Synthesis of 5/7-, 5/8- And 5/9-bicyclic lactam templates as constraints for external β-turns

Article abstract of DOI:10.1039/b503014e

The 5/7-, 5/8- and 5/9-bicyclic lactams 3, 17, 5 and 6 have been synthesised as single diastereoisomers by a route involving ring closing olefin metathesis. The X-ray crystal structure of the amino acid hydrochloride 17 has been carried out and compared t

Full text of DOI:10.1039/b503014e

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A R T I C L E
Synthesis of 5/7-, 5/8- and 5/9-bicyclic lactam templates as
constraints for external b-turns
Heather M. E. Duggan, Peter B. Hitchcock and Douglas W. Young*
Department of Chemistry, University of Sussex, Falmer, Brighton, UK BN1 9QJ
Received 1st March 2005, Accepted 19th April 2005
First published as an Advance Article on the web 10th May 2005
The 5/7-, 5/8- and 5/9-bicyclic lactams 3, 17, 5 and 6 have been synthesised as single diastereoisomers by a route
involving ring closing olefin metathesis. The X-ray crystal structure of the amino acid hydrochloride 17 has been
carried out and compared to that of the saturated external b-turn constraint 18.
Following our work on the synthesis and use of the 5/7-
Introduction
bicyclic lactam 2 as an external constraint for a LDV containing
b-turn,10 we became interested in preparing a series of modified
bicyclic lactams to which external tetrapeptides might be
attached. We have therefore embarked on the synthesis of the
5/7-, 5/8- and 5/9-bicyclic lactams 3, 4, 5 and 6 by a common
synthetic route.
The reverse turn, a tetrapeptide motif, frequently occurs on the
surface of large functional proteins and so it is an important
motiffor molecular recognition processes, which maybe targeted
for therapeutic intervention.1,2 b-Turns have been classified3
and, because synthetic analogues of the turn motif need not
be part of a large protein to be constrained in appropriate stable
conformations and they are less liable to proteolysis than natural
turns, they have been increasingly investigated as potential
drugs.4 The first bicyclic dipeptide to be used in this way was
the so-called “Bicyclic Turned Dipeptide” (BTD) 1, prepared
by Nagai and Sato.5 This had a CD spectrum which was close
to that of a known type IIꢀ b-turn and, when incorporated into
peptides in place of natural b-turns, showed useful biological
activity.6 In addition, BTD has also been used as an external
constraint on which to synthesise a peptide which will adopt a b-
turn conformation. Thus, a cyclo-BTD-tetrapeptide containing
the LDV motif has been shown to inhibit the interaction between
the integrin a4b1 and vascular cell adhesion molecule-1 (VCAM-
1).7 Other bicyclic dipeptide mimetics have been investigated and
the 5/7-bicyclic lactam 2 has been used both as a b-turn mimetic8
and as an external restraint for a cyclic tetrapeptides containing
either the RGD motif9 or the LDV motif.10 Both RGD and
LDV occur in b-turns in extracellular matrix adhesive proteins
recognised by integrins.
Results and discussion
Our strategy is outlined in Scheme 1, where ring closing olefin
metathesis of the compounds 8 (n = 0, 1 or 2) would lead to the
corresponding bicyclic lactams 7 (n = 0, 1 or 2). The compounds
8 might be obtained by condensation of the allylpyrollidine 9
with an appropriate protected amino acid 10 (n = 0, 1 or 2).
A ring closing olefin metathesis strategy has been developed by
Moeller et al. to prepare 5/6- and 5/7-bicyclic lactams.11
Since the synthon 9 is common for all of our target syntheses,
its preparation was our first goal and we opted for a route
which had been used by Scolastico et al.12 to prepare the
corresponding tert-butyl ester. We first converted benzyl-N-tert-
butoxycarbonylpyroglutamate 1113 into the carbinolamine 12 by
reduction with Super-Hydrideꢀ in THF at −78 ◦C, as shown
R
in Scheme 2. The unstable carbinolamine 12 was stirred in
methanol containing para-toluenesulfonic acid to yield the ether
13 and this was reacted with allyltributylstannane and BF3·Et2O
in dichloromethane at −78 ◦C to give a 73% yield of the
protected 5-allylpyrrolidine 14 as mixture of diastereoisomers.
Although the 1H NMR spectrum was complicated by rotational
isomerism, some signals for the individual diastereoisomers
in the mixture could be assigned by the NOE experiments
summarised in Fig. 1. Irradiation at 3.9 ppm for H-2 caused
a 0.7% enhancement to the signal for H-5cis at 4.27 ppm and
no enhancement to the signal for H-5trans at 4.37 ppm. There
was also a 4.7% enhancement in the combined multiplet for H-
7 at 5.75 ppm. Integration suggested a cis : trans ratio of 2 :
1. This is in keeping with the findings of Scolastico et al.,12
who obtained a cis : trans ratio of ca. 2 : 1 when the
corresponding tert-butyl ester was prepared. It is interesting
Fig. 1 NOE experiments on the cis-component of the diastereoisomeric
mixture 14.
T h i s j o u r n a l i s
T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 5
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 2 2 8 7 – 2 2 9 5
2 2 8 7
©

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Scheme 1
Scheme 2 Reagents and conditions: (i) LiB(Et)3H, THF, −78 ◦C, 2 h (99%); (ii) MeOH, ptsa, rt, overnight (89%); (iii) BF3·Et2O, allylSn(Bu)3,
CH2Cl2, −78 ◦C, 3 h (73%); (iv) (a) TFA, CH2Cl2, rt, overnight (56%), (b) Et3N, CH2Cl2, H2O, 2 h.
that when Pedregal and coworkers14 conducted the reaction
using Grignard derived organocopper reagents in the ethyl ester
series, a 94 : 6 trans : cis ratio was obtained. Deprotection using
trifluoroacetic acid in dichloromethane gave the desired product
as its trifluoroacetate 9a. The free amine 9 was prepared as
required, using triethylamine in dichloromethane–water.
To prepare the 5/7-bicyclic lactam 3, the protected vinyl-
glycine 10 (n = 0), was required. L-Vinylglycine was therefore
prepared from L-methionine by the method of Rapaport and
Afzali-Ardakani15 and this was converted into the urethane 10
(n = 0) by the method of Gottlieb et al.16 On reacting 10 (n = 0)
Fig. 2 NOE experiments on the 5/7-bicyclic lactam 3a.
with isobutyl chloroformate and condensing the resultant mixed
anhydride with the amine 9, the desired product 16 was obtained
in 20% yield, together with a 23% yield of the urethane 15, as
shown in Scheme 3. The diene 16 was then heated at reflux
in dichloromethane containing a catalytic quantity of Grubbs’
catalyst to give two cyclised products, which could be separated
by chromatography on silica gel. The first, obtained in 58%
yield, was the (2S,5R,9S)-isomer 3a and the second, obtained
in 9% yield, was the (2S,5R,9R)-isomer 3b. The stereochemistry
of these compounds was deduced using NOE experiments, as
shown in Fig. 2 and Fig. 3. When the signal due to H-5 at
3.40 ppm in compound 3a was irradiated, a 1.8% enhancement at
4.53 ppm (H-2) and a 15% enhancement at 5.35 ppm (H-9) were
observed, as shown in Fig. 2. This indicates a cis-relationship
between H-2, H-5 and H-9 and defines the stereochemistry
relative to H-2 as (2S,5R,9S). When the signal due to H-5 at
4.27 ppm in compound 3b was irradiated, a 0.4% enhancement
in the signal at 4.61 ppm (H-2) and a 4.1% enhancement in the
Fig. 3 NOE experiments on the 5/7-bicyclic lactam 3b.
signal at 4.97 ppm (NH) were observed, as shown in Fig. 3a.
This suggests (2S,5R,9R)-stereochemistry which was confirmed
by the additional NOE experiments summarised in Fig. 3b.
◦
i
=
Scheme 3 Reagents and conditions: (i) (a) ClCO2 Bu, pyridine, THF, 0 C, 15 min, (b) 9, THF, rt, 3 h (23% 15, 20% 16); (ii) ([c-C6H10)3]P)2Cl2Ru
H2Cl2, reflux, 24 h (58% 3a, 9% 3b); (iii) 6 N HCl, 60 ◦C, overnight (quant.).
