Tremorgenic indole alkaloids. The total synthesis of (-)-penitrem D

Article abstract of DOI:10.1021/ja034842k

A convergent, stereocontrolled total synthesis of the architecturally complex tremorgenic indole alkaloid (-)-penitrem D (4) has been achieved. Highlights of the synthesis include an efficient, asymmetric synthesis of the western hemisphere; the stereocon

Full text of DOI:10.1021/ja034842k

Published on Web 06/11/2003
Tremorgenic Indole Alkaloids. The Total Synthesis of
(-)-Penitrem D
Amos B. Smith, III*, Naoki Kanoh, Haruaki Ishiyama, Noriaki Minakawa,
Jon D. Rainier, Richard A. Hartz, Young Shin Cho, Haifeng Cui, and
William H. Moser
Contribution from the Department of Chemistry, Monell Chemical Senses Center, and
Laboratory for Research on the Structure of Matter, UniVersity of PennsylVania,
Philadelphia, PennsylVania 19104
Received February 24, 2003; E-mail: smithab@sas.upenn.edu
Abstract: A convergent, stereocontrolled total synthesis of the architecturally complex tremorgenic indole
alkaloid (-)-penitrem D (4) has been achieved. Highlights of the synthesis include an efficient, asymmetric
synthesis of the western hemisphere; the stereocontrolled assembly of the I-ring; discovery of a novel
autoxidation to introduce the C(22) tertiary hydroxyl group, required for tremorgenic activity; union of fully
elaborated eastern and western hemispheres, exploiting an indole synthetic protocol developed expressly
for this purpose; and a late-stage, stereoselective construction of the A and F rings exploiting a
Sc(OTf)3-promoted reaction cascade. The longest linear sequence leading to (-)-penitrem D (4) was 43
steps.
Ergot fungi produce a wide variety of architecturally complex
natural products possessing significant bioregulatory properties.
Among these, the indole-diterpenes pose significant economic
problems for the livestock industry.1 Members of this family
of environmental toxins are responsible for Dallisgrass poisoning
(also called “paspalum staggers”),1a ryegrass staggers,1b-d and
other related neurological disorders known to occur sporadically
in the Southwest United States, Australia, and New Zealand.
Domestic sheep and cattle that graze on ergot-infected grasses
suffer from motion-induced tremors, limb weakness, ataxia,
convulsions, and eventual death. Fortunately, the symptoms are
reversible.1 From the perspective of human disorders, the
symptoms presented by the livestock are similar to those
associated with Wilson’s disease, multiple sclerosis, Parkinson’s
Penitrem A was first isolated by Wilson and co-workers in
disease, and epilepsy and are thereby suggestive of a possible
common neurochemical mechanism.2
1968 from the ergot fungus Penicillium cyclopium.4a Subse-
quently, Steyne and co-workers reported the complete structures
of the penitrems, isolated from the closely related Penicillium
crustosum.3b,c,4b,c The absolute configuration was established by
the partial resolution method of Horeau.5 To date, no X-ray
structures have been achieved, although we and others have
attempted to obtain suitable crystals. Importantly, all six
In addition to like biological profiles, the indole-diterpenes
share common architectural features, the signature elements
being an indole core, biosynthetically derived from tryptophan;
a diterpene framework arising from mevalonate; and the trans
vicinal quaternary methyl substituents.3 Among the indole
tremorgens, the penitrems [A-F (1-6)] represent the most
complex members of the indole-diterpene alkaloid family.
(3) (a) Acklin, W.; Weibel, F.; Arigoni, D. Chimia 1977, 31, 63. (b) de Jesus,
A. E.; Hull, W. E.; Steyn, P. S.; van Heerden, F. R.; Vleggaar, R.; Wessels,
P. L. J. Chem. Soc., Chem. Commun. 1982, 837-838. (c) 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-
1868.
(4) (a) Wilson, B. J.; Wilson, C. H.; Hayes, A. W. Nature 1968, 220, 77-78.
(b) de Jesus, A. E.; Steyn, P. S.; van Heerden, F. R.; Vleggaar, R.; Wessels,
P. L.; Hull, W. E. J. Chem. Soc., Chem. Commun. 1981, 289-291. (c) de
Jesus, A. E.; Steyn, P. S.; van Heerden, F. R.; Vleggaar, R.; Wessels, P.
L.; Hull, W. E. J. Chem. Soc., Perkin Trans. 1 1983, 1847-1856.
(5) (a) Horeau, A. Tetrahedron Lett. 1961, 506-512. (b) Horeau, A.;
Sutherland, J. K. J. Chem. Soc., Org. 1966, 247-248. (c) Herz, W.; Kagan,
H. B. J. Org. Chem. 1967, 32, 216-218.
(1) (a) Cole, R. J.; Dorner, J. W.; Lansden, J. A.; Cox, R. H.; Pape, C.; Cunfer,
B.; Nicholson, S. S.; Bedell, D. M. J. Agric. Food Chem. 1977, 25, 1197-
1201. (b) Mantle, P. G.; Mortimer, P. H.; White, E. P. Res. Vet. Sci. 1978,
24, 49-56. (c) di Menna, M. E.; Mantle, P. G. Res. Vet. Sci. 1978, 24,
347-351. (d) Mantle, P. G.; Day, J. B.; Haigh, C. R.; Penny, R. H. Vet.
