γ- and δ-Hydroxynitriles: Diastereoselective electrophile-dependent alkylations

Article abstract of DOI:10.1016/j.tet.2012.10.016

Deprotonating γ- and δ-hydroxynitriles with i-PrMgCl allows highly diastereoselective alkylations controlled by the asymmetry of the remote carbinol stereocenter. Mechanistic experiments are consistent with γ-hydroxynitriles alkylating via a chelated magnesiated nitrile whereas δ-hydroxynitriles favor alkylation from acyclic magnesiated nitriles. Collectively these alkylations; are the first electrophile-dependent alkylations of acyclic nitriles, exhibit a unique influence on the nature of the Grignard used for the deprotonation, and address the challenge of installing quaternary centers in conformationally mobile, acyclic nitriles.

Full text of DOI:10.1016/j.tet.2012.10.016

Tetrahedron 69 (2013) 366e376
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
g
- and
d
-Hydroxynitriles: diastereoselective electrophile-dependent
alkylations
*
Robert J. Mycka, William T. Eckenhoff, Omar W. Steward, Nathan Z. Barefoot, Fraser F. Fleming
Department of Chemistry and Biochemistry, Duquesne University, Pittsburgh, PA 15282-1530, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 21 August 2012
Received in revised form 2 October 2012
Accepted 3 October 2012
Available online 22 October 2012
Deprotonating
g
- and
d
-hydroxynitriles with i-PrMgCl allows highly diastereoselective alkylations con-
trolled by the asymmetry of the remote carbinol stereocenter. Mechanistic experiments are consistent
with -hydroxynitriles alkylating via a chelated magnesiated nitrile whereas -hydroxynitriles favor
g
d
alkylation from acyclic magnesiated nitriles. Collectively these alkylations; are the first electrophile-
dependent alkylations of acyclic nitriles, exhibit a unique influence on the nature of the Grignard used
for the deprotonation, and address the challenge of installing quaternary centers in conformationally
mobile, acyclic nitriles.
Keywords:
Nitriles
Alkylation
Stereoselectivity
Ó 2012 Elsevier Ltd. All rights reserved.
1. Introduction
Metalated nitriles are exceptional nucleophiles.1 The nitrile’s
compact, cylindrical geometry,2 combined with the strong inductive
stabilization,3 localizes a high charge density on an extremely
small,4 nucleophilic carbon. Attack from the small, charged nucle-
ophile permits the facile installation of quaternary centers,5 even in
cases where comparable enolate alkylations are unsuccessful.6
Diastereoselective alkylations of acyclic nitriles are challenging
because; chiral auxiliaries are not readily incorporated on or near the
nitrile unit,7 chiral ligands complexed to N-lithiated-nitriles lie in
a remote position from the nucleophilic carbon and poorly relay the
chiral asymmetry,8 C-metalated nitriles rapidly epimerize,9 and in-
herently flexible, rotatable, single bonds in alkanenitriles make access
toone reactiveconformerdifficult.10 Highlystereoselectivealkylations
of acyclic, metalated nitriles require restricting conformational mo-
bility. An effective strategy for 1,2-asymmetric induction is to install
a sterically biased stereocenter immediately adjacent to the nucleo-
philic carbon in combination with judiciously positioned alkyl sub-
stituents and unsaturation.11 More remote 1,3-asymmetric induction
with the chiral center two carbons removed from the metalated center
diminishes the selectivity into the range of 3e5:1 (1/3, Scheme 1),12
reflecting the difficulty of selectively accessing and alkylating one di-
amond lattice conformation (cf. 2a%2b).
Scheme 1. 1,3-Induction in the alkylation of an acyclic nitrile.
Applying the strategy to acyclic,
g-hydroxynitriles 4, by deproto-
nating with a Grignard reagent, generates a magnesiated nitrile
tentatively identified as the chiral, racemic, cyclic magnesiate 5
(Scheme 2).14 Alkylations of 5 exhibit a highly unusual diaster-
eoselectivity dependence on the nature of the electrophile;15 alkyl
halides afford syn-diastereomers 60, reactive carbonyl electrophiles
alkylate non-selectively (600), and less reactive ester and carbonate
electrophiles alkylate to afford anti-diastereomers (6000).16
The present manuscript describes mechanistic experiments to
probe the structure and reactivity of the intermediate magnesiated
nitrile, additional alkylations of
substituted alkyl halides, an application to the synthesis of an anti-
tussive agent, and alkylations with homologous -hydroxynitriles. In
g-hydroxynitriles with a series of
Temporary chelation provides a robust method for restricting
conformational mobility for diastereoselective alkylations.13
d
addition, a series of ester acylations are described where the in-
termediate ketones are reduced tothe corresponding dihydroxynitriles
by a stereoselective hydride transfer from the Grignard-derived iso-
* Corresponding author. Tel.: þ1 412 396 6031; fax: þ1 412 396 5683; e-mail
address: flemingf@duq.edu (F.F. Fleming).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2012.10.016

R.J. Mycka et al. / Tetrahedron 69 (2013) 366e376
367
Table 1
Diastereoselective alkylations of g-hydroxynitriles
Entry
1
Hydroxynitrilea
Electrophile
Quaternary nitrile
Yield % (dr)
79 (16.0:1)
91 (16.2:1)
91b (16.2:1)
64 (16.2:1)c
95b (9.4:1)
95 (8.0:1)
Scheme 2. Diastereoselective chelation-controlled alkylations of d-hydroxynitriles.
propyl group. Collectively these studies define the limits of this
hydroxynitrile chelation strategy, address the long-standing challenge
of installing quaternary centers in conformationally mobile, acyclic
nitriles, and provides a robust, predictive model that accounts for the
unusual electrophile-dependent stereoselectivity in alkylations of
2
3
4
5
6
g-hydroxynitriles.
2. Results and discussion
Preliminary alkylations of d-hydroxynitriles employed the tert-
butyl-substituted nitrile 4a17 as a prototype to accentuate the
emerging stereoselectivity trends (Table 1). Screening several base-
additive combinations18 identified i-PrMgCl as the most effective
base for doubly deprotonating hydroxynitrile 4a. Directly deproto-
nating alkylnitriles with Grignard reagents is unusual because nu-
cleophilicadditiontothenitrile grouptypicallycompetes withproton
abstraction.19 In the present case, the hydroxyl group serves to direct
internal deprotonation without detectable attack on the nitrile.
Operationally, i-PrMgCl is added to a ꢀ78 ꢁC, THF solution of the
hydroxynitrile, which is warmed to rt for 30 min and then re-
cooled to ꢀ78 ꢁC before addition of the electrophile. Although the
double deprotonation formally requires 2 equiv of i-PrMgCl, vir-
tually no deprotonation is observed until 4 equiv of i-PrMgCl is
added.20 Increasing the amount of i-PrMgCl to 5 equiv improves the
conversion by at least 25% and was therefore employed in all
subsequent deprotonations (Table 1, compare the yield for entry 4
with entries 1e3).
MeI
MeI
CD3I
7
8
9
96 (7.5:1)
82 (6.5:1)
47d (5.5:1)
The alkylation diastereoselectivity of 4a is independent of the
stereochemistry at the nitrile-bearing carbon. Sequentially depro-
tonating and alkylating diastereomerically pure 4aa, a 1:1, or
a 3.4:1 ratio of diastereomers 4a and alkylating with propyl iodide,
affords the quaternary nitrile 6aa with essentially the same dia-
stereoselectivity and in comparable yield (Table 1, entries 1e3).
Forming the same ratio of diastereomers 6aa, independent of the
starting configuration of 4a, implies forming a common magne-
siated nitrile having the same configuration at the nucleophilic
carbon. Presumably deprotonation provides a facile epimerization
mechanism, consistent with the rapid equilibration of cyclic mag-
nesiated nitriles9b and the configurational lability of C-lithiated
cyanohydrin-derived carbamates.21
10
11
75b (5.0:1)
93b (4.7:1)
Large variations in the size of the alkyl substituent at the nitrile-
bearing carbon have only a modest influence on the alkylation
12
56 (2.5:1)b,e
diastereoselectivity. Substituting the prototypical
a-methyl sub-
stituent of 4a with a propyl- or iso-propyl-substituent, in 4b and 4c
(Table 1, entries 5 and 6, respectively), and alkylating with MeI, or
CD3I for 4a (Table 1, entry 7), allows the diastereoselectivity to be
compared with electrophiles having virtually the same steric de-
mand. Despite the A values varying from 1.70 to 2.15 kcal molꢀ1, for
methyl, propyl, and iso-propyl groups, the diastereoselectivity
remains very similar.4 Presumably the C-2 substituent is positioned
a
Unless otherwise specified, the hydroxynitriles are mixtures of diastereomers.
Previously reported.16
i-PrMgCl of 4 equiv was employed.
Recovered 42% starting hydroxynitrile.
MeMgCl was employed as the base in place of i-PrMgCl.
b
c
d
e

368
R.J. Mycka et al. / Tetrahedron 69 (2013) 366e376
Table 2
away from the incoming electrophile in the magnesiated nitrile
22
Diastereoselective ester acylations of 4a
complex, consistent with a retentive alkylation (SE2Ret
)
from the
nucleophilic CeMg bond in magnesiate 5a.
