Asymmetric synthesis of dimethyl swazinecate and structural confirmation of its parent alkaloid (-)-swazine

Article abstract of DOI:10.1039/a800011e

Synthesis of dimethyl swazinecate, a principal component of the pyrrolizidine alkaloid swazine, was completed from (S)-(-)-β-citronellal; an X-ray crystallographic analysis of natural swazine confirmed its absolute stereostructure.

Full text of DOI:10.1039/a800011e

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Asymmetric synthesis of dimethyl swazinecate and structural confirmation of
its parent alkaloid (2)-swazine
James D. White,*† John C. Amedio, Jr., Peter Hrnciar, Nadine C. Lee, Susumu Ohira and Alexandre F. T.
Yokochi
Department of Chemistry, Oregon State University, Corvallis, OR 97331-4003, USA
O
Synthesis of dimethyl swazinecate, a principal component of
the pyrrolizidine alkaloid swazine, was completed from
H
OH
OH
i, ii
iii, iv
(S)-(2)-b-citronellal; an X-ray crystallographic analysis of
natural swazine confirmed its absolute stereostructure.
Pyrrolizidine alkaloids are widespread among plants of the
Senecio family, many of which possess toxic properties that
pose serious risk to human and animal health.1 (2)-Swazine 1,
OMe
v
4
5
6
OH
O
OH
OH
+
O
O
OH
O
OH
O
O
O
O
OR
O
O
9
O
O
7
RO
H
O
OMe
OMe
O
7
6.5 : 1
8
N
Scheme 1 Reagents and conditions: i, LDA, CH2NN+Me2I2, MeI,
NaHCO3, 94%; ii, NaBH4, CeCl3·7H2O, 93%; iii, PhSeCl, NaHCO3, THF–
MeOH; iv, H2O2, NaHCO3, THF–H2O, 82% (from 5); v, ButOOH,
Ti(OPri)4, (+)-DIPT, CH2Cl2, 92%
1
2 R = H
21 R = Me
3
first isolated from Senecio swaziensis Compton,2 is among the
more complex members of this class of alkaloids, consisting of
a functionalized adipic acid derivative 2 (swazinecic acid) that
bridges the C7 and C9 hydroxy groups of the pyrrolizidine
retronecine to form a twelve-membered dilactone. Neither
acidic nor careful basic hydrolysis of 1 has permitted isolation
of intact 2. Instead, the constitution of this dicarboxylic (necic)
acid was inferred from the spirolactone 3 obtained upon
treatment of 1 with hot, 1.5 m sulfuric acid. The structure of 3
was established by X-ray crystallographic analysis of its
p-bromobenzoate.2 Initially, swazine was formulated as the
dilactone isomeric with 1, in which swazinecic acid 2 was
connected to retronecine in the reverse orientation to that
shown. This assignment was subsequently revised,3 and the
revision was accepted after a more complete degradative and
spectroscopic investigation.4 Herein, we report the first synthe-
sis of swazinecic acid, characterized as its dimethyl ester, which
confirms its absolute stereostructure as 2. We also describe an
X-ray crystallographic analysis of natural swazine which now
substantiates the designation of this alkaloid as 1.
tartrate (DIPT) as the chiral adjuvant12 gave 7 and 8 in the ratio
6.5:1.
After chromatographic separation, 7 was oxidized to alde-
hyde 12 which was converted to alcohol 13 upon treatment with
vinylmagnesium bromide at low temperature (Scheme 2).
Further oxidation with Dess–Martin periodinane produced a,b-
unsaturated ketone 14. Chelation-controlled Grignard addition
to this ketone was expected to occur selectively at the re face of
the carbonyl group, and when 14 was treated carefully with
methylmagnesium bromide at low temperature a single alcohol,
OH
O
H
ii
i
O
O
7
OMe
OMe
12
13
Our approach, which employs b-citronellal as the starting
material,5 hinges upon oxidative truncation of an elaborated
terpenoid structure to generate a dicarboxylic acid having the
requisite functionality and configuration of the necic acid.6–10
Since our planned route to 2 involved early introduction of a
relatively sensitive epoxide, it was essential that later steps in
the sequence avoid reagents which would destroy this func-
tion.
iii
O
OR
iv
O
O
a-Methylenation of (2)-4, followed by Luche reduction of
the resultant a,b-unsaturated aldehyde (as described for the
enantiomeric series),9 gave the allylic alcohol 5 (Scheme 1).
The trisubstituted olefin of this diene underwent selective
methoxyselenation using Toshimitsu’s conditions,11 and the
intermediate alkyl selenide was oxidized to afford 6 in good
yield. Asymmetric epoxidation of 6 using (S,S)-(+)-diisopropyl
OMe
15 R = H
16 R = TBDMS
OMe
14
v
Scheme 2 Reagents and conditions: i, (COCl)2, DMSO, Et3N, CH2Cl2,
95%; ii, vinylmagnesium bromide, THF, 278 °C, 72%; iii, Dess–Martin
periodinane, 100%; iv, methylmagnesium bromide, Et2O, 278 °C, 60%; v,
TBDMSOTf, 2,6-lutidine, CH2Cl2, 235 °C, 76%
Chem. Commun., 1998
603

