Synthesis of silodosin glucuronide and its deuterated counterpart: Solving a problematic O-glycosylation of a nitrogen-containing molecule

Article abstract of DOI:10.1515/hc-2017-0092

We report here the first chemical synthesis of silodosin glucuronide, a metabolite of the α_1A-adrenoceptor antagonist silodosin, and its deuterium-labeled counterpart. As a key synthetic step, the incorporation of a glucuronosyl unit onto silodosin invariably led to either an undesired orthoester or a complex mixture under an array of standard glycosylation conditions. This problematic O-glycosylation may be attributed to the presence of multiple basic groups that could neutralize the acidic activators, decrease the nucleophilicity of a hydroxy group via hydrogen bond or even facilitate acyl migration side reactions. After elaborate tuning of reaction conditions, success was eventually achieved by using perbenzoylated d-glucuronosyl N-phenyltrifluroacetimidate (PTFA) as donor in combination with a procedure of sequential addition of TMSOTf. This protocol is potentially general for the glycosylation of other nitrogen-containing small molecule drugs.

Full text of DOI:10.1515/hc-2017-0092

Heterocycl. Commun. 2017; aop
Jun Zhou, Yunpeng Liu, Hailiang Zhu, He Zhu and Peng George Wang*
Synthesis of silodosin glucuronide and its
deuterated counterpart: solving a problematic
O-glycosylation of a nitrogen-containing molecule
DOI 10.1515/hc-2017-0092
(UGT2B7) to generate silodosin glucuronide (2) (Scheme 1)
[2]. As a drug metabolite, glucuronide 2 is in high demand
for pharmacokinetic studies and pharmacological evalu-
ations [3]. However, quantities available from tedious
isolation are insufficient, and the chemical synthesis of
glucuronide 2 has not been reported to date. We present
here the first synthesis of silodosin glucuronide (2) and its
deuterium-labeled counterpart 3.
Received May 2, 2017; accepted May 9, 2017
Abstract: We report here the first chemical synthesis of sil-
odosin glucuronide, a metabolite of the α1A-adrenoceptor
antagonist silodosin, and its deuterium-labeled counter-
part. As a key synthetic step, the incorporation of a glu-
curonosyl unit onto silodosin invariably led to either an
undesired orthoester or a complex mixture under an array
of standard glycosylation conditions. This problematic
O-glycosylation may be attributed to the presence of multi-
ple basic groups that could neutralize the acidic activators, Results and discussion
decrease the nucleophilicity of a hydroxy group via hydro-
gen bond or even facilitate acyl migration side reactions. At first sight, the chemical synthesis of glucuronides 2 and
After elaborate tuning of reaction conditions, success was 3 seems to be very straightforward, by the coupling of a
eventually achieved by using perbenzoylated d-glucurono- glucuronosyl selectively to the primary hydroxyl group of
syl N-phenyltrifluroacetimidate (PTFA) as donor in combi- the silodosin moiety via a simple glycosylation (Scheme 2).
nation with a procedure of sequential addition of TMSOTf. However, its secondary and tertiary amines might conflict
This protocol is potentially general for the glycosylation of with the glycosylation because most of the activators are
other nitrogen-containing small molecule drugs.
strong acids. Indeed, glycosyl acceptors in traditional gly-
cosylations are either simple alcohols or protected sac-
charide fragments [4]. When the glycosyl acceptor is a
complex multi-functionalized molecule, the glycosylation
might result in the formation of side products [5, 6]. In such
circumstances, elaborate screening of glycosyl donors
and activators is critical to the success of glycosylation.
Nevertheless, glycosylation of basic nitrogen-containing
Keywords: glucuronide; glycosylation; metabolite;
silodosin.
