz; CDCl3;
Me4Si) 1.65–1.95 (2H, m, 4-H), 1.95–2.32 (2H, m, 3-H), 3.03
(1H, dd, J3Јa,2Ј 6.6 J3Јa,3Јb 13.7, 3Јa-H), 3.16 (1H, dd, J3Јb,2Ј 5.9
J3Јb,3Јa 13.7, 3Јb-H), 3.55–3.7 (2H, m, 5-H), 3.77 (0.9H, s, OMe),
3.9 (2.1H, s, OMe), 4.54 (0.7H, m, 2-H), 4.73 (0.3H, dd, J2,3a 7.3
J2,3b 4.0, 2-H), 4.86–4.91 (1H, ddd, J2Ј,3Јa 6.6 J2Ј,3Јb 5.9 J2Ј,NH 7.7,
2Ј-H), 5.12 (2H, overlapping AB system, J4Јa,4Јb 12.1 J4Јb,4Јa 12.1,
4Ј-H), 6.25 (0.3H, d, JNH,2Ј 7.7, NH), 6.9 (0.7H, d, JNH,2Ј 7.7,
NH), 7.05–7.4 (10H, m, 2 × Ph); δC(100 MHz; CDCl3; Me4Si);
21.9 and 24.8 (3-C), 27.3 and 31.6 (4-C), 37.7 and 37.9 (3Ј-C),
47.6 and 48.3 (5-C), 52.9 and 53.1 (OMe), 53.2 and 53.4 (2Ј-C),
60.3 and 61.7 (2-C), 67.2 and 67.4 (4Ј-C), 126.9–135.7 (Ph),
158.2 and 159.1 (NCO2Me), 161.6 and 161.7 (CO2Me), 169.4
(NCO amide), 170.9 (CO2Bn) (Found: MHϩ, 439.2102.
C24H26N2O6 requires MH, 439.2090).
References
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Acknowledgements
Stephen Gorsuch and Shimon Yoshida thank the University of
Reading for Studentships, and we also thank Archie Jahans
(for help with the X-ray experiments) and Peter Heath (for
assistance with variable temperature NMR experiments).
Paper 8/00756J
Received 28th January 1998
Accepted 10th March 1998
1636
J. Chem. Soc., Perkin Trans. 1, 1998