Noncommunicating photoreaction paths in some pregna-1,4-diene-3,20-diones

Article abstract of DOI:10.1021/jo015884z

The photochemistry of three pregna-1,4-diene-3,20-diones bearing a hydroxy or alkoxy group at C₁₇ (4-6) has been examined. Irradiation at 254 or 366 nm, where absorption by the cross-conjugated ketone moiety in ring A is predominant or exclusive, causes the 'lumiketone' rearrangement of this chromophore in low to medium quantum yield (Φ_r 0.05 to 0.31). On the contrary, irradiation at 310 nm, where the isolated ketone at C₂₀ absorbs a large portion of light causes Norrish-I fragmentation of that chromophore with a higher Φ_r (0.11-0.83). This leads to end-products arising from the conversion of the C₁₇ alkyl radical, in a way depending on the structure and the medium (reduction by hydrogen donating solvent, addition of oxygen when present). No intramolecular T-T energy transfer between the separated chromophores occurs. The 'lumiketone' rearrangement occurs independently from the irradiation wavelength (Φ_r 0.06-0.18) with the strictly related androsta-1,4-dien-3-one 8 lacking the C₂₀ ketone function.

Full text of DOI:10.1021/jo015884z

8086
J . Org. Chem. 2001, 66, 8086-8093
Non com m u n ica tin g P h otor ea ction P a th s in Som e
P r egn a -1,4-d ien e-3,20-d ion es
Andrea Ricci, Elisa Fasani, Mariella Mella, and Angelo Albini*
Department Organic Chemistry, University of Pavia, v. Taramelli 10, 27100 Pavia
albini@chifis.unipv.it
Received J uly 2, 2001
The photochemistry of three pregna-1,4-diene-3,20-diones bearing a hydroxy or alkoxy group at
C17 (4-6) has been examined. Irradiation at 254 or 366 nm, where absorption by the cross-conjugated
ketone moiety in ring A is predominant or exclusive, causes the ‘lumiketone’ rearrangement of
this chromophore in low to medium quantum yield (Φr 0.05 to 0.31). On the contrary, irradiation
at 310 nm, where the isolated ketone at C20 absorbs a large portion of light causes Norrish-I
fragmentation of that chromophore with a higher Φr (0.11-0.83). This leads to end-products arising
from the conversion of the C17 alkyl radical, in a way depending on the structure and the medium
(reduction by hydrogen donating solvent, addition of oxygen when present). No intramolecular T-T
energy transfer between the separated chromophores occurs. The ‘lumiketone’ rearrangement occurs
independently from the irradiation wavelength (Φr 0.06-0.18) with the strictly related androsta-
1,4-dien-3-one 8 lacking the C20 ketone function.
Sch em e 1
Polyfunctional molecules have long been a subject of
investigation in photochemistry. Of particular interest
is establishing the mechanisms for delocalizing and
transmitting electronic excitation in molecules in which
the chromophores are connected by a rigid hydrocarbon
framework.1 A considerable part of this work made use
of steroid derivatives, from which a variety of models with
unambiguous geometry can be prepared.2,3 As an ex-
ample, Morrison established through a series of elegant
papers2 that intramolecular energy transfer (both sin-
glet-singlet and triplet-triplet) occurred from the phenyl
‘antenna’ to the C17 keto group in steroids 1 (see Scheme
1) by way of a through-bond mechanism. This led to a
chemistry different from that observed by direct excita-
tion of the ketone chromophore. Additional keto groups
in 6 or in 11 increased the efficiency of the through-bond
energy transfer.
Further photochemical work on steroidal ketones has
been extensively carried out, both in solution4-8 and in
(1) (a) Kroon, J .; Oliver, A. M.; Paddon-Row: M. N.; Verhoven, J .
W. J . Am. Chem. Soc. 1990, 112, 4868. (b) Closs, G. L.; J ohnson, M.
D.; Miller, J . R.; Piotrowiak, P J . Am. Chem. Soc. 1989, 111, 3751. (c)
Morrison, H. Rev. Chem. Intermed. 1987, 8, 125.
(2) (a) Wu, Z. Z.; Nash, J .; Morrison, H. J . Am. Chem. Soc. 1992,
114, 6640. (b) Wu, Z. Z.; Morrison, H. J . Am. Chem. Soc. 1992, 114,
4119. (c) Morrison, H.; Pallmer, M.; Loeschen, R.; Pandey, B.; Muth-
uramu, K.; Maxwell, B. J . Org. Chem. 1986, 51, 4676. (d) Wu, Z. Z.;
Morrison, H. Photochem. Photobiol. 1989, 50, 525.
(3) Ren, Y.; Wang, Z.; Zhu, H.; Weininger, S. J .; McGimpsey, W. G.
J . Am. Chem. Soc. 1995, 117, 4367.
(4) (a) Williams, J . R.; Moore, R. H.; Blount, J . F. J . Am. Chem. Soc.
1979, 15, 5019. (b) Williams, J . R.; Moore, R. H.; Li, R.; Weeks, C. M.
J . Org. Chem. 1980, 45, 2324.
the solid state,8,9 and is a classical chapter of organic
photochemistry. There is also a pharmacological motiva-
(5) (a) Barton, D. H. R.; Taylor, W. C. J . Am. Chem. Soc. 1958, 80,
244. (b) Barton, D. H. R.; Taylor, W. C. J . Chem. Soc. 1958, 2500.
(6) (a) Dutler, H.; Ganter, C.; Ryf, H.; Uttzinger, E. C.; Weinberg,
K.; Schaffner, K.; Arigoni, D.; J eger, O. Helv. Chim. Acta 1962, 45,
2346. (b) Frei, J .; Ganter, C.; Kaegi, D.; Kocsis, K.; Miljkovic, M.;
Siewinski, A.; Wenger, R.; Schaffner, K.; J eger, O. Helv. Chim. Acta
1966, 49, 1049.
(7) (a) Cereghetti, M.; Wehrli, H.; Schaffner, K.; J eger, O. Helv.
Chim. Acta 1960, 43, 354. (b) Wehrli, H.; Cereghetti, M.; Schaffner,
K.; J eger, O. Helv. Chim. Acta 1960, 43, 369.
(8) (a) Chambers, R. J .; Marples, B. A. Chem. Commun. 1972, 1122.
(b) Ogata, M.; Noro, Y.; Yamada, M.; Tahara, T.; Nishimura, T. J .
Pharm. Sci. 1998, 87, 91. (c) Cornell, D. G.; Avram, E.; Filipescu, N.
Steroids 1979, 33, 485. (d) Reisch, J .; Topaloglu, Y.; Henkel, G. Acta
Pharm. Technol. 1986, 32, 115. (e) Arawaka, Y.; Fukaya, C.; Yamaou-
chi, K.; Yokoyama, K. Yakagaku Zasshi 1985, 105, 1029. (f) Hidaka,
T.; Huruumi, S.; Tamaki, S.; Shiraishi, M.; Minato, H. Yakagaku
Zasshi 1980, 100, 72. (g) Thoma, K.; Kerker, R.; Weissbach, C. Pharm.
Ind. 1987, 49, 961. (h) Ogata, M.; Noro, Y.; Yamada, M.; Tahara, T.;
Nishimura, T. J . Pharm. Sci. 1998, 87, 91.
