Synthesis of demissidine by a ring fragmentation 1,3-dipolar cycloaddition approach

Article abstract of DOI:10.1021/ol4004993

A synthesis of the steroidal alkaloid demissidine from epiandrosterone is reported. A ring fragmentation reaction that efficiently ruptured the D-ring of a diazo ester derivative of epiandrosterone to provide an aldehyde tethered ynoate product was key to this sequence. Incorporation of the indolizidine framework was achieved by an azomethine ylide 1,3-dipolar cycloaddition.

Full text of DOI:10.1021/ol4004993

ORGANIC
LETTERS
2013
Vol. 15, No. 9
2100–2103
Synthesis of Demissidine by a Ring
Fragmentation 1,3-Dipolar Cycloaddition
Approach
Zhe Zhang, Geoffrey M. Giampa, Cristian Draghici, Qiufeng Huang, and
Matthias Brewer*
The University of Vermont, 82 University Place, Burlington, Vermont 05405,
United States
Matthias.Brewer@uvm.edu
Received February 22, 2013
ABSTRACT
A synthesis of the steroidal alkaloid demissidine from epiandrosterone is reported. A ring fragmentation reaction that efficiently ruptured
the D-ring of a diazo ester derivative of epiandrosterone to provide an aldehyde tethered ynoate product was key to this sequence. Incorporation of
the indolizidine framework was achieved by an azomethine ylide 1,3-dipolar cycloaddition.
The Solanum alkaloids are steroidal glycoalkaloids
isolated from potatoes and other Solanaceous plants.
These toxic alkaloids are known to act as natural insect
deterrents,1 have antimicrobial properties,2,3 can inhibit
acetylcholinesterase,4 and can disrupt cell membranes.5
Demissine, commersonine (Figure 1), and their aglycon
steroidal alkaloid demissidine (Scheme 1) are the principal
alkaloids isolated from several wild potato species includ-
ing Solanum demissum6 and Solanum acaule.7 Demissidine
is structurally similar to solanidine (5-dehydrodemissidine),
the steroidal alkaloid aglycon of solanine, the principal
alkaloid isolated from Solanum tuberosum, the crop potato.
Demissidine was prepared by Kuhn et al.8 in 1952 and
later by Sato and Latham9 by semisynthesis from the
related steroidal alkaloid dihydrotomatidine. In 1963
Figure 1. Structure of demissine and commersonine. Abbrevia-
tions: Gla = galactose; Glu = glucose; Xyl = xylose.
(1) Schreiber, K. Zuchter 1957, 27, 289.
(2) Tingey, W. Am. J. Potato. Res. 1984, 61, 157.
(3) Schreiber, K. In The Alkaloids: Chemistry and Physiology; Manske,
R. H. F., Ed.; Academic Press: 1968; Vol. 10, p 1.
Adam and Schreiber10 prepared demissidine in low yields
from pregnenolone acetate by addition of 2-lithio-5-
methylpyridine followed by unselective hydrogenation
(4) Harris, H.; Whittaker, M. Ann. Hum. Genet. 1962, 26, 73.
(5) Keukens, E. A. J.; de Vrije, T.; Fabrie, C. H. J. P.; Demel, R. A.;
Jongen, W. M. F.; de Kruijff, B. BBA-Biomembranes 1992, 1110, 127.
(6) Osman, S. F.; Sinden, S. L. Phytochemistry 1982, 21, 2763.
(7) Gregory, P. Am. J. Potato. Res. 1984, 61, 115.
€
and a HofmannÀLofflerÀFreytag cyclization. In this
€
(8) Kuhn, R.; Low, I.; Trischmann, H. Angew. Chem. 1952, 64, 397.
letter we report an efficient synthesis of demissidine
from epiandrosterone by a sequence that involves a ring
(9) Sato, Y.; Latham, H. G. J. Am. Chem. Soc. 1956, 78, 3146.
(10) Adam, G.; Schreiber, K. Tetrahedron Lett. 1963, 4, 943.
r
10.1021/ol4004993
Published on Web 04/15/2013
2013 American Chemical Society

