Synthesis of taurospongin A

Article abstract of DOI:10.1021/ol100906k

(Figure presented) Two new routes to the C(1-10) carboxylic acid core of taurospongin A are presented. In the first route, overall asymmetric hydration of a C(2)-C(3) alkene is achieved by Sharpless AD and selective deoxygenation at C(2); in the second route, the C(3) stereogenic center is set by Tietze asymmetric allylation. A short synthesis of the C(1′-25′) fatty acid combines with the product from the first route to complete the total synthesis of taurospongin A.

Full text of DOI:10.1021/ol100906k

ORGANIC
LETTERS
2010
Vol. 12, No. 12
2818-2821
Synthesis of Taurospongin A
BoShen Wu, Aure´lie Mallinger, and Jeremy Robertson*
Department of Chemistry, Chemistry Research Laboratory, UniVersity of Oxford,
Mansfield Road, Oxford OX1 3TA, U.K.
jeremy.robertson@chem.ox.ac.uk
Received April 20, 2010
ABSTRACT
Two new routes to the C(1-10) carboxylic acid core of taurospongin A are presented. In the first route, overall asymmetric hydration of a
C(2)-C(3) alkene is achieved by Sharpless AD and selective deoxygenation at C(2); in the second route, the C(3) stereogenic center is set by
Tietze asymmetric allylation. A short synthesis of the C(1′-25′) fatty acid combines with the product from the first route to complete the total
synthesis of taurospongin A.
Kobayashi reported the isolation and structural elucidation
of taurospongin A (1, Scheme 1) from the sponge Hippo-
spongia sp. and described its inhibitory activity against DNA
polymerase ꢀ (IC50 ) 7.0 µM, Ki ) 1.7 µM) and HIV reverse
transcriptase (IC50 ) 6.5 µM, Ki ) 1.3 µM).1 Assignment
of the stereochemistry in the natural product was supported
by a synthesis of the enantiomer of the C(1-10) core in
which the C(3) stereogenic center was imported as (R)-
mevalonolactone and the C(7,9) diol was created without
stereocontrol. In subsequent synthetic work,2a,3 the C(3) and
C(7,9) centers were treated as essentially separate stereo-
chemical problems. Ley’s total synthesis2b,c differs in this
respect by the use of π-allyltricarbonyl lactone complexes
to direct stereoselective delivery of hydride (to generate the
syn-C(7,9) diol) or methyl (to generate the C(3) center).
We became interested in taurospongin A as a starting point
for identifying selective inhibitors of proteins associated with
cellular repair mechanisms and their potential to synergize
with cancer chemotherapeutic drugs. Accordingly, we re-
quired a synthesis of the C(1-10) core that is practical,
amenable to reasonable scale-up, and sufficiently flexible to
allow a variety of stereoisomers and derivatives to be
prepared. In this paper, we describe two candidate solutions
to this problem and carry one of these through to a new total
synthesis of the natural product.
In our original plan, summarized in Scheme 1, we aimed
to achieve, in a single fluoride-mediated step, deprotection
of the C(9) hydroxyl group (in 4), its esterification with acyl
fluoride 2, and release of the C(1) carboxylic acid group.
This guided our choice to protect the carboxylic acid as a
2-(trimethylsilyl)ethyl ester. A second guiding feature was
based on functionalization of R,ꢀ-unsaturated ester 5 by
asymmetric dihydroxylation in both enantiomeric series, and
subsequent selective R-deoxygenation for the total synthesis.
We had in mind the possibility of retaining the R-hydroxyl
group for the preparation of analogues or using asymmetric
aminohydroxylation for access to 3-amino analogues.
(1) Ishiyama, H.; Ishibashi, M.; Ogawa, A.; Yoshida, S.; Kobayashi, J.
J. Org. Chem. 1997, 62, 3831–3836.
(2) Total syntheses: (a) Lebel, H.; Jacobsen, E. N. J. Org. Chem. 1998,
63, 9624–9625. (b) Hollowood, C. J.; Ley, S. V.; Yamanoi, S. Chem.
Commun. 2002, 1624–1625. (c) Hollowood, C. J.; Yamanoi, S.; Ley, S. V.
Org. Biomol. Chem. 2003, 1, 1664–1675
.
(3) Formal syntheses: (a) Zheng, G. R.; Lu, W.; Cai, J. C. Chin. Chem.
Lett. 2001, 12, 961–964. (b) Ghosh, A. K.; Lei, H. Tetrahedron: Asymmetry
2003, 14, 629–634. (c) Moreau, X.; Bazan-Tejeda, B.; Campagne, J. M.
J. Am. Chem. Soc. 2005, 127, 7288–7289. (d) Fujino, A.; Sugai, T. AdV.
Synth. Catal. 2008, 350, 1712–1716. (e) See also: Zheng, G. R.; Lu, W.;
This analysis identified ketone 6 as a key intermediate,
and this was prepared in an efficient seven-step sequence
Cai, J. C. Chin. Chem. Lett. 2000, 11, 663–664
.
10.1021/ol100906k  2010 American Chemical Society
Published on Web 05/18/2010