Introduction
Silodosin (1),
a potent and highly selective α1A- molecules has been reported in only a few examples and
adrenoceptor antagonist, is a marketed drug for the requires much more attention [7]. On the other hand, gly-
treatment of benign prostatic hyperplasia (BPH) with cosylation with a glucuronosyl donor usually suffers from
fewer cardiovascular side effects compared with other the presence of the electron-withdrawing C-6 carboxylate,
α-androgen receptor (AR) antagonists [1]. With respect which gives rise to decreased anomeric reactivity and defi-
to chemical structure, silodosin is composed of an indo- cient stability of the oxacarbenium intermediate [8]. We
line core scaffold linked with a catechol head piece and aimed to tackle the anticipated synthetic challenges with
a primary alcohol tail (Scheme 1). A major metabolic the targeted glucuronides 2 and 3.
pathway of silodosin is O-glucuronidation at the primary
Our synthetic plan (Scheme 2) of silodosin glucu-
hydroxyl group via UDP-glucuronosyltransferase-2B7 ronides 2 and 3 suggested a late-stage glycosylation of
properly protected silodosin derivatives 5 employing the
glucuronosyl donor 4 to construct the β-glucuronosidic
*Corresponding author: Peng George Wang, Department of
linkage. Thus, silodosin derivatives 5 could be protected
Chemistry, Georgia State University, Atlanta, GA 30303, USA,
at the secondary amine to prevent neutralization of the
e-mail: pwang11@gsu.edu
acidic promotor, and the amide (CONH2) group could
Jun Zhou, Yunpeng Liu, Hailiang Zhu and He Zhu: Department of
Chemistry, Georgia State University, Atlanta, GA 30303, USA
remain free. In turn, 5 could easily be derived from the
Brought to you by | New York University
Authenticated
Download Date | 7/3/17 9:22 AM

ꢀꢀꢀꢁ
2ꢀ
ꢀJ. Zhou et al.: Synthesis of silodosin glucuronide and its deuterated counterpart
HO2C
O
O
HO
HO
NH
O
P
O
P
HO
O
O
O
N
O
OH OH
O
UDP-glucuronate
CF3
CF3
OH OH
O
O
O
O
H
N
H
N
UGT2B7
N
N
Silodosin glucuronide (2)
Silodosin (1)
CONH2
CONH2
HO2C
HO
OH
O
O
HO
OH
CF3
O
O
D D
H
N
D D
N
CONH2
Silodosin glucuronide
deuterated counterpart (3)
HO2C
O
HO
O
HO
OH
Scheme 1ꢀMetabolism of silodosin by O-glucuronidation and the structure of glucuronides 2 and 3.
CF3
O
R R
H
N
R = H, Silodosin glucuronide (2)
R = D, d4-derivative (3)
O
R R
N
CONH2
HO2C
HO
HO
O
O
OH
O-glycosylation of
nitrogen-containing molecule
CF3
CF3
MeO2C
PGO
PGO
H2N
O
R R
O
R R
PG2
O
Br
LG
N
Br
N
O
OH
OPG
R R
R R
CONH2
N
Glucuronosyl donor (4)
5: R = H or D
6
7: R = H or D
8
OBz
CONH2
OH
Scheme 2ꢀSynthetic plan of glucuronides 2 and 3.
