Synthesis and stereochemical assignment of (+)-chamuvarinin

Article abstract of DOI:10.1021/ol1028699

A stereocontrolled total synthesis of (+)-chamuvarinin, isolated from the root extract of Uvaria Chamae, utilizes a convergent modular strategy to construct the adjacently linked C15-C28 ether array, followed by a late-stage Julia-Kocienski olefination to

Full text of DOI:10.1021/ol1028699

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2011
Vol. 13, No. 3
514-517
Synthesis and Stereochemical
Assignment of (+)-Chamuvarinin
Gordon J. Florence,* Joanne C. Morris, Ross G. Murray, Jonathan D. Osler,
Vanga R. Reddy, and Terry K. Smith
School of Chemistry and Centre for Biomolecular Sciences, UniVersity of St. Andrews,
North Haugh, St. Andrews, KY16 9ST, U.K.
gjf1@st-andrews.ac.uk.
Received November 30, 2010
ABSTRACT
A stereocontrolled total synthesis of (+)-chamuvarinin, isolated from the root extract of Uvaria Chamae, utilizes a convergent modular strategy
to construct the adjacently linked C15-C28 ether array, followed by a late-stage Julia-Kocienski olefination to append the butenolide motif.
This constitutes the first total synthesis of (+)-chamuvarinin, defining the relative and absolute configuration of this unique annonaceous
acetogenin.
Isolated in 2004 by Laurens and co-workers from root
extracts of the West African plant, UVaria chamae, chamu-
varinin (1, Scheme 1)1,2 is a unique member of the
annonaceous acetogenin family of natural products.3 The
crude extracts of UVaria chamae are widely used in
traditional medicinal practices for the treatment of a range
of ailments including parasitic-borne West African sleeping
sickness and has proven to be a rich source of novel
acetogenins.4 An initial biological screening of chamuvarinin
showed significant cytotoxicity toward KB 3-1 cervix cancer
cell lines (IC50 ) 0.8 nM). Structurally, chamuvarinin is the
first acetogenin to contain a tetrahydropyran (THP) ring
linked adjacently to a bis-tetrahydrofuran (THF) ring system,
spanning the C15-28 region of the carbon backbone. In
common with the majority of acetogenins,3 1 bears the 36S-
configuration, but the assignment of the relative and absolute
configuration within the C15-C28 region proved to be a
more significant challenge. This quandary was partially
resolved by Poupon and co-workers in 2007,2 who showed
that 1 is not derived directly from squamocin leading to the
proposed relative configuration as shown,3,5 with two pos-
sible diastereomeric structures for the structure of 1. Herein,
we report the total synthesis of chamuvarinin and stereo-
chemical assignment of 1, utilizing a highly convergent
strategy for the construction of the central C15-C28 region.
We chose to pursue the 15R-diastereomeric series based on
(1) Fall, D.; Duval, R. A.; Gleye, C.; Laurens, A.; Hocquemiller, R. J.
Nat. Prod. 2004, 67, 1041
(2) Derbre´, S.; Poupon, E.; Gleye, C.; Hocquemiller, R. J. Nat. Prod.
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Estornell, E.; Cortes, D. Nat. Prod. Rep. 2005, 22, 269. (b) Spurr, I. B.;
Brown, R. C. D. Molecules 2010, 15, 460. (c) Alali, F. Q.; Liu, X.-X.;
McLaughlin, J. L. J. Nat. Prod. 1999, 62, 504. (d) Zafra-Polo, M. C.;
Figade`re, B.; Gallardo, T.; Tormo, J. R.; Cortes, D. Phytochemistry 1998,
48, 1087. (e) Zafra-Polo, M. C.; Gonza´lez, M. C.; Estornell, E.; Sahpaz,
S.; Cortes, D. Phytochemistry 1996, 42, 253. (f) Zeng, L.; Ye, Q.; Oberlies,
N. H.; Shi, G.; Gu, Z.-M.; He, K.; McLaughlin, J. L. Nat. Prod. Rep. 1996,
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1990, 53, 237.
