Enantioselective Synthesis of Spiro Ethers and Spiro Ketals via Photoaddition of Dihydro-4-pyrones to Chiral 1,3-Dioxin-4-ones 1

Article abstract of DOI:10.1021/jo970816r

A versatile and highly stereoselective synthesis of spiro ethers and spiro ketals is presented. The key step in the developed synthetic sequence is based on diastereoselective intramolecular photoaddition of dihydro-4-pyrones to chiral 1,3-dioxin-4-ones. Subsequent fragmentation of the produced four-membered ring provides spiro ether structures. The spiro ethers can be transformed to their corresponding spiro ketals, with retention of configuration at the spiro center, via Baeyer-Villager oxidation. The configuration of the spiro center is defined by the facial selectivity at the photocycloaddition step. Two examples of complete stereofacial selectivity were achieved. The unique and important application of the developed sequence was demonstrated in enantioselective synthesis of a less thermodynamically stable spiro ketal 43.

Full text of DOI:10.1021/jo970816r

J . Org. Chem. 1997, 62, 7629-7636
7629
En a n tioselective Syn th esis of Sp ir o Eth er s a n d Sp ir o Keta ls via
P h otoa d d ition of Dih yd r o-4-p yr on es to Ch ir a l 1,3-Dioxin -4-on es†
Nizar Haddad,* Igor Rukhman, and Zehavit Abramovich
Department of Chemistry, Technion-Israel Institute of Technology, Haifa 32000, Israel
Received May 6, 1997X
A versatile and highly stereoselective synthesis of spiro ethers and spiro ketals is presented. The
key step in the developed synthetic sequence is based on diastereoselective intramolecular
photoaddition of dihydro-4-pyrones to chiral 1,3-dioxin-4-ones. Subsequent fragmentation of the
produced four-membered ring provides spiro ether structures. The spiro ethers can be transformed
to their corresponding spiro ketals, with retention of configuration at the spiro center, via Baeyer-
Villager oxidation. The configuration of the spiro center is defined by the facial selectivity at the
photocycloaddition step. Two examples of complete stereofacial selectivity were achieved. The
unique and important application of the developed sequence was demonstrated in enantioselective
synthesis of a less thermodynamically stable spiro ketal 43.
In tr od u ction
between anomeric stabilization and the preference of
substituents for equatorial orientation. Mixtures of
products are obtained and tedious separations required
when these factors are in conflict.6 Thermodynamically
less stable spiro ketal structure in talaromycins C and
D were proposed in the biosynthetic pathway as the
precursors of other biologically active thermodynamically
more stable isomers talaromycins A, B, E, and F (Figure
1). Talaromycins A and B have been synthesized6 by
utilizing the thermodynamic stability of the spiro ketal
systems. To the best of our knowledge, the synthesis of
the thermodynamically less stable metabolites, talaro-
mycins D and F, has not yet been reported.
The spiro ketal unit can be found as a substructure in
a wide variety of naturally occurring compounds isolated
from many sources, including plants, insects, microbes,
fungi, and marine organisms;1 for example, it is found
in the milbemycin/avermectin macrolides,2 which possess
significant antibiotic as well as insecticidal activity,3
antitumor toxic metabolites from blue-green algae,4 and
the talaromycins,5,6 which represent a class of spiro ketal
mycotoxins. The increasing pharmacological importance
of such compounds and their synthetically challenging
structures have led to intense interest in the synthesis
and chemical reactivity of these compounds. The con-
ventional synthetic approaches to spiro ketals involve
acid-promoted intramolecular spiro cyclization of acyclic
dihydroxy ketones or their equivalents.1 The stereo-
chemistry of the spiro center results from a balance
Stereoselective synthesis of spiro ethers is still a
challenge, as could be seen, for example, in the recently
reported synthesis of oscilatoxin D.7 A mixture of
isomeric spiro ethers was obtained upon treatment of 7
with camphorsulfonic acid (CSA), the desired spiro ether
8 being obtained in 12% yield (Scheme 1).
† Presented in part at the 62nd Annual Meeting of the Israel
Chemical Society, Feb. 1997.
We have recently been interested in developing a
versatile and highly stereoselective method for the
synthesis of spiro structures that allows enantioselective
synthesis of spiro ethers and thermodynamically less
stable spiro ketals.8 The synthetic sequence is sum-
marized in the following retrosynthetic scheme (Scheme
2). The key step is based on a diastereoselective in-
tramolecular photocycloaddition of chiral 1,3-dioxin-4-
one9 to dihydro-4-pyrone10 in photosubstrates of type 12.
Stereofacial selective photocyclization introduces four
stereogenic centers with the corresponding configurations
defined by the approach of the chiral dioxinone (R1 * R2)
toward the dihydropyrone. The dioxinone functionality11
plays four important roles: (a) it provides the desired
CdC double bond, incorporated in the photocycloaddition
reaction; (b) it enables selective fragmentation of the
produced four-membered ring; (c) it introduces a ketone
X Abstract published in Advance ACS Abstracts, September 15, 1997.
(1) For reviews in this area, see: (a) Perron, F.; Albizati, F. Chem.
Rev. 1989, 89, 1617. (b) Davies, H. G.; Green, R. H. Chem. Soc. Rev.
1991, 20, 211; 271. (c) Westley, J . W.; Seto, H. J . Antibiotics 1979,
32, 959. For other reviews of polyether antibiotics, see: (d) Hodgson,
K. O. Intra Sci. Chem. Rep. 1974, 8, 27. (e) Westley, J . W. Annu. Rep.
Med. Chem. 1975, 10, 246. (f) Pressman, B. C. Annu. Rev. Biochem.
1976, 45, 501.
(2) For a review of Milbemycin synthesis see: (a) Boeckman, R. K.,
J r.; Goldman, S. W. The Total Synthesis of Natural Products; Simon,
J ., Ed.; Wiley: New York, 1988; Vol. 7, pp 88-92. See also: (b)
Crimmins, M. T.; Al-awar, R. S.; Vallin, I. M.; Hollis, W. G.; O’Mahony,
R.; Lever, J . G.; Bankaitis, D. M. J . Am. Chem. Soc. 1996, 118, 7513
and references cited therein. (c) Ley, S. V.; Madin, A.; Monck, N. J . T.
Tetrahedron Lett. 1993, 34, 7479 and references cited therein. For
Avermectin synthesis, see: (d) Ferezou, J . P.; J ulia, M.; Li, Y.; Liu, L.
W.; Pancrazi, A. Bull. Soc. Chim. Fr. 1995, 132, 428. (e) Danishefsky,
S. J .; Armistead, D. M.; Wincott, F. E.; Selnick, H. G.; Hungate, R. J .
Am. Chem. Soc. 1989, 111, 2967. (f) Danishefsky, S. J .; Armistead,
D. M.; Wincott, F. E.; Selnick, H. G.; Hungate, R. J . Am. Chem. Soc.
1987, 109, 8117. (g) Hanessian, S.; Ugolini, A.; Hodges, P. J .; Beaulieu,
P.; Dube, A. C. Pure Appl. Chem. 1987, 59, 299.
(3) Mishima, H.; J unya, I.; Muramatsu, S.; Ono, M. J . Antibiotics
1983, 36, 980.
(4) Moore, R. E. Marine Natural Products-Chemical and Biological
Prespectives; Scheuer P. J ., Ed.; Academic Press: New York, 1981; Vol.
4, Chapter 1. Bhakuni, D. S. J . Sci. Ind. Res. 1995, 54, 702 and
references cited therein.
(5) Phillips, N. J .; Cole, R. J .; Lynn, D. G. Tetrahedron Lett. 1987,
28, 1619.
(6) (a) Kurth, M. J .; Brown, E. G.; Hendra, E.; Hope, H. J . Org.
