Enantioselective synthesis of polyzonimine and nitropolyzonamine, spirocyclic compounds from the defensive glands of a millipede, Polyzonium rosalbum

Article abstract of DOI:10.1016/S0040-4039(00)01133-3

Asymmetric Michael addition of the enamine derived from 2,2-dimethylcyclopentanecarboxaldehyde and (S)-prolinol methyl ether to nitroethylene afforded the adduct of 76% ee, which finally yielded enantiomerically pure (+)-polyzonimine and (+)-nitropolyzonamine, compounds from the defensive glands of a millipede, Polyzonium rosalbum. The absolute configuration of (+)-polyzonimine was determined as S. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)01133-3

Tetrahedron Letters 41 (2000) 6623±6625
Enantioselective synthesis of polyzonimine and
nitropolyzonamine, spirocyclic compounds from the
defensive glands of a millipede, Polyzonium rosalbum
Kenji Mori* and Yasuyo Takagi
Department of Chemistry, Faculty of Science, Science University of Tokyo, Kagurazaka 1-3, Shinjuku-ku,
Tokyo 162-8601, Japan
Received 12 June 2000; revised 27 June 2000; accepted 30 June 2000
Abstract
Asymmetric Michael addition of the enamine derived from 2,2-dimethylcyclopentanecarboxaldehyde
and (S)-prolinol methyl ether to nitroethylene a€orded the adduct of 76% ee, which ®nally yielded
enantiomerically pure (+)-polyzonimine and (+)-nitropolyzonamine, compounds from the defensive glands
of a millipede, Polyzonium rosalbum. The absolute con®guration of (+)-polyzonimine was determined as S.
# 2000 Elsevier Science Ltd. All rights reserved.
Keywords: asymmetric synthesis; insects; Michael reaction; nitro compounds; spiro compounds.
In 1975, in the course of their studies on compounds from the defensive glands of a millipede
Polyzonium rosalbum, Meinwald and co-workers isolated and identi®ed the following two nitrogen-
containing spirocyclic compounds.1,2 (+)-Polyzonimine {6,6-dimethyl-2-azaspiro[4.4]non-1-ene (1)}
was isolated as a volatile insect repellent,1 and its racemate (þ)-11,3 as well as enantiomerically
enriched (+)-1 (68% ee)4 were synthesized. (+)-Nitropolyzonamine [20,20-dimethyl-6-nitrospiro-
{1-azabicyclo[3.3.0]octane-4,10-cyclopentane} (2)] was also isolated as a minor (ca. 15% of 1), less
volatile and crystalline component of the secretion,2 and its structure including absolute
con®guration was determined as (4S,5R,6S)-2 by the X-ray analysis of its perchlorate salt.5
Synthesis of (þ)-2 from (þ)-1 was also achieved.2,3 Since (+)-polyzonimine (1) co-occurs with
(+)-nitropolyzonamine (2), it is highly probable that the former shares the same S con®guration at
the spiro center as that of the latter. However, this must be proved. The only existing synthesis of
(+)-1 (68% ee) could not tell us anything about its absolute con®guration.4 We report herein a
synthesis of enantiomerically pure (+)-2 via (+)-1, which establishes the absolute con®guration of
(+)-1 as S.
* Corresponding author. Fax: +81-3-3235-2214.
0040-4039/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)01133-3

6624
As shown in Scheme 1, our synthesis of 1 is based on a simple assumption that asymmetric
Michael addition (4!5) must be successful, if a proper chiral auxiliary is chosen. We are not too
optimistic, however, to expect 100% asymmetric yield in this step, and therefore the enantiomeric
purity of the product should be enriched via an appropriate derivative. Our synthesis started from
the known aldehyde 3,1,3 which was converted to enamines 4a and 4b by treatment with (S)-
proline tert-butyl ester6 and (S)-prolinol methyl ether,7 respectively, in the presence of MS 4A.8
Due to its bulkiness, (S)-1-amino-2-(1-methoxy-1-ethylpropyl)pyrrolidine9 did not a€ord enam-
ine 4c. Addition of the enamines 4a or 4b to nitroethylene was executed under the standard con-
ditions employing 2-nitroethyl acetate and N-ethylmorpholine in acetonitrile.10 Because neither
the determination of its absolute con®guration nor the estimation of its enantiomeric purity was
possible, the crude product 5 was further processed to give 1. The absolute con®guration of 5 as
depicted in the formula became clear only after its conversion to (+)-2. Protection of the formyl
group of 5 as an acetal to give 6 was followed by its reduction with lithium aluminum hydride to
a€ord 7. Catalytic hydrogenation of 6 was less successful. Treatment of 7 with hydrochloric acid
gave (+)-1, which could be analyzed by GC on Chirasil-DEX1-CB. The enamine 4b turned out to
be a superior one in the asymmetric Michael reaction to give (+)-1 of 76% ee, while 4a furnished
(+)-1 of only 4% ee. The overall yield of (+)-1 prepared via 4b was 42% based on 3 (®ve steps).
Scheme 1. Synthesis of polyzonimine (1) and nitropolyzonamine (2). Reagents: (a) (S)-proline-derived chiral auxiliary,
MS 4A, C6H6; (b) (i) AcOCH2CH2NO2, N-ethylmorpholine, MeCN; (ii) chromatog; (c) HO(CH2)2OH, TsOH,
HC(OEt)3 (78% based on 3 via 4b); (d) LiAlH4, THF; (e) 2 M HCl, THF (54% based on 6); (f) d-(^)-tartaric acid
(1 equiv.), recrystallization from EtOH (23%); (g) K2CO3, H2O, extraction, distillation (44%); (h) I(CH2)3NO2,
C5H5N (34%)

