Divergent synthesis of pseudoenantiomers for ABC-ring moiety of steroids

Article abstract of DOI:10.1016/j.tetlet.2014.04.018

Steroid family has various bioactivities and characteristic polycyclic structure. Although several synthetic methods have been reported, more efficient way is desired for medicinal chemistry. In this Letter, we synthesized pseudoenantiomers of tricyclic enones toward both enantiomers for ABC-ring moiety of steroids utilizing d-mannitol as a chiral source. The key steps are radical domino cyclization of polyalkenyl-β-keto ester into tricyclic keto ester and subsequent dealkoxycarbonylation.

Full text of DOI:10.1016/j.tetlet.2014.04.018

Tetrahedron Letters 55 (2014) 3189–3191
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Divergent synthesis of pseudoenantiomers for ABC-ring moiety
of steroids
⇑
Miyu Furuta, Kengo Hanaya, Takeshi Sugai, Mitsuru Shoji
Department of Pharmaceutical Science, Faculty of Pharmacy, Keio University, 1-5-30 Shibakoen, Minato-ku, Tokyo 105-8512, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Steroid family has various bioactivities and characteristic polycyclic structure. Although several synthetic
methods have been reported, more efficient way is desired for medicinal chemistry. In this Letter, we syn-
thesized pseudoenantiomers of tricyclic enones toward both enantiomers for ABC-ring moiety of steroids
Received 11 March 2014
Revised 2 April 2014
Accepted 7 April 2014
Available online 12 April 2014
utilizing
D-mannitol as a chiral source. The key steps are radical domino cyclization of polyalkenyl-b-keto
ester into tricyclic keto ester and subsequent dealkoxycarbonylation.
Ó 2014 Elsevier Ltd. All rights reserved.
Keywords:
Steroid
Domino reaction
Radical cyclization
Dealkoxycarbonylation
b-Keto ester
Steroids are widely distributed in nature and they have a wide
variety of bioactivities and unique polycyclic framework. They are
biosynthesized from prochiral squalene via enantioselective poly-
cyclization into cholesterol.1 Interestingly, not only natural type
of steroids but also their enantiomers have bioactivities. For
example, progesterone (1, Fig. 1) is an ovarian hormone whereas
unnatural progesterone ent-1 shows neuroprotective effect after
traumatic brain injury.2 Deoxycholic acid (2), an endogenous
secondary bile acid, and its enantiomer ent-2 decrease cell prolifer-
ation for several human colon cancer cell lines such as HT-29 and
HCT-116.3 Therefore, preparation of enantiomeric pair of steroids
is highly demanded and utilization of easily available chiral source
such as sugar is reliable and desirable.
Many synthetic chemists have been attracted to the synthesis of
characteristic polycyclic framework of steroids and terpenoids.
Corey and Lee accomplished elegant total synthesis of oleanolic
acid via Lewis acid-mediated biomimetic polycyclization of chiral
epoxypolyene.4 Zoretic et al. constructed trans-decalin skeleton
via radical cyclization of b-keto ester using Mn(OAc)3 and
Cu(OAc)2.5 Our group reported stereoselective preparation of
cis-decalin by modification of Zoretic’s polycyclization condition.6
MacMillan and Rendler achieved imidazolidinone-catalyzed
enantioselective radical polycyclization to produce steroidal
skeleton.7 Herein, we described the synthesis of pseudoenanitom-
ers for ABC-ring moiety of steroids via manganese(III) and
copper(II)-mediated radical polycyclization utilizing one chiral
center constructed from D-mannitol.
We envisaged that Mn(III)/Cu(II)-mediated radical domino
cyclization of b-keto ester 3 would produce tricyclic ketones 5a
and 5b via radical intermediate 4 (Scheme 1). Cyano group at C8
position would stabilize tertiary radical intermediate and
enhanced 6-endo/5-exo selectivity in the second cyclization. Keto
esters 5a and 5b would be converted into tricyclic enones 6a and
6b, respectively, via dealkoxycarbonylation and b-elimination of
hydrogen chloride.
Figure 1. Structures of progesterone (1), ent-1, deoxycholic acid (2), and ent-2.
⇑
Corresponding author. Tel./fax: +81 3 5400 2695.
E-mail address: shoji-mt@pha.keio.ac.jp (M. Shoji).
http://dx.doi.org/10.1016/j.tetlet.2014.04.018
0040-4039/Ó 2014 Elsevier Ltd. All rights reserved.