10.1021/jo015884z CCC: $20.00 © 2001 American Chemical Society
Published on Web 11/07/2001

Pregna-1,4-diene-3,20-diones
J . Org. Chem., Vol. 66, No. 24, 2001 8087
Sch em e 2
tion for such studies, since many steroids are used as
topical drugs and absorb in the near UV, and phototoxic
effects have been reported.10,11
In particular, we like to point out the work on pred-
nisone and prednisolone (2), which contain two separated
carbonyl chromophores, the conjugated ketone in ring A,
and the isolated ketone function at C20. Williams,4
following pioneering work by Barton,5 showed that ir-
radiation at 254 nm of these molecules caused the
characteristic12 rearrangement of cross-conjugated cyclo-
hexadienone chromophore to a bicyclo[3.1.0]hexenone,
just as it happens in analogues lacking the C20 ketone,6
while the latter function was unaffected. Reaction at C20
ketone occurred when no other photoactive function was
present, as shown by Shaffner,7 (e.g., in the case of
monoketones of structure 3).
In contrast, the irradiation in the solid state of several
steroids strictly related to 2 was reported to leave intact
the cross-conjugated chromophore in ring A and rather
involve the side chain with the keto group at C20. This
different course of the photoreaction in the solid state
may have resulted from lattice control, and at any rate
the reported isolated yields after irradiation in the solid
state were quite low, thus making it difficult to arrive at
mechanistic conclusions. However, the difference was
intriguing and suggested the question whether there was
any interaction between the two chromophores present
in these diketones. It appeared to us that bichromophoric
systems similar to 2 were worth further investigation,
since both chromophores were expected to be highly
photochemically reactive, and it was useful to assess the
mode and extent of local reaction at either chromophore
after electronic excitation and the possible role of energy
transfer.
Sch em e 3
Sch em e 4
Resu lts
Various pregna-1,4-diene-3,20-diones were considered.
As discussed in the Introduction, the subject of the study
was the competition between chemical reactions of
separated excited moieties incorporated in a rigid skel-
eton. To make the ketone function in position 20 a
sensitive probe of energy transfer, maximal unimolecular
reactivity was desired. This led to the choice of steroid
derivatives bearing hydroxy or alkoxy substituents at
both C17 and C21. Thus, two 11,21-dihydroxy-16,17-
acetonylpregnadiendiones, the 9-fluoro (4), and the 6,9-
difluoro derivative (5) (Scheme 2) were studied, along
with the 11,17,21-trihydroxypregnadienone 6 (see Scheme
4 below). All of these compounds are used in therapy as
antiinflammatory agents, and thus a photochemical
study may have some relevance for the mechanism of
phototoxicity. As it will be showed in the following, the
photochemistry of a related androstadienone lacking the
C-20 keto group was also studied for the sake of com-
parison.
The absorption spectrum of all of the steroids studied
showed a maximum at 235 nm (log ꢀ ca. 4.2) and a longer-
wavelength absorption with a shoulder or maximum at
290-295 nm (log ꢀ ca. 2) extending to 375 nm (see Figure
1).
P h otoch em istr y of P r egn a d ien d ion e 4. Irradiation
at 254 nm of the 3,20-dione 4 (1 × 10-3 M) in argon-
flushed acetonitrile gave a main product in 75% yield
along with a minor one in ca. 3% yield (yields in low
conversion experiments are reported in Table 1 for
comparison with quantum yield data, see below; isolated
yields from preparative reactions are reported in the
Experimental Section). The NMR spectrum of the main
(9) Reisch, J .; Henkel, G.; Ekiz-Guecer, N.; Nolte, G. Liebigs Ann.
Chem. 1992, 63.
(10) (a) Suzuki, T.; Kato, T.; Kitagachi, T.; Ono, M.; Shirawaka, K.;
Nagata, M.; Konishi, R. J . Toxicol. Sci. 1996, 21, 475. (b) Keknes, A.;
J ahn, P.; Lange, L. J . Am. Acad. Dermatol. 1993, 28, 786. (c) Uchiyama,
H.; Tanaka, T.; Uehara, N.; Nakamura, M.; Tsuji, M.; Shinomiya, M.;
Tanaka, H. J . Toxicol. Sci. 1992, 17, 283.
(11) Albini, A.; Fasani, E. Drugs: Photochemistry and Photostability;
The Royal Society of Chemistry, Cambridge: 1998.
(12) (a) Schuster, D. I. Acc. Chem. Res. 1978, 11, 65. (b) Schaffner,
K.; Demuth, M. In Rearrangements in the Ground and Excited State;
De Mayo, P., Ed.; Academic Press: New York: 1980; Vol. 3, p 281. (c)
Barton, D. H. R. Helv. Chim. Acta 1959, 42, 2604. (d) Caine, D. In
Horspool, W. M., Song, P. S., Eds. CRC Handbook of Organic
Photochemistry and Photobiology; CRC Press: Boca Raton: 1995; p.
701. (e) Schultz, A. G. in ref 12d, p 716.

8088 J . Org. Chem., Vol. 66, No. 24, 2001
Ricci et al.
supported the structure of androstanedienone 8 for this
compound. The reaction quantum yield in MeCN was
higher (0.45) than at 254 nm and still higher (0.83) in
2-propanol, where ketone 8 was again the main product,
though with a somewhat lower yield (see Scheme 2, Table
1).
At this irradiation wavelength saturation of the solu-
tion with oxygen affected not only the quantum yield
(with a stronger decrease than at 254 nm, by 31 and 58%
in the two solvents) but also the product distribution. In
i-PrOH dienone 8 was not formed and was substituted
as the main product by a different compound, again
maintaining the starting structure in rings A-C and
having lost the C17 chain. This showed a strongly
deshielded O-H signal. This compound could be reduced
by sodium sulfite or triphenylphosphine. The latter
reaction was studied in more detail and gave a further
product recognized 16-hydroxy-17-keto derivative 10.
This chemical evidence along with spectroscopic indica-
tions (see Experimental Section) allowed assignment of
the structure of semiacetalic hydroperoxide 9 to the
initial photolysis product (Scheme 3, Table 1). In aceto-
nitrile a more complex products mixture was obtained.
This contained a not fully identified steroidic carboxylic
acidic, but, significantly, compound 8 was not formed also
in this case. Furthermore, when the a similar experiment
was carried out in the presence of 0.1 M dodecanthiol,
isolated yields were high again, with androstanone 8 and
androstanhydroperoxide 9 as the main products.
When the irradiation wavelength was further changed
to 366 nm, the main process returned to be rearrange-
ment to 7, even though the yield of this compound was
lower because of an efficient secondary photoreaction
occurring under this condition. Compound 8 was not
formed at all.
In view of the difference observed upon direct irradia-
tion, sensitization and quenching experiments were
carried out. Irradiation of a 1 × 10-2 M benzophenone
solution containing 1 × 10-3 M 4 at 366 nm caused
decomposition of the latter, but none of the above
compounds was formed in an appreciable extent, nor
indeed was any product isolated. The same observations
applied to the irradiation at 310 nm of an acetone
solution of 4 (light absorption by the solvent). In the
presence of piperylene the photoreaction (λirr 310 nm) was
quenched to some extent (K 2.5 M-1).
P h otoch em istr y of F u r th er P r egn a d ien ed ion es.
