New, scalable route for the synthesis of a trans-fused hexahydro-1H-phenanthren-2-one from a conjugated tetrahydro-3H-phenanthren-2-one

Article abstract of DOI:10.1081/SCC-120016349

A three-step, readily scalable route for the conversion of a ring-conjugated tetrahydro-3H-phenanthren-2-one to a trans-fused hexahydro-1H-phenanthren-2-one is described. The key step is the hydrogenation of a double bond using a nearby ketal moiety to as

Full text of DOI:10.1081/SCC-120016349

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New, Scalable Route for the Synthesis of a trans-Fused
Hexahydro-1H-phenanthren-2-one from a Conjugated
Tetrahydro-3H-phenanthren-2-one
Bradley P. Morgan a , Richard V. Trilles a & Graeme F. Woodworth a
a Pfizer Global Research and Development , Pfizer Inc. , Groton, Connecticut, USA
Published online: 17 Aug 2006.
To cite this article: Bradley P. Morgan , Richard V. Trilles & Graeme F. Woodworth (2003) New, Scalable Route for the
Synthesis of a trans-Fused Hexahydro-1H-phenanthren-2-one from a Conjugated Tetrahydro-3H-phenanthren-2-one, Synthetic
Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry, 33:6, 915-920, DOI:
10.1081/SCC-120016349
To link to this article: http://dx.doi.org/10.1081/SCC-120016349
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SYNTHETIC COMMUNICATIONSÕ
Vol. 33, No. 6, pp. 915–920, 2003
New, Scalable Route for the Synthesis of
a trans-Fused Hexahydro-1H-
phenanthren-2-one from a Conjugated
Tetrahydro-3H-phenanthren-2-one
*
Bradley P. Morgan, Richard V. Trilles, and
Graeme F. Woodworth
PfizerGlobal Research and Development,
PfizerInc., Groton, Connecticut, USA
ABSTRACT
A three-step, readily scalable route for the conversion of a
ring-conjugated tetrahydro-3H-phenanthren-2-one to a trans-fused
hexahydro-1H-phenanthren-2-one is described. The key step is the
hydrogenation of a double bond using a nearby ketal moiety to assist
in the stereoselective delivery of the hydrogen.
*Correspondence: Bradley P. Morgan, Pfizer Global Research and Development,
Pfizer Inc., Groton, Connecticut 06371, USA; E-mail: bradley_p_morgan@
groton.pfizer.com.
915
DOI: 10.1081/SCC-120016349
Copyright & 2003 by Marcel Dekker, Inc.
0039-7911 (Print); 1532-2432 (Online)
www.dekker.com

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916
Morgan, Trilles, and Woodworth
INTRODUCTION
In conjunction with our recently reported development of non-
steroidal, selective glucocorticoid receptor modulators,[1] we needed an
efficient process for the conjugate reduction of the double bond of the
enone system in 1 to the trans-fused A-B ring system in 2. On a modest
scale, this was accomplished by a classical dissolving metal reduction with
lithium in ammonia.[2] However, difficulties encountered on the scale-
up of this reaction included the need for high dilution conditions to
obtain adequate yields of the product and the need for column
chromatography to provide pure 2 for further elaboration. Experimenta-
tion with several, alternate conditions for the direct stereoselective
reduction of the steroid-mimetic 1 to 2 including the use of sodium and
calcium in dissolving metal reductions, direct hydrogenation,[3] or
phase-transfer hydrogenation[4] did not prove fruitful for the large-scale
synthesis of this system. We, therefore, investigated an alternate route for
this transformation (Sch. 1).
RESULTS AND DISCUSSION
Formation of the C-2 ketal of 1 with concomitant migration of the
double bond from the A to the B-ring afforded 3. Purification was
Scheme 1.

