Parallel kinetic resolution of methyl (RS)-5-tris(phenylthio)methyl-cyclopent-1-ene-carboxylate for the asymmetric synthesis of (1R,2S,5S)- and (1S,2R,5R)-5-methyl-cispentacin

Article abstract of DOI:10.1016/j.tetasy.2008.05.016

Parallel kinetic resolution of methyl (RS)-5-tris(phenylthio)methyl-cyclopent-1-ene-carboxylate with a 50:50 pseudoenantiomeric mixture of lithium (S)-N-benzyl-N-(α-methylbenzyl)amide and lithium (R)-N-3,4-dimethoxybenzyl-N-(α-methylbenzyl)amide provides an efficient entry to the corresponding homochiral methyl (1R,2S,5S)- and (1S,2R,5R)-2-amino-5-tris(phenylthio)methyl-cyclopentane-carboxylate derivatives in >98% de, with subsequent, sequential desulfurisation with Raney Nickel, N-debenzylation and ester hydrolysis furnishing (1R,2S,5S)- and (1S,2R,5R)-5-methyl-cispentacin in high yield, >98% de and >98% ee.

Full text of DOI:10.1016/j.tetasy.2008.05.016

Tetrahedron: Asymmetry 19 (2008) 1356–1362
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Parallel kinetic resolution of methyl (RS)-5-tris(phenylthio)methyl-
cyclopent-1-ene-carboxylate for the asymmetric synthesis of (1R,2S,5S)-
and (1S,2R,5R)-5-methyl-cispentacin
*
Elin Abraham, Stephen G. Davies , Alexander J. Docherty, Kenneth B. Ling, Paul M. Roberts, Angela J. Russell,
James E. Thomson, Steven M. Toms
Department of Chemistry, Chemistry Research Laboratory, University of Oxford, Mansfield Road, Oxford OX1 3TA, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 15 April 2008
Accepted 16 May 2008
Parallel kinetic resolution of methyl (RS)-5-tris(phenylthio)methyl-cyclopent-1-ene-carboxylate with a
50:50 pseudoenantiomeric mixture of lithium (S)-N-benzyl-N-(
a-methylbenzyl)amide and lithium (R)-
N-3,4-dimethoxybenzyl-N-( -methylbenzyl)amide provides an efficient entry to the corresponding
a
homochiral methyl (1R,2S,5S)- and (1S,2R,5R)-2-amino-5-tris(phenylthio)methyl-cyclopentane-carbox-
ylate derivatives in >98% de, with subsequent, sequential desulfurisation with Raney Nickel, N-debenzy-
lation and ester hydrolysis furnishing (1R,2S,5S)- and (1S,2R,5R)-5-methyl-cispentacin in high yield, >98%
de and >98% ee.
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
tuted-cyclopent-1-ene-carboxylates 1–3 bearing an a-branched
5-substituent, high levels of substrate control were observed, pro-
moting addition of lithium dibenzylamide 5 anti to the 5-substitu-
ent, with subsequent protonation of the resultant enolate
occurring exclusively anti to the amino group, giving the corre-
sponding 1,2-syn-diastereoisomers 6, 8 and 10 as the major prod-
ucts.5c In the case of 5-methyl 4, however, poor substrate control
was noted, giving a 78:22 mixture of the 1,2-syn-diastereoisomers
12:13. In accordance with the low levels of substrate control, at-
tempted mutual kinetic resolution of (RS)-5-methyl 4 upon addi-
The simple cyclic b-amino acid (1R,2S)-2-amino-cyclopentane-
carboxylic acid (cispentacin) has attracted considerable synthetic
attention,1 with a number of efficient methodologies having been
developed for its synthesis in enantioenriched form.2 In order to
enhance the structural diversity of monomeric cispentacin deriva-
tives available for both secondary structural3 and bioactivity stud-
ies,4 we recently reported the efficient kinetic and parallel kinetic
resolution of a range of 3- and 5-substituted cyclopent-1-ene-car-
boxylates, utilising the conjugate addition of either homochiral or a
pseudoenantiomeric mixture of homochiral lithium amides,
respectively, for the asymmetric synthesis of homochiral 3- and
5-substituted cispentacin and transpentacin derivatives.5 We have
also promulgated the view that a full understanding of the ob-
served stereoselectivity in these systems is best achieved by ini-
tially evaluating the level of substrate control upon addition of
tion of lithium (RS)-N-benzyl-N-(a-methylbenzyl)amide (RS)-14
gave an 80:20 mixture of the 1,2-syn-diastereoisomeric products
21:22, consistent with E = 4,6 indicating that 4 is not suitable for ki-
netic or parallel kinetic resolution via this conjugate addition pro-
tocol (Scheme 1).
In order to extend this parallel kinetic resolution methodology
for the preparation of 5-methyl-cispentacin derivatives it was
envisaged that the use of a latent methyl group equivalent, incor-
an achiral lithium amide to the racemic
a,b-unsaturated ester.
For those substrates offering high facial selectivity upon conjugate
addition, the levels of enantiorecognition between the chiral
acceptor and chiral lithium amides was assessed through their mu-
porating an a-branch, would give the desired substrate control
during lithium amide conjugate addition; subsequent deprotection
would then reveal the C(5)-methyl group. Details of these investi-
gations are delineated herein.
tual kinetic resolution (addition of racemic
a,b-unsaturated ester
to an excess of racemic lithium amide). If high enantiorecognition
was seen between the reacting partners, then efficient kinetic and
parallel kinetic resolution in these systems was expected. Upon
application of this protocol to a range of methyl (RS)-5-substi-
2. Results and discussion
Dithianes and thio orthoesters have frequently been employed
as acyl anion equivalents in synthesis.7 In an elegant protocol,
Smith et al. demonstrated that the tris(phenylthio)methyl group
could act as a latent methyl group equivalent via exhaustive
* Corresponding author.
E-mail address: steve.davies@chem.ox.ac.uk (S. G. Davies).
0957-4166/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2008.05.016

E. Abraham et al. / Tetrahedron: Asymmetry 19 (2008) 1356–1362
1357
and 92% yield, respectively (Scheme 3). The relative configurations
within 27–30 were assigned on the assumption that addition of
the lithium amide occurs exclusively anti to the bulky 5-substi-
tuent,5c with protonation of the resultant b-amino enolate occurring
exclusively anti to the amino group;14 1H NMR NOE difference anal-
ysis of 27, 29 and 30 corroborated this assignment.
Ph
Ph
CO2Me
Ph
N
Ph
N
(i)
+
CO2Me
CO2Me
R
1,R = tBu
iPr
2,R =
R
major
diastereoisomer
R
minor
diastereoisomer
3,R = Ph
,R = Me
4
Ph
Products
R
Ratio
Yield%
80
Ph
Ph
R
N
:
tBu >99:<1
6 7
8:9
10:11
12:13
iPr
Ph
Me
90:10
90:10
78:22
59
Ph
N
Ph
N
42
50
CO2Me
S
CO2Me
S
Li
Li
(RS)-14
(i) or (ii)
5
Ph
N
Ph
S
S
CO2Me
Ph
Ph
N
(ii)
+
24
(i). , R = Bn, 61%
27
CO2Me
CO2Me
(ii). , R = iPr, 53%
R
28
,R = tBu
Ph
Ph
1
2,R = iPr
3,R = Ph
4,R = Me
R
major
diastereoisomer
R
minor
Ph
N
N
Ph
Li
Li
26
diastereoisomer
R
N
5
Products
R
Ratio
E
Yield%
85
:
tBu >99:<1 >99
iPr 96.5:3.5 >25
15 16
:
19
81
17 18
CO2Me
CO2Me
(i) or (ii)
:20
Ph
Me
94:6
80:20
>16
4
84
:
60
21 22
C(SPh)3
C(SPh)3
Scheme 1. Reagents and conditions: (i) lithium dibenzylamide 5, THF, ꢀ78 °C, 2 h,
(i). , R = Bn, 88%
(ii). , R = iPr, 92%
25
29
30
then NH4Cl (satd aq); (ii) lithium (RS)-N-benzyl-N-(
a-methylbenzyl)amide (RS)-14,
THF, ꢀ78 °C, 2 h, then NH4Cl (satd aq).
