Asymmetric synthesis of (-)-(R)-pyrrolam A starting from (S)-malic acid

Article abstract of DOI:10.1016/S0957-4166(99)00395-X

An asymmetric synthesis of natural (-)-pyrrolam A starting from natural (S)-malic acid is described. The stereogenic center was established via a highly trans-diastereoselective reductive alkylation procedure. A tandem base-induced intramolecular amide N-

Full text of DOI:10.1016/S0957-4166(99)00395-X

Pergamon
Tetrahedron: Asymmetry 10 (1999) 3827–3832
Asymmetric synthesis of (−)-(R)-pyrrolam A starting from
(S)-malic acid
Pei Qiang Huang,∗ Quan Feng Chen, Chang Lin Chen and Hong Kui Zhang
Department of Chemistry, Xiamen University, Xiamen, Fujian 361005, People’s Republic of China
Received 9 August 1999; accepted 31 August 1999
Abstract
An asymmetric synthesis of natural (−)-pyrrolam A starting from natural (S)-malic acid is described. The
stereogenic center was established via a highly trans-diastereoselective reductive alkylation procedure. A tandem
base-induced intramolecular amide N-substitution and tosic acid elimination led to the target molecule. © 1999
Elsevier Science Ltd. All rights reserved.
1. Introduction
More than 200 pyrrolizidine alkaloids have been isolated from plants and insects.1 In 1990, four
structurally related pyrrolizidinones, namely, pyrrolams A–D, were isolated from Streptomyces olivaceus
(strain, TU3082).2 Among them, pyrrolam A 1, a structurally simple but biosynthetically new pyrroli-
zidinone, has attracted recent attention due both to its bioactivity2 of causing damage to fertilized eggs
at a low concentration and to the presence of a double bond, which is important to the hepatotoxic,
mutagenic and carcinogenic activities of common pyrrolizidine alkaloids.3 To date two asymmetric
syntheses of natural enantiomer (−)-(R)-pyrrolam A 14 and one asymmetric synthesis of ent-15 have
been reported. However, the existing methods for (−)-(R)-pyrrolam A 1, although efficient, need to
use expensive unnatural D-proline as starting material.4 Moreover, none of the known syntheses have
been achieved via asymmetric induction. In continuation of our efforts to use cheap and easily available
(S)-malic acid in the asymmetric synthesis of N-containing bioactive compounds,6 we now report an
asymmetric synthesis of natural enantiomer (−)-(R)-pyrrolam A 1.
∗
Corresponding author. E-mail: pqhuang@xmu.edu.cn
0957-4166/99/$ - see front matter © 1999 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(99)00395-X

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2. Results and discussion
The synthetic route is displayed in Scheme 1. The requisite C3 unit 6 was prepared from 1,3-
propanediol by successive monobenzylation,7 tosylation,7 bromination and Grignard reagent formation.
On the other hand, natural (S)-malic acid was converted to the known (S)-malimide 88 by a one-pot
procedure.6,8 Cleavage of the acetyl group under acidic conditions (AcCl, EtOH, 50°C) gave compound
9 (91% yield), which was protected as its benzyl ether 10 (94% yield).
