Enantiospecific total synthesis of the hapalindoles, fischerindoles, and welwitindolinones via a redox economic approach

Article abstract of DOI:10.1021/ja806981k

Full details are provided for the total synthesis of several members of the hapalindole family of natural products, including hapalindole Q, 12-epi-hapalindole D, 12-epi-fischerindole U, 12-epi-fischerindole G, 12-epi-fischerindole I, and welwitindolinone

Full text of DOI:10.1021/ja806981k

Published on Web 11/26/2008
Enantiospecific Total Synthesis of the Hapalindoles,
Fischerindoles, and Welwitindolinones via a Redox Economic
Approach
Jeremy M. Richter, Yoshihiro Ishihara, Takeshi Masuda, Brandon W. Whitefield,
Toma´s Llamas, Antti Pohjakallio, and Phil S. Baran*
Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road,
La Jolla, California 92037
Received September 3, 2008; E-mail: pbaran@scripps.edu
Abstract: Full details are provided for the total synthesis of several members of the hapalindole family of
natural products, including hapalindole Q, 12-epi-hapalindole D, 12-epi-fischerindole U, 12-epi-fischerindole
G, 12-epi-fischerindole I, and welwitindolinone A. Use of the recently developed direct indole coupling
enabled an efficient, practical, scalable, and protecting-group-free synthesis of each of these natural products.
The original biosynthetic proposal is reviewed, and a revised biosynthetic hypothesis is suggested, validated
by the above syntheses. The syntheses are also characterized by an adherence to the concept of “redox
economy”. Analogous to “atom economy” or “step economy”, “redox economy” minimizes the superfluous
redox manipulations within a synthesis; rather, the oxidation state of intermediates linearly and steadily
increases throughout the course of the synthesis.
Introduction
Reports have surfaced of antialgal activity from the hapalin-
doles,1 antimycotic activity from the hapalindoles,1,2e,i
The first members of the hapalindole-type natural products
were isolated from the Stigonemataceae family of cyanobacteria
in 1984 by Moore and colleagues.1 In the 24 years since their
initial discovery, 63 members2 have been added to this family
of alkaloids, which include the hapalindoles, fischerindoles,
welwitindolinones, ambiguines, hapalindolinones, hapaloxin-
doles, and fontonamides (see Chart 1). These natural products
have been isolated from soil samples in a myriad of habitats
around the globe,3 and a broad range of biological activities
arises from the different structural classes. Insecticidal activity
is observed for several hapalindoles2l and welwitindolinones.2f
welwitindolinones,2f and ambiguines,2d,k and antibacterial activ-
ity from the hapalindoles2m,4 and ambiguines.2k Additionally,
it has been found that hapalindolinone A inhibits arginine
vasopression binding.2b Finally, potent anticancer activity against
multiple drug-resistant ovarian cancer cell lines has been
reported for the welwitindolinones,2f,5 which apparently exert
this effect through microtubule depletion.6
Not only do a vast number of the members of this natural
product family exhibit potent and exciting biological activities,
but they also all contain intriguing and unprecedented molecular
architectures. Though distinct, they are united by several
structural features, most notably an indole (or indole-derived)
heterocycle with a monoterpene unit appended at C(3) (see
Scheme 1 for numbering), comprising the core of these
molecules. All but a handful of them contain an isonitrile or an
isothiocyanate at C(11), with an all-carbon quaternary center,
comprised of a methyl and vinyl group, vicinal to this moiety
(C(12)). The hapalindoles are the simplest members of this
family, containing the core structure described above, housed
within a tricyclic framework. Many contain further function-
alization, in the form of either unsaturation (at C(10)) or
chlorination (at C(13)), and several contain an additional
carbocycle arising from the union of C(4) of indole with the
isopropylidene unit at C(15). The fischerindoles, tetracycles
(1) Moore, R. E.; Cheuk, C.; Patterson, G. M. L. J. Am. Chem. Soc. 1984,
106, 6456–6457.
(2) (a) Moore, R. E.; Cheuk, C.; Yang, X.-Q. G.; Patterson, G. M. L.;
Bonjouklian, R.; Smitka, T. A.; Mynderse, J. S.; Foster, R. S.; Jones,
N. D.; Swartzendruber, J. K.; Deeter, J. B. J. Org. Chem. 1987, 52,
1036–1043. (b) Schwartz, R. E.; Hirsch, C. F.; Springer, J. P.;
Pettibone, D. J.; Zink, D. L. J. Org. Chem. 1987, 52, 3704–3706. (c)
Moore, R. E.; Yang, X.-Q. G.; Patterson, G. M. L. J. Org. Chem.
1987, 52, 3773–3777. (d) Smitka, T. A.; Bonjouklian, R.; Doolin, L.;
Jones, N. D.; Deeter, J. B.; Yoshida, W. Y.; Prinsep, M. R.; Moore,
R. E.; Patterson, G. M. L. J. Org. Chem. 1992, 57, 857–861. (e) Park,
A.; Moore, R. E.; Patterson, G. M. L. Tetrahedron Lett. 1992, 33,
3257–3260. (f) Stratmann, K.; Moore, R. E.; Bonjouklian, R.; Deeter,
J. B.; Patterson, G. M. L.; Shaffer, S.; Smith, C. D.; Smitka, T. A.
J. Am. Chem. Soc. 1994, 116, 9935–9942. (g) Huber, U.; Moore, R. E.;
Patterson, G. M. L. J. Nat. Prod. 1998, 61, 1304–1306. (h) Jimenez,
J. I.; Huber, U.; Moore, R. E.; Patterson, G. M. L. J. Nat. Prod. 1999,
62, 569–572. (i) Klein, D.; Daloze, D.; Braekman, J. C.; Hoffmann,
L.; Demoulin, V. J. Nat. Prod. 1995, 58, 1781–1785. (j) Moore, R. E.;
Yang, X.-Q. G.; Patterson, G. M. L.; Bonjouklian, R.; Smitka, T. A.
Phytochemistry 1989, 28, 1565–1567. (k) Raveh, A.; Carmeli, S. J.
Nat. Prod. 2007, 70, 196–201. (l) Becher, P. G.; Keller, S.; Jung, G.;
Su¨ssmuth, R. D.; Ju¨ttner, F. Phytochemistry 2007, 68, 2493–2497.
(m) Asthana, R. K.; Srivastava, A.; Singh, A. P.; Deepali; Singh, S. P.;
Nath, G.; Srivastava, R.; Srivastava, B. S. J. Appl. Phycol. 2006, 18,
33–39.
(3) These locations include the Marshall Islands (ref 1), the Everglades
in Florida (ref 2b), Australia (ref 2f), Micronesia (ref 2h), Papua New
Guinea (ref 2i), and Israel (ref 2k).
(4) (a) Doan, N. T.; Rickards, R. W.; Rothschild, J. M.; Smith, G. D.
J. Appl. Phycol. 2000, 12, 409–416. (b) Doan, N. T.; Stewart, P. R.;
Smith, G. D. FEMS Microbiol. Lett. 2001, 196, 135–139.
(5) Smith, C. D.; Zilfou, J. T.; Stratmann, K.; Patterson, G. M. L.; Moore,
R. E. Mol. Pharmacol. 1995, 47, 241–247.
(6) Zhang, X.; Smith, C. D. Mol. Pharmacol. 1996, 49, 288–294.
9
17938 J. AM. CHEM. SOC. 2008, 130, 17938–17954
10.1021/ja806981k CCC: $40.75  2008 American Chemical Society

Redox Economic Synthesis of the Hapalindole Family
A R T I C L E S
Chart 1. All Known Hapalindole-Type Natural Products
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A R T I C L E S
Richter et al.
Scheme 1. Moore’s Proposed Biosynthetic Relationships between the Hapalindole-Type Alkaloidsa
a [O], oxidation; [S], sulfur insertion.
formed Via the union of C(2) of indole with the isopropylidene
unit at C(15), are also characterized by varying degrees of
functionalization and oxidation. The hapaloxindoles and fon-
tonamides are structurally related to the tetracyclic hapalindoles,
although the indole has been either oxidized to give the oxindole
or oxidatively cleaved to form the formylkynurenine. Also
related to the hapalindoles, albeit much more complex, are the
ambiguines, which contain additional functionalization at C(2)
of indole, specifically a tert-prenyl moiety. In the most complex
ambiguines, this tert-prenyl group is further cyclized and
oxidized. In addition to the unifying structural features of this
family of natural products, the hapalindolinones contain a unique
component within their molecular architecture, specifically a
spirocyclic cyclopropane that joins C(11) with C(3) of the
oxindole heterocycle. Finally, the welwitindolinones are found
in one of two structural classes, the first being welwitindolinone
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Redox Economic Synthesis of the Hapalindole Family
A R T I C L E S
A, which contains a spirocyclic cyclobutane centered around
C(3). The remaining welwitindolinones are comprised of a
[4.3.1]bicyclononanone core, which contains an assortment of
oxidative functionalization.
inability of chemists to attain the chemo-, regio-, and stereo-
control characterizing most enzymatic processes. The careful
practitioner can make use of many abiotic tools in solving these
problems; however, these methods usually demand significant
departure from the ideal biomimetic route. In light of these
difficulties, it is certainly possible, and perhaps prudent, to find
an appropriate balance when designing a retrosynthesis. An ideal
synthesis might entail the use of powerful synthetic methods,
coupled with a flexible adherence to the general synthetic
blueprint provided by Nature.
