Asymmetric synthesis of β-amino carbonyl compounds with N-sulfinyl β-amino Weinreb amides

Article abstract of DOI:10.1021/jo0402780

(Chemical Equation Presented) Diverse organometallic reagents readily add to enantiopure N-sulfinyl β-amino Weinreb amides providing the corresponding, stable, N-sulfinyl β-amino carbonyl compounds in good to excellent yields. This new methodology represe

Full text of DOI:10.1021/jo0402780

Asymmetric Synthesis of â-Amino Carbonyl Compounds with
N-Sulfinyl â-Amino Weinreb Amides
Franklin A. Davis,* M. Brad Nolt, Yongzhong Wu, Kavirayani R. Prasad,† Danyang Li,
Bin Yang, Kerisha Bowen, Seung H. Lee, and John H. Eardley
Department of Chemistry, Temple University, Philadelphia, Pennsylvania 19122
fdavis@temple.edu
Received October 29, 2004
Diverse organometallic reagents readily add to enantiopure N-sulfinyl â-amino Weinreb amides
providing the corresponding, stable, N-sulfinyl â-amino carbonyl compounds in good to excellent
yields. This new methodology represents a general solution to the problem of â-amino carbonyl
syntheses, which are important chiral building blocks and constituents of natural products.
N-Sulfinyl â-amino Weinreb amides are prepared by reaction of the potassium enolate of N-methoxy
N-methylacetamide with sulfinimines (N-sulfinyl imines) or lithium N,O-dimethylhydroxylamine
with N-sulfinyl â-amino esters.
Introduction
protected, are unstable and undergo self-condensation or
â-elimination of the amino group.9 Indeed there are only
a few methods for the asymmetric synthesis of stable
â-amino aldehydes and ketones and most of these pro-
cedures are target specific.6,8-11 In this paper we report
full details of a general method for the asymmetric
synthesis of diverse â-amino aldehydes and ketones from
sulfinimine-derived N-sulfinyl â-amino Weinreb amides.6
Nonracemic â-amino carbonyl compounds are valuable
chiral building blocks for the asymmetric syntheses of
biorelevant nitrogen-containing molecules.1,2 For ex-
ample, â-amino carbonyls are precursors of â-amino
acids3 and 1,3-amino alcohols4-6 and are also found in
natural products3 and other pharmacologically active
compounds. Mannich-type reactions, the aminoalkylation
of CH-acidic compounds, represent the most direct method
for the preparation of â-amino carbonyl compounds;2,7
however, to date this methodology has found limited
success in the asymmetric synthesis of diversely substi-
tuted â-amino aldehydes and ketones.8 The reason is
â-amino aldehydes and ketones, unless suitably N-
Results and Discussion
â-Amino Weinreb Amides from Sulfinimines. Wein-
reb amides, introduced by Nahm and Weinreb in 1981,12
(8) For a review on the catalytic asymmetric Mannich reaction see:
Cordova, A. Acc. Chem. Res. 2004, 37, 102.
† Present address: Department of Organic Chemistry, Indian
Institute of Science, Bangalore 560 012, India.
(1) (a) Tramontini, M. Synthesis 1973, 703. (b) Tramontini, M.;
Angiolini, L. Tetrahedron 1990, 46, 1791. (c) Kleinman, E. F. In
Comprehensive Organic Synthesis; Heathcock, C. H., Ed.; Pergamon
Press: Oxford, UK, 1991; Vol. 2, Chapter 4, p 893.
(2) Arend, M.; Westermann, B.; Risch, N. Angew. Chem., Int. Ed.
1998, 37, 1044.
(9) Toujas, J.-L.; Jost, E.; Vaultier, M. Bull. Soc. Chem. Fr. 1997,
134, 713.
(10) Davis, F. A.; Yang, B. Org. Lett. 2003, 5, 5011.
(11) Asymmetric syntheses of â-amino aldehydes and ketones: (a)
reduction of â-amino esters, or nitriles: refs 5 and 9 of this article
and: Davis, F. A.; Szewczyk J. M. Tetrahedron Lett. 1998, 39, 5951.
(b) Addition of methyl ketone enolates to sulfinimines, see ref 10. (c)
Oxidation of γ-amino alcohols, see: Davies, S. B.; McKervey, M. A.
Tetrahedron Lett. 1999, 40, 1229. (d) Arndt-Eistert reaction: (i)
Rodriguez, M.; Aumelas, A.; Martinez, J. Tetrahedron Lett. 1990, 31,
5153. (ii) Rodriguez, M.; Heitz, A.; Martinez, J. Tetrahedron Lett. 1990,
31, 7319. (iii) Limal, D.; Quesnel, A.; Briand, J.-P. Tetrahedron Lett.
1998, 39, 4239. (e) Hydrolysis of 1,3-oxazines, see: Gizecki, P.; Dhal,
R.; Toupet, L.; Dujardin, G. Org. Lett. 2000, 2, 585. (f) Rearrangement
of 2,3-aziridinio alcohols, see: Wang, B. M.; Song, Z. L.; Fan, C. A.;
Tu, Y. Q.; Shi, Y. Org. Lett. 2002, 4, 363.
(3) For recent reviews on the asymmetric synthesis of â-amino acids
see: (a) Liu, M.; Sibi, M. P. Tetrahedron 2002, 58, 7991. (b) Cole, D.
C. Tetrahedron 1994, 50, 9517.
(4) For a review see: Bates, R. W.; Sa-Ei, K. Tetrahedron 2002, 58,
5957.
(5) Jefford, C. W.; Wang, J. B. Tetrahedron Lett. 1993, 34, 2911.
(6) Davis, F. A.; Prasad, K. R.; Nolt, M. B.; Wu, Y. Org. Lett. 2003,
5, 925.
(7) For leading references see: Ishimaru, K.; Kojima, T. J. Org.
Chem. 2000, 65, 8395.
(12) Nahm, S.; Weinreb, S. M. Tetrahedron Lett. 1981, 22, 3815.
10.1021/jo0402780 CCC: $30.25 © 2005 American Chemical Society
Published on Web 02/12/2005
2184
J. Org. Chem. 2005, 70, 2184-2190

Synthesis of â-Amino Carbonyl Compounds
TABLE 1. Synthesis of â-Amino Weinreb Amides 3 and 4 from Sulfinimines and N-Methoxy-N-methylacetamide at -78
°C
sulfinimine
entry
R1
R2
base (solvent)
Weinreb amide
dr (% de)a
% yieldc
65d
1
2
1a
p-tolyl
Ph
LiHMDS (THF)
NaHMDS (THF)
KHMDS (THF)
KHMDS (PhMe)
KHMDS (Et2O)
KHMDS (THF)
KHMDS (THF)
KHMDS (THF)
KHMDS (THF)
KHMDS (THF)
KHMDS (THF)
KHMDS (THF)
KHMDS (THF)
KHMDS (THF)
(+)-3a
79:21 (58)b
82:18 (64)
85:15 (70)
51:49 (2)
54:46 (8)
77:23 (54)e
92:8 (84)
99:1 (98)
99:1 (98)
99:1 (98)
99:1 (98)
52:48 (4)e
86:14 (72)e
88:12 (76)e
3
4
5
6
1b
1c
1d
1e
1f
1g
2a
2d
2e
p-tolyl
p-tolyl
p-tolyl
p-tolyl
p-tolyl
p-tolyl
t-Bu
p-CF3Ph
Me
(+)-3b
(+)-3c
(+)-3d
(+)-3e
(+)-3f
(+)-3g
(+)-4a
(+)-4d
(+)-4e
7
52
68
68
76
82
8
n-Pr
t-Bu
9
10
11
12
13
14
Cl-(CH2)4-
E-MeCHdCH-
Ph
t-Bu
t-Bu
n-Pr
t-Bu
1
a Determined by H NMR of the crude reaction mixture unless otherwise noted. b Estimated by isolation of the two diastereoisomers.
c Isolated yield of major diastereoisomer. d Isolated by fractional crystallization. e Inseparable mixture of diastereoisomers.
