Nucleophilic addition of organozinc reagents to 2-sulfonyl cyclic ethers: stereoselective synthesis of manassantins a and B

Article abstract of DOI:10.1021/ol8024617

A convergent route to the synthesis of manassantins A and B, potent inhibitors of HIF-1, is described. Central to the synthesis is a stereoselective addition of an organozinc reagent to a 2-benzenesulfonyl cyclic ether to achieve the 2,3-cis-3,4-trans-4,5

Full text of DOI:10.1021/ol8024617

ORGANIC
LETTERS
2009
Vol. 11, No. 1
89-92
Nucleophilic Addition of Organozinc
Reagents to 2-Sulfonyl Cyclic Ethers:
Stereoselective Synthesis of
Manassantins A and B
Hyoungsu Kim,† Amanda C. Kasper,† Eui Jung Moon,‡ Yongho Park,† Ceshea
M. Wooten,† Mark W. Dewhirst,*,‡,§ and Jiyong Hong*,†
Department of Chemistry, Duke UniVersity, Durham, North Carolina 27708, Department of
Pathology, Duke UniVersity Medical Center, Durham, North Carolina 27708, and
Department of Radiation Oncology, Duke UniVersity Medical Center,
Durham, North Carolina 27708
jiyong.hong@duke.edu; dewhi001@mc.duke.edu
Received October 24, 2008
ABSTRACT
A convergent route to the synthesis of manassantins A and B, potent inhibitors of HIF-1, is described. Central to the synthesis is a stereoselective
addition of an organozinc reagent to a 2-benzenesulfonyl cyclic ether to achieve the 2,3-cis-3,4-trans-4,5-cis-tetrahydrofuran of the natural
products. Preliminary structure-activity relationships suggested that the (R)-configuration at C-7 and C-7′′′ is not critical for HIF-1 inhibition.
In addition, the hydroxyl group at C-7 and C-7′′′ can be replaced with a carbonyl group without loss of activity.
Tumor cells function under a condition of low physiological
oxygen levels known as hypoxia. To cope with this environ-
ment, tumor cells have developed a number of essential
mechanisms to promote angiogenesis and cell survival.1
Among these coping mechanisms is a response mediated by
hypoxia-inducible factor 1 (HIF-1).2 More than 60 target
genes that HIF-1 regulates have been identified, and the
products of these genes act at various steps in tumor
progression.3 In addition, tumor cells characterized by
overexpression of HIF-1 have been shown to be more
resistant to traditional cancer treatments such as radiation
and chemotherapy.4 Due to the importance of HIF-1 in tumor
development and progression, a considerable amount of effort
has been made to identify HIF-1 inhibitors for treatment of
cancer. Several small molecules have been reported to inhibit
the HIF-1 signaling pathway;5 however, these compounds
often exhibit biological activities other than HIF-1 inhibition.
(3) Semenza, G. L. Nat. ReV. Cancer 2003, 3, 721–732.
(4) (a) Moon, E. J.; Brizel, D. M.; Chi, J. T.; Dewhirst, M. W. Antioxid.
Redox. Signal. 2007, 9, 1237–1294. (b) Dewhirst, M. W.; Cao, Y.; Moeller,
B. Nat. ReV. Cancer 2008, 8, 425–437.
† Department of Chemistry, Duke University.
‡ Department of Pathology, Duke University Medical Center.
§ Department of Radiation Oncology, Duke University Medical Center.
(1) Harris, A. L. Nat. ReV. Cancer 2002, 2, 38–47.
(5) (a) Giaccia, A.; Siim, B. G.; Johnson, R. S. Nat. ReV. Drug DiscoV.
2003, 2, 803–811. (b) Semenza, G. L. Drug DiscoVery Today 2007, 12,
853–859.
(2) Semenza, G. L. Annu. ReV. Cell DeV. Biol. 1999, 15, 551–578.
10.1021/ol8024617 CCC: $40.75
Published on Web 12/03/2008
2009 American Chemical Society

