Stereochemically versatile synthesis of the C1-C12 fragment of tedanolide c

Article abstract of DOI:10.1021/ol300194x

A flexible synthesis of the C1-C12 fragment of Tedanolide C has been accomplished in eight steps from 2-methyl-2,4-pentadienal. Asymmetric hydroformylation of a 1,3-diene allows for the late-stage generation of either C10 epimer with complete catalyst con

Full text of DOI:10.1021/ol300194x

ORGANIC
LETTERS
2012
Vol. 14, No. 6
1452–1455
Stereochemically Versatile Synthesis
of the C1ÀC12 Fragment of Tedanolide C
Thomas E. Smith,* Sarah J. Fink, Zebulon G. Levine, Kerani A. McClelland,
Adrian A. Zackheim, and Mary E. Daub
Department of Chemistry, Williams College, Williamstown, Massachusetts 01267,
United States
tsmith@williams.edu
Received January 24, 2012
ABSTRACT
A flexible synthesis of the C1ÀC12 fragment of Tedanolide C has been accomplished in eight steps from 2-methyl-2,4-pentadienal. Asymmetric
hydroformylation of a 1,3-diene allows for the late-stage generation of either C10 epimer with complete catalyst control. Diastereoselective
addition of an isobutyryl β-ketoester dianion to an R,β-disubstituted chiral aldehyde sets the C5 stereochemistry while installing the geminal
dimethyl unit. Differential protection of a syn-1,3-diol is performed as a highly efficient single-pot operation.
Tedanolide C (1) is a marine natural product isolated
from a species of Ircina sponge off the coast of Papua New
Guinea. Characterized by Ireland in 2006,1 tedanolide C is
one of the more recently reportedmembers of anintriguing
family of marine macrolides that include tedanolide (2),2
13-deoxytedanolide (3),3 and the candidaspongiolides (4),4
which exhibit in vitro cytotoxicities in the nanomolar to
picomolar range (Figure 1).5 The diversity of genera and
geographies yielding these structuralcongeners, along with
their low natural abundance, suggests that these toxins are
derived from symbiotic microorganisms.4
Tedanolide C resembles other members of the tedano-
lide family in the fundamental structure of its complex 18-
membered macrolide core and epoxide-bearing side chain
yet differs in its substitution pattern and proposed stereo-
chemistry; every analogous stereocenter beyond C7 (other
than the epoxide positions) is assigned a configuration
epimeric to the other tedanolides. Relative stereochemistry
between the different subunitsof the moleculewas deduced
(1) Chevallier, C.; Bugni, T. S.; Feng, X.; Harper, M. K.; Orendt,
A. M.; Ireland, C. M. J. Org. Chem. 2006, 71, 2510–2513.
(2) Schmitz, F. J.; Gunasekera, S. P.; Yalamanchili, G.; Hossain,
M. B.; Van der Helm, D. J. Am. Chem. Soc. 1984, 106, 7251–7252.
(3) Fusetani, N.; Sugawara, T.; Matsunaga, S. J. Org. Chem. 1991,
56, 4971–4974.
(4) (a) Meragelman, T. L.; Willis, R. H.; Woldemichael, G. M.;
Heaton, A.; Murphy, P. T.; Snader, K. M.; Newman, D. J.; van Soest,
R.; Boyd, M. R.; Cardellina, J. H., II; McKee, T. C. J. Nat. Prod. 2007,
70, 1133–1138. (b) Whitson, E. L.; Pluchino, K. M.; Hall, M. D.;
McMahon, J. B.; McKee, T. C. Org. Lett. 2011, 13, 3518–3521.
(5) Tedanolide: ED50 = 16 pg/mL (26 pM) against cultured leukemia
lymphocytes (ref 2). 13-Deoxytedanolide: IC50 = 94 pg/mL (158 pM)
against P388 murine leukemia cells (ref 3). Candidaspongiolide core:
mean GI50 = 14 ng/mL (20 nM) against NCI 60 tumor cell line (ref 4a).
Tedanolide C: IC50 = 57 ng/mL (95 nM) against HCT-116 cells (ref 1).
r
10.1021/ol300194x
Published on Web 02/29/2012
2012 American Chemical Society

