Synthesis of ent-19-nortestosterone from its naturally occurring antipode

Article abstract of DOI:10.1016/S0040-4039(01)00296-9

The synthesis of ent-19-nortestosterone from natural 19-nortestosterone is described. The synthetic sequence takes advantage of the 'near symmetry' properties of the steroid; removal/introduction of a methyl group and conversion of the A- into the D-ring and vice versa eventually results in overall inversion of the stereochemistry.

Full text of DOI:10.1016/S0040-4039(01)00296-9

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 2869–2871
Synthesis of ent-19-nortestosterone from its naturally
occurring antipode
N. Miranda Teerhuis, Ine`s A. M. Huisman and Marinus B. Groen*
Research & Development, N.V. Organon, PO Box 20, 5340 BH Oss, The Netherlands
Received 29 January 2001; revised 2 February 2001; accepted 20 February 2001
Abstract—The synthesis of ent-19-nortestosterone from natural 19-nortestosterone is described. The synthetic sequence takes
advantage of the ‘near symmetry’ properties of the steroid; removal/introduction of a methyl group and conversion of the A- into
the D-ring and vice versa eventually results in overall inversion of the stereochemistry. © 2001 Elsevier Science Ltd. All rights
reserved.
Steroids play an extremely important role in biological
processes. While their properties have been widely stud-
ied in a broad range of applications, their enantiomers,
the so-called ent-steroids, in comparison have received
only very little attention.1 Nevertheless, information
about the interaction of ent-steroids with hormonal
receptors might lead to new valuable insights in recep-
tor binding. Obtaining ent-steroids on the other hand is
a far from trivial issue. In the quest for attaining the
unnatural enantiomers of steroids, a number of groups
used a classical resolution of a racemic intermediate or
product. In more recent syntheses, the required chirality
was introduced at some point via an enantioselective
transformation of an achiral precursor.2 Although both
methods in principle may give the desired products in
very high enantiomeric excess, they do not afford the
enantiomer in absolute (100%) purity. With the goal of
studying the hormonal properties of ent-steroids, it is
necessary to have these compounds enantiomerically
pure, since minute traces of the extremely potent natu-
ral enantiomers may mask the weak activities of the
ent-steroids.
as the starting material. Logically, such an approach
affords ent-steroids with the same enantiomeric purity
as their natural counterparts, which is believed to be
complete. This strategy was applied to the synthesis of
ent-19-nortestosterone ent-1, starting from its natural
enantiomer, 19-nortestosterone 1. Our strategy takes
advantage of the near-symmetrical properties of the
steroid skeleton. A 180° rotation of the molecule of
19-nortestosterone 1 about the axis perpendicular to the
skeleton shows that the rotated structure is enan-
tiomeric to the original with respect to the ring junc-
tions. In fact, the only differences between the two
skeletons are the different sizes of the A- and D-rings
and the angular methyl group. Therefore, ‘correction’ of
these two differences will result in overall conversion of
the 19-nortestosterone skeleton into its enantiomer! The
forward synthesis is outlined in Scheme 1.
19-Nortestosterone (1) was epoxidized with H2O2 and
NaOH to afford selectively the b-epoxyketone 2 in
quantitative yield.3 Hydrazone formation with tosylhy-
drazine in acetic acid led to fragmentation of the A-ring
to give the acetylenic ketone 3a.4 The radical cyclization
of this compound under the influence of sodium naph-
thalenide in THF proceeded smoothly, but separation
Therefore, we devised a strategy for the synthesis of
ent-steroids which utilizes naturally occurring steroids
* Corresponding author. Tel.: +31 (0)412 662470; fax: +31 (0)412 662546; e-mail: m.groen@organon.oss.akzonobel.nl
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)00296-9

