Synthesis of B-ring-modified steroids through BF3-promoted rearrangement/substitution of 6β-hydroxy-5,19-cyclosteroids

Article abstract of DOI:10.1021/ol301532w

The BF₃?Et₂O-promoted reaction of 3β-acetoxy-5,19-cyclo-pregnan-6β-ol-20-one with different nucleophiles was investigated. B-homo steroids (3β-acetoxy-B-homo-6a-β-alkoxy- pregna-5(10)-en-20-ones) were obtained with primary and secondary alcohols, while the reaction with common carboxylic acids selectively afforded the corresponding 3β-acetoxy-6β-(acyloxymethyl)-pregna-5(10)-en-20-ones. The transformations are supposed to proceed via the rearrangement of a cyclopropyl-methyl cation (bicyclobutonium) intermediate, which is regioselectively opened in dependence on the nucleophile employed. The method represents an efficient, diversity-oriented entry to new B-ring-modified steroids, which are of potential pharmaceutical relevance.

Full text of DOI:10.1021/ol301532w

ORGANIC
LETTERS
2012
Vol. 14, No. 14
3692–3695
Synthesis of B-Ring-Modified Steroids
through BF3-Promoted Rearrangement/
Substitution of 6β-Hydroxy-5,
19-cyclosteroids
€
Darius P. Kranz, Slim Chiha, Aike Meier zu Greffen, Jorg-Martin Neudorfl, and
€
€
Hans-Gunther Schmalz*
€
Department of Chemistry, University of Cologne, Greinstr. 4, 50939 Koln, Germany
schmalz@uni-koeln.de
Received June 4, 2012
ABSTRACT
The BF3 Et2O-promoted reaction of 3β-acetoxy-5,19-cyclo-pregnan-6β-ol-20-one with different nucleophiles was investigated. B-homo steroids
3
(3β-acetoxy-B-homo-6a-β-alkoxy-pregna-5(10)-en-20-ones) were obtained with primary and secondary alcohols, while the reaction with common
carboxylic acids selectively afforded the corresponding 3β-acetoxy-6β-(acyloxymethyl)-pregna-5(10)-en-20-ones. The transformations are
supposed to proceed via the rearrangement of a cyclopropyl-methyl cation (bicyclobutonium) intermediate, which is regioselectively opened
in dependence on the nucleophile employed. The method represents an efficient, diversity-oriented entry to new B-ring-modified steroids, which
are of potential pharmaceutical relevance.
As a consequence of their unparallelled biological im-
portance and structural diversity, steroids enjoy a continu-
ing interest in biological and medicinal chemistry.1 In
recent years, unusual steroids with rearranged AB-ring
systems such as the cyclocitrinols2 or the cortistatins3 have
revitalized the interest of chemists in the synthesis of
B-homo steroids, only a few of which had been prepared
in the past either by target-oriented synthesis4 or as com-
ponents of mixtures resulting from cationic rearrangement
processes starting from 19-oxy steroids.5 In the course of our
interest in the synthesis of the cyclocitrinols,2b we recently
discovered a high yielding access to the B-homo steroid 2 by
BF3-mediated acetylation/rearrangement of the 19,5-cy-
closteroid 1 (Scheme 1).6
The unprecedented efficiency of the formation of 2 now
prompted us to also explore the use of the cyclopropylcar-
binol 4 as an alternative substrate in related acid or Lewis
(1) (a) Fieser, L.; Fieser, M.; Steroids; Reinhold Publishing Corp.: New
York, 1959. (b) Sarma, N. S.; Krishna, M. S.; Pasha, S. G.; Rao, T. S. P.;
Venkateswarlu, Y.; Parameswaran, P. S. Chem. Rev. 2009, 109, 2803–2828.
(c) Hanson, J. R. Nat. Prod. Rep. 2010, 27, 887–899.
(2) Structure elucidation: (a) Amagata, T.; Amagata, A.; Tenney, K.;
Valeriote, F. A.; Lobkovsky, E.; Clardy, J.; Crews, P. Org. Lett. 2003, 5,
4393–4396. For a synthetic approach, see: (b) El Sheikh, S.; Meier zu
(4) (a) Ringold, H. J. J. Am. Chem. Soc. 1960, 82, 961–963. (b)
Galantay, E.; Weber, H. P. Experimentia 1969, 25, 571–572. (c) Kupchan,
S. M.; Findlay, J. W. A.; Hackett, T.; Kennedy, R. M. J. Org. Chem. 1972,
37, 2523–2525. (d) Groen, M. B.; Zeelen, F. J. Recl. Trav. Chim. Pays-Bas
1984, 103, 169–173.
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1881–1884.
(3) Structure elucidation: (a) Aoki, S.; Watanabe, Y.; Sanagawa, M.;
Setiawan, A.; Kotoku, N.; Kobayashi, M. J. Am. Chem. Soc. 2006, 128,
3148–3149. Synthesis (selected references): (b) Magnus, P.; Littich, R.
Org. Lett. 2009, 11, 3938–3941. (c) Shenvi, R. A.; Guerrero, C. A.; Shi,
J.; Li, C.-C.; Baran, P. S. J. Am. Chem. Soc. 2008, 130, 7241–7243. (d)
Lee, H. M.; Nieto-Oberhuber, C.; Shair, M. D. J. Am. Chem. Soc. 2008,
(5) (a) Knox, L.; Velarde, E.; Berger, S.; Dephın, I.; Grezemkovsky,
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R.; Cross, A. D. J. Org. Chem. 1965, 30, 4160–4165. (b) Tadanier, J. J.
Org. Chem. 1966, 31, 2124–2135. (c) Nussim, M.; Mazur, Y. Tetrahedron
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1968, 24, 5337–5359. (d) Ferret, H.; Dechamps, I.; Pardo, D. G.; Van
Hijfte, L.; Cossy, J. ARKIVOC 2010, viii, 126–259.
(6) Kranz, D. P.; Meier zu Greffen, A.; El Sheikh, S.; Neudorfl,
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130, 16864–16866. (e) Kurti, L.; Czako, B.; Corey, E. J. Org. Lett. 2008,
10, 5247–5250. (f) Flyer, A. N.; Si, C.; Myers, A. G. Nat. Chem. 2010, 2,
886–892. (g) Narayan, A. R. H.; Simmons, E. M.; Sarpong, R. Eur. J.
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r
10.1021/ol301532w
Published on Web 07/05/2012
2012 American Chemical Society

