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,
Tomás 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
welwitindolinones,2f and ambiguines,2d,k and antibacterial activ-
were isolated from the Stigonemataceae family of cyanobacteria
ity from the hapalindoles2m,4 and ambiguines.2k Additionally,
in 1984 by Moore and colleagues.1 In the 24 years since their
it has been found that hapalindolinone A inhibits arginine
initial discovery, 63 members2 have been added to this family
vasopression binding.2b Finally, potent anticancer activity against
of alkaloids, which include the hapalindoles, fischerindoles,
multiple drug-resistant ovarian cancer cell lines has been
welwitindolinones, ambiguines, hapalindolinones, hapaloxin-
reported for the welwitindolinones,2f,5 which apparently exert
doles, and fontonamides (see Chart 1). These natural products
this effect through microtubule depletion.6
have been isolated from soil samples in a myriad of habitats
Not only do a vast number of the members of this natural
around the globe,3 and a broad range of biological activities
product family exhibit potent and exciting biological activities,
arises from the different structural classes. Insecticidal activity
but they also all contain intriguing and unprecedented molecular
is observed for several hapalindoles2l and welwitindolinones.2f
architectures. Though distinct, they are united by several
structural features, most notably an indole (or indole-derived)
(1) Moore, R. E.; Cheuk, C.; Patterson, G. M. L. J. Am. Chem. Soc. 1984, heterocycle with a monoterpene unit appended at C(3) (see
106, 6456–6457.
(2) (a) Moore, R. E.; Cheuk, C.; Yang, X.-Q. G.; Patterson, G. M. L.; Scheme 1 for numbering), comprising the core of these
Bonjouklian, R.; Smitka, T. A.; Mynderse, J. S.; Foster, R. S.; Jones, molecules. All but a handful of them contain an isonitrile or an
N. D.; Swartzendruber, J. K.; Deeter, J. B. J. Org. Chem. 1987, 52, isothiocyanate at C(11), with an all-carbon quaternary center,
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) comprised of a methyl and vinyl group, vicinal to this moiety
Moore, R. E.; Yang, X.-Q. G.; Patterson, G. M. L. J. Org. Chem. (C(12)). The hapalindoles are the simplest members of this
1987, 52, 3773–3777. (d) Smitka, T. A.; Bonjouklian, R.; Doolin, L.; family, containing the core structure described above, housed
Jones, N. D.; Deeter, J. B.; Yoshida, W. Y.; Prinsep, M. R.; Moore, within a tricyclic framework. Many contain further function-
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, alization, in the form of either unsaturation (at C(10)) or
3257–3260. (f) Stratmann, K.; Moore, R. E.; Bonjouklian, R.; Deeter, chlorination (at C(13)), and several contain an additional
J. B.; Patterson, G. M. L.; Shaffer, S.; Smith, C. D.; Smitka, T. A. carbocycle arising from the union of C(4) of indole with the
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, isopropylidene unit at C(15). The fischerindoles, tetracycles
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, (3) These locations include the Marshall Islands (ref 1), the Everglades
L.; Demoulin, V. J. Nat. Prod. 1995, 58, 1781–1785. (j) Moore, R. E.; in Florida (ref 2b), Australia (ref 2f), Micronesia (ref 2h), Papua New
Yang, X.-Q. G.; Patterson, G. M. L.; Bonjouklian, R.; Smitka, T. A. Guinea (ref 2i), and Israel (ref 2k).
Phytochemistry 1989, 28, 1565–1567. (k) Raveh, A.; Carmeli, S. J. (4) (a) Doan, N. T.; Rickards, R. W.; Rothschild, J. M.; Smith, G. D.
Nat. Prod. 2007, 70, 196–201. (l) Becher, P. G.; Keller, S.; Jung, G.; J. Appl. Phycol. 2000, 12, 409–416. (b) Doan, N. T.; Stewart, P. R.;
Süssmuth, R. D.; Jüttner, F. Phytochemistry 2007, 68, 2493–2497. Smith, G. D. FEMS Microbiol. Lett. 2001, 196, 135–139.
(m) Asthana, R. K.; Srivastava, A.; Singh, A. P.; Deepali; Singh, S. P.; (5) Smith, C. D.; Zilfou, J. T.; Stratmann, K.; Patterson, G. M. L.; Moore,
Nath, G.; Srivastava, R.; Srivastava, B. S. J. Appl. Phycol. 2006, 18, R. E. Mol. Pharmacol. 1995, 47, 241–247.
33–39. (6) Zhang, X.; Smith, C. D. Mol. Pharmacol. 1996, 49, 288–294.

17938 9 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 ARTICLES

Chart 1. All Known Hapalindole-Type Natural Products

J. AM. CHEM. SOC. 9 VOL. 130, NO. 52, 2008 17939

ARTICLES 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 of indole, specifically a tert-prenyl moiety. In the most complex
unit at C(15), are also characterized by varying degrees of ambiguines, this tert-prenyl group is further cyclized and
functionalization and oxidation. The hapaloxindoles and fon- oxidized. In addition to the unifying structural features of this
tonamides are structurally related to the tetracyclic hapalindoles, family of natural products, the hapalindolinones contain a unique
although the indole has been either oxidized to give the oxindole component within their molecular architecture, specifically a
or oxidatively cleaved to form the formylkynurenine. Also spirocyclic cyclopropane that joins C(11) with C(3) of the
related to the hapalindoles, albeit much more complex, are the oxindole heterocycle. Finally, the welwitindolinones are found
ambiguines, which contain additional functionalization at C(2) in one of two structural classes, the first being welwitindolinone
17940 J. AM. CHEM. SOC. 9 VOL. 130, NO. 52, 2008
Redox Economic Synthesis of the Hapalindole Family ARTICLES