synthetic chemists,10 with notable total syntheses reported
by Smith,11 Roush,12 and Kalesse,13 only two studies on
tedanolide C have been reported to date;both of which
are concerned with the “southwest” hemisphere of the
natural product.14 In planning an asymmetric synthesis
of the C1ÀC12 “northeast” fragment of tedanolide C, we
kept several design concepts in mind: We desired equally
easyaccess toboth enantiomers and we valued flexibility in
reliably setting relative stereochemistry throughout the
fragment. In particular, because of plausible stereochemi-
cal ambiguity at C10, we wished to establish this stereo-
center late in the synthesis to maximize common
intermediates on the route to both C10 epimers.
We viewed this last challenge of installing the C10
stereochemistry as the most difficult. Due to the isolated
location of this stereocenter relative to others, substrate-
based asymmetric induction was unlikely to be advanta-
geous. Survey of the literature confirmed that most ap-
proaches to this problem relied upon chiral pool starting
materials that already contained this C10 stereochemical
information. These solutions were not attractive. Particu-
larly intriguing here is that the structural motif represented
by the C7ÀC11 fragment;also including a critical
E-trisubstituted olefin;is common to an array of complex
natural products and a solution to this problem could have
broader synthetic relevance.15
Figure 1. Tedanolide family of natural products.
In 2001, Jacobsen installed the corresponding
(C14ÀC18) subunit within ambruticin by way of an asym-
metric diene hydroformylation (Scheme 1).16 Nozaki had
shown that simple 1,3-dienes undergo regio- and enantio-
selective hydroformylations in the presence of a chiral
rhodium catalyst.17 Yet, despite the potential utility of this
transformation to selectively modify structurally elaborate
dienes, Jacobsen’s work remains the only application within
the core of a complex synthesis. We anticipated that early
installation of a relatively unreactive diene unit followed
by late-stage unmasking of a latent chiral β,γ-unsaturated
by comparison of measured and calculated NMR coupling
constants.1 The absolute configuration of tedanolide C has
not yet been ascertained, nor has the relative stereochem-
istry between the subunits been definitively proven.
The tedanolides’ exceedingly potent cytotoxicity might
someday be harnessed for chemotherapeutic use if the
molecular basis of their biological activity can be
elucidated.6 Initial biological testing indicated that both
tedanolide and tedanolide C cause accumulation of cells in
the S phase of the cell cycle without further progression
and division.1,2 13-Deoxytedanolide selectively inhibits
eukaryotic protein synthesis by binding to the 60S large
ribosomal subunit,7 likely as a competitive inhibitor of
tRNA at the E site via binding of the C17 hydroxyl and
the side-chain epoxide.8 Indeed, limited SAR studies on
13-deoxytedanolide derivatives implicate these interac-
tions and bolster the supposition that macrolide confor-
mation is also important for effective binding.9
(10) For a review of synthetic studies through 2007, see: (a) Roy, M.;
Kalesse, M. Nat. Prod. Rep. 2008, 25, 862–870 and references cited
therein. For more recent synthetic studies, see: (b) Park, S. H.; Min,
J. K.; Park, S. H.; Lee, H. W. Bull. Korean Chem. Soc. 2009, 30, 537–538.
(c) Jung, M. E.; Yoo, D. Tetrahedron 2011, 67, 10281–10286.
(11) (a) Smith, A. B., III; Adams, C. M.; Barbosa, S. A. L.; Degnan,
A. P. J. Am. Chem. Soc. 2003, 125, 350–351. (b) Smith, A. B., III; Adams,
C. M.; Barbosa, S. A. L.; Degnan, A. P. Proc. Natl. Acad. Sci. U.S.A.
2004, 101, 12042–12047. (c) Smith, A. B., III; Lee, D. J. Am. Chem. Soc.
2007, 129, 10957–10962.
(12) (a) Julian, L. D.; Newcom, J. S.; Roush, W. R. J. Am. Chem. Soc.
2005, 127, 6186–6187. (b) Dunetz, J. R.; Julian, L. D.; Newcom, J. S.;
Roush, W. R. J. Am. Chem. Soc. 2008, 130, 16407–16416.
(13) (a) Ehrlich, G.; Hassfeld, J.; Eggert, U.; Kalesse, M. J. Am.
Chem. Soc. 2006, 128, 14038–14039. (b) Ehrlich, G.; Hassfeld, J.; Egert,
U.; Kalesse, M. Chem.;Eur. J. 2008, 14, 2232–2247.
With the hope of further explicating these pharmacolo-
gical and stereochemical issues, we initiated synthetic
studies on tedanolide C. While tedanolide and 13-deoxy-
tedanolide have attracted considerable attention among
(14) (a) Barth, R.; Roush, W. R. Org. Lett. 2010, 12, 2342–2345.
(b) Bulow, L.; Mani, A.; Fohrer, J.; Kalesse, M. Org. Lett. 2011, 13,
6038–6041.
(15) Notable examples include rapamycin, geldanamycin, calyculin,
bafilomycin, and dictyostatin.
€
(6) (a) Taylor, R. E. Nat. Prod. Rep. 2008, 25, 854–861. (b) Daniela,
T.; Uranchimeg, B.; Cardellina, J. H.; Meragelman, T. L.; Matsunaga,
S.; Fusetani, N.; Del Bufalo, D.; Shoemaker, R. H.; Melillo, G. J. Nat.
Cancer Inst. 2008, 100, 1233–1246.
(7) Nishimura, S.; Matsunaga, S.; Yoshida, M.; Hirota, H.; Yokoyama,
S.; Fusetani, N. Bioorg. Med. Chem. 2005, 13, 449–454.
(8) Schroeder, S. J.; Blaha, G.; Tirado-Rives, J.; Steitz, T.; Moore,
P. B. J. Mol. Biol. 2007, 367, 1471–1479.
(9) Nishimura, S.; Matsunaga, S.; Yoshida, S.; Nakao, Y.; Hirota,
(16) Liu, P.; Jacobsen, E. J. Am. Chem. Soc. 2001, 123, 10772–10773.
(17) (a) Horiuchi, T.; Ohta, T.; Shirakawa, E.; Nozaki, K.; Takaya,
H. Tetrahedron 1997, 53, 7795–7804. Landis has recently shown that
diazaphospholane ligands are also highly effective for the hydroformy-
lation of simple dienes: (b) Watkins, A. L.; Landis, C. R. Org. Lett. 2011,
13, 164–167.
H.; Fusetani, N. Bioorg. Med. Chem. 2005, 13, 455–462.
Org. Lett., Vol. 14, No. 6, 2012
1453

