The total synthesis of the galbulimima alkaloid GB 13

Article abstract of DOI:10.1021/ja029725o

This contribution describes a synthetic approach to alkaloid GB 13, previously isolated from the North Australian and Papua New Guinean rain forest tree Galbulimima belgraveana. A Birch reductive alkylation of 2,5-dimethoxybenzoic acid by 3-methoxybenzyl bromide, followed by an acid-catalyzed cyclization was used to synthesize the [3.3.1]bicyclononane 8. A ring contraction performed on the diazo derivative 9 of the [3.3.1]bicyclononane led to [3.2.1]bicyclooctane 10. This [3.2.1]bicyclooctane was converted into a dienophile and subjected to a Diels-Alder reaction to generate a pentacyclic intermediate 13 with a carbon skeleton closely resembling the target alkaloid. The surplus substituent, required for activation and regioselectivity in the Diels-Alder reaction, was removed using Birch reductive conditions to effect a decyanation. It was discovered that a Birch reduction of the aromatic ring also present in the molecule could be performed at the same time to give the enone 15, which was cleaved by means of an Eschenmoser fragmentation. The piperidine ring found in the natural product was formed by reductive cyclization of the bis-oxime 18 derived from the alkynyl ketone 17 and the resulting material further elaborated to GB 13 (1) via ketone 20. Copyright

Full text of DOI:10.1021/ja029725o

Published on Web 02/07/2003
The Total Synthesis of the Galbulimima Alkaloid GB 13
Lewis N. Mander* and Matthew M. McLachlan
Research School of Chemistry, Australian National UniVersity Canberra, A.C.T. 0200, Australia
Received December 12, 2002 ; E-mail: mander@rsc.anu.edu.au.
Structures 1-4 are representative of a family of 28 unusual
Scheme 1
alkaloids isolated from the bark of the Northern Australia and Papua
New Guinea rain forest tree, Galbulimima belgraVeana,1 the sole
surviving species from the relic family Himantandraceae. The bark
of G. belgraVeana was used as a medicinal substance by some
-3
4
Papua New Guinean tribes for a variety of purposes. Considerable
interest is presently centered on himbacine (3), a potent muscarinic
antagonist and a lead compound in the search for drugs to treat
Alzheimer’s disease. As a consequence three total syntheses have
been completed recently. 5
Scheme 2
Our own interests have been concerned with the assembly of
the more complex alkaloids from this series, exemplified by 1, 2,
and 4, and in this communication we describe the first total synthesis
of (()-alkaloid GB 13 (1) by a strategy that should also allow access
to 2 and 4 as well. Our approach is outlined in Scheme 1 and is
based on the annelation of the tricyclic intermediate 5, with
subsequent elaboration of the benzenoid moiety in the adduct 6 to
afford the piperidine ring of the target structure.
A suitable analogue of 5 could be readily assembled following
the route outlined in Scheme 2. Thus, 2-(3-methoxybenzyl)-1,3-
dienol ether 7 could be synthesized in excellent yield and on a
large scale as reported previously.6
to the endo adduct was most effectively catalyzed by ytterbium
tris(2,2,6,6-tetramethyl-3,5-heptane-dionate). Hydrolysis of the
resulting silyl enol ether 13 and reduction of the ketone and
protection of the corresponding alcohol as its MOM ether gave
material suitable for the synthesis of the piperidine ring found in
alkaloid GB 13 (1).
This material could be cyclized to the [3.3.1]bicyclononane 8
by treatment with 60% v/v aqueous sulfuric acid at 0 °C. After
decarboxylation and protection of the hydroxyl as its MOM ether,
a Wolff ring contraction to a suitable analogue of 5 was explored.
The required diazoketone 9 was synthesized using the two-step
Treatment of compound 14 with lithium metal in ammonia for
2 h resulted in quantitative reductive decyanation of the superfluous
9
cyano group on C6a, and then addition of ethanol resulted in Birch
7
Regitz procedure and then subjected to photolysis in the presence
reduction of the aromatic ring. The resulting methyl enol ether was
converted to enone 1510 by treatment with a catalytic amount of
10 M HCl in methanol.
of hexamethyldisilazane to give amide 10 after an acidic workup.
Amide 10 could be dehydrated to the corresponding nitrile in high
yield by treatment with trichloroacetyl chloride. This nitrile was
resistant to deprotonation with most common bases, but potassium
diisopropyl amide was effective.8 Trapping of the anion with
diphenyl diselenide gave the corresponding R-phenylseleno nitrile,
which, after oxidation and elimination, gave alkene 11.
An Eschenmoser fragmentation was planned next, but enone 15
proved to be resistant to direct epoxidation; however, a sequence
involving reduction to the allylic alcohol, epoxidation, and then
oxidation gave the epoxy ketone 16 in good yield. Treatment of
the epoxy ketone under traditional Eschenmoser fragmentation
11
Alkene 11 was a suitable dienophile for a Diels-Alder reaction
with diene 12, as shown in Scheme 3. The desired reaction leading
conditions gave only low yields of the desired alkynyl ketone 17,
but this result could be improved significantly by the use of the
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10.1021/ja029725o CCC: $25.00 © 2003 American Chemical Society

