Scalable total syntheses of (-)-hapalindole U and (+)-ambiguine H

Article abstract of DOI:10.1016/j.tet.2014.11.010

The Stigonemataceae family of cyanobacteria produces a class of biogenetically related indole natural products that include hapalindoles and ambiguines. In this full account, a practical route to the tetracyclic hapalindole family is presented by way of a

Full text of DOI:10.1016/j.tet.2014.11.010

Tetrahedron xxx (2014) 1e14
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Scalable total syntheses of (ꢀ)-hapalindole U and (þ)-ambiguine H
,
Thomas J. Maimone a, Yoshihiro Ishihara b, Phil S. Baran b
*
a Department of Chemistry, University of California, Berkeley, 826 Latimer Hall, Berkeley, CA 94720, USA
b Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
The Stigonemataceae family of cyanobacteria produces a class of biogenetically related indole natural
products that include hapalindoles and ambiguines. In this full account, a practical route to the tetracyclic
hapalindole family is presented by way of an eight-step, enantiospecific, protecting-group-free total
synthesis of (ꢀ)-hapalindole U that features an oxidative indoleeenolate coupling. With gram-scale
access to hapalindole U, the first total synthesis of an ambiguine alkaloid, (þ)-ambiguine H, was com-
pleted via an isonitrile-assisted prenylation of an indole followed by a photofragmentation cascade.
Ó 2014 Elsevier Ltd. All rights reserved.
Received 28 September 2014
Received in revised form 28 October 2014
Accepted 5 November 2014
Available online xxx
Keywords:
Total synthesis
Alkaloid
Terpene
Indole
Protecting-group-free
1. Introduction: isolation and structures of complex
cyanobacteria-derived indole alkaloids
products contain an asymmetric chlorine atom as well as multiple
sites of further oxygenation. Moore has proposed that the entire
conserved unit of these intriguing natural products (i.e., the tri-
cyclic hapalindole core 3) arises from an exotic chloronium (or
proton) induced cyclization of tryptophan-derived isonitrile 1 with
The Stigonemataceae family of cyanobacteria produces a pleth-
ora of biogenetically related and structurally fascinating indole
natural products. Comprising over 70 members, these compounds
form the basis of the hapalindole,1 fischerindole,2 welwitindoli-
none,3 ambiguine,4 and related alkaloid classes.5e7 In 1984, iso-
lation efforts by Moore and co-workers opened an exciting new
door in marine natural products chemistry.1a Isolated from soil
samples found all over the world (e.g., Marshall Islands,1a Ever-
glades,5b Australia,2b Micronesia,2b,3b Papua New Guinea,1c Israel4c),
many of these natural products exhibit a broad range of biological
profiles. In particular, numerous hapalindole,1 welwitindolinone,3
and ambiguine4 alkaloids have shown insecticidal,1d,2b antialgal,1a
antimycotic,1a,1c,2b,4a,4c or antibacterial4c,8 properties. In addition,
the hapalindolinones have been found to inhibit arginine vaso-
pression binding.5b Finally, the welwitindolinones show anticancer
activity against multiple drug resistant ovarian cancer cell lines.9
Although the biological activities of many of these complex al-
kaloids are noteworthy, it is truly their molecular structures that
piqued our interest as targets for total synthesis.6,10,11 All com-
pounds shown in Fig. 1 are related by the presence of an indole (or
indole-derived) subunit merged to a monoterpene fragment. In
addition, a rather unusual isonitrile or isothiocyanate group is
present in nearly all members. Finally, many of these natural
the monoterpene
b
-ocimene (2) (Fig. 2A).2a,2b This putative re-
action forms the hallmark five continuous stereocenters unique to
this alkaloid family. It should be noted, however, that nature makes
many permutations of this stereochemical array (both with and
without a halogen), an observation that could be attributed to
imperfections in the biosynthetic machinery.4c From 3, an oxidative
CeC bond formation between C3 of the indole ring with the
isonitrile-bearing carbon (C11) leads to the spirocyclopropyl
hapalindolinone framework,
a cyclization between the iso-
propylidene group and C2 of the indole ring furnishes the fischer-
indole family, and further oxidative rearrangements furnish the
welwitindolinones in Moore’s biosynthetic hypothesis. The tetra-
cyclic hapalindole nucleus 4 (which nature makes in both cis- and
trans-fused forms across the C10eC15 bond) is presumably formed
via cyclization of the isopropylidene onto the indole C4 position.6
Further ‘reverse’ prenylation of the tetracyclic hapalindoles leads
to the basic ambiguine framework (5). Only trans-fused hapa-
lindoles appear to be substrates for processing into ambiguines.
Finally, an enzymatic cyclization between the isonitrile-bearing
carbon (C11) and the terminus of the reverse prenyl group leads
to the pentacyclic ambiguine skeleton (6), which represents the
pinnacle of complexity in this natural product family. The recently
isolated fischambiguines show divergent regiochemical preference
in this late-stage cyclization, affording 6-membered rings as op-
posed to the usual 7-membered ambiguine carbocycles.
* Corresponding author. Tel.: þ1 858 784 7373; fax: þ1 858 784 7375; e-mail
address: pbaran@scripps.edu (P.S. Baran).
http://dx.doi.org/10.1016/j.tet.2014.11.010
0040-4020/Ó 2014 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Maimone, T. J.; et al., Tetrahedron (2014), http://dx.doi.org/10.1016/j.tet.2014.11.010

2
T.J. Maimone et al. / Tetrahedron xxx (2014) 1e14
Fig. 1. Isolated members of the hapalindole family of alkaloids.
Please cite this article in press as: Maimone, T. J.; et al., Tetrahedron (2014), http://dx.doi.org/10.1016/j.tet.2014.11.010

T.J. Maimone et al. / Tetrahedron xxx (2014) 1e14
3
hapalonamide H and some fischerindoles have been completed as
well.14m There have been many reports of approaches toward the
welwitindolinones,15 however, total syntheses from our labo-
ratory16a and the Wood group16b,16c were the only synthetic routes
to these challenging molecules at the time of the first communi-
cation of this research campaign.11 (Thereafter, the Rawal16d,16f and
Garg16e,16g,16h,16i groups have reported elegant total syntheses in
this area.) At the beginning of this work, there was not a single
report of an approach toward an ambiguine alkaloid, however,
since then, a few reports have surfaced.17 A simple yet flexible entry
to the hapalindole and ambiguine families was accomplished
through the efficient synthesis of hapalindole U (4a) and ambiguine
H (5a), which was reported briefly in an earlier article11 and is
described herein as a full account (Fig. 2D).
2. Results and discussion
2.1. Retrosynthetic analysis: oxidative enolate coupling
The direct indoleeenolate coupling reaction initially employed
for the synthesis of hapalindole Q and 12-epi-fischerindole U iso-
thiocyanate stands as the key retrosynthetic disconnection to form
the core of all of the structural types found in this family.10a
Treatment of ketone, ester, or amide enolates with indole anion
followed by the addition of a single-electron oxidant (Cu(II) 2-
ethylhexanoate is optimal) allows for single-step access to a num-
ber of interesting heterocyclic structures that would be difficult to
synthesize by other means.18 This powerful reaction allowed for
exceedingly concise syntheses of the hapalindole, fischerindole and
welwitindolinone natural products.6,10,11 Ambiguine H (5a), the
simplest ambiguine natural product, was targeted for total syn-
thesis and a retrosynthetic blueprint was developed (Fig. 3).11 We
planned to proceed via the tetracyclic hapalindole family, namely
hapalindole U (4a), by way of a late-stage reverse prenylation.
Hapalindole U (4a), in turn, could be traced back to tetracyclic ke-
tone 7. We had hoped to form the tetracyclic core of 7 by a bio-
mimetic-type cyclization of compound 8, which would be the
product of an oxidative indoleeenolate coupling reaction. Ketone 9
could then be generated by manipulation of the chiral terpene pool.
Fig. 2. Evolution of biosynthetic hypotheses regarding the origins of the hapalindoles
and ambiguines: A. Moore’s classic halonium (or proton) induced cyclization of
b-
ocimene (2). B. Carmeli’s alternative one-step enzymatic cyclization to the tetracyclic
hapalindole core (4). C. Liu’s recent biosynthetic studies. D. Tetracyclic hapalindoles (4)
and ambiguines (5) of interest in this synthesis campaign. GPP¼geranyl pyrophos-
phate; DMAPP¼dimethylallyl pyrophosphate; NHI¼non-heme iron.
Despite Moore’s unifying biosynthetic hypothesis, it should be
noted that Carmeli and co-workers have suggested that the entire
tetracyclic hapalindole framework could also be formed in a single
biosynthetic step rather than from the tricyclic hapalindole series
(Fig. 2B).4c Recent biosynthetic studies by Liu and co-workers,
which have identified the ambiguine biosynthetic gene cluster in
Fischerella ambigua, point to geranyl pyrophosphate (GPP) as the
likely origin of the terpene framework in the hapalindole core and
not b
-ocimene (2) (Fig. 2C).12 Furthermore, Liu’s group has also
Fig. 3. Initial retrosynthetic analysis of the tetracyclic ambiguine and hapalindole al-
kaloids as exemplified by the targets ambiguine H (5a) and hapalindole U (4a).
suggested that non-heme-iron (NHI) dependent oxygenases are
responsible for late-stage CeH activation events including the in-
troduction of the chlorine atom,12c, which many members possess.
With so many unique structural types found in this natural
product family, it is not surprising that many syntheses have been
attempted.13e17 Synthetic approaches toward hapalindoles,13 as
well as total syntheses of hapalindoles A,14k G,14h,14k H,14e,14m
J,14b,14c,14d,14l K,14k M,14b,14c,14d O,14g,14n Q,10a,14f,14i,14j,14m and
U11,14e,14l have been reported. Very recently, the total synthesis of
2.2. Development of a gram-scale route to (L)-hapalindole U
Initial forays into the hapalindoles began by procuring large
amounts of ketone 9 (Fig. 4). It should be noted that the chlorinated
version of this ketone had already been prepared by Fukuyama and
Please cite this article in press as: Maimone, T. J.; et al., Tetrahedron (2014), http://dx.doi.org/10.1016/j.tet.2014.11.010

4
T.J. Maimone et al. / Tetrahedron xxx (2014) 1e14
amount of the desired cyclization product. We briefly screened an
assortment of Lewis acids and unfortunately never observed any of
the desired compound 7. Not surprisingly, only C2-cyclized ketone
14 was observed when cyclization occurred.
A logical solution to this problem was to remove the indole C2,
C3
p-bond completely, thus arriving at indoline 15 (Fig. 4). Such
a compound, if found to cyclize to structure 16, could then be ox-
idized back to the indole nucleus. Unfortunately, compound 15
proved troublesome to prepare via Gribble-type reduction.20 This
fact, coupled with an inelegant oxidation state fluctuation, led us to
move on to a more direct solution. A more attractive idea was to
block the indole C2, C3
p-bond with the bulky reverse prenyl
moiety, thereby forcing bond formation to occur at the C4 position
(Fig. 5). Although this strategy would rule out direct access to the
tetracyclic hapalindoles, it would offer an extremely expedient
entry into the ambiguine carbon skeleton. To this end, indole 8 was
subjected to Danishefsky’s reverse prenylation protocol21 and fur-
nished prenylated indole 19 in 78% yield (structure verified by X-
ray crystallographic analysis). Interestingly, the compound first
isolated after column chromatography appeared to still have the
boron attached and was presumably the highly non-polar com-
pound 18. After dissolution in CDCl3 for NMR analysis, a new, much
more polar compound formed quantitatively, which turned out to
be desired product 19.
Fig. 4. Synthesis of ketone 9, oxidative coupling with indole (10), and attempts at
forging the tetracyclic core of the hapalindole family.
co-workers in their elegant synthesis of hapalindole G (4b).14h
Chemistry developed by Mehta19 was amenable to solve the
problem at hand. Starting with the chiral terpene, p-menth-1-en-9-
ol (11a), a dichloroketene [2þ2] cycloaddition (Cl3COCl, Zn) fol-
lowed by sodium methoxide-induced rearrangement led to cyclo-
propane 12 in 61% yield as an inconsequential mixture of four
diastereomers. DIBAL reduction, mesylation, and cyclopropane
fragmentation then furnished mesylate 13 in good yield (73% over
two steps, again as an inconsequential mixture of diastereomers).
Displacement of the mesylate with iodide, followed by E2 elimi-
nation, furnished ketone 9.
With compound 9 in hand, work on the key ring-forming re-
actions was initiated. Oxidative coupling of 9 with indole (10)
proceeded smoothly and provided coupled product 8 as a single
diastereomer in 61% yield on gram scale. As mentioned earlier, the
simplest solution to the tetracyclic hapalindole skeleton would
proceed via a FriedeleCrafts cyclization at the indole C4 position. As
Fig. 5. Synthesis of reverse-prenylated product 19, and attempts at forging the tetra-
cyclic core of the ambiguine family.
Despite significant experimentation and a fairly extensive Lewis
acid screen, we were unfortunately not able to realize the cycliza-
tion from 19 to 20. Under most conditions, only starting material
and decomposition were observed. In a few instances, we observed
very small amounts (w10%) of compounds tentatively appearing to
be olefinic mixtures resembling structures 21. These compounds
were presumably formed via initial protonation of the electron-rich
indole ring, which is then trapped in Prins-type fashion followed by
proton loss. It should be noted that this undesired mode of
the locus of reactivity resides in the indole C2, C3
p-bond, we
recognized that this bond formation would be difficult, if not im-
possible. Furthermore, the undesired cyclization at the C2 position
had already been documented by Fukuyama and co-workers,14h as
well as in our laboratory,10 as this is one of the key steps in the
fischerindole synthesis. Nevertheless, we had hoped that a certain
combination of acids/temperatures might lead to at least some
Please cite this article in press as: Maimone, T. J.; et al., Tetrahedron (2014), http://dx.doi.org/10.1016/j.tet.2014.11.010

