Structure, bioactivity and synthesis of natural products with hexahydropyrrolo[2,3-b]indole.

Abstract

Research on natural products containing hexahydropyrrolo[2,3-b]indole (HPI) has dramatically increased during the past few years. Newly discovered natural products with complex structures and important biological activities have recently been isolated and synthesized. This review summarizes the structures, biological activities, and synthetic routes for natural compounds containing HPI, emphasizing the different strategies for assembling this motif. It covers a broad range of molecules, from small alkaloids to complex peptides.

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Structure, Bioactivity and Synthesis of Natural Products with
Hexahydropyrrolo[2,3-b]indole
Pau Ruiz-Sanchis,[a, d]Svetlana A. Savina,[a, b]Fernando Albericio,*[a, b, c]and
Mercedes ?lvarez*[a, b, d]
? 2011 Wiley-VCH Verlag GmbH&Co. KGaA, WeinheimChem. Eur. J. 2011, 17, 1388–1408
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DOI: 10.1002/chem.201001451

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Introduction
From the lushest forests to the deepest oceans, from the
simplest organisms to the most complex, nature is replete
with compounds containing either a hexahydropyrrolo[2,3-
b]indole (HPI) unit, or the corresponding 2-carboxylate or
2-carboxamide (both abbreviated HPIC) (Scheme 1). Bio-
synthetically, the simplest of these compounds stem from
the amino acid Trp, whereas the more complex ones derive
from Trp-containing peptides. Some HPI- and HPIC-con-
taining compounds contain two Trp or more units.
Structure and Bioactivity
The first structures reported to contain HPI or HPIC were
alkaloids; however, advances in the isolation and characteri-
zation of natural products later enabled identification of
medium-sized cyclic peptides containing HPI or HPIC and
exhibiting myriad biological activities. Some of these prod-
ucts are very small and are based around an HPI core, for
example, (+ +)-alline (1),[1,2]a small alkaloid with a hydroxyl
group at C3aand a methyl group at Nb. (?)-Physostigmine
(2), isolated from the seeds of the Calabar bean plant (Phys-
ostigma venenosum) is a cholinesterase inhibitor. (?)-Phys-
ostigmine is currently used to treat myasthenia gravis, glau-
coma, Alzheimer?s disease and delayed gastric emptying,
and has recently been employed to treat orthostatic hypo-
tension.[3]Further examples of these compounds alkylated
at C3ainclude the flustramines A–M (3–7), a family of alka-
loids isolated from the marine organism Flustra foliacea:[4–9]
the flustramides A, B (8), and E;[10,11]dihydroflustramine C
(9);[12](3aR*,8aS*)-6-bromo-3a-[(2E)-3,7-dimethyl-2,6-octa-
dienyl]-1,2,3,3a,8,8a-hexahydropyrrolo[2,3-b]indol-7-ol;[13]
debromoflustramines B[8]and H;[9]five recently discovered
alkaloids isolated from the plant Selaginella moellendorfii;[14]
the flustraminols A and B,[6]both part of the flustramines
family and characterized by a hydroxyl group at C3a; and
(?)-pseudophrynaminol (10), extracted from the Australian
frog Pseudophryne coriacea[15](Scheme 1).
The HPIC unit is found in products such as the okara-
mines A–Q (11), isolated from the fungus Penicillium sim-
plicissum.[16–22]In okaramines the HPIC is condensed to a di-
ketopiperazine (DKP) unit formed from a second amino
acid. Leptosins D–F (12–14),[23]gliocladines C–E (15–17),[24]
gliocladins A–C,[25]plectosphaeroic acids A–C (18, 19),[26]
(+ +)-asperazine (20),[27]and naseseazines A and B[28]have an
analogous DKP unit containing an extra indole, bound be-
tween C3and C3a(except for in the case of (+ +)-asperazine
and the naseseazines, in which the indole binds via C7and
C6, respectively). Brevicompanines A–H (21: A, 22: B),
allo-brevicompanine B and fructigenine B[29–31]are also alky-
lated at C3a; as is ardeemin, isolated from a strain of Asper-
gillus fischeri;[32]roquefortines C, D (23), F and G;[33–36]and
aszonalenin (24).[37]Brevianamide E (25),[38]the sporides-
mins[39–42]and notoamide D[43]are all hydroxylated at C3a
(Scheme 1).
Natural compounds containing two or more HPI or HPIC
units are shown in Scheme 2. These include amauromine
(26) and gypsetin (27), dimeric alkaloids in which two HPIC
units are condensed through a DKP. Amauromine, obtained
from the culture broth of Amauroascus sp, has vasodilating
activity,[44,45]and gypsetin is an inhibitor of acyl-CoA.[46,47]
Natural products containing two HPI units comprise the
botanical compound (?)-chimonanthine (28)[48–51]or its opti-
cal antipode, (+ +)-chimonanthine, found in the skin of the
Colombian poison dart frog, Phyllobates terribilis[49]and in
Psychotria colorata flowers.[52]Chimonanthines are dimeric
HPIs linked between the C3aof each unit. Related com-
pounds include meso-chimonanthine;[53](?)-chimonanthi-
dine (29);[51](?)-calycanthidine (30);[51]Nb-desmethyl-meso-
Abstract:
Research onnaturalproductscontaining
hexahydropyrrolo[2,3-b]indole (HPI) has dramatically in-
creased during the past few years. Newly discovered natu-
ral products with complex structures and important bio-
logical activities have recently been isolated and synthe-
sized. This review summarizes the structures, biological
activities, and synthetic routes for natural compounds con-
taining HPI, emphasizing the different strategies for as-
sembling this motif. It covers a broad range of molecules,
from small alkaloids to complex peptides.
Keywords: alkaloids · heterocycles · natural products ·
peptides
[a] P. Ruiz-Sanchis, Dr. S. A. Savina, Prof. Dr. F. Albericio,
Prof. Dr. M. ?lvarez
Institute for Research in Biomedicine, Barcelona Science Park
Baldiri i Reixac 10, 08028 Barcelona (Spain)
[b] Dr. S. A. Savina, Prof. Dr. F. Albericio, Prof. Dr. M. ?lvarez
CIBER-BBN, Networking Centre on Bioengineering
Biomaterials and Nanomedicine, Barcelona Science Park
Baldiri i Reixac 10, 08028 Barcelona (Spain)
[c] Prof. Dr. F. Albericio
Department of Organic Chemistry, University of Barcelona
08028 Barcelona (Spain)
E-mail: fernando.albericio@irbbarcelona.org
mercedes.alvarez@irbbarcelona.org
[d] P. Ruiz-Sanchis, Prof. Dr. M. ?lvarez
Laboratory of Organic Chemistry, Faculty of Pharmacy
University of Barcelona, 08028 Barcelona (Spain)
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chimonanthine;[50]and the antifungal agent (?)-folicanthine
(31)[54]which was isolated from both Calycanthus flori-
dus[55,56]and the seeds of Chimonanthus praecox.[51]The ab-
solute configuration of (?)-31 was determined by chemical
correlation with (?)-28[51]and the total synthesis of its enan-
tiomer (+ +)-31.[57]Furthermore, psycholeine,[58]meso-pseudo-
phrynamine A[15]and the recently isolated flustramines O
(32) and P (33)[9]each have two HPI units (Scheme 2).
