Stereoselective synthesis of α-methyl and α-alkyl ketones from esters and alkenes: Via cyclopropanol intermediates

Article abstract of DOI:10.1039/c8cc00888d

Alkenes bearing a stereocenter in the allylic position were found to undergo Kulinkovich hydroxycyclopropanation with good diastereoselectivity. For the isomerization of the resulting cyclopropanols to diastereomerically enriched α-methyl ketones, a new mild regioselective method has been developed. A sequence of stereoselective cyclopropanation and cyclopropanol ring opening was successfully employed for the construction of the C20 stereocenter in steroids.

Full text of DOI:10.1039/c8cc00888d

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2018, DOI: 10.1039/C8CC00888D.
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Stereoselective synthesis of α-methyl and α-alkyl ketones from
esters and alkenes via cyclopropanol intermediates
Maryia V. Barysevich,a Volha V. Kazlova,a Aliaksandr G. Kukel,a Aliaksandra I. Liubina, a
Alaksiej L. Hurski,*a Vladimir N. Zhabinskii a and Vladimir A. Khripach a
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
Alkenes bearing a stereocenter in allylic position were found to with alkylmagnesium halides. However, intermolecular
undergo Kulinkovich hydroxycyclopropanation with good stereoselective hydroxycyclopropanation of alkenes with
diastereoselectivity. For the isomerization of the resulting esters is less developed and limited to a substrate-controlled
cyclopropanols to diastereomerically enriched α-methyl ketones, reaction of secondary homoallylic alcohols reported by Cha.9
a
new mild regioselective method has been developed. A
sequence of stereoselective cyclopropanation and cyclopropanol
ring opening was successfully employed for the construction of
the C20 stereocenter in steroids.
Chiral α-methyl substituted ketone units are widely abundant
in natural products and numerous methods have been
developed for their asymmetric synthesis (Scheme 1). The
most common approaches are based on auxiliary- or catalyst-
controlled reactions of enolates (pathway a).1 An alternative
disconnection strategy was utilized in the synthesis of the unit
via reductive acyl cross-coupling,2 carbonylative cross-
Scheme 1. Strategies toward stereoselective synthesis of α-
methyl ketones.
coupling3
(pathway
b)
and
through
Kulinkovich
cyclopropanation4 followed by the cyclopropanol ring opening
(pathway c).5 The latter approach remains underdeveloped but
its implementation in synthesis would allow to trace the chiral
α-methylketones back to esters and terminal olefins, which are
stable and readily accessible starting materials. Coupling of
functionalized esters with alkenes into advanced
cyclopropanol intermediates has been successfully used in the
synthesis of natural compounds4b,6 but in all these reports the
three-carbon rings were further transformed to achiral or
racemic fragments. For successful employment of the
cyclopropanation strategy in the synthesis of chiral α-
methylketones, both efficient asymmetric modification of
Kulinkovich reaction and a reliable procedure for the ring
opening of stereoisomerically enriched cyclopropanols are
required.
Scheme 2. Asymmetric Kulinkovich cyclopropanation and
isomerization of cyclopropanols to α-methyl ketones
Numerous regioselective methods for opening the ring in 1,2-
disubstituted cyclopropanols have been discovered.4b,5
Reactions with bases or electrophiles usually lead to the
cleavage of C1-C3 bond, while reactions proceeding via radical
mechanism result in breaking of the C1-C2 bond.5 However,
preparation of chiral α-methyl ketones from cyclopropanols is
still a challenging task. The isomerization may proceed with
low regioselectivity5a,8a and the α-stereocenter in ketones is
To date, significant progress has been achieved in the
development
of
the
asymmetric
Kulinkovich
hydroxycyclopropanation (Scheme 2). Twenty years after the
first report on enantioselective synthesis of 1(S)-methyl-2(R)-
phenylcyclopropanol in 1994 by Corey,7 Kulinkovich8 disclosed
a general catalyst-controlled protocol for the reaction of esters
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prone to racemization. Only organozinc reagents10 and tartaric complex 6c
Journal Name
/
6d in which repulsive interactions between the
acid on alumina8a have been reported to promote this substrate and titanium ligands are minimized in contrast to
transformation but the scope of these methods is narrow. the disfavored complex 6b 6a. In addition, insertion of ester
In this communication, we report a new group of alkenes that carbonyl group into C-Ti bond of titanacyclopropane 6d to
undergoes Kulinkovich hydroxycyclopropanation with good form might proceed faster than the insertion into 6a because
diastereoselectivity and a new mild method for regioselective of steric considerations.