T.J. Maimone et al. / Tetrahedron xxx (2014) 1e14
5
cyclization was also observed in our laboratory’s previous studies
toward the fischerindoles.6 Once again, the electron-rich nature of
the indole C2, C3 p-bond thwarted attempts at C4 cyclization.
AIBN, refluxing benzene) was attempted. Unfortunately, the re-
action underwent 7-endo closure rather than the desired 6-exo
pathway, producing compound 26 as an approximate 2.5:1 mixture
of diastereomers (major isomer verified by X-ray crystallographic
analysis). Molecular models suggest that the terminus of the iso-
propylidene group is probably closer to the indole C4 position.
Coupled with the fact that a more stable tertiary radical is formed
during the 7-endo cyclization, this observed result is not entirely
surprising. We next turned our attention to palladium-based
methods in the hope to elicit a reductive Heck cyclization23 form-
ing the desired 6-membered ring. We returned to the real system
bearing a vinyl group and prepared compound 22 (again in 50%
yield) via oxidative coupling of 4-bromoindole (24) and ketone 9
(Fig. 6C). The first attempt using literature conditions (Pd(OAc)2,
HCO2Na, Et3N, TBAC, DMF) were encouraging and formed tetracycle
7 in 25% isolated yield. Although the yield was modest, this was the
first time that the desired tetracyclic ring system was observed and
optimization of this reaction was then undertaken. It took extensive
screening of reaction parameters (over 80 experiments performed)
to optimize this reaction (22 to 7) to synthetically useful yields
(Fig. 6C, table). Catalyst destruction in the highly reducing formate
environment as well as debromination without cyclization proved
to be significant challenges. A wide variety of bases were screened
and found to have a minimal impact on the outcome of this
transformation, thus the use of Et3N was continued. Catalyst
screening showed the palladacycle of Herrmann and co-workers
(27)24 to be particularly robust. DMF and toluene emerged as the
optimal solvents, and sodium formate as the ideal formate source.
The additive tetrabutylammonium bromide (TBAB) gave higher
yields than its chloro (TBAC) and iodo (TBAI) counterparts. Even
with many of these parameters somewhat optimized, we were still
faced with poor catalyst turnover. Thus, while catalyst 27 was ideal
at minimizing the amount of debrominated material, the reactions
never reached completion even with generous catalyst loadings
(i.e., 10% Pd). Perhaps the most important finding in the entire
screening process was a slow addition experiment wherein a DMF
solution of 27 (5 mol %) was added over 5 h to the heated reaction
mixture. To our satisfaction, when the addition was complete, all of
the starting material had been consumed and tetracycle 7 was
obtained in 65% isolated yield. Furthermore, this reaction was ro-
bust and could be conducted on a gram-scale.
At this juncture, the retrosynthesis needed to be revised to one
in which the indole C4 position would possess greater reactivity
(Fig. 6A). A logical solution would be to place a halogen at this
position and thereby switch the reaction pathways from ones in-
volving acid-catalyzed cyclizations to those involving radicals or
transition metals. As a model study, we prepared brominated in-
dole 25, which results from the oxidative coupling of 4-
bromoindole (24) with simplified ketone 23 (Fig. 6B). Significant
optimization was required to coax the electron-deficient indole
into coupling; in the end, it was discovered that 3 equiv of the
brominated indole and 2 equiv of Cu(II) 2-ethylhexanoate oxidant
were required to obtain synthetically useful yields of product (50%).
With 25 in hand, a standard radical-based cyclization22 (Bu3SnH,
With ketone 7 in hand, the completion of hapalindole U (4a)
was rather straightforward (Fig. 7).11 A stereoselective microwave-
assisted reductive amination followed by formylation of the
resulting amine furnished compound 28 as a mixture of formamide
Fig. 6. A. Revised retrosynthesis of key intermediate 7 that invokes a reductive cy-
clization pathway. B. Model radical cyclization. C. Successful reductive Heck cyclization
and reaction optimization.
Fig. 7. Completion of a gram-scale, enantiospecific synthesis of (ꢀ)-hapalindole U (4a).
Please cite this article in press as: Maimone, T. J.; et al., Tetrahedron (2014), http://dx.doi.org/10.1016/j.tet.2014.11.010

6
T.J. Maimone et al. / Tetrahedron xxx (2014) 1e14
rotamers. It should be noted that diastereocontrol in this reaction
without microwave assistance is poor (w2.5:1 dr).14e Dehydration
of formamide 28 with COCl2 then provided (ꢀ)-hapalindole U (4a)
in 62% overall yield from 7. Pleasingly, this natural product was
amenable to single crystal X-ray diffraction analysis. The described
route allowed for gram quantities of the natural product to be
synthesized, which was fortunate because the seemingly simple
task of attaching the reverse prenyl group proved to be extremely
challenging.
indole nucleus in 4a might allow the reaction to take place. The
methods of Trost26 and Tamaru27 for indole C3 reverse prenylation
also failed to afford compound 32, which we had hoped to rear-
range to ambiguine (5a).
Given the early success of Danishefsky’s protocol21 in delivering
a C2 reverse prenylated indole (see transformation from 8 to 19 in
Fig. 5), we returned to ketone intermediate 22 with plans of pre-
nylation then Pd-catalyzed cyclization to ketone 20 (Fig. 9A). Un-
fortunately, 22 was largely resistant to this methodology, perhaps
due to the mildly electron-withdrawing character of bromine, thus
inhibiting initial chloroindolenine formation at low temperature.
This setback turned out to be insignificant because the Danishefsky
reaction worked satisfactorily on cyclized ketone 7. Surprisingly,
the desired compound (20) was formed in nearly equal quantities
with its C6 isomer (34), which is presumably formed via the
mechanism shown in Fig. 9B. With ketone 20 in hand, we were
poised to complete the first ambiguine synthesis. Unfortunately, we
were never able to incorporate a nitrogen source into 20 via re-
ductive amination or even oxime formation to give 36ae36c. Mo-
lecular modeling suggested that the terminus of the reverse prenyl
group lies directly over the ketone moiety, thus inhibiting the ap-
proach of the amine nucleophile. At this juncture, we realized that
the nitrogen functionality would have to be incorporated prior to
the reverse prenyl group. Taking a variety of nitrogen-containing
intermediates 35ae35c from the hapalindole U synthesis and
subjecting them to the Danishefsky protocol failed to afford any C2
reverse prenylated product 36ae36c. A variety of prenyl-based
metal nucleophiles were screened as well as the standard prenyl-
2.3. Total synthesis of (D)-ambiguine H
All that remained to gain entry into the ambiguine alkaloid
family was the attachment of the reverse prenyl group at the indole
C2 position. Many methods to install a reverse prenyl group, or its
equivalent, were attempted on hapalindole U (4a), and a small
summary of failures are shown in Fig. 8. FriedeleCrafts reactions of
4a with prenyl chloride in the presence of silver salts failed to
furnish even trace quantities of ambiguine H (5a). Michael-type
reaction of 4a with dimethylacrolein also failed to furnish C2-
substituted product 29. N-Prenylated indoles are known to un-
dergo acid-mediated rearrangement to mixtures of C2-reverse
prenylated indoles and C2-prenylated indoles,25 and therefore,
conversion of 4a to N-prenyl compound 30 was achieved with NaH
and prenyl bromide (75% yield). Unfortunately, this compound
failed to undergo the rearrangement to ambiguine H (5a) under
thermal or Lewis acidic conditions. Furthermore, an oxidative
enolate coupling between 4a and ethyl 2-methylpropanoate was
unsuccessful at providing 31. Although the oxidative indole-
eenolate coupling at the C2 position has never been observed in
this laboratory, we had hoped that the relatively electron-rich
t
9-BBN reagent (17). In addition to the standard BuOCl conditions,
several ‘Xþ’ activating reagents known to react with indoles were
screened (NBS, NCS, MTAD28). While disappointing, we did gain
some intelligence into shortcomings of this reaction. Analysis of the
crude reaction mixtures indicated mixtures of C2-chlorinated in-
dole, recovered starting material, and at times even N-prenylated
indoles (Fig. 9C). The recovered starting material was suspicious
since TLC analysis indicated that it had been completely consumed
t
after addition of BuOCl. Thus, we believed that we were forming
the putative 3-chloroindolenine species (39) cleanly, however, it
was either: a) rapidly undergoing a 1,2-chloro shift (to afford
structures resembling 40), or b) acting as a chlorinating agent to the
prenyl nucleophile thus returning starting material. This latter
pathway would also produce prenyl chloride, which could alkylate
the indole ring leading to N-prenylated compound 41 in what is
formally a substitution reaction at nitrogen.
Despite some of the failures in adapting Danishefsky’s protocol
to hapalindole intermediates, we attempted the reverse pre-
nylation with the natural product, hapalindole U (4a), resulting in
an unexpected yet interesting transformation (Fig. 10). The chlori-
nating reagent reacted with the isonitrile moiety forming a highly
reactive electrophile, which was trapped by the neighboring indole
p-bond, presumably leading to intermediate imine 42. This com-
pound then reacted with the prenyl-9-BBN reagent (17) affording
pentacycle 43, which showed the entire incorporation of 17 via X-
ray analysis. This fortuitous discovery avoided the problems en-
countered earlier since: a) intermediate 42 cannot undergo the 1,2-
shift reminiscent of the C3-chloro species; b) nucleophiles cannot
attack at nitrogen since there is no leaving group at the C3 position,
and c) 42 cannot act as a halogenating source to quench the prenyl
nucleophile. It is of note that the 9-BBN group is strongly bound to
the indoline nitrogen in 43 and typical conditions for boron re-
moval could not cleave it (vide infra).
Although 43 incorporates the desired reverse prenyl group, it
also contains an unwanted quaternary CeC bond and is missing the
key isonitrile group. We had hoped that it might be possible to
cleave the unwanted CeC bond by using photochemistry somewhat
reminiscent of the venerable Norrish type I process (albeit with an
Fig. 8. Failed attempts to introduce the reverse prenyl group onto (ꢀ)-hapalindole U
(4a).
Please cite this article in press as: Maimone, T. J.; et al., Tetrahedron (2014), http://dx.doi.org/10.1016/j.tet.2014.11.010

T.J. Maimone et al. / Tetrahedron xxx (2014) 1e14
7
Fig. 10. A novel isonitrile-assisted reverse prenylation of an indole followed by a light-
induced fragmentation cascade to furnish (þ)-ambiguine H (5a). brsm¼based on re-
covered starting material.
iminyl chloride rather than a ketone chromophore).29 Gratifyingly,
when 43 was irradiated in benzene with Et3N, ambiguine H (5a)
was formed directly (Fig. 10).
A plausible mechanism is shown in Fig. 10 and supported by the
side products shown in Fig. 11, namely hapalindole U (4a) and C6
reverse prenylated compound 46. The initial benzylic radical in-
termediate (44), formed after excitation and CeC cleavage, can
undergo homolytic CeC scission, thus restoring aromaticity to the
indole group (47) and liberating tertiary allylic radical 48. This
tertiary radical can serve as a hydrogen source leading to hapa-
lindole U (4a) via 49, and isoprene (50). Radical 48 can also
recombine with the electron-rich indole ring to give intermediate
51, affording 46 after rearomatization and losses of HCl and the
boron group, respectively. As in the production of compound 34
(see Fig. 9B), the hapalindole aromatic nucleus displays significant
reactivity at the unexpected C6 position. It should be mentioned
that thermal heating of 43 (temperatures of 180 to 250 ꢁC) fails to
produce any ambiguine H (5a). To probe the role of the boron atom
in the fragmentation, we endeavored to prepare non-boronated
compound 52 (Fig. 12A). As mentioned earlier, the 9-BBN group
could not be removed in compound 43, so an alternative procedure
was developed. By switching the nucleophile in the Danishefsky
prenylation reaction from prenyl-9-BBN (17) to prenylmagnesium
Fig. 9. A. Attempts at prenylating various indole-containing intermediates. B. Mech-
anism of the prenylation reaction of 7, leading to side product 34. C. Observed and
undesired pathways from chlorinated intermediate 39.
Please cite this article in press as: Maimone, T. J.; et al., Tetrahedron (2014), http://dx.doi.org/10.1016/j.tet.2014.11.010

