Direct Lewis Acid Catalyzed Conversion of Enantioenriched N-Acyloxazolidinones to Chiral Esters, Amides, and Acids

Article abstract of DOI:10.1021/acs.joc.8b02451

The identification of Yb(OTf)₃ through a multivariable high-throughput experimentation strategy has enabled a unified protocol for the direct conversion of enantioenriched N-acyloxazolidinones to the corresponding chiral esters, amides, and carboxylic acids. This straightforward and catalytic method has shown remarkable chemoselectivity for substitution at the acyclic N-acyl carbonyl for a diverse array of N-acyloxazolidinone substrates. The ionic radius of the Lewis acid catalyst was demonstrated as a key driver of catalyst performance that led to the identification of a robust and scalable esterification of a pharmaceutical intermediate using catalytic Y(OTf)₃.

Full text of DOI:10.1021/acs.joc.8b02451

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Featured Article
Direct Lewis Acid-Catalyzed Conversion of Enantioenriched
N-Acyl Oxazolidinones to Chiral Esters, Amides, and Acids
Jason M Stevens, Ana Cristina Parra-Rivera, Darryl D Dixon, Gregory L. Beutner, Albert
J DelMonte, Doug E. Frantz, Jacob M. Janey, James Paulson, and Micheal R Talley
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b02451 • Publication Date (Web): 09 Nov 2018
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Page 1 of 18
The Journal of Organic Chemistry
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Direct Lewis Acid-Catalyzed Conversion of Enantioenriched N-Acyl
Oxazolidinones to Chiral Esters, Amides, and Acids
*,†
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††
†
†
Jason M. Stevens, Ana Cristina Parra-Rivera, Darryl D. Dixon, Gregory L. Beutner, Albert J. Del-
*,††
†
†
†
†
Monte, Doug E. Frantz, Jacob M. Janey, James Paulson, and Michael R. Talley
† Chemical and Synthetic Development, Bristol-Myers Squibb, 1 Squibb Dr, New Brunswick, NJ 08901, USA.
†† Department of Chemistry, The University of Texas at San Antonio, San Antonio, Texas 78249, United States
Supporting Information Placeholder
O
Me
H2N
R
OH
O
O
H
O
O
10 mol% Yb(OTf)3
R2
0.5-10 mol% Yb(OTf)3
ROH, 20-80 °C
hydroxide
R2
R2
O
N
RO
R
N
H
DMAc or iPAc, 40-80 °C
R1
one-pot
R1
R1
RI
RII
H
F
Esters
34 examples
52-99%
Amides
21 examples
up to 88% yield
N-Acyl Oxazolidinone
N
Acids
100 g scale
ABSTRACT: The identification of Yb(OTf)3 through a multivariable high-throughput experimentation strategy has enabled a unified
protocol for the direct conversion of enantioenriched N-acyl oxazolidinones to the corresponding chiral esters, amides and carboxylic
acids. This straightforward and catalytic method has shown remarkable chemoselectivity for substitution at the acyclic N-acyl car-
bonyl for a diverse array of N-acyl oxazolidinone substrates. The ionic radius of the Lewis acid catalyst was demonstrated as a key
driver of catalyst performance that lead to the identification of a robust and scalable esterification of a pharmaceutical intermediate
using catalytic Y(OTf)3.
chiral scaffolds, the identification and development of direct and
general methods to access their respective chiral esters and chiral
amides has lingered as an unsolved problem for over three decades.
Presently, the most common transformations of N-acyl oxazolidin
ones are LiBH4-mediated reduction to the corresponding alcohol
and hydrolysis to the carboxylic acid using LiOH/H2O2 (Figure
1).6–8 Direct access to the corresponding chiral esters and amides
would be advantageous and desirable as the oxidation state of the
starting material would be retained, thereby rendering redox ma-
nipulations and additional synthetic steps unnecessary. Herein we
report a general method to access esters and amides bearing a-ste-
reocenters with high levels of selectivity from functionalized N-
acyl oxazolidinone intermediates in a single step; moreover, a one-
pot variation of the esterification protocol enables access to chiral
acids as an alternative to in situ generated LiOOH.
¢
INTRODUCTION
N-Acyl oxazolidinones are mainstays of modern organic synthe-
sis as substrates for diastereoselective alkylation1 and aldol2 reac-
tions as well as for enantioselective catalytic transformations.3 Re-
actions of N-acyl oxazolidinones for the synthesis of chiral natural
products4 and pharmaceutical intermediates5 have enjoyed endur-
ing popularity due to overall reaction efficiency, reliable predictive
models for stereoinduction, and excellent observed stereoselectiv-
ity. Despite the privileged status of N-acyl oxazolidinones as latent
O
O
n Readily accessible chiral scaffolds
n Numerous functional group interconversions
n Amenable to commercial scale
R2
O
N
R1
RI
Common derivatives of N-acyl oxazolidinones
OH
O
O
O
Since the seminal report of utilizing oxazolidinones as chiral
auxiliaries by Evans in 1981, only a sparse number of methods have
been developed to convert N-acyl oxazolidinone reaction products
to esters, amides or carboxylic acids.7–11 The most frequently uti-
lized method to access esters relies on the in situ generation of stoi-
chiometric Ti(OBn)4 for generation of the corresponding benzyl es-
ters.8 A recent report demonstrated access to ester products via cat-
alytic Ni(cod)2/2,2`-bpy although glovebox conditions were re-
quired to generate the active catalyst.9 The direct access of amides
most frequently employs the stoichiometric AlMe37c procedure de-
veloped by Evans although many reports access the amides indi-
rectly through the carboxylic acid prepared using the LiOH/H2O2
R2
R2
R2
R2
R
N
H
RO
HO
R1
R1
R1
R1
LiBH4
AlMe3
9 records
MeOMgX, 83 records
Ti(OR)4, 52 records
LiOH, H2O2
2759 records
1024 records
no general method
Figure 1. Common derivatization of N-acyl oxazolidinones based
on literature search
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Page 2 of 18
protocol. Since the N-acyloxazolidinone motif is utilized so fre-
quently – the hydrolytic conditions alone appearing in the literature
nearly 2,000 times – and on significant scale (e.g. > 100 kg),5e
general and operationally simple unified strategy to access each
chiral esters, amides, and acids from N-acyloxazolidinones would
be highly desirable. We would like to mention, however, that dur-
ing the course of our work a report from the Evano group appeared
for the direct synthesis of esters, amides and acids from N-acylox-
azolidinones using similar conditions to those reported here.10
Evano report where Evans’ alkylation and aldol products were
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2
3
4
5
6
7
found not to be viable substrates as the hydroxyamides were af-
forded as the predominant products.10 A similar survey of the liter-
ature found that the direct amidation protocols were even more lim-
ited and that access to acids relies on the use of super stoichiometric
peroxide. Therefore, it was pertinent for the progression of a clini-
cal asset that this longstanding problem of N-acyl oxazolidinone
diversification be addressed sufficiently.
a
8
9
Table 2. High-Throughput Lewis Acid Screena,b,c
¢
RESULTS AND DISCUSSION
Development of a broadly applicable and general method for
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preparation of high value chiral esters. The pressing need for in-
novation toward the direct transesterification of N-acyl oxazoli-
dinones was starkly revealed during the progression of 3 through
the clinic as a potential inhibitor of indoleamine 2,3-deoxygenase
(IDO)12 (Table 1). During synthetic route innovation it became crit-
ical to access ester 2 from N-acyl oxazolidinone 1. The most expe-
dient method to access the desired ester appeared to be through a
transesterification reaction utilizing conditions originally reported
by Evans.8 It was therefore disappointing to find that initial at-
tempts using these conditions were not promising. A literature
search revealed several additional methods for Lewis acid mediated
generation of esters from N-acyl oxazolidinones had appeared since
Evans MgX2 and Ti(OBn)4 mediatedprotocols11 as well as methods
for the general transesterification of amides.13 However, upon a de-
tailed inspection of these methods it was found that their limitations
were exceptional. In particular, the existing methods had focused
mainly on substrates that were of low synthetic complexity, whose
achiral ester products could have either been purchased from com-
mercial suppliers or prepared from the commercially available acid
or acid chloride. When these methods were analyzed for complex
substrates that produced chiral esters, it was found that the only vi-
11f
able conditions were using 30 mol% Sm(OTf)3 (3 chiral exam-
ples) or 100 mol% LaI3.11c Furthermore, only in the latter case was
tolerance outside of methanol reported and ee values of the
Table 1. Initial Investigation of Known Esterification Protocols to
a Pharmaceutical Intermediatea
aAll reactions were screened at 50 mol% catalyst loading except for lanthanides that
were screened at 10 mol% catalyst loading. bThe reaction performance was determined
by UHPLCMS area percent at a single 20 h time point, cSubstrate 5 was only surveyed
in MeOH as the solvent.
The criteria for a successful method would include the use of
bench stable reaction components, wide substrate scope, high
chemoselectivity for substitution at the acyclic N-acyl carbonyl7b
and minimal risk of epimerization. Therefore, the identification of
a broadly applicable Lewis acid catalyst for the direct synthesis of
esters from N-acyl oxazolidinones was initiated through the use of
high-throughput experimentation (HTE). It was envisioned that a
successful catalytic esterification method would be readily trans-
lated to the analogous transamidation and that a single flask proto-
col to access the carboxylic acids could be achieved via hydrolysis.
A multivariable approach was undertaken that examined each of
the critical factors previously outlined for a successful method to
accelerate the identification of globally optimized reaction condi-
tions using HTE.14 A panel of 24 Lewis acid catalysts were exam-
ined against two substrates featuring different chiral auxiliaries and
acyl components in both methanol and ethanol solvents (Table 2).
aAcyl oxazolidinone (1.0 equiv), 150 mol% catalyst at 60 °C. Selectivity refers to the
ratio of the desired ester to the undesired oxazolidinone ring-opened hydroxyamide.
product esters provided. The difficulty associated with direct
Lewis acid catalyzed esterification of complex enantioenriched N-
acyl oxazolidinones substrates was exemplified yet again by the
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The Journal of Organic Chemistry
Table 3. Auxiliary and Alcohol Scopea
O
O
2.0 mol%
Lanthanide(III) triflate
O
O
1
2
Bn
Bn
O
NH
O
N
MeO
+
MeOH, 50 °C
Me
Me
Ph
3
4
5
6
7
8
9
Ph
(S)-6
9
10
10
11
12
13
14
15
16
17
18
19
Figure 2. Examination of the effect of lanthanide ionic radius on
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time to reaction completion.
Many common Lewis acids such as Al(OTf)3, AlCl3, Bi(OTf)3,
FeCl3, and MgBr2 provided a significant amount of the desired me-
thyl ester product 6 from oxazolidinone 4, but were ineffective for
the generation of the corresponding ethyl ester product 7. These
catalysts were similarly ineffective for generating the methyl ester
8 from the more sterically demanding substrate 5. In these instances
the reactions formed significant quantities of hydroxyamide side
product resulting from solvent attack at the oxazolidinone car-
bonyl.7b,15–16 Several lanthanide catalysts, Gd(OTf)3, Er(OTf)3, and
Yb(OTf)3, afforded high levels of methyl esters 6 and 8 from N-
acyl oxazolidinones 4 and 5, respectively, while ethyl ester product
7 was delivered in up to 37 area percent by UHPLCMS analysis.
Although the conversion to the ethyl ester was low, the results were
encouraging as these catalysts afforded the highest mean results
across the HTE array. Additionally, these catalysts did not produce
any significant side products such as the hydroxyamide that were
observed with other Lewis acids. The utilization of a multivariable
HTE strategy provided clear differentiation of catalyst performance
and engendered high confidence for the identification a broadly ap-
plicable catalytic system moving forward.
aAcyl oxazolidinone (1.0 equiv), ROH (30 mL/g), 2–10% Yb(OTf)3, 20–80 °C; iso-
lated yields of chromatographically pure products are displayed, unless otherwise
noted. bThe de of the input material was 93%. c The de of the input material was
98%. dReaction was performed with 5 mol% TfOH and analyzed at 24 h by
UHPLCMS.
The data from the Lewis acid HTE demonstrated a trend of in-
creasing reactivity across the row of lanthanides (La(OTf)3
<
Sm(OTf)3 < Gd(OTf)3 = Er(OTf)3 = Yb(OTf)3). To gain additional
insight into this trend the methanolysis of 9 was examined against
the complete set of lanthanide(III) triflates. Kinetic data were col-
lected for each catalyst at 2 mol% catalyst loading over the course
of 24 h and a regression model was constructed to determine the
time of reaction completion. When the kinetic data were analyzed
against literature data for lanthanide ionic radii17 it was observed
that the catalysts with smallest ionic radii Er(OTf)3 (106.2 Å),
Tm(OTf)3 (105.2 Å), Yb(OTf)3 (104.2 Å), and Lu(OTf)3 (103.2 Å)
reached completion in 0.60 h, 0.66 h, 0.50 h, & 0.50 h, respectively.
In contrast, the catalyst with the largest ionic radius, La(OTf)3
(121.6 Å) required a reaction time of 25.70 h (Figure 2). Of the four
lanthanide catalysts that afforded the shortest reaction times,
Yb(OTf)3 was of particular interest for further optimization due its
broad utility as a Lewis acid catalyst18 and its known propensity for
catalyzing reactions involving amines as the corresponding trans-
amidation would be subsequently investigated. It is noteworthy that
Yb(OTf)3 has been identified as an effective catalyst for other
transformations using oxazolidinones.19
The general utility of the Yb(OTf)3 catalytic protocol was
gauged through a systematic study of the solvolysis of four chiral
N-acyl oxazolidinones, featuring four common chiral auxiliaries,
with four alcohols (Table 3). It was observed that the methanolysis
of all four auxiliaries occurred readily at 60 °C with 2 mol%
Yb(OTf)3 (87–99%, Entries 2, 7, 11, 15) and even milder condi-
tions at 20 °C (97%, Entries 1, 6). Moving to longer chain alcohols,
it was found that ethanolysis required 10 mol% catalyst and 75 °C
to achieve full conversion (85–88%, Entries 3, 8, 12, 16). Similarly,
solvolysis with allyl alcohol (92–99%, Entries 4, 9, 13, 17) and n-
butanol (79–99%, Entries 5, 10, 14, 18) could be achieved with 10
mol% catalyst at 80 °C. In all cases, (Entries 1–18) no erosion of
stereochemistry was observed. Control experiments that were per-
formed using 5 mol% TfOH in the absence of Yb(OTf)3 (Entry 19)
as well as in absence of both the acid and the Lewis acid (Entry 20)
did not show any detectable ester product.
To further examine the scope of this method both the alcohol
component and impact of the oxazolidinone stereochemistry were
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Table 4. Alcohol Scopea
Assessment of the substrate scope with respect to the acyl compo-
1
2
3
4
5
6
7
8
nent was conducted using a diverse set of enantioenriched sub-
strates (Table 5). The method was amenable to sterically demand-
ing substrates such as 5 to produce methyl ester 8, which was note-
worthy as many of the surveyed Lewis acids were ineffective for
this substrate (Table 2). Heteroaryl substrates were tolerated as
shown by the isolation of isoxazole ester 22a. Glycoloxy ethers, a
common N-acyl oxazolidinone modality accessible through glyco-
late alkylation,1b were readily translated to the corresponding ester,
such as glycoloxy ester 22b.The preparation of methyl ester 22c
bearing a b-stereocenter was also observed to be highly efficient.
Both b-amino and b-hydroxy substrates were able to deliver methyl
esters 22d and 22e, respectively. These two results also demon-
strate the tolerance of aryl bromides and fluorides to the reaction as
reflected by the yields for these methyl esters. Methyl ester 22f was
obtained from the corresponding N-acyl oxazolidinone protected as
the primary TBS ether, demonstrating that acid labile functional
groups may be impacted.
9
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aAcyl oxazolidinone (1.0 equiv), ROH (30 mL/g), isolated yields of chromatograph-
ically pure products are displayed, unless otherwise noted. b2 mol% Yb(OTf)3 at 20
°C. c2 mol% Yb(OTf)3 at 60 °C; d10 mol% Yb(OTf)3 at 75 °C. e10 mol% Yb(OTf)3
at 80 °C. fUtilized (R,S)-19. gUtilized (R,R)-19.
explored in greater detail (Table 4). A series of enantioenriched
phenylacetic esters were prepared from a selection of alcohols to
give the methyl (20a, 95%), ethyl (20b, 92%), n-propyl (20c, 83%),
n-butyl (20d, 79%), allyl (20e, 94%), propargyl (20f, 96%), and
cyclopropylmethyl (20g, 79%) ester products in high yield with no
detectable stereoerosion. Additionally, the products from this series
(20a–g ) were prepared from both diastereomers of the N-acyl ox-
azolidinone, indicating there was no detectable matched/mis-
matched phenomenon. Further exploration of the alcohol compo-
nent revealed isopropanol, and benzyl alcohol failed to deliver ap-
preciable amounts of the ester products 20h, and 20i, respectively,
giving the undesired hydroxyamide side product.
Figure 3. Examination of kinetic isotope effect
The nature of the catalytic species was examined spectroscopi-
cally to gain insight into the mechanism of N-acyl oxazolidinone
solvolysis. From these experiments it was observed that triflic acid
(1178 cm-1 by IR and -78 ppm by 19F NMR) was generated instan-
taneously upon exposure of Yb(OTf)3 to methanol. These results
were consistent with previous studies suggesting that lanthanide
alkoxides were the true catalytic species in lanthanide triflate me-
diated alcoholyses.20 However, as was previously demonstrated,
triflic acid itself did not appear to be catalytically active (Table 3,
Entry 19). Additionally, experiments measuring the rates of con-
version of N-acyl oxazolidinone 9 to the methyl and d3-methyl es-
ters 6 and 23 with methanol and d4-methanol, respectively, showed
a kinetic isotope effect of 2.1, suggesting proton transfer in the rate
determining step (Figure 3).21 Although kinetically slower, the d4-
methanol reacted efficiently to give d3-methylester 23 in 98% yield
on 2 mmol scale.
