Concise synthesis of a steroid C/D-ring system using a bicyclo[3.2.1]octane chiral building block: A new route to 25-hydroxy-Grundmann's ketone

Article abstract of DOI:10.1055/s-2002-19353

A concise route to a steroid C/D-ring system leading to 25-hydroxy-Grundmann's ketone has been developed along with a new chemical resolution of the chiral starting material containing a bicyclo[3.2.1]octane framework.

Full text of DOI:10.1055/s-2002-19353

LETTER
125
Concise Synthesis of A Steroid C/D-Ring System Using a Bicyclo[3.2.1]octane
Chiral Building Block: A New Route to 25-Hydroxy-Grundmann’s Ketone
C
oncise Synthesis
e
of A Steroid C/D
-
s
R
ing
S
yst
u
e
m
ke Hanada, Norio Miyazawa, Hiroshi Nagata, Kunio Ogasawara*
Pharmaceutical Institute, Tohoku University, Aobayama, Sendai 980-8578, Japan
Fax +81(22)2176845; E-mail: konol@mail.cc.tohoku.ac.jp
Received 1 October 2001
Abstract: A concise route to a steroid C/D-ring system leading to
25-hydroxy-Grundmann’s ketone has been developed along with a
new chemical resolution of the chiral starting material containing a
bicyclo[3.2.1]octane framework.
OH
ref. 6
H
Key words: chiral building block, convex-face selective stereose-
lection, asymmetric hydrogen transfer reaction, vitamin D, steroid
synthesis, Dieckmann cyclization, aldol reaction
HO
OH
calcitriol 1
We have recently developed a preparation of the bicyclic
enone 5 containing a bicyclo[3.2.1]octane framework in
both enantiomeric forms by employing an enzymatic res-
olution method.1 Because of its inherent stereochemical
and chemical nature with a sterically biased structure con-
ref. 5
OTBDPS
OH
taining two oxygen functionalities,2,3 we expect it to be a
O
H
versatile chiral building block. It has already been used in
O
3
2
the efficient stereocontrolled syntheses of the analgesic
alkaloid (-)-morphine4 and the antibiotic diterpene (+)-
ferruginol,1 both of which have a hydrophenanthrene
framework. We have now attempted the diastereoselec-
tive construction of a steroid C/D-ring system with a hy-
drindane framework utilizing 5 to extend its versatility as
a chiral building block. We report here a concise diastere-
ocontrolled route leading to the keto-ester 4 and its trans-
formation into the known siloxy-enone 3,5 which serves
as a precursor of 25-hydroxy-Grundmann’s ketone 2,6 the
C/D-ring moiety of calcitriol (1)7 as well as a new route to
the chiral building block 5 which employs a ruthenium-
chiral diamine catalyzed kinetic resolution8,9 (Scheme 1).
present
study
present
study
CO2Me
O
OMOM
O
(–)-5
4
Scheme 1
allyl alcohol 7. Likewise, the enantiomerically pure11 (+)-
allyl alcohol 7 may be obtained by using the enantiomeric
chiral catalyst RuII-(1R, 2R)-TsDPEN (Scheme 2).
We first describe a new preparation of the chiral building
block 5 under kinetic asymmetric hydrogen transfer con-
ditions using the ruthenium catalyst,8 prepared from
Exposure of the enantiopure alcohol 7 to manganese (IV)
oxide in dichloromethane afforded the (-)-enone 5, [ ]D
26
6
[{RuCl2( -cymene)}2] and (1S,2S)-1-N-(p-toluenesulfo-
-438.6 (c 1.6, CHCl3), in 98% yield without loss of the
original chiral integrity. The (-)-enone 5 obtained was
then transformed into the isomeric enone 10, [ ]D27+204.1
(c 0.7, CHCl3), in three steps in 68% overall yield by a
1,3-ketone transposition sequence involving alkaline ep-
nyl)-1,2-diphenylethylenediamine (TsDPEN). Thus, the
racemic allyl alcohol1 ( )-7, prepared from norbornadiene
via diketone ( )-6,1 was stirred in acetone (2 M) in the
presence of RuII-(1S, 2S)-TsDPEN (10 mol%) at room
temperature for 2.5 h to give the (+)-enone 5, in 52% yield
with 73% ee,11 leaving the enantiopure (-)-allyl alcohol 7,
28
oxidation of 5 to the exo-epoxide 8, [ ]D -59.7 (c 1.0,
28
CHCl3) and Wharton rearrangement of 8 to the exo-alco-
hol 9, [ ]D30+109.8 (c 1.1, CHCl3), followed by oxidation
of 9 with manganese (IV) oxide1 (Scheme 3).