Scheme 1. Reagents and conditions: (i) Louwrier et al.;8 (ii) AcCl, EtOH, 50°C, 91%; (iii) BnBr, Ag2O, Et2O, room temperature,
94%; (iv) BnO(CH2)3MgBr, THF, 0°C, 90%; (v) Et3SiH, BF3·OEt2, CH2Cl2, −78°C to rt, 68%; (vi) H2, 1 atm, 10% Pd/C, 95%
EtOH, rt, 80%; (vii) p-TsCl, Py., cat. DMAP, CH2Cl2, 0°C to rt, 60%; (viii) CAN, MeCN:H2O (3:1), 0°C, 77%; (ix) NaH, THF,
−15–0°C, 83.5%
Reaction of an excess of 3-benzyloxy propyl magnesium bromide 6 to malimide 10 at 0°C led to a
diastereomeric mixture (in ca. 50:50 ratio, combined yield 90%) of 11 in high regioselectivity which
was deduced from the followed step. The high regioselectivity (>95%) of Grignard reagent addition
to the more hindered carbonyl α to the C-3 benzyloxy group could be attributed to complex induced
proximity effects (CIPE).9 Presumably, the oxygen atom at C-3 chelates to magnesium to deliver the
alkylmetal to the neighboring C-2 carbonyl group. One observation in support of this hypothesis is that
the sodium borohydride reduction of 10 (at C-2 carbonyl group) to the γ-carbinol lactam completed in 15
min at −10°C, while the reduction of the C-3 unsubstituted N-benzyl malimide required several hours at
room temperature. In addition, the explanation proposed by Speckamp10 to account for the regioselective

P. Q. Huang et al. / Tetrahedron: Asymmetry 10 (1999) 3827–3832
3829
reduction of gem-disubstituted succinimides can also be used to explain the observed regioselectivity.
Such an explanation is based on both the observed complete coplanarity of the imide carbonyl groups and
the general proposal for nucleophilic addition to carbonyl groups. Thus, the Grignard reagent approaches
via the less hindered carbonyl group and adds to the carbon atom of the more hindered one along a
straight line through the C–O bond.
The poor stereoselectivity observed in the Grignard reagent addition might reflect the overall results
of the CIPE (cis-directing effect) and steric effects (trans-directing effect). The stereochemistry of the
isomeric 11 was not assigned. This diastereomeric mixture, although separable by flash chromatography,
was used in the next step as it was, since the following Lewis acid mediated ionic hydrogenation11 was
considered to proceed by the intermediacy of an N-acyliminium.11a,b,12 Indeed, in the presence of 3.1
equivalents of boron trifluoride etherate, hydroxylactams 11 were reduced with excess of triethylsilane11c
(CH2Cl2, −78°C to rt) to yield predominantly trans-12 in 68% yield. The trans/cis diastereoselectivity
was more than 95:5 according to chromatographic separation. The stereochemistry of compounds 12 was
tentatively assigned to trans according to the observed vicinal coupling constants6,13 (J4,5=1.6 Hz). This
was further confirmed by converting 12 to (−)-(R)-pyrrolam A 1. The observed high regioselectivity in
the Grignard addition to 10 and the high diastereoselectivity in the ionic hydrogenation of 11 were in
agreement with our earlier results.6 A chelation controlled model6a has been proposed to account for the
observed high diastereoselectivity.
Catalytic hydrogenation (10% Pd/C, H2, 1 atm) of 12 afforded diol 13 in a yield of 80%. Ditosylation
of 13 led to 14 (60% yield) which, after oxidative N-deprotection using ceric ammonium nitrate in a
mixed MeCN–H2O solvent system, provided 15 in 77% yield. The remaining steps were the base-induced
cyclization and tosic acid elimination. It was considered that these two steps could be accomplished in
a single vessel. Indeed, treatment of a THF solution of 15 with an excess of sodium hydride at low
20
temperature provided the desired (−)-(R)-pyrrolam A 1 {83.5% yield, mp 60.5°C, [α]D −26.3 (c 0.4,
CHCl3) [lit.: mp 62°C, [α]D20 −29.3 (c 1.0, CHCl3);2 mp 60–62°C, [α]D20 −26.3 (c 0.31, CHCl3);4a mp
59°C, [α]D −26.3 (c 0.8, CHCl3)4b]}. The physical data of the synthetic molecule were identical with
20
those of the natural product.2,4,5
In summary, we have developed the first asymmetric synthesis of natural enantiomer (−)-(R)-pyrrolam
A 1 from cheap and easily available natural (S)-malic acid.
3. Experimental
Melting points were determined on a Yanaco MP-500 micro melting point apparatus. Infrared spectra
were measured with a Nicholet Avatar 360 FT-IR spectrometer using film NaCl or KBr pellet techniques.
