Concise and stereoselective synthesis of the N7-C25 fragment of psymberin

Article abstract of DOI:10.1021/ol0520267

(Chemical Equation Presented) The N₇-C₂₅ fragment of the potent and selective cytotoxic agent psymberin has been prepared through a short (12 linear steps, 15 total steps) and stereoselective sequence. Highlights of this route includ

Full text of DOI:10.1021/ol0520267

ORGANIC
LETTERS
2005
Vol. 7, No. 23
5175-5178
Concise and Stereoselective Synthesis
of the N7 C25 Fragment of Psymberin
−
Jason C. Rech and Paul E. Floreancig*
Department of Chemistry, UniVersity of Pittsburgh, Pittsburgh, PennsylVania 15260
florean@pitt.edu
Received August 22, 2005
ABSTRACT
The N7−C25 fragment of the potent and selective cytotoxic agent psymberin has been prepared through a short (12 linear steps, 15 total steps)
and stereoselective sequence. Highlights of this route include a very rapid construction of the pentasubstituted arene, a substrate-controlled
diastereoselective fragment coupling using a Mukaiyama aldol reaction, and an efficient entry into a key tetrahydropyranyl cyanide.
The family of compounds that contains pederin,1 the myca-
lamides,2 the theopederins,3 and the onnamides4 has attracted
a considerable amount of attention5 from practitioners of
organic synthesis due to their unique structures and potent
biological activity. Synthetically challenging structural motifs
include the stable acylaminal linkage, the high density of
stereocenters, and the unstable â,γ-unsaturated acetal. From
a biological perspective, these compounds demonstrate potent
cytotoxic6 and immunosuppressive7 activities and moderate
antiviral activity.2 Studies from Burres and Clement8 have
shown that these compounds inhibit protein synthesis.
Recently, Fusetani and co-workers demonstrated9 that pederin
and theopederin A (Figure 1) are high-affinity ribosome-
binding agents.
(1) (a) Pavan, M.; Bo, G. Physiol. Comp. Oecol. 1953, 3, 307. (b)
Cardani, C.; Ghiringhelli, D.; Mondelli, R.; Quilico, A. Tetrahedron Lett.
1965, 2537. (c) Matsumoto, T.; Yanagiya, M.; Maeno, S.; Yasuda, S.
Tetrahedron Lett. 1968, 6297.
(2) (a) Perry, N. B.; Blunt, J. W.; Munro, M. H. G. J. Am. Chem. Soc.
1988, 110, 4850. (b) Perry, N. B.; Blunt, J. W.; Munro, M. H. G.; Thompson,
A. M. J. Org. Chem. 1990, 55, 223.
(3) Fusetani, N.; Sugawara, T.; Matsunaga, S. J. Org. Chem. 1992, 57,
3828.
(4) Sakemi, S.; Ichiba, T.; Kohmoto, S.; Saucy, G.; Higa, T. J. Am. Chem.
Soc. 1988, 110, 4851.
While the biological activities of these compounds are
mechanistically intriguing, the lack of cell line specific
toxicity casts doubts upon their viability as clinical agents.
In 2004, Pettit10 and Crews11 independently reported the
(5) Representative total and formal syntheses: (a) Sohn, J.-H.; Waizumi,
N.; Zhong, H. M.; Rawal, V. H. J. Am. Chem. Soc. 2005, 127, 7290. (b)
Trost, B. M.; Yang, H.; Probst, G. D. J. Am. Chem. Soc. 2004, 126, 48. (c)
Kocienski, P.; Narquizian, R.; Raubo, P.; Smith, C.; Farrugia, L. J.; Muir,
K.; Boyle, F. T. J. Chem. Soc., Perkin Trans. 1 2000, 2357. (d) Roush, W.
R.; Pfeifer, L. A. Org. Lett. 2000, 2, 859. (e) Nakata, T.; Fukui, H.;
Nakagawa, T.; Matsukura, H. Heterocycles 1996, 42, 159. (f) Hong, C. Y.;
Kishi, Y. J. Am. Chem. Soc. 1991, 113, 9694. (g) Hong, C. Y.; Kishi, Y.
