Asymmetric synthesis of α-substituted N-methylsulfonamides

Article abstract of DOI:10.1002/1522-2675(200211)85:11<3657::AID-HLCA3657>3.0.CO;2-A

A novel amine auxiliary for the asymmetric synthesis of α-substituted N-methylsulfonamides is described. The reaction of 4-([1,1′-biphenyl]-4-yl)-2,2-dimethyl-1,3-dioxan-5-amine (16) with various aliphatic sulfonyl chlorides afforded the corresponding sulfonamides, which were lithiated and subsequently reacted with electrophiles to give the corresponding products in high yields and good-to-excellent asymmetric inductions (de 83-95%). Racemization-free cleavage of the auxiliary led to the α-alkylated N-methylsulfonamides in acceptable yields and high enantiomer purities (ee 91 to ≥ 98).

Full text of DOI:10.1002/1522-2675(200211)85:11<3657::AID-HLCA3657>3.0.CO;2-A

Helvetica Chimica Acta Vol. 85 (2002)
3657
Asymmetric Synthesis of a-Substituted N-Methylsulfonamides
by Dieter Enders*, Christian R. Thomas, Nicola Vignola, and Gerhard Raabe
Institut f¸r Organische Chemie der RWTH Aachen, Professor-Pirlet-Strasse 1, D-52074 Aachen
(fax: (‡49)241-8092-127; e-mail: Enders@RWTH-Aachen.de)
Dedicated to Professor Dieter Seebach on the occasion of his 65th birthday
A novel amine auxiliary for the asymmetric synthesis of a-substituted N-methylsulfonamides is described.
The reaction of 4-([1,1'-biphenyl]-4-yl)-2,2-dimethyl-1,3-dioxan-5-amine (16) with various aliphatic sulfonyl
chlorides afforded the corresponding sulfonamides, which were lithiated and subsequently reacted with
electrophiles to give the corresponding products in high yields and good-to-excellent asymmetric inductions (de
83 95%). Racemization-free cleavage of the auxiliary led to the a-alkylated N-methylsulfonamides in
acceptable yields and high enantiomer purities (ee 91to ꢀ98).
Introduction. Since the discovery of the antibacterial activity of streptozone and
sulfachrysoidine by Domagk (for reviews, see [1]), sulfonamides have found wide-
spread application in the development of new antibiotics. Numerous examples of a-
substituted sulfonamides of the general type 1a displaying potent pharmacological
activity are known. The racemic a-substituted sulfonylmethanesulfonamide derivatives
1b and 1c are reported to be inhibitors of carbonic anhydrase (CA) [2]. In particular,
the fluorosulfonamide 1c was determined as the most potent inhibitor among the
compounds of this type examined.
O
O
O
O O O
R1
S
H3C
S
S
*
*
NR2
NH2
R2
R
1b R = CH3
1c R = F
1a
Jones et al. [3] reported the synthesis and medical evaluation of a cyclic
sulfonamido-prostaglandin analogue with a stereogenic center in the a-position to
the sulfonamido group. Moreover, a-substituted sultam fragments have been utilized
as P1scaffolds in the synthesis and biological evaluation of novel HIV protease
inhibitors [4].
Despite the obvious biological relevance of this class of compounds, only very few
efficient methods for their asymmetric synthesis are known. Davis et al. [5] described
the asymmetric synthesis of a-substituted primary sulfonamides involving the
diastereoselective a-alkylation of N-sulfonylcamphorimine dianions. Acidic hydrolysis
gave rise to the enantiomer-enriched sulfonamides with medium to good selectivities.

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Helvetica Chimica Acta Vol. 85 (2002)
Huart and Ghosez reported an enantioselective synthesis of bicyclic cyclopentenones
via stereoselective 1,4-addition of metalated enantiomerically pure sulfonamides to
cyclic enones [6].
In a preceding communication, we described the enantioselective synthesis of N-
methylsulfonamides by means of a novel amine as chiral auxiliary [7]. Herein, we
present in detail the development of this methodology.
Results and Discussion. The aim of our project was to develop an efficient chiral
auxiliary that would allow, for the first time, efficient asymmetric a-alkylation of
sulfonamides. In the course of this study, a large number of enantiomerically pure
amines were converted to their sulfonamides to evaluate them for their diastereose-
lectivity of the a-alkylation reaction.
For first alkylation tests, various pyrrolidine derivatives were synthesized. The (2S)-
[(methoxymethoxy)methyl]pyrrolidine (2a), (2S)-(methoxymethyl)pyrrolidine (2b),
and (2S)-(1-methoxy-1-methylethyl)pyrrolidine (2c), which are known as precursors
for hydrazine auxiliaries [8], were converted to the corresponding sulfonamides 3a c
by treatment with ethanesulfonyl chloride (Scheme 1). The sulfonamides 3a c were
then lithiated with lithium diisopropylamide (LDA) and allowed to react with benzyl
bromide at À 788 to afford the alkylated sulfonamides 4a c (Tables 1 and 2).
Scheme 1
1) LDA, TMEDA,
EtSO2Cl, Et3N,
CH2Cl2, r.t.
THF, 0°
2) BnBr, THF, –78°
R1
R1
N
S
N
S
R1
57–71%
78–94%
N
H
O
O
*
O
O
CH3
CH3
2a–c
3a–c
4a–c
de 4–27%
a R1 = MeOCH2OCH2, b R1 = MeOCH2, c R1 = MeOC(Me)2
Table 1. Synthesis of Chiral Sulfonamides 3a
c
r:t:
D
Product
R1
Yield [%]
‰aŠ (c, CHCl3)
3a
3b
3c
MeOCH2OCH2
MeOCH2
MeOC(Me)2
57
63
71
À 36.9 (1.0)
À 43.0 (1.15)
À 19.4 (1.07)
Table 2. a-Benzylation of Sulfonamides 3a c Affording Sulfonamides 4a
c
Product
R1
Yield [%]
de [%]a)
4a
4b
4c
MeOCH2OCH2
MeOCH2
MeOC(Me)2
85
94
78
4
11
27
a) Determined by 13C-NMR spectroscopy.

Helvetica Chimica Acta Vol. 85 (2002)
3659
Although all a-alkylated sulfonamides 4 were obtained in unsatisfactory dia-
stereoselectivities, it was observed that better diastereoisomer excesses (de) could be
obtained when the steric demand of the side chain at the pyrrolidine ring was increased.
We then turned to the readily available amine auxiliary (4S,5S)-2,2-dimethyl-4-phenyl-
1,3-dioxan-5-anine ((S,S)-5), which has already been applied in a series of auxiliary-
controlled reactions [9] or in the preparation of a chiral ligand for chromium(0)
complexes [10]. (S,S)-5 was converted to the tertiary N-methylsulfonamide (S,S)-7 in
two steps via the secondary derivative (S,S)-6 and subsequent N-methylation
(Scheme 2).
Scheme 2
H3C CH3
H3C CH3
EtSO2Cl, Et3N,
CH2Cl2
O
O
O
O
87%
NH2
HN
S
CH3
O
O
(S,S)-5
(S,S)-6
H3C CH3
1) BuLi, THF,
O
O
–78 °
2) MeI, r.t.
81%
N
S
CH3
H3C
O
O
(S,S)-7
(S,S)-7 was lithiated with LDA in presence of N,N,N',N'-tetramethylethane-1,2-
diamine (TMEDA) and alkylated with benzyl bromide (Scheme 3). TMEDA was used
to activate the intermediate carbanion to get satisfactory yields. After chromatography
the corresponding a-alkylated sulfonamide (S,S,R)-8 was isolated in 59% yield and an
improved de of 63% (Scheme 3).
Scheme 3
H3C CH3
H3C CH3
1) LDA, TMEDA, THF,
0°
2) BnBr, THF, –100°
O
O
O
O
59%
N
N
H3C
H3C
S
CH3
S
CH3
O
O
O
O
(S,S,R)-8
(S,S)-7
de 63% ( 96%, after chromatography)

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Helvetica Chimica Acta Vol. 85 (2002)
(S,S,R)-8 was obtained as the diastereomerically pure product after prep. HPLC
purification (de ꢀ 96%). To gain some insight into the mechanism of the a-alkylation
and the origin of the asymmetric induction, the configuration of the newly formed
stereogenic center had to be determined. Single-crystal X-ray analysis of (S,S,R)-8
revealed the absolute configuration at C(a) to be R (Fig. 1).
Fig. 1. X-Ray crystal structure of (S,S,R)-8 (for the program for the graphical presentation, see [11])
According to the information obtained from the X-ray structure, it was reasonable
to assume that the phenyl group at the dioxane ring (substrate A, Scheme 4) should
provide the main contribution to the diastereoselectivity of the alkylation process. An
increase of the steric demand of the aromatic moiety should, therefore, give a better
diastereofacial shielding of the prochiral reaction center. Therefore, we decided to
synthesize a substrate bearing a biphenyl-yl group instead of the phenyl group at the
dioxane moiety (substrate B, Scheme 4).
Scheme 4
O
O
O
O
H3C
H3C
S
R
S
R
N
N
O
O
H3C
H3C
O
O
CH3
CH3
A
B
A successful procedure was performed according to Erlenmeyer×s phenylserine
synthesis [12] starting from [1,1'-biphenyl]-4-carbaldehyde (9) and glycine (10)
(Scheme 5). The reaction afforded the aldol adduct rac,syn-11, which was transformed
into the corresponding methyl ester rac,syn-12. The NMR spectra of the product
showed a de of 86% for the syn-isomer. The diastereoisomerically pure syn-
diastereoisomer was obtained by flash chromatography. Reduction of rac,syn-12 with
various reducing reagents gave rise to the corresponding diol, but in very low yield.
Therefore, it was necessary to protect the functional groups. Protection of the OH
group with (tert-butyl)dimethylsilyl chloride (TBSCl) and reaction of the amine moiety
with allyl bromide resulted in the doubly protected compound rac,syn-13, which was
subsequently converted to the diol rac,syn-14 by reduction with diisobutylaluminium

Helvetica Chimica Acta Vol. 85 (2002)
3661
Scheme 5
1) NaOH,
EtOH/H2O
2) 2N HCl
OH
*
O
O
+
*
H2N
CO2H
99%
Biph
OR
Biph
H
NH2
9
10
rac,syn-11 R = H
SOCl2, MeOH,
0°
rac,syn-12 R = CH3
57%
de 86% ( 96%, after chromatography)
1) TBSCl, 1H-imidazole,
MeCN, 40°
2) Allyl bromide,
iPr2NEt, toluene
reflux
1) DIBAL-H,
CH2Cl2, r.t.
OH OH
TBSO
O
2) Bu4NF, THF
*
*
Biph
*
*
Biph
OMe
72%
95%
N(Allyl)2
N(Allyl)2
rac,syn-13 TBS = tBuMe2Si
rac,syn-14
H3C CH3
H3C CH3
[RhCl(Ph3P)3],
MeCN/H2O
O
*
O
2,2-Dimethoxypropane,
CSA, toluene, reflux
O
*
O
*
Biph
99%
*
84%
Biph
N(Allyl)2
NH2
rac,cis-16
rac,cis-15
H3C CH3
H3C CH3
resolution
O
O
O
O
+
Biph
Biph
NH2
NH2
(R,R)-16
(S,S)-16
hydride (DIBAL-H) and deprotection of the OH group with Bu4NF in 72% yield. Ring
closure to the acetonide rac,cis-15 and deprotection of the amino group by allylic
rearrangement with Wilkinson catalyst [13] led to the racemic cis-configured amine
rac,cis-16. The enantiomers were separated by resolution with tartaric acid.
The amines were converted to the Mosher amides to determine the absolute
configuration by NOE experiments. Confirmation of the enantiomer purity was
conducted by 13C-NMR spectroscopy. In the course of these measurements, the ability
of the amine 16 to act as a chiral shift reagent for molecules bearing an acidic proton
was demonstrated in a parallel project [14].

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Helvetica Chimica Acta Vol. 85 (2002)
After the development of a suitable synthesis of the amines (S,S)- and (R,R)-16,
they were transformed via the secondary sulfonamides cis-17a c into the correspond-
ing sulfonamide precursors cis-18a c, respectively, according to the procedure
described in Scheme 3 (see Scheme 6 and Table 3).
Scheme 6
H3C CH3
H3C CH3
R1CH2SO2Cl,
O
*
O
O
*
O
Et3N, CH2Cl2, r.t.
*
Biph
81–97%
*
Biph
N
NH2
H
S
R1
O
O
cis-16
cis-17a–c
H3C CH3
1) BuLi, THF,
O
*
O
–78°
2) MeI, r.t.
*
Biph
81–87%
N
S
R1
H3C
O
O
cis-18a–c
a R1 = Me, b R1 = Et, c R1 = iPr
Table 3. Synthesis of the Sulfonamides 17 and 18
R1
Product 17
Yield [%]
Product 18
Yield [%]
Me
Et
Et
iPr
(S,S)-17a
(S,S)-17b
(R,R)-17b
(R,R)-17c
81(
97
94
90
S,S)-18a
(S,S)-18b
(R,R)-18b
(R,R)-18c
87
85
83
81
The alkylation of (S,S)-18a and (S,S)-7 was carried out with BuLi as base and
benzyl bromide, and indeed the alkylation of (S,S)-18a resulted in a higher
diastereoselectivity as compared to the corresponding reaction with (S,S)-7 (Scheme 7;
Table 4, Entries 1 and 2).
In further experiments, we examined the dependency of both the diastereoselec-
tivity and the yield on the solvent and the effect of chelating additives (Table 4,
Entries 3 6). By using 1equiv. of hexamethylphosphoric triamide (HMPA), the yield
could be improved without loss of selectivity (Table 4, Entry 5). In THF, the yield was
higher but with a diminished diastereoselectivity (Entry 6).
Consequently, the enantiomerically pure sulfonamides cis-18a c were metalated
with 1equiv. of BuLi in Et 2O at À 788 in the presence of HMPA (Scheme 8).
Subsequent alkylation with aliphatic electrophiles R2X (X ˆ Br or I) gave a-substituted
sulfonamides cis-19a j in good yields (67 86%) and high diastereomer excesses (de

