A new route to (+)-estrone using a bicyclo[3.2.1]octane chiral building block.

Article abstract of DOI:10.1248/cpb.51.104

A new route to (+)-estrone has been developed starting from the chiral building block having a bicyclo[3.2.1]octane framework based on the inherent stereochemical chemical nature of the chiral building block.

Full text of DOI:10.1248/cpb.51.104

104
Communications to the Editor
Chem. Pharm. Bull. 51(1) 104—106 (2003)
Vol. 51, No. 1
the secondary alcohol 4, [a]D23 ꢁ73.2° (cꢂ1.3, CHCl3), di-
astereoselectively which was transformed into the benzyl
ether 5, [a]D25 ꢀ20.7° (cꢂ1.3, CHCl3), under standard condi-
tions. On sequential removal of the MOM-protecting group
and oxidation, the ether 5 gave the ketone 7, [a]D24 ꢁ135.8°
(cꢂ1.6, CHCl3), via the secondary alcohol 6, [a]D24 ꢁ29.4°
(cꢂ1.5, CHCl3). Owing to its molecular bias, the ketone 7 al-
lowed diastereoselective installation of the quaternary stere-
ogenic center to give the single dialkylated ketone 8, [a]D24
ꢁ63.6° (cꢂ1.4, CHCl3), by sequential methylation and ally-
lation under basic conditions. After debenzylation with 2,3-
dichloro-5,6-dicyanobenzoquinone (DDQ),6,20) the resulting
keto-alcohol 9, [a]D23 ꢀ38.7° (cꢂ1.4, CHCl3), was oxidized
to the b-diketone 10, [a]D24 ꢁ228.4° (cꢂ1.4, CHCl3), with
pyridinium chlorochromate (PCC). As observed in the previ-
ously reported synthesis of the C/D-ring moiety of cal-
citriol,2,3) and (ꢀ)-vernolepine,6) exposure of the diketone 10
to sodium methoxide in methanol induced a facile regiose-
lective retro-Dieckmann reaction to afford the single cy-
clopentanone 12, [a]D24 ꢀ96.6° (cꢂ1.3, CHCl3), in excellent
yield. The observed regioselective cleavage may be due to
the steric environment of the two carbonyl functionalities in
which the less congested cyclohexanone carbonyl was prefer-
entially attacked by methoxide ion to generate a transient b-
keto-alkoxide intermediate 11 to lead exclusively to the cy-
clopentanone 12 destined for the BCD-ring moiety of (ꢀ)-
estrone 1 (Fig. 2).
A New Route to (ꢀ)-Estrone Using a
Bicyclo[3.2.1]octane Chiral Building
Block
Keisuke HANADA, Norio MIYAZAWA, and
Kunio OGASAWARA*
Pharmaceutical Institute, Tohoku University; Aobayama, Sendai
980–8578, Japan.
Received November 5, 2002; accepted December 3, 2002
A new route to (ꢀ)-estrone has been developed starting from
the chiral building block having a bicyclo[3.2.1]octane frame-
work based on the inherent stereochemical chemical nature of
the chiral building block.
Key words chiral building block; diastereo-controlled synthesis; aldol
reaction; Dieckmann condensation; steroid
We have recently developed an efficient preparation of the
chiral building block 2 by a route involving either an enzy-
matic1) or a chemical2) resolution step. Because of its inher-
ent stereochemical and chemical nature with a sterically bi-
ased structure, it serves as a versatile chiral building block
and has already been used in the efficient stereocontrolled
syntheses of the antibiotic diterpene (ꢀ)-ferruginol,1) the cal-
citriol A-ring3) and C/D-ring2) precursors, the analgesic alka-
loid (ꢁ)-morphine4) and the structurally related morphinan
alkaloid (ꢁ)-O-methylpallidinine,5) the antitumor sesquiter-
pene (ꢀ)-vernolepin,6) and the 18-yohimbones.7) We have
now attempted its conversion into the representative estro-
genic steroid hormone (ꢀ)-estrone 18—15) applying the same
synthetic methodology employed in the syntheses of the
above mentioned natural products. We report here a new
route leading to (ꢀ)-estrone 1 starting with the building
block (ꢁ)-2 by employing the regioselective retro-Dieck-
mann reaction and the ring-closing metathesis16—19) as key
steps (Fig. 1).
In order to construct the C-ring moiety of (ꢀ)-estrone 1,
the cyclopentanone 12 was refluxed with the Grubbs’ reagent
in dichloromethane to initiate the ring-closing metathesis.
The expected reaction took place readily to give the hydroin-
danone 13, [a]D23 ꢀ90.4° (cꢂ1.4, CHCl3), the C/D-ring moi-
ety of (ꢀ)-estrone 1, in excellent yield. The bicyclic ketone
Because of its sterically biased structure, the bicyclic
enone (ꢁ)-2 exhibited convex-face selectivity to allow di-
astereoselective introduction of the vinyl functionality at the
b-position to give the single ketone 3, [a]D24 ꢁ101.9° (cꢂ1.5,
CHCl3). Reduction of 3 with sodium borohydride afforded
Fig. 1
Fig. 2.
Reagents and conditions: i) vinylmagnesium bromide, CuBr–Me2S, TMSCl, HMPA, THF, ꢁ78 °C then TBAF (93%). ii) NaBH4, MeOH, ꢁ78—ꢁ30 °C (92%), iii) BnBr, NaH,
Bu4NI, THF, reflux (80%), iv) HCl–MeOH (94%). v) PCC, CH2Cl2 (94%). vi) MeI, NaH, THF, then allyl bromide, ButOK, THF (77%, 2 steps). vii) DDQ, H2O, CH2Cl2 (77%).
viii) PCC, CH2Cl2 (94%). ix) NaOMe, MeOH (93%).
∗ To whom correspondence should be addressed. e-mail: konol@mail.cc.tohoku.ac.jp
© 2003 Pharmaceutical Society of Japan

