Diastereoselective addition of chiral azomethine ylides to cyclic α,β-unsaturated N-enoylbornanesultams

Article abstract of DOI:10.1039/b200579d

Doubly diastereoselective 1,3-dipolar cycloaddition reactions of chiral non-racemic azomethine ylides to cyclic five-and six-membered α,β-unsaturated N-enoylbornanesultams were carried out. When suitable solvents were used, the fused bicyclic adducts form

Full text of DOI:10.1039/b200579d

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Diastereoselective addition of chiral azomethine ylides to cyclic
ꢀ,ꢁ-unsaturated N-enoylbornanesultams
Staffan Karlsson* and Hans-Erik Högberg*
1
Chemistry, Department of Natural and Environmental Sciences, Mid Sweden University,
SE-851 70 Sundsvall, Sweden. E-mail: staffan.karlsson@mh.se.
E-mail: hans-erik.hogberg@mh.se
Received (in Cambridge, UK) 18th January 2002, Accepted 15th February 2002
First published as an Advance Article on the web 15th March 2002
Doubly diastereoselective 1,3-dipolar cycloaddition reactions of chiral non-racemic azomethine ylides to cyclic five-
and six-membered α,β-unsaturated N-enoylbornanesultams were carried out. When suitable solvents were used,
the fused bicyclic adducts formed were obtained in good diastereoselectivity. Moreover, a change of the absolute
configuration of the starting ylide precursor reversed the diastereoselectivity of some such reactions. Cleavage of the
chiral auxiliary of the cycloadducts furnished amino alcohols and a β-amino ester. The latter was transformed into a
known precursor of an antibacterial compound.
Introduction
One of the most powerful reactions for the construction of
substituted five-membered heterocyclic compounds is the 1,3-
dipolar cycloaddition reaction.1 When an ylide containing a
heteroatom reacts with dipolarophiles, up to four new chiral
centers are created in one step. Moreover, when either the di-
polarophile or the ylide is chiral and non-racemic, diastereo-
facial selectivity is expected.2 For example, achiral nonstabilized
azomethine ylides react with α,β-unsaturated acyl moieties
attached to chiral auxiliaries with varying degrees of facial
selectivity to give substituted pyrrolidines.3 The diastereofacial
selectivity can often be improved, if both the reacting partners
are chiral. We have recently studied acyclic dipolarophiles
attached to chiral auxiliaries in reactions with non-racemic
azomethine ylides, derived from enantiomerically pure phenyl-
ethylamine.4 When such and other types of chiral ylides are
used, the induction of facial selectivity is generally small to
moderate.4–6 This can probably be explained by minor inter-
actions between the chiral N-substituent of the ylide and the
substituent(s) of the dipolarophile.
Azomethine ylides have previously been used in inter-
molecular 1,3-dipolar cycloadditions to non-racemic bicyclic
lactams and cyclopent-1-enecarboxylic acid methyl ester.6,7
However, azomethine ylide additions to monocyclic five-
and six-membered α,β-unsaturated acyl derivatives attached to
chiral auxiliaries have, to our knowledge, not been investigated.
Some derivatives of the resulting azabicyclo[3.3.0]octanes have
been found to exhibit antibacterial activity.7 Furthermore,
the cycloadducts can be used for further transformation into
enantiopure amino alcohols and β-amino acids.
Scheme 1 1,3-Dipolar cycloadditions of achiral or chiral azomethine
ylide precursors 1–3 to cyclic dipolarophiles 4–6.
(Table 1, entry 5). In contrast to our earlier studies with acyclic
dipolarophiles,3a these experiments had to be performed in the
presence of only a trace of TFA, because no conversion
occurred at higher concentrations (20–50 mol% of TFA).
Moreover, the reactions were slower, less stereoselective and
more sensitive to the reaction conditions than those with acyclic
dipolarophiles.
It has been shown earlier that, compared with α-unsub-
stituted α,β-unsaturated dipolarophiles attached to bornane-
sultam, α-substituted examples show reduced reactivity and
diastereoselectivity in other cycloaddition reactions.8 In the
latter case, the α-substituent is expected to force the alkene
moiety out of the plane of the carbonyl group. The resulting
loss of conjugation is thought to be partly responsible for the
reduced reactivity of α-substituted acryloyl compounds.8a
A change of the solvent in the reaction of the dipolarophile 4
with the ylide from 1 could have an effect on the diastereo-
We now present singly and doubly diastereoselective 1,3-
dipolar cycloadditions of azomethine ylides, both achiral
and chiral, to cyclic dipolarophiles attached to (2R)-(Ϫ)-
bornanesultam.
Results and discussion
When an excess of the achiral azomethine ylide precursor 1 was
treated with a catalytic amount (∼1 mol%) of trifluoroacetic
acid (TFA) in the presence of the dipolarophile 4 (Scheme 1)
in THF at room temperature, a mixture of the cycloadducts 7
and 8 was obtained in a low diastereomeric ratio (dr = 60 : 40)
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J. Chem. Soc., Perkin Trans. 1, 2002, 1076–1082
This journal is © The Royal Society of Chemistry 2002
DOI: 10.1039/b200579d

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Table 1 Diastereomeric ratio in the 1,3-dipolar cycloaddition of azomethine ylides derived from 1–3 to dipolarophiles 4 and 5
Entrya, b
Precursor
Dipolarophile
Solvent
Temp./ЊC
Dr (major : minor)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
2
2
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
5
5
Xylene
Dioxane
CCl4
DMF
THF
Acetone
CH3CN
Toluene
CH2Cl2
Xylene
Dioxane
CCl4
110
40 : 60 (7 : 8)c
52 : 48 (7 : 8)c
41 : 59 (7 : 8)c
54 : 46 (7 : 8)c
60 : 40 (7 : 8)c
52 : 48 (7 : 8)c
57 : 43 (7 : 8)c
41 : 59 (7 : 8)c
57 : 43 (7 : 8)c
20 : 80 (9 : 10)d
25 : 75 (9 : 10)d
20 : 80 (9 : 10)d
30 : 70 (9 : 10)d
32 : 68 (9 : 10)d
32 : 68 (9 : 10)d
32 : 68 (9 : 10)d
22 : 78 (9 : 10)d
32 : 68 (9 : 10)d
48 : 52 (11 : 12)c
57 : 43 (11 : 12)c
43 : 57 (11 : 12)c
68 : 32 (11 : 12)c
75 : 25 (11 : 12)c
73 : 27 (11 : 12)c
74 : 26 (11 : 12)c
55 : 45 (11 : 12)c
82 : 18 (11 : 12)c
25 : 75 (13 : 14)c
23 : 77 (13 : 14)c
Reflux
Reflux
100
20
Reflux
Reflux
Reflux
Reflux
110
Reflux
Reflux
100
DMF
THF
20
Acetone
CH3CN
Toluene
CH2Cl2
Xylene
Dioxane
CCl4
Reflux
Reflux
Reflux
Reflux
110
Reflux
Reflux
100
DMF
THF
20
Acetone
CH3CN
Toluene
CH2Cl2
Xylene
CH2Cl2
Reflux
Reflux
Reflux
Reflux
110
20
a Compound 1, 2 or 3 (0.21 mmol) was added to a solution of 4 or 5 (0.07 mmol) in the solvent (0.2 ml) specified and trifluoroacetic acid (0.001
mmol), at 0.25 h intervals in four portions at the temperature specified. After 0.5 h, Na2CO3 (aq. sat., 3 ml) was added and the mixture was diluted
with EtOAc (5 ml). The organic phase was dried (MgSO4) and concentrated. Diastereomeric ratios were determined for the crude products.
