A highly efficient asymmetric synthesis of homotaurine derivatives via diastereoselective ring-opening of γ-sultones

Article abstract of DOI:10.1055/s-2004-831256

A highly efficient asymmetric synthesis of α,γ-substituted γ-amino sulfonates via diastereoselective ring-opening of enantiopure α,γ-substituted γ-sultones with inversion of configuration at the attacked γ-carbon is described. In the key step sodium azide

Full text of DOI:10.1055/s-2004-831256

2910
PAPER
A Highly Efficient Asymmetric Synthesis of Homotaurine Derivatives via
Diastereoselective Ring-Opening of g-Sultones
Highly Efficient
A
i
symme
e
tric
S
ynthe
t
sis of
H
e
omotaurine
r
D
erivatives Enders,* Wacharee Harnying
Institut für Organische Chemie, Rheinisch-Westfälische Technische Hochschule, Professor-Pirlet-Str. 1, 52074 Aachen, Germany
Fax +49(241)8092127; E-mail: Enders@rwth-aachen.de
Received 23 July 2004
On the other hand, aminoalkanesulfonic acid derivatives
Abstract: A highly efficient asymmetric synthesis of a,g-substitut-
can provide interesting applications in the field of peptide
ed g-amino sulfonates via diastereoselective ring-opening of enan-
mimetics. Over the past several years, the syntheses of
tiopure a,g-substituted g-sultones with inversion of configuration at
a-,9 b-,10 and vinylogous sulfono peptides11 have drawn
the attacked g-carbon is described. In the key step sodium azide is
used as the nucleophilic nitrogen source. Secondary and tertiary g- great attention. Therefore, it is of importance to develop
amino sulfonates were synthesized in very good yields and excel-
lent diastereo- and enantiomeric excesses (de, ee 98%).
asymmetric approaches to amino sulfonic acid derivatives
as building blocks for the synthesis of sulfono peptides.
Key words: amino sulfonates, sultones, asymmetric synthesis,
Recently, an efficient asymmetric synthesis of b-amino
ring-opening, azide
sulfonates via aza-Michael addition of the enantiopure hy-
drazines SAMP or RAMBO to a,b-unsaturated sulfonates
in the presence of a Lewis acid as catalyst has been de-
Derivatives of sulfonic acids are important constituents in
scribed by our group.12
mammals and are involved in various physiological pro-
cesses.1 The best known are 2-aminoethanesulfonic acid
(taurine, TA) and related compounds. Homotaurine
(HTA, 3-aminopropanesulfonic acid) is a structural ana-
logue of g-aminobutyric acid (GABA), which is of great
importance as a specific inhibitor of impulse transmission
in the central nervous system (CNS).2 It has been reported
that homotaurine has more potent inhibitory effects than
taurine.3 In addition, it increases the synthesis of dopam-
ine in the brain,1 and shows antinociceptive activity.4 The
medication acamprosate (calcium acetylhomotaurine) has
been available in Europe for the treatment of alcohol de-
pendence since 1989.5 However, in many cases the phys-
iological role of these sulfonic acid derivatives remain
unclear. To get a further insight into their mode of action,
a stereoselective access to these derivatives is desirable
and compulsory for further physiological tests.
In our ongoing research concerning the chemistry of sul-
tones with the purpose to develop an efficient asymmetric
route to pharmacologically interesting sulfonic acid deriv-
atives, we envisioned to gain access to g-amino sulfonates
via ring-opening reaction of diastereo- and enantiopure g-
sultones.
In previous communications and a full paper, we have de-
scribed efficient asymmetric electrophilic a-substitutions
of benzyl sulfonates bearing 1,2:5,6-di-O-isopropylidene-
a-D-allofuranose as a chiral auxiliary with various alkyl
halides and nitroalkenes.13 In subsequent investigations,
we have shown the extension of this methodology using
allylic halides as electrophiles in the diastereo- and enan-
tioselective synthesis of the a,g-substituted g-sultones 1
(Scheme 1).14 Moreover, in our synthesis of optically ac-
tive a,g-substituted g-alkoxy15 and g-hydroxy sulfonates16
from these sultones, we have explored that the ring-open-
ing reaction of these g-sultones proceeded via a SN2
mechanism with an inversion of configuration at the at-
tacked g-carbon.
Several reports have been devoted to the asymmetric syn-
thesis of b-amino sulfonates,6 whereas the literature con-
cerning optically active g-amino sulfonates is scarce.
Interestingly, Prager and co-workers have synthesized 3-
amino-2-(4-chlorophenyl)propanesulfonic acid (saclofen)
R2
R3
and
3-amino-2-(4-chlorophenyl)-2-hydroxypropane-
sulfonic acid (hydroxysaclofen) whose racemates exhibit-
ed activity as specific antagonists of GABA at the GABAB
receptors.7 Moreover, they reported the synthesis and bio-
logical tests of both enantiomers of hydroxysaclofen.8
(R)-(–)-Hydroxysaclofen was completely inactive, where-
as (S)-(+)-hydroxysaclofen was a potent and specific an-
tagonist with an activity 2 to 3 times that of the racemate.
ref. 14
SO3R*
O
S
R1
R1
O
O
de, ee ≥ 98%
(R,R)-1a: R1 = H, R2 = Me, R3 = H
(R,R)-1b: R1 = t-Bu, R2 = Me, R3 = H
(R,R)-1c: R1 = H, R2 = Et, R3 = H
(R,R)-1d: R1 = t-Bu, R2 = Et, R3 = H
(R)-1e: R1 = H, R2 = Me, R3 = Me
(R)-1f: R1 = t-Bu, R2 = Me, R3 = Me
O
O
H3C
R* =
O
O
H3C
CH3
CH3
O
SYNTHESIS 2004, No. 17, pp 2910–2918
Advanced online publication: 07.10.2004
DOI: 10.1055/s-2004-831256; Art ID: Z15304SS
x
x.
x
x
.
2
0
0
4
Scheme 1 Asymmetric synthesis of the enantiopure g-sultones
1a–f.
© Georg Thieme Verlag Stuttgart · New York

PAPER
Highly Efficient Asymmetric Synthesis of Homotaurine Derivatives
2911
R2
We now wish to describe herein the successful application
of these enantiopure g-sultones to the asymmetric synthe-
sis of a very important class of sulfonic acid derivatives,
namely homotaurine and its derivatives.
R3 R2
N3
NaO3S
R3
a
O
O
S
R1
O
R1
2
(R,R)-1
de, ee ≥ 98%
In fact, there have been many reports on the ring-opening
of sultones with amines to introduce the amino group.17,18
However, sultones bearing a stereogenic center at the a-
position of the sulfonyl group would probably undergo
epimerization at this center. To circumvent this problem,
we planned an indirect synthetic strategy using sodium
azide as a reagent in the ring-opening reaction of sultones.
b
R3 R2
N3
R3 R2
i-PrO3S
HO3S
c
N3
74–98%
(3 steps)
R1
R1
(R,S)-4
de, ee ≥ 98%
3
We assumed that using the azide ion (a strong nucleophile
but weakly basic synthetic equivalent of the amino group)
should allow an epimerization-free ring-opening of sul-
tones. After this, the amino group would be obtained by a
mild reduction of the azido group. To yield the desired g-
amino sulfonates, the sulfonic acid group would have to
be protected appropriately in order to warrant its stability
under the reduction conditions. Ethyl and isopropyl sul-
fonates can be prepared directly from sulfonic acids using
triethyl orthoacetate19 and triisopropyl orthoformate,20 re-
spectively. Isopropyl sulfonates were assumed to be more
stable to the reduction conditions required for the conver-
sion of the azido group due to their lower reactivity via
SN2 reaction pathways.
Scheme 2 Asymmetric synthesis of g-azido isopropyl sulfonates 4
from the corresponding g-sultones 1. Reagents and conditions: a)
NaN3 (5.0 equiv), NH4Cl (2.2 equiv), DMF, 60 °C, 2 h; b) 3 N HCl/
MeOH; c) HC(Oi-Pr)3, CH2Cl2, reflux, 2 h.
This three-step sequence showed to be general in scope,
providing a range of substituted g-azido isopropyl sul-
fonates derived from secondary and tertiary g-sultones as
summarized in Table 1. The g-azido isopropyl sulfonates
(R,S)-4a-d were obtained in excellent yields (96–98%) as
well as diastereo- and enantiomeric excesses (de, ee
≥98%). In the cases of tertiary g-sultones (R)-1e and (R)-
1f, the products arising from the ring-opening reaction,
namely (R)-4e and (R)-4f, respectively, could be isolated
in acceptable yields along with the major by-products b,g-
and g,d-unsaturated sulfonates arising from elimination
reactions.
