Stieglitz rearrangement of N,N-dichloro-β,β-disubstituted taurines under mild aqueous conditions

Article abstract of DOI:10.1016/j.bmcl.2008.12.109

New topical anti-infectives comprised of N,N-dichloro-β,β-disubstituted taurines [Tetrahedron Lett. 2008, 49, 2193; Biorg. Med. Chem. Lett. 2009, 19, 196] have been examined for structure-stability relationships (SSR) based upon various alkyl, heteroalkyl

Full text of DOI:10.1016/j.bmcl.2008.12.109

Bioorganic & Medicinal Chemistry Letters 19 (2009) 1110–1114
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Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Stieglitz rearrangement of N,N-dichloro-b,b-disubstituted taurines under
mild aqueous conditions
*
*
Timothy P. Shiau , Ashley Houchin, Satheesh Nair, Ping Xu, Eddy Low, Ramin (Ron) Najafi, Rakesh Jain
NovaBay Pharmaceuticals, 5980 Horton St. Suite 550, Emeryville, CA 94608, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
New topical anti-infectives comprised of N,N-dichloro-b,b-disubstituted taurines [Tetrahedron Lett. 2008,
49, 2193; Biorg. Med. Chem. Lett. 2009, 19, 196] have been examined for structure–stability relationships
(SSR) based upon various alkyl, heteroalkyl and cycloalkyl b-substitutions. These substitutions affect
order-of-magnitude changes in the aqueous stability of these N,N-dichloroamines which can undergo
Stieglitz rearrangement of alkyl groups under extremely mild conditions (H2O, pH 4–7, 0–20 mM acetate
or phosphate buffer, 20–40 °C). This process produces b-ketosulfonic acids which function as substrates
for chlorination by the N-chlorotaurines which leads to their further degradation.
Received 26 November 2008
Accepted 30 December 2008
Available online 3 January 2009
Keywords:
Taurine
Chlorotaurine
Chloroamines
Dichloroamines
Stieglitz
Ó 2009 Elsevier Ltd. All rights reserved.
Rearrangement
Antimicrobial
Sulfinimine addition
Halogens and halogenating agents have long been used as disin-
fectants,2 antiseptics,3 and antimicrobials.4 While effectively kill-
ing bacteria,4 fungi,4f,5 and viruses,6 many of these chlorinating
agents are also toxic to mammalian cells,7 which limits their appli-
cation as therapeutics for sensitive topical applications such as
wounds and ocular infections.
activity of the N,N-dichloramines that are generated under these
conditions.
The N,N-dichloramines, which are the dominant species at the
more desirable low pH region,9a,15 undergo dehydrochlorination
if hydrogens are present on the carbon adjacent to the dichloro-
amine in the molecule.16 With the b,b-disubstitution of the N,N-
dichlorotaurines, this decomposition pathway is prevented.1 We
expected that these derivatives would retain their antimicrobial
activity and exhibit greater stability than N,N-dichlorotaurine or
N-chlorotaurine. Moreover, this substitution would increase the
lipophilicity of the derivatives which is critical for many topical
therapeutic agents. In the present study, we report the synthesis
of a number of novel b,b-disubstituted N,N-dichlorotaurines (1a–
k) examining their stabilities to assess their suitability as antimi-
crobial agents (see Fig. 1).
Synthesis of N,N-dichloro-b,b-disubstituted taurines (1). The syn-
thesis of b,b-disubstituted taurines (5) was accomplished by one
of two general synthetic schemes based upon the commercial
availability of the required starting materials. In the first approach,
we developed a route in which a sulfur atom, either as sulfite17 or
sulfide,18 opens an aziridine generated in situ from a suitably deriv-
atized b,b-disubstituted b-amino alcohol (Scheme 1). These, in
turn, are readily prepared by the reduction of the corresponding
amino acids. The aminosulfonates 5a–c, 5f–h, and 5k were pre-
pared through this protocol (Table 1).
In particular, chloramine8 and organic N-chloramines4f,9 have
been used as mild antimicrobials and as CNS drugs.10 These exhibit
lower mammalian cytotoxicity versus chlorine and chloramides
while maintaining their antimicrobial activities. In the body, the
generation of hypochlorous acid in neutrophils which contain high
concentration of taurine11 leads to N-chlorinated taurines.12 Due to
their nonspecific mechanism of action, these compounds have low
potential for the development of spontaneous resistance.
