Convenient method for the functionalization of the 4- and 6-positions of the androgen skeleton

Article abstract of DOI:10.1039/c2cc31973j

The preparation and reactivity of steroidal vinyldiazo compounds is reported, providing a convenient, substituent tolerant, chemo- and stereoselective entry into 4- and 6-substituted androgen analogues from a common precursor. Under dirhodium catalysis, O-H insertion occurs at the carbenoid site, leading to 4-substituted steroids, but under silver catalysis, O-H insertion occurs at the vinylogous position, leading to 6-substituted steroids.

Full text of DOI:10.1039/c2cc31973j

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COMMUNICATION
Convenient method for the functionalization of the 4- and 6-positions of
the androgen skeletonw
Daniel Morton,a Allison R. Dick,b Debashis Ghoshc and Huw M. L. Davies*a
Received 18th March 2012, Accepted 20th April 2012
DOI: 10.1039/c2cc31973j
The preparation and reactivity of steroidal vinyldiazo compounds
is reported, providing a convenient, substituent tolerant, chemo-
and stereoselective entry into 4- and 6-substituted androgen
analogues from a common precursor. Under dirhodium catalysis,
O–H insertion occurs at the carbenoid site, leading to 4-substituted
steroids, but under silver catalysis, O–H insertion occurs at the
vinylogous position, leading to 6-substituted steroids.
The steroid skeleton is one of Nature’s privileged motifs.1
The ubiquity of this structure throughout a variety of human
biochemical pathways has made it a target of considerable
interest to a range of drug discovery programs.2 These efforts
have revolved around either total syntheses of specific analogues3
or hemisynthesis as a means of accessing the tetracyclic core.4
Scheme 1 Synthesis of vinyldiazo steroids 2 and 4.
Aromatase cytochrome P450 is the enzyme responsible
for the oxidation of androgens to estrogens. It is the only
the complementary dirhodium(II)- or silver(I)-catalyzed donor/
mammalian enzyme capable of converting an aliphatic six-
acceptor carbene O–H insertion chemistry that has recently
membered ring to an aromatic ring. As such it is essential to
been developed.9
the modulation of steroidal biogenesis. However, it has been
Our investigations began by developing an efficient method
found to be over-expressed in 475% of postmenopause breast
cancer cells.5 Consequently, it has been a significant clinical
for the installation of the diazo functionality at the 4-position
target.6 Until recently, the mechanism of aromatization was
(Scheme 1). The synthesis of the diazo compounds 2 and 4 was
achieved through a three-step process. The synthesis began
not completely understood, and many current medications
from the commercially available 1,4-androstadienedione 1 and
have been designed without the benefit of access to a detailed
structural analysis of the active site of the enzyme.7
1,4-androstenedione 3. Radical bromination10 followed by zinc
promoted de-bromination and concommitent de-conjugation11
afforded the diazo precursors. Use of a water-soluble diazo-
transfer reagent12 was essential in the preparation of the
steroidal diazo compounds 2 and 4 as removal of the water-
soluble by-products greatly facilitated their isolation.
The first X-ray crystal structure of aromatase P450 was
solved by Ghosh et al. in 2009.8 As part of a collaborative
program with the Ghosh group we have sought to construct a
series of androgen analogues to futher probe the active site
and ultimately develop, through informed design, highly
selective aromatase P450 inhibitors. In order to achieve this
goal, we required ready access to 4- and 6-functionalized
alkoxy analogues. This paper describes a carbene approach
that allows selective 4- or 6-functionalization by exploiting
We then examined the optimization of the O–H insertion of
the rhodium carbenes derived from these diazo compounds
(Table 1). Formation of the rhodium carbene from 2 and
subsequent insertion into the O–H bond of ethanol afforded
the 4-ethoxy substituted steroid 5a, the product of direct O–H
insertion. The product was found to exist as a mixture of
tautomers, predominantly favoring the enol form, likely due to
internal H-bonding stabilization. Low yields were obtained
when the alcohol was used as the solvent (entry 1). When
hexane was used low conversion was observed (entry 2),