Chem. 1985, 50, 1115. Smith, A. B., III; Thompson, A. S. J . Org. Chem.
1984, 49, 1469. (b) Schreiber, S. L.; Sommer, T. J .; Satake, K.
Tetrahedron Lett. 1985, 26, 17. (c) Mori, K.; Ikuuaki, M. Tetrahedron
1987, 43, 45. (d) Baker, R.; Boyes, A. L.; Swain, C. J . J . Chem. Soc.,
Perkin Trans. 1, 1990, 1415.
(7) (a) Toshima, H.; Goto, T.; Ichihara, A. Tetrahedron Lett. 1995,
36, 3373. (b) Toshima, H.; Goto, T.; Ichihara, A. Tetrahedron Lett.
1994, 35, 4361.
(8) (a) Haddad, N.; Abramovich, Z.; Rukhman, I. Tetrahedron Lett.
1996, 37, 3521. (b) Haddad, N.; Abramovich, Z.; Rukhman, I. Recent
Research Developments in Organic Chemistry; Pahdalai, S. G.; Ed.;
Transworld Research Network: New York, 1997, Vol. 1, 35.
(9) Haddad, N.; Abramovich, Z. J . Org. Chem. 1995, 60, 6883.
(10) Haddad, N.; Kuzmenkov, I. Tetrahedron Lett. 1993, 34, 6127.
(11) For elegant synthetic applications of the intramolecular pho-
toadditions of dioxinones to alkenes, see: Winkler, J . D.; Bowen, C.
M.; Liotta, F. Chem. Rev. 1995, 95, 2003.
S0022-3263(97)00816-5 CCC: $14.00 © 1997 American Chemical Society

7630 J . Org. Chem., Vol. 62, No. 22, 1997
Haddad et al.
Sch em e 3
photocycloaddition of dioxinone 13b with the preferred
approach of the alkene being from the equatorial tert-
butyl side. The observed stereoselectivity was attributed
to the steric hindrance of the axial methyl at the ketal
center.
F igu r e 1. Talaromycins A-F (Reference 5).
Sch em e 1
Stereoselective intramolecular photocycloaddition of
alkenes to enones with a chiral auxiliary located at the
enone chromophore, which can be expected to be of
general application, is not a well-explored approach. The
first example of a very high stereofacial selectivity in the
intramolecular photocycloaddition of alkenes to chiral
dioxinones was recently reported by Sato and Kaneko.14
Resu lts a n d Discu ssion
P r ep a r a tion of th e P h otosu bstr a tes. The synthesis
of photosubstrates 29-32 is general and based on
coupling of the corresponding bromide of dihydropyrone
16 (Scheme 4) with diethyl malonate,15 followed by
another coupling reaction with the corresponding dioxi-
nones 22, 25, 26, and 28 (Scheme 5). Dihydropyrone 16
was prepared by dianion condensation of acetylacetone
with formaldehyde,16 followed by cyclization of the cor-
responding â-diketo â′-alcohol17 under acidic conditions
(3 N HCl). Allylic radical bromination18 of 16 with 1
equiv of N-bromosuccinimide (NBS) and 0.1 equiv of 2,2′-
azobisisobutyronitrile (AIBN) afforded a mixture of mono-
bromide 17 and dibromide 18 in a 92:8 ratio and 65%
yield. However, bromination with 2.5 equiv of NBS
afforded a separable mixture of dibromide 18 and tri-
bromide 19 in 87:13 ratio and 75% yield. Chiral dioxi-
none 21 was best prepared, in racemic form, by refluxing
the commercially available dioxinone 20 and pivalde-
hyde19 in mesitylene for 1 h. Bromination18 of 21 (NBS
2 equiv, sun lamp, benzoyl peroxide) provided a single
product (22) in 70% yield. Dioxinones 23 and 24 were
prepared in racemic form upon treatment of tert-butyl
acetoacetate with isopropyl methyl ketone or acetophe-
none, respectively, under acidic conditions (H2SO4, Ac2O),
following a literature procedure.20 Bromination of 23 and
Sch em e 2
functionality at the spiro ring, necessary for oxidative
enlargement leading to spiro ketals; and (d) it provides
for asymmetric induction.
High stereofacial selectivity in the intermolecular pho-
tocycloaddition of alkenes to chiral dioxinones was first
reported by the pioneering studies of Demuth and co-
workers12 on the photocycloaddition of a chiral 1,3-dioxin-
4-one, possessing a (-)-menthone auxiliary, to cyclic al-
kenes. Poor facial selectivity was obtained in the inter-
molecular photoaddition of dioxinone 13a to various al-
kenes (Scheme 3). However, Lange and co-workers13
have succeeded in obtaining high facial selectivity in the
(13) (a) Organ, M. G.; Forese, R. D.; Goodard, J . D.; Taylor, N. J .;
Lange, G. L. J . Am. Chem. Soc. 1994, 116, 3312. (b) Lange, G. L.;
Organ, M. G. Tetrahedron Lett. 1993, 34, 1425.
(14) Sato, M.; Abe, Y.; Kaneko, C. Heterocycles 1990, 30, 217.
(15) Winkler, J . D.; Hey, J . P.; Hannon, F. J . Heterocycles 1987, 25,
55. Karpcho, A. P. Synthesis 805 (1982).
(16) Huckin, S. N.; Weiler, L. J . Am. Chem. Soc. 1974, 96, 1082.
(17) Curran, D. P.; Heffner, T. A. J . Org. Chem. 1990, 65, 4585.
(18) (a) Allylic bromination (NBS + AIBN): Hyp, J .; Dauben, J . R.;
McCoy, L. L. J . Am. Chem. Soc. 1959, 81, 4863. (b) Allylic bromination
(NBS + hν): Dauben, W. G.; Kohler, B.; Roesle, A. J . Org. Chem. 1985,
50, 2007.
(12) (a) Demuth, M.; Palomer, A.; Sluma, H. D.; Dey, A. K.; Kruger,
C.; Tsay, Y. H. Angew, Chem. Int. En. Engl. 1986, 25, 1117. (b)
Demuth, M. Pure Appl. Chem. 1986, 58, 1233.
(19) Sato, M.; Abe, Y.; Kaneko, C. J . Chem. Soc. Perkin Trans. 1
1990, 1779.

Spiro Ethers and Spiro Ketals via Photoaddition
J . Org. Chem., Vol. 62, No. 22, 1997 7631
Sch em e 4
Sch em e 5
Sch em e 6
24 afforded the corresponding monobromides 25 and 26
in 60% yield.
Photosubstrates 29, 31, and 32 were prepared by
coupling of 18 with diethyl malonate, followed by reduc-
tive cleavage of the vinyl bromide then coupling of the
corresponding product (27) with the bromodioxinones 28,
25, and 26, respectively, as described in Scheme 5. Pho-
tosubstrate 30 was prepared by coupling of dihydropy-
rone 33 with dioxinone 22 followed by reductive cleavage
of the vinyl bromides by catalytic hydrogenation.21 Com-
pound 36 was prepared by coupling of dioxinone 34 with
iodide 3522 following a previously described procedure.9
Exa m in a tion of th e Syn th etic Sequ en ce. The
utility of the synthetic sequence, described in the ret-
rosynthetic Scheme 2, was first examined with the
achiral photosubstrate 29. Compound 29 possesses two
different chromophores, the dihydropyrone and the di-
oxinone. The former undergoes intramolecular photocy-
cloaddition to alkenes upon direct irradiation via a Pyrex
glass filter (λ > 295),10 whereas photocycloaddition of
(20) (a) Sato, M.; Ogasawara, H.; Oi, K.; Kato, T. Chem. Pharm. Bull.