Among the alkyl halide electrophiles, no clear correlation emerges
between the steric demand of the alkyl group and the diaster-
eoselectivity; PrI (16.2:1)>EtI (6.5:1)>i-PrI (5.5:1)>HC^CCH2Br
(5.0:1)>H2C]CHCH2Br (4.7:1).23 Propyl iodide alkylates significantly
more selectively than the sterically similar, but more reactive, allyl
and propargyl bromides (Table 1, compare entry 3 with entries 10 and
11). Collectively, the alkylation trends with alkyl halides are not
consistent with steric approach control and suggest that the diaster-
eoselectivity results from stereoelectronic controlled24 SE2
substitutions.22
entry
1
Electrophile
Quaternary nitrile
Yield (%)
87
Unlike most metalated nitrile alkylations where the diaster-
eoselectivity depends only on the steric trajectory,5 the alkylations
of 4 exhibit an unusual dependence on the nature of the electro-
phile. Intercepting the magnesiated nitrile derived from 4a with
esters affords dihydroxynitriles 8 in which the stereochemistry at
the nitrile-bearing carbon is inverted relative to that obtained from
alkylations of 4a with alkyl halides (Scheme 3). Deprotonating 4a
with i-PrMgCl and adding ethyl isobutyrate affords the dihydrox-
ynitrile 8aa in 87% yield and as a single diastereomer. The relative
configuration of the two new stereocenters was determined by
X-ray crystallography (Fig. 1).25
2
84
64a
3
17
a
Requires 10 equiv of i-PrMgCl.
diastereoselectivityoftheacylationandthereductionisexcellentwith
only one diastereomer detected in the 1H NMR of the crude reaction
mixture. The acylation of 5b with the sterically encumbered ester,
ethyl pivalate, is delicately poised between reduction to 8ca and
intramolecularcyclizationtolactol 9ca (Table 2, entry3). Using 5 equiv
of i-PrMgCl for the deprotonationeacylation results in cyclization to
lactol 9ca16 whereas 10 equiv of i-PrMgCl allows reduction to diol 8ca
(Table 2, entry 3). The ability of an additional 5 equiv of i-PrMgCl to
cause complete reduction of the intermediate lactol 9ca to the corre-
sponding diol nitrile 8ca again identifies the Grignard reagent as the
hydride source in these reductions.
Scheme 3. Sequential acylationereductions with ester electrophiles.
2.1. Mechanism
Insight into the nature of the intermediate magnesiated nitrile
came from otherwise identical alkylations of 4a with PrI in which
deprotonations with MeMgCl or i-PrMgCl give dramatically differ-
ent diastereoselectivities. Deprotonating 4a with i-PrMgCl is sig-
nificantly more selective than deprotonating with MeMgCl (Table 1,
compare entries 3 and 12; 16.2:1 vs 2.5:1, respectively), suggesting
that a Grignard-derived alkyl group is incorporated within the
magnesiated nitrile. Incorporation of an iso-propyl group within 5
is consistent with the reduction of ester electrophiles and the re-
activity and stereoselectivity differences of related C-magnesiated
nitriles.28 A working mechanism that accounts for the structure of
the Grignard reagent, the electrophile-dependent alkylations, the
acylationereduction sequence with ester electrophiles, and the
requirement for an excess of the Grignard reagent is for alkylation
via the cyclic, nitrile-stabilized magnesiate 5 (Scheme 4).
Fig. 1. ORTEP of the dihydroxynitrile 8aa.
The formation of dihydroxynitriles 8 is consistent with an initial,
invertiveacylation(SE2Inv)
22 of themagnesiatednitrile5b(Scheme 3).
Preferential attack by the ester on the small nucleophilic orbital al-
lows a collinear orbital overlap. Subsequent selective26 reduction of
the intermediate ketone 7 through internal hydride delivery27 is fa-
vored by the close proximity of the Grignard-derived iso-propyl
group.
Five equivalents of Grignard reagent is optimal for deprotonat-
ing the hydroxynitriles 4 (Scheme 4). In addition to the 2 equiv
consumed in the deprotonation, one additional equivalent of i-
PrMgCl is likely required to form the magnesiate 10 and facilitate
the deprotonation to the doubly deprotonated nitrile 11. Although
The ester acylationereduction sequence is effective with alky-
lesters bearing one or two
a-substituents (Table 2). The

R.J. Mycka et al. / Tetrahedron 69 (2013) 366e376
369
Scheme 5. Lithiated nitrile diastereoselectivity probe.
Scheme 4. Tentative alkylation mechanism.
the requirement for 4 equiv, ideally five, of i-PrMgCl is uncertain,
the related formation of an oxygenated, magnesiated nitrile re-
quired 5 equiv of EtMgCl.29 Possibly, i-PrMgCl is sequestered in an
association with the alkoxide oxygen (see 5, Scheme 4). Signifi-
cantly, the diastereoselectivity is the same with 4 or 5 equiv of i-
PrMgCl (Table 1, entries 4 and 3, respectively).
After the double deprotonation, 11 should preferentially cyclize
to the sterically less congested iso-propyl-containing magnesiate 5.
Assuming a chloromagnesium cation30 complexes the most ac-
cessible face of the electron rich alkyloxy oxygen in 5, then the
adjacent iso-propyl group should lie on the opposite side of the
five-membered ring and preferentially eclipse the small nitrile
group rather than the larger R2 group (cf. 5 and 500, Scheme 4).
Assuming alkylations from the cyclic magnesiate 5 explains the
Fig. 2. ORTEP of the lactone-nitrile 12aa.
Diethyl carbonate could potentially acylate first on carbon and
then lactonize or through a reversed O- then C-acylation sequence
(13/14/12a, Scheme 5). The potential acylation sequences were
discriminated by independently preparing 13 and deprotonating
the nitrile with lithium diethylamide. The absence of any diaster-
eoselectivity in the cyclization of 13 with LiNEt2, implies that the
acylation of 4a with diethyl carbonate16 occurs first on carbon in
a stereoelectronically controlled acylation.
unusual electrophile-dependent alkylations of
d-hydroxynitriles,
although other mechanistic scenarios cannot be excluded.31 The re-
tentive alkylations of alkyl halides are consistent with a side-on
overlap of the carbon-magnesium bond (5000/syn 6aef, Scheme 4).
An electrophilic approach to the CeMg bond is relatively remote from
the alkyl substituent R2, whose steric demand has minimal influence
on the diastereoselectivity (Table 1, entries 5e7). The alternative,
invertive attack on 5000 with an sp3 hybridized electrophile would
impose severe steric compression in the transition structure and
should be strongly correlated with the steric demand of the adjacent
substituent R2, which is not the case. Carbonyl electrophiles have
a diminished steric demand and larger anti-bonding orbitals that
should facilitate backside attack onto the small nucleophilic orbital of
the CeMg bond. Alkylations of carbonyl electrophiles progressing
through 50 benefit from progression through a co-linear, two-center,
two-electron transition structure whereas a retentive alkylation re-
quires a three-center, two-electron transition structure.
Although the N-lithiated nitrile 14 cyclizes non-selectively, the
corresponding C-magnesiated nitrile could potentially impart
greater internal asymmetric induction. Only recently has method-
ology become available to access the requisite C-magnesiated
nitrile34 to test whether this is a viable intermediate. Sequentially
acylating and oxidizing a 9.5:1 ratio35 of nitrile diastereomers with
6ga predominating (Scheme 6), provides sulfinyl nitrile 15 that was
engaged in
a
rapid sulfinylemagnesium exchange.34 Adding
i-PrMgCl to 15 generates the lactone 12aa in a 3.4:1 ratio,36 which is
significantly lower than the acylation of 4a with diethylcarbonate
(>20:1, Scheme 5). Consequently the C-magnesiated nitrile 16
seems unlikely as an intermediate,37 again supporting stereo-
electronically controlled acylation of 4a from magnesiate 5.
The predominant lactone diastereomer 12aa is that expected
from a retentive sulfinylemagnesium exchange 15/16 followed by
an invertive acylation 16/12aa, consistent with the general trend
of magnesiated nitriles to acylate with inversion. Presumably the
The invertive alkylation of carbonyl electrophiles is evident from
the acylation of 4a with diethylcarbonate (Scheme 5). The highly
selective (>20:1 dr) invertive acylation of 4a is followed by an at-
tack of the alkoxide onto the carbonyl to form the lactone 12aa.32
The relative stereochemistry of 12aa was secured by X-ray
diffraction (Fig. 2).33

370
R.J. Mycka et al. / Tetrahedron 69 (2013) 366e376
Table 3
Diastereoselective alkylations of
d-hydroxynitriles
Entry
1
d
-Hydroxyl
nitrile
Electrophile
Quaternary
nitrile
Yield
% (dr)
93
(2.5:1)
Scheme 6. Intramolecular acylation of a C-magnesiated nitrile.
64
(4.0:1)
2
3
4
5
6
3.4:1 ratio of lactone diastereomers arises because of transient
configurational stability of the C-magnesiated nitrile 16.9,21
Collectively the intramolecular acylations of 13 (Scheme 5) and
15 (Scheme 6) imply that the diastereoselective alkylations of the
magnesiated nitriles are stereoelectronically controlled.
90
(2.7:1)
The diastereoselective
g-hydroxynitrile alkylations stimulated
synthesizing hydroxynitrile 19aa in a formal synthesis of the cough
suppressant isoaminile (20, Scheme 7).38 Adding excess i-PrMgCl to
hydroxynitrile 4d17 affords a magnesiated nitrile intermediate that
very efficiently alkylates i-PrI, i-PrBr, and i-PrOTs (17/18/19aa).
The modest diastereoselectivity could arise from alkylation from
two different chelates (cf. 5 and 500, Scheme 4) because of the small
steric demand of the methyl carbinol substituent. Alternatively, the
strong resonance delocalization of charge into the adjacent phenyl
group3b may favor the non-chelated conformer12 18 from which
alkylation is only modestly selective. Hydroxynitrile 19aa has pre-
viously been converted into isoaminile (20) by activating the
hydroxyl group and displacing with dimethylamine.38
88
(1.4:1)
85
(5.9:1)
86
(3.7:1)
62
(3.5:1)
7
Scheme 7. Formal synthesis of isoaminile.
difference in steric demand between Me and t-Bu groups (1.7 and
4.7 kcal molꢀ1)4 implies that a cyclic chelate is not formed and that
the diastereoselectivity arises from modest diastereofacial differ-
ences in electrophilic attack on an acyclic conformer. A modest
decrease in stereoselectivity occurs as the steric demand of the
2.2. Homologous alkylations
A series of hydroxyl-directed deprotonationealkylations were
performed with homologous
d-hydroxynitriles to determine the
a-substituent changes from a methyl to phenyl group (Table 3,
viability of 1,4-asymmetric induction. Compared to
g-hydroxyni-
compare entries 2 and 3).
triles, positioning the carbinol center four carbons removed from
Alkylations of the tert-butyl
d-hydroxynitrile 21c are
the nucleophile leads to significantly lower diastereoselectivity
increasingly selective in the series iso-propyl iodide, propyl iodide,
propargyl bromide, allyl bromide (Table 3, entries 3e6)dalmost
(Table 3). Surprisingly, increasing the steric demand of the
d-
hydroxynitrile carbinol group from methyl to tert-butyl, only
marginally increases the diastereoselectivity (2.5:1 compared to
2.7:1, Table 3, entries 1 and 3, respectively). The enormous
opposite the order for the g-hydroxynitrile 4a (Table 1). Acylating
21c with methyl cyanoformate affords a 3.5:1 ratio of bis-acylated
nitrile diastereomers with acylation on both oxygen and carbon,

R.J. Mycka et al. / Tetrahedron 69 (2013) 366e376
371
favoring 22ga with the same relative configuration as for alkyl-
4.2. General alkylation procedure
ations with alkyl halides. The bis-acylation of 21c and the absence
of electrophile-dependent diastereoselectivity, are consistent with
reaction from an acyclic magnesiated nitrile rather than a cyclic
magnesiate.39 At a minimum, the modest selectivities suggest that
A THF solution of i-PrMgCl (5.0 equiv, 2.0 M solution) was added
to a ꢀ78 ꢁC, THF solution of the hydroxynitrile (1 equiv). After
5 min, the cold bath was removed and the reaction mixture was
allowed to warm up to rt. After 30 min, the reaction mixture was
cooled to ꢀ78 ꢁC, neat electrophile (5e10 equiv) was added, and
then the cooling bath was removed. After 16 h a saturated, aqueous
solution of NH4Cl was added, the phases were separated, and the
aqueous phase was extracted three times with EtOAc. The com-
bined organic extracts were dried over Na2SO4, concentrated, and
purified by either silica gel column chromatography (230e400
mesh) or radial chromatography, to afford analytically pure
material.
the magnesiated nitriles derived from
g- and d-hydroxynitriles
have significantly different structural integrity.
