Total synthesis and stereochemical confirmation of manassantin A, B, and B1

Article abstract of DOI:10.1021/ol0621710

Stereocontrolled total syntheses of manassantins A, B, and B₁ and saucerneol are described for the first time based on a novel cycloetherification of end-differentiated benzylic alcohols as a common intermediate.

Full text of DOI:10.1021/ol0621710

ORGANIC
LETTERS
2006
Vol. 8, No. 24
5477-5480
Total Synthesis and Stereochemical
Confirmation of Manassantin A, B, and
B1
Stephen Hanessian,* Gone Jayapal Reddy, and Navjot Chahal
Department of Chemistry, UniVersite´ de Montre´al, C.P. 6128, Succursale Centre-Ville,
Montre´al, Que´bec H3C 3J7, Canada
stephen.hanessian@umontreal.ca
Received September 1, 2006
ABSTRACT
Stereocontrolled total syntheses of manassantins A, B, and B1 and saucerneol are described for the first time based on a novel cycloetherification
of end-differentiated benzylic alcohols as a common intermediate.
The manassantin group of structurally related and function-
ally unique dineolignans has been recently isolated from
active root extracts of Saururus cernuus L. (Saururaceae),
also referred to as “lizard tail”. This fragrant aquatic plant
is found in the eastern United States1 as well as in parts of
the orient (Saururus chinensis).2 Although their structures
and relative stereochemistries were only recently determined,1c
the medicinal value of the plant has long been recognized
by Native Americans, early colonists, and practitioners of
Korean folk medicine for a host of diseases.3 Many medically
relevant activities have been associated with manassantin A
(1) and B (2) in particular (Figure 1).1-3 For example,
manassantin B has been shown to be a potent inhibitor of
the key transcription factor HIF-1 (hypoxia-inducible factor-
1).1c,d Overexpression of HIF-1 in solid tumors is detrimental
to tumor suppression and compromises anticancer treatment
regimens.4 Thus, selective inhibition of HIF-1 is an important
objective in the quest for a chemotherapeutic agent against
solid tumors.4 Remarkably, manassantins A and B are also
reported to inhibit PC-3 prostate cancer cell growth5 and
other cell lines with IC50 values superior to those for cis-
platin and doxorubicin.6 Inhibition of TNF-R in conjunction
(1) (a) Rao, K. V.; Alvarez, F. M. Tetrahedron Lett. 1983, 24, 4947. (b)
Rao, K. V.; Oruganty, R. S. J. Liq. Chromatogr. Rel. Technol. 1997, 20,
3121. (c) Hodges, T. W.; Hossain, C. F.; Kim, Y.-P.; Zhou, Y.-D.; Nagle,
D. G. J. Nat. Prod. 2004, 67, 767. (d) Hossain, C. F.; Kim, Y.-P.; Baerson,
S. R.; Zhang, L.; Bruick, R. K.; Mohammed, K. A.; Agarwal, A. K.; Nagle,
D. G; Zhou, Y.-D. Biochem. Biophys. Res. Commun. 2005, 333, 1026.
(2) (a) Hwang, B. Y.; Lee, J.-H.; Nam, J. B.; Hong, Y.-S.; Lee, J. J.
Phytochemistry 2003, 64, 765. (b) Lee, W. S.; Lee, D.-W.; Baek, Y.-I.;
An, S.-J.; Cho, K.-H.; Choi, Y.-K.; Kim, H.-C.; Park, H. Y.; Bae, K.-H.;
Jeong, T.-S. Bioorg. Med. Chem. Lett. 2004, 14, 3109.
(3) (a) Hartwell, J. L. Lloydia 1971, 34, 204. (b) Phares, D. L. Am. J.
Pharm. 1987, 39, 468. (c) Chung, B. S.; Shin, M. G. Dictionary of Korean
Folk Medicine; Young Lim sa: Seoul, 1990; p 813.
Figure 1. Structures of the manassantins and saucerneol.
10.1021/ol0621710 CCC: $33.50
© 2006 American Chemical Society
Published on Web 10/24/2006

