Sulfenate substitution as a complement and alternative to sulfoxidation in the diastereoselective preparation of chiral β-substituted β-amino sulfoxides

Article abstract of DOI:10.1021/jo302769b

Building from a previous communication, the reaction of sulfenate anions with chiral N-Boc-protected β-substituted β-amino iodides was evaluated as a conceptually different synthetic approach to chiral β-substituted β-amino sulfoxides. Using arenesulfenat

Full text of DOI:10.1021/jo302769b

Article
pubs.acs.org/joc
Sulfenate Substitution as a Complement and Alternative to
Sulfoxidation in the Diastereoselective Preparation of Chiral
β‑Substituted β‑Amino Sulfoxides
Stefan C. Soderman and Adrian L. Schwan*
̈
Department of Chemistry, University of Guelph, Guelph, ON, Canada N1G 2W1
S
* Supporting Information
ABSTRACT: Building from a previous communication, the reaction of
sulfenate anions with chiral N-Boc-protected β-substituted β-amino iodides
was evaluated as a conceptually different synthetic approach to chiral β-
substituted β-amino sulfoxides. Using arenesulfenates, yields typically ranged
from 71% to 92%, and dr’s were often near 9:1. Alkanesulfenates proved less
reactive, delivering lower yields and dr’s. 1-Alkenesulfenates demonstrated high
reactivity, returning chemical yields of 60−86% and dr’s often close to 9:1 and as high as 95:5. (S)-β-Amino iodide electrophiles
yielded (RS,SC)-β-amino sulfoxides, whereas (R)-amino iodides afford (SS,RC)-β-amino sulfoxides. The absolute configuration of
the products makes the sulfenate protocol complementary to other existing preparations, including the commonly employed
sulfoxidation of β-amino sulfides. The reactivity of N-Boc-protected 2-benzyl-2-aminoethyl iodide was found to be superior to the
less sterically encumbered n-butyl iodide. A transition state model is proposed to account for the stereochemistry of the products
and also for the high reactivity of the electrophile. Overall, the chemistry represents a new means of introducing sulfur
stereogenicity in a molecule.
Scheme 1. Retrosynthetic Accesses to β-Amino Sulfoxides
INTRODUCTION
■
The sulfoxide functionality has remained a staple for developing
new synthetic methodology.1−4 The stability of homochiral
sulfoxides and their ability to induce chirality elsewhere in the
molecule have proved useful on a vast number of fronts. The
evolution of modern synthetic methodology has, more recently,
led to the use of sulfoxide-containing compounds as chiral
ligands5−17 and organocatalysts18−22 for inducing chirality in
other molecules.
Homochiral β-amino sulfoxides and derivatives of them
represent a set of sulfoxides that have been used in
organocatalysis,23−25 as ligands in organometallic chemis-
try,26−33 and as valuable precursors of larger synthetic
targets.34−40 Furthermore, the β-amino sulfoxide unit has
been recognized and assembled as a constituent of many
biologically and/or medicinally important compounds.39−53
Scheme 1 demonstrates the main synthetic protocols that
have been used to prepare representative β-amino sulfoxides or
their derivatives. Deprotonated homochiral sulfoxides can add
diastereoselectively to imines for the rapid construction of N-
functionalized β-amino sulfoxides (A).35,39,40,54−57 Using this
method, chemical yields and diastereoselection are maximized
when the system carries stereogenicity in both the sulfoxide and
The oxidation of homochiral β-amino sulfides has been
employed the most extensively, presumably since the protocol
gives the most rapid access to sulfoxide by way of a readily
accessible amino sulfide (D).26,28,36−38,42,50−53,66−79 Surpris-
ingly, despite the presence of the stereogenic carbon, the
diastereoselection of oxidation protocols has only rarely
exceeded dr values of 90%.77,80,81 In most cases, ratios range
from 1:1 to 3:2,26,28,36,37,42,51,67−71,79 and on many occasions,
diastereoselectivities are not even reported or acknowl-
edged.38,52,53,66,72−76 In the few instances when an asymmetric
oxidizing agent was employed to complement the stereogenic
carbon in the substrate, selected de values reach 95% but only
for particular substrates and conditions.78,82−84
R2 substituent of the imino nitrogen.35,39,40,45−47,54−56,58
A
useful and effective alternative involves the asymmetric
reduction of homochiral β-imino sulfoxides under Lewis acid
catalysis34,59−61 or reduction of the corresponding β-aminovinyl
sulfoxide tautomer48,62(B). The conjugate addition of amine to
chiral vinyl sulfoxide (C) has been evaluated, but the reaction
requires the application of heat and de’s have not proved to be
synthetically useful.49,63−66
Received: December 21, 2012
Published: January 31, 2013
© 2013 American Chemical Society
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In this paper, we expand upon a previously introduced85 and
conceptually different synthetic access to N-Boc-protected β-
substituted β-amino sulfoxides, utilizing a sulfenate nucleophile
as a tool to simultaneously deliver the sulfur and oxygen into a
substrate (Scheme 1, E). Sulfenic acid anions, or sulfenates (1,
Scheme 2), are an emerging functionality that can effect S−C
Scheme 3. General Mode of Release and Capture of
Arenesulfenates
Scheme 2. Common Preparations of Sulfenate Anions
of 5a was obtained and the ratio of diastereomers obtained was
91:9. Other nucleophiles provided lower yields and/or dr’s.
Similarly, the lithium counterion proved superior to sodium or
potassium. It should be noted that the sulfenate-generating
reaction conditions limit a comprehensive evaluation of solvent
effects.
These conditions were then employed for the chemistry of
other arenesulfenates with electrophiles (S)-4a and (R)-4a, and
the results are indicated in Chart 1 (a and b). The
diastereomeric ratios were usually determined by HPLC on a
Daicel OJ-H column. Additional examples were prepared under
the optimized conditions by changing substituents on the
electrophile; variation of the R groups was performed, using
bond formation while carrying a single oxygen on the sulfur
during the process.86−88 The additional atom on the sulfur
renders the sulfenate prochiral, in contrast to oxygen-free
thiolates.
There are a growing number of reports of the enantiose-
lective,89−92 diastereoselective93−98 or regioselective99 prepara-
tions of sulfoxides by way of sulfenate chemistry. In many of
those reports,95,97,99 the sulfenate oxygen and, perhaps more
importantly, its accompanying counterion are alleged to play a
role in setting the chirality during C−S bond formation. It was
thought here that some of the principles proposed by others for
counterion-to-heteroatom complexation could also be active in
an intermolecular sense. Although a variety of electrophiles
have been documented for sulfenate alkylations,86,100 most have
not possessed heteroatoms proximal to the alkylation site.
Chart 1. Products from the Alkylation of Aryl Sulfenates
a
with Chiral Electrophiles 4
RESULTS
■
Arenesulfenates. Over the past decade, two principle
methods have emerged for the generation of arene- and
alkanesulfenates (1) as indicated in Scheme 2.92,101 The Perrio/
Metzner method involves the deprotonation and retro-Michael
fragmentation of sulfoxides (2) bearing a strong EWG on a β-
carbon.92 A method developed in our lab invokes addition/
elimination chemistry in β-sulfinyl acrylate esters (3). Both
protocols have the benefit of facile preparation of starting
materials. The Perrio/Metzner method can accommodate
reaction temperatures up to 70 °C.89,90 To begin this
investigation, it was decided to go with the “home-grown”
method because of our familiarity with the protocols and since
the chemistry has been shown to be suitable with base sensitive
substrates.97
For preliminary work, p-toluenesulfenate was selected as a
trial sulfenate and methyl (Z)-2-(p-tolylsulfinyl)acrylate was
prepared as the starting substrate. (S)-N-Boc-2-Amino-3-
phenylpropyl iodide ((S)-4a (R = Bn)) was selected as a
representative electrophile. The protocol requires the addition
of a nucleophile to a β-sulfinyl acrylate, and several options are
available.101 A number of reactions were performed, with
variation of the nucleophile and other parameters, and the
outcome of these key experiments has been summarized
previously.85,102
The working conditions evolving from that study suggest the
use of nBuLi as the base, with addition of it to methyl (Z)-2-(p-
tolylsulfinyl)acrylate at −78 °C in THF. After 15 min at −78
°C, 2 equiv of the iodide was added, and stirring was continued
at −78 °C for 3 h, before the solution was permitted to slowly
warm to rt (Scheme 3). Under these conditions, an 87% yield
a
dr’s were determined by HPLC on a Daicel OJ-H column except for
1
5e and 9, which were established by H NMR.
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both configurations of the electrophile. The electrophiles
employed were (S)-N-Boc-2-aminopropyl iodide ((S)-4b),
(S)-N-Boc-2-amino-3-methylbutyl iodide ((S)-4c), (S)-N-Boc-
2-amino-4-methylpentyl iodide ((S)-4d), (S)-N-Boc-2-amino-
3-(tert-butyldiphenylsilyloxy)propyl iodide ((S)-4e), (S)-N-
Boc-2-(iodomethyl)pyrrolidine ((S)-4f), (R)-N-Boc-2-amino-
butyl iodide ((R)-4g), (R)-N-Boc-2-amino-2-phenylethyl io-
dide ((R)-4h), and (R)-N-Boc-2-amino-3-phenylpropyl iodide
((R)-4a). The examples are compiled in Chart 1 (c and d).
Confirmation of the absolute configuration of 5f was
established through X-ray crystal structure analysis.85 There-
after the stereochemistry of the other products was established
through comparative optical rotations, consistency of elution
sequence in the HPLC, and matching with literature data for 6,
ent-6, and a deprotected form of 6.81 A noteworthy observation
from the whole chart is that the configuration of the sulfinyl
group of the major diastereomer changes with the stereo-
genicity of the electrophilic iodide.
chemistry occurred only after the mixture reached 50 °C. A
maximum yield of sulfoxide was obtained only after refluxing
the mixture in THF (2−3 h) (entry 6).
Entries 7−9 of Table 1 depict the outcome when three other
alkyl sulfenates were treated with iodide (S)-4a under the same
conditions. Compared to the standards established in Chart 1
for arenesulfenates, the yields and dr’s are a little lower except
for lithium cyclohexanesulfenate, which gave suitable results,
providing sulfoxide 10d in 78% yield with 91:9 dr. Lithium tert-
butanesulfenate provided sulfoxide 10c in 63% and a dr of
78:22. This outcome was particularly disappointing, as tert-
butyl sulfoxides possess value as ligands6,13−17 and as a source
of sulfenic acids.104−106 Given that these alkanesulfenates
collectively failed to provide useful results, this aspect of the
investigation was no longer pursued.
