Intramolecular carbolithiation reactions for the preparation of 3-alkenylpyrrolidines.

Article abstract of DOI:10.1039/b303670g

Tin-lithium exchange allows the formation of alpha-amino-organolithium species that undergo anionic cyclization onto allylic ethers to give 3-alkenylpyrrolidines. The methodology has been applied to the synthesis of an advanced intermediate related to the natural product (-)-alpha-kainic acid.

Full text of DOI:10.1039/b303670g

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Intramolecular carbolithiation reactions for the preparation of
3-alkenylpyrrolidines
Iain Coldham,* Kathy N. Price and Richard E. Rathmell
School of Chemistry, University of Exeter, Stocker Road, Exeter, UK EX4 4QD.
E-mail: i.coldham@ex.ac.uk
Received 3rd April 2003, Accepted 1st May 2003
First published as an Advance Article on the web 14th May 2003
Tin–lithium exchange allows the formation of α-amino-organolithium species that undergo anionic cyclization onto
allylic ethers to give 3-alkenylpyrrolidines. The methodology has been applied to the synthesis of an advanced
intermediate related to the natural product (–)-α-kainic acid.
Introduction
It is well-known that organolithium species undergo ready
cyclization onto suitably positioned terminal alkenes.1 The
chemistry provides a convenient and high-yielding synthesis of,
in particular, substituted cyclopentanes, tetrahydrofurans and
pyrrolidines.1,2 The cyclization is thought to proceed by way of
a chair-shaped transition state and is highly stereoselective. Our
work has centred on the use of α-amino-organolithium species,
generated by tin–lithium exchange, and results in the formation
of cyclic amine products.3 Cyclization of organolithium species
onto an alkene bearing an electron-withdrawing substituent
(such as Ph, SPh or SiMe3) is also known.4 We were attracted to
reports that cyclization onto allylic ethers is possible.5 In this
chemistry, displacement of an alkoxide (SNЈ addition) takes
place to provide a cyclic product with a new alkene group. Such
alkenes could be manipulated further or could be present in the
desired final product. For example, the natural product (–)-α-
kainic acid 16 contains an alkenyl substituent that might be able
to be accessed using such anionic cyclization chemistry, for
example, from a suitably protected substrate 2 (Scheme 1). This
paper outlines in full our work on the simple model system,7
and our studies on the application of this methodology to a
more advanced intermediate, suitable for the preparation of the
kainoids and related compounds.
Scheme
2
Reagents and conditions: i, Ph3᎐᎐CHCO2Et or Ph3P᎐
᎐
C(Me)CO2Et, THF, 40 ЊC, R = H 68% or R = Me 72%; ii, DIBAL-H,
PhMe, Ϫ78 ЊC, R = H 67%, R = Me 41%; iii, NaH, THF then MeI, R =
H 96%, R = Me 71%; iv, TFA, CH2Cl2, R = H 96%, R = Me 98%; v,
MsOCH2SnBu3, MeCN, K2CO3, R = H 70%, R = Me 50%.
Scheme 3 Cyclization onto an E-allylic ether.
Alternatively, the products 9 could be obtained using THF as
the solvent, although yields were better in the non-polar solvent
system. The successful cyclization to give the product 9, R =
Me, paves the way for this methodology to be applied to the
kainoid alkaloids. Prior to extending this study to more substi-
tuted systems, we investigated the possibility of cyclization onto
the Z-allylic ether 14 (Scheme 4).
The corresponding Z-isomeric series was accessed from the
same aldehyde 3 using the Still modification of the Horner–
Wadsworth–Emmons reaction with the anion of bis(2,2,2-tri-
fluoroethyl) (ethoxycarbonylmethyl)phosphonate (Scheme 4).10
This reaction gave a low yield (unoptimized) of the product 10,
but as essentially a single Z-stereoisomer (ratio Z : E 20 : 1,
separable by chromatography). Analogous transformations to
those described in Scheme 2 above provided the Z-allylic ether
14.
Scheme 1 Retrosynthesis of α-kainic acid.
Results and discussion
The simplest substrates to test the methodology are the organo-
lithium species derived from tin–lithium exchange of the
stannanes 8 (R = H or Me, Scheme 2). These were prepared
from the known aldehyde 3,8 using Wittig olefination to give the
esters 4 (R = H or Me), reduction with DIBAL-H to give the
allylic alcohols 5 and O-methylation to the allylic ethers 6, fol-
lowed by N-Boc deprotection to the secondary amines 7 and
N-alkylation with O-methanesulfonyltributylstannylmethanol.9
Treatment of the stannanes 8, R = H or Me, with n-BuLi in
hexane–Et2O (10 : 1) at Ϫ78 ЊC, followed by warming to room
temperature gave the pyrrolidine products 9, R = H or Me
(Scheme 3).
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 3
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 2 1 1 1 – 2 1 1 9
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Scheme 6 Reagents and conditions: i, Ph3P᎐CHCO2Me, THF, 40 ЊC,
᎐
72%; ii, MeOCH2C(Me)᎐CHCu(R)CNLi2 (R = Me, hexyl or 2-thienyl),
᎐
TMSCl or BF3ؒOEt2 or HMPA, various temperatures, 0%.
An alternative approach was investigated using the un-
saturated lactam 19, prepared from γ-methyl glutamic acid
according to a reported procedure.15 Formation of different
organocuprate species from the iodide 18 was performed
but these failed to add to the unsaturated lactam 19. A small
amount (22% yield) of the conjugate addition product was
obtained when the N-protecting group was N-COPh rather
than N-Boc (using 10 equivalents of the vinyllithium derived
from 18 and 5 equivalents of CuI in Et2O and TMSCl). More
success was obtained using vinylmagnesium bromide and
CuBr2ؒSMe2 to give the conjugate addition product 20 (Scheme
7).16 Treatment of the product 20 with fluoride ion resulted in
ring-opening of the lactam and formation of the lactone 21.
Unfortunately, all attempts to protect the lactone or to func-
tionalise or deprotect the N-Boc group failed to give identifiable
products or resulted in recovered lactone 21.
Scheme 4 Reagents and conditions: i, (CF3CH2O)2P(O)CH2CO2Me,
KHMDS, THF, 18-crown-6, 22%; ii, DIBAL-H, PhMe, Ϫ78 ЊC, 70%;
iii, NaH, THF then MeI, 85%; iv, TFA, CH2Cl2, 98%; v, MsOCH2-
SnBu3, MeCN, K2CO3, 70%.
Treatment of the Z-allylic ether 14 with n-BuLi in hexane–
Et2O (10 : 1) at Ϫ78 ЊC, followed by warming to room temper-
ature gave the pyrrolidine product 9 (R = H) (Scheme 5).
The yield was essentially identical to that from the E-isomer 8,
R = H, indicating that the geometry of the alkene does not
influence the extent of cyclization.
Scheme 5 Cyclization onto a Z-allylic ether.
For a route to the kainoid alkaloids, we required a substi-
tuted allylic ether such as compound 2 (Scheme 1). On cycliz-
ation, a new chiral centre is generated and the stereochemistry
is dependent upon the existing chiral centres in the substrate.1
Based on literature precedent, it is likely that compound 2
would cyclize to give the incorrect stereoisomer (corresponding
to allokainic acid), although the presence of heteroatom groups
in the substituents, the choice of solvent or the use of a cyclic
substrate which is later cleaved could invert this preference.11
We were therefore interested in determining the stereoselectivity
on cyclization of a substituted allylic ether substrate.
The first route to the kainoid ring system that we studied
commenced with the Garner aldehyde 15 (Scheme 6).12 Wittig
olefination gave the unsaturated ester 16 in high yield. There is
some precedent for conjugate addition in the presence of
Me3SiCl of organocuprates generated from Grignard reagents
or organolithium species to unsaturated esters such as 16.13 For
the preparation of the desired allylic ether 17, we required the
conjugate addition of a vinylmetal species to unsaturated ester
16. The vinyliodide 18 was prepared from the known corre-
sponding alcohol,14 by O-methylation (NaH, THF, MeI, 81%).
We were unable to prepare the Grignard reagent from this iod-
ide using conventional procedures with activated magnesium,
however, iodine–lithium exchange with tert-butyllithium
occurred smoothly. Subsequent formation of a variety of dif-
ferent higher order organocuprates was investigated, but the
resulting organometallic species failed to undergo conjugate
addition to the unsaturated ester 16 under a variety of condi-
tions (different additives and temperatures).
Scheme 7 Reagents and conditions: i, CH2᎐᎐CHMgBr, CuBrؒSMe2,
THF, Ϫ40 ЊC, 72%; ii, TBAF, THF, 100%.
With the failure to provide a suitable substrate starting from
the unsaturated carbonyl compounds 16 and 19, a different
approach was needed. We had shown in our model studies
(Schemes 2,3) that the required allylic ether group could be
introduced by Wittig olefination and reduction. We therefore
required a substituted β-aminoaldehyde such as 23 which would
be converted to the allylic ether 22 (Scheme 8). The choice of a
cyclopentane ring to tether the latent carboxylic acid groups
(which should be accessible by diol cleavage) was made on the
Scheme 8 Alternative retrosynthesis of α-kainic acid.
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 2 1 1 1 – 2 1 1 9
2112

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basis of the expected stereochemical outcome in the anionic
cyclization reaction. Broka and co-workers have shown that
treatment of the stannane 24 with n-butyllithium gave
predominantly the product 25, with a cis-arrangement of the
substituents at C-3 and C-4 of the tetrahydrofuran ring
(Scheme 9).5a We therefore anticipated that the substrate 22
would cyclize to give the desired relative stereochemistry at C-3
and C-4, although a direct comparison is not completely
appropriate as 22 is a cyclopentane whereas 24 is a cyclohexane.
If successful, the product would later require epimerisation at
C-2 (a known process).17
Scheme 9 Cyclization to an oxabicyclo[4.3.0]nonane ring system.
The β-lactam 26 (Scheme 10) was prepared according to the
modified procedure reported by Evans and Biller, using cyclo-
pentadiene and chlorosulfonyl isocyanate in Et2O at Ϫ20 ЊC.18
Ring-opening of the β-lactam with ethanol–HCl gave the
amineؒhydrochloride salt 27, which was protected as the
N-benzoyl derivative 28. Dihydroxylation using catalytic
osmium tetroxide and N-methyl morpholine N-oxide (NMO)
gave a single diol product 29, which was protected as its aceto-
nide 30 using dimethoxypropane in acetone. The relative
stereochemistry of the acetonide was confirmed by NOESY
studies.
