A New Chiral Director for the Highly Diastereoselective Borane Reduction of Steroid-20-ones

Article abstract of DOI:10.1007/s007060070037

The synthesis of a new chiral boroxazolidine was achieved which was used to control the stereochemistry of the borane reduction of the 20-keto group of steroids. The otherwise hardly accessible 20α-(20S)-alcohol can thus be prepared in a yield of 91 percent.

Full text of DOI:10.1007/s007060070037

Monatshefte fuÈr Chemie 131, 1055±1059 (2000)
A New Chiral Director for the Highly
Diastereoselective Borane Reduction
of Steroid-20-ones
1;Ã
2
3
È È È È
Gyorgy Gondos , Gyorgy Dombi , and James C. Orr
1
Department of Organic Chemistry, University of Szeged, H-6720 Szeged, Hungary
Department of Pharmaceutical Analysis, University of Szeged, H-6720 Szeged, Hungary
Faculty of Medicine, Memorial University of Newfoundland, St Jone's, Canada A1B 3V6
2
3
Summary. The synthesis of a new chiral boroxazolidine was achieved which was used to control the
stereochemistry of the borane reduction of the 20-keto group of steroids. The otherwise hardly
accessible 20ꢀ-(20S)-alcohol can thus be prepared in a yield of 91%.
Keywords. Asymmetric reduction; Chiral boranes; Steroid-20-one.
Introduction
High enantioselectivity has been reported in the asymmetric reduction of prochiral
ketones with mixtures of borane and chiral aminoalcohols in tetrahydrofuran [1±5].
The asymmetric reduction of chiral 20-keto-steroids with nucleophilic organobor-
ohydrides and electrophilic organoboranes has likewise been studied [6]. The
hydroboration of steroid-20-ones via anti-Cram addition provided predominantly
the (20S)-(20ꢀ)-hydroxy products [6]. We have found that the asymmetric
reduction of chiral steroid-20-ones with borane-methyl sul®de (BMS) in the
presence of ꢀR†-( )-2-amino-2-phenyl-1-ethanol gives a moderate excess of the
(20S) products [7].
Corey et al. have prepared the sterically hindered ꢁ-aminoalcohol ꢀS†-
diphenylprolinol (ꢀS†-4) and the corresponding B-methyl-oxazaborolidine ꢀS†-7
which provided useful enantioselectivity in the reduction of prochiral ketones [2].
They have further proposed that the borane complex of the resulting oxaza-
borolidine [8, 9] is an important intermediate responsible for the enantioselectivity
of ketone reduction. This phenomenon is supported by recent results found in the
literature [11].
Results and Discussion
In order to achieve a higher diastereoselectivity for the preparation of the (20S)-
hydroxy isomer 2 in the reduction of 5ꢁ-pregnan-3ꢀ-ol-20-one (1) than previously
Ã
Corresponding author

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G. Gondos et al.
1056
Scheme 1
Table 1. Asymmetric reduction of 5ꢁ-pregnan-3ꢀ-ol-20-one (1) in the presence of various chiral
directors with borane at room temperature
Chiral
Reaction time
(h)
Yielda
(%)
Product/%b
Entry
director
2 (20S-OH)
3 (20R-OH)
1
2
3
4
5
6
7
8
(R)-(‡)-4
(S)-( )-4
(R)-(‡)-7
(S)-( )-7
(R)-( )-5
(S)-(‡)-5
(R)-( )-6
(R)-( )-8
48.0
48.0
40.0
40.0
0.5
39
30
34.0
0.0
66.0
100.0
82.0
72.0
24.4
100.0
51.2
8.5
25
18.0
28.0
75.6
0.0
27
99
0.5
97
24.0
0.5
45
48.8
91.5
100
a
Isolated product; bHPLC, Merck Partisil PXS 10/25, CHCl3 :MeOH ˆ 95:5 or CH2Cl2 :
MeOH ˆ 95:5
reported [7], we applied the ꢀR†-(‡)- and ꢀS†-( )-diphenylprolinols (ꢀR†-4 and
ꢀS†-4) [2] and the corresponding ꢀR†-(‡)- and ꢀS†-( )-B-methyl-oxazaborolidines
(ꢀR†-7 and ꢀS†-7) [5] as chiral directors. Initially, 1 was reduced with BMS in the
presence of ꢀR†-4 and ꢀS†-4 applying a method published earlier [7] (Scheme 1).
The resulting diastereoisomeric ratios are listed in Table 1.
High diastereoselectivity was achieved with ꢀS†-4, but the common (20R)-
hydroxy isomer was formed in a large excess (Table 1, entry 2). Lower
diastereoselectivity was observed in the presence of ꢀR†-4, but the (20S)-hydroxy
isomer was obtained in higher quantity (Table 1, entry 1) compared to Ref. [7].
However, the selectivity for the (20S)-hydroxy isomer was insuf®cient. The
stoichiometric reaction of ketone 1 with the enantiomeric borane complexes ꢀR†-7
and ꢀS†-7 was achieved by the method reported by Mathre et al. [10]. It was found
that the selectivity of the reductions were high, but both products contained a large
excess of the (20R)-diastereoisomer (Table 1, entries 3 and 4). It is noteworthy that
with ꢀS†-7 the yield of the (20S)-hydroxy isomer was much higher than with ꢀR†-7.
The data in Table 1 indicate that the yields of the reductions with all chiral
directors mentioned above were very low. We suppose this to be due to the steric

