On the steric course of transmetallations on enantiomerically defined α-carbamoyloxy organolithiums

Article abstract of DOI:10.1016/S0022-328X(01)00641-6

The steric courses of the transmetallations of the title organolithiums to the Sn(IV)-, Mg(II)-, Ce(III)-, Zn(II)-, and Cu(I)-species are described.

Full text of DOI:10.1016/S0022-328X(01)00641-6

Journal of Organometallic Chemistry 624 (2001) 364–366
www.elsevier.nl/locate/jorganchem
Communication
On the steric course of transmetallations on enantiomerically
defined a-carbamoyloxy organolithiums
Katsuhiko Tomooka, Hideo Shimizu, Takeshi Nakai *
Department of Chemical Technology, Tokyo Institute of Technology, Meguro-ku, Tokyo 152-8552, Japan
Received 3 October 2000; accepted 20 December 2000
Abstract
The steric courses of the transmetallations of the title organolithiums to the Sn(IV)-, Mg(II)-, Ce(III)-, Zn(II)-, and Cu(I)-species
are described. © 2001 Published by Elsevier Science B.V.
Keywords: Transmetallation; Stereochemistry; Phenomena; Organocerium; Organozinc
Transmetallation constitutes one of the key processes
in organometallic reactions and finds broad synthetic
application. However, the exact steric course (retention
vs. inversion) of transmetallation processes remains
largely undefined and are often hard to elucidate,
mainly because in most cases the configurational stabil-
ities of the organometallic species involved are poorly
defined or unknown and/or the steric course of the
subsequent demetallation process remains obscure. If
the organometallic species to be transmetallated is
enantiomerically defined and configurationally stable, it
would become feasible to elucidate the steric course of
transmetallation proceeding at the metal-bearing sp3-
carbon with a high degree of reliability. Disclosed
herein is our preliminary report on the stereochemistry
of several transmetallations on the enantiomerically
defined and configurationally stable a-carbamoyloxy
organolithiums [1].
Scheme 1 shows our general approach to elucidate
the steric course of transmetallation on chiral organo-
lithium 2, generated in situ from the highly enantio-en-
riched stannanes (S)-1 which are obtainable via the
(−)-sparteine-mediated enantioselective lithiation fol-
lowed by stannylation [1,2]. Since the Sn/Li transmetal-
lation in general is well established to proceed with
complete retention of configuration [3], the steric course
of the transmetallation in question could be elucidated
from the stereochemistry of the final product 4, as long
as the steric course of the SE2-type reaction of the
transmetallated species 3 is reasonably defined. How-
ever, note that this approach is only applicable to the
cases where product 4 is obtained in reasonably high
%ee; otherwise, the steric course remains obscure due to
the racemization problem with species 3.
First, we examined the Li/Sn transmetallation on the
chiral a-N,N-diisopropylcarbamoyloxy organolithiums
2. Thus, alkylstannane (S)-1a (\95%ee) [2] was treated
with n-BuLi in THF at −78°C to generate (S)-2a, then
trapped with tributyltin chloride to give stannane (S)-
1a [ret-3a (M=Sn)] with exactly the same %ee as that
of the starting stannane (chiral HPLC, Chiralcel OD).
Since the initial Sn/Li transmetallation is retentive [3],
Scheme 1.
* Corresponding author. Tel.: +81-3-57342150; fax: +81-3-
57342885.
E-mail address: takeshi@o.cc.titech.ac.jp (T. Nakai).
0022-328X/01/$ - see front matter © 2001 Published by Elsevier Science B.V.
PII: S0022-328X(01)00641-6

