Asymmetric synthesis of anti-α-substituted β-amino ketones from sulfinimines

Article abstract of DOI:10.1021/jo2002352

Previously unknown, enantiopure, β-amino ketones were prepared in modest yield by addition of lithium reagents to N-sulfinyl anti-α- substituted β-amino Weinreb amides. Grignard reagents failed to add to these Weinreb amides in contrast to the syn-α-substituted isomers which did. The anti-α-substituted β-amino Weinreb amides were prepared by addition of LiN(OMe)Me to the corresponding N-sulfinyl anti-α-substituted β-amino esters because α-alkylation of N-sulfinyl β-amino Weinreb amide enolates resulted in poor diastereoselectivities.

Full text of DOI:10.1021/jo2002352

ARTICLE
pubs.acs.org/joc
Asymmetric Synthesis of anti-r-Substituted β-Amino Ketones
from Sulfinimines
Franklin A. Davis* and Peng Xu
Department of Chemistry, Temple University, Philadelphia, Pennsylvania 19122, United States
S Supporting Information
b
ABSTRACT: Previously unknown, enantiopure, β-amino ketones
were prepared in modest yield by addition of lithium reagents to
N-sulfinyl anti-R-substituted β-amino Weinreb amides. Grignard
reagents failed to add to these Weinreb amides in contrast to the syn-
R-substituted isomers which did. The anti-R-substituted β-amino
Weinreb amides were prepared by addition of LiN(OMe)Me to the
corresponding N-sulfinyl anti-R-substituted β-amino esters because
R-alkylation of N-sulfinyl β-amino Weinreb amide enolates resulted
in poor diastereoselectivities.
’ INTRODUCTION
was treated at ꢀ78 °C with 2.4 equiv of LDA followed by addition
of MeI. Both the corresponding anti-(SS,2S,2R)-(þ)-2a and
syn-(SS,2R,3R)-(þ)-3a β-amino Weinreb amides were formed in
a 1:1 ratio (Table 1, entry 1) (Scheme 1). Addition of LiCl to
the preformed enolate improved the anti:syn ratio to 2:1 (Table 1,
entry 2). Importantly, alkylation of the N-tosyl enolate, derived
from (R)-(þ)-1b, under the reaction conditions, resulted in a 3:1
anti:syn ratio (Table 1, entry 3). Use of LiCl improved the anti:syn
to 12:1 affording (2S,3R)-(þ)-2b in 37% isolated yield (Table 1,
entry 4).
Before trying to optimize the yield of (þ)-2b it was necessary
to determine whether it would react with Grignard and lithium
reagents without epimerization at the R-center (Scheme 2).
Surprisingly, reaction of (þ)-2b with 3 to 5 equiv of methyl-
magnesium bromide under varying conditions resulted in
no reaction. However, with 5 equiv of n-butyllithium (n-BuLi)
a 61% yield of ketone (þ)-4 was obtained and epimerization
was not detected. Removal of the N-tosyl group in (þ)-4
was next explored. While a number of methods are available
for removal of N-tosyl amine groups (sodium naphthalide, Li/
NH3, HBr in HOAc) the harshness of these conditions would
be incompatible with enolizable ketones such as (þ)-4.8 How-
ever, cleavage of arenesulfonamides by reduction with Mg-
MeOH under ultrasonic conditions is reported to be tolerant
of carbonyl groups.8e Sonication of (þ)-4 under varying condi-
tions of time and temperature gave, under optimal conditions,
the β-amino ketone 5 as an inseparable 3:1 mixture of isomers
in poor yield (Scheme 2). For this reason the use of N-tosyl anti-
β-amino-R-substituted β-amino Weinreb amides such as (þ)-2b
was abandoned as a practical method for the synthesis of the
corresponding ketones.
Enantiopure β-amino ketones have emerged as versatile chiral
building blocks for the asymmetric synthesis of natural products
and nitrogen-containing bioactive compounds.1 Arguably the
best and most reliable method for their synthesis is the addition
of Grignard reagents to enantiopure N-sulfinyl β-amino Weinreb
amides (Figure 1).2,3 β-Amino Weinreb amides are readily
prepared by addition of Weinreb enolates to sulfinimines (N-
sulfinyl imines).3,4 syn-R-Substituted β-amino Weinreb amides
are available by addition of prochiral Weinreb amide enolates to
the sulfinimines.1,5 These enolate additions are highly diaster-
eoselective, and the absolute stereochemistry of the new car-
bonꢀnitrogen stereocenter is predictable.3,5 With Grignard
reagents the β-amino Weinreb amides afford the corresponding
ketones in excellent yield without epimerization.
The utility of R-substituted β-amino ketones in the asym-
metric synthesis of stereodefined nitrogen heterocycles1 makes
the development of methods for the synthesis of anti-R-sub-
stituted β-amino ketones of considerable importance. To the
best of our knowledge there are no reports of their syntheses in
enantiopure form. Conceptually, the addition of lithium and
Grignard reagents to the unknown anti-R-substituted β-amino
Weinreb amides would represent a general route to such ketones.
We describe here a new method for the asymmetric synthesis of
anti-R-substituted β-amino Weinreb amides and their applica-
tion in the first enantioselective syntheses of anti-R-substituted
β-amino ketones.
’ RESULTS AND DISCUSSION
The R-alkylation of β-amino ester enolates is reported to
occur with good to excellent levels of diastereoselectivity afford-
ing the anti-R-alkylation product.6,7 The alkylation of β-amino
Weinreb amide enolates has not been described, and to explore
this method Weinreb amide (SS,3R)-(þ)-1a (Z = p-tolyl(S(O)ꢀ)
Received: February 4, 2011
Published: March 21, 2011
r
2011 American Chemical Society
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|

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ARTICLE
Scheme 1
Scheme 2
Figure 1. Synthesis of N-sulfinyl β-amino Weinreb amides and ketones.
Table 1. Alkylation of β-Amino Weinreb Amide Enolates at
ꢀ78 °C
entry
1 (Z =)
conditions
products anti:syn 2:3a (% yield)
1
2
3
4
1a (p-tolylS(O)ꢀ)
1:1 (19)
2:1 (46)a,b
3:1 (16)
10 equiv of LiCl
10 equiv of LiCl
1b (Ts)
influenced by additives such as LiCl. We speculate that the
improved yields on addition of LiCl may reflect easier access of
the alkylating species to the enolate. Enhanced intramolecular
chelation caused by added LiCl, as illustrated in structure 13,
where the R group occupies a pseudoaxial position, could also
12:1 (37)c
a Determined by 1H NMR on the crude reaction mixture. b Combined
yield of inseparable anti:syn isomers. c Isolated yield of pure
diastereoisomer.
explain the improved anti:syn stereoselectivities for
2
(Scheme 3).6
Our earlier studies had shown that N-sulfinyl syn-R-substi-
tuted β-amino Weinreb amides react with Grignard and lithium
reagents to give good yields of the corresponding ketones, and
the N-sulfinyl group was easily removed under mild acid
conditions.5 Epimerization at the R-center was not observed.
Unfortunately, the selectivity for R-alkylation of N-sulfinyl β-
amino Weinreb amide enolates was poor (Table 1, entries 1 and
2). Better selectivity was anticipated for the R-alkylation of N-
sulfinyl β-amino ester enolates,6,7,9 which can be readily trans-
formed to the Weinreb amides by reaction with lithium N,O-
dimethylhydroxy amine.3
Assignment of Stereochemistry. Earlier studies suggested
that the major isomer formed in the alkylation of N-sulfinyl
β-amino ester enolates is the anti-isomer (Scheme 3).6 To
confirm these stereochemical assignments two methods were
employed to establish the stereochemistry. Not only did these
methods confirm the anti-stereochemistry, but they illustrate the
utility of anti-R-substituted β-amino esters as valuable new chiral
building blocks.
Removal and replacement of the N-sulfinyl group in (þ)-10b
with a Boc group gave amino diene (ꢀ)-14 in 63% isolated yield
for the two steps (Scheme 4). With 5 mol % of Grubbs II at rt for
8 h in DCM (ꢀ)-14 gave anti-cyclopentene β-amino acid (þ)-
15 in 58% yield as a single isomer, and hydrogenation (PdꢀC/
H2) gave the cyclic trans-β-amino ester (þ)-16 in 90% yield.