1983, 31, 1896. (b) Huckin, S.; Weiler, L. J . Am. Chem. Soc. 1974, 96,
1082.
(21) (a) Seebach, D.; Zimmermann, J . Helv. Chim. Acta. 1987, 70,
1104. (b) Seebach, D.; Noda, Y. Helv. Chim. Acta. 1987, 70, 2137.
(22) (a) Corey, E. J .; Udea, Y.; Ruden, R. A. Tetrahedron Lett. 1975,
16, 4347. (b) Millar, J . G.; Underhill, E. W. J . Org. Chem. 1986, 51,
4726.

7632 J . Org. Chem., Vol. 62, No. 22, 1997
Haddad et al.
Sch em e 7
dynamically less stable spiro ketal structures was dem-
onstrated in a stereoselective synthesis of spiro ketal 43.
Epimerization of the spiro center of 43 will afford R ) H
at the axial position in the corresponding structure 44
instead of the axial oxygen at the lactone moiety in 43,
leading to a thermodynamically more stable isomer.
Stereoselective synthesis of spiro ketal 43 (R ) H) was
achieved as follows: Reduction of the photoproduct 38
with NaBH4 took place at the cyclic ketone with high
selectivity of approach from the convex face, leading to
the expected23 spontaneous formation of the correspond-
ing lactone via fragmentation of the cyclobutane ring,
introducing the ketone functionality at the cyclopentane
ring which was over reduced under the reaction condi-
tions to the corresponding alcohol 40a . J ones oxidation26
of this alcohol afforded 40b in 60% total yield from 38.
Baeyer-Villager oxidation of 40b afforded a single
compound 43 in 80% yield. Controlled epimerization of
the spiro center was performed by treatment of 43 with
p-TsOH in the presence of 4-tert-butylcyclohexanone as
an internal standard (IS). This experiment led to clean
and rapid isomerization, affording a mixture of 43 and
44 in a 1:2.5 ratio.27 This result demonstrates the utility
of the developed sequence in the preparation of thermo-
dynamically less stable spiro ketals. Enantioselective
synthesis of spiro ketals should be possible following this
method upon irradiation of optically pure chiral dioxi-
nones. High stereofacial selectivity in the intramolecular
photocycloaddition of chiral dioxinones is essential in the
enantioselective synthesis of spiro structures.
En a n tioselective Syn th esis of Sp ir o Str u ctu r es
via P h otocycloa d d ition of Ch ir a l Dioxin on es. The
demonstrated synthetic utility of the photocycloaddition
of cyclic enones to alkenes in organic synthesis28 and the
absence of information on the intramolecular photocy-
cloaddition of alkenes, connected to the C(â) position of
the chiral dioxinones, triggered systematic investigation
of the steric effect of substituents at the chiral dioxinone
and/or the alkenyl side chain on the diastereofacial
selectivity of this reaction. Recently, we have shown9
that photocycloaddition of 45 at 0 °C afforded 46 and 47
in a 1:2 ratio (Scheme 8). The major product (47) was
formed by approach of the dioxinone from the more
exposed side (equatorial tert-butyl group), and the ste-
reoselectivity was increased to 1:4 upon irradiation of 45
at -70 °C.
dioxinones to alkenes requires a triplet sensitizer such
as acetone, acetophenone, or benzophenone.9 In contrast
to the intramolecular photocycloaddition of dihydropy-
rones to alkenes, no photoreaction could be detected upon
irradiation of 23 for several hours (over 10 h). However,
highly efficient photocyclization was obtained upon ir-
radiation of 29 in the presence of benzophenone as triplet
sensitizer, providing a single product 38 in over 90%
isolated yield. A 9% NOE enhancement in each of the
proton signals on the produced four-membered ring,
obtained upon irradiation of its vicinal proton resonance,
allowed assignment of the syn stereochemistry. The
failure of the photocycloaddition in the absence of triplet
sensitizer could be attributed to efficient quenching of
the electronically excited dihydropyrone by the dioxinone
chromophore.
Selective cleavage of the cyclobutane ring in 38 was
achieved upon treatment with hydrochloric acid in etha-
nol solution,23 affording spiro ether 39 in a 57% isolated
yield. The produced ketone functionality is needed for
the oxidative enlargement as described in the retrosyn-
thetic analysis (Scheme 2). The produced lactone pro-
hibits any possible epimerizations of this part during the
subsequent step of oxidative enlargement of the spiro
ketone, planned for the preparation of spiro ketal struc-
tures, and allows accurate detection of epimerization at
the spiro center during the oxidation step. Baeyer-
Villager oxidation24 of 39 provided a single product 41
in 80% yield with no detectable amount of is correspond-
Increasing the steric hindrance at the alkenyl side
chain was expected to affect the diastereofacial selectiv-
ity.9 This was examined by the photocycloaddition of 36
at 0 °C and -70 °C, which resulted in this case in
decreasing the facial selectivity to a 1:1 mixture of 48
and 49 at both temperatures. These results suggest the
preferred facial selectivity from the opposite side of the
tert-butyl substituent upon decreasing the steric hin-
drance of the pseudo-axial substituent at the acetal
center of the chiral dioxinone. Moreover, high selectivity
from the pseudo-equatorial substituent could be expected
upon replacing the tert-butyl substituent with a less
1
ing epimer 42 by H-NMR.
The structure of 41 was determined by NMR experi-
ments25 and confirmed by X-ray analysis. The preferred
conformation of the spiro structure possesses two axial
C-O bonds at the spirocenter. The utility of this
synthetic method in selective preparation of a thermo-
(23) (a) Winkler, J . D.; Hershberger, P. M. J . Am. Chem. Soc. 1989,
111, 4852. (b) Winkler, J . D.; Hershberger, P. M.; Spiringer, J . P.
Tetrahedron Lett. 1986, 27, 5177.
(24) For an example of selective Baeyer-Villager oxidation, see: (a)
Shishido, K.; Takahashi, K.; Fukumoto, K. J . Org. Chem. 1987, 52,
5704. (b) Baldwin, S. W.; Wilkinson, J . M. Tetrahedron Lett. 1979,
20, 2657.
(25) The relative stereochemical relationship of the stereogenic
centers was determined by NOE difference. Determination of these
protons resonances carried out by COSY-45, XH-CORR, and J MOD-
XH methods and was supported by NOE experiments.
(26) Brown, H. C.; Garg, C. P.; Liu, K. T. J . Org. Chem. 1971, 36,
387.
(27) The isomeric ratio was determined by 1H-NMR.
(28) (a) Haddad, N. The Chemistry of Functional Groups, Supple-
ment A3: The Chemistry of Double-bonded Functional Groups; Patai,
S., Eds.; Wiley: New York, 1997; Chapter 13, p 641. (b) Schuster, D.
I.; Lem, G.; Caprinidis, N. A. Chem. Rev. 1993, 93, 3. (c) Demuth, M.;
Mikhail, G. Synthesis 1989, 145. (d) Becker, D.; Haddad, N. Organic
Photochemistry; Padwa, A., Ed.; Dekker press: New York, 1989; Vol.
10, 1. (e) Crimmins, M. T. Chem. Rev. 1988, 88, 1453.

Spiro Ethers and Spiro Ketals via Photoaddition
J . Org. Chem., Vol. 62, No. 22, 1997 7633
Sch em e 8
Sch em e 10
result is consistent with our above assumptions and
provides unprecedented high facial selectivity in the
intramolecular photocycloadditions of chiral 1,3-dioxin-
4-ones to alkenes connected at the C(â) position of the
dioxinone.
