Total synthesis of sintokamide C

Article abstract of DOI:10.1021/ol100095p

(Figure Presented) A convergent stereoselective synthesis of sintokamide C was accomplished in 14 steps with an overall yield of 3.8% starting from Garner's aldehyde, unambiguously confirming its structure.

Full text of DOI:10.1021/ol100095p

ORGANIC
LETTERS
2010
Vol. 12, No. 5
1100-1103
Total Synthesis of Sintokamide C
Ying Jin,† Yuqing Liu,‡ Zhuo Wang,‡ Shuqin Kwong,‡ Zhengshuang Xu,*,†,‡ and
Tao Ye*,†,‡
Laboratory of Chemical Genomics, Peking UniVersity Shenzhen Graduate School,
UniVersity Town of Shenzhen, Xili, Nanshan District, Shenzhen, China, 518055, and
Department of Applied Biology & Chemical Technology, The Hong Kong Polytechnic
UniVersity, Hung Hom, Kowloon, Hong Kong, China
bctaoye@inet.polyu.edu.hk; xuzs@szpku.edu.cn
Received January 14, 2010
ABSTRACT
A convergent stereoselective synthesis of sintokamide C was accomplished in 14 steps with an overall yield of 3.8% starting from Garner’s
aldehyde, unambiguously confirming its structure.
Almost five thousand natural products that contain one or
more carbon-halogen bonds have been isolated. The struc-
tures vary from simple phenolic and aliphatic compounds
to complex polyketides and oligopeptides.1,2 These natural
products exhibit a variety of biological activities, including
analgesic,2 antitumor,3 anti-HIV,4 insecticidal,5 antimicro-
bial,6 and antibiotic properties.7 Most of these halogenated
natural products are secondary metabolites produced by
marine organisms, which have been found among various
species of algae, fungi, sediment-derived bacteria, sponges,
mollusks, coelenterates, and several marine worms. Some
of these compounds have been proven useful in studies
directed toward the elucidation of their biochemical path-
ways. Several groups of halogenating enzymes have been
discovered and investigated on the biochemical and genetic
levels.8 Enzymatic halogenation through oxidative mecha-
† Peking University Shenzhen Graduate School.
‡ The Hong Kong Polytechnic University.
(1) (a) Vaillancourt, F. H.; Yeh, E.; Vosburg, D. A.; Garneau-Tsodikova,
S.; Walsh, C. T. Chem. ReV 2006, 106, 3364–3378. (b) Anderson, J. L. R.;
Chapman, S. K. Mol. BioSyst. 2006, 2, 350–357. (c) Vetter, W. ReV.
EnViron. Contam. Toxicol. 2006, 188, 1–57. (d) Gribble, G. W. J. Chem.
(5) (a) Watanabe, K.; Miyakado, M.; Ohno, N.; Okada, A.; Yanagi, K.;
Moriguchi, K. Phytochemistry 1989, 28, 77–78. (b) Crews, P.; Myers, B. L.;
Naylor, S.; Clason, E. L.; Jacobs, R. S.; Staal, G. B. Phytochemistry 1984,
23, 1449–1451.
Educ. 2004, 81, 1441–1449
.
(6) (a) van Pe´e, K.-H.; Ligon, J. M. Nat. Prod. Rep. 2000, 17, 157–
164. (b) Nowak-Thompson, B.; Chaney, N.; Wing, J. S.; Gould, S. J.; Loper,
J. E. J. Bacteriol. 1999, 181, 2166–2174. (c) Ehrlich, J.; Bartz, Q. R.; Smith,
R. M.; Joslyn, D. A.; Burkholder, P. R. Science 1947, 106, 417. (d) Ding,
W.; Williams, D. R.; Northcote, P.; Siegel, M.; Tsao, R.; Ashcroft, J.;
Morton, G. O.; Alluri, M.; Abbanat, D.; Maiese, W. M.; Ellestad, G. E. J.
