Progress toward the total synthesis of (±)-actinophyllic Acid

Article abstract of DOI:10.1021/ol901746c

This paper describes ongoing progress toward the synthesis of the novel Indole alkaloid actinophyllic acid via a synthetic strategy that allows for the Installation of all C-atoms (highlighted In red) requisite for completion of a total synthesis.

Full text of DOI:10.1021/ol901746c

ORGANIC
LETTERS
2009
Vol. 11, No. 20
4532-4535
Progress Toward the Total Synthesis of
(()-Actinophyllic Acid
Rishi G. Vaswani, Joshua J. Day, and John L. Wood*
Department of Chemistry, Colorado State UniVersity, Fort Collins,
Colorado 80523-1872
john.l.wood@colostate.edu
Received July 29, 2009
ABSTRACT
This paper describes ongoing progress toward the synthesis of the novel indole alkaloid actinophyllic acid via a synthetic strategy that allows
for the installation of all C-atoms (highlighted in red) requisite for completion of a total synthesis.
Actinophyllic acid (1) was identified in 2005 by Carroll
and co-workers during a program to screen natural
products as potential therapeutic agents for the treatment
of cardiovascular disorders.1 Isolated from the leaves of
the tree Alstonia actinophylla, 1 was reported to inhibit
(IC50 ) 0.84 µM) carboxypeptidase U (CPU) during a
coupled enzyme assay. The enzyme CPU is an endogenous
inhibitor of fibrinolysis, the process that the body uses to
clear fibrin clots, and suppression of fibrinolysis by CPU
can lead to a variety of pathological consequences (i.e.,
acute myocardial infarction, pulmonary embolism, cerebral
infarction, etc.).2 It thus follows that compounds that
inhibit the action of CPU, and thereby facilitate fibrin
degradation, demonstrate potential as therapeutic agents
for the treatment of cardiovascular disorders in which
blood clots are implicated.
Figure 1. Structure of actinophyllic acid.
1,7,8-(methanetriyloxymethano)pyrrol[1′,2′:1,2]azocino-[4,3-
b]indole-8(5H)-carboxylic acid architecture. While the carbon
connectivity and relative stereochemistry of 1 were deter-
mined by extensive NMR analysis,1 assignment of the
absolute stereochemical configuration3 was only recently
made possible after the first total synthesis was disclosed
by Overman and co-workers.4 The imposing molecular
architecture and activity of 1 provided the impetus for our
synthetic efforts. Herein we report our ongoing progress
toward the total synthesis of 1.
Retrosynthetic simplification began with scission of the
C21-N bond of 1 (Scheme 1). In the synthetic direction,
cyclization of the pendant secondary amine is envisioned to
involve the intermediacy of an indole-quinonemethide5
Structurally, actinophyllic acid (1) comprises an impressive
fusion of ring systems (Figure 1). The molecular framework
represents an unprecedented 2,3,6,7,9,13c-hexahydro-1H-
(1) Carroll, A. R.; Hyde, E.; Smith, J.; Quinn, R. J.; Guymer, G.; Forster,
P. I. J. Org. Chem. 2005, 70, 1096–1099.
(2) (a) Willemse, J. L.; Hendriks, D. F. Front. Biosci. 2007, 12, 1973–
1987. (b) Schatteman, K.; Goossens, F.; Leurs, J.; Verkerk, R.; Scharpe´,
S.; Michiels, J. J.; Hendriks, D. Clin. Appl. Thromb. Hemost. 2001, 7, 93–
101. (c) Luers, J.; Hendriks, D. Thromb. Haemost. 2005, 94, 471–487. (d)
Polla, M. O.; Tottie, L.; Norde´n, C.; Linschoten, M.; Mu¨sil, M.; Trumpp-
Kallmeyer, S.; Aurkurst, I. R.; Ringom, R.; Holm, K. H.; Neset, S. M.;
Sandberg, M.; Thurmond, J.; Yu, P.; Hategan, G.; Anderson, H. Biorg.
Med. Chem. 2004, 12, 1151–1175. (e) Cesarman-Maus, G.; Hajjar, K. A.
Br. J. Hamaetol. 2005, 129, 307–321.
(3) Taniguchi, T.; Martin, C. L.; Monde, K.; Nakanishi, K.; Berova,
N.; Overman, L. E. J. Nat. Prod. 2009, 72, 430–432.
(4) For an account of this elegant approach, see: Martin, C. L.; Overman,
L. E.; Rohde, J. M. J. Am. Chem. Soc. 2008, 130, 7568–7569.
10.1021/ol901746c CCC: $40.75
Published on Web 09/16/2009
 2009 American Chemical Society