With a family of such diverse and unique molecular archi-
tectures, it should come as no surprise that several syntheses
have been reported for these natural products, specifically
focusing on the simpler members of the family. Syntheses have
been reported for hapalindoles G,7 H,8 J,9 M,9 Q,10 O,11 and
U,8 in addition to approaches to various other hapalindoles.12
There are no reported efforts toward the hapalindolinones,
hapaloxindoles and fontonamides, and only one approach toward
an ambiguine.13 The first total synthesis of an ambiguine
(ambiguine H) was reported from our laboratory.14 Despite the
many approaches toward the welwitindolinones,15 at the time
of our initial communication16 of the work presented herein,
the members of the welwitindolinone family had not yet
succumbed to synthesis; however, the Wood group reported a
very elegant synthesis of welwitindolinone A shortly thereafter.17
Given these considerations, and with such a large and diverse
family of complex natural products, a biosynthetic proposal that
comprehensively describes the interrelationships between the
members would undoubtedly be enlightening to any synthetic
undertaking. The Moore group, in conjunction with their elegant
isolation studies, put forth many plausible biosynthetic rumina-
tions that are summarized in Scheme 1. Moore’s biosynthesis
begins with the tryptophan derivative (1a) and terpene (1b),
which are enzymatically joined Via chloronium-promoted poly-
olefin cyclization to provide the tricyclic hapalindole core (i.e.,
12-epi-hapalindole E (2), Scheme 1). At this point, Moore and
co-workers proposed that the tricycle can proceed through
multiple divergent pathways, the first of which (path A)
commences with a cyclization between C(4) of indole and the
isopropylidene unit at C(15), leading to the tetracyclic hapal-
indoles (i.e., 12-epi-hapalindole G (3)). These natural products
can then undergo further oxidation at the indole moiety, leading
to the oxindole (i.e., anhydrohapaloxindole A (4)), which can
be oxidatively cleaved to give the formylkynurenine (i.e.,
hapalonamide V (5)). Alternatively, the tetracyclic hapalindoles
can have a tert-prenyl moiety attached to C(2) (i.e., ambiguine
A (6)), which can be engaged in an intramolecular cyclization,
leading to the pentacyclic ambiguines (i.e., ambiguine E (7)).
These alkaloids can then be further oxidized (i.e., ambiguine D
(8)) or rearranged (i.e., ambiguine G (9)). Furthermore (path
B), the tricyclic hapalindoles can undergo cyclization between
C(2) and the isopropylidene at C(15), providing the fischerin-
doles (i.e., 12-epi-fischerindole G (10)). Finally, Moore and co-
workers proposed that the tricyclic hapalindoles can be oxidized
to give the putative intermediate 11, which has not been isolated
as a natural product (path C). They further proposed that this
intermediate undergoes an acid-catalyzed cyclization to afford
welwitindolinone A (12), presumably in the pocket of an
enzyme. If 12 could be further oxidized, leading to the
intermediate epoxide 13, the [4.3.1]bicyclononane system could
be formed after rearrangement (i.e., “welwitindolinone B
isonitrile” (14a), which is likely to be a natural product that
has yet to be isolated). Moore and co-workers suggested that
methylation and oxidation of 14a could lead to N-methylwel-
witindolinone C (15) and further demonstrated the conversion
of 15 into 3-hydroxy-N-methylwelwitindolinone C (17) and
N-methylwelwitindolinone D (19).
Biosynthetic Relationships and Retrosynthetic
Analysis
Biomimetic syntheses are often more efficient due to the
tactics that Nature employs, namely rapid assembly of skeletal
complexity, a linear increase of oxidation state, use of mild and
simple reagents, and the ability to control chemoselectivity (lack
of protecting groups).18 Despite their inherent advantages,
biomimetic syntheses can be exceedingly difficult, due to the
(7) Fukuyama, T.; Chen, X. J. Am. Chem. Soc. 1994, 116, 3125–3126.
(8) Muratake, H.; Kumagami, H.; Natsume, M. Tetrahedron 1990, 46,
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1818. (b) Muratake, H.; Natsume, M. Tetrahedron 1990, 46, 6331–
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6350.
(10) (a) Baran, P. S.; Richter, J. M. J. Am. Chem. Soc. 2004, 126, 7450–
7451. (b) Vaillancourt, V.; Albizati, K. F. J. Am. Chem. Soc. 1993,
115, 3499–3502. (c) Kinsman, A. C.; Kerr, M. A. Org. Lett. 2001, 3,
3189–3191. (d) Kinsman, A. C.; Kerr, M. A. J. Am. Chem. Soc. 2003,
125, 14120–14125.
(11) Sakagami, M.; Muratake, H.; Natsume, M. Chem. Pharm. Bull. 1994,
42, 1393–1398.
(12) (a) Kinsman, A. C.; Kerr, M. A. Org. Lett. 2000, 2, 3517–3520. (b)
Brown, M. A.; Kerr, M. A. Tetrahedron Lett. 2001, 42, 983–985. (c)
Banwell, M. G.; Ma, X.; Taylor, R. M.; Willis, A. C. Org. Lett. 2006,
8, 4959–4961.
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5029.
(14) Baran, P. S.; Maimone, T. J.; Richter, J. M. Nature 2007, 446, 404–
408.
(15) (a) Wood, J. L.; Holubec, A. A.; Stoltz, B. M.; Weiss, M. M.; Dixon,
J. A.; Doan, B. D.; Shamji, M. F.; Chen, J. M.; Heffron, T. P. J. Am.
Chem. Soc. 1999, 121, 6326–6327. (b) Deng, H.; Konopelski, J. P.
Org. Lett. 2001, 3, 3001–3004. (c) Jung, M. E.; Slowinski, F.
Tetrahedron Lett. 2001, 42, 6835–6838. (d) Lo´pez-Alvarado, P.;
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Garc´ıa-Granda, S.; Alvarez-Ru´a, C.; Avendan˜o, C. Eur. J. Org. Chem.
2002, 1702–1707. (e) Avendan˜o, C.; Mene´ndez, J. C. Curr. Org. Synth.
2004, 1, 65–82. (f) Ready, J. M.; Reisman, S. E.; Hirata, M.; Weiss,
M. M.; Tamaki, K.; Ovaska, T. V.; Wood, J. L. Angew. Chem., Int.
Ed. 2004, 43, 1270–1272. (g) MacKay, J. A.; Bishop, R. L.; Rawal,
V. H. Org. Lett. 2005, 7, 3421–3424. (h) Baudoux, J.; Blake, A. J.;
Simpkins, N. S. Org. Lett. 2005, 7, 4087–4089. (i) Greshock, T. J.;
Funk, R. L. Org. Lett. 2006, 8, 2643–2645. (j) Lauchli, R.; Shea, K. J.
Org. Lett. 2006, 8, 5287–5289.
While the Moore biosynthetic hypothesis provides an ad-
equate explanation of the possible relationships between many
of the distinct structural classes, a few points remained uncertain,
primarily relating to the formation of the welwitindolinones.
First, the proposal that 12 arises from the unsaturated intermedi-
ate 11 Via an acid-catalyzed cyclization seems unlikely. The
fact that 63 members of this natural product family have been
(16) Baran, P. S.; Richter, J. M. J. Am. Chem. Soc. 2005, 127, 15394–
15396.
(17) (a) Reisman, S. E.; Ready, J. M.; Hasuoka, A.; Smith, C. J.; Wood,
J. L. J. Am. Chem. Soc. 2006, 128, 1448–1449. (b) Reisman, S. E.;
Ready, J. M.; Weiss, M. M.; Hasuoka, A.; Hirata, M.; Tamaki, K.;
Ovaska, T. V.; Smith, C. J.; Wood, J. L. J. Am. Chem. Soc. 2008,
130, 2087–2100.
(18) See the following texts, and references therein: (a) Nicolaou, K. C.;
Sorensen, E. J. Classics in Total Synthesis; Wiley-VCH: Weinheim,
1996. (b) Nicolaou, K. C.; Snyder, S. A. Classics in Total Synthesis
II; Wiley-VCH: Weinheim, 2003.
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Richter et al.
Scheme 2. Alternative Biosynthetic Proposal
isolated, while 11 has not been one of them, casts doubt on
whether this compound is a plausible intermediate. Given the
stability that 11 should demonstrate, at least trace quantities of
this compound would be expected in the isolation broths. More
importantly, there seems to be little thermodynamic driving force
for the conversion of 11 into 12, due to the generation of a
strained spirocyclobutane in this transformation. Second, the
mechanistic explanation for the conversion of welwitindolinone
A (12) into “welwitindolinone B isonitrile” (14a) lacks proper
literature precedence. Third, the proposal that N-methylwelwit-
indolinone C (15) arises from remote oxidation of 14a could
conceivably be explained by an alternate hypothesis. Finally,
the isolation literature lacks a biosynthetic hypothesis to account
for the genesis of the hapalindolinones.
Given the concerns delineated above, an alternative biosyn-
thetic hypothesis is proposed in Scheme 2. Rather than arising
from hypothetical metabolite 11, welwitindolinone A (12) could
arise from an oxidative ring contraction of 12-epi-fischerindole
I (21); the latter could be formed Via a benzylic oxidation of
12-epi-fischerindole G (10), which could in turn arise from the
tricyclic hapalindole 12-epi-hapalindole E (2). Furthermore, an
alternative, albeit untested, mechanistic hypothesis for the
conversion of 12 into “welwitindolinone B isonitrile” (14a) is
put forth that is more in line with literature precedence.
Isonitriles are relatively electron-withdrawing, inductively sta-
bilizing negative charges, and have not been invoked as electron-
donating entities.19 It is therefore unlikely that the isonitrile
would participate in a fracture of the epoxide Via electron
donation that would lead to a fissure of the cyclobutane ring.