SCHEME 1
As summarized in the table N-(p-toluenesulfinyl) imi-
nes (S)-(+)-1 gave better yields and higher diastereose-
lectivities than the corresponding N-(tert-butylsulfinyl)
imines (S)-(+)-2 (compare entries 3, 6-11 with 12-14
in Table 1). Indeed the diastereomeric Weinreb amides
4, derived from the latter sulfinimine, could not be
separated by chromatography. For (S)-(+)-1, the best
yields and highest diastereoselectivities of 3 were ob-
served for the potassium enolate of N-methoxy-N-me-
thylacetamide in THF. With three exceptions, the dias-
tereoselectivities for (SS,R)-3 were better than 98%. The
exceptions were sulfinimines (S)-(+)-1a (R2 ) Ph), (S)-
(+)-1b (R2 ) p-CF3Ph), and 1c (R2 ) Me), where the
maximum de values for 3a, 3b, and 3c were 70%, 54%,
and 84%, respectively (Table 1, entries 3, 6, and 7).
Crystallization and chromatography were employed to
isolate the pure diastereoisomers (SS,R)-3a and (SS,R)-
(+)-3c in 65% and 52% yields, but the isomers of 3b were
inseparable.
The absolute stereochemistry of the major diastereo-
isomers for enolate additions to sulfinimines (S)-1 and
(S)-2 was determined to be R by independent syntheses
(see below). The addition of organometallic reagents to
the C-N double bond of sulfinimines generally can be
predicted by assuming six-membered chairlike transition
states where the metal ion, usually Li+, Na+, or Zn2+, is
coordinated to the sulfinyl oxygen.15 The results obtained
here are in agreement with this chelation-control transi-
tion-state hypothesis. However, the fact that the potas-
sium enolate of N-methoxy-N-methylacetamide gave
better diastereoselectivities than either the lithium or
sodium enolates was not anticipated (Table 1: entries
1-3) because potassium ions are generally thought to be
poorer coordinating ions than lithium or sodium.
are important carbonyl equivalents and have found many
applications in the synthesis of carbonyl compounds.13
While â-amino Weinreb amides have been reported, there
are only a few applications that use them, either because
of difficult syntheses or problems in the removal of the
N-substitutents.14 Here, however, we have found that
addition of the enolate of commercially available N-
methoxy-N-methylacetamide to sulfinimines affords the
corresponding N-sulfinyl â-amino Weinreb amides in
good yield and excellent diastereoselectivity (Scheme 1).15
The synthesis of the Weinreb amides 3 and 4 was ac-
complished by addition of sulfinimine (S)-(+)-1 (R1 ) p-
tolyl) or (S)-(+)-2 (R1 ) t-Bu) to 1.5 equiv of the preformed
enolate of N-methoxy-N-methylacetamide at -78 °C
(Scheme 1). Workup consisted of quenching at this
temperature and isolation by chromatography or crystal-
lization. These results are summarized in Table 1.
(13) For an excellent review on applications of Weinreb amides
see: Sibi, M. P. Org. Prep. Proced. Int. 1993, 25, 15.
â-Amino Weinreb Amides from â-Amino Esters.
N-Sulfinyl â-amino Weinreb amides 3 can also be pre-
pared in good yield by treating methyl N-sulfinyl â-amino
carboxylates (SS,R)-5 with 5 equiv of lithium N,O-
dimethylhydroxyamine (Table 2, Scheme 2). Fewer equiva-
lents of LiN(OMe)Me resulted in incomplete reaction.
Because the amino stereocenter in 3 is not affected by
this transformation, it serves to establish the absolute
stereochemistry of 3 as R. The fact that the addition of
potassium N-methoxy-N-methylacetamide to sulfinimine
(14) (a) Burke, A. J.; Davies, S. G.; Garner, A. C.; McCarthy, T. D.;
Roberts, P. M.; Smith, A. D.; Rodrigues-Solla, H.; Vickers, R. J. Org.
Biomol. Chem. 2004, 2, 1387. (b) Davies, S. G.; Iwamoto, K.; Smethurst,
C. A. P.; Smith, A. D.; Rodrigues-Solla, H. Synlett 2002, 1146. (c)
Davies, S. G.; McCarthy, T. D. Synlett. 1995, 700. (d) Reference 11d of
this article.
(15) For reviews on the chemistry of sulfinimines see: (a) Zhou, P.;
Chen, B.-C.; Davis, F. A. In Advances in Sulfur Chemistry; Rayner, C.
M., Ed.; JAI Press: Stamford, CT, 2000; Vol. 2, pp 249-282. (b) Davis,
F. A.; Zhou, P.; Chen, B.-C. Chem. Soc. Rev. 1998, 27, 13. (c) Ellman,
J. A.; Owens, T. D.; Tang, T. P. Acc. Chem. Res. 2002, 35, 984. (d)
Zhou, P.; Chen, B.-C.; Davis, F. A. Tetrahedron 2004, 60, 8003.
J. Org. Chem, Vol. 70, No. 6, 2005 2185

Davis et al.
TABLE 2. Synthesis of â-Amino Weinreb Amides from
N-Sulfinyl â-Amino Methyl Esters and Lithium
N,O-Dimethylhydroxyamine at -78 °C in THF
â-amino ester
equiv of
Weinreb % isolated
entry
R1
R2
LiN-(OMe)Me amide
yield
1
2
3
4
5
6
7
5a p-tolyl Ph
5
3
5
5
5
5
5
3a
78
61
54
66
68
82
79
5b p-tolyl p-CF3Ph
5c p-tolyl Me
3b
3c
3e
3g
4a
5e p-tolyl t-Bu
5g p-tolyl E-MeCHdCH-
6
t-Bu Ph
SCHEME 2
FIGURE 1. Reactions of N-sulfinyl Weinreb amides with
organometallic reagents.
