Electrophile-Dependent Alkylations of Lithiated 4-Alkoxyalk-4-enenitriles

Article abstract of DOI:10.1021/acs.joc.7b03205

Alkylations of acyclic, lithiated 4-alkoxyalk-4-enenitriles are highly diastereoselective with an unusual electrophile-dependent preference. Alkyl halides, sulfur, chlorine, and acyl cyanide electrophiles intercept a series of lithiated 4-alkoxyalk-4-enenitriles to install contiguous tertiary-quaternary stereocenters with high diastereoselectivity, whereas acylations with ester and carbonate electrophiles are modestly selective. The diastereoselectivity is consistent with electrophilic attack on the most accessible face of the lithated nitrile for most electrophiles except ester and carbonate electrophiles, which likely precoordinate the lithiated nitrile before acylation. Intercepting the lithiated 4-alkoxyalk-4-enenitriles with a range of electrophiles provide insight into the criteria for otherwise challenging diastereoselective alkylations and acylations of acyclic nitriles.

Full text of DOI:10.1021/acs.joc.7b03205

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Article
Electrophile-Dependent Alkylations of Lithiated 4-Alkoxyalk-4-enenitriles
Bhaskar R. Pitta, Omar W. Steward, and Fraser F. Fleming
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b03205 • Publication Date (Web): 12 Feb 2018
Downloaded from http://pubs.acs.org on February 13, 2018
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ElectrophileꢀDependent Alkylations of Lithiated 4ꢀ
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Alkoxyalkꢀ4ꢀenenitriles
Bhaskar R. Pitta,a Omar W. Steward,b and Fraser F. Flemingc *
a Biophore India, Hyderabad, Telangana 500033, India.
b Department of Chemistry and Biochemistry, Duquesne University, Pittsburgh, PA 15282, USA
c Department of Chemistry, Drexel University, Philadelphia, PA 19104, USA
flemingf@duq.edu
RECEIVED DATE (to be automatically inserted after your manuscript is accepted if
required according to the journal that you are submitting your paper to)
Abstract. Alkylations of acyclic, lithiated 4ꢀalkoxyalkꢀ4ꢀenenitriles are highly
diastereoselective with an unusual electrophileꢀdependent preference. Alkyl halides, sulfur,
chlorine, and acyl cyanide electrophiles intercept a series of lithiated 4ꢀalkoxyalkꢀ4ꢀenenitriles to
install contiguous tertiaryꢀquaternary stereocenters with high diastereoselectivity whereas
acylations with ester and carbonate electrophiles are modestly selective. The diastereoselectivity
is consistent with electrophilic attack on the most accessible face of the lithated nitrile for most
electrophiles except ester and carbonate electrophiles which likely preꢀcoordinate the lithiated
nitrile before acylation. Intercepting the lithiated 4ꢀalkoxyalkꢀ4ꢀenenitriles with a range of
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electrophiles provide insight into the criteria for otherwise challenging diastereoselective
alkylations and acylations of acyclic nitriles.
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R1O
R2
CN
R1O
LiNEt2
THF, R2X
13 electrophiles
CN
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dr > 12:1 Except for
esters and carbonates!
R1 = Li, Bn, Me
Introduction
Metalated nitriles are exceptional nucleophiles capable of forging new carbonꢀcarbon bonds in
sterically demanding environments.1 Two unusual characteristics lie at the heart of the
extraordinary nucleophilicity, the minuscule steric demand of the nitrile unit,2 roughly eight
times smaller than a methyl group,3 and an inductive charge stabilization that localizes electron
density on the nucleophilic carbon atom.4 Harnessing the exceptional nucleophilicity in
stereoselective alkylations is largely confined to cyclic, conformationally constrained nitriles
where the electrophile trajectory is dictated by a sterically biased topology.1
Stereoselective alkylations of acyclic nitriles are significantly more challenging.5 The
difficulty lies partly in constraining rotatable single bonds6 and partly from the inherent bonding
of metalated nitriles.7 Asymmetric induction from chiral ligands complexed to lithium locates the
chirality remote from the site of electrophilic attack because lithiated nitriles favor planar,
nitrogenꢀcoordinated dimers in the solid state8 and solution9 (1a, Figure 1). Consequently, highly
selective asymmetric alkylations of lithiated nitriles are challenging10 unless a proximal ligand
redirects metal coordination to the nucleophilic carbon (1b, Figure 1).11
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Figure 1. Equilibrating Nꢀ and CꢀLithiated Nitrile Structures
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One strategy for the stereoselective alkylation of acyclic metalated nitriles is to constrain the
flexible backbone to bias electrophilic attack from one reactive conformation. The approach is
illustrated in the alkylations of lithiated nitriles derived from 2 for which the
diastereoselectivities are well above 20:1 (Scheme 1).12 Allylic strain between R1 and the
aromatic ring favors an orthogonal orientation of the two groups; the metalated nitrile
preferentially adopts the perpendicular arrangement 3'' with the small nitrile gauche to the Cꢀ3
methyl group to avoid the larger R1ꢀMe eclipsing interaction (3'). Electrophilic attack on the
more accessible face of 3'' installs the quaternary center in 4 as essentially one diastereomer
(Scheme 1).
Scheme 1. Diastereoselective Alkylation of Acyclic Nitriles
R1
LDA
R1
CN Li
CN
H
2
3'
R1
R2
CN
R2X
Li NC
R1
H
4
3''
Quaternary
center
Electrophilic
approach
Conceptually, a similar topology is anticipated upon double deprotonation of oxonitriles 5
because the resulting dianion should have a similar substitution and hybridization pattern
(Scheme 2, cf. 6 with 3).13 Although the alkylations of oxonitriles 5 proved to be modestly
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diastereoselective, alkylations of analogous oxygenꢀsubstituted alkꢀ4ꢀenenitriles were generally
efficient and highly diastereoselective. Surveying an array of electrophiles revealed an unusual
electrophileꢀdependent diastereoselectivity not previously observed with lithiated nitriles while
defining conditions for selectively installing contiguous tertiaryꢀquaternary stereocenters.
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Scheme 2. Alkylation of Dilithiated Ketonitriles
Results and Discussion
Exploring diastereoselective alkylations of acyclic γꢀoxonitriles required a readily accessible
prototype with easily varied substituents. Oxonitrile 5a proved to be an ideal prototype whose
synthesis was rapid and modular: ozonolysis of 8 and αꢀmethylenation14 provided enal 9 which
reacted with MeMgCl to afford the rather labile15 alcohol 10a that was immediately chlorinated
with Nꢀchlorosuccinimide to provide the more stable chloride 11a (Scheme 1).16 The allylic
chloride 11a was then united with lithiobutyronitrile in a relatively rare SN2 displacement at a
secondary center (Scheme 3).17 Subsequent hydrolysis of the enol etherꢀnitrile 12a afforded
oxonitrile 5a.
Scheme 3. Synthesis of Oxonitrile 5a
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Exploratory alkylations of oxonitrile 5a were frustrated by difficulties in forming the dianion
and by over alkylation. The dilithiated nitrile, best prepared from LDA (1.2 equivalents) and
excess BuLi (2.2 equivalents), was extremely reactive, affording a 2.0:1 diastereomeric mixture
of the methylated oxonitriles 7a within 5 minutes at ꢀ78 °C (Eq. 1).18 An analogous mixed
lithiumꢀmagnesium species prepared by sequential deprotonation with LDA followed by addition
of iꢀPrMgCl, was significantly less nucleophilic; methylation with MeI required temperatures of
at least ꢀ40 °C which afforded 7a as a 2.8:1 ratio of diastereomers accompanied by the
dimethylated nitrile 13a.19
(eq. 1)
The low alkylation diastereoselectivity of oxonitrile 5a stimulated a series of comparative
20
methylations with structurally related 4ꢀalkoxyalkꢀ4ꢀenenitriles 12. The LiNEt2 deprotonation
of nitrile 12a in THF and methylation with MeI afforded 15a in higher diastereomeric ratios than
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for the analogous methylation of the oxonitrile 5a (Table 1).21 The diastereoselectivity increased
in moving from Et2O to THF with minimal influence in performing the methylation in THF with
added HMPA (5 equiv, Table 1, compare entries 1, 3, and 4). As expected, the diasteroselectivity
increased when the reaction temperature was lowered from ꢀ78 to ꢀ98 °C (Table 1, compare
entries 4 and 7). Methylation of the corresponding magnesiated nitrile prepared by chlorineꢀ
magnesium exchange22, through addition of iꢀPrMgCl to the lithiated nitrile, or by metathesis
afforded 15a in very similar ratios to methylation of the lithiated nitrile (compare Table 1, entries
2, 5, 6, with entry 4). The similar diastereoselectivity with magnesium and lithium cations
implies alkylation through the same type of intermediate, most likely a Cꢀmetalated nitrile 14
favored by internal complexation.11,23
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Table 1. Comparative Alk-4-enenitrile Methylationsa
entry
1
conditions
Et2O
yield (%)
79
ratio
4.3:1
2
3
4
5
6
7
12a
12a
12a
12a
12a
12a
i-PrMgClb
HMPA
78
85
88
86
87
85
6.1:1
6.4:1
6.5:1
6.6:1
6.7:1
8.3:1
-
i-PrMgClc
MgBr2.OEt2
(-98 °C)
c
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-
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82
8.5:1
>19:1
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a The alkylations were performed by adding the electrophile at -78 °C and
b
allowing the reaction mixture to slowly warm to rt overnight.
The
magnesiated nitrile was generated by an i-PrMgCl exchange of the
corresponding chloronitrile 15e (See Table 2, entry 3). c Added after the
initial deprotonation.