The steroidal diketone 5, differing from 4 for a further
fluorination in position 6, was next examined (see Scheme
2). The photochemistry observed was similar to the case
of 4 in that a closely related wavelength-dependent
product distribution was demonstrated, though the quan-
tum yields were somewhat lower. Thus, rearrangement
to pentacyclic dione 11 took place by irradiation at 254
nm and Φr was 1/3rd with respect to 4, and the same
product predominated at 366 nm. On the other hand,
irradiation at 310 nm induced loss of the C17 chain to
give monoketone 12 with a quantum yield 2/3rd of that
of 4.
F igu r e 1. UV absorption spectra of pregna-1,4-diene-3,20-
dione 4 (upper curve) and of pregnan-20-one 18 (lower curve)
in acetonitrile.
Ta ble 1. P h otoch em ica l Rea ction s of Ster oid s 4, 5, a n d 6
steroid solvent
conditions
Φr
products (% yield)a
4
4
4
4
4
4
4
4
4
4
5
5
5
6
6
8
8
8
8
MeCN 254 nm, Ar satd 0.18
254 nm, O2 satd 0.13
i-PrOH 254 nm, Ar satd 0.29
254 nm, O2 satd 0.23
7 (75), 8 (3)
7 (85)
7 (80), 8 (3)
7 (82)
7 (11), 8 (65)
7 (9)
7 (10), 8 (38), 9 (40)
7 (17), 8 (24)
7 (31), 9 (52)
7 (50)
11 (85), 12 (10)
11 (5), 12 (85)
11 (50)
13 (80), 14 (10)
13 (10), 14 (65)
15 (90)
MeCN 310 nm, Ar satd 0.45
310 nm, O2 satd 0.31
310 nm, O2 satdb 0.32
i-PrOH 310 nm, Ar satd 0.83
310 nm, O2 satd 0.35
MeCN 366 nm Ar satd
0.06
MeCN 254 nm, Ar satd 0.05
MeCN 310 nm, Ar satd 0.31
MeCN 366 nm, Ar satd 0.04
MeCN 254 nm, Ar satd 0.05
MeCN 310 nm, Ar satd 0.11
MeCN 254 nm, Ar satd 0.18
MeCN 254 nm, O2 satd 0.13
MeCN 310 nm, Ar satd 0.08
15 (90)
15 (90)
MeCN 310 nm, O2 satd 0.055 15 (90)
a
At ca. 30% conversion (20% for the irradiations at 366 nm).
b
In the presence of 0.1 M dodecanthiol.
compound showed that rings B-D were unaffected, while
ring A was strongly modified since only two of the olefinic
CH were conserved, and the third was substituted by a
sp3 carbon. This, along with further evidence (see Experi-
mental Section, in particular as far as the stereochem-
istry is concerned) allowed the assignment of the struc-
ture, as that of the acetonide of the pentacyclic enone 7
(see Scheme 2). The quantum yield of reaction was 0.18.
The photoreaction of substrate 4 in 2-propanol followed
a similar course, with a somewhat higher quantum yield
(0.29). Quantum yield values along with product distri-
butions, measured at ca. 30% conversion in order to
minimize secondary reactions, are reported in Table 1.
In both of the solvents tested, the pentacyclic derivative
7 remained the main product also in oxygen-equilibrated
solution, though the quantum yield was moderately
decreased (by 20 and 28%, respectively, in the two
solvents) under these conditions.
When diketone 4 was irradiated at 310 nm in aceto-
nitrile, however, the product distribution was reversed.
The yield of rearranged ketone 7 was reduced to 11%,
while the compound observed in a low amount at 254 nm
was now the main product with 60% yield. The NMR
spectrum of this compound showed that it had conserved
the cross-conjugated dienone moiety and in general that
the whole skeleton was hardly affected, while the side-
chain in C-17 had been lost. All of the other properties
The further pregnadiendione 6 had the same substitu-
tion pattern as 5, but differed for bearing a single hydroxy
group in position 17 instead of the 16, 17-acetonyl
functionality characteristic of both of the previously
considered substrates. Similarly to the previous cases,
this substance rearranged by irradiation at 254 nm to
give a pentacyclic derivative, dione 13 (Scheme 4). By

Pregna-1,4-diene-3,20-diones
Sch em e 5
J . Org. Chem., Vol. 66, No. 24, 2001 8089
Sch em e 6
irradiation at 310 nm the yield of 13 was reduced to 10%
and a different compound, present in a low amount at
254 nm, was now the main product.
Spectroscopic examination showed that this was the
17-keto-16-methyl derivative 14 resulting from the loss
of the C17 chain and oxidation of the hydroxyl group at
that position, while the other stereocenters in ring D were
unchanged. The yield of this product was 65% at 50%
conversion, though it decreased at more extensive reac-
tion.
P h otoch em istr y of An d r osta d ien on e 8. Finally, the
photochemistry of androstadiene ketone 8 (obtained from
the photocleavage of 4 as reported above) was examined.
This was chosen as model since the structure was
identical to that of 4 but lacked the side-chain ketone
function. The photoreaction gave a single photoproduct,
identified as the rearranged pentacyclic ketone 15 (Scheme
5) on the basis of the analytical and spectroscopic
properties (see Experimental Section). This was formed
in ca. 90% yield irrespectively of the irradiation wave-
length and on the presence of oxygen, though these
factors induced some change in the quantum yield.
low Φr with the present steroidal ketones is probably
linked to the fluorine substitution. Notably, introduction
of a second fluorine atom in position 6 (X ) F in Scheme
6) leads to a strong decrease of Φr (compare 5 and 4 in
Table 1).
With model 2,5-cyclohexadienones, it has been previ-
ously reported that an electron-withdrawing substituent
(trichloromethyl,15a carbonyl, carboxyl)15b,c in position 4
(see formula 17) affects the course of the ‘lumi’-rearrange-
ment15a and may lead to different products.15b,c
This is possibly because the substituent disfavors the
positive charge in the zwitterionic intermediate (the same
holds when the same groups are present in position 2).15b,c
A group (carboxyl, cyano) in position 3 has been reported
not to change the regioselectivity, though it is not known
whether it affects the efficiency.16 As for the presently
considered dienones, compound 4 bears a CR2F group in
position 4 (with respect to the ketone function in ring A,
see formula 17 and Scheme 6) and compound 5 a further
CR2F group in position 3. The reaction is clean, the ‘lumi’
rearrangement being virtually the only photoprocess
involving this moiety, but, as mentioned above, the
quantum yield is low. According to Scheme 6, the
unfavorable effect of the added fluorines may be under-
stood as an effect of the electron-withdrawing groups
which disfavor the formation of the zwitterion.
In turn, the lumiketones 7 and 11 (as well as 15),
undergo secondary photorearrangements, that we have
not examined beyond the fact that these are quite
efficient by irradiation at 366 nm, limiting the amount
of lumiketones obtainable under such conditions. The
easy occurrence of secondary photoreactions by irradia-
tion at long wavelength has been documented in the
previous literature.17
Discu ssion
All of the examined pregna-1,4-diene-3,20-diones (4, 5,
6) exhibit a wavelength dependent photochemistry. Reac-
tion at the dienone chromophore predominates by ir-
radiation at 254 and is the exclusive process at 366 nm,
while reaction at the 20-keto function is the main path
at 310 nm. The two kinds of chemistry observed are both
largely precedented in related systems.
