Asymmetric, stereocontrolled total synthesis of paraherquamide A

Article abstract of DOI:10.1021/ja036713+

The first total synthesis of paraherquamide A, a potent anthelmintic agent isolated from various Penicillium sp. with promising activity against drug-resistant intestinal parasites, is reported. Key steps in this asymmetric, stereocontrolled total synthesis include a new enantioselective synthesis of (α-alkylated-β-hydroxyproline derivatives to access the substituted proline nucleus and a highly diastereoselective intramolecular S _N2′ cyclization to generate the core bicyclo[2.2.2]diazaoctane ring system.

Full text of DOI:10.1021/ja036713+

Published on Web 09/11/2003
Asymmetric, Stereocontrolled Total Synthesis of
Paraherquamide A
Robert M. Williams,* Jianhua Cao, Hidekazu Tsujishima, and Rhona J. Cox
Contribution from the Department of Chemistry, Colorado State UniVersity,
Fort Collins, Colorado 80523
Received June 16, 2003; E-mail: rmw@chem.colostate.edu
Abstract: The first total synthesis of paraherquamide A, a potent anthelmintic agent isolated from various
Penicillium sp. with promising activity against drug-resistant intestinal parasites, is reported. Key steps in
this asymmetric, stereocontrolled total synthesis include a new enantioselective synthesis of R-alkylated-
â-hydroxyproline derivatives to access the substituted proline nucleus and a highly diastereoselective
intramolecular SN2′ cyclization to generate the core bicyclo[2.2.2]diazaoctane ring system.
Introduction
than a spiro-oxindole, and the asperparalines, which contain a
spiro-succinimide,11 are also structurally comparable (Figure 1).
The paraherquamides1-4 are an unusual family of fungal
natural products which contain a bicyclo[2.2.2]diazaoctane core
structure, a spiro-oxindole, and a substituted proline moiety.
The parent member, paraherquamide A (1), was first isolated
from cultures of Penicillium paraherquei by Yamazaki and co-
workers in 1981.1 Since then, paraherquamides B-G,2 VM55595,
VM55596, and VM55597,3 SB203105 and SB200437,4 and
sclerotamide5 have been isolated from various Penicillium and
Aspergillus species. Marcfortines A-C are structurally similar,
containing a pipecolic acid unit in place of proline.6 Also closely
related are VM55599,3 aspergamides A and B,7 avrainvillamide
(CJ-17,665),8 and the most recently isolated members of this
family, stephacidins A and B .9 These last six compounds
contain a 2,3-disubstituted indole in place of the spiro-oxindole.
Brevianamides A and B,10 which contain a spiro-indoxyl rather
The paraherquamides have attracted considerable attention
due to their molecular complexity, intriguing biogenesis,12,13 and
biological activity. Some members, most notably paraherqua-
mide A, display potent anthelmintic activity and antinematodal
properties.14 Due to the appearance of drug resistance developed
by helminths, broad spectrum anthelmintic agents such as the
macrolide endectocides, benzimidazoles, tetrahydropyrimidines,
and imidazothiazoles are beginning to lose efficacy and there
has arisen an urgent need to discover new families of antipara-
sitic agents. The paraherquamides represent an entirely new
structural class of anthelmintic compounds, and as such, they
hold great potential as drugs for the treatment of intestinal para-
sites in animals.15 The mode of action of the paraherquamides
is, as yet, incompletely characterized, but recent work suggests
that they are selective competitive cholinergic antagonists.16
(1) Yamazaki, M.; Okuyama E.; Kobayashi, M.; Inoue, H. Tetrahedron Lett.
1981, 22, 135-136.
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Biosci. Biotechnol. Biochem. 2000, 64, 111-115.
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L. J. Antibiot. 1990, 43, 1375-1379. (b) Liesch, J. M.; Wichmann, C. F.
J. Antibiot. 1990, 43, 1380-1386. (c) Blanchflower, S. E.; Banks, R. M.;
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Whaley, H. A.; Marshall, V. P. J. Antibiot. 1996, 49, 1006-1013.
