Diastereoselective [4 + 4]-photocycloaddition reactions of pyran-2-ones: Rapid access to functionalized 5-8-5 skeletons

Article abstract of DOI:10.1021/ol061576h

Fused bicyclic pyran-2-ones with pendant furan side chains and an oxygenated stereogenic center adjacent to the pyranone ring oxygen were prepared via FeCl₃-catalyzed Michael addition. Irradiation furnished the corresponding lactone-bridged tri

Full text of DOI:10.1021/ol061576h

ORGANIC
LETTERS
2006
Vol. 8, No. 18
4075-4078
Diastereoselective
[4 4]-Photocycloaddition Reactions of
Pyran-2-ones: Rapid Access to
Functionalized 5 5 Skeletons
+
−8−
Dong Song, Robert McDonald,† and F. G. West*
Department of Chemistry, UniVersity of Alberta, Edmonton, AB, Canada T6G 2G2
frederick.west@ualberta.ca
Received June 27, 2006
ABSTRACT
Fused bicyclic pyran-2-ones with pendant furan side chains and an oxygenated stereogenic center adjacent to the pyranone ring oxygen were
prepared via FeCl3-catalyzed Michael addition. Irradiation furnished the corresponding lactone-bridged tricyclic [4 4]-cycloadducts with
good facial selectivity. Surprisingly, the major isomer resulted from approach of the furan from the same face as the protected alcohol.
+
Cyclooctane rings are found in a wide variety of biologically
significant and structurally complex natural products. The
well-documented challenges associated with formation of
eight-membered rings1 have prompted the development of
a number of elegant strategies toward this ring system.2
Cycloaddition approaches have attracted considerable atten-
tion since they furnish the target structure in a highly
convergent fashion from relatively simple, unsaturated
precursors. Several important transition-metal-catalyzed meth-
ods have been described, including Ni-mediated 4 + 4
cycloaddition of 1,3-dienes3 and rhodium-catalyzed three-
component coupling processes.4 Concerted [4 + 3]-cycload-
ditions of cyclopentenyl cations and 1,2-dienes function as
formal [4 + 4]-cycloadditions, providing keto-bridged cy-
clooctenes5 whose one-carbon bridge can then be syntheti-
cally modified en route to various cyclooctane-containing
structures.6 Photochemical [4 + 4]-cycloadditions have also
proven to be effective in assembling cyclooctanoids.7 In this
regard, we have previously examined the crossed [4 +
(3) (a) Wender, P. A.; Nuss, J. M.; Smith, D. B.; Sua´rez-Sobrino, A.;
Vågberg, J.; Decosta, D.; Bordner, J. J. Org. Chem. 1997, 62, 4908-4909.
For other recent examples of transition metal mediated 4 + 4 processes,
see: (b) Murakami, M.; Itami, K.; Ito, Y. Synlett 1999, 951-953. (c)
Takahashi, T.; Sun, W.-H.; Liu, Y.; Nakajima, K.; Kotora, M. Organome-
tallics 1998, 17, 3841-3843.
(4) (a) Wender, P. A.; Gamber, G. G.; Williams, T. J. In Modern
Rhodium-Catalyzed Organic Reactions; Evans, P. A., Ed.; Wiley-VCH:
Weinheim, 2005; 263-299. (b) Evans, P. A.; Robinson, J. E.; Baum, E.
W.; Razal, A. N. J. Am. Chem. Soc. 2002, 124, 8782-8783. (c) Gilbertson,
S. R.; DeBoef, B. J. Am. Chem. Soc. 2002, 124, 8784-8785.
(5) (a) West, F. G.; Hartke-Karger, C.; Koch, D. J.; Kuehn, C. E.; Arif,
A. M. J. Org. Chem. 1993, 58, 6795-6803. (b) Harmata, M.; Elahmad, S.;
Barnes, C. L. J. Org. Chem. 1994, 59, 1241-1242. (c) Cha, J. K.; Jin,
S.-J.; Choi, J.-R.; Oh, J.; Lee, D. J. Am. Chem. Soc. 1995, 117, 10914-
10921. (d) Wang, Y.; Arif, A. M.; West, F. G. J. Am. Chem. Soc. 1999,
121, 876-877. (e) Wang, Y.; Schill, B. D.; Arif, A. M.; West, F. G. Org.
Lett. 2003, 5, 2747-2750.
† X-ray Crystallography Laboratory, Department of Chemistry, University
of Alberta.
(1) Illuminati, G.; Mandolini, L. Acc. Chem. Res. 1981, 14, 95-102.
(2) Review: Mehta, G.; Singh, V. Chem. ReV. 1999, 99, 881-930.
(6) Harmata, M.; Rashatasakhon, P. Org. Lett. 2000, 2, 2913-2915.
10.1021/ol061576h CCC: $33.50
© 2006 American Chemical Society
Published on Web 08/11/2006

