Norrish-Prins reaction as a key step in the synthesis of 14β-hydroxy-5α (or 5β or Δ5,6)-pregnane derivatives

Article abstract of DOI:10.1016/j.steroids.2011.05.004

Numerous bioactive glycosteroids are characterized by aglycones bearing a 14β-hydroxy pregnane skeleton like boucerin and isoramanone. In general, the syntheses of the latter are achieved by acidic hydrolysis of the corresponding glycosteroids. These agly

Full text of DOI:10.1016/j.steroids.2011.05.004

Steroids 76 (2011) 1166–1175
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Norrish–Prins reaction as a key step in the synthesis of 14␤-hydroxy-5␣ (or 5␤ or
ꢀ5,6)-pregnane derivatives
Philippe Geoffroya, Blandine Ressaulta, Eric Marchionib, Michel Miescha,∗
a Université de Strasbourg, Institut de Chimie, Université, UMR 7177, Laboratoire de Chimie Organique Synthétique, 1 rue Blaise Pascal, BP 296/R8, 67008 Strasbourg-Cedex, France
b Université de Strasbourg, Faculté de Pharmacie, IPHC, UMR 7178, Laboratoire de Chimie Analytique et de Science de l’Aliment, 74 route du Rhin, 67640 Illkirch Graffenstaden, France
a r t i c l e i n f o
a b s t r a c t
Article history:
Numerous bioactive glycosteroids are characterized by aglycones bearing a 14␤-hydroxy pregnane
skeleton like boucerin and isoramanone. In general, the syntheses of the latter are achieved by acidic
hydrolysis of the corresponding glycosteroids. These aglycones were also obtained by a combined Nor-
rish type I–Prins reaction starting from the corresponding 12-keto-pregnane derivatives. However, for
the Norrish–Prins reaction, no reports describe the influence of the A/B ring junction (cis or trans or ꢀ5,6
double bond) or the influence of the substitution pattern at position 20. Herein, we describe the use of
Norrish type I–Prins reactions to synthesize isoramanone and boucerin derivatives and their A/B cis and
trans analogs. The influence of the parameters mentioned above is also presented. These studies showed
that the A/B ring junction has little influence on the Norrish type I–Prins reaction but that the substitution
pattern at position 20 is important. The presence of a dioxolane group induced not only the formation of
the desired 14␤-hydroxy pregnane derivatives in the highest yields but also the formation of new spiro
derivatives.
Received 24 March 2011
Received in revised form 9 May 2011
Accepted 13 May 2011
Available online 23 May 2011
Keywords:
Norrish type I reaction
Prins reaction
Photochemistry
Boucerin
Isoramanone
Spiro derivatives
© 2011 Elsevier Inc. All rights reserved.
1. Introduction
influence of the substitution pattern at position 20 on the outcome
of the combined Norrish–Prins reaction have been described. We
In a Norrish type-I reaction, the UV-induced ␣-cleavage of a
carbonyl compound leads to an acyl-alkyl diradical as the primary
photoproduct that evolves toward an aldehyde and an alkene [1].
On the other hand, the acid catalyzed condensation of an alkene
with an aldehyde is known as a Prins reaction [2]. Starting from
hecogenin acetate 1, Bladon et al. showed that the Norrish type
I reaction gave lumihecogenin acetate 3 [3]. Relevant extensions
of this pioneering work were achieved by Chinn [4], Welzel [5],
Winterfeld [6] and Fuchs [7] who first used Norrish type I reac-
tions to prepare aldehyde 3 via the diradical intermediate 2. Under
acidic conditions, aldehyde 3 afforded the 14␤-hydroxy deriva-
tive 4, resulting from a Prins reaction, and the ꢀ14,15-derivative
5, resulting from an ene reaction (Scheme 1).
wish to report our results concerning the synthesis of isoramanone
(or digipurpurogenin II) [9a,b] and boucerin [10] derivatives, and
their A/B cis and trans analogs using Norrish type I–Prins reac-
tions (Fig. 1). Isoramanone and boucerin represent the aglycones
of numerous bioactive glycosteroids and therefore their synthesis
is of interest [9b–f].
2. Experimental
2.1. General
Melting points were measured on a Stuart Scientific melting
point apparatus (SMP 3) and are uncorrected. Reactions were
carried out under argon with magnetic stirring and degassed
solvents. Et2O and THF were distilled from Na/benzophenone.
Thin layer chromatography (TLC) was carried out on silica gel
plates (Merck 60F254) and the spots were visualized under UV
lamp (254 or 365 nm) and sprayed with phosphomolybdic acid
solution (25 g phosphomolybdic acid, 10 g cerium sulfate, 60 mL
H2SO4, 940 mL H2O) followed by heating on a hot plate. For column
chromatography, silica gel (Merck Si 60 40–60 ␮m) was used. IR
spectra were recorded on Bruker Alpha (ATR) spectrophotomer.
1H NMR spectra were recorded at 300 MHz (Bruker AC-300) and
13C NMR spectra at 75 MHz (Bruker AC-300) using the signal of the
Welzel et al. showed that combining the photolysis with an
acidic treatment of compounds 6 (or 7) promoted the formation of
ene products 8 (9) and a mixture of 5, 6-dihydro-boucerin deriva-
tives 10–13. The ratio of the latter was related to the substitution
pattern of compound 3 at position 20 (Scheme 2) [8].
To the best of our knowledge, no studies dealing with the influ-
ence of the A/B ring junction (cis or trans or ꢀ5,6 double bond) or the
∗
Corresponding author. Tel.: +33 0368851752; fax: +33 068851754.
E-mail address: m.miesch@unistra.fr (M. Miesch).
0039-128X/$ – see front matter © 2011 Elsevier Inc. All rights reserved.
doi:10.1016/j.steroids.2011.05.004

P. Geoffroy et al. / Steroids 76 (2011) 1166–1175
1167
Scheme 1. Norrish-Prins reaction starting from hecogenin acetate.
Scheme 2. Reagents and reaction conditions: (a) i: hꢁ, CH2Cl2, 1 h, 25 ◦C; ii: AcOH/H2O/CF3CO2H (2.5/1/0.6), 4 h, 10 ◦C.
residual non-deuterated solvent as internal reference. Significant
1H NMR data are tabulated in the following order: chemical shift
(ı) expressed in ppm, multiplicity (s, singlet; d, doublet; t, triplet;
q, quartet; m, multiplet), coupling constants in hertz, number of
protons. High-resolution mass spectra (HRMS) were performed on
a Agilent 6520 Accurate Mass Q-TOF.
in a refrigerated quartz vessel. The solvent was evaporated under
reduced pressure to afford the corresponding crude seco alde-
hyde. To a solution of the latter in THF was added a solution of
AcOH/H2O/CF3COOH (2.5/1/0.6). After 2 h stirring at r.t., the reac-
tion mixture was diluted with CH2Cl2, washed with water and with
sat. NaHCO3, dried over Na2SO4, filtered and concentrated under
reduced pressure. The crude material was purified by silica gel
chromatography (petroleum ether/EtOAc (8:2–6:4) to afford the
resulting products.