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J. Am. Chem. Soc. 1996, 118, 7008-7009. (b) Williams, R. M.; Sanz-
Cervera, J. F.; Sanceno´n, F.; Marco, J. A.; Halligan, K. M. Bioorg. Med.
Chem. 1998, 6, 1233-1241. (c) Stocking, E. M.; Williams, R. M.; Sanz-
Cervera, J. F. J. Am. Chem. Soc. 2000, 122, 9089-9098. (d) Stocking, E.
M.; Martinez, R. A.; Silks, L. A.; Sanz-Cervera, J. F.; Williams, R. M. J.
Am. Chem. Soc. 2001, 123, 3391-3392. (e) Stocking, E. M.; Sanz-Cervera,
J. F.; Unkefer, C. J.; Williams, R. M. Tetrahedron 2001, 57, 5303-5320.
(f) Stocking, E. M.; Sanz-Cervera, J. F.; Williams, R. M. Angew. Chem.,
Int. Ed. 2001, 40, 1296-1298.
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12172
J. AM. CHEM. SOC. 2003, 125, 12172-12178
10.1021/ja036713+ CCC: $25.00 © 2003 American Chemical Society

Total Synthesis of Paraherquamide A
A R T I C L E S
Scheme 1. Retrosynthetic Plan for Paraherquamide A
Synthesis of an r-Alkylated-â-Hydroxyproline
Despite the apparent similarity in the structures of paraher-
quamides A and B, synthesis of the former turned out to be a
significantly more challenging endeavor owing to the presence
of the unusual â-hydroxy-â-methyl proline residue. In the
semisynthesis of paraherquamide A from marcfortine A (3), the
final step was addition of methylmagnesium bromide to 14-
oxoparaherquamide B (14).17 We planned to use this same
methodology to complete our total synthesis and to construct
14 using a similar strategy to that used for paraherquamide B,
that is, coupling of suitably functionalized indole (19) and
diketopiperazine (18) units and then an intramolecular SN2′
cyclization followed by palladium-mediated closure of the
seventh ring, and finally oxidation and rearrangement of the
2,3-disubstituted indole to the spiro-oxindole of 14-oxopara-
herquamide B19 (Scheme 1).
New methodology was now required to prepare a suitably
functionalized R-alkylated-â-hydroxyproline residue. A variety
of methods were investigated for the asymmetric construction
of this class of compound, leading to the development of a
potentially general synthetic method which uses dianion alky-
lation of the readily available N-t-BOC-â-hydroxyproline ethyl
ester derivative 12 with net retention of stereochemistry.21 This
methodology has now successfully been applied to a concise
asymmetric and stereocontrolled total synthesis of paraherqua-
mide A.
Figure 1. Structures of some paraherquamides and related compounds.
The small quantities of paraherquamide A that can be isolated
from cultures for biological study have slowed the development
of these agents. Recently, Lee and Clothier reported the
interesting semisynthetic conversion of marcfortine A (3), a
metabolite more readily available by fermentation, into para-
herquamide A via paraherquamide B (2).17 Following synthetic
studies on brevianamide B (12),18 our laboratory reported the
first total synthesis of a member of the paraherquamide family,
ent-paraherquamide B, in 1993, in which a diastereoselective
intramolecular SN2′ cyclization reaction was used to construct
the core bicyclo[2.2.2]diazaoctane ring system.19 We have
further exploited this reaction strategy, and we described the
first total synthesis of paraherquamide A in 2000.20 Herein, we
detail a full account of this work.
(15) (a) Blizzard, T. A.; Marino, G.; Mrozik, H.; Fisher, M. H.; Hoogsteen, K.;
Springer, J. P. J. Org. Chem. 1989, 54, 2657-2663. (b) Blizzard, T. A.;
Mrozik, H.; Fisher, M. H.; Schaeffer, J. M. J. Org. Chem. 1990, 55, 2256-
2259. (c) Blizzard, T. A.; Margiatto, G.; Mrozik, H.; Schaeffer, J. M.; Fisher,
M. H. Tetrahedron Lett. 1991, 32, 2437-2440. (d) Blizzard, T. A.;
Margiatto, G.; Mrozik, H.; Schaeffer, J. M.; Fisher, M. H. Tetrahedron
Lett. 1991, 32, 2441-2444. (e) Lee, B. H.; Clothier, M. F.; Johnson,
S. S. Bioorg. Med. Chem. Lett. 2001, 11, 553-554. (f) Lee, B. H.; Clothier,
M. F.; Dutton, F. E.; Nelson, S. J.; Johnson, S. S.; Thompson, D. P.;
Geary, T. G.; Whaley, H. D.; Haber, C. L.; Marshall, V. P.; Kornis, G. I.;
McNally, P. L.; Ciadella, J. I.; Martin, D. G.; Bowman, J. W.; Baker, C.