Helvetica Chimica Acta Vol. 85 (2002)
3663
Scheme 7
H3C CH3
1) BuLi, Et2O,
H3C CH3
–78°
O
O
O
O
2) BnBr, solvent,
R1
H3C
additive, –78°
R1
H3C
N
N
S
CH3
S
CH3
O
O
O
O
(R,S,S)-8 R1 = Ph
(S,S)-7 R1 = Ph
1
1
(R,S,S)-19a
R = Biph
(S,S)-18a
R = Biph
Table 4. Asymmetric a-Benzylation of Sulfonamides (S,S)-7 and (S,S)-18a under Different Conditions Leading
to Sulfonamides (R,S,S)-8 and (R,S,S)-19a, Respectively
Entry
R1
Solvent
Additive (equiv.)
Yield [%]
de [%]a)
1
2
3
4
5
6
Ph
Et2O
Et2O
Et2O
Et2O
Et2O
THF
29
35
77
78
68
77
59
83
18
50
83
75
Biph
Biph
Biph
Biph
Biph
TMEDA (3)
HMPA (3)
HMPA (1)
HMPA (1)
a) Determined by 13C-NMR spectroscopy.
Scheme 8
H3C CH3
H3C CH3
1) BuLi, Et2O,
HMPA, –78°
O
*
O
O
*
O
2) R2X, Et2O,
HMPA, –78°
67–86%
R2
*
*
*
Biph
Biph
N
N
S
R1
H3C
S
R1
H3C
O
O
O O
cis-19a–j a)
cis-18a–c
de 83–94% ( 98%, after HPLC)
a) For R1 and R2, see Table 5.
72 94%, Table 5). Diastereoisomerically pure sulfonamides (de ꢀ 98%) could be
obtained by prep. HPLC purification.
With increasing steric demand of the substituent R1, generally higher diastereose-
lectivity was observed when the same electrophile was used. In the case of MeI as
electrophile, a rather low de of 72% was reached ( ! (R,R,R)-19h). A higher de of
94% was achieved with dimethyl sulfate as electrophile. The configuration of the newly
formed stereogenic center was determined to be R by single-crystal X-ray-analysis in
the case of product (R,S,S)-19a [7]. By assuming a uniform reaction mechanism, all
examples described should possess the same configuration.
To explain the high diastereofacial selectivity of the electrophilic substitutions in a-
position to the sulfonamide function, the solution structure and aggregation of the

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Helvetica Chimica Acta Vol. 85 (2002)
Table 5. Asymmetric a-Alkylation of Sulfonamides 18a c Affording Sulfonamides 19a
j
Product
R1
R2
Yield [%]
de [%]a)b)
(R,S,S)-19a
(R,S,S)-19b
(R,S,S)-19c
(R,S,S)-19d
(R,S,S)-19e
(R,S,S)-19f
(S,R,R)-19f
(S,R,R)-19g
(R,R,R)-19h
(R,R,R)-19h
(R,R,R)-19i
(R,R,R)-19j
Me
Me
Et
Et
Et
Et
Et
Et
iPr
iPr
iPr
iPr
PhCH2
67
68
7189 (
80
62
78
76
82
86
83 (ꢀ 98)
CH2ˆCHCH2
88
Bu
ꢀ 98)
Pr
88 (ꢀ 98)
Me(CH2)5
PhCH2
83 (ꢀ 98)
94
PhCH2
94
4-tBuC6H4CH2
Me
91( ꢀ 98)
72
94
91
92
Mec)
PhCH2
83
75
78
CH2ˆCHCH2
a) Value in parentheses after prep. HPLC (SiO2, pentane/Et2O 1 : 1). b) Determined by 13C-NMR spectroscopy.
c) Dimethyl sulfate was used as electrophile.
lithiated chiral sulfonamide remains to be determined. However, a plausible hypothesis
is based on earlier reported structural investigations of closely related a-lithiated
sulfones [15] and carbanions in general (for a review about acceptor-substituted
carbanions, see [16]). Therefore, we assume that the resulting alkyl-substituted a-
sulfonamide carbanion is pyramidalized, and the lone pair of electrons is oriented
gauche to the two sulfonyl O-atoms (Fig. 2).
EX
L
L
Li
S
O
O
H3C
N
R
O
H3C
O
CH3
EX
block by "biphenyl wall"
Fig. 2. Electrophilic substitution by EX in a-position to the sulfonamide function
On the rigid dioxane core, the sulfonamido group occupies the axial position and
the sterically demanding biphenyl group the equatorial position. The main parameter
that determines the asymmetric induction is the steric hindrance of the electrophilic
attack by the −biphenyl wall×. So the carbanionic reaction center would be accessible
only from the less shielded face. Important facts concerning the favored preliminary
substituent orientation at the reaction centre remain open. Therefore, information
about the SÀN(a) and SÀC(a) rotation barrier and also the inversion barrier of the

Helvetica Chimica Acta Vol. 85 (2002)
3665
carbanion should be investigated. The aggregation of the organolithium and the exact
position of the lithium cation, which we suppose is bound to the sulfonyl O-atoms
according to the references on a-lithiated sulfones, remains to be determined, too.
Finally, many procedures were screened for an efficient racemization-free cleavage
of the auxiliary. The best results were achieved by refluxing the sulfonamides cis-19 in
conc. hydrochloric acid for three days (Method A). Although we expected an acidic
hydrolysis giving sulfonic acids and the starting auxiliary, we obtained the N-
methylsulfonamides 20 in good yields and enantioselectivities (Scheme 9, Table 6).
For nonaromatic starting materials like (R,S,S)-19c and (R,R,R)-19h, better yields were
achieved with 1equiv. of conc. sulfuric acid in refluxing CHCl 3 (Method B).
Scheme 9
H3C CH3
O
*
O
R2
*
H
N
method A or B
53–63%
R2
*
*
Biph
S
R1
H3C
N
O
O
H3C
S
R1
O
O
20a–ea)
ee 91 to 98%
cis-19
de 91 to 98%
Method A: conc. HCl soln., reflux, 3 d;
Method B: H2SO4, CHCl3, reflux, 1 d
a) For R1 and R2, see Table 6.
Table 6. Removal of the Chiral Auxiliary from 19a i to Give the a-Alkylated Sulfonamides 20a
e
r:t:
D
Product
R1
R2
Method
Yield [%]
ee [%]a)
‰aŠ (c, CHCl3)
(R,S,S)-19a
(R,S,S)-19c
(R,S,S)-19f
(S,R,R)-19f
(R,R,R)-19h
(R,R,R)-19i
(R)-20a
(R)-20b
(R)-20c
(S)-20c
(R)-20d
(R)-20e
Me
Et
Et
Et
iPr
iPr
PhCH2
Bu
PhCH2
PhCH2
Me
A
B
A
A
B
A
55
63
53
55
54
57
ꢀ 98
ꢀ 98
94
95
94
À 3.1(1.0)
‡ 4.0 (1.0)
‡ 2.0 (1.0)
À 2.0 (1.0)
À 5.1(1.0)
PhCH2
91
À 2.7 (1.0)
a) Determined by GC on chiral stationary phase (Lipodex E).
In another attempt to synthesize enantiomer-enriched a-substituted secondary
sulfonamides, the amination of a-substituted sulfonyl chlorides was examined. An a-
substituted sulfonyl chloride (R)-22, prepared from the corresponding sodium
sulfonate (R)-21 [17], was allowed to react with benzylamine (Scheme 10). This
amination gave the sulfonamide 24 in a good yield but with complete racemization. The
racemization during the amination is due to the intermediate formation of the achiral
sulfene 23 [18]. The result is the formation of the racemic sulfonamide 24.
Consequently, at present, our protocol seems to be the method of choice to synthesize
enantiomer-enriched a-substituted secondary sulfonamides.

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Helvetica Chimica Acta Vol. 85 (2002)
Scheme 10
1) SOCl2, DMF
2) Benzylamine,
CH2Cl2, 0°
H
N
ONa
70%
*
S
S
O
O
O
O
(R)-21
24
ee 98%
ee 0%
SOCl2, DMF
Benzylamine,
CH2Cl2, 0°
TMS
O
S
S
O
O
O
(R)-22
23
Conclusions. We have developed a novel and efficient method for the asymmetric
a-alkylation of sulfonamides bearing the chirality information in the amine moiety,
cleavable under acidic conditions. The racemization-free acidic hydrolysis led to the
title secondary sulfonamides in acceptable overall yields and with high enantiomer
purities (ee 91to ꢀ98).
This work was supported by the Deutsche Forschungsgemeinschaft (Leibniz Award and Sonderforschungs-
bereich 380) and by the Fonds der Chemischen Industrie. We thank the companies Degussa AG, BASF AG, Bayer
AG, and former Boehringer-Mannheim for the donation of chemicals.
Experimental Part
General. All reagents were purchased from commercial suppliers and used without further purification.
Asymmetric alkylations were carried out under Ar in dry solvents. BuLi (1.6m in hexane) was purchased from
Merck, Darmstadt. DIBAL-H (1.0m in CH2Cl2) was purchased from Aldrich. The 2-methylpropanesulfonyl
i
chloride was prepared as described in [19]. HMPA, TMEDA, and Pr2NH were distilled from CaH2 and kept
under Ar. The sodium sulfonate (R)-21 was prepared from the corresponding methyl sulfonate [20]. FC ˆ flash
chromatography. M.p.: Tottoli melting-point apparatus; uncorrected. Optical rotations: Perkin-Elmer P-241
polarimeter. IR Spectra: Perkin-Elmer 1750-FT-IR spectrometer; in cmÀ1. 1H- and 13C-NMR Spectra: at 300 or
400 MHz and 75 or 100 MHz, resp.; Varian Gemini 300 or Varian Inova 400; d in ppm rel. to SiMe4 as internal
standard, J in Hz; ds of minor diastereoisomers in brackets. Electron-impact (EI) MS: Finnigan SSQ 7000 and,
for high-resolution (HR), Finnigan MAT 95; in m/z (rel. %). Microanalyses were performed on Elementar
Vario EL.
General Procedure A (GP A): Sulfonamides by Amination of Sulfonyl Chlorides. A soln. of the amine
(1.0 equiv.) and Et3N (1.2 equiv.) in CH2Cl2 (2 ml/mmol amine) was cooled to 08. After adding the sulfonyl

Helvetica Chimica Acta Vol. 85 (2002)
3667
chloride (1.1 equiv.), the soln. was stirred overnight at r.t. The mixture was then washed with brine, the org. layer
dried (MgSO4) and evaporated, and the residue purified by FC (silica gel).
General Procedure B (GP B): Metallation of the Enantiomerically Pure Sulfonamides with LDA and
Subsequent Alkylation. The sulfonamide (1.0 equiv.) was dissolved in dry THF (10 ml/mmol sulfonamide) and
metallated with LDA (1.0 equiv., freshly prepared 0.25m soln. in THF) at 08 in the presence of TMEDA
(3 equiv.). After 1h, the mixture was cooled to À 788 and the electrophile (1.2 equiv.) was added dropwise.
After 24 h, the reaction was quenched by addition of sat. NH4Cl soln. (2 ml). The mixture was partitioned
between H2O and CH2Cl2, the aq. layer extracted 3 Â with CH2Cl2, the combined org. phase dried (MgSO4) and
evaporated, and the crude product purified by FC (silica gel).
General Procedure C (GP C): Tertiary Sulfonamides from Secondary Sulfonamides and Methyl Iodide. A
soln. of the secondary sulfonamide (1.0 equiv.) in dry THF (7 ml/mmol sulfonamide) was cooled to À 788. After
30 min, BuLi (1.0 equiv.) was added dropwise. The soln. was then stirred for an additional hour after which MeI
(1.1 equiv.) was added dropwise. After 2 h, the reaction was quenched by addition of sat. NH4Cl soln. (2 ml/
mmol). The mixture was then partitioned between H2O and CH2Cl2, the aq. layer extracted 3 Â with CH2Cl2;
the combined org. phase dried (MgSO4) and evaporated and the crude product purified by FC (silica gel).
General Procedure D (GP D): Metallation of the Enantiomerically Pure Sulfonamides with BuLi and
Subsequent Alkylation. A soln. of the sulfonamide (1.0 equiv.) and HMPA (1.0 equiv.) in dry Et2O was cooled to
À 788. After 30 min, BuLi (1.1 equiv.) was added dropwise. The soln. was then stirred for an additional hour
after which the electrophile (2.0 equiv.) was added dropwise. After 24 h, the reaction was quenched by addition
of sat. NH4Cl soln. (2 ml/mmol). The mixture was partitioned between H2O and CH2Cl2, the aq. layer further
extracted 3 Â with CH2Cl2, the combined org. phase dried (MgSO4) and evaporated and the crude product
purified by FC (silica gel).
General Procedure E (GP E): Removal of the Chiral Auxiliary with Hydrochloric Acid (Method A). The
suspension of the sulfonamide in conc. HCl soln. was refluxed for 3 days and then extracted 10 Â with CH2Cl2.
The combined org. phase was washed with sat. NaHCO3 soln. and then with brine, dried (Na2SO4), and
evaporated, and the crude product purified by FC (silica gel).
General Procedure F (GP F): Removal of the Chiral Auxiliary with Sulfuric Acid (Method B). To the soln.
of the sulfonamide in CHCl3, conc. H2SO4 soln. (1.0 equiv.) was added. The mixture was refluxed for 24 h and
was then extracted 10 Â with CH2Cl2. The combined org. phase was washed with NaHCO3 soln. and then with
brine, dried (Na2SO4), and evaporated, and the crude product purified by FC (silica gel).
(2S)-1-(Ethylsulfonyl)-2-[(methoxymethoxy)methyl]pyrrolidine (3a). According to GP A, with 2a (0.72 g,
5.00 mmol), ethanesulfonyl chloride (0.71g, 5.50 mmol), Et 3N (0.61g, 6.00 mmol), and CH 2Cl2 (10 ml). FC
30
D
(pentane/AcOEt 3 :2) gave 3a (0.67 g, 57%). Colorless oil. ‰aŠ ˆ À36.9 (c ˆ 1.10, CHCl3). IR (Film): 2943,
2884, 2825, 1459, 1415, 1330, 1288, 1241, 1200, 1149, 1111, 1040, 991, 967, 919, 814, 783. 1H-NMR (300 MHz,
CDCl3): 1.38 (t, J ˆ 7.4, MeCH2SO2); 1.85 2.10 (m, CH2CH2CH2N); 3.03 (q, J ˆ 7.4, MeCH2SO2); 3.30 3.52
(m, CH2N); 3.37 (s, MeO); 3.49 (dd, J ˆ 6.8, 9.9, 1H, OC H2CHN); 3.63 (dd, J ˆ 4.9, 9.9, 1H, OC H2CHN); 4.04
(m, CHN); 4.63 (s, MeOCH2O). 13C-NMR (75 MHz, CDCl3): 8.0; 24.8; 29.0; 44.9; 48.9; 55.4; 58.8; 70.2; 96.7.
‡
‡
EI-MS (70 eV): 206 (3, [C9H19SO4N À MeO] ), 176 (5, [C9H19SO4N À C2H5O2] ), 162 (100, [C9H19SO4N À
‡
‡
‡
C3H7O2] ), 70 (67, C4H8N ). HR-MS: 206.0851([C H19SO4N À MeO] ; calc. 206.0851).
9
(2S)-1-(Ethylsulfonyl)-2-(methoxymethyl)pyrrolidine (3b). According to GP A, with 2b (5.61g,
48.70 mmol), ethanesulfonyl chloride (6.92 g, 53.60 mmol), Et3N (5.94 g, 58.44 mmol), and CH2Cl2 (100 ml).
27
D
FC (hexane/AcOEt 1:1) gave 3b (6.34 g, 63%). Pale yellow oil. ‰aŠ ˆ À43.0 (c ˆ 1.15, CHCl3). IR (CHCl3):
2978, 2939, 2882, 2830, 1460, 1417, 1384, 1330, 1288, 1241, 1198, 1146, 1112, 1047, 990, 972, 813, 782, 718, 620, 602,
557. 1H-NMR (300 MHz, CDCl3): 1.37 (t, J ˆ 7.4, MeCH2SO2); 1.86 2.04 (m, CH2CH2CH2N); 3.04 (m, MeCH2-
SO2); 3.29 3.50 (m, CH2N, MeOCH2CHN); 3.36 (s, MeO); 3.98 (m, CHN). 13C-NMR (75 MHz, CDCl3): 8.0;
‡
24.8; 28.9; 45.0; 48.8; 58.6; 59.0; 75.0. EI-MS (70 eV): 162 (100, [C8H17NO3S À C2H5O] ), 114 (6, [C8H17NO3S À
‡
‡
‡
C2H5SO2] ), 98 (4), 82 (3), 70 (92, C4H8N ), 55 (4), 45 (13, C2H5O ). Anal. calc. for C8H17NO3S (207.30):
C 46.35, H 8.27, N 6.76; found: C 46.66, H 8.44, N 6.94.
(2S)-1-(Ethylsulfonyl)-2-(1-methoxy-1-methylethyl)pyrrolidine (3c). According to GP A, with 2c (4.85 g,
33.86 mmol), ethanesulfonyl chloride (4.81g, 37.25 mmol), Et 3N (4.1g, 40.63 mmol), and CH 2Cl2 (70 ml). FC
27
D
(hexane/AcOEt 2 :1) gave 3c (5.67 g, 71%). Pale yellow oil. ‰aŠ ˆ À19.4 (c ˆ 1.07, CHCl3). IR (CHCl3): 2979,
2943, 2903, 2831, 1633, 1461, 1416, 1385, 1366, 1328, 1287, 1242, 1217, 1180, 1138, 1109, 1087, 1065, 996, 933, 917,
895, 860, 795, 755, 723, 667, 613. 1H-NMR (300 MHz, CDCl3): 1.14 (s, 3 H, MeOC(Me)2CHN); 1.17 (s, 3 H,
MeOC(Me)2CHN); 1.37 (t, J ˆ 7.4, MeCH2SO2); 1.74 2.03 (m, 4 H, CH2CH2CH2N); 3.04 3.19 (m, MeCH2-
SO2, 1 H of CH2N); 3.21( s, 3 H); 3.82 (ddd, J ˆ 2.8, 7.4, 11.7, 1 H, CH2N); 4.09 (dd, J ˆ 4.7, 8.4, CHN). 13C-NMR
(75 MHz, CDCl3): 8.1; 21.3; 21.6; 26.4; 27.3; 46.7; 49.3; 50.1; 66.1; 78.0. EI-MS (70 eV): 162 (15, [C10H21NO3S À