2.2. General procedure for the Norrish type I–Prins (NP) reaction
A solution of 12-keto derivative (14–16, 19, 20, 24, 30, 32, 33)
in CH2Cl2 was deoxygenated with argon for 15 min and irradiated
with a high pressure mercury lamp (Philips HPK 125) for 15 min
2.3. NP reaction starting from 3ˇ,20R-bis(acetoxy)-5˛-
pregnan-12-one (14), leading to compounds 34, 36, 38 and 40
Norrish type I reaction: 14 (1.00 g, 2.39 mmol); CH2Cl2 (280 mL).
Prins reaction: THF (1.1 mL), AcOH/H2O/CF3COOH (2.5/1/0.6,
11 mL).
3␤,20R-bis(acetoxy)-5␣-12␣-hydroxy-pregn-14-ene (34): as a
white solid (175 mg, 26% yield, mp 86–90 ◦C). IR (ATR): 3577,
1731, 1714. 1H NMR (CDCl3): 5.24 (s, 1H, H-15); 4.95 (dq, 1H,
J = 6.1–10.8 Hz, H-20); 4.67 (tt, 1H, J = 4.9–11.2 Hz, H-3␣); 3.70 (t,
1H, J = 2.9 Hz, H-12␤); 2.74 (td, 1H, J = 8.2–10.8 Hz, H-17␣); 2.25
(ddd, 1H, J = 2.6–8.2–15.1 Hz, H-16); 2.02 (s, 3H, CH3, Ac); 2.01 (s,
3H, CH3, Ac); 1.95–0.90 (m, 17H); 1.22 (d, 3H, J = 6.0 Hz, CH3, H-
Fig. 1. Isoramanone and boucerin, aglycones of numerous bioactive glycosteroids.

1168
P. Geoffroy et al. / Steroids 76 (2011) 1166–1175
8.4 (CH3). HRMS (ESI) m/z: C23H37O5 [M+H+] calcd. 393.2563, found
393.2623. [˛]D20: +16 (c. 0.031, CHCl3).
21); 0.84 (s, 3H, CH3); 0.83 (s, 3H, CH3). 13C NMR (CDCl3): 170.7
(C O, OAc); 170.5 (C O, OAc); 151.6 (C, C-14); 119.2 (CH, C-15);
73.5 (CH, C-12); 72.9 (CH, C-3); 72.6 (CH, C-20); 51.3 (C, C-13); 46.5
(CH); 45.2 (CH); 44.1 (CH); 36.5 (CH2); 35.1 (C, C-10); 34.5 (CH);
33.9 (CH2); 32.4 (CH2); 29.5 (CH2); 28.8 (CH2); 28.1 (CH2); 27.3
(CH2); 21.5 (CH3); 21.4 (CH3); 19.6 (CH3); 17.2 (CH3); 17.2 (CH3);
11.7 (CH3). HRMS (ESI) m/z: C25H38NaO5 [M+Na+] calcd. 441.2611,
found 441.2623. [˛]D20: +46.5 (c. 0.016, CHCl3).
3␤,20R-bis(acetoxy)-5␣-12␣-hydroxy-pregn-8-ene (36): as a
white solid (77 mg, 11%, mp 120–123 ◦C). IR (ATR): 3504, 1715.
1H NMR (CDCl3): 4.90 (dq, 1H, J = 6.2–10.1 Hz, H-20) ; 4.71 (tt, 1H,
J = 4.9–11.3 Hz, H-3␣) ; 3.77 (s, 1H, H-12␤) ; 2.45–2.10 (m, 4H); 2.05
(s, 3H, CH3, Ac); 2.02 (s, 3H, CH3, Ac); 1.90–1.00 (16H, m); 1.22 (d,
3H, J = 6.3 Hz, CH3, H-21); 0.82 (s, 3H, CH3); 0.71 (s, 3H, CH3). 13C
NMR (CDCl3): 170.7 (C O, OAc); 170.3 (C O, OAc); 137.2 (C C);
127.1 (C C); 73.4 (CH, C-12); 72.5 (CH, C-3); 71.8 (CH, C-20); 47.1
(CH); 46.9 (C, C-13); 44.4 (CH); 43.9 (CH); 36.6 (C, C-10); 36.0 (CH2);
34.1 (CH2); 29.2 (CH2); 28.5 (CH2); 27.4 (CH2); 26.2 (CH2); 25.9
(CH2); 24.3 (CH2); 21.5 (CH3); 21.4 (CH3); 19.7 (CH3); 19.5 (CH3);
12.9 (CH3). HRMS (ESI) m/z: C25H38NaO5 [M+Na+] calcd. 441.2611,
found 441.2622. [˛]D20: +25 (c. 0.01, CHCl3).
3␤,20R-bis(acetoxy)-5␣-12␣-14␤-dihydroxy-pregnane (38):
as a white solid (61 mg, 9%, mp 152–153 ◦C). IR (ATR): 3402, 1730.
1H NMR (CDCl3): 4.90 (dq, 1H, J = 6.1–9.5 Hz, H-20); 4.68 (tt, 1H,
J = 4.9–11.3 Hz, H-3␣); 3.65 (t, 1H, J = 3.5 Hz, H-12␤); 2.40 (q, 1H,
J = 9.0 Hz); 2.02 (s, 3H, CH3, Ac); 2.01 (s, 3H, CH3, Ac); 1.95–0.95 (m,
21H); 1.22 (d, 3H, J = 6.0 Hz, CH3, H-21); 0.92 (s, 3H, CH3); 0.82 (s,
3H, CH3). 13C NMR (CDCl3): 170.7 (C O, OAc), 170.4 (C O, OAc),
85.6 (C, C-14), 76.2 (CH, C-12), 74.2 (CH, C-3), 73.5 (CH, C-20),
50.3 (C, C-13), 47.6 (CH), 44.2 (C), 42.7 (CH), 41.2 (CH), 36.7 (CH2),
35.5 (C, C-10), 33.8 (CH2), 33.4 (CH2), 28.5 (CH2), 28.4 (CH2), 27.3
(CH2), 26.4 (CH2), 21.6 (CH3), 21.4 (CH3), 19.4 (CH3), 15.9 (CH3),
12.0 (CH3). HRMS (ESI) m/z: C25H40NaO6 [M+Na+] calcd. 459.2717,
found 459.2722. [˛]D20: +32 (c. 0.009, CHCl3).
