Synthesis of taurospongin A: a potent inhibitor of DNA polymerase and HIV reverse transcriptase, using pi-allyltricarbonyliron lactone complexes.

Article abstract of DOI:10.1039/b204994p

The synthesis of taurospongin A has been achieved using, as a key step, a pi-allyltricarbonyliron lactone complex to control a highly stereoselective addition of a methyl group to a carbonyl unit located in the side chain of the complex.

Full text of DOI:10.1039/b204994p

Synthesis of taurospongin A: a potent inhibitor of DNA polymerase and
HIV reverse transcriptase, using p-allyltricarbonyliron lactone
complexes
Christopher J. Hollowood, Steven V. Ley* and Shigeo Yamanoi
Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge, UK CB2 1EW.
E-mail: svl1000@cam.ac.uk; Fax: +44 (0)1223 336442; Tel: +44 (0)1223 336398
Received (in Cambridge, UK) 22nd May 2002, Accepted 5th June 2002
First published as an Advance Article on the web 1st July 2002
The synthesis of taurospongin A has been achieved using, as
a key step, a p-allyltricarbonyliron lactone complex to
control a highly stereoselective addition of a methyl group to
a carbonyl unit located in the side chain of the complex.
the complex. This general process had been established earlier
by our group to install 1,5-, 1,7- and 1,5,7-hydroxylated
stereogenic centres in alkyl chains.4
The synthesis begins from ethyl (3R)-hydroxybutanoate 2 by
a known sequence5 of reactions comprising tert-butyldime-
thylsilyl protection, DIBAL reduction, Swern oxidation, Wittig
coupling and then a further reduction to afford the allylic
alcohol 3 in good overall yield. Compound 3 was subjected to
the Sharpless asymmetric epoxidation procedure,6 which gave 4
with 93% d.e. again in good yield (Scheme 1). Following
oxidation of 4, to an intermediate aldehyde, reaction with the
diethyl phosphonate derivative 5 gave 6 as the precursor for the
iron carbonyl chemistry. The phosphonate 5, in turn, was
prepared from b-propiolactone by ring opening with methoxide
followed by protection with tert-butyldimethylsilyl chloride
and coupling with diethylmethylphosphonate in the usual
way.
Taurospongin A (1) (Fig. 1) is an unusual acetylene containing
natural product consisting of two fatty acid residues and a
taurine unit. This compound was isolated from a purple
coloured sponge Hippospongia sp. in 1997 and shown to be a
potent inhibitor of DNA polymerase b and HIV reverse
transcriptase.1
One elegant synthesis of 1 has already been reported in which
the three stereogenic centres were created in three separate
reagent controlled processes.2 Here we report a conceptually
different approach whereby a p-allyltricarbonyliron lactone
complex3 is used to transfer chiral information, through
tethering, to achieve a highly stereoselective addition of a
methyl group to a carbonyl unit appended to the side-chain of
Next the alkenyl epoxide 6 was reacted with diiron
nonacarbonyl in THF7 to give the p-allyltricarbonyliron lactone
complexes 7 and 8 in 14 and 48% yields respectively. These
complexes were readily separated by silica gel chromatog-
raphy.
The major endo-complex 8 was then reacted with trimethyla-
luminium to give the tertiary alcohol 9 in 81% yield and
excellent stereocontrol owing to the preferred s-cis conforma-
tion of the carbonyl group in the appended side chain.4b
Following our previously established reductive decomplexation
protocol8 using sodium acetoxyborohydride followed by hydro-
genation, 9 was smoothly converted to the protected polyol 10
Fig. 1 Taurospongin A (1): R = H. Taurospongin A methyl ester (20): R =
Me.
Scheme 1 Reagents and conditions: (a) TBSCl, imidazole, DMF, 0 °C, 100%; (b) DIBAL-H, PhMe, 0 °C, 83%; (c) (COCl)2, DMSO, NEt3, CH2Cl2, 278
°C; (d) Ph3PCHCO2Me, CH2Cl2, rt, 78% for two steps; (e) DIBAL-H, PhMe, 0 °C, 82%; (f) Ti(Oi-Pr)4, -diisopropyl tartrate, t-BuOOH, 4 Å MS, CH2Cl2,
D
220 °C, 82%; (g) (COCl)2, DMSO, NEt3, CH2Cl2, 278 °C, 88%; (h) 5, NaH, THF, 76%; (i) Fe2(CO)9, THF, rt, 7 14%, 8 48%; (j) AlMe3, CH2Cl2, 0 °C,
81%; (k) NaBH(OAc)3, THF, rt; (l) H2, Pd/C, EtOAc, rt, 81% for two steps; (m) Ac2O, DMAP, NEt3, CH2Cl2, 0 °C, 98%; (n) TBAF, AcOH, THF, 0 °C,
81%.
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CHEM. COMMUN., 2002, 1624–1625
This journal is © The Royal Society of Chemistry 2002