January 2003
105
Fig. 3.
Reagents and conditions: i) Grubbs’ catalyst (5 mol%), CH2Cl2, reflux (90%). ii) (TMS–OCH2)2, TMS–OTf, CH2Cl2, ꢁ78—0 °C (93%). iii) LiAlH4, THF (98%). iv) PCC,
CH2Cl2. v) 3-MeOC6H4MgBr, THF, ꢁ78 °C (71%, 2 steps). vi) CS2, MeI, NaH, THF (93%). vii) Bu3SnH, AIBN, toluene, reflux (86% for 22).
Fig. 4.
Reagents and conditions: i) m-CPBA, NaHCO3, CH2Cl2 (98%). ii) DIBAL, CH2Cl2, ꢁ78 °C (64%). iii) PCC, CH2Cl2 (84%). iv) (CH2OH)2, p-TsOH (cat.), toluene, reflux. v) p-
TsOH, aq. acetone, reflux (88%, 2 steps). vi) Et3SiH, CF3CO2H, benzene (82%). viii) BBr3, CH2Cl2, ꢁ30—0 °C (84%).
13 obtained was ketalized and the resulting ethylene ketal 14, single secondary alcohol 24, [a]D24 ꢁ35.4° (cꢂ1.3, CHCl3),
[a]D23 ꢁ64.6° (cꢂ1.4, CHCl3), was transformed into the alde- which, obtained regioselectively, was then oxidized with
hyde 16 via the primary alcohol 15, [a]D24 ꢁ65.7° (cꢂ1.5, PCC to give the ketone 25, [a]D24 ꢁ7.1° (cꢂ1.3, CHCl3).
CHCl3), by sequential reduction with lithium aluminum hy- When the ketone 25 was refluxed with ethylene glycol in
dride and oxidation with PCC gave the benzyl alcohol 17 as toluene in the presence of p-toluenesulfonic acid, a facile cy-
an epimeric mixture which without separation was trans- clization occurred, as we have so far observed in certain
formed into the xanthate 18. Our first intention was a reduc- cases,1,4,5,7) to give the tetracyclic product 26 as a mixture of
tive cyclization of the xanthate 18 to give rise to the tetra- two regio-isomers. After acid-catalyzed deketalization of the
cyclic steroid framework 21 via mesomeric radical interme- mixture 26, the resulting keto-olefin mixture 27, consisting
diates such as 19 and 20. However, the product obtained was of the D9,11-isomer and the D8,9-isomer in a 7 : 3 ratio esti-
not the expected tetracyle 21 but the simple reduction prod- mated by 1H-NMR analysis, was treated with triethylsilane in
uct 22, [a]D25 ꢁ82.1° (cꢂ1.2, CHCl3), when the xanthate 18 benzene containing trifluoroacetic acid10—12,21) to give (ꢀ)-
was treated with tributylstannane in toluene at reflux in the estrone methyl ether 28, mp. 174—175 °C, [a]D27 ꢀ152.6°
presence of azobisisobutylonitrile (AIBN) (Fig. 3).
(cꢂ1.2, CHCl3) [lit.10): mp 174—175.5 °C, [a]D27 ꢀ159.2°
We, therefore, explored an alternative route to (ꢀ)-estrone (cꢂ0.72, CHCl3)], as a single product which was identical in
1 using the reduction product 22. Thus, the product 22 was all respects with an authentic material. Since the methyl ether
transformed into the epoxide 23, [a]D23 ꢁ63.1° (cꢂ1.2, 28 has been transformed into (ꢀ)-estrone 1 in a single
CHCl3), on reaction with m-chloroperbenzoic acid (m- step,8—15) a new route has been established at this stage in a
CPBA) which generated a single diastereomer. Since direct formal sense. Actually, the ether 28 furnished (ꢀ)-estrone 1,
transformation of the epoxide 23 into the ketone 25 under mp 265—266 °C, [a]D26 ꢀ151.8° (cꢂ0.5, CHCl3) [lit.10): mp
acid-catalyzed conditions failed, it was treated with di- 265.0—266.5 °C, [a]D27 ꢀ152.2° (cꢂ0.31, CHCl3)], on expo-
isobutylaluminum hydride (DIBAL) at ꢁ78 °C to give the sure to boron tribromide in dichloromethane (Fig. 4).