Alkenesulfenates. Several years ago, a facile procedure for
the stereoselective generation of exclusively (E)-1-alkenesulfen-
ates (11) by way of deprotonation and rearrangement of anti-
alkyl thiirane S-oxides (12, eq 1) was reported.107,108 Although
Alkanesulfenates. Attention was turned to the substitution
chemistry of alkanesulfenates. Continuing with the fact that a
lithium counterion is preferred, lithium α-toluenesulfenate
(benzyl sulfenate) was generated by the standard method
(Scheme 3). However, this compound could not be alkylated
with iodide (S)-4a (Table 1, entry 1) even with after raising the
a small variation of electrophiles was demonstrated to react
with the alkenesulfenates, there was no experimentation with
the iodides utilized in the current study. Given the success with
the arenesulfenates noted above, this chemistry was pursued,
beginning with 1-propenesulfenate (11a), which can be
generated from anti-methyl thiirane S-oxide. Some reaction
optimization was done, and moreover, the methodology
permitted some variation solvent polarity on the reaction
yield and the corresponding dr.
Table 1. Alkylations of Selected Alkyl Sulfenates with (S)-4a
a
bc
,
no. method
temp
R1
Bn
product (yield %/dr)
1
2
3
4
5
6
7
8
9
1
1
2
2
2
2
2
2
2
−78 °C to rt
−78 °C to rt
−78 °C
10a (0/−)
10b (0/−)
10a (0/−)
10a (0/−)
As above with arenesulfenates, the lithium counterion
provided superior dr’s compared to sodium or potassium and
the highest yield (Table 2, entries 1−3). Other trials provided
nC6H13
Bn
−78 to 0 °C
Bn
−78 to 50 °C
−78 °C to reflux
−78 °C to reflux
−78 °C to reflux
−78 °C to reflux
Bn
10a (tr/−)
Table 2. Optimization of Diastereoselective Alkylations of 1-
Propenesulfenate
Bn
10a (54/85:15)
10b (42/82:18)
10c (63/78:22)
10d (78/91:9)
nC6H13
tBu
cC6H11
a
Method 1 = sulfenate release as shown in Chart 1. Method 2 =
b
sulfenate release as per the reaction shown in the table. dr’s were
determined by HPLC on a Daicel OJ-H column for 10a−c and by 1H
yield %
a
b
c
no.
base
solvent
temp
(dr)
NMR for 10d. The configuration of the major diastereomer is shown
in the equation above and was assigned to be (RS,SC) for 10a, 10c, and
10d and (SS,SC) for 10b (due to a change in atomic priority) through
comparison of optical rotation trends set by the aromatic congeners
(Chart 1).
1
2
3
4
5
6
7
8
9
LiHMDS
NaHMDS
KHMDS
THF
THF
THF
THF
THF
−78 °C to rt
−78 °C to rt
−78 °C to rt
−78 °C to rt
−40 °C to rt
68 (84:16)
62 (76:24)
31 (73:27)
70 (87:13)
77 (86:14)
54 (90:10)
tr (−)
c
MeLiLiBr
LiHMDS
LiHMDS
LiHMDS
LiHMDS
LiHMDS
temperature to rt. Similarly, lithium hexanesulfenate proved
unreactive with (S)-4a (Table 1, entry 2). It has previously
been established that the alkylated sulfenates generated by the
addition/elimination protocol decompose if not alkylated near
0 °C.103 So, in order to probe alkylation chemistry at higher
temperatures, the alkanesulfenates had to be generated by a
different protocol. Given that the Perrio/Metzner method can
withstand temperatures at least up to 70 °C, that protocol was
adopted.92 Four 3-(alkylsulfinyl)propionates (2) were prepared
as described in the literature; the chemistry of ethyl 3-
(phenylmethylsulfinyl)propionate was initially reacted to
generate lithium benzyl sulfenate, which in turn was probed
for its alkylation chemistry with iodide (S)-4a. Entries 3−5 of
Table 1 demonstrated that the onset of some alkylation
1,4-dioxane/THF (25:1) rt
DMSO/THF (12:1)
pentane/THF (6:1)
Et2O/THF (4.5:1)
rt
−78 °C to rt
−78 °C to rt
70 (89:11)
81 (90:10)
a
b
In THF unless otherwise indicated. dr established by chiral HPLC.
In ether.
c
results close to entry 1. However, varying the solvent brought
about change. Although the electrophile was presented as a
THF solution, sulfenate 11a could be generated in other
solvents. The use of 1,4-dioxane lowered the yield of alkylation
but with a dr of 9:1 (entry 6), whereas DMSO did not permit
alkylation. Changing to a less polar solvent maintained the dr
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near 9:1 (entries 8 and 9), and ether as a cosolvent provided
the highest yield.
Given the optimized conditions, other lithium (E)-1-
alkenesulfenates were alkylated with some of the electrophiles
employed above, and the products obtained comprise Chart 2.
Alkylation Competition Experiments. Rarely if ever has
the nature of the electrophile been a significant factor in the
simple alkylation of sulfenate anions. Past chemistry has
focused on methods for the generation of sulfenates, some of
which possessed chirality. Sulfenate alkylations were then
carried out with reactive electrophiles such as benzyl bromides,
methyl iodide, or primary halides, often employing more than a
single molar equivalent.114−119
Chart 2. Products of the Diastereoselective Alkylations of 1-
a
Alkenesulfenates
The alkylation chemistry of this paper not only unveils the
value of chiral electrophiles but also indicates that iodides
possessing β-substitution and heteroatoms are suitable, even
when only 2 equiv are used.120 This was viewed as a surprising
mode of reactivity and as such, some sulfenate competition
reactions were performed to establish the relative reactivity of
(S)-4a in relation to other common or representative
electrophiles (Table 3). Both lithium p-toluenesulfenate and
lithium (E)-1-propenesulfenate reacted with (S)-4a at a faster
rate than with nBuI (entries 1 and 2). On the other hand
pyrrolidine-based iodide (S)-4f is slower to react than nBuI
(entry 4). A competition of (S)-4a and BnBr demonstrated the
latter to be substantially more reactive; no amino sulfoxide was
observed in the mixture (entry 3). In a competition of two
sulfenates, lithium p-toluenesulfenate proved substantially more
reactive than lithium 2-pyridinesulfenate (entries 5 and 6).
DISCUSSION
■
The configurations of the products displayed in Charts 1 and 2
and Table 1 arise from substitutions that consistently afford the
same relative relationship between the sulfoxide and that of the
carbon chirality of the electrophile.121 In this regard, the
substitution occurs in a stereospecific manner. Figure 1 offers
possible transition states that can account for the high
stereoselectivity of the substitution using a generic Sc
electrophile and a sulfenate. A key element to the proposed
structures is a precoordination of the lithium of the sulfenate to
the nitrogen lone pair of the electrophile. Such an interaction
has been invoked previously in an intramolecular sense95,97 and
would explain the surprising reactivity of the electrophiles used
in this paper. The outcomes of the competition experiments of
Table 3 (entries 1 and 2) clearly support some sort of reaction-
accelerating feature, and nitrogen precoordination can serve as
a suitable one, despite the higher steric demands of the chiral
electrophiles.
Accepting the role of Li−N precoordination, the two reactive
atoms can then assume a reactive orientation forming a six-
membered transition state. Two possibilities are presented in
Figure 1. Structure I has three groups of the electrophile
positioned in an equatorial or pseudoequatorial arrangement,
with the key destabilizing feature being the eclipsing iodide and
the R group. This arrangement also requires that the sulfenate
R1 group assume an axial position to deliver the RS
stereocenter.
a
dr’s were established by 1H NMR analysis except for 13a and ent-13a
(chiral HPLC).
Many entries exhibit dr’s near or exceeding 9:1, and all dr’s are
≥8:2. Also noteworthy are some of the chemical yields that
exceed 80%, a level of alkylation efficiency that had never
previously been achieved with alkenesulfenates.107−109 The
stereochemical outcome of this reaction was firmly established
by X-ray diffraction analysis of compound 13a.110 Thereafter,
optical rotations were telling of the configurations of the other
vinylic aminosulfoxides. The configurations obtained match the
trends established for the aromatic sulfenate alkylations of
Chart 1.
Nitrogen Deprotection. The release of amines from Boc
protection in the presence of an enriched sulfoxide is well
established.41,111−113 This reaction was executed on aromatic
derivative 6 to reiterate the ease of deprotection, creating 14
and also to obtain a substrate to confirm the absolute
configuration of 6 (vide supra), eq 2. The deprotection of
vinylic sulfoxide 13a was also executed, and the ammonium
form 15 was isolated in high yield as its trifluoroacetate salt, eq
3.
Structure II represents a chair ring flip of I such that the
electrophile R group adopts an axial position. This structure
would appear to be advantageous since the departing iodide
would only eclipse a C−H bond. To provide the major
stereoisomer, the sulfenate R1 group fills the equatorial space
ensuring no unfavorable 1,3-diaxial interaction between R and
R1 groups. The minor isomer may arise from the other sulfur
lone pair participating in either I or II or through breakdown of
these models.
The dr’s are among the lowest for R = phenyl of the
electrophile using an aryl and an alkenyl sulfenate. The phenyl
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a
Table 3. Competitive Sulfenate Alkylation Reactions
b
c
sulfenate (equiv)
E-I (equiv)
alk-X (equiv)
ratio
1:1.2
1.4:1
krel
1
2
3
4
5
6
pTolSOLi (1)
11 (R2 = Me) (1)
(S)-4a (2)
(S)-4a (2)
(S)-4a (5)
(S)-4f (2)
nBuI (10)
nBuI (10)
BnBr (5)
nBuI (10)
BnBr (2.5)
∼4
∼7
pTolSOLi (1)
pTolS(O)Bn
pTolS(O)nBu
pTolS(O)Bn
5a
pTolSOLi (1)
pTolSOLi (5) and 2-PySOLi (5)
pTolSOLi (5) and 2-PySOLi (5)
(S)-4a (1)
a
b
See Experimental Section for a description of these experiments. Ratio of products with E-containing sulfoxide is initially listed. The entry of a
c
single compound means only that product was obtained. Obtained by adjusting the ratio for relative equivalents of competitive reactant. No entry
suggests a reactivity difference of ≥50 times.
sulfoxides are less compelling and that family of compounds has
less applicability going forward and as such, will not be part of
the remaining discussion.
