An improved synthesis of a hydroxymethyl tricyclic ketone from cyclohexanone, the key processes for the synthesis of a highly potent anti-inflammatory and cytoprotective agent

Article abstract of DOI:10.1055/s-0033-1339900

An improved synthesis of hydroxymethyl tricyclic ketone, (±)-(4aS,8aS)-8a-(hydroxymethyl)-1,1,4a-trimethyl-3,4,4a,6,7,8,8a,9,10, 10a-decahydrophenanthren-2(1H)-one, in five steps (34% yield) from cyclohexanone has been successfully established. Accordingly, 10 grams of a highly potent anti-inflammatory and cytoprotective agent, (±)-(4bS,8aR,10aS)-10a- ethynyl-4b,8,8-trimethyl-3,7-dioxo-3,4b,7,8,8a,9,10,10a-octahydrophenanthrene-2, 6-dicarbonitrile (TBE-31), was obtained in 15 steps (9.2% overall yield) via the hydroxymethyl tricyclic ketone from 32 grams of cyclohexanone. Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0033-1339900

PAPER
▌3251
pAapner Improved Synthesis of a Hydroxymethyl Tricyclic Ketone from
Cyclohexanone, the Key Processes for the Synthesis of a Highly Potent
Anti-inflammatory and Cytoprotective Agent
a
Synthesis of a Hydroxymethyl Tricyclic Ketone from Cyclohexanone
a
a
a
a,b
a
Institute of Chemical Biology and Drug Discovery, Stony Brook University, Stony Brook, New York 11794, USA
b
Department of Chemistry, Stony Brook University, Stony Brook, New York 11794, USA
Fax +1(631)6327942; E-mail: tadashi.honda@stonybrook.edu
Received: 16.06.2013; Accepted after revision: 11.09.2013
O
Abstract: An improved synthesis of hydroxymethyl tricyclic ketone, (±)-
(
4aS,8aS)-8a-(hydroxymethyl)-1,1,4a-trimethyl-3,4,4a,6,7,8,8a,9,10,10a-
a, b
c
decahydrophenanthren-2(1H)-one, in five steps (34% yield) from
cyclohexanone has been successfully established. Accordingly, 10
grams of a highly potent anti-inflammatory and cytoprotective
agent, (±)-(4bS,8aR,10aS)-10a-ethynyl-4b,8,8-trimethyl-3,7-dioxo-
CO H
2
O
2
(70%)
d
3
,4b,7,8,8a,9,10,10a-octahydrophenanthrene-2,6-dicarbonitrile
(TBE-31), was obtained in 15 steps (9.2% overall yield) via the hy-
droxymethyl tricyclic ketone from 32 grams of cyclohexanone.
CO2Me
R
Key words: anti-inflammatory agents, antitumor agents, oxidation,
reduction, reductive methylation, regioselectivity
O
O
H
3
(64%)
4a R = CO2H (38%)
4b R = CO2Me (15%)
4c R = CH2OH (36%)
Tricyclic compound 1 (code number in house, TBE-31,
Scheme 1) is the most potent activator of the
Keap1/Nrf2/ARE (antioxidant response element) path-
way so far. The oral administration of 1 indicated excel-
lent oral bioavailability, and resulted in a dose-dependent
induction of cytoprotective enzymes, NAD(P)H:quinone
O
1
10 steps
1 steps
12 steps
CN
4
c
1
NC
O
4b
oxidoreductase 1 (NQO1), and glutathione S-transferase
4
a
2
(
GST) in the stomach, skin, and liver. Furthermore, long-
H
(TBE-31)
term (five days per week for four weeks) daily topical ap-
plications in small quantities (200 nmol) of 1 caused a ro-
1
bust systemic induction of the Keap1/Nrf2/ARE pathway Scheme 1 Previous synthesis of 4c. Reagents and conditions: (a)
Me CO , NaH, KH, THF; (b) 1-chloropentan-3-one, Na, MeOH; (c)
and decreased 6-thioguanine incorporation into DNA of
skin, blood, and liver of azathioprine-treated mice, indi-
cating extraordinary bioavailability and efficacy. Tricy-
2
3
Cs CO , Me SO , DMF; (d) Li, NH , H O, MeI, THF.
