Enantioselective Synthesis of Silacyclopentanes

Article abstract of DOI:10.1002/anie.201511728

A variety of functionalized silacyclopentanes were synthesized by highly enantioselective β-eliminations of silacyclopentene oxides followed by stereospecific transformations. The reaction mechanism of the β-elimination was elucidated by DFT calculations. An in vitro biological assay with an oxy-functionalized silacyclopentane showed substantial binding to a serotonin receptor protein.

Full text of DOI:10.1002/anie.201511728

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International Edition: DOI: 10.1002/anie.201511728
German Edition: DOI: 10.1002/ange.201511728
Asymmetric Synthesis Very Important Paper
Enantioselective Synthesis of Silacyclopentanes
Kazunobu Igawa,* Daisuke Yoshihiro, Yusuke Abe, and Katsuhiko Tomooka*
In memory of Robert J. P. Corriu
Abstract: A variety of functionalized silacyclopentanes were
synthesized by highly enantioselective b-eliminations of sila-
cyclopentene oxides followed by stereospecific transforma-
tions. The reaction mechanism of the b-elimination was
elucidated by DFT calculations. An in vitro biological assay
with an oxy-functionalized silacyclopentane showed substan-
tial binding to a serotonin receptor protein.
afford silacyclopentenol 2 enantioselectively; silacyclopente-
nol 2 has a silacyclopentane skeleton and a synthetically
versatile allylic alcohol moiety (Scheme 1).
A large number of methods have been reported for the
enantioselective b-elimination of carbon congeners of 1.[10]
However, a similar reaction of silacyclopentene oxides has
only been reported by Kozmin and Liu, but the stereochem-
istry of the silicon center was not considered.[11,12]
F
unctionalized chiral cyclopentane A and its heterocyclic
congeners B are some of the most fundamental chiral motifs
and key components in biologically important natural prod-
ucts, such as sugars, steroids, prostaglandins, and alkaloids
(Figure 1).[1] To bring new perspectives to the chemistry of
chiral five-membered cyclic compounds, we envisaged the
synthesis of silacyclopentane C with a chiral silicon center.[2–7]
Scheme 1. Synthetic strategy towards functionalized silacyclopentanes.
First, we investigated the b-elimination of silacyclopen-
tene oxides syn-1a (R1 = Ph, R2 = tBu) and anti-1a (R1 = tBu,
R2 = Ph) as the model compounds with chiral lithium amide
bases.[13,14] The reaction of syn-1a with one of the most
classical chiral lithium amides, 3a (1.0 equiv),[15] as the chiral
base in toluene afforded a trace amount of the b-elimination
product 2a (Table 1, entry 1). The use of an excess amount of
3a (3.0 equiv) improved the reaction efficiency, affording
(SSi,S)-2a in 28% yield with moderate enantioselectivity
(66% ee; entry 2).[16,17] After several attempts, the reaction of
syn-1a in the presence of 3.0 equiv of N,N,N’,N’-tetramethyl-
ethylenediamine (TMEDA) afforded (SSi,S)-2a in quantita-
tive yield and with excellent enantioselectivity (92% ee;
entry 3). Furthermore, the use of the newly developed
diamine-derived chiral lithium amide 3b also afforded
(SSi,S)-2a in moderate yield and enantioselectivity (61%,
40% ee; entry 4). The enantioselectivity was slightly
improved to 55% ee by the addition of TMEDA (entry 5).
The addition of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU)
was also beneficial to the overall efficiency; in particular, the
use of 6.0 equiv DBU afforded 2a in 90% ee (entries 6 and
7).[18] Similar reactions with lithium amides 3c and 3d, which
had been utilized for the enantioselective b-elimination of
carbocyclic epoxides and silacyclopentene oxides by Asami
and Kozmin,[10,11] respectively, afforded 2a in moderate
enantioselectivity (38% ee for 3c, 53% ee for 3d; entries 8
and 9).[18] As described above, the reactions of syn-1a with
lithium amides 3a and 3b afforded (SSi,S)-2a in a highly
enantioselective manner when suitable additives were used
(entries 3 and 7); 3b, in particular, showed a diverse substrate
scope. For example, the reaction of anti-1a with 3b in the
Figure 1. Design of chiral silacyclopentanes. FG=functional group.
Chiral silacyclopentanes are not available in nature; they
would have unique chemical properties and bioactivities
owing to the embedded silicon atom being more electro-
positive and forming longer covalent bonds than the carbon
congener.[8,9] Herein, we have developed a practical method
for the asymmetric synthesis of highly functionalized silacy-
clopentanes and found that an oxy-functionalized silacyclo-
pentane displays significant bioactivity.