Natural compounds containing more than two HPI units
comprise idiospermuline(34)[59]
(35),[50,52,60,61]with three HPI units; psychopentamine[62]and
quadrigemines A, B, C (36), and I,[50,52,58,61,63]with four.
Quadrigemine C is a weak antagonist of the SRIF (somatos-
tatin) receptor, like psycholeine and meso-pseudophryna-
mine A. Isopsychotridines A and B (37)[61]and psychotri-
dine, with five;[50,61]oleoidine,[50]with six; and caledonine,[50]
with seven.
Another important group comprises dimeric HPICs
linked by the C3aof each unit, each of which contains a
DKP.Theseincludetheneurokinin
WIN64821 (38) and (+ +)-WIN64745 (39), both isolated from
a strain of Aspergillus sp.;[64–66](?)-ditryptophenaline (40),
obtained from Aspergillus flavus;[67]the antiviral agent (+ +)-
asperdimin (41), isolated from extracts of Aspergillus
niger;[68]chaetocin (42), isolated from the fermentation
broth of Chaetomium minutum;[69]verticillins A (43), B, and
C, obtained from Verticillium sp., exhibit antimicrobial ac-
tivity against Gram-positive bacteria and potent antitumor
activity in HeLa cell lines;[70–72]gliocladines A (44) and B
(45);[24]11,11’-dideoxyverticillin A and 11’-deoxyverticillin
A;[24,73]melinacidins;[74–76]Sch52900 and Sch52901;[24]and
some leptosins A (46), B (47), and C (48).[23]Leptosins C
and F, isolated from the marine fungus Leptoshaeria sp.,
have inhibitory activity against topoisomerases I and II[77]
(Scheme 2).
Several products isolated (Scheme 3) recently feature a
bond between the C3aof an HPI or HPIC unit and the N1of
a modified tryptamine or Trp, such as that found in the alka-
loid psychotrimine (49).[62]Another noteworthy example is
the epipolythiodioxopiperazine family, whose members ex-
hibit numerous bioactivities, including antitumor, antimicro-
bial, antinematodal and cytotoxicity; notable members in-
clude the chetomin (50), chaetocochins A (51), B (52), and
C, and dethio-tetra(methylthio)chetomin, all isolated from
the solid-state fermented rice culture of the fungus Chaeto-
mium cochliodes.[78–84]An extra degree of complexity is
shown in kapakahines C (53) and D (54), which are macro-
cyclic peptides formed through a bond between the N8of an
HPIC located at the N-terminal of the linear structure and
the C4aof an a-carboline unit, located close to the C-termi-
nal.[85]
Natural products with an HPIC integrated into the pep-
tide chain include omphalotins B–I (D: 55),[86,87]phakellista-
tin 3 (56) and isophakellistatin 3;[88]himastatin (57), in
which the HPIC is part of a depsipeptide-chain;[89,90]its
structure and stereochemistry was revised after the total
synthesis.[91,92]Other similar natural products are chloptosin
and the hodgkinsines
antagonists(+ +)-
Pau Ruiz-Sanchis is currently a doctoral
student at the Institute for Research in Bio-
medicine at the Barcelona Science Park
under the supervision of Dr. Mercedes ?l-
varez and Dr. Fernando Albericio. His
thesis project is on the synthesis of marine
natural products containing heterocyclic
peptides.Mr.Ruiz-Sanchis earned
B.Sc. in chemistry at the University of Va-
lencia. His research interests include the
development of new methodologies for
solid- and solution-phase synthesis as well
as the discovery and isolation of new bio-
active compounds.
his
Dr. Svetlana A. Savina is a postdoctoral
researcher at the Barcelona Science Park?s
Institute for Research in Biomedicine and
the University of Barcelona. She received
her MS in 2002 at Moscow State Academy
of Fine Chemical Technology and her
PhD in Organic Chemistry in 2004 from
D. Mendeleev?s University of Chemical
Technology, also in Moscow. She began
her university studies in 1998 at the State
Research Centre of Organic Intermediates
and Dyes (NIOPIC; Dept. of Medicinal
Chemistry) and continued her research
career at the State Research Center for An-
tibiotics (GNCA; Dept. of Medicinal Chemistry) from 2003 to 2007 under
the supervision of Prof. Vladimir G. Granik.
Dr. Fernando Albericio is currently Gener-
al Director of the Barcelona Science Park,
Professor at the University of Barcelona,
and Group Leader at the Institute for Re-
search in Biomedicine. He received his
PhD in Chemistry at the University of Bar-
celona. He has published over 500 papers,
several review articles and 35 patents, and
has co-authored three books. Dr. Albericio
is an editor for various scientific journals
and serves on the editorial board of several
others. His major research interests cover
practically all aspects of peptide synthesis
and combinatorial chemistry methodolo-
gies, as well as the synthesis of therapeutically interesting peptides and
small molecules.
Dr. Mercedes ?lvarez presently holds a
double appointment as Professor at the
University of Barcelona and Researcher at
the Barcelona Science Park?s Institute for
Research in Biomedicine. She earned her
PhD in Chemistry from the University of
Barcelona (UB) under the supervision of
Prof. Ricardo Granados. Dr. ?lvarez spent
a sabbatical year at Manchester University
working with Prof. John A. Joule. In 2002
she moved her research group to the Bar-
celona Science Park (PCB). Her research
interests comprise the synthesis of natural
products, heterocyclic chemistry, combina-
torial chemistry and solid-phase methodology.
www.chemeurj.org
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(58);[93]NW-G01, an antibiotic isolated from Streptomyces
alboflavus;[94]and kutznerides 1–9 (1: 59)[95,96](Scheme 4).
Most of these complex structures have only recently been
isolated. The literature contains a few reviews, although
these appear to cover only specific aspects of these com-
pounds. These include works by Schmidt and Movassaghi,[97]
on biosynthetic hypotheses; Steven and Overman,[98]on syn-
theses of poly-HPI compounds; and Crich and Banerjee,[99]
on the stereochemistry of HPI containing-compounds, as
well as classical publications on the Calabar bean alka-
loids,[100,101]phenserine,[102]chimonanthine and related natu-
ral products,[103,104]chaetocin and related natural prod-
ucts,[105]and the chemistry of cyclic tautomers of tryptamines
and Trp.[106,107]
This article provides an exhaustive overview of the struc-
ture, synthesis and bioactivity of HPI and HPIC containing
natural products from all of the aforementioned structural
classes, emphasizing the synthetic routes to polycyclic com-
pounds of this type published until December 2009. Alka-
loids containing a poly-HPI linked at the quaternary car-
bons, such as quadrigemine C, have been omitted here be-
cause they have already been covered in an excellent report
by Steven and Overman.[98]
Syntheses of Natural Products Containing HPI or
HPIC
Several procedures have been developed for the synthesis of
HPI and HPIC units, chiefly in the context of natural prod-
uct syntheses. Scheme 5 illustrates known routes to tricyclic
HPI and HPIC.