A.; Coscarelli, E. M.; Alexander-Bowman, S. J.; Davis, J. P.; Zinser, E.
W.; Wiley, V.; Lipton, M. F.; Mauragis, M. A. Curr. Top. Med. Chem.
2002, 2, 779-793. (g) Lee, B. H.; Clothier, M. F. U.S. Patent 5,750,695,
1998.
(16) (a) Robertson, A. P.; Clark, C. L.; Burns, T. A.; Thompson, D. P.; Geary,
T. G.; Trailovic, S. M.; Martin, R. J. J. Pharmacol. Exp. Ther. 2002, 302,
853-860. (b) Zinser, E. W.; Wolfe, M. L.; Alexander-Bowman, S. J.;
Thomas, E. M.; Davis, J. P.; Groppi, V. E.; Lee, B. H.; Thompson, D. P.;
Geary, T. G. J. Vet. Pharmacol. Ther. 2002, 25, 241-250.
(17) (a) Lee, B. H.; Clothier, M. F. J. Org. Chem. 1997, 62, 1795-1798. (b)
Lee, B. H.; Clothier, M. F.; Pickering, D. A. J. Org. Chem. 1997, 62, 7836-
7840.
Epoxide 20, which is commercially available or made by
epoxidation of isoprene with mCPBA, was treated with
n-Bu4NI and TBSCl to provide iodide 21 as a mixture of geo-
metrical isomers (E:Z ≈ 6:1) in 58% overall yield. Diester 22
was prepared in two steps from ethyl glycinate and ethyl acry-
late, and then a Dieckmann cyclization was conducted, using a
slight modification of the procedure described by Rapoport,22
(18) Williams, R. M.; Glinka, T.; Kwast, E.; Coffman, H.; Stille, J. K. J. Am.
Chem. Soc. 1990, 112, 808-821.
(21) Williams, R. M.; Cao, J. Tetrahedron Lett. 1996, 37, 5441-5444.
(22) (a) Blake, J.; Willson, C. D.; Rapoport, H. J. Am. Chem. Soc. 1964, 86,
5293-5299. For more regioselective methods, see: (b) Yamada, Y.; Ishii,
T.; Kimura, M.; Hosaka, K. Tetrahedron Lett. 1981, 22, 1353-1354. (c)
Sibi, M. P.; Christensen, J. W.; Kim, S.-G.; Eggen, M.; Stessman, C.; Oien,
L. Tetrahedron Lett. 1995, 36, 6209-6212.
(19) Cushing, T. D.; Sanz-Cervera, J. F.; Williams, R. M. J. Am. Chem. Soc.
1996, 118, 557-579.
(20) Williams, R. M.; Cao, J.; Tsujishima. H. Angew. Chem., Int. Ed. 2000, 39,
2540-2544.
9
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A R T I C L E S
Williams et al.
Scheme 3. Assignment of Absolute Chemistry of 25
Figure 2. Assignment of relative stereochemistry of 25.
Scheme 2. Synthesis of R-Alkylated-â-Hydroxyproline 25
Scheme 4. Preparation of the Diketopiperazine 34
to yield racemic â-ketoester 23 (Scheme 2). Baker’s yeast
reduction afforded the optically active â-hydroxyester 24 with
an enantiomeric ratio of ca. 95:5 as described by Knight et al.23
Alkylation of the dianion of 24 with substituted allyl iodide 21
proceeded with retention of stereochemistry and excellent
diastereoselectivity under the conditions previously developed.21
The desired R-alkylated product 25 was obtained in 58-70%
isolated yield with little or no O-monoalkylation or O-,C-
dialkylation taking place. It was interesting to note during large
scale synthesis of 25 that the amount of HMPA required in the
alkylation reaction ranged from 1.4 to 13.6 equiv depending
on the batch of 24 that was used, despite the batches being
apparently identical by 1H NMR, IR, TLC, and optical rotation.