The most efficient methods for the preparation enriched β-
aminoalkyl aryl sulfoxides appears to be two from the Garcia
Ruano group.54,60 One key contribution involves the Lewis acid
mediated DIBAL reduction of N-benzyl protected (R)-p-tolyl
2-iminoalkyl sulfoxides (path B, Scheme 1).60 That reduction
delivers exclusively the (RS,RC)-amino sulfoxides, generally in
Figure 1. Possible transition states for alkylations with electrophiles
good yields. Our contribution is the complement of that work,
as the products possess a similar backbone, but with the (RS,SC)
stereochemistry.
(S)-4.
group is well recognized for its larger steric demands compared
to benzyl, isopropyl, etc.,122 and presumably the size of the
phenyl hinders the rigorous alignment required by transition
state II. There is probably no significant involvement of the
hydrogen on the nitrogen of the electrophile in determining the
stereochemistry of the product, since compound 5f forms with
high diastereoselection. Of note, however, is that (S)-4f
alkylates rather slowly (Table 3, entry 4). Although this could
be due to increased steric encumbrance for this particular
electrophile, one cannot rule out a possible rate-accelerating
role for the carbamate hydrogen of other electrophiles during
alkylation chemistry.
Product 5g is formed with one of the lowest dr’s in the
current work. For amino sulfoxide substrates with aryl groups
on the sulfoxide (R1 = Ar) and also α to the amino group (R =
Ph), an alternative protocol by Garcia Ruano should be
considered.54 The reaction of (S)-benzylidine-p-toluenesulfina-
mide with (R)- or (S)-methyl p-tolyl sulfoxide (path A, Scheme
1) delivers the corresponding (RS,RC) or (RS,SC) versions of 5g,
respectively, albeit bearing p-toluenesulfinyl rather than Boc
nitrogen protection. Although that protocol employs two chiral
influences, it is the preferred one, particular for the “matched”
pair of reactants, which provide the (RS,RC) isomer in 99% yield
with >99:1 dr.54
The Garcia Ruano methods begin with a chiral sulfoxide and
deliver good yields and dr’s for selected β-amino sulfoxides of
certain configurations.54,60 The chemistry shown herein clearly
fulfills a function for synthetic access selected target β-amino
sulfoxides of complementary configurations. However, a closer
comparison of our chemistry is sulfoxidation. As outlined in the
introduction section, this protocol has been used extensively
and in essence, instinctively by chemists targeting β-amino
sulfoxides. In many cases, dr’s fail to exceed 60:40. However,
there are two general papers that perform simple oxidation
creating sulfoxides similar to the ones presented herein.77,81 In
a communication, the Skarzewski group outlines the diaster-
eoselctive oxidation of simple chiral amino sulfides using
NaOCl/KBr/cat. TEMPO.77 In a follow-up full paper, the
authors outline additional noteworthy oxidations, offer
thorough characterization of the sulfoxides, and mention the
low diastereoselectivity of NaIO4 and MCPBA oxidations.81
In the Skarzewski papers, the authors prepare β-amino
sulfoxides in good yields, with high dr’s such as 85:15, 94:6,77
98:2, and 92:8.81 Some of the lower dr ratios were found at
53:47 or 64:36.81 Most importantly, the major isomers were the
(RS,RC) or (SS,SC) diastereomers in every case. Among the
other rare examples of oxidation reactions delivering high
diastereoselectivity, the MCPBA oxidation of protected S-
alkylated cysteine gave high yields of the corresponding (RS,RC)
amino sulfoxides.80 Similarly an enzyme-catalyzed oxidation
As presented in our previous communication85 and again
encountered with the vinylic sulfenates, the counterion of the
sulfenate has a clear dependence on the yield and
diastereoselectivity of the alkylation, with lithium clearly
exhibiting the superior dr values. When the solvent system
was composed of a solvent with cation coordination propensity
weaker than that of THF,123−125 the experiments yielded dr’s
slightly improved compared to those with the use of THF
alone. Presumably, the weaker solvent coordination facilitates
formation of a transition state such as II. Weaker coordination
may also minimize the separation of lithium and sulfenate
ions.124 The chemical yields were highest when using a high
percentage of ethyl ether.
Lithium 2-pyridinesulfenate was alkylated in good yield, but
with an attenuated dr (9, Chart 1). Table 3 (entries 5 and 6)
indicates this sulfenate is slow to alkylate compared to α-
toluenesulfenate, whether using BnBr or (S)-4a. Lithium 2-
pyridinesulfenate likely adopts an internal nitrogen-to-lithium
complex mirroring the behavior of alkoxides derived from 2-
pyridyl carbinols.126 Such an arrangement would be expected to
hinder the precomplexation with (S)-4a, retarding the rate of
alkylation but also presumably obstructing clean formation of a
transition state such as II.
The protocol presented herein is for the synthesis of (RS,SC)
and (SS,RC) β-substituted β-amino sulfoxides. When the
sulfoxide substituent (R1) is aryl or 1-alkenyl, the dr’s are
generally near 9:1. The yields and dr’s of the alkylated
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protocol also brings about the (RS,RC) isomer.83 Again the
complementarity of the sulfenate protocol is underscored upon
comparison. It should be mentioned that many of the high dr’s
reported in the literature are isolated examples. The
arenesulfenate substitution reactions exhibit significantly more
uniformity of results across all the examples studied. As a
methodology, the arenesulfenate substitution appears to hold
more generality than oxidation protocols, at least based on the
family of electrophiles studied.
Sulfoxides 13 are all new compounds, and the synthesis of
close analogues of 13 by way of sulfide oxidation has not been
explored; no comparison of methodologies is possible. There is
one example of 1-propenethiolate reaction with serinyl chloride
hydrochloride,52 but the ratio of sulfinyl isomers obtained by
way of subsequent oxidation was not reported. Other examples
of oxidations of (S)-1-alkenyl cysteine derivatives are also
known, but either the existence of two sulfinyl isomers was not
recognized,127,128 or low dr’s were obtained.97,129 Indeed, in
one case, the authors suggest the use of an alternative
(asymmetric oxidation) protocol if one is seeking superior
diastereoselectivity.129
In the current work, the overall transformation of thiirane S-
oxide to (E)-1-alkenyl β-aminoalkyl sulfoxides is an example of
a one-pot double diastereoselection. The thiirane S-oxide ring-
opening gives exclusively the (E)-1-alkenesulfenate, while the
ensuing sulfenate substitution delivers products 13, with at least
4:1 dr and many products exhibiting a dr close to 9:1. Given the
insignificant dr’s of the oxidation reactions the S-1-alkenyl
cysteine derivatives, it is unlikely that oxidation of sulfide
precursors of oxides 13 will demonstrate significant diaster-
eoselection. Furthermore, 1-alkenesulfenates are actually easier
to prepare than 1-alkenethiolates, as then do not require
reducing metal conditions.52,130−133 The sulfenate method-
ology provides compounds 13 with good dr’s and should be
viewed as a preferred methodology on its own merits and
because of the few alternatives available. Exploration the
diastereoselection of intramolecular aza-Michael addition
chemistry of these compounds is underway.
EXPERIMENTAL SECTION
■
Many general experimental methods have recently been reported.135
All dry and pure solvents were obtained from a solvent purification
system. All chemicals were obtained from commercial sources unless
otherwise noted. All air- and water-sensitive reagents were transferred
via oven-dried nitrogen-purged syringes into flame-dried flasks. HPLC
experiments were performed using a Chiralcel OJ-H or OD-H (0.46
cm × 25 cm) column with i-PrOH/hexane as the eluant. The synthesis
of β-arylsulfinyl acrylate esters 3 has been reported previously.85,136
Homochiral amino iodides were prepared as previously described.85,137
Thiirane S-oxides prepared in this paper were prepared and purified as
previously described.138−141 The experimental procedures for the
alkanesulfenate substitution chemistry can be found in the Supporting
Information section.
General Procedure for Preparation of Aryl β-Amino
Sulfoxides 5−9. 2-Carbomethoxyethenyl aryl sulfoxide (1.0 equiv)
was dissolved in THF (1 mL/0.1 mmol) under nitrogen and stirred at
−78 °C. To the sulfoxide was added n-BuLi (1.6 M/hexanes, 1.0
equiv) via syringe. Following 5−10 min of stirring, a solution of the
chiral iodide (2.0 equiv) in THF (4 mL/mmol) at −78 °C was added
via syringe to the sulfenate. The mixture was stirred at −78 °C for 3−4
h and then allowed to slowly warm to rt overnight. Solvent was
removed under reduced pressure, and diastereomers were isolated by
flash chromatography using EtOAc/hexanes as the eluent. Diastereo-
i
meric ratios were determined by HPLC using PrOH/hexanes as the
eluent. The major diastereomer was purified by recrystallization from
EtOAc/hexanes. β-Amino sulfoxide yields were derived from 2-
carbomethoxyethenyl sulfoxides. Experimental details and character-
ization data for 5a−5d, 5f, 6−8, and ent-6 have been listed
elsewhere.85 The absolute stereochemistry of the major product is
listed as part of the compounds name.
(RS,2S)-N-Boc-1-Phenyl-3-(2-pyridylsulfinyl)propan-2-amine
(9). A mixture of 2-carbomethoxyethenyl 2-pyridyl sulfoxide (0.100 g,
0.473 mmol) in THF (3 mL), n-BuLi (0.295 mL), and electrophile
(S)-4a (0.341 g, 0.947 mmol) in THF (3 mL) afforded a
diastereomeric mixture of β-amino sulfoxides 9 (82%, 0.140 g, dr =
63:37 by NMR integration) following flash chromatography (30%
EtOAc/hexanes). Recrystallization attempts failed to improve optical
1
purity: mp 100−104 °C; H NMR (400 MHz, CDCl3) δ 8.60−8.57
(m, 2H), 8.01−7.89 (m, 4H), 7.38−7.18 (m, 12 H), 5.51 (br s, 1H,
minor isomer), 4.85 (br s, 1H, major isomer), 4.40−4.31 (m, 2H),
3.43−2.93 (m, 8H), 1.43 (s, 9H, minor isomer), 1.38 (s, 9H, major
isomer); 13C NMR (100.6 MHz, CDCl3) δ major isomer 164.6, 154.8,
149.7, 138.0, 137.1, 129.46, 128.54, 126.7, 124.5, 120.1, 79.5, 58.0,
48.2, 40.4, 28.3; minor isomer 164.6, 155.1, 149.7, 138.1, 137.2, 129.5,
128.6, 127.3, 124.6, 119.9, 79.5, 58.2, 49.2, 41.6, 28.4; IR (neat) cm−1
3288, 3084, 3052, 3028, 2976, 2929, 1707, 1562, 1522, 1452, 1422,
1391, 1365, 1251, 1169, 1084, 1036, 771; [α]2D5 −14.80 (c 1.25,
CHCl3); HRMS (TOF, ESI) calcd for C19H24N2O3S [M] + H
361.1586, found 361.1573.
