Electrophile-Directed Diastereoselective Oxonitrile Alkylations

Article abstract of DOI:10.1002/chem.201705791

Diastereoselective alkylation of prochiral oxonitrile dianions with secondary alkyl halides efficiently installs two contiguous stereogenic centers. The confluence of nucleophilic trajectory and the electrophile chirality causes distinct steric differences that allow efficient discrimination for one of the six possible conformers. Numerous oxonitrile-derived dianions efficiently displace secondary alkyl halides propagating the electrophile chirality to efficiently install two contiguous tertiary centers. The prevalence of chiral, secondary electrophiles makes the interdigitated alkylation of chiral electrophiles a particularly attractive route because the resulting oxonitriles are readily transformed into bioactive heterocycles.

Full text of DOI:10.1002/chem.201705791

A Journal of
Accepted Article
Title: Electrophile-Directed Diastereoselective Oxonitrile Alkylations
Authors: Fraser Fergusson Fleming, Sergiy Chepyshev, Bhaskar
Reddy Pitta, Saidi Reddy Vangala, J. Armando Lujan-
Montelongo, and Omar Steward
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Chem. Eur. J. 10.1002/chem.201705791
Link to VoR: http://dx.doi.org/10.1002/chem.201705791
Supported by

10.1002/chem.201705791
Chemistry - A European Journal
COMMUNICATION
Electrophile-Directed Diastereoselective Oxonitrile Alkylations
Sergiy V. Chepyshev,[a] Bhaskar Reddy Pitta,[b] Saidi Reddy Vangala,[c] J. Armando Lujan-
Montelongo,[d] Omar W. Steward,[e] and Fraser F. Fleming[a]*
Abstract: Diastereoselective alkylation of prochiral oxonitrile dianions
with secondary alkyl halides efficiently installs two contiguous
stereogenic centers. The confluence of nucleophilic trajectory and the
electrophile chirality causes distinct steric differences that allow
efficient discrimination for one of the six possible conformers.
Numerous oxonitrile-derived dianions efficiently displace secondary
alkyl halides propagating the electrophile chirality to efficiently install
two contiguous tertiary centers. The prevalence of chiral, secondary
electrophiles makes the interdigital alkylation of chiral electrophiles a
particularly attractive route because the resulting oxonitriles are
readily transformed into bioactive heterocycles.
inherently valuable because they efficiently forge tertiary
stereocenters with the potential for propagating chirality to
additional centers with substituted enolates.
CO2Et
H
O
H
OEt
H
LDA, THF
-50 C
OTf
OEt
O
O
OLi
1
3
4
(dr 10-15:1)
2
O
Scheme 1. Electrophile-induced diastereoselective alkylation.
Electrophile-induced diastereoselectivity arises from an
interdigitation of the nucleophile and electrophile that minimizes
steric interactions and maximizes orbital overlap. Prior
calculations with the enolate derived from acetaldehyde place the
attack angle on methyl fluoride at 106°[5] (Figure 1, 5) although
higher level calculations revise the trajectory to 116°.[6] The acute
trajectory interdigitates the enolate protons with one proton, H*, of
the electrophile (Figure 1) in excellent qualitative agreement with
experimental models for enolate alkylations,[7] aldol reactions[8]
and conjugate additions.[9]
Over the past three decades roughly twice as many
enantioselective processes were reported compared to
diastereoselective ones (Chart 1). Asymmetric catalysis has been
particularly effective in delivering functionalized enantiomers with
excellent selectivity.[ 1 ] These advances provide an extensive
array of chiral precursors with excellent potential for propagating
the asymmetry of chiral precursors in carbon-carbon bond
constructions.
SciFinder Hits for "Enantio" and "Diastereo"
References
H*
H
H
O
11400
H
H
H
Enantio
Diastereo
H
H
H*92°
85°
116°
9400
7400
5400
3400
1400
H
H
O
H
5
F
Figure 1. Attack trajectory in enolate alkylations.
Assuming one enolate geometry, alkylation of a chiral,
secondary electrophile (7) with a prochiral enolate can proceed
through attack on one of two faces leading to six possible
alignments (Scheme 2, 8a-c and 8d-f, respectively). Conformers
8a and 8d minimize the steric interactions by straddling the
methine proton between the enolate substituents R1 and H; less
steric compression is present in conformer 8d because the large
electrophile substituent L eclipses a proton (Scheme 2, cf. R1↔M
in 8d vs R1↔L in 8a). Achieving the selective alkylation through
8d would begin to address the challenge "of asymmetric -
alkylation of simple ketone enolates."[10]
1990
1995
2000
2005
Publication Year
2010
2015
2020
Chart 1. SciFinder hits for "enantio" and "diastereo"
Sporadic alkylations with secondary electrophiles[2] powerfully
demonstrate the potential for propagating one chiral center into
two contiguous stereocenters.[3] For example, alkylating ketone 1
with the chiral pyruvate-derived electrophile
2 selectively
E-Enolate - re face attack
generated a ketoester with two new stereocenters (3 → 4,
Scheme 1).[ 4 ] Alkylations with secondary electrophiles are
H
L
M
R1
L
R1
M
R1
H
O
Base
H
H
H
H
M
L
H LG
R2
MO
R2
MO
R2
MO
R2
[a]
Dr. Sergiy Chepyshev and Prof. Fraser F. Fleming
Department of Chemistry, Drexel University, Philadelphia, PA
19104.
R1
M
L
6
7
8a
8b
8c
E-mail: fleming@drexel.edu
[b]
[c]
[d]
Dr. Bhaskar Pitta Reddy
Biophore India, Hyderabad, India
Dr. Saidi Reddy Vangala
Clearsynth Labs, Hyderabad, India
Prof. J. Armando Lujan-Montelongo
Departamento de Química
E-Enolate - si face attack
H
H
L
M
H
R1
M
R1
H
R1
H
L
H
M
H
H
L
L
R2
R2 OM
R2 OM
R2 OM
Centro de Investigación y de Estudios Avanzados (Cinvestav)
Av. Instituto Politécnico Nacional 2508, Ciudad de México, 07360
(México)
9
8d
8e
8f
[e]
Prof. Omar Steward
Duquesne University, Pittsburgh, PA 15282
This article is protected by copyright. All rights reserved.