Antibiot. 1994, 47, 1250–1257. (e) Sundaramoorthy, M.; Terner, J.; Poulos,
T. L. Structure 1995, 3, 1367–1377.
(2) Gribble, G. W. Acc. Chem. Res. 1998, 31, 141–152
.
(3) (a) Prudhomme, M. Curr. Med. Chem 2000, 7, 1189–1212. (b)
Subbarajim, G. V.; Golakoti, T.; Patterson, G. M. L.; Moore, R. E. J. Nat.
Prod. 1997, 60, 302–305. (c) Sa´nchez, C.; Butovich, I. A.; Branˇa, A. F.;
Rohr, J.; Me´ndez, C.; Salas, J. A. Chem. Biol. 2002, 9, 519–531. (d) Yeh,
E.; Garneau, S.; Walsh, C. T. Proc. Natl. Acad. Sci. U.S.A. 2005, 102, 3960–
3965. (e) Fuller, R. W.; Cardellina, J. H., II.; Kato, Y.; Brinen, L. S.; Clardy,
J.; Snader, K. M.; Boyd, M. R. J. Med. Chem. 1992, 35, 3007–3011. (f)
Ciminiello, P.; Fattorusso, E.; Forino, M.; Di Rosa, M.; Ianaro, A.; Poletti,
R. J. Org. Chem. 2001, 66, 578–582.
(7) (a) Chiu, H. T.; Hubbard, B. K.; Shah, A. N.; Eide, J.; Fredenburg,
R. A.; Walsh, C. T.; Khosla, C. Proc. Natl. Acad. Sci. U.S.A. 2001, 98,
8548–8553. (b) Puk, O.; Bischoff, D.; Kittel, C.; Pelzer, S.; Weist, S.;
Stegmann, E.; Su¨ssmuth, R. D.; Wohlleben, W. J. Bacteriol. 2004, 186,
6093–6100.
(4) (a) Itabashi, T.; Ogasawara, N.; Nozawa, K.; Kawai, K. Chem.
Pharm. Bull. 1996, 44, 2213–2217. (b) Falch, B. S.; Konig, G. M.; Wright,
A. D.; Sticher, O.; Ru¨egger, H.; Bernardinelli, G. J. Org. Chem. 1993, 58,
6570–6575.
(8) Wagner, C.; EI Omari, M.; Ko¨nig, G. M. J. Nat. Prod. 2009, 72,
540–553.
10.1021/ol100095p  2010 American Chemical Society
Published on Web 02/11/2010

nisms is the most common route to these metabolites, though
direct halogenation via halide anion incorporation is also
known to proceed through both enzymatic and nonenzymatic
pathways.1a,9
encountered and they have only been reported in the context
of dysamide B14 and dysithiazolamide.15
Retrosynthetic analysis (Figure 1) suggested that sintoka-
mide C (1) might arise from bis-aldehyde 2. As the gem-
Marine cyanobacterium Lyngbya majuscula10 and sponge
genus Dysidea produced chlorinated peptides.11 We have
been interested for some time in marine peptides and view
their syntheses as a key route to structural modification and
subsequent activity control.12 Early on, we have reported the
total synthesis of dichlorinated cyclodepsipeptide lyngbya-
bellin A.12h Here we report on our efforts in the total
synthesis of tetrachlorinated peptide sintokamide C.
Sintokamides were isolated from specimens of the marine
sponge Dysidea sp. collected in Indonesia.13 Their structures
were elucidated by a combination of spectroscopic and
single-crystal X-ray diffraction analyses. The sintokamides
are the first small molecules known to selectively block
transactivation of the N-terminus of the androgen receptor
in prostate cancer cells.13 The biological potential as well
as the remarkably novel tetrachloride structure of sintokamide
C makes it an interesting synthetic target.
Figure 1. Retrosynthetic analysis.
Structurally, sintokamide C contains an unusual N-acylpyr-
rolinone moiety that is connected by an amide linkage. The
tetrachlorinated-peptide-based natural products are rarely
chloride is highly labile and undergoes base-promoted
dehydrohalogenation, the gem-chloride moieties in 1 would
be formed at the final stage in the synthesis. Further
disconnection of 2 at the N-acyl-pyrrolinone linkage provides
two intermediates (3 and 4) of similar structural complexity.