Alkylations with the nitrile analogs 12bꢀc were performed to probe the structural requirements
for high selectivity. The size of the alkyl ether has a minimal influence on the methylation
diastereoselectivity (Table 1, compare entry 4 with 8) whereas the replacement of the alkoxy
substituent (A value = 0.55 kcal molꢀ1) with a more sterically demanding methyl group (A value
= 1.74 kcal molꢀ1)3 afforded only one detectable diastereomer (Table 1, entry 9; cf. Scheme 1) .24
The olefin is essential for the diastereoselective alkylation; the deprotonation of 16 and trapping
with iodopropane afforded a 1.7:1 ratio of diastereomers (compare 17 eq 2 with 12a, Table 1,
entry 4).
(eq 2)
The stereoselectivity trends for the methylations of 12aꢀc implied that trapping with
electrophiles having a steric demand greater than that of MeI would increase the
diastereoselectivity (Table 2). Surprisingly, the diastereoselectivity exhibited an unusual
electrophile dependency. Intercepting the lithiated nitrile derived from 12a with the heteroatom
electrophiles diphenyl disulfide, Sꢀphenyl benzenesulfonothioate, 2ꢀchloroꢀ2ꢀfluoroꢀ2ꢀ
phenylacetonitrile22 (Table 2, entries 1ꢀ3), and primary alkyl halides (Table 2, entries 4, 5, 8, and
9) proceeded with high diastereoselectivity. Diastereoselective alkylations with BnBr and
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cyclopropylmethyl iodide (Table 2, entries 5 and 8) implicate alkylation via SN2 displacement
rather than through single electron transfer processes.25 Alkylation of 12a with isopropyl iodide,
a secondary electrophile, was reasonably efficient but not selective (Table 2, entry 11).
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In contrast to the diastereoselective alkylations, the acylations of 12a exhibited variable
diastereoselectivities. Acylations with benzoyl cyanide and methyl cyanoformate were highly
selective (Table 2, entries 6 and 7, respectively) whereas analogous acylations with diethyl
carbonate and electron rich or electron deficient methyl benzoates (Table 2, entries 9 and 10 and
12, respectively) were relatively unselective. For the diastereoselective synthesis of oxonitriles or
esterꢀnitriles with this substitution pattern, electrophilic trapping with acyl cyanides is far
superior than the use of the corresponding carbonates or esters (Table 2, compare entries 6 and 7
with entries 9ꢀ10 and 12). Understanding the conditions required for stereoselectively accessing
quaternary acylnitriles is important because of their use in the synthesis of bioactive targets.26
Table 2. Alkylations of 12a with Diverse Electrophilesa
Yield
(%)
entry
1
electrophile
quaternary nitrile
ratio
BnO
SPh
CN
89
>19:1
15d
BnO
SPh
CN
2
3
4
78
88
87
>19:1
>19:1
>19:1
15d
BnO
Cl
F
Cl
CN
CN
Ph
15e
BnO
Pr
CN
15f
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BnO
Ph
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89
88
>19:1
>19:1
CN
15g
BnO
O
Ph
O
CN
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NC
Ph
15h
BnO
O
OMe
O
7
8
9
87
79
87
16.6:1b
12.0:1
3.2:1c
CN
NC OMe
15i
BnO
I
CN
15j
O
BnO
OEt
CN
O
EtO OEt
15k
OMe
MeO
OMe
O
MeO
MeO
OMe
BnO
10
84
2.7:1
O
CN
OMe
15l
BnO
11
12
66
76
2.3:1c
CN
15m
CF3
O
OMe
2.2:1
BnO
O
CN
F3C
15n
a
The alkylations were performed by adding the electrophile at -78 °C and
allowing the reaction mixture to slowly warm to rt overnight.27 Sequentially
adding MeCu and methyl cyanoformate at -78 °C affords a 17.2:1 ratio of
diastereomers (88% yield). Allowing the reaction mixture to warm to 0 °C prior
to adding methyl cyanoformate afforded a 1.1:1 ratio of diastereomers (62%
b
c
yield). The same ratio was obtained when the reaction temperature was
maintained at -78 °C for 6 h.
The configurational assignments were made through a series of chemical correlations to the
crystalline benzoate 19 whose structure was determined by xꢀray crystallography (Scheme 4).
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Reduction of the esterꢀnitriles 15i and 15k, to alcohol 18, followed by treatment with pꢀ
nitrobenzoyl chloride (PNBCl) provided the crystalline benzoate 19. Oxidation of 18 with Dessꢀ
Martin periodinane (DMP) afforded aldehydeꢀnitrile 20 which allowed correlation with 15h
through sequential phenyl addition and oxidation. Aldehydeꢀnitrile 20 was subjected to a threeꢀ
step olefination, hydrolysis, hydrogenation (20 → 21 → 22 → 23) to provide 23, the same
ketonitrile obtained from hydrolysis of 15f.
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Scheme 4. Chemical Correlation of Configuration
A tentative rationale for the selectivity trends is that primary alkyl halides and highly reactive
electrophiles attack the lithiated nitrile at the most sterically accessible carbon whereas carbonate
and ester electrophiles competitively coordinate to the lithiated nitrile leading to some alkylation
through electrophilic attack on the opposite face. Electrophilic attack is most likely on the more
accessible face of lithiated nitrile conformer 24b where the steric compression is minimized by
instead eclipsing the small nitrile with the vicinal methyl group rather than eclipsing the two
alkyl groups as in 24a (Scheme 5). Acyl cyanides likely follow the same trajectory. Carbonates
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and esters may competitively chelate to the lithium cation by displacing ligated THF leading to
internal delivery of the electrophile to the opposite face of the lithiated nitrile (Scheme 5, 24c →
15a'). Coordination of carbonyl electrophiles to metalated nitriles in similar contexts is
sufficiently strong to control both stereoselectivity28 and chemoselectivity.29
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Scheme 5. Tentative Alkylation Mechanism
BnO
BnO
R
R
BnO
LiNEt2
+
CN
CN
15a'
CN
THF
RX
12a
15a
LiNEt2
Coordinated attack
O
Bn
THF
THF
Bn
H
THF
Bn
THF
R1
X
O Li
O Li
O Li
THF
O
C
X
N
R1
C
C
H
H
N
N
24a
24b
24c
External attack
Conclusion
Diastereoselective alkylations with a series of 4ꢀoxygenated alkenenitrilesꢀ4ꢀ revealed unusual
electrophileꢀdependent stereoselectivity preferences. Whereas the alkylations of a dilithiated
enolateꢀnitrile were relatively unselective, the alkylations of the corresponding 4ꢀalkoxy alkꢀ4ꢀ
enenitriles with primary alkyl halides, and sulfur, chlorine, and acyl cyanide electrophiles were
highly selective. Analogous acylations with acyl cyanides were highly selective whereas trapping
with carbonate and ester electrophiles was modestly selective. The stereoselectivity trends are
consistent with an approachꢀcontrolled electrophilic attack on the most accessible face of a Cꢀ
lithiated nitrile and a less selective alkylation of esters and carbonates caused by electrophile
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coordination prior to acylation. Collectively, these represent the first electrophileꢀdependent
trapping of lithiated nitriles and define conditions for installing an array of vicinal tertiaryꢀ
quaternary centers with high diastereoselectivity.
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Experimental Section
General Experimental Procedures. All nonꢀaqueous reactions were performed in ovenꢀ or
flameꢀdried glassware under a nitrogen atmosphere. All chemicals were purchased from
commercial vendors and used as received unless otherwise specified. Anhydrous tetrahydrofuran
(THF) and diethyl ether were distilled from benzophenoneꢀsodium under N2 before use.
Reactions were magnetically stirred and monitored by thin layer chromatography (TLC) with
250 ꢁm precoated silica gel plates. Preparative radial chromatography was performed on 1 or 2
mm plates prepared inꢀhouse that were coated with silica (PGFꢀPrep TLC w/Gypsum UV/254, 5ꢀ
1
50 µm). H NMR and 13C NMR high resolution nuclear magnetic resonance spectra were
recorded on a Varian Inova 300 (300 MHz/75 MHz) or Varian Inova 500 (500 MHz/126 MHz
1
spectrometers at 25 °C. Chemical shifts are reported relative to TMS (δ 0.00) for H NMR and
chloroform (δ 77.16) for 13C NMR. IR spectra were recorded as thin films (PerkinElmer
Spectrum 100 FTꢀIR Spectrometer). High resolution mass spectra (HRMS) were recorded on an
Agilent 6200 TOF LC MS system using a nano ESI and APCIꢀTOF interface.
(((3ꢀChlorobutꢀ1ꢀenꢀ2ꢀyl)oxy)methyl)benzene (11a): A stream of ozone was bubbled through a
ꢀ78 °C, CH2Cl2 solution (15 mL) of the allyl benzyl ether (1.5 g, 10.12 mmol, 1.0 equiv) until the
distinctive blue color of ozone was clearly observed. Ozonolysis was then terminated and excess
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ozone was displaced by passing a stream of nitrogen through the solution for 5 min. Neat
dimethyl sulfide (0.94 g, 15.2 mmol, 1.5 equiv) was added, the solution was allowed to warm to
room temperature and then stirred overnight. The crude reaction mixture was washed twice with
water and brine, and was then dried (Na2SO4), and concentrated to afford the crude aldehyde
(1.52 g). Propionic acid (0.075 g, 1.01 mmol, 0.1 equiv) and pyrrolidine (72.0 mg, 1.01 mmol,
0.1 equiv) were added to a mixture of iꢀPrOH (1.0 mL), aqueous formaldehydehyde solution
(10.1 mmol, 37% formaldehyde in water, 1.0 equiv) and the crude 2ꢀ(benzyloxy)acetaldehyde14
(1.52 g, 10.62 mmol, 1.05 equiv) and then the reaction mixture was stirred at 45 °C. After 24 h
saturated, aqueous NaHCO3 was added and then the mixture was extracted with Et2O (3 x 15
mL). The combined organic extracts were washed with brine, dried (Na2SO4), and concentrated
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to afford 1.61 g of crude 2ꢀ(benzyloxy)acrylaldehyde
(9).14 A THF solution of
methylmagnesium bromide solution (5.46 mL, 10.9 mmol, 1.1 equiv) was added dropwise to a
THF solution (15 mL) of the crude 2ꢀ(benzyloxy)acrylaldehyde (1.61 g, 9.93 mmol, 1 equiv).