Scheme 11 Reagents and conditions: i, LiAlH4, THF, 0 ЊC, 95%; ii,
IBX, DMSO, room temp., 86%; iii, Ph3P᎐C(Me)CO2Et, THF, 40 ЊC,
᎐
89%; iv, NaBH4, CaCl2, EtOH, room temp., 92%; v, NaOH(aq), Bu4NI,
CH2Cl2, Me2SO4, room temp., 93%; vi, NaH, THF, ICH2SnBu3, room
temp., 46%; vii, LiAlH4, AlCl3, Et2O, 0 ЊC, 98%.
34 was carried out under phase-transfer conditions with di-
methylsulfate and tetrabutylammonium iodide in a mixture of
CH2Cl2 and 50% NaOH.19 Finally, N-alkylation with sodium
hydride and iodomethyl tributylstannane in THF gave the
amide 35, which was reduced to the amino-stannane 36 with
alane.
The crucial tin–lithium exchange and cyclization was carried
out with n-butyllithium in hexane–Et2O (4 : 1) at Ϫ78 ЊC, fol-
lowed by warming to room temperature. We were pleased to
find that the desired pyrrolidine products 37 and 38 were
formed in reasonable yield (Scheme 12). To our surprise,
NOESY experiments indicated that the major product was in
fact the stereoisomer 37, contrary to expectations (based on the
formation of the tetrahydrofuran 25, Scheme 9). For example,
irradiation of the signal corresponding to the methyl group of
the 6-isopropenyl group caused an enhancement (3.0%) of the
Scheme 10 Reagents and conditions: i, EtOH, HCl, 96%; ii, PhCOCl,
Et3N, Et2O, 0 ЊC, 85%; iii, 1 mol% OsO4, NMO, H2O, acetone, tBuOH,
room temp., 85%; iv, Me2C(OMe)2, acetone, CSA, 87%.
Reduction of the ester 30 with DIBAL-H (1.1 equiv., PhMe,
Ϫ78 ЊC) gave a mixture of the aldehyde and alcohol products
(and recovered ester 30), so the ester 30 was reduced with
LiAlH4 to give the alcohol 31 and oxidised to the aldehyde 23
with iodoxybenzoic acid (IBX) in DMSO (Scheme 11). Use of
the Swern oxidising system was also successful but gave variable
amounts of the epimeric aldehyde, presumably formed by
enolisation and re-protonation under the mildly basic (Et3N)
conditions.
Wittig olefination of the aldehyde 23 with carboethoxy-
ethylidene triphenylphosphorane gave the unsaturated ester 32,
which was reduced to the allylic alcohol 33 with calcium boro-
hydride. Attempts to use DIBAL-H or LiAlH4 to effect this
transformation gave only low yields of the desired alcohol 33.
Treatment of the alcohol 33 with sodium hydride and iodo-
methane (DMF, 0 ЊC) resulted in the formation of a mixture of
products, so the O-methylation to give the desired allylic ether
Scheme 12 Cyclization to the azabicyclo[3.3.0]octane ring system.
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 2 1 1 1 – 2 1 1 9
2113

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signal for the ring junction proton (at C-6a); other enhance-
ments supported this assignment (irradiation of the vinylic
protons enhanced the signal for the proton at C-6a and for one
of the protons on the NCH2 group; irradiation of the NCH
ring junction proton at C-4a enhanced the same proton on
the NCH2 group and enhanced the proton at C-6a, indicating
that all these protons are on the same face of the molecule). The
major product from this cyclization reaction has trans-stereo-
chemistry across C-3 and C-4, corresponding to allokainic
acid, rather than kainic acid. Attempts to alter the stereo-
selectivity, for example by changing the solvent were unsuccess-
ful (addition of THF or TMEDA gave no isolated products).
If the intramolecular carbolithiation reaction takes place
through a six-membered chair-shaped transition state,1 then
different conformations must be preferred for the two different
cyclizations leading to products 37 and 25. We conclude that
this substrate does not lead to the expected stereoisomer and
we therefore did not take this chemistry further, other than to
show that the N-benzyl group could be cleaved with ethyl
chloroformate, to give the product 39. The chemistry there-
fore allows access to the bicyclic amine 39, related to the
kainoid alkaloids, and this methodology could find application
for the stereoselective synthesis of a variety of substituted
3-alkenylpyrrolidines.
added carbethoxymethylene triphenylphosphorane (1.05 g,
3.0 mmol). After stirring for 48 h, MeOH (2 mL) was added.
The solvent was evaporated and the residue was purified by
column chromatography on silica gel, eluting with petrol–Et2O
(2 : 1), to give the ester 4, R = H (616 mg, 68%) as an oil; Rf 0.34
[petrol–Et2O (2 : 1)]; νmax(film)/cmϪ1 1715 (C᎐O), 1690 (C᎐O),
᎐
᎐
1660 (C᎐C); δ (400 MHz, CDCl ) 7.35–7.15 (5H, m, Ph), 6.85
᎐
H
3
(1H, dt, J 16 and 7, CH᎐CHCO Et), 5.75 (1H, br d, J 16, CH᎐
᎐
᎐
2
CHCO2Et), 4.44 (2H, br s, CH2Ph), 4.15 (2H, q, J 7, OCH2),
3.30 (2H, br s, NCH2CH2), 2.35 (2H, br s, NCH2CH2), 1.45
[9H, br s, C(CH3)3], 1.25 (3H, t, J 7, OCH2CH3); δC(100 MHz,
CDCl3) 167.2, 158.8, 145.4, 138.5, 128.4, 127.6, 127.1, 122.8,
79.8, 60.3, 50.8, 49.9, 31.2, 28.2, 14.1; Found: Mϩ, 333.1940.
C19H27NO4 requires M, 333.1946; m/z 333 (8%, Mϩ), 276 [100,
M Ϫ C(CH3)3].
E-Ethyl N-benzyl-N-tert-butoxycarbonyl-5-amino-2-methyl-2-
pentenoate 4, R ؍ Me
In the same way as the ester 4, R = H, the (crude) aldehyde
3 (2.74 g, 10.0 mmol) and carbethoxyethylidene triphenyl-
phosphorane (4.00 g, 11.0 mmol) gave, after 24 h at 40 ЊC, the
ester 4, R = Me (4.04 g, 72%) as an oil; Rf 0.34 [petrol–Et2O
(2 : 1)]; νmax(film)/cmϪ1 1715 (C᎐O), 1690 (C᎐O), 1670 (C᎐C),
᎐
᎐
᎐
1600 (Ph); δH(300 MHz, CDCl3) 7.35–7.20 (5H, m, Ph), 6.67
(1H, t, J 7, CH᎐C), 4.44 (2H, br s, NCH Ph), 4.15 (2H, q, J 7,
᎐
2
OCH2), 3.25 (2H, br s, NCH2CH2), 2.35 (2H, br s, NCH2CH2),
Conclusions
1.92 (3H, s, C᎐CCH ), 1.47 [9H, br s, C(CH ) ], 1.25 (3H, t, J 7,
᎐
3
3 3
Organolithium species α- to an amino substituent can be
generated by tin–lithium exchange and cyclize onto allylic
ethers to give 3-alkenylpyrrolidine products. The methodology
can be used for the stereoselective synthesis of complex cyclic
amines, including those related to the kainoid natural
products.
OCH2CH3); δC(75 MHz, CDCl3) 167.8, 155.4, 138.1, 129.6,
128.5, 127.7, 127.2, 127.2, 76.8, 60.4, 54.7, 43.4, 28.4, 14.2, 14.1,
12.3; Found: Mϩ, 347.2096. C20H29NO4 requires M, 347.2086;
m/z 347 (0.5%, Mϩ), 57 [100, C(CH3)3].
E-N-Benzyl-N-tert-butoxycarbonyl-5-aminopent-2-en-1-ol 5,
R ؍ H
Experimental
Diisobutylaluminium hydride (12 mL, 1 M in toluene, 12.0
mmol) was added dropwise to the ester 4, R = H (1.0 g,
3.0 mmol) in dry toluene (10 mL) at Ϫ78 ЊC under nitrogen.
After 2.5 h MeOH (4 mL) was added and the mixture was
allowed to warm to room temperature. The mixture was filtered
over Celite and washed with EtOAc (100 mL). The filtrate was
evaporated and the residue was purified by column chromato-
graphy on silica gel, eluting with petrol–EtOAc (1 : 1), to give
the alcohol 5, R = H (550 mg, 63%) as an oil; Rf 0.44 [petrol–
IR spectra were recorded as liquid films on NaCl plates unless
otherwise stated, using a Nicolet FT-IR Magna 550 or a
Perkin–Elmer 881 spectrometer. Optical rotations were
recorded on an AA-1000 polarimeter using a cell of either
0.5 or 0.1 dm path length and are recorded in 10Ϫ1 deg cm2 gϪ1.
Elemental analyses were recorded on a Carlo Erba EA1110
elemental analyser. 1H NMR spectra were recorded on a Bruker
AM 300 MHz or a Bruker DRX 400 MHz spectrometer using
the residual solvent peak as an internal reference. Chemical
shifts are given in parts per million. Coupling constants, J,
are given in Hz. 13C NMR spectra are recorded on the above
spectrometers operating at 75 or 100 MHz respectively and are
proton decoupled. Additional analysis by DEPT, COSY,
NOESY or HMQC experiments were performed where neces-
sary. Mass spectra were recorded on a Kratos Profile HV3 or a
Micromass Quattro II spectrometer or a ThermoQuest AS2000
GCMS machine, using electron impact, chemical ionisation or
electrospray techniques. Accurate mass measurements were per-
formed on the Kratos Profile spectrometer, a Finnigan MAT
900 XLT spectrometer or a Micromass Autospec spectrometer.
Petrol refers to light petroleum (bp 40–60 ЊC). Tetrahydro-
furan (THF) and diethyl ether (Et2O) were distilled from
sodium–benzophenone. Flash column chromatography was
performed on silica gel (Merck 60H, 230–400 mesh) or basic
aluminium oxide (Sigma type WB-2, activity grade 1). Thin
layer chromatography was performed on Kieselgel 60F254
0.25 mm plates, and visualised by UV irradiation at 254 nm or
alkaline potassium permanganate.
