Regioselectivity in the Hydroboration of Steroidal δ3-Allylic Alcohols

Article abstract of DOI:10.1039/a605946e

The presence of an allylic 5α-hydroxy group in an androst-3-ene increases the proportion of addition of a borane to the adjacent C-4 compared to the unsubstituted steroid and directs the addition to the face of the alkene anti to the hydroxy group with stereochemical effects that may oppose those of the C-10β-methyl group.

Full text of DOI:10.1039/a605946e

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56 J. CHEM. RESEARCH (S), 1996
Regioselectivity in the Hydroboration of Steroidal D3-Allylic
Alcohols†
J. Chem. Research (S),
1997, 56–57†
Muzaffar Alam, James R. Hanson,* Mansur Liman and Sivajini Nagaratnam
School of Molecular Sciences, University of Sussex, Brighton, Sussex BN1 9QJ, UK
The presence of an allylic 5a-hydroxy group in an androst-3-ene increases the proportion of addition of a borane to the
adjacent C-4 compared to the unsubstituted steroid and directs the addition to the face of the alkene anti to the hydroxy
group with stereochemical effects that may oppose those of the C-10b-methyl group.
Hydroboration proceeds in a cis-manner on the less-hindered
face of an alkene with anti-Markownikoff regioselectivity.1,2
The directing effects of electronegative substituents in allyl
derivatives modify the regiospecificity favouring addition of
the borane at the 2-position.3 In cyclohex-2-en-1-ols, the
hydroxy group also affects the stereospecificity and directs
the addition of the borane to the opposite face of the alkene.4
Other directing effects in cyclic systems may arise from trans-
annular diaxial interactions between the borane and sterically
bulky groups. The relative contributions of these effects
The C-10 angular methyl group can also affect the stereo-
chemistry of reactions of the disubstituted androst-3-enes.
The absence of a Markownikoff effect can afford greater
potential for an adjacent hydroxy group to modify both the
regiochemistry and stereochemistry of hydroboration. The
hydroboration of 17b-acetoxy-5a-hydroxyandrost-3-ene and
17b-acetoxy-5a-hydroxy-19-norandrost-3-ene was compared
to 17b-acetoxy-5a-androst-3-ene and 17b-acetoxy-19-nor-
5a-androst-3-ene to contrast the directing role of the 10b-
methyl group with that of the pseudo-axial 5a-hydroxy group.
Table 1 Yields (%) of hydroboration products of androst-3-enes
require evaluation. In the steroid series, the directing effect
of an allylic hydroxy group on the hydroboration of the tri-
substituted alkene, androst-4-ene, is sufficient to overturn the
normal directing effect of the C-10 methyl group.
The results are shown in Table 1. The structures of the
products were readily established from the multiplicity of the
1
CH(OH) resonances in the H NMR spectra6 and by com-
parison with literature data.7
The 5a-hydroxy group increased the proportion of addition
at C-4 in the hydroboration of androst-3-enes despite the fact
that this is a more hindered position than C-3. The trans
directing effect of the 5a-hydroxy group opposed the steric
hindrance of the 10b-methyl group and increased the amount
*To receive any correspondence.
†This is a Short Paper as defined in the Instructions for Authors,
Section 5.0 [see J. Chem. Research (S), 1997, Issue 1]; there is there-
fore no corresponding material in J. Chem. Research (M).