Scheme 3. Reagents and conditions: (i) lithium dibenzylamide
5 (1.6 equiv),
THF, ꢀ78 °C, 2 h, then NH4Cl (satd aq); (ii) lithium N-benzyl-N-isopropylamide 26
hydrogenolytic deprotection mediated by Raney Nickel.8 In an
analogous manner, exhaustive hydrogenolysis of 1,3-dithianes
has been extensively reported.9 Thus, two 5-substituted acceptors
were identified and evaluated for their utility in this protocol:
(1.6 equiv), THF, ꢀ78 °C, 2 h, then NH4Cl (satd aq).
With high levels of substrate control displayed upon conjugate
addition of both lithium dibenzylamide 5 and lithium N-benzyl-N-
methyl
(bearing an
thio)methyl-cyclopent-1-ene-carboxylate 25 (bearing
5-(10,30-dithian-20-yl)cyclopent-1-ene-carboxylate
-branched 5-substituent) and methyl 5-tris(phenyl-
bis-a-
24
isopropylamide 26 to racemic
high levels of enantiorecognition between lithium (RS)-N-benzyl-
N-( -methylbenzyl)amide (RS)-14, and both 24 and 25 were antic-
a,b-unsaturated esters 24 and 25,
a
a
a
branched 5-substituent). The required racemic 5-substituted
cyclopent-1-ene-carboxylates 24 and 25 were readily prepared
from 5-acetoxy-23.5c,10 Under optimised conditions, treatment of
23 with the lithium anion of tris(phenylthio)methane gave 25 in
89% yield, whilst addition of the lithium anion of 1,3-dithiane to
2311 gave a complex mixture of products (potentially a result of
competing 1,2-addition and Michael addition, and polymerisa-
tion)12 from which 24 was isolated in 18% yield (Scheme 2).
ipated. Under optimised conditions, conjugate addition of racemic
lithium amide (RS)-14 (4 equiv) to (RS)-5-(10,30-dithian-20-yl)-24
gave b-amino ester (1RS,2SR,5SR,aSR)-31 in >98% de and 48% yield,
whilst addition of (RS)-14 to (RS)-5-tris(phenylthio)methyl-25
gave b-amino ester (1RS,2SR,5SR,aSR)-32 in >98% de and 93% yield,
consistent with E >996 in both cases. The relative configurations of
31 and 32 were assigned by 1H NMR NOE difference analysis and
are consistent with high levels of enantiorecognition between the
CO2Me
CO2Me
CO2Me
Ph
(i)
(ii)
S
Ph
N
C(SPh)3
OAc
23
S
CO2Me
S
CO2Me
S
, 18%
, 89%
25
24
(i)
Scheme 2. Reagents and conditions: (i) BuLi, 1,3-dithiane, ꢀ78 °C to rt, 48 h; (ii)
BuLi, tris(phenylthio)methane, THF, ꢀ78 °C to rt, 48 h.
S
S
24
Thelevelofsubstratecontrolofferedby24and25uponconjugate
addition of a lithium amide was probed with achiral lithium dib-
enzylamide 55,13 and lithium N-benzyl-N-isopropylamide 26, the
latter being employed as an even better mimic of the steric bias of
, 48%, >98% de
31
Ph
the chiral lithium N-benzyl-N-(a
-methylbenzyl)amide.5c Conjugate
Ph
N
addition of both lithium amides 5 and 26 to (RS)-5-(10,30-dithian-20-
yl)-24 gave quantitative conversion to the corresponding adducts
(1RS,2SR,5SR)-27 and (1RS,2SR,5SR)-28 in >98% de in each case,
which were isolated in 61% and 53% yield, respectively. Analogous
conjugate addition of lithium amides 5 and 26 to (RS)-5-tris(phenyl-
thio)methyl-25 gave the corresponding adducts (1RS,2SR,5SR)-29
and (1RS,2SR,5SR)-30 as single diastereoisomers (>98% de) in 88%
CO2Me
CO2Me
(i)
C(SPh)3
C(SPh)3
25
, 93%, >98% de
32
Scheme 4. Reagents and conditions: (i) lithium (RS)-N-benzyl-N-(
zyl)amide (RS)-14 (4 equiv), THF, ꢀ78 °C, 2 h, then NH4Cl (satd aq).
a-methylben-

1358
E. Abraham et al. / Tetrahedron: Asymmetry 19 (2008) 1356–1362
chiral
a
,b-unsaturated ester and chiral lithium amide, with addi-
Reduction of (1R,2S,5S,
ulfurisation furnishing b-amino ester (1R,2S,5S,
and >98% de. Analogous treatment of (1S,2R,5R,
Nickel gave b-amino ester (1S,2R,5R, R)-36 in >98% de and 67% iso-
lated yield. Attempted epimerisation of 36 upon treatment with
NaOMe in MeOH for 24 h returned only starting material.5c The
recalcitrance of this class of compound to epimerisation at C(1)
may be due to C(1)H and the carbonyl group being oriented
approximately coplanar, as revealed in the X-ray crystal structure
of 34.5c Oxidative debenzylation of 36 with DDQ furnished
a
S)-32 with Raney Nickel resulted in des-
S)-35 in 79% yield
R)-34 with Raney
tion of the lithium amide occurring exclusively anti to the bulky
5-substituent, and protonation of the resultant b-amino enolate
occurring exclusively anti to the amino group14 (Scheme 4).
The high levels of enantiorecognition observed between lithium
amide (RS)-14 and both 5-substituted cyclopent-1-ene-carboxyl-
ates 24 and 25 suggest that both are suitable for either kinetic or
parallel kinetic resolution upon treatment with homochiral or a
50:50 pseudoenantiomeric mixture of homochiral lithium amides,
respectively. Even with E >99, the parallel kinetic resolution proto-
col was investigated, not only as it is experimentally more facile
but also, unlike a simple kinetic resolution, can be run to comple-
tion and requires no further optimisation studies. Additionally,
both enantiomeric series of the desired 5-methyl-cispentacin
derivatives are available from a parallel kinetic resolution method.
Due to the superior yields obtained upon conjugate addition to
(RS)-5-tris(phenylthio)methyl-25, its amenability to parallel ki-
netic resolution was chosen for investigation. Thus, addition of a
a
a
a
(1S,2R,5R,aR)-37 in >98% de and 82% yield (Scheme 6).
Ph
Ph
Ph
N
Ph
N
(i)
CO2Me
CO2Me
Me
C(SPh)3
50:50 pseudoenantiomeric mixture of lithium (S)-N-benzyl-N-(
methylbenzyl)amide (S)-14 and lithium (R)-N-3,4-dimethoxybenz-
yl-N-( -methylbenzyl)amide (R)-33 to (RS)-25 furnished a 50:50
mixture of b-amino esters (1R,2S,5S, S)-32 and (1S,2R,5R, R)-34
a-
(1R,2S,5S,αS -
35
)
(1R,2S,5S,αS)-
32
79%, >98% de
a
OMe
OMe
a
a
OMe
OMe
only, in >98% de in each case, which were isolated in 42% and
41% yield, respectively, after chromatography (Scheme 5). The rel-
ative configuration within b-amino ester 34 was unambiguously
established via single crystal X-ray analysis, with the absolute
(1S,2R,5R,aR)-configuration assigned from the known (R)-a-meth-
ylbenzyl stereocentre (Fig. 1).
Ph
NH
Ph
N
Ph
N
(i)
(ii)
CO2Me
CO2Me
CO2Me
Me
C(SPh)3
(1S,2R,5R,αR)-
Me
(1S,2R,5R,αR)-36
(1S,2R,5R,αR)-37
34
OMe
82%, >98% de
67%, >98% de
OMe
Scheme 6. Reagents and conditions: (i) Raney Nickel, THF, rt, 8 h; (ii) DDQ, DCM/
H2O (5:1), rt, 24 h.
