Intramolecular Wittig reaction: A new synthesis of (S)-pyrrolam A

Article abstract of DOI:10.1002/hlca.200890163

A straightforward synthesis of (S)-pyrrolam A is described. The synthesis involves in situ generation of the phosphorane 3, followed by an intramolecular Wittig reaction to furnish (S)-pyrrolam A.

Full text of DOI:10.1002/hlca.200890163

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Helvetica Chimica Acta – Vol. 91 (2008)
Intramolecular Wittig Reaction: A New Synthesis of (S)-Pyrrolam A
by Mahesh S. Majika), Perunninakulath S. Parameswaranb), and Santosh G. Tilve*a)
a) Department of Chemistry, Goa University, Taleigao Plateau, Goa 403206, India
(fax: þ 918322451184; e-mail: stilve@unigoa.ac.in)
b) Chemical Oceanography Division, National Institute of Oceanography (CSIR),
Dona Paula-Goa 403004, India
A straightforward synthesis of (S)-pyrrolam A is described. The synthesis involves in situ generation
of the phosphorane 3, followed by an intramolecular Wittig reaction to furnish (S)-pyrrolam A.
Introduction. – The pyrrolidine motif is found in a wide range of natural products
and biologically active compounds including indolizidine and pyrrolizidine alkaloids
[1 – 3]. Pyrrolizidine alkaloids such as pyrrolam A (1) and necines (2) have caught our
attention as synthetic targets due to their interesting biological activities [3]. The
presence of a C¼C bond in these ring systems is crucial for the observed hepatotoxic,
mutagenic, and carcinogenic activities associated with these molecules. Pyrrolam A (1)
is a pyrrolizidine alkaloid belonging to the community of naturally occurring pyrrolams,
which was isolated in 1993 by the Zeeck group from the bacterial strain, Streptomyces
olivaceus along with pyrrolams B – D [4].
Owing to its interesting structural feature, (S)- and (R)-pyrrolam A have been a
popular target and have been prepared via nine different routes ranging from three
steps to over twelve steps. The majority (seven routes) of these syntheses exploited the
advantage of the pre-existing chiral center of proline or its derivative as chiral pool [5]
with the number of synthetic steps ranging from five to seven. Huang et al. [6a] have
achieved the synthesis of (R)-pyrrolam A from (S)-malic acid in twelve steps, while
Watson et al. have synthesized it via asymmetric deprotonation methodology from N-
Boc pyrrolidine in three steps [6b]. Herein, we report a new synthesis of (S)-pyrrolam
A by employing an intramolecular Wittig reaction as the key step.
ꢀ 2008 Verlag Helvetica Chimica Acta AG, Zürich

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Results and Discussion. – Our retrosynthesic path for 1 is shown in Scheme 1. We
envisioned that the formation of the bicyclic ring would take place via intramolecular
Wittig olefination of 3 as the key intermediate, which in turn would arise from N-
substituted prolinol 4. Further, 4 is readily accessible from l-proline (5).
Scheme 1. Retrosynthesic Path for (S)-Pyrrolam A (1)
Thus, (S)-prolinol (6) [7], which was obtained from l-proline (5), on addition of
bromoacetyl chloride in the presence of AcONa provided (S)-N-(bromoacetyl)pro-
linol (4) in good yield. The latter was treated with PPh3 to give the corresponding
phosphonium salt, which, on deprotonation with aqueous NaOH, provided phosphor-
ane 7, which was subjected to our domino primary alcohol oxidation/Wittig reaction
protocol using PCC/AcONa [8]. However, we could not isolate any product other than
Ph3PO. Similar tandem oxidation procedures (TOP) using MnO2 [9], Dess – Martin
periodinane [10] or IBX [11] failed also to provide the expected 1. So, 4 was oxidized to
(S)-N-(bromoacetyl)prolinal (8) with PCC, which formed the corresponding phos-
phonium salt on reacting with PPh3. However, deprotonation of the salt with aq. NaOH
did not lead to 1. Hence, anhydrous conditions using NaH as base were used. This
provided 1 along with Ph3PO. In this step, the phosphorane 3 generated in situ, reacted
intramolecularly with the aldehyde group as envisaged in Scheme 2.
Scheme 2. Synthesis of( S)-Pyrrolam A (1)
a) AcONa, ClCOCH2Br, 08, 2 h, 6 5%.b) 1. PPh3, benzene, r.t., overnight; 2. 2n NaOH, benzene, 82% (2
steps). c) PCC, CH2Cl2, r.t., 6 h, 68%. d) 1. PPh3, benzene, r.t., overnight; 2. NaH, THF, 14 h, 41% (2 steps).