but 1-propynylmagnesium bromide and 3a (R1 ) Ph) re-
quired more than 12 h and warming to room temperature
to give alkynyl ketone 11 in 72% and 95% yield (Table 3,
entries 8 and 9). All attempts to treat 3a with the lithium
enolate of methyl acetate to prepare N-sulfinyl δ-amino
â-ketoester 12, an important chiral building block for pi-
peridine18 and pyrrolidine alkaloid synthesis,19 were un-
successful (Table 3: entry 11). On the other hand, lithium
dimethyl methyl phosphonate with 3a (R1 ) Ph) gave
N-sulfinyl δ-amino â-ketophosphonate 13 in 88% yield
(Table 3: entry 13).20 This new sulfinimine-derived chiral
building block has been recently employed in the asym-
metric syntheses of 4-aminocyclopentenones, valuable
intermediates in the asymmetric construction of carbocy-
clic nucleosides,20a and cis-5-substituted pyrrolidine phos-
phonates, proline surrogates.20b
The reaction of unsaturated Weinreb amide 3g with
vinylmagnesium bromide warrants special comment. The
addition of vinyl Grignard reagents to Weinreb amides
generally results in low yields of the vinyl ketone.21 The
reason is that the Michael addition product of the
liberated N,O-dimethylhydroxylamine reacts very rapidly
with the desired vinyl ketone product producing a â-(N-
methoxy-N-methyl) aminoethyl ketone. Attempts to mini-
(S)-(+)-1a (R ) Ph) affords the R isomer provides
additional support for our chelation control-transition
state model for addition of organometallic reagents to
sulfinimines.15 Similar results were observed for the
addition of LiN(OMe)Me to the (SSR)-(+)-methyl-N-(tert-
butylsulfinyl)-3-amino-3-phenyl propanoate (6), which
afforded (SS,R)-4a in 79% isolated yield (Table 2). The
â-amino esters were prepared as previously described by
addition of the sodium enolate of methyl acetate in ether
to the sulfinimine.17
N-Sulfinyl â-Amino Aldehydes and Ketones. N-
Sulfinyl â-amino Weinreb amides 3 react with various
organometallic reagents to give good-to-excellent yields
of the corresponding N-sulfinyl â-amino aldehydes and
ketones (Figure 1, Table 3).16 Usually 5 equiv of the
organometallic reagents was found to be best for yields
and reaction times. Excess organometallic reagent may
be required because of the acidity of the sulfinyl NH
proton, which is undoubtedly first removed. With DIBAL-
H, 3a and 3e gave aldehydes 7a and 7b in 84% and 70%,
respectively (Table 3, entries 1 and 15). Methylmagne-
sium bromide with 3a, 3b, and 3f afforded the corre-
sponding methyl ketones 8a-c, respectively, in good yield
(Table 3, entries 2, 14, and 17). The reaction of the
N-(tert-butylsulfinyl) imine Weinreb amide (SS,R)-4a
reacts similarly with methylmagnesium bromide to give
ketone 16 in 81% yield (Figure 1). Phenylmagnesium
bromide with 3a and 3e gives the phenyl ketones 10a
and 10b in 84% and 88% yields (Table 3, entries 5 and
16). Generally Grignard reagents gave better yields than
lithium reagents although n-butyllithium with 3a af-
forded n-butyl ketone 9 in 88% yield (Table 3: entry 7).
Reagent additions were usually complete within 1-2 h,
(18) For references to the application of N-sulfinyl δ-amino â-keto
esters for the asymmetric synthesis of piperidine derivatives see: (a)
Davis, F. A.; Chao, B.; Fang, T.; Szewczyk, J. M. Org. Lett. 2000, 2,
1041. (b) Davis, F. A.; Chao, B. Org. Lett. 2000, 2, 2623. (c) Davis, F.
A.; Fang, T.; Chao, B.; Burns, D. M. Synthesis 2000, 2106. (d) Davis,
F. A.; Chao, B.; Rao, A. Org. Lett. 2001, 3, 3169. (e) Davis, F. A.; Zhang,
Y.; Anilkumar, G. J. Org. Chem. 2003, 68, 8061. (f) Davis, F. A.; Rao,
A.; Carroll, P. J. Org. Lett. 2003, 5, 3855.
(19) For references to the application of N-sulfinyl δ-amino â-keto
esters for the asymmetric synthesis of pyrrolidine derivatives see: (a)
Davis, F. A.; Fang, T.; Goswami, R. Org. Lett. 2002, 4, 1599. (b) Davis,
F. A.; Yang, B.; Deng, J. J. Org. Chem. 2003, 68, 5147. (c) Davis, F.
A.; Deng, J. Tetrahedron 2004, 60, 5111.
(20) (a) Davis, F. A.; Wu, Y. Org. Lett. 2004, 6, 1269. (b) Davis, F.
A.; Wu, Y.; Xu, H.; Zhang, J. Org. Lett. 2004, 6, 4523.
(16) For a preliminary account of this work see ref 6 of this article.
(17) Davis, F. A.; Reddy, R. E.; Szewczyk, J. M. J. Org. Chem. 1995,
60, 7037.
2186 J. Org. Chem., Vol. 70, No. 6, 2005

Synthesis of â-Amino Carbonyl Compounds
TABLE 3. Synthesis of N-Sulfinyl â-Amino Aldehyde and Ketones from â-Amino Weinreb Amides and Organometallic
Reagents
Weinreb
conditions:
â-amino
% isolated
yield (R3)
entry
amide (R2)
R3 (equiv)
DiBAL-H (5)
MeMgBr (5)
MeMgBr (3)
MeLi (5)
PhMgBr (5)
PhLi (5)
n-BuLi (8)
MeCtCMgBr (5.0)
MeCtCMgBr (5.0)
PhC(O)Me
CH3CO2Me
CH3P(O)(OMe)2 (2.0)
- (2.0)
solvent, h, °C
carbonyl compd
1
2
Ph
3a
THF, 1.0, -78
THF, 2.5, -78 to rt
THF, 2.5, -78 to rt
7a
8a
8a
8a
10a
84 (H)
92 (Me)
3
67 (Me)
4
60 (Me)
5
THF, 2.5, -78 to rt
THF, 1.0, 78 to rt
THF, 0.5, -78
84 (Ph)
6
49 (Ph)
7
9
88 (n-Bu)
72 (MeC≡C)
95 (MeC≡C)
8
THF, 2.5, -78 to rt
THF, 12, -78 to rt
LDA
11
11
NR
13
NR
14
8b
7b
10b
8c
14
15
14
16
9
10
11
12
13
14
15
16
17
18
LHMDS
0
LHMDS, THF, 3, -78
n-BuLi, THF, 2, -78
THF, 2.5, -78 to rt
THF, 2, -78
88 (CH2P(O)(OMe)2
63 (Me)
p-CF3Ph
t-Bu
3b
3e
MeMgBr (5)
DIBAL-H (5)
PhMgCl (5)
MeMgBr (5)
CH2dCHMgBr (10)
70 (H)
THF, 2,5 h, -78 to rt
THF, 0.5, -78 to rt
THF, 0.5, 0a
88 (Ph)
Cl-(CH4)4-
E-MeCHdCH-
3f
3g
77 (Me)
29 (CH2dCH-)
43 (CH2dCH-)
56 (CH2dCH-)
81 (Me)
THF, 0.5, 0a
19
20
THF, 0.5, 0b
Ph
4a
MeMgBr (5)
THF, 3, -78 to rt
a Quenched by addition of aqueous saturated NH4Cl to the reaction mixture. b Quenched by addition of the reaction mixture to 5:1
H2O:AcOH.
mize this side product have not been successful. Indeed
when we used our normal quenching procedure with
aqueous saturated NH4Cl, â-amino vinyl ketone 14 was
isolated in only 29% yield and the major product was the
Michael addition product 15, which was obtained in 43%
yield (Figure 1, Table 3, entry 18). However, quenching
with 5:1 H2O:AcOH resulted in isolation of the vinyl
ketone 14 in 56% yield (Table 3, entry 18). The fact that
the Michael addition product 15 was not detected when
the reaction was quenched with acetic acid likely results
from the reduced nucleophilicity of the N,O-dimethylhy-
droxylamine under these conditions.22
All of the Weinreb amide derived N-sulfinyl â-amino
aldehydes and ketones (Figure 1) were stable compounds
and could be stored for long periods of time. These results
further confirm the unique nitrogen protecting-group
abilities of the sulfinyl group.15 The N-sulfinyl group can
be oxidized with m-CPBA to the N-tosyl nitrogen protect-
ing group6 or removed with acid and the products used
to prepare polysubstituted piperidines and indoliz-
idines.10
In conclusion, new and general methodology has been
introduced for the asymmetric synthesis of N-sulfinyl
â-amino Weinreb amides by addition of the potassium
enolate of N-methoxy-N-methylacetamide to sulfinimines
or by treating N-sulfinyl â-amino esters with lithium
N,O-dimethylhydroxyamine. In the former reaction, N-p-
toluenesulfinyl imines 1 gave better yields and diaster-
eoselectivities when compared to N-tert-butylsulfinyl
imines 2 with the same substituents. Various organo-
metallic reagents readily react with N-sulfinyl â-amino
Weinreb amides to give good to excellent yields of
â-amino aldehydes and ketones, which are valuable chiral
building blocks for the asymmetric syntheses of biorel-
evant nitrogen-containing compounds.