Ph
Hydrogenolysis of (1R,2S,5S,aS)-35 furnished b-amino ester
Ph
N
Ph
N
OMe
(1R,2S,5S)-38 in 91% yield, >98% de and >98% ee,15 with ester
hydrolysis and purification via ion-exchange chromatography fur-
nishing b-amino acid (1R,2S,5S)-39 in 95% yield and >98% de. Sim-
ilarly, the enantiomeric b-amino acid (1S,2R,5R)-39 was
Li
(S)-
Li
OMe
14
(
R
)-
33
Ph
synthesised by hydrogenolysis of b-amino ester (1S,2R,5R,aR)-37
Ph
N
Ph
N
to yield b-amino ester (1S,2R,5R)-38 in 95% yield, >98% de and
>98% ee.15 Ester hydrolysis and ion exchange chromatography pro-
vided the b-amino acid (1S,2R,5R)-39 in 93% yield and >98% de
(Scheme 7). 1H NMR NOESY analysis of 39 was supportive of the
assigned 1,2-syn-1,5-anti-configuration, consistent with ester
hydrolysis not being accompanied by epimerisation of the C(1)-
stereocentre (vide supra).
(i)
CO2Me
CO2Me
CO2Me
+
C(SPh)3
C(SPh)3
C(SPh)3
25
(1R,2S,5S, S)-
α
32
(1S,2R,5R, R)-
34
41%, >98%de
α
42%, >98%de
Scheme 5. Reagents and conditions: (i) lithium (S)-N-benzyl-N-(
yl)amide (S)-14 (2 equiv), lithium (R)-N-3,4-dimethoxybenzyl-N-(
yl)amide (R)-33 (2 equiv), THF, ꢀ78 °C, 2 h, then NH4Cl (satd aq).
a
a
-methylbenz-
-methylbenz-
3. Conclusion
In conclusion, parallel kinetic resolution of methyl (RS)-5-
tris(phenylthio)methyl-cyclopent-1-ene-carboxylate with a 50:50
pseudoenantiomeric mixture of homochiral lithium amides repre-
sents an efficient route to homochiral 5-substituted-cispentacin
derivatives, which can be deprotected to furnish (1R,2S,5S)- and
(1S,2R,5R)-5-methyl-cispentacin in high de and ee. The application
of these substrates as organocatalysts, and as monomers for the con-
struction of b-peptides is currently ongoing within our laboratory.
4. Experimental
4.1. General experimental
All reactions involving organometallic or other moisture-sensi-
tive reagents were carried out under a nitrogen or argon atmo-
Figure 1. Chem 3D representation of the X-ray crystal structure of 34 (some H
atoms removed for clarity).

E. Abraham et al. / Tetrahedron: Asymmetry 19 (2008) 1356–1362
1359
6.6. Found: C, 54.2; H, 6.65; mmax (film) 1716 (C@O), 1628 (C@C);
dH (400 MHz, CDCl3) 1.65–1.76 (1H, m, C(50)HA), 1.99–2.03 (1H,
m, C(50)HB), 2.04–2.07 (1H, m, C(4)HA), 2.12–2.20 (1H, m, C(4)HB),
2.33–2.42 (1H, m, C(3)HA), 2.47–2.57 (1H, m, C(3)HB), 2.69–2.79
(3H, m, C(40)H2, C(60)HA), 2.84–2.92 (1H, dt, J 2.5, 11.9, C(60)HB),
3.34–3.37 (1H, m, C(5)H), 3.68 (3H, s, OMe), 4.72 (1H, d, J 3.8,
C(20)H), 6.80–6.82 (1H, m, C(2)H); dC (100 MHz, CDCl3) 26.0
(C(40), C(60)), 30.2 (C(4)), 30.4 (C(50)), 32.7 (C(3)), 49.1 (C(5)), 51.4
(OMe), 52.1 (C(20)), 135.0 (C(1)), 146.3 (C(2)), 164.9 (CO2Me); m/z
(FI+) 244 ([M]+, 100%); HRMS (FI+) C11H16O2S2 ([M]+) requires:
244.0592; found, 244.0602.
Ph
NH2
NH2
Ph
N
(i)
(ii), (iii)
CO2Me
.TFA
CO2H
CO2Me
Me
Me
Me
(1R,2S,5S,αS)-35
(1R,2S,5S)-38, 91%
(1R,2S,5S)-39
>98% de
>98% de, >98% ee
95%, >98% de
NH2
NH2
Ph
NH
(i)
(ii), (iii)
CO2Me
CO2H
CO2Me
4.3. Methyl (RS)-5-tris(phenylthio)methyl-cyclopent-1-ene-
carboxylate 25
.TFA
Me
Me
Me
(1S,2R,5R,αR)-37
(1S,2R,5R)-38, 95%
(1S,2R,5R)-39
BuLi (1.6 M in hexanes, 3.08 mL, 4.92 mmol) was added drop-
wise via syringe to a stirred solution of tris(phenylthio)methane
(1.27 g, 4.92 mmol) in THF (10 mL) at ꢀ78 °C and stirred for
1.5 h. The mixture was then added dropwise via cannula to a stir-
red solution of 23 (1.0 g, 4.10 mmol) in THF (10 mL) at ꢀ78 °C. The
resultant mixture was allowed to warm slowly to rt over 24 h be-
fore the addition of satd aq NH4Cl (30 mL). The aqueous layer was
separated and extracted with Et2O (3 ꢁ 30 mL). The combined or-
ganic extracts were dried and concentrated in vacuo. Purification
via flash column chromatography (eluent 30–40 °C petrol/Et2O,
10:1) gave 25 as a colourless, viscous oil (1.70 g, 89%); mmax (film)
1721 (C@O); dH (400 MHz, CDCl3) 1.98–2.88 (4H, m, C(3)H2,
C(4)H2), 3.60 (1H, d, J 8.8, C(5)H), 3.71 (3H, s, OMe), 6.76 (1H, s,
C(2)H), 7.22–7.53 (15H, m, Ph); dC (100 MHz, CDCl3) 29.4 (C(4)),
32.8 (C(3)), 51.6 (C(5)), 55.7 (OMe), 81.9 (C(SPh)3), 128.3, 129.1,
132.0 (o-, m-, p-Ph), 135.4 (C(1)), 136.6 (i-Ph), 146.3 (C(2)), 167.1
>98% de
>98% de, >98% ee
93%, >98% de
Scheme 7. Reagents and conditions: (i) Pd(OH)2/C, H2 (1 atm), MeOH/AcOH (40:1),
rt, 2 h then TFA/DCM (1:1); (ii) LiOH, THF/H2O, rt, 16 h; (iii) HCl then Dowex 50-
WX8-200.
sphere using standard vacuum line techniques, and glassware that
was flame dried and cooled under nitrogen before use. Solvents
were dried according to the procedure outlined by Grubbs and
co-workers.16 Water was purified by an ElixÒ UV-10 system. All
other solvents were used as supplied (analytical or HPLC grade)
without prior purification. Organic layers were dried over MgSO4.
Thin layer chromatography was performed on aluminium plates
coated with 60 F254 silica. Plates were visualised using UV light
(254 nm), iodine, 1% aq KMnO4 or 10% ethanolic phosphomolybdic
acid. Flash column chromatography was performed on Kieselgel 60
silica.
(CO2Me); m/z (ESI+) 487 ([M+Na]+, 100%); HRMS (ESI+)
26H24NaO2S3 ([M+Na]+) requires: 487.0831; found, 487.0836.
þ
C
Elemental analyses were recorded by the microanalysis service
of the Inorganic Chemistry Laboratory, University of Oxford, UK.
Melting points were recorded on a Gallenkamp Hot Stage appara-
tus and are uncorrected. Optical rotations were recorded on a Per-
kin–Elmer 241 polarimeter with a water-jacketed 10 cm cell.