Both 3 and 4 could be synthesized rapidly from commercially
available compounds.
(9) (a) Fujimori, D. G.; Walsh, C. T. Curr. Opin. Chem. Biol 2007, 11,
553–560. (b) Neumann, C. S.; Fujimori, D. G.; Walsh, C. T. Chem. Biol.
2008, 15, 99–109. (c) Eusta´quio, A. S.; Pojer, F.; Noel, J. P.; Moore, B. S.
Nat. Chem. Biol. 2008, 4, 69–74. (d) van Pe´e, K. H.; Dong, C. J.; Flecks,
S.; Naismith, J.; Patallo, E. P.; Wage, T. AdV. Appl. Microbiol. 2006, 59,
127–157. (e) van Pe´e, K. H.; Patallo, E. P. Appl. Microbiol. Biotechnol.
2006, 70, 631–641
.
(10) (a) Flatt, P. M.; O’Connell, S. J.; McPhail, K. L.; Zeller, G.; Willis,
C. L.; Sherman, D. H.; Gerwick, W. H. J. Nat. Prod 2006, 69, 938–944.
(b) Galonic´, D. P.; Vaillancourt, F. H.; Walsh, C. T. J. Am. Chem. Soc.
2006, 128, 3900–3901. (c) Ramaswamy, A. V.; Sorrels, C. M.; Gerwick,
W. H. J. Nat. Prod 2007, 70, 1977–1986. (d) Williams, P. G.; Luesch, H.;
Yoshida, W. Y.; Moore, R. E.; Paul, V. J. J. Nat. Prod. 2003, 66, 595–
598. (e) Marquez, B. L.; Watts, K. S.; Alexandre Yokochi, A.; Roberts,
M. A.; Pascal Verdier-Pinard, P.; Jimenez, J. I.; Ernest Hamel, E.; Scheuer,
P. J.; Gerwick, W. H. J. Nat. Prod. 2002, 65, 866–871. (f) Milligan, K. E.;
Marquez, B. L.; Williamson, R. T.; Gerwick, W. H. J. Nat. Prod. 2000,
63, 1440–1443. (g) Luesch, H.; Yoshida, W. Y.; Moore, R. E.; Paul, V. J.
J. Nat. Prod. 2000, 63, 1437–1439. (h) Luesch, H.; Yoshida, W. Y.; Moore,
R. E.; Paul, V. J.; Mooberry, S. L. J. Nat. Prod. 2000, 63, 611–615.
(11) (a) Venkateswarlu, Y.; Ramesh, P.; Reddy, N. S. Nat. Prod. Sci.
1998, 4, 115–129. (b) Skepper, C. K.; Molinski, T. F. J. Org. Chem. 2008,
73, 2592–2597. (c) Stapleton, B. L.; Cameron, G. M.; Garson, M. J.
Tetrahedron 2001, 57, 4603–4607. (d) MacMillan, J. B.; Trousdale, E. K.;
Molinski, T. F. Org. Lett. 2000, 2, 2721–2723. (e) MacMillan, J. B.;
Molinski, T. F. J. Nat. Prod. 2000, 63, 155–157.
The fragment 3 (Scheme 1) was constructed in three steps
from the known intermediate 5.15b Condensation of acid 5
Scheme 1
(12) (a) Chen, B.; Dai, L.; Zhang, H.; Tan, W.; Xu, Z. S.; Ye, T. Chem.
Commun. 2010, 46, 574–576. (b) Liang, S.; Xu, Z. S.; Ye, T. Chem.