3. Conclusion
g
- and
ations that efficiently install nitrile-bearing, quaternary centers. The
alkylations of -hydroxynitriles are typically highly diaster-
d-Hydroxynitriles undergo double deprotonationealkyl-
d
eoselectivewith the stereochemistry being dependenton the nature
of the electrophile; alkyl halides install the alkyl group syn to the
hydroxyl whereas reactive carbonyl electrophiles alkylate non-
selectively. In contrast, less reactive ester and carbonate electro-
philes selectively install the carbonyl anti to the hydroxyl group.
4.2.1. (2RS,4SR)- and (2RS,4RS)-4-Hydroxy-2,5,5-trimethyl-2-
propylhexanenitrile (6aa and 6ab, respectively). Performing the
general procedure using nitrile 4a17 (57.1 mg, 0.368 mmol),
i-PrMgCl (0.92 mL, 1.84 mmol), and PrI (0.36 mL, 3.70 mmol) gave
a crude product that was purified by radial chromatography (95:5,
hexanes/EtOAc) to afford 66.1 mg (91% yield) of 6a (16.2:1 ratio of
diastereomers 6aa and 6ab, respectively) as a colorless oil spec-
trally identical to material previously isolated.16 Alternate pro-
cedure using MeMgCl as the base: performing the general
procedure with nitrile 4a17 (65.1 mg, 0.419 mmol), MeMgCl
(0.70 mL, 2.10 mmol), and PrI (0.50 mL, 5.14 mmol) gave a crude
product that was purified by radial chromatography (95:5,
hexanes/EtOAc) to afford 46.1 mg (56% yield) of pure 6a as an oily
mixture of diastereomers in a 2.5:1 ratio of 6aa and 6ab, re-
spectively. Preparation of 6aa by hydrogenating 6ea: a methanolic
solution (15 mL) of hydroxynitrile 6ea (44.2 mg, 0.229 mmol) was
hydrogenated for 4 h in a Parr shaker at 50 psi using 5% Pd/C
(6.3 mg, 0.059 mmol). The reaction mixture was then concentrated,
the crude product was redissolved in EtOAc, and then passed
through a short pad of silica gel to afford 42.5 mg (94% yield) of pure
6aa as a colorless oil. Preparation of 6aa by hydrogenating 6fa:
Mechanistically the alkylations of g-hydroxynitriles are consis-
tent with forming a highly unusual, nitrile-stabilized magnesiate
that incorporates a Grignard-derived alkyl group. Alkylations with
ester electrophiles afford dihydroxynitriles arising from an ex-
tremely selective reduction of the intermediate ketones triggered
by
b
-hydride elimination within the magnesiate. Comparable al-
-hydroxynitriles
kylations and acylations of the homologous
d
exhibit modest stereoselectivities that suggest alkylation through
an acyclic conformation with significantly different structural in-
tegrity to that derived from
g-hydroxynitriles. Collectively these
alkylations are the first electrophile-dependent alkylations of acy-
clic nitriles, exhibit a unique influence on the nature of the Grignard
used for the deprotonation, demonstrate an unusual acyla-
tionereduction in acylations with esters, and address the challenge
of installing quaternary centers in conformationally mobile, acyclic
nitriles.
a
MeOH solution (15 mL) of hydroxynitrile 6fa (75.4 mg,
4. Experimental
0.386 mmol) was hydrogenated for 4 h in a Parr shaker at 50 psi
using 5% Pd/C (5.1 mg, 0.048 mmol). The reaction mixture was then
concentrated, the residue redissolved in EtOAc, and then passed
through a short pad of silica gel to afford 67.1 mg (88% yield) of pure
6aa.
4.1. (2RS,4SR)- and (2SR,4SR)-4-Hydroxy-5,5-dimethyl-2-
propylhexanenitrile (4b)
Modifying a known procedure,17 neat pentanenitrile (2.75 mL,
31.5 mmol) was added to a ꢀ78 ꢁC THF solution (30 mL) of LDA
prepared from diisopropylamine (4.52 mL, 32.3 mmol) and butyl-
lithium (32.1 mmol). After 45 min, neat 3,3-dimethyl-1,2-
epoxybutane (4.00 mL, 32.5 mmol) was added and then the cool-
ing bath was removed. After 1 h, the solution was cooled to ꢀ78 ꢁC,
solid NH4Cl (2.21 g, 41.3 mmol) was added, followed after 20 min,
by an aqueous solution of 2 M HCl (50 mL). The resultant solution
was allowed to warm to rt overnight, the phases were separated,
and then the aqueous phase was extracted with ether. The com-
bined organic phase was dried (Na2SO4) and then the solvent was
removed under reduced pressure to yield an oil that was purified by
flash chromatography (95:5, hexanes/EtOAc) to yield 3.35 g (58%
yield) of 4b as an oily mixture of diastereomers: IR (neat): 3471,
2240 cmꢀ1. Careful chromatography provided a small, pure, sample
of each diastereomer for 1H NMR analysis. Major isomer: 1H NMR
4.2.2. (2RS,4SR)-4-Hydroxy-2,5,5-trimethyl-2-propylhexanenitrile
(6aa and 6ab, respectively). Performing the general procedure with
nitrile 4b17 (101.5 mg, 0.554 mmol), i-PrMgCl (1.39 mL, 2.78 mmol),
and methyl iodide (0.35 mL, 5.62 mmol) gave a crude product that
was purified by radial chromatography (90:10, hexanes/EtOAc) to
afford 103.9 mg (95% yield) of 6a (9.4:1 ratio of diastereomers 6aa
and 6ab, respectively) spectrally identical to material previously
isolated.16
4.2.3. (2RS,4SR)- and (2RS,4RS)-4-Hydroxy-2-isopropyl-2,5,5-
trimethylhexanenitrile (6ba and 6bb, respectively). Performing the
general procedure using nitrile 4c17 (94.5 mg, 0.52 mmol), i-PrMgCl
(1.29 mL, 2.58 mmol), and methyl iodide (1.00 mL, 16.1 mmol) gave
a crude product that was purified by radial chromatography
employing (90:10, hexanes/EtOAc) to afford 96.6 mg (95% yield) of
6b (8.0:1 ratio of diastereomers 6ba and 6bb, respectively) as
(500 MHz, CDCl3):
2.96e2.90 (m, 1H), 1.76e1.48 (m, 12H), 0.99e0.95 (m, 6H), 0.92 (s,
9H). Minor isomer: 1H NMR (500 MHz, CDCl3):
3.30 (m, 1H),
2.82e2.79 (m, 1H), 1.76e1.48 (m, 12H), 0.99e0.95 (m, 6H), 0.91 (s,
9H). 13C NMR (100 MHz, CDCl3):
123.13,122.40, 77.15, 76.80, 34.94,
d
3.52 (br d, J¼10.5 Hz, 1H), 3.30 (m, 1H),
a colorless oil: IR (neat): 3489, 2254 cmꢀ1 40
raphy provided a small, pure, sample of each diastereomer for 1H
NMR analysis. For 6ba: 1H NMR (500 MHz, CDCl3):
3.58e3.55 (m,
.
Careful chromatog-
d
d
d
1H), 1.95e1.87 (m, 1H), 1.84e1.82 (m, 1H), 1.72 (dd, J¼8.5, 14.0 Hz,
1H), 1.59e1.58 (m, 2H), 1.38 (s, 3H), 1.08 (d, J¼6.5 Hz, 3H), 1.03 (d,
J¼6.5 Hz, 3H), 0.92 (s, 9H). For 6bb: 1H NMR (500 MHz, CDCl3):
34.82, 34.24, 33.90, 33.11, 28.96, 28.43, 25.40, 20.47, 20.32, 13.62,
13.58. HRMS (ESI) m/z calcd for C11H21NONa (MþNa) 206.1521,
found 206.1532.
d
3.51e3.47 (m, 1H), 1.95e1.87 (m, 1H), 1.84e1.82 (m, 1H), 1.72 (dd,

372
R.J. Mycka et al. / Tetrahedron 69 (2013) 366e376
J¼8.5, 14.0 Hz, 1H), 1.59e1.58 (m, 2H), 1.38 (s, 3H), 1.08 (d, J¼6.5 Hz,
3H), 1.03 (d, J¼6.5 Hz, 3H), 0.92 (s, 9H). 13C NMR (100 MHz, CDCl3):
chromatography (95:5, hexanes/EtOAc) to afford 114.0 mg (84%
yield) of 8ba as a gel: IR (neat): 3359, 3270, 2250 cmꢀ1 1H NMR
(500 MHz, CDCl3):
;
d
124.8, 124.6, 77.3, 76.3, 40.7, 39.5, 38.8, 38.1, 35.4, 35.3, 25.4, 25.4,
d
4.16 (br s, 1H), 3.70 (d, J¼8.5 Hz, 1H), 3.30 (s,
21.2, 20.9, 18.3, 17.4, 17.2. HRMS (ESI)40 m/z calcd for C12H23NONa
(MþNa) 220.1677, found 220.1682. Performing the general pro-
cedure using nitrile 4a17 (128.0 mg, 0.83 mmol), i-PrMgCl (2.06 mL,
4.12 mmol), and iso-propyl iodide (1.00 mL, 10.0 mmol) gave
a crude product that was purified by radial chromatography (95:5,
hexanes/EtOAc) to afford 76.5 mg (47% yield) of 6b (5.5:1 ratio of
diastereomers 6bb and 6ba, respectively) as a colorless oil.