with E-selective expression may have relevance in the
prevention of atherosclerosis and endothelial activation.7
Manassantin A has also been associated with selective
neuroleptic activity.8 In their intial report, Rao and Alvarez1a
revealed the gross structure and only partial relative config-
uration of 1 and 2. They coined the name manassantin from
the Sanskrit words “manas” or mind and “santi” or peace
(i.e., peace of mind). The tranquilizing effect of a nitrogen-
free natural product from an aquatic plant was unprecedented
at the time.
Subsequently, Nagle and co-workers1c relied on the
Mosher ester method to determine the configuration of the
benzylic carbon in the quasi-C2 symmetrical alcohols in the
side chains and, by inference, the adjacent ether bearing
carbon atoms. The absolute configuration of a syn-anti-
syn-substituted central tetrahydrofuran ring was not deter-
mined. The Nagle group has recently isolated a previously
unreported diastereomer B1 (3) with an inverted configuration
of one of the C-methyl groups in the side chain and also
reported physical constants for manassantins A and B.1d
Saucerneol (4) is a neolignan, also found in the Saururus
cernuus L.1a Recently, the absolute configuration in the side
chain was determined by Lee and co-workers using the
Mosher ester method.2a
anti-syn-tetrahydrofuran unit A can be derived from an
intramolecular cycloetherification of a functionally dif-
ferentiated acyclic precursor B. The intended stereochemistry
of the ether-protected hydroxyl group in B would be
generated from aldehyde C, already harboring three contigu-
ous stereogenic centers. Sequential introduction of the
requisite two C-methyl groups in a stereocontrolled manner
would capitalize on 1,2-inductions of resident groups starting
with γ-alkoxy-R,â-unsaturated ester D. Chirality would be
derived from a catalytic asymmetric cyanohydrin formation
of E, starting from the 3,4-dialkoxy benzaldehyde F. Thus,
a major initial challenge resided in the introduction of vicinal
syn-related C-methyl groups in an acyclic carbon chain
harboring four contiguous stereogenic centers (DfCfB).
The cycloetherification without racemization (BfA) of a
para-activated benzylic position was another concern in the
synthesis plan. Finally, steps to install the phenolic append-
ages (Af1, 2, 3) including two vicinal hydroxyethyl
stereogenic centers would present the penultimate hurdle in
the stereocontrolled projected assembly of manassantins A,
B, and B1.
Cyanohydrin 5 (>99% ee after recrystallization), obtained
from the corresponding aldehyde by a catalytic asymmetric
protocol according to Belokon,9 was converted to the ester
6 in excellent overall yield (Scheme 1). Treatment with
Dibal-H gave an intermediate aldehyde, which was extended
to the enoate 7 via a Wittig olefination in over 85% yield
(for two steps). Treatment of 7 with lithium dimethylcuprate
in the presence of TMSCl afforded the anti-C-methyl adduct
as the major diastereomer in 87% yield, which was converted
to the K-enolate and alkylated with MeI to give 8 in excellent
diastereomeric ratio.10 The ester group in 8 was first reduced
to the corresponding alcohol, and the latter was back oxidized
with the Dess-Martin periodinane reagent to afford aldehyde
9 in excellent overall yield. A critical step was to be tested
at this juncture in the anticipated threo-controlled addition
of the 3-methoxy-4-benzyloxyphenylmagnesium bromide to
doubly sterically biased aldehyde 9. After numerous trials,11
efficient addition took place in the presence of CeCl3 as an
activator12 to give a 2.5:1 mixture of epimeric alcohols 10a
and 10b which could not be separated at this stage. Protection
of the epimeric mixture of alcohols as the MOM ethers,
followed by treatment with TBAF, and de-O-allylation gave
a separable mixture of 11a (55%) and 11b (21% for three
steps). The intended intramolecular etherification was best
We undertook the total synthesis of the three manassantins
(1-3) and saucerneol 4 (Figure 1) to confirm the previously
assigned configurations and to provide viable synthetic
methods that could supplement the relatively small quantities
of products isolated by extraction. Visual analysis of the
structure of manassantin A immediately reveals its ex-
quisite C2 symmetry. Except for the methylenedioxy group,
manassantin B is also endowed with the same symmetry
element unifying the disconnective analysis with a common
intermediate (Figure 2). Thus, the core tetrasubstituted syn-
(4) (a) Semenza, G. L. Nat. ReV. Cancer 2003, 3, 721. (b) Clottes, E.
Bull. Cancer 2005, 92, 119. (c) Moeller, B. J.; Dewhirst, M. W. Br. J.
Cancer 2006, 95, 1.
(5) Song, S.-Y.; Lee, I.; Park, C.; Lee, H.; Hahm, J.-C.; Kang, W. K.
Int. J. Mol. Med. 2005, 16, 517.
(6) Hahm, J.-C.; Lee, I.-K.; Kang, W.-K.; Kim, S.-U.; Ahn, Y.-J. Planta
Med. 2005, 71, 464.
(7) Kwon, O. E.; Lee, H. S.; Lee, S. W.; Chung, M. Y.; Bae, K. H.;
Rho, M.-C.; Kim, Y.-K. Arch. Pharm. Res. 2005, 28, 55.
(8) Rao, K. V.; Puri, V. N.; Sawaf, H. A. E. Eur. J. Pharmacol. 1990,
179, 367.
(9) Belokon, Y. N.; North, M.; Parsons, T. Org. Lett. 2000, 2, 1617.
(10) (a) Hanessian, S.; Sumi, K. Synthesis 1991, 1083. (b) Hanessian,
S.; Gai, Y.; Wang, W. Tetrahedron Lett. 1996, 37, 7473. (c) Hanessian, S.;
Wang, W.; Gai, Y. Tetrahedron Lett. 1996, 37, 7477.
(11) See Supporting Information (Table 1).
(12) Imamoto, T.; Takiyama, N.; Nakamura, K.; Hatajima, T.; Kamiya,
Y. J. Am. Chem. Soc. 1989, 111, 4392.
Figure 2. Disconnective analysis for the manassantins.
5478
Org. Lett., Vol. 8, No. 24, 2006

