Total synthesis of (-)-21-isopentenylpaxilline.

Article abstract of DOI:10.1021/ol027575g

[structure: see text] The total synthesis of (-)-21-isopentenylpaxilline (1) has been achieved. Key elements of the synthesis include the stereocontrolled construction of the advanced eastern hemisphere (-)-5, a highly efficient union of the eastern and w

Full text of DOI:10.1021/ol027575g

ORGANIC
LETTERS
2003
Vol. 5, No. 4
587-590
Total Synthesis of
(−)-21-Isopentenylpaxilline
Amos B. Smith, III* and Haifeng Cui
Department of Chemistry, Monell Chemical Senses Center, and Laboratory for
Research on the Structure of Matter, UniVersity of PennsylVania,
Philadelphia, PennsylVania 19104
smithab@sas.upenn.edu
Received December 31, 2002
ABSTRACT
The total synthesis of (−)-21-isopentenylpaxilline (1) has been achieved. Key elements of the synthesis include the stereocontrolled construction
of the advanced eastern hemisphere (−)-5, a highly efficient union of the eastern and western fragments (−)-5 and 4, respectively, exploiting
our 2-substituted indole synthesis, and a new protocol for the construction of ring C.
In 1995, Belofsky and Gloer reported the isolation, structure
elucidation, and biological activity of (-)-21-isopentenyl-
paxilline (1),1 an indole tremorgenic alkaloid derived from
the sclerotioid ascostromata of Eupenicillium shearii (NR-
RL3324). Extensive spectroscopic analysis established the
complete relative stereochemistry, albeit the absolute ster-
eochemistry remained undefined. Key architectural features
include six fused rings, an indole core punctuated at C(21)
with an isopentenyl moiety, a fully substituted tetrahydro-
pyran, and six stereogenic centers. Although (-)-21-isopen-
tenylpaxilline (1) displays modest antiinsectan activity, the
extreme scarcity of 1 has to date precluded comprehensive
evaluation of the biological profile. Recently, we embarked
on the total synthesis of 1, as part of a program on the
synthesis of bioactive indole diterpenes to provide additional
material for further biological evaluation.2a-g Herein we
disclose the successful conclusion of this synthetic venture.
The synthetic strategy, reminiscent of our recently com-
pleted total synthesis of (-)-penitrem D,2f is outlined in
Scheme 1. To elaborate the γ-hydroxyl-enone functionality
that adorns the E and F rings and is required for tremorge-
netic activity,3 we envisioned fragmentation of epoxyketone
2 initiated by ketone enolization. Disconnection of the C(17,-
18) σ-bond in ring C then leads to the 2-substituted indole
Scheme 1
3, which in turn would be assembled exploiting the 2-sub-
stituted indole synthetic protocol developed in our laboratory
(1) Belofsky, G. N.; Gloer, J. B. Tetrahedron 1995, 51, 3959. Indole 1
is also referred to as (-)-9-prenylpaxilline.
10.1021/ol027575g CCC: $25.00 © 2003 American Chemical Society
Published on Web 01/28/2003

