A Unified Strategy for the Asymmetric Synthesis of Highly Substituted 1,2-Amino Alcohols Leading to Highly Substituted Bisoxazoline Ligands

Article abstract of DOI:10.1021/acs.joc.0c02899

A general procedure for the asymmetric synthesis of highly substituted 1,2-amino alcohols in high yield and diastereoselectivity is described that uses organometallic additions of a wide range of nucleophiles to tert-butylsulfinimines as the key step. The addition of organolithium reagents to these imines follows a modified Davis model. The diastereoselectivity for this reaction depends significantly on both the nucleophile and electrophile. These highly substituted 1,2-amino alcohols are used to synthesize stereochemically diverse and structurally novel, polysubstituted 2,2′-methylene(bisoxazoline) ligands in high yields.

Full text of DOI:10.1021/acs.joc.0c02899

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Article
A Unified Strategy for the Asymmetric Synthesis of Highly
Substituted 1,2-Amino Alcohols Leading to Highly Substituted
Bisoxazoline Ligands
Bijay Shrestha, Brennan T. Rose, Casey L. Olen, Aaron Roth, Adon C. Kwong, Yang Wang,
and Scott E. Denmark*
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ABSTRACT: A general procedure for the asymmetric synthesis of highly
substituted 1,2-amino alcohols in high yield and diastereoselectivity is described
that uses organometallic additions of a wide range of nucleophiles to tert-
butylsulfinimines as the key step. The addition of organolithium reagents to these
imines follows a modified Davis model. The diastereoselectivity for this reaction
depends significantly on both the nucleophile and electrophile. These highly
substituted 1,2-amino alcohols are used to synthesize stereochemically diverse and
structurally novel, polysubstituted 2,2′-methylene(bisoxazoline) ligands in high
yields.
ligand catalyst system can also affect the enantioselective
aziridination of alkenes.33 Mukaiyama aldol reactions are
effectively catalyzed by chiral tin−BOX complexes as
illustrated in the synthesis of the marine natural product
phorboxazole B.34 A palladium catalyst and a chiral
bisoxazoline ligand afford five- and six-membered ring
heterocycles and carbocycles in good yields in the allylic
reaction of allenes with aryl and vinyl iodides.35 Porter et al.
reported the use of a zinc−BOX complex to promote radical
reactions of alkyl iodides, acryloyloxazolidinones, and
allyltributylstannanes, resulting in substituted acrylamides
products.36 An Evans copper−BOX hexafluoroantimonate
complex is used to catalyze a Diels−Alder reaction of an α-
methylene lactam and an (E)-diene to construct a highly
functionalized spiro lactam as a single diastereomer in high
enantioselectivity. This spiro lactam is a key intermediate in
the total synthesis of the marine toxin gymnodimine.37
INTRODUCTION
■
1,2-Amino alcohols are found in a wide range of natural and
synthetic compounds. Naturally occurring bioactive molecules
like bestatin, hapalosin, and vancomycin contain 1,2-amino
alcohols (Chart 1).1−6 Cyclic amino alcohols are found in
biologically active alkaloids such as vinblastine,7 (+)-castano-
spermine,8 and anisomycin.9 Bioactive lipids such as
sphingosine10 and myriocin11 also contain a 1,2-amino
alcohol moiety. 1,2-Amino alcohols are found as aminoglyco-
sides in various natural products such as daunomycin,12
elsamicin A,13 and neomycin B.14 In addition to these natural
products, synthetic, pharmacologically active molecules like
saquinavir possess these moieties.15 1,2-Amino alcohols and
their derivatives are also popular as chiral auxiliaries for
various asymmetric reactions (Figure 1).16 Asymmetric
alkylation of acyclic chiral auxiliaries such as pseudoephedrine
and ephedrine are well known.17,18 Proline-derived ligands
such as oxazaborolidines are widely used in reduction of
carbonyl compounds.19−21 Oxazolidinones accomplish various
asymmetric reactions such as alkylation,22 α-halogenation,23
α-amination,24 oxygenation,25 sulfenylation,26 aldol,27 and
conjugate additions.28
1,2-Amino alcohols are employed in the synthesis of C2-
symmetric, chiral bisoxazoline (BOX) ligands, which are
frequently used in metal-catalyzed asymmetric reactions.29,30
These ligands possess a conformationally rigid geometry as
well as Lewis basic nitrogen atoms, which can ligate metal
ions to produce chiral catalysts for myriad enantioselective
carbon−carbon and carbon−heteroatom bond-forming reac-
tions (Scheme 1). BOX ligands are widely used with copper
salts for catalytic intermolecular and intramolecular enantio-
selective cyclopropanation reactions.31,32 The copper−BOX
BACKGROUND
■
1,2-Amino Alcohols. Given the importance and utility of
1,2-amino alcohols, many methods are reported for the
enantioselective and diastereoselective synthesis of this motif
(Scheme 2).1,38 Generally, 1,2-amino alcohols are synthesized
through the functional group manipulation of molecules
Received: December 7, 2020
Published: February 4, 2021
https://dx.doi.org/10.1021/acs.joc.0c02899
© 2021 American Chemical Society
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Chart 1. Selected Examples of Natural Products and Pharmaceutically Active Compounds with 1,2-Amino Alcohol Motifs
used for the synthesis of 1,2-amino alcohols.40 Illustrations of
these disconnections are summarized in Scheme 3.
For the functional group manipulation approach, syn- or
anti-1,2-amino alcohols are prepared by the addition of chiral
allylboronates to Garner’s aldehyde.41 For the epoxide ring
opening reaction approach, treatment of benzhydryl amine
with an epoxide prepared from the corresponding allylic
Figure 1. Examples of 1,2-amino alcohol-containing chiral
auxiliaries.
alcohol via a Katsuki−Sharpless asymmetric epoxidation
provides the vicinal amino alcohol in good yield.42 Opening
of an aziridine ring employs aza-Payne rearrangements of
hydroxy aziridines to provide an epoxy amine intermediate,
which is then treated with an organocuprate to give
diastereomerically pure N-protected 1,2-amino alcohols.43
1,2-Amino alcohols generated by the addition of one
heteroatom are exemplified in the Schenk ene reaction of
an allylamine with singlet oxygen in the presence of
tetraphenylporphyrin.44,45 Sharpless46 and co-workers have
developed the aminohydroxylation method for the prepara-
tion of α-hydroxy-β-amino esters from the corresponding α,β-
unsaturated esters. Nitro aldol or Henry reactions have been
employed to obtain syn-1,2-amino alcohols in high yield and
enantioselectivity.47 Similarly, pinacol-type coupling reactions
with chemoenzymatic methods are available for the synthesis
of a wide range of enantiopure 1,2-amino alcohols.48 During
the synthesis of protected imino-digitoxose, a key 1,2-amino
alcohol intermediate was prepared via an L-threonine
containing two heteroatoms on vicinal carbons, for example,
by reduction or nucleophilic addition to carbonyl or imine
groups. The ring-opening reactions of an epoxide or aziridine
with a nitrogen or oxygen nucleophile also provide the 1,2-
amino alcohol.1 The addition of one heteroatom to a
molecule already containing a heteroatom also gives 1,2-
amino alcohols. Here, the configuration of the resident
heteroatom controls or directs the stereochemical approach
of the incoming nucleophile. Another commonly used
method for the synthesis of 1,2-amino alcohols is amino-
hydroxylation of an alkene, in which both nitrogen and
oxygen are added in a single reaction. Nucleophilic addition
of an α-heteroalkylmetal reagent and an aldehyde or imine or
pinacol-type coupling between an aldehyde and imine also
produces 1,2-amino alcohols.39 Chemoenzymatic strategies
such as the use of transaminases, kinetic resolutions, dynamic
resolutions, or biocatalytic C−C bond formations are also
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Scheme 1. Examples of Enantioselective Reactions of BOX Ligands
aldolase-catalyzed aldol condensation of (2S,3S)-2,3-O-iso-
propyriden-4-penten-1-al and glycine.49,50
closure of the bisamide can also be accomplished by using
the Masamune protocol using dibutyltin dichloride.59 You
and co-workers successfully cyclized the bisamide using
triphenylphosphine under basic conditions with overall
retention of configuration.60 Owing to low catalytic activities,
these reactions need an excess of reagent or a high reaction
temperature. Furthermore, these catalytic methods are limited
to simple acid- or base-tolerant substrates, resulting in poor
functional group tolerance.
Bisoxazolines. The classic approach for the synthesis of
bisoxazoline ligands combines a malonyl dichloride with a
1,2-amino alcohol to give a key bisamide intermediate
(Scheme 4).29,51−53 The resulting bisamide can undergo
cyclization with either inversion or retention of configuration
at a substituted C(5) carbon. Dehydrating agents such as
titanium(IV) isopropoxide,54 methanesulfonic acid,55 ammo-
nium molybdate,56 lanthanide chloride salts,57 or a zeolite58
affect retentive cyclization of the bisamide. Retentive ring
In addition to formation of bisamides from 1,2-amino
alcohols, other condensation reactions have been employed
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to construct BOX ligands retentively. For example, a Ritter
reaction between a malononitrile and indanediol gives the
BOX ligand in high regio- and diastereoselectivity.61
Cadmium diacetate catalyzed synthesis of a BOX ligand
from (R,R)-threoninol and dimethylmalononitrile has also
been reported.62 Condensation of (+)-(1S,2S)-2-amino-1-
phenylpropane-1,3-diol with the bisimidate prepared from
treatment of malononitrile with ethanol in the presence of
HCl gas in a Pinner reaction also produces BOX ligands.63
The reaction between a bisimidate and L- or D-serine amide
hydrochloride produces BOX ligands as well.64 Zinc(II)
chloride has also been used to prepare BOX ligands from
bisamides.65
Scheme 2. Various Approaches for the Synthesis of 1,2-
Amino Alcohols
To affect invertive cyclization, the hydroxyl groups of the
bisamides are converted to mesyl or tosyl groups. Invertive
cyclization then occurs under basic conditions.66 Similarly,
diethylaminosulfur trifluoride (DAST) also affects invertive
cyclization of bisamides.67 One of the major challenges of the
invertive cyclization method is the formation of the
monocyclized product owing to partial formation of the
activated hydroxyl group. Since, the cyclization occurs by an
invertive displacement of the carbon bearing the leaving
Scheme 3. Examples of Asymmetric Synthesis of 1,2-Amino Alcohols
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Scheme 4. Various Strategies for the Retentive and Invertive Construction of BOX Ligands
group, the efficacy of this displacement is strongly dependent
upon substitution at the C(5) position.
modeling. This training set will comprise highly substituted
ligands bearing substituents at the C(4)-position that have
never been prepared before, as well as both cis- and trans-
diastereomers at the C(4)- and C(5)-positions. In early
synthesis campaigns, existing methods to prepare the requisite
1,2-amino alcohols failed to provide a general solution. This
paper reports a general, asymmetric synthesis of highly
substituted 1,2-amino alcohols from sulfinyl imines as the
common intermediate. Diverse 1,2-amino alcohols are then
used to synthesize novel 4,5-polysubstituted BOX ligands.
RESEARCH PLAN
■
In general, the challenge in constructing highly substituted
BOX ligands is not in the ring-closure step, but rather in the
synthesis of the requisite 1,2-amino alcohols in stereodefined
form. Key to the success of the BOX ligand architecture as a
privileged class is the ability to extensively vary the
substituents at the C(4)- and C(5)-positions of the
oxazolines. In most of the commonly employed BOX ligands,
the substituents at the C(4)- and C(5)-positions are rather
simple, generally derived from chiral pool sources such as
natural amino acids. Many of them lack substituents at the 5-
position altogether.51,52,65,68,69 The lack of structural diversity
ultimately relates back to the 1,2-amino alcohols or 1,2-diols
from which the ligands are prepared.61,70,71
RESULTS
■
Failures of Classical and Modern Methods to
Provide a General Synthesis of Stereodefined 1,2-
Amino Alcohols. Although it is generally ill advised to
document failures in publications, given the widespread belief that
BOX ligand synthesis is a solved problem, it is appropriate to
briefly summarize why that belief is misguided.
In the context of our chemoinformatic workflow for the
discovery and optimization of enantioselective catalysts,72−74
we targeted the 2,2′-(methylene)bisoxazoline architecture as a
highly diversifiable scaffold via modular construction. This
workflow requires the generation of an in silico library of
104−105 synthetically accessible, hypothetical ligands, with
significant structural diversity at the C(4)-center. Ultimately,
a training set of 20−30 representatives will have to be
prepared in quantity to generate data for machine-learning
Depending upon the substituent pattern on the target final
BOX ligands, different synthetic routes were explored. First,
those ligands bearing benzyl substituents at the C(4)-position
(e.g., phenylalanine derivatives) would be synthesized using
the method described by Yu (Scheme 5).75 Here, phenyl-
alanine derivatives prepared by insertion into the methyl C−
H bond of the parent alanine would provide a convenient
route to unnatural amino acids. After testing this route,
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Scheme 5. Various Routes Examined for the Synthesis of 1,2-Amino Alcohols
several limitations were encountered. First, this method gave
lower yields on a large scale. Second, excessive amounts of
palladium(II) trifluoroacetate and silver carbonate were
needed. Alternatively, for targets with stereocenters also at
the C(5)-position of the oxazoline ring, the Reetz route76 was
evaluated but abandoned over concerns regarding the
configurational stability of the intermediate α-amino
aldehyde. Ultimately, the C(4)-benzyl-substituted BOX
ligands were to be accessed through the enantioselective
O’Donnell phase-transfer-catalyzed alkylation reaction.77,78
Although this reaction gave high yield and high enantiose-
lectivity, the substrate scope was limited.
Next, those ligands bearing aryl substituents at the C(4)-
position (e.g., aryl glycine derivatives) were to be prepared by
an enantioselective Strecker reaction.79 The transformation
worked well, but the hydrolysis of the Strecker products
required much optimization on a case-by-case basis. An
alternative approach employed the Sharpless enantioselective
dihydroxylations of stilbenes or styrenes and subsequent
functional group interconversions.80,81 Despite being a good
method for the introduction of stereocenters, the number of
diverse BOX ligands which could be prepared in this manner
was limited, owing to the substrate requirements for
enantioselective dihydroxylation. Furthermore, many bulky
substituents lead to sluggish reactions, and increasing the
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Scheme 6. General Routes for the Synthesis of α-Siloxy Sulfinimines from Hydroxy Acids and Esters
catalyst loading failed to produce a substantial increase in
yield owing to slow turnover. Similarly, Shi epoxidation82
failed to provide any conversion for these substrates with
nearly quantitative recovery of the starting material.
a benzylating agent,95 the diisobutylaluminum hydride
reduction gave low yield. Consequently, esters 2c−f were
protected with tert-butyldimethylsilyl chloride (TBSCl).96
The PMB-protected esters 3a−b were reduced with lithium
aluminum hydride to provide the corresponding alcohols
4a,b, which were further subjected to Swern oxidation to
afford the corresponding aldehydes. TBS protected esters
3c−f were directly converted to the corresponding aldehydes
using diisobutylaluminum hydride reduction at −78 °C with
no loss of stereochemical purity. Aldehydes 5a−e were
condensed with (R)-tert-butylsulfinamine using titanium(IV)
ethoxide to generate the requisite α-siloxy sulfinimines.
Aldehyde 5f required copper(II) sulfate to affect condensa-
tion.87,97
Addition of Organometallic Nucleophiles to the
Sulfinimines. The initial optimization of the organometallic
additions began with α-siloxy (R)-sulfinimine 6c as a model
system. Treatment of 6c with phenylmagnesium bromide in
CH2Cl2 resulted in no conversion at −40 °C (Table 1, entry
1). Increasing the temperature to −20 °C led to 25%
conversion to the desired product with 88:12 dr (entry 2).
Full consumption of the starting material was achieved at 0
°C, but the dr of the product was unacceptably low at 57:43
(entry 3). Changing the solvent to toluene allowed for 80%
conversion at cryogenic temperatures, but again with a low dr
(entry 4). Using THF as solvent provided 71% conversion
with a modest increase in diastereoselectivity compared to
toluene (entry 5) and addition of TMEDA90 had no effect on
the results (entry 6). Changing the absolute configuration of
the sulfinimine to (S) provided the corresponding product in
a low 77:33 dr apparently corresponding to the mismatched
case (entry 7). Organolithium reagents are also competent
nucleophiles for 1,2-addition to chiral sulfinimines to afford
β-amino alcohols.90 Accordingly, using phenyllithium resulted
in complete consumption of the starting material and
provided the corresponding 1,2-addition product in a 91:9
dr (entry 8). Once again, no change was observed by the
addition of TMEDA (entry 9). All these reactions were run
on a 0.2 mmol scale for 24 h.
Another approach envisioned the diastereoselective con-
struction of a stable, secondary tin reagent which could then
undergo enantiospecific cross coupling to furnish a library of
amino alcohol precursors.83,84 Installation of the organotin
unit by directed lithiation was first attempted on an N-Boc-
oxazolidinone, which was unsuccessful. Addition of the
organotin nucleophile to ((R)-5-methyl-5H-1,2,3-oxathiazole
2,2-dioxide) was also unsuccessful.85 Samarium iodide
mediated cross couplings of N-tert-butanesulfinyl imines
with α-branched aliphatic aldehydes to access the correspond-
ing amino alcohols with high enantio- and diastereoselectivity
have been reported.86 These couplings worked as reported
for the electron-rich or -neutral sulfinimines, but the yield
suffered for electron-deficient sulfinimines as well as
polyaromatic systems.
The Robustness and Generalizability of the Ellman
Imine Approach. Synthesis of the Sulfinimine Substrates.
Inspired by two concurrent reports by Ellman and Barrow
regarding the diastereoselective addition of Grignard reagents
to α-siloxy sulfinimines followed by global deprotection to
give the corresponding 1,2-amino alcohols,87−90 the synthesis
of α-silyloxy sulfinimines was initiated. These building blocks
are easily prepared from commercially available hydroxy acids
and esters, including benzilic acid, methyl 2-hydroxyisobuty-
rate, L-(+)-mandelic acid, L-(−)-ethyl lactate, and methyl
glycolate (Scheme 6). Hydroxy acid 1c bearing an isopropyl
group was prepared from L-valine.91 The esterification of
hydroxy acids 1a,92 1c,91 and 1d93 using thionyl chloride and
methanol gave the corresponding methyl esters. The hydroxyl
group of esters 2a,b was protected using 4-methoxybenzyl
chloride (PMBCl).94 The 4-methoxybenzyl protection of the
hydroxy group of chiral esters 2c−e was unsuccessful because
sodium hydride (NaH) caused epimerization of the stereo-
genic center. Though PMB protection of these chiral esters
was successful using 4-methoxybenzyl trichloroacetimidate as
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Deprotection to Form 1,2-Amino Alcohols. Global
deprotection under the action of 6 N HCl in methanol
provided the 1,2-amino alcohols after basic workup in
excellent yields. HCl in dioxane has been reported to affect
global deprotection,98 but HCl in methanol was used to
simplify workup. Under these conditions, sulfinamides 8−14,
16, and 17 were cleanly deprotected to give corresponding
1,2-amino alcohols 22−28, 30, and 31 after basic workup in
good to excellent yields (Table 3).
The global deprotection of compound 15 was difficult
using the standard conditions. Instead, sulfinamide 15 was
treated with 12 N HCl in methanol which removed tert-
butylsulfinyl group. Then, the crude product obtained after
basic workup was further heated at 60 °C with tetra-N-
butylammonium fluoride (TBAF) to remove the TBS group,
resulting in the isolation of the desired 1,2-amino alcohol 29
in excellent yield.
Construction of the BOX Ligands. The condensation of
1,2-amino alcohols 22−31 with dimethylmalonyl dichloride
was carried out in the presence of triethylamine to afford the
corresponding bisamides 34−43 in good to excellent yield
(Table 4). Synthesis of another series of bisamides 44 and
45, which contained different substituents on the methylene
bridge, were also investigated. Bisamide 44 was prepared by
condensation of the amino alcohol 32 and 2,2-bis(4-
methoxybenzyl)malonyl dichloride III while the bisamide
45 was prepared by condensation of the amino alcohol 33
and 2,2-Bis(naphthalen-2-ylmethyl)malonyl dichloride VI,
which in turn was synthesized from 2,2-dimethyl-1,3-
dioxane-4,6-dione following the three-step sequence shown
in Scheme 7.
The cyclization of the bisamides 34−37 in the presence of
catalytic amounts of titanium(IV) isopropoxide afforded the
corresponding bisoxazoline ligands 46−49 in good to
excellent yields (Table 5). The cyclization afforded novel
BOX ligands with gem-diphenyl groups at pro-C(5), with the
biphenyl group (46) and 3,5-di-tert-butylphenyl group (47)
at the pro-C(4) position. The same cyclization condition was
effective with gem-dimethyl substitution at pro-C(5) with a
benzyl derivative (48) and a sterically hindered aryl group
(49) at the pro-C(4) position. For those bisamides with an
oxygen-bearing stereogenic center, the cyclizations proceeded
with retention of configuration. Thus, this method was
effective with an isopropyl group at pro-C(5) and an
electron-deficient aryl group (50) or a sterically hindered
aryl group (51) at pro-C(4). Similarly, the BOX ligand with a
phenyl group at pro-C(5) and an electron-rich aryl group
(52) at pro-C(4) was prepared. The BOX ligands containing
a heterocyclic group (53) and a polyaromatic group (54) at
pro-C(4) with a methyl group at pro-C(5) were also
synthesized in a similar fashion.
Table 1. Optimization of Diastereoselective Addition to
Imine 6c
a
b
solvent
(0.05 M)
temp
(°C)
conv
(%)
c
entry
M
dr
1
2
3
4
5
6
7
8
9
MgBr
MgBr
MgBr
MgBr
MgBr
MgBr/TMEDA
MgBr
Li
CH2Cl2
CH2Cl2
CH2Cl2
toluene
THF
THF
THF
THF
THF
−40
−20
0
−60
−70
−70
−70
−78
−78
0
25
100
80
71
68
73
>99
>99
88:12
57:43
82:18
88:12
87:13
77:33
91:9
d
Li/TMEDA
91:9
a
b
Reactions were run on a 0.2 mmol scale for 24 h. Conversion was
determined by 1H NMR spectroscopy of the crude mixture.
c
1
Diastereomeric ratio was determined by H NMR spectroscopy of
d
the crude mixture. (S)-N-((S,E)-2-((tert-Butyldimethylsilyl)oxy)-3-
methylbutylidene)-2-methylpropane-2-sulfinamide was used for the
reaction.
The scope of electronically and sterically diverse
aryllithium species was examined in the addition to various
α-oxy (R)-sulfinimines. Both [1,1′-biphenyl]-4-yllithium and
(3,5-di-tert-butylphenyl)lithium were cleanly incorporated in
sulfinimine 6a to afford the corresponding products 8 and 9
with excellent dr of 99:1 for both (Table 2, entries 1 and 2).
Addition of 1-(lithiomethyl)naphthalene to sulfinimine 6b
provided the corresponding product 10 in full conversion and
85:15 dr (entry 3). Addition of 2,6-dimethylphenyllithium to
6b provided the corresponding product 11 in full conversion
but significantly reduced 60:40 dr (entry 4). Next, addition of
4-(trifluoromethyl)phenyllithium and 1,3,5-trimethoxyphenyl-
lithium to sulfinimine 6c provided the corresponding
products 12 and 13 in full conversion and 99:1 dr for both
(entries 5 and 6). Addition of (4-methoxyphenyl)lithium and
(2,4,6-triisopropylphenyl)lithium to the sulfinimine 6d
afforded the corresponding products 14 and 15 with 98:2
and 99:1 dr, respectively (entries 7 and 8). Heterocyclic 2-
pyridyllithium produced 16 with 95:5 dr (entry 9) with
sulfinimine 6e, while polyaromatic 1-pyrenyllithium afforded
17 with 99:1 dr (entry 10). Addition of more challenging
nucleophiles such as (3,3″,5,5″-tetrakis(trifluoromethyl)-
[1,1′:3′,1″-terphenyl]-5′-yl)lithium and 9-anthracenyllithium
to sulfinimine 6f afforded the corresponding products 18 and
19 with poorer dr of 67:33 and 69:31 respectively (entries 11
and 12). The configurations of the major diastereomers for
the addition products 11, 13, 18, and 19 were established by
X-ray crystallography at various stages on the way to the final
bisoxazoline ligands (see Establishment of Absolute Config-
uration of the Products by X-ray Crystallography).