1H NMR spectra were recorded on either a Varian unity +500 or a Varian unity +360 spectrometer
with tetramethylsilane as an internal standard. Chemical shifts are expressed in δ (ppm) units downfield
from TMS. Mass spectra were recorded on an HP 5988A apparatus or a Finnigan MAT-GCQ apparatus
(direct injection). HRFABMS spectra were recorded on a Bruker APEX-II FTMS apparatus. MS
spectra were presented as m/z (% rel. int.). Optical rotations were measured with a Perkin–Elmer 341
MC automatic polarimeter. Elemental analyses were performed by the Micro Analytical Laboratory
at Shanghai Institute of Organic Chemistry. Tetrahydrofuran and diethyl ether used in the reactions
were dried by distillation over metallic sodium and benzophenone; CH2Cl2 was distilled over CaH2.
Silica gel (Qingdao, 400 mesh) was used for column chromatography, eluting (unless otherwise stated)
with ethyl acetate/petroleum ether (PE) (60–90°C) mixtures. (S)-4-Acetoxy-1-(4-methoxybenzyl)-2,5-
pyrrolidinedione 88 was prepared according to the literature procedure.

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3.1. (S)-4-Hydroxy-1-(4-methoxybenzyl)-2,5-pyrrolidinedione 9
To a solution of 88 (4.217 g, 15.2 mmol) in 56 mL of absolute ethanol was added dropwise AcCl (3.2
mL, 45.0 mmol). The resulting mixture was stirred at 50°C for 5 h and concentrated in vacuo. Benzene
was added, then concentrated in vacuo (this procedure was repeated three times). Flash chromatography
20
(EtOAc:PE, 1:1.5) afforded 9 as a white solid (3.266 g, 91% yield). Mp 114.5–115.5°C (CH2Cl2), [α]D
−15.4 (c 0.52, CHCl3). IR (KBr) νmax: 3440, 1695, 1610, 1510, 1430, 1300, 1250, 1100 cm−1. 1H NMR
(500 MHz, CDCl3): 2.67 (dd, J=4.8, 18.0 Hz, 1H, H-4), 3.06 (dd, J=8.5, 18.0 Hz, 1H, H-4), 3.09 (s, 1H,
OH), 3.79 (s, 3H, OCH3), 4.61 (s+m, 3H, PhCH2 and H-3), 6.84 (d, J=8.5 Hz, 2H, Ar-H), 7.33 (d, J=8.5
Hz, 2H, Ar-H). MS (EI): 235 (M+, 93), 178 (20), 121 (100), 91 (9), 77 (18), 43 (15). Anal. calcd for
C12H13O4N: C, 61.26; H, 5.58; N, 5.96; found: C, 61.24; H, 5.37; N, 5.81.
3.2. (S)-4-Benzyloxy-1-(4-methoxybenzyl)-2,5-pyrrolidinone 10
To a solution of 9 (549 mg, 2.34 mmol) in 20 mL of diethyl ether were added benzyl bromide (0.83 mL,
6.98 mmol) and silver oxide (1.95 g, 8.43 mmol). After stirring in the dark for 2 days at room temperature,
the mixture was filtered through Celite and concentrated in vacuo. Flash chromatography (EtOAc:PE, 1:5
20
then 1:3) afforded 10 (714 mg, 94% yield) as a white solid. Mp 67.5–68.5°C (EtOAc:PE), [α]D −70.8
(c 0.94, CHCl3). IR (KBr) νmax: 2900, 1710, 1615, 1520, 1440, 1400, 1340, 1305, 1255, 1180, 1035,
1
910, 840, 750, 710 cm−1. H NMR (500 MHz, CDCl3): 2.66 (dd, J=4.2, 18.2 Hz, 1H, H-4), 2.94 (dd,
J=8.0, 18.2 Hz, 1H, H-4), 3.79 (s, 3H, OCH3), 4.35 (dd, J=4.2, 8.0 Hz, 1H, H-4), 4.59 (d, J=14.1 Hz,
1H, PhCH2N), 4.63 (d, J=14.1 Hz, 1H, PhCH2N), 4.79 (d, J=11.7 Hz, 1H, PhCH2O), 4.99 (d, J=11.7
Hz, PhCH2O), 6.92–7.38 (m, 9H, ArH). MS (EI): 325 (M+, 2), 234 (2), 219 (17), 162 (11), 121 (100),
91 (31). Anal. calcd for C19H19O4N: C, 76.07; H, 6.88; N, 3.41; found: C, 76.29; H, 6.65; N, 3.22.