sequential coupling of fragments 6, 7 and 8 via alkyla- amides, the intermediate 9 was then used for further cou-
tion. With the readily prepared glucuronosyl donor 10 pling with peracetylated glucuronosyl trichloroacetimi-
[9] in hand, the synthesis of glucuronide 2 commenced date 10 (Scheme 3). Our first trial with the glycosylation
from N-benzyloxycarbamate (Cbz) protection with com- was performed under the activation of TMSOTf (0.4 eq) at
mercially available silodosin (1) (Scheme 3). To our sur- 0°C and the major product obtained was the orthoester [10],
prise, the amide (CONH2) group underwent dehydration an isoform of 11 (Entry 1, Table 1). Increasing the amount
to cyanide (CN) by treating compound 1 with CbzCl in a of TMSOTf to 1.2 eq for the coupling (Entry 2) promoted
mixed solution of THF/H2O, providing intermediate 9 rearrangement of the orthoester, resulting in a 15% yield
(71%). As a cyano group can serve as a protecting group of of desired glycoside 11. Unfortunately, a further increase
Brought to you by | New York University
Authenticated
Download Date | 7/3/17 9:22 AM

ꢁꢀꢀꢀ
ꢂ3
J. Zhou et al.: Synthesis of silodosin glucuronide and its deuterated counterpartꢂ
CF3
MeO2C
O
BzO
BzO
O
O
OBz
1) N2H4-HOAc, DMF
2) CF3C(NPh)Cl, Cs2CO3, acetone; 36%
H
OBz
N
15
N
MeO2C
BzO
BzO
Silodosin (1)
NPh
CF3
O
H2N
O
16
O
O
HO
CbzCl, NaHCO3
THF, H2O; 71%
OBz
or
CF3
MeO2C
AcO
AcO
MeO2C
BzO
BzO
O
O
NH
CCl3
NH
CCl3
Cbz
N
O
O
O
OAc
OBz
N
10
9
13
CN
Glycosylation
conditions
(see Table 1)
Glycosylation
conditions
(see Table 1)
HO
CF3
CF3
O
O
O
Cbz
Cbz
N
N
O
N
N
11
14
CN
MeO2C
CN
MeO2C
O
O
BzO
AcO
O
O
BzO
AcO
OBz
OAc
CF3
CF3
MeO2C
BzO
BzO
NPh
CF3
16
O
O
O
O
O
O
Fmoc
N
FmocCl
DIPEA, DCM; 99%
H
OBz
N
Glycosylation
conditions
(see Table 1)
N
N
Silodosin (1)
17
H2N
O
H2N
O
HO
HO
CF3
O
Fmoc
N
NaOH, MeOH
THF, H2O; 71%
O
2
2
N
18
CONH2
MeO2C
BzO
BzO
O
O
OBz
Scheme 3ꢀSynthesis of glucuronide 2 by glycosylation.
of the amount of TMSOTf to 1.8 eq (Entry 3) gave rise to glucuronosyl trichloroacetimidate 13 [12] was synthesized
significant migration [11] of acetyl from the donor to the according to the literature (Scheme 3). As expected, acyl
primary alcohol, and the use of BF3·OEt2 (1.5 eq) at −10°C migration was eliminated by using a benzoylated donor
provided acetylated compound 9 as the major product with TMSOTf (0.3 eq) at 0°C (Entry 5). However, the reac-
(Entry 4).
tion was still not productive due to the formation of the
Considering the acid labile property of acetyl ester, glycosyl amide side product through O,N-rearrangement
we decided to examine the benzoyl (Bz) group as a pro- [13]. To prevent this side reaction, we turned our attention
tecting group on the glycosyl donor. Thus, perbenzoylated to the donor N-phenyltrifluoroacetimidate (PTFA) [14],
Brought to you by | New York University
Authenticated
Download Date | 7/3/17 9:22 AM

ꢀꢀꢀꢁ
4ꢀ ꢀJ. Zhou et al.: Synthesis of silodosin glucuronide and its deuterated counterpart
Table 1ꢀStudies on glycosylation of silodosin using glucuronosyl donors.
