Metalated nitriles: Internal 1,2-asymmetric induction

Article abstract of DOI:10.1002/anie.200701550

(Chemical Equation Presented) Steric screening: In alkylations of metalated nitriles containing vicinal methyl groups and a trisubstituted C=C bond, the butene moiety screens electrophilic attack from one diastereotopic face as the quaternary stereocenter

Full text of DOI:10.1002/anie.200701550

Communications
DOI: 10.1002/anie.200701550
Asymmetric Induction
Metalated Nitriles: Internal 1,2-Asymmetric Induction**
Fraser F. Fleming,* Wang Liu, Somraj Ghosh, and Omar W. Steward
Installing quaternary asymmetric centers is a fundamental
challenge in asymmetric synthesis.[1] Alkylation reactions
creating quaternary centers from carbonyl derivatives typi-
cally combine controlled enolate formation within a sterically
biased scaffold to direct electrophilic alkylations.[2] Chiral
lactams and lactones[3] obviate selective (E)- or (Z)-enolate
Scheme 1. Diastereoselective alkylation of an N-metalated nitrile.
LDA=lithium diisopropylamide; yield given in parentheses.
formation by employing small rings; they use strategically
oriented substituents to impart topological differences to
direct selective electrophilic attack on one face of the enolate.
Asymmetric alkylations of acyclic a,a-disubstituted enolates
are more challenging because of the difficulty in selectively
generating one (E)- or (Z)-enolate and restricting conforma-
tional mobility for facial discrimination during alkylation.[4]
Stereoselective alkylations of acyclic nitriles are even
more challenging.[5] The difficulty lies partly in the inherent
bonding of metalated nitriles, which precludes direct attach-
ment of a chiral auxiliary to the CN group, and partly in the
site of metal coordination. Lithiated nitriles demonstrate an
inherent propensity for coordination to the nitrile nitrogen
atom,[6] which places lithium-bound chiral ligands relatively
far away from the stereogenic “carbanion.”[7] Despite these
challenges, metalated nitriles remain ideal nucleophiles for
installing quaternary centers because of their exceptional
nucleophilicity and minimal steric demand.[8]
Intermittent alkylations of metalated nitriles bearing an
adjacent chiral center induce modest to excellent stereose-
lectivity.[9] A highly selective allylation of a naphthyl-sub-
stituted butyronitrile[10] suggested the phenethyl-bearing
nitrile 1[11] as a viable candidate for diastereoselective
alkylations. Deprotonating 1 with a lithium amide base is
expected to generate an N-lithiated nitrile that is predisposed
toward a conformation that minimizes the inherent allylic
strain (Scheme 1).[12] Conformer 2a incurs a Me–Me gauche-
type interaction, whereas the analogous Me–CN interaction
in 2b is significantly smaller because of the extremely small
steric demand of a nitrile group (the A value is a mere
0.2 kcalmolÀ1).[13] Conformer 2b minimizes the steric inter-
actions with the benzylic methyl group by placing the small
nitrile group in the more sterically demanding environment.
This conformation projects the phenyl group over the planar,
N-lithiated nitrile to favor electrophilic attack from the
opposite face. Experimentally, deprotonation of the racemic
nitrile 1 with subsequent addition of methyl cyanoformate
affords 3a as a single diastereomer.[14]
X-ray crystallography confirmed that the configuration of
the newly installed quaternary center in 3a was consistent
with the alkylation model given in Scheme 1. Although the
N metalation inherent in this predictive model is almost
always favored with lithium counterions, unusual structural
features[15] and ligand effects[16] sporadically lead to C-
lithiated nitriles. C-metalated nitriles, particularly C-magne-
siated nitriles, are capable of stereodivergent alkylations with
alkyl halides (retention), methyl cyanoformate (inversion),
and allylic halides (unselective), thus prompting alkylations of
2 with two additional test electrophiles.[17] Intercepting the
lithiated nitrile 2 with 4-pentenyl bromide and cinnamyl
bromide affords 3b and 3c, respectively, as single diastereo-
mers[18] (Scheme 2) with asymmetric induction analogous to
Scheme 2. Investigation of alkylation selectivity with test electrophiles.
3a (Scheme 1). Installing the quaternary centers in 3a–c with
the same stereochemical sense is fully consistent with the
sterically controlled alkylation of the N-lithiated nitrile via
conformer 2b.
The stereoselective alkylations of 1 stimulated analogous
alkylations with 8 as a potentially attractive synthetic
precursor for installing quaternary centers. Acylation of
racemic alcohol 4[19] provided the ester 5; an Ireland–Claisen
rearrangement then afforded acid 7 (Scheme 3).[20] Conver-
sion to the corresponding amide with subsequent dehydration
provided the requisite nitrile 8. Sequential deprotonation and
alkylation with methyl cyanoformate affords 9a as a single
nitrile diastereomer[14] with the same relative configuration as