‘Lu m ik eton e P h otor ea r r a n gem en t’. The first reac-
tion corresponds to the well-known ‘lumiketone’ rear-
rangement of cross-conjugated cyclohexadienones12 and
occurs in the same way with the androsta-1,4-dien-3-one
8, lacking the second ketone functionality. It occurs
stereoselectively (with configuration inversion at C10) and
with the same regiochemistry observed with other
steroidal dienones.4-8 There is a large consensus that this
rearrangement occurs from the low-lying nπ* triplet via
a zwitterionic intermediate (16 in Scheme 6).12,13
The reaction occurs with a low to moderate quantum
yield and is somewhat more efficient in 2-propanol,
possibly due to the increased energy of the nπ* triplet.
With simpler cyclohexadienone models quantum yields
are larger than observed here (0.75 to 1),14a and this holds
also for the strictly related ∆1-dehydrotestosterone, where
the rearrangement quantum yield is 0.58, though the
value is lower with some 4-alkyl derivatives.14b Thus, the
Nor r ish I P h otoclea va ge. The second reaction ob-
served with the pregnadiendiones is Norrish I cleavage
involving the C17 side chain, which contains an R-alkoxy
(or hydroxy in the case of dione 6)-R′-hydroxy ketone. The
reaction is the most efficient photoprocess in these
steroids (see further below for the comparison of Φ
values). The cleavage is regioselective, involving the C17-
(13) (a) Schultz, A. G.; Antoulinakis, E. G. J . Org. Chem. 1996, 61,
4555. (b) Pirrung, M. C.; Nunn, D. S. Tetrahedron 1996, 52, 5707. (c)
West, F. G.; Koch, D. J . Chem. Commun. 1993, 1681. (d) Hong, F. T.;
Lee, K. S.; Liou, C. C. Tetrahedron Lett. 1992, 33, 2155. (e) Caine, D.;
Kotran, P. L. J . Org. Chem. 1992, 57, 6587.
(14) (a) Schuster, D. I.; Patel, D. J . J . Am. Chem. Soc. 1968, 90,
5145. (b) Schuster, D. I.; Barringer, W. C. J . Am. Chem. Soc. 1971,
93, 731.
(15) (a) Schuster, D. I.; Abraitis, Y. Y. Chem. Commun. 1969, 419.
(b) Caine, D.; Brake, P. F.; de Bardeleben, J . F.; Dawson, J . B. J . Org.
Chem. 1973, 38, 967. (c) Broka, C. A. J . Org. Chem. 1988, 53, 575.
(16) (a) Stille, C. J . K.; Rettig, T. A.; Kneunerle, E. W. J . Org. Chem.
1976, 41, 2950. (b) Zimmerman, H. E.; Pasteris, R. J . J . Org. Chem.
1980, 45, 4864.
(17) Kropp, P. J . Org. Photochem. 1967, 1, 1.

8090 J . Org. Chem., Vol. 66, No. 24, 2001
Ricci et al.
Ta ble 3. F r a ction a l Absor p tion of th e Tw o
Ch r om op h or es a n d Qu a n tu m Yield for Ster oid 4 in
Aceton itr ile
Sch em e 7
a
a
b
c
c
λirr
FD
FK
Φr
ΦD
ΦK
254
310
366
0.992
0.57
1
0.008
0.43
0.00
0.18
0.45
0.06
0.173
0.065
0.06
0.007
0.385
0.00
a
From Table 2. bFrom Table 1. Φr times the ratio. Yield of
products of dienone rearrangement (or respectively of ketone
fragmentation)/total yield.
chromophores in these diketones. In Table 2 and Figure
1 the absorption spectra of dione 4 and that of a related
steroid derivative bearing only the ketone function at C20
(tetrahydroxypregnan-20-one 18) are compared.
Ta ble 2. Sp ectr oscop ic Da ta for Ster oid s 4 a n d 18
steroid
λ (log ꢀ)
ꢀ254
ꢀ310
ꢀ366
4
18
240 (4.15), 300 (1.95)
208 (3.04), 282 (2.01)
8200
63
70
30
10
0
From these data, the fraction of light absorbed by the
isolated ketone (FK) and by the dienone chromophore (FD)
are obtained for bichromophoric 4 in acetonitrile (Table
3). If each chromophore reacts independently, the overall
quantum yield of reaction (Φr, Table 1) is the sum of the
efficiencies of reaction at each moiety (η, see eq 1)
C20 rather than the C20-C21 bond, despite the fact that
there is an oxygen-bonded substituent at both C17 and
C21. This is reasonably due to the optimal alignment of
the nonbonding orbital of the acetonyl oxygen atom with
the cleaving bond in the rigid system of the two fused
five-membered rings (for 4 and 5) or simply in the
polysubstituted cyclopentane ring (in 6). This favors the
observed reaction more that does the hydroxyl on freely
rotating C21. Efficient Norrish I cleavage of the C-CR had
been previously reported for some R,â-acetonylcyclohex-
anones, which have a partially analogous geometric
arrangement.18,19
Φr ) FKηK + FDηD
(1)
The quantum yields (Φr × yield of the product, see
Table 1) of each of the two photoprocesses, the Norrish I
fragmentation (ΦK) and the dienone rearrangement (ΦD)
are compared in Table 3. One can see that ΦK = FK both
at 254 and at 310, thus ηK = 1. The localized triplet at
the saturated ketone chromophore reacts with unitary
efficiency. This state is short-lived, but measurably
quenched, and both the experiments in oxygenated
solution and those in the presence of piperylene indicate
a lifetime of a few nanoseconds. The reaction at the
dienone chromophore is much less efficient. For 4, ηD
() ΦD/FD) is 0.17 in the strongly allowed first absorption
band (λir 254 nm) and drops to 011 and 0.06 in the long
wavelength absorption bands (λir 310 and 366 nm).
Similar values are obtained with 8, which bears only the
dienone chromophore. The diminishing efficiency of the
dienone rearrangement upon decreasing excitation en-
ergy is not accompanied by increasing reaction at the
isolated ketone, thus does not involve intramolecular
energy transfer. Literature data suggest that dienone
triplets are also short-lived (they have not been detected
by flash photolysis).20 Intramolecular triplet-triplet en-
ergy transfer over such a distance (ca. 7.5 Å) is expected
to be slow from theory,21 although this fact has been
rarely documented experimentally.22 Thus, while T-T
energy transfer from the long-lived benzene triplet in the
The C17 alkyl radical formed abstracts hydrogen from
the solvent (see increased Φ in i-PrOH) or from the caged
HOCH2CO• radical (path a, Scheme 7) yielding monoke-
tones 8 from 4 and 12 from 5 (Scheme 2).
Trapping by oxygen is quite efficient, and in oxygen-
saturated solution the alkyl radicals are intercepted (path
b). In a hydrogen donating solvent such as i-PrOH the
thus-formed peroxyl radical abstracts a hydrogen and
gives the isolated hydroperoxy derivative (9, Table 1 and
Scheme 3). In acetonitrile, hydrogen transfer from the
solvent is slow, and some rearrangement takes place
forming a not fully identified carboxylic acid arising from
the cleavage of ring D. On the other hand, adding a
strong reducing agent (C12H25SH, 0.1 M) leads to com-
petition for the alkyl radical, which in part abstracts
hydrogen (giving 8), in part adds oxygen, giving the
peroxy radical that in this case is smoothly reduced to
hydroperoxide 9 (Table 1). The ‘lumi’ rearrangement, a
minor path under these conditions, is unaffected, as one
may expect (Table 1). Finally, when a hydroxy rather
than an alkoxy group is present at C17, as in dione 6,
hydrogen transfer takes place and leads to ketone 14
(path c in Scheme 7).