3.3. (+)-(4S,5R)-4-Benzyloxy-5-(30 -benzyloxypropyl)-1-(4-methoxybenzyl)-2-pyrrolidinone 12
A solution of 10 (2.302 g, 7.08 mmol) in anhydrous THF (28 mL) was cooled to 0°C under argon, and
the Grignard reagent (24 mL, 1.5 mol L−1, 36 mmol) in diethyl ether was added dropwise. After stirring at
0°C for 2 h, the reaction was quenched with a saturated aqueous solution of NH4Cl (72 mL) and extracted
with CH2Cl2 (3×45 mL). The combined extracts were washed with brine, dried with anhydrous MgSO4
and concentrated in vacuo. Filtration through a short pad of column eluting with ethyl acetate:petroleum
ether (60:40) yielded a mixture of two diastereomers 11 (3.042 g, 90%). The diastereomeric mixture was
used as it was in the next step.
A mixture of the diastereomers obtained above (2.225 g, 4.7 mmol) was dissolved in dry CH2Cl2
(12 mL) under argon. The solution was cooled to −78°C, and triethylsilane (9.8 mL, 43.3 mmol) and
trifluoroboron etherate (1.80 mL, 14.4 mmol) were added. After stirring at −78°C for 6 h, the reaction
temperature was allowed to rise slowly to room temperature and quenched by a saturated aqueous
solution of NaHCO3 and extracted with CH2Cl2 (3×20 mL). The combined extracts were dried (Na2SO4)
and concentrated in vacuo. The crude was flash chromatographed (EtOAc:PE, 1:1) to give trans-12 (1.449
20
g, yield 68%) as colorless oils. [α]D +19.9 (c 1.0, CHCl3). IR (film) νmax: 2940, 2860, 1685, 1610,
1510, 1450, 1245, 1095, 1025 cm−1. 1H NMR (500 MHz, CDCl3): 1.40–1.90 (m, 4H, 2CH2), 2.52 (dd,
J=2.0, 17.5 Hz 1H, H-3), 2.72 (dd, J=6.3, 17.5 Hz, 1H, H-3), 3.40 (t, J=6.0 Hz, 2H, BnOCH2), 3.49
(ddd, J=1.6, 5.7, 8.8 Hz, 1H, H-5), 3.78 (s, 3H, OCH3), 3.86 (ddd, J=6.3, 2.0, 1.6 Hz, 1H, H-4), 3.89 (d,
J=15.2 Hz, 1H, NCH2Ar), 4.38 (d, J=11.8 Hz, 1H, PhCH2OCH), 4.43 (d, J=11.8 Hz, 1H, PhCH2OCH),
4.45 (s, 2H, PhCH2OCH2), 4.98 (d, J=15.2 Hz, 1H, NCH2Ar), 6.82, 7.14–7.36 (2m, 2H+12H, 2×H-aro).

P. Q. Huang et al. / Tetrahedron: Asymmetry 10 (1999) 3827–3832
3831
MS (EI): 459 (M+, 4), 368 (4), 351 (43), 340 (13), 279 (8), 260 (10), 230 (10), 217 (57), 121 (100), 91
(44). HRFABMS calcd for [C29H34NO4+H]+: 460.2482; found: 460.2475.
3.4. (+)-(4S,5R)-4-Hydroxyl-5-(30 -hydroxypropyl)-1-(4-methoxybenzyl)-2-pyrrolidinone 13
To a solution of 12 (1.414 g, 3.08 mmol) in 20 mL of 95% ethanol was added 10% Pd/C (375 mg).
The mixture was hydrogenated under 1 atm hydrogen pressure and stirred at room temperature for 78 h.