Rec. 1978, 103, 403. (e) Springer, J. P.; Clardy, J. Tetrahedron Lett. 1980,
21, 231-234. (f) Gallagher, R. T.; Clardy, J.; Wilson, B. J. Tetrahedron
Lett. 1980, 21, 239-242. (g) Dorner, J. W.; Cole, R. J.; Cox, R. H.; Cunfer,
B. M. J. Agric. Food Chem. 1984, 32, 1069-1071.
(2) Brimblecombe, R. W.; Pinder, R. M. Tremorgens and Tremorgenic Agents;
Scientechnia; Bristol, U.K., 1972; pp 14-15.
9
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J. AM. CHEM. SOC. 2003, 125, 8228-8237
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Tremorgenic Indole Alkaloids
A R T I C L E S
Scheme 1
penitrems bear a tertiary hydroxyl at C(22), the requisite
structural element required for the neurotoxicity.1g Penitrem D
(4), the simplest member of the penitrem class, also possesses
a cyclobutane ring and an eight-membered oxocane cyclic ether,
but is devoid of the epoxide and chlorine substituents found in
the more complex members of the penitrem family.
The structural complexity of the indole diterpenes, in
conjunction with their tremorgenic activity, first captured our
attention in the early 1980s and has since led to the first total
syntheses of (-)-paspaline (7),6a,b (+)-paspalicine (8),6c,d (+)-
paspalinine (9),6c,d and quite recently (-)-21-isopentenylpaxilline
(10).6e Armed with this experience, we embarked on the total
synthesis of (-)-penitrem D (4). Several strategies were
explored.6f-n Herein, we describe a full account of this program,
which culminated in the first, and to date only, total synthesis
of a member of the penitrem family.6n,7
Initial Synthetic Plan. From the outset we desired a
convergent approach (Scheme 1). Retrosynthetically this entailed
removal of the C(22) hydroxyl and refunctionalization of the
C(11)-exo olefin to afford advanced intermediate 11, which we
envisioned could serve as a common precursor for members of
the penitrem family. For this plan to be successful, a viable
tactic would be required to introduce the C(22) hydroxyl.
Continuing this analysis, opening of the tetrahydropyran, the
oxocane, and the F rings next led to a 2-substituted indole (12),
which could be further dissected to reveal three subtargets (13,
14, and 15). In the synthetic direction, the 2-substituted indole
(12) was anticipated to arise via union of a benzylic anion
generated from 13 with an electrophile such as lactone 14,
followed by ring closure. Rings A and F would then be
constructed via oxidation of the primary hydroxyl to an
aldehyde, execution of an intramolecular cyclization to furnish
ring F and in turn a gramine-like fragmentation and capture by
the C(16) hydroxyl to complete ring A.8 We reasoned that this
cascade of reactions might be possible in one operation. The
requisite eastern hemisphere 14, known as the Nolen-Sprengeler
lactone,6k,l was readily available in our laboratory, having been
designed as a common advanced intermediate for the synthesis
of several indole-diterpene tremorgens.9 To construct the I ring,
we anticipated attachment of the C(24) side chain via a Stork
metalloenamine alkylation10 of the hydrazone derived from 14
with epoxide 15. Stereocontrolled cyclization would then
generate the tetrahydropyran.11 At the outset, the precise order
of indole construction and elaboration of the I ring was unclear.
As will be presented, this flexibility of strategic events would
prove central to the eventual successful completion of the
penitrem D synthesis.
To implement this synthetic plan, we required (1) a viable
2-substituted indole synthesis; (2) methods to construct the A,
F, and I rings; and (3) a protocol to insert the C(22) hydroxyl.
Although preliminary accounts describing these methods have
appeared,6f-n their critical importance to the overall development
of the penitrem D program demands their brief introduction here.
(6) (a) Smith, A. B., III; Mewshaw, R. J. Am. Chem. Soc. 1985, 107, 1769-
1771. (b) Mewshaw, R. E.; Taylor, M. D.; Smith, A. B., III. J. Org. Chem.
1989, 54, 3449-3462. (c) Smith, A. B., III; Sunazuka, T.; Leenay, T. L.;
Kingery-Wood, J. J. Am. Chem. Soc. 1990, 112, 8197-8198. (d) Smith,
A. B., III; Kingery-Wood, J.; Leenay, T. L.; Nolen, E. G.; Sunazuka, T. J.
Am. Chem. Soc. 1992, 114, 1438-1449. (e) Smith, A. B., III; Cui, H. Org.
Lett. 2003, 5, 587-590. (f) Smith, A. B., III; Visnick, M. Tetrahedron
Lett. 1985, 26, 3757-3760. (g) Smith, A. B., III; Visnick, M.; Haseltine,
J. N.; Sprengeler, P. A. Tetrahedron 1986, 42, 2957-2969. (h) Haseltine,
J.; Visnick, M.; Smith, A. B., III. J. Org. Chem. 1988, 53, 6160-6162. (i)
Smith, A. B., III; Haseltine, J. N.; Visnick, M. Tetrahedron 1989, 45, 2431-
2449. (j) Smith, A. B., III; Ohta, M.; Clark, W. M.; Leahy, J. W.