Entryꢁ
Donor
ꢁ Acceptorꢁ
Condition
ꢁ
Desired product (yield)ꢁ
Side product (yield)
1
2
3
4
5
6
7
8
9
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
10
10
10
10
13
16
16
16
16
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
9ꢃ
9ꢃ
TMSOTf (0.4 eq), CH2Cl2, 0°C, 1 h
TMSOTf (1.2 eq), CH2Cl2, 0°C, 1 h
TMSOTf (1.8 eq), CH2Cl2, 0°C, 1 h
ꢃ
ꢃ
ꢃ
11 (trace)
11 (15%)
11 (trace)
11 (trace)
14 (trace)
14 (trace)
14 (47%)
18 (61%)
18 (85%)
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
Orthoester isoform of 11 (73%)
Orthoester isoform of 11 (48%)
Acetyl ester of acceptor 9
9ꢃ
9ꢃ
BF3·OEt2 (1.5 eq), CH2Cl2, −10°C, 1 h ꢃ
Acetyl ester of acceptor 9
9ꢃ
TMSOTf (0.3 eq), CH2Cl2, 0°C, 1 h
TMSOTf (0.3 eq), CH2Cl2, 0°C, 1 h
TMSOTf (0.9 eq), CH2Cl2, 0°C, 1 h
TMSOTf (1.2 eq), CH2Cl2, 0°C, 1 h
TMSOTf (0.9 eq), CH2Cl2, 0°C, 1 h;
then TMSOTf (0.3 eq), 0°C, 30 min
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
Glycosyl amide isoform of 13
Orthoester isoform of 14
Orthoester isoform of 14
Glycal from 16, benzoyl ester of 17
No significant side product
9ꢃ
9ꢃ
17ꢃ
17ꢃ
which is moderately reactive without generating a com- TLC and MS. However, when the amount of TMSOTf was
peting nucleophilic amide-leaving entity. Accordingly, the increased to 0.9 eq (Entry 7), the desired glycoside 14 was
glucuronosyl PTFA donor 16 was synthesized from 15 [12] obtained in an acceptable 47% yield with only a minor
by sequential anomeric debenzoylation and treatment orthoester yield.
with CF3C(NPh)Cl/Cs2CO3 (47%). We then investigated the
To avoid transformation of the cyano group to amide
glycosylation of acceptor 9 using 16 as a glycosylating in the final stage, as for the coupling products 11 and 14,
agent. The use of TMSOTf (0.3 eq) at 0°C (Entry 6) still led we protected the secondary amine of 1 with fluorenyl-
to the corresponding orthoester as the major product by methyloxycarbonyl (Fmoc) (Scheme 3). The acceptor 17
Plausible hydrogen bond network in nitrogen-containing silodosin Decreased nucleophilicity for glycosylation
R
R
R
R
R
N
N
N
N
H
N
H
O
O
H2N
O
O
O
NH
NH2
N
N
H
O
H
H
O
O
H
MeO2C
AcO
AcO
Weak nucleophile favors
SN1-like orthoester formation
MeO2C
AcO
AcO
O
Not favored
O
OR
O
O
OAc
OR
TMSOTf
MeO2C
AcO
AcO
MeO2C
AcO
AcO
NH
CCl3
MeO2C
AcO
AcO
Elimination
O
O
O
O
O
O
OAc
OAc
MeO2C
AcO
AcO
H
N
O
NH2
CCl3
O
O,N-rearrangement
O
OAc
CCl3
Tertiary amine serves as an “acyl shuttle”
MeO2C
AcO
AcO
O
R
R
R
R
OAc
Acyl migration
O
N
N
N
H2N
O
H2N
O
H2N
O
OAc
MeO2C
AcO
HO
H
O
O
OH
R
OAc
Scheme 4ꢀThe plausible side reaction pathways in the glucuronidation of silodosin.
Brought to you by | New York University
Authenticated
Download Date | 7/3/17 9:22 AM

ꢁꢀꢀꢀ
ꢂ5
J. Zhou et al.: Synthesis of silodosin glucuronide and its deuterated counterpartꢂ
was obtained in a quantitative yield by treatment with O,N-rearrangement to give glycosyl amide, could become
FmocCl in the presence of N,N-diisopropylethylamine major reaction pathways; however, this could be reduced by
(DIPEA). To further enhance the glycosylation yield, 1.2 using N-phenyltrifluoroacetimidate (PTFA) as donor. (5) The
eq of TMSOTf was utilized for the glycosylation of 16 with tertiary amine might serve as a nucleophilic ‘acyl shuttle’ to
17 (Entry 8) in the hope of complete conversion of the promote migration of the acyl group, and this could be pre-
orthoester to glycoside. Indeed, the coupling delivered vented by using the benzoylated glycosyl donor.