b Complete conversion was not achieved here, but occurred in reactions performed on a larger scale, as described in the Experimental section.
c Determined by GC analyses. d Determined by 1H NMR integration.
selectivity (Table 1). Reversed facial selectivity was observed in
some solvents (compare entries 1, 3 and 8 with entries 2, 4–7
and 9). When performing this reaction at a high temperature,
e.g. in xylene at 110 ЊC, we noticed that an acid catalyst such as
TFA was not a prerequisite for azomethine ylide generation.
Smaller amounts of the azomethine ylide precursor were
consumed, and higher yields were obtained under acid-free
conditions (see Experimental section).
All of the reactions studied so far (entries 1–9, Table 1)
involved the achiral ylide 1 and took place with low diastereo-
selectivity. In order to increase this selectivity, we treated the
dipolarophile 4 with the ylide enantiomers obtained from the
Fig. 1 Diastereomeric ratio (dr) as a function of solvent and dipole
phenylethylamine-derived precursors 2 and 3. Most of these
precursor used (1, 2 or 3) in the reaction with 4. Negative bars mean an
reactions resulted in improved diastereoselectivity, but reversed
excess of diastereomer 7 or 11 and positive bars mean an excess of
facial selectivity was observed in some of them. For example,
when the reaction was performed in refluxing CH2Cl2 in the
presence of either one of the ylide precursors 2 or 3, the facial
selectivity switched from a preference for the diastereomer 10
(dr 9 : 10, 32 : 68) to 11 (dr 11 : 12, 82 : 18) (entries 18 and 27,
Table 1). The significant effect observed here (Fig. 1) of the
chiral phenylethylamine-derived azomethine ylides is in sharp
contrast to our earlier results obtained with the same ylides in
reactions with acyclic dipolarophiles.4 The non-racemic ylide
derived from 2 reacted with the dihydrothiophene 5 under the
same conditions as in entry 10, to afford a diastereomeric
mixture of the cycloadducts 13 and 14 (1 : 3, entry 28). We tried,
without success, to make the six-membered cyclic dipolarophile
6 react with a large excess of either enantiomer of the chiral
azomethine ylides derived from 2 and 3 under a variety of
conditions. Only trace amounts (1–4% conversion) of two
diastereomeric cycloadducts were produced. However, they
were obtained in good diastereoselectivity (up to 85 : 15 dr).
The optimal conditions for achieving high diastereoselec-
tivity were different for each set of reactants. Using such con-
ditions (see Experimental section) we also performed the
diastereomer 8, 10 or 12.
1,3-dipolar cycloaddition reactions on a larger scale. Thus,
the crude mixture of the diastereomeric cycloadducts 7 and 8
(obtained from 1 and 4 in THF), 9 and 10 or 13 and 14
(obtained from 2 and 4 or 2 and 5, respectively, in xylene at
110 ЊC), was separated on silica gel to give the individual
diastereomers, all in >200 : 1 diastereomeric ratio (dr). Thus,
the major cycloadducts 7, 10 and 14 were obtained in 54, 59 and
56% isolated yield, respectively. The diastereomers 11 and 12,
obtained from 3 and 4 in THF, were not separable on silica gel.
Fortunately, one recrystallisation of the crude mixture from
cyclohexane afforded the major diastereomer 11 (>200 : 1 dr) in
58% isolated yield. The minor diastereomer 12 could not be
isolated in a diastereomerically pure form. The sultam auxiliary
of the major diastereomeric cycloadducts 7, 10, 11 and 14
was then cleaved off as shown in Scheme 2 to give the amino
alcohols 15–18 (88–99% yield) along with the recovered
bornanesultam (97–99%).
Hydrogenation of the benzyl group of 15 and the phenylethyl
groups of 16 and 17, using Pd/C, furnished the enantiomers 19
J. Chem. Soc., Perkin Trans. 1, 2002, 1076–1082
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salt (Ϫ)-23 in 80% overall yield, [α]2D5 = Ϫ1.0 (c 5.8, MeOH).
Thus, our sample of (Ϫ)-23 had the same configuration as that
of the previously prepared (Ϫ)-23, lit.7 [α]2D4 = Ϫ0.9 (c 49,
MeOH). The configurations of the compounds 7 and 11 could
then be determined by comparison of the sign of optical
rotation of ent-19 (Scheme 2) obtained from 7 and 11 with that
of compound 19 prepared from 10. The absolute configurations
of the diastereomeric bicyclic adducts 13 and 14 were not
determined, but were assumed to be as shown (Scheme 1), pro-
vided that the dihydrothiophene 5 reacted with the azomethine
ylide derived from 2 in the same fashion as the cyclopentenoic
1
derivative 4. This assumption was supported by the H NMR
chemical shifts of 13 and 14, which showed the same pattern of
relative positions of the signals as the shifts of samples of 9
and 10. Other data of 13 and 14 also had the same relative
values as those observed for samples of 9 and 10 (see Experi-
mental section).
We wished to explain the reversed stereoselectivity obtained
when letting the cyclopentenecarboxamide 4 react with either
the ylide from 2 or its enantiomer 3. Hence, we also investigated
the reaction of 2 with two achiral cyclic dipolarophiles,
cyclopent-1-enecarboxylic acid ethyl ester and 2,5-dihydro-
thiophene-3-carboxylic acid methyl ester, using the conditions
in entry 29 (Table 1). Two separable diastereomeric cyclo-
adducts were formed in both cases (64 : 36 dr). Both major
adducts were formed with the same sense of π-facial selectivity
as that observed in the reactions of the ylide derived from
2 with the corresponding chiral dipolarophile 4 or 5. This
indicates that there was an interaction in the transition state
between the five- membered cyclic framework and the chiral
phenylethyl moiety of the ylide, resulting in a discrimination of
one of the π-faces of the dipolarophile.
Scheme 2 Reductive cleavage of the chiral auxiliary and preparation
of amino alcohols 19–20. (a) (i) LiAlH4, THF; (ii) H3Oϩ, 88–99%;
(b) Pd/C, H2; (c) (i) ClCOOCH(Cl)CH3, 1,8-bis(dimethylamino)-
naphthalene; (ii) methanol, reflux; (iii) MeOH, HCl (aq.) (77% over
3 steps).
and ent-19. The phenylethyl group of the sulfur-containing
compound 18 could not be removed under the same conditions.