The reasons for this phenomenon are presently unclear.24
The assignment of the relative stereochemistry of 25 was
1
obtained by comparison of the H NMR and optical rotation
However, because of problems with selectivity and purification
later in the synthesis, the less bulky and more polar methoxy-
methyl (MOM) protecting group was used in the final synthetic
route. After MOM protection of the alcohol, the N-t-BOC group
was smoothly removed with ZnBr2 in dichloromethane25 and
the exposed secondary amine (31) was acetylated with bro-
moacetyl bromide under Schotten-Baumann conditions (Scheme
4). Treatment of the bromoacetamide with methanolic ammonia
afforded the corresponding glycinamide (32) which was directly
subjected to cyclization in the presence of sodium hydride in
toluene/HMPA to afford the bicyclic compound 33 in 75%
overall yield from 25. An interesting observation about the ease
of closure of hydroxylated diketopiperazines was made during
this study. When there is no hydroxyl substituent (e.g., in 28)
or the protected hydroxyl group is trans to the ester, the
diketopiperazine typically forms spontaneously from the ami-
noester in methanol at room temperature. On the other hand, a
cis-isomer such as 31 can be isolated as the aminoester from
the amination reaction, and formation of the diketopiperazine
requires much more forcing conditions. On amination of a
data of 25 to those of 26, which was obtained by alkylation of
24 with 1,4-dibromobutane. The relative stereochemistry of 26
was assigned unambiguously through single-crystal X-ray
analysis (Figure 2).21 The absolute stereochemistry of 25 was
confirmed by Barton deoxygenation and conversion to dike-
topiperazine (+)-29 as illustrated in Scheme 3. This same
diketopiperazine could be obtained, as the enantiomer, from 30.
This compound has previously been converted to (+)-paraher-
quamide B, a substance whose absolute stereochemistry has been
confirmed.19
Synthesis of a Functionalized Diketopiperazine
It was necessary to convert the substituted proline (25) into
a suitably functionalized diketopiperazine for a similar Somei-
Kametani coupling reaction to that used in our total synthesis
of paraherquamide B. Initial studies on this system were carried
out with the secondary alcohol protected as a benzyl ether.
(23) (a) Cooper, J.; Gallagher, P. T.; Knight, D. W. J. Chem. Soc., Perkin Trans.
1 1993, 1313-1317. For alternative baker’s yeast reductions, see: (b) Sibi,
M. P.; Christensen, J. W. Tetrahedron Lett. 1990, 31, 5689-5692. (c) Bhide,
R.; Mortezaei, R.; Scilimati, A.; Sih, C. J. Tetrahedron Lett. 1990, 31,
4827-4830.
(25) Nigam, S. C.; Mann, A.; Taddei, M.; Wermuth, C.-G. Synth. Commun.
1989, 19, 3139-3142.
(24) Seebach, D. Angew. Chem., Int. Ed. Engl. 1988, 27, 1624-1654.
9
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Total Synthesis of Paraherquamide A
A R T I C L E S
Scheme 5. Preparation of the Gramine Derivative 51
mixture of diastereomeric bromoacetamides 35, the aminoester
36 and the diketopiperazine 37 are produced. This is pre-
sumably because the cis-diketopiperazine is significantly more
sterically hindered. After diketopiperazine formation, a one-
pot double carbomethoxylation reaction was performed by the
sequential addition of n-BuLi in THF followed by addition of
methylchloroformate, which carbomethoxylates the amide ni-
trogen. Subsequent addition of more methylchloroformate
followed by LHMDS afforded 34 in 93% yield as an ∼6:1
mixture of E and Z isomers, with the newly created stereogenic
center as a single stereoisomer (relative configuration was not
assigned).