2 2 8 8
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 2 2 8 7 – 2 2 9 5

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Table 1 Torsion angles for compopunds 1, 17 and 18
Irradiation at H-5 showed a 4.0% enhancement in the signal at
2.55 ppm for H-6a and irradiation at 2.28 ppm (H-6b) resulted
in a 2.1% enhancement in the signal at 4.74 ppm for H-9.
Although the starting material 16 was a 2 : 1 mixture of C-5
epimers, the products 3 both had cis-stereochemistry between
H-2 and H-5 but were epimeric at C-9. This may reflect
loss of stereochemistry in the final steps of the synthesis of
vinylglycine, where our use of the stronger base of Gottlieb
et al.16 for the Schotten–Baumann urethenylation of vinylglycine
may have caused some racemisation. The major bicyclic lactam
stereoisomer 3a was hydrolysed to the amino acid hydrochloride
17 in quantitative yield using 6 N aq. hydrochloric acid at
60 ◦C. An X-ray structure determination (Fig. 4) confirmed
our stereochemical assignments.
Torsion angle Compound 1
Compound 17
Compound 18
w2
φ3
−161
+169
+175
−58
−69.4
−86.5
unwanted urethane 15. Ring closing olefin metathesis using
Grubbs’ catalyst now gave the 5/8-bicyclic lactam 5 as a single
diastereoisomer in 65% yield (Scheme 4). NOE studies, shown
in Fig. 5, indicated that H-2, H-5 and H-10 were cis to one
another, since irradiation at 4.86 ppm for H-10 caused a 6.7%
enhancement at 4.14 ppm for H-5 and irradiation at 4.55 ppm
for H-2 caused a 0.7% enhancement at H-5.
Fig. 5 NOE experiments on the 5/8-bicyclic lactam 5.
Fig. 4 X-Ray structure of the amino acid hydrochloride 17.
For our final target, the 5/9-bicyclic lactam 6, we required 10
(n = 2), the ester 23 of which had been reported in preliminary
form by Martinez et al.19 We accessed this ester by reducing
the known Weinreb amide 2221 to the corresponding aldehyde
using lithium tri-tert-butoxyaluminium hydride, followed by
Wittig reaction. Hydrolysis using 6 N aq. HCl in THF gave the
corresponding amino acid, which was protected using Boc2O
under Schotten–Baumann conditions to give the desired acid
10 (n = 2). Conversion into the mixed anhydride and reaction
with the allylproline ester 9 as before gave the diene 24 in
27% yield together with the ubiquitous urethane 15. Overlap
in the 1H NMR spectrum did not allow assessment of the
relative stereochemistry by NOE experiments. Ring closing
olefin metathesis using Grubbs’ catalyst gave the 5/9-bicyclic
lactam 6 as a single diastereoisomer in 84% yield (Scheme 5).
NOE studies, shown in Fig. 6, suggested that H-2, H-5 and H-11
were cis to one another, since irradiation at 3.98 ppm for H-5
caused a 1% enhancement in the signal at 4.37 ppm for H-2 and
a 15% enhancement at 4.30 ppm for H-11.
The dihedral angles w2 and φ3 from the X-ray structure are
shown in Table 1 where they are compared with these angles
from the X-ray structures of the saturated compound 1817 and
the turn BTD 1.18 The double bond in the seven membered ring
has a evidently made a difference to the conformation of the
5/7-system in the solid state.
Our next target, the 5/8-bicyclic lactam 5, required the
protected allylglycine 10 (n = 1). The corresponding tert-butyl
ester has been reported in a note,19 and we have prepared it
by in situ Wittig reaction from the known protected aspartic
semialdehyde 19.20 The required protected allylglycine 10 (n = 1)
was prepared from this by hydrolysis using 6 N aq. hydrochloric
acid in THF and treatment of the resultant amino acid with
Boc2O under Schotten–Baumann conditions. This was now
reacted with isobutyl chloroformate to give the mixed anhydride,
which was condensed in situ with the allylproline ester 9
to give the desired diene 21 in 13% yield together with the
Scheme 4 Reagents and conditions: (i) MePPh3·Br, KHMDS, THF, rt, 1 h (40%); (ii) 6 N HCl, THF, rt, overnight (67%); (iii) NaOH, H2O, tBuOH,
◦
i
=
Boc2O, rt, overnight (94%); (iv) (a) ClCO2 Bu, pyridine, THF, −78 C, 15 min, (b) 9, CH2Cl2, rt, 3 h (33% 15, 15% 21); (v) ([c-C6H10)3]P)2Cl2Ru CHPh,
CH2Cl2, reflux, 24 h (65%).
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 2 2 8 7 – 2 2 9 5
2 2 8 9

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Scheme 5 Reagents and conditions: (i) (a) LiAlH(OtBu)3, THF, rt, 3 h, (b) MePPh3·Br, KHMDS, THF, rt, 1 h (14%); (iii) 6 N HCl, THF, rt, overnight
◦
(81%); (iv) NaOH, H2O, tBuOH, Boc2O, rt, overnight (59%); (v) ClCO2 Bu, pyridine, THF, −78 C, 15 min, (b) 9, CH2Cl2, rt, 3 h (36% 15, 27% 24);
i
=
(vi) ([c-C6H10)3]P)2Cl2Ru CHPh, CH2Cl2, reflux, 24 h (84%).
was removed in vacuo and the aqueous residue was extracted
with dichloromethane (3 × 10 ml). The organic extracts were
combined and dried (MgSO4), and the solvent was removed
in vacuo to give benzyl (2S,5RS)-N-tert-butoxycarbonyl-5-
hydroxypyrrolidine-2-carboxylate 12 as a clear oil (995 mg, 99%)
which was not further purified; m/z [ES+] (found 339.1921;
[C17H23NO5 + NH4]+ requires 339.1920); m/z [+ve FAB (3-
NBA)] 344 ([M + Na]+); mmax (film)/cm−1 3428 (br, OH), 1746
(ester) and 1694 (urethane); dH (300 MHz, C2HCl3, mixture of
Fig. 6 NOE experiments on the 5/9-bicyclic lactam 6.
diastereoisomers and rotamers, ratio 62 : 38 at 26 ◦C) 7.28 (5H,
br, ArH), 5.50 (1H, br m, H-5), 5.08 (2H, m, OCH2Ar), 4.28 (1H,
m, H-2), 2.58–1.74 (4H, br m, H-4 and H-3), 1.41 (9H, s, C(CH3)3
Conclusions
minor) and 1.26 (9H, s, C(CH3)3 major); dC (75.5 MHz, C2HCl3,
mixture of diastereoisomers and rotamers at 26 ◦C) 173.4, 173.1,
172.7 and 172.5 (ester), 154.4, 154.2 and 153.6 (urethane), 135.9
and 129.0–127.3 (Ar), 82.7, 82.4, 82.1 and 81.6 (C-5), 77.9, 77.4
and 77.0 (OC(CH3)3), 67.3, 37.2 and 67.1 (OCH2Ar), 59.81 and
59.6 (C-2), 32.6 and 31.4 (C-4), 28.7 and 28.5 (C(CH3)3), 28.2
and 27.5 (C-3).
We have therefore prepared the 5/7-, 5/8- and 5/9-bicyclic
lactams 3, 17, 5 and 6 as single enantiomers by a common route
involving metathesis. These are available as potential external
b-turn constraints. The X-ray crystal structure of the amino
acid hydrochloride 17 has been carried out, showing significant
differences from the saturated compound 18 and so should act
as a different external turn template.
Benzyl (2S,5RS)-N-tert-butoxycarbonyl-5-methoxypyrrolidine-
2-carboxylate (13)
Experimental
A
solution of benzyl (2S,5RS)-N-tert-butoxycarbonyl-5-
Melting points were determined on a Kofler hot stage apparatus
and are uncorrected. Optical rotations (given in units of
10−1deg cm2 g−1) were measured on a Perkin Elmer PE241
polarimeter using a 1 dm path length cell. IR spectra were
recorded on a Perkin Elmer Spectrum 1710 FT-IR spectrometer.
1H NMR spectra were recorded on Bruker DPX300 (300 MHz)
and AMX500 (500 MHz) Fourier transform instruments and
COSY and NOE experiments were carried out to aid assignment
of signals. J values are given in Hertz. 13C NMR spectra (1H
decoupled) were recorded on Bruker DPX300 (75.5 MHz)
and AMX500 (125.8 MHz) Fourier transform instruments.