The invertive cyclization of bisamides 38, 40, and 41 was
achieved by treating with methanesulfonyl chloride (5.0
equiv) and triethylamine (6.0 equiv) in dichloromethane at 0
°C (Table 6). This afforded the corresponding bismesylates,
which were then heated at reflux in an aqueous ethanolic
solution of sodium hydroxide (NaOH) (5.0 equiv) for 12 h
to afford the corresponding bisoxazolines 55−57 in high
yield. Bisamides 43−45 were also closed by cyclization using
diethylaminosulfur trifluoride (DAST, 3.0 equiv) and
potassium carbonate to afford the corresponding bisoxazo-
lines 58−60 in high yield. Invertive cyclization for bisamide
39 by treatment with thionyl chloride was successful but was
Simple aliphatic organometallic nucleophiles were neither
problematic nor of interest for our chemoinformatic training
set. Nevertheless, in preliminary experiments, n-BuLi added
to 6a and 6b in 71% yield (99:1 dr) and 88% yield (86:14
dr), respectively. Finally, t-BuLi added to 6d in 30% yield
(99:1 dr); the major product arose from reduction.
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Table 2. Substrate Scope for Diastereoselective 1,2-Additions
a
b
1
Isolated yield of analytically pure material. The absolute configuration at sulfur is (R). Diastereomeric ratio was determined by H NMR
c
spectroscopy of the crude mixture. Switch in configuration of the major isomer, vide infra.
nonreproducible on scale up. Other invertive cyclization
methods for bisamide 39 did not produce the desired BOX
ligand.
Establishment of Absolute Configuration of the Prod-
ucts by X-ray Crystallography. To establish the absolute
configuration of 20, 21, 27, and 37, single crystals were
grown for X-ray structure determination. The major (R,R)
isomer always had the higher Rf value on silica gel
chromatography. However, the diastereomers of products
18 and 19 could not be separated by silica gel column
chromatography and thus were subjected to TBS depro-
tection using tetrabutylammonium fluoride. The deprotected
products 20 and 21 were separable by silica gel
chromatography. Owing to the low diastereoselectivity for
the addition of terphenyllithium and anthracenyllithium, these
hydroxy sulfinamines were analyzed by X-ray crystallography.
The major diastereomer (20) formed from the addition of
the terphenyl-derived organolithium reagent had the expected
(R,R) configuration, whereas the major diastereomer (21)
formed from addition of 9-anthracenyllithium had the (R,S)
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a
Table 3. Substrate Scope for 1,2-Amino Alcohols
a
b
Isolated yield of analytically pure material. Reaction run with 12.1 N HCl in MeOH for 12 h. After neutralization with 8 N NaOH, the crude was
c
refluxed at 60 °C in the presence of TBAF for further 12 h. Reaction run with 1 N HCl in Et2O (0.02 M) at 25 °C for 20 min.
configuration (Figure 2). In keeping with the established
trend, 21 had the lower Rf value on silica gel chromatog-
raphy. Similarly, the major diastereomers of adducts 11 and
13 were established be (R,R) by X-ray crystallographic
analysis of amino alcohol 27 and bisamide 37, respectively.99
The configuration of the rest of the compounds were
assumed by analogy.
In subsequent investigations, Ellman reported the addition
of Grignard reagents to N-tert-butylsulfinylimines derived
from O-protected S-lactaldehydes.103 Addition of aryl- and
alkyl-Grignard reagents afforded the corresponding 1,2-
disubstituted amino alcohols in good yields and diaster-
eoselectivities, though the dr was weakly dependent upon the
O-protecting group (Figure 4). The major isomer was
obtained in good yield and high diastereoselectivity with
either the tert-butyldimethylsilyl or benzyl ether. The bulkier
tert-butyldiphenylsilyl protecting group also provided the
major isomer in good yield but with slightly lower
diastereoselectivity.
Given the dependence of diastereoselectivity on various
factors, including solvent and substrate structure, extrapolat-
ing these trends to reactions with organolithium reagents in
pure THF is tenuous. Nevertheless, several studies on record
do report the use of a wide variety of organolithium
nucleophiles (aryl- or alkyllithium) for addition into N-
sulfinyl aldimines.87,88,100 Some reports suggest that aryl-
lithium reagents are superior to their Grignard counterparts
and afford a broader scope, improved yields, and higher
diastereoselectivities.104,105 Despite having limited substrate
scope with respect to the aryllithium nucleophile addition to
ketimines bearing coordinating α-substituents,87,106 α-stereo-
centers106 have also been reported. Although direct
comparisons are not possible, the general sense of
diastereoselectivity persists, namely that (R)-sulfinimines
with (S)-α-oxy aldimines represent the matched auxiliary
case, leading to selective addition to the Re face of the imine
to afford the (R)-nitrogen-bearing center. Ellman rationalizes
this behavior as follows:103 “The anti-selectivity observed for
DISCUSSION
■
Diastereoselectivity of Addition to Sulfinimines.
Early on, Ellman developed a working model for the
diastereoselectivity of the addition of nucleophiles to chiral
tert-butylsulfinylimines.100 The model posits that coordination
of the organometallic reagent to the sulfinyl oxygen leads to a
chairlike transition state with equatorial substituents, ration-
alizing the observed sense of diastereoselectivity (ul
selectivity, R-sulfinimine leads to Si−face attack) (Figure 3,
eq 1). In 2001, both Barrow88 and Ellman87 reported that the
addition to α-alkoxy aldimines led to a different diastereomer.
To explain this reversal, Barrow and co-workers postulated
the formation of a chairlike transition state wherein the α-
alkoxy group coordinates to the organometallic nucleophile,
thus presenting the Re face for attack (lk selectivity) (Figure
3, eq 2). Alternatively, Barrow and co-workers also proposed
an open transition state analogous to that suggested by
Davis101,102 for addition to α-imino esters in which
coordination of the sulfinyl oxygen by a Lewis acid (e.g., a
magnesium cation) interrupts binding of the nucleophile and
shields the Si face of the imine from nucleophile attack,
resulting in the observed selectivity (Figure 3, eq 3).
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Table 4. Preparation of Bisamides
a
b
Isolated yield of analytically pure bisamide. Bisamide prepared using 2.2 equiv of 1,2-amino alcohols.
the addition of nucleophiles is consistent with both Felkin−
Anh107−109 and Cornforth110,111 models, as well as the
inherent selectivity previously observed for nucleophilic
additions to N-sulfinyl R-silyloxyacetaldimines.87” Our results
support that analysis and, as illustrated in Figure 5, constitute
modifications of the Davis open transition-state model.
This trend was observed in the majority of the cases
reported herein. The structures of both the nucleophile and
the electrophile are influential in determining the diaster-
eoselectivity for the addition reaction. Two limiting cases can
be identified. In the first case, composed of the electrophiles
derived from lactic acid, mandelic acid, and valine-containing
α stereocenters, the matched diastereocontrol leads to
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Scheme 7. Preparation of Malonyl Dichlorides with Various Bridging Substituents
Table 5. Preparation of Bisoxazolines by Retentive Ring Closure
a
Isolated yield of analytically pure bisoxazoline ligand.
excellent selectivity in all cases independent of the bulk of the
nucleophile (Table 2, entries 5−10). In the second case,
composed of the geminally disubstituted electrophiles 6a, 6b,
and 6f, the steric bulk of the nucleophile is an important
factor in the diastereoselectivity of addition. Considering
reactions with diphenyl-substituted substrate 6a, nonhindered
aryl nucleophiles furnished the products in excellent
selectivity. For the less sterically demanding dimethyl-
substituted substrate 6b, addition of the less hindered 1-
(lithiomethyl)naphthalene afforded diminished selectivity
(85:15) whereas addition of the hindered 2,6-dimethylphe-
nyllithium was much poorer (60:40). Without the additional
α-stereocenters, the stereochemical course of the reaction was
entirely dependent on the control exerted by the auxiliary.
The most dramatic illustrations of that dependence were
observed with the unsubstituted substrate 6f for which the
additions of bulky nucleophiles derived from anthracene and
a terphenyl led to poor selectivities and in fact an inversion of
the major diastereomer in the 9-anthrancenyllithium addition
(Table 2, entries 11 and 12). It is very difficult to speculate
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Table 6. Preparation of Bisoxazolines by Invertive Ring Closure
a
b
Isolated yield of analytically pure bisoxazoline ligand. Conditions: triethylamine and MsCl in CH2Cl2 at −78 °C for 1.5 h followed by heating
c
with NaOH in ethanol. Conditions: DAST in CH2Cl2 at −78 °C for 1.5 h followed by treatment with K2CO3.
Figure 2. X-ray crystal structures of compounds 20, 21, 27, and 37.
about the origin of the low selectivities given uncertainty
around the relevant transition state models, but in the Davis
model (Figure 3, eq 3) it is possible that a sufficiently bulky
nucleophile may begin to experience repulsive interactions
with the tert-butyl group in the Re face addition (Figure 6).
CONCLUSION
■
In summary, a general procedure for the asymmetric synthesis
of highly substituted 1,2-amino alcohols has been described
that affords high yields and diastereoselectivities from tert-
butylsulfinimines as the common intermediates. Syntheses of
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Figure 3. Transition-state hypothesis rationalizing the reversal of diastereoselectivity in the addition to α-alkoxy imines.
Figure 4. Influence of protecting group on diastereoselectivity and
yield.
novel polysubstituted BOX ligands were achieved in high
yields using these 1,2-amino alcohols. The addition of
structurally diverse organolithium reagents to imines follows
a modified Davis model. The steric properties of both
nucleophile and electrophile play vital roles for the
determination of diastereoselectivity of the addition. This
method enables the expansion of diversity for other chiral
auxiliaries and ligand classes such as oxazaborolidines,
oxazolidinones, Py-BOX and spiro-BOX ligands. The utility
of these interesting novel chiral BOX ligands in asymmetric,
metal-catalyzed reactions will be the subject of future reports.
EXPERIMENTAL SECTION
■
General Experimental Procedures. All reactions were
performed in oven- (150 °C) and/or flame-dried glassware under
an atmosphere of dry nitrogen, unless otherwise indicated. Room
temperature (rt) was approximately 23 °C. “Brine” refers to a
saturated solution of sodium chloride in H2O.
NMR Spectroscopy. 1H and 13C[1H] NMR spectra were
recorded Bruker 500 (500 MHz, 1H; 126 MHz, 13C) MHz
spectrometers. Acquisition times were 4.096 s for 1H NMR and
Figure 5. Modified Davis models for matched and mismatched
additions.
1.024 s for 13C NMR. Spectra are referenced to residual chloroform
1
(δ = 7.26 ppm, H; 77.16 ppm, 13C). Chemical shifts are reported
in parts per million (ppm). Multiplicities are indicated by s (singlet),
d (doublet), t (triplet), q (quartet), quint (quintet), sept (septet)
and m (multiplet). Coupling constants, J, are reported in hertz.
Mass Spectrometry. Mass spectrometry (MS) was performed
by the University of Illinois Mass Spectrometry Laboratory. Electron
Impact (EI+) spectra were performed at 70 eV using methane as the
carrier gas, with either a double-focusing sector field (DFSF) or
time-of flight (TOF) mass analyzer. Chemical ionization (CI+)
spectra were performed with methane reagent gas, with either a
double-focusing sector field (DFSF) or time-of-flight (TOF) mass
analyzer. Electrospray ionization (ESI+) spectra were performed
1
Integration is provided, and assignments are indicated. H and 13C
assignments are corroborated through 2-D NMR experiments
(COSY, HSQC, HMBC).
Infrared Spectroscopy. Infrared (IR) spectra were recorded on
a PerkinElmer FT-IRATR system as thin films. Peaks are reported in
cm−1 with indicated relative intensities: s (strong, 0−33% T); m
(medium, 34−66% T), w (weak, 67−100% T), and br (broad).
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Aldrich), 4-bromobiphenyl (Aldrich, 98%), 1-Bromo-3,5-ditert-
butylbenzene (Oakwood, 99%), 2,6-dimethylbromobenzene (Oak-
wood, 98%), 1-(bromomethyl)naphthalene (Chem Impex, 99.4%),
4-bromobenzotrifluoride (Oakwood, 99%), 1,3,5-trimethoxybenzene
(Aldrich, 99%), 4-bromoanisole (Oakwood, 99%), 1-bromo-2,4,6-
triisopropylbenzene (Oakwood, 97%), 1-bromopyridine (Aldrich,
99%), 1-bromopyrene (AK Scientific, 98%), 2-(bromomethyl)-
naphthalene (Oakwood, 96%), Meldrum’s acid (Chem Impex,
99.5%), potassium carbonate (96%), tert-butyldimethylchlorosilane
(Oakwood, 99%), diethylaminosulfur trifluoride (Oakwood, 95%),
methanesulfonyl chloride (Aldrich, 99.7%), imidazole (Aldrich,
99.5%), dimethylmalonic acid (Oakwood, 99%), and tetra-n-
butylammonium bromide (Aldrich, 99%) were used as received.
Literature Preparations. 2,2-Dimethylmalonyl dichloride was
prepared from 2,2-dimethylmalonic acid and the characterization
data matched those previously reported.112 3,5-Bis(3,5-bis-CF3-
phenyl)iodobenzene was prepared by literature method, and the
characterization data matched those previously reported.113
Figure 6. Origin of decreased selectivity in addition to 6f with bulky
nucleophiles.
using a time-of-flight (TOF) mass analyzer. Data are reported in the
form of m/z (intensity relative to the base peak = 100).
Melting Points. Melting points (mp) were determined on a
̈
Thomas-Hoover capillary melting point apparatus and Buchi melting
point B-540 apparatus in vacuum-sealed capillary tubes and are
corrected.
Elemental Analysis. Elemental analysis was performed by the
University of Illinois Microanalysis Laboratory. Reported data is the
average of at least two runs.
Experimental Procedures. Synthesis of Bisoxazoline Ligands
with a Geminal Diphenyl Substituent at the C(5)-Position.
Distillation. Bulb-to-bulb distillation was performed on a Buchi
̈
Kugelrohr, with boiling points (bp) corresponding to uncorrected
air-bath temperatures (ABT). A vacuum of 10−5 mm Hg was
achieved using a BOC Edwards SI100 diffusion pump.
Preparation of Methyl 2-Hydroxy-2,2-diphenylacetate (2a). A
250 mL, one-necked Schlenk flask containing an egg-shaped stir bar
(50.8 × 19.1 mm) was charged with benzilic acid (11.41 g, 50.0
mmol) and MeOH (distilled, 120 mL) under nitrogen. The solution
was cooled in an ice bath for 10 min, and SOCl2 (17.84 g, 10.94
mL, 150.0 mmol, 3.0 equiv) was added dropwise by syringe over 5
min at 0 °C. The mixture was heated to reflux using a condenser in
75 °C oil bath for 12 h. After the solution was cooled to 25 °C, the
volatile components are removed by rotary evaporation (30 °C, 50
mbar). The resulting residue was diluted with ethyl acetate (200
mL), and satd aq NaHCO3 (200 mL) was added slowly because of
the evolution of gas. The mixture was transferred to a 500 mL
separatory funnel, and the organic layer was removed. The aqueous
layer was extracted with ethyl acetate (3 × 100 mL), and the
organic layers were combined, washed with brine (1 × 100 mL),
dried over anhydrous Na2SO4 (10 g), decanted, and concentrated by
rotary evaporation (30 °C, 50 mbar) to afford the crude product.
The crude product was purified by recrystallization with hot hexane
(300 mL) to afford (11.00 g, 91%) 2a as a white solid. The
spectroscopic data for 2a matched the literature values.114 Data for
Chromatography. Analytical thin-layer chromatography was
performed on Merck silica gel 60 F254 plates. Visualization was
accomplished with UV light and/or potassium permanganate
(KMnO4) solution. Retention factor (Rf) values reported were
measured using a 10 × 2 cm TLC plate in a developing chamber
containing the solvent system (10 mL) described. Flash column
chromatography was performed using Silicycle SiliaFlashP60 (40−63
μm particle size, 230−400 mesh) (SiO2). Unless otherwise specified,
“silica” refers to P60 grade silica gel. Automatic flash chromatog-
raphy was performed by ISCO (50 μm particle size).
Solvents. Reaction solvents tetrahydrofuran (THF) (Fisher,
HPLC grade), ether (Et2O) (Fisher, BHT stabilized ACS grade),
and CH2Cl2 (CH2Cl2) (Fisher, unstabilized HPLC grade) were
dried by percolation through two columns packed with neutral
alumina under a positive pressure of argon. Reaction solvent toluene
(ACS grade) was dried by percolation through a column packed
with neutral alumina and a column packed with Q5 reactant
(supported copper catalyst for scavenging oxygen) under a positive
pressure of argon. Reaction solvent dimethylformamide (DMF)
(Fischer, ACS grade) was dried by percolation through two columns
of activated molecular sieves. Reaction solvent ethanol (absolute,
Decon Laboratories) was used as received. Solvents for filtration,
transfers, chromatography, and recrystallization CH2Cl2 (CH2Cl2)
(amylene stabilized, ACS grade), ether (Et2O) (BHT stabilized,
ACS grade), ethyl acetate (EtOAc) (ACS grade), hexane (HPLC
grade), ethanol (EtOH) (ACS grade), isopropyl alcohol (IPA)
(ACS grade), methanol (MeOH) (ACS grade), pentane (ACS
grade), xylenes (ACS grade), n-hexane (95%) (EMD Millipore), and
petroleum ether (35−60 °C, ACS grade).
1
2a: H NMR (500 MHz, CDCl3) δ 7.48−7.46 (m, 4H), 7.40−7.34
(m, 6H), 4.29 (s, 1H), 3.87 (s, 3H).
Chemicals. Sodium hydride (Alfa Aesar, 57−63% oil dispersion)
was washed with hexane and dried and used. Benzilic acid (Aldrich,
99%), methyl 2-hydroxyisobutyrate (Chem impex, 99.26%), n-
butyllithium (1.6 M in hexanes, Aldrich), L-valine (Oakwood, 99%),
L-(+)-mandelic acid (Oakwood, 99%), (−)-ethyl L-lactate (Oak-
wood, 99%), methyl 2-hydroxy acetate (Oakwood, 99%), (R)-
(+)-tert-butylsulfinamide (Chem Impex, 99.6%), thionyl chloride
(TCI, 98%), 4-methoxybenzyl chloride (AK Scientific, 95%), lithium
aluminum hydride (Alfa Aesar, 95%), dimethyl sulfoxide (Macro fine
chemical, ACS grade), oxalyl chloride (Aldrich, 99%), triethylamine
(Acros, 99%), titanium ethoxide (Oakwood, 95%), titanium
isopropoxide (Aldrich, 97%), sodium nitrite (Aldrich, 97%),
diisobutylaluminum hydride (1.0 M in hexane, Acros), sulfuric
acid (Macron Fine Chemical, concentrated), hydrochloric acid
(Macron Fine Chemical, concentrated), sodium hydroxide (Fisher
Chemical, pellets), tetra-n-butylammonium fluoride (1.0 M in THF,
Preparation of Methyl 2-((4-Methoxybenzyl)oxy)-2,2-dipheny-
lacetate (3a). A 250 mL, one-necked Schlenk flask containing an
egg-shaped stir bar (50.8 × 19.1 mm) was charged with 2a (11.00 g,
45.5 mmol), NaH (1.20 g, 50.0 mmol, 1.1 equiv), and DMF (SDS,
75 mL) under nitrogen. The solution was stirred at 25 °C for 10
min, and PMBCl (7.12 g, 6.17 mL, 45.5 mmol, 1.0 equiv) was
added dropwise by syringe over 5 min. The mixture was stirred at
25 °C for 12 h. The resulting mixture was diluted in ethyl acetate
(200 mL), transferred to 500 mL separatory funnel, washed with
water (3 × 100 mL) and brine (1 × 100 mL), dried over anhydrous
Na2SO4 (10 g), decanted, and concentrated by rotary evaporation
(30 °C, 50 mbar). The resulting residue was recrystallized from hot
hexane (200 mL) to afford 3a as a white solid (14.00 g, 84% yield).
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Data for 3a: mp 106−108 °C (hexanes); 1H NMR (500 MHz,
CDCl3) δ 7.51 (d, J = 6.5 Hz, 4H, HC(5)), 7.34 (m, 6H, HC(6,7)),
7.30 (d, J = 8.1 Hz, 2H, HC(10)), 6.88 (d, J = 8.5 Hz, 2H,
HC(11)), 4.29 (s, 2 H, HC(8)), 3.81 (s, 6 H, HC(1,13)); 13C{1H}
NMR (126 MHz, CDCl3) δ 172.5 (C(2)), 159.1 (C(12)), 141.1
(C(4)), 130.9 (C(9)), 129.3 (C(10)), 128.7 (C(5)), 128.2 (C(7)),
128.1 (C(6)), 113.8 (C(11)), 87.0 (C(3)), 67.7 (C(8)), 55.4
(C(13)), 52.7 (C(1); IR (neat) 2949 (w), 1733 (s), 1586 (w), 1513
(m), 1490 (w), 1462 (w), 1445 (m), 1384 (w), 1304 (w), 1238 (s),
1197 (m), 1179 (s), 1111 (w), 1094 (m), 1069 (m), 1030 (m),
1021 (m), 1011 (s), 943 (w), 902 (w), 854 (w), 823 (m), 808 (m),
767 (m), 752 (m), 724 (m), 696 (s), 675 (m), 641 (w), 630 (m),
612 (m), 549 (m), 517 (m), 503 (w), 483 (w); HRMS (ESI) m/z
(M + Na)+ calcd for C23H22O4Na 385.1416, found 385.1416; TLC
Rf 0.48 (silica gel, hexanes/EtOAc, 8:2, UV, KMnO4).
Preparation of 2-((4-Methoxybenzyl)oxy)-2,2-diphenylacetalde-
hyde (5a). A 200 mL, three-necked round-bottomed flask equipped
with nitrogen inlet, an egg-shaped stir bar (50.8 × 19.1 mm), an
internal temperature probe, and two rubber septa was charged with
oxalyl chloride (5.70 g, 3.86 mL 45.0 mmol, 1.5 equiv) and CH2Cl2
(40 mL, SDS) under nitrogen. The solution was cooled to −78 °C
using a cryocooler in an i-PrOH bath, and DMSO (3.50 g, 3.19 mL,
45.0 mmol, 1.5 equiv) was added dropwise to maintain internal
temperature below −70 °C. The solution was stirred at −78 °C for
10 min, and the solution of 4a (10.00 g, 30.0 mmol, solution in 10
mL of CH2Cl2 was added dropwise to maintain the internal
temperature below −70 °C. The resulting mixture was stirred at
−78 °C for 3 h, and triethylamine (freshly distilled, 9.10 g, 12.50
mL, 90.0 mmol, 3.0 equiv) was added dropwise to maintain the
internal temperature below −70 °C and was stirred for 2 h. The
mixture was slowly warmed to 0 °C, and 30 mL of water was added.
The two phases were transferred to a 250 mL separatory funnel, and
the organic layer was separated. The aqueous layer was extracted
with CH2Cl2 (2 × 100 mL), and the organic layers were combined,
washed with water (1 × 100 mL) and brine (1 × 100 mL), dried
over Na2SO4 (10 g), decanted, and concentrated by rotary
evaporation (30 °C, 50 mbar) to afford the crude product. The
crude product was purified by recrystallization with hot hexane (250
mL) to afford (8.40 g, 84%) 5a as a white solid. Data for 5a: mp
Preparation of 2-((4-Methoxybenzyl)oxy)-2,2-diphenylethan-1-
ol (4a). A 250 mL, one-necked Schlenk flask containing an egg-
shaped stir bar (50.8 × 19.1 mm) was charged with 3a (12.30 g,
34.0 mmol) and THF (120 mL, SDS) under nitrogen. The solution
was cooled to 0 °C in an ice bath, and LiAlH4 (2.58 g, 68.0 mmol,
2.0 equiv) was added portionwise under nitrogen flow over 5 min.
The slurry was slowly warmed to 25 °C and was stirred for 12 h.