Cyclic β-amino ester (þ)-16 was previously prepared in 9 steps,
12% overall yield from (S)-methionine.11 Cyclic β-amino acid
derivatives are important building blocks for the synthesis of
natural products and β-peptides.1,12 Our synthesis of (þ)-16 is
particularly efficient: five steps, 25% overall yield from β-amino
ester (þ)-6b. Furthermore the double bond (þ)-15 is readily
functionalized making this route to cyclic anti-β-amino acids
derivatives particularly useful.1
Treatment of (þ)-6a with 2.4 equiv of LDA at ꢀ78 °C
followed by addition of 1.6 equiv of MeI resulted in a 2:1 mixture
of the anti- and syn-isomers 7a and 8 (Scheme 3) (Table 2, entry
1). The selectivity improved to 7:1 on addition of 10 equiv of
LiCl (Table 2, entry 2). Alkylation of the enolate of (þ)-6a with
allyl iodide and benzyl iodide afforded the corresponding R-
substituted derivatives (þ)-7b and (þ)-7c in good yields and
excellent selectivities (Table 2, entries 3 and 4). In each of these
examples 5ꢀ10% (E)-methyl cinnamate (9) was observed
resulting from elimination of p-toluenesulfinamide (p-TolylS-
(O)NH2) (Table 2, entries 2ꢀ4). Enolate alkylations of N-
sulfinyl β-amino esters (þ)-6b (R = vinyl), (þ)-6c (R = n-Pr),
and (þ)-6d (R = BnO(CH2)2) gave similar high anti:syn
selectivities (Table 2, entries 5ꢀ9). However, in none of these
examples was it possible to separate the isomers. Fortunately, the
corresponding Weinreb amides were readily separable (see
below).
Treatment of the 7:1 anti:syn mixture of β-amino ester (þ)-7a
with 6 equiv of LiN(OMe)Me at ꢀ78 °C gave a 75% yield of anti-
β-amino Weinreb amide (þ)-2a (Scheme 5). Importantly, (þ)-
2a was obtained as a single isomer with spectral properties
identical to those of an authentic sample.5a Similar results were
found for the conversion of β-amine esters (þ)-10b, (þ)-11,
and (þ)-12 to their corresponding Weinreb amides where single
In solution enolates, including β-amino ester enolates,10 exist
as mixed aggregates and their dynamic structures can be
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Scheme 3
Table 2. Alkylation of N-Sulfinyl β-Amino Esters 6 with LDA in THF
entry
sster 6: R1 =
R2I
added LiCla
temp, °C
alkylation product: anti:synb (% yield)c
1
2
3
4
5
6
7
8
9
6a: Ph
Me
ꢀ78
7a: 2:1 (NA)
7a: 7:1 (80)d
Me
10
10
10
10
10
10
10
10
ꢀ78 to ꢀ50
ꢀ50
allyl
7b: 92:8 (64)d
7c: 96:4 (72)d
10a: 89:11 (88)
10b: 91:9 (76)
10c: 95:5 (82)
11: >99:1(82)
12: >99:1 (62)
BnCH2
Me
ꢀ50
6b: vinyl
ꢀ50
allyl
ꢀ50
BnCH2
Me
ꢀ50
6c: n-Pr
ꢀ50
6d: BnO(CH2)2
Me
ꢀ78
a Equivalents of added LiCl. b Isomer ratio determined by 1H NMR on the crude reaction mixture. c Combined yield of anti:syn isomers. d (E)-methyl
cinnamate (9), 5ꢀ10% was isolated.
isomers were obtained in good yield (Scheme 5). In general the
anti-R-protons in these Weinreb amides appear upfield com-
pared to the syn isomers.5a For example, in anti-(þ)-2a this
proton comes at δ 4.49 ppm whereas in the syn isomer this
proton is at δ 4.74 ppm.5a
20b was formed in modest yield along with reduced amide (þ)-
23a and the starting material (þ)-2a (Table 3, entry 6). Reduced
amides such as (þ)-23a are often observed in reactions of
Weinreb amides with highly basic reagents, and they are thought
to be formed via an E2 pathway with formation of
formaldehyde.2d,13,14 Increasing the amount of n-BuLi to 10
equiv, although decreasing the amount of recovered starting
material, resulted in an increase in the reduced amide (þ)-23a
(Table 3, entry 7). Optimum conditions, 5 equiv of n-BuLi at
ꢀ50 °C, afforded ketone (þ)-20b (R1 = n-Bu) and the reduced
amide (þ)-23a in 38% and 33% yield, respectively (Table 3,
entry 8). Attempts to improve the yield of (þ)-20b by varying
the temperature, time, and amount of n-BuLi, or by addition of
additives such as LiCl and CeCl3 failed. However, under these
conditions with 5 equiv of MeLi and PhLi better yields of the
corresponding methyl and phenyl ketones (þ)-20a (R1 = Me),
73% and (þ)-20c (R1 = Ph), 61%, respectively, were observed
(Table 3, entries 9 and 10). Interestingly little, if any, of the
Synthesis of β-Amino Ketones. Results for the addition of
Grignard and lithium reagents to anti-R-methyl-β-amino Wein-
reb amides are given in Scheme 6 and summarized in Table 3.
Addition of 5 or 10 equiv of methylmagnesium bromide to
Weinreb amide (þ)-2a at ꢀ78 °C resulted in no reaction
(Table 3, entry 1). However, on addition at 0 °C a better than
95% yield of methyl ketone (þ)-20a was obtained (Table 3,
entry 2). Unexpectedly, reaction of (þ)-2a with either n-
butylmagnesium chloride or n-butylmagnesium bromide failed
(Table 3, entries 3 and 4). Warming the reaction to 25 °C and
addition of LiCl, CeCl3, and HMPA had no effect, and starting
material was recovered in all cases. However, with 5 equiv of n-
butyllithium at ꢀ78 °C for 2 h the desired n-butyl ketone (þ)-
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ARTICLE
reduced amide (þ)-23a was detected. Employing these opti-
mized conditions anti-R-methyl β-amino Weinreb amides (þ)-
18 (R = n-Pr) and (þ)-19 (R = BnO(CH2)2ꢀ) were treated
with MeLi and n-BuLi at ꢀ50 °C to afford low to modest yields,
33ꢀ45%, of the corresponding ketones (þ)-21, (þ)-22a, and
(þ)-22b (Table 3, entries 11, 14, and 17). Methylmagnesiun
bromide failed to react with either of these amides (Table 3,
entries 12 and 15). In all cases epimerization at the R-center was
not detected and is attributable to the protecting group ability of
the N-sulfinyl group, which stabilizes anions at nitrogen.4a
Our results for the addition of Grignard and lithium reagents
to anti-R-methyl β-amino Weinreb amides are puzzling. While
MeMgBr reacts with N-sulfinyl anti-R-methyl β-amino Weinreb
amide (þ)-2a to give an excellent yield of the methyl ketone
(þ)-20a (Talbe 3, entry 2) it failed to add to the corresponding
N-tosyl derivative (þ)-2b or with Weinreb amides derived from
N-alkyl sulfinimines, i.e. (þ)-18 and (þ)-19 (Scheme 2 and
Table 3). On the other hand, lithium reagents react with these
Weinreb amides to give the corresponding ketones, albeit in low
to moderate yields, because addition competes with reduction of
the Weinreb amide. By contrast the corresponding N-sulfinyl syn-
R-methyl β-amino Weinreb amides give excellent yield of the
corresponding ketones with lithium and Grignard reagents and
reduction is not observed.1,5
Scheme 4
Scheme 5
Scheme 6
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Table 3. Synthesis of β-Amino Ketones from β-Amino Weinreb Amides in THF for 2 h
entry
Weinreb amide (R1 =)
RM (equiv)
temp, °C
ketone (% yield)a
no reaction
1
2
(þ)-2a (Ph)
MeMgBr (10)
MeMgBr (10)
n-BuMgCl (10)
n-BuMgBr (10)
n-BuMgBr (10)
n-BuLi (5)
ꢀ78
0
20a (95)
3
0
no reaction
no reaction
no reaction
20b:23a:2a (34:16:50)b
20b:23a:2a (38:41:21)b
21b (38), 23a (33)
20a (73)c
4
0
5
0 to 24
ꢀ78
ꢀ78
ꢀ50
ꢀ50
ꢀ50
ꢀ50
0
6
7
n-BuLi (10)
n-BuLi (5)
8
9
MeLi (5)
10
11
12
13
14
15
16
17
PhLi (5)
20d (61)c
(þ)-18 (n-Pr)
MeLi (5)
21 (33), 23c (13)
no reaction
MeMgBr (10)
n-BuMgCl (10)
MeLi
(þ)-19- (BnO(CH2)2)
24
no reaction
ꢀ50
0
22a (45), 23b (20)
no reaction
MeMgBr (10)
n-BuLi (5)
ꢀ78
ꢀ50
22b (25), 23b (26)
22b (40), 23b (27)
n-BuLi (5)
a Isolated yield of pure diastereoisomer. b Ratio of products determined by 1H NMR. c Reduced amide 23a was detected.