approach circumvents these problems. Instead, we directly used
the mixture of nitrobenzaldehydes 39 and 40. After a three-
step transformation,28 39 provided the desired acid 41, and 40
provided the undesired acid 42. Reduction of the nitro group
was originally carried out in 95% yield by hydrogenation over
palladium on carbon at 40 psi and 80 °C. However, this protocol
could prove awkward on a large scale, so an alternative approach
was developed using iron and NH4Cl29 which, while the yield
(74%) is more moderate, proved easier to scale-up. On reduction
to the corresponding amines, the amine intermediate from 41
cyclized to oxindole 43, but 42 was simply reduced to amino
acid 44, which cannot undergo an intramolecular cyclization
reaction due to geometric restriction. On extraction of the reac-
tion mixture, the amino acid (44) was removed with aqueous
acid leaving the oxindole (43) in the organic phase. Demethy-
lation then proceeded smoothly as already described to give
45.30
Prenylation of 45 is partially selective for the 7-hydroxy
position due to the greater acidity of this hydroxyl group.
However, under the prenylation conditions originally developed
for paraherquamide B, small amounts of the 6-prenyloxy and
6,7-diprenyloxy isomers were also formed, and the three
compounds are difficult to separate by flash chromatography.
In this modification of our original route, replacement of the
base with Cs2CO3 improves the selectivity and yield of 46.
Improved Synthesis of the Gramine Derivative
With this functionalized diketopiperazine in hand, we turned
our attention to improvement of the synthesis of the dioxepin-
containing indole fragment that we originally described in
1990.26 The original route provides compound 51 in 14 steps
with no chromatography required until the ninth step. However,
further optimization was necessary to achieve a more rapid and
efficient large-scale synthesis. The route we have developed is
illustrated in Scheme 5. Vanillin (38) was acetylated with acetic
anhydride and then treated with fuming nitric acid to afford
39, the desired regioisomer, and 40, the undesired isomer, in
an ∼10:1 ratio. Initially, these regioisomers were separated by
hydrolysis of the acetate group and isolation of the desired phe-
nol isomer by crystallization.27 Analysis of the product mixture
by TLC revealed that 39 had a lower Rf and 40 had exactly the
same Rf as that of the starting material, and it was possible to
isolate 39 by flash chromatography. However, neither purifica-
tion method proved optimal for a large-scale protocol. The new
(28) (a) MacDonald, S. F. J. Chem. Soc. 1948, 376-378. (b) Beer, R. J. S.;
Clarke, K.; Davenport, H. F.; Robertson, A. J. Chem. Soc. 1951, 2029-
2032.
(29) Wissner, A.; Berger, D. M.; Boschelli, D. H.; Floyd, M. B., Jr.; Greenberger,
L. M.; Gruber, B. C.; Johnson, B. D.; Mamuya, N.; Nilakantan, R.; Reich,
M. F.; Shen, R.; Tsou, H.-R.; Upeslacis, E.; Wang, Y. F.; Wu, B.; Ye, F.;
Zhang, N. J. Med. Chem. 2000, 43, 3244-3256.
(30) Since this route was developed, McWhorter and Savall have published a
route to 45 which is shorter and higher yielding, but the applicability of
their synthesis on a large scale has not yet been demonstrated. Savall, B.
M.; McWhorter, W. W. J. Org. Chem. 1996, 61, 8696-8697.
(26) Williams, R. M.; Cushing, T. D. Tetrahedron Lett. 1990, 31, 6325-6328.
(27) Raiford, L. C.; Stoesser, W. C. J. Am. Chem. Soc. 1928, 50, 2556-2563.
9
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A R T I C L E S
Williams et al.
Scheme 6. Coupling of the Indole and Diketopiperazine
Extraction into base during the workup procedure also removes
the diprenylated byproduct which allowed for easier purification.