Alternatively, based on evidence gleaned in this laboratory,20
it is more reasonable to invoke electron donation from the N(1)
lone pair through the aromatic ring to break the cyclobutane,
leading to the R-isocyanoketone enolate (22). This enolate could
then attack the highly unstable, extremely electrophilic aza-
orthoquinodimethane generated in the reaction, leading to 14a
after tautomerization.21 Additionally, the remote oxidation of
14a to N-methylwelwitindolinone C (15), although perhaps
possible with enzymatic intervention, is unlikely. Rather, if 21
were to undergo allylic oxidation, intermediate 23 could be
accessed. Upon oxidative ring contraction, similar to that
proposed for 12, the direct product would contain an unstable
cyclobutane with vicinal exocyclic olefins. The trisubstituted
olefin might then isomerize to form the vinyl chloride (24), thus
alleviating this additional strain on the cyclobutane. Oxidative
ring expansion of 24 and methylation of the indole nitrogen
atom could then lead directly to 15. Finally, we propose that
the hapalindolinones could arise from an oxidative coupling
event between the C(3) and C(11) carbons of an appropriate
tricyclic hapalindole (i.e., 12-epi-hapalindole Q (25)), generating
the oxindole with the spirocyclopropane moiety (i.e., hapalin-
dolinone B (26)).
With a compelling biosynthetic hypothesis in hand, attention
could be turned toward designing a synthesis of welwitindoli-
none A (12). However, before such a task was undertaken, it
seemed prudent to first consider a synthesis of simpler members
of the family, such as hapalindole Q (27) and 12-epi-fischer-
indole U (29). It was envisioned that such efforts would reveal
hidden clues into the fundamental reactivity of these alkaloids
(20) (a) Baran, P. S.; Shenvi, R. A.; Mitsos, C. A. Angew. Chem., Int. Ed.
2005, 44, 3714–3717. (b) Baran, P. S.; Shenvi, R. A. J. Am. Chem.
Soc. 2006, 128, 14028–14029.
(19) Ugi, I. Isonitrile Chemistry; Academic Press: New York, 1971.
(21) Fuchs, J. R.; Funk, R. L. Org. Lett. 2005, 7, 677–680.
9
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Redox Economic Synthesis of the Hapalindole Family
A R T I C L E S
Scheme 3. Retrosynthetic Analysis of Hapalindole Q (27) and
12-epi-Fischerindole U (29)
(33) in excellent yield. Unfortunately, reduction of this inter-
mediate proved to be problematic. All methods investigated to
directly reduce this compound to indole 37 (e.g., LiAlH4,
BH3 ·THF) were met with failure, so a stepwise solution was
sought. Assuming that the C(3) hydroxyl group was preventing
reduction of the oxindole, various deoxygenation conditions
(e.g., Barton,22 CS(imid)2/hν23) were brought to bear for the
removal of this alcohol (38) prior to indole reduction; however,
all attempts were unsuccessful.24 Reasoning that elimination of
the hydroxyl moiety would provide an intermediate upon which
further reductions could be performed, various conditions were
screened to elicit dehydration (e.g., Martin sulfurane,25 MsCl/
base, TFA/TFAA) before Burgess reagent26 successfully pro-
vided the enone (36). However, the yield of this process was
irreparably dismal, precluding further chemistry. Since the
alcohol could not be reduced, removed, or efficiently eliminated,
methods to exchange this moiety for a chlorine atom, which
could theoretically be removed with greater facility, were
investigated. Employing the conditions developed by Nicolaou,27
33 was dissolved in thionyl chloride, providing the cyclic ether
35 (colorless cubes, mp 166-168 °C, see Scheme 4 for X-ray
crystallographic analysis) and the unexpectedly stable, semi-
deprotected compound 34, which led to a dead-end once again.
The resistance of intermediate 33 to reduction necessitated
the investigation of alternate means to forge the key bond in
31. Since removal of the tertiary alcohol had proved to be an
intractable problem in the previous route, an approach that
circumvented the generation of this group was sought, leading
to an oxidative enolate coupling approach to form the desired
bond (Scheme 5). The oxidative dimerization of carbonyl
compounds has been known for more than 70 years; however,
it has yet to become widely utilized by the synthetic community.
This reaction has been reviewed,28 most recently during the full
account of the oxidative indole coupling reaction developed in
our laboratory,29 and therefore this information will not be
reviewed here. Even though a myriad of literature procedures
concerning oxidative enolate couplings was available, many
potential drawbacks, could be encountered while pursuing this
route. By the inception of this work, only one example of an
oxindole oxidative dimerization had been reported.30a Addition-
ally, in order to achieve high yields of heterodimerized products
and that they would help develop a general route by which to
access the core structure. Hapalindole Q (27) had been
synthesized previously by the Albizati (8 steps, 8.2% overall
yield)10b and Kerr (12 steps, 1.7% overall yield)10c,d groups,
but the synthesis of 29 had not been reported prior to our initial
communication of this work.10a Since a route to 12 was the
ultimate goal, a more efficient route to the core (i.e., 27 and
29) of this alkaloid was required (Scheme 3). Although a
cyclization of 27 could certainly be investigated to form 29,
this transformation was instead planned at the ketone stage (28),
given the acid-sensitivity of the isothiocyanate group. As such,
both natural products could be traced back to their respective
ketone analogues 28 and 30, the latter of which should be
accessible from the former Via an acid-catalyzed cyclization.
Ketone 28 can be further simplified to the indole/carvone adduct
31 through straightforward functional group transformations.
At this stage, a strictly biomimetic synthesis would require a
chloronium-promoted polyolefin cyclization to install the terpene
moiety; however, a potentially more direct and powerfully
simplifying transformation would involve direct formation of
the key C(3)-C(10) bond.
´
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Baran, P. S.; Ambhaikar, N. A.; Guerrero, C. A.; Hafensteiner, B. D.;
Lin, D. W.; Richter, J. M. ARKIVOC 2006, Vii, 310–325.
(29) Richter, J. M.; Whitefield, B. W.; Maimone, T. J.; Lin, D. W.;
Castroviejo, M. P.; Baran, P. S. J. Am. Chem. Soc. 2007, 129, 12857–
12869.
Total Synthesis of Hapalindole Q
Several strategies were investigated for the synthesis of the
requisite indole/carvone adduct (31) before a method was finally
developed to successfully provide the desired material. Initially,
it was reasoned that 31 could be accessed from an aldol reaction
with subsequent reduction to form the requisite indole moiety
(Scheme 4). Indeed, quenching the enolate of carvone with
MOM-protected isatin (32) provided the desired aldol product
(30) (a) Fang, C -L.; Horne, S.; Taylor, N.; Rodrigo, R. J. Am. Chem. Soc.
1994, 116, 9480–9486. (b) Ito, Y.; Konoike, T.; Saegusa, T. J. Am.
Chem. Soc. 1975, 97, 2912–2914. (c) Ito, Y.; Konoike, T.; Harada,
T.; Saegusa, T. J. Am. Chem. Soc. 1977, 99, 1487–1493.
9
J. AM. CHEM. SOC. VOL. 130, NO. 52, 2008 17943

A R T I C L E S
Richter et al.
Scheme 4. Attempted Synthesis of Hapalindole Q via an Aldol Reactiona
a Reagents and conditions: (a) carvone, LDA (1.0 equiv), THF, -78 °C, 30 min; then 32 (0.83 equiv), 30 min, -78 to 23 °C, 92%; (b) SOCl2, 23 °C,
100 min, 34, 44% and 35, 37%; (c) Burgess reagent (2.0 equiv), PhH, 50 °C, 3 h, 12%. LDA, lithium diisopropylamide; THF, tetrahydrofuran; PhH,
benzene.
Scheme 5. Oxindole Oxidative Coupling Route to Hapalindole Qa
Table 1. Optimization of the Oxidative Oxindole Couplinga
oxidant
yield (%)
PhI(OAc)2
Cu(2-ethylhexanoate)2
FeCl3
Fe(PhCOCHCOCH3)3
Fe(CH3COCHCOCF3)3
Fe(C10H7COCHCOCF3)3
Fe(CH3COCHCOCH3)3
Fe(t-BuCOCHCOCH3)3
10
15
∼15
30
40
40
45
83
a Reagents and conditions: (a) carvone (1.0 equiv), 39 (1.0 equiv), LDA
(2.1 equiv), THF, -78 °C, 30 min; then oxidant (2.0 equiv), 23 °C, 20
min. LDA, lithium diisopropylamide; THF, tetrahydrofuran; [O], oxidation.
a LDA, lithium diisopropylamide; [O], oxidation.
Specifically, Fe(t-BuCOCHCOCH3)3 was exceptionally efficient,
providing an 83% isolated yield of the desired product (as a
1:1 mixture of diastereomers at C(3)), utilizing equimolar
quantities of both coupling partners! These results have led to
the hypothesis that careful tuning of the oxidant’s oxidation
potential to more closely match one of the coupling partners
could lead to selective heterodimerizations.32 With high-yielding
access to intermediate 40, efforts were turned toward the
reduction of oxindole 40 to indole 37 (Scheme 5). Once again,
the reduction proved recalcitrant, necessitating yet another
reevaluation of the synthetic strategy.
in an oxidative enolate coupling, 3 equiv or more of one
coupling partner was usually required.30b,c Finally, few inves-
tigations into the factors that govern the heterodimerization event
had been performed; thus, it was unknown whether any of the
desired heterocoupled product would be obtained. Despite such
potential drawbacks, an examination of the oxidative oxindole
coupling was undertaken, which would at least provide further
insight into the elements that govern such transformations.