8
T.J. Maimone et al. / Tetrahedron xxx (2014) 1e14
Fig. 11. Side products 51 and (ꢀ)-hapalindole
U (4a) formed during the photo-
fragmentation reaction: involvement of benzylic radical intermediates.
chloride, we were able to prepare 52 in 45% from hapalindole U
(4a). Subjecting 52 to the photofragmentation conditions smoothly
formed ambiguine H (5a) in higher chemical yield and conversion
(75%), and more interestingly, without the formation of C6 reverse
prenylated compound 46 and hapalindole U (4a). Assuming that
both intermediates 44 and 54 are formed in the reactions of 43 and
52, respectively (Fig. 12B), it is interesting that intermediate 44
leads to 3 products (4a, 5a, and 46) while 54 produces only ambi-
guine H (5a). It is tempting to consider that resonance contributor
53 could play a role in increasing the lifetime of the radical in-
termediate, thereby allowing for alternative pathways to compete
with hydrogen radical abstraction. Alternatively, relief of unfavor-
able steric congestion between the large 9-BBN group and the re-
verse prenyl moiety in 44 may provide an additional driving force
for CeC bond cleavage.
Fig. 12. A. Two ways to access (þ)-ambiguine H (5a) from (ꢀ)-hapalindole U (4a), as
well as the unusual heterolytic stability of the NeB bond in compound 43. B. Boron
substituent influencing reaction pathways.
4. Experimental section
4.1. General
All reactions were carried out under a nitrogen atmosphere with
dry solvents under anhydrous conditions, unless otherwise noted.
Dry tetrahydrofuran (THF), triethylamine (Et3N), dichloromethane
(DCM), methanol (MeOH), dimethylformamide (DMF), diethyl
ether (Et2O) and benzene were obtained by passing commercially
available pre-dried, oxygen-free formulations through activated
alumina columns. Tetra-n-butyl ammonium bromide (TBAB), so-
dium formate, ammonium acetate, sodium iodide, and copper(II) 2-
ethylhexanoate were dried and kept stored under high vacuum
prior to use. Herrmann’s catalyst 27 [Pd(P(o-tol)3)OAc]2 was freshly
prepared according to standard procedures.24 Yields refer to chro-
matographically and spectroscopically (1H NMR) homogeneous
materials, unless otherwise stated. Reagents were purchased at the
highest commercial quality and used without further purification,
unless otherwise stated. Reactions were monitored by thin-layer
chromatography (TLC) carried out on 0.25 mm E. Merck silica gel
plates (60F-254) using UV light as visualizing agent and p-ani-
saldehyde in ethanol/aqueous H2SO4/CH3CO2H and heat as de-
veloping agents. NMR spectra were recorded on a Bruker DRX 600,
DRX 500, or AMX 400 spectrometer and were calibrated using re-
sidual undeuterated solvent as an internal reference. The following
3. Conclusion: a strategic perspective
In conclusion, we developed concise, enantiospecific syntheses
of the alkaloids hapalindole U (4a) and ambiguine H (5a) without
resorting to protecting group manipulations.11,30 It is interesting to
note that the first disclosure of these syntheses11 and a review in
200930b have led to an explosive increase in the number of
protecting-group-free syntheses.30c While the avoidance of pro-
tecting groups is obviously beneficial in terms of streamlining these
syntheses (both by step count and atom economy),11 one could
argue that, in this work, the real benefit to their exclusion was in
the arena of discovery. Novel intermediates and cascade reactions
would likely have not been observed had typical bond construc-
tions with protected heteroatoms been performed. These en-
deavors also highlight the role serendipity plays in natural product
synthesis, as one could argue that the final synthetic routes are
more interesting than the original, more concise, retrosynthesis of
ambiguine H.
Please cite this article in press as: Maimone, T. J.; et al., Tetrahedron (2014), http://dx.doi.org/10.1016/j.tet.2014.11.010

T.J. Maimone et al. / Tetrahedron xxx (2014) 1e14
9
abbreviations were used to explain the multiplicities: s¼singlet,
d¼doublet, t¼triplet, q¼quartet, m¼multiplet, b¼broad. IR spectra
were recorded on a PerkineElmer Spetrum BX spectrometer. High-
resolution mass spectra (HRMS) were recorded on an Agilent mass
spectrometer using ESI-TOF (electrospray ionization-time-of-
flight) or a ThermoFinnigan mass spectrometer using FAB (fast
atom bombardment) or EI (electron impact). Low-resolution mass
spectra (LRMS) were recorded on an Agilent or ThermoFinnigan
mass spectrometer. Photochemical reactions were conducted using
a 450-watt Hanovia lamp with a quartz filter. Melting points (mp)
are uncorrected and were recorded on a Fisher-Johns 12-144
melting point apparatus. Optical rotations were obtained on a Per-
kineElmer 431 polarimeter. All microwave reactions were per-
formed in a Biotage initiator microwave. Sonications were carried
out in a Fisher Scientific FS30H ultrasonic cleaning bath. Azeo-
troping refers to dissolving the compound to be dried in benzene
and removing the solvent by rotary evaporation.
1:1 to 3:2 to 1:0 EtOAc:hexanes) furnished the corresponding diol
(560 mg, 82%, inseparable but inconsequential mixture of di-
astereomers). The diol (540 mg, 2.36 mmol, mixture of di-
astereomers) was dissolved in anhydrous pyridine (25 mL) and
cooled to 0 ꢁC. Methanesulfonyl chloride (0.55 mL, 7.10 mmol,
3.0 equiv) was slowly added dropwise to the solution at 0 ꢁC and
stirring was continued for 75 min at this temperature. The reaction
mixture was then warmed to room temperature and stirred for an
additional 30 min before pouring into a mixture of 1 N HCl (100 mL)
and Et2O (200 mL). The aqueous layer was extracted with Et2O
(100 mL, 4ꢂ). The combined organic extracts were washed with 1 N
HCl (200 mL, 2ꢂ) and brine (200 mL). The solvent was removed in
vacuo to give an oil, which was then dissolved in 4:1 AcOH:H2O
(35 mL) and stirred for 2.5 h at 23 ꢁC (to hydrolyze any enol ethers
that are formed). The reaction mixture was diluted with Et2O
(150 mL) and H2O (150 mL) and the aqueous layer was extracted
with Et2O (100 mL, 4ꢂ). The combined organic layers were washed
with saturated NaHCO3 (500 mL, 4ꢂ, carefully) then brine (250 mL,
2ꢂ), then dried (Na2SO4) and concentrated in vacuo. Flash column
chromatography (silica gel, gradient from 1:1 to 2:1 Et2O:hexanes)
gave 13 as a clear oil (576 mg, 89%, mixture of two diastereomers).
4.2. Experimental procedures and data of synthetic
intermediates
4.2.1. Cyclopropane 12. Step 1: A flame-dried flask was charged
with p-menth-1-en-9-ol (11a: 6.79 g, 44.1 mmol, 1.0 equiv, in-
separable but inconsequential mixture of diastereomers), Zn dust
(11.5 g, 176.0 mmol, 4.0 equiv), and Et2O (400 mL). The flask was
placed in an ultrasound bath, and freshly distilled trichloroacetyl
chloride (19.5 mL, 174.7 mmol, 4.0 equiv) in Et2O (200 mL) was
added dropwise to the sonicating solution over the course of 1 h at
25 ꢁC. Sonication was continued for 6 h while maintaining a bath
temperature of 25e30 ꢁC by the periodic addition of ice. The re-
action mixture was filtered through a plug of CeliteÒ and concen-
trated in vacuo. The dark red oil was partitioned between Et2O
(350 mL) and water (350 mL). The aqueous layer was extracted with
Et2O (100 mL, 4ꢂ). The combined organic layers were washed with
saturated NaHCO3 (400 mL, 2ꢂ) then brine (400 mL, 2ꢂ), then dried
(Na2SO4). The solvent was removed in vacuo to give a dark red oil.
Flash column chromatography (silica gel, gradient from 2:1 to 1:1
hexanes:DCM) gave a yellow oil (10.9 g, 66%). [NOTE: the in-
termediate cyclobutanone was prone to slight decomposition on
silica gel. Using crude material for the next step gives a similar
overall yield.] Step 2: To a flame-dried flask was added the afore-
mentioned cyclobutanone (1.06 g, 2.82 mmol, 1.0 equiv), NaOMe
(765 mg, 13.4 mmol, 4.8 equiv), and anhydrous MeOH (28 mL). The
mixture was placed into a pre-heated oil bath at 65 ꢁC and heated
for 30 min. Upon cooling, the reaction mixture was poured into 1 N
HCl (100 mL) and extracted with EtOAc (100 mL, 3ꢂ). The combined
organic layers were washed with 1 N HCl (200 mL, 2ꢂ) then brine
(200 mL, 2ꢂ), then dried (Na2SO4). The solvent was removed in
vacuo to give a red oil. Flash column chromatography (silica gel,
gradient from 2:1 to 1:1 hexanes:Et2O) yielded a yellow oil
(671 mg, 61% yield over 2 operations) as an inseparable but in-
consequential mixture of four diastereomers (two at the ester
bearing carbon, each of which is a mixture of two diastereomers at
4.2.3. Ketone (ꢀ)-9. Mesylate 13 (485 mg, 1.76 mmol) was dis-
solved in acetone (10 mL). Dry sodium iodide (2.63 g, 17.6 mmol,
10.0 equiv) was added and the reaction mixture was heated at
reflux for 15 h. Upon cooling to 23 ꢁC, the reaction was partitioned
between Et2O (100 mL) and H2O (100 mL) and the aqueous layer
was extracted with Et2O (75 mL, 3ꢂ). The combined organic layers
were washed with saturated Na2S2O3 (200 mL, 2ꢂ) then brine
(200 mL, 2ꢂ), then dried (Na2SO4). The solvent was removed in
vacuo to give an oil, which was azeotropically dried with benzene,
then dissolved in THF (10 mL). To this solution was added DBU
(1.33 mL, 8.82 mmol, 5.0 equiv) and the reaction was degassed by
bubbling argon through the mixture for 5 min in an ultrasound
bath. The reaction mixture was then heated for 3 h at 65 ꢁC under
argon atmosphere. Upon cooling to 23 ꢁC, the mixture was parti-
tioned between 1 N HCl (50 mL) and Et2O (100 mL) and the aqueous
layer was extracted with Et2O (50 mL, 4ꢂ). The combined organic
layers were washed with 1 N HCl (200 mL, 2ꢂ) then brine (200 mL,
2ꢂ), then dried (Na2SO4). The solvent was removed in vacuo to give
a yellow liquid. Flash column chromatography (silica gel, 15:1
hexanes:Et2O) gave (ꢀ)-9 (272 mg, 87%) as a clear liquid. TLC:
20
Rf¼0.66
(silica
gel,
hexanes:Et2O,
2:1
v/v);
[a]
D
(deg cm3 gL1 dmL1): ꢀ24.9 (c¼2.4 g cmꢀ3 in DCM); 1H NMR
(400 MHz, CDCl3):
d
6.04 (dd, J¼10.9, 17.6 Hz, 1H), 5.09 (d,
J¼10.9 Hz, 1H), 4.98 (d, J¼18.2 Hz, 1H), 4.77 (s, 1H), 4.67 (s, 1H),
2.54e2.40 (m, 3H), 1.88e1.72 (m, 4H), 1.70 (s, 3H), 1.20 (s 3H); 13C
NMR (126 MHz, CDCl3, APT): d 213.1, 146.9, 142.6, 113.3, 110.6, 50.6,
44.8, 42.9, 35.9, 25.4, 22.8, 20.9; IR (film):
n
¼3082, 2932,1707,1644,
1453, 1311, 1246, 1097, 1000, 896 cmꢀ1; HRMS (m/z): [MþH]þ calcd
for C12H18OþHþ, 179.1430; found, 179.1422.
4.2.4. Coupled product 8. Indole (10: 1.00 g, 8.54 mmol, 1.9 equiv)
was azeotropically dried with benzene (2ꢂ) and the residual sol-
vent was removed under high vacuum. ent-9 (792 mg, 4.44 mmol,
1.0 equiv) and THF (25 mL) were added, and the mixture was cooled
to ꢀ78 ꢁC under an atmosphere of dry nitrogen. Freshly prepared
LiHMDS (1.0 M in THF, 15 mL, 15 mmol, 3.4 equiv) was added
dropwise to the solution at ꢀ78 ꢁC and the reaction was stirred for
30 min at that temperature. Copper(II) 2-ethylhexanoate (0.2 M
solution in THF, 33 mL, 6.6 mmol, 1.5 equiv) was added rapidly via
syringe. The mixture was stirred for 5 min at ꢀ78 ꢁC then warmed
to 23 ꢁC and immediately poured into 1 N HCl (150 mL) and EtOAc
(150 mL). The aqueous layer was extracted with EtOAc (100 mL,
3ꢂ). The combined organic layers were washed with 1 N HCl
(500 mL), 1 N NaOH (500 mL) then brine (500 mL), then dried
the a-hydroxy bearing carbon).
4.2.2. Mesylate 13. To a solution of cyclopropane 12 (767 mg,
2.99 mmol, mixture of diastereomers) in DCM (30 mL) was added
a solution of DIBAL (1.5 M in toluene, 10.0 mL, 15.0 mmol, 5.0 equiv)
dropwise at ꢀ78 ꢁC. The reaction mixture was stirred for 30 min at
ꢀ78 ꢁC, then quenched by the dropwise addition of MeOH (5 mL).
The reaction mixture was warmed to room temperature, diluted
with EtOAc (200 mL) and saturated Rochelle’s salt solution
(200 mL) and vigorously stirred overnight. The layers were sepa-
rated and the aqueous layer was extracted with EtOAc (100 mL, 4ꢂ).
The combined organic layers were dried (Na2SO4) and concentrated
in vacuo. Flash column chromatography (silica gel, gradient from
Please cite this article in press as: Maimone, T. J.; et al., Tetrahedron (2014), http://dx.doi.org/10.1016/j.tet.2014.11.010