fragmentation and a 1,3-dipolar cycloaddition as key
steps.
tert-butyldiphenylsilyl ether and subsequent displacement
ofbromide withhydroxide toprovide alcohol 7. Protection
of the free alcohol as the TBS ether and subsequent aldol
type addition of ethyl lithiodiazoacetate to the carbonyl
provided syn-diol 4 in 61% yield over the two steps.
Treating diazo 4 with SnCl4 resulted in fragmentation of
the steroid’s D-ring to provide aldehyde tethered ynoate 2
in 75% yield.
With the requisite dipolar cycloaddition precursor in
hand we turned our attention to preparing (5S)-5-methyl-
pipecolic acid (Scheme 3). This was most conveniently
achieved by resolution of racemic 3-methylpiperidine by
cocrystallization with (S)-mandelic acid as described by
Wong et al.15 to provide (S)-3-methylpiperidine•(S)-man-
delate in 98% ee.16 Boc protection of the amine followed
by R-lithiation17À19 and trapping with CO2 provided N-
Boc-(2R,5S)-5-methylpipecolic acid (9) in 78% yield as a
single diastereomer.20 Subsequent TFA mediated Boc
removal provided the TFA salt of (2R,5S)-5-methylpipe-
colic acid in 81% yield. In prior studies13 we had noted that
aldehyde tethered ynoates reacted with amino acids via a
decarboxylative intramolecular azomethine ylide 1,3-dipo-
lar cycloaddition more productively when the amino acid
component was protected as the trimethylsilyl ester. With
this in mind, the TFA salt of the amino acid was passed
Our synthetic approach to demissidine takes advantage
of our discovery that γ-silyloxy-β-hydroxy-R-diazocarbo-
nyls undergo efficient rupture of the CγÀCβ bond in the
presence of a Lewis acid to provide tethered aldehyde
ynoates or ynones in high yield.11,12 These bifunctional
molecules are excellent precursors for intramolecular azo-
methine ylide 1,3-dipolar cycloadditions and give poly-
cyclic 2,5-dihydropyrrole products in high yield.13 As
shown in Scheme 1, we envisioned using this sequence of
reactions to create the indolizidine frameworkcontained in
demissidine. The requisite steroid-based tethered aldehyde
ynoate (2) would be formed by fragmentation of γ-sily-
loxy-β-hydroxy-R-diazoester 4, which in turn could be
prepared from epiandrosterone.
Our synthetic route started from epiandrosterone (6),
which was converted into R-hydroxy ketone 7 (Scheme 2)
by a modification of the procedure reported by Numazawa
and Nagaoka14 for the conversion of epiandrosterone
to 16-hydroxy epiandrosterone. This sequence in-
volved a CuBr2 mediated bromination R to the ketone
followed by protection of the secondary alcohol as the
Scheme 1. Retrosynthetic Analysis of Demissidine
Scheme 3. Preparation of (5S)-5-Methylpipecolic Acid
Scheme 2. Preparation of Steroid-Based Tethered Aldehyde Ynoate
Org. Lett., Vol. 15, No. 9, 2013
2101

