Total synthesis of (-)-himgaline

Article abstract of DOI:10.1021/ja065198n

The first total synthesis of (-)-himgaline and a highly enantioselective synthesis of its congener (-)-GB 13 are described. Decarboxylative aza-Michael reaction of the hexacyclic lactone precursor under acidic conditions, followed by basic workup, yielded (-)-GB 13 in 80% yield. Cyclization of (-)-GB 13 to oxohimgaline under acidic conditions, followed by internally coordinated sodium triacetoxyborohydride reduction, gave (-)-himgaline as the exclusive product. Copyright

Full text of DOI:10.1021/ja065198n

Published on Web 09/08/2006
Total Synthesis of (-)-Himgaline
Unmesh Shah,†,‡ Samuel Chackalamannil,*,† Ashit K. Ganguly,*,‡ Mariappan Chelliah,†
Sergei Kolotuchin,† Alexei Buevich,† and Andrew McPhail§
Schering-Plough Research Institute, 2015 Galloping Hill Road, Kenilworth, New Jersey 07033,
SteVens Institute of Technology, Hoboken, New Jersey 07030, and P.M. Gross Chemistry Laboratory,
Duke UniVersity, Durham, North Carolina 27708-0346
Received July 20, 2006; E-mail: samuel.chackalamannil@spcorp.com
Scheme 1
The rare rain forest tree Galbulimima belgraVeana, found in
Northern Australia and Papua New Guinea, has been the source of
several complex alkaloids.1 Among these, himbacine has attracted
considerable synthetic attention due to its promising pharmacologi-
cal properties.2 A synthetic analogue of himbacine is currently in
clinical trials as an antithrombotic agent.3
Himgaline (3), GB 13 (4), and its N-methyl derivative himbadine
(5) are among the congeners of himbacine with even more
pronounced structural complexity.4 The pharmacological properties
of these compounds remain unexplored. A common biosynthetic
precursor to himbacine (1), GB 13 (4), himgaline (3), and related
alkaloids was proposed by Taylor et al. in the early report of
isolation of these alkaloids.4a The assignment of absolute stereo-
chemistry of himgaline and related alkaloids has been established
very recently using X-ray crystallographic analysis.5 The first total
synthesis of racemic GB 13 was reported by Mander’s group.6
Recently, Movassaghi’s group has reported the total synthesis of
both antipodes of GB 13 and confirmed the absolute stereochem-
istry.7 We report here the first total synthesis of (-)-himgaline.
The retrosynthetic analysis presented in Scheme 1 envisions the
synthesis of himgaline from GB 13 via an intramolecular aza-
Michael reaction, followed by a diastereoselective reduction of the
Scheme 2
C16 ketone. Hexacyclic intermediate 6 was expected to provide GB
13 via a decarboxylative intramolecular aza-Michael reaction,
followed by a retro-Michael reaction. Intermediate 6 could be
constructed, via the pentacyclic intermediate 7, from the optically
pure tricyclic carboxylic acid 8. We have previously reported the
synthesis of 8 employing a highly diastereoselective intramolecular
Diels-Alder reaction of precursor 9.3c
The implementation of the above approach is outlined in Schemes
2 and 3. The previously reported aldehyde 11 was converted to the
alkene 12 by Wittig reaction.3c Lithium aluminum hydride reduction
of the lactone 12, followed by selective protection of the primary
alcohol and subsequent oxidation of the secondary alcohol, gave
the methyl ketone 13 in an overall 90% yield. Ozonolysis of the
alkene, followed by Emmons-Wadsworth reaction and subsequent
R-bromination of the methyl ketone 14, gave 15. Under radical
conditions, 15 underwent a highly diastereoselective ring closure
to give the tricyclic intermediate 16. The high degree of diaste-
reoselectivity of C20-C8 bond formation, critical to the success of
the synthetic plan, is attributed to the preferred conformation of
the trans-alkene that engenders the required configuration at C8. It
should be mentioned that attempted cyclization of 14 under anionic
conditions failed.
The construction of the bicyclo[3.2.1] C-D ring system was
achieved via a Lewis acid-catalyzed intramolecular cyclization of
â-keto ester 18.8 The requisite â-keto ester was prepared from the
carboxylic acid derived from 16 via dicyclohexylcarbodiimide-
mediated coupling with Meldrum’s acid, followed by treatment of
the intermediate with benzyl alcohol.
† Schering-Plough Research Institute.
‡ Stevens Institute of Technology.
§ Duke University.
9
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J. AM. CHEM. SOC. 2006, 128, 12654-12655
10.1021/ja065198n CCC: $33.50 © 2006 American Chemical Society