In summary, the first asymmetric synthesis of anti-R-substi-
tuted β-amino Weinreb amides and their corresponding ketones
is reported. This was accomplished by reaction of lithium
dimethylhydroxylamine with N-sulfinyl anti-R-substituted β-
amino esters. Alkylation of N-sulfinyl β-amino Weinreb amide
enolates resulted in poor diastereoselectivities. Grignard reagents
do not react with N-sulfinyl anti-R-substituted β-amino Weinreb
amides, perhaps for steric reasons. However, lithium reagents
react with these Weinreb amides affording the corresponding
ketones in low to moderate yields because addition competes
with reduction of the Weinreb amide.
’ EXPERIMENTAL SECTION
Figure 2. Reaction of β-amino Weinreb amides with organometallic
reagents.
Weinreb amide (SS,3R)-(þ)-N-(p-toluenesulfinyl)-3-amino-N-
methoxy-N-methyl-3-phenylpropionamide (1a),3 N-sulfinyl β-amino
esters, (SS,R)-(þ)-methyl 3-(4-methylphenylsulfinamido)-3-phenyl-
propanoate (6a), and (SS,R)-(þ)-methyl 3-(4-methylphenylsulfina-
mido)-3-pent-4-enonate (6b) were prepared as previously described.17
(S)-(þ)-N-(3-(Benzyloxy)propylidene)-p-toluenesulfina-
mide. In a flame-dried, 50-mL round-bottomed flask equipped with a
magnetic stirring bar, rubber septum, and argon inlet were placed
(S)-(þ)-p-toluenesulfinamide (0.500 g, 3.23 mmol), 3-(benzyloxyl)-1-
propanal (0.636 g, 3.88 mmol), and DCM (10 mL). To the solution was
added Ti(OEt)4 (3.56 mL, 16.15 mmol), then the reaction mixture was
stirred for 8 h at rt at which time the solution was poured into a 50-mL
ice/water mixture and stirred vigorously. The reaction mixture was
filtered through Celite, and the Celite was washed with DCM (2 ꢁ
5 mL) and the organic phase was washed with satd aqueous NaHCO3
(10 mL) and brine (10 mL), dried (MgSO4), and concentrated.
Chromatography (EtOAc/hexanes 1:1) gave 0.597 g (61%) of a clear
oil: [R]25D þ268 (c 1.7, CHCl3); IR (thin film) 2865, 2365, 2335, 1624,
1094 cmꢀ1; 1H NMR (CDCl3) δ 2.40 (s, 3H), 2.80 (m, 2H), 3.78 (m,
2H), 4.50 (s, 2H), 7.32 (m, 7H), 7.55 (m, 2H), 8.30 (t, J = 4.8 Hz, 1H);
13C NMR (CDCl3) δ 21.7, 36.7, 66.4, 73.5, 125.0, 125.7, 128.0, 128.2,
128.8, 128.82, 130.0, 130.2, 165.5. HRMS calcd for C17H20NO2S (M þ
H) 302.1215, found 302.1215.
It is reasonable to assume that addition of an organometallic
reagent R2M to the β-amino Weinreb amides results first in depro-
tonation of the acidic N-sulfinyl NH proton to give species A
(Figure 2). Deprotonation of N-sulfinyl amines derived from addi-
tion of organometallic reagents to sulfinimine has often been used to
explain the exceptional protecting group ability of the N-sulfinyl
group in sulfinimine chemistry.4 Species A is probably formed as a
complex mixture of aggregates resulting from both intra- and
intermolecular chelation. We speculated that formation of the
tetrahedral intermediate B results from addition of the organome-
tallic reagent R2M to the amide carbonyl from the least hindered
direction. For steric reasons this should be more favorable in the syn-
R-substituted β-amino Weinreb amide than in the anti-derivative.
Dimeric lithium acetylide is reported to react with Weinreb amides
via a monosolvated monomer-based transition state to form the
tetrahedral intermediate.15 In a study of displacements at the
nitrogen atom of lithioalkoxyamides by organometallic reagents,
lithium reagents were more reactive than Grignard reagents, and this
is consistent with our findings.16 While this simple steric argument
can be used to interpret our findings, the situation is undoubtedly
much more complex because these organometallic species exist as
mixtures of aggregates.
(R)-(þ)-N-Methoxy-N-methyl-3-phenyl-3-(tosylamino)-
propanamide (1b). Into a 25-mL round-bottomed flask was placed
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ARTICLE
m-CPBA (77% of 0.183 g, 0.820 mmol), then a solution of (þ)-1a (0.142
g, 0.410 mmol) in dry CHCl3 (6 mL) was added and the reaction mixture
was stirred at rt for 8 h. At this time satd aqueous Na2S2O3 (2 mL) was
added, then the organic phase was washed with satd aqueous NaHCO3
(5 mL), dried (MgSO4), and concentrated. Chromatography (EtOAc/
warmed to ꢀ50 °C (dry ice/MeCN), stirred for 1 h, and quenched at
this temperature by addition of satd aqueous NH4Cl (2 mL). The
solution was diluted with H2O (2 mL), THF was evaporated, and the
residue was extracted with EtOAc (2 ꢁ 5 mL). The combined organic
phases were washed with brine (5 mL), dried (MgSO4), and concen-
trated. Chromatography (hexanes/EtOAc, 1:1) gave 0.0096 g (37%) of
hexane 50:50) gave 0.128 g (86%) of a white solid: mp 105ꢀ6 °C; [R]25
D
1
þ58.3 (c 2.46, CHCl3); IR (KBr) 1641, 1462, 1327 cmꢀ1; H NMR
a clear oil: [R]25 þ71.0 (c 0.3, CHCl3); IR (thin film) 1639, 1452,
D
(CDCl3) δ 2.36 (s, 3H), 2.77 (dd, J = 5.6, 16.0 Hz, 1H), 2.97 (dd, J = 5.6,
16.0 Hz, 1H), 3.02 (s, 3H), 3.43 (s, 3H), 4.71 (q, J = 6.0, 13.2 Hz, 1H), 6.40
(d, J = 6.8 Hz, 1H), 7.17 (m, 7H), 7.59 (m, 2H); 13C NMR (CDCl3) δ
21.8, 32.1, 38.4, 55.0, 61.6, 127.0, 127.5, 127.8, 128.7, 129.7, 138.0, 140.5,
143.3, 171.5. HRMS calcd for C18H23N2O4S (M þ H) 363.1379, found
363.1376.
1329 cmꢀ1; 1H NMR (CDCl3) δ 1.23 (d, J = 6.8 Hz, 3H), 2.31 (s, 3H),
2.99 (s, 3H), 3.10 (s, 3H), 3.28 (m, 1H), 4.56 (dd, J = 4.4, 8.4 Hz, 1H),
7.00 (d, J = 8.4 Hz, 1H), 7.05 (m, 4H), 7.10 (m, 3H), 7.50 (m, 2H); 13C
NMR (CDCl3) δ 16.5, 21.7, 32.0, 40.7, 61.1, 61.5, 126.8, 127.1, 127.2,
127.5, 128.5, 129.4, 138.8, 140.6, 142.8, 175.7. HRMS calcd for
C19H25N2O4S (M þ H) 377.1535, found 377.1530.