In addition, most of them lack the desired selectivity for the
HIF-1 signaling pathway or toxicity profiles required for a
useful therapeutic agent.
achieve the 2,3-cis-3,4-trans-4,5-cis-tetrahydrofuran moiety
of the natural products and preliminary structure-activity
relationships.
Figure 1 describes our approach to the synthesis of
manassantins A (1) and B (2). Previously, we reported a
stereoselective synthesis of 2,3-cis-3,4-trans-4,5-trans- and
2,3-trans-3,4-trans-4,5-trans-tetrahydrofurans via BF3·OEt2-
promoted reductive deoxygenation of cyclic hemiketals.8 The
stereochemical outcome was rationalized on the basis of
Woerpel’s “inside attack” model.9 Based on the same
rationale, we envisioned that the organozinc reagent 4 would
be added to the sterically more favorable conformation (B)
of the 2-benzenesulfonyl cyclic ether 5 from the inside face
of the envelope conformer to stereoselectively provide the
2,3-cis-3,4-trans-4,5-cis-tetrahydrofuran (3a). This core tet-
rahydrofuran unit 3a could be coupled to the appropriate side
arms via SN2 reactions to complete the synthesis of 1 and 2.
As shown in Scheme 1, reduction of 68 with DIBALH
Interestingly, the dineolignans manassantins A (1) and B
(2) (Figure 1), isolated from the aquatic plant Saururus
Scheme 1. Nucleophilic Addition of
(4-Benzyloxy-3-methoxyphenyl)zinc(II) Bromide to
2-Benzenesulfonyl Cyclic Ether
Figure 1. Retrosynthetic plan for manassantins A (1) and B (2).
cernuus L., have been shown to be potent inhibitors of HIF-
1.6 However, their molecular mechanisms of action have yet
to be established. Hanessian and co-workers recently reported
the first total synthesis of 1 and 2 as well as confirmed the
absolute configuration of the natural products.7 In broad
connection with our interest in the stereoselective synthesis
of tetrasubstituted tetrahydrofurans,8 we undertook the
synthesis of 1 and 2 to develop a synthetic route to the natural
products that would be easily amenable to the development
of analogues for biological studies. Herein, we report a
synthesis of 1 and 2 through nucleophilic addition of an
organozinc reagent to a 2-benzenesulfonyl cyclic ether to
followed by treatment with PhSO2H and camphorsulfonic
acid provided the 2-benzenesulfonyl cyclic ether 5.10 Un-
fortunately, the key nucleophilic substitution reaction of 5
with (4-benzyloxy-3-methoxyphenyl)zinc(II) bromide 4,
derived in situ from (4-benzyloxy-3-methoxyphenyl)mag-
nesium bromide and ZnBr2,10 provided a 2:1 diastereomeric
mixture of 2,5-diaryl-3,4-dimethyl tetrahydrofurans. Careful
1
analysis of H NMR spectral data revealed that the major
diastereomer had the desired 2,3-cis-3,4-trans-4,5-cis-con-
figuration (3a) and the minor diastereomer had the 2,3-cis-
3,4-trans-4,5-trans-configuration (3b). We reasoned that the
(6) (a) Rao, K. V.; Alvarez, F. M. Tetrahedron Lett. 1983, 24, 4947–
4950. (b) Hodges, T. W.; Hossain, C. F.; Kim, Y.-P.; Zhou, Y.-D.; Nagle,
D. G. J. Nat. Prod. 2004, 67, 767–771. (c) 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, 1026–1033.
(9) (a) Shaw, J. T.; Woerpel, K. A. J. Org. Chem. 1997, 62, 6706–
6707. (b) Larsen, C. H.; Riggway, B. H.; Shaw, J. T.; Woerpel, K. A. J. Am.
Chem. Soc. 1999, 121, 12208–12209. (c) Shaw, J. T.; Woerpel, K. A.
Tetrahedron 1999, 55, 8747–8756. (d) Bear, T. J.; Shaw, J. T.; Woerpel,
K. A. J. Org. Chem. 2002, 67, 2056–2064. (e) Smith, D. M.; Woerpel,
K. A. Org. Lett. 2004, 6, 2063–2066.
(7) Hanessian, S.; Reddy, G. J.; Chahal, N. Org. Lett. 2006, 8, 5477–
5480.
(10) (a) Brown, D. S.; Ley, S. V. Tetrahedron Lett. 1988, 29, 4869–
4872. (b) Brown, D. S.; Bruno, M.; Davenport, R. J.; Ley, S. V. Tetrahedron
1989, 45, 4293–4308.
(8) Kim, H.; Wooten, C. M.; Park, Y.; Hong, J. Org. Lett. 2007, 9, 3965–
3968.
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Org. Lett., Vol. 11, No. 1, 2009

