Medium-Sized Carbocycles and Ethers from 4-Pyrones: A Photocyclization-Fragmentation Approach

Full text of DOI:10.1021/jo980274t

2806
J . Org. Chem. 1998, 63, 2806-2807
Sch em e 1
Med iu m -Sized Ca r bocycles a n d Eth er s fr om
4-P yr on es: A P h otocycliza tion -
F r a gm en ta tion Ap p r oa ch 1
Clare M. Amann, Peter V. Fisher, Mark L. Pugh, and
F. G. West*
Department of Chemistry, University of Utah,
Salt Lake City, Utah 84112
Received February 18, 1998
Eight- and nine-membered rings are prominently featured
in many natural products. The well-known energetic penal-
ties incurred in direct closure of medium rings2 have
prompted the development of a number of novel approaches
to their formation by routes not involving direct ring
closure.3 Grob fragmentation has proven to be an effective
strategy for the formation of medium rings,4 but its applica-
tion can be limited by the necessary complexity of the bicyclic
precursor. We report here a concise approach to function-
alized medium-sized ethers and carbocycles utilizing an
efficient photocyclization of 4-pyrone derivatives followed by
reduction and fragmentation of the resulting adduct.
We have shown that readily available 4-pyrones bearing
pendant heteroatom or carbon nucleophiles undergo photo-
chemical conversion to reactive bicyclic oxyallyl zwitterions.
These intermediates are efficiently trapped by the internal
nucleophile to directly form diquinane, hydrindan, benzo-
hydrindene, oxabicyclo[3.3.0]octane, or oxabicyclo[4.3.0]-
nonane skeletons (eq 1).5 In all cases, the bicyclic photoad-
Substrates examined included bicyclic ethers 2a -c,
diquinanes 2d -e, and benzohydrindenone 2f, prepared in
good yield from the corresponding 4-pyrones 1a -f (Scheme
1). The necessary cyclopentane-1,3-diols 3a -f could be
obtained by catalytic hydrogenation followed by metal hy-
dride reduction of the resulting cyclopentanone or in some
cases via one-pot reduction with NaBH4 in hot EtOH.7 It
was difficult to prevent epimerization adjacent to the car-
bonyl during and after hydrogenation of 2b,8 and in this
case, the major (trans) diastereomer was carried on. For
ketone reduction in the preparation of 3f, LiAlH4 was found
to be preferable to NaBH4 due to slow reduction relative to
enolization.
Tosylation was generally preferable to mesylation in order
to better select for the secondary hydroxyl over the angular
hydroxyl. However, in some cases (e.g., 2d -f), tosylation
was prohibitively slow, necessitating use of the mesylate
(Scheme 2). After extensive experimentation using 3a , it
was determined that dimsylsodium in DMSO or KO-t-Bu
in t-BuOH were the most effective fragmentation conditions.
Unfortunately, the desired oxacyclononenone 4a was ac-
companied by comparable amounts of the simple elimination
product 5. Nevertheless, formation of some of the function-
alized nine-membered cyclic ether fragmentation product
was encouraging and, to our knowledge, unprecedented. We
reasoned that the fragmentation pathway might be en-
hanced by blocking elimination with an angular alkyl
substituent. In the event, substrate 3b gave the desired
ether 4b in good yield and in five steps overall from
hydroxypropyl-4-pyrone starting material 1b. Interestingly,
3c gave none of the corresponding eight-membered ether,
yielding instead acetylcyclohexanone 6 and bridged bicyclic
ketone 7 in varying amounts (vide infra). All-carbon sub-
strates 3d -f all underwent clean fragmentation to yield
cyclooctenone 4d , bicyclo[6.4.0]dodecenone 4e, and benzo-
duct contains an angular hydroxyl group in a 1,3-relationship
to the cyclopentenone carbonyl, providing a handle for
cleavage of the ring-fusing bond through a fragmentation
approach. Direct cleavage via the well-precedented retro-
aldol fragmentation6 was deemed unlikely in these cases,
since the ring strain inherent in the cyclopentenone would
not be sufficient to drive the equilibrium toward the medium
ring. On the other hand, an irreversible Grob-type frag-
mentation should be possible by reduction of the enone and
selective activation of the resulting secondary hydroxyl
group.