3668
Helvetica Chimica Acta Vol. 85 (2002)
‡
‡
‡
‡
‡
C4H9O] ), 73 (100, C4H9O ), 70 (37, C4H8N ), 57 (12, C4H9 ), 55 (10, C4H8 ). Anal. calc. for C10H21NO3S
(235.35): C 51.03, H 8.99, N 5.95; found: C 51.17, H 9.12, N 6.08.
(2S)-2-[(Methoxymethoxy)methyl]-1-{[(1S)-and(1R)-1-methyl-2-phenylethyl]sulfonyl}pyrrolidine (4a).
According to GP B, with 3a (0.25 g, 1.1mmol), LDA (1.1mmol), benzyl bromide (0.21g, 1.2 mmol), TMEDA
(0.35 g, 3.3 mmol), and THF (10 ml). FC (pentane/AcOEt 2 :1) gave 4a (0.22 g, 85%). Colorless oil. de 4%
(13C-NMR). IR (Film): 3062, 3028, 2939, 2882, 2824, 1603, 1496, 1455, 1377, 1323, 1245, 1202, 1142, 1111, 1042,
991, 919, 757. 1H-NMR (300 MHz, CDCl3): 1.24 [1.23] (d, J ˆ 6.9, PhCH2CH(Me)SO2); 1.86 2.1 3
(m, CH2CH2CH2N); 2.67 [2.65] (dd, J ˆ 11.0, 12.7, 1 H, PhCH2CH(Me)SO2); 3.25 3.68 (m, 4 H,
PhCH2CH(Me)SO2, CH2N); 3.37 (s, MeO); 3.54 [3.52] (dd, J ˆ 6.3, 9.9, 1H, OC H2CHN); 3.64 [3.62]
(dd, J ˆ 4.7, 9.9, 1H, OC H2CHN); 4.18 [4.20] (m, CHN); 4.65 [4.62] (s, 2 H, MeOCH2O); 7.16 7.36 (m, Ph).
13C-NMR (75 MHz, CDCl3): 13.4 [13.2]; 25.1; 29.0 [28.9]; 36.4; 49.3 [49.2]; 55.4; 58.9 [59.1]; 59.5 [59.7]; 69.7
‡
[67.1]; 96.7; 126.8; 128.7; 129.2; 137.6 [137.7]. EI-MS (70 eV): 296 (2, [C16H25NO4S À OCH3] ), 252 (68,
‡
‡
‡
‡
[C16H25NO4S À C3H7O2] ), 188 (45), 119 (46, C9H11 ), 91(100, C 7H7 ), 70 (55, C4H8N ). Anal. calc. for
C16H25NO4S (235.35): C 58.69, H 7.70, N 4.28; found: C 58.57, H 7.73, N 4.51.
(2S)-2-(Methoxymethyl)-1-{[(1S)-and(1R)-1-methyl-2-phenylethyl]sulfonyl}pyrrolidine (4b). According
to GP B, with 3b (0.61g, 2.90 mmol), LDA (2.90 mmol), benzyl bromide (0.59 g, 3.43 mmol), TMEDA
(1.0 g, 8.70 mmol), and THF (30 ml). FC (hexane/AcOEt 4 :1) gave 4b (0.81 g, 94%). Colorless oil. de 11%
(13C-NMR). IR (CHCl3): 3027, 2977, 2935, 2878, 2830, 1603, 1496, 1456, 1377, 1323, 1245, 1201, 1142, 1112, 1063,
991, 926, 757, 723, 700, 631, 583. 1H-NMR (300 MHz, CDCl3): 1.23 (d, J ˆ 7.1, PhCH2CH(Me)SO2); 1.84 2.08
(m, CH2CH2CH2N); 2.66 [2.67] (dd, J ˆ 11.3, 13.3, PhCH2(Me)SO2); 3.26 3.51( m, 5 H, PhCH2CH(Me)SO2,
CH2CHN, CH2N); 3.34 [3.38] (s, MeO); 3.58 [3.66] (m, 1H, CH 2N); 4.19 [4.18] (m, CHN); 7.17 7.35 (m, Ph).
13C-NMR (75 MHz, CDCl3): 13.2 [13.3]; 25.2; 28.8; 36.4 [36.5]; 49.2 [49.4]; 58.9 [58.8]; 58.9; 59.7 [59.6]; 75.0
‡
[74.9]; 126.8; 128.7; 129.16; 129.19; 137.9 [137.7]. EI-MS (70 eV) (CI): 252 (63, [C15H23NO3S À C2H5O] ), 188
‡
‡
‡
‡
‡
‡
(50), 119 (54, C9H11 ), 91(100, C 7H7 ), 77 (4, C6H5 ), 70 (73, C4H8N ), 65 (4, C5H5 ), 55 (4), 41(15, C 2H5O )
Anal. calc. for C15H23NO3S (297.42): C 60.58, H 7.79, N 4.71; found: C 60.52, H 8.00, N 4.95.
(2S)-2-(1-Methoxy-1-methylethyl)-1-{[(1S)-and (1 R)-1-methyl-2-phenylethyl]sulfonyl}pyrrolidine (4c).
According to GP B, with 3c (0.67 g, 2.83 mmol), LDA (2.80 mmol), benzyl bromide (0.58 g, 3.40 mmol),
TMEDA (0.99 g, 8.50 mmol), and THF (30 ml). FC (hexane/AcOEt 6 :1) gave 4c (0.72 g, 78%). White foam. de
27% (13C-NMR). IR (KBr): 3085, 3067, 3026, 2985, 2973, 2942, 2880, 2284, 1603, 1497, 1455, 1385, 1370, 1354,
1
1323, 1306, 1253, 1219, 1142, 1113, 1087, 1065, 1055, 998, 938, 790, 752, 729. H-NMR (300 MHz, CDCl3): 1.08
[1.18] (s, MeOC(Me)2CHN); 1.14 [1.20] (s, 3 H, MeOC(Me)2CHN); 1.21 [1.23] (d, J ˆ 6.9, PhCH2CH(Me)SO2);
1.68 2.11 (m, 4 H, CH2CH2CH2N); 2.64 [2.63] (dd, J ˆ 11.5, 13.3, 1 H, CH2CH2CH2N); 3.02
(m, PhCH2CH(Me)SO2); 3.23 [3.25] (s, MeO); 3.53 [3.41] (dd, J ˆ 3.0, 13.3, 1 H, CH2CH2CH2N); 3.68
(m, 1H, PhC H2CH(Me)SO2); 3.98 (m, 1H, PhC H2CH(Me)SO2); 4.31[4.34] ( dd, J ˆ 6.0, 8.7, CHN); 7.18 7.34
(m, Ph). 13C-NMR (75 MHz, CDCl3): 13.3; 20.6; 21.5; 26.9; 28.1; 36.2; 49.3; 50.9; 59.9; 65.8; 78.2; 126.6; 128.6;
‡
129.2; 138.2. EI-MS (70 eV): 252 (11, [C17H27NO3S À C4H9O] ), 188 (13), 142 (8, [C17H27NO3S À C9H11SO2],
‡
‡
‡
‡
‡
119 (18, C9H11 ), 91(34, C 7H7 ), 73 (100, C4H9O ), 70 (34, C4H8N ), 43 (9, C2H5N ). Anal. calc. for
C17H27NO3S (325.47): C 62.74, H 8.36, N 4.30; found: C 62.83, H 8.35, N 4.40.
N-[(4S,5S)-2,2-Dimethyl-4-phenyl-1,3-dioxan-5-yl]ethanesulfonamide ((S,S)-6). According to GP A, with
(S,S)-5 (2 g, 10 mmol), ethanesulfonyl chloride (1.4 g, 11 mmol), Et3N (1.1 g, 11 mmol), and CHCl2 (20 ml). FC
2
25
(pentane/AcOEt 3 :1) gave (S,S)-6 (2.6 g, 87%). Colorless solid. M.p. 798. ‰aŠ ˆ ‡104 (c ˆ 1.05, CHCl3). IR
D
(CHCl3): 3310, 2998, 2940, 2880, 1503, 1455, 1415, 1380, 1310, 1210, 1170, 1145, 1130, 971, 945, 920, 865, 845, 792,
1
746, 710, 652. H-NMR (CDCl3): 0.77 (t, J ˆ 7.4, MeCH2SO2); 1.53 (s, 1 MeÀC(2)); 1.54 (s, 1 MeÀC(2)); 2.07
(dq, J ˆ 7.1, 14.1, 1 H, MeCH2SO2); 2.28 (dq, J ˆ 7.4, 14.1, 1 H, MeCH2SO2); 3.50 (dddd, J ˆ 9.7, 2.0, 2.0, 2.0,
HÀC(5)); 3.98 (dd, J ˆ 2.0, 12.1, 1 HÀC(6)); 4.27 (dd, J ˆ 2.0, 12.1, 1 HÀC(6)); 5.13 (d, J ˆ 2.0, HÀC(4)); 5.26
(d, J ˆ 9.74, NH); 7.20 7.41( m, Ph). 13C-NMR (CDCl3): 7.8; 18.6; 29.6; 47.8; 52.7; 66.2; 72.4; 99.7; 125.8; 127.8;
‡
‡
128.4; 139.2. EI-MS (70 eV): 284 (5, [C14H21NO4S À Me] ), 134 (100), 106 (83), 91 (22), 77 (11, C6H5 ). Anal.
calc. for C14H21NO4S (299.38): C 56.17, H 7.07, N 4.68; found: C 56.04, H 7.26, N 4.64.
N-[(4S,5S)-2,2-Dimethyl-4-phenyl-1,3-dioxan-5-yl]-N-methylethanesulfonamide ((S,S)-7). According to
GP C, with 6 (2.0 g, 6.7 mmol), BuLi (6.7 mmol), MeI (1.7 g, 7.3 mmol), and THF (45 ml). FC (hexane/
27
D
AcOEt 3 :1) gave (S,S)-7 (1.7 g, 81%). Colorless solid. M.p. 948. ‰aŠ ˆ ‡77.0 (c ˆ 1.00, CHCl3). IR (KBr): 3065,
3034, 2994, 2966, 2945, 2885, 2834, 1637, 1608, 1501, 1453, 1413, 1382, 1328, 1282, 1269, 1246, 1205, 1182, 1159,
1
1131, 1082, 1043, 1023, 976, 954, 940, 924, 900, 839, 782, 753, 734, 633, 571. H-NMR (300 MHz, CDCl3): 0.84
(t, J ˆ 7.4, MeCH2SO2); 1.56 (s, 2 MeÀC(2)); 1.96 (dq, J ˆ 7.4, 7.4, 1H, MeC H2SO2); 2.25 (dq, J ˆ 7.4, 7.4, 1H,
MeCH2SO2); 3.17 (s, MeN); 4.06 (ddd, J ˆ 1.6, 3.6, 3.8, HÀC(5)); 4.13 (dd, J ˆ 1.6, 12.9, 1 HÀC(6)); 4.45
(dd, J ˆ 3.8, 12.9, 1 HÀC(6)); 5.28 (d, J ˆ 3.6, HÀC(4)); 7.26 7.44 (m, Ph). 13C-NMR (75 MHz, CDCl3): 7.7;

