Solvent and TMEDA effects on the configurational stability of chiral lithiated aryloxiranes

Article abstract of DOI:10.1002/chem.201100351

The employment of hexane/N,N,N',N'-tetramethylethylenediamine (TMEDA) dramatically hinders the racemization of those lithiated styrene oxides (trifluoromethyl-, chloro-, and phenylthio-substituted) that have been proven to be configurationally unstable in THF on the timescale of their reactions. The barriers to inversion and the activation parameters, calculated (Eyring equation) for reactions performed in THF, THF/TMEDA, and hexane/TMEDA, suggest the intervention of particular enantiomerization mechanisms for each case. The role of TMEDA in both coordinating and noncoordinating solvents has also been questioned and discussed in light of the kinetic data gathered and a model for deprotonation in hexane/TMEDA has also been proposed. The synthetic benefits of our results became apparent on establishing an asymmetric synthesis of an industrially important antifungal agent.

Full text of DOI:10.1002/chem.201100351

DOI: 10.1002/chem.201100351
Solvent and TMEDA Effects on the Configurational Stability of Chiral
Lithiated Aryloxiranes
Filippo Maria Perna, Antonio Salomone, Mariangela Dammacco, Saverio Florio, and
Vito Capriati*[a]
Dedicated to Professor Alfredo Ricci on the occasion of his retirement, who enriched the lives of all he met
Abstract: The employment of hexane/
N,N,N’,N’-tetramethylethylenediamine
(TMEDA) dramatically hinders the
racemization of those lithiated styrene
oxides (trifluoromethyl-, chloro-, and
phenylthio-substituted) that have been
proven to be configurationally unstable
in THF on the timescale of their re-
(Eyring equation) for reactions per-
formed in THF, THF/TMEDA, and
hexane/TMEDA, suggest the interven-
tion of particular enantiomerization
mechanisms for each case. The role of
TMEDA in both coordinating and non-
coordinating solvents has also been
questioned and discussed in light of the
kinetic data gathered and a model for
deprotonation in hexane/TMEDA has
also been proposed. The synthetic ben-
efits of our results became apparent on
establishing an asymmetric synthesis of
an industrially important antifungal
agent.
Keywords: configurational stability ·
epoxides · kinetics · ligand effects ·
lithiation · solvent effects
ACHTUNGTRENNUNGactions. The barriers to inversion and
the activation parameters, calculated
Introduction
As part of an ongoing investigation into the structures
and dynamics of chiral oxiranyllithiums we recently reported
that an ortho-positioned para-tolylsulfinyl group,[10] as well
as ortho-, meta-, and para-positioned trifluoromethyl
groups,[11] on the phenyl ring of optically active styrene
oxides induce epimerization upon lithiation. Although in
practice it is much easier to use reagents that are “configu-
rationally stable”, it is intellectually rewarding and fascinat-
ing to use “configurationally labile” chiral organolithium
species after defining the factors that increase their configu-
rational stability on the reaction timescale. Considerable
effort has been and is currently being made to slow down
the racemization of stereolabile chiral organolithiums by
using different solvents and/or cosolvents that are known to
significantly influence the reactivity and configurational sta-
bility of organolithiums.[12] However, a general “recipe” for
the proper conditions in terms of solvents and ligands able
to promote a “fine-tuning” of the racemization rate of a
chiral organolithium has not yet been established. This is
also because enantiomerization can occur by a number of
different and competing mechanisms[13] and the effects of
Chiral lithium carbenoids are invaluable synthons for the
stereoselective synthesis of substituted carbon backbones.[1]
However, the question of their configurational stability
under the conditions of their generation, thermal lability/sta-
bility, dichotomous reactivity (carbanionic/carbene-like be-
havior),[2] and the steric course of their electrophilic substi-
tutions (retentive and invertive pathways or the intervention
of a single-electron-transfer mechanism)[3] are important
issues that always need to be addressed before planning an
asymmetric synthesis.[4] At the same time, aggregation and
solvation are also important factors to be taken into consid-
eration when rationalizing the stereochemical pathway ob-
served[5] because of their influence on the structure–reactivi-
ty relationship.[6]
Chiral oxiranyllithiums (which are peculiar Li/OR car-
ACHTUNGTRENNUNG
benoids),[1d,2,7] in particular, play increasingly important
roles in stereoselective organic synthesis.[8] Although known
to be more stable than the corresponding acyclic a-lithiated
ethers, the racemization of such key intermediates is always
a possibility depending upon the conditions employed.[9]
ligACTHNUGRTENUNGands on the inversion barriers are not straightforward.