/
7
isomerization of chiral cyclopropanols to α-methyl ketones.
We started the investigation with the preparation of
stereoisomerically enriched cyclopropanols. Our efforts were
directed toward their synthesis from alkenes, which are more
readily available and stable than Grignard reagents. We
speculated that alkenes bearing a stereocenter adjacent to
Table 1. Scope for the diastereoselective synthesis of
cyclopropanols 5 a
.
double
diastereoselectively.11 To test this assumption, substrate
reacted with ethyl acetate and 2:1 mixture of
diastereomeric cyclopropanols (±)- was obtained (Scheme 3).
With this promising result, we further examined the substrate
4a (Table 1) in which the steric volumes of allylic substituents
bond
might
be
hydroxycyclopropanated
OH
OH
1
was
OTBS
(
2
)
3
a
H
H
O
OH
Ph
O
O
O
(±)-5c, 42%,d dr 87:13c
(±)-5a, 76%, dr 86:14b
(±)-5b, 77%, dr 94:6c
differ stronger than those in alkene
cyclopropanol 5a was obtained in a 76% yield and with a good
1. The resulting
OH
OH
6:1 diastereoselectivity.12, 13
H
TBSO
TBSO
OH
OTBS
H
H
S
S
(±)-5d, 86%, dr 90:10c
5f, 53%, dr 91:9c
(±)-5e, 67%, trans:cis 6:1c
dr 100:0c (for trans-isomer)
OH
OH
20
20
H
H
Scheme 3. Diastereoselective Kulinkovich reaction of alkene
with ethyl acetate ( ).
1
H
H
OTBS
2
H
H
H
H
TBSO
TBSO
Next, we explored the scope of the diastereoselective
cyclopropanation and the results are summarized in Table 1.
The reactions were carried out in THF for substrates with
dioxolane and dithiolane groups or in ether for other
substrates. Hydroxycyclopropanation of all tested alkenes
proceeded at the same diastereotopic face of the double bond
and in most cases cis-1,2-dialkylcyclopropanols were formed.
Cyclopropanols (±)-5b, (±)-5d-e and 5f-j were obtained with up
to 94:6 diastereoselectivity and in good yields. Only alkene 4c
was significantly less reactive. A satisfactory 42% yield of (±)-5c
was achieved using an excess of ester, catalyst and Grignard
reagent. Surprisingly, cyclopropanol (±)-5e was formed
5g, 68%, dr 94:6c
5h, 59%, dr 94:6b
OH
OH
dr 87:13e (C24)
20
20
24
H
H
H
H
H
H
H
H
H
H
H
H
TBSO
TBSO
5j, 59%, dr 92:8b
5i, 58% dr n.d. (C20)
H
OTBS
preferentially as
a trans-1,2-dialkyl isomer. High trans-
selectivity is typical for the hydroxycyclopropanation of
homoallylic alcohols because of the coordination of catalyst
with a hydroxyl group.9 It is likely that silyloxy group in 4e
assists formation of trans-(±)-5e through the coordination with
the titanium center. Then our attention was turned to easily
available bi- and tetracyclic substrates 4f and 4g14 since their
diastereoselective hydroxycyclopropanation could be used in
synthesis of steroids. To our delight, 4f and 4g underwent
smooth reaction with appropriate ester partners to furnish
cyclopropanols 5f-i. Diastereomeric purity at the created C20
stereocenter in the obtained steroidal cyclopropanols was
aReaction conditions: alkene (1 equiv.), ester (2 equiv. of EtOAc, 1 equiv. of
other esters), Ti(OiPr)4 (1 equiv.), cyclopentylmagnesium chloride (4 equiv.),
THF (0.05 M, synthesis of (±)-5b-c
,
5f) or ether (0.05 M, synthesis of (±)-5a
,
(±)-5d-e, 5g-j) at 0 °C ((±)-5a, (±)-5d-e
,
5g-h, 5i) or at rt ((±)-5b-c, 5f
,
5i). bdr of
α-methylketones obtained by isomerization of crude cyclopropanols.
cDetermined from 1H NMR spectra of crude cyclopropanol. d4 equiv. of
EtOAc, 2 equiv. of Ti(OiPr)4 and 8 equiv. of cyclopentylMgCl were used. eer of
the ester precursor.