3␤,20R-bis(acetoxy)-5␣-12␤-14␤-dihydroxy-pregnane (40):
as a white solid (106 mg, 15%, mp 81–84 ◦C). IR (ATR): 3435, 1713.
1H NMR (CDCl3): 4.95–4.75 (m, 1H, H-20); 4.75–4.60 (m, 1H,
H-3␣); 3.28 (dd, 1H, J = 3.7–11.9 Hz, H-12␣); 2.04 (s, 3H, CH3, Ac);
2.01 (s, 3H, CH3, Ac); 1.98–0.70 (m, 22H); 1.21 (d, 3H, J = 6.0 Hz,
CH3, H-21); 0.88 (s, 3H, CH3); 0.81 (s, 3H, CH3). 13C NMR (CDCl3):
170.7 (C O, OAc); 170.2 (C O, OAc); 86.1 (C, C-14); 77.1 (CH,
C-12); 73.7 (CH, C-3); 73.4 (CH, C-20); 60.4 (CH2); 52.6 (CH); 51.6
(C, C-13); 46.3 (CH); 44.3 (CH); 41.3 (CH); 36.8 (CH2); 35.6 (CH2);
33.7 (C, C-10); 32.1 (CH2); 29.7 (CH2); 28.4 (CH2); 27.7 (CH2); 27.3
(CH2); 21.4 (CH3); 19.0 (CH3); 14.2 (CH3); 12.1 (CH3); 7.9 (CH3).
HRMS (ESI) m/z: C25H40NaO6 [M+Na+] calcd. 459.2717, found
459.2723. [˛]D20: +6 (c. 0.033, CHCl3).
2.5. NP reaction starting from 3ˇ-acetoxy-5˛-cyclic 20-(ethylene
acetal)-pregnan-12-one (16) leading to compounds 15, 42, 47
Norrish type I reaction: 16 (800 mg, 1.91 mmol); CH2Cl2 (250 mL).
Prins reaction: THF (3.5 mL), AcOH/H2O/CF3COOH (2.5/1/0.6,
18 mL).
3␤-Acetoxy-5␣-pregnan-12,20-dione (15): as a white solid
(69 mg, 10%, mp 189–192 ◦C). IR(ATR): 1723, 1699. 1H NMR
(CDCl3): 4.68 (tt, 1H, J = 4.9–11.2 Hz, H-3␣); 3.30 (t, 1H, J = 9.3 Hz,
H-17␣); 2.48 (t, 1H, J = 13.2 Hz, H-11); 2.30–2.05 (m, 2H); 2.26 (s,
3H, CH3, Ac); 2.02 (s, 3H, CH3, Ac); 1.90–0.95 (15H, m); 0.94 (s, 3H,
CH3); 0.91 (s, 3H, CH3). 13C NMR (CDCl3): 212.7 (C O, C-12); 209.1
(C O, C-20); 169.0 (C O; OAc); 72.5 (CH, C-3); 57.5 (C, C-13), 56.7
(CH, C-17); 55.5 (CH); 53.6 (CH); 43.8 (CH); 37.4 (CH2); 35.7 (CH2);
35.5 (C); 34.1 (CH2); 33.1 (CH2); 30.7 (CH); 30.6(CH3); 27.5 (CH2);
26.5 (CH2); 23.4 (CH2); 21.9 (CH2), 20.7 (CH3); 12.9 (CH3); 11.2
(CH3). HRMS (ESI) m/z: C23H35O4 [M+H+] calcd. 375.2530, found
375.2547. [˛]D20: +135 (c. 0.016, CHCl3).
3␤-Acetoxy-5␣-12␤-14␤-dihydroxy-pregnan-20-one
(231 mg, 31% yield) is described above.
(42)
3␤-Acetoxy-12␣-hydroxy-5␣-12,14␣-cyclo-12,13-
secopregna-13(17)-20-one (47): as a white solid (138 mg, 19%, mp
139–140 ◦C). IR (ATR): 3415, 1726, 1666, 1611. 1H NMR (CDCl3):
4.70 (tt, 1H, J = 5.1–11.1 Hz, H-3␣); 4.17–4.02 (m, 1H, H-12␤);
2.80–2.40 (m, 2H); 2.30–0.70 (m, 20H); 2.22 (s, 3H, CH3, H-21);
2.02 (s, 3H, CH3, Ac); 1.95 (t, 3H, J = 2.1 Hz, CH3, H-18); 0.81 (s,
3H, CH3, H-19). 13C NMR (CDCl3): 198.7 (C O, C-20); 170.6 (C O,
OAc); 154.2 (C C); 137.7 (C C); 78.6 (CH, C-12); 73.5 (CH, C-3);
66.2 (C, C-14); 51.4 (CH); 44.6 (CH); 43.3 (CH); 37.2 (CH2); 35.5 (C,
C-10); 33.4 (CH2); 32.5 (CH2); 30.9 (CH2); 30.4 (CH3); 28.7 (CH2);
27.0 (CH2); 25.8 (CH2); 22.2 (CH2); 21.4 (CH3); 12.2 (CH3); 11.3
(CH3). HRMS (ESI) m/z: C23H35O4 [M+H+] calcd. 375.2457, found
375.2537. [˛]D20: +19 (c. 0.007, CHCl3).
2.6. NP reaction starting from 3ˇ,20R-bis(acetoxy)-5ˇ-
pregnan-12-one (19) leading to compounds 35, 39 and 41
Norrish type I reaction: 19 (264 mg, 0.63 mmol), CH2Cl2 (200 mL).
Prins reaction: THF (1.0 mL), AcOH/H2O/CF3COOH (2.5/1/0.6,
4.3 mL).
3␤,20R-bis(acetoxy)-5␤-12␣-hydroxy-pregn-14-ene (35): as a
white solid (76 mg, 28%). IR (ATR): 3573, 1731, 1707. 1H NMR
(CDCl3): 5.27 (s, 1H, H-15); 5.04 (t, 1H, J = 2.7 Hz, H-3␣); 5.03–4.95
(m, 1H, H-20); 3.71 (t, 1H, J = 2.4 Hz, H-12␤); 2.75 (td, 1H,
J = 8.1–10.8 Hz); 2.26 (dddd, 1H, J = 1.5–2.7–8.1–14.7 Hz); 2.20–0.70
(m, 15H); 2.04 (s, 3H, CH3, Ac); 2.02 (s, 3H, CH3, Ac); 1.23 (d, 3H,
J = 6.0 Hz, CH3, H-21); 0.97 (s, 3H, CH3); 0.85 –s, 3H, CH3). 13C NMR
(CDCl3): 170.5 (C O, 2OAc); 152.2 (C C, C-14); 119.0 (C CH, C-
15); 73.0 (CH, C-12); 72.6 (CH, C-3); 70.7 (CH, C-20); 51.4 (C, C-13);
46.8 (CH); 37.2 (CH); 36.4 (C, C-10); 34.7 (CH); 32.3 (CH2); 31.4
(CH3); 30.4 (CH2); 29.1 (CH2); 26.1 (CH2); 25.0 (CH2); 23.7 (CH2);
23.3 (CH3); 21.6 (CH3); 19.7 (CH3); 17.3 (CH3). HRMS (ESI) m/z:
C25H38NaO5 [M+Na+] calcd. 441.2611, found 441.2623. [˛]D20: +35
(c. 0.011, CHCl3).