For instance, one of the most useful cosolvents is N,N,N’,N’-
tetramethylethylenediamine (TMEDA), which is known to
either retard[12c,g,h,13] racemization or accelerate epimeriza-
tion.[12b,d] We describe herein the effect of TMEDA on the
configurational stability of a-lithiated trifluoromethyl-,
chloro-, and phenylthio-substituted aryloxiranes in both co-
ordinating and noncoordinating solvents.[14] The role of this
ligand will also be tackled in light of the calculated barriers
to inversion and activation parameters. A general trend be-
comes apparent for such reactive intermediates with a
[a] Dr. F. M. Perna, Dr. A. Salomone, Dr. M. Dammacco, Prof. S. Florio,
Prof. V. Capriati
Dipartimento Farmaco-Chimico, Universitꢀ di Bari “A. Moro”
Consorzio Interuniversitario Nazionale
“Metodologie e Processi Innovativi di Sintesi”
C.I.N.M.P.I.S., Via E. Orabona 4, I-70125 Bari (Italy)
Fax : (+39)080-5442539
E-mail: capriati@farmchim.uniba.it
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201100351.
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FULL PAPER
subtle interplay of the different enantiomerization mecha-
nisms involved depending on the stereoelectronic require-
ments of the aryl substituent.
[D]1 mirrored that of the starting epoxide (99:1, entry 3,
Table 1).
The barrier to enantiomerization of 1-Li was then calcu-
lated for reactions performed in THF in the presence of
TMEDA (1 equiv) by determination of the e.r. after quench-
ing with a deuterium source and on aging enantioenriched
1-Li for different times at 195 K, as previously described.[11]
The first-order plot obtained indicated an estimated racemi-
zation half-life (t1/2) of 10.6 min, which equates to an enan-
Results and Discussion
We recently reported[11] the temperature dependence of the
racemization rate of (S)-1-Li (obtained by deprotonating
enantiomerically enriched m-trifluoromethylstyrene oxide
¼
tiomerization barrier (DGenant) of 14.2 kcalmolꢀ1 at 195 K
((S)-1) with sBuLi) in THF (t1/2 =43.4 min at 175 K, t1/2
=
(see the Supporting Information).[15] Similar deprotonation/
deuteration kinetic studies were also carried out on 1-Li
after lowering the temperature to 183 and 175 K, at which
272.4 min at 157 K).
On the basis of the calculated activation parameters
¼
¼
(DHenant =5.5 kcalmolꢀ1 and DSenant =ꢀ44ꢁ1 calmolꢀ1 Kꢀ1
;
the free energies of activation for 1-Li were estimated to be
¼
Scheme 1), the transformation of a contact ion pair (CIP)
DG =14.1 (t1/2 =100.3 min) and 14.0 kcalmolꢀ1 (t1/2
=
417.7 min), respectively (see the Supporting Information).
From these studies, the activation parameters for the
enantiomerization of 1-Li in THF/TMEDA could also be
determined. An Eyring plot (Figure 1) revealed an enthalpy
Scheme 1. Enantiomerization barriers and activation parameters of lithi-
ated m-trifluoromethylstyrene oxide ((S)-1-Li, 99:1 e.r.) in THF in the
presence and absence of TMEDA.
into a solvent-separated ion pair (SSIP) was determined to
be the rate-determining step. Interestingly, we have now ob-
served that the rate of racemization proved to be dramati-
cally affected by the presence of TMEDA in the reaction
mixture and by the nature of the solvent employed. Indeed,
when a 0.05m solution of (S)-1 underwent deprotonation/
deuteration with sBuLi (1.5 equiv)/TMEDA (1 equiv) in
THF, [D]1 could be recovered after 30 min (175 K) with an
enantiomeric ratio (e.r.) of 96:4, 85:15 being the observed
e.r. in the absence of the above ligand (entries 1 and 2,
Table 1). Surprisingly, upon changing the solvent from THF
to hexane (at a reaction temperature of 183 K), the e.r. of
Figure 1. Eyring plot and activation parameters for the enantiomerization
of 1-Li.
¼
of activation (DH ) of 12.1ꢁ0.5 kcalmolꢀ1 and an entropy
¼
of activation (DS ) of ꢀ11ꢁ3 calmolꢀ1 Kꢀ1. It has been re-
ported that the relative affinities of TMEDA and THF for
lithium are highly substrate-dependent.[16] The above data
are consistent with a surprising and successful competition
of TMEDA with the bulk THF for coordination sites on lith-
ium. The presence of TMEDA has, in fact, the interesting
Table 1. Lithiation/deuteration of m-trifluoromethylstyrene oxide ((S)-1)
at different temperatures and with different solvents.
ꢀ
effect of increasing the enthalpy of activation (C Li bond
breaking), thereby hindering the formation of an SSIP
(Scheme 1).
This finding is in line with what had previously been
found in the case of lithiated styrene oxide[2] for which a
multinuclear spectroscopic investigation demonstrated that,
at least with reference to the monomeric TMEDA complex,
this ligand competed with bulk THF for lithium. Hoffmann
and co-workers[12h] pointed out that the fact that some addi-
tives (e.g., TMEDA) affect the nature of a CIP does not
Entry
Solvent
T [K]
Ligand
D [%][a]
e.r.[b]
1
2
3
THF
THF
hexane
175
175
183
–
>95
>95
>95
85:15
96:4
99:1
TMEDA (1 equiv)
TMEDA (1 equiv)
1
[a] Evaluated by H NMR analysis of the crude reaction mixture. [b] De-
termined by chiral stationary phase HPLC (see the Experimental Sec-
tion).