presumeably due to solubility issues. However, effective O–H
insertion was observed when the reaction was conducted
in trifluorotoluene (TFT) with ten equivalents of alcohol
(entry 3 vs. 4). The reaction was found to be catalyzed by a
a Department of Chemistry, Emory University, 1515 Dickey Drive,
Atlanta, GA 30322, USA. E-mail: hmdavie@emory.edu;
Tel: 001 404 727 6839
b Department of Chemistry, University at Buffalo,
The State University of New York, Buffalo, NY 14260-3000, USA
c Pharmacology and Upstate Cancer Research Institute,
SUNY Upstate Medical University, Room 6310, Weiskotten Hall,
750 East Adams Street, Syracuse, NY 13210, USA
w Electronic supplementary information (ESI) available: Experimental
details and spectral data. CCDC 829542. For ESI and crystallographic
data in CIF or other electronic format see DOI: 10.1039/c2cc31973j
c
5838 Chem. Commun., 2012, 48, 5838–5840
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Table 1 Optimization of the catalyst and solvent
Table 3 Rhodium-catalyzed O–H insertion of 4
Product Time (h) C-4 : C-6a Yield (%)b
Entry
Rh2L4
Solventb
Equiv. EtOH
Yield (%)
a
Entry
R
1
2
3
–CH2CH3 6a
8
10
10
90 : 10
93 : 7
495 : 5
53
44
45
1
2
3
4
5
6
7
Rh2(S-DOSP)4
Rh2(S-DOSP)4
Rh2(S-DOSP)4
Rh2(S-DOSP)4
Rh2(Ooct)4
Neat
Hexanes
TFT
TFT
TFT
10
10
5
10
10
10
10
12
8
–CH3
–CH2Ph
6b
6c
51
61
48
38
50
a
Ratio determined by 1H NMR spectroscopy of the crude reaction
mixture. All reactions were run at a concentration of 0.15 M with
Rh2(S-PTAD)4
Rh2(OAc)4
TFT
TFT
b
respect to 2. Isolated yield of the C-4 regioisomer.
a
In all reactions 1 mol% of catalyst was employed. The reaction was
b
allowed to react for 4 h after addition of the solution of 2. All
The nature of the metal catalyst employed to form the
stabilized donor/acceptor carbene has been established to have
a profound effect on the reaction outcome.9 Previous studies
on the donor/acceptor vinyldiazoacetate functionality have
demonstrated that while rhodium carbenes typically react
at the carbene carbon, the silver(I) salts promote reactions
predominantly at the vinylogous position via a carbene
intermediate.9 We chose to exploit this to provide an expedient
entry into 6-substituted androgens from the same vinylcarbenoid
precursors 2 and 4. Indeed, by employing 10 mol% of silver
triflate, reaction of the carbene derived from 2 afforded the
6-substituted analogues 7a–g, arising from vinylogous inser-
tion (Table 4). The scope of the reaction is general, affording
both the 6-substituted ethers and esters in moderate to good
yield (39–71%). The insertion proceeds with excellent diastereo-
selectvity, favoring the 6-b-isomer, and regioselectivity, with
the 4-substituted analogues generally present in only trace
amounts.
reactions were run at a concentration of 0.15 M with respect to 2.
Table 2 Rhodium-catalyzed O–H insertion
Entry
R
Product Time (h) C-4 : C-6a Yield (%)b
1
2
3
4
5
6
–CH2CH3
–CH3
–CH2Ph
–(CO)CH3
–(CO)CH2CH3 5e
–(CO)CH2Ph 5f
5a
5b
5c
5d
6
6
12
8
6
16
495 : 5
76 : 24
495 : 5
92 : 8
88 : 12
495 : 5
61
49
52
68
55
41
The silver triflate promoted vinylogous reaction was also
efficient in the saturated system. The O–H insertion of the
silver carbene derived from 4 led to essentially exclusive
formation of the corresponding 6-substituted ethers 8a–d with
a
Ratio determined by 1H NMR spectroscopy of the crude reaction
mixture. All reactions were run at a concentration of 0.15 M with
b
respect to 2. Isolated yield of the C-4 regioisomer.
range of dirhodium(II) catalysts, though Rh2(S-DOSP)4
proved to be the most efficient (entry 4).
Table 4 Silver-catalyzed O–H insertion of 2
With conditions established for the efficient O–H insertion,
our focus turned to the scope of this transformation. The
reaction with a range of alcohols and acids is described in
Table 2. The O–H insertion of the rhodium carbene derived
from diazoketone 2 proved to be general, with a range of
aliphatic and aromatic 4-substituted ethers and esters 5a–f
afforded in moderate to good yield (41–68%). Sterically and
electronically diverse alcohols are suitable for this reaction
system. The O–H insertion reaction proceeds with excellent
regioselectivity. The 6-substituted androgens, which arise from
vinylogous reaction of the rhodium carbene, were generally
observed in only trace amounts.