K. Tomooka et al. / Journal of Organometallic Chemistry 624 (2001) 364–366
365
this outcome proves that the Li/Sn transmetallation
concerned also proceeds with complete retention of
configuration, presumably via the pre-coordination
pathway A. The same observation had been made by
Hoppe’s group in the stannylation of the lithio species
generated from alkyl carbamates (with a different car-
bamoyl group) with s-BuLi/(−)-sparteine [1,4]. In con-
trast, a similar Li/Sn transmetallation of benzyllithium
2b, generated from stannane (S)-1b (22%ee) [2], was
found to result in complete racemization. This observa-
tion is not surprising in view of Hoppe’s observation
that the (−)-sparteine-bound benzyllithium species 2b
is configurationally labile [1]. Thus, this outcome is best
explained as a result of the racemization of Li-species
2b prior to stannylation, and hence the exact steric
course of the Li/Sn transmetallation remains obscure.
In fact, trapping of 2b with benzaldehyde that might
direct the reaction to the highly retentive course by
virtue of its ability to pre-coordinate with lithium also
led to complete racemization. Of interest in this context
is that the racemic species 2b once generated from
(9)-1b was treated with (−)-sparteine followed by
stannylation to give stannane 1b in enantio-enriched
form (S, 22%). Since the %ee-value is the same as
observed in the direct stannylation of the Li-species
generated from the benzyl carbamate with s-BuLi/(−)-
sparteine, the asymmetric induction is likely to occur at
the stannylation step, probably under a dynamic kinetic
resolution. Here, it should be noted that the complete
in6ersion has been observed by Hoppe’s group for the
stannylation of the a-carbamoyloxy-a-methybenzyl-
lithium 5 (configurationally stable!); they have pro-
posed the pathway B [5]. Anyway, these results caution
us that the transmetallation stereochemistry of benzylic
lithiums is in general more complicated due to the
configurational instabilities thereof.
tion of the chiral center in question of adduct 6a was
assigned after hydrogenation (H2, Pd-C) forming the
cyclohexyl derivative which was identical in chiral
HPLC with the authentic (R)-isomer obtained via reac-
tion of Li-species (S)-2a with cyclohexanone. It thus
appears likely that the Mg-species thus generated is
configurationally and chemically more stable (up to
+20°C) than Li-species 2a which is known to undergo
the 1,2-carbamoyl migration at −20°C [2]. Of special
note in this context is Hoffmann’s recent observation
that a chiral, sec-alkylmagnesium chloride is configura-
tionally stable in THF up to −30°C [6]. A similar
transmetallation with CeCl3 at −78°C afforded 50%
yield of (R)-6a in 94%ee with dr=91:9; none of 7a was
obtained. Interestingly, the reaction of the Mg- and
Ce-species provided a significantly higher diastereose-
lectivity than that of Li-species 2a (dr=63:37, 68%
yield at −78°C). McGarvey et al. have reported that
the Li/Mg transmetallation of an a-(benzy-
loxymethoxy)alkyllithium leads to an enhanced
diastereoselectivity in the reaction with benzaldehyde
[7]. Most significantly, in both cases, the absolute
configuration at the chiral center in question of the final
product and its enantio-purity are essentially the same
as those of Li-species 2a, suggesting strongly that both
the Li/Mg and Li/Ce transmetallation proceed with
almost complete retention of configuration through the
pre-coordination pathway like A; the inversion/inver-
sion pathway is very unlikely since carbonyl com-
pounds usually react with organometallics in retentive
fashion through the pre-coordination with the metal
center.
Furthermore, we examined the Li/Zn and Li/Cu
transmtallation on alkyllithium 2a. Thus, (S)-2a, gener-
ated from (S)-1a (\95%ee), was treated with ZnBr2 in
THF (−78°C, 1 h) and then reacted with ethyl propio-
late (1 h) followed by the addition of D2O. While none
of the propiolate adduct was obtained (indicating the
formation of a Zn-species), the deuterated product (S)-
7a was obtained in 73% yield and \95%ee. Note that
under the same conditions Li-species 2a reacted com-
pletely with the propiolate to give a complex mixture.
The (S)-configuration and enantio-purity of 7a were
determined by 1H NMR comparisons of the (R)-MTPA
ester 7a% [prepared via reduction (deprotection) with
DIBAL-H [8] followed by reaction with (R)-MTPACl]
with the authentic samples derived in the same way
from (9)- and (S)-7a (\95%ee) obtained via direct
deuteration of the Li-species (9)- and (S)-2a, respec-
tively. Given the reasonable postulate that the deutera-
tion concerned occurs in retentive fashion [9], this
Next, our interest was turned to the Li/Mg and Li/Ce
transmetallation on alkyllithium (S)-2a. Thus, (S)-2a,
generated from (S)-1a (\95%ee), was treated with
MgBr2 [freshly prepared from 1,2-dibromoethane and
magnesium metal] in THF at −78°C for 1 h and then
reacted with 2-cyclohexenone at −5°C or ca. +20°C
for 1 h followed by treatment with D2O to give a
diastereomeric mixture of 1,2-adduct (R)-6a in \
95%ee (HPLC, Chiralcel AD), together with or without
the deuterated product 7a; the yield [diastereomeric
ratio (1H NMR assay)] of 6a was 19% [80:20] at −5°C
and 44% [79:21] at +20°C, and the yield of 7a was
50% at −5°C and 0% at +20°C. The (R)-configura-

