Total synthesis of (±)- and (-)-actinophyllic acid

Article abstract of DOI:10.1021/ja100178u

Development of efficient sequences for the total syntheses of (±)-actinophyllic acid (rac-1) and (-)-actinophyllic acid (1) are described. The central step in these syntheses is the aza-Cope/Mannich reaction, which constructs the previously unknown hexacyclic ring system of actinophyllic acid in one step from much simpler tetracyclic precursors. The tetracyclic hexahydro-1,5-methano-1H-azocino[4,3-b]indole ketone rac-37 is assembled from o-nitrophenylacetic acid in four steps, with oxidative cyclization of a dienolate derivative of tricyclic precursor rac-35 being the central step. In the first-generation synthesis, this intermediate is transformed in two steps to homoallyl amine rac-43, whose formaldiminium derivative undergoes efficient aza-Cope/Mannich reaction to give pentacyclic ketone rac-44. In four additional steps, this intermediate is advanced to (±)-actinophyllic acid. The synthesis is streamlined by elaborating ketone rac-37 to β-hydroxyester intermediate rac-53, which is directly transformed to (±)-actinophyllic acid upon exposure to HCl and paraformaldehyde. This concise second-generation total synthesis of (±)-actinophyllic acid is realized in 22% overall yield from commercially available di-tert-butyl malonate and o-nitrophenylacetic acid by a sequence that proceeds by way of only six isolated intermediates. The first enantioselective total synthesis of (-)-actinophyllic acid (1) is accomplished by this direct sequence from tricyclic keto malonate (S)-35. Catalytic enantioselective reduction of α,β-unsaturated ketone 66 is the key step in the preparation of intermediate (S)-35 from the commercially available Boc-amino acid 65. Discussed also is the possibility that the aza-Cope/Mannich reaction might be involved in the biosynthesis of (-)-actinophyllic acid.

Full text of DOI:10.1021/ja100178u

Published on Web 03/10/2010
Total Synthesis of (()- and (-)-Actinophyllic Acid
Connor L. Martin, Larry E. Overman,* and Jason M. Rohde†
Department of Chemistry, 1102 Natural Sciences II, UniVersity of California,
IrVine, California 92697-2025
Received January 14, 2010; E-mail: leoverma@uci.edu
Abstract: Development of efficient sequences for the total syntheses of (()-actinophyllic acid (rac-1) and
(-)-actinophyllic acid (1) are described. The central step in these syntheses is the aza-Cope/Mannich
reaction, which constructs the previously unknown hexacyclic ring system of actinophyllic acid in one step
from much simpler tetracyclic precursors. The tetracyclic hexahydro-1,5-methano-1H-azocino[4,3-b]indole
ketone rac-37 is assembled from o-nitrophenylacetic acid in four steps, with oxidative cyclization of a
dienolate derivative of tricyclic precursor rac-35 being the central step. In the first-generation synthesis,
this intermediate is transformed in two steps to homoallyl amine rac-43, whose formaldiminium derivative
undergoes efficient aza-Cope/Mannich reaction to give pentacyclic ketone rac-44. In four additional steps,
this intermediate is advanced to (()-actinophyllic acid. The synthesis is streamlined by elaborating ketone
rac-37 to ꢀ-hydroxyester intermediate rac-53, which is directly transformed to (()-actinophyllic acid upon
exposure to HCl and paraformaldehyde. This concise second-generation total synthesis of (()-actinophyllic
acid is realized in 22% overall yield from commercially available di-tert-butyl malonate and o-nitrophenylacetic
acid by a sequence that proceeds by way of only six isolated intermediates. The first enantioselective total
synthesis of (-)-actinophyllic acid (1) is accomplished by this direct sequence from tricyclic keto malonate
(S)-35. Catalytic enantioselective reduction of R,ꢀ-unsaturated ketone 66 is the key step in the preparation
of intermediate (S)-35 from the commercially available Boc-amino acid 65. Discussed also is the possibility
that the aza-Cope/Mannich reaction might be involved in the biosynthesis of (-)-actinophyllic acid.
Introduction
Thrombotic diseases are a major cause of mortality and
morbidity in the developed world. In healthy individuals, a
complex network of enzymatic processes carefully regulates the
balance between blood clotting and blood thinning.1 Inhibition
of activated thrombin-activatable fibrinolysis inhibitor (TAFIa),
an unstable zinc-dependent carboxypeptidase, is a promising
approach toward upregulating fibrinolysis, the process whereby
small blood clots are removed from circulation.2,3 In a screening
program designed to discover natural product inhibitors of
TAFIa, 40000 extracts from Australian plants and marine
organisms were screened by Carroll and co-workers, initially
leading to the identification of promising extracts from the tree
Alstonia actinophylla, growing on the Cape York Peninsula,
Far North Queensland.4 Ultimately, a new indole alkaloid, (-)-
actinophyllic acid (1, Figure 1), was identified from this source
as a potent inhibitor in the coupled enzyme assay TAFIa/
hippuricase (IC50 ) 0.84 µM).
Figure 1. Structure of (-)-actinophyllic acid and its three unique fragments.
The carbon connectivity and relative configuration of acti-
nophyllic acid (1) were determined largely by detailed NMR
analysis.4 The 2,3,6,7,9,13c-hexahydro-1H-1,7,8-(methanetriy-
loxymethano)pyrrolo[1′,2′:1,2]azocino[4,3-b]indole-8(5H)-car-
boxylic acid skeleton5 of actinophyllic acid is unique among
naturalproducts.Moreover,thesimpler1-azabicyclo[4.4.2]dodecane
(2), 1-azabicyclo[4.2.1]nonane (3), and octahydropyrrolo[1,2-
a]azocine (4) fragments that define its structure are found in no
other indole alkaloids. The absolute configuration depicted in
structure 1 for (-)-actinophyllic acid was advanced on the basis
of its proposed biogenesis from precondylocarpine via a novel
† Current address: Ironwood Pharmaceuticals, Inc., 320 Bent Street,
Cambridge, MA 02141.
(1) Cesarman-Maus, G.; Hajjar, K. A. Br. J. Hamaetol. 2005, 129, 307–
321.
(2) For reviews of the role of TAFIa in fibrinolysis, see: (a) Leurs, J.;
Hendriks, D. Thromb. Haemost. 2005, 94, 471–487. (b) Willemse,
J. L.; Hendriks, D. F. Front. Biosci. 2007, 12, 1973–1987. (c) For a
review of small molecule inhibitors of TAFIa, see: (d) Bunnage, M. E.;
Owen, D. R. Curr. Opin. Drug DiscoVery DeV. 2008, 11, 480–486.
(3) Also known as carboxypeptidase U or plasma carboxypeptidase B.
(4) Carroll, A. R.; Hyde, E.; Smith, J.; Quinn, R. J.; Guymer, G.; Forster,
P. I. J. Org. Chem. 2005, 70, 1096–1099.
(5) ThisringsystemisnameddifferentlyinChemicalAbstracts:2,3,3a,4,8,12c-
hexahydro-4-hydroxy-1,4,7-[1]propanyl[3]ylidene-1H-pyrrolo[2′,3′:
6,7]oxocino[4,5-b]indole-7(6H)-carboxylic acid.
9
4894 J. AM. CHEM. SOC. 2010, 132, 4894–4906
10.1021/ja100178u  2010 American Chemical Society