The most widely used starting materials for the synthesis
of tricyclic HPI and HPIC are functionalized indoles (or oxi-
dized indoles), tryptamines or Trp?s (see Scheme 5). Routes
A through C comprise bond formation between Nband C8a.
In route D, the bonds C8a?Nband C2?Nbare formed from a
diketo derivative of indole. Route E entails introduction of
C2by formation of the bonds Nb?C2and C2?C3, using di-
chloroketene and an indolyl sulfylimine. In route F, HPI is
performed by reductive cyclization. Route G affords HPI
after the rearrangement of an acyloxy group. Route H in-
Scheme 1. Natural products containing a single HPI or HPIC unit (shown in red).
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volves bond formation between N8and C8afrom a 3-(nitro-
cyclohex-1-enyl)pyrrolidin-2-one. Route I comprises Fischer
indolization, namely, via condensation of phenylhydrazines
with latent aldehydes. Route J involves simultaneous forma-
tion of the bonds N8?C8aand Nb?C8a. Lastly, route K, in
which HPIC is assembled via formation of the bonds C3a?
C8aand Nb?C2, is based on the aza-Pauson–Khand reaction
(APKR).
Acid-catalyzed cyclization
In route A (Scheme 5), HPIC ring closure is acid-catalyzed.
This involves protonation of indole at C3, followed by cap-
ture of the resulting indoline by the protected amine of the
lateral chain. This procedure has been extensively used,
starting from protected tryptamine, Trp or even more com-
plex compounds.
The Trp derivative 60 cyclized in 85% H3PO4to yield two
diastereomers of the corresponding HPIC in a thermody-
namic ratio of 9:1 (61/62, endo/exo).[108]However, if these
products are not stabilized in solution by acylation or sulfo-
nylation of N8, they degenerate back to the starting material
(Scheme 6).[106]
A solution of Na-methoxycarbonyl-l-Trp 60 in trifluoro-
acetic acid (TFA) gave, after equilibration, mainly the endo-
HPIC 61 plus minor amounts of the exo-HPIC 62 and start-
ing material. Addition of trifluoroacetic acid anhydride
(TFAA) to the solution afforded the two corresponding tri-
fluoroacetyl analogues.[109]
Scheme 2. Natural products containing two or more HPI or HPIC units (shown in red).
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Treatment of 60 with TFAA in dry pyridine afforded a
complex mixture. The main constituents were the adduct 63
(50%) and the N1-trifluoroacetylated Trp 64.[110]The exact
structure of 63, including the stereochemistry of its three
stereogenic centers, were unequivocally established by X-
ray analysis (Scheme 7).[111]
Crich et al. described a diastereoselective synthesis of the
non-naturally occurring (+ +)-debromoflustramine B (69) and
related compounds from the l-Trp-derived HPIC 65.[112]
Diastereomerically and enantiomerically pure sulfonamide
65 obtained by phenylsulfonylation of 61 was used to pre-
pare HPI alkaloids. The main transformations comprised
functionalization and C?C bond formation at C3a; Barton et
al.[113]reductive decarbomethoxylation at C2; and sequential
selective deprotection and alkylation of the two nitrogen
centers (Scheme 8).
Sequential oxidation-cyclization (A, Scheme 5)
This methodology exploits the reactivity of compounds such
as tryptamine or Trp at their 3-substituted indole position to
oxidants such as 2,2-dimethyldioxirane (DMDO), N-bromo-
Scheme 3. Natural products containing an HPI or HPIC unit (show in red) bound through C3ato the N of an HPIC unit, tryptamine or Trp.
Scheme 4. Natural products containing HPIC (shown in red) as part of a peptide chain.
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succinimide (NBS), and phenyl-
selenyl chlorides, whereby the
resulting imine or iminium salt
intermediate is captured by the
lateral nitrogen.
Bromination–cyclization:
Witkop et al. prepared the tri-
cyclic pyrrolo[2,3-b]indoles 73
and 74 by reacting Trp 71 and
tryptamine
72,
with NBS at pH 9.2 in a very
dilute solution at room temper-
ature.[114,115]Compound 73 was
slowly reduced over Rh/Al2O3
(as catalyst) in EtOAc to yield
HPIC 77, which was then acety-
lated with Ac2O in pyridine to
give 78. Reaction of tBuOCl
with 73 gave the unstable 3a-
respectively,
chloroindolenine 75. Analogously, oxidation of 73 with Pb-
(OAc)4in CH2Cl2gave the 3a-acetoxyindolenine 76, which
was rapidly reduced by NaBH4in MeOH to the 3a-acetox-
yindoline 79, which in turn was converted to the correspond-
ing diacetyl derivative 80 for structural characterization
(Scheme 9).
Lobo and Prabhakar reported a total synthesis of (?)-de-
bromoflustramine B (69) from the Witkop HPIC 81
(Scheme 10).[116,117]Their route starts with consecutive C3a
allylation of 81, followed by reduction and N8-allylation to
afford a diastereomeric mixture of endo and exo methyl
esters. These esters had to be transformed into the corre-
sponding Barton esters[118]for separation. Oxidative removal
of 2-carboxylate from exo-83 using Sb(SPh)3, followed by re-
duction, Nb-deprotection and methylation furnished (?)-69.
Likewise, endo-83 gave (+ +)-69 (not shown).
Using Br2or NBS without base enabled bromination-cyc-
lization of protected Trp or derivatives. Danishefsky et al.
Scheme 5. Synthetic strategies for constructing tricyclic HPI and HPIC.
Scheme 6. Acid-catalyzed cyclization of N-protected-l-Trp 60.[108]a) 85%
H3PO4.
Scheme 7. Cyclization of protected N-protected-l-Trp 60.[110]a) TFAA,
Pyr.
Scheme 8. Synthesis of (+ +)-debromoflustramine B (69) by Crich.[112]
a) NBS, CCl4, D, 60–70%; b) Bu3SnCH2CH=CH2, D, 80%; c) NaIO4,
OsO4, 83%; d) Ph3P=CMe2, 64%; e) KOH, MeOH, 89%; f) 70, Et3N;
g) tBuSH, hn, 61% (2 steps); h) KOH, MeOH, D, 99%; i) NaBH3CN,
HCHO, AcOH; j) KOH, MeOH, 79% (2 steps); k) Na, NH3; l) prenyl
bromide, 57% (2 steps). NBS = N-bromosuccinimide.
Scheme 9. Cyclization of tryptamine and Trp by Witkop et al.[114]a) NBS,
pH 9.2; b) tBuOCl or Pb(OAc)4, 23–57%; c) H2, Rh/Al2O3, 30%;
d) NaBH4, MeOH, 08 8C; e) Ac2O, Pyr.