3␤,20R-bis(acetoxy)-5␤-12␣-hydroxy-pregn-8-ene (39): as a
white solid (40 mg, 15%). IR (ATR): 3469, 1722. 1H NMR (CDCl3):
5.09 (1H, t, J = 2.7 Hz, H-3␣); 4.94–4.82 (1H, m, H-20); 3.78 (1H, t,
J = 3.0 Hz, H-12␤); 2.60–0.70 (20H, m); 2.04 (3H, s, CH3, Ac); 2.03
(3H, s, CH3, Ac); 1.22 (3H, d, J = 6.0 Hz, CH3, H-21); 0.85 (3H, s, CH3);
0.81 (3H, s, CH3). 13C NMR (CDCl3): 170.7 (C O, OAc); 170.3 (C O,
OAc); 136.4 (C C); 127.8 (C C); 72.5 (CH); 71.8 (CH); 70.5 (CH);
2.4. NP reaction starting from 3ˇ-acetoxy-5˛-pregnan-
12,20-dione (15), leading to compounds 42
Norrish type I reaction: 15 (402 mg, 1.07 mmol); CH2Cl2 (230 mL).
Prins reaction: THF (2.0 mL), AcOH/H2O/CF3COOH (2.5/1/0.6,
10 mL).
3␤-Acetoxy-5␣-12␤-14␤-dihydroxy-pregnan-20-one (42): as a
white solid (83 mg, 20%, mp 93–95 ◦C). IR (ATR): 3434, 1728, 1692.
1H NMR (CDCl3): 4.65 (tt, 1H, J = 4.9–11.5 Hz, H-3␣) ; 3.53 (t, 1H,
J = 6.6 Hz, H-17␣) ; 3.26 (dd, 1H, J = 4.2–11.7 Hz, H-␣) ; 2.23 (s, 3H,
CH3, H-21) ; 2.10–0.60 (m, 21H); 1.99 (s, 3H, CH3, Ac); 0.87 (s, 3H,
CH3); 0.80 (s, 3H, CH3). 13C NMR (CDCl3): 218.1 (C O, C-20) ; 170.8
(C O, OAc) ; 85.2 (C, C-14) ; 73.8 (CH, C-12) ; 73.4 (CH, C-3) ; 56.8
(CH) ; 55.2 (C, C-13) ; 46.4 (CH); 44.4 (CH); 39.2 (CH); 36.9 (CH2);
35.6 (C, C-10); 33.9 (CH2); 33.7 (CH2); 33.0 (CH3); 29.8 (CH2); 28.3
(CH2); 27.8 (CH2); 27.3 (CH2); 24.7 (CH2); 21.4 (CH3); 12.1 (CH3);

P. Geoffroy et al. / Steroids 76 (2011) 1166–1175
1169
47.2 (CH); 46.8 (C, C-13); 37.5 (CH); 36.3 (C, C-10); 30.8 (CH); 30.2
3␤-Acetoxy-5␤-12␤,14␤-dihydroxy-pregnan-20-one (43): as a
(CH2); 30.1 (CH2); 26.5 (CH2); 26.1 (CH2); 26.0 (CH2); 25.3 (CH2);
white solid (52 mg, 10%). (described above).
20
24.3 (CH2); 24.2 (CH2); 21.5 (CH3); 19.7 (CH3); 19.4 (CH3). [˛]D
+36 (c. 0.02, CHCl3).
:
3␤,20R-bis(acetoxy)-5H␤-12␤,14␤-dihydroxy-pregnane (41):
as a white solid (42 mg, 15%). IR (ATR): 3485, 1714. 1H NMR
(CDCl3): 5.05 (1H, s, H-3␣); 4.92–4.76 (1H, m, H-20); 3.29 (1H, dd,
J = 3.7–11.9 Hz, H-12␣); 2.20–0.80 (22H, m); 2.03 (3H, s, CH3, Ac);
2.02 (3H, s, CH3, Ac); 1.21 (3H, d, J = 3.0 Hz, CH3, H-21); 0.95 (3H, s,
CH3); 0.87 (3H, s, CH3). 13C NMR (CDCl3): 170.7 (C O, OAc); 170.2
(C O, OAc); 86.3 (C, C-14); 77.3 (CH); 73.7 (CH); 70.3 (CH); 52.7 (C,
C-13); 51.7 (CH); 41.5 (CH); 36.8 (CH); 35.0 (C, C-10); 32.4 (CH);
32.1 (CH2); 30.4 (2CH2); 28.4 (CH2); 26.3 (CH2); 26.1 (CH2); 25.0
(CH2); 23.6 (CH3); 21.5 (CH3); 21.4 (CH3); 19.0 (CH3); 8.0 (CH3).
[˛]D20: +12 (c. 0.03, CHCl3).
2.9. NP reaction starting from
3ˇ,20R-bis(acetoxy)-preg-5-ene-12-one (30) leading to
compounds 44 and 45
Norrish type I reaction: 30 (184 mg, 0.44 mmol), CH2Cl2 (150 mL).
Prins reaction: THF (0.5 mL), AcOH/H2O/CF3COOH (2.5/1/0.6,
5.0 mL).
