Total synthesis of (-)-penitrem D [15]

Full text of DOI:10.1021/ja0030820

11254
J. Am. Chem. Soc. 2000, 122, 11254-11255
Scheme 1
Total Synthesis of (-)-Penitrem D
Amos B. Smith, III,* Naoki Kanoh, Haruaki Ishiyama, and
Richard A. Hartz
Department of Chemistry
UniVersity of PennsylVania
Philadelphia, PennsylVania 19104
ReceiVed August 18, 2000
The indole-diterpene tremogens comprise an important family
of environmental toxins, produced by ergot fungi that grow on a
variety of grasses endemic to South Africa, New Zealand and
the United States. Among the indole tremogens, penitrems A-F
(1-6)1 constitute a rare class of remarkably complex synthetic
targets. Our long standing interest in this area, having led to the
first total syntheses of (-)-paspaline,2a,b (+)-paspalicine,2c,d and
(+)-paspalinine,2c,d set the stage for a synthetic venture directed
toward the penitrems, with penitrem D selected as the initial target.
In a recent letter,2e we reported studies on the assembly of the A,
F, and I rings of penitrem D. Although the A and F rings were
elaborated in a highly stereoselective fashion, considerable
difficulty was encountered in the construction of ring I possessing
the correct stereogenicity at C(28). In this contribution, we
disclose a solution to this problem, culminating in the first total
synthesis of (-)-penitrem D (4).
to be highly successful,2e,3a would then complete the construction
of rings A and F.
The synthesis of the eastern hemisphere (9) began with lactone
(+)-10,2g,h available from (-)-Wieland-Miesher ketone4 (15 steps,
8.3% yield; Scheme 2). A three-step sequence furnished the
individual acetals (+)-11a and b, substrates for Stork metallo-
enamine alkylation.5 Toward that end, conversion of (+)-11a and
b individually to the corresponding dimethyl hydrazones followed,
in turn, by metalloenamine coupling with epoxide (-)-136 in the
presence of (+)-12 (1.2 equiv) and protection of the hydroxyls
as the benzoates, furnished (+)-14a and b, respectively. Presum-
ably, the host hydrazone (+)-12 is required to promote anion
equilibrium.7 Hydrolytic removal of the hydrazone and acetal (2
steps), followed by PDC oxidation reinstalled the lactone carbonyl
Scheme 2
Penitrem D possesses a number of intriguing structural ele-
ments, including a highly substituted indole core, a cyclobutane
moiety, an eight-membered cyclic ether (oxocane), nine fused
rings, eleven stereogenetic carbons, and two allylic hydroxyl
groups. To assemble the complex penitrem skeleton with complete
control of stereochemistry, we envisioned union of the fully
elaborated western and eastern hemispheres 82h,3a,b and 9 (Scheme
1). Toward this end, we developed an efficient synthesis of
2-substituted indoles exploiting the reaction of o-toluidine deriva-
tives with esters and lactones.2f,i Oxidation of the C(18) primary
hydroxyl in 7, followed by an acid-promoted cyclization-gramine
fragmentation/addition cascade, demonstrated in model systems
(1) (a) Wilson, B. J.; Wilson, C. H.; Hayes, A. W. Nature 1968, 220, 77.
(b) De Jesus, A. E.; Gorst-Allman, C. P.; Steyn, P. S.; Van Heerden, F. R.;
Vleggaar, R.; Wessels, P. L.; Hull, W. E. J. Chem. Soc., Perkin Trans. 1
1983, 1863 and references therein.
(2) (a) Smith, A. B., III; Mewshaw, R. J. Am. Chem. Soc. 1985, 107, 1769.
(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.; 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; Visnick,
M.; Haseltine, J. N.; Sprengeler, P. A. Tetrahedron 1986, 42, 2957. (g) Smith,
A. B., III; Hartz, R. A.; Spoors, P. G.; Rainier, J. D. Isr. J. Chem. 1997, 37,
69. (h) Smith, A. B., III; Nolen, E. G., Jr.; Shirai, R.; Blase, F. R.; Ohta, M.;
Chida, N.; Hartz, R. A.; Fitch, D. M.; Clark, W. M.; Sprengeler, P. A. J. Org.
Chem. 1995, 60, 7837. (i) Smith, A. B., III; Visnick, M. Tetrahedron Lett.
1985, 26, 3757.
to yield (+)-15. For preparative purposes acetals (+)-11a and
(+)-11b were carried forward without separation.
(4) Gutzwiller, J.; Buchshacher, P.; Fu¨rst, A. Synthesis 1977, 167.
(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 (-)-13 was prepared in four steps; Smith, A. B., III; Ohta,
M.; Clark, W. M.; Leahy, J. W. Tetrahedron Lett. 1993, 34, 3033; also see
Supporting Material.
(7) Our initial attempt at Stork metalloenamine alkylation of the hydrazones
derived from (+)-11a and b with (-)-13 resulted in low yield. Considerable
experimentation led to the observation that a host dimethyl hydrazone was
required; see Supporting Material.
(3) A closely related derivative of (+)-8 has been prepared; see: (a) Smith,
A. B., III; Haseltine, J. N.; Visnick, M. Tetrahedron 1989, 45, 2431. (b) Hartz,
R. A.; Ph.D. Thesis, University of Pennsylvania, 1996; also see Supporting
Material.
10.1021/ja0030820 CCC: $19.00 © 2000 American Chemical Society
Published on Web 11/01/2000