(SS,3S)-(þ)-Methyl 3-(4-Methylphenylsulfinamido)hexano-
(SS,2S,3R)-(þ)-Methyl 2-Methyl-3-(4-methylphenylsulfin-
ate (6c):
amido)-3-phenylpropanoate (7a):
Typical Procedure In a Schlenk tube equipped with a magnetic
stirring bar, rubber septum, and argon inlet were added NaHMDS
solution (0.54 mmol, 0.54 mL of 1 M NaHMDS in THF) by syringe and
ether (5 mL) at rt. The solution was cooled to ꢀ78 °C, a solution of
methyl acetate (0.04 mL, 0.503 mmol) in ether (2 mL) was added
dropwise, and the reaction mixture was stirred for 1 h. At this time
(S)-(þ)-N-butylidiene-p-toluenesulfinamide16 (0.070 g, 0.335 mmol)
in ether (2 mL) was added dropwise, then the reaction mixture was
stirred at ꢀ78 °C for 40 min and quenched with satd aqueous NH4Cl
solution (2 mL). Water (2 mL) was added, the aqueous phase was
extracted with EtOAc (3 ꢁ 5 mL), and the combined organic phases
were washed with satd aqueous NH4Cl solution (2 mL) and brine
(2 mL), dried (MgSO4), and concentrated. Chromatography (hexanes/
EtOAc, 67:33) gave 0.071 g (75%) of a clear oil: [R]25D þ118 (c 1.0,
Typical Procedure for the r-Alkylation of N-Sulfinyl
β-Amino Esters In a Schlenk tube equipped with a magnetic stirring
bar and rubber septum was placed LiCl (0.033 g, 0.789 mmol), then the
tube was flame-dried under vacuum and filled with Argon. This
procedure was repeated three times at which time the Schlenk tube
was cooled to ambient temperature. To the Schlenk tube was added
diisopropylamine (0.042 mL, 0.296 mmol) and THF (1 mL) and the
solution was cooled to 0 °C. At this time n-BuLi (0.237 mmol, 0.14 mL
of 1.73 M in hexane) was added dropwise, and the solution was stirred
for 15 min and then cooled to ꢀ78 °C. To the preformed LDA solution
was added dropwise β-amino ester (þ)-6a (0.025 g, 0.0789 mmol) in
THF (1 mL) and the reaction mixture was stirred at ꢀ78 °C for 1 h. At
this time MeI (0.205 mmol, 0.1 mL of a 2 M solution in tert-butyl methyl
ether) was then added dropwise and the solution was stirred at this
temperature for 1 h and warmed to ꢀ50 °C (dry ice MeCN) and stirred
for 1 h. The reaction mixture was quenched at ꢀ78 °C by addition of
satd aqueous NH4Cl (2 mL), warmed to rt, and diluted with H2O
(2 mL). The THF was evaporated, the residue was extracted with EtOAc
(2 ꢁ 5 mL), and the combined organic phases were washed with brine
(5 mL), dried (MgSO4), and concentrated. Chromatography (hexanes/
EtOAc, 2:1) gave 0.020 g (80%) of a clear oil as a mixture of inseparable
1
CHCl3); IR (thin film) 1738, 1178, 1092, 1061, 811 cmꢀ1; H NMR
(CDCl3) δ 0.89 (t, J = 7.2 Hz, 3H), 1.51 (m, 4 overlapping H), 2.36 (s,
3H), 2.55 (dq, J = 5.6, 12, 16 Hz, 2H), 3.61 (s, 3H), 3.62 (m, 1H), 4.56
(d, J = 8.8 Hz, 1H), 7.24 (d, J = 8.0 Hz, 2H), 7.53 (m, 2H); 13C NMR
(CDCl3) δ 14.1, 19.6, 21.7, 38.3, 40.8, 52.0, 52.7, 125.9, 129.8, 141.6,
142.7, 172.4. HRMS calcd for C14H22NO3S (M þ H) 284.1320, found
284.1319.
anti/syn (88:12) isomers: [R]25 þ64.7 (c 0.7, CHCl3); IR (CHCl3)
(SS,3S)-(þ)-Methyl-3-(4-methylphenylsulfinamido)-5-
benzyloxypentanoate (6d). The title compound was prepared
from (S)-(þ)-N-(3-(benzyloxy)propylidene)-p-toluenesulfinamide in
67% yield. Chromatography (hexanes/EtOAc, 67:33) gave 0.125 g
D
1423, 1263, 1218 cmꢀ1; major isomer 1H NMR (CDCl3): δ 1.06 (d, J =
7.2 Hz, 3H), 2.41 (s, 3H), 2.85 (m, 1H), 3.63 (s, 3H), 4.54 (dd, J = 5.2,
7.6 Hz, 1H), 5.09 (d, J = 5.6 Hz, 1H), 7.34 (m, 7H), 7.54 (d, J = 8.0 Hz,
2H); major isomer: 13C NMR (CDCl3) δ 15.5, 21.7, 46.7, 52.4, 61.2,
125.7, 125.8, 126.1, 127.6, 128.1, 128.4, 129.0, 129.9, 130.0, 140.2, 141.7,
142.7, 175.3. HRMS calcd for C18H22NO3S (M þ H) 332.1320, found
332.1317.
(67%) of a clear oil: [R]25 þ64 (c 0.8, CHCl3); IR (CHCl3) 2360,
D
2340, 1734, 1459, 1094 cmꢀ1; 1H NMR (CDCl3) δ 1.94 (m, 2H), 2.40
(s, 3H), 2.62 (dq, J = 5.6, 16, 42 Hz, 2H), 3.62 (s, 3H), 3.63 (m, 2H),
3.90 (m, 1H), 4.51 (q, J = 11.6, 18.4 Hz, 2H), 4.86 (d, J = 9.2 Hz, 1H),
7.26 (m, 3H), 7.32 (m, 4H), 7.50 (m, 2H); 13C NMR (CDCl3) δ 21.1,
35.1, 39.9, 49.6, 51.3, 66.5, 72.8, 125.3, 125.6, 127.1, 127.3, 127.4, 127.5,
127.9, 128.1, 129.2, 137.9, 140.9, 141.9, 171.7. HRMS calcd for
C20H26NO4S (M þ H) 376.1583, found 376.1580.
(SS,2S,3R)-(þ)-Methyl 2-(2-Propenyl)-3-(4-methylphenyl-
sulfinamido)-3-phenylpropanoate (7b). Chromatography (hexanes/
EtOAc, 2:1) gave 64% of a clear oil. Mixture of inseparable anti/syn (92:8)
isomers: [R]25 þ102 (c 1.7, CHCl3); IR (thin film) 2365, 2340, 1734,
D
1059 cmꢀ1; major isomer: 1H NMR (CDCl3) δ 2.19 (m, 1H), 2.32 (m,
1H), 2.41 (s, 3H), 2.85 (m, 1H), 3.58 (s, 3H), 4.60 (t, J = 6.8 Hz, 1H), 5.03
(m, 2H),5.17(d,J= 6.4 Hz, 1H), 5.64 (m, 1H), 7.30 (m, 5H), 7.37 (m, 2H),
7.53 (m, 2H); major isomer: 13C NMR (CDCl3) δ 21.7, 34.5, 52.2, 52.5,
59.9, 118.1, 125.7, 125.9, 127.7, 128.1, 128.4, 128.9, 129.1, 129.9, 130.0, 134.5,
140.7, 141.7, 142.5, 174.2. HRMS calcd for C20H24NO3S (M þ H)
358.1477, found 358.1474.
(2S,3R)-(þ)-N-Methoxy-N,2-dimethyl-3-phenyl-3-(tosyl-
amino)propanamide (2b). In a Schlenk tube equipped with a
magnetic stirring bar and rubber septum was placed LiCl (0.029 g,
0.691 mmol), then the tube was flame-dried under vacuum and filled
with argon. This procedure was repeated three times, then the Schlenk
tube was cooled to rt and diisopropylamine (0.036 mL, 0.259 mmol) and
THF (1 mL) were added and the solution was cooled to 0 °C. At this
time n-BuLi (0.207 mmol, 0.12 mL of 1.73 M in hexane) was added
dropwise, then the solution was stirred for 15 min and cooled to ꢀ78 °C.
In a separated 25 mL round-bottomed flask equipped with a magnetic
stir bar and argon inlet was placed Weinreb amide (þ)-1b (0.025 g,
0.0691 mmol) in THF (1 mL) and the solution was cooled to ꢀ78 °C.