(1) Presented in preliminary form: West, F. G.; Amann, C.; Fisher, P.
V.; Pugh, M. Abstracts of Papers, 205th National Meeting of the American
Chemical Society, Denver, CO, March 1993; American Chemical Society:
Washington, DC, 1993; ORGN 249.
(2) Illuminati, G.; Mandolini, L. Acc. Chem. Res. 1981, 14, 95.
(3) (a) Oishi, T.; Ohtsuka, Y. In Studies in Natural Products Chemistry;
Atta-ur-Rahman, Ed.; Elsevier: Amsterdam, 1989; Vol. 3, pp 73-115. (b)
Petasis, N. A.; Patane, M. A. Tetrahedron 1992, 48, 5757. (c) Moody, C. J .;
Davies, M. J . In Studies in Natural Product Chemistry; Atta-ur-Rahman,
Ed.; Elsevier: Amsterdam, 1992; Vol. 10, pp 201-239.
(4) (a) Grob, C. A. Angew. Chem., Int. Ed. Engl. 1969, 8, 535. (b) Corey,
E. J .; Mitra, R. B.; Uda, H. J . Am. Chem. Soc. 1964, 86, 485. (c) Hesse, M.
Ring Enlargement in Organic Chemistry; VCH: Weinheim, 1991; pp 163-
177. (d) Weyerstahl, P.; Marschall, H. In Comprehensive Organic Synthesis;
Trost, B. M., Fleming, I., Eds., Pergamon: Oxford, 1991; Vol. 6, pp 1041-
1070. (e) Ho, T.-L. Heterolytic Fragmentation of Organic Molecules; Wiley:
New York, 1993.
(5) (a) West, F. G.; Fisher, P. V.; Willoughby, C. A. J . Org. Chem. 1990,
55, 5936. (b) West, F. G.; Fisher, P. V.; Arif, A. M. J . Am. Chem. Soc. 1993,
115, 1595. (c) West, F. G.; Willoughby, D. W. J . Org. Chem. 1993, 58, 3796.
(d) West, F. G.; Amann, C. M.; Fisher, P. V. Tetrahedron Lett. 1994, 35,
9653.
(7) Brown, H. C.; Hess, H. M. J . Org. Chem. 1969, 34, 2206.
(6) (a) de Mayo, P. Acc. Chem. Res. 1971, 4, 41. (b) Oppolzer, W. Acc.
Chem. Res. 1982, 15, 135. (c) Coates, R. M.; Muskopf, J . W.; Senter, P. A.
J . Org. Chem. 1985, 50, 3541.
(8) The tosylate derived from 3b was subjected to X-ray diffraction
analysis and the indicated stereochemistry confirmed: Amann, C. M.;
Fisher, P. V.; Pugh, M.; Arif, A. M.; West, F. G. Manuscript in preparation.
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Published on Web 04/08/1998

Communications
J . Org. Chem., Vol. 63, No. 9, 1998 2807
Sch em e 2
Sch em e 3
stereoselectivity seen in fragmentations of fused bicyclic
substrates.4 Although in each case three of the stereocenters
of the substrate are sacrificed in the stereoselective forma-
tion of the medium-ring olefin, other centers set during the
reduction of the double bond in 2b-f were preserved. The
disappointingly large amount of simple â-elimination seen
with 3a was surprising but could be rationalized in terms
of the stability of the double bond in bicyclic enol ether 5.11
The unexpected cyclohexanone product 6 is assumed to
result from desired fragmentation of 3c to give oxocenone
4c, followed by a retrograde Michael elimination of the enol
ether oxygen from the newly formed ketone (Scheme 3).
Recyclization by Michael addition of the resultant enolate
into the enone through carbon instead of oxygen would then
furnish 6, while subsequent intramolecular aldol condensa-
tion would lead to 7.12 Unfortunately, use of a deficiency of
base still resulted in formation of 6 and 7, along with
incomplete consumption of 3c, while the MsCl/pyridine
protocol used with 3d ,e did not effect fragmentation at all.