Table 5. Scope of the Acyl Componenta
The initial HTE effort lead to the identification of Yb(OTf)3 as a
suitable catalyst for the esterification of a broad spectrum of com-
plex chiral N-acyl oxazolidinone substrates. The combined
knowledge from the lanthanide ionic radius study and the investi-
gation into the catalytic species and mechanism illustrated that the
unique characteristics of Yb(OTf)3 provided that it was an optimal
catalyst for these challenging substrates. With the goal of deliver-
ing a unified strategy for the synthesis of each chiral esters, amides,
and acids, the synthesis of chiral amides with this system was ini-
tiated.
aAcyl oxazolidinone (1.0 equiv), ROH (30 mL/g), isolated yields of chromatograph-
ically pure products are displayed, unless otherwise noted. bReaction was performed
at 20 °C. cReaction was performed at 60 °C.
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The Journal of Organic Chemistry
Development of a protocol for the synthesis of chiral amides.
N,N-dimethylacetamide (DMA) and isopropyl acetate (iPAc) were
suitable solvents for the aminolysis reaction allowing for the use of
three equivalents of amine and 10 mol % of Yb(OTf)3 to obtain the
enantioenriched amides in high yields under relatively mild reac-
tion conditions (Table 6). A broad range of primary amines has
been successfully employed with excellent functional group toler-
ability, chemoselectivity (e.g., 25e) and stereoretention. Even ani-
lines proved successful under these conditions (25l), albeit
1
2
3
4
5
6
7
8
The aminolysis of chiral N-acyloxazolidinones to access enantioen-
riched chiral amides represents one of the most direct synthetic ap-
proaches to these valuable building blocks.22 Given the success
with alcohols under Yb-catalysis, it was envisioned that a comple-
mentary method using amines might be plausible. From the onset,
however, it was recognized that the higher Lewis basicity of amines
might negatively attenuate the catalytic activity of the Yb-catalyst.
Table 6. Scope of the Amine Componenta
Table 7. Application of the Esterification Protocol to a Pharmaceu-
tical Intermediatea
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
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42
43
44
45
46
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48
49
50
51
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53
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60
R
NH2
O
O
O
R2
10 mol% Yb(OTf)3
R2
O
N
R
N
*
*
H
DMA or iPAc, 40-80°C
R1
R1
Bn
24, 21c, 21e, 21f
25a-u
O
O
O
Me
Bn
Bn
Bn
N
N
N
H
H
H
Me
Me
Me
25c, iPAc
70%, >99% ee
25b, DMA
25a, DMA
77%, >99% ee
73%, >99% ee
O
O
O
Bn
MeO
Bn
Bn
HO
N
H
N
H
N
H
Me
Me
Me
25e, iPAc
25d, iPAc
73%, >99% ee
25f, DMA
45%, >99% ee
70%, >99% ee
O
O
O
Bn
Bn
Bn
EtO
N
N
H
N
H
H
Me
Me
Me
25h, DMA
25i, DMA
61%, >98% ee
25g, iPAc
63%, >99% ee
57%, >98% ee
O
O
MeO
O
Bn
a Solution yields as determined by HPLC method calibrated against a reference stand-
ard of the product 2 unless otherwise specified. bThe selectivity refers to the ratio of
product 2 to the oxazolidinone ring opened products. cThe starting material was the
mono-hydrate (1.5 wt% water), 1 g scale. dThe starting material was the anhydrous
Me
S
N
H
Bn
N
H
Bn
N
H
Me
Me
Bn
Me
25j, iPAc
53%, 98% ee
25l, iPAc
22%, >99% ee
25k, iPAc
46%, >99% ee
e
form, 1 g scale. Reaction was run on 10 g scale with 1-monohydrate. fIsolated yield
on 10 g scale from 1-monohydrate.
O
O
O
Bn
Bn
S
O
N
H
N
H
N
H
Me
Cl
Me
Me
in lower yields that can be attributed to the decreased nucleophilic-
ity of these substrates. Additional examples worth highlighting in-
clude the success with glycine as the nucleophile (25s) with poten-
tial implications towards peptide synthesis and the extension to O-
alkyl hydroxylamines as in 25r that have served as synthetic pre-
cursors towards vasopeptidase inhibitors as well as reverse hydrox-
amate inhibitors of Bone Morphogentic Protein 1 (BMP1).23 In
contrast to the mild catalytic reaction conditions used here for hy-
droxylamines, previous methods have relied on the use of pyro-
phoric AlMe3 to effect the same transformation.
25m, DMA
66%, >99% ee
25n, DMA
71%, 97% ee
25o, DMA
74%, >99% ee
O
O
O
O
Bn
O
N
H
Bn
N
Bn
N
H
N
H
Me
Me
Me
N
25p, iPAc
48%, 95% ee
25r, DMA
67%, 99% ee
25q, DMA
44%, 96% ee
O
OH
O
O
HO
Bn
N
N
H
N
H
H
O
Me
During the course of the study with amine nucleophiles, several
limitations were discovered that were worth discussion. First, pri-
mary amines with a-substitution (e.g., a-methylbenzylamine, and
cyclohexylamine) failed to provide any of the corresponding chiral
amide. Likewise, secondary amines such as diethylamine also
proved ineffective in the aminolysis reaction even at elevated reac-
tion temperatures (80 °C). These failures were attributed to the in-
creased steric bulk around these nucleophiles in combination with
the intrinsic steric bulk of the starting chiral N-acyloxazolidinones
that impeded product formation. However, it is worth emphasizing
that more forcing conditions with these nucleophiles may promote
product formation but the central focus was to demonstrate general
substrate scope under practical, scalable reaction parameters.
F
25s,b DMA
40%, 85% ee
25t, DMA
88%, 97% ee
25u,c,d DMA
30%, dr = >99:1
aIsolate yields reported. bProduct was isolated as the methyl ester after treatment of the
crude reaction mixture (TMSCl/MeOH). c(R)-enantiomer of the Evans’ chiral
auxillary was used in this case. dIsolated as the TBDMS-protected alcohol.
Furthermore, the large excess of the amine nucleophile that could
potentially promote racemization of the amide product was a point
of concern. Nonetheless, it was envisioned that the increased nu-
cleophilicity of amines compared to alcohols would counterbalance
these concerns. With this in mind, initial efforts focused on the
identification of compatible solvents that would assist in minimiz-
ing the equivalents of amine necessary for high conversion while
minimizing the potential for racemization. It was found that both
5
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Page 6 of 18
Development of an optimized system for the multi-gram Y(OTf)3 catalyst system was highly effective, delivering the prod-
1
2
3
4
5
6
7
8
scale synthesis of a pharmaceutical intermediate. The protocol
for the transesterification of N-acyl oxazolidinones had shown a
broad tolerance for variation in the structure of the alcohol compo-
nent and substitution on the N-acyl oxazolidinone substrate. Addi-
tionally, the experimental evidence that ionic radius was a reliable
predictor of reaction performance enabled a strong position to de-
velop a highly efficient catalytic system for the preparation of 2. It
was envisioned that the knowledge at hand could be exploited to
identify a catalytic system that combined lower cost and process
mass intensity (PMI)24 while maintaining reaction performance and
uct in 94% in process yield with slightly improved selectivity over
the Yb(OTf)3 system. It was then verified that no background reac-
tion was occurring and the optimal results were demonstrated on
10 g scale to deliver 2 in 93% in process yield using only 0.5 mol%
catalyst and in 95% isolated yield utilizing 2 mol% catalyst. The
foundational work exploring the critical attributes for catalyst per-
formance yielded a cheaper, greener, and more robust catalytic sys-
tem.27
Development of a protocol for the synthesis of carboxylic ac-
ids. A primary objective for pursuing this work was to identify an
operationally simple protocol for the preparation of acids from the
chiral esters using mild and safe reaction conditions. This transfor-
mation was of particular interest as derivatization to chiral carbox-
ylic acids was found to be the most common transformation of en-
antioenriched oxazolidinones (Figure 1). Toward that end, a one-
pot esterification/hydrolysis protocol was demonstrated on 5 g
scale (15.4 mmol) as N-acyl oxazolidinone 4 was converted in a
single flask to the corresponding carboxylic acid 26 (97% yield, >
99% ee) with 97% recovery of the chiral auxiliary 16 with 0.5
mol% Yb(OTf)3 (Scheme 1, eq 1). The only additional operation
needed to accomplish this transformation was a solvent exchange
from methanol to THF followed by the addition of aqueous lithium
hydroxide. Furthermore, it was shown that a one pot protocol could
be employed to effect the net hydrolysis of 1 on 100 g scale to af-
ford carboxylic acid 27 (Scheme 1, eq 2). Many catalytic processes
have derived their value from the use of safe and mild reaction con-
ditions in place of highly reactive ones. The present case was no
exception, providing for the use of 2 mol% Lewis acid catalyst and
stoichiometric hydroxide as an alternative to highly energetic per-
oxide based system.28
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16
17
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19
20
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22
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25
26
27
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60
O
O
O
i. 0.5 mol% Yb(OTf)3
O
MeOH, 65 °C
Bn
Bn
(1)
O
N
O
NH
Bn
+
HO
ii. LiOH (1.25 equiv )
THF/water (3:1), 20 °C
Me
Me
Bn
4
26: 97% yield
>99% ee
16: 97% recovery
5 g scale
O
O
O
2 mol% Y(OTf)3
4 mol% TfOH
Me
H
Me
OH
N
O
F
H
3:1 MeOH/TMOF, 60 °C, 2h
Ph
(2)
then 5 N NaOH, DMA
45 °C, 16 h
H
H
F
N
N
100 g scale
1
27: 85% yield
>99% ee
Scheme 1. One-Pot Synthesis of Carboxylic Acids
robustness. An extensive literature search of Lewis acid catalysts
and cost information from several commercial vendors revealed
that Y(OTf)3 (ionic radius = 102 Å)25 would be of interest due to
lower cost/kg catalyst ($1,252 vs $1,359)26 and lower MW (536.11
vs 620.25) compared to Yb(OTf)3, respectively. To test the hypoth-
esis the Y(OTf)3 system was compared to Yb(OTf)3 (Table 7). Sur-
prisingly, it was found that the initial attempt gave only 60% yield
and only 1.8:1 selectivity for the desired methyl ester versus the
undesired hydroxyamide side product (Table 7, Entry 1). After
careful consideration it was hypothesized that the key difference
could be the water content of the reaction mixture even though an-
hydrous methanol was utilized. In fact, the material for the initial
verification was discovered to be the monohydrate form (1.5 wt%
water). To verify the hypothesis a sample of the monohydrate was
dried to the anhydrous form and the reaction was conducted in a
glovebox. Under these strictly anhydrous conditions it was found
that the expected reactivity had been restored (93% yield, 12.9:1
selectivity). The unexpected sensitivity to water presented a signif-
icant challenge for process development as the need to utilize an-
hydrous methanol would drive up processing costs immensely on a
commercial scale. A cost-effective and readily implementable so-
lution was thus required.
¢
CONCLUSION
In summary, a Lewis acid-catalyzed protocol has been developed
for the direct conversion of enantioenriched N-acyl oxazolidinones
to their corresponding esters and amides using Yb(OTf)3 while pre-
serving the integrity of the adjacent stereocenters. A multivariable
approach to HTE was utilized to rapidly identify a globally opti-
mized catalyst system. The resulting chemistry addressed a
longstanding problem for the diversification of the products of re-
liable and widespread auxiliary based synthetic methods to an array
of complex enantioenriched esters, amides, and carboxylic acids.
The method was applied to the one-pot synthesis of a complex
pharmaceutical intermediate on 100 g scale using equally efficient
Y(OTf)3. Future work will be aimed at additional mechanistic un-
derstanding and optimizing the catalyst framework to increase ef-
ficiency and reaction scope.
The water sensitivity issue could potentially be addressed
through the addition of a dessicant to remove moisture in situ dur-
ing the reaction (Table 7). This hypothesis was tested by drying the
monohydrate of 1 in plant grade methanol by adding 20 vol% tri-
methylorthoformate (TMOF) and catalytic triflic acid to sequester
the water through the generation of methyl formate and methanol.
Under these conditions it was found that the initial reaction stream
containing 1, methanol, and TMOF afforded a Karl Fischer (KF)
titration of 0.32 weight% water that was reduced to a measured KF
of 39 ppm water after the addition of the catalytic triflic acid. Un-
der these conditions the reaction proceeded as expected (92% yield,
11.7:1 selectivity). With a reliable and robust method to achieve the
desired reactivity the reaction was explored using the more cost ef-
fective Y(OTf)3 catalyst. Gratifyingly, it was observed that the
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The Journal of Organic Chemistry
1, 2.5, 4, 6, 9, and 24.5 h into 4:1 acetonitrile/water diluent. Reac-
1
2
3
4
5
6
7
8
¢
tion progress was determined by UHPLCMS analysis using a
Supelco Ascentis Express C18 2.7 µm 2.1 x 50 mm column at 40
C (Solvent A/B = 0.05% TFA in acetonitrile/water (5:95)/0.05%
TFA in acetonitrile/water (95:5) at 0.8 mL/min; %B = 0 min 0%,
2.5 min 100%, stop time = 3.0 min).
EXPERIMENTAL SECTION
General Information. Standard benchtop techniques were em-
ployed for handling air-sensitive reagents. NMR spectra were rec-
orded on a 400 or 500 MHz spectrometer. The chemical shifts (d)
and coupling constants (J) are reported in ppm and Hz, respec-
tively. Analytical thin-layer chromatography (TLC) was performed
on TLC silica gel plates (0.25 mm) pre-coated with a fluorescent
indicator. Visualization of the TLC plates was effected with ultra-
violet light and ceric ammonium molybdate (CAM) stain with heat.
Chiral HPLC analysis was carried out on an HPLC with a multiple
wavelength detector by commercial chiral columns. HRMS sam-
ples were run on the Thermo LTQ-Orbitrap with Acquity Classic
inlet.
General Procedure for Alcoholysis of N-Acyl Oxazoli-
dinones. On the benchtop, 0.5–10 mol% Yb(OTf)3 was added to a
40 mL vial followed by anhydrous methanol (30 mL/g). The vial
was sealed with a pressure relief cap and warmed to the desired
temperature for 30 min (room temperature or 60 °C). The catalyst
solution was removed from the heat for 10 min then treated with
the desired substrate in one portion and warmed to the desired tem-
perature (23 – 60 °C). If the substrate is an oil, a solution can be
prepared in anhydrous methanol (15 mL/g) and added to the cata-
lyst solution (15 mL/g). When the reaction was deemed complete
by HPLC (or UHPLCMS) analysis, the solvent was carefully re-
moved under reduced pressure and the crude mixture was purified
by silica gel chromatography (10–80% CH2Cl2/hexanes unless oth-
erwise specified).
9
10
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15
16
17
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25
26
27
28
29
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60
General Procedure for Coupling Carboxylic Acids with Ox-
azolidinones. To a nitrogen flushed round bottomed flask, with ac-
tive nitrogen flow, was added oxazolidinone (1.0 equiv) and
DMAP (0.05 equiv) followed by anhydrous dichloromethane (10
mL/g). The reaction mixture was cooled with a room temperature
water bath followed by the addition of the carboxylic acid (1.3
equiv) and the drop-wise addition of N,N’-diisopropylcarbodiimide
(1.15 equiv) at a rate sufficient to maintain the internal temperature
below 30 °C. The reaction mixture was then stirred overnight at
room temperature. Solids were removed via filtration then the fil-
trate was concentrated in vacuo. The crude product was purified by
column chromatography.
Parallel Kinetic Isotope Experiment
Yb(OTf)3 (25 mg, 0.040 mmol) was dissolved in CD3OD (18.0
mL, 100 mass%) and methanol (18.0 mL, 99.5 mass%) in separate
vials then warmed to 60 °C for 30 min. The catalyst solution was
then allowed to cool to room temperature followed by the addition
of 9 (0.62 g, 2.0 mmol) all at once to each catalyst solution. Each
reaction mixture was sampled at 0.25, 0.5, 1, 2, 6, and 8 h and an-
alyzed by HPLC.
General Procedure for Alkylation of N-Acyl Oxazolidinones.
To a nitrogen flushed 3-neck round bottomed flask with active ni-
trogen flow was added oxazolidinone (1.0 equiv) followed by an-
hydrous THF (10.0 mL/g). The solution was cooled to -78 °C then
treated with NaHMDS 40 wt% solution in THF (1.22 equiv) at a
rate sufficient to keep the internal temperature below -70 °C. The
reaction mixture was aged for 15 minutes. then treated with alkyl
halide (1.20 equiv) at a rate sufficient to keep the internal tempera-
ture below -70 °C. The reaction was aged 1 h at -78 °C, warmed to
-40 °C and aged for 1 h, then warmed to 0 °C and quenched by the
addition of 23 wt% ammonium chloride in water (10 mL/g) and
diluted with 2-methyltetrahydrofuran (20 mL/g). The aqueous layer
was removed and the organic layer was washed 2 x aqueous 0.25
M KOH solution (10 mL/g), 1 x 23 wt% ammonium chloride in
water (10 mL/g), then 1 x saturated aqueous sodium bicarbonate
solution (10 mL/g). The isolated organic layer was dried over so-
dium sulfate, filtered, and concentrated in vacuo. The crude product
was purified by silica gel column chromatography unless otherwise
specified.
