A diastereomerically enriched, dimeric organolithium compound and the stereochemical course of its transformations

Article abstract of DOI:10.1039/c1cc15872d

A dimeric α-silylated ethyllithium compound is presented featuring stereogenic metalated carbon centres with defined configurations. It can be generated by diastereoselective deprotonation of the corresponding ethylsilane. Reaction with Me₃SnCl proceeds under inversion and the transfer of the stereoinformation is possible with dr's of up to 97:3. The Royal Society of Chemistry 2012.

Full text of DOI:10.1039/c1cc15872d

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A diastereomerically enriched, dimeric organolithium compound
and the stereochemical course of its transformations
The diastereoselective α-lithiation of a chirally functionalised
ethylsilane is reported which furthermore reveals the lithiated
product to possess a novel dimeric structure with defined
configurations at the two metalated carbon centres. Quenching
of the dimeric species with Me3SnCl proceeds under inversion
with a d.r. of up to 97:3.
See Carsten Strohmann et al.,
Chem. Commun., 2012, 48, 2492.
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COMMUNICATION
A diastereomerically enriched, dimeric organolithium compound and the
stereochemical course of its transformationsw
Christian Unkelbach, Bors C. Abele, Klaus Lehmen, Daniel Schildbach, Benedikt Waerder,
Kerstin Wild and Carsten Strohmann*
Received 21st September 2011, Accepted 4th November 2011
DOI: 10.1039/c1cc15872d
A dimeric a-silylated ethyllithium compound is presented featuring
stereogenic metalated carbon centres with defined configurations.
It can be generated by diastereoselective deprotonation of the
corresponding ethylsilane. Reaction with Me3SnCl proceeds under
inversion and the transfer of the stereoinformation is possible with
dr’s of up to 97 : 3.
Highly stereomerically enriched organolithium compounds
are versatile and sought-after synthetic intermediates in stereo-
selective syntheses.1 A silicon centre next to the metalated
carbon centre plays an important role in stabilizing its configu-
ration and can serve as a synthetic break point in the later
Scheme 1 Synthesis of optically active ethylsilane (S)-5.
steps of a synthetic protocol.2 In the past, a-silylated highly
diastereomerically enriched organolithiums have been reported
which have been successfully employed in the transfer of the
chiral information on the metalated carbon centre in further
transformations.3 The synthetic potential of silicon-substituted
organolithium reagents so far has been limited to diastereo-
selective deprotonation reactions of silanes which bear a second
stabilizing group besides the silicon centre next to the methylene
group undergoing metalation, i.e. allyl-, benzyl- or trimethylsilyl-
methyl silanes.4 However, alkylsilanes other than methylsilanes
have not been successfully subjected to metalation attempts in the
past. Thus, our initial investigations concerned the question
whether an ethylsilane as the most basic example for an
alkylsilane with a longer side-chain could be readily metalated
next to the silicon centre.
Scheme 2 Deprotonation of (S)-5 with tert-butyllithium.
which are exclusively monomeric,5 (R,S)-6 forms a dimeric
aggregate in the solid state (Fig. 1).
(R,S)-6 crystallises from pentane/toluene in the monoclinic
crystal system, space group C2. The asymmetric unit contains
one molecule which then forms the C2-symmetric dimer [(R,S)-6]2.
Each lithium centre shows contacts to both metalated carbon
centres as well as to the nitrogen and oxygen donors of their
respective SMP moiety. The central structural motif of the dimer
is a four-membered C–Li ring formed by the two metalated
carbon and the two lithium atoms. This ring exhibits a slight kink
which is reflected by an angle of 10.21 between the C1–Li–C10
and the C1–Li0–C10 planes’ normals. Despite nominally
possessing five contacts each, the configuration at the metalated
carbon centres can be unambiguously assigned as R since the
angle between each carbon and the two lithium centres is only
65.71.6 The metalated carbon centres of each moiety are distinctly
pyramidalised with a sum of the angles around each carbanionic
unit (consisting of C1, C2, H1 and Si) of 330.41. This grade
of pyramidalization is remarkably close to a tetrahedral environ-
ment and considerably more eminent than in monomeric silyl-
substituted organolithiums or in comparable, centrosymmetric
dimeric a-silylated secondary alkyllithiums.4,7
Starting compound (S)-5 was obtained in a four-step synthesis
using standard procedures in an overall yield of 32% (Scheme 1).
