Enantioselective synthesis of the C(1)-C(11) fragment of tedanolide C

Article abstract of DOI:10.1021/ol303089w

A convergent synthesis of the protected C(1)-C(11) fragment 6 of the targeted enantiomer of tedanolide C is described. The key step of the synthesis is the Felkin-Ahn addition of vinyl iodide 7 to aldehyde 8 that proceeds in 80% yield with 4:1 diastereose

Full text of DOI:10.1021/ol303089w

ORGANIC
LETTERS
2013
Vol. 15, No. 1
58–61
Enantioselective Synthesis of the
C(1)ÀC(11) Fragment of Tedanolide C
Julie G. Geist, Roland Barth, and William R. Roush*
Department of Chemistry, The Scripps Research Institute, Scripps Florida,
130 Scripps Way, Jupiter, Florida 33458, United States
roush@scripps.edu
Received November 9, 2012
ABSTRACT
A convergent synthesis of the protected C(1)ÀC(11) fragment 6 of the targeted enantiomer of tedanolide C is described. The key step of the
synthesis is the FelkinÀAhn addition of vinyl iodide 7 to aldehyde 8 that proceeds in 80% yield with 4:1 diastereoselectivity.
The isolation and structure determination of tedanolide
C (1), a marine natural product isolated from a Papua New
Guinea sponge of the Ircinia species, was reported by
Ireland and co-workers in 2006.1 Other members of the
tedanolide family include tedanolide (2),2 13-deoxyteda-
nolide (3),3 and the candidaspongiolides (4, Figure 1).4 The
structure and relative stereochemistry of tedanolide C (1)
was assigned by using NMR methods and DFT calculations,
but the absolute stereochemistry remains unconfirmed.1
Tedanolide C exhibits excellent potency against HCT-116
cells (colorectal cell line), with an IC50 value of 0.057 μg/mL
(90 nM), and stops the growth of HCT-116 cells in the
S-phase after 24 h of exposure at 0.2 μg/mL.1 It has been
postulated that tedanolide C is a protein synthesis inhibitor,
like its closely related congener, 13-deoxytedanolide. Sur-
prisingly, however, the structure reported for 1 depicts the
Figure 1. Tedanolide natural product family.
C(11)ÀC(23) fragment with an enantiomeric configuration
(except for the epoxide) relative to other members of the
tedanolide family. The C(10)ÀC(23) fragment has been
identified as the key pharmacophoric unit of 13-deoxy-
tedanolide.5 Therefore, in planning a synthesis of tedanolide
(1) Chevallier, C.; Bugni, T. S.; Feng, X.; Orendt, A. M.; Ireland,
C. M. J. Org. Chem. 2006, 71, 2510.
(2) Schmitz, F. J.; Gunasekera, S. P.; Yalamanchili, G.; Bilayet
Hossain, M.; Van Der Helm, D. J. Am. Chem. Soc. 1984, 106, 7251.
(3) Fusetani, N.; Sugawara, T.; Matsunaga, S.; Hirota, H. J. Org.
Chem. 1991, 56, 4971.
(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.; McKee, T. C. J. Nat. Prod. 2007, 70,
1133. (b) Whitson, E. L.; Pluchino, K. M.; Hall, M. D.; McMahon, J. B.;
McKee, T. C. Org. Lett. 2011, 13, 3518.
(5) (a) Nishimura, S.; Matsunaga, S.; Yoshida, M.; Hirota, H.;
Yokoyama, S.; Fusetani, N. Bioorg. Med. Chem. 2005, 13, 449.
(b) Nishimura, S.; Matsunaga, S.; Yoshida, S.; Nakao, Y.; Hirota, H.;
Fusetani, N. Bioorg. Med. Chem. 2005, 13, 455.
r
10.1021/ol303089w
Published on Web 12/18/2012
2012 American Chemical Society