Then the reaction mixture was cooled in an ice bath and was
quenched by the addition of 2.7 mL of water, 2.7 mL of 15% aq
NaOH solution, and 8.2 mL of water with vigorous stirring. The
mixture was stirred for 10 min and then was filtered through
Buchner funnel (90 mm diameter) to a filter flask (250 mL) to
remove the precipitates, and the filter cake was washed with diethyl
ether (2 × 75 mL). The filtrate was transferred to a 500 mL
separatory funnel, diluted with ethyl acetate (300 mL), washed with
satd aq Na2CO3 (1 × 100 mL), and brine (1 × 100 mL), dried over
Na2SO4 (10 g), decanted, and concentrated by rotary evaporation
(30 °C, 50 mbar) to afford the crude product. The crude product
was purified by recrystallization from hot hexane (250 mL) to afford
(10.00 g, 88%) 4a as a white solid. Data for 4a: mp 103−105 °C
1
71−73 °C (hexanes); H NMR (500 MHz, CDCl3) δ 9.96 (s, 1H,
HC(1)), 7.53 (m, 4H, HC(4)), 7.44−7.35 (m, 8H, HC(5,6,9)),
6.94 (d, J = 8.5 Hz, 2H, HC(10)), 4.36 (s, 2H, HC(7)), 3.83 (s,
3H, HC(12)); 13C{1H} NMR (126 MHz, CDCl3) δ 198.4 (C(1)),
159.2 (C(11)), 138.0 (C(3)), 130.3 (C(8)), 129.2 (C(9)), 128.7
(C(6)), 128.6 (C(4)), 128.4 (C(5)), 113.8 (C(10)), 88.9 (C(2)),
67.1 (C(7)), 55.3 (C(12)); IR (neat) 2909 (w), 2800 (w), 1728
(m), 1587 (w), 1515 (m), 1492 (w), 1461 (w), 1445 (m), 1380
(w), 1304 (w), 1238 (s), 1175 (m), 1115 (w), 1091 (m), 1066 (s),
1032 (m), 1017 (m), 998 (m), 917 (w), 834 (m), 819 (m), 773
(m), 761 (m), 752 (m), 711 (m), 696 (s), 671 (m), 635 (w), 628
(w), 575 (s), 546 (m), 516 (m), 488 (m), 752 (s), 729 (s), 720 (s),
713 (m), 697 (s), 649 (s), 623 (m), 572 (m), 531 (m), 509 (m),
465 (w); HRMS (ESI) m/z (M + Na)+ calcd for C22H20O3
355.1300, found 355.1310; TLC Rf 0.50 (silica gel, hexanes/
EtOAc, 8:2, UV, KMnO4).
1
(hexanes); H NMR (500 MHz, CDCl3) δ 7.47 (d, J = 7.2 Hz, 4H,
HC(5)), 7.34 (m, 8H, HC(6,7,10)), 6.94 (d, J = 8.2 Hz, 2H,
HC(11)), 4.43 (d, J = 6.4 Hz, 2H, HC(2)), 4.32 (s, 2H, HC(8)),
3.84 (s, 3H, HC(13)), 1.90 (t, J = 6.3 Hz, 1H, HC(1)); 13C{1H}
NMR (126 MHz, CDCl3) δ 159.1 (C(12)), 142.6 (C(4)), 130.8
(C(9)), 129.0 (C(10)), 128.3 (C(6)), 127.5 (C(7)), 127.3 (C(5)),
113.9 (C(11)), 83.1 (C(3)), 65.9 (C(2)), 64.9 (C(8)), 55.3
(C(13)); IR (neat) 3479 (w), 3023 (w), 2995 (w), 2933 (w), 2876
(w), 2835 (w), 1611 (m), 1586 (w), 1513 (m), 1490 (w), 1463
(w), 1447 (m), 1421 (w), 1384 (w), 1324 (w), 1305 (w), 1249 (s),
1231 (m), 1206 (m), 1175 (m), 1101 (m), 1069 (m), 1035 (m),
1004 (s), 987 (m), 947 (m), 935 (m), 907 (m), 869 (m), 855 (w),
826 (m), 811 (m), 784 (w), 752 (s), 729 (s), 720 (s), 713 (m), 697
(s), 649 (s), 623 (m), 572 (m), 531 (m), 509 (m), 465 (w);
HRMS (ESI) m/z (M + Na)+ calcd for C22H22O3Na 357.1475,
found 357.1467; TLC Rf 0.27 (silica gel, hexanes/EtOAc, 8:2, UV,
KMnO4.
Preparation of (R,E)-N-(2-((4-Methoxybenzyl)oxy)-2,2-dipheny-
lethylidene)-2-methylpropane-2-sulfinamide (6a). A 100 mL, one-
necked Schlenk flask with an egg-shaped stir bar (38.1 × 15.9 mm)
was charged with 5a (8.40 g, 25.3 mmol), (R)-2-methylpropane-2-
sulfinamide (3.21 g, 26.5 mmol, 1.05 equiv), and titanium(IV)
ethoxide (11.54 g, 10.6 mL, 50.6 mmol, 2.0 equiv) under nitrogen.
The mixture was stirred in 70 °C oil bath for 60 min and then was
diluted with ethyl acetate (50 mL). The resulting solution was
poured into a 200 mL Erlenmeyer flask with an egg-shaped stir bar
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(50.8 × 19.1 mm) and brine (5 mL), and the flask was rinsed with
ethyl acetate (2 × 25 mL) to help the transfer. The suspension was
stirred at 25 °C for 10 min and then was filtered through fritted
funnel (7.5 mm diameter) containing Celite. The Celite cake was
washed with ethyl acetate (2 × 100 mL). The combined filtrates
were transferred to a 250 mL separatory funnel, washed with water
(1 × 100 mL) and brine (1 × 100 mL), dried over Na2SO4 (10 g),
decanted, and concentrated by rotary evaporation (30 °C, 50 mbar).
The crude product was purified by column chromatography (silica,
4 cm ⌀ × 12 cm column) eluting with hexanes/diethyl ether, 7:3 to
afford 6a (9.40 g, 85%) as a white solid. Data for 6a: mp 91−93 °C
(hexanes/Et2O); 1H NMR (500 MHz, CDCl3) δ 8.58 (s, 1H,
HC(1)), 7.46 (m, 4H, HC(4, 4′)), 7.38−7.29 (m, 8H, HC-
(5,5′6,6′,9)), 6.88 (d, J = 8.6 Hz, 2H, HC(10)), 4.36 (q, J = 10.6
Hz, 2H, HC(7)), 3.81 (s, 3H, HC(12)), 1.16 (s, 9H, HC(14));
13C{1H} NMR (126 MHz, CDCl3) δ 169.0 (C(1)), 159.1 (C(11)),
141.3 (C(3)), 141.0 (C(3′)), 130.8 (C(9)), 129.1 (C(8)), 128.4
(C(5)), 128.4 (C(5′)), 128.4 (C(6)), 128.3 (C(6′)), 128.2 (C(4)),
128.1 (C(4′)), 113.7 (C(10)), 86.4 (C(2)), 66.7 (C(7)), 57.7
(C(13)), 55.3 (C(12)), 22.6 (C(14)); IR (neat) 2955 (w), 1615
(m), 1514 (m), 1489 (w), 1447 (m), 1379 (w), 1365 (w), 1304
(w), 1241 (m), 1172 (m), 1127 (m), 1084 (s), 1072 (s), 1030 (m),
924 (w), 831 (m), 817 (s), 760 (m), 749 (m), 697 (s), 636 (w),
583 (w), 542 (w), 514 (s), 455 (m); HRMS (ESI) m/z (M + H)+
calcd for C26H30NO3S 436.1945, found 436.1946; TLC Rf 0.27
(silica gel, hexanes/EtOAc, 8:2, UV, KMnO4).
(C(6′)), 129.7 (C(6)), 128.6 (C(5)), 128.3 (C(5′)), 128.1 (C(8)),
127.9 (C(9)), 127.7 (C(23)), 127.5 (C(4′)), 127.2 (C(4)), 126.9
(C(21)), 125.4 (C(18)), 113.6 (C(10)), 86.8 (C(2)), 65.5 (C(7)),
62.3 (C(1)), 55.5 (C(14)), 55.2 (C(12)), 22.6 (C(15)); IR (neat)
3290 (w), 3032 (w), 2956 (w), 2235 (w), 1613 (w), 1585 (w),
1513 (m), 1488 (w), 1447 (w), 1365 (w), 1301 (w), 1247 (m),
1173 (m), 1065 (s), 1035 (m), 1008 (m), 908 (m), 839 (m), 822
(m), 762 (m), 730 (s), 698 (s), 646 (m), 624 (m), 586 (m), 561
(w), 524 (m), 478 (m); HRMS (ESI) m/z (M + H)+ calcd for
C38H40NO3S 590.2735, found 590.2729; TLC Rf 0.18 (silica gel,
hexanes/EtOAc, 7:3, UV, KMnO4).
Preparation of (R)-N-((R)-1-(3,5-Di-tert-butylphenyl)-2-((4-
methoxybenzyl)oxy)-2,2-diphenylethyl)-2-methylpropane-2-sulfi-
namide (9). A 100 mL, one-necked Schlenk flask containing an egg-
shaped stir bar (38.1 × 15.9 mm) was charged with 1-bromo-3,5-di-
tert-butylbenzene (5.38 g, 20.0 mmol, 2.0 equiv) and THF (25 mL)
under nitrogen. The solution was cooled to −78 °C using a
cryocooler in an i-PrOH bath, and n-butyllithium (1.28 g, 13.0 mL,
1.6 M in hexane, 20.0 mmol, 2.0 equiv) was added dropwise by
syringe. The resulting solution was stirred at −78 °C using a
cryocooler in an i-PrOH bath for 1 h. Then another 50 mL Schlenk
flask containing a stir bar was charged with 6a (4.35 g, 10.0 mmol)
and THF (25 mL) under nitrogen and was cooled to −78 °C using
a cryocooler in an i-PrOH bath. The N-sulfinyl imine solution was
transferred to an organolithium solution using a syringe dropwise
over 5 min. The resulting mixture was stirred at −78 °C using a
cryocooler in i-PrOH bath for 12 h. The reaction was quenched by
the addition of satd aq NH4Cl solution (50 mL) at −78 °C and
slowly warmed to 25 °C. The mixture was transferred to a 250 mL
separatory funnel. The aqueous layer was extracted with ethyl
acetate (3 × 50 mL), and the organic layers were combined, washed
with brine (1 × 100 mL), dried over Na2SO4 (10 g), decanted, and
concentrated by rotary evaporation (30 °C, 50 mbar). The dr of the
Preparation of (R)-N-((R)-1-([1,1′-Biphenyl]-4-yl)-2-((4-
methoxybenzyl)oxy)-2,2-diphenylethyl)-2-methylpropane-2-sulfi-
namide (8). A 100 mL, one-necked Schlenk flask containing an egg-
shaped stir bar (38.1 × 15.9 mm) was charged with 4-bromo-1,1′-
biphenyl (4.66 g, 20.0 mmol, 2.0 equiv) and THF (25 mL) under
nitrogen. The solution was cooled to −78 °C using a cryocooler in
an i-PrOH bath, and n-butyllithium (1.28 g, 13.0 mL, 1.6 M in
hexane, 20.0 mmol, 2.0 equiv) was added dropwise by syringe. The
resulting solution was stirred at −78 °C using a cryocooler in an i-
PrOH bath for 1 h. Then another 50 mL Schlenk flask containing
an egg-shaped stir bar (19.1 × 9.5 mm) was charged with 6a (4.35
g, 10.0 mmol) and THF (25 mL) under nitrogen and was cooled to
−78 °C using a cryocooler in an i-PrOH bath. The N-sulfinyl imine
solution was transferred to the organolithium solution using a
syringe dropwise over 5 min. The resulting mixture was stirred at
−78 °C using a cryocooler in an i-PrOH bath for 12 h. The reaction
was quenched by the addition of satd aq NH4Cl solution (50 mL)
at −78 °C and slowly warmed to 25 °C. The mixture was
transferred to a 250 mL separatory funnel. The organic layer was
removed, the aqueous layer was extracted with ethyl acetate (3 × 50
mL), and the organic layers were combined, washed with brine (1 ×
100 mL), dried over Na2SO4 (10 g), decanted, and concentrated by
rotary evaporation (30 °C, 50 mbar). The dr of the crude product
1
crude product was 99:1 H NMR analysis. The crude product was
purified by column chromatography (silica, 4 cm ⌀ × 12 cm
column) eluting with hexanes/EtOAc, 1:1 to afford 9 (5.4 g, 86%)
1
as a white solid. Data for 9: mp 61−63 °C (hexanes/EtOAc); H
NMR (500 MHz, CDCl3); δ 7.42−7.29 (m, 10H, HC(4,5,6)),
7.24−7.19 (m, 3H, HC(9,19)), 6.86 (d, J = 8.5 Hz, 2H, HC(10)),
6.67 (s, 2H, HC(17)), 5.67 (s, 1H, HC(1)), 4.43 (s, 1H, HN(13)),
4.20 (d, J = 11.1 Hz, 1H, HC(7)), 4.02 (d, J = 11.1 Hz, 1H,
HC(7)), 3.79 (s, 3H, HC(12)), 1.15 (s, 9H, HC(15)), 1.13 (s,
18H, HC(21)); 13C{1H} NMR (126 MHz, CDCl3) δ 158.8
(C(11)), 148.6 (C(18)), 138.4 (C(3)), 138.2 (C(3′)), 134.8
(C(16)), 130.7 (C(8)), 130.2 (C(5)), 129.8 (C(5′)), 128.3 (C(9)),
127.9 (C(6)), 127.7 (C(6′)), 127.6 (C(4)), 127.4 (C(4′)), 125.1
(C(17)), 121.4 (C(19)), 113.6 (C(10)), 87.0 (C(2)), 65.6 (C(7)),
63.4 (C(1)), 55.4 (C(14)), 55.2 (C(12)), 34.5 (C(20)), 31.3
(C(21)), 22.6 (C(15)); IR (neat) 2954 (m), 2866 (w), 1614 (w),
1600 (w), 1514 (m), 1494 (w), 1447 (m), 1362 (m), 1302 (m),
1247 (s), 1173 (m), 1067 (s), 1036 (s), 908 (m), 876 (m), 822
(m), 757 (m), 725 (s), 702 (s), 654 (m), 625 (m), 591 (m), 507
(m); HRMS (ESI) m/z (M + H)+ calcd for C40H52NO3S 626.3696,
found 626.3668; TLC Rf 0.33 (silica gel, hexanes/EtOAc, 7:3, UV,
KMnO4).
1
was 99:1 by H NMR analysis. The crude product was purified by
column chromatography (silica, 4 cm ⌀ × 12 cm column) eluting
with hexanes/EtOAc, 1:1 to afford 8 (5.20 g, 88%) as a white solid.
1
Data for 8: mp 87−89 °C (hexanes/EtOAc); H NMR (500 MHz,
CDCl3) δ 7.66−7.61 (m, 2H, HC(21)), 7.50−7.35 (m, 15H,
HC(4,4′,5,5′,6,18,22,23)), 7.29 (d, J = 8.6 Hz, 2H, HC(9)), 6.97 (d,
J = 7.9 Hz, 2H, HC(17)), 6.94 (d, J = 8.6 Hz, 2H, HC(10)), 5.79
(s, 1H, HC(1)), 4.53 (s, 1H, HN(13)), 4.35 (d, J = 11.1 Hz, 1H,
HC(7)), 4.16 (d, J = 11.1 Hz, 1H, HC(7)), 3.85 (s, 3H, HC(12)),
1.22 (s, 9H, HC(15)); 13C{1H} NMR (126 MHz, CDCl3) δ 158.8
(C(11)), 140.7 (C(19)), 140.2 (C(20)), 138.5 (C(3)), 138.5
(C(3′)), 135.5 (C(16)), 131.2 (C(17)), 130.6 (C(22)), 130.1
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(M + H)+ calcd for C28H36NO 402.2810, found 402.2797; TLC Rf
0.41 (silica gel, hexanes/EtOAc, 8:2, UV, KMnO4).
Preparation of (R)-2-([1,1′-Biphenyl]-4-yl)-2-amino-1,1-dipheny-
lethan-1-ol (22). A 250 mL, one-necked Schlenk flask with an egg-
shaped stir bar (50.8 × 19.1 mm) was charged with 8 (5.13 g, 8.7
mmol) and methanol (10 mL) under nitrogen. HCl (10 N) in
MeOH (87 mL) was added dropwise by syringe. The reaction was
stirred for 2 h at 25 °C, and then the solvent was removed by rotary
evaporation (30 °C, 50 mbar). The crude solid was suspended in
ethyl acetate (50 mL), and 8 N NaOH in H2O (130 mL) was
added while the solution was stirred vigorously. The solution was
stirred for 10 min and then was transferred to a 500 mL separatory
funnel. The organic layer was separated, and the aqueous layer was
extracted with ethyl acetate (2 × 50 mL). pH paper was used to
check the neutralization of the solution (pH = 7). The organic
layers were combined, dried over anhydrous Na2SO4 (10 g),
decanted, and concentrated by rotary evaporation (30 °C, 50 mbar).
The crude product was purified by column chromatography (silica,
4 cm ⌀ × 12 cm column) eluting with hexanes/EtOAc, 7:3 to afford
22 (2.40 g, 77%) as a white solid. The spectroscopic data for 22
Preparation of N1,N3-Bis((R)-1-([1,1′-Biphenyl]-4-yl)-2-hydroxy-
2,2-diphenylethyl)-2,2-dimethylmalonamide (34). A 50 mL, one-
necked Schlenk flask containing an egg-shaped stir bar (15.9 × 6.35
mm) was charged with 22 (1.50 g, 4.1 mmol, 2.0 equiv), Et3N (1.04
g, 1.43 mL, 10.2 mmol, 5.0 equiv), and CH2Cl2 (10 mL) under
nitrogen. The solution was cooled to 0 °C using an ice bath, and
2,2-dimethylmalonyl dichloride (0.34 g, 0.27 mL, 2.05 mmol) was
added dropwise by syringe over 2 min. The resulting mixture was
slowly warmed to 25 °C and was stirred at 25 °C for 12 h. The
mixture was transferred to a 125 mL separatory funnel. The reaction
mixture was washed with water (1 × 50 mL) and then brine (1 ×
50 mL). The organic layer was removed, the aqueous layer was
extracted with CH2Cl2 (2 × 20 mL), and the organic layers were
combined, dried over Na2SO4 (10 g), decanted, and concentrated by
rotary evaporation (30 °C, 50 mbar). The crude product was
purified by column chromatography (silica, 3 cm ⌀ × 15 cm
column) eluting with hexanes/EtOAc, 7:3 gradient to 0:1 to afford
34 (1.40 g, 81%) as a white solid. Data for 34: mp 214−216 °C
matched the literature values.115 Data for 22: H NMR (500 MHz,
1
CD2Cl2) δ 7.74 (d, J = 7.6 Hz, 2H), 7.56−7.00 (m, 16H), 5.16 (s,
1H), 4.76 (s, 1H), 1.66 (s, 2H).
1
(hexanes/EtOAc); H NMR (500 MHz, CDCl3) δ 7.78 (d, J = 8.6
Hz, 2H, HN(4)), 7.61 (d, J = 7.7 Hz, 4H, HC(9)), 7.39−7.33 (m,
8H, HC(10,17)), 7.32−7.25 (m, 12H, HC(9′,10′,18)), 7.25−7.17
(m, 8H, HC(14,11′,19)), 7.17−7.12 (m, 2H, HC(11)), 6.94 (d, J =
8.2 Hz, 4H, HC(13)), 6.10 (d, J = 8.6 Hz, 2H, HC(5)), 2.67 (s,
2H, HO(7)), 0.97 (s, 6H, HC(1)); 13C{1H} NMR (126 MHz,
CDCl3) δ 172.5 (C(3)), 144.1 (C(8′)), 144.1 (C(8)), 140.3
(C(16)), 140.1 (C(15)), 136.2 (C(12)), 128.9 (C(13)), 128.8
(C(18)), 128.4 (C(10′)), 128.2 (C(9′)), 127.3 (C(14)), 127.2
(C(19)), 127.2 (C(17)), 126.8 (C(10)), 126.5 (C(9)), 125.8
(C(11′)), 125.6 (C(11)), 81.0 (C(6)), 59.1 (C(5)), 49.0 (C(2)),
23.4 (C(1)); IR (neat) 3407 (w), 1639 (m), 1511 (m), 1493 (m),
1449 (w), 1332 (w), 1189 (w), 1157 (m), 1058 (m), 1008 (w), 977
(w), 898 (m), 796 (w), 753 (s), 741 (s), 694 (s), 668 (w), 635
(m), 614 (m), 546 (m), 479 (m); HRMS (ESI) m/z (M + H)+
calcd for C57H51N2O4 827.3884, found 827.3849; TLC Rf 0.18
(silica gel, hexanes/EtOAc, 7:3, UV, KMnO4).
Preparation of (R)-2-Amino-2-(3,5-di-tert-butylphenyl)-1,1-di-
phenylethan-1-ol (23). A 250 mL, one-necked Schlenk flask with
an egg-shaped stir bar (50.8 × 19.1 mm) was charged with 9 (5.32
g, 8.5 mmol) and methanol (10 mL) under nitrogen. HCl (10 N) in
MeOH (85 mL) was added dropwise by syringe. The reaction was
stirred for 2 h at 25 °C, and then the solvent was removed by rotary
evaporation (30 °C, 50 mbar). The crude solid was suspended in
ethyl acetate (50 mL), and 8 N NaOH in H2O (127 mL) was
added while the solution was stirred vigorously. The solution was
stirred for 10 min and then was transferred to a 500 mL separatory
funnel. The organic layer was separated, and the aqueous layer was
extracted with ethyl acetate (2 × 50 mL). pH paper was used to
check the neutralization of the solution (pH = 7). The organic
layers were combined, dried over anhydrous Na2SO4 (10 g),
decanted, and concentrated by rotary evaporation (30 °C, 50 mbar).
The crude product was purified by column chromatography (silica,
4 cm ⌀ × 12 cm column) eluting with hexanes/EtOAc, 7:3 to afford
23 (2.60 g, 75%) as a white solid. Data for 23: mp 156−158 °C
Preparation of N1,N3-Bis((R)-1-(3,5-Di-tert-butylphenyl)-2-hy-
droxy-2,2-diphenylethyl)-2,2-dimethylmalonamide (35). A 50
mL, one-necked Schlenk flask containing an egg-shaped stir bar
(15.9 × 6.35 mm) was charged with 23 (1.76 g, 4.4 mmol, 2.0
equiv), Et3N (1.11 g, 1.53 mL, 11.0 mmol, 5.0 equiv), and CH2Cl2
(10 mL) under nitrogen. The solution was cooled to 0 °C using an
ice bath, and 2,2-dimethylmalonyl dichloride (0.37 g, 0.29 mL, 2.2
mmol) was added dropwise by syringe over 2 min. The resulting
mixture was slowly warmed to 25 °C and was stirred at 25 °C for
12 h. The mixture was transferred to a 125 mL separatory funnel.
The reaction mixture was washed with water (1 × 50 mL) and then
brine (1 × 50 mL). The organic layer was removed, the aqueous
layer was extracted with CH2Cl2 (2 × 20 mL), and the organic
layers were combined, dried over Na2SO4 (10 g), decanted, and
concentrated by rotary evaporation (30 °C, 50 mbar). The crude
product was purified by column chromatography (silica, 3 cm ⌀ ×
1
(hexanes/EtOAc); H NMR (500 MHz, CDCl3) δ 7.77 (d, J = 8.5
Hz, 2H, HC(4)), 7.42 (t, J = 7.4 Hz, 2H, HC(5)), 7.30 (t, J = 7.3
Hz, 1H, HC(6)), 7.18 (s, 1H, HC(12)), 7.11−6.94 (m, 5H,
HC(4′,5′,6′)), 6.89 (s, 2H, HC(10)), 4.99 (s, 1H, HC(1)), 4.66 (s,
1H, HO(7)), 1.65 (s, 2H, HN(8)), 1.19 (s, 18H, HC(14));
13C{1H} NMR (126 MHz, CDCl3) δ 149.5 (C(11)), 146.5 (C(3)),
144.2 (C(3′)), 138.8 (C(9)), 128.5 (C(5)), 127.3 (C(5′)), 127.0
(C(6)), 126.9 (C(4)), 126.3 (C(4′)), 126.2 (C(6′)), 123.0
(C(10)), 121.0 (C(12)), 79.7 (C(2)), 62.2 (C(1)), 34.7 (C(13)),
31.5 (C(14)); IR (neat) 2955 (m), 1601 (w), 1449 (m), 1362 (m),
1249 (w), 1178 (w), 1051 (w), 969 (w), 887 (m), 872 (m), 748
(s), 705 (s), 692 (s), 645 (s), 582 (m), 486 (m); HRMS (ESI) m/z
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15 cm column) eluting with hexanes/EtOAc, 7:3 gradient to 0:1 to
× 6.35 mm) was charged with 35 (0.41 g, 0.50 mmol) and xylenes
(12 mL) under nitrogen. The mixture was heated to reflux in a 160
°C oil bath using a condenser connected to a Dean−Stark apparatus
which was itself connected to Schlenk flask. Once the bisamide
alcohol dissolved completely then Ti(Oi-Pr)4 (0.028 g, 0.030 mL,
20 mol %) was added to the solution in one portion. The reaction
mixture was refluxed for 12 h with removal of the water byproduct.