Specific rotations are reported in 10ꢀ1 deg cm2 gꢀ1 and concentra-
tions in g/100 mL. IR spectra were recorded on a Bruker Tensor 27
FT-IR spectrometer as either a thin film on NaCl plates (film) or a
KBr disc (KBr), as stated. Selected characteristic peaks are reported
in cmꢀ1. NMR spectra were recorded on Bruker Avance spectrom-
eters in the deuterated solvent state. The field was locked by exter-
nal referencing to the relevant deuteron resonance. Low-resolution
mass spectra were recorded on either a VG MassLab 20-250 or a
Micromass Platform 1 spectrometer. Accurate mass measurements
were run on either a Bruker MicroTOF internally calibrated with
polyalanine, or a Micromass GCT instrument fitted with a Scientific
Glass Instruments BPX5 column (15 m ꢁ 0.25 mm) using amyl ace-
tate as a lock mass.
4.4. General procedure for lithium amide conjugate addition
BuLi (as a solution in hexanes) was added dropwise via syringe
to a stirred solution of the requisite amine (or 50:50 mixture of
amines) in THF at ꢀ78 °C. After stirring for 30 min, a solution of
the requisite
a,b-unsaturated ester in THF at ꢀ78 °C was added
dropwise via cannula. After stirring for a further 2 h at ꢀ78 °C,
the reaction mixture was quenched with satd aq NH4Cl and al-
lowed to warm to rt before being concentrated in vacuo. The resi-
due was partitioned between EtOAc (50 mL) and 10% aq citric acid
(50 mL). The organic layer was separated and the aqueous layer
was extracted with EtOAc (2 ꢁ 50 mL). The combined organic ex-
tracts were washed sequentially with satd aq NaHCO3 (100 mL)
and brine (100 mL), dried and concentrated in vacuo.
4.5. Methyl (1RS,2SR,5SR)-2-(N,N-dibenzylamino)-5-(10,30-
dithian-20-yl)cyclopentane-carboxylate 27
4.2. Methyl (RS)-5-(10,30-dithian-20-yl)cyclopent-1-ene-
carboxylate 24
Following the General procedure, BuLi (1.6 M in hexanes, 0.4 mL,
0.64 mmol), dibenzylamine (0.12 mL, 0.66 mmol) in THF (2 mL),
and 24 (100 mg, 0.41 mmol) in THF (2 mL) gave (1RS,2SR,5SR)-27
in >98% de. Purification via flash column chromatography (eluent
30–40 °C petrol/Et2O, 10:1) gave (1RS,2SR,5SR)-27 as a colourless
viscous oil (110 mg, 61%, >98% de); mmax (film) 1731 (C@O); dH
(400 MHz, CDCl3) 1.50–1.61 (1H, m, C(4)HA), 1.71–1.80 (1H, m,
C(3)HA), 1.81–2.10 (4H, m, C(3)HB, C(4)HB, C(50)H2), 2.76–2.88
(4H, m, C(40)H2, C(60)H2), 2.92–3.01 (1H, m, C(5)H), 3.20–3.27
(1H, m, C(1)H), 3.39–3.46 (1H, m, C(2)H), 3.69 (4H, s, N(CH2Ph)2),
3.75 (3H, s, OMe), 3.98 (1H, d, J 7.1, C(20)H), 7.13–7.43 (10H, m,
Ph); dC (100 MHz, CDCl3) 25.9, 28.2, 28.3, 29.8, 30.0 (C(3), C(4),
C(40), C(50), C(60)), 46.3 (C(5)), 51.3 (C(1)), 51.9 (OMe), 52.7 (C(20)),
56.0 (N(CH2Ph)2), 66.1 (C(2)), 126.7, 127.0, 128.2, 128.3, 128.5,
BuLi (1.6 M in hexanes, 12.9 mL, 18.9 mmol) was added drop-
wise via syringe to a stirred solution of 1,3-dithiane (2.27 g,
18.9 mmol) in THF (10 mL) at ꢀ78 °C and stirred for 1.5 h. The mix-
ture was then added dropwise via cannula to a stirred solution of
23 (1.0 g, 4.10 mmol) in THF (10 mL) at ꢀ78 °C. The resultant mix-
ture was allowed to warm slowly to rt over 24 h before the addi-
tion of satd aq NH4Cl (20 mL). The aqueous layer was separated
and extracted with Et2O (3 ꢁ 30 mL). The combined organic ex-
tracts were dried and concentrated in vacuo. Purification via flash
column chromatography (eluent 30–40 °C petrol/Et2O, 10:1) gave
24 as a yellow oil (430 mg, 18%); C11H16O2S2 requires: C, 54.1; H,

1360
E. Abraham et al. / Tetrahedron: Asymmetry 19 (2008) 1356–1362
128.6 (o-, m-, p-Ph), 139.8, 140.2 (i-Ph), 174.7 (CO2Me); m/z (ESI+)
4.9. Methyl (1RS,2SR,5SR,aSR)-2-[N-benzyl-N-(a-methyl-
442 ([M+H]+, 100%); HRMS (ESI+) C25H32NO2S2
442.1869; found, 442.1869.
requires:
benzyl)amino]-5-(10,30-dithian-20-yl)cyclopentane-carboxylate
31
þ
4.6. Methyl (1RS,2SR,5SR)-2-(N-benzyl-N-isopropylamino)-5-
Following the General procedure, BuLi (1.6 M in hexanes, 0.4 mL,
(10,30-dithian-20-yl)cyclopentane-carboxylate 28
0.64 mmol), (RS)-N-benzyl-N-(
1.64 mmol) in THF (2 mL), and 24 (100 mg, 0.41 mmol) gave
(1RS,2SR,5SR, SR)-31 in >98% de. Purification via flash column
chromatography (eluent 30–40 °C petrol/Et2O, 10:1) gave
(1RS,2SR,5SR, SR)-31 as a white solid (89 mg, 48%, >98% de); mp
59–61 °C; mmax (KBr) 1727 (C@O); dH (400 MHz, C6D6) 1.19 (3H,
d, J 6.8, C(
)Me), 1.33–1.43 (3H, m, C(3)HA, C(4)HA, C(50)HA),
a-methylbenzyl)amine (344 mg,
Following the General procedure, BuLi (1.6 M in hexanes, 0.4 mL,
0.64 mmol), N-benzyl-N-isopropylamine (0.12 mL, 0.66 mmol) in
THF (2 mL), and 24 (100 mg, 0.41 mmol) in THF (2 mL) gave
(1RS,2SR,5SR)-28 in >98% de. Purification via flash column chroma-
tography (eluent 30–40 °C petrol/Et2O, 10:1) gave (1RS,2SR,5SR)-28
as a colourless viscous oil (85 mg, 53%, >98% de); mmax (film) 1731
(C@O); dH (400 MHz, CDCl3) 0.93 (3H, d, J 6.6, CH3CHCH3), 0.99 (3H,
d, J 6.6, CH3CHCH3), 1.49–1.60 (1H, m, C(50)HA), 1.66–1.72 (1H, m,
C(3)HA), 1.77–1.88 (2H, m, C(3)HB, C(50)HB), 1.93–2.00 (1H, m,
C(4)HA), 2.02–2.08 (1H, m, C(4)HB), 2.76–2.89 (5H, m, C(5)H,
C(40)H2, C(60)H2), 3.03–3.17 (2H, m, C(1)H, NCH), 3.45–3.52 (1H,
m, C(2)H), 3.63 (1H, d, J 14.4, NCHA), 3.65 (1H, J 14.4, NCHB), 3.70
(3H, s, OMe), 3.97 (1H, d, J 6.8, C(20)H), 7.15–7.30 (5H, m, Ph); dC
(100 MHz, CDCl3) 17.8 (CH3CHCH3), 19.0 (CH3CHCH3), 25.9, 28.2,
28.3, 29.9, 30.1 (C(3), C(4), C(40), C(50), C(60)), 46.1 (C(5)), 49.6
(CH3CHCH3), 51.1 (NCH2), 51.6 (OMe), 52.2 (C(1)), 52.8 (C(2)),
64.0 (C(20)), 126.2, (p-Ph), 127.8, 127.9 (o-, m-Ph), 142.3 (i-Ph),
a
a
a
1.45–1.50 (1H, m, C(50)HB), 1.74–1.92 (2H, m, C(3)HB, C(4)HB),
2.16–2.40 (4H, m, C(40)H2, C(60)H2), 3.05–3.15 (1H, m, C(5)H),
3.27 (1H, dd, J 6.5, 9.3, C(1)H), 3.36–3.45 (1H, m, C(2)H), 3.55
(3H, s, OMe), 3.58 (1H, d, J 6.8, C(20)H), 3.65 (1H, d, J 14.4, NCHA),
3.78 (1H, d, J 14.4, NCHB), 4.22 (1H, q, J 6.8, C(
(10H, m, Ph); dC (125 MHz, C6D6) 15.6 (C(
)Me), 26.1 (C(50)), 28.3,
28.5, 29.5, 30.1 (C(3), C(4), C(40), C(60)), 46.7 (C(5)), 51.5, 52.0,
52.1 (C(1), C(2), C(20)), 57.5 (OMe), 59.2 (NCH2), 64.2 (C(
)),
a)H), 7.07–7.47
a
a
126.8, 127,8, 129.1 (o-, m-, p-Ph), 141.8, 143.3 (i-Ph), 174.8
(CO2Me); m/z (ESI+) 457 ([M+H]+, 85%), 352 (100); HRMS (ESI+)
C26H34NO2S2 ([M+H]+) requires: 456.2025; found, 456.2031.