1H), 2.72 (br s, 1H), 2.03e1.99 (m, 1H), 1.86 (dd, J¼14.8, 1.0 Hz, 1H),
1.83e1.76 (m, 2H), 1.68 (dd, J¼14.8, 9.5 Hz, 1H), 1.67e1.60 (m, 1H),
1.51 (td, J¼8.5, 3.0 Hz, 2H), 1.35 (s, 3H), 1.33e1.15 (m, 5H), 0.94 (s,
9H); 13C NMR (100 MHz, CDCl3):
d 123.2, 80.0, 76.8, 43.7, 41.0, 40.3,
35.1, 31.6, 26.7, 26.1, 26.1, 25.5, 25.1, 23.7. HRMS (ESI) m/z calcd for
C16H29NO2Na (MþNa) 290.2096, found 290.2106.
4.2.8. (2SR,4SR)-4-Hydroxy-2-((RS)-1-hydroxy-2,2-dimethylpropyl)-
2,5,5-trimethylhexanenitrile (8ca). Performing the general pro-
cedure with nitrile 4a17 (60.1 mg, 0.508 mmol), i-PrMgCl (0.97 mL,
1.94 mmol), and distilled ethyl trimethylacetate (0.30 mL,
1.97 mmol) gave a crude product that was purified by column
chromatography employing (95:5, hexanes/EtOAc) to afford
22.6 mg (17%) of 9ca, spectrally identical to material previously
isolated,16 and 59.8 mg (64% yield) of 8ca as a white powder (mp
83e84 ꢁC): IR (neat): 3296, 2242 cmꢀ1; 1H NMR (400 MHz, CDCl3):
4.2.4. (2RS,4SR)- and (2SR,4SR)-4-Hydroxy-2,5,5-trimethyl-2-(tri-
deuteromethyl)hexanenitrile (6ca and 6cb, respectively). Performing
the general procedure using nitrile 4a17 (128.4 mg, 0.83 mmol),
i-PrMgCl (2.07 mL, 4.14 mmol), and CD3I (1.00 mL, 16.1 mmol) gave
a crude product that was purified by radial chromatography (90:10,
hexanes/EtOAc) to afford 136.8 mg (96% yield) of 6ca (7.5:1 ratio of
diastereomers 6ca and 6cb, respectively) as a colorless oil: IR
(neat): 3499, 2235 cmꢀ1 40
3.51 (dd, J¼9.3, 2.0 Hz, 1H), 1.72 (dd, J¼14.5, 2.0 Hz, 1H), 1.68 (d,
J¼4.5 Hz, 1H), 1.55 (dd, J¼14.5, 9.3 Hz, 1H), 1.45 (s, 3H), 0.92 (s, 9H);
13C NMR (100 MHz, CDCl3):
125.6, 76.9, 42.4, 35.1, 31.2, 27.5, 25.3.
For (2SR,4SR)-6c: 1H NMR (500 MHz, CDCl3):
.
For 6ca: 1H NMR (500 MHz, CDCl3):
d
d
3.57 (br d, J¼8.8 Hz, 1H), 3.51 (br s, 1H), 2.62 (br s, 1H), 2.06 (dd,
J¼14.6, 1.2 Hz, 1H), 1.87 (br s, 1H), 1.67 (dd, J¼14.6, 9.6 Hz, 1H), 1.50
(s, 3H), 1.14 (s, 9H), 0.94 (s, 9H); 13C NMR (100 MHz, CDCl3):
125.2,
d
d
d
3.51 (dd, J¼9.3,
80.4, 76.4, 42.3, 39.6, 37.2, 35.4, 28.0, 25.4, 20.5. HRMS (ESI) m/z
calcd for C14H27NO2Na (MþNa) 264.1939, found 264.1948.
2.0 Hz, 1H), 1.72 (dd, J¼14.5, 2.0 Hz, 1H), 1.68 (d, J¼4.5 Hz, 1H), 1.55
(dd, J¼14.5, 9.3 Hz,1H),1.39 (s, 3H), 0.92 (s, 9H); 13C NMR (100 MHz,
CDCl3):
d
125.6, 76.9, 42.4, 35.1, 31.2, 27.5, 25.3. HRMS (ESI)40 m/z
4.2.9. (3SR,5SR)- and (3SR,5RS)-5-(tert-Butyl)-3-methyl-2-oxotetra-
hydrofuran-3-carbonitrile (12aa and 12ab, respectively). A THF so-
lution of i-PrMgCl (0.38 mL, 0.76 mmol) was added to a ꢀ78 ꢁC, THF
solution (5 mL) of nitrile 6g16 (166.4 mg, 0.632 mmol). After 5 min,
neat methyl cyanoformate (0.05 mL, 0.630 mmol) was added and
the cooling bath was then removed. After 5 min, saturated, aqueous
NH4Cl was added, the phases separated, and the aqueous phase was
then extracted with EtOAc. The combined organic phase was dried
(Na2SO4), filtered through a short pad of silica gel, and concentrated
to afford a crude oil that was used without further purification. The
crude nitrile was added to a ꢀ40 ꢁC, CH2Cl2 solution (3 mL) con-
taining m-CPBA (268.7 mg, 1.20 mmol) previously dried over
calcd for C10H16D3NONa (MþNa) 195.1553, found 195.1542.
4.2.5. (2RS,4SR)- and (2SR,4SR)-2-Ethyl-4-hydroxy-2,5,5-trimethyl-
hexanenitrile (6da and 6db, respectively). Performing the general
procedure with nitrile 4a17 (76.4 mg, 0.492 mmol), i-PrMgCl
(1.24 mL, 2.48 mmol), and ethyl iodide (1.00 mL, 12.5 mmol) gave
a crude product that was purified by radial chromatography (95:5,
hexanes/EtOAc) to afford 73.9 mg (82% yield) of 6d (6.5:1 ratio of
diastereomers 6da and 6db, respectively) as a light yellow oil: IR
(neat): 3462, 2235 cmꢀ1 40 For 6da: 1H NMR (400 MHz, CDCl3):
.
d
3.56e3.52 (m, 1H), 1.82e1.70 (m, 3H), 1.54 (dd, J¼7.6, 14.0 Hz, 1H),
41
1.48e1.41 (m, 1H), 1.41 (s, 3H), 1.08 (t, J¼7.4 Hz, 3H), 0.92 (s, 9H); 13C
Na2SO4 and the cooling bath was then removed. After 4 h, satu-
NMR (100 MHz, CDCl3):
d
124.7, 76.9, 40.6, 36.7, 35.3, 33.0, 25.3,
rated, aqueous NH4Cl was added, the crude mixture was extracted
with CH2Cl2, the combined organic phase was dried (Na2SO4), fil-
tered through a short pad of silica gel, and concentrated to afford
178.4 mg of crude sulfinyl nitrile 15 that was used without further
purification. A THF solution of i-PrMgCl (0.15 mL, 0.30 mmol) was
added to a ꢀ78 ꢁC, THF solution (2 mL) of 15 (96.4 mg, 0.286 mmol)
and then the cooling bath was removed. After 16 h, saturated,
aqueous NH4Cl was added and the phases were separated. The
aqueous phase was extracted with EtOAc, the combined organic
phase was dried (Na2SO4), and then the mixture was evaporated
under reduced pressure to afford an oil. The crude oil was then
purified by radial chromatography (98:2, hexanes/EtOAc) to afford
28.9 mg (56% yield) of 12a (3.4:1 ratio of diastereomers 12aa and
12ab, respectively) as a colorless oil spectrally identical to material
previously isolated.16
24.3, 9.2. For (2SR,4SR)-6d: 1H NMR (400 MHz, CDCl3):
d 3.50e3.48
(m, 1H), 1.82e1.70 (m, 3H),1.66e1.60 (m, 1H), 1.48e1.41 (m, 1H),
1.35 (s, 3H), 1.08 (t, J¼7.4 Hz, 3H); 13C NMR (100 MHz, CDCl3):
d
124.9, 76.4, 40.9, 36.0, 35.2, 33.0, 25.4, 23.8, 9.2. HRMS (ESI)40 m/z
calcd for C11H21NONa (MþNa) 206.1521, found 206.1533.
4.2.6. (2SR,4SR)-4-Hydroxy-2-((RS)-1-hydroxy-2-methylpropyl)-
2,5,5-trimethylhexanenitrile
(8aa). Performing
the
general
procedure with nitrile 4a17 (112.1 mg, 0.722 mmol), i-PrMgCl
(1.80 mL, 3.60 mmol), and ethyl isobutyrate (0.49 mL, 3.66 mmol)
gave a crude product that was purified by column chromatography
(90:10, hexanes/EtOAc) to afford 154.8 mg (90%) of 8aa as a white
crystalline solid (mp 65e67 ꢁC) whose structure was determined by
X-ray crystallography:16 IR (mull): 3385, 3294, 2245 cmꢀ1; 1H NMR
(500 MHz, CDCl3):
d
4.12 (br s, 1H), 3.72 (d, J¼8.5 Hz, 1H), 3.36 (d,
J¼2.2 Hz, 1H), 2.53 (br s, 1H), 1.97e2.06 (m, 1H), 1.88 (dd, J¼13.5,
1.3 Hz, 1H), 1.69 (dd, J¼13.5, 8.5 Hz, 1H), 1.35 (s, 3H), 1.10 (d,
J¼6.9 Hz), 1.06 (d, J¼6.9 Hz, 1H), 0.94 (s, 9H); 13C NMR (100 MHz,
4.2.10. (2RS,4RS) and (2SR,4RS)-4-Hydroxy-2-isopropyl-2-phenyl-
pentanenitrile (19aa and 19ab, respectively). Performing the gen-
eral procedure with nitrile 4d17 (101.3 mg, 0.578 mmol), i-PrMgCl
(1.45 mL, 2.90 mmol), and i-PrI (1 mL, 10.02 mmol) gave a crude
product that was purified by column chromatography (90:10,
hexanes/EtOAc) to afford 116.2 mg (93% yield) of 19a (2.45:1 ratio of
diastereomers 19aa and 19ab, respectively) as a colorless oil
exhibiting spectral data analogous to that reported previously.38
Performing the general procedure with nitrile 4d17 (150.0 mg,
0.856 mmol), i-PrMgCl (2.14 mL, 4.28 mmol), and i-PrOTs42 (1.28 g,
5.97 mmol) gave a crude product that was purified by column
chromatography (90:10, hexanes/EtOAc) to afford 185.7 mg (95%
CDCl3): d 123.0, 79.7, 77.0, 43.8, 41.3, 35.1, 30.0, 25.5, 23.7, 21.8, 14.6.