for this purpose.2g,4 For indole 3, a western hemisphere
aniline (4) and a fully elaborated eastern hemisphere lactone
(5) would be required.2f,g, 4
the overall yield for this three-step sequence proved to be
modest, sufficient material could be prepared to continue the
synthesis. Selective hydrolysis of the methyl acetal in the
presence of the MTM ether,9 achieved with HClO4 (4:1
MeOH-H2O), furnished a mixture of lactols; oxidation with
N-iodosuccimide (NIS) and tetrabutylammonium iodide
(TBAI) led to lactone (+)-11. To elaborate the F-ring
tetrahydropyran, we envisioned a cascade of reactions,
involving removal of the MTM group, cyclization to an
intermediate carbocation (e.g., 12), and capture with hydride.
The optimal conditions for this reaction sequence proved to
be TfOH in 1:1 Me2EtSiH-CH2Cl2.10 A similar tactic,
employed in our penitrem venture,2f was initially developed
by Nicolaou for the construction of oxepanes.11 In this case,
the three-step sequence furnishes exclusively cis-tetrahydro-
pyran (-)-13 in 81% yield.12 Stereoselective epoxidation with
m-CPBA then afforded (-)-14, possessing the desired
R-epoxide, requisite for eventual conversion to the γ-hy-
droxyl-enone in (-)-21-isopentenylpaxilline (1). A minor
amount of the â-epoxide was also obtained (14%).
Construction of lactone 5 began with methyl acetal (+)-
6, an advanced intermediate employed in our (-)-penitrem
D synthesis2f (Scheme 2). After conversion to hydrazone (+)-
Scheme 2
At this juncture a protecting group interchange was
necessary to permit application of the 2-substituted indole
synthesis. To this end, removal of the benzoate (KOH,
MeOH/H2O), followed by treatment with 1-[3-(dimethyl-
amino)propyl]-3-ethylcarbodiimide hydrochloride (EDCI)
and 4-(dimethylamino)pyridine (DMAP) in CH2Cl2 to rein-
stall the lactone moiety that had undergone partial hydrolysis,
proceeded in excellent yield (91% for two steps). To confirm
the stereochemistry, (+)-15 was converted via transfer
hydrogenation to (+)-16; single-crystal X-ray analysis
established both the structure and stereochemistry. Silylation
of (+)-15 completed construction of the eastern hemisphere
(-)-5.
(2) For related indole-diterpene synthesis, see: (-)-paspaline (a,b), (+)-
paspalicine (c,d), (+)-paspalinine (c,d) and (-)-penitrem D (e,f). (a) Smith,
A. B., III; Mewshaw, R. E. J. Am. Chem. Soc. 1985, 107, 1796. (b)
Mewshaw, R. E.; Taylor, M. D.; Smith, A. B., III. J. Org. Chem. 1989, 54,
3449. (c) Smith, A. B., III; Sunazuka, T.; Leenay, T. L.; Kingery-Wood, J.
J. Am. Chem. Soc. 1990, 112, 8197. (d) Smith, A. B., III; Kingery-Wood,
J.; Leenay, T. L.; Nolen, E. G., Jr.; Sunazuka, T. J. Am. Chem. Soc. 1992,
114, 1438. (e) Smith, A. B., III; Kanoh, N.; Minakawa, N.; Rainier, J. D.;
Blase, F. R.; Hartz, R. A. Org. Lett. 1999, 1, 1263. (f) Smith, A. B., III;
Kanoh, N.; Ishiyama, H.; Hartz, R. A. J. Am. Chem. Soc. 2000, 114, 1438.
(g) Smith, A. B., III; Visnick, M.; Haseltine, J. N.; Sprengeler, P. A.
Tetrahedron 1986, 42, 2957.
(3) Dorner, J. W.; Cole, R. J,; Cox, R. H.; Cunfer, B. M. J. Agric. Food
Chem. 1984, 32, 1069-1071.
(4) Smith, A. B., III; Visnick, M. Tetrahedron Lett. 1985, 26, 3757.
(5) (a) Stork, G.; Benaim, J. J. Am. Chem. Soc. 1971, 93, 5938. (b) Stork,
G.; Benaim, J. Org. Synth. 1977, 57, 69.
(6) Epoxide (+)-9 was prepared in eight steps and 22% overall yield;
see Supporting Information.
(7) Our initial attempt at Stork metalloenamine alkylation of the
hydrazone (+)-7 with (+)-9 without the auxiliary hydrazone (+)-(8)
resulted in low yield. Presumably (+)-8 is required to promote equilibration
of the initially quenched kinetic anion. Considerable experimentation led
to the observation that DMPU as a cosolvent was required; see Supporting
Information.
(8) Best results were obtained with the hydrazone (+)-7 concentration
at 1 M.
(9) Byproducts, comprising ca. 25% of the product mixture, which
derived from both acetal and MTM ether hydrolysis, were converted to
(-)-13 in two steps; see Supporting Information.
7, a three-step sequence involving Stork metalloenamine
acylation5 employing epoxide (+)-9,6 in the presence of the
equilibration auxiliary (+)-82f,7 and DMPU,7 followed in turn
by benzoylation of the derived hydroxyl, and hydrolytic
removal of the hydrazone furnished enone (+)-10.8 Although
(10) Use of Me2EtSiH instead of Et3SiH significantly improved the yield.
(11) Nicolaou, K. C.; Hwang, C.-K.; Nugiel, D. A. J. Am. Chem. Soc.
1989, 111, 4136.
(12) NOESY NMR experiments confirmed the cis stereochemistry of
pyran (-)-13.
588
Org. Lett., Vol. 5, No. 4, 2003