Another example of high stereofacial selectivity was
obtained in the photocycloaddition of 32 from the methyl
side. Irradiation of 32 at -70 °C afforded a single
product 55 in 73% isolated yield, with no detectable
amount of the corresponding diastereomer 54. The key
NOE enhancements, summarized in Scheme 10, allowed
assignment of the stereogenic centers in 55. Interest-
ingly, the selectivity is consistent with the conformation
of the chiral dioxinone 24b in the crystal structure30 and
could suggest a similar orientation of the phenyl and
methyl substituents in the active triplet excited state of
32.
Sch em e 9
Epimerization of the dioxanone ketal center in photo-
products 53 and 55 was examined by treatment with
oxalic acid, camphorsulfonic acid, and p-toluenesulfonic
acid, which led to efficient epimerization in similar
compounds.9 However, treating 53 and 55 under these
conditions, failed to provide a significant amount of the
less stable epimers 52 and 54, respectively, and resulted
in a mixture of undefined products.
The high stereofacial selectivity obtained in the pho-
tocycloaddition of 31 and 32 allows enantioselective
synthesis of spiro ethers and spiro ketals, starting from
optically pure dioxinones 23 and 24 (Scheme 4) or their
enantiomers. The desired optically pure dioxinones could
be prepared from (R)-hydroxybutanoic acid31 or (S)-
hydroxybutanoic acid,32 following literature procedures.33
sterically hindered one. The first possibility was exam-
ined by the photocycloaddition of 30 at -70 °C, which
afforded a mixture of 50 and 51 in a 1.8:1 ratio and 90%
yield. The preferred stereofacial selectivity was obtained
from the hydrogen side of the acetal center. On the basis
of the above assumption, we have anticipitated high
selectivity in the cycloaddition of a chiral dioxinone
possessing isopropyl and methyl substituents, from the
isopropyl side.
Irradiation of 31, possessing a methyl and isopropyl
substituent, was examined under the usual conditions
at -70 °C. A single product (53) was obtained in 80%
isolated yield, with no detectable amount of the corre-
sponding diastereomer 52. The structure of 53 was
determined by NMR.25,29 A 12.5% NOE enhancement
between the proton resonances of the four-membered
ring, allows assignment of the syn stereochemistry. NOE
enhancement between the methyl substituent at the
ketal center and the cyclobutyl protons resonances,
summarized in Scheme 9, allowed unambiguous deter-
mination of facial selectivity from the isopropyl side. This
Exp er im en ta l Section
THF was distilled from the potassium benzophenone ketyl,
and HMPA was distilled over CaH2. Silica gel 60 (230-400
mesh ASTM) for column chromatography was used. Melting
(30) Sato, M.; Uehara, F.; Kamaya, H.; Murakami, M.; Kaneko, C.;
Furuya, T.; Kurihara, H. J . Chem. Soc., Chem. Commun. 1996, 1063.
(31) (a) Seebach, D.; Zuger, M. Helv. Chim. Acta 1982, 65, 495. (b)
Seebach, D.; Beck, A. K.; Breitschuh, R.; J ob, K. Org. Synth. 1992, 71,
39.
(32) (a) Cainelli, G.; Manescalchi, F.; Martelli, G.; Panunzio, M.;
Plessi, L. Tetrahedron Lett. 1985, 26, 3369. (b) Griesbeck, A.; Seebach,
D. Helv. Chim. Acta 1987, 70, 1320. (c) Seebach, D.; Sutter, M. A.;
Weber, R. H.; Zuger, M. F. Org. Synth. 1990, Collect. Vol. VII 1990,
215.
(29) For determination of similar structures by NMR, c.f.: (a)
Becker, D.; Haddad, N. Tetrahedron 1993, 49, 947. (b) Becker, D.;
Haddad, N. Isr. J . Chem. 1989, 29, 303.
(33) Lange, G. L. Organ, M. G.; Roche, M. R. J . Org. Chem. 1992,
57, 6000.

7634 J . Org. Chem., Vol. 62, No. 22, 1997
Haddad et al.
points are uncorrected. EI-HR-MS spectra were recorded on
a Varian Matt-71.
dioxinone (13.3 mmol) in dry CCl4 (60 mL) was irradiated by
sun lump and stirred at 40 °C for 4-5 h (followed by TLC).
The reaction mixture was cooled down to 0 °C, filtered through
Celite, and then concentrated under reduced pressure, the
crude product was purified by flash chromatography to afford
the desired product in 50-60% yield.
5-Br om o-6-(b r om om et h yl)-2-ter t -b u t yl-1,3-d ioxin -4-
on e (22) was prepared from 21 as described above, using 2.5
equiv of NBS: 1H-NMR (CDCl3) δ 5.14 (s, 1H), 4.18 (dd, 2H),
1.10 (s, 9H).
6-(Br om om et h yl)-2-isop r op yl-2-m et h yl-1,3-d ioxin -4-
on e (25) was prepared from 23 as described above: 1H-NMR
(CDCl3) δ 5.48 (s, 1H), 3.87 (s, 2H), 2.25 (m, 1H), 1.59 (s, 3H),
1.07 (d, J ) 1.3 Hz, 3H), 1.03 (d, J ) 1.3 Hz, 3H); HR-MS
calcd for C9H13O3Br m/z 248.0014, 250.0004, found m/z 248.0011,
250.0002 respectively.
6-(Br om om et h yl)-2-m et h yl-2-p h en yl-1,3-d ioxin -4-on e
(26) was prepared from 24 as described above: 1H-NMR
(CDCl3) δ 7.52 (m, 2H), 7.37 (m, 3H), 5.43 (s, 1H), 3.87 (dd, J
) 10.9 Hz, 2H), 1.92 (s, 3H).
2-Meth yl-5,6-d ih yd r o-4H-p yr a n -4on e (16). A solution of
acetylacetone (10 g, 0.1 mol) in THF (20 mL) was added
dropwise to a cold (0 °C) suspension of sodium hydride (0.12
mol, 3.6 g) in HMPA (15 mL) and THF (150 mL) mixture. The
reaction was stirred for 20 min, then a 2.5 M solution of n-BuLi
in hexane (0.12 mol, 48 mL) was introduced in a dropwise
addition. The resulted mixture was stirred for 30 min, then
dry paraformaldehyde powder (0.2 mol, 6 g) was added in a
one portion. The reaction mixture was stirred vigorously for
an additional 2 h at rt and treated with HCl (3 M, ∼150 mL)
until pH ) 2 was reached. The resulted mixture was stirred
2.5 h, and the aqueous layer was separated and then extracted
with diethyl ether. The organics were combined, washed with
brine, dried over Na2SO4, and then concentrated under reduced
pressure. Purification of the residue by flash chromatography
(hexane/EtOAc ) 4:1, Rf ) 0.2) afforded 5.6 g of dihydropyrone
16 in 50% yield: 1H-NMR (CDCl3) δ 5.30 (s, 1H), 4.42 (t, J )
6.8 Hz, 2H), 2.47 (t, J ) 6.8 Hz, 2H), 1.97 (s, 3H).
3-Br om o-2-(b r om om e t h yl)-5,6-d ih yd r o-4H -p yr a n -4-
on e (18). A mixture of 2-methyl-5,6-dihydro-4H-pyran-4-one
(1.0 g, 8.93 mmol), NBS (1.9 g, 11.2 mmol), and AIBN (40 mg)
in 30 mL of CCl4 was refluxed for 2.5 h, and additional
amounts of NBS (1.5 g) and AIBN (2 × 40 mg) were added at
1 h intervals. The reaction mixture was stirred for an
additional 30 min, cooled to 0 °C, filtered, and then concen-
trated under reduced pressure to afford 18 and 19. Separation
of the products by flash chromatography [hexane/EtOAc 10:
1; Rf (18) ) 0.2, Rf (19) ) 0.25] afforded 1.57 g of 18 (65% yield)
and 312 mg of 19 (10% yield).