General Procedures for the Aminolysis of N-Acyl Oxazoli-
dinones. Procedure A: On the benchtop, 10 mol% Yb(OTf)3 was
added to a 5 mL vial with a stir bar, sealed with a pressure relief
cap and purged with N2 for 5 min followed by the addition of cor-
responding amine (3.0 equiv) and anhydrous DMAc or iPAc (5M
). The solution was left stirring for 30 minutes at the desired tem-
perature (40 or 80 °C). The solution was removed from the heat
then treated with the desired substrate (1.0 equiv) in one portion
and warmed back to the desired temperature (40 or 80°C). When
the reaction was deemed complete by HPLC analysis, the crude
mixture with solvent was purified by silica gel chromatography
(10–80% CH2Cl2/hexanes or EtOAc/hexanes).
Procedure B: On the benchtop, 10 mol% Yb(OTf)3 was added to
a 5 mL vial with a stir bar, sealed with a pressure relief cap and
purged with N2 for 5 min followed by the addition of corresponding
amine hydrochloride (3.0 equiv), DBU (3.5 equiv), and anhydrous
DMAc or iPAc (5M ). The solution was left stirring for 30 min at
desired temperature (40 or 80 °C). The solution was removed from
the heat then treated with the desired substrate (1.0 equiv) in one
portion and warmed back to the desired temperature (40 or 80°C).
When the reaction was deemed complete by HPLC analysis, the
crude mixture with solvent was purified by silica gel chromatog-
raphy (10–80% CH2Cl2/hexane or EtOAc/hexanes).
Experimental Procedure for Esterification HTE. In a glove-
box, solid Lewis acids (16.1 µmol; 3.21 µmol for Lanthanides)
were transferred to 1.0 mL vials in a deep well plate. Substrate 5
(20 mg, 32.1 µmol) was transferred to the appropriate vials fol-
lowed by a solution of biphenyl in MeOH (600 µL of a 5.35 µM
solution). A stock solution of substrate 4 and biphenyl (53.5 µM 4,
5.35 µM biphenyl) in both MeOH (600 µL) and EtOH (600 µL)
were transferred to their respective vials. The liquid Lewis acid
(16.1 µmol) was transferred to the appropriate vials. The plate was
sealed, heated to 65 °C, and aged for 20 h. The plate was cooled
and the reactions were sampled for UPLCMS analysis.
Experimental Data of Substrates.
(S)-4-benzyl-3-((R)-2-methyl-3-phenylpropanoyl)oxazolidin-2-
one, 4. Prepared according to the general alkylation procedure with
purification by silica gel chromatography (0–30 % ethyl ace-
tate/hexanes gradient) to afford 4 in 56% yield (15.5 g, 48.0 mmol)
from (4S)-4-benzyl-3-propanoyl-oxazolidin-2-one (20.0 g, 85.7
mmol). Spectral data matches that of previously reported.38 1H
NMR (400 MHz, chloroform-d) δ 7.35–7.18 (m, 8H), 7.11–7.04
(m, 2H), 4.68 (ddt, J = 9.2, 7.9, 3.2 Hz, 1H), 4.23–4.08 (m, 3H),
3.21–3.04 (m, 2H), 2.69 (dd, J = 13.1, 7.6 Hz, 1H), 2.57 (dd, J =
13.4, 9.3 Hz, 1H), 1.20 (d, J = 6.8 Hz, 3H).
Experimental Procedure for Lanthanide Kinetic Study. Pro-
cedure: In a glovebox, solid Lewis acids (9.7 µmol) were trans-
ferred to 8.0 mL vials. Substrate 9 (150 mg, 485 µmol) and bi-
phenyl (7.5 mg, 48.5 µmol) were transferred to the appropriate vi-
als as a stock solution in MeOH (4500 µL). The reactions were set
into a pre-heated 50 °C deep-well stirring block and sampled at 0.5,
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(R)-3-((R)-2-cyclohexyl-3-phenylpropanoyl)-4-phenyloxazoli- (4S,5R)-4-methyl-3-((R)-2-methyl-3-phenylpropanoyl)-5-phe-
Page 8 of 18
1
2
3
4
5
6
7
8
din-2-one, (5). Prepared according to the general acid coupling pro-
cedure with purification by silica gel chromatography(5 – 50%
ethylacetate/hexanes) to afford (4R)-3-(2-cyclohexylacetyl)-4-phe-
nyl-oxazolidin-2-one in in 92% yield (22.6 g, 78.5 mmol) as a
white solid starting from (4R)-4-phenyloxazolidin-2-one (13.60 g,
83.35 mmol). 1H NMR (400 MHz, chloroform-d) δ 7.42–7.27 (m,
5H), 5.44 (dd, J = 8.8, 3.8 Hz, 1H), 4.69 (t, J = 8.8 Hz, 1H), 4.27
(dd, J = 9.0, 3.7 Hz, 1H), 2.88 (dd, J = 16.0, 6.2 Hz, 1H), 2.76 (dd,
J = 16.0, 7.5 Hz, 1H), 1.87–1.72 (m, 1H), 1.70–1.57 (m, 5H), 1.29–
1.06 (m, 3H), 1.06–0.88 (m, 2H); 13C{H} NMR (101 MHz, chlo-
roform-d) δ 172.1, 153.7, 139.2, 129.1, 128.7, 125.9, 69.8, 57.6,
42.7, 34.2, 33.0, 32.9, 26.1, 26.1, 26.0. (R)-3-((R)-2-cyclohexyl-3-
phenylpropanoyl)-4-phenyloxazolidin-2-one, (5) was prepared ac-
cording to the general alkylation procedure starting from (4R)-3-
(2-cyclohexylacetyl)-4-phenyloxazolidin-2-one (7.0 g, 24.35
mmol). The isolated crude product was dissolved in EtOAc (65
mL) at 60 °C and treated dropwise with heptane (50 mL) over 20
min at 60 °C. The stirring was halted and the solution was allowed
to cool to 23 °C over 2 h and held for 3 days at 23 °C to give white
crystals. The solids were isolated by filtration to afford 5 (6.9 g,
nyloxazolidin-2-one, (13). Prepared according to the general alkyl-
ation procedure with purification by silica gel chromatography (0–
30 % ethyl acetate/hexanes gradient) to afford 13 in 64% yield
(9.57 g, 29.6 mmol) as a colorless gum starting from (4S,5R)-4-
methyl-5-phenyl-3-propionyloxazolidin-2-one (10.79 g, 46.25
mmol). Purified using semi-preparative supercritical fluid chroma-
tography (column: Chiral Technologies OJ-H, 5 µm, 21 mm x 250
mm; mobile phase A: carbon dioxide; mobile phase B: methanol;
injections: stacked isocratic at 10 %B; flow: 70 mL/min; back-
pressure regulation: 100 bar; column temperature: 40 °C; detec-
tion: UV at 220 nm). Spectral data matches that of previously re-
ported.40 1H NMR (400 MHz, chloroform-d) δ 7.43–7.17 (m, 10H),
5.64 (d, J = 7.6 Hz, 1H), 4.83–4.72 (m, 1H), 4.16 (dt, J = 8.1, 6.8
Hz, 1H), 3.13 (dd, J = 13.4, 6.8 Hz, 1H), 2.66 (dd, J = 13.3, 8.0 Hz,
1H), 1.20 (d, J = 6.8 Hz, 3H), 0.74 (d, J = 6.6 Hz, 3H); 13C{H}
NMR (101 MHz, chloroform-d) δ 176.4, 152.6, 139.0, 133.3,
129.2, 128.7, 128.6, 128.2, 126.3, 125.6, 78.7, 54.7, 39.8, 39.3,
16.5, 14.4.
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60
(R)-4-phenyl-3-((S)-2-phenylpropanoyl)oxazolidin-2-one, (19).
Prepared according to the general alkylation procedure with purifi-
cation by silica gel chromatography (0 – 50% ethyl acetate/hex-
anes) to afford 19 in 80% combined yield (7.23 g, 24.48 mmol) of
diastereomers as white solids starting from (4R)-4-phenyloxazoli-
din-2-one (5.00 g, 30.6 mmol). Spectral data matches that of previ-
ously reported.40 (R)-4-phenyl-3-((S)-2-phenylpropanoyl)oxazoli-
1
17.78 mmol) in 73% yield. H NMR (400 MHz, chloroform-d) δ
7.31–7.08 (m, 6H), 7.08–6.99 (m, 2H), 6.78–6.71 (m, 2H), 5.38
(dd, J = 8.6, 3.8 Hz, 1H), 4.58 (t, J = 8.7 Hz, 1H), 4.36 (ddd, J =
11.2, 7.0, 4.3 Hz, 1H), 4.07 (dd, J = 8.8, 3.8 Hz, 1H), 2.95 (dd, J =
13.4, 4.0 Hz, 1H), 2.81 (dd, J = 13.4, 11.4 Hz, 1H), 1.96 (br d, J =
12.1 Hz, 1H), 1.86–1.64 (m, 5H), 1.35–1.09 (m, 5H); 13C{H} NMR
(100 MHz, chloroform-d) δ 175.2, 153.3, 139.3, 138.7, 129.0,
128.9, 128.3, 127.9, 125.9, 125.2, 69.4, 57.6, 49.4, 41.2, 35.4, 30.8,
29.9, 26.3; IR (film) vmax 3034, 2928, 2848, 1698, 1493, 1454,
1380, 1302, 1240, 1203, 1188 cm-1; HRMS (ESI-TOF) m/z:
1
din-2-one: H NMR (400 MHz, chloroform-d) δ 7.38–7.19 (m,
6H), 7.19–7.09 (m, 2H), 6.97 (br d, J = 7.8 Hz, 2H), 5.49 (br dd, J
= 9.1, 5.3 Hz, 1H), 5.14 (q, J = 6.8 Hz, 1H), 4.68 (br t, J = 9.0 Hz,
1H), 4.13 (dd, J = 9.0, 5.2 Hz, 1H), 1.44 (d, J = 7.1 Hz, 3H); 13C{H}
NMR (101 MHz, chloroform-d) δ 173.7, 153.1, 139.8, 138.2,
128.8, 128.6, 128.4, 128.2, 127.1, 125.8, 69.5, 57.8, 43.8, 18.6. (R)-
4-phenyl-3-((R)-2-phenylpropanoyl)oxazolidin-2-one: 1H NMR
(400 MHz, chloroform-d) δ 7.47–7.24 (m, 10H), 5.35 (dd, J = 8.6,
3.3 Hz, 1H), 5.14 (q, J = 6.9 Hz, 1H), 4.57 (t, J = 8.6 Hz, 1H), 4.23
(dd, J = 8.8, 3.3 Hz, 1H), 1.43 (d, J = 7.1 Hz, 3H); 13C{H} NMR
(101 MHz, chloroform-d) δ 174.0, 153.2, 140.1, 139.3, 129.2,
128.7, 128.6, 128.2, 127.2, 125.8, 69.7, 58.0, 43.1, 19.4.
[M+H]+ calcd for C24H28NO3 378.2064; found 378.2067; [α]D
81.5 (c 0.850, CHCl3); mp: 152.6 °C (DSC).
-
20
(R)-3-((S)-2-methyl-3-phenylpropanoyl)-4-phenyloxazolidin-2-
one, (9). Prepared according to the general alkylation procedure
with purification by silica gel chromatography (0–30 % ethyl ace-
tate/hexanes gradient) to afford 9 in 50% yield (7.06 g, 22.8 mmol)
as a white solid starting from (R)-4-phenyl-3-propionyloxazolidin-
2-one (10 g, 45.61 mmol). Recrystallized after column chromatog-
raphy from 100 mL 1:1 PhMe:heptane at 60 °C then cooled to room
(R)-4-benzyl-3-((R)-2-(3,5-dimethylisoxazol-4-yl)-3-phenylpro-
panoyl)oxazolidin-2-one, (21a). Prepared according to the general
acid coupling procedure with purification by silica gel chromatog-
raphy (25–100% ethyl acetate/hexanes) to afford (R)-4-benzyl-3-
(2-(3,5-dimethylisoxazol-4-yl)acetyl)oxazolidin-2-one in 40%
yield (2.97 g, 9.46 mmol) as a white solid starting from (4R)-4-
benzyloxazolidin-2-one (4.19 g, 23.65 mmol). 1H NMR (400 MHz,
chloroform-d) δ 7.42–7.24 (m, 3H), 7.24–7.16 (m, 2H), 4.78–4.65
(m, 1H), 4.38–4.16 (m, 2H), 4.09–4.00 (m, 1H), 4.00–3.92 (m, 1H),
3.29 (dd, J = 13.4, 3.3 Hz, 1H), 2.82 (dd, J = 13.4, 9.6 Hz, 1H),
2.41–2.34 (m, 3H), 2.23 (s, 3H); 13C{H} NMR (101 MHz, chloro-
form-d) δ 169.4, 166.7, 160.0, 153.5, 134.8, 129.3, 129.0, 127.5,
106.6, 66.5, 55.3, 37.8, 29.4, 11.2, 10.4; IR (film) vmax 3061, 3030,
2998, 2974, 2920, 1769, 1713, 1396, 1384, 1287, 1169 cm-1;
HRMS (ESI-TOF) m/z: [M+H]+ calcd for C17H19N2O4 315.1339;
found 315.1345; [α]D20 -70.6 (c 1.12, CHCl3); mp: 131.1 °C (DSC).
Prepared according to general alkylation procedure with purifica-
tion by silica gel chromatography (0–30 % ethyl acetate/hexanes
gradient) to afford 21a in 41% yield (1.32 g, 3.26 mmol) as a white
solid starting from (R)-4-benzyl-3-(2-(3,5-dimethylisoxazol-4-
1
temperature. Isolated via filtration. H NMR (400 MHz, chloro-
form-d) δ 7.36–7.29 (m, 3H), 7.25–7.18 (m, 3H), 7.16–7.08 (m,
4H), 5.44 (dd, J = 8.8, 4.0 Hz, 1H), 4.68 (t, J = 8.8 Hz, 1H), 4.32–
4.12 (m, 2H), 3.06 (dd, J = 13.4, 7.1 Hz, 1H), 2.52 (dd, J = 13.3,
7.7 Hz, 1H), 1.14 (d, J = 6.6 Hz, 3H); 13C{H} NMR (101 MHz,
chloroform-d) δ 176.0, 153.4, 138.9, 138.8, 129.2, 129.1, 128.4,
128.3, 126.2, 125.7, 69.7, 57.7, 39.7, 39.5, 16.3; IR (film) vmax
3061, 3031, 2972, 2922, 2878, 1760, 1703, 1450, 1389, 1180 cm-1;
HRMS (ESI-TOF) m/z: [M+H]+ calcd for C19H20NO3 310.1438;
found 310.1451; [α]D -15.5 (c 0.787, CHCl3); mp: 121.5 °C
20
(DSC).
(R)-4-isopropyl-3-((S)-2-methyl-3-phenylpropanoyl)oxazolidin-
2-one, (12). Prepared according to the general alkylation procedure
with purification by silica gel chromatography (0 – 30%
ethylacetate/hexanes) to afford 12 in 60% yield (8.92 g, 32.41
mmol, 93% de) as a white solid starting from (R)-4-isopropyl-3-
propionyloxazolidin-2-one (10.0 g, 54.02 mmol). Spectral data
matches that of previously reported.39 1H NMR (400 MHz, chloro-
form-d) δ 7.27–6.81 (m, 5H) 4.27 (dt, J = 8.3, 3.4 Hz, 1H), 4.11–
3.93 (m, 3H), 2.97 (dd, J = 13.1, 7.3 Hz, 1H), 2.47 (dd, J = 13.1,
7.6 Hz, 1H), 2.00 (dtd, J = 14.0, 7.0, 3.8 Hz, 1H), 1.00 (d, J = 6.8
Hz, 3H), 0.67 (d, J = 7.1 Hz, 3H), 0.44 (d, J = 6.8 Hz, 3H); 13C{H}
NMR (101 MHz, chloroform-d) δ 176.5, 153.7, 139.2, 129.2,
128.3, 126.3, 63.0, 58.4, 40.2, 39.4, 28.3, 17.9, 16.5, 14.3.
