Nazarov reagents for convergent and expedient synthesis of new steroids.

Article abstract of DOI:10.1021/ol017274r

[reaction: see text] A new methodology for the convergent synthesis of tetracyclic compounds was developed. Two new bicyclic Nazarov reagents of type II were synthesized, and their cycloaddition with 2-carbomethoxy-2-cyclohexenone I was studied. This cycl

Full text of DOI:10.1021/ol017274r

ORGANIC
LETTERS
2002
Vol. 4, No. 7
1091-1094
Nazarov Reagents for Convergent and
Expedient Synthesis of New Steroids
Olivier Lepage, Charles Stone, and Pierre Deslongchamps*
Laboratoire de synthe`se organique, Institut de pharmacologie de Sherbrooke,
UniVersite´ de Sherbrooke, Sherbrooke, Que´bec, Canada J1H 5N4
pierre.deslongchamps@courrier.usherb.ca
Received December 19, 2001
ABSTRACT
A new methodology for the convergent synthesis of tetracyclic compounds was developed. Two new bicyclic Nazarov reagents of type II were
synthesized, and their cycloaddition with 2-carbomethoxy-2-cyclohexenone I was studied. This cycloaddition afforded new interesting steroidal
backbones.
Several years ago, our laboratory discovered a new stereo-
controlled synthesis of decalins. It was found that the reaction
between cyclohexenone 1 and Nazarov reagent 2 afforded
the cis,cis-decalin 3 in good yield and with very good
diastereoselectivity, after selective decarboxylation of the
tert-butyl ester (Scheme 1).1,2 Cyclic Nazarov reagent 4 was
also studied,2 opening the way to a new methodology for
the synthesis of tricyclic compounds.
the unconjugated ketone and subsequent protection of the
alcohol as a methoxy methyl ether, an acylation was
performed with magnesium methyl carbonate at the R
position of the R,â-unsaturated ketone 7.4 The resulting acid
was esterified with diazomethane, and compound 8 having
the trans ring junction was obtained after catalytic hydro-
We recently decided to synthesize some new bicyclic
Nazarov reagents and study their reactions with cyclohex-
enone 1. This reaction could be the key step in a new steroid
synthesis via a convergent approach starting with a CD
bicyclic building block. In this Letter we wish to report the
synthesis of the two new Nazarov reagents 11 and 15, having
respectively a trans and a cis ring junction. We also report
their cycloaddition with the cyclohexenones 1 and 20.
The Hajos-Parrish ketone 63 was selected as starting
material for the synthesis of Nazarov reagent 11 having a
trans ring junction (Scheme 2). After selective reduction of
Scheme 1a
(1) Lavalle´e, J.-F.; Deslongchamps, P. Tetrahedron Lett. 1988, 29, 5117.
(2) Lavalle´e, J.-F.; Spino, C.; Ruel, R.; Hogan, K.; Deslongchamps, P.
Can. J. Chem. 1992, 70, 1406.
(3) Hajos, Z. G.; Parrish, D. R. Org. Synth. 1985, 63, 26.
(4) Micheli, R. A.; Hajos, Z. G.; Cohen, N.; Parrish, D. R.; Portland, L.
A.; Sciamanna, W.; Scott, M. A.; Wehrli, P. A. J. Org. Chem. 1975, 40,
675.
a Reagents and conditions: (a) Cs2CO3, CHCl3, rt; (b) p-TsOH,
C6H6, reflux, 69% (two steps); (c) CF3CO2H, C6H6, reflux, 66%
(two steps).
10.1021/ol017274r CCC: $22.00 © 2002 American Chemical Society
Published on Web 03/03/2002