10
T.J. Maimone et al. / Tetrahedron xxx (2014) 1e14
(MgSO4). The solvent was removed in vacuo and the crude material
was purified by flash column chromatography (silica gel, gradient
from 10:1 to 5:1 hexanes:EtOAc) to give the coupled product ent-8
(794 mg, 61%) as a white solid. [Note: this compound was prepared
with ent-compound 9, i.e., whose absolute configuration is opposite
to the ones depicted in the figures.] mp: 151e153 ꢁC; TLC: Rf¼0.33
a white crystalline solid. [Note: this compound was prepared with
ent-compound 8, i.e., whose absolute configuration is opposite to
the ones depicted in the figures.] Recrystallization from EtOAc gave
slightly yellow cubes that were suitable for X-ray diffraction
(CCDC# 1023595); mp: 170e173 ꢁC; TLC: Rf¼0.23 (silica gel, hex-
20
anes:Et2O, 2:1 v/v);
[
a
]
D
(deg cm3 gL1 dmL1): þ13.6
(silica gel, hexanes:Et2O, 1:1 v/v); [
a
]
D
20 (deg cm3 gL1 dmL1): þ47.4
(c¼4.2 g cmꢀ3 in CHCl3); 1H NMR (600 MHz, CDCl3):
d 7.85 (br s,
(c¼3.65 g cmꢀ3 in DCM); 1H NMR (500 MHz, CDCl3):
d
8.14 (br s,
1H), 7.30 (d, J¼6 Hz, 1H), 7.25 (d, J¼6 Hz, 1H), 7.06 (t, J¼6 Hz, 1H),
6.97 (t, J¼6 Hz, 1H), 6.32 (dd, J¼12, 18 Hz, 1H), 6.10 (dd, J¼6, 12 Hz,
1H), 5.20 (dd, J¼18 Hz,1H), 5.11 (dd, J¼12 Hz, 2H), 5.07 (dd, J¼18 Hz,
1H), 4.53 (d, J¼24 Hz, 2H), 4.48 (d, J¼12 Hz, 1H), 3.26 (dt, J¼6, 12 Hz,
1H), 2.18e2.05 (m, 2H), 1.96e1.94 (m, 1H), 1.91e1.87 (m, 1H), 1.47 (s,
3H), 1.46 (s, 3H), 1.42 (s, 3H), 1.41 (s, 3H); 13C NMR (126 MHz,
1H), 7.37 (d, J¼7.8 Hz, 1H), 7.16 (d, J¼7.9 Hz, 1H), 7.12 (t, J¼6.8 Hz,
1H), 7.07 (t, J¼7.3 Hz, 1H), 6.61 (d, J¼2.35 Hz, 1H), 6.35 (dd, J¼11.0,
17.7 Hz, 1H), 5.18 (d, J¼11.0 Hz, 1H), 5.14 (d, J¼17.7 Hz, 1H), 4.64 (s,
1H), 4.57 (s, 1H), 4.23 (d, J¼12.4 Hz,1H), 2.97 (td, J¼3.9,12.0 Hz,1H),
2.27e2.18 (m, 1H), 2.11 (td, J¼3.8, 13.4 Hz, 1H), 2.02 (dt, J¼3.5,
13.5 Hz, 1H), 1.96e1.91 (m, 1H), 1.60 (s, 3H), 1.57 (s, 3H); 13C NMR
CDCl3):
d 211.3, 146.8, 146.5, 143.6, 140.5, 134.7, 128.5, 121.0, 120.9,
(126 MHz, CDCl3):
d 212.2, 146.4, 143.0, 136.0, 127.1, 123.6, 121.2,
119.0,112.3, 112.1, 111.5, 110.7,108.4, 50.5, 50.0, 49.8, 38.9, 36.8, 28.3,
118.8, 118.7, 112.2, 112.0, 111.3, 110.8, 52.3, 50.6, 47.9, 36.7, 27.5, 22.9,
27.7, 27.4, 23.0, 21.2; IR (film):
n
¼3407, 2920, 2850,1701,1460,1375,
18.5; IR (film):
n
¼3369, 2931, 1701, 1642, 1457, 1373, 1340, 1247,
1012, 912, 739 cmꢀ1; HRMS (m/z): [MþH]þ calcd for C25H31NOþHþ,
1099, 1011, 914, 893 cmꢀ1; HRMS (m/z): [MþH]þ calcd for
362.2478; found, 362.2475.
C
20H23NOþHþ, 294.1852; found, 294.1848.
4.2.7. Model compound 25. 4-Bromoindole (24: 1.65 g, 8.4 mmol,
3.0 equiv) was azeotropically dried with benzene (2ꢂ) and the
residual solvent removed under high vacuum. Ketone 23 (465 mg,
2.80 mmol, 1.0 equiv) and THF (2.8 mL) were then added, and the
mixture was cooled to ꢀ78 ꢁC under a dry nitrogen atmosphere.
LiHMDS (1.0 M in THF, 12.3 mL, 12.3 mmol, 4.4 equiv) was added
dropwise at ꢀ78 ꢁC and stirring was continued for 30 min. The
rubber septum was quickly removed and solid copper(II) 2-
ethylhexanoate (1.96 g, 5.6 mmol, 2.0 equiv) was added rapidly in
one portion at ꢀ78 ꢁC followed by immediate replacement of the
rubber septum. [Note: rapid stirring is essential and brief exposure
of the reaction mixture to the atmosphere had a negligible effect on
the overall outcome of the reaction]. The reaction was stirred for
5 min at ꢀ78 ꢁC, then warmed to 23 ꢁC and immediately poured
into 1 N HCl (50 mL) and EtOAc (50 mL). The aqueous layer was
extracted with EtOAc (50 mL, 3ꢂ). The combined organic layers
were washed with 1 N HCl (250 mL), 1 N NaOH (250 mL) then brine
(250 mL), then dried (MgSO4). The solvent was removed in vacuo
and the crude material was purified by flash column chromatog-
raphy (silica gel, gradient from 7:1 to 5:1 hexanes:EtOAc) to give
4.2.5. C2-cyclized side product 14. Representative procedure for
undesired cyclization: To a flame-dried flask was added coupled
product ent-8 (11.4 mg, 0.039 mmol, 1 equiv), DCM (0.75 mL), and
MeOH (4.7
and TMSOTf (23
m
L, 0.12 mmol, 3.0 equiv). The flask was cooled to 0 ꢁC
mL, 0.12 mmol, 3.0 equiv) was added dropwise. The
reaction mixture was stirred at 0 ꢁC for 1 h, then quenched with
saturated aqueous sodium bicarbonate (1 mL) at 0 ꢁC. DCM (5 mL)
was added and the layers separated. The aqueous layer was
extracted with DCM (5 mL, 3ꢂ). The combined organic layers were
washed with brine (25 mL), then dried (MgSO4). The solvent was
removed in vacuo and the crude material was purified by pre-
parative thin-layer silica gel chromatography (1:1 hexanes:Et2O) to
give ent-14 (2.0 mg, 18%) as a white foam and recovered starting
material (8.4 mg, 74%). [Note: this compound was prepared with
ent-8, i.e., whose absolute configuration is opposite to the ones
depicted in the figures.] TLC: Rf¼0.32 (silica gel, hexanes:Et2O, 2:1
20
v/v); [
a]
(deg cm3 gL1 dmL1): ꢀ109.3 (c¼4.0 g cmꢀ3 in CHCl3);
D
1H NMR (600 MHz, CDCl3):
d 7.86 (br s, 1H), 7.76 (m, 1H), 7.31e7.28
(m, 1H), 7.12e7.10 (m, 2H), 6.24 (dd, J¼12, 18 Hz, 1H), 5.17 (d,
J¼12 Hz, 1H), 5.14 (d, J¼18 Hz, 1H), 4.05 (d, J¼12 Hz, 1H), 2.44e2.39
(m, 1H), 2.03e1.91 (m, 3H), 1.87e1.83 (m, 1H), 1.47 (s, 3H), 1.38 (s,
the title compound (498 mg, 50%) as
a white solid; mp:
20
185e187 ꢁC; TLC: Rf¼0.22 (silica gel, hexanes:Et2O, 1:1 v/v); [
a]
D
3H), 1.16 (s, 3H); 13C NMR (126 MHz, CDCl3):
d
211.9, 151.2, 143.0,
139.8, 124.6, 121.2, 120.5, 120.4, 113.2, 113.0, 111.5, 63.1, 51.6, 51.3,
41.2, 39.0, 25.3, 23.8, 21.4, 20.6; IR (film):
¼3393, 2958, 2927, 2864,
(deg cm3 gL1 dmL1): þ50.9 (c¼4.3 g cmꢀ3 in CHCl3); 1H NMR
(600 MHz, CDCl3):
d
8.43 (br s, 1H), 7.15 (d, J¼12 Hz, 1H), 7.06 (t,
n
J¼16 Hz, 1H), 6.90 (m, 1H), 6.86 (dt, J¼2, 8 Hz, 1H), 5.25 (d, J¼12 Hz,
1H), 4.76 (s, 1H), 4.65 (s, 1H), 2.81 (dt, J¼3, 12 Hz, 1H), 2.26e2.18 (m,
1H), 1.93e1.90 (m, 1H), 1.82e1.75 (m, 2H), 1.63 (s, 3H), 1.49 (s, 3H),
1705, 1449, 1386, 1297, 1245, 1164, 1109, 1033, 1008, 918, 743 cmꢀ1
;
HRMS (m/z): [MþH]þ calcd for C20H23NOþHþ, 294.1852; found,
294.1847.
1.12 (s, 3H); 13C NMR (126 MHz, CDCl3):
d
214.9, 147.4, 137.4, 125.6,
125.1, 124.0, 122.4, 113.6, 112.4, 112.2, 110.9, 53.5, 47.2, 45.5, 40.8,
4.2.6. C2-reverse prenylated indole 19. ent-8 (26 mg, 0.09 mmol,
1 equiv) was azeotropically dried with benzene. THF (0.85 mL) and
28.9, 26.0, 25.3, 18.7; IR (film):
n
¼3340, 2967, 2932, 1701, 1645,
1471, 1337, 1187, 1075, 910, 756 cmꢀ1; HRMS (m/z): [MþH]þ calcd
for C19H22BrNOþHþ, 360.0957; found, 360.0957.
Et3N (15 mL, 0.11 mmol, 1.2 equiv) were added and the solution was
cooled to ꢀ78 ꢁC. Freshly prepared tBuOCl (13
mL, 0.11 mmol,
1.3 equiv) was added and the reaction mixture was stirred for
30 min at ꢀ78 ꢁC. Prenyl-9-BBN (17: 1.0 M solution in THF, 0.18 mL,
0.18 mmol, 2 equiv) was added dropwise at ꢀ78 ꢁC and the mixture
was stirred for 45 min at this temperature, then warmed to 23 ꢁC.
The mixture was poured into saturated aqueous NaHCO3 (5 mL) and
EtOAc (5 mL). The aqueous layer was extracted with EtOAc (5 mL,
3ꢂ). The combined organic layers were washed with water (25 mL)
then brine (25 mL), then dried (MgSO4). The solvent was removed
in vacuo and the crude material was purified by flash column
chromatography (silica gel, 15:1 hexanes:EtOAc) to give tentative
intermediate 18. This compound was allowed to stand in CDCl3 for
30 min then concentrated in vacuo and dried under high vacuum.
The material was re-purified by flash column chromatography
(silica gel, 10:1 hexanes:EtOAc) to give ent-19 (25.1 mg, 78%) as
4.2.8. 7-Endo products 26 (major) and 260 (minor). To a sealable
vial was added compound 25 (15 mg, 0.04 mmol, 1 equiv) and AIBN
(5 mg, 0.04 mmol, 1.1 equiv). The flask was then evacuated and
back-filled with argon. Dry, degassed benzene (0.85 mL) and
Bu3SnH (28 mL, 0.10 mmol, 2.5 equiv) were added and the sealed
vial was placed into a 100 ꢁC oil bath for 1 h. After cooling to 23 ꢁC,
the volatiles were removed in vacuo and the crude material was
purified by preparative thin-layer silica gel chromatography (2:1
hexanes:Et2O) to yield ‘upper diastereomer’ 260 (2.6 mg, 22%) as
a white crystalline solid and ‘lower diastereomer’ 26 (6.2 mg, 53%)
as a white crystalline solid as well.
The lower (major) diastereomer was recrystallized from cyclo-
hexane/EtOAc to yield colorless needles suitable for X-ray diffrac-
tion (CCDC# 1023596). Data for ‘lower diastereomer’ (major
Please cite this article in press as: Maimone, T. J.; et al., Tetrahedron (2014), http://dx.doi.org/10.1016/j.tet.2014.11.010