10.1002/chem.201705791
Chemistry - A European Journal
COMMUNICATION
Table 1. Interdigital Alkylations with Secondary Electrophiles
Scheme 2. Alkylation of a secondary electrophile having
medium (M) and large (L) substituents.
KHMDS
(2.1 equiv)
-78 °C;
R1
H
Ar1
Ar1
O
Ar2
Exploratory
diastereoselective
alkylations
employed
R1
O
11
]
oxonitrile-derived dianions[
because the excellent
X
Ar2
CN
CN
6
7
9
nucleophilicity was deemed beneficial for SN2 displacements of
secondary electrophiles (Scheme 3).[12] After some optimization,
the dianion derived from 3-oxo-4-phenylbutanenitrile (6a) [13] was
found to be readily generated with two equivalents of a metal
amide base. Deprotonation with LDA and LiHMDS allowed
efficient alkylation with secondary bromide 7a but afforded 9a as
an equal mixture of diastereomers whereas KHMDS afforded 9a
as a 3.6:1 mixture of diastereomers (Table 1, entry 1).
Entry
1
Oxonitrile
Electrophile
Alkylated nitrile
Yield
79%
3.6:1
MNR2
(2.1 equiv)
-78 °C;
H
R
H
H
R
2
3
H
65%
Br
8.0:1[a]
O
O
O
CN
R
CN
M
C
N
M
6a
7a R=H
10
9a R=H
9b R=Me
7b R=Me
67%
6.9:1
Br
Br
90°
CH3
CH3
H3C
H
H
CH3
7b''
7b'
Scheme 3. Electrophile optimization in interdigital alkylations.
4
5
6
7
63%
6.6:1
Commercial (1-bromoethyl)benzene (7a) was initially
selected as the electrophile because some conformational rigidity
was anticipated from alignment of the σ*c-x bond with the aromatic
 system, the "benzylic anomeric effect" (Scheme 3).[ 14 ] The
modest diastereoselectivity with 7a stimulated alkylation with 7b
in which the ortho-methyl substituent favors conformer 7b'' to
avoid a syn-pentane-type interaction in 7b', a strategy developed
to constrain flexible molecules into a defined shape (Scheme
3).[15] Alkylation of 6a with 7b increased the stereoselectivity to
8.0:1 (Table 1, entry 2), consistent with alkylation through
interdigitated conformer 10.[16]
63%
2.0:1
Diastereoselective alkylations with a series of oxonitriles and
secondary electrophiles are stereoselective and efficient (Table
1). Varying the ortho-substituent from methyl (7a) to methoxy (7c)
or bromine (7d) had little impact on the diastereoselectivity (Table
1, entries 2-4) despite the potential for adverse chelation with a
methoxy substituent. In contrast, alkylations of 6a with the
isopropyl-substituted bromide 7e and the pyridyl electrophile 7f[17]
were minimally selective (Table 1, entries 5 and 6). Alkylations of
the naphthyl oxonitrile 6b (Table 1, entries 7 and 8), electron
deficient (Table 1, entries 9 and 10) and electron rich oxonitriles
(Table 1, entries 11 and 12) installed the contiguous
stereocenters with good diastereoselectivity. Alkylations with 2-
thienyl and 3-thienyl oxonitriles 6f and 6g afforded diastereomeric
ratios of 6.5:1 and 7.1:1 (Table 1, entries 13 - 15) whereas
alkylation with the sterically less demanding furan 6f afforded a
2.5:1 ratio of diastereomers (Table 1, entry 16).[18] Collectively the
alkylations of the thiophene and furan-containing oxonitriles
suggest that ring size is a more important control element than a
potential heteroatom binding site. Alkylation of the dianion derived
from the oxoester 11 with 7b afforded the ketoester 12 with a
diastereoselectivity greater than 20:1 (Table 1, entry 16).
63%
1.2:1
72%[a]
8.0:1
This article is protected by copyright. All rights reserved.

