A route to the fully substituted cyclopentane unit of viridenomycin using a tandem radical cyclisation-trapping strategy

Article abstract of DOI:10.1016/j.tetlet.2004.12.063

A silicon-tethered intramolecular radical cyclisation, in tandem with a radical trapping with allyltri-n-butylstannane forms the basis of a new synthetic strategy to the cyclopentane core of the antitumoral antibiotic substance viridenomycin isolated from

Full text of DOI:10.1016/j.tetlet.2004.12.063

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 937–939
A route to the fully substituted cyclopentane unit of
viridenomycin using a tandem radical
cyclisation–trapping strategy
Nicholas P. Mulholland and Gerald Pattenden*
School of Chemistry, The University of Nottingham, Nottingham NG7 2RD, England, UK
Received 19 November 2004; accepted 10 December 2004
Abstract—Asilicon-tethered intramolecular radical cyclisation, in tandem with a radical trapping with allyltri- n-butylstannane
forms the basis of a new synthetic strategy to the cyclopentane core of the antitumoral antibiotic substance viridenomycin isolated
from Streptomyces viridochromogenes and S. gannmycicus.
Ó 2004 Elsevier Ltd. All rights reserved.
Viridenomycin 1 is an antitumoral antibiotic substance
isolated from S. viridochromogenes and S. gannmycicus1
which is capable of prolonging the life span of trans-
genic mice who express P388 leukaemia and B16 mela-
noma. The compound has a structure based on a
polyene macrolactam core linked to a highly substituted
cyclopentane, viz 2, by a quaternary centre and via an
enolised b-keto ester unit. Although neither the absolute
stereochemistry nor the stereochemistry at the benzylic
centre in viridenomycin is known, the striking structural
features it accommodates, alongside its interesting bio-
logical properties, have combined to make the natural
product a challenging target for synthesis.
Arrington and Meyers2 were the first to describe a con-
cise synthesis of the cyclopentane core in viridenomycin
and more recently Ishihara et al.3 and Trost and Jiang4
presented alternative solutions to this demanding syn-
thetic problem. In this paper we describe a different syn-
thetic approach to the cyclopentane ring system in
viridenomycin which uses an intramolecular radical
cyclisation from a silicon tethered 2-cyclopentenol, that
is, 3, in tandem with in situ trapping of the product
radical with allyltri-n-butylstannane, leading to 4, as
the key stratagem (Scheme 1).5
Thus, the known substituted tetrahydrofuran 6 derived
from commercially available 1,2-5,6-di-O-isopropylid-
ene-a-D-glucofuranose6 5 was first converted into the
corresponding c-lactone 7 in four straightforward steps
(Scheme 2). Addition of methyllithium to 7, followed by
protection of the resulting c-hydroxyketone 8a next led
to the methyl ketone 8b, which was then converted into
the corresponding alkene 9 using the Nysted reagent
((Zn(CH2ZnBr)2ÆTHF–TiCl4).7 The 1,6-diene 9 under-
went smooth ring closure metathesis in the presence of
Grubbsꢀ catalyst8 at 80 °C to give the cyclopentene 10
in 90% yield.
Ph
OR
R'
O
OH
OH
NH
O
O
MeO
MeO
O
OH
OH
1
2
Deprotection of the silyl ether 10, followed by treatment
of the resulting cyclopentenol with (bromomethyl)chlo-
rodimethylsilane in the presence of DMAP and Et3N
then gave the key a-bromosilyl ether 11 in 80% yield
(Scheme 3). To our satisfaction, when a solution of the
a-bromosilyl ether 11, allyltri-n-butylstannane and
*
Corresponding author. Tel.: +44 115 9513530; fax: +44 115 951
3535; e-mail: gp@nottingham.ac.uk
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.12.063