(19) For a discussion of the Norrish I photoprocess see Weiss, D. S.
Org. Photochem. 1981, 5, 347. Bohne, C. in ref 12d, p 416.
(20) Schuster, D. I.; Lam, K. Mol. Photochem. 1969, 1, 415.
(21) (a) Dexter, D. L. J . Chem. Phys. 1953, 21, 836. (b) Wagner, P.
J .; Kochevar, I. J . Am. Chem. Soc. 1968, 90, 2232. (c) Birks, J . B.
Organic Molecular Photophysics; Wiley: New York: 1973.
(22) (a) Ren, Y.; Wang, Z.; Zhu, H.; Weininger, S. J .; McGimpsey,
W. G. J . Am. Chem. Soc. 1995, 117, 4367. (b) Toledano, E.; Rubin, M.
B.; Speiser, S. J . Photochem. Photobiol. A: Chem. 1996, 94, 93. (c)
Becker, H. D.; Burgdorff, C.; Loehmannsroeben, H. B. J . Phootochem.
Photobiol. A: Chem. 1995, 86, 133.
Wavelen gth -Depen den t P h otoch em istr y. The wave-
length-dependent chemistry observed can be rationalized
with reference to the absorption by the two separated
(18) (a) Collins, P. M.; Musaninghe, V. R. N.; Oparaeche, N. N. J .
Chem. Soc., Perkin Trans. 1 1977, 2424. (b) Collins, P. M.; Travis, A.
S. J . Chem. Soc., Perkin Trans. 1 1980, 780 and therein cited
references.

Pregna-1,4-diene-3,20-diones
J . Org. Chem., Vol. 66, No. 24, 2001 8091
means of 0.04-0.063 silica gel column eluting with the above
antenna has been documented to occur over a somewhat
larger distance in the case of ketone 1 (X ) CH2),2 the
short lifetime of the dienone triplet precludes such
transfer with ketones 4-6. At the low concentration
attainable with these steroids (1 × 10-3), intermolecular
energy transfer is inefficient, and attempted sensitization
by acetone or benzophenone (in the latter case potentially
involving only the conjugated ketone) leads to no clean
result, with considerable destruction of the substrate via
paths different from the previous ones, reasonably in-
volving radical processes initiated by hydrogen abstrac-
tion.
solvent mixtures.
The characterization of the new compounds was based on
analytical and spectroscopic techniques. [R]D were measured
at 20 °C in MeOH (5 mg/mL), and NMR spectra were recorded
on a 300 MHz spectrometer. Chemical shifts are reported
relative to TMS as internal standard. The details of the
structure were deduced from 1H, 13C, DEPT-135, and 2D-
correlation experiments (H,H-COSY, HSQC for all of the
products, HMBC, and/or NOESY when appropriate).
P h otolysis of P r egn a d ien ed ion e 4 in Ar gon -Equ ili-
br a ted Aceton itr ile a t 254 n m . A solution of compound 4
(1 g, 2.3 mmol) in acetonitrile (2.3 L) was irradiated for 2 h,
and a 80% conversion was reached. Crystallization of the
residue from ethyl acetate gave 560 mg (70% yield) of 11â,21-
dihydroxy-16R,17R-(1-methylethylidenedioxy)-9R-fluoro-1,5-
cyclopregn-3-ene-2,20-dione (7). Mp 227 °C (AcOEt); [R]D -2.2.
Anal. Calcd for C24H31O6F: C, 65.54; H, 7.17. Found: C, 65.7;
Con clu sion
The intriguing difference between solid-state and solu-
tion photochemistry reported for some pregnadiendiones
in solution and in the solid state is presumably due to
the different light source used.23 Although absorption by
the dienone chromophore is more intensive and extends
more to the red than that by the isolated ketone moiety,
there is window in the region 280-320 nm where
absorption and reaction (Norrish I fragmentation, Φ )
1) by the latter chromophore predominates. In the other
regions of the spectrum, reaction at this moiety is
proportional to the (in most cases marginal) fraction of
light absorbed, and no T-T energy transfer intervenes.
Reaction at the excited cross-conjugated chromophore is
less efficient and is dependent on structure and condi-
tions. From the phototoxicological point of view, it is
noteworthy that both UV-A and UV-C cause a concerted
rearrangement at ring A, whereas UV-B causes a ho-
molytic cleavage. Thus, two different phototoxic mecha-
nisms may operate, the latter one via radicals (acyl, alkyl,
and, in the presence of oxygen, peroxyl radicals) and the
photobiological action spectrum of these compounds does
not simply coincide with the overall photoreactivity
spectrum.
1
H, 7.3. IR (KBr) 3500, 1700 cm-1. H NMR (CD3COCD3) δ 0.8
(s, 3H), 1.2 (s, 3H), 1.3 (s, 3H), 1.5 (s, 3H), 1.4-1.8 (m, 6H),
2.0-2.4 (m, 5H), 3.2 (br, exch, 1H), 3.5 (t, J ) 5 Hz, exch, 1H),
4.3 (dd, J ) 20, 5 Hz, 1H), 4.4 (m, 1H), 4.6 (dd, J ) 20, 5 Hz,
1H), 5.1 (d, J ) 5. Hz, 1H), 6.0 (d, J ) 5, 1H), 7.3 (d, J ) 5 Hz,
1H). 13C NMR (CD3COCD3) δ 8.1 (d, J C-F ) 3 Hz, CH3), 16.4
(CH3), 19.9 (CH2), 22.9 (CH2), 25.4 (CH2), 26.3 (CH3), 32.4 (d,
J C-F ) 21 Hz, CH), 33.4 (CH2), 34.7 (CH2), 38.1, 39.0 (d, J
C-F
) 6 Hz, CH), 41.6 (CH), 45.3, 52.8 (d, J C-F ) 27 Hz), 67.0 (CH2),
69.2 (d, J C-F ) 30 Hz, CH), 81.5 (CH), 95.4 (d, J C-F ) 175
Hz), 97.2, 111.1, 132.1 (CH), 165.2 (CH), 205.7, 210.3. The
detailed structure assignment was obtained by combined
HSQC, HMBC, and NOESY experiments. The presence of the
C1-C5 bond was evidenced by the long-range correlations
observed in the HMBC spectrum: C-1 (39.0 ppm) correlated
with H-19 (1.29 ppm), H-3 (5.95 ppm), and H-4 (7.31 ppm);
the last one was absent in the starting steroid 4, so confirming
the presence of the bond between C-1 and C-5. The orientation
of 19-Me and ring A was defined considering the characteristic
cross-peak in the NOESY spectrum: H-19 (1.29 ppm) with
H-11 (4.35 ppm), H-3 and H-4, thus proving their spatial
proximity. Thus the stereochemistry deducted from NMR data
was completely consistent with previous assignments on
related ‘lumiketones’ mainly based upon circular dichroism
measurements.24
P h otolysis of P r egn a d ien ed ion e 4 in Ar gon -Equ ili-
br a ted Aceton itr ile a t 310 n m . A solution of compound 4
(0.434 g, 1 mmol) in acetonitrile (1 L) was irradiated for 40
min, and a 80% conversion was reached. Chromatography of
the residue (eluting with a cyclohexane-ethyl acetate 70/30
mixture) gave 34 mg (11%) of compound 7 and 180 mg (60%)
of 9R-fluoro-11â-hydroxy-16R, 17R-(1-methylethylidenedioxy)-
androsta-1,4-dien-3-one (8). Mp 255 °C (cyclohexane); [R]D
+10.5. Anal. Calcd for C22H29O4F: C, 70.19; H, 7.76. Found:
Exp er im en ta l Section
Samples of pregnadienediones 4, 5, and 6 were kindly
supplied by Farmabios, Gropello Cairoli, Italy. Their purity
was checked by HPLC and NMR spectroscopy. Tetrahydroxy-
pregnanone 18 was of commercial origin (Sigma-Aldrich). The
solvents used in the photoreactions were spectroscopic grade.