Scheme 1
achieved using the p-nitrobenzoate ester 12 as a precursor.
supported borohydride 18 to give the desired diastereomer
(dr >5:1) as the major product. Cleavage of the benzyl ether
gave 20, and application of the same protocol as that
described above first gave the bis-ether 21, which was
subjected to the three-step sequence to give manassantin B
(2) as a major product (dr 6.5:1). Synthetic manassantin B
was found to be identical, in all aspects, with an authentic
sample kindly provided by Novartis (Basel).
Treatment of 12 with mesyl chloride in CH2Cl2 (Scheme 1)
in the presence of Et3N gave the desired THF isomer 13a as
the major product (7:1). Cleavage of the p-nitrobenzoate ester
in 13a gave the C2 symmetrical and end-differentiated core
THF unit 14a. Hydrogenolysis of the benzyl ether led to the
known saucernetin diol 15.1b The triflate ester of S-methyl
lactate proved to be an excellent electrophilic partner in the
double intermolecular SN2 displacement with the phenolic
hydroxyl group in 15. Using a phosphazene base (BEMP),13
reaction took place with complete inversion to give 16 in
95% yield. Conversion of 16 to the corresponding Weinreb
amide14 followed by treatment with the Grignard reagent
prepared from 3,4-methylenedioxy-1-bromobenzene gave the
ketone 17 in 90% yield. The selective reduction of the two
carbonyl groups in 17 was best accomplished with a polymer
supported borohydride 1815 to afford manassantin A (1) as
the major product, easily separable from the minor syn-
alcohol diastereomer (dr 5.5:1) in a total yield of 76%. The
physical constants of 1 were in full accord with published
data.1a
The synthesis of manassantin B1 presented a new challenge
because it contains a syn-oriented hydroxylethyl ether linker
in the methylenedioxyaryl portion of the molecule (Figure
Scheme 2
The synthesis of manassantin B (2) was achieved in the
same manner starting from the enantiopure common inter-
mediate 14a (Scheme 2). An SN2 displacement of the triflate
ester of S-methyl lactate with 14a as described above gave
the ether 19 in excellent yield. Conversion to the Weinreb
amide and treatment with 3,4-dimethoxy phenylmagnesium
bromide gave a ketone, which was reduced with the polymer
(13) Schwesinger, R.; Schlemper, H. Angew. Chem., Int. Ed. Engl. 1987,
26, 1167.
(14) Shimizu, T.; Osako, K.; Nakata, T. Tetrahedron Lett. 1997, 38, 2685.
See also: Basha, A.; Lipton, M.; Weinreb, S. M. Tetrahedron Lett. 1977,
18, 4171.
(15) Lee, A.-L.; Ley, S. V. Org. Biomol. Chem. 2003, 1, 3957.
Org. Lett., Vol. 8, No. 24, 2006
5479