in 81% overall yield. Lastly this was acetylated using acetic
anhydride and 4-dimethylaminopyridine (DMAP) and depro-
tected selectively using buffered tetra(n-butyl)ammonium fluo-
ride (TBAF) to give the known2 taurospongin fragment 11
(Scheme 1). The spectral and optical rotational data were
identical to the sample previously synthesised by Jacobsen et
al.2
For the synthesis of the other fatty acid side chain (Scheme
2), octadec-1-yne 12 was deprotonated with n-butyllithium and
coupled with 2-(3-bromopropoxy)tetrahydro-2H-pyran fol-
lowed by acidic work-up to give the alcohol 13. This compound
was selectively hydrogenated with the Lindlar catalyst and
oxidised with periodinane9 to the aldehyde 14, which was
homologated with the Ohira reagent 1510 to give the enyne 16 in
84% yield over three steps. This compound was extended
further by deprotonation with n-butyllithium and alkylation
with 2-(3-bromopropoxy)tetrahydro-2H-pyran to give a product
(82% yield) which, upon direct oxidation with Jones reagent,
gave the required acid 17 in 92% yield (46% overall yield from
the acetylene 12).
The final steps of the synthesis were achieved by a
modification of the literature route.2 Diol 11 was transformed to
the corresponding acid via oxidation with TEMPO, KBr,
NaHCO3 and NaOCl, and converted to the allyl ester 18 by
alkylation with allyl bromide in the presence of Hünigs’ base (i-
Pr2NEt). Removal of the tert-butyldimethylsilyl protecting
group from 18 using HF–pyridine was successful and the
product was then coupled directly with the acid 17 using
1,3-diisopropylcarbodiimide (DIC), Hünigs’ base and DMAP
to give 19.
Lastly, removal of the allyl protecting group using standard
procedures with Pd(PPh3)4 and pyrrolidine gave an intermediate
carboxylic acid that was activated by forming N-hydrox-
ysuccinic ester with DCC and finally coupled with taurine
(H2NCH2CH2SO3H) to give natural product taurospongin A 1
(Scheme 3).1 The NMR data for 1 was consistent with the
previously synthesised material.2† For full characterization, our
synthetic sample was treated with diazomethane to give the
corresponding methyl ester 20,1 which turned out to be in
complete agreement with previously reported data of the
samples derived either from isolated or synthetic natural
products.1,2
Scheme 3 Reagents and conditions: (a) cat. TEMPO, Aliquat® 336, KBr,
aq. NaOCl, aq. NaHCO3, CH2Cl2; (b) allyl bromide, i-Pr2NEt, CH2Cl2,
87% for two steps; (c) HF·py, THF; (d) 17, DIC, i-Pr2NEt, DMAP, CH2Cl2,
63% for two steps; (e) Pd(PPh3)4, pyrrolidine, CH2Cl2; (f) N-hydrox-
ysuccinimide, DCC, 1,4-dioxane; (g) taurine, NEt3, 1,4-dioxane, H2O, 97%
for three steps; (h) CH2N2, ether, 75%.
inhibitor of DNA polymerase b and HIV reverse tran-
scriptase.
We gratefully acknowledge the financial support from the BP
endowment and the Novartis Research Fellowship (to SVL),
Uehara Foundation for a Postdoctoral Fellowship (to SY).
Notes and references
† The NMR data for 1: dH (600 MHz, CDCl3) 0.88 (3H, t, J = 7.0 Hz), 1.18
(3H, br s), 1.23–1.33 (33H, m), 1.42–1.60 (4H, m), 1.67–1.68 (1H, m),
1.91–1.95 (1H, m), 1.99–2.04 (2H, m), 2.05 (3H, s), 2.14–2.22 (4H, m), 2.31
(2H, br s), 2.44–2.46 (4H, m), 3.13 (2H, br s), 3.66 (2H, br s), 4.70 (1H, br
s), 4.91–4.95 (2H, m), 5.35–5.44 (2H, m), 7.74 (1H, br s); dC (150 MHz,
CDCl3) 14.1, 14.8, 19.1, 19.6, 20.0, 21.2, 22.7, 26.1, 26.8, 27.3, 29.3–31.9,
34.3, 34.9, 35.2, 40.4, 42.2, 46.5, 50.0, 68.5, 71.1, 71.8, 78.2, 80.7, 127.8,
In summary, we report new syntheses of the two fatty acid
components that are then used to construct taurospongin A, an
25
131.2, 171.0, 171.6, 173.2. Measured aD of synthetic product 1, [a]D
23.5 (c 0.37, CHCl3) has opposite sign to the reported data, [a]D27 +2.4 (c
25
0.2), although the aD of methyl ester 20, [a]D 21.4 (c 0.49, CHCl3) is
27
consistent with the reported data, [a]D 21.4 (c 0.78, CHCl3, ref. 1) and
[a]D 23.00 (c 0.53, CHCl3, ref. 2).
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Scheme 2 Reagents and conditions: (a) n-BuLi, n-C16H33I, HMPA, THF,
220 °C ? rt, then 6 M H2SO4, 0 °C, 73%; (b) H2, Lindlar cat., quinoline;
(c) Dess–Martin periodinane, CH2Cl2, rt; (d) 15, K2CO3, MeOH, 84% for
three steps; (e) n-BuLi, 2-(3-bromopropoxy)tetrahydro-2H-pyran, HMPA,
THF, 220 ? 0 °C , 82%; (f) Jones reagent, acetone, 0 °C ? rt, 92%.
CHEM. COMMUN., 2002, 1624–1625
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