6625
After some experimentation, (+)-polyzonimine (1) was found to give a nicely crystalline salt 8
with an equimolar amount of d-(^)-tartaric acid. The salt 8 was recrystallized from ethanol
several times to furnish a pure sample, mp 136±139ꢀC, ‰ꢀŠD25=^11 (c 0.22, MeOH). Alkaline
decomposition of 8 with potassium carbonate gave back pure (+)-polyzonimine (1, ca. 100% ee),
‰ꢀŠ2D2=+3.3 (c 0.26, CHCl3) {Ref. 1, ‰ꢀŠ2D0=+3.26 (CHCl3)}.11 Conversion of (+)-1 to nitropoly-
zonamine (2) by treatment with 3-iodo-1-nitropropane and pyridine2,3 yielded crystalline and
dextrorotatory product (4S,5R,6S)-(+)-2, mp 69.5±70.5ꢀC, ‰ꢀŠD24=+6.1 (c 1.0, CHCl3) {Ref. 2, mp
65.5±66.5ꢀC, ‰ꢀŠD20=+12 (CHCl3)}.11 Accordingly, (+)-polyzonimine (1) possesses S con®guration
at its spiro center.
In conclusion, enantiomerically pure (+)-polyzonimine (1) and (+)-nitropolyzonamine (2) were
synthesized for the ®rst time, and the absolute con®guration of (+)-1 was established as S. The
opposite enantiomer of polyzonimine (^)-10, ‰ꢀŠD23=^3.3 (c 0.25, CHCl3), was also synthesized by
starting from 4b0. The results of bioassay of 1 and 10 to compare their insect repellent activity will
be reported in our full paper, which will appear in J. Brazil. Chem. Soc. in due course.
References
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2370.
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5. Miller, R. W.; McPhail, A. T. J. Chem. Res. (S), 1978, 76.
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8. Taguchi, K.; Westheimer, F. H. J. Org. Chem. 1971, 36, 1570±1572.
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3
11. Spectral properties of (+)-1 and (+)-2 as summarized below are in good accord with those reported.1 (+)-1: bp
81ꢀC/10 torr.; nD23=1.4781; IR (®lm): ꢁmax (cm^1)=2955 (s), 2870 (s), 1620 (s), 1465 (m), 1385 (m), 1370 (m), 1080
1
(w), 960 (w), 920 (w); H NMR (300 MHz, CDCl3): ꢂ=0.89 (3H, s), 0.91 (3H, s), 1.48±1.93 (8H, m), 3.71±3.88
(2H, m), 7.40 (1H, t, J=2.4 Hz); 13C NMR (75 MHz, CDCl3): ꢂ=20.4, 23.8, 24.5, 30.5, 35.3, 39.9, 43.5, 60.6, 66.2,
173.1; GC (Chirasil-DEX1-CB, 0.25 mmÂ25 m, 110ꢀC+0.5ꢀC/min, He, 110 kPa) tR=17.00 min (100%) [(^)-10:
tR=17.88 min (100%)]. Compound (+)-2: IR (KBr): ꢁmax (cm^1)=2950 (br. s), 2670 (w), 1540 (s), 1490 (s), 1430
(s), 1365 (s), 1350 (s), 1310 (s), 1270 (s), 1225 (s), 1195 (s), 1180 (s), 1150 (s), 1115 (s), 1080 (s), 1065 (s), 1025 (m),
1000 (m), 980 (m), 970 (m), 950 (m), 930 (m), 910 (m), 885 (s), 850 (s), 820 (s), 710 (s), 670 (s); 1H NMR (300 MHz,
CDCl3): ꢂ=0.87 (3H, s), 0.96 (3H, s), 1.36±1.51 (4H, m), 1.62±1.80 (3H, m), 1.98 (1H, ddd, J=6.9, 12.0, 12.0 Hz),
2.13±2.26 (1H, m), 2.36±2.50 (2H, m), 2.85 (1H, ddd, J=4.2, 7.5, 11.7 Hz), 3.06 (1H, ddd, J=2.1, 9.0, 11.1 Hz),
3.25 (1H, ddd, J=6.6, 9.0, 11.7 Hz), 3.74 (1H, d, J=4.2 Hz), 4.80 (1H, td, J=3.9, 3.9, 7.5 Hz); 13C NMR (75
MHz, CDCl3): ꢂ=19.5, 23.4, 24.8, 31.9, 32.3, 35.1, 39.1, 42.7, 52.3, 53.3, 56.6, 73.5, 88.1.