(4) (a) Fall, D.; Gleye, C.; Franck, X.; Laurens, A.; Hocquemiller, R.
Nat. Prod. Lett. 2002, 16, 315. (b) Fall, D.; Gleye, C.; Laurens, A.;
Hocquemiller, R. Planta Med. 2006, 72, 938
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Fujimoto, Y. Chem. Pharm. Bull. 1994, 42, 1163
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10.1021/ol1028699  2011 American Chemical Society
Published on Web 12/21/2010

Scheme 1
.
Synthetic Strategy for Chamuvarinin 1
Scheme 3.
Synthesis of C9-C20 Subunit 4a
a PTSH ) 1H-mercaptophenyltetrazole; Mo(VI) ) (NH4)6Mo7O24·4H2O.
Scheme 2. Synthesis of C1-C8 Aldehyde 2
followed by cleavage of the C8-benzyl ether with BCl3·SMe2,
provided alcohol 9 (81% over 2 steps).10 Finally, Dess-Martin
oxidation of 9 provided the C1-C8 aldehyde 2 in excellent
yield, as required for the final C8-C9 bond coupling.
As shown in Scheme 3, the synthesis of the C9-C20
subunit 4 began with the Cu(I)-promoted opening of (S)-
TBS-glycidol ether 10 with allylmagnesium bromide to
provide 11 (82%). TBS ether formation (TBSCl, ImH) gave
12 (98%). Ozonolysis and reductive PPh3 workup of 12
provided aldehyde 13 which was used directly in the
Julia-Kocienski olefination with sulfone 1411,12 (readily
prepared from alcohol 1513 via Mitsunobu with DIAD, PPh3,
1H-mercaptophenyltetrazole, and Mo(VI)/H2O2 oxidation).
Treatment of sulfone 14 with NaHMDS in DME at -78 °C,
followed by addition of aldehyde 13, provided olefin 16 in
86% yield from 12 (E/Z ) 97:3). The C16-C19 THF ring
was conveniently installed by sequential application of
a comparison of acetogenins bearing a C15-carbinol linked
to a bis-THF motif and the biosynthetic likelihood that 1
would share the common 15R-configuration.5,6 Our synthetic
strategy relied on a late-stage olefination of the C1-C8
aldehyde 2 and a suitable coupling partner derived from the
C9-C34 intermediate 3, as outlined in Scheme 1. In turn,
assembly of the central C15-C28 polyether array found in
3 would arise from the coupling of aldehyde (4, C9-C20)
and alkyne (5, C21-C34), followed by reduction and
cyclization to install the C20-C23 THF motif.
(8) Marshall, J. A.; Piettre, A.; Paige, M. A.; Valeriote, F. J. Org. Chem.
2003, 68, 1771.
(9) Lactone 7 was prepared from (S)-propylene oxide and (phenylthio)
As outlined in Scheme 2, the synthesis of the C1-C8
aldehyde 2 started with the alkylation of iodide 67 with the
lithium enolate of lactone 7 to provide 8 in 75% yield.8,9
Oxidation to the sulfoxide (mCPBA) and 1,2-syn elimination,
i
acetic acid ((i) n-BuLi, Pr2NEt, THF, -78 f rt; (ii) p-TsOH, PhMe, rt,
78%); see: White, J. D.; Somers, T. C.; Reddy, G. N. J. Org. Chem. 1992,
57, 4991.
(10) Congreve, M. S.; Davidson, E. C.; Fuhry, M. A. M.; Holmes, A. B.;
Payne, A. N.; Robinson, A.; Ward, S. E. Synlett 1993, 663.
(11) Blakemore, P. R.; Cole, W. J.; Kocienski, P. J.; Morley, A. A.
(6) (a) Hoye, T. R.; Hanson, P. R.; Kovelsky, A. C.; Ocain, T. D.;
Zhuang, Z. J. Am. Chem. Soc. 1991, 113, 9369. (b) Hoye, T. R.; Tan, L.
Tetrahedron Lett. 1995, 36, 1981. (c) Yang, H.; Zhang, N.; Li, X.; Chen,
Synlett 1998, 26.