T.J. Maimone et al. / Tetrahedron xxx (2014) 1e14
11
product) 26: mp: 185 ꢁC; TLC: Rf¼0.24 (silica gel, hexanes:Et2O, 2:1
(30 mL) was then added, followed by Et3N (0.94 mL, 6.74 mmol,
2.2 equiv). This mixture was degassed by three freeze-pump-thaw
iterations and finally back-filled with argon. A solution of Herr-
mann’s catalyst (27: 142 mg, 0.15 mmol, 0.05 equiv) in DMF (20 mL)
was degassed by three freeze-pump-thaw iterations and added
dropwise over 5 h (syringe pump) to the substrate at 80 ꢁC. The
mixture was heated for an additional 3 h at 80 ꢁC. Upon cooling to
23 ꢁC, the reaction mixture was diluted with Et2O (100 mL) and
filtered through a plug of CeliteÒ. The mixture was poured into Et2O
(100 mL) and H2O (100 mL) and the aqueous layer was thoroughly
extracted with Et2O (100 mL, 5ꢂ). The combined organic layers
were washed with 1 N HCl (500 mL), 1 N NaOH (500 mL) then brine
(500 mL), then dried (MgSO4). The solvent was removed in vacuo
and the crude material was purified by flash column chromatog-
raphy (silica gel, gradient from 8:1 to 5:1 hexanes:Et2O) to give
v/v); [
a]
20 (deg cm3 gL1 dmL1): ꢀ190 (c¼6.2 g cmꢀ3 in CHCl3); 1H
D
NMR (600 MHz, CDCl3):
d
8.24 (br s, 1H), 7.18 (d, J¼6 Hz, 1H), 7.15 (s,
1H), 7.05 (t, J¼12 Hz, 1H), 6.86 (d, J¼6 Hz, 1H), 4.06 (d, J¼12 Hz, 1H),
3.21 (d, J¼18 Hz, 1H), 3.13 (dd, J¼6, 18 Hz, 1H), 2.23e2.10 (m, 3H),
1.90e1.87 (m, 1H), 1.75e1.69 (m, 2H), 1.34 (s, 3H), 1.15 (s, 3H), 1.01
(d, J¼6 Hz, 3H); 13C NMR (126 MHz, CDCl3):
d 215.2, 135.7, 132.3,
126.7, 125.0, 121.3, 120.2, 110.4, 108.6, 51.4, 47.3, 44.9, 43.4, 40.6,
37.5, 29.5, 26.2, 25.2,12.8; IR (film):
n
¼3383, 2928,1716,1458,1329,
1249, 1123, 1064, 1018, 776, 746 cmꢀ1; HRMS (m/z): [MþH]þ calcd
for C19H23NOþHþ, 282.1852; found, 282.1846.
The upper (minor) diastereomer is a white crystalline solid that
can be recrystallized from cyclohexane/EtOAc to yield colorless
needles. Data for ‘upper diastereomer’ (minor product) 260: mp:
20
129e131 ꢁC; TLC: Rf¼0.40 (silica gel, hexanes:Et2O, 2:1 v/v); [
a]
D
(deg cm3 gL1 dmL1): þ47.8 (c¼3.7 g cmꢀ3 in CHCl3); 1H NMR
tetracyclic ketone (ꢀ)-7 (579 mg, 65%) as white crystals; mp:
20
(600 MHz, CDCl3):
d
7.96 (br s, 1H), 7.66 (s,1H), 7.16 (d, J¼12 Hz,1H),
149e151 ꢁC; TLC: Rf¼0.14 (silica gel, hexanes:Et2O, 3:1 v/v); [
a]
D
7.03 (t, J¼6 Hz, 1H), 6.76 (d, J¼12 Hz, 1H), 4.39 (d, J¼12 Hz, 1H), 3.67
(dd, J¼3, 15 Hz, 1H), 2.68 (dd, J¼5, 15 Hz, 1H), 2.21e2.16 (m, 1H),
1.92e1.78 (m, 3H),1.67e1.62 (m,1H),1.38e1.34 (m, 1H),1.27 (s, 3H),
1.15 (s, 3H), 0.89 (d, J¼7 Hz, 3H); 13C NMR (126 MHz, CDCl3):
(deg cm3 gL1 dmL1): ꢀ18.1 (c¼1.7 g cmꢀ3 in DCM); 1H NMR
(600 MHz, CDCl3):
d
8.08 (br s, 1H), 7.49 (t, J¼1.9 Hz, 1H), 7.19e7.15
(m, 2H), 7.03 (dd, J¼1.0, 6.5 Hz, 1H), 6.24 (dd, J¼10.9, 17.6 Hz, 1H),
5.17 (d, J¼10.9 Hz, 1H), 5.11 (d, J¼17.7 Hz, 1H), 3.96 (dd, J¼1.0,
11.5 Hz, 1H) 2.11e1.92 (m, 5H), 1.54 (s, 3H), 1.48 (s, 3H), 1.24 (s, 3H);
d
216.6, 135.0, 132.9, 127.5, 122.0, 119.6, 114.4, 108.9, 52.9, 47.6, 45.2,
39.6, 38.9, 38.1, 29.4, 26.3, 25.8, 20.8; IR (film):
n
¼3400, 2959, 2923,
13C NMR (151 MHz, CDCl3):
d
212.3, 143.0, 139.9, 133.4, 125.2, 122.4,
1703, 1456, 1338, 1105, 746 cmꢀ1; HRMS (m/z): [MþH]þ calcd for
120.7, 112.7, 112.6, 108.6, 108.2, 51.6, 50.3, 44.4, 38.0, 37.1, 24.7, 24.6,
C
19H23NOþHþ, 282.1852; found, 282.1847.
23.0, 21.3; IR (film):
n
¼3400, 3058, 2964, 1867, 1698, 1438, 1334,
1175, 1044, 1019, 911, 745 cmꢀ1; HRMS (m/z): [MþH]þ calcd for
4.2.9. Brominated coupled product (ꢀ)-22. 4-Bromoindole (24:
3.13 g, 16.0 mmol, 2.8 equiv) was azeotropically dried with benzene
(2ꢂ) and the residual solvent was removed under high vacuum.
Ketone (ꢀ)-9 (1.00 g, 5.61 mmol, 1.0 equiv) and THF (5.6 mL) were
then added, and the mixture was cooled to ꢀ78 ꢁC under a dry
nitrogen atmosphere. LiHMDS (1.0 M in THF, 24.6 mL, 24.6 mmol,
4.4 equiv) was added dropwise at ꢀ78 ꢁC and stirring was con-
tinued for 30 min. The rubber septum was quickly removed and
solid copper(II) 2-ethylhexanoate (4.0 g, 11.4 mmol, 2.0 equiv) was
added rapidly in one portion at ꢀ78 ꢁC followed by immediate
replacement of the rubber septum. [Note: rapid stirring is essential
and brief exposure of the reaction mixture to the atmosphere had
a negligible effect on the overall outcome of the reaction]. The re-
action was stirred for 5 min at ꢀ78 ꢁC, then warmed to 23 ꢁC and
immediately poured into 1 N HCl (200 mL) and EtOAc (200 mL). The
aqueous layer was extracted with EtOAc (125 mL, 3ꢂ). The com-
bined organic layers were washed with 1 N HCl (600 mL), 1 N NaOH
(600 mL) then brine (600 mL), then dried (MgSO4). The solvent was
removed in vacuo and the crude material was purified by flash
column chromatography (silica gel, gradient from 4:1 to 3:1 to 2.5:1
to 1:1 hexanes:Et2O) to give (ꢀ)-22 (1.04 g, 50%) as a white solid
C
20H23NOþHþ, 294.1852; found, 294.1847.
4.2.11. Formamide (ꢀ)-28. A flame-dried 20 mL Biotage microwave
vessel was charged with dry NH4OAc (750 mg, 9.7 mmol,
40.0 equiv), NaCNBH3 (115 mg,1.83 mmol, 9.3 equiv) and dry MeOH
(10 mL) under a dry nitrogen atmosphere. Ketone (ꢀ)-7 (57.9 mg,
0.20 mmol, 1.0 equiv) in THF (1 mL) was added to the MeOH so-
lution and the mixture was exposed to microwave irradiation at
150 ꢁC for 2.5 min [caution: high pressures and toxic gases are
formed]. Upon cooling and venting the gases in a well-ventilated
fume hood, the contents from 10 successive runs were combined,
diluted with EtOAc (200 mL), poured into 1 N NaOH (250 mL), and
the aqueous layer was thoroughly extracted with EtOAc (100 mL,
5ꢂ). The combined organic layers were washed with 1 N NaOH
(500 mL, 2ꢂ), then dried (Na2SO4). The solvent was removed in
vacuo and the crude amine was passed through a short plug of silica
gel eluting with a gradient from 1:1 EtOAc:hexanes to 100% EtOAc
to give a solid (430 mg), which was subsequently dissolved in DCM
(20 mL). The following compounds were added sequentially to the
mixture: formic acid (0.11 mL, 2.9 mmol, 2.0 equiv), 2-chloro-4,6-
dimethoxy-1,3,5-triazine (565 mg, 3.22 mmol, 2.2 equiv), 4-
(dimethylamino)pyridine (10 mg, 0.08 mmol, 0.056 equiv), and N-
methylmorpholine (0.36 mL, 3.28 mmol, 2.2 equiv). The resulting
slurry was stirred at 23 ꢁC for 2 h, diluted with DCM (100 mL), and
poured into saturated NaHCO3 (150 mL). The aqueous layer was
thoroughly extracted with DCM (100 mL, 5ꢂ). The combined or-
ganic layers were washed with 1 N HCl (500 mL, 2ꢂ), brine
(500 mL, 2ꢂ), and dried (Na2SO4). The solvent was removed in
vacuo to give a solid, which was purified by flash column chro-
matography (silica gel, gradient from 2:1 to 4:1 Et2O:hexanes) to
[Note: excess 4-bromoindole can also be easily recovered]; mp:
20
130e132 ꢁC; TLC: Rf¼0.59 (silica gel, hexanes:EtOAc, 1:1 v/v); [
a]
D
(deg cm3 gL1 dmL1): ꢀ19.1 (c¼9.2 g cmꢀ3 in DCM); 1H NMR
(400 MHz, CDCl3):
d
8.41 (br s, 1H), 7.15 (d, J¼7.5 Hz, 1H), 7.06 (d,
J¼7.9 Hz, 1H), 6.87e6.83 (m, 2H); 6.28 (dd, J¼11.0, 17.6 Hz, 1H), 5.30
(d, J¼12.6 Hz, 1H), 5.11 (d, J¼10.9 Hz, 1H), 5.06 (d, J¼17.8 Hz, 1H),
4.77 (s, 1H), 4.66 (s, 1H), 2.84 (td, J¼3.8, 12.3 Hz, 1H), 2.31e2.20 (m,
1H), 2.05e1.87 (m, 3H), 1.64 (s, 3H), 1.61 (s, 3H); 13C NMR (151 MHz,
CDCl3):
d 212.8, 147.0, 143.2, 137.2, 125.4, 125.0, 123.9, 122.2, 113.4,
112.4, 112.0, 111.7, 110.7, 52.9, 50.7, 47.2, 37.5, 28.4, 22.6, 18.5; IR
give formamide (ꢀ)-28 (411 mg, 64%, mixture of E and Z isomers) as
20
(film):
n
¼3349, 2934, 1699, 1426, 1337, 1186, 1120, 910, 735,
a white solid; mp: >250 ꢁC; TLC: Rf¼0.37 (silica gel, Et2O); [
a]
D
610 cmꢀ1
;
HRMS (m/z): [MþH]þ calcd for C20H22BrNOþHþ,
(deg cm3
g
L1 dmL1): ꢀ79.7 (c¼0.77 g cmꢀ3 in DCM:MeOH 2:1 v/
372.0957; found, 372.0966.
v); 1H NMR (600 MHz, CDCl3):
d
8.16 (br s, 1H), 7.90 (d, J¼1.9 Hz,
1H), 7.17e7.15 (m, 2H), 7.02 (dd, J¼1.8, 6.1 Hz, 1H) 6.96 (t, 1.86 Hz,
1H), 5.98 (dd, J¼10.9, 17.5 Hz, 1H), 5.51 (d, J¼10.7 Hz, 1H), 5.01 (dd,
J¼1.0, 10.9 Hz, 1H), 4.98 (dd, J¼1.0, 17.5 Hz, 1H), 4.75 (dd, J¼3.4,
10.9 Hz, 1H), 3.42 (ddd, J¼1.4, 3.5, 12 Hz, 1H), 1.98e1.96 (m, 1H),
1.74e1.62 (m, 4H), 1.50 (s, 3H), 1.32 (s, 3H), 1.15 (s, 3H); 13C NMR
4.2.10. Reductive Heck cyclization product (ꢀ)-7. Brominated cou-
pled product (ꢀ)-22 (1.12 g, 3.03 mmol, 1.0 equiv) was azeotropi-
cally dried with benzene. Dry sodium formate (258 mg, 3.79 mmol,
1.2 equiv) and dry TBAB (1.96 g, 6.08 mmol, 2.0 equiv) were added
and the flask was evacuated, then backfilled with argon. DMF
(151 MHz, CDCl3):
d 161.4, 146.8, 140.6, 133.9, 125.5, 122.6, 117.3,
Please cite this article in press as: Maimone, T. J.; et al., Tetrahedron (2014), http://dx.doi.org/10.1016/j.tet.2014.11.010