2-(2,2-Dica r b e t h oxye t h yl)-5,6-d ih yd r o-4H -p yr a n -4-
on e (27). A solution of diethyl malonate (0.54 g, 3.4 mmol)
in THF (2 mL) was added dropwise to a suspension of sodium
hydride (0.13 g, 4.26 mmol) in THF (30 mL). The reaction
mixture was stirred under reflux for 15 min and cooled to room
temperature, then dibromide 18 (0.77 g, 2.84 mmol) was added,
and the mixture was stirred at room temperature for ad-
ditional 2 h, quenched by addition of saturated aqueous
solution of NaHCO3, extracted with ether, dried over MgSO4,
and concentrated under reduced pressure. Purification by
flash chromatography afforded 0.77 g of 3-bromo-2-(2,2-dicar-
bethoxyethyl)-5,6-dihydro-4H-pyran-4-one (33) in 77% yield:
1H-NMR (CDCl3) δ 4.48 (t, 2H), 4.2 (q, 4H), 3.72 (t, 1H), 3.21
(d, 2H), 1.28 (t, 6H). Bromopyrone 33 (1.0 g, 3.11 mmol) was
added to a suspension of 40 mL of THF, 1.2 equiv of Et3N,
and 10% Pd/C (200 mg) under atmospheric pressure of H2 at
room temperature. The reaction was completed after 20 min.
Filtration of the catalyst then concentration of the filtrate
under reduced pressure afforded the crude product which was
purified by flash chromatography (hexane/EtOAc 1:1, Rf ) 0.4)
to give 0.65 g of the desired product (27) in 90% yield: 1H-
NMR (CDCl3) δ 5.34 (s, 1H), 4.43 (t, J ) 6.9 Hz, 2H), 4.2 (m,
4H), 3.66 (t, J ) 8.3 Hz, 1H), 2.37 (d, J ) 8.3 Hz, 2H), 2.5 (t,
J ) 6.5 Hz, 2H), 1.28 (t, 6 H); HR-MS calcd for C13H18O6 m/z
270.1103, found m/z 270.1112.
2,2-Dim et h yl-6-[2,2-d ica r b et h oxy-3-[2-(5,6-d ih yd r o-4-
oxo-4H-p yr a n )yl)]p r op yl]-1,3-d ioxin -4-on e (29). Photo-
substrate 29 was prepared by coupling of dihydropyrone 27
(580 mg, 2.16 mmol) with bromodioxinone 28 (720 mg, 3.24
mmol) following the procedure described for the preparation
of 33. Purification of the crude product by flash chromatog-
raphy afforded 0.6 g of the desired product as a white powder
in 68% yield: mp 112-114 °C; 1H-NMR (CDCl3) δ 5.32 (s, 1H),
5.30 (s, 1H), 4.38 (t, J ) 8.5 Hz, 2H), 4.18 (q, J ) 7.2 Hz, 4H),
2.95 (s, 2H), 2.89 (s, 2H), 2.51 (t, J ) 8.4 Hz, 2H), 1.63 (s, 6H),
1.25 (t, J ) 7.3 Hz, 6H); HR-MS calcd for C22H30O9 m/z
438.1890, found m/z 438.1850.
2-ter t-Bu t yl-6-[2,2-d ica r b et h oxy-3-[2-(5,6-d ih yd r o-4-
oxo-4H-p yr a n )yl]p r op yl]-2-m eth yl-1,3-d ioxin -4-on e (30).
Photosubstrate 30 was prepared by coupling of dihydropyrone
33 (200 mg, 0.66 mmol) with dibromodioxinone 22 (229 mg,
0.73 mmol) following the procedure described for the prepara-
tion of 33. Purification of the crude product by flash chroma-
tography afforded 310 mg of the corresponding dibromoproduct
in 79% yield: 1H-NMR (CDCl3) δ 5.32 (s, 1H), 5.06 (s, 1H),
4.42 (t, 2H), 4.18 (q, 4H), 3.42 (d, 2H), 2.96 (d, 2H), 2.50 (t,
2H), 1.25 (t, 6H), 1.01 (s, 9H).
Reduction of the vinyl bromides, following the procedure
described for the preparation of 27, and then purification of
the crude product by flash chromatography afforded 171 mg
of the desired product as a white powder in 75% yield: mp
89-91 °C; 1H-NMR (C6D6) δ 5.37 (s, 1H), 5.26 (s, 1H), 4.66 (s,
1H), 3.91 (m, 6H), 3.53 (t, J ) 7.0 Hz, 2H), 3.00-2.8 (m, 4H),
1.93 (t, J ) 7.0 Hz, 2H), 0.89 (t, 3H), 0.88 (s, 9H), 0.87 (t, 3H);
HR-MS calcd for C22H30O9 m/z 438.1890, found m/z 438.1850.
18: 1H-NMR (CDCl3) δ 4.55 (t, J ) 8.2 Hz, 2H), 4.21 (s, 2H),
2.8 (t, J ) 8.2 Hz, 2H); HR-MS calcd for C6H6O2Br2 m/z
269.8714, 270.8793, 271.8694; found m/z 269.8685, 270.8828,
271.8685, respectively.
19: 1H-NMR (CDCl3) δ 6.78 (s, 1H), 4.68 (t, J ) 6.8 Hz, 2H),
2.87 (t, J ) 6.8 Hz, 2H). 3-Br om o-2-m eth yl-5,6-d ih yd r o-
4H-p yr a n -4-on e (17) was obtained in 60% isolated yield
following the above procedure, using 1 equiv of NBS: 1H-NMR
(CDCl3) δ 4.45 (t, J ) 6.8 Hz, 2H), 2.70 (t, J ) 6.8 Hz, 2H),
2.25 (s, 3H); HR-MS calcd for C6H7O2Br m/z 189.9730, 191.9733;
found m/z 189.9629, 191.9609, respectively.
2-ter t-Bu tyl-6-m eth yl-1,3-d ioxin -4-on e (21). A solution
of the dioxinone 20 (213 mg, 1.5 mmol) and pivaldehyde (387
mg, 4.5 mmol) in mesitylene (3 mL) was stirred under reflux
for 1 h. The reaction mixture was concentrated under reduced
pressure and then the crude mixture was purified by flash
chromatography (hexane/EtOAc ) 7:1, Rf ) 0.3) to give 190
mg of the desired product in 60% yield: 1H-NMR (CDCl3) δ
5.26 (s, 1H), 5.02 (s, 1H), 2.02 (s, 3H), 1.04 (s, 9H).
P r ep a r a tion of Dioxin on es 23 and 24 (Gen er a l P r oce-
d u r e). Concentrated sulfuric acid (1.63 mL, 0.03 mol) was
added dropwise to a cold solution (-10 °C) of tert-butyl
acetoacetate (0.03 mol, 5 mL) and the corresponding ketone
(0.06 mol) in acetic anhydride (10 mL). The mixture was
stirred for 15 h at 0 °C and then carefully transferred to an
ice-cooled saturated solution of potassium carbonate (∼70 mL)
and stirred for 30 min at room temperature. The aqueous
layer was separated and extracted with chloroform (3 × 50
mL), and the organic layers were combined, washed with brine,
dried over MgSO4, and then concentrated under reduced
pressure. Purification by flash chromatography afforded the
desired dioxinone in 65-75% yield.
2-Isop r op yl-2,6-d im eth yl-1,3-d ioxin -4-on e (23) was ob-
tained as described above in 75% yield from isopropyl methyl
ketone: 1H-NMR (CDCl3) δ 5.17 (s, 1H), 2.20 (m, 1H), 1.95 (s,
3H), 1.53 (s, 3H), 1.01 (d, J ) 1.4 Hz, 3H), 0.98 (d, J ) 1.4 Hz,
3H); HR-MS calcd for C9H14O3 m/z 170.0943, found m/z
170.0942.