Only unreacted starting material could be recovered, along with
small amounts of the corresponding desulfurised compound
(18 with Y = H2 instead of S) as judged by GC-MS analysis.
Catalyst poisoning by the divalent sulfur was a probable reason
why 18 was unreactive towards hydrogenation.9 However,
an alternative reagent, α-chloroethyl chloroformate,10 accom-
plished the removal of the phenylethyl group of 18 to give
compound 20 (77% yield) after methanolysis and hydrolysis.
In order to confirm the configuration of the stereocenters in
the cycloadducts 7–12, we converted the major diastereomer 10,
obtained from the reaction of the ylide 2 with the dipolarophile
4, in a few steps (Scheme 3) to compound (Ϫ)-23, a known
synthetic precursor of an antibacterial compound.7
The results described above show that the chirality of the
ylide is more important than that of the dipolarophile for
achieving high diastereoselectivity in ylide additions to cyclic
alkenoyl derivatives attached to bornanesultam.
In summary, we have demonstrated that five-membered
cycloalkenylcarbonyl derivatives attached to (2R)-(Ϫ)-bornane-
sultam can serve as dipolarophiles in reactions with both chiral
and achiral azomethine ylides, giving fused bicyclic hetero-
cycles. A good diastereoselectivity and a high yield can be
obtained with the correct choice of reaction conditions. The
cycloadducts are potential building blocks for further manip-
ulation into natural alkaloids, chiral ligands and auxiliaries,
suitable for use in enantioselective reactions. The utility of the
reactions studied here has been demonstrated by the synthesis
of the known7 enantiomerically pure (Ϫ)-23.
Experimental
All chemicals were used as received unless otherwise stated.
THF (K, benzophenone), xylene, dioxane, acetone, acetonitrile,
toluene, CH2Cl2 (all CaH2) were distilled from the indicated
1
drying agents. Other solvents were used as recieved. H NMR
and 13C NMR spectra were recorded on a Bruker DMX 250
(250 MHz 1H and 62.9 MHz 13C) instrument. Preparative liquid
chromatography was performed on straight phase silica gel
(Merck 60, 230–400 mesh, 0.040–0.063 mm) using an increasing
concentration of distilled ethyl acetate in distilled cyclohexane
as eluent. GC analyses were carried out using a capillary
column EC-5, 30 m, 0.32 mm id, df = 0.25µm, carrier gas N2.
The elemental analyses (C, H, N) were performed by Mikro
Kemi AB, SE-752 28 Uppsala, Sweden. Boiling points are
uncorrected and given as air bath temperatures (bath temp./
mbar) in a bulb to bulb (Büchi GKR-51) apparatus. Optical
rotations were measured (10Ϫ1 deg cm2 gϪ1) with a Perkin-Elmer
241 MC polarimeter in a 1 dm cell. Mass spectra were recorded
on a Saturn 2000 instrument, coupled to a Varian 3800 GC
instrument. Compounds 1, 2 and 3 were prepared using the
procedure reported by Hosomi et al.12 The work up procedure
Scheme 3 Preparation of (Ϫ)-23.
Ethanolysis11 of compound 10 [Ti(OEt)4, EtOH, reflux]
afforded the ester 21 (90%). Aminolysis through treatment in
THF under reflux, with an excess of lithium amide, furnished
the corresponding amide 22 in 77% yield. This amide was
reduced with LAH, which yielded the corresponding primary
amine. Without further purification, this was subjected to
hydrogenation of the phenylethyl group (H2, Pd/C). The result-
ing diamine was treated with aqueous HBr to give the known7
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J. Chem. Soc., Perkin Trans. 1, 2002, 1076–1082

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followed another alternative method.6b Compound 613 was
obtained following the procedure for the preparation of 4
described below.
C, 68.0; H, 7.8; N, 6.4. Calc. for C25H34N2O3S: C, 67.8; H, 7.7;
N, 6.3%.
8 (Minor): mp 158–160 ЊC, [α]2D5 = Ϫ37.7 (c 0.45, CHCl3).
1H NMR (CDCl3) δ 0.95 (3H, s), 1.13 (3H, s), 1.30–1.50 (4H,
m), 1.71–2.45 (11H, m), 2.76 (1H, d, J = 9.7 Hz), 3.13 (1H, d,
J = 9.7 Hz), 3.27–3.38 (1H, m), 3.40 (1H, d, J = 13.3 Hz), 3.42
(2H, s), 3.70 (1H, d, J = 13.3 Hz), 3.95 (1H, dd, J = 4.4, 7.6 Hz),
7.18–7.34 (5H, m). 13C NMR (CDCl3) δ 19.9, 20.5, 26.6,
26.9, 32.6, 33.0, 38.5, 38.8, 44.1, 47.1, 47.8, 48.1, 53.4, 59.2,
59.9, 63.1, 63.7, 66.6, 126.8, 128.1, 128.5, 139.2, 176.1. MS (EI):
m/z (%) 443 [14, (M ϩ H)ϩ], 379 (25), 352 (4), 229 (7), 200 (100),
91 (99). Found: C, 67.6; H, 7.8; N, 6.4. Calc. for C25H34N2O3S:
C, 67.8; H, 7.7; N, 6.3%.
N-(1-Cyclopent-1-en-1-ylcarbonyl)-(2ЈR)-bornane-10,2-sultam 4
Thionyl chloride (5 ml, 68.5 mmol) was added to a solution of
cyclopent-1-enecarboxylic acid (2.4 g, 21.4 mmol) in CH2Cl2
(20 ml). The solution was allowed to reflux for 2 hours followed
by concentration in vacuo to give the corresponding acid
chloride. MeMgBr (3 M in diethyl ether, 6.7 ml, 20.1 mmol)
was added to a 0 ЊC solution of (2R)-(Ϫ)-bornane-10,2-sultam
(4.3 g, 20.0 mmol) in THF (150 ml). After 0.5 h the acid
chloride in THF (20 ml) was slowly added and the solution was
allowed to stir for 1 h. Addition of NH4Cl (aq. sat., 100 ml) was
followed by dilution with EtOAc (200 ml). The organic phase
was extracted with 2 M NaOH (2 × 100 ml), dried (MgSO4),
filtered and concentrated. Chromatography of the residue
[SiO2, EtOAc–cyclohexane (10–>60%) as eluent] yielded com-
pound 4 (5.5 g, 17.8 mmol, 89%) as a colourless solid in >99%
purity (GC). Mp 148–150 ЊC, [α]2D5 = Ϫ65.7 (c 0.40, CHCl3). 1H
NMR (CDCl3) δ 0.99 (3H, s), 1.23 (3H, s), 1.31–1.46 (2H, m),
1.83–2.09 (7H, m), 2.43–2.82 (4H, m), 3.40 (1H, d, J = 13.6 Hz),
3.51 (1H, d, J = 13.6 Hz), 4.05 (1H, dd, J = 4.9, 7.3 Hz), 6.68–
6.74 (1H, m). 13C NMR (CDCl3) δ 19.8, 21.2, 22.5, 26.4, 32.5,
33.1, 34.0, 38.3, 45.1, 47.6, 47.9, 53.5, 65.5, 137.8, 144.3, 167.3.