Total Synthesis of (()- and (-)-Actinophyllic Acid
A R T I C L E S
Scheme 2. Pivotal Aza-Cope/Mannich Rearrangement Step
Scheme 1. Retrosynthetic Analysis of Actinophyllic Acid
biogenetic pathway.4 Rigorous definition of the absolute con-
figuration of (-)-actinophyllic acid (1) by spectroscopic and
computational methods6 was realized only after this laboratory
completed the first total synthesis of (()-actinophyllic acid in
2008.7
We describe in this paper the development of an efficient
strategy for assembling the ring system of actinophyllic acid,
which culminated in the first total synthesis of this unique
alkaloid. A simplification of the later stages of this sequence
leading to an improved second-generation total synthesis of (()-
actinophyllic acid is also reported. In addition, the first enan-
tioselective total synthesis of (-)-actinophyllic acid (1), which
confirms the spectroscopic assignment of its absolute configu-
ration, is disclosed.8 The possibility that the aza-Cope/Mannich
reaction is involved in the biosynthesis of natural products is
considered and a potential biosynthetic route to actinophyllic
acid is proposed.
the aza-Cope/Mannich transformation with precursor 7, and
subsequently elaborate the product to intermediate 5 by reaction
of an ester or acid enolate with formaldehyde. Disconnecting
the allylic alcohol intermediates 6 and 7 identifies tetracyclic
ketone 8 as an important subgoal of our synthesis plan.
The pivotal aza-Cope/Mannich rearrangement step of our
projected synthesis plan is analyzed in more detail in Scheme
2. Although this reaction had not been employed previously to
transform a 3-vinylpiperidine to a 1-azabicyclo[4.2.1]nonan-5-
one (atoms highlighted in red in Scheme 2), the prospects for
success appeared good. Molecular modeling of intermediates
such as 11 showed that the overlap between the vinyl and
iminium fragments, although far from ideal, was comparable
to that of several other successful aza-Cope/Mannich processes.9,10
Moreover, there was evidence from early studies of Grob and
co-workers that the proposed cationic aza-Cope rearrangement
step, 11 f 12 (Scheme 2), would likely take place readily.11
Specifically, they had shown that solvolytic Grob-fragmentation
of tosylate 13 generated largely 4-azocine iminium ion 14, which
was transformed rapidly to the 3-vinylpiperidine iminium ion
15 (eq 1). By the principle of microscopic reversibility, the
reverse transformation, as postulated in the conversion of
intermediate 11 to 12, should be possible. That the equilibrium
of the proposed iminium ion isomers likely lies on the side of
the 3-vinylpiperidine isomer should be of no concern, as a
stereoelectronically favorable intramolecular Mannich reaction
would be expected to capture iminium ion isomer 12 in the
postulated aza-Cope/Mannich transformation.
Results and Discussion
Synthesis Plan. The retrosynthetic analysis that guided our
efforts to prepare (-)-actinophyllic acid (1) is outlined in
Scheme 1. Disconnecting the tetrahydrofuran ring at the
hemiketal C-O bond reveals pentacyclic ketone 5. This
intermediate contains a 3-acylpyrrolidine unit, which suggests
its potential formation by aza-Cope/Mannich rearrangement of
formaldiminium ions derived from hexahydro-1,5-methano-1H-
azocino[4,3-b]indole precursors such as 6 or 7.9 Of these
possibilities, the postulated transformation of intermediate 6 to
5 is particularly attractive as actinophyllic acid would result
directly. If the relative configuration of the ester and hydroxym-
ethyl side chains of precursor 6 could not be established in an
efficient fashion, an alternate possibility would be to carry out
The hexahydro-1,5-methano-1H-azocino[4,3-b]indole ring
system of intermediate 8 is a structural feature of several indole
alkaloid families and the ring system of the uleine alkaloids.12
As a result, a number of methods for assembling this tetracyclic
(6) Taniguchi, T.; Martin, C. L.; Monde, K.; Nakanishi, K.; Berova, N.;
Overman, L. E. J. Nat. Prod. 2009, 72, 430–432.
(7) Martin, C. L.; Overman, L. E.; Rohde, J. M. J. Am. Chem. Soc. 2008,
130, 7568–7569.
(10) Bru¨ggemann, M.; McDonald, A. I.; Overman, L. E.; Rosen, M. D.;
Schwink, L.; Scott, J. P. J. Am. Chem. Soc. 2003, 125, 15284–15285.
(11) Grob, C. A.; Kunz, W.; Marbet, P. R. Tetrahedron Lett. 1973, 16,
2613–2616.
(8) For progress toward the total synthesis of actinophyllic acid by a
different approach, see: Vaswani, R. G.; Day, J. J.; Wood, J. L. Org.
Lett. 2009, 11, 4532–4535.
(9) (a) Overman, L. E.; Humphreys, P. G.; Welmaker, G. S. Org. React.
2010, 75, in press. (b) Overman, L. E. Tetrahedron 2009, 65, 6432–
6446.
(12) The Monoterpene Indole Alkaloids; Saxton, J. E., Ed.; The Chemistry
of Heterocyclic Compounds; Wiley: New York, 1983; Vol. 25, Part
4.
9
J. AM. CHEM. SOC. VOL. 132, NO. 13, 2010 4895

A R T I C L E S
Martin et al.
Scheme 3. Initial Plan for Preparing a Tetracyclic Precursor from
an Indole-2-malonate and a Pyridinium Salt
scaffold have been developed.13,14 Particularly attractive to us
was a new construction in which intermediate 8 would be
assembled from two fragments of similar complexity: an indole-
2-malonate (9) and a six-membered, azacyclic synthon having
electrophilic sites for bond construction at C2 and C4.
Several aspects of the plan adumbrated in Scheme 1 warrant
additional comment. The aza-Cope/Mannich disconnection is
highly productive because this transformation, if successful in
the synthetic direction, would construct the previously unknown
hexacyclic ring system of actinophyllic acid in one step from a
much simpler tetracyclic precursor. However, this strategy is
not without significant risk. Besides deferring the pivotal aza-
Cope/Mannich step to a late stage of the synthesis,15 intermedi-
ate 8, and later ones derived from this structure, contain a
potentially labile gramine fragment that could result in unravel-
ing of the piperidine ring. At the outset, we hoped that we could
arrive at intermediate 8 by a sufficiently direct sequence that
these key issues could be addressed relatively quickly in our
experimental studies.
Total Synthesis of (()-Actinophyllic Acid. Attempted
Formation of the 2,5,6,7-Tetrahydro-1,5-methano-1H-azocino[4,3-b]-
indole Ring System by Sequential Pyridinium Ion Alkylation/
Pictet-Spengler-Type Cyclization. One of our early attempts to
assemble the hydro-1,5-methano-1H-azocino[4,3-b]indole ring
system followed the general approach to this ring system
developed by Bosch and co-workers.16 We envisioned con-
structing tetracyclic ketone intermediate 8 by the sequence
enunciated in Scheme 3. Intermediate 17 would arise from
addition of the conjugate base of indole malonate 9 to C4 of
pyridinium salt 16.17 Oxidation of one of the prochiral double
bonds of the dihydropyridine fragment of this adduct could
potentially promote intramolecular attack by the pendant indole
with introduction of an oxygen substituent on the resulting one-
carbon bridge of the product.
To pursue this potential construction of tetracyclic ketone 8,
dimethyl indole-2-malonate (19)18,19 was deprotonated with 1.2
equiv of a variety of strong bases [LDA, NaHMDS, KHMDS
or BrMgN(i-Pr)2] in THF at temperatures between 0 and -78
°C,20 and the resulting anion was allowed to react at -78 °C
with the pyridinium salt generated in situ from the reaction of
pyridine with 2,2,2-trichloroethyl chloroformate (Troc-Cl).21
Product 20 resulting from the addition of the malonate side chain
to C4 of the pyridinium salt was never observed. The major
product produced in these reactions, adduct 21, resulted from
coupling at the 3-position of the indole malonate nucleophile.
When the bromomagnesium salt of indole-2-malonate 19 was
used, adduct 21 was formed in high yield (Scheme 4).
As an alternative approach, we investigated the reaction of a
less-basic anion generated from R-keto malonate 2218 with
several pyridinium salts, with the goal of forming the indole
following the contruction of the azabicyclo[3.2.1]octane ring
system (Scheme 5). The initial condensation was most efficient
with the in situ generated N-triflylpyridinium triflate salt,22
giving product 23 in excellent yield. However, attempted
epoxidation of the N-sulfonylenamine functionality of adduct
23 with a variety of oxidants (DMDO, m-chloroperbenzoic acid,
(13) For representative examples of syntheses of the hexahydro-1,5-
methano-1H-azocino[4,3-b]indole ring system, see: (a) Jackson, A.;
Wilson, N. D. V.; Gaskell, A. J.; Joule, J. A. J. Chem. Soc. C 1969,
19, 2738–2747. (b) Bu¨chi, G.; Gould, S. J.; Na¨f, F. J. Am. Chem.
Soc. 1971, 93, 2492–2501. (c) Grierson, D. S.; Harris, M.; Husson,
H.-P. Tetrahedron 1983, 39, 3683–3694. (d) Magnus, P.; Sear, N. L.;
Kim, C. S.; Vicker, N. J. Org. Chem. 1992, 57, 70–78. (e) Gra`cia, J.;
Casamitjana, N.; Bonjoch, J.; Bosch, J. J. Org. Chem. 1994, 59, 3939–
3951. (f) Micouin, L.; Diez, A.; Castells, J.; Lo´pez, D.; Rubiralta,
M.; Quirion, J.-C.; Husson, H.-P. Tetrahedron Lett. 1995, 36, 1693–
1696. (g) Blechert, S.; Knier, R.; Schroers, H.; Wirth, T. Synthesis
1995, 592–604. (h) Saito, M.; Kawamura, M.; Hiroya, K.; Ogasawara,
K. Chem. Commun. 1997, 765–766. (i) Amat, M.; Hadida, S.;
Pshenichnyi, G.; Bosch, J. J. Org. Chem. 1997, 62, 3158–3175. (j)
Ergu¨n, Y.; Patir, S.; Okay, G. J. Heterocycl. Chem. 2002, 39, 315–
317. (k) Jiricek, J.; Blechert, S. J. Am. Chem. Soc. 2004, 126, 3534–
3538. (l) Ishikura, M.; Takahashi, N.; Takahashi, H.; Yanada, K.
Heterocycles 2005, 66, 45–50. (m) Uludag, N.; Ho¨kelek, T.; Patir, S.
J. Heterocycl. Chem 2006, 43, 585–591. (n) Bennasar, M.-L.; Roca,
T.; Garc´ıa-D´ıaz, D. J. Org. Chem. 2008, 73, 9033–9039.
(17) For reviews, see: (a) Bennasar, M.-L.; Lavilla, R.; Alvarez, M.; Bosch,
J. Heterocycles 1988, 27, 789–824. (b) Comins, D. L.; Joseph, S. P.
Alkaloid Synthesis Using 1-Acylpyridinium Salts as Intermediates.
In AdVances in Nitrogen Heterocycles; Moody, C. J., Ed.; JAI:
Greenwich, CT, 1996; Vol. 2, pp 251-294.
(18) Mahboobi, S.; Bernauer, K. HelV. Chim. Acta 1988, 71, 2034–2041.
(19) Indole-2-malonate 19 contains variable amounts (8-94%) of the
indolin-2-ylidene tautomer i depending upon the method employed
to purify this intermediate. Purification by recrystallization gives the
indole tautomer predominantly, whereas purification by column
chromatography gives i as the major tautomer.18 For simplicity, these
structures are depicted only in their indole form. In cases where we
have examined the issue, we have not observed differences in reaction
outcome depending upon tautomer composition.
(14) For a review that covers the synthesis of uleine alkaloids, see: Alvarez,
M.; Joule, J. A. In The Alkaloids; Cordell, G. A., Ed.; Academic Press:
New York, 2001; Vol. 57, pp 247-258.
(20) In DMSO, the pKa’s of indole and dimethyl malonate are 21.0 and
15.9, respectively: (a) Bordwell, F. G. Acc. Chem. Res. 1988, 21, 456–
463. (b) Arnett, E. M.; Maroldo, S. G.; Schilling, S. L.; Harrelson,
J. A. J. Am. Chem. Soc. 1984, 106, 6759–6767.
(15) Our motivations for pursuing such potentially high-risk strategies are
discussed briefly in ref 9b.
(16) (a) Bennasar, M.-L.; Alvarez, M.; Lavilla, R.; Zulaica, E.; Bosch, J.
J. Org. Chem. 1990, 55, 1156–1168. (b) Bosch, J.; Bennasar, M.-L.
Synlett 1995, 587–596.
(21) Akiba, K.; Nishihara, Y.; Wada, M. Tetrahedron Lett. 1983, 24, 5269–
5272.
(22) Corey, E. J.; Tian, Y. Org. Lett. 2005, 7, 5535–5537.
9
4896 J. AM. CHEM. SOC. VOL. 132, NO. 13, 2010