After 15 minutes, a solution of saturated, aqueous NH4Cl was added (5 mL), the phases were
separated and the aqueous phase was extracted with ethyl acetate (2 x 20 mL). The combined
organic phase was washed with brine, dried (Na2SO4), and concentrated to afford 1.73 g of crude
3ꢀ(benzyloxy)butꢀ3ꢀenꢀ2ꢀol (10a). Triphenyl phosphine (7.68 g, 29.3 mmol, 3.0 equiv), and NCS
(3.91 g, 29.3 mmol, 3.0 equiv) were added sequentially to a 0 °C, THF solution (100 mL) of
crude 3ꢀ(benzyloxy)butꢀ3ꢀenꢀ2ꢀol (1.74 g, 9.76 mmol, 1.0 equiv). After 2 h, the reaction mixture
was allowed to warm to room temperature. After 16 h, the reaction mixture was poured in to a
flask containing a solution of saturated, aqueous NaHCO3 (25 mL) and diethyl ether (30 mL).
The phases were separated and the aqueous phase was then extracted with ether (2 x 20 mL). The
combined organic extracts were washed with brine, dried (Na2SO4), and concentrated to afford a
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crude product that was purified by silica gel column chromatography (pure hexanes to 1:49,
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EtOAc/hexanes) to afford 0.5 g (25% for 4 steps) of pure chloride 11a as an oil: IR (film) 1629,
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2930 cmꢀ1; H NMR: δ 1.71 (d, J = 6.9 Hz, 3H), 4.14 (d, J = 2.9 Hz, 1H), 4.35 (d, J = 2.9 Hz,
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1H), 4.54 (q, J = 6.9 Hz, 1H), 4.87 (s, 2H), 7.32ꢀ7.42 (m, 5H); C NMR: δ 22.90, 57.2, 69.8,
84.1, 127.2, 127.85, 128.5, 136.7, 161.5; HRMS(EI) [M+Na]+ calcd for C11H13ClONa 219.0553;
found 219.0547.
4ꢀ(Benzyloxy)ꢀ2ꢀethylꢀ3ꢀmethylpentꢀ4ꢀenenitrile (12a): A THF solution (0.3 M) of
butyronitrile (527 mg, 7.63 mmol, 3.0 equiv) was added to a ꢀ78 °C, THF solution (0.1 M) of
LDA, generated from butyllithium (3.05 equiv) and diisopropylamine (3.15 equiv). After 30
minutes at ꢀ78 °C, a THF (3.0 mL) solution of (((3ꢀchlorobutꢀ1ꢀenꢀ2ꢀyl)oxy)methyl)benzene
(11a, 500 mg, 2.54 mmol, 1.0 equiv) was added and then the reaction was allowed to warm to rt.
After 16h, saturated, aqueous NH4Cl (5 mL) was added, the phases were separated and the crude
product was extracted with EtOAc (2 x 15 mL). The combined organic phase was dried
(Na2SO4), and concentrated to afford a crude product that was purified by radial chromatography
(4 mm plate, 3:97, EtOAc/hexanes) to afford 507 mg (87%, dr = 1.3:1) of 4ꢀ(benzyloxy)ꢀ2ꢀethylꢀ
3ꢀmethylpentꢀ4ꢀenenitrile (12a) as an oily liquid: For the major diastereomer: IR (film) 1628,
2236, 2278, 2936, 2972 cmꢀ1; 1H NMR: δ 1.11ꢀ1.13 (m, 3H), 1.36 (d, J = 7.2 Hz, 3H), 1.60ꢀ1.68
(m, 2H), 2.48ꢀ2.52 (m, 1H), 2.78ꢀ2.82 (m, 1H), 4.13 (s, 2H), 4.78 (ABq, ∆ν =14.5 Hz, J =12.0
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Hz, 2H), 7.34ꢀ7.43 (m, 5H); C NMR: δ 11.8, 16.9, 23.9, 37.4, 41.3, 69.5, 83.9, 121.3, 127.4,
128.0, 128.6, 136.8, 162.0; HRMS(EI) m/z [M+Na]+ calcd for C15H19NONa 252.1364; found
252.1356. For the minor diastereomer: IR (film) 1627, 2236, 2278, 2936, 2971 cmꢀ1; 1H NMR: δ
1.10ꢀ1.13 (m, 3H), 1.27 (d, J = 7.2 Hz, 3H), 1.56ꢀ1.69 (m, 2H), 2.56ꢀ2.61 (m, 1H), 2.73ꢀ2.77 (m,
1H), 4.14 (d, J = 2.8 Hz, 1H), 4.16 (d, J = 2.8 Hz, 1H), 4.76ꢀ4.83 (ABq, ∆ν = 20.4 Hz, J = 11.6
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Hz, 2H), 7.34ꢀ7.41 (m, 5H); C NMR: δ 12.0, 16.2, 22.4, 37.5, 40.8, 69.6, 83.8, 121.4, 127.5,
127.9, 128.5, 136.9, 162.5; HRMS(EI) m/z [M+Na]+ calcd for C15H19NONa 252.1364; found
252.1362.
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2ꢀEthylꢀ3ꢀmethylꢀ4ꢀoxopentanenitrile (5a): An aqueous solution of HCl (0.24 µl, 0.0065
mmol, 0.01 equiv) was added to an acetonitrile solution (3 mL) of 4ꢀ(benzyloxy)ꢀ2ꢀethylꢀ2,3ꢀ
dimethylpentꢀ4ꢀenenitrile (150 mg, 0.654 mmol, 1.0 equiv) and then H2O (59 mg, 3.27 mmol, 5
equiv) was added. After 30 min, a solution (5 mL) of saturated, aqueous NaHCO3 was added, the
phases were separated, and the aqueous phase was extracted with CH2Cl2 (2 x 15 mL). The
combined organic extracts were washed with brine, dried (Na2SO4), and concentrated to afford
the crude nitrile that was purified by radial chromatography (2 mm plate, 4:96 to 8:92,
EtOAc/hexanes) to afford 84.6 mg (93%) of pure 2ꢀethylꢀ3ꢀmethylꢀ4ꢀoxopentanenitrile as a
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colorless mixture of diastereomers: For the major diastereomer: IR (film) 1711, 2237 cmꢀ1; H
NMR: δ 1.08ꢀ1.11 (m, 3H), 1.34 (d, J = 7.2 Hz, 3H), 1.53ꢀ1.59 (m, 2H), 2.22 (s, 3H), 2.69ꢀ2.75
(m, 1H), 2.92ꢀ2.96 (m, 1H); 13C NMR: δ 11.8, 15.2, 24.2, 28.9, 35.3, 47.8, 120.6, 208.2;
HRMS(EI) m/z [M+H]+ calcd for C8H14NO 140.1075; found 140.1063. For the minor
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diastereomer: IR (film) 1712, 2237 cmꢀ1; H NMR: δ 1.12ꢀ1.14 (m, 3H), 1.28 (d, J = 6.6 Hz,
3H), 1.59ꢀ1.66 (m, 2H), 2.26 (s, 3H), 2.79ꢀ2.86 (m, 2H); 13C NMR: δ 11.8, 14.0, 21.9, 28.7, 34.8,
47.8, 121.0, 208.1; HRMS(EI) m/z [M+H]+ calcd for C8H14NO 140.1075; found 140.1062.
