A formal synthesis of psymberin

Article abstract of DOI:10.1021/ol063143k

(Chemical Equation Presented) A formal synthesis of psymberin (irciniastatin A) is presented. Notable features of the synthesis include the chemo-, regio-, and stereoselective oxidation of a 1,3-disubstituted allene, a configuration-dependent spirodiepoxi

Full text of DOI:10.1021/ol063143k

ORGANIC
LETTERS
2007
Vol. 9, No. 6
1093-1096
A Formal Synthesis of Psymberin
Ning Shangguan, Sezgin Kiren, and Lawrence J. Williams*
Department of Chemistry and Chemical Biology, Rutgers, The State UniVersity of New
Jersey, Piscataway, New Jersey 08854
ljw@rutchem.rutgers.edu
Received December 30, 2006
ABSTRACT
A formal synthesis of psymberin (irciniastatin A) is presented. Notable features of the synthesis include the chemo-, regio-, and stereoselective
oxidation of a 1,3-disubstituted allene, a configuration-dependent spirodiepoxide opening, the efficient syntheses of functionalized trans-2,6-
disubstituted pyrans, and the union of a highly functionalized aldehyde with a pentasubstituted aryl homoenolate to give a dihydroisocumarin.
Psymberin1 (irciniastatin A2) (1) is one of 36 natural products
of which pederin (2) is the archetype. In contrast to other
members of this class, psymberin is both potent and selective,
with an index of >104 against certain solid tumors. These
natural products are characterized by an amide side chain, a
pyran core, and a polyacetate appendage (e.g., 1-4, Figure
1).3 With the exception of psymberin, the pederamide side
chain is invariant, although potential structural similarities
between these side chains have been noted.4 The pyran core
is limited primarily to either a pyran (see 1 and 2) or a
trioxadecalin system (see 3 and 4). The polyacetate chain
varies considerably for the pederins.3 Although other mem-
bers have a C12 side chain with unsaturation (e.g., 4-Z-
onnomide A, 3), the dihydroisocumarin appendage in
psymberin is unique.
(1) Isolated from Psammocinia sp. in the waters of Papua, New Guinea.
(a) Cichewicz, R. H.; Valeriote, F. A.; Crews, P. Org. Lett. 2004, 6, 1951.
(b) A list of all the pederin natural products can be found in the Supporting
Information of ref 1a.
(2) Isolated from Ircinia sp. near Samporna, Borneo. Pettit, G. R.; Xu,
J.-P.; Chapuis, J.-C.; Pettit, R. K.; Tackett, L. P.; Doubek, D. L.; Hooper,
J. N. A.; Schimdt, J. M. J. Med. Chem. 2004, 47, 1149.
(3) (a) Piel, J.; Hui, D.; Wen, G.; Butzke, D.; Platzer, M.; Fusetani, N.;
Matsunaga, S. Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 16222. (b) Piel, J.;
Butzke, D.; Fusetani, N.; Hui, D.; Platzer, M.; Wen, G.; Matsunaga, S. J.
Nat. Prod. 2005, 68, 472.
(4) Segment synthesis and analysis: (a) Green, M. E.; Rech, J. C.;
Floreancig, P. E. Org. Lett. 2005, 7, 4117. (b) Kiren, S.; Williams, L. J.
Org. Lett. 2005, 7, 2905.
Figure 1. Members of the pederin family.
10.1021/ol063143k CCC: $37.00
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Published on Web 02/24/2007

The cellular targets the pederin family acts upon have not
been identified. Structure-activity correlations of the ped-
erins have appeared,5 and a recent preliminary report on
psymberin has determined that the dihydroisocumarin moiety
cannot be deleted without significantly compromising the
activity.6 The combined structural and biological data
demonstrate that a high degree of both activity and selectivity
is possible based on the pederin scaffold. We sought,
therefore, to prepare psymberin by a route amenable to the
synthesis of pederin family hybrids.
the psymberin architecture, to the final stage of the synthesis.
Although aware of the Kocienski precedent,9 where a closely
related amide was carried through a multistep sequence, we
set as our initial goal preparation of an amide of type 10
(Scheme 1). Conversion of this amide, as the peracetate, to
psymberin is known following a three-step sequence.7a
Schemes 2-7 provide a summary of our findings. We
began with the preparation of 12, directly available by the
acid-induced rearrangement and concomitant aromatization
of dimedone10 followed by formylation.11 A subsequent
protection/oxidation/esterification sequence, which does not
require purification of the intermediates, gave pentasubsti-
tuted arene 13 (Scheme 2). Multigram quantities of the right-
Our strategy focused on generalized intermediates 5-10
(Scheme 1). We reasoned that oxidation of 5 via spirodiep-
Scheme 1. Synthetic Plan
Scheme 2. Arene Side Chain Synthesis
hand segment of the target system were thereby prepared.