2
3
2
4
3
2
3
clic compound 1 is orally highly active against aflatoxin- the consequent conversion of 4a and 4b into TBE-31 re-
4
1,5
induced liver cancer in rats. Thus, we envision the pre- quires additional steps than that of 4c (Scheme 1). Al-
clinical and future clinical studies on 1 as a first in class though these three intermediates 4a–c were very useful
6
therapeutic agent for the treatment of inflammation and for the synthesis of various other tricyclic compounds,
1
cancer.
the previously reported synthesis of 1 could not give a
sufficient amount of 1 for preclinical studies. For the effi-
cient synthesis of 1, only intermediate 4c is necessary.
Thus we envisioned that, if the new compound 8a can be
obtained in a few steps from the previously reported acid
For this objective, initially we had to improve the synthe-
sis of hydroxymethyl tricyclic ketone 4c, (±)-(4aS,8aS)-8a-
(hydroxymethyl)-1,1,4a-trimethyl-3,4,4a,6,7,8,8a,9,10,10a-
decahydrophenanthren-2(1H)-one, from cyclohexanone
in order to obtain 10–100 grams of 1. Herein, we report
the improved synthesis of 4c from cyclohexanone.
6
,7
2
, which is prepared in two steps from cyclohexanone,
reductive methylation of 8a would only produce 4c
Scheme 2).
(
We have previously reported the synthesis of 4c from cy-
clohexanone, but under these processes the reductive
methylation step of 3 gives three compounds 4a–c, whose
separation requires column chromatography. Moreover,
Initially we attempted to directly prepare 8a from 2 by se-
lective reduction of the carboxyl group with diborane
(strategy A). This method did not give 8a, instead it gave
some undesired compounds without UV absorption at 254
nm on TLC. Secondly, we tried to obtain 8a through se-
lective reduction of acyl chloride 5 with reducing agents
SYNTHESIS 2013, 45, 3251–3254
Advanced online publication: 23.09.2013
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
(
strategy B in Scheme 2). Acyl chloride 5 was prepared in
DOI: 10.1055/s-0033-1339900; Art ID: SS-2013-M0419-OP
Georg Thieme Verlag Stuttgart · New York
©

3252
A. Saito et al.
PAPER
quantitative yield from 2 with thionyl chloride. Attempted
reduction of 5 with sodium borohydride was unsuccessful
and starting material 5 was recovered unchanged. Reduc-
tion of 5 with zinc borohydride also did not give 8a, but
instead gave inseparable compounds whose structures
could not be elucidated. Thirdly, we planned to reduce the
carboxyl group to the hydroxymethyl group after protec-
tion of the carbonyl group of 2 (strategy C in Scheme 2).
Ketalization of 2 with ethylene glycol in the presence of
pyridinium p-toluenesulfonate in toluene was very slow.
A mixture of 6a and 6b was obtained in only 49% yield
and 2 was recovered in 39% yield after reflux for 24
hours. Reduction of the mixture with lithium aluminum
hydride, followed by deprotection with pyridinium p-tol-
uenesulfonate in acetone, afforded 8a and 8b. Reductive
methylation of the mixture gave 4c in very low yield
a
2
+
HO
OH
HO
OH
7
a and 7b (77%)
b
c
O
OH
O
OH
H
8a (82%)
4c (78%)
Scheme 3 New synthesis of 4c. Reagents and conditions: (a) Red-
Al, toluene; (b) DDQ, 1,4-dioxane; (c) Li, NH , H O, MeI, THF.
3
2
From 4c, tricyclic compound 1 was synthesized in 10
steps (27% yield) similar to the previously published syn-
thetic sequence.
(22%).
1
In summary, according to the improved synthesis of 4c
from cyclohexanone, we have successfully obtained 10
grams of tricyclic compound 1, a highly potent anti-in-
flammatory and cytoprotective agent, in 15 steps from cy-
clohexanone (32 grams, 9.2% overall yield). We are
planning to have 100 grams of 1 synthesized using this
method by a custom synthesis company for further biolog-
ical evaluation including a subacute toxicological test.