While chloroamides are more active at higher pH,13 the antimi-
crobial9a,3a and chlorinating activity14 of organic N-chloramines in-
creases in mildly acidic solution. Unfortunately, N-chloramines
readily disproportionate to give amines and N,N-dichloram-
ines.9a,15 Because N,N-dichloramines themselves are antimicrobial
agents,4f it is difficult to separate the contribution to the antimicro-
bial activity of N-chloramines at neutral or acidic pH from the
* Corresponding authors. Tel.: +1 510 899 8862; fax: +1 510 740 3469 (T.P.S.);
tel.: +1 510 899 8871 (R.J.).
E-mail addresses: tshiau@novabaypharma.com (T.P. Shiau), rjain@novabayphar-
ma.com (R. Jain).
Our second synthetic approach to 5 involves the nucleophilic
addition of ethoxysulfonylmethyl anions to imines to provide the
0960-894X/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2008.12.109

T. P. Shiau et al. / Bioorg. Med. Chem. Lett. 19 (2009) 1110–1114
1111
Secondary Substituents
1d:
t1/2 < 10 min @ 25oC
Primary Substituents
1b
: t1/2 = 1 d @ 40oC
1c: t1/2 = 0.5 d @ 40oC
1f: t1/2 = 5 d @ 40oC
1g: t1/2 = 7 d@ 40oC
Primary Substituents with Ring Strain
Methyl Substituents
1a
1e: t1/2 = 6 h @ 25oC
>>
>>
: t1/2 > 2 yr @ 40oC
: t1/2 = 2 d @ 40oC
Cation-Stabilizing Substituents
1h
: t1/2 = 1.5 d @ 25oC
: t1/2 = 1 d @ 40oC
1j
1i
1k: t1/2 < 1 d @ 25oC
increasing decomposition rate
Figure 1. Summary for the relative stabilities of 1.
1
2
R1 R2
R1 R2
(a)
R R
R1R2
(b)
O
S
R1
R2
O
S
R1
R2
(b)
(a)
SO3Et
OH
H2N CO2H
BocHN CO2Me
tBu
N
H
7
BocHN
O
tBu
N
2
3
6
R1R2
R1R2
R1R2
(c)
(d)
(c)
-
-
SO3
OMs
+H3N
SO3
+H3N
BocHN
5
4
5
Scheme 2. Reagents and conditions: (a) t-BuSONH2, Ti(OEt)4, 50–70 °C, 2–18 h; (b)
MeSO3Et, n-BuLi, THF, HMPA, À78 °C, 4 h; (c) 1—LiOH, THF/MeOH/H2O, 25 °C, 4–
18 h; 2—HCl, MeOH, 1,4-dioxane, 25 °C, 15 min.
Scheme 1. Reagents and conditions: (a) 1—Boc2O, NaHCO3, THF/H2O, 0 °C, 2–18 h;
2—TMSCHN2, MeOH/THF, 0–20 °C, 2–4 h; (b) LiBH4, THF/EtOH, 0–20 °C, 18–24 h;
(c) MsCl, NEt3, CH2Cl2, 0 °C, 1–3 h; (d) 1—HCl, 1,4-dioxane, 25 °C, 1 h; 2—Na2SO3,
H2O, 20–50 °C, 2–18 h.
Table 2
Alternative synthesis of b,b-disubstituted taurines 5
Table 1
Synthesis of b,b-disubstituted taurines 5
R1, R2
Series
6 (%)
7 (%)
5 (%)
R1, R2
Series
2 (%)
3 (%)
4 (%)
5 (%)
Me, Me
i-Pr, i-Pr
(CH2)3
(CH2CMe2)2CH2
Me, CH2OMe
a
d
e
i
37
19
64
78
26b
21
41
30
15
42c
NAa
35
Me, Me
Et, Et
Pr, Pr
(CH2)4
(CH2)5
(CH2)6
(CH2)2OCH2
a
b
c
NA
96
56
NA
NAb
94
90a
86
82
85
55
95
96
65
79
50
61
41
93
71
36
32
NAa
7
86
83a
79b
88
j
100
f
g
h
k
a
Not isolated.
Formed as a 2:1 E/Z mixture.
Formed as a 2:1 mixture of diastereomers.
b
42
88
c
a
Yield given for Boc-protection of corresponding amino alcohol (Boc2O, NEt3,
CH2Cl2, 0 °C, 2 h) rather than reduction of methyl ester.
b
Yield over two steps.