We envisioned that the stereoselective b-elimination of
achiral silacyclopentene oxide 1 with a chiral base would
[*] Dr. K. Igawa, Prof. Dr. K. Tomooka
Institute for Materials Chemistry and Engineering
Kyushu University
Kasuga, Fukuoka 816-8580 (Japan)
E-mail: kigawa@cm.kyushu-u.ac.jp
ktomooka@cm.kyushu-u.ac.jp
D. Yoshihiro, Y. Abe
Department of Molecular and Material Sciences
Kyushu University (Japan)
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under http://dx.doi.org/10.
1002/anie.201511728.
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Table 1: Enantioselective b-elimination of silacyclopentene oxide 1a.
substituted silacyclopentene oxides syn-1d and anti-1e
afforded (SSi,S)-2d and (RSi,S)-2e in 93% ee each.
The catalytic reaction was also efficient when PhLi was
used as an achiral base for the regeneration of 3b.[20,21] For
example, the reaction of syn-1a with 3b-H (5 mol%) and
PhLi (3.0 equiv) in the presence of DBU (6.0 equiv) afforded
(SSi,S)-2a in 93% yield with > 98% d.r. and 84% ee [Eq. (1)].
Entry
1a
3 (x)
Additive (y)
2a
Yield [%][a]
ee [%]
1
2
3
4
5
6
7
8
9
syn-1a
syn-1a
syn-1a
syn-1a
syn-1a
syn-1a
syn-1a
syn-1a
syn-1a
3a (1.0)
3a (3.0)
3a (3.0)
3b (3.0)
3b (3.0)
3b (3.0)
3b (3.0)
3c (3.0)
3d (3.0)
–
–
trace
28
99
61
70
–
66[b]
92[b]
40[b]
55[b]
88[b]
90[b]
38[c]
53[b]
TMEDA (3.0)
–
TMEDA (3.0)
DBU (3.0)
DBU (6.0)
DBU (6.0)
DBU (6.0)
51
quant.
quant.
94
10
11
anti-1a
anti-1a
3a (3.0)
3b (3.0)
TMEDA (3.0)
DBU (6.0)
trace
83
–
To evaluate the effect of the silicon center on the reaction,
we compared the reaction of silacyclopentene oxide 1 f with
that of its carbon congener 4 [Eq. (2)]. The reaction of 1 f at
room temperature for 1 h afforded 2 f in 84% yield (91% ee)
whereas a similar reaction of 4 for a longer reaction time (6 h)
afforded the corresponding b-elimination product 5 in only
10% yield and 88% ee. The observed difference in the
reaction rates can be attributed to the a-effect of silicon,
increasing the acidity of the a-proton,[22] and the longer
covalent bonds in the silicon congener, decreasing the steric
hindrance at the a-position of the silicon center.[23]
95[d]
[a] Yields of isolated products are given. [b] The major isomer is (SSi,S)-
2a. [c] The major isomer is (RSi,R)-2a. [d] The major isomer is (RSi,S)-2a.
presence of DBU afforded (RSi,S)-2a in 83% yield with
excellent enantioselectivity (95% ee; entry 11) whereas only
a trace amount of product was obtained when 3a was used in
combination with TMEDA (entry 10).[19]
As for syn- and anti-1a, b-elimination of silacyclopentene
oxides 1 with 3b afforded diverse silacyclopentenols 2 in
a highly enantioselective manner (Scheme 2). The diastereo-
mers of methyl-substituted silacyclopentene oxide 1b were
also quantitatively converted into (SSi,S)-2b and (RSi,S)-2b
with > 98% and 93% ee, respectively.[17] Despite the bulki-
ness of the substituents, a similar reaction of syn-1c pro-
ceeded smoothly, affording (SSi,S)-2c in quantitative yield and
with 87% ee. Furthermore, the reactions of the alkoxy-
To gain insight into the transition states, density functional
theory (DFT) calculations were performed for the reaction of
syn-1b (R1 = Ph, R2 = Me) and 3b with DBU at the B3LYP/6-
31G + (d,p) level of theory.[24,25] We surveyed eight transition-
state geometries considering the following three factors:
1) selection of an enantiotopic proton in the deprotonation
step, 2) orientation of DBU, and 3) conformation of the chiral
lithium amide 3b. The most stable transition-state geometry
for (SSi,S)-2b was thus determined to be TS1 (Figure 2).[26]
The calculated enantioselectivity at 08C based on the free
energy barriers of all eight transition-state geometries is 86%
ee for (SSi,S)-2b, which is in good agreement with the
experimental result.[27]
The obtained stereochemically defined silacyclopentenols
2 (> 98% d.r.) can be easily converted into diverse function-
alized silacyclopentane derivatives in a stereospecific manner.