[ ]D -142.3 (c 1.0, CHCl3), in 42% yield. Although the
present procedure did not furnish both products in enanti-
omerically pure forms, the enantiomerically enriched
enone 5 may be optically purified after reconversion to the
Synlett 2002, No. 1, 28 12 2001. Article Identifier:
1437-2096,E;2002,0,01,0125,0127,ftx,en;Y20501ST.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0936-5214

126
K. Hanada et al.
LETTER
(c 1.5, CHCl3). The ketone functionality of 11 was then re-
duced diastereoselectively and the resulting endo-alcohol
12, [ ]D29+70.5 (c 1.5, CHCl3), was protected as the 4-
O
ref. 10
ref. 1
OH
OMOM
O
29
methoxybenzyl (MPM) ether 13, [ ]D -11.7 (c 1.4,
norbornadiene
(±)-6
(±)-7
CHCl3). The methoxymethyl (MOM) protecting group of
13 was removed at this stage and the resulting alcohol 14,
[ ]D27+20.3 (c 1.4, CHCl3), was oxidized to give the five-
membered ketone 15, [ ]D28+125.4 (c 1.3, CHCl3). Again
the ketone 15 exhibited inherent convex-face selectivity
to allow diastereoselective construction of a quaternary
stereogenic center next to the carbonyl functionality.
Thus, sequential methylation and crotylation occurred in
turn from the convex-face to furnish ketone 16,
[ ]D26+62.7 (c 1.1, CHCl3), with endo-methyl and exo-
crotyl moieties. Having constructed the requisite C17-ter-
tiary and C13-quaternary stereogenic centers (steroid
numbering), we next carried out regioselective modifica-
tion of the crotyl moiety under Wacker oxidation condi-
tions.12 As we have observed previously, regioselective
oxygenation13 occurred to afford the methyl ketone 17,
[ ]D26+67.1 (c 1.2, CHCl3) as a single product. The O-pro-
tecting group was removed at this stage and the resulting
alcohol 18, [ ]D27+26.2 (c 1.0, CHCl3), was oxidized to
give the triketone 19, [ ]D27+178.9 (c 1.9, CHCl3)
(Scheme 4).
RuII-(S,S)-TsDPEN (cat.)
+
O
OH
OMOM
acetone
r.t., 2.5 h
OMOM
(–)-7
(42%; >99%ee)
(+)-5
(52%; 73%ee)
Ts
Ph
N
RuII-(S,S)-TsDPEN (cat.)
=
Ru
N
Ph
H
Scheme 2
O
a
b
(–)-7
O
O
OMOM
OMOM
8
(–)-5
OH
O
d
c
We were very interested in the reaction of 19 under basic
conditions, since at least three primary pathways might be
envisaged an intramolecular aldol reaction between the
methyl ketone and the cyclopentanone carbonyl and two
regiochemically different retro-Dieckmann reactions of
the non-enolizable 1,3-dicarbonyl moiety. When sodium
methoxide was added to a stirred solution of the triketone
19, a facile reaction occurred instantly to afford the diketo
ester 20 accompanied by a minor amount of an insepar-
able byproduct, presumably the aldol product of 20. Al-
though completion of the intramolecular aldol cyclizaion
of 20 under these basic conditions or under more forcing
conditions using a stronger base was found to be unex-
OMOM
OMOM
(+)-10
9
Scheme 3 a) MnO2, CH2Cl2 (96%). b) 30% H2O2, 10% aq. NaOH,
MeOH (97%). c) NH2NH2-HCl, Et3N, MeCN (75%). d) MnO2,
CH2Cl2 (93%).