Scheme 1
.
Retrosynthetic Strategy
Scheme 3. Completion of the C(1-10) Core (First Route)
tion of the separated E-isomer (f 11, Scheme 3).7 We
then faced the issue of selective R-deoxygenation and, in
the absence of suitable precedent for this transformation
with ꢀ,ꢀ-disubstituted substrates, we surveyed many
methods to achieve this, without success.8 Eventually,
homolytic reduction9 of cyclic thionocarbonate derivative
12 was found to be reliable, affording the desired C(1-10)
unit (4) in good yield along with a small amount of
eliminated material (5).
A second route to the C(1-10) core was based on a more
convenient access to analogues of ketone 6 using Wacker
oxidation to install the carbonyl group (Scheme 4). This
employed commercially available 5-bromo-1-pentene in the
first step in place of 5-bromo-2-methyl-1-pentene, the
synthesis of which is somewhat tedious and temperamental.10
The efficiency of the Wacker oxidation depended on the
protecting groups; in the C(7,9)-differentiated diol 15, the
PdCl2/Cu(OAc)2 conditions11 shown were most reliable.
However, with model compounds 19 and 20 the mild
Pd(OAc)2/pyridine conditions12 were more successful (f 22
and 23) but this was a poor reaction for di-O-benzyl substrate
21 for which the classical conditions13 were effective (f
24).
from Weinreb amide 74 (Scheme 2). Key steps include the
syn-stereoselective reduction5 to give diol 8 whose hydroxyl
groups were differentiated by selective iodoetherification and
subsequent zinc-mediated ring-opening (from 9).
Scheme 2. Synthesis of Protected Keto-Diol 6 (First Route)
(7) Kolb, H. C.; Van Nieuwenhze, M. S.; Sharpless, K. B. Chem. ReV.
1994, 94, 2483–2547.
(8) For example: borohydride reduction of the cyclic sulfite/sulfate: (a)
Gao, Y.; Sharpless, K. B. J. Am. Chem. Soc. 1988, 110, 7538–7539. (b)
Upadhya, T. T.; Nikalje, M. D.; Sudalai, A. Tetrahedron Lett. 2001, 42,
4891–4893. Iodide-mediated reduction of the R-triflate: (c) Elliott, R. P.;
Fleet, G. W. J.; Gyoung, Y. S.; Ramsden, N. G.; Smith, C. Tetrahedron
Lett. 1990, 31, 3785–3788. Reduction of the R-mesylate: (d) [Na(Hg)]:
Stork, G.; Rychnovsky, S. D. J. Am. Chem. Soc. 1987, 109, 1564–1565.
(e) [Zn/NaI]: Ueki, T.; Kinoshita, T. Org. Biomol. Chem. 2004, 2, 2777–
2785. Selenide reduction of the R,ꢀ-epoxide: (f) Miyashita, M.; Suzuki,
T.; Hoshino, M.; Yoshikoshi, A. Tetrahedron 1997, 53, 12469–12486.
(9) Rho, H.-S. Synth. Commun. 1997, 27, 3887–3893.
This ketone was elaborated straightforwardly (f 5, E-/
Z-, 4:1) by HWE reaction6 and asymmetric dihydroxyla-
(10) From methallyl alcohol: (a) CH3C(OEt)3, cat. CH3CO2H, 140 °C;
(b) LiAlH4, Et2O; (c) TsCl, pyridine; (d) LiBr, acetone (38% overall); step
(d) has to be performed with care to avoid alkene isomerization and loss of
the volatile product during isolation.
(4) Cohen, F.; Overman, L. E. J. Am. Chem. Soc. 2001, 123, 10782–
10783.
(5) Chen, K.-M.; Hardtmann, G. E.; Prasad, K.; Repic, O.; Shapiro, M. J.
Tetrahedron Lett. 1987, 28, 155–158.
(11) Smith, A. B., III; Cho, Y. S.; Friestad, G. K. Tetrahedron Lett.
1998, 39, 8765–8768.
(6) Phosphonate 10 was prepared according to the procedure described
in: Cushman, M.; Casimiro-Garcia, A.; Hejchman, E.; Ruell, J. A.; Huang,
M.; Schaeffer, C. A.; Williamson, K.; Rice, W. G.; Buckheit, R. W., Jr.
J. Med. Chem. 1998, 41, 2076–2089.
(12) Nishimura, T.; Kakiuchi, N.; Onoue, T.; Ohe, K.; Uemura, S.
J. Chem. Soc., Perkin Trans. 1 2000, 1915–1918.
(13) Tsuji, J.; Nagashima, H.; Nemoto, H. Organic Syntheses; Wiley:
New York, 1990; Collect. Vol. VII, pp 137-139.
Org. Lett., Vol. 12, No. 12, 2010