3␤,20R-bis(acetoxy)-12␣-hydroxy-pregnan-5,14-diene (44):
as a white solid (32 mg, 17%, mp 117–119 ◦C). IR (ATR): 3487, 1725,
1710. 1H NMR (CDCl3): 5.44 (m, 1H, H-6); 5.32 (d, 1H, J = 1.5 Hz,
H-15); 4.98 (dq, 1H, J = 6.0–11.1 Hz, H-20); 4.61 (m, 1H, H-3␣); 3.76
(s, 1H, H-12␤); 2.76 (dt, 1H, J = 8.3–10.6 Hz); 2.50–0.70 (m, 15H);
2.04 (s, 3H, CH3, Ac); 2.03 (s, 3H, CH3, Ac); 1.22 (d, 3H, J = 6.0 Hz,
CH3, H-21); 1.03 (s, 3H, CH3); 0.89 (s, 3H, CH3). 13C NMR (CDCl3):
170.5 (2C O, OAc); 150.6 (C C); 139.0 (C C); 122.2 (C CH);
120.9 (C CH); 76.6 (CH, C-12); 72.7 (CH, C-3); 72.6 (CH, C-20);
51.4 (C, C-13); 46.4 (CH); 42.2 (CH); 38.0 (CH2); 36.6 (CH2); 32.5
(CH2); 30.3 (CH2); 29.4 (CH); 28.4 (CH2); 27.6 (CH2); 21.5 (CH3);
21.4 (CH3); 19.7 (CH3); 18.9 (CH3); 17.0 (CH3). HRMS (ESI) m/z:
C25H36NaO5 [M+Na+] calcd. 439.2455, found 439.2460. [˛]D20: +8
(c. 0.017, CHCl3).
3␤,20R-bis(acetoxy)-12␤,14␤-dihydroxy-pregn-5-ene (45): as
a white solid (22 mg, 12%, mp 131–133 ◦C). IR (ATR): 3461, 1715.
1H NMR (CDCl3): 5.43 (m, 1H, H-6); 4.87 (dq, 1H, J = 5.8–9.7 Hz, H-
20); 4.60 (tt, 1H, J = 5.2–10.9 Hz, H-3␣); 3.34 (dd, 1H, J = 3.9–11.7 Hz,
H-12␣); 2.50–0.60 (m, 19H); 2.03 (s, 3H, CH3, Ac); 2.02 (s, 3H,
CH3, Ac); 1.22 (d, 3H, J = 6.0 Hz, H-21); 1.01 (s, 3H, CH3); 0.92 (s,
3H, CH3). 13C NMR (CDCl3): 170.6 (C O, OAc); 170.2 (C O, OAc);
138.4 (C C, C-5); 122.4 (C CH, C-6); 86.5 (C, C-14); 76.3 (CH, C-
12); 73.7 (CH, C-3); 73.6 (CH, C-20); 52.4 (C, C-13); 51.5 (CH); 43.4
(CH); 37.9 (CH2); 37.0 (CH); 36.9 (CH2); 32.6 (CH2); 28.4 (CH2);
27.6 (CH2); 27.1 (CH2); 25.8 (CH2); 21.5 (C, C-10); 21.4 (2CH3);
19.4 (CH3); 19.0 (CH3); 7.87 (CH3). HRMS (ESI) m/z: C25H38NaO6
[M+Na+] calcd. 457.2561, found 457.2569. [˛]D20: −4 (c. 0.011,
CHCl3).
2.7. NP reaction starting from 3ˇ-acetoxy-5ˇ-cyclic 20-(ethylene
acetal) pregnan-12-one (20) leading to compounds 24, 43 and 48
Norrish type I reaction: 20 (201 mg, 0.48 mmol), CH2Cl2 (150 mL).
Prins reaction: THF (1 mL), AcOH/H2O/CF3COOH (2.5/1/0.6,
6.5 mL).
3␤-Acetoxy-5␤-pregnan-12,20-dione (24): as a white solid
(10 mg, 5%, mp 150–153 ◦C). IR (ATR): 1722, 1702. 1H NMR (CDCl3):
5.03 (t, 1H, J = 2.1 Hz, H-3␣); 3.29 (t, 1H, J = 9.8 Hz, H-17␣); 2.43 (t,
1H, J = 12.5 Hz, H-11); 2.23 (s, 3H, CH3, H-21); 2.15–0.75 (m, 19H);
2.02 (s, 3H, CH3, Ac); 1.03 (s, 3H, CH3); 0.92 (s, 3H, CH3). 13C NMR
(CDCl3): 213.3 (C O); 209.6 (C O); 170.5 (C O, OAc); 70.1 (CH, C-
3); 58.4 (C, C-13); 57.7 (CH); 54.3 (CH); 42.7 (CH); 37.8 (CH2); 36.8
(CH); 35.5 (C, C-10); 35.0 (CH); 31.3 (CH3); 30.6 (CH2); 30.5 (CH2);
26.3 (CH2); 25.8 (CH2); 24.8 (CH2); 24.1 (CH2); 23.2 (CH3); 22.7
(CH2); 21.4 (CH3); 13.5 (CH3). HRMS (ESI) m/z: C23H35O4 [M+H+]
calcd. 375.2457, found 375.2550. [˛]D20: +150 (c. 0.016, CHCl3).
3␤-Acetoxy-5␤-12␤,14␤-dihydroxy-pregnan-20-one (43): as a
white solid (29 mg, 15%). IR (ATR): 3426, 1729, 1692. 1H NMR
(CDCl3): 5.05 (s, 1H, H-3␤) ; 3.55 (t, 1H, J = 6.3 Hz, H-17␣) ; 3.29 (dd,
1H, J = 3.9–11.7 Hz, H-12␣); 2.25 (s, 3H, CH3, H-21); 2.20–0.80 (m,
21H); 2.04 (s, 3H, CH3, Ac); 0.96 (s, 3H, CH3); 0.88 (s, 3H, CH3).
13C NMR (CDCl3): 218.1 (C O, C-20); 170.8 (C O, OAc); 85.4 (C,
C-14); 74.0 (CH, C-12); 70.5 (CH, C-3); 56.8 (CH, C-17); 55,3 (C, C-
13); 39.4 (CH); 36.9 (CH); 35.0 (C, C-13); 34.1 (CH2); 33.1 (CH);
32.3 (CH3); 30.5 (CH2); 29.8 (CH2); 26.2 (CH2); 25.0 (CH2); 24.7
(CH2); 23.7 (CH3); 21.6 (CH3); 21.5 (CH2); 8.4 (CH3). HRMS (ESI)
m/z: C23H37O5 [M+H+] calcd. 393.2563, found 393.2624. [˛]D20: +24
(c. 0.022, CHCl3).
2.10. NP reaction starting from 3ˇ-acetoxy-pregn-5-ene-
12,20-dione (32) leading to compounds 46
Norrish type I reaction: 32 (114 mg, 0.31 mmol), CH2Cl2 (150 mL).
Prins reaction: THF (0.5 mL), AcOH/H2O/CF3COOH (2.5/1/0.6,
2.5 mL).
3␤-Acetoxy-12␣-hydroxy-5␤-12,14␣-cyclo-12,13-
secopregna-13(17)-20-one (48): as a white solid (45 mg, 25%).