aldehyde would inspire a highly efficient and flexible
tedanolide C fragment synthesis.
Table 1. Synthesis and Hydroformylation of a Model Diene
Scheme 1. Diene Hydroformylation as a Key Step in Jacobsen’s
Synthesis of Ambruticin
To test the validity of our strategy as quickly as possible,
we set out to prepare model diene 13 and investigate its
rhodium-catalyzed hydroformylation with a variety of
ligands (Table 1). Enacting these plans, a thizolidinethione-
directed aldol reaction of known dienal 1018 was used to set
the stereochemistry at C6 and C7 and install the diene
component at the outset of the synthesis. Protection of the
C7 hydroxyl group and reductive cleavage of the chiral
auxiliary provided rapid access to model system 13.19
Hydroformylation using an achiral control ligand (entry 1)
verified that there was negligible substrate control over the
reaction diastereoselectivity. Commercially available chir-
al ligands (entries 2À5), with documented success for the
asymmetric hydroformylation of simple olefins,20 demon-
strated high branched/linear regioselectivity but unexcep-
tional R/S diastereoselectivity. Ultimately, Nozaki’s
original conditions proved to be the best of those
evaluated;17 (R,S)-Binaphos (entry 6) led to a 93:7 ratio
of C10 epimers 14 and 15, while the (S,R)-Binaphos (entry 7)
provided complete reversal of the selectivity.21,19
With corroboration that the C10 stereochemistry of
tedanolide C fragments could be catalyst controlled, con-
struction of our actual hydroformylation substrate was
resumed in earnest (Scheme 2). We envisaged that the
entire C1ÀC4 subunit could be installed efficiently via
nucleophilic addition of a β-ketoester dianion. For direct
addition to an R,β-aldehyde such as 17, however, predic-
tion of the (C5) stereochemical outcome was complicated
by conflicting precedents. Evans’ polar model predicts that
the 1,3-anti induction from the β-silyloxy substituent and
the Felkin 1,2-syn directing effects from the R-methyl
temp time conv.
branched/
linear
entry
ligand
(°C)
(h)
(%)
R/S
1
2
3
4
5
6
7
PPh3
35
24 95
86:14
100:0
95:5
48:52
57:43
59:41
(R,R)-Chiraphite 35
72 85
24 87
(R,R)-Kelliphite
(R,R)-Ph-Bpe
(R,R)-Ph-Bpe
(R,S)-Binaphos
(S,R)-Binaphos
35
35
80
35
35
24 trace
18 100
113 100
113 100
96:4
96:4
92:8
52:48
93:7
6:94
group should be stereo-nonreinforcing and therefore lead
topoor selectivity, yet several notableexceptionshavebeen
observed in complex systems.22 In the event, addition of 18
proceeded with g10:1 selectivity for the desired all-syn
product (19).23,19 The large steric demand of the nucleo-
phile likely contributes to the dominance of Felkin
selectivity.
Stereoselective C3 reduction of β-hydroxy ketone 19
required extensive optimization. The only other example
ofa 1,3-syn reduction on a substrate bearing anintervening
gem-dimethyl group was reported by Jamison in his synthe-
sis of acutiphycin.24 The catecholborane protocol used
therein gave incomplete conversion and poor yields with
our system. Prasad conditions25 gave excellent syn
(18) Prepared in one step from 3-ethoxymethacrolein and vinylma-
gesium bromide: Spangler, C. W.; McCoy, R. K.; Karavakis, A. A.
J. Chem. Soc., Perkin Trans. 1 1986, 7, 1203–1207.
(19) See Supporting Information for details.
(20) Klosin, J.; Landis, C. R. Acc. Chem. Res. 2007, 40, 1251–1259.
(21) The absolute stereochemistry at C10 was proved by chemical
correlation and is consistent with previous reports.
(22) (a) Evans, D. A.; Dart, M. J.; Duffy, J. L.; Yang, M. G. J. Am.
Chem. Soc. 1996, 118, 4322–4343 and references cited therein. (b) Balog,
A.; Bertinato, P.; Su, D.-S.; Meng, D.; Sorensen, E.; Danishefsky;
Zheng, Y.-H.; Chou, T.-C.; He, L.; Horwitz, S. B. Tetrahedron Lett.
1997, 38, 4529–4532. (c) Liu, J.; Wong, C.-H. Angew. Chem., Int. Ed.
2002, 41, 1404–1407.
(23) Confirmed by NMR analysis of the corresponding acetonide.
(24) Moslin, R. M.; Jamison, T. F. J. Org. Chem. 2007, 72, 9736–
9745.
(25) Chen, K. M.; Hardtmann, G. E.; Prasad, K.; Repic, O.; Shapiro,
M. J. Tetrahedron Lett. 1987, 28, 155–158.
1454
Org. Lett., Vol. 14, No. 6, 2012