With the synthesized cyclopropanols in our hands, we started
investigations toward the development of the procedure for
their isomerization to α-methyl ketones. Disappointingly, both
of known approaches failed to provide smooth ring opening of
cyclopropanol 5g. Treatment of the latter compound with
EtZnCH2I10 led to a complex mixture while the reaction with
tartaric acid on alumina8a proceeded with unsatisfactory
regioselectivity and was accompanied by desilylation. After
experimentation with salts and oxides (for details, see SI), we
good including the product 5i 15
Coupling of the steroidal
.
alkene 4g with similar in size ester also proceeded successfully
providing cyclopropanol 5j without a significant drop in yield
or stereoselectivity.
The observed diastereoselectivity may be explained by the
preferential formation of the intermediate Ti(II)-alkene
2 | J. Name., 2012, 00, 1-3
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found that the transformation of 5g to α-methyl ketone 8g steroidal side chains with the natural configuration at C20.16
proceeds smoothly in the presence of the excess of Compounds 8f-i belonging to cholestane, 25-
magnesium methylate at 40 °C within 45 min. The best results hydroxycholestane or campestane series were synthesized
were obtained in hexane, although other solvents could be from alkenes 4f or 4g and readily available appropriate esters
used as well (for details, see SI). Only very little epimerization (see SI). To confirm the configuration at C20, ketone 8ia was
was observed under the reaction conditions (see Table 2). transformed to the known phytosterol 6-deoxocathasterone
Cyclopropanols
desired ketones
5
were successfully isomerized providing the
(
9
),17 an intermediate in the biosynthesis of plant growth
in good yields with excellent regioselectivity hormone brassinolide (Scheme 4).18 Spectra of
9 were identical
8
and high diastereomeric purity. The only exception was to those reported in the literature.19
cyclopropanol 5i. Its isomerization proceeded more slowly (3
h) and less regioselectively affording a 4:1 mixture of 8ia and
its isomer 8ib
. This mixture was chromatographically
inseparable but its recrystallization from methanol provided
the pure α-methyl ketone 8ia. Low regioselectivity in the
isomerization of 5i could be explained by increased steric
hindrance around its cyclopropanol unit. Presence of the
methyl branch at C24 may disfavour the proper coordination
of Mg(OMe)2 with the hydroxyl group.
Scheme 4. Synthesis of 6-deoxocathasterone (9).
After successful application of cyclopropanols 5f-j in the
synthesis of steroids with natural side chains, we assumed that
their metal-catalyzed cross-coupling reactions5b,20 could be
suitable for construction of homoallyl-, propargyl- or benzyl-
substituted at C20 steroids. Replacement of the natural methyl
group at C20 with bulkier substituents was successfully applied
to decrease undesired side effects of vitamin D derivatives
possessing anti-cancer activity.21 Ring opening of 5g with Et2Zn
followed by allylation22 or alkynylation23 of the intermediate
homoenolate 10 led to steroids 11 and 12 bearing the
modified at C20 side chains. Palladium-catalyzed arylation24 of
5g also proceeded smoothly furnishing arylated steroid 13
Table 2. Scope for the Mg(OMe)2-mediated isomerization of
to α-methyl ketones 8 a
cyclopropanols 5 .
(Scheme 5).
Scheme 5. Synthesis of the 21-substituted steroids 11-13
.
In conclusion, we have developed a convenient protocol for
the transformation of stereoisomerically enriched
cyclopropanols to α-methyl ketones. We have also established
that alkenes bearing a stereocenter at the allylic carbon
undergo Kulinkovich hydroxycyclopropanation with a good
level of diastereoselectivity. The developed transformation has
been applied for the attachment of side chains to the steroidal
nucleus. In addition, a synthesized steroidal cyclopropanol was
successfully tested in the ring opening cross-coupling reactions
providing corresponding α-alkyl ketones.
aReaction conditions: Mg(OMe)2 (10 fold w/w excess), hexane (5% w/w
solution of ), 40 °C, 45 min; diastereomeric ketones are inseparable by
column chromatography, dr of the products was determined from 1H NMR
spectra of crude
bdr of the starting cyclopropanols cReaction time: 3 h.
5
8.
5.
dAfter recrystallization from MeOH, pure 8ia was obtained.
We thank Belarusian Foundation for Fundamental Research
(project X17PM-039) and Russian Science Foundation (№ 16-
16-04057, preparation of steroids 8g-i) for the financial
support. We thank Dr. A. Baranovsky for assistance with NMR
The investigated sequence of diastereoselective Kulinkovich
hydroxycyclopropanation of alkene 4g and isomerization of the
resulting cyclopropanols offers a novel way for the synthesis of
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Complete preparative separation of the major isomers was
performed only for the products (±)-5b-c. dr of
cyclopropanols (±)-5b-e, 5f,g was determined from 1H NMR
spectra but for cyclopropanols (±)-5a, 5h,j, direct
determination of dr was not possible. To evaluate their
diastereomeric purity, crude cyclopropanols were
transformed to α-methyl ketones (±)-8a, 8h,j. Their dr were
easily obtained from 1H NMR spectra (see SI).
spectroscopy, Dr. A. Yantsevich, M. Trawkina and Dr. Y.