(2R*, 3R*)ꢀ and (2R*, 3S*)ꢀ2ꢀEthylꢀ2,3ꢀdimethylꢀ4ꢀoxopentanenitrile (7a). A THF solution
(0.3 M) of 2ꢀethylꢀ3ꢀmethylꢀ4ꢀoxopentanenitrile (25 mg, 0.18 mmol, 1.0 eq) was added to a ꢀ78
°C, THF solution (0.1 M) of LDA, generated from butyllithium (1.2 equiv) and diisopropylamine
(1.25 equiv). After 30 min a hexanes solution (2.5 M) of butyllithium (0.395 mmol, 2.2 equiv) in
hexne was added and then the reaction was allowed to warm to rt. After 30 min the solution was
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cooled ꢀ78 °C and then neat iodomethane (76 mg, 0.539 mmol, 3.0 equiv) was added. After 5
minutes, a solution (4 mL) of saturated, aqueous NH4Cl was added. The phases were separated
and then the crude product was extracted with EtOAc (2 x 10 mL), dried (Na2SO4), concentrated,
and purified by radial chromatography (2 mm plate, 4:96 to 8:92, EtOAc/hexanes) to afford 24
mg (87%, dr 2.0:1) of analytically pure 2ꢀethylꢀ2,3ꢀdimethylꢀ4ꢀoxopentanenitrile as a colorless
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mixture of diastereomers. For (2R*, 3R* 7a): IR (film) 1713, 2233 cmꢀ1; H NMR: δ 1.07ꢀ1.11
(m, 3H), 1.27 (d, J = 7.0 Hz, 3H), 1.36 (s, 3H), 1.57ꢀ1.64 (m, 1H), 1.69ꢀ1.76 (m, 1H), 2.29 (s,
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3H), 2.73 (q, J = 7.0 Hz, 1H); C NMR: δ 9.2, 12.4, 21.1, 30.0, 30.1, 38.7, 52.4, 123.0, 208.9;
HRMS(EI) calcd for (M + H+), C9H15NOH+ 154.1232, found 154.1224. For (2R*, 3S* 7a): IR
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(film) 1712, 2233 cmꢀ1; H NMR: δ 1.09ꢀ1.12 (m, 3H), 1.34 (d, J = 7.2 Hz, 3H), 1.37 (s, 3H),
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1.52ꢀ1.59 (m, 1H), 1.83ꢀ1.90 (m, 1H), 2.26 (s, 3H), 2.73 (q, J = 7.2 Hz, 1H).; C NMR: δ 9.2,
12.4, 21.0, 30.0, 30.2, 38.7, 52.3, 123.0, 208.8; HRMS(EI) m/z [M + Na]+ calcd for C9H15NONa
176.1051; found 176.1038. Preparation of (2R*, 3R*)ꢀ7a by ozonolysis for configurational
correlation: A stream of ozone was bubbled through a ꢀ78 °C, dichloromethane solution (10 mL)
of (2R*, 3R*)ꢀ15c (45 mg, 0.297 mmol, 1.0 equiv) until the distinctive blue color of ozone was
clearly observed. Ozonolysis was then terminated and the excess ozone was purged by passing a
stream of nitrogen through the solution for 5ꢀ10 min. Neat dimethyl sulfide (28 mg, 0.446 mmol,
1.5 equiv) was added and then the reaction was allowed to warm to rt. After 16 h the solution
was washed with water and then brine. The organic phase was dried (Na2SO4), concentrated, and
then purified by radial chromatography (1 mm plate, 8:92, EtOAc/hexanes) to afford 42.4 mg
(93%) of (2R*, 3R*)ꢀ7a spectrally identical to material previously isolated.
(2R*, 3R*)ꢀ2ꢀethylꢀ2,3ꢀdimethylꢀ4ꢀoxohexanenitrile (13a). A THF solution (0.3 M) of 2ꢀ
ethylꢀ3ꢀmethylꢀ4ꢀoxopentanenitrile (25 mg, 0.18 mmol, 1.0 eq) was added to a ꢀ78 °C, THF
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solution (0.1 M) of LDA, generated from butyllithium (1.2 equiv) and diisopropylamine (1.25
equiv). After 30 min, a THF solution (2.0 M) of iꢀPrMgCl solution (0.395 mmol, 2.2 equiv) was
added and then the reaction was allowed to warm to rt. After 30 min the reaction was cooled to ꢀ
78 °C, neat iodomethane (38 mg, 0.269 mmol, 1.5 equiv) was added, and then the reaction was
allowed to warm slowly to ꢀ45 °C. After 5 h, a solution (4 mL) of saturated, aqueous NH4Cl was
added and then the phases were separated. The organic phase was extracted with EtOAc (2 x 10
mL), dried (Na2SO4), and concentrated and purified by radial chromatography (2 mm plate, 4:96
to 8:92, EtOAc/hexanes) to afford 19.5 mg (72%, dr 2.8:1) of analytically pure 2ꢀethylꢀ2,3ꢀ
dimethylꢀ4ꢀoxopentanenitrile and 6 mg (21%, dr 2.9:1) of 2ꢀethylꢀ2,3ꢀdimethylꢀ4ꢀ
oxohexanenitrile (13a) as a colorless mixture of diastereomers. For (2R*, 3R*)ꢀ13a: IR (film)
1714, 2233 cmꢀ1; 1H NMR: δ 1.05ꢀ1.08 (m, 6H), 1.21 (d, J = 7.3 Hz, 3H), 1.33 (s, 3H), 1.53ꢀ1.59
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(m, 1H), 1.65ꢀ1.72 (m, 1H), 2.53ꢀ2.60 (m, 2H), 2.72 (q, J = 7.3 Hz, 1H); C NMR: δ 7.6, 9.3,
12.6, 21.0, 29.9, 36.4, 38.9, 51.3, 123.0, 211.6; HRMS(EI) m/z [M + Na]+ calcd for C10H17NONa
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190.1208; found 190.1196. For (2R*, 3S*)ꢀ13a: IR (film) 1715, 2233 cmꢀ1; H NMR: δ 1.04ꢀ
1.07 (m, 6H), 1.29 (d, J = 7.3 Hz, 3H), 1.34 (s, 3H), 1.47ꢀ1.84 (m, 2H), 2.53ꢀ2.71 (m, 2H), 2.74
(q, J = 7.3 Hz, 1H); 13C NMR: δ 7.6, 9.2, 13.7, 20.2, 29.9, 36.5, 39.7, 50.9, 123.0, 211.6;
HRMS(EI) m/z [M + Na]+ calcd for C10H17NONa 190.1208; found 190.1196.
General alkꢀ4ꢀenenitrile deprotonation and alkylation procedure: A THF solution (0.3 M) of
the alkꢀ4ꢀenenitrile (1.0 equiv) was added to a ꢀ78 °C, THF solution (0.1 M) of lithium
diethylamide, generated from butyllithium (1.05 equiv) and diethylamine (1.15 equiv). The
reaction was allowed to warm to rt over 30 min and then cooled to ꢀ78 °C. Neat electrophile
(1.15 equiv) was added and then the reaction was allowed to slowly warm to rt. After 16 h, a
solution (3 mL) of saturated, aqueous NH4Cl was added, the phases were separated, and the
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aqueous phase was extracted with EtOAc (2 x 10 mL). The combined organic extract was dried
(Na2SO4), concentrated, and purified by radial chromatography to afford analytically pure
material.
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(2R*, 3R*)ꢀ and (2R*, 3S*)ꢀ4ꢀ(Benzyloxy)ꢀ2ꢀethylꢀ2,3ꢀdimethylpentꢀ4ꢀenenitrile (15a):
Following the general procedure with the variation of performing the reaction in diethyl ether in
place of THF, and with lithium diethylamide (0.115 mmol), 12a (25 mg, 0.109 mmol) and
iodomethane (16 mg, 0.115 mmol), afforded, after purification on a Chromatotron (1 mm plate,
1:99 to 3:97 hexanes: ethyl acetate), 21 mg (79%, 4.3:1 dr) of 15a as an oil: For (2R*, 3R*)ꢀ15a:
IR (film) 1628, 2233 cmꢀ1; 1H NMR: δ 1.09ꢀ1.11 (m, 3H), 1.32 (s, 3H), 1.37 (d, J = 7.2 Hz, 3H),
1.49ꢀ1.56 (m, 1H), 1.82ꢀ1.89 (m, 1H), 2.41 (q, J = 7.2 Hz, 1H), 4.10 (d, J = 2.5 Hz, 1H), 4.14 (d,
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J = 2.5 Hz, 1H), 4.77 (ABq, ∆ν = 18.5 Hz, J = 11.6 Hz, 2H), 7.32ꢀ7.40 (m, 5H); C NMR: δ
9.3, 15.4, 20.9, 31.3, 40.8, 45.7, 69.4, 84.7, 123.9, 127.2, 127.8, 128.5, 136.9, 162.4; HRMS(EI)
calcd for (M+H+), C16H22NO+ 244.1701, found 244.1684. For (2R*, 3S*)ꢀ15a: IR (film) 696,
739, 811, 1286, 1626, 2233, 2881, 2940, 2976 cmꢀ1; 1H NMR: δ 1.07ꢀ1.10 (m, 3H), 1.33 (d, J =
7.2 Hz, 3H), 1.36 (s, 3H), 1.49ꢀ1.54 (m, 1H), 1.76ꢀ1.81 (m, 1H), 2.37 (q, J = 7.2 Hz, 1H), 4.12
(d, J = 2.5 Hz, 1H), 4.14 (d, J = 2.5 Hz, 1H), 4.79 (ABq, ∆ν = 20.7 Hz, J = 11.9 Hz, 2H), 7.32ꢀ
7.43 (m, 5H); 13C NMR: δ 9.4, 14.8, 22.2, 30.1, 40.7, 46.6, 69.4, 84.6, 123.7, 127.2, 127.7,
128.4, 136.9, 162.6; HRMS(EI) m/z [M+H]+ calcd for C16H22NO 244.1701; found 244.1698.
From 15f, (Table 1. Entry 2). A THF solution of iꢀPrMgCl (0.327 mmol, 3.0 equiv) was added to
a ꢀ78 °C, THF (2.0 mL) solution of 15f (25 mg, 0.109 mmol, 1.0 equiv) and then the cooling
bath was removed. After 30 min, the solution was cooled to ꢀ78 °C, neat iodomethane (46 mg,
0.327 mmol, 3.0 equiv) was added, and then the reaction was allowed to slowly warm to rt.
Saturated, aqueous NH4Cl (3 mL) was added, the phases were separated, and the aqueous phase
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was extracted with EtOAc (2 x 10 mL). The combined organic extracts were dried (Na2SO4),
concentrated, and purified on a Chromatotron (1 mm plate, 1:99 to 3:97 hexanes: ethyl acetate),
to afford 20.7 mg (78%, 6.1:1 dr) of 15a. (Table 1. Entry 3). Performing the general procedure
with lithium diethylamide (0.115 mmol), 12a (25 mg, 0.109 mmol) with the variation of adding
HMPA (0.545 mmol) and stirring for 5 min at ꢀ78 °C prior to the addition of iodomethane (16
mg, 0.115 mmol), afforded, after purification on a Chromatotron (1 mm plate, 1:99 to 3:97
hexanes: ethyl acetate), 22.6 mg (85%, 6.4:1 dr) of 15a. (Table 1, Entry 4): Performing the
general procedure with lithium diethylamide (0.115 mmol), 12a (25 mg, 0.109 mmol) and
iodomethane (16 mg, 0.115 mmol), afforded, after purification on a Chromatotron (1 mm plate,
1:99 to 3:97 hexanes: ethyl acetate), 23.3 mg (88%, 6.5:1 dr) of 15a. (Table 1. Entry 5).