CONCLUSIONS
■
Sulfenate substitution represents a viable protocol for the
preparation of diastereomerically enriched β-substituted β-
amino sulfoxide, particularly when the other sulfoxide group is
aryl or 1-alkenyl. The identity of the counterion to the sulfenate
was found to be vital and should be lithium. The configurations
of the possible products, which can be (RS,SC) or (SS,RC), are
complementary to other protocols including oxidation. Indeed,
sulfenate substitution presents a new alternative to the
paradigm of sulfoxidation, which actually does not typically
deliver useful dr’s. Vinylic sulfoxides 13 represent a new family
of β-amino sulfoxides.
(RS,2S)-N-Boc-O-TBDPS-1-Hydroxy-3-(p-tolylsulfinyl)propan-
2-amine (5e). A mixture of 2-carbomethoxyethenyl p-tolyl sulfoxide
(0.100 g, 0.446 mmol) in THF (3 mL), n-BuLi (0.281 mL), (S)-4e
(0.481 g, 0.892 mmol) in THF (3 mL) afforded a diastereomeric
mixture of β-amino sulfoxides 5e (84%, 0.206 g, dr = 87:13 by NMR
integration) following flash chromatography (30% EtOAc/hexanes).
The major diastereomer was isolated via recrystallization from EtOAc/
hexanes. Major isomer: mp 109−110 °C; 1H NMR (400 MHz,
CDCl3) δ 7.67−7.65 (m, 4H), 7.51 (d, J = 8.2 Hz, 2H), 7.45−7.36 (m,
6H), 7.31 (d, J = 8.2 Hz, 2H), 5.63 (br d, J = 6.8 Hz, 1H), 4.24 (br m,
1H), 3.90 (m, 2H); 3.13−3.11 (m, 1H), 3.00−2.97 (m, 1H), 2.41 (s,
3H), 1.44 (s, 9H), 1.08 (s, 9H); 13C NMR (100.6 MHz, CDCl3) δ
155.2, 141.7, 140.9, 135.6, 132.9, 130.1, 129.9, 128.0, 123.9, 79.6, 64.7,
59.1, 49.4, 28.4, 27.0, 21.5, 19.3; IR (neat) cm−1 3276, 3071, 3049,
2999, 2961, 2930, 2892, 2858, 1709, 1525, 1494, 1427, 1391, 1364,
1276, 1248, 1171, 1111, 1087, 1027, 910, 809; [α]2D5 +96.80 (c 5.40,
CHCl3). Anal. Calcd for C31H41NO4SSi: C, 67.47; H, 7.49. Found: C,
A model is proposed to account for the observed
diastereoselection during the substitution reactions. Precoordi-
nation of the sulfenate lithium to the nitrogen of the
electrophile is believed to be essential for both the stereo-
selection and as a rate accelerating feature of the overall
substitution. The transition state model suggests that electro-
philic centers with appropriately positioned proximal heter-
oatoms such as oxygen, halogen,134 or nitrogen in other forms
can react with various sulfenates at an accelerated pace and may
do so stereoselectively. We plan to evaluate some of the amino
sulfoxides and/or their derivatives as ligands in organocatalytic
transformations.
1
67.30; H, 7.60. Minor isomer, partial characterization: H NMR (400
MHz) δ 4.96 (br s, 1H), 2.39 (s, 3 H), 1.40 (s, 9H), 1.04 (s, 9H); 13C
1643
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NMR (100.6 MHz) δ 155.1, 140.9, 139.9, 135.5, 132.7, 130.0, 129.9,
128.0, 125.0, 79.6, 64.7, 59.0, 49.3, 28.4, 26.7, 21.4, 19.3.
after addition of electrophile the reaction mixture was refluxed for 2−3
h. Solvent was removed under reduced pressure, and diastereomers
were isolated by flash chromatography using EtOAc/hexanes as the
eluent. Diastereomeric ratios were determined by HPLC using
iPrOH/hexanes as the eluent or by 1H NMR peak integration. β-
Amino sulfoxide yields were derived from starting sulfoxides. The
absolute stereochemistry of the major product is listed as part of the
compounds name.
Generation and Alkylation of Alkanesulfenates. Use of
Methyl 2-(Alkylsulfinyl) Acrylates for Alkylation Chemistry
with (S)-4a. Methyl 2-(benzylsulfinyl) acrylate and methyl 2-(n-
hexylsulfinyl) acrylate have been prepared previously.101 These
compounds were evaluated for their release of alkanesulfenates
according to the procedure above (Preparation of Aryl β-Amino
Sulfoxides 5−9). Capture with (S)-4a as outlined above did not result
in an alkyl β-amino sulfoxide.
(RS,2S)-N-Boc-1-Phenyl-3-(benzylsulfinyl)propan-2-amine
(10a). 2-(Carboethoxy)ethyl benzyl sulfoxide (2a) (0.100 g, 0.416
mmol) in THF (3 mL) was treated dropwise with LiHMDS (0.437
mL). Next, electrophile 4a (0.360 g, 0.832 mmol) in THF (3 mL) was
added to sulfenate via syringe. A diastereomeric mixture of β-amino
sulfoxides 10a (54%, 0.084 g, dr = 85:15 HPLC integration) was
isolated following flash chromatography (30% EtOAc/hexanes).
HPLC (5% i-PrOH/hexanes, 0.4 mL/min flow rate, OD-H column):
39.47 min (minor), 60.03 min (major). The diastereomeric mixture
was recrystallized from EtOAc/hexanes to give improved optical purity
General Preparation of 2-(Carboethoxy)ethyl Alkyl Sulf-
oxides (2). Ethyl acrylate (1 equiv) was added dropwise to a
suspension of potassium carbonate (0.05 equiv) and thiol (1 equiv) in
DCM (1 mL/mmol of thiol). The resulting mixture was stirred at
room temperature for 12 h. Next, the reaction mixture was washed
successively with aqueous 1 M NaOH solution, water, and then brine
and dried over MgSO4. Filtration and solvent evaporation under
reduced pressure provided 2-(carboethoxy)ethyl alkyl sulfide, which
was used in the next step without further purification. A solution of the
2-(carboethoxy)ethyl alkyl sulfide (1 equiv) in MeOH (2 mL/mmol
sulfide) was cooled to 0 °C, and a solution of NaIO4 (1.05 equiv) in
water (1 mL/mmol sulfide) was added dropwise. The reaction mixture
was stirred for 18 h at room temperature. Sodium iodate was filtered,
methanol was removed under vacuum, and the residue extracted with
EtOAc. The combined organic layers were washed with brine solution,
dried over MgSO4, filtered, and evaporated under reduced pressure.
The crude product was then purified by column chromatography on
silica gel to afford pure 2-(carboethoxy)ethyl alkyl sulfoxide 2. The
data for 2-(carboethoxy)ethyl benzyl sulfoxide (2a) and 2-
(carboethoxy)ethyl tert-butyl sulfoxide (2c) matched that from the
literature.92
1
of 97:3: mp 203−204 °C; H NMR (400 MHz, CDCl3) δ 7.50 (m,
3H), 7.26−7.21 (m, 5H), 7.10 (d, J = 6.8 Hz, 2H), 5.47 (br d, J = 6.4
Hz, 1H), 4.20 (m, 1H), 4.00 (ABq, ΔδAB = 0.09, JAB = 4.4 Hz, 2H),
3.18−3.15 (m, 1H), 2.91 (dd, J = 12.8, 8 Hz, 1H), 2.83−2.78 (m, 1H),
2.72−2.69 (m, 1H), 1.40 (s, 9H); 13C NMR (100.6 MHz, CDCl3) δ
155.2, 137.4, 130.1, 129.4, 129.3, 129.0, 128.6, 128.5, 126.7, 79.6, 58.9,
53.3, 49.5, 39.9, 28.4; IR (neat) cm−1 3354, 3028, 2962, 2932, 1688,
1523, 1266, 1251, 1170, 1045, 1013; [α]2D5 +70.00 (c 0.1, CHCl3).
Anal. Calcd for C21H27NO3S: C, 67.53; H, 7.29. Found: C, 67.42; H,
7.50. Minor isomer, partial characterization: 1H NMR (400 MHz,
CDCl3) δ 5.13 (br s, J = 7.2 Hz, 1H), 1.35 (s, 9H); 13C NMR (100.6
MHz, CDCl3) δ 155.3, 136.8, 136.8, 130.3, 129.3, 128.8, 128.6, 128.3,
126.9, 79.8, 57.5, 53.4, 49.4, 39.9, 28.4.
2-(Carboethoxy)ethyl n-Hexyl Sulfoxide (2b). Application of
the general procedure above to n-hexyl mercaptan (5.97 mL, 42.3
mmol) provided crude 2-(carboethoxy)ethyl n-hexyl sulfide. Yield 81%
(7.45 g). 1H NMR (400 MHz, CDCl3) δ 4.15 (q, J = 7.2 Hz, 2H), 2.78
(t, J = 7.2 Hz, 2H), 2.59 (t, J = 7.6 Hz, 2H), 2.53 (t, J = 7.2 Hz, 2H),
1.62- 1.54 (m, 2H), 1.41- 1.25 (m, 9H), 0.89 (t, J = 6.0 Hz, 3H); 13C
NMR (100.6 MHz, CDCl3) δ 172.0, 60.6, 35.0, 32.1, 31.4, 29.5, 28.5,
27.0, 22.5, 14.2, 14.0. Application of the general oxidation procedure
above to the crude sulfide (1.00 g, 4.58 mmol) afforded sulfoxide 2b.
(RS,2S)-N-Boc-1-Phenyl-3-(n-hexylsulfinyl)propan-2-amine
(10b). 2-(Carboethoxy)ethyl n-hexyl sulfoxide (2a) (0.100 g, 0.426
mmol) in THF (3 mL) was treated dropwise with LiHMDS (0.447
mL). Next, electrophile 4a (0.307 g, 0.892 mmol) in THF (3 mL) was
added to sulfenate via syringe. A diastereomeric mixture of β-amino
sulfoxides 10b (42%, 0.065 g, dr = 82:18 HPLC integration) was
isolated following flash chromatography (30% EtOAc/hexanes).
