Stereoselective synthesis of (2S, 8S)-2-benzyl hexahydro-pyrrodizin-3-one starting from (L)-proline based on stereoselective benzylation

Article abstract of DOI:10.1081/SCC-200028616

A pyrrolizidine alkaloid, (2S, 8S)-2-benzyl hexahydro-pyrrodizin-3-one, was synthesized from (L)-proline using diastereoselective benzylation as the key step. The absolute configuration of the target compound was confirmed through 2D H-H COSY and H-H NOES

Full text of DOI:10.1081/SCC-200028616

SYNTHETIC COMMUNICATIONSw
Vol. 34, No. 17, pp. 3191–3196, 2004
Stereoselective Synthesis of (2S, 8S)-2-
Benzyl Hexahydro-pyrrodizin-3-one
Starting from (L)-Proline Based on
Stereoselective Benzylation
Jing Yi Jin†, Ming Hua Zheng, Xue Wu, and
*
Guan Rong Tian
Department of Chemistry, Yan Bian University, Yan Ji City, Ji Lin, China
ABSTRACT
A pyrrolizidine alkaloid, (2S, 8S)-2-benzyl hexahydro-pyrrodizin-3-one,
was synthesized from (L)-proline using diastereoselective benzylation
as the key step. The absolute configuration of the target compound was
confirmed through 2D H-H COSY and H-H NOESY spectra.
Key Words: (L)-Proline; (2S, 8S)-2-benzyl hexahydro-pyrrodizin-
3-one; Stereoselective benzylation.
†Now as a post-doc fellow of Peking University.
*
Correspondence: Guan Rong Tian, Department of Chemistry, Yan Bian University,
Yan Ji City, Ji Lin 133002, China; E-mail: zpzhan@xmu.edu.cn.
3191
DOI: 10.1081/SCC-200028616
0039-7911 (Print); 1532-2432 (Online)
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Copyright # 2004 by Marcel Dekker, Inc.

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Pyrrolizidine alkaloids constitute a large class of naturally occurring com-
pounds, which are found in a great variety of plant species. Many of them with
a necine base moiety are hypertotoxic and some are carcinogenic.[1] Their
diverse and potent biological properties have made themselves a class of
attractive molecules in pharmacology, and abundance of stereochemistry of
the bicyclic system also provides wide opportunities to construct pyrrolizidine
alkaloids as well as the other structurally related unnatural compounds
through a number of different asymmetric synthetic strategies.[2] Pyrrolizidin-
3-one and its derivatives are good precursors to various chiral necine bases,
and their preparation has also been intensively pursued (for recent review,
see Ref.[3]). Moreover, a chiral pyrrolizidine derived from 8-substituted
pyrrolizidin-3-one has been used as a catalyst in the asymmetric Baylis-
Hillman reaction.[4] Therefore, asymmetric construction of the substituted
pyrrolizidin-3-one systems is of both biological and synthetic importance.
Here we report a new stereoselective synthesis of (2S, 8S)-2-benzyl
hexahydro-pyrrodizin-3-one starting from (L)-proline.
The target compound was synthesized starting from (L)-proline. (L)-N-
Carbobenzyloxy homoproline (compound 1) was prepared according to the
literatures,[5] which was converted to the corresponding diazo ketone (com-
pound 2) and subject to the following Wolff rearrangement. Thermal
decomposition of 2 under catalysis of silver oxide in ethanol provided the pre-
cursor (compound 3) for the subsequent benzylation (Compounds 2–3 were
prepared using different methods, and gave satisfactory agreements to the
literature, see Ref.[6]) After treating 3 with lithium bis(trimethylsilyl)amide
(LHDMS) at 2788C and then adding the anhydrous THF solution containing
1.3 eq. benzyl bromide, benzylation occurred stereoselectively and no exist-
ence of the diastereomers was detected by high-pressure liquid chromato-
graphy (HPLC). Purification by silica gel column chromatography
(EtOAc : n-hexane ¼ 1 : 15) provided the single diastereomer (compound 4)
yield up to 86%,a which was hydrolyzed to give the acid (compound 5)
under the basic condition (3 eq. LiOH, THF : MeOH : H2O ¼ 3 : 1 : 1).b
Hydrogenation of 5 on 10% Pd-C in ethanol removed the Z group and pro-
vided compound 6.c Preparation of the target pyrrolizidine (compound 7)
aCompound 4: oil, yield: 86%. [a]D20 2 18.8 (c 0.04, CHCl3). IR (cm21, KBr): 1728,
1700. HRMS: 367.1784 (C24H29NO4).
bCompound 5: oil, yield: 92%. [a]D20 2 2.35 (c0.04, CHCl3). IR (cm21, KBr): 3031,
1703. HRMS: 395.2097 (C22H25NO4). For both compounds 4 and 5, the existence of
rotator is observed on the NMR spectra.
cCompound 6: white powder, yield: 95%. m.p. 1828–1838C. [a]D20 2 6.4 (c 0.1, H2O).
IR (cm–1, KBr): 2959, 2943, 2910, 1644. 1H-NMR (d ppm, D2O, 400 MHz): 7.27–7.16
(m, 5H), 3.42–3.32 (m, 1H), 3.17–3.14 (m, 2H), 2.81–2.76 (dd, 1H, J ¼ 8.0,

