Synthesis of crossed [2 + 2] photocycloadducts: a novel approach to the synthesis of bridged bicyclic alkenes.

Article abstract of DOI:10.1021/ol991272d

[reaction: see text] A solution to the synthesis of "crossed" intramolecular [2 + 2] photocycloadducts has been achieved. Through the use of a temporary heteroatom linker, the equivalent of a crossed photocycloadduct can be accessed at the expensive of the normal "straight" adduct. Selectivity as high as 94:6 for the "crossed" adduct has been observed.

Full text of DOI:10.1021/ol991272d

ORGANIC
LETTERS
2
000
Vol. 2, No. 3
81-284
Synthesis of Crossed [2 + 2]
Photocycloadducts: A Novel Approach
to the Synthesis of Bridged Bicyclic
Alkenes
2
Michael T. Crimmins* and E. Bryan Hauser
Venable and Kenan Laboratories of Chemistry, The UniVersity of North Carolina at
Chapel Hill, Chapel Hill, North Carolina 27599-3290
crimmins@email.unc.edu
Received November 23, 1999
ABSTRACT
A solution to the synthesis of “crossed” intramolecular [2 + 2] photocycloadducts has been achieved. Through the use of a temporary
heteroatom linker, the equivalent of a crossed photocycloadduct can be accessed at the expensive of the normal “straight” adduct. Selectivity
as high as 94:6 for the “crossed” adduct has been observed.
The intramolecular [2 + 2] photocycloaddition is a powerful
reaction in the repertoire of the synthetic organic chemist,
plication to the synthesis of spiro-fused and linearly-fused
systems have been reported, including those noted above.
The excellent selectivity of intramolecular photocycload-
ditions is a result of geometric constraints and conformational
bias imposed by substituents on the tether between the two
π-bonds involved in the cycloaddition. The straight adduct
is produced as a result of the preference for the initial
formation of a five-membered ring in the cyclization of the
1
particularly for the construction of quaternary carbon centers
in sterically compressed environments. The recent applica-
tions of the intramolecular [2 + 2] photocycloaddition in
2
3
4
7
such syntheses as ginkgolide B, saudin, bilobalide, lau-
5
6
renene, and manzamine evidence its utility in the construc-
tion of sterically congested carbon frameworks. The normal
mode of cycloaddition for enone 1 (Scheme 1) results in
(
1) De Keukeleire, D.; He, S.-L. Chem. ReV. 1993, 93, 359-380 and
references therein. Crimmins, M. T. Chem. ReV. 1988, 88, 1453. Crimmins,
M. T.; Reinhold: T. L. Organic Reactions; John Wiley and Sons: New
York, 1993; Vol. 44, p 297.
Scheme 1
(2) Crimmins, M. T.; Pace, J. M.; Nantermet, P. G.; Kim-Meade, A. S.;
Thomas, J. B.; Wagman, A. S.; Watterson, S. H. J. Am. Chem. Soc. 1999,
1
7
1
6
6
21, 10249-10250.
3) Winkler, J. D.; Doherty, E. M. J. Am. Chem. Soc. 1999, 121, 7425-
426.
(
(4) Crimmins, M. T.; Gray, J. L.; Jung, D. K. J. Am. Chem. Soc. 1993,
15, 3146-3155.
(
5) Crimmins, M. T.; Bredon, L. D. J. Am. Chem. Soc. 1987, 109, 6199-
200.
(
6) Winkler, J. D.; Axten, J. M. J. Am. Chem. Soc. 1998, 120, 6425-
426.
high regioselectivity for the “straight” adduct 2, with none
of the “crossed” adduct 3 observed. Because of the high
regioselectivity for the straight adduct, particularly when the
enone is tethered to the olefin by three or four atoms, many
examples of intramolecular photocycloadditions in the ap-
(7) For recent discussions of the mechanism of [2 + 2] enone-olefin
photocycloadditions, see: Schuster, D. I.; Lem, G.; Kaprinidis, N. A. Chem.
ReV. 1993, 93, 3-22. Andrew, D.; Hastings, D. J.; Weedon, A. C. J. Am.
Chem. Soc. 1994, 116, 10870-10882. Maradyn, D. J. Weedon, A. C.
Tetrahedron Lett. 1994, 35, 8107-8110. Maradyn, D. J. Weedon, A. C. J.
Am. Chem. Soc. 1995, 117, 5359-5360.
1
0.1021/ol991272d CCC: $19.00 © 2000 American Chemical Society
Published on Web 01/20/2000