Tetrahedron Lett. 1993, 34, 3033-3036. (k) Smith, A. B., III; Nolen, E.
G.; 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, 7837-7848.
(l) Smith, A. B., III; Hartz, R. A.; Spoors, P. G.; Rainier, J. D. Isr. J. Chem.
1997, 37, 69-80. (m) Smith, A. B., III; Kanoh, N.; Minakawa, N.; Rainier,
J. D.; Blase, F. R.; Hartz, R. A. Org. Lett. 1999, 1, 1263-1266. (n) Smith,
A. B., III; Kanoh, N.; Ishiyama, H.; Hartz, R. A. J. Am. Chem. Soc. 2000,
122, 11254-11255.
(8) For examples of gramine-type fragmentations, see: Brewster, J. H.; Eliel,
E. L. Org. React. 1953, VII, 99-197.
(9) Lactone (+)-14 can be prepared from commercially available (-)-Wieland-
Miescher ketone in 16 steps and 8% overall yield.
(10) (a) Stork, G.; Benaim, J. J. Am. Chem. Soc. 1971, 93, 5938-5939. (b)
Stork, G.; Benaim, J. Org. Synth. 1977, 57, 69-72.
(11) A similar protocol had also proven effective in our paspalicine and
paspalinine synthetic ventures.
(7) Rivkin, A.; Nagashima, T.; Curran, D. P. Org. Lett. 2003, 5, 419-422.
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A R T I C L E S
Smith et al.
New Indole Synthesis, Model Studies to Construct the A,
F, and I Rings, and a Protocol to Introduce the C(22)
Hydroxyl. Since the earliest annals of natural products chem-
istry, bioactive indole alkaloids have evoked enormous interest
in the development of new synthetic approaches to the indole
ring.12 In 1985, based on the above penitrem D synthetic
scenario, we designed an expedient method for the regiospecific
synthesis of mono- and disubstituted indoles (Scheme 2).6f,g This
protocol involves treatment of N-trimethylsilyl-o-toluidine or a
related derivative with 2.2 equiv of n-BuLi to generate the
lithium dianion 17, which upon acylation with either esters or
lactones leads to an intermediate (18) capable of intramolecular
heteroatom Peterson olefination13 to furnish the desired substi-
tuted indole 19; yields are in general good (50-98%).
converted to the o-nitroselenide,14 treated with camphorsulfonic
acid in benzene, and subjected to oxidative-elimination of the
seleno group.15 Pleasingly, the hexacyclic ABCDEF analogue
of penitrem D (e.g., 22), possessing spectroscopic data that
correlated well with that of (-)-penitrem D (4), was obtained
in 38% for the three steps. Structural confirmation of 22 was
achieved by single-crystal X-ray analysis of the bromo derivative
23.
To model a possible tactic for elaboration of the I ring of
penitrem D, we prepared acetate 27 (Scheme 4), exploiting the
Stork metalloenamine alkylation of the hydrazone10 derived from
(+)-24 with epoxide (-)-25.6j Camphorsulfonic acid-promoted
cyclization, followed by removal of the MOM group with 1 M
HCl in methanol, provided cis-tetrahydropyran (+)-28, along
with what was thought to be the minor trans isomer (ca. 3.4:
1). The structure of (+)-28 was again secured by X-ray
crystallographic analysis.
Scheme 2
Scheme 4
To test the feasibility of constructing the A and F rings in a
single operation via a cyclization-gramine-like fragmentation-
cyclization cascade, we selected the ABCDEF hexacycle 22 in
racemic form as an early target.6h,i Indole 20 was therefore
prepared from aniline 13,6h oxidized to the corresponding
aldehyde, and subjected to camphorsulfonic acid in methanol
(Scheme 3). The resultant mixed methyl aminal 21 was next
Scheme 3
The fact that formation of the A and F rings in 22 and the I
ring in (+)-28 proceeded with good stereoselectivity fortuitously
under the identical mild acidic conditions (i.e., camphorsulfonic
acid/benzene) proved highly seductive, suggesting the intriguing
possibility of a combined “one-flask” A, F, and I ring con-
struction.16 As will become apparent, this prospect markedly
influenced the evolution of the penitrem D synthetic program.
The remaining synthetic issue prior to committing to the
penitrem D venture concerned installation of the C(22) hydroxyl.
A third model study was performed.6j Oxidation of (+)-28 with
singlet oxygen employing methylene blue as sensitizer in
(12) For a review on the synthesis of indole derivatives, see: Sundberg, R. J.
Indoles; Academic Press Inc.: San Diego, 1996.
(13) Kru¨ger, C.; Rochow, E. G.; Wannagat, U. Chem. Ber. 1963, 96, 2132-
2137.
(14) Grieco, P. A.; Gilman, S.; Nishizawa, M. J. Org. Chem. 1976, 41, 1485-
1486.