At this time the preformed LDA solution was added dropwise and the
reaction mixture was stirred at ꢀ78 °C for 1 h, then MeI (0.180 mmol,
0.09 mL of a 2 M solution in tert-butyl methyl ether) was added dropwise
at this time. The reaction mixture was stirred at this temperature for 1 h,
(SS,2S,3R)-(þ)-Methyl 2-Benzyl-3-(4-methylphenylsulfin-
amido)-3-phenyl-propanoate (7c). Chromatography (hexanes/
EtOAc, 2:1) gave 72% of a clear oil. Mixture of inseparable anti/syn
(96:4) isomers: [R]25D þ50.1 (c 1.2, CHCl3); IR (thin film) 2365, 2340,
1
1734, 1459, 1059 cmꢀ1; major isomer: H NMR (CDCl3) δ 2.42 (s,
3H), 2.77 (dd, J = 6, 13.6 Hz, 1H), 2.92 (m, 1H), 3.06 (m, 1H), 3.45 (s,
3H), 4.63 (t, J = 6.8 Hz, 1H), 5.33 (d, J = 6.8 Hz, 1H), 7.12 (m, 2H), 7.18
(m, 1H), 7.25 (m, 2H), 7.31 (m, 5H), 7.38 (m, 2H), 7.55 (m, 2H); major
isomer: 13C NMR (CDCl3) δ 21.7, 36.5, 52.1, 54.9, 60.1,125.7, 125.9,
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126.8, 126.9, 127.5, 128.1, 128.3, 128.5, 128.8, 129.10, 129.15, 129.9,
130.2, 138.7, 141.1, 141.7, 142.5, 174.2. HRMS calcd for C24H26NO3S
(M þ H) 408.1633, found 408.1624.
extracted with DCM (5 mL), and the combined organic phases were
washed with brine, dried (MgSO4), and concentrated. To the residue
was added DCM (2 mL) and (Boc)2O solution (1 mmol, 1 mL of 1 M
(Boc)2O in THF) and the reaction mixture was stirred for 8 at rt. At this
time satd aqueous NaHCO3 (4 mL) was added, the solution was diluted
with H2O (2 mL), and the mixture was extracted with EtOAc (2 ꢁ
5 mL). The combined organic phases were washed with brine (5 mL),
dried (MgSO4), and concentrated. Chromatography (hexanes/EtOAc,
80:20) gave 0.048 g (86%) of a clear oil: [R]25D ꢀ45.9 (c 1.7, CHCl3);
IR (thin film) 2980, 1721, 1506, 1170 cmꢀ1; 1H NMR (CDCl3) δ 1.43
(s, 9H), 2.33 (m, 1H), 2.40 (m, 1H), 2.68 (m, 1H), 3.64 (s, 3H), 4.36
(m, 1H), 5.11 (m, 4H), 5.43 (d, J = 8.8 Hz, 1H), 5.74 (m, 2H); 13C NMR
(CDCl3) δ 27.7, 28.7, 34.2, 49.2, 52.9, 53.3, 115.8, 118.0, 134.8, 137.1,
155.8, 174.7. HRMS calcd for C14H23NNaO4 (M þ Na) 292.1525,
found 292.1522.
(1S,2R)-(þ)-Methyl-2-(tert-butoxycarbonylamino)cyclo-
pentene Carboxylate (15). In a Schlenk tube equipped with a
magnetic stirring bar, rubber septum, and argon inlet was placed Grubbs
II catalyst (0.012 g, 0.0138 mmol). The brown solid were dried under
vacuum for 5 min and then the tube was filled with argon. After the above
procedure was repeated three times, a solution of (ꢀ)-14 (0.074 g, 0.275
mmol) in DCM (3 mL) was added at rt and the reaction mixture was
stirred overnight. The solution was concentrated and chromatography
(hexanes/EtOAc, 80:20) gave 0.038 g (58%) of a clear oil: [R]25D þ98.5
(c 0.65, CHCl3); IR (thin film) 2978, 1699, 1508, 1169 cmꢀ1; 1H NMR
(CDCl3) δ 1.44 (s, 9H), 2.60 (m, 1H), 2.74 (m, 1H), 2.83 (m, 1H), 3.72
(s, 3H), 4.63 (br s, 1H), 4.96 (br s, 1H), 5.62 (d, J = 2.8 Hz, 1H), 5.83 (m,
1H); 13C NMR (CDCl3) δ 28.7, 30.0, 35.7, 51.0, 52.4, 61.1, 130.9, 132.4,
155.4, 175.3. HRMS calcd for C12H19NNaO4 (M þ Na) 264.1212, found
264.1208.
(SS,2S,3R)-(þ)-Methyl 2-Methyl-3-(4-methylphenylsulfin-
amido)-3-pent-4-enonate (10a). Chromatography (hexanes/
EtOAc, 2:1) gave 88% of a clear oil. Mixture of in separable anti/syn
isomers: (89:11): [R]25D þ92.3 (c 1.15, CHCl3); IR (thin film) 2365,
2340, 1734, 1459, 1059 cmꢀ1; major isomer: 1H NMR (CDCl3) δ 1.11
(d, J = 7.2 Hz, 3H), 2.40 (s, 3H), 2.63 (m, 1H), 3.65 (s, 3H), 3.97 (dd, J =
1.2, 6.8 Hz, 1H), 4.76 (d, J = 7.2 Hz, 1H), 5.28 (m, 2H), 5.84 (m, 1H),
7.29 (m, 2H), 7.58 (m, 2H); major isomer: 13C NMR (CDCl3) δ 14.4,
21.7, 44.6, 52.2, 59.1, 118.4, 125.96, 126.02, 129.8, 136.0, 137.4, 141.7,
142.2, 175.0. HRMS calcd for C14H20NO3S (M þ H) 282.1164, found
282.1163.
(SS,2S,3R)-(þ)-Methyl 2-(2-Propenyl)-3-(4-methylphenyl-
sulfinamido)-3-pent-4-enonate (10b). Chromatography (hexanes/
EtOAc, 2:1) gave 76% of a clear oil. Mixture of inseparable anti/syn (91:9)
isomers: [R]25D þ51.4 (c 0.8, CHCl3); IR (thin film) 2365, 2340, 1734,
1459, 1169, 1059 cmꢀ1; major isomer: 1H NMR (CDCl3) δ 2.19 (m, 1H),
2.36 (m, 1H), 2.41 (s, 3H), 2.62 (dt, J = 5.6, 8.8 Hz, 1H), 3.63 (s, 3H), 3.98
(m, 1H), 4.90 (d, J = 7.6 Hz, 1H), 5.03 (m, 2H), 5.27 (m, 2H), 5.63 (m,
1H), 5.88 (dq, J = 7.2, 10.4, 17.2 Hz, 1H), 7.29 (m, 2H), 7.57 (m, 2H);
major isomer: 13C NMR (CDCl3) δ21.7, 33.9, 50.2, 52.1, 58.0, 117.7, 117.8,
118.0, 126.0, 129.9, 134.9, 137.7, 137.9, 141.7, 142.1, 174.1. HRMS calcd for
C16H22NO3S (M þ H) 308.1320, found 308.1316.
(SS,2S,3R)-(þ)-Methyl 2-Benzyl-3-(4-methylphenylsulfin-
amido)-3-pent-4-enonate (10c). Chromatography (hexanes/
EtOAc, 2:1) gave 78% of a clear oil. Mixture of inseparable anti/syn
(95:5) isomers: [R]25 þ40.7 (c 1.25, CHCl3); IR (thin film) 2360,
D
2340, 1734, 1459, 1059 cmꢀ1; major isomer: 1H NMR (CDCl3) δ 2.42
(s, 3H), 2.85 (m, 2H), 2.95 (m, 1H), 3.53 (s, 3H), 4.03 (m, 1H), 4.97 (d,
J = 8.0 Hz, 1H), 5.29 (m, 2H), 5.91 (m, 2H), 7.14 (m, 2H), 7.20 (m, 1H),
7.28 (m, 4H), 7.60 (m, 2H); major isomer: 13C NMR (CDCl3) δ 21.7,
35.7, 52.0, 52.4, 58.2, 117.8, 117.9, 126.1, 126.9, 128.9, 129.0, 129.2,
129.4, 129.9, 135.6, 138.1, 138.9, 141.8, 142.1, 174.1; HRMS calcd for
C20H24NO3S (M þ H) 358.1477, found 358.1475.
(1S,2S)-(þ)-Methyl 2-(tert-Butoxycarbonylamino)cyclo-
pentanecarboxylate (16). In a 25-mL round-bottomed flask
equipped with a magnetic stirring bar and rubber septum were placed
(þ)-15 (0.021 g, 0.0871 mmol) and 10% Pd/C (0.004 g, 20% w/w).
The flask was connected to the vacuum, then filled with hydrogen. After
this procedure was repeated three times, MeOH (2 mL) was added via
syringe and the dark suspension was stirred at rt for 4 h. At this time the
solution was filtered through a short pad of Celite, the Celite was washed
with MeOH (2 ꢁ 2 mL), and the combined solutions were concentrated
to give 0.019 g (90%) of a white solid: mp 66ꢀ67 °C; [R]25D þ39.3 (c
(SS,2S,3S)-(þ)-Methyl 2-Methyl-3-(4-methylphenylsulfin-
amido)hexanoate (11). Chromatography (hexanes/EtOAc, 50:50)
gave 89% of a clear oil: [R]25 þ108 (c 0.97, CHCl3); IR (thin film)
D
3205, 2962, 1728, 1199, 1055 cmꢀ1; 1H NMR (CDCl3) δ 0.92 (t, J = 7.2
Hz, 3H), 1.14 (d, J = 7.2 Hz, 3H), 1.45 (m, 3H), 1.58 (m, 1H), 2.40 (s,
3H), 2.67 (m, 1H), 3.43 (m, 1H), 3.66 (s, 3H), 4.63 (d, J = 9.6 Hz, 1H),
7.29 (d, J = 8.0 Hz, 2H), 7.59 (m, 2H); 13C NMR (CDCl3) δ 14.2, 14.3,
19.8, 21.7, 37.4, 43.6, 52.1, 57.8, 126.0, 129.8, 141.6, 142.8, 175.7. HRMS
calcd for C15H24NO3S (M þ H) 298.1477, found 298.1474.