A, which contains a spirocyclic cyclobutane centered around inability of chemists to attain the chemo-, regio-, and stereo-
C(3). The remaining welwitindolinones are comprised of a control characterizing most enzymatic processes. The careful
[4.3.1]bicyclononanone core, which contains an assortment of practitioner can make use of many abiotic tools in solving these
oxidative functionalization. problems; however, these methods usually demand significant
With a family of such diverse and unique molecular archi- departure from the ideal biomimetic route. In light of these
tectures, it should come as no surprise that several syntheses difficulties, it is certainly possible, and perhaps prudent, to find
have been reported for these natural products, specifically an appropriate balance when designing a retrosynthesis. An ideal
focusing on the simpler members of the family. Syntheses have synthesis might entail the use of powerful synthetic methods,
been reported for hapalindoles G,7 H,8 J,9 M,9 Q,10 O,11 and coupled with a flexible adherence to the general synthetic
U,8 in addition to approaches to various other hapalindoles.12 blueprint provided by Nature.
There are no reported efforts toward the hapalindolinones, Given these considerations, and with such a large and diverse
hapaloxindoles and fontonamides, and only one approach toward family of complex natural products, a biosynthetic proposal that
an ambiguine.13 The first total synthesis of an ambiguine comprehensively describes the interrelationships between the
(ambiguine H) was reported from our laboratory.14 Despite the members would undoubtedly be enlightening to any synthetic
many approaches toward the welwitindolinones,15 at the time undertaking. The Moore group, in conjunction with their elegant
of our initial communication16 of the work presented herein, isolation studies, put forth many plausible biosynthetic rumina-
the members of the welwitindolinone family had not yet tions that are summarized in Scheme 1. Moore’s biosynthesis
succumbed to synthesis; however, the Wood group reported a begins with the tryptophan derivative (1a) and terpene (1b),
very elegant synthesis of welwitindolinone A shortly thereafter.17 which are enzymatically joined Via chloronium-promoted poly-
olefin cyclization to provide the tricyclic hapalindole core (i.e.,
Biosynthetic Relationships and Retrosynthetic 12-epi-hapalindole E (2), Scheme 1). At this point, Moore and
Analysis co-workers proposed that the tricycle can proceed through
multiple divergent pathways, the first of which (path A)
Biomimetic syntheses are often more efficient due to the commences with a cyclization between C(4) of indole and the
tactics that Nature employs, namely rapid assembly of skeletal isopropylidene unit at C(15), leading to the tetracyclic hapal-
complexity, a linear increase of oxidation state, use of mild and indoles (i.e., 12-epi-hapalindole G (3)). These natural products
simple reagents, and the ability to control chemoselectivity (lack can then undergo further oxidation at the indole moiety, leading
of protecting groups).18 Despite their inherent advantages, to the oxindole (i.e., anhydrohapaloxindole A (4)), which can
biomimetic syntheses can be exceedingly difficult, due to the be oxidatively cleaved to give the formylkynurenine (i.e.,
hapalonamide V (5)). Alternatively, the tetracyclic hapalindoles
(7) Fukuyama, T.; Chen, X. J. Am. Chem. Soc. 1994, 116, 3125–3126. can have a tert-prenyl moiety attached to C(2) (i.e., ambiguine
(8) Muratake, H.; Kumagami, H.; Natsume, M. Tetrahedron 1990, 46, A (6)), which can be engaged in an intramolecular cyclization,
6351–6360.
(9) (a) Muratake, H.; Natsume, M. Tetrahedron Lett. 1989, 30, 1815– leading to the pentacyclic ambiguines (i.e., ambiguine E (7)).
1818. (b) Muratake, H.; Natsume, M. Tetrahedron 1990, 46, 6331– These alkaloids can then be further oxidized (i.e., ambiguine D
6342. (c) Muratake, H.; Natsume, M. Tetrahedron 1990, 46, 6343– (8)) or rearranged (i.e., ambiguine G (9)). Furthermore (path
6350.
(10) (a) Baran, P. S.; Richter, J. M. J. Am. Chem. Soc. 2004, 126, 7450–
B), the tricyclic hapalindoles can undergo cyclization between
7451. (b) Vaillancourt, V.; Albizati, K. F. J. Am. Chem. Soc. 1993, C(2) and the isopropylidene at C(15), providing the fischerin-
115, 3499–3502. (c) Kinsman, A. C.; Kerr, M. A. Org. Lett. 2001, 3, doles (i.e., 12-epi-fischerindole G (10)). Finally, Moore and co-
3189–3191. (d) Kinsman, A. C.; Kerr, M. A. J. Am. Chem. Soc. 2003, workers proposed that the tricyclic hapalindoles can be oxidized
125, 14120–14125.
(11) Sakagami, M.; Muratake, H.; Natsume, M. Chem. Pharm. Bull. 1994, to give the putative intermediate 11, which has not been isolated
42, 1393–1398. as a natural product (path C). They further proposed that this
(12) (a) Kinsman, A. C.; Kerr, M. A. Org. Lett. 2000, 2, 3517–3520. (b) intermediate undergoes an acid-catalyzed cyclization to afford
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, welwitindolinone A (12), presumably in the pocket of an
8, 4959–4961. enzyme. If 12 could be further oxidized, leading to the
(13) Chandra, A.; Viswanathan, R.; Johnston, J. N. Org. Lett. 2007, 9, 5027– intermediate epoxide 13, the [4.3.1]bicyclononane system could
5029. be formed after rearrangement (i.e., “welwitindolinone B
(14) Baran, P. S.; Maimone, T. J.; Richter, J. M. Nature 2007, 446, 404–
408. isonitrile” (14a), which is likely to be a natural product that
(15) (a) Wood, J. L.; Holubec, A. A.; Stoltz, B. M.; Weiss, M. M.; Dixon, has yet to be isolated). Moore and co-workers suggested that
J. A.; Doan, B. D.; Shamji, M. F.; Chen, J. M.; Heffron, T. P. J. Am. methylation and oxidation of 14a could lead to N-methylwel-
Chem. Soc. 1999, 121, 6326–6327. (b) Deng, H.; Konopelski, J. P.
Org. Lett. 2001, 3, 3001–3004. (c) Jung, M. E.; Slowinski, F. witindolinone C (15) and further demonstrated the conversion
Tetrahedron Lett. 2001, 42, 6835–6838. (d) López-Alvarado, P.; of 15 into 3-hydroxy-N-methylwelwitindolinone C (17) and
Garcı́a-Granda, S.; Álvarez-Rúa, C.; Avendaño, C. Eur. J. Org. Chem. N-methylwelwitindolinone D (19).
2002, 1702–1707. (e) Avendaño, C.; Menéndez, J. C. Curr. Org. Synth.
2004, 1, 65–82. (f) Ready, J. M.; Reisman, S. E.; Hirata, M.; Weiss,
While the Moore biosynthetic hypothesis provides an ad-
M. M.; Tamaki, K.; Ovaska, T. V.; Wood, J. L. Angew. Chem., Int. equate explanation of the possible relationships between many
Ed. 2004, 43, 1270–1272. (g) MacKay, J. A.; Bishop, R. L.; Rawal, of the distinct structural classes, a few points remained uncertain,
V. H. Org. Lett. 2005, 7, 3421–3424. (h) Baudoux, J.; Blake, A. J.; primarily relating to the formation of the welwitindolinones.
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. First, the proposal that 12 arises from the unsaturated intermedi-
Org. Lett. 2006, 8, 5287–5289. ate 11 Via an acid-catalyzed cyclization seems unlikely. The
(16) Baran, P. S.; Richter, J. M. J. Am. Chem. Soc. 2005, 127, 15394– fact that 63 members of this natural product family have been
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.; (18) See the following texts, and references therein: (a) Nicolaou, K. C.;
Ready, J. M.; Weiss, M. M.; Hasuoka, A.; Hirata, M.; Tamaki, K.; Sorensen, E. J. Classics in Total Synthesis; Wiley-VCH: Weinheim,
Ovaska, T. V.; Smith, C. J.; Wood, J. L. J. Am. Chem. Soc. 2008, 1996. (b) Nicolaou, K. C.; Snyder, S. A. Classics in Total Synthesis
130, 2087–2100. II; Wiley-VCH: Weinheim, 2003.
J. AM. CHEM. SOC. 9 VOL. 130, NO. 52, 2008 17941
ARTICLES Richter et al.