þ
174.8 (CO2Me); m/z (ESI+) 394 ([M+H]+, 100%); HRMS (ESI+)
4.10. Methyl (1RS,2SR,5SR,aSR)-2-[N-benzyl-N-(a-methyl-
benzyl)amino]-5-tris(phenylthio)methyl-cyclopentane-
þ
C
21H32NO2S2 ([M+H]+) requires: 394.1869; found, 394.1874.
carboxylate 32
4.7. Methyl (1RS,2SR,5SR)-2-(N,N-dibenzylamino)-5-
tris(phenylthio)methyl-cyclopentane-carboxylate 29
Following the General procedure, BuLi (1.6 M in hexanes, 0.5 mL,
0.80 mmol), (RS)-N-benzyl-N-(
0.84 mmol) in THF (2 mL), and 25 (100 mg, 0.21 mmol) in THF
(2 mL) gave (1RS,2SR,5SR, SR)-32 in >98% de. Purification via flash
column chromatography (eluent 30–40 °C petrol/Et2O, 10:1) gave
(1RS,2SR,5SR, SR)-32 as a white solid (132 mg, 93%, >98% de);
41H41NO2S3 requires: C, 72.85; H, 6.1; N, 2.1; S, 14.2. Found: C,
72.8; H, 6.4; N, 1.9; S, 14.1; mp 53–55 °C; mmax (KBr) 1731
(C@O); dH (400 MHz, CDCl3) 1.38 (3H, d, J 6.8, C( )Me), 1.45–1.59
a-methylbenzyl)amine (180 mg,
Following the General procedure, BuLi (1.6 M in hexanes,
0.11 mL, 0.17 mmol), dibenzylamine (0.03 mL, 0.18 mmol) in THF
(2 mL), and 25 (50 mg, 0.11 mmol) in THF (2 mL) gave
(1RS,2SR,5SR)-29 in >98% de. Purification via flash column chroma-
tography (eluent 30–40 °C petrol/Et2O, 10:1) gave (1RS,2SR,5SR)-29
as a white solid (64 mg, 88%, >98% de); mp 51–53 °C; mmax (KBr)
1733 (C@O); dH (400 MHz, C6D6) 1.63–1.72 (1H, m, C(3)HA),
1.89–2.11 (3H, m, C(3)HB, C(4)H2), 3.51 (3H, s, OMe), 3.70–3.76
(1H, m, C(2)H), 3.82 (4H, m, N(CH2Ph)2), 3.90–3.98 (1H, m,
C(5)H), 4.18–4.21 (1H, m, C(1)H), 7.05–7.89 (25H, m, Ph); dC
(125 MHz, C6D6) 27.4 (C(4)), 30.5 (C(3)), 31.7 (C(1)), 49.4 (OMe),
56.5 (C(5)), 67.1 (C(2)), 82.2 (C(SPh)3), 127.2, 128.2, 128.9 (o-, m-,
p-Ph), 134.7, 138.6 (i-Ph), 171.9 (CO2Me); m/z (ESI+) 662
a
a
C
a
(3H, m, C(4)HA, C(3)H2), 1.63–1.67 (1H, m, C(4)HB), 3.26–3.31
(1H, m, C(5)H), 3.37 (1H, d, J 15.6, NCHA), 3.51–3.57 (1H, m,
C(2)H), 3.62 (3H, s, OCH3), 3.78 (1H, dd, J 3.8, 8.5, C(1)H), 3.92
(1H, d, J 15.6, NCHB), 4.30 (1H, q, J 6.8, C(
m, Ph), 7.54–7.56 (5H, m, Ph); dC (100 MHz, CDCl3) 17.0 (C(
27.5 (C(3)), 30.2 (C(4)), 50.7 (C(1)), 51.0 (NCH2), 51.7 (OMe), 52.5
(C(5)), 57.9 (C( )), 65.7 (C(2)), 80.7 (C(SPh)3), 126.3, 126.3, 126.9,
a)H), 7.24–7.41 (20H,
a)Me),
([M+Na]+, 100%); HRMS (ESI+) C40H40NO2S3 ([M+H]+) requires:
a
þ
662.2216; found, 662.2216.
127.6, 128.0, 128.0, 128.4, 128.5, 129.0 (o-, m-, p-Ph), 132.0 (i-
Ph), 135.9 (Ph), 141.7, 142.5 (i-Ph), 175.3 (CO2Me); m/z (ESI+) 676
([M+H]+, 45%), 461 (100); HRMS (ESI+) C41H42NO2S3 ([M+H]+) re-
þ
4.8. Methyl (1RS,2SR,5SR)-2-(N-benzyl-N-isopropylamino)-5-
tris(phenylthio)methyl-cyclopentane-carboxylate 30
quires: 676.2378; found, 676.2372.
Following the General procedure, BuLi (1.6 M in hexanes,
0.11 mL, 0.17 mmol), N-benzyl-N-isopropylamine (0.03 mL,
0.18 mmol) in THF (2 mL), and 25 (50 mg, 0.11 mmol) in THF
(2 mL) gave (1RS,2SR,5SR)-30 in >98% de. Purification via flash col-
umn chromatography (eluent 30–40 °C petrol/Et2O, 10:1) gave 30
as a white solid (62 mg, 92%, >98% de); mp 52–54 °C; mmax (KBr)
1731 (C@O); dH (500 MHz, C6D6) 1.04 (3H, d, J 6.6, CH3CHCH3),
1.10 (3H, d, J 6.6, CH3CHCH3), 1.60–1.67 (1H, m, C(3)HA), 1.82–
1.93 (1H, m, C(3)HB), 1.96–2.04 (1H, m, C(4)HA), 2.11–2.22 (1H,
m, C(4)HB), 3.37–3.43 (1H, m, CH3CHCH3), 3.49 (3H, s, OMe), 3.61
(2H, m, NCH2), 3.77–3.86 (2H, m, C(2)H, C(5)H), 4.01–4.06 (1H,
m, C(1)H), 6.91–7.78 (20H, m, Ph); dC (125 MHz, C6D6) 16.4
(CH3CHCH3), 20.4 (C(4)), 28.5 (C(3)), 30.7 (C(1)), 50.2, 50.9, 51.3,
51.8, 53.2 (C(2), C(5), NCH2, OMe, CH3CHCH3), 81.7 (C(SPh)3),
132.8, 136.3 (o-, m-, p-Ph), 140.3 (i-Ph), 174.9 (CO2Me); m/z (ESI+)
4.11. Methyl (1R,2S,5S,
amino]-5-tris(phenylthio)methyl-cyclopentane-carboxylate
32 and methyl (1S,2R,5R, R)-2-[N-(3,4-dimethoxybenzyl)-
N-( -methylbenzyl)amino]-5-tris(phenylthio)methyl-
aS)-2-[N-benzyl-N-(a-methylbenzyl)-
a
a
cyclopentane-carboxylate 34
Following the General procedure, BuLi (1.6 M in hexanes,
13.0 mL, 20.7 mmol), (S)-N-benzyl-N-(
a-methylbenzyl)amine
(2.25 mL, 10.8 mmol) and (R)-N-(3,4-dimethoxybenzyl)-N-(
methylbenzyl)amine (2.90 mL, 10.8 mmol) in THF (20 mL), and
25 (2.50 g, 5.38 mmol) in THF (20 mL) gave a 50:50 mixture of
a-
(1R,2S,5S,aS)-32 (>98% de) and (1S,2R,5R,aR)-34 (>98% de) only.