Commun. 2010, 46, 153–155. (c) Tang, S. B.; Xu, Z. S.; Ye, T. Tetrahedron:
Asymmetry 2009, 20, 2027–2032. (d) Li, S.; Liang, S.; Tan, W. F.; Xu,
Z. S.; Ye, T. Tetrahedron 2009, 65, 2695–2702. (e) Ren, Q.; Dai, L.; Zhang,
H.; Tan, W.; Xu, Z. S.; Ye, T. Synlett 2008, 2379–2383. (f) Li, S.; Liang,
S.; Xu, Z. S.; Ye, T. Synlett 2008, 569–574. (g) Chen, Z.; Ye, T. New
J. Chem. 2006, 30, 518–520. (h) Pang, H. W.; Xu, Z. S.; Chen, Z. Y.; Ye,
T. Lett. Org. Chem. 2005, 2, 699–702. (i) Pang, H. W.; Xu, Z. S.; Ye, T.
Lett. Org. Chem. 2005, 2, 703–706. (j) Xu, Z. S.; Ye, T. Tetrahedron:
Asymmetry 2005, 16, 1905–1912. (k) Chen, H. L.; Xu, Z. S.; Ye, T.
Tetrahedron 2005, 61, 11132–11140. (l) Chen, Z. Y.; Ye, T. Synlett 2005,
2781–2785. (m) Xu, Z. S.; Chen, Z. Y.; Ye, T. Tetrahedron: Asymmetry
2004, 15, 355–363. (n) Peng, Y. G.; Pang, H. W.; Ye, T. Org. Lett. 2004,
6, 3781–3784. (o) Chen, Z. Y.; Deng, J. G.; Ye, T. ARKIVOC 2003, (Part
VII), 268–285. (p) Xu, Z. S.; Peng, Y. G.; Ye, T. Org. Lett. 2003, 5, 2821–
2824.
with Meldrum’s acid in the presence of DCC and DMAP,
followed by thermolysis of the intermediate produced tet-
ramic acid 7 in good yield.16 Conversion of tetramic acid 7
into its O-methylated derivative (8) was accomplished by
(14) (a) Su, J.-Y.; Zhong, Y.-L.; Zheng, L.-M.; Wei, S.; Wong, Q.-W.;
Mak, T. C. W.; Zhou, Z.-Y. J. Nat. Prod. 1993, 56, 637–642. (b) Durow,
A. C.; Long, G. C.; O’Connell, S. J.; Willis, C. L. Org. Lett. 2006, 8, 5401–
5404.
(15) (a) Flatt, P. M.; O’Connell, S. J.; McPhail, K. L.; Zeller, G.; Willis,
C. L.; Sherman, D. H.; Gerwick, W. H. J. Nat. Prod. 2006, 69, 938–944.
(b) Arda´, A.; Soengas, R. G.; Nieto, M. I.; Jime´nez, C.; Rodr´ıguez, J. Org.
Lett. 2008, 10, 2175–2178.
(13) Sadar, M. D.; Williams, D. E.; Mawji, N. R.; Patrick, B. O.;
Wikanta, T.; Chasanah, E.; Irianto, H. E.; Van Soest, R.; Andersen, R. J.
Org. Lett. 2008, 10, 4947–4950.
Org. Lett., Vol. 12, No. 5, 2010
1101

treatment with diazomethane. Removal of the N-Boc protect-
ing group in 8 with TFA produced tetramic acid 3 in 92%
yield.
Scheme 3
The synthesis of the amino acid derivative 13 (Scheme 2)
commenced with Horner-Wadsworth-Emmons olefination
Scheme 2
wherein the N-propionylation was performed before repro-
tection of the amide nitrogen with Boc2O in the presence of
DMAP. Thus, benzyl ester 17 was prepared from acid 13
with benzyl chloroformate and DMAP.21 After removal of
the Boc protecting group in 17, the resulting amine was
treated with propionyl chloride in the presence of triethy-
lamine to afford amide 18 in 90% yield. Reprotection of the
amide nitrogen in 18 as its Boc derivative next produced 19
in 87% yield. Hydrogenolytic cleavage of the benzyl ester
produced the corresponding carboxylic acid, which was then
converted into its pentafluorophenol ester 4 under the
condition described for the synthesis of 14.
