Strained polycycles by H5C5x free-radical cascades

Article abstract of DOI:10.1021/ol060231w

An H⁵C^5x-type free-radical chain reaction selectively generates up to three new bonds and three new stereocenters in one pot. This previously unexploited strategy provides a straightforward route to the tricyclic cyclopenta[c]indene

Full text of DOI:10.1021/ol060231w

ORGANIC
LETTERS
Strained Polycycles by H5C5x
Free-Radical Cascades†
2006
Vol. 8, No. 6
1249-1251
Edelmiro Moman, Daniel Nicoletti, and Antonio Mourin˜o*
Departamento de Qu´ımica Orga´nica y Unidad Asociada al CSIC, UniVersidad de
Santiago de Compostela, E-15782 Santiago de Compostela, Spain
qomourin@usc.es
Received January 26, 2006
ABSTRACT
An H5C5x-type free-radical chain reaction selectively generates up to three new bonds and three new stereocenters in one pot. This previously
unexploited strategy provides a straightforward route to the tricyclic cyclopenta[c]indene skeleton, present in a wide range of pharmacologically
active natural products, and can significantly simplify the synthesis of other strained polycyclic structures by sidestepping protection,
deprotection, and functional group interconversion steps.
Remarkable examples of complex asymmetric structures
accessed by radical chain reactions have been reported in
the last two decades,1,2 and free-radical processes are
increasingly considered as late-stage strategies in total
syntheses. More particularly, the activation of C-H bonds
via intramolecular hydrogen abstraction by alkoxy radicals
has found important synthetic applications in the formation
of the tetrahydrofuran core and in the functionalization of
numerous natural products with oxygen, nitrogen, halogen,
and sulfur.3-6
situ formation of new carbocycles at nonactivated carbons
would considerably simplify the preparation of such com-
pounds by reducing the number of functional group inter-
conversion steps. To our surprise, we found that the
intramolecular addition of free radicals generated in situ at
nonactivated carbons7 to olefins has scarcely been investi-
gated. Indeed, what appears to have been the only systematic
study of such processes was reported by Cˇ ekovic´ in a brief
communication8 on the photolysis of nitrites and hypochlo-
rites derived from 8-nonenol and 9-decenol. We, therefore,
decided to explore the synthetic scope of this reaction.
As a start, we decided to test the hypothesis that 1 might
be accessible from 3 (Scheme 1) through a one-pot process
involving the formation of an alkoxy radical at C89 followed
In the course of our work, in the synthesis of strained
polycyclic vitamin D analogues, it occurred to us that the in
† Dedicated to Professors J. Castells and J. Elguero.
(1) (a) Dhimane, A. L.; Aissa, C.; Malacria, M. Angew. Chem., Int. Ed.
2002, 41, 3284-3287. (b) Aubert, C.; Courillon, C.; Dhimane, A. L.;
Fensterbank, L.; Lacote, E.; Thorimbert, S.; Malacria, M. Curr. Opin. Drug
DiscoV. DeV. 2002, 5, 928-936. (c) Zard, S. Z. Radicals Reactions in
Organic Synthesis; Oxford University Press: New York, 2003. (d)
Pattenden, G.; Gonzalez, M. A.; McCulloch, S.; Walter, A.; Woodhead, S.
J. Proc. Natl. Acad. Sci. 2004, 101, 12024-12029.
(4) (a) Barton, D. H. R.; Beaton, J. M.; Geller, L. E.; Pechet, M. M. J.
Am. Chem. Soc. 1960, 82, 2640-2641. (b) Hartung, J.; Gottwald, T.; CÄ pehar,
K. Synthesis 2002, 11, 1469-1498.
(5) Feray, L.; Kuznetsov, N.; Renaud, P. In Radicals in Organic
Synthesis; Renaud, P., Sibi, M. P., Eds.; Wiley-VCH: Weinheim, 2001;
pp 246-254.
(2) (a) Curran, D. P. Synthesis 1988, 417-439. (b) Jarperse, C. P.; Curran,
D. P.; Fevig, T. L. Chem. ReV. 1991, 91, 1237-1286. (c) Beckwith, A. L.
J. Chem. Soc. ReV. 1993, 22, 143-151. (d) Giese, B. In Radicals in Organic
Synthesis; Renaud, P., Sibi, M. P., Eds.; Wiley-VCH: Weinheim, 2001;
pp 381-399.
(6) (a) Cˇ ekovic´, Zˇ. Tetrahedron 2003, 59, 8073-8090. (b) Cˇ ekovic´, Zˇ.
J. Serb. Chem. Soc. 2005, 70, 287-318.
(7) (a) Majetich, G. Tetrahedron 1995, 51, 7095-7129. (b) Reese, P.
B. Steroids 2001, 66, 481-497. (c) Pellissier, H.; Santelli, M. Org. Prep.
Proced. Int. 2001, 33, 455-476.
(3) ActiVation and Functionalization of C-H Bonds; Goldberg, K. I.,
Goldman, A. S., Eds.; Oxford University Press: New York, 2004.
(8) Cˇ ekovic´, Zˇ.; Ilijev, D. Tetrahedron Lett. 1988, 29, 1441-1444.
10.1021/ol060231w CCC: $33.50
© 2006 American Chemical Society
Published on Web 02/21/2006