Other solvents such as acetontrile, THF, or 2-methyl-
THF were not effective (formation of complex mixtures).
Best results were obtained in CH2Cl2 using 2 equiv of
Scheme 1. Synthesis of the B-homo Steroid 2 according to Ref 6
BF3 Et2O and 3 equiv of MeOH. An excess of MeOH
3
(in relation to BF3 Et2O) proved to be beneficial to avoid
3
the formation of unseparable mixtures. The structure
(constitution and relative configuration) of 6a was un-
ambiguously confirmed by X-ray crystal structure analy-
sis (Figure 1).
acid mediated transfomations.7 In analogy to the mecha-
nism proposed for the conversion of 1 to 26 we envisioned
that a rearranged cyclopropylmethyl cation5a of type 5
could possibly react with different nucleophiles to give rise
to 6aβ-substituted B-homo steroids of type 6 in a diversity-
oriented manner (Scheme 2).
Scheme 2. Projected Conversion of the 19,5-Cyclosteroid 4 into
B-homo Steroids of Type 6
Figure 1. Structure of the B-homo steroid 6a in the crystal.
Having identifiedefficient and reliable conditions for the
preparation of the methoxy derivative 6a we next probed
the scope of the method employing a set of different nucle-
ophiles (always using 4 as the substrate). The results shown
in Figure 2 reveal the formation of the expected products
(of type 6) with a seven-membered ring B in moderate to
high yields. Related products (i.e., the esters 6g and 6h)
were also obtained when acetic or trifluoroacetic anhy-
dride were used instead of an alcohol. In all cases a single
diastereomer was observed, and the similarity of the NMR
spectra suggested all products belong to the same config-
urational series (6a-β) as 6a.
Having so far observed a seemingly general transforma-
tion pattern (Figure 2), we were surprised to find that the
reaction outcome was completely different when formic acid
Following the procedures disclosed before,6,8 the cyclo-
steroid 4 was synthesized in four steps (25% overall yield)
starting from commerciallyavailable pregnenolone acetate
(3). In a first set of experiments we then investigated the
reaction of 4 with methanol as a nucleophile. Using
was used instead of an alcohol in the BF3 Et2O-mediated
reaction of 4.
3
In this case, the 6β-formyloxymethyl-substituted 19-nor-
steroid 7a was isolated in 85% isolated yield (Scheme 4).
Again, the NMR-based structural assignments were con-
firmed by X-ray crystallography (Figure 3).
CH2Cl2 as a solvent and an excess of BF3 Et2O as a Lewis
3
acid, we were pleased to find that the envisioned reaction
indeed proceeded smoothly at 0 °C to give the methoxy-
substituted product 6a in 93% yield with virtually com-
plete stereoselectivity (Scheme 3).
Besides formic acid, acetic acid, methanesulfonic acid,
and tert-BuOH also gave rise to the corresponding 6-sub-
stituted 19-nor-steroids of type 7 in the BF3 Et2O-mediated
3
reaction of 4 under the standard conditions (Figure 4).
Treatment of 4 with BF3 Et2O in the presence of some
3
other nucleophilic reagents (allyl-TMS, KSCN, and TMS-N3)
afforded the rearranged alcohol 7e (in up to 76% isolated
yield) as the sole major product after quenching the reaction
mixture with water. Attempts to react 4 with amines, phtha-
limide, diethyl malonate, or ferrocene only led to the formation
of unseparable mixtures.
Scheme 3. Conversion of 4 into the B-homo Steroid 6a
(8) (a) Heusler, K.; Kalvoda, J. Angew. Chem., Int. Ed. Engl. 1964, 3,
525–596. (b) Kalvoda, J.; Heusler, K. Synthesis 1971, 501–526.
Org. Lett., Vol. 14, No. 14, 2012
3693