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pursued NBS cyclization[91,119]in preliminary studies on the
total synthesis and structural characterization of himastatin
(57). In the total synthesis of (+ +)-11,11’-dideoxyverticillin A,
Movassaghi et al. used bromine and acetonitrile to obtain
3a-bromo-HPIC.[120]de Lera et al. studied the mechanism
and proposed the addition of pyridinium p-toluenesulfonate
(PPTS) to improve the yield of the bromocyclized product
in the reaction with NBS.[121]
Synthesis of 3a-hydroxy-HPIC: Photochemical oxidation of
Nb,N1-dimethyltryptamine (85) in CH2Cl2using pyridine N-
oxide as oxygen source afforded the HPI (?)-87.[122]The
proposed mechanism involves opening of intermediate 2,3-
oxide 86 by methylamine residue (Scheme 11).
Photocyclization of N-methoxycarbonyltryptamine in the
presence of (?)-nicotine followed by treatment with triphe-
nylphosphine produced 3-hydroxy-1-methoxycarbonyl-HPI
with modest enantioselectivity.[123]Similar results were ob-
tained using protected Trp.
Danishefsky et al. developed a route to 3a-hydroxy-HPIC
based on oxidative cyclization of Trp,[92]in work on the total
synthesis of himastatin (57). They also revised and con-
firmed stereochemistry of the natural product. The tert-butyl
ester of Na-Tr-l-Trp (88) reacts with DMDO to give 89. Pro-
tecting groups exchange and iodination at position 5 gave 90
which was later dimerized (Scheme 12).
Oxidative cyclization was the key step in the enantioselec-
tive total synthesis of the complex alkaloid okaramine N
(93) by Corey et al.[124]They developed a new method for
the selective differentiation of the two indole subunits of 91.
The commercially available reagent N-methyl-1,3,4-triazo-
line-2,5-dione (MTAD) was used in a novel application: re-
versible blocking of the N-unsubstituted indole subunit,
which enabled oxidative ring-closure between the DKP and
the N-substituted indole ring. The bisindole 91 underwent
highly selective reaction with MTAD to form exclusively the
ene product at C3of the N-unsubstituted indole subunit.
Subsequent photooxidation, employing methylene blue as
photosensitizer under sunlamp irradiation, followed by re-
duction of the resulting product by Me2S in MeOH, afford-
ed the hydroxylated octacycle 92 cleanly (with only a minor
amount of diastereomer). The blocking group was eliminat-
ed by thermolysis of the mixture of 92 and the diastereomer
to furnish 93 in good total yield (Scheme 13).
Phenylselenocyclization: The total synthesis of amauromine
26 from 95 (Scheme 14) has been reported. The keystone of
this approach was kinetic stereoselective synthesis of 95
from Ni,Na-diBoc protected l-Trp methyl ester via seleno-
cyclization reaction.[125]Treatment of protected Trp 94 with
N-phenylselenophthalimide (N-PSP) and PPTS gave 95. The
Scheme 10. Total
a) NaH, DMF, prenyl bromide, 60%; b) NaBH3CN, MeOH, 85%;
c) K2CO3, THF, prenyl bromide, 71%; d) NaOH, aq. MeOH; e) H3O+ +;
f) 84, PBu3, CH2Cl2, 08 8C, 62% (3 steps); g) diastereomeric separation;
synthesis of(?)-debromoflustramineB(69).[116]
h) Sb(SPh)3, O2, Et2O, 0 ! 188 8C, 64%; i) xylene, D, 72%; j) 4.7m
NaOMe, MeOH, NH2NH2, H2O, D, 54%; k) LiAlH4, Et2O, 08 8C, 70%;
l) NaH, MeI, THF, 46%.
Scheme 11. Photochemical oxidation of Nb,N1-dimethyltryptamine (85)
by pyridine N-oxides.[122]a) hn, 253–7 nm; b) 11%.
Scheme 12. Tandem oxidation-cyclization of Trp by Danishefsky et al.[92]
a) DMDO, CH2Cl2, ?788 8C, 70%; b) AcOH, MeOH, CH2Cl2; c) CbzCl,
Pyr, CH2Cl2; d) TBSCl, DBU, MeCN; e) ICl, 2,6-di-tert-butylpyridine,
CH2Cl2, 75%.
Scheme 13. Enantioselective
a) MTAD, CH2Cl2, ?58 8C; b) O2, hn, MeOH, methylene blue, ?288 8C;
c) SMe2, MeOH, ?28 ! ?108 8C; d) 1108 8C, 70% (4 steps).
synthesisofokaramineN(93).[124]
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synthesis of 95 was the first construction of exo-HPIC from
a protected Trp in a high diastereoselective manner. Trans-
formation of phenylselanylHPIC 95 with methyl trifluoro-
methanesulfonate (MeOTf) in the presence of 2,6-di(tert-bu-
tyl)pyridine and prenyltri(n-butyl)tin gave the angular re-
verse prenyl derivative 97.
Roquefortine D (23) was prepared from the inverse pre-
nylated-HPI 97, which was reacted with protected His under
peptide coupling conditions followed by removal of both N-
tert-butoxycarbonyl (Boc) groups, cyclization, and finally,
photolytic elimination of the o-nitrobenzyl protecting group
(ONB) of the resulting imidazole.[126,127]
Ley et al. described a path to stereocontrolled synthesis of
the 3a-hydroxypyrrolo[2,3-b]indole skeleton (Scheme 15).[128]
The procedure is based on a two-step selenocyclization–oxi-
dative deselenation sequence. Treatment of 99 in the condi-
tions described by Danishefsky[125]gave 100 as a simple dia-
stereomer with an excellent yield. The following oxidation
with m-chloroperbenzoic acid (mCPBA) gave the desired
product exo-101.
The same group later used this two-step sequence in an
elegant and concise total synthesis of (+ +)-okaramine C (11)
by epimerization at C2of 100 to obtain endo-101, formation
of the DKP with the Trp 104 and introduction of isoprenyl
on N8(Scheme 16). Isoprenyl group was afforded after par-
tial reduction of the alkyne introduced by N8-alkylation
using 2-bromo-2-methylbut-3-yne.[129]
Alkylative cyclization
Cyclization with electrophiles (A, Scheme 5): This proce-
dure uses the reactivity of indole nucleous of tryptamine or
tryptophan with alkylating agents over the substituted 3-po-
sition, followed by in situ capture of the resulting indoline
by the protected lateral amine.
Nakagawa and Kawahara described a concise synthesis of
desoxyeseroline (108),[130]a precursor of physostigmine (2)
(Scheme 17<xschr17).[131]Their route was based on a Lewis
acid-catalyzed alkylative cyclization of 1,3-dimethylindole
with N-benzyloxycarbonyl (Cbz) protected aziridine to form
compound 107, which is readily converted into physostig-
mine. They tested several Lewis acids, finding Sc(OTf)3and
TMSCl in dichloromethane to be the best conditions.