DEPT experiments were used to help assign 13C resonances
where necessary. Low resolution mass spectra were recorded
by Dr A. Al Sada on Kratos MS-80RF and MS25 double
focusing spectrometers. High resolution mass measurements
were performed by the EPSRC Central Mass Spectrometry
Service at Swansea, or by Dr A. Abdul Sada at Sussex using
a Bruker BioApex III 4.7 FT-IRC spectrometer. Microanalyses
were carried out by Medac Ltd. Column chromatography was
performed using Fluka silica gel 60 (230–400 mesh). Petroleum
ether refers to that fraction of hexanes of bp 60–80 ◦C.
hydroxypyrrolidine-2-carboxylate 12 (896 mg, 2.79 mmol) in
methanol (13 ml) was stirred at rt under nitrogen. para-
Toluenesulfonic acid monohydrate (53 mg, 0.279 mmol) was
added and stirring was continued overnight. Saturated aq.
sodium hydrogen carbonate (6 ml) was added and the methanol
was removed in vacuo. The aqueous layer was extracted with
ether (3 × 50 ml). The organic extracts were combined and
dried (Na2SO4), and the solvent was removed in vacuo to give
benzyl (2S,5RS)-N-tert-butoxycarbonyl-5-methoxypyrrolidine-
2-carboxylate 13 as a clear oil (836 mg, 89%); m/z [ES+] (found
336.1813; [C18H25NO5 + H]+ requires 336.1811); m/z [+ve FAB
(3-NBA)] 358 ([M + Na]+); mmax (film)/cm−1 1748 (ester) and 1708
(urethane); dH (300 MHz, C2HCl3, mixture of diastereoisomers
and/or rotamers, ratio 55 : 45 at 26 ◦C) 7.27 (5H, br, ArH), 5.20
(1H, m, H-5), 5.05 (2H, br m, OCH2Ar), 4.30 (1H, m, H-2),
3.29 (3H, 4 × s, OCH3), 2.40–1.61 (4H, br m, H-4 and H-3),
1.40 (9H, s, C(CH3)3 minor) and 1.26 (9H, s, C(CH3)3 major); dC
(75.5 MHz, C2HCl3, mixture of diastereoisomers and rotamers)
172.9 and 172.7 (ester), 154.6, 154.4 and 154.2 (urethane), 136.1,
136.0 and 135.8 and 129.0–127.3 (Ar), 89.67, 89.62, 88.8 and
88.7 (OCH3), 81.2, 81.0 and 80.9 (OC(CH3)3), 67.17, 67.11 and
67.0 (OCH2Ar), 60.0, 59.7, 59.4 and 59.3 (C-5), 56.6, 56.3, 55.7
and 55.3 (C-2), 33.3, 32.6, 31.4 and 30.4 (C-4), 28.6 and 28.4
(C(CH3)3), 27.4 and 27.3 (C-3).
Benzyl (2S,5RS)-N-tert-butoxycarbonyl-5-hydroxypyrrolidine-
2-carboxylate (12)
A solution of benzyl (2S)-N-tert-butoxycarbonypyroglutamate
1113 (1.0 g, 3.13 mmol) in tetrahydrofuran (20 ml) was stirred
at −78 ◦C under nitrogen. Lithium triethylborohydride (Super-
added slowly and the mixture was stirred for 2 h at −78 ◦C. Sat-
urated aq. sodium hydrogen carbonate◦(3 ml) was added and
the mixture was allowed to warm to 0 C. Hydrogen peroxide
(27.5 wt%, in H2O, 39 drops) was added and the reaction
was stirred at 0 ◦C for a further 20 min. The organic solvent
Benzyl (2S,5RS)-N-tert-butoxycarbonyl-5-allylpyrrolidine-2-
carboxylate (14)
R
Hydrideꢀ) (1 M in tetrahydrofuran, 4.69 ml, 4.69 mmol) was
A solution of 2-benzyl (2S,5RS)-N-tert-butoxycarbonyl-5-
methoxypyrrolidine-2-carboxylate 13 (500 mg, 1.49 mmol)
in dichloromethane (50 ml) was stirred under nitrogen at
−78 ◦C. Boron trifluoride diethyl etherate (0.183 ml, 1.49 mmol)
was added dropwise and the solution was stirred for 20 min at
2 2 9 0
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 2 2 8 7 – 2 2 9 5

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−78 ◦C. Allyltributylstannane (0.55 ml, 1.78 mmol) was added
slowly and the reaction was stirred at −78 ◦C for 3 h. Deionised
water (120 ml) was added and the solution was allowed to warm
to rt. The aqueous layer was extracted with dichloromethane
(3 × 40 ml). The organic extracts were dried (MgSO4) and the sol-
vent was removed in vacuo to give a white solid. Purification by
flash column chromatography on silica gel using ethyl acetate–
petroleum ether (15 : 85) as eluent gave benzyl (2S,5RS)-N-tert-
butoxycarbonyl-5-allylpyrrolidine-2-carboxylate 14 as a clear oil
(376 mg, 73%); mmax (film)/cm−1 1749 (ester) and 1699 (urethane);
dH (500 MHz, C2HCl3, 10 ◦C, 2 : 1 mixture of diastereoisomers
and/or rotamers at 26 ◦C) 7.32 (5H, br, ArH), 5.75 (1H, m,
H-7), 5.75 (2H, m, H-8), 5.17 (1H, AB, JAB 12.5, OCHAAr),
5.15 (1H, AB, JBA 12.5, OCHBAr), 4.37 and 4.27 (1H, 2 × m,
H-5trans and H-5cis), 3.90 (1H, m, H-2), 2.25–1.69 (6H, br m,
H-4, H-3 and H-6), 1.46, 1.32 and 1.31 (9H, 3 × s, C(CH3)3);
dC (75.5 MHz, C2HCl3, mixture of diastereoisomers) 172.1,
and 171.9 (ester), 152.5 (urethane), 134.6, 134.3, 134.08 and
134.0 (C-7), 127.5, 127.4, 127.3, 127.2 and 126.9 (Ar), 116.2
and 115.8 (C-8), 78.9 (OC(CH3)3), 65.6 (OCH2Ar), 59.2, 58.9
and 58.6 (C-5), 56.9 and 56.5 (C-2), 38.0, 37.9, 37.2 and 37.0
(C-6), 29.9 (C-4), 27.4–26.8 (C(CH3)3), 16.4 (C-3).
stirred under nitrogen at 0 ◦C. Pyridine (112 lml) was added
and the mixture was stirred for 15 min. Isobutyl chloroformate
(182 lml, 0.139 mmol) was added and stirring was continued
for 15 min at 0 ◦C. Benzyl (2S,5RS)-5-allylpyrrolidine-2-
carboxylate 9 (34 mg, 0.139 mmol) in THF (1.5 ml) was added
followed by further THF (0.5 ml). The mixture was allowed
to warm to rt over 3 h. The solvent was removed in vacuo
and the residue was dissolved in dichloromethane (17 ml).