Total Synthesis of (()- and (-)-Actinophyllic Acid
A R T I C L E S
Scheme 4. Addition of Conjugate Bases of Indole-2-malonate 19 to
a 1-Acyloxypyridinium Salt
dro-1,5-methano-1H-azocino[4,3-b]indole ring system would
then be fashioned by bond formation between the starred carbons
of intermediate 26. One possibility we envisioned for this bond
construction was oxidative coupling of a dienolate intermediate
such as 27.
The formation of C-C bonds by oxidative coupling of
enolates generated from ester, ketone, and carboxylate precursors
has a long history.24,25 Throughout the 1970s and 1980s,
intramolecular oxidative couplings of dienolates to form three-,
four-, five-, and six-membered rings were disclosed,26 as was
the intramolecular couplings of enolates derived from two
different functional groups.27 Nonetheless, this C-C bond-
forming method has received only modest attention for the
construction of more elaborate structures such as polyfunctional
natural products.28 Three impressive examples from the Paquette,
Cohen, and Baran laboratories are summarized in Scheme 7.29
Absent from existing precedent was the intramolecular coupling
of malonate and ketone enolates, as well as a demonstration
that an unprotected indole might survive such a sequence.
Nonetheless, because of the potential brevity of the synthetic
sequence postulated in Scheme 6, we were drawn to examine
the prospect that tricarbonyl intermediates such as 26 could
be transformed directly to 1,5-methanoazocino[4,3-b]indole
ketone 8.
Scheme 5. Addition of Tricarbonyl Intermediate 22 to a
1-(Trifluoromethanesulfonyl)pyridinium Salt
The short sequence for assembling 1,5-methanoazocino[4,3-
b]indole ketones 36 and 37 that ultimately resulted from these
studies is summarized in Scheme 8. The synthesis begins with
acylation of the methoxymagnesium salts of dimethyl (28) or
di-tert-butyl malonate (29) with acid chloride 30, to give keto
malonates 2218 and 31 in good yields. On small scales, dimethyl
intermediate 22 could be transformed to indole dimethyl
malonate 19 in a yield of 62% by catalytic hydrogenation over
Pd(OH)2/C in methanol.18 However, over multiple runs we
found the yields of indole malonates 19 and 32 to be irrepro-
ducible using this procedure. These reactions suffered from
formation of variable amounts of N-hydroxyindole products,
which underwent reduction of the N-O bond only slowly.
Forcing conditions, such as elevated reaction temperatures or
high catalyst loadings, did lead to reduction of the N-O bond;
however, these conditions also promoted competitive reduction
of the indole C2-C3 double bond. Difficulties in optimizing
Scheme 6. Revised Plan for Preparing Ketone 8 by Intramolecular
Oxidative Dienolate Coupling
(24) Ivanoff, D.; Spassoff, A. Bull. Soc. Chim. Fr. 1935, 2, 76–78.
(25) For a recent historical summary and leading references, see: (a) Richter,
J. M.; Whitefield, B. W.; Maimone, T. J.; Lin, D. W.; Castroviejo,
M. P.; Baran, P. S J. Am. Chem. Soc. 2007, 129, 12857–12869. (b)
For a brief review, see: Csa´ky¨, A. G.; Plumet, J. Chem. Soc. ReV.
2001, 30, 313–320.
Shi’s dioxirane23) did not lead to the formation of tetracyclic
product 24. The major mode of reactivity observed under most
of the conditions examined was fragmentation of bond a of
adduct 23 to regenerate keto malonate 22.
(26) (a) Ito, Y.; Konoike, T.; Harada, T.; Saegusa, T. J. Am. Chem. Soc.
1977, 99, 1487–1493. (b) Kobayashi, Y.; Taguchi, T.; Morikawa, T.
Tetrahedron Lett. 1978, 19, 3555–3556. (c) Kobayashi, Y.; Taguchi,
T.; Morikawa, T.; Tokuno, E.; Sekiguchi, S. Chem. Pharm. Bull. 1980,
28, 262–267. (d) Chung, S. K.; Dunn, L. B., Jr. J. Org. Chem. 1983,
48, 1125–1127. (e) Babler, J. H.; Sarussi, S. J. J. Org. Chem. 1987,
52, 3462–3464.
Formation of the Keto-Bridged Hexahydro-1,5-methano-1H-
azocino[4,3-b]indole Ring System by Intramolecular Oxidative
Dienolate Coupling. The observation that anions derived from
indole malonate 19 reacted with electrophiles at C3 of the indole
suggested that the order of bond formation in the construction
of hexahydro-1,5-methano-1H-azocino[4,3-b]indole ketone 8 be
reversed (Scheme 6). In such a sequence, coupling of the indole
malonate with a six-membered iminium electrophile, in the ideal
case one derived from a precursor such as 25 that incorporates
a carbonyl group at C3, would deliver adduct 26. The hexahy-
(27) (a) Kawabata, T.; Sumi, K.; Hiyama, T. J. Am. Chem. Soc. 1989, 111,
6843–6845. (b) Kawabata, T.; Minami, T.; Hiyama, T. J. Org. Chem.
1992, 57, 1864–1873.
(28) For an early example, see Hendrickson, J. B.; Rees, R.; Go¨schke, R.
Proc. Chem. Soc. 1962, 383.
(29) (a) Paquette, L. A.; Snow, R. A.; Muthard, J. L.; Cynkowski, T. J. Am.
Chem. Soc. 1978, 100, 1600–1602. (b) Ramig, K.; Kuzemko, M. A.;
McNamara, K.; Cohen, T. J. Org. Chem. 1992, 57, 1968–1969. (c)
Cohen, T.; McNamara, K.; Kuzemko, M. A.; Ramig, K.; Landi, J. J.,
Jr.; Dong, Y. Tetrahedron 1993, 49, 7931–7942. (d) Baran, P. S.;
Guerrero, C. A.; Ambhaikar, N. B.; Hafensteiner, B. D. Angew. Chem.,
Int. Ed. 2005, 44, 606–609. (e) Baran, P. S.; Hafensteiner, B. D.;
Ambhaikar, N. B.; Guerrero, C. A.; Gallagher, J. D. J. Am. Chem.
Soc. 2006, 128, 8678–8693.
(23) Shi, Y. Acc. Chem. Res. 2004, 37, 488–496.
9
J. AM. CHEM. SOC. VOL. 132, NO. 13, 2010 4897