Performing the general procedure with lithium diethylamide (0.115 mmol), 12a (25 mg, 0.109
mmol) with the variation of adding iꢀPrMgCl solution (0.115 mmol) in THF (2.0 M) and stirring
for 1.0 h prior to the addition of iodomethane (16 mg, 0.115 mmol), afforded, after purification
on a Chromatotron (1 mm plate, 1:99 to 3:97 hexanes: ethyl acetate), 22.8 mg (86%, 6.6:1 dr) of
15a. (Table 1. Entry 6). Performing the general procedure with lithium diethylamide (0.115
mmol), 12a (25 mg, 0.109 mmol) with the variation of adding MgBr2.OEt2 (0.115 mmol) and
stirring for 1.0 h prior to the addition of iodomethane (16 mg, 0.115 mmol), afforded, after
purification on a Chromatotron (1 mm plate, 1:99 to 3:97 hexanes: ethyl acetate), 23 mg (87%,
de ratio 6.7:1) of 15a. (Table 1. entry 7): Performing the general procedure with lithium
diethylamide (0.115 mmol), 12a (25 mg, 0.109 mmol) with the variation of cooling the reaction
to ꢀ98 °C prior to the addition of iodomethane (16 mg, 0.115 mmol), afforded, after purification
on a Chromatotron (1 mm plate, 1:99 to 3:97 hexanes: ethyl acetate), 22.5 mg (85%, 8.3:1 dr) of
15a.
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2ꢀEthylꢀ4ꢀmethoxyꢀ3ꢀmethylpentꢀ4ꢀenenitrile (12b): A THF solution (0.3 M) of butyronitrile
(527 mg, 7.63 mmol, 3.0 equiv) was added to a ꢀ78 °C, THF solution (0.1 M) of LDA, generated
from butyllithium (3.05 equiv) and diisopropylamine (3.15 equiv). After 30 minutes, a THF
solution (3.0 mL) of 3ꢀbromoꢀ2ꢀmethoxybutꢀ1ꢀene17b (306 mg, 2.54 mmol, 1.0 equiv) was added
and then the reaction was allowed to warm to rt. Saturated, aqueous NH4Cl (5 mL) was added,
the phases were separated, and the aqueous phase was extracted with EtOAc (2 x 15 mL). The
combined organic extracts were dried (Na2SO4), and concentrated to afford a crude product that
was purified by radial chromatography (4 mm plate, 3:97, EtOAc/hexanes) to afford 338 mg
(87%, 1.3:1 dr) of 12b as an oil. For the major diastereomer: IR (film) 1624, 1659, 2236 cmꢀ1; 1H
NMR: δ 1.07 (t, J = 7.3 Hz, 3H), 1.26 (d, J = 7.0 Hz, 3H), 1.54ꢀ1.60 (m, 2H), 2.36ꢀ2.43 (m, 1H),
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2.67ꢀ2.72 (m, 1H), 3.53 (s, 3H), 3.97 (d, J = 9.0 Hz 1H), 3.99 (d, J = 9.0 Hz, 1H); C NMR: δ
11.7, 16.7, 23.9, 37.4, 41.0, 54.9, 82.3, 121.3, 163.2; HRMS(EI) m/z [M+Na]+ calcd for
C9H15NONa 176.1051; found 176.1041. For the minor diastereomer: IR (film) 1624, 1658, 2236
1
cmꢀ1; H NMR: δ 1.06ꢀ1.10 (m, 3H), 1.20 (d, J = 7.0 Hz, 3H), 1.50ꢀ1.63 (m, 2H), 2.45ꢀ2.52 (m,
1H), 2.63ꢀ2.68 (m, 1H), 3.55 (s, 3H), 4.00 (d, J = 3.8 Hz, 1H), 4.02 (d, J = 3.8 Hz, 1H; 13C
NMR: δ 11.9, 16.1, 22.3, 37.5, 40.5, 54.9, 82.2, 121.3, 163.5; HRMS(EI) [M+Na]+ calcd for
C9H15NONa 176.1051; found 176.1041.
(2R*,3R*)ꢀ2ꢀethylꢀ4ꢀmethoxyꢀ2,3ꢀdimethylpentꢀ4ꢀenenitrile (15b). Performing the general
procedure with lithium diethylamide (0.115 mmol), 12b (25 mg, 0.163 mmol) and iodomethane
(24 mg, 0.170mmol), afforded, after purification on a Chromatotron (1 mm plate, 1:99 to 3:97
hexanes: ethyl acetate), 22.9 mg (84%, 8.5:1 dr) of (2R*, 3R*)ꢀ15b as an oil: IR (film) 1623,
1655, 2233 cmꢀ1; 1H NMR: δ 1.07ꢀ1.07 (m, 3H), 1.25 (d, J = 7.0 Hz, 3H), 1.30 (s, 3H), 1.36ꢀ1.49
(m, 1H), 1.68ꢀ1.87 (m, 1H), 2.28 (q, J = 7.0 Hz, 1H), 3.54 (s, 3H), 4.00 (s, 2H); 13C NMR: δ 9.4,
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14.8, 22.1, 30.0, 40.5, 46.4, 54.7, 83.1, 123.7, 163.7; HRMS(EI) [M+Na]+ calcd for C10H17NONa
190.1208; found 190.1196.
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2ꢀEthylꢀ3,4ꢀdimethylpentꢀ4ꢀenenitrile (12c). A hexanes solution (2.5 M) of butyllithium (1.03
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mmol, 1.19 equiv) was
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ꢀ78 °C, THF suspension (5.0
mL) of methyltriphenylphosphonium iodide (418 mg, 1.03 mmol, 1.2 equiv). After 30 min, a
THF solution of 5a (120 mg, 0.862 mmol, 1.0 equiv) was added dropwise and then the solution
was allowed to warm to rt. After 12 h, saturated, aqueous NH4Cl (3 mL) was added, the phases
were separated, and the aqueous phase was extracted with diethyl ether (2 x 10 mL). The
combined organic phase was dried (Na2SO4) and concentrated to give crude nitrile that was
purified by radial chromatography (1 mm plate, 2:98, EtOAc/hexanes) to afford 79 mg (67%) of
pure nitrile: IR (film) 1648, 2235 cmꢀ1; HRMS(EI) m/z [M + H]+ calcd for C9H15NH 138.1283;
found 138.1272. For the major diastereomer: 1H NMR: δ 1.08ꢀ1.12 (m, 3H), 1.24 (d, J = 6.9 Hz,
3H), 1.52ꢀ1.65 (m, 2H), 1.68 (s, 3H), 2.35ꢀ2.52 (m, 2H), 4.84ꢀ4.90 (m, 2H); 13C NMR: δ 11.7,
1
17.4, 18.8, 24.1, 37.9, 42.7, 113.0, 121.4, 145.4. For the minor diastereomer: H NMR: δ 1.08ꢀ
1.12 (m, 3H), 1.17 (d, J = 6.9 Hz, 3H), 1.52ꢀ1.65 (m, 2H), 1.77 (s, 3H), 2.35ꢀ2.52 (m, 2H), 4.84ꢀ
4.90 (m, 2H); 13C NMR: δ 11.9, 17.0, 19.8, 22.6, 38.0, 42.3, 113.2, 121.5, 145.5.
(2R*, 3R*)ꢀ2ꢀethylꢀ2,3,4ꢀtrimethylpentꢀ4ꢀenenitrile (15c): A THF solution (0.3 M) of 12c (70
mg, 510 mmol, 1.0 equiv) was added to a ꢀ78 °C, THF solution (0.1 M) of LiNEt2, generated
from butyllithium (1.05 equiv) and diethylamine (1.15 equiv). The solution was warmed to rt and
after 30 min the solution was cooled to ꢀ78 °C, and neat iodomethane (83 mg, 587 mmol, 1.15
equiv) was then added. After 5 minutes, saturated, aqueous NH4Cl (2 mL) was added, the phases
were separated, and the aqueous phase was extracted with EtOAc (2 x 10 mL). The combined
organic extracts were dried (Na2SO4), concentrated, and purified by radial chromatography (1
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mm plate, 2:98, EtOAc/hexanes) to afford 63 mg (82%) of (2R*, 3R*)ꢀ15c as an oil: IR (film)
1646, 2232 cmꢀ1; 1H NMR: δ 1.06ꢀ1.09 (m, 3H), 1.26 (d, J = 7.0 Hz, 3H), 1.33 (s, 3H), 1.31ꢀ1.43
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(m, 1H), 1.70ꢀ1.80 (m, 1H), 1.84ꢀ1.85 (m, 3H), 2.22 (q, J = 7.0 Hz, 1H), 4.85ꢀ4.89 (m, 2H); C
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NMR: δ 9.3, 15.7, 20.2, 22.4, 30.6, 40.0, 48.5, 114.3, 123.9, 146.0; HRMS(EI) m/z [M + H]+
calcd for C10H17NH 152.1439; found 152.1428.