J. Org. Chem. 1990, 55, 4242. (h) Wilson, T. M.; Kocienski, P.; Jarowicki,
K.; Isaac, K.; Hitchcock, P. M.; Faller, A.; Campbell, S. F. Tetrahedron
1990, 46, 1767. (i) Matsuda, F.; Tomiyoshi, N.; Yanagiya, M.; Matsumoto,
T. Tetrahedron 1988, 44, 7063.
(6) Ogawara, H.; Higashi, K.; Uchino, K.; Perry, N. B. Chem. Pharm.
Bull. 1991, 39, 2152.
(7) Galvin, F.; Freeman, G. J.; Razi-Wolf, Z.; Benacerraf, B.; Nadler,
L.; Reiser, H. Eur. J. Immunol. 1993, 23, 283.
(8) Burres, N. S.; Clement, J. J. Cancer Res. 1989, 49, 2935.
(9) Nishimura, S.; Matsunaga, S.; Yoshida, M.; Hirota, H.; Yokoyama,
S.; Fusetani, N. Bioorg. Med. Chem. 2005, 13, 449.
(10) Pettit, G. R.; Xu, J.; Chapuis, J.; Pettit, R. K.; Tackett, L. P.; Doubek,
D. L.; Hooper, J. N. A.; Schmidt, J. M. J. Med. Chem. 2004, 47, 1149.
10.1021/ol0520267 CCC: $30.25
© 2005 American Chemical Society
Published on Web 10/08/2005

Mukaiyama aldol reaction to a diastereoselective fragment
coupling and an efficient construction of an amide group
that is suitable for elaboration into the natural product and
its analogues.
Scheme 1. Retrosynthetic Analysis
Figure 1. Representative acylaminal-containing cytotoxic agents.
isolation and structure of compound 1 from South Pacific
sponges Ircinia ramosa and Psammocinia sp. The Pettit
group named the structure irciniastatin A and the Crews
group named it psymberin on the basis of its proposed12
biogenesis from symbiotic bacteria. Psymberin is structurally
related to pederin through the acylaminal group and the
dimethyl tetrahydropyran ring but is unique in this family
because of the acyclic acyl group and the presence of the
dihydroisocoumarin (Figure 2). Of particular importance is
We envisioned 1 to be accessible (Scheme 1) through the
classic coupling strategy that was developed for pederin
syntheses in which the acylaminal arises from a reductive
coupling between a left-hand acid chloride and a right-hand
methyl imidate. Therefore, amide 2, or a suitable structural
variant, was selected as our initial target. The carbon
framework of 2 was seen to be accessbile through the
addition of ketone 3 into aldehyde 4. Pentasubstituted arene
5 was selected as a logical precursor of 4.
Due to the importance of accessing bulk quantities of 5,
we needed a pentasubstituted arene synthesis that is not
excessively lengthy and is amenable to large-scale reactions.
Thus, we chose to approach this problem through de novo
arene synthesis (Scheme 2) rather than through arene
Figure 2. Structure of psymberin.
that psymberin shows exceptional cell line specific cytotox-
icity, with LC50 values for even some closely related cell
lines varying by more than 4 orders of magnitude.11 The
structural basis for this selectivity apparently resides in either
the dihydroisocoumarin, the acyclic acyl group, or both.
Synthesis is a uniquely powerful tool for addressing this
issue. We have had a long-term interest in this class of
molecules13 and were drawn to the potential for identifying
the structural origin of psymberin’s selectivity through
rational analogue design. Prompted by De Brabander’s
elegant completion of psymberin’s total synthesis,14 we report
our studies on the preparation of the N7-C25 subunit.15
Notable features include the use of cycloaddition chemistry
to access the pentasubstituted arene, the application of a
Scheme 2. Arene Synthesis and Elaboration
(11) Cichewicz, R. H.; Valeriote, F. A.; Crews, P. Org. Lett. 2004, 6,
1951.
(12) Piel, J.; Butzke, D.; Fusetani, N.; Hui, D. Q.; Platzer, M.; Wen, G.
P.; Matsunaga, S. J. Nat. Prod. 2005, 68, 472.
(13) Rech, J. C.: Floreancig, P. E. Org. Lett. 2003, 5, 1495.
(14) Jiang, X.; Garc´ıa-Fortanet, J.; De Brabander, J. K. J. Am. Chem.
Soc. 2005, 127, 11254.