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8217

V. Capriati et al.
necessarily imply that they should facilitate the formation of
an SSIP because the direction or magnitude of these effects
is not easily predicted in each case. In the case of 1-Li, in
ꢀ
the presence of TMEDA, the nature of the C Li bond was
significantly affected and the racemization rate was reduced
considerably in THF and completely blocked in hexane.[17]
a-Lithiated p-trifluoromethylstyrene oxide (2-Li), generat-
ed in THF/Et2O (3:2) by lithiation of optically active (R)-2
(99:1 e.r.) with sBuLi (1.5 equiv), was found to undergo
faster racemization than the meta isomer 1-Li even at a tem-
Scheme 2. Enantiomerization barriers of lithiated p-trifluoromethyl-
AHCTUNGTREGsNNUN tyrene oxide (2-Li) in THF and in hexane in the presence of TMEDA
(1 equiv).
¼
perature as low as 157 K (t1/2 =14 s, DGenant =10.1ꢁ
0.1 kcalmolꢀ1).[11] After a reaction time of 10 s, the corre-
sponding deuterated product [D]2 was recovered with
61:39 e.r. (entry 1, Table 2). In the presence of TMEDA, a
TMEDA, anion decomposition was also seriously accelerat-
ed (yields below 70%).
On the other hand, in the presence of more than 1 equiva-
lent of TMEDA (3–10 equiv), the enantiomerization rate
was similar to that calculated with 1 equivalent of TMEDA.
Table 2. Lithiation/deuteration of p-trifluoromethylstyrene oxide ((R)-2)
at different temperatures and with different solvents.
¼
In fact, the corresponding Eyring plots revealed DGenant
values for 2-Li ranging from 14.0 to 14.1 kcalmolꢀ1 (t1/2
-
AHCTUNGTRENNUNG
(rac)=91.2–105.0 min) at 183 K.[18] Therefore, for the above-
described deprotonation processes, as well as for the other
processes (see below), described herein, the employment of
just 1 equivalent of TMEDA in hexane proved to be suffi-
cient either to control the configurational stability of the
corresponding oxiranyllithiums or to achieve the highest
% D and chemical yield for the a-deuterated adducts at a
reasonable metalation rate.
Entry Solvent
T [K] t [s] Ligand
D [%][a] e.r.[b]
1
2
3
4
THF/Et2O (3:2) 157
THF
THF
hexane
10
10
10
15
–
>95
TMEDA[c] >95
PMDTA[c]
72
TMEDA[c] >95
61:39
60:40
56:44[d]
96:4
175
175
183
This TMEDA/hexane effect also held for lithiated aryl-
AHCTUNGTREGNUNoN xiranes with two CF3 groups in a meta orientation. It has
1
[a] Evaluated by H NMR analysis of the crude reaction mixture. [b] De-
termined by chiral stationary phase HPLC (see the Experimental Sec-
tion). [c] 1 equivalent. [d] Corrected for the percentage deuterium found.
been reported[11] that oxiranyllithium 3-Li (Scheme 3), gen-
erated in a polar medium (THF/Et2O), also undergoes very
quick racemization at 157 K to give, after quenching with
MeOD, completely racemic [D]3 after a deprotonation time
of 5 s. Interestingly, optically active 3,5-bis(trifluoromethyl)-
styrene oxide ((R)-3; 98:2 e.r.), deprotonated with sBuLi/
TMEDA (1 equiv) in hexane at 195 K and quenched with
MeOD, gave enantioenriched [D]3 with 90:10 e.r. (90% D,
>95% yield) after a deprotonation time of 40 s (Scheme 3).
Now, the following questions need to be addressed. What
are the factors responsible for the higher configurational sta-
bility of oxiranyllithiums in noncoordinating solvents in the
presence of a diamine such as TMEDA? Is this general be-
havior for styrene oxides with electron-withdrawing sub-
stituents? In the first place, it is interesting to observe that
in the absence of TMEDA, no deprotonation occurs with
sBuLi in hexane even when using an excess of this base.
Secondly, it is also noteworthy that sBuLi exists largely asso-
similar e.r. (60:40) was detected for [D]2, but this time at a
higher temperature, namely 175 K (entry 2, Table 2). By
changing the ligand from TMEDA to N,N,N’,N’,N’’-penta-
ACHTUNGTRENNUNGmethyldiethylenetriamine (PMDTA), the addition of MeOD
essentially gave racemic [D]2 (56:44 e.r.) with a lower deute-
rium content (72% D; entry 3, Table 2). The deprotonation
time was maintained at 10 s. Therefore, the employment of
this tridentate ligand in THF surprisingly contributed to an
increase in the racemization rate. The use of TMEDA in
hexane proved to be successful in reducing the racemization
of 2-Li; after a deprotonation time of 15 s, the e.r. of [D]2
was still as high as 96:4 (entry 4, Table 2).