Scheme 2a
Scheme 3a
a Reagents and conditions: (a) NaBH4, CH2Cl2, MeOH, -78 °C,
90%; (b) MOMCl, (i-Pr)2EtN, CH2Cl2, rt, 61%; (c) MeOCO2Mg-
OMe‚xCO2/DMF, DMF, 125 °C; (d) CH2N2, Et2O, 0 °C; (e) H2 (1
atm), Pd/BaSO4, EtOH, rt; (f) NaBH4, MeOH, -78 °C, 49% (four
steps); (g) MsCl, Et3N, CH2Cl2, -5 °C, 93%; (h) DIBAL, Et2O,
-78 °C, 65%; (i) Dess-Martin periodinane, CH2Cl2, rt, 91%; (j)
NaI, Pyridine, DMF, 100 °C, 97%; (k) i. LDA, allyl acetate, THF,
-78 °C, ii. 10, -78 °C, 88%; (l) Dess-Martin periodinane, CH2Cl2,
rt, 96%.
a Reagents and conditions: (a) MOMCl, (i-Pr)2EtN, CH2Cl2, rt,
82%; (b) BH3/THF, THF, rt, 71%; (c) (ClCO)2, DMSO, Et3N,
CH2Cl2, -78 °C, 79%; (d) i. LDA, THF, -78 °C, ii. Comins’
reagent (16), -30 °C, 60%; (e) CO (1 atm), PdCl2(PPh3)2, K2CO3,
MeOH, THF, rt, 67%; (f) i. LDA, tert-butyl acetate, THF, -78
°C, ii. 14, 0 °C; (g) AllylOH, DMAP, toluene, reflux, 46% (two
steps).
homologation was then performed on the enol triflate using
a carbonylation reaction.11 A Claisen condensation was then
performed on the ester 14 with the anion of tert-butyl acetate,
and Nazarov reagent 15 was obtained by transesterification
using the conditions developed by Taber.12
genation. This reaction is known to give the trans junction
on similar compounds.4 The ketone of the â-keto-ester was
reduced and converted into mesylate 9. The ester was then
reduced using diisobutylaluminum hydride, and the resulting
alcohol was oxidized with Dess-Martin periodinane.5 At this
point, basic conditions were used to eliminate the mesylate,
affording the R,â-unsaturated aldehyde 10.6 Attempts to
eliminate the mesylate on compound 9 gave low yield and
selectivity. An aldol reaction was performed on the unsatur-
ated aldehyde 10 with the anion of allyl acetate to obtain
the â-hydroxy ester. Finally, oxidation of the alcohol with
Dess-Martin periodinane5 afforded Nazarov reagent 11.
To compare its reactivity, the Nazarov reagent 15 with a
cis ring junction was synthesized using alcohol 12 as starting
material (Scheme 3). Alcohol 12 was obtained in three steps
from Hajos-Parrish ketone 6.7 After protection of the alcohol
as a methoxy methyl ether and hydroboration on the
unsaturation, the resulting cis ring junction alcohol7 was
oxidized to the ketone 13.8 The kinetically formed enolate
was trapped in situ by Comins’ reagent,9,10 and a one-carbon
With Nazarov reagents 11 and 15 in hand, cycloaddition
studies began (Scheme 4). The reaction was first performed
with cyclohexenone 1 and Nazarov reagent 11. This reaction
afforded, after selective decarboxylation,13 only the cis-anti-
cis-anti-trans tetracyclic compound 17. The structure of the
tetracycle was proved by X-ray diffraction analysis14 of its
nitrobenzoate derivative 19. We believe that the anionic
cyclization process takes place either via a highly asymmetric
Diels-Alder reaction or by two consecutive Michael addi-
tions where the first step would be reversible. In this manner,
the cycloaddition can occur on the R face of Nazarov reagent
11 to avoid a steric interaction with the C-13 (steroid
numbering) tertiary methyl group (Figure 1, approach B was
favored over A).
We then tried to force the reaction to proceed on the other
face of the Nazarov reagent by utilizing the chiral cyclo-
hexenone 20 having a protected alcohol in position 4
(Scheme 4). This alcohol partially blocks the â face of the
(5) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155.
(6) Baggiolini, E. G.; Iacobelli, J. A.; Hennessy, B. M.; Uskokovic, M.
R. J. Am. Chem. Soc. 1982, 104, 2945.
(11) Titus, M. A.; Kamali Kannangara, G. S. J. Org. Chem. 1990, 55,
(7) Fernandez, B.; Martinez Pe´rez, J. A.; Granja, J. R.; Castedo, L.;
Mourino, A. J. Org. Chem. 1992, 57, 3173.
(8) Mancuso, A. J.; Swern, D. Synthesis 1981, 165.
(9) Castedo, L.; Mourino, A.; Sarandeses, L. A. Tetrahedron Lett. 1986,
27, 1523.
(10) Comins, D. L.; Dehghani, A.; Foti, C. J.; Joseph, S. P. Org. Synth.
1997, 74, 77.
5711.
(12) Taber, D. F.; Amedio, J. C.; Patel, Y. K. J. Org. Chem. 1985, 50,
3618.
(13) (i) Tsuji, J.; Nisar, M.; Shimizu, I. J. Org. Chem. 1985, 50, 3416.
(ii) Kunz, H. HelV. Chim. Acta 1988, 71, 1868.
(14) The authors wish to thank Mr. M. Drouin for X-ray diffraction
analysis.
1092
Org. Lett., Vol. 4, No. 7, 2002