Experimental Section
The preparation of sulfinimines (S)-(+)-N-(benzylidene)-p-
toluenesulfinamide (1a),23 (S)-(+)-N-(p-trifluoromethylben-
zylidene)-p-toluenesulfinamide (1b),24 (S)-(+)-N-(acetylidene)-
p-toluenesulfinamide (1c),23 (S)-(+)-N-(butylidene)-p-tolu-
enesulfinamide (1d),23 (S)-(+)-N-(2,2-dimethylpropylidene)-p-
toluenesulfinamide (1e),23 (S)-(+)-N-(pentylidine)-5-chloro-p-
toluenesulfinamide (1f),6 (S)-(+)-N-(crotonylidene)-p-toluene-
sulfinamide (1g),23 (S)-(+)-N-(benzylidene)-2-methylpropane-
sulfinamide (2a),25and (S)-(+)-N-(2,2-dimethylpropylidene)-2-
methylpropanesulfinamide (2e);25 and Weinreb amides (SS,3R)-
(+)-N-(p-toluenesulfinyl)-3-amino N-methoxy-N-methyl-3-phen-
ylpropionamide (3a)6 and (SS,3S)-(+)-7-chloro-N-(p-toluene-
sulfinyl)-3-amino-N-methoxy-N-methylheptanoamide (3f);6
â-amino esters (SS,R)-(+)-methyl N-(p-toluenesulfinyl)-3-amino-
3-phenylpropanoate (5a),26 (SS,R)-(+)-methyl N-(p-toluene-
sulfinyl)-3-amino-3-tert-butylpropanoate (5e),19b (SS,R)-(+)-
methyl N-(p-toluenesulfinyl)-3-amino-3-(E)-propenylpropanoate
(5g),11a (SS,R)-(-)-methyl N-(2-methylpropanesulfinyl)-3-amino-
3-phenylpropanoate (6),27 (SS,3R)-(+)-N-(p-toluenesulfinyl)-3-
amino-3-phenylpropionaldehyde (7a),6 (SS,3R)-(+)-N-(p-tolu-
enesulfinyl)-3-amino-1-methyl-3-phenylpropan-1-one (8a),6
(SS,3R)-(+)-N-(p-toluenesulfinyl)-3-amino-1-(n-butyl)-3-phenyl-
propan-1-one (9),10 and (SS,3R)-(+)-N-(p-toluenesulfinyl)-3-
amino-1,3-diphenylpropan-1-one (10a)6 were prepared accord-
ing to literature procedures.
(S)-(+)-N-(Butylidene)-2-methylpropanesulfinamide
(2d). In a two-neck, 100-mL, round-bottom flask equipped with
a magnetic stirring bar, rubber septum, and argon inlet was
(23) Davis, F. A.; Zhang, Y.; Andemichael, Y.; Fang, T.; Fanelli, D.;
Zhang, H. J. Org. Chem. 1999, 64, 1403.
(21) (a) Wuts, P. G. M.; Putt, S. R.; Ritter, A. R. J. Org. Chem. 1988,
53, 4503. (b) Gomtsyan, A.; Koenig, R. J.; Lee, C.-H. J. Org. Chem.
2001, 66, 3613. (c) Hong, J. H.; Shim, M. J.; Ro, B. O.; Ko, K. H. J.
Org. Chem. 2002, 67, 6837. (d) Kulesza, A.; Ebetino, F. H.; Mazur, A.
W. Tetrahedron Lett. 2003, 44, 5511.
(22) Jackson, M. M.; Leverett, C.; Toczko, J. F.; Roberts, J. C. J.
Org. Chem. 2002, 67, 5032.
(24) Davis, F. A.; Liu, H.; Zhou, P.; Fang, T.; Reddy, G. V.; Zhang,
Y. J. Org. Chem. 1999, 64, 7559.
(25) Liu, G.; Cogan, D. A.; Owens, T. D.; Tang, T. P.; Ellman, J. J.
Org. Chem. 1999, 64, 1278.
(26) Davis, F. A.; Reddy, R. E.; Szewczyk, J. M. J. Org. Chem. 1995,
60, 7037.
(27) Davis, F. A.; Szewczyk, J. M. Tetrahedron Lett. 1998, 39, 5951.
J. Org. Chem, Vol. 70, No. 6, 2005 2187

Davis et al.
placed n-butylaldehyde (0.22 mL, 2.5 mmol), Ti(OEt)4 (0.63
mL, 3.0 mmol), and (S)-(-)-tert-butylsulfinamide (0.121 g, 1.00
mmol) in DCM (10 mL). After the reaction mixturewas stirred
for 3 h it was cooled to 0 °C, brine (1 mL) was added, and the
solution was stirred vigorously for 10 min. At this time the
solution was filtered through packed Celite and rinsed with
DCM (2 × 10 mL). The filtrate was extracted with Et2O (3 ×
10 mL), washed with brine (5 mL), dried (MgSO4), and
concentrated. Chromatography (EtOAc/n-hexanes, 1:1) gave
(0.070 g, 0.22 mmol) in ether (5 mL) was added via cannula.
After being stirred at this temperature for 4 h, the reaction
mixture was quenched by addition of saturated aqueous NH4-
Cl solution (1 mL) and warmed to room temperature and H2O
(5 mL) was added. The solution was extracted with EtOAc (3
× 10 mL), and the combined organic phases were washed with
brine (5 mL), dried (Na2SO4), and concentrated. Flash chro-
matography (EtOAc/n-hexanes, 2:5) afforded 0.060 g (73%) of
a slightly yellow oil: [R]20 60 (c 3.8, CHCl3); IR (neat) 3189,
D
0.191 g (100%) of a clear oil; [R]25 122.3 (c 0.5, CHCl3); IR
2955, 1739, 1327; 1H NMR (CDCl3) δ 2.41 (s, 3 H), 2.85-2.86
(m, 2 H), 3.59 (s, 3 H), 4.91 (dd, J ) 12.0, 12.5 Hz, 1 H), 5.26
(d, J ) 6.0 Hz, 1 H), 7.29-7.31 (m, 2 H), 7.53-7.63 (m, 6 H);
13C NMR (CDCl3) δ 21.4, 41.7, 52.0, 54.2, 76.7, 77.1, 77.5, 125.4,
125.7, 125.80, 125.85, 127.6, 129.7, 141.7, 144.7, 170.9. HRMS
calcd for C18H18NO3F3SNa (M + Na) 408.0856, found 408.0857.
D
1
2960; H NMR (CDCl3) δ 8.04 (t, J ) 5.0 Hz, 1 H), 2.50-2.46
(m, 2 H), 1.64 (sextet, J ) 7.5 Hz, 2 H), 1.17 (s, 9 H), 0.97 (t,
J ) 7.0 Hz, 3 H); 13C NMR (CDCl3) δ 14.2, 19.4, 22.7, 38.5,
56.9, 170.2. HRMS calcd for C8H17NOS (M + H) 176.1109,
found 176.1106.