A R T I C L E S
Martin et al.
Scheme 7. Selected Examples of Intramolecular Oxidative Enolate
Couplings Used in Complex Molecule Syntheses
excess zinc in acetic acid at 50 °C delivered indole malonate
19 reliably in 48-55% yield.30 However, this procedure was
problematic in the di-tert-butyl ester series, particularly in large-
scale runs wherein the reaction exotherm was difficult to control.
In these cases, zinc and acetic acid reduction gave product 32
contaminated with various amounts of tert-butyl 2-indoleacetate.
After examining several alternative procedures, we finally found
that transfer hydrogenation over Pd/C in a 2:1 mixture of formic
acid and triethylamine in the presence of catalytic amounts of
ammonium metavanadate at 50 °C promoted reproducible
transformation of keto malonate 31 to indole di-tert-butyl
malonate 32 in 74-79% yield.31 In the absence of NH4VO3,
the reaction rapidly produced a mixture of the desired indole
malonate 32 and the corresponding N-hydroxyindole, which was
slow to undergo further reduction. Inclusion of a catalytic
amount of NH4VO3 accelerated reduction of the hydroxyin-
dole.32
We next examined methods for joining indole malonate and
piperidone fragments. We soon found that the desired trans-
formation could be accomplished by simply allowing the indole
to react at room temperature in N,N-dimethylformamide (DMF)
with crude bromopiperidone 33, a reactant readily generated
by radical bromination of commercially available 1-tert-bu-
toxycarbonyl-3-piperidone.33 This condensation was carried out
on multigram scale to provide indole piperidones rac-34 and
rac-35 in 74% and 85% yield, respectively. Presumably the
highly reactive N-acyloxy-C-acyliminium cation generated by
ionization of bromide 33 is an intermediate in this coupling
step.34
Scheme 8. Synthesis of Hexahydro-1,5-methano-1H-
azocino[4,3-b]indole Ketones 36 and 37
With convenient access to keto malonates rac-34 and rac-
35 in hand, we turned to examine the intramolecular oxidative
coupling of dienolates generated from these intermediates. In
early studies carried out largely with dimethyl malonate
precursor rac-34, we surveyed several bases including lithium
diisopropylamide (LDA), lithium hexamethyldisilazide, and
potassium hexamethyldisilazide, along with various metal
oxidants including ferrocenium hexafluorophosphate, iron(III)
chloride, iron(III) acetylacetonate, [Fe(DMF)3Cl2][FeCl4], Cu(II)
2-ethylhexanoate, and Cu(II) chloride. The best results were
obtained with a combination of LDA and [Fe(DMF)3Cl2][FeCl4],
a complex simply formed by combining FeCl3 with DMF.35
Deprotonation of indole piperidone rac-34 or rac-35 with 3.2
equiv of LDA in tetrahydrofuran (THF) at -78 °C followed
by adding a THF solution of 3.5 equiv of [Fe(DMF)3Cl2][FeCl4]
and allowing the reaction to warm to room temperature over
60-90 min provided crystalline tetracyclic ketones rac-36
(68-73% yield) or rac-37 (60-63% yield) on scales up to 10 g.
(30) The major byproduct under these conditions is 2-oxindole.
(31) This procedure is a modification of Heck’s procedure for transfer
hydrogenation with triethylammonium formate. For the original
procedure, see: Weir, J. R.; Patel, B. A.; Heck, R. F. J. Org. Chem.
1980, 45, 4926–4931.
(32) For the use of NH4VO3 as a promotor in the catalytic hydrogenation
of nitroarenes, see: Baumeister, P.; Blaser, H.-U.; Studer, M. Catal.
Lett. 1997, 49, 219–222.
(33) Brosius, A. D.; Overman, L. E.; Schwink, L. J. Am. Chem. Soc. 1999,
121, 700–709.
(34) For the closest precedent of which we are aware, see: Whitlock, C. R.;
Cava, M. P. Tetrahedron Lett. 1994, 35, 371–374.
(35) For the use of this oxidant in phenolic couplings, see: (a) Tobinaga,
S.; Kotani, E. J. Am. Chem. Soc. 1972, 94, 309–310. For the use of
FeCl3 in DMF for oxidative coupling of enolates, see, inter alia (b)
Frazier, R. H.; Harlow, R. L. J. Org. Chem. 1980, 45, 5408–5411. (c)
Paquette, L. A.; Bzowej, E. I.; Branan, B. M.; Stanton, K. J. J. Org.
Chem. 1995, 60, 7277–7283. (d) Poupart, M.-A.; Paquette, L. A.
Tetrahedron Lett. 1988, 29, 269–272, and refs 29b and 29c.
the Pd(OH)2/C reduction prompted us to investigate alternative
methods for reducing the nitro group of intermediates 22 and
31. In the dimethyl series, simply carrying out the reaction with
9
4898 J. AM. CHEM. SOC. VOL. 132, NO. 13, 2010

Total Synthesis of (()- and (-)-Actinophyllic Acid
A R T I C L E S
Scheme 9. Vinylation of Ketones rac-36 and rac-37
Single-crystal X-ray analysis of rac-37 confirmed the 1,5-
methanoazocino[3,4-b]indole structure of this product.36a
Although mechanistic details of this oxidative cyclization
have not been examined thoroughly, several aspects merit
mention. To avoid destabilizing A1,3 interactions between the
indole and tert-butoxycarbonyl (Boc) groups,37 the piperidine
ring of the piperidone indole malonate precursors should exist
in a conformation, 38, in which the indole moiety is axial, thus
positioning the methine hydrogen adjacent to the indole
orthogonal to the π-bond of the carbonyl group (eq 2). For this
reason, we anticipated that regioselection in the deprotonation
of the 3-piperidinone at the methylene carbon would be high.
As the yields of the cyclized products rac-36 and rac-37 were
reduced significantly if only 2.2 equiv of LDA were employed,
it is possible that the indole of 38 is also converted to its
conjugate lithium base.38 However, it is also plausible that the
third equivalent of LDA deprotonates the indole of the cyclized
product as it forms.
First-Generation Synthesis of (()-Actinophyllic Acid
(rac-1). The next step in advancing tetracyclic ketones rac-36
and rac-37 to (()-actinophyllic acid was introduction of a vinyl
group from the Re face of the carbonyl group (Scheme 9). It
was anticipated that the proximal ester substituents, particularly
in the tert-butyl ester series, would shield the Si faces of the
ketones during addition of a vinyl nucleophile (see the X-ray
model in Scheme 8). Vinyllithium and vinylmagnesium bromide
did not add to ketones rac-36 or rac-37 at -78 °C in THF and
produced complex product mixtures at higher temperatures.
However, premixing these ketones with anhydrous cerium(III)
chloride in THF, followed by addition of vinylmagnesium
bromide at -78 °C, did bring about addition to the ketone
carbonyl group.41 In the dimethyl series, this reaction resulted
in formation of lactone rac-41 (IR 1790 cm-1) in 29-44% yield,
with 22-30% of the starting ketone recovered. Under the same
conditions, di-tert-butyl ketone precursor rac-37 was converted
solely to allylic alcohol rac-42 in nearly quantitative yield. Both
the lactone and allylic alcohol products were viewed as viable
intermediates in route to (()-actinophyllic acid (rac-1). We
chose to investigate elaboration of allylic alcohol rac-42 first.
The first sequence developed to elaborate intermediate rac-
42 to (()-actinophyllic acid (rac-1) is summarized in Scheme
10. Reaction of allylic alcohol rac-42 with trifluoroacetic acid
(TFA) at 0 °C selectively cleaved the Boc group to deliver,
after aqueous base workup, amino alcohol rac-43 in high yield.
This intermediate was not purified but immediately allowed to
react with 1 equiv of paraformaldehyde and a catalytic amount
of camphorsulfonic acid (CSA) in benzene at 70 °C to promote
aza-Cope/Mannich transformation to yield pentacyclic keto
diester rac-44. Exposure of this crude product to neat TFA at
room temperature gave the amino acid trifluoroacetate salt rac-
45a as a single stereoisomer in 76% overall yield from rac-42.
Fischer esterification of this amino acid, followed by counterion
exchange delivered amino ester trifluoroacetate salt rac-46 as
a 2:1 mixture of R and ꢀ ester epimers in 92% yield. For
characterization purposes, these methyl ester epimers could be
separated by HPLC.42
A major byproduct produced under the reaction conditions
of the oxidative dienolate cyclization of precursor rac-35 is a
symmetrical homodimer resulting from coupling at the meth-
ylene carbon adjacent to the piperidone carbonyl group, rac-
40. Although a solid, we have thus far been unable to obtain
single crystals to allow its structure to be fully established.
Nonetheless, its relative configuration can be assigned, because
the same dimer is produced as a byproduct in the oxidative
dienolate coupling of enantioenriched (S)-35 (see below).39 In
the enantiomerically enriched series, the only symmetrical
dimers that could result would have C2-symmetry, of which two
are possible. The C2-symmetric dimer assigned as rac-40 would
result from dimerization of intermediate 39 from the face of
the piperidone enolate opposite to the quasi-axial indole
fragment. Fortunately, the yield of the dimer decreased as the
oxidative coupling reaction was carried out at higher concentra-
tion.40
(36) Crystallographic data for this compound were deposited at the
Cambridge Crystallographic Data Centre: (a) CCDC 701592; (b)
CCDC 759087.
(37) Johnson, F. Chem. ReV. 1968, 68, 375–413.
The total synthesis (()-actinophyllic acid (rac-1) was then
completed in two additional steps. Deprotonation of the 2:1
mixture of R and ꢀ ester epimers rac-46 with LDA at -78 °C,
followed by addition of a THF solution of monomeric formal-
(38) Deuteration experiments showed that the malonate and R-methylene
had been deprotonated. However, because of rapid exchange of the
indole hydrogen under all the quenching conditions that we examined,
no information about the fate of the indole hydrogen was obtained.
(39) This dimer is formed in 18% yield in cyclizations carried out at a
substrate concentration of 0.08 M.
(41) Imamoto, T.; Takiyama, N.; Nakamura, K.; Hatajima, T.; Kamiya,
Y. J. Am. Chem. Soc. 1989, 111, 4392–4398.
(40) (a) See the Supporting Information for more details. (b) Investigations
into the mechanism of the oxidative cyclization of intermediate 35,
which hopefully will clarify the origin of this unexpected trend, are
currently underway.
(42) The R-epimer, rac-46a, provided single crystals from methanol,
allowing its constitution and relative configuration to be confirmed
by X-ray analysis; however, diffraction data from these crystals was
of insufficient quality to refine to high precision.
9
J. AM. CHEM. SOC. VOL. 132, NO. 13, 2010 4899