As a starting point for the examination of this heterocoupling
reaction, treatment of carvone and MOM-protected oxindole
(39)31 with FeCl3 in DMF provided the desired product (40) in
ca. 15% yield. Given the success of this coupling, an optimiza-
tion of this particular reaction was undertaken, centering
primarily on oxidant selection (Table 1). Hypervalent iodine
and cupric-based oxidants were less efficient at promoting the
coupling than the ferric-based systems, so the focus of further
studies was narrowed. Success was finally realized when
acetylacetonate-type ligands were utilized on the iron center.
As with the aldol route, an alternative to the oxindole coupling
was sought: one that would avoid a problematic reduction step.
As such, the most straightforward method by which to circum-
vent this difficulty would be to directly attach the indole to the
carvone moiety. Unfortunately, no such method had been
reported, requiring the invention of chemistry to fill this gap.
Inspired by the oxidative coupling literature, in conjunction with
Barton’s classic synthesis of usnic acid,33the oxidative indole
coupling was conceived. In this reaction,10a,29 an indole can be
(31) Wang, J.-J.; Hu, W.-P. J. Org. Chem. 1999, 64, 5725–5727.
9
17944 J. AM. CHEM. SOC. VOL. 130, NO. 52, 2008

Redox Economic Synthesis of the Hapalindole Family
A R T I C L E S
Scheme 6. Oxidative Indole and Pyrrole Couplings
Chart 2. Reductive Alkylation Byproduct
Scheme 7. Total Syntheses of Hapalindole Q (27),
ent-12-epi-Hapalindole D (42), and ent-12-epi-Fischerindole U
Isothiocyanate (29)a
With gram quantities of 31 in hand, attention was turned to
the completion of the total synthesis of 27 and 29, which first
required reductive alkylation of the C(12)-C(13) olefin.35
Treatment of 31 with 2 equiv of L-Selectride was expected to
first deprotonate N(1)-H and then perform a conjugate reduc-
tion to generate the enolate, which could subsequently be trapped
with acetaldehyde. Surprisingly, 1,4-hydride addition preceded
N(1)-H deprotonation, thus generating the enolate, which in
turn deprotonated N(1), forming the corresponding reduced
enone (see Chart 2). Rather than protecting the indole nitrogen
atom, N(1)-H was first deprotonated with LHMDS, followed
by addition of L-Selectride, and the resulting enolate was trapped
with acetaldehyde. This intermediate alcohol was immediately
dehydrated with Martin sulfurane to give vinylated compound
41, which intersected the Albizati synthesis.10b Reductive
amination using Albizati’s conditions (NH4OAc, NaCNBH3,
room temperature, 7 days) provided the desired amine in 61%
yield as a 3:1 mixture of diastereomers. Alternatively, micro-
wave irradiation (150 °C, 2 min) provided an identical yield of
the product, with an increased diastereomeric ratio of 6:1. To
the best of our knowledge, this is a unique example of an
increase in diastereoselectivity as a consequence of microwave
irradiation. Treatment of the resulting amine with CS(imid)2
installed the isothiocyanate, thus completing the total synthesis
of 27 and the first total synthesis of ent-12-epi-hapalindole D
(42). Tricyclic ketone 41 could also undergo a biomimetic7 acid-
catalyzed cyclization to provide the tetracyclic ketone 43 upon
exposure to in situ-generated triflic acid.36 Reductive amination
and formation of the isothiocyanate completed the first total
synthesis of 29, which also allowed the determination of the
absolute stereochemistry of the fischerindole-type natural prod-
ucts (i.e., opposite to that depicted in Scheme 7). The syntheses
of 27, 42, and 29 proceeded enantiospecifically in 15%, 4.8%,
and 9.8% overall yields, respectively, without resorting to
protecting groups or superfluous redox manipulations.10a
a Reagents and conditions: (a) indole (2.0 equiv), carvone (1.0 equiv),
LHMDS (3.3 equiv), THF, -78 °C, 30 min; then copper(II) 2-ethylhex-
anoate (1.5 equiv), -78 to 23 °C, 15 min, 49-53%; (b) LHMDS (1.5 equiv),
THF, -78 °C, 20 min; then L-Selectride (1.05 equiv), 1 h, then CH3CHO
(6.0 equiv), -78 to 23 °C, 2 h; (c) Martin sulfurane (1.1 equiv), CHCl3, 10
min, 75% (2 steps); (d) TMSOTf (3 equiv), MeOH (1.1 equiv), DCM, 0
°C, 1 h, 31% isolated, 75% brsm; (e) NaCNBH3 (10 equiv), NH4OAc (40
equiv), MeOH, THF, microwave, 150 °C, 2 min, 61% combined; (f)
CS(imid)2 (1.1 equiv), DCM, 0 to 23 °C, 3 h; (g) NaCNBH3 (10 equiv),
NH4OAc (40 equiv), MeOH, THF, 23 °C, 7 d, 55%. LHMDS, lithium
hexamethyldisilazide; THF, tetrahydrofuran; TMSOTf, trimethylsilyl tri-
fluoromethanesulfonate; DCM, dichloromethane.
Retrosynthetic Analysis of Welwitindolinone A
Having demonstrated that the direct indole coupling could
enable rapid access to several of the simpler members of the
hapalindole family of natural products, attention could then be
turned to the more complex members. Welwitindolinone A (12)
was an attractive target for total synthesis due to its strikingly
unique molecular architecture. It contains three all-carbon
quaternary centers, two of which are chiral, and an asymmetri-
cally disposed neopentyl chlorine atom, all incorporated into a
highly strained spirocyclobutane-containing oxindole. As already
discussed (Vide supra), the revised biosynthetic hypothesis
proposes that 12-epi-fischerindole I (21) is converted into 12
Via oxidative ring contraction.37 Such ring contractions are
primarily utilized for the preparation of spirocyclic five-
membered rings from annulated six-membered rings and often
directly attached to a variety of carbonyl compounds in good
yields (Scheme 6). The method was found to generate the
desired indole/carvone adduct (31, colorless cubes, mp 129-130
°C, structure verified by X-ray crystallographic analysis) in good
yield and in one synthetic operation from commodity starting
materials (Scheme 7); this has also been extended to the coupling
of unfunctionalized pyrroles.34
(32) (a) Baran, P. S.; DeMartino, M. P. Angew. Chem., Int. Ed. 2006, 45,
7083–7086. (b) DeMartino, M. P.; Chen, K.; Baran, P. S. J. Am. Chem.
Soc. 2008, 130, 11546–11560.
(33) Barton, D. H. R.; Deflorin, A. M.; Edwards, O. E. J. Chem. Soc. 1956,
530–534.
(35) Fortunato, J. M.; Ganem, B. J. Org. Chem. 1976, 41, 2194–2200.
(36) Prolonged exposure to triflic acid led to product decomposition;
therefore, the reaction was quenched early and the starting material
was recycled.
(34) Baran, P. S.; Richter, J. M.; Lin, D. W. Angew. Chem., Int. Ed. 2005,
44, 609–612.
9
J. AM. CHEM. SOC. VOL. 130, NO. 52, 2008 17945

A R T I C L E S
Richter et al.
Chart 3. Strained ꢀ-Lactam in Chartelline C
Chart 4. Fukuyama’s Chloroketone: Diastereomer of 46 at C(12)
(see Chart 4) is diastereomeric at C(12), and the chemistry
utilized for its preparation was unfortunately not amenable for
the preparation of 46.
Scheme 8. Retrosynthetic Analysis of Welwitindolinone A (12)
Total Synthesis of ent-Fischerindole G
Historically, installation of chlorine atoms adjacent to qua-
ternary centers has been met with difficulty, and it was
anticipated that 46 would not be an exception.40 Forays into
the preparation of this compound focused on direct means for
concurrent installation of the chlorine atom and the quaternary
stereocenter. As such, attempts were made to apply a modified
Baylis-Hillman-type reaction41 in which ꢀ-chloroketones are
generated from the corresponding enones (Scheme 9), with
concomitant incorporation of an aldehyde. However, this
reaction was never utilized to install a quaternary center at the
R-position prior to this work. Unfortunately, none of the desired
product (52) was obtained using these conditions. Given the
limited prospects for direct installation of the hallmark chlorine
atom, attention was instead focused on a variety of chlorine
equivalents. Carboxylic acids can be readily converted into
chlorines Via a Hunsdiecker reaction, so several acyl anion
equivalents (e.g., 1,3-dithiane derivatives, (MeO)3CH,
(PhS)3CH) were examined in 1,4-additions to carvone, but none
of them provided the desired product. Encouragingly, successful
1,4-addition was observed with phenylcuprate, and the incipient
enolate was trapped with acetaldehyde to give 47. However,
attempts to oxidatively degrade the aromatic ring42 led to
significant overoxidation. A thiophenyl group was next targeted
as a chlorine equivalent, due to the propensity of such moieties
to undergo R-chlorination or Pummerer rearrangements. Thio-
phenol participated in an efficient vicinal difunctionalization of
carvone with aluminum catalysis43 to provide, after dehydration
with Martin sulfurane, thioether 49. Attempts to directly
chlorinate 49 were unsuccessful using a variety of reagents (e.g.,
NCS, Raney Ni/CCl4, SO2Cl2, CCl4/hν, Cl3CCOCCl3). Chlori-
nation with concomitant removal of the thiol under numerous
conditions (e.g., PIFA/LiCl, LiNaphthalenide/TsCl, TiCl4/CCl4,
MeI/NaCl44) was also investigated, but to no avail. Routes in
which the ketone was first converted into the chloride, followed
by sulfide oxidation, were also considered. Direct reductive
chlorination of the ketone,45 instead of providing the desired
product, led to the unexpected bicycle 50. Attempts to generate
the vinyl chloride Via POCl3, which could potentially be
carefully hydrogenated to the alkyl chloride, were also fruitless.