X3
X2 X1
R1 R2
R1R2
-
SO3Na
SO3
R3
SO3Na
+H3N
+
Cl2N
b-aminosulfonate skeleton. Anion additions to imines are well-
precedented for carbanions,19 cyanide,20 enolates,21 diethyl-
methylphosphonate anions,22 fluorosulfonate,23 and phenylsulfo-
nyl-(difluoro)methyl anions.24 We reasoned that the addition of
ethoxysulfonylmethides to N-sulfinyl ketimines would also occur
to provide an alternative route to 5 for cases where the amino acid
or amino alcohol precursors were either unavailable or prohibi-
tively expensive.
Condensation of a variety of ketones with tert-butanesulfina-
mide under the conditions developed by Ellman provided the cor-
responding N-sulfinyl imines 6.25 A variety of bases and co-
solvents were screened to find the best conditions for the forma-
tion of ethoxysulfonylmethide and its addition to 6a (MeSO3Et,
n-BuLi, THF, HMPA, À78 °C, 4 h). While the results for the optimi-
zation were disappointing, these conditions did provide an alterna-
tive entry to 5 which was employed for the synthesis of several b,b-
disubstituted taurines 5 (Scheme 2 and Table 2). The intermediate
adducts 7 were hydrolyzed, first under basic conditions and the
sulfinyl protecting group removed with acidic methanol to give
the corresponding b-aminosulfonates 5a, 5d–e, and 5i–j. (Scheme
3).
O
1
5
(Table 3)
(where R2 = R3-CH2)
1
2
3
8
(X =X =X =H)
9 (X1=Cl, X2=X3=H)
10 (X1=X2=Cl, X3=H)
1
2
3
11
(X =X =X =Cl)
X3
X2 X1
+H3N
Cl2N
NC
+
-
SO3Na
SO3Na
SO3
n
O
n
1
n
1
2
3
12
(X =X =X =H)
5
1
2
3
(Table 3, n=2-4)
13
(X =Cl, X =X =H)
14 (X1=X2=Cl, X3=H)
1
2
3
15
(X =X =X =Cl)
Scheme 3.
The N-chlorinations of 5 were performed using one of three
methods: A (trichloroisocyanuric acid (TCI) in water), B (HOCl, pre-
pared in situ by the acidification with 6 M HCl of commercial

1112
T. P. Shiau et al. / Bioorg. Med. Chem. Lett. 19 (2009) 1110–1114
Table 3
their chlorinated derivatives. (Scheme 3). Stieglitz rearrangements
Compound 1 from the chlorination of 5
have been reported in organic solvents for aryl and stabilized alkyl
migrating groups, but not under mild aqueous conditions with
unstabilized alkyl groups.27
R1R2
[Cl+]
R1 R2
-
SO3
+H3N
SO3Na
Cl2N
Several aspects of the data presented in Table 5 warrant further
discussion. As noted above, the de-N-chlorinated taurines 5 were
always observed in the decomposition process. The b-ketosulfo-
nates were also observed together with their chlorinated counter-
parts which each successively increasing by 34 mass units
corresponding to the replacement of one hydrogen atom with a
chlorine atom. The characteristic isotopic distributions for one,
two or three chlorine atoms are observed in the MS of each of these
products. In the acyclic cases, the b-ketosulfonates 8 are lower in
mass than 5, while in the cyclic cases, these b-ketosulfonates 12
are higher in mass than their taurine counterparts 5. Moreover,
in the acyclic cases, the b-ketosulfonates have masses which are
a different odd–even parity than 5 consistent with the loss of a
nitrogen atom. Also, by comparing the diethyl and dipropyl deriv-
atives, we can observe that the difference in mass between the
degradants 8 is only 14 amu (1Â CH2), while the difference be-
tween the 5b and 5c is 28 amu (2Â CH2) indicating that only one
side chain is retained in 8. This data is wholly consistent with
the assigned structures.