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(2S*, 3S*)ꢀ4ꢀ(Benzyloxy)ꢀ2ꢀethylꢀ3ꢀmethylꢀ2ꢀ(phenylthio)pentꢀ4ꢀenenitrile (15d). Performing
the general procedure with lithium diethylamide (0.115 mmol), 12a (25 mg, 0.109 mmol) and
diphenyl disulfide (25 mg, 0.115 mmol), afforded, after purification on a Chromatotron (1 mm
plate, 1:99 to 3:97 hexanes: ethyl acetate), 32 mg (89%) of (2S*, 3S*)ꢀ15d as an oil: IR (film)
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1624, 2229 cmꢀ1; H NMR: δ 1.13ꢀ1.16 (m, 3H), 1.55 (d, J = 7.2 Hz, 3H), 1.71ꢀ1.80 (m, 2H),
2.62 (q, J = 7.2 Hz, 1H), 4.15 (d, J = 2.8 Hz, 1H), 4.18 (d, J = 2.8 Hz, 1H), 4.81 (ABq, ∆ν =
13
22.0 Hz, J = 11.9 Hz, 2H), 7.27ꢀ7.48 (m, 8H), 7.68ꢀ7.70 (m, 2H); C NMR: δ 8.9, 16.4, 28.5,
44.6, 54.4, 69.6, 85.3, 120.3, 127.2, 127.7, 128.4, 129.2, 129.5, 130.1, 136.6, 137.2, 161.5;
HRMS(EI) m/z [M+Na]+ calcd for C21H23NOSNa 360.1398, found 360.1404. Performing the
general procedure with lithium diethylamide (0.115 mmol), 12a (25 mg, 0.109 mmol) and Sꢀ
phenyl benzenethiosulfonate (28.6 mg, 0.115 mmol), afforded, after purification on a
Chromatotron (1 mm plate, 1:99 to 3:97 hexanes: ethyl acetate), 28.7 mg (78%) of 15d as an oil
identical to material previously synthesized.
(2S*, 3S*)ꢀ4ꢀ(Benzyloxy)ꢀ2ꢀchloroꢀ2ꢀethylꢀ3ꢀmethylpentꢀ4ꢀenenitrile (15e). Performing the
general procedure with lithium diethylamide (0.115 mmol), 12a (25 mg, 0.109 mmol) and 2ꢀ
chloroꢀ2ꢀfluoroꢀ2ꢀphenylacetonitrile (19.5 mg, 0.115 mmol), afforded, after purification on a
Chromatotron (1 mm plate, 1:99 to 3:97 hexanes: ethyl acetate), 25 mg (88%) of (2S*, 3S*)ꢀ15e
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as an oil: IR (film) 1625, 2237 cmꢀ1; H NMR: δ 1.25 (t, J = 7.4 Hz, 3H), 1.56 (d, J = 6.9 Hz,
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3H), 1.94ꢀ1.98 (m, 1H), 2.11ꢀ2.15 (m, 1H), 2.75 (q, J = 6.9 Hz, 1H), 4.20ꢀ4.22 (m, 2H), 4.80
(ABq, ∆ν = 5.0 Hz, J = 12.0 Hz, 2H), 7.32ꢀ7.46 (m, 5H); 13C NMR: δ 9.7, 16.0, 33.8, 50.2, 66.4,
69.6, 85.9, 117.9, 127.2, 127.9, 128.5, 136.4, 160.4. HRMS(EI) m/z [M + H]+ calcd for
C15H18ClNOH 264.1155; found 264.1142.
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(2S*, 3R*)ꢀ4ꢀ(Benzyloxy)ꢀ2ꢀethylꢀ3ꢀmethylꢀ2ꢀpropylpentꢀ4ꢀenenitrile (15f). Performing the
general procedure with lithium diethylamide (0.115 mmol), 12a (25 mg, 0.109 mmol) and 1ꢀ
iodopropane (19.5 mg, 0.115 mmol), afforded, after purification on a Chromatotron (1 mm
plate, 1:99 to 3:97 hexanes: ethyl acetate), 25.7 mg (87%) of (2S*, 3R*)ꢀ15f as an oil: IR (film)
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1621, 2230 cmꢀ1; H NMR: δ 0.94 (t, J = 7.2 Hz, 3H), 0.98ꢀ1.10 (m, 3H), 1.31 (d, J = 7.2 Hz,
3H), 1.38ꢀ1.48 (m, 2H), 1.54ꢀ1.76 (m, 4H), 2.48 (q, J = 7.2 Hz, 1H), 4.11 (d, J = 2.8 Hz, 1H),
4.13 (d, J = 2.8 Hz, 1H), 4.73ꢀ4.80 (ABq, ∆ν = 21.7 Hz, J = 11.9 Hz, 2H), 7.29ꢀ7.41 (m, 5H);
13C NMR: δ 9.0, 14.2, 15.2, 17.4, 26.4, 35.7, 43.4, 44.6, 69.4, 84.6, 123.3, 127.3, 127.7, 128.4,
136.9, 162.7; HRMS(EI) m/z [M+H]+ calcd for C18H26NO 272.2014; found 272.2005.
(2S*, 3R*)ꢀ2ꢀBenzylꢀ2ꢀethylꢀ3ꢀmethylꢀ4ꢀoxopentanenitrile (15g'). Performing the general
procedure with lithium diethylamide (0.115 mmol), 12a (25 mg, 0.109 mmol) and benzyl
bromide (19.6 mg, 0.115 mmol), afforded crude 15g that hydrolyzed to the corresponding ketone
upon purification on a Chromatotron (1 mm plate, 1:99 to 3:97 hexanes: ethyl acetate) affording
21 mg (89%) of (2S*, 3R*)ꢀ15g' as an oil: IR (film) 1712, 2232 cmꢀ1; 1H NMR: δ 1.09ꢀ1.12 (m,
3H), 1.32 (d, J = 7.2 Hz, 3H), 1.66ꢀ1.74 (m, 1H), 1.86ꢀ1.92 (m, 1H), 2.16 (s, 3H), 2.73 (q, J =
7.2 Hz, 1H), 2.91 (d, J = 13.9 Hz, 1H), 3.09 (d, J = 13.9 Hz, 1H), 7.27ꢀ7.35 (m, 5H); 13C NMR:
δ 9.4, 12.9, 25.9, 30.0, 38.7, 44.8, 48.8, 122.4, 127.4, 128.6, 130.3, 135.4, 208.9; HRMS(EI) m/z
[M+Na]+ calcd for C15H19NONa 252.1364, found 252.1357.
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(2S*, 3R*)ꢀ2ꢀBenzoylꢀ4ꢀ(benzyloxy)ꢀ2ꢀethylꢀ3ꢀmethylpentꢀ4ꢀenenitrile (15h). Performing the
general procedure with lithium diethylamide (0.115 mmol), 12a (25 mg, 0.109 mmol) and
benzoyl cyanide (15 mg, 0.115 mmol), afforded, after purification on a Chromatotron (1 mm
plate, 1:99 to 3:97 hexanes: ethyl acetate), 32 mg (88%) of (2S*, 3R*)ꢀ15h as an oil: IR (film)
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1625, 1685, 2234 cmꢀ1; H NMR: δ 0.99ꢀ1.03 (m, 3H), 1.35 (d, J = 7.0 Hz, 3H), 1.96ꢀ2.03 (m,
1H), 2.20ꢀ2.27 (m, 1H), 3.14 (q, J = 7.0 Hz, 1H), 4.20ꢀ4.22 (m, 2H), 4.74 (ABq, ∆ν = 3.5 Hz, J
= 11.8 Hz, 2H), 7.26ꢀ7.38 (m, 5H), 7.44ꢀ7.47 (m, 2H), 7.55ꢀ7.59 (m, 1H), 8.00ꢀ8.02 (m, 2H);
13C NMR: δ 10.1, 16.2, 30.0, 45.7, 57.0, 69.5, 85.8, 120.9, 127.3, 127.7, 128.4, 128.4, 128.9,
133.1, 136.5, 136.8, 161.1, 196.2; HRMS(EI) m/z [M + H]+ calcd for C22H23NO2H 334.1807;
found 334.1827. Prepared from iv: A THF solution (2.0 M) of PhMgBr (0.184 mmol, 1.05
equiv) was added dropwise to a rt, THF solution (1 mL) of (2S*, 3R*)ꢀiv (45 mg, 0.175 mmol,
1.0 equiv). After 15 min, saturated aqueous NH4Cl solution was added (5 mL), the phases were
separated, and the aqueous phase was extracted with ethyl acetate (2 x 10 mL). The combined
organic extract was washed with brine, dried (Na2SO4), and concentrated to afford crude (2S*,
3R*)ꢀ4ꢀ(benzyloxy)ꢀ2ꢀethylꢀ2ꢀ((R)ꢀhydroxy(phenyl)methyl)ꢀ3ꢀmethylpentꢀ4ꢀenenitrile (58 mg)
that was oxidized without purification. A CH2Cl2 solution (15% wt solution) of DessꢀMartin
periodinane (0.190 mmol, 1.1 equiv) was added to a CH2Cl2 solution (3.0 mL) of (2S*, 3R*)ꢀ4ꢀ
(benzyloxy)ꢀ2ꢀethylꢀ2ꢀ((R)ꢀhydroxy(phenyl)methyl)ꢀ3ꢀmethylpentꢀ4ꢀenenitrile (58 mg, 0.173
mmol, 1.0 equiv). After 1 h, the mixture was filtered through Celite, the solid was washed with
CH2Cl2 (5 mL), and then the solvent was removed. Purification of the crude ketone by radial
chromatography (1 mm plate, 4:96, EtOAc/hexanes) provided 42 mg (72%) of (2S*, 3S*)ꢀ15h as
a light yellow oil spectrally identical to material previously characterized.