(15) Sharpless, K. B.; Young, M. W. J. Org. Chem. 1975, 40, 947-949.
(16) This cascade of reactions is affectionately referred to as the “Shazam”
approach, a term to the best of our knowledge first employed by Eaton to
describe unsuccessful attempts by several research groups to effect the
Lewis acid-promoted isomerization of C20H20 and C22H24 polycycloalkanes
to dodecahedrane and dimethyl dodecahedrane, see: Eaton, P. E. Tetra-
hedron 1979, 35, 2189-2223, and references therein.
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A R T I C L E S
CHCl3, followed by NaBH4 reduction of the resulting hydro-
peroxide, furnished (-)-29 (54% yield, two steps), as the sole
isolable product (Scheme 5). The yield for this transformation
could be improved to 63% using the sensitizer hematoporphyrin
IX, in pyridine, followed by reduction with PPh3 prior to
isolation.17 The stereogenicity of the newly generated hydroxyl
was again secured by single-crystal X-ray analysis.
Semmler-Wolff aniline aromatization.20 The sequence proved
highly efficient, requiring 13 steps and furnishing (-)-13 in 17%
overall yield.
Union of the Eastern and Western Hemispheres and
Elaboration of an ABCDEFGH Octacyclic Model. With both
aniline (-)-13 and the protected Nolen-Sprengeler lactone (-)-
336k,l in hand, we explored their union via the aforementioned
indole synthesis (Scheme 7).6m Treatment of the N-silylated
derivative of (-)-13 with 2 equiv of s-BuLi, followed by
addition of lactone (-)-33 and work up involving exposure of
the intermediate product to silica gel, provided indole (-)-34
in near quantitative yield.21 Parikh-Doering oxidation22 of the
primary hydroxyl, and in turn treatment with methanolic HCl
to remove simultaneously the hydroxyl protecting groups and
ketal, and then selective reinstallation of the TIPS silyl group
furnished (+)-35 as a single isomer (stereochemistry undefined)
in 41% yield for three steps.
Scheme 5
Scheme 7
Initiation of the Penitrem Synthetic Venture: Construc-
tion of Western Aniline (-)-13. Having achieved experimental
support for the strategic transformations required by our
synthetic plan, we initiated work on (-)-penitrem D (4) with
the synthesis of 13 possessing the requisite absolute stereo-
chemistry (Scheme 6), employing a sequence essentially identi-
cal to that of our earlier racemic synthesis of 13, which was
used to access the ABCDEF model 22.18 Highlights of this
sequence include an effective four-step photochemical genera-
tion of (-)-31 from (-)-30,6k which proceeded in 49% overall
yield, a Woodward-Wilds19 modification of the Robinson
annulation to append the carbon skeleton for ring D, and a
Scheme 6
At this juncture, we decided to evaluate the tandem AF ring
construction tactic with the more complex substrate (+)-35. An
alternative would have been to introduce the I ring first (vide
infra). As in the earlier model study, treatment with camphor-
sulfonic acid in benzene furnished the octacyclic enone (-)-36
in 39% yield based on recovered (+)-35 (Scheme 8). The
structure of (-)-36 was confirmed by X-ray crystallography.
“One-Pot” Formation of the A, F, and I Rings. Having
achieved access to the advanced ABCDEFGH model system
[(-)-36], we turned to the possibility of the “one-pot” construc-
(20) (a) Semmler, W. Chem. Ber. 1892, 25, 3352-3354. (b) Wolff, L. Annalen
1902, 322, 351-391. (c) For a review of the transformation, see: Conley,
R. T.; Chosh, S. In Mechanism of Molecular Migrations; Thyagarajin, B.
S., Ed.; Interscience: New York, 1971; Vol. 4, pp 251-308.
(17) See the Supporting Information for the experimental procedure.
(18) Hartz, R. A. Ph.D. Thesis, University of Pennsylvania, 1996.
(19) (a) Shunk, H.; Wilds, A. L. J. Am. Chem. Soc. 1949, 71, 3946-3950. (b)
Woodward, R. B.; Sondheimer, F.; Taub, D.; Heusler, K.; McLamore, W.
M. J. Am. Chem. Soc. 1952, 74, 4223-4251.
(21) With the fully elaborated coupling partners, the heteroatom Peterson
olefination did not go to completion without external promoters such as
silica gel or heating; see also ref 6e.
(22) Parikh, J. R.; Doering, W. E. J. Am. Chem. Soc. 1967, 89, 5505-5507.
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A R T I C L E S
Smith et al.