Helvetica Chimica Acta Vol. 85 (2002)
3669
18.7; 29.3; 33.9; 45.9; 52.6; 65.7; 73.4; 99.5; 125.7; 127.7; 128.4; 139.1. EI-MS (70 eV): 298 (5, [C15H23NO4S À
‡
‡
‡
‡
Me] ), 255 (3), 238 (6, [C15H23NO4S À Me] ), 207 (3), 149 (80, C5H11SO2N ), 120 (100), 105 (3, C8H9 ), 91(8,
‡
‡
C7H7 ), 77 (5, C6H5 ), 57 (23). Anal. calc. for C15H23NO4S (313.42): C 57.48, H 7.40, N 4.47; found: C 57.24, H
7.38, N 4.66.
(aR)-N-[(4S,5S)-2,2-Dimethyl-4-phenyl-1,3-dioxan-5-yl]-N,a-dimethylbenzeneethanesulfonamide
((S,S,R)-8). According to GP B, with (S,S)-7 (0.31g, 1.00 mmol), LDA (1.1mmol), benzyl bromide (0.19 g,
1.10 mmol), TMEDA (0.11 g, 3.00 mmol), and THF (10 ml). FC (pentane/Et2O 3 :1) gave (S,S,R)-8 (0.24 g,
59%). Colorless solid. de 63% (13C-NMR). The major diastereoisomer was isolated by HPLC. de ꢀ 96%
(13C-NMR). M.p. 1018. IR (CHCl3): 3055, 3032, 2992, 2975, 2962, 2940, 2873, 1638, 1605, 1586, 1499, 1453, 1382,
1366, 1321, 1305, 1265, 1240, 1200, 1177, 1153, 1131, 1083, 972, 948, 929, 895, 852, 832, 762, 730, 704, 670, 656.
1H-NMR (major diastereoisomer, 300 MHz, CDCl3): 0.75 (d, J ˆ 6.9, PhCH2CH(Me)SO2); 1.56
(s, 2 MeÀC(2)); 2.35 (dd, J ˆ 11.3, 12.9, 1 H, PhCH2CH(Me)SO2); 2.9 (ddq, J ˆ 3.1, 6.9, 11.3, PhCH CH(Me)-
2
SO2); 3.01( dd, J ˆ 3.1, 12.9, 1 H, PhCH2CH(Me)SO2); 3.21( s, MeN); 4.08 (ddd, J ˆ 1.4, 3.6, 3.6, HÀC(5)); 4.17
(dd, J ˆ 1.4, 12.9, 1 HÀC(6)); 4.43 (dd, J ˆ 3.6, 12.9, 1 HÀC(6)); 5.31( d, J ˆ 3.6, HÀC(4)); 6.96 7.45 (m, 2 Ph).
13C-NMR (major diastereoisomer; 75 MHz, CDCl3): 12.9; 18.5; 29.2; 34.8; 36.0; 52.7; 58.9; 65.6; 73.5; 99.6;
‡
125.8; 126.7; 127.7; 128.3; 128.5; 129.2; 137.3; 138.5. EI-MS (70 eV): 388 (2, [C22H29NO4S À Me] ), 328 (1,
‡
‡
‡
[C22H29NO4S À C3H7O2] ), 264 (2), 239 (59), 146 (5), 118 (100), 105 (3, C8H9 ), 91(98, C 7H7 ), 84 (25), 77 (4,
‡
C6H5 ), 70 (5), 58 (38). Anal. calc. for C22H29NO4S (403.55): C 65.48, H 7.24, N 3.47; found: C 65.57, H 7.34, N
3.73.
Crystal-Structure Analysis of (S,S,R)-8. A suitable crystal (colorless, ca. 0.3 Â 0.3 Â 0.3 mm) of (S,S,R)-8 was
obtained by recrystallization from hexane/CH2Cl2. The compound (C22H29NO4S, Mr 403.5) crystallizes in the
monoclinic space group P21(4) with the cell parameters a ˆ 9.078(4) ä, b ˆ 12.361(3) ä, c ˆ 12.259(1) ä, and
b ˆ 114.74(1)8. Vˆ 1045.5 ä3 and Z ˆ 2 yield a calculated density 1calc ˆ 1.282 g cmÀ3. At r.t., 4936 reflections
(Vmax ˆ 75.28) were collected on an Enraf-Nonius CAD4 diffractometer with graphite-monochromated CuKa
radiation (l 1.54179 ä). Data were corrected for Lorentz and polarization factors but not for absorption effects
(m ˆ 1.56 mmÀ1). The structure was solved by direct methods as implemented in the Xtal3.2 set of
crystallographic routines [21], employing GENSIN for the generation of structure-invariant relationships and
GENTAN for the general tangent phasing procedure. In the final full-matrix least-squares refinement on F, 1968
observed reflections (I > 2s(I)) were included, involving 252 parameters and converging at R(Rw) ˆ 0.052
(0.050, w ˆ sÀ2), a residual electron density of À 0.5/ ‡ 0.3 eäÀ3, and a goodness-of-fit S ˆ 2.501. The absolute
configuration as shown in Fig. 1 was determined by the known configuration at atoms C(1) and C(2) of the
starting material. The H-atoms were calculated in idealized positions. Their equivalent displacement parameters
were fixed at 1.5 U of the relevant heavy atom. All H-atom parameters were kept constant in the refinement
process. Supplementary crystallographic data for this paper have been deposited with the Cambridge
Crystallographic Data Centre as CCDC No. 186700. These data can be obtained free of charge via
www.ccdc.cam.ac.uk/conts/retrieving.html (or from the CCDC, 12, Union Road, Cambridge CB2 1EZ, UK
(fax: ‡44 1223 336033; e-mail: deposit@ccdc.cam.ac.uk).
rac,syn-2-Amino-3-([1,1'-biphenyl]-4-yl)-3-hydroxypropanoic Acid (rac,syn-11). To a soln. of glycine
(20.6 g, 274 mmol) and NaOH (27.4 g, 685 mmol) in H2O (70 ml), [1,1'-biphenyl]-4-carbaldehyde (9; 100 g,
548 mmol) was added, and the mixture was warmed slightly. After precipitation of a colorless solid, EtOH
(170 ml) and H2O (60 ml) were added, and the mixture was allowed to stand for further 3 h. After addition of
EtOH (100 ml) and H2O (50 ml), the mixture was stirred for 1.5 h. Then 2n HCl (700 ml) was added, and the
mixture was refluxed until a clear soln. was obtained and a green oil separated. After the separation of the green
oil, the hot aq. soln. was poured into an ice-cooled sat. NaOAc soln. (2 l). The solid that precipitated was filtered
by suction and air-dried for 5 days: 75 g of rac,syn-11. Colorless product that was used in the next step without
further purification.
Methyl rac,syn-2-Amino-3-([1,1'-biphenyl]-4-yl)-3-hydroxypropanoate (rac,syn-12). To MeOH (450 ml),
SOCl2 (138 g, 1.17 mol) was added, followed by rac,syn-11 (75 g) in small portions. The mixture was then
refluxed for 5 h. After evaporation of the solvent, the crude product was dissolved in CH2Cl2 and the mixture
treated carefully with sat. NaHCO3 soln. until the formation of CO2 stopped. After separation of the org. layer,
the aq. soln. was extracted 3 Â with CH2Cl2, the combined org. layer dried (MgSO4) and evaporated, and the
residue purified by FC (CH2Cl2/MeOH 9 :1): rac,syn-12 (42.2 g, 57%). Colorless solid. de 86% (13C-NMR). The
major diastereoisomer was separated by FC. de ꢀ 96% (13C-NMR). M.p. 1128. IR (KBr): 3147, 1725, 1586, 1488,
1451, 1435, 1405, 1385, 1355, 1285, 1273, 1252, 1214, 1193, 1158, 1132, 1121, 1054, 1011, 918, 830, 763, 743.
1H-NMR (major diastereoisomer; 300 MHz, CDCl3): 3.70 (d, J ˆ 4.4, HÀC(2)); 3.71( s, COOMe); 4.96 (d, J ˆ
4.4, HÀC(3)); 7.31 7.61( m, 9 H, Biph). 13C-NMR (major diastereoisomer, 75 MHz, CDCl3): 52.3; 60.5; 73.9;

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Helvetica Chimica Acta Vol. 85 (2002)
‡
126.5; 127.1; 127.2; 127.4; 128.8; 140.0; 173.7. EI-MS (70 eV): 271 (1, C16H17NO3 ), 212 (3, [C16H17NO3 À
‡
‡
‡
‡
‡
C2H3O2] ), 183 (24, C13H11O ), 153 (20, C12H9 ), 89 (100, C3H7NO ), 74 (5, C3H6O ). Anal. calc. for
C16H17NO3 (271.32): C 70.83, H 6.32, N 5.16; found: C 71.03, H 6.14, N 5.09.
Methyl rac,syn-3-([1,1'-Biphenyl]-4-yl)-3-{[(tert-butyl)dimethylsilyl]oxy}-2-[di(prop-2-enyl)amino]propa-
noate (rac,syn-13). A soln. of rac,syn-12 (42.2 g, 156 mmol) in MeCN (187 ml) was treated with TBSCl (28.2 g,
187 mmol) in the presence of 1H-imidazole (22.4 g, 390 mmol). After heating the mixture for 3 h at 408, the
solvent was evaporated. Et2O was then added to the residue, and the mixture was washed twice with brine. The
aq. soln. was then extracted 3 times with Et2O. The combined org. phase was dried (MgSO4) and evaporated.
The crude product was dissolved in toluene (250 ml), and the mixture was treated with allyl bromide (41.5 g,
343 mmol) in the presence of iPr2NEt (38.3 g, 390 mmol). The mixture was then refluxed for 4 days. The mixture
was filtered, the soln. evaporated, and the residue purified by FC (pentane/AcOEt 20 :1): rac,syn-13 (69 g,
95%). Yellow oil. IR (Film): 3078, 3029, 3006, 2953, 2929, 2894, 2857, 1734, 1487, 1472, 1463, 1362, 1255, 1204,
1161, 1115, 1089, 1019, 1007, 921, 838. 1H-NMR (300 MHz, CDCl3): À 0.21( s, 1MeSi); 0.06 ( s, 1MeSi); 0.89
(s, tBuSi); 3.21( dd, J ˆ 7.4, 14.7, 2 H, (CH2ˆCHCH2)2N); 3.54 3.60 (m, 5 H, (CH2ˆCHCH2)2N, COOMe);
3.66 (d, J ˆ 5.8, HÀC(2)); 5.00 (d, J ˆ 10.2, 2 H, Hcis of (CH2ˆCHCH2)2N); 5.06 (d, J ˆ 17.3, 2 H, Htrans of
(CH2ˆCHCH2)2N); 5.24 (d, J ˆ 5.8, HÀC(3)); 5.60 (m, (CH2ˆCHCH2)2N); 7.15 7.65 (m, 9 H, Biph).
13C-NMR (75 MHz, CDCl3): À 5.2; À 4.4; 18.1; 25.8; 51.0; 54.8; 68.3; 75.3; 116.4; 126.4; 127.0; 127.2; 127.7;
‡
128.8; 137.3; 139.9; 141.0; 141.3; 171.9. EI-MS (70 eV): 406 (2, [C28H39NSiO3 À C2H3O2] ), 297 (100,
‡
‡
‡
‡
‡
C19H25SiO ), 283 (2), 226 (4), 168 (34, C9H14NO2 ), 115 (4, C6H15Si ), 73 (59, C3H5O2 ), 59 (5, C2H3O2 ).
Anal. calc. for C28H39NSiO3 (465.71): C 72.21, H 8.44, N 3.32; found: C 72.26, H 8.32, N 3.30.
rac,syn-3-([1,1'-Biphenyl]-4-yl)-2-[di(prop-2-enyl)amino]propane-1,3-diol (rac,syn-14). To a soln. of
rac,syn-13 (69 g, 148 mmol) in dry CH2Cl2 (150 ml), a soln. of DIBAL-H (440 mmol) was added slowly at 08.
The mixture was stirred for 8 h, and the reaction was then quenched by adding MeOH (22 ml) and H2O (67 ml),
and the precipitate was removed by filtration. The filtrate was then partitioned between H2O and CH2Cl2, and
the aq. layer was further extracted 3 Â with CH2Cl2. The combined org. phase was dried (MgSO4) and
evaporated. The residue was dissolved in THF (200 ml), and the soln. was treated with Bu4NF (148 mmol).
After stirring for 2 h, evaporation and FC (pentane/AcOEt 3 :1) gave rac,syn-14 (34.5 g, 72%). Colorless solid.
M.p. 698. IR (KBr): 3462, 3203, 3079, 3032, 3004, 2978, 2915, 2865, 1643, 1487, 1452, 1405, 1315, 1292, 1274, 1255,
1193, 1154, 1114, 1067, 987, 922, 844, 764, 730. 1H-NMR (300 MHz, CDCl3): 3.01( ddd, J ˆ 4.1, 7.7, 9.6, HÀC(2));
3.30 (dd, J ˆ 7.4, 14.0, 2 H, (CH2ˆCHCH2)2N); 3.49 3.60 (m, 4 H, (CH2ˆCHCH2)2N, CH2OH); 4.46 (d, J ˆ
9.6, HÀC(3)); 5.20 (d, J ˆ 9.9, 2 H, Hcis of (CH2ˆCHCH2)2N); 5.21( d, J ˆ 17.3, 2 H, H trans of
(CH2ˆCHCH2)2N); 5.88 (m, (CH2ˆCHCH2)2N); 7.25 7.60 (m, 9 H, Biph). 13C-NMR (75 MHz, CDCl3):
53.6; 59.1; 66.7; 71.2; 117.9; 127.1; 127.3; 127.4; 127.6; 128.8; 136.5; 140.8; 141.0; 141.1. EI-MS (70 eV): 324 (3,
‡
‡
‡
‡
[C21H25NO2 ‡ 1] ), 297 (3), 181 (9), 155 (16, C12H11), 140 (100, C8H14NO ), 98 (25), 77 (16, C6H5 ), 70 (29), 55
‡
(8). HR-MS: 323.1885 (C21H25NO2 ; calc. 323.1883).
rac,cis-4-([1,1'-Biphenyl]-4-yl)-2,2-dimethyl-N,N-di(prop-2-enyl)-1,3-dioxan-5-amine (rac,cis-15). To a
soln. of rac,syn-14 (34.4 g, 107 mmol) in toluene (200 ml), 2,2-dimethoxypropane (55.8 g, 535 mmol) was
added, and the mixture was refluxed for 4 days in the presence of camphorsulfonic acid (CSA; 1.24 g, 5.0 mmol).
The soln. was then evaporated and FC (pentane/AcOEt 15 :1) gave rac,cis-15 (32.67 g, 84%). Colorless solid.
M.p. 938. IR (KBr): 3374, 3029, 2991, 2939, 2921, 2859, 2809, 2865, 1641, 1488, 1450, 1418, 1314, 1263, 1239, 1224,
1199, 1181, 1157, 1131, 1085, 1020, 998, 964, 918, 855, 754. 1H-NMR (300 MHz, CDCl3): 1.46 (s, 1 MeÀC(2)); 1.50
(s, 1 MeÀC(2)); 2.83 (ddd, J ˆ 1.4, 3.8, 4.1, HÀC(5)); 3.02 (dd, J ˆ 8.0, 14.8, 2 H, (CH2ˆCHCH2)2N); 3.49 3.57
(m, 2 H, (CH2ˆCHCH2)2N); 4.00 (dd, J ˆ 3.8, 11.8, 1 HÀC(6)); 4.10 (dd, J ˆ 1.4, 11.8, 1 HÀC(6)); 4.88 (d, J ˆ
16.6, 2 H, Htrans of (CH2ˆCHCH2)2N); 4.90 (d, J ˆ 11.0, 2 H, Hcis of (CH2ˆCHCH2)2N); 5.17 (d, J ˆ 4.1,
HÀC(4)); 5.44 (m, (CH2ˆCHCH2)2N); 7.15 7.60 (m, 9 H, Biph). 13C-NMR (75 MHz, CDCl3): 19.1; 29.1; 54.1;
54.4; 59.8; 74.1; 99.0; 115.8; 126.1; 126.5; 126.7; 127.0; 137.7; 139.3; 141.1. EI-MS (70 eV): 364 (1, [C24H29NO2 ‡
‡
‡
‡
1] ), 348 (4, [C24H29NO2 À Me] ), 288 (3, [C24H29NO2 À C3H7O2] ), 276 (8), 181 (17), 165 (12), 138 (17), 122
‡
(100, C8H12N ), 108 (40), 81 (36), 68 (16), 55 (26). Anal. calc. for C24H29NO2 (363.50): C 79.30, H 8.07, N 3.85;
found: C 79.26, H 7.92, N 3.65.
rac,cis-4-([1,1'Biphenyl]-4-yl)-2,2-dimethyl-1,3-dioxan-5-amine (rac,cis-16). A soln. of rac,cis-15 (32.6 g,
90 mmol) in MeCN (252 ml) and H2O (48 ml) was refluxed in the presence of [RhCl(Ph3P)3] (1.00 g,
1.00 mmol), and the formed propanal was distilled off during the procedure. After 1.5 h, the solvent was
evaporated. FC (CH2Cl2/MeOH 9 :1) gave rac,cis-16 (25.2 g, 99%). Colorless solid. M.p. 1168. IR (KBr): 3375,
1
2988, 2938, 2913, 2857, 1489, 1378, 1361, 1238, 1197, 1160, 1127, 1074, 1050, 942, 859, 761. H-NMR (300 MHz,
CDCl3): 1.56 (s, 1 MeÀC(2)); 1.58 (s, 1 MeÀC(2)); 2.80 (ddd, J ˆ 1.0, 1.9, 2.2, HÀC(5)); 3.94 (dd, J ˆ 1.9, 11.8,
1HÀC(6)); 4.31( dd, J ˆ 2.2, 11.8, 1 HÀC(6)); 5.15 (d, J ˆ 1.0, HÀC(4)); 7.25 7.64 (m, 9 H, Biph). 13C-NMR