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J. CHEM. RESEARCH (S), 1996 57
10.5%); vmax/cmꢀ1 3498, 3409, 3335; dH 0.73 (3 H, s, 18-H), 0.94
(3 H, s, 19-H), 3.65 (2 H, m, 4b- and 17a-H). The 4a,17b-diacetate,
prepared with acetic anhydride in pyridine, had mp 170–172 °C
of addition to the b-face of the 3-ene. In the case of the
19-nor steroid, lacking this methyl group, only products aris-
ing from addition to the b-face were obtained when a 5a-
hydroxy group was present. Comparison of the results of
hydroboration of 5a-hydroxyandrost-3-ene and the corre-
sponding 19-nor steroid suggests that the 10b-methyl group
and the 5a-hydroxy group have approximately equivalent
directing effects.
(Found: C, 70.7; H, 9.5. C23H36O5 requires C, 70.4; H, 9.2%); vmax
/
cmꢀ1 3380, 1720; dH 0.71 (3 H, s, 18-H), 0.91 (3 H, s, 19-H), 1.96
and 1.99 (each 3 H, s, OAc), 4.51 (1 H, t, J 7.8 Hz, 17a-H), 4.91
(1 H, dd, J 6.0 and 10.5 Hz, 4b-H). Further chromatography gave
4b,5a,17b-trihydroxyandrostane (281 mg), prisms, 223–225 °C
.
(Found: C, 71.5; H, 10.3. C19H32O3 0.5H2O requires C, 71.9; H,
10.5%); vmax/cmꢀ1 3490, 3400, 3367; dH 0.74 (3 H, s, 18-H), 1.18
(3 H, s, 19-H), 3.54 (1 H, t, J 2.8 Hz, 4a-H), 3.64 (1 H, t, J 8.4 Hz,
17a-H). The 4b,17b-diacetate, prepared with acetic anhydride in
pyridine, had mp 181–183 °C (Found: C, 70.2; H, 9.0. C23H36O5
requires C, 70.4; H, 9.2%); vmax/cmꢀ1 3240, 1740, 1720; dH 0.74
(3 H, s, 18-H), 1.10 (3 H, s, 19-H), 1.96 and 1.99 (each 3 H, s, OAc),
4.54 (1 H, t, J 7.8 Hz, 17a-H), 4.65 (1 H, t, J 2.6 Hz, 4a-H). Further
elution gave 3b,5a,17b-trihydroxyandrostane (201 mg), mp
192–194 °C (lit.,9 193–196 °C).
Experimental
General experimental details have been described previously.5
Steroids were crystallized from ethyl acetate or acetone–light
petroleum mixtures.
Hydroboration Experiments.s17b-Acetoxy-5a-androst-3-ene. The
steroid (1 g) in dry THF (30 cm3) was treated with borane in THF
(30 cm3, 1 ) for 4 h. Water (10 cm3) was added and the solution
M
cooled to 0 °C. Aqueous sodium hydroxide (20 cm3, 10%) was
added followed by the dropwise addition of hydrogen peroxide (20
cm3, 30%). The mixture was stirred overnight. Sodium sulfite (2 g)
was added followed by acetic acid (1 cm3), water (50 cm3), dil.
hydrochloric acid (50 cm3) and ethyl acetate (100 cm3). The organic
layer was separated, washed with water, brine and then dried. The
solvent was evaporated and the residue chromatographed on silica.
Elution with 25% ethyl acetate–light petroleum gave successively
(i) 3b,17b-dihydroxy-5a-androstane (64 mg), needles, mp
167–169 °C (lit.,7 168–169 °C), vmax/cmꢀ1 3450, 3304; dH (3 H, s,
18-H), 0.79 (3 H, s, 19-H), 3.61 (2 H, m, 3a- and 17a-H); (ii)
4a,17b-hydroxy-5a-androstane (263 mg), prisms, mp 231–233 °C
(lit.,8 235–237 °C), vmax/cmꢀ1 3506, 3433; dH 0.73 (3 H, s, 18-H), 0.81
(3 H, s, 19-H), 3.45 (1 H, dt, J 4.6 and 10.5 Hz, 4b-H), 3.63 (1 H, t,
J 8.6 Hz, 17a-H); (iii) 4b,17b-dihydroxy-5a-androstane (92 mg),