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The expected problematic separation [6b] of pyrrolam A from Ph3PO was effected
taking advantage of differing solubilities of the products to get partially enriched
pyrrolam A. Further purification was done by reverse phase HPLC using 70% MeOH
in H2O as mobile phase to provide pure pyrrolam A in 18.5% overall yield from (S)-
prolinol (6). With the aim of avoiding the cumbersome separation step of pyrrolam A
from Ph3PO, (S)-N-(bromoacetyl)prolinal (8) was treated with triethyl phosphite for
obtaining the corresponding phosphonate for a Horner – Wadsworth – Emmons
(HWE) reaction. This provided an inseparable mixture whose 1H-NMR analysis
indicated the presence of only trace amounts of pyrrolam A. Use of polystyrene-bound
triphenylphosphine [12] also failed in our hands to give 1. Further, our attempt to
obtain 1,2-dihydroxyhexahydropyrrolizin-3-one [13] from the mixture of pyrrolam A
and Ph3PO or pyrrolam A itself using Sharpless asymmetric dihydroxylation was
unsuccessful. This may be due to the unstability of 1 under the reaction conditions.
Conclusions. – In conclusion, a new short synthesis of (S)-pyrrolam A comprising of
three steps from (S)-prolinol via intramolecular Wittig reaction has been elaborated.
Troublesome separation of pyrrolam A from Ph3PO using reverse phase HPLC was
effected.
We thank DST, New Delhi for financial support and IISc. Bangalore for HR-MS facility.
Experimental Part
General. Solvents were purified and dried by standard procedure before use. Column chromatog-
raphy (CC) was performed on silica gel (SiO2; 60 – 120 mesh). Purification was done on a Jasco HPLC
model MX-2080-31 instrument. Optical rotations: NaD-line on an ADP220 polarimeter. IR Spectra:
Shimadzu FT-IR spectrophotometer. 1H- and 13C-NMR spectra: Bruker 300 MHz instrument with CDCl3
as solvent and Me4Si as internal standard. The multiplicities of the C-atom signals were obtained from
DEPT experiments.
(S)-N-(Bromoacetyl)prolinol (4). A soln. of bromoacetyl chloride (3.73 g, 23.7 mmol) in acetone
(5 ml) was added dropwise to a stirred soln. of (S)-prolinol (6) (2.19 g, 21.5 mmol) and AcONa (3.53 g,
43.1 mmol) in a mixture of acetone (40 ml) and H2O (20 ml) at 0 – 58. The mixture was stirred and
allowed to reach r.t. over a period of 2 h. The solvent was evaporated under vacuum, the residue was
suspended in CHCl3 (50 ml), and washed with H2O. The CHCl3 layer was separated, dried (Na2SO4),
evaporated under vacuum, and the crude product was further purified by CC (SiO2; hexane/AcOEt, 1:1)
to give 4 as pale yellow oil. Yield: 3.11 g (65%). [a]2D8 ¼ ꢀ25.85 (c ¼ 1.18, CHCl3). IR (neat): 3400, 1643.
1H-NMR (300 MHz): 1.63 – 1.94 (m, 4 H, CH2(3), CH2(4)); 3.45 – 3.58 (m, 4 H, CH2(5), CH2OH); 3.99
(s, 2 H, CH2Br); 4.02 – 4.09 (m, 1 H, HꢀC(2)). 13C-NMR (75 MHz): 24.3 (C(3)); 27.9 (C(4)); 42.4
(C(2’)); 47.9 (C(5)); 61.5 (C(2)); 65.4 (OCH2); 167.3 (C¼O).
1-[(2S)-2-(Hydroxymethyl)pyrrolidin-1-yl]-2-(triphenyl-l5-phosphanylidene)ethanone (7). A soln.
containing PPh3 (0.824, 3.14 mmol) and 4 (0.664, 2.99 mmol) in benzene (30 ml) was stirred overnight at
r.t. Evaporation of benzene gave a white sticky solid which was washed with Et2O. The stirred soln. of the
above salt in H2O (50 ml) and benzene (50 ml) was neutralized by 2n aq. NaOH. The benzene layer was
separated, dried (Na2SO4), and concentrated to afford the white sticky solid 7. Yield: 0.993 g (82%). IR
1
(neat): 3400, 1616. H-NMR (300 MHz): 1.83 – 2.05 (m, 4 H, CH2(3), CH2(4)); 2.50 (s, 1 H, CHPPh3);
3.45 – 3.71 (m, 3 H, HꢀC(2), CH2(5)); 4.18 – 4.21, 5.16– 5.19 (2 m, 2 H, CH2OH); 7.54 – 7.91 (m, 15 H,
arom. H). 13C-NMR (75 MHz): 22.9 (CHPPh3); 24.3 (C(3)); 28.4 (C(4)); 48.9 (C(5)); 63.4 (C(2)); 67.1
(OCH2); 128.4, 128.5, 132.0, 132.1, 133.2 (PPh3); 171.8 (C¼O).
(S)-N-(Bromoacetyl)prolinal (8). To a magnetically stirred suspension of PCC (0.62 g, 2.88 mmol) in
anh. CH2Cl2 (30 ml) was added 4 (0.40 g, 1.80 mmol) in anh. CH2Cl2 (10 ml). The mixture was stirred at