P r ep a r a tive P h otoch em ica l Rea ction s. Irradiations at
254 nm were carried out in an immersion well apparatus fitted
C, 70.2; H, 7.8. IR (KBr) 3410, 1664, 1620 cm-1 1H NMR
.
with
a 20 W low-pressure mercury arc. In the argon-
(DMSO-d6) δ 0.9 (s, 3H), 1.2 (s, 3H), 1.3 (s, 3H), 1.5 (s, 3H),
1.2-1.9 (m, 5H), 2.2-2.6 (m, 4H), 4.0 (d, J ) 5 Hz,1H), 4.2
(m, 1H), 4.7 (m, 1H), 5.1 (d, J ) 5. Hz, 1H), 5.4 (bs, exch, 1H),
6.0 (d, J ) 1.5 Hz, 1H), 6.2 (dd, J ) 10, 1.5 Hz, 1H), 7.3 (d, J
) 10 Hz, 1H). 13C NMR (DMSO-d6) δ 22.9 (CH3), 26.8 (d, J C-F
) 5 Hz,CH3), 27.8 (CH3), 30.0 (CH3), 31.6 (CH2), 34.1 (CH),
36.6 (d, J C-F ) 20 Hz, CH), 37.2 (CH2), 40.7 (CH2), 44.5 (CH2),
46.0, 51.8 (d, J C-F ) 23 Hz), 74.4 (d, J C-F ) 30 Hz, CH), 89.8
(CH), 90.7 (CH), 105.1(d, J C-F ) 175 Hz), 112.7, 128.1 (CH),
132.9 (CH); 156.6 (CH); 170.8, 189.2.
P h otolysis of P r egn a d ien ed ion e 4 in Oxygen -Equ ili-
br a ted 2-P r op a n ol a t 310 n m . A solution of compound 4 (1
g, 2.3 mmol) in 2-propanol (2.3 L) was irradiated for 55 min,
and a 77% conversion was reached. Column chromatography
eluting with a 40/60 cyclohexane-ethyl acetate mixture fol-
lowed by recrystallization of the main fraction afforded 432
mg (60%) of 9R-fluoro-17â-hydroperoxy-11â-hydroxy-16R,17R-
(1-methylethylidenedioxy)androsta-1,4-dien-3-one (9). Mp 175
°C (AcOEt); [R]D +41.9. Anal. Calcd for C22H29O6F: C, 64.69;
equilibrated reactions, the solutions was stirred and flushed
with purified argon for 2 h before irradiating, and a low gas
flux was maintained during the reactions. In the oxygen-
equilibrated reactions, it proceeded analogously. For the
irradiations at 310 or 366 nm, the solution was distributed in
a series of serum-capped quartz tubes which were flushed with
argon or oxygen and irradiated in a multilamp apparatus fitted
with eight 15 W phosphor-coated lamps with the appropriate
emission band.
The course of the reactions was followed by HPLC (Hypersil
ODS2, 4.6 × 25 mm, 5 µm column, eluting with acetonitrile -
water mixtures) and TLC (eluting with cyclohexane-ethyl
acetate or chloroform-acetone mixtures).
When the desired conversion was reached, the solvent was
rotary evaporated and the products were purified by recrys-
tallization or by preparative chromatographic separations by
(23) Either a high-pressure or a low-pressure mercury arc have been
used as the light source in the various photochemical studies of
crystalline steroid ketones, ref 8 and 9. It is not clear whether there is
a wavelength effect.
(24) Schaffner, K.; Snatzke, G. Helv. Chim. Acta 1965, 48, 347.

8092 J . Org. Chem., Vol. 66, No. 24, 2001
Ricci et al.
H, 7.16. Found: C, 64.3; H, 7.2. IR (KBr) 3400, 1680, 1620
28.0 (CH3), 30.2 (CH3), 35.2 (dd, J C-F ) 19, 11 Hz, CH), 37.3
(CH2), 38.5 (d, J C-F ) 11 Hz,CH2), 40.8 (CH2), 44.7 (CH), 46.5,
52.4 (d, J C-F ) 23 Hz), 74.5 (d, J C-F ) 36 Hz, CH), 85.1 (CH),
90.1 (CH), 91.1 (d, J C-F ) 175 Hz), 104.5 (d, J C-F ) 175 Hz),
113.1, 123.5 (d, J C-F ) 3 Hz, CH), 133.2 (CH), 158.5 (CH), 167.4
(d, J C-F ) 15 Hz, CH), 188.9.
cm-1 1H NMR (CD3COCD3) δ 1.2 (s, 3H), 1.3 (s, 3H), 1.4 (s,
.
3H), 1.6 (s, 3H), 1.2-1.7 (m, 2H), 1.8-2.2 (m, 5H), 2.2-2.8
(m, 3H), 4.2 (m, 1H), 4.3 (d, J ) 5.5 Hz, 1H), 4.4 (br, exch,
1H), 6.0 (br t, J ) 1.5 Hz, 1H), 6.2 (dd, J ) 10, 1.5 Hz, 1H),
7.3 (d, J ) 10 Hz, 1H), 11.1 (br s, exch, 1H). 13C NMR (CD3-
COCD3) δ 15.4 (CH3), 22.7 (d, J C-F ) 5 Hz, CH3), 25.9 (CH3),
P h otolysis of P r egn a d ien ed ion e 6 in Ar gon -Equ ili-
br a ted Aceton itr ile a t 254 n m . A solution of compound 6
(0.52 g, 1.27 mmol) in acetonitrile (260 mL) was irradiated
for 2.5 h, and a 50% conversion was reached. Column chro-
matography (eluting with chloroform-acetone 98/2 mixture),
and recrystallization of the main fraction gave 154 mg (60%)
of 6R,9R-difluoro-16R-methyl-11â,17R,21-trihydroxy-1,5-cyclo-
pregn-3-ene-2,20-dione (13). Mp 251 °C (AcOEt); [R]D -20.8.
Anal. Calcd for C22H28O5F2: C, 64.38; H, 6.88. Found: C, 64.3;
26.5 (CH3), 27.1 (CH2), 30.4 (CH2), 32.5 (CH2), 33.1 (d, J C-F
20 Hz, CH), 38.3 (CH2), 43.0 (d, J C-F ) 2 Hz, CH), 46.1, 48.1
(d, J ) 22 Hz), 71.2 (d, J ) 33 Hz, CH), 82.7 (CH),
)
C-F
C-F
100.7 (d, J
) 175 Hz), 111.8, 120.6, 124.4 (d, J
) 2 Hz,
C-F
C-F
CH), 129.2 (CH); 151.8 (CH); 165.8 (d, J
) 2 Hz), 185.0.