EtOAc (1 : 1)]; νmax(film)/cmϪ1 3610 (OH), 1690 (C᎐O), 1660
᎐
(C᎐C), 1600 (Ph); δ (400 MHz, CDCl ) 7.33–7.21 (5H, m, Ph),
᎐
H
3
5.60 (2H, br s, CH᎐CH), 4.42 (2H, br s, NCH Ph), 4.05 (2H,
᎐
2
br s, CH2O), 3.20 (2H, br s, NCH2CH2), 2.24 (2H, br s,
NCH2CH2), 1.47 [9H, br s, C(CH3)3]; δC(100 MHz, CDCl3)
155.8, 138.5, 131.1, 129.1, 128.6, 128.0, 127.1, 79.7, 63.5, 50.7,
50.2, 31.4, 28.4; Found: Mϩ, 291.1834. C17H25NO3 requires M,
291.1828; m/z 291 (1%, Mϩ), 57 [100, C(CH3)3].
E-N-Benzyl-N-tert-butoxycarbonyl-5-amino-2-methylpent-2-en-
1-ol 5, R ؍ Me
In the same way as the alcohol 5, R = H, diisobutylaluminium
hydride (23.5 mL, 1 M in toluene, 23.5 mmol) and the ester 4,
R = Me (2.0 g, 5.76 mmol) gave, after purification by column
chromatography on silica gel, eluting with petrol–EtOAc (1 : 1),
the alcohol 5, R = Me (1.49 g, 85%) as an oil; Rf 0.44 [petrol–
EtOAc (1 : 1)]; νmax(film)/cmϪ1 3610 (OH), 1690 (C᎐O), 1670
᎐
(C᎐C), 1600 (Ph); δ (300 MHz, CDCl ) 7.35–7.15 (5H, m, Ph),
᎐
H
3
5.32 (1H, br s, CH᎐C), 4.45 (2H, br s, NCH Ph), 3.55 (2H, br s,
᎐
2
CH2O), 3.25 (2H, br d, J 7, NCH2CH2), 2.25 (2H, br s,
NCH CH ), 1.65 (3H, s, C᎐CCH ), 1.45 [9H, br s, C(CH ) ];
᎐
2
2
3
3 3
E-Ethyl N-benzyl-N-tert-butoxycarbonyl-5-amino-2-pentenoate
4, R ؍ H
To the freshly prepared crude aldehyde 38 (722 mg, 2.7 mmol)
δC(75 MHz, CDCl3) 155.8, 138.5, 131.1, 129.6, 129.1, 128.9,
121.9, 79.7, 68.5, 58.4, 53.5, 30.2, 28.4, 14.2; Found: Mϩ,
305.1990. C18H27NO3 requires M, 305.2001; m/z 305 (1%, Mϩ),
t
in dry THF (7 mL) under nitrogen at room temperature was
304 (28, M Ϫ CO2 Bu), 57 [100, C(CH3)3].
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 2 1 1 1 – 2 1 1 9
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E-N-Benzyl-N-tert-butoxycarbonyl-5-amino-1-methoxypent-2-
ene 6, R ؍ H
CDCl3) 138.5, 131.1, 128.6, 127.1, 126.8, 121.9, 79.7, 68.5, 58.4,
50.5, 30.2, 14.2; Found: Mϩ, 219.1615. C14H21NO requires M,
219.1623; m/z 219 (12%, Mϩ), 91 (100, PhCH2); Found: C, 76.9;
H, 9.65; N, 6.4. C14H21NO requires C, 76.7; H, 9.55; N, 6.4%.
Sodium hydride (83 mg, 2.1 mmol, 60% dispersion in mineral
oil) was added to the alcohol 5, R = H (530 mg, 1.8 mmol)
in dry THF (5 mL) under nitrogen. After 1.5 h, iodomethane
(0.19 mL, 3.04 mmol) was added and after a further 30 min,
water (5 mL) was added and the mixture was extracted with
CH2Cl2 (3 × 25 mL). The combined extracts were dried
(MgSO4), evaporated and purified by column chromatography
on silica gel, eluting with petrol–EtOAc (4 : 1), to give the ether
6, R = H (556 mg, 96%) as an oil; Rf 0.21 [petrol–EtOAc
(10 : 1)]; νmax(film)/cmϪ1 1690 (C᎐O), 1660 (C᎐C), 1600 (Ph);
E-N-Benzyl-N-tributylstannylmethyl-5-amino-1-methoxy-
pent-2-ene 8, R ؍ H
Potassium carbonate (315 mg, 2.28 mmol) was added to the
amine 7, R = H (236 mg, 1.14 mmol) in dry acetonitrile (5 mL)
under nitrogen at room temperature. After 5 min, tributyl-
stannylmethyl methanesulfonate9 (545 mg, 1.40 mmol) was
added. After 24 h water (10 mL) was added and the mixture was
extracted with CH2Cl2 (2 × 20 mL). The combined extracts
were dried (MgSO4), evaporated and purified by column
chromatography on silica gel, eluting with petrol–EtOAc
(10 : 1), to give the stannane 8, R = H (403 mg, 70%) as an oil;
᎐
᎐
δH(300 MHz, CDCl3) 7.35–7.15 (5H, m, Ph), 5.60–5.52 (2H, m,
CH᎐CH), 4.43 (2H, br s, NCH Ph), 3.85 (2H, br s, CH O),
᎐
2
2
3.28–3.21 (5H, m, NCH2CH2 and OCH3), 2.25 (2H, br s,
NCH2CH2), 1.48 [9H, br s, C(CH3)3]; δC(75 MHz, CDCl3)
155.7, 138.5, 130.8, 129.3, 128.3, 127.7, 127.5, 79.7, 73.0, 70.2,
58.5, 50.1, 46.3, 28.4; Found: Mϩ 305.1990. C18H27NO3 requires
Rf 0.24 [petrol–EtOAc (10 : 1)]; νmax(film)/cmϪ1 1675 (C᎐C),
᎐
1605 (Ph); δH(300 MHz, CDCl3) 7.36–7.21 (5H, m, Ph),
5.72–5.50 (2H, m, CH᎐CH), 3.88 (2H, d, J 8, NCH Ph),
t
M, 305.2001; m/z 305 (1%, Mϩ), 205 (32, M Ϫ CO2 Bu), 57 [100,
᎐
2
C(CH3)3].
3.51 (2H, s, CH2O), 3.33 (3H, s, OCH3), 2.64 (2H, s, NCH2-
Sn), 2.46–2.19 (4H, m, NCH2CH2), 1.68–0.80 {27H, m,
Sn[(CH2)3CH3]3}; δC(75 MHz, CDCl3) 139.9, 132.5, 128.7,
128.1, 127.2, 126.7, 73.2, 62.8, 57.6, 54.8, 42.9, 32.2, 29.2, 27.8,
13.6, 10.2; Found: Mϩ 509.2669. C26H47NO120Sn requires M,
509.2679; m/z 509 (0.5%, Mϩ), 218 [24, M Ϫ Sn(C4H9)3], 31
(100, OCH3).
E-N-Benzyl-N-tert-butoxycarbonyl-5-amino-2-methyl-1-
methoxypent-2-ene 6, R ؍ Me
In the same way as the ether 6, R = H, sodium hydride (354 mg,
8.85 mmol), the alcohol 5, R = Me (1.79 g, 5.9 mmol) and
iodomethane (0.72 mL, 12.0 mmol) gave, after purification by
column chromatography on silica gel, eluting with petrol–
EtOAc (4 : 1), the ether 6, R = Me (1.33 g, 71%) as an oil; Rf
E-N-Benzyl-N-tributylstannylmethyl-5-amino-2-methyl-1-
methoxypent-2-ene 8, R ؍ Me
0.25 [petrol–EtOAc (10 : 1)]; νmax(film)/cmϪ1 1690 (C᎐O), 1660
᎐
(C᎐C), 1605 (C᎐C); δ (300 MHz, CDCl ) 7.35–7.15 (5H, m,
In the same way as the stannane 8, R = H, potassium carbonate
(126 mg, 2.28 mmol), the amine 7, R = Me (250 mg, 1.14 mmol)
and tributylstannylmethyl methanesulfonate (470 mg, 1.21
mmol) gave, after purification by column chromatography on
silica gel, eluting with petrol–EtOAc (10 : 1), the stannane 8,
R = Me (298 mg, 50%) as an oil; Rf 0.23 [petrol–EtOAc (10 : 1)];
᎐
᎐
H
3
Ph), 5.32 (1H, br s, CH᎐C), 4.45 (2H, br s, NCH Ph), 3.55 (2H,
᎐
2
br s, CH2O), 3.25–3.19 (5H, m, NCH2CH2 and OCH3), 2.25
(2H, br s, NCH CH ), 1.63 (3H, s, C᎐CCH ), 1.49 [9H, br s,
᎐
2
2
3
C(CH3)3]; δC(75 MHz, CDCl3) 155.8, 138.5, 131.1, 129.7, 128.6,
127.1, 121.3, 79.7, 68.5, 58.4, 53.5, 50.5, 30.2, 28.4, 14.2; Found:
Mϩ, 319.2105. C19H29NO3 requires M, 319.2114; m/z 319 (1%,
νmax(film)/cmϪ1 1675 (C᎐C), 1600 (Ph); δ (300 MHz, CDCl )
᎐
H
3
Mϩ), 318 (46, M Ϫ CO2 Bu), 57 [100, C(CH3)3].
7.42–7.20 (5H, m, Ph), 5.46 (1H, t, J 7, CH᎐C), 3.79 (2H, s,
t
᎐
NCH2Ph), 3.47 (2H, s, CH2O), 3.35 (3H, s, OCH3), 2.61 (2H, s,
NCH2Sn), 2.42–2.31 (2H, m, NCH2CH2), 2.28–2.20 (2H, m,
E-N-Benzyl-5-amino-1-methoxypent-2-ene 7, R ؍ H
NCH CH ), 1.62 (3H, s, C᎐CCH ), 1.50–0.80 {27H, m,
᎐
2
2
3
Trifluoroacetic acid (0.25 mL, 3.6 mmol) was added to the ether
6, R = H (358 mg, 1.2 mmol) in dry CH2Cl2 (4 mL) under
nitrogen at 0 ЊC and the mixture was allowed to warm to room
temperature. After 16 h NaHCO3 (10 mL) was added, the
organic phase was dried (MgSO4), evaporated and purified by
column chromatography on silica gel, eluting with CH2Cl2–
EtOH (15 : 1), to give the amine 7, R = H (236 mg, 95%) as
needles after recrystallisation from Et2O; mp 145–146 ЊC; Rf
0.24 [CH2Cl2–EtOH (15 : 1)]; νmax(film)/cmϪ1 3490 (NH), 1660
Sn[(CH2)3CH3]3}; δC(75 MHz, CDCl3) 139.1, 132.8, 128.7,
128.1, 126.1, 121.9, 78.6, 62.6, 57.5, 54.2, 42.8, 29.3, 27.5, 26.0,
13.8, 10.2, 8.5; Found: Mϩ, 523.2841. C27H49NO120Sn requires
M, 523.2836; m/z 523 (1%, Mϩ), 291 [42, Sn(C4H9)3], 31 (100,
OCH3).