1
yl)acetyl)oxazolidin-2-one (2.50 g, 7.95 mmol). H NMR (400
MHz, chloroform-d) δ 6.63–6.35 (m, 10H), 4.38–4.28 (m, 1H),
4.02–3.84 (m, 1H), 3.38 (d, J = 4.8 Hz, 2H), 2.65 (br dd, J = 13.4,
7.1 Hz, 1H), 2.44 (dd, J = 13.4, 3.0 Hz, 1H), 2.20 (br dd, J = 13.4,
8.6 Hz, 1H), 1.97 (dd, J = 13.4, 9.3 Hz, 1H), 1.48 (s, 3H), 1.43 (s,
3H); 13C{H} NMR (101 MHz, chloroform-d) δ 171.8, 171.2, 167.3,
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The Journal of Organic Chemistry
panoyl-oxazolidin-2-one (5.10 g, 21.9 mmol), 4-fluorobenzalde-
159.7, 152.7, 138.1, 134.9, 129.4, 129.3, 129.0, 128.5, 127.4,
1
2
3
4
5
6
7
8
126.8, 110.0, 65.9, 60.4, 55.6, 41.0, 37.7, 37.6, 21.1, 14.2, 11.3,
10.6; IR (film) vmax 3086, 3061, 3029, 2979, 2920, 2858, 1772,
1694, 1396, 1228 cm-1; HRMS (ESI-TOF) m/z: [M+H]+ calcd for
hyde (2.5 mL, 23.0 mmol) and MgCl2 (0.21 g, 2.2 mmol) in EtOAc
(40.0 mL) at room temperature was added trimethylamine (6.4 mL,
46 mmol) and TMSCl (4.3 mL, 34 mmol). The reaction mixture
was then stirred overnight and monitored for completion by TLC
and UHPLC-MS. Filtered through a pad of silica gel and rinsed
with EtOAc. The filtrate was concentrated in vacuo followed by the
addition of MeOH (40 mL). TFA (3.0 mL) was added to the sus-
pension at room temperature and stirred for 1 h. Concentrated in
vacuo, triturated with MeOH, washed with MeOH then heptane,
and dried in a vacuum oven at 50 °C with a N2 sweep affording 21e
in 81% yield (6.30 g, 17.62 mmol) as a white solid. 1H NMR (400
MHz, chloroform-d) δ 7.46–7.38 (m, 2H), 7.38–7.26 (m, 3H),
7.22–7.16 (m, 2H), 7.13–7.04 (m, 2H), 4.83 (d, J = 8.1 Hz, 1H),
4.76–4.68 (m, 1H), 4.36–4.27 (m, 1H), 4.26–4.15 (m, 2H), 3.22
(dd, J = 13.6, 3.3 Hz, 1H), 3.20 (br s, 1H), 2.71 (dd, J = 13.4, 9.3
Hz, 1H), 1.11 (d, J = 6.8 Hz, 3H); 13C{H} NMR (101 MHz, chlo-
roform-d) δ 176.4, 162.4 (d, J = 246.6 Hz, 1C), 153.5, 137.8 (d, J
= 2.9 Hz, 1C), 135.1, 129.4, 128.9, 128.3 (d, J = 8.1 Hz, 1C), 127.3,
115.4 (d, J = 22.0 Hz, 1C), 76.7, 66.0, 55.4, 44.4, 37.6, 14.8; 19F
NMR (376 MHz, chloroform-d) δ -114.07 – -114.47 (m, 1F); IR
(film) vmax 3487 (br), 3079, 2970, 2940, 2889, 1782, 1682, 1384,
1212 cm-1; HRMS (DCI-CH4) m/z: [M+H-H2O]+ C20H19FNO3
340.1349; found 340.1359; [α]20D 10.42 (c 0.787, CHCl3).
C24H25N2O4 405.1819; found 405.1812; [α]D -159.8 (c 0.525,
20
CHCl3); mp: 111.6 °C (DSC).
(S)-4-benzyl-3-((R)-2-(benzyloxy)pent-4-enoyl)oxazolidin-2-
one, (21b). Prepared according to general alkylation procedure in
with purification by silica gel chromatography (10–100% ethyl ac-
etate/hexanes) to afford 21b in 50% yield (1.29 g, 3.54 mmol) as a
colorless gum from ((4S)-4-benzyl-3-(2-benzyloxyacetyl)oxazoli-
din-2-one (2.30 g, 7.07 mmol). Spectral data matches that of previ-
ously reported.43 1H NMR (400 MHz, DMSO-d6) d 7.42–7.20 (m,
10H), 5.84 (ddt, J = 17.1, 10.2, 6.8 Hz, 1H), 5.23–5.00 (m, 3H),
4.81–4.65 (m, 1H), 4.54 (d, J = 11.9 Hz, 1H), 4.46–4.33 (m, 1H),
4.25 (dd, J = 8.8, 3.3 Hz, 1H), 4.10 (q, J = 5.1 Hz, 1H), 3.02 (br dd,
J = 13.4, 3.3 Hz, 1H), 2.92 (br dd, J = 13.5, 8.0 Hz, 1H), 2.48–2.34
(m, 2H); 13C{H} NMR (101 MHz, DMSO-d6) δ 171.5, 153.2,
138.1, 135.6, 133.8, 129.5, 128.5, 128.2, 127.6, 127.5, 127.0,
117.6, 76.3, 71.0, 66.9, 54.3, 36.8, 36.6.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(R)-4-phenyl-3-((R)-3-phenylbutanoyl)oxazolidin-2-one, (21c).
Prepared according to the general acid coupling procedure with pu-
rification by silica gel chromatography (80–100 % dichloro-
methane/hexanes gradient)to afford 21c in 96% yield (1.82 g, 5.88
mmol) as a white solid from (4R)-4-phenyloxazolidin-2-one (1.00
g, 6.13 mmol). Spectral data matches that of previously reported.41
1H NMR (400 MHz, chloroform-d) δ 7.41–7.16 (m, 10H), 5.31 (dd,
J = 8.6, 3.5 Hz, 1H), 4.55 (t, J = 8.7 Hz, 1H), 4.22 (dd, J = 8.8, 3.3
Hz, 1H), 3.48–3.25 (m, 2H), 3.14 (dd, J = 15.9, 5.8 Hz, 1H), 1.26
(d, J = 6.8 Hz, 3H); 13C{H} NMR (101 MHz, chloroform-d) δ
171.3, 153.7, 145.6, 139.0, 129.1, 128.6, 128.4, 127.0, 126.3,
125.9, 69.9, 57.5, 43.2, 35.9, 22.2.
(R)-4-benzyl-3-((R)-6-((tert-butyldimethylsilyl)oxy)-2-
methylhexanoyl)oxazolidin-2-one, (21f). A 500-mL 3-neck round
bottom flask was charged with tetrahydrofuran (342 mL) and
LiHMDS 1.0 M in THF (107.9 mL, 107.9 mmol, 1.25 equiv) and
cooled to -5 °C. To the mixture was added a (R)-4-benzyl-3-(6-
((tert-butyldimethylsilyl)oxy)hexanoyl)oxazolidin-2-one (34.7 g,
85.7 mmol) dissolved in tetrahydrofuran (100 mL) over 1 h. The
reaction mixture aged at -5 °C for 20 min and was then treated with
iodomethane (16.0 mL, 257 mmol, 3.0 equiv) dissolved in tetrahy-
drofuran (30 mL) dropwise over 45 min at -5 °C. The reaction mix-
ture aged for 45 min at -5 °C and was determined to be complete
by HPLC analysis. A 0.5 M aqueous ammonium chloride solution
(171 mL; 682 mmol) was added to the reaction mixture and the
heterogeneous mixture was warmed to 23 °C. To the mixture was
added water (30 mL) and ethyl acetate (100 mL). The layers were
separated and the isolated aqueous layer was extracted with ethyl
acetate (3 x 100 mL). The combined organic extracts were dried
over MgSO4, filtered, and concentrated to orange oil. 1H NMR of
the crude oil indicated a 9.1:1 diastereomeric mixture. Purification
by silica gel chromatography (5–10% ethyl acetate/hexanes gradi-
ent) afforded 21f (31.7 g, 75.54 mmol) in 70% yield as a single
diastereomer. Spectral data matches that of previously reported.42
1H NMR (400 MHz, chloroform-d) δ 7.37–7.19 (m, 5H), 4.68 (ddt,
J=9.8, 6.7, 3.2 Hz, 1H), 4.25–4.13 (m, 2H), 3.79–3.66 (m, 1H), 3.60
(td, J=6.4, 1.0 Hz, 2H), 3.27 (dd, J=13.4, 3.3 Hz, 1H), 2.78 (dd,
J=13.1, 9.6 Hz, 1H), 1.83–1.66 (m, 1H), 1.56–1.32 (m, 5H), 1.28–
1.22 (m, 3H), 0.94–0.86 (m, 9H), 0.00–0.06 (m, 6H) ; 13C{H} NMR
(101 MHz, chloroform-d) δ 177.2, 153.0, 135.3, 129.4, 128.9,
127.3, 66.0, 62.9, 55.3, 37.9, 37.6, 33.2, 32.8, 25.9, 25.6, 23.5, 18.3,
17.3, -5.3.
N-((1R,2S)-1-(4-bromophenyl)-2-methyl-3-oxo-3-((R)-2-oxo-4-
phenyloxazolidin-3-yl)propyl)-4-methylbenzenesulfonamide,
(21d). Sodium bis(trimethylsilyl)amide (2.6 mL, 5.2 mmol, 2.0 M)
was added drop-wise to a solution of (4R)-4-benzyl-3-propanoyl-
oxazolidin-2-one (1.00 g, 4.29 mmol) in THF (15 mL) at -78 °C
under nitrogen then stirred for 30 min. N-[(4-bromophenyl)meth-
ylene]-4-methyl-benzenesulfonamide (1.59 g, 4.70 mmol) in THF
(35 mL) was added drop-wise over 10 min, stirred for 2.5 h at -78
°C, then quenched with saturated NH4Cl (20 mL), extracted with
EtOAc (2 x 50 mL), washed with brine (50 mL) then concentrated
in vacuo. Purified by semi-preparative supercritical fluid chroma-
tography (column: Chiral Technologies OD-H, 5 µm, 30 mm x 250
mm; mobile phase A: carbon dioxide; mobile phase B: acetoni-
trile; injections: stacked isocratic at 35 %B; flow: 100 mL/min;
backpressure regulation: 100 bar; column temperature: 40 °C; de-
tection: UV at 220 nm) affording the first peak 21d in 40% yield
1
(987.5 mg, 1.73 mmol) as a colorless gum. H NMR (400 MHz,
chloroform-d) δ 7.49–7.42 (m, 2H), 7.35–7.21 (m, 5H), 7.13–7.02
(m, 4H), 7.01–6.94 (m, 2H), 6.21–6.06 (m, 1H), 4.72–4.58 (m, 1H),
4.58–4.48 (m, 1H), 4.37–4.23 (m, 1H), 4.23–4.12 (m, 2H), 3.25–
3.11 (m, 1H), 2.64–2.51 (m, 1H), 2.39–2.28 (m, 3H), 1.18–1.06 (m,
3H); 13C{H} NMR (101 MHz, chloroform-d) δ 174.8, 153.9, 143.2,
137.9, 137.7, 135.1, 131.5, 129.4, 129.2, 128.9, 128.6, 127.3,
126.9, 126.8, 121.6, 66.2, 61.0, 55.7, 42.6, 37.3, 21.3, 15.5, 15.4;
IR (film) vmax 3540 (br), 3282 (br), 3062, 3028, 2979, 2922, 1776,
1701, 1489, 1455, 1387, 1340, 1212, 1161 cm-1; HRMS (ESI-TOF)
m/z: [M+H]+ calcd for C27H28BrN2O5S 573.0880; found 573.0867;
[α]20D -20.4 (c 0.515, CHCl3).
(S)-4-benzyl-3-((S)-2-methyl-3-phenylpropanoyl)oxazolidin-2-
one, (24). Prepared according to the general alkylation procedure
with purification by silica gel chromatography (0-30% ethyl ace-
tate/hexanes gradient) to afford 24 in 57% yield (6.30 g, 19 mmol)
from (S)-4-benzyl-3-(3-phenylpropanoyl)oxazolidin-2-one (10.6 g,
1
34 mmol). H NMR (500 MHz, Chloroform-d) δ 7.36 – 7.31 (m,
2H), 7.28 – 7.16 (m, 7H), 4.55 – 4.50 (m, 1H), 4.17 – 4.06 (m, 2H),
3.96 (t, J = 8.4 Hz, 1H), 3.24 (dd, J = 13.4, 3.3 Hz, 1H), 3.02 (dd,
J = 13.3, 7.8 Hz, 1H), 2.79 – 2.67 (m, 2H), 1.25 (d, J = 6.8 Hz, 3H).
13C{H} NMR (126 MHz, Chloroform-d) δ 176.4, 152.9, 139.1,
(R)-4-benzyl-3-((2S,3R)-3-(4-fluorophenyl)-3-hydroxy-2-
methylpropanoyl)oxazolidin-2-one, (21e). To (4R)-4-benzyl-3-pro-
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The Journal of Organic Chemistry
Page 10 of 18
135.2, 129.3, 129.1, 128.8, 128.2, 127.2, 126.3, 65.9, 55.3, 39.8,
39.3, 37.8, 16.9. HRMS (ESI-TOF) m/z: [M+H]+ calcd for
NO 324.1594; found 324.1603.
Yb(OTf)3 at 80 °C (48 h) to give (R)-14 (392 mg) as colorless oil
1
2
3
4
5
6
7
in 96% yield and >99% ee from 4. Table 1 Entry 13: Prepared ac-
cording to the general procedure on 2 mmol scale with 10 mol%
Yb(OTf)3 at 80 °C (96 h) to give (S)-14 (380 mg) as colorless oil
in 93% yield and 93% ee from 12. Diastereomeric excess of 12 is
93%. Table 1 Entry 17: Prepared according to the general proce-
dure on 2 mmol scale with 10 mol% Yb(OTf)3 at 80 °C (30 h) to
give (R)-14 (376 mg) as colorless oil in 92% yield and 98% ee from
C
H
20 22
3
Experimental Procedures for the Preparation of the Ester Prod-
ucts.
Methyl 2-methyl-3-phenylpropanoate, (6).29 Table 1 Entry 1:
1
13. Diastereomeric excess of 12 is 98%. H NMR (400 MHz,
Prepared according to the general procedure on 2 mmol scale with
2 mol% Yb(OTf)3 at 20 °C (8 h) to give (S)-6 (346 mg) as colorless
oil in 97% yield and >99% ee from 9. Table 1 Entry 2: Prepared
according to the general procedure on 2 mmol scale with 2 mol%
Yb(OTf)3 at 60 °C (1 h) to give (S)-6 (353 mg) as colorless oil in
99% yield and >99% ee from 9. Table 1 Entry 6: Prepared accord-
ing to the general procedure on 2 mmol scale with 2 mol%
Yb(OTf)3 at 20 °C (12 h) to give (R)-6 (346 mg) as colorless oil in
97% yield and >99% ee from 4. Table 1 Entry 7: Prepared accord-
ing to the general procedure on 2 mmol scale with 2 mol%
Yb(OTf)3 at 60 °C (1 h) to give (R)-6 (310 mg) as colorless oil in
87% yield and >99% ee from 4. Table 1 Entry 11: Prepared accord-
ing to the general procedure on 2 mmol scale with 2 mol%
Yb(OTf)3 at 60 °C (1 h) to give (S)-6 (310 mg) as colorless oil in
87% yield and 93% ee from 12. Diastereomeric excess of 12 is
93%. Table 1 Entry 15: Prepared according to the general proce-
dure on 2 mmol scale with 2 mol% Yb(OTf)3 at 60 °C (2 h) to give
(R)-6 (356 mg) as colorless oil in 99% yield and 98% ee from 8.
Diastereomeric excess of 13 is 98%. 1H NMR (400 MHz, chloro-
form-d) δ 7.35–7.15 (m, 5H), 3.66 (s, 3H), 3.05 (dd, J = 13.1, 6.6
Hz, 1H), 2.81–2.66 (m, 2H), 1.18 (d, J = 6.8 Hz, 3H); 13C{H} NMR
(101 MHz, chloroform-d) δ 176.6, 139.4, 129.0, 128.4, 126.3, 51.6,
41.4, 39.7, 16.8. Enantioselectivity was determined by HPLC anal-
ysis using a Phenomenex Lux Cellulose-1 column at 20 °C (Solvent
A/B = Heptane/iPrOH at 1.0 mL/min; %B = 0 min 3%, 2 min 3%,
3 min 60%, 9 min 60%, stop time = 9 min), giving retention times
of 3.63 min (R enantiomer) and 4.10 min (S enantiomer). The ab-
solute stereochemistry was assumed by analogy.
Ethyl 2-methyl-3-phenylpropanoate (7).29 Table 1 Entry 3: Pre-
pared according to the general procedure on 2 mmol scale with 10
mol% Yb(OTf)3 at 75 °C (16 h) to give (S)-7 (338 mg) as colorless
oil in 88% yield and >99% ee from 9. Table 1 Entry 8: Prepared
according to the general procedure on 2 mmol scale with 10 mol%
Yb(OTf)3 at 75 °C (24 h) to give (R)-7 (327 mg) as colorless oil in
85% yield and >99% ee from 4. Table 1 Entry 12: Prepared accord-
ing to the general procedure on 2 mmol scale with 10 mol%
Yb(OTf)3 at 75 °C (20 h) to give (S)-7 (331 mg) as colorless oil in
86% yield and 93% ee from 12. Diastereomeric excess of 12 is
93%. Table 1 Entry 16: Prepared according to the general proce-
dure on 2 mmol scale with 10 mol% Yb(OTf)3 at 75 °C (27 h) to
give (R)-7 (342 mg) as colorless oil in 89% yield and 98% ee from
13. Diastereomeric excess of 13 is 98%. 1H NMR (400 MHz, chlo-
roform-d) δ 7.41–7.17 (m, 5H), 4.11 (q, J = 7.2 Hz, 2H), 3.09–3.01
(m, 1H), 2.86–2.66 (m, 2H), 1.26–1.15 (m, 6H); 13C{H} NMR (101
MHz, chloroform-d) δ 176.1, 139.4, 129.0, 128.3, 126.2, 60.2, 41.5,
39.7, 16.8, 14.1. Enantioselectivity was determined by HPLC anal-
ysis using a Chiralpak OB-H 5 µm 4.6 x 150 mm column at 30 °C
(Solvent A/B = Heptane/iPrOH at 0.7 mL/min; 2% B isocratic, stop
time = 10 min), giving retention times of 4.28 min (R enantiomer)
and 4.68 min (S enantiomer). The absolute stereochemistry was as-
sumed by analogy.