Scheme 2. Alternative Biosynthetic Proposal

isolated, while 11 has not been one of them, casts doubt on it is more reasonable to invoke electron donation from the N(1)
whether this compound is a plausible intermediate. Given the lone pair through the aromatic ring to break the cyclobutane,
stability that 11 should demonstrate, at least trace quantities of leading to the R-isocyanoketone enolate (22). This enolate could
this compound would be expected in the isolation broths. More then attack the highly unstable, extremely electrophilic aza-
importantly, there seems to be little thermodynamic driving force orthoquinodimethane generated in the reaction, leading to 14a
for the conversion of 11 into 12, due to the generation of a after tautomerization.21 Additionally, the remote oxidation of
strained spirocyclobutane in this transformation. Second, the 14a to N-methylwelwitindolinone C (15), although perhaps
mechanistic explanation for the conversion of welwitindolinone possible with enzymatic intervention, is unlikely. Rather, if 21
A (12) into “welwitindolinone B isonitrile” (14a) lacks proper were to undergo allylic oxidation, intermediate 23 could be
literature precedence. Third, the proposal that N-methylwelwit- accessed. Upon oxidative ring contraction, similar to that
indolinone C (15) arises from remote oxidation of 14a could proposed for 12, the direct product would contain an unstable
conceivably be explained by an alternate hypothesis. Finally, cyclobutane with vicinal exocyclic olefins. The trisubstituted
the isolation literature lacks a biosynthetic hypothesis to account olefin might then isomerize to form the vinyl chloride (24), thus
for the genesis of the hapalindolinones. alleviating this additional strain on the cyclobutane. Oxidative
Given the concerns delineated above, an alternative biosyn- ring expansion of 24 and methylation of the indole nitrogen
thetic hypothesis is proposed in Scheme 2. Rather than arising atom could then lead directly to 15. Finally, we propose that
from hypothetical metabolite 11, welwitindolinone A (12) could the hapalindolinones could arise from an oxidative coupling
arise from an oxidative ring contraction of 12-epi-fischerindole event between the C(3) and C(11) carbons of an appropriate
I (21); the latter could be formed Via a benzylic oxidation of tricyclic hapalindole (i.e., 12-epi-hapalindole Q (25)), generating
12-epi-fischerindole G (10), which could in turn arise from the the oxindole with the spirocyclopropane moiety (i.e., hapalin-
tricyclic hapalindole 12-epi-hapalindole E (2). Furthermore, an dolinone B (26)).
alternative, albeit untested, mechanistic hypothesis for the With a compelling biosynthetic hypothesis in hand, attention
conversion of 12 into “welwitindolinone B isonitrile” (14a) is could be turned toward designing a synthesis of welwitindoli-
put forth that is more in line with literature precedence. none A (12). However, before such a task was undertaken, it
Isonitriles are relatively electron-withdrawing, inductively sta- seemed prudent to first consider a synthesis of simpler members
bilizing negative charges, and have not been invoked as electron- of the family, such as hapalindole Q (27) and 12-epi-fischer-
donating entities.19 It is therefore unlikely that the isonitrile indole U (29). It was envisioned that such efforts would reveal
would participate in a fracture of the epoxide Via electron hidden clues into the fundamental reactivity of these alkaloids
donation that would lead to a fissure of the cyclobutane ring.
Alternatively, based on evidence gleaned in this laboratory,20 (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.
17942 J. AM. CHEM. SOC. 9 VOL. 130, NO. 52, 2008
Redox Economic Synthesis of the Hapalindole Family ARTICLES