IR (ATR): 3408, 1730, 1707, 1673. 1H NMR (CDCl3): 5.05 (s, 1H,
H-3␣); 4.15–4.05 (m, 1H, H-12␤); 2.70–2.55 (m, 1H); 2.30–0.80
(m, 19H); 2.20 (s, 3H, CH3, H-21); 2.03 (s, 3H, CH3, Ac); 1.94 (t, 3H,
J = 1.8 Hz, CH3, H-18); 0.94 (s, 3H, CH3, H-19). 13C NMR (CDCl3):
198.3 (C O, C-20); 170.7 (C O, OAc); 154.5 (C C); 137.6 (C C);
76.0 (CH, C-12); 70.4 (CH, C-3); 66.7 (C, C-14); 43.6 (CH); 37.6 (CH);
36.2 (CH); 34.7 (C, C-10); 32.5 (CH2); 31.7 (CH2); 31.0 (CH2); 30.6
(CH2); 30.5 (CH3); 27.0 (CH2); 25.1 (CH2); 22.5 (CH2 + CH3); 21.5
(CH3); 20.6 (CH2); 12.2 (CH3). HRMS (ESI) m/z: C23H35O4 [M+H+]
calcd. 375.2457, found 375.2527. [˛]D20: +25 (c. 0.028, CHCl3).
3␤-Acetoxy-12␤,14␤-dihydroxy-pregn-5-ene-20-one (46): as
a white solid (16 mg„ 13%, mp 140–142 ◦C). 1H NMR (CDCl3):
5.42 (m, 1H, H-6); 4.65–4.50 (m, 1H, H-3␣); 4.37 (s, 1H, OH);
3.61 (t, 1H, J = 6.3 Hz, H-17␣); 3.35 (dd, 1H, J = 4.2–11.7, H-12␣);
2.40–2.15 (m, 3H); 2.27 (s, 3H, CH3, H-21); 2.10–0.80 (m, 14H);
2.03 (s, 3H, CH3, Ac,); 1.01 (s, 3H, CH3, H-18); 0.92 (s, 3H, CH3,
H-19). 13C NMR (CDCl3): 218.0 (C O, C-20); 170.6 (C O, OAc);
137.8 (C C, C-5); 123.1 (C CH, C-6); 85.5 (C, C-14); 73.6 (CH,
C-12); 73.4 (CH, C-3); 56.9 (CH, C-17); 55.0 (C, C-13); 43.3 (CH,
C-9); 37.8 (CH2, C-1); 37.0 (CH2, C-4); 36.8 (C, C-10); 35.6 (CH3,
C-21); 34.5 (CH2, C-15); 33.1 (CH, C-8); 29.9 (CH2, C-11); 27.6
(CH2, C-2); 27. (CH2, C-7); 24.4 (CH2, C-16); 21.4 (CH3, OAc);
19.3 (CH3, C-19); 8.3 (CH3, C-18). HRMS (ESI) m/z: C23H34NaO5
[M+Na+] calcd. 413.2298, found 413.2308. [˛]D20: +145 (c. 0.01,
CHCl3).
2.8. NP reaction starting from 3ˇ-acetoxy-5ˇ-pregnan-
12,20-dione (24) leading to compound 43
Norrish type I reaction: 24 (377 mg, 1.00 mmol), CH2Cl2 (200 mL).
Prins reaction: THF (1.5 mL), AcOH/H2O/CF3COOH (2.5/1/0.6,
6.5 mL).

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2.11. NP reaction starting from 3ˇ-acetoxy-12-keto, cyclic
20-(ethylene acetal) pregn-5-ene (33) leading to compounds 32,
46 and 49
the starting material. Compound 19 was obtained according to a
known literature procedure [14]. To prepare the A/B cis pregnane
analog 20 bearing a dioxolane group at position 20, we transformed
3␣,12␣-bis (acetoxy), 5␤, pregna-20-one into the ketoderivative 21
which was then subjected to a Mitsunobu reaction to yield the 3␤-
benzoate derivative 22 [15]. Protection of the keto group followed
by a double saponification afforded the diol 23. Finally, a regios-
elective protection of the 3␤-hydroxy group and oxidation of the
12␣-hydroxy group yielded the desired compound 20 (Scheme 4).
The synthesis of the A/B cis pregnane analog 24 bearing a car-
bonyl group at position 20 was achieved starting from desoxycholic
acid 25, which was first transformed into compound 26 according
to a known literature procedure [14]. Deprotection of the benzoate
group followed by a reprotection of the resulting hydroxy as an
acetate yielded the desired A/B cis pregnane analog 24 (Scheme 5).
Norrish type I reaction: 33 (895 mg, 2.15 mmol), CH2Cl2 (280 mL).
Prins reaction: THF (4.0 mL), AcOH/H2O/CF3COOH (2.5/1/0.6,
20.0 mL).
3␤-Acetoxy-pregn-5-ene-12,20-dione (32): as a white solid
(153 mg, 19%, mp 192–194 ◦C). IR (ATR): 1729, 1703. 1H NMR
(CDCl3): 5.42–5.40 (m, 1H, H-6); 4.59 (tt, 1H, J = 4.6–11.4 Hz, H-
3␣); 3.34 (t, 1H, J = 9.6 Hz, H-17␣); 2.62 (t, 1H, J = 13.2 Hz, H-11);
2.50–2.00 (m, 4H); 2.26 (s, 3H, CH3, H-21); 2.03 (s, 3H, CH3,
Ac); 2.00–0.80 (m, 12H); 1.12 (s, 3H, CH3); 0,98 (s, 3H, CH3). 13C
NMR (CDCl3): 213.0 (C O); 209.4 (C O); 170.2 (C O, OAc); 139.2
(C C, C-5); 121.9 (C CH, C-6); 73.1 (CH, C-3); 57.6 (C, C-13); 57.4
(CH); 54.0 (CH); 527 (CH); 52.7 (CH); 37.6 (CH2); 37.4 (CH2); 37.2
(C, C-10); 36.4 (CH2); 31.1 (2CH + CH2); 27.3 (CH2); 24.0 (CH2);
22.4 (CH2); 21.2 (CH3); 18.7 (CH3); 13.2 (CH3). HRMS (ESI) m/z:
3.1.3. A/B ꢀ5,6 ring junction
Pregnenolone analogs bearing either an acetate or a carbonyl
group at position 20 are precursors of derivatives of isoramanone
and boucerin. These analogs were prepared starting from the diketo
derivative 27 [16]. Addition of acetyl chloride to the latter gave the
dienol acetate 28 [17] which led to the triol 29 after sodium boro-
hydride reduction [18] followed by a KOH promoted saponification
reaction. A regioselective protection of the 3␤-and 17␤-hydroxyl
groups followed by Jones oxidation [19] of the 12␣-hydroxy group
afforded the desired compound 30. On the other hand, the diox-
olane 31 was obtained by successive protection of the carbonyl
group as a dioxolane, sodium borohydride reduction and KOH
saponification of the dienol acetate 28. Finally, the deprotection
of the dioxolane, followed by a regioselective protection of the 3␤-
hydroxy as an acetate and an oxidation of the 12␣-hydroxy group
gave the desired compound 32 (Scheme 6). The corresponding diox-
olane derivative 33 was obtained by a regioselective protection of
the 3␤-hydroxy group of 31 before a Dess–Martin oxidation.