Diastereoselective Reduction of Steroid-20-ones
1057
Scheme 2
hindrance of the applied chiral reagents. When the two phenyl substituents were
removed from the reagents 4 and 7 and the reductions were performed with BMS in
the presence of ꢀR†-( )-prolinol ꢀR†-5 employing our previous method [7], the
major product was the (20S)-hydroxy isomer (2, Table 1, entry 5) rather than the
(20R)-hydroxy isomer (3). However, when 1 was reduced with BMS in the
presence of ꢀS†-5, 3 was formed exclusively (Table 1, entry 6). Reactions were
carried out under very mild conditions and were complete after 30 minutes.
In order to increase the amount of 2 in the resulting mixture of diastereoisomers
2 and 3, the corresponding oxazaborolidine 6 was prepared in crystalline form by
sublimation of the residue obtained from a molar equivalent mixture of ꢀR†-5 and
BMS. When the reduction of 1 was attempted with two equivalents of BMS in the
presence of the chiral director 6 via the method reported by Youn et al. [3], both
diastereoselectivity and yield (Table 1, entry 7) were lower than expected from the
previous experiment where 6 was generated in situ. In accordance with literature
data [10] we presume that 6 was partly converted to the corresponding dimer
before the reduction occurred. To avoid this problem, we prepared a new B-methyl-
boroxazolidine ((R)-8) from ꢀR†-5 (Scheme 2).
The synthesis of ꢀR†-8 could be driven to completion by sequential addition of
trimethylboroxine (molar equivalent) to a toluene solution of ꢀR†-5 and azeotropic
removal of both water and the excess of methylboronic acid as described by
Mathre et al. [10].
The solution of ꢀR†-8 itself in toluene did not reduce ketone 1. However, a
mixture of ꢀR†-8 and BMSÁBH3 (1±1.2 molar equivalents) afforded complete
reduction of 1 in 30 min at ambient temperature with excellent yield (98%) and
considerable diastereoselectivity (ꢀ20S† : ꢀ20R† ˆ 91:5:8:5; Table 1, entry 8).
Experimental
Melting points were determined on a Boetius apparatus and are uncorrected. 1H and 13C NMR
spectra were run at ambient temperature on a Bruker AVANCE DRX 400 spectrometer at 400.24 and
100.06 MHz, respectively, with TMS as internal standard using the deuterium signal of CDCl3
(solvent) to lock the ®eld.
5ꢁ-Pregnan-3ꢀ-ol-20-one (1) and ꢀR†-( )- and ꢀS†-(‡)-prolinols (ꢀR†-5 and ꢀS†-5) were
purchased from Aldrich, ꢀR†-(‡)- and ꢀS†-( )-ꢀ,ꢀ-diphenyl-prolinols (ꢀR†-4 and ꢀS†-4) from
Lancaster Synthesis Ltd. (England); all substances were used as received. ꢀR†- and ꢀS†-Tetrahydro-1-
methyl-3,3-diphenyl-1H,3H-pyrrolo[1,2-c][1,3,2]oxazaborole (ꢀR†-7 and ꢀS†-7) was kindly supplied
by Dr. D. J. Mathre from Merck Sharp & Dohme Research Laboratories (New Jersey, USA) and used
without further puri®cation.