Thus, at present it appears that eight-membered enol ethers
may not be accessible via this route.
cyclononadienone 4f. Diquinane triols 3d ,e were found to
undergo clean, in situ fragmentation when stirred with MsCl
in hot pyridine.9 Thus, functionalized cyclooctenones 4d ,e
are efficiently obtained in three steps from the simple
4-pyrone precursors 1d ,e. We believe this will serve as
powerful methodology in the synthesis of cyclooctanoid
targets.10
In summary, we have reported a short and efficient
approach to medium-sized ethers or carbocycles by using a
combination of 4-pyrone photocyclizations and Grob frag-
mentations. The substrates are easily prepared, and the
fragmentation proceeds in most cases in good yield. Ap-
plication of this methodology to the synthesis of medium-
ring-containing natural products is under active investiga-
tion and will be reported in due course.
In all cases, the Z stereochemistry shown for the double
bonds was assumed by analogy to the well-precedented
(9) (a) A two-step procedure analogous to that used for 3f could also be
used, but was found inferior to the direct, one-pot protocol. (b) For an earlier
report of a strain-driven in situ fragmentation mediated by MsCl/pyridine,
see: Ikeda, M.; Ohno, K.; Takahashi, M.; Homma, K.; Uchino, T.; Tamura,
Y. Heterocycles 1983, 20, 1005.
(10) Fragmentation approaches have been elegantly applied to construc-
tion of the B-ring of the taxanes: (a) Nagaoka, H.; Ohsawa, K.; Takata, T.;
Yamada, Y. Tetrahedron Lett. 1984, 25, 5389. (b) Holton, R. A.; J uo, R. R.;
Kim, H. B.; Williams, A. D.; Harusawa, S.; Lowenthal, R. E.; Yogai, S. J .
Am. Chem. Soc. 1988, 110, 6558. (c) Wender, P. A.; Mucciaro, T. P. J . Am.
Chem. Soc. 1992, 114, 5878. (d) Holton, R. A.; Somoza, C.; Kim, H.-B.; Liang,
F.; Biediger, R. J .; Boatman, P. D.; Shindo, M.; Smith, C. C.; Kim, S.;
Nadizadeh, H.; Suzuki, Y.; Tao, C.; Vu, P.; Tang, S.; Zhang, P.; Murthi, K.
K.; Gentile, L. N.; Liu, J . J . Am. Chem. Soc. 1994, 116, 1597. (e) Wender,
P. A.; Badham, N. F.; Conway, S. P.; Floreancig, P. E.; Glass, T. E.;
Gra¨nicher, C.; Houze, J . B.; J a¨nichen, J .; Lee, D.; Marquess, D. G.; McGrane,
P. L.; Meng, W.; Mucciaro, T. P.; Mu¨hlebach, M.; Natchus, M. G.; Paulsen,
H.; Rawlins, D. B.; Satkofsky, J .; Shuker, A. J .; Sutton, J . C.; Taylor, R. E.;
Tomooka, K. J . Am. Chem. Soc. 1997, 119, 2755.
Ack n ow led gm en t. We thank the National Institutes
of Health for their generous support of this research (GM-
44720), the American Cancer Society for a J unior Faculty
Research Award (F.G.W.), Eli Lilly for a Granteeship
(F.G.W.), and the University of Utah for a University
Research Fellowship (P.V.F.) and a Henry Eyring Research
Fellowship (M.P.).
Su p p or tin g In for m a tion Ava ila ble: Experimental proce-
dures and physical data for 3a -f, 4a ,b,d -f and 5-7 and NMR
spectra for 3a ,d ,f, 4a ,b,d -f, and 5-7 (21 pages).
(11) Rhoads, S. J .; Waali, E. E. J . Org. Chem. 1970, 35, 3358.
(12) Upon subjection to reaction conditions, pure 6 was converted to a
mixture of 6 and 7. The relative stereochemistry of these unexpected
products was not determined.
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