(12) (a) Blakemore, P. R. J. Chem. Soc., Perkin Trans. 1 2002, 2563.
(b) Dumeunier, R. I.; Marko´, E. Modern Carbonyl Olefination; Takeda, T.,
J.; Cai, B. Biorg. Med. Chem. Lett. 2009, 19, 2199
.
Ed.; WILEY-VCH: Weinheim, Germany, 2004; Chapter 3, p 104.
(7) Iodide 6 was prepared from 1,6-hexanediol ((i) BnBr, NaH, DMF,
44%; (ii) I2, PPh3, ImH, Et2O/MeCN (2:1), 88%); see: (a) Narayan, R. S.;
Borhan, B. J. Org. Chem. 2006, 71, 1416. (b) Shimojo, M.; Matsumoto,
K.; Hatanaka, M. Tetrahedron 2000, 56, 9281.
(13) Alcohol 15 was prepared from 1,7-heptanediol (BnBr, NaH, TBAI,
THF, 69%); see: (a) Morimoto, Y.; Yokoe, C. Tetrahedron Lett. 1997, 38,
8981. (b) Morimoto, Y.; Yokoe, C.; Kurihara, H.; Kinoshita, T. Tetrahedron
1998, 54, 12197.
Org. Lett., Vol. 13, No. 3, 2011
515

23R configuration in 88% yield (8:1 dr).19 The minor 23S
diastereomer proved readily separable by column chroma-
tography, and Mitsunobu inversion of the C23-hydroxyl in
24,20 followed by base-mediated methanolysis/desilylation
(K2CO3, MeOH), gave 25 (64%) with the requisite 23S
configuration. TBS protection (TBSCl/ImH, 91%) then
completed the C21-C34 subunit 5 in six steps and 11%
overall yield.
Scheme 4.
Synthesis of C21-C34 Subunit 5a
With our key subunits in hand our attention turned to the
C20-C21 bond construction and the installation of the
central C20-C23 syn-substituted THF motif. In practice,
treatment of 5 with n-BuLi, followed by addition of the
resulting lithium anion to 4, gave the expected Felkin-Anh
adduct 26 in 71% yield with good levels of stereocontrol at
C20 (3:1 dr). Diimide reduction of 26 with TsNHNH2 and
NaOAc in DME at reflux proved the most efficient reduction
protocol to afford 27 in 79% yield.21 At this point the C20
diastereomers were readily separated by column chroma-
tography.19 The stage was now set for the construction of
the central C20-C23 THF ring. In the event the C20-
hydroxyl in 27 was readily activated as its mesylate (MsCl,
Et3N), which upon treatment with TBAF promoted silyl ether
cleavage and concomitant 5-exo ring closure to provide 3
a Ar ) 4-BrC6H4.
protocols developed by Forsyth and co-workers.14,15 Cleav-
age of the TBS ethers in 16 with TBAF gave diol 17, which
was cleanly converted to epoxide 18 by treatment with NaH
and TrisIm (98%).14 Subsequent asymmetric dihydroxylation
of 18 (AD-mix-ꢀ),16 followed by base-mediated 5-exo
cyclization (K2CO3, MeOH), provided the 2,5-anti-THF diol
19 in 89% yield with >97:3 dr.15 A three-step sequence was
then required to complete the C9-C20 aldehyde 4, involving
TBS ether formation (TBSOTf, 2,6-lutidine), selective
primary silyl cleavage, and Dess-Martin oxidation (41%
over three steps). Using this approach the C9-C20 subunit
was completed in ten steps and 21% overall yield from 10.