C (1) we decided to pursue the enantiomeric structure 5 as
the synthetic target (Scheme 1) in anticipation that the
configuration of the C(11)ÀC(23) unit of tedanolide C
should be the same as that for the key C(10)ÀC(23)
pharmacophore of 13-deoxytedanolide.
Scheme 1. Strategy for the Synthesis of the Protected
C(1)ÀC(11) Fragment of the Targeted Enantiomer of Tedanolide C
In 2010 our laboratory reported the synthesis of the
C(15)ÀC(21) fragment of 5.6 Kalesse et al. subsequently
published their synthesis of the C(14)ÀC(23) fragment of a
diastereomeric analog of tedanolide C using a Kiyooka
aldol reaction.7,8 More recently still, a synthesis of the
C(1)ÀC(12) fragment has been reported by Smith et al. by
a route involving an asymmetric hydroformylation of a
1,3-diene.9 We report herein our synthesis of 6, a protected
version of the C(1)ÀC(11) fragment of the targeted en-
antiomer of tedanolide C.
Our strategy for the synthesis of fragment 6 (Scheme 1)
involves the formation of the secondary C(7) hydroxyl
group by addition of vinyl iodide 7 to aldehyde 8. We
anticipated that the C(7) alcohol stereochemistry would be
controlled by accessing a FelkinÀAhn transition state for
the carbonyl addition.10 Aldehyde 8 was synthesized start-
ing from the known aldehyde 911 (Scheme 2). Subjection of
9 to an enantioselective Reformatsky-type reaction12 with
oxazolidinone 1013 in the presence of SnCl2 afforded 11 in
56% yield with >98:2 dr. The absolute configuration of
the hydroxyl group at C(3) of 11 was confirmed by using
the advanced Mosher ester method.14 Protection of alcohol
11 as a TBS ether using TBSOTf and 2,6-lutidine, followed
by reduction of the acyl oxazolidinone with LiBH4 and
subsequent ParishÀDoering oxidation15 of the primary
alcohol, afforded aldehyde 12.16 The syn aldol reaction
between 12 and propionyl oxazolidinone 1317 was per-
formed in the presence of TiCl4 and (À)-sparteine18 and
gratifyingly afforded aldol 14 in 76% yield as a single
diastereomer. The use of (À)-sparteine in this reaction
was essential to obtain synthetically useful diastereoselec-
tivity; the aldol reaction of the titanium enolate generated
with diisopropylethyl amine (DIPEA) as the base af-
forded a 1:1 mixture of diastereomers. Protection of the
Scheme 2. Synthesis of Aldehyde 8
(6) Barth, R.; Roush, W. R. Org. Lett. 2010, 12, 2342.
newly formed hydroxyl group of 14 as a TMS ether,
followed by reduction of the acyl oxazolidinone with LiBH4
€
(7) Bulow, L.; Naini, A.; Fohrer, J.; Kalesse, M. Org. Lett. 2011,
13, 6038.
(8) Kalesse’s synthetic target has the C(10)ÀC(23) stereochemistry,
the same as that for our target 5, but has C(1)ÀC(7) stereochemistry, the
same as that in the originally proposed structure for tedanolide C (1).
(9) Smith, T. E.; Fink, S. J.; Levine, Z. G.; McClelland, K. A.;
Zackheim, A. A.; Daub, M. E. Org. Lett. 2012, 14, 1452.
(10) (a) Cherest, M.; Felkin, H.; Prudent, N. Tetrahedron Lett. 1968,
2199. (b) Anh, N. T.; Eisenstein, O. Nouv. J. Chim. 1977, 1, 61.
(11) Oka, T.; Murai, A. Tetrahedron 1998, 54, 1.
and oxidation of the primary alcohol with SO3 pyridine,15
completed this synthesis of aldehyde 8.
3
The stereochemistry of aldol 14 was verified by the
studies summarized in Scheme 3. Alcohol 15, obtained in
two steps from 14, was elaborated into diol 16 in 62% yield
by benzylation of the primary alcohol19 and deprotection
of the two silyl ethers. Analysis of the 13C NMR spectrum
of the derived acetonide 17 using Rychnovsky’s method20
confirmed the syn relationship between C(3)ÀOH and
C(5)ÀOH. Independently, acetonide 18was alsogenerated
in two steps from alcohol 15. The small HaÀHb and
HaÀHc coupling constants (J < 2 Hz) observed in the
1H NMR spectrum of 18 suggested that this compound
€
(12) (a) Kogl, M.; Brecker, L.; Warrass, R.; Mulzer, J. Angew. Chem.,
€
Int. Ed. 2007, 46, 9320. (b) Kogl, M.; Brecker, L.; Warrass, R.; Mulzer, J.
Eur. J. Org. Chem. 2008, 2714.
(13) Kende, A. S.; Kawamura, K.; Orwat, M. J. Tetrahedron Lett.
1989, 30, 5821.
(14) (a) Dale, J. A.; Mosher, H. S. J. Am. Chem. Soc. 1973, 95, 512. (b)
Hoye, T. R.; Jeffrey, C. S.; Shao, F. Nat. Protoc. 2007, 2, 2451.
(15) Parikh, J. R.; von Doering, E. W. J. Am. Chem. Soc. 1967, 89,
5505.
(16) Hartung, I. V.; Niess, B.; Haustedt, L. O.; Hoffmann, H. M. R.
Org. Lett. 2002, 4, 3239.
(17) Evans, D. A.; Bartroli, J.; Shih, T. L. J. Am. Chem. Soc. 1981,
103, 2127.
(18) Crimmins, M. T.; King, B. W.; Tabet, E. A.; Chaudhary, K.
J. Org. Chem. 2001, 66, 894.
(19) Brummond, K. M.; Hong, S.-P. J. Org. Chem. 2005, 70, 907.
(20) Rychnovsky, S. D.; Rogers, B.; Yang, G. J. Org. Chem. 1993, 58,
3511.
Org. Lett., Vol. 15, No. 1, 2013
59