Purification via flash column chromatography (eluent 30–40 °C
petrol/Et2O, 10:1) gave (1R,2S,5S,
a
S)-32 as a white solid (1.52 g,
42%, >98% de); ½a D23
ꢂ
¼ ꢀ81:9 (c 1.0, CHCl3). Further elution (eluent
614 ([M+Na]+, 100%); HRMS (ESI+) C36H40NO2S3 ([M+H]+) re-
30–40 °C petrol/Et2O, 1:1) gave (1S,2R,5R,
aR)-34 as a white solid
þ
quires: 614.2216; found, 614.2216.
(1.60 g, 41%, >98% de); mp 54–56 °C; ½a D23
ꢂ
¼ þ72:0 (c 1.0, CHCl3);

E. Abraham et al. / Tetrahedron: Asymmetry 19 (2008) 1356–1362
1361
mmax (KBr) 1729 (C@O); dH (400 MHz, CDCl3) 1.39 (3H, d, J 6.7,
C( )Me), 1.49–1.59 (2H, m, C(3)HA, C(4)HA), 1.62–1.73 (2H, m,
C(3)HB, C(4)HB), 3.30 (1H, dt, J 8.3, 4.0, C(5)H), 3.36 (1H, d, J 15.6,
NCHA), 3.50–3.56 (1H, m, C(2)H), 3.61 (3H, s, CO2Me), 3.77 (1H,
dd, J 4.0, 8.3, C(1)H), 3.85 (3H, s, ArOMe), 3.86 (1H, d, J 15.6, NCHB),
as a colourless oil (0.28 g, 67%, >98% de); ½a D23
ꢂ
¼ þ27:0 (c 0.9,
a
CHCl3); mmax (KBr) 2951 (N–H), 1731 (C@O); dH (400 MHz, CDCl3)
0.93 (3H, d, J 6.3, C(5)Me), 0.97–1.07 (1H, m, C(4)HA), 1.31 (3H, d,
J 6.8, C(a)Me), 1.70–1.77 (1H, m, C(3)HA), 1.94–2.07 (2H, m,
C(3)HB, C(4)HB), 2.38–2.43 (2H, m, C(1)H, C(5)H), 3.47–3.53 (1H,
3.92 (3H, s, ArOMe), 4.29 (1H, q, J 6.7, C(
6.99–7.02 (1H, m, Ar), 7.25–7.58 (20H, m, Ph); dC (100 MHz, CDCl3)
16.5 (C( )Me), 27.6, 30.0 (C(3), C(4)), 50.8 (C(1)), 50.8 (NCH2), 51.7
(CO2Me), 52.5 (C(5)), 55.8 (ArOMe), 55.9 (ArOMe), 57.5 (C( )), 65.5
a)H), 6.75–6.81 (2H, m, Ar),
m, C(2)H), 3.64 (3H, s, CO2Me), 3.75 (2H, s, NCH2), 3.87 (3H, s, Ar-
OMe), 3.93 (3H, s, ArOMe), 3.96 (1H, q, J 6.8, C(a)H), 6.79 (1H, d, J
a
8.2, C(60)H), 6.87 (1H, dd, J 1.1, 8.2, C(50)H), 7.11 (1H, d, J 1.1,
C(30)H), 7.21–7.37 (5H, m, Ph); dC (100 MHz, CDCl3) 13.6
a
(C(2)), 80.7 (C(SPh)3), 110.4, 110.6, 111.0, 119.3, 126.9, 128.0,
(C(a)Me), 20.6 (C(5)Me), 28.8 (C(3)), 33.1 (C(4)), 37.0 (C(5)), 51.2
128.4, 129.0, 132.0, 134.8, 135.9, 141.9, 147.4, 148.8 (Ar, Ph),
(CO2Me), 51.7 (NCH2), 55.8 (ArOMe), 55.8 (ArOMe), 56.9 (C(
a
)),
175.4 (CO2Me); m/z (ESI+) 736 ([M+H]+, 20%), 476 (100); HRMS
61.4 (C(2)), 110.5, 111.7, 120.3, 126.5, 127.7, 128.0, 133.8, 143.6,
(ESI+) C43H46NO4S3
736.2584.
([M+H]+) requires: 736.2589; found,
147.6, 148.8 (Ar, Ph), 174.7 (CO2Me); m/z (ESI+) 412 ([M+H]+,
þ
100%); HRMS (ESI+) C25H34NO4 ([M+H]+) requires: 412.2483;
þ
found, 412.2488.
4.12. X-ray crystal structure determination for 34
4.15. Methyl (1S,2R,5R,aR)-2-[N-(a-methylbenzyl)amino]-5-
Data were collected using an Enraf-Nonius
ter with graphite monochromated Mo K radiation using standard
procedures at 150 K. The structure was solved by direct methods
SIR92), all non-hydrogen atoms were refined with anisotropic ther-
mal parameters. Hydrogen atoms were added at idealised posi-
j
-CCD diffractome-
methyl-cyclopentane-carboxylate 37
a
DDQ (0.67 g, 2.90 mmol) was added portionwise to a stirred
solution of b-amino ester 36 (0.60 g, 1.47 mmol) in a solution of
DCM (60 mL) and H2O (8 mL) at rt. The resultant mixture was stir-
red for 18 h before the addition of satd aq NaHCO3 (50 mL). The
aqueous layer was separated and extracted with DCM
(2 ꢁ 50 mL). The combined organic layers were washed with brine
(150 mL), dried and concentrated in vacuo. Purification via flash
column chromatography (eluent 30–40 °C petrol/EtOAc, 5:1) gave
(
17
tions. The structure was refined using CRYSTALS
.
X-ray crystal structure data for 34 [C43H45NO4S3]: M = 736.03,
orthorhombic, space group P212121, a = 9.82860(10) Å, b =
17.4111(2) Å, c = 22.6109(3) Å, V = 3869.33(8) Å3, Z = 4,
l = 0.23
mmꢀ1, colourless plate, crystal dimensions = 0.1 ꢁ 0.1 ꢁ 0.2 mm3.
A total of 8780 unique reflections were measured for 5 < h < 27
and 6671 reflections were used in the refinement. The final param-
37 as a colourless oil (0.31 g, 82%, >98% de); ½a D20
¼ þ126 (c 1.0,
ꢂ
CHCl3). mmax (film) 1725 (C@O); dH (400 MHz, CDCl3) 0.99 (3H, d,
eters were wR2 = 0.031 and R1 = 0.029 [I > 3
r
(I)]. Crystallographic
J 6.6, C(5)Me), 1.02 (1H, m, C(4)HA), 1.25 (3H, d, J 6.7, C(a)Me),
data (excluding structure factors) have been deposited with the
Cambridge Crystallographic Data Centre as supplementary publi-
cation number CCDC 665858. Copies of the data can be obtained,
free of charge, on application to CCDC, 12 Union Road, Cambridge
CB2 1EZ, UK [fax: +44(0)-1223-336033 or e-mail: deposit@
ccdc.cam.ac.uk].