As expected, the ring-opening of the sultone (R,R)-1a
with an excess of sodium azide could be performed
smoothly in DMF under anhydrous conditions. The reac-
tion was complete after stirring at 60 °C for 2 hours yield-
ing the corresponding sodium sulfonate 2a, which could
be directly converted to its isopropyl sulfonate in a two-
step sequence. Protonation with methanolic HCl and sub-
sequent treatment with triisopropyl orthoformate in re-
fluxing CH2Cl2 provided the desired g-azido isopropyl
sulfonate (R,S)-4a in 96% overall yield (Scheme 2).
The ring-opening of the enantiopure sultones (R,R)-1a–d
proceeded with very high degree of diastereoselectivity to
give the corresponding g-azido sulfonates (R,S)-4a–d as a
single isomer, respectively. To get more insight into these
ring-opening reactions, we also investigated the reaction
of the (racemic) g-epimeric sultone (R,S)-1a, i.e. trans-1a.
As expected, the g-azido isopropyl sulfonate rac-syn-4a
was obtained as a single isomer. Both diastereomers ob-
tained clearly differed from each other as shown by their
1H NMR spectra in Figure 1.
Table 1 Synthesis of the g-Azido Isopropyl Sulfonates 4 from the Enantiopure Sultones 1
Product 4
(R,S)-4a
(R,S)-4b
(R,S)-4c
(R,S)-4d
(R)-4e
R1
R2
R3
H
Yield (%)
de (%)a
≥98
≥98
≥98
≥98
-
ee (%)b
≥98c
≥98
H
Me
Me
Et
96
97
97
98
77
74
t-Bu
H
H
H
≥98
t-Bu
H
Et
H
≥98
Me
Me
Me
Me
≥98c
≥98c
(R)-4f
t-Bu
-
a Determined by 1H NMR and HPLC.
b Based on the ee-values of the enantiopure sultones.
c Determined by HPLC using a chiral stationary phase.
Synthesis 2004, No. 17, 2910–2918 © Thieme Stuttgart · New York

2912
D. Enders, W. Harnying
PAPER
R3 R2
N3
R3 R2
NHBoc
i-PrO3S
i-PrO3S
CHS
CHO
a
i-PrO3S
N3
-CH2-
79–91%
CH3
R1
R1
CHN
(R,S)-4
de, ee ≥ 98%
(R,S)-5
de, ee ≥ 98%
anti-4a
[(R,S)-4a]
Scheme 3 Transformation of the g-azido sulfonates 4 to the N-Boc-
protected g-amino sulfonates 5. Reagents and conditions: a) H2, Pd/
C, (Boc)2O, EtOAc, r.t., 18–22 h.
CHO
-CH2-
CHS
i-PrO3S
N3
greater than 98% based on the ee-values of the corre-
sponding enantiopure sultones.
CH3
CHN
rac-syn-4a
Thus, this simple four-step sequence provides a new route
to enantiopure N-Boc-protected g-amino isopropyl sul-
fonates starting from enantiopure sultones. Moreover, it
seems to be of special interest that both protecting groups
in (R,S)-5a can be cleaved independently without epimer-
ization as illustrated in Scheme 4.
1
Figure 1 Comparison of H NMR spectra of the epimeric isomers
anti-4a [(R,S)-4a] and rac-syn-4a.
Therefore, it is reasonable to assume that the reactions
proceed via a bimolecular nucleophilic substitution with
inversion of configuration at the attacked g-carbon atom
rather than via a unimolecular reaction, which should re-
sult in an epimeric mixture. The absolute configurations
of the g-azido isopropyl sulfonates 4a–d are assigned to
be (1R,3S) based on the assumption of a uniform reaction
mechanism operating in all the substitutions.
NaO3S
NHBoc
CH3
a
91%
(R,S)-6
de ≥ 96%, ee ≥ 98%
i-PrO3S
NHBoc
CH3
i-PrO3S
NHCbz
CH3
The conversion of the azido group into a N-Boc-protected
amino group was finally carried out in a one-pot proce-
dure according to a reported method21 by using Pd/C-cat-
alyzed hydrogenation in the presence of (Boc)2O
(Scheme 3). The N-Boc-protected g-amino sulfonates 5
were obtained in very good yields and excellent diastereo-
and enantiomeric excesses (de, ee ≥98%) as summarized
in Table 2.
(R,S)-5a
de, ee ≥ 98%
b
96%
(R,S)-7
de ≥ 96%, ee ≥ 98%
Scheme 4 Selective deprotection of the g-amino sulfonates (R,S)-
5a. Reagents and conditions: a) NaI, acetone, reflux, 2 d; b) i. 30%
TFA–CH2Cl2, r.t., 30 min, ii. CbzCl, K2CO3, CH2Cl2/H2O, r.t., 15 h.
The ee-values of (R,S)-5a and (R)-5e were determined by
HPLC analysis using a chiral stationary phase. This re-
vealed that these reactions proceed without any detectable
amount of epimerization at the a-position of the sulfonyl
group. Accordingly, the ee-values of other N-Boc-protect-
ed g-amino isopropyl sulfonates are also expected to be
The isopropyl group was deprotected using NaI in reflux-
ing acetone for 2 days leading to the corresponding sodi-
um sulfonate (R,S)-6 in 91% yield and in acceptable
purity. On the other hand, the Boc group could be depro-
Table 2 Transformation of the g-Azido Sulfonates 4 to the N-Boc-Protected g-Amino Sulfonates 5
Product 5
(R,S)-5a
(R,S)-5b
(R,S)-5c
(R,S)-5d
(R)-5e
R1
R2
R3
H
Yield (%)
de (%)a
≥98
≥98
≥98
≥98
–
ee (%)b
≥98c
≥98
H
Me
Me
Et
91
90
86
80
79
81
t-Bu
H
H
H
≥98
t-Bu
H
Et
H
≥98
Me
Me
Me
Me
≥98c
≥98
(R)-5f
t-Bu
–
a Determined by 1H NMR and HPLC.
b Based on the ee-values of the enantiopure sultones.
c Determined by HPLC using a chiral stationary phase.
Synthesis 2004, No. 17, 2910–2918 © Thieme Stuttgart · New York

PAPER
Highly Efficient Asymmetric Synthesis of Homotaurine Derivatives
2913
tected selectively with TFA in CH2Cl2 at room tempera- azido sulfonyl chloride 9 with phosgene at room tempera-
ture. The resultant amine was not isolated but directly ture. It is noteworthy that we observed a severe loss of ste-
protected with CbzCl to give the carbamate (R,S)-7 in an reochemical integrity at the a-position of the sulfonyl
excellent yield of 96%.
group in the product 9 under these conditions. After re-
moval of the polar impurity by filtration through a short
column of silica gel, the g-azido sulfonyl chloride 9 was
hydrogenated in the presence of Pd/C as catalyst. In this
fashion, the azido group was reduced with a concomitant
reductive cleavage of the sulfonyl group leading to the
primary amine 10, which was directly used for the acety-
lation step by treatment with acetic acid anhydride in
CH2Cl2 in the presence of triethylamine. The desired N-
acetylamine 11 was obtained in 70% overall yield. Its ab-
solute configuration was established to be S by compari-
son of its optical rotation with the value reported in the
The free g-amino sulfonic acid could be easily synthe-
sized from the g-sultone in a three step sequence as depict-
ed in Scheme 5. Ring-opening of the sultone (R,R)-1a
with sodium azide was followed by protonation of the re-
sulting sodium sulfonate with an excess of methanolic
HCl. The resultant g-azido sulfonic acid was directly re-
duced employing Pd/C-catalyzed hydrogenation to give
the free g-amino sulfonic acid (R,S)-8 in 92% overall
yield.
+
–
CH3
26
literature {[a]D24 = –34.1 (c = 0.65, EtOH), Lit.22 [a]D
SO3 NH2
–35.2 (c = 0.7, EtOH)}.
a, b, c
CH3
O
92% (3 steps)
S
In summary, we have developed an efficient asymmetric
access to N-Boc-protected g-amino isopropyl sulfonates
in a simple four-step sequence starting from diastereo-
and enantiopure g-sultones. The diastereoselective ring-
opening of g-sultones with sodium azide proceeded via a
SN2 mechanism with inversion of configuration at the at-
tacked carbon atom. The following steps, a protonation of
the resultant sodium sulfonates, a protection of the sulfon-
ic acids as their isopropyl sulfonates and finally a conver-
sion of the azido group into a N-Boc-protected amino
group afforded the title compounds in very good yields
and excellent diastereo- and enantiomeric excesses (de, ee
≥98%). In addition, we have shown a selective removal of
either the isopropyl or the Boc protecting groups without
epimerization.
O
O
(R,S)-8
de ≥ 96%, ee ≥ 98%
(R,R)-1a
de, ee ≥ 98%
Scheme 5 Synthesis of the free g-amino sulfonic acid (R,S)-8 from
the g-sultone (R,R)-1a. Reagents and conditions: a) NaN3 (5.0 equiv),
NH4Cl (2.2 equiv), DMF, 60 °C, 2 h; b) 3 N HCl/MeOH; c) H2, Pd/C,
MeOH, r.t., 16 h.