4]-photocycloaddition reactions of pyran-2-ones with pendant
furan traps.8,9 We were especially interested in the use of
this methodology to the construction of tricyclic intermediates
suitable for use in the synthesis of various members of the
fusicoccin family of diterpenoid fungal products,10 including
traversianal11 (Scheme 1). Here, we describe its successful
Scheme 2
Scheme 1
application in a concise stereocontrolled route to function-
alized 5-8-5 tricyclic skeletons in which the key step
proceeds with remarkable selectivity in favor of approach
by the furan trap from the sterically more demanding face
of the bicyclic pyran-2-one.
The synthetic plan called for a fused bicyclic pyran-2-
one such as 1, in which the cyclopentene stereogenic center
at the carbon corresponding to C-512 would control the
approach of the furan in the cycloaddition to give 2. The
bridging lactone would serve as a precursor to the cis-
disposed angular hydroxyl at C-6 and the methyl at C-11,
while the stereochemical control element at C-5 would be
oxidized to the necessary ketone. Hydrogenation of the
cyclooctadiene would also be required, with selective
delivery to the C-1/C-2 alkene from the top face. A protected
ketone in the 3-carbon tether could provide a suitable handle
for reductive opening of the furan bridge, as well as
introduction of the isopropenyl group at C-14. The question
of endo vs exo diastereomers in the [4 + 4]-cycloaddition
could be ignored, since C-7 would become an sp2 center and
C-10 would be subject to epimerization during reductive
cleavage of the bridging ether.13 Thus, initial efforts focused
on the efficient preparation of compound 1.
We previously prepared a similar substrate via Pd(0)-
catalyzed allylation of a bicyclic hydroxypyrone.8b However,
incorporation of the C-5 alcohol and C-14 ketal required a
modified route (Scheme 2). 2-Silyloxycyclopentanone 3 was
prepared via dihydroxylation of trimethylsilyloxycyclopen-
tene followed by protection of the secondary alcohol, and
then converted to silyl enol ether 4. To evaluate the feasibility
(7) Reviews: (a) West, F. G. In AdVances in Cycloaddition; Lautens,
M., Ed.; JAI Press: Greenwich, CT, 1997; Vol. 4, pp 1-40. (b) Nuss, J.
M.; West, F. G. In The Chemistry of Dienes and Polyenes; Rappoport, Z.,
Ed.; Wiley-Interscience: Chichester; 1997; Vol. 1, pp 263-324. (c)
Sieburth, S. McN. In AdVances in Cycloaddition; Harmata, M., Ed.; JAI
Press: Greenwich, CT, 1999; Vol. 5, pp 85-118. (d) Sieburth, S. Mc. In
Synthetic Organic Photochemistry; Griesbach, A., Mattay, J., Eds.; Marcel
Dekker: New York, 2005; pp 239-268.
(8) (a) West, F. G.; Chase, C. E.; Arif, A. M. J. Org. Chem. 1993, 58,
3794-3795. (b) Chase, C. E.; Bender, J. A.; West, F. G. Synlett 1996,
1173-1175.
(9) For seminal studies on pyran-2-one photodimerization, see: (a) de
Mayo, P.; Yip, R. W. Proc. Chem. Soc. London 1964, 84. (b) de Mayo, P.;
McIntosh, C. L.; Yip, R. W. In Organic Photochemical Synthesis;
Srinivasan, R., Roberts, T. D., Eds.; Wiley-Interscience: New York; 1971;
Vol. 1, pp 99-100.
(13) Endo and exo in this context refer to the relative orientations of the
two diene reactants in the [4 + 4]-cycloaddition transition state. The endo
transition state places the furan C-3 and C-4 over the internal carbons of
the pyran-2-one diene system, leading to a product in which the lactone
and ether bridges are cis in the newly formed cyclooctadiene. The exo
transition state places the furan C-3 and C-4 over the lactone moiety, leading
to a product with the lactone and ether bridges trans disposed on the
cyclooctadiene. For substrates such as 1 possessing a preexisting stereo-
center, two endo and two exo products are possible, corresponding to
approach of the furan from the same or the opposite face as the OR group.
(10) (a) de Boer, A. H. Biochem. Soc. Trans. 2002, 30, 416-421. (b)
Aducci, P.; Camoni, L.; Fullone, M. R.; Marra, M.; Sabina, V. In Bacterial,
Plant and Animal Toxins; Ascenzi, P., Polticelli, F., Visca, P., Eds.; Research
Signpost: Trivandrum, India, 2003; pp 59-67.
(11) (a) Stoessl, A.; Rock., G. L.; Stothers, J. B.; Zimmer, R. C. Can. J.
Chem. 1988, 66, 1084-1090. (b) Stoessl, A.; Cole, R. J.; Abramowski, Z.;
Lester, H. H.; Towers, G. H. N. Mycopathologia 1989, 106, 41-46.
(12) The fusicoccane/cotylen numbering system is used. See Scheme 1.
4076
Org. Lett., Vol. 8, No. 18, 2006