5
1
Series
R1, R2
Methoda
1 (%)
a
b
c
d
e
f
g
h
i
Me, Me
Et, Et
Pr, Pr
A
C
B
B
B
B
A
C
C
B
B
28
76b
60
i-Pr, i-Pr
(CH2)3
(CH2)4
(CH2)5
(CH2)6
(CH2CMe2)2CH2
Me, CH2OMe
(CH2)2OCH2
NAc
NAc
34
24
43b
51b
61
j
k
NAc
a
A (trichloroisocyanuric acid (TCI) in water), B (HOCl, prepared in situ by the
acidification with 6 M HCl of commercial bleach to pH 4–5), or C (t-BuOCl in
methanol).
b
Chlorination by tert-butylhypochlorite gives the sulfonic acid.
Unstable compound, not isolated in pure form.
c
Through preparative-scale HPLC, analytically pure fractions of
many of these decomposition products (see Table 5) were isolated
and 1H NMR was employed to confirm the assigned structures
(D2O, 400 MHz).
Table 4
Summary of stability data for 1
Compound
Conditions
t1/2
1a
1b
1b
1c
1c
1d
1e
1f
pH 4, 40 °C
pH 4, 40 °C
pH 7 buffer, 40 °C
pH 4, 40 °C
pH 7 buffer, 40 °C
pH 4, 25 °C
>2 y
1 d
0.5 d
0.5 d
2 d
<10 min
6 h
5 d
1 d
7 d
2 d
1 d
Proposed mechanism. Our proposed mechanism is shown in
Scheme 4. It involves an initial Stieglitz rearrangement of the alkyl
and cycloalkyl derivatives to generate an intermediate N-chloroi-
minium species, which is readily hydrolyzed to the ketone and
the N-chloroalkylamine (Scheme 4). Acyclic derivatives produce 8
(Scheme 4a). However, the formation of the nitrile moiety in
12f–h from the cyclic derivatives 1f–h suggests that the corre-
sponding hydrolysis of A giving B may be reversible, stabilizing B
until it is further chlorinated to C through transchlorination
(Scheme 4b). The double dehydrochlorination of C could then pro-
vide the observed nitrile 12. Any free imine originating from the
dehydrochlorination of B would be expected to be readily hydro-
lyzed to the corresponding aldehyde which was not observed.
Chlorination of the enolic forms of the b-ketosulfonates leads to
the observed mono- (9b–c, 13f–h), di- (10b–c, 14f–h) and tri-
chloro- (11b–c, 15f–h) derivatives (Scheme 4c).
Previous studies on the migratory aptitudes for the Lewis acid-
mediated Stieglitz rearrangement support the assertion that the
instability of a compound should be proportional to the cation-sta-
bilizing ability of the migrating side chain.28 This is wholly consis-
tent with our observations in that there are dramatic differences in
the stabilities of 1 which follow the order Me > 1° > 2° for the b-al-
kyl substituents.
pH 4, 25 °C
pH 4 buffer, 40 °C
pH 7 buffer, 40 °C
pH 4 buffer, 40 °C
pH 4 buffer, 40 °C
pH 4, 40 °C
1f
1g
1h
1i
1j
1k
pH 4, 25 °C
pH 4, 25 °C
1.5 d
<1 d
bleach to pH 4–5), or C (t-BuOCl in methanol). The resulting N,N-
dichlorotaurines 1 appear to be stable to either silica gel chroma-
tography or preparative-scale reverse-phase HPLC. Compounds
1a–1c and 1f–1j were stored as purified powders for several
months at À20 °C. However, the inherent instability of the other
derivatives prevented their isolation in pure form and their charac-
terization could only be accomplished through LC–MS (Table 3).
Results and discussion. Solution stabilities of 1–4 mM com-
pounds 1a–1k were evaluated at a variety of pH values (4–7) and
buffer concentrations (4–20 mM). The samples were incubated at
25 or 40 °C and quantified either by the UV signature of the dichlo-
roamine chromophore (A300–310) or by HPLC (Table 4).
Surprisingly, the stabilities of 1 varied by several orders of mag-
nitude for the examples studied. Thus, some decomposed at room
temperature in minutes, while others were stable for years at ele-
vated temperatures. Since only small differences were found for
compounds at different pH values and buffers, the large variations
in stabilities with seemingly small structural changes were
puzzling.
Derivatives 1j and 1k, which contain a c-oxygen capable of sta-
bilizing a cation at the b-position, also show accelerated decompo-
sition relative to their respective non-oxygenated counterparts, 1c
and 1f. The mechanistic pathways proposed are also consistent
with the observed accelerated rate of decomposition of 1e, which
undergoes the Stieglitz rearrangement to relieve ring strain, form-
ing the corresponding N-chloro cyclic iminium ions (see Scheme
5). These intermediates can hydrolyze and be further chlorinated
with dehydrochlorination providing nitrile derivatives of the b-
ketosulfonates (e.g., 12).