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(2S*, 3R*)ꢀmethyl 4ꢀ(benzyloxy)ꢀ2ꢀcyanoꢀ2ꢀethylꢀ3ꢀmethylpentꢀ4ꢀenoate (15i). Performing
the general procedure with lithium diethylamide (0.115 mmol), 12a (25 mg, 0.109 mmol) and
methyl cyanoformate (10 mg, 0.115 mmol), afforded, after purification on a Chromatotron (1
mm plate, 1:99 to 3:97 hexanes: ethyl acetate), 27.3 mg (87%) of 15i as an oily mixture of
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diastereomers.30 For (2S*, 3R*)ꢀ15i IR (film) 1628, 1742, 2230 cmꢀ1; H NMR: δ 1.01ꢀ1.04 (m,
3H), 1.31 (d, J = 6.9 Hz, 3H), 1.82ꢀ1.88 (m, 1H), 1.92ꢀ1.97 (m, 1H), 2.82 (q, J = 6.9 Hz, 1H),
3.75 (s, 3H), 4.18 (d, J = 2.8 Hz, 1H), 4.19 (d, J = 2.8 Hz, 1H), 4.77 (ABq, ∆ν = 17.1 Hz, J =
12.2 Hz, 2H), 7.29ꢀ7.41 (m, 5H); 13C NMR: δ 10.1, 15.9, 29.2, 45.7, 53.2, 54.7, 69.5, 85.6,
118.2, 127.3, 127.8, 128.4, 136.6, 160.6, 169.5; HRMS(EI) m/z [M+Na]+ calcd for
C17H21NO3Na 310.1419; found 310.1444.
(2S*, 3R*)ꢀ4ꢀ(benzyloxy)ꢀ2ꢀ(cyclopropylmethyl)ꢀ2ꢀethylꢀ3ꢀmethylpentꢀ4ꢀenenitrile (15j).
Performing the general procedure with lithium diethylamide (0.115 mmol), 12a (25 mg, 0.109
mmol) and (iodomethyl)cyclopropane (21 mg, 0.115 mmol), afforded a 12.0:1 ratio of
diastereomers which, after purification on a Chromatotron (1 mm plate, 1:99 to 3:97 hexanes:
ethyl acetate), afforded 24.4 mg (79%) of a single isomer30 of (2S*, 3R*)ꢀ15j as an oil: IR (film)
1621, 2230 cmꢀ1; 1H NMR: δ 0.14ꢀ0.23 (m, 2H), 0.52ꢀ0.56 (m, 2H), 0.75ꢀ0.81 (m, 1H), 1.01ꢀ1.05
(m, 3H), 1.30 (d, J = 7.0 Hz, 3H), 1.43ꢀ1.49 (m, 1H), 1.75ꢀ1.81 (m, 3H), 2.62 (q, J = 7.0 Hz,
1H), 4.12ꢀ4.14 (m, 2H), 4.77 (ABq, ∆ν = 5.5 Hz, J = 12.0 Hz, 2H), 7.29ꢀ7.41 (m, 5H); 13C
NMR: δ 4.2, 5.0, 6.2, 9.3, 15.1, 26.8, 38.0, 43.4, 45.2, 69.4, 84.7, 123.3, 127.3, 127.7, 128.4,
136.9, 162.8; HRMS(EI) m/z [M+H]+ calcd for C19H25NOH 284.2014; found 284.1998.
Ethyl (2S*, 3R*)ꢀ and (2R*, 3R*)ꢀ4ꢀ(benzyloxy)ꢀ2ꢀcyanoꢀ2ꢀethylꢀ3ꢀmethylpentꢀ4ꢀenoate
(15k): Using the general procedure with lithium diethylamide (0.115 mmol), 12a (25 mg, 0.109
mmol) and diethyl carbonate (13.5 mg, 0.115 mmol), afforded, after purification on a
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Chromatotron (1 mm plate, 1:99 to 3:97 hexanes: ethyl acetate), 28.6 mg (87%) of 15k as an oily
mixture of diastereomers (3.2:1 dr). For (2S*, 3R*)ꢀ15k: IR (film) 1738, 2230 cmꢀ1; 1H NMR: δ
1.01ꢀ1.04 (m, 3H), 1.30ꢀ1.32 (m, 6H), 1.81ꢀ1.88 (m, 1H), 1.91ꢀ1.98 (m, 1H), 2.80 (q, J = 7.2
Hz, 1H), 4.15ꢀ4.29 (m, 4H), 4.78 (ABq, ∆ν = 17.6 Hz, J = 11.9 Hz, 2H), 7.29ꢀ7.42 (m, 5H); 13C
NMR: δ 10.0, 14.1, 16.0, 29.3, 45.6, 54.8, 62.7, 69.5, 85.6, 118.3, 127.8, 127.2, 128.4, 136.6,
160.7, 169.0; HRMS(EI) m/z [M+H]+ calcd for C18H24NO3 302.1756, found 302.1759. For (2S*,
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3S*)ꢀ15k: IR (film) 1738, 2230 cmꢀ1; H NMR: δ 1.05ꢀ1.08 (m, 3H), 1.16 (t, J = 7.2 Hz, 3H),
1.36 (d, J = 7.2 Hz, 3H), 1.91ꢀ1.99 (m, 2H), 2.80 (q, J = 7.2 Hz, 1H), 3.95ꢀ4.04 (m, 2H), 4.11 (d,
J = 2.8 Hz, 1H), 4.13 (d, J = 2.8 Hz, 1H), 4.68ꢀ4.76 (ABq, ∆ν = 28.6 Hz, J = 11.6 Hz, 2H),
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7.28ꢀ7.42 (m, 5H); C NMR: δ 10.0, 14.0, 14.4, 29.7, 45.4, 54.9, 62.2, 69.8, 84.5, 118.2, 127.5,
127.8, 128.4, 136.6, 161.7, 168.4; HRMS(EI) m/z [M+H]+ calcd for C18H24NO3 302.1756; found
302.1761.
(2S*, 3R*)ꢀ and (2R*, 3R*)ꢀ4ꢀ(Benzyloxy)ꢀ2ꢀethylꢀ3ꢀmethylꢀ2ꢀ(3,4,5ꢀtrimethoxybenzoyl)ꢀ
pentꢀ4ꢀenenitrile (15l): Performing the general procedure with lithium diethylamide (0.115
mmol), 12a (25 mg, 0.109 mmol) and methyl 3,4,5ꢀtrimethoxybenzoate (26 mg, 0.115 mmol),
afforded, after purification on a Chromatotron (1 mm plate, 1:99 to 3:97 hexanes: ethyl acetate),
38.8 mg (84%) of 4ꢀ(benzyloxy)ꢀ2ꢀethylꢀ3ꢀmethylꢀ2ꢀ(3,4,5ꢀtrimethoxybenzoyl)pentꢀ4ꢀenenitrile
as on oily mixture of diastereomers: IR (film) 1590, 1676, 2938 cmꢀ1; HRMS(EI) m/z [M + H]+
calcd for C25H29NO5H 424.2124; found 424. 2113. For (2S*, 3R*)ꢀ15l: 1H NMR: δ 0.99ꢀ1.05 (m,
3H), 1.35 (d, J = 7.0 Hz, 3H), 1.98ꢀ2.08 (m, 1H), 2.18ꢀ2.31 (m, 1H), 3.14 (q, J = 7.0 Hz, 1H),
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3.74 (s, 3H), 3.89 (s, 6H), 4.14ꢀ4.25 (m, 2H), 4.71 (s, 2H), 7.18ꢀ7.44 (m, 7H); C NMR: δ 10.1,
14.5, 30.2, 46.0, 53.5, 56.2, 60.9, 69.5, 85.1, 107.0, 121.1, 127.2, 127.4, 128.4, 131.4, 136.5,
152.6, 161.1, 193.8. For (2S*, 3S*)ꢀ15l: 1H NMR: δ 0.99ꢀ1.05 (m, 3H), 1.41 (d, J = 7.3 Hz, 3H),
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1.98ꢀ2.08 (m, 1H), 2.18ꢀ2.31 (m, 1H), 3.03 (q, J = 7.3 Hz, 1H), 3.88 (s, 3H), 3.93 (s, 6H), 4.14ꢀ
4.25 (m, 2H), 4.54 (ABq, ∆ν = 4.5 Hz, J = 11.8 Hz, 2H), 7.18ꢀ7.44 (m, 7H); 13C NMR: δ 10.3,
16.0, 30.8, 46.8, 56.3, 56.5, 61.0, 69.5, 85.8, 106.8, 121.4, 127.1, 127.7, 128.3, 131.9, 136.1,
152.7, 161.8, 194.1.
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(2S*, 3R*)ꢀ and (2S*, 3S*)ꢀ4ꢀ(Benzyloxy)ꢀ2ꢀethylꢀ2ꢀisopropylꢀ3ꢀmethylpentꢀ4ꢀenenitrile
(15m). Using the general procedure with lithium diethylamide (0.115 mmol), 12a (25 mg, 0.109
mmol) and isopropyl iodide (19.5 mg, 0.115 mmol), afforded, after purification on a
Chromatotron (1 mm plate, 1:99 to 3:97 hexanes: ethyl acetate), 19.5 mg (66%) of 15m as an
oily mixture of diastereomers (2.3:1): IR (film) 1621, 2228, 2882, 2941, 2972 cmꢀ1; HRMS(EI)
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m/z [M+H]+ calcd for C18H26NO 272.2014; found 272.2007. For (2S*, 3R*)ꢀ15m: H NMR: δ
1.02 (d, J = 6.9 Hz, 3H), 1.04ꢀ1.07 (m, 3H), 1.12 (d, J = 6.9 Hz, 3H), 1.35 (d, J = 7.2 Hz, 3H),
1.63ꢀ1.76 (m, 2H), 2.10ꢀ2.16 (m, 1H), 2.55ꢀ2.60 (m, 1H), 4.10ꢀ4.16 (m, 2H), 4.71ꢀ4.78 (m, 2H),
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7.30ꢀ7.43 (m, 5H); C NMR: δ 11.6, 16.6, 17.5, 18.6, 24.0, 32.8, 43.2, 49.0, 69.4, 84.7, 122.5,
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127.2, 127.7, 128.4, 136.8, 163.3. For (2S*, 3S*)ꢀ15m: H NMR: δ 1.01 (d, J = 6.9 Hz, 3H),
1.07 (d, J = 6.9 Hz, 3H), 1.10ꢀ1.12 (m, 3H), 1.35 (d, J = 7.2 Hz, 3H), 1.63ꢀ1.76 (m, 2H), 2.10ꢀ
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2.16 (m, 1H), 2.55ꢀ2.60 (m, 1H), 4.10ꢀ4.16 (m, 2H), 4.71ꢀ4.78 (m, 2H), 7.30ꢀ7.43 (m, 5H); C
NMR: δ 11.6, 16.6, 17.5, 19.2, 25.1, 32.2, 43.2, 48.8, 69.4, 84.7, 122.5, 127.3, 127.6, 128.4,
136.9, 163.3.