As outlined in Scheme 4, the synthesis of the C21-C34
subunit 5 began with the opening of (S)-1-epoxyoctane 2017
with homoallylmagnesium bromide18 and catalytic CuI to
afford 21. In light of the initial uncertainty around the
substitution of the C24-C28 THP ring system in 1,1 we
adopted a divergent approach to access both syn-22 and anti-
23 from 21. Thus, epoxidation of 21 with mCPBA, followed
by addition of catalytic CSA (20 mol %) cleanly promoted
the in situ 6-exo cyclization to provide readily separable THP
alcohols 22 (41%) and 23 (32%). Oxidation of 22 and
addition of the lithium anion of trimethylsilylacetylene to
the intermediate aldehyde provided 24 with the undesired
1
in excellent yield. At this point, comparison of the H and
13C NMR spectra of the advanced C9-C34 intermediate 3
with the reported data for the C15-C28 region of chamu-
varinin showed them to be essentially in complete agree-
ment,1,2 providing us with the first clear indication of the
correct stereochemical assignment of the relative configu-
ration of the C15-C28 region of chamuvarinin.
With the advanced intermediate 3 in hand, attachment of
a suitable C1-C8 subunit at C9 was required to facilitate
the completion of chamuvarinin. In considering a suitable
C8-C9 coupling reaction, we initially focused on using a
C9-C34 aldehyde for olefination with either a C1-C8
Wittig salt or sulfone derived from 9; however this approach
proved unsuccessful. As a result we employed the reversed
coupling strategy detailed in Scheme 5. Thus, the C15-OH
in 3 was readily protected as its TBS ether (TBSOTf, 2,6-
lutidine, 88%) and subsequent hydrogenolysis of 28 provided
alcohol 29 in excellent yield. Treatment of 29 with 1H-
mercaptophenyltetrazole under Mitsunobu conditions (99%)
and subsequent oxidation of the intermediate sulfide (H2O2,
cat Mo(VI), 77%) provided the corresponding sulfone 30,
in readiness for the final C8-C9 Julia-Kocienski olefina-
tion.11,12,22 In the event, treatment of sulfone 30 with
(14) (a) Cink, R. D.; Forsyth, C. J. J. Org. Chem. 1995, 60, 8122. (b)
Corey, E. J.; Weigel, L. O.; Chamberlin, A. R.; Lipshutz, B. J. Am. Chem.
(19) The configurations of the carbinol stereocenters at C23 in 24 and
at C20 in 27 were assigned by advanced Mosher ester analysis. (a) Ohtani,
I.; Kusumi, T.; Kashman, Y.; Kakisawa, H. J. Am. Chem. Soc. 1991, 113,
4092. (b) Kusumi, T.; Hamada, T.; Ishitsuka, M. O.; Ohtani, I.; Kakisawa,
H. J. Org. Chem. 1992, 57, 1033. (c) Sullivan, J. R.; Dale, J. A.; Mosher,
H. S. J. Org. Chem. 1973, 38, 2143. (d) Hoye, T. R.; Jeffrey, C. S.; Shao,
F. Nat. Protoc. 2007, 2, 2451.
Soc. 1980, 102, 1439
.
(15) (a) Dounay, A. B.; Florence, G. J.; Saito, A.; Forsyth, C. J.
Tetrahedron 2002, 58, 1865. (b) Dounay, A. B.; Forsyth, C. J. Org. Lett.
2001, 3, 975
.
(16) Kolb, H. C.; VanNieuwenhze, M. S.; Sharpless, K. B. Chem. ReV.
1994, 94, 2483.
(20) For a review of the Mitsunobu reaction, see: Swamy, K. C. K.;
Kumar, N. N. B.; Balaraman, E.; Kumar, K. V. P. P. Chem. ReV. 2009,
109, 2551.
(17) Enantioenriched (S)-1-epoxyoctane 20 was prepared by hydrolytic
kinetic resolution of (()-epoxyoctane in 41% yield with g95% ee; see: (a)
Paddon-Jones, G. C.; McErlean, C. S. P.; Hayes, P.; Moore, C. J.; Konig,
W. A.; Kitching, W. J. Org. Chem. 2001, 66, 7487. (b) Schaus, S. E.;
Brandes, A. D.; Larrow, J. F.; Tokunga, M.; Hansen, K. B.; Gould, A. E.;
Furrow, M. E.; Jacobsen, E. N. J. Am. Chem. Soc. 2002, 124, 1307.