3a (Table 1, entry 1).
[*] Prof. F. F. Fleming, W. Liu, S. Ghosh, Prof. O. W. Steward
Department of Chemistry and Biochemistry
Duquesne University
Pittsburgh, PA 15282-1530 (USA)
Fax: (+1)412-396-5683
E-mail: flemingf@duq.edu
Homepage: http://www-home.cr.duq.edu/~flemingf/
[**] Financial support from the National Science Foundation (USA) is
gratefully acknowledged (CHE 0515715).
Excellent stereoselectivity is maintained in alkylations of
nitrile 8 with a diverse array of electrophiles (Table 1). In each
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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Chemie
Scheme 4. Diastereoselective alkylations of lithiated nitrile 10.
alkylated nitriles 9 with the same stereochemical sense as the
alkylation of 1 to give 3 (Scheme 1).
In contrast to the exceptionally selective alkylations of
nitriles 1 and 8, alkylation of the analogous ester 11 affords 13
and 14 in a 6:1 ratio (Scheme 5).[21] Presumably, the modest
Scheme 3. Claisen rearrangement route to nitrile 8. TMS=Me3Si.
Table 1: Diastereoselective alkyations of nitrile 8.
Entry
Electrophile
Quaternary nitrile[a]
Yield [%]
1
58
2
3
84[b]
80
4
5
72
79
Scheme 5. Diastereoselective alkylations of ester 11.
selectivity reflects a preferential electrophilic attack on the
sterically less congested rotamer 12b. Rotamer 12b incurs a
Me–Me gauche-type interaction, whereas the analogous Me–
OR interaction in 12a is significantly greater, because the
enolate geometry forces the alkoxy substituent to project
toward the benzylic methyl group.
Exceptional diastereoselectivity is observed in alkylations
of appropriately substituted metalated nitriles. Embedding
vicinal methyl groups in an alkyl chain containing a trisub-
stituted alkene, or a benzene ring, creates a strong bias for the
stereoselective installation of quaternary stereocenters.
Excellent stereoselectivity is maintained with a diverse
range of electrophiles, providing the first general strategy
for diastereoselective alkylations of acyclic nitriles.
6
78
7
8
9
82
72
52
[a] The configuration of 9a was determined by derivatization followed by
X-ray crystallography with the remaining stereochemical assignments
made by analogy. [b] Oxidation affords a single ketone diastereomer.
instance, only one diastereomer is detectable in the crude
reaction mixture, except with cyclohexanecarboxaldehyde,
for which the stereoselectivity is maintained at the nitrile-
bearing carbon atom with a 1:1 ratio of carbinol diastereo-
mers (Table 1, entry 2). The alkylation is equally effective
with reactive carbonyl electrophiles (Table 1, entries 1–3) as
with less reactive alkyl halides (Table 1, entries 7–9). Inter-
cepting the metalated nitrile with the secondary alkyliodide
iPrI (Table 1, entry 9) is less efficient and probably reflects the
increased steric demand accompanying the installation of a
contiguous array of tertiary–quaternary–tertiary centers.
Mechanistically, the stereoselective alkylations of 8 are
consistent with an electrophilic approach to rotamer 10 from
the face opposite the alkene (Scheme 4). The trisubstituted
alkene in 8 effectively acts as a truncated benzene ring
(relative to 1, which has a full phenyl ring), affording the
Experimental Section
General deprotonation–alkylation procedure: The nitrile (1.0 equiv)
in THF (0.3 m) was added to a solution of LDA, generated from
butyllithium (1.05 equiv) and diisopropylamine (1.15 equiv), in THF
(0.1m) at À788C. After 50 min at À788C, neat electrophile (1.2 equiv)
was added. After 3 h at À788C, saturated, aqueous NH4Cl was added,
the crude product was extracted with EtOAc, dried (MgSO4),
concentrated, and purified by radial chromatography to afford
analytically pure material.
Received: April 9, 2007
Published online: August 9, 2007
Keywords: alkylation · diastereoselectivity ·
.
internal asymmetric induction · metalated nitriles ·
quaternary asymmetric centers
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Communications
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[14] a) 1H NMR spectroscopic analysis of the crude reaction mixture
failed to identify any diastereomer; b) stereochemical assign-
ment is based on X-ray crystallography of a derivative (see the
Supporting Information).
À
[3] “Formation of C CBonds by Addition of Enolates to Carbonyl
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[18] The configurations of 3b and 3c were secured by chemical
correlation with that of the ester nitrile 3a as outlined in the
Supporting Information.
[19] Employed as a racemate, although potentially available in either
enantiomeric series: M. Hayashi, T. Kaneko, N. Oguni, J. Chem.
Soc. Perkin Trans. 1 1991, 25.
[20] R. E. Ireland, P. Wipf, D. J. Armstrong III, J. Org. Chem. 1991,
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[21] The configuration of 14 was chemically correlated with that of 3c
(Scheme 2).
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