The mixture was filtered through Celite and the filtrate was evaporated in vacuo. Flash chromatography
20
(EtOAc:MeOH, 25:1) afforded 13 (685 mg, 80%) as a pale yellow oil. [α]D +31.0 (c 1.5, CHCl3). IR
(film) νmax: 3375, 2930, 2860, 1650, 1615, 1510, 1440, 1245, 1030 cm−1. 1H NMR (500 MHz, CDCl3):
1.41 (m, 1H), 1.54 (m, 2H), 1.75 (m, 1H), 2.42 (d, br, J=17.2 Hz, 1H, H-3), 2.62 (s, 2H, 2OH), 2.83 (dd,
J=6.0, 17.2 Hz, 1H, H-3), 3.35 (d, m, J=7.8 Hz, 1H, H-5), 3.61 (m, 2H, CH2OH), 3.78 (s, 3H, OCH3),
3.94 (d, J=15.0 Hz, 1H, CH2Ar), 4.19 (d, br, J=6.0 Hz, 1H, H-4), 4.92 (d, J=15.0 Hz, CH2Ar), 6.86 (d,
J=8.6 Hz, 2H, C6H4), 7.19 (d, J=8.6 Hz, 2H, C6H4). MS (EI): 280 (M++1, 8), 279 (M+, 38), 261 (4), 217
(59), 167 (48), 149 (100), 121 (64). HRFABMS calcd for [C15H22NO4+H]+: 280.1543; found: 280.1540.
3.5. (+)-(4S,5R)-1-(4-Methoxybenzyl)-4-(4-methylphenylsulfonyloxy)-5-[30 -(4-ethylbenzylsulfonyloxy)-
propyl]-2-pyrrolidinone 14
To an ice-bath cooled solution of 13 (624 mg, 2.24 mmol) in CH2Cl2 containing a catalytic amount of
DMAP (32 mg) and dry pyridine (0.5 mL, 6.27 mmol) was added p-TsCl (1.09 g, 5.70 mmol). The
mixture was stirred at room temperature for 76 h. The reaction was quenched with water (15 mL)
and extracted with diethyl ether (3×5 mL). The combined extracts were washed with brine, dried with
anhydrous Na2SO4 and concentrated in vacuo. Flash chromatography (EtOAc:PE, 1:1) afforded 14 (794
20
mg, 60% yield) as a pale yellow oil. [α]D +10.2 (c 2.2, CHCl3). IR (film) νmax: 2955, 2920, 1690,
1
1610, 1595, 1510, 1440, 1354, 1245, 1170, 1095, 900, 810, 660 cm−1. H NMR (500 MHz, CDCl3):
1.20–1.72 (m, 4H, 2CH2), 2.41 (dd, J=1.8, 18.2 Hz, 1H, H-3), 2.45 (s, 3H, CH3), 2.46 (s, 3H, CH3),
2.66 (dd, J=6.7, 18.2 Hz, 1H, H-3). 3.48 (ddd, J=1.7, 3.3, 9.1 Hz, 1H, H-5), 3.81 (s, 3H, OCH3), 3.85
(d, J=15.0 Hz, 1H, NCH2), 3.91 (t, J=5.9 Hz, 2H, TsOCH2), 4.72 (ddd, J=1.7, 1.8, 6.7 Hz, 1H, H-4),
4.85 (d, J=15.0 Hz, 1H, NCH2Ar), 6.83 (d, J=8.6 Hz, 2H, C6H4), 7.09 (d, J=8.6 Hz, 2H, C6H4), 7.32 (d,
J=8.0 Hz, 2H, C6H4SO2), 7.35 (d, J=8.0 Hz, 2H, C6H4SO2), 7.66 (d, J=8.2 Hz, 2H, C6H4SO2), 7.76 (d,
