A concise synthesis of the functionalised cyclopentane unit in the antitumoural antibiotic viridenomycin

Article abstract of DOI:10.1016/j.tetlet.2005.01.070

A concise seven-step synthesis of the cyclopentane unit in viridenomycin, which uses a regio- and stereo-selective rhodium catalysed intramolecular C-H insertion reaction as the key step, is described.

Full text of DOI:10.1016/j.tetlet.2005.01.070

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 1913–1915
A concise synthesis of the functionalised cyclopentane unit in
the antitumoural antibiotic viridenomycin
Gerald Pattenden,* Alexander J. Blake and Louis Constandinos
School of Chemistry, The University of Nottingham, Nottingham NG7 2RD, UK
Received 20 December 2004; accepted 14 January 2005
Abstract—A concise seven-step synthesis of the cyclopentane unit in viridenomycin, which uses a regio- and stereo-selective rhodium
catalysed intramolecular C–H insertion reaction as the key step, is described.
ꢀ 2005 Elsevier Ltd. All rights reserved.
The polyene macrolactam viridenomycin 1 isolated from
the culture broth of the actinomycetes Streptomyces
gannmycicus and S. viridochromogenes is an interesting
antitumoural antibiotic substance which prolongs the
life of mice with B16 melanoma.1 The compound is re-
lated structurally to the macrolactam hitachimycin,2
and several oxygenated cyclopentanes have been iso-
lated from microorganisms including pentenomycins,3
methylenomycins,4 sarkomycin5 and terrein.6 It is likely
that these antibiotic antitumoural compounds share a
common biosynthetic origin involving cyclisations of
modified poly b-ketide precursors,7 in some instances
with ring contraction of 6-ring (aromatic/quinonoid)
intermediates.8 Our interest in the synthesis of, and bio-
genetic interrelationships between, families of, naturally
occurring cyclopentanes has attracted us to the synthesis
of viridenomycin 1. Already Arrington and Meyers,9
Ishihara et al.10 and Trost and Jiang,11 have described
their approaches to the synthesis of the unusually substi-
tuted cyclopentane ring system 2 in viridenomycin. In
this paper we describe a concise seven-step synthesis
of the cyclopentane unit 2 which uses the ubiquitous
Ph
O
HO
NH
O
O
MeO
HO
1
O
HO
N2
CO2Et
CO2Et
MeO
MeO
RO
RO
3
2
Keywords: Viridenomycin; Intramolecular C–H insertion; Diazo ester.
*
Corresponding author. Tel.: +44 115 951 3530; fax: +44 115 951 3535; e-mail: gerald.pattenden@nottingham.ac.uk
0040-4039/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.01.070

1914
G. Pattenden et al. / Tetrahedron Letters 46 (2005) 1913–1915
O
χc
O
χc
H
O
ii - iv
O
MeO
MeO
MeO
i
TBSO
HO
4
6
5
HO
O
CO2Et
CO2Et
v
vi
vii
3
MeO
MeO
TBSO
R = TBS
TBSO
8
7
MeO
HO
O
CO2Et
viii, ix
N
MeO
χc
=
O
Bn
9
Scheme 1. Reagents and conditions: (i) n-Bu2BOTf, Et3N, PhMe, À50 ꢁC, 89%; (ii) TBSOTf, 2,6-lutidine, DCM, 0 ꢁC, 80%; (iii) LiBH4 THF, 0 ꢁC–
rt, N2, then H2O; (iv) (COCl)2, DMSO, DCM, À78 ꢁC, then Et3N and H2O; (v) SnCl2, EtO2CCHN2, DCM, rt, 89% over three steps;
(vi) p-acetamidobenzenesulfonylazide (p-ABSA), 84%; (vii) 5 mol% Rh2(OAc)4, DCM, reflux, 62%; (viii) Me2SO4, NaH, THF, 84%; (ix) TBAF,
THF, 89%.
rhodium-mediated intramolecular C–H insertion, from
the diazo ester 3, as the key reaction12,13 (see Scheme 1).
treatment with p-acetamidobenzenesulfonyl azide and
Et3N.17 When the diazo b-keto ester 3 (R = TBS) was
heated under reflux in DCM in the presence of
Rh2(OAc)4 (5 mol%) it underwent a smooth intramo-
lecular C–H insertion reaction with retention of the
absolute configuration18 and gave the substituted
cyclopentane 8 in a satisfying 62% yield. The stereo-
chemistry of 8 was confirmed following methylation to
the corresponding methyl ether and deprotection of
the TBS group which gave the cyclopentanol 9 as col-
ourless crystals. The X-ray crystal structure of 9 is
shown in Figure 1.19 Our efforts are now being directed
towards a total synthesis of viridenomycin and similar
highly funtionalised cyclopentane-based macrolactams.
Thus, a diastereoselective syn-aldol reaction between the
Evans substrate 414 and S-2-methylpent-4-enal15 in the
presence of n-Bu2BOTf at À50 ꢁC first led to the inter-
mediate 5 in 89% yield. After protection of the sec-OH
group in 5 as its TBS ether, sequential reduction and
oxidation next led to the a-methoxyaldehyde 6. Treat-
16
ment of 6 with ethyl diazoacetate–SnCl2 then gave
the substituted b-keto ester 7, which was smoothly con-
verted into the corresponding diazo species 3 following
Acknowledgements
We thank AstraZeneca for support, especially for the
purchase of chemicals used in this study.
References and notes
1. Hasegawa, T.; Kamiya, T.; Henmi, T.; Iwasaki, H.;
Yamatodani, S. J. Antibiot. 1975, 28, 167–175; Nakagawa,
M.; Furihata, K.; Hayakawa, Y.; Seto, H. Tetrahedron
Lett. 1991, 32, 659–662.
2. Omura, S.; Nakagawa, A.; Shibata, K.; Sano, H. Tetra-
hedron Lett. 1982, 23, 4713–4716.
3. Umino, K.; Furumai, T.; Matsuzawa, N.; Awataguchi, Y.;
Ito, Y.; Okuda, T. J. Antibiot. 1973, 26, 506–512.
4. Haneishi, T.; Kitahara, N.; Takiguchi, Y.; Arai, M.;
Sugawara, S. J. Antibiot. 1974, 27, 386–392.
Figure 1. X-ray Structure of the cyclopentanol 9.