To establish that the conversion of the enantiopure sul-
tones (R,R)-1 to the corresponding g-azido sulfonates
(R,S)-4 had occurred with an inversion of configuration,
the g-sultone (R,R)-1a was converted into the known N-
acetylamine (S)-11 via the intermediate g-azido sulfonate
(R,S)-2a as depicted in Scheme 6.
After opening of the sultone (R,R)-1a with sodium azide,
the sodium sulfonate (R,S)-2a was converted into the g-
Preparative column chromatography: Merck silica gel 60, particle
size 0.040–0.063 mm (230–240 mesh, flash). Analytical TLC: silica
gel 60, F254 plates from Merck, Darmstadt. Optical rotation values
were measured on a Perkin–Elmer P241 polarimeter. IR spectra
CH3
NHAc
1
were taken on a Perkin-Elmer FT/IR 1760 spectrophotometer. H
and 13C NMR spectra were recorded on a Gemini 300 or a Varian
Inova 400 and all measurements were performed with tetramethyl-
silane as internal standard. Mass spectra were acquired on a Finni-
gan SSQ 7000 spectrometer (CI 100 eV; EI 70 eV). High-resolution
mass spectra were recorded with a Finnigan MAT 95 spectrometer.
Microanalyses were obtained with a Vario EL element analyzer.
Melting points were determined on a Tottoli melting point appara-
tus and are uncorrected.
CH3
O
S
70% (4 steps)
O
O
(S)-11
(R,R)-1a
ee ≥ 98%
de, ee ≥ 98%
a
d
NaO3S
N3
NH2
CH3
a,g-Substituted g-Azido Isopropyl Sulfonates 4a–f; General
Procedure 1 (GP 1)
CH3
A mixture of the enantiopure sultone 1 (0.5 mmol), NaN3 (2.5
mmol) and NH4Cl (1.1 mmol) in anhyd DMF (5 mL) was heated at
60 °C under argon for 2 h. DMF was removed under vacuum and
the resulting sodium sulfonate 2 was treated with an excess of meth-
anolic HCl. After removal of MeOH under vacuum, the solid was
triturated with CH2Cl2 for 30 min and filtered twice. The combined
CH2Cl2 fractions were evaporated under reduced pressure to give
the sulfonic acid 3. A solution of the crude sulfonic acid and triiso-
propyl orthoformate (5 mmol) in CH2Cl2 (5 mL) was refluxed for 2
h. The solvent was evaporated under reduced pressure and the crude
product was purified by flash column chromatography (SiO2, Et2O–
n-pentane) to give the g-azido isopropyl sulfonate 4.
(R,S)-2a
10
b
ClO2S
N3
c
CH3
9
Scheme 6 Conversion of the g-sultone (R,R)-1a to the known N-
acetylamine 11. Reagents and conditions: a) NaN3, NH4Cl, DMF, 60
°C, 2 h; b) COCl2, CH2Cl2–DMF, r.t., 1 h; c) H2, Pd/C, MeOH, r.t., 16
h; d) Ac2O, Et3N, CH2Cl2, r.t., 1 h.
Synthesis 2004, No. 17, 2910–2918 © Thieme Stuttgart · New York

2914
D. Enders, W. Harnying
PAPER
a,g-Substituted N-Boc-Protected g-Amino Isopropyl Sulfonates
5a–f; General Procedure 2 (GP 2)
13C NMR (75 MHz, CDCl3): d = 19.1 (CH3), 22.4, 23.4
[(CH3)2CHO3S], 31.2 [C(CH3)3], 34.6 [C(CH3)3], 37.2 (CH2), 55.3
(CHN3), 64.3 (CHSO3), 78.3 (SO3CH), 125.8, 129.0 (CHarom),
129.7, 152.3 (Carom).
MS (CI, 100 eV, methane): m/z (%) = 354 (2) [M+ + 1], 338 (4), 312
(4), 284 (17), 269 (4), 230 (16), 202 (100), 187 (22), 161 (15), 146
(21), 131 (3), 105 (2).
A suspension of 10% Pd/C in EtOAc was stirred vigorously under
H12 at atmospheric pressure for 2 h, after which a mixture of the g-
azido sulfonate 4 and Boc2O (1.2 equiv) in EtOAc was added. The
reaction mixture was stirred at r.t. until all starting material had dis-
appeared (18–22 h, TLC monitoring). The catalyst was removed by
filtration through a pad of Celite and washed with EtOAc. The fil-
trate was evaporated under reduced pressure and the crude product
was purified by flash column chromatography (SiO2, Et2O–n-pen-
tane) to give the N-Boc-protected g-amino sulfonate 5.
Anal. Calcd for C17H27N3O3S: C, 57.76; H, 7.70; N, 11.89. Found:
C, 57.56; H, 7.54; N, 12.02.
Isopropyl (1R,3S)-3-Azido-1-phenylpentanesulfonate [(R,S)-4c]
According to GP 1, a mixture of the enantiopure sultone (R,R)-1c
(116 mg, 0.5 mmol), NaN3 (160 mg, 2.5 mmol) and NH4Cl (90 mg,
1.1 mmol) in anhyd DMF (5 mL) was heated at 60 °C under argon
for 2 h. The resulting sodium sulfonate was first treated with meth-
anolic HCl (3 N, 10 mL). After removal of MeOH, a solution of the
crude sulfonic acid and triisopropyl orthoformate (1.0 mL, 6 mmol)
in CH2Cl2 (8 mL) was refluxed for 2 h. The crude product was pu-
rified by column chromatography (SiO2, Et2O–n-pentane, 1:19) to
give (R,S)-4c as a colorless solid (154 mg, 97%); de ≥98% (NMR);
ee ≥98% (based on the ee-value of the sultone); mp 35 °C;
[a]D26 +17.5 (c = 1.1, CHCl3).
Isopropyl (1R,3S)-3-Azido-1-phenylbutanesulfonate [(R,S)-4a]
According to GP 1, a mixture of the enantiopure sultone (R,R)-1a
(265 mg, 1.25 mmol), NaN3 (405 mg, 6.25 mmol) and NH4Cl (150
mg, 2.75 mmol) in anhyd DMF (10 mL) was heated at 60 °C under
argon for 2 h. The resulting sodium sulfonate was first treated with
methanolic HCl (3 N, 10 mL). After removal of MeOH, a solution
of the crude sulfonic acid and triisopropyl orthoformate (1.5 mL,
9.2 mmol) in CH2Cl2 (10 mL) was refluxed for 2 h. The crude prod-
uct was purified by column chromatography (SiO2, Et2O–n-pen-
tane, 1:19) to give (R,S)-4a as a colorless liquid (355 mg, 96%); de
≥98% (NMR and HPLC); ee ≥98% (HPLC, Chiralpak AD 2, n-hep-
tane–i-PrOH, 97:3); [a]D23 +45.2 (c = 1.1, CHCl3).
IR (KBr): 2968 (m), 2934 (m), 2122 (s), 1499 (m), 1459 (m), 1351
(s), 1266 (m), 1160 (s), 1087 (m), 909 (s), 777 (m), 702 (m), 589
(m), 562 (m) cm–1.
1H NMR (300 MHz, CDCl3): d = 1.00 (t, J = 7.4 Hz, 3 H, CH2CH3),
1.10, 1.30 [two d, J = 6.2 Hz, 6 H, SO3CH(CH3)2], 1.43–1.63 (m, 2
H, CH2CH3), 2.15 (ddd, J = 6.9, 8.7, 14.6 Hz, 1 H, CHHCHN3),
2.60 (ddd, J = 5.2, 6.9, 14.6 Hz, 1 H, CHHCHN3), 3.54 (m, 1 H,
CHN3), 4.34 (t, J = 7.0 Hz, 1 H, ArCHSO3), 4.64 [sept, J = 6.2 Hz,
1 H, (CH3)2CHO3S], 7.35–7.44 (m, 5 H, ArH).
13C NMR (75 MHz, CDCl3): d = 10.1 (CH2CH3), 22.5, 23.4
[(CH3)2CHO3S], 27.4 (CH2CH3), 35.5 (CH2), 61.8 (CHN3), 64.8
(CHSO3), 78.4 (SO3CH), 128.9, 129.1, 129.3 (CHarom), 133.3
(Carom).
IR (film): 2983 (m), 2937 (m), 2111 (s), 1497 (w), 1456 (m), 1348
(s), 1251 (m), 1170 (s), 1095 (m), 913 (s), 883 (s), 778 (m), 700 (m),
627 (m), 585 (m) cm–1.