Owing to its sterically biased framework, the reaction of
10 with the cuprate complex generated from methylmag-
nesium iodide proceeded diastereoselectively from the
convex-face to give the single 1,4-adduct 11, [ ]D29+92.7
O
e
b
a
OR1
OMPM
(+)-10
OR2
O
OMOM
12:R1=H,R2=MOM
13:R1=MPM,R2=MOM
14:R1=MPM,R2=H
15
11
c
d
O
g
OR
i
f
OMPM
O
O
O
O
O
16
17:R=MPM
18:R=H
19
h
Scheme 4 a) MeMgI, CuCN, LiCl, THF, -78 °C (92%). b) NaBH4, MeOH (95%). c) 4-MeOC6H4CH2Cl, NaH, TBAI, DMF (73%, 22% re-
covery). d) HCl-MeOH (80%). e) PCC, CH2Cl2 (92%). f) MeI, NaH, THF (91%), then crotyl-Br, ButOK, THF (62%). g) PdCl2, CuCl, O2, DMF-
H2O (10:1), 5 days (72%, 22% recovery). h) DDQ, CH2Cl2-H2O (8:1) (99%). i) PCC, CH2Cl2 (96%).
Synlett 2002, No. 1, 125–127 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Concise Synthesis of A Steroid C/D-Ring System
127
OR
OH
CO2Me
CO2Me
b
a
c
d
19
O
HO
O
O
O
22:R=H
21
20
4
e
3:R=TBDPS
Scheme 5 a) NaOMe, MeOH. b) p-TsOH, toluene, reflux (90%, 2 steps). c) LiAlH4, THF (96%). d) MnO2, CH2Cl2 (80%). e) TBDPS-Cl,
imidazole, DMF (70%).
pectedly difficult, exposure of the mixture to p-toluene-
(2) Nagata, H.; Miyazawa, N.; Ogasawara, K. Synthesis 2000,
sulfonic acid in toluene at reflux furnished the
hydrindanone 4, [ ]D29+64.0 (c 1.1, CHCl3), cleanly in
one step in excellent yield. Thus, it was concluded that the
retro-Dieckmann reaction took place regioselectively by
nucleophilic attack of methoxide on the cyclohexanone
carbonyl functionality of 19 to give 20 having a cyclopen-
tanone ring. We believe that the observed regioselective
reaction was mostly due to steric reasons, namely that the
methoxide ion reacted preferentially with the less hin-
dered ketone on the bicyclo[3.2.1]octane moiety.
2013.
(3) Nagata, H.; Kawamura, M.; Ogasawara, K. Synthesis 2000,
1825.
(4) Nagata, H.; Miyazawa, N.; Ogasawara, K. Chem. Commun.
2001, 1094.
(5) Nagasawa, K.; Matsuda, N.; Noguchi, Y.; Yamanashi, M.;
Zako, Y.; Shimizu, I. J. Org. Chem. 1993, 58, 1483.
(6) (a) Baggiolini, E. G.; Iacobelli, J. A.; Hennessy, B. M.;
Batcho, A. D.; Sereno, J. F.; Uskokovic, M. R. J. Org. Chem.
1986, 51, 3098. (b) Daniewski, A. R.; Liu, W. J. Org. Chem.
2001, 66, 626.
(7) Pertinent reviews, see: (a) Zhu, G.-D.; Okamura, W. Chem.
Rev. 1995, 95, 1877. (b) Jankowski, P.; Marczak, S.; Wicha,
J. Tetrahedron 1998, 54, 12071.
(8) (a) Haack, K.-J.; Hashiguchi, S.; Fujii, A.; Ikariya, T.;
Noyori, R. Angew. Chem. Int. Ed. Engl. 1997, 36, 285.
(b) Hashiguchi, S.; Fujii, A.; Haack, K.-J.; Matsumura, K.;
Ikariya, T.; Noyori, R. Angew. Chem. Int. Ed. Engl. 1997,
36, 288.
(9) (a) Kanada, R. M.; Taniguchi, T.; Ogasawara, K. Chem.