Scheme 3
of this approach, the substrate was prepared as a racemate,
yield. The identity of the major pair of isomers was assumed
to be 8b and 9b, based on predicted approach of the furan
from the sterically less demanding face. Irradiation in
nonpolar solvents led to increased facial selectivity, and
hexane was used in subsequent experiments due to the greater
solubility of the photosubstrates 1 in this solvent as compared
with benzene.
Given the improved selectivity, crystalline derivatives of
the two major isomers were sought in order to make
unequivocal assignments. In the event, two suitably crystal-
line alcohols were obtained and their structures determined
by X-ray diffraction (Scheme 4). To our surprise, these
but optically pure material is available by various methods.14
Attempted cyclocondensation of malonyl dichloride with 4
failed to yield the desired pyran-2-one 5, despite its close
structural analogy to other silyl enol ethers that successfully
undergo this process.15,16 Instead, 3 was converted to its
morpholine enamine and treated with methyl malonyl
chloride, and the intermediate diketoester was cyclized by
stirring with DBU to give 5. Compound 5 underwent iron-
(III) choride catalyzed Michael addtion to acryloyl furan to
give 6.17 In anticipation of the eventual need for deoxygen-
ation at C-1 of the tricyclic skeleton, the hydroxypyrone was
converted to the triflate 7a.18 Minor amounts of the isomeric
pyran-4-one 7b formed in this reaction could be recycled
by conversion to 6 upon treatment with tetrabutylammonium
fluoride. Ketalization of the ketone in the tether then
furnished 1a. Reductive removal of the triflate (Pd0/Et3SiH)19
gave deoxygenated substrate 1b.
Scheme 4
With these substrates in hand, we set out to examine their
photochemical behavior, using the standard conditions
developed for related pyran-2-one substrates.8b Substrates
were anticipated to provide four stereoisomers: endo and
exo cycloadducts 8 and 9 resulting from approach of the
furan opposite to the C-5 OR group and endo and exo
adducts 10 and 11 resulting from furan delivery from the
same face as the OR group (Scheme 3). Initial experiments
with substrate 1b revealed relatively poor facial selectivity
in methanol: two pairs of apparent endo/exo isomers were
isolated in a disappointing 4:3 ratio, albeit in good combined
structures proved to be tricyclic compounds 12 and 11e,
indicating that the major isomers from irradiation of 1b were
10b and 11b and that the dominant pathway involves
approach of the furan from the same face as the bulky
OTBDPS group!20
This unexpected diastereoselectivity prompted us to ex-
amine the effects of the alcohol protecting group R and ring
substituent X (Table 1). Substrates 1c-e were prepared by
deprotection of 1b (TBAF) and (for 1c,d) derivatization with
the appropriate reagents (TBDMSCl/imidazole or Ac2O/
pyridine/DMAP). Following irradiation, the photocycload-
ducts in each case were deprotected and correlated with 8e,
9e, 10e, and 11e.
(14) (a) Lee, L. G.; Whitesides, G. M. J. Org. Chem. 1986, 51, 25-36.
(b) Easwar, S.; Desai, S. B.; Narshinha, P.; Ganesh, K. N. Tetrahedron:
Asymmetry 2002, 13, 1367-1371. (c) Tanyeli, C.; Turkut, E.; Mecidoglu
Akhmedov, I. Tetrahedron: Asymmetry 2004, 15, 1729-1733.
(15) Effenberger, F.; Ziegler, T.; Scho¨walder, K.; Kesmarsky, T.; Bauer,
B. Chem. Ber. 1986, 119, 3394-3404.
(16) The corresponding TBS and MOM ethers also failed to react with
malonyl dichloride. Thus, although sterics may play a role, we believe that
inductive deactivation of the silyl enol ether is the principal reason for the
negative outcome of this annulation.
(17) Jens, C. Synlett 2001, 723-732.
(18) We anticipated removal of the triflate could take place either before
or after photocycloaddition. The latter approach would rely on our previous
observation that hydrogenolysis of vinyl triflates in [4 + 4]-cycloadducts
of 4-trifloxypyran-2-ones occurs efficiently under conditions for hydrogena-
tion of the cyclooctadiene (see ref 8b).
(19) Scott, W. J.; Stille, J. K. J. Am. Chem. Soc. 1986, 108, 3033-3040.
(20) X-ray data in CIF format can be found in the Supporting Information.
Org. Lett., Vol. 8, No. 18, 2006
4077