After the reaction mixture was cooled to room temperature, the
solution was concentrated by rotary evaporation (60 °C, 50 mbar).
The crude product was purified by column chromatography (silica,
1 cm ⌀ × 15 cm column) eluting with n-hexane (95%)/EtOAc, 7:3
to afford 47 (0.30 g, 75%) as a white solid. Recrystallization from n-
hexane (95%) afforded 0.27 g (70%) of 47 as a white solid. Data for
47: mp 106−108 °C (n-hexane (95%)); 1H NMR (500 MHz,
CDCl3) δ 7.85−7.77 (m, 4H, HC(7)), 7.55−7.46 (m, 8H,
HC(8,12)), 7.44−7.37 (m, 6H, HC(15,17)), 7.37−7.29 (m, 10H,
HC(9′,11,16)), 7.24−7.20 (m, 4H, HC(7′)), 7.04−6.94 (m, 6H,
HC(8′,9)), 6.18−5.15 (m, 2H, HC(4)), 1.86 (s, 6H, HC(1));
13C{1H} NMR (126 MHz, CDCl3) δ 168.7 (C(3)), 144.6 (C(6)),
140.8 (C(14)), 140.1 (C(13)), 139.8 (C(6′)), 137.6 (C(10)), 128.9
(C(11)), 128.7 (C(12)), 128.5 (C(16)), 128.2 (C(8)), 127.3
(C(15)), 127.1 (C(8′)), 127.0 (C(9)), 126.9 (C(7′)), 126.8
(C(9′)), 126.5 (C(7)), 126.4 (C(16)), 95.4 (C(5)), 78.7 (C(4)),
39.5 (C(2)), 24.6 (C(1)); IR (neat)1655 (s), 1487 (s), 1446 (s),
1306 (s), 1240 (s), 1147 (s), 1122 (s), 1084 (s), 962 (s), 815 (s),
749 (m), 694 (m), 502 (s); LRMS [ESI+, TOF] 246.1(1),
791.3(100), 792.3(75), 793.3(27), 794.3(7), 813.3(4); HRMS
(ESI) m/z (M + H)+ calcd for C57H47N2O2 791.3647, found
791.3638; TLC Rf 0.49 (silica gel, hexanes/EtOAc, 8:2, UV,
afford 35 (1.70 g, 85%) as a white solid. Data for 35: mp 123−125
1
°C (hexanes/EtOAc); H NMR (500 MHz, CDCl3) δ 7.92 (d, J =
9.2 Hz, 2H, HN(4)), 7.68−7.61 (m, 4H, HC(9)), 7.33−7.26 (m,
8H, HC(10,9′)), 7.23−7.16 (m, 6H, HC(10′,11)), 7.10 (t, J = 1.6
Hz, 4H, HC(11′,17)), 6.69 (d, J = 1.7 Hz, 4H, HC(13)), 6.12 (d, J
= 9.2 Hz, 2H, HC(5)), 2.52 (s, 2H, HO(17)), 1.01 (s, 36H,
HC(16)), 0.90 (s, 6H, HC(1)); 13C{1H} NMR (126 MHz, CDCl3)
δ 172.4 (C(3)), 150.1 (C(14)), 144.6 (C(8′)), 144.0 (C(8)), 135.3
(C(12)), 128.3 (C(10)), 128.105 (C(9′)), 127.055 (C(11′)),
126.975 (C(11)), 125.895 (C(9)), 125.5 (C(12)), 122.4 (C(13)),
121.6 (C(17)), 81.0 (C(6)), 59.4 (C(5)), 48.6 (C(2)), 34.6
(C(15)), 31.3 (C(16)), 23.8 (C(1)); IR (neat) 2962 (m), 1665
(m), 1495 (m), 1448 (m), 1362 (m), 1249 (m), 1199 (m), 1056
(w), 898 (w), 747 (m), 697 (s), 658 (m), 588 (m); HRMS (ESI)
m/z (M + H)+ calcd for C61H74N2O4 899.5755, found 899.5727;
TLC Rf 0.30 (silica gel, hexanes/EtOAc, 8:2, UV, KMnO4).
Preparation of (4R,4′R)-2,2′-(Propane-2,2-diyl)bis(4-(3,5-di-tert-
butylphenyl)-5,5-diphenyl-4,5-dihydrooxazole)) (46). A 25 mL,
one-necked Schlenk flask containing an egg-shaped stir bar (15.9 ×
6.35 mm) was charged with 34 (0.45 g, 0.50 mmol) and xylenes (12
mL) under nitrogen. The mixture was heated to reflux in a 160 °C
oil bath using a condenser connected to a Dean−Stark apparatus
which was itself connected to Schlenk flask. Once the bisamide
alcohol dissolved completely, Ti(Oi-Pr)4 (0.028 g, 0.030 mL, 20 mol
%) was added to the solution in one portion. The reaction mixture
was refluxed for 12 h with removal of the water byproduct. After the
reaction mixture was cooled to room temperature, the solution was
concentrated by rotary evaporation (60 °C, 50 mbar). The crude
product was purified by column chromatography (silica, 1 cm ⌀ ×
15 cm column) eluting with n-hexane (95%)/EtOAc, 7:3 to afford
46 (0.37 g, 85%) as a white solid. Data for 46: mp 85−87 °C (n-
24
KMnO4); [α]D +507.0 (c = 1.0, CHCl3). Anal. Calcd for
C57H46N2O2·0.35H2O: C, 86.55; H, 5.86; N, 3.54. Found: C,
85.87; H, 5.90; N, 3.51.
Synthesis of Bisoxazoline Ligands with a Geminal Dimethyl
Substituent at the C(5)-position.
1
hexane (95%)/EtOAc); H NMR (500 MHz, CDCl3) δ 7.65 (d, J =
7.8 Hz, 4H, HC(7)), 7.35−7.27 (m, 6H, HC(7′,9)), 7.03−6.98 (m,
6H, HC(8,13)), 6.93−6.89 (m, 6H, HC(8′,9′)), 6.86 (d, J = 1.6 Hz,
4H, HC(11)), 5.97 (s, 2H, HC(4)), 1.89 (s, 6H, HC(1)), 1.11 (s,
36H, HC(15)); 13C{1H} NMR (126 MHz, CDCl3) δ 168.4 (C(3)),
149.7 (C(12)), 145.1 (C(6)), 140.5 (C(6′)), 137.5 (C(10)), 128.3
(C(7′)), 127.9 (C(9)), 127.0 (C(8′)), 127.0 (C(8)), 126.6 (C(7)),
126.2 (C(9′)), 123.0 (C(11)), 120.7 (C(13)), 95.0 (C(5)), 80.4
(C(4)), 39.7 (C(2)), 34.6 (C(14)), 31.3 (C(15)), 25.3 (C(1)); IR
(neat) 2961 (s), 1660 (s), 1600 (s), 1447 (s), 1361 (s), 1248 (s),
1146 (s), 1123 (s), 964 (s), 871 (s), 821 (s), 753 (s), 601 (s);
LRMS [ESI+, TOF] 843.6(2), 863.5(100), 864.5(70), 865.5(25),
866.5(8), 881.5(2); HRMS (ESI) m/z (M + H)+ calcd for
C61H71N2O2 863.5526, found 863.5516; TLC Rf 0.40 (silica gel,
Preparation of Methyl 2-((4-Methoxybenzyl)oxy)-2-methylpropa-
noate (3b). A 250 mL, one-necked Schlenk flask containing an egg-
shaped stir bar (50.8 × 19.1 mm) was charged with methyl 2-
hydroxy-2-methylpropanoate (5.90 g, 5.76 mL, 50.0 mmol), NaH
(1.32 g, 55.0 mmol, 1.1 equiv), and DMF (SDS, 80 mL) under
nitrogen. The solution was stirred at 25 °C for 10 min, and PMBCl
(7.83 g, 6.77 mL, 50.0 mmol, 1.0 equiv) was added dropwise over 5
min. The mixture was stirred at 25 °C for 12 h. The resulting
mixture was diluted in ethyl acetate (200 mL), transferred to 500
mL separatory funnel, washed with water (3 × 100 mL) and brine
(1 × 100 mL), dried over anhydrous Na2SO4 (10 g), decanted, and
concentrated by rotary evaporation (30 °C, 50 mbar). The crude
product was purified by column chromatography (silica, 4 cm ⌀ ×
12 cm column) eluting with hexanes/EtOAc, 9:1 to afford 3b
(11.07 g, 93%) as a colorless oil. Data for S3b: 1H NMR (500
MHz, CDCl3); δ 7.31 (d, J = 8.5 Hz, 2H, HC(7)), 6.87 (d, J = 8.7
Hz, 2H, HC(8)), 4.39 (s, 2H, HC(5)), 3.77 (s, 3H, HC(1)), 3.75
(s, 3H, HC(10)), 1.51 (s, 6H, HC(4)); 13C{1H} NMR (126 MHz,
CDCl3) δ 175.1 (C(2)), 159.1 (C(9)), 130.6 (C(6)), 129.2 (C(7)),
113.7 (C(8)), 77.8 (C(3)), 66.7 (C(5)), 55.1 (C(10)), 51.9
(C(1)), 24.9 (C(4)); IR (neat) 2991 (w), 2952 (w), 1733 (s), 1614
(m), 1587 (w), 1514 (s), 1465 (m), 1383 (m), 1362 (w), 1301
(m), 1279 (m), 1247 (s), 1172 (s), 1139 (s), 1034 (s), 1003 (m),
913 (w), 822 (m), 755 (w), 731 (m), 648 (w), 612 (w), 575 (w),
519 (w); HRMS (ESI) m/z (M + Na)+ calcd for C13H18O4Na
24
hexanes/EtOAc, 9:1, UV, KMnO4); [α]D +319.6 (c = 1.0, CHCl3).
Anal. Calcd for C61H70N2O2: C, 84.87; H, 8.17; N, 3.25. Found: C,
84.85; H, 8.08; N, 3.23.
Preparation of (4R,4′R)-2,2′-(propane-2,2-diyl)bis(4-([1,1′-bi-
phenyl]-4-yl)-5,5-diphenyl-4,5-dihydrooxazole) (47). A 25 mL,
one-necked Schlenk flask containing an egg-shaped stir bar (15.9
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261.1103, found 261.1103; TLC Rf 0.46 (silica gel, hexanes/EtOAc,
8:2, UV, KMnO4).
−78 °C for 3 h and triethylamine (freshly distilled, 13.00 g, 18.0
mL, 130.0 mmol, 3.0 equiv) was added dropwise to maintain the
internal temperature below −70 °C and was stirred for 2 h. The
mixture was slowly warmed to 0 °C, and 30 mL of water was added.
The two phases were transferred to a 250 mL separatory funnel, and
the organic layer was separated, The aqueous layer was extracted
with CH2Cl2 (2 × 100 mL), and the organic layers were combined,
washed with water (1 × 100 mL) and brine (1 × 100 mL), dried
over Na2SO4 (10 g), decanted, and concentrated by rotary
evaporation (30 °C, 50 mbar) to afford the crude product. The
crude product was purified by column chromatography (silica, 4 cm
⌀ × 12 cm column) eluting with hexanes/Et2O, 7:3 to afford 5b
1
(7.60 g, 87%) as a colorless oil. Data for 5b: H NMR (500 MHz,
Preparation of 2-((4-Methoxybenzyl)oxy)-2-methylpropan-1-ol
(4b). A 250 mL, one-necked Schlenk flask containing an egg-shaped
stir bar (50.8 × 19.1 mm) was charged with 3b (11.20 g, 47.0
mmol) and THF (150 mL, SDS) under nitrogen. The solution was
cooled to 0 °C in an ice bath, and LiAlH4 (3.56 g, 94.0 mmol, 2.0
equiv) was added portionwise under nitrogen flow over 5 min. The
slurry was slowly warmed to 25 °C and was stirred for 12 h. Then,
the reaction mixture was cooled in an ice bath and was quenched by
the addition of 3.76 mL of water, 3.76 mL of 15% NaOH solution,
and 11.28 mL of water with vigorous stirring. The mixture was
stirred for 10 min and then was filtered through Buchner funnel (90
mm diameter) to a filter flask (250 mL) to remove the precipitates,
and the filter cake was washed with diethyl ether (2 × 75 mL). The
filtrate was transferred to a 500 mL separatory funnel, diluted with
ethyl acetate (300 mL), washed with satd aq Na2CO3 (1 × 100 mL)
and brine (1 × 100 mL), dried over Na2SO4 (10 g), decanted, and
concentrated by rotary evaporation (30 °C, 50 mbar) to afford the
crude product. The crude product was purified by column
chromatography (silica, 4 cm ⌀ × 12 cm column) eluting with
hexanes/EtOAc, 8:2 to afford 4b (8.80 g, 89%) as a colorless oil.
CDCl3) δ 9.63 (s, 1H, HC(1)), 7.29 (d, J = 9.0 Hz, 2H, HC(6)),
6.89 (d, J = 8.8 Hz, 2H, HC(7)), 4.40 (s, 2H, HC(4)), 3.79 (s, 3H,
HC(9)), 1.35 (s, 6H, HC(3)); 13C{1H} NMR (126 MHz, CDCl3)
δ 204.3 (C(1)), 159.3 (C(8)), 130.3 (C(5)), 129.2 (C(6)), 113.9
(C(7)), 80.3 (C(2)), 66.3 (C(4)), 55.2 (C(9)), 21.0 (C(3)); IR
(neat) 2981 (w), 2837 (w), 1732 (m), 1613 (m), 1587 (w), 1514
(s), 1465 (m), 1385 (m), 1361 (w), 1302 (m), 1246 (s), 1168 (s),
1110 (w), 1034 (s), 821 (m), 774 (w), 749 (w), 638 (w), 611 (w),
520 (w); HRMS (ESI) m/z (M + Na)+ calcd for C12H16O3Na
231.1001, found 233.0997; TLC Rf 0.50 (silica gel, hexanes/EtOAc,
8:2, UV, KMnO4).
1
Data for 4b: H NMR (500 MHz, CDCl3) δ 7.29 (d, J = 8.6 Hz,
2H, HC(7)), 6.90 (d, J = 8.6 Hz, 2H, HC(8)), 4.40 (s, 2H,
HC(5)), 3.80 (s, 3H, HC(10)), 3.48 (d, J = 6.2 Hz, 2H, HC(2)),
2.59 (td, J = 6.3, 1.5 Hz, 1H, HO(1)), 1.28 (s, 6H, HC(4));
13C{1H} NMR (126 MHz, CDCl3) δ 158.9 (C(9)), 131.2 (C(6)),
128.9 (C(7)), 113.6 (C(8)), 75.5 (C(3)), 69.5 (C(2)), 63.6
(C(5)), 55.1 (C(10)), 21.9 (C(4)); IR (neat) 2971 (w), 2836 (w),
1613 (m), 1587 (w), 1513 (s), 1464 (m), 1385 (w), 1364 (w),
1301 (m), 1244 (s), 1172 (m), 1155 (m), 1110 (w), 1033 (s), 888
(m), 820 (s), 780 (w), 741 (m), 637 (w), 564 (m), 519 (m);
HRMS (ESI) m/z (M + Na)+ calcd for C12H18O3Na 233.1148,
found 233.1154; TLC Rf 0.30 (silica gel, hexanes/EtOAc, 7:3, UV,
KMnO4).
Preparation of (R,E)-N-(4-(4-Methoxyphenyl)-2,2-dimethylbuty-
lidene)-2-methylpropane-2-sulfinamide (6b). A 100 mL, one-
necked Schlenk flask with an egg-shaped stir bar (38.1 × 15.9
mm) was charged with 5b (7.60 g, 36.0 mmol), (R)-2-
methylpropane-2-sulfinamide (4.60 g, 38.0 mmol, 1.05 equiv), and
titanium(IV) ethoxide (17.00 g, 15 mL, 73.0 mmol, 2.0 equiv)
under nitrogen. The mixture was stirred in a 70 °C oil bath for 60
min and then was diluted with ethyl acetate (50 mL). The resulting
solution was poured into a 200 mL Erlenmeyer flask with a stir bar
and brine (5 mL), and the vial was rinsed with ethyl acetate (2 × 25
mL) to help transfer. The suspension was stirred at 25 °C for 10
min and then was filtered through a fritted glass funnel (7.5 mm
diameter) containing Celite. The Celite cake was washed with ethyl
acetate (2 × 100 mL). The combined filtrates were transferred to a
250 mL separatory funnel and then were washed with water (1 ×
100 mL) and brine (1 × 100 mL), dried over Na2SO4 (10 g),
decanted, and concentrated by rotary evaporation (30 °C, 50 mbar).
The crude product was purified by column chromatography (silica,
4 cm ⌀ × 12 cm column) eluting with hexanes/diethyl ether, 7:3 to
1
afford 6b (8.80 g, 77%) as a yellow oil. Data for 6b: H NMR (500
MHz, CDCl3) δ 8.07 (s, 1H, HC(1)), 7.20 (d, J = 8.7 Hz, 2H,
HC(6)), 6.80 (d, J = 8.7 Hz, 2H, HC(7)), 4.31 (s, 2H, HC(4)),
3.70 (s, 3H, HC(9)), 1.41 (d, J = 8.5 Hz, 6H, HC(3,3′)), 1.16 (s,
9H, HC(11)); 13C{1H} NMR (126 MHz, CDCl3) δ 172.6 (C(1)),
158.9 (C(8)), 130.2 (C(5)), 128.9 (C(6)), 113.6 (C(7)), 77.7
(C(2)), 65.8 (C(4)), 56.6 (C(10)), 54.9 (C(9)), 24.2 (C(3′)), 23.8
(C(3)), 22.2 (C(11)); IR (neat) 2980 (w), 1615 (m), 1587 (w),
1514 (s), 1459 (m), 1382 (m), 1362 (m), 1324 (w), 1302 (m),
1247 (s), 1159 (s), 1086 (s), 1035 (s), 910 (m), 821 (m), 793 (w),
730 (s), 646 (w), 583 (m), 523 (w), 479 (w); HRMS (ESI) m/z
(M + H)+ calcd for C16H26NO3S 312.1636, found 312.1633; TLC
Rf 0.29 (silica gel, hexanes/EtOAc, 8:2, UV, KMnO4).
Preparation of 2-((4-Methoxybenzyl)oxy)-2-methylpropanal
(5b). A 250 mL, three-necked round-bottomed flask equipped
with nitrogen inlet, an egg-shaped stir bar (50.8 × 19.1 mm), an
internal temperature probe, and two rubber septa was charged with
oxalyl chloride (8.00 g, 5.40 mL 63.0 mmol, 1.5 equiv) and CH2Cl2
(120 mL, SDS) under nitrogen. The solution was cooled to −78 °C
using a cryocooler in an i-PrOH bath, and DMSO (4.90 g, 4.50 mL,
63.0 mmol, 1.5 equiv) was added dropwise to maintain the internal
temperature below −70 °C. The solution was stirred at −78 °C for
10 min and the solution of 4b (8.80 g, 42.0 mmol, solution in 10
mL of CH2Cl2 was added dropwise to maintain the internal
temperature below −70 °C. The resulting mixture was stirred at
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Preparation of (R)-N-((R)-1-(2,6-Dimethylphenyl)-2-((4-
methoxybenzyl)oxy)-2-methylpropyl)-2-methylpropane-2-sulfina-
mide (11). A 100 mL, one-necked Schlenk flask containing an egg-
shaped stir bar (38.1 × 15.9 mm) was charged with 2-bromo-1,3-
dimethylbenzene (5.55 g, 3.99 mL, 30.0 mmol, 2.0 equiv) and THF
(25 mL) under nitrogen. The solution was cooled to −78 °C using
a cryocooler in an i-PrOH bath, and n-butyllithium (1.92 g, 18.75
mL, 1.6 M in hexane, 30.0 mmol, 2.0 equiv) was added dropwise by
syringe. The resulting solution was stirred at −78 °C using a
cryocooler in an i-PrOH bath for 1 h. Then another 25 mL Schlenk
flask containing a stir bar was charged with 6b (4.67 g, 15.0 mmol,
1.0 equiv) and THF (10 mL) under nitrogen and was cooled to
−78 °C using a cryocooler in an i-PrOH bath. The N-sulfinyl imine
solution was transferred to organolithium solution using a syringe
dropwise over 5 min. The resulting mixture was stirred at −78 °C
using a cryocooler in an i-PrOH bath for 12 h. The reaction was
quenched by the addition of satd aq NH4Cl solution (50 mL) at
−78 °C and slowly warmed to 25 °C. The mixture was transferred
to a 250 mL separatory funnel. The aqueous layer was extracted
with ethyl acetate (3 × 50 mL), and the organic layers were
combined, washed with brine (1 × 100 mL), dried over Na2SO4 (10
g), decanted, and concentrated by rotary evaporation (30 °C, 50
Preparation of (R)-N-((R)-3-((4-Methoxybenzyl)oxy)-3-methyl-1-
(naphthalen-1-yl)butan-2-yl)-2-methylpropane-2-sulfinamide
(10). A 100 mL, one-necked Schlenk flask containing an egg-shaped
stir bar (38.1 × 15.9 mm) was charged with hexane-washed small
pieces of lithium (0.62 g, 6.0 mmol, 6.0 equiv) and was stirred with
pure hexane (SDS, 25 mL) for 25 min at 25 °C, so as to remove
lithium oxide (white solid). After 25 min, hexane was removed using
a syringe, and lithium pieces were dried in vacuum. Then THF (30
mL) was added under nitrogen. The solution of 1-(bromomethyl)-
naphthalene (6.63 g, 30.0 mmol, 2.0 equiv) in THF (20 mL) was
added dropwise by syringe. The resulting solution was stirred at 25
°C for 1 h, and the color of the mixture turned into rust (dark
brown). The formation of the organolithium was confirmed by
quenching an aliquot by NH4Cl solution and confirming through
proton NMR analysis. Then, the organolithium solution was cooled
to −78 °C. using a cryocooler in an i-PrOH bath and the
temperature was monitor using an internal temperature probe.
Another 25 mL, one-necked Schlenk flask containing 6b (4.66 g,
15.0 mmol) and THF (10 mL) under nitrogen was cooled to −78
°C using a cryocooler in an i-PrOH bath. This cooled imine was
added dropwise into Schlenk flask containing cooled organolithium
using a syringe maintaining the internal temperature below −70 °C.
The reaction was quenched by the addition of satd aq NH4Cl
solution (50 mL) at −78 °C, and was slowly warmed to 25 °C. The
mixture was transferred to a 250 mL separatory funnel. The aqueous
layer was extracted with ethyl acetate (3 × 50 mL), and the organic
layers were combined, washed with brine (1 × 100 mL), dried over
Na2SO4 (10 g), decanted, and concentrated by rotary evaporation
1
mbar). The dr of the crude product was 60:40 by H NMR analysis.