Helvetica Chimica Acta Vol. 85 (2002)
3671
(75 MHz, CDCl3): 18.6; 29.8; 49.7; 66.2; 73.7; 99.3; 126.2; 127.1; 127.2; 127.3; 128.8; 138.7; 140.4; 140.9. EI-MS
‡
‡
‡
(70 eV): 284 (2, [C18H21NO2 ‡ 1] ), 268 (21, [C18H21NO2 À Me] ), 225 (49), 208 (70, [C18H21NO2 À C3H7O2] ),
‡
‡
‡
182 (57), 152 (100, C12H8 ), 150 (23), 114 (15), 101 (75, C5H9O2 ), 77 (24, C6H5 ), 59 (21) Anal. calc. for
C18H21NO2 (283.37): C 76.29, H 7.47, N 4.94; found: C 76.24, H 7.45, N 4.92.
(4R,5R)-4-([1,1'-Biphenyl]-4-yl)-2,2-dimethyl-1,3-dioxan-5-amine ((R,R)-16). rac-16 (17 g, 60 mmol) was
refluxed in EtOH (100 ml). After a clear soln. was obtained, d(À)-tartaric acid (9,0 g, 60.0 mmol) was added. To
the formed salt, EtOH was added successively under reflux until a clear soln. was obtained. The soln. was kept at
‡ 28 for 24 h, and the formed crystals were separated by filtration and recrystallized again in EtOH. The
isolated crystals were dissolved in 2n NaOH, and the aq. layer was extracted 3 Â with CH2Cl2. The combined
org. phase was dried (MgSO4) and evaporated: 3.54 g (22%) of enantiomerically pure (R,R)-16. Recrystalliza-
25
D
tion of the concentrated mother liquors gave further 3 g (19%) of (R,R)-16. ‰aŠ ˆ À5.6 (c ˆ 1.00, CHCl3).
(4S,5S)-4-([1,1'-Biphenyl]-4-yl)-2,2-dimethyl-1,3-dioxan-5-amine ((S,S)-16). The resolution of rac-16 was
performed with l-(‡)-tartaric acid as resolving agent according to the above described procedure: (S,S)-16.
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D
‰aŠ ˆ ‡5.6 (c ˆ 1.00, CHCl3).
N-[(4S,5S)-4-([1,1'-Biphenyl]-4-yl)-2,2-dimethyl-1,3-dioxan-5-yl]ethanesulfonamide ((S,S)-17a). Accord-
ing to GPA, with (S,S)-16 (1.98 g, 7.0 mmol), ethanesulfonyl chloride (1.0 g, 7.7 mmol), Et3N (0.85 g, 8.4 mmol),
30
D
and CH2Cl2 (15 ml). FC (pentane/AcOEt 3 :1) gave (S,S)-16 (2.14 g, 81%). Colorless solid. M.p. 1738. ‰aŠ
ˆ
‡8.8 (c ˆ 1.00, CHCl3). IR (KBr): 3271, 3030, 2981, 2963, 2882, 1602, 1487, 1462, 1451, 1421, 1382, 1333, 1313,
1286, 1267, 1236, 1206, 1166, 1143, 1124, 1077, 1010, 970, 853, 832. 1H-NMR (300 MHz, CDCl3): 0.79 (t, J ˆ 7.4,
MeCH2SO2); 1.56 (s, 1 MeÀC(2)); 2.17 (dq, J ˆ 7.4, 14.8, 1 H, MeCH2SO2); 2.37 (dq, J ˆ 7.4, 14.8, 1 H,
MeCH2SO2); 3.52 (dddd, J ˆ 1.7, 1.9, 1.9, 9.9, HÀC(5)); 4.02 (dd, J ˆ 1.9, 12.1, 1 HÀC(6)); 4.30 (dd, J ˆ 1.7, 12.1,
1 HÀC(6)); 5.19 (d, J ˆ 1.9, HÀC(4)); 7.32 7.63 (m, 9 H, Biph). 13C-NMR (75 MHz, CDCl3): 7.8; 18.5; 29.6;
‡
48.0; 52.7; 66.0; 73.3; 99.8; 126.2; 127.0; 127.5; 128.9; 138.0; 140.6; 140.9. EI-MS (70 eV): 375 (1, C20H25NO4S ),
‡
‡
‡
360 (2, [C20H25NO4S À Me] ), 317 (15, [C20H25NO4S À C3H6O] ), 300 (11, [C20H25NO4S À C3H7O2] ), 194 (11),
‡
‡
‡
‡
182 (100, C13H10O ), 163 (C6H13NO2S ), 152 (17, C12H8O ), 135 (60, C4H9NO2S ), 106 (46). Anal. calc. for
C20H25NO4S (375.49): C 63.97, H 6.71, N 3.73; found: C 63.47, H 6.67, N 3.65.
N-[(4S,5S)-4-([1,1'-Biphenyl]-4-yl)-2,2-dimethyl-1,3-dioxan-5-yl]propane-1-sulfonamide ((S,S)-17b). Ac-
cording to GP A, with (S,S)-16 (2.83 g, 10.0 mmol), propanesulfonyl chloride (1.57 g, 11.0 mmol), Et3N (1.21 g,
28
D
12 mmol), and CH2Cl2 (20 ml). FC (pentane/AcOEt 3 :1) gave (S,S)-17b (3.78 g, 97%). Colorless foam. ‰aŠ
ˆ
‡8.5 (c ˆ 1.00, CHCl3). IR (KBr): 3260, 3054, 3031, 2990, 2970, 2934, 2861, 1600, 1490, 1455, 1423, 1408, 1385,
1330, 1317, 1288, 1263, 1234, 1199, 1167, 1145, 1131, 1086, 1015, 972, 832. 1H-NMR (300 MHz, CDCl3): 0.60
(t, J ˆ 7.4, MeCH2CH2SO2); 1.05 1.40 (m, MeCH2CH2SO2); 1.57 (s, 1 MeÀC(2)); 1.58 (s, 1 MeÀC(2)); 2.08
2.28 (m, MeCH2CH2SO2); 3.54 (dddd, J ˆ 1.7, 1.9, 1.9, 9.9, HÀC(5)); 4.02 (dd, J ˆ 1.9, 12.1, 1 HÀC(6)); 4.30
(dd, J ˆ 1.7, 12.1, 1 HÀC(6)); 5.19 (d, J ˆ 1.9, HÀC(4)); 7.33 7.64 (m, 9 H, Biph). 13C-NMR (75 MHz, CDCl3):
12.7; 16.9; 18.5; 29.6; 52.8; 55.4; 66.1; 72.4; 99.8; 126.2; 127.0; 127.5; 128.9; 138.0; 140.5; 141.0. EI-MS (70 eV):
‡
‡
‡
388 (1, C21H26NO4S ), 374 (3, [C21H26NO4S À CH3] ), 331(51, [C 21H26NO4S À C3H6O] ), 314 (11,
‡
‡
‡
[C21H26NO4S À C3H7O2] ), 194 (10), 182 (100, C13H10O ), 149 (C5H11NO2S ), 106 (17). HR-MS: 374.1424
‡
([C21H26NO4S À Me] ; calc. 374.1426).
N-[(4R,5R)-4-[(1,1'-Biphenyl]-4-yl)-2,2-dimethyl-1,3-dioxan-5-yl]propane-1-sulfonamide ((R,R)-17b).
According to GP A, with (R,R)-16 (1.4 g, 5.0 mmol), propanesulfonyl chloride (0.79 g, 5.5 mmol), Et3N
(0.61g, 6.0 mmol), and CH 2Cl2 (20 ml). FC (pentane/AcOEt 3 :1) gave (R,R)-16 (1.78 g, 94%). Colorless foam.
28
D
‰aŠ ˆ À8.5 (c ˆ 1.00, CHCl3).
N-[(4R,5R)-4-[1,1'-Biphenyl]-4-yl)-2,2-dimethyl-1,3-dioxan-5-yl]-2-methylpropane-1-sulfonamide ((R,R)-
17c). According to GP A, with (R,R)-16 (3.63 g, 12.8 mmol), 2-methylpropanesulfonyl chloride (2.21 g,
14.1 mmol), Et3N (1.56 g, 15.4 mmol), and CH2Cl2 (25 ml). FC (pentane/AcOEt 3 :1) gave (R,R)-17c (4.64 g,
25
D
90%). Colorless foam. ‰aŠ ˆ À7.6 (c ˆ 1.10, CHCl3). IR (KBr): 3282, 3058, 3030, 2990, 2961, 2873, 1601, 1489,
1467, 1451, 1408, 1384, 1331, 1311, 1264, 1234, 1200, 1168, 1147, 1130, 1080, 1009, 969, 939. 1H-NMR (300 MHz,
CDCl3): 0.71( d, J ˆ 6.6, 3 H, Me2CHCH2SO2); 0.75 (d, J ˆ 6.6, 3 H, Me2CHCH2SO2); 1.56 (s, 1 MeÀC(2)); 1.57
(s, 1 MeÀC(2)); 1.76 (m, Me2CHCH2SO2); 1.89 (dd, J ˆ 6.9, 14.1, 1 H, Me2CHCH2SO2); 2.08 (dd, J ˆ 6.9, 14.0,
1H, Me 2CHCH2SO2); 3.55 (dddd, J ˆ 1.6, 1.7, 1.9, 9.9, HÀC(5)); 4.01( dd, J ˆ 1.9, 12.1, 1 HÀC(6)); 4.30 (dd, J ˆ
1.7, 12.1, 1 HÀC(6)); 5.18 (d, J ˆ 1.6, HÀC(4)); 7.32 7.64 (m, 9 H, Biph). 13C-NMR (75 MHz, CDCl3): 18.5;
22.2; 22.3; 24.3; 29.5; 52.6; 61.1; 66.2; 72.4; 99.7; 126.5; 127.0; 127.4; 128.8; 138.2; 140.5; 140.8. EI-MS (70 eV):
‡
‡
‡
388 (2, [C22H29NO4S À Me] ), 345 (17,[C22H29NO4S À C3H6O] ), 328 (11, [C22H29NO4S À C3H7O2] ), 182 (100,
‡
‡
‡
‡
‡
C13H10O ), 163 (11, C6H13NO2S ), 152 (12, C12H8 ), 57 (17, C4H9 ). HR-MS: 388.1583 ([C22H29NO4S À Me] ;
calc. 388.1584).