Table 1. [4 + 4]-Photocycloaddition Reactions of 1a-ea
Scheme 5
overall
ratio
facial selectivity
entry substrate yielda (%)
8/9/10/11
(10 + 11)/(8 + 9)
1
2
3
4
5
1b
1c
1d
1e
1a
90
75
70
84
95
0c:1.0:3.7:3.3
1.0:2.4:10.0:9.4
1.0:1.9:3.1:3.8
1.0:2.0:4.0:3.5
1.5:1.0:8.3:2.7
7.0:1
5.7:1
2.3:1
2.5:1
4.4:1
causes the lactone to move away from OR and toward the
methine hydrogen. Further examples are under study in order
to better understand the origins of this effect; however, from
the standpoint of a stereocontrolled route to traversianal and
related compounds, this surprising result does not abrogate
the original synthetic plan. The site of the original stereo-
chemical control element will ultimately become an sp2
center, although the enantiomer of the initially proposed
substrate will be required.
a Photoreactions were carried out at ice-water bath temperature in hexane
(0.1 M) under N2 atmosphere using a Hanovia 450 W medium-pressure
Hg vapor lamp. Irradiation was continued until complete consumption of
starting material (typically 0.5-3 h). b Yields based on isolated material
after chromatography. Ratios were determined by integration of the isolated
trisubstituted alkene protons of 8e-11e following deprotection step. c In
some runs, trace amounts of 8a were isolated.
In all cases, overall photocycloaddition yields were good,
and isomers 10 and 11 were the major products; however,
as the size of the R groups decreased, the relative amounts
of the minor isomers increased (entries 1-4). Triflate-
substituted compound 1a gave comparable results (entry 5).
In this case, the major photoproducts were correlated with
the 10b and 11b by reductive removal of the triflate (Pd-
(PPh3)4/Bu3SnH).
Our assumption that isomers 8 and 9 would predominate
was based upon a steric approach control selectivity argu-
ment. For 1b, it was expected that the bulky TBDPS group
would inhibit delivery of the furan from that face. Clearly,
other factors are dominant in the cycloaddition transition
state. It is possible that the silyl ether assumes a pseudoequa-
torial situation on the cyclopentene ring, with approach from
the opposite face hindered by the pseudoaxial hydrogen atom
(conformers A and B, Scheme 5). Alternatively, a product
development control argument may explain both the overall
facial selectivity and the increased selectivity seen with larger
R groups. Approach of the furan from the opposite face as
the OR group entails movement of the lactone bridge toward
an eclipsing interaction with OR as bonding proceeds
(conformers C and D), whereas approach from the same face
We have described a novel strategy for the stereoselective
construction of functionalized 5-8-5 tricyclic systems using
the crossed intramolecular [4 + 4]-photocycloaddition of
pyran-2-ones. By this route, complex polycycles that are
potentially suitable intermediates for the synthesis of tra-
versianal and members of the fusicoccin class of fungal
metabolites are available in 7-9 steps from 2-siloxycyclo-
pentanone 3a. By inclusion of a preexisting stereocenter on
a cyclopentene ring fused to the pyran-2-one, facial selectivi-
ties of up to 7:1 are obtained. Notably, the major isomers
arise from approach of the furan trap from the same face as
the bulky substituent. Further studies of this interesting
example of stereocontrol, and progress toward various natural
product targets, will be reported in due course.
Acknowledgment. We thank NSERC for support of this
work.
Supporting Information Available: Experimental pro-
cedures and spectral data for all intermediates. This material
is available free of charge via the Internet at http://pubs.acs.org.
OL061576H
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Org. Lett., Vol. 8, No. 18, 2006