1H NMR (300 MHz, CDCl3): d = 1.11 [d, J = 6.4 Hz, 3 H,
SO3CH(CH3)CH3], 1.27 (d, J = 6.7 Hz, 3 H, CH3CHN3), 1.31 [d,
J = 6.2 Hz, 3 H, SO3CH(CH3)CH3], 2.21 (ddd, J = 7.4, 8.2, 14.4 Hz,
1 H, CHHCHN3), 2.52 (ddd, J = 6.2, 6.7, 14.4 Hz, 1 H, CHHCHN3),
3.70 (m, 1 H, CHN3), 4.32 (t, J = 7.0 Hz, 1 H, ArCHSO3), 4.64
[sept, J = 6.2 Hz, 1 H, (CH3)2CHO3S], 7.39 (m, 5 H, ArH).
13C NMR (75 MHz, CDCl3): d = 19.2 (CH3), 22.5, 23.3
[(CH3)2CHO3S], 37.3 (CH2), 55.3 (CHN3), 64.6 (CHSO3), 78.4
(SO3CH), 128.9, 129.2, 129.3 (CHarom), 133.0 (Carom).
MS (CI, 100 eV, methane): m/z (%) = 312 (2) [M+ + 1], 270 (2), 242
(26), 227 (6), 188 (3), 160 (100), 145 (31), 131 (4), 118 (6), 105
(11), 91 (3).
MS (CI, 100 eV, methane): m/z (%) = 298 (10) [M+ + 1], 255 (12),
228 (32), 213 (9), 174 (4), 146 (100), 131 (16), 105 (6).
Anal. Calcd for C13H19N3O3S: C, 52.51; H, 6.44; N, 14.13. Found:
C, 53.05; H, 6.54; N, 14.22.
Anal. Calcd for C14H21N3O3S: C, 54.00; H, 6.80; N, 13.49. Found:
C, 54.05; H, 6.72; N, 13.41.
Isopropyl (1R,3S)-3-Azido-1-(4-tert-butylphenyl)butane-
sulfonate [(R,S)-4b]
Isopropyl (1R,3S)-3-Azido-1-(4-tert-butylphenyl)pentane-
sulfonate [(R,S)-4d]
According to GP 1, a mixture of the enantiopure sultone (R,R)-1b
(61 mg, 0.22 mmol), NaN3 (80 mg, 1.25 mmol) and NH4Cl (30 mg,
0.55 mmol) in anhyd DMF (3 mL) was heated at 60 °C under argon
for 2 h. The resulting sodium sulfonate was first treated with meth-
anolic HCl (3 N, 5 mL). After removal of MeOH, a solution of the
crude sulfonic acid and triisopropyl orthoformate (0.5 mL, 3 mmol)
in CH2Cl2 (5 mL) was refluxed for 2 h. The crude product was pu-
rified by column chromatography (SiO2, Et2O–n-pentane, 1:19) to
give (R,S)-4b as a colorless liquid (78 mg, 97%); de ≥98% (NMR);
ee ≥98% (based on the ee-value of the sultone); [a]D26 +37.6 (c =
1.1, CHCl3).
According to GP 1, a mixture of the enantiopure sultone (R,R)-1d
(100 mg, 0.35 mmol), NaN3 (120 mg, 1.75 mmol) and NH4Cl (41
mg, 0.77 mmol) in anhyd DMF (4 mL) was heated at 60 °C under
argon for 2 h. The resulting sodium sulfonate was first treated with
methanolic HCl (3 N, 8 mL). After removal of MeOH, a solution of
the crude sulfonic acid and triisopropyl orthoformate (0.6 mL, 3.7
mmol) in CH2Cl2 (5 mL) was refluxed for 2 h. The crude product
was purified by column chromatography (SiO2, Et2O–n-pentane,
1:19) to give (R,S)-4d as a colorless liquid (128 mg, 98%); de ≥98%
(NMR); ee ≥98% (based on the ee-value of the sultone);
[a]D24 +26.6 (c = 1.2, CHCl3).
IR (film): 2966 (s), 2872 (m), 2112 (s), 1513 (m), 1463 (m), 1344
(s), 1250 (m), 1170 (s), 1095 (m), 916 (s), 882 (s), 607 (m) cm–1.
IR (film): 2966 (s), 2857 (m), 2100 (s), 1513 (m), 1464 (m), 1345
(s), 1270 (m), 1169 (s), 1096 (m), 914 (s), 883 (m), 756 (m), 608 (s)
cm–1.
1H NMR (400 MHz, CDCl3): d = 0.99 (t, J = 7.4 Hz, 3 H, CH2CH3),
1.09 (d, J = 6.3 Hz, 3 H, SO3CH(CH3)CH3), 1.31 [d, J = 6.3 Hz, 3
H, SO3CH(CH3)CH3], 1.31 [s, 9 H, C(CH3)3], 1.46–1.68 (m, 2 H,
CH2CH3), 2.14 (ddd, J = 6.9, 8.5, 14.6 Hz, 1 H, CHHCHN3), 2.58
(ddd, J = 5.5, 7.1, 14.6 Hz, 1 H, CHHCHN3), 3.55 (m, 1 H, CHN3),
4.32 (t, J = 7.1 Hz, 1 H, ArCHSO3), 4.64 [sept, J = 6.3 Hz, 1 H,
(CH3)2CHO], 7.33, 7.40 [two d (AB system), J = 8.5 Hz, 4 H, ArH].
1H NMR (300 MHz, CDCl3): d = 1.10 [d, J = 6.2 Hz, 3 H,
SO3CH(CH3)CH3], 1.26 (d, J = 6.4 Hz, 3 H, CH3CHN3), 1.31 [d,
J = 6.2 Hz, 3 H, SO3CH(CH3)CH3], 1.31 [s, 9 H, C(CH3)3], 2.21 (dt,
J = 7.8, 14.3 Hz, 1 H, CHHCHN3), 2.50 (dt, J = 6.6, 14.3 Hz, 1 H,
CHHCHN3), 3.70 (m, 1 H, CHN3), 4.32 (t, J = 7.2 Hz, 1 H,
ArCHSO3), 4.64 [sept, J = 6.2 Hz, 1 H, (CH3)2CHO3S], 7.31, 7.40
[two d (AB system), J = 8.4 Hz, 4 H, ArH].
Synthesis 2004, No. 17, 2910–2918 © Thieme Stuttgart · New York

PAPER
Highly Efficient Asymmetric Synthesis of Homotaurine Derivatives
2915
13C NMR (100 MHz, CDCl3): d = 10.2 (CH2CH3), 22.6, 23.6
[(CH3)2CHO3S], 27.5 (CH2CH3), 31.4 [C(CH3)3], 34.8 [C(CH3)3],
35.6 (CH2), 61.8 (CHN3), 64.5 (CHSO3), 78.4 (SO3CH), 125.8,
128.9 (CHarom), 130.1, 152.2 (Carom).
13C NMR (75 MHz, CDCl3): d = 22.4, 23.4, 26.2, 27.1 (CH3), 31.2
[C(CH3)3], 34.6 [C(CH3)3], 41.1 (CH2), 60.8 (CN3), 64.2 (CHSO3),
78.2 (SO3CH), 125.7, 129.4 (CHarom), 130.3, 152.2 (Carom).
MS (CI, 100 eV, methane): m/z (%) = 368 (9, [M+ + 1]), 352 (10),
298 (87), 283 (22), 216 (100), 201 (38), 163 (54), 145 (14), 84 (6).
MS (CI, 100 eV, methane): m/z (%) = 368 (1) [M+ + 1], 352 (6), 326
(3), 298 (32), 244 (7), 216 (100), 201 (26), 160 (24), 145 (10), 104
(2).
Anal. Calcd for C18H29N3O3S: C, 58.83; H, 7.95; N, 11.43. Found:
C, 59.03; H, 7.89; N, 11.17.
Anal. Calcd for C18H29N3O3S: C, 58.83; H, 7.95; N, 11.43. Found:
C, 58.77; H, 7.67; N, 11.78.
Isopropyl (1R,3S)-3-tert-Butoxycarbonylamino-1-phenylbu-
tanesulfonate [(R,S)-5a]
Isopropyl (1R)-3-Azido-3-methyl-1-phenylbutanesulfonate
[(R)-4e]
According to GP 2, a mixture of the g-azido sulfonate (R,S)-4a (45
mg, 0.15 mmol) and Boc2O (0.05 mL, 0.2 mmol) in EtOAc (5 mL)
containing a catalytic amount of 10% Pd/C was stirred under a H2
atmosphere for 18 h at r.t. The crude product was purified by flash
column chromatography (SiO2, Et2O–n-pentane, 1:3) to give (R,S)-
5a as a colorless solid (51 mg, 91%); de ≥98% (NMR and HPLC);
ee ≥98% (HPLC, Chiral OD, n-heptane& ndash;EtOH, 95:5); mp
88 °C; [a]D30 +4.4 (c = 1.1, CHCl3).
