Total synthesis of (+)-fastigiatine

Article abstract of DOI:10.1021/ja104575h

The first total synthesis of the Lycopodium alkaloid (+)-fastigiatine has been accomplished in 15 steps and 30% overall yield from known compounds. Noteworthy transformations include a convergent fragment coupling via a nucleophilic cyclopropane opening, a highly diastereoselective formal [3 + 3]-cycloaddition, and a transannular Mannich reaction to construct the core of the natural product.

Full text of DOI:10.1021/ja104575h

Published on Web 06/22/2010
Total Synthesis of (+)-Fastigiatine
Brian B. Liau and Matthew D. Shair*
Department of Chemistry & Chemical Biology, HarVard UniVersity, Cambridge, Massachusetts 02138
Received May 26, 2010; E-mail: shair@chemistry.harvard.edu
Abstract: The first total synthesis of the Lycopodium alkaloid (+)-
fastigiatine has been accomplished in 15 steps and 30% overall
yield from known compounds. Noteworthy transformations include
a convergent fragment coupling via a nucleophilic cyclopropane
opening, a highly diastereoselective formal [3 + 3]-cycloaddition,
and a transannular Mannich reaction to construct the core of the
natural product.
Figure 1. Selected Lycopodium alkaloids.
Scheme 1. Retrosynthetic Analysis of (+)-Fastigiatine (1)
The Lycopodium alkaloids are a family of complex natural
products that have long been synthetic targets in organic chemistry.1
Since Stork’s inaugural synthesis of lycopodine,2 these diverse
alkaloids have continued to attract synthetic interest due to their
polycyclic architecture and diverse biological activity. (+)-Fasti-
giatine (1)3 and (-)-himeradine A (2) are unique members of the
lycodine stuctural class (Figure 1). Each molecule has an unprec-
edented pentacyclic core with a C4-C10 bond in contrast to
lycodine (3). The additional C4-C10 linkage adds considerable
strain and complexity to these molecules, creating a densely
functionalized pyrrolidine ring and an array of five contiguous
stereocenters, two of which are vicinal quaternary carbons. Herein
we report the first total synthesis of (+)-fastigiatine (1).
Our retrosynthetic analysis of (+)-fastigiatine (1) is outlined in
Scheme 1. Inspired by the proposed biosynthesis of lycodine,1 we
envisioned that the core skeleton of 1 could be constructed from
tetracycle 4 via a transannular Mannich reaction to form the
C4-C13 bond. Tetracycle 4 could be formed from diamine 5 by
an intramolecular 1,4-conjugate addition and condensation of NR
and Nꢀ with the C5- and C13-carbonyls, respectively. At this point,
the order of bond-forming events was considered flexible. Diamine
5 could then be convergently assembled from several building
blocks via nucleophilic opening of cyclopropane 6 with organo-
metallic 7 and subsequent alkylation.
overall yield. Addition of the lithium enolate of tert-butylacetate
to 13 at -78 °C cleanly delivered the corresponding ꢀ-ketoester,
which underwent an intramolecular aza-Wittig reaction10 to afford
vinylogous urethane (Z)-14 as an inconsequential ∼3:2 mixture of
C4-epimers in 88% overall yield.
With all of the carbons and nitrogens of the core of (+)-
fastigiatine (1) in place, we were eager to test the intramolecular
1,4-conjugate addition on 14. Our initial strategy involved forming
the C13-iminium ion with Nꢀ prior to 1,4-conjugate addition, where
the C10-stereocenter would then control the formation of the
remaining stereocenters. Unfortunately, removal of the Ns group
led to exclusive formation of the five-membered vinylogous
urethane. A similar phenomenon was observed with N-Boc-2-
pyrrolidinone 12, where attempts to break the C5-Nꢀ bond and
form the C5-NR bond were ultimately unsuccessful, suggesting a
preference for the five-membered ring system. With these results,
it became clear that the Ns group was needed to maintain the correct
C-N connectivity and should be removed at a later stage.
Consequently, we attempted direct 1,4-conjugate addition to the
latent 2-cyclohexenone of 14.11 Remarkably, exposure of 14 to
aqueous hydrochloric acid led to tetracycle 16 as a single diaste-
reomer in 92% yield. This formal [3+3]-cycloaddition12 is believed
to occur via initial C13-dioxolane cleavage, 7-endo-trig intramo-
lecular conjugate addition to form the C6-C7 bond, tautomerization
to secure the C12 stereocenter, and finally a transannular aldol
reaction to form the C4-C13 bond. The high diastereoselectivity
of the initial 7-endo-trig cyclization can be rationalized by
stereoelectronically favored axial attack anti to the C16-methyl
group.11
The synthesis began with cyclopropane 8,4 which was prepared
in four steps from (S)-epichlorohydrin on multigram scale according
to literature protocol. Transesterification of 8 with 2-(trimethyl-
silyl)ethanol,5 followed by N-Boc formation, afforded cyclopropane
9 in 83% overall yield (Scheme 2). Upon exposure to mixed cuprate
10,6 cyclopropane 9 underwent facile, regioselective opening7 at
C11 to provide imide 11 in 93% yield. Conveniently, this
convergent fragment coupling could be conducted on greater than
5-g scale. Imide 11 was then transformed in 89% yield to N-Boc-
2-pyrrolidinone 12 in three steps: (1) alkylation with 1-chloro-3-
iodopropane, (2) displacement of the resultant primary chloride with
sodium azide, and (3) cleavage of the 2-(trimethylsilyl)ethyl ester
with concomitant decarboxylation,8 followed by in situ base-
catalyzed epimerization to yield a >10:1 mixture of C4-epimers.
Although the C4-stereocenter of 12 is ultimately inconsequential,
this epimerization facilitated characterization. At this point, the
N-Boc group of 12 was cleaved9 and replaced with a 2-nitroben-
zenesulfonyl (Ns) group to afford N-Ns-2-pyrrolidinone 13 in 89%
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9594 J. AM. CHEM. SOC. 2010, 132, 9594–9595
10.1021/ja104575h  2010 American Chemical Society