species to furnish the completed core of 1. Pentacycle 2 was
expected to arise from indole lactam 3 wherein formation
of the desired C16 quaternary center and indole ring system
occur through sequential substrate-controlled alkylation and
indolization reactions, respectively, applied to ꢀ-keto lactam
4. Further antithetic simplification revealed that 4 could
possibly evolve from a cis-divinylcyclopropane rearrange-
ment of cyclopropyl lactam 5, which in turn would arise via
an intramolecular cyclopropanation of dienyl diazoacetoac-
etamide 6.
Scheme 2. Preparation of Dienyl Diazoacetoacetamide 6
Scheme 1. Retrosynthetic Analysis to 1
to be comprised of C-H insertion products (11 and 12), in
addition to the desired cyclopropanation product (5). After
a survey of reaction parameters it was realized that copper(II)
bis(salicylidene-tert-butylamine)13 [Cu(TBS)2] effectively
promoted the cyclopropanation of 6.11,14 In the event, slow
addition of 6 to a solution of 10 mol % Cu(TBS)2 in 1,2-
dichloroethane induced the formation of the desired
3-azabicyclo[4.1.0]heptan-2-one system (5) as a single di-
astereomer, albeit in 50-60% yield.15
To construct the [6,7]-fused bicyclic lactam 4, ketone 5
was initially treated under soft enolization conditions (with
TBSOTf and Et3N) at -40 °C (Scheme 4).16,17 The resultant
enoxysilane (13) was thus poised to intercept the 1,1-
disubstituted olefin in a divinylcyclopropane rearrangement.
Accordingly, subsequent warming of enoxysilane 13 to
ambient temperatures promoted the facile [3,3]-sigmatropic
rearrangement (13 f 14), thereby unveiling 4 as a mixture
of keto-/enol-tautomers.18 The release of ring strain associ-
ated with a cyclopropane in conjunction with the syn-
stereochemical predisposition of the enoxysilane and vinyl
moiety facilitated the [3,3]-sigmatropic process.17
The synthesis commenced with the efficient and expedient
preparation of dienyl diazoacetoacetamide 6, a requisite
precursor for constructing the [6,7]-fused ꢀ-keto lactam 5
(Scheme 2). Accordingly, homopropargylic silyl ether6 7 was
treated with Grubbs’ second-generation catalyst, 4-bromo-
1-butene, and ethylene gas to furnish the bromo diene 8 via
an enyne cross-metathesis reaction.7-9 Displacement of the
bromide with benzylamine (8 f 9),10 followed by acetoac-
etamide formation using diketene (9 f 10) and a standard
Regitz diazotransfer reaction using Et3N and p-acetamido-
benzenesulfonyl azide11 (p-ABSA), afforded 6 in 75% yield
over three steps.
(12) For studies on the cyclopropanation of diazoacetamides, see: (a)
Doyle, M. P.; Eismont, M. Y.; Protopopova, M. N.; Kwan, M. M. Y
Tetrahedron 1994, 50, 1665–1674. (b) Doyle, M. P; Austin, R. E.; Bailey,
A. S.; Dwyer, M. P.; Dyatkin, A. B.; Kalinin, A. V.; Kwan, M. M. Y.;
Liras, S.; Oalmann, C. J.; Pieters, R. J.; Protopopova, M. N.; Raab, C. E.;