Scheme 8
alcohol, and removal of the MTM group, then furnished (+)-
39, embodying the complete carbon skeleton and functionality
required to attempt the proposed A, F, and I ring construction
in a single operation.25
Initial observations were encouraging. Treatment of (+)-39
with camphorsulfonic acid in benzene did indeed result in the
required reaction cascade, furnishing the A and F rings, and in
the formation of the tetrahydropyran I ring (Scheme 10). The
stereochemical outcome was, of course, the question. After
extensive NMR analysis, we were forced to conclude that,
although formation of rings A and F had proceeded correctly,
as predicted by model (-)-36, the stereogenicity at C(28) in
the I ring was incorrect vis-a`-vis the penitrem skeleton. This
result was clearly unexpected given the earlier successful I ring
model study (see Scheme 4).6m
Scheme 10
tion of the A, F, and I rings. Stork metalloenamine alkylation10
of the dimethylhydrazone derived from (+)-35 with epoxide
(-)-15 as the electrophile (Scheme 9), followed by protection
of the newly generated hydroxyl (PivCl, DMAP), furnished (+)-
38, albeit in 27% yield for the three steps.23 In our hands, a
particularly troubling (and recurring) aspect of the Stork protocol
is the necessity to carry out the reaction on a reasonable scale
Scheme 9
The I Ring Model Study Revisited. After considerable
analysis, we recognized that the major product obtained by initial
treatment of model 27 (ca. 3.4:1 mixture) with camphorsulfonic
acid was not the desired cis-tetrahydropyran (Scheme 11), but
instead the trans isomer (+)-41, the result of a kinetically
Scheme 11
when advanced (+)-35 was in limited supply. To circumvent
this problem, we added the readily available auxiliary hydrazone
37.6j We surmised that the auxiliary hydrazone would also
facilitate anion equilibration, required for successful Stork
metalloenamine alkylation. The use of 37 did improve the yield
of (+)-38 to 38%.24 Hydrolysis of the hydrazone, followed in
turn by reduction of the enone, acetylation of the resultant
(23) Attempts to use a MOM protecting group at C(25) as in the earlier model
study failed due to our inability to differentiate the secondary and tertiary
hydroxyls at C(25) and C(16), respectively.
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A R T I C L E S
controlled cyclization, and that (+)-28, the thermodynamically
more stable isomer, for which we had structural confirmation
by X-ray analysis, had arisen during the 1 N HCl treatment to
remove the MOM protecting group. This scenario was easily
confirmed both by conversion of (+)-43 to the corresponding
MOM ether (+)-41 and by isomerization of (+)-43 to (+)-28
monitored by NMR.26 Unfortunately, all attempts to effect a
similar isomerization of the advanced penitrem D ABCDEF-
GHI nonacycle [(-)-40] to access the correct penitrem core
(11), via HCl treatment, proved unsuccessful due to the inherent
acid lability of the A ring oxocane.
not be feasible and that independent approaches to the A, F,
and I ring systems would have to be achieved. The successful
construction of the three rings in (-)-40 nonetheless was taken
as a milestone in our penitrem D venture.
Penitrem D: A Revised Synthetic Plan. To preserve the
convergent strategy, we chose to move the AF ring construction
tactic that had proven so successful in the early model
studies6h,i,m to late in the synthetic sequence. This strategic
reorganization suggested 45 (Scheme 12), possessing a prein-
Scheme 12
Given the critical nature of the required isomerization, we
thought it prudent to explore other solvent and acid systems.
Again, initial studies proved encouraging. Treatment of 44 with
a catalytic amount of several acids including the Grieco solvent
system27 (Table 1), followed by removal of the benzoyl moiety,
Table 1. Tetrahydropyran Formation
entry
conditions
yield for two steps
1
2
3
0.25 equiv CSA, benzene, 4 h
3 M LiClO4-Et2O, 5 °C f rt, 23 h
0.01 equiv AcOH, 3 M LiClO4-Et2O,
5 °C f rt, 18 h
52% (1:1)
no reaction
85% (1:1)
4
5
0.01 equiv CSA, 3 M LiClO4-Et2O,
88% (8:1)
5 °C f rt, 16 h
0.01 equiv HClO4, 3 M LiClO4-Et2O,
0 °C f rt, 1.5 h
84% (13:1)
stalled tetrahydropyran I ring, to be a more viable advanced
intermediate. A similar 2-substituted indole synthesis employing
western hemisphere aniline 46, with a fully elaborated eastern
hemisphere 47, would then be required.
furnished (+)-28. The highest level of selectivity for the desired
cis-tetrahydropyran (+)-28 (ca. 13:1) was obtained with 0.01
equiv of HClO4. These conditions however failed to generate
the requisite A and F rings with (+)-35. Taken together these
results forced the conclusion that construction of the A, F, and
I rings, employing a single set of reaction conditions, would
A Second-Generation Eastern Hemisphere (47). To gener-
ate 47, we first explored installation of the C(23) side chain
onto the now familiar Nolen-Sprengeler lactone (-)-14,6k,l
again via a Stork metalloenamine alkylation.10 The lactone
moiety however precluded direct Stork alkylation with epoxide
(-)-15. Lactone (-)-14 was therefore converted to a mixture
of acetals (+)-48a and (+)-48b via a three-step sequence
(Scheme 13). The acetals, after separation, were individually
converted to the corresponding dimethyl hydrazones. Stork
metalloenamine alkylation with epoxide (-)-15, employing
again the auxiliary hydrazone (+)-37,6j followed by benzoylation
of the derived hydroxyls led to (+)-49a and -b. In this case the
yields were somewhat improved to 58% and 76% respectively,
compared to (+)-38 (see Scheme 9). Hydrolysis of both the
hydrazones and methyl acetals in turn, followed by PDC
oxidation, furnished lactone (+)-50. For the purposes of material
advancement, the overall sequence could, of course, be carried
forward with the mixture of 48a and 48b.