The organic phase was washed with 5% aq. sodium hydrogen
carbonate, 5% aq. HCl and brine, then dried (MgSO4). The
solvent was removed in vacuo and the residue was purified
by flash column chromatography on silica gel using ethyl
acetate–petroleum ether (1 : 4) as eluent. 2-Benzyl 1-isobutyl
(2S,5RS)-5-allylpyrrolidine-1,2-dicarboxylate 15 eluted as a
clear colourless oil (11 mg, 23%); m/z [ES+] (found 346.2015;
[C20H27NO4+H]+ requires 346.2018); m/z [+ve FAB (3-NBA)]
368 ([M + Na]+) and 346 ([M + H]+); mmax (film)/cm−1 1750
(ester) and 1705 (urethane); dH (300 MHz, C2HCl3, mixture of
diastereoisomers and rotamers at 26 ◦C) 7.31 (5H, br, ArH),
5.72 (1H, m, H-7), 5.14–4.96 (4H, m, OCH2Ar and H-8), 4.31
(1H, m, H-2), 3.96–3.73 (3H, m, H-5 and OCH2CH(CH3)2),
2.65 (1H, m, CH2CH(CH3)2), 2.10 (2H, m, H-6), 1.97–1.58
(4H, m, H-4 and H-3), 0.91 (3H, m, CHCH3) and 0.80 (3H,
d, JAB 6.3, CHCH3); dC (75.5 MHz, C2HCl3, mixture of
diastereoisomers and rotamers at 26 ◦C) 173.2 and 173.1 (ester),
155.6 and 154.9 (urethane), 135.9, 135.5, 135.4 and 133.9
(C-7), 129.1–128.4 (Ar), 118.9, 118.0 and 117.4 (C-8), 71.9 and
71.7 (OCH2Ar), 68.0, 67.6 and 67.1 (C-6), 61.0, 60.9 and 60.6
(C-5), 58.8 and 58.4 (C-2), 39.3, 38.6 and 37.7 (C-4), 30.5, 29.8
and 29.6 (C-3 and CH2CH(CH3)2), 28.2 (OCH2CH(CH3)2),
19.5 and 19.3 (CH(CH3)2). Benzyl (2S,5RS)-5-allyl-1-(2-tert-
butoxycarbonylaminobut-3-enoyl)-pyrrolidine-2-carboxylate
16 eluted as a clear colourless oil (12 mg, 20%); m/z [ES+]
(found 429.2392; [C24H32N2O5+H]+ requires 429.2389); m/z
[+ve FAB (3-NBA)] 429 ([M + H]+); mmax (film)/cm−1 3323
(NH), 1747 (ester), 1712 (urethane) and 1650 (lactam); dH
(500 MHz, C2HCl3, mainly cis isomer, rotamers at 26 ◦C)
7.35 (5H, m, ArH), 5.85 (1H, ddd, J11,9 5.4, J11,12A 10.3, J11,12B
17.2, H-11), 5.73 (1H, dddd, J7,6A 2.1, J7,6B 6.8, J7,8A 9.3, J7,8B
Benzyl (2S,5RS)-5-allylpyrrolidine-2-carboxylate
trifluoroacetate (9a)
2-Benzyl (2S,5RS)-N-tert-butoxycarbonyl-5-allylpyrrolidine-2-
carboxylate 14 (70 mg, 0.202 mmol) was dissolved in
dichloromethane (1.4 ml) and stirred at rt under nitrogen.
Trifluoroacetic acid (0.70 ml) was added and the reaction was
stirred at rt overnight. The solvents were removed in vacuo to
give a brown oil which was recrystallised from cold diethyl ether
and petroleum ether to give benzyl (2S,5RS)-5-allylpyrrolidine-
2-carboxylate trifluoroacetate 9a as a yellow solid (41 mg, 56%),
mp 54.0–55.9 ◦C; (found C, 56.8; H, 5.6; N, 3.8%; C17H20NO4F3
requires C, 56.8; H, 5.6; N, 3.9%); m/z [+ve FAB (3-NBA)] 246
([Mfree amine + H]+); mmax (KBr)/cm−1 3418 (NH), 1754 (ester),
1694 and 1667 (salt); dH (300 MHz, C2H3O2H, mixture of
diastereoisomers) 7.15 (5H, m, ArH), 5.59 (1H, m, H-7), 5.12–
4.86 (4H, m, H-8 and OCH2Ar), 4.28 (1H, m, H-5), 3.48 (1H, m,
H-2) and 2.24–1.42 (6H, m, H-4, H-6 and H-3); dC (75.5 MHz,
C2H3O2H, mixture of diastereoisomers) 170.3 (ester), 134.4 (Ar),
132.0 (C-7), 129.4, 129.2, 129.1 and 128.9 (Ar), 120.9 and 119.3
(C-8), 69.2 and 68.6 (OCH2Ar), 62.0 and 60.0 (C-5), 59.2 and
59.5 (C-2), 36.8 (C-4), 29.6 and 28.9 (C-3).
19.5, H-7), 5.49 (1H, d, JNH
,
8.9, NH), 5.43–5.05 (6H, m,
10
OCH2Ar, H-8 and H-12), 4.58 (1H, m, H-10), 4.52 (1H, m,
H-2), 4.35 (1H, m, H-5), 2.33–1.91 (6H, m, H-6, H-4 and
H-3), 1.44, 1.43 and 1.41 (9H, 3 × s, C(CH3)3); dC (75.5 MHz,
C2HCl3) 172.3 and 172.2 (ester), 155.5 (ketone), 135.9–133.8
(C-7 and C-11), 129.0–128.4 (Ar), 119.5–117.6 (C-8, C-12 and
OCH2Ar), 80.3 and 80.0 (OC(CH3)3), 68.1 and 67.2 (C-6), 60.2,
60.1 and 59.8 (C-5), 59.2, 58.9 and 58.2 (C-10), 55.6, 55.2 and
54.1 (C-2), 39.1 and 38.2 (C-4), 30.7, 29.7 and 27.1 (C-3) and
28.7 (C(CH3)3).
Benzyl (2S,5RS)-5-allylpyrrolidine-2-carboxylate (9)
A solution of benzyl (2S,5RS)-5-allylpyrrolidine-2-carboxylate
trifluoroacetate 9a (50.3 mg, 0.14 mmol) in dichloromethane–
water (2 : 1, 8 ml) was stirred vigorously and triethylamine
(0.070 ml, 0.5 mmol) was added. Stirring was continued at rt
for 2 h. The phases were separated and the aqueous phase was
extracted with dichloromethane. The organic extracts were dried
(Na2SO4), and the solvent was removed in vacuo to give benzyl
(2S,5RS)-5-allylpyrrolidine-2-carboxylate 9 as a clear oil which
was used without further purification; mmax (film)/cm−1 3416
(NH) and 1747 (ester); dH (300 MHz, C2H3COC2H3, mixture
of diastereoisomers) 7.34–7.19 (5H, m, ArH), 5.69 (1H, m, H-
7), 5.13–4.86 (4H, m, H-8 and OCH2Ar), 4.39 (1H, m, H-5),
3.52 (1H, m, H-2), 3.0 (2H, m, H-6), 2.56 (1H, m, H-3A), 2.15
(1H, m, H-4) and 1.50–1.40 (1H, m, H-3B).
Benzyl (2S,5R,9S)-9-tert-butoxycarbonylamino-5-oxo-
2,3,5,6,9,9a-hexahydro-1H-pyrrolo[1,2-a]azepine-3-carboxylate
(3a) and benzyl (2S,5R,9R)-6-tert-butoxycarbonylamino-5-oxo-
2,3,5,6,9,9a-hexahydro-1H-pyrrolo[1,2-a]azepine-3-carboxylate
(3b)
Bis(tricyclohexylphosphine)benzylideneruthenium(IV) dichlo-
ride (Grubbs catalyst) (147 mg, 0.179 mmol) was added
to a solution of benzyl (2S,5RS)-5-allyl-1-(2-tert-butoxycar-
bonylaminobut-3-enoyl)-pyrrolidine-2-carboxylate 16 (385 mg,
0.898 mmol) in dichloromethane (100 ml) and the solution was
heated at reflux for 24 h. The mixture was cooled to 20 ◦C,
lead tetraacetate (0.119 mg, 0.269 mmol) was added and stirring
was continued for 12 h. The solvent was removed in vacuo to
give a black oil which was flash chromatographed on silica
gel using petroleum ether–diethyl ether (1 : 2) as eluent. Ben-
zyl (2S,5R,9S)-9-tert-butoxycarbonylamino-5-oxo-2,3,5,6,9,9a-
hexahydro-1H-pyrrolo [1,2-a]azepine-3-carboxylate 3a was ob-
tained as an oil (208 mg, 58%); m/z [ES+] (found 401.2076;
2-Benzyl (2S,5RS)-N-iso-butoxycarbonyl-5-allylpyrrolidine-2-
carboxylate (15) and benzyl (2S,5RS)-5-allyl-1-(2-tert-
butoxycarbonylaminobut-3-enoyl)-pyrrolidine-2-carboxylate
(16)
A solution of 2-tert-butoxycarbonylaminobut-3-enoic acid (10,
n = 0)15,16 (28 mg, 0.139 mmol) in anhydrous THF (1 ml) was
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 2 2 8 7 – 2 2 9 5
2 2 9 1

View Article Online
[C22H28N2O5 + H]+ requires 401.2076); m/z [+ve FAB (3-NBA)]
423 ([M + Na]+) and 401 ([M + H]+); mmax (film)/cm−1 3409 (NH),
1741 (ester), 1714 (urethane) and 1661 (lactam); dH (500 MHz,
Cambridge Crystallography Data Centre, University Chemical
Laboratory, Lensfield Road, Cambridge, CB2 1EW (deposition
number)†.