Using tert-butyllithium as the base, the lithiation of (S)-5
can be conducted at low temperatures in pentane yielding
a-lithiated product 6 after a reaction time of 1 h (Scheme 2).
In addition, the resulting lithiated species can be successfully
crystallised from pentane/toluene. In contrast to previously pub-
lished structures of silyl-substituted optically active alkyllithiums
Anorganische Chemie, Technische Universitat Dortmund,
¨
Otto-Hahn-Straße 6, D-44227 Dortmund, Germany.
E-mail: mail@carsten-strohmann.de; Fax: +49 231 755 7062;
Tel: +49 231 755 3807
w Electronic supplementary information (ESI) available: Experi-
mental, computational and crystallographical data. CCDC [836557
and 836558]. For ESI and crystallographic data in CIF or other
electronic format see DOI: 10.1039/c1cc15872d
c
2492 Chem. Commun., 2012, 48, 2492–2494
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Table 1 Influence of the temperature on the stereoselectivity of the
lithiation/Me3SnCl quenching sequence of (S)-5 to obtain (S,S)-7
Entry Solvent
Tlithiation/1C Tmaxa/1C Tquenching/1C dr
1
2
3
4
5
6
7
8
Pentane
Pentane
Pentane
THF
ꢀ110
ꢀ78
ꢀ40
ꢀ78
ꢀ90
ꢀ40
ꢀ40
ꢀ78
ꢀ78
ꢀ40
ꢀ40
20
ꢀ78
ꢀ78
ꢀ78
ꢀ78
ꢀ78
ꢀ78
ꢀ78
ꢀ78
86 : 14
73 : 27
66 : 34
b
—
Pentane
Pentane
Pentane/THFc
86 : 14
66 : 34
91 : 9
20
ꢀ20
Pentane/TMEDAc ꢀ40
ꢀ20
97 : 3
a
Highest temperature to which the reaction mixture was allowed to
b
c
warm prior to quenching. No lithiation of (S)-5 detected. THF and
TMEDA added at ꢀ20 1C.
Fig. 1 Molecular structure and numbering scheme of [(R,S)-6]2
(some hydrogen atoms omitted for clarity).6 Selected bond lengths
(A) and angles (1): Si–C1 1.827(2), Li–C1 2.281(3), Li–C10 2.305(4),
Li–Li0 2.488(6), Li–C1–Li0 65.7(1), C1–Li–C10 113.6(1), C2–C1–Si
113.0(2), H1–C1–C2 114.0(1), H1–C1–Si 118.7(3).
and are sterically shielded by the organic hull—the lithiated
stereogenic carbon centres are tetrahedral rather than planar.
The a-deprotonation of (S)-5 was also investigated using
theoretical methods: computations conducted using the M052X
method9 and 6-31+G(d) basis set reveal a barrier of 63 kJ molꢀ1
for the abstraction of the pro-R a-proton by tert-butyllithium
corresponding to a slow, controlled deprotonation at low
temperatures as demonstrated in the experiment. In comparison,
the abstraction of the pro-S proton is 67 kJ molꢀ1. The small
difference of 4 kJ molꢀ1 between the two diastereo-differentiating
transition states reflects the tendency of the stereoselectivity
under kinetic conditions (86 : 14) which disallow for an epimeri-
zation of the configuration at the metalated carbon centre.
Consecutively, we found that the dr observed in the experiment
was governed by the initial temperature at which the deprotona-
tion was performed (Table 1, entries 1–3).