Scheme 14. Total synthesis of amauromine (26).[125]a) N-PSP, CH2Cl2,
PPTS, 93%; b) MeOTf, 2,6-di(tert-butyl)pyridine, Me2C=CHCH2SnBu3,
CH2Cl2, ?788 8C ! reflux, 60% (9:1 exo/endo); c) NaOH, THF, MeOH,
H2O, reflux, 98%; d) TMSI, MeCN, 08 8C, 83%; e) 97, BOP-Cl, Et3N,
CH2Cl2, 58%; f) TMSI, MeCN, 08 8C, 58%. BOP = (benzotriazol-1-yloxy)-
tris(dimethylamino)phosphonium chloride.
Scheme 15. Two-step route to 3a-hydroxy HPIC exo-101 by Ley et al.[128]
a) N-PSP, PPTS, Na2SO4, CH2Cl2, 93%; b) wet mCPBA, K2CO3, CH2Cl2,
0!258 8C, quant.
Scheme 16. Total synthesis of (+ +)-okaramine C (11).[129]a) H3PO4aq.,
CH2Cl2; b) H2, Pd/C, MeOH, 93% (2 steps); c) HATU, DMF, 104, Et3N,
95%; d) TASF, DMF, 97%; e)HC?CC(Me)2Br, CuCl, THF, DIEA, RT,
88%; f) Lindlar’s cat., H2, 99:1 MeOH/Pyr, 95%. HATU = 2-(7-aza-1H-
benzotriazole-1-yl)-1,1,3,3-tetramethyluronium
TASF = tris(dimethylamino)sulfonium difluorotrimethylsilicate.
hexafluorophosphate;
Scheme 17. Alkylative cyclization of 1,3-dimethylindole.[130]a) Sc(OTf)3,
TMSCl, CH2Cl2, ?308 8C, 52%; b) Red-Al, toluene, reflux, 95%.
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Reaction of Nb-protected tryptamine with allyl bromides
afforded the Nb-protected 3a,8-bisallyl-HPI,[133](?)-debro-
moflustramides B and E and (?)-debromoflustramines B
and E have been prepared using this procedure.[134]
Nakagawa et al. synthesized (?)-esermethole (112) using
an alkylative cyclization.[135]Reaction of Corey–Kim reagent
(113) with tryptamine carbamate 109 and iPr2NEt gave the
HPI 110. Simultaneous reductive methylation and desulfuri-
zation of 110 were achieved by hydrogenation using Raney
Ni (W2) and aqueous HCHO to give 111, which was then
reduced with Red-Al to give (?)-112 in quantitative yield
(Scheme 18).
The Ganesan group published a fast and elegant three-
step total synthesis of (?)-debromoflustramine B (69) via
zinc triflate-mediated biomimetic alkylative cyclization from
tryptamine (Scheme 19).[136]
(?)-Flustramine B (4) and
(?)-debromoflustramine B (69)
were enantioselectively synthe-
sized in routes based on orga-
nocatalytic preparation of pyr-
roloindoline (Scheme 20). Ad-
dition of tryptamine 116 to a,b-
unsaturated aldehydes in the
presence of
catalysts 119 gave the cyclized
pyrroloindoline adduct 117 in
high yield and with excellent
imidazolidinone
enantioselectivities. Adduct 117 was transformed into (?)-4
and (?)-69 using common synthetic procedures, in excellent
yields and with high ee values.[137]
A one-pot synthesis of (?)-deoxypseudophrynaminol[138]
was afforded with moderate yield from the commercially
available Nb-methyltryptamine by transformation into the
corresponding Grignard reagent, followed by addition of 4-
bromo-2-methyl-2-butene, the target in moderate yield. Sim-
ilar chemistry was recently exploited to synthesize isoroque-
fortine C and roquefortine C.[139]
A slightly modified version of this strategy recently ena-
bled preparation of isoroquefortine E (122).[140]A Horner–
Wadsworth–Emmons reaction was the key step to building
the dehydroamino acid 121, which was then underwent
DKP formation (Scheme 21).
(?)-Ardeemin (127) and its N-acyl analogues have been
synthesized from l-Trp in 20 steps in approximately 2%
overall yield (Scheme 22).[141]One-pot reaction of 123 with
the diazoester 128 gave the chiral 3a-substituted HPI 124
containing the proper configuration in three stereocenters.
(?)-127 was prepared from the tetracyclic compound 124
via the following steps: transformation of the ethyl acetate
Scheme 18. Synthesis of (?)-esermethole (112) by Nakagawa et al.[135]
a) 113, iPr2NEt, ?788 8C, 88%; b) H2, Ni-Raney (W2), aq. HCHO, EtOH,
reflux, 80%; c) Red-Al, toluene, reflux, 96%.
Scheme 20. Enantioselective syntheses of (?)-flustramine B (4) and (?)-
debromoflustramine B (69).[137]a) Propenal, 119; b) NaBH4, MeOH,
78%, 90% ee (2 steps); c) MsCl; d) NO2PhSeCN, H2O2, 89% (2 steps);
e) Grubbs metathesis, 2-methyl-2-butene, 94%; f) TMSI; g) NaBH4,
HCHO, 89% (2 steps); h) LiAlH4, 91%.
Scheme 21. Synthesis of isoroquefortine E (122).[140]
CH2Cl2, 24%; b) TMSI; c) Et3N, 78% (2 steps).
a) 5-Isoprenyl-1H-imidazole-4-carbaldehyde, DBU,
Scheme 19. Total synthesis of (?)-debromoflustramine B (69) by Gane-
san et al.[136]a) Prenyl bromide (4 equiv), Zn(OTf)2, Bu4NI, iPr2NEt, tolu-
ene, RT, 70%; b) Red-Al, toluene, reflux, 96%.
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substituent into the corresponding isoprenyl group, hydroly-
sis of the cyclic carbamate, and orthogonal protection of
both amino groups to give 125, which was converted into
the DKP 126. Finally, formation of the last benzopyrimidone
condensed-ring by acylation with o-azidobenzoic anhydride
followed by cyclization.
Li et al. recently devised an innovative route to aszonale-
nin (24) and similar alkaloids structure. They employed the
enzyme AnaPT, a prenyltransferase, to catalyze the prenyla-
tion of (R)-benzodiazepinedione 129 in the presence of di-
methylallyldiphosphate
(Scheme 23).[142]
(DMAPP) toafford
24
Cyclization with nucleophiles (B, Scheme 5): This procedure
is based on a Michael addition of a nucleophile on the 3-po-
sition of 2-hydroxyindolin-3-ylideneacetate followed by in
situ lactonization.
The Joseph-Nathan group devised total syntheses of (?)-
flustramines A (3) and B (4), (?)-flustramides A (134) and
B (8), and (?)-debromoflustramines A (135) and B (69)
(Scheme 24).[143,144]A conjugate addition of a prenylmagne-
sium bromide specie to 2-hydroxyindolenines 130 to give
the C3-epimeric lactone 131. Decyanation of the resulting a-
cyano-g-lactones with wet alumina in refluxing THF, fol-
lowed by N-deprotection and allylation, gave compounds
133, which, upon N-methyl insertion under the appropriate
conditions, afforded the desired target natural compounds.