needles, mp 179–181 °C (lit.,8 176–178 °C), vmax/cmꢀ1 3490, 339; dH
0.72 (3 H, s, 18-H), 0.99 (3 H, s, 19-H), 3.62 (1 H, t, J 8.6 Hz,
17a-H), 3.88 (1 H, m, 4a-H); (iv) 3a,17b-dihydroxy-5a-androstane
(278 mg), prisms, mp 220–223 °C (lit.,7 222–224 °C), vmax/cmꢀ1
3490, 3400; dH 0.73 (3 H, s, 18-H), 0.79 (3 H, s, 19-H), 3.62 (1 H, t,
J 8.6 Hz, 17a-H), 4.05 (1 H, brs, 3b-H).
17b-Acetoxy-5a-hydroxy-19-norandrost-3-ene. The 5a-hydroxy-
19-nor steroid (1 g) gave successively (i) 5a,17b-dihydroxy-19-nor-
androstane (40 mg) as a gum, m/z 292 (Mǹ), 274 (MꢀH2O) 256
(Mꢀ2H2O); vmax/cmꢀ1 3512; dH 0.75 (3 H, s, 18-H), 3.65 (1 H, t, J
8.2 Hz, 17a-H); (ii) 17b-acetoxy-4b,5a-dihydroxy-19-norandrostane
(160 mg), plates, mp 187–189 °C (Found: C, 71.3; H, 9.7. C20H32O4
requires C, 71.4; H, 9.6%); vmax/cmꢀ1 3320, 1742; dH 0.78 (3 H, s,
18-H), 2.02 (3 H, s, OAc), 3.47 (1 H, t, J 3.0 Hz, 4a-H), 4.58 (1 H,
t, J 8 Hz, 17a-H); (iii) 17b-acetoxy-3b,5a-dihydroxy-19-norandros-
tane (80 mg), needles, mp 218–220 °C (Found: C, 70.7; H, 9.6.
C20H32O4 requires C, 71.4; H, 9.6%); vmax/cmꢀ1 3358, 1720; dH 0.75
(3 H, s, 18-H), 2.04 (3 H, s, OAc), 3.98 (1 H, tt, J 9.6 and 4.5 Hz,
3a-H), 4.62 (1 H, t, J 8.2 Hz, 17a-H); (iv) 4b,5a-17b-trihydroxy-
19-norandrostane (410 mg), prisms, 203–205 °C (Found: C, 71.5; H,
10.2. C18H30O3 0.5H2O requires C, 71.2; H, 10.3%); vmax/cmꢀ1 3450;
.
d
H 0.74 (3 H, s, 18-H), 3.48 (1 H, t, J 2.8 Hz, 4a-H), 3.65 (1 H, t, J 8
Hz, 17a-H).
Received, 28th August 1996; Accepted, 22nd October 1996
Paper E/6/05946E
17b-Acetoxy-19-nor-5a-androst-3-ene. The 19-nor steroid (1 g)
gave (i) 4b-17b-dihydroxy-19-nor-5a-androstane (63 mg), needles,
mp 167–169 °C (Found: C, 77.5; H, 10.8. C18H30O2 requires C, 77.6;
H, 10.9%); vmax/cmꢀ1 3305; dH 0.74 (3 H, s, 18-H), 3.64 (1 H, t, J 8.2
Hz, 17a-H), 3.76 (1 H, brs, 4a-H); (ii) 4a,17b-dihydroxy-19-nor-
5a-androstane (240 mg), plates, mp 200–220 °C (Found: C, 77.5; H,
10.9. C18H30O2 requires C, 77.5; H, 10.9%); vmax/cmꢀ1 3230; dH 0.75
(3 H, s, 18-H), 3.21 (1 H, td, J 10.5 and 4.6 Hz, 4b-H), 3.64 (1 H, t,
J 8.2 Hz, 17a-H); (iii) 3a,17b-dihydroxy-19-nor-5a-androstane (145
mg), needles, mp 163 °C (Found: C, 77.6; H, 11.0. C18H30O2
requires c, 77.6; H, 10.9%); vmax/cmꢀ1 3279; dH 0.72 (3 H, s, 18-H),
3.64 (1 H t, J 8.2 Hz, 17a-H), 4.12 (1 H, brs, 3b-H); (iv) 3b,17b-dihy-
droxy-19-nor-5a-androstane (120 mg), needles, mp 141–143 °C
(Found: C, 77.5; H, 10.7. C18H30O2 requires C, 77.6; H, 10.9%);
References
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max/cmꢀ1 3348; dH 0.74 (3 H, s, 18-H), 3.57 (1 H, t, J 10.5 and 4.5
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Hz, 3a-H) 3.62 (1 H, t, J 8.1 Hz, 17a-H).
17b-Acetoxy-5a-hydroxyandrost-3-ene. The 5a-hydroxy steroid
(1 g) gave 4a,17b-dihydroxy-5a-androstane (147 mg) and
4b,17b-dihydroxy-5b-androstane (30 mg) which were identified by
their 1H NMR spectra. Further chromatography gave
4a,5a,17b-trihydroxyandrostane (90 mg), prisms, mp 219–220 °C
.
(Found: C, 71.7; H, 10.3. C19H32O3 0.5H2O requires C, 71.9; H,