A R T I C L E S
Martin et al.
Scheme 10. Elaboration of Allylic Alcohol rac-42 to
(()-Actinophyllic Acid Hydrochloride (rac-1·HCl)
Figure 2. Rationale for stereoselection in the reaction between the ester
enolate of rac-46 and formaldehyde; for clarity, water molecules rather than
THF are shown as ligands on lithium.
Scheme 11. Streamlined First-Generation Total Synthesis of
(()-Actinophyllic Acid
dehyde,43 gave largely one aldol adduct (diastereomer ratio, dr
) 14-20:1), which was partially purified by reversed-phase
chromatography to give (()-actinophyllic acid methyl ester
trifluoroacetate salt (rac-47).44,45 Hydrolysis of this product with
4 M HCl and purification of the product by reversed-phase
HPLC provided pure (()-actinophyllic acid hydrochloride (rac-
1·HCl) in 48% yield from amino ester rac-46.
The predominant formation of (()-actinophyllic acid methyl
ester from the aldol reaction of the lithium enolate of rac-46
with formaldehyde is attributable to steric factors. As depicted
in Figure 2, approach of formaldehyde from the Re (R) face of
the enolate is hindered by the relatively bulky 2-carbon bridge
(atoms a and b). In contrast, approach to the Si (ꢀ) face of the
double bond is relatively free of obstruction, as the ketone bridge
is small and tilted away from the π bond of the enolate.46
purified in this way containing variable small amounts of the
conjugate acid. To confirm this supposition, incremental amounts
of sodium methylsulfinylmethylide-d5 were added to a sample
of (()-actinophyllic acid hydrochloride in DMSO-d6, which
resulted in substantial changes for several 1H NMR resonances.
1
When just less than 1 equiv of base was added, a H NMR
spectrum identical to that reported for natural 1 was obtained
(see the Supporting Information). Unfortunately, a sample of
natural actinophyllic acid is no longer available for direct
comparison.47a
Purification of synthetic (()-actinophyllic acid hydrochloride
(rac-1·HCl) by HPLC, as reported for the natural product,4 does
not reproducibly give samples of (()-actinophyllic acid (rac-
This first-generation total synthesis of (()-actinophyllic acid
hydrochloride (rac-1·HCl) could be streamlined by combining
the four acid-catalyzed steps in the conversion of rac-42 f rac-
46 into a single operation (Scheme 11). Reaction of allylic
alcohol rac-42 with neat trifluoroacetic acid at room temperature
resulted in cleavage of the Boc group and the tert-butyl esters,
promoting decarboxylation to provide amino acid salt rac-48
as a single stereoisomer. Removal of trifluoroacetic acid in
vacuo, dissolution of the crude residue in acetonitrile, addition
of 1 equiv of paraformaldehyde, and heating at 70 °C for 3 h
promoted aza-Cope/Mannich reorganization to the carboxylic
1
1
1) that exhibit identical H NMR spectra. Moreover, the H
NMR spectra in DMSO-d6 of these samples does not precisely
match those reported for natural 1 in this solvent. We ascribe
these differences to samples of (()-actinophyllic acid (rac-1)
(43) (a) Schlosser, M.; Coffinet, D. Synthesis 1971, 380–381. (b) We
prepared monomeric formaldehyde by an improved procedure, see:
Schlosser, M.; Jenny, T.; Guggisberg, Y. Synlett 1990, 704.
(44) These samples were contaminated with minor quantities of two
inseparable byproducts (5-10% of each). We tentatively assign these
compounds as the aldol product resulting from addition of formalde-
hyde from the R-face of the lithium ester enolate and an aldol product
that incorporates an additional hydroxymethylene fragment attached
to the nitrogen atom of the indole. These assignments were made on
(47) (a) The natural sample of actinophyllic acid (1) degraded sometime
after its isolation and bioassay. (b) The concentration reported for the
optical rotation of natural (-)-actinophyllic acid is incorrect in ref 4;
it should be (0.05 M); the low reported rotation could be the result of
the low solubility of this zwitterionic amino acid or that the natural
sample started to degrade prior to analysis. Personal communications
from Professor Tony Carroll, Griffith University, Gold Coast Campus,
Australia.
1
the basis of diagnostic peaks in the H NMR spectra corresponding
to hydroxymethylene fragments and on the basis of LRMS data.
(45) Comparable yields for this transformation were obtained when the
pure R-epimer, rac-46a, was used or when a 1:1 mixture of R and ꢀ
epimers of rac-46 was employed.
(46) The prediction would be the same if lithium was not chelated to the
indole nitrogen.
9
4900 J. AM. CHEM. SOC. VOL. 132, NO. 13, 2010

Total Synthesis of (()- and (-)-Actinophyllic Acid
A R T I C L E S
acid salt rac-45.48 Removal of acetonitrile in vacuo, followed
by dissolution of the resulting residue in a 0.5 M methanolic
solution of HCl and heating at 50 °C provided amino ester
trifluoroacetate salt rac-46 as a 1:1 mixture of R and ꢀ ester
epimers in 62% overall yield. In this streamlined fashion, the
first-generation total synthesis of actinophyllic acid was com-
pleted in 8% overall yield by a sequence that proceeds via only
seven isolated intermediates.
Scheme 12. Synthesis of (()-Actinophyllic Acid Hydrochloride via
Lactone Intermediate rac-41
In an attempt to shorten the synthesis even further, we
examined the aldol reaction between carboxylic acid rac-45 and
formaldehyde in an attempt to generate (()-actinophyllic acid
(rac-1) directly from this precursor. In one such experiment,
carboxylic acid trifluoroacetate salt rac-45, which is available
in 73% yield from precursor rac-42, was deprotonated with 4.5
equiv of LDA at 0 °C in THF and after 30 min was cooled to
-78 °C (eq 3). Addition of a THF solution of monomeric
formaldehyde,43 followed by quenching with trifluoroacetic acid
before allowing the reaction to warm to room temperature,
returned a mixture of the unreacted amino acid starting material,
lactone rac-49, actinophyllic acid hydrotrifluoroacetate (rac-
1·CF3CO2H), and N-hydroxymethylindole rac-50 after reversed-
phase C18 column chromatography. The relative configuration
of aldol adduct rac-49 was assigned on the basis of a diagnostic
lactone carbonyl stretch at 1762 cm-1 and 2D NMR analysis.
The unexpected reversal in diastereoselection in the aldol
reaction of the carboxylic acid dianion compared to that of the
corresponding methyl ester led us to abandon this shorter
sequence.49
quaternary carbon stereocenter of (()-actinophyllic acid. The
formation of pentacyclic lactone rac-41 from vinyl cerium
addition to the keto dimethyl ester rac-36 (Scheme 9) showed
that it would be possible to differentiate the two ester substit-
uents of the malonate fragment prior to the aza-Cope/Mannich
step. Thus, we turned to examine the possibility of optimizing
the generation of such pentacyclic lactone intermediates and
subsequently transforming them to actinophyllic acid.
Successful elaboration of pentacyclic ketone rac-36 via
lactone intermediate rac-41 to (()-actinophyllic acid is sum-
marized in Scheme 12. The formation of lactone intermediate
rac-41 was improved by employing 2.5 equiv of cerium(III)
chloride and 3.5 equiv of vinylmagnesium bromide in the
reaction with ketone dimethyl ester intermediate rac-36. Under
these conditions, all of the starting ketone was consumed at
-78 °C, with lactone rac-41 being formed reproducibly in
49-51% yield.50 Selective reduction of the lactone carbonyl
of this intermediate with excess sodium borohydride in methanol/
THF at -20 °C delivered hydroxy ester rac-51 in 56% yield.
Removal of the Boc group with TFA in dichloromethane at
room temperature, followed by concentration in vacuo, dissolu-
tion of the residue in acetonitrile, and heating with 1 equiv of
paraformaldehyde at 70 °C generated (()-actinophyllic acid
methyl ester hydrotrifluoroacetate (rac-47). This intermediate
was not purified, but directly hydrolyzed with 4 M HCl to
furnish (()-actinophyllic acid hydrochloride (rac-1·HCl) in 69%
yield.
The sequence summarized in Scheme 12 showed that the
primary alcohol side chain generated by chemoselective reduc-
tion of lactone rac-41 presented no problem in the pivotal aza-
Cope/Mannich transformation. This improved synthesis of (()-
actinophyllic acid would be further streamlined if a related
sequence could be realized in the di-tert-butyl ester series
because a global deprotection-aza-Cope/Mannich sequence
could potentially directly deliver actinophyllic acid.
Second-Generation Total Synthesis of (()-Actinophyllic
Acid (rac-1): An Improved Endgame. The total synthesis of (()-
actinophyllic acid (rac-1) summarized in Schemes 8-11 suf-
fered from a low-yielding aldol-hydrolysis sequence (Scheme
10) used to transform aza-Cope/Mannich product rac-46 to (()-
actinophyllic acid. Moreover, in this inaugural route the all-
carbon quaternary center present in allylic alcohol intermediate
rac-42 is sacrificed by the decarboxylation-formaldehyde aldol
sequence used to establish the relative configuration of the
(48) The ꢀ-epimer, rac-45b, crystallized from an aqueous solution of this
mixture of carboxylic acid epimers. The relative configuration of this
sample was established by single-crystal X-ray analysis; crystal-
lographic data for this compound were deposited at the Cambridge
Crystallographic Data Centre: CCDC 752916.
(49) Several other conditions that employed LiCl or TMEDA additives
or potassium diisopropylamide as the base were also examined. In
no case was actinophyllic acid the major product of this aldol reac-
tion.
(50) (a) A complex mixture of byproducts was formed; products arising
from competitive addition of the organometallic reagent to the methyl
ester of the lactone product rac-41 were isolated, but they did not
account for the entire mass balance of the reaction. (b) In contrast to
rac-37, complete consumption of keto diester rac-36 was not possible
when 2.5 equiv of vinylmagnesium bromide were used.
9
J. AM. CHEM. SOC. VOL. 132, NO. 13, 2010 4901