MS (EI): m/z (%) 310 [30, (M ϩ H)ϩ], 95 (100). Found: C, 62.2;
H, 7.6; N, 4.6. Calc. for C16H23NO3S: C, 62.1; H, 7.5; N, 4.5%.
N-{(3aS,6aS)-2-[(1R)-1-Phenylethyl]octahydrocyclopenta[c]-
pyrrol-3a-ylcarbonyl}-(2R)-bornane-10,2-sultam 11
The title compound was prepared from compound 4 (700 mg,
2.26 mmol) and (R)-N-(1-phenylethyl)-N-(methoxymethyl)-N-
(trimethylsilylmethyl)amine (3, 1.68 g, 6.68 mmol) following
the same procedure as for the preparation of 7 and 8 with the
following exception. The crude product mixture consisting of
two diastereomers (inseparable on silica gel) in a 75 : 25 ratio
(GC) was recrystallised from cyclohexane (60 ml) which
furnished 11 (601 mg, 1.32 mmol, 58%) as a colourless solid in
>99% de (GC) and in chemical purity >99% (GC). Mp 217–219
ЊC, [α]2D5 = ϩ5.7 (c 0.53, CHCl3). 1H NMR (CDCl3) δ 0.95 (3H,
s), 1.18 (3H, s), 1.25 (3H, dd, J = 6.5 Hz), 1.27–2.25 (15H, m),
2.74 (1H, t, J = 8.5 Hz), 3.07 (1H, q, J = 6.5 Hz), 3.25–3.40 (1H,
m), 3.42 (2H, s), 3.80 (1H, d, J = 10.3 Hz), 3.94 (1H, dd, J = 5.0,
7.2 Hz), 7.16–7.30 (5H, m). 13C NMR (CDCl3) δ 19.8, 20.4,
23.1, 26.5, 26.7, 31.3, 32.4, 35.5, 38.5, 44.0, 47.2, 47.9, 48.3,
53.2, 59.7, 62.6, 63.3, 64.7, 66.3, 126.7, 126.9, 128.2, 145.6,
177.3. MS (EI): m/z (%) 457 [14, (M ϩ H)ϩ], 442 (25), 393 (37),
243 (7), 214 (100), 105 (63). Found: C, 68.7; H, 8.0; N, 6.2. Calc.
for C26H36N2O3S: C, 68.4; H, 8.0; N, 6.1%.
N-(2,5-Dihydro-3-thienylcarbonyl)-(2ЈR)-bornane-10,2-sultam 5
Following the same procedure for the preparation of 4 the title
compound (5.7 g, 17.4 mmol, 94%) was obtained as a colourless
solid from (2R)-(Ϫ)-bornane-10,2-sultam (4.0 g, 18.6 mmol)
and 2,5-dihydrothiophene-1-carboxylic acid (2.6 g, 20.0 mmol)
which was prepared from the corresponding methyl ester14
(via hydrolysis, NaOH–H2O–MeOH). Mp 171–173 ЊC, [α]2D5
=
Ϫ98.1 (c 0.59, CHCl3). 1H NMR (CDCl3) δ 1.00 (3H, s),
1.22 (3H, s), 1.30–1.47 (2H, m), 1.82–2.10 (5H, m), 3.42 (1H, d,
J = 13.7 Hz), 3.53 (1H, d, J = 13.7 Hz), 3.83–4.20 (5H, m), 6.71–
6.76 (1H, m). 13C NMR (CDCl3) δ 19.8, 21.2, 26.4, 33.1, 38.0,
38.2, 39.7, 45.1, 47.7, 48.0, 53.5, 65.5, 136.4, 140.2, 165.7. MS
(EI): m/z (%) 327 (80, Mϩ), 263 (50), 113 (100). Found: C, 55.2;
H, 6.4; N, 4.3. Calc. for C15H21NO3S2: C, 55.0; H, 6.5; N, 4.3%.
N-{(3aR,6aR)-2-[(1S)-1-Phenylethyl]octahydrocyclopenta[c]-
pyrrol-3a-ylcarbonyl}-(2R)-bornane-10,2-sultam 10 and
N-{(3aS,6aS)-2-[(1S)-1-phenylethyl]octahydrocyclopenta-
[c]pyrrol-3a-ylcarbonyl}-(2R)-bornane-10,2-sultam 9
To a 110 ЊC solution of compound 4 (1.5 g, 4.85 mmol) in
xylene (mixture of o-, m-, p-isomers, 20 ml) was added (S)-N-
(1-phenylethyl)-N-(methoxymethyl)-N-(trimethylsilylmethyl)-
amine (2, 2.1 g, 8.4 mmol) over a period of 2 h. Full conversion
was achieved after an additional 10 min. The crude product
mixture, consisting of the two diastereomers 10 and 9 in a
80 : 20 ratio (NMR), was worked up using the same protocol as
for the work up of 7 and 8. This afforded the two individual
diastereomers 10 (1.32 g, 2.89 mmol, 59%) and 9 (0.45 g,
0.99 mmol, 20%), both as colourless solids in >99% purity
(GC). The compounds 10 and 9 were diastereomerically pure
according to NMR analyses.
N-[(3aS,6aS)-2-Benzyloctahydrocyclopenta[c]pyrrol-3a-yl-
carbonyl]-(2R)-bornane-10,2-sultam 7 and N-[(3aR,6aR)-2-
benzyloctahydrocyclopenta[c]pyrrol-3a-ylcarbonyl]-(2R)-
bornane-10,2-sultam 8
N-Benzyl-N-(methoxymethyl)trimethylsilylmethylamine (1, 780
mg, 3.3 mmol) was added to a solution of 4 (500 mg, 1.6 mmol)
in a 5 mM solution of TFA–THF (5 ml) over a period of 1.5 h.
After an additional 0.25 h NH4Cl (aq. sat., 25 ml) was added
followed by EtOAc (50 ml). The organic phase was washed with
Na2CO3 (aq. sat., 25 ml), dried (MgSO4), filtered and concen-
trated at 130 ЊC, 1 mbar. The residue which consisted of two
diastereomers 7 and 8 in a 60 : 40 ratio (GC) was purified by
column chromatography [SiO2, EtOAc–cyclohexane (5–60%
as eluent)] to give the two individual pure diastereomers 7
(381 mg, 0.86 mmol, 54%) and 8 (230 mg, 0.52 mmol, 32%).
Both diastereomers were obtained as colourless solids in >200 :
1 diastereomeric ratio (GC).
10 (Major): mp 117–119 ЊC, [α]2D5 = Ϫ74.3 (c 0.54, CHCl3).