G. Pattenden et al. / Tetrahedron Letters 46 (2005) 1913–1915
1915
5. Umezawa, H.; Yamamoto, T.; Takeuchi, T.; Osato, T.;
Okami, Y.; Yamaoka, S.; Okuda, T.; Nitta, K.; Yagishita,
K.; Utahara, R.; Umezawa, S. Antibiot. Chemother. 1954,
4, 514–520.
6. Dunn, A. W.; Entwistle, I. D.; Johnstone, R. A. W.
Phytochemistry 1975, 14, 2081–2082; Barton, D. H. R.;
Miller, E. J. Chem. Soc. 1955, 1028–1029.
14. Chakraborty, T. K.; Suresh, V. R. Tetrahedron Lett. 1998,
39, 7775–7778.
15. Ishibashi, M.; Kobayashi, J. Heterocycles 1997, 44, 543–572.
16. Holmquist, C. R.; Roskamp, E. J. J. Org. Chem. 1989, 54,
3258–3260.
17. Baum, J. S.; Shook, D. A.; Davies, H. M. L.; Smith, H. D.
Synth. Commun. 1987, 17, 1709–1716.
7. Cf. Hill, R. A.; Carter, R. H.; Staunton, J. J. Chem Soc.,
Perkin Trans. 1 1981, 2570–2576.
8. See for example: Birch, A. J.; Elliott, P. Aust. J. Chem.
1956, 9, 95–104; Liu, S.-Y.; Ogihara, Y. J. Pharm. Soc.
Jpn. 1975, 95, 1114–1118; Lee, H. H.; Tan, C. H. J. Chem.
Soc. C 1967, 1583–1585, and also Ref. 7.
9. Arrington, M. P.; Meyers, A. I. Chem. Commun. 1999,
1371–1372.
10. Ishihara, J.; Hagihara, K.; Chiba, H.; Ito, K.; Yanagis-
awa, Y.; Totani, K.; Tadano, K. Tetrahedron Lett. 2000,
41, 1771–1774.
18. Kaneno, D.; Tomoda, S. Org. Lett. 2003, 5, 2947–2949;
Taber, D. F.; You, K. K.; Rheingold, A. L. J. Am. Chem.
Soc. 1996, 118, 547–556; Taber, D. F.; Ruckle, R. E., Jr.
Tetrahedron Lett. 1985, 26, 3059–3062; Taber, D. F.;
Petty, E. H.; Raman, K. J. Am. Chem. Soc. 1985, 107,
196–199; Taber, D. F.; Ruckle, R. E., Jr. J. Am. Chem.
Soc. 1986, 108, 7686–7693.
19. A colourless tabular crystal of 9 (0.31 · 0.15 · 0.04mm 3)
was encapsulated in a film of silicone grease and mounted
on a dual-stage glass fibre before transfer to the diffrac-
tometer.
11. Trost, B. M.; Jiang, C. H. Org. Lett. 2003, 5, 1563–1
565.
Crystal data: C14H22O5, M = 270.32, monoclinic,
˚
a = 7.5506 (13), b = 8.2729 (14), c = 12.416 (2) A,
3
b = 104.423(3)O, U = 751.1(4) A , T = 150(2) K, space
˚
12. Adams, J.; Spero, D. M. Tetrahedron 1991, 47, 1765–1808;
Taber, D. F.; Stiriba, S. E. Chem. Eur. J. 1998, 4, 990–992;
Taber, D. F.; Petty, E. H. J. Org. Chem. 1982, 47, 4808–
4809; Doyle, M. P.; Forbes, D. C. Chem. Rev. 1998, 98,
911–935; Doyle, M. P. Chem. Rev. 1986, 86, 919–939;
Davies, H. M. L.; Beckwith, R. E. J. Chem. Rev. 2003,
103, 2861–2903; Ye, T.; Mckervey, M. A. Chem.Rev. 1994,
94, 1091–1160.
13. For an alternative synthesis of the cyclopentane unit in
viridenomycin from our laboratory see: Mulholland, N.
P.; Pattenden, G. Tetrahedron Lett. 2005, 46, 937–
939.
group P 21 (No. 4), Z = 2, Dc = 1.195 gcmÀ3, l(Mo-
Ka) = 0.090 mmÀ1, 1835 unique reflections measured and
used in all calculations. Final R1 [1606 F > 4r(F)] = 0.0475
and wR [all F2] was 0.104. Crystallographic data (exclud-
ing structure factors) for the structures in this paper have
been deposited with the Cambridge Crystallographic Data
Centre as supplementary publication number CCDC
261952. Copies of the data can be obtained, free of
charge, on application to CCDC, 12 Union Road,
Cambridge, CB2 1EZ, UK [fax: +44(0)-1223-336033 or
e-mail: deposit@ccdc.cam.ac.uk].