Helvetica Chimica Acta – Vol. 91 (2008)
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r.t. for 6h. Et 2O (50 ml) was added, and the supernatant soln. was decanted from the black granular solid.
The combined org. soln. was filtered through bed of Celite, and the filtrate obtained was dried (Na2SO4),
and evaporated under vacuum to give crude 8 as viscous liquid. Yield: 0.27 g (68%). [a]2D9 ¼ ꢀ64.21 (c ¼
0.366, CHCl3). IR (neat): 1743, 1647. 1H-NMR (300 MHz): 1.08 – 1.91 (m, 4 H, CH2(3), CH2(4)); 3.56–
3.65 (m, 2 H, CH2(5)); 4.05 (s, 2 H, CH2Br); 4.45 – 4.53 (m, 1 H, HꢀC(2)); 9.48 (d, J ¼ 1.5 Hz, 1 H,
CHO). 13C-NMR (75 MHz): 24.8 (C(3)); 25.7 (C(4)); 41.6(C(2 ’)); 47.3 (C(5)); 65.2 (C(2)); 165.7
(C¼O); 198.2 (CHO).
(S)-Pyrrolam A (¼(7aS)-5,6,7,7a-Tetrahydro-3H-pyrrolo[1,2-a]pyrrol-3-one; 1). A soln. containing
PPh3 (90.4 mg, 0.34 mmol) and 8 (68.9 mg, 0.31 mmol) in benzene (20 ml) was stirred overnight at r.t.
Evaporation of benzene resulted in a solid, which was washed with Et2O. THF (20 ml) was added. The
mixture was cooled to 08. NaH ((22.5 mg, 0.56mmol) 60% in mineral oil washed with THF) was added,
and the mixture was stirred for 14 h under N2 atmosphere. H2O (20 ml) was added. The mixture was
extracted with CHCl3 (3 ꢁ 25 ml). The org. layer was separated, washed with brine, and dried over
(Na2SO4). Evaporation of the solvent under vacuum gave the crude product, which was dissolved in Et2O
(5 ml); hexane (2 ml) was added, and the mixture was kept in refrigerator. After 1 h, the soln. was
decanted from solidified Ph3PO. A maximum amount of Ph3PO was removed by repeating (3 times) the
above step. The decanted soln. containing (S)-pyrrolam A (1) and a small amount of Ph3PO was
separated by reverse phase HPLC on a HiQSil column (C8 – C15 on SiO2, MeOH/H2O, 70 : 30 (v/v), flow
rate 1.0 ml/min, detection at l 254 nm). The (S)-pyrrolam A eluted first with a retention time of
10.82 min, followed by the Ph3PO at 20.81 min. Yield: 16mg (41%). [ a]3D2 ¼ þ25.06( c ¼ 0.133, CHCl3);
([5b]: [a]2D0 ¼ þ25.7 (c ¼ 1, CHCl3)). IR (CHCl3): 1678. 1H-NMR (300 MHz): 0.95 – 1.25 (m, 1 H of
CH2(7)); 1.80 – 2.05 (m, 1 H of CH2(7)); 2.05 – 2.50 (m, 2 H, CH2(6)); 3.10 – 3.25 (m, 1 H of CH2(5));
3.25 – 3.45 (m, 1 H of CH2(5)); 4.20 (m, 1 H, HꢀC(7a)); 5.97 (dd, J ¼ 5.4, 1.5, 1 H, HꢀC(2)); 7.15 (dd, J ¼
5.7, 1.5, 1 H, HꢀC(1)). 13C-NMR (75 MHz; CDCl3): 28.8 (C(6)); 29.7 (C(7)); 41.7 (C(5)) 67.7 (C(7a));
128.1 (C(2)); 148.9 (C(1)); 175.4 (C(3)).
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Received March 11, 2008