Scheme 3. Stereochemical Assignments
Scheme 4. Synthesis of the C(1)ÀC(11) Fragment 6 of
Tedanolide C
adopts a chairlike conformation in which Ha is in an
1
equatorial position. Furthermore, the H NOE data ob-
tained for 18 highlighted in Scheme 3 supported the assign-
ment of syn stereochemistry between C(5)ÀOH and
C(6)ÀCH3 in aldol 14.
Vinyliodide 7 was synthesizedfrom alkyne 19,21 which is
available in five steps from commercial methyl (R)-β-
hydroxyisobutyrate (Scheme 4). We considered 19 to be
a useful intermediate as the protecting group for the
primary hydroxyl group can be easily removed and mod-
ified. Deprotection of the p-methoxybenzyl (PMB) ether
was accomplished by treatment of 19 with DDQ at 0 °C in
a 1:1 mixture of pH 7 phosphate buffer and CH2Cl2. The
volatile propargyl alcohol was quickly treated with di-
methoxytrityl chloride (DMTrCl) to give 20 in 88% yield
over these two steps. Hydrostannylationof20using freshly
distilled Bu3SnH proceeded in 82% yield and with 93:7
regioselectivity. Treatment of the vinylstannane with I2
afforded vinyl iodide 7 almost quantitatively.22
In a first attempt toward the coupling of 7 and 8,
treatment of 7 with tBuLi (2.2 equiv) at À78 °C, followed
by addition of 8 at À78 °C, provided 21 as a 1:1 ratio of
diastereomers. It has been reported that vinyl zincates
provide higher diastereoselectivity upon addition to chiral
aldehydes than the corresponding vinyl lithium reagents.23
Thus, as shown in Scheme 4, treatment of vinyl iodide 7
with 2.2 equiv of tBuLi at À78 °C for 10 min, followed by
addition of 1.1 equiv of ZnMe2 at À78 °C for 5 min,
afforded a solution of the vinyl zincate reagent. To this
solution was added a solution of aldehyde 8, and the
mixture was stirred for 3 h at À78 °C prior to workup.
This procedure provided alcohol 21 in 80% yield as a 4:1
mixture of diastereomers that were not separated at this
stage. The absolute configuration of the C(7) hydroxyl
group of the major diastereomer was assigned by using the
advanced Mosher ester method.14 Protection of the C(7)
hydroxyl group of 21 as a TBS ether proceeded in 70%
yield. In the next step, the DMTr protecting group was
removed selectively by treatment of the fully protected
intermediate with a 1:1:1 mixture of AcOH, trifluoroetha-
nol, and CH2Cl2 without removal of the TMS ether.24
Gratifyingly, this step enabled the separation of the two
C(7)-diastereomers by standard column chromatography;
the major diastereomer was isolated in 62% yield from this
sequence (86% b.r.s.m.). The hindered C(5)ÀOTMS ether
protecting group was removed in a subsequent step by
using a solution of 40% HCO2H in methanol, which
afforded diol 22 in 81% yield.
For the final step of the synthesis of 6, we expected the
oxidation of the very hindered C(5)-hydroxyl group to
be slower than the oxidation of the primary alcohol and
were concerned that problems could arise with the
β,γ-unsaturated aldehyde which in related systems is known
to be sensitive toward epimerization at C(10). We selected
the Dess-Martin periodinane reagent25 for this step, since
(21) Organ, M. G.; Wang, J. J. Org. Chem. 2003, 68, 5568.
(22) Sun, X. -Y.; Tian, X. -Y.; Li, Z. -W.; Peng, X. -S.; Wong,
H. N. C. Chem.;Eur. J. 2011, 17, 5874.
(23) (a) Hayashi, Y.; Shoji, M.; Ishikawa, H.; Yamaguchi, J.;
Tamura, T.; Imai, H.; Nishigaya, Y.; Takabe, K.; Kakeya, H.; Osada, H.
Angew. Chem., Int. Ed. 2008, 47, 6657. (b) Marshall, J. A.; Eidam, P.
Org. Lett. 2004, 6, 445.
€
(24) Matysiak, S.; Boldicke, T.; Tegge, W.; Frank, R. Tetrahedron
Lett. 1998, 39, 1733.
60
Org. Lett., Vol. 15, No. 1, 2013

