664
M. S. Majik et al.
SHORT PAPER
13C NMR (75 MHz): d = 14.0 (CH3), 22.5 and 23.7 (C3¢), 30.7 and
31.6 (C4¢), 46.4 and 46.8 (C5¢), 57.7 and 58.0 (C2¢), 60.4 (OCH2),
66.9 (CH2Ph), 120.8 (C2), 127.9, 128.0, 128.9, 136.6 (Ph), 147.4
and 147.8 (C3), 154.7 (Cbz), 166.3 (C1).
intermediate instead as during this reduction step, hydro-
genation of the double bond took place together with con-
comitant deprotection. The expected one-pot cyclization
did not take place even after carrying out the reaction at a
higher temperature (70 °C). Hence, the amine intermedi-
ate, without purification, was refluxed with a catalytic
amount of sodium ethoxide in ethanol leading to (S)-dehy-
dropyrrolam (5) in 67% overall yield. The next crucial
step was the regioselective dehydrogenation of 5 to give
1. This was done by treatment of 5 with lithium diisopro-
pylamide at –78 °C followed by trapping the enolate with
benzeneselenenyl chloride (1.2 equiv) to give a phenylse-
lanyl intermediate that was oxidized9 with hydrogen per-
oxide at 0 °C to give the crude pyrrolam A (1). Attempted
purification of 1 using silica gel column chromatography
gave, instead, pyrrolam C. Such rearrangement of pyrro-
lam A to pyrrolam C has been previously reported.5g
Therefore, the phenylselanyl intermediate was purified
first by column chromatography and then this was sub-
jected to oxidative elimination to give pure (+)-(S)-pyrro-
lam A (1) with [a]D27 +22.37 (c 0.961, CHCl3) and whose
physical and spectroscopic data is in accordance with
those reported.5g Our attempts to avoid cryogenic condi-
tions required during the dehydrogenation step via the use
of the corresponding selenated or halogenated phospho-
rane or phosphonate failed.
HRMS: m/z [M + Na]+ calcd for C17H21NNaO4: 326.1368; found:
326.1361.
(S)-Dehydropyrrolam A [(5S)-1-Azabicyclo[3.3.0]octan-2-one]
(5)
A soln of 4 (1.46 g, 4.8 mmol) in EtOH (20 mL) was stirred at r.t.
with 10% Pd/C (140 mg) under H2 atmosphere (0.28 bar) for 10 h.
The catalyst was filtered off and washed with EtOH and the com-
bined filtrate and washings (50 mL) were treated with 2 M NaOEt
(1 mL) and refluxed for 6 h. Then mixture was concentrated and fur-
ther treated with aq 10% HCl and subsequently extracted with
CHCl3 (4 × 20 mL). The combined organic layers were dried
(Na2SO4), concentrated and purified by column chromatography
(silica gel, EtOAc) to afford 5 as a pale yellow oil; yield: 401 mg
(67%).
[a]D27 –20.49 (c 0.244, CHCl3).
IR (CHCl3): 2960, 2890, 1670 cm–1 (C=O).
1H NMR (400 MHz): d = 1.32 (m, 1 H, H6b), 1.73 (m, 1 H, H4b),
1.96–2.28 (m, 3 H, H6a, H7), 2.3 (m, 1 H, H4a), 2.44 (dddd,
J = 1.56, 1.6, 1.52, 1.52 Hz, 1 H, H3b), 2.75 (m, 1 H, H3a), 3.06 (m,
1 H, H8b), 3.56 (ddd, J = 7.88, 3.92, 7.84 Hz, 1 H, H8a), 3.90 (m, 1
H, H5).
13C NMR (75 MHz): d = 27.0 (C7), 27.2 (C6), 32.2 (C3), 35.4 (C4),
41.0 (C8), 62.1 (C5), 174.8 (C2).
HRMS: m/z [M + H]+ calcd for C7H12NO: 126.0913; found:
126.0899.
In conclusion, we have demonstrated the utility of the
domino alcohol oxidation–Wittig reaction approach for a
new synthesis of (S)-pyrrolam A (1) from L-proline.
