Tetraquinanes via [4 + 4] photocycloaddition/transannular ring closure

Article abstract of DOI:10.1021/ol101802s

Intramolecular [4 + 4] photocycloaddition of a furan and a cyclopentane-annulated 2-pyridone yields a cyclooctadiene product with four new stereogenic centers. Transannular ring closure produces the 5 - 5 - 5 - 5 fused ring system of the crinipellins, inc

Full text of DOI:10.1021/ol101802s

ORGANIC
LETTERS
2010
Vol. 12, No. 20
4510-4512
Tetraquinanes via [4 + 4]
Photocycloaddition/Transannular Ring
Closure
Peiling Chen,† Patrick J. Carroll,‡ and Scott McN. Sieburth*,†
Department of Chemistry, UniVersity of PennsylVania,
Philadelphia, PennsylVania 19104, and Department of Chemistry, Temple UniVersity,
1901 North 13th Street, Philadelphia, PennsylVania 19122
scott.sieburth@temple.edu
Received August 2, 2010
ABSTRACT
Intramolecular [4 + 4] photocycloaddition of a furan and a cyclopentane-annulated 2-pyridone yields a cyclooctadiene product with four new
stereogenic centers. Transannular ring closure produces the 5-5-5-5 fused ring system of the crinipellins, including three contiguous
quaternary carbons, with the correct absolute stereochemistry derived from (-)-carvone.
Among the many polyquinane natural products,1 the crin-
ipellins remain the only tetraquinane, incorporating both
linear and angularly fused triquinane substructures (Figure
1).2 This challenging synthetic target, with its eight stereo-
genic centers, three contiguous quaternary carbons, and
notable biological activity,3 has stimulated many approaches4
and two total syntheses of (()-crinipellin B 2.5 We describe
here completion of a model system that assembles the four
stereogenic centers and the three quaternary carbons of 1
with the correct absolute stereochemistry using a 2-pyridone/
furan [4 + 4] photocycloaddition followed by transannular
ring closure as the central synthetic strategy.6,7
† Temple University.
‡ University of Pennsylvania.
(1) Mehta, G.; Srikrishna, A. Chem. ReV. 1997, 97, 671–719. Singh,
V.; Thomas, B. Tetrahedron 1998, 54, 3647–3692.
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S.; Hashimoto, A.; Hamanaka, A.; Endo, A.; Hasumi, K. J. Antibiot. 2000,
53, 262–268.
Figure 1. Crinipellin A 1, B 2, and potential precursor 3.
(4) Mehta, G.; Rao, K. S. Chem. Commun. 1987, 157, 8–80. Mehta,
G.; Rao, K. S.; Reddy, M. S. Tetrahedron Lett. 1988, 29, 5025–8. Schwartz,
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A.; Sonoda, N.; Nagahara, K.; Ryu, I. J. Chem. Soc., Perkin Trans. 1998,
1, 1591–1593.
Pyridone 4 is a promiscuous partner in photo-[4 + 4]
cycloadditions, undergoing reactions with itself, 1,3-dienes,
(6) Transannular ring closure of cyclooctanoids to diquinanes can be
be effected in many ways. For lead references see: Ader, T. A.; Champey,
C. A.; Kuznetsova, L. V.; Li, T.; Lim, Y.-H.; Rucando, D.; Sieburth, S.
(5) Piers, E.; Renaud, J.; Rettig, S. J. Synthesis 1998, 590–602. Wender,
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McN. Org. Lett. 2001, 3, 2165–2167
.
10.1021/ol101802s  2010 American Chemical Society
Published on Web 09/21/2010