use of approximately stoichiometric quantities of reagents
afforded equimolecular mixtures of 2a and the tricyclic
alcohol 1a (Scheme 2, entry 2). Ultrasound14 was an efficient
substitute for irradiation (Scheme 2, entry 3). The intermedi-
ate iodide 2b was also isolated, as a 62:38 mixture of C23
epimers.15 Remarkably, the hypoiodite reaction thus provides
up to three new bonds and three stereogenic centers.
The stereochemistry of 1a at C22, elucidated by NOE 1H
NMR experiments on the corresponding C8-OTBDMS
derivative (see Supporting Information), is as predicted by
molecular mechanics conformational analysis of 3a and
complies with that observed for 4-substituted hexenyl
radicals.16 Compound 1a would follow by abstraction of
hydrogen from the solvent by the new carbon radical C.
We next reasoned that using a Barton-type4a strategy to
generate the alkoxy radical would preclude the initiation of
a second radical cascade from 1 and therefore the formation
of compounds of type 2 (Scheme 1). Thus, homolytic
cleavage of 4-nitrophenylsulfenate17,18 3b in cyclohexane at
room temperature yielded the desired tricyclic alcohol 1a
and thioether 1b along with ketone 4a, which can be easily
converted to the starting alcohol (Scheme 3, entry 1).19
Reduction of isolated 1b with Raney nickel provided the
tricyclic alcohol 1a in 95% yield. More conveniently, direct
reduction of the reaction mixture 1a + 1b + 4a under the
same conditions gave a mixture of alcohol 1a and ketone
4a (entry 2). The use of benzene as cosolvent favored the
formation of 4a (entry 3). Irradiation of 3c produced only
thioether 1d and ketone 4b (entry 4), but direct reduction of
the reaction mixture afforded only 1c and 4b (entry 5).
Irradiation of 3d followed by reduction of the reaction
mixture yielded sulfone 1e (entry 6), which can be further
manipulated by R-carbanion chemistry.
Scheme 1. Proposed Mechanism of the H5C5x Radical
Cascadea
a WG ) electron-withdrawing group (CO2Et, CN, SO2Ph). X )
H, I, 4-nitrophenylsulfenyl.
by an H5C5x radical cascade10 consisting of abstraction of a
C18 hydrogen and intramolecular addition of the resulting
radical to an electron-deficient double or triple bond.11 To
this end, Michael acceptors 3 were prepared from vitamin
D2, which required three steps and no protecting groups (see
Supporting Information).
Irradiation of alcohol 3a with a 300 W tungsten lamp under
Sua´rez’s12 hypoiodite13 conditions afforded unstable dia-
stereomeric R-iodoesters that were immediately reduced with
Zn in HOAc (Scheme 2). When more than 2 equiv of
Scheme 2. Irradiation of 3a under the Hypoiodite Conditionsa
Irradiation of 3e,20 in which the unsaturation is a triple
bond, produced the expected mixture of (E)- and (Z)-R,â-
unsaturated esters 1g along with ketone 4d (Scheme 4). The
(10) (a) McCarroll, A. J.; Walton, J. C. Angew. Chem., Int. Ed. 2001,
40, 2224-2248. (b) McCarroll, A. J.; Walton, J. C. J. Chem. Soc., Perkin
Trans. 1 2001, 3215-3229.
(11) Zhang, W. Tetrahedron 2001, 57, 7237-7262.
(12) de Armas, P.; Concepcio´n, J. I.; Francisco, C. G.; Herna´ndez, R.;
Salazar, J. A.; Sua´rez, E. J. Chem. Soc., Perkin Trans. 1 1989, 405-411.
(13) (a) Heusler, K.; Kalvoda, J. Angew. Chem., Int. Ed. 1964, 3, 525-
538. (b) Kalvoda, J.; Heusler, K. Synthesis 1971, 501-526.
(14) Costa, S. C. P.; Miranda, M. J. S.; Sa´ e Melo, M. L.; Campos, A.
S. Tetrahedron Lett. 1999, 40, 8711-8714.
(15) Typical procedure for the hypoiodite-type reaction: 2a; DIB (0.36
g, 1.12 mmol) and I2 (0.24 g, 0.95 mmol) were added to deoxygenated 9:1
cyclohexane/benzene (50 mL). A solution of ester 3a (0.1 g, 0.36 mmol)
in CyH (5 mL) was added. The reaction mixture was irradiated with a 500
W lamp for 130 min and concentrated to dryness. Zn powder (1.6 g, 24.47
mmol) was added to a solution of the residue in HOAc (30 mL), and this
mixture was stirred for 16 h.
a WG ) CO2Et.
(16) (a) Beckwith, A. L. J.; Schiesser, C. H. Tetrahedron Lett. 1985,
26, 373-376. (b) Beckwith, A. L. J.; Schiesser, C. H. Tetrahedron 1985,
41, 3925-3941. (c) Spellmeyer, D. C.; Houk, K. N. J. Org. Chem. 1987,
52, 959-974. (d) Beckwith, A. L. J.; Zimmermann, J. J. Org. Chem. 1991,
56, 5791-5796.
diacetoxyiodobenzene (DIB) and I2 were employed, the
cyclic ether 2a was obtained in 81% yield (Scheme 2, entry
1), presumably because of a second radical cascade initiated
from the alkyl hypoiodite derivative of 1 (Scheme 1). The
(17) Hartung, J. Eur. J. Org. Chem. 2001, 619-632.
(18) Pasto, J.; Cottard, F. Tetrahedron Lett. 1994, 35, 4303-4306.
(19) Refluxing in toluene also promotes the reaction (data not shown).
(20) Typical procedure for the Barton-type reaction: 1a; a solution of
sulfenate 3b (0.200 g, 0.46 mmol) in CyH (60 mL) was irradiated with a
300 W tungsten lamp for 60 min. After concentration, nickel Raney W-2
(0.5 g, 8.5 mmol, Fluka) was added to a solution of the residue (0.2 g) in
anhydrous ethyl alcohol (20 mL), and this mixture was refluxed for 1 h.
(9) To facilitate structural comparison, IUPAC-IUB steroid numbering
is used: (a) Pure Appl. Chem. 1989, 61, 1783-1822. (b) Eur. J. Biochem.
1989, 186, 429-458. (c) Eur. J. Biochem. 1993, 213, 2.
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Org. Lett., Vol. 8, No. 6, 2006