glycoside 18 in a moderate yield (61%), with glycal as a
Having established the optimal conditions, the cou-
minor product derived from the elimination of donor 16 pling of 16 and 17 was scaled up to gram scale to obtain a
and slight benzoyl migration side product. To our delight, sufficient amount of 18, which was subjected to the one-pot
the coupling of 16 and 17 was eventually optimized to an final deprotection of Fmoc, C-6 methyl ester and O-benzoyl
85% yield (Entry 9) by sequentially adding 0.9 eq and 0.3 ester by using NaOH in a mixed solution of H2O, MeOH and
eq of TMSOTf.
THF (Scheme 3). Finally, reverse-phase C-18 column puri-
Based on the observation of problematic glycosylations, fication afforded silodosin glucuronide (2) in a 71% yield.
we hypothesize that the side reactions are imparted by the The deuterium-labeled counterpart 3 was synthesized in
presence of multiple basic nitrogen groups (Scheme 4) and a similar manner using optimal glycosylation conditions
suggest the following five points: (1) The influence of the ter- (Scheme 5). The deuterium-labeled aglycon 21 was syn-
tiary amine is not eliminated because it cannot be protected. thesized starting from simple fragments. Thus, the alkyla-
(2) The tertiary amine and free amide group might form a tion of 2-O-(2,2,2-trifluoroethyl)catechol (6) with excess
hydrogen bond network, which deactivates the primary deuterium-labeled 1,2-dibromoethane 7D in the presence
hydroxyl group and thus favors SN1-like orthoester formation. of K2CO3 in acetone afforded the monobromide 19 (73%),
(3) The tertiary amine could partially neutralize the acidic which was coupled with optically pure amine 8 under basic
promotor, preventing the rearrangement of orthoester conditions to provide 20 (64%). Subsequent deprotec-
to glycoside. (4) Due to the low reactivity of the acceptor tion of the benzoyl ester and hydrolysis of cyanide gave 21
hydroxyl group, the competing side reactions, including (93%), which was then protected at the secondary amine by
elimination of the oxacarbenium ion to form glycal and the Fmoc group to deliver 22. Finally, the glycosylation of 22
CF3
CF3
K2CO3,
Acetone; 73%
D D
O
O
H2N
O
Br
D D
Br
Br
D
D
N
OH
OBz
D
D
CN
6
7D
19
8
K2CO3, TBAI,
CH3CN; 64%
CF3
R3
N
20: R1 = Bz; R2 = CN; R3 = H
O
O
1) NaOH, MeOH, THF
D D
D
2) NaOH, H2O2, DMSO; 93%
21: R1 = H; R2 = CONH2; R3 = H
FmocCl, DIPEA, DCM; 99%
22: R1 = H; R2 = CONH2; R3 = Fmoc
D
N
OR1
R2
MeO2C
BzO
BzO
NPh
CF3
CF3
O
O
O
OBz
Fmoc
D D
N
1) TMSOTf (0.9 eq), CH2Cl2, 0 oC, 1 h
2) TMSOTf (0.3 eq), 0 o C, 30 min
O
NaOH, MeOH
D D
THF, H2O; 85%
N
3
22
23
CONH2
85%
MeO2C
BzO
BzO
O
O
OBz
Scheme 5ꢀSynthesis of glucuronide 3.
Brought to you by | New York University
Authenticated
Download Date | 7/3/17 9:22 AM

ꢀꢀꢀꢁ
6ꢀ ꢀJ. Zhou et al.: Synthesis of silodosin glucuronide and its deuterated counterpart
Orthoester form of 11
with the donor 16 was achieved with a high yield of 85%,
and the global deprotection of 23 produced the deuterium-
labeled counterpart 3 in an 85% yield.