N-Benzyl-3-vinylpyrrolidine 9, R ؍ H
n-Butyllithium (0.59 mL, 1.47 mmol, 2.5 M in hexanes) was
added to the stannane 8, R = H (375 mg, 0.74 mmol) in hexane–
Et2O (7.5 mL, 10 : 1) at Ϫ78 ЊC. The mixture was warmed
slowly to room temperature and then was cooled to Ϫ78 ЊC and
MeOH (0.2 mL) was added. The solvent was evaporated and
the residue was purified by column chromatography on silica
gel, eluting with petrol–EtOAc (4 : 1), to give the pyrrolidine 9,
R = H (112 mg, 81%) as an oil; Rf 0.13 [petrol–EtOAc (4 : 1)];
(C᎐C), 1600 (Ph); δ (300 MHz, CDCl ) 7.39–7.30 (5H, m, Ph),
᎐
H
3
5.61–5.53 (2H, m, CH᎐CH), 3.98 (2H, d, J 6, CH O), 3.63 (2H,
᎐
2
br s, NCH2Ph), 3.28 (3H, s, OCH3), 2.86 (2H, br s, NCH2CH2),
2.32–2.27 (2H, m, CH CH C᎐C); δ (75 MHz, CDCl ) 140.4,
᎐
2
2
C
3
131.9, 129.3, 128.1, 127.6, 126.9, 73.0, 57.7, 53.9, 48.5, 32.8;
Found: Mϩ 205.1467. C13H19NO requires M, 205.1466; m/z 205
(1%, Mϩ), 91 (100, M Ϫ CH2Ph); Found: C, 75.8; H, 9.2; N, 6.8.
C13H19NO requires C, 76.0; H, 9.3; N, 6.8%.
νmax(film)/cmϪ1 1660 (C᎐C), 1600 (Ph); δ (300 MHz, CDCl )
᎐
H
3
7.33–7.21 (5H, m, Ph), 5.85–5.78 (1H, ddd, J 17, 10 and 7.5,
E-N-Benzyl-5-amino-2-methyl-1-methoxypent-2-ene 7, R ؍ Me
CH᎐CH ), 4.98 (1H, dd, J 17 and 1.5, CH᎐CHAHB), 4.91 (1H,
᎐
᎐
2
dd, J 10 and 1.5, CH᎐CHAHB), 3.63 (2H, ABq, J 16, NCH Ph),
᎐
2
In the same way as the amine 7, R = H, trifluoroacetic acid
(0.96 mL, 12.5 mmol) and the ether 6, R = Me (1.0 g, 3.13
mmol) gave, after purification by column chromatography on
silica gel, eluting with CH2Cl2–EtOH (15 : 1), the amine 7,
R = Me (652 mg, 95%) as needles; mp 130–131 ЊC; Rf 0.31 [CH2-
2.89–2.69 (3H, m, CH2NCH), 2.56–2.46 (1H, m, CH), 2.29–
2.18 (1H, m, CH), 2.14–2.00 (1H, m, CH), 1.65–1.56 (1H, m,
CH); δC(75 MHz, CDCl3) 155.7, 141.7, 128.9, 128.7, 127.0,
113.5, 60.5, 59.9, 53.9, 41.8, 28.4; Found: Mϩ 187.1362.
C13H17N requires M, 187.1361); m/z 187 (4%, Mϩ), 77 (100, Ph).
Cl2–EtOH(15:1)];νmax(KBr)/cmϪ1 3540(NH), 1670(C᎐C), 1605
᎐
(Ph); δH(300 MHz, CDCl3) 7.35–7.15 (6H, m, Ph and NH), 5.32
N-Benzyl-3-isopropenylpyrrolidine 9, R ؍ Me
(1H, br s, CH᎐C), 4.45 (2H, br s, NCH Ph), 3.55 (2H, br s,
᎐
2
CH2O), 3.24 (3H, s, OCH3), 2.76 (2H, br s, NCH2CH2), 2.59–
In the same way as the pyrrolidine 9, R = H, n-butyllithium
(0.3 mL, 0.76 mmol) and the stannane 8, R = Me (200 mg, 0.38
2.53 (2H, m, NCH CH ), 1.63 (3H, s, C᎐CCH ); δ (75 MHz,
᎐
2
2
3
C
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 2 1 1 1 – 2 1 1 9
2115

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mmol) gave, after purification by column chromatography on
silica gel, eluting with petrol–EtOAc (4 : 1), the pyrrolidine 9,
R = Me (49 mg, 64%) as an oil; Rf 0.16 [petrol–EtOAc (4 : 1)];
305.2001. C18H27NO3 requires M, 305.1990; m/z 305 (4%, Mϩ),
57 [100, C(CH3)3].
νmax(film)/cmϪ1 1660 (C᎐C); δ (300 MHz, CDCl ) 7.41–7.20
Z-N-Benzyl-5-amino-1-methoxypent-2-ene 13
᎐
H
3
(5H, m, Ph), 4.74 (1H, s, C᎐CH), 4.69 (1H, s, C᎐CH), 3.63 (2H,
᎐
᎐
In the same way as the amine 7, R = H, trifluoroacetic acid
(0.116 mL, 1.5 mmol) and the ether 12 (230 mg, 0.75 mmol)
gave, after purification by column chromatography on silica gel,
eluting with CH2Cl2–EtOH (15 : 1), the amine 13 (154 mg, 99%)
as an oil; Rf 0.24 [CH2Cl2–EtOH (15 : 1)]; νmax(film)/cmϪ1 3255
ABq, J 13, NCH2Ph), 2.91–2.71 (3H, m, 3 × CH), 2.55–2.46
(1H, m, CH), 2.37–2.28 (1H, m, CH), 2.10–1.94 (1H, m, CH),
1.80–1.69 (1H, m, CH), 1.74 (3H, s, CH3); δC(75 MHz, CDCl3)
147.4, 139.4, 128.7, 128.1, 126.8, 109.1, 60.7, 58.6, 54.2,
44.7, 29.3, 20.7; Found: Mϩ, 201.1517. C14H19N requires M,
201.1518; m/z 201 (11%, Mϩ), 77 (100, Ph).
(NH), 1670 (C᎐C); δH(300 MHz, CDCl3) 7.39–7.32 (5H, m, Ph),
᎐
5.90–5.80 (1H, m, C᎐CH), 5.65–5.50 (1H, m, CH᎐C), 4.18 (2H,
᎐
᎐
s, NCH2Ph), 3.95 (2H, d, J 6, CH2O), 3.28 (3H, s, OCH3), 3.12
(2H, q, J 6, NCH2CH2), 2.52 (2H, t, J 7, NCH2CH2); δC(75
MHz, CDCl3) 130.1, 129.6, 129.5, 129.4, 129.0, 127.9, 68.2,
57.9, 52.3, 46.2, 22.7; Found: Mϩ 205.2851. C13H18NO requires
M, 205.2868; m/z 205 (7%, Mϩ), 77 (100, Ph).
Z-Methyl N-benzyl-N-tert-butoxycarbonyl-5-amino-2-
pentenoate 10
To a suspension of potassium hydride (1.18 g, 35% dispersion
in mineral oil, 10.4 mmol) in dry THF (10 mL) was added
hexamethyldisilazane (2.18 mL, 10.4 mmol) at 0 ЊC under
argon. The mixture was cooled to Ϫ78 ЊC and a solution of
18-crown-6 (12.9 g, 50.0 mmol) and bis(2,2,2-trifluoro-
ethyl)(ethoxycarbonylmethyl)phosphonate10 (2.8 g, 10.0 mmol)
in dry THF (20 mL) was added. After 10 min, the aldehyde
3 (2.48 g, 9.50 mmol) in dry THF (5 mL) was added. After
30 min, NH4Cl (20 mL) was added and the mixture was allowed
to warm to room temperature and was extracted with Et2O
(3 × 40 mL). The combined extracts were dried (MgSO4), evap-
orated and purified by column chromatography on silica gel,
eluting with petrol–EtOAc (4 : 1), to give the ester 10 (670 mg,
22%) as an oil; Rf 0.21 [petrol–EtOAc (4 : 1)]; νmax(film)/cmϪ1
Z-N-Benzyl-N-tributylstannylmethyl-5-amino-1-methoxypent-2-
ene 14
In the same way as the stannane 8, R = H, the amine 13
(236 mg, 1.15 mmol) and tributylstannylmethyl methane-
sulfonate9 (545 mg, 1.40 mmol) gave, after purification by
column chromatography on silica gel, eluting with petrol–
EtOAc (10 : 1), the stannane 14 (403 mg, 69%) as an oil; Rf 0.24
[petrol–EtOAc (10 : 1)]; νmax(film)/cmϪ1 1675 (C᎐C), 1605 (Ph);
᎐
δH(300 MHz, CDCl3) 7.21–7.36 (5H, m, Ph), 5.50–5.72 (2H, m,
CH᎐CH), 4.41–4.28 (2H, m, PhCH N), 4.06 (2H, d, J 7,
᎐
2
CH2O), 3.85 (2H, br s, NCH2CH2), 3.49 (2H, t, J 7, NCH2CH2),
3.40 (3H, s, OCH3), 2.61 (2H, s, SnCH2N), 1.68–0.80 {27H, m,
Sn[(CH2)3CH3]3}; δC(75 MHz, CDCl3) 139.8, 131.3, 128.7,
128.1, 126.9, 126.8, 68.2, 62.8, 57.8, 57.5, 42.9, 29.2, 27.4, 26.7,
13.6, 12.1; Found: Mϩ 509.2669. C26H47NO120Sn requires M,
509.2679); m/z 509 (0.5%, Mϩ), 291 [20, Sn(C4H9)3], 31 (100,
OCH3).
1720 (C᎐O), 1695 (C᎐O), 1650 (C᎐C), 1605 (Ph); δ (75 MHz,
᎐
᎐
᎐
C
CDCl ) 7.31–7.10 (5H, m, Ph), 6.24 (1H, d, J 11.5, C᎐CH),
᎐
3
5.79 (1H, dt, J 11.5 and 1.5, CH᎐C), 4.47 (2H, s, NCH Ph),
᎐
2
3.65 (3H, s, OCH3), 3.29 (2H, br s, NCH2CH2), 2.95–2.80 (2H,
m, NCH2CH2), 1.48 [9H, br s, C(CH3)3]; δC(75 MHz, CDCl3)
166.7, 156.7, 146.8, 138.7, 129.3, 128.4, 127.1, 120.9, 70.9,
55.0, 50.3, 45.2, 28.4, 15.4; Found: Mϩ, 319.1784. C18H25-
NO4 requires M, 319.1783; m/z 319 (8%, Mϩ), 219 (33,
(4S,5S )-N-tert-Butoxycarbonyl-5-tert-butyldimethylsiloxy-
methyl-4-vinyl-1,5-dihydro-2H-pyrrol-2-one 20
t
M Ϫ CO2 Bu), 57 [100, C(CH3)3].