HPLC (8% i-PrOH/hexanes, 0.4 mL/min flow rate, OD-H column):
18.89 min (minor), 20.15 min (major). The diastereomeric mixture
was recrystallized from EtOAc/hexanes to give improved optical purity
1
Yield 87% (994 mg). White solid. Mp: 28−29 °C; H NMR (600
1
MHz, CDCl3) δ 4.18 (q, J = 4.8 Hz, 2H), 3.05−3.01 (m, 1H), 2.90−
2.74 (m, 4H), 2.70−2.68 (m, 1H), 1.78 (m, 2H), 1.46 (m, 2H), 1.34−
1.31 (m, 4H), 1.28 (t, 4.8 Hz, 3H), 0.90 (t, J = 4.4 Hz, 3H); 13C NMR
(150 MHz, CDCl3) δ 171.4, 61.2, 52.8, 46.8, 31.4, 28.5, 27.2, 22.6,
22.4, 14.2, 14.0; IR (neat) cm−1 2978, 2953, 2924, 2857, 1740, 1467,
1421, 1374, 1242, 1179, 1019, 980. Anal. Calcd for C11H22O3S: C,
56.37; H, 9.46. Found: C, 56.51; H, 9.44.
of 93:7: mp 142−144 °C; H NMR (400 MHz, CDCl3) δ 7.32−7.22
(m, 5H), 5.56 (br d, J = 8.0 Hz, 1H), 4.24 (m, 1H), 3.22 (dd, J = 13.6,
6.8 Hz, 1H), 3.00 (dd, J = 13.6, 8.4 Hz, 1H), 2.89−2.70 (m, 3H),
2.66−2.58 (m, 1H), 1.82−1.68 (m, 2H), 1.49−1.38 (m, 2H), 1.42 (s,
9H), 1.32−1.28 (m, 4H), 0.89 (t, J = 6.8 Hz, 3H); 13C NMR (100.6
MHz, CDCl3) δ 155.2, 137.6, 129.3, 128.6, 126.7, 79.5, 54.6, 53.1,
49.6, 39.9, 31.3, 28.4, 28.4, 22.5, 22.4, 14.0.; IR (neat) cm−1 3362,
3244, 3062, 3028, 3005, 2957, 2926, 2857, 1689, 1523, 1454, 1366,
1268, 1251, 1171, 1043, 1016; [α]2D5 +28.66 (c 0.15, CHCl3); HRMS
(TOF, ESI) calcd for C20H33NO3S [M + Na] 390.2079, found
390.2079. Minor isomer, partial characterization: 1H NMR (400 MHz,
CDCl3) δ 4.95 (br s,1H); 13C NMR (100.6 MHz, CDCl3) δ 155.2,
137.0, 129.5, 128.6, 126.9, 56.5, 53.0, 48.8, 40.8, 31.3, 28.5, 28.3, 22.4,
14.
2-(Carboethoxy)ethyl c-Hexyl Sulfoxide (2d). Application of
the general procedure above to c-hexyl mercaptan (4.22 mL, 34.4
mmol). Yield 81% (6.01 g). Colorless oil. 1H NMR (300 MHz,
CDCl3) δ 4.16 (q, J = 7.2 Hz, 2H), 2.82 (m, 2H), 2.58 (t, J = 7.4 Hz,
3H), 2.00−1.95 (m, 2H), 1.79−1.76 (m, 2H), 1.63−1.51 (m, 1H),
1.38−1.24 (m, 8H); 13C NMR (100.6 MHz, CDCl3) δ 172.0, 60.5,
43.2, 35.3, 33.6, 26.0, 25.8, 25.0, 14.3. Application of the general
oxidation procedure above to the crude sulfide (6.01 g, 20.2 mmol)
afforded sulfoxide 2d. Yield 84% (3.50 g). Yellow oil.1H NMR (600
MHz, CDCl3) δ 4.18 (q, J = 7.2 Hz, 2H), 3.06−2.99 (m, 1H), 2.89−
2.81 (m, 3H), 2.59 (m, 1H), 2.15−2.12 (m, 1H), 1.96−1.88 (m, 3H),
1.72 (m, 1H), 1.51−1.27 (m, 5H), 1.28 (t, J = 7.4 Hz, 3H); 13C NMR
(150 MHz, CDCl3) δ 171.6, 61.2, 59.4, 43.7, 27.4, 26.2, 25.5, 25.4,
25.1, 25.0, 14.2; IR (neat) cm−1 2981, 2932, 2856, 1735, 1450, 1393,
1373, 1348, 1235, 1184, 1039, 851. Anal. Calcd for C11H20O3S: C,
56.86; H, 8.68. Found: C, 56.69; H, 8.52.
(RS,2S)-N-Boc-1-Phenyl-3-(tert-butylsulfinyl)propan-2-amine
(10c). 2-(Carboethoxy)ethyl tert-butyl sulfoxide (2c) material (0.100
g, 0.485 mmol) in THF (3 mL) was treated dropwise with LiHMDS
(0.509 mL). Next, electrophile 4a (0.350 g, 0.970 mmol) in THF (3
mL) was added to sulfenate via syringe. A diastereomeric mixture of β-
amino sulfoxides 10c (63%, 0.104 g, dr = 78:22 HPLC integration)
was isolated following flash chromatography (30% EtOAc/hexanes).
HPLC (5% i-PrOH/hexanes, 1.0 mL/min flow rate, OD-H column):
9.59 min (minor), 10.51 min (major). The diastereomeric mixture was
recrystallized from EtOAc/hexanes to give improved optical purity of
General Procedure: Synthesis of Alkyl β-Amino Sulfoxides.
Sulfoxide 2 (1.0 equiv) was dissolved in THF (1 mL/0.1 mmol) under
nitrogen and stirred at −78 °C. To the sulfoxide was added LiHMDS
(1.0 M/hexanes, 1.00−1.2 equiv) via syringe. Following 15−20 min of
stirring, a solution of the chiral iodide (∼2.0 equiv) in THF (4 mL/
mmol) at −78 °C was added via syringe to the sulfenate. Immediately
1
84:16: mp 130−133 °C; H NMR (400 MHz, CDCl3) δ 7.32−7.20
(m, 5H), 5.78 (br d, J = 8.0 Hz, 1H), 4.24 (m, 1H), 3.28 (dd, J = 13.6,
6.8 Hz, 1H), 3.02 (dd, J = 13.6, 8.8 Hz, 1H), 2.74 (dd, J = 12.8, 6.4 Hz,
1H), 6.60 (dd, J = 13.2, 4.0 Hz, 1H), 1.42 (s, 9H), 1.21 (s, 9H); 13C
NMR (100.6 MHz, CDCl3) δ 155.2, 137.9, 129.4, 128.6, 126.7, 79.4,
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53.2, 50.1, 46.8, 39.7, 28.4, 22.7; IR (neat) cm−1 3266, 3028, 2976,
2930, 2869, 1708, 1525, 1455, 1391, 1365, 1271, 1252, 1172, 1043,
1011, 733, 699; [α]2D5 +32.66 (c 0.75, CHCl3); HRMS (TOF, ESI)
calcd for C18H29NO3S [M + Na] 362.1766, found 362.1748. Minor
17.8; IR (neat) cm−1 3358, 3267, 3086, 3062, 2978, 2915, 1691, 1522,
1366, 1268, 1251, 1171, 1047, 1022, 959; [α]2D5 +16.58 (c 1.2, CHCl3);
HRMS (HRMS (TOF, ESI) calcd for C17H25NO3S [M]+: 323.1555;
found: 323.1547. Minor isomer, partial characterization: 1H NMR
(400 MHz, CDCl3) δ 4.85 (br s, 1H), 1.42 (s, 9H); 13C NMR (100.6
MHz, CDCl3) δ 155.1, 137.02, 136.99, 133.3, 129.5, 128.6, 126.8, 79.4,
58.3, 48.2, 40.8, 28.4, 17.8.
(SS, 2R)-N-Boc-1-Phenyl-3-((E)-propenylsulfinyl)propan-2-
amine (ent-13a). A solution of LiHMDS (1.22 mL), propylene
thiirane S-oxide (0.100 g, 1.11 mmol), and (R)-4a (0.441 g, 1.22
mmol) afforded a diastereomeric mixture of β-amino sulfoxide ent-13a
(78%, 0.289 g, dr = 90:10) following flash chromatography (60%
EtOAc/hexanes); HPLC (1% i-PrOH/hexanes, 1.0 mL/min flow
rate): 25.37 min (major), 37.31 min (minor). The major diastereomer
was isolated via recrystallization from EtOAc/hexanes. Major isomer:
mp 145−147 °C. See enantiomer above for spectral data [α]2D5 −16.69
(c 1.6, CHCl3). Anal. Calcd for C17H25NO3S: C, 63.13; H, 7.79.
Found: C, 62.90; H, 7.50 .
1
isomer, partial characterization: H NMR (400 MHz, CDCl3) δ 5.05
(br s,1H); 2.48 (dd, J = 13.2, 5.6 Hz, 1H) 13C NMR (100.6 MHz,
CDCl3) δ 155.2, 137.4, 129.6, 128.5, 126.6, 79.6, 53.4, 49.8, 47.0, 41.3,
28.3, 22.7.