106
Vol. 51, No. 1
9) For some recent examples, see: Quinkert G., Grosso M. D., Bucher A.,
Bauch M., Döring W., Bats J. W., Dürner G., Tetrahedron Lett., 33,
3617—3620 (1992).
10) For some recent examples, see: Takano S., Moriya M., Ogasawara K.,
Tetrahedron Lett., 33, 1909—1910 (1992).
In summary, we have developed a new route to (ꢀ)-es-
trone 1 starting with our bicyclo[3.2.1]octane building block
(ꢁ)-2 and have extended the versatility of our chiral building
block.
11) For some recent examples, see: Quinkert G., Grosso M. D., Döring A.,
Döring W., Schenkel R. I., Bauch M., Dambacher F. T., Bats J. W.,
Zimmermann G., Dürner G.. Helv. Chim. Acta, 78, 1345—1391
(1995).
12) For some recent examples, see: Sugahara T., Ogasawara K., Tetrahe-
dron Lett., 37, 7403—7406 (1996).
Acknowledgements We are grateful to the Ministry of Education, Cul-
ture, Sports, Science and Technology, Japan, for support of this research and
to Professor Yoshiharu Iwabuchi, Pharmaceutical Institute, Tohoku Univer-
sity, for his kind suggestions.
13) For some recent examples, see: Tietze L. F., Nöbel T., Spesch M., J.
Am. Chem. Soc., 120, 8971—8977 (1998).
References and Notes
1) Nagata H., Miyazawa N., Ogasawara K., Org. Lett., 3, 1737—1740
14) For some recent examples, see: Rigby J. H., Warshakoon N. C., Payen
A. J., J. Am. Chem. Soc., 121, 8237—8245 (1999).
(2001).
2) Hanada K., Miyazawa N., Nagata H., Ogasawara K., Synlett, 2002,
15) For some recent examples, see: Tanaka K., Nakashima H., Taniguchi
T., Ogasawara K., Org. Lett., 2, 1915—1917 (2000).
16) For pertinent reviews, see: Grubbs R. H., Chang S., Tetrahedron, 54,
4413—4450 (1998).
17) For pertinent reviews, see: Roy R., Das S. K., Chem. Commun., 2000,
519—529 (2000).
18) For pertinent reviews, see: Fürstner A., Angew. Chem. Int. Ed., 39,
3012—3043 (2000).
19) For pertinent reviews, see: Trnka T. M., Grubbs R. H., Acc. Chem.
Res., 34, 18—29 (2002).
125—127 (2002).
3) Miyazawa N., Tosaka A., Hanada K., Ogasawara K., Heterocycles, in
press.
4) Nagata H., Miyazawa N., Ogasawara K., Chem. Commun., 2001,
1094—1095 (2001).
5) Hanada K., Miyazawa N., Ogasawara K., Org. Lett., in press (ASAP
ol027040n).
6) Miyazawa N., Nagata H., Ogasawara K., Synlett, 2002, 1065—1068
(2002).
7) Miyazawa N., Ogasawara K., Tetrahedron Lett., 43, 4773—4776
(2002).
20) Matsumura R., Suzuki T., Hagiwara H., Hashi T., Ando M., Tetrahe-
dron Lett., 42, 1543—1546 (2001).
21) Posner G. H., Switzer C., J. Am. Chem. Soc., 108, 1239—1244 (1986).
8) For some recent examples, see: Quinkert G., Grosso M. D., Bucher A.,
Bats J. W., Dürner G., Tetrahedron Lett., 32, 3357—3360 (1991).