3:1 ratio, each as a mixture of four diastereomers (Scheme 6).33
Decarbomethoxylation was effected by treatment of 52 and 53
individually with LiCl in hot, aqueous HMPA to provide, in
both cases, a mixture of 54 (anti-isomer) and 55 (syn-isomer),
which could now be separated into the E and Z isomers, each
of which as a mixture of two diastereomers (epimeric at the
dioxepin secondary alcohol). However, as separation of the
geometric isomers proved to be difficult, the compounds were
usually carried through the synthetic sequence as a mixture and
separated only for analytical purposes. Protection of the second-
ary amide as the corresponding methyl lactim ether was
accomplished by treating 54 and 55 with trimethyloxonium
tetrafluoroborate and Cs2CO3 in dichloromethane. Model studies
had shown that Cs2CO3 was a more efficient base than
Na2CO3 for this reaction, as it leads to a lower incidence of
TBS cleavage and N-methylation. Next, the indole nitrogen was
protected as the corresponding N-t-BOC derivative by treatment
with di-tert-butyl dicarbonate in the presence of DMAP, and
then the silyl ethers were removed with tetrabutylammonium
fluoride (TBAF) to provide 58 (anti) and 59 (syn). From this
point onward, the E and Z isomers were utilized separately.
Unfortunately, the Corey procedure,34 which had been successful
A major problem in our first generation synthesis of the
gramine derivative was during reduction of the oxindole to the
indole, when over-reduction to the indoline occurred in variable
quantities giving a ratio of 4:1 to 2:1 of indole/indoline. Attempts
were made, without success, to effect a more selective reduction
of the oxindole. However, the problem was solved in an indirect
fashion as it proved possible to oxidize the indoline byproduct
to the indole with DDQ31 in greater than 90% yield.
Formation of TBS ethers on hindered alcohols is known to
be very sensitive to the concentration of the reaction mixture.
The silylation reaction was optimized by concentrating the
reaction mixture to give an improved yield of 95% from 82%.
Finally indole 50 was converted to the gramine derivative 51
under standard conditions. The advantages of this new approach
are significant in terms of increased yield, lower cost, and faster
synthesis on a large scale.
Coupling of the Indole and Diketopiperazine
Somei-Kametani coupling32 of diketopiperazine 34 with the
gramine derivative 51 in the presence of tri-n-butylphosphine
gave a separable mixture of two diastereomers 52 and 53 in a
(33) The stereochemistry at the newly formed stereogenic centers in 52 and 53,
and in all subsequent compounds, was assigned on the basis of 1H NMR
data. In compounds where the indole substituent is on the same face of the
diketopiperazine as the MOM ether, the signal for the methoxy group is at
significantly higher field than in the situation where these two substituents
are on opposite faces. This is due to the proximity of the methoxy group
to the shielding effects of the aromatic system.
(31) He, F.; Foxman, B. M.; Snider, B. B. J. Am. Chem. Soc. 1998, 120, 6417-
6418.
(32) (a) Somei, M.; Karasawa, Y.; Kaneko, C. Heterocycles 1981, 16, 941-
949. (b) Kametani, T.; Kanaya, N.; Ihara, M. J. Chem. Soc., Perkin Trans.
1 1981, 959-963.
(34) Corey, E. J.; Kim, C. U.; Takeda, M. Tetrahedron Lett. 1972, 13, 4339-
4342.
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12176 J. AM. CHEM. SOC. VOL. 125, NO. 40, 2003

Total Synthesis of Paraherquamide A
A R T I C L E S
Scheme 7. Formation of the Heptacycle
in the synthesis of paraherquamide B for conversion of an allylic
alcohol to the corresponding chloride, proved unreliable when
applied to the paraherquamide A system. Under the conditions
used previously, cleavage of the lactim ether and chlorination
at the 2-position of the indole were observed. Extensive
investigation into suitable conditions was carried out, and it was
eventually found that selective conversion of the primary
alcohols 58 and 59 to the corresponding mesylates was possible
in the presence of the hindered base collidine. Displacement of
mesylate by a chloride ion under these reaction conditions was
very slow so Bu3BnNCl (as an external chloride source) and a
polar solvent were added to accelerate the reaction, allowing
formation of the allylic chlorides (60 and 61) in up to 90% yield.
This is a simple, practical, and reproducible method for
preparing allylic chlorides in molecules bearing labile functional
groups. Finally, careful reprotection of the secondary alcohols
with tert-butyldimethylsilyl triflate in the presence of 2,6-lutidine
afforded the key allylic chlorides 62 and 63.