C
23H33O4 [M+H+] calcd. 373.2301, found 373.2376. [˛]D20: +55 (c.
0.009, CHCl3).
3␤-Acetoxy-12␤,14␤-dihydroxy-pregn-5-ene-20-one
210 mg, 25% yield (described above).
(46):
3␤-Acetoxy-12␣-hydroxy-12,14␣-cyclo-12,13-secopregna-
5,13(17)-diene-20-one (49): as a white solid (118 mg, 15%, mp
116–117 ◦C). IR (ATR): 3430, 1729, 1666, 1608. 1H NMR (CDCl3):
5.36 (d, 1H, J = 4.8 Hz, H-6); 4.58 (tt, 1H, J = 4.8–11.4 Hz, H-3␣); 4.14
(dt, 1H, J = 8.2–9.7 Hz, H-12␤); 2.80–0.80 (m, 17H); 2.22 (s, 3H,
CH3, H-21); 2.02 (s, 3H, CH3, Ac); 1.96 (t, 3H, J = 2.1 Hz, CH3, H-18);
1.04 (s, 3H, CH3, H-19). 13C NMR (CDCl3): 198.7 (C O, C-20); 170.5
(C O, OAc); 153.7 (C C); 140.5 (C C); 137.9 (C C); 122.6 (C CH);
76.5 (CH, C-12); 73.7 (CH, C-3); 65.7 (C, C-14); 48.3 (CH); 39.9 (CH);
37.9 (CH2); 37.7 (CH2); 37.2 (C, C-10); 32.4 (CH2); 30.5 (CH); 30.3
(CH2); 27.4 (CH2); 25.9 (CH2); 21.8 (CH2); 21.4 (CH3); 18.0 (CH3);
12.1 (CH3). [˛]D20: −12 (c. 0.006, CHCl3).
3.2. Norrish–Prins reactions
3. Results and discussion
At this stage, nine different compounds 14–16, 19, 20, 24, 30,
32, 33 were suitable for a combined Norrish type I–Prins reaction.
The photolysis was carried out in a water refrigerated quartz ves-
sel using a high pressure mercury lamp Philips HPK 125 for 15 min.
Longer reaction times led to decomposition, as shown by TLC anal-
ysis of the crude reaction mixture. The Prins reaction was carried
out directly on the product of the photolysis, using a 2.5/1/0.6
AcOH/H2O/TFA mixture. It was possible to isolate the Norrish type I
products, i.e. the aldehydes 16a, 20a and 33a (Scheme 7); however
these products were unstable. Furthermore, the overall yield of the
Norrish–Prins reaction did not increase when the Prins reaction
was carried out on the purified Norrish type I product (Table 1).
The expected 12␣ (or 12␤),14␤-dihydroxy derivatives 38–46
were always obtained in 10–31% yield starting from the corre-
sponding 12-keto derivatives 14–16, 19, 20, 24, 30, 32, 33 (entries
1–9). On the other hand, products 34, 36 and 35, 39 [the structure
of compound 36 was confirmed by X-ray analysis (Fig. 2)] resulting
from a Conia-ene rearrangement were isolated as major products
starting from 20-acetoxy derivatives 14 and 19 (entries 1 and 4).
Welzel et al. also noticed the formation of Conia ene derivatives
[20]; however these authors never observed the formation of the
ꢀ8,14 derivatives. Starting from protected preganolone derivatives
16, 20 and 33, products 15 (10%), 24 (<5%) and 32 (10%) resulting
from a deprotection reaction of the dioxolane group were isolated.
Surprisingly, spiro derivatives 47 (19%), 48 (25%) and 49 (15%) were
also isolated (entries 3, 6 and 9). The structure of the spiro deriva-
tive 47 was confirmed by X-ray analysis (Fig. 3). The overall yields
ranged from 10% to 60%. The lowest yields were obtained starting
from 20-keto derivatives 15, 24 and 32 (entries 2, 5 and 7) and the
Before presenting the Norrish type I–Prins reactions, we
described the synthesis of the 12-keto pregnane derivatives bearing
A/B trans, A/B cis and ꢀ5,6 ring junctions with different substituents
at position 20 (carbonyl, acetoxy and dioxolane groups).
3.1. Synthesis of the starting material for the Norrish–Prins
reactions
3.1.1. A/B trans ring junction
Hecogenin acetate 1 was used as the starting material for the
synthesis of pregnane analogs bearing an A/B trans ring junction
and an acetate, a carbonyl or a dioxolane group at position 20.
First, hecogenin acetate was transformed into the 12-keto preg-
nane analogs 14 and 15 bearing a A/B trans ring junction [11].
For the pregnane analog 16 bearing a dioxolane group at position
20, the regioselective protection of the diketo derivative 15 was
impossible. Indeed, the usual protection reaction condition (pTsOH,
ethylene glycol) led to an inseparable mixture of compounds. Thus,
to synthesize compound 16, we transformed hecogenin acetate 1
into the keto derivative 17 [12]. After protection of the keto group
as a dioxolane, the resulting compound was treated with potas-
sium hydroxide to give diol 18. Regioselective protection of the
3␤-hydroxy group followed by a Dess–Martin periodinane oxida-
tion gave the desired dioxolane derivative 16 (Scheme 3) [13].
3.1.2. A/B cis ring junction
For the synthesis of pregnane analogs bearing an A/B cis ring
junction, 3␣,12␣-bis(acetoxy), 5␤, pregnan-20-one was used as

P. Geoffroy et al. / Steroids 76 (2011) 1166–1175
1171
Scheme 3. Reagents and reaction conditions: (a) see Ref. [11]; (b) see Ref. [12]; (c) i: ethylene glycol, trimethyl orthoformate cat, CH2Cl2, 23 h, reflux (90%); ii: KOH, MeOH,
16 h, reflux (83%); (d) i: Ac2O, DMAP cat, Py, CH2Cl2, 19 h, 25 ◦C (70%); ii: Dess–Martin periodinane, CH2Cl2, 1 h, 25 ◦C (80%).