Scheme 3. Retrosynthetic Analysis of Hapalindole Q (27) and (33) in excellent yield. Unfortunately, reduction of this inter-
12-epi-Fischerindole U (29) 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
and that they would help develop a general route by which to account of the oxidative indole coupling reaction developed in
access the core structure. Hapalindole Q (27) had been our laboratory,29 and therefore this information will not be
synthesized previously by the Albizati (8 steps, 8.2% overall reviewed here. Even though a myriad of literature procedures
yield)10b and Kerr (12 steps, 1.7% overall yield)10c,d groups, concerning oxidative enolate couplings was available, many
but the synthesis of 29 had not been reported prior to our initial potential drawbacks, could be encountered while pursuing this
communication of this work.10a Since a route to 12 was the route. By the inception of this work, only one example of an
ultimate goal, a more efficient route to the core (i.e., 27 and oxindole oxidative dimerization had been reported.30a Addition-
29) of this alkaloid was required (Scheme 3). Although a ally, in order to achieve high yields of heterodimerized products
cyclization of 27 could certainly be investigated to form 29,
this transformation was instead planned at the ketone stage (28), (22) (a) Kovács-Kulyassa, Á.; Herczegh, P.; Sztaricskai, F. Tetrahedron
given the acid-sensitivity of the isothiocyanate group. As such, 1997, 53, 13883–13896. (b) Barton, D. H. R.; Crich, D. J. Chem. Soc.,
both natural products could be traced back to their respective Chem. Commun. 1984, 774–775.
(23) (a) Nicolaou, K. C.; Vassilikogiannakis, G.; Kranich, R.; Baran, P. S.;
ketone analogues 28 and 30, the latter of which should be Zhong, Y.-L.; Natarajan, S. Org. Lett. 2000, 2, 1895–1898. (b) Barton,
accessible from the former Via an acid-catalyzed cyclization. D. H. R.; McCombie, S. W. J. Chem. Soc., Perkin Trans. 1 1975,
Ketone 28 can be further simplified to the indole/carvone adduct 1574–1585.
31 through straightforward functional group transformations. (24) The retro-aldol reaction was the major competing pathway.
(25) Martin, J. C.; Arhart, R. J. J. Am. Chem. Soc. 1971, 93, 4327–4329.
At this stage, a strictly biomimetic synthesis would require a (26) Burgess, E. M.; Penton, H. R., Jr.; Taylor, E. A. J. Org. Chem. 1973,
chloronium-promoted polyolefin cyclization to install the terpene 38, 26–31.
moiety; however, a potentially more direct and powerfully (27) Nicolaou, K. C.; Hao, J.; Reddy, M. V.; Rao, P. B.; Rassias, G.; Snyder,
S. A.; Huang, X.; Chen, D. Y.-K.; Brenzovich, W. E.; Giuseppone,
simplifying transformation would involve direct formation of N.; Giannakakou, P.; O’Brate, A. J. Am. Chem. Soc. 2004, 126, 12897–
the key C(3)-C(10) bond. 12906.
(28) (a) Weinberg, N. L.; Weinberg, H. R. Chem. ReV. 1968, 68, 449–
Total Synthesis of Hapalindole Q 523. (b) Kauffmann, T. Angew. Chem., Int. Ed. 1974, 13, 291–305.
(c) Csákÿ, A. G.; Plumet, J. Chem. Soc. ReV. 2001, 30, 313–320. (d)
Several strategies were investigated for the synthesis of the Baran, P. S.; Ambhaikar, N. A.; Guerrero, C. A.; Hafensteiner, B. D.;
Lin, D. W.; Richter, J. M. ARKIVOC 2006, Vii, 310–325.
requisite indole/carvone adduct (31) before a method was finally (29) Richter, J. M.; Whitefield, B. W.; Maimone, T. J.; Lin, D. W.;
developed to successfully provide the desired material. Initially, Castroviejo, M. P.; Baran, P. S. J. Am. Chem. Soc. 2007, 129, 12857–
it was reasoned that 31 could be accessed from an aldol reaction 12869.
with subsequent reduction to form the requisite indole moiety (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.
(Scheme 4). Indeed, quenching the enolate of carvone with Chem. Soc. 1975, 97, 2912–2914. (c) Ito, Y.; Konoike, T.; Harada,
MOM-protected isatin (32) provided the desired aldol product T.; Saegusa, T. J. Am. Chem. Soc. 1977, 99, 1487–1493.
J. AM. CHEM. SOC. 9 VOL. 130, NO. 52, 2008 17943
ARTICLES 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 10
Cu(2-ethylhexanoate)2 15
FeCl3 ∼15
Fe(PhCOCHCOCH3)3 30
Fe(CH3COCHCOCF3)3 40
Fe(C10H7COCHCOCF3)3 40
Fe(CH3COCHCOCH3)3 45
a
Reagents and conditions: (a) carvone (1.0 equiv), 39 (1.0 equiv), LDA Fe(t-BuCOCHCOCH3)3 83
(2.1 equiv), THF, -78 °C, 30 min; then oxidant (2.0 equiv), 23 °C, 20
a
min. LDA, lithium diisopropylamide; THF, tetrahydrofuran; [O], oxidation. LDA, lithium diisopropylamide; [O], oxidation.

Specifically, Fe(t-BuCOCHCOCH3)3 was exceptionally efficient,

in an oxidative enolate coupling, 3 equiv or more of one
providing an 83% isolated yield of the desired product (as a
coupling partner was usually required.30b,c Finally, few inves-
tigations into the factors that govern the heterodimerization event 1:1 mixture of diastereomers at C(3)), utilizing equimolar
had been performed; thus, it was unknown whether any of the quantities of both coupling partners! These results have led to
desired heterocoupled product would be obtained. Despite such the hypothesis that careful tuning of the oxidant’s oxidation
potential drawbacks, an examination of the oxidative oxindole potential to more closely match one of the coupling partners
coupling was undertaken, which would at least provide further could lead to selective heterodimerizations.32 With high-yielding
insight into the elements that govern such transformations. access to intermediate 40, efforts were turned toward the
As a starting point for the examination of this heterocoupling reduction of oxindole 40 to indole 37 (Scheme 5). Once again,
reaction, treatment of carvone and MOM-protected oxindole the reduction proved recalcitrant, necessitating yet another
(39)31 with FeCl3 in DMF provided the desired product (40) in reevaluation of the synthetic strategy.
ca. 15% yield. Given the success of this coupling, an optimiza- As with the aldol route, an alternative to the oxindole coupling
tion of this particular reaction was undertaken, centering was sought: one that would avoid a problematic reduction step.
primarily on oxidant selection (Table 1). Hypervalent iodine As such, the most straightforward method by which to circum-
and cupric-based oxidants were less efficient at promoting the vent this difficulty would be to directly attach the indole to the
coupling than the ferric-based systems, so the focus of further carvone moiety. Unfortunately, no such method had been
studies was narrowed. Success was finally realized when reported, requiring the invention of chemistry to fill this gap.
acetylacetonate-type ligands were utilized on the iron center. Inspired by the oxidative coupling literature, in conjunction with
Barton’s classic synthesis of usnic acid,33the oxidative indole
(31) Wang, J.-J.; Hu, W.-P. J. Org. Chem. 1999, 64, 5725–5727. coupling was conceived. In this reaction,10a,29 an indole can be
17944 J. AM. CHEM. SOC. 9 VOL. 130, NO. 52, 2008
Redox Economic Synthesis of the Hapalindole Family ARTICLES