COCl
O
5
B
C
2
O
CO2H
O
OH
O
6
a
8a
Melting points were determined on a Thomas Hoover capillary
D
1
13
melting point apparatus and are uncorrected. H (400 MHz) and
C
(
100 MHz) NMR spectra were measured on a Bruker Avance 400
1
NMR spectrometer referenced to δ = 7.27 in CHCl ( H NMR) and
δ = 77.23 in CDCl ( C NMR) as internal standards. LR-MS and
3
13
3
HO
OH
HRMS data were obtained on a Micromass 70-VSE (EI method)
and Micromass Q-Tof Ultima (ESI+ method). Elemental analyses
were performed by Atlantic Microlab Inc. All samples prepared for
elemental analysis were dried at 50–60 °C at reduced pressure
7
(
<0.13 mbar) in a National Appliance Company model 5831 vacu-
O
CO2H
um oven. TLC was performed using plates precoated with silica gel
60 F254. Flash column chromatography used silica gel (230–400
mesh). Anhyd THF and CH Cl were obtained from a solvent puri-
fication system. All other solvents (analytical grade) including an-
hyd solvents and reagents were used as received. All experiments
O
OH
O
2
2
6b
8b
Scheme 2 Strategies B, C, and D for the synthesis of 8a from 2
were performed under a N atmosphere.
2
Finally, we thought that selective oxidation of the allyl al- 2-(Methoxycarbonyl)cyclohexanone6
A mixture of NaH (60% oil dispersion, 10 g, 250 mmol, 3.1 equiv)
cohol in 7 would give the desired enone 8a (strategy D in
Scheme 2 and Scheme 3). Reduction of 2 with sodium
bis(2-methoxyethoxy)aluminum hydride (Red-Al) in tol-
uene afforded a mixture of new α-alcohol 7a [NMR (400
and dimethyl carbonate (18.02 g, 200 mmol, 2.5 equiv) in anhyd
THF (50 mL) was heated under reflux. To the mixture was added a
solution of cyclohexanone (7.8 g, 80 mmol) in anhyd THF (20 mL)
dropwise using a syringe pump over a period of 1 h; 2 min after the
MHz, CDCl ): δ = 3.87, s at 2β-H], and new β-alcohol 7b addition of the cyclohexanone–THF solution began, KH (30% oil
3
dispersion, 0.9 g) was added to initiate the reaction. When the addi-
[
NMR (400 MHz, CDCl ): δ = 4.01, dd, J = 7.2 and 7.2
3
tion was complete, the mixture was heated under reflux for an addi-
tional 30 min. The mixture was cooled in an ice-water bath, and then
it was hydrolyzed by slow addition of 3 M aq AcOH (75 mL) and
poured into brine (100 mL). The aqueous mixture was extracted
Hz at 2α-H] in 77% yield (ratio = 1:3). Selective oxidation
of the mixture with 2,3-dichloro-5,6-dicyano-1,4-benzo-
quinone in 1,4-dioxane produced the new desired enone
8
8
a in 82% yield. As we expected, only 4c was obtained by with CH Cl (4 × 150 mL). The combined extracts were dried
2 2
reductive methylation of 8a in 78% yield. Overall, 4c was (MgSO
), filtered, and concentrated in vacuo to give a thick yellow
liquid (17.2 g). The liquid was distilled under reduced pressure to
4
synthesized in five steps (34% yield) from cyclohexa-
none. Thus, our objective has been successfully achieved
by strategy D.
give the product (11.3 g, 91%) as a colorless liquid; bp 38–
43 °C/0.067–0.01 mbar, bath temp: 75–78 °C.
Synthesis 2013, 45, 3251–3254
© Georg Thieme Verlag Stuttgart · New York

PAPER
Synthesis of a Hydroxymethyl Tricyclic Ketone from Cyclohexanone
3253
(
±)-(4aS,8aS)-1,4a-Dimethyl-2-oxo-2,3,4,4a,6,7,8,8a,9,10-deca-
1.52 (m, 2 H), 1.39 (br s, 1 H), 1.30 (br s, 1 H), 1.22 (s, 3 H), 1.25–
1.05 (m, 2 H).