Stereoselective Synthesis
3193
a. (i) ClCOOBui, Et2O; (ii) CH2N2; b. Ag2O, TEA, EtOH; C. LHMDS, PhCH2Br,
2788C, 1 h; d. 3 eq. LiOH, THF/MeOH/H2O ¼ 3 : 1 : 1; e. 10 % Pd-C, H2; f.
SOCl2, EtOH, refluxing.
Scheme 1.
was achieved by treating 6 with 1.1 eq. thionyl chloride in ethanol at room
temperature for 2 hrs and then further refluxing for 2 hrs.d (Sch. 1).
The antiselectivity observed in the a-benzylation of compound 3 could be
explained according to the similar asymmetric a-alkylation of b-amino
esters.[7] The confirmed lithium chelated enolate hindered the proximity of
the benzyl bromide from the syn plane, which resulted in the preferred
formation of (2S, 20S)-2-benzyl-3-(N-phenylmethoxycarbonyl-pyrrolidine-
20-yl)propanoic acid ethyl ester 4 (Fig. 1).
12.6 Hz), 2.69–2.64 (dd, 1H, J ¼ 6.4, 12.6 Hz), 2.49–2.47 (m, 1H), 2.11–2.08 (m, 1H),
1.97–1.84 (m, 3H), 1.63–1.56 (m, 1H), 1.51–1.46 (m, 1H). 13C NMR (d D2O,
100 MHz): 181.12, 138.54, 127.89, 127.44, 125.33, 57.99, 47.18, 43.76, 37.86,
33.22, 28.28, 21.88. Anal. Calcd. for C14H19NO2: C, 72.07; H, 8.21; N, 6.00. Found:
C, 71.75; H, 8.20; N, 5.97.
dCompound 7: oil, yield: 87%. [a]D20 2 3.0 (c 0.2, EtOAc). IR (cm21, CHCl3): 1693.
1H-NMR (d ppm, CDCl3, 300 MHz): 7.30–7.17 (m, 5H), 3.73–3.69 (m, 1H), 3.56–
3.52 (m, 1H), 3.45–3.28 (dd, 1H, J ¼ 4.0, 13.8 Hz), 3.10–3.03 (m, 2H), 2.59–2.51
(dd, 1H, J ¼ 10.2, 13.8 Hz), 2.33–2.27 (m, 1H), 2.09–1.96 (m, 3H), 1.43–1.35
(m, 1H), 1.26–1.19 (m, 1H). 13C NMR (CDCl3, 100 MHz): 175.22, 140.34, 129.26,
128.77, 126.51, 59.76, 48.64, 41.47, 37.39, 35.38, 32.61, 27.09. HRMS: 215.1310
(C14H17NO).

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Jin et al.
Figure 1.
Figure 2.
The absolute configuration of 7 was experimentally determined with
2D H-H chemical shift correlated spectroscopy (COSY) and H-H nuclear
Overhauser enhancement spectroscopy (NOESY) technologies.e In
the NOESY spectrum of 7, no NOE effects were observed between H-2 and
H-1b, but the other NOE effects were observed between H-8 and H-1a, H-8
and H-7a, H-2 and H-7b, and H-2 and H-5b, respectively. These results
strongly suggested (2S, 8S) configuration of 7 (Fig. 2).
e2D H-H COSY (d, CDCl3, 500 MHz): 3.76–3.68 (m, 1H, H-8); 3.59–3.50 (m, 1H,
H-5); 3.07–3.00 (m, 2H, H-2 and H-5); 2.33–2.26 (m, 1H, H-1); 2.09–2.05 (m, 1H,
H-6); 2.06–1.95 (m, 2H, H-7); 1.43–1.35 (m, 1H, H-1); 1.26–1.19 (m, 1H, H-6).
2D H-H NOESY (d, CDCl3, 500 MHz): 3.76–3.68 (m, 1H, H-8); 3.59–3.50 (m, 1H,
H-5b); 3.07–3.00 (m, 2H, low field, H-2; high field, H-5a); 2.33–2.26 (m, 1H,
H-1b); 2.09–2.05 (m, 1H, H-6b); 2.06–1.95 (m, 2H, low field, H-7a; high field,
H-7b); 1.43–1.35 (m, 1H, H-1a); 1.26–1.19 (m, 1H, H-6a). NOE effects were observed
between H-8 and H-7a, H-8 and H-1a, H-5b and H-6b, H-5b and H-2, H-2 and H-7b,
H-5a and H-7a, H-6b and H-7b, and H-7a and H-6a, respectively.

Stereoselective Synthesis
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Compared to the reported asymmetric benzylation of chiral g-lactam,
which also provided the only one diastereomer with S configuration (yield:
76%),[8] our reported stereocontrolled benzylation of the acyclic substrate
showed a higher yield (up to 86%) without losing diastereoselectivity. For
the reaction with the other electrophiles, such as methyl iodide, further
research is under way in spite of being hindered by the separation
difficulties.[2f]
In conclusion, we synthesized a new pyrrolizidinone derivative stereo-
selectively using asymmetric alkylation as the key step. This route showed
a high diastereoselectivity and good yield when benzylation occurred at
2788C. The absolute configurations of (2S, 8S)-2-benzyl hexahydro-pyrrodi-
zin-3-one were confirmed through 2D H-H COSY and H-H NOESY
technologies.
ACKNOWLEDGMENTS
This work was supported by grants from the National Natural Science
Foundation of China and the Science and Technology Committee of Ji Lin
Province, China. We thank Professor D. H. Kim and his group of Postech
in Korea for their great help in this research.
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Received in Japan March 31, 2004