1.52 (1H, m, C(3)HA), 1.67 (1H, br s, NH), 1.80–1.90 (2H, m,
C(3)HB, C(4)HB), 2.49 (1H, t, J 8.0, C(1)H), 3.22 (1H, m, C(2)H),
3.69 (1H, q, J 6.7, C(
7.30–7.33 (4H, m, Ph); dC (100 MHz, CDCl3) 20.6 (C(5)Me), 24.8
(C( )Me), 32.2 (C(4)), 34.2 (C(3)), 37.7 (C(5)), 51.4 (OMe), 54.9
(C(1)), 56.7 (C(
a)H), 3.76 (3H, s, OMe), 7.25 (1H, m, Ph),
a
a
)H), 59.5 (C(2)), 126.7, 126.8, 128.3 (o-, m-, p-Ph),
146.1 (i-Ph), 175.4 (C@O); m/z (ESI+) 262 ([M+H]+, 97%); HRMS
(ESI+) C16H23NNaO2
284.1620.
([M+Na]+) requires: 284.1621; found,
þ
4.13. Methyl (1R,2S,5S,aS)-2-[N-benzyl-N-(
a-methyl-
benzyl)amino]-5-methyl-cyclopentane-carboxylate 35
Raney Nickel (50% slurry in H2O, 8 mL) was added in five equal
portions to a stirred solution of 32 (1.62 g, 2.40 mmol) in THF
(40 mL) over a period of 8 h. The reaction mixture was filtered
through Celite and concentrated in vacuo. Purification via flash col-
umn chromatography (eluent 30–40 °C petrol/EtOAc, 12:1) gave 35
4.16. Methyl (1R,2S,5S)-2-ammonio-5-methyl-cyclopentane-
carboxylate trifluoroacetate (1R,2S,5S)-38
Pd(OH)2/C (20 mg) was added to a degassed solution of 35
(95 mg, 0.35 mmol) in AcOH/MeOH (40:1, 5 mL) and stirred for
2 h under H2 (1 atm). The reaction mixture was filtered through
Celite and concentrated in vacuo. The residue was redissolved in
DCM (2 mL) and treated with TFA (2 mL). After 15 min stirring
the solution was concentrated in vacuo. This process was repeated
twice to give (1R,2S,5S)-38 as a colourless oil (67 mg, 91%, >98% de,
as a colourless oil (0.66 g, 79%, >98% de); ½a D20
¼ ꢀ50:4 (c 1.1,
ꢂ
CHCl3); mmax (film) 1730 (C@O); dH (400 MHz, CDCl3) 0.97 (3H, d,
J 6.3, C(5)Me), 1.04 (1H, m, C(4)HA), 1.36 (3H, d, J 6.8, C(a)Me),
1.74 (1H, m, C(3)HA), 1.74–2.09 (2H, m, C(3)HB, C(4)HB), 2.37–
2.49 (2H, m, C(1)H, C(5)H), 3.53 (1H, m, C(2)H), 3.74 (3H, s, OMe),
3.87 (2H, m, NCH2), 4.02 (1H, q, J 6.8, C(
Ph), 7.33–7.46 (8H, m, Ph); dC (100 MHz, CDCl3) 14.1 (C(5)Me),
20.7 (C( )Me), 29.2 (C(3)), 33.1 (C(4)), 37.0 (C(5)), 51.4 (OMe),
51.9 (NCH2), 56.5 (C( )), 56.6 (C(1)), 61.8 (C(2)), 126.6, 127.8,
a)H), 7.23–7.30 (2H, m,
>98% ee); ½a 2D0
¼ þ29:8 (c 1.0, CHCl3); mmax (film) 1700 (C@O); dH
ꢂ
(400 MHz, CD3OD) 1.14 (3H, d, J 6.5, C(5)Me), 1.33–1.37 (1H, m,
C(4)HA), 1.78–1.83 (1H, m, C(3)HA), 2.03–2.10 (1H, m, C(4)HB),
2.19–2.25 (1H, m, C(3)HB), 2.34–2.41 (1H, m, C(5)H), 2.65 (1H,
dd, J 2.3, 7.5, C(1)H), 3.76 (3H, s, OMe), 3.85 (1H, q, J 6.5, C(2)H);
dC (100 MHz, CDCl3) 18.5 (C(5)Me), 30.4 (C(3)), 31.3 (C(4)), 37.7
a
a
128.0, 128.1, 128.4 (o-, m-, p-Ph), 141.4, 143.5 (i-Ph), 174.9
(CO2Me); m/z (ESI+) 352 ([M+H]+, 100%); HRMS (ESI+) C23H30NO2
þ
([M+H]+) requires: 352.2271; found, 352.2273.
(C(5)), 51.7 (OMe), 53.0 (C(2)), 53.1 (C(1)), 116.2 (q, JC–F 280,
1
2
CF3), 160.3 (q, JC–F 37, CF3CO), 173.3 (C@O); m/z (ESI+) 158
([M+H]+, 100%); HRMS (ESI+) C8H16NO2 ([M+H]+) requires:
þ
4.14. Methyl (1S,2R,5R,aR)-2-[N-(3,4-dimethoxybenzyl)-N-(
a-
methylbenzyl)amino]-5-methyl-cyclopentane-carboxylate 36
158.1176; found, 158.1175.
Raney Nickel (50% slurry in H2O, 4 mL) was added in five equal
portions to a stirred solution of 34 (0.74 g, 0.34 mmol) in THF
(20 mL) over a period of 8 h. The reaction mixture was filtered
through Celite and concentrated in vacuo. Purification via flash col-
umn chromatography (eluent 30–40 °C petrol/EtOAc, 6:1) gave 36
4.17. Methyl (1S,2R,5R)-2-ammonio-5-methyl-cyclopentane-
carboxylate trifluoroacetate (1S,2R,5R)-38
Pd(OH)2/C (26 mg) was added to a degassed solution of 37
(110 mg, 0.41 mmol) in AcOH/MeOH (40:1, 5 mL) and stirred for

1362
E. Abraham et al. / Tetrahedron: Asymmetry 19 (2008) 1356–1362
Martinek, T. A.; Táth, G. K.; Vass, E.; Hollósi, M.; Fülöp, F. Angew. Chem., Int. Ed.
2002, 41, 1718.
4. Babler, J. H.; Sarussi, S. J. J. Org. Chem. 1987, 52, 3462.
2 h under H2 (1 atm). The reaction mixture was filtered through
Celite and concentrated in vacuo. The residue was redissolved in
DCM (2 mL) and treated with TFA (2 mL). After 15 min stirring
the solution was concentrated in vacuo. This process was repeated
twice to give (1S,2R,5R)-38 as a colourless oil (100 mg, 95%, >98%
5. For kinetic resolution of 3-alkyl-cyclopent-1-ene-carboxylates see: (a) Bailey,
S.; Davies, S. G.; Smith, A. D.; Withey, J. M. Chem. Commun. 2002, 2910;
Bunnage, M. E.; Chippindale, A. M.; Davies, S. G.; Parkin, R. M.; Smith, A. D.;
Withey, J. M. Org. Biomol. Chem. 2003, 1, 3698; Bunnage, M. E.; Davies, S. G.;
Parkin, R. M.; Roberts, P. M.; Smith, A. D.; Withey, J. M. Org. Biomol. Chem. 2004,
2, 3337; For parallel kinetic resolution of 3-alkyl-cyclopent-1-ene-carboxylates
see: (b) Davies, S. G.; Garner, A. C.; Long, M. J. C.; Smith, A. D.; Sweet, M. J.;
Withey, J. M. Org. Biomol. Chem. 2004, 2, 3355; For kinetic and parallel kinetic
resolution of 5-alkyl-cyclopent-1-ene-carboxylates see: (c) Davies, S. G.; Díez,
D.; El Hammouni, M. M.; Garner, A. C.; Garrido, N. M.; Long, M. J. C.; Morrison,
R. M.; Smith, A. D.; Sweet, M. J.; Withey, J. M. Chem. Commun. 2003, 2410;
Davies, S. G.; Garner, A. C.; Long, M. J. C.; Morrison, R. M.; Roberts, P. M.; Savory,
E. D.; Smith, A. D.; Sweet, M. J.; Withey, J. M. Org. Biomol. Chem. 2005, 3, 2762;
For parallel kinetic resolution of 3-oxy-substituted cyclopent-1-ene-
carboxylates see: (d) Aye, Y.; Davies, S. G.; Garner, A. C.; Roberts, P. M.;
Smith, A. D.; Thomson, J. E. Org. Biomol. Chem. 2008. doi:10.1039/b802428f.