DMSO-d6) δ 7.32–7.16 (m, 5H), 5.83 (ddt, J = 17.2, 10.6, 5.4 Hz,
1H), 5.27–5.11 (m, 2H), 4.50 (dt, J = 5.3, 1.4 Hz, 2H), 2.96–2.85
(m, 1H), 2.83–2.56 (m, 2H), 1.08 (d, J = 6.8 Hz, 3H); 13C{H} NMR
(101 MHz, DMSO-d6) δ 174.8, 139.1, 132.6, 128.9, 128.2, 126.2,
117.6, 64.2, 40.6, 38.9, 16.7; IR (film) vmax 3086, 3028, 2975, 2937,
2878, 1735, 1496, 1454, 1380, 1165 cm-1; HRMS (ESI-TOF) m/z:
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
[M+H]+ calcd for C13H17O2 205.1223; found 205.1223; [α]D
-
20
25.73 (c 0.715, DMSO). Enantioselectivity was determined by
HPLC analysis using a Chiralpak ID-3 3 µm 4.6 x 150 mm column
at 30 °C (Solvent A/B = 0.05% TFA in MeOH/Water (1:4)/0.05%
TFA in MeOH/acetonitrile (1:4) at 1.2 mL/min; %B = 0 min 0%, 2
min 0%, 20 min 100%, 24 min 100%, stop time = 24 min), giving
retention times of 13.35 min (R enantiomer) and 13.59 min (S en-
antiomer). The absolute stereochemistry was assumed by analogy.
n-Butyl 2-methyl-3-phenylpropanoate (15).27 Table 1 Entry 5:
Prepared according to the general procedure on 2 mmol scale with
10 mol% Yb(OTf)3 at 80 °C (96 h) to give (S)-15 (436 mg) as col-
orless oil in 94% yield and >99% ee from 9. Table 1 Entry 10: Pre-
pared according to the general procedure on 2 mmol scale with 10
mol% Yb(OTf)3 at 80 °C (60 h) to give (R)-15 (414 mg) as color-
less oil in 94% yield and >99% ee from 4. Table 1 Entry 14: Pre-
pared according to the general procedure on 2 mmol scale with 10
mol% Yb(OTf)3 at 80 °C (120 h) to give (S)-15 (383 mg) as color-
less oil in 87% yield and 92% ee from 12. Diastereomeric excess
of 12 is 93%. Table 1 Entry 18: Prepared according to the general
procedure on 2 mmol scale with 10 mol% Yb(OTf)3 at 80 °C (72
h) to give (R)-15 (361 mg) as colorless oil in 82% yield and 98%
1
ee from 13. Diastereomeric excess of 13 is 98%. H NMR (400
MHz, chloroform-d) δ 7.32–7.25 (m, 2H), 7.24–7.12 (m, 3H), 4.04
(t, J = 6.6 Hz, 2H), 3.03 (dd, J = 13.0, 6.4 Hz, 1H), 2.79–2.64 (m,
2H), 1.62–1.50 (m, 2H), 1.31 (dq, J = 15.0, 7.5 Hz, 2H), 1.16 (d, J
= 6.8 Hz, 3H), 0.91 (t, J = 7.3 Hz, 3H); 13C{H} NMR (101 MHz,
chloroform-d) δ 176.2, 139.4, 128.9, 128.3, 126.2, 64.2, 41.5, 39.8,
30.6, 19.0, 16.8, 13.7. Enantioselectivity was determined by HPLC
analysis using a Phenomenex Lux Cellulose-3 3 µm 4.6 x 150 mm
column at 25 °C (Solvent A/B = 0.05% TFA in MeOH/Water
(1:4)/0.05% TFA in MeOH/acetonitrile (1:4) at 1.2 mL/min; %B =
0 min 0%, 2 min 0%, 20 min 100%, 24 min 100%, stop time = 24
min), giving retention times of 15.10 min (S enantiomer) and 15.55
min (R enantiomer). The absolute stereochemistry was assumed by
analogy.
Methyl (R)-2-phenylpropanoate (20a).31 Prepared according to
the general procedure on 2 mmol scale with 2 mol% Yb(OTf)3 at
60 °C (1 h) to give 20a (312 mg) as colorless oil in 95% yield and
>99% ee from 19. 1H NMR (400 MHz, chloroform-d) δ 7.48–7.22
(m, 5H), 3.76 (q, J = 7.1 Hz, 1H), 3.69 (s, 3H), 1.54 (d, J = 7.1 Hz,
3H); 13C{H} NMR (101 MHz, chloroform-d) δ 175.0, 140.6, 128.7,
127.5, 127.2, 52.0, 45.4, 18.6. Enantioselectivity was determined
by HPLC analysis using a Chiralpak ID-3 3 µm 4.6 x 150 mm col-
umn at 30 °C (Solvent A/B = 0.05% TFA in MeOH/Water
(1:4)/0.05% TFA in MeOH/acetonitrile (1:4) at 1.2 mL/min; %B =
0 min 30%, 2 min 30%, 7 min 37%, 9 min 100%, 12 min 100%,
stop time = 12 min), giving retention times of 4.87 min (major R
enantiomer) and 5.49 min (minor S enantiomer). The absolute ste-
reochemistry was assumed by analogy.
Allyl 2-methyl-3-phenylpropanoate (14). Table 1 Entry 4: Pre-
pared according to the general procedure on 2 mmol scale with 10
mol% Yb(OTf)3 at 80 °C (20 h) to give (S)-14 (404 mg) as colorless
oil in 99% yield and >99% ee from 9. Table 1 Entry 9: Prepared
according to general procedure on 2 mmol scale with 10 mol%
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Ethyl (S)-2-phenylpropanoate, (20b).31 Prepared according t the
127.2, 77.5, 74.8, 52.2, 45.2, 18.5; IR (film) vmax 3291, 3064, 3030,
2981, 2938, 2877, 2129, 1736, 1496, 1453, 1377, 1326, 1199, 1154
cm-1; HRMS (DCI-CH4) m/z: [M]+ calcd for C12H12O2 188.0837;
1
2
3
4
5
6
7
8
general procedure on 2 mmol scale with 10 mol% Yb(OTf)3 at 75
°C (12 h) to give 20b (328 mg) as colorless oil in 92% yield and
>99% ee from 19. 1H NMR (400 MHz, chloroform-d) δ 7.43–7.32
(m, 4H), 7.32–7.24 (m, 1H), 4.28–4.02 (m, 2H), 3.74 (q, J = 7.2
Hz, 1H), 1.53 (d, J = 7.1 Hz, 3H), 1.24 (t, J = 7.1 Hz, 3H); 13C{H}
NMR (101 MHz, chloroform-d) δ 174.6, 140.7, 128.6, 127.5,
127.1, 60.7, 45.6, 18.6, 14.1. Enantioselectivity was determined by
HPLC analysis using a Chiralpak IG 5 µm 4.6 x 150 mm column
at 30 °C (Solvent A/B = 0.05% TFA in acetonitrile/water
(5:95)/0.05% TFA in acetonitrile/water (95:5) at 1.2 mL/min; %B
= 0 min 30%, 2 min 30%, 12 min 45%, 15 min 100%, 18 min 100%,
stop time = 18 min), giving retention times of 11.69 min (major S
enantiomer) and 12.39 min (minor R enantiomer). The absolute ste-
reochemistry was assumed by analogy.
found 188.0835; [α]D -52.5 (c 1.12, CHCl3). Enantioselectivity
20
was determined by HPLC analysis using a Chiralpak OB-H 5 µm
4.6 x 150 mm column at 30 °C (Solvent A/B = 0.05% TFA in
MeOH/Water (1:4)/0.05% TFA in MeOH/acetonitrile (1:4) at 1.2
mL/min; %B = 0 min 25%, 27 min 25%, 31 min 100%, 35 min
100%, stop time = 35 min), giving retention times of 19.23 min
(minor S enantiomer) and 21.37 min (major R enantiomer). The ab-
solute stereochemistry was assumed by analogy.
9
Cyclopropylmethyl (R)-2-phenylpropanoate (20g). Prepared ac-
cording to the general procedure on 2 mmol scale with 10 mol%
Yb(OTf)3 at 80 °C (22 h) to give 20g (323 mg) as colorless oil in
79% yield and >99% ee from 19. 1H NMR (400 MHz, chloroform-
d) δ 7.35–7.17 (m, 5H), 3.96–3.77 (m, 2H), 3.70 (q, J = 7.3 Hz,
1H), 1.46 (d, J = 7.1 Hz, 3H), 1.22–0.98 (m, 1H), 0.56–0.38 (m,
2H), 0.24–0.14 (m, 2H); 13C{H} NMR (101 MHz, chloroform-d) δ
174.7, 140.7, 128.5, 127.5, 127.0, 69.3, 45.5, 18.6, 9.7, 3.1 (2); IR
(film) vmax 3085, 3029, 2979, 2939, 2877, 1735, 1496, 1453, 1204,
1165 cm-1 HRMS (ESI-TOF) m/z: [M+H]+ calcd for C13H17O2
205.1223; found 205.1230; [α]D20 -37.5 (c 0.850, CHCl3). Enanti-
oselectivity was determined by HPLC analysis using a Regis (R,R)
Whelk-O1 3 µm 4.6 x 150 mm column at 25 °C (Solvent A/B =
Heptane/iPrOH at 1.0 mL/min; %B = 4% isocratic, stop time = 10
min), giving retention times of 4.38 min (minor S enantiomer) and
4.92 min (minor R enantiomer). The absolute stereochemistry was
assumed by analogy.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
n-Propyl (R)-2-phenylpropanoate (20c).32 Prepared according to
the general procedure on 2 mmol scale with 10 mol% Yb(OTf)3 80
°C (20 h) to give 20c (319 mg) as colorless oil in 83% yield and
1
98% ee from 19. H NMR (400 MHz, chloroform-d) δ 7.35–7.18
(m, 5H), 3.99 (t, J = 6.7 Hz, 2H), 3.68 (q, J = 7.1 Hz, 1H), 1.60–
1.45 (m, 5H), 0.82 (t, J = 7.5Hz, 3H); 13C{H} NMR (101 MHz,
chloroform-d) δ 174.6, 140.7, 128.5, 127.5, 127.0, 66.3, 45.6, 21.9,
18.5, 10.2. Enantioselectivity was determined by HPLC analysis
using a Regis (R,R) Whelk-O1 3 µm 4.6 x 150 mm column at 25
°C (Solvent A/B = Heptane/iPrOH at 1.0 mL/min; %B = 4% iso-
cratic, stop time = 10 min), giving retention times of 4.17 min (mi-
nor S enantiomer) and 4.56 min (major R enantiomer). The absolute
stereochemistry was assumed by analogy.
n-Butyl (S)-2-phenylpropanoate (20d).32 Prepared according to
the general procedure on 2 mmol scale with 10 mol% Yb(OTf)3 at
80 °C (24 h) to give 20d (326 mg) as colorless oil in 79% yield and
>99% ee from 19. 1H NMR (400 MHz, chloroform-d) δ 7.35–7.19
(m, 5H), 4.09–3.98 (m, 2H), 3.68 (q, J = 7.1 Hz, 1H), 1.56–1.44
(m, 5H), 1.32–1.20 (m, 2H), 0.84 (t, J = 7.5 Hz, 3H); 13C{H} NMR
(101 MHz, chloroform-d) δ 174.6, 140.7, 128.5, 127.4, 127.0, 64.6,
45.6, 30.5, 19.0, 18.5, 13.6. Enantioselectivity was determined by
HPLC analysis using a Regis (R,R) Whelk-O1 3 µm 4.6 x 150 mm
column at 25 °C (Solvent A/B = Heptane/iPrOH at 1.0 mL/min;
%B = 4% isocratic, stop time = 10 min), giving retention times of
3.96 min (major S enantiomer) and 4.38 min (minor R enantiomer).
The absolute stereochemistry was assumed by analogy.
Allyl (S)-2-phenylpropanoate (20e).33 Prepared according to the
general procedure on 2 mmol scale with 10 mol% Yb(OTf)3 at 80
°C (22 h) to give 20e (358 mg) as colorless oil in 94% yield and
>99% ee from 19. 1H NMR (500 MHz, DMSO-d6) δ 7.35–7.24 (m,
5H), 5.85 (ddt, J = 17.2, 10.6, 5.3 Hz, 1H), 5.18–5.11 (m, 2H), 4.54
(dt, J = 5.2, 1.5 Hz, 2H), 3.83 (q, J = 7.1 Hz, 1H), 1.40 (d, J = 7.2
Hz, 3H); 13C{H} NMR (126 MHz, DMSO-d6) δ 173.4, 140.5,
132.5, 128.5, 127.3, 127.0, 117.4, 64.5, 44.4, 18.4. Enantioselec-
tivity was determined by HPLC analysis using a Regis (R,R)
Whelk-O1 3 µm 4.6 x 150 mm column at 25 °C (Solvent A/B =
Heptane/iPrOH at 1.0 mL/min; %B = 4% isocratic, stop time = 10
min), giving retention times of 4.15 min (major S enantiomer) and
4.51 min (minor R enantiomer). The absolute stereochemistry was
assumed by analogy.
Methyl (R)-2-cyclohexyl-3-phenylpropanoate (8). Prepared ac-
cording to the general procedure on 2 mmol scale with 2 mol%
Yb(OTf)3 at 60 °C (20 h) to give 8 (478 mg) as colorless oil in 97%
1
yield and >99% ee from 5. H NMR (400 MHz, chloroform-d) δ
7.34–7.25 (m, 2H), 7.25–7.13 (m, 3H), 3.54 (s, 3H), 3.01–2.79 (m,
2H), 2.53 (ddd, J = 10.3, 7.3, 5.2 Hz, 1H), 1.91 (br d, J = 12.4 Hz,
1H), 1.85–1.74 (m, 2H), 1.74–1.57 (m, 3H), 1.39–1.03 (m, 5H);
13C{H} NMR (101 MHz, chloroform-d) δ 175.4, 140.0, 128.8,
128.3, 126.1, 54.3, 51.1, 40.4, 35.7, 30.9, 30.8, 26.4, 26.3, 26.3; IR
(film) vmax 3086, 3064, 3030, 2919, 2853, 2670, 1739, 1733, 1604,
1495, 1456, 1360, 1160 cm-1; HRMS (ESI-TOF) m/z: [M+H]+
calcd for C16H23O2 247.1693; found 247.1693; [α]D20 33.19 (c 1.12,
CHCl3). Enantioselectivity was determined by HPLC analysis us-
ing a Phenomenex Lux Amylose 3 µm 4.6 x 150 mm column at 30
°C (Solvent A/B = 0.05% TFA in acetonitrile/water (5:95)/0.05%
TFA in acetonitrile/water (95:5) at 1.2 mL/min; %B = 0 min 40%,
2 min 40%, 16 min 100%, 20 min 100%, stop time = 20 min), giv-
ing retention times of 9.65 min (major R enantiomer) and 10.26 min
(minor S enantiomer). The absolute stereochemistry was assumed
by analogy.
Methyl (R)-2-(3,5-dimethylisoxazol-4-yl)-3-phenylpropanoate,
(22a). Prepared according to the general procedure on 2 mmol scale
with 2 mol% Yb(OTf)3 at 60 °C (20 h) to give 22a (493 mg) as
colorless oil after silica gel purification (0-40% ethyl acetate/hex-
1
anes) in 95% yield and >99%ee from 21a. H NMR (400 MHz,
chloroform-d) δ 7.28–7.19 (m, 3H), 7.08–7.01 (m, 2H), 3.71 (s,
3H), 3.63 (dd, J= 9 .1, 6.3 Hz, 1H), 3.42 (br d, J = 13.6 Hz, 1H),
2.92 (dd, J = 13.6, 9.4 Hz, 1H), 2.14 (s, 3H), 2.13 (s, 3H); 13C{H}
NMR (101 MHz, chloroform-d) δ 172.6, 166.4, 159.1, 138.3,
128.9, 128.5, 126.7, 110.8, 52.2, 42.4, 37.2, 11.1, 10.5; IR (film)
vmax 3087, 3030, 3003, 2849, 1729, 1634, 1496 cm-1; HRMS (ESI-
TOF) m/z: [M+H]+ calcd for C15H18NO3 260.1281; found
260.1284; [α]D20 -98.5 (c 0.585, CHCl3). Enantioselectivity was de-
termined by HPLC analysis using a Phenomenex Lux Cellulose-1
3 µm 4.6 x 150 mm column at 30 °C (Solvent A/B = 0.05% TFA
Propargyl (R)-2-phenylpropanoate (20f). Prepared according to
the general procedure on 2 mmol scale with 10 mol% Yb(OTf)3 at
80 °C (22 h) to give 20f (361 mg) as colorless oil in 96% yield and
>99% ee from 19. The product has a strong acrylic odor. 1H NMR
(400 MHz, chloroform-d) δ 7.34–7.19 (m, 5H), 4.67 (dd, J = 15.7,
2.5 Hz, 1H), 4.56 (dd, J = 15.7, 2.5 Hz, 1H), 3.73 (q, J = 7.2 Hz,
1H), 2.39 (t, J = 2.5 Hz, 1H), 1.48 (d, J = 7.3 Hz, 3H); 13C{H}
NMR (101 MHz, chloroform-d) δ 173.7, 139.9, 128.6, 127.5,
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in acetonitrile/water (5:95)/0.05% TFA in acetonitrile/water (95:5)
115.5, 115.3, 75.7, 52.0, 47.1, 14.4; 19F NMR (376 MHz, chloro-
1
2
3
4
5
6
7
8
at 1.2 mL/min; %B = 0 min 40%, 2 min 40%, 16 min 100%, 20 min
= 100%, stop time = 20 min), giving retention times of 7.21 min
(minor S enantiomer) and 7.69 min (major R enantiomer). The ab-
solute stereochemistry was assumed by analogy.
form-d) δ -114.14 – -114.27 (m, 1F). Enantioselectivity was deter-
mined by HPLC analysis using a Chiralpak IG 5 µm 4.6 x 150 mm
column at 30 °C (Solvent A/B = 0.05% TFA in acetonitrile/water
(5:95)/0.05% TFA in acetonitrile/water (95:5) at 1.2 mL/min; %B
= 0 min 20%, 2 min 20%, 10 min 40%, 13 min 100%, 16 min =
100%, stop time = 16 min), giving retention times of 10.31 min
(minor 2S/3R enantiomer) and 11.35 min (minor 2R/3R enantio-
mer). The absolute stereochemistry was assumed by analogy.