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Hexahydro-1H-phenanthren-2-one
917
accomplished simply by stirring an ethyl acetate solution of 3 with
activated carbon (DarcoÕ).
In steroids that contain C5-C6 unsaturation in their B-ring, similar to
3, it is known that catalytic hydrogenation of this C5-C6 B-ring double
bond results in good trans-selectivity of an angular substituted A-B ring
system.[5] However, when a C5-C6 B-ring double bond is combined with
a ketal in the same proximity in the A-ring as in 3, these moieties can be
used as a protecting group for the enone system, while catalytic
hydrogenation occurs elsewhere on the molecule.[6] Therefore, the
reduction of 3 to 4 required relatively vigorous conditions. Using
activated palladium hydroxide on carbon under a 50-psi hydrogen
atmosphere at 50ꢀC, 3 was converted cleanly to 4 with interesting solvent
effects on the trans:cis stereoselectivity (Sch. 1).[7] Presumably, the
pseudo-axial oxygen of the ketal moiety coordinates the palladium to
assist in the beta face addition of hydrogen to 3. This ketal oxygen–
palladium coordination becomes more important for the selectivity of
the reduction as the ability of the solvent to coordinate to palladium is
decreased. When toluene was used as a ‘‘non-coordinating’’ solvent under
the aforementioned reduction conditions, 4 was isolated as a 19:1 mixture
of trans:cis ring junction isomers. This highly enriched mixture could be
taken to the ketal hydrolysis step of the synthetic sequence without
further purification.
Hydrolysis of the ketal was accomplished on acidic silica gel in
dichloromethane.[8] After a single recrystallization, 2 was isolated as a
single diastereomer,[9] in 40–50% overall yields.
CONCLUSION
In summary, a stereoselective, readily scalable route for the
conversion of 1 to 2 has been developed. This route relies on a nearby
ketal moiety to coordinate the palladium catalyst and deliver the
hydrogen to the desired face of the molecule. This process may
have wider application for the stereoselective reduction of other
steroid-like systems that prove difficult by other methods.

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918
Morgan, Trilles, and Woodworth
EXPERIMENTAL
General
All reagents and anhydrous solvents were obtained from commercial
sources. Activated carbon, DarcoÕ G-60, 100 mesh was obtained from
Aldrich. Palladium hydroxide on carbon was activated by first
suspending the catalyst in acetone and decanting off the solvent to a
minimum volume. This process was repeated. The palladium hydroxide
on carbon was then suspended in toluene and the toluene was then dec-
anted leaving a minimum of solvent. Again, this process was repeated.
The palladium hydroxide on carbon catalyst-toluene slurry was used
1
directly in the subsequent reduction. H NMR spectra were measured
on Varian XL-400 spectrometers using residual NMR solvent as
reference. Mass spectra determinations were performed by the
Exploratory Medicinal Sciences Department of Pfizer Global Research
and Development at Groton, CT. Thin layer chromatography was
performed with EM separation technology silica gel F254. Silica gel chro-
matography was carried out with E. Merck silica gel (230–400 mesh).
Large-scale hydrogenations were carried out in a 2 gallon stainless steel
Parr reactor equipped with motorized stirrer, gas inlet valves, block
heaterand 200 psi pressure gauge.
4a(S )-Benzyl-7-hydroxy-3,4,4a,9-tetrahydro-1H-phenanthren-2-one,
ethylene ketal (3): To a stirring solution of 48.2 g (0.158 mol) of 4a(S )-
benzy1-7-hydroxy-4,4a,9,10-tetrahydro-3H-phenanthren-2-one (1) in
CH2C12 at room temperature under N2 atmosphere was added 3 g
(0.15 mol) of p-toluenesulfonic acid. The resultant solution was cooled
to 0ꢀC and 3.5 mL (0.063 mol) ethylene glycol was added. To this solu-
tion, 22.6 mL (0.237 mol) 2-methoxy-l,3-dioxolane was added dropwise.
The resultant solution was stirred at 0ꢀC for2 h. An additional 5 mL of
2-methoxy-1,3-dioxolane was added and the solution was stirred at 0ꢀC
foran additional 1.5 h. One L of sat. NaHCO solution was added, the
3
resultant mixture was stirred for 15 min, then the mixture was poured
into a 4 L separatory funnel containing CH2Cl2 (500 mL) and H2O
(500 mL). The ogranic layerwas sepaarted and the aqueous layerwas
extracted with CH2Cl2 (4X). The combined organic layers were dried
overNa 2SO4, filtered, and concentrated to give a dark gum. This residue
was dissolved in 250 mL of hot toluene. To this solution was added 7 g of
activated carbon and 19 g of solid KHCO3. The resultant mixture was
stirred at room temperature overnight, then filtered over a pad of diato-
maceous earth and concentrated to give 51 g of 3 as an orange-red solid.
1H NMR (400 MHz, CD2Cl2) ꢀ 1.82–1.89 (m, 2H), 2.06–2.17 (m, 2H),