7
hydrophenanthrene-8a-carboxylic Acid (2)
To anhyd MeOH (256 mL) cooled in an ice-water bath, Na metal
13
C NMR (CDCl ): δ = 146.6, 139.7, 127.1, 123.6, 71.4, 66.9, 40.9,
3
(
11.8 g, 0.512 mol, 4.0 equiv) was added. When the Na was com-
pletely dissolved in MeOH, 2-(methoxycarbonyl)cyclohexanone
20.0 g, 0.128 mol) was added and the mixture was heated to reflux.
To the mixture at reflux 1-chloropentan-3-one (40 mL, 0.30 mol,
.3 equiv) was added using a syringe pump over 14 h. After the ad-
39.6, 36.6, 35.6, 34.3, 29.8, 29.7, 25.8, 22.8, 17.9, 15.2.
(
MS (ESI+): m/z = 285.2 [M + Na]+.
+
HRMS (ESI+): m/z [M + Na] calcd for C H O Na: 285.1830;
1
7
26
2
2
found: 285.1825.
dition was complete, the mixture was heated under reflux for an ad-
ditional 6 h. The MeOH was removed in vacuo, and CH Cl (200
mL) and 5% aq HCl (200 mL) were added to acidify the mixture.
Anal. Calcd for C H O : C, 77.82; H, 9.99. Found: C, 77.93; H,
17 26
2
2
2
9.91.
The acidic mixture was extracted with CH Cl (200 mL). The or-
2
2
(
±)-(4aS,8aS)-8a-(Hydroxymethyl)-1,4a-dimethyl-
ganic solution was extracted with 1 M aq NaOH (2 × 300 mL). The
basic solution was washed with CH Cl (500 mL) and acidified with
4
,4a,6,7,8,8a,9,10-octahydrophenanthren-2(3H)-one (8a)
2
2
A mixture of 7a and 7b (14.9 g, 57.0 mmol) and DDQ (19.4 g, 85.5
mmol, 1.5 equiv) in 1,4-dioxane (710 mL) was stirred at 40 °C for
1
was dissolved in CH Cl (500 mL). The mixture was washed with 1
M aq NaOH (500 mL), H O (500 mL), and brine (500 mL), dried
concd aq HCl (100 mL) to give a precipitate. The mixture contain-
ing precipitates was extracted with CH Cl (2 × 300 mL). The com-
2
2
2 h. After removal of 1,4-dioxane in vacuo, the resulting residue
bined extracts were washed with brine (500 mL), dried (MgSO4),
filtered, and then concentrated in vacuo to give 2 (27.1 g, 77%) as
an amorphous solid that was used in the next reaction without fur-
ther purification.
2
2
2
(MgSO ), and concentrated in vacuo to give a residue that was fil-
4
tered through a pad of silica gel (hexanes–EtOAc, 2:1) to afford 8a
as a crystalline solid (12.1 g, 82%); mp 135–136 °C.
1
H NMR (400 MHz, CDCl ): δ = 5.88 (t, J = 3.8 Hz, 1 H), 2.66–2.43
3
(
m, 5 H), 2.25 (ddd, J = 2.2, 2.2, 18.5 Hz, 1 H), 2.20–2.07 (m, 1 H),
1
H NMR (CDCl ): δ = 5.74 (dd, J = 3.8, 3.8 Hz, 1 H), 3.85 and 3.74
3
2
2
1
.07–1.97 (m, 2 H), 1.88–1.76 (m, 1 H), 1.77 (s, 3 H), 1.73–1.62 (m,
H), 1.55 (ddd, J = 3.4, 13.7, 13.7 Hz, 1 H), 1.46–1.36 (m, 1 H),
.29 (s, 3 H).
(
ABq, J = 11.2 Hz, each 1 H), 2.59 (ddd, J = 4.2, 5.7, 15.7 Hz, 1 H),
.58–2.41 (m, 3 H), 2.20–2.13 (m, 2 H), 2.10–2.05 (m, 2 H), 2.01
ddd, J = 4.2, 5.7, 13.6 Hz, 1 H), 1.86–1.80 (m, 2 H), 1.78 (d, J = 0.9
Hz, 3 H), 1.67–1.58 (m, 2 H), 1.32 (s, 3 H), 1.30–1.14 (m, 2 H).