2
C6 H6) 7.10 (5H, br, ArH), 6.14 (1H, d, JNH,9 4.6, NH), 5.42
(1H, m, J8,7 10, J8,9 4, J8,6 2, H-8), 5.35 (1H, m, H-9), 5.21 (1H,
m, H-7), 4.98 (1H, AB, JAB 11, OCHAAr), 4.96 (1H, BA, JAB
11, OCHBAr), 4.53 (1H, dd, J2,3A 6.0, J2,3B 3.5, H-2), 3.40 (1H,
m, H-5), 2.05 (1H, m, H-6A), 1.55 (2H, m, H-3B and H-6B),
1.50 (9H, s, C(CH3)3), 1.38 (1H, m, H-3A), 1.24 (1H, m, H-4A)
and 0.80 (1H, m, H-4B); dC (75.5 MHz, C2HCl3) 172.2 (ester),
169.6 (lactam), 156.1 (urethane), 135.8 and 128.9–128.1 (Ar,
C-7 and C-8), 80.1 (OC(CH3)3), 60.5 (C-2), 55.9 (C-5), 52.1 (C-
9), 35.2 (C-6), 31.9 (C-4), 28.7 (C(CH3)3), and 28.3 (C-3). Ben-
zyl (2S,5R,9R)-6-tert-butoxycarbonylamino-5-oxo-2,3,5,6,9,9a-
hexahydro-1H-pyrrolo [1,2-a]azepine-3-carboxylate 3b was ob-
tained as an oil (33 mg, 9%); m/z [ES+] (found 401.2082,
[C22H28N2O5 + H]+ requires 401.2076); m/z [+ve FAB (3-NBA)]
423 ([M + Na]+) and 401 ([M + H]+); mmax (film)/cm−1 3314
(br, NH), 1738 (ester), 1698 (urethane) and 1645 (lactam); dH
(500 MHz, C2HCl3, 45 ◦C) 7.33 (5H, m, ArH), 5.86 (1H, ddd, J7,8
tert-Butyl (2S)-2-tert-butoxycarbonylaminopent-4-enoate (20)
Potassium hexamethyldisilazide (1 M in THF, 2.63 ml,
1.317 mmol) was added slowly to a suspension of methyltriph-
enylphosphonium bromide (522 mg, 1.45 mmol) in THF (5 ml)
at rt. The solution was stirred for 30 min at rt and a solution
of freshly prepared aldehyde 1920 (175 mg, 0.64 mmol) in THF
(2 ml) was added. The solution was stirred for 1 h and saturated
aq. ammonium chloride (10 ml) was added. The aqueous layer
was extracted with diethyl ether (2 × 20 ml), the organic extracts
were washed with water (2 × 10 ml) and brine, (2 × 10 ml)
then dried (MgSO4). The solvent was removed in vacuo and the
residue was purified by flash column chromatography on silica
gel using ethyl acetate–petroleum ether (1 : 9) to give tert-butyl
(2S)-2-tert-butoxycarbonylaminopent-4-enoate 20 as a clear oil
(68 mg, 40%); [a]3D1 −31.45 (c 1.03, MeOH); m/z [+ve FAB (3-
NBA)] 295 ([M + Na]+), 272 ([M + H]+); mmax (nujol)/cm−1 3440
and 3365 (NH), 1717 (ester), 1642 (u◦rethane); dH (500 MHz,
C2HCl3, 2 rotamers, ratio 95 : 5 at 10 C) 5.66 (1H, dd t, J4,5cis
11.5, J4,5A 4.6, J4,5trans 18.8, J4,3B 2.5, H-4), 5.10 (3H, m, H-5 and
NH major), 4.80 (1H, d, JNH,2 7.6, NH minor), 4.25 (1H, m, H-2
major), 4.04 (1H, m, H-2 minor), 2.45 (2H, m, H-3), 1.42 (9H, s,
C(CH3)3) and 1.41 (9H, s, C(CH3)3); dC (75.5 MHz, C2HCl3)
171.5 (ester), 155.5 (urethane), 132.8 (C-4), 119.1 (C-5), 82.2
and 79.9 (2 × OC(CH3)3), 53.6 (C-2), 37.4 (C-3), 28.6 and 28.3
(2 × C(CH3)3).
11.0, J7,6A 3.0, J7,6B 5.9, H-7), 5.81 (1H, ddt, J8,7 11.0, J8,9 7.2, J8,6A
,
2.4, J8,6B 0.7, H-8), 5.17 (1H, AB, JAB 11, OCHAAr), 5.15 (1H,
BA, JBA 11, OCHBAr), 4.97 (1H, br s, NH), 4.74 (1H, br, H-9),
4.61 (1H, dd, J2,3A 8.6, J2,3B 3.5, H-2), 4.27 (1H, br, H-5), 2.55 (1H,
m, H-6a), 2.28 (1H, m, J6B,6A 17.6, J6B,7 5.9, J6B,5 2.3, H-6b), 2.22
(1H, m, H-4B), 2.10 (1H, m, H-3B), 2.00 (1H, m, H-3A), 1.76
(1H, m, H-4A), 1.45 (9H, s, C(CH3)3); dC (75.5 MHz, C2HCl3)
172.4 (ester), 168.7 (lactam), 155.1 (urethane), 136.0 and 128.9–
128.4 (Ar, C-7 and C-8), 80.7 (OC(CH3)3), 67.2 (OCH2Ar),
61.2 (C-2), 55.3 (C-5), 35.1 (C-6), 32.5 (C-4), 30.7 (C-9), 28.7
(C(CH3)3) and 27.7 (C-3).
(2S)-2-Aminopent-4-enoate hydrochloride
A solution of tert-butyl (2S)-2-tert-butoxycarbonylaminopent-
4-enoate 20 (105 mg, 0.39 mmol) in THF (6 ml) was stirred at rt
under nitrogen. 6 N Aq. hydrochloric acid (6 ml) was added and
the reaction was stirred overnight. The solvents were removed
in vacuo to give an off-white solid which was recrystallised from
methanol and diethyl ether to give (2S)-2-aminopent-4-enoate
hydrochloride as a pure white solid (40 mg, 67%); mp 154–156 ◦C
(decomposed); [a]3D3 +196.6 (c 0.5, MeOH); m/z [ES+] (found
231.1341; [2 × C5H9NO2 + H]+ requires 231.1339); m/z [+ve
FAB (3-NBA)] 231 ([2Mfree amine + H]+) and 116 ([Mfree amine + H]+);
mmax (KBr)/cm−1 3431 (br, NH) and 1730 (acid); dH (300 MHz,
C2H3O2H) 5.81 (1H, m, H-4), 5.35 (1H, br, H-5A), 5.29 (1H, d,
J5B,4 9.4, H-5B), 4.09 (1H, t, J2,3 6.0, H-2), 2.70 (2H, m, H-3);
dC (75.5 MHz, C2H3O2H) 171.6 (acid), 132.2 (C-4), 121.9 (C-5),
53.7 (C-2) and 36.1 (C-3).