Figure 3. Structure of the 6β-formyloxymethyl-substituted
19-nor steroid 7a in the crystalline state.
Figure 2. Preparation of B-homo steroids of type 6 by reaction of
4 with primary or secondary alcohols in the presence of BF3 or
by heating 4 in neat Ac2O or (TFAc)2O. Conditions: BF3 Et2O
3
(2 equiv), ROH or (RCO)2O (3 equiv), CH2Cl2, 0 °C, 2ꢀ3 h.
Isolated yields given in parentheses. For 6e, reaction performed
at ꢀ78 °C (2 h) and ꢀ30 °C (30 min).
Figure 4. Preparation of 6β-oxymethyl-substituted 19-nor ste-
roids of type 7 by reaction of 4 with HCO2H, AcOH, MeSO3H,
or tertBuOH in the presence of BF3. Conditions: BF3 Et2O
3
(2 equiv), ROH (3 equiv), CH2Cl2, 0 °C, 2ꢀ3 h. Isolated yields
given in parentheses. 7e was obtained (after aqueous workup)
upon replacement of ROH by allyl-TMS (76%), KSCN (42%),
or TMS-N3 (35%).
Scheme 4. Formation of the 6-Substituted 19-nor Steroid 7a by
BF3-Mediated Reaction of 4 with Formic Acid
Scheme 5. Formation of the Arylated B-homo Steroid 6i by
BF3-Mediated Reaction of 4 with Anisole
Besides a variety of O-nucleophiles, which reliably af-
forded rearranged steroids of type 6 or 7, respectively, in a
highly regio- and stereoselective manner under the Lewis
acid mediated conditions (Figures 2 and 4), we identified
anisole as a suitable C-nucleophile giving rise to the
arylated B-homo steroid 6i in good yield as a 1:5 mixture
of ortho/para-isomers (Scheme 5). Of note, the use of
phenol resulted in the formation of a mixture of C- and
of O-substituted products (of type 6).
We assume the transformation of 4 to products of type
6 or 7 being initiated by the (BF3-induced) formation
of a cationic intermediate (5a) which is in equilibrium with
The mechanistic rationalization of the observed selectiv-
ities remains, at least in part, speculative (Scheme 6).
3694
Org. Lett., Vol. 14, No. 14, 2012

to pathway B) deserves notice. The latter pathway seems
to be preferred in the case of sterically more hindered
nucleophiles (e.g., tert-butanol). However, we have no
explanation for why the nucleophilic attack of the carbox-
ylate (and mesylate) anions (or their BF3 complexes)
follows either pathway A or pathway B, in subtle
dependence on the reaction conditions.10 Of note, the
rearrangement of the initial cation 5a only takes place
at ꢀ20 °C or above. At lower temperatures (ꢀ40 °C),
Scheme 6. Proposed Mechanistic Pathway
treatment of 4 with MeOH in the presence of BF3 Et2O
3
(compare Scheme 3) afforded the corresponding methyl
ether resulting from MeOH attack at the β-face of 5a.
Treatment of 6g with BF3 Et2O in CH2Cl2 in the
3
presence of MeOH did not result in any conversion.
This at least indicates that the (thermodynamically less
stable)11 product 6g is not reconverted into a cationic
species under the reaction conditions.
In conclusion, we have developed efficient protocols for
the synthesis of new ring-B-modified steroids starting from
4 as a readily available precursor. Due to the operational
simplicity the method might find future exploitation in the
preparation of compound libraries in the context of phar-
maceutical research.
Acknowledgment. This work was supported by the
€
Universitat zu Koln and the Fond der Chemischen Indus-
trie. We thank Dr. Niels Schlorer, University of Cologne,
€
€
for his help concerning NOESY NMR spectra.
the rearranged cation 5b probably through a bicyclo-
butonium-type9 intermediate 50. While the formation of
B-homo steroids of type 6 throughattackof the nucleophile
according to pathway A (Scheme 6) was in accordance
with our expectations, the change of the reaction pathway
in certain cases (to give compounds of type 7 according
Supporting Information Available. Detailed experimen-
1
tal procedures, characterization data, and copies of H
and 13C NMR spectra of all new compounds. X-ray crystal-
lographic data for 6a and 7a. This material is available free
of charge via the Internet at http://pubs.acs.org.
(9) See, for instance: Olah, G. K.; Prakash, S.; Rasul, G. J. Am.
Chem. Soc. 2008, 130, 9168–9172 and references cited therein.
(10) In some experiments, especially in the presence of traces of
water, the reaction of 4 with acetic acid (Figure 4) afforded 6g instead
of 7b (for unknown reasons). However, the reaction of 4 with formic acid
to give 7a proved to be fully reproducible.
(11) According to MM3 calculations (Maestro), 6 is by 43 kJ molꢀ1
less stable than its isomer 7 (for nuc = OMe).
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 14, 2012
3695