After esterification with methyl chloroformate, the reaction
of (SSi,S)-2a with the enolate of dimethyl malonate in the
presence of a catalytic amount of Pd2(dba)3·CHCl3 (5 mol%)
and P(o-tolyl)3 (25 mol%) afforded Tsuji reaction product 6
in a stereospecific manner (61% over two steps, > 98% d.r.;
Scheme 2. Enantioselective b-elimination of silacyclopentene oxide 1.
Yields of isolated products are given. 3,5-Xy=3,5-dimethylphenyl.
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a vinyl ether using Wilkinsonꢀs catalyst followed by acidic
hydrolysis. Similar reactions of (RSi)-8a and (RSi)-8b also
afforded (RSi)-10a (> 98% d.r.) and (RSi)-10b (> 98% d.r.),
respectively. Nucleophilic substitution reactions of (SSi)-8a
with MgBr2·OEt2 and (SSi)-8b with NaN3 also proceeded
selectively at the C2 position, affording bromide 11 (quanti-
tatively) and azide 12 (53% yield), respectively, in a stereo-
specific manner.
Next, the biological activities of the novel silacyclopen-
tane derivatives were evaluated. Triol (SSi)-10a showed
significant binding to a serotonin receptor, 5-HT2B, as
determined by a binding inhibition assay (IC50: 6.4 mm;
Figure 3). In sharp contrast to (SSi)-10a, the silicon epimer
(RSi)-10a and methyl-substituted (RSi)-10b did not exhibit any
significant activity (IC50: > 100 mm). This large difference in
the biological activities of the silacyclopentanes highlights the
importance of the silicon chirality as a key structural feature
of bioactive molecules.[9]
Figure 2. The most stable transition state according to the DFT
calculations for the b-elimination of silacyclopentene oxide syn-1b with
3b and DBU. Hydrogen atoms are omitted for clarity, except for the
proton that is removed during deprotonation.
Scheme 3).[28] Cyclopropanation of (SSi,S)-2a with Et2Zn and
CH2I2 afforded 7 in 98% yield and with excellent stereose-
lectivity, probably because of chelation to the hydroxy
group.[29] In a similar manner, the epoxidation of 2 with
mCPBA also proceeded with excellent selectivity from the
side of the hydroxy group to afford epoxides 8. Furthermore,
the BF3-promoted alcoholysis of epoxide (SSi)-8a with an allyl
alcohol proceeded selectively at the C2 position,[30] affording
(SSi)-9a (R1 = Ph, R2 = tBu). This product can be converted
into triol (SSi)-10a by isomerization of the allyl ether moiety to
Figure 3. The binding inhibition activities of silacyclopentane triols 10
for the specific binding of 5-HT2B with the ligand. [a] IC50 value for the
specific binding of 5-HT2B with 1.20 nm [3H]-lysergic acid diethylamide
as the ligand.
In summary, diverse chiral silacyclopentanes have been
synthesized by enantioselective b-elimination reactions using
a newly developed chiral lithium amide followed by stereo-
specific transformations. A silacyclopentane triol showed
significant binding to the serotonin receptor 5-HT2B; the
binding affinity depended substantially on the stereochemis-
try of the silicon chiral center. Therefore, this study has
revealed these chiral silicon molecules as a new class of
bioactive molecules with a unique structural feature. Further
studies on the physical, metabolic, and spectroscopic proper-
ties of silacyclopentanes as well as the structure–activity
relationships of 5-HT2B binding are underway.
Acknowledgements
This research was supported by JSPS KAKENHI Grants
(24350048, 15K13697, 15J07532), and the MEXT Project of
Integrated Research on Chemical Synthesis. We thank T.
Nishi (IMCE, Kyushu University) for the HRMS measure-
ments.
Scheme 3. Transformations of silacyclopentenol 2. a,b) 61% over two
steps, >98% d.r. from (SSi,S)-2a. c) 98%, >98% d.r. from (SSi,S)-2a.
d) (SSi)-8a: 81%, >98% d.r. from (SSi,S)-2a; (RSi)-8a: 78%, >98% d.r.
from (RSi,S)-2a; (RSi)-8b: 81%, >98% d.r. from (SSi,S)-2b; (SSi)-8b:
95%, >98% d.r. from (RSi,S)-2b. e,f) (SSi)-10a: 61% over 2 steps,
>98% d.r. from (SSi)-8a; (RSi)-10a: 64% over 2 steps, >98% d.r. from
(RSi)-8a; (RSi)-10b: 51% over 2 steps, >98% d.r. from (RSi)-8b.
g) quant., >98% d.r. from (SSi)-8a. h) 53%, >98% d.r. from (SSi)-8b.
DABCO=1,4-diazabicyclo[2.2.2]octane, dba=dibenzylideneacetone.