SN2′ Cyclization and Closure of the Seventh Ring
The stage was now set for the critical intramolecular SN2′
cyclization, that sets the relative stereochemistry at C-20 during
formation of the bicyclo[2.2.2]diazaoctane ring nucleus. Based
on precedent from the paraherquamide B synthesis,19 63E was
treated with NaH in refluxing benzene. However, the reaction
was very slow and gave the desired cyclization product 64 in
only 25% yield, accompanied by products from competing
pathways. The acidic proton in 63E is more sterically hindered
than in the corresponding substrate for the paraherquamide B
synthesis, due to the presence of the MOM ether. Since NaH
likely exists as heterogeneous clusters in benzene, it was
expected that use of a more coordinating solvent may break up
the clusters and render deprotonation more facile. Conveniently,
use of NaH in refluxing THF afforded the desired SN2′
cyclization product 64 in 87% yield from 63E exclusively as
the desired syn-isomer.35 This remarkably diastereoselective
intramolecular SN2′ cyclization reaction proceeds, in a nonpolar
solvent like THF, via a tight, intramolecular ion-pair driven
cyclization (“closed” transition state)36 as shown in Scheme 7.
Compound 62E also underwent the same transformation to give
64 in 82% yield. In both cases, the product was sometimes
accompanied by a small amount of Boc-deprotected cyclized
product which could be reprotected under standard conditions.
In addition, it was interesting to note that the Z-isomer, 63Z,
provides the same cyclization product, again with exclusive syn
selectivity, in 50% yield.
been successful in the paraherquamide B synthesis.19 However,
the only products isolated under the same conditions with 64
were those appearing to arise from removal of the N-t-BOC,
MOM and lactim ether protecting groups, presumably by HBF4
generated in situ. To buffer the reaction mixture, propylene oxide
was added as an acid scavenger and the reaction now proceeded
to give the desired 2,3-disubstituted indole (65) in 85% yield.
Completion of the Synthesis
Conditions could not be found which would allow direct and
high-yielding conversion of the lactim ether (65) to the amide.
However, use of 0.1 M aqueous HCl in THF gave the
corresponding ring-opened amine methyl ester (66) which was
recyclized to the bicyclo[2.2.2]diazaoctane (67) by treatment
of 66 with catalytic 2-hydroxypyridine in hot toluene. Chemose-
lective reduction of the tertiary amide in the presence of the
secondary amide to give 68 could be effected by treatment of
the diamide 67 with the AlH3-Me2NEt complex followed by
quenching with sodium cyanoborohydride, methanol, and acetic
acid, as used in the synthesis of paraherquamide B. However,
use of excess diisobutylaluminum hydride (DIBAL-H) in
dichloromethane was a simpler experimental procedure and gave
improved yields of 68.38 N-Methylation of the secondary amide
proceeded smoothly and was followed by cleavage of the MOM
ether with bromocatecholborane.39 Oxidation of the secondary
alcohol with Dess-Martin periodinane40 and concomitant
removal of the N-t-BOC group and TBS ether with TFA gave
ketone 70 (Scheme 8).
Closure of the seventh ring was attempted using PdCl2 and
AgBF4 in acetonitrile followed by NaBH4 to reduce the incipient
heptacyclic σ-palladium adduct,37 reaction conditions which had
(35) The syn/anti relationship in this case refers to the relative stereochemistry
between the C-20 stereogenic center (see paraherquamide numbering) and
the proline residue.
The final critical oxidative spirocyclization of the 2,3-
disubstituted indole was effected by a two-step procedure.
(37) Trost, B. M.; Fortunak, J. M. D. Organometallics 1982, 1, 7-13.
(38) Fukuyama, T.; Liu, G. Pure Appl. Chem. 1997, 69, 501-505.
(39) Boeckman, R. K., Jr.; Potenza, J. C. Tetrahedron Lett. 1985, 26, 1411-
1414.
(36) (a) Denmark, S. E.; Henke, B. R. J. Am. Chem. Soc. 1989, 111, 8032-
8034. (b) Denmark, S. E.; Henke, B. R. J. Am. Chem. Soc. 1991, 113,
2177-2194.