The activation free energies of enantiomerization
(DGenant) for 2-Li in THF/TMEDA and in hexane/TMEDA
¼
calculated from the corresponding Eyring equation were
11.0ꢁ0.1 kcalmolꢀ1 at 175 K (t
(rac)=6 s) and 14.0ꢁ
N
0.1 kcalmolꢀ1 at 183 K (t
1/2ACTHNUTRGENUG(N rac)=91.1 min), respectively
(Scheme 2 and the Supporting Information). Next, the rate
of enantiomerization of 2-Li with varying amounts of
TMEDA was investigated in hexane at 183 K. With less than
1 equivalent of TMEDA, the rate of lithiation was reduced
significantly (% D ranging from 56 to 87% with 0.3–
0.5 equiv TMEDA), and with less than 0.3 equivalents of
Scheme 3.
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Configurational Stability of Lithiated Aryloxiranes
FULL PAPER
ciated as a tetramer in hydrocarbon solvents (e.g., cyclopen-
tane[19a] and cyclohexane[19b]). Furthermore, kinetic data
from Beak and co-workers[19b] suggest that the major inter-
action of TMEDA with sBuLi in cyclohexane is just an addi-
tion of such a ligand to aggregated sBuLi.[19c,d] Therefore,
also in consideration of the fact that the formation of a com-
plex-induced proximity effect (CIPE)[20] is crucial for the
lithiation of styrene oxide to take place,[2] we assume, in line
with the data reported for the lithiation of carboxamides by
Beak and co-workers,[19b] that tetrameric sBuLi in hexane
binds to oxirane to form a relatively unreactive complex,
which is then made more reactive in the presence of
TMEDA.[21] Thus, a reactive lithiumorganyl is more likely to
be released from its associated lithiums in the transition
state (T.S.) of the deprotonation reaction in which TMEDA
also provides complexation. Adaptation of Beakꢂs model to
the present case leads to Scheme 4.
tional stability of other a-lithiated aryl-substituted styrene
oxides was investigated under different conditions of tem-
perature, solvent, and cosolvent. Optically active o-chloro-
AHCTUNGTREGsNNNU tyrene oxide ((R)-4, 99:1 e.r.; Scheme 5) was deprotonated
Scheme 5. Enantiomerization barriers and activation parameters of lithi-
ated o-chlorostyrene oxide (4-Li) in THF in the presence or absence of
TMEDA.
with sBuLi in THF for time t and quenched with MeOD to
give [D]4 to obtain information about the enantiomerization
dynamics of the corresponding lithiated oxirane 4-Li. A plot
of lnACTHUNRTGNEUNG(ee/100) versus time (see the Supporting Information)
showed good linearity at three different temperatures for re-
actions performed with or without TMEDA. The corre-
sponding calculated enantiomerization barriers are reported
in Scheme 5. The Eyring plots of lnACHTUNGTRNE(UNG kenant/T) versus 1/T also
show a very good linear relationship over three half-lives for
the two sets of reactions and allowed the calculation of the
¼
¼
activation parameters: DH =11.5ꢁ0.5 kcalmolꢀ1 and DS
¼
=ꢀ12ꢁ3 calmolꢀ1 Kꢀ1
in
THF
and
DH =12.3ꢁ
Scheme 4. Proposed mechanism for the lithiation of styrene oxides in
hexane/TMEDA. Lithiated oxirane is shown as a monomeric species for
simplicity.
0.2 kcalmolꢀ1 and DS =ꢀ9ꢁ1 calmolꢀ1 Kꢀ1 in THF/
¼
TMEDA (Figure 2).
If we compare this case with that of lithiated m-trifluoro-
methylstyrene oxide 1-Li, two main differences are worth
noting. In the first place, in the case of 4-Li, the enthalpic
and entropic barriers to enantiomerization are similar in
both the absence and presence of TMEDA, whereas they
are quite different for 1-Li. In the second place, both entro-
pies of activation are still negative, but smaller for 4-Li than
for 1-Li in the absence of TMEDA.
A few years ago, Hoppe and co-workers reported the first
highly enantioenriched a-thioallyllithium compound, which
showed a remarkable configurational stability in Et2O and
THF but underwent quick racemization in toluene.[22] This
behavior was rationalized by Brandt and Haeffner; in the
case of coordinating solvents, racemization is hindered by
reduced solvent affinity in the transition state, whereas in
noncoordinating solvents, the inversion of the configuration
is facilitated by aggregation.[5d] In striking contrast to such a
a-thioallyllithium compound, as for chiral oxiranyllithiums
1–3-Li, inversion takes place almost as quickly in THF, but
is considerably slowed down in hexane/TMEDA. It is un-
likely that in such a solvent (hexane) the above lithiated ox-
iranes exist as monomers.[23] In any case, the point is that
even though aggregated, they are resistant to fast racemiza-
tion in hexane/TMEDA.[24]
The results obtained in THF suggest either minimal addi-
tional solvation in the transition state or that TMEDA does
ꢀ
not affect the C Li bond strength of 4-Li as strongly as it
does for 1-Li. Thus, it is reasonable to think that a different
enantiomerization mechanism, such as the “conducted tour”
mechanism, may be involved in 4-Li because of favorable
intramolecular coordination between lithium and chlorine.[25]
Once again, the combined use of a noncoordinating solvent
and TMEDA proved to be successful for preserving the con-
figurational stability of 4-Li. In fact, the lithiation of (R)-4
in hexane/TMEDA at 183 K led to (R)-[D]4 with 99:1 e.r.
upon quenching with MeOD with a deprotonation time of
12 min (Scheme 6).