Scheme 4. Synthesis of Demissidine
through poly(vinylpyridine) to provide the free base,21
which was treated with N,N-diethyltrimethylsilylamine to
give the requisite amino acid silyl ester (3).
The key azomethine ylide 1,3-dipolar cycloaddition of
aldehyde ynoate 2 and silyl ester 3 proceeded smoothly to
provide an easily separable mixture of dihydropyrrole 10
and pyrrole 11 in a combined 80% yield in a ratio that
varied from 2:1 to 1:1 (Scheme 4).22 The formation of
dihydropyrrole 10 was exquisitely diastereoselective, but
unfortunately provided the product with incorrect stereo-
chemistry at the C16 position.23 Attempts to epimerize the
with the correct stereochemistry at C16, C17, and C22 if the
angular methyl were to prevent the catalyst from ap-
proaching the methyl bearing face. In the event, hydro-
genation of pyrrole 11 over PtO2 in acetic acid at 60 °C and
600 psi provided the pyrrolidine product in a uniquely
diastereoselective manner in which all of the protons were
delivered from the face opposite the C13 angular
methyl. We were pleased to note that extending the
reaction time led to in situ epimerization at C20 and
provided the desired pyrrolidine product 12 in which
all the stereocenters were set correctly. Although
pyrrole 11 is presumably formed by air oxidation of
dihydropyrrole 10 during the 1,3-dipolar cycloaddi-
tion reaction, attempts to increase the yield of pyrrole
11 by extending the reaction time in the presence of
oxygen failed. However, platinum black24 dehydroge-
nated dihydropyrrole 10 to provide pyrrole 11 in 85%
yield.
C16 vinylogous ester position via deprotonation failed. We
reasoned that hydrogenation of the fortuitously formed
pyrrole 11 might lead to the corresponding pyrrolidine
(11) Bayir, A.; Draghici, C.; Brewer, M. J. Org. Chem. 2010, 75, 296.
(12) Draghici, C.; Brewer, M. J. Am. Chem. Soc. 2008, 130, 3766.
(13) Draghici, C.; Huang, Q.; Brewer, M. J. Org. Chem. 2009, 74,
8410.
To complete the synthesis of demissidine, the ethyl ester
was reduced by lithium aluminum hydride to the corre-
sponding primary alcohol in 98% yield, which was in turn
converted to mesylate 13 in 81% yield. Reductive cleavage
of the mesylate by lithium triethylborohydride proceeded
in 93% yield to give the requisite methyl at position C20 of
the steroid. Removal of the silyl protecting group occurred
in 90% yield to provide demissidine.
In summary, demissidine has been synthesized from
epiandrosterone. This synthetic approach takes advantage
of a Lewis acid mediated fragmentation of a γ-silyloxy-β-
hydroxy-R-diazoester to provide a tethered aldehyde yno-
ate. This key intermediate was successfully used in a
subsequent azomethine ylide 1,3-dipolar cycloaddition to
provide the indolizidine framework present in the natural
product.
(14) Numazawa, M.; Nagaoka, M.; Osawa, Y. J. Org. Chem. 1982,
47, 4024.
(15) Wong, W. C.; Lagu, B.; Nagarathnam, D.; Marzabadi, M. R.;
Gluchowski, C. Synaptic Pharmaceutical Corporation, USA. June 12,
2001; Vol. US6245773 B1, 314 pp.
(16) The enantiomeric excess was determined by HPLC analysis of
the corresponding Boc-3-methylpiperidine derivative on a Chiralpak IC
column using a 99:1 n-hex/IPA eluent system.
(17) Beak, P.; Lee, W. K. Tetrahedron Lett. 1989, 30, 1197.
(18) Beak, P.; Lee, W. K. J. Org. Chem. 1990, 55, 2578.
(19) Beak, P.; Lee, W. K. J. Org. Chem. 1993, 58, 1109.
(20) Relative configuration assigned by comparison of the salt of the
free amino acid to literature values. See: Oinuma, H.; Suda, S.; Yoneda,
N.; Kotake, M.; Mizuno, M.; Matsushima, T.; Fukuda, Y.; Saito, M.;
Matsuoka, T.; Et, A. Preparation of substituted thiazolo[3,2-R]azepine
derivatives. WO 9602549, Febuary 1, 1996.
(21) Jewett, D. M.; Ehrenkaufer, R. L. Anal. Biochem. 1982, 122, 319.
(22) The dipolar cycloaddition was conveniently run in a CEM
Corporation Discover series microwave reactor in a sealed reaction
vessel. The reaction temperature and pressure are controlled by the
reactor.
(23) The relative stereochemistry at C16 was assigned based on the
oberservation of a positive NOE between the C16 proton and the
angular methyl at C13.
(24) Platinum black was formed by suspending platinum oxide in
decalin under an atmosphere of hydrogen gas for 2 h. The dark black
solid was isolated by filtration, placed under vacuum overnight, and
then exposed to air for 1 h before use.
Acknowledgment. This work is dedicated to Prof. Larry
Overman on the occasion of his 70th birthday. We thank
Bruce O’Rourke (University of Vermont) for obtaining
mass spectral data and Dr. Bruce Deker (University
2102
Org. Lett., Vol. 15, No. 9, 2013

of Vermont) for assistance with NMR characterization.
This work was financially supported by the NIH (National
Institute of General Medical Sciences Award Number
R01GM092870) and was made possible by use of a facility
supported by the Vermont Genetics Network through
Grant Number 8P20GM103449 from the INBRE Pro-
gram of the National Institute of General Medical Sciences
(NIGMS), a component of the National Institutes of
Health (NIH). Its contents are solely the responsibility
of the authors and do not necessarily represent the official
views of the NIGMS or NIH. The National Science
Foundation supported this work through instrumentation
grants CHE-1126265 and CHE-0821501.
Supporting Information Available. Experimental proce-
dures, characterization data, and copies of NMR spectra.
This material is available free of charge via the Internet at
http://pubs.acs.org.
The authors declare no competing financial interest.
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