A R T I C L E S
Martin et al.
ester rac-53 in 86% yield.54 The use of cerium(III) chloride
was crucial to obtain high yields in this transformation. Carrying
out the reduction of the lactone with sodium borohydride in
methanol/THF at 0 °C provided a 3.4:1.0 mixture of hydroxy
ester rac-53 and formate ester rac-56 in 75% yield, whereas
this formate byproduct was not formed under Luche conditions.
Exposure of hydroxy ester rac-53 to 5 N aqueous HCl at 60 °C
removed the two protecting groups. Concentration of this
reaction mixture, dissolution of the residue of rac-54 in 5:1
acetonitrile/water, addition of 1.1 equiv of paraformaldehyde,
and heating to 70 °C promoted aza-Cope/Mannich reaction to
furnish (()-actinophyllic acid hydrochloride (rac-1·HCl) in 93%
yield.55 This considerably improved second-generation total
synthesis of (()-actinophyllic acid was realized in 22% overall
yield from commercially available di-tert-butyl malonate and
o-nitrophenylacetic acid by a sequence that proceeds by way
of only six isolated intermediates.
Scheme 13. Improved Endgame of the Concise
Second-Generation Total Synthesis of (()-Actinophyllic Acid
Enantioselective Total Synthesis of (-)-Actinophyllic Acid.
As noted previously, there was no experimental evidence
concerning the absolute configuration of (-)-actinophyllic acid
(1) at the time our investigations in this area began. Contem-
poraneously with our collaboration with the Nakanishi group
that established the absolute configuration of (-)-actinophyllic
acid (1) by chiroptical methods,6 we initiated efforts to ascertain
its absolute configuration by enantioselective total synthesis. The
first chiral intermediate in our synthetic route to actinophyllic
acid is indole piperidone 35 (Scheme 8). Before beginning to
prepare this intermediate enantioselectively, we wished to
confirm that it would not be racemized under the basic
conditions of the ensuing oxidative dienolate coupling step. To
pursue this issue, the enantiomers of rac-35 were separated by
enantioselective HPLC. As illustrated in eq 4, conversion of
these enantiomers to hexahydro-1,5-methano-1H-azocino[4,3-
b]indole ketone 37 was accompanied by little, if any, racem-
ization.56
The optimized second-generation total synthesis of (()-
actinophyllic acid that resulted from these considerations is
summarized in Scheme 13. The first obstacle to overcome was
transformation of keto tert-butyl diester rac-37 to lactone rac-
52. After some experimentation, we found that this conversion
could be realized in good yield by first allowing rac-37 to react
with 2.5 equiv of both cerium(III) chloride and vinylmagnesium
bromide at -78 f -70 °C in THF. After the ketone was
consumed, as judged by thin-layer chromatography, 1.5 equiv
of acetic acid were added to quench the excess organometallic
reagent; allowing the reaction to then warm to -20 °C promoted
lactonization to give pentacyclic lactone rac-52 in 83% yield.51
The rate of vinylation was increased if 5 equiv of lithium
chloride was added to the reaction mixture,52 however carbonate
rac-55 was then a significant byproduct (rac-52:rac-55 ) 6:1).
This byproduct was not observed when lithium chloride was
absent. Lithium chloride likely activated the ester carbonyl and
promoted elimination of the tert-butyl ester enolate from the
tetrahedral intermediate formed upon cyclization. The propensity
of lanthanides to interact only weakly with esters likely explains
why byproduct rac-55 was not formed in the absence of lithium
chloride.53
Success has been registered recently in several laboratories
in accomplishing some bimolecular nucleophilic additions to
N-acyliminium ions in catalytic asymmetric fashion.57 As a
result, we examined briefly the possibility of preparing (S)-35
directly by coupling of 1-(tert-butoxycarbonyl)-2-methoxy-3-
piperidone (the methoxy analogue of 33) with indole malonate
32 in the presence of several Bronsted acid catalysts derived
from (R)-1,1′-bi(2-naphthol).58 Thus far, our efforts in this area
have not led to a satisfactory enantioselective synthesis of
intermediate (S)-35 (see the Supporting Information for details).
In three additional steps, pentacyclic lactone rac-52 was
elaborated in high yield to (()-actinophyllic acid. Chemose-
lective Luche reduction of lactone rac-52 delivered hydroxy
(54) (a) Luche, J.-L. J. Am. Chem. Soc. 1978, 100, 2226–2227. For Luche
reduction of a lactone having a ꢀ ester substituent, see: (b) Kusama,
H.; Mori, T.; Mitani, I.; Kashima, H.; Kuwajima, I. Tetrahedron Lett.
1997, 38, 4129–4132.
(51) This partial quench resulted in slightly improved yields, but it is not
crucial.
(52) Dunn, T. B.; Ellis, J. M.; Kofink, C, C.; Manning, J. R.; Overman,
L. E. Org. Lett. 2009, 11, 5658–5661.
(55) Because of the limited solubility of hydrochloride salt rac-54 in
acetonitrile, the solvent was a mixture of acetonitrile and water.
(56) The absolute configurations of the structures depicted in eq 4 were
established later in our studies.
(53) (a) For a review of the complexation of lanthanides with various
functional groups, see: Cockerill, A. F.; Davies, G. L. O.; Harden,
R. C.; Rackham, D. M. Chem. ReV. 1973, 73, 553–588, and references
cited therein.
(57) For some representative examples, see: Doyle, A. G.; Jacobsen, E. N.
Chem. ReV. 2007, 107, 5713–5743.
9
4902 J. AM. CHEM. SOC. VOL. 132, NO. 13, 2010