12
T.J. Maimone et al. / Tetrahedron xxx (2014) 1e14
112.9, 112.6, 111.4, 108.3, 52.3, 44.7, 40.1, 37.4, 33.6, 30.1, 24.9, 24.5,
0.10 mmol, 1 equiv) was azeotropically dried with benzene and the
residual solvent was removed under high vacuum. THF (2.0 mL)
23.6, 21.2; IR (film):
n
¼3402, 2961, 1672, 1517, 1393, 1100, 906, 769,
734, 581 cmꢀ1; HRMS (m/z): [MþH]þ calcd for C21H26N2OþHþ,
and Et3N (16.5 mL, 0.12 mmol, 1.2 equiv) were added and the mix-
323.2118; found, 323.2115.
ture was cooled to ꢀ78 ꢁC. Freshly prepared tBuOCl (13.5
mL,
0.12 mmol, 1.2 equiv) was added to the cooled solution. After
25 min, prenyl-9-BBN (17: 1.0 M solution in THF, 0.20 mL, 2.0 equiv)
was added dropwise over the course of 5 min to the solution at
ꢀ78 ꢁC. The reaction color turned bright orange. The reaction
mixture was stirred for 45 min at ꢀ78 ꢁC then warmed to 23 ꢁC and
immediately partitioned between 1 N NaOH (5 mL) and EtOAc
(5 mL). The reaction mixture was thoroughly extracted with EtOAc
(5 mL, 5ꢂ). The combined organic layers were washed with 1 N
NaOH (25 mL, 2ꢂ), 1 N HCl (25 mL) then brine (25 mL), then dried
(MgSO4). The solvent was removed in vacuo and the crude material
was purified by preparative thin-layer silica gel chromatography
(5:1 hexanes:Et2O) to give 20 (9.3 mg, 26%) and 34 (7.0 mg, 19%) as
white solids.
4.2.12. Hapalindole U (ꢀ)-4a. A flame-dried flask was charged with
formamide (ꢀ)-28 (315 mg, 0.98 mmol, 1.0 equiv) under an atmo-
sphere of dry nitrogen. DCM (60 mL) and Et3N (2.4 mL, 17.2 mmol,
17.6 equiv) were added, and the mixture was cooled to 0 ꢁC.
Phosgene (20 wt % solution in toluene) was carefully added drop-
wise until TLC analysis showed complete consumption of starting
material [caution: phosgene is highly toxic and this reaction should
be performed carefully in a well-ventilated fume hood]. The re-
action was quenched at 0 ꢁC by the dropwise addition of saturated
NaHCO3 (50 mL) and then warmed to 23 ꢁC. The reaction mixture
was thoroughly extracted with DCM (75 mL, 5ꢂ). The combined
organic layers were washed with saturated NaHCO3 (400 mL, 2ꢂ)
then brine (400 mL, 2ꢂ), then dried (Na2SO4). The solvent was
removed in vacuo and the crude material was purified by flash
column chromatography (silica gel, gradient from 3:1 to 2:1 hex-
anes:Et2O) to give hapalindole U (ꢀ)-4a as a white solid (277 mg,
93%). Crystallization from hexanes/Et2O/MeOH yielded white nee-
dles of suitable quality for X-ray diffraction (CCDC# 623050); mp:
Data for C2-reverse prenylated tetracyclic ketone 20: The full
compound characterization has not been obtained. Its structure has
been assigned by its 1H NMR spectrum and by comparison to the
data for 34 (shown below). 1H NMR (500 MHz, acetone-d6):
d 9.70
(br s, 1H), 7.06 (d, J¼5 Hz, 1H), 6.96 (t, J¼5 Hz, 1H), 6.88 (d, J¼5 Hz,
1H), 6.30 (dd, J¼15, 20 Hz, 1H), 6.15 (dd, J¼10, 15 Hz, 1H), 5.10e5.02
(m, 4H), 4.42 (d, J¼15 Hz, 1H), 2.12e1.97 (m, 3H), 1.82e1.73 (m, 2H),
1.57 (s, 3H), 1.51 (s, 3H), 1.48 (s, 3H), 1.47 (s, 3H), 1.09 (s, 3H).
Compound 34 can be recrystallized from EtOAc to yield colorless
needles suitable for X-ray diffraction (CCDC# 1023597). Data for
241 ꢁC (decomposition); TLC: Rf¼0.32 (silica gel, hexanes:Et2O, 1:1
20
v/v); [
a
]
D
(deg cm3 gL1 dmL1): ꢀ2.0 (c¼0.6 g cmꢀ3 in DCM); 1H
NMR (600 MHz, CDCl3):
d 8.00 (br s, 1H), 7.19e7.18 (m, 2H),
7.04e7.03 (m, 1H), 6.90 (bt, 1H), 6.05 (dd, J¼10.9, 17.5 Hz, 1H), 5.19
(d, J¼10.9 Hz, 1H), 5.18 (d, J¼17.4 Hz, 1H), 4.10 (bd, 1H), 3.28e3.27
(m, 1H), 2.03e1.90 (m, 3H), 1.68e1.59 (m, 2H), 1.50 (s, 3H), 1.28 (s,
C6-reverse prenylated tetracyclic ketone 34: mp: 162e165 ꢁC (de-
20
composition); TLC: Rf¼0.30 (silica gel, hexanes:Et2O, 2:1 v/v); [
a]
D
3H), 1.15 (s, 3H); 13C NMR (151 MHz, CDCl3):
d
156.4, 145.4, 140.9,
(deg cm3 gL1 dmL1): ꢀ7.6 (c¼4.6 g cmꢀ3 in CHCl3); 1H NMR
134.1, 125.6, 123.0, 116.3, 113.3, 112.9, 112.8, 108.2, 63.4, 43.4, 39.3,
(600 MHz, CDCl3):
d 7.98 (br s, 1H), 7.43 (s, 1H), 7.18 (s, 1H), 7.04 (s,
37.1, 33.7, 30.0, 25.2, 24.4, 21.6, 21.0; IR (film):
n
¼3378, 2962, 2142,
1H), 6.22 (dd, J¼6, 18 Hz, 1H), 6.12 (dd, J¼6, 12 Hz, 1H), 5.16 (d,
J¼6 Hz, 1H), 5.09 (d, J¼18 Hz, 2H), 5.04 (d, J¼12 Hz, 1H), 3.92 (d,
J¼12 Hz, 1H), 2.09e1.88 (m, 5H), 1.52 (s, 3H), 1.46 (s, 9H), 1.22 (s,
1602, 1437, 1334, 1173, 914, 771; HRMS (m/z): [MþNa]þ calcd for
C
21H24N2þNaþ, 327.1832; found, 327.1846.
3H); 13C NMR (151 MHz, CDCl3):
d 212.5, 149.2, 143.6, 143.2, 139.2,
4.2.13. N-Prenylated hapalindole 30. Hapalindole U (ꢀ)-4a (6.0 mg,
0.02 mmol, 1 equiv) was azeotropically dried with benzene and the
residual solvent was removed under high vacuum. DMF (0.50 mL)
was added and the reaction was cooled to 0 ꢁC. NaH (60% dispersion
in mineral oil, 2.0 mg, 0.05 mmol, 2.5 equiv) was added, at which
point the mixture became bright yellow. The solution was stirred
133.5, 123.7, 120.6, 112.8, 112.1, 110.1, 108.6, 105.7, 51.9, 50.5, 44.6,
41.8, 38.4, 37.2, 29.1, 29.0, 24.8, 24.8 23.2, 21.4; IR (film):
n
¼3404,
2926, 1707, 1464, 1362, 1011, 918, 862 cmꢀ1; HRMS (m/z): [MþH]þ
calcd for C25H31NOþHþ, 362.2478; found, 362.2478.
4.2.15. Borono-chlorinated indoline (þ)-43. Hapalindole U (ꢀ)-4a
(100.0 mg, 0.33 mmol, 1.0 equiv) was azeotropically dried with
benzene (2ꢂ) and the residual solvent was removed under high
vacuum. DCM (5.0 mL) was added, and the solution was cooled to
for 15 min at 0 ꢁC, then prenyl bromide (10
mL, 0.09 mmol,
4.4 equiv) was added and the solution became clear. After stirring
for 7 min at 0 ꢁC, the reaction was quenched with 1 N HCl (1 mL).
The mixture was partitioned between saturated NH4Cl (5 mL) and
Et2O (2 mL) and the aqueous layer was extracted with Et2O (5 mL,
2ꢂ). The combined organic layers were washed with brine (10 mL),
then dried (MgSO4). The solvent was removed in vacuo and the
crude material was purified by preparative thin-layer silica gel
chromatography (3:1 hexanes:Et2O) to give N-prenylated product
ꢀ78 ꢁC under an argon atmosphere. Freshly prepared tBuOCl (43
mL,
0.38 mmol, 1.2 equiv) was added dropwise and the solution was
stirred at ꢀ78 ꢁC for 12 min. Freshly prepared prenyl-9-BBN (17:
1.12 M solution in DCM, 600 mL, 0.672 mmol, 2.0 equiv) was slowly
added dropwise down the flask walls over the course of 5 min.
Stirring was continued for 40 min at ꢀ78 ꢁC before the reaction was
quenched at low temperature by quickly transferring the contents
of the flask to a small plug of silica gel and eluting with EtOAc. The
solvent was removed in vacuo and the crude material was purified
by flash column chromatography (silica gel, 20:1 hexanes:Et2O) to
give borono-chlorinated indoline (þ)-43 (104 mg, 60%) as a white
solid. Crystallization from Et2O/DCM yielded clear plates of suitable
30 (5.5 mg, 75%) as a white solid; mp: 115 ꢁC; TLC: Rf¼0.41 (silica
20
gel, hexanes:Et2O, 4:1 v/v); [
a
]
(deg cm3 gL1 dmL1): þ184
D
(c¼4.7 g cmꢀ3 in CHCl3); 1H NMR (600 MHz, CDCl3):
d 7.17 (t,
J¼12 Hz, 1H), 7.11 (d, J¼12 Hz, 1H), 7.0 (d, J¼12 Hz, 1H), 6.8 (s, 1H),
6.05 (dd, J¼12, 18 Hz, 1H), 5.4 (t, J¼6 Hz, 1H), 5.18 (d, J¼12 Hz, 1H),
5.17 (d, J¼18 Hz, 1H), 4.67 (d, J¼6 Hz, 2H), 4.07 (s, 1H), 3.27 (d,
J¼6 Hz, 1H), 2.02e1.88 (m, 3H), 1.82 (s, 3H), 1.76 (s, 3H), 1.65e1.58
(m, 2H), 1.49 (s, 3H), 1.26 (s, 3H), 1.14 (s, 3H); 13C NMR (151 MHz,
quality for X-ray diffraction (CCDC# 623051). mp: 244 ꢁC (de-
20
composition); TLC: Rf¼0.48 (silica gel, hexanes:Et2O, 7:1 v/v); [
a]
D
CDCl3):
d
155.5, 145.7, 141.1, 136.2, 134.6, 126.3, 122.5, 120.5, 119.7,
(deg cm3 gL1 dmL1): þ46.8 (c¼1.8 g cmꢀ3 in DCM); 1H NMR
113.4, 112.5, 111.5, 107.0, 63.5, 44.5, 43.6, 39.4, 37.3, 33.9, 30.2, 25.8,
(500 MHz, CDCl3):
d
7.19 (t, J¼7.8 Hz,1H), 6.96 (d, J¼7.9 Hz,1H), 6.93
25.4, 24.6, 24.6, 21.7, 21.1, 18.2; IR (film):
n
¼2928, 2137, 1608, 1455,
(d, J¼7.7 Hz, 1H), 6.33 (dd, J¼10.9, 17.7 Hz, 1H), 5.73 (dd, J¼10.7,
17.4 Hz,1H), 5.14 (dd, J¼1.3,10.9 Hz,1H), 5.11 (dd, J¼1.3,17.6 Hz,1H),
5.00 (dd, J¼1.0,17.5 Hz,1H), 4.96 (dd, J¼1.0,10.7 Hz,1H), 4.10 (s, 1H),
3.81 (d, J¼2.1 Hz, 1H), 2.87 (dd, J¼3.5, 11.4 Hz, 1H), 2.05e1.87 (m,
9H), 1.79e1.64 (m, 5H), 1.57e1.42 (m, 5H), 1.34 (s, 3H), 1.14 (s, 3H),
1.04 (s, 3H), 0.99 (s, 3H), 0.60 (s, 3H); 13C NMR (151 MHz, CDCl3):
1363, 1319, 1279, 1165, 1039, 918, 780 cmꢀ1; HRMS (m/z): [MþH]þ
calcd for C26H32N2þHþ, 373.2638; found, 373.2635.
4.2.14. C2-Reverse prenylated tetracyclic ketone 20 and C6-reverse
prenylated tetracyclic ketone 34. Tetracyclic ketone 7 (29 mg,
Please cite this article in press as: Maimone, T. J.; et al., Tetrahedron (2014), http://dx.doi.org/10.1016/j.tet.2014.11.010