Unable to perform a direct reductive chlorination of the
carbonyl, 49 was first reduced to the neopentyl alcohol (51)
and then unsuccessfully subjected to a variety of chlorination
require relatively harsh reaction conditions to proceed.38 Only
one example has been reported for the direct preparation of a
spirocyclic four-membered ring from an annulated five-
membered ring;39 however, a related conversion has been
observed in this laboratory to generate a strained ꢀ-lactam (see
Chart 3).20 Furthermore, it is conceivable that 21 could arise
from 12-epi-fischerindole G (10) Via benzylic oxidation (Scheme
8). Through straightforward functional group manipulations, 10
could be derived from the tetracyclic ketone 44, which in turn
could arise from an acid-catalyzed cyclization of tricyclic ketone
45. Exploiting the direct coupling methodology developed for
the synthesis of 27, 45 could be obtained from the coupling of
indole with 46. Chloroketone 46 was a new chemical entity;
however, a very similar analogue had been prepared by
Fukuyama en route to hapalindole G.7 Fukuyama’s chloroketone
(40) (a) Gorthey, L. A.; Vairamani, M.; Djerassi, C. J. Org. Chem. 1985,
50, 4173–4182. (b) Albone, K. S.; Macmillan, J.; Pitt, A. R.; Willis,
C. L. Tetrahedron 1986, 42, 3203–3214.
(37) Witkop, B.; Patrick, J. B. J. Am. Chem. Soc. 1953, 75, 2572–2576.
(38) (a) Dhanak, D.; Neidle, S.; Reese, C. B. Tetrahedron Lett. 1985, 26,
2017–2020. (b) Lee, B. H.; Clothier, M. F.; Johnson, S. S. Bioorg.
Med. Chem. Lett. 2001, 11, 553–554. (c) Williams, R. M.; Cao, J.;
Tsujishima, H.; Cox, R. J. J. Am. Chem. Soc. 2003, 125, 12172–12178.
(39) Wenkert, E.; Moeller, P. D. R.; Piettre, S. R.; McPhail, A. T. J. Org.
Chem. 1987, 52, 3404–3409.
(41) Li, G.; Gao, J.; Wei, H. -X.; Enright, M. Org. Lett. 2000, 2, 617–620.
(42) Carlsen, P. H. J.; Katsuki, T.; Martin, V. S.; Sharpless, K. B. J. Org.
Chem. 1981, 46, 3936–3938.
(43) Lee, C. A.; Floreancig, P. E. Tetrahedron Lett. 2004, 45, 7193–7196.
(44) Corey, E. J.; Jautelat, M. Tetrahedron Lett. 1968, 9, 5787–5788.
(45) Onishi, Y.; Ogawa, D.; Yasuda, M.; Baba, A. J. Am. Chem. Soc. 2002,
124, 13690–13691.
9
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Redox Economic Synthesis of the Hapalindole Family
A R T I C L E S
Scheme 9. Failed Attempts To Synthesize the Key Chloroketonea
a Reagents and conditions: (a) CuI (1.0 equiv), THF, PhMgBr (1.1 equiv), -78 to 0 to -78 °C, 1 h; then carvone (1 equiv), 30 min; then CH3CHO (2.0
equiv), -78 to 23 °C, 30 min, 61%; (b) Me3Al (1.2 equiv), DCM, PhSH (1.2 equiv), 0 °C, 20 min; then carvone (1.0 equiv), -78 °C, 15 min; then THF,
CH3CHO (1.2 equiv), 20 min, 62%; (c) CCl4, Martin sulfurane (1.1 equiv), 91%; (d) In(OH)3 (0.05 equiv), CHCl3, Me2HSiCl (1.2 equiv), 23 °C, 5 h, 9%;
(e) THF, L-Selectride (1.2 equiv), -78 °C, 4.5 h, 73%; (f) MeOH, H2O2 (3.0 equiv), 6 N NaOH (0.5 equiv), 10 °C, 2.5 h, 87%; (g) TiCl4 (1.1 equiv), THF,
-78 °C; then LiCl (1.1 equiv), -20 °C; then 53 (1 equiv), -78 to -20 °C, 6 h, 89%; (h) KHMDS (1.0 equiv), DME, -78 °C, 25 min; then Ac2O, -20
°C, 54%; (i) NaOAc (2.2 equiv), HONH3Cl (1.1 equiv), MeOH, 0 °C, 100 min, 68%. THF, tetrahydrofuran; DCM, dichloromethane; KHMDS, potassium
hexamethyldisilazide; DME, dimethoxyethane.
conditions (SOCl2/base, PPh3/CCl4,46 TCT/DMF47). These
chlorinations failed presumably due to the extremely hindered
nature of this particular alcohol. Before further effort was
expended on this chlorination, the Pummerer rearrangement of
thioether 49 was investigated to determine its feasibility in this
system, which revealed that the reaction was not possible under
a variety of conditions (IBX,48 m-CPBA,49 H2O2,50 tBuOOH,
PhI(OAc)2).
Repeated failure to convert carvone into the desired chlo-
roketone Via any sort of vicinal difunctionalization necessitated
yet another strategic reevaluation. Therefore, carvone oxide (53)
was examined as a starting material for the production of
chloroketone 46. It was reasoned that vinylmagnesium bromide
addition into the carbonyl group of the R,ꢀ-epoxyketone,
followed by a semipinacol rearrangement, could allow instal-
lation of the quaternary stereocenter, contingent upon ꢀ-face
attack of the organometallic reagent. Unfortunately, such
conformationally constrained systems are known to favor axial
(i.e., R-face) attack of nucleophiles,51 thus sterically precluding
a successful semipinacol rearrangement. However, if the ring
were less conformationally constrained, a nucleophile might
favor equatorial approach, especially if the R-carbon could
synergistically shield the R-face. As such, chlorohydrin 55 met
these criteria and was prepared from carvone oxide in good
yield. Unfortunately, 55 was unstable, even upon storage in an
inert atmosphere, and failed to provide any desired product when
treated with a variety of nucleophiles. Attempts were also made
to trap the alcohol with an appropriate leaving group (mesyl or
tosyl groups) before addition of the nucleophile, but to no avail.
Investigations subsequently turned toward sequences that
would install the quaternary stereocenter and perform the
chlorination in separate operations. Initial attempts to install the
vinyl group Via dissolving metal-promoted reductive alkylation
of the epoxide52 to give 54 proved fruitless, as any electrophile
that could be subsequently converted into the vinyl group (e.g.,
TBSOCH2CH2I, oxirane) failed to participate in the reaction.
Alternatively, reduction of the carbonyl group to the known
carveol oxide allowed investigations into the direct chlorination
of this alcohol, which would be followed by installation of the
quaternary stereocenter and regeneration of the ketone. Unfor-
tunately, such chlorinations were unsuccessful due to the
instability of the resulting epoxyalcohol. In an alternative
strategy, enol acetate 56 was prepared from carvone oxide in
order to test an intramolecular enolate addition into the epoxide,
but this also proved to be fruitless. Condensation with hydroxyl-
amine provided oxime 57, which was seemingly poised to
undergo an R-substitution reaction, as was reported by Corey
(46) Haufe, G.; Wolf, A.; Schulze, K. Tetrahedron 1986, 42, 4719–4728.
(47) De Luca, L.; Giacomelli, G.; Porcheddu, A. Org. Lett. 2002, 4, 553–
555.
(48) Nicolaou, K. C.; Mathison, C. J. N.; Montagnon, T. J. Am. Chem.
Soc. 2004, 126, 5192–5201.
(49) Iwama, T.; Matsumoto, H.; Shimizu, H.; Kataoka, T.; Muraoka, O.;
Tanabe, G. J. Chem. Soc., Perkin Trans. 1 1998, 1569–1576.
(50) Kreh, D. W.; Krug, R. C. J. Org. Chem. 1967, 32, 4057–4059.
(51) (a) Che´rest, M.; Felkin, H. Tetrahedron Lett. 1968, 9, 2205–2208. (b)
Huet, J.; Maroni-Barnaud, Y.; Anh, N. T.; Seyden-Penne, J. Tetra-
hedron Lett. 1976, 17, 159–162. (c) Stork, G.; Stryker, J. M.
Tetrahedron Lett. 1983, 24, 4887–4890. (d) Gung, B. W. Chem. ReV.
1999, 99, 1377–1386.
(52) Caine, D.; McCloskey, C. J.; Van Derveer, D. J. Org. Chem. 1985,
50, 175–179.
9
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A R T I C L E S
Richter et al.
Chart 5. Anticipated Vinylnitroso Intermediate
of this particular coupling are noteworthy. First, it is remarkable
that chloride elimination is not observed during the course of
this coupling. Second, it was discovered that, as the reaction
concentration was increased, the yield improved. Third, any
C(13) diastereomer of 46 present in the reaction mixture does
not participate in the coupling reaction and rather suffers
elimination, presumably due to the axial disposition of the
chlorine atom. Finally, this effective method for direct C-C
bond formation enables all the necessary carbon atoms of these
complex natural products to be secured in only three steps and
was routinely carried out on multigram scale. Functional group
manipulations are all that remained to complete the synthesis
of 12.
and co-workers.53 Reaction of the oxime with 2 equiv of a
cuprate reagent would first deprotonate the oxime, which could
then open the epoxide and lead to the corresponding vinylnitroso
compound (see Chart 5). The second equivalent of cuprate
reagent could then participate in a 1,4-addition into the
vinylnitroso group, thereby installing the quaternary center.
Unfortunately, divinylcuprate was unsuccessful at accomplishing
this transformation.