(S)-Pyrrolam A [(5S)-1-Azabicyclo[3.3.0]oct-3-en-2-one] (1)
To a stirred soln of LDA (2.26 mmol) in THF (10 mL) [prepared by
adding 1.6 M BuLi in n-hexane (1.41 mL, 2.26 mmol) to i-Pr2NH
(0.32 mL, 2.26 mmol)] under a N2 atmosphere at –78 °C, was added
dropwise a soln of (S)-dehydropyrrolam (5, 0.235 g, 1.88 mmol) in
THF (2 mL) over a period of 5 min. After stirring for an additional
10 min, a soln of PhSeCl (0.432 g, 2.26 mmol) in THF (2 mL) was
added rapidly. The mixture was stirred to attain r.t. The solvent was
removed under reduced pressure and the crude mixture was extract-
ed with CHCl3 (3 × 20 mL). The combined organic layers were
evaporated and then purified by column chromatography (hexanes–
EtOAc, 6:4) to afford the corresponding pure phenylselanyl inter-
mediate. To the ice-cooled (0 °C) soln of this intermediate in THF
(5 mL) was added H2O (3 mL) and AcOH (0.6 mL) followed by
slow addition of 30% H2O2 (2.47 g, 2.24 mL), keeping the temper-
ature below 25 °C. After stirring at 25 °C for 30 min, the mixture
was concentrated under vacuum and then CHCl3 (25 mL) and 7%
NaHCO3 soln (20 mL) were added. The aqueous layer was extract-
ed with CHCl3 (2 × 10 mL), the combined organic layers were then
washed with H2O (2 × 10 mL) and dried (Na2SO4). The solvent was
removed under vacuum to obtain pure product 1 as a white solid;
yield: 142 mg (61%).
Solvents were purified and dried by standard procedures before use;
column chromatography was performed on silica gel (60–120
mesh). IR spectra were recorded on Shimadzu FT-IR spectropho-
tometer. 1H NMR and 13C NMR spectra were recorded on a Brucker
300 MHz and 400 MHz instruments using CDCl3 as solvent and
TMS as internal standard. The multiplicities of carbon signals were
obtained from DEPT experiments. Optical rotations were measured
using sodium D line on ADP220 polarimeter. HRMS were recorded
on a MicroMass ES-QTOF.
Ethyl (E)-3-[(2S)-1-(Benzyloxycarbonyl)pyrrolidin-2-yl]prop-
2-enoate (4)
To a magnetically stirred suspension of PCC (3.66 g, 17 mmol) and
NaOAc (1.40 g, 17 mmol) in anhyd CH2Cl2 (40 mL) was added L-
prolinol 3 (2.00 g, 8.51 mmol) in anhyd CH2Cl2 (15 mL), followed
by the addition of (ethoxycarbonylmethylene)triphenylphosphor-
ane (4.45 g, 12.8 mmol) in one portion. The mixture was stirred at
r.t. for 7 h. Et2O (50 mL) was added and the supernatant solution
was decanted from the black granular solid. The combined organic
solns were filtered through a short bed of Celite and the filtrate ob-
tained was evaporated to give a residue that was purified by column
chromatography (silica gel, hexanes–EtOAc, 6:4) to give pure 4 as
colorless viscous liquid; yield: 1.95 g (76%).
[a]D27 +22.37 (c O.961, CHCl3).
IR (CHCl3): 1678 cm–1.
1H NMR (300 MHz): d = 0.95–1.25 (m, 1 H, H6a), 1.80–2.05 (m, 1
H, H6b), 2.05–2.50 (m, 2 H, H7), 3.10–3.25 (m, 1 H, H8a), 3.25–
3.45 (m, 1 H, H8b), 4.20 (m, 1 H, H5), 5.97 (dd, J = 5.4, 1.5 Hz, 1
H, H3), 7.15 (dd, J = 5.7, 1.5 Hz, 1 H, H4).
[a]D27 –42.553 (c 0.094, CHCl3).
IR (neat): 3032 (arom), 1716, 1708, 1699 cm–1 (C=O, C=C).
1H NMR (400 MHz): d = 1.3 (t, J = 7.0 Hz, 3 H, CH3), 1.75–1.90
and 2.01–2.12 (2 m, 4 H, H3¢a, H3¢b, H4¢a, H4¢b), 3.39–3.50 and
3.62–3.76 (2 m, 2 H, H5¢a, H5¢b), 4.20 (q, J = 7.0 Hz, 2 H, OCH2),
4.47 and 4.54 (2 m, 1 H, H2¢), 5.07 and 5.14 (2 d, J = 12.6 Hz, 2 H,
CH2Ph), 5.76 and 5.86 (2 d, J2,3 = 15.4 Hz, 1 H, H2), 6.80 and 6.84
(2 dd, J2¢,3 = 5.6 Hz, 1 H, H3), 7.28–7.35 (m, 5 H, Ar-H).
13C NMR (75 MHz, CDCl3): d = 28.8 (C7), 29.7 (C6), 41.7 (C8),
67.7 (C5), 128.1 (C3), 148.9 (C4), 175.4 (C2).
HRMS: m/z [M + H]+ calcd for C7H10NO: 124.0756; found:
124.0745.
Synthesis 2007, No. 5, 663–665 © Thieme Stuttgart · New York