General Procedure for the Synthesis of N-Methoxy-
N-methylAcetamide(N-sulfinylWeinrebamides): (SS,3S)-
(+)-N-(p-Toluenesulfinyl)-3-amino-N-methoxy- N-meth-
ylbutanoamide (3c). In an oven-dried, 25-mL, one-neck,
round-bottom flask equipped with a magnetic stirring bar and
argon balloon was placed KHMDS (0.43 mmol, 0.86 mL of 0.5
M solution in toluene) in ether (5 mL). The solution was cooled
to -78 °C and N-methoxy-N-methyl acetamide (0.043 mL, 0.40
mmol, Aldrich) was added, and the solution was stirred at this
temperature for 1 h. At this time a solution of (+)-1c (0.049 g,
0.27 mmol) in ether (2 mL) was added and the reaction mixture
was stirred for 2 h and then quenched at -78 °C by addition
of saturated aqueous NH4Cl (2 mL). After warming to room
temperature the solution was poured into H2O (2 mL) and
extracted with EtOAc (3 × 5 mL). The combined organic
phases were washed with brine (2 mL), dried (Na2SO4), and
concentrated. Chromatography (EtOAc/n-hexanes, 1:1) gave
0.148 g (52%) of a clear, viscous oil. The physical properties
are identical with those of (+)-3c, prepared from the â-amino
ester (+)-5c (see below).
(SS,3S)-(+)-N-(p-Toluenesulfinyl)-3-amino-N-methoxy-
N-methylhexanoamide (3d). Chromatography (1:1, EtOAc/
n-hexanes) gave 68% of a clear viscous oil (96:4 ratio of
inseparable diastereomers); [R]20D 116.7 (c 2.6, CHCl3, 92% de);
IR (neat) 3231, 2958, 1652; major diastereomer 1H NMR
(CDCl3) δ 0.94 (t, J ) 7.5 Hz, 3 H), 1.40-1.44 (m, 1 H), 1.47-
1.54 (m, 1 H), 1.58-1.12 (m, 1 H), 1.68-1.73 (m, 1 H), 2.39 (s,
3 H), 2.77 (s, 2 H), 3.15, (s, 3 H), 3.65 (s, 3 H), 3.69-3.72 (m,
1 H), 4.94 (d, J ) 8.5 Hz, 1 H), 7.28 (d, J ) 8.0 Hz, 2 H), 7.58
(d, J ) 7.5 Hz, 2 H); major diastereomer 13C NMR (CDCl3) δ
14.2, 19.9, 21.7, 32.2, 37.9, 38.3, 53.4, 61.6, 125.7, 129.8, 141.4,
143.2, 172.7. HRMS calcd for C15H24N2O3SNa (M + Na)
335.1412, found 335.1405.
(SS,3S)-(+)-Methyl N-(p-toluenesulfinyl)-3-aminobu-
tanoate (5c). Chromatography (EtOAc/n-hexanes, 1:1) gave
0.184 g (72%) of a clear oil which solidified upon standing at
-20 °C; [R]25 131.3 (c 2.4, CHCl3); IR (CHCl3) 3208, 2951,
D
1
1733; H NMR (CDCl3) δ 1.37 (d, J ) 6.5 Hz, 3 H), 2.40 (s, 3
H), 2.53 (m, 2H), 3.64 (s, 3 H), 3.80-3.75 (m, 1 H), 4.63 (d, J
) 7.5 Hz, 1 H), 7.30 (d, J ) 5.0 Hz, 2 H), 7.56 (d, J ) 8.0 Hz,
2 H); 13C NMR (CDCl3) δ 21.7, 22.8, 42.5, 47.5, 52.1, 126.1,
129.9, 141.7, 142.2, 172.1. HRMS calcd for C12H17NO2SNa (M
+ Na) 278.0827, found 278.0827.
General Procedure for the Synthesis of â-Amino
Weinreb Amides from N-Sulfinyl â-Amino Esters: (SS,3R)-
(+)-N-(p-Toluenesulfinyl)-3-amino-N-methoxy-N-methyl-
3-tert-butylpropionamide (3e). In an oven-dried, 50-mL,
round-bottom flask equipped with a magnetic stirring bar,
rubber septum, and argon balloon was placed N,O-dimethyl-
hydroxyamine hydrochloride (0.21 g, 2.06 mmol, Aldrich) in
THF (4 mL). The solution was stirred and cooled to -78 °C,
and n-BuLi (2.10 mL, 2.0 M in cyclohexane, 4.11 mmol) was
added dropwise via syringe. After the reaction was stirred at
this temperature for 5 min, the cooling bath was removed for
ca. 15 min, the solution was cooled to -78 °C, and (+)-5e (0.122
g, 0.41 mmol) in THF (5 mL) was added via syringe. After
being stirred at this temperature for 4 h, the reaction mixture
was warmed to -60 °C for 1 h, quenched by addition of
saturated NH4Cl solution (1.5 mL), and warmed to room
temperature. Water (3 mL) was added and the solution was
extracted with Et2O (15 mL) and EtOAc (3 × 15 mL). The
combined organic phases were washed with brine (3 mL), dried
(MgSO4), and concentrated. Flash chromatography (EtOAc/n-
hexanes, 60:40) gave 0.091 g (68%) of a white solid: mp 99-
101° C; [R]20D 137.6 (c 0.5, CHCl3); IR (neat) cm-1 3226 (NH),
2960, 1659, 1416, 1065; 1H NMR (CDCl3) δ 0.91 (s, 9 H), 2.32
(s, 3 H), 2.66-2.68 (m, 2 H), 3.15 (s, 3 H), 3.64 (m, 4 H), 4.63
(d, J ) 8.8 Hz, 1 H), 7.20 (d, J ) 8.0 Hz, 2 H), 7.54 (d, J ) 8.0
Hz, 2 H); 13C NMR (CDCl3) δ 21.7, 27.0, 32.8, 34.4, 36.1, 61.8,
62.6, 63.1, 125.7, 129.9, 141.5, 144.0, 173.1. Anal. Calcd for
C16H26N2O3S: C 58.87, H 8.03, N 8.58. Found: C 59.02, H 8.21,
N 8.28.
(SS,3R)-(+)-N-(p-Toluenesulfinyl)-3-amino-N-methoxy-
N-methyl-3-tert-butylpropionamide (3e). Chromatography
(EtOAc/n-hexanes, 60:40) gave 72% of a white solid; mp 99-
101 °C. The physical properties are identical with those of (+)-
3e prepared from the â-amino ester (+)-5e (see below).
(SS,3R)-(+)-N-(p-Toluenesulfinyl)-3-amino-N-methoxy-
N-methyl-hex-4-enamide (3g). Chromatography (EtOAc/n-
hexanes, 1:1) gave 82% of a clear oil: [R]20D 118.3 (c 5.4, CHCl3);
(SS,3R)-(+)-N-(p-Toluenesulfinyl)-3-amino-N-methoxy-
N-methyl-3-(p-trifluoromethylphenyl)propionamide (3b).