Total Synthesis of (()- and (-)-Actinophyllic Acid
A R T I C L E S
Scheme 14. Diastereoselective Heteroarylation of Piperidine Diol
Derivatives
indole nucleophile was isolated in 9% yield. Similar reaction
of the 2-methoxy derivative rac-57b led to a decreased yield
of adduct rac-58 (trans/cis ) 5:1) and an increased yield (35%)
of byproduct 60. The piperidine ring-opening pathway was not
significantly suppressed by employing an electron-withdrawing
2,2,2-trifluoroethoxy substituent at C2, as the reaction of
piperidine rac-57c with indole 32 gave a product distribution
similar to that of piperidine derivative rac-57b. In contrast,
diacetoxypiperidine rac-57d60c condensed with indole malonate
32 in good yield to deliver indole piperidine rac-59 as a 20:1
mixture of inseparable trans and cis stereoisomers.61 In this case,
no products arising from ring opening of the piperidine were
detected.
With conditions for diastereoselective heteroarylation in hand,
we sought to develop an efficient enantioselective synthesis of
the 3R isomer of diacetoxypiperidine 57d.62 Initial work focused
on sequential enantioselective epoxidation-hydrolysis of com-
mercially available tetrahydropyridine 61 (eq 5).63 Shi epoxi-
dation was unselective and provided the diol product as a
mixture of epimers, each in 7% ee.64,65 Two conditions were
examined for enantioselective epoxidation with Jacobsen’s
catalyst:66 use of aqueous sodium hypochlorite as the stoichio-
metric oxidant67 and the low temperature procedure that employs
m-chloroperbenzoic acid as the stoichiometric oxidant.68 The
low temperature procedure was more successful; however,
enantioselectivity was still modest (59-60% ee for both diol
diastereomers).65
As a result, we turned to develop a diasteroselective construction
of this key intermediate.
The obvious approach was to replace piperidone intermediate
33 with an appropriate piperidine electrophile bearing an alcohol
substituent (or alcohol derivative) at C3 that would direct bond
formation at C2. Prospects for success in such an endeavor
appeared promising, as Kobayashi and co-workers had reported
high trans diasteroselectivity in Lewis acid-catalyzed reactions
of 2-acetoxy-3-acyloxy(or 3-alkoxy)-1-(benzyloxycarbonyl)pi-
peridine with ꢀ-substituted enoxysilanes and silyl ketene ac-
etals.59
Proline-catalyzed R-oxidation69 of Boc-protected amino al-
dehyde6270 provedhighlyenantioselective,providingalkoxyamine
63 as a single stereoisomer in 98% ee (eq 6). However, under
the best conditions we identified the yield was low, likely
(61) The trans configuration of indole piperidine 59 was determined by
X-ray analysis of N-sulfonyl derivative ii.
Salient results of our initial examination of the coupling of
indole malonate 32 with related precursors in the N-Boc
piperidine series are summarized in Scheme 14. Kobayashi’s
conditions were effective in promoting the desired transforma-
tion, as combining piperidine diol rac-57a60 and indole 32 in
chloroform with a catalytic amount of scandium(III) triflate at
0 °C provided indole piperidine rac-58 in 40% yield, as a 5:1
mixture of trans and cis stereoisomers. Byproduct 60 arising
from the reaction of piperidine rac-57a with two equiv of the
(62) (3S)-1-(Benzyloxycarbonyl)-2,3-diacetoxypiperidine has been prepared
enantioselectively by Kobayashi and co-workers in six steps from a
commercially available precursor.59a
(58) (a) Uraguchi, D.; Sorimachi, K.; Terada, M. J. Am. Chem. Soc. 2004,
126, 11804–11805. (b) Terada, M.; Sorimachi, K. J. Am. Chem. Soc.
2007, 129, 292–293. (c) Terada, M.; Machioka, K.; Sorimachi, K.
Angew. Chem., Int. Ed. 2009, 48, 2553–2556. (d) Terada, M.; Toda,
Y. J. Am. Chem. Soc. 2009, 131, 6354–6355.
(63) Sharpless asymmetric dihydroxylation of this alkene is reported to
give the cis-diol product in only 40% ee. See: Sukemoto, S.; Oshige,
M.; Sato, M.; Mimura, K.; Nishioka, H.; Abe, H.; Harayama, T.;
Takeuchi, Y. Synthesis 2008, 3081–3087.
(64) Shu, L.; Wang, P.; Gan, Y.; Shi, Y. Org. Lett. 2003, 5, 293–296.
(65) Enantiomeric excesses were determined by enantioselective HPLC
analysis of the dibenzoate derivative.
(59) (a) Okitsu, O.; Suzuki, R.; Kobayashi, S. J. Org. Chem. 2001, 66,
809–823. (b) Okitsu, O.; Suzuki, R.; Kobayashi, S. Synlett 2000, 989–
990.
(66) Larrow, J. F.; Jacobsen, E. N. Org. Synth. 1998, 75, 1–11.
(67) Jacobsen, E. N.; Zhang, W.; Muci, A. R.; Ecker, J. R.; Deng, L. J. Am.
Chem. Soc. 1991, 113, 7063–7064.
(60) (a) Piperidine derivatives 57 were prepared from commercially
available 1-(tert-butoxycarbonyl)-1,4,5,6-tetrahydropyridine using pro-
cedures similar to those employed by Kobayashi to prepare the related
compounds in the benzyloxycarbonyl series; see the Supporting
Information for details.59 (b) Neat samples of diol 57a decomposed
shortly after being concentrated but could be stored for months in
solution at -20 °C. (c) In contrast to the report of Kobayashi and
coworkers,59 we found diacetate 57d to be sufficiently stable to be a
viable synthetic intermediate.
(68) Palucki, M.; Pospisil, P. J.; Zhang, W.; Jacobsen, E. N. J. Am. Chem.
Soc. 1994, 116, 9333–9334.
(69) (a) Zhong, G. Angew. Chem., Int. Ed. 2003, 42, 4247–4250. (b) Brown,
S. P.; Brochu, M. P.; Sinz, C. J.; MacMillan, D. W. C. J. Am. Chem.
Soc. 2003, 125, 10808–10809.
(70) Lee, B. H.; Miller, M. J.; Prody, C. A.; Neilands, J. B. J. Med. Chem.
1985, 28, 317–323.
9
J. AM. CHEM. SOC. VOL. 132, NO. 13, 2010 4903

A R T I C L E S
Martin et al.
Scheme 16. Total Synthesis of (-)-Actinophyllic Acid
Hydrochloride (1·HCl)
Scheme 15. Enantioselective Synthesis of Diacetoxypiperidine
(3R)-57d
reflecting the facile cyclization of aldehyde 62 to hydroxypip-
eridine 64.71
We eventually discovered that diacetoxypiperidine (3R)-57d
could be prepared by the convenient sequence shown in Scheme
15. Commercially available amino acid 65 was initially con-
verted to its Weinreb amide,72 which underwent cerium(III)
chloride-mediated vinylation to furnish enone 66 in 88% yield
over the two steps.73 In a sequence carried out without
purification of intermediates, R,ꢀ-unsaturated ketone 66 was
hydrogenated using Noyori’s catalyst 6874 in 2-propanol to give
allylic alcohol (R)-67 in 91% ee.75,76 Concentration of this
reaction mixture, dissolution of the residue with dichlo-
romethane, ozonolysis at -78 °C, quenching with triph-
enylphosphine, and finally addition of acetic anhydride, trieth-
ylamine, and a catalytic amount of 4-dimethylaminopyridine
(DMAP) at room temperature gave diacetoxypiperidine (3R)-
57d in 73% yield from enone 66.
The elaboration of diacetoxypiperidine (3R)-57d to (-)-
actinophyllic acid is summarized in Scheme 16. Piperidine
electrophile (3R)-57d was added to a stirring mixture of 1.3
equiv of indole malonate 32 and 5 mol % of scandium(III)
triflate in dichloromethane at 0 °C to give adduct (2S,3R)-59 in
88% yield (dr ) 17:1) on a multigram scale. Deacetylation of
this product with diisobutylaluminum hydride (DIBAL) in
toluene at -78 °C delivered, after column chromatography, the
pure trans-alcohol (2S,3R)-58 in 82% yield.77 Attempts to cleave
the acetyl group of (2S,3R)-59 with sodium or potassium
methoxide in methanol resulted in competitive transesterification
of the tert-butyl esters. Swern oxidation of alcohol (2S,3R)-58
furnished indole piperidone (S)-35,78 which underwent intramo-
lecular oxidative dienolate coupling to provide ketone (1S,5R)-
37 in 57-59% yield and 91% ee. Whereas the corresponding
racemate could be recrystallized from toluene, this enantioen-
riched ketone could not be purified in this fashion. Instead,
tetracyclic ketone (1S,5R)-37 was purified by column chroma-
tography followed by trituration with diethyl ether; this change
in the purification procedure likely accounts for the slightly
lower yield realized in the enantioenriched series. Elaboration
of (1S,5R)-37 as described in Scheme 13 furnished (-)-
actinophyllic acid hydrochloride (1·HCl) in high yield. Reversed-
phase HPLC of 1·HCl afforded the zwitterion, which was
crystallized from methanol to provide single crystals of a
methanol and water solvate, allowing the first X-ray analysis
of (-)-actinophyllic acid (1) to be accomplished (Figure 3).36b
The optical rotation of an analytical specimen of synthetic 1
(>99% ee) showed [R]D -199 (c 0.67, MeOH). A nearly
identical rotation was observed for the hydrochloride salt 1·HCl.
The optical rotation of 1 at the sodium D line did not compare
well to the reported rotation of [R]D -29 (c 0.001, MeOH).4,47b
The total synthesis of enantioenriched (-)-actinophyllic acid
(71) Aldehyde 62 cyclizes upon silica gel chromatography or upon storage
for a few days as a solution in benzene at 25 °C to give 2-hydroxy-
1-(tert-butoxycarbonyl)piperidine (64).
(72) Nahm, S.; Weinreb, S. M. Tetrahedron Lett. 1981, 22, 3815–3818.
(73) The use of a non-basic organometallic reagent was essential to suppress
lactam formation.
(74) (a) Ohkuma, T.; Koizumi, M.; Mun˜iz, K.; Hilt, G.; Kabuto, C.; Noyori,
R. J. Am. Chem. Soc. 2002, 124, 6508–6509. (b) Careful control of
reaction time was necessary to avoid over-hydrogenation.
(75) The R absolute configuration of allylic alcohol 67 was determined by
Mosher ester analysis: (a) Dale, J. A.; Mosher, H. S J. Am. Chem.
Soc. 1973, 95, 512–519. (b) Hoye, T. R.; Jeffrey, C. S.; Shao, F. Nature
Protocols 2007, 2, 2451–2458.
(77) To isolate 58 in good yield, it was essential to use a NaF workup;
see: Yamamoto, H.; Maruoka, K. J. Am. Chem. Soc. 1981, 103, 4186–
4194.
(78) (a) Mancuso, A. J.; Huang, S.-L.; Swern, D. J. Org. Chem. 1978, 43,
2480–2482. (b) It was essential to remove triethylamine prior to
concentration of the crude reaction mixture to prevent deterioration
of the enantiopurity of this product.
(76) Enantiomeric excess was determined by enantioselective HPLC
analysis of the benzoate derivative.
9
4904 J. AM. CHEM. SOC. VOL. 132, NO. 13, 2010