(24) Without the auxiliary hydrazone 37, we were unable to detect the desired
coupling product between (+)-35 and (-)-15.
(25) Intermediates (+)-38 and (+)-39 were both single isomers; the stereo-
chemistry was not determined.
(26) Heating (e.g., 80 °C) was required for isomerization in benzene due to the
lower polarity of the solvent compared to that of methanol. Due to the
overlap of signals from residual MeOH, water, and compounds (+)-43 and
(+)-28, we decided to utilize benzene-d6 instead of CD3OD.
(27) Grieco and co-workers exploited these conditions in an elegant synthesis
of yuehchukene, see: (a) Grieco, P. A.; Clark, J. D.; Jagoe, C. T. J. Am.
Chem. Soc. 1991, 113, 5488-5489. (b) Henry, K. J., Jr.; Grieco, P. A. J.
Chem. Soc., Chem. Commun. 1993, 510-512.
To elaborate the I ring, we explored the conditions that had
proven successful with model system 44 (vide supra). Lactone
51 was prepared from (+)-50 by 1,2-reduction of the enone,
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A R T I C L E S
Smith et al.
Scheme 13
observed was of considerable significance. To implement this
tactic, we first removed the MTM protecting group in (+)-50
(Table 2; entry 1) and then subjected the resultant alcohol to
the conditions of TMSOTf and Et3SiH; surprisingly diene (-)-
53, the product of elimination, as opposed to silane reduction
was the exclusive product. Replacement of TMSOTf with TfOH
led to the desired cis-tetrahydropyran (+)-52 in 38% yield for
the two steps, albeit still accompanied by the diene in 45% yield
(entry 2). Importantly, none of the trans-isomer was observ-
ed. A one-pot procedure comprising MTM removal, cyclization,
and silane reduction proved feasible with Et3SiH-TfOH, to
furnish a mixture (1:1.8) of (+)-52 and (-)-53, respectively
(entry 3). Although we could transform (-)-53 to (+)-52 in
35% yield [82% yield based on recovered (-)-53],30 employing
the same Et3SiH-TfOH conditions, we sought further optimiza-
tion. Eventually, use of toluene as solvent in place of CH2Cl2,
with careful control of reaction temperature, proved effective,
furnishing the cis-tetrahydropyran (+)-52 in 60% yield.
Table 2. Reductive Cyclization Leading to (+)-52
acetylation of the resultant hydroxyl, and removal of the MTM
protecting group (Scheme 14). Treatment of 51 with HClO4
(0.01 equiv) in 3 M LiClO4-ether furnished a mixture of cis-
and trans-tetrahydropyrans 52. Unfortunately, the yield (32%)
and stereoselectivity (cis:trans ) 1:1) of the ring closure proved
incommensurate with material advancement.28 Clearly, an
alternate approach to the I ring was required.
yield (%)
entry
conditions
(+)-52
(−)-53
1
(1) MeI, CaCO3, CH3CN-THF-H2O (4:1:1),
55 °C
(2) 1.2 equiv TMSOTf, 9.7 equiv Et3SiH,
0
82
CH2Cl2, 0 °C
2
(1) MeI, CaCO3, CH3CN-THF-H2O (4:1:1),
55 °C
38
45
Scheme 14
(2) 4.8 equiv TfOH, Et3SiH-CH2Cl2 (1:1),
0 °C
3
4
4.9 equiv TfOH, Et3SiH-CH2Cl2 (1:1),
-78 °C f -20 °C
8.4 equiv TfOH, Et3SiH-toluene (1:1),
-40 °C f rt
35
60
63
0
To complete construction of the advanced lactone (+)-54,
the benzoyl group was removed (methanolic K2CO3), followed
by regeneration of the partially hydrolyzed lactone with 1-(3-
dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (ED-
CI);31 the overall yield for the two steps was 90% (Scheme
15).
In 1989 Nicolaou reported an elegant synthesis of oxepanes
via reductive cyclization of simple hydroxy ketones through the
intermediacy of an oxonium ion.29 The conditions of choice were
Et3SiH and TMSOTf. That complete syn diastereoselectivity was
Scheme 15
(28) The major byproduct was a diene i (32% yield).
Introduction of the C(22) Hydroxyl. Having arrived at the
complete carbon skeleton of the eastern hemisphere, we turned
to introduce the C(22) hydroxyl employing the photo-oxidation
(29) Nicolaou, K. C.; Hwang, C.-K.; Nugiel, D. A. J. Am. Chem. Soc. 1989,
111, 4136-4137.
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8234 J. AM. CHEM. SOC. VOL. 125, NO. 27, 2003

Tremorgenic Indole Alkaloids
A R T I C L E S
Scheme 17
conditions developed with model (+)-28 (see Scheme 5).