(2S,5R,9S)-6-Amino-5-oxo-2,3,5,6,9,9a-hexahydro-1H-
pyrrolo[1,2-a]azepine-3-carboxylate hydrochloride (17)
Benzyl (2S,5R,9S)-9-tert-butoxycarbonylamino-5-oxo-2,3,5,-
6,9,9a-hexahydro-1H-pyrrolo[1,2-a]azepine-3-carboxylate 3a
(25 mg, 0.0625 mmol) was suspended in 6 N aq. HCl (2 ml)
and warmed to 60 ◦C under nitrogen. The mixture was
left stirring at 60 ◦C overnight. The aqueous layer was
lypholised to give a yellow oil which was dissolved in a
minimum of methanol and addition of cold diethyl ether
gave
(2S,5R,9S)-6-amino-5-oxo-2,3,5,6,9,9a-hexahydro-1H-
pyrrolo[1,2-a]azepine-3-carboxylate hydrochloride 17 as an
off-white solid (16 mg, quant.); [a]2D5 −51.75 (c 0.4, MeOH);
(found C, 47.2; H, 6.2; N, 10.7%. C10H15N2O3Cl. 0.5 H2O
requires C, 47.0; H, 6.3; N, 11.0%.); m/z [EI] (found 210.1000;
[C10H14N2O3]+ requires 210.1004); m/z [+ve FAB (3-NBA)]
211 ([Mfree amine + H]+); mmax (film)/cm−1 3440 (br, NH), 1704
(acid) and 1670 (lactam); dH (500 MHz, C2H3O2H) 5.89 (1H,
ddt, J8,7 11.4, J8,9 3.2, J8,6A 4.7, J8,6B 4.0, H-8), 5.38 (1H, ddd,
J7,8 11.4, J7,6A 4.4, J7,6B 2.4, H-7), 5.23 (1H, t, J9,8 3.2, H-9),
4.52 (1H, dd, J2,3A 8.2, J2,3B 5.8, H-2), 4.47 (1H, m, H-5), 2.49
(1H, m, H-6B), 2.40 (1H, m, H-6A), 2.33 (1H, m, H-4A), 2.28
(1H, m, H-3A), 2.12 (1H, m, H-3B), 1.81 (1H, m, H-4B); dC
(125.8 MHz, C2H3O2H) 175.3 (acid), 168.3 (urethane), 133.5
(C-8), 121.1 (C-7), 62.2, 57.2 and 53.1 (C-2, C-5 and C-9), 36.3,
32.8 and 29.6 (C-6, C-4 and C-3).
(2S)-2-tert-Butoxycarbonylaminopent-4-enoate (10, n = 1)
(2S)-2-Aminopent-4-enoate hydrochloride (32 mg, 0.211 mmol)
was dissolved in tert-butanol–water (2 : 1) (2 ml). 1 N Aq.
sodium hydroxide (0.192 ml, 0.192 mmol) and di-tert-butyl
dicarbonate (55 mg, 0.252 mmol) were added and the reaction
was stirred overnight at rt. The reaction was diluted with
deionised water, washed with hexane (3 × 3 ml) and acidified
to pH 2 by dropwise addition of aq. 1 N potassium hydrogen
sulfate. The acidic aqueous layer was extracted with ethyl acetate
(3 × 5 ml). The combined organic phases were dried (MgSO4)
and the solvent was removed in vacuo to give (2S)-2-tert-
butoxycarbonylaminopent-4-enoate 10 (n = 1) as a clear oil
(43 mg, 94%); [a]2D7 +2.8 (c 0.5, CHCl3); m/z [+ve FAB (3-
NBA)] 238 ([M + Na]+) and 216 ([M + H]+); mmax (film)/cm−1
3326 (NH) and 1719 (br, acid); dH (300 MHz C2H3COC2H3 2
rotamers, ratio 87 : 13 at 26 ◦C) 5.91 (1H, br s, NH), 5.71 (1H, m,
Crystal Data. Compound 17, C10H15ClN2O3, M = 246.69,
orthorhombic, space group P212121 (No. 19), a = 6.4839(4),
3
˚
˚
b = 12.5501(10), c = 13.7734(7) A, V = 1120.8(1) A ,
Z = 4, Dcalc = 1.46 mg/m3, l (Mo–Ka) 0.34 mm−1, T =
173(2) K, 1971 independent reflections, final residuals were
R1 = 0.036 for 1735 reflections with I>2r(I), wR2 = 0.080
for all reflections. Data collection was carried out using a
Kappa CCD diffractometer, structure analysis using program
package WinGX and refinement using SHELXL-97. The
atomic coordinates are available on request from The Director,
† CCDC reference number 265180. See http://www.rsc.org/suppdata/
ob/b5/b503014e/ for crystallographic data in CIF or other electronic
format.
2 2 9 2
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 2 2 8 7 – 2 2 9 5

View Article Online
H-4), 5.01 (1H, d, J5trans,4 17.1, H-5trans), 4.94 (1H, d, J5cis,4 9.9,
H-5cis), 4.09 (1H, t, J2,3 5.0, H-2 major), 3.26 (1H, t, J2,NH 6.9,
H-2 minor), 2.48–2.32 (2H, m, H-3), 1.27 (9H, s, C(CH3)3); dC
(75.5 MHz, C2H3COC2H3) 173.9 (acid), 156.6 (urethane), 135.0
(C-4), 118.6 (C-5), 79.6 (OC(CH3)3), 54.2 (C-2), 37.1 (C-3) and
28.9 (C(CH3)3).
2.14 (1H, m, H-4A), 2.05 (1H, m, H-3A), 1.97 (1H, m, H-4B),
1.89 (1H, m, H-3B) and 1.43 (9H, s, C(CH3)3); dC (75.5 MHz,
C2HCl3) 172.0 (ester), 171.4 (ketone), 155.5 (urethane), 136.0
(Ar), 129.6 (C-7), 128.8 and 128.6 (Ar), 125.9 (C-8), 79.9
(OC(CH3)3), 67.1 (OCH2Ar), 60.7 (C-2), 59.0 (C-10), 52.1
(C-5), 35.6 (C-6), 33.2 (C-9), 33.1 (C-4), 28.7 (C(CH3)3) and
27.5 (C-3).
Benzyl (2S,5R)-5-allyl-1-(2-tert-butoxycarbonylamino-5-pent-4-
enoyl)-pyrrolidine-2-carboxylate (21)
1-tert-Butyl (2S)-2-tert-butoxycarbonylaminohex-5-enoate (23)
Pyridine (10% w/v in THF, 0.23 ml, 0.29 mmol) was added
to a solution of (2S)-2-tert-butoxycarbonylaminopent-4-enoate
10 (n = 1) (66 mg, 0.307 mmol) in THF (8 ml) with
stirring at −78 ◦C under nitrogen. Isobutyl chloroformate
(10% w/v solution in THF, 0.39 ml 0.285 mmol) was
added and the solution was stirred at −78 ◦C for 15 min.
Benzyl (2S,5RS)-5-allylpyrrolidine-2-carboxylate 9 (75 mg,
0.307 mmol) in THF (2 ml) was added slowly followed by
further THF (1 ml). The solution was allowed to warm to
rt over 3 h, the organic solvent was removed in vacuo and
the residue was dissolved in dichloromethane. The organic
layer was extracted with 5% aq. sodium hydrogen carbonate
(5 ml), 5% aq. hydrochloric acid (5 ml) and brine (5 ml)
and dried (MgSO4). The solvent was removed in vacuo to
give a brown oil which was purified by flash column chro-
matography on silica gel using ethyl acetate–petroleum ether
(1 : 4) as eluent to give 2-benzyl 1-iso-butyl (2S,5RS)-5-
allylpyrrolidine-1,2-dicarboxylate 15 as a clear oil (34 mg, 33%)
with spectra identical to those of the sample prepared above
and benzyl (2S,5R)-5-allyl-1-(2-tert-butoxycarbonylamino-5-
pent-4-enoyl)-pyrrolidine-2-carboxylate 21 as a clear oil (20 mg,
15%); [a]2D7 −4.72 (c 2, MeOH); m/z [ES+] (found 443.2543;
[C25H34N2O5 + H]+ requires 443.2540); m/z [ES+] 465 ([M +
Na]+) and 443 ([M + H]+); mmax (film)/cm−1 3291 (NH), 1745
(ester), 1701 (urethane) and 1638 (lactam); dH (300 MHz,
C2HCl3) 7.27 (5H, br s, ArH), 5.70 (2H, m, H-7 and H-12),
5.21–4.87 (7H, m, H-13, H-8, CH2Ar and NH), 4.49–4.33 (3H,
br m, H-2, H-5 and H-10), 2.44–1.82 (8H, m, H-3, H-4, H-6 and
H-11) and 1.34 (9H, s, C(CH3)3); dC (75.5 MHz, C2HCl3) 172.3
and 171.8 (ester and lactam), 155.7 (urethane), 136.0 (Ar), 134.3
and 133.5 (C-7 and C-12), 128.9, 128.6 and 128.5 (Ar), 118.7
(C-8 and C-13), 80.1 (OC(CH3)3), 67.2 (OCH2Ar), 59.2 (C-2),
58.6 (C-10), 51.3 (C-5), 39.8 (C-6), 38.2 (C-11), 29.9 (C-4), 28.6
(C(CH3)3) and 27.2 (C-3).