(15) For studies on the acyl fragment, see: (a) Kiren, S.; Williams, L. J.
Org. Lett. 2005, 7, 2907. (b) Green, M. E.; Rech, J. C.; Floreancig, P. E.
Org. Lett. 2005, 7, 4117.
manipulation. Cycloaddition16 of allene dicarboxylate 6,
available in one step from commercially available dimethyl
1,3-acetonedicarboxylate,17 with silylketene acetal 718 at
(16) Langer, P.; Kracke, B. Tetrahedron Lett. 2000, 41, 4545.
Org. Lett., Vol. 7, No. 23, 2005
5176

ambient temperature and in the absence of solvent provided,
after treatment with ethanolic Et3N‚HF,19 arene 8 in 70%
yield. Protection of the phenolic groups proceeded in
essentially quantitative yield with TBSOTf and lutidine. This
rapid arene construction can be scaled to proVide multigram
quantities without loss of efficiency. Selective monoreduction
of the aliphatic ester with a single equivalent of DIBAL-H
at -78 °C yielded aldehyde 9 in sufficient purity to obviate
the need for further purification. The stereocenters at C16
and C17 were established through a Brown crotylation
reaction20 which provided 10 as a single diastereomer in 90%
ee as determined through HPLC (Chiralcel OD-H column).
Protection of the C17 hydroxyl group followed by ozonolysis
resulted in the uneventful formation of aldehyde 11 in
excellent yield.
Scheme 4. Fragment Coupling
The preparation of the nucleophilic component of the aldol
coupling (Scheme 3) commenced with the addition of
reaction between 11 and 15 in the presence of BF3‚OEt2
proceeded with good preference (6:1) for the formation of
16. Evidence for the presence of the syn,syn-stereoisomer
was tentatively provided by analyzing the NMR chemical
shifts and coupling constants of the C14 hydrogens, in accord
with the model reported by the Roush group,26 and was
verified in subsequent intermediates. Chelation-controlled
reduction of the resulting â-hydroxy ketone with Et2BOMe
and NaBH427 provided diol 17 with excellent stereocontrol.
While 16 and its anti,syn-isomer were inseparable, the diols
that formed from the reduction were readily purified as single
stereoisomers. The syn-relationship in the major product was
confirmed through a 13C chemical shift analysis28 of ac-
etonide 18.
Scheme 3. Enolsilane Preparation
With the carbon framework intact we turned our attention
to the formation of the tetrahydropyran ring (Scheme 5).
Toward this goal the terminal alkene of 17 was subjected to
ozonolytic cleavage. The resulting lactol was acetylated at
C9 and C15 under standard conditions to yield 19. Selective
ionization of the anomeric acetoxy group and trapping the
intermediate oxocarbenium ion with TMSCN provided nitrile
20 as a single stereoisomer in excellent yield.29 Hydrating
the cyano group under classical conditions resulted in
extensive and nonselective protecting group cleavage. To
circumvent this problem, we employed the remarkably
selective Parkin catalyst (21)30 to produce amide 22 in nearly
quantitative yield, thereby completing the synthesis of the
N7-C25 fragment of psymberin.
Leighton’s allylsilane 1221 to keto aldehyde 13.22 This
reaction proceeded efficiently and in 94% ee as determined
by GC (Chiraldex G-TA column) to form 14. No ketone
addition was observed. Protection of the resulting alcohol
and enolsilane formation proceeded in quantitative yield to
provide 15.
The Lewis acid-mediated coupling of 15 with 11 (Scheme
4) proceeds with antagonistic stereodirection from the
substituents at C16 and C17. A Felkin-Anh approach23 (R-
direction) of the nucleophile is expected to provide the
syn,syn-stereotriad, while direction from the â-silyloxy group
is expected to yield the anti,syn-triad.24 Congruent with
Evans’ observations25 that R-direction overrides â-direction
when bulky nucleophiles are employed, the Mukaiyama aldol
While optimzing workup conditions for 20 we isolated
varying amounts of monodesilylated product 23. Since the
structure of 1 was determined solely by NMR, we felt that
(17) Node, M.; Fujiwara, T.; Ichihashi, S.; Nishide, K. Tetrahedron Lett.
1998, 39, 6331.