To establish the scope and limitations of such deprotona-
tion reactions in the presence of TMEDA, the configura-
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V. Capriati et al.
Scheme 7. Enantiomerization barriers of lithiated m-chlorostyrene oxide
(5-Li) in THF and THF/TMEDA (1 equiv).
Scheme 8.
99:1 e.r.) with sBuLi (1.5 equiv), also proved to be configu-
rationally stable in THF alone at 195 K; quenching the re-
AHCTUNGTREGaNNUN ction mixture with MeOD gave the deuterated epoxide
(R)-[D]6 with the configuration of the benzylic-type carbon
atom unaffected (99:1 e.r.), even after 1 h (Scheme 9).
Figure 2. Eyring plots and activation parameters for the enantiomeri-
zation of 4-Li in a) THF and b) THF/TMEDA.
Scheme 9.
Scheme 6.
Thus, with regard to the relationship between the elec-
tron-withdrawing inductive strength provided by a certain
aryl substituent and the configurational stability of the cor-
responding a-lithiated aryl epoxide, it seems as though a
Hammett s value of 0.37 (with this constant mainly measur-
ing field/inductive effects, as in the case of a meta-positioned
chlorine atom), is enough to trigger racemization in THF.
This is consistent with the fact that lithiated m-fluorostyrene
oxide (for which sm(F)=0.34) is, indeed, configurationally
stable.[11,26] Not surprisingly, and in line with what has just
been stated, electron-donating groups on the phenyl ring do
not affect the configurational stability of lithiated styrene
oxides in THF. Both a-lithiated o-tolyl- and o-methoxy-
The time-dependent deuteration (see the Supporting In-
formation) of a-lithiated m-chlorostyrene oxide (5-Li) in
THF, obtained by deprotonating optically active m-chloro-
ACHTUNGTRENNUNGstyrene oxide ((R)-5, 99:1 e.r.) with sBuLi (1.5 equiv), re-
vealed enantiomerization kinetics slower than 4-Li with a
racemization half-life of 24.3 min at 195 K, which corre-
¼
sponds to an inversion barrier (DGenant
)
of 14.4(8)ꢁ
0.1 kcalmolꢀ1 (>95% D, >95% yield; Scheme 7).
In the presence of TMEDA (1 equiv), the activation free
¼
energy (DGenant) calculated for 5-Li almost mirrors the value
obtained in THF alone: 14.5(1)ꢁ0.1 kcalmolꢀ1 (t1/2
=
ACHTUNGTRENpNUNG henyloxiranes (R)-7-Li and (R)-8-Li (generated by treating
26.4 min) at 195 K in THF (>95% D, >95% yield;
Scheme 7). Once again, racemization was completely
blocked in hexane/TMEDA even at 195 K ((R)-[D]5: 99:1
e.r., >95% D, >95% yield, reaction time 25 min;
Scheme 8).
the optically active epoxides (R)-7 (88:12 e.r.) and (R)-8
(90:10 e.r.) with sBuLi (1.5 equiv) in THF) could, indeed, be
successfully trapped with a deuterium source to give (R)-
[D]7 and (R)-[D]8, respectively, with the same e.r. as the
starting oxiranes (Scheme 10).
On the other hand, oxiranyllithium 6-Li, generated by
treatment of optically active p-chlorostyrene oxide ((R)-6,
Finally, the case of the phenylthio substituent was also in-
vestigated. In a preliminary communication we recently re-
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Configurational Stability of Lithiated Aryloxiranes
FULL PAPER
which the CH3S group has a slightly acidifying effect[28] com-
pared with the PhS group.
After generating oxiranyllithiums 10-Li and 11-Li with
sBuLi (1.5 equiv) at 157 K in THF/Et2O (3:2), quenching
with MeOD gave, after 5 min, deuterated [D]10 as an essen-
tially racemic mixture and [D]11, as expected, with a higher
e.r. of 70:30 (Scheme 13).
Scheme 10.
ported[27] that although a-lithiated o- and p-phenylthio-
ACHTUNGTRENNUNGstyrene oxides are configurationally unstable at 175 K in
THF on the timescale of their reactions, a-lithiated m-
phenylthiostyrene oxide is not. A series of deprotonation/
deuteration experiments have now been performed with op-
tically active o-phenylthiostyrene oxide ((R)-9, 95:5 e.r.;
Scheme 11) and p-phenylthiostyrene oxide ((R)-10, 98:2 e.r.;
Scheme 13.
Next, the influence of TMEDA on the configurational sta-
bility of the above lithiated systems was also evaluated. The
reactions of oxiranes (R)-9 (95:5 e.r.) and (R)-10 (98:2 e.r.)
in hexane with sBuLi (1.5 equiv) in the presence of
TMEDA (1 equiv) and the subsequent deuteration with
MeOD gave epoxides (R)-[D]9 with 95:5 e.r. (85% D, 95%
yield) and (R)-[D]10 with 98:2 e.r. (95% D, 95% yield)
after a metalation time of 10 s and 30 min, respectively
(Scheme 14). These results are once more consistent with
the higher configurational stability that a-lithiated aryl-
Scheme 11. Enantiomerization barrier of lithiated o-phenylthiostyrene
oxide (9-Li) in THF/Et2O.