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 With gram quantities of 31 in hand, attention was turned to
Isothiocyanate (29)a
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
a
absolute stereochemistry of the fischerindole-type natural prod-
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-
ucts (i.e., opposite to that depicted in Scheme 7). The syntheses
anoate (1.5 equiv), -78 to 23 °C, 15 min, 49-53%; (b) LHMDS (1.5 equiv), of 27, 42, and 29 proceeded enantiospecifically in 15%, 4.8%,
THF, -78 °C, 20 min; then L-Selectride (1.05 equiv), 1 h, then CH3CHO and 9.8% overall yields, respectively, without resorting to
(6.0 equiv), -78 to 23 °C, 2 h; (c) Martin sulfurane (1.1 equiv), CHCl3, 10 protecting groups or superfluous redox manipulations.10a
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 Retrosynthetic Analysis of Welwitindolinone A
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), Having demonstrated that the direct indole coupling could
NH4OAc (40 equiv), MeOH, THF, 23 °C, 7 d, 55%. LHMDS, lithium
enable rapid access to several of the simpler members of the
hexamethyldisilazide; THF, tetrahydrofuran; TMSOTf, trimethylsilyl tri-
fluoromethanesulfonate; DCM, dichloromethane. 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
directly attached to a variety of carbonyl compounds in good unique molecular architecture. It contains three all-carbon
yields (Scheme 6). The method was found to generate the quaternary centers, two of which are chiral, and an asymmetri-
desired indole/carvone adduct (31, colorless cubes, mp 129-130 cally disposed neopentyl chlorine atom, all incorporated into a
°C, structure verified by X-ray crystallographic analysis) in good highly strained spirocyclobutane-containing oxindole. As already
yield and in one synthetic operation from commodity starting discussed (Vide supra), the revised biosynthetic hypothesis
materials (Scheme 7); this has also been extended to the coupling proposes that 12-epi-fischerindole I (21) is converted into 12
of unfunctionalized pyrroles.34 Via oxidative ring contraction.37 Such ring contractions are
primarily utilized for the preparation of spirocyclic five-
(32) (a) Baran, P. S.; DeMartino, M. P. Angew. Chem., Int. Ed. 2006, 45, membered rings from annulated six-membered rings and often
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, (35) Fortunato, J. M.; Ganem, B. J. Org. Chem. 1976, 41, 2194–2200.
530–534. (36) Prolonged exposure to triflic acid led to product decomposition;
(34) Baran, P. S.; Richter, J. M.; Lin, D. W. Angew. Chem., Int. Ed. 2005, therefore, the reaction was quenched early and the starting material
44, 609–612. was recycled.
J. AM. CHEM. SOC. 9 VOL. 130, NO. 52, 2008 17945
ARTICLES 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
Scheme 8. Retrosynthetic Analysis of Welwitindolinone A (12) the preparation of 46.

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.,
require relatively harsh reaction conditions to proceed.38 Only NCS, Raney Ni/CCl4, SO2Cl2, CCl4/hν, Cl3CCOCCl3). Chlori-
one example has been reported for the direct preparation of a nation with concomitant removal of the thiol under numerous
spirocyclic four-membered ring from an annulated five- conditions (e.g., PIFA/LiCl, LiNaphthalenide/TsCl, TiCl4/CCl4,
membered ring;39 however, a related conversion has been MeI/NaCl44) was also investigated, but to no avail. Routes in
observed in this laboratory to generate a strained -lactam (see which the ketone was first converted into the chloride, followed
Chart 3).20 Furthermore, it is conceivable that 21 could arise by sulfide oxidation, were also considered. Direct reductive
from 12-epi-fischerindole G (10) Via benzylic oxidation (Scheme chlorination of the ketone,45 instead of providing the desired
8). Through straightforward functional group manipulations, 10 product, led to the unexpected bicycle 50. Attempts to generate
could be derived from the tetracyclic ketone 44, which in turn the vinyl chloride Via POCl3, which could potentially be
could arise from an acid-catalyzed cyclization of tricyclic ketone carefully hydrogenated to the alkyl chloride, were also fruitless.
45. Exploiting the direct coupling methodology developed for Unable to perform a direct reductive chlorination of the
the synthesis of 27, 45 could be obtained from the coupling of carbonyl, 49 was first reduced to the neopentyl alcohol (51)
indole with 46. Chloroketone 46 was a new chemical entity; and then unsuccessfully subjected to a variety of chlorination
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. (41) Li, G.; Gao, J.; Wei, H. -X.; Enright, M. Org. Lett. 2000, 2, 617–620.
(38) (a) Dhanak, D.; Neidle, S.; Reese, C. B. Tetrahedron Lett. 1985, 26, (42) Carlsen, P. H. J.; Katsuki, T.; Martin, V. S.; Sharpless, K. B. J. Org.
2017–2020. (b) Lee, B. H.; Clothier, M. F.; Johnson, S. S. Bioorg. Chem. 1981, 46, 3936–3938.
Med. Chem. Lett. 2001, 11, 553–554. (c) Williams, R. M.; Cao, J.; (43) Lee, C. A.; Floreancig, P. E. Tetrahedron Lett. 2004, 45, 7193–7196.
Tsujishima, H.; Cox, R. J. J. Am. Chem. Soc. 2003, 125, 12172–12178. (44) Corey, E. J.; Jautelat, M. Tetrahedron Lett. 1968, 9, 5787–5788.
(39) Wenkert, E.; Moeller, P. D. R.; Piettre, S. R.; McPhail, A. T. J. Org. (45) Onishi, Y.; Ogawa, D.; Yasuda, M.; Baba, A. J. Am. Chem. Soc. 2002,
Chem. 1987, 52, 3404–3409. 124, 13690–13691.
17946 J. AM. CHEM. SOC. 9 VOL. 130, NO. 52, 2008
Redox Economic Synthesis of the Hapalindole Family ARTICLES