of Garner’s aldehyde with phosphonate 9 to provide the
corresponding (E)-R,ꢀ-unsaturated oxazolidinone 10, in 72%
yield.17 Enoate 10 was hydrogenated to give 11, which was
then converted into its sodium enolate and methylated to give
6 in 68% yield with >93% diastereoselectivity.18
Reductive cleavage of the auxiliary followed by protection
of the primary alcohol as its tert-butyldiphenylsilyl ether gave
the acetonide, which was cleaved under acidic conditions to
afford 12 in 71% yield (over three steps). Oxidation of the
resulting primary alcohol with TEMPO-BAIB19 afforded the
corresponding acid 13, which set the stage for fragment
assembly.
Scheme 4
Our initial approach for assembling the core structure of
sintokamide C envisioned capture of the anion derived from
deprotonation of the secondary amide of tetramic acid 3 by
an active ester derived from acid 13 (Scheme 3). Thus,
activation of the carboxylic functionality of 13 as its
pentafluorophenol ester (14),20 followed by condensation
with the lithium amide of 3 afforded 15 in 30% yield. To
our disappointment and surprise, all attempts to achieve the
N-propionylation of tert-butyl carbamate 15 with propionyl
chloride were unsuccessful.
In an effort to facilitate the installation of the propionyl
side chain, a revised route was developed (Scheme 4)
Further review of the literatures indicated the optimized
conditions for N-acylation of 4-alkylated pyrroline-2-ones has
been developed by Tønder and co-workers.22 With the synthesis
(16) (a) Jouin, P.; Castro, B.; Nisato, D. J. Chem. Soc., Perkin Trans.
1987, 1, 1177–1182. (b) Jiang, J.; Li, W.-R.; Przeslawski, R. M.; Joullie´,
M. M. Tetrahedron Lett. 1993, 34, 6705–6708.
(17) Dias, L. C.; Melgar, G. Z.; Jardim, L. S. A. Tetrahedron Lett. 2005,
46, 4427–4431.
(18) Evans, D. A.; Ennis, M. D.; Mathre, D. J. J. Am. Chem. Soc. 1982,
104, 1737–1739.
(21) Kim, S.; Lee, J. I.; Kim, Y. C. J. Org. Chem. 1985, 50, 560–565.
(22) (a) Hosseini, M.; Kringelum, H.; Murray, A.; Tønder, J. E. Org.
Lett. 2006, 8, 2103–2106. (b) Hosseini, M.; Tanner, D.; Murray, A.; Tønder,
J. E. Org. Biomol. Chem. 2007, 5, 3486–3494.
(19) Epp, J. B.; Widlanski, T. S. J. Org. Chem. 1999, 64, 293–295.
(20) Schon, I.; Kisfaludy, L. Synthesis 1986, 303–305.
1102
Org. Lett., Vol. 12, No. 5, 2010

of the key subunits 3 and 4 completed, the assembling of these
subunits leading to 20 was investigated (Scheme 5). Thus,
treatment of 3 in THF with lithum hexamethyldisilazide at -55
°C for 20 min provided the lithium anion, which was reacted
Finally, the Boc group of 22 was removed uneventfully with
trifluoroacetic acid in dichloromethane to deliver 1 in 73% yield
after chromatography over silica gel. The spectral data for
synthetic 1 (1H, 13C NMR and HMRS) were identical with those
published for the natural product,13 and the optical rotation of
our product, [R]20D +63.3 (c 0.1, CH2Cl2), corresponded well
with the literature value,13 [R]25 +58.7 (c 0.26, CH2Cl2),
D
Scheme 5
leading us to conclude that synthetic 1 was of the same absolute
stereochemistry as natural sintokamide C. In addition, we also
synthesized the dichlorides analogue (1b).27
The synthetic sample of sintokamide C was observed to
exert its biological activity by inhibiting cell proliferation
on the androgen receptor-expressing LNCaP cell line with
IC50 at 35 µM (Figure 2). However, 1 did not suppress the
Figure 2. Effect of sintokamide C and 1b on prostate cancer cell
proliferation. LNCaP and PC3 were cultured for 48 h in the presence
of various concentrations of sintokamide C and 1b. Proliferation
was measured by MTS assay as described in the Supporting
Information.
with pentafluorophenol ester 4 at -55 to -45 °C for 3 h to
afford 20 in 71% yield after chromatography over silica gel.