Our focus then shifted to the preparation of allene 18 from
aldehyde 1412 according to the sequence in Scheme 3.
Scheme 3. Allene Synthesis
oxide (SDE) 6 would give a pyran of type 7 and thus enable
entry to highly oxygenated (X ) O) and simpler pederins
(X ) H2). The biological profile of this class is sensitive to
the oxidation state of the pyran ring (e.g., irciniastatin B2 is
the C11 ketone analogue of 1). Of further interest was
sequential insertion of a propionate equivalent (8) and
dihydroisocumarin assembly using 9.
One advantage of this strategy (5f7f10) is the straight-
forward preparation of a suite of analogues and hybrids that
vary in the central pyran as well as the two side chains.
Indeed, as will be shown, this route enabled the preparation
of several pyran derivatives that are not accessible from
current psymberin syntheses or from the natural product
itself.7,8 The plan also postpones the preparation of the N-acyl
aminal, arguably the primary synthetic challenge posed by
Conversion of 14 to the alkyne13 followed by addition to a
glycolic acid-derived Weinreb amide,14 and then asym-
(9) (a) Kocienski, P. J.; Narquizian, R.; Raubo, P.; Smith, C.; Farrugia,
L. J.; Muir, K.; Boyle, F. T. J. Chem. Soc., Perkin Trans. 1 2000, 2357. (b)
Kocienski, P.; Jarowicki, K.; Marczak, S. Synthesis 1991, 1191. For other
representative synthetic studies, see: (c) Kagawa, N.; Ihara, M.; Toyota,
M. Org. Lett. 2006, 8, 875. (d) Sohn, J.-H.; Rawal, V. H. J. Am. Chem.
Soc. 2005, 127, 7290. (e) Trost, B. M.; Yang, H.; Probst, G. D. J. Am.
Chem. Soc. 2004, 126, 48. (f) Roush, W. R.; Pfeifer, L. A. Org. Lett. 2000,
2, 859. (g) Takemura, T.; Nishiii, Y.; Takabashi, S.; Kobayashi, J.; Nakata,
T. Tetrahedron 2002, 58, 6359.
(5) (a) Jacobs-Lorena, M.; Brega, A.; Bagloni, C. Biochem. Biophys. Acta
1971, 240, 293. (b) Jimenez, A.; Carrasco, L.; Vazquez, D. Biochemistry
1977, 16, 4727. (c) Brega, A.; Falaschi, A.; De CArli, L.; Pavan, M. J.
Cell Biol. 1968, 36, 485. (d) Burres, N. S.; Clement, J. J. Cancer Res. 1989,
49, 2935. (e) Richter, A.; Kocienski, P.; Raubo, P.; Davies, D. E. Anti-
Cancer Drug Des. 1997, 12, 217.
(6) Analogue synthesis: Jiang, X.; Williams, N.; De Brabander, J. K.
Org. Lett. 2007, 9, 227-230.
(10) Nelson, P. H.; Nelson, J. P. Synthesis 1992, 1287.
(11) Robertson, A.; Whalley, W. B. J. Chem. Soc. 1949, 3033.
(12) Available in multigram quantities from the corresponding diol.
Paterson, I.; Francesco, M. E.; Kuhn, T. Org. Lett. 2003, 5, 599.
(13) Roth, G. J.; Liepold, B.; Mueller, S. G.; Bestmann, H. J. Synthesis
2004, 59.
(7) Total synthesis: (a) Jiang, X.; Garcia-Fortanet, J.; De Brabander, J.
K. J. Am. Chem. Soc. 2005, 127, 11254. Formal synthesis: (b) Rech, J. C.;
Floreancig, P. E. Org. Lett. 2005, 7, 5175.
(8) The logic is in accord with the diverted synthesis concept. See, for
example: Wilson, R. M.; Danishefsky, S. J. J. Org. Chem. 2006, 71, 8329.
(14) Nahm, S.; Weinreb, S. M. Tetrahedron Lett. 1981, 22, 3815.
1094
Org. Lett., Vol. 9, No. 6, 2007

metric reduction15 provided 15, a single isomer according
to Mosher ester analysis. Propargyl alcohol 15 was trans-
formed into the allene by the Myers16 procedure, and the
PMB group was then removed (f16). Oxidation of 16 to
the aldehyde, addition of acetylide to give the propargyl
alcohols (17/18, dr ) 1:1), oxidation of this mixture to the
corresponding ynone, and then CBS17 reduction gave 18.