Vinylmagnesium bromide (13.1 mL, 13 mmol, 1.0 M in THF)
was added to a suspension of CuBrؒSMe2 (1.34 g, 6.55 mmol)
in dry THF (20 mL) at Ϫ40 ЊC under argon. The black suspen-
sion was stirred at Ϫ40 ЊC for 30 min and then was cooled to
Ϫ78 ЊC. The lactam 19 (320 mg, 0.97 mmol) in dry THF (5 mL)
and chlorotrimethylsilane (0.40 mL, 2.93 mmol) were added.
The mixture was stirred at Ϫ78 ЊC for 1 h, diluted with Et2O (50
mL) and quenched with NH4Cl (20 mL). This mixture was
allowed to warm to room temperature and was extracted with
NH4Cl (3 × 20 mL). The organic phase was dried (MgSO4),
evaporated and purified by column chromatography on silica
gel, eluting with petrol–EtOAc (4 : 1), to give the lactam 20
(240 mg, 61%) as an oil; Rf 0.6 [petrol–EtOAc (4 : 1)]; [α]2D5
Ϫ14.2 (c 1.0, CHCl3); νmax(film)/cmϪ1 1725 (C᎐O), 1695 (C᎐O),
Z-N-Benzyl-N-tert-butoxycarbonyl-5-aminopent-2-en-1-ol 11
In the same way as the alcohol 5, R = H, diisobutylaluminium
hydride (2.7 mL, 1.5 M in toluene, 4.05 mmol) and the ester 10
(420 mg, 1.32 mmol) gave, after purification by column chrom-
atography on silica gel, eluting with petrol–EtOAc (2 : 1),
the alcohol 11 (268 mg, 70%) as an oil; Rf 0.35 [petrol–EtOAc
(1 : 1)]; νmax(film)/cmϪ1 3215 (OH), 1720 (C᎐O), 1670 (C᎐C),
᎐
᎐
1600 (Ph); δH(300 MHz, CDCl3) 7.36–7.10 (5H, m, Ph), 5.72–
5.55 (1H, m, CH᎐C), 5.45–5.39 (1H, m, C᎐CH), 4.41 (2H, s,
᎐
᎐
NCH2Ph), 4.13 (2H, d, J 6.5, CH2O), 3.23–3.18 (2H, m,
NCH2CH2), 2.28–2.24 (2H, m, NCH2CH2), 1.49 [9H, br s,
(CH3)3]; δC(75 MHz, CDCl3) 160.7, 138.4, 131.0, 129.7, 129.1,
128.5, 127.2, 79.9, 68.9, 58.2, 46.1, 28.4, 26.2; Found: MHϩ
292.1903. C17H25NO3 requires M, 292.1912; m/z 292 (8%,
᎐
᎐
1660 (C᎐C); δ (300 MHz, CDCl ) 5.91–5.81 (1H, m, CH᎐CH ),
᎐
᎐
H
3
2
MHϩ), 191 (62, M Ϫ CO2 Bu), 57 [100, C(CH3)3].
t
5.12–5.05 (2H, m, CH᎐CH ), 3.94 (1H, dd, J 16 and 7,
᎐
2
CHAHBO), 3.91–3.88 (1H, m, NCH), 3.75 (1H, dd, J 16 and 7,
CHAHBO), 2.95–2.89 (2H, m, O᎐CCHAHB and CHCH᎐C),
Z-N-Benzyl-N-tert-butoxycarbonyl-5-amino-1-methoxypent-2-
ene 12
᎐
᎐
2.31–2.26 (1H, m, O᎐CCHAHB), 1.53 [9H, s, C(CH ) ], 1.42
᎐
3 3
[9H, s, C(CH3)3], 0.04 [6H, s, Si(CH3)2]; δC(75 MHz, CDCl3)
173.7, 150.5, 139.3, 115.0, 82.8, 64.4, 63.3, 38.0, 37.1, 28.1, 25.9,
18.1, Ϫ5.5; Found: Mϩ, 355.2184. C18H33NO4Si requires M,
In the same way as the ether 6, R = H, sodium hydride (43 mg,
1.08 mmol), the alcohol 11 (260 mg, 0.89 mmol) and iodo-
methane (253 mg, 1.78 mmol) gave, after purification by
column chromatography on silica gel, eluting with petrol–
EtOAc (4 : 1), the ether 12 (230 mg, 85%) as an oil; Rf 0.48 [pet-
rol–EtOAc (4 : 1)]; νmax(film)/cmϪ1 1690 (C᎐O), 1665 (C᎐C),
355.2179; m/z 355 (10%, Mϩ), 254 (35, M Ϫ CO2 Bu), 57 [100,
t
C(CH3)3].
᎐
᎐
(4S,5S )-N-tert-Butoxycarbonyl-5-amino-4-vinyl-2-pyrone 21
1605 (Ph); δH(300 MHz, CDCl3) 7.34–7.16 (5H, m, Ph), 5.61–
5.49 (2H, m, CH᎐CH), 4.48 (2H, s, NCH Ph), 3.91 (2H, d,
Tetrabutylammonium fluoride (1.8 mL, 1.8 mmol, 1.0 M in
THF) was added to the lactam 20 (160 mg, 0.45 mmol) in dry
THF (2 mL) at 0 ЊC under nitrogen and the mixture was stirred
at room temperature for 4 days. The solvent was evaporated,
CH2Cl2 (10 mL) was added and the organic phase was washed
᎐
2
J 5.5, CH2O), 3.30 (3H, s, OCH3), 3.27–3.21 (2H, m,
NCH2CH2), 2.27–2.23 (2H, m, NCH2CH2), 1.49 [9H, s, (CH3)3];
δC(75 MHz, CDCl3) 160.7, 138.5, 129.7, 129.7, 128.5, 127.6,
127.2, 79.7, 67.9, 57.9, 51.2, 46.4, 28.4, 26.4; Found: Mϩ
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 2 1 1 1 – 2 1 1 9
2116

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with NH4Cl (3 × 10 mL). The organic phase was dried
(MgSO4), evaporated and purified by column chromatography
on silica gel, eluting with Et2O, to give the lactone 21 (108 mg,
100%) as needles; mp 55–56 ЊC; Rf 0.31 (Et2O); [α]2D5 Ϫ32.0
was evaporated. The residue was extracted with CH2Cl2 (3 ×
25 mL), the organic extracts were dried (MgSO4) and evapor-
ated to give the crude solid, which was recrystallised from
CH2Cl2 to give the diol 29 (1.92 g, 85%) as needles; mp 129–130
ЊC; Rf 0.47 [CH2Cl2–MeOH (9 : 1)]; νmax(film)/cmϪ1 3300 (OH)
(c 0.5, CHCl3); νmax(film)/cmϪ1 3675 (NH), 1735 (C᎐O), 1695
᎐
(C᎐O), 1625 (C᎐C); δ (300 MHz, CDCl ) 5.92 (1H, br s, NH),
and (NH), 1730 (C᎐O), 1535 (C᎐O); δ (400 MHz, CDCl ) 1.27
᎐ ᎐
H 3
᎐
᎐
H
3
5.76 (1H, dt, J 8 and 2, CH᎐CH ), 5.14–5.06 (2H, m, CH᎐CH ),
(3H, t, J 7, OCH2CH3), 2.16–2.30 (2H, m, CH2CHCO), 3.19
(1H, s, OH), 3.47 (1H, q, J 9, CHCO), 4.09–4.12 (1H, m,
CHOH), 4.16–4.22 (3H, m, OCH2CH3 and CHOH), 4.55–4.63
(1H, m, CHN), 5.01 (1H, s, OH), 7.42–7.80 (5H, m, Ph), 8.05
(1H, br d, J 8, NH); δC(100 MHz, CDCl3) 14.1, 34.6, 41.0, 56.7,
61.4, 70.4, 80.1, 127.0, 128.7, 131.9, 133.4, 169.1, 175.2; Found:
Mϩ, 293.1252. C15H19NO5 requires M, 293.1263; m/z 293 (1%,
Mϩ), 105 (100, PhCO); Found: C, 61.3; H, 6.45; N, 4.65.
C15H19NO5 requires C, 61.4; H, 6.55; N, 4.8%.
᎐
᎐
2
2
4.28 (1H, dd, J 8 and 3.3, OCHAHB), 3.89 (1H, dd, J 8 and 4.2
OCHAHB), 3.63 (1H, dt, J 7.5 and 3.3, CHN), 2.76 (1H, quin-
tet, J 8.5, CHCH᎐C), 2.55 (1H, dd, J 8 and 8.5, O᎐CCHAHB),
᎐
᎐
2.27 (1H, dd, J 8 and 8.5, O᎐CCHAHB), 1.48 [9H, s, C(CH ) ];
᎐
3
3
δC(75 MHz, CDCl3) 176.0, 153.2, 137.0, 117.3, 82.9, 67.9, 58.2,
41.5, 36.1, 27.7; Found: MHϩ, 242.1314. C12H20NO4 requires
MH, 242.1315; m/z 242 (9%, MHϩ), 57 [100, C(CH3)3]; Found:
C, 59.8; H, 7.9; N, 5.8. C12H19NO4 requires C, 59.75; H, 7.95;
N, 5.8%.