According to GP 1, a mixture of the enantiopure sultone (R)-1e (233
mg, 1.0 mmol), NaN3 (330 mg, 5 mmol) and NH4Cl (120 mg, 2.2
mmol) in anhyd DMF (10 mL) was heated at 60 °C under argon for
2 h. The resulting sodium sulfonate was first treated with methanol-
ic HCl (3 N, 10 mL). After removal of MeOH, a solution of the
crude sulfonic acid and triisopropyl orthoformate (1.5 mL, 9 mmol)
in CH2Cl2 (10 mL) was refluxed for 2 h. The crude product was pu-
rified by column chromatography (SiO2, Et2O–n-pentane, 1:19) to
give (R)-4e as a colorless liquid (240 mg, 75%); ee ≥98% (HPLC,
(S,S)-Whelk 01, n-Heptane–i-PrOH, 9:1); [a]D24 –6.8 (c = 1.0,
CHCl3).
IR (CHCl3): 3389 (m), 2979 (m), 2934 (m), 1702 (s), 1511 (m),
1455 (m), 1364 (s), 1247 (m), 1169 (s), 1095 (m), 1059 (m), 913 (s),
883 (s), 757 (s), 699 (m) cm–1.
1H NMR (400 MHz, CDCl3): d = 1.10 (d, J = 6.9 Hz, 3 H,
CH3CHNH), 1.12, 1.30 [two d, J = 6.0 Hz, 6 H, SO3CH(CH3)2],
1.40 [s, 9 H, C(CH3)3], 2.35 (ddd, J = 4.4, 7.7, 13.7 Hz, 1 H,
CHHCHNH), 2.46 (ddd, J = 6.2, 10.2, 13.7 Hz, 1 H, CHHCHNH),
3.63 (br s, 1 H, CHNH), 4.23 (dd, J = 4.1, 10.4 Hz, 1 H, ArCHSO3),
4.28 (br d, J = 7.7 Hz, 1 H, NHCH), 4.62 [sept, J = 6.3 Hz, 1 H,
(CH3)2CHO3S], 7.34–7.45 (m, 5 H, ArH).
IR (film): 2981 (m), 2938 (m), 2102 (s), 1497 (m), 1458 (m), 1346
(s), 1259 (m), 1170 (s), 1095 (m), 914 (s), 884 (s), 767 (m), 701 (m),
643 (m), 614 (m), 579 (m) cm–1.
1H NMR (400 MHz, CDCl3): d = 1.00 [s, 3 H, N3C(CH3)CH3], 1.12
[d, J = 6.3 Hz,
3 H, SO3CH(CH3)CH3], 1.30 [s, 3 H,
N3C(CH3)CH3], 1.32 [d, J = 6.0 Hz, 3 H, SO3CH(CH3)CH3], 2.38
(dd, J = 10.2, 14.3 Hz, 1 H, CHHCH), 2.57 (dd, J = 1.9, 14.3 Hz, 1
H, CHHCH), 4.38 (dd, J = 1.9, 10.2 Hz, 1 H, ArCHSO3), 4.65 [sept,
J = 6.3 Hz, 1 H, (CH3)2CHO3S], 7.35–7.41 (m, 3 H, ArH), 7.43–
7.47 (m, 2 H, ArH).
13C NMR (100 MHz, CDCl3): d = 22.6, 23.6, 26.4, 27.2 (CH3), 41.3
(CH2), 60.9 (CN3), 64.6 (CHSO3), 78.4 (SO3CH), 128.8, 129.1,
129.8 (CHarom), 133.6 (Carom).
13C NMR (100 MHz, CDCl3): d = 20.3 (CH3), 22.5, 23.3
[(CH3)2CHO3S], 28.3 [C(CH3)3], 36.7 (CH2), 44.8 (CHN), 65.4
(CHSO3), 78.0 (SO3CH), 83.8 [C(CH3)3], 128.6, 128.9, 129.4
(CHarom), 132.2 (Carom), 154.6 (NCO2).
MS (EI, 70 eV): m/z (%) = 371 (0.1, [M+]), 315 (12), 271 (5), 229
(12), 192 (37), 174 (9), 144 (40), 131 (15), 104 (15), 88 (100), 70
(10), 57 (61).
Anal. Calcd for C18H29NO5S: C, 58.20; H, 7.87; N, 3.77. Found: C,
58.66; H, 7.55; N, 3.75.
MS (CI, 100 eV, methane): m/z (%) = 312 (1, [M+ + 1]), 270 (3),
242 (68), 227 (72), 160 (100), 145 (41), 105 (20), 91 (3).
Anal. Calcd for C14H21N3O3S: C, 54.00; H, 6.80; N, 13.49. Found:
C, 53.97; H, 6.61; N, 13.55.
Isopropyl (1R,3S)-3-tert-Butoxycarbonylamino-1-(4-butylphe-
nyl)butanesulfonate [(R,S)-5b]
According to GP 2, a mixture of the g-azido sulfonate (R,S)-4b (57
mg, 0.16 mmol) and Boc2O (0.05 mL, 0.23 mmol) in EtOAc (5 mL)
containing a catalytic amount of 10% Pd/C was stirred under a H2
atmosphere for 20 h at r.t. The crude product was purified by flash
column chromatography (SiO2, Et2O–n-pentane, 1:3) to give (R,S)-
5b as a colorless viscous liquid (62 mg, 90%); de ≥98% (NMR); ee
≥98% (based on the ee-value of the sultone); [a]D23 +5.6 (c = 1.1,
CHCl3).
Isopropyl (R)-3-Azido-1-(4-tert-butylphenyl)-3-methylbutane-
sulfonate [(R)-4f]
According to GP 1, a mixture of the enantiopure sultone (R)-1f (280
mg, 1.0 mmol), NaN3 (330 mg, 5 mmol) and NH4Cl (120 mg, 2.2
mmol) in anhyd DMF (10 mL) was heated at 60 °C under argon for
2 h. The resulting sodium sulfonate was first treated with methanol-
ic HCl (3 N, 10 mL). After removal of MeOH, a solution of the
crude sulfonic acid and triisopropyl orthoformate (1.5 mL, 9 mmol)
in CH2Cl2 (10 mL) was refluxed for 2 h. The crude product was pu-
rified by column chromatography (SiO2, Et2O–n-pentane, 1:19) to
give (R)-4f as a colorless liquid (269 mg, 74%); ee ≥98% (HPLC,
Chiralpak AD, n-heptane–i-PrOH, 98:2); [a]D24 –6.3 (c = 1.0,
CHCl3).
IR (film): 3387 (m), 2969 (s), 2874 (m), 1700 (s), 1516 (s), 1459
(m), 1363 (s), 1249 (m), 1170 (s), 1096 (m), 1061 (m), 1021 (m),
916 (s), 883 (s), 757 (s), 614 (s) cm–1.
1H NMR (300 MHz, CDCl3): d = 1.10 (d, J = 6.4 Hz, 3 H,
CH3CHNH), 1.11 [d, J = 6.2 Hz, 3 H, SO3CH(CH3)CH3], 1.30 [d,
J = 4.9 Hz, 3 H, SO3CH(CH3)CH3], 1.31 [s, 9 H, CO2C(CH3)3], 1.40
[s, 9 H, C(CH3)3], 2.34 (ddd, J = 4.2, 7.7, 13.9 Hz, 1 H, CHHCH-
NH), 2.46 (br ddd, J = 6.9, 9.9, 13.9 Hz, 1 H, CHHCHNH), 3.66 (br
s, 1 H, CHNH), 4.21 (dd, J = 4.2, 10.1 Hz, 1 H, ArCHSO3), 4.28 (br
d, J = 7.4 Hz, 1 H, NHCH), 4.62 [sept, J = 6.2 Hz, 1 H,
(CH3)2CHO3S], 7.34, 7.40 [two d (AB system), J = 8.4, 4 H, ArH].
IR (KBr): 2968 (s), 2102 (s), 1514 (m), 1466 (m), 1339 (s), 1262
(m), 1219 (m), 1166 (s), 1094 (m), 920 (s), 886 (s), 847 (m), 604 (m)
cm–1.
1H NMR (300 MHz, CDCl3): d = 1.02 [s, 3 H, N3C(CH3)CH3], 1.11
[d, J = 6.2 Hz,
3 H, SO3CH(CH3)CH3], 1.30 [s, 3 H,
N3C(CH3)CH3], 1.31 [s, 9 H, C(CH3)3], 1.33 [d, J = 6.4 Hz, 3 H,
SO3CH(CH3)CH3], 2.36 (dd, J = 10.1, 14.3 Hz, 1 H, CHHCH), 2.56
(dd, J = 1.7, 14.3 Hz, 1 H, CHHCH), 4.36 (dd, J = 1.7, 10.1 Hz, 1
H, ArCHSO3), 4.63 [sept, J = 6.2 Hz, 1 H, (CH3)2CHO3S], 7.37 (m,
4 H, ArH).
13C NMR (75 MHz, CDCl3): d = 20.4 (CH3), 22.5, 23.4
[(CH3)2CHO3S], 28.4 [C(CH3)3], 31.3 [CO2C(CH3)3], 34.6
[C(CH3)3], 36.6 (CH2), 44.9 (CHN), 65.2 (CHSO3), 78.1 (SO3CH),
Synthesis 2004, No. 17, 2910–2918 © Thieme Stuttgart · New York

2916
D. Enders, W. Harnying
PAPER
79.3 [CO2C(CH3)3], 125.8, 129.3 (CHarom), 129.1, 152.1 (Carom),
(CHSO3), 78.0 (SO3CH), 79.1 [CO2C(CH3)3], 125.7, 129.2
154.9 (NCO2).