HRMS (ESI) m/z calcd for C13H25NO2Na (MþNa) 250.1783, found
250.1790.
4.2.7. (2SR,4SR)-2-((RS)-Cyclohexyl(hydroxy)methyl)-4-hydroxy-
2,5,5-trimethylhexanenitrile (8ba). Performing the general pro-
cedure with nitrile 4a17 (78.9 mg, 0.508 mmol), i-PrMgCl (1.28 mL,
2.56 mmol), and distilled ethyl cyclohexanecarboxylate (0.43 mL,
2.58 mmol) gave a crude product that was purified by column

R.J. Mycka et al. / Tetrahedron 69 (2013) 366e376
373
yield) of 19a (2.13:1 ratio of diastereomers 19aa and 19ab,
respectively) as a colorless oil exhibiting spectral data analogous to
that reported previously.38 Performing the general procedure with
nitrile 4d (205.0 mg, 1.170 mmol), i-PrMgCl (2.92 mL, 5.84 mmol),
and i-PrBr (1 mL,10.7 mmol) gave a crude product that was purified
by column chromatography (90:10, hexanes/EtOAc) to afford
229.6 mg (90% yield) of 19a (1.78:1 ratio of diastereomers 19aa and
19ab, respectively) as a colorless oil exhibiting spectral data anal-
ogous to that reported previously.38
d 7.41e7.35 (m, 3H), 7.32e7.27 (m, 2H), 3.81e3.74 (m,1H), 2.14e1.85
(m, 6H), 1.63e1.42 (m, 2H), 1.34e1.16 (m, 1H), 1.14 (d, J¼6.5 Hz, 3H),
0.88 (t, J¼7.3 Hz, 3H); 13C NMR (100 MHz, CDCl3):
d 138.2, 128.8,
127.5, 125.8, 122.5, 67.5, 47.9, 43.5, 37.0, 34.5, 23.5, 18.5, 13.8. For
22ab: 1H NMR (500 MHz, CDCl3):
d 7.41e7.35 (m, 4H), 7.32e7.27 (m,
1H), 3.73e3.68 (m, 1H), 2.21 (ddd, J¼13.5, 5.0, 4.5 Hz, 1H), 1.14 (d,
J¼6.5 Hz, 3H), 0.88 (t, J¼7.3 Hz, 3H); 13C NMR (100 MHz, CDCl3):
d
138.4, 128.8, 127.5, 125.8, 122.4, 67.4, 47.9, 43.1, 36.9, 34.6, 23.4,
18.5, 13.8. HRMS (ESI) m/z calcd for C14H21NONa (MþNa) 254.1521,
found 254.1527.
4.2.11. (2RS,5RS)- and (2SR,5RS)-5-Hydroxy-2-phenylhexanenitrile
(21a).43 Solid NaBH4 (1.52 g, 40.18 mmol) was added in four por-
tions over 30 min to a 0 ꢁC, methanolic solution (15 mL) of 5-oxo-2-
phenylhexanenitrile44 After 1 h, the solvent was removed under
reduced pressure, the resultant crude material was dissolved in
EtOAc, and then the solution was extracted with saturated, aqueous
NH4Cl. The organic layer was dried (Na2SO4), evaporated under
reduced pressure to give a crude oil, and the resulting material was
purified by column chromatography (70:30, hexanes/EtOAc) to
afford 1.86 g of 21a (98% yield, 1:1 ratio of diastereomers)45 as
4.2.14. (2RS,5SR)- and (2SR,5SR)-5-Hydroxy-2,6,6-trimethyl-2-
propylheptanenitrile (22ba and 22bb, respectively). Performing the
general procedure with nitrile vi50 (76.9 mg, 0.495 mmol), i-PrMgCl
(1.24 mL, 2.48 mmol), and MeI (0.04 mL, 0.643 mmol) afforded
crude 21b that was filtered through a small plug of silica and used
without further purification. Employing the general procedure with
nitrile 21b (85.6 mg, 0.506 mmol), i-PrMgCl (1.27 mL, 2.54 mmol),
and PrI (1 mL, 10.3 mmol) afforded a crude product that was
purified by column chromatography (95:5, hexanes/EtOAc) to give
68.6 mg (64% yield based on 21b) of 22b (4.0:1 ratio of di-
astereomers 22ba and 22bb, respectively)51 as a colorless oil: IR
(neat): 3486, 2234 cmꢀ1. For 22ba: 1H NMR (500 MHz, CDCl3):
a light yellow oil: IR (neat): 3397, 2241 cmꢀ1 1H NMR (500 MHz,
;
CDCl3):
d 7.37e7.30 (m, 5H), 3.86e3.74 (m, 2H), 2.11e1.91 (m, 3H),
1.61e1.52 (m, 2H), 1.18 (d, J¼7.5 Hz, 3H), 1.17 (d, J¼7.5 Hz, 3H)*; 13C
NMR (100 MHz, CDCl3):
d
135.7, 135.6
*
, 129.0, 127.9, 127.1
*
, 127.1,
, 23.6,
d
3.19 (br d, J¼10.5 Hz, 1H), 1.81 (ddd, J¼12.5, 4.5, 4.5 Hz, 1H),
1.74e1.65 (m, 1H), 1.63e1.36 (m, 7H), 1.30 (s, 3H), 0.97 (t, J¼7.0 Hz,
3H), 0.92 (s, 9H); 13C NMR (100 MHz, CDCl3):
124.6, 80.0, 42.2,
37.2, 36.6, 35.1, 25.6, 23.7, 18.2, 14.1. For 22bb: 1H NMR (500 MHz,
120.8
23.5
*
, 120.7, 67.3, 66.8
*
, 37.2, 36.9
*
, 36.1, 35.8
*
, 32.3, 31.8
*
*
. HRMS (ESI) m/z calcd for C12H15NONa (MþNa) 212.1051,
d
found 212.1065.
CDCl3):
d
3.17e3.14 (m, 1H), 1.98 (ddd, J¼12.5, 4.5, 4.0 Hz, 1H),
4.2.12. (2RS,5SR)- and (2SR,5SR)-5-Hydroxy-6,6-dimethyl-2-
phenylheptanenitrile (21c).46 A THF solution (3 mL) of 4-iodo-2-
phenylbutanenitrile (i)47 (1.57 g, 5.80 mmol) was added to a rt,
THF suspension (1 mL) of activated zinc48 (0.488 g, 7.46 mmol).
After consumption of the iodide, approximately 4 h, the solution
was cooled to 0 ꢁC and a 1 M THF solution of CuCN$2LiCl48 (7.0 mL,
7.0 mmol) was added. After 5 min, neat pivaloyl chloride (0.86 mL,
6.99 mmol) was added followed, after 1 h, by saturated, aqueous
NH4Cl (50 mL). After 30 min, the phases were separated, the
aqueous phase was extracted with Et2O, the organic phase was
combined and then successively washed with saturated, aqueous
NaOAc and saturated, aqueous NaHCO3. The organic phase was
dried (Na2SO4), and then the solvent was removed under reduced
pressure to give a crude ketone ii that was dissolved in 20 mL of
methanol and cooled to 0 ꢁC and then solid NaBH4 (0.88 g,
23.3 mmol) was added in one portion. After 1 h, the methanol was
evaporated, the residue was dissolved in EtOAc, and the organic
phase was then washed with saturated, aqueous NH4Cl. The organic
phase was dried (Na2SO4), the solvent was removed under reduced
pressure, and the resulting crude oil was purified by column
chromatography (90:10, hexanes/EtOAc) to afford 912.5 mg (68%
overall yield) of 21c (1:1 ratio of diastereomers) as a light yellow oil:
1.74e1.36 (m, 8H),1.32 (s, 3H), 0.97 (t, J¼7.0 Hz, 3H), 0.92 (s, 9H); 13C
NMR (100 MHz, CDCl3): d 124.5, 80.0, 41.3, 37.3, 36.7, 35.1, 26.7, 24.3,
18.1, 14.1. HRMS (ESI)40 m/z calcd for C13H25NONa (MþNa)
234.1834, found 234.1823.
4.2.15. (2RS,5SR)- and (2RS,5RS)-5-Hydroxy-6,6-dimethyl-2-phenyl-
2-propylheptanenitrile (22ca and 22cb, respectively). Performing
the general procedure with nitrile 21c (119.8 mg, 0.518 mmol), i-
PrMgCl (1.30 mL, 2.60 mmol), and PrI (1.00 mL, 10.3 mmol) gave
a crude product that was purified by column chromatography
(85:15, hexanes/EtOAc) to afford 127.6 mg (90% yield) of 22c (2.7:1
ratio of diastereomers 22ca and 22cb, respectively) as a colorless
oil: IR (neat): 3481, 2240 cmꢀ1 40
.