Roos, G. H. P.; Zhou, Q.-L.; Martin, S. F. J. Am. Chem. Soc. 1995, 117,
5763–5775.
Following the successful synthesis of 6, the metal-
catalyzed cyclopropanation reaction was investigated (Scheme
3).12 To this end, 1H NMR analysis of crude reaction
mixtures produced upon reaction of 6 in the presence of
various achiral rhodium- or copper-based catalysts clearly
indicated the presence of complex mixtures that appeared
(13) For synthesis of Cu(TBS)2, see: Charles, R. G. J. Org. Chem. 1957,
22, 677–679.
(14) Under these conditions only minimal quantities of side products
(5) For examples of amine trapping of indole-quinonemethide species,
see: (a) Magnus, P.; Sear, N. L.; Kim, C. S.; Vicker, N J. Org. Chem.
1992, 57, 70–78. (b) Ohshima, T.; Xu, Y.; Takita, R.; Shibasaki, M.
Tetrahedron 2004, 60, 9569–9588. (c) Ohori, K.; Shimizu, S.; Ohshima,
T.; Shibasaki, M. Chirality 2000, 12, 400–403.
were observed.
(15) These conditions remain unoptimized, and current efforts are
focusing on both improving efficiency and utilizing chiral metal catalysts
to induce asymmetry.
(16) (a) Simchen, G.; Kober, W. Synthesis 1976, 259–261. (b) Koba-
yashi, M.; Masumoto, K.; Nakai, E.; Nakai, T. Tetrahedron Lett. 1996, 37,
(6) Nicolaou, K. C.; Lizos, D. E.; Kim, D. W.; Schlawe, D.; de Noronha,
R. G.; Longbottom, D. A.; Rodriquez, M.; Bucci, M.; Cirino, G. J. Am.
Chem. Soc. 2006, 128, 4460–4470.
3005–3008
.
(17) For a review on the use enoxysilane formation with silyl triflates,
see: Emde, H.; Domsch, D.; Feger, H.; Frick, U.; Gotz, A.; Hergott, H. H.;
Hofmann, K.; Kober, W.; Kra¨geloh, K.; Oesterle, T.; Steppan, W.; West,
(7) Lee, H. -Y.; Kim, B. G.; Snapper, M. L. Org. Lett. 2003, 5, 1855–
1853
.
(8) For a review on enyne cross-metathesis, see: Diver, S. T.; Giessert,
A. J. Chem. ReV. 2004, 104, 1317–1382
(9) Importantly, bromo diene 8 was produced in 60%-80% yield with
exclusive trans-olefin selectivity under these reaction conditions
W.; Simchen, G. Synthesis 1982, 1–26.
.
(18) For some examples of enoxysilane-mediated divinylcyclopropane
rearrangement in the synthesis of functionalized cycloheptene rings, see:
(a) Piers, E.; Burmeister, M. S.; Reissig, H.-U. Can. J. Chem. 1986, 64,
180–187. (b) Piers, E.; Jung, G. L. Can. J. Chem. 1987, 65, 1668–1675.
(c) Piers, E.; Jung, G. L.; Ruediger, E. H. Can. J. Chem. 1987, 65, 670–
682. (d) Hudlicky, T.; Nguyen, P. V. J. Org. Chem. 1992, 57, 1933–1935.
(e) Fox, M. E.; Li, C.; Marino, J. P., Jr.; Overman, L. E. J. Am. Chem. Soc.
1999, 121, 5467–5480.
.
(10) Amine displacement of homoallylic dienyl bromide was adapted
from: Arnold, H.; Overman, L. E.; Sharp, M. J.; Witschel, M. C. Org. Synth.
1992, 70, 111–118.
(11) Baum, J. S.; Shook, D. A.; Davies, H. M. L.; Smith, D. Synth.
Commun. 1987, 17, 1709–1716.
Org. Lett., Vol. 11, No. 20, 2009
4533