Scheme 12), varying the racemization time from 5 to 30 s, to
give deuterated [D]9 and [D]10. From the slopes of the cor-
responding Eyring plots (see the Supporting Information),
AHCTUNGTREGoNNNU xiranes, such as (R)-9-Li and (R)-10-Li, have in hexane/
TMEDA.
¼
the activation free energies (DGenant) of the oxiranyllithiums
9-Li (157 K (THF/Et2O, 3:2)) and 10-Li (175 K (THF)) were
found to be 9.8 (t1/2 =4 s) and 11.1 kcalmolꢀ1 (t1/2 =8 s), re-
spectively (Schemes 11 and 12).
Scheme 12. Enantiomerization barrier of lithiated p-phenylthiostyrene
oxide (10-Li) in THF.
Scheme 14.
Under the aforementioned conditions, the asymmetric
synthesis of a sulfurated amino alcohol such as (S)-16
(Scheme 15), with the properties of an industrially important
antifungal agent,[29] was also successfully established. First,
optically active p-chlorophenylthiostyrene oxide ((S)-14,
98:2 e.r., 50% yield) was prepared by bromine/lithium ex-
change in (S)-12 and subsequent coupling with S-(4-chloro-
phenyl) 4-chlorobenzenethiosulfonate (13). The deprotona-
tion of (S)-14 with sBuLi (1.3 equiv)/TMEDA (1 equiv) in
It has been said[27] that when the phenylthio substituent is
at the ortho or para position of the phenyl ring, strong con-
jugative interactions involving the low-lying 3d orbitals of
the sulfur might play a key role in providing stabilization of
the above oxiranyllithiums, thereby triggering racemization.
To prove this, the outcome of the deprotonation/deuteration
of optically active p-phenylthiostyrene oxide ((R)-10) was
compared with that of p-methylthiostyrene oxide ((R)-11) in
Chem. Eur. J. 2011, 17, 8216 – 8225
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8221

V. Capriati et al.
position and stereochemical isomerization related to such
reactive intermediates “could be resolved, the utility of the
oxiranyl anion methodology would be dramatically en-
hanced”.
With regard to this, Yoshida and co-workers successfully
overcame such issues by employing a flow microreactor
system with efficient temperature control and short resi-
dence times. In this paper, we have shown for the first time
that deprotonation of the above substituted styrene oxides
in hexane/TMEDA at 183 K not only minimizes the car-
bene-like reactivity,[31] but also racemization, which whenev-
er it occurs in THF, can mostly be blocked.
Scheme 15.
Table 3. Enantiomerization barriers and racemization half-lives of lithiated styrene
oxides 1,2,4,5,9,10-Li in THF, THF/TMEDA, and hexane.
pentane at 173 K (1 min reaction time) followed by
quenching with MeI gave the corresponding a-me-
thylated adduct (S)-15 (50% conversion). The
latter, without isolation, was then subjected to re-
gioselective ring opening promoted by 1-adamantyl-
amine to furnish the enantiomerically enriched
target molecule (S)-16 (98:2 e.r., 45% overall isolat-
ed yield; Scheme 15).
¼
[a]
Lithiated
oxirane
R
Solvent
T
[K]
TMEDA DGenant
t
G
s[b]
[equiv]
[kcalmolꢀ1
]
1-Li
2-Li
4-Li
m-CF3 THF
THF
195
183
175
1
1
1
–
1
1
–
–
–
1
1
1
–
1
–
–
14.2
14.1
14.0
10.1
11.0
14.0
14.0
13.8
13.7
14.0
13.9
13.8
14.4(8)
14.5(1)
9.8
10.6 min 0.43
100.3 min 0.43
417.7 min 0.43
THF
p-CF3 THF/Et2O (3:2) 157
14 s
6 s
0.54
0.54
Conclusion
THF
hexane
THF
THF
THF
THF
THF
THF
THF
THF
175
183
195
190
175
195
183
175
195
195
91.1 min 0.54
The configurational stability of differently aryl-sub-
stituted a-lithiated styrene oxides has been (re)in-
vestigated in both coordinating and noncoordinat-
ing solvents, and in the presence or absence of
TMEDA. Whereas electron-donating groups (e.g.,
methyl and methoxy) do not alter the configura-
tional stability in THF and at low temperatures,
electron-withdrawing groups (e.g., chloro and tri-
fluoromethyl) trigger racemization in THF at a rate
dependent on their position on the phenyl ring.