(3aR,4SR,5SR,6aS )-Ethyl 4-(benzoylamino)-2,2-dimethyl-
tetrahydrocyclopenta[1,3]dioxole-5-carboxylate 30
(1SR,2RS )-Ethyl 2-aminocyclopent-3-enecarboxylate
hydrochloride 27
The diol 29 (13.34 g, 45 mmol) was added to (1R)-(Ϫ)-10-cam-
phorsulfonic acid (211 mg, 0.91 mmol) and 2,2-dimethoxy-
propane (42.6 g, 409 mmol) in anhydrous acetone (500 mL) at
room temperature. After 1 h NaHCO3 (3 g, 36 mmol) was
added and the mixture was filtered through silica gel, eluting
with petrol–EtOAc (1 : 1). The solvent was evaporated and
the residue was recrystallised from Et2O to give the ester 30
(13.28 g, 87%) as needles; mp 175–177 ЊC; Rf 0.53 [petrol–
Hydrogen chloride (prepared from addition of concentrated
sulfuric acid to anhydrous ammonium chloride) was bubbled
through a solution of the lactam 2618 (9.75 g, 89 mmol) in
EtOH (100 mL) at Ϫ20 ЊC for 30 min. After 2 h at room tem-
perature, the solvent was evaporated and the residue was
recrystallised from EtOH to give the hydrochloride salt of
the ester 27 (16.42 g, 96%) as needles; mp 175–176 ЊC; Rf
0.30 [CH2Cl2 Ϫ MeOH (9 : 1)]; νmax(film)/cmϪ1 3100 (NH), 1725
EtOAc (1 : 1)]; νmax(film)/cmϪ1 3300 (NH), 1730 (C᎐O), 1550
᎐
A
B
(C᎐O), 1640 (C᎐C); δ (400 MHz, MeOD) 1.30 (3H, t, J 7,
(C᎐O); δ (400 MHz, CDCl ) 1.24–1.28 [6H, m, C(CH )CH
᎐
H 3 3 3
A B
᎐
᎐
H
OCH CH ), 2.78–2.82 (2H, m, CH᎐CHCH ), 3.50 (1H, q, J 8,
and OCH2CH3], 1.48 [3H, s, C(CH3 )CH3 ], 2.17–2.24 (2H,
m, CH2CHCO, 3.32–3.39 (1H, m, CHCO), 4.14–4.21 (2H, m,
OCH2CH3), 4.46 (1H, t, J 6, CHN), 4.72–4.75 (2H, m, HOCH-
CHOH), 7.05 (1H, br d, J 6, NH), 7.39–7.77 (5H, m, Ph);
δC(100 MHz, CDCl3) 14.1, 23.8, 26.2, 35.3, 42.8, 58.0, 61.4,
78.7, 84.7, 110.3, 126.9, 128.6, 131.7, 134.0, 167.3, 173.7;
Found: Mϩ, 333.1579. C18H23NO5 requires M, 333.1576; m/z
333 (1%, Mϩ), 105 (100, PhCO); Found: C, 64.8; H, 7.1; N, 4.1.
C18H23NO5 requires C, 64.85; H, 6.95; N, 4.2%.
᎐
2
3
2
CHCO2Et), 4.17–4.31 (2H, m, OCH2CH3), 4.39–4.41 (1H, m,
CHN), 5.84–5.86 (1H, m, CH᎐C), 6.27–6.29 (1H, m, C᎐CH);
᎐
᎐
δC(100 MHz, MeOD) 13.0, 34.3, 43.4, 55.8, 61.1, 126.3, 138.1,
171.7; Found: MHϩ Ϫ HCl, 156.1024. C8H14NO2 requires M,
156.1024; m/z 156 (100%, MHϩ Ϫ HCl), 82 [100, M Ϫ (HCl ϩ
CO2Et)]; Found: C, 50.05; H, 7.45; N, 7.15. C8H14NO2Cl
requires C, 50.25; H, 7.4; N, 7.30%.
(1SR,2RS )-Ethyl 2-(benzoylamino)cyclopent-3-enecarboxylate
28
(3aR,4SR,5SR,6aS )-N-[5-(Hydroxymethyl)-2,2-dimethyl-
tetrahydrocyclopenta[1,3]dioxol-4-yl]benzamide 31
Benzoyl chloride (13.2 g, 94 mmol) was added to Et3N (17.4 g,
172 mmol) and the hydrochloride salt 27 (15 g, 78 mmol) in
Et2O (500 mL) at 0 ЊC. After 18 h, water (250 mL) was added
and the mixture was extracted with Et2O (3 × 100 mL). The
combined Et2O extracts were washed with saturated NaHCO3
(2 × 100 mL), water (2 × 100 mL), brine (100 mL), dried
(MgSO4) and filtered. The solvent was evaporated and the solid
residue was recrystallised from Et2O to give the ester 28
(17.25 g, 85%) as needles; mp 83–85 ЊC; Rf 0.53 [petrol–EtOAc
(1 : 1)]; νmax(film)/cmϪ1 3275 (NH), 1730 (C᎐O), 1640 (C᎐C),
The ester 30 (1.29 g, 3.9 mmol) in THF (20 mL) was added to
lithium aluminium hydride (290 mg, 7.7 mmol) in THF (20 mL)
at 0 ЊC. After 15 min at room temperature, the mixture was
cooled to 0 ЊC and water was added until the precipitated
inorganic salts became granular. The mixture was filtered
through Celite and washed with THF. The filtrate was evapor-
ated and the residue was purified by column chromatography
on silica gel, eluting with petrol–EtOAc (1 : 1) to give the
alcohol 31 (1.07 g, 95%) as platelets; mp 145–146 ЊC; Rf 0.31
[petrol–EtOAc (1 : 1)]; νmax(film)/cmϪ1 3300 (OH and NH), 1540
᎐
᎐
1540 (C᎐O); δ (400 MHz, CDCl ) 1.16 (3H, t, J 7, OCH CH ),
᎐
H
3
2
3
2.55–2.65 (1H, m, CHAHBCH᎐C), 2.85–2.91 (1H, m, CHA-
(C᎐O); δ (400 MHz, MeOD) 1.30 [3H, s, C(CH )CH ], 1.45
A
B
᎐
᎐
H
3
3
HBCH᎐C), 3.45 (1H, td, J 9 and 6, CHCO), 4.02–4.12 (2H, m,
[3H, s, C(CH3 )CH3 ], 1.75–1.89 (2H, m, CH2CHOH), 2.57–
2.64 (1H, m, CHCH2OH), 3.63 (2H, d, J 6, CH2OH), 4.33 (1H,
d, J 6, CHN), 4.58 (1H, d, J 6, CHOH), 4.76–4.79 (1H, m,
CHOH), 7.44–7.81 (5H, m, Ph); δC(100 MHz, MeOD) 22.7,
25.1, 32.8, 41.7, 57.8, 60.4, 79.4, 85.3, 109.7, 127.0, 128.2, 131.4,
134.0, 169.6; Found: Mϩ, 291.1469. C16H21NO4 requires M,
291.1470; m/z 291 (0.1%, Mϩ), 105 (100, PhCO); Found: C,
65.8; H, 7.3; N, 4.65. C16H21NO4 requires C, 65.95; H, 7.25; N,
4.8%.
A
B
᎐
OCH CH ), 5.55–5.62 (1H, m, CHN), 5.70–5.72 (1H, m, CH᎐
᎐
2
3
C), 5.97–5.99 (1H, m, C᎐CH), 6.50 (1H, br d, NH), 7.39–7.74
᎐
(5H, m, Ph); δC(100 MHz, CDCl3) 14.1, 35.1, 45.7, 56.1, 60.9,
126.9, 128.5, 129.9, 131.5, 133.5, 134.4, 166.5, 173.7; Found:
Mϩ, 259.1211. C15H17NO3 requires M, 259.1208); m/z 259 (3%,
Mϩ), 154 (61, M Ϫ PhCO), 105 (100, PhCO); Found: C, 69.45;
H, 6.6; N, 5.35. C15H17NO3 requires C, 69.5; H, 6.6; N, 5.4%.
(1SR,2SR,3RS,4SR)-Ethyl 2-(benzoylamino)-3,4-dihydroxy-
cyclopentanecarboxylate 29
[(3aR,4SR,5SR,6aS )-N-[5-Formyl-2,2-dimethyltetrahydro-
cyclopenta[1,3]dioxol-4-yl]benzamide 23
The ester 28 (2.0 g, 7.7 mmol) was added to N-methyl-
morpholine-N-oxide (0.96 g, 8.2 mmol) and osmium tetroxide
(20 mg, 0.077 mmol) in H2O : acetone :tBuOH (16 mL, 5 : 2 : 1)
at room temperature. After 18 h sodium hydrosulfite (270 mg,
1.5 mmol), magnesium silicate (2.9 g, 7.7 mmol) and water
(20 mL) were added, the mixture was filtered and the solvent
o-Iodoxybenzoic acid (1.92 g, 6.9 mmol) was added to dimethyl
sulfoxide (10 mL) at room temperature. After 20 min the alco-
hol 31 (1.0 g, 3.4 mmol) was added and the mixture was stirred
at room temperature for 2 h. Water (20 mL) was added, the
mixture was filtered and extracted with CH2Cl2 (3 × 20 mL).
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 2 1 1 1 – 2 1 1 9
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The combined organic extracts were dried (MgSO4), evaporated
and purified by column chromatography on silica gel, eluting
with CH2Cl2–MeOH (9 : 1) to give the aldehyde 23 (852 mg,
86%) as a foam; Rf 0.50 [CH2Cl2–MeOH (9 : 1)]; νmax(film)/cmϪ1
(25 mmol) and CH2Cl2 (4 mL) at room temperature. After
30 min, dimethyl sulfate (340 mg, 2.7 mmol) was added. After
18 h, concentrated ammonia (1 mL) and water (10 mL) were
added and the mixture was extracted with CH2Cl2 (3 × 5 mL).
The organic extracts were dried (MgSO4), evaporated and puri-
fied by column chromatography on silica gel, eluting with
petrol–EtOAc (1 : 1), to give the ether 34 (581 mg, 93%) as a
foam; Rf 0.48 [petrol–EtOAc (1 : 1)]; νmax(film)/cmϪ1 3300 (NH),
3300 (NH), 1720 (C᎐O), 1540 (C᎐O); δ (400 MHz, CDCl ) 1.29
᎐
᎐
H
3
A
B
A
B
[3H, s, C(CH3 )CH3 ], 1.49 [3H, s, C(CH3 )CH3 ], 2.03–2.10
(1H, m, CHAHBCHCO), 2.19–2.26 (1H, m, CHAHBCHCO),
3.56–3.62 (1H, m, CHC᎐O), 4.63–4.65 (1H, m, CHOH), 4.70–
᎐
4.77 (2H, m, CHN and CHOH), 6.48 (1H, br d, NH), 7.37–7.69
(5H, m, Ph), 9.93 (1H, s, CHO); δC(100 MHz, CDCl3) 23.9,
26.3, 31.7, 51.8, 56.7, 78.5, 85.1, 110.7, 126.9, 128.6, 131.8,
133.8, 167.5, 201.9; Found: Mϩ, 289.1318. C16H19NO4 requires
M, 289.1314; m/z 289 (0.5%, Mϩ), 105 (100, PhCO); Found: C,
66.3; H, 6.6; N, 4.65. C16H19NO4 requires C, 66.4; H, 6.6; N,
4.85%.