Unfortunately, all attempts to achieve this transformation with
the advanced system (+)-54 proved totally unrewarding (Table
3). We speculate, as illustrated, that the vicinal quaternary
Table 3. Photo-Oxidation of (+)-54
entry
conditions
1
2
3
4
1O2, hν, py, 35 °C, hematoporphyrin IX; PPh3
1O2, hν, benzene, reflux, hematoporphyrin IX, TPP; PPh3
1O2, hν, CHCl3, 35 °C, methylene blue; NaBH4, MeOH
1O2, hν, MeOH-benzene (1:1), 35 °C, methylene blue;
NaBH4, MeOH
5
1O2, hν, MeOH-benzene (1:1), 35 °C, methylene blue; PPh3
(TPP ) 5,10,15,20-tetraphenyl-21H,23H-porphyrin)
methyl groups block the appropriate trajectory of singlet oxygen,
possible with (+)-28, to both faces of the tetrasubstituted olefin.
At this juncture, we recalled that during our earlier syntheses
of (+)-paspalicine and (+)-paspalinine, a model â,γ-unsaturated
ketone (+)-56 had proven highly susceptible to autoxidation,
quantitatively affording the corresponding hydroperoxide (+)-
57 (Scheme 16).6d Similar autoxidation of steroids has been
is not the rate-limiting step. Instead, we suggest that silica gel-
promoted keto-enol tautomerization, to generate the C(22-
24) dienol, may be the rate-limiting step.34 The alpha stereo-
selectivity of the autoxidation process presumably derives from
stereoelectronic factors, namely, a “product-like” transition state
wherein direct chair formation (pathway a) is favored as opposed
to a twist boat (pathway b) as illustrated in Scheme 17.35
To arrive at the fully elaborated eastern hemisphere, all that
remained was stereoselective reduction of the C(25) carbonyl
and protection of the secondary hydroxyl as the TES ether.
Several reducing agents were screened; L-selectride produced
the highest level of stereoselectivity (Table 4). Protection of
the hydroxyl completed the synthesis of the eastern hemi-
sphere(-)-47, the structure being confirmed by single-crystal
X-ray analysis.
Scheme 16
attributed to hydrogen atom abstraction, followed by the addition
of oxygen to the resultant radical.32 To explore this possibility,
(+)-54 was oxidized to the corresponding â,γ-unsaturated
ketone (+)-60 with the Dess-Martin periodinane.33 During the
purification of (+)-60, we observed a minor amount of
hydroperoxide formation. This observation led us to develop a
three-step oxidation/autoxidation/reduction protocol employing
in turn the Dess-Martin periodinane, air/silica gel oxidation,
and PPh3 reduction to furnish (-)-59 in 60% yield for the three
steps (Scheme 17). In an effort to accelerate the oxidation, the
radical initiator AIBN was added. No improvement in the
reaction rate occurred, suggesting that hydrogen atom abstraction
Fragment Union. Recognizing the potential acid sensitivity
of the intermediates anticipated to arise post 2-substituted indole
construction, we chose to replace the MOM protecting group
in (-)-13 with the more easily removable TMS group. Not
surprisingly, the harsh conditions required to remove the MOM
group also led to loss of the TBS group. Reprotection was
(30) Higher reaction temperature and/or longer reaction time resulted in over-
reduction of the olefin in the side chain.
(31) Dhaon, M. K.; Olsen, R. K.; Ramasamy, K. J. Org. Chem. 1982, 47, 1962-
1965.
(32) Nickon, A.; Mendelson, W. L. J. Org. Chem. 1965, 30, 2087-2089.
(33) Dess, D. B.; Martin, J. C. J. Am. Chem. Soc. 1991, 113, 7277-7287.
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A R T I C L E S
Smith et al.
Table 4. Reduction of (-)-59
Scheme 19
yield (%)
(47:63)
entry
conditions
1
2
3
4
NaBH4, CeCl3, MeOH, 0 °C
96 (1:8)
94 (1:2)
no reaction
86 (19:1)
Li(O t-Bu)3AlH, THF, 0 °C f rt
NaBH(OAc)3, AcOH, 80 °C f 100 °C
L-Selectride, THF, -78 °C
End Game. The last major hurdle to overcome was genera-
tion of the A and F rings (Scheme 20). Parikh-Doering
oxidation22 of the primary hydroxyl followed by selective
removal of the TMS and TES groups afforded a serviceable
equilibrium mixture of 64, 65a, and 65b (3:1:3). Initial attempts
to construct the A and F rings with CSA in benzene provided
the desired oxocane (-)-66, albeit in low yield (ca. 19%), along
with a considerable amount of the elimination product (-)-67
(56%). The structure of (-)-67 was deduced via 2D NMR
experiments. In an attempt to improve the ratio of (-)-66 and
(-)-67, a series of Lewis acids was screened; best results were
obtained with 1.2 equiv of Sc(OTf)3 in benzene.37 These
conditions furnished (-)-66 in 62% yield. The requisite â-ster-
achieved with a TIPS group at the primary hydroxyl36 and a
TMS at the C(16) hydroxyl to furnish (+)-46 [48% yield, 100%
yield based on recovered starting material (Scheme 18)].