2
(
(
±)-(2R,4aS,8aS)-8a-(Hydroxymethyl)-1,4a-dimethyl-
,3,4,4a,6,7,8,8a,9,10-decahydrophenanthren-2-ol (7a) and (±)-
2S,4aS,8aS)-8a-(Hydroxymethyl)-1,4a-dimethyl-
,3,4,4a,6,7,8,8a,9,10-decahydrophenanthren-2-ol (7b)
13
2
C NMR (CDCl ): δ = 198.6, 163.4, 145.3, 128.4, 124.6, 66.3, 41.1,
3
(
2
3
9.4, 35.0, 34.2, 34.1, 33.1, 27.6, 25.6, 25.0, 17.5, 11.4.
MS (ESI+): m/z = 261.2 [M + H]+.
To a solution of 2 (13.6 g, 49.6 mmol) in toluene (550 mL) heated
to 110 °C, a 3.5 M solution of Red-Al in toluene (56.6 mL, 198
mmol, 4.0 equiv) was added. The solution was stirred at this tem-
perature for 14 h. The mixture was cooled in an ice-water bath and
then 1 M aq NaOH (4 mL) and H O (14 mL) were successively add-
ed. The organic layer was washed with 1 M aq NaOH (400 mL),
+
HRMS (ESI+): m/z [M + H] calcd for C H O : 261.1855; found:
2
17
25
2
61.1849.
Anal. Calcd for C H O : C, 78.42; H, 9.29. Found: C, 78.26; H,
9
17
24
2
2
.26.
H O (400 mL), and brine (400 mL), then it was dried (MgSO ), fil-
tered, and concentrated in vacuo to give a residue. The residue was
filtered through a pad of silica gel (hexanes–EtOAc, 2:1) to afford
2
4
(
±)-(4aS,8aS)-8a-(Hydroxymethyl)-1,1,4a-trimethyl-
3
,4,4a,6,7,8,8a,9,10,10a-decahydrophenanthren-2(1H)-one (4c)
Li (sliced ribbon 98%, 2.40 g, 339 mmol, 7.2 equiv) was added to
liquid NH (400 mL), and then the solution was stirred at –78 °C for
1
7a and 7b [9.97 g, 77% as a mixture of two diastereomers (1:3)] as
3
a colorless solid. Analytical samples of 7a and 7b were obtained by
flash column chromatography (hexanes–EtOAc, 3:1).
h. A solution of 8a (12.5 g, 48.0 mmol) and H O (864 mg, 48.0
2
mmol, 1.0 equiv) in THF (192 mL) were added dropwise and the
mixture was stirred under reflux at –33 °C (bp of NH , with the aid
3
7
a
of a CCl bath) for 1 h. The mixture was cooled to –78 °C and iso-
4
Mp 145–146 °C.
prene (approx. 10.5 mL) was injected until the blue color disap-
peared turning the solution cloudy white. To this mixture, THF
(69.6 mL) and MeI (69.6 mL, 1.12 mol, 23 equiv) were successively
added dropwise. The mixture was stirred under reflux at –33 °C for
1 h. After removal of the NH with the aid of a N stream, sat. aq
1
H NMR (CDCl ): δ = 5.80 (dd, J = 3.8, 3.8 Hz, 1 H), 3.87 (s, 1 H),
3
3.78 and 3.76 (ABq, J = 11.0 Hz, each 1 H), 2.45 (ddd, J = 1.5, 1.5,
14.6 Hz, 1 H), 2.19–2.08 (m, 3 H), 1.99–1.74 (m, 5 H), 1.78 (d,
J = 0.7 Hz, 3 H), 1.69 (m, 1 H), 1.67–1.52 (m, 2 H), 1.47 (br s, 1 H),
3
2
1.33 (br s, 1 H), 1.23–1.13 (m, 2 H), 1.14 (s, 3 H).