(RS,2S)-N-Boc-1-Phenyl-3-(c-hexylsulfinyl)propan-2-amine
(10d). 2-(Carboethoxy)ethyl c-hexyl sulfoxide (2d) (0.100 g, 0.431
mmol) in THF (3 mL) was treated dropwise with LiHMDS (0.431
mL). Next, electrophile 4a (0.374 g, 1.034 mmol) in THF (3 mL) was
added to sulfenate via syringe. A diastereomeric mixture of β-amino
sulfoxides 10d (78%, 0.122 g, dr = 91:9 by NMR integration) was
isolated following flash chromatography (30% EtOAc/hexanes). The
product was isolated as a 91:9 diastereomeric mixture: mp 152−154
°C; 1H NMR (400 MHz, CDCl3) δ 7.312−7.23 (m, 5H), 5.72 (br d, J
= 6.8 Hz, 1H), 4.26 (m, 1H), 3.24 (dd, J = 13.2, 6.4 Hz, 1H), 3.01 (dd,
J = 12.8, 8.4 Hz, 1H), 2.88−2.83 (m, 1H), 2.76 (dd, J = 12.8, 3.2 Hz,
1H), 2.57 (m, 1H), 2.12−2.09 (m, 1H), 1.93- 1.71 (m, 4H), 1.69- 1.27
(m, 5 H), 1.42 (s, 9H); 13C NMR (100.6 MHz, CDCl3) δ 155.3,
137.8, 129.4, 128.6, 126.7, 79.4, 59.9, 50.9, 50.0, 39.8, 28.4, 26.2, 25.5,
25.3, 25.1, 25.0; IR (neat) cm−1 3365, 3260, 3062, 3028, 2976, 2929,
2853, 1690, 1519, 1450, 1391, 1365, 1298, 1268, 1250, 1169, 1042,
1016, 742, 699; [α]2D5 +24.42 (c 0.95, CHCl3); HRMS (TOF, ESI)
calcd for C20H31NO3S [M + Na] 388.1922, found 388.1927. Minor
(RS,2S)-N-Boc-3-Methyl-1-((E)-1-propenylsulfinyl)butan-2-
amine (13b). A solution of LiHMDS (1.22 mL), propylene thiirane
S-oxide (0.100 g, 1.11 mmol), and 4c (0.381 g, 1.22 mmol) afforded a
diastereomeric mixture of β-amino sulfoxide 13b (70%, 0.215 g, dr =
80:20 by 1H NMR integration of mixture) following flash
chromatography (60% EtOAc/hexanes). The major diastereomer
was isolated via recrystallization from EtOAc/hexanes. Major isomer:
1
mp 149−150 °C; H NMR (400 MHz, DMSO-d6) δ 6.89 (br d, J =
1
8.9 Hz, 1H), 6.51 (dd, J = 15.0, 1.4 Hz, 1H), 6.30 (dq, J = 15.0, 6.7 Hz,
1H), 3.68 (m, 1H), 2.78−2.68 (m, 1H), 2.59 (dd, J = 13, 2.5 Hz, 1H),
1.85 (dd, J = 6.8, 1.3 Hz, 3H), 1.74 (m, 1H), 1.37 (s, 9H), 0.80 (dd, J
= 6.8, 2.0 Hz, 6H); 13C NMR (100.6 MHz, DMSO-d6) δ 155.2, 134.8,
134.1, 77.6, 56.6, 50.1, 32.2, 28.2, 18.4, 18.0, 17.3; IR (neat) cm−1
3230, 3034, 2969, 2915, 2872, 1700, 1542, 1449, 1367, 1297, 1252,
1174, 1038, 1018, 957 [α]2D5 +23.88 (c 0.90, CHCl3). Anal. Calcd for
C13H25NO3S: C, 56.69; H, 9.15. Found: C, 56.52; H, 9.30. Minor
isomer, partial characterization: H NMR (400 MHz, CDCl3) δ 4.97
(br s, 1H); 13C NMR (150 MHz, CDCl3) δ 155.3, 137.8, 129.6, 128.9,
126.8, 79.4, 58.9, 52.7, 49.2, 40.4, 28.3, 26.5, 25.5, 25.3, 25.1, 25.0.
General Procedure: Synthesis of 1-Alkenyl β-Amino Sulf-
oxides. All sulfenate reactions were performed under anhydrous
conditions under an inert N2(g) atmosphere. To a solution of
LiHMDS (1.0 M in THF, 1.1 equiv) in Et2O (10 mL/mmol
LiHMDS) at −78 °C was added dropwise a solution of the thiirane S-
oxide (1.0 equiv) in Et2O (∼5.4 mL/mmol thiirane S-oxide) at −78
°C. The mixture was allowed to stir for ca. 15 min, at which time a
precooled (−78 °C) solution of the amino iodide (4, 1.1 equiv) in
THF (∼2.5 mL/mmol iodide) was added dropwise via syringe. After
2−3 h of stirring at −78 °C the reaction vessel was removed form the
cold bath and allowed to warm to rt. Reactions were stirred until
completion as monitored by TLC (usually 1 h at rt). Following
completion the solvent was removed under reduced pressure, and the
residue was dissolved in DCM. The organic layer was washed with satd
ammonium chloride solution, water, and brine and then dried over
MgSO4. The organic layer was then filtered, and solvent was removed
under reduced pressure. The crude reaction mixture was subjected to
flash chromatography using mixtures of ethyl acetate/hexanes as the
eluent, which yielded the β-amino sulfoxides 13 as a mixture of
diastereomers. The diastereomeric ratios were determined by
comparison of relative 1H NMR peak integrations and/or relative
integrations of peaks from an HPLC separation on a chiral column
(Daicel chiralpak OJ-H or OD-H column). In most cases the
diastereomeric mixture could be recrystallized from mixtures of ethyl
acetate and hexanes to provide the major diastereomer. The absolute
stereochemistry of the major product is listed as part of the
compounds name.
1
isomer, partial characterization: H NMR (400 MHz, CDCl3) δ 6.95
(br d, J = 9.2 Hz, 1H), 1.35 (s, 9H); 13C NMR (100.6 MHz, CDCl3) δ
155.1, 135.4, 134.3, 77.7, 56.2, 49.9, 32.0, 28.0, 18.7, 17.8, 17.4.
(RS,2S)-N-Boc-((E)-1-pPropenylsulfinyl)propan-2-amine
(13c). A solution of LiHMDS (1.11 mL), propylene thiirane S-oxide
(0.100 g, 1.11 mmol), and (S)-4b (0.443 g, 1.55 mmol) afforded a
diastereomeric mixture of β-amino sulfoxide 13c (67%, 0.187 g, dr =
82:18 by 1H NMR integration of mixture) following flash
chromatography (60% EtOAc/hexanes). The major diastereomer
was isolated via recrystallization from EtOAc/hexanes. Major isomer:
1
mp 107−108 °C; H NMR (400 MHz, CDCl3) δ 6.51 (dq, J = 15.2,
6.8 Hz, 1H), 6.29 (dd, J = 15.2, 1.6 Hz, 1H), 5.31 (br s, 1H), 4.14 (m,
1H), 2.90−2.89 (m, 1H), 2.83 (dd, J = 12.8, 4.8 Hz, 1H), 1.94 (dd, J =
6.8, 1.6 Hz, 3H), 1.438 (s, 9H) 1.41 (d, J = 6.8 Hz, 3H); 13C NMR
(100.6 MHz, CDCl3) δ 155.0, 137.1, 133.4, 79.5, 59.7, 43.8, 28.4, 20.4,
17.9; IR (neat) cm−1 3232, 3040, 2973, 2930, 2872, 1698, 1539, 1449,
1364, 1272, 1252, 1174, 1093, 1028; [α]2D5 +19.33 (c 0.15, CHCl3).
Anal. Calcd for C11H21NO3S: C, 53.41; H, 8.56. Found: C, 53.49; H,
8.51. Minor isomer, partial characterization: 1H NMR (400 MHz,
CDCl3) δ 6.40 (d, J = 15.4 Hz, 1H), 5.63 (br d, J = 7.9 Hz, 1H), 4.01
(m, 1H); 13C NMR (100.6 MHz, CDCl3) δ 155.0, 136.3, 133.2, 79.0,
60.9, 42.8, 28.3, 20.9, 17.7.
(RS,2S)-N-Boc-1-Phenyl-3-((E)-4-phenyl-1-butenylsulfinyl)-
propan-2-amine (13d). A solution of LiHMDS (0.61 mL), 4-
phenylbut-1-ene thiirane S-oxide (0.100 g, 0.555 mmol), and (S)-4a
(0.221 g, 0.610 mmol) afforded a diastereomeric mixture of β-amino
(RS,2S)-N-Boc-1-Phenyl-3-((E)-propenylsulfinyl)propan-2-
amine (13a). A solution of LiHMDS (1.22 mL), propylene thiirane S-
oxide (0.100 g, 1.11 mmol), and (S)-4a (0.441 g, 1.22 mmol) (3 mL)
afforded a diastereomeric mixture of β-amino sulfoxide 13a (82%,
0.292 g, dr = 90:10) following flash chromatography (60% EtOAc/
hexanes); HPLC (1% i-PrOH/hexanes, 1.0 mL/min flow rate): 21.23
min (major), 28.52 min (minor). The major diastereomer was isolated
via recrystallization from EtOAc/hexanes. Major isomer: mp 145−147
°C; 1H NMR (400 MHz, CDCl3) δ 7.32−7.21 (m, 5H), 6.47 (sextet, J
= 6.7 Hz, 1H), 6.23 (d, J = 15.1 Hz, 1H), 5.50 (br d, J = 6.3 Hz, 1H),
4.21 (m, 1H), 3.18 (dd, J = 13.0, 6.5 Hz, 1H), 2.99 (dd, J = 12.8, 7.7
Hz, 1H), 2.91−2.87 (m, 1H), 2.82 (dd, J = 13.2, 3.9 Hz, 1H), 1.91 (d,
J = 6.7 Hz, 3H), 1.42 (s, 9H); 13C NMR (100.6 MHz, CDCl3) δ 155.2,
137.5, 137.0, 133.3, 129.4, 128.6, 126.7, 79.5, 56.6, 49.4, 39.9, 28.4,
1
sulfoxide 13d (84%, 0.192 g, dr = 92:8 by H NMR integration of
mixture) following flash chromatography (60% EtOAc/hexanes). The
major diastereomer was isolated via recrystallization from EtOAc/
hexanes. Major isomer: mp 154−155 °C; 1H NMR (400 MHz,
CDCl3) δ 7.31−7.12 (m, 10H), 6.49 (dt, J = 15.1, 6.8 Hz, 1H), 6.16
(d, J = 15.1 Hz, 1H), 5.42 (br d, J = 7.2 Hz, 1H), 4.20 (m, 1H), 3.17
(dd, J = 13.5, 6.4 Hz, 1H), 2.97 (dd, J = 13.4, 7.9 Hz, 1H), 2.84−2.72
(m, 4H), 2.55 (q, J = 7.6 Hz, 2H), 1.42 (s, 9H); 13C NMR (100.6
MHz, CDCl3) δ 155.2, 140.4, 139.9, 137.5, 132.8, 129.4, 128.7, 128.5,
128.4, 126.8, 126.3, 79.6, 56.7, 49.4, 39.9, 34.4, 33.7, 28.4; IR (neat)
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cm−1 3362, 3269, 3061, 3025, 2977, 2924, 2857, 1690, 1522, 1267,
1252, 1170, 1102, 1046, 1020, 894; [α]2D5 +16.59 (c 1.2, CHCl3). Anal.
Calcd for C24H31NO3S: C, 69.70; H, 7.56. Found: C, 70.05; H, 7.12.