2,6-Dim et h yl-2-p h en yl-1,3-d ioxin -4-on e (24) was ob-
tained as described above in 65% yield from acetophenone: 1H-
NMR (CDCl3) δ 7.42 (m, 5H), 5.14 (s, 1H), 1.99 (s, 3H), 1.86
(s, 3H).
Br om in a t ion of Dioxin on es 21, 23, a n d 24 (Gen er a l
P r oced u r e). A suspension of NBS (26.6 mmol, 4.74 g),
benzoyl peroxide (1.33 mmol, 0.32 g), and the corresponding

Spiro Ethers and Spiro Ketals via Photoaddition
J . Org. Chem., Vol. 62, No. 22, 1997 7635
2-Isop r op yl-2-m eth yl-6-[2,2-d ica r beth oxy-3-[2-(5,6-d i-
h yd r o-4-oxo-4H-p yr a n )yl]p r op yl]-1,3-d ioxin -4-on e (31).
Photosubstrate 31 was prepared by coupling of dihydropyrone
27 (270 mg, 1.0 mmol) with bromodioxinone 25 (247 mg, 1.1
mmol) following the procedure described for the preparation
of 33. Purification of the crude product by flash chromatog-
raphy afforded 326 mg of the desired product as a white
t r ioxa -5,8-d ioxo-13r,15r-t et r a cyclo[4.9.0.01,12.07,12]p en -
1
ta d eca n e (50): H-NMR (C6D6) δ 4.34 (s, 1H), 4.12 (m, 1H),
4.05-3.78 (m, 4H), 3.38 (dt, J ) 5.9, 11.8 Hz, 1H), 3.13 (d, J ab
) 9.9 Hz, 1H), 2.95 (d, J ab ) 9.9 Hz, 1H), 2.90 (d, J ab ) 13.7
Hz, 1H), 2.88 (d, J ab ) 13.6 Hz, 1H), 2.59 (d, J ab ) 13.7 Hz,
1H), 2.52 (d, J ab ) 13.6 Hz, 1H), 2.38 (dt, J ) 3.9, 15.7 Hz,
1H), 2.01 (m, 1H), 0.93 (m, 3H), 0.87 (s, 9H), 0.83 (t, 3H); HR-
MS calcd for C22H30O9 m/z 438.1890, found m/z 438.1897. 3r-
ter t-Bu tyl-14,14-dicar beth oxy-6â,7â-dih ydr o-2,4,11-tr ioxa-
5,8-d ioxo-13â,15â-tetr a cyclo[4.9.0.01,12.07,12]p en ta d eca n e
(51): 1H-NMR (C6D6) δ 4.51 (s, 1H), 3.95 (m, 4H), 3.70 (d, J )
7.7 Hz, 1H), 3.52 (d, J ) 7.7 Hz, 1H), 3.42 (m, 1H), 3.08 (t, J
) 11.1 Hz, 1H), 2.95 (d, J ) 13.6 Hz, 1H), 2.69 (d, J ab ) 11.2
Hz, 1H), 2.57 (d, J ab ) 11.2 Hz, 1H), 2.48 (d, J ) 13.8 Hz, 1H),
2.38 (m, 1H), 1.77 (bd, J ) 15.5 Hz, 1H), 0.91 (m, 6H), 0.86 (s,
9H); CI-MS [M+H]: 439.2; HR-MS calcd for C22H30O9 m/z
438.1890, found m/z 438.1910.
14,14-Dicar beth oxy-6â,7â-dih ydr o-3r-isopr opyl-3â-m eth -
yl-2,4,11-tr ioxa-5,8-dioxo-13â,15â-tetr acyclo[4.9.0.01,12.07,12]-
p en ta d eca n e (53). Irradiation of 31 at -70 °C, afforded 53
in 80% isolated yield: 1H-NMR (CDCl3) δ 4.38 (m, 1H), 4.22
(m, 4H), 3.90 (m, 1H), 3.45 (d, J ) 11.0 Hz, 1H), 3.02 (d, J )
14.5 Hz, 1H), 2.91 (d, J ) 14.5 Hz, 1H), 2.69 (d, J ) 12.1 Hz,
1H), 2.58-2.46 (m, 3H), 2.38 (m, 1H), 2.04 (m, 1H), 1.48 (s,
3H), 1.29-1.22 (m, 6H), 1.04 (d, J ) 1.7 Hz, 3H), 1.03 (d, J )
1.7 Hz, 3H); HR-MS calcd for [M - C5H10O, typical fragmenta-
tion of isopropyl methyl ketone] C17H20O8 m/z 352.1158, found
m/z 352.1189; CI-MS [M + H] 438.8; calcd for C22H30O9 m/z
439.19.
1
powder in 75% yield: mp 95-97 °C; H-NMR (CDCl3) δ 5.32
(s, 1H), 5.27 (s, 1H), 4.38 (t, 2H), 4.18 (m, 4H), 2.90 (m, 4H),
2.50 (t, 2H), 2.12 (m, 1H), 1.55 (s, 3H), 1.25 (t, 6H), 1.00 (d,
6H); CI-MS [M + H] 439.1, calcd for C22H30O9 m/z 438.19.
2-Met h yl-2-p h en yl-6-[2,2-d ica r b et h oxy-3-[2-(5,6-d ih y-
d r o-4H-p yr a n )yl]p r op yl]-1,3-d ioxin -4-on e (32). Photosub-
strate 32 was prepared by coupling of dihydropyrone 27 (270
mg, 1.0 mmol) with bromodioxinone 26 (311 mg, 1.1 mmol)
following the procedure described for the preparation of 33.
Purification of the crude product by flash chromatography
afforded 330 mg of the desired product as a white powder in
70% yield: mp 89-91 °C; 1H-NMR (CDCl3) δ 7.36 (m, 2H),
7.24 (m, 3H), 5.25 (s, 1H), 5.23 (s, 1H), 4.35 (m, 2H), 4.20 (m,
4H), 2.92 (m, 4H), 2.50 (m, 2H), 1.84 (s, 3H), 1.25 (m, 6H);
CI-MS [M + H] 473.0, calcd for C25H28O9 m/z 472.17.
2-Cyclop en ten yl-1-iod oeth a n e (35) was prepared from
2-cyclopentenylethan-1-ol22a in 70% yield, following Millar’s
procedure:22b 1H-NMR (CDCl3) δ 5.44 (s, 1H), 3.25 (t, 2H), 2.68
(t, 2H), 2.26 (m, 4H), 1.89 (m, 2H).
2-ter t-Bu t yl-2-m et h yl-6-[3-(1-cyclop en t en yl)p r op yl]-
1,3-d ioxin -4-on e (36). LDA in THF solution was prepared
by dropwise addition of n-BuLi (0.9 mL, 2.3 mmol, 2.5 M in
hexane) to a solution of diisopropylamine (0.3 mL, 2.2 mmol)
and HMPA (0.6 mL) in THF (8 mL), cooled to -70 °C. The
mixture was stirred for 30 min at the same temperature to
ensure complete formation of LDA. Solution of dioxinone 34
(357 mg, 1.94 mmol) in THF (3 mL) was added dropwise over
a 20 min period. After the mixture was stirred for additional
45 min at -70 °C, alkenyl iodide 35 (460 mg, 2.13 mmol) in
THF (2 mL) was added dropwise, then the temperature was
slowly raised to room temperature over 1 h period and the
resulted red solution was stirred for an additional 40 min. The
reaction quenched by addition of 10% HCl (4 mL) and
extracted with ether (3 × 10 mL). The combined organics were
washed with brine, dried over MgSO4, and concentrated under
reduced pressure. Purification by flash chromatography af-
forded the desired product 36 (154 mg) and its corresponding
C(R) isomer 37 (62 mg) in 40% total yield.