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Helvetica Chimica Acta Vol. 85 (2002)
N-[(4S,5S)-4-([1,1'-Biphenyl]-4-yl)-2,2-dimethyl-1,3-dioxan-5-yl]-N-methylethanesulfonamide ((S,S)-18a).
According to GP C, with (S,S)-17a (2.14 g, 5.7 mmol), BuLi (5.7 mmol), MeI (0.89 g, 6.3 mmol), and THF
30
D
(40 ml). FC (pentane/AcOEt 3 :1) gave (S,S)-18a (1.93 g, 87%). Colorless solid. M.p. 125 1288. ‰aŠ ˆ ‡6.6
(c ˆ 1.00, CHCl3). IR (KBr): 3028, 2993, 2941, 2876, 1600, 1487, 1459, 1382, 1327, 1288, 1267, 1237, 1198, 1180,
1132, 1107, 1085, 1019, 976, 900, 850, 822. 1H-NMR (300 MHz, CDCl3): 0.81( t, J ˆ 7.4, MeCH2SO2); 1.55
(s, 1 MeÀC(2)); 1.56 (s, 1 MeÀC(2)); 2.05 (dq, J ˆ 7.4, 14.8, 1 H, MeCH2SO2); 2.31( dq, J ˆ 7.4, 14.8, 1 H,
MeCH2SO2); 3.19 (s, MeN); 4.13 (ddd, J ˆ 1.4, 3.6, 3.6, HÀC(5)); 4.15 (dd, J ˆ 1.4, 12.9, 1 HÀC(6)); 4.43
(dd, J ˆ 3.6, 12.9, 1 HÀC(6)); 5.31( d, J ˆ 3.6, HÀC(5)); 7.30 7.63 (m, 9 H, Biph). 13C-NMR (75 MHz, CDCl3):
7.6; 18.7; 29.3; 34.0; 46.0; 52.6; 65.6; 73.2; 99.5; 126.1; 126.9; 127.0; 127.5; 128.9; 138.2; 140.6; 140.7. EI-MS
‡
‡
‡
(70 eV): 374 (1, [C21H27NO4S À Me] ), 314 (7, [C21H27NO4S À C3H7O2] ), 182 (12, C13H10O ), 149 (100,
‡
C5H11NO2S ), 120 (93), 57 (20). Anal. calc. for C21H27NO4S (389.52): C 64.74, H 6.99, N 3.60; found: C 64.32, H
7.10, N 3.40.
N-[(4S,5S)-4-([1,1'-Biphenyl]-4-yl)-2,2-dimethyl-1,3-dioxan-5-yl]-N-methylpropane-1-sulfonamide ((S,S)-
18b). According to GP C, with (S,S)-17b (0.67 g, 1.7 mmol), BuLi (1.7 mmol), MeI (0.29 g, 2 mmol), and
26
D
THF (20 ml). FC (pentane/AcOEt 4 :1) gave (S,S)-18b (0.59 g, 85%). ‰aŠ ˆ ‡6.7 (c ˆ 1.00, CHCl3). IR (KBr):
3059, 3031, 2991, 2967, 2939, 2876, 1601, 1490, 1460, 1408, 1383, 1323, 1292, 1267, 1241, 1199, 1181, 1160, 1131,
1106, 1079, 1020, 977, 950, 900, 852, 822, 762. 1H-NMR (300 MHz, CDCl3): 0.61( t, J ˆ 7.4, MeCH2CH2SO2);
1.15 1.45 (m, MeCH2CH2SO2); 1.52 (s, 1 MeÀC(2)); 1.55 (s, 1 MeÀC(2)); 1.82 (m, 1H, MeCH 2CH2SO2); 2.22
(m, 1H, MeCH 2CH2SO2); 3.19 (s, MeN); 4.08 (ddd, J ˆ 1.1, 3.3, 3.6, HÀC(5)); 4.10 (dd, J ˆ 1.2, 12.9,
1HÀC(6)); 4.42 (dd, J ˆ 3.6, 12.9, 1 HÀC(6)); 5.28 (d, J ˆ 3.3, HÀC(4)); 7.28 7.63 (m, 9 H, Biph). 13C-NMR
(75 MHz, CDCl3): 13.5; 17.4; 19.3; 30.0; 34.5; 53.2; 53.9; 66.3; 73.9; 100.1; 126.9; 127.6; 128.1; 128.5; 139.0; 141.1;
‡
‡
141.2. EI-MS (70 eV): 388 (2, [C22H29NO4S À Me] ), 345 (1, [C22H29NO4S À C3H6O] ), 328 (11, [C22H29NO4S À
‡
‡
‡
C3H7O2] ), 210 (8), 182 (10, C13H10O ), 163 (100, C6H13NO2S ), 120 (44), 57 (62). Anal. calc. for C22H29NO4S
(403.54): C 65.48, H 7.24, N 3.74; found: C 65.19, H 7.25, N 3.44.
N-[(4R,5R)-4-([1,1'-Biphenyl]-4-yl)-2,2-dimethyl-1,3-dioxan-5-yl]-N-methylpropane-1-sulfonamide
((R,R)-18b). According to GP C, with (R,R)-17b (0.4 g, 1.0 mmol), BuLi (1.0 mmol), MeI (0.15 g, 1.2 mmol),
26
D
and THF (12 ml). FC (pentane/AcOEt 4 :1) gave (R,R)-18b (0.33 g, 83%). Colorless foam. ‰aŠ ˆ À6.7 (c ˆ
1.00, CHCl3).
N-[(4R,5R)-4-([1,1'-Biphenyl]-4-yl)-2,2-dimethyl-1,3-dioxan-5-yl)-N,2-dimethylpropane-1-sulfonamide
((R,R)-18c). According to GP C, with (R,R)-17c (1.99 g, 4.9 mmol), BuLi (4.9 mmol), MeI (0.77 g, 5.4 mmol),
25
D
and THF (35 ml). FC (pentane/AcOEt 4 :1) gave (R,R)-18c (1.65 g, 81%). Colorless solid. M.p. 1168. ‰aŠ
ˆ
À6.4 (c ˆ 1.20, CHCl3). IR (KBr): 3060, 3029, 2998, 2968, 2939, 2877, 1600, 1493, 1460, 1410, 1383, 1323, 1292,
1
1267, 1241, 1199, 1181, 1160, 1131, 1106, 1079, 1020, 977, 950, 903, 855, 822, 766. H-NMR (300 MHz, CDCl3):
0.75 (d, J ˆ 6.9, 3 H, Me2CHCH2SO2); 0.77 (d, J ˆ 6.9, 3 H, Me2CHCH2SO2); 1.58 (s, 2 MeÀC(2)); 1.41 (dd, J ˆ
7.1, 13.7, 1 H, Me CHCH2SO2); 1.84 (m, Me2CHCH2SO2); 2.16 (dd, J ˆ 7.1, 13.7, 1 H, Me CHCH2SO2); 3.20
2
2
(s, MeN); 4.11 4.17 (m, 1 HÀC(6)); 4.48 (dd, J ˆ 3.9, 13.2, 1 HÀC(6)); 5.31( d, J ˆ 3.3, HÀC(4)); 7.32 7.63
(m, 9 H, Biph). 13C-NMR (75 MHz, CDCl3): 18.7; 22.3; 22.5; 24.3; 29.4; 33.5; 52.4; 58.2; 65.8; 73.5; 99.6; 126.4;
‡
127.0; 127.1; 127.5; 128.9; 138.3; 140.5; 140.8. EI-MS (70 eV): 402 (2, [C23H31NO4S À Me] ), 359 (1,
‡
‡
‡
[C23H31NO4S À C3H6O] ), 342 (7, [C23H31NO4S À C3H7O2] ), 222 (5), 182 (16, C13H10O ), 177 (95,
‡
‡
‡
C7H15NO2S ), 152 (C12H8 ), 120 (23), 98 (27), 57 (100, C4H9 ). Anal. calc. for C23H31NO4S (417.57): C 66.16,
H 7.48, N 3.35; found: C 65.81, H 7.44, N 3.26.
(aR)-N-[(4S,5S)-4-([1,1'-Biphenyl]-4-yl)-2,2-dimethyl-1,3-dioxan-5-yl]-N,a-dimethylbenzeneethanesulfon-
amide ((R,S,S)-19a). According to GP D, with (S,S)-18a (0.39 g, 1.00 mmol), BuLi (1.1 mmol), benzyl bromide
(0.34 g, 2.0 mmol), HMPA (0.17 g, 1 mmol), and Et2O (20 ml). FC (pentane/AcOEt 4 :1) gave (R,S,S)-19a
(0.32 g, 67%). Colorless solid. de 83% (1H-NMR). The major diastereoisomer was separated by HPLC. de
ꢀ 98% (1H-NMR). M.p. 1658. IR (KBr): 3060, 3029, 2990, 2939, 2868, 1602, 1490, 1456, 1382, 1316, 1266, 1239,
1200, 1176, 1131, 1107, 1082, 1018, 974, 949, 898, 848, 821, 762, 731, 699. 1H-NMR (major diastereoisomer;
300 MHz, CDCl3): 0.78 (d, J ˆ 6.9, PhCH2CH(Me)SO2); 1.58 (s, 2 MeÀC(2)); 2.33 (dd, J ˆ 11.5, 13.0, 1 H,
PhCH2CH(Me)SO2); 2.90 (ddq, J ˆ 3.3, 6.9, 11.5, PhCH2CH(Me)SO2); 2.99 (dd, J ˆ 3.3, 13.0, 1 H,
PhCH2CH(Me)SO2); 3.25 (s, MeN); 4.13 (ddd, J ˆ 1.5, 3.6, 3.6, 1 H, HÀC(5)); 4.21( dd, J ˆ 1.5, 12.9,
1 HÀC(6)); 4.45 (dd, J ˆ 3.6, 12.9, 1 HÀC(6)); 5.36 (d, J ˆ 3.6, HÀC(4)); 6.91 7.65 ( m, 14 H, Ph, Biph).
13C-NMR (major diastereoisomer; 75 MHz, CDCl3): 13.0; 18.8; 29.3; 35.1; 36.0; 52.8; 59.3; 65.7; 73.3; 99.7;
126.3; 126.6; 127.0; 127.1; 127.4; 128.5; 128.8; 129.2; 137.1; 137.4; 137.7; 140.4; 140.5. EI-MS (70 eV): 464 (3,
‡
‡
‡
‡
[C28H33NO4S À Me] ), 404 (5, [C28H33NO4S À C3H7O2] ), 340 (4), 239 (55, C12H17NO2S ), 152 (8, C12H8 ), 118
‡
‡
‡
(100, C10H10), 91(89, C 7H7 ), 57 (19, C4H9 ). Anal. calc. for C28H33NO4S (479.64): C 70.12, H 6.93, N 2.92; found:
C 70.11, H 6.86, N 2.81.

Helvetica Chimica Acta Vol. 85 (2002)
3673
(2R)-N-[(4S,5S)-4-([1,1'-Biphenyl]-4-yl)-2,2-dimethyl-1,3-dioxan-5-yl]-N-methylpent-4-ene-2-sulfonamide
((R,S,S)-19b). According to GP D, with (S,S)-18a (0.39 g, 1.0 mmol), BuLi (1.1 mmol), allyl bromide (0.24 g,
2.0 mmol), HMPA (0.17 g, 1 mmol), and Et2O (20 ml). FC (pentane/AcOEt 4 :1) gave (R,S,S)-19b (0.29 g,
68%). Colorless solid. de 88% (1H-NMR). IR (KBr): 3076, 3061, 3038, 2998, 2987, 2937, 2885, 1602, 1487, 1452,
1
1410, 1383, 1371, 1328, 1306, 1286, 1260, 1232, 1210, 1200, 1171, 1133, 1117. H-NMR (300 MHz, CDCl3): 0.92
[0.70] (d, J ˆ 7.1, CH 2ˆCHCH2CH(Me)SO2); 1.57 (s, , 2 MeÀC(2)); 1.83 (m, 1H, CH 2ˆCHCH2CH(Me)SO2);
2.06 (m, 1H, CH 2ˆCHCH2CH(Me)SO2); 2.51( m, 1H, CH 2ˆCHCH2CH(Me)SO2); 3.22 (s, MeN); 4.01
(ddd, J ˆ 1.4, 3.6, 3.6, HÀC(5)); 4.18 (dd, J ˆ 1.4, 12.9, 1 HÀC(6)); 4.43 (dd, J ˆ 3.6, 12.9, 1 HÀC(6)); 4.82
(dd, J ˆ 1.4, 11.5, Hcis of CH2ˆCHCH2CH(Me)SO2); 4.91( dd, J ˆ 1.4, 15.7, 1 H, Htrans of CH2ˆCHCH2CH(Me)-
SO2); 5.24 (m, CH2ˆCHCH2CH(Me)SO2); 5.34 (d, J ˆ 3.6, HÀC(4)); 7.30 7.63 (m, 9 H, Biph). 13C-NMR
(75 MHz, CDCl3): 13.0; 18.7; 29.3; 34.4; 35.0; 52.9 [53.2]; 57.5; 65.7; 73.2; 99.6; 118.1 [118.0]; 126.1; 127.1; 127.4;
‡
128.8; 133.6; 137.9; 140.6; 140.7. EI-MS (70 eV): 413 (3, [C24H31NO4S À Me] ), 353 (4, [C24H31NO4S À
‡
‡
‡
‡
‡
C3H7O2] ), 189 (14, C8H15NO2S ), 161 (100, C6H11NO2S ), 83 (27, C5H9 ), 57 (13, C4H9 ). Anal. calc. for
C24H31NO4S (428.57): C 67.10, H 7.27, N 3.26; found: C 66.73, H 7.45, N 3.10.
(3R)-N-[(4S,5S)-4-([1,1'-Biphenyl]-4-yl)-2,2-dimethyl-1,3-dioxan-5-yl]-N-methylheptane-3-sulfonamide
((R,S,S)-19c). According to GP D, with (S,S)-18b (1.87 g, 4.6 mmol), BuLi (5.1 mmol), BuI (1.7 g, 9.3 mmol),
HMPA (0.78 g, 4.6 mmol), and Et2O (40 ml). FC (pentane/AcOEt 5 :1) gave (R,S,S)-19c (1.5 g, 71%).
Colorless oil. de 89% (1H-NMR). The major diastereoisomer was separated by HPLC. de ꢀ 98% (1H-NMR).
IR (CHCl3): 3058, 3029, 2990, 2958, 2871, 1601, 1489, 1461, 1407, 1382, 1314, 1265, 1239, 1200, 1177, 1158, 1124,
1106, 1082, 1019, 1009, 975, 950, 898, 853, 822. 1H-NMR (major diastereoisomer; 300 MHz, CDCl3): 0.71( t, J ˆ
7.4, Me(CH2)3CH(MeCH2)SO2); 0.76 (t, J ˆ 7.4, Me(CH2)3CH(MeCH2)SO2); 0.80 1.42 (m, Me(CH2)3CH-
(MeCH2)SO2); 1.56 (s, 1 MeÀC(2)); 1.57 (s, 1 MeÀC(2)); 2.32 (m, CHSO2); 3.19 (s, MeN); 4.04 (ddd, J ˆ 1.7,
3.6, 3.6, HÀC(5)); 4.18 (dd, J ˆ 1.7, 12.9, 1 HÀC(6)); 4.44 (dd, J ˆ 3.6, 12.9, 1 HÀC(6)); 5.33 (d, J ˆ 3.6,
HÀC(4)); 7.31 7.64 ( m, 9 H, Biph). 13C-NMR (major diastereoisomer; 75 MHz, CDCl3): 10.7; 13.7; 18.8; 20.6;
22.9; 26.8; 28.0; 29.3; 34.8; 52.8; 63.4; 65.8; 73.3; 99.6; 126.1; 126.9; 127.0; 127.4; 128.8; 138.0; 140.4; 140.5. EI-MS
‡
‡
‡
(70 eV): 444 (1, [C26H37NO4S À Me] ), 384 (1, [C26H37NO4S À C3H7O2] ), 219 (32, C10H21NO2S ), 204 (23), 152
‡
‡
(5, C12H8 ), 57 (30, C4H9 ). Anal. calc. for C26H37NO4S (459.65): C 67.94, H 8.11, N 3.05; found: C 67.98, H 8.17, N
2.96.
(3R)-N-[(4S,5S)-4-([1,1'-Biphenyl]-4-yl)-2,2-dimethyl-1,3-dioxan-5-yl]-N-methylhexane-3-sulfonamide
((R,S,S)-19d). According to GP D, with (S,S)-18b (1.32 g, 3.3 mmol), BuLi (3.6 mmol), PrI (1.1 g, 6.5 mmol),
HMPA (0.59 g, 3.3 mmol), and Et2O (33 ml). FC (pentane/Et2O 2 :1) gave (R,S,S)-19d (1.2 g, 80%). Colorless
solid. de 88% (1H-NMR). The major diastereoisomer was separated by HPLC. de ꢀ 98% (1H-NMR). M.p.
1788. IR (CHCl3): 3027, 2991, 2964, 2935, 2873, 1601, 1488, 1463, 1463, 1382, 1318, 1238, 1216, 1200, 1178, 1158,
1124, 1106, 1084, 1020, 1009, 975, 949, 898, 853, 821, 761, 727, 699, 668. 1H-NMR (major diastereoisomer;
300 MHz, CDCl3): 0.69 1.50 (m, Me(CH2)2CH(MeCH2)SO2); 1.57 (s, 1 MeÀC(2)); 1.58 (s, 1 MeÀC(2)); 2.33
(m, Me(CH2)2CH(MeCH2SO2); 3.20 (s, MeN); 4.05 (ddd, J ˆ 1.7, 3.6, 3.6, HÀC(5)); 4.18 (dd, J ˆ 1.65, 12.9,
1 HÀC(6)); 4.46 (dd, J ˆ 3.6, 12.9, 1 HÀC(6)); 5.33 (d, J ˆ 3.57, HÀC(4)); 7.30 7.70 (m, 9 H, Biph). 13C-NMR
(major diastereoisomer; 75 MHz, CDCl3): 10.8; 14.2; 18.8; 19.3; 20.7; 29.2; 29.3; 34.8; 52.8; 63.3; 65.8; 73.3; 99.6;
‡
126.1; 126.9; 127.0; 127.4; 128.8; 137.9; 140.5. EI-MS (70 eV): 430 (6, [C25H35NO4S À Me] ), 387 (2,
‡
‡
[C25H35NO4S À C3H6O] ), 370 (7, [C25H35NO4S À C3H7O2] ), 205 (65), 190 (46), 181 (11), 126 (15), 85 (19),
‡
57 (100, C4H9 ). Anal. calc. for C25H35NO4S (445.62): C 67.38, H 7.92, N 3.14; found: C 67.27, H 8.36, N 3.44.
(3R)-N-[(4S,5S)-4-([1,1'-Biphenyl]-4-yl)-2,2-dimethyl-1,3-dioxan-5-yl]-N-methylnonane-3-sulfonamide
((R,S,S)-19e). According to GP D, with (S,S)-18b (0.8 g, 2.0 mmol), BuLi (2.2 mmol), hexyl iodide (0.85 g,
4.0 mmol), HMPA (0.36 g, 2 mmol), and Et2O (20 ml). FC (pentane/AcOEt 5 :1) gave (R,S,S)-19e (0.6 g,
62%). Colorless oil. de 83% (1H-NMR). The major diastereoisomer was separated by HPLC. de ꢀ 98%
(1H-NMR). M.p. 998. IR (KBr): 3061, 3030, 2986, 2953, 2939, 2888, 2867, 1601, 1489, 1460, 1408, 1384, 1365, 1305,
1283, 1263, 1237, 1195, 1175, 1124, 1108, 1083, 1018, 973, 949, 896, 855, 842, 824. 1H-NMR (major
diastereoisomer; 300 MHz, CDCl3): 0.73 0.81( m, Me(CH2)5CH(MeCH2)SO2); 1.00 1.43 (m, Me(CH2)5CH-
(MeCH2)SO2); 1.53 (s, 1 MeÀC(2)); 1.56 (s, 1 MeÀC(2)); 2.30 (m, CHSO2); 3.19 (s, MeN); 4.02 (ddd, J ˆ 1.2,
3.6, 3.6, HÀC(5)); 4.17 (dd, J ˆ 1.2, 12.9, 1 HÀC(6)); 4.43 (dd, J ˆ 3.6, 12.9, 1 HÀC(6)); 5.31( d, J ˆ 3.6,
HÀC(4)); 7.29 7.63 (m, 9 H, Biph). 13C-NMR (major diastereoisomer; 75 MHz, CDCl3): 10.7; 14.0; 18.7; 20.5;
22.5; 25.8; 27.0; 29.3; 29.5; 31.6; 34.8; 52.8; 63.4; 65.8; 73.3; 99.5; 126.1; 126.8; 127.4; 128.8; 138; 140.3; 140.4. EI-
‡
‡
‡
MS (70 eV): 472 (1, [C28H41NO4S À Me] ), 412 (2, [C28H41NO4S À C3H7O2] ), 247 (34, C12H25NO2S ), 232 (20,
‡
‡
‡
‡
‡
C11H22NO2S ), 222 (6), 183 (15, C13H11O ), 121 (14), 85 (16, C6H13), 71(25, C 5H11), 57 (100, C4H9 ). Anal. calc.
for C28H41NO4S (487.71): C 68.96, H 8.47, N 2.87; found: C 68.49, H 8.60, N 2.69.