1
0.9, CHCl3); IR (thin film) 2971, 1717, 1522, 1172 cmꢀ1; H NMR
(CDCl3) δ 1.43 (s, 9H), 1.47 (m, 1H), 1.65 (m, 1H), 1.72 (m, 2H), 1.87
(m, 1H), 1.98 (m, 1H), 2.11 (m, 1H), 2.57 (dd, J = 8.0, 16.0 Hz, 1H),
3.68 (s, 3H), 4.10 (m, 1H), 4.58 (br s, 1H); 13C NMR (CDCl3) δ 23.1,
28.5, 28.7, 30.0, 33.2, 51.2, 52.2, 56.4, 155.6, 175.6. HRMS calcd for
C12H21NNaO4 (M þ Na) 266.1368, found 266.1367.
(SS,2S,3S)-(þ)-Methyl 2-Methyl-3-(4-methylphenylsulfin-
amido)-5-benzyloxy-5-benzyloxpentanoate (12). Chromato-
graphy (hexanes/EtOAc 1:1) gave 70% of a clear oil: [R]25D þ67 (c 0.8,
(SS,2S,3R)-(þ)-N-Methoxy-N,2-dimethyl-3-(4-methylphe-
nylsulfinamido)-3-phenylpropanamide (2a):
CHCl3); IR (thin film) 1734, 1454, 1204, 1089 cmꢀ1 1H NMR
;
Typical Procedure In a Schlenk tube equipped with a magnetic
stirring bar, rubber septum, and argon inlet was placed N,O-dimethyl
hydroxylamine hydrochloride (0.187 g, 1.88 mmol, Aldrich) in THF
(3 mL). The formed suspension was cooled to ꢀ78 °C, n-BuLi (3.71
mmol, 1.48 mL of 2.5 M in hexane) was added dropwise, the reaction
mixture was slowly warmed to rt, and the solution was stirred for 1 h. At
this time the solution was cooled to ꢀ78 °C and a solution of (þ)-6a
(0.104 g, 0.314 mmol) in THF (2 mL) was added dropwise, then the
reaction mixture was stirred for 4 h and quenched by addition of satd
aqueous NH4Cl (3 mL). The solution was warmed to rt and diluted with
H2O (3 mL), the aqueous phase was extracted with EtOAc (2 ꢁ 5 mL),
and the combined organic phases were washed with satd aqueous
NH4Cl (5 mL) and brine (5 mL), dried (MgSO4), and concentrated.
Chromatography (EtOAc:n-hexane, 50:50) gave 0.085 g (75%) of a
clear oil: [R]25D þ133.6 (c 1.73, CHCl3); IR (CHCl3) 2404, 1640, 1518,
1428, 1217 cmꢀ1; 1H NMR (CDCl3) δ 1.19 (d, J = 6.8 Hz, 3H), 2.4 (s,
(CDCl3) δ 1.14 (d, J = 7.6 Hz, 3H), 1.86 (q, J = 5.6, 6.8 Hz, 2H),
2.64 (m, 1H), 3.58 (m, 1H), 3.62 (s, 3H), 3.65 (m, 1H), 4.50 (s, 2H),
4.87 (d, J = 9.2 Hz, 1H), 7.26 (m, 3H), 7.32 (m, 4H), 7.52 (m, 2H); 13C
NMR (CDCl3) δ 14.6, 21.7, 35.1, 43.6, 52.1, 55.1, 67.3, 73.4, 125.8,
126.0, 128.0, 128.1, 128.8, 129.8, 138.6, 141.5, 142.5, 175.7. HRMS calcd
for C21H28NO4S (M þ H) 390.1739, found 390.1735.
(2S,3R)-(ꢀ)-Methyl 2-(2-Propenyl)-3-(tert-butoxycarbo-
nylamino)pent-4-enonate (14). In a single-necked, oven-dried,
25-mL round-bottomed flask equipped with a magnetic stirring bar and
rubber septum was placed (þ)-10b (0.064 g, 0.208 mmol) in MeOH
(4 mL) and HCl Et2O solution (1.04 mmol, 1.04 mL of 1 M hydrogen
chloride in ether, 1.04 mmol) was added via syringe at rt. The reaction
mixture was stirred for 2 h and concentrated, then the residue was
dissolved with DCM (10 mL), and the solution was neutralized to pH 8
by dropwise addition of satd aqueous NaHCO3. The aqueous phase was
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3H), 3.03 (s, 3H), 3.27 (s, 3H), 4.49 (t, 1H), 5.97 (d, J = 6.8 Hz, 1H),
7.25 (m, 3H), 7.33 (m, 4H), 7.57 (m, 2H); 13C NMR (CDCl3) δ 16.5,
21.7, 32.2, 41.6, 61.6, 62.0, 125.6, 126.1, 127.6, 127.9, 128.5, 128.8, 129.0,
129.8, 130.0, 141.4, 142.2, 142.7, 175.9. HRMS calcd for C19H25N2O3S
(M þ H) 361.1586, found 361.1588.
4.53 (t, J = 6.4 Hz, 1H), 5.19 (d, J = 5.6 Hz, 1H), 7.29 (m, 3H), 7.36 (m,
4H), 7.54 (m, 2H); 13C NMR (CDCl3) δ 14.1, 15.7, 21.7, 22.5, 25.6,
42.8, 52.4, 61.3, 125.8, 127.9, 128.2, 129.0, 129.9, 140.9, 141.6, 142.7,
214.7. HRMS calcd for C21H28NO2S (M þ H) 358.1841, found
358.1840.
(SS,3S,3R)-(þ)-N-Methoxy-N-methyl-2-(2-propenyl)-3-(4-
methylphenylsulfinamido)pent-4-eneamide (17). Chroma-
(2S,3R)-(þ)-2-Methyl-3-(4-methylphenylsulfonyl)-1-butyl-
3-phenylpropan-1-one (4). To a 25-mL round-bottomed flask
equipped with a magnetic stirring bar, rubber septum, and argon inlet
was placed a solution of compound (þ)-2b (0.025 g, 0.0665 mmol) in
THF (2 mL) at rt. The solution was cooled to ꢀ50 °C, n-BuLi (0.333
mmol, 0.13mLof2.48Minhexane)wasadded dropwise, andthe reaction
mixture was stirred at ꢀ50 °C for 1 h. At this time the reaction was
quenched by dropwise addition of satd aqueous NH4Cl (1 mL), the
solution was diluted with H2O (1 mL), and the aqueous phase was
extracted with EtOAc (3 ꢁ 3 mL). The combined organic phases were
washed with brine (5 mL), dried (MgSO4), and concentrated. Chroma-
tography (EtOAc:n-hexane, 50:50) gave 0.015 g (61%) of a white solid:
mp 78ꢀ79 °C; [R]25D þ39.2, (c 0.5, CHCl3); IR (thin film) 3275, 2960,
2360, 1709, 1459 cmꢀ1; 1H NMR (CDCl3) δ 0.76 (t, J = 7.6 Hz, 3H),
1.08 (m, 2H), 1.11 (d, J = 7.2 Hz, 3H), 1.29 (m, 2H), 1.98 (dt, J = 7.2, 17.6
Hz, 1H), 2.27 (dt, J = 7.2, 17.6 Hz, 1H), 2.30 (s, 3H), 2.96 (m, 1H), 4.50
(dd, J = 5.6, 9.2 Hz, 1H), 6.23 (d, J = 9.2 Hz, 1H), 6.97 (m, 2H), 7.04 (d,
J = 7.6 Hz, 2H), 7.09 (m, 3H), 7.48 (m, 2H); 13C NMR (CDCl3) δ 14.1,
15.9, 21.7, 22.3, 25.4, 43.2, 51.5, 60.7, 126.8, 127.2, 127.6, 128.6, 129.5,
138.3, 139.8, 143.1, 215.4. HRMS calcd for C20H26NO3S (M þ H)
374.1790, found 374.1785.
tography (EtOAc:n-hexane, 33:67) gave 81% of a clear oil: [R]25
D
þ94.3 (c 1.15, CHCl3); IR (thin film) 3260, 2935, 1644, 1389 cmꢀ1; 1H
NMR (CDCl3) δ 2.27 (m, 1H), 2.39 (s, 3H), 2.41 (m, 1H), 3.09 (s,
3H), 3.62 (s, 3H), 3.92 (m, 1H), 4.98 (m, 1H), 5.07 (dd, J = 1.6 , 17.2 Hz,
1H), 5.22 (m, 2H), 5.55 (d, J = 8 Hz, 1H), 5.64 (m, 1H), 5.90 (m, 1H),
7.28 (d, J = 8.0 Hz, 2H), 7.58 (m, 2H); 13C NMR (CDCl3) 21.7, 32.3,
34.3, 44.9, 58.5, 61.9, 116.9, 117.7, 125.8, 126.2, 129.8, 135.4, 139.1,
141.4, 142.2, 174.9. HRMS calcd for C17H24N2O3S (M þ H) 337.1586,
found 337.1584.