Keywords: asymmetric synthesis · biological activity · chirality ·
elimination · silicon
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with an allyl Grignard reagent, 2) ring-closing metathesis with
Grubbsꢀ 1st generation catalyst, and 3) epoxidation with m-
CPBA, in an overall yield of 52–65%. The syn/anti diastereo-
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[16] All ee values were determined by HPLC analysis on a chiral
stationary phase unless otherwise noted. See the Supporting
Information for details.
[17] The absolute configurations of (SSi,S)-2a, (RSi,S)-2a, (SSi,S)-2b,
and (SSi,S)-2c were determined by X-ray crystallographic
analysis of crystalline derivatives. The absolute configurations
of (RSi,S)-2b, (SSi,S)-2d, and (RSi,S)-2e were assigned by analogy.
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For details of the X-ray crystallographic analysis, see the
Supporting Information.
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with a simplified model system; see: a) T. Yoshida, K. Sakaki-
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M. Asami, K. Sakakibara, J.-H. Lii, N. L. Allinger, Tetrahedron
2008, 64, 575 – 581.
[25] DFT calculations were performed with the Gaussian09 program
(RevisionC.01) on the TATARA system at Kyushu University.
For details, see the Supporting Information.
[18] Similar additive effects with DBU in enantioselective b-elimi-
nations of carbocyclic epoxides with diamine-type lithium
amides have been reported by the groups of Asami and
Andersson; see: a) M. Asami, H. Kirihara, Chem. Lett. 1987,
389 – 392; b) M. Asami, T. Ishizaki, S. Inoue, Tetrahedron:
Asymmetry 1994, 5, 793 – 796; c) M. J. Sçdergren, P. G. Ander-
sson, J. Am. Chem. Soc. 1998, 120, 10760 – 10761.
[19] The low reactivity of anti-1a is probably due to steric repulsion
between the lithium amide (e.g., 3a) and the bulky tBu group on
the silicon atom in syn configuration with the epoxide oxygen
atom, which suggests that the b-elimination of silacyclopentene
oxides should proceed in a syn fashion. In a related study,
Morgan and Gajewski reported that the b-elimination of
carbocyclic epoxides with lithium amides generally proceeds in
syn fashion; see: K. M. Morgan, J. J. Gajewski, J. Org. Chem.
1996, 61, 820 – 821.
[20] The groups of Asami and Andersson reported catalytic enantio-
selective b-eliminations of carbocyclic epoxides with 3c and 3d,
respectively; see Ref. [18b, c]; Kozmin and Liu reported cata-
lytic enantioselective b-eliminations of silacyclopentene oxides
with 3d; see Ref. [11].
[21] The use of other achiral bases (e.g., nBuLi, lithium diisopropyl-
amide, lithium tetramethylpiperidide) instead of PhLi led to side
reactions and/or a decrease in enantioselectivity, which are
probably due to concomitant nucleophilic addition to the silicon
center and b-elimination mediated by the achiral base, respec-
tively.
[26] The calculated transition states feature a coordinatively satu-
rated lithium cation in a tetrahedral coordination arrangement.
A similar tetrahedral structure was reported for monomeric
complexes of alkyllithium reagents; see: J. O. Bauer, C. Stroh-
mann, Angew. Chem. Int. Ed. 2014, 53, 8167 – 8171; Angew.
Chem. 2014, 126, 8306 – 8310.
[27] The theoretical enantioselectivity was evaluated on the basis of
the gas-phase free energies of the calculated eight transition
geometries; see: T. Lu, R. Zhu, Y. An, S. E. Wheeler, J. Am.
Chem. Soc. 2012, 134, 3095 – 3102. For details, see the Supporting
Information.
[28] The similar Tsuji reaction of (SSi,S)-2a with PPh3 instead of
P(o-tolyl)3 afforded 6 as a diastereomeric mixture.
[29] W. G. Dauben, G. H. Berezin, J. Am. Chem. Soc. 1963, 85, 468 –
472.
[30] Highly regioselective nucleophilic substitution at the a-silicon
position has been generally observed with a-epoxysilanes; see:
a) J. J. Eisch, J. T. Trainor, J. Org. Chem. 1963, 28, 2870 – 2876;
b) G. Manuel, R. Boukherroub, J. Organomet. Chem. 1993, 447,
167 – 175; see also Ref. [11].
[22] a) S. Zhang, X.-M. Zhang, F. G. Bordwell, J. Am. Chem. Soc.
1995, 117, 602 – 606; b) C. Eaborn, R. Eidenschink, P. M.
Jackson, D. R. M. Walton, J. Organomet. Chem. 1975, 101,
C40 – C42.
[23] W. S. Sheldrick in The Chemistry of Organic Silicon Compounds,
Vol. 1 (Eds.: S. Patai, Z. Rappoport), Wiley, Chichester, 1989,
chap. 3, pp. 245 – 249.
Received: December 18, 2015
Published online: April 1, 2016
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