14,14-Dica r beth oxy-6â,7â-d ih yd r o-3r-m eth yl-3â-p h en -
yl-2,4,11-tr ioxa-5,8-dioxa-13â,15â-tetr acyclo[4.9.0.01,12.07,12]-
p en ta d eca n e (55). Irradiation of 32 at -70 °C afforded 55
in 73% isolated yield: 1H-NMR (CDCl3) δ 7.38 (m, 5H), 4.46
(m, 1H), 4.15 (m, 4H), 3.90 (m, 1H), 2.98 (d, J ) 12.0 Hz, 1H),
2.76 (d, J ) 12.0 Hz, 1H), 2.70 (m, 1H), 2.56 (dd, J 1 ) 13.0
Hz, J 2 ) 17.1 Hz, 2H), 2.48 (d, J ) 14.9 Hz, 1H), 2.40 (m, 1H),
2.02 (d, J ) 14.9 Hz, 1H), 1.85 (s, 3H), 1.20 (m, 6H); CI-MS
[M + H] 472.9; calcd for C24H28O9 m/z 472.17.
Ir r a d ia tion of 36: Irradiation of 36 at 0 and -70 °C
afforded a mixture of 48 and 49 in a 1:1 ratio and 70% isolated
yield.
3R-ter t-Bu tyl-6r,7r-d ih yd r o-3â-m eth yl-2,4-d ioxa -5-oxo-
12r,14r-tetr a cyclo[4.9.0.01,11.07,11]bu ta d eca n e (48). 1H-
NMR (C6D6) δ 2.51 (d, 1H), 2.19 (dd, J ) 13.4, 6.4 Hz, 1H),
2.04 (dd, J ) 10.0, 8.1 Hz, 1H), 1.96 (dd, J ) 13.5, 7.3 Hz,
1H), 1.81 (m, 1H), 1.70 (m, 1H), 1.57 (m, 2H), 1.42 (m, 2H),
1.41 (s, 3H), 1.35 (m, 2H), 1.18 (m, 2H), 0.84 (s, 9H); HR-MS
calcd for C17H26O3 m/z 278.1881, found m/z 278.1881.
3r-ter t-Bu tyl-6â,7â-d ih yd r o-3â-m eth yl-2,4-d ioxa -5-oxo-
12â,14R-t et r a cyclo[4.9.0.01,11.07,11]b u t a d eca n e (49): 1H-
NMR (C6D6) δ 2.39 (d, 1H), 2.37 (t, 1H), 2.10 (dd, J ) 11.4, 9.5
Hz, 1H), 1.96 (dd, J ) 17.1, 7.6 Hz, 1H), 1.81 (m, 1H), 1.60
(m, 1H), 1.50 (m, 2H), 1.32 (m, 4H), 1.18 (m, 1H), 1.10 (m,
1H), 1.02 (bs, 12H); HR-MS calcd for C17H26O3 m/z 278.1881,
found m/z 278.1946.
4′,4′-Dica r b e t h oxy-6r-e t h oxy-3,7â-d ioxa -8,2′-d ioxo-
bicyclo[4.3.0]n on a n e-2â-sp ir o-1′-cyclop en ta n e (39). A so-
lution of 38 (52.5 mg, 0.13 mmol) and a catalytic amount of
p-TsOH (5 mg) in 5 mL of absolute EtOH was stirred at room
temperature for 18 h. The solvent was removed under reduced
pressure and the residue purified by flash chromatography to
afford 29.3 mg of the desired product in 57% yield: 1H-NMR
(C6D6) δ 4.02 (m, 2H), 3.84 (m, 2H), 3.41 (dd, J ) 1.7, 18.5 Hz,
1H), 3.31 (m, 3H), 3.15 (m, 1H), 2.92 (dd, J ) 1.7, 17.3 Hz,
1H), 2.53 (dd, J ) 8.5, 17.4 Hz, 1H), 2.37 (d, J ) 8.6 Hz, 1H),
2.32 (d, J ) 13.2 Hz, 1H), 2.16 (dd, J ) 5.6, 17.8 Hz, 1H), 2.01
(dd, J ) 5.3, 8.5 Hz, 1H), 1.54 (dt, J ) 5.1, 13.9 Hz, 1H), 1.41
(m, 1H), 0.92 (t, 6H), 0.83 (t, 3H); HR-MS calcd for C19H26O9
m/z 398.1577, found m/z 398.1559.
1
P h otosu bstr a te 36: H-NMR (CDCl3) δ 5.31 (s, 1H), 5.11
(s, 1H), 2.14 (m, 8H), 1.81 (m, 2H), 1.65 (m, 2H), 1.54 (s, 3H),
1.03 (s, 9H); HR-MS calcd for C17H26O3 m/z 278.1881, found
m/z 278.1893.
1
C(R) isom er 37: H-NMR (CDCl3) δ 5.33 (s, 1H), 2.23 (m,
8H), 1.94 (s, 3H), 1.83 (m, 2H), 1.52 (s, 3H), 1.03 (s, 9H); HR-
MS calcd for C17H26O3 m/z 278.1881, found m/z 278.1840.
Gen er a l P r oced u r e for th e Ir r a d ia tion s of Dioxin on es
29-32. An 80-W mercury vapor lamp (Q-81) was used for
irradiations via a Pyrex glass filter (λ > 295). The irradiations
were carried out in a solution of benzophenone (100 mg) in 18
mL of acetonitrile (0 °C) or 50% acetone/acetonitrile as solvent
(-70 °C) under a nitrogen atmosphere. The concentrations
always kept below 0.05 M, and the reactions were followed by
the UV absorption of the starting materials on TLC and were
usually completed after 3 h at -70 °C. The solvents removed
under reduced pressure and the crude photoproducts were
separated by flash chromatography to afford the corresponding
products, as a white solid in all cases, in 70-92% total yield.
14,14-Dica r beth oxy-6r,7r-d ih yd r o-3,3-d im eth yl-2,4,11-
t r ioxa -5,8-d ioxo-13r,15r-t et r a cyclo[4.9.0.01,12.07,12]p en -
ta d eca n e (38). Irradiation of 29 at 0 °C afforded single
product 38 in 90% yield. 1H-NMR (CDCl3) δ 4.39 (m, 1H), 4.2
(m, 4H), 3.89 (m, 1H) 3.41 (d, J ) 11.2 Hz, 1H), 3.05 (d, J )
14.6 Hz, 1H), 2.92 (d, J ) 11.6 Hz, 1H), 2.66 (d, J ) 14.0 Hz,
1H), 2.53 (m, 3H), 2.38 (m, 1H), 1.61 (s, 3H), 1.57 (s, 3H), 1.24
(t, 3H), 1.22 (t, 3H); HR-MS calcd for C20H26O9 m/z 410.1577,
found m/z 410.1577.
4′,4′-Dica r beth oxy-3,7â-d ioxa -8,2′-d ioxobicyclo[4.3.0]-
n on a n e-2-sp ir o-1′-cyclop en ta n e (40b). Photoproduct 38
(58.0 mg, 0.142 mmol) in THF solution (0.3 mL) was added in
one portion to a cold mixture (-70 °C) of NaBH4 (7.5 mg, 0.2
mmol) and EtOH (0.1 mL) in THF (0.9 mL). After 25 min at
this temperature, H2O was added, the organic solvents were
evaporated under reduced pressure, and then the residue was
Ir r a d ia tion of 30: Irradiation of 30 at -70 °C afforded
mixture of 50 and 51 in a 1.8:1 ratio and 90% isolated yield.