T.J. Maimone et al. / Tetrahedron xxx (2014) 1e14
13
d
168.1, 150.3, 147.2, 145.8, 145.5, 129.3, 129.1, 119.8, 115.3, 112.2,
(deg cm3 gL1 dmL1): þ144 (c¼4.6 g cmꢀ3 in CHCl3); 1H NMR
111.4, 75.9, 66.7, 44.3, 42.0, 41.2, 38.9, 36.0, 33.6, 33.5, 33.4, 33.3,
32.9, 30.2, 28.0, 27.6, 26.0, 24.6, 24.3, 23.2, 22.9, 21.8, 21.1, 20.7; IR
(600 MHz, CDCl3):
d
7.09 (t, J¼6 Hz,1H), 6.69 (d, J¼6 Hz,1H), 6.46 (d,
J¼6 Hz, 1H), 6.33 (dd, J¼12, 18 Hz, 1H), 5.72 (dd, J¼6, 12 Hz, 1H),
5.13e5.01 (m, 4H), 4.03 (br s, 1H), 3.84 (d, J¼2 Hz, 1H), 3.42 (s, 1H),
2.86 (dd, J¼6, 12 Hz, 1H), 1.76e1.73 (m, 1H), 1.70e1.65 (m, 1H),
1.58e1.52 (m, 2H), 1.39e1.34 (m, 1H), 1.32 (s, 3H), 1.16 (s, 3H), 1.00
(film):
n
¼2927, 1596, 1452, 1405, 1340, 1006, 910 cmꢀ1; HRMS (m/
z): [MþH]þ calcd for C34H46BClN2þHþ, 529.3515; found, 529.3526.
4.2.16. Ambiguine H (þ)-5a and C6-reverse prenylated hapalindole
46. Borono-chlorinated indoline 43 (22.5 mg, 0.04 mmol,1.0 equiv)
was dissolved in degassed benzene (2.3 mL), and freshly distilled
(s, 3H), 0.87 (s, 6H); 13C NMR (151 MHz, CDCl3):
d 169.1, 151.9, 147.2,
145.5, 145.3, 129.9, 122.1, 115.1, 113.3, 111.5, 105.7, 76.7, 75.2, 67.3,
45.1, 42.5, 41.6, 39.1, 36.1, 34.2, 26.8, 24.9, 24.1, 23.4, 22.5, 21.0; IR
and degassed Et3N (30
m
L) was added in a 5-mL Biotage microwave
(film):
n
¼3378, 2967, 2933, 1601, 1455, 1414, 1363, 1246, 1098, 1064,
vessel. The mixture was sealed under an atmosphere of argon and
irradiated for 5 h, at which point the solvent was decanted (to
remove the highly crystalline Et3NHCl that is formed). The crude
material was purified by preparative thin-layer chromatography to
give recovered starting material (8.2 mg, 36%) along with ambi-
guine H (þ)-5a (6.5 mg, 41%, 63% based on recovered starting
material) as a white solid. [Note: the reaction cannot be run to full
conversion since the product itself is photoreactive; under similar
experimental conditions, de-boronated product 52 cleanly forms
ambiguine H (þ)-5a in w75% isolated yield in 2.5 h].
1013, 912, 788, 743 cmꢀ1
;
HRMS (m/z): [MþH]þ calcd for
C
26H33ClN2þHþ, 409.2405; found, 409.2402.
4.3. X-ray crystallographic data
Crystallographic data for structures 4a, 5a, 19, 26, 34 and 43
have been deposited with the Cambridge Crystallographic Data
Centre. Copies of the data can be obtained free of charge from
http://www.ccdc.cam.ac.uk/products/csd/request/ (CCDC number
623050 for 4a, 623052 for 5a, 1023595 for 19, 1023596 for 26,
1023597 for 34, and 623051 for 43).
Ambiguine H (þ)-5a was crystallized from hexanes/Et2O to give
off-white plates suitable for X-ray diffraction (CCDC# 623052). Data
for (þ)-5a: mp: 228e231 ꢁC; TLC: Rf¼0.57 (silica gel, hexanes:Et2O,
Acknowledgements
1:1 v/v); [
a
]
20 (deg cm3 gL1 dmL1): þ20.0 (c¼0.18 g cmꢀ3 in DCM);
D
1H NMR (600 MHz, CDCl3):
d
7.98 (br s, 1H), 7.13e7.09 (m, 2H), 6.98
We thank D.-H. Huang and L. Pasternack for assistance in NMR
spectroscopy, G. Siuzdak for assistance in mass spectrometry, and R.
Chadha for assistance in X-ray crystallographic analysis. Financial
support for this work was provided by the NIH/NIGMS (GM-
071498), the Arnold and Mabel Beckman Foundation, the Searle
Scholarship Fund, and the Sloan Foundation.
(d, J¼6.5 Hz, 1H), 6.21 (dd, J¼10.6, 17.5 Hz, 1H), 5.93 (dd, J¼10.9,
17.5 Hz, 1H), 5.25 (d, J¼17.5 Hz, 1H), 5.19 (d, J¼10.6 Hz, 1H), 5.14 (d,
J¼10.9 Hz, 1H), 5.11 (d, J¼17.5 Hz, 1H), 4.49 (s, 1H), 3.18e3.16 (m,
1H), 2.10e1.90 (m, 3H), 1.60e1.50 (m, 2H), 1.58 (s, 3H), 1.52 (s, 3H),
1.50 (s, 3H), 1.23 (s, 3H), 1.02 (s, 3H); 13C NMR (151 MHz, CDCl3):
d
146.3, 145.8, 140.6, 136.7, 132.2, 127.3, 122.0, 113.0, 112.9, 112.4,
107.5, 106.7, 65.1, 43.9, 39.9, 38.7, 36.3, 34.8, 30.6, 29.7, 29.2, 27.8,
Appendix A. Supplementary data
24.9, 24.0, 21.71, 21.68; IR (film):
n
¼3345, 2923, 2362, 2134, 1636,
1444, 1327, 998, 915 cmꢀ1; HRMS (m/z): [MþH]þ calcd for
Supplementary data related to this article can be found at http://
dx.doi.org/10.1016/j.tet.2014.11.010.
C
26H32N2þHþ, 373.2638; found, 373.2636.
Data for C6-reverse prenylated hapalindole 46: white solid; TLC:
20
Rf¼0.25
(silica
gel,
hexanes:Et2O,
2:1
v/v);
[a]
D
References and notes
(deg cm3 gL1 dmL1): ꢀ10.0 (c¼1.0 g cmꢀ3 in DCM); 1H NMR
(600 MHz, CDCl3):
d
7.92 (br s, 1H), 7.18 (d, J¼1 Hz, 1H), 7.06 (d,
1. Isolation of novel hapalindoles. Hapalindoles A through X, along with some 12-
epi variants, are currently known: (a) Moore, R. E.; Cheuk, C.; Patterson, G. M. L.
J. Am. Chem. Soc. 1984, 106, 6456e6457; (b) 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,
1036e1043; (c) Klein, D.; Daloze, D.; Braekman, J. C.; Hoffmann, L.; Demoulin, V.
J. Nat. Prod. 1995, 58, 1781e1785; (d) Becher, P. G.; Keller, S.; Jung, G.; Sussmuth,
R. D.; Juttner, F. Phytochemistry 2007, 68, 2493e2497; (e) Kim, H.; Lantvit, D.;
Hwang, C. H.; Kroll, D. J.; Swanson, S. M.; Franzblau, S. G.; Orjala, J. Bioorg. Med.
Chem. 2012, 20, 5290e5295.
J¼1 Hz, 1H), 6.86 (t, J¼2 Hz, 1H), 6.12 (dd, J¼12, 18 Hz, 1H), 6.04 (dd,
J¼12, 18 Hz, 1H), 5.19 (d, J¼6 Hz, 1H), 5.17 (d, J¼12 Hz, 1H), 5.10 (dd,
J¼1,18 Hz,1H), 5.05 (dd, J¼1, 12 Hz,1H), 4.08 (s, 1H), 3.25 (d, J¼6 Hz,
1H), 2.01e1.88 (m, 4H), 1.66e1.60 (m, 1H), 1.48 (s, 3H), 1.47 (s, 6H),
1.27 (s, 3H), 1.14 (s, 3H); 13C NMR (151 MHz, CDCl3):
d 156.6, 149.1,
145.6,144.2,140.2,134.2,124.0,116.2, 113.4,112.7,112.2, 110.2,105.7,
63.5, 43.8, 41.9, 39.4, 37.5, 33.9, 30.2, 29.0, 29.0, 25.4, 24.5, 21.7, 21.1;
2. Isolation of novel fischerindoles. Fischerindoles were named based on their
similarity to the hapalindoles, and therefore many alphabets are missing in the
nomenclature of the fischerindole alkaloids: (a) Park, A.; Moore, R. E.; Patter-
son, G. M. L. Tetrahedron Lett. 1992, 33, 3257e3260; (b) 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, 9935e9942; (c) Kim, H.; Krunic, A.;
Lantvit, D.; Shen, Q.; Kroll, D. J.; Swanson, S. M.; Orjala, J. Tetrahedron 2012, 68,
3205e3209.
3. Isolation of novel welwitindolinones. Welwitindolinones A through D, along
with some 3-epi, N-methyl, and isothiocyanate variants are known: (a) Ref. 2b;
(b) Jimenez, J. I.; Huber, U.; Moore, R. E.; Patterson, G. M. L. J. Nat. Prod. 1999, 62,
569e572.
4. Isolation of novel ambiguines and fischambiguines. Ambiguines A through Q
are known: (a) 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, 857e861; (b) Huber, U.; Moore, R. E.; Patterson, G. M. L. J. Nat. Prod.
1998, 61, 1304e1306; (c) Raveh, A.; Carmeli, S. J. Nat. Prod. 2007, 70, 196e201;
(d) Shunyan, M.; Krunic, A.; Chlipala, G.; Orjala, J. J. Nat. Prod. 2009, 72,
894e899; (e) Shunyan, M.; Krunic, A.; Santarsiero, B. D.; Franzblau, S. G.; Orjala,
J. Phytochemistry 2010, 71, 2116e2123.
5. Isolation of hapalindolinones, anhydrohapaloxindoles, and fontonamides: (a)
Refs. 1e,4e; (b) Schwartz, R. E.; Hirsch, C. F.; Springer, J. P.; Pettibone, D. J.; Zink,
D. L. J. Org. Chem. 1987, 52, 3704e3706; (c) Moore, R. E.; Yang, X.-q. G.; Pat-
terson, G. M. L. J. Org. Chem. 1987, 52, 3773e3777; (d) Moore, R. E.; Yang, X.-q.
G.; Patterson, G. M. L.; Bonjouklian, R.; Smitka, T. A. Phytochemistry 1989, 28,
1565e1567.
IR (film):
n
¼3411, 2967, 2844, 2136, 1454, 1346, 1054, 1033, 1012,
911 cmꢀ1; HRMS (m/z): [MþH]þ calcd for C26H32N2þHþ, 373.2638;
found, 373.2634.
4.2.17. Chlorinated indoline (þ)-52. Hapalindole U (ꢀ)-4a (10 mg,
0.03 mmol, 1.0 equiv) was azeotropically dried with benzene and
the residual solvent was removed under high vacuum. DCM
(0.6 mL) was added, and the solution was cooled to ꢀ78 ꢁC under an
argon atmosphere. Freshly prepared tBuOCl (4.5
mL, 0.04 mmol,
1.2 equiv) was added dropwise and the solution was stirred at
ꢀ78 ꢁC for 15 min. Freshly prepared prenylmagnesium chloride
(0.75 M solution in THF, 90 mL, 0.07 mmol, 2.1 equiv) was slowly
added dropwise down the flask walls over the course of 2 min.
Stirring was continued for 25 min at ꢀ78 ꢁC before the reaction was
warmed to 0 ꢁC and quickly transferred to a small plug of silica gel
and eluted with EtOAc. The solvent was removed in vacuo and the
crude material was purified by preparative thin-layer silica gel
chromatography (1:1 hexanes:Et2O) to give chlorinated indoline
(þ)-52 (5.3 mg, 40%) as an oil that slowly solidified to a white solid;
20
TLC: Rf¼0.50 (silica gel, hexanes:Et2O, 1:1 v/v);
[a]
D
Please cite this article in press as: Maimone, T. J.; et al., Tetrahedron (2014), http://dx.doi.org/10.1016/j.tet.2014.11.010