Same procedure was used by for the synthesis of dihydro-
flustramine C (9) and flustramine E.[145]
Successive alkylation cyclization of oxoindoles (C, Scheme 5)
Pyrrolidine formation of HPIC from 2-oxoindoles consists in
an enolate alkylation followed by Nb?C8areductive bond
formation.
Julian and Pilk synthesized (?)-eserethole (138)[146]based
on their previous work on HPI assembly.[147,148]Their ap-
proach was actually part of a formal synthesis of physostig-
mine (2).[149–150]The route shown in Scheme 25 comprises a-
alkylation of the oxoindole 136, followed by reduction of
the nitrile, N-methylation, and finally, reductive cyclization
to give the racemic (?)-138.
The Julian and Pilk procedure has been used extensively
to prepare Calabar alkaloids. It has been modified to im-
Scheme 22. Total synthesis of (?)-ardeemin (127).[141]a) 128, Cu(OTf)2,
CH2Cl2, ?358 8C, 82%; b) LDA, MeI, THF, ?788 8C ! RT; c) LDA, MeI,
THF, ?78 8 8C ! RT, 72% (2 steps); d) LiBH4, THF, MeOH, 08 8C, 61%;
e) DMP, CH2Cl2, RT, 92%; f) Ph3PMeI, LHMDS, THF, ?788 8C ! RT,
93%; g) KOtBu, aq tBuOH, quant.; h) (Boc)2O, CH2Cl2, RT, 95%;
i) DMP, CH2Cl2, RT, 92%; j) PCC, CH2Cl2, RT, 76%; k) NaClO2,
NaH2PO4buffer, RT, quant.; l) ClCO2iBu, Et3N, d-Ala-OMe, CH2Cl2,
08 8C, 81%; m) TMSI, MeCN, 08 8C, 98%; n) LiOH, aq. MeOH, 95%;
o) ClCO2iBu, Et3N, CH2Cl2, 08 8C ! RT, 71%; p) diastereomeric separa-
tion; q) nBuLi, o-azidobenzoic anhydride, THF, ?788 8C, 42%; r) nBu3P,
benzene, RT, 93%. LDA = lithium diisopropylamide; LHMDS = lithi-
um hexamethyldisilazide. PCC = pyridinium chlorochromate.
Scheme 23. Enzyme catalyzed synthesis of aszonalenin (24) by Li
et al.[142]
Scheme 24. Total syntheses of (?)-flustramines A (3) and B (4), (?)-flus-
tramides A (134) and B (8), and (?)-debromoflustramines A (135) and
B (69).[144]a) RMgBr, THF/Et2O, 30–47%; b) Al2O3, THF, H2O, reflux,
64–95%; c) NaOMe, MeOH, reflux; d) prenyl bromide, K2CO3, acetone,
reflux, 60–70% (2 steps); e) MeNH2, MeOH, 92–98%; f) LiAlH4, THF,
reflux, 98%; g) EtN(Me)2, AlH3, THF, 96–97%.
Scheme 25. Synthesis of (?)-eserethole (138).[146]a) ClCH2CN, NaOEt
(or Na), 84%; b) H2, Pd, 91%; c) PhCHO, then MeI followed by hydrol-
ysis, 86%; d) Na, EtOH, 99%.
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prove the oxoindole preparation,[151–160]adapted to the use
of protecting groups,[161–164]performed with chemical resolu-
tion of different intermediates,[163,165–168]and combined with
asymmetric alkylation of oxindole.[169,170]Furthermore, a
modified Julian and Pilk procedure has been used to pre-
pare numerous analogues of physostigmine (2) and related
alkaloids.[166,171–175]A. Bossi reported an interesting ver-
sion[176]to prepare a 3-aminoethyloxoindole from 5-methox-
ytryptamine.
A total synthesis of (?)-pseudophrynaminol (10) based
on diastereoselective a-alkylation of the chiral oxoindole
139 with methyl 4-bromo-2-methylbut-2-enoate (Scheme 26)
has been reported.[177]The yield and diastereoselectivity of
the process strongly depend on the solvent and base used.
Separation of the two isomers, followed by reduction of (?)-
140 with LiAlH4, gave (?)-10. The 1-phenylethylcarbamoyl
substituent on the oxoindole nitrogen not only acts as a pro-
tecting group, but also as a prochiral group for asymmetric
induction in the diastereoselective alkylation, enabling sepa-
ration of diastereomer (?)-140. Moreover, this group is
readily eliminated during reduction of the methyl ester and
the carbamate.
Identical final ring formation for the Calabar alkaloids
(?)-physovenine and (?)-2 was performed using a chiral
building block for the diastereocontrolled construction of in-
doline 142, a precursor of compound 144 (Scheme 27).[132,178]
The oxidation level of compound 144 obviates reduction
after the cyclization to form the HPI skeleton.
Hayashi employed a similar route oxoindole alkylation in
the total synthesis of CPC-1.[179]Overman?s group used the
same cyclization strategy (D, Scheme 5) for an elegant total
synthesis of (?)-phenserine (150),[180]in which alkylation of
compound 146 with the chiral bistriflate 147 was the key
step in the preparation of 149, in excellent yield and with
more than 99% ee (Scheme 28).
Same last steps (D, Scheme 5) were used in an efficient
route to either enantiomer of (?)-physostigmine (2), and
theirrespective congeners,
Scheme 29.[181–183]It is based on versatile, asymmetric prepa-
ration of HPIs having carbon substituents at C3a, starting
from (Z)-butenoic acid 151 and N-methyl-p-anisidine (154).
The central step is catalytic asymmetric Heck cyclization of
(Z)-2-methyl-2-butenanilide (155) to form oxindole alde-
issummarizedin
hyde (S)-149. The same group later prepared several deriva-
tives with aryl substituents at C3aof the HPI.[184]
Joseph-Nathan synthesized (?)-debromoflustramine B
(69) and its enantiomer via the racemic lactone 133
(Scheme 30). Reaction of 133 with (S)-1-phenylethylamine
provided the diastereomeric lactams 157, which were sepa-
rated, then independently reacted with methylamine and re-
duced to provide the desired targets.[185]
Trost described the earliest examples of molybdenum cat-
alyzed enantioselective allylation of prochiral nucleophiles,
reported an interesting route to (?)-esermethole (145)
based on this chemistry (Scheme 31).[186]Excellent yields
and good-to-excellent enantioselectivities were obtained
with a large variety of functionalities at the three positions
of the starting oxoindole 146, which provided 3-allyloxoin-
dole (159) with 82% ee. Oxidation of the terminal double
Scheme 26. Total synthesis of (?)-pseudophrynaminol (10).[177]a) Methyl
4-bromotiglate, NaOMe, MeOH, 08 8C, 75%, 51% d.e.; b) LiAlH4, diox-
ane, reflux, 76%.