poor diastereoselectivity of the reaction would stem from
two competing factors. According to Woerpel’s “inside
attack” model, 4 would be delivered to 5 from the inside
face of the envelope conformer (7B) to provide the desired
tetrahydrofuran (3a). However, the addition of 4 to the
oxocarbenium intermediate via 7B also causes an unfavorable
repulsive interaction with the C-4 methyl group leading to
poor diastereoselectivity. We hypothesized that minimization
of the steric repulsion between the incoming nucleophile and
the C-4 methyl group would improve the disastereoselec-
tivity.
Scheme 3. Stereoselective Synthesis of
2,3-cis-3,4-trans-4,5-cis-Tetrahydrofuran
To prove this hypothesis, we tested two model systems
where the repulsive interaction was reduced by addition of
a smaller nucleophile or removal of the C-4 methyl group
(Scheme 2). As expected, addition of a sterically less
Scheme 2. Model Studies for Nucleophilic Addition Reaction
or diimide reduction of 14 only gave the desired 2,3-cis-
3,4-trans-4,5-cis-tetrahydrofuran as a minor diastereomer (dr
) 1:1-1:4). After extensive search of reaction conditions,
we were delighted to find that asymmetric hydrogenation of
14 in the presence of Ir and (4S,5S)-ThrePHOX12 provided
3a in 99% yield (dr ) 4:1).13
With the desired tetrahydrofuran 3a in hand, we turned
our attention to the installation of the side arms (Scheme 4).
We anticipated that coupling of 16 and 17 by Mitsunobu
coupling or oxidation-reduction condensation via alkoxy-
diphenylphosphines14 would proceed to afford 18. However,
our efforts for coupling reactions were unsuccessful in all
attempts and led us to adopt the procedures reported by Ley15
and Hanessian.7 A BEMP-mediated SN2 reaction of 16 and
1716 followed by stereocontrolled reduction using polymer-
supported BH4 completed the synthesis of manassnatins A
(1). In order to accomplish the synthesis of 2, 16 was
subjected to the BEMP-mediated SN2 reaction with 1 equiv
of 17 to form the monoalkylation product 19 (29%) in
addition to 18 (21%). Compound 19 was then subjected to
a second BEMP-mediated SN2 reaction with 2016 to give 21
(77%). Reduction of 21 with polymer-supported BH4 then
afforded manassantin B (2).
demanding PhZnBr to 5 gave a 3.5:1 diastereomeric mixture
of 10a and 10b. In addition, when 4 was added to the cyclic
ether 9, the reaction proceeded with excellent diastereose-
lectivity (dr ) 20:1). Based on the observations, we
envisioned that the installation of a sterically less demanding
exo-methylene group as a precursor to the C-4 methyl group
and stereoselective reduction of the double bond would
provide 3a in good stereoselectivity.
As shown in Scheme 3, alkylation of 8 with Eschen-
moser’s salt and m-CPBA oxidation smoothly proceeded to
afford 12 (80% for two steps).11 Reduction of 12 with
DIBALH followed by treatment with PhSO2H provided 13
in 64% yield. As expected, the exo-methylene group in 13
directed the addition of 4 via “inside attack” model to provide
the desired 2,3-cis-2,5-trans-tetrahydrofuran 14 as a major
diastereomer (dr ) 10:1, 41%). However, catalytic hydro-
genation under conventional conditions (e.g., Pd/C, PtO2)
ODD-Luc assay17 to assess HIF-1 inhibitory activity of
1, 18, and anti-diol diastereomer 22 ((7S,7′′′S)-epimer)
revealed that 1, 18, and 22 exhibited similar levels of HIF-1
inhibitory activity (IC50 ) 1-10 nM, Figure 2). The data
(12) McIntyre, S.; Hoermann, E.; Menges, F.; Smidt, P.; Pfaltz, A. AdV.
Synth. Catal. 2005, 347, 282–288.
(13) Asymmetric hydrogenation of 14 in the presence of Ir and (4R,5R)-
ThrePHOX provided 3a as a minor diastereomer (dr ) 1:2).
(14) Shintou, T.; Mukaiyama, T. J. Am. Chem. Soc. 2004, 126, 7359–
7367.
(11) (a) Schreiber, J.; Maag, H.; Hashimoto, N.; Eschenmoser, A. Angew.
Chem., Int. Ed. Engl. 1971, 10, 330–331. (b) Mandal, M.; Yun, H.; Dudley,
G. B.; Lin, S.; Tan, D. S.; Danishefsky, S. J. J. Org. Chem. 2005, 70, 10619–
10637.
(15) Lee, A.-L.; Ley, S. V. Org. Biomol. Chem. 2003, 1, 3957–3966.
Org. Lett., Vol. 11, No. 1, 2009
91