Commun. 1998, 1755. (b) Iura, Y.; Sugahara, T.;
Ogasawara, K. Tetrahedron Lett. 1999, 40, 5735.
(c) Kanada, R. M.; Taniguchi, T.; Ogasawara, K.
Tetrahedron Lett. 1999, 41, 3631.
Reduction of 4 with lithium aluminum hydride afforded
the diol 21, [ ]D28+32.5 (c 0.6, CHCl3), diastereoselec-
tively, as a single product5 which was oxidized with man-
ganese (IV) oxide to afford the hydroxy enone 22, mp 74–
75 °C, [ ]D27+83.5 (c 1.0, CHCl3), chemoselectively, as a
single product without any oxidation of the primary hy-
droxy functionality. Finally, the enone 22 was trans-
formed into the tert-butyldiphenylsilyl (TBDPS) ether 3,
[ ]D26+34.1 (c 1.3, CHCl3){ref.5:[
]
24+37.0 (c 2.5,
D
CHCl3)}, the physical and spectroscopic data of which
were identical with those reported.5 Since the ether 3 has
been transformed5 into 25-hydroxy-Grundmann’s ketone
2, the C/D-ring moiety of calcitriol 1, this constitutes the
development of new formal route to these compounds
(Scheme 5).
(10) Hawkins, R. T.; Hsu, R. S.; Wood, S. G. J. Org. Chem. 1978,
43, 4648.
(11) Optical purity of the product was determined by 1H NMR
measurement after transformation into the MTPA (both
enantiomeric) esters of the allyl alcohol 7. 1H NMR(300
MHz, CDCl3) of (-)-enone 5: = 1.45 (qd, J = 1.1, 8.5 Hz, 1
H), 1.71 (dtd,, J = 1.1, 4.7, 8.5 Hz, 1 H), 2.02 (d, J = 1.8 Hz,
1 H), 2.47 (td, J = 8.2, 14.6 Hz, 1 H), 2.79 (t, J = 5.8 Hz, 1
H), 3.08 (q, J = 5.5 Hz, 1 H), 3.37 (s, 3 H), 4.50 (td, J = 5.2,
14.3 Hz, 1 H), 4.65 (d, J = 1.4 Hz, 1 H), 6.04 (dd, J = 1.4, 9.9
Hz, 1 H), 7.11 (ddd, J = 1.4, 6.6, 8.5 Hz, 1 H). 1H NMR(300
MHz, CDCl3) of (-)-allyl alcohol 7: = 1.64–1.71 (m, 2 H),
1.77 (d, J = 11.5 Hz, 1 H), 1.81 (dd,, J = 6.0, 14.3 Hz, 1 H),
2.02 (td, J = 9.3, 13.2 Hz, 1 H), 2.34–2.36 (m, 1 H), 2.54 (q,
J = 4.9 Hz, 1 H), 3.38 (s, 3 H), 4.23 (td, J = 5.5, 11.3 Hz, 1
H), 4.60 (br.s, 1 H), 4.65 (s, 2 H), 5.53 (td, J = 2.2, 9.6 Hz, 1
H), 5.88 (td, J = 1.4, 6.3 Hz, 1 H).
In summary, we have demonstrated a new utilization of
our bicyclo[3.2.1]octenone chiral building block and its
new preparation employing a catalytic asymmetric hydro-
gen transfer protocol.
Acknowledgement
We are grateful to the Ministry of Education, Culture, Sports, Sci-
ence and Technology, Japan for support of this research.
(12) For a pertinent review, see: Tsuji, J. In Comprehensive
Organic Synthesis, Vol. 7; Trost, B. M.; Fleming, I., Eds.;
Pergamon: Oxford, 1991, 469.
(13) Takano, S.; Imamura, Y.; Ogasawara, K. Tetrahedron Lett.
1981, 22, 4479.
References
(1) Nagata, H.; Miyazawa, N.; Ogasawara, K. Org. Lett. 2001,
3, 1737.
Synlett 2002, No. 1, 125–127 ISSN 0936-5214 © Thieme Stuttgart · New York