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K. Tomooka et al. / Journal of Organometallic Chemistry 624 (2001) 364–366
outcome reveals that the Li/Zn transmetallation pro-
ceeds in a completely retentive manner. Of special note
in this context is Normant and Marek’s observation [9]
that the Li/Zn transmetallations of the benzylic lithi-
ums generated via addition of n-BuLi onto (E)-cin-
namyl alcohol and the N,N-dimethylamino derivative
occur at completely in6erti6e fashion at −30°C, while
the Zn-species thus formed undergo complete epimer-
ization at +50°C. In a similar way, the Li/Cu
transmetallation was examined. Thus, Li-species 2a was
treated successively with a THF mixture of CuCN and
TMEDA (one equivalent each, −78°C, 1 h), Me3SiCl
(1 equivalent, 5 mm), and the propiolate (1 h) to afford
41% yield of 1,4-adduct (R)-8a in 83%ee (HPLC, Chi-
ralcel AD), along with 17% of the dimeric product 9a
as an E/Z mixture (79:21); neither of 7a nor the silyla-
tion product were obtained, indicating that the
transmetallation was completed. Note that the forma-
tion of 9a has been observed when Li-species 2a was
warmed up to +25°C [2]. The (R)-configuration of
adduct 8a was assigned after its conversion to (R)-(+)-
4-phenyl-l,2-butanediol (via ozonolysis followed by re-
duction with NaBH4) which was correlated with an
authentic (R)-(+)-isomer obtained by DIBAL-H re-
duction of (R)-2-hydroxy-4-phenylbutanoic acid. Since
the 1,4-addition step is likely to proceed in a retentive
manner [10,11], this outcome strongly suggests that the
Li/Cu transmetallation proceeds predominantly, but
not completely, with retention of configuration, al-
though the inversion/inversion pathway cannot be com-
pletely excluded. The high stereospecificity observed
here is in sharp contrast to Linderman’s observation
[11] that a similar Li/Cu transmetallation of a-
(methoxymethoxy)alkyllithium (configurationally sta-
ble!) followed by 1,4-addition onto the propiolate
resulted in considerable racemization. Anyway, the chi-
ral Cu-species thus generated is configurationally less
stable than other organometallic species examined in
this work.
By contrast, a similar transmetallation with ZnBr2 pro-
vided (R)-12 in much lower ee’s (6–43%), varying with
the reaction conditions. This observation is best inter-
preted as a result that the Li/Zn transmetallation af-
fords a mixture of invertive and retentive processes,
although the possibility that the Zn-species thus formed
is configurationally labile cannot be totally excluded [9].
In summary, we have elucidated the steric courses of
several transmetallation processes on the enantiomeri-
cally defined, configurationally stable a-carbamoyloxy
alkyllithiums. Although most of the stereochemical out-
comes thus observed are what one might anticipate and
the organolithiums studied in this work are rather
special in type, the observations outlined herein provide
unique and useful insights into the stereochemical as-
pect of transmetallation processes and the configura-
tional stabilities of organometallic species involved
therein.
Acknowledgements
This work was supported by a grant from the ‘‘Re-
search for the Future Program,’’ administered by the
Japan Society of Promotion of Science.
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Finally, we examined the transmetallations on the
chiral Li-species 11 (an analogue of Hoppe’s Li-species
5 [5]) generated from enantiopure (R)-a-methylbenzyl
N,N-diethylcarbamate (10) with s-BuLi/TMEDA in
ether at −78°C. By analogy, 11 should be configura-
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with MeOD gave (R)-12 in 84%ee, as determined after
its conversion to the MTPA ester 12% in the same way
as described for (S)-7a. Successive treatment of 11 with
MgBr2 at −78°C for 5 min and MeOD was found to
give (R)-12 in 83%ee, suggesting that the Li/Mg
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