The behavior of allene 18 upon oxidation was one of our
central chemical interrogatives. We reasoned that dimethyl
dioxirane (DMDO) would oxidize an allene more rapidly
than an alkyne (e.g., 5, 17, and 18).18 Furthermore, the
oxygen substituent (PO in 5) should deactivate the proximal
allenic double bond and thereby induce regioselective
oxidation of the distal double bond,19 which should occur
from the most accessible face. The second oxidation should
occur on the face opposite the sterically demanding tert-
butyl-like appendage.20 Certain allenic alcohols spontane-
ously cyclize to give pyrans upon oxidation,21 and the
corresponding SDE intermediates are not observed. Accord-
ingly, we expected oxidation of 18, and related allenes, to
proceed rapidly and selectively.
Scheme 5. Spirodiepoxide Cyclization Model
with the analogous conformers of the diastereomeric SDE
derived from 18 (21a and 21b). Conformational preferences,
perhaps reinforced by hydrogen bonding, may render 21a
stable. Moreover, the reactive conformer (21b) may be
further destabilized by unfavorable steric interactions between
the alkyne and the SDE. The combined effect could account
for the observed resistance of this SDE toward cyclization.
Analogous conformers of diastereomeric secondary alcohol
(17a) would be disfavored due to severe steric interactions,
whereas 17b would be favored and lead to product. This
model would also predict that cyclization of the SDE derived
from 16 would be faster than the SDE derived from 18, as
observed. Indeed, conditions expected to disrupt hydrogen
bonding induced cyclization of the otherwise stable SDE
deriVed from 18. Thus, after complete oxidation, addition
of methanol as cosolvent to the mixture effected the slow
(12 h) conversion of 18 to trans-pyran 22 in 72% yield.24
Scheme 6 presents the preparation of a suite of related
pyrans en route to psymberin, which are also related to the
trioxadecalin system of more complex pederins (cf. 3 and
4). Stereoselective reduction25 of 22 gave the trans-diol 23,
which was converted directly to the epoxide (24) under the
action of sodium hydride and toluenesulfonyl chloride,
provided that wet THF was used as solvent.26 Reduction of
the epoxide27 and then treatment with MOM-Cl gave 25.
Hydroboration of 25 (f26), introduction of C17-C18 by
asymmetric aldol addition,28 conversion to the Weinreb
amide,29 and silylation were followed by reduction30 to
aldehyde 28.
During protecting group optimization studies,22 oxidation
of allenes of type 16 led directly to pyrans 19 and oxidation
of allenes of type 17 led directly to cis-substituted pyrans
20 (Scheme 4). The cyclizations, although unoptimized, were
Scheme 4. Spirodiepoxide Cyclization
efficient (50-70% yield), and no SDE was observed.
Remarkably, oxidation of allenes of type 18 gaVe stable
spirodiepoxides (e.g., 21).23
Presumably, these configuration-dependent cyclizations
reflect conformational biases. Two conformers of the SDE
derived from 17 (17a and 17b) are shown in Scheme 5 along
(15) Matsumura, K.; Hashiguchi, S.; Ikariya, T.; Noyori, R. J. Am. Chem.
Soc. 1997, 119, 8738. Ru catalyst ) {[(1S,2S)-TsDPEN]RuCl(η6-p-
cymene)}.
(16) Myers, A. G.; Zheng, B. J. Am. Chem. Soc. 1996, 118, 4492.
(17) (a) Corey, E. J.; Bakshi, R. K.; Shibata, S. J. Am. Chem. Soc. 1987,
109, 1797. (b) Corey, E. J.; Helal, C. J. Angew. Chem., Int. Ed. 1998, 37,
1986.
(18) Murray, R. W.; Singh, M. J. Org. Chem. 1993, 58, 5076.
(19) (a) Henbest, H. B. Proc. Chem. Soc. 1963, 159. (b) Chamberlin,
P.; Roberts, M. L.; Whitham, G. H. J. Chem. Soc. (B) 1970, 1374.
(20) For a steric model of allene oxidation, see: (a) Katukojvala, S.;
Barlett, K. N.; Lotesta, S. D.; Williams, L. J. J. Am. Chem. Soc. 2004, 126,
15348. (b) Crandall, J. K.; Batal, D. J.; Sebesta, D. P.; Lin, F. J. Org. Chem.