Minor isomer, partial characterization: 1H NMR (400 MHz, CDCl3) δ
6.23 (d, J = 15.2 Hz, 1H), 4.95 (br d, J = 7.9 Hz, 1H), 4.09 (m, 1H);
13C NMR (100.6 MHz, CDCl3) δ 155.2, 140.6, 140.0, 137.0, 132.7,
(0.59 mL), propylene thiirane S-oxide (0.050 g, 0.554 mmol), and 4e
(0.538 g, 0.997 mmol) afforded a diastereomeric mixture of β-amino
sulfoxide 13h (65%, 0.181 g, dr = 87:13 by H NMR integration of
1
mixture) following flash chromatography (60% EtOAc/hexanes). The
major diastereomer was isolated via recrystallization from EtOAc/
hexanes. Major isomer: mp 167−169 °C; 1H NMR (400 MHz,
CDCl3) δ 7.65−7.63 (m, 4H), 7.46−7.37 (m, 6H), 6.47 (dq, J = 15.2,
6.8 Hz, 1H), 6.26 (dd, J = 15.2, 1.6 Hz, 1H), 5.40 (br d, J = 8.0 Hz,
1H), 4.19 (m, 1H), 3.87−3.83 (m, 2H), 3.03 (dd, J = 12.8, 6.8 Hz,
1H), 2.92 (m, 1H), 1.92 (dd, J = 6.8, 1.6 Hz, 3H), 1.43 (s, 9H), 1.07
(s, 9H); 13C NMR (100.6 MHz, CDCl3) δ 155.1, 137.1, 135.6, 133. 7,
132.9, 129.9, 127.9, 79.6, 64.8, 55.5, 48.9, 28.4, 26.9, 19.3, 17.9; IR
(neat) cm−1 3234, 3071, 3050, 3027, 2971, 2957, 2933, 2908, 2859,
1705, 1543, 1443, 1427, 1315, 1280, 1249, 1175, 1106, 1012, 961, 828
706 [α]2D5 +297.33 (c 0.75, CHCl3). Anal. Calcd for C27H41NO4SSi: C,
64.37; H, 8.20. Found: C, 64.63; H, 7.87. Minor isomer, partial
characterization: 1H NMR (400 MHz, CDCl3) δ 6.43 (dd, J = 13.2, 6.8
Hz, 1H), 4.99 (br d, J = 8.4 Hz, 1H), 4.01 (m, 1H), 1.44 (s, 9H); 13C
NMR (100.6 MHz, CDCl3) δ 155.1, 137.2, 135.5, 133.3, 133.0, 129.9,
127.9, 79.6, 65.4, 57.3, 48.2, 28.4, 26.9, 19.3, 17.9.
129.5, 129.0, 129.0, 128.66, 126.9, 126.3, 79.6, 58.4, 48.3, 40.8, 34.4,
33.7, 28.4.
(RS,2S)-N-Boc-1-Phenyl-3-(vinylsulfinyl)propan-2-amine
(13e). A solution of LiHMDS (1.45 mL), ethylene thiirane S-oxide
(0.100 g, 1.314 mmol), and iodide (S)-4a (0.569 g, 1.58 mmol)
afforded a diastereomeric mixture of β-amino sulfoxide 13e (84%,
1
0.341 g, dr = 89:11 by H NMR integration of mixture) following
column chromatography (60% EtOAc/hexanes). The major diaster-
eomer was isolated via recrystallization from EtOAc/hexanes. Major
1
isomer: mp 137−139 °C; H NMR (400 MHz, CDCl3) δ 7.32−7.21
(m, 5H), 6.60 (dd, J = 16.4, 9.8 Hz, 1H), 6.12 (d, J = 16.5 Hz, 1H),
5.96 (d, J = 9.8 Hz, 1H), 5.41 (br d, J = 6.2 Hz, 1H), 4.23 (m, 1H),
3.20 (dd, J = 12.3, 7.0 Hz, 1H), 3.00 (dd, J = 13.5, 7.6 Hz, 2H), 2.78
(dd, J = 13.2, 3.9 Hz, 1H), 1.43 (s, 9H); 13C NMR (100.6 MHz,
CDCl3) δ 155.2, 140.5, 137.3, 129.4, 128.7, 126.8, 122.0, 79.7, 56.5,
49.4, 39.9, 28.4; IR (neat) cm−1 3455, 3359, 3033, 2980, 2920, 1690,
1522, 1267, 1250, 1170, 1052,1022; [α]2D5 +41.86 (c 0.80, CHCl3).
Anal. Calcd for C16H23NO3S: C, 62.11; H, 7.49; Found; C, 61.96;
7.48. Minor isomer, partial characterization: 1H NMR (400 MHz,
CDCl3) δ 6.73 (dd, J = 16.8, 9.8 Hz, 1H), 5.97 (d, J = 9.8 Hz, 1H),
4.84 (br s, 1H); 13C NMR (100.6 MHz, CDCl3) δ 155.2, 140.5, 136.8,
128.6, 128.4, 126.9, 122.1, 79.7, 57.9, 49.0, 40.7, 28.3.
(SS,1R)-N-Boc-2-((E)-3,3-Dimethyl-1-butenylsulfinyl)-1-phe-
nylethanamine (13i). A solution of LiHMDS (0.83 mL), propylene
thiirane S-oxide (0.100 g, 0.757 mmol), and 4h (0.315 g, 0.908 mmol)
afforded a diastereomeric mixture of β-amino sulfoxide 13i (65%,
0.172 g, dr = 84:16 by NMR integration of diastereomeric mixture)
was isolated following flash column chromatography (60% EtOAc/
hexanes). The major diastereomer was isolated via recrystallization
from EtOAc/hexanes. Major isomer: mp 180−182 °C; 1H NMR (600
MHz, CDCl3) δ 7.38−7.33 (m, 4H), 7.32−7.28 (m, 1H), 6.44 (d, J =
15.4 Hz, 1H), 6.24 (br s, 1H), 6.11 (d, J = 15.4 Hz, 1H), 5.24 (br s,
1H), 3.12−3.10 (m, 2H), 1.41 (s, 9H), 1.08 (s, 9H); 13C NMR (150.6
MHz, CDCl3) δ 155.1, 151.7, 140.3, 128.8, 127.8, 127.8, 126.3, 79.8,
59.8, 51.9, 34.3, 28.8, 28.4; IR (neat) cm−1 3264, 3033, 2963, 2868,
1707, 1528, 1365, 1251, 1170, 1045, 1019; [α]2D5 −32.00 (c 0.75,
CHCl3). Anal. Calcd for C19H29NO3S: C, 64.92; H, 8.32. Found: C,
(RS,2S)-N-Boc-1-(Cyclohexenylsulfinyl)-3-phenylpropan-2-
amine (13f). A solution of LiHMDS (0.92 mL) in THF (6 mL),
cyclohexene thiirane S-oxide (0.100 g, 0.767 mmol) in THF (3 mL),
and (S)-4a (0.332 g, 0.920 mmol) in THF (3 mL) afforded two β-
amino sulfoxide diastereomers (13f), which were isolated from one
another by flash column chromatography (40% EtOAc/hexanes)
(71%, 0.197 g, dr = 93:7 (based on peak integration of diastereomeric
mixture)). Major isomer: mp 131−133 °C; 1H NMR (400 MHz,
CDCl3) δ 7.32−7.21 (m, 5H), 6.44 (s, 1H), 5.60 (br d, 5.7 Hz, 1H),
4.16 (m, 1H), 3.22 (dd, J = 13.4, 6.0 Hz, 1H). 3.00 (dd, J = 13.5, 8.1
Hz, 1H), 2.87−2.77 (m, 2H), 2.22−2.15 (m, 3H), 2.04−2.01 (m, 1H),
1.67 (m, 4H), 1.43 (s, 9H); 13C NMR (100.6 MHz, CDCl3) δ 155.2,
140.8, 137.7, 132.3, 129.4, 128.6, 126.7, 79.4, 53.6, 49.8, 39.9, 28.4,
25.5, 22.2, 21.9, 20.7; IR (neat) cm−1 3263, 3027, 2975, 2932, 2860,
1709, 1525, 1364, 1269, 1252, 1171, 1043, 1007, 699; [α]2D5 +81.1 (c
0.45, CHCl3). Anal. Calcd for C20H29NO3S: C, 66.08; H, 8.04. Found:
1
64.70; H, 8.12. Minor isomer, partial characterization: H NMR (400
MHz, CDCl3) δ 6.47 (d, J = 15.2 Hz, 1H), 6.13 (d, J = 15.2 Hz, 1H),
5.07 (br m,1H); 13C NMR (150.6 MHz, CDCl3) δ 154.9, 151.6, 140.4,
128.8, 128.1, 127.8, 126.3, 79.7, 61.0, 51.7, 34.2, 28.7, 28.3.
(SS,2R)-N-Boc-1-((E)-3,3-Dimethyl-1-butenylsulfinyl)butan-2-
amine (13j). A solution of LiHMDS (0.83 mL), propylene thiirane S-
oxide (0.100 g, 0.757 mmol), and 4g (0.248 g, 0.832 mmol) afforded a
diastereomeric mixture of β-amino sulfoxide 13j (71%, 0.163 g, dr =
95:5 by 1H NMR integration of mixture) following flash
chromatography (60% EtOAc/hexanes). The major diastereomer
was isolated via recrystallization from EtOAc/hexanes. Major isomer:
mp 146−147 °C; 1H NMR (400 MHz, CDCl3) δ 6.47 (d, J = 15.4 Hz,
1H), 6.16 (d, J = 15.4 Hz, 1H), 5.31 (br d, J = 7.5 Hz, 1H), 3.92
(sextet, J = 7.7 Hz, 1H), 2.95 (dd, J = 13.0, 7.2 Hz, 1H), 2.85 (dd, J =
13.1, 3.4 Hz, 1H), 1.78 (m, 2H), 1.44 (s, 9H), 1.10, (s, 9H), 0.99 (t, J
= 7.4 Hz, 3H); 13C NMR (100.6 MHz, CDCl3) δ 155.3, 151.1, 128.3,
79.4, 58.3, 49.3, 34.2, 28.8, 28.4, 27.3, 10.7; IR (neat) cm−1 3220, 3039,
2966, 1698, 1545, 1363, 1289, 1249, 1174, 1053, 1028, 979; [α]D25
−5.71 (c 0.18, CHCl3). Anal. Calcd for C15H29NO3S: C, 59.37; H,
9.63. Found: C, 59.26; H, 9.42. Minor isomer, partial characterization:
1H NMR (400 MHz, CDCl3) δ 4.86 (br s, 1H); 13C NMR (100.6
1
C, 66.04; H, 7.87. Minor isomer, partial characterization: H NMR
(400 MHz, CDCl3) δ 5.00 (br d, J = 8.0 Hz, 1H), 4.01 (br m, 1H);
13C NMR (100.6 MHz, CDCl3) δ 155.2, 140.5, 137.2, 134.1, 129.5,
129.0, 126.8, 79.4, 54.4, 49.7, 40.9, 28.4, 25.6, 22.1, 21.9, 19.6.