10.1002/chem.201705791
Chemistry - A European Journal
COMMUNICATION
8
76%
17
7.5:1
80%
>20:1
9
[a] The stereochemistry was unambiguously secured by crystallography. [19]
62%
8.6:1
The diastereoselective oxonitrile alkylations are predicated on
stereoselectively generating one enolate geometry. Insight into
the enolate stereochemistry was gained by trapping the dianion
13 with TBSCl; isolation of the two enol silyl ethers 14 and 15
imply that the enolate exists as the Z-diastereomer 13 (Scheme
4).
10
74%
8.3:1
Ph
O
Ph
H
Ph
TBS
Ph
KHMDS
TBSCl
(94%)
K
+
TBS
CN
O
TBSO
TBSO
C
N
11
12
13
14
15
16
CN
K
13
CN
dr >20:1
6a
14
15
Scheme 4. Probing the configuration of the oxonitrile dianion.
76%
12.5:1
Several oxonitriles were efficiently transformed into
pyrimidines and pyrazoles by sequential condensation with N,N-
dimethylformamide dimethyl acetal (DMF-DMA) and bis-nitrogen
nucleophiles (Table 2, 9 → 16 → 17).[20] Performing the sequence
with oxonitrile 9b, DMF-DMA and amidine hydrochloride afforded
methylpyrimidine 17a (Table 2, entry 1) whereas oxonitrile 9j
reacted with DMF-DMA and guanidine hydrochloride to afford
predominantly the aminopyrimidine 17b (Table 2, entry 2). An
analogous sequence with the naphthalene-containing oxonitrile
9g afforded a 7.2:1 ratio of aminopyrimidines 17d and 17e (table
2, entry 3). Sequential condensation of 9j with DMF-DMA and
hydrazine afforded pyrazoles 17f and 17g (Table 2, entry 4).[21]
Selective nitrile reduction[22] of the oxonitrile 9b with i-Bu2AlH and
subsequent addition of hydrazine provided the pyrrazole 17h
(Table 2, entry 5). Direct addition of hydrazine to the ketoester 12
afforded the hydroxypyrazole 17i (Table 2, entry 6).
78%
4.9:1
67%
6.5:1
68%
7.1:1
Table 2. Oxonitrile Conversion to Heterocycles
Entry
1
Oxonitrile
Reagent(s)
DMF-DMA;
Heterocycle
67%
10.0:1
63%
2.5:1
2
DMF-DMA;
This article is protected by copyright. All rights reserved.