The crude product was purified by column chromatography (silica,
4 cm ⌀ × 12 cm column) eluting with hexanes/EtOAc, 1:1 to afford
11 (3.24 g, 52%) and 11′ (2.16 g, 34%) as a colorless oil. Data for
1
11 (Major isomer): H NMR (500 MHz, CDCl3) δ 7.27 (d, J = 8.6
Hz, 2H, HC(9)), 7.04 (t, J = 7.4 Hz, 1H, HC(16)), 7.02−6.95 (m,
2H, HC(15,15′)), 6.87 (d, J = 8.6 Hz, 2H, HC(10)), 5.00 (d, J =
4.4 Hz, 1H, HC(4)), 4.65 (d, J = 4.3 Hz, 1H, HC(3)), 4.47 (d, J =
10.3 Hz, 1H, HC(7)), 4.40 (d, J = 10.3 Hz, 1H, HC(7)), 3.81 (s,
3H, HC(12)), 2.45 (d, J = 4.2 Hz, 6H, HC(17,17′)), 1.48 (s, 3H,
HC(6′)), 1.14 (s, 3H, HC(6)), 1.13 (s, 9H, HC(1)); 13C{1H}
NMR (126 MHz, CDCl3) δ 159.0 (C(11)), 138.3 (C(13)), 137.6
(C(14′)), 136.0 (C(14)), 131.0 (C(8)), 130.8 (C(15′)), 129.3
(C(9)), 128.4 (C(15)), 127.0 (C(16)), 113.8 (C(10)), 78.7 (C(5)),
63.5 (C(7)), 62.4 (C(4)), 55.5 (C(2)), 55.3 (C(12)), 24.2 (C(6′)),
23.5 (C(6)), 22.7 (C(1)), 22.5 (C(17′)), 22.5 (C(17)); IR (neat)
2955 (s), 1613 (s), 1513 (m), 1464 (s), 1364 (s), 1301 (s), 1247
(m), 1173 (s), 1145 (s), 1066 (m), 1032 (m), 958 (s), 923 (s), 873
(s), 821 (s), 792 (s), 770 (m), 728 (m), 587 (s), 519 (s), 493 (s);
HRMS (ESI) m/z (M + H)+ calcd for C24H36NO3S 418.2406,
found 418.2416; TLC Rf 0.50 (silica gel, hexanes/EtOAc, 6:4, UV,
KMnO4). Data for 11′ (minor isomer): 1H NMR (500 MHz,
CDCl3) δ 0.25 (d, J = 8.5 Hz, 2H, HC(9)), 7.04 (d, J = 7.0 Hz, 1H,
HC(16)), 6.99 (d, J = 7.4 Hz, 2H, HC(15,15′)), 6.90 (d, J = 8.5
Hz, 2H, HC(10)), 4.82 (q, J = 8.6 Hz, 2H, HC(4,3)), 4.40 (s, 2H,
HC(7)), 3.83 (s, 3H, HC(12)), 2.53 (s, 3H, HC(17)), 2.44 (s, 3H,
HC(17′)), 1.53 (s, 3H, HC(6′)), 1.14 (s, 9H, HC(1)), 1.10 (s, 3H,
HC(6)); 13C{1H} NMR (126 MHz, CDCl3) δ 158.9 (C(11)),
138.0 (C(13)), 137.1 (C(14′)), 136.7 (C(14)), 131.1 (C(8)), 130.8
(C(15′)), 129.0 (C(9)), 128.3 (C(15)), 126.9 (C(16)), 113.6
(C(10)), 78.6 (C(5)), 63.5 (C(7)), 61.2 (C(4)), 56.5 (C(2)), 55.2
(C(12)), 24.9 (C(6′)), 22.8 (C(17)), 22.7 (C(6)), 22.5 (C(1)),
22.3 (C(17)); IR (neat) 2973 (s), 1612 (s), 1513 (m), 1463 (s),
1387 (s), 1301 (s), 1247 (m), 1172 (s), 1148 (m), 1109 (m), 1033
(m), 958 (s), 955 (s), 910 (s), 822 (s), 791 (s), 769 (m), 729 (m),
644 (s), 572 (s), 528 (s); HRMS (ESI) m/z (M + H)+ calcd for
C24H36NO3S 418.2416, found 418.2416; TLC Rf 0.0.53 (silica gel,
hexanes/EtOAc, 6:4, UV, KMnO4).
1
(30 °C, 50 mbar). The dr of the crude product was 85:15 by H
NMR analysis. The crude product was purified by column
chromatography (silica, 4 cm ⌀ × 12 cm column) eluting with
hexanes/EtOAc, 1:1 to afford 10 (3.60 g, 80%) as a yellow oil. Data
1
for 10: H NMR (500 MHz, CDCl3) δ 8.07 (d, J = 8.8 Hz, 1H,
HC(16)), 7.85−7.83 (m, 1H, HC(19)), 7.73 (d, J = 7.7 Hz, 1H,
HC(21)), 7.51−7.45 (m, 2H, HC(18,22)), 7.43−7.34 (m, 4H,
HC(9,17,23)), 6.92 (d, J = 8.7 Hz, 2H, HC(10)), 4.49 (dd, J =
20.0, 10.0 Hz, 2H, HC(7)), 3.90 (d, J = 6.2 Hz, 1H, HN(3)), 3.87−
3.78 (m, 4H, HC(4,12)), 3.54 (dd, J = 14.2, 4.2 Hz, 1H, HC(13)),
3.24 (dd, J = 14.2, 9.8 Hz, 1H, HC(13)), 1.53 (s, 3H, HC(6′)),
1.44 (s, 3H, HC(6)), 0.81 (s, 9H, HC(1)); 13C{1H} NMR (126
MHz, CDCl3) δ 158.9 (C(11)), 135.4 (C(14)), 133.9 (C(15)),
132.5 (C(20)), 131.3 (C(8)), 129.1 (C(9)), 128.8 (C(19)), 128.3
(C(22)), 127.2 (C(21)), 126.0 (C(18)), 125.4 (C(17)), 125.2
(C(23)), 123.8 (C(16)), 113.8 (C(10)), 77.6 (C(5)), 63.5 (C(4)),
63.3 (C(7)), 55.8 (C(2)), 55.3 (C(12)), 34.9 (C(13)), 23.2
(C(6′)), 23.0 (C(6)), 22.3 (C(1)); IR (neat) 2955 (s), 1612 (s),
1512 (m), 1463 (s), 1388 (s), 1365 (s), 1301 (s), 1246 (m), 1173
(s), 1143 (s), 1035 (m), 908 (s), 821 (s), 790 (m), 729 (m), 644
(s), 581 (s), 515 (s); HRMS (ESI) m/z (M + H)+ calcd for
C27H36NO3S 454.2410, found 454.2416; TLC Rf 0.6 (silica gel,
hexanes/EtOAc, 1:1, UV, KMnO4).
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The crude product was purified by column chromatography (silica,
4 cm ⌀ × 12 cm column) eluting with MeOH/EtOAc, 1:9 to afford
1
25 (0.94 g, 90%) as a colorless oil. Data for 25: H NMR (500
MHz, CDCl3) δ 7.11−6.93 (m, 3H, HC(8,8′,9)), 4.43 (s, 1H,
HC(2)), 3.05 (s, 3H, HN, HO(1,5)), 2.61 (s, 3H, HC(10′)), 2.36
(s, 3H, HC(10)), 1.37 (s, 3H, HC(4′)), 1.01 (s, 3H, HC(4));
13C{1H} NMR (126 MHz, CDCl3) δ 138.63 (C(6)), 136.93
(C(7′)), 136.83 (C(7)), 130.93 (C(8′)), 128.33 (C(8)), 126.63
(C(9)), 72.63 (C(3)), 59.13 (C(2)), 30.43 (C(4′)), 26.63 (C(4)),
22.53 (C(10′)), 22.3 (C(10)); IR (neat) 2969 (s), 1581 (s), 1449
(s), 1465 (s), 1375 (s), 1162 (s), 954 (s), 908 (w), 960 (m), 769
(m), 728 (w), 645 (s), 601 (s), 567 (s), 474 (s); HRMS (ESI) m/z
(M + H)+ calcd for C12 H20 N O 194.1538, found 194.1545; TLC
Rf 0.32 (silica gel, MeOH/EtOAc, 0.5:9.5, UV, KMnO4).
Preparation of (R)-3-Amino-2-methyl-4-(naphthalen-1-yl)-
butan-2-ol (24). A 300 mL, one-necked Schlenk flask with an
egg-shaped stir bar (50.8 × 19.1 mm) was charged with 10 (2.85 g,
6.3 mmol) and methanol (10 mL) under nitrogen. HCl (6 N) in
MeOH (63 mL) was added dropwise by syringe. The mixture was
stirred for 2 h at 25 °C, and then the solvent was removed rotary
evaporation (30 °C, 50 mbar). The crude solid was suspended in
ethyl acetate (50 mL), and 8 N NaOH in H2O (94.5 mL) was
added while the solution was stirred vigorously. The solution was
stirred for 10 min and then was transferred to a 500 mL separatory
funnel. The organic layer was separated and the aqueous layer was
extracted with ethyl acetate (2 × 50 mL). pH paper was used to
check the neutralization of the solution (pH= 7). The organic layers
were combined, dried over anhydrous Na2SO4 (10 g), decanted, and
concentrated by rotary evaporation (30 °C, 50 mbar). The crude
product was purified by column chromatography (silica, 4 cm ⌀ ×
12 cm column) eluting with MeOH/EtOAc, 1:9 to afford 24 (1.36
g, 92%) as a white solid. Data for 24: mp 124−126 °C(MeOH/
Preparation of N1,N3-Bis((R)-1-(2,6-Dimethylphenyl)-2-hydroxy-
2-methylpropyl)-2,2-dimethylmalonamide (37). A 50 mL, one-
necked Schlenk flask containing an egg-shaped stir bar (15.9 × 6.35
mm) was charged with 25 (0.81 g, 4.2 mmol, 2.0 equiv), Et3N (1.06
g, 1.46 mL, 10.5 mmol, 5.0 equiv), and CH2Cl2 (7 mL) under
nitrogen. The solution was cooled to 0 °C using an ice bath, and
2,2-dimethylmalonyl dichloride (0.35 g, 0.27 mL, 2.1 mmol) was
added dropwise over 2 min by syringe. The resulting mixture was
slowly warmed to 25 °C and was stirred at 25 °C for 12 h. The
mixture was transferred to a 125 mL separatory funnel. The reaction
mixture was washed with water (1 × 50 mL) and then brine (1 ×
50 mL). The organic layer was removed, the aqueous layer was
extracted with CH2Cl2 (2 × 20 mL), and the organic layers were
combined, dried over Na2SO4 (10 g), decanted, and concentrated by
rotary evaporation (30 °C, 50 mbar). The crude product was
purified by column chromatography (silica, 3 cm ⌀ × 15 cm
column) eluting with hexanes/EtOAc, 1:1 to afford 37 (0.81 g,
80%) as a white solid. The compound 37 was crystallized from 1:1
mixture of hexanes/EtOAc at −35 °C. Data for 37: mp 213-215 °C
1
EtOAc); H NMR (500 MHz, CDCl3) δ 8.05 (d, J = 8.2 Hz, 1H,
HC(9)), 7.88 (d, J = 7.9 Hz, 1H, HC(12)), 7.77 (d, J = 8.3 Hz, 1H,
HC(14)), 7.52 (p, J = 7.1 Hz, 2H, HC(11,15)), 7.42 (t, J = 7.7 Hz,
1H, HC(10)), 7.33 (d, J = 6.9 Hz, 1H, HC(16)), 3.61 (d, J = 13.9
Hz, 1H, HC(6′)), 3.02 (d, J = 11.2 Hz, 1H, HC(2)), 2.64 (t, J =
12.6 Hz, 1H, HC(6)), 1.38 (d, J = 42.5 Hz, 6H, HC(4,4′));
13C{1H} NMR (126 MHz, CDCl3) δ 135.7 (C(7)), 134.1 (C(13)),
132.0 (C(8)), 128.9 (C(12)), 127.5 (C(16)), 127.3 (C(14)), 126.0
(C(15)), 125.7 (C(10)), 125.4 (C(11)), 123.6 (C(9)), 71.7 (C(3)),
60.1 (C(2)), 36.2 (C(6)), 27.1 (C(4′)), 24.1 (C(4)); IR (neat)
2963 (s), 1568 (s), 1449 (s), 1384 (s), 1153 (s), 1092 (s), 1023
(s), 969 (w), 960 (s), 904 (s), 781 (s), 597 (s), 572 (s), 499 (s);
HRMS (ESI) m/z (M + H)+ calcd for C15H20NO 230.1540, found
230.1545; TLC Rf 0.45 (silica gel, MeOH/EtOAc, 2:8, UV,
KMnO4).
1
(hexanes/EtOAc); H NMR (500 MHz, CDCl3) δ 7.70 (d, J = 8.5
Hz, 2H, HC(4)), 7.01−6.94 (m, 4H, HC(11,11′)), 6.78 (dd, J =
6.9, 2.2 Hz, 2H, HC(12)), 5.34 (d, J = 8.5 Hz, 2H, HC(5)), 2.46
(s, 6H, HC(11)), 2.41 (s, 2H, HC(8)), 2.15 (s, 6H, HC(13)), 1.52
(s, 6H, HC(1)), 1.33 (s, 6H, HC(7′)), 1.00 (s, 6H, HC(7));
13C{1H} NMR (126 MHz, CDCl3) δ 172.5 (C(3)), 137.6 (C(9)),
136.8 (C(10′)), 135.4 (C(10)), 130.7 (C(12)), 128.4 (C(11′)),
126.8 (C(11)), 73.6 (C(6)), 57.4 (C(5)), 49.6 (C(2)), 29.7
(C(7′)), 27.4 (C(7)), 23.9 (C(1)), 22.0 (C(13′)), 21.7 (C(13)); IR
(neat) 3423 (s), 1665 (s), 2975 (s), 1652 (s), 1504 (s), 1470 (s),
1371 (s), 1303 (s), 1159 (s), 1133 (s), 1081 (s), 964 (s), 932 (s),
895 (s), 827 (s), 765 (s), 732 (s), 711 (s), 578 (s); HRMS (ESI)
m/z (M + H)+ calcd for C61H74N2O4 899.5755, found 899.5727;
TLC Rf 0.33 (silica gel, hexanes/EtOAc, 6:4, UV, KMnO4).
Preparation of (R)-1-Amino-1-(2,6-Dimethylphenyl)-2-methyl-
propan-2-ol (25). A 300 mL, one-necked Schlenk flask with an
egg-shaped stir bar (50.8 × 19.1 mm) was charged with 11 (2.25 g,
5.4 mmol) and methanol (10 mL) under nitrogen. HCl (6 N) in
MeOH (54 mL) was added dropwise by syringe. The mixture was
stirred for 2 h at 25 °C, and then the solvent was removed rotary
evaporation (30 °C, 50 mbar). The crude solid was suspended in
ethyl acetate (50 mL), and 8 N NaOH in H2O (81 mL) was added
while the solution was stirred vigorously. The solution was stirred
for 10 min and then was transferred to a 500 mL separatory funnel.
The organic layer was separated, and the aqueous layer was
extracted with ethyl acetate (2 × 50 mL). pH paper was used to
check the neutralization of the solution (pH = 7). The organic
layers were combined, dried over anhydrous Na2SO4 (10 g),
decanted, and concentrated by rotary evaporation (30 °C, 50 mbar).
Preparation of N1,N3-Bis((R)-3-Hydroxy-3-methyl-1-(naphtha-
len-1-yl)butan-2-yl)-2,2-dimethylmalonamide (36). A 50 mL,
one-necked Schlenk flask containing an egg-shaped stir bar (15.9
× 6.35 mm) was charged with 24 (1.05 g, 4.6 mmol, 2.0 equiv),
Et3N (1.16 g, 1.60 mL, 11.5 mmol, 5.0 equiv), and CH2Cl2 (8 mL)
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under nitrogen. The solution was cooled to 0 °C using an ice bath,
and 2,2-dimethylmalonyl dichloride (0.38 g, 0.30 mL, 2.3 mmol)
was added dropwise over 2 min by syringe. The resulting mixture
was slowly warmed to 25 °C and was stirred at 25 °C for 12 h. The
mixture was transferred to a 125 mL separatory funnel. The reaction
mixture was washed with water (1 × 50 mL) and then brine (1 ×
50 mL). The organic layer was removed, the aqueous layer was
extracted with CH2Cl2 (2 × 20 mL), and the organic layers were
combined, dried over Na2SO4 (10 g), decanted, and concentrated by
rotary evaporation (30 °C, 50 mbar). The crude product was
purified by column chromatography (silica, 3 cm ⌀ × 15 cm
column) eluting with hexanes/EtOAc, 1:9 to afford 36 (1.00 g,
80%) as a white solid. Data for 36: mp 156−158 °C (hexanes/
for C35H38N2O2·0.1H2O: C, 81.05; H, 7.38; N, 5.40. Found: C,
80.35; H, 7.08; N, 5.43; HRMS (ESI) m/z (M + H)+ calcd for
C35H39N2O4 519.3016, found 519.3012; TLC Rf 0.26 (silica gel,
hexanes/EtOAc, 8:2, UV, KMnO4); [α]D +152.6 (c = 1.0, 100%
CHCl3).
24
1
EtOAc); H NMR (500 MHz, CDCl3) δ 7.99 (d, J = 8.4 Hz, 2H,
Preparation of (4R,4′R)-2,2′-(Propane-2,2-diyl)bis(4-(2,6-dime-
thylphenyl)-5,5-dimethyl-4,5-dihydrooxazole) (49). A 25 mL, one-
necked Schlenk flask containing an egg-shaped stir bar (15.9 × 6.35
mm) was charged with 37 (0.24 g, 0.50 mmol) and xylenes (12
mL) under nitrogen. The mixture was heated to reflux in a 160 °C
oil bath using a condenser connected to a Dean−Stark apparatus
which was itself connected to Schlenk flask. Once the bisamide
alcohol dissolved completely then Ti(OiPr)4 (0.028 g, 0.030 mL, 20
mol %) was added to the solution in one portion. The reaction
mixture was refluxed for 12 h with removal of the water byproduct.
After the reaction mixture was cooled to room temperature, the
solution was concentrated by rotary evaporation (60 °C, 50 mbar).
The crude product was purified by column chromatography (silica,
1 cm ⌀ × 15 cm column) eluting with n-hexane (95%)/EtOAc, 7:3
to afford 49 (0.18 g, 82%) as a white solid. Recrystallization from n-
hexane (95%) afforded 0.17 g (78%) of analytically pure 49 as a
HC(18)), 7.80 (d, J = 8.0 Hz, 2H, HC(15)), 7.66 (d, J = 8.2 Hz,
2H, HC(13)), 7.46 (dt, J = 24.2, 7.1 Hz, 4H, HC(12,16)), 7.30 (t, J
= 7.6 Hz, 2H, HC(17)), 7.23 (d, J = 6.9 Hz, 2H, HC(11)), 6.42 (d,
J = 9.2 Hz, 2H, HC(4)), 4.19 (ddd, J = 12.5, 9.4, 3.8 Hz, 2H,
HC(5)), 3.49 (dd, J = 14.4, 3.7 Hz, 2H, HC(9′)), 3.39 (s, 2H,
HC(8)), 3.03 (dd, J = 14.3, 11.6 Hz, 2H, HC(9)), 1.30 (s, 6H,
HC(7′)), 1.25 (s, 6H, HC(7)), 0.55 (s, 6H, HC(1)); 13C{1H}
NMR (126 MHz, CDCl3) δ 173.8 (C(3)), 134.5 (C(10)), 133.8
(C(14)), 132.2 (C(19)), 128.9 (C(15)), 127.3 (C(11)), 127.3
(C(13)), 126.3 (C(12)), 125.6 (C(16)), 125.2 (C(17)), 123.3
(C(18)), 73.5 (C(6)), 58.5 (C(5)), 49.1 (C(2)), 32.3 (C(9,9′)),
27.9 (C(7)), 25.8 (C(7′)), 22.9 (C(1)); IR (neat) 3381 (s), 2974
(s), 2975 (s), 1659 (s), 1639 (s), 1512 (s), 1456 (s), 1365 (s),
1165 (s), 1077 (s), 952 (s), 789 (s), 771 (m), 727 (s), 569 (s), 518
(s), 484 (m); HRMS (ESI) m/z (M + H)+ calcd for C35H43N2O4
555.3218, found 555.3223; TLC Rf 0.39 (silica gel, hexanes/EtOAc,
3:7, UV, KMnO4).
1
white solid. Data for 49: mp 105−107 °C (n-hexane (95%)); H
NMR (500 MHz, CDCl3) δ 7.05−7.00 (m, 2H, HC(11)), 6.99−
6.92 (m, 4H, HC(10,10′)), 5.36 (s, 2H, HC(4)), 2.36 (d, J = 16.9
Hz, 12H, HC(9,9′)), 1.62 (s, 6H, HC(1)), 1.56 (s, 6H, HC(6)),
1.09 (s, 6H, HC(6′)); 13C{1H} NMR (126 MHz, CDCl3) δ 167.3
(C(3)), 138.1 (C(8)), 136.5 (C(7)), 135.0 (C(8′)), 130.5 (C(10)),
128.4 (C(10′)), 127.1 (C(11)), 86.7 (C(5)), 75.1 (C(4)), 38.9
(C(2)), 30.8 (C(6)), 23.7 (C(6′)), 22.9 (C(1)), 22.0 (C(9′)), 21.7
(C(9)); IR (neat) 2973 (s), 1739 (s), 1654 (m), 1466 (s), 1385
(s), 1263 (s), 1124 (m), 1109 (m), 1010 (s), 973 (s), 916 (s), 837
(s), 767 (m), 736 (s); LRMS [ESI+, TOF] 399.2(6), 447.3(100),
448.3(37), 449.3(8), 450.3(2); Anal. C29H39N2O2 (446.623): C,
77.99; H, 8.58; N, 6.27. Found: C, 77.62; H, 8.46; N, 6.32; HRMS
(ESI) m/z (M + H)+ calcd for C29H39N2O2 447.3003, found
447.3012; TLC Rf 0.44 (silica gel, hexanes/EtOAc, 8:2, UV,
Preparation of (4R,4′R)-2,2′-(Propane-2,2-diyl)bis(5,5-dimethyl-
4-(naphthalen-1-ylmethyl)-4,5-dihydrooxazole (48). A 25 mL,
one-necked Schlenk flask containing an egg-shaped stir bar (15.9
× 6.35 mm) was charged with 36 (0.27 g, 0.50 mmol) and xylenes
(12 mL) under nitrogen. The mixture was heated to reflux in a 160
°C oil bath using a condenser connected to a Dean−Stark apparatus
which was itself connected to Schlenk flask. Once the bisamide
alcohol dissolved completely then Ti(Oi-Pr)4 (0.028 g, 0.030 mL,
20 mol %) was added to the solution in one portion. The reaction
mixture was refluxed for 12 h with removal of the water byproduct.
After the reaction mixture was cooled to room temperature, the
solution was concentrated by rotary evaporation (60 °C, 50 mbar).
The crude product was purified by column chromatography (silica,
1 cm ⌀ × 15 cm column) eluting with n-hexane (95%)/EtOAc, 7:3
to afford 48 (0.210 g, 80%) as a white solid. Recrystallization from
anhydrous diethyl ether afforded 0.20 g (77%) of 48 as a white
24
KMnO4); [α]D +188.3 (c = 1.0, CHCl3).
Synthesis of Bisoxazoline Ligands with an Isopropyl Sub-
stituent at the C(5)-position.
Preparation of (S)-2-Hydroxy-3-methylbutanoic Acid (1c). L-
Valine (8.78 g, 75.0 mmol) was placed into a 300 mL, three-necked
flask containing an egg-shaped stir bar (50.8 × 19.1 mm), and water
(75 mL) was added. The flask was fitted with two addition funnels.
In one addition funnel concentrated H2S04 (14.71 g, 8.0 mL, 150.0
mmol, 2.0 equiv) was added. To the other addition funnel a
solution of NaNO2 (10.35 g, 150 mmol, 2.0 equiv) dissolved in
H2O (25 mL) was added. The reaction vessel was cooled to 0 °C
using an ice bath, and the acid was added dropwise with stirring for
2 min. After the L-valine dissolved, the sodium nitrite solution was
added dropwise by syringe, and the rate of addition of the acid was
adjusted similarly so as to maintain the internal temperature below 0
°C. After the addition was complete, the mixture was stirred at 0 °C
for 1 h and then was stirred at 25 °C for 12 h. After this time, the
reaction mixture was transferred to 500 mL separatory funnel and
was extracted with ethyl acetate (3 × 100 mL). The organic layers
were combined, washed with brine (1 × 100 mL), dried over
anhydrous Na2SO4 (10 g), decanted, and concentrated by rotary
1
solid. Data for 48: mp 155−157 °C (Et2O); H NMR (500 MHz,
CDCl3) δ 8.15 (d, J = 8.4 Hz, 2H, HC(16)), 7.88 (d, J = 8.1 Hz,
2H, HC(13)), 7.77 (d, J = 8.0 Hz, 2H, HC(11)), 7.58−7.41 (m,
8H, HC(9,10,14,15)), 4.19 (dd, J = 8.3, 6.5 Hz, 2H, HC(4)), 3.31
(qd, J = 14.2, 7.3 Hz, 4H, HC(7)), 1.54 (s, 6H, HC (1)), 1.45 (s,
6H, HC(6)), 1.35 (s, 6H, HC(6′)); 13C{1H} NMR (126 MHz,
CDCl3) δ 167.8 (C(3)), 135.3 (C(8)), 134.0 (C(12)), 132.2
(C(17)), 128.8 (C(13)), 127.1 (C(11)), 127.0 (C(15)), 125.7
(C(14)), 125.4 (C(10)), 125.4 (C(9)), 124.1 (C(16)), 86.4 (C(5)),
74.0 (C(4)), 38.6 (C(2)), 34.4 (C(7)), 28.2 (C(6′)), 23.7 (C(1)),
21.7 (C(6)); IR (neat) 2972 (s), 1651 (s), 1460 (s), 1386 (s), 1372
(s), 1275 (s), 1133 (s), 1114 (s), 1075 (s), 971 (s), 935 (s), 818
(s), 786 (m), 508 (s); LRMS [ESI+, TOF] 195.1(5), 326.1(8),
519.3(100), 520.3(38), 537.3(10), 659.3(9), 843.6(3); Anal. Calcd
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evaporation (30 °C, 50 mbar) to afford the crude product. The
crude product was purified by recrystallization with hot hexane (300
mL) to afford 1c (5.80 g, 65%) as a white crystalline solid. The
spectroscopic data for 1c matched the literature values.116 Data for
1c: H NMR (500 MHz, CDCl3) δ 4.11 (d, J = 3.6 Hz, 1H), 2.11
(septd, J = 6.8, 3.5 Hz, 1H), 1.03 (d, J = 7.1 Hz, 3H), 0.90 (d, J =
equiv) was added dropwise by syringe to maintain the internal
temperature below −70 °C. The solution was stirred at −78 °C for
1 h, and then reaction was quenched with H2O (6 mL). The
mixture was slowly warmed to 25 °C. The mixture was stirred for
additional 1 h. Then the mixture was filtered through a fritted glass
funnel (7.5 mm diameter) containing Celite into a 250 mL filter
flask. The Celite cake was washed with Et2O (2 × 75 mL). The
combined filtrates were transferred to a 250 mL separatory funnel,
washed with water (1 × 100 mL) and brine (1 × 100 mL), dried
over Na2SO4 (10 g), decanted, and concentrated by rotary
evaporation (30 °C, 50 mbar). The crude product was purified by
column chromatography (silica, 4 cm ⌀ × 12 cm column) eluting
with hexanes/Et2O, 7:3 to afford 5c (5.40 g, 80%) as a colorless oil.