A solution of 1-tert-butyl (2S)-2-tert-butoxycarbonylamino-
pentan-1,5-dioate c -N-methoxy-N-methylamide 2221 (300 mg,
0.865 mmol) in THF (10 ml) was stirred under nitrogen at rt.
Lithium tri-tert-butoxyaluminium hydride (1 M in THF, 2.59 ml,
2.59 mmol) was added slowly and stirring was continued for 3 h.
5% Aq. potassium hydrogen sulfate (5 ml) and diethyl ether
(50 ml) were added. The aqueous phase was separated and
extracted with diethyl ether (3 × 50 ml). The organic extracts
were combined and washed with 3 N aq. HCl (3 × 10 ml),
saturated aq. sodium hydrogen carbonate (3 × 10 ml) and brine
(3 × 10 ml). The organic phases were combined and dried
(MgSO4) and the solvent was removed in vacuo to give aldehyde
(197 mg) as a clear colourless oil which was used immediately
without further purification. Potassium hexamethyldisilazide
(0.5 M in THF, 3.11 ml, 1.55 mmol) was added slowly to a stirred
suspension of methyltriphenylphosphonium bromide (618 mg,
1.72 mmol) in THF (5 ml) and stirring was continued for 30 min
at rt. A solution of the aldehyde (197 mg) in THF (5 ml) was
added slowly to the yellow ylide and the reaction was stirred for
1 h. Saturated aq. ammonium chloride (10 ml) was added and
the aqueous layer was extracted with diethyl ether (2 × 20 ml).
The organic extracts were washed with deionised water (2 ×
10 ml), brine (2 × 10 ml) and dried (MgSO4). The solvent was
removed in vacuo to give a pale yellow oil which was purified by
flash column chromatography on silica gel, using ethyl acetate–
petroleum ether (1 : 9) as eluent, to give 1-tert-butyl (2S)-2-
tert-butoxycarbonylaminohex-5-enoate 23 as a clear oil (35 mg,
14%); [a]2D6 −17.9 (c 1.18, MeOH), (lit.19 [a]2D0 −19.0 (c 1, MeOH));
m/z [+ve FAB (3-NBA)] 308 ([M + Na]+) and 286 ([M + H]+);
mmax (film)/cm−1 3378 (NH), 1698 (br, ester) and 1642 (urethane);
dH (500 MHz, C2HCl3, 2 rotamers, ratio 84 : 16, at 10 ◦C) 5.78
(1H, dd t, J5,6cis 9.5, J5,6trans 17.0, J5,4 5.7, H-5), 5.11 (1H, d, JNH,2
8.5, NH major), 4.80 (1H, d, JNH,2 4.7, NH minor), 5.02 (1H,
ddd, J6trans,5 17.0, J6trans,4 1.6, J6B,6A 3.9, H-6trans), 4.96 (1H, ddd,
J6cis,5 9.5, J6A,4B 6.7, J6A,4A 3.9, H-6cis), 4.19 (1H, ddd, J2,NH 8.5,
J2,3A 7.7, J2,3B 4.9, H-2 major), 3.99 (1H, ddd, J2,NH 4.7, J2,3A 12.8,
Benzyl 12-tert-butoxycarbonylamino-(2S,5R,12S)-5-oxo-
1,2,3,5,6,7,10,10a-octahydro-1H-pyrrolo[1,2a]azocine-3-
carboxylate (5)
J
2,3B 7.8, H-2 minor), 2.08 (2H, m, H-4), 1.84 (1H, m, H-3A), 1.64
(1H, m, H-3B), 1.44 (9H, s, (C(CH3)3) and 1.41 (9H, s, (C(CH3)3);
dC (75.5 MHz, C2HCl3) 172.3 (ester), 155.7 (urethane), 137.7 (C-
5), 115.7 (C-6), 82.1 and 79.9 (2 × OC(CH3)3), 53.9 (C-2), 32.6
(C-4), 29.8 (C-3), 28.7 and 28.3 (2 × C(CH3)3).
Bis(tricyclohexylphosphine)benzylideneruthenium(IV) dichlo-
ride (Grubbs’ catalyst) (12.9 mg, 0.015 mmol) was added to
a solution of benzyl (2S,5R)-5-allyl-1-(2-tert-butoxycarbonyl-
amino-5-pent-4-enoyl-pyrrolidine-2-carboxylate 21 (33 mg,
0.075 mmol) in dichloromethane (10 ml) and the mixture was
heated at reflux for 24 h under nitrogen. The reaction was
allowed to cool to rt and the solvent was removed in vacuo to give
a brown oil which was purified by flash column chromatography
on silica gel using petroleum ether–diethyl ether (1 : 2) as eluent
to give benzyl 12-tert-butoxycarbonylamino-(2S 5R,12S)-5-
oxo-1,2,3,5,6,7,10,10a-octahydro-1H-pyrrolo[1,2a]azocine-3-
carboxylate 5 as a white foam (20.1 mg, 65%), [a]2D8 −7.51 (c
2.01, MeOH); m/z [ES+] (found 437.2022; [C23H30N2O5+Na]+
requires 437.2046); mmax (film)/cm−1 3421 (NH), 1745 (ester),
1707 (urethane) and 1641 (lactam); dH (500 MHz, C2HCl3,
25 ◦C) 7.34 (5H, br, ArH), 5.61 (3H, m, H-7, H-8 and NH), 5.19
(1H, AB, JAB 12, OCHAAr), 5.06 (1H, BA, JBA 12, OCHBAr),
4.86 (1H, ddd, J10,9A 10.1, J10,NH 7.7, J10,9B 5.9, H-10), 4.55 (1H,
dd, J2,3A 9.1, J2,3B 3.2, H-2), 4.14 (1H, m, H-5), 2.78 (2H, m,
H-6A and H-9A), 2.38 (1H, m, H-9B), 2.24 (1H, m, H-6B),
(2S)-2-Aminohex-5-enoate hydrochloride
1-tert-Butyl (2S)-2-tert-butoxycarbonylaminohex-5-enoate 23
(125 mg, 0.439 mmol) was dissolved in THF (10 ml) and 6
N aq. HCl (10 ml) and stirred at rt overnight. The aqueous
layer was lyophilised to give a white solid which was purified by
recrystallisation from methanol and diethyl ether to give (2S)-2-
aminohex-5-enoate hydrochloride as a white solid (59 mg, 81%);
◦
mp 165–167 C; [a]3D0 +30.0 (c 0.97, MeOH); (found C, 39.8:
H, 7.2: N, 7.9%. C6H12NO2Cl.H2O requires C, 39.2; H, 7.6: N,
7.6%.); m/z [EI] (found 130.0866; C6H11NO2 requires 130.0868);
mmax (film)/cm−1 3414 (NH) and 1738 (acid); dH (300 MHz,
C2H3O2H) 5.87 (1H, dd t, J5,6cis 10.2, J5,6trans 17.1, J5,4 6.3, H-
5), 5.16 (1H, dd, J6B,6A 1.6, J6trans,5 17.1, H-6trans), 5.11 (1H, dd,
J
6A,6B 1.6, J6cis,5 10.2, H-6cis), 3.99 (1H, t, J2,3 6.3, H-2), 2.30 (2H,
m, H-4) and 2.0 (2H, m, H-3); dC (75.5 MHz, C2H3O2H) 172.1
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 2 2 8 7 – 2 2 9 5
2 2 9 3

View Article Online
(acid), 137.7 (C-5), 117.2 (C-6), 53.7 (C-2), 31.3 and 30.4 (C-4
and C-3).
Benzyl (2S,5R,11S)-11-tert-butoxycarbonylamino-5-oxo-
2,3,5,6,7,8,11,11a-octahydro-1H-pyrrolo[1,2a]azonine-3-
carboxylate (6)
Bis(tricyclohexylphosphine)benzylideneruthenium(IV) dichlo-
ride (Grubbs’ catalyst) (8.8 mg, 0.010 mmol) was added
to a solution of benzyl (2S,5R)-5-allyl-1-(2-tert-butoxycar-
bonylaminohex-5-enoyl)-pyrrolidine-2-carboxylate 24 (24.6 mg,
0.054 mmol) in dichloromethane (8 ml). The solution was heated
at reflux for 24 h under nitrogen and allowed to cool to rt.