The issue of selective C-ring closure at C(18),13 was
initially addressed with the 2-substitued model indole 19,
available from aniline 4 and butyrolactone, exploiting our
indole protocol (Scheme 3). This two-step, one-flask se-
TMS moiety (TBAF) then provided indole 22 in 72% yield.
Interestingly, 22 proved to be highly unstable upon exposure
to air and silica gel chromatography. The product, eight-
membered ring lactam 23, was obtained in near quantitative
yield.15
The second tactic (Scheme 5), albeit lower yielding with
model indole 19, entailed mesylation followed by treatment
with t-BuMgCl (1.5 equiv) in toluene at reflux; indole 22
was isolated in an unoptimized yield of 31%.
Scheme 3
Scheme 5
quence involves generation of the N-TMS aniline, metalation
with s-BuLi, acylation with butyrolactone, and in situ
heteroatom Peterson olefination.14 Aqueous workup furnished
19 in excellent yield (ca. 73%).
With ample quantities of both the western and eastern
hemispheres [4 and (-)-5, respectively] in hand, we executed
the 2-substituted indole synthesis (Scheme 6). In this case,
in situ heteroatom Peterson olefination did not occur.
However, heating the intermediate aminoketone in toluene
at reflux after workup led to indole ring formation. The
excellent yield of (-)-25 (76%) is a testament to the utility
of this indole construction.
Two tactics for C-ring closure were explored. In the first
approach, the primary hydroxyl in 19 (Scheme 4) was
Scheme 4
Turning to generation of ring C, elaboration of the bromo
iodide, corresponding to that employed in the first model
study proved to be unworkable.16 However, mesylation of
(-)-25 followed by treatment of t-BuMgCl in toluene at
reflux resulted in C ring closure in 73% yield. Removal of
the silyl group to provide (-)-28, followed by oxidation with
concomitant epoxide ring opening employing Ph3BiCO3 as
an oxidant,17 furnished enone (+)-29. The yield for this
critical fragmentation was 69%. Transfer hydrogenation then
completed the synthesis of (-)-21-isopentenylpaxilline (1).18
The synthetic material was identical in all respects to the
1
natural material (i.e., 500 MHz H NMR, 125 MHz 13C
NMR, HRMS, and chiroptic properties), thus confirming both
the original structural assignment and defining for the first
time the absolute stereochemistry of (-)-21-isopentenyl-
paxilline (1).
converted to the corresponding bromide, followed in turn
by treatment with NIS to generate the iodide and protection
of the indole nitrogen with a TBS group to provide 21. Upon
lithium-iodide exchange (n-BuLi; -78 °C), five-membered
ring formation occurred selectively at C(3). Removal of the
(15) There is precedent for similar facile oxidations in the indole diterpene
field. See ref 1 and: Ondeyka, J. G.; Helms, G. L.; Hensens, O. D.; Goets,
M. A.; Zink, D. L.; Tsipouras, A.; Shoop, W. L.; Slayton, L.; Dombrowski,
A. W.; Polishook, J. D.; Ostlind, D. A.; Tsou, N. N.; Ball, R. G.; Singh, S.
B. J. Am. Chem. Soc. 1997, 119, 8809.
(13) There is precedent for five-membered ring closure on nitrogen
instead of C-3 with MeMgBr; see: Haseltine, J. N. Ph.D. Thesis, University
of Pennsylvania, 1992.
(14) Kruger, C.; Rochow, E. G.; Wannagat, U. Chem. Ber. 1963, 96,
2132.
(16) Attempted installation of the iodide with NIS led to decompostion.
(17) Barton, D. H. R.; Kitchin, J. P.; Lester, D. J.; Motherwell, W. B.;
Papoula, M. T. B. Tetrahedron 1981, 37, 73.
(18) Minor amount (ca. 10%) of the over reduction product was obtained;
separation was by HPLC.
Org. Lett., Vol. 5, No. 4, 2003
589

In summary, the first total synthesis of (-)-21-isopenten-
ylpaxilline (1) has been achieved. Key elements of the
synthesis include the stereocontrolled construction of the
advanced eastern hemisphere (-)-5, a highly efficient union
of the eastern and western fragments (-)-5 and 4, respec-
tively, exploiting our 2-substituted indole synthesis, and a
new protocol for the construction of ring C.
Scheme 6
Acknowledgment. Financial support was provided by the
National Institutes of Health (Institute of General Medical
Science) through Grant GM-29028. We thank Professor J.
B. Gloer (University of Iowa) for providing a generous
sample of natural (-)-21-isopentenylpaxilline. We also wish
to thank Dr. G. Furst, Dr. R. K. Kohli, and Dr. P. J. Caroll,
Directors of the University of Pennsylvania Spectroscopic
Facilities, for assistance in obtaining NMR spectra, high-
resolution mass spectra, and X-ray analyses, respectively.
Supporting Information Available: Spectroscopic and
analytical data for compounds (-)-1, 4, (-)-5, (+)-9, (+)-
10, (+)-11, (-)-13, (-)-14, 19, 20, 22, 23, (-)-25, (-)-26,
(-)-27, and (+)-29 and selected experimental procedures.
This material is available free of charge via the Internet at
http://pubs.acs.org.
OL027575G
590
Org. Lett., Vol. 5, No. 4, 2003