Conditions (i.e., TfOH) previously applied to the conversion
of 41 to 43 unfortunately provided significant quantities of
several byproducts in the attempted conversion of 45 to 44,57
including 65, 66, and 67 (Scheme 11). In this particular
cyclization reaction, two modes of activation are feasible at the
gem-disubstituted olefin. This olefin can be protonated to give
the tertiary carbocation, which is intercepted by the indole ring
to give intermediate 61, which in turn leads to the desired
product (44). Alternatively, protonation to give the primary
carbocation, which is also intercepted by the indole ring, leads
to intermediate 62. A [1,5]-sigmatropic shift generates 63, which
can then rearrange to carbocation 64. The three possible modes
of elimination to quench this carbocation provide the three
observed products (65, 66, and 67; 67 as clear cubes, mp
128-129 °C, see Scheme 11 for X-ray crystallographic
analysis). In order to circumvent the formation of such undesired
byproducts, a variety of Lewis and Brønsted acids were screened
(TFA, HCl, MeOSO2H, H2SO4, heat, TsOH, BF3 ·Et2O, AcOH,
Tf2NH, Dy(OTf)3, PPTS, AlCl3, FeCl3, silicotungstic acid, PtCl2,
zeolite NaY, RuCl3/AgOTf, Cu(OTf)2, Pd(OAc)2, Co(acac)2/
PhSiH3), many of which did not catalyze the cyclization and
none of which provided either any improvement in the yield or
reduction in the quantity of byproducts. Attempted cyclizations
of the amine or alcohol derivatives of 45 were equally
unsuccessful. Finally, it was found that Montmorillonite K-10
acidic clay, with microwave irradiation, provided the desired
product (44) without formation of the undesired byproducts,
although recycling of unreacted starting material was required.
It was assumed, based on the reactivity observed for 43, that
reductive amination of the ketone 44 would provide amine 60
directly. However, reductive amination under the previously
employed conditions (see Scheme 7)58 provided amine 70 (see
Scheme 13) as a single diastereomer, which was epimeric at
C(11) (as was required for 10). This unexpected complete
inversion in diastereoselectivity seems to be solely due to the
presence of the C(13) chlorine atom. A more circuitous route
was therefore required to access the desired amine (60),
necessitating reduction to the alcohol, mesylation, azidation, and
reduction (Scheme 10), similar to the sequence developed by
Fukuyama and co-workers for hapalindole G.7 Formylation59
of the amine (60) followed by dehydration with Burgess
reagent60 provided ent-12-epi-fischerindole G (10),16 which was
spectroscopically identical to the natural material with the
exception of optical rotation. Thus, in principle, the naturally
After several other failed attempts to generate the desired
chloroketone 46, a successful route was finally developed,
inspired by a reaction developed in the Wender laboratory.54
In Wender’s study, R,ꢀ-epoxyketones were first treated with
strong base to form the corresponding enolate. Nucleophilic
addition of an organometallic reagent (usually Grignard re-
agents) to this epoxyenolate at the R-carbon (as opposed to the
usual ꢀ-attack) formed the corresponding R-alkyl-ꢀ-hydroxy-
ketone, and subsequent elimination of the hydroxyl group
furnished the R-substituted enone. However, a quaternary carbon
installation during the course of this reaction was unprecedented.
Despite this potential limitation, the reaction was attempted on
carvone oxide to provide 59 in about 30% yield (Scheme 10).
Extensive optimization efforts (solvent, nucleophile, base,
additives, temperature, addition rates) did not result in significant
improvement in the overall efficiency of the reaction. The low
yield is likely due to the sterically hindered nature at the
R-position of the R,ꢀ-epoxyketone, causing SN2′ attack (58, red
arrow) to be favored over the desired SN2 attack (58, blue
arrow).55 Nevertheless, with alcohol 59 readily available, the
chlorination was accomplished (NCS/PPh3) in acceptable yield
to provide the key chloroketone (46).56 Despite the modest
overall yield of this two-step sequence, it can be used to rapidly
prepare multigram quantities of 46 and was therefore deemed
as an acceptable solution to this problem, especially given the
difficulties in preparing 46 Via other routes (Vide supra). It is
noteworthy that 59 was the only neopentyl alcohol that could
be successfully chlorinated during the course of these studies.
It is also interesting that varying amounts of the diastereomer
(at C(13)) are generated, although these chlorination conditions
often proceed with complete inversion of stereochemistry.
Perhaps this alcohol is more accessible to electrophiles due to
a slight bond-lengthening effect (i.e., retro-aldol ability), thus
mitigating the neopentyl hindrance and allowing epimerization
to a minor extent.
With 46 in hand, the stage was finally set to invoke the direct
indole coupling reaction, which proceeded smoothly to provide
the coupled product (45) in 62% yield as a single diastereomer
(verified by X-ray crystallographic analysis). Several aspects
(53) Corey, E. J.; Melvin, L. S., Jr.; Haslanger, M. F. Tetrahedron Lett.
1975, 16, 3117–3120.
(54) Wender, P. A.; Erhardt, J. M.; Letendre, L. J. J. Am. Chem. Soc. 1981,
103, 2114–2116.
(57) In fact, the reactivity of 47 and downstream intermediates differed
significantly from that observed with the 12-epi-fischerindole U series.
(58) Attempts to utilize microwave irradiation to promote this reaction led
to dechlorination of the compound and were therefore not amenable
for this series of chlorinated natural products.
(59) De Luca, L.; Giacomelli, G.; Porcheddu, A.; Salaris, M. Synlett 2004,
14, 2570–2572.
(55) This alternate reaction pathway was also noted in Wender’s studies.
(56) Alternative chlorination conditions were attempted (SOCl2/base, PPh3/
CCl4, PPh3/ZnCl2/DEAD, MsCl/Pyr., PPh3/Cl2, DMAP/CS(imid)2,
(COCl)2, TCT, TMSCl/BiCl3) but were unsuccessful at providing the
desired product, and retro-aldol product was observed on at least one
occasion.
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Redox Economic Synthesis of the Hapalindole Family
A R T I C L E S
Scheme 10. Total Synthesis of ent-12-epi-Fischerindole Ga
a Reagents and conditions: (a) LHMDS (1.2 equiv), THF, -78 °C, 30 min; then H2CdCHMgBr, -15 °C, 15 min, 30%; (b) PPh3 (1.0 equiv), NCS (1.0
equiv), THF, 18 h, 55%; (c) indole (2.0 equiv), LHMDS (3.2 equiv), THF, -78 °C, 30 min; then copper(II) 2-ethylhexanoate (1.5 equiv), -78 to 23 °C, 20
min, 62%; (d) Montmorillonite K-10 (10 wt equiv), DME, microwave, 120 °C, 6 min, 26% isolated, 40% isolated after one recycling, 57% brsm; (e) NaBH4
(1.5 equiv), MeOH, 0 °C, 5 min, 100%; (f) Ms2O (2.0 equiv), Pyr., 23 °C, 30 min, 69%; (g) LiN3 (3.0 equiv), DMF, 120 °C, 48 h, 58%; (h) Na(Hg) (10
equiv), EtOH, reflux, 4 h, 66%; (i) HCO2H (1.3 equiv), CDMT (1.4 equiv), DMAP (0.03 equiv), NMM (1.4 equiv), DCM, 23 °C, 30 min, 87%; (j) Burgess
reagent (2.0 equiv), PhH, 23 °C, 30 min, 82%. LHMDS, lithium hexamethyldisilazide; THF, tetrahydrofuran; NCS, N-chlorosuccinimide; DME,
dimethoxyethane; Pyr., pyridine; DMF, dimethylformamide; EtOH, ethanol; CDMT, 2-chloro-4,6-dimethoxy-1,3,5-triazine; DMAP, 4-(dimethylamino)pyridine;
NMM, N-methylmorpholine; DCM, dichloromethane; DMT-MM, 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride; PhH, benzene.
Scheme 11. Formation of the Acid-Catalyzed Cyclization Byproducts
Scheme 12. Attempted Conversion of ent-12-epi-Fischerindole G
(10) into ent-12-epi-Fischerindole I (21)
occurring enantiomer of 10 could be prepared from (S)-carvone
oxide (Vide infra).61
Total Synthesis of Fischerindole I
With reasonable quantities of 10 available, the oxidation to
form 12-epi-fischerindole I (21) could be investigated. Treatment
of 10 with a variety of oxidants (e.g., DDQ, MnO2, p-chloranil,
t-BuOCl) failed to produce any 21 (Scheme 12). Reasoning that
the isonitrile could preferentially react with these oxidants, the
formamide derivative (68) was subjected to various oxidants,62
but this also failed to form any of the desired product. Putative
formation of stable 3-chloro- or 3-hydroxyindolenines was the
was ineffective for the preparation of 10, it was hoped that this
intermediate would allow the desired oxidation to proceed
through subtle stereoelectronic differences. Amine 70 was
formylated in quantitative yield to give 71, which was then
subjected to various oxidation conditions.64 Remarkably, 21 was
produced in 46% overall yield when formamide 71 was treated
only reactivity observed with either 10 or 68, but these could
not be utilized to install the required element of unsaturation.
Turning to the amine diastereomer 70 (Scheme 13),63 which
(60) Creedon, S. M.; Crowley, H. K.; McCarthy, D. G. J. Chem. Soc.,
Perkin Trans. 1 1998, 1015–1017.
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A R T I C L E S
Richter et al.