(18) Franc¸ais, A.; Bedel, O.; Picoul, W.; Meddour, A.; Courtien, J.;
Haudrechy, A. Tetrahedron: Asymmetry 2005, 16, 1141.
(21) (a) Marshall, J. A.; Chen, M. J. Org. Chem. 1997, 62, 5996. (b)
Crimmins, M. T.; Zhang, Y.; Diaz, F. A. Org. Lett. 2006, 8, 2369.
(22) (a) Wilcox, C. S.; Gudipati, V.; Lu, H.; Turkyilmaz, S.; Curran,
D. P. Angew. Chem., Int. Ed. 2005, 44, 6938. (b) Curran, D. P.; Zhang, Q.;
Richard, C.; Lu, H.; Gudipati, V.; Wilcox, C. S. J. Am. Chem. Soc. 2006,
128, 9561
.
516
Org. Lett., Vol. 13, No. 3, 2011

Scheme 5.
Completion of Chamuvarinina
a PTSH ) 1H-mercaptophenyltetrazole; Mo(VI) ) (NH4)6Mo7O24·4H2O.
NaHMDS in THF at -78 °C followed by the addition of
aldehyde 2 and warming to -20 °C over 4 h gave the
advanced intermediate 31 in 41% yield. Diimide reduction
of the C8-C9 alkene (TsNHNH2/NaOAc in DME/H2O),21
followed by deprotection of the C15-TBS ether (3 N HCl,
MeOH), provided the 15R, 16R, 19R, 20R, 23S, 24S, 28S, 36S-
diastereomer 32 in excellent yield over two steps. Gratify-
ingly, the spectroscopic data obtained for 32 (1H and 13C
NMR, IR, and MS) correlated fully with that of natural
chamuvarinin.1 In the absence of an authentic sample for
direct specific rotation and HPLC comparison, the measured
In conclusion, we have resolved the stereochemical
ambiguity surrounding the structure of chamuvarinin by
completing the first total synthesis (20 longest linear steps,
1.4% overall yield) and enabling further biological studies.
The present work demonstrates the versatility of our modular
alkyne coupling/cyclization strategy to construct adjacently
linked acetogenin frameworks in an efficient manner to
provide synthetic access to these rare bioactive metabolites
and for establishing their full stereochemistry.
Acknowledgment. We thank EPSRC (EP/F011458/1), the
Royal Society (G.J.F.), EaStChem (V.R.R.), the Wellcome
Trust (T.K.S.), and AstraZeneca for support; Dr. Dusan Uhrin
(Edinburgh) and Dr. Tomas Lebl (St Andrews) for NMR
spectra; Professor Erwan Poupon (Universite Paris Sud) for
copies of 1H and 13C NMR spectra of natural chamuvarinin;
and the EPSRC National Mass Spectrometry Service Centre,
Swansea, U.K.
20
specific rotation [R]D +9.9 (c 0.1, CHCl3) [lit.1 +25 (c
0.026, CHCl3)] was consistent with that of the natural
material. Further convincing evidence for 32 being the correct
stereostructure of 1 is provided by the comparable levels of
biological activity displayed by the synthetic material. In
screening assays against the HeLa cervix cancer cell line
and the bloodstream form of the parasite Trypanasoma
brucei, the synthetic material displayed ED50 values of 2.88
( 0.66 and 1.37 ( 0.08 µM, respectively,23 providing
unambiguous proof of the relative and absolute configuration
of (+)-chamuvarinin (1), as that being indicated in structure
32.
Supporting Information Available: Experimental pro-
cedures and spectroscopic data for new compounds and
copies of 1H and 13C NMR spectra for synthetic and natural
chamuvarinin. This material is available free of charge via
the Internet at http://pubs.acs.org.
(23) The trypanocidal activity of 32 was tested against cultured
bloodstream T. brucei (strain 427), and their cytotoxicity against HeLa cells
was determined using the Alamar Blue viability test, as described in: Mikus,
J.; Steverding, D. Parasitol. Int. 2000, 48, 265.
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