In summary, we applied a direct nucleophilic addition of
the organozinc reagent 4 to the 2-benzenesulfonyl cyclic ether
5 followed by an asymmetric hydrogenation to synthesize
the 2,3-cis-3,4-trans-4,5-cis-tetrahydrofuran moiety of 1 and
2, potent inhibitors of HIF-1. The stereoselectivity of the
nucleophilic addition reaction was improved by introduction
of the sterically less demanding exo-methylene group as a
surrogate for the C-9′ methyl group in 1 and 2. The synthetic
strategy would allow access to more potent and selective
analogues of 1 and 2 for biological studies to identify their
molecular mechanism of action.
Scheme 4
.
Completion of Synthesis of Manassantins A (1) and
B (2)
Figure 2. Inhibition of HIF-1 by 1, 18, and 22.
Acknowledgment. We thank Dr. Chuan-Yuan Li (Depart-
ment of Radiation Oncology, University of Colorado Health
Sciences Center) for the 4T1-ODD-Luc. This work was
supported by Duke University, Duke Chemistry Undergradu-
ate Summer Research Program, NIH PO1 CA42745, and
NIH/NCI CA40355. H.K. gratefully acknowledges the Korea
Research Foundation Grant funded by the Korean Govern-
ment (MOEHRD) (KRF-2006-352-E00028) for a postdoc-
toral fellowship.
suggested that the (R)-configuration at C-7 and C-7′′′ is not
critical for HIF-1 inhibition. In addition, the hydroxyl group
at C-7 and C-7′′′ can be replaced with carbonyl group without
significant loss of activity.
Supporting Information Available: General experimental
procedures including spectroscopic and analytical data for
1, 2, 3a, 3b, 5, 9, 10a, 10b, 11a, and 12-21 along with
copies of 1H and 13C NMR spectra; detailed assay procedure.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(16) Following the procedures reported in ref 15, 17 and 20 were
prepared from 1,2-dimethyl-4-(2-propen-1-yl)benzene and 5-(2-propen-1-
yl)-1,3-benzodioxole, respectively.
(17) Li, F.; Sonveaux, P.; Rabbani, Z. N.; Liu, S.; Yan, B.; Huang, Q.;
Vujaskovic, Z.; Dewhirst, M. W.; Li, C. Y. Mol. Cell 2007, 26, 63–74.
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