Quenching of (R,S)-6 was performed using Me3SnCl
at ꢀ78 1C to ensure an immediate and stereoselective reaction
under mild conditions. Respective stannylated compound (S,S)-7
was afforded in 91% yield and a dr of 86 : 14 (determined via
1H NMR). The absolute configuration of the major stereoisomer
which is formed could be determined after quaternization of the
SMP nitrogen centre with iodomethane and crystallization of the
resulting ammonium iodide species (R,S,S)-8 (Scheme 3).
It was observed that the major stereoisomer obtained in the
experiment exhibits (S)-configuration at the stannylated carbon
centre. This corresponds to a reaction of the lithiated species
with the chlorostannane under inversion of the configuration at
the metalated carbon centre. This stereochemical reaction
course is known e.g. for benzyl- or allyllithium species with a
planarized ‘‘carbanionic’’ centre without free coordination sites
at the lithium.1,3,8 While the latter is also fulfilled in the dimeric
species [(R,S)-6]2—both lithium centres exhibit four contacts
Warming the reaction mixture to 20 1C for at least 1 h prior
to quenching with Me3SnCl at ꢀ78 1C had no effect on the dr
(cf. Table 1, entries 5 and 6). This indicates a remarkable
stability of the configuration at the metalated carbon centers
of [(R,S)-6]2 in the absence of epimerization processes even at
room temperature. However, once a coordinating component
like TMEDA or THF is added to a reaction mixture containing
[(R,S)-6]2 and the mixture allowed to warm to ꢀ20 1C, an
alteration of the resultant dr of up to 97 : 3 ensued (Table 1,
entries 8 and 9). This indicates the occurrence of an epimeriza-
tion with a further enrichment of the diastereoisomer which is
obtained preferentially under kinetic reaction conditions. It can
be assumed that an intermediary cleavage of [(R,S)-6]2 and the
other possible diastereomeric dimers to monomeric THF or
TMEDA solvates takes place which decreases the barrier for an
interconversion of the diastereomers into each other so that the
epimerization towards the most stable dimeric species, [(R,S)-6]2,
can proceed at ꢀ20 1C, resulting in a further enrichment of
[(R,S)-6]2 and improved dr’s in the quenching experiment. It
should be noted that even from reaction mixtures containing
both [(R,S)-6]2 and stoichiometric amounts of THF or TMEDA,
only the former, dimeric species could be isolated rather than
solvates or other hetero- or homochiral dimers.10 As such, we
assume that it is the dimeric species which is responsible for the
observed stereoselectivity with Me3SnCl even in the presence of
coordinating additives. The HOMO of the dimeric species [(R,S)-6]2
was computed to examine the possibility of an electrophilic
attack under inversion as proposed after the experimentally
determined stereoselectivities of the quenching reactions
Scheme 3 (left) Lithiation/quenching sequence towards (S,S)-7 and
subsequent quaternization of SMP nitrogen with iodomethane. (right)
Molecular structure and numbering scheme of (R,S,S)-8 exhibiting
(R)-configuration at the quaternary nitrogen and (S)-configuration at
the metalated carbon centre.
c
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Fig. 2 M052X/6-31G(d)-optimised structure of [(R,S)-6]2 (some hydrogen atoms omitted for clarity). (left) Conolly surface (probe radius 1.4 A)
mapped with electrostatic potential. (middle) Visualization of the HOMO of [(R,S)-6]2 (Molekel representation;10 surface cut-off = 0.065). (right)
Transition state of the substitution reaction of simplified11 [(R,S)-6]2 with Me3SnCl.
(Fig. 2). It was found that, despite the considerable pyramid-
Notes and references
alization of the carbanionic centres, the orbital coefficients
1 D. Hoppe and T. Hense, Angew. Chem., Int. Ed. Engl., 1997,
36, 2282.
located at their backside are still significant and comparable in
size to those coefficients located in the central C–Li four-
membered ring, thereby making the backside attack of the
carbanionic centre of [(R,S)-6]2 to an electrophile like Me3SnCl
feasible. This is also reflected in the electrostatic potential map
of the compound which shows a considerable negative potential
at the backside of the carbanionic centres and furthermore
supported by the computation of the transition state for the
2 K. Itami, T. Kamei, K. Mitsudo, T. Nokami and J. Yoshida,
J. Org. Chem., 2001, 66, 3970; T. H. Chan and D. Wang,
Tetrahedron Lett., 1989, 30, 3041.