triplet excited state to form the intermediate triplet biradical.
Formation of the crossed adduct is disfavored since it would
require initial cyclization to form either a six- or seven-
membered ring.
Scheme 3
If a method could be developed to allow selective access
to the “crossed” photocycloadduct, a fundamentally unique
approach to the synthesis of bridged bicyclic systems would
be possible. We reasoned that if a temporary tether were
incorporated into the photosubstrate as in enone 4, the initial
cyclization could proceed through the formation of a five-
membered ring in the production of either the straight adduct
6
or the crossed adduct 5 (Scheme 2). Since either adduct
Scheme 2
The synthesis of enone 7 is illustrated in Scheme 3.
9
Oxidation of 4-penten-1-ol under Swern conditions was
followed by addition of ethynylmagnesium bromide to
produce acetylenic alcohol 12. The alcohol was readily
converted to allyl ether 13 by alkylation of the sodium
could be accessed through an initial five-membered ring
formation, it might be possible to fine tune the tether to favor
the crossed adduct by manipulating various structural features
such as steric interactions, bond lengths, and bond angles.
Subsequent cleavage of the temporary tether would result
in the equivalent of a crossed adduct from a simple enone-
alkene photocycloaddition.
10
alkoxide with allyl bromide. Carboxylation of the acetylene
provided 97% of acetylenic ester 14 which was subsequently
treated under our standard conjugate addition-cyclization
1
1
conditions to produce 2-carbalkoxycyclopentenone 15 in
7% yield. Finally, exposure of the diene 15 to 5 mol % of
Cy P) Cl RudCHPh [40 °C, CH Cl ] produced the desired
photosubstrate 7 in 90% yield.
6
(
3
2
2
2
2
Molecular mechanics calculations of a variety of possible
substrates indicated that the cyclic ether 7 or the cyclic acetal
1
2
Cyclic acetal 8 was prepared in a similar manner as shown
in Scheme 4. Acetylenic alcohol 12 was protected as
8
would possibly favor the crossed adduct (Figure 1). MM2
Scheme 4
Figure 1. Substrates for crossed-selective photoadditions.
approximations indicated a difference of approximately 1.7-
1.9 kcal per mol in favor of the transition state 9 leading to
the crossed adduct in preference to transition state 10 to
8
produce the straight adduct for enone 7 (Figure 2).
triethylsilyl ether 16, and the acetylene was converted to
acetylenic ester 16 in 81% overall yield. The acetylenic ester
Figure 2. Transition states for photocycloaddition of 7.
(8) Energy minimizations were performed by restricting the distance
between the enone carbon and the alkene carbon to 2.5 Å.
282
Org. Lett., Vol. 2, No. 3, 2000

was transformed to the cyclopentenone as described for 14,
and removal of the triethylsilyl ether provided alcohol 18.
Alcohol 18 was exposed to acrolein diethyl acetal in the
presence of catalytic PPTS, and the resultant mixed acetal
for the cleavage of the temporary linker. The ether linkage
of photoadduct 19 was selectively cleaved to iodoacetate 23
in 98% yield by exposure of ether 19 to aluminum trichloride
and sodium iodide followed by immediate trapping of the
alcohol with acetic anhydride. The efficiency of this reaction
prompted the investigation of similar ether fragmentations
with other nucleophile-Lewis acid combinations. Exposure
of ether 19 to phenyl trimethylsilylselenide and zinc iodide15
led to near quantitative conversion to selenide 24 which was
readily hydrolyzed to alcohol 25 (Scheme 6). The alcohol
1
4
was treated with Grubbs catalyst [5 mol % of (Cy
RudCHPh, 40 °C, CH Cl ] to afford the desired cyclic acetal
in good overall yield.1
Irradiation of a solution of cyclopentenone 7 in 1:4
3 2 2
P) Cl -
2
2
3
8
dichloromethane:hexanes with a 450 W Hanovia lamp
filtered with a uranium glass sleeve (>350 nm) resulted in
the production of a 94:6 mixture of two diastereomeric
photocycloadducts 19 and 20 in 85% yield (Scheme 5).
Scheme 6
Scheme 5
Similarly, acetal 8 produced a 93:7 mixture of two regioi-
someric products each as a 1:1 mixture of acetal isomers
21:22. Structural proof of the individual isomers was obtained
by a combination of one- and two-dimensional NMR
experiments. Most critically, coupling and NOE interaction
of Ha in 19 with the adjacent methylene group of the ether
linkage confirmed the regiochemistry of the photoaddition
of 7. Final confirmation was obtained by a single-crystal
X-ray analysis of crossed photocycloadduct 21 as illustrated
in Figure 3.
was protected as the acetate in 98% yield by treatment with
acetic anhydride in the presence of Et N and DMAP.
3
Subsequent exposure of selenide 26 to buffered hydrogen
peroxide led to elimination of the selenoxide to give 90%
of exocyclic olefin 27. Alkene 27 is the equivalent of the
hypothetical crossed photoadduct of allene 28 (Figure 4).
Figure 4. Hypothetical photoaddition of allene 28.
Thus, the approach described here provides efficient access
to crossed photoadducts through an indirect strategy.
(
9) Swern, D.; Mancuso, A. J.; Huang, S. J. Org. Chem. 1978, 43, 2480-
482.
10) All new compounds were characterized by H and 13C NMR and
IR. Yields are for isolated, chromatographically purified products.
11) Crimmins, M. T.; Nantermet, P. G.; Trotter, B. W.; Vallin, I. M.;
Watson, P. S.; McKerlie, L. A.; Reinhold: T. L.; Cheung, A. W. H.; Stetson,
K. A.; Dedopoulou, D.; Gray, J. L. J. Org. Chem. 1993, 58, 1038-1047.
Figure 3.
2
1
(
(
With a viable approach to the preparation of crossed
photoadducts available, it remained to establish a protocol
Org. Lett., Vol. 2, No. 3, 2000
283