10.1002/chem.201705791
Chemistry - A European Journal
COMMUNICATION
i-Bu2AlH;
H2NNH2.H2O
5
6
H2NNH2.H2O
3
DMF-DMA;
[a] Exists as a mixture of tautomers.
Alkylations of oxonitrile dianions with secondary electrophiles
provides one solution to the longstanding challenge of
asymmetric ketone enolate alkylations. The strategy exploits the
inherent asymmetry of secondary electrophiles in
a
diastereoselective alkylation with stereodefined oxonitrile-derived
dianions. The interdigitation between the dianion and the
secondary electrophile propagates the asymmetry of one center
to install two contiguous stereocenters with high stereochemical
fidelity. Combining the interdigital alkylation with a postoperative
heterocycle synthesis provides diverse heterocycles bearing two
adjacent tertiary centers that are otherwise challenging to
synthesize. Forging new chiral centers by co-opting the chirality
of an electrophile is attractive because of the inherent chiral
efficiency, the prevalence of methods to access chiral secondary
halides, and the excellent stereoselectivity.
DMF-DMA;
H2NNH2.H2O
4
Acknowledgements: Financial support from the National
Science Foundation is gratefully acknowledged (CHE 1111406
and 1464494).
Keywords: interdigital • alkylation • oxonitrile •
diastereoselectivity • heterocycles
[1]
Catalytic Asymmetric Synthesis, 3rd Ed, I. Ojima John Wiley & Sons,
Hoboken, NJ, 2010.
[2]
[3]
S. D. Lepore, D. Mondal Tetrahedron 2007, 63, 5103–5122
S. D. Bull, S. G. Davies, S. W. Epstein, A. C. Garner, N. Mujtaba, P. M.
Roberts, E. D. Savory, A. D. Smith, J. A. Tamayo, D. J. Watkin
Tetrahedron, 2006, 62, 7911-7925. b) W. M. Kazmierski, Z. Urbanczyk-
Lipowska, V. J. Hruby, J. Org. Chem. 1994, 59, 1789-1795. c) R. Fitzi,
D. Seebach, Tetrahedron, 1988, 44, 5277-5292. d) D. Seebach, M.
Hoffmann, Eur. J. Org. Chem, 1998, 1337-1351.
a) E. Vedejs, O. Daugulis, J. Am. Chem. Soc. 2003, 125, 4166-4173. b)
E. Vedejs, O. Daugulis, J. Am. Chem. Soc. 1999, 121, 5813-5814.
Houk, K. N.; Paddon-Row, M. N. J. Am. Chem. Soc. 1986, 108, 2659-
2662.
[4]
[5]
[6]
Professor Jeffrey Evanseck, unpublished results using the MO5-2x
functional and the basis set 6-311G(2d,p).
[7]
Fleming, I.; Lewis, J. J. J. Chem. Soc., Perkin Trans 1 1992, 3257-3266.
Oare, D. A.; Heathcock, C. H. J. Org. Chem. 1990, 55, 157-172.
Seebach, D.; Goliński, J. Helv. Chim. Acta 1981, 64, 1413-1423.
R. Cano, A. Zakarian, G. P. McGlacken Angew. Chem. Int. Ed. 2017, 56,
9278-9290; Angew. Chem. 2017, 129, 9406-9418.
a) F. F. Fleming, P. S. Iyer Synthesis 2006, 893-913. b) T. M. Harris, C.
M. Harris, T. A. Oster, L. E. Brown, Jr., J. Y. C. Lee J. Am. Chem. Soc.
1988, 110, 6180-6. c) T. M. Bargar, R. J. Broersma, L. C. Creemer, J. R.
[8]
[9]
[10]
[11]
This article is protected by copyright. All rights reserved.