(RS,2S)-N-Boc-1-((E)-3,3-Dimethyl-1-butenylsulfinyl)-3-phe-
nylpropan-2-amine (13g). A solution of LiHMDS (0.83 mL),
propylene thiirane S-oxide (0.100 g, 0.757 mmol), and iodide (S)-4a
(0.300 g, 0.832 mmol) afforded a diastereomeric mixture of β-amino
sulfoxide 13g (60%, 0.166 g, dr = 92:8 by NMR integration of
diastereomeric mixture) following flash chromatography (60% EtOAc/
hexanes). The major diastereomer was isolated via recrystallization
from EtOAc/hexanes. Major isomer: mp 147−149 °C; 1H NMR (400
MHz, CDCl3) δ 7.32−7.22 (m, 5H), 6.46 (d, J = 15.4 Hz, 1H), 6.09
(d, J = 15.4 Hz, 1H), 5.50 (br d, J = 6.9 Hz, 1H), 4.21 (m, 1H), 3.21
(dd, J = 13.3, 6.8 Hz, 1H), 3.00 (dd, J = 13.5, 8.0 Hz, 1H), 2.89 (m,
1H), 2.81 (dd, J = 13.2, 3.9 Hz, 1H), 1.43 (s, 9H), 1.09 (s, 9H); 13C
NMR (100.6 MHz, CDCl3) δ 155.2, 151.1, 137.6, 129.4, 128.7, 128.0,
126.7, 79.5, 56.7, 49.6, 39.9, 34.2, 28.8, 28.4; IR (neat) cm−1 3361,
3251, 3039, 2963, 2906, 2867, 1706, 1525, 1365, 1270, 1253, 1173,
1046, 1020; [α]D25 +14.20 (c 1.0, CHCl3). Anal. Calcd for
C20H31NO3S: C, 65.72; H, 8.55. Found: C, 65.44; H, 8.68. Minor
MHz, CDCl3) δ 155.3, 151.1, 128.3, 79.4, 58.3, 49.3, 34.2, 28.8, 28.4,
28.0, 10.7.
Deprotection of β-Amino Sulfoxides. (RS,2S)-1-Phenyl-3-
(phenylsulfinyl)propan-2-amine (14). To a 1:1 solution of TFA/
DCM (20 mL) at 0 °C was added a solution of protected β-amino
sulfoxide 6 (0.250 g, 0.70 mmol) in DCM (3 mL). The reaction
mixture was stirred for 1 h at 0 °C to reach completion. A 2 M
aqueous solution of NaOH was added until a basic pH was achieved.
The aqueous layer was extracted with DCM (3 × 10 mL). Organic
layers were then combined, washed with water, followed by brine, and
then dried over MgSO4, filtered, and concentrated under reduced
pressure. Known sulfoxide 1481 (0.138 g, 77% yield) was isolated
following workup as a clear oil. [α]2D5 −223.9 (c 0.2, CHCl3) [lit.81
−225.0 (c 0.2, CHCl3).
1
isomer, partial characterization: H NMR (400 MHz, CDCl3) δ 5.00
(br d, J = 8 Hz, 1H); 13C NMR (100.6 MHz, CDCl3) δ 155.2, 151.3,
137.0, 129.5, 129.0, 128.0, 126.8, 79.5, 58.3, 48.4, 40.7, 34.2, 28.8, 28.4.
( R S , 2 S ) - N - B o c - O - T B D P S - 1 - H y d r o x y - 3 - ( ( E ) - 1 -
propenylsulfinyl)propan-2-amine (13h). A solution of LiHMDS
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(RS,2S)-1-Phenyl-3-((E)-1-propenylsulfinyl)propan-2-ammo-
nium Trifluoroacetate (15). To a 1:1 solution of TFA/DCM (20
mL) at 0 °C was added a solution of protected β-amino sulfoxide
(0.673 g, 2.08 mmol) in DCM (3 mL). The reaction mixture was
stirred for 1 h at 0 °C at which time TLC exhibited reaction
completion. Solvent was removed under reduced pressure, and then 20
mL of hexanes was added to the residue and removed under reduced
pressure. This process was repeated three times in order to ensure
removal of trifluoroacetic acid. Crude product was purified by flash
chromatography using MeOH/DCM (9:1) as the eluent to give the
(neat) cm−1 3008, 2959, 2933, 2873, 1636, 1465, 1458, 1405, 1090,
1035, 956.
Experiment 5. A 1:1 molar solution of 2-(carbomethoxy)ethenyl 2-
pyridyl sulfoxide (0.094 g, 0.446 mmol) and 2-(carbomethoxy)ethenyl
tolyl sulfoxide (0.100 g, 0.446 mmol) in THF (3 mL) at −78 °C was
treated dropwise with 1.6 M n-BuLi (0.558 mL, 0.892 mmol). The
solution was stirred for ∼10 min at −78 °C to ensure sulfenate
generation. Next a −78 °C solution of benzyl bromide (0.026 mL,
0.223 mmol) in THF (3 mL) was added to sulfenate pot via syringe.
The reaction was stirred for 3 h at −78 °C and then allowed to warm
to rt overnight. Following standard workup the crude 1H NMR
revealed the sole formation of the p-tolyl benzyl sulfoxide,92 which was
isolated via column chromatography using EtOAc/hexanes (40:60) as
the eluent.
Experiment 6. A 1:1 molar solution of 2-(carbomethoxy)ethenyl 2-
pyridyl sulfoxide (0.094 g, 0.446 mmol) and 2-(carbomethoxy)ethenyl
tolyl sulfoxide (0.100 g, 0.446 mmol) in THF (3 mL) at −78 °C was
treated dropwise with 1.6 M n-BuLi (0.558 mL, 0.892 mmol). The
solution was stirred for ∼10 min at −78 °C to ensure sulfenate
generation. Next a −78 °C solution of (S)-4a (0.032 g, 0.089 mmol)
in THF (3 mL) was added to sulfenate pot via syringe. The reaction
was stirred for 3 h at −78 °C and then allowed to warm to rt
overnight. Following standard workup the crude NMR revealed the
sole formation of the 5a (78%, 0.025 g), which was isolated via column
chromatography using EtOAc/hexanes (40:60) as the eluent.
1
pure product as a clear colorless oil (95%, 0.668 g). H NMR (400
MHz, CDCl3) δ 8.78 (br s, 3H), 7.34−7.16 (m, 5H), 6.51 (dq, J =
14.8, 6.8 Hz, 1H), 5.87 (dd, J = 14.8, 1.6 Hz, 1H), 4.06 (m, 1H), 3.41
(dd, J = 14.8, 9.6 Hz, 1H), 3.34 (dd, J = 13.6, 4.8 Hz, 1H), 2.98 (dd, J
= 13.6, 10.8 Hz, 1H), 2.53 (dd, J = 14.8, 1.6 Hz, 1H), 1.94 (dd, J = 6.8,
1.6 Hz, 3H); 13C NMR (100.6 MHz, CDCl3) δ 140.5, 134.2, 129.2,
129.1, 128.6, 127.9, 49.4, 48.3, 38.6, 17.8; IR (neat) cm−1 3420, 3032,
2977, 2923, 1680, 1497, 1436, 1203, 1135, 1009, 952, 837, 801, 747;
[α]2D5 −56.8 (c 2.0, CHCl3). Anal. Calcd for C14H18F3NO3S: C, 49.84;
H, 5.38. Found: C, 49.83; H, 5.31.
Sulfenate Alkylation Competition Experiments (see Table
3). Experiment 1. 2-Carbomethoxyethenyl ar(alk)yl sulfoxide (0.100
g, 0.446 mmol) was dissolved in THF (3 mL) under nitrogen and
stirred at −78 °C. To the sulfoxide was added n-BuLi (0.279 mL,1.6 M
in hexanes) via syringe. Following 5−10 min of stirring, a solution of
the chiral iodide (S)-4a (0.805 g, 2.23 mmol) and benzyl bromide
(0.237 mL, 2.23 mmol) in THF (3 mL) at −78 °C was added via
syringe to the sulfenate. The mixture was stirred at −78 °C for 3−4 h
and then allowed to slowly warm to rt overnight. Solvent was removed
under reduced pressure. Column chromatography using an EtOAc/
hexanes (30:70) mixture as the eluent provided p-tolyl benzyl sulfoxide
as a white solid and the sole product (96%, 0.101 g). Mp: 138−140 °C
[lit.92 139−140 °C].
ASSOCIATED CONTENT
■
S
* Supporting Information
Data relating to X-ray crystallographic identification of 13a; 1H
NMR and 13C NMR spectra of new starting materials and new
amino sulfoxides. This material is available free of charge via the
Internet at http://pubs.acs.org.
Experiment 2. 2-Carbomethoxyethenyl ar(alk)yl sulfoxide (0.100 g,
0.446 mmol) was dissolved in THF (3 mL) under nitrogen and stirred
at −78 °C. To the sulfoxide was added n-BuLi (0.279 mL,1.6 M in
hexanes) via syringe. Following 5−10 min of stirring, a solution of the
chiral iodide (S)-4a (0.322 g, 0.892 mmol) and butyl iodide (0.508
mL, 4.46 mmol) in THF (3 mL) at −78 °C was added via syringe to
the sulfenate. The mixture was stirred at −78 °C for 3−4 h and then
allowed to slowly warm to rt overnight. Solvent was removed under
reduced pressure. Column chromatography using an EtOAc/hexanes
(30:70) mixture as the eluent provided p-tolyl butyl sulfoxide142 (33%,
0.029 g) as an orange oil and a 91:9 diastereomeric mixture of 5a as a
solid (27%, 0.043 g).
Experiment 3. 2-Carbomethoxyethenyl ar(alk)yl sulfoxide (0.100 g,
0.446 mmol) was dissolved in THF (3 mL) under nitrogen and stirred
at −78 °C. To the sulfoxide was added n-BuLi (0.279 mL,1.6 M in
hexanes) via syringe. Following 5−10 min of stirring, a solution of the
chiral iodide (S)-4a (0.277 g, 0.892 mmol) and butyl iodide (0.508
mL, 4.46 mmol) in THF (3 mL) at −78 °C was added via syringe to
the sulfenate. The mixture was stirred at −78 °C for 3−4 h and then
allowed to slowly warm to rt overnight. Solvent was remove under
reduced pressure. Column chromatography using an EtOAc/hexanes
(30:70) mixture as the eluent provided p-tolyl butyl sulfoxide142 as the
sole product as an orange oil (92%, 0.081 g).
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: schwan@uoguelph.ca.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Acknowledgment is made to the Donors of the American
Chemical Society Petroleum Research Fund and to the Natural
Sciences and Engineering Research Council of Canada for
partial support of this research. S.C.S. also thanks NSERC for a
postgraduate scholarship. The authors are grateful to Dr. Alan
Lough (Univ. of Toronto) for the crystallographic work. The
authors also thank Ms. Kerrin Flisar for technical assistance.
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