For 22ca: 1H NMR (500 MHz,
CDCl3):
d
7.42e7.26 (m, 5H), 3.20 (d, J¼13.5 Hz, 1H), 2.30 (ddd,
J¼18.5, 5.5, 2.0 Hz, 1H), 2.03e1.39 (m, 4H), 1.21e0.96 (m, 2H), 0.88
(t, J¼9.3 Hz, 3H), 0.81 (s, 9H); 13C NMR (100 MHz, CDCl3):
d 138.3,
128.8, 127.6, 125.9, 122.8, 79.8, 48.1, 43.9, 38.4, 35.0, 27.1, 25.5, 18.6,
13.9. For 22cb: 1H NMR (500 MHz, CDCl3):
d 7.42e7.26 (m, 5H),
3.03e2.98 (m, 1H), 2.43e2.35 (m, 1H), 2.03e0.99 (m, 8H), 0.88 (t,
J¼9.3 Hz, 3H), 0.80 (s, 9H); 13C NMR (100 MHz, CDCl3):
d 138.8,
128.8, 127.6, 125.8, 122.5, 80.0, 48.2, 43.0, 38.7, 35.0, 27.3, 25.5, 18.6,
13.9. HRMS (ESI)40 m/z calcd for C17H27NONa (MþNa) 296.1990,
found 296.1974. Preparation of 22ca by hydrogenation of 22ea:
a methanolic solution (15 mL) of hydroxynitrile 22ea (75.6 mg,
0.279 mmol) was hydrogenated for 4 h in a Parr shaker at 50 psi
using 5% Pd/C (7.0 mg, 0.066 mmol). The reaction mixture was then
concentrated, the crude product was redissolved in EtOAc, and then
passed through a short pad of silica gel to afford 73.3 mg (96% yield)
of pure 22ca as a colorless oil. Preparation of 22ca by hydrogenation
of 22fa: a methanolic solution (15 mL) of hydroxynitrile 22fa
(95.5 mg, 0.355 mmol) was hydrogenated for 4 h in a Parr shaker at
50 psi using 5% Pd/C (8.1 mg, 0.076 mmol). The reaction mixture
was then concentrated, the crude product was redissolved in EtOAc,
and then passed through a short pad of silica gel to afford 92.4 mg
(95% yield) of pure 22ca as a colorless oil.
IR (neat): 3502, 2234 cmꢀ1; 1H NMR (500 MHz, CDCl3):
d 7.41e7.31
(m, 5H), 3.91e3.84 (m, 1H), 3.22 (m, 1H), 2.26e2.15 (m, 1H),
1.99e1.87 (m, 1H), 1.82e1.65 (m, 1H), 1.52e1.33 (m, 2H), 0.90 (s,
9H); 13C NMR (100 MHz, CDCl3):47
d
136.0, 135.9
*
, 129.0, 127.9
*
,
,
127.2, 127.1
28.9, 28.4
*
, 121.0, 120.8
*
, 79.5, 78.8
*
, 37.5, 36.9 , 35.0, 33.8, 33.2
, 25.5. HRMS (ESI) m/z calcd for C15H21NONa (MþNa)
*
*
*
254.1521, found 254.1509.
4.2.13. (2RS,5RS)- and (2SR,5RS)-5-Hydroxy-2-phenyl-2-
propylhexanenitrile (22aa and 22ab, respectively). Performing the
general procedure with nitrile 21a (206.0 mg, 1.09 mmol), i-PrMgCl
(2.72 mL, 5.54 mmol), and PrI (1.0 mL, 10.3 mmol) gave a crude
product that was purified by column chromatography (70:30,
hexanes/EtOAc) to afford 234.7 mg (93% yield) of 22a (2.5:1 ratio of
diastereomers 22aa and 22ab, respectively)49 as a colorless oil: IR
4.2.16. (2SR,5SR)- and (2SR,5RS)-5-Hydroxy-2-isopropyl-6,6-dimethyl-
2-phenylheptanenitrile (22da and 22db, respectively). Performing the
(neat): 3478, 2253 cmꢀ1 40
.
For 22aa: 1H NMR (500 MHz, CDCl3):

374
R.J. Mycka et al. / Tetrahedron 69 (2013) 366e376
general procedure with nitrile 21c (105.1 mg, 0.454 mmol), i-PrMgCl
(1.14 mL, 2.28 mmol), and i-PrI (1 mL, 10.0 mmol) gave a crude
product that was purified by column chromatography (90:10, hex-
anes/EtOAc) to afford 109.8 mg (88% yield) of 22d (1.4:1 ratio of di-
astereomers 22da and 22db, respectively)51 as a colorless oil: IR
(neat): 3472, 2236 cmꢀ1. For 22da: 1H NMR (500 MHz, CDCl3):
afford 6.2 mg of vii (3.4:1 ratio of diastereomers)53 as a yellow oil
and 91.1 mg (62% yield) of 22g (3.5:1 ratio of diastereomers 22ga
and 22gb, respectively) as a colorless oil: IR (neat): 2245,1719 cmꢀ1
.
For 22ga: 1H NMR (500 MHz, CDCl3):
d 7.55e7.50 (m, 2H), 7.45e7.35
(m, 3H), 4.57 (dd, J¼7.5, 3.0 Hz, 1H), 3.79 (s, 3H), 3.78 (s, 3H), 2.39
(m, 1H), 2.26e2.16 (m, 1H), 1.79e1.58 (m, 2H), 0.90 (s, 9H); 13C NMR
d
7.40e7.27 (m, 5H), 3.21 (dd, J¼5.5, 2.0 Hz, 1H), 2.59e2.49 (m, 1H),
(100 MHz, CDCl3):
85.0, 54.9, 54.0, 53.7, 35.0, 25.9, 25.7. For 22gb: 1H NMR (500 MHz,
CDCl3): 7.55e7.50 (m, 2H), 7.45e7.35 (m, 3H), 4.51e4.45 (m, 1H),
3.80 (s, 3H), 2.51e2.44 (m, 1H), 2.16e2.11 (m, 1H), 1.79e1.58 (m,
2H), 0.90 0.87 (s, 9H); 13C NMR (100 MHz, CDCl3):
167.8, 156.3,
134.0, 129.3, 129.0, 126.0, 118.1, 85.1, 54.9, 54.0, 53.8, 35.1, 35.0, 25.8,
25.6. For (3RS,6SR)-methyl 6-(tert-butyl)-2-oxo-3-phenyltetrahydro-
2H-pyran-3-carboxylate (vii): 1H NMR (500 MHz, CDCl3):
d 167.9, 156.3, 134.0, 129.3, 129.0, 126.0, 118.1,
2.16e2.08 (m, 3H), 1.81 (ddd, J¼11.0, 4.5, 2.5 Hz, 1H), 1.36e1.21 (m,
2H), 1.21 (d, J¼7.5 Hz, 3H), 0.96e0.85 (m, 2H), 0.78 (s, 9H); 13C NMR
d
(100 MHz, CDCl3):
d 138.1, 128.7, 127.5, 126.4, 121.5, 80.1, 53.7, 38.2,
35.2, 27.7, 25.5, 18.9, 18.60. For 22db: 1H NMR (500 MHz, CDCl3):
7.40e7.27 (m, 5H), 2.96 (dd, J¼7.5, 2.0 Hz,1H), 2.26 (ddd, J¼11.0, 4.0,
2.0 Hz, 1H), 1.60e1.52 (m, 1H), 1.36e1.21 (m, 2H), 1.19 (d, J¼7.5 Hz,
d
d
3H), 0.75 (s, 9H); 13C NMR (100 MHz, CDCl3):
d 137.9, 128.7, 121.3,
79.8, 53.5, 37.8, 35.0, 27.4, 18.8, 18.5. HRMS (ESI)40 m/z calcd for
C17H27NONa (MþNa) 296.1990, found 296.1984.
d
7.35e7.26 (m, 5H), 4.54 (dd, J¼10.5, 2.8 Hz, 1H), 3.81 (s, 3H),
2.78e2.73 (m, 1H), 2.71e2.64 (m, 1H), 1.73e1.58 (m, 2H), 0.85 (s,
9H).
4.2.17. (2SR,5SR)- and (2SR,5RS)-2-Allyl-5-hydroxy-6,6-dimethyl-2-
phenylheptanenitrile (22ea and 22eb, respectively). Performing the
general procedure with nitrile 21c (74.8 mg, 0.323 mmol), i-PrMgCl
(0.81 mL, 1.62 mmol), and allyl bromide (1 mL, 11.6 mmol) gave
a crude product that was purified by column chromatography
(85:15, hexanes/EtOAc) to afford 75.0 mg (85% yield) of 22e (5.9:1
ratio of diastereomers 22ea and 22eb, respectively)52 as a colorless
4.2.20. (3SR,6SR)-6-Methyl-3-phenyl-3-propyltetrahydro-2H-pyran-
2-one (iii).43
A diethylene glycol solution of (2RS,5RS)- and
(2SR,5RS)-5-hydroxy-2-phenyl-2-propylhexanenitrile (2.5:1 ratio
of diastereomers, 448.0 mg, 1.94 mmol) and KOH (548.7 mg,
9.77 mmol) was heated to 250 ꢁC. After 6 h, the mixture was
allowed to cool to rt, diluted with ether, and then aqueous 6M HCl
(100 mL) was added. The phases were separated, the aqueous phase
was extracted with ether, the combined aqueous phase was washed
with brine, dried (Na2SO4), and concentrated under reduced pres-
sure to yield a crude oil that was purified by column chromatog-
raphy (90:10, hexanes/EtOAc) to afford 360.4 mg (80% yield) of (iii)
oil: IR (neat): 3479, 2237 cmꢀ1 40
.
For 22ea: 1H NMR (500 MHz,
CDCl3): 7.43e7.36 (m, 4H), 7.32e7.28 (m, 1H), 5.70e5.59 (m, 1H),
d
5.14e5.09 (m, 2H), 3.20 (dd, J¼11.0, 2.0 Hz, 1H), 2.67 (d, J¼7.0 Hz,
2H), 2.33 (ddd, J¼12.5, 4.5, 1.5 Hz, 1H), 2.00 (ddd, J¼14.0, 4.5, 2.0 Hz,
1H),1.69e1.62 (m,1H),1.37 (br s,1H),1.11e1.02 (m,1H), 0.82 (s, 9H);
13C NMR (100 MHz, CDCl3):
d
137.7, 131.8, 128.9, 127.7, 126.1, 122.2,
112.0, 79.7, 47.8, 46.1, 37.2, 35.0, 27.0, 25.5. For 22eb: 1H NMR
(500 MHz, CDCl3): 7.43e7.36 (m, 4H), 7.32e7.28 (m, 1H),
as a yellow oil (2.5:1 ratio of diastereomers): IR (neat): 1725 cmꢀ1
For (3SR,6SR)-iii: 1H NMR (500 MHz, CDCl3):
7.45e7.10 (m, 5H),
.
d
d
4.01e3.94 (m, 1H), 2.58e2.52 (m, 1H), 2.14 (td, J¼3.5, 14.0 Hz, 1H),
2.05e1.60 (m, 9H), 1.44e1.33 (m, 1H), 1.31e1.23 (m, 2H), 1.20 (d,
J¼6.0 Hz, 3H), 1.19e1.05 (m, 3H), 0.89 (t, J¼7.0 Hz, 3H), 0.82 (t, J¼7.0,
5.70e5.59 (m, 1H), 5.14e5.09 (m, 2H), 3.04e3.00 (m, 1H),
2.44e2.39 (m, 1H), 1.92e1.86 (m, 1H), 1.46e1.00 (m, 5H), 0.81 (s,
9H); 13C NMR (100 MHz, CDCl3):
d
138.1, 131.7, 128.8, 127.8, 126.0,
3H); 13C NMR (100 MHz, CDCl3):
d 175.6, 142.8, 140.2, 128.9, 127.1,
122.0, 119.9, 79.9, 47.9, 45.2, 37.6, 35.0, 27.2, 25.5. HRMS (ESI)40 m/z
calcd for C17H25NONa (MþNa) 294.1834, found 294.1863.