Scheme 27. Synthesis of (?)-physostigmine (2).[132,178]a) ArNHNH2, HCl,
Pyr/H2O 9:1, reflux; b) LiAlH4, THF, 08 8C then Cbz-Cl, aq. K2CO3, 70%
(2steps); c) TBAF,THF,89%;
e) MeNH2·HCl, NaBH3CN, MeOH, 908 8C, 83%; f) Boc2O, NaHCO3,
d) Zn,AcOH/EtOH1:9,97%;
MeOH, 94%; g) Pb(OAc)4, benzene, 608 8C; h) 10% HCl, EtOAc, reflux,
80% (2 steps); i) H2, 10% Pd/C, 36% HCHO, MeOH, 80%.
Scheme 28. Total synthesis of (?)-phenserine (150) by Overman et al.[180]
a) KHMDS, THF/DMPU (98:2), ?788 8C, 70%; b) pTsOH, MeOH, H2O;
c) NaIO4, THF, H2O, 92% (2 steps), >90% ee; d) MeNH2·HCl, LiAlH4,
MgSO4, THF, 90%; e) BBr3, CH2Cl2, 91%; f) NaH, PhNCO, THF, 82%.
DMPU = 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone; KHMDS
= potassium bis(trimethylsilyl)amide.
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bond in 159 and reductive cyclization of the resulting alde-
hyde with methylamine afforded (?)-145.
A total synthesis of (?)-flustramine B (4) starting from
the spiro compound 161, enantioselectively prepared via
one-pot intramolecular Ullmann coupling and Claisen rear-
rangement of the iodoindole 160, has been reported
(Scheme 32).[187]Compound 161 into 162 was transformed
by double-bond oxidation, Wittig reaction and isomeriza-
tion. N-Prenylation of the resulting product, and subsequent
Nb?C8abond formation, yielded (?)-4.[188]
Synthesis of HPI system by rearrangements processes
[3.3]-Sigmatropic rearrangements (E, F, G, Scheme 5):
Marino et al. showed that 2-(methylsulfinyl)indole reacts
with dichloroketene to produce a lactone[189]useful for as-
sembling an HPI core. The same group later established
that lactonization of chiral vinyl sulfoxides with dichloroke-
tene occurs with complete control of the relative and abso-
lute configurations. They employed a then new class of sul-
foxylating agents, N-(alkylsulfinyl)oxazolidinones, to pre-
pare the starting chiral indolyl sulfoxide. They reported that
the size of the alkyl group on the sulfoxide positively corre-
lates with the degree of asymmetric induction.[190]Lactoniza-
tion of isopropyl indolyl sulfoxide 164, followed by desulfo-
nylation and dechlorination, gave 165 (in good enantiomeric
excess),whichwas then
(Scheme 33).
A close procedure (E, Scheme 5) was developed by
Padwa for the synthesis of (?)-desoxyeseroline (108) using
anefficientrouteto highly
transformedinto(?)-2
functionalized
g-lactams
Scheme 29. Asymmetric synthesis of (?)-physostigmine (2).[183]a) Et3N,
CH2Cl2, 238 8C; b)608 8C, 67% (2 steps); c) 10% [Pd2(dba)3]·CHCl3, 23%,
(S)-BINAP, PMP, DMA, 1008 8C; d) 3m HCl, 238 8C, 84% (2 steps), 95%
ee; e) MeNH2·HCl, Et3N, LiAlH4, THF, reflux, 88%; f) BBr3, CH2Cl2,
238 8C, then Na, Et2O, MeNCO, 63%. BINAP = 2,2’-bis(diphenylphosphi-
no)-1,1’-binaphthyl. PMP = 1,2,2,6,6-pentamethylpiperidine.
Scheme 30. Synthesis of (?)-debromoflustramine B (69).[185]a) Prenyl
bromide, 15% aq. NaOH, CH2Cl2, TBAHS, ?58 8C, 76%; b) 15% aq.
NaOH, MeOH, 40–508 8C, 87%; c) NaH, THF, RT; d) LiBHEt3, THF, 25–
308 8C, 64% (2 steps); e) (S)-1-phenylethylamine, 558 8C, then diastereo-
meric separation, 39%; f) 50% aq. AcOH, benzene, sealed tube, 1808 8C,
30%; g) 40% aq. MeNH2, MeOH, 98%; h) LiAlH4, THF, 99%.
Scheme 31. Synthesis of (?)-esermethole (145) by enantioselective allyla-
tion of 2-oxoindole by Trost.[186]a) [Mo(C7H8)(CO)3], LiOtBu, allyl tert-
butyl carbonate, THF, 98%, 82% ee; b) OsO4, NMO, NaIO4, 92%, 82%
ee; c) MeNH2, Et3N, LiAlH4, THF, reflux. NMO = N-methylmorpho-
line-N-oxide.
Scheme 32. Total synthesis of (?)-flustramine B (4).[187]a) CuCl, 2-amino-
pyridine, NaOMe, MeOH, triglyme, 1008 8C, 69%; b) OsO4, NMO, ace-
tone, H2O, RT; c) NaIO4, THF, H2O, RT; d) NaClO2, NaH2PO4?2H2O,
2-methyl-2-butene, tBuOH, H2O, THF, RT, 84% (3 steps); e) Ph3PMeBr,
nBuLi, THF, ?258 8C to RT; f) H2SO4, then MgSO4, 1,4-dioxane, 608 8C;
g) prenyl bromide, K2CO3, acetone, reflux, 18% (3 steps); h) aq. MeNH2,
MeOH, RT, 67%.
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(Scheme 34).[191]This route comprised reaction of the indolyl
sulfylimine 167 with the highly electrophilic dichloroketene
to generate a zwitterionic intermediate. Subsequent [3.3]-
sigmatropic rearrangement, followed by intramolecular trap-
ping of the Pummerer cation by the amido anion, furnished
the g-lactam product 169 in good yield. Reduction of this
compound with Zn and AcOH, followed by treatment with
HCO2H, provided 170. Removal of the N-tosyl group, fol-
lowed by N-methylation and subsequent reduction of the
lactam and the formamide, afforded (?)-108 in good total
yield.
A formal synthesis of (?)-physostigmine (2) via 3,3-rear-
rangement of a bis(enamine) was described by Lobo, Prab-
hakar et al.[192,193]
(?)-Desoxyeseroline (108) was obtained via [3.3]-sigma-
tropic rearrangement of the N-methylvinylamino skeleton of
171 (F, Scheme 5). Thermolysis of the enaminoester 171 in
o-dichlorobenzene gave the tricyclic compound 172 in excel-
lent yield. Compound 172 was easily transformed into the
carbamate 173 by a two-step sequence of N-methoxycarbo-
nylation and catalytic hydrogenation. The best conditions
they found for removing the carboxylic ester at C3com-
prised irradiation of the benzophenone oxime ester 174 in
THF/iPrOH containing a large excess of tert-butylthiol
(Scheme 35).