Chromatography (EtOAc/n-hexanes, 1:1) gave 54% of a slightly
1
IR (neat) 3221 (NH), 1656 cm-1; H NMR (CDCl3) δ 1.64 (dd,
yellow oil: [R]20 43.51 (c 0.37, CHCl3); IR (neat) 3229, 2923,
J ) 1.0 Hz, J ) 6.4 Hz, 3 H), 2.31 (s, 3 H), 2.57-2.71 (m, 2 H),
3.04 (s, 3 H), 3.56 (s, 3 H), 4.14-4.20 (m, 1 H), 5.10 (d, J ) 5.6
Hz, 1 H), 5.45-5.51 (m, 1 H), 5.66-5.75 (m, 1 H), 7.18 (d, J )
8.4 Hz, 2 H), 7.50-7.52 (m, 2 H); 13C NMR (CDCl3) δ 18.1,
21.6, 32.2, 38.6, 53.7, 61.6, 125.8, 129.1, 129.8, 131.1, 141.4,
142.9, 172.2. HRMS calcd for C15H23N2O3S (M + H) 311.1429,
found 311.1432.
D
1
1636, 1326; H NMR (CDCl3) δ 2.36 (s, 3 H), 2.95-2.96 (m, 2
H), 3.05 (s, 3 H), 3.54 (s, 3 H), 4.89 (dd, J ) 11.6, 12.0 Hz, 1
H), 5.59 (d, J ) 5.6 Hz, 1 H), 7.24-7.26 (m, 2 H), 7.54-7.59
(m, 6 H); 13C NMR (CDCl3) δ 21.4, 29.7, 29.7, 31.9, 39.1, 54.7,
61.3, 76.6, 77.0, 77.5, 125.3, 125.71, 125.76, 125.9, 127.7, 129.7,
141.5, 145.3, 171.4. HRMS calcd for C19H21N2O3F3SNa (M +
Na) 437.1126, found 437.1123.
(SS,3R)-(+)-Methyl N-(p-Toluenesulfinyl)-3-amino-3-(p-
trifluoromethylphenyl)propanoate (5b). In an oven-dried,
50-mL, round-bottom flask equipped with a magnetic stirring
bar, rubber septum, and argon balloon was placed NaHMDS
(0.34 mmol, 0.34 mL of a 1.0 M solution in THF) in ether (5
mL). The solution was cooled to -78 °C, and anhydrous methyl
acetate (0.34 mmol, 0.027 mL) was added via syringe. After
the solution was stirred at this temperature for 1 h, (+)-1b
(SS,3S)-(+)-N-(p-Toluenesulfinyl)-3-amino-N-methoxy-
N-methylbutanoamide (3c). Chromatography (EtOAc/n-
hexanes, 1:1) gave 66% of a clear, viscous oil: [R]25 154.8 (c
D
2.7, CHCl3); IR (neat) 3482, 3220, 2970, 1652; 1H NMR (CDCl3)
δ 1.42 (d, J ) 6.6 Hz, 3 H), 2.42 (s, 3 H), 2.67 (d, J ) 5.5 Hz,
2 H), 3.16 (s, 3 H), 3.62 (s, 3H), 3.85 (quintet, J ) 6.6, 13.9
Hz, 1 H), 5.06 (d, J ) 7.6 Hz, 1 H), 7.3 (d, J ) 8.4 Hz, 2 H),
2188 J. Org. Chem., Vol. 70, No. 6, 2005

Synthesis of â-Amino Carbonyl Compounds
7.61 (q, J ) 4.9, 8.2 Hz, 2 H); 13C NMR (CDCl3) δ 21.8, 22.7,
40.0., 47.9, 61.6, 126.1, 129.9, 141.5, 142.6, 172.2. HRMS calcd
for C13H20 N2O3SNa (M + Na) 307.1092, found 307.1090.
(dd, J ) 12.0, 12.0 Hz, 1 H), 5.05 (d, J ) 5.5 Hz, 1 H), 7.30-
7.32 (m, 2 H), 7.53-7.64 (m, 6 H); 13C NMR (CDCl3) δ 21.6,
32.2, 51.9, 55.1, 61.6, 77.0, 77.3, 77.7, 125.4, 125.5, 125.6, 126.0,
128.0, 129.9, 141.8, 145.7, 171.7. HRMS calcd for C18H18-
NO2F3S (M + Na) 392.0908, found 392.0916.
(SS,3R)-(+)-N-(2-Methylpropanesulfinyl)-3-amino-N-
methoxy-N-methyl-3-phenylpropionamide-(4a). Chroma-
tography (EtOAc/n-hexanes, 1:1) gave 79% of a clear viscous
(SS,3R)-(+)-N-(p-Toluenesulfinyl)-3-amino-1,3-diphen-
ylpropan-1-one (10a). In an oven-dried, 25-mL, single-neck,
round-bottom flask equipped with a magnetic stirring bar, a
rubber septum, and an argon balloon was placed (+)-3a (0.034
g, 0.1 mmol) in THF (3 mL). The solution was cooled to -78
°C, and PhLi (0.27 mL of a 1.8 M solution in cyclohexanes-
ether, 0.5 mmol) was introduced into the flask. The reaction
mixture stirred at -78 °C for 0.5 h, warmed to room temper-
ature, and stirred for 20 min, then cooled to -78 °C and
cautiously quenched with saturated NH4Cl (2 mL) solution.
The reaction mixture was diluted with water (2 mL) and
extracted with EtOAc (3 × 5 mL), and the combined organic
phases were washed with brine (2 mL) and dried (MgSO4).
Chromatography (n-hexane:EtOAc, 30:70) gave 0.030 g (84%)
oil: [R]20 184.1 (c 0.78, CHCl3); IR (neat) cm-1 3236 (NH),
D
1652; 1H NMR (CDCl3) δ 1.23 (s, 9 H), 2.87-2.90 (dd, J ) 9.0
Hz, 7.0 Hz, 1 H), 3.05-3.08 (m, 1 H), 3.16 (s, 3 H), 3.61 (s, 3
H), 4.77-4.80 (m, 1 H), 5.39 (s, 1 H), 7.27-7.31 (m, 2 H), 7.33-
7.38 (m, 3 H); 13C NMR (CHCl3) δ 23.1, 32.3, 39.5, 55.9, 56.0,
61.7, 127.7, 128.1, 141.8, 172.4; HRMS calcd for C15H25N2O3S
(M + H) 313.1586, found 313.1586.
(SS,3R)-(+)-N-(p-Toluenesulfinyl)-3-amino-3-tert-butyl-
propionaldehyde (7b). In an oven-dried, 10-mL, round-
bottomed flask equipped with a magnetic stirring bar, rubber
septa, and argon balloon was placed (+)-3e (0.033 g, 0.1 mmol)
in THF (2 mL). The solution was cooled to -78 °C and
DIBAL-H (0.5 mmol, 0.5 mL of a 1 M solution in CH2Cl2) was
introduced. After being stirring for 1 h at -78 °C, the reaction
mixture was quenched with saturated NH4Cl (2 mL) solution,
filtered through packed Celite, poured into H2O (5 mL), and
extracted with EtOAc (2 × 10 mL). The combined organic
phases were dried (MgSO4) and concentrated. Chromatography
(EtOAc/n-hexanes, 85:15) gave 0.019 g (70%) of a thick,
colorless oil: [R]20D 123.3 (c 0.33, CHCl3); IR (neat) cm-1 3168,
1724; 1H NMR (CDCl3) δ 0.91 (s, 9 H), 2.34 (s, 3 H), 2.55 (ddd,
J ) 1.6, 4.8, 17.2 Hz, 1 H), 3.65-3.71 (m, 1 H), 3.86 (d, J )
9.2 Hz, 1 H), 4.77-4.80 (m, 1 H), 5.39 (s, 1 H), 7.19-7.24 (m,
2 H), 7.51-7.53 (m, 2 H), 9.73 (t, J ) 1.1 Hz, 1 H); 13C NMR
(CHCl3) δ 21.7, 26.9, 35.8, 46.9, 60.2, 125.6, 130.0, 142.0, 143.2,
201.3. HRMS calcd for C14H22NO2S (M + H) 268.1371, found
268.1378.
of a white solid, mp 94-96 °C; [R]25 +80.08 (c 1.25, CHCl3);
D
IR (CHCl3) 3017, 1683, 1464 cm-1; 1H NMR (CDCl3, 400 MHz)
δ 2.28 (s, 3 H), 3.42 (d, J ) 6.5 Hz, 2 H), 5.11 (d, J ) 4.9 Hz,
1 H), 5.04 (q, J ) 6.0 Hz, 1 H), 7.17 (m, 3 H), 7.29 (m, 4 H),
7.40 (m, 3 H), 7.50 (m, 2 H), 7.73 (d, J ) 7.2 Hz, 2 H); 13C
NMR (CDCl3) δ 21.5, 47.0, 55.1, 125.8, 128.0, 128.4, 128.5,
129.0, 129.2, 130.0, 133.9, 136.8, 141.2, 141.7, 142.8, 198.2.