Scheme 3. Irradiation of p-Nitrophenylsulfenates 3b-da
a ArS ) 4-nitrophenylsulfenyl.
configuration of the C22 double bond in (Z)-1g and (E)-1g
was established by 1D DPFGSE-NOESY analysis of the pure
isomers (see Supporting Information). No cross-coupled
thioether products were observed, presumably because the
vinylic radicals C (Scheme 1) capture a hydrogen radical
from the solvent. Hydrogenation of the mixture (Z/E)-1g to
alcohol 1a was achieved with a variety of catalysts. Remark-
ably, irradiation of 3e followed by hydrogenation of the
reaction products provided alcohol 1a in 80% yield.
In conclusion, these results show that the H5C5x-type
radical cascade is a predictable and synthetically useful
process. In this work, it provided a straightforward route to
the tricyclic cyclopenta[c]indene skeleton,21 which is present
in a wide range of pharmacologically active natural products
as well as in a novel family of vitamin D3 analogues.22
Scheme 4. Irradiation of 3ea
Acknowledgment. This work was supported by the
Spanish DIGICYT (Projects SAF-2001-3187 and SAF-2004-
1885). We thank Solvay Pharmaceuticals BV (Weesp, The
Netherlands) for the gift of vitamin D2. D.N. thanks the
Argentinian National Council for Scientific Research
(CONICET) for a postdoctoral fellowship.
Supporting Information Available: Detailed experi-
1
mental procedures, characterization data, and copies of H
and 13C spectra. This material is available free of charge via
the Internet at http://pubs.acs.org.
OL060231W
(21) Pennigton, L. D.; Overman, L. E. J. Org. Chem. 2003, 68, 7143-
7157.
(22) Varela, C.; Nilsson, K.; Torneiro, M.; Mourin˜o, A. HelV. Chim.
Acta 2002, 85, 3251-3261.
a WG ) CO2Et.
Org. Lett., Vol. 8, No. 6, 2006
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