C O MMU N I C A T I O N S
Scheme 3
then be oxidized by treatment with Dess-Martin periodinane, and
the 7-hydroxy group was reprotected as its MOM ether. Enolization
of the ketone 20, with subsequent trapping of the enolate with
TMSCl, gave the 5,6-silyl enol ether, which could be subjected to
Saegusa dehydrosilylation conditions14 to give the protected (()-
GB 13 derivative 21.
Gentle heating with aqueous potassium carbonate effected
removal of the trifluoroacetamide protecting group, and then
warmingwith dilute hydrochloric acid resulted in removal of the
1
MOM ether function. The material from this sequence gave H and
13
C NMR and mass spectral data matching those of naturally
occurring GB 13 (1).
This communication has described the first total synthesis of (()-
alkaloid GB 1315 and provides yet another example of the utility
of benzenoid synthons for the synthesis of complex polycyclic
natural products.16 A special feature of this synthetic strategy is
the use of the nitrile function for activation and regiocontrol in the
Diels-Alder reaction, followed by its efficient removal using
dissolving metal conditions. This work also lays a foundation for
the preparation of himgaline (2)17 and himandridine (4) and its
1
8
analogues by a modification of this synthetic sequence.
Acknowledgment. We are grateful to Professor W. C. Taylor
for an authentic sample of GB 13.
Scheme 4
Supporting Information Available: Experimental procedures and
characterization data for all novel compounds reported (PDF). This
material is available free of charge via the Internet at http://pubs.acs.org.
References
(
1) Ritchie, E.; Taylor, W. C. In The Alkaloids; Manske, R. H. F., Ed.;
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81. (b) Mander, L. N.; Ritchie, E.; Taylor, W. C. Aust. J. Chem. 1967,
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(
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1
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(
(
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p-nitrobenzenesulfonylhydrazide in place of toluenesulfonylhy-
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10) An X-ray crystal analysis was performed on this material, confirming the
relative stereochemistry as that shown.
(11) Eschenmoser, A.; Felix, D.; Ohloff, G. HelV. Chim. Acta 1967, 708.
(12) See Akamanchi, K. G.; Divakaran, P. P.; Pradhan, P. M.; Pradhan, S. K.
Heterocycles 1989, 28, 813 for a proposed mechanism for this reaction.
(
An attempt at a reductive amination of compound 17 was
unsuccessful, but treatment of the alkynyl ketone with an excess
of hydroxylamine in pyridine gave the bis-oxime 18,1 as shown
in Scheme 4. A reductive cyclization was effected on this bis-oxime
by treatment with zirconium tetrachloride and sodium borohydride
to give an N-hydroxypiperidine compound.13 NOE experiments on
the N-acetoxy derivative confirmed that the major product from
this reaction had the desired all-cis-piperidine ring stereochemistry
required for the synthesis of alkaloid GB 13. Reduction of the
hydroxylamine and protection of the resulting amine as its trifluo-
roacetamide gave the desired compound 19 as the major product.
Heating with dilute hydrochloric acid effected deprotection of
the two MOM ether functions, and the C5 hydroxyl group could
2
(
(
13) Ito, K.; Itsuno, S.; Sakurai, Y. Synthesis 1988, 995.
14) Hirao, T.; Ito, Y.; Saegusa, T. J. Org. Chem. 1978, 43, 1011.
(15) An enantioselective synthesis utilizing the methodology of Schultz is
planned. Schultz, A. G. Acc. Chem. Res. 1990, 23, 207.
(
(
16) Mander, L. N. Synlett 1991, 134.
17) Intramolecular Michael addition of the nitrogen to the enone, followed
by reduction of the ketone should lead to himgaline 2 (cf. refs 3d and
3e).
(
18) By employing the equivalent ester analogous to the nitrile 11, we envisage
a subsequent Curtius rearrangement to establish the N-C6a bond in a
precursor to 4.
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