C-F
Triphenylphosphine (26.2 mg) was added to a solution of
hydroperoxide 9 (20 mg) in dichloromethane (15 mL), and
stirring was pursued for 2 h, when the starting material was
consumed (TL). Extraction with water (3 × 20 mL) and
evaporation gave 18 mg (94%) of 9R-fluoro-11â,16R-dihidroxyan-
drosta-1,4-diene-3,17-dione (10). Anal. Calcd for C19H23O4F: C,
68.25; H, 6.93. Found: C, 68.0; H, 7.0. IR (KBr) 3400, 1740,
1
H, 7.0. IR (KBr) 3500, 1700 cm-1. H NMR (DMSO) δ 0.8 (d,
J ) 7 Hz, 3H), 0.9 (s, 3H), 1.2 (s, 3H), 1.1 and 1.5 (m, 2H),
1.7-1.8 (m, 1H), 1.4 and 1.9 (m, 2H), 1.4 and 2.2 (m, 2H), 2.2
(m, 1H), 2.3 (m, 1H), 2.9 (m, 1H), 4.0 (dd, J ) 19, 5.5 Hz, 1H),
4.1 (m, 1H), 4.5 (dd, J ) 19, 5.5 Hz, 1H), 4.7 (t, J ) 5.5 Hz,
exch, 1H), 5.0 (br s, exch, 1H), 5.1 (d, J ) 4.5 Hz, exch, 1H),
5.3 (dt, J ) 50, 7.5, 1H), 6.1 (d, J ) 5.5 Hz, 1H), 7.7 (d, J ) 5.5
Hz, 1H). 13C NMR (DMSO) δ 8.0 (d, J C-F ) 3 Hz, CH3), 15.6
(CH3), 17.1 (CH3), 28.5 (d, J C-F ) 23 Hz, CH2), 29.3 (dd, J C-F
) 18, 8 Hz, CH), 32.0 (CH2), 35.1 (CH2), 35.2 (CH), 36.4 (t,
J C-F ) 7 Hz, CH), 41.3 (d, J C-F ) 26 Hz), 42.4 (CH), 47.7, 52.3
(d, J C-F ) 27 Hz), 66.6 (CH2), 68.5 (d, J C-F ) 35 Hz, CH), 87.5
(d, J C-F ) 175 Hz), 90.4, 96.5 (d, J C-F ) 175 Hz), 134.0 (CH),
160.1 (d, J C-F ) 10 Hz, CH), 203.4, 211.4. The following long-
range correlations in HMBC experiment supported the struc-
ture attribution: H-1 (2.32 ppm) with C-3 (134.0 ppm), C-4
(160.1 ppm) and C-9 (96.5); C-1 (36.4 ppm) with H-3 (6.1 ppm),
H-4 (7.65 ppm) and H-19 (1.2 ppm). The relative stereochem-
istry was confirmed with NOESY experiment: H-1 gave NOE
correlation with H-6 (5.3 ppm), H-19 with H-3, H-4 and H-11
(4.1 ppm).
1
1660, 1600 cm-1. H NMR (DMSO) δ 1.1 (s, 3H), 1.5 (s, 3H),
1.3-1.7 (m, 2H), 1.7-2.3 (m, 5H), 2.4-2.7 (m, 3H), 4.2 (m, 1H),
4.3 (m, 1H), 5.3 (d, J ) 6 Hz, exch, 1H), 5.6 (d, J ) 3 Hz, exch,
1H), 6.0 (d, J ) 1.5 Hz, 1H), 6.3 (dd, J ) 10, 1.5 Hz, 1H), 7.3
(d, J ) 10 Hz, 1H). 13C NMR (DMSO) δ 16.0 (CH3), 23.3 (d,
J C-F ) 5 Hz, CH3), 26.3 (CH2), 30.3 (CH2), 31.6 (CH2), 33.2 (d,
J C-F ) 20 Hz, CH), 36.6 (CH2), 42.2 (CH), 46.4, 48.2 (d, J C-F
) 22 Hz), 70.2 (CH), 70.4 (d, J C-F ) 36 Hz, CH), 101.5 (d, J C-F
) 175 Hz), 124.6 (d, J C-F ) 2 Hz, CH), 129.3 (CH); 152.8 (CH),
166.9 (d, J C-F ) 2 Hz), 185.5, 217.5.
P h otolysis of P r egn a d ien ed ion e 5 in Ar gon -Equ ili-
br a ted Aceton itr ile a t 254 n m . A solution of compound 5
(1 g, 2.2 mmol) in acetonitrile (440 mL) was irradiated for 2.5
h, and a 50% conversion was reached. Column chromatography
(eluting with cyclohexane-ethyl acetate 40-40 mixture), and
recrystallization of the main fraction afforded 497 mg (50%)
of 6R,9R-difluoro-11â,21-dihydroxy-16R,17R -(1-methylethyli-
denedioxy)-1,5-cyclopregn-3-ene-2,20-dione(11). Mp 247 °C
(AcOEt); [R]D -20.8. Anal. Calcd for C24H30O6F2: C, 63.71; H,
P h otolysis of P r egn a d ien ed ion e 6 in Ar gon -Equ ili-
br a ted Aceton itr ile a t 310 n m . A solution of compound 6
(1 g, 2.44 mmol) in acetonitrile (490 mL) was irradiated for 1
h, and a 20% conversion was reached. Column chromatography
(eluting with chloroform) and recrystallization of the main
photoproduct gave 84 mg (50%) of 6a,9R-difluoro-16R-methyl-
11â-hydroxy-androsta-1,4-dien-3-one (14). Mp 249 °C (cyclo-
hexane); [R]D +18.4. Anal. Calcd for C20H24O3F2: C, 68.55; H,
6.90. Found: C, 68.6; H, 6.9. IR (KBr) 3400, 1740, 1680, 1640
cm-1. 1H NMR (CDCl3) δ 1.2 (d, J ) 7 Hz, 3H), 1.3 (s, 3H), 1.6
(s, 3H), 1.7-1.9 (m, 3H), 1.6 and 2.1 (m, 2H), 1.8 and 2.4 (m,
2H), 2.5-2.8 (m, 2H), 4.4 (m, 1H), 5.5 (dddd, J ) 50, 13, 7.2
Hz, 1H), 6.4 (dd, J ) 10, 1.5 Hz, 1H), 6.5 (bt, J ) 1.5 Hz, 1H),
7.1 (d, J ) 10 Hz, 1H). 13C NMR (CDCl3) δ 16.4 (CH3), 16.9
6.68. Found: C, 63.8; H, 6.7. IR (KBr) 3500, 1700, 1580 cm-1
.