126.3, 78.8, 72.7, 51.8, 44.0, 27.6, 26.4, 22.2, 17.5, 14.4. For (3SR,6RS)-
iii: 1H NMR (500 MHz, CDCl3):
d
7.45e7.10 (m, 5H), 4.51e4.48 (m,
1H), 2.27 (dt, J¼14.5, 3.5 Hz, 1H), 1.52e1.45 (m, 1H), 1.27 (d,
4.2.18. (2SR,5SR)- and (2SR,5RS)-5-Hydroxy-6,6-dimethyl-2-phenyl-2-
(prop-2-yn-1-yl)heptanenitrile (22fa and 22fb, respectively).
Performing the general procedure with nitrile 21c (103.4 mg,
0.447 mmol), i-PrMgCl (1.12 mL, 2.24 mmol), and neat propargyl
bromide (1 mL,13.3 mmol) gave a crude product that was purified by
column chromatography (90:10, hexanes/EtOAc) to afford 103.2 mg
(86% yield) of 22f (3.7:1 ratio of diastereomers 22fa and 22fb, re-
spectively)52 as a colorless oil: IR (neat): 3495, 3295, 2241, 2226.40
J¼6.0 Hz, 3 H), 0.89 (t, J¼7.0 Hz, 3H); 13C NMR (100 MHz, CDCl3):
d
174.1, 142.7, 140.0, 128.6, 126.8, 126.0, 50.4, 27.3, 21.5.
4.2.21. 6,6-Dimethyl-5-oxoheptanenitrile (v). A THF solution (5 mL)
of 4-iodobutyronitrile54 (2.90 g, 14.87 mmol) was added to a rt THF
suspension (1 mL) of activated zinc48 (1.21 g, 18.51 mmol). After
consumption of the iodide, approximately 1 h, the solution was
cooled to 0 ꢁC and 1 M CuCN$2LiCl48 (18.50 mL, 18.5 mmol) was
added. After 5 min, neat pivaloyl chloride (2.00 mL, 16.3 mmol) was
added followed, after 1 h, by saturated, aqueous NH4Cl (100 mL).
After 30 min, the phases were separated, the aqueous phase was
extracted with Et2O, and the combined organic phase was succes-
sively washed with saturated, aqueous NaOAc and saturated,
aqueous NaHCO3. The organic phase was dried (Na2SO4), the sol-
vent was removed under reduced pressure, and the crude ketone
was purified by column chromatography (90:10, hexanes/EtOAc) to
afford 2.10 g (92% yield) of (v) as a pale yellow colored oil: IR (neat):
For 22fa: 1H NMR (500 MHz, CDCl3):
d 7.50e7.45 (m, 2H),
7.43e7.31 (m, 2H), 7.36e7.31 (m, 1H), 3.24 (dd, J¼10.5, 2.3 Hz, 1H),
2.82 (d, J¼2.5 Hz, 2H), 2.42 (ddd, J¼12.0, 4.5, 1.5 Hz, 1H), 2.18 (ddd,
J¼11.5, 4.5, 2.7 Hz, 1H), 2.13 (t, J¼2.5 Hz, 1H), 1.72e1.64 (m, 1H),
1.16e1.09 (m, 1H), 0.83 (s, 9H); 13C NMR (100 MHz, CDCl3):
d 137.0,
129.0, 128.2, 126.0, 121.6, 80.0, 78.1, 72.7, 47.1, 36.2, 35.0, 32.3, 27.1,
25.5. For 22fb: 1H NMR (500 MHz, CDCl3):
d
7.50e7.45 (m, 2H),
7.43e7.31 (m, 2H), 7.36e7.31 (m, 1H), 3.09e3.05 (m, 1H), 2.85 (ABq
Dn¼27.5 Hz, J¼17.0, 2.5 Hz, 1H), 2.60e2.52 (m, 1H), 2.11 (t, J¼2.5 Hz,
1H), 2.01e1.94 (m, 3H), 1.52e1.40 (m, 2H), 1.16e1.09 (m, 1H), 0.82 (s,
2246, 1709 cmꢀ1
2H), 2.42 (t, J¼6.9 Hz, 2H), 1.92 (quintet, J¼6.9 Hz, 2 H), 1.16 (s, 9H);
13C NMR (125 MHz, CDCl3):
214.3, 119.3, 44.0, 34.3, 26.3, 19.5, 16.3.
;
1H NMR (500 MHz, CDCl3):
d
2.69 (t, J¼6.9 Hz,
9H); 13C NMR (100 MHz, CDCl3):
d 137.7, 128.9, 128.2, 125.9, 121.4,
79.8, 78.2, 72.7, 47.2, 36.6, 35.0, 31.5, 27.3, 25.5. HRMS (ESI)40 m/z
calcd for C17H23NONa (MþNa) 292.1677, found 292.1667.
d
HRMS (ESI) m/z calcd for C9H15NONa (MþNa) 176.1051, found
176.1002.
4.2.19. (2SR,5SR)- and (2SR,5RS)-Methyl-2-cyano-5-((methoxy-
carbonyl)oxy)-6,6-dimethyl-2-phenylheptanoate (22ga and 22gb,
respectively). Performing the general procedure with nitrile 21c
(97.5 mg, 0.421 mmol), i-PrMgCl (1.05 mL, 2.10 mmol), and methyl
cyanoformate (0.27 mL, 3.40 mmol) gave a crude product that was
purified by column chromatography (98:2, hexanes/EtOAc) to
4.2.22. 5-Hydroxy-6,6-dimethylheptanenitrile (vi). Solid NaBH4
(1.37 g, 36.2 mmol) was added to a 0 ꢁC methanolic solution (15 mL)
of 6,6-dimethyl-5-oxoheptanenitrile (v, 1.385 g, 9.04 mmol). After
30 min, the methanol was evaporated under reduced pressure, the
crude alcohol was dissolved in EtOAc and then washed with

R.J. Mycka et al. / Tetrahedron 69 (2013) 366e376
375
18. Deprotonating with LDA or BuLi in different solvents and in the presence or
absence of HMPA afforded dianions that less efficiently alkylated allyl bromide
as a test electrophile.
19. (a) Hauser, C. R.; Humphlett, W. J. J. Org. Chem. 1950, 15, 359; Deprotonating
alkylnitriles is favored in a few situations, particularly for the more acidic
phenyl acetonitrile: (b) Fauvarque, J.-F.; Meklati, B.; Dearing, C. C.R. Chim. 1968,
267, 1162; (c) Ivanov, C.; Markov, P.; Arnaudov, M. Chem. Ber. 1967, 100, 690; (d)
Ivanov, C.; Markov, P.; Arnaudov, M. Chem. Ber. 1964, 97, 2987.
20. Prior to the deprotonation, the molarity of i-PrMgCl was determined by titra-
tion: Krasovskiy, A.; Knochel, P. Synthesis 2006, 890.
a saturated, aqueous solution of NH4Cl. The organic phase was dried
(Na2SO4), concentrated under reduced pressure, and the resulting
crude oil was purified by column chromatography (70:30, hexanes/
EtOAc) to afford 1.40 g (>99% yield) of (vi) as a light yellow colored
oil: IR (neat): 3458, 2248 cmꢀ1 1H NMR (500 MHz, CDCl3):
; d 3.22
(br d, J¼11 Hz, 1H), 2.46e2.37 (m, 2H), 1.98e1.94 (m, 1H), 1.74e1.68
(m, 2H), 1.43e1.38 (m, 2H), 0.91 (s, 9H); 13C NMR (100 MHz, CDCl3):
d
119.8, 79.1, 35.0, 30.1, 25.5, 23.0, 17.1. HRMS (ESI) m/z calcd for
21. Sasaki, M.; Takegawa, T.; Ikemoto, H.; Kawahata, M.; Yamaguchi, K.; Takeda, K.
Chem. Commun. 2012, 2897.
22. For an excellent overview of terms, steric constraints, and orbital overlap see:
C9H17NONa (MþNa): 178.1208, found 178.1246.
Gawley, R. E. Tetrahedron Lett. 1999, 40, 4297.
Acknowledgements
23. The relative configurations of the hydroxynitriles 6 were determined through
a combination of NOE, NOESY, and chemical correlation as described in detail
in Supplementary data.
24. Kirby, A. J. Stereoelectronic Effects; Oxford University Press: Oxford, 1996, pp
38e40.
Financial support for this research from NSF (CHE 1111406 and
0808996, CRIF 024872 for X-ray facilities, CHE 0421252 for HRMS
instrumentation, and CHE 0614785 for NMR facilities) is gratefully
acknowledged.
25. The authors have deposited the crystallographic data for 8aa with the Cam-
bridge Crystallographic Data Center (CCDC# 814019). The data can be obtained,
on request, from the Director, Cambridge Crystallographic Data Center, 12
Union Road, Cambridge CB2 1EZ, UK
26. No diastereomers were discernable in the 1H NMR of the crude reaction
mixture.
Supplementary data
27. Dunn, G. E.; Warkentin, J. Can. J. Chem. 1956, 34, 75.
Experimental procedures, 1H NMR, and 13C NMR spectra for all
new compounds and ORTEPs for all of the crystal structures. Sup-
plementary data associated with this article can be found in the
online version, at http://dx.doi.org/10.1016/j.tet.2012.10.016.