was achieved under standard conditions to afford alcohol
16.21 The indolization of 16 was realized via a Fischer indole
synthesis (Table 1). Unfortunately, under conventional
conditions only low to modest yields of the desired indole
17 were observed. Additionally, the formation of the
undesired pyrazolone 18 was also detected as a major side
product.
Scheme 3. Metal-Catalyzed Reaction of 6
Table 1. One-Pot Fischer Indolization
With the mixture of keto-/enol-4 in hand, we next turned
to installation of the hydroxymethyl moiety residing at the
C16 quaternary center. Initial attempts to functionalize
directly via an aldol reaction were met with limited success
(not shown). As an alternative, 4 was subjected to a
TsujisTrost allylation reaction using catalytic Pd(PPh3)4 and
allyl methylcarbonate. Gratifyingly, this substrate-controlled
allylation reaction provided the allylated ꢀ-keto amide 15
as essentially a single diastereomer.19,20 At this stage, NOE
studies on 15 failed to offer conclusive evidence for the
relative stereochemical configuration of the newly generated
C16 center; however, this issue was eventually resolved on
a subsequent intermediate (vide infra).
entry
1
conditions
17 (%) 18 (%) 16 (%)
PhNHNH2·HCl (3.6 equiv)
EtOH, reflux
PhNHNH2·HCl (1.2 equiv)
EtOH, seal tube, 100 °C
PhNHNH2·HCl (1.4 equiv)
EtOH, 150 °C (microwave), 2 h
10
2
3
28
42
37
14
20
To improve the yield of this pivotal transformation, we
next attempted an alternative protocol for the installation of
the indole moiety. Ultimately, addition of 10 mol %
scandium(III) triflate [Sc(OTf)3] to 15 in the presence of
phenylhydrazine efficiently provided phenylhydrazone 19 as
a single regioisomer (Scheme 5).22-25 At this point, nOe
studies on hydrazone 19 revealed the relative syn-stereo-
chemical relationship between the C16 quaternary and the
C15 positions (see red arrows in Scheme 5). Subsequent
microwave irradiation of unpurified 19 in the presence of
anhydrous ZnCl2 at elevated temperature cleanly afforded
the desired indole 3 in 64% yield (unoptimized) from ketone
15. Importantly, 3 embodies all of the C-atoms required
(highlighted in red in Scheme 5) for the completion of a
total synthesis of 1.
Scheme 4. Elaboration of Cyclopropane 5
In summary, herein we have disclosed the efficient
construction of 6 and its application in an intramolecular
cyclopropanation reaction which, in turn, holds potential for
an asymmetric synthesis via chiral metal catalysis. Subse-
quent facile cis-divinyl cyclopropane rearrangement of 5
(21) Initial attempts to employ phenylhydrazine hydrochloride in the
Fischer indolization reaction of substrate 15 led to mixtures of products,
which arose from non-deprotected and deprotection of the silyl ether.
(22) Attempts to condense phenylhydrazine with ketone 15 under either
neutral or protic acid conditions provided only low conversions to the desired
hydrazone 19
.
(23) For examples of the use of Sc(OTf)3 as a Lewis acid activator for
aldehydes in the presence of hydrazines, see: (a) Furrow, M. E.; Myers,
A. G. J. Am. Chem. Soc. 2004, 126, 5436–5445. (b) Kobayashi, S.; Hamada,
Our attention next turned to examining protocols for the
installation of the indole moiety. Removal of the silyl ether
T.; Manabe, K. Synlett 2001, 1140–1142
.
(19) (a) Tsuji, J.; Shimizu, I.; Minami, I.; Ohashi, Y. Tetrahedron Lett.
(24) Sc(OTf)3-catalyzed formation of hydrazone 19 proceeded quanti-
1982, 23, 4809–4812
.
tatively as judged by 1H NMR analysis of the unpurified reaction mixture.
(20) For a review of palladium-catalyzed allylic alkylations, see: (a)
Isolation yields of 19 typically ranged between 84%-97% yield
(25) The configuration of hydrazone 19 (i.e., E-hydrazone vs. Z-
hydrazone) could not be determined by NMR
.
Trost, B. M. Angew. Chem., Int. Ed. Engl. 1989, 28, 1173–1192. (b) Tsuji,
J. Tetrahedron 1986, 42, 4361–4401
.
.
4534
Org. Lett., Vol. 11, No. 20, 2009

center and the indole nucleus. The former via a substrate-
controlled Tsuji-Trost allylation and latter using a modified
Fischer indolization reaction. Overall, this synthetic strategy
allowed for the assembly of all the requisite carbon atoms
in only eight steps.
Scheme 5. Improved Construction of Indole Nucleus
Acknowledgment. We thank Dr. Christopher Rithner, Don
Heyse, and Don Dick of the CSU Central Instrumentation
Facility for assistance in obtaining NMR and mass spectro-
metric data. In addition, we thank Colorado State University,
Bristol-Myers Squibb, and Amgen, Inc., for financial support.
Supporting Information Available: Experimental pro-
cedures, compound characterization, 1H NMR and 13C NMR
data for all compounds. 2D-NMR spectral data for selected
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
provided access to the seven membered core of 1 and set
the stage for subsequent incorporation of the C16 quaternary
OL901746C
Org. Lett., Vol. 11, No. 20, 2009
4535