naphthalene and other heterocycles including furan.8,9 Studies
of 2-pyridone photodimerization as a route to cyclooctane-
containing natural products demonstrated that highly strained
photoproducts containing substructures 5 and 6 could be
prepared with stereocontrol, and that subsequent reactions
were also highly stereoselective.10 Two postphotocycload-
dition reactions are shown in Scheme 1. Trans dimer 5
Scheme 2. Preparation of the Photosubstrate and Cycloaddition
Scheme 1. Pyridone Photodimers, Their Halogenation
Reactions, and an Approach to the Tetraquinanes
Oxidation of the aldehyde and coupling with ethyl amine
gave 14. Double deprotonation of 14 gave the dienolate 15
which condensed with Weinreb amide 21 to yield ketone
16 which could be cyclized to the desired pyridone under
acidic conditions. Removal of the tert-butyldimethylsilyl
group then gave photosubstrate 17.
Two different selectivities are at play in the photocycload-
dition of 17. Irradiation of 17 gave a slow conversion to [4
+ 4] product 18. The isopropyl group was anticipated to
provide steric shielding of one face of the pyridone 17 (as
well as 9), augmented by the cis alcohol group, and led to
>90% facial selectivity for the furan approach.13 This
pyridone face selectivity was supplemented by cis/trans
selectivity engendered by the furan methyl group and its
potential interaction with the pyridone N-ethyl group,
disfavoring the pro-trans addition 20.14 These two interac-
tions yield cis isomer 18 via conformation 19. Notably, three
fully substituted carbons are formed in this cycloaddition
step as well as four stereogenic centers.
undergoes nitrogen migration when treated with chlorine,
while cis 6 undergoes transannular ring closure to diquinane
8.11 Amalgamation of these studies led to a synthetic plan
for the crinipellins, explored using ether 9. Conditions for
cis-selective photocycloaddition to give 10 were found (see
below); however, the key electrophilic reorganization step
to give 11 was frustrated by conversion of the cyclooctadiene
to a 4-6 ring system, among others (e.g., 23, Scheme 3),
instead of the anticipated 5-5 ring system.12
Reformulation of chlorination substrate 10 with an ad-
ditional carbonyl situated at C14 (crinipellin numbering) led
to 17 as the photosubstrate, Scheme 2. The role of this ketone
in 22, Scheme 3, was to forestall tertiary carbocation
generation at the adjacent carbon, preventing the undesired
formation of a 4-6 ring system over the desired 5-5
product. To introduce this ketone, preparation of the pho-
tosubstrate began with (-)-carvone 12, carrying the correct
absolute stereochemistry of the isopropenyl corresponding
to the C-12 isopropyl of target 1. Reduction of the isolated
alkene and the ketone gave the known cis-alcohol 13.
Protection of this alcohol followed by oxidative cleavage of
the alkene to the keto-aldehyde, and then piperidine-mediated
aldol condensation, formed the cyclopentene carboxaldehyde.
The expectation that C-14 ketone would inhibit formation
of the 6-4 ring system and compel formation of the desired
(10) (a) Sieburth, S. McN.; Chen, J.; Ravindran, K.; Chen, J.-l. J. Am.
Chem. Soc. 1996, 118, 10803–10810. (b) Sieburth, S. McN.; Lin, C.-H. J.
Org. Chem. 1994, 59, 3597–3599. (c) Sieburth, S. McN.; McGee, K. F.,
Jr.; Al-Tel, T. H. J. Am. Chem. Soc. 1998, 120, 587–588.
(11) Lim, Y.-H.; Li, T.; Chen, P.; Schreiber, P.; Kutnetsova, L.; Carroll,
P. J.; Lauher, J. W.; Sieburth, S. McN. Org. Lett. 2005, 7, 5413–5415, See
also reference6.
(12) Initial studies Chen, P.; Chen, Y.; Carroll, P. J.; Sieburth, S. McN.
Org. Lett. 2006, 8, 3367–3370.
(7) For a related, elegant approach to polyquinanes based on [4 + 4]
photocycloaddition of a 2-pyrone with a furan, see: Li, L.; McDonald, R.;
West, F. G. Org. Lett. 2008, 10, 3733–3736.
(13) In a closely related study of the effect of stereochemistry on
2-pyrone-furan [4 + 4]-photocycloaddition, with the opposite steric effect,
see: Song, D.; McDonald, R.; West, F. G. Org. Lett. 2006, 8, 4075–4078.
(14) For a recent discussion of cis-trans.stereoselectivity in 2-pyrone-
furan [4 + 4]-photocycloadditions, see: Li, L.; Chase, C. E.; West, F. G.
Chem. Commun. 2008, 4025–4027. Li, L.; Bender, J. A.; West, F. G.
Tetrahedron Lett. 2009, 50, 1188–1192.
(8) Sieburth, S. McN.; McGee, K. F., Jr.; Zhang, F.; Chen, Y. J. Org.
Chem. 2000, 65, 1972–1977.
(9) Sieburth, S. McN. in CRC Handbook of Organic Photochemistry
and Photobiology, (Eds: Horspool, W.; Lenci, F.), CRC Press, Boca Raton,
FL, 2004, pp103/1-103/18.
Org. Lett., Vol. 12, No. 20, 2010
4511