The spectroscopic data for 5c matched the literature values.111 Data
1
7.0 Hz, 3H).
Preparation of Methyl (S)-2-Hydroxy-3-methylbutanoate (2c).
A 250 mL, one-necked Schlenk flask containing an egg-shaped stir
bar (50.8 × 19.1 mm) was charged with 1c (5.80 g, 49.1 mmol) and
MeOH (distilled, 120 mL) under nitrogen. The solution was cooled
in an ice bath for 10 min, and SOCl2 (17.52 g, 10.74 mL, 147.3
mmol, 3.0 equiv) was added dropwise by syringe over 5 min at 0
°C. The mixture was heated to reflux using a condenser in a 75 °C
oil bath for 12 h. After the solution was cooled to 25 °C, the volatile
components are removed by rotary evaporation (30 °C, 50 mbar).
The resulting residue was diluted with ethyl acetate (200 mL) and
satd aq NaHCO3 (200 mL) was added slowly because of evolution
of gas. The mixture was transferred to a 500 mL separatory funnel,
and the organic layer was removed. The aqueous layer was extracted
with ethyl acetate (3 × 100 mL), and the organic layers were
combined, washed with brine (1 × 100 mL), dried over anhydrous
Na2SO4 (10 g), decanted, and concentrated by rotary evaporation
(30 °C, 50 mbar) to afford the crude product. The crude product
was purified by trituration with hot hexane (300 mL) to afford (4.40
g, 68%) 2c as a colorless oil. The spectroscopic data for 2c matched
1
for 5c: H NMR (500 MHz, CDCl3) δ 9.58 (s, 1H), 3.71 (dd, J =
4.9, 2.2 Hz, 1H), 2.07−1.96 (m, 1H), 0.96 (d, J = 6.9 Hz, 3H), 0.92
(s, 9 H), 0.91 (d, J = 6.9 Hz, 3H), 0.05 (s, 6H).
Preparation of (R)-N-((S,E)-2-((tert-Butyldimethylsilyl)oxy)-3-
methylbutylidene)-2-methylpropane-2-sulfinamide (6c). A 100
mL, one-necked Schlenk flask with an egg-shaped stir bar (38.1 ×
15.9 mm) was charged with 5c (4.98 g, 23.05 mmol), (R)-2-
methylpropane-2-sulfinamide (2.93 g, 24.20 mmol, 1.05 equiv), and
titanium(IV) ethoxide (10.51 g, 9.66 mL, 46.1 mmol, 2.0 equiv)
under nitrogen. The mixture was stirred in a 70 °C oil bath for 60
min and then was diluted with ethyl acetate (50 mL). The resulting
solution was poured into a 200 mL Erlenmeyer flask with a stir bar
and brine (5 mL), and the vial was rinsed with ethyl acetate (2 × 25
mL) to help the transfer. The suspension was stirred at 25 °C for 10
min and then filtered through a fritted glass funnel (7.5 mm
diameter) containing Celite. The Celite cake was washed with ethyl
acetate (2 × 100 mL). The combined filtrates were transferred to a
250 mL separatory funnel, washed with water (1 × 100 mL) and
brine (1 × 100 mL), dried over Na2SO4 (10 g), decanted, and
concentrated by rotary evaporation (30 °C, 50 mbar). The crude
product was purified by column chromatography (silica, 4 cm ⌀ ×
12 cm column) eluting with hexanes/EtOAc, 9:1 to afford 6c (6.93
the literature values.116 Data for 2c: H NMR (500 MHz, CDCl3) δ
1
4.02 (dd, J = 6.0, 3.6 Hz, 1H), 3.76 (s, 3H), 2.78 (d, J = 6.1 Hz,
1H), 2.04 (septd, J = 6.9, 3.6 Hz, 1H), 0.99 (d, J = 6.9 Hz, 4H),
0.83 (d, J = 6.9 Hz, 4H).
Preparation of Methyl (S)-2-((tert-Butyldimethylsilyl)oxy)-3-
methylbutanoate (3c). A 250 mL, one-necked Schlenk flask
containing an egg-shaped stir bar (50.8 × 19.1 mm) was charged
with 2c (4.40 g, 33.3 mmol), TBSCl (6.27 g, 41.6 mmol, 1.25
equiv), imidazole (3.06 g, 44.95 mmol, 1.35 equiv), and DMF (SDS,
45 mL) under nitrogen. The mixture was stirred at 25 °C for 12 h.
The resulting mixture was diluted in Et2O (200 mL), transferred to
500 mL separatory funnel, washed with water (3 × 100 mL) and
brine (1 × 100 mL), dried over anhydrous Na2SO4 (10 g),
decanted, and concentrated by rotary evaporation (30 °C, 50 mbar).
The crude product was purified by column chromatography (silica,
4 cm ⌀ × 12 cm column) eluting with hexanes/EtOAc, 9:1 to afford
3c (7.50 g, 92%) as a colorless oil. The spectroscopic data for S28
1
g, 94%) as a yellow oil. Data for 6c: H NMR (500 MHz, CDCl3) δ
7.88 (d, J = 5.3 Hz, 1H, HC(3)), 4.12 (t, J = 5.1 Hz, 1H, HC(4)),
1.93−1.79 (m, 1H, HC(5)), 1.15 (s, 9H, HC(1)), 0.89 (dd, J = 6.9,
2.5 Hz, 6H, HC(6)), 0.84 (s, 9H, HC(9)), 0.01 (s, 3H, HC(7′)),
−0.04 (s, 3H, HC(7); 13C{1H} NMR (126 MHz, CDCl3) δ 171.6
(C(3)), 78.8 (C(4)), 56.7 (C(2)), 33.8 (C(5)), 25.8 (C(9)), 22.5
(C(1)), 18.8 (C(6′)), 18.1 (C(8)), 17.9 (C(6)), −4.2 (C(7′)),
−4.9 (C(7)); IR (neat) 2958 (m), 2930 (m), 2859 (w), 1622 (w),
1472 (m), 1388 (w), 1363 (m), 1253 (m), 1139 (w), 1090 (s),
1006 (w), 938 (w), 860 (m), 837 (s), 776 (s), 683 (w), 665 (w),
584 (w), 501 (w); HRMS (ESI) m/z (M + H)+ calcd for
C15H34NO2SSi 320.2076, found 320.2080; TLC Rf 0.50 (silica gel,
hexanes/EtOAc, 9:1, UV, KMnO4).
matched the literature values.117 Data for 3c: H NMR (500 MHz,
1
CDCl3) δ 3.86 (d, J = 4.7 Hz, 1H), 3.58 (s, 3H), 1.99−1.86 (m,
1H), 0.83 (d, J = 6.9 Hz, 3H), 0.81 (s, 9H), 0.78 (d, J = 6.8 Hz,
3H), −0.06 (s, 3H), −0.07 (s, 3H).
Preparation of (S)-2-((tert-Butyldimethylsilyl)oxy)-3-methylbu-
tanal (5c). A 250 mL, three-necked round-bottomed flask equipped
with nitrogen inlet, an egg-shaped stir bar (50.8 × 19.1 mm), an
internal temperature probe, and two rubber septa was charged with
3c (7.60 g, 31.0 mmol) and Et2O (60 mL, SDS) under nitrogen.
The solution was cooled to −78 °C using a cryocooler in an i-PrOH
bath, and DIBAL-H (1.0 M in heptane, 34.1 mL, 34.1 mmol, 1.1
Preparation of (R)-N-((2S)-2-((tert-Butyldimethylsilyl)oxy)-3-
methyl-1-(4-(trifluoromethyl)phenyl)butyl)-2-methylpropane-2-
sulfinamide (12). A 100 mL, one-necked Schlenk flask containing
an egg-shaped stir bar (38.1 × 15.9 mm) was charged with 1-
3513
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bromo-4-(trifluoromethyl)benzene (3.15 g, 1.96 mL, 14.0 mmol, 2.0
equiv) and THF (17 mL) under nitrogen. The solution was cooled
to −78 °C using a cryocooler in an i-PrOH bath, and n-butyllithium
(0.89 g, 8.8 mL, 1.6 M in hexane, 14.0 mmol, 2.0 equiv) was added
dropwise by syringe. The resulting solution was stirred at −78 °C
using a cryocooler in i-PrOH bath for 1 h. Then another 50 mL
Schlenk flask containing an egg-shaped stir bar (19.1 × 9.5 mm)
was charged with 6c (2.23 g, 7.0 mmol) and THF (17 mL) under
nitrogen and was cooled to −78 °C using a cryocooler in an i-PrOH
bath. The N-sulfinyl imine solution was transferred to the
organolithium solution using a syringe dropwise over 5 min. The
resulting mixture was stirred at −78 °C using a cryocooler in an i-
PrOH bath for 12 h. The reaction was quenched by the addition of
satd aq NH4Cl solution (50 mL) at −78 °C and then was slowly
warmed to 25 °C. The mixture was transferred to a 250 mL
separatory funnel. The organic layer was removed, the aqueous layer
was extracted with ethyl acetate (3 × 50 mL), and the organic layers
were combined, washed with brine (1 × 100 mL), dried over
Na2SO4 (10 g), decanted, and concentrated by rotary evaporation
25 °C. The mixture was transferred to a 250 mL separatory funnel.
The organic layer was removed, the aqueous layer was extracted
with ethyl acetate (3 × 60 mL), and the organic layers were
combined, washed with brine (1 × 100 mL), dried over Na2SO4 (10
g), decanted, and concentrated by rotary evaporation (30 °C, 50
1
mbar). The dr of the crude product was >99:1 by H NMR analysis.
The crude product was purified by column chromatography (silica,
4 cm ⌀ × 12 cm column) eluting with hexanes/EtOAc, 1:1 to afford
13 (4.60 g, 78%) as a yellow solid. Data for 13: mp 97−99 °C
1
(hexanes/EtOAc); H NMR (500 MHz, CDCl3) δ 5.97 (d, J = 10.6
Hz, 2H, HC(13,13′)), 4.76 (t, J = 9.6 Hz, 1H, HC(4)), 4.48 (d, J =
10.1 Hz, 1H, HN(3)), 3.80 (d, J = 9.2 Hz, 1H, HC(5)), 3.70 (s,
3H, HC(15)), 3.67 (s, 3H, HC(16)), 3.62 (s, 3H, HC(15′)), 2.29
(sept, J = 6.7 Hz, 1H, HC(6)), 0.90 (d, J = 6.7 Hz, 3H, HC(7)),
0.85 (d, J = 7.1 Hz, 3H, HC(7′)), 0.83 (s, 9H, HC(1)), 0.61 (s,
9H, HC(10)), −0.21 (s, 3H, HC(8)), −0.81 (s, 3H, HC(8′));
13C{1H} NMR (126 MHz, CDCl3) δ 160.3 (C(14)), 158.9
(C(12)), 158.6 (C(12′)), 110.7 (C(11)), 90.7 (C(13)), 90.6
(C(13′)), 77.8 (C(5)), 55.6 (C(2)), 55.4 (C(16)), 55.1 (C(15)),
55.0 (C(15′)), 54.5 (C(4)), 29.1 (C(6)), 25.8 (C(10)), 21.8
(C(1)), 21.4 (C(7′)), 18.0 (C(9)), 14.2 (C(7)), −4.1 (C(8)), −5.5
(C(8′)); IR (neat) 2957 (w), 2856 (w), 2231 (w), 1608 (m), 1592
(m), 1497 (w), 1465 (m), 1419 (w), 1363 (w), 1331 (w), 1250
(w), 1221 (m), 1204 (m), 1151 (m), 1124 (s), 1105 (m), 1061 (s),
1009 (w), 951 (m), 924 (m), 909 (m), 858 (m), 831 (s), 813 (m),
773 (s), 729 (s), 671 (w), 644 (m), 601 (w), 558 (m), 465 (w);
HRMS (ESI) m/z (M + H)+ calcd for C24H46NO5SSi 488.2859,
found 488.2866; TLC Rf 0.17 (silica gel, hexanes/EtOAc, 7:3, UV,
KMnO4).
1
(30 °C, 50 mbar). The dr of the crude product was 99:1 by H
NMR analysis. The crude product was purified by column
chromatography (silica, 4 cm ⌀ × 12 cm column) eluting with
hexanes/EtOAc, 1:1 to afford 12 (2.60 g, 80%) as a yellow solid.
Data for 12: mp 103−105 °C (hexanes/EtOAc); 1H NMR (500
MHz, CDCl3) δ 7.55 (d, J = 8.1 Hz, 2H, HC(12)), 7.43 (d, J = 8.1
Hz, 2H, HC(13)), 4.68 (d, J = 6.7 Hz, 1H, HC(4)), 4.12 (d, J = 1.6
Hz, 1H, HN(3)), 3.78 (dd, J = 5.0, 2.4 Hz, 1H, HC(5)), 1.57−1.47
(septd, J = 6.8, 2.4 Hz, 1H, HC(6)), 1.21 (d, J = 1.2 Hz, 9H,
HC(1)), 0.93 (d, J = 1.6 Hz, 12H, HC(7,10)), 0.71 (d, J = 7.0 Hz,
3H, HC(7′)), 0.16 (s, 3H, HC(8)), 0.08 (s, 3H, HC(8′)); 13C{1H}
NMR (126 MHz, CDCl3) δ 143.2 (C(11)), 129.8 (C−F, 2JC−F
=
31.3 Hz, C(14)), 128.5 (C(12)), 125.3 (C−F, 3JC−F = 3.8 Hz,
C(13)), 124.1 (C−F, 1JC−F = 270.0 Hz, C(15)), 79.1 (C(5)), 61.9
(C(4)), 55.5 (C(2)), 29.0 (C(6)), 26.0 (C(10)), 22.5 (C(1)), 21.7
(C(7′)), 18.2 (C(9)), 16.9 (C(7)), −3.9 (C(8)), −4.6 (C(8′));
19FNMR (471 MHz, CDCl3) −62.51; IR (neat) 2958 (w), 2931
(w), 2860 (w), 1620 (w), 1473 (w), 1419 (w), 1389 (w), 1365 (w),
1324 (s), 1254 (m), 1165 (m), 1125 (s), 1067 (s), 1047 (s), 1017
(m), 1005 (m), 921 (m), 908 (m), 869 (m), 833 (s), 776 (s), 731
(s), 702 (m), 674 (w), 645 (m), 597 (m), 527 (w), 500 (w);
HRMS (ESI) m/z (M + H)+ calcd for C22H39NO2F3SSi 466.2429,
found 466.2423; TLC Rf 0.46 (silica gel, hexanes/EtOAc, 8:2, UV,
KMnO4).
Preparation of (1R,2S)-1-Amino-3-methyl-1-(4-(trifluoromethyl)-
phenyl)butan-2-ol (26). A 250 mL, one-necked Schlenk flask with
an egg-shaped stir bar (50.8 × 19.1 mm) was charged with 12 (2.32
g, 5.0 mmol) and methanol (10 mL) under nitrogen. HCl (6 N) in
MeOH (50 mL) was added dropwise by syringe. The reaction was
stirred for 2 h at 25 °C, and then the solvent was removed rotary
evaporation (30 °C, 50 mbar). The crude solid was suspended in
ethyl acetate (30 mL), and 8 N NaOH in H2O (75 mL) was added
while the solution was stirred vigorously. The solution was stirred
for 10 min and then was transferred to a 500 mL separatory funnel.
The organic layer was separated, and the aqueous layer was
extracted with ethyl acetate (2 × 50 mL). pH paper was used to
check the neutralization of the solution (pH= 7). The organic layers
were combined, dried over anhydrous Na2SO4 (10 g), decanted, and
concentrated by rotary evaporation (30 °C, 50 mbar). The crude
product was purified by column chromatography (silica, 4 cm ⌀ ×
12 cm column) eluting with MeOH/EtOAc, 2:8 to afford 26 (0.98
g, 80%) as a white solid. Data for 26: mp 139−141 °C (MeOH/
EtOAc); 1H NMR (500 MHz, CD3OD) δ 7.63−7.58 (m, 4H,
HC(8,9)), 4.86 (s, 1H, HO(6)), 3.94 (d, J = 5.7 Hz, 1H, HC(2)),
3.45 (t, J = 6.1 Hz, 1H, HC(3)), 1.70−1.46 (m, 1H, HC(4)), 0.99
(d, J = 6.8 Hz, 3H, HC(5)), 0.94 (d, J = 6.7 Hz, 3H, HC(5′));
13C{1H} NMR (126 MHz, CD3OD) δ 148.7 (C(7)), 129.8 (C−F,
2JC−F = 31.3 Hz, C(10)), 129.8 (C(8)), 125.9 (C−F, 3JC−F = 3.8
Hz, C(9)), 125.8 (C−F, 1JC−F = 270.0 Hz, C(11)), 80.8 (C(3)),
58.4 (C(2)), 31.3 (C(4)), 20.1 (C(5)), 17.7 (C(5′)); 19FNMR
(471 MHz, CD3OD) −59.87; IR (neat) 2931 (w), 2291 (w), 1617
(w), 1424 (w), 1364 (w), 1326 (s), 1162 (m), 1108 (s), 1065 (s),
1018 (s), 974 (m), 924 (w), 887 (m), 857 (m), 843 (s), 781 (m),
747 (m), 700 (w), 678 (m), 610 (s), 586 (m), 526 (w), 496 (w);
HRMS (ESI) m/z (M + H)+ calcd for C12H17NOF3 248.1261,
found 248.1262; TLC Rf 0.35 (silica gel, MeOH/EtOAc, 2:8, UV,
KMnO4).
Preparation of (R)-N-((1R,2S)-2-((tert-Butyldimethylsilyl)oxy)-3-
methyl-1-(2,4,6-trimethoxyphenyl)butyl)-2-methylpropane-2-sulfi-
namide (13). A 100 mL, one-necked Schlenk flask containing an
egg-shaped stir bar (38.1 × 15.9 mm) was charged with 1,3,5-
trimethoxybenzene (4.03 g, 24.0 mmol, 2.0 equiv) and THF (30
mL) under nitrogen. The solution was cooled to 0 °C using an ice
bath, and n-butyllithium (1.53 g, 15.0 mL, 1.6 M in hexane, 24.0
mmol, 2.0 equiv) was added dropwise by syringe. The resulting
mixture was slowly warmed to 25 °C and was stirred at 25 °C for 3
h. Then the organolithium solution was cooled to −78 °C using a
cryocooler in an i-PrOH bath, and the temperature was monitored
using an internal temperature probe. Then another 50 mL Schlenk
flask containing an egg-shaped stir bar (19.1 × 9.5 mm) was
charged with 6c (3.83 g, 12.0 mmol) and THF (30 mL) under
nitrogen and was cooled to −78 °C using a cryocooler in an i-PrOH
bath. The N-sulfinyl imine solution was transferred to the
organolithium solution using a syringe dropwise over 5 min. The
resulting mixture was stirred at −78 °C using a cryocooler in i-
PrOH bath for 12 h. The reaction was quenched by the addition of
satd aq NH4Cl solution (50 mL) at −78 °C and slowly warmed to
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(m, 2H, HC(6)), 2.63 (d, J = 5.8 Hz, 2H, HO(9)), 1.37 (s, 6H,
HC(1)), 1.36−1.29 (m, 2H, HC(7)), 0.93 (d, J = 6.5 Hz, 6H,
HC(8)), 0.87 (d, J = 6.4 Hz, 6H, HC(8′)); 13C{1H} NMR (126
MHz, CDCl3) δ 172.7 (C(3)), 142.5 (C(10)), 129.9 (C−F, 2JC−F
=
32.5 Hz, C(13)), 128.6 (C(11)), 125.3 (C−F, 3JC−F = 3.8 Hz,
C(12)), 124.1 (C−F, 1JC−F = 270.0 Hz, C(14)), 120.8 (C(6)), 78.8
(C(5)), 49.4 (C(2)), 30.7 (C(7)), 23.7 (C(1)), 19.1 (C(8)), 18.3
(C(8′)); 19FNMR (471 MHz, CDCl3) −62.64; IR (neat) 2916 (s),
2848 (s), 1738 (m), 1662 (w), 1518 (w), 1472 (m), 1366 (m),
1328 (m), 1229 (w), 1217 (m), 1164 (w), 1125 (m), 1069 (w),
1019 (w), 847 (w), 730 (w), 719 (m), 618 (w), 528 (w); HRMS
(ESI) m/z (M + H)+ calcd for C29H37N2O4F6 591.2650, found
591.2658; TLC Rf 0.33 (silica gel, hexanes/EtOAc, 6:4, UV,
KMnO4).
Preparation of (1R,2S)-1-Amino-3-methyl-1-(2,4,6-
trimethoxyphenyl)butan-2-ol (27). A 250 mL, one-necked Schlenk
flask with an egg-shaped stir bar (50.8 × 19.1 mm) was charged
with 13 (3.90 g, 8.0 mmol) and methanol (15 mL) under nitrogen.
HCl (6 N) in MeOH (80 mL) was added dropwise by syringe. The
reaction was stirred for 2 h at 25 °C, and then the solvent was
removed rotary evaporation (30 °C, 50 mbar). The crude solid was
suspended in ethyl acetate (30 mL), and 8 N NaOH in H2O (120
mL) was added while the solution was stirred vigorously. The
solution was stirred for 10 min and then was transferred to a 500
mL separatory funnel. The organic layer was separated, and the
aqueous layer was extracted with ethyl acetate (2 × 75 mL). pH
paper was used to check the neutralization of the solution (pH = 7).