3674
Helvetica Chimica Acta Vol. 85 (2002)
(aR)-N-[(4S,5S)-4-([1,1'-Biphenyl]-4-yl)-2,2-dimethyl-1,3-dioxan-5-yl-a-ethyl-N-methylbenzeneethanesul-
fonamide ((R,S,S)-19f). According to GP D, with (S,S)-18b (1.32 g, 3.3 mmol), BuLi (3.6 mmol), benzyl
bromide (1.11 g, 6.5 mmol), HMPA (0.89 g, 3.3 mmol), and Et2O (33 ml). FC (pentane/AcOEt 5 :1) gave
(R,S,S)-19f (1.27 g, 78%). Colorless foam. de 94% (1H-NMR). IR (KBr): 3061, 3028, 2991, 2939, 2900, 2877,
1601, 1489, 1456, 1409, 1384, 1315, 1263, 1238, 1197, 1177, 1157, 1132, 1108, 1080, 1017, 974, 950, 897, 855, 846, 822,
764, 739, 728, 697. 1H-NMR (300 MHz, CDCl3): 0.65 (t, J ˆ 7.2, PhCH2CH(MeCH2)SO2); 1.30
(m, PhCH2CH(MeCH2)SO2 ;
1
.57 s(, 1 MeÀC(2)); 1.58 (s, 1 MeÀC(2)); 2.56 (dd, J ˆ 10.2, 13.5, 1 H,
PhCH2CH(MeCH2)SO2); 2.80 (m, CHSO2); 2.89 (dd, J ˆ 3.9, 13.5, 1 H, PhCH2CH(MeCH2)SO2); 3.24 [3.25]
(s, MeN); 4.13 (ddd, J ˆ 1.7, 3.6, 3.6, HÀC(5)); 4.18 (dd, J ˆ 1.7, 12.9, 1 HÀC(6)); 4.46 (dd, J ˆ 3.6, 12.9,
1 HÀC(6)); 5.35 (d, J ˆ 3.6, HÀC(4)); 6.93 7.64 (m, 9 H, Biph). 13C-NMR (75 MHz, CDCl3): 11.1; 18.8; 21.0;
29.3; 34.0; 34.8; 52.8; 64.4; 65.7; 73.4 [73.2]; 99.6; 126.2; 126.6; 127.0; 127.1; 127.4; 128.5; 128.8; 129.0; 137.4; 137.7;
‡
‡
140.5; 140.6. EI-MS (70 eV): 478 (2, [C29H35NO4S À Me] ), 418 (3, [C29H35NO4S À C3H7O2] ), 253 (55,
‡
‡
‡
‡
C13H19NO2S ), 132 (86, C10H12), 91(100, C 7H7 ), 57 (30, C4H9 ). Anal. calc. for C29H35NO4S (493.67): C 70.56, H
7.15, N 2.84; found: C 70.52, H 7.02, N 2.81.
(aS)-N-[(4R,5R)-4-([1,1'-Biphenyl]-4-yl)-2,2-dimethyl-1,3-dioxan-5-yl]-a-ethyl-N-methylbenzeneethane-
sulfonamide ((S,R,R)-19f). According to GP D, with (R,R)-18b (1.32 g, 3.3 mmol), BuLi (3.6 mmol), benzyl
bromide (1.11 g, 6.5 mmol), HMPA (0.89 g, 3.3 mmol), and Et O (20 ml). FC (pentane/AcOEt 5 :1) (S,R,R)-
2
19f (1.23 g, 76%). Colorless foam. de 94% (1H-NMR).
(aS)-N-[(4R,5R)-4-([1,1'-Biphenyl]-4-yl)-2,2-dimethyl-1,3-dioxan-5-yl]-4-(tert-butyl)-a-ethyl-N-methyl-
benzeneethanesulfonamide ((S,R,R-19g). According to GP D, with (R,R)-18b (0.8 g, 2.0 mmol), BuLi
(2.2 mmol), 4-(tert-butyl)benzyl bromide (0.9 g, 4.0 mmol), HMPA (0.36 g, 2.0 mmol), and Et2O (20 ml). FC
(pentane/Et2O 3 :1) gave (S,R,R)-19g (0.9 g, 82%). Colorless solid. de 91% (1H-NMR). The major
diastereoisomer was separated by HPLC. de ꢀ 98% (1H-NMR). M.p. 1588. IR (KBr): 2965, 2869, 2190, 1621,
1583, 1563, 1545, 1511, 1486, 1461, 1409, 1384, 1365, 1309, 1267, 1241, 1197, 1180, 1133, 1085, 1018, 974, 91, 923,
1
897, 760, 700, 570. H-NMR (major diastereoisomer; 300 MHz, CDCl3): 0.69 (t, J ˆ 7.42, 3 H, tBuC6H4CH2CH-
(MeCH2)SO2); 1.22 (s, tBu); 1.33 (m, tBuC6H4CH2CH(MeCH2)SO2); 1.57 (s, 1 MeÀC(2)); 1.58
t
(s, 1 MeÀC(2)); 2.54 (dd, J ˆ 10.4, 13.5, 1 H, BuC6H4CH2CH(MeCH2)SO2); 2.76 (m, CHSO2); 2.83 (dd, J ˆ
3.9, 13.5, 1 H, tBuC6H4CH2CH(MeCH2)SO2); 3.25 (s, MeN); 4.14 (ddd, J ˆ 1.7, 3.6, 3.6, HÀC(5)); 4.19 (dd, J ˆ
1.7, 12.9, 1 HÀC(6)); 4.46 (dd, J ˆ 3.9, 12.9, 1 HÀC(6)); 5.35 (d, J ˆ 3.6, HÀC(4)); 6.80 7.70 (m, 1 3 H,
tBuC6H4CH2CH(MeCH2)SO2, Biph). 13C-NMR (major diastereoisomer; 75 MHz, CDCl3): 10.9; 18.8; 20.9;
29.2; 31.3; 33.4; 34.3; 34.9; 52.8; 64.5; 65.8; 73.3; 99.6; 125.3; 126.2; 127.0; 127.1; 127.2; 128.6; 128.8; 127.4; 134.1;
‡
‡
137.8; 140.4. EI-MS (70 eV): 534 (1, [C33H43NO4S À Me] ), 309 (30), 188 (100), 147 (63), 57 (26, C4H9 ). Anal.
calc. for C33H43NO4S (549.77): C 72.10, H 7.88, N 2.55; found: C 71.79, H 7.71, N 2.39.
(2R)-N-[(4R,5R)-4-([1,1'-Biphenyl]-4-yl)-2,2-dimethyl-1,3-dioxan-5-yl]-N,3-dimethylbutane-2-sulfon-
amide ((R,R,R)-19h). According to GP D, with (R,R)-18c (1.12 g, 2.7 mmol), BuLi (3.0 mmol), dimethyl
sulfate (0.68 g, 5.4 mmol), HMPA (0.48 g, 2.7 mmol), and Et2O (30 ml). FC (pentane/AcOEt 5 :1) gave
(R,R,R)-19h (0.96 g, 83%). Colorless solid. de 94% (1H-NMR). M.p. 1088. IR (KBr): 3030, 2990, 2965, 2943,
2874, 1602, 1489, 1467, 1406, 1383, 1315, 1265, 1240, 1200, 1177, 1159, 1129, 1081, 1019, 973, 949, 896, 846, 821,
762. 1H-NMR (300 MHz, CDCl3): 0.60 (d, J ˆ 6.9, 3 H, Me2CHCH(Me)SO2); 0.71( d, J ˆ 6.9, 3 H, Me2CHCH-
(Me)SO2); 0.80 (d, J ˆ 7.1, Me 2CHCH(Me)SO2); 1.56 (s, 2 MeÀC(2)); 2.04 2.14 (m, CHSO2); 3.24 (s, MeN);
3.95 (ddd, J ˆ 1.7, 3.6, 3.6, HÀC(5)); 4.17 (dd, J ˆ 1.7, 12.9, 1 HÀC(6)); 4.45 (dd, J ˆ 3.6, 12.9, 1 HÀC(6)); 5.32
(d, J ˆ 3.6, 1H ÀC(4)); 7.32 7.62 (m, 9 H, Biph). 13C-NMR (75 MHz, CDCl3): 7.9; 16.5; 18.7; 21.4; 27.4; 29.7;
34.9; 53.2; 63.3; 65.8; 73.4; 99.6; 126.2; 127.0; 127.1; 127.5; 128.9; 138.2; 140.6; 140.8. EI-MS (70 eV): 416
‡
‡
‡
(1, [C24H33NO4S À Me] ), 373 (1, [C24H33NO4S À C3H6O] ), 356 (1, [C24H33NO4S À C3H7O2] ), 191 (31,
‡
‡
‡
‡
‡
C8H17NO2S ), 182 (13, C13H10O ), 152 (10, C12H8 ), 71(49, C 7H11), 57 (100, C4H9 ). Anal. calc. for C24H33NO4S
(431.60): C 66.79, H 7.71, N 3.25; found: C 66.46, H 7.78, N 3.14.
(aR)-N-[(4R,5R)-4-([1,1'-Biphenyl]-4-yl)-2,2-dimethyl-1,3-dioxan-5-yl]-N-methyl-a-(1-methylethyl)ben-
zeneethanesulfonamide ((R,R,R)-19i). According to GP D, with (R,R)-18c (1.25 g, 3.0 mmol), BuLi
(3.3 mmol), benzyl bromide (1.0 g, 4.5 mmol), HMPA (0.54 g, 3.0 mmol), and Et2O (30 ml). FC (pentane/
AcOEt 6 :1) gave (R,R,R)-19i (1.14 g, 75%). Colorless foam. de 91% (1H-NMR). IR (KBr): 3029, 2991, 2989,
2964, 2938, 2872, 1602, 1489, 1456, 1407, 1382, 1315, 1267, 1240, 1200, 1176, 1158, 1126, 1106, 1081, 1018, 973, 949,
896, 850, 821, 762. 1H-NMR (300 MHz, CDCl3): 0.63 (d, J ˆ 7.2, 3 H, Me2CHCH(PhCH2SO2); 0.90 [0.95] (d, J ˆ
7.1, 3 H, Me2CHCH(PhCH2)SO2); 1.53 (s, 1 MeÀC(2)); 1.54 (s, 1 MeÀC(2)); 1.72 (m, Me2CHCH(PhCH2)-
SO2); 2.69 2.98 (m, 3 H, Me2CHCH(PhCH2)SO2); 3.13 [3.22] (s, MeN); 4.10 (ddd, J ˆ 1.4, 3.6, 3.6, HÀC(5));
4.36 (dd, J ˆ 3.6, 12.9, 1 HÀC(6)); 4.48 (dd, J ˆ 3.9, 13.2, 1 HÀC(6)); 5.31( d, J ˆ 3.6, HÀC(4)); 6.98 7.64
(m, 9 H, Ph, Biph). 13C-NMR (75 MHz, CDCl3): 18.1; 18.8; 20.6; 27.7; 29.2; 31.1; 34.2; 52.5 [52.1]; 65.4 [65.7];