Yield
(%)b
Entry R
Product Time (h) C-4 : C-6a a : ba
1
2
3
4
5
6
7
–CH2CH3
–CH3
–CH2Ph
–C(CH3)
–(CO)CH3
7a
7b
7c
7d
7e
4
4
6
3
4
10 : 90
8 : 92
5 : 4 95 22 : 78
5 : 4 95 8 : 92
15 : 85
12 : 88
41
46
39
70
5 : 4 95 5 : 4 95 66
5 : 4 95 11 : 89 71
5 : 4 95 5 : 4 95 38
The rhodium carbene arising from the decomposition of 4
was also found to be capable of O–H bond insertion reactions
(Table 3). The 4-substituted ethers 6a–c were prepared in
moderate yield (entries 1–3; 44–53%). The regioselectivity
of the reaction was high, with only trace amounts of the
6-substituted analogues detected.
–(CO)CH2CH3 7f
–(CO)CH2Ph 7g
10
6
Ratio determined by 1H NMR spectroscopy of the crude reaction
mixture. All reactions were run at a concentration of 0.15 M with
a
b
respect to 2. Isolated yield of the 7-b diastereomer.
c
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Table 5 Silver-catalyzed O–H insertion of 4
Entry R
Product Time (h) C-4 : C-6a a : ba
Yield (%)b
Fig. 2 Stereoelectronic rationalization of the formation of the 6-b
substituted ethers and esters.
1
2
3
4
5
–CH2CH3 8a
–CH3
–CH2Ph
–C(CH3) 8d
–(CO)CH3 8e
6
8
12
10
16
5 : 4 95 12 : 88
8 : 92 10 : 90
5 : 4 95 5 : 4 95 61
5 : 4 95 5 : 4 95 46
42
39
8b
8c
was controlled effectively through choice of metal catalyst
employed. Rhodium-catalyzed reactions result in selective
reactions at the carbenoid site, whereas silver catalyzed reac-
tions preferentially functionalize the vinylogous position of
the carbenoid. Substrate-controlled diastereoselectivity was
observed in the vinylogous reaction mediated by silver triflate,
allowing the preparation of 6-b-substituted analogues. These
compounds are currently being used to probe the active site
of the aromatase P450 enzyme, the results of which will be
disclosed in due course.
—
—
o5
a
Ratio determined by 1H NMR spectroscopy of the crude reaction
mixture. All reactions were run at a concentration of 0.15 M with
b
respect to 2. Isolated yield of the 8-b diastereomer.
only trace amounts of the 6-substituted analogues detected
(Table 5). The ethers were prepared in moderate yield (39–61%),
with high levels of both regio- and diastereoselectivity.
The 6-b-androgens again were found to be highly favored.
Attempts at preparing the acetate derivative 8e were unsuc-
cessful as the compound appeared to be unstable and prone to
elimination.
This research was supported by the National Institutes of
Health (R01GM086893). We thank Dr Kenneth I. Hardcastle
for the X-ray crystallographic structure determination.
The remarkable diastereoselectivity of the O–H insertion
reaction of the silver carbenes derived from 2 and 4, deserves
further comment. In all instances the 6-b-androgen product
was strongly favored. The stereochemical assignment was
initially made on the basis of the distinctive coupling constants
for the C-6 proton, which indicated that the alkoxy group was
in the 6-b-position. This assignment was then confirmed by the
single crystal X-ray analysis of 7d (Fig. 1).13
Notes and references
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An inspection of the parent diazo structures might suggest
that substrate-controlled stereoselection would be dictated by
the C-19 b-methyl groups; this would direct the reaction to the
a-face. We can account for the observed stereoselectivity if we
consider the transition state (9) (Fig. 2). While pathway b
reduces the steric clash with the C-19 methyl group, pathway a
is favored on stereoelectronic grounds, representing axial
attack to form the conformationally preferred chair product.
In summary, we have developed a convenient procedure
to regioselectively functionalize the steroid skeleton at the
4- and 6-positions, with a broad range of analogues accessible
via common intermediates. The regioselectivity of the reaction
10 S. Kaufmann, J. Pataki, G. Rosenkranz, J. Romo and C. Djerassi,
J. Am. Chem. Soc., 1950, 72, 4531.
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12 R. L. Moreau and E. J. Sorensen, Tetrahedron, 2007, 63, 6446.
13 The crystal structure of 8d has been deposited at the Cambridge
Crystallographic Data Centre under deposition number CCDC
829542A.
Fig. 1 Single crystal X-ray analysis of 6-b androgen 7d.
c
5840 Chem. Commun., 2012, 48, 5838–5840
This journal is The Royal Society of Chemistry 2012