The organic layers were combined, dried over anhydrous Na2SO4
(10 g), decanted, and concentrated by rotary evaporation (30 °C,
50 mbar). The crude product was purified by column chromatog-
raphy (silica, 4 cm ⌀ × 12 cm column) eluting with MeOH/EtOAc,
2:8 to afford 27 (1.70 g, 77%) as a white solid. The compound 27
was crystallized from EtOAc at −35 °C. Data for 27: mp 107−109
Preparation of N1,N3-Bis((1R,2S)-2-hydroxy-3-methyl-1-(2,4,6-
trimethoxyphenyl)butyl)-2,2-dimethylmalonamide (39). A 50 mL
Schlenk flask containing an egg-shaped stir bar (15.9 × 6.35 mm)
was charged with 27 (1.45 g, 5.4 mmol, 2.0 equiv), Et3N (1.36 g,
1.87 mL, 13.5 mmol, 5.0 equiv), and CH2Cl2 (15 mL) under
nitrogen. The solution was cooled to 0 °C using an ice bath, and
2,2-dimethylmalonyl dichloride (0.45 g, 0.35 mL, 2.7 mmol) was
added dropwise by syringe over 2 min. The resulting mixture was
slowly warmed to 25 °C and was stirred at 25 °C for 12 h. The
mixture was transferred to a 125 mL separatory funnel. The reaction
mixture was washed with water (1 × 50 mL) and then brine (1 ×
50 mL). The organic layer was removed, and then the aqueous layer
was extracted with CH2Cl2 (2 × 30 mL), and the organic layers
were combined, dried over Na2SO4 (10 g), decanted, and
concentrated by rotary evaporation (30 °C, 50 mbar). The crude
product was purified by column chromatography (silica, 3 cm ⌀ ×
15 cm column) eluting with hexanes/EtOAc, 3:7 to afford 39 (1.4 g,
81%) as a white solid. Data for 39: mp 68−70 °C (hexanes/
1
°C (MeOH/EtOAc); H NMR (500 MHz, CDCl3) δ 6.05 (s, 2H,
HC(9,9′)), 4.36 (d, J = 7.9 Hz, 1H, HC(2)), 3.70 (d, J = 6.6 Hz,
9H, HC(11,11′,12)), 3.57 (dd, J = 7.9, 4.0 Hz, 1H, HC(3)), 2.19
(s, 3H, HN, HO(1,6)), 1.85−1.79 (m, 1H, HC(4)), 0.90 (d, J = 7.1
Hz, 3H, HC(5)), 0.84 (d, J = 6.9 Hz, 3H, HC(5′)); 13C{1H} NMR
(126 MHz, CDCl3) δ 160.0 (C(10)), 158.9 (C(8,8′)), 111.3
(C(7)), 90.9 (C(9)), 78.5 (C(3)), 55.5 (C(11,11′)), 55.0 (C(12)),
49.5 (C(2)), 29.7 (C(4)), 20.3 (C(5)), 15.3 (C(5′)); IR (neat)
3353 (w), 2952 (m), 1589 (s), 1491 (w), 1455 (m), 1437 (m),
1414 (m), 1375 (m), 1337 (w), 1270 (w), 1220 (m), 1202 (s),
1181 (m), 1166 (m), 1148 (s), 1120 (s), 1058 (m), 1039 (m),
1016 (m), 1001 (m), 961 (s), 816 (s), 794 (m), 635 (m), 567 (m),
528 (m); HRMS (ESI) m/z (M + H)+ calcd for C14H24NO4
270.1711, found 270.1705; TLC Rf 0.16 (silica gel, MeOH/EtOAc,
2:8, UV, KMnO4).
1
EtOAc); H NMR (500 MHz, CDCl3); δ 7.98 (d, J = 9.5 Hz, 2H,
HC(4)), 6.08 (s, 4H, HC(12)), 5.70 (t, J = 8.5 Hz, 2H, HC(5)),
3.79 (s, 12H, HC(14,14′)), 3.76 (s, 6H, HC(15)), 3.59 (ddd, J =
10.0, 5.0 Hz, 2H, HC(6)), 1.80 (d, J = 5.7 Hz, 2H, HO(9)), 1.69
(qqd, J = 17.5, 10.0, 7.0, 3.0 Hz, 2H, HC(7)), 1.35 (s, 6H, HC(1)),
0.99 (d, J = 6.8 Hz, 6H, HC(8)), 0.95 (d, J = 6.7 Hz, 6H, HC(8′));
13C{1H} NMR (126 MHz, CDCl3); δ 172.3 (C(3)), 160.6 (C(13)),
159.1 (C(11)), 107.4 (C(10)), 91.1 (C(12)), 78.1 (C(6)), 55.9
(C(14,15)), 55.3 (C(14′)), 49.4 (C(2)), 47.4 (C(5)), 29.8 (C(7)),
23.7 (C(1)), 20.5 (C(8)), 15.3 (C(8′)); IR (neat) 3450 (w), 2969
(w), 2840 (w), 1739 (m), 1666 (m), 1608 (s), 1591 (m), 1498 (s),
1454 (s), 1419 (m), 1365 (m), 1331 (m), 1219 (s), 1204 (s), 1149
(s), 1120 (s), 1059 (m), 1035 (m), 999 (m), 950 (m), 920 (m),
813 (m), 728 (m), 634 (m), 547 (m), 527 (m); HRMS (ESI) m/z
(M + H)+ calcd for C33H51N2O10 635.3549, found 635.3544; TLC
Rf 0.16 (silica gel, hexanes/EtOAc, 1:1, UV, KMnO4).
Preparation of N1,N3-Bis((1R,2S)-2-hydroxy-3-methyl-1-(4-
(trifluoromethyl)phenyl)butyl)-2,2-dimethylmalonamide (38). A
50 mL Schlenk flask containing an egg-shaped stir bar (15.9 ×
6.35 mm) was charged with 26 (0.74 g, 3.0 mmol, 2.0 equiv), Et3N
(0.75 g, 1.04 mL, 7.5 mmol, 5.0 equiv), and CH2Cl2 (10 mL) under
nitrogen. The solution was cooled to 0 °C using an ice bath, and
2,2-dimethylmalonyl dichloride (0.25 g, 0.19 mL, 1.5 mmol) was
added dropwise by syringe over 2 min. The resulting mixture was
slowly warmed to 25 °C and was stirred at 25 °C for 12 h. The
mixture was transferred to a 125 mL separatory funnel. The reaction
mixture was washed with water (1 × 50 mL) and then brine (1 ×
50 mL). The organic layer was removed, the aqueous layer was
extracted with CH2Cl2 (2 × 20 mL), and the organic layers were
combined, dried over Na2SO4 (10 g), decanted, and concentrated by
rotary evaporation (30 °C, 50 mbar). The crude product was
purified by column chromatography (silica, 3 cm ⌀ × 15 cm
column) eluting with hexanes/EtOAc, 1:1 to afford 38 (0.74 g,
83%) as a white solid. Data for 38: mp 175−177 °C (hexanes/
Preparation of (4R,4′R,5S,5′S)-2,2′-(Propane-2,2-diyl)bis(5-iso-
propyl-4-(2,4,6-trimethoxyphenyl)-4,5-dihydrooxazole) (51). A 25
mL, one-necked Schlenk flask containing an egg-shaped stir bar
(15.9 × 6.35 mm) was charged with 39 (0.31 g, 0.50 mmol) and
xylenes (12 mL) under nitrogen. The mixture was heated to reflux
1
EtOAc); H NMR (500 MHz, CDCl3) δ 7.62 (d, J = 7.9 Hz, 2H,
HN(4)), 7.49 (d, J = 7.7 Hz, 4H, HC(12)), 7.40 (d, J = 7.8 Hz,
4H, HC(11)), 5.04 (dd, J = 8.1, 4.3 Hz, 2H, HC(5)), 3.58−3.39
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in a 160 °C oil bath using a condenser connected to a Dean−Stark
apparatus which was itself connected to Schlenk flask. Once the
bisamide alcohol dissolved completely then Ti(Oi-Pr)4 (0.028 g,
0.030 mL, 20 mol %) was added to the solution in one portion. The
reaction mixture was refluxed for 12 h with removal of the water
byproduct. After the reaction mixture was cooled to room
temperature, the solution was concentrated by rotary evaporation
(60 °C, 50 mbar). The crude product was purified by column
chromatography (silica neutralized with triethylamine, 1 cm ⌀ × 15
cm column) eluting with n-hexane (95%)/EtOAc, 3:7 to afford 51
(0.25 g, 85%) as a white solid. Recrystallization from n-hexane
(95%)/Et2O (1:1) afforded 0.23 g (80%) of analytically pure 51 as
a white solid. Data for 51: mp 134−136 °C (n-hexane (95%)/
+ H)+ calcd for C29H33F6N2O2 555.2455, found 555.2446; TLC Rf
0.21 (silica gel, hexanes/EtOAc, 7:3, UV, KMnO4); [α]D +193.6
(c = 1.0, CHCl3). Anal. Calcd for C29H33F6N2O2 (554.566): C,
62.56; H, 5.82; N, 5.05. Found: C, 62.48; H, 5.90; N, 5.08.
24
Preparation of (4R,4′R,5R,5′R)-2,2′-(Propane-2,2-diyl)bis(5-iso-
propyl-4-(4-(trifluoromethyl)phenyl)-4,5-dihydrooxazole) (55). A
25 mL, one-necked Schlenk flask containing an egg-shaped stir
bar (15.9 × 6.35 mm) was charged with 38 (0.29 g, 0.50 mmol),
Et3N (0.30 g, 0.41 mL, 3.0 mmol, 6.0 equiv), and CH2Cl2 (5 mL)
under nitrogen. The solution was cooled to 0 °C using an ice bath,
and methanesulfonyl chloride (0.28 g, 0.19 mL, 2.5 mmol, 5.0
equiv) was added dropwise by syringe over 2 min. The mixture was
quenched with H2O (1 mL) and extracted with CH2Cl2 (5 × 2 mL
portions). The organic layers were combined and concentrated by
rotary evaporation (30 °C, 50 mbar). A 25 mL, one-necked Schlenk
flask containing an egg-shaped stir bar (15.9 × 6.35 mm) was
charged with the residue, and ethanol (5 mL). NaOH (0.10 g, 2.5
mmol, 5.0 equiv) in water (0.5 mL) was added dropwise. The
mixture was heated to reflux using a condenser in 85 °C oil bath for
12 h. After the solution was cooled to 25 °C, the volatile
components were removed by rotary evaporation (30 °C, 50 mbar).
The resulting residue was diluted with CH2Cl2 (20 mL). The
mixture was transferred to a 60 mL separatory funnel. The reaction
mixture was washed with water (1 × 5 mL) and then brine (1 × 5
mL). The organic layer was removed, the aqueous layer was
extracted with CH2Cl2 (2 × 10 mL), and the organic layers were
combined, dried over Na2SO4 (0.30 g), decanted, and concentrated
by rotary evaporation (30 °C, 50 mbar). The crude product was
purified by column chromatography (silica, 1 cm ⌀ × 15 cm
column) eluting with n-hexane (95%)/EtOAc, 1:1 to afford 55 (0.22
g, 81%) as a white solid. Recrystallization from n-hexane (95%)
afforded 0.21 g (76%) of analytically pure 55 as a white solid. Data
for 55: mp 89−91 °C (n-hexane (95%)); 1H NMR (500 MHz,
CDCl3); δ 7.53 (d, J = 8.3 Hz, 4H, HC(10)), 7.37 (d, J = 8.2 Hz,
4H, HC(9)), 4.90 (d, J = 6.1 Hz, 2H, HC(4)), 4.16 (t, J = 6.2 Hz,
2H, HC(5)), 1.95 (dqq, J = 7.7, 7.7, 6.2 Hz, 2H, HC(6)),1.69 (s,
6H, HC(1)), 1.11−0.93 (m, 12H, HC(7,7′)); 13C{1H} NMR (126
1
Et2O); H NMR (500 MHz, CDCl3); δ 6.05 (s, 4H, HC(10,10′)),
5.74 (d, J = 10.4 Hz, 2H, HC(4)), 4.06 (t, J = 10.5 Hz, 2H,
HC(5)), 3.74 (s, 6H, HC(13)), 3.73 (s, 6H, HC(12)), 3.67 (s, 6H,
HC(12′)), 1.63 (dqq, J = 10.5, 6.6, 6.5 Hz, 2H, HC(6)), 1.54 (s,
6H, HC(1)), 0.97 (d, J = 6.5 Hz, 6H, HC(7)), 0.50 (d, J = 6.6 Hz,
6H, HC(7′)); 13C{1H} NMR (126 MHz, CDCl3); δ 169.9 (C(3)),
161.0 (C9)), 160.6 (C(11)), 158.8 (C(9′)), 107.3 (C(8)), 90.9
(C(10)), 90.2 (C(10′)), 88.5 (C(5)), 61.0 (C(6)), 55.7 (C(4)),
55.2 (C(13)), 54.9 (C(12)), 38.9 (C(12′)), 28.7 (C(2)), 24.3
(C(1)), 20.7 (C(7′)), 19.1 (C(7)); IR (neat) 1657 (s), 1633 (s),
1603 (s), 1596 (s), 1417 (s), 1326 (S), 1223 (s), 1137 (s), 1117
(m), 1074 (s), 990 (s), 939 (s), 895 (s), 775 (m), 518 (s); LRMS
[ESI+, TOF] 204.1(2), 335.1(4), 309.3(3), 599.3(100), 600.3(39),
601.3(9), 602.3(2); Anal. Calcd for C33H46N2O8 (598.725): C,
66.20; H, 7.74; N, 4.68. Found: C, 66.11; H, 7.68; N, 4.85; HRMS
(ESI) m/z (M + H)+ calcd for C33H47N2O8 599.3320, found
599.3332; TLC Rf 0.29 (silica gel, hexanes/EtOAc, 1:9, UV,
24
KMnO4); [α]D +187.7 (c = 1.0, CHCl3).
Preparation of (4R,4′R,5S,5′S)-2,2′-(Propane-2,2-diyl)bis(5-iso-
propyl-4-(4-(trifluoromethyl)phenyl)-4,5-dihydrooxazole) (50). A
25 mL, one-necked Schlenk flask containing an egg-shaped stir
bar (15.9 × 6.35 mm) was charged with 38 (0.29 g, 0.50 mmol)
and xylenes (12 mL) under nitrogen. The mixture was heated to
reflux in a 160 °C oil bath using a condenser connected to a Dean−
Stark apparatus which was itself connected to a Schlenk flask. Once
the bisamide alcohol dissolved completely then Ti(OiPr)4 (0.028 g,
0.030 mL, 20 mol %) was added to the solution in one portion. The
reaction mixture was refluxed for 12 h with removal of the water
byproduct. After the reaction mixture was cooled to room
temperature, the solution was concentrated by rotary evaporation
(60 °C, 50 mbar). The crude product was purified by column
chromatography (silica, 1 cm ⌀ × 15 cm column) eluting with n-
hexane (95%)/EtOAc, 1:1 to afford 50 (0.22 g, 80%) as a white
solid. Recrystallization from n-hexane (95%) afforded 0.21 g (77%)
of analytically pure 50 as a white solid. Data for 50: mp 99−101 °C
MHz, CDCl3); δ 170.5 (C(3)), 147.0 (C(8)), 130.2 (C−F, 2JC−F
=
31.5 Hz, C(11)), 127.3 (C(9)), 125.7 (C−F, 1JC−F = 3.8 Hz,
C(10)), 124.2 (C−F, 1JC−F = 272.2 Hz, C(12)), 123.1 (C(5)), 93.0
(C(4)), 39.3 (C(2)), 32.7 (C(6)), 24.4 (C(1)), 17.6 (C(7′)), 17.3
(C(7)); 19FNMR (471 MHz, CDCl3) −62.58; IR (neat) 2973 (s),
1650 (s), 1620 (s), 1519 (s), 1416 (s), 1325 (S), 1228 (s), 1128
(m), 1114 (m), 1067 (m), 980 (s), 905 (s), 867 (s), 724 (s), 512
(s); LRMS [ESI+, TOF] 215.1(1), 306.1(1), 553.5(1), 555.2(100),
556.2(32), 573.2(8), 574.2(3); HRMS (ESI) m/z (M + H)+ calcd
for C29H33F6N2O2 555.2438, found 555.2446; TLC Rf 0.19 (silica
24
gel, hexanes/EtOAc, 9:1, UV, KMnO4); [α]D +193.4 (c = 1.0,
CHCl3). Anal. Calcd for C29H33F6N2O2 (554.566): C, 62.81; H,
5.82; N, 5.05, Found: C, 62.88; H, 5.75; N, 5.31.
Synthesis of Bisoxazoline Ligands with a Phenyl Substituent at
the C(5)-Position.
1
(n-hexane (95%)); H NMR (500 MHz, CDCl3) δ 7.52 (d, J = 8.2
Hz, 4H, HC(10)), 7.38 (d, J = 8.1 Hz, 4H, HC(9)), 5.17 (d, J = 9.1
Hz, 2H, HC(4)), 4.38 (t, J = 9.4 Hz, 2H, HC(5)), 1.67 (s, 6H,
HC(1)), 1.56 (dqq, J = 9.4, 6.6, 6.6 Hz, 2H, HC(6)), 0.99 (d, J =
6.6 Hz, 6H, HC(7)), 0.68 (d, J = 6.6 Hz, 6H, HC(7′)); 13C{1H}
NMR (126 MHz, CDCl3) δ 171.0 (C(3)), 141.8 (C(8)), 129.8
(C−F, 2JC−F = 32.8 Hz, C(11)), 129.1 (C(9)), 125.1 (C−F, 3JC−F
= 3.8 Hz, C(10)), 124.1 (C−F, 1JC−F = 272.1 Hz, C(12)), 120.94
(C(5)), 90.5 (C(4)), 71.1 (C(2)), 39.3 (C(6)), 24.5 (C(1)), 19.9
(C(7′)), 18.9 (C(7)); 19FNMR (471 MHz, CDCl3) −62.58; IR
(neat) 2967 (s), 1665 (s), 1646 (s), 1621 (s), 1467 (s), 1326 (S),
1232 (s), 1157 (s), 1121 (m), 1099 (m), 989 (s), 900 (s), 868 (s),
731 (m), 500 (s); LRMS [ESI+, TOF] 344.1(1), 553.2(1),
555.2(100), 556.2(33), 573.2(8), 574.2(3); HRMS (ESI) m/z (M
Preparation of Methyl (S)-2-Hydroxy-2-phenylacetate (2d). A 250
mL, one-necked Schlenk flask containing an egg-shaped stir bar
(50.8 × 19.1 mm) was charged with (S)-2-hydroxy-2-phenylacetic
acid (7.60 g, 50.0 mmol) and MeOH (distilled, 120 mL) under
nitrogen. The solution was cooled in an ice bath for 10 min, and
SOCl2 (17.84 g, 10.94 mL, 150.0 mmol, 3.0 equiv) was added
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dropwise by syringe over 5 min at 0 °C. The mixture was heated to
reflux using a condenser in 75 °C oil bath for 12 h. After the
solution was cooled to 25 °C, the volatile components are removed
by rotary evaporation (30 °C, 50 mbar). The resulting residue was
diluted with ethyl acetate (200 mL), and satd aq NaHCO3 (200
mL) was added slowly because of the evolution of gas. The mixture
was transferred to a 500 mL separatory funnel, and the organic layer
was removed. The aqueous layer was extracted with ethyl acetate (3
× 100 mL), and the organic layers were combined, washed brine (1
× 100 mL), dried over anhydrous Na2SO4 (10 g), decanted, and
concentrated by rotary evaporation (30 °C, 50 mbar) to afford the
crude product. The crude product was purified by column
chromatography (silica, 4 cm ⌀ × 15 cm column) eluting with
hexanes/EtOAc, 7:3 to afford 2d (7.25 g, 87%) as a white solid. The
spectroscopic data for 2d matched the literature values.93 Data for
Preparation of (R)-N-((S,E)-2-((tert-Butyldimethylsilyl)oxy)-2-
phenylethylidene)-2-methylpropane-2-sulfinamide (6d). A 100
mL, one-necked Schlenk flask with an egg-shaped stir bar (38.1 ×
15.9 mm) was charged with 5d (8.61 g, 34.4 mmol), (R)-2-
methylpropane-2-sulfinamide (4.37 g, 36.12 mmol, 1.05 equiv), and
titanium(IV) ethoxide (15.60 g, 14.4 mL, 68.8 mmol, 2.0 equiv)
under nitrogen. The mixture was stirred in a 70 °C oil bath for 60
min and then was diluted with ethyl acetate (50 mL). The resulting
solution was poured into a 200 mL Erlenmeyer flask with a stir bar
and brine (10 mL), and the vial was rinsed with ethyl acetate (2 ×
25 mL) to help the transfer. The suspension was stirred at 25 °C for
10 min and then filtered through a fritted glass funnel (7.5 mm
diameter) containing Celite. The Celite cake was washed with ethyl
acetate (2 × 100 mL). The combined filtrates were transferred to a
250 mL separatory funnel, washed with water (1 × 100 mL) and
brine (1 × 100 mL), dried over Na2SO4 (10 g), decanted, and
concentrated by rotary evaporation (30 °C, 50 mbar). The crude
product was purified by column chromatography (silica, 4 cm ⌀ ×
12 cm column) eluting with hexanes/Et2O, 8:2 to afford 6d (11.00
1
2d: H NMR (500 MHz, CDCl3) δ 7.43−7.40 (m, 2H), 7.40−7.33
(m, 3H), 5.18 (d, J = 5.1 Hz, 1H), 3.74 (s, 3H), 3.65 (d, J = 5.2
Hz, 1H).
Preparation of Methyl (S)-2-((tert-Butyldimethylsilyl)oxy)-2-
phenylacetate (3d). A 250 mL, one-necked Schlenk flask containing
an egg-shaped stir bar (50.8 × 19.1 mm) was charged with 2d (7.24
g, 43.6 mmol), TBSCl (8.21 g, 54.5 mmol, 1.25 equiv), imidazole
(4.00 g, 58.86 mmol, 1.35 equiv), and DMF (SDS, 45 mL) under
nitrogen. The mixture was stirred at 25 °C for 12 h. The resulting
mixture was diluted in Et2O (200 mL), transferred to 500 mL
separatory funnel, washed with water (3 × 100 mL) and brine (1 ×
100 mL), dried over anhydrous Na2SO4 (10 g), decanted, and
concentrated by rotary evaporation (30 °C, 50 mbar). The crude
product was purified by column chromatography (silica, 4 cm ⌀ ×
12 cm column) eluting with hexanes/Et2O, 9:1 to afford 3d (11.00
g, 92%) as a colorless oil. The spectroscopic data for 3d matched
1
g, 89%) as a yellow oil. Data for 6d: H NMR (500 MHz, CDCl3) δ
8.00 (d, J = 4.9 Hz, 1H), HC(3)), 7.40 (d, J = 7.4 Hz, 2H),
HC(6)), 7.33 (t, J = 7.5 Hz, 2H), HC(7)), 7.26 (t, J = 7.4 Hz, 1H),
HC(8)), 5.50 (d, J = 4.9 Hz, 1H), HC(4)), 1.06 (s, 9H), HC(1)),
0.92 (s, 10H), HC(11)), 0.10 (s, 3H), HC(9)), 0.03 (s, 3H,
HC(9′)); 13C{1H} NMR (126 MHz, CDCl3) δ 169.6 (C(3)), 139.8
(C(5)), 128.5 (C(7)), 128.1 (C(8)), 126.3 (C(6)), 76.8 (C(4)),
57.3 (C(2)), 25.7 (C(11)), 22.3 (C(1)), 18.2 (C(10)), −4.6
(C(9)), −4.7 (C(9′)); IR (neat) 2956 (w), 2929 (w), 2858 (w),
1624 (w), 1472 (w), 1454 (w), 1390 (w), 1363 (m), 1254 (m),
1193 (w), 1088 (s), 1066 (s), 1027 (w), 1006 (w), 939 (w), 867
(s), 836 (s), 777 (s), 756 (m), 699 (s), 665 (m), 581 (m), 511
the literature values.118 Data for 3d: H NMR (500 MHz, CDCl3) δ
1
(m), 456 (w); HRMS (ESI) m/z (M
+
H)+ calcd for
7.50 (dd, J = 7.6, 1.9 Hz, 2H), 7.41−7.24 (m, 3H), 5.28 (s, 1H),
3.67 (s, 3H), 0.96 (s, 9H), 0.15 (s, 3H), 0.07 (s, 3H).
C18H32NO2SSi 354.1918, found 354.1923; TLC Rf 0.45 (silica gel,
hexanes/Et2O, 7:3, UV, KMnO4).
Preparation of (S)-2-((tert-Butyldimethylsilyl)oxy)-3-methylbu-
tanal (5d). A 250 mL, three-necked round-bottomed flask equipped
with nitrogen inlet, an egg-shaped stir bar (50.8 × 19.1 mm), an
internal temperature probe, and two rubber septa was charged with
3d (10.99 g, 39.2 mmol) and Et2O (80 mL, SDS) under nitrogen.