28. Cyclic alkylmagnesium alkoxides react selectively with benzaldehyde, whereas
5 reacts non-selectively, but are not reactive toward activated allylic or benzylic
halides unless in the presence of HMPA: Fleming, F. F.; Wang, Q.; Steward, O. W.
J. Org. Chem. 2003, 68, 4235.
ꢁ
ꢁ
29. Cruz, D. C.; Yuste, F.; Díaz, E.; Ortiz, B.; Sanchez-Obregon; Walls, F.; García
Ruano, J. L. Arkivoc 2005, vi, 211.
30. (a) Layfield, R. A.; Bullock, T. H.; Garcia, F.; Humphrey, S. M.; Schueler, P. Chem.
Commun. 2006, 2039; (b) Sakamoto, S.; Imamoto, T.; Yamaguchi, K. Org. Lett.
2001, 3, 1793.
References and notes
31. As carbonyl electrophiles react non-selectively or with the opposite sense of
diastereoselectivity to alkyl halides,16 the possibility exists that carbonyl elec-
trophiles react by precoordination whereas alkyl halides react through a non-
coordinated process that occurs with opposite diastereoselectivity.
32. Vu, V. A.; Marek, I.; Polborn, K.; Knochel, P. Angew. Chem., Int. Ed. 2002, 41, 351.
33. The authors have deposited the crystallographic data for 12aa with the Cam-
bridge Crystallographic Data Center (CCDC# 814018). The data can be obtained,
on request, from the Director, Cambridge Crystallographic Data Center, 12
Union Road, Cambridge CB2 1EZ, UK.
34. Nath, D.; Fleming, F. F. Angew. Chem., Int. Ed. 2011, 50, 11790.
35. The diastereomeric ratio refers to the syn/anti ratio of hydroxyl and phenyl-
sulfide groups. No effort was made to separate the sulfoxide diastereomers
resulting from m-CPBA oxidation because this stereocenter is cleaved during
the magnesium exchange procedure.
1. Kaumanns, O.; Appel, R.; Lemek, T.; Seeliger, F.; Mayr, H. J. Org. Chem. 2009, 74,
75.
ꢀ
2. The cylindrical diameter of the
p
-system is only 3.6 A: Sheppard, W. A. In The
Chemistry of the Cyano Group; Rappoport, Ed.; Interscience Pub., The University
of Virginia: Virginia, 1970, Chapter 5.
3. (a) Richard, J. P.; Williams, G.; Gao, J. J. Am. Chem. Soc. 1999, 121, 715; (b)
Bradamante, S.; Pagani, G. A. J. Chem. Soc., Perkin Trans. 2 1986, 1035; (c) Dayal,
S. K.; Ehrenson, S.; Taft, R. W. J. Am. Chem. Soc. 1972, 94, 9113.
4. The A value of a nitrile is a mere 0.2 kcal molꢀ1: Eliel, E. L.; Wilen, S. H.; Mander,
L. N. Stereochemistry of Organic Compounds; Wiley: New York, NY, 1994, pp
696e697.
5. (a) Fleming, F. F.; Shook, B. C. Tetrahedron 2002, 58, 1; (b) Arseniyadis, S.; Kyler,
K. S.; Watt, D. S. Organic Reactions: Addition and Substitution Reactions of Nitrile-
stabilized Carbanions; Wiley: New York, NY, 1984.
6. (a) Pellissier, H.; Michellys, P. Y.; Santelli, M. Steroids 2007, 72, 297; (b) Barton,
D. H. R.; Bringmann, G.; Motherwell, W. B. Synthesis 1980, 68.
7. For chiral auxiliaries bearing an adjacent nitrile group see: (a) Partogyan-Halim,
K.; Besson, L.; Aitken, D. J.; Husson, H.-P. Eur. J. Org. Chem. 2003, 268; (b)
Cativiela, C.; Diaz-de-Villegas, D. M.; Galvez, A. J.; Lapena, Y. Tetrahedron 1995,
51, 5921; (c) Cativiela, C.; Diaz-de-Villegas, D. M.; Galvez, A. J. J. Org. Chem. 1994,
59, 2497; (d) Hanamoto, T.; Katsuki, T.; Yamaguchi, M. Tetrahedron Lett. 1986, 27,
2463; (e) Maigrot, N.; Mazaleyrat, J.-P.; Welvart, Z. J. Org. Chem. 1985, 50, 3916.
8. (a) Carlier, P. R.; Lam, F. W.; Wan, C. N.; Williams, D. I. Angew. Chem., Int. Ed.
1998, 37, 2252; (b) Brunner, H.; Zintl, H. Monatsh. Chem. 1991, 122, 841; (c) Suto,
Y.; Kumagai, N.; Matsunaga, S.; Kanai, M.; Shibasaki, M. Org. Lett. 2003, 5, 3147;
(d) Mi, Q. A.; Wang, Y. Z.; Jiang, Z. Y. Tetrahedron: Asymmetry 1993, 4, 1957; (e)
Soai, K.; Hirose, Y.; Sakata, S. Tetrahedron: Asymmetry 1992, 3, 677; (f) Soai, K.;
Mukaiyama, T. Bull. Chem. Soc. Jpn. 1979, 52, 3371.
9. (a) Carlier, P. R.; Zhang, Y. Org. Lett. 2007, 9, 1319; (b) Fleming, F. F.; Gudipati, S.;
Zhang, Z.; Liu, W.; Steward, O. W. J. Org. Chem. 2005, 70, 3845.
10. (a) Hoffmann, R. W. Angew. Chem., Int. Ed. 2000, 39, 2054; (b) Hoffmann, R. W.
Angew. Chem., Int. Ed. Engl. 1992, 31, 1124.
11. (a) Fleming, F. F.; Liu, W.; Ghosh, S.; Steward, O. W. J. Org. Chem. 2008, 73, 2803;
(b) Fleming, F. F.; Liu, W.; Ghosh, S.; Steward, O. W. Angew. Chem., Int. Ed. 2007,
46, 7098.
12. Fleming, F. F.; Liu, W. Eur. J. Org. Chem. 2009, 699.
13. Mikami, K.; Shimizu, M.; Zhang, H.-C.; Maryanoff, B. E. Tetrahedron 2001, 57,
2917.
36. Presumably, the epimerization of magnesiated nitrile 16 competes with the
internal acylation to form 12aa.
37. The sulfinylemagnesium exchange of 23 employed 1 equiv of i-PrMgCl to avoid
iso-propyl addition to the lactone by excess i-PrMgCl. Consequently 24 is an
acylated magnesiated nitrile rather than an acylated nitrile-stabilized mag-
nesiate that would ideally correlate with O-acylation of 18a.
38. Sold as the isoaminile-cyclamate salt under the name PeraconÒ Antoneitti, F.;
Brenna, E.; Fuganti, C.; Gatti, F. G.; Giovenzana, T.; Grande, V.; Malpezzi, L.
Synthesis 2005, 1148.
39. No mechanistic work was pursued after obtaining modest diastereoselectivity
in these optimized alkylations.
40. Obtained from a mixture of diastereomers.
41. Kopp, F.; Sklute, G.; Polborn, K.; Marek, I.; Knochel, P. Org. Lett. 2005, 7, 3789 The
procedure is described in Supplementary data SI51.
42. Granander, J.; Sott, R.; Hilmersson, G. Tetrahedron 2002, 58, 4717.
43. Adjoran, I.; Frobel, K. Process for preparation of tetrahydropyranone de-
rivatives. World Patent WO 2010144937 A2 20101223, Appl., 2010.
44. Protiva, M.; Novak, L.; Borovicka, M. Collect. Czech. Chem. Commun. 1962, 27,
559.
45. The signals for the individual diastereomers were not unequivocally distin-
guished and therefore the signals assigned to one diastereomer are designated
with an asterisk.
46. The following sequence was used to prepare 21c from 4-iodo-2-
phenylbutanenitrile (i):47
14. For an excellent discussion of related alkylations with chiral organolithiums
see: Clayden, J. Organolithiums: Selectivity for Synthesis; Pergamon: Amsterdam,
2002, Chapter 6.
15. For the electrophile-dependent alkylations of a related, but cyclic, nitrile see:
Fleming, F. F.; Zhang, Z.; Wei, G.; Steward, O. W. J. Org. Chem. 2006, 71, 1430.
16. For a preliminary account see: Mycka, R. J.; Steward, O. W.; Fleming, F. F. Org.
Lett. 2010, 12, 3030.
17. The hydroxynitriles were prepared by condensing the appropriate lithiated
nitrile with an epoxide: Taylor, S. K.; De Young, D.; Simons, L. J.; Vyvyan, J. R.;
Wemple, M. A.; Wood, N. K. Synth. Commun. 1998, 28, 1691; When the reaction
was complete, solid NH4Cl was added, followed after 20 min, by an aqueous
solution of 2 M HCl. The latter modification prevents cyclization to the corre-
sponding lactone: Larcheveque, M.; Debal, A. Synth. Commun. 1980, 10, 49.
47. Cheng, C. Y.; Lu, H. Y.; Lee, F. M.; Tam, S. W. J. Pharm. Sci. 1990, 79, 758.
48. Knochel, P.; Yeh, M. C. P.; Berk, S. C.; Talbert, J. J. Org. Chem. 1988, 53, 2390.

376
R.J. Mycka et al. / Tetrahedron 69 (2013) 366e376
49. The relative configuration was determined by cyclizing, and hydrolyzing hy-
droxynitrile 22a to the corresponding lactone iii whose configuration was as-
signed from NOESY correlations.
51. The configuration is based on a correlation with diagnostic spectral patterns in
the diastereomers of 22c and 22c0.
52. Hydrogenation of the major diastereomer afforded 32c allowing the configu-
ration to be assigned.
53. Lactone vii likely arises through acylation and cyclization of hydroxynitrile 21c
followed by hydrolysis. Separation of the major lactone diastereomer provided
a sample for NOSEY from which the relative stereochemistry was obtained.
50. Nitrile vi was prepared from 4-iodobutanenitrile (iv) by sequentially reacting
the mixed cuprate derived from iv with pivaloyl chloride and reducing the
resulting halonitrile with NaBH4 to afford vi.48
54. Powell, D. A.; Fu, G. C. J. Am. Chem. Soc. 2004, 126, 7788.