(SS,2S,3S)-(þ)-N-Methoxy-N,2-dimethyl-3-(4-methylphe-
nylsulfinamido)-3-hexanamide (18). Chromatography (hexanes/
EtOAc, 50:50) gave 87% of a clear oil: [R]25D þ103 (c 0.5, CHCl3); IR
(thin film) 1657, 1560 cmꢀ1; 1H NMR (CDCl3) δ 0.92 (t, J = 6.8 Hz, 3H),
1.19 (d, J = 6.8 Hz, 3H), 1.39 (m, 1H), 1.50 (m, 2H), 1.59 (m, 1H), 2.39 (s,
3H), 3.15 (m, 4 overlapping H), 3.35 (m, 1H), 3.68 (s, 3H), 5.41 (d, J = 9.2
Hz, 1H), 7.27 (d, J = 9.2 Hz, 2H), 7.60 (m, 2H); 13C NMR (CDCl3) δ
13.3, 14.2, 20.0, 21.7, 32.3, 38.2, 38.4, 59.0, 62.0, 126.1, 129.7, 141.3, 143.2,
176.9. HRMS calcd for C16H27N2O3S (M þ H) 327.1742, found
327.1742.
(SS,2S,3R)-(þ)-2-Methyl-3-(4-methylphenylsulfinamido)-
1,3-diphenylpropan-1-one (20c). Chromatography (EtOAc:n-
hexane, 50:50) gave 61% of a clear oil: [R]25D þ35.7 (c 0.95, CHCl3);
IR (thin film) 3195, 3060, 2924, 1680, 1452 cmꢀ1; 1H NMR (CDCl3) δ
1.14 (s, 3H), 2.39 (s, 3H), 3.92 (m, 1H), 4.78 (m, 1H), 5.17 (d, J = 5.2
Hz, 1H), 7.28 (m, 4H), 7.38 (m, 6H), 7.53 (m, 2H), 7.81 (m, 2H); 13C
NMR (CDCl3) δ 16.8, 21.7, 47.4, 61.5, 125.9, 128.3, 128.7, 129.0, 129.1,
129.8, 133.7, 136.6, 140.4, 141.6, 142.7, 203.4. HRMS calcd for
C23H24NO2S (M þ H) 378.1528, found 378.1524.
(SS2S,3S)-(þ)-N-Methoxy-N,2-dimethyl-3-(4-methylphe-
nylsulfinamido)-5-benzyloxypentanamide (19). Chromatogra-
phy (hexanes/EtOAc 1:1) gave 83% of a clear oil: [R]25 þ66 (c 0.5,
D
CHCl3); IR (thin film) 1654, 1459, 1089, 1064 cmꢀ1; 1H NMR (CDCl3)
δ 1.17 (d, J = 14 Hz, 1H), 1.89 (m, 2H), 2.40 (s, 1H), 3.13 (s, 3H), 3.61
(m, 1H), 3.62 (s, 3H), 3.69 (s, 1H), 4.53 (dd, J = 5.6, 12 Hz, 2H), 5.61 (d, J
= 8.8 Hz, 1H), 7.25 (d, J = 8 Hz, 2H), 7.29 (m, 1H), 7.34 (m, 4H), 7.55 (d,
J = 8.4 Hz, 2H); 13C NMR (CDCl3) δ 17.6, 23.6, 34.1, 38.0, 40.5, 57.9,
63.8, 69.2, 75.1, 75.3, 127.7, 127.9, 129.9, 130.0, 130.1, 130.4, 130.6, 131.6,
140.5, 143.1, 144.9, 178.7. HRMS calcd for C22H31N2O4S (M þ H)
419.2005, found 419.2004.
(SS,3S,4S)-(þ)-N-(4-p-Toluenesulfinyl)-4-amino-3-methyl-
4-heptan-2-one (21). Chromatography (EtOAc:n-hexane, 50:50)
gave 33% of a clear oil: [R]25D þ126.5 (c 0.2, CHCl3); IR (thin film)
3219, 2959, 2922, 1705, 1454 cmꢀ1; 1H [R]25D þ126.5 (c 0.2, CHCl3);
IR (thin film), 1705, 1454 cmꢀ1; 1H NMR (CDCl3) δ 0.92 (t, J = 7.2 Hz,
3H), 1.10 (d, J = 7.2 Hz, 3H), 1.42 (m, 4H), 2.09 (s, 3H), 2.41 (s, 3H),
2.75 (m, 1H), 3.47 (m, 1H), 4.61 (d, J = 9.2 Hz, 1H), 7.29 (d, J = 8.0 Hz,
2H), 7.59 (m, 2H); 13C NMR (CDCl3) δ 13.3, 14.2, 19.9, 21.7, 29.9,
36.7, 50.9, 57.4, 125.9, 129.9, 141.6, 142.7, 212.0. HRMS calcd for
C15H24NO2S (M þ H) 282.1528. HRMS calcd for C15H24NO2S (Mþ)
282.1528, found 282.1529.
N-[(SS,3S,4S)-(þ)-1-(Benzyloxy)-4-methyl-5-oxohexan-3-yl]-
4-methylbenzenesulfinamide (22a). Chromatography (EtOAc:n-
hexane, 50:50) gave 45% of a clear oil: [R]25D þ64.8 (c 0.5, CHCl3); IR
(thin film) 3232, 2922, 2868, 1709, 1452 cmꢀ1; 1H NMR (CDCl3) δ 1.01
(d, J = 7.2 Hz, 3H), 1.76 (m, 2H), 1.97 (s, 3H), 2.34 (s, 3H), 2.66 (m, 1H),
3.50 (m, 1H), 3.57 (m, 2H), 4.43 (m, 2H), 4.89 (d, J = 9.2 Hz, 1H), 7.19
(m, 3H), 7.25 (m, 4H), 7.45 (m, 2H); 13C NMR (CDCl3) δ 13.6, 21.7,
29.8, 34.7, 50.6, 54.8, 67.5, 73.4, 126.1, 128.1, 128.2, 128.8, 129.8, 138.6,
141.6, 142.4, 212.2. HRMS calcd for C21H28NO3S (M þ H) 374.1790,
found 374.1786.
(SS,2S,3R)-(þ)-N-(4-p-Toluenesulfinyl)-4-amino-3-methyl-
4-phenylbutan-2-one (20a):
Typical Procedure In a Schlenk tube equipped with a magnetic
stirring bar, rubber septum, and argon inlet was placed a solution of
compound (þ)-2a (0.014 g, 0.0389 mmol) in THF (2 mL) at rt. The
solution was cooled to 0 °C, MeMgBr (0.389 mmol, 0.13 mL of 3.0 M in
THF) was added dropwise, and the reaction mixture was stirred at 0 °C
for 10 min and warmed to rt. After 1 h the solution was cooled to ꢀ78 °C
and quenched by dropwise addition of satd aqueous NH4Cl (1 mL). The
mixture was warmed to rt then diluted with H2O (1 mL), and the
aqueous phase was extracted with EtOAc (3 ꢁ 3 mL). The combined
organic phases were washed with brine (5 mL), dried (MgSO4), and
concentrated. Chromatography (EtOAc:n-hexane, 50:50) gave 0.011 g
(90%) of a clear oil: [R]25 þ125.9 (c 2.73, CHCl3); IR (thin film)
D
2404, 1525, 1428, 1217 cmꢀ1; 1H NMR (CDCl3) δ 0.95 (d, J = 7.2 Hz,
3H), 1.98 (s, 3H), 2.34 (s, 3H), 2.90 (m, 1H), 4.46 (dd, J = 5.2, 7.6 Hz,
1H), 4.98 (d, J = 5.6 Hz), 7.26 (m, 3H), 7.35 (m, 4H), 7.45 (m, 2H); 13C
NMR (CDCl3) δ 15.3, 21.7, 29.8, 53.4, 60.9, 125.8, 128.2, 128.4, 129.0,
129.1, 129.9, 130.0, 140.0, 141.7, 142.5, 212.2. HRMS calcd for
C18H22NO2S (M þ H) 316.1371, found 316.1365.