Scheme 13. Original and Improved Total Synthesis of 12-epi-Fischerindole I (21)a
a Reagents and conditions: (a) NH4OAc (40 equiv), NaCNBH3 (7.5 equiv), 3 Å molecular sieves, MeOH, THF, sonication, 18 h, 42%; (b) HCO2H (2.0
equiv), CDMT (2.2 equiv), DMAP (0.1 equiv), NMM (2.2 equiv), DCM, 23 °C, 30 min, 100%; (c) THF, TEA (1.0 equiv), t-BuOCl (1.5 equiv), 0 °C, 10
min, then SiO2/TEA (PTLC); then CDCl3, then Burgess reagent (2.0 equiv), PhH, 23 °C, 30 min, 46% overall; (d) TEA (17.5 equiv), DCM, COCl2 (2.0
equiv), 0 °C, 10 min, 95%; (e) DDQ (2.5 equiv), H2O, THF, 0 °C, 30 min, 92%. THF, tetrahydrofuran; CDMT, 2-chloro-4,6-dimethoxy-1,3,5-triazine;
DMAP, 4-(dimethylamino)pyridine; NMM, N-methylmorpholine; DCM, dichloromethane; DMT-MM, 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmor-
pholinium chloride; TEA, triethylamine; PTLC, preparative thin-layer chromatography; PhH, benzene; DDQ, 2,3-dichloro-5,6-dicyanobenzoquinone.
first with t-BuOCl and triethylamine and subsequently with
Burgess reagent. Although the intermediates in this reaction are
unstable and difficult to purify, it is reasonable to assume that
the reaction proceeds Via the intermediates delineated in Scheme
13. Initial chlorination of the indole leads to chloroindolenine
72, which undergoes elimination to generate methylene indo-
lenine 73. This intermediate can tautomerize to 12-epi-fischer-
indole I formamide (69), which is unstable and immediately
dehydrates upon exposure to Burgess reagent to provide 21.16
Methylene indolenine 73 can alternatively be hydrated (presum-
ably on silica gel) at the imine carbon. Reprotonation of the
Figure 1. Calculated stability of the 12-epi-fischerindole I penultimate
intermediate.
olefin from the ꢀ-face and attack by water at C(3), Via the
due to a severe steric interaction between the formamide N-H
intermediacy of an azaorthoquinodimethane intermediate, pro-
and the C(4)-H of the indole ring, leading to an approximate
vides the major side product (74, confirmed by X-ray crystal-
lographic analysis). It is to be noted that the presence of the
25 kcal/mol calculated destabilization compared to its olefin-
translocated isomer (76).65 Therefore, an alternate sequence was
epimerized C(10) center provides evidence for the existence of
sought to accomplish this transformation while bypassing these
73 en route to 21.
difficulties. It was subsequently discovered that initial dehydra-
tion of formamide 71 (Scheme 13) provided isonitrile 75, which
Although this sequence provided the first synthetic sample
of 21, it was plagued with numerous problems, specifically low
is epimeric at C(11) to 12-epi-fischerindole G (10), in 95% yield.
Treatment of this compound with DDQ,66 in contrast to the
overall yields, difficult and unscalable synthetic procedures, the
formation of byproducts, and the intermediacy of several
DDQ reaction for 10, provided 12-epi-fischerindole I (21) in
unstable intermediates. It was reasoned that the low overall
92% yield, allowing access to large quantities of this natural
product in short order.14 Based on these results, although it is
efficiency of this route likely stemmed from two controlling
factors. First, t-BuOCl is not commonly employed as an oxidant
quite possible that 10 could be enzymatically promoted to 21,
for benzylic oxidations. Perhaps an oxidant more chemoselective
it is equally possible that 75 (not yet isolated as a natural
product), rather than 10, could be the actual biosynthetic
for such transformations would provide a higher yield of the
desired product. Second, the penultimate intermediate (69,
precursor to 21.
Figure 1) in this sequence is an extremely unstable compound
Total Synthesis of Welwitindolinone A
(61) Until this point, for initial studies into the synthesis of these natural
With 12-epi-fischerindole I (21) in hand, it was finally
products, (R)-carvone oxide was used because of its significantly lower
possible to investigate the conversion of this natural product
into welwitindolinone A (12). Although the proposed conversion
of 21 to 12 might appear intuitive, practical difficulties were
cost.
(62) The same oxidants were utilized as for 10, as well as DMDO and
DMP.
(63) From this point on, (S)-carvone oxide was utilized to allow access to
the correct enantiomer of the natural product.
(64) It was assumed that the isonitrile might react disastrously with various
oxidants; therefore, the formamide was utilized in these trials.
(65) As determined by AM1 calculations.
(66) Oikawa, Y.; Yonemitsu, O. J. Org. Chem. 1977, 42, 1213–1216.
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Redox Economic Synthesis of the Hapalindole Family
A R T I C L E S
Scheme 14. Model System for the Total Synthesis of
Welwitindolinone A (12)a
Scheme 15. Original and Improved Total Syntheses of
Welwitindolinone A (12)a
a Reagents and conditions: (a) THF, TEA (1.0 equiv), t-BuOCl (1.7
equiv), 0 °C, 10 min; then 40:20:1 MeOH:H2O:AcOH, 5 min. THF,
tetrahydrofuran; TEA, triethylamine.
expected due to the sensitivity of both alkaloids to acidic media
and the sheer ring strain of the resulting product. Such concerns
were intensified by the knowledge that oxidative ring contrac-
tions to generate five- and six-membered rings typically require
elevated temperatures, and hence, forming a strained four-
membered ring should be even more difficult.37 Before using
valuable material to probe this transformation, a model system
was sought on which to test this ring contraction. To our delight,
treatment of cyclized ketone 44 with t-BuOCl and then dilute
AcOH furnished two major products: the oxidized compound
77 and ring-contracted compound 78 in ∼20% unoptimized
yield each (Scheme 14). Given the aforementioned consider-
ations, it is remarkable that this reaction occurs at low
temperature and within minutes. Although ketone 78 represents
a potentially viable intermediate to complete the synthesis of
12,67 attention was returned to 21 in the hope that it could be
directly converted into 12, thus lending credence to the proposed
biosynthetic hypothesis (Vide supra).
a Reagents and conditions: (a) THF, TEA (1.0 equiv), t-BuOCl (1.5
equiv), -30 °C, 1 min; then 95:4:1 THF:H2O:TFA, -30 to 0 °C, 5 min,
25%; (b) XeF2 (1.0 equiv), H2O, MeCN, 23 °C, 5 min, 44%. THF,
tetrahydrofuran; TEA, triethylamine; TFA, trifluoroacetic acid; MeCN,
acetonitrile.
Chart 6. 3-epi-Welwitindolinone A
Extensive experimentation led to conditions by which 21
could be converted directly into 12. 12-epi-Fischerindole I (21)
was exposed to t-BuOCl and triethylamine in THF at -30 °C
for 1 min, and the solvent was rapidly removed (Scheme 15).
The crude residue was then dissolved in a THF:H2O:TFA
mixture (95:4:1) and warmed to 0 °C. Strict adherence to this
protocol resulted in the first total synthesis of 12 in 25% yield,16
along with minor amounts of its C(3) epimer (see Chart 6). This
transformation most likely proceeds through initial chlorination
of the indole to provide 79, followed by attack of water to give
80. Elimination of the chloride to generate azaorthoquin-
odimethane 81, followed by [1,5]-sigmatropic rearrangement,
would then install the spirocyclobutane of 12. Although 12 was
accessible Via this procedure, there were several problems with
this route, most notably the low yield and the exclusive
formation of the C(3) diastereomer upon scale-up. Seeking to
circumvent these obstacles, it was determined that the chief
difficulty arose from the isonitrile moiety, which has been shown
to be unstable to electrophilic chlorinating reagents in this
laboratory.14 It was reasoned that a hitherto-unknown fluoro-
hydroxylation of indole rather than chlorohydroxylation should
suppress isonitrile-derived byproduct formation, owing to the
increased hardness of fluorine over chlorine. Therefore, a milder
method to accomplish this transformation was developed, in
which 21 was treated with a solution of XeF2 in wet acetonitrile
to provide 12 in 44% yield, Via the intermediacy of 82.14 This
reaction was routinely performed on more than 50 mg of 21,
and more than 580 mg of 12 has been prepared to date. A screen
of various halogenating reagents confirmed that XeF2 was the
most efficient at promoting this reaction (Table 2). The
chemoselectivity of this reagent is also noteworthy, given the
presence of an olefin, which is known to react with XeF2,68
and the reactive isonitrile moiety.
(67) The Wood group recently reported that their attempts to convert 10-
epi-78 into 12 were unsuccessful, utilizing a variety of conditions (see
ref 17b).
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A R T I C L E S
Richter et al.
Scheme 16. Synthesis of Isothiocyanate Derivativesa
indolinone A (12) upon exposure to TFDO69 (Scheme 17).
However, this particular analogue exhibited greater instability
than the isonitrile and isothiocyanate derivatives, and dimerized
to the urea dimer 87 upon storage in air at room temperature.
Despite this reactivity, it is conceivable that such intermediates
might be useful for the preparation of further members of the
welwitindolinone alkaloid family.
Oxidation Attempts toward Welwitindolinone B
In order to test the biosynthetic hypothesis delineated in
Scheme 2, and in an attempt to generate the welwitindolinone
B core structure, welwitindolinone A (12) was subjected to a
variety of epoxidation and general oxidation conditions. With
the exception of TFDO that generated the corresponding
isocyanate 86 (Vide supra), all attempted conditions led to either
recovered starting material or decomposition (see Supporting
Information for a list of failed conditions). Consequently, three-
step alternatives were envisioned, with the hope that the
electronics of the tetrasubstituted olefin would be modified in a
subtle fashion so as to permit oxidative rearrangement (see
Scheme 18). Although not ideal, transformation of the isonitrile
moiety into a gem-dibromide (such as 88) or a formamide (such
as 90), oxidative rearrangement into the corresponding welwit-
indolinone B framework (89 or 91, respectively), followed by
restoration of the original isonitrile group, could enable the
formation of “welwitindolinone B isonitrile” (14a). With this
strategy in mind, gem-dibromide 88 and formamide 90 were
prepared from welwitindolinone A using phenyltrimethyl-
ammonium tribromide and formic acid, respectively, both in
quantitative yields; functional group restoration to the original
isonitrile 12 was also verified by using triethyl phosphite and
phosgene, respectively. Unfortunately, all oxidation conditions
experimented upon 88 or 90 resulted in either recovered starting
material, welwitindolinone A (only when using 88), or decom-
position (see Supporting Information). Since some welwitin-
dolinones are methylated at the indole nitrogen atom (see Chart
1), N(1)-methylformamide 92 was prepared from 12 in an
attempt to alter reactivity, but this substrate also failed to
undergo oxidative rearrangement (see Supporting Information).