Having developed a solution to the production of the
crossed photocycloadduct, the selective cleavage of the
cyclobutane was investigated. If the exocyclic olefin of
cyclobutane 27 could be oxidized to a carbonyl, diol, or
epoxide, and the acetoxy group converted to a radical
precursor, cleavage of the cyclobutane to yield a bridgehead
olefin might be possible. Molecular models indicate a nearly
perfect antiperiplanar arrangement between the C-O bond
of the acetate and the internal cyclobutane bond which would
be cleaved. The added influence of the ester and ketone
carbonyl groups could also help to weaken the cyclobutane
bond and stabilize the developing radical center. Oxidation
of the alkene proved difficult under standard conditions such
as ozonolyis and osmium tetroxide dihydroxylation, but
Figure 5. Structure of CP263,114.
An indirect solution to the preparation of the previously
elusive crossed adducts of intramolecular photocycloadditions
has been developed. The incorporation of a temporary tether
allows the reversal of regioselectivity in the photoaddition
and subsequent removal of the temporary linker gives the
desired crossed photoadduct. The crossed cyclobutane adduct
has also been further elaborated to a bridged bicyclic alkene
through the use of a selective cyclobutylcarbinyl radical
fragmentation. Application of this strategy to more highly
substituted substrates for the synthesis of CP263,114 and
other novel bicyclic compounds is in progress.
1
6
epoxidation could be effected with dimethyldioxirane to
produce epoxide 29. The acetate was removed with potas-
sium carbonate in methanol to give the corresponding alcohol
30 that was readily converted to thiocarbamate 31 in 92%
yield in the presence of thiocarbonyl diimidazole (Scheme
7). Exposure of thiocarbamate 31 to tributylstannane in
Scheme 7
Acknowledgment. This work was supported by a re-
search grant from the National Institutes of Health (GM38904).
OL991272D
(
12) Schwab, P.; Grubbs, R. H.; Ziller, J. W. J. Am. Chem. Soc. 1996,
1
1
1
18, 100-110. Grubbs, R. H.; Miller, S. J.; Fu, G. C. Acc. Chem. Res.
995, 28, 446-452. Fu, G. C.; Grubbs, R. H. J. Am. Chem. Soc. 1992,
14, 7324-7325.
(13) Crimmins, M. T.; King, B. W.J. Am. Chem. Soc. 1998, 120, 9084-
9
085.
14) Node, M.; Kajimoto, T.; Nishide, K.; Fujita, E.; Fuji, K. Tetrahedron
Lett. 1984, 25, 219-222.
15) Miyoshi, N.; Hatayama, Y.; Ryu, I.; Kambe, N.; Murai, T.; Murai,
(
(
S.; Sonoda, N. Synthesis 1988, 175-178.
(
16) Murray, R. W. Chem. ReV. 1989, 89, 1187-1201.
(17) For an excellent review on radical rearrangements, see: Dowd, P.;
Zhang, W. Chem. ReV. 1993, 93, 2091-2115. See also: Rawal, V. H.;
Dufour, C.; Iwasa, S. Tetrahedron Lett. 1995, 36, 19-22. Zheng, W.;
Collins, M. R.; Mahmood, K.; Dowd, P.; Tetrahedron Lett. 1995, 36, 2729-
benzene resulted in selective cleavage of the more substituted
2
732. Lange, G. L. J. Org. Chem. 1995, 60, 2183-2187. Lange, G. L.;
cyclobutane bond, generating bicyclic alkene 32 in good
Gottardo, C. Tetrahedron 1990, 31, 5985-5988. Lange, G. L.; Gottardo,
C. Tetrahedron 1994, 35, 8513-8516. Ranu, B.; Das, A. R. J. Chem. Soc.,
Perkin Trans. 1 1994, 921-922.
17
yield. Alkene 32 contains much of the required functionality
and all the carbon framework of the core of the novel natural
(18) Dabrah, T. T.; Kaneko, T.; Massefski, W., Jr.; Whipple, E. B. J.
18
product CP263,114 (Figure 5).
Am. Chem. Soc. 1997, 119, 1594-1598.
284
Org. Lett., Vol. 2, No. 3, 2000