The solvent was removed in vacuo to give a brown oil which
was purified by flash column chromatography on silica gel
using petroleum ether–diethyl ether (1 : 2) as eluent to
give benzyl (2S,5R,11S)-11-tert-butoxycarbonylamino-5-oxo-
2,3,5,6,7,8,11,11a-octahydro-1H-pyrrolo[1,2a]azonine-3-carbo-
xylate 6 as a white foam (19.5 mg, 84%), [a]3D5 −58.4 (c
1.95, MeOH); m/z [ES+] (found 429.2362; [C24H32N2O5+H]+
requires 429.2384); mmax (film)/cm−1 3446 (NH), 1743 (ester),
1697 (urethane) and 1633 (lactam); dH (500 MHz, C2HCl3 +
(2S)-2-tert-Butoxycarbonylaminohex-5-enoate (10, n = 2)
(2S)-2-Aminohex-5-enoate hydrochloride (61 mg, 0.368 mmol)
was dissolved in tert-butanol–water (2 : 1) (v/v) (5 ml) and 1 N
aq. sodium hydroxide (0.735 ml, 0.736 mmol) and di-tert-butyl
dicarbonate (104 mg, 0.478 mmol) were added. The solution
was stirred under nitrogen at rt overnight, diluted with deionised
water and washed with hexane (3 × 3 ml). The aqueous phase
was acidified to pH 2 with 1 N aq. potassium hydrogen sulfate
and extracted with ethyl acetate. The combined organic extracts
were dried (MgSO4) and the solvent was removed in vacuo to
give (2S)-2-tert-butoxycarbonylaminohex-5-enoate 10 (n = 2)
as a clear oil (50 mg, 59%); [a]2D7 +37.24 (c 0.5, CHCl3); m/z
[ES+] (found 252.1218; [C11H19NO4 + Na]+ requires 252.1206);
m/z [+ve FAB (3-NBA)] 252 ([M + Na]+) and 230 ([M + H]+);
mmax (film)/cm−1 3329 (NH) and 1717 (br, acid); dH (500 MHz,
C2H3COC2H3, rotamers at 253 K, ratio 8 : 2) 6.54 (1H, d, JNH,2
8.5, NH major), 6.42 (1H, d, JNH,2 7.3, NH minor), 5.82 (1H, dd
t, J5,6cis 10.3, J5,6trans 17.0, J5,4 6.5, H-5), 5.06 (1H, ddd, J6trans,5 17.2,
◦
C2H3O2H, 25 C) 7.18 (5H, br, ArH), 5.67 (1H, m, H-7), 5.48
(1H, m, H-8), 5.08 (1H, AB, JAB 12, OCHAAr), 4.97 (1H, AB,
JBA 12, OCHBAr), 4.37 (1H, dd, J2,3A 10.0, J2,3B 7.6, H-2), 4.30
(1H, br dd, J11,10A 11.3, J11,10B 3.5, H-11), 3.98 (1H, t, J5,6A 7.5,
H-5), 2.75 (1H, m, H-6A), 2.22 (2H, m, H-9A and H-3A), 2.02
(1H, m, H-4A), 1.80 (3H, m, H-4B, H-6B and H-3B), 1.69 (2H,
m, H-10A and H-9B), 1.50 (1H, m, H-10B) and 1.33 (9H, s,
C(CH3)3); dC (75.5 MHz, C2HCl3 + C2H3O2H) 177.4 and 176.6
(ester and lactam), 160.0 (urethane), 139.6 (Ar), 136.5 (C-7),
132.8, 132.6 and 132.5 (Ar), 132.1 (C-8), 84.0 (OC(CH3)3), 71.3
(OCH2Ar), 64.7 (C-2), 64.2 (C-11), 54.2 (C-5), 39.6 (C-6), 38.6
and 38.4 (C-9 and C-10), 32.4 (C(CH3)3), 31.5 (C-4) and 27.7
(C-3).
J
6B,4 3.6, J6B,6A 1.5, H-6trans), 4.98 (1H, m, H-6cis), 4.12 (1H, m,
H-2), 2.15 (2H, m, H-4), 1.90 (1H, m, H-3A), 1.75 (1H, m, H-3B),
1.38 (9H, s, OC(CH3)3 minor) and 1.37 (9H, s, C(CH3)3 major);
dC (75.5 MHz, C2H3COC2H3) 174.7 (acid), 156.9 (urethane),
138.8 (C-5), 116.1 (C-6), 79.5 (OC(CH3)3), 54.1 (C-2), 32.3 (C-
4), 31.9 (C-3) and 28.9 (C(CH3)3).
Benzyl (2S,5R)-5-allyl-1-(2-tert-butoxycarbonylaminohex-5-
enoyl)-pyrrolidine-2-carboxylate (24)
Pyridine (10% w/v solution in THF, 0.155 ml, 0.192 mmol) was
added to a solution of (2S)-2-tert-butoxycarbonylaminohex-5-
enoate 10 (n = 2) (44.2 mg, 0.192 mmol) in THF (6 ml) and the
mixture was stirred at −78 ◦C under nitrogen for 15 min. Isobutyl
chloroformate (10% w/v solution in THF, 0.25 ml, 0.183 mmol)
was added and the solution was stirred for a further 15 min. A
solution of benzyl (2S,5RS)-5-allylpyrrolidine-2-carboxylate 9
(47.2 mg, 0.192 mmol) in THF (2 ml) was slowly added to the
cooled mixture and further THF (1 ml) was added. The mixture
was allowed to warm to rt over 3 h. The solvent was removed
in vacuo and the residue was dissolved in dichloromethane
(5 ml). The organic phase was extracted with 5% aq. sodium
hydrogen carbonate (5 ml), 5% aq. hydrochloric acid (5 ml)
and brine (5 ml). The organic phase was dried (MgSO4) and the
solvent was removed in vacuo to give a brown oil. Purification by
flash column chromatography on silica gel using ethyl acetate–
petroleum ether as eluent to give 2-benzyl 1-iso-butyl (2S,5RS)-
5-allylpyrrolidine-1,2-dicarboxylate 15 (24.4 mg, 36%), with
identical spectra to the sample isolated above, and ben-
zyl (2S,5R)-5-allyl-1-(2-tert-butoxycarbonylaminohex-5-enoyl)-
pyrrolidine-2-carboxylate 24 (24.6 mg, 27%); [a]2D6 −3.91 (c
2.4, MeOH); (m/z [ES+] found 457.2701; [C26H36N2O5+H]+
requires 457.2702); mmax (film)/cm−1 3293 (NH), 1748 (ester),
1702 (lactam) and 1640 (urethane); dH (500 MHz C2HCl3, 2
rotamers, ratio 86 : 14 at 3 ◦C) 7.30 (5H, s, ArH), 5.72 (2H, m,
H-7 and H-13), 5.54 (1H, d, JNH,10 9.2, NH major), 5.44 (1H,
d, JNH,10 9.3, NH minor), 5.18 (1H, AB, JAB 12, OCHAAr), 5.14
(1H, AB, JAB 12, OCHBAr), 5.0 (4H, m, H-8 and H-14), 4.44
(1H, m, H-2), 4.36 (2H, m, H-5 and H-10), 2.34 (1H, m, H-6A),
2.25 (3H, m, H-6B, H-3B and H-4B), 1.65 (2H, q, J 7.3, H-11),
1.38 (9H, s, C(CH3)3 minor) and 1.37 (9H, s, C(CH3)3 major);
dC (75.5 MHz C2HCl3 + C2H3O2H) 172.7 and 172.3 (ester and
lactam), 156.0 (urethane), 137.4 (C-7), 135.8 (Ar), 134.1 (C-
13), 128.8, 128.6 and 128.4 (Ar), 118.7 (C-8), 116.0 (C-14), 80.1
(OC(CH3)3), 67.2 (OCH2Ar), 59.9 (C-2), 58.6 (C-5), 50.9 (C-10),
39.5, 32.7, 29.9, 29.7 and 27.1 (C-12, C-11, C-6, C-4 and C-3)
and 28.6 (C(CH3)3).
Acknowledgements
We thank Dr A. G. Avent for NMR spectroscopic experiments
and Dr Ali Al Sada and the EPSRC Central Mass Spectrometry
Service at Swansea for mass spectra.
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