(CHarom), 129.8, 152.0 (Carom), 155.3 (NCO2).
MS (EI, 70 eV): m/z (%) = 427 (0.1, [M+]), 371 (12), 327 (14), 285
(12), 248 (53), 230 (12), 188 (7), 161 (11), 145 (12), 131 (4), 88
(100), 57 (34).
MS (CI, 100 eV, methane): m/z (%) = 422 (2, [M+ + 1]), 386 (17),
344 (15), 300 (10), 262 (100), 244 (10), 189 (2), 145 (2), 130 (3),
102 (24).
Anal. Calcd for C22H37NO5S: C, 61.80; H, 8.72; N, 3.28. Found: C,
61.68; H, 8.78; N, 3.08.
Anal. Calcd for C23H39NO5S: C, 62.26; H, 8.90; N, 3.17. Found: C,
61.99; H, 9.02; N, 2.97.
Isopropyl (1R,3S)-3-tert-Butoxycarbonylamino-1-phenylpen-
tanesulfonate [(R,S)-5c]
Isopropyl (R)-3-tert-Butoxycarbonylamino-3-methyl-1-phe-
nylbutanesulfonate [(R)-5e]
According to GP 2, a mixture of the g-azido sulfonate (R,S)-4c (64
mg, 0.2 mmol) and Boc2O (0.05 mL, 0.23 mmol) in EtOAc (5 mL)
containing a catalytic amount of 10% Pd/C was stirred under a H2
atmosphere for 20 h at r.t. The crude product was purified by flash
column chromatography (SiO2, Et2O–n-pentane, 1:4) to give (R,S)-
5c as a colorless solid (68 mg, 86%); de ≥98% (NMR); ee ≥98%
(based on the ee-value of the sultone); mp 68 °C; [a]D22 –5.2 (c =
0.8, CHCl3).
According to GP 2, a mixture of the g-azido sulfonate (R)-4e (78
mg, 0.25 mmol) and Boc2O (0.06 mL, 0.3 mmol) in EtOAc (8 mL)
containing a catalytic amount of 10% Pd/C was stirred under a H2
atmosphere for 22 h at r.t. The crude product was purified by flash
column chromatography (SiO2, Et2O–n-pentane, 1:4) to give (R)-5e
as a colorless viscous liquid (76 mg, 79%); ee ≥98% (HPLC, Chiral-
cel OD, n-heptane–i-PrOH, 95:5); [a]D23 +8.6 (c = 1.0, CHCl3).
IR (film): 3387 (m), 2978 (s), 2935 (m), 1715 (s), 1502 (s), 1455 (s),
1363 (s), 1271 (m), 1246 (m), 1168 (s), 1076 (s), 914 (s), 881 (s),
780 (m), 700 (s), 631 (m), 585 (m) cm–1.
1H NMR (300 MHz, CDCl3): d = 1.09 [d, J = 5.9 Hz, 3 H,
SO3CH(CH3)CH3], 1.14 [br s, 3 H, NHC(CH3)CH3], 1.27 [s, 3 H,
NHC(CH3)CH3], 1.31 [d, J = 6.4 Hz, 3H, SO3CH(CH3)CH3], 1.34
[s, 9 H, C(CH3)3], 2.67 (br s, 2 H, CH2CNH), 4.29 (dd, J = 5.9, 11.9
Hz, 1 H, ArCHSO3), 4.33 (br s, 1 H, NH), 4.60 [sept, J = 6.2 Hz, 1
H, (CH3)2CHO3S], 7.32–7.41 (m, 3 H, ArH), 7.41–7.48 (m, 2 H,
ArH).
13C NMR (75 MHz, CDCl3): d = 22.5, 23.4 [(CH3)2CHO3S], 28.0
(br, CH3), 28.3 [C(CH3)3], 39.7 (CH2), 52.2 (CNH), 65.0 (CHSO3),
78.0 (SO3CH), 78.8 [C(CH3)3], 128.7, 128.8, 129.9 (CHarom), 134.1
(Carom), 152.2 (NCO2).
MS (CI, 100 eV, methane): m/z (%) = 386 (4, [M+ + 1]), 330 (20),
286 (65), 270 (10), 244 (100), 227 (13), 206 (53), 158 (49), 145
(21), 102 (45), 84 (4).
IR (KBr): 3394 (s), 2970 (m), 2932 (m), 1686 (s), 1522 (s), 1455
(m), 1349 (s), 1276 (m), 1245 (m), 1173 (s), 1095 (m), 919 (s), 875
(s), 807 (m), 776 (m), 698 (m), 632 (m), 560 (m) cm–1.
1H NMR (400 MHz, CDCl3): d = 0.87 (t, J = 7.4 Hz, 3 H, CH2CH3),
1.13, 1.31 [two d, J = 6.3, 6.1 Hz, 6 H, SO3CH(CH3)2], 1.38 [s, 9 H,
C(CH3)3], 1.30–1.48 (m, 1 H, CHHCH3), 1.48–1.57 (m, 1 H,
CHHCH3),2.30 (m, 1 H, CHHCHNH), 2.50 (m, 1 H, CHHCHNH),
3.58 (br s, 1 H, CHNH), 4.16 (br d, J = 9.1 Hz, 1 H, NHCH), 4.27
(br dd, J = 3.9, 9.2 Hz, 1 H, ArCHSO3), 4.62 [sept, J = 6.3 Hz, 1 H,
(CH3)2CHO3S], 7.33–7.44 (m, 5 H, ArH).
13C NMR (100 MHz, CDCl3): d = 9.8 (CH2CH3), 22.5, 23.3
[(CH3)2CHO3S], 27.4 (CH2CH3), 28.3 [C(CH3)3], 35.2 (CH2), 50.6
(CHN), 65.4 (CHSO3), 77.9 (SO3CH), 79.0 [C(CH3)3], 128.6,
128.7, 129.3 (CHarom), 132.9 (Carom), 155.0 (NCO2).
MS (CI, 100 eV, methane): m/z (%) = 386 (2, [M+ + 1]), 356 (6),
330 (31), 316 (7), 288 (100), 272 (8), 256 (7), 244 (37), 206 (64),
188 (6), 158 (12), 145 (5), 132 (6), 102 (30).
Anal. Calcd for C19H31NO5S: C, 59.19; H, 8.11; N, 3.63. Found: C,
59.54; H, 8.09; N, 3.66.
Anal. Calcd for C19H31NO5S: C, 59.19; H, 8.11; N, 3.63. Found: C,
59.48; H, 8.11; N, 3.75.
Isopropyl (R)-3-tert-Butoxycarbonylamino-1-(4-butylphenyl)-
3-methylbutanesulfonate [(R)-5f]
Isopropyl (1R,3S)-3-tert-Butoxycarbonylamino-1-(4-butylphe-
nyl)pentanesulfonate [(R,S)-5d]
According to GP 2, a mixture of the g-azido sulfonate (R)-4f (104
mg, 0.28 mmol) and Boc2O (0.07 mL, 0.33 mmol) in EtOAc (8 mL)
containing a catalytic amount of 10% Pd/C was stirred under a H2
atmosphere for 20 h at r.t. The crude product was purified by flash
column chromatography (SiO2, Et2O–n-pentane, 1:5) to give (R)-5f
as a colorless viscous liquid (101 mg, 81%); ee ≥98% (based on the
ee-value of the sultone); [a]D23 +4.5 (c = 1.1, CHCl3).
According to GP 2, a mixture of the g-azido sulfonate (R,S)-4d (70
mg, 0.2 mmol) and Boc2O (0.05 mL, 0.23 mmol) in EtOAc (5 mL)
containing a catalytic amount of 10% Pd/C was stirred under a H2
atmosphere for 19 h at r.t. The crude product was purified by flash
column chromatography (SiO2, Et2O–n-pentane, 1:4) to give (R,S)-
5d as a colorless solid (67 mg, 80%); de ≥98% (NMR); ee ≥98%
(based on the ee-value of the sultone); mp 58 °C; [a]D24 –6.1 (c =
1.2, CHCl3).
IR (CHCl3): 3393 (m), 2971 (s), 1714 (s), 1506 (s), 1364 (s), 1272
(m), 1245 (m), 1168 (s), 1080 (s), 917 (s), 883 (s), 758 (s), 668 (m),
614 (m) cm–1.