C O M M U N I C A T I O N S
Scheme 3
showed only small equatorial coupling with neighboring protons
in the 1H NMR, indicating that the axial alcohol was the exclusive
product. Use of other standard reducing agents gave similar results.
To circumvent this problem, we decided to use an internally
coordinated hydride reduction of the C16 carbonyl group employing
the C19 hydroxyl group. When crude oxohimgaline was treated with
sodium (triacetoxy)borohydride in acetonitrile, himgaline (3) was
formed exclusively in 60% yield.11 The 1H NMR spectrum of
synthetic himgaline showed two large diaxial couplings for the C16
proton, suggesting the equatorial disposition of the hydroxyl group.
Synthetic himgaline showed spectroscopic properties identical to
those of natural himgaline and comparable specific rotation.4b,10
Acknowledgment. The authors thank Dr. Birendra Pramanik
and Dr. T.-M. Chan for mass spectrometric and NMR data, Dr. T.
K. Thiruvengadam for a supply of (R)-3-butyn-2-ol, and Drs.
William Greenlee, John Piwinski, and Craig Boyle for their sup-
port. We also thank Prof. W. C. Taylor for authentic samples of
(-)-himgaline and (-)-GB 13 and Prof. Lewis Mander for sharing
the results of X-ray crystallographic analysis of natural himgaline.
U.S. thanks Schering-Plough Research Institute for educational
assistance for graduate studies at Stevens Institute of Technology.
Next, we turned our attention to the diastereospecific construction
of the piperidine E-ring. Toward this end, the â-keto ester 7 was
subjected to conjugate addition with methyl vinyl ketone, and the
resulting product yielded diketone 20 after debenzylation and
decarboxylation. Selective reductive amination of the methyl ketone
of 20 with (R)-R-methylbenzylamine, followed by N-debenzylation
and subsequent sodium cyanoborohydride reduction, gave the ring-
fused crude piperidine intermediate which was trifluoroacetylated
to give an overall 61% yield of 21 as the major diastereomer.
Ruthenium oxide-mediated oxidation of the tetrahydrofuran ring
system of 21 gave the corresponding γ-lactone 22 in excellent
yield.9 Structural confirmation of crystalline acetamide 23, initially
derived using extensive 2-D NMR experiments, was conclusively
established by single-crystal X-ray crystallographic analysis.
Thiomethylation of the enolate derived from lactone 22 gave
predominantly the cis-substituted thiomethyl ether 24. Oxidation
of sulfide to the corresponding sulfoxide, followed by thermally
induced cis-elimination, gave predominantly the tetrasubstituted
R,â-unsaturated lactone 25. Allylic bromination of 25, followed
by silver trifluoroacetate-mediated allylic displacement, gave the
corresponding acetate 27 as a mixture of diastereomers, which was
hydrolyzed and oxidized to the ketone 28 in an overall yield of
77% from 25.
Supporting Information Available: Spectral data and procedures
for all new compounds, including natural and synthetic himgaline, and
2-D NMR analysis data for 3, 4, 25, and 32. This material is available
free of charge via the Internet at http://pubs.acs.org.
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The decarboxylative unraveling of the lactone to generate GB
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reaction of 6. Treatment of 28 with 1 N sodium hydroxide gave
only 10% yield of GB 13. The N-deacylated lactone 6 was isolated
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in dioxane at 100 °C for 1 h, GB 13 was isolated in 80% yield
after basic workup. This result is consistent with the original report
that GB 13 cyclizes to oxohimgaline under acidic conditions.4a The
NMR data of synthetic (-)-GB 13 were identical to those of an
authentic natural sample, and the synthetic and natural products
showed comparable specific rotation.4b,6,7,10
In the final phase of the synthesis, treatment of GB 13 with
Sc(OTf)3 in chloroform that contained trace amounts of HCl,
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galine (31), gave 16-epi-himgaline (32) as the only product. Het-
eronuclear multiple-bond correlation correlation studies of 32
confirmed N1-C18 bond formation. However, the C16 proton
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