8.2 Hz, 2H, C6H4SO2). HRFABMS calcd for [C29H34NO8S4+H]+: 588.1720; Found: 588.1711.
3.6. (+)-(4S,5R)-4-(4-Methylbenzylsulfonyloxy)-5-[30 -(4-methylphenylsulfonyloxy)propyl)]-2-pyrroli-
dinone 15
To a solution of compound 14 (636 mg, 1.08 mmol) dissolved in a mixed MeCN:H2O solvent system
(3:1, 4 mL) was added, at 0°C, ceric ammonium nitrate (2.368 g, 4.32 mmol). After stirring at the same
temperature for 20 min, glacial H2O (15 mL) was added. The resulting mixture was extracted with ethyl
acetate (4×5 mL). The combined extracts were washed with a saturated aqueous sodium bicarbonate,
dried with anhydrous MgSO4, filtered and concentrated in vacuo. Flash chromatography (EtOAc:PE,
2:1) afforded 15 (388 mg, 77% yield) as a white crystal. Mp 159–160°C, [α]D20 +5.2 (c 0.9, CHCl3). IR
(KBr) νmax: 3450, 1707, 1370, 1355, 1187, 1170, 950, 656 cm−1. 1H NMR (360 MHz, CDCl3): 1.60–1.80
(m, 4H, 2CH2), 2.31 (dd, J=3.0, 18.1 Hz, 1H, H-3), 2.46 (s, 3H, ArCH3), 2.47 (s, 3H, ArCH3), 2.58 (dd,
J=7.0, 18.1 Hz, H-3), 3.69 (m, 1H, H-5), 4.01 (t, J=5.5 Hz, 2H, TsOCH2), 4.74 (ddd, J=3.0, 3.0, 7.0 Hz,

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P. Q. Huang et al. / Tetrahedron: Asymmetry 10 (1999) 3827–3832
1H, H-4), 6.09 (s, 1H, NH), 7.38, 7.78 (2m, each 4H, H-aro). HRFABMS calcd for [C21H25NO7S2+H]+:
468.1145; found: 468.1149.
3.7. (−)-(R)-1-Azabicyclo[3.3.0]oct-3-ene-2-one (Pyrrolam A) 1
A solution of 15 (50 mg, 0.11 mmol) in anhydrous THF (18 mL) was cooled to −10°C under argon, and
a suspension of NaH (14 mg, 0.58 mmol) in anhydrous THF (7 mL) was added dropwise. After stirring
at the same temperature for 1 h, then at 0°C for 2.5 h, the reaction was quenched with a saturated aqueous
solution of NH4Cl (8 mL) and extracted with dichloromethane (4×15 mL). The combined extracts were
washed with brine, dried with anhydrous Na2SO4 and concentrated in vacuo. Filtration through a short
pad of column (SiO2, CHCl3:MeOH, 90:10) yielded a crude which was further purified by HPLC (using
20
CHCl3 as eluent) to give (R)-1 (11 mg, 83.5%) as a colorless solid. Mp 61.5°C, [α]D −26.3 (c 0.4,
CHCl3) [lit.: mp 62°C, [α]D −29.3 (c 1.0, CHCl3);2 mp 60–62°C, [α]D −26.3 (c 0.31, CHCl3);4a
20
20
mp 59°C, [α]D −26.3 (c 0.8, CHCl3)4b for natural (R)-1; mp 60°C, [α]D +25.7 (c 1, CHCl3)5 for
unnatural (S)-1]. IR (KBr) νmax: 3083, 2972, 2891, 1675, 1374, 1326, 1245, 1096, 811 cm−1. 1H NMR
(500 MHz, CD3OD): 1.19 (m, 1H), 2.20 (m, 1H), 2.30–2.45 (m, 2H), 3.20–3.45 (m, 2H), 4.42 (m, 1H,
H-5), 6.05 (dd, J=1.5, 5.7 Hz, 1H, H-3), 7.45 (dd, 1H, J=1.6, 5.7 Hz, H-4). MS (EI): 124 (M++1, 22),
123 (M+, 66), 95 (61), 94 (78), 67 (100), 59 (61). HRFABMS calcd for [C7H9NO+H]+: 124.0757; found:
124.0758.
20
20
Acknowledgements
This work is supported by the National Science Fund for Distinguished Young Investigator under grant
No. 29 625 204. The National NSF of China (grant No. 29572065) is thanked for additional support.
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