1991, 56, 1153.
(21) Crandall, J. K.; Batal, D. J.; Lin, F.; Reix, T.; Nadol, G. S.; Ng, R.
A. Tetrahedron 1992, 48, 1427.
(22) The TBDPS protecting group, in contrast to TBS and MOM, was
found to be optimal for the sequence 14f21.
(23) The SDE was stable to analytical thin-layer chromatography and
standing in solution for three days, whereas flash column chromatography
induced decomposition of the SDE to several products.
(24) Minor products were observed but do not appear to be simple
diastereomeric pyrans. The methanol adduct was observed as a minor
product (<5%) when the reaction was run on a large scale (∼3 g).
(25) Evans, D.; Clark, J.; Metternich, R.; Novack, V.; Sheppard, G. J.
Am. Chem. Soc. 1990, 112, 866.
(26) When dry THF was used, the tosylate was obtained.
(27) Kim, S.; Ko, H.; Lee, T.; Kim, D. J. Org. Chem. 2005, 70, 5756.
(28) Evans, D. A.; Takacs, J. M.; Mcgee, L. R.; Ennis, M. D.; Mathre,
D. J.; Bartolli, L. Pure Appl. Chem. 1981, 53, 1109.
(29) Evans, D. A.; Bender, S. L.; Morris, J. J. Am. Chem. Soc. 1988,
110, 2506.
(30) Evans, D. A.; Kaldor, S. W.; Jones, T. K.; Clardy, J.; Stout, T. J. J.
Am. Chem. Soc. 1990, 112, 7001.
Org. Lett., Vol. 9, No. 6, 2007
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Scheme 6. Elaborated Pyran Synthesis
Scheme 7. Formal Synthesis
highly oxygenated and simpler pyrans have been prepared
(19-28). Notable features of this study include: (1) the
chemo-, regio-, and stereoselective oxidation of 1,3-disub-
stituted allenes; (2) an unexpected configuration-dependent
SDE opening; (3) the efficient synthesis of a functionalized
trans-2,6-disubstituted pyran from an SDE; and (4) union
of a highly functionalized aldehyde with a pentasubstituted
aryl homoenolate to give a dihydroisocumarin. Studies to
further develop these transformations and this strategy toward
designed hybrid targets and related analogues are ongoing.
Completion of the synthesis is presented in Scheme 7. The
anion derived from 13 smoothly added to 28, and the adduct
spontaneously cyclized to give dihydroisocumarin 29.31
Although both isomers are of interest, the product that
matches psymberin was favored (dr 3:1) and taken on to
complete the synthesis. The protecting groups were consoli-
dated by treatment with catecholborane32 and then acetic
anhydride followed by silyl ether cleavage and oxidation
(29f30). Further oxidation and subsequent conversion to
the amide gave 31, which proved identical to earlier reports,7
1
as judged by optical rotation and H and 13C NMR.
Acknowledgment. Financial support from Merck & Co.,
Johnson & Johnson (Discovery Award), donors of the
American Chemical Society Petroleum Research Fund, and
Rutgers, The State University of New Jersey, is gratefully
acknowledged.
The strategy presented here enables a flexible synthesis
of psymberin from allene, arene, and amide subunits. Both
(31) This appears to be among the most sophisticated couplings of this
sort to date. See: (a) Hauser, F. M.; Rhee, R. Synthesis 1977, 245. (b)
Hauser, F. M.; Rhee, R.; Prasanna, S. Synthesis 1980, 1, 72. (c) Leeper, F.
J.; Staunton, J. J. Chem. Soc., Chem. Commun. 1979, 205. (d) Carpenter,
T. A.; Evans, G. E.; Leeper, S. J.; Staunton, J.; Wilkinson, M. R. J. Chem.
Soc., Perkin 1 1984, 1043. (e) Ward, R. A.; Procter, G. Tetrahedron 1995,
51, 12301. (f) Barber, J. A.; Staunton, J.; Wilkinson, M. R. J. Chem. Soc.,
Perkin Trans. 1 1986, 2101. (g) Chevenier, E.; Lucatelli, C.; Pandya, U.;
Wang, W.; Gimbert, Y.; Greence, A. E. Synlett 2004, 15, 2693. (h) Zhang,
Z.; Yu, B. J. Org. Chem. 2003, 68, 6309.
Supporting Information Available: Synthetic methods
and characterization data (PDF). This material is available
free of charge via the Internet at http://pubs.acs.org.
(32) Cao, B.; Park, H.; Joullie´, M. J. Am. Chem. Soc. 2002, 124, 520.
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