5-5 ring system was, however, overly optimistic. Treatment
of 22 with chlorine gave a 6-7 carbon ring system by
rearrangement of the 5-8 rings.12 In contrast, when 22 was
treated with bromine in pyridine, the 4-6 ring formation
was revisited, incorporating both halogen atoms for the first
time.15 A possible reaction path leading to 23 is shown in
Scheme 3, trapping the bromonium ion intermediate by the
enone dienol, 25.16 No trace of 24 was detected.
Scheme 4
.
Completion of the Tetraquinane Construction and
Crystal Structure of 30
Scheme 3
.
Bromination of Enone 22 Converts Cyclooctadiene
to a 4-6 Fused Ring System
It was clear that unsaturation at C-2 was the Achilles heel
of the proposed transannular cyclization, and an alternative
sequence was explored, Scheme 4. Epoxidation of the more
electron rich alkene gave 27. Hydrogenation of the interfering
enone alkene, followed by thermodynamic enolization of the
resulting ketone 28 in the presence of tert-butyldimethylsilyl
chloride gave enol ether 29 as the sole product.17 It was
anticipated that the epoxide and enol ether juxtaposition
would ensure formation of the long sought C-C bond and
two new quaternary carbons. In the event, treatment of 29
with titanium tetrachloride at -78 °C for ten minutes gave
tetraquinane 30 in near quantitative yield! The desired bond
construction and stereochemistry of 30 was confirmed by
X-ray crystallography, Scheme 4.18
diene with four new stereogenic centers. Five additional steps
are then used to set up and execute the transannular bond
construction that completes formation of four contiguous
five-membered rings. One of the natural product’s three
contiguous quaternary carbons is formed in the cycloaddition,
and the other two are formed during the transannular bond
formation, all with the correct absolute stereochemistry,
derived from (-)-carvone.
In this approach to the crinipellins, an intramolecular furan/
2-pyridone [4 + 4] photocycloaddition forms a cycloocta-
(15) Compound 23 crystallizes in the orthorhombic space group P212121,
with a)6.6549(5)Å, b)13.8696(11)Å, c)21.495(2)Å, V) 1984.0(3)Å3 and
Z)4. Solution using direct methods gave R1)0.0392 and wR2)0.0843.
See Supporting Information.
To adapt this chemistry to preparation of the natural
product 1, the central ether of 3a must be replaced with a
ketone, 3b. These studies are in progress.
(16) A reviewer has made the very reasonable suggestion that the
formation of 23 could also be explained by addition of a radical bromination
process.
Supporting Information Available: Experimental details,
characterization data, proton and carbon NMR spectra for
new compounds and crystal structure data. This material is
available free of charge via the Internet at http://pubs.acs.org.
(17) Brown, C. A. J. Org. Chem. 1974, 39, 1324–1325. Brown, C. A.
J. Org. Chem. 1974, 39, 3913–3918. Hudrlik, P. F.; Takacs, J. M. J. Org.
Chem. 1978, 43, 3861–3865.
(18) Compound 30 crystallizes in the orthorhombic space group P212121,
with a)7.4039(5)Å, b)13.4534(10)Å, c)17.6386(13)Å, V)1756.9(2)Å3
and Z)4. Solution using direct methods gave R1)0.0370 and wR2)0.0850.
See Supporting Information.
OL101802S
4512
Org. Lett., Vol. 12, No. 20, 2010