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 were less conformationally constrained, a nucleophile might
chlorinations failed presumably due to the extremely hindered favor equatorial approach, especially if the R-carbon could
nature of this particular alcohol. Before further effort was synergistically shield the R-face. As such, chlorohydrin 55 met
expended on this chlorination, the Pummerer rearrangement of these criteria and was prepared from carvone oxide in good
thioether 49 was investigated to determine its feasibility in this yield. Unfortunately, 55 was unstable, even upon storage in an
system, which revealed that the reaction was not possible under inert atmosphere, and failed to provide any desired product when
a variety of conditions (IBX,48 m-CPBA,49 H2O2,50 tBuOOH, treated with a variety of nucleophiles. Attempts were also made
PhI(OAc)2). to trap the alcohol with an appropriate leaving group (mesyl or
Repeated failure to convert carvone into the desired chlo- tosyl groups) before addition of the nucleophile, but to no avail.
roketone Via any sort of vicinal difunctionalization necessitated
Investigations subsequently turned toward sequences that
yet another strategic reevaluation. Therefore, carvone oxide (53)
would install the quaternary stereocenter and perform the
was examined as a starting material for the production of
chloroketone 46. It was reasoned that vinylmagnesium bromide chlorination in separate operations. Initial attempts to install the
addition into the carbonyl group of the R,-epoxyketone, vinyl group Via dissolving metal-promoted reductive alkylation
followed by a semipinacol rearrangement, could allow instal- of the epoxide52 to give 54 proved fruitless, as any electrophile
lation of the quaternary stereocenter, contingent upon -face that could be subsequently converted into the vinyl group (e.g.,
attack of the organometallic reagent. Unfortunately, such TBSOCH2CH2I, oxirane) failed to participate in the reaction.
conformationally constrained systems are known to favor axial Alternatively, reduction of the carbonyl group to the known
(i.e., R-face) attack of nucleophiles,51 thus sterically precluding carveol oxide allowed investigations into the direct chlorination
a successful semipinacol rearrangement. However, if the ring of this alcohol, which would be followed by installation of the
quaternary stereocenter and regeneration of the ketone. Unfor-
(46) Haufe, G.; Wolf, A.; Schulze, K. Tetrahedron 1986, 42, 4719–4728. tunately, such chlorinations were unsuccessful due to the
(47) De Luca, L.; Giacomelli, G.; Porcheddu, A. Org. Lett. 2002, 4, 553– instability of the resulting epoxyalcohol. In an alternative
555.
(48) Nicolaou, K. C.; Mathison, C. J. N.; Montagnon, T. J. Am. Chem.
strategy, enol acetate 56 was prepared from carvone oxide in
Soc. 2004, 126, 5192–5201. order to test an intramolecular enolate addition into the epoxide,
(49) Iwama, T.; Matsumoto, H.; Shimizu, H.; Kataoka, T.; Muraoka, O.; but this also proved to be fruitless. Condensation with hydroxyl-
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.
amine provided oxime 57, which was seemingly poised to
(51) (a) Chérest, M.; Felkin, H. Tetrahedron Lett. 1968, 9, 2205–2208. (b) undergo an R-substitution reaction, as was reported by Corey
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. (52) Caine, D.; McCloskey, C. J.; Van Derveer, D. J. Org. Chem. 1985,
1999, 99, 1377–1386. 50, 175–179.
J. AM. CHEM. SOC. 9 VOL. 130, NO. 52, 2008 17947
ARTICLES 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
and co-workers.53 Reaction of the oxime with 2 equiv of a chlorine atom. Finally, this effective method for direct C-C
cuprate reagent would first deprotonate the oxime, which could bond formation enables all the necessary carbon atoms of these
then open the epoxide and lead to the corresponding vinylnitroso complex natural products to be secured in only three steps and
compound (see Chart 5). The second equivalent of cuprate was routinely carried out on multigram scale. Functional group
reagent could then participate in a 1,4-addition into the manipulations are all that remained to complete the synthesis
vinylnitroso group, thereby installing the quaternary center. of 12.
Unfortunately, divinylcuprate was unsuccessful at accomplishing Conditions (i.e., TfOH) previously applied to the conversion
this transformation. of 41 to 43 unfortunately provided significant quantities of
After several other failed attempts to generate the desired several byproducts in the attempted conversion of 45 to 44,57
chloroketone 46, a successful route was finally developed, including 65, 66, and 67 (Scheme 11). In this particular
inspired by a reaction developed in the Wender laboratory.54 cyclization reaction, two modes of activation are feasible at the
In Wender’s study, R,-epoxyketones were first treated with gem-disubstituted olefin. This olefin can be protonated to give
strong base to form the corresponding enolate. Nucleophilic the tertiary carbocation, which is intercepted by the indole ring
addition of an organometallic reagent (usually Grignard re- to give intermediate 61, which in turn leads to the desired
agents) to this epoxyenolate at the R-carbon (as opposed to the product (44). Alternatively, protonation to give the primary
usual -attack) formed the corresponding R-alkyl--hydroxy- carbocation, which is also intercepted by the indole ring, leads
ketone, and subsequent elimination of the hydroxyl group to intermediate 62. A [1,5]-sigmatropic shift generates 63, which
furnished the R-substituted enone. However, a quaternary carbon can then rearrange to carbocation 64. The three possible modes
installation during the course of this reaction was unprecedented. of elimination to quench this carbocation provide the three
Despite this potential limitation, the reaction was attempted on observed products (65, 66, and 67; 67 as clear cubes, mp
carvone oxide to provide 59 in about 30% yield (Scheme 10). 128-129 °C, see Scheme 11 for X-ray crystallographic
Extensive optimization efforts (solvent, nucleophile, base, analysis). In order to circumvent the formation of such undesired
additives, temperature, addition rates) did not result in significant byproducts, a variety of Lewis and Brønsted acids were screened
improvement in the overall efficiency of the reaction. The low (TFA, HCl, MeOSO2H, H2SO4, heat, TsOH, BF3 · Et2O, AcOH,
yield is likely due to the sterically hindered nature at the Tf2NH, Dy(OTf)3, PPTS, AlCl3, FeCl3, silicotungstic acid, PtCl2,
R-position of the R,-epoxyketone, causing SN2′ attack (58, red zeolite NaY, RuCl3/AgOTf, Cu(OTf)2, Pd(OAc)2, Co(acac)2/
arrow) to be favored over the desired SN2 attack (58, blue PhSiH3), many of which did not catalyze the cyclization and
arrow).55 Nevertheless, with alcohol 59 readily available, the none of which provided either any improvement in the yield or
chlorination was accomplished (NCS/PPh3) in acceptable yield reduction in the quantity of byproducts. Attempted cyclizations
to provide the key chloroketone (46).56 Despite the modest of the amine or alcohol derivatives of 45 were equally
overall yield of this two-step sequence, it can be used to rapidly unsuccessful. Finally, it was found that Montmorillonite K-10
prepare multigram quantities of 46 and was therefore deemed acidic clay, with microwave irradiation, provided the desired
as an acceptable solution to this problem, especially given the product (44) without formation of the undesired byproducts,
difficulties in preparing 46 Via other routes (Vide supra). It is although recycling of unreacted starting material was required.
noteworthy that 59 was the only neopentyl alcohol that could It was assumed, based on the reactivity observed for 43, that
be successfully chlorinated during the course of these studies. reductive amination of the ketone 44 would provide amine 60
It is also interesting that varying amounts of the diastereomer directly. However, reductive amination under the previously
(at C(13)) are generated, although these chlorination conditions employed conditions (see Scheme 7)58 provided amine 70 (see
often proceed with complete inversion of stereochemistry. Scheme 13) as a single diastereomer, which was epimeric at
Perhaps this alcohol is more accessible to electrophiles due to C(11) (as was required for 10). This unexpected complete
a slight bond-lengthening effect (i.e., retro-aldol ability), thus inversion in diastereoselectivity seems to be solely due to the
mitigating the neopentyl hindrance and allowing epimerization presence of the C(13) chlorine atom. A more circuitous route
to a minor extent. was therefore required to access the desired amine (60),
With 46 in hand, the stage was finally set to invoke the direct necessitating reduction to the alcohol, mesylation, azidation, and
indole coupling reaction, which proceeded smoothly to provide reduction (Scheme 10), similar to the sequence developed by
the coupled product (45) in 62% yield as a single diastereomer Fukuyama and co-workers for hapalindole G.7 Formylation59
(verified by X-ray crystallographic analysis). Several aspects 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
(53) Corey, E. J.; Melvin, L. S., Jr.; Haslanger, M. F. Tetrahedron Lett.
1975, 16, 3117–3120. exception of optical rotation. Thus, in principle, the naturally
(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
(55) This alternate reaction pathway was also noted in Wender’s studies. significantly from that observed with the 12-epi-fischerindole U series.
(56) Alternative chlorination conditions were attempted (SOCl2/base, PPh3/ (58) Attempts to utilize microwave irradiation to promote this reaction led
CCl4, PPh3/ZnCl2/DEAD, MsCl/Pyr., PPh3/Cl2, DMAP/CS(imid)2, to dechlorination of the compound and were therefore not amenable
(COCl)2, TCT, TMSCl/BiCl3) but were unsuccessful at providing the for this series of chlorinated natural products.
desired product, and retro-aldol product was observed on at least one (59) De Luca, L.; Giacomelli, G.; Porcheddu, A.; Salaris, M. Synlett 2004,
occasion. 14, 2570–2572.
17948 J. AM. CHEM. SOC. 9 VOL. 130, NO. 52, 2008
Redox Economic Synthesis of the Hapalindole Family ARTICLES