3190
M. Furuta et al. / Tetrahedron Letters 55 (2014) 3189–3191
Table 1
Domino cyclization toward tricyclic ketones 15a/b and 16a/b
Entry
Substrate
Solvent
Yield (%)
1
2
13
13
13
13
14
MeCN
MeOH
EtOH
EtOH
EtOH
15a (12), 15b (15)
15a (20), 15b (22)
15a (25), 15b (30)
15a (34), 15b (29)
16a (30), 16b (27)
Scheme 1. Synthesis plan of pseudoenantiomers 6a and 6b for ABC-ring moiety of
steroids.
3
4a
5a
a
Preparation of cyclization precursor 3 was started from stereo-
controlled alcohol 7 via homoallylation of (R)-cyclohexylidene
Performed at 40 °C for 3 h.
glyceraldehyde derived from D
-mannitol (Scheme 2).8 Protection
in acetic acid5 gave only incomplete monocyclic b-keto ester and
no further cyclization proceeded. Alteration of reaction solvent
from acetic acid to 1,4-dioxane did not provide tricyclic product
at all. On the other hand, cyclization in acetonitrile afforded the
desired tricyclic b-keto esters 15a and 15b in 12% and 15% yield,
respectively (entry 1). Alcoholic solvents such as methanol and
ethanol improved yields (entries 2 and 3). The best result was
obtained when the reaction was performed in ethanol at 40 °C to
furnish 15a and 15b in 34% and 29% yield, respectively (entry 4).
The combined yield of 63% over three cyclizations means 86% yield
per cyclization. The optimized reaction condition was adopted for
methyl ester 14 to make 16a and 16b in 30 and 27% yield, respec-
tively (entry 5). Tricyclic ketones 15a and 16a were produced more
than the other diastereomers at 40 °C (entries 1–3 vs 4 and 5). To
our delight, diastereomers 16a and 16b were separable on silica
gel column chromatography. Stereochemistry of 16a was deter-
mined by NOESY (Fig. 2) and that of 16b was elucidated after con-
version into enone 6b (Fig. 3, vide infra).
of alcohol 7 as benzyl ether followed by the removal of cyclohexy-
lidene acetal group produced diol 8. Oxidative cleavage of glycol 8
gave
Emmons reaction with potassium enolate of cyanophosphonate 95
afforded ,b-unsaturated nitrile 10 with high Z selectivity. Geom-
a-benzyloxy aldehyde and subsequent. Horner–Wadsworth–
a
etry of newly formed carbon–carbon double bond was determined
by NOE measurement between C7 and C9 protons.
Removal of tetrahydropyranyl (THP) group on triene 10 under
acidic condition provided allylic alcohol 11. Attempt at direct bro-
mination of alcohol 11 resulted in the formation of undesired sec-
ondary bromide via SN20 reaction along with the desired primary
bromide 12. Then, we performed two-step transformation of allylic
alcohol 11 into bromide 12. That is, treatment of alcohol 11 with
methanesulfonic anhydride and subsequent substitution with bro-
mide afforded primary allylic bromide 12 in high yield. Alkylation
of 12 with dianions derived from ethyl and methyl 2-chloroace-
toacetates furnished domino cyclization precursors 13 and 14,
respectively.
Since cyclization precursors were in hand, the key radical dom-
ino cyclization was investigated (Table 1). Unfortunately, Zoretic’s
cyclization condition using manganese(III) and copper(II) acetates
The final step was the conversion of
a-chloro-b-keto esters 15
and 16 into enones. Attempts of Krapcho dealkoxycarbonylation9
on ethyl esters 15a or 15b did not proceed at all because of steric
Scheme 2. Preparation of cyclization precursors 13 and 14.

M. Furuta et al. / Tetrahedron Letters 55 (2014) 3189–3191
3191
framework toward steroids could be constructed via functionaliza-
tion of the exo methylene and allylic position on alkenes 6a and 6b.
In conclusion, we synthesized pseudoenantiomers of tricyclic
enones toward both enantiomers for ABC-ring moiety of steroids.
The key steps are radical domino cyclization of polyalkenyl-b-keto
ester and subsequent formation of enone from
a-chloro-b-keto
ester via dealkoxycarbonylation followed by elimination of hydro-
gen chloride. Reductive removal of functional groups at C8 and C11
positions of 6a and 6b would afford enantiomeric pair for ABC-ring
moiety of progesterone and our method would exploit the utility
on antipode of natural steroids.
Figure 2. NOE correlations on tricyclic b-keto ester 16a.
Acknowledgments
This work was supported by Platform for Drug Discovery,
Informatics, and Structural Life Science from the Ministry of
Education, Culture, Sports, Science, and Technology, Japan. We also
thank Keio University Doctorate Student Grant-in-Aid Program
2012 (M.F.).
Supplementary data
Supplementary data (experimental section, full characterization
data, and 1H and 13C NMR spectra) associated with this article
can be found, in the online version, at http://dx.doi.org/10.1016/
j.tetlet.2014.04.018.
Figure 3. NOE correlations on tricyclic enone 6b.
References and notes
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Scheme 3. Synthesis of tricyclic enones 6a and 6b.