For all those derivatives (1–5-Li, 9-Li, and 10-Li)
proven to be configurationally unstable on the time-
scale of their reactions, the presence of TMEDA in
o-Cl
5.8 min
11.2 min
185.9 min
6.8 min
–
–
–
–
–
–
55.8 min
287.3 min
5-Li
m-Cl
24.3 min 0.37[c]
26.4 min 0.37[c]
9-Li
10-Li
o-PhS THF/Et2O (3:2) 157
p-PhS THF 175
4 s
8 s
–
11.1
0.23[d]
¼
[a] The estimated error for all DGenant values is ꢁ0.1 kcalmolꢀ1. [b] Hammett s con-
stant (see ref. [26]). [c] For comparison, the Hammett s constants for the m-F, p-F, and
p-Cl substituents are 0.34, 0.06, and 0.23, respectively. In contrast to 4-Li and 5-Li, all
the corresponding lithiated oxiranyllithiums proved to be configurationally stable in
THF on the timescale of their reactions in the temperature range 175–195 K (see also
coordinating solvents such as THF often contributes ref. [11]). [d] For comparison, the Hammett s constant for the m-PhS substituent is
0.15 (see also ref. [28]).
to lowering their rate of enantiomerization (thereby
increasing the barriers to inversion DGenant), where-
¼
as in noncoordinating solvents, such as hexane, all
the above oxiranyllithiums showed remarkable configura-
Table 4. Activation parameters for the enantiomerization of lithiated
tional stability. The calculated barriers to inversion and acti-
vation parameters (the values of which are collected in
Tables 3 and 4) also suggest a subtle interplay of different
mechanisms in the enantiomerization process. It was also
observed that deprotonation does not take place in hexane
with sBuLi in the absence of TMEDA. A model that high-
lights the role that either pre-lithiation or more reactive
complexes may have on deprotonation reactions in hexane/
TMEDA has been proposed.
styrene oxides 1-Li and 4-Li in THF with or without TMEDA.
¼
¼
Lithiated
oxirane
R
TMEDA
[equiv]
DHenant
DSenant
G
[kcalmolꢀ1
]
[calmolꢀ1 Kꢀ1
]
1-Li
m-CF3
o-Cl
–
1
–
1
5.5ꢁ0.5
12.1ꢁ0.5
11.5ꢁ0.5
12.3ꢁ0.2
ꢀ44ꢁ1
ꢀ11ꢁ3
ꢀ12ꢁ3
ꢀ9ꢁ1
4-Li
Reactions in which stereochemistry is controlled have
become invaluable tools for organic chemists. With refer-
ence to oxiranyllithiums, in particular, Yoshida and co-work-
ers stated in a recent paper[30] that if the problems of decom-
To prove how this can be crucial to asymmetric synthesis,
we have successfully prepared an industrially important anti-
fungal agent ((S)-16) in a highly enantioenriched form
(98:2 e.r.). In addition, the quest for “solvents in which race-
8222
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ꢁ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2011, 17, 8216 – 8225

Configurational Stability of Lithiated Aryloxiranes
FULL PAPER
action times (less than 30 s, Table 2, Schemes 11 and 12) proved to be re-
producible within the error limits of 5%.
mization occurs only slowly”, in the words of Haeffner
et al.,[5c] could also be accomplished in the case of lithiated
styrene oxides by carrying out their deprotonation reactions
under certain experimental conditions (e.g., THF/TMEDA)
and by modulating the temperature. This may also be of in-
terest for establishing fruitful and efficient dynamic resolu-
tions starting from racemic epoxides. This issue is currently
being investigated in our laboratory.
Lithiation/deuteration of optically active epoxides—general procedure:
Standard solutions (0.05m) of the respective optically active epoxide
(0.1 mmol in 2 mL of dry solvent) and TMEDA (when required;
0.1 mmol) were cooled to the fixed temperature and treated with sBuLi
(0.15 mmol, 1.3m solution in cyclohexane) under N2. After stirring the re-
sulting mixture for the given time (see the main text and Supporting In-
formation), MeOD (10 mmol) was added. The cooling bath was removed
and the reaction mixture was allowed to warm to room temperature,
then diluted with brine (5 mL) and extracted with Et2O (3ꢃ5 mL). The
combined organic phases were dried over Na2SO4 and concentrated in
vacuo. The crude product was analyzed without further purification to
determine the enantiomeric ratio as described above.
Experimental Section
General: Tetrahydrofuran (THF), pentane, and hexane were freshly dis-
tilled under nitrogen, THF over sodium/benzophenone ketyl, and pen-
tane and hexane over calcium hydride. For the 1H and 13C NMR spectra
(1H NMR: 600 MHz; 13C NMR: 150 MHz, Bruker Avance 600), CDCl3
was used as solvent. GC-MS analyses were performed on a HP 5890 gas
chromatograph (dimethylsilicon capillary column, 30 m, 0.25 mm i.d.)
equipped with a mass selective detector operating at 70 eV (EI). Optical
rotations were measured with a Perkin-Elmer 341 polarimeter using a
cell of 1 dm pathlength at 258C; the concentration (c) is expressed in g/
100 mL. Analytical thin-layer chromatography (TLC) was carried out on
precoated 0.25 mm thick plates of Kieselgel 60 F254; visualization was
accomplished by using UV light (254 nm) or by spraying with a solution
Acknowledgements
This work was carried out under the framework of the National Project
“Stereoselezione in Sintesi Organica. Metodologie ed Applicazioni” and
financially supported by the University of Bari and by the Interuniversity
Consortium C.I.N.M.P.I.S. The authors would like to acknowledge Dr.