1H NMR (DMSO-d6) δ 0.7 (s, 3H), 1.1 (s, 3H), 1.2 (s, 3H), 1.4
(s, 3H), 1.5 (m, 2H), 1.9 (m, 1H), 2.2 and 2.6 (m, 2H), 2.1 (m,
2H), 2.2 (m, 1H), 2.4 (br s, 1H), 4.0 (d, J ) 19 Hz, 1H), 4.1 (m,
1H), 4.5 (d, J ) 19 Hz, 1H), 4.9 (d, J ) 5 Hz, 1H), 5.1 (br,
exch, 1H), 5.2 (d, J ) 5 Hz, exch, 1H), 5.3 (dt, J ) 50, 7.5 Hz,
1H), 6.1 (d, J ) 5.5 Hz, 1H), 7.7 (d, J ) 5.5 Hz, 1H). 13C NMR
(DMSO) δ 7.9 (d, J C-F ) 3 Hz, CH3), 16.8 (CH3), 25.5 (CH3),
26.7 (CH3), 28.3 (dd, J C-F ) 18, 8 Hz, CH), 28.5 (d, J C-F ) 21
Hz, CH2), 33.0 (CH2), 35.4 (CH2), 36.2 (t, J C-F ) 6 Hz, CH),
41.2 (d, J C-F ) 26 Hz), 42.0 (CH), 45.0, 52.0 (d, J C-F ) 27 Hz),
66.3 (CH2), 68.2 (d, J C-F ) 37 Hz, CH), 81.0 (CH), 87.5 (d, J C-F
) 175 Hz), 95.9 (d, J C-F ) 175 Hz), 97.3, 110.7, 134.0 (CH),
160 (d, J C-F ) 9 Hz, CH), 203.3, 210.1. As for the case of
compound 7, the detailed structural attribution was based
upon NMR evidence. A similar correlation was found in the
HMBC spectrum: C-1 (36.1 ppm) with H-4 (7.7 ppm), H-19
(1.2 ppm) with C-1, C-10 (52.0 ppm) and C-5 (41.2 ppm), H-1
(2.4 ppm) with C-9 (95.9 ppm). In the NOESY spectrum, H-1
gave NOE correlation with H-6 (5.25 ppm) and H-8 (1.9 ppm);
H-19 (1.2 ppm) with H-4, H-3 (6.1 ppm) and H-11 (4.1 ppm).
P h otolysis of P r egn a d ien ed ion e 5 in Ar gon -Equ ili-
br a ted Aceton itr ile a t 310 n m . A solution of compound 5
(0.3 g, 0.663 mmol) in acetonitrile (290 mL) was irradiated
for 2 h, and a 90% conversion was reached. Column chroma-
tography (eluting with cyclohexane-ethyl acetate 60/40 mix-
ture) gave 5 mg (5%) of compound 11 and 188 mg (80%) of
6R,9R-difluoro-11â-hydroxy-16R,17R-(1-methylethylidenedioxy)-
androsta-1,4-dien-3-one (12). Mp 245 °C (cyclohexane); [R]D
+12.4. Anal. Calcd for C22H28O4F2: C, 66.99; H, 7.15. Found:
(CH3), 23.5 (d, J C-F ) 5 Hz, CH3), 30.2 (CH2), 32.8 (d, J C-F
)
28 Hz, CH), 33.1 (d, J C-F ) 21 Hz, CH2), 37.9 (CH2), 39.1 (CH),
42.3 (CH), 47.4, 48.5 (d, J C-F ) 26 Hz), 71.9 (d, J C-F ) 36 Hz,
CH), 86.8 (d, J C-F ) 175 Hz), 99.7 (d, J C-F ) 175 Hz), 121.6
(d, J C-F ) 5 Hz, CH3), 130.6 (CH), 150.9 (CH), 161.6 (d, J C-F
) 9 Hz, CH), 186.0, 220.2.
P h otolysis of An d r osta d ien on e 8 in Ar gon -Equ ili-
br a ted Aceton itr ile a t 254 n m . A solution of compound 8
(1 g, 2.44 mmol) in acetonitrile (490 mL) was irradiated for 1
h, and a 20% conversion was reached. Column chromatography
eluting with chloroform gave 84 mg (43% yield) of 9R-fluoro-
11â-hydroxy-16R,17R-(1-methylethylidenedioxy)-1,5-cycloan-
drost-3-en-2-one (15). Mp 150 (AcOEt); [R]D -69.8. Anal. Calcd
for C22H29O4F: C, 66.82; H, 7.39. Found: C, 66.7; H, 7.5. IR
1
(KBr) 1650 cm-1. H NMR (CDCl3) δ 0.9 (s, 3H), 1.3 (s, 3H),
1.4 (s, 3H), 1.5 (s, 3H), 1.3-1.8 (m, 6H), 2.0-2.2 (m, 3H), 1.9
(br, exch, 1H), 2.2 (br s, 1H), 2.3 (m, 1H), 4.1 (d, J ) 5.5 Hz,
1H), 4.4 (m, 1H), 4.7 (t, J ) 5.5 Hz, 1H), 5.9 (d, J ) 5.5 Hz,
C, 67.2; H 7.2. IR (KBr) 3450, 1660, 1640 cm-1
.
1H NMR
1H), 7.3 (d, J ) 5.5 Hz, 1H). 13C NMR (CDCl3) δ 8.3 (d, J C-F
)
(DMSO-d6) δ 1.0 (s, 3H), 1.2 (s, 3H), 1.3 (s, 3H), 1.5 (s, 3H),
1.2-1.6 (m, 4 H), 1.7-1.8 (m, 2H), 2.3 (m, 1H), 2.4-2.6 (m,
1H), 4.0 (d, J ) 5 Hz, 1H), 4.2 (m, 1H), 4.6 (m, 1H), 5.5 (dd,,
exch, 1H), 5.7 (dddd, J ) 50, 13, 7.5 Hz, 1H), 6.1 (br t, J ) 1.5
Hz, 1H), 6.3 (dd, J ) 10, 1.5 Hz, 1H), 7.3 (d, J ) 10 Hz, 1H).
13C NMR (DMSO-d6) δ 23.1 (CH3), 26.9 (d, J C-F ) 3 Hz,.CH3),
3 Hz, CH3), 19.1 (CH3), 20.0 (CH2), 22.9 (CH2), 23.8 (CH3), 25.9
(CH3), 32.6 (d, J C-F ) 19 Hz, CH), 33.5 (CH2), 35.4 (CH2), 38.2,
39.1 (d, J C-F ) 6 Hz, CH), 39.5 (d, J ) 3 Hz, CH), 42.2, 52.7
(d, J C-F ) 27 Hz), 69.9 (d, J C-F ) 37 Hz, CH), 79.6 (CH), 86.4
(CH), 95.5 (d, J C-F ) 175 Hz), 109.6, 132.0 (CH), 164.9 (CH),
205.3. The structural attribution was based on correlations

Pregna-1,4-diene-3,20-diones
J . Org. Chem., Vol. 66, No. 24, 2001 8093
similar to those observed with the above ‘lumiketones’. In the
HMBC spectrum H-1 (2.2 ppm) correlated with C-6 (22.9 ppm)
and C-4 (132.0 ppm), H-19 (1.3 ppm) with C-5 (38.2 ppm); C-5
with H-3 (5.9) and H-4 (7.3).
Qu a n tu m Yield Mea su r em en ts. Quantum yield measure-
ments were carried out in 3 mL samples of solutions (1 × 10-3
M for steroids 4 and 8, 5 × 10-3 M for 5 and 6) in spectropho-
tometric sealed couvettes. The light source was a low-pressure
mercury arc for 254 nm, a focalized high-pressure mercury arc
fitted with the appropriate interference filter for 313 and 366
nm. The extent of light absorbed was determined by means of
a photon-counter. The extent of the reaction was assessed by
HPLC. The light flow was measured by ferrioxalate actinom-
etry.
Ack n ow led gm en t. Partial support of this reaction
by Istituto Superiore di Sanita`, Rome, in the frame of
the special program on the safe use of drugs, and by
University of Pavia, in the frame of the special program
on radiation and safe use of drugs are gratefully
acknowledged.
J O015884Z