1H NMR (CDCl3) δ 0.93 (3H, s), 1.11 (3H, s), 1.30 (3H, d,
J = 6.6 Hz), 1.32–1.49 (4H, m), 1.70–2.15 (9H, m), 2.40 (1H, dd,
J = 4.0, 8.7 Hz), 2.47–2.56 (1H, m), 2.72 (1H, d, J = 10.0 Hz),
2.91 (1H, d, J = 10.0 Hz), 3.18 (1H, q, J = 6.6 Hz), 3.25–3.35
(1H, m), 3.37 (2H, s), 3.94 (1H, dd, J = 4.3, 7.4 Hz), 7.15–7.33
(5H, m). 13C NMR (CDCl3) δ 19.9, 20.5, 22.8, 26.5, 26.6, 32.7
(2 ×C), 38.2, 38.8, 44.2, 46.7, 47.7, 48.0, 53.4, 58.8, 61.7, 63.3,
64.0, 66.7, 126.7, 127.0, 128.1, 145.5, 176.3. MS (EI): m/z (%)
457 [25, (M ϩ H)ϩ], 441 (100), 392 (20), 242 (14), 213 (95), 105
(83). Found: C, 68.7; H, 8.1; N, 6.2. Calc. for C26H36N2O3S: C,
68.4; H, 8.0; N, 6.1%.
7 (Major): mp 92–94 ЊC, [α]2D5 = Ϫ23.4 (c 0.41, CHCl3). H
1
NMR (CDCl3) δ 0.89 (6H, s), 1.20–2.23 (14H, m), 2.34 (1H, d,
J = 10.4 Hz), 2.92 (1H, t, J = 8.4 Hz), 3.29–3.49 (5H, m), 3.61
(1H, d, J = 12.9 Hz), 3.89 (1H, dd, J = 4.8, 7.6 Hz), 7.21–7.32
(5H, m). 13C NMR (CDCl3) δ 19.9, 20.0, 26.5, 26.7, 31.4, 32.4,
35.9, 38.5, 43.9, 47.5, 47.8, 48.1, 53.1, 59.7, 60.4, 63.4, 64.4,
66.3, 126.8, 128.2, 128.7, 138.9, 176.8. MS (EI): m/z (%) 443 [18,
(M ϩ H)ϩ], 379 (30), 352 (5), 229 (5), 200 (100), 91 (68). Found:
9 (Minor): mp 118–121 ЊC, [α]2D5 = Ϫ37.1 (c 0.52, CHCl3). 1H
NMR (CDCl3) δ 0.86 (3H, s), 0.88 (3H, s), 1.31 (3H, d, J =
6.6 Hz), 1.32–2.19 (14H, m), 2.40 (1H, d, J = 10.6 Hz), 2.95 (1H,
t, J = 8.4 Hz), 3.08 (1H, q, J = 6.6 Hz), 3.15 (1H, d, J = 10.6 Hz),
3.28 (1H, d, J = 13.6 Hz), 3.34 (1H, d, J = 13.6 Hz), 3.34–3.45
J. Chem. Soc., Perkin Trans. 1, 2002, 1076–1082
1079

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(1H, m), 3.87 (1H, dd, J = 4.9, 7.6 Hz), 7.15–7.27 (5H, m). 13
C
general method for reductive removal of bornanesultam, fur-
nished alcohol 16 (0.315 g, 1.28 mmol, 93%) as a colourless oil
in >99% purity (GC). Bp 140 ЊC, 1.4 mbar, [α]2D5 = Ϫ53.7 (c 0.54,
NMR (CDCl3) δ 19.8, 20.6, 22.8, 26.3, 26.6, 31.6, 32.5, 36.9,
38.7, 44.0, 47.2, 47.8, 47.9, 53.1, 58.9, 62.8, 63.6, 64.9, 66.5,
126.6, 127.0, 128.2, 145.1, 176.7. MS (EI): m/z (%) 457 [90, (M
ϩ H)ϩ], 442 (37), 393 (25), 242 (10), 213 (100), 105 (75). Found:
C, 68.4; H, 7.9; N, 6.2. Calc. for C26H36N2O3S: C, 68.4; H, 8.0;
N, 6.1%.
1
MeOH). H NMR (CDCl3) δ 1.05–1.70 (7H, m), 1.30 (3H, d,
J = 6.6 Hz), 2.02 (1H, d, J = 8.9 Hz), 2.25–2.38 (1H, m), 2.84
(1H, t, J = 8.8 Hz), 3.02–3.15 (2H, m), 3.32 (1H, dd, J = 0.9, 9.4
Hz), 3.67 (1H, d, J = 9.4 Hz), 4.10 (1H, br s), 7.12–7.26 (5H, m).
13C NMR (CDCl3) δ 23.0, 24.9, 31.5, 33.8, 45.0, 54.8, 61.3, 62.3,
64.9, 71.6, 126.9, 127.0, 128.4, 144.6. MS (EI): m/z (%) 246 [100,
(M ϩ H)ϩ], 230 (75), 105 (8). Found: C, 78.3; H, 9.6; N, 5.9.
Calc. for C16H23NO: C, 78.3; H, 9.4; N, 5.7%.
N-{(3aS,6aR)-5-[(1S)-1-Phenylethyl]hexahydro-1H-thieno-
[3,4-c]pyrrol-3a-ylcarbonyl}-(2R)-bornane-10,2-sultam 14 and
N-{(3aR,6aS)-5-[(1S)-1-phenylethyl]hexahydro-1H-thieno-
[3,4-c]pyrrol-3a-ylcarbonyl}-(2R)-bornane-10,2-sultam 13
{(3aS,6aS)-2-[(1R)-1-Phenylethyl]octahydrocyclopenta[c]-
Following the procedure described for the preparation of 9
and 10, compounds 5 (5.38 g, 16.4 mmol) and (S)-N-(1-phenyl-
ethyl)-N-(methoxymethyl)-N-(trimethylsilylmethyl)amine (2,
5.4 g, 21.5 mmol) gave the two diastereomeric products 14 and
13 in a 75 : 25 ratio (GC). The mixture was purified by flash
column chromatography [SiO2, EtOAc–cyclohexane (10–>50%
as eluent)] to give the individual diastereomers 14 and 13, each
compound in >200 : 1 diastereomeric ratio (GC). The major
diastereomer 14 and the minor diastereomer 13 were further
purified through recrystallisations from heptane–EtOAc (95 : 5)
and heptane, respectively, to give chemically and diastereo-
merically pure 14 (4.34 g, 9.1 mmol, 56%) and 13 (1.70 g,
3.6 mmol, 22%) as colourless solids.
pyrrol-3a-yl}methanol 17
Compound 11 (0.52 g, 1.13 mmol) when subjected to the
general method for reductive removal of bornanesultam,
furnished alcohol 17 (0.275 g, 1.12 mmol, 99%) as a colourless
oil in >99% purity (GC). [α]2D5 = ϩ57.2 (c 0.52, MeOH). All
other data were identical to those for the enantiomer described
above.