Valentina Mallardo for her contribution to the Experimental Section.
of 5% (w/v) ammonium molybdate and 0.2% (w/v) ceriumACTHNUTRGNE(NUG III) sulfate in
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100 mL of a 17.6% (w/v) aqueous solution of sulfuric acid and heating at
473 K for some time until blue spots appeared. All reactions involving
air-sensitive reagents were performed under nitrogen in oven-dried glass-
ware using the syringe/septum cap technique. Lithiation/deuteration re-
ACHTUNGTRENNUNGactions were performed in an ethanol/liquid N2 (157 K), methanol/liquid
N2 (175 K), acetone/liquid N2 (183 K), diethyl ether/dry ice (190 K), or
acetone/dry ice (195 K) cold bath. The enantiomeric ratios were deter-
mined as follows: compound (S)-16 by 1H NMR analysis (600 MHz,
CDCl3) in the presence of the Mosher acid ((R)-(+)-3,3,3-trifluoro-2-me-
thoxy-2-phenylpropanoic acid;[32] molar ratio of the Mosher acid/16, 1:1),
compounds 8–10 by HPLC analysis employing a Daicel Chiralcel OD-H
column (250ꢃ4.6 mm), compounds 1, 2, 4–6, 11, 12, and 14 by HPLC
analysis (HPLC: pump 1525, detector 996 PDA) employing a Cellulose
Lux-2 column (250ꢃ4.6 mm), and compounds 3 and 7 by GC analysis
(HP 6890) employing a Chirasil-DEX CB column (250ꢃ0.25 mm, column
head pressure 18 psi, He flow 1.5 mLminꢀ1, oven temperature 100–
1108C). Racemic oxiranes were prepared by either the Corey–Chaykov-
sky epoxidation procedure[33] starting from the corresponding benzalde-
hyde derivatives (epoxides 2, 4–8, and 12) or the methodology of Durst
and co-workers[34] (epoxides 1 and 3). The optically active epoxides 1–8
and 12 were synthesized as follows: compounds 2, 4–7, and 12 starting
from the corresponding racemic mixtures by using Jacobsen and co-work-
ersꢂ hydrolytic kinetic resolution[35] and compounds 1, 3, and 8 starting
from the corresponding a-chloro ketones[36] exploiting Noyoriꢂs asymmet-
ric reduction. a-Chloro ketones were prepared from the commercially
available acetophenone derivatives following reported procedures.[37]
Racemic and optically active oxiranes 9–11 and 14 were prepared from
racemic or optically active 4-(bromophenyl)oxiranes (12) according to
previously reported procedures.[27] The spectroscopic data of epoxides
1,[38] 2,[38] 3,[39] 4,[35] 5,[35] 6,[35] 7,[40] 8,[41] 9,[27] 10,[27] 12,[40] 14[27] and of amino
alcohol 16[27] have been reported previously. For the spectroscopic data
of compound 11 see the Supporting Information.
Kinetic studies: All the kinetic experiments were conducted in a closed
vessel immersed in the appropriate cold bath for the temperature em-
ployed (see above). The temperatures were monitored by using a cali-
brated digital thermometer. The rate constants for the racemization of
optically active oxiranylithiums were determined by plotting enantiomer-
ic ratios against time after performing a series of lithiation/deuteration
experiments on the corresponding epoxides at different temperatures and
times as reported in the main text. Each point in the plot corresponds to
a single experiment. The enantiomeric ratios determined at very short re-
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Chem. Eur. J. 2011, 17, 8216 – 8225
ꢁ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
8223

V. Capriati et al.
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ꢀ
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of reactions. For example, a recent paper by Nagashima and co-
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coupling reactions of ArMgX with alkyl halides: D. Noda, Y.
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a collective measure of the total electronic effects (resonance and
inductive effects) exerted by a certain aryl substituent on the re-
AHCTUNGERTGaNNUN ction centre. Thio groups can, indeed, either conjugatively donate
Chem. Soc. 2009, 131, 6078–6079.
electrons to the phenyl ring or withdraw electrons through d-orbital
participation, the former effect being even less effective in the pres-
ence of an additional phenyl group on sulfur (just as in the case of
the p-PhS group), which decreases its electron density; this accounts
for why p-PhS is somewhat more electron-withdrawing than p-
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¼
[15] Activation free energy for enantiomerization (DGenant in kcalmolꢀ1
)
has been calculated by application of the Eyring equation in which
T is the absolute temperature and kenant is the rate constant in sꢀ1
¼
(kenant =krac/2): DGenant =4.574T[10.318+log
Chem. Rev. 1935, 17, 65–77.
10 ACHTUNGNERTN(UNG T/kenant)]: H. Eyring,
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ꢀ
[17] The influence of Li C bond lengths and mixed aggregates on the
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8224
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Chem. Eur. J. 2011, 17, 8216 – 8225

Configurational Stability of Lithiated Aryloxiranes
FULL PAPER
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Received: January 31, 2011
Published online: May 25, 2011
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