(2S*, 3R*)ꢀand (2S*, 3S*)ꢀ4ꢀ(Benzyloxy)ꢀ2ꢀethylꢀ3ꢀmethylꢀ2ꢀ(4ꢀ(trifluoromethyl)benzoyl)ꢀ
pentꢀ4ꢀenenitrile (15n). Using the general procedure with lithium diethylamide (0.115 mmol),
12a (25 mg, 0.109 mmol) and methyl 4ꢀ(trifluoromethyl)benzoate (23.37 mg, 0.115 mmol),
afforded, after purification on a Chromatotron (1 mm plate, 1:99 to 3:97 hexanes: ethyl acetate),
33.3 mg (76%) of 15n as an oily mixture of diastereomers (2.2:1). For (2S*, 3R*)ꢀ15n: IR (film)
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1690, 2940 cmꢀ1; H NMR: δ 1.02ꢀ1.06 (m, 3H), 1.44 (d, J = 7.3 Hz, 3H), 2.04ꢀ2.13 (m, 1H),
2.17ꢀ2.25 (m, 1H), 3.08 (q, J = 7.3 Hz, 1H), 4.14 (m, 2H), 4.52 (s, 2H), 7.11ꢀ7.26 (m, 6H), 7.55
(d, J = 8.2 Hz, 2H), 7.96 (d, J = 8.2 Hz, 2H); 13C NMR: δ 10.2, 14.8, 31.3, 46.7, 57.5, 69.6, 85.4,
120.3, 125.1, 127.2, 127.8, 128.3, 129.0, 132.5, 133.7, 135.7, 140.2, 161.3, 196.0; HRMS(EI)
m/z [M + H]+ calcd for C23H22F3NO2H 402.1681; found 402.1675. For (2S*, 3S*)ꢀ15n: IR (film)
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1692, 2938 cmꢀ1; H NMR: δ 1.01ꢀ1.05 (m, 3H), 1.37 (d, J = 7.3 Hz, 3H), 1.92ꢀ2.01 (m, 1H),
2.20ꢀ2.29 (m, 1H), 3.12 (q, J = 7.3 Hz, 1H), 4.22 (s, 2H), 4.69 (s, 2H), 7.26ꢀ7.34 (m, 6H), 7.68
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(d, J = 8.3, 2H), 8.05 (d, J = 8. 3 Hz, 2H); C NMR: δ 10.1, 15.8, 29.5, 45.9, 56.9, 69.6, 86.0,
120.6, 125.4, 127.3, 127.8, 128.4, 129.2, 134.1, 134.4, 136.2, 139.6, 160.6, 195.4; HRMS(EI)
m/z [M + H]+ calcd for C23H22F3NO2H 402.1681; found 402.1675.
(2S*, 3R*)ꢀ and (2S*, 3S*)ꢀ2ꢀethylꢀ4ꢀmethoxyꢀ3ꢀmethylꢀ2ꢀ(4ꢀ(trifluoromethyl)benzoyl)pentꢀ
4ꢀenenitrile (15o): Performing the general procedure with lithium diethylamide (0.115 mmol),
12b (25 mg, 0.163 mmol) and methyl 4ꢀ(trifluoromethyl)benzoate (35 mg, 0.171 mmol),
afforded, after purification on a Chromatotron (1 mm plate, 1:99 to 3:97 hexanes: ethyl acetate),
41 mg (77 %, 1.6:1 dr) of 15o as an oily mixture of diastereomers (1.6:1 dr). For (2S*, 3R*)ꢀ15o:
IR (film) 1692, 1727, 2973 cmꢀ1; 1H NMR: δ 1.01ꢀ1.05 (m, 3H), 1.31 (d, J = 7.0 Hz, 3H), 1.89ꢀ
1.98 (m, 1H), 2.17ꢀ2.26 (m, 1H), 3.05 (q, J = 7.0 Hz, 1H), 3.49 (s, 3H), 4.10 (d, J = 2.5 Hz, 1H),
4.14 (d, J = 2.5 Hz, 1H), 7.75 (d, J = 8.3, 2H), 7.96 (d, J = 8.3 Hz, 2H); 13C NMR: δ 10.1, 15.9,
29.9, 45.9, 54.7, 57.0, 84.5, 120.5, 125.5, 129.1, 130.0, 134.4, 139.8, 161.8, 195.8; HRMS(EI)
m/z [M + Na]+ calcd for C17H18F3NO2Na 348.1187; found 348.1178. For (2S*, 3S*)ꢀ15o: IR
(film) 1691, 1727 2942 cmꢀ1; 1H NMR: δ 1.04 (t, J = 7.3 Hz, 3H), 1.38 (d, J = 7.0 Hz, 3H), 2.03ꢀ
2.09 (m, 1H), 2.15ꢀ2.22 (m, 1H), 2.98 (q, J = 7.0 Hz, 1H), 3.32 (s, 3H), 4.00 (d, J = 3.0 Hz, 1H),
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[M + Na]+ calcd for C17H18F3NO2Na 348.1187; found 348.1178.
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4ꢀ(Benzyloxy)ꢀ2ꢀethylꢀ3ꢀmethylbutanenitrile (16): A THF solution (0.3 M) of butyronitrile
(2.5 g, 36.2 mmol, 1.0 equiv) was added to a ꢀ78 °C, THF solution (0.1 M) of LDA, generated
from butyllithium (1.05 equiv) and diisopropylamine (1.15 equiv). After 30 min, 3ꢀbenzyloxyꢀ2ꢀ
bromopropane31 (8.70 g, 37.98 mmol, 1.05 equiv.) was added, and then the reaction was allowed
to warm to rt. After 16 h, saturated aqueous NH4Cl was added (5 mL), the phases were
separated, and the aqueous phase was extracted with EtOAc (2 x 20 mL). The combined organic
extract was dried (Na2SO4), and concentrated to afford a crude nitrile that was purified by silica
gel column chromatography (5:95, EtOAc/hexanes) to afford 7.0 g (85 %) 16 as a colorless oil:
IR (film) 2234, 2877, 2968 cmꢀ1; HRMS(EI) m/z [M + Na]+ calcd for C14H19NONa 240.1364,
found 240.1355. Diastereomer 1: 1H NMR: δ 1.05 (d, J = 7.03 Hz, 3H), 1.09ꢀ1.13 (m, 3H), 1.52ꢀ
1.179 (m, 2H), 1.99ꢀ2.05 (m, 1H), 2.88ꢀ2.93 (m, 1H), 3.39ꢀ3.52 (m, 2H), 4.50ꢀ4.59 (m, 2H),
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7.31ꢀ7.41 (m, 5H); C NMR: δ 12.26, 12.89, 23.69, 35.32, 35.78, 72.97, 73.39, 120.71, 127.74,
127.82, 128.46, 138.05. Diastereoisomer 2: 1H NMR: δ 1.09 (d, J = 7.03 Hz, 3H), 1.09ꢀ1.13 (m,
3H), 1.52ꢀ1.179 (m, 2H), 2.09ꢀ2.15 (m, 1H), 2.63ꢀ2.68 (m, 1H), 3.39ꢀ3.52 (m, 2H), 4.50ꢀ4.59 (m,
2H), 7.31ꢀ7.41 (m, 5H); 13C NMR: δ 12.06, 15.01, 21.86, 35.24, 36.41, 72.39, 73.30, 121.58,
127.64, 127.69, 128.51, 138.17.
2ꢀ(1ꢀ(Benzyloxy)propanꢀ2ꢀyl)ꢀ2ꢀethylpentanenitrile (17): A THF solution (0.3 M) of i (25 mg,
0.115 mmol, 1.0 equiv.) was added to a ꢀ78 °C, THF (0.1 M) solution of LiNEt2, generated from
butyllithium (1.05 equiv) and diethylamine (1.15 equiv). The reaction was allowed to warm to rt
and after 30 min the solution was cooled to ꢀ78 °C and then neat 1ꢀiodopropane (20.5 mg, 0.121
mmol, 1.05 equiv) was added. After 15 min, saturated aqueous NH4Cl was added (5 mL), the
phases were separated, and the aqueous phase was extracted with EtOAc. The combined organic
extracts were dried (Na2SO4), concentrated, and purified by radial chromatography (1 mm plate,
2:98, EtOAc/hexanes) to afford 26.0 mg (88%) of 17 as an oily mixture of diastereomers (1.7:1).
IR (film) 2230, 2875, 2967 cmꢀ1; HRMS(EI) m/z [M + H]+ calcd for C17H25NOH 260.2009;
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found 260.2003. For diastereomer 1: H NMR: δ 0.95ꢀ0.98 (m, 3H), 1.01ꢀ1.05 (m, 3H), 1.12 (d,
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