È È
G. Gondos et al.
1058
The ratios of steroid alcohol isomers (2 and 3) were determined by TLC and HPLC as described
earlier [7]. The physical and spectroscopic data of compounds 2 and 3 are available from Ref. [7].
(R)-( )-Tetrahydro-1H,3H-pyrrolo[1,2-c][1,3,2]oxazaborole (6; C5H10BNO)
To a stirred solution of 0.1 g aminoalcohol 5 (1 mmol) in 5 cm3 THF, 0:6 cm3 BMS (1.2 mmol; 2 M
solution in THF, Aldrich) were added at 70ꢁC. The resulting solution was gradually warmed
to 50ꢁC and stirred for 5 h. Removal of solvent, sublimation at 145±160ꢁC (0.8 mbar), and
resublimation of 145±160ꢁC (0.3 mbar), afforded 6 as a white solid.
1
Yield: 0.097 g (88.18%); m.p.: 61±65ꢁC (decomp); EIMS: m=z ˆ 110.95 (calcd.: 110.94); H
NMR (CDCl3; ꢂ, 400 MHz): 1.5±1.9 (m, 4H, 4-CH2, 5-CH2), 3.0 (m, 1H, 3a-CH), 3.4 (m, 2H, 6-
CH2), 3.6 (m, 2H, 3-CH2), 5.0 (b, 1H, 1-BH) ppm.
(R)-(‡)-Tetrahydro-1-methyl-1H,3H-pyrrolo[1,2-c][1,3,2]oxazaborole (8R; C6H12BNO)
A solution of 103 mg 5 (1 mmol) in 6 cm3 toluene was treated with 125 mg trimethylboroxine
(1 mmol) at room temperature for 1 h. The ¯ask was ®tted with a distillation head, toluene (50 cm3)
was added, and the mixture was heated and concentrated by distillation (1 atm) to 50 cm3. During
distillation the vessel was swept with N2. The toluene addition followed by concentration was
repeated three times to insure complete removal of H2O and excess of methylboronic acid. Removal
of the excess of solvent in vacuo yielded 8 (116 mg, 92.8%) as a pale yellow oil.
1
EIMS: m=z ˆ 124:95 (calcd.: 124.976); H NMR (CDCl3; ꢂ, 400 MHz):-0.06 (s, 3H, B-CH3),
1.4±1.8 (m, 4H, 4-CH2, 5-CH2), 2.8 (m, 1H, 3a-CH), 3.3 (m, 2H, 6-CH2), 3.5 (m, 2H, 3-2CH2) ppm;
13C NMR (CDCl3; ꢂ, 100 MHz): 26.7 and 28.2 (4- and 5-C, respectively), 47.0 (6-C), 60.2 (3a-C),
65.5 (3-C) ppm.
Stoichiometric reduction of ketone 1
To a stirred solution of 124.9 mg boroxazolidine 8 (1 mmol) and 75.9 mg BMS (1 mmol) in 5 cm3 dry
THF, a THF (3 cm3) solution of 318.5 mg ketone 1 (1 mmol) was added over 20 min at room
temperature under N2. The reaction mixture was stirred at room temperature for 30 min, and
2 cm315% aqueous HCl were added at 5ꢁC. The precipitated steroid alcohol was extracted three
times with 15 cm3 ether, and the combined extracts were washed with H2O until neutral and dried
over anhydrous Na2SO4. After removal of the solvent the residue was analyzed by TLC and HPLC as
described earlier [7].
Acknowledgements
We are grateful to Dr. D. J. Mathre for the chiral B-methyl-boroxazolidine reagents ꢀR†-7 and ꢀS†-7.
This research was supported by the Hungarian Ministry of Education (Grant No FKFP-0526/1999).
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Diastereoselective Reduction of Steroid-20-ones
1059


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Received April 10, 2000. Accepted (revised) May 2, 2000