Total Synthesis of (()- and (-)-Actinophyllic Acid
A R T I C L E S
Scheme 17. Plausible Biosynthesis of (-)-Actinophyllic Acid (1)
from an Intermediate Having a Uleine Aklaloid Skeleton by an
Aza-Cope/Mannich Reaction
Figure 3. X-ray model of (-)-actinophyllic acid. The asymmetric unit
has two molecules each of actinophyllic acid, methanol, and water; for
clarity, only one molecule of actinophyllic acid is shown.
potentially beginning with (+)-stemmadenine (72),85,86 that
delivers alkaloids 69-71 could plausibly lead to an intermediate
such as tetracyclic diol 73 (Scheme 17). Oxidative transforma-
tion of this intermediate to formaldiminium ion 74 would give
rise to (-)-actinophyllic acid (1) by an aza-Cope/Mannich
sequence.
1·HCl summarized in Scheme 15 proceeds by way of nine
isolated intermediates and was accomplished in 18% overall
yield (91% ee); enantiopure 1·HCl (>99% ee) was accessed in
8% yield.79
Potential Biosynthetic Relevance of the Aza-Cope/Mannich
Reaction. The aza-Cope/Mannich reaction has proven to be a
remarkably robust reaction that has been employed to construct
a wide variety of pyrrolidine-containing ring systems.9 This
cascade reaction typically takes place in high yields under
extremely mild reaction conditions, often at or near room
temperature and at neutral pH. It is these features, along with
the wide occurrence of pyrrolidine-containing natural products,
that has led us over the years to wonder whether the aza-Cope/
Mannich reaction is utilized in natural product biosynthesis. Our
demonstration that (-)-actinophyllic acid (1) is formed in high
yield in one step from a much simpler tetracyclic precursor (+)-
54 by an aza-Cope/Mannich reaction (see Scheme 16) surely
raises this question in the current context.
Conclusion
The first total syntheses of (()-actinophyllic acid (rac-1) and
(-)-actinophyllic acid (1) have been accomplished by short and
efficient synthetic routes. (()-Actinophyllic acid was prepared
in 22% overall yield from commercially available di-tert-butyl
malonate and o-nitrophenylacetic acid by a sequence that
proceeds by way of only six isolated intermediates. The
enantioselective total synthesis of (-)-actinophyllic acid (1)
proceeds by way of nine isolated intermediates to deliver
enantioenriched (-)-actinophyllic acid 1 (91% ee) in 18%
overall yield or enantiopure 1 (>99% ee) in 8% overall yield.79
In these syntheses, no protecting groups are introduced, and in
the notably concise synthesis of rac-1, nearly all steps form
skeletal bonds of actinophyllic acid.
A number of steps in the synthetic sequence are noteworthy.
The aza-Cope/Mannich reaction allows the previously unknown
hexacyclic ring system of actinophyllic acid to be constructed
in one step from much simpler tetracyclic precursors. These
total syntheses entail the first use of this powerful cascade
reaction for forming medium azacyclic rings and 1-azabicyclic
ring systems. An oxidative intramolecular dienolate cyclization
is the pivotal step in an efficient construction of the commonly
occurring 2,3,4,5,6,7-hexahydro-1,5-methano-1H-azocino[4,3-
b]indole ring system found in the uleine alkaloids. This step
represents the first intramolecular coupling of malonate and
ketone enolates, as well as the first demonstration that an
unprotected indole can survive such a coupling reaction.
The possibility that the biogenesis of (-)-actinophyllic acid
(1) involves an aza-Cope/Mannich reaction is hightened by the
isolation from Alstonia plant species indigineous to Malaysia
of the indole alkaloids (-)-undulifoline (69)80 and (-)-
alstilobanines C (70) and B (71)81 that contain a uleine alkaloid
ring system and the complete carbon scaffold found in synthetic
aza-Cope/Mannichprecursor(+)-54.Abiosyntheticsequence,82-84
(83) (a) Kutney, J. P.; Nelson, V. R.; Wigfield, D. C. J. Am. Chem. Soc.
1969, 91, 4278–4279. (b) Kutney, J. P.; Nelson, V. R.; Wigfield, D. C.
J. Am. Chem. Soc. 1969, 91, 4279–4280.
(79) The yield of enantiopure (-)-1 undoubtedly can be increased, as no
attempt was made to optimize the recrystallization of intermediate (+)-
54.
(84) For reviews, see: (a) Kutney, J. P. Heterocycles 1976, 4, 429–451.
(b) Herbert, R. B. Structural and Biosynthetic Relationships. In The
Monoterpene Indole Alkaloids; Saxton, J. E., Ed.; The Chemistry of
Heterocyclic Compounds; Wiley: New York, 1983; Vol. 25, Part 4,
Chapter I, pp 13-14.
(80) Massiot, G; Boumendjel, A.; Nuzillard, J.-M.; Richard, B.; Le Men-
Olivier, L.; David, B.; Hadi, H. A. Phytochemistry 1992, 31, 1078–
1079.
(81) Koyama, K.; Hirasawa, Y.; Zaima, K.; Hoe, T. C.; Chan, K.-L.; Morita,
H. Bioorg. Med. Chem. 2008, 16, 6483–6488.
(85) The laboratory formation of the “nor” alkaloid vallesamine from
stemmadenine by a Polonovski fragmentation86 is the basis of most
biosynthetic proposals for the synthesis of uleine-type alkaloids.81,84b
(86) (a) Scott, A, I.; Yeh, C.-L.; Greenslade, D. J. Chem. Soc., Chem.
Commun. 1978, 947–948. (b) Ahond, A.; Cave´, A.; Kan-Fan, C.;
Langlois, Y.; Potier, P. Chem. Commun. 1970, 517.
(82) At the experimental level, little is known about the biosynthesis of
monoterpene indole alkaloids that lack the normal tryptophan side
chain and have only one-carbon linking the ꢀ-carbon of the indole
and the basic nitrogen,83 particularly for natural products having the
uleine skeleton.84
9
J. AM. CHEM. SOC. VOL. 132, NO. 13, 2010 4905

A R T I C L E S
Martin et al.
rotation of this natural product. Professor Phil Baran, The Scripps
Research Institute, La Jolla, is acknowledged for useful discussion
and samples of metal salts, and Dr. Joe Ziller, UC Irvine, is
acknowledged for X-ray analyses. NMR, mass spectra, and X-ray
analyses were obtained at UC Irvine using instrumentation acquired
with the assistance of NSF and NIH Shared Instrumentation
programs.
Tetracyclic intermediates 36 and 37 produced in this way could
well serve as precursors of other families of indole alkaloids.
In conclusion, the efficient construction of actinophyllic acid
by an aza-Cope/Mannich reaction suggests the possibility that
nature utilizes this powerful cascade reaction in natural product
biosynthesis.
Acknowledgment. This research was supported by the NIH
Neurological Disorders & Stroke Institute (NS-12389); fellowship
assistance for CLM (UC Irvine Chancellor’s Fellowship, Bristol-
Myers Squibb Graduate Fellowship, and ACS Division of Organic
Chemistry Fellowship sponsored by Amgen) is gratefully acknowl-
edged. We thank Professor Tony Carroll, Griffith University, Gold
Coast Campus, Australia for providing NMR spectra of natural
actinophyllic acid and correspondence regarding the reported optical
Supporting Information Available: Experimental details and
1
copies of H and 13C NMR spectra of new compounds; CIF
files for compounds (-)-1, rac-45b, and ii. This material is
available free of charge via the Internet at http://pubs.acs.org.
JA100178U
9
4906 J. AM. CHEM. SOC. VOL. 132, NO. 13, 2010