IR (CHCl3): 3389 (m), 2969 (s), 2875 (m), 1702 (s), 1514 (s), 1460
(m), 1364 (s), 1243 (m), 1170 (s), 1094 (m), 1070 (m), 915 (s), 882
(s), 757 (s), 615 (m) cm–1.
1H NMR (400 MHz, CDCl3): d = 1.07 [br s,
3
H,
SO3CH(CH3)CH3], 1.19 (br s, 3 H, NHCCH3), 1.27 (s, 3 H,
NHCCH3), 1.30 [s, 18 H, CO2C(CH3)3 and ArC(CH3)3], 1.31 (d,
J = 8.0 Hz, 3 H, SO3CH(CH3)CH3], 2.62 (br m, 2 H, CH2CNH),
4.25 (dd, J = 2.2, 9.1 Hz, 1 H, ArCHSO3), 4.33 (br s, 1 H, NH), 4.60
[br sept, J = 6.0 Hz, 1 H, (CH3)2CHO3S], 7.36 (m, 4 H, ArH).
1H NMR (300 MHz, CDCl3): d = 0.88 (t, J = 7.4 Hz, 3 H, CH2CH3),
1.11, 3.31 [2 d, J = 6.2, 5.9 Hz, 6 H, SO3CH(CH3)2], 1.31 [s, 9 H,
CO2C(CH3)3], 1.39 [s, 9 H, C(CH3)3], 1.25–1.44 (m, 1 H,
CHHCH3), 1.45-1.61 (m, 1 H, CHHCH3), 2.30 (m, 1 H, CHHCH-
NH), 2.48 (m, 1 H, CHHCHNH), 3.63 (br s, 1 H, CHNH), 4.13 (br
d, J = 8.9 Hz, 1 H, NHCH), 4.24 (dd, J = 4.0, 9.4 Hz, 1 H,
ArCHSO3), 4.63 [sept, J = 6.2 Hz, 1 H, (CH3)2CHO3S], 7.33, 7.39
[2 d (AB system), J = 8.4 Hz, 4 H, ArH].
13C NMR (100 MHz, CDCl3): d = 22.3, 23.4 [(CH3)2CHO3S], 27.7
(br, CH3), 28.3 [C(CH3)3], 31.2 [C(CH3)3], 34.5 [C(CH3)3], 39.6
(CH2), 52.1 (CNH), 64.6 (CHSO3), 77.9 (SO3CH), 78.8 [C(CH3)3],
125.4, 129.3 (CHarom), 130.6 (Carom), 151.6 (Carom and NCO2).
MS (CI, 100 eV, methane): m/z (%) = 442 (1, [M+ + 1]), 386 (7),
342 (69), 300 (49), 262 (100), 244 (15), 201 (10), 158 (9), 145 (5),
130 (3), 102 (57).
13C NMR (75 MHz, CDCl3): d = 9.7 (CH2CH3), 22.5, 23.4
[(CH3)2CHO3S], 27.5 (CH2CH3), 28.4 [C(CH3)3], 31.3
[CO2C(CH3)3], 34.6 [C(CH3)3], 35.1 (CH2), 50.6 (CHN), 65.3
Synthesis 2004, No. 17, 2910–2918 © Thieme Stuttgart · New York

PAPER
Highly Efficient Asymmetric Synthesis of Homotaurine Derivatives
2917
Anal. Calcd for C23H39NO5S: C, 62.26; H, 8.90; N, 3.17. Found: C,
62.51; H, 9.01; N, 3.60.
combined CH2Cl2 fractions were evaporated under reduced pres-
sure to provide the sulfonic acid 3a. A solution of the crude g-azido
sulfonic acid in MeOH (10 mL) containing a catalytic amount of
10% Pd/C was stirred under a H2 atmosphere for 16 h at r.t. The cat-
alyst was filtered off through a pad of Celite and washed with
MeOH. The filtrate was evaporated under reduced pressure and the
resulting solid was washed with Et2O providing the desired product
(R,S)-8 as a colorless solid (210 mg, 92%); de ≥96% (NMR); ee
≥98% (based on the ee-value of sultone); mp >300 °C; [a]D22 +4.1
(c = 1.1, H2O).
Sodium (1R,3S)-3-tert-Butoxycarbonylamino-1-phenylbutane-
sulfonate [(R,S)-6]
The isopropyl sulfonate (R,S)-5a (70 mg, 0.19 mmol) was dissolved
in acetone (20 mL) and NaI (34 mg, 0.23 mmol) was added. The re-
action mixture was refluxed for 2 d after which the solvent was
evaporated under reduced pressure. The resulting solid was washed
with Et2O providing the desired product (R,S)-6 as a colorless solid
(60 mg, 91%) which was contaminated with a small amount of NaI;
de ≥96% (NMR); ee ≥98% [based on the ee-value of (R,S)-5a].
IR (KBr): 3062 (s), 2966 (s), 1632 (m), 1529 (s), 1453 (m), 1398
(m), 1240 (s), 1195 (s), 1157 (s), 1038 (s), 785 (m), 701 (s), 651 (s),
591 (m), 523 (m) cm–1.
1H NMR (300 MHz, D2O): d = 1.13 (d, J = 6.6 Hz, 3 H, CH3CHN),
2.25 (ddd, J = 4.4, 10.4, 13.5 Hz, 1 H, CHHCHN), 2.43 (ddd,
J = 4.1, 11.8, 13.5 Hz, 1 H, CHHCHN), 2.94 (m, 1 H, CHN), 4.01
(dd, J = 4.1, 11.8 Hz, 1 H, CH2CHSO3), 7.31 (m, 5 H, ArH).
IR (KBr): 3395 (s), 2977 (m), 1689 (s), 1524 (m), 1454 (m), 1391
(m), 1367 (m), 1177 (s), 1048 (s), 703 (m), 644 (m) cm–1.
1H NMR (300 MHz, CD3OD): d = 1.05 (d, J = 6.6 Hz, 3 H,
CH3CHNH), 1.39 [s, 9 H, C(CH3)3], 2.32 (br s, 2 H, CH2CHNH),
3.48 (br m, 1 H, CHNH), 3.93 (t, J = 7.1 Hz, 1 H, CHSO3), 7.22–
7.34 (m, 3 H, ArH), 7.44 (d, J = 7.4, 2 H, ArH).
13C NMR (100 MHz, CD3OD): d = 18.5 (CH3), 26.9 [C(CH3)3],
37.1 (CH2), 44.1 (CHN), 63.4 (CHSO3), 77.8 [C(CH3)3], 126.5,
127.2, 128.8 (CHarom), 136.2 (Carom), 155.6 (NCO2).
13C NMR (75 MHz, D2O): d = 16.0 (CH3), 34.2 (CH2), 45.0 (CHN),
62.0 (CHSO3), 128.3, 128.5, 128.7 (CHarom), 133.3 (Carom).
–
MS (ESI): m/z (%) = 228 (100) [C10H14NSO3 ].
Anal. Calcd for C10H15NO3S: C, 52.38; H, 6.59; N, 6.11. Found: C,
52.09; H, 6.88; N, 5.92.
Isopropyl (1R,3S)-3-Benzylcarbonylamino-1-phenylbutane-
sulfonate [(R,S)-7]
(S)-N-Acetyl-4-phenyl-2-butylamine [(S)-11]
To a solution of the sulfonate (R,S)-5a (22 mg, 0.06 mmol) in
CH2Cl2 (1 mL) was added a solution of 30% TFA in CH2Cl2 (1 mL).
After stirring for 30 min at r.t., the solvent was evaporated in vacuo.
The resulting amine was dissolved in a mixture of CH2Cl2 and H2O
(9:1, 2.5 mL) after which CbzCl (0.03 mL, 0.18 mmol) and K2CO3
(50 mg, 0.36 mmol) were added. The reaction mixture was vigor-
ously stirred at r.t. for 16 h. After separation of the organic layer, the
aqueous phase was extracted with CH2Cl2. The combined organic
layers were washed with H2O, brine and dried (MgSO4). The sol-
vent was evaporated under reduced pressure and the crude product
was purified by flash column chromatography (SiO2, Et2O–n-pen-
tane, 1:3) to give the product (R,S)-7 as a colorless viscous liquid
(23 mg, 96%); de ≥96% (NMR); ee ≥98% [based on the ee-value of
(R,S)-5a]; [a]D23 +3.3 (c = 1.0, CHCl3).
A mixture of the enantiopure sultone (R,R)-1a (75 mg, 0.354
mmol), NaN3 (115 mg, 1.77 mmol) and NH4Cl (42 mg, 0.78 mmol)
in anhyd DMF (3 mL) was heated at 60 °C under argon for 2 h.