There is a utile route to 3-allyl-3-cyanomethylindolin-2-
ones which is also amenable to prepare structurally diverse
libraries of 3a-allyl-HPI that is based on domino reactions
of 2-allyloxyindolin-3-ones
(Scheme 36).[194,195]The process comprises olefination, iso-
of thetype
175
merization, Claisen rearrangement, and deacetylation to
give 3-allyl-3-cyanomethylindolin-2-ones of the type 178.
Reductive cyclization enabled preparation of 3a-allyl-HPI-
containing alkaloids (G, Scheme 5).
(?)-Flustramines A (3) and C, (?)-flustramide A, and
(+ +)- and (?)-debromoflustramine A were ultimately ob-
tained by this route.[196]
While studying nucleophilic substitution in indoles, the
Somei group reacted N-methoxyindole derivatives with alk-
oxides to obtain useful route for the synthesis of (?)-debro-
moflustramine B (69).[197]Further studies of the same au-
thors conducted tothe
HPIC[198,199]by a rearrangement of the 1-benzoyloxy group
of tryptamine 179 followed by cyclization to give the tricy-
clic system 181 (F, Scheme 5). The stereoselectivity of the
process was demonstrated by heating (?)-182 in refluxing
DMF to produce (?)-183 as the sole product (Scheme 37).
synthesis of3a-oxygenated
Scheme 33. Enantioselective
a) Zn/CuCl, Cl3CCOCl, THF, 08 8C; b) nBu3SnH, AIBN, toluene, reflux,
37% (2 steps), 70–75% ee; c) HCO2H, then MeCO2CHO, 94%;
d) MeNH2, ?308 8C to RT, then H2SO4 cat., DMF, 1158 8C, 68%;
e) BH3·THF, 08 8C to reflux, 64%; f) Ni-Raney (W2), THF, reflux; g) Na
cat., MeNCO, 60% (2 steps). AIBN = azobisisobutyronitrile;
synthesisof(?)-physostigmine(2).[190]
Scheme 34. Synthesis of (?)-desoxyeseroline (108).[191]a) Zn/Cu, THF,
Cl3CCOCl, 78%; b) Zn, AcOH, TMEDA, EtOH, then HCO2H, 72%;
c) Na, naphthalene, THF, 81%; d) MeI, NaH, THF, 87%; e) BH3·THF,
THF, 80%. TMEDA = tetramethylethylenediamine.
Scheme 35. Synthesis of (?)-desoxyeseroline (108) via [3,3]-sigmatropic
rearrangement.[193]a) o-Cl2C6H4, reflux, 91%; b) ClCO2Me, DMAP, Et2O,
08 8C to RT, 81%; c) H2, PtO2, MeOH, 45 psi, 93%; d) aq. NaOH, MeOH,
reflux; e) ClCO2iBu, THF, ?208 8C; f) Ph2C=NOH, Et3N, 75% (3 steps);
g) hn, iPrOH, THF, excess tBuSH, 92%; h) LiAlH4, THF, reflux, 69%;
i) aq. HCHO, NaBH3CN, 67%.
Scheme 36. Synthesis
a) Ph3P=CHCN, toluene, reflux, 70%; b) DBU, 808 8C, 72%.
of 3-allyl-3-cyanomethylindolin-2-one(178).[195]
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[1.2]-Rearrangements: (?)-Flustramine C (185) was synthe-
sized in five steps starting from Nb-methyltryptamine. The
key step was biomimetic oxidation of the natural product
deformylflustrabromine (184), causing selective [1.2]-rear-
rangement of the inverse isoprenyl group and simultaneous
cyclization (Scheme 38).[200]
Formation of HPI by elaboration of indole heterocyclic ring
Reductive cyclization (H, Scheme 5): A formal total synthe-
sis of (?)-physostigmine (2) was accomplished from the
chiral nitro olefin 186 (Scheme 39) and stereochemistry of
the product was confirmed.[131]Aromatization of cyclohex-
ene, reduction of the nitro group, and subsequent aniline
protection gave 187, which was submitted to reductive cycli-
zation. Bromination of the aromatic ring, followed by
copper-catalyzed methoxy–bromine exchange afforded (?)-
esermethole (112), which was later converted to (?)-physos-
tigmine. This work constituted the first total synthesis of
(?)-2.[132]
(?)-Physovenine and (?)-2 were enantioselectively syn-
thesized from the optically active enone 188, which was first
transformed into the enone 190 via Fischer indolization and
retro-Diels–Alder chemistries.[201]Oxidation of 190 to the
lactam 192, followed by reductive cyclization, gave (?)-eser-
methole (112) (Scheme 40). The product was subsequently
transformed into (?)-physostigmine via (?)-eseroline in two
steps as had previously been described.[132]The Takano
group used the same route to assemble the non-naturally oc-
curring (+ +)-2.[202]
An efficient formal total synthesis of (?)-physostigmine
(2) in which a new vicarious nucleophilic substitution reac-
tion between p-nitroanisole and a C-silylated derivative of
N-methylpyrrolidinone was exploited to give 195.[203]a-
Methylation and reductive cyclization of 195 provided the
key intermediate N-demethylesermethole (197) in high
yield, which was transformed into the (?)-2 as had previ-
ously been described (Scheme 41).[132]
Scheme 37. Somei?s synthesis of 3a-oxygenated HPI 183.[198]a) Heating;
b) DMF, reflux.
Scheme 38. Synthesis of flustramine C (185).[200]a) NBS, THF, RT, 90%.
Scheme 39. Synthesis of (?)-esermethole (112).[131]a) Br2, KOtBu, 83%;
b) KOtBu, DMSO; c) H2, PtO2; d) ClCO2Et, 29% (3 steps); e) LiAlH4;
f) NBS, 35% (2 steps); g) NaOMe, CuI, 35%.
Scheme 40. Enantiocontrolled
(112).[201]
a) p-MeOC6H4NHNH2·HCl, aq. Pyr (1:10), reflux, 82%;
b) Ac2O, Pyr; c) NaH, MeI, DMF/THF 1:1, 86% (2 steps); d) o-Cl2C6H4,
reflux, 66%; e) O3, MeOH, then NaBH4, ?788 8C to RT, 10% HCl then
NaIO4, 62%; f) Ag2CO3on Celite, benzene, reflux, 88%; g) 40% aq.
MeNH2, sealed tube, 1808 8C, 76%; h) iBu2AlH, CH2Cl2, ?788 8C, then
NH4OH; i) LiAlH4, THF, reflux, 34% (2 steps).
totalsynthesesof(?)-ersemethole
Scheme 41. Formal total synthesis of (?)-physostigmine (2).[203]a) TASF,
THF, ?788 8C to RT; b) DDQ, 85% (2 steps); c) MeI, CsOH·H2O, CH3Ph,
TBAB, RT, 94%; d) H2, 10% Pd/C, EtOAc, 50 psi, quant.; e) LiAlH4,
THF, 60%.
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F. Albericio, M. ?lvarez et al.