Donor 10 (132 mg, 0.27 mmol) and acceptor 9 (87 mg, 0.14 mmol)
were dissolved in anhydrous CH2Cl2 (5 mL). Freshly activated 4-Å
molecular sieves (500 mg) were added, and the mixture was stirred at
room temperature for 1 h under a nitrogen atmosphere, then cooled
to 0°C and treated dropwise with TMSOTf (10 μL, 0.4 eq). After stir-
ring at 0°C for 1 h, the mixture was treated with a saturated solution
of NaHCO3, extracted with ethyl acetate and the extract was con-
centrated under reduced pressure. Flash chromatography on silica
gel (gradient 0–35%, ethyl acetate/hexanes) afforded an orthoester
Conclusion
Silodosin glucuronide (2) is a major metabolite of silodosin
by O-glucuronidation at the primary hydroxyl group. The
first synthesis of compound 2 and its deuterium-labeled
analogue 3 by late-stage glycosylation of the appropriately
protected silodosin derivative with a glucuronosyl donor
is reported here. In a challenging step, the coupling of the
glucuronosyl compound to the primary alcohol resulted
in a range of side reactions under several standard glyco-
sylation conditions. It was proposed that the problematic
glycosylations are imparted by the basic nitrogen groups,
which could neutralize the acidic activators, decrease
the nucleophilicity of the hydroxy group via hydrogen
bonds or even facilitate acyl migration side reactions. This
problem was solved by elaborate tuning of reaction para-
meters and conditions, and the best result (85% yield)
was achieved by using perbenzoylated d-glucuronosyl
N-phenyltrifluroacetimidate (PTFA) as the donor in com-
bination with the sequential addition of 0.9 eq and 0.3 eq
of TMSOTf.
1
form of 11 (96 mg, 73%). H NMR (600 MHz, CDCl3): δ 7.45–7.32 (m,
5H), 7.07–6.76 (m, 6H), 5.91 (d, Jꢀ=ꢀ4.5 Hz, 1H), 5.29–5.23 (m, 1H), 5.16
(ddd, Jꢀ=ꢀ41.0, 21.5, 16.2 Hz, 3H), 4.42–4.30 (m, 4H), 4.18–4.07 (m, 2H),
4.04–3.91 (m, 1H), 3.79 (s, 3H), 3.68–3.47 (m, 8H), 2.92–2.72 (m, 3H),
2.61–2.52 (m, 1H), 2.13 (s, 3H), 2.10 (s, 3H), 1.96–1.88 (m, 2H), 1.77 (s,
3H), 1.35–1.22 (m, 3H); 13C NMR (150 MHz, CDCl3): δ 169.4, 168.9, 168.9,
156.4, 155.5, 151.7 and 151.7 (rotamers), 149.3 and 149.1 (rotamers), 147.2
and 147.0 (rotamers), 136.7 and 136.4 (rotamers), 132.7 and 132.7 (rota-
mers), 131.3, 129.5 and 129.4 (rotamers), 128.6, 128.2 and 128.1 (rotam-
ers), 128.1, 127.9, 127.7 and 127.5 (rotamers), 123.9 and 123.9 (rotamers),
122.4, 121.4 and 121.2 (rotamers), 119.4, 119.4, 116.9 and 116.7 (rotam-
ers), 113.9 and 113.6 (rotamers), 961, 87.7, 73.1, 69.2, 68.3, 68.1, 67.7, 67.5,
67.4, 67.0, 60.6, 55.5, 53.2, 52.7, 45.2, 44.0, 40.4, 39.6, 27.7, 27.3, 21.8, 20.7,
+
18.7 and 17.9 (rotamers). ESI-HRMS. Calcd for C46H53F3N3O14 (Mꢀ+ꢀH) :
m/z 928.3480. Found: m/z 928.3490.