NH Cl soln (100 mL) was added and the aqueous mixture was ex-
4
1
3
tracted with EtOAc (3 × 100 mL). The extract was dried (MgSO4),
filtered, and then concentrated in vacuo to give a residue that was
filtered through a pad of silica gel (hexanes–EtOAc, 3:1) to afford
4c as a crystalline solid (10.3 g, 78%); mp 109–110 °C.
1
C NMR (CDCl ): δ = 147.1, 140.6, 125.6, 123.9, 69.5, 66.6, 40.4,
3
3
9.5, 36.3, 35.1, 31.6, 28.3, 28.2, 25.9, 22.3, 17.91, 17.85.
+
MS (ESI+): m/z = 245.2 [M – H O + H] .
2
+
HRMS (ESI+): m/z [M – H O + H] calcd for C H O: 245.1900;
found: 245.1899.
2
17 25
H NMR (CDCl ): δ = 5.67 (dd, J = 3.8, 3.8 Hz, 1 H), 3.68 (s, 2 H),
3
2.68 (ddd, J = 6.6, 12.5, 15.7 Hz, 1 H), 2.43 (ddd, J = 3.3, 5.9, 15.7
Anal. Calcd for C H O ·0.25 H O: C, 76.50; H, 10.01. Found: C,
Hz, 1 H), 2.20–1.00 (m, 14 H), 1.20 (d, J = 0.6 Hz, 3 H), 1.08 (s, 3
H), 1.06 (s, 3 H).
1
7
26
2
2
76.74; H, 9.94.
13
C NMR (CDCl ): δ = 217.0, 148.0, 123.0, 67.0, 54.1, 47.9, 39.7,
3
7
b
3
9.0, 38.0, 37.1, 36.7, 34.9, 26.1, 26.0, 22.6, 21.8, 19.7, 18.1.
Mp 147–150 °C.
+
1
MS (EI): m/z = 276 [M] , 245, 227, 203.
HRMS (EI): m/z [M]+ calcd for C H O : 276.2089; found:
H NMR (CDCl ): δ = 5.71 (dd, J = 3.8, 3.8 Hz, 1 H), 4.01 (dd,
3
J = 7.2, 7.2 Hz, 1 H), 3.76 (s, 2 H), 2.44 (ddd, J = 3.9, 3.9, 14.6 Hz,
1
8
28
2
1
4
H), 2.19 (m, 1 H), 2.13 (dd, J = 3.9, 4.9 Hz, 1 H), 2.11 (dd, J = 1.1,
.0 Hz, 1 H), 2.04 (m, 1 H), 1.92–1.70 (m, 5 H), 1.73 (s, 3 H), 1.63–
276.2082.
Anal. Calcd for C H O : C, 78.21; H, 10.21. Found: C, 77.92; H,
1
8
28
2
1
0.12.
©
Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 3251–3254

3254
A. Saito et al.
PAPER
Acknowledgement
Finlayson, S.; Mierke, D. F.; Honda, T. J. Biol. Chem. 2010,
2
85, 33747.
This work was supported by funds from Stony Brook Foundation
and Reata Pharmaceuticals. A. S. and S. Z. are grateful to the Insti-
tute of Chemical Biology & Drug Discovery Postdoctoral Scholar-
ships. M.T. was a visiting scholar from Hamari Chemicals, Ltd
(
3) Kalra, S.; Knatko, E. V.; Zhang, Y.; Honda, T.; Yamamoto,
Y.; Dinkova-Kostova, A. T. Cancer Prev. Res. 2012, 5, 973.
4) Liby, K.; Yore, M. M.; Roebuck, B. D.; Baumgartner, K. J.;
Honda, T.; Sundararajan, C.; Yoshizawa, H.; Gribble, G. W.;
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Kostova, A. T.; Stephenson, K. K.; Egner, P. A.; Yates, M.
S.; Groopman, J. D.; Kensler, T. W.; Sporn, M. B. Cancer
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(
(Japan).
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis. SnuIoipgfmr tooatrin guSIopi
nnfo itrmart
(
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Synthesis 2013, 45, 3251–3254
© Georg Thieme Verlag Stuttgart · New York