1). The common precursor 19 was first elaborated to the
ketone 22 as described above in excellent yield (Scheme 3).
allylboration of aromatic aldehydes to R-methylene lactones
are of interest.20
The successful application of the sequential cuprate
addition and enolate C-methylation in our protocol is note-
worthy in view of the paucity of methods for the stereo-
controlled synthesis of vicinal carbon substitution in acyclic
substrates.10 The added practical advantage of our approach
is the MOM-mediated SN2 displacement of end-differentiated
benzylic alcohols in the elaboration of the syn-anti-syn-
tetrasubstituted THF core unit. This was best done with a
para-nitrobenzoate phenolic ester.21 The last stereochemical
hurdle to overcome in the assembly of the manassantins
consisted of the deployment of the phenolic ether side chain.
An approach to this construct in relation to the synthesis of
neolignans was reported by Lee and Ley.15 Phenolic inter-
mediates were used in SN2 displacement reactions of R-keto
tosylates, prepared in a three-step sequence employing an
asymmetric dihydroxylation of Z-propenyl aromatics as a
source of chirality.
Scheme 3
An expedient method to prepare phenolic ethers of lactic
acid consists of an SN2-type displacement of the correspond-
ing mesylates. Despite the simplicity of this method, there
are only a few reports of documented examples.22 Unfortu-
nately in the case of Cs phenolate and the mesylate ester of
L-ethyl lactate, a partially racemized product was observed.22
We reasoned that the use of a hindered strong nitrogen base
such as a phosphazene13 in conjunction with an excellent
leaving group such as a triflate would be a good combination.
Indeed, smooth displacement took place to give the inverted
ether in high yield. The reaction could also be successfully
carried out in a bidirectional mode en route to manassantin
A.
In conclusion, we have described an efficient and stereo-
controlled route for the first total synthesis of manassantins
A, B, and B1 and the neolignan saucerneol. Definitive
confirmation of the previously proposed absolute confirma-
tion of these biologically important complex lignans has now
been established through total synthesis.
Polymer supported borohydride reduction led, as expected,
to the anti-alcohol (dr 6.5:1), which was converted to
saucerneol 4 by hydrogenolysis. BEMP-mediated displace-
ment of the triflate ester of R-methyl lactate with 4 proceeded
smoothly to give 23 in 93% yield. Conversion to the Weinreb
amide followed by reaction with the 3,4-methylenedioxy
phenylmagnesium bromide led to the expected ketone 24.
Reduction with NaBH4 in a mixture of MeOH and CH2Cl2
at low temperature gave manassantin B1 (3) as the prepon-
derant product (dr 17:1) in 89% yield. Comparison of
physical constants provided definitive proof of its structure
and absolute configuration.1d
The main challenge in the synthesis of the diversely
substituted 2,5-diaryl-3,4-dimethyl tetrahydrofurans related
to the manassantins is to control the relative and absolute
stereochemistry of four contiguous stereogenic centers in the
central ring and two in the side chains. Historically, expedient
access to racemic 2,5-diaryl-3,4-dimethyl lignans has relied
on the synthesis of 1,4-diaryl-2,3-dimethyl-1,4-diketones,
followed by reduction to 1,4-diols and cyclization by
treatment with MsCl and base.16 This simple protocol
produces diastereomeric mixtures of the racemic tetrasub-
stituted tetrahydrofurans. Cycloetherification can also be
accompanied by unwanted Friedel-Crafts reaction on the
benzylic mesylates.17 Other methods have also been reported
that rely on oxidative cyclization followed by functional
group adjustments to give racemic lignans.18 Recent methods
relying on a chiral auxiliary mediated aldol reaction19 and
Acknowledgment. We thank NSERC for financial as-
sistance and Dr. Ying Wang (Novartis Pharma) for an
authentic sample of manassantin B. We also acknowledge
fruitful discussions with Dr. Silvio Roggo (Natural Products
Unit, Novartis Institute for Biomedical Research, Basel).
Supporting Information Available: Full experimental
procedures, compound characterizations, and selected 1H and
13C NMR spectra. This material is available free of charge
via the Internet at http://pubs.acs.org.
OL0621710
(19) Esumi, T.; Hojyo, D.; Zhai, H.; Fukuyama, Y. Tetrahedron Lett.
2006, 47, 3979.
(20) (a) Coleman, R. S.; Gurrala, S. R. Org. Lett. 2004, 6, 4025. (b) Yu,
S. H.; Ferguson, M. J.; McDonald, R.; Hall, D. G. J. Am. Chem. Soc. 2005,
127, 12808.
(21) The minor isomer 13b had resulted from a face-selective attack of
the distal benzylic alcohol via a quinonoid oxocarbenium ion with ejection
of the OMOM group to giva an anti-anti-anti pattern. See Supporting
Information (Scheme 1).
(22) Otera, J.; Nakazawa, K.; Sekoguchi, K.; Orita, A. Tetrahedron 1997,
53, 13633.
(16) Biftu, T.; Gamble, N. F.; Doebber, T.; Hwang, S.-B.; Shen, T.-Y.;
Snyder, J.; Springer, J. P.; Stevenson, R. J. Med. Chem. 1986, 29, 1917.
(17) Yamauchi, S.; Okazaki, M.; Akiyama, K.; Sugahara, T.; Kishida,
T.; Kashiwagi, T. Org. Biomol. Chem. 2005, 3, 1670.
(18) (a) Moinuddin, S. G. A.; Hishiyama, S.; Cho, M.-H.; Davin, L. B.;
Lewis, N. G. Org. Biomol. Chem. 2003, 1, 2307. (b) Stevenson, R.;
Williams, J. R. Tetrahedron 1977, 33, 285.
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Org. Lett., Vol. 8, No. 24, 2006