DMF was removed under vacuum almost completely and the re-
maining sodium sulfonate (R,S)-2a in a small amount of DMF
(about 0.2 mL) was suspended in anhyd CH2Cl2 (5 mL). A solution
of 20% COCl2 in toluene (0.5 mL) was added dropwise at 0 °C and
the mixture was stirred at r.t. for 1 h. The mixture was then filtered
and the solid was triturated with CH2Cl2 and refiltered. The com-
bined CH2Cl2 fractions were evaporated under reduced pressure and
the crude product was filtered again through a short-path silica gel
column in order to remove the polar impurities. The solvent was re-
moved to give the sulfonyl chloride 9, which was used in the next
step without further purification. A solution of the crude g-azido
sulfonyl chloride 9 in MeOH (10 mL) containing a catalytic amount
of 10% Pd/C was stirred under a H2 atmosphere for 16 h at r.t. The
catalyst was removed by filtration off through a pad of Celite and
the filtrate was evaporated under reduced pressure to give the amine
10 as a colorless solid which was used in the acetylation step with-
out further purification.
IR (CHCl3): 3377 (m), 3031 (m), 2982 (m), 1709 (s), 1525 (s), 1455
(s), 1342 (s), 1246 (s), 1168 (s), 1093 (m), 1061 (s), 912 (s), 755 (s),
699 (s), 631 (m), 591 (m) cm–1.
1H NMR (300 MHz, CDCl3): d = 1.10 [d, J = 6.2 Hz, 3 H,
SO3CH(CH3)CH3], 1.13 (d, J = 7.2 Hz, 3 H, CH3CHNH), 1.29 [d,
J = 6.2 Hz, 3 H, SO3CH(CH3)CH3], 2.46 (m, 2 H, CH2CHNH), 3.72
(br m, 1 H, CHNH), 4.23 (br dd, J = 3.7, 10.1 Hz, 1 H, ArCHSO3),
4.49 (br d, J = 7.4 Hz, 1 H, NHCH), 4.61 [sept, J = 6.2 Hz, 1 H,
(CH3)2CHO3S], 4.97, 5.03 [2 d (AB system), J = 7.5 Hz, 2 H,
CH2Ph], 7.25–7.43 (m, 10 H, ArH).
13C NMR (75 MHz, CDCl3): d = 20.3 (CH3), 22.5, 23.3
[(CH3)2CHO3S], 36.8 (CH2), 45.5 (CHN), 65.5 (CHSO3), 66.6
(CH2Ph), 78.2 (SO3CH), 128.2, 128.5, 128.8, 129.1, 129.6 (CHarom),
132.2, 136.3 (Carom), 155.3 (NCO2).
1H NMR (300 MHz, CDCl3): d = 1.41 (d, J = 6.3 Hz, 3 H, CHCH3),
1.91, 2.14 (m each, 1 H, CH2CH2CH), 2.73 (t, J = 8.0 Hz, 2 H,
PhCH2), 3.30 (sext, 1 H, CHNH2), 7.14–7.22 (m, 3 H, ArH), 7.14–
7.28 (m, 5 H, ArH), 7.80 (br s, 2 H, NH2).
13C NMR (75 MHz, CDCl3): d = 20.0 (CH3), 31.7 (CH2), 36.7
(CH2), 47.9 (CHN), 126.3, 128.5, 128.6 (CHarom), 140.2 (Carom).
To a solution of the amine 10 and Ac2O (0.04 mL, 0.425 mmol) in
anhyd CH2Cl2 (2 mL) was added Et3N (0.06 mL, 0.39 mmol) drop-
wise at 0 °C. The mixture was stirred at r.t. for 1 h after which the
mixture was diluted with CH2Cl2 and washed with H2O. The com-
bined organic layers were dried (MgSO4) and evaporated under re-
duced pressure. The crude product was purified by flash column
chromatography (SiO2, MeOH–CH2Cl2, 2:98) to give the desired
product (S)-11 as a colorless solid (47 mg, 70%); ee ≥98% (based
on the ee-value of the sultone); [a]D24 –34.1 (c = 0.65, EtOH) {Lit.22
[a]D26 –35.2 (c = 0.7, EtOH)}.
MS (EI, 70 eV): m/z (%) = 405 (6, [M+]), 363 (4), 282 (6), 228 (3),
178 (22), 134 (30), 108 (14), 91 (100).
HRMS (EI, M+): m/z calcd for C21H27NO5S: 405.160996; found:
405.160935.
(1R,3S)-3-Amino-1-phenylbutanesulfonic Acid [(R,S)-8]
A mixture of the enantiopure sultone (R,R)-1a (212 mg, 1.0 mmol),
NaN3 (324 mg, 5.0 mmol) and NH4Cl (120 mg, 2.2 mmol) in anhyd
DMF (5 mL) was heated at 60 °C under argon for 2 h. The DMF was
removed under vacuum and the resulting sodium sulfonate (R,S)-2a
was treated with an excess of methanolic HCl. After removal of
MeOH, the solid was triturated with CH2Cl2 and filtered twice. The
IR (KBr): 3307 (s), 3066 (m), 3027 (m), 2965 (m), 2925 (m), 2855
(m), 1641 (s), 1547 (s), 1447 (m), 1371 (m), 1293 (m), 1191 (w),
1149 (m), 744 (m), 697 (m), 609 (m) cm–1.
Synthesis 2004, No. 17, 2910–2918 © Thieme Stuttgart · New York

2918
D. Enders, W. Harnying
PAPER
1H NMR (300 MHz, CDCl3): d = 1.17 (d, J = 6.6 Hz, 3 H, CHCH3),
1.75 (m, 2 H, CH2CH), 1.93 (s, 3 H, CO2CH3), 2.65 (t, J = 8.0 Hz,
2 H, PhCH2), 4.05 (m, 1 H, CHNH), 5.44 (br s, 1 H, NH), 7.14–7.22
(m, 3 H, ArH), 7.24–7.32 (m, 2 H, ArH).
13C NMR (75 MHz, CDCl3): d = 21.1 (CH3), 23.5 (CH3), 32.5
(CH2), 38.6 (CH2), 45.3 (CHN), 125.9, 128.3, 128.4 (CHarom), 141.8
(Carom), 169.5 (C=O).
(9) (a) Dujols, F. J. M.; Mullíez, M. E. J. Org. Chem. 1996, 61,
5648. (b) Paik, S.; White, E. H. Tetrahedron 1996, 52, 5303.
(10) (a) Moree, W. J.; van Gent, L. C.; van der Marel, G. A.;
Liskamp, R. M. J. Tetrahedron 1993, 49, 1133. (b) Moree,
W. J.; van der Marel, G. A.; Liskamp, R. M. J. J. Org. Chem.
1995, 60, 5157. (c) Paik, S.; White, E. H. Tetrahedron Lett.
1996, 37, 4663. (d) Gude, M.; Piarulli, U.; Potenza, D.;
Salom, B.; Gennari, C. Tetrahedron Lett. 1996, 37, 8589.
(e) Gennari, C.; Gude, M.; Potenza, D.; Piarulli, U. Chem.
Eur. J. 1998, 4, 1924. (f) Monnee, M. C. F.; Marijne, M. F.;
Brouwer, A. J.; Liskamp, R. M. J. Tetrahedron Lett. 2000,
41, 7991.
(11) (a) Gennari, C.; Salom, B.; Potenza, D.; Williams, A.
Angew. Chem., Int. Ed. Engl. 1994, 33, 2067; Angew. Chem.
1994, 106, 2181. (b) Gennari, C.; Nestler, H. P.; Salom, B.;
Still, W. C. Angew. Chem., Int. Ed. Engl. 1995, 34, 1763,
1765; Angew. Chem. 1995, 107, 1892.
MS (EI, 70 eV): m/z (%) = 191 (52, [M+]), 132 (22), 117 (51), 87
(100), 72 (23), 58 (13).
Acknowledgment
This work was supported by the Deutsche Forschungsgemeinschaft
(SFB 380, Graduiertenkolleg 440) and the Fonds der Chemischen
Industrie. We thank Degussa AG, BASF AG and Bayer AG for the
donation of chemicals.
(12) (a) Enders, D.; Wallert, S. Synlett 2002, 304. (b) Enders,
D.; Wallert, S.; Runsink, J. Synthesis 2003, 1856.
(13) (a) Enders, D.; Vignola, N.; Berner, O. M. Angew. Chem.
Int. Ed. 2002, 41, 109; Angew. Chem. 2002, 114, 116.
(b) Enders, D.; Berner, O. M.; Vignola, N. Chem. Commun.
2001, 2498. (c) Enders, D.; Berner, O. M.; Vignola, N.;
Harnying, W. Synthesis 2002, 1945.
(14) (a) Enders, D.; Harnying, W.; Vignola, N. Synlett 2002,
1727. (b) Enders, D.; Harnying, W.; Vignola, N. Eur. J. Org.
Chem. 2003, 20, 3939.
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Synthesis 2004, No. 17, 2910–2918 © Thieme Stuttgart · New York