These preliminary results do not necessarily contradict the
biosynthetic hypothesis toward welwitindolinone B put forth
in Scheme 2; perhaps the oxidation requisite for this transforma-
tion is enzymatically controlled.
a Reagents and conditions: (a) DCM, CS(imid)2 (3.3 equiv), 23 °C, 24 h,
60%; (b) THF, H2O, DDQ (2.5 equiv), 0 °C, 30 min, 68%; (c) DCM, XeF2
(1.0 equiv), 23 °C, 15 min, 27%. DCM, dichloromethane; THF, tetra-
hydrofuran; DDQ, 2,3-dichloro-5,6-dicyanobenzoquinone.
Scheme 17. Synthesis and Degradation of 86a
Strategy Analysis and Conclusions
a Reagents and conditions: (a) DCM, TFDO (1.0 equiv), -78 °C, 5 min,
100%; (b) air, 23 °C, 6 d. DCM, dichloromethane; TFDO, methyl(trifluoro-
methyl)dioxirane.
Due to their stunning molecular architectures and potent
bioactivities, the hapalindoles, fischerindoles, and welwitindoli-
nones were targeted for total synthesis, with the goals of
inventing useful chemistry, discovering basic reactivity, under-
standing their biosynthesis, and allowing access to large
quantities of these rare marine natural products. It is instructive
to evaluate these syntheses from the vantage points of chemose-
lectivity, stereocontrol, and “redox economy”.
Numerous steps throughout this synthesis exhibited high
levels of chemoselectivity, despite the presence of other reactive
functionality. For example, the conversion of 46 to 45 proceeds
in good yield in the presence of a chlorine atom that could
potentially be eliminated under the reaction conditions. The vast
majority of conditions screened for the cyclization of 45 to 44
formed numerous byproducts (including 65, 66, and 67);
In addition to 21 and 12 (Vide infra), the isothiocyanate
analogues can be readily synthesized Via the sequence described
herein (Scheme 16). Treatment of amine 70 with CS(imid)2
provides isothiocyanate 83, which can be oxidized to the 12-
epi-fischerindole I analogue 84 (colorless cubes, mp 202 °C
decomposition, see Scheme 16 for X-ray crystallographic
analysis) in 76% yield. Treatment of 84 with XeF2 provides
the isothiocyanate analogue of welwitindolinone A (85) in an
unoptimized 27% yield. Furthermore, the isocyanate analogue
of welwitindolinone A (86) is directly available from welwit-
(68) Shellhamer, D. F.; Carter, D. L.; Chiaco, M. C.; Harris, T. E.;
Henderson, R. D.; Low, W. S. C.; Metcalf, B. T.; Willis, M. C.;
Heasley, V. L.; Chapman, R. D. J. Chem. Soc., Perkin Trans. 2 1991,
401–403.
(69) Mello, R.; Fiorentino, M.; Fusco, C.; Curci, R. J. Am. Chem. Soc.
1989, 111, 6749–6757.
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Redox Economic Synthesis of the Hapalindole Family
A R T I C L E S
Scheme 18. Oxidative Rearrangement Attemptsa
a Reagents and conditions: (a) PTAT (1 equiv), DCM, -78 °C, 3 min, 100%; (b) P(OEt)3, DCM, 23 °C, 3 min, 100%; (c) HCO2H, H2O, THF, 4 °C, 12 h,
100%; (d) TEA, COCl2, DCM, 0° C, 10 min, 82%; (e) MeI, K2CO3, acetone, 23 °C, 12 h, 100%; (f) HCO2H, H2O, THF, 4 °C, 12 h, 100%, PTAT,
phenyltrimethylammonium tribromide; DCM, dichloromethane; THF, tetrahydrofuran; TEA, triethylamine.
Table 2. Ring Contraction Optimization
potentially have been employed to circumvent undesirable
reactivity. In fact, rather than resorting to protecting group
chemistry, the innate reactivities of the functional groups were
employed, which led to the invention of new chemistry (direct
indole coupling, extremely mild fluorohydroxylative ring-
contraction using XeF2, installation of the key quaternary
stereocenter and neopentyl chlorine atom) or discovery of
intriguing reactivity (49 to 50, 45 to 65, 66, and 67, 71 to 21
and 74, 75 to 21, 44 to 78, and 21 to 12).
oxidant
yield (%)
High levels of stereochemical induction are observed through-
out the synthesis. For example, the direct indole coupling
reaction (31 and 45) provides a single diastereomer of coupled
product, and the reductive alkylation of 31 to provide 41 gives
only a single diastereomer. The reductive aminations proceed
in moderate (41 to 27, which could be increased with the use
of microwave irradiation) to complete diastereoselectivity (43
to 29 and 44 to 70). Furthermore, by utilizing XeF2, complete
diastereomeric induction is observed in the conversion of 21 to
12, even though the facial bias for this transformation is
minimal.
t-BuOCl
NBS
Synfluor
Selectfluor
BMAST
NFSI
0-25
0
0
0
0
16
44
XeF2
however, the use of Montmorillonite K-10 acidic clay com-
pletely avoided such chemical entities. The conversion of 75
into 21 proceeds in excellent yield, despite the ease with which
isonitriles can be oxidized, and the conversion of 21 to 12
proceeds in good yield, even though isonitriles have been
observed to react with halogenating reagents.14 Functional group
manipulations were minimized, and the percentage of C-C
bond-forming reactions was maximized. It is difficult to imagine
how any steps could be “removed” from these syntheses, since
all are necessary for the installation of requisite C-C bonds,
functional groups, or key stereocenters. Furthermore, no protect-
ing groups are utilized throughout the course of this entire
synthesis, despite numerous opportunities in which they could
Finally, the syntheses are characterized by an adherence to
the concept of “redox economy”. Analogous to “atom
economy” 70 or “step economy”,71 “redox economy” 72 mini-
mizes superfluous redox manipulations within a synthesis; rather,
(70) Trost, B. M. Science 1991, 254, 1471–1477.
(71) Wender, P. A.; Miller, B. L. In Organic Synthesis: Theory and
Applications; Hudlicky, T., Ed.; JAI Press: Greenwich, CT, 1993, Vol.
2.
(72) For illuminating discussions of oxidation state control in synthesis,
see: (a) Evans, D. A.; Andrews, G. C. Acc. Chem. Res. 1974, 7, 147–
155. (b) Hendrickson, J. B. J. Am. Chem. Soc. 1975, 97, 5784–5800.
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A R T I C L E S
Richter et al.
predoctoral fellowships (J.M.R.), The Scripps Research Institute
for a predoctoral fellowship (Y.I.), Daiichi-Sankyo Co. for a
postdoctoral fellowship (T.M.), Helsinki University of Technology
for a predoctoral fellowship (A.P.), and Universidad Auto´noma de
Madrid for a predoctoral fellowship (T.L.). Financial support for
this work was provided by The Scripps Research Institute, Amgen,
AstraZeneca, the Beckman Foundation, Bristol-Myers Squibb,
DuPont, Eli Lilly, GlaxoSmithKline, Pfizer, Roche, the Searle
Scholarship Fund, the Sloan Foundation, and the NIH (NIGMS).
the oxidation state of intermediates linearly and steadily
increases throughout the course of the synthesis. Only one
reduction step (reductive amination) is utilized during these
syntheses, which is strategically placed to install a key stereo-
center. In fact, the flexible adherence of these syntheses to the
proposed biogenesis of these alkaloids reinforces the minimiza-
tion of redox reactions, as is commonly observed in Nature’s
biosynthesis of terpenes and alkaloids. Such considerations
allowed the efficient, practical, and concise syntheses of
numerous members of this natural product family (10, 12, 21,
27, 29, and 42). Overall, this total synthesis program is
characterized by inventive retrosynthetic disconnections, which
rapidly assemble the skeletal structure and allow for rapid
increase in complexity. These studies are yet another example
of how natural products can catalyze new discoveries in
chemical reactivity.
Note Added after ASAP Publication. Due to a production error
the graphics for Schemes 4, 10, 11, 13, 14, and 16 were incomplete.
These errors have been corrected for the versions posted on
December 3, 2008, and in print.
Supporting Information Available: Full characterization,
including 1H and 13C NMR spectra, and experimental procedures
for selected compounds; X-ray crystallographic data, in CIF
format, for 31, 35, 45, 67, 74, 78, and 84. This material is
available free of charge Via the Internet at http://pubs.acs.org.
Acknowledgment. We thank Dr. D. H. Huang and Dr. L.
Pasternack for NMR spectroscopic assistance, Dr. G. Siuzdak for
mass spectrometric assistance, and Dr. A. Rheingold and Dr. R.
Chadha for X-ray crystallographic assistance. We are grateful to
the National Science Foundation and Bristol-Myers Squibb for
JA806981K
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17954 J. AM. CHEM. SOC. VOL. 130, NO. 52, 2008