10.1002/chem.201705791
Chemistry - A European Journal
COMMUNICATION
McCarthy, J. M. Hornsperger, P. V. Attwood, M. J. Jung, J. Am. Chem. Soc. 1988, 110, 2975-2976.
a) Z. Xi Acc. Chem. Res. 2010, 43, 1342-1351. b) P. Langer, W. Freiberg Chem. Rev. 2004, 104, 4125-4149.
a) Y. Chen, S. M. Sieburth Synthesis 2002, 2191-2194. b) N. Rasool, M. A. Rashid, H. Reinke, C. Fischer, P. Langer Tetrahedron 2007, 63, 11626-11635.
G. H. Penner, T. Schaefer, R. Sebastian, S. Wolfe Can. J. Chem., 1987, 65, 1845-1852.
a) R. W. Hoffmann Angew. Chem., Int. Ed. 2000, 39, 2055-2070; Angew. Chem., Int. Ed. 2000, 112, 2134. b) R. W. Hoffmann Chem. Rev. 1989, 89,
1841-60.
[12]
[13]
[14]
[15]
[16]
Control experiments demonstrate that the reaction is under kinetic, not thermodynamic, control. Equilibration of 9b required treatment with 4 equiv of
LDA for 16 h, see the Supporting Information for details.
[17]
[18]
[19]
Prepared by a modification of an earlier procedure: M. N. Magubane, M. G. Alam, S. O. Ojwach, O. Q. Munro J. Mol. Struct. 2017, 1135, 197-201.
F. H. Allen, O. Kennard, D. G. Watson, L. Brammer, A. G. Orpen, R. Taylor J. Chem. Soc. Perkin Trans II 1987, S1-S19.
For 9b the configuration was determined by NaBH4 reduction, separation of the diastereomers, and crystallographic analysis of the major diastereomer.
The supplementary crystallographic data for the crystal structure of (3S*, 4S*, 5R*)-3-hydroxy-4-phenyl-5-(o-tolyl)hexanenitrile, CCDC# 795809) can
be obtained free of charge via www.ccdc.cam.ac.uk/conts/retrieving.html or from the Cambridge Crystallographic Data Center, 12 Union Road,
Cambridge CB2 1EZ, UK (fax +44 1223 336033; or deposit@ccdc.cam.ac.uk.)
a) S. Bondock, A. E.-G. Tarhoni, A. A. Fadda Curr. Org. Chem. 2011, 15, 753-781. B) A. W. Erian, Chem. Rev. 1993, 93, 1991-2005.
D. E. Tupper, M. R. Bray Synthesis 1997, 337-341.
S. R. Pollack, J. T. Kuethe Org. Lett. 2016, 18, 6388-6391.
[20]
[21]
[22]
COMMUNICATION
Two for one! Interdigital alkylations of oxonitrile dianions with
secondary alkyl halides propagates the singular electrophile
stereocenter into two new chiral centers. The confluence of
nucleophilic trajectory and electrophile chirality favors one of six
possible conformers to efficiently install two contiguous tertiary
centers in oxonitriles that are readily transformed into bioactive
heterocycles.
Author(s), Corresponding
Author(s)*
Page No. – Page No.
Title
This article is protected by copyright. All rights reserved.