938
N. P. Mulholland, G. Pattenden / Tetrahedron Letters 46 (2005) 937–939
Br
Si
Si
O
Si
O
O
radical
trapping
radical
MeO
MeO
MeO
cyclisation
RO
RO
RO
SnBu3
3
4
Scheme 1.
O
O
O
O
O
ref 6
i-iv
O
O
O
HO
MeO
MeO
O
O
OBn
6
7
5
OMe
O
TBSO
MeO
OMe
v
vii
viii
OR
OBn
OTBS OBn
BnO
8
10
9
a R = H
b R = TBS
vi
Scheme 2. Reagents and conditions: (i) EtOH, HCl in dioxane, 60 °C (91%); (ii) BnBr, NaH, DMF, 0 °C (89%); (iii) AcOH, H2O (98%); (iv) DMSO,
Ac2O (91%); (v) MeLi, THF, ꢀ78 °C; (vi) TBSCl, imidazole, DMF (54%); (vii) Zn(CH2ZnBr)2ÆTHF, TiCl4, THF, 0 °C–rt (98%); (viii) 1,3-
(bis(mesityl)-2-imidazolidinylidene)dichloro-(phenylmethylene)(tricyclohexylphosphine)ruthenium, benzene, 80 °C (90%).
Br
Si
O
HO
iii
iv
i, ii
OH
4
10
MeO
MeO
BnO
BnO
11
12
Scheme 3. Reagents and conditions: (i) TBAF, THF (80%); (ii) Et3N, (CH3)2Si(CH2Br)Cl, DMAP, DCM (80%); (iii) ACCN, n-heptane, 100 °C,
allyltri-n-butylstannane; (iv) H2O2, KF, KHCO3, MeOH, THF, 80 °C (50% over two steps).
1,10-azobis(cyclohexanecarbonitrile) (ACCN) in n-hep-
tane, was heated at 100 °C for 24 h, work-up gave the
silicon heterocycle (4, R = Bn) which was immediately
treated with H2O2–KF in THF–MeOH under reflux,
that is, Tamao–Fleming oxidation conditions,9 to give
the cyclopentane-substituted diol 12 containing five con-
tiguous chiral centres, in 50% overall yield. The stereo-
chemistry of 12 followed unambiguously from NOE
studies. Thus irradiation of the quaternary methyl group
at d 1.1 in 12, gave enhancements at d 3.9 and d 3.8 due
to the CH2OH protons (5.1 and 5.3%, respectively), and
irradiation at d 4.3 (CHÆCH2OH) resulted in enhance-
ments at d 3.8 (CH2OH; 4.8%) and d 2.2 (CH2CH:CH2;
20.1%).
The primary alcohol group in 12 was next converted
into the corresponding carboxylic acid ester 13a in
straightforward steps, which was then deprotected to
the secondary alcohol 13b (Scheme 4). Oxidation of
13b using Moffatt conditions,10 followed by methylation
of the enol of the resulting b-keto ester, finally gave the
cyclopentane unit 14 of viridenomycin, appropriately

N. P. Mulholland, G. Pattenden / Tetrahedron Letters 46 (2005) 937–939
939
OMe
OMe
RO
MeO
i -v
vii-viii
O
O
12
MeO
MeO
BnO
BnO
14
13
a
b
R = TBS
R = H
vi
Scheme 4. Reagents and conditions: (i) TBSCl, imidazole, DMF (92%); (ii) PPTS, EtOH (71%, based on recovered starting material); (iii) DMP,
pyridine, DCM; (iv) NaClO2, KH2PO4, H2O, t-BuOH, 2-methyl-2-butene; (v) TMSCHN2, PhH, MeOH; (vi) TBAF, THF (69%, over four steps);
(vii) EDC, DMSO, PyÆTFA, DMAP (89%); (viii) Me2SO4, DMSO, K2CO3 (97%).
Soc. 1986, 108, 6384–6385; For silicon tethered cyclisa-
tions see: Nishiyama, H.; Kitajima, T.; Matsumoto, M.;
Itoh, K. J. Org. Chem. 1984, 49, 2298–2300; Stork, G.;
Kahn, M. J. Am. Chem. Soc. 1985, 107, 500–501; Stork,
G.; Sofia, M. J. J. Am. Chem. Soc. 1986, 108, 6826–6828;
Crimmins, M. T.; OꢀMahony, R. J. Org. Chem. 1989, 54,
1157–1161; Journet, M.; Malacria, M. J. Org. Chem. 1992,
57, 3085–3093; Vandewalle, M. Synlett 1994, 228–230;
Jenkins, P. R.; Wood, A. J. Tetrahedron Lett. 1997, 38,
1853–1856; For the development of radical traps in
synthesis see: Keck, G. E.; Burnett, D. A. J. Org. Chem.
1987, 52, 2960, and references cited therein; See also:
Nagano, H.; Seko, Y.; Nakai, K. J. Chem. Soc., Perkin
Trans. 1 1991, 1291–1295; Bacque, E.; Pautrat, F.; Zard,
S. Z. Org. Lett. 2003, 5, 325–328.
functionalised for elaboration to the natural product.
These and other studies with highly functionalised 5-
ring carbocycles, are now underway in our laboratory.
Acknowledgements
We thank AstraZeneca for financial support (student-
ship to N.P.M.) and Dr. Iain Walters for his enthusiastic
interest in this project.
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