HRMS calcd for C22H21NO2SNa (M + Na) 386.1191, found
386.1198.
(SS,3R)-(+)-N-(p-Toluenesulfinyl)-3-amino-3-phenyl-1-
propynyl-1-one (11). This reaction required 12 h at room
temperature for completion. Chromatography (EtOAc/hexane
70%) gave 95% of a colorless oil: [R]20D 91.17 (c 0.60, CHCl3);
IR (neat) 3191, 2216, 1669 cm-1; 1H NMR (CDCl3) δ 1.97 (s, 3
H), 2.42 (s, 3 H), 3.06 (d, J ) 6.5 Hz, 2 H), 4.82 (d, J ) 6.5 Hz,
1 H), 4.98 (q, 1 H), 7.28-7.29 (m, 3 H), 7.38 (t, 2 H), 7.42 (d,
J ) 8.5 Hz, 2 H), 7.57 (d, J ) 8.5 Hz, 2 H); 13C NMR (CDCl3)
δ 4.3, 21.6, 52.8, 54.4, 80.3, 92.3, 125.6, 127.7, 128.3, 129.0,
129.8, 140.3, 141.6, 142.3, 184.9. HRMS calcd for C19H19NO2-
SNa (M + Na) 348.1034, found 348.1037.
(SS,3R)-(+)-N-(p-Toluenesulfinyl)-3-amino-3-phenyl-
propinoaldehyde (7a). Chromatography (n-hexane:EtOAc,
15:85) gave 84% of a thick colorless oil; [R]25 +175.1 (c 0.41,
D
1
CHCl3); H NMR (CDCl3, 400 MHz) δ 2.33 (s, 3 H), 2.87 (dd,
J ) 1.2, 6.4, 2 H), 4.66 (d, J ) 5.2, 1 H), 4.90 (q, J ) 6.4, 1 H),
7.25-7.21 (m, 3 H), 7.35-7.28 (m, 4 H), 7.50 (d, J ) 8.4, 2 H),
9.53 (t, J ) 1.6, 1 H); 13C NMR (CDCl3, 400 MHz) δ 21.8, 51.3,
53.4, 125.8, 127.7, 128.6, 129.3, 130.0, 140.8, 142.0, 142.3,
200.2. HRMS calcd for C16H17NO2SNa (M + Na) 310.0878,
found 310.0884.
(SS,R)-(+)-Dimethyl 2-Oxo-4-N-(p-toluenesulfinylamino)-
4-phenylbutylphosphonate (13). In a 25 mL, single-necked,
round-bottom flask equipped with a magnetic stirring bar,
rubber septum, and argon balloon was placed dimethyl me-
thylphosphonate (0.394 mL, 3.53 mmol) in THF (5 mL), cooled
to -78 °C, and n-BuLi (2 M in cyclohexane, 1.77 mL, 3.54
mmol) was added by syringe. After 15 min, the reaction
mixture was transferred to a 50-mL, round-bottom flask
containing (+)-3a (0.153 g, 0.443 mmol) in THF (10 mL) at
-78 °C, and the solution was stirred at this temperature for
2 h. At this time the reaction was quenched by addition of
saturated aqueous NH4Cl (2 mL) and the solution was warmed
to room temperature. After dilution with H2O (2 mL) the
solution was extracted with Et2O (10 mL) and EtOAc (2 × 15
mL). The combined organic phases were washed with brine
(2 mL), dried (MgSO4), and concentrated. Flash chromatog-
raphy (EtOAc) afforded a colorless oil that was subjected to
Kugelrohr vacuum distillation (60 °C under 2.5 mmHg), to
remove the excess dimethyl methylphosphonate, affording
General Procedure for Addition of Grignard Reagents
to N-Sulfinyl â-Amino Weinreb Amides: (SS,3R)-(+)-N-
(p-Toluenesulfinyl)-3-amino-3-tert-butyl-1-phenylpropan-
1-one (10b). In an oven-dried, 25 mL, round-bottom flask
equipped with a magnetic stirring bar, a rubber septum, and
an argon balloon was placed (+)-3e (0.033 g, 0.10 mmol) in
THF (3 mL). The solution was cooled to -78 °C, phenylmag-
nesium chloride (0.25 mL of a 2.0 M solution in THF, 0.50
mmol) was added, and the reaction mixture was warmed to
room temperature. After being stirred for 3 h, the solution was
cooled to -78 °C and quenched by addition of a saturated
aqueous NH4Cl (1 mL) solution. The reaction mixture was
poured into H2O (1 mL) and extracted with EtOAc (3 × 2 mL),
and the combined organic phases were washed with brine (1
mL), dried (MgSO4), and concentrated. Chromatography (EtOAc:
0.159 g (88%) of a colorless oil; [R]20 72.5 (c 1.0, CHCl3); IR
n-hexanes, 1:1) gave 0.031 g (88%) of a white solid: mp 78-
D
(neat) cm-1 3188 (NH), 1717; 1H NMR (CDCl3) δ 2.34 (s, 3 H),
1
80 °C; [R]20 153.9 (c 0.46, CHCl3); IR (neat) 1685.7 cm-1; H
D
2
2.93 (d, JHP ) 22.8 Hz, 2 H), 3.12 (d, J ) 6.04 Hz, 2 H), 3.61
NMR (CDCl3) δ 0.93 (s, 9 H), 2.31 (s, 3 H), 3.21-3.24 (m, 2
H), 3.87-3.89 (m, 1 H), 4.25 (d, J ) 8.8 Hz, 1 H), 7.18 (d, J )
7.6 Hz, 2 H), 7.36-7.40 (m, 2 H), 7.46-7.51 (m, 3 H), 7.86-
7.88 (m, 2 H); 13C NMR (CDCl3) δ 23.6, 29.5, 37.9, 43.4, 63.6,
127.6, 130.4, 130.9, 131.8, 135.4, 139.4, 143.49, 145.5, 200.8.
Anal. Calcd for C20H25NO2S: C 69.93, H 7.34, N 4.08. Found:
C 70.13, H 7.53, N 3.72.
3
(d, JHP ) 11.3 Hz, 6 H), 4.86-4.90 (m, 2 H), 7.29 (m, 7 H),
7.50 (d, J ) 8.1 Hz, 2 H); 13C NMR (CDCl3) δ 21.7, 41.8 (d,
1JCP ) 127.4 Hz), 51.4, 53.4 (2 × d, 2JCP ) 6.3 Hz), 54.7, 125.7,
127.7, 128.3, 129.1, 129.1, 129.9, 140.9, 141.8, 142.7, 200.1 (d,
2JCP ) 5.2 Hz); 31P NMR (CDCl3) δ 21.84. HRMS calcd for
C19H24NO5PNa (M + Na) 432.1011, found 432.1016.