Scheme 18
Scheme 20
Following our 2-substituted indole protocol, o-toluidine (+)-
46 was converted to the N-trimethylsilyl-o-toluidine derivative
and, in turn, treated with 2.1 equiv of s-BuLi. Addition of lactone
(-)-47 furnished the coupled product, which upon exposure to
silica gel underwent the requisite heteroatom Peterson olefina-
tion to provide indole (-)-45 (Scheme 19).6n The excellent yield
(e.g., 81% yield) was quite gratifying.
(34) A similar autoxidation of an enol (ii) was observed by Kuwajima and co-
workers during the synthesis of (+)-taxusin, see: Hara, R.; Furukawa, T.;
Kashima, H.; Kusama, H.; Horiguchi, Y.; Kuwajima, I. J. Am. Chem. Soc.
1999, 121, 3072-3082.
(35) (a) House, H. O.; Tefertiller, B. A.; Olmstead, H. D. J. Org. Chem. 1968,
33, 935-942. (b) Paquette, L. A.; Belmont, D. T.; Hsu, Y.-L. J. Org. Chem.
1985, 50, 4667-4672. (c) Stereoselective Alkylation Reactions of Chiral
Metal Enolates. Evans, D. A. Asymmetric Synthesis; Morrison, J. D., Ed.;
Academic Press: New York, 1983; Vol. 3, Chapter 1, pp 1-110.
(36) The lability of the TBS protecting group suggested that the use of the more
robust TIPS ether would prove advantageous.
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8236 J. AM. CHEM. SOC. VOL. 125, NO. 27, 2003

Tremorgenic Indole Alkaloids
A R T I C L E S
eochemistry at C(18) of (-)-66, as in the earlier model studies,
was again obtained with excellent selectivity (>95:5 by H
NMR).
manner. The initial approach afforded nonacycle (-)-40,
possessing the undesired stereogenicity at C(28) via a dramatic
one-pot construction of the A, F, and I rings. The second-
generation strategy called for the construction of the fully
elaborated eastern hemisphere (-)-47, possessing a preinstalled
I ring; highlights of the I ring construction included a Stork
metalloenamine alkylation, an acid-promoted reductive cycliza-
tion, and autoxidation at C(22). Union of the fully elaborated
eastern and western hemispheres was then achieved employing
the 2-substituted indole synthesis, developed expressly for the
(-)-penitrem D synthetic venture. The excellent efficiency of
this union (81%) stands as a testimony for the application of
this method in complex molecule synthesis. Finally, a Sc(OTf)3-
promoted cationic cascade completed construction of the A-I
nonacyclic system. The longest linear sequence to (-)-penitrem
D (4) required 43 steps from (-)-Wieland-Miescher ketone.
1
With the critical A and F rings secure, final conversion to
penitrem D (4) proved straightforward. Acetylation of the C(25)
hydroxyl (Scheme 21), followed by removal of the TIPS group,
furnished alcohol (-)-68, which in turn was subjected to Grieco
selenation14 of the primary hydroxyl followed by oxidative
elimination to install the C(11) exo olefin.15 Saponification then
provided (-)-penitrem D (4), identical in all respects to a sample
of the natural product (e.g., 1H and 13C NMR, IR, HRMS, and
chiroptic properties).
Scheme 21
Acknowledgment. Support was provided by the National
Institutes of Health (Institute of General Medical Sciences)
through grant GM-29028. Postdoctoral fellowships are gratefully
acknowledged by N.K. (the Japan Society for the Promotion of
Science for Young Scientists), H.I. (Uehara Memorial Founda-
tion), and J.D.R. and W.H.M. (The National Institutes of Health).
We are also indebted to Dr. Mike Kaufmann and Professor Keiji
Tanino (Hokkaido University) for helpful discussions on the I
ring formation and autoxidation, respectively, and Christopher
M. Adams for help with the preparation of this manuscript. In
addition, we thank Drs. George Furst, Rakesh Kohli, and Patrick
Carroll, Directors of the University of Pennsylvania Spectro-
scopic Facilities, for assistance in obtaining high-field NMR
spectra, high resolution mass spectra, and X-ray crystallographic
analysis, respectively.
Supporting Information Available: Experimental procedures
and analytical data for compounds (-)-13, (+)-28-(-)-36, (+)-
38-(+)-41, (+)-43, (-)-45-(+)-50, (+)-52-(+)-54, (-)-59,
(+)-60, (+)-62, (+)-63, (-)-66-(-)-68. This material is
available free of charge via the Internet at http://pubs.acs.org.
JA034842K
(37) (a) Kobayashi, S.; Hachiya, I.; Araki, M.; Ishitani, H. Tetrahedron Lett.
1993, 34, 3755-3758. (b) Kobayashi, S.; Hachiya, I.; Ishitani, H.; Araki,
M. Synlett 1993, 472-474.
Summary. The first total synthesis of (-)-penitrem D has
been achieved in a highly convergent and stereocontrolled
9
J. AM. CHEM. SOC. VOL. 125, NO. 27, 2003 8237