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Hexahydro-1H-phenanthren-2-one
919
2.32–2.38 (m, 2H), 2.7 (d, 1H, J ¼ 13), 2.79–2.85 (m, 2H), 3.20 (d, 1H,
J ¼ 13), 3.3 (d, 1H, J ¼ 13), 3.9 (m, 4H), 4.77 (s, 1H), 4.9 (dd, 1H,
J ¼ 4.77), 6.2 (s, 1H), 6.54 (d, 2H, J ¼ 7.27), 6.71 (m, 1H), 7.0 (m, 2H),
7.03 (m, 1H), 7.25 (d, 1H, J ¼ 8.51); MS m/z 349 (M þ H).
4a(S)-Benzyl-7-hydroxy-3,4,4a,9,10,10a(R)-hexahydro-1H-phenanth-
ren-2-one,ethylene ketal(4): A Parr apparatus was charged with 89 g of 3
in 50 mL toluene, 27 g of activated Pd(OH)2/C (see general experimental),
18 g of solid KHCO3 and 2.5 L of toluene. The reaction mixture was
sealed, heated to 50ꢀC, pressurized to 50 psi H2 and stirred for 2 days.
The reaction mixture was cooled and filtered over diatomaceous earth
with toluene. The motherliquorwas subjected to the afoermentioned
conditions of Pd catalyst and KHCO3, heat, hydrogen pressure, and
time for two additional cycles to ensure complete reduction. After the
final cycle, the resultant solution was concentrated to give 60 g of 4 as a
1
light yellow gum. H NMR (400 MHz, CD3OD) ꢀ 1.35 (m, lH), 1.6–2.1
(m, 8H), 2.59 (d, 1H, J ¼ 12.8), 2.9 (m, 3H), 3.94 (m, 4H), 6.09 (d, 1H,
J ¼ 8.51), 6.19 (m, 2H), 6.54 (m, 3H), 7.03 (m, 3H); MS m/z 351 (M þ H).
4a(S)-Benzyl-7-hydroxy-3,4,4a,9,10,10a(R)-hexahydro-1H-phenanth-
ren-2-one (2): Into a round bottom flask equipped with an overhead
stirrer under N2 atmosphere containing 2.8 L CH2Cl2 was added
1.06 kg SiO2 (70–230 mesh; E. Merck) with stirring. To the stirring
slurry was added 106 g of 15% aq. oxalic acid followed by 88.5 g 4 in
150 mL CH2Cl2. The mixture was stirred for 2 days at room temperature.
The stirring mixture was cooled to 0ꢀC, 21 g solid NaHCO3 was added,
and the resultant mixture was allowed to warm to room temperature over
approximately 1 h. The reaction mixture was filtered through a 2 L sin-
tered glass funnel containing 500 g of sand, rinsed with 14 L of CH2Cl2,
and the CH2Cl2 solution was concentrated to dryness. The residue was
dissolved into boiling EtOAc (1.5 L) and to the boiling, stirring EtOAc
solution was added 700 mL hexanes. The reaction was allowed to cool to
room temperature with stirring, overnight. The resultant solid was fil-
tered, rinsed with hexanes, and air-dried to give 33.69 of 2 as a white
solid (43% overall). 1H NMR (400 MHz, CD3OD) ꢀ 1.52 (dt, 1H, J ¼ 4.5,
13), 1.64–1.71 (m, 1H), 1.90–2.15 (m, 2H), 2.27 (ddd, IH, J ¼ 2.5, 3.7, 15),
2.39 (dm, 1H, J ¼ 15), 2.48 (ddd, 1H, J ¼ 2.0, 6.5, 13), 2.72 (t, 1H, J ¼ 14),
2.84 (d, lH, J ¼ 13), 2.89–3.01 (m, 3H), 3.22 (d, lH, J ¼ 13), 6.17 (d, lH,
J ¼ 8.5), 6.24 (dd, lH, J ¼ 2.5, 8.5), 6.53 (d, 1H, J ¼ 2.5), 6.65–6.68 (m,
1H), 7.04–7.13, (m, 3H); 13C NMR (100 MHz, CD3OD) ꢀ 27.9, 33.7, 34.8,
36.0, 37.6, 39.4, 43.6, 44.0, 111.3, 114.6, 125.7, 127.0, 127.9, 130.5,133.4,
20
136.8, 138.0, 155.1, 212.7: MS m/z 307 (M þ H)þ. ½ꢁꢁD ¼ ꢂ120ꢀ (c ¼
0.0104 g/mL, MeOH). Anal. Calcd. forC 21H22O2: C, 82.32; H, 7.24;
N, 0. Found: C, 82.27; H, 7.61; N, <0.10.

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920
Morgan, Trilles, and Woodworth
ACKNOWLEDGMENT
The authors would like to thank Mr. Mark Shaffer and Mr. Alex
Grodski for their technical assistance.
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1
tion from the H NMR of 4.
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1
9. Diastereomeric purity >98% by H NMR. Relative configuration
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material.
Received in the USA April 3, 2002