Kozyrkov for HRMS analysis, T. Shkel for MALDI MS analysis,
Dr. V. Gromak for IR spectra.
Conflicts of interest
There are no conflicts to declare.
13 Relative configuration of the synthesized cyclopropanols was
determined after their transformation to α-methyl ketones
by considering coupling constants and 2D NOESY NMR
spectra or by transformation to known compounds (see SI).
14 For the synthesis of 4g from commercial pregnenolone
acetate, see: R. D. Dawe, J. L. C. Wright, Can. J. Chem., 1987,
65, 666-669.
15 dr of 5i was not determined precisely as the analysis was
complicated by the presence of the additional impure C24
stereocenter.
16 Attachment of side chains to steroidal cores is a laborious
task. For a review see: B. B. Shingate, B. G. Hazra, Chem.
Rev., 2014, 114, 6349-6382.
17 C. Yong-Hwa, S. Fujioka, T. Nomura, A. Harada, T. Yokota, S.
Takatsuto, A. Sakurai, Phytochemistry, 1997, 44, 609-613.
18 V. A. Khripach, V. N. Zhabinskii, A. E. de Groot,
Brassinosteroids: A New Class of Plant Hormones, Academic
Press, San Diego, 1999.
19 (a) S. Takatsuto, H. Kuriyama, T. Noguchi, H. Suganuma, S.
Fujioka, A. Sakurai, J. Chem. Res., Synop., 1997, 418-419; (b)
A. L. Hurski, V. N. Zhabinskii, V. A. Khripach, Steroids, 2012,
77, 780-790.
20 (a) D. Rosa, A. Nikolaev, N. Nithiy, A. Orellana, Synlett, 2015,
26, 441-448; (b) G. Fumagalli, S. Stanton, J. F. Bower, Chem.
Rev., 2017, 117, 9404-9432.
21 P. Gonzalo, L. R. Marcos, P.-G. Xenxo, G. Zoila, P. Manuel,
Curr. Top. Med. Chem., 2014, 14, 2388-2397.
22 P. P. Das, K. Belmore, J. K. Cha, Angew. Chem. Int. Ed., 2012,
51, 9517-9520.
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For reviews on reactions of cyclopropanols, see: (a) O. G.
Kulinkovich, Chem. Rev., 2003, 103, 2597-2632; (b) A.
Nikolaev, A. Orellana, Synthesis, 2016, 48, 1741-1768; for
recent examples on ring opening of 1,2-disubstituted
cyclopropanols, see: (c) H. Zhao, X. Fan, J. Yu, C. Zhu, J. Am.
Chem. Soc., 2015, 137, 3490-3493; (d) C. Zhu, X. Fan, H. Zhao,
4
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Tumma, E. Gyanchander, J. K. Cha, J. Org. Chem., 2017, 82
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Kaabel, I. Järving, M. Lopp, D. G. Kananovich, Org. Biomol.
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6
For review, see: (a) I. Haym, M. A. Brimble, Org. Biomol.
Chem., 2012, 10, 7649-7665; for application of the
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for convergent coupling of functionalized subunits, see: (b) K.
A. Keaton, A. J. Phillips, Org. Lett., 2007, 9, 2717-2719; (c) K.
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7
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10 P. P. Das, B. B. Parida, J. K. Cha, Arkivoc, 2012, 74-84.
11 Hydroxycyclopropanation of alkenes bearing a methyl
branch at the allylic carbon has been reported previously but
diastereoselectivity of the reaction was not noted: (a) S.-G.
Li, Y. Wu, Chem. Asian J., 2013, 8, 2792-2800; (b) W.-B. Han,
S.-G. Li, X.-W. Lu, Y. Wu, Eur. J. Org. Chem. 2014, 2014, 3841-
3846. See also Ref.6c,f
12 Diastereomeric cyclopropanols
5 have very close Rf values
and for most of the products only partial separation of
isomers is possible by column chromatography on silica gel.
4 | J. Name., 2012, 00, 1-3
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Diastereoselective Kulinkovich hydroxycyclopropanation of alkenes with esters and a protocol for isomerization of
chiral cyclopropanols to α-methyl ketones have been developed.