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

occurring enantiomer of 10 could be prepared from (S)-carvone (10) into ent-12-epi-Fischerindole I (21)
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
only reactivity observed with either 10 or 68, but these could was ineffective for the preparation of 10, it was hoped that this
not be utilized to install the required element of unsaturation. intermediate would allow the desired oxidation to proceed
Turning to the amine diastereomer 70 (Scheme 13),63 which through subtle stereoelectronic differences. Amine 70 was
formylated in quantitative yield to give 71, which was then
(60) Creedon, S. M.; Crowley, H. K.; McCarthy, D. G. J. Chem. Soc., subjected to various oxidation conditions.64 Remarkably, 21 was
Perkin Trans. 1 1998, 1015–1017. produced in 46% overall yield when formamide 71 was treated
J. AM. CHEM. SOC. 9 VOL. 130, NO. 52, 2008 17949
ARTICLES 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
Figure 1. Calculated stability of the 12-epi-fischerindole I penultimate
Methylene indolenine 73 can alternatively be hydrated (presum- intermediate.
ably on silica gel) at the imine carbon. Reprotonation of the
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- 25 kcal/mol calculated destabilization compared to its olefin-
lographic analysis). It is to be noted that the presence of the 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-
Although this sequence provided the first synthetic sample tion of formamide 71 (Scheme 13) provided isonitrile 75, which
of 21, it was plagued with numerous problems, specifically low is epimeric at C(11) to 12-epi-fischerindole G (10), in 95% yield.
overall yields, difficult and unscalable synthetic procedures, the Treatment of this compound with DDQ,66 in contrast to 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
efficiency of this route likely stemmed from two controlling product in short order.14 Based on these results, although it is
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
for such transformations would provide a higher yield of the product), rather than 10, could be the actual biosynthetic
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
cost. possible to investigate the conversion of this natural product
(62) The same oxidants were utilized as for 10, as well as DMDO and into welwitindolinone A (12). Although the proposed conversion
DMP. of 21 to 12 might appear intuitive, practical difficulties were
(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 (65) As determined by AM1 calculations.
oxidants; therefore, the formamide was utilized in these trials. (66) Oikawa, Y.; Yonemitsu, O. J. Org. Chem. 1977, 42, 1213–1216.
17950 J. AM. CHEM. SOC. 9 VOL. 130, NO. 52, 2008
Redox Economic Synthesis of the Hapalindole Family ARTICLES

Scheme 14. Model System for the Total Synthesis of Scheme 15. Original and Improved Total Syntheses of
Welwitindolinone A (12)a 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 a
Reagents and conditions: (a) THF, TEA (1.0 equiv), t-BuOCl (1.5
yield each (Scheme 14). Given the aforementioned consider- equiv), -30 °C, 1 min; then 95:4:1 THF:H2O:TFA, -30 to 0 °C, 5 min,
ations, it is remarkable that this reaction occurs at low 25%; (b) XeF2 (1.0 equiv), H2O, MeCN, 23 °C, 5 min, 44%. THF,
temperature and within minutes. Although ketone 78 represents tetrahydrofuran; TEA, triethylamine; TFA, trifluoroacetic acid; MeCN,
acetonitrile.
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 Chart 6. 3-epi-Welwitindolinone A
biosynthetic hypothesis (Vide supra).
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 laboratory.14 It was reasoned that a hitherto-unknown fluoro-
transformation most likely proceeds through initial chlorination hydroxylation of indole rather than chlorohydroxylation should
of the indole to provide 79, followed by attack of water to give suppress isonitrile-derived byproduct formation, owing to the
80. Elimination of the chloride to generate azaorthoquin-
increased hardness of fluorine over chlorine. Therefore, a milder
odimethane 81, followed by [1,5]-sigmatropic rearrangement,
would then install the spirocyclobutane of 12. Although 12 was method to accomplish this transformation was developed, in
accessible Via this procedure, there were several problems with which 21 was treated with a solution of XeF2 in wet acetonitrile
this route, most notably the low yield and the exclusive to provide 12 in 44% yield, Via the intermediacy of 82.14 This
formation of the C(3) diastereomer upon scale-up. Seeking to reaction was routinely performed on more than 50 mg of 21,
circumvent these obstacles, it was determined that the chief and more than 580 mg of 12 has been prepared to date. A screen
difficulty arose from the isonitrile moiety, which has been shown of various halogenating reagents confirmed that XeF2 was the
to be unstable to electrophilic chlorinating reagents in this most efficient at promoting this reaction (Table 2). The
chemoselectivity of this reagent is also noteworthy, given the
(67) The Wood group recently reported that their attempts to convert 10- presence of an olefin, which is known to react with XeF2,68
epi-78 into 12 were unsuccessful, utilizing a variety of conditions (see
ref 17b). and the reactive isonitrile moiety.

J. AM. CHEM. SOC. 9 VOL. 130, NO. 52, 2008 17951

ARTICLES 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
a
Reagents and conditions: (a) DCM, CS(imid)2 (3.3 equiv), 23 °C, 24 h, as 90), oxidative rearrangement into the corresponding welwit-
60%; (b) THF, H2O, DDQ (2.5 equiv), 0 °C, 30 min, 68%; (c) DCM, XeF2 indolinone B framework (89 or 91, respectively), followed by
(1.0 equiv), 23 °C, 15 min, 27%. DCM, dichloromethane; THF, tetra- restoration of the original isonitrile group, could enable the
hydrofuran; DDQ, 2,3-dichloro-5,6-dicyanobenzoquinone. formation of “welwitindolinone B isonitrile” (14a). With this
strategy in mind, gem-dibromide 88 and formamide 90 were
Scheme 17. Synthesis and Degradation of 86a 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.