this reagent is known to be useful for oxidations that give
aldehyde products that are highly prone to epimerization
when other oxidation conditions are used.26 However
complete oxidation of 22 could not be achieved by using
5 equiv of the DessÀMartin periodinane even when the
reaction was performed for 1 h at ambient temperature. The
reaction had to be gently heated to 40 °C for 20 min to drive
the oxidation of the C(5) alcohol to completion. In this way,
the fully protected C(1)ÀC(11) fragment 6 of tedanolide C
was obtained as a single isomer in almost quantitative yield,
with no evidence of epimerization at C(10).
In summary, we developed a diastereoselective synthesis
of the protected C(1)ÀC(11) fragment 6 of the targeted
enantiomer of tedanolide C in 13 steps starting from the
known aldehyde 9. The synthesis involves a SnCl2 mediated
enantioselective Reformatsky-type reaction to set the C(3)
stereocenter and an EvansÀCrimmins aldol reaction to set
the syn relationship between C(5) and C(6). The C(7)
stereocenter was set by the FelkinÀAhn controlled addition
of the vinylzincate derived from vinyl iodide 7 to aldehyde 8.
The synthesis of 6 was completed by the Dess-Martin
periodinane oxidation of the C(5)ÀC(11) diol unit. Further
progress toward completion of a synthesis of tedanolide C
will be reported in due course.
Acknowledgment. Financial support provided by the
National Institutes of Health (GM038436) is gratefully
acknowledged. J.G.G. thanks the Swiss National Science
Foundation (SNSF) for a postdoctoral fellowship. Wealso
thank Dr. Souad Ouizem for proofreading the manuscript.
Supporting Information Available. Experimental pro-
1
cedures and copies of H and 13C NMR spectra of new
compounds. This material is available free of charge via
the Internet at http://pubs.acs.org.
(25) Dess, D. B.; Martin, J. C. J. Am. Chem. Soc. 1991, 113, 7277.
(26) Myers, A. G.; Zhong, B.; Movassaghi, M.; Kung, D. W.; Lanman,
B. A.; Kwon, S. Tetrahedron Lett. 2000, 41, 1359.
The authors declare no competing financial interest.
Org. Lett., Vol. 15, No. 1, 2013
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