The solution was cooled to −78 °C using a cryocooler in an i-PrOH
bath, and DIBAL-H (1.0 M in heptane, 43.12 mL, 43.12 mmol, 1.1
equiv) was added dropwise by syringe to maintain the internal
temperature below −70 °C. The solution was stirred at −78 °C for
1 h and then reaction was quenched with H2O (6 mL). The mixture
was slowly warmed to 25 °C. The mixture was stirred for additional
1 h. Then the mixture was filtered through a fritted glass funnel (7.5
mm diameter) containing Celite into a 250 mL filter flask. The
Celite cake was washed with Et2O (2 × 75 mL). The combined
filtrates were transferred to a 250 mL separatory funnel, washed with
water (1 × 100 mL) and brine (1 × 100 mL), dried over Na2SO4
(10 g), decanted, and concentrated by rotary evaporation (30 °C,
50 mbar). The crude product was purified by column chromatog-
raphy (silica, 4 cm ⌀ × 12 cm column) eluting with hexanes/Et2O,
9:1 to afford 5d (8.60 g, 88%) as a yellow oil. The spectroscopic
Preparation of (R)-N-((1R,2S)-2-((tert-Butyldimethylsilyl)oxy)-1-
(4-methoxyphenyl)-2-phenylethyl)-2-methylpropane-2-sulfina-
mide (14). A 100 mL, one-necked Schlenk flask containing an egg-
shaped stir bar (38.1 × 15.9 mm) was charged with 1-bromo-4-
methoxybenzene (3.74 g, 2.50 mL, 20.0 mmol, 2.0 equiv) and THF
(30 mL) under nitrogen. The solution was cooled to −78 °C using
a cryocooler in an i-PrOH bath, and n-butyllithium (1.28 g, 12.50
mL, 1.6 M in hexane, 20.0 mmol, 2.0 equiv) was added dropwise by
syringe. The resulting solution was stirred at −78 °C using a
cryocooler in an i-PrOH bath for 1 h. Then another 50 mL Schlenk
flask containing an egg-shaped stir bar (19.1 × 9.5 mm) was
charged with 6d (3.53 g, 10.0 mmol) and THF (30 mL) under
nitrogen and was cooled to −78 °C using a cryocooler in an i-PrOH
bath. The N-sulfinyl imine solution was transferred to the
organolithium solution using a syringe dropwise over 5 min. The
resulting mixture was stirred at −78 °C using a cryocooler in i-
PrOH bath for 12 h. The reaction was quenched by the addition of
satd aq NH4Cl solution (100 mL) at −78 °C and then was slowly
warmed to 25 °C. The mixture was transferred to a 250 mL
separatory funnel. The organic layer was removed, the aqueous layer
data for 5d matched the literature values.118 Data for 5d: H NMR
1
(500 MHz, CDCl3) δ 9.54 (d, J = 2.3 Hz, 1H), 7.48−7.28 (m, 5H),
5.04 (d, J = 2.2 Hz, 1H), 0.98 (s, 9H), 0.15 (s, 3H), 0.07 (s, 3H).
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was extracted with ethyl acetate (3 × 75 mL), and the organic layers
were combined, washed with brine (1 × 100 mL), dried over
Na2SO4 (10 g), decanted, and concentrated by rotary evaporation
−0.33 (s, 3H, HC(10)), −0.49 (s, 3H, HC(10′)); 13C{1H} NMR
(126 MHz, CDCl3) δ 150.2 (C(16)), 148.2 (C(14 or 14′)), 142.1
(C(6)), 128.8 (C(13)), 128.5 (C(8)),128.5 (C(9)), 128.5 (C(7)),
122.6 (C(15′)), 121.2 (C(15)), 79.2 (C(5)), 58.1 (C(4)), 55.5
(C(2)), 34.2 (C(19)), 29.6 (C(21)), 28.9 (C(17)), 26.2 (C(18)),
25.7 (C(12)), 25.0 (C(20)), 24.8 (C(20′)), 24.5 (C(18′)), 24.1
(C(22)), 24.0 (C(22′)), 22.7 (C(1)), 17.9 (C(11)), −4.5 (C(10)),
−5.1 (C(10′)); IR (neat) 3266 (s), 2929 (w), 2954 (s), 2927 (s),
1608 (s), 1457 (s), 1382 (s), 1361 (s), 1325 (s), 1255 (s), 1198
(s), 1085 (m), 1066 (w), 1038 (m), 1012 (s), 939 (s), 911 (m),
908 (s), 875 (s), 863 (s), 850 (m), 834 (m), 814 (m), 773 (m),
734 (m), 700 (m). HRMS (ESI) m/z (M + H)+ calcd for
C33H56NO2SSi 558.3811, found 558.3801; TLC Rf 0.28 (silica gel,
hexanes/Et2O, 9:1, UV, KMnO4).
1
(30 °C, 50 mbar). The dr of the crude product was 98:2 by H
NMR analysis. The crude product was purified by column
chromatography (silica, 4 cm ⌀ × 12 cm column) eluting with
hexanes/EtOAc, 7:3 to afford 14 (4.61 g, 76%) as a white solid.
Data for 14: mp 103−105 °C (hexanes/EtOAc); 1H NMR (500
MHz, CDCl3) δ 7.27−7.19 (m, 3H, HC(7,9)), 7.12 (dd, J = 7.3, 2.2
Hz, 2H, HC(8)), 7.05 (d, J = 8.6 Hz, 2H, HC(14)), 6.77 (d, J = 8.7
Hz, 2H, HC(15)), 4.75 (d, J = 6.0 Hz, 1H, HC(5)), 4.46 (dd, J =
6.0, 2.4 Hz, 1H, HC(4)), 3.74 (s, 3H, HC(17)), 3.69 (d, J = 1.8
Hz, 1H, HN(3)), 1.10 (s, 9H, HC(1)), 0.80 (s, 9H, HC(12)),
−0.14 (s, 3H, HC(10)), −0.29 (s, 3H, HC(10′)); 13C{1H} NMR
(126 MHz, CDCl3) δ 159.0 (C(16)), 140.3 (C(6)), 130.1 (C(13)),
129.9 (C(14)), 128.8 (C(9)), 127.8 (C(9)), 127.8 (C(7)), 127.2
(C(8)), 113.0 (C(15)), 79.2 (C(5)), 63.6 (C(4)), 55.2 (C(2)),
55.0 (C(17)), 25.5 (C(12)), 22.4 (C(1)), 17.8 (C(11)), −4.9
(C(10)), −5.4 (C(10′)); IR (neat) 2955 (w), 2929 (w), 2857 (w),
1612 (w), 1586 (w), 1513 (m), 1472 (m), 1389 (w), 1363 (w),
1303 (w), 1249 (s), 1173 (m), 1069 (s), 1035 (m), 1009 (m), 985
(w), 911 (m), 828 (s), 777 (s), 731 (s), 700 (s), 673 (m), 635 (m),
602 (m), 570 (m), 479 (w); HRMS (ESI) m/z (M + H)+ calcd for
C25H40NO3SSi 462.2490, found 462.2498; TLC Rf 0.47 (silica gel,
hexanes/EtOAc, 7:3, UV, KMnO4).
Preparation of (1S,2R)-2-Amino-2-(4-methoxyphenyl)-1-phenyl-
ethan-1-ol (28). A 250 mL, one-necked Schlenk flask with an egg-
shaped stir bar (50.8 × 19.1 mm) was charged with 14 (3.23 g, 7.0
mmol) and methanol (10 mL) under nitrogen. HCl (6 N) in
MeOH (70 mL) was added dropwise by syringe. The mixture was
stirred for 2 h at 25 °C, and then the solvent was removed rotary
evaporation (30 °C, 50 mbar). The crude solid was suspended in
ethyl acetate (50 mL), and 8 N NaOH in H2O (105 mL) was
added while the solution was stirred vigorously. The solution was
stirred for 10 min and then was transferred to a 500 mL separatory
funnel. The organic layer was separated, and the aqueous layer was
extracted with ethyl acetate (2 × 50 mL). pH paper was used to
check the neutralization of the solution (pH= 7). The organic layers
were combined, dried over anhydrous Na2SO4 (10 g), decanted, and
concentrated by rotary evaporation (30 °C, 50 mbar). The crude
product was purified by column chromatography (silica, 4 cm ⌀ ×
12 cm column) eluting with MeOH/EtOAc, 1:1 to afford 28 (1.29
g, 76%) as a white solid. The compound was further recrystallized
with hot EtOAc (15 mL) to afford 28 (1.22 g, 72%) as a white
Preparation of (R)-N-((1R,2S)-2-((tert-Butyldimethylsilyl)oxy)-2-
phenyl-1-(2,4,6-triisopropylphenyl)ethyl)-2-methylpropane-2-sulfi-
namide (15). A 100 mL, one-necked Schlenk flask containing an
egg-shaped stir bar (38.1 × 15.9 mm) was charged with 2-bromo-
1,3,5-triisopropylbenzene (8.49 g, 7.60 mL, 30.0 mmol, 2.0 equiv)
and THF (30 mL) under nitrogen. The solution was cooled to −78
°C using a cryocooler in an i-PrOH bath, and n-butyllithium (1.92
g, 18.75 mL, 1.6 M in hexane, 30.0 mmol, 2.0 equiv) was added
dropwise by syringe. The resulting solution was stirred at −78 °C
using a cryocooler in an i-PrOH bath for 1 h. Then another 50 mL
Schlenk flask containing an egg-shaped stir bar (19.1 × 9.5 mm)
was charged with 6d (5.30 g, 15.0 mmol) and THF (30 mL) under
nitrogen and was cooled to −78 °C using a cryocooler in an i-PrOH
bath. The N-sulfinyl imine solution was transferred to the
organolithium solution using a syringe dropwise over 5 min. The
resulting mixture was stirred at −78 °C using a cryocooler in an i-
PrOH bath for 12 h. The reaction was quenched by the addition of
satd aq NH4Cl solution (100 mL) at −78 °C and then was slowly
warmed to 25 °C. The mixture was transferred to a 250 mL
separatory funnel. The organic layer was removed, the aqueous layer
was extracted with ethyl acetate (3 × 80 mL), and the organic layers
were combined, washed with brine (1 × 100 mL), dried over
Na2SO4 (10 g), decanted, and concentrated by rotary evaporation
1
crystalline solid. Data for 28: mp 49−151 °C (EtOAc); H NMR
(500 MHz, CDCl3) δ 7.36−7.27 (m, 3H, HC(5,7)), 7.25 (dd, J =
7.9, 1.8 Hz, 2H, HC(6)), 7.19 (d, J = 8.7 Hz, 2H, HC(10)), 6.86
(d, J = 8.7 Hz, 2H, HC(11)), 4.69 (d, J = 6.3 Hz, 1H, HC(3)), 4.10
(d, J = 6.4 Hz, 1H, HC(2)), 3.82 (s, 3H, HC(13)), 1.57 (s, 3H,
HN, HO(1,8)); 13C{1H} NMR (126 MHz, CDCl3) δ 159.1
(C(12)), 141.0 (C(4)), 133.6 (C(9)), 128.7 (C(10)), 128.2 (C(5)),
127.8 (C(7)), 127.0 (C(6)), 113.7 (C(11)), 78.5 (C(3)), 61.4
(C(2)), 55.3 (C(13)); IR (neat) 3357 (w), 2833 (w), 1578 (w),
1509 (m), 1449 (m), 1359 (w), 1234 (s), 1182 (m), 1095 (m),
1035 (m), 988 (s), 858 (m), 833 (s), 818 (m), 744 (s), 697 (s),
664 (s), 629 (m), 566 (s), 526 (m), 460 (s); HRMS (ESI) m/z (M
+ H)+ calcd for C15H18NO2 244.1342, found 244.1338; TLC Rf 0.12
(silica gel, MeOH/EtOAc, 0.5:9.5, UV, KMnO4).
1
(30 °C, 50 mbar). The dr of the crude product was 99:1 by H
NMR analysis. The crude product was purified by column
chromatography (silica, 4 cm ⌀ × 12 cm column) eluting with
hexanes/Et2O, 1:1 to afford 15 (6.90 g, 82%) as a white solid. The
compound was further recrystallized with hot hexane (50 mL) to
afford 15 (6.27 g, 75%) as a white crystalline solid. Data for 15: mp
1
170−172 °C (hexanes); H NMR (500 MHz, CDCl3) δ 7.58−7.36
(m, 4H, HC(7,8)), 7.35−7.28 (m, 1H, HC(9)), 7.03 (d, J = 4.0 Hz,
2H, HC(15)), 5.04 (d, J = 8.8 Hz, 1H, HC(5)), 4.94 (dd, J = 8.5,
2.2 Hz, 1H, HC(4)), 3.89 (sept, J = 6.3 Hz, 1H, HC(17)), 3.60
(sept, J = 6.8 Hz, 1H, HC(19)), 3.08 (d, J = 2.4 Hz, 1H, HN(3)),
2.87 (sept, J = 6.9 Hz, 1H, HC(21)), 1.44 (d, J = 6.9 Hz, 3H,
HC(18)), 1.38 (d, J = 6.8 Hz, 3H, HC(20′)), 1.34 (d, J = 6.7 Hz,
3H, HC(20)), 1.24 (d, J = 7.0 Hz, 6H, HC(22,22′)), 1.17 (d, J =
6.6 Hz, 3H, HC(18′)), 0.92 (s, 9H, HC(1)), 0.57 (s, 9H, HC(12)),
Preparation of (1S,2R)-2-Amino-1-phenyl-2-(2,4,6-
triisopropylphenyl)ethan-1-ol (29). A 500 mL, one-necked Schlenk
flask with an egg-shaped stir bar (50.8 × 19.1 mm) was charged
with 15 (5.58 g, 10.0 mmol) and methanol (15 mL) under nitrogen.
HCl (12.1 N) in MeOH (100 mL) was added dropwise by syringe.
The reaction was stirred for 12 h at 25 °C, and then the solvent was
removed by rotary evaporation (30 °C, 50 mbar). The crude solid
was suspended in ethyl acetate (50 mL), and 8 N NaOH in H2O
3518
https://dx.doi.org/10.1021/acs.joc.0c02899
J. Org. Chem. 2021, 86, 3490−3534

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
(200 mL) was added while the solution was stirred vigorously. The
solution was stirred for 10 min and then was transferred to a 500
mL separatory funnel. The organic layer was separated, and the
aqueous layer was extracted with ethyl acetate (2 × 100 mL). pH
paper was used to check the neutralization of the solution (pH = 7).
The organic layers were combined, dried over anhydrous Na2SO4
(10 g), decanted, and concentrated by rotary evaporation (30 °C,
50 mbar). The 1H NMR analysis of crude product showed the
removal of chiral auxiliary only while the TBS group was still intact.
The crude residue was moved to the next step of removal of TBS
group without further purification. A 250 mL, one-necked Schlenk
flask containing an egg-shaped stir bar (50.8 × 19.1 mm) was
charged with the crude residue and THF (50 mL) under nitrogen.
Tetra-n-butylammonium fluoride (5.20 g, 20.0 mL, 1.0 M in THF,
20.0 mmol, 2.0 equiv) was added dropwise by syringe. The mixture
was heated to reflux using a condenser in a 60 °C oil bath for 12 h.
After the solution was cooled to 25 °C, the volatile components are
removed by rotary evaporation (30 °C, 50 mbar). The resulting
residue is diluted with ethyl acetate (100 mL) and water (100 mL).
The mixture was transferred to a 250 mL separatory funnel, and the
organic layer was removed. The aqueous layer was extracted with
ethyl acetate (2 × 50 mL), and the organic layers were combined,
washed with brine (1 × 100 mL), dried over anhydrous Na2SO4 (10
g), decanted, and concentrated by rotary evaporation (30 °C, 50
mbar) to afford the crude product. The crude product was purified
by column chromatography (silica, 4 cm ⌀ × 15 cm column)
eluting with hexanes/Et2O, 1:1 to afford 29 (3.00 g, 87%) as a white
solid. The compound was further recrystallized with hot hexane (30
mL) to afford 29 (2.80 g, 82%) as a white crystalline solid. Data for
29: mp 149−151 °C (hexanes); 1H NMR (500 MHz, CDCl3) δ
7.61 (d, J = 7.3 Hz, 2H, HC(5)), 7.46 (t, J = 7.5 Hz, 2H, HC(6)),
7.38 (t, J = 7.3 Hz, 1H, HC(7)), 7.19 (d, J = 1.7 Hz, 1H, HC(11)),
7.11 (d, J = 2.0 Hz, 1H, HC(11′)), 5.05 (d, J = 9.4 Hz, 1H,
HC(3)), 4.74 (d, J = 9.4 Hz, 1H, HC(2)), 4.26 (sept, J = 6.6 Hz,
1H, HC(13)), 3.56 (sept, J = 6.6 Hz, 1H, HC(15)), 2.96 (sept, J =
6.8 Hz, 1H, HC(17)), 1.87 (s, 1H, HO (8)), 1.45 (d, J = 6.8 Hz,
3H, HC(18)), 1.38 (dd, J = 9.8, 6.8 Hz, 6H, HC(16.16′)), 1.34 (d,
J = 6.9 Hz, 6H, HC(14,14′)), 1.30 (d, J = 6.8 Hz, 3H, HC(18′)),
1.21 (s, 2H, HN(1)); 13C{1H} NMR (126 MHz, CDCl3) δ 149.2
(C(12)), 148.5 (C(10′)), 148.0 (C(10)), 142.7 (C(4)), 131.8
(C(9)), 128.5 (C(6)), 128.0 (C(7)), 127.1 (C(5)), 12.7 (C(11′)),
121.3 (C(11)), 78.0 (C(3)), 57.2 (C(2)), 34.1 (C(15)), 29.8
(C(17)), 29.3 (C(13)), 25.2 (C(18)), 25.1 (C(16′)), 25.0 (C(16)),
24.4 (C(14′)), 24.0 (C(14)), 23.9 (C(18′)); IR (neat) 3555 (s),
3310 (s), 2954 (s), 2926 (s), 2867 (s), 1607 (s), 1569 (s), 1492
(s), 1455 (s), 1380 (s), 1361 (s), 1264 (s), 1201 (s), 1155 (s),
1102 (s), 1078 (s), 1040 (s), 913 (s), 880 (s), 563 (s), 499 (s);
HRMS (ESI) m/z (M + H)+ calcd for C23H34NO 340.2644, found
340.2640; TLC Rf 0.36 (silica gel, hexanes/Et2O, 8:2, UV, KMnO4).
combined, dried over Na2SO4 (10 g), decanted, and concentrated by
rotary evaporation (30 °C, 50 mbar). The crude product was
purified by column chromatography (silica, 3 cm ⌀ × 15 cm
column) eluting with hexanes/EtOAc, 3:7 to afford 40 (1.05 g,
70%) as a white solid. Data for 40: mp 179−181 °C (hexanes/
1
EtOAc); H NMR (500 MHz, CDCl3) δ 7.30 (d, J = 8.3 Hz, 2H
HC(4)), 7.27−7.21 (m, 6H HC(8,10)), 7.09−7.02 (m, 4H HC(9)),
6.85 (d, J = 8.7 Hz, 4H HC(13)), 6.68 (d, J = 8.6 Hz, 4H
HC(14)), 5.21 (dd, J = 8.3, 4.4 Hz, 2H HC(6)), 5.00 (t, J = 4.3
Hz, 2H HC(5)), 3.75 (s, 6H HC(16)), 3.49 (d, J = 4.4 Hz, 2H,
HC(11)), 1.34 (s, 6H, HC(1)); 13C{1H} NMR (126 MHz, CDCl3)
δ 173.2 (C(3)), 158.9 (C(15)), 139.7 (C(7)), 129.2 (C(12)), 128.7
(C(13)), 128.0 (C(10)), 127.8 (C(8)), 126.6 (C(9)), 113.5
(C(14)), 76.5 (C(5)), 58.8 (C(6)), 55.1 (C(16)), 49.6 (C(2)),
23.6 (C(1)); IR (neat) 3307 (w), 2936 (w), 1652 (m), 1634 (m),
1614 (m), 1512 (s), 1455 (m), 1395 (w), 1288 (m), 1249 (s), 1178
(s), 1114 (w), 1033 (s), 912 (m), 866 (w), 814 (m), 777 (w), 756
(m), 730 (m), 697 (s), 574 (s), 532 (s); HRMS (ESI) m/z (M +
H)+ calcd for C35H39N2O6 583.2807, found 583.2808; TLC Rf 0.49
(silica gel, hexanes/EtOAc, 3:7, UV, KMnO4).
Preparation of N1,N3-Bis((1R,2S)-2-hydroxy-2-phenyl-1-(2,4,6-
triisopropylphenyl)ethyl)-2,2-dimethylmalonamide (41). A 50 mL
Schlenk flask containing an egg-shaped stir bar (15.9 × 6.35 mm)
was charged with 29 (2.04 g, 6.0 mmol, 2.0 equiv), Et3N (1.52 g,
2.09 mL, 15.0 mmol, 5.0 equiv), and CH2Cl2 (20 mL) under
nitrogen. The solution was cooled to 0 °C using an ice bath, and
2,2-dimethylmalonyl dichloride (0.50 g, 0.39 mL, 3.0 mmol) was
added dropwise by syringe over 2 min. The resulting mixture was
warmed slowly to 25 °C and was stirred at 25 °C for 12 h. The
mixture was transferred to a 125 mL separatory funnel. The reaction
mixture was washed with water (1 × 50 mL) and then brine (1 ×
50 mL). The organic layer was removed, the aqueous layer was
extracted with CH2Cl2 (2 × 30 mL), and the organic layers were
combined, dried over Na2SO4 (10 g), decanted, and concentrated by
rotary evaporation (30 °C, 50 mbar). The crude product was
purified by column chromatography (silica, 3 cm ⌀ × 15 cm
column) eluting with hexanes/Et2O, 1:1 to afford 41 (2.00 g, 85%)
as a white solid. The compound was further recrystallized with hot
hexane (20 mL) to afford 41 (1.90 g, 80%) as a white crystalline
solid. Data for 41: mp 201−203 °C (hexanes); 1H NMR (500
MHz, CDCl3) δ 7.41 (d, J = 7.0 Hz, 4H, HC(8)), 7.34 (t, J = 7.4
Hz, 4H, HC(9)), 7.29 (t, J = 7.2 Hz, 2H, HC(10)), 6.98 (d, J = 8.3
Hz, 4H, HC(4,14′)), 6.89 (s, 2H, HC(14)), 5.76 (t, J = 8.8 Hz, 2H,
HC(5)), 4.88 (d, J = 9.1 Hz, 2H, HC(6)), 3.64 (sept, J = 6.7, 6.2
Hz, 2H, HC(18)), 2.93 (sept, J = 6.6, 6.2 Hz, 2H, HC(16)), 2.85
(sept, J = 6.9 Hz, 2H, HC(20)), 1.88 (s, 2H, HC(11)), 1.31 (d, J =
6.7 Hz, 6H, HC(19)), 1.28−1.23 (m, 18H, HC(17,21,21′)), 1.19
(d, J = 6.7 Hz, 6H, HC(19′)), 0.80 (d, J = 6.7 Hz, 6H, HC(17′)),
0.74 (s, 6H, HC(1)); 13C{1H} NMR (126 MHz, CDCl3) δ 172.2
(C(3)), 149.2 (C(15)), 148.2 (C(13)), 147.1 (C(13′)), 141.1
(C(7)), 129.0 (C(12)), 128.5 (C(9)), 128.4 (C(10)), 127.2 (C(8)),
123.0 (C(14′)), 121.8 (C(14)), 77.7 (C(6)), 54.2 (C(5)), 48.8
(C(2)), 34.2 (C(20)), 30.8 (C(16)), 29.5 (C(18)), 24.8 (C(19′)),
24.8 (C(17′)), 24.4 (C(17)), 24.1 (C(21,21′)), 24.0 (C(19)), 23.9
(C(1)); IR (neat) 3413 (s), 2958 (s), 2923 (s), 2867 (s), 1668 (s),
1609 (s), 1505 (s), 1456 (s), 1382 (s), 1363 (s), 1316 (s), 1249
(s), 1187 (s), 1103 (s), 1052 (s), 1038 (s), 909 (s), 877 (s), 847
(s), 756 (s), 622 (s), 472 (s); HRMS (ESI) m/z (M + H)+ calcd
for C51H71N2O4 775.5427, found 775.5414; TLC Rf 0.27 (silica gel,
hexanes/Et2O, 8:2, UV, KMnO4).
Preparation of N1,N3-Bis((1R,2S)-2-hydroxy-1-(4-methoxyphen-
yl)-2-phenylethyl)-2,2-dimethylmalonamide (40). A 50 mL
Schlenk flask containing an egg-shaped stir bar (15.9 × 6.35 mm)
was charged with 28 (1.28 g, 5.2 mmol, 2.0 equiv), Et3N (1.31 g,
1.8 mL, 13.0 mmol, 5.0 equiv), and CH2Cl2 (20 mL) under
nitrogen. The solution was cooled to 0 °C using an ice bath, and
2,2-dimethylmalonyl dichloride (0.43 g, 0.34 mL, 2.6 mmol) was
added dropwise by syringe over 2 min. The resulting mixture was
warmed slowly to 25 °C and was stirred at 25 °C for 12 h. The
mixture was transferred to a 125 mL separatory funnel. The reaction
mixture was washed with water (1 × 50 mL) and then brine (1 ×
50 mL). The organic layer was removed, the aqueous layer was
extracted with CH2Cl2 (2 × 30 mL), and the organic layers were
3519
https://dx.doi.org/10.1021/acs.joc.0c02899
J. Org. Chem. 2021, 86, 3490−3534