[(3aS,6aS)-2-Benzyloctahydrocyclopenta[c]pyrrol-3a-yl]-
methanol 15
Compound 7 (0.355 g, 0.80 mmol) when subjected to the
general method for reductive removal of bornanesultam,
furnished alcohol 15 (0.174 g, 0.75 mmol, 94%) as a colourless
oil in 99% purity (GC). Bp 130 ЊC, 0.8 mbar, [α]2D5 = Ϫ15.6
(c 0.39, MeOH). 1H NMR (CDCl3) δ 1.11–1.28 (1H, m), 1.41–
1.73 (5H, m), 1.85 (1H, t, J = 8.4 Hz), 2.07 (1H, d, J = 9.1 Hz),
2.40–2.52 (1H, m), 2.89 (1H, d, J = 9.1 Hz), 3.15 (1H, t, J =
8.6 Hz), 3.37 (1H, dd, J = 1.0, 9.5 Hz), 3.53 (2H, s), 3.64 (1H, d,
J = 9.5 Hz), 3.72 (1H, br s), 7.19–7.36 (5H, m). 13C NMR
(CDCl3) δ 25.0, 31.5, 33.8, 45.4, 55.1, 59.7, 62.0, 63.9, 71.1,
127.0, 128.3, 128.6, 138.4. MS (EI): m/z (%) 232 [87, (M ϩ H)ϩ],
214 (2), 140 (32), 91 (100). Found: C, 77.5; H, 9.2; N, 6.1. Calc.
for C15H21NO: C, 77.9; H, 9.2; N, 6.0%.
14 (Major): mp 139–141 ЊC, [α]2D5 = Ϫ81.3 (c 0.51, CHCl3).
1H NMR (CDCl3) δ 0.93 (3H, s), 1.08 (3H, s), 1.32 (3H, d, J =
6.6 Hz), 1.32–1.51 (2H, m), 1.80–2.05 (5H, m), 2.43 (1H, dd,
J = 5.5, 9.0 Hz), 2.52–2.65 (2H, m), 2.88–3.08 (4H, m), 3.30
(1H, q, J = 6.6 Hz), 3.39 (2H, s), 3.54 (1H, d, J = 12.6 Hz), 3.68–
3.80 (1H, m), 3.90–3.97 (1H, m), 7.17–7.31 (5H, m). 13C NMR
(CDCl3) δ 19.8, 20.2, 22.4, 26.6, 32.4, 36.7, 38.4, 41.8, 43.9, 47.8,
48.3, 50.6, 53.2, 56.8, 59.0, 63.7, 66.3, 68.2, 126.9 (2 × C), 128.2,
144.8, 174.1. MS (EI): m/z (%) 475 [80, (M ϩ H)ϩ], 460 (100),
370 (7), 231 (26), 105 (73). Found: C, 63.2; H, 7.3; N, 6.0. Calc.
for C25H34N2O3S2: C, 63.3; H, 7.2; N, 5.9%.
13 (Minor): mp 144–147 ЊC, [α]2D5 = Ϫ10.6 (c 0.74, CHCl3).
1H NMR (CDCl3) δ 0.80 (3H, s), 0.87 (3H, s), 1.31 (3H, d, J =
6.6 Hz), 1.31–1.47 (2H, m), 1.79–2.08 (5H, m), 2.13 (1H, t,
J = 8.4 Hz), 2.37 (1H, d, J = 10.6 Hz), 2.52 (1H, dd, J = 1.9, 11.8
Hz), 2.96 (1H, dd, J = 6.6, 11.8 Hz), 3.12 (2H, s), 3.15–3.23 (2H,
m), 3.27 (1H, d, J = 13.6 Hz), 3.34 (1H, d, J = 13.6 Hz), 3.41
{(3aS,6aR)-5-[(1S)-1-Phenylethyl]hexahydro-1H-thieno[3,4-c]-
pyrrol-3a-yl}methanol 18
Compound 14 (0.50 g, 1.05 mmol) when subjected to the
general method for reductive removal of bornanesultam,
furnished alcohol 18 (0.243 g, 0.92 mmol, 88%) as a colourless
oil in 99% purity (GC). Bp 150 ЊC, 0.8 mbar, [α]2D5 = Ϫ83.3
(c 0.97, MeOH). 1H NMR (CDCl3) δ 1.37 (3H, d, J = 6.6 Hz),
2.00 (1H, t, J = 8.2 Hz), 2.42 (1H, d, J = 8.2 Hz), 2.47–2.51 (1H,
m), 2.53 (1H, d, J = 12.1 Hz), 2.60 (1H, d, J = 12.1 Hz), 2.70
(1H, dq, J = 2.4, 7.5 Hz), 2.86 (1H, d, J = 8.5 Hz), 2.92 (1H,
dd, J = 7.2, 12.0 Hz), 3.13 (1H, d, J = 8.8 Hz), 3.21 (1H, q, J =
6.6 Hz), 3.49 (1H, dd, J = 1.0, 9.5 Hz), 3.76 (1H, d, J = 9.5 Hz),
4.05 (1H, br s), 7.19–7.35 (5H, m). 13C NMR (CDCl3) δ 22.9,
37.5, 39.3, 49.0, 59.5, 60.0, 61.4, 64.6, 70.0, 126.8, 127.1, 128.4,
144.7. MS (EI): m/z (%) 263 (17, Mϩ), 248 (100), 158 (11), 105
(30). Found: C, 68.7; H, 8.0; N, 5.3. Calc. for C15H21NOS: C,
68.4; H, 8.0; N, 5.3%.
(1H, d, J = 10.6 Hz), 3.79–3.91 (2H, m), 7.15–7.27 (5H, m). 13
C
NMR (CDCl3) δ 19.8, 20.6, 22.5, 26.6, 32.4, 37.0, 38.6, 40.4,
43.9, 47.8, 48.0, 52.1, 53.0, 57.6, 63.1, 64.5, 66.6, 67.2, 126.7,
127.0, 128.2, 144.8, 174.6. MS (EI): m/z (%) 475 [74, (M ϩ H)ϩ],
460 (100), 370 (8), 231 (37), 105 (100). Found: C, 63.4; H, 7.4;
N, 6.0. Calc. for C25H34N2O3S2: C, 63.3; H, 7.2; N, 5.9%.
General method for reductive removal of bornanesultam
A solution of one of the cycloadducts in THF (0.11 mmol mlϪ1
)
was added dropwise to a stirred solution of LiAlH4 (3 mol
equivalents) in THF (0.33 mmol mlϪ1) at 0 ЊC. The reaction was
then allowed to reach room temperature and after 0.5 h HCl
(aq., 1 M, 35 ml per mmol substrate) was added followed
by EtOAc (100 ml per mmol substrate). The organic phase
was extracted with HCl (1 M, 2 × 35 ml per mmol substrate),
dried (MgSO4), filtered and concentrated to give recovered
bornanesultam in 97–99% yield and purity >99% (GC). The
aqueous phase was basified (6 M NaOH) and extracted with
EtOAc (3 × 50 ml per mmol substrate). The organic phase was
dried (MgSO4), filtered and concentrated to yield the crude
alcohol. Distillation furnished the pure alcohol in the yields
specified for each compound below.
(3aR,6aR)-Octahydrocyclopenta[c]pyrrol-3a-ylmethanol 19
To a solution of 16 (250 mg, 1.02 mmol) in MeOH (5 ml) 10%
Pd/C (70 mg) was added. The suspension was allowed to stir
at room temperature under hydrogen for 15 h. The Pd/C was
filtered off and the residue was concentrated to give 19 (129 mg,
0.91 mmol, 89%) as a semi-solid in >99% purity (GC). [α]2D5
=
1
ϩ13.9 (c 1.27, MeOH, free base). H NMR (D2O, HCl salt)
δ 1.45–1.90 (6H, m), 2.45–2.58 (1H, m), 2.97 (1H, dd, J = 6.9,
12.1 Hz), 3.05 (1H, d, J = 12.2 Hz), 3.40 (1H, d, J = 12.2 Hz),
3.45–3.58 (3H, m). 13C NMR (D2O, HCl salt) δ 25.0, 31.5, 35.0,
45.2, 52.1, 54.3, 56.0, 67.1. MS (EI, free base): m/z (%) 142 [100,
(M ϩ H)ϩ], 123 (7), 111 (4). Found: C, 54.0; H, 9.1; N, 7.9. Calc.
for C8H15NOؒHCl: C, 54.1; H, 9.1; N, 7.9%.
{(3aR,6aR)-2-[(1S)-1-Phenylethyl]octahydrocyclopenta[c]-
pyrrol-3a-yl}methanol 16
Compound 10 (0.62 g, 1.37 mmol) when subjected to the
1080
J. Chem. Soc., Perkin Trans. 1, 2002, 1076–1082

View Article Online
(3aS,6aS)-Octahydrocyclopenta[c]pyrrol-3a-ylmethanol ent-19
(CDCl3) δ 1.39 (3H, d, J = 6.6 Hz), 1.38–1.78 (6H, m), 2.03 (1H,
d, J = 9.4 Hz), 2.17–2.33 (1H, m), 2.63 (1H, q, J = 7.6 Hz), 2.96
(1H, t, J = 8.8 Hz), 3.24 (1H, q, J = 6.5 Hz), 3.45 (1H, d, J =
Following the same procedure for the preparation of 19, com-
pounds 15 and 17 furnished ent-19. [α]2D5 = Ϫ14.3 (c 1.25,
MeOH, free base). All other data were identical to those for the
enantiomer 19.
9.4 Hz), 5.78 (1H, br s), 7.22–7.36 (5H, m), 7.58 (1H, br s). 13
C
NMR (CDCl3) δ 22.9, 24.8, 31.2, 31.6, 49.2, 58.7, 60.2, 62.3,
64.5, 126.7, 127.2, 128.4, 144.8, 180.8. MS (EI): m/z (%) 259 [97,
(M ϩ H)ϩ], 243 (100), 214 (10), 153 (62), 105 (67). Found: C,
74.8; H, 8.7; N, 10.9. Calc. for C16H22N2O: C, 74.4; H, 8.6; N,
10.8%.
(3aS,6aR)-Hexahydro-1H-thieno[3,4-c]pyrrol-3a-ylmethanol
hydrochloride 20
The title compound was prepared following a procedure similar
to that reported by Bonjoch et al.15 To a solution of 18 (140 mg,
0.53 mmol) and 1,8-bis(dimethylamino)naphthalene (250 mg,
1.17 mmol) in dry 1,2-dichloroethane (20 ml) at 0 ЊC 1-chloro-
ethyl chloroformate (0.29 ml, 2.66 mmol) was slowly added.
After 0.25 h the solution was allowed to stir overnight at room
temperature. The reaction was then heated at reflux for 3 h
followed by cooling and addition of HCl (aq., 1 M, 20 ml)
and CH2Cl2 (50 ml). The organic phase was extracted with HCl
(aq., 1 M, 20 ml) and Na2CO3 (aq., sat., 30 ml). The organic
phase was dried (MgSO4), filtered and concentrated followed by
purification of the residue by flash chromatography [SiO2,
EtOAc–cyclohexane (5–50%)]. Without further purification the
resulting carbamate–carbonate intermediate was dissolved in
MeOH (10 ml) and refluxed (1 h) followed by addition of HCl
(3 M, 4 ml). Reflux for 2 h followed by concentration, gave 20
(80.0 mg, 0.41 mmol, 77%) as a colourless solid in >98% purity
(GC, free base). Recrystallisation from MeOH–EtOAc
furnished 20 in >99% purity. Mp 156–158 ЊC, [α]2D5 = 0.0 (c 2.1,
MeOH). 1H NMR (D2O) δ 2.65–2.74 (2H, m), 2.81 (1H, d, J =
12.5 Hz), 2.85–2.96 (1H, m), 3.02 (1H, dd, J = 6.5, 12.2 Hz),
3.08 (1H, dd, J = 8.0, 11.8 Hz), 3.16 (1H, d, J = 12.2 Hz), 3.53
(1H, d, J = 12.2 Hz), 3.62 (2H, s), 3.64 (1H, dd, J = 8.2, 12.0
Hz). 13C NMR (D2O) δ 36.4, 39.4, 48.9, 51.4, 53.7, 60.4, 65.6.
MS (EI, free base): m/z (%) 159 (100, Mϩ), 142 (11), 128 (60).
Found: C, 42.7; H, 7.1; N, 7.0. Calc. for C7H13NOSؒHCl: C,
43.0; H, 7.2; N, 7.2%.