HF/pyridine cleavage of two primary TBDPS ethers afforded
alcohol 21, which was subsequently oxidized by using the
Parikh-Doering protocol23 to afford the corresponding bis-
aldehyde 2 in 80% yield. The stage was now set for the
generation of the two critical dichloromethyls. Although the
use of various chlorination agents for the conversion of
aldehydes to the corresponding dichloromethyls is known, only
the Rodr´ıguez’s modification24 of the Takeda conditions25 has
been successfully applied to the total synthesis of dysamide B14b
and (-)-dysithiazolamide.15b Much to our disappointment,
reaction of bis-aldehyde 2 under the modified Takeda conditions
yielded multiple degradation products. Recently, Prati and co-
workers26 developed a mild protocol for the synthesis of gem-
dihalides using triphenyl phosphate-halogen-based reagents.
Gratifyingly, chlorination of bis-aldehyde 2 according to Prati’s
procedure proceeded without any complications to afford
tetrachlorides 22 in 70% yield.
proliferation of the androgen-independent PC3 cell line (Figure
2). The proliferation of LNCaP and PC3 was completely
unaffected by analogue 1b.27 Our findings indicated that
sintokamide C inhibited the proliferation of prostate cancer cells
through blocking androgen receptor activity.
In summary, we have developed a convergent synthesis of
sintokamide C. Key steps en route to this natural product include
the application of Tønder protocol for N-acylation of 4-alkylated
pyrroline-2-ones and the chlorination of bis-aldehyde by the
use of Prati’s procedure to produce gem-dihalides.
Acknowledgment. We acknowledge financial support from
the Hong Kong Research Grants Council (project nos.
PolyU5407/06M and PolyU5638/07M) and financial support
from the Shenzhen Bureau of Science, Technology and
Information (JC200903160367A and ZD200806180051A). Xu
thanks the support from Shenzhen Foundation for R&D
(SY200806300179A), Nanshan Science
(NANKEYUAN2009083, 2009 083).
& Technology
(23) Parikh, J. R.; Doering, W. von E. J. Am. Chem. Soc. 1967, 89,
5505–5507.
Supporting Information Available: Full details for ex-
perimental procedures for compounds 1, 1b, 3, 4, 6-8, 10-15,
(24) (a) Arda´, A.; Jime´nez, C.; Rodr´ıguez, J. Tetrahedron Lett. 2004,
45, 3241–3243. (b) Arda´, A.; Rodriguez, J.; Nieto, R.; Bassarello, C.;
Gomez-Paloma, L.; Bifulco, G.; Jime´nez, C. Tetrahedron 2005, 61, 10093–
10098. (c) Arda´, A.; Jime´nez, C.; Rodr´ıguez, J. Eur. J. Org. Chem. 2006,
3645–3651.
1
and 17-22, and H and 13C NMR spectra for compounds 1,
1b, 2-4, 6-8, 10-12, 15, and 17-22. This material is available
free of charge via the Internet at http://pubs.acs.org.
(25) Takeda, T.; Sasaki, R.; Yamaguchi, S.; Fujiwara, T. Tetrahedron
1997, 53, 557–566.
OL100095P
(26) Spaggiari, A.; Vaccari, D.; Davoli, P.; Torre, G.; Prati, F. J. Org.
Chem. 2007, 72, 2216–2219. For a recent application of this method in the
total synthesis of nakiterpiosin, see: Gao, S.; Wang, Q.; Chen. C. J. Am.
Chem. Soc. 2009, 131, 1410-1412.
(27) For the synthesis of dichlorides analogue 1b, please see the
Supporting Information.
Org. Lett., Vol. 12, No. 5, 2010
1103