C O M M U N I C A T I O N S
Scheme 2. Synthesis of (+)-Fastigiatine (1)a
a Conditions: (a) 15 mol % KH, 2-(trimethylsilyl)ethanol, THF; (b) Boc2O, 10 mol % 4-DMAP, Et3N, CH2Cl2, 83% (two steps); (c) 1.4 equiv of 10, THF,
-78 f 0 °C, 93%; (d) Cs2CO3, 1-chloro-3-iodopropane, DMF; (e) NaN3, NaI, DMF, 65 °C; (f) TBAF, 25 mol % DBU, THF, 50 °C, 89% (three steps); (g)
20 mol % Mg(ClO4)2, MeCN, 60 °C; (h) LiHMDS, THF; NsCl, 0 °C f RT, 89% (two steps); (i) LDA, t-BuOAc, THF, -78 °C; then 13, -78 °C; (j) PPh3,
PhH, 50 °C, 88% (two steps); (k) HCl, THF/H2O, 92%; (l) K2CO3, MeI, DMF, 0 °C f RT; then PhSH, 0 °C f RT, 87%; (m) CF3CH2OH, 80 °C, ∼85%;
(n) p-TsOH·H2O, PhH, 80 °C, 95%; (o) Ac2O, Et3N, CH2Cl2, 85%.
Completion of the pentacyclic core required exchanging the C13-
hydroxyl with Nꢀ. To this end, alkylation of 16 with methyl iodide
in the presence of potassium carbonate, followed by subsequent
addition of thiophenol,13 yielded tetracyclic N-methylamine 17 in
87% yield in a one-pot sequence. Gratifyingly, heating 17 in 2,2,2-
trifluoroethanol cleanly afforded pentacycle 18 in ∼85% yield. This
exchange presumably occurs via initial retro-aldol reaction followed
by iminium ion formation to afford intermediate 4, which then
undergoes the pivotal transannular Mannich reaction to afford 18.
The remarkable ease of this transformation may suggest that an
intermediate similar to 4 could be involved in the biosynthesis of
1 and 2, in contrast to what is currently proposed.1a,c Treatment of
18 with p-toluenesulfonic acid induced facile tert-butoxycarbonyl
loss to yield the corresponding pentacyclic imine, which upon
exposure to acetic anhydride and triethylamine afforded (+)-
Supporting Information Available: Experimental procedures,
spectroscopic data, copies of 1H and 13C NMR spectra, and X-ray
structure of 1. This material is available free of charge via the Internet
at http://pubs.acs.org.
References
(1) For reviews of the Lycopodium alkaloids, see: (a) Kobayashi, J.; Morita,
H. In The Alkaloids; Cordell, G. A., Ed.; Academic Press: New York, 2005;
Vol. 61, pp 1-57. (b) Ma, X.; Gang, D. R. Nat. Prod. Rep. 2004, 21,
752–772. (c) Ayer, W. A.; Trifonov, L. S. In The Alkaloids; Cordell, G. A.,
Brossi, A., Eds.; Academic Press: New York, 1994; Vol. 45, pp 233-266.
(2) Stork, G.; Kretchmer, R. A.; Schlessinger, R. H. J. Am. Chem. Soc. 1968,
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fastigiatine (1) in 82% overall yield ([R]24 ) +375 (c 1.4,
D
CHCl3)).14 The 1H and 13C NMR spectra for synthetic (+)-1
matched those reported for the natural compound, and the structure
of synthetic (+)-1 was unequivocally established via single crystal
X-ray diffraction analysis.
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In summary, we have reported the first total synthesis of (+)-
fastigiatine (1) in 15 steps and ∼30% overall yield from cyclo-
propane 8. Noteworthy transformations include a convergent
fragment coupling via a cyclopropane opening, a highly diastereo-
selective formal [3+3]-cycloaddition to generate four contiguous
stereocenters, and a transannular Mannich reaction to construct the
core of (+)-fastigiatine (1) and (-)-himeradine A (2).
(11) For a similar intramolecular 7-endo-trig cyclization, see: (a) Beshore, D. C.;
Smith, A. B., III. J. Am. Chem. Soc. 2007, 129, 4148–4149. (b) Beshore,
D. C.; Smith, A. B., III. J. Am. Chem. Soc. 2008, 130, 13778–13789.
(12) For other examples of formal [3+3]-cycloadditions, see: (a) Ghosh, S. K.;
Buchanan, G. S.; Long, Q. A.; Wei, Y.; Al-Rashid, Z. F.; Sklenicka, H. M.;
Hsung, R. P. Tetrahedron 2008, 64, 883–893, and references therein. (b)
Movassaghi, M.; Chen, B. Angew. Chem., Int. Ed. 2007, 46, 565–568.
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6374.
Acknowledgment. B.B.L. is thankful for an NSF predoctoral
fellowship. Dr. Shao-Liang Zheng is acknowledged for assistance
with X-ray crystallography. Amy S. Lee and Shota Kikuchi are
acknowledged for thoughtful discussions.
(14) The reported optical rotation for (+)-fastigiatine (1), which contains a minor
amount of des-N-methylfastigiatine, is ([R]23 ) +290 (c 1.36, CHCl3).
D
See ref 3b.
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