Methyl (R)-6-hydroxy-2-methylhexanoate (22f).35 Prepared ac-
cording to the general procedure on 0.67 mmol scale (1.5 mol%
Yb(OTf)3) at 20 °C (16 h) to give 22f (98 mg) as colorless oil in
91% yield and 97% ee from 21f. Diastereomeric excess of 21f is
97%. Spectral data matches that of previously reported.1H NMR
(400 MHz, chloroform-d) δ 3.71–3.58 (m, 5H), 2.45 (dq, J =13.8,
7.0 Hz, 1H), 1.93 (s, 1H), 1.75–1.63 (m, 1H), 1.61–1.51 (m, 2H),
1.49–1.29 (m, 3H), 1.21–1.13 (d, J =4.0 Hz, 3H); 13C{H} NMR
(101 MHz, chloroform-d) δ 177.3, 62.6, 51.5, 39.4, 33.4, 32.5,
23.4, 17.0 Enantioselectivity was determined by GC analysis using
a Restek RT-bDEXsm column 30 m x 0.25 mm x 0.25 µm (80 °C
at 0 min with increase of 2 °C/min to 230 °C; Inj 200 °C, Det 250
°C; He 1.9 mL/min 30:1), giving retention times of 25.48 min (ma-
jor R enantiomer) and 25.71 min (minor S enantiomer). The abso-
lute stereochemistry was assumed by analogy.
Methyl (R)-2-(benzyloxy)pent-4-enoate (22b). Prepared accord-
ing to the general procedure on 2 mmol scale with 2 mol%
Yb(OTf)3 at 60 °C (30 h) to give 22b (344 mg) as colorless oil after
purification by silica gel chromatography in 78% yield and >99%
1
ee from 21b. H NMR (400 MHz, methanol-d4) d 7.42–7.26 (m,
9
5H), 5.82 (ddt, J = 17.2, 10.2, 7.0 Hz, 1H), 5.17–5.03 (m, 2H), 4.65
(d, J = 11.6 Hz, 1H),4.44 (d, J = 11.4 Hz, 1H), 4.06 (dd, J = 6.9,
5.4 Hz, 1H), 3.72 (s, 3H), 2.58-2.43 (m, 2H); 13C{H} NMR (101
MHz, methanol-d4) δ 174.3, 139.1, 134.6, 129.5, 129.3, 129.0,
118.4, 79.2, 73.5, 52.4, 38.5; IR (film) vmax 3480 (br), 3066, 3032,
2953, 2873, 1748, 1643, 1455, 1435, 1275, 1203, 1112 cm-1;
HRMS (ESI-TOF) m/z: [M+H]+ calcd for C13H17O3 221.1172;
found 221.1167; [α]20D 45.8 (c 1.005, CH3CN). Enantioselectivity
was determined by HPLC analysis using a Chiralpak IG 5 µm 4..6
x 150 mm column at 30 °C (Solvent A/B = 0.05% NH4OAc in ac-
etonitrile/water (5:95)/0.05% NH4OAc in acetonitrile/water (95:5)
at 1.2 mL/min; %B = 0 min 35%, 2 min 35%, 10 min 50%, 15 min
100%, stop time = 19 min), giving retention times of 9.2 min (minor
S enantiomer) and 10.2 min (major R enantiomer). The absolute
stereochemistry was assumed by analogy.
Methyl (R)-3-phenylbutanoate, (22c).34 Prepared according to
the general procedure on 2 mmol scale with 2 mol% Yb(OTf)3 at
60 °C (1 h) to give 22c (353 mg) as colorless oil in 99% yield and
>99% ee from 21c. 1H NMR (400 MHz, chloroform-d) δ 7.42–7.22
(m, 5H), 3.66 (s, 3H), 3.48–3.27 (m, 1H), 2.75–2.56 (m, 2H), 1.34
(d, J = 7.1 Hz, 3H); 13C{H} NMR (101 MHz, chloroform-d) δ
172.8, 145.7, 128.5, 126.7, 126.4, 51.5, 42.7, 36.4, 21.7.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Methyl-d3 (S)-2-methyl-3-phenylpropanoate (23). Prepared ac-
cording to the general procedure on 2 mmol scale with 2 mol%
Yb(OTf)3 at 20 °C (10 h) to give 23 (355 mg) as colorless oil in
98% yield and >99% ee from 9. 1H NMR (400 MHz, chloroform-
d) δ 7.34–7.13 (m, 5H), 3.02 (dd, J = 13.0, 6.4 Hz, 1H), 2.80–2.62
(m, 2H), 1.14 (d, J = 6.8 Hz, 3H); 13C{H} NMR (101 MHz, chlo-
roform-d) δ 176.6, 139.3, 128.9, 128.3, 126.3, 77.0, 41.4, 39.7,
16.7; IR (film) vmax 3449, 3029, 2976, 2936, 2879, 1732, 1496,
1455, 1366, 1291, 1219, 1188, 1088 cm-1; HRMS (DCI-CH4) m/z:
Methyl
(2S,3R)-3-(4-bromophenyl)-2-methyl-3-((4-
[M+H]+ calcd for C11H12D3O2 181.1182; found 181.1185; [α]20
D
methylphenyl)sulfonamido)propanoate (22d). Prepared according
to the general procedure on 2 mmol scale with 2 mol% Yb(OTf)3
at 60 °C (8 h) to give 22d (657 mg) as colorless oil in 77% yield
and >99% ee from 21d. 1H NMR (400 MHz, chloroform-d) δ 7.47
(br d, J = 8.1 Hz, 2H), 7.26–7.18 (m, 2H), 7.07 (br d, J = 8.3 Hz,
2H), 6.89 (br d, J = 8.3 Hz, 2H), 6.23 (br d, J = 9.1 Hz, 1H), 4.47
(br dd, J = 9.1, 6.8 Hz, 1H), 3.59 (s, 3H), 2.90–2.75 (m, 1H), 2.35
(s, 3H), 1.12 (d, J = 7.1 Hz, 3H); 13C{H} NMR (101 MHz, chloro-
form-d) δ 174.7, 143.1, 137.7, 137.5, 131.3, 129.2, 128.4, 126.9,
121.4, 59.7, 52.0, 45.7, 21.4, 15.2; IR (film) vmax 3270, 3067, 3047,
2947, 2920, 1737, 1705, 1491, 1448, 1335, 1265, 1106 cm-1;
HRMS (ESI-TOF) m/z: [M+H]+ calcd for C18H21BrNO4S
+25.9 (c 1.415, CHCl3). Enantioselectivity was determined by
HPLC analysis using a Phenomenex Lux Cellulose-1 column at 25
°C (Solvent A/B = Heptane/iPrOH at 0.7 mL/min; %B = 0 min
3%, 2 min 3%, 3 min 60%, 9 min 60%, stop time = 9 min), giving
retention times of 4.86 min (minor R enantiomer) and 4.10 min (S
enantiomer). The absolute stereochemistry was assumed by anal-
ogy.
(S)-N-allyl-2-methyl-3-phenylpropanamide (25a). Prepared ac-
cording to procedure A on 0.62 mmol scale at 40 °C (4 h) to give
(S)-25a (97 mg) as a white solid in 77% yield and >99 ee% from
24. 1H NMR (500 MHz, Chloroform-d) δ 7.29 – 7.26 (m, 2H), 7.21
– 7.16 (m, 3H), 5.68 (ddt, J = 17.2, 10.3, 5.7 Hz, 1H), 5.23 (s, 1H),
5.03 (dq, J = 10.3, 1.4 Hz, 1H), 4.99 (dq, J = 17.1, 1.6 Hz, 1H),
3.84 – 3.73 (m, 2H), 2.97 (dd, J = 13.4, 8.4 Hz, 1H), 2.68 (dd, J =
13.4, 6.5 Hz, 1H), 2.47 - 2.40 (m, 1H), 1.21 (d, J = 6.9 Hz, 3H).
13C{H} NMR (126 MHz, Chloroform-d) δ 175.4, 140.0, 134.3,
129.1, 128.5, 126.4, 116.3, 44.2, 41.8, 40.7, 17.9. Spectral data
matches that of previously reported.22c HRMS (ESI-TOF) m/z:
[M+H]+ calcd for C13H18NO 204.1383; found 204.1386. Enantiose-
lectivity was determined by HPLC analysis using Chiral Cel OJ-
RH 5 µm 4.6 x 150 mm column at 30 °C (Solvent A/B= 0.1% for-
mic acid in H2O/MeOH (1:1.2) stop time = 20 min), giving reten-
tion of 12.18 min (major S enantiomer) and 13.21 min (minor R
enantiomer). The absolute stereochemistry was assumed by anal-
ogy.
428.0350; found 428.0363; [α]20 +61.6 (c 0.525, CHCl3); mp:
D
119.3 °C (DSC). Enantioselectivity was determined by HPLC anal-
ysis using a Phenomenex Lux Cellulose-3 3 µm 4.6 x 150 mm col-
umn at 30 °C (Solvent A/B = 0.05% TFA in MeOH/Water
(1:4)/0.05% TFA in MeOH/acetonitrile (1:4) at 1.2 mL/min; %B =
0 min 30%, 2 min 30%, 11 min 51%, 14 min 100%, 18 min = 100%
stop time = 18 min), giving retention times of 9.88 min (major
2S/3R diastereomer) and 10.55 min (minor 2R/3R diastereomer).
The absolute stereochemistry was assumed by analogy.
Methyl
(2S,3R)-3-(4-fluorophenyl)-3-hydroxy-2-methylpro-
panoate, (22e).36 Prepared according to the general procedure on 2
mmol scale with 2 mol% Yb(OTf)3 20 °C (24 h) to give 22e (221
mg) as white solids in 52% yield and >99% ee from 21e. 1H NMR
(400 MHz, chloroform-d) δ 7.38–7.25 (m, 2H), 7.10–7.01 (m, 2H),
4.75 (dd, J = 8.3, 4.3 Hz, 1H), 3.74 (s, 3H), 3.06 (br s, 1H), 2.84–
2.72 (m, 1H), 1.01 (d, J = 7.1 Hz, 3H); 13C{H} NMR (101 MHz,
chloroform-d) δ 176.1, 163.7, 161.2, 137.3, 137.3, 128.3, 128.2,
(S)-2-methyl-3-phenyl-N-propylpropanamide (25b). Prepared
according to procedure A on 0.62 mmol scale at 40 °C (4 h) to give
(S)-25 (92 mg) as a white solid in 73% yield and >99 ee% from 24.
1H NMR (500 MHz, Chloroform-d) δ 7.28 – 7.25 (m, 2H), 7.21 –
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2H), 7.20 – 7.13 (m, 3H), 5.60 (s, 1H), 3.38 – 3.26 (m, 3H), 3.24
7.16 (m, 3H), 5.14 (s, 1H), 3.18 – 3.02 (m, 2H), 2.95 (dd, J = 13.4,
1
2
3
4
5
6
7
8
8.5 Hz, 1H), 2.68 (dd, J = 13.5, 6.4 Hz, 1H), 2.44 - 2.34 (m, 1H),
1.39 – 1.31 (m, 2H), 1.18 (d, J = 6.8 Hz, 3H), 0.78 (t, J = 7.4 Hz,
3H). 13C{H} NMR (126 MHz, Chloroform-d) δ 175.8, 140.4,
129.4, 128.8, 126.6, 44.5, 41.4, 41.0, 23.1, 18.2, 11.6. HRMS (ESI-
TOF) m/z: [M+H]+ calcd for C13H20NO 206.1539; found 206.1542.
Enantioselectivity was determined by HPLC analysis using Chiral
Cel OJ-RH 5 µm 4.6 x 150 mm column at 30 °C (Solvent A/B=
0.1% formic acid in H2O/MeOH (1:1.9) stop time = 10 min), giving
retention of 5.36 min (major S enantiomer) and 5.94 min (minor R
enantiomer). The absolute stereochemistry was assumed by anal-
ogy.
(s, 3H), 3.22 – 3.20 (m, 1H), 2.94 (dd, J = 13.5, 8.3 Hz, 1H), 2.66
(dd, J = 13.5, 6.6 Hz, 1H), 2.47 – 2.39 (m, 1H), 1.18 (d, J = 6.9 Hz,
3H). 13C{H} NMR (126 MHz, Chloroform-d) δ 175.7, 140.0,
129.1, 128.5, 126.4, 71.3, 58.8, 44.0, 40.6, 39.0, 17.8. Spectral data
matches that of previously reported.22b HRMS (ESI-TOF) m/z:
[M+H]+ calcd for C13H20NO2 222.1489; found 222.1491. Enanti-
oselectivity was determined by HPLC analysis using Chiral Cel OJ-
RH 5 µm 4.6 x 150 mm column at 30 °C (Solvent A/B= 0.1% for-
mic acid in H2O/MeOH (1:1.9) stop time = 10 min), giving reten-
tion of 4.06 min (major S enantiomer) and 4.55 min (minor R en-
antiomer). The absolute stereochemistry was assumed by analogy.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(S)-2-methyl-3-phenyl-N-(prop-2-yn-1-yl)propenamide (25c).
Prepared according to procedure A on 0.53 mmol scale at 40 °C (4
h) to give (S)-25c (74 mg) as a white solid in 70% yield and >99
ee% from 24.1H NMR (500 MHz, Chloroform-d) δ 7.29 – 7.25 (m,
3H), 7.22 – 7.15 (m, 2H), 5.35 (s, 1H), 4.06 – 3.89 (m, 2H), 2.98
(dd, J = 13.5, 8.1 Hz, 1H), 2.68 (dd, J = 13.5, 6.7 Hz, 1H), 2.47 –
2.40 (m, 1H), 2.18 (t, J = 2.6 Hz, 1H), 1.19 (d, J = 6.8 Hz, 3H).
13C{H} NMR (126 MHz, Chloroform-d) δ 175.3, 139.8, 129.1,
128.6, 126.5, 79.6, 71.7, 43.8, 40.5, 29.2, 17.6. HRMS (ESI-TOF)
m/z: [M+H]+ calcd for C13H16NO 202.1226; found 202.1231. En-
antioselectivity was determined by HPLC analysis using Chiral Cel
OJ-RH 5 µm 4.6 x 150 mm column at 30 °C (Solvent A/B= 0.1%
formic acid in H2O/MeOH (1:4) stop time = 10 min), giving reten-
tion of 3.20 min (major S enantiomer) and 3.51 min (minor R en-
antiomer). The absolute stereochemistry was assumed by analogy.
(S)-N-(3-ethoxypropyl)-2-methyl-3-phenylpropanamide (25g).
Prepared according to procedure A on 0.62 mmol scale at 40 °C (12
h) to give (S)-25g (98 mg) as a white solid in 63% yield and >99
ee% from 24. 1H NMR (500 MHz, Chloroform-d) δ 7.28 – 7.24 (m,
2H), 7.20 – 7.13 (m, 3H), 5.92 (s, 1H), 3.43 – 3.30 (m, 4H), 3.30 –
3.26 (m, 2H), 2.97 (dd, J = 13.4, 8.0 Hz, 1 H), 2.66 (dd, J = 13.4,
6.8 Hz, 1H), 2.42 – 2.35 (m, 1H), 1.70 – 1.57 (m, 2H), 1.17 (d, J =
7.0 Hz, 3H), 1.15 (t, J = 3.6 Hz, 3H). 13C{H} NMR (126 MHz,
Chloroform-d) δ 175.5, 140.1, 129.1, 128.5, 126.3, 69.9, 66.5, 44.1,
40.7, 38.4, 29.0, 17.6, 15.4. HRMS (ESI-TOF) m/z: [M+H]+ calcd
for C15H24NO2 250.1802; found 250.1805. Enantioselectivity was
determined by HPLC analysis using Chiral Cel OJ-RH 5 µm 4.6 x
150 mm column at 30 °C (Solvent A/B= 0.1% formic acid in
H2O/MeOH (1:1.9) stop time = 10 min), giving retention of 5.09
min (major S enantiomer) and 5.77 min (minor R enantiomer). The
absolute stereochemistry was assumed by analogy.