(SS,3R)-(+)-N-(p-Toluenesulfinyl)-3-amino-1-methyl-3-
(p-trifluoromethylphenyl)-1-one (8b). Flash chromatogra-
phy (EtOAc/n-hexanes, 7:3) gave 63% of an oil; [R]20D 40.93 (c
0.43, CHCl3); IR (neat) 3178, 2952, 1716, 1365; 1H NMR
(CDCl3) δ 2.09 (s, 3 H), 2.42 (s, 3 H), 3.03-3.04 (m, 2 H), 4.93
(SS,3R)-(+)-p-Toluenesulfinic Acid (3-Oxo-1-propenyl-
pent-4-enyl)amide (14). In a 50-mL, single-necked, round-
bottom flask equipped with a magnetic stirring bar, rubber
septum, and argon balloon was placed (+)-3g (0.058 g, 0.187
mmol) in THF (10 mL). The solution was cooled to 0 °C and
J. Org. Chem, Vol. 70, No. 6, 2005 2189

Davis et al.
vinylmagnesium bromide (1.87 mL, 1 M in THF, 1.87 mmol)
was added by syringe. After 30 min, the reaction mixture was
quenched by addition of saturated aqueous NH4Cl (2 mL)
solution and warmed to room temperature. Water (2 mL) was
added and the solution was extracted with Et2O (10 mL) and
EtOAc (3 × 10 mL). The combined organic phases were washed
with brine (5 mL), dried (MgSO4), and concentrated. Flash
chromatography (EtOAc) afforded 0.015 g (29%) of 14 as a
H2O (5 mL) and acetic acid (1 mL) via cannula. The solution
was extracted with Et2O (20 mL) and EtOAc (3 × 20 mL). The
combined organic phases were washed with brine (5 mL), dried
(MgSO4), and concentrated. Flash chromatography (EtOAc)
afforded 0.033 g (56%) of colorless oil with properties identical
with those of (+)-14 prepared above.
(SS,3R)-(+)-N-(2-Methylpropanesulfinyl)-3-amino-1-
methyl-3-phenylpropan-1-one (+)-(16). In an oven-dried,
25-mL, single-neck, round-bottom flask equipped with a
magnetic stirring bar, a rubber septum, and argon balloon was
placed (+)-4a (0.031 g, 0.1 mmol) in THF (3 mL). The solution
was cooled to -78 °C and methylmagnesium chloride (0.17 mL
of a 3 M solution in THF, 0.5 mmol) was added via syringe.
The reaction mixture was stirred at -78 °C for 0.5 h, warmed
to room temperature, and stirred for 20 min. At this time the
reaction mixture was cooled to -78 °C and quenched by
addition of saturated aqueous NH4Cl solution (2 mL). The
solution was diluted with H2O (2 mL) and extracted with
EtOAc (3 × 5 mL), and the combined organic phases were
washed with brine (2 mL), dried (MgSO4), and concentrated.
Chromatography (EtOAc/n-hexanes, 1:1) gave 0.022 g (81%)
of a clear oil; [R]20D 94.6 (c 1.54, CHCl3); IR (neat) 3227, 1715;
1H NMR (CDCl3) δ 1.14 (s, 9 H), 2.07 (s, 3 H), 2.92 (dd, J )
17.2, 7.2 Hz, 1 H), 2.98 (dd, J ) 17.2, 5.2 Hz, 1 H), 4.53 (d, J
) 4.4 Hz, 1 H), 4.71 (ddd, J ) 4.8, 3.6, 2.4 Hz, 1 H), 7.21-7.29
(m, 5 H); 13C NMR (CDCl3) δ 23.0, 31.2, 51.0, 55.6, 56.0, 127.7,
128.2, 129.0, 141.2, 207.7. HRMS calcd for C14H22NO2S (M +
H) 268.1371, found 268.1373.
colorless oil; [R]20 94.5 (c 0.7, CHCl3); IR (neat) 3203 (NH),
D
1
1709 cm-1; H NMR (CDCl3) δ 1.63 (dd, J ) 0.8 Hz, J ) 6.4
Hz, 3 H), 2.33 (s, 3 H), 2.81-2.82 (m, 2 H), 4.22-4.25 (m, 1
H), 4.62 (d, J ) 5.6 Hz, 1 H), 5.43-5.49 (m, 1 H), 5.65-5.72
(m, 1 H), 5.75 (dd, J ) 0.8 Hz, J ) 10.4 Hz, 1 H), 6.07-6.11
(m, 1 H), 6.17 (dd, J ) 10.4 Hz, J ) 17.6 Hz, 1 H), 7.20 (d, J
) 8.2 Hz, 2 H), 7.50 (d, J ) 8.2 Hz, 2 H); 13C NMR (CDCl3) δ
15.7, 19.2, 43.6, 50.8, 123.3, 126.9, 127.0, 127.4, 128.3, 134.4,
139.1, 140.2, 196.5. HRMS calcd for C15H20NO2S (M + H)
278.1215, found 278.1216.
(SS,3R)-(+)-p-Toluenesulfinic Acid {1-[4-(N-Methoxy-
N-methylamino)-2-oxobutyl]but-2-enyl}amide (15). The
second fraction to elute (EtOAc/n-hexanes, 1:1) yielded 43%
of a clear oil: [R]20 82.9 (c 0.9, CHCl3); IR (neat) 3203 (NH),
D
1
1710 cm-1; H NMR (CDCl3) δ 1.63 (dd, J ) 0.8 Hz, J ) 6.4
Hz, 3 H), 2.33 (s, 3 H), 2.45 (s, 3 H), 2.51 (t, J ) 6.8 Hz, 2 H),
2.67 (d, J ) 5.6 Hz, 2 H), 2.76 (t, J ) 6.8 Hz, 2 H), 3.34 (s, 3
H), 4.17-4.20 (m, 1 H), 4.64 (d, J ) 5.6 Hz, 1 H), 5.40-5.46
(m, 1 H), 5.66-5.72 (m, 1 H), 7.20 (d, J ) 8.0 Hz, 2 H), 7.49-
7.51 (m, 2 H); 13C NMR (CDCl3) δ 18.1, 21.7, 41.6, 45.3, 49.1,
53.2, 55.2, 60.2, 125.8, 129.4, 129.8, 130.8, 141.6, 142.8, 208.3.
HRMS calcd for C17H26N2O3NaS (M + Na) 361.1562, found
361.1565.
Acknowledgment. This work was supported by
grants from the National Institutes of General Medical
Sciences (GM 51982 and GM57870).
(SS,3R)-(+)-p-Toluenesulfinic Acid (3-Oxo-1-propenyl-
pent-4-enyl)amide (14) Using Acid Quench. In a 50-mL,
single-necked, round-bottom flask equipped with a magnetic
stirring bar, rubber septum, and argon balloon was placed (+)-
3g (0.060 g, 0.193 mmol) in THF (10 mL), and the reaction
was cooled to 0 °C and vinylmagnesium bromide (1.93 mL, 1
M in THF, 1.93 mmol) was added by syringe. After 30 min,
the mixture was quenched by transferring it to a mixture of
Supporting Information Available: Spectral data for all
new compounds. This material is available free of charge via
the Internet at http://pubs.acs.org.
JO0402780
2190 J. Org. Chem., Vol. 70, No. 6, 2005