1640 (C᎐C), 1540 (C᎐O); δ (400 MHz, CDCl ) 1.30 [3H,
᎐ ᎐
H 3
A B A B
s, C(CH3 )CH3 ], 1.51 [3H, s, C(CH3 )CH3 ], 1.70 (3H, s,
C᎐CCH ), 1.73–1.83 (1H, m, CHAHBCHC᎐C), 2.06–2.12 (1H,
᎐
᎐
3
m, CHAHBCHC᎐C), 3.26 (3H, s, OCH ), 3.38–3.43 (1H,
᎐
3
m, CH CHC᎐C), 3.78 (2H, s, CH O), 4.36 (1H, t, J 7, CHN),
᎐
2
2
4.65 (1H, d, J 6, OCH), 4.74 (1H, t, J 6, OCH), 5.36 (1H, d, J 9,
CH᎐C), 6.02 (1H, br d, J 7, NH), 7.39–7.71 (5H, m, Ph); δ (100
᎐
C
MHz, CDCl3) 14.6, 23.9, 26.3, 37.1, 37.8, 57.7, 59.2, 77.8, 79.1,
85.3, 110.3, 122.7, 126.8, 128.6, 131.5, 134.6, 136.9, 167.6;
Found: MHϩ, 346.2016. C20H28NO4 requires M, 346.2018; m/z
346 (100%, MHϩ), 139 (100); Found: C, 69.25; H, 8.0; N, 3.9.
C20H27NO4 requires C, 69.5; H, 7.9; N, 4.0%.
(3aR,4SR,5RS,6aS )-E-Ethyl [4-(benzoylamino)-2,2-dimethyl-
tetrahydrocyclopenta[1,3]dioxol-5-yl]-2-methylpropenoate 32
1-Carboethoxyethylidene triphenylphosphorane (4.37 g, 12
mmol) was added to the aldehyde 23 (3.17 g, 11 mmol) in THF
(100 mL) at room temperature and the mixture was warmed to
40 ЊC. After 5 h the solvent was evaporated and the residue was
purified by column chromatography on silica gel, eluting with
petrol–EtOAc (1 : 1), to give the ester 32 (3.63 g, 89%) as
needles; mp 136–138 ЊC; Rf 0.50 [petrol–EtOAc (1 : 1)]; νmax(film)/
cmϪ1 3300 (NH), 1710 (C᎐O), 1640 (C᎐C), 1540 (C᎐O);
(3aR,4SR,5RS,6aS )-E-N-[5-(3-Methoxy-2-methylprop-1-enyl)-
2,2-dimethyltetrahydrocyclopenta[1,3]dioxol-4-yl]-N-tributyl-
stannylmethylbenzamide 35
Sodium hydride (46 mg, 1.1 mmol, 60% dispersion in mineral
oil) was added to the amide 34 (133 mg, 0.4 mmol) in THF
(2 mL) under nitrogen at room temperature. After 2 h iodo-
methyltributyltin (249 mg, 0.6 mmol) was added. After 70 h the
solvent was evaporated and the residue was purified by column
chromatography on silica gel, eluting with petrol–EtOAc (9 : 1),
to give the stannane 35 (115 mg, 46%) as an oil; Rf 0.47 [petrol–
EtOAc (4 : 1)]; νmax(film)/cmϪ1 1650 (C᎐O), 1640 (C᎐C); δ (400
᎐
᎐
᎐
δH(400 MHz, CDCl3) 1.23 (3H, t, J 7, OCH2CH3), 1.30 [3H, s,
A
B
A
B
C(CH3 )CH3 ], 1.51 [3H, s, C(CH3 )CH3 ], 1.86–1.94 (4H, m,
C᎐CCH and CHAHBCHC᎐C), 2.08–2.15 (1H, m, CHAHB-
᎐
᎐
3
CHC᎐C), 3.41–3.47 (1H, m, CH CHC᎐C), 4.11–4.19 (2H, m,
᎐
᎐
2
OCH2CH3), 4.44 (1H, t, J 7, CHN), 4.66 (1H, d, J 6, OCH),
4.78 (1H, t, J 6, OCH), 6.12 (1H, br d, J 7, NH), 6.70 (1H, d,
᎐
᎐
H
MHz, CDCl3) 0.85–0.95 [15H, m, (CH3CH2CH2CH2)3Sn], 1.30
J 9, CH᎐C), 7.38–7.70 (5H, m, Ph); δ (100 MHz, CDCl ) 13.1,
᎐
C
3
A
B
[3H, s, C(CH3 )CH3 ], 1.31–1.36 [6H, m, (CH3CH2CH2CH2)3-
14.1, 23.9, 26.3, 37.4, 38.1, 59.1, 60.7, 79.2, 85.5, 110.5, 126.9,
128.6, 131.2, 131.6, 134.4, 137.6, 167.6, 167.8; Found: Mϩ,
373.1896. C21H27NO5 requires M, 373.1889; m/z 373 (10%, Mϩ),
105 (100, PhCO); Found: C, 67.3; H, 7.4; N, 3.55. C21H27NO5
requires C, 67.5; H, 7.3; N, 3.75%.
A
B
Sn], 1.38 [3H, s, C(CH3 )CH3 ], 1.47–1.57 [9H, m, (CH3CH2-
CH CH ) Sn and C᎐CCH ], 2.06–2.10 (2H, m, CH CHC᎐C),
᎐
᎐
2
2
3
3
2
2.30 (1H, d, J 12, NCHAHBSn), 2.76 (1H, d, J 12, NCHAHBSn),
3.19–3.24 (1H, m, CH CHC᎐C), 3.30 (3H, s, OCH ), 3.79–3.86
᎐
2
3
(2H, m, CH2O), 4.36 (1H, d, J 8, CCHN), 4.72 (1H, d, J 6,
OCH), 4.82–4.87 [1H, m, OCH), 5.30–5.35 (1H, m, CH᎐C),
᎐
(3aR,4SR,5RS,6aS )-E-N-[5-(3-Hydroxy-2-methylprop-1-enyl)-
2,2-dimethyl tetrahydrocyclopenta[1,3]dioxol-4-yl]benzamide 33
7.26–7.38 (5H, m, Ph); δC(100 MHz, CDCl3) 11.1, 13.7, 14.3,
23.5, 26.3, 27.5, 29.2, 31.9, 38.8, 40.5, 57.8, 69.3, 78.2, 80.5,
85.4, 109.9, 124.8, 127.3, 128.3, 129.0, 135.9, 136.2, 171.7;
Found: MHϩ, 650.3224. C33H56NO4120Sn requires M, 650.3231;
m/z 650 (6%, MHϩ), 105 (82, PhCO).
Calcium chloride (9.54 g, 86 mmol) was added to the ester 32
(5.35 g, 14 mmol) in EtOH (150 mL) at 0 ЊC. Sodium boro-
hydride (6.5 g, 172 mmol) was added and the mixture was
stirred at room temperature for 3 h. Aqueous K2CO3 (50 mL,
2 M) was added, the solvent was evaporated and the residue
partitioned between water (100 mL) and EtOAc (100 mL). The
aqueous layer was extracted with EtOAc (3 × 50 mL), the
organic extracts were dried (MgSO4), evaporated and purified
by column chromatography on silica gel, eluting with petrol–
EtOAc (1 : 1), to give the alcohol 33 (4.37 g, 92%) as a foam; Rf
0.18 [petrol–EtOAc (1 : 1)]; νmax(film)/cmϪ1 3300 (OH and
(3aR,4SR,5RS,6aS )-E-N-[5-(3-Methoxy-2-methylprop-1-enyl)-
2,2-dimethyltetrahydrocyclopenta[1,3]dioxol-4-yl]-N-tributyl-
stannylmethylbenzylamine 36
Et2O (1.5 mL) was added to lithium aluminium hydride (12 mg,
0.3 mmol) and aluminium chloride (14 mg, 0.1 mmol) under
nitrogen at Ϫ78 ЊC. The mixture was allowed to warm to 0 ЊC
for 1 h and the amide 35 (100 mg, 0.15 mmol) in Et2O (1.5 mL)
was added. After 1 h water (5 mL) was added and the mixture
was extracted with EtOAc (3 × 5 mL). The organic extracts
were dried (MgSO4), evaporated and purified by column chrom-
atography on alumina, eluting with petrol–EtOAc (49 : 1), to
give the stannane 36 (96 mg, 98%) as an oil; Rf 0.60 [petrol–
EtOAc (4 : 1)]; νmax(film)/cmϪ1 1640 (C᎐C); δ (400 MHz,
NH), 1640 (C᎐C), 1540 (C᎐O); δ (400 MHz, CDCl ) 1.28 [3H,
᎐
᎐
H
3
A
B
A
B
s, C(CH3 )CH3 ], 1.50 [3H, s, C(CH3 )CH3 ], 1.69 (3H, s,
C᎐CCH ), 1.73–1.82 (1H, m, CHAHBCHC᎐C), 2.00–2.05 (1H,
᎐
᎐
3
m, CHAHBCHC᎐C), 3.34–3.45 (1H, m, CH CHC᎐C), 3.95
᎐
᎐
2
(2H, s, CH2O), 4.35 (1H, t, J 7, CHN), 4.59 (1H, d, J 6, OCH),
4.71 (1H, t, J 6, OCH), 5.36 (1H, d, J 9, CH᎐C), 6.28 (1H, br d,
᎐
᎐
H
J 7, NH), 7.35–7.70 (5H, m, Ph); δC(100 MHz, CDCl3) 14.4,
23.9, 26.3, 37.2, 37.6, 59.1, 67.9, 79.1, 85.3, 110.3, 120.8, 126.9,
128.6, 131.6, 134.4, 139.1, 168.0; Found: MHϩ, 332.1861.
C19H26NO4 requires M, 332.1862; m/z 332 (84%, MHϩ), 139
(100), 105 (36, PhCO).