3r-ter t-Bu t yl-14,14-d ica r b et h oxy-6r,7r-d ih yd r o-2,4,11-

7636 J . Org. Chem., Vol. 62, No. 22, 1997
Haddad et al.
extracted with CH2Cl2 (3×5 mL), dried over MgSO4, and
concentrated under reduced pressure. The crude product was
purified by flash chromatography to afford 33.9 mg of the
corresponding alcohols 40a in 67% yield: 1H-NMR (CDCl3) δ
4.70 (m, 1H), 4.20 (m, 4H), 4.09 (q, J ) 7.9, 14.3 Hz, 1H), 3.90
(q, J ) 7.8, 16.0 Hz, 1H), 3.82 (dd, J ) 5.2, 12.0 Hz, 1H), 3.62
(t, J ) 11.9 Hz, 1H), 2.92 (d, J ) 14.6 Hz, 1H), 2.83 (dd, J )
13.0, 17.2 Hz, 1H), 2.53 (m, 1H), 2.36 (m, 3H), 2.05 (s, 2H),
1.62 (m, 1H), 1.23 (m, 6H); HR-MS calcd for C17H24O8 m/z
356.1471, found m/z 356.1451.
The alcohols (10 mg, 0.03 mmol) were dissolved in a 1:1
solution of EtOAc/Et2O (2 mL), followed by addition of J ones
reagent (0.03 mL) at room temperature. The mixture was
stirred for 6 h and extracted with EtOAc, and the combined
organics were washed with saturated aqueous solution of
NaHCO3, dried over MgSO4, and then concentrated under
reduced pressure. Purification by flash chromatography af-
forded 8 mg of the desired ketone (40b) in 80% yield: 1H-NMR
(CDCl3) δ 4.66 (q, 1H), 4.20 (m, 4H), 3.69 (m, 1H), 3.57 (m,
1H), 3.34 (d, J ) 19.8 Hz, 1H), 2.83 (d, J ) 14.9 Hz, 1H), 2.64
(d, J ) 19.5 Hz, 1H), 2.55 (d, J ) 14.6 Hz, 1H), 2.52 (s, 2H),
1.98 (m, 1H), 1.92 (m, 1H), 1.25 (m, 7H); HR-MS calcd for [M
- C2H5O] C15H17O7 m/z 309.0974, found m/z 309.0978; CI-MS
[M + H] 355.2; calcd for C17H22O8 m/z 354.36.
P r ep a r a tion of Sp ir o Keta ls 41 a n d 43 (Gen er a l P r o-
ced u r e). MCPBA (0.068 mmol) was added to a mixture of
the corresponding spiro ether (39 or 40) (0.045 mmol) and a
catalytic amount of Li2CO3 in CH2Cl2 (1.0 mL). The reaction
was stirred for 5 h at room temperature, quenched by addition
of 10% aqueous solution of Na2S2O4 (0.5 mL), and extracted
with CHCl3 (3×5 mL), and the combined organics were washed
with 10% aqueous solution of K2CO3 and brine and then dried
over Na2SO4 and concentrated. Purification by flash chroma-
tography afforded the desired product in 70-75% yield.
5′,5′-Dica r b e t h oxy-6r-e t h oxy-3,7â,2′â-t r ioxa -8,3′-d i-
oxobicyclo[4.3.0]n on an e-2-spir o-1′-cycloh exan e (41):34 1H-
NMR (C6D6) δ 3.95 (q, 2H), 3.82 (m, 2H), 3.66 (td, J ) 3.6, 7.2
Hz, 1H), 3.40 (d, J ) 16.6 Hz, 1H), 3.30 (m, 1H), 3.11 (m, 2H),
2.5 (dd, J ) 6.2, 15.0 Hz, 1H), 2.42 (d, J ) 16.1 Hz, 2H), 2.17
(d, J ) 14.8 Hz, 1H), 2.12 (d, J ) 14.8 Hz, 1H), 1.51 (d, J )
7.2 Hz, 1H), 1.68 (d, J ) 13.8 Hz, 1H), 1.25 (td, J ) 6.8, 13.0
Hz, 1H), 0.9 (m, 6H), 0.82 (t, 3H); HR-MS calcd for C19H26O10
m/z 414.1526, found m/z 414.1518. 5′,5′-Dica r b et h oxy-
3,7â,2′â-tr ioxa -8,3′-d ioxobicyclo[4.3.0]n on a n e-2-n on a n e-
1′-cycloh exa n e (43): 1H-NMR (C6D6) δ 3.90 (q, 2H), 3.81 (m,
2H), 3.75 (t, J ) 11.8 Hz, 1H), 3.59 (bs, 1H), 3.40 (d, J ) 16.6
Hz, 1H), 2.93 (dd, J ) 7.8, 12.0 Hz, 1H), 2.49 (d, J ) 16.8 Hz,
1H), 2.40 (d, J ab ) 14.7 Hz, 1H), 2.24 (d, J ab ) 14.7 Hz, 1H),
2.23 (d, J ab ) 17.1 Hz, 1H), 1.82 (dd, J ) 8.1, 16.0 Hz, 1H),
1.43 (bd, J ) 14.5 Hz, 1H), 1.32 (dd, J ) 2.1, 8.5 Hz, 1H), 1.09
(m, 1H), 0.87 (t, 3H), 0.83 (t, 3H); HR-MS calcd for C17H22O9
m/z 370.1264, found m/z 370.1256.
5′,5′-Dicar beth oxy-3,7â,2′r-tr ioxa-8,3′-dioxobicyclo[4.3.0]-
n on a n e-2-sp ir o-1′-cycloh exa n e (44). A catalytic amount of
p-TsOH was added to a mixture of spiro ketal 43 (20 mg, 0.054
mmol) in CH2Cl2 (2 mL), then the reaction mixture was stirred
at room temperature, until a constant ratio of 29:71 between
the isomers 43 and 44 was achieved (45 min). Separation of
the isomers by flash chromatography afforded 5.5 mg (28.5%
yield) of 43 and 14.1 mg (71% yield) of 44: 1H-NMR (C6D6) δ
4.22 (dt, J ) 6.7, 10.6 Hz, 1H), 3.92 (q, 2H), 3.84 (q, 2H), 3.36
(d, J ) 16.8 Hz, 1H), 3.27 (t, J ) 11.5 Hz, 1H), 2.91 (q, J )
5.2, 11.6 Hz, 1H), 2.43 (d, J ) 16.8 Hz, 1H), 2.31 (d, J ) 14.6
Hz, 1H), 1.90 (d, J ) 14.7 Hz, 1H), 1.85 (t, J ) 7.3 Hz, 1H),
1.74 (t, J ) 13.2 Hz, 1H), 1.65 (dd, J ) 8.6, 16.4 Hz, 1H), 1.23
(m, 2H), 0.89 (t, 3H), 0.84 (t, 3H); HR-MS calcd for C17H22O9
m/z 370.1264, found m/z 370.1296.
Ack n ow led gm en t. This research was supported by
the Israel Science Foundation administered by the
Israel Academy of Sciences and Humanities. The Mass
Spectrometry Center at the Technion, Haifa, is acknowl-
edged.
Su p p or tin g In for m a tion Ava ila ble: Copies of 1H-NMR
spectra of all key compounds, 13C-NMR spectra of 29-32, 48,
and 49, COSY-45 and selected NOE difference spectra of 38,
41, 43-51, 53, and 55, 1H-NMR spectra of the isomerization
studies of 43, and ORTEP presentation of the X-ray structure
of 41 (61 pages). This material is contained in libraries on
microfiche, immediately follows this article in the microfilm
version of the journal, and can be ordered from the ACS; see
any current masthead page for ordering information.
(34) The author has deposited atomic coordinates for this structure
with the Cambridge Crystallographic Data Centre the coordinates can
be obtained, on request, from the Director, Cambridge Crystallographic
Data Centre, 12 Union Road, Cambridge, CB2 1EZ, UK.
J O970816R