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OTBDMS
CHO
i
BnO2C
16
O
O
17
O
ii, iii
OH
iv, v
O
O
O
BnO2C
CO2Me
O
O
CO2Me
vi, vii
O
18
19
O
O
iv, v
viii
ix
x
O
2
21
3
O
O
N
CO2Me
20
Fig. 1 ORTEP plot of the crystal structure of swazine 1. Thermal ellipsoids
Scheme 3 Reagents and conditions: i, O3, (CF3CO)2O, BnOH–CH2Cl2,
NaHCO3, Et3N, 278 °C; ii, NaClO2, ButOH, Me2CNCHMe; iii, CH2N2,
Et2O, 65% from 16; iv, H2, Pd/C; v, 2-chloro-1-methylpyridinium iodide
(Mukaiyama’s reagent), 99% from 18; vi, LDA, CH2O, 55%; vii, MsCl,
Et3N, 96%; viii, KOH, MeOH–H2O; ix, CH2N2, Et2O, 63% from 20; x,
H2SO4
are drawn at the 50% probability level.
Notes and References
† E-mail: whitej@ccmail.orst.edu
‡ Selected data for 21: [a]2D7 238.4 (c 0.25, CHCl3); dH (400 MHz, CDCl3)
1.19 (3 H, d, J 7), 1.47 (3 H, s), 2.44 (1 H, d, J 4), 2.91 (1 H, d, J 4), 3.62
(1 H, q, J 7), 3.77 (3 H, s), 3.81 (3 H, s), 5.52 (1 H, s), 6.17 (1 H, s); dC (100
MHz, C6D6) 17.2, 22.8, 30.5, 45.2, 51.9, 52.7, 63.8, 77.8, 123.0, 141.3,
168.0, 175.0; nmax/cm21 3472, 2959, 1733, 1450, 1269, 1156, 1103, 1035;
m/z (CI) 259 (M+ + 1), 241, 227, 209, 199, 181, 177, 167, 155, 125.
§ Crystal data for 1: C18H23NO6, (MW = 349.37), orthorhombic, space
group P212121 (No. 19), a = 8.940(2), b = 12.229(2), c = 16.706(3) Å,
V = 1826.4(6) Å3, Z = 4, Dc = 1.271 Mg m23. A total of 1936 data were
collected on a Siemens P4 diffractometer equipped with Cu-Ka radiation
assigned structure 15, was obtained accompanied by the product
of conjugate addition.
Alcohol 15 was protected as its tert-butyldimethylsilyl ether
16 in a process that retained the epoxide intact. Ozonolytic
cleavage of 16 in the presence of benzyl alcohol, trifluoroacetic
anhydride and triethylamine at low temperature gave the
aldehyde ester 17 in excellent yield (Scheme 3).13 Un-
fortunately, the inherent instability of 17 resulting from its
propensity towards intramolecular aldol condensation deman-
ded immediate oxidation of this aldehyde to a carboxylic acid,
during which the silyl ether was cleaved. Treatment of the
resultant a-hydroxy acid with diazomethane afforded 18 which
underwent hydrogenolysis of the benzyl ester followed by
lactonization with Mukaiyama’s reagent14 to give 19. Con-
densation of the lithium enolate of 19 with formaldehyde
produced a stereoisomeric mixture of hydroxymethyl lactones
which, when exposed to methanesulfonyl chloride and base, led
directly to exo methylene d-lactone 20. Saponification of 20
furnished swazinecic acid 2 which was characterized as its
dimethyl ester 21.‡
(l
(Rint
=
1.54178 Å, m
0.0335). A solution was obtained using direct methods as
=