Fully degraded samples were analyzed by LC–MS (see Support-
ing Information) employing a H2O/MeOH gradient. Detection and
analysis was performed by ELSD and MS (ESI-APCI dual ionization,
negative mode). These data are presented in Table 5. The degrada-
tion products were identified by MS and NMR as either de-N-chlo-
rinated taurines 5 or b-ketoalkanesulfonates (8 or 12) which we
view as arising from a Stieglitz rearrangement,26 together with
The decomposition of two other cycloalkyl derivatives, 1e
(cyclobutyl) and 1i (tetramethylcyclohexyl), did not follow the ex-
pected pathway, but rather led to products consistent with
x-ami-
no-b-ketosufonates 16 and cyclic imines 17, which are chlorinated
products corresponding to intermediates A and B in Scheme 4b (in
addition to 5e and 5i). While it is not definitively known why the

T. P. Shiau et al. / Bioorg. Med. Chem. Lett. 19 (2009) 1110–1114
1113
Table 5
Analysis of degraded samples of 1a
Parent compound
1b
1 = R2 = Et
1c
1f
1g
1h
R
R1 = R2 = Pr
R1, R2 = (CH2)4
R1, R2 = (CH2)5
R1, R2 = (CH2)6
Degradants
8b 1.0 (151)
5b 1.4 (180)
9b 1.5 (185*)
10b 2.5 (219**)
11b 3.3 (253***)
8c 1.4 (165)
9c 2.3 (199*)
5c 2.7 (208)
10c 3.2 (233**)
11c 3.7 (267***)
—
12g 1.4 (204)
5g 1.6 (192)
13g 1.9 (238*)
14g 2.6 (272**)
—
12h 1.9 (218)
5h 2.1 (206)
13h 2.5 (252*)
14h 3.1 (286**)
15h 3.8 (320***)
5f 1.2 (178)
13f 1.6 (224*)
14f 2.2 (258**)
15f 2.7 (292***)
a
Degradants (bold), with their ELSD retention times (min) and mass-to-charge ratios (in parentheses). Asterisks (*) indicate the presence of chlorine(s) as evidenced by the
isotopic ratio in the mass spectrum (e.g., 200* indicates a 3:1 ratio of m/z 200 to m/z 202, while 286** indicates a 9:6:1 ratio of m/z 286 to m/z 288 to m/z 290). Italicized
entries were isolated by preparative-scale HPLC.
R1R2
R2
R2
(a)
(b)
+H2O
-R1NHCl
R1
SO3Na
SO3Na
Cl
Cl
SO3Na
SO3Na
N+
N
O
Cl
Cl
8
Cl
N
Cl
H
N
N+
2
+H O
Cl
O
SO3Na
SO3Na
Cl
n
n
n
A
B
O
Cl
O
+
Cl
O
SO3Na
[Cl ]
N
SO3Na
N
SO3Na
N
H
n
H
n
H
n
12
C
Cl
SO3Na
repeat
(c)
10, 11
14, 15
R3
SO3Na
R3
SO3Na
R3
O
OH
O
9, 13
Scheme 4.
References and notes
Cl
N
+H3N
H2O
-
Cl
SO3Na
SO3
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X
X
1e (X = -CH2-)
5e
5i
1i (X = -CMe2CH2CMe2-)
Cl Cl
Cl Cl
O
X
N
+
H2N
SO3Na
+
SO3Na
X
16e
16i
17e
17i
Scheme 5.
5. Nagl, M.; Lass-Florl, C.; Neher, A.; Gunkel, A.; Gottardi, W. J. Antimicrob. Chem.
2001, 47, 871.
x
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hypothesize that the equilibrium between A and B is shifted in fa-
vor of the cyclic imines in some cases. Evidence for the precise
mechanism by which these products are formed is underway and
will be disclosed in a separate report.
Acknowledgments
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The authors thank Alcon Laboratories for financial funding of
this project; Dr. David Stroman, Dr. Lu Wang, Dr. Charles Francavil-
la, and Bum Kim for helpful discussions on stability studies; and
Dr. Nafsika Dakou for editorial assistance.
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Supplementary data
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