Helvetica Chimica Acta Vol. 85 (2002)
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68.1 [68.0]; 73.5 [73.1]; 99.5; 126.2; 126.9; 127.0; 127.3; 128.5; 128.8; 128.9; 137.7; 138.7; 140.4; 140.6. EI-MS
‡
‡
‡
(70 eV): 492 (1, [C30H37NO4S À Me] ), 342 (1, [C30H37NO4S À C3H7O2] ), 267 (31, C14H21NO2S ), 182 (9,
‡
‡
‡
‡
‡
C13H10O ), 146 (71, C11H14), 105 (2, C8H9 ), 91(100, C 7H7 ), 57 (52, C4H9 ). Anal. calc. for C30H37NO4S (507.70):
C 70.97, H 7.35, N 2.76; found: C 70.67, H 7.42, N 2.48.
(3R)-N-[(4R,5R)-4-([1,1'-Biphenyl]-4-yl)-2,2-dimethyl-1,3-dioxan-5-yl]-N,2-dimethylhex-5-ene-3-sulfona-
mide ((R,R,R)-19j). According to GP D, with (R,R)-18c (0.6 g, 1.4 mmol), BuLi (1.6 mmol), allyl bromide
(0.34 g, 2.8 mmol), HMPA (0.25 g, 1.4 mmol), and Et2O (15 ml). FC (pentane/AcOEt 6 :1) gave (R,R,R)-19j
(0.5 g, 78%). Colorless oil. de 92% (1H-NMR). IR (CHCl3): 3077, 3061, 3029, 2990, 2965, 2940, 2874, 1678, 1641,
1602, 1488, 1464, 1436, 1408, 1382, 1324, 1265, 1239, 1200, 1177, 1157, 1130, 1106, 1082, 1019, 1009, 974, 950, 897,
846, 822, 762. 1H-NMR (300 MHz, CDCl3): 0.78 (d, J ˆ 7.1, 3 H, CH2ˆCHCH2CH(Me2CH)SO2); 0.90 [0.95]
(d, J ˆ 7.1, 3 H, CH2ˆCHCH2CH(Me)2CH)SO2); 1.53 (s, 1 MeÀC(2)); 1.55 (s, 1 MeÀC(2)); 1.86 (ddd, J ˆ 1.9,
7.1, 7.1, CH2ˆCHCH2CH(Me2CH)SO2); 2.07 2.40 (m, CH2ˆCHCH2CH(Me2CH)SO2); 3.20 [3.17] (s, MeN);
4.00 (ddd, J ˆ 1.4, 3.6, 3.6, HÀC(5)); 4.17 (dd, J ˆ 1.4, 12.9, 1 HÀC(6)); 4.42 (dd, J ˆ 3.6, 12.9, 1 HÀC(6)); 4.82
(dd, J ˆ 1.4, 9.9, 1 H, Hcis of CH2 ˆ CHCH2CH(Me2CH)SO2); 4.91( dd, J ˆ 1.4, 17.0, 1 H,
H
of
trans
CH2ˆCHCH2CH(Me2CH)SO2); 5.28 (m, CH2ˆCHCH2CH(Me2CH)SO2); 5.32 (d, J ˆ 3.6, HÀC(4)); 7.30
7.63 (m, 9 H, Biph). 13C-NMR (75 MHz, CDCl3): 18.1 [17.7]; 18.7; 20.6 [21.0]; 27.6 [27.4]; 29.3 [29.6]; 30.0 [29.7];
34.7 [34.5]; 52.9 [52.4]; 65.8 [65.7]; 66.9 [66.5]; 73.2 [73.1]; 99.5; 116.8 [116.6]; 126.1 [126.0]; 127.1 [127.3]; 127.4;
‡
128.8 [128.7]; 135.5 [136.0]; 138.0; 140.5; 140.6. EI-MS (70 eV): 442 (3, ([C25H32NO4S À Me] ), 382 (1,
‡
‡
‡
[C25H32NO4S À C3H7O2] ), 217 (31, C10H19NO2S ), 189 (92, C8H15NO2S ), 153 (36), 124 (18), 97 (26), 83 (66),
‡
55 (100). HR-MS: 442.2053 ([C25H32NO4S À Me] ); calc. 442.2052).
(aR)-N,a-Dimethylbenzeneethanesulfonamide ((R)-20a). According to GP E, with (R,S,S)-19a (290 mg,
0.6 mmol) and conc. HCl soln. (10 ml). FC (pentane/AcOEt 4 :1) gave (R)-20a (71mg, 55%). Colorless solid.
25
D
M.p. 698. ‰aŠ ˆ À3.1( c ˆ 1.1, CHCl3). ee ꢀ 98% (GC, Lipodex E). IR (KBr): 3305, 3028, 2979, 2937, 1602, 1496,
1455, 1429, 1311, 1147, 1081, 1019, 845. 1H-NMR (300 MHz, CDCl3): 1.32 (d, J ˆ 7.4, PhCH2CH(Me)SO2); 2.72
(dd, J ˆ 3.6, 13.5, 1 H, PhCH2CH(Me)SO2); 2.78 (d, J ˆ 5.2, MeN); 3.28 (ddq, J ˆ 3.6, 4.4, 7.4, 1H,
PhCH2CH(Me)SO2); 3.38 (dd, J ˆ 4.4, 13.5, 1 H, PhCH2CH(Me)SO2); 3.88 (q, J ˆ 5.2, NH); 7.20 7.36
(m, Ph). 13C-NMR (75 MHz, CDCl3): 13.7; 29.7; 36.7; 58.2; 126.9; 128.8; 129.1; 137.5. EI-MS (70 eV): 118
‡
‡
‡
‡
(100, C9H10), 91(83, C 7H7 ), 77 (7, C6H5 ), 65 (9, C5H5 ). Anal. calc. for C10H15NO2S (213.3): C 56.31, H 7.09, N
6.57; found: C 56.19, H 7.04, N 6.48.
(3R)-N-Methylheptane-3-sulfonamide ((R)-20b). According to GP F, with (R,S,S)-19c (770 mg, 1.7 mmol),
conc. H2SO4 soln. (167 mg, 1.7 mmol), and CHCl3 (30 ml). FC (pentane/AcOEt 4 :1) gave (R)-20b (203 mg,
25
D
63%). Colorless oil. ‰aŠ ˆ ‡4.0 (c ˆ 1.1, CHCl3). ee ꢀ 98% (GC, Lipodex E). IR (Film): 3306, 2959, 2937, 2873,
1462, 1428, 1384, 1310, 1232, 1139, 1083, 855. 1H-NMR (300 MHz, CDCl3): 0.93 (t, J ˆ 7.1, Me(CH2)3CH-
(MeCH2SO2); 1.07 (t, J ˆ 7.1, Me(CH2)3CH(MeCH2)SO2); 1.29 1.97 (m, Me(CH2)3CH(MeCH2)SO2); 2.79
(d, J ˆ 5.2, MeN); 2.84 (m, Me(CH2)3CH(MeOH2)SO2); 4.55 (q, J ˆ 5.2, NH). 13C-NMR (75 MHz, CDCl3):
‡
‡
11.2; 13.9; 21.7; 22.7; 27.8; 28.9; 29.6; 62.5. EI-MS (70 eV): 194 (8, [C8H19NO2S ‡ 1] ), 163 (32, C7H15SO2 ), 98
‡
‡
(54, C7H14), 57 (100, C4H9 ). Anal. calc. for C8H19NO2S (193.31): C 49.71, H 9.91, N 7.25; found: C 49.93, H 10.29,
N 7.59.
(aR)-a-Ethyl-N-methylbenzeneethanesulfonamide ((R)-20c). According to GP E, with (R,S,S)-19f
(380 mg, 0.8 mmol) and conc. HCl soln. (10 ml). FC (pentane/AcOEt 4 :1) gave (R)-20c (96 mg, 53%).
25
D
Colorless oil. ‰aŠ ˆ ‡2.0 (c ˆ 1.1, CHCl3). ee 94% (GC, Lipodex E). IR (CHCl3): 3307, 3028, 2970, 2938, 2880,
1602, 1495, 1455, 1429, 1386, 1311, 1232, 1146, 1077, 1031, 857, 828. 1H-NMR (300 MHz, CDCl3): 1.02 (t, J ˆ 7.4,
PhCH2CH(MeCH2)SO2); 1.76 (m, 1H, PhCH 2CH(MeCH2)SO2); 1.90 (m, 1H, PhCH 2CH(MeCH2)SO2); 2.64
(d, J ˆ 5.2, MeN); 2.89 (dd, J ˆ 7.7, 13.2, 1 H, PhCH2CH(MeCH2)SO2); 3.22 (m, 2 H, PhCH2CH(MeCH2)SO2);
4.51( q, J ˆ 5.2, NH); 7.21 7.34 ( m, Ph). 13C-NMR (75 MHz, CDCl3): 11.9, 22.3, 30.0, 35.5, 64.0, 127.5, 129.4,
‡
‡
‡
‡
129.6, 138.6. EI-MS (70 eV): 132 (91, C10H13), 117 (73), 91 (5, C7H7 ), 77 (8, C6H9 ), 65 (14, C5H5 ). Anal. calc.
for C11H17NO2S (227.32): C 58.12, H 7.54, N 6.16; found: C 58.11, H 7.55, N 6.38.
(aS)-a-Ethyl-N-methylbenzeneethanesulfonamide ((S)-20c). According to GP E, with (S,R,R)-19f
(550 mg, 1.1 mmol) and conc. HCl soln. (10 ml). FC (pentane/AcOEt 4 :1) gave (S)-20c (139 mg, 55%).
25
D
Colorless oil. ‰aŠ ˆ À2.0 (c ˆ 1.1, CHCl3). ee 95% (GC, Lipodex E).
(2R)-N,3-Dimethylbutane-2-sulfonamide ((R)-20d). According to GP F, with (R,R,R)-19h (830 mg,
1.9 mmol), conc. H2SO4 soln. (186 mg, 1.9 mmol), and CHCl3 (40 ml). FC (pentane/AcOEt 3 :1) gave (R)-20d
25
D
(169 mg, 54%). Colorless oil. ‰aŠ ˆ À5.1( c ˆ 1.1, CHCl3). ee ꢀ 94% (GC, Lipodex E). IR (Film): 3307, 2965,
2879, 1467, 1450, 1427, 1393, 1310, 1257, 1159, 1137, 1069, 844. 1H-NMR (300 MHz, CDCl3): 1.02 (d, J ˆ 7.4, 3 H,
Me2CHCH(Me)SO2); 1.04 (d, J ˆ 7.4, 3 H, Me2CHCH(Me)SO2); 2.42 (dqq, J ˆ 2.9, 7.1, 7.1, Me2CHCH(Me)-
SO2); 2.76 (d, J ˆ 5.0, MeN); 2.99 (dq, J ˆ 2.9, 7.1, Me2CHCH(Me)SO2); 5.12 (q, J ˆ 5.0, NH). 13C-NMR

3676
Helvetica Chimica Acta Vol. 85 (2002)
‡
(75 MHz, CDCl3): 9.0; 17.2; 22.1; 27.9; 29.8; 61.0. EI-MS (70 eV): 166 (1, [C6H15NO2S ‡ 1] ), 94 (10,
‡
‡
‡
CH4NO2S ), 71(100, C 5H11), 55 (72, C4H7 ). Anal. calc. for C6H15NO2S (165.26): C 43.61, H 9.15, N 8.48; found:
C 43.70, H 9.21, N 8.78.
(aR)-N-Methyl-a-(1-methylethyl)benzeneethanesulfonamide ((R)-20e). According to GP E, with (R,R,R)-
19i (630 mg, 1.2 mmol) and conc. HCl soln. (10 ml). FC (pentane/AcOEt 4 :1) gave (R)-20e (167 mg, 57%).
25
D
Colorless oil. ‰aŠ ˆ À2.7 (c ˆ 1.1, CHCl3). ee 91% (GC, Lipodex E). IR (CHCl3): 3300, 3025, 2967, 2921, 2876,
1603, 1496, 1464, 1420, 1391, 1311, 1265, 1243, 1150, 1125, 1091, 1030, 842, 757. 1H-NMR (300 MHz, CDCl3): 1.07
(d, J ˆ 7.1, 3 H, Me2CHCH(PhCH2)SO2); 1.13 (d, J ˆ 7.1, 3 H, Me2CHCH(PhCH2)SO2); 2.37 (d, J ˆ 5.2, MeN);
2.50 (dqq, J ˆ 2.2, 7.1, 7.1, Me2CHCH(PhCH2)SO2); 2.96 (dd, J ˆ 5.5, 14.6, 1 H, Me2CHCH(PhCH2)SO2); 3.08
(dd, J ˆ 7.7, 14.6, 1 H, Me2CHCH(PhCH2)SO2); 3.21( ddd, J ˆ 2.2, 5.5, 7.7, Me2CHCH(PhCH2)SO2); 4.06 (q, J ˆ
5.2, NH); 7.18 7.34 (m, Ph). 13C-NMR (75 MHz, CDCl3): 18.6; 21.5; 28.5; 29.6; 31.7; 67.2; 127.4; 129.3; 129.4;
‡
‡
‡
‡
139.6. EI-MS (70 eV): 146 (79, C11H14), 131 (68), 91 (100, C7H7 ), 77 (7, C6H5 ), 65 (12, C5H5 ). Anal. calc. for
C12H19NO2S (241.36): C 59.72, H 7.93, N 5.80; found: C 59.68, H 8.36, N 5.78.
rac-N-Benzyl-a-phenylbenzeneethanesulfonamide (24). To a soln. of (R)-21 (0.2 g, 0.7 mmol), in dry DMF
(10 ml), SOCl2 (0.3 ml) was added slowly at 08. The mixture was stirred for 2 h and poured into ice-water. The
aq. phase was then extracted with AcOEt and the org. phase washed with H2O. The org. phase was dried
(MgSO4) and evaporated. The crude product was then dissolved in CH2Cl2 (5 ml), and the mixture was treated
with benzylamine (0.22 g, 2.1mmol). After 20 min, the mixture was washed with H 2O and the org. phase was
dried (MgSO4) and evaporated. FC (pentane/Et2O 1:1) gave 24 (0.17 g, 70%). Colorless solid M.p. 1378. IR
(KBr): 3279, 3029, 2964, 2943, 1601, 1585, 1496, 1454, 1413, 1310, 1143, 1056, 923, 892, 847, 821, 793, 750, 699, 635,
549, 501. 1H-NMR (400 MHz, CDCl3): 3.34 (dd, J ˆ 11.0, 14.0, 1 H, PhCH2CH(Ph)SO2); 3.71( dd, J ˆ 3.9, 14.0,
1H, PhC H2CH(Ph)SO2); 3.90 (dd, J ˆ 6.1, 14.0, 1 H, PhCH2NH); 4.05 (dd, J ˆ 6.0, 14.0, 1 H, PhCH2NH); 4.23
(dd, J ˆ 3.9, 11.0, PhCH2CH(Ph)SO2); 4.29 (dd, J ˆ 6.0, 6.1, NH); 6.90 7.40 (m, 3 Ph). 13C-NMR (100 MHz,
CDCl3): 36.2; 47.6; 70.7; 126.5; 127.8; 127.9; 128.2; 128.5; 128.6; 128.7; 128.8; 129.5; 132.9; 136.6; 136.9. EI-MS
‡
‡
(70 eV): 261 (1, [C21H21NO2S À C7H7] ), 245 (2, [C21H21NO2S À C7H7NH] ), 196 (32), 181 (100,
‡
‡
‡
[C21H21NO2S À C7H7NHSO2] ), 166 (14), 91 (11, C7H7 ), 77 (8, C6H5 ). Anal. calc. for C21H21NO2S (351.46):
C 71.77, H 6.02, N 3.99; found: C 71.79, H 5.86, N 3.84.
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Received June 4, 2002