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N. M. Teerhuis et al. / Tetrahedron Letters 42 (2001) 2869–2871
Scheme 1. Reagents and conditions: (a) H2O2, NaOH, MeOH, 0°C, 2 h, 99%; (b) TsNHNH2, AcOH, −18°C“rt, 18 h, 73%; (c)
TBSCl, imidazole, DMF, 0°C, 3 h, quant.; (d) Na, naphthalene, THF, rt, 63%; (e) m-CPBA, CH2Cl2, 0°C, 2 h, 75%; (f) LiAlH4,
ether, rt, 30 min, 95%; (g) TBAF, THF, reflux, 18 h, 87%; (h) conc. HCl, MeOH, reflux, 2 h, 20%.
of the product from the remaining starting material was
troublesome. Therefore, prior to the cyclization the
hydroxyl group was protected as a TBDMS-ether to
afford 3b. Treatment of 3b with sodium naphthalenide
in THF resulted in completely diastereoselective
cyclization to the allylic alcohol 4 in 63% yield after
recrystallization.5 Having the five-membered ring in
place, introduction of the methyl-substituent was in
order. Thus, directed epoxidation of the double bond
with m-CPBA provided 5, which was reduced using
lithium aluminum hydride to afford diol 6a in 70%
yield (two steps). Initially, we anticipated that forma-
tion of ketone 7 could be achieved using a pinacol
rearrangement so that 6a was refluxed in HCl/MeOH
for 2 h.6 Unfortunately, only a trace of the desired
rearranged product was obtained, whereas the major
part of the product turned out to be a complex mixture
of elimination and desilylation products. Interestingly,
application of identical conditions after removal of the
TBDMS group (TBAF, THF, reflux) led to the desired
ketone 7 in 20% yield. The use of different acids, e.g.
acetic acid and tosic acid, did not significantly improve
the yield of the rearrangement. Since we considered
such a low yielding step not very practical for this
multistep sequence, an alternative route to arrive at
ketone 7 was investigated (Scheme 2).
This alternative pathway proceeded via the tetra-substi-
tuted olefin 8b, which in line with literature precedent6
was considered a useful intermediate to arrive at ketone
7. Alkene 8a was obtained from 4 via TFA/TFAA-
mediated generation of the corresponding allylic cation,
followed by in situ reduction with Et3SiH from the less
hindered site to give the desired olefin. Subsequent
cleavage of the trifluoroacetate with potassium carbon-
ate then gave 8b in 50% yield over two steps. In the
next step, the double bond had to be selectively epoxi-
dized to the corresponding b-epoxide 9. Studies on
similar systems revealed that treatment with m-CPBA
leads to the a-isomer, whereas reaction with t-BuOOH
and Mo(CO)6 favors formation of the b-epoxide.7
Indeed, applying the latter conditions led to the desired
epoxide 9 as the sole product, which in a Lewis acid-
mediated rearrangement was converted into the desired
ketone 7 in 46% yield. Unfortunately, although the
rearrangement itself proceeded in a higher yield than in
the earlier described route, the overall yield was not
significantly improved. The final part of the synthesis
involved transformation of the hydroxy-substituted
five-membered ring into a six-membered ring enone
system. To this end, a well-known method for this type
of transformation was used (Scheme 3).
Scheme 2. Reagents and conditions: (a) CF3CO2H, (CF3CO)2O, Et3SiH, CH2Cl2, rt, 2.5 h, 72%; (b) K2CO3, MeOH/heptane, rt,
15 min, 69%; (c) t-BuOOH, Mo(CO)6, toluene, 80°C, 3 h, 68%; (d) BF3·OEt2, toluene, 0°C, 45 min, 46%.

N. M. Teerhuis et al. / Tetrahedron Letters 42 (2001) 2869–2871
2871
Scheme 3. Reagents and conditions: (a) Ts2O, pyridine, 0°C, 2 h, 92%; (b) NaBH4, MeOH, 0°C, 1.5 h, 92%; (c) EtMgBr, benzene,
reflux, 1 h, quant.; (d) KMnO4, NaIO4, NaHCO3, t-BuOH, reflux, 45 min, 42%; (e) KOH, MeOH, rt, 2 h, 74%.
First, the hydroxyl group was reacted with p-toluene-
sulfonic anhydride to afford tosylate 10. Since the
projected rearrangement involved reaction with ethyl-
magnesium bromide, the carbonyl group first had to be
protected as the alcohol 11 via reduction with NaBH4
in methanol. Then, reaction with ethylmagnesium bro-
mide in refluxing benzene afforded alkene 12,8 which in
the next step was oxidatively cleaved using a mixture of
potassium permanganate and sodium periodate to give
13 in reasonable overall yield. Finally, a classical
Robinson annulation under the influence of KOH in
methanol afforded the desired enantiomer of 19-
nortestosterone in 74% yield.9
Chem. 1998, 41, 2604 and references cited therein.
2. (a) Rychnovsky, S. D.; Mickus, D. E. J. Org. Chem. 1992,
57, 2732; (b) Ohloff, G.; Maurer, B.; Winter, B.; Giersch,
W. Helv. Chim. Acta 1983, 66, 192.
3. Menberu, D.; Nguyen, P. V.; Onan, K. D.; Quesne, P. W.
L. J. Org. Chem. 1992, 57, 2100.
4. (a) Boar, R. B.; Jones, S. L.; Patel, A. C. J. Chem. Soc.,
Perkin Trans. 1 1982, 513; (b) Eschenmoser, A.; Felix, D.;
Ohloff, G. Helv. Chim. Acta 1967, 50, 708; (c) Tanabe, M.;
Crowe, D. F.; Dehn, R. L.; Detre, G. Tetrahedron Lett.
1967, 38, 3739.
5. (a) Pradhan, S. K.; Kadam, S. R.; Kolhe, J. N.; Radhakr-
ishnan, T. V.; Sohani, S. V.; Thaker, V. B. J. Org. Chem.
1981, 46, 2622; (b) Pradhan, S. K.; Radhakrishnan, T. V.;
Subramanian, R. J. Org. Chem. 1976, 41, 1943; (c) Prad-
han, S. K.; Girijavallabhan, V. M. Steroids 1969, 13,
11.
In summary, we have clearly demonstrated the viability
of the principle that steroids can be converted into the
corresponding ent-steroids. In this case, we started
form 19-nortestosterone, which in 13 steps was con-
verted into its enantiomer in 1.9% overall yield. The
interaction of this compound with different steroid
receptors is currently under investigation.
6. Bascoul, J.; Reliaud, C.; Guinot, A.; Crastes de Paulet, A.
Bull. Soc. Chim. Fr. 1968, 4074.
7. Groen, M. B.; Zeelen, F. J. Tetrahedron Lett. 1982, 23,
3611.
8. Engel, C. R.; Lachance, P.; Capitaine, J.; Zee, J.; Mukher-
jee, D.; Me´rand, Y. J. Org. Chem. 1983, 48, 1954.
9. Fe´tizon, M.; Gramain, J.-C.; Mourgues, P. Bull. Soc.
Chim. Fr. 1969, 1673.
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