(S)-N-benzyl-2-methyl-3-phenylpropanamide (25d). Prepared
according to procedure A on 0.62 mmol scale at 80 °C (12 h) to
give (S)-25d (114 mg) as a white solid in 73% yield and >99 ee%
from 24. 1H NMR (500 MHz, Chloroform-d) δ 7.28 – 7.16 (m, 8H),
7.05 – 7.00 (m, 2H), 5.44 (s, 1H), 4.40 (dd, J = 14.7, 6.0 Hz, 1H),
4.29 (dd, J = 14.7, 5.3 Hz, 1H), 2.99 (dd, J = 13.4, 8.7 Hz, 1H),
2.72 (dd, J = 13.4, 6.2 Hz, 1H), 2.50 – 2.42 (m, 1H), 1.22 (d, J =
6.8 Hz, 3H). 13C{H} NMR (126 MHz, Chloroform-d) δ 175.4,
140.0, 138.3, 129.1, 128.7, 128.6, 127.8, 127.5, 126.4, 44.3, 43.5,
40.7, 18.0. Spectral data matches that of previously reported.22a
HRMS (ESI-TOF) m/z: [M+H]+ calcd for C17H20NO 254.1539;
found 254.1542. Enantioselectivity was determined by HPLC anal-
ysis using Chiral Cel OJ-RH 5 µm 4.6 x 150 mm column at 30 °C
(Solvent A/B= 0.1% formic acid in H2O/MeOH (1:4) stop time =
10 min), giving retention of 5.98 min (major S enantiomer) and
7.43 min (minor R enantiomer). The absolute stereochemistry was
assumed by analogy.
(S)-N-(but-3-en-1-yl)-2-methyl-3-phenylpropanamide
(25h).
Prepared according to procedure B on 0.53 mmol scale at 40 °C (12
h) to give (S)-25h (66 mg) as a white solid in 57% yield and 98
ee% from 24. 1H NMR (500 MHz, Chloroform-d) δ 7.29 – 7.26 (m,
2H), 7.21 – 7.15 (m, 3H), 5.61 (ddt, J = 17.1, 10.2, 6.8 Hz, 1H),
5.19 (s, 1H), 5.00 (dq, J = 10.2, 2.2, 1.2 Hz, 1H), 4.96 (dq, J = 17.1,
1.6 Hz, 1H), 3.30 – 3.15 (m, 2H), 2.95 (dd, J = 13.4, 8.5 Hz, 1H),
2.66 (dd, J = 13.4, 6.4 Hz, 1H), 2.42 - 2.35 (m, 1H), 2.17 – 2.02 (m,
2H), 1.17 (d, J = 6.9 Hz, 3H). 13C{H} NMR (126 MHz, Chloro-
form-d) δ 175.5, 140.1, 135.4, 129.1, 128.5, 126.4, 117.2, 44.2,
40.7, 38.2, 33.8, 17.9. HRMS (ESI-TOF) m/z: [M+H]+ calcd for
C14H20NO 218.1539; found 218.1542. Enantioselectivity was de-
termined by HPLC analysis using Chiral Cel OJ-RH 5 µm 4.6 x
150 mm column at 30 °C (Solvent A/B= 0.1% formic acid in
H2O/MeOH (1:1.9) stop time = 10 min), giving retention of 6.84
min (major S enantiomer) and 7.55 min (minor R enantiomer). The
absolute stereochemistry was assumed by analogy.
(S)-N-(3-hydroxypropyl)-2-methyl-3-phenylpropanamide (25e).
Prepared according to procedure A on 0.62 mmol scale at 40 °C (4
h) to give (S)-25e (97 mg) as a white solid in 70% yield and >99
ee% from 24. 1H NMR (500 MHz, Chloroform-d) δ 7.28-7.20 (m,
3H), 7.19 – 7.14 (m, 2H), 5.56 (s, 1H), 3.46 – 3.33 (m, 2H), 3.28 –
3.22 (m, 2H), 2.97 – 2.90 (m, 2H), 2.71 (dd, J = 13.5, 6.2 Hz, 1H),
2.49 – 2.42 (m, 1H), 1.56 – 1.47 (m, 2H), 1.22 (d, J = 6.8 Hz, 3H).
13C{H} NMR (126 MHz, Chloroform-d) δ 177.2, 140.2, 129.4,
128.8, 126.7, 59.5, 44.5, 40.9, 36.4, 32.6, 18.4. HRMS (ESI-TOF)
m/z: [M+H]+ calcd for C13H20NO2 222.1489; found 222.1492. En-
antioselectivity was determined by HPLC analysis using Chiral Cel
OJ-RH 5 µm 4.6 x 150 mm column at 30 °C (Solvent A/B= 0.1%
formic acid in H2O/MeOH (1:1) stop time = 10 min), giving reten-
tion of 5.42 min (major S enantiomer) and 5.99 min (minor R en-
antiomer). The absolute stereochemistry was assumed by analogy.
(S)-2-methyl-N-phenethyl-3-phenylpropanamide (25i). Prepared
according to procedure B on 0.62 mmol scale at 40 °C (12 h) to
give (S)-25i (101 mg) as a white solid in 61% yield and 98 ee%
from 24. 1H NMR (500 MHz, Chloroform-d) δ 7.29 – 7.21 (m, 4H),
7.21 – 7.15 (m, 4H), 7.01 (d, 2H), 5.17 (s, 1H), 3.52 – 3.45 (m, 1H),
3.37 – 3.31 (m, 1H), 2.95 (dd, J = 13.4, 8.5 Hz, 1H), 2.73 - 2.63 (m,
2H), 2.61 - 2.55 (m, 1H), 2.37 – 2.30 (m, 1H), 1.16 (d, J = 6.8 Hz,
3H). 13C{H}C NMR (126 MHz, Chloroform-d) δ 175.8, 140.4,
139.3, 129.4, 129.1, 129.0, 128.8, 126.8, 126.7, 44.5, 40.9, 40.8,
36.1, 18.2. HRMS (ESI-TOF) m/z: [M+H]+ calcd for C18H22NO
268.1696; found 268.1701. Enantioselectivity was determined by
HPLC analysis using Chiral Pak AY-H 5 µm 4.6 x 250 mm column
at 30 °C (Solvent A/B= hexanes/iPrOH (3:1) stop time = 11 min),
giving retention of 9.78 min (major S enantiomer) and 9.36 min
(minor R enantiomer). The absolute stereochemistry was assumed
by analogy.
(S)-N-(2-methoxyethyl)-2-methyl-3-phenylpropanamide (25f).
Prepared according to procedure A on 0.62 mmol scale at 40 °C (12
h) to give (S)-25f (61 mg) as a colorless oil in 45% yield and >99
ee% from 24. 1H NMR (500 MHz, Chloroform-d) δ 7.28 – 7.23 (m,
(S)-N-(2-(ethylthio)ethyl)-2-methyl-3-phenylpropanamide (25j).
Prepared according to procedure B on 0.62 mmol scale at 40 °C (12
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h) to give (S)-25j (82 mg) as a white solid in 53% yield and 98 ee% (S)-N-(2-chlorobenzyl)-2-methyl-3-phenylpropanamide (25n).
1
2
3
4
5
6
7
8
from 24. 1H NMR (500 MHz, Chloroform-d) δ 7.27 – 7.24 (m, 2H),
7.20 – 7.15 (m, 3H), 5.73 (s, 1H), 3.38 – 3.24 (m, 2H), 2.94 (dd, J
= 13.4, 8.5 Hz, 1H), 2.67 (dd, J = 13.4, 6.5 Hz, 1H), 2.57 – 2.52
(m, 1H), 2.47 – 2.38 (m, 4H), 1.21 (t, J = 7.4 Hz, 3 H), 1.18 (d, J
= 6.8 Hz, 3H). 13C{H} NMR (126 MHz, Chloroform-d) δ 175.6,
139.9, 129.0, 128.5, 126.4, 43.9, 40.6, 38.1, 31.3, 25.4, 17.7, 14.8.
HRMS (ESI-TOF) m/z: [M+H]+ calcd for C14H22NOS 252.1417;
found 252.1426. Enantioselectivity was determined by HPLC anal-
ysis using Chiral Cel OJ-RH 5 µm 4.6 x 150 mm column at 30 °C
(Solvent A/B= 0.1% formic acid in H2O/MeOH (1:4) stop time =
12 min), giving retention of 3.81 min (major S enantiomer) and
4.59 min (minor R enantiomer). The absolute stereochemistry was
assumed by analogy.
Prepared according to procedure A on 0.62 mmol scale at 80 °C (12
h) to give (S)-25n (126 mg) as a white solid in 71% yield and 97
ee% from 24. 1H NMR (500 MHz, Chloroform-d) δ 7.32 – 7.24 (m,
2H), 7.21 – 7.07 (m, 7H), 5.61 (s, 1H), 4.51 – 4.34 (m, 2H), 2.95
(dd, J = 13.5, 8.7 Hz, 1H), 2.70 (dd, J = 13.5, 6.1 Hz, 1H), 2.53 -
2.42 (m, 1H), 1.22 (d, J = 6.8 Hz, 3H). 13C{H} NMR (126 MHz,
Chloroform-d) δ 175.8, 140.1, 136.0, 133.9, 130.4, 129.8, 129.3,
129.1, 128.8, 127.4, 126.7, 44.4, 41.6, 40.9, 18.2. HRMS (ESI-
TOF) m/z: [M+H]+ calcd for C17H19ClNO 288.1150; found
288.1155. Enantioselectivity was determined by HPLC analysis us-
ing Chiral Cel OJ-RH 5 µm 4.6 x 150 mm column at 30 °C (Solvent
A/B= 0.1% formic acid in H2O/MeOH (1:4) stop time = 10 min),
giving retention of 6.34 min (major S enantiomer) and 7.16 min
(minor R enantiomer). The absolute stereochemistry was assumed
by analogy.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(S)-N-(cyclohexylmethyl)-2-methyl-3-phenylpropanamide
(25k). Prepared according to procedure A on 0.62 mmol scale at 40
°C (12 h) to give (S)-25k (119 mg) as a colorless oil in 46% yield
and >99 ee% from 24. 1H NMR (500 MHz, Chloroform-d) δ 7.28
– 7.25 (m, 2H), 7.20 – 7.16 (m, 3H), 5.18 (s, 1H), 3.07 - 3.02 (m,
1H), 2.96 – 2.87 (m, 2H), 2.68 (dd, J = 13.5, 6.1 Hz, 1H), 2.44 –
2.37 (m, 1H), 1.67 – 1.59 (m, 3H), 1.52 – 1.41 (m, 2H), 1.31 – 1.22
(m, 1H), 1.19 (d, J = 6.9 Hz, 3H), 1.15 – 1.05 (m, 3H), 0.80 – 0.72
(m, 2H). 13C{H} NMR (126 MHz, Chloroform-d) δ 175.2, 139.9,
128.8, 128.3, 126.1, 45.4, 44.1, 40.5, 37.7, 30.6, 30.5, 26.2, 25.7,
25.7, 17.8. HRMS (ESI-TOF) m/z: [M+H]+ calcd for C17H26NO
260.2009; found 260.2014. Enantioselectivity was determined by
HPLC analysis using Chiral Cel OJ-RH 5 µm 4.6 x 150 mm column
at 30 °C (Solvent A/B= 0.1% formic acid in H2O/MeOH (1:4) stop
time = 12 min), giving retention of 3.73 min (major S enantiomer)
and 4.85 min (minor R enantiomer). The absolute stereochemistry
was assumed by analogy.
(S)-2-methyl-3-phenyl-N-(thiophen-2-ylmethyl)propenamide
(25o). Prepared according to procedure A on 0.62 mmol scale at 80
°C (12 h) to give (S)-25o (119 mg) as a white solid in 74% yield
and >99 ee% from 24. 1H NMR (500 MHz, Acetone-d6) δ 7.46 (s,
1H), 7.27 – 7.14 (m, 6H), 6.89 (dd, J = 5.1, 3.5 Hz, 1H), 6.84 (dq,
J = 3.4, 1.0 Hz, 1H), 4.50 (dd, J = 5.9, 1.0 Hz, 2H), 3.03 – 2.96 (m,
1H), 2.66 – 2.57 (m, 2H), 1.09 (d, J = 6.6 Hz, 3H). 13C{H} NMR
(126 MHz, Chloroform-d) δ 175.0, 140.7, 139.6, 128.8, 128.3,
126.7, 126.2, 125.8, 125.0, 43.7, 43.6, 40.3, 38.0, 17.5. HRMS
(ESI-TOF) m/z: [M+H]+ calcd for C15H18NOS 260.1104; found
260.1111. Enantioselectivity was determined by HPLC analysis us-
ing Chiral Cel OJ-RH 5 µm 4.6 x 150 mm column at 30 °C (Solvent
A/B= 0.1% formic acid in H2O/MeOH (1:4) stop time = 12 min),
giving retention of 6.02 min (major S enantiomer) and 7.97 min
(minor R enantiomer). The absolute stereochemistry was assumed
by analogy.
(S)-N-(4-methoxyphenyl)-2-methyl-3-phenylpropanamide (25l).
Prepared according to procedure A on 0.62 mmol scale at 80 °C (24
h) to give (S)-25l (36 mg) as a white solid in 22% yield and >99
ee% from 24. 1H NMR (500 MHz, Chloroform-d) δ 7.30 – 7.24 (m,
3H), 7.24 – 7.20 (m, 4H), 6.81 (d, 2H), 3.77 (s, 3H), 3.03 (dd, J =
13.5, 8.6 Hz, 1H), 2.76 (dd, J = 13.5, 6.2 Hz, 1H), 2.59 – 2.52 (m,
1H), 1.27 (d, J = 6.8 Hz, 3H). 13C{H} NMR (126 MHz, Chloro-
form-d) δ 173.8, 156.5, 139.9, 130.8, 129.1, 128.7, 126.6, 122.1,
114.2, 55.6, 44.9, 40.8, 17.9. HRMS (ESI-TOF) m/z: [M+H]+ calcd
for C17H20NO2 270.1489; found 270.1494. Enantioselectivity was
determined by HPLC analysis using Chiral Cel OJ-RH 5 µm 4.6 x
150 mm column at 30 °C (Solvent A/B= 0.1% formic acid in
H2O/MeOH (1:4) stop time = 12 min), giving retention of 7.49 min
(major S enantiomer) and 8.14 min (minor R enantiomer). The ab-
solute stereochemistry was assumed by analogy.
(S)-2-methyl-N-(2-morpholinoethyl)-3-phenylpropanamide
(25p). Prepared according to procedure A on 0.62 mmol scale at 40
°C (12 h) to give (S)-25p (82.3 mg) as a white solid in 48% yield
and 95% ee from 24. 1H NMR (500 MHz, Chloroform-d) δ 7.27 –
7.24 (m, 3H), 7.19 – 7.16 (m, 2H), 5.70 (s, 1H), 3.64 – 3.56 (m,
4H), 3.23 – 3.18 (m, 2H), 2.92 (dd, J = 13.4, 8.9 Hz, 1H), 2.70 (dd,
J = 13.4, 6.1 Hz, 1H), 2.48 – 2.41 (m, 1H), 2.38 – 2.31 (m, 3H),
2.27 – 2.21 (m, 3H), 1.19 (d, J = 6.8 Hz, 3H). 13C{H} NMR (126
MHz, Chloroform-d) δ 175.3, 139.9, 128.8, 128.2, 126.0, 66.8,
56.5, 52.9, 43.8, 40.6, 35.1, 17.6. HRMS (ESI-TOF) m/z: [M+H]+
calcd for C16H25N2O2 277.1911; found 277.1921. Enantioselectiv-
ity was determined by HPLC analysis using Chiralpak IG-3 3 µm
4.6 x 150 mm column at 30 °C (Solvent A = 0.1% H4NOAc in ac-
etonitrile/water (1:20), Solvent B = 0.1% H4NOAc in acetoni-
trile/water (20:1) at 1.2 mL/min; %B = 0 min 20%, 2 min 20%, 8
min 30%, 10 min 100%, stop time = 13 min), giving retention of
5.66 min (major S enantiomer) and 5.24 min (minor R enantiomer).
The absolute stereochemistry was assumed by analogy
(S)-N-(furan-2-ylmethyl)-2-methyl-3-phenylpropanamide
(25m). Prepared according to procedure A on 0.62 mmol scale at
40 °C (12 h) to give (S)-25m (100 mg) as a white solid in 66% yield
1
and >99 ee% from 24. H NMR (500 MHz, Chloroform-d) δ 7.31
- 7.12 (m, 6H), 6.28 (dd, J = 3.2, 1.9 Hz, 1H), 6.08 (dd, J = 3.2, 0.8
Hz, 1H), 5.48 (s, 1H), 4.36 (d, J = 5.5 Hz, 2H), 2.97 (dd, J = 13.5,
8.2 Hz, 1H), 2.69 (dd, J = 13.5, 6.5 Hz, 1H), 2.47 – 2.40 (m, 1H),
1.20 (d, J = 6.8 Hz, 3H). 13C{H} NMR (126 MHz, Chloroform-d)
δ 175.4, 151.4, 142.2, 139.9, 129.1, 128.6, 126.4, 110.5, 107.4,
43.9, 40.6, 36.5, 17.8. HRMS (ESI-TOF) m/z: [M+H]+ calcd for
C15H18NO2 244.1332; found 244.1337. Enantioselectivity was de-
termined by HPLC analysis using Chiral Cel OJ-RH 5 µm 4.6 x
150 mm column at 30 °C (Solvent A/B= 0.1% formic acid in
H2O/MeOH (1:4) stop time = 10 min), giving retention of 4.02 min
(major S enantiomer) and 5.13 min (minor R enantiomer). The ab-
solute stereochemistry was assumed by analogy.
(S)-2-methyl-3-phenyl-N-(pyridin-3-ylmethyl)propenamide
(25q). Prepared according to procedure A on 0.62 mmol scale at 80
°C (12 h) to give (S)-25q (70 mg) as a white solid in 43% yield
(corrected for 3 wt% EtOAc) and 96 ee% from 24. 1H NMR (500
MHz, Chloroform-d) δ 8.34 (d, J = 69.9 Hz, 2H), 7.31 – 7.11 (m,
7H), 5.56 (s, 1H), 4.44 (dd, J = 15.1, 6.4 Hz, 1H), 4.23 (dd, J =
15.1, 5.5 Hz, 1H), 2.95 (dd, J = 13.4, 9.1 Hz, 1H), 2.73 (dd, J =
13.4, 6.0 Hz, 1H), 2.51 – 2.44 (m, 1H), 1.24 (d, J = 6.8 Hz, 3H).