Scheme 4. Reagents and reaction conditions: (a) K2CO3, MeOH, 1 h, 25 ◦C (83%); (b) C6H5COOH, P(C6H5)3, EtO2C–N N–CO2Et, THF, 15 h, 25 ◦C (quant.); (c) i: ethylene glycol,
pTsOH cat., toluene, 2 h 30, reflux (76%); ii: KOH, MeOH, 2 h, reflux (25%); (d) i: Ac2O, DMAP cat, Py, CH2Cl2, 7 h, 25 ◦C (53%); ii: Dess–Martin periodinane, CH2Cl2, 50 min,
25 ◦C (97%); (e): see Ref. [14].
Scheme 5. Reagents and reaction conditions: (a) see Ref. [14]; (b) i: KOH, MeOH, 2 h, reflux (quant.); ii: Ac2O, DMAP cat, Py, CH2Cl2, 6 h, reflux (60%).
highest yields starting from dioxolane derivatives 16, 20 and 33
(entries 3, 6 and 9).
The formation of the spiro derivatives 47–49 could be explained
as follows: after formation of the Norrish type I products (i.e. alde-
hydes 16a, 20a and 33a), acidic treatment gave intermediate A
that evolved toward intermediate B according to a Conia ene reac-
tion. Deprotection of the dioxolane group and isomerisation of the
exo cyclic double bond yielded the spiro derivatives 47, 48 and 49
(Scheme 7).
However, this explanation does not account for the fact that
the formation of spiro derivatives was not observed starting from
compounds 14, 19, 30 and 15, 24, 32 bearing respectively an acetate
group or a carbonyl group at position 20. To explain these results,
we postulate that an acidic acetal hydrolysis takes place to give
Fig. 2. ORTEP drawing of compound 36 (ꢀ8,14 isomer) with thermal ellipsoids at
the 30% probability level [21].

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P. Geoffroy et al. / Steroids 76 (2011) 1166–1175
Scheme 6. Reagents and reaction conditions: (a) see Ref. [16]; (b) Ac2O, AcCl, 1 h, reflux (85%); (c) i: NaBH4, THF/MeOH (1/1), 0–25 ◦C, 19 h, ii: KOH, MeOH, 2 h, reflux (overall
yield: quant.); (d) Ac2O, DMAP, py, CH2Cl2, 7 h, 25 ◦C (63%); ii: CrO3, acetone, 45 min, 25 ◦C (81%); (e) i: ethylene glycol, PPTS, toluene, 3 h 30, reflux (quant.), ii: NaBH4,
THF/MeOH (1/1), 1 h 30, 25 ◦C, iii: KOH, MeOH, 4 h, reflux (ii + iii: 60%); (f) i: oxalic acid, SiO2, CH2Cl2, 1 h, 25 ◦C (quant.), ii: Ac2O, DMAP cat, Py, CH2Cl2, 4 h 30, 25 ◦C (28%), iii:
CrO3, acetone, 30 min, 25 ◦C (53%); (g) i: Ac2O, DMAP cat, Py, CH2Cl2, 3 h, 25 ◦C (80%), ii: Dess–Martin periodinane, CH2Cl2, 1 h, 25 ◦C (99%).
Scheme 7.
intermediate D (Scheme 8). The latter is in equilibrium with the
dienol E which, after the addition of water, leads to intermediate
F that is a direct precursor of the spiro derivatives 47, 48 and 49.
Thus, the formation of spiro derivatives did not occur starting from
compounds 14, 19, 30 and 15, 24, 32, because the formation of a
type E intermediate cannot occur (Scheme 8).
Three findings are clear from these results. First it is possible to
run a Norrish–Prins reaction starting from pregnenolone deriva-
Scheme 8.

P. Geoffroy et al. / Steroids 76 (2011) 1166–1175
1173
Table 1
Norrish–Prins reaction.
Entry
Starting material
Products
14␤-Hydroxy derivatives
Spiro derivatives
Other products
1
2
3
–
–
–
4
5
–
–
–
6
7
8
–
–
–
9
tives, this being reported for the first time. Second, the A/B ring
junction (trans, cis or ꢀ5,6) has little influence on the unfolding of
the Norrish–Prins reaction but the substitution pattern at position
20 is of importance. The best results were achieved starting from
dioxolane derivatives 16, 20 and 33. Finally, the unexpected
formation of spiroderivatives, which is also reported for the first
time, is closely related to the substitution pattern at position 20
and takes place exclusively starting from dioxolane derivatives.
The influence of an acidic medium on the Prins reaction was
studied by treating the crude reaction mixture resulting from the

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P. Geoffroy et al. / Steroids 76 (2011) 1166–1175
Scheme 9. Reagents and reaction conditions: i: (a) hꢁ, CH2Cl2, 15 min, 25 ◦C; (b) BF3, Et2O, toluene, 25 min, 0 ◦C [34 (17%)]; ii: (a) hꢁ, CH2Cl2, 15 min, 25 ◦C; (b) SnCl4, CH2Cl2,
1.5 h, 25 ◦C (30%); iii: (a) hꢁ, CH2Cl2, 15 min, 25 ◦C; (b) HBF4, Et2O, 40 min, 25 ◦C [34 (38%), 38 (10%)].
Appendix A. Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.steroids.2011.05.004.
References
[1] (a) Norrish RGW, Appleyard MES. Primary photochemical reactions. Part IV.
decomposition of methyl ethyl ketone and methyl butyl ketone. J Chem Soc
1934:874–80;
Fig. 3. ORTEP drawing of spiro derivative 47 with thermal ellipsoids at the 30%
probability level [22].
(b) Weiss RG. The Norrish type I reaction in cycloalkanone photochemistry.
In: Padwa A, editor. Organic Photochemistry, vol. 5. New York: Marcel Dekker;
1981. p. 347–420;
(c) Klan P, Wirz J. Photochemistry of organic compounds: from concepts to
practice. In: Postgraduate Chemistry Series. Wiley; 2009, and references cited
therein.
Norrish type I reaction of compound 14 with different Lewis acids
like BF3. Et2O and SnCl4. Conia ene products 34 and 36 were exclu-
sively obtained. However, in the presence of HBF4, the 14␤-hydroxy
derivative 38 was isolated as a minor product (10%) in addition to
the Conia ene product 34 (38%). It is also reasonable to postulate
that compounds 34, 36 could arise from a Lewis acid-promoted
water elimination starting from compound 38. Thus, the use of
this type of Lewis acids must be avoided to obtain 14␤-hydroxy
pregnane derivatives (Scheme 9).
[2] (a) Prins HJ. The reciprocal condensation of unsaturated organic compound.
Chem Week 1919;16:1510–26;
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Acknowledgements
Support for this work was provided by Université de Strasbourg,
CNRS and ANR (No. 07-PCVI-0016). B.R. thanks Région Alsace and
CNRS for a research fellowship. The authors thank Dr. Jennifer
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