CDCl3) 0.85–0.89 [15H, m, (CH3CH2CH2CH2)3Sn], 1.26–1.31
A
B
[9H, m, (CH3CH2CH2CH2)3Sn and C(CH3 )CH3 ], 1.42–1.50
A
B
[9H, m, (CH3CH2CH2CH2)3Sn and C(CH3 )CH3 ], 1.58 (3H, s,
C᎐CCH ), 1.98–2.01 (2H, m, CH CHC᎐C), 2.62–2.67 (2H, m,
᎐
᎐
3
2
NCH2Sn), 2.82 (1H, dd, J 6 and 5, CHN), 3.24–3.29 (4H, m,
CH CHC᎐C and OCH ), 3.41 (1H, d, J 14, CHAHBPh), 3.66
᎐
2
3
(3aR,4SR,5RS,6aS )-E-N-[5-(3-Methoxy-2-methylprop-1-enyl)-
2,2-dimethyltetrahydrocyclopenta[1,3]dioxol-4-yl]benzamide 34
(1H, d, J 14, CHAHBPh), 3.82–3.83 (2H, m, CH2O), 4.67–4.71
(1H, m, OCH), 4.71–4.77 (1H, m, OCH), 5.67 (1H, d, J 9, CH᎐
᎐
Tetrabutylammonium iodide (7 mg, 18 µmol) was added to
C), 7.19–7.32 (5H, m, Ph); δC(100 MHz, CDCl3) 10.8, 13.6,
the alcohol 33 (600 mg, 1.8 mmol) in 50% aqueous NaOH
13.7, 24.6, 27.1, 27.5, 29.3, 38.5, 41.7, 41.7, 57.3, 60.1, 74.0,
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 2 1 1 1 – 2 1 1 9
2118

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78.5, 79.3, 83.9, 112.3, 126.6, 127.9, 128.1, 128.3, 132.7, 140.1;
Found: MHϩ, 636.3438. C33H58NO3120Sn requires M, 636.3438;
m/z 636 (100%, MHϩ), 345 (100, MH Ϫ 120SnBu3).
Acknowledgements
We thank the EPSRC for funding, the EPSRC mass spectro-
metry service at the University of Wales, Swansea and the
EPSRC Chemical Database Service at Daresbury.
(3aR,3bS,6S,6aR,7aS ) and (3aR,3bS,6R,6aR,7aS )-4-Benzyl-6-
isopropenyl-2,2-dimethyloctahydro[1,3]dioxolo[4,5]cyclopenta-
[1,2]pyrrole 37 and 38
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(21 mg, 50%) as an oil; Rf 0.54 [petrol–EtOAc (4 : 1)]; νmax(film)/
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(b) C. A. Broka and T. Shen, J. Am. Chem. Soc., 1989, 111, 2981;
(c) M. Lautens and S. Kumanovic, J. Am. Chem. Soc., 1995, 117,
1954; (d ) W. F. Bailey and P. H. Aspris, J. Org. Chem., 1995, 60, 754;
(e) A. Krief, B. Remacle and J. Mercier, Synlett, 2000, 1443;
( f ) A. Deiters, B. Wibbeling and D. Hoppe, Adv. Synth. Catal.,
2001, 343, 181; (g) G. Christoph and D. Hoppe, Org. Lett., 2002, 4,
2189.
6 For a review, see: A. F. Parsons, Tetrahedron, 1996, 52, 4149; for
recent syntheses of α-kainic acid, see: (a) H. Nakagawa, T. Sugahara
and K. Ogasawara, Org. Lett., 2000, 2, 3181; (b) A. D. Campbell,
T. M. Raynham and R. J. K. Taylor, J. Chem. Soc., Perkin Trans. 1,
2000, 3194; (c) Q. Xia and B. Ganem, Org. Lett., 2001, 3, 485;
(d ) H. Hirasawa, T. Taniguch and K. Ogasawara, Tetrahedron Lett.,
2001, 42, 7587; (e) J. Clayden, C. J. Menet and K. Tchabanenko,
Tetrahedron, 2002, 58, 4727.
A
cmϪ1 1645 (C᎐C); δ (400 MHz, CDCl ) 1.31 [3H, s, C(CH )-
᎐
H
3
3
B
A
B
CH ], 1.47 [3H, s, C(CH )CH ], 1.70 (3H, s, C᎐CCH ),
᎐
3
3
3
3
1.83–1.88 (1H, m, CHAHBCHO), 2.14 (1H, t, J 9, NCHA-
HBCH), 2.22–2.28 (1H, m, CHAHBCHO), 2.40–2.45 (1H, m,
NCH2CH ), 2.72–2.76 (1H, m, NCHCHCH2), 2.96 (1H, d, J 8,
NCH), 3.08 (1H, dd, J 9 and 7, NCHAHBCH), 3.25 (1H, d,
J 13, NCHAHBPh), 4.09 (1H, d, J 13, NCHAHBPh), 4.46 (1H,
d, J 5, OCH), 4.68 (2H, s, C᎐CH ), 4.82 (1H, dd, J 5 and 4,
᎐
2
OCH), 7.23–7.33 (5H, m, Ph); δC(100 MHz, CDCl3) 21.1, 24.7,
27.0, 39.8, 46.2, 50.9, 58.4, 59.5, 76.5, 83.1, 84.5, 109.5, 109.8,
126.9, 128.2, 128.7, 139.0, 146.3; Found: MHϩ, 314.2117.
C20H28NO2 requires M, 314.2120); m/z 314 (100%, MHϩ), 223
(15, MH–PhCH2) and the amine 38 (5 mg, 12%) as an oil; Rf
0.62 [petrol–EtOAc (4 : 1)]; νmax(film)/cmϪ1 1650 (C᎐C); δ (400
᎐
H
A
B
A
MHz, CDCl3) 1.30 [3H, s, C(CH3 )CH3 ], 1.46 [3H, s, C(CH3 )-
B
CH ], 1.72 (3H, s, C᎐CCH ), 1.76–1.78 (2H, m, CH CHO),
᎐
3
3
2
2.51 (1H, t, J 9, NCHAHBCH), 2.86–2.92 (1H, m, NCH2CH ),
2.93–3.00 (1H, m, NCHCHCH2), 3.10 (1H, t, J 9, NCHAHB-
CH), 3.18 (1H, d, J 5, NCH), 3.46 (1H, d, J 14, NCHAHBPh),
4.05 (1H, d, J 14, NCHAHBPh), 4.44 (1H, d, J 5, OCH), 4.62
(1H, s, C᎐CH), 4.78 (1H, s, C᎐CH), 4.82 (1H, br s, OCH),
᎐
᎐
7.24–7.32 (5H, m, Ph); δC(100 MHz, CDCl3) 23.3, 24.0,
26.5, 32.7, 44.3, 44.7, 54.5, 58.3, 78.0, 82.5, 83.7, 109.0, 109.7,
126.7, 128.2, 128.3, 139.0, 144.2; Found: MHϩ, 314.2122.
C20H28NO2 requires M, 314.2120; m/z 314 (100%, MHϩ), 223
(14, MH Ϫ PhCH2).
7 I. Coldham, M. M. S. Lang-Anderson, R. E. Rathmell and
D. J. Snowden, Tetrahedron Lett., 1997, 38, 7621.
8 A. Barco, S. Benetti, C. De Risi, G. P. Pollini, R. Romagnoli,
G. Spalluto and V. Zanirato, Tetrahedron, 1994, 50, 2583.
9 D. E. Seitz, J. J. Carroll, C. P. Cartaya, S.-H. Lee and A. Zapata,
Synth. Commun., 1983, 13, 129.
10 W. C. Still and C. Gennari, Tetrahedron Lett., 1983, 24, 4405.
11 The stereoselectivity on cyclization of
a methoxy-substituted
(3aR,3bS,6S,6aR,7aS )-Ethyl 6-isopropenyl-2,2-dimethylocta-
hydro[1,3]dioxolo[4,5]cyclopenta[1,2]pyrrole-4-carboxylate 39
organolithium species has been found to be dependent on the
solvent system used, see : W. F. Bailey and X.-L. Jiang, J. Org.
Chem., 1994, 59, 6528; for a cyclic substrate that gives predomin-
antly the desired 3,4-cis substitution pattern after anionic
cyclization, see Scheme 9, ref. 5a.
Ethyl chloroformate (66 mg, 0.6 mmol) was added to the
pyrrolidine 37 (32 mg, 0.1 mmol) in CH2Cl2 (1 mL) and the
mixture was heated under reflux for 18 h. The solvent was evap-
orated and the residue was purified by column chromatography
on silica gel, eluting with petrol–EtOAc (4 : 1), to give the carb-
amate 39 (20 mg, 66%) as an oil; Rf 0.32 [petrol–EtOAc (4 : 1)];
νmax(film)/cmϪ1 1700 (C᎐O), 1650 (C᎐C); δ (400 MHz, CDCl )
12 P. Garner and J. M. Park, J. Org. Chem., 1987, 52, 2361.
13 (a) I. Jako, P. Uiber, A. Mann and C.-G. Wermuth, J. Org. Chem.,
1991, 56, 5729; (b) S. Hanessian, W. Wang and Y. Gai, Tetrahedron
Lett., 1996, 37, 7477; (c) C. Flamant-Robin, Q. Wang, A. Chiaroni
and N. A. Sasaki, Tetrahedron, 2002, 58, 10475.
14 R. Baker and J. L. Castro, J. Chem. Soc., Perkin Trans. 1, 1990, 47.
15 K. Shimamoto, M. Ishida, H. Shinozaki and Y. Ohfune, J. Org.
Chem., 1991, 56, 4167.
16 For a related conjugate addition see: C. Herdeis and H. P. Hubmann,
Tetrahedron: Asymmetry, 1992, 3, 1213.
17 (a) H. Maeda and G. A. Kraus, J. Org. Chem., 1997, 62, 2314;
(b) P. Klotz and A. Mann, Tetrahedron Lett., 2003, 44, 1927.
18 (a) D. A. Evans and S. A. Biller, Tetrahedron Lett., 1985, 26, 1907;
(b) J. R. Malpass and N. J. Tweddle, J. Chem. Soc., Perkin Trans. 1,
1977, 874.
᎐
᎐
B
H
3
A
1.25–1.35 [6H, br m, C(CH3 )CH3 and OCH2CH3], 1.45 [3H,
s, C(CH3 )CH3 ], 1.58–1.65 (1H, m, CHAHBCHO), 1.72 (3H, s,
C᎐CCH ), 2.12–2.18 (1H, m, CHAHBCHO), 2.40–2.45 (1H, m,
A
B
᎐
3
NCH2CH ), 2.85–2.95 (1H, m, NCHCHCH2), 3.44–3.65 (2H,
m, NCH2CH), 3.97–4.25 (3H, m, NCH and OCH2CH3), 4.56–
4.84 (4H, m, OCHCHO and C᎐CH ); δ (100 MHz, CDCl )
᎐
2
C
3
14.8, 21.4, 24.4, 26.8, 36.5, 45.9, 47.0, 50.1, 61.3, 68.2, 81.1,
86.1, 110.1, 110.3, 145.7, 155.3; Found: MHϩ, 296.1868.
C16H26NO4 requires M, 296.1862; m/z 296 (72%, MHϩ).
19 A. Merz, Angew. Chem., Int. Ed. Engl., 1973, 12, 846.
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 2 1 1 1 – 2 1 1 9
2119