6. Horeau, A. Tetrahedron 1975, 31, 1307.
de, >98% ee); ½a 1D7
¼ ꢀ30:0 (c 1.0, CHCl3).
ꢂ
4.18. (1R,2S,5S)-2-Amino-5-methyl-cyclopentane-carboxylic
acid (1R,2S,5S)-39
LiOH (2 M, 0.75 mL, 1.5 mmol) was added to a stirred solution
of (1R,2S,5S)-38 (82 mg, 0.3 mmol) in THF (3 mL) at rt and stirred
for 16 h. The reaction mixture was concentrated in vacuo, re-dis-
solved in 1 M aq HCl (5 mL) and then concentrated in vacuo. Puri-
fication via ion exchange chromatography (Dowex 50WX8-200
resin) gave (1R,2S,5S)-39 as a white solid (41 mg, 95%, >98% de);
7. For examples see: Takahata, H.; Uchida, Y.; Momose, T. J. Org. Chem. 1995, 60,
5628; Fernandez, F.; Otero, J. M.; Estevez, J. C.; Estevez, R. J. Tetrahedron:
Asymmetry 2006, 17, 3063; Perreault, S.; Spino, C. Org. Lett. 2006, 8, 4385;
Shingate, B. B.; Hazra, B. G.; Pore, V. S.; Gonnade, R. G.; Bhadbhada, M. M.
Tetrahedron 2007, 63, 5622.
mp >360 °C; ½a 1D7
¼ þ19:0 (c 1.0, H2O); mmax (film) 1695 (C@O);
ꢂ
dH (400 MHz, D2O) 1.03 (3H, d, J 6.6, C(5)Me), 1.22–1.26 (1H, m,
C(4)HA), 1.66–1.70 (1H, m, C(3)HA), 1.93–1.97 (1H, m, C(4)HB),
2.07–2.17 (2H, m, C(5)H, C(3)HB), 2.27 (1H, dd, J 6.6, 10.1, C(1)H),
3.69–3.75 (1H, m, C(2)H); dC (125 MHz, D2O) 18.8 (C(5)Me), 29.6
(C(3)), 30.5 (C(4)), 37.4 (C(5)), 53.1 (C(2)), 55.2 (C(1)), 180.4
8. Manas, A.-R. B.; Smith, R. A. J. J. Chem. Soc., Chem. Commun. 1975, 216; See also:
Stork, G.; Rychnovsky, S. D. J. Am. Chem. Soc. 1987, 109, 1564.
9. For examples see: Braun, M.; Laicher, F.; Meier, T. Angew. Chem., Int. Ed. 2000,
39, 3494; Smith, A. B., III; Pitram, S. M.; Boldi, A. M.; Gaunt, M. J.; Sfouggatakis,
C.; Moser, W. H. J. Am. Chem. Soc. 2003, 125, 14435; Amat, M.; Perez, M.; Llor,
N.; Escolano, C.; Luque, F. J.; Molins, E.; Bosch, J. J. Org. Chem. 2004, 69, 8681;
Shiina, J.; Nishiyama, S. Tetrahedron Lett. 2005, 46, 7683.
(C@O); m/z (ESIꢀ) 142 ([M–H]ꢀ, 89%); HRMS (ESI+) C7H13NNaO2
þ
([M+Na]+) requires: 166.0838; found, 166.0837.
10. Dambrin, V.; Villiéras, M.; Moreau, C.; Amri, H.; Toupet, L.; Villiéras, J.
Tetrahedron Lett. 1996, 37, 6323; Dambrin, V.; Villiéras, M.; Janvier, P.;
Toupet, L.; Amri, H.; Lebreton, J.; Villiéras, J. Tetrahedron 2001, 57, 2155.
11. Le Diguarher, T.; Chollet, A.-M.; Bertrand, M.; Hennig, P.; Raimbaud, E.;
Sabatini, M.; Guilbaud, N.; Pierre, A.; Tucker, G. C.; Casara, P. J. Med. Chem. 2003,
46, 3840.
12. Ager, D. J.; East, M. B. J. Org. Chem. 1986, 51, 3983; Kar, A.; Argade, N. P.
Tetrahedron 2003, 59, 2991.
13. Cailleau, T.; Cooke, J. W. B.; Davies, S. G.; Ling, K. B.; Naylor, A.; Nicholson, R. L.;
Price, P. D.; Roberts, P. M.; Russell, A. J.; Smith, A. D.; Thomson, J. E. Org. Biomol.
Chem. 2007, 5, 3922.
14. The high stereocontrol exerted upon protonation of an enolate anti to an
adjacent heteroatom is well documented; see: Mohrig, J. R.; Rosenberg, R. E.;
Apostol, J. W.; Bastienaansen, M.; Evans, J. W.; Franklin, S. J.; Frisbie, C. D.; Fu, S.
S.; Hamm, M. L.; Hirose, C. B.; Hunstad, D. A.; James, T. L.; King, R. W.; Larson, C.
J.; Latham, H. A.; Owen, D. A.; Stein, K. A.; Warnet, R. J. Am. Chem. Soc. 1997, 119,
479; Banfi, L.; Guanti, G. Tetrahedron: Asymmetry 1999, 10, 439; Davies, H. M.
L.; Hodges, L. M.; Gregg, T. M. J. Org. Chem. 2001, 66, 7898.
15. Enantiomeric excesses were determined by derivatisation with both
homochiral and racemic Mosher’s acid chloride, and subsequent analysis of
the resultant amides by 1H and 19F NMR spectroscopy; see Dale, J. A.; Dull, D.
L.; Mosher, H. S. J. Org. Chem. 1969, 34, 2543.
16. Pangborn, A. B.; Giardello, M. A.; Grubbs, R. H.; Rosen, R. K.; Timmers, F. J.
Organometallics 1996, 15, 1518.
17. Betteridge, P. W.; Carruthers, J. R.; Cooper, R. I.; Prout, C. K.; Watkin, D. J.
CRYSTALS, Issue 11, Chemical Crystallography Laboratory, University of Oxford:
UK, 2001.
4.19. (1S,2R,5R)-2-Amino-5-methyl-cyclopentane-carboxylic
acid (1S,2R,5R)-39
LiOH (2 M, 0.5 mL, 1.0 mmol) was added to a stirred solution of
(1S,2R,5R)-38 (49 mg, 0.18 mmol) in THF (3 mL) at rt and stirred for
16 h. The reaction mixture was concentrated in vacuo, re-dissolved
in 1 M aq HCl (5 mL) and then concentrated in vacuo. Purification
via ion exchange chromatography (Dowex 50WX8-200 resin) gave
(1S,2R,5R)-39 as a white solid (24 mg, 93%, >98% de); ½a D17
¼ ꢀ18:8
ꢂ
(c 1.0, H2O).
References
1. For a review see: Fülöp, F. Chem. Rev. 2001, 2181.
2. For example see: Aggarwal, V. K.; Roseblade, S. J.; Barrell, J. K.; Alexander, R.
Org. Lett. 2002, 4, 1227; Bohm, C.; Schiffers, I.; Atodiresi, I.; Hackenberger, C. P.
R. Tetrahedron: Asymmetry 2003, 14, 3455; Aggarwal, V. K.; Roseblade, S. J.;
Alexander, R. Org. Biomol. Chem. 2003, 1, 684.
3. Gellman and co-workers have shown that b-peptides derived from
transpentacin adopt a helical structure in the solid state and solution; see:
Dado, G. P.; Gellman, S. H. J. Am. Chem. Soc. 1994, 116, 1054; Appella, D. H.;
Christianson, L. A.; Klein, D. A.; Powell, D. R.; Huang, X.; Barchi, J. J.; Gellman, S.
H. Nature 1997, 387, 381; Fülöp and co-workers have shown that b-peptides
derived from cispentacin form a sheetlike secondary structure in solution; see: