Reductive cyclisation of azidolactams with Bu3P/LiAlH 4

Article abstract of DOI:10.1055/s-2004-837292

Octahydropyrrolo[2,3-b]pyrroles were synthesised by treatment of azidolactams successively with tri-n-butylphosphine and LiAlH₄. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2004-837292

PAPER
475
Reductive Cyclisation of Azidolactams with Bu3P/LiAlH4
S
ynthesis of Bicyc
u
lic
A
minalsrdeep S. Nandra,a Michael J. Porter,*a Jason M. Elliottb
a
Department of Chemistry, University College London, Christopher Ingold Building, 20 Gordon Street, London WC1H 0AJ, UK
Fax +44(20)76797463; E-mail: m.j.porter@ucl.ac.uk
Merck Sharp & Dohme Research Laboratories, The Neuroscience Research Centre, Terlings Park, Eastwick Road, Harlow, Essex CM20
2QR, UK
b
Received 5 October 2004
azide followed by treatment with allyl bromide gave the
a-allylated product in moderate yield (Scheme 1).2 Ozo-
nolysis with a NaBH4 work-up gave alcohol 4,3 which was
subjected to mesylation and azide displacement to afford
alkyl azide 5.
Abstract: Octahydropyrrolo[2,3-b]pyrroles were synthesised by
treatment of azidolactams successively with tri-n-butylphosphine
and LiAlH4.
Key words: azides, lactams, aminals, bicyclic Compounds, hetero-
cycles
Initial attempts to convert azide 5 into the desired bicycle
6 used LiAlH4 at low temperature (Scheme 2; Table 1).
Under these conditions amine 7, resulting from reduction
of the azide, was the major product, and no evidence was
seen for reduction of the lactam carbonyl.4 Attempts to
convert 7 to 6 with hydride reducing agents proved unsuc-
cessful.
The octahydropyrrolo[2,3-b]pyrrole ring system (1,
Figure 1) has not been extensively studied, although a
benzo-fused congener is found in a diverse range of alka-
loids. Indeed, other than benzo-fused and 2,5-dioxo ana-
logues (in which both rings are lactams), there is only one
literature synthesis of compounds of this type. This route,
reported by Thorsett et al. in 1978, involves reduction of
amino-lactams such as 2 with diisobutylaluminium hy-
dride in Et2O.1
Conducting the reduction of 5 at room temperature result-
ed in formation of some of the desired bicycle 6, together
with amine 7; however, the reaction was not clean, and
several other products were apparent in the 1H NMR spec-
trum of the crude reaction mixture. Similar results were
obtained when either DIBAL1 or Red-Al®5 was used.
Ar
NHMe
Successful reductive cyclisation was achieved by treating
azide 5 sequentially with tri-n-butylphosphine and
LiAlH4. Under these conditions, clean cyclisation was ob-
served, and the bicycle 6 could be isolated in 54% yield.
The compound was identified as the cis-fused isomer by
the coupling constant of 7.0 Hz between the ring junction
protons.6 No evidence was seen for formation of any of
the trans-fused isomer.
N
N
N
O
H
H
Me
1
2
Figure 1
As part of a study towards the synthesis of alkaloids of the
sarain class, we were interested in developing routes to
simple octahydro[2,3-b]pyrroles in which the two nitro-
gen atoms were differentially protected. In this paper, we
report a variation of Thorsett’s chemistry, which utilises
azido- rather than amino-lactams.
H
N3
NH2
N
N
N
N
O
O
Bn
Bn
H
Bn
H
The starting point for these studies was N-benzylpyrrolid-
inone (3). Deprotonation with lithium hexamethyldisil-
( )-5
( )-6
( )-7
Scheme 2
i, ii
iii, iv
Bicycle 6 could be protected as a p-toluenesulfonamide
derivative 8, by reaction with p-toluenesulfonyl chloride
and Et3N, or as a formamide by heating a solution of 6 in
ethyl formate (Scheme 3).
OH
N3
N
N
N
O
O
O
Bn
Bn
Bn
3
( )-4
( )-5
Scheme 1 Reagents and conditions: (i) LHMDS, THF, –78 °C, then
allyl bromide, –78 °C to r.t., 40%; (ii) O3, MeOH, –78 °C, then
NaBH4, –78 °C, 84%; (iii) MsCl, Et3N, CH2Cl2, 0 °C, 97%; (iv) NaN3,
DMSO, 60 °C, 76%.
The methodology was next applied to the synthesis of a
related compound bearing a vinyl substituent, which we
required for our projected synthesis of the sarain core
(Scheme 4). N-Benzylpyrrolidinone (3) was converted to
an iminium salt by reaction with dimethyl sulfate. Treat-
ment of this salt with the lithium alkoxide of an allylic al-
cohol under conditions reported by Stevenson7 led, via
sigmatropic rearrangement of 10, to a mixture of diastere-
SYNTHESIS 2005, No. 3, pp 0475–0479
x
x
.
x
x
.2
0
0
5
Advanced online publication: 16.12.2004
DOI: 10.1055/s-2004-837292; Art ID: P11704SS
© Georg Thieme Verlag Stuttgart · New York

476
G. S. Nandra et al.
PAPER
Table 1 Reductive Cyclisation of 5
TBSO
Conditionsa
Product(s)
7b
H
i
3
LiAlH4, -78 °C, 10–60 min
LiAlH4, r.t., 10 min
DIBAL, r.t., 30 min
Red-Al, r.t., 30 min
OTBS
N
N
O
O
Bn
Bn
6 + 7c
6 + 7c
6 + 7c
6 (54%)
10
( )-11
ii-iv
H
H
H
i) Bu3P, r.t., 20 min
ii) LiAlH4, r.t., 1 h
v, vi
N3
a All reactions were conducted in THF solution, and worked up with
potassium sodium tartrate.
N
N
N
O
Bn
CHO
Bn
b Major product; not isolated.
( )-13
( )-12
c Both 6 and 7 were identified as components of an intractable mix-
ture.
Scheme 4 Reagents and conditions: (i) Me2SO4, 50 °C; then BuLi,
TBSOCH2CH=CHCH2OH,8 THF, 70 °C, 56%; (ii) TBAF, THF, 0 °C
to r.t., 77%; (iii) MsCl, Et3N, CH2Cl2, 0 °C, 84%; (iv) NaN3, DMSO,
60 °C, 74%; (v) Bu3P, THF, r.t.; then LiAlH4, r.t.; (vi) HCO2Et, 60 °C,
25% from 12.
H
H
i or ii
N
N
N
N
15 to afford an amidine (17) does not occur. Instead, addi-
tion of LiAlH4 leads to partial reduction of the lactam car-
bonyl, to give the iminium ion 18. Cyclisation of the
nucleophilic iminophosphorane nitrogen onto the imini-
um ion leads to bicycle 19, and aqueous work-up cleaves
the nitrogen-phosphorus bond to generate the observed
product 20, which may subsequently undergo epimerisa-
tion, and tri-n-butylphosphine oxide.
Bn
H
Bn
R
H
H
( )-6
( )-8 R=Ts
( )-9 R=CHO
Scheme 3 Reagents and conditions: (i) TsCl, Et3N, CH2Cl2, r.t.,
64%; (ii) HCO2Et, 60 °C, 40% from 5.
omeric compounds from which 11 was isolated in 56%
yield. The relative stereochemistry of this major diaste-
reomer was tentatively assigned by analogy with Steven-
son’s work. Following removal of the silyl protecting
group, the primary alcohol was converted to an azide by
mesylation and nucleophilic substitution.
In conclusion, we have developed a novel method for cy-
clisation of g-lactams bearing a 2-azidoethyl side-chain to
octahydropyrrolo[2,3-b]pyrroles. The conversion is ef-
fected by successive treatment with tri-n-butylphosphine
and LiAlH4; use of either reagent alone, or of various oth-
er metal hydride reducing agents, is ineffective.
Cyclisation of azidolactam 12 using the conditions devel-
oped previously gave a mixture of diastereomeric prod-
ucts in a 2:1 ratio. Protection of the secondary amine gave
an inseparable 4:1 mixture of two formamides 13; in both
compounds the ring fusion can be assigned as cis- on the
basis of the coupling between the ring junction protons
[6.6 Hz (major isomer) and 6.0 Hz (minor isomer)], and of
an nOe enhancement observed in the H-3a ring junction
protons on irradiation of the aminal protons. However, the
relative stereochemistry of the C-3 vinyl substituent can-
not be assigned.
IR spectra were recorded as CHCl3 casts on a SHIMADZU FT-IR
8700 spectrometer. 1H and 13C NMR spectra were recorded in
CDCl3 on Bruker AMX300, AMX400 or AVANCE500 spectrom-
eters. Flash chromatography was carried out on silica gel (40–63
mm) or neutral alumina (grade III, 50–200 mm). All reagents were
obtained from commercial sources and were used without further
purification. Reactions were performed under an inert atmosphere
of N2, using anhyd solvents. Alcohol 4 was prepared by known pro-
cedures.2,3
(3RS)-3-(2-Methanesulfonyloxyethyl)-1-(phenylmethyl)pyrro-
lidin-2-one
The epimerisation observed in the cyclisation of 12 was
also noted by Thorsett et al. in closely related com-
pounds,1 and was attributed to reversible ring-opening of
the aminal system and conversion to an enamine which
could be protonated from either face. Thus the epimerisa-
tion is of the ring-junction stereocenters rather than that
bearing the vinyl group.
3-(2-Hydroxyethyl)-1-(phenylmethyl)pyrrolidin-2-one (4, 1.1 g,
5.0 mmol) was dissolved in CH2Cl2 (30 mL) and cooled to 0 °C.
Et3N (1.4 mL, 10 mmol) was added dropwise, followed by meth-
anesulfonyl chloride (0.78 mL, 10 mmol) dropwise and the result-
ing solution was stirred at 0 °C for 3 h. Water (20 mL) and brine (10
mL) were added followed by CH2Cl2 (100 mL) and the organic lay-
er was separated. The aqueous layer was extracted further with
CH2Cl2 (3 × 100 mL). The combined organic extracts were dried
(MgSO4) and concentrated in vacuo. Flash chromatography (SiO2;
EtOAc–petroleum ether, 1:1) afforded the title mesylate (1.38 g,
97%).
A putative mechanism for the reductive cyclisation step is
outlined in Scheme 5. Tri-n-butylphosphine reacts with
the azide moiety of 14 to generate an iminophosphorane
15. Work-up of the reaction at this stage gives a primary
amine product 16, which suggests that further reaction of
IR: 2924, 1678, 1433, 1352, 1173 cm–1.
Synthesis 2005, No. 3, 475–479 © Thieme Stuttgart · New York

PAPER
Synthesis of Bicyclic Aminals
477
R
O
R
R
Bu3P
N3
N
N
N
N
N
O
PBu3
Bn
Bn
Bn
14
15
17
H2O
LiAlH4
R
R
H
NH2
N
–
N
N
O
PBu3
Bn
Bn
OAlH3
16
R
R
R
H2O
N
(– Bu3PO)
N
N
N
N
N
PBu3
Bn
H
Bn
Bn
PBu3
20
19
18
Scheme 5 Proposed mechanism of reductive cyclisation.
1H NMR (300 MHz): d = 1.65–1.73 (m, 1 H), 1.83–1.90 (m, 1 H),
2.24–2.33 (m, 2 H), 2.59–2.64 (m, 1 H), 3.02 (s, 3 H), 3.19–3.24 (m,
2 H), 4.40–4.50 (m, 4 H), 7.20–7.34 (m, 5 H).
13C NMR (75 MHz): d = 25.3, 31.2, 37.3, 38.5, 44.8, 46.8, 68.3,
127.6, 128.1, 128.7, 136.3, 175.3.
MS (CI): m/z (%) = 298 (20) [MH+], 202 (25), 91 (25), 40 (100).
HRMS: m/z [MH+] calcd for C14H20NO4S: 298.1113; found:
(m, 2 H), 3.10–3.22 (m, 2 H), 4.42 (d, J = 14.7 Hz, 1 H), 4.45 (d,
J = 14.7 Hz, 1 H), 7.18–7.33 (m, 5 H).
13C NMR (75 MHz): d = 25.1, 35.4, 39.8, 40.2, 44.9, 46.8, 127.5,
128.1, 128.7, 136.6, 176.6.
MS (CI): m/z (%) = 219 (100) [MH+], 202 (75), 175 (85), 91 (40).
HRMS: m/z [MH+] calcd for C13H19N2O: 219.1497; found:
219.1494.
298.1115.
(3aRS,6aSR)-cis-1-(Phenylmethyl)octahydropyrrolo[2,3-b]pyr-
role (6)
(3RS)-3-(2-Azidoethyl)-1-(phenylmethyl)pyrrolidin-2-one (5)
A
solution of 3-(2-methanesulfonyloxyethyl)-1-(phenylmeth-
Tri-n-butylphosphine (1.0 mL, 4.1 mmol) was added to a solution
of azidolactam 5 (0.5 g, 0.2 mmol) in anhyd THF (25 mL) and the
mixture was stirred at r.t. for 20 min. LiAlH4 (1 M in THF, 1.2 mL,
1.2 mmol) was added dropwise and the resulting solution was
stirred at r.t. for 1 h. Potassium sodium tartrate tetrahydrate (1 M in
water, 20 mL) was added dropwise and the mixture was stirred at
r.t. for 30 min. The mixture was then saturated with solid NaCl and
extracted with EtOAc (2 × 400 mL). The combined organic extracts
were dried (MgSO4) and concentrated in vacuo. Flash chromatogra-
phy (Al2O3; petroleum ether then EtOAc–petroleum ether, 1:5) af-
forded bicycle 6 (0.22 g, 54%).
yl)pyrrolidin-2-one (0.57 g, 2.0 mmol) and sodium azide (0.39 g,
6.0 mmol) in dimethyl sulfoxide (5 mL) was stirred at 60 °C for 2 h
and then cooled to r.t. Water (10 mL) was added followed by EtOAc
(100 mL) and the organic layer was separated. The aqueous layer
was extracted further with EtOAc (3 × 100 mL). The combined or-
ganic extracts were dried (MgSO4) and concentrated in vacuo. Flash
chromatography (SiO2; EtOAc–petroleum ether, 1:2) afforded azi-
dolactam 5 (0.42 g, 86%).
IR: 2932, 2097, 1678, 1427, 1261 cm–1.
1H NMR (300 MHz): d = 1.56–1.72 (m, 2 H), 2.11–2.27 (m, 2 H),
2.48–2.59 (m, 1 H), 3.16–3.20 (m, 2 H), 3.40–3.53 (m, 2 H), 4.42
(d, J = 14.8 Hz, 1 H), 4.45 (d, J = 14.8 Hz, 1 H), 7.19–7.34 (m, 5 H).
13C NMR (75 MHz): d = 25.2, 30.8, 39.5, 44.7, 46.8, 46.6, 127.6,
128.1, 128.7, 136.5, 175.6.
MS (CI): m/z (%) = 245 (50) [MH+], 217 (85), 189 (50), 91 (100).
HRMS: m/z [MH+] calcd for C13H17N4O: 245.1402; found:
IR: 2956, 2792, 1484, 1452, 1101 cm–1.
1H NMR (400 MHz): d = 1.38–1.45 (m, 1 H), 1.47–1.53 (m, 1 H),
1.68–1.79 (m, 2 H), 1.90–1.98 (m, 1 H), 2.30–2.36 (m, 1 H), 2.58–
2.65 (m, 1 H), 2.74–2.79 (m, 1 H), 2.81–2.93 (m, 2 H), 3.64 (d, J =
13.0 Hz, 1 H), 3.84 (d, J = 13.0 Hz, 1 H), 4.10 (d, J = 7.0 Hz, 1 H),
7.19–7.34 (m, 5 H).
13C NMR (75 MHz): d = 30.7, 33.8, 41.6, 45.1, 52.0, 57.2, 83.2,
126.8, 128.2, 128.9, 139.6.
245.1399.
MS (CI): m/z (%) = 203 (100) [MH+], 159 (30), 91 (25).
HRMS: m/z calcd [MH+] for C13H19N2: 203.1548; found: 203.1545.
(3RS)-3-(2-Aminoethyl)-1-(phenylmethyl)pyrrolidin-2-one (7)
Azidolactam 5 (0.20 g, 0.82 mmol) and triphenylphosphine (0.26 g,
0.98 mmol) were dissolved in anhyd THF (2 mL) and stirred at r.t.
for 30 min. Water (0.5 mL) was added dropwise and the resulting
solution was stirred for 16 h at r.t. The solvent was removed in vac-
uo and flash chromatography (SiO2; MeOH–CH2Cl2, 1:4) afforded
aminolactam 7 (0.14 g, 76%).
IR: 3358, 2926, 2870, 1674, 1583, 1495, 1437, 1304 cm–1.
1H NMR (300 MHz): d = 1.42 (br s, 2 H), 1.48–1.70 (m, 2 H), 1.94–
2.04 (m, 1 H), 2.11–2.23 (m, 1 H), 2.48–2.58 (m, 1 H), 2.73–2.95
(3aRS,6aSR)-cis-1-(4-Methylphenylsulfonyl)-6-(phenylmeth-
yl)octahydropyrrolo[2,3-b]pyrrole (8)
Bicycle 6 (0.27 g, 1.3 mmol) was dissolved in CH2Cl2 (10 mL).
Et3N (0.4 mL, 2.9 mmol) was added dropwise followed by 4-meth-
ylphenylsulfonyl chloride (0.56 g, 2.9 mmol) and the resulting so-
lution was stirred at r.t. for 1 h. Water (10 mL) was added, followed
by CH2Cl2 (100 mL) and the organic layer was separated. The or-
ganic extract was dried (MgSO4) and concentrated in vacuo. Flash
Synthesis 2005, No. 3, 475–479 © Thieme Stuttgart · New York

478
G. S. Nandra et al.
PAPER
chromatography (SiO2; MeOH–CH2Cl2, 1:49) afforded sulfona-
MS (CI): m/z (%) = 360 (100) [MH+], 302 (55), 228 (20), 91 (20).
mide 8 (0.30 g, 64%).
IR: 3028, 2963, 1452, 1344, 1303, 1217 cm–1.
HRMS: m/z [MH+] calcd for C21H34NO2Si: 360.2360; found:
360.2359.
1H NMR (400 MHz): d = 1.19–1.29 (m, 1 H), 1.36–1.45 (m, 2 H),
1.86–1.95 (m, 1 H), 2.40 (s, 3 H), 2.26–2.40 (m, 1 H), 2.56–2.65 (m,
2 H), 3.28 (td, J = 12.2, 5.6 Hz, 1 H), 3.59 (dd, J = 12.2, 7.5 Hz, 1
H), 3.98 (d, J = 13.8 Hz, 1 H), 4.03 (d, J = 13.8 Hz, 1 H), 5.03 (d,
J = 6.8 Hz, 1 H), 7.19–7.32 (m, 7 H), 7.73 (d, J = 8.2 Hz, 2 H).
13C NMR (75 MHz): d = 21.5, 29.9, 32.3, 42.0, 48.0, 50.5, 55.5,
84.7, 126.7, 127.1, 128.1, 128.8, 129.7, 137.4, 139.3, 143.1.
(3RS,3¢SR)-3-(4-Hydroxybut-1-en-3-yl)-1-(phenylmethyl)pyr-
rolidin-2-one9
To a stirred solution of lactam 11 (302 mg, 0.84 mmol) in THF (1.5
mL) at 0 °C was added tetra-n-butylammonium fluoride (1 M in
THF, 1.0 mL, 1.0 mmol). The resulting solution was warmed to r.t.
and stirred for 2 h, then concentrated in vacuo, diluted with EtOAc
(20 mL) and washed with sat. aq NaHCO3 (4 mL). The organic ex-
tract was dried (MgSO4) and concentrated in vacuo. Flash chroma-
tography [SiO2; EtOAc–petroleum ether (40–60) 1:1] afforded the
title alcohol (154 mg, 75%).
MS (CI): m/z (%) = 357 (100) [MH+], 201 (85), 91 (50).
HRMS: m/z [MH+] calcd for C20H25N2O2S: 357.1637; found:
357.1633.
IR: 3403, 2928, 2856, 1686, 1429, 1258, 1094 cm–1.
1H NMR (400 MHz): d = 1.81–1.90 (m, 1 H), 2.02–2.13 (m, 1 H),
2.43–2.48 (m, 1 H), 2.85 (td, J = 9.0, 3.0 Hz, 1 H), 3.17–3.24 (m, 2
H), 3.78 (dd, J = 11.1, 5.4 Hz, 1 H), 3.88 (dd, J = 11.1, 4.1 Hz, 1 H),
4.38 (d, J = 14.6 Hz, 1 H), 4.47 (d, J = 14.6 Hz, 1 H), 5.13–5.20 (m,
2 H), 5.84 (dt, J = 17.0, 10.1 Hz, 1 H), 7.19–7.34 (m, 5 H).
13C NMR (75 MHz): d = 22.5, 45.3, 45.6, 47.0, 48.0, 65.9, 118.9,
127.7, 128.1, 128.7, 135.3, 136.1, 175.8.
(3aRS,6aSR)-cis-6-(Phenylmethyl)octahydropyrrolo[2,3-b]pyr-
role-1-carboxaldehyde (9)
Azidolactam 5 (0.5 g, 2.1 mmol) was converted to bicycle 6 as de-
scribed above. The crude mixture was dissolved in ethyl formate (4
mL, 50 mmol) and the resulting mixture was heated to reflux for 6
h. The solution was cooled and concentrated in vacuo. Flash chro-
matography (Al2O3; EtOAc–petroleum ether, 1:2) afforded forma-
mide 9 (0.18 g, 40% from 5).
MS (electrospray): m/z (%) = 268 (100) [MNa+].
HRMS: m/z [MNa+] calcd for C15H19NO2Na: 268.1308; found:
IR: 3445, 2939, 2872, 1674, 1385 cm–1.
1H NMR (500 MHz, major rotamer): d = 1.54–1.61 (m, 1 H), 1.71–
1.76 (m, 1 H), 1.85–1.91 (m, 1 H), 2.08–2.12 (m, 1 H), 2.58–2.63
(m, 1 H), 2.72 (dt, J = 9.3, 6.6 Hz, 1 H), 2.90–2.96 (m, 1 H), 3.10
(td, J = 11.5, 6.7 Hz, 1 H), 3.68 (d, J = 13.4 Hz, 1 H), 3.87 (d, J =
13.4 Hz, 1 H), 3.99–4.04 (m, 1 H), 4.75 (d, J = 6.7 Hz, 1 H), 7.20–
7.35 (m, 5 H), 8.06 (s, 1 H).
13C NMR (125 MHz): d = 30.5, 31.5, 41.2, 42.4, 51.7, 55.5, 80.9,
127.2, 128.4, 128.9, 138.3, 161.2.
MS (EI): m/z (%) = 230 (20) [MH+], 172 (22), 158 (50), 91 (100).
HRMS: calcd m/z [MH+] for C14H19N2O: 230.1414; found:
268.1306.
(3RS,3¢SR)-3-(4-Methanesulfonyloxybut-1-en-3-yl)-1-(phenyl-
methyl)pyrrolidin-2-one9
To a stirred solution of (3RS,3¢SR)-3-(4-hydroxybut-1-en-3-yl)-1-
(phenylmethyl)pyrrolidin-2-one (0.15 g, 0.59 mmol) in CH2Cl2 (2
mL) at 0 °C were added dropwise Et3N (0.10 mL, 1.2 mmol) and
methanesulfonyl chloride (0.17 mL, 1.2 mmol), and the resulting
solution was stirred at 0 °C for 3 h. Water (3 mL) and brine (3 mL)
were added, and the aqueous layer was extracted with CH2Cl2 (50
mL + 2 × 100 mL). The combined organic extracts were dried
(MgSO4) and concentrated in vacuo. Flash chromatography (SiO2;
EtOAc–petroleum ether, 1:2) afforded the title mesylate (0.16 g,
84%).
230.1416.
(3RS,3¢SR)-3-(4-tert-Butyldimethylsilyloxybut-1-en-3-yl)-1-
(phenylmethyl)pyrrolidin-2-one (11)9
Dimethyl sulfate (0.27 mL, 2.85 mmol) was added dropwise to lac-
tam 3 (0.50 g, 2.85 mmol) and the mixture was stirred at 50 °C for
3 h. A second equivalent of dimethyl sulfate (0.27 mL, 2.85 mmol)
was added dropwise and stirring at 50 °C was continued for 1 h.
IR: 2924, 1676, 1439, 1354, 1192, 1177 cm–1.
1H NMR (400 MHz): d = 1.76–1.86 (m, 1 H), 2.05–2.13 (m, 1 H),
2.73–2.86 (m, 2 H), 3.03 (s, 3 H), 3.13–3.21 (m, 2 H), 4.35–4.46 (m,
3 H), 4.65 (dd, J = 9.8, 8.1 Hz, 1 H), 5.23–5.28 (m, 2 H), 5.63 (dt,
J = 17.6, 9.4 Hz, 1 H), 7.18–7.33 (m, 5 H).
13C NMR (75 MHz): d = 21.9, 37.2, 41.3, 45.1, 45.5, 46.7, 70.6,
120.7, 127.6, 128.1, 128.7, 133.3, 136.3, 174.1.
MS (electrospray): m/z (%) = 346 (55) [MNa+], 268 (100).
HRMS: calcd m/z [MNa+] for C16H21NO4SNa: 346.1084; found:
In a separate flask, n-BuLi (1.6 M in hexanes, 4.9 mL, 6.3 mmol)
was added dropwise to a solution of (E)-4-(tert-butyldimethylsilyl-
oxy)but-2-en-1-ol8 (1.15 g, 5.71 mmol) in anhyd THF (20 mL) and
the mixture was stirred at r.t. for 1 h. The resulting THF alkoxide
solution was added in one portion to the lactam–dimethyl sulfate re-
action mixture, and the resulting solution was stirred at 70 °C for 3
h. The solution was cooled and concentrated in vacuo, the residue
was dissolved in CH2Cl2 (50 mL) and washed with sat. aq NaHCO3
(5 mL) and brine (5 mL). The organic extract was dried (MgSO4)
and concentrated in vacuo. Flash chromatography (SiO2; EtOAc–
petroleum ether, 1:9) afforded lactam 11 (571 mg, 56%) as a single
diastereoisomer, which was tentatively assigned as (3RS,3¢SR).
346.1083.
(3RS,3¢SR)-3-(4-Azidobut-1-en-3-yl)-1-(phenylmethyl)pyrroli-
din-2-one (12)9
A solution of (3RS,3¢SR)-3-(4-methanesulfonyloxybut-1-en-3-yl)-
1-(phenylmethyl)pyrrolidin-2-one (0.15 g, 0.47 mmol) and sodium
azide (91 mg, 1.4 mmol) in dimethyl sulfoxide (1.5 mL) was stirred
at 60 °C for 2 h. The mixture was cooled, water (5 mL) was added
and the mixture was extracted with EtOAc (4 × 25 mL). The com-
bined organic extracts were dried (MgSO4) and concentrated in
vacuo. Flash chromatography (SiO2; EtOAc–petroleum ether, 1:3)
afforded azidolactam 12 (94 mg, 74%).
IR: 2874, 2097, 1682, 1439, 1263, 1194 cm–1.
1H NMR (400 MHz): d = 1.67–1.76 (m, 1 H), 1.95–2.02 (m, 1 H),
2.46–2.53 (m, 1 H), 2.67 (td, J = 9.1, 3.3 Hz, 1 H), 3.04–3.11 (m, 2
IR: 2960, 2880, 1666, 1435, 1194 cm–1.
1H NMR (400 MHz): d = 0.04 (s, 6 H), 0.86 (s, 9 H), 1.82–1.92 (m,
1 H), 2.00–2.08 (m, 1 H), 2.48–2.54 (m, 1 H), 2.79 (td, J = 8.9, 3.5
Hz, 1 H), 3.08–3.17 (m, 2 H), 3.73 (dd, J = 10.0, 6.3 Hz, 1 H), 3.92
(dd, J = 9.9, 7.0 Hz, 1 H), 4.38 (d, J = 14.7 Hz, 1 H), 4.43 (d, J =
14.7 Hz, 1 H), 5.08–5.14 (m, 2 H), 5.70–5.79 (m, 1 H), 7.19–7.31
(m, 5 H).
13C NMR (75 MHz): d = 18.3, 22.2, 25.9, 42.0, 45.0, 46.6, 48.3,
64.2, 117.7, 127.4, 128.2, 128.6, 136.7, 136.9, 175.1.
Synthesis 2005, No. 3, 475–479 © Thieme Stuttgart · New York

PAPER
Synthesis of Bicyclic Aminals
479
H), 3.52 (dd, J = 12.2, 7.9 Hz, 1 H), 3.61 (dd, J = 12.2, 7.0 Hz, 1 H),
4.29 (d, J = 14.6 Hz, 1 H), 4.39 (d, J = 14.6 Hz, 1 H), 5.12–5.17 (m,
2 H), 5.62 (dt, J = 17.1, 9.3 Hz, 1 H), 7.11–7.26 (m, 5 H).
13C NMR (75 MHz): d = 22.0, 42.7, 45.0, 45.8, 46.7, 53.0, 119.4,
127.6, 128.2, 128.7, 135.6, 136.4, 174.2.
MS (FAB): m/z (%) = 271 (100) [MH+].
HRMS: m/z [MH+] calcd for C15H19N4O: 271.1559; found:
petroleum ether, 1:5) afforded formamides 13 (94 mg, 25%) as a 4:1
mixture of diastereomers.
IR : 3029, 2960, 1679, 1465, 1266, 1149 cm–1.
1H NMR (500 MHz, major rotamer of major diastereomer): d =
1.58–1.66 (m, 1 H), 2.02–2.12 (m, 1 H), 2.43–2.49 (m, 1 H), 2.57–
2.61 (m, 1 H), 2.65–2.71 (m, 1 H), 2.91–2.99 (m, 1 H), 3.57–3.61
(m, 1 H), 3.72 (d, J = 13.4 Hz, 1 H), 3.85 (d, J = 13.4 Hz, 1 H), 4.05–
4.08 (m, 1 H), 4.83 (d, J = 6.6 Hz, 1 H), 5.06–5.16 (m, 2 H), 5.73–
5.83 (m, 1 H), 7.22–7.33 (m, 5 H), 8.00 (s, 1 H).
271.1568.
(3RS,3aRS,6aRS)-cis- and (3RS,3aSR,6aSR)-cis-4-Ethenyl-1-
(phenylmethyl)octahydropyrrolo[2,3-b]pyrrole
13C NMR (125 MHz): d = 28.8, 44.6, 45.4, 47.6, 48.9, 55.8, 81.2,
117.4, 128.1, 128.4, 128.9, 138.1, 134.9, 161.5.
Tri-n-butylphosphine (0.09 mL, 0.37 mmol) was added dropwise to
a stirred solution of azidolactam 12 (83 mg, 0.31 mmol) in anhyd
THF and the resulting mixture was stirred for 20 min. LiAlH4 (1 M
in THF, 0.18 mL, 0.18 mmol) was added dropwise and the solution
was stirred at r.t. for 1 h. Potassium sodium tartrate tetrahydrate (1
M in water, 3 mL) was added and the resulting mixture was stirred
at r.t. for 30 min. The mixture was then saturated with solid NaCl
and extracted with EtOAc (3 × 100 mL). The organic extracts were
combined, dried (MgSO4) and concentrated in vacuo to afford the
title compound, which was used without further purification.
MS (CI): m/z (%) = 257 (100) [MH+], 247 (35), 219 (70), 158 (71).
HRMS: m/z [MH+] calcd for C16H21N2O: 257.1654; found:
257.1651.
Acknowledgment
We thank the Engineering and Physical Sciences Research Council
and Merck Sharp & Dohme for a ‘CASE for New Academics’
award.
A clean sample of the title compound (as a 2:1 ratio of diastereoiso-
mers) was obtained by preparative TLC (SiO2; CH2Cl2–MeOH,
9:1).
References
IR: 3368, 3030, 2958, 1674, 1465, 1456, 1147 cm–1.
(1) Thorsett, E. D.; Harris, E. E.; Patchett, A. A. J. Org. Chem.
1978, 43, 4276.
(2) Daoust, B.; Lessard, J. Tetrahedron 1999, 55, 3495.
(3) Masamune, S.; Kaiho, T.; Garvey, D. S. J. Am. Chem. Soc.
1982, 104, 5521.
(4) Amine 7 was identified in the crude reaction mixture by
comparison with an authentic sample, generated by
reduction of 5 with Ph3P/H2O; see: Gololobov, Y. G.;
Zhmurova, I. N.; Kasukhin, L. F. Tetrahedron 1981, 37, 437.
(5) Red-Al® has previously been used for the reductive
cyclisation of azido-oxindoles: Overman, L. E.; Paone, D. V.
J. Am. Chem. Soc. 2001, 123, 9465.
1H NMR (400 MHz, major diastereomer): d = 1.42–1.46 (m, 1 H),
1.86–1.98 (m, 2 H), 2.34–2.45 (m, 2 H), 2.62–2.77 (m, 3 H), 3.07
(dd, J = 10.2, 5.7 Hz, 1 H), 3.62 (d, J = 13.1 Hz, 1 H), 3.81 (d, J =
13.1 Hz, 1 H), 4.21 (d, J = 6.3 Hz, 1 H), 4.87–5.02 (m, 2 H), 5.60–
5.77 (m, 1 H), 7.15–7.30 (m, 5 H).
13C NMR (100 MHz): d = 29.8, 45.8, 47.8, 50.5, 51.1, 56.0, 83.8,
113.9, 126.9, 128.2, 128.9, 139.4, 140.5.
MS (electrospray): m/z (%) = 229 (100) [MH+], 228 (12) [M+], 217
(46), 203 (25).
HRMS: m/z [MH+] calcd for C15H21N2: 229.1699; found: 229.1696.
(6) Thorsett et al. (ref.1) report a coupling constant of 7 Hz
between the ring junction protons in a cis-fused
octahydro[2,3-b]pyrrole.
(7) Coates, B.; Montgomery, D. J.; Stevenson, P. J. Tetrahedron
1994, 50, 4025.
(8) Abdel-Baky, S.; Giese, R. W. J. Org. Chem. 1986, 51, 3390.
(9) The relative stereochemistry of this compound is assigned
by analogy to reactions in ref.7
(3RS,3aRS,6aSR)-cis- and (3RS,3aSR,6aRS)-cis-3-Ethenyl-6-
(phenylmethyl)octahydropyrrolo[2,3-b]pyrrole-1-carboxalde-
hyde (13)
4-Ethenyl-1-(phenylmethyl)octahydropyrrolo[2,3-b]pyrrole (0.96
g, 4.2 mmol) was dissolved in ethyl formate (3.4 mL, 42 mmol) and
the resulting mixture was heated to reflux for 2 h. The solution was
concentrated in vacuo and flash chromatography (Al2O3; EtOAc–
Synthesis 2005, No. 3, 475–479 © Thieme Stuttgart · New York