Scheme 2. Synthesis and Hydroformylation of a Model Diene
Scheme 3. Hydroformylation and Completion of Fragment
selectivity for the reduction,23,19 but nondestructive libera-
tion of the product diol (20) from its unusually stable
boron complex proved challenging. Ultimately, a sodium
acetate-buffered hydrogen peroxide workup was found to
give reproducible yields.26 Sequential addition of TBSOTf
and TESOTf enabled the differential protection of diol 20
as a highly efficient single-pot operation27 and completed
the synthesis of hydroformylation substrate 21.28
Gratifyingly, hydroformylations on this real system
proceeded smoothly (Scheme 3). Using conditions opti-
mized for the model system, each C10 epimer was gener-
ated with >95:5 diastereoselectivity depending upon the
enantiomer of Binaphos ligand employed. Although it was
possible to isolate the aldehyde products (22 and 25)
directly;or derive the primary alcohols by quenching
the reactions with sodium borohydride;addition of the
mild methylating agent MeTi(iPrO)3 provided the corre-
sponding methyl carbinols (23 and 26) as an inconsequen-
tial mixture of C11 epimers.29 Dess-Martin oxidation then
delivered the desired methyl ketones (24 and 27), which
were isolated as single stereoisomers.
Additional synthetic and stereochemical studies on teda-
nolide C and its analogs are underway. Further develop-
ment of our general diene elaboration/hydroformylation
strategy and application toward other natural product
challenges will be forthcoming.
Acknowledgment. This work was supported by a Grant
(R15CA132072) from the National Cancer Institute. A
Pfizer Summer Undergraduate Research Fellowship to
S.J.F. is also gratefully acknowledged. Special thanks to
Wesley Yoshida of the University of Hawaii, Manoa
NMR facility for many helpful discussions.
In summary, the C1ÀC12 fragment of tedanolide C has
been prepared in protected form. The synthesis is short,
only eight steps from 2-methyl-2,4-pentadienal (10),
and enables efficient access to both C10 epimers via late-
stage hydroformylation of a common diene intermediate.
Supporting Information Available. Experimental pro-
cedures and full spectroscopic data for all new com-
pounds. A stereochemical proof for model diene
hydroformylation is also included. This material is
available free of charge via the Internet at http://pubs.
acs.org.
(26) Galobardes, M.; Mena, M.; Romea, P.; Urpi, F.; Vilarrasa, J.
Tetrahedron Lett. 2002, 43, 6145–6148.
(27) No TBS protection was observed at the C5ÀOH at À78 °C, even
in the presence of excess TBSOTf.
(28) Although C5 is eventually needed in its ketone oxidation state,
we elected to prepare the fragment in reduced and protected form.
(29) This reagent may be used in excess with no concern for over-
addition to the ester: Weidmann, B.; Seebach, D. Helv. Chim. Acta 1980,
63, 2451–2454.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 6, 2012
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