14
T.J. Maimone et al. / Tetrahedron xxx (2014) 1e14
6. For a previous tabulation of hapalindole, fischerindole, ambiguine and welwi-
Baudoux, J.; Blake, A. J.; Simpkins, N. S. Org. Lett. 2005, 7, 4087e4089; (i) Gre-
shock, T. J.; Funk, R. L. Org. Lett. 2006, 8, 2643e2645; (j) Lauchli, R.; Shea, K. J.
Org. Lett. 2006, 8, 5287e5289; (k) Tian, X.; Huters, A. D.; Douglas, C. J.; Garg, N.
K. Org. Lett. 2009, 11, 2349e2351; (l) Trost, B. M.; McDougall, P. J. Org. Lett. 2009,
11, 3782e3785; (m) Freeman, D. B.; Holubec, A. A.; Weiss, M. W.; Dixon, J. A.;
Kakefuda, A.; Ohtsuka, M.; Inoue, M.; Vaswani, R. G.; Ohki, H.; Doan, B. D.;
Reisman, S. E.; Stoltz, B. M.; Day, J. J.; Tao, R. N.; Dieterich, N. A.; Wood, J. L.
Tetrahedron 2010, 66, 6647e6655; (n) Bhat, V.; Rawal, V. H. Chem. Commun.
2011, 9705e9707; (o) Zhang, M.; Tang, W. Org. Lett. 2012, 14, 3756e3759; (p)
Cleary, L.; Pitzen, J.; Brailsford, J. A.; Shea, K. J. Org. Lett. 2014, 16, 4460e4463.
16. Total synthesis of welwitindolinone natural products: (a) Refs. 6,10b,11; (b)
Reisman, S. E.; Ready, J. M.; Hasuoka, A.; Smith, C. J.; Wood, J. L. J. Am. Chem. Soc.
2006, 128, 1448e1449; (c) 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, 2087e2100; (d) Bhat, V.; Allan, K. M.; Rawal, V. H. J. Am. Chem. Soc.
2011, 133, 5798e5801; (e) Huters, A. D.; Quasdorf, K. W.; Styduhar, E. D.; Garg,
N. K. J. Am. Chem. Soc. 2011, 133, 15797e15799; (f) Allan, K. M.; Kobayashi, K.;
Rawal, V. H. J. Am. Chem. Soc. 2012, 134, 1392e1395; (g) Quasdorf, K. W.; Huters,
A. D.; Lodewyk, M. W.; Tantillo, D. J.; Garg, N. K. J. Am. Chem. Soc. 2012, 134,
1396e1399; (h) Styduhar, E. D.; Huters, A. D.; Weires, N. A.; Garg, N. K. Angew.
Chem., Int. Ed. 2013, 52, 12422e12425; (i) Weires, N. A.; Styduhar, E. D.; Baker,
E. L.; Garg, N. K. J. Am. Chem. Soc. 2014, 136, 14710e14713 For a formal synthesis
of welwitindolinone C, see;; (j) Fu, T.-h.; McElroy, W. T.; Shamszad, M.; Martin,
S. F. Org. Lett. 2012, 14, 3834e3837.
tindolinone natural products, see: Richter, J. M.; Ishihara, Y.; Masuda, T.;
ꢀ
Whitefield, B. W.; Llamas, T.; Pohjakallio, A.; Baran, P. S. J. Am. Chem. Soc. 2008,
130, 17938e17954.
7. For a recent review on the hapalindole, fischerindole, ambiguine and welwi-
tindolinone natural products, see: Bhat, V.; Dave, A.; MacKay, J. A.; Rawal, V. H. In
€
The Alkaloids; Knolker, H.-J., Ed.; Elsevier: Waltham, MA, 2014; Vol. 73, pp 65e160.
8. For examples of investigations regarding the bioactivity of the hapalindole
family, see: (a) Doan, N. T.; Rickards, R. W.; Rothschild, J. M.; Smith, G. D. J. Appl.
Phycol. 2000, 12, 409e416; (b) Doan, N. T.; Stewart, P. R.; Smith, G. D. FEMS
Microbiol. Lett. 2001, 196, 135e139; (c) Asthana, R.; Srivastava, A.; Singh, A.;
Singh, S.; Nath, G.; Srivastava, R.; Srivastava, B. J. Appl. Phycol. 2006, 18, 33e39.
9. For examples of investigations regarding the bioactivity of the welwitindoli-
none family, see: (a) Smith, C. D.; Zilfou, J. T.; Stratmann, K.; Patterson, G. M.;
Moore, R. E. Mol. Pharmacol. 1995, 47, 241e247; (b) Zhang, X.; Smith, C. D. Mol.
Pharmacol. 1996, 49, 288e294.
10. (a) Baran, P. S.; Richter, J. M. J. Am. Chem. Soc. 2004, 126, 7450e7451; (b) Baran,
P. S.; Richter, J. M. J. Am. Chem. Soc. 2005, 127, 15394e15396.
11. Baran, P. S.; Maimone, T. J.; Richter, J. M. Nature 2007, 446, 404e408.
12. For more recent studies in the biosynthesis of hapalindole, fischerindole, am-
biguine and welwitindolinone natural products, see: (a) Hillwig, M. L.; Zhu, Q.;
Liu, X. ACS Chem. Biol. 2014, 9, 372e377; (b) Hillwig, M. L.; Fuhrman, H. A.;
Ittiamornkul, K.; Sevco, T. J.; Kwak, D. H.; Liu, X. ChemBioChem 2014, 15,
665e669; (c) Hillwig, M. L.; Liu, X. Nat. Chem. Biol. 2014, 10, 921e923.
13. Synthesis approaches toward the hapalindole family of natural products: (a)
Kinsman, A. C.; Kerr, M. A. Org. Lett. 2000, 2, 3517e3520; (b) Brown, M. A.; Kerr,
M. A. Tetrahedron Lett. 2001, 42, 983e985; (c) Banwell, M. G.; Ma, X.; Taylor, R.
M.; Willis, A. C. Org. Lett. 2006, 8, 4959e4961.
17. Synthetic approaches toward the ambiguine family of natural products: (a) Ref.
14n; (b) Chandra, A.; Viswanathan, R.; Johnston, J. N. Org. Lett. 2007, 9,
5027e5029; (c) Rafferty, R. J.; Williams, R. M. Tetrahedron Lett. 2011, 52,
2037e2040.
14. Total synthesis of hapalindole natural products: (a) Refs. 6,10a,11; (b) Muratake,
H.; Natsume, M. Tetrahedron Lett. 1989, 30, 1815e1818; (c) Muratake, H.; Nat-
sume, M. Tetrahedron 1990, 46, 6331e6342; (d) Muratake, H.; Natsume, M.
Tetrahedron 1990, 46, 6343e6350; (e) Muratake, H.; Kumagami, H.; Natsume,
M. Tetrahedron 1990, 46, 6351e6360; (f) Vaillancourt, V.; Albizati, K. F. J. Am.
Chem. Soc. 1993, 115, 3499e3502; (g) Sakagami, M.; Muratake, H.; Natsume, M.
Chem. Pharm. Bull. 1994, 42, 1393e1398; (h) Fukuyama, T.; Chen, X. J. Am. Chem.
Soc. 1994, 116, 3125e3126; (i) Kinsman, A. C.; Kerr, M. A. Org. Lett. 2001, 3,
3189e3191; (j) Kinsman, A. C.; Kerr, M. A. J. Am. Chem. Soc. 2003, 125,
14120e14125; (k) Chandra, A.; Johnston, J. N. Angew. Chem., Int. Ed. 2011, 50,
7641e7644; (l) Rafferty, R. J.; Williams, R. M. J. Org. Chem. 2012, 77, 519e524;
(m) Lu, Z.; Yang, M.; Chen, P.; Xiong, X.; Li, A. Angew. Chem., Int. Ed. 2014, http://
dx.doi.org/10.1002/anie.201406626 Early View. For a formal synthesis, see: (n)
Rafferty, R. J.; Williams, R. M. Heterocycles 2012, 86, 219e231.
18. Richter, J. M.; Whitefield, B. W.; Maimone, T. J.; Lin, D. W.; Castroviejo, M. P.;
Baran, P. S. J. Am. Chem. Soc. 2007, 129, 12857e12869.
19. Mehta, G.; Acharyulu, P. V. R. J. Chem. Soc., Chem. Commun. 1994, 2759e2760.
20. Gribble, G. W.; Lord, P. D.; Skotnicki, K.; Dietz, S. E.; Eaton, J. T.; Johnson, J. L. J.
Am. Chem. Soc. 1974, 96, 7812e7814.
21. Schkeryantz, J. M.; Woo, J. C. G.; Siliphaivanth, P.; Depew, K. M.; Danishefsky, S.
J. D. J. Am. Chem. Soc. 1999, 121, 11964e11975.
22. Schultz, A. G.; Guzzo, P. R.; Nowak, D. M. J. Org. Chem. 1995, 60, 8044e8050.
23. (a) Larock, R. C.; Babu, S. Tetrahedron Lett. 1987, 28, 5291e5294; (b) Burns, B.;
Grigg, R.; Ratananukul, P.; Sridharan, V.; Stevenson, P.; Worakun, T. Tetrahedron
Lett. 1988, 29, 4329e4332.
€
24. Herrmann, W. A.; Brossmer, C.; Ofele, K.; Reisinger, C.-P.; Priermeier, T.; Beller,
M.; Fischer, H. Angew. Chem., Int. Ed. 1995, 34, 1844e1848.
25. Baird, K. J.; Grundon, M. F.; Harrison, D. M.; Magee, M. G. Heterocycles 1981, 15,
713e717.
26. Trost, B. M.; Quancard, J. J. Am. Chem. Soc. 2006, 128, 6314e6315.
27. Kimura, M.; Futamata, M.; Mukai, R.; Tamaru, Y. J. Am. Chem. Soc. 2005, 127,
4592e4593.
28. Baran, P. S.; Guerrero, C. A.; Corey, E. J. Org. Lett. 2003, 5, 1999e2001.
29. Turro, N. J. Modern Molecular Photochemistry, Chapter 13; University Science
Books: Sausalito, CA, 1991.
30. For reviews in protecting-group-free synthesis, see: (a) Hoffmann, R. W. Syn-
thesis 2006, 3531e3541; (b) Young, I. S.; Baran, P. S. Nat. Chem. 2009, 1,
193e205; (c) Saicic, R. N. Tetrahedron 2014, 70, 8183e8218.
15. Synthetic approaches toward the welwitindolinone family of natural products:
(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,
6326e6327; (b) Deng, H.; Konopelski, J. P. Org. Lett. 2001, 3, 3001e3004; (c)
ꢀ
Jung, M. E.; Slowinski, F. Tetrahedron Lett. 2001, 42, 6835e6838; (d) Lopez-Al-
ꢀ
~
varado, P.; García-Granda, S.; Ivarez-Rua, C.; Avendano, C. Eur. J. Org. Chem.
~
ꢀ
2002, 1702e1707; (e) Avendano, C.; Menendez, J. C. Curr. Org. Synth. 2004, 1,
65e82; (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, 1270e1272; (g)
MacKay, J. A.; Bishop, R. L.; Rawal, V. H. Org. Lett. 2005, 7, 3421e3424; (h)
Please cite this article in press as: Maimone, T. J.; et al., Tetrahedron (2014), http://dx.doi.org/10.1016/j.tet.2014.11.010