Strategy Analysis and Conclusions

a
Reagents and conditions: (a) DCM, TFDO (1.0 equiv), -78 °C, 5 min, Due to their stunning molecular architectures and potent
100%; (b) air, 23 °C, 6 d. DCM, dichloromethane; TFDO, methyl(trifluoro-
methyl)dioxirane. bioactivities, the hapalindoles, fischerindoles, and welwitindoli-
nones were targeted for total synthesis, with the goals of
inventing useful chemistry, discovering basic reactivity, under-
In addition to 21 and 12 (Vide infra), the isothiocyanate
standing their biosynthesis, and allowing access to large
analogues can be readily synthesized Via the sequence described
quantities of these rare marine natural products. It is instructive
herein (Scheme 16). Treatment of amine 70 with CS(imid)2
to evaluate these syntheses from the vantage points of chemose-
provides isothiocyanate 83, which can be oxidized to the 12-
lectivity, stereocontrol, and “redox economy”.
epi-fischerindole I analogue 84 (colorless cubes, mp 202 °C
Numerous steps throughout this synthesis exhibited high
decomposition, see Scheme 16 for X-ray crystallographic
levels of chemoselectivity, despite the presence of other reactive
analysis) in 76% yield. Treatment of 84 with XeF2 provides
functionality. For example, the conversion of 46 to 45 proceeds
the isothiocyanate analogue of welwitindolinone A (85) in an
in good yield in the presence of a chlorine atom that could
unoptimized 27% yield. Furthermore, the isocyanate analogue
potentially be eliminated under the reaction conditions. The vast
of welwitindolinone A (86) is directly available from welwit-
majority of conditions screened for the cyclization of 45 to 44
formed numerous byproducts (including 65, 66, and 67);
(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, (69) Mello, R.; Fiorentino, M.; Fusco, C.; Curci, R. J. Am. Chem. Soc.
401–403. 1989, 111, 6749–6757.
17952 J. AM. CHEM. SOC. 9 VOL. 130, NO. 52, 2008
Redox Economic Synthesis of the Hapalindole Family ARTICLES

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-
t-BuOCl 0-25 out the synthesis. For example, the direct indole coupling
NBS 0 reaction (31 and 45) provides a single diastereomer of coupled
Synfluor 0 product, and the reductive alkylation of 31 to provide 41 gives
Selectfluor 0
BMAST 0
only a single diastereomer. The reductive aminations proceed
NFSI 16 in moderate (41 to 27, which could be increased with the use
XeF2 44 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
however, the use of Montmorillonite K-10 acidic clay com- 12, even though the facial bias for this transformation is
pletely avoided such chemical entities. The conversion of 75 minimal.
into 21 proceeds in excellent yield, despite the ease with which Finally, the syntheses are characterized by an adherence to
isonitriles can be oxidized, and the conversion of 21 to 12 the concept of “redox economy”. Analogous to “atom
proceeds in good yield, even though isonitriles have been economy” 70 or “step economy”,71 “redox economy” 72 mini-
observed to react with halogenating reagents.14 Functional group mizes superfluous redox manipulations within a synthesis; rather,
manipulations were minimized, and the percentage of C-C
bond-forming reactions was maximized. It is difficult to imagine (70) Trost, B. M. Science 1991, 254, 1471–1477.
how any steps could be “removed” from these syntheses, since (71) Wender, P. A.; Miller, B. L. In Organic Synthesis: Theory and
all are necessary for the installation of requisite C-C bonds, Applications; Hudlicky, T., Ed.; JAI Press: Greenwich, CT, 1993, Vol.
functional groups, or key stereocenters. Furthermore, no protect- 2.
(72) For illuminating discussions of oxidation state control in synthesis,
ing groups are utilized throughout the course of this entire see: (a) Evans, D. A.; Andrews, G. C. Acc. Chem. Res. 1974, 7, 147–
synthesis, despite numerous opportunities in which they could 155. (b) Hendrickson, J. B. J. Am. Chem. Soc. 1975, 97, 5784–5800.
J. AM. CHEM. SOC. 9 VOL. 130, NO. 52, 2008 17953
ARTICLES Richter et al.

the oxidation state of intermediates linearly and steadily predoctoral fellowships (J.M.R.), The Scripps Research Institute
increases throughout the course of the synthesis. Only one for a predoctoral fellowship (Y.I.), Daiichi-Sankyo Co. for a
reduction step (reductive amination) is utilized during these postdoctoral fellowship (T.M.), Helsinki University of Technology
syntheses, which is strategically placed to install a key stereo- for a predoctoral fellowship (A.P.), and Universidad Autónoma de
center. In fact, the flexible adherence of these syntheses to the Madrid for a predoctoral fellowship (T.L.). Financial support for
proposed biogenesis of these alkaloids reinforces the minimiza- this work was provided by The Scripps Research Institute, Amgen,
tion of redox reactions, as is commonly observed in Nature’s AstraZeneca, the Beckman Foundation, Bristol-Myers Squibb,
biosynthesis of terpenes and alkaloids. Such considerations DuPont, Eli Lilly, GlaxoSmithKline, Pfizer, Roche, the Searle
allowed the efficient, practical, and concise syntheses of Scholarship Fund, the Sloan Foundation, and the NIH (NIGMS).
numerous members of this natural product family (10, 12, 21,
27, 29, and 42). Overall, this total synthesis program is Note Added after ASAP Publication. Due to a production error
characterized by inventive retrosynthetic disconnections, which the graphics for Schemes 4, 10, 11, 13, 14, and 16 were incomplete.
rapidly assemble the skeletal structure and allow for rapid These errors have been corrected for the versions posted on
increase in complexity. These studies are yet another example December 3, 2008, and in print.
of how natural products can catalyze new discoveries in
chemical reactivity. Supporting Information Available: Full characterization,
including 1H and 13C NMR spectra, and experimental procedures
Acknowledgment. We thank Dr. D. H. Huang and Dr. L. for selected compounds; X-ray crystallographic data, in CIF
Pasternack for NMR spectroscopic assistance, Dr. G. Siuzdak for format, for 31, 35, 45, 67, 74, 78, and 84. This material is
mass spectrometric assistance, and Dr. A. Rheingold and Dr. R.
available free of charge Via the Internet at http://pubs.acs.org.
Chadha for X-ray crystallographic assistance. We are grateful to
the National Science Foundation and Bristol-Myers Squibb for JA806981K

17954 J. AM. CHEM. SOC. 9 VOL. 130, NO. 52, 2008