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. Author manuscript; available in PMC: 2014 May 3.
Published in final edited form as: Org Lett. 2013 Apr 15;15(9):2100–2103. doi: 10.1021/ol4004993

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

Zhe Zhang 1, Geoffrey M Giampa 1, Cristian Draghici 1, Qiufeng Huang 1, Matthias Brewer 1,✉
PMCID: PMC3671602  NIHMSID: NIHMS468431  PMID: 23586838

Abstract

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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 acetylcholinesterase4 and can disrupt cell membranes.5 Demissine, commersonine (Figure 1) and their aglycon steroidal alkaloid demissidine (Scheme 1) are the principle alkaloids isolated from several wild potato species including Solanum demissum6 and Solanum acaule.7 Demissidine is structurally similar to solanidine (5-dehydrodemissidine), the steroidal alkaloid aglycon of solanine, the principle alkaloid isolated from Solanum tuberosum, the crop potato.

Figure 1.

Figure 1

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Structure of demissine and commersonine. Abbreviations: Gla = galactose; Glu = glucose; Xyl = xylose.

Scheme 1.

Scheme 1

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Retrosynthetic analysis of demissidine

Demissidine was prepared by Kuhn et al.8 in 1952 and later by Sato and Latham9 by semi-synthesis from the related steroidal alkaloid dihydrotomatidine. In 1963 Adam and Schreiber10 prepared demissidine in low yield from pregnenolone acetate by addition of 2-lithio-5-methylpyridine followed by unselective hydrogenation and a Hofmann-Löffler-Freytag cyclization. In this letter we report an efficient synthesis of demissidine from epiandrosterone by a sequence that involves a ring fragmentation and a 1,3-dipolar cycloaddition as key steps.

Our synthetic approach to demissidine takes advantage of our discovery that γ-silyloxy-β-hydroxy-α-diazocarbonyls undergo efficient rupture of the Cγ-Cβ bond in the presence of Lewis acid to provide tethered aldehyde ynoates or ynones in high yield.11, 12 These bifunctional molecules are excellent precursors for intramolecular azomethine ylide 1,3-dipolar cycloadditions and give polycyclic 2,5-dihydropyrrole products in high yield.13 As shown in Scheme 1, we envisioned using this sequence of reactions to create the indolizidine framework contained in demissidine. The requisite steroid-based tethered aldehyde ynoate (2) would be formed by fragmentation of γ-silyloxy-β-hydroxy-α-diazoester 4, which in turn could be prepared from epiandrosterone.

Our synthetic route started from epiandrosterone (6), which was converted into α-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 involved a CuBr2 mediated bromination α to the ketone followed by protection of the secondary alcohol as the tert-butyldiphenylsilyl ether and subsequent displacement of bromide with hydroxide to provide 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.

Scheme 2.

Scheme 2

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Preparation of steroid-based tethered aldehyde ynoate

With the requisite dipolar cycloaddition precursor in hand we turned our attention to preparing (5S)-5-methylpipecolic acid (Scheme 3). This was most conveniently achieved by resolution of racemic 3-methylpiperidine by co-crystallization with (S)-mandelic acid as described by Wong et al.15 to provide (S)-3-methylpiperidine•(S)-mandelate in 98% ee.16 Boc protection of the amine followed by α-lithiation17–19 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-methylpipecolic 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-dipolar 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 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).

Scheme 3.

Scheme 3

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Preparation of (5S)-5-methylpipecolic acid

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 stereochemistry at the C16 position.23 Attempts to epimerize the C16 vinylogous ester position via deprotonation failed. We reasoned that hydrogenation of the fortuitously formed pyrrole 11 might lead to the corresponding pyrrolidine with the correct stereochemistry at C16, C17 and C22 if the angular methyl were to prevent the catalyst from approaching the methyl bearing face. In the event, hydrogenation 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 cycloaddition reaction, attempts to increase the yield of pyrrole 11 by extending the reaction time in the presence of oxygen failed. However, platinum black24 dehydrogenated dihydropyrrole 10 to provide pyrrole 11in 85% yield.

Scheme 4.

Scheme 4

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Synthesis of demissidine

To complete the synthesis of demissidine, the ethyl ester was reduced by lithium aluminum hydride to the corresponding 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-α-diazoester to provide a tethered aldehyde ynoate. 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.

Supplementary Material

1_si_001

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 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 Program 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 NIGMS or NIH. The National Science Foundation supported this work through instrumentation grants CHE-1126265 and CHE-0821501.

Footnotes

Supporting Information Available Experimental procedures, characterization data, and copies of NMR spectra. This material is available free of charge via the Internet at http://pubs.acs.org.

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Supplementary Materials

1_si_001
NIHMS468431-supplement-1_si_001.pdf (2.4MB, pdf)

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