0.795 mm21) of which 1775 were unique
=
programmed in SHELXS-90 and refined against all data using the program
SHELXL 97. The final residuals are R1 = 0.0366 (all data), wR2 = 0.0990
(all data) with a GoF = 1.071. Supplementary materials in electronic format
(CIF file) are available from the authors upon request. CCDC 182/758.
1 A. R. Mattocks, Chemistry and Toxicology of Pyrrolizidine Alkaloids,
Academic Press, Orlando, Florida, 1986.
2 C. G. Gordon-Gray, R. B. Wells, N. Hallak, M. B. Hursthouse, S. Neidle
and T. B. Toube, Tetrahedron Lett., 1972, 707.
3 M. Laing and P. Sommerville, Tetrahedron Lett., 1972, 5183.
4 C. G. Gordon-Gray and R. B. Wells, J. Chem. Soc., Perkin Trans. 1,
1974, 1556.
5 T. L. Ho, Enantioselective Synthesis of Natural Products from Chiral
Terpenes, Wiley, New York, 1992, p. 16.
6 J. D. White and S. Ohira, J. Org. Chem., 1986, 51, 5492.
7 J. D. White and L. R. Jayasinghe, Tetrahedron Lett., 1988, 29, 2139.
8 J. D. White, J. C. Amedio, Jr., S. Gut and L. R. Jayasinghe, J. Org.
Chem., 1989, 54, 4268.
9 J. D. White, J. C. Amedio, Jr., S. Gut and L. R. Jayasinghe, J. Org.
Chem., 1992, 57, 2270.
10 M. P. Dillon, N. C. Lee, F. Stappenbeck and J. D. White, J. Chem. Soc.,
Chem. Commun., 1995, 1645.
11 A. Toshimitsu, T. Aoai, H. Owada, S. Menwra and M. Okano,
Tetrahedron, 1985, 41, 5301.
12 Y. Gao, R. M. Hanson, J. M. Klunder, A. Y. Do, H. Masamune and
K. B. Sharpless, J. Am. Chem. Soc., 1987, 109, 5765.
13 S. L. Schreiber, R. E. Claus and J. Reagan, Tetrahedron Lett., 1982, 23,
3867.
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15 H. Ru¨eger and M. Benn, Heterocycles, 1983, 20, 1331.
Since there is no record of either 2 or 21 having been obtained
by degradation of swazine 1, the structure of synthetic dimethyl
swazinecate was confirmed by its conversion to the spir-
odilactone 3 upon treatment with sulfuric acid in hot THF. The
spectroscopic properties of 3 obtained by this method matched
those recorded for the same substance derived from 1.
Final confirmation of the structure, including absolute
configuration, of swazinecic acid was obtained by X-ray
crystallographic analysis of swazine itself (Fig. 1).§ Since
hydrolysis of swazine is known to yield (+)-retronecine, whose
absolute configuration has been determined by independent
synthesis,15 the full structure of 1 and hence 2 is as shown.
We are indebted to Professor S. E. Drewes, University of
Natal, South Africa, for a sample of natural swazine. Financial
support was provided by the National Institute of Environ-
mental Health Sciences (ES03334).
Received in Cambridge, UK, 2nd January 1998; 8/00011E
604
Chem. Commun., 1998