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Scheme 4. Second Route to the C(1-10) Core
From this ketone (16) an alternative to the HWE/AD/
deoxygenation procedure was developed. Grignard allylation
of methyl ketone 22 was completely nonstereoselective but
application of Tietze’s procedure,14 that employs (R)-1,2-
diphenylethanol as a chiral auxiliary, showed very high
reagent control15 to establish the C(3) center in 17. Alkene
oxidation and hydrogenolysis revealed both the C(7) hy-
droxyl and carboxylic acid groups to complete the second
C(1-10) synthesis.
the N-hydroxysuccinimide method used by Ley,2b,c following
Kobayashi,1 worked very well to complete the total synthesis.
Scheme 6. Completion of the Synthesis (RCO2H ) 3)
From intermediate 4 it then remained to deprotect and
acylate at C(9) and release the carboxylic acid. To date, we
have been unable to effect clean formation of acyl fluoride
2 and our trials with this approach have been inconclusive.16
However, stepwise deprotection and esterification with acid
3, prepared as shown in Scheme 5, was successful following
Interestingly, although the 13C NMR data in CDCl3
matched those reported,2c some of the peaks were weak and
broadened, and we suggest that in the nonpolar solvent,
aggregation, such as reverse micelle formation, may be
responsible. In this context, we note that the 13C data listed
by Kobayashi1 are missing many of the resonances reported
Scheme 5. Synthesis of C(1′-25′) Fatty Acid
1
by Ley. In CD3OD, all 13C and H NMR resonances are
sharp, presumably because the polar, protic solvent is
effective at solvating taurospongin A fully.
Our total synthesis of taurospongin A requires 15 steps
from Weinreb amide 7 and was achieved in ca. 13.5% overall
(14) Tietze, L. F.; Kinzel, T.; Wolfram, T. Chem.sEur. J. 2009, 15,
6199–6210. We are very grateful to Professor Tietze and his group for their
invaluable advice in relation to this procedure.
(15) The stereochemistry at C(3) in compound 17 was assumed on the
basis of Tietze’s model (ref 14). None of the resonances in the 13C NMR
spectrum for 17 were doubled, including that at 34.6 ppm, which was
sensitive to stereochemical change (34.4 ppm in the adduct generated using
the (S)-configured auxiliary).
Jacobsen’s procedure (Scheme 6). Removal of the 2-(trim-
ethylsilyl)ethyl group proceeded poorly with TBAF, but
TASF17 produced the acid very cleanly. In our hands, the
mixed anhydride method described by Jacobsen2a for the
coupling with taurine was not satisfactory; fortunately,
(16) We will report further details in a full description of this work.
2820
Org. Lett., Vol. 12, No. 12, 2010

yield (average ca. 88% per step). The original aim of
developing a practical synthesis has been met, and with two
routes to the C(1-10) core in hand, we are in a position to
survey broad structure-activity relationships through ana-
logue testing.
sur le Cancer for a fellowship (A.M.), the China Oxford
Scholarship Fund, the Overseas Research Student Awards
Scheme, and The Henry Lester Trust for funding (B.W.),
and Drs. T. D. W. Claridge and B. Odell, University of
Oxford, for extensive NMR support.
Acknowledgment. We thank Leanne Reynolds for pre-
Supporting Information Available: Procedures and cop-
ies of NMR spectra for all compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
liminary experiments,18 the Association pour la Recherche
(17) Scheidt, K. A.; Chen, H.; Follows, B. C.; Chemler, S. R.; Coffey,
D. S.; Roush, W. R. J. Org. Chem. 1998, 63, 6436–6437.
(18) Reynolds, L. Chemistry Part II Thesis, Oxford, 2008.
OL100906K
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