(40) (a) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155-4156. (b)
Dess, D. B.; Martin, J. C. J. Am. Chem. Soc. 1991, 113, 7277-7287.
9
J. AM. CHEM. SOC. VOL. 125, NO. 40, 2003 12177

A R T I C L E S
Williams et al.
Scheme 8. Manipulation of the Heptacycle
Scheme 9. Spirocyclization and Completion of the Synthesis
MeMgBr with our synthetic ketone gave (-)-paraherquamide
A (1) as the exclusive product (the C-14 epimer was not
detected) in 42% yield. This product was identical to a natural
sample of paraherquamide A by 1H NMR, 13C NMR, IR, exact
mass, and mobility on TLC (Rf). A synthetic sample was
25
recrystallized from ether and had mp 250 °C (dec), [R]D
)
-22 (c ) 0.2, MeOH). Natural paraherquamide A recrystallized
from ether under the same conditions yielded a sample with
25
mp 250 °C (dec) and [R]D ) -21 (c ) 0.2, MeOH). All
intermediates up to the final product have an enantiomeric ratio
of approximately 97.5:2.5; the final synthetic paraherquamide
A upon recrystallization from ether is approximately optically
pure.
We have reported here the first total synthesis of paraher-
quamide A, the most biologically potent member of this family
of compounds. This asymmetric synthesis proceeds in 46 steps
from commercially available materials, with the longest linear
sequence being 34 steps.
The approach developed in this study makes it feasible to
examine the design and synthesis of other members of the para-
herquamide family and should also permit access to structurally
unique paraherquamides that may have significant biological
properties. The application of this methodology to the asym-
metric, stereocontrolled total synthesis of other members of the
paraherquamide family, and evaluation of their properties is
currently under study in these laboratories.
Treatment of 70 with tert-butyl hypochlorite in pyridine
provided a labile 3-chloroindolenine, from which it was found
necessary to rigorously remove, by azeotroping with benzene,
all of the pyridine prior to the next step. Pinacol-type rear-
rangement with TsOH in aqueous THF then generated the
desired spiro-oxindole (73). From our investigations during the
paraherquamide B synthesis, it was found that use of a sterically
demanding amine such as pyridine gives the best stereoselec-
tivity during the chlorination reaction. It is assumed that addition
of chlorine to 70 proceeds from the least hindered face of the
indole giving the R-chloroindolenine 71. Hydration of the imine
functionality, interestingly, must also occur from the same
R-face, that is, syn-to the relatively large chlorine atom, to
furnish the syn-chlorohydrin 72 which subsequently rearranges
stereospecifically to the desired spiro-oxindole 73 (Scheme 9).
Dehydration of the seven-membered ring in 73 with methyl
triphenoxyphosphonium iodide (MTPI) in DMPU afforded 14-
oxoparaherquamide B (14) in moderate yield.17 This intermedi-
ate has been previously obtained semisynthetically from marc-
fortine A by a group from Pharmacia-Upjohn, and comparison
of the authentic and synthetic materials confirmed the identity
of this substance. Addition of methylmagnesium bromide to the
ketone group of 14 has been previously described to give
paraherquamide A along with the corresponding C-14 epimer
in around 50% yield.17a Employment of this protocol using
Acknowledgment. This work was supported by the NIH
(Grant CA 70375). The Japanese Society for the Promotion of
Science (JSPS) is acknowledged for providing fellowship
support to H.T. Mass spectra were obtained on instruments
supported by the NIH Shared Instrumentation Grant GM49631.
We also wish to thank Dr. Timothy Blizzard of Merck & Co.
for providing an authentic sample of natural paraherquamide
A. We also wish to acknowledge Dr. Byung H. Lee of the
Pharmacia-Upjohn Co. (now Pfizer) for providing NMR spectra
and an authentic specimen of 14-oxoparaherquamide B. We also
wish to thank Dr. Alfredo Vazquez for assistance with purifica-
tion and characterization of synthetic paraherquamide A.
Supporting Information Available: Complete experimental
procedures and spectroscopic and analytical data for all new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
JA036713+
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12178 J. AM. CHEM. SOC. VOL. 125, NO. 40, 2003