Glucuronide 11
The coupling procedure described above provided compound 11
(20 mg, 15%). 1H NMR (600 MHz, CDCl3): δ 7.44–7.30 (m, 5H), 7.07–6.74
(m, 6H), 5.30–5.21 (m, 2H), 5.18–5.06 (m, 2H), 5.06–5.01 (m, 1H), 4.59
(d, Jꢀ=ꢀ7.7 Hz, 1H), 4.41–4.30 (m, 2H), 4.16–3.92 (m, 5H), 3.77 (s, 3H),
3.70–3.47 (m, 7H), 2.94–2.72 (m, 3H), 2.62–2.51 (m, 1H), 2.06 (s, 3H),
2.05 (s, 3H), 2.04 (s, 3H), 2.02–1.90 (m, 2H), 1.28–1.26 (m, 3H); 13C NMR
(150 MHz, CDCl3): δ 170.1, 169.4, 169.3, 167.2, 151.6, 149.3, 149.1, 147.2,
147.0, 141.3, 136.7, 135.7, 132.8, 132.8, 131.2, 131.2, 131.7, 129.5, 129.4,
129.3, 128.6, 128.2, 128.1, 128.1, 128.0, 123.9, 123.9, 121.5, 121.2, 119.5,
116.9, 116.7, 113.9, 113.6, 100.8, 90.3, 72.5, 72.1, 71.3, 69.5, 67.7, 67.6, 67.5,
67.0, 55.5, 53.4, 52.9, 44.8, 43.8, 40.4, 39.6, 27.7, 27.3, 20.7, 20.6, 20.5, 17.9.
Experimental
(R)-Benzyl (1-(7-cyano-1-(3-hydroxypropyl)indolin-5-yl)
propan-2-yl)(2-(2-(2,2,2 trifluoroethoxy)phenoxy)ethyl)
carbamate (9)
To a solution of 1 (100 mg, 0.20 mmol) in THF/H2O (1:1, 8 mL) were
added Na2CO3 (32 mg, 0.3 mmol) and CbzCl (86 μL, 0.6 mmol) at 0°C
under nitrogen. The mixture was warmed to room temperature and
stirred for 12 h. The mixture was treated with a saturated solution
of NaHCO3, extracted with ethyl acetate and the extract was concen-
trated under reduced pressure. Flash chromatography on silica gel
(gradient 0–60%, acetone/hexanes) afforded 9 (87 mg, 71%). 1H NMR
(400 MHz, CDCl3): δ 7.48–7.31 (m, 5H), 7.11–6.72 (m, 6H), 5.26–5.02
(m, 2H), 4.47–4.28 (m, 2H), 4.21–3.92 (m, 3H), 3.81 (t, Jꢀ=ꢀ5.7 Hz, 2H),
3.75–3.46 (m, 6H), 3.03–2.51 (m, 4H), 2.04–1.80 (m, 3H), 1.34–1.24 (m,
3H); 13C NMR (100 MHz, CDCl3): δ 156.4, 155.6, 151.9, 149.3 and 149.1
(rotamers), 147.2 and 147.0 (rotamers), 136.7 and 136.4 (rotamers),
132.7 and 132.7 (rotamers), 131.2, 129.5 and 129.4 (rotamers), 128.6,
128.1, 127.9, 127.7 and 127.5 (rotamers), 123.9 and 123.9 (rotamers), 123.5
(q, Jꢀ=ꢀ279.1Hz), 121.5 and 121.2 (rotamers), 119.9 and 119.8 (rotam-
ers), 116.9 and 116.7 (rotamers), 113.9 and 113.6 (rotamers), 87.5, 67.6
(q, Jꢀ=ꢀ35.1 Hz),, 67.4, 67.0, 60.4, 55.5, 53.3, 45.5, 44.0, 40.4 and 39.6
(rotamers), 30.5, 27., 18.75 and 17.8 (rotamers). ESI-HRMS. Calcd for
+
ESI-HRMS. Calcd for C46H53F3N3O14 (Mꢀ+ꢀH) : m/z 928.3480. Found: m/z
928.3484.