Scheme 4a
Scheme 5a
a Reagents and conditions: (a) Cs2CO3, CH2Cl2, rt; (b) Pd(PPh3)4,
morpholine, THF, rt, 87% (two steps); (c) HCl concentrated, MeOH,
reflux, 85%; (d) 4-nitrobenzoyl chloride, pyridine, DMAP, CH2Cl2,
rt, 80%; (e) Pd(PPh3)4, morpholine, THF, rt, 50% (two steps); (f)
HF‚pyridine, THF, 80 °C, 78%.
a Reagents and conditions: (a) Cs2CO3, CH2Cl2, rt.; (b) Pd-
(PPh3)4, morpholine, THF, rt, 24% (two steps); (c) HCl concen-
trated, MeOH, reflux, 85%; (d) Pd(PPh3)4, morpholine, THF, rt 60%
(two steps); (e) HCl concentrated, MeOH, reflux, 99%; (f) aqueous
HF, CH3CN, 75 °C, 75%.
cyclohexenone and could favor the â face of the Nazarov
reagent for the cycloaddition.15,16 The cycloaddition was
carried out, and after selective decarboxylation, a new
tetracycle, compound 21, was produced showing that again
the angular methyl group on Nazarov reagent 11 controlled
the face of the attack (Figure 1, approach D was favored
over C). A slight amount of epimeric tetracycle (ap-
proximately 8:1) at position 8 was also observed during the
reaction. The alcohols on 21 were deprotected, the resulting
tetracyclic compound 22 was crystallized, and its structure
was confirmed by X-ray diffraction analysis.14
a separable mixture of two tetracyclic compounds 23 and
23a (unknown configuration at C-8) with low yields and
selectivities. The yield can be explained by the low reactivity
of Nazarov reagent 15 and the instability of cyclohexenone
1. On the other hand, the lack of selectivity can be explained
by the similarity of steric interactions on the two faces of
reagent 15. After deprotection of the alcohol, an X-ray
diffraction analysis14 of compound 24 proved the structure
of the major product.
The cycloaddition of cis Nazarov reagent 15 was then
studied (Scheme 5). Its reaction with cyclohexenone 1 gave
To obtain better selectivity in the reaction, the cyclo-
addition was tried with the more stable cyclohexenone 20.
This reaction gave a 1:1 mixture of epimeric compounds at
position 8 that under acidic conditions was converted
completely into the thermodynamically more stable com-
pound 25. This result shows that steric interactions produced
by the protected alcohol blocking the â face of the cyclo-
hexenone were able to control the cycloaddition’s selectivity
(Figure 2, approach A was favored over B). X-ray diffraction
analysis14 of compound 26 proved the structure of 25.
In conclusion, we have demonstrated that it is possible to
perform a double Michael cycloaddition using a bicyclic
Nazarov reagent. We also have shown that the tertiary methyl
group on the Nazarov reagent controls the selectivity of the
(15) The cycloaddition of cyclohexenone 20 with Nazarov reagent 2
produced 5 â-H, 9 â-Me, and 10 â-E decalin with high yield and
stereoselectivity.
Figure 1. Comparison of the cycloaddition approaches of 1 and
11 (A, B) and of 20 and 11 (C, D).
(16) Belzile, J.; Chapdelaine, D.; Deslongchamps, P. Unpublished results.
Org. Lett., Vol. 4, No. 7, 2002
1093

seems promising for the total synthesis of steroidal natural
products. Further developments on this approach with other
bicyclic Nazarov reagents are presently being pursued in our
laboratories and will be reported in due course.
Acknowledgment. A research Chair in organic chemistry
to P. Deslongchamps from BioChem Pharma Inc. is deeply
appreciated. Fellowships from FCAR-Quebec, Boehringer
Ingelheim Inc., and NSERC-Canada to O. Lepage are highly
appreciated. The authors wish to thank Dr. D. Chapdelaine
and Dr. E. Marsault for assistance.
Figure 2. Comparison of the cycloaddition approaches of 20 and
15.
Supporting Information Available: Experimental details
and characterization data for all compounds and X-ray crystal
structure data for compounds 19, 22, 24, and 26. This
material is available free of charge via the Internet at
http://pubs.acs.org.
cycloaddition when the reagent ring junction is trans (11)
by blocking its â face. The use of a chiral 4-substituted-2-
carbomethoxy-2-cyclohexenone controls the selectivity when
the reaction was carried out with the Nazarov reagent bearing
a cis ring junction (15). This methodology allowed us to
obtain in a convergent manner tetracyclic compounds and
OL017274R
1094
Org. Lett., Vol. 4, No. 7, 2002