3 T. H. Chan and P. Pellon, J. Am. Chem. Soc., 1989, 111, 8738;
S. Lamothe, K. L. Cook and T. H. Chan, Can. J. Chem., 1992,
70, 1733.
4 T. H. Chan and K. T. Nwe, J. Org. Chem., 1992, 23, 6107;
R. C. Hartley, S. Lamothe and T. H. Chan, Tetrahedron Lett.,
1992, 34, 1449; C. Strohmann, D. H. M. Buchold, T. Seibel,
K. Wild and D. Schildbach, Eur. J. Inorg. Chem., 2003, 3453;
C. Strohmann, B. C. Abele, K. Lehmen and D. Schildbach, Angew.
11
substitution reaction of [(R,S)-6]2 with Me3SnCl. With an
activation energy of merely 15 kJ molꢀ1, the reaction of the
aggregate with the electrophile can readily and selectively
proceed even at low temperatures.
Chem., Int. Ed., 2005, 44, 3136; H. Ott, C. Daschlein, D. Leusser,
¨
D. Schildbach, T. Seibel, D. Stalke and C. Strohmann, J. Am.
Chem. Soc., 2008, 130, 11901.
In summary, we herein present the optically active ethylsilane
(S)-5 which undergoes stereoselective a-deprotonation in pentane
with tert-butyllithium at low temperatures. The product persists
as a dimeric species which proved to be configurationally stable
in apolar solvents at room temperature for at least 1 h. Stereo-
isomer [(R,S)-6]2 is preferentially obtained under kinetic condi-
tions and can be further enriched by epimerization in the presence
of coordinating additives. It exhibits well-defined configurations
at the stereogenic metalated carbon centres and both experiments
and calculations support the preference of the formation of this
stereoisomer. Furthermore, the reaction of [(R,S)-6]2 with
trimethyltin chloride proceeds under inversion of the configu-
ration at the metalated carbon centres and with good diastereo-
selectivities. The stereochemical outcome of the reaction could
be elucidated and rationalised by a combination of crystal-
lographic and computational means.
5 ‘‘Optically active alkyllithiums’’ in this case refers to alkyllithium
species bearing a stereogenic lithiated carbon centre, a class of
compounds for which—to the best of our knowledge—at the time
of submission no dimeric example has been reported in the
literature.
6 Upon formal separation of [(R,S)-6]2 into two monomeric species,
no matter which of the two lithiums is attributed to the carbanionic
centre, the same configuration—R—ensues.
7 F. Feil and S. Harder, Organometallics, 2001, 20, 4616;
G. Fraenkel, A. Chow, R. Fleischer and H. Liu, J. Am. Chem.
Soc., 2004, 126, 3983; C. Unkelbach and C. Strohmann, J. Am.
Chem. Soc., 2009, 131, 17044.
8 T. Hemery, R. Huenerbein, R. Frohlich, S. Grimme and
¨
D. Hoppe, J. Org. Chem., 2010, 75, 5716.
9 M. J. Frisch, et al., Gaussian 03, revision D.01, Gaussian, Inc.,
Wallingford, CT, 2004. For a recent benchmark and evaluation of
computational methods for the accurate description of organolithium
species see: V. H. Gessner, S. G. Koller, C. Strohmann, A.-M. L. Hogan
and D. F. O’Shea, Chem.–Eur. J., 2011, 17, 2996.
10 For additional information on [(R,S)-6]2 and computations
regarding other diastereomeric species see the ESIw.
11 The computation of the transition state was accomplished by
simplifying the dimer via substitution of the SiPh2 for SiMe2
groups.
This publication is dedicated to the occasion of the retirement of
Prof. Dr. Bernhard Lippert. The authors gratefully acknowledge
the German Research Foundation DFG for financial support.
c
2494 Chem. Commun., 2012, 48, 2492–2494
This journal is The Royal Society of Chemistry 2012