13C{H} NMR (126 MHz, Chloroform-d) δ 175.4, 148.8, 148.6,
139.6, 135.4, 133.8, 128.8, 128.4, 126.3, 123.4, 44.0, 40.7, 40.5,
17.8. HRMS (ESI-TOF) m/z: [M+H]+ calcd for C16H19N2O
255.1492; found 255.1497. Enantioselectivity was determined by
HPLC analysis using Chiral Cel OJ-RH 5 µm 4.6 x 150 mm column
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The Journal of Organic Chemistry
at 30 °C (Solvent A/B= 0.1% formic acid in H2O/MeOH (1:1.9)
TOF) m/z: [M+H]+ calcd for C19H31FNO2Si 352.2103; found
352.2103.
(2R)-2-methyl-3-phenyl-propanoic acid (26).37 Prepared ac-
1
2
3
4
5
6
7
8
stop time = 10 min), giving retention of 3.19 min (major S enanti-
omer) and 3.62 min (minor R enantiomer). The absolute stereo-
chemistry was assumed by analogy.
cording to the general esterification procedure on 15.5 mmol scale
with 0.5 mol% Yb(OTf)3 at 60 °C (3 h). The solvent was then re-
moved by evaporation and diluted with a tetrahydrofuran/water
mixture (3:1 vol/vol, 110 mL) and treated with lithium hydroxide
(0.56 g, 23.3 mmol) and stirred at 23 °C for 2 h. The reaction mix-
ture was treated with conc. HCl to bring the pH to 4.0 and the mix-
ture was diluted with saturated aqueous ammonium chloride (100
mL) and the layers were separated. The organic layer was washed
with saturated aqueous sodium chloride (100 mL), dried over mag-
nesium sulfate, filtered, and concentrated to crude oil. The oil was
purified by silica gel chromatography (10–100% ethyl acetate/hex-
anes) to give 26 (2.46 g, 15.0 mmol) as colorless oil in 97% yield
and >99% ee and 16 (2.65 g, 14.94 mmol) as white solids from 4.
(S)-N-(benzyloxy)-2-methyl-3-phenylpropanamide (25r). Pre-
pared according to procedure A on 0.62 mmol scale at 40 °C (12 h)
to give (S)-25r (112 mg) as a white solid in 67% yield and 99 ee%
from 24. 1H NMR (500 MHz, Chloroform-d) δ 7.61 (s, 1H), 7.33 –
7.24 (m, 5H), 7.22 – 7.16 (m, 5H), 4.83 (d, J = 11.5 Hz, 1H), 4.66
(d, J = 11.4 Hz, 1H), 2.97 (dd, J = 13.5, 9.2 Hz, 1H), 2.67 (dd, J =
13.5, 5.8 Hz, 1H), 2.24 (s, 1H), 1.19 (d, J = 6.8 Hz, 3H). 13C NMR
(126 MHz, Chloroform-d) δ 129.7, 129.4, 129.1, 128.9, 126.9,
78.6, 41.3, 40.5, 18.2. HRMS (ESI-TOF) m/z: [M+H]+ calcd for
C17H20NO2 270.1489; found 270.1493. Enantioselectivity was de-
termined by HPLC analysis using Chiral Cel OJ-RH 5 µm 4.6 x
150 mm column at 30 °C (Solvent A/B= 0.1% formic acid in
H2O/MeOH (1:1) stop time = 30 min), giving retention of 25.93
min (major S enantiomer) and 28.01 min (minor R enantiomer).).
The absolute stereochemistry was assumed by analogy.
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25
26
27
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Spectral data matches that as previously reported. H NMR (400
MHz, chloroform-d) δ 7.40 - 7.20 (m, 5H), 3.13 (dd, J = 13.4, 6.3
Hz, 1H), 2.89 - 2.76 (m, 1H), 2.76 - 2.68 (m, 1H), 1.23 (d, J = 6.8
Hz, 3H); Enantioselectivity was determined by HPLC analysis us-
ing a Chiralcel OJ-3 3 µm 4.6 x 150 mm column at 30 °C (Solvent
A/B = Heptane/iPrOH at 1.0 mL/min; %B = 1% isocratic, stop time
= 37 min), giving retention times of 15.3 min (major R enantiomer)
and 18.3 min (minor S enantiomer). The absolute stereochemistry
was assumed by analogy.
methyl (S)-(2-methyl-3-phenylpropanoyl)glycinate (25s). Pre-
pared according to procedure B on 0.62 mmol scale at 80 °C (12 h)
to give (S)-25s (59 mg) as a white solid in 40% yield and 85 ee%
1
from 24. H NMR (500 MHz, Chloroform-d) δ 7.29 - 7.24 (m, 2
H), 7.21 – 7.14 (m, 3H), 5.77 (s, 1H), 4.04 (dd, J = 18.4, 5.4 Hz,
1H), 3.91 (dd, J = 18.5, 4.8 Hz, 1H), 3.73 (s, 2H), 3.00 (dd, J =
13.5, 7.7 Hz, 1H), 2.68 (dd, J = 13.5, 7.1 Hz, 1H), 2.53 (h, J = 7.1
Hz, 1H), 1.20 (d, J = 6.9 Hz, 3H). 13C NMR (126 MHz, Chloro-
form-d) δ 176.1, 170.8, 140.0, 129.3, 128.8, 126.7, 52.7, 43.8, 41.5,
40.6, 17.9. HRMS (ESI-TOF) m/z: [M+H]+ calcd for C13H18NO3
236.1281; found 236.1282. Enantioselectivity was determined by
HPLC analysis using Chiral Cel OJ-RH 5 µm 4.6 x 150 mm column
at 30 °C (Solvent A/B= 0.1% formic acid in H2O/MeOH (4:1) stop
time = 10 min), giving retention of 2.86 min (major S enantiomer)
and 3.16 min (minor R enantiomer).). The absolute stereochemistry
was assumed by analogy.
(R)-2-((1S,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanoic
acid (27) To an inert 5 L reaction vessel was added 1 (100 g, 224
mmol) followed by a prepared solution of 3:1 methanol/trime-
thylorthoformate (2.9 L, 0.32 wt% water by Karl Fischer titration).
The reaction mixture was heated to 45 °C then treated trifluoro-
methanesulfonic acid (0.8 mL, 9 mmol) and aged for 45 min. The
reaction mixture was then heated to 60 °C internal temperature and
treated with a prepared solution of yttrium trifluoromethanesul-
fonate (2.43 g, 448 mmol) in 3:1 methanol/trimethylorthofor-
mate solution (100 mL) and aged for 2 h. The reaction was cooled
to 40 °C and the solvent was removed in vacuo. The concentrated
reaction mass was treated with dimethylacetamide (500
mL) and warmed to 45 °C. The reaction mixture was treated
with 5N NaOH (135 mL, 680 mmol) over 10 min, aged for 16 h,
then quenched by the addition of 50 wt% citric acid aqueous solu-
tion (250 mL). The temperature was raised to 70 °C, treated with
water (250 mL) over 40 min, then cooled to 20 °C over 6 h and held
at 20 °C for an additional 12 h. The product was isolated by filtra-
tion and the wet cake was washed with 1:1 DMAc/water (500 mL)
followed by 1:3 acetonitrile/water (600 mL) and dried in a 50
°C vacuum oven for 18 h to afford 27 (57.3 g, 190 mmol) as a light
tan solid in 85% yield. 1H NMR (600 MHz, DMSO-d6) δ 12.09 (s,
1H), 8.80 (d, J = 4.5 Hz, 1H), 8.06 (dd, J = 9.2, 5.8 Hz, 1H), 7.91
(dd, J = 10.9, 2.8 Hz, 1H), 7.61 (ddd, J = 9.1, 8.2, 2.8 Hz, 1H), 7.45
(d, J = 4.5 Hz, 1H), 3.41-3.27 (m, 1H), 2.72 - 2.63 (m, 1H), 1.86 -
1.61 (m, 9H), 1.08 (d, J = 6.8 Hz, 3H); 13C{H} NMR (101 MHz,
DMSO-d6) δ 177.7, 159.9 (d, J = 245.4 Hz, 1C), 152.2, 149.8,
145.1, 132.6 (d, J = 10.1 Hz, 1C), 127.2 (d, J = 10.1 Hz, 1C), 118.9
(d, J = 26.3 Hz, 1C), 118.7, 107.1 (d, J = 22.2 Hz, 1C), 37.2, 35.7,
28.7, 27.8, 27.2, 26.2, 15.6; HRMS (ESI-TOF) m/z: [M+H]+ calcd
for C18H22FNO2 302.1551, found 302.1563. Stereochemical purity
was determined by HPLC analysis using Chiral Cel OJ-3 .0 mm 4.6
x 150 mm column at 25 °C (Solvent A = heptane, Solvent B
= MeOH/EtOH (1:1) at 1.0 mL/min; %B = 0 min 5%, 25 min 15%,
30 min 15% stop time = 30 min), giving retention of 10.10 min
(major R diastereomer) and 13.20 min (minor S diastereomer). The
absolute stereochemistry was confirmed through comparison to an
authentic sample.
(R)-N-allyl-3-phenylbutanamide (25t). Prepared according to
procedure A on 0.62 mmol scale at 40 °C (12 h) to give (S)-25t
(111 mg) as a white solid in 88% yield and 98 ee% from 21c. 1H
NMR (500 MHz, Chloroform-d) δ 7.32 – 7.29 (m, 2H), 7.26 – 7.18
(m, 3H), 5.68 (m, 1H), 5.24 (s, 1H), 5.04 (dd, J = 10.3, 1.5 Hz, 1H),
4.98 (dd, J = 17.2, 1.6 Hz, 1H), 3.83 – 3.75 (m, 2H), 3.32 (h, J =
7.2 Hz, 1H), 2.48 - 2.40 (m, 2H), 1.32 (d, J = 7.0 Hz, 3H). 13C NMR
(126 MHz, Chloroform-d) δ 171.5, 146.0, 134.3, 128.8, 126.9,
126.6, 116.3, 46.1, 41.9, 37.2, 21.9. HRMS (ESI-TOF) m/z:
[M+H]+ calcd for C13H18NO 204.1383; found 204.1383. Enantiose-
lectivity was determined by HPLC analysis using Chiral Cel OJ-
RH 5 µm 4.6 x 150 mm column at 30 °C (Solvent A/B= 0.1% for-
mic acid in H2O/MeOH (1:1.9) stop time = 10 min), giving reten-
tion of 7.73 min (major R enantiomer) and 6.24 min (minor S en-
antiomer).). The absolute stereochemistry was assumed by anal-
ogy.
(2S,3R)-N-allyl-3-((tert-butyldimethylsilyl)oxy)-3-(4-fluoro-
phenyl)-2-methylpropanamide (25u). Prepared according to proce-
dure A on 0.618 mmol scale at 40 °C (12 h) to give (S,R)-25u (65
mg) as a white solid in 30% yield and >99:1 d.r from 21e. 1H NMR
(500 MHz, Chloroform-d) δ 7.26 – 7.21 (m, 2H), 7.00 (t, J = 8.7
Hz, 2H), 5.92 – 5.80 (m, 2H), 5.19 (dq, J = 17.3, 1.6 Hz, 1H), 5.14
(dq, J = 10.1, 1.3 Hz, 1H) 4.70 (d, J = 7.8 Hz, 1H), 4.02 – 3.94 (m,
1H), 3.82 – 3.75 (m, 1H), 2.40 (p, J = 7.2 Hz, 1H), 0.93 (d, J = 7.0
Hz, 3H), 0.83 (s, 9H), 0.0 (s, 3H), -0.24 (s, 3H). 13C NMR (126
MHz, Chloroform-d) δ 174.3, 138.7, 134.4, 128.4, 128.4, 117.0,
115.3, 115.1, 51.0, 42.2, 26.0, 18.2, 15.1, -4.6, -5.1. HRMS (ESI-
.
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Acyloxazolidinones with Copper(II)-bisoxazoline Catalysts and Dia-
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ASSOCIATED CONTENT
ryliodonium Salts. J. Am. Chem. Soc. 2011, 133, 13778–13781. (d) Ev-
ans, D. A.; Scheidt, K. A.; Johnston, J. N.; Willis, M. C. Enantioselec-
tive and Diastereoselective Mukaiyama−Michael Reactions Catalyzed
by Bis(oxazoline) Copper(II) Complexes. J. Am. Chem. Soc. 2001, 123,
4480–4491. (e) Evans, D. A.; Johnston, J. N. Catalytic Enantioselective
Michael Additions to Unsaturated Ester Derivatives Using Chiral Cop-
per(II) Lewis Acid Complexes. Org. Lett. 1999, 1, 865–868. (f) Evans,
D. A.; Johnson, D. S. Catalytic Enantioselective Amination of
Enolsilanes Using C2-Symmetric Copper(II) Complexes as Chiral
Lewis Acids. Org. Lett. 1999, 1, 595–598. (g) Evans, D. A.; Woerpel,
K. A.; Hinman, M. M.; Faul, M. M. Bis(oxazolines) as Chiral Ligands
in Metal-Catalyzed Asymmetric Reactions. Catalytic, Asymmetric Cy-
clopropanation of Olefins. J. Am. Chem. Soc. 1991, 113, 726–728. (h)
Evans, D. A.; Rovis, T.; Johnson, J. S. Chiral Copper (II) Complexes
as Lewis Acids for Catalyzed Cycloaddition, Carbonyl Addition, and
Conjugate Addition Reactions. Pure Appl. Chem. 1999, 71, 1407–
1415.
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Supporting Information
The Supporting Information is available free of charge on the ACS
Publications website at DOI: ( )
High-throughput data, regression Model R-Code, parallel kinetic
isotope experiment, spectral and HPLC data for all compounds
(PDF)
¢
AUTHOR INFORMATION
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Corresponding Authors
* Jason.Stevens@BMS.com
* Doug.Frantz@UTSA.edu
ORCID
4
Heravi, M. M.; Zadsirjan, V.; Farajpour, B. Applications of Oxazoli-
dinones as Chiral Auxiliaries in the Asymmetric Alkylation Reaction Ap-
plied to Total Synthesis. RSC Adv. 2016, 6, 30498–30551.
Jason M. Stevens: 0000-0003-1671-1539
Doug E. Frantz: 0000-0002-4509-4579
5 For recent applications of chiral N-acyl oxazolidinones on large scale,
see (a) Cini, E.; Banfi, L.; Barreca, G.; Carcone, L.; Malpezzi, L.;
Manetti, F.; Marras, G.; Rasparini, M.; Riva, R.; Roseblade, S.; Russo,
A.; Taddei, M.; Vitale, R.; Zanotti-Gerosa, A. Convergent Synthesis of
the Renin Inhibitor Aliskiren Based on C5–C6 Disconnection and
CO2H–NH2 Equivalence. Org. Process Res. Dev. 2016, 20, 270–280.
(b) Pan, X.; Xu, S.; Huang, R.; Yu, W.; Liu, F. A Facile, Six-Step Pro-
cess for the Synthesis of (3S,5S)-3-Isopropyl-5-((2S,4S)-4-isopropyl-5-
oxo-tetrahydrofuran-2-yl)-2-oxopyrrolidine-1-carboxylic Acid tert-
Butyl Ester, The Key Synthetic Intermediate of Aliskiren. Org. Process
Res. Dev. 2015, 19, 611–617. (c) Remarchuk, T.; St-Jean, F.; Carrera,
D.; Savage, S.; Yajima, H.; Wong, B.; Babu, S.; Deese, A.; Stults, J.;
Dong, M. W.; Askin, D.; Lane, J. W.; Spencer, K. L. Synthesis of Akt
Inhibitor Ipatasertib. Part 2. Total Synthesis and First Kilogram Scale-
up Org. Process Res. Dev. 2014, 18, 1652–1666. (d) Wang, F.; Xu, X.-
Y.; Wang, F.-Y.; Peng, L.; Zhang, Y.; Tian, F.; Wang, L.-X. An Im-
proved and Economical Process for the Manufacture of the Key Inter-
mediate of Aliskiren, a New Potent Renin Inhibitor. Org. Process Res.
Dev. 2013, 17, 1458–1462. (e) Murtagh, L.; Dunne, C.; Gabellone, G.;
Panesar, N. J.; Field, S.; Reeder, L. M.; Saenz, J.; Smith, G. P.; Kissick,
K.; Martinez, C.; Van Alsten, J. G.; Evans, M. C.; Franklin, L. C.; Nan-
ninga, T. Chemical Development of an α2δ Ligand, (3S,5R)-3-(Ami-
nomethyl)-5-methyloctanoic Acid. Org. Process. Res. Dev. 2011, 15,
1315–1327.
Notes
The authors declare no competing interest
¢
ACKNOWLEDGMENT
We thank Merrill Davies and Frederick Roberts for their assistance
with chiral HPLC and GC method development as well as Michael
Peddicord for assistance with mass spectrometry analysis. D.E.F.
would also like to thank the National Science Foundation (CHE-
1362953 and MRI-1625963) for partially supporting this work.
High-resolution mass spectrometry data at UTSA were obtained
through support from the National Institute of Minority Health and
Health Disparities (G12MD007591) within the NIH. D.E.F. would
also like to thank the Max and Minnie Tomerlin Voelcker Fund for
providing unrestricted support.
¢
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