(18) Barker, D.; Brimble, M.; Do, P.; Turner, P. Tetrahedron 2003, 59,
2441.
(19) Other sources of fluoride led to the formation of significant quantities
of the C23 ethyl ether.
(20) Brown, H. C.; Bhat, K. S. J. Am. Chem. Soc. 1986, 108, 5919.
(21) Kinnaird, J. W. A.; Ng, P. Y., Kubota, K.; Wang, X.; Leighton, J.
A. J. Am. Chem. Soc. 2002, 124, 7920.
(22) Prepared from the condensation of the enamine of isobutyraldehyde
with acetyl chloride. See: Inukai, T.; Yoshizawa, R. J. Org. Chem. 1967,
32, 404.
(23) (a) Cherest, M.; Felkin, H.; Prudent, N. Tetrahedron Lett. 1968, 9,
2199. (b) Anh, N. T.; Eisenstein, O. NouV. J. Chem. 1977, 1, 61. (c) Lodge,
E. P.; Heathcock, C. H. J. Am. Chem. Soc. 1987, 109, 3353.
(24) Evans, D. A.; Duffy, J. L.; Dart, M. J. Tetrahedron Lett. 1994, 35,
8537.
(25) (a) Evans, D. A.; Allison, B. D.; Yang, M. G.; Masse, C. E. J. Am.
Chem. Soc. 2001, 123, 10840. (b) Evans, D. A.; Dart, M. J.; Duffy, J. L.;
Yang, M. G. J. Am. Chem. Soc. 1996, 118, 4322.
(26) Roush, W. R.; Bannister, T. D.; Wendt, M. D.; VanNieuwenhze,
M. S.; Gustin, D. J.; Dilley, G. J.; Scheidt, K. A.; Smith, W. J. J. Org.
Chem. 2002, 67, 4284.
(27) Chen, K.-M.; Hardtmann, G. E.; Prasad, K.; Repic, O.; Shapiro,
M. J. Tetrahedron Lett. 1987, 28, 155.
(28) (a) Rychnovsky, S. D.; Skalitzky, D. J. Tetrahedron Lett. 1990, 31,
945. (b) Evans, D. A.; Rieger, D. L.; Gage, J. R. Tetrahedron Lett. 1990,
31, 7099.
(29) For a related strategy, see: Hoffmann, R. W.; Schlapbach, A.
Tetrahedron Lett. 1993, 34, 7903.
(30) (a) Ghaffar, T.; Parkins, A. W. J. Mol. Catal. A 2000, 160, 249. (b)
Ghaffar, T.; Parkins, A. W. Tetrahedron Lett. 1995, 36, 8657.
Org. Lett., Vol. 7, No. 23, 2005
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Scheme 5. Completion of the N7-C25 Fragment
Scheme 6. Dihydroisocoumarin Formation and NMR
Analysisa
a 1H NMR signals in CD3OD. Values for 24 are in red, and
reported11 values for the corresponding hydrogens in psymberin
are in blue.
reoselective fragment coupling through a Mukaiyama aldol
reaction, and a chemoselective nitrile hydration reaction. This
approach is well-suited for completing the total synthesis
and, more importantly, for preparing analogues that can be
used to study the structural basis for psymberin’s uniquely
selective cytotoxicity.
a correlation study would be beneficial. Therefore, we
subjected 23 to TBAF to cleave all remaining silyl ethers
and close the dihydroisocoumarin and then to K2CO3 in
1
MeOH to form 24 (Scheme 6). The H NMR of 24 in the
C11-C25 region matched that of psymberin remarkably well,
providing strong indication that Crews’ structural assignment
is indeed valid.
Acknowledgment. This work was supported by generous
funding from the National Institutes of Health (GM-62924).
We have completed the synthesis of the N7-C25 fragment
of psymberin through an efficient and stereoselective route.
The longest linear sequence is 12 steps from known materials
and proceeds in 15% overall yield (13 steps from com-
mercially available reagents), with a total step count of 15
steps from known materials (17 steps from commercially
available reagents). Significant transformations include a
rapid de novo pentasubstituted arene construction, a diaste-
Supporting Information Available: Experimental pro-
cedures and characterization for all reactions and procedures
for enantiomeric excess determination. This material is
available free of charge via the Internet at http://pubs.acs.org.
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