(3aS,6aR)-Octahydrocyclopenta[c]pyrrol-3a-ylmethylamine
dihydrobromide (؊)-23
Compound 22 (251 mg, 0.97 mmol) dissolved in THF (5 ml)
was added to a 0 ЊC solution of LiAlH4 (111 mg, 2.9 mmol) in
THF (2 ml). The reaction was allowed to reach room temper-
ature for 0.2 h followed by heating at reflux for 0.5 h. Addition
of H2O (0.5 ml), filtration, rinsing the solid collected with ether
and concentration of the filtrate furnished the corresponding
primary amine (222 mg, 0.91 mmol, 94%) as a semi solid
in >99% purity (GC). 1H NMR (2 × HCl salt, D2O, * denotes
peaks arising from a minor conformer) δ 1.45–1.89 (6H, m),
1.70 (3H, d, J = 6.9 Hz), 2.05–2.20* (0.3H, m), 2.38–2.50 (0.7H,
m), 2.63–2.73 (1H, m), 3.01–3.50 (4H, m), 3.74* (0.3 H, d, J =
11.0 Hz), 4.09 (0.7H, d, J = 12.2 Hz), 4.35–4.45 (1H, m), 7.42–
7.55 (5H, m). 13C NMR (2 × HCl salt, D2O, * denotes peaks
arising from a minor conformer) δ 18.4, 24.4, 26.0*, 30.0, 33.1*,
35.9, 36.0*, 46.1*, 46.6, 46.7, 52.2, 52.3*, 58.3, 59.6*, 61.1,
62.2*, 66.5, 67.8*, 128.8, 128.9*, 130.0, 130.7, 136.0. MS (EI,
free base): m/z (%) 245 [100, (M ϩ H)ϩ], 229 (9), 139 (12), 110
(30). Without any further purification this primary amine was
dissolved in MeOH (3 ml), 10% Pd/C (50 mg) was added and
the resulting suspension was allowed to stir over night under an
atmosphere of hydrogen. The Pd/C was filtered off and rinsed
with MeOH. HBr (0.5 ml, 48%) was added followed by concen-
tration of the solution. This furnished (Ϫ)-23 (236 mg, 0.78
mmol, 80%) as a red–brown solid, pure according to NMR
analysis. Recrystallisation from MeOH–EtOAc gave colourless
crystals of (Ϫ)-23. [α]2D5 = Ϫ1.0 (c 5.8, MeOH), lit.7 [α]2D4 = Ϫ0.9
(c 49.5, MeOH). MS (EI, free base): m/z (%) 141 [100, (M ϩ
H)ϩ], 123 (7). All other data agreed with those reported for the
enantiomer.7
Ethyl (3aR,6aR)-2-[(1S)-1-phenylethyl]octahydrocyclopenta[c]-
pyrrole-3a-carboxylate 21
Ti(OEt)4 (2.5 g, 11.0 mmol) was added to a solution of 10
(1.0 g, 2.19 mmol) in EtOH (99.5%, 5 ml). After reflux for 3 h,
the solvent was evaporated off and the residue was purified by
column chromatography [SiO2, EtOAc–cyclohexane (0–80% as
eluent)]. After distillation, compound 21 (570 mg, 1.98 mmol,
90%) was obtained as a colourless oil in >99% purity (GC)
along with recovered bornanesultam (458 mg, 2.13 mmol,
97%) in >99% purity. Bp 130 ЊC, 0.9 mbar, [α]2D5 = Ϫ70.0 (c 0.65,
CHCl3). 1H NMR (CDCl3) δ 1.22 (3H, t, J = 7.0 Hz), 1.32 (3H,
d, J = 6.1 Hz), 1.45–2.05 (6H, m), 2.38 (1H, d, J = 9.4 Hz), 2.47–
2.55 (2H, m), 2.75 (1H, d, J = 9.4 Hz), 2.79–2.89 (1H, m), 3.13
(1H, q, J = 6.2 Hz), 4.11 (2H, q, J = 7.0 Hz), 7.15–7.35 (5H, m).
13C NMR (CDCl3) δ 14.2, 23.4, 26.8, 34.0, 38.6, 47.0, 59.2, 59.5,
60.4, 62.8, 64.8, 126.7, 127.0, 128.2, 146.0, 177.3. MS (EI): m/z
(%) 288 [10, (M ϩ H)ϩ], 272 (100), 244 (12), 182 (15), 105 (20).
Found: C, 75.5; H, 8.8; N, 5.0. Calc. for C18H25NO2: C, 75.2; H,
8.8; N, 4.9%.
Acknowledgements
This work was supported by the Swedish Research Council and
Mid Sweden University.
References
1 1,3-Dipolar Cycloaddition Chemistry, ed. A. Padwa, Wiley, New
York, vol. 1 and 2, 1984.
2 (a) S. Karlsson and H.-E. Högberg, Org. Prep. Proced. Int., 2001, 33,
103; (b) K. V. Gothelf and K. A. Jörgensen, Chem. Rev., 1998, 98,
863.
3 See for example: (a) S. Karlsson, F. Han, H.-E. Högberg and
P. Caldirola, Tetrahedron: Asymmetry, 1999, 10, 2605; (b) Z. Ma,
S. Wang, C. S. Cooper, A. K. L. Fung, J. K. Lynch, F. Plagge and
D. T. W. Chu, Tetrahedron: Asymmetry, 1997, 8, 883; (c) G. Pandey,
J. K. Laha and A. K. Mohanakrishnan, Tetrahedron Lett., 1999, 40,
6065.
(3aR,6aR)-2-[(1S)-1-Phenylethyl]octahydrocyclopenta[c]-
pyrrole-3a-carboxamide 22
4 S. Karlsson and H.-E. Högberg, Tetrahedron: Asymmetry, 2001, 12,
NH2Li (250 mg, 10.9 mmol) was added to a solution of 21
(440 mg, 1.53 mmol) in THF (4 ml). After 6 h of reflux,
MeOH–H2O was added. The mixture was diluted with EtOAc
(50 ml) and extracted with HCl (1 M, 2 × 40 ml). The pooled
aqueous phase was made basic with NaOH (6 M) and extracted
with EtOAc (100 ϩ 50 ml). The organic phase was dried
(MgSO4) and concentrated. Flash column chromatography
[SiO2, EtOAc–cyclohexane (10–80% as eluent)] furnished 22
(305 mg, 1.18 mmol, 77%) as a colourless solid in >99% purity
1975.
5 See for example: (a) E. M. Beccalli, G. Broggini, C. L. Rosa,
D. Passarella, T. Pilati, A. Terraneo and G. Zecchi, J. Org. Chem.,
2000, 65, 8924; (b) C. M. Tice and B. Ganem, J. Org. Chem., 1983,
48, 5048; (c) P. Garner, W. B. Ho, S. K. Grandhee, W. J. Youngs and
V. O. Kennedy, J. Org. Chem., 1991, 56, 5893.
6 (a) A. H. Fray and A. I. Meyers, Tetrahedron Lett., 1992, 33, 3575;
(b) A. H. Fray and A. I. Meyers, J. Org. Chem., 1996, 61, 3362.
7 M. Ogata, H. Matsumoto, S. Shimizu, S. Kida, H. Nakai,
K. Motokawa, H. Miwa, S. Matsuura and T. Yoshida, Eur. J. Med.
Chem., 1991, 26, 889.
(GC). Mp 125–126 ЊC, [α]2D5 = Ϫ2.6 (c 1.68, CHCl3). H NMR
1
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8 (a) B. H. Kim and D. P. Curran, Tetrahedron, 1993, 49, 293;
(b) D. P. Curran and T. A. Heffner, J. Org. Chem., 1990, 55, 4585.
9 R. Baltzly, J. Org. Chem., 1976, 41, 928.
10 R. A. Olofson, J. T. Martz, J.-P. Senet, M. Piteau and T. Malfroot,
J. Org. Chem., 1984, 49, 2081.
12 A. Hosomi, Y. Sakata and H. Sakurai, Chem. Lett., 1984, 1117.
13 W. Oppolzer, A. J. Kingma and G. Poli, Tetrahedron, 1989, 45,
479.
14 J. Leonard, A. B. Hague, M. F. Jones and R. A. Ward, Synthesis,
1999, 507.
11 D. Seebach, E. Hungerbühler, R. Naef, P. Schnurrenberger,
B. Weidmann and M. Züger, Synthesis, 1982, 138–141.
15 J. Bonjoch, D. Solé, S. G. Rubio and J. Bosch, J. Am. Chem. Soc.,
1997, 119, 7230.
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J. Chem. Soc., Perkin Trans. 1, 2002, 1076–1082