N-[(Ss,3S,4S)-(þ)-1-(Benzyloxy)-4-methyl-5-oxononan-3-yl]-
(Ss,2S,3R)-(þ)-2-Methyl-3-(4-methylphenylsulfinamido)-
1-butyl-3-phenyl-3-phenylpropan-1-one (20b). Chromatogra-
4-methylbenzenesulfinamide (22b). Chromatography (EtOAc:n-
hexane, 50:50) gave 40% of a clear oil: [R]25 þ68.5 (c 1.25, CHCl3);
D
1
phy (EtOAc:n-hexane, 50:50) gave (0.011 g) 38% of a clear oil: [R]25
IR (thin film) 3365, 2919, 2852, 1708, 1449, 1049 cmꢀ1; H NMR
D
þ109 (c 0.5, CHCl3); IR (thin film) 3190, 2958, 2931, 2872, 1709,
1452 cmꢀ1; 1H NMR (CDCl3) δ 0.8 (t, J = 7.2 Hz, 3H), 1.06 (d, J = 7.2
Hz, 3H), 1.15 (m, 2H), 1.38 (m, 2H), 2.12 (dt, J1 = 7.2 Hz, J2 = 17.2 Hz,
1H), 2.27 (dt, J1 = 7.2 Hz, J2 = 17.2 Hz, 1H), 2.41 (s, 3H), 2.98 (m, 1H),
(CDCl3) δ 0.86 (t, J = 7.2 Hz, 3H), 1.07 (d, J = 7.2 Hz, 3H), 1.22 (m,
2H), 1.43 (m, 2H), 1.81 (m, 2H), 2.31 (m, 2H), 2.41 (s, 3H), 2.71 (m, 1H),
3.57 (m, 1H), 3.64 (m, 2H), 4.5 (s, 2H), 5.07 (d, J = 8.8 Hz, 1H), 7.26 (m, 3
overlapping H), 7.33 (m, 4H), 7.53 (d, J = 8.0 Hz, 2H); 13C NMR(CDCl3)
3336
dx.doi.org/10.1021/jo2002352 |J. Org. Chem. 2011, 76, 3329–3337

The Journal of Organic Chemistry
ARTICLE
δ 14.0, 14.2, 21.7, 22.6, 25.9, 34.9, 42.4, 49.6, 54.9, 67.5, 73.4, 125.8, 126.1,
128.0, 128.1, 128.2, 128.6, 128.7, 129.8, 138.6, 141.5, 141.6, 142.5, 214.7.
HRMS calcd for C24H34NO3S (M þ H) 416.2259, found 416.2259.
(SS,2S,3R)-(þ)-3-Amino-N,2-dimethyl-3-(4-methylphenyl-
sulfinamido)- 3-phenylpropanamide (23a). Chromatography
Chem. 2000, 1569. (c) Davies, S G.; Walters, I. A. S. J. Chem. Soc., Perkin
Trans. I 1994, 1129.
(8) (a) (Naphthalene-Na):Closson, W. D.; Ji, S.; Schulenberg, S.
J. Am. Chem. Soc. 1970, 92, 650. (b) (HOAc-HBr): Roemmele, R. C.;
Rapoport, H. J. Org. Chem. 1988, 53, 2367. (c) (SmI2): Vedejs, E.; Lin, S.
J. Org. Chem. 1994, 59, 1602. (d) (Na-liq NH3): Magnus, P.; Coldham, I.
J. Am. Chem. Soc. 1991, 113, 672. (e) (MeOH-Mg): Kumar, V.; Ramesh,
N. G. Tetrahedron 2006, 62, 1877. (f) (Na/NH3): Davis, F. A.;
Ramachandar, T.; Liu, H. Org. Lett. 2004, 6, 3393.
(9) For leading references to the asymmetric synthesis of anti-R-
alkyl β-amino esters, see: Davis, F. A.; Qiu, H.; Song, M.; Gaddiraju,
N. V. J. Org. Chem. 2009, 74, 2798.
(10) McNeil, A.; Toombes, G. E. S.; Chandramouli, S. V.; Vanasse,
B. J.; Ayers, T. A.; O’Brein, M. K.; Lobkovsky, E.; Gruner, S. M.; Marohn,
J. A.; Collum, D. B. J. Am. Chem. Soc. 2004, 126, 5938.
(11) Gardiner, J.; Anderson, K. H.; Downard, A.; Abell, A. D. J. Org.
Chem. 2004, 69, 3375.
(12) For reviews on cyclic β-amino acids see: (a) Fulop, F. Chem.
Rev. 2001, 101, 2181. (b) Miller, J. A.; Nguyen, S. T. Mini-Rev. Org.
Chem. 2005, 2, 39.(c) Reference 1.
(EtOAc:n-hexane, 50:50) gave 24% of a clear oil; [R]25 þ153.4 (c
D
1
0.5, CHCl3); IR 3293, 2920, 1651, 1556 cmꢀ1; H NMR (CDCl3) δ
1.18 (d, J = 7.2 Hz, 3H), 2.40 (s, 3H), 2.51 (m, 1H), 2.63 (d, J = 5.2 Hz,
3H), 4.46 (t, J = 5.6 Hz, 1H), 5.29 (br s, 1H), 5.82 (d, J = 5.6 Hz, 1H),
7.32 (m, 7H), 7.56 (m, 2H); 13C NMR (CDCl3) δ 16.7, 21.7, 26.5, 47.9,
61.8, 125.9, 127.5, 127.7, 128.1, 128.9, 129.8, 141.5, 141.8, 142.7, 174.9.
HRMS calcd for C18H23N2O2S (M þ H) 353.1300, found 353.1302.
(SS,2S,3S)-(þ)-N,2-Dimethyl-3-(4-methylphenylsulfina-
mido)-5-benzyloxypentanamide (19). Chromatography (EtOAc:
n-hexane, 50:50) gave 30% of a clear oil; [R]25D þ47.7 (c 0.3, CHCl3); IR
3296, 2918, 2850, 1666, 1454 cmꢀ1; 1H NMR (CDCl3) δ 1.14 (d, J = 6.8
Hz, 3H), 1.95 (m, 1H), 2.09 (m, 1H), 2.40 (s, 3H), 2.49 (m, 1H), 3.23 (s,
3H), 3.40 (m, 1H), 3.62 (m, 2H), 4.51 (m, 2H), 5.29 (d, J = 8.8 Hz, 1H),
6.46 (br s, 1H), 7.31 (m, 7H), 7.55 (m, 2H); 13C NMR (CDCl3) δ 15.9,
21.7, 30.1, 36.3, 44.0, 56.7, 68.2, 71.5, 73.7, 126.2, 128.3, 128.8, 128.9,
129.8, 138.2, 141.5, 142.2, 175.9. HRMS calcd for C21H28N2O3S (Mþ)
388.1821, found 388.1821.
(13) (a) Graham, S. L.; Scholz, T. H. Tetrahedron Lett. 1990,
31, 6269. (b) Graham, S. L.; Scholz, T. H. J. Org. Chem. 1991, 56, 4260.
(14) See also: Keck, G. E.; McHardy, S. F.; Murry, J. A. Tetrahedron
Lett. 1993, 34, 6215.
(15) For an excellent study and leading references on the mechanism
of acylation of lithium reagents with Weinreb amides see: Qu, B.;
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(16) Beak, P.; Selling, G. W. J. Org. Chem. 1989, 54, 5574.
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’ ASSOCIATED CONTENT
S
Supporting Information. Experimental general proce-
b
dures and spectroscopic data, H and 13C NMR, for all new
1
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
’ AUTHOR INFORMATION
Corresponding Author
*E-mail: fdavis@temple.edu.
’ ACKNOWLEDGMENT
We thank Paul Willard, Brown University, for helpful discus-
sions. This research was supported in part by the National
Institutes of General Medicinal Sciences (GM 57870).
’ REFERENCES
(1) For leading references see: Davis, F. A.; Theddu, N. J. Org. Chem.
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3337
dx.doi.org/10.1021/jo2002352 |J. Org. Chem. 2011, 76, 3329–3337