Communications to the Editor
J. Am. Chem. Soc., Vol. 122, No. 45, 2000 11255
Assembly of the I ring entailed a reaction cascade initiated by
treatment of (+)-15 with TfOH in Et3SiH-toluene (1:1) (Scheme
3). A similar reaction sequence was described by Nicolaou for
the elegant construction of oxepanes.8 In our case the sequence
involved removal of the MTM moiety, cyclization, and silane
reduction of the resulting hemiacetal to furnish exclusively cis-
pyran (+)-16. Removal of the benzoyl group (K2CO3/MeOH-
H2O) also resulted in partial hydrolysis of the lactone; the lactone
functionality was restored with EDCI. Introduction of the C(22)
hydroxyl was next achieved via Dess-Martin oxidation of (+)-
17 to the corresponding â,γ unsaturated ketone, followed by
autoxidation (i.e., air) in the presence of silica gel to furnish the
tertiary hydroperoxide. Reduction with PPh3 provided alcohol (-)-
18. Stereoselective reduction (L-selectride) of the C(25) ketone
followed by protection of the secondary hydroxyl completed the
synthesis of the eastern hemisphere (-)-9. The structure of (-)-9
was confirmed by X-ray analysis.9
Scheme 4
Scheme 3
With both the western and eastern hemispheres (+)-82h,3a,b and
(-)-9 in hand, we turned to the 2-substituted indole synthetic
protocol2f,i (Scheme 4). Treatment of the TMS derivative of (+)-8
with s-BuLi, followed by addition of (-)-9 resulted in acylation
at the highly hindered lactone carbonyl; subsequent in situ hetero-
Peterson olefination10 furnished (-)-7. The efficiency of the
2-substituted indole protocol is clearly demonstrated by the 81%
overall yield. Parikh-Doering11 oxidation followed by selective
removal of the TMS and TES groups then afforded an equilibrium
mixture of 19, 20a and 20b (3:1:3).
Tandem assembly of the AF ring system was next achieved
by treatment of the mixture with Sc(OTf)312 (1.2 equiv) in benzene
to provide indole (-)-21 in 62% yield, possessing the complete
penitrem D carbon skeleton.13 As anticipated, Sc(OTf)3 promoted
a reaction cascade involving an aldehyde cyclization-gramine
fragmentation, followed by capture of the intermediate carbocation
by the tertiary C(16) hydroxy to construct rings A and F in a
highly stereoselective fashion (>95:5). The required â-stereo-
chemistry at C(18) was anticipated, given earlier model studies.3a,b
Acetylation followed by removal of the TIPS group then furnished
alcohol (-)-23, which upon selenation a la´ Grieco14a and
oxidative-elimination14b of the selenide installed the C(11) exo
olefin in (-)-25. Hydrolytic removal of the acetate completed
the synthesis of (-)-penitrem D, which proved identical in all
respects to the natural material (i.e., 500 MHz 1H and 125 MHz
13C NMR, IR, HRMS, and chiroptic properties).15
In summary, the first total synthesis of (-)-penitrem D has
been achieved. Key elements of the synthesis include the
stereocontrolled elaboration of the advanced eastern hemisphere
(-)-9, a highly efficient union of the hemispheres (+)-8 and (-)-9
exploiting a 2-substituted indole synthesis, and the efficient
construction of rings A and F via a Sc(OTf)3 promoted cation
cascade.
(8) Nicolaou, K. C.; Hwang, C.-K.; Nugiel, D. A. J. Am. Chem. Soc. 1989,
111, 4136.
(9) Carroll, P. J., Department of Chemistry, University of Pennsylvania.
(10) Kru¨ger, C.; Rochow, E. G.; Wannagat, U. Chem. Ber. 1963, 96, 2132.
(11) Parikh, J. R.; Doering, W. E. J. Am. Chem. Soc. 1967, 89, 5505.
(12) Sc(OTf)3 is known as water-tolerant Lewis acid; See: Kobayashi, S.;
Hachiya, I.; Araki, M.; Ishitani, H. Tetrahedron Lett. 1993, 34, 3755.
(13) In some experiments, as much as 25% of an elimination product i
was observed; the structure of i was assigned via a NOESY NMR experiment.
Acknowledgment. Financial support was provided by the National
Institutes of Health (Institute of General Medical Sciences) through grant
GM-29028. We also gratefully acknowledge a Postdoctoral Fellowship
from Uehara Memorial Foundation to H. I.
Supporting Information Available: Specrotoscopic and analytical
data for 4, 7-25, as well as representative experimental procedures (PDF).
This material is available free of charge via the Internet at http://pubs.acs.org.
JA0030820
(14) (a) Grieco, P. A.; Gilman, S.; Nishizawa, M. J. Org. Chem. 1976, 41,
1485. (b) Sharpless, K. B.; Young, M. W. J. Org. Chem. 1975, 40, 947.
(15) We thank Professor Ken-ichi Kawai (Hoshi University) for a generous
sample of (-)-penitrem D.