N-Phenyltrifluoroacetimidate (16)
To a solution of 15 (563 mg, 1.0 mmol) in DMF (10 mL) at 0°C was
added N2H4ꢀ·ꢀHOAc (230 mg, 2.5 mmol). The mixture was warmed to
room temperature and stirred for 1 h, quenched with acetone and
concentrated under reduced pressure. Flash chromatography on
silica gel (gradient 0–35%, ethyl acetate/hexanes) afforded the 1-OH
intermediate product (210 mg). This compound was dissolved in ace-
tone (5 mL) at 0°C under nitrogen and the solution was treated with
Cs2CO3 (197 mg, 0.61 mmol) and CF3C(NPh)Cl (127 μL, 0.81 mmol).
The mixture was filtered and concentrated. Flash chromatography
on silica gel (gradient 0–15% ethyl acetate/hexanes) afforded 16
(251 mg, 36% for 2 steps); 1H NMR (600 MHz, CDCl3): δ 8.06–7.98 (m,
+
C33H37F3N3O5 (Mꢀ+ꢀH) : m/z 612.2685. Found: m/z 612.2678.
Brought to you by | New York University
Authenticated
Download Date | 7/3/17 9:22 AM

ꢁꢀꢀꢀ
ꢂ7
J. Zhou et al.: Synthesis of silodosin glucuronide and its deuterated counterpartꢂ
143.8 (rotamers), 141.5 and 141.4 (rotamers), 141.3, 133.6, 129.6 and
129.5 (rotamers), 128.1 and 127.9 (rotamers), 127.8, 127.7, 127.6, 127.1,
127.1, 124.7, 124.6, 124.0, 123.9, 123.6 (q, Jꢀ=ꢀ279 Hz), 121.3, 121.2, 120.1 and
120.0 (rotamers), 119.9, 117.7, 117.1, 117.0, 113.9, 113.6, 67.7 (q, Jꢀ=ꢀ35 Hz),
67.1, 66.7, 66.7, 59.4, 54.7, 53.6, 50.3, 50.2, 47.5 and 47.4 (rotamers), 43.3,
39.9, 30.9, 28.1, 18.6 and 18.2 (rotamers); 19F NMR (377 MHz, CDCl3): δ
5H), 7.94 (d, Jꢀ=ꢀ7.8 Hz, 2H), 7.61–7.57 (m, 2H), 7.49 (t, Jꢀ=ꢀ7.3 Hz, 1H), 7.44
(t, Jꢀ=ꢀ7.6 Hz, 4H), 7.36 (t, Jꢀ=ꢀ7.5 Hz, 2H), 7.16 (t, Jꢀ=ꢀ7.5 Hz, 2H), 7.05 (t,
Jꢀ=ꢀ7.3 Hz, 1H), 6.44 (s, 2H), 6.28 (t, Jꢀ=ꢀ9.9 Hz, 1H), 5.79 (t, Jꢀ=ꢀ9.8 Hz,
1H), 5.68 (d, Jꢀ=ꢀ8.7 Hz, 1H), 4.79 (d, Jꢀ=ꢀ8.6 Hz, 1H), 3.74 (s, 3H); 13C NMR
(150 MHz, CDCl3): δ 167.2, 165.5, 165.3, 165.2, 142.6, 133.8, 133.7, 133.5,
130.0, 129.9, 129.8, 128.8, 128.7, 128.7, 128.6, 128.6, 128.5, 128.5, 128.4,
124.5, 119.3, 119.1, 115.9 (dd, Jꢀ=ꢀ571.5, 285.7 Hz), 91.88, 70.96, 70.01,
69.50, 69.25, 53.15; 19F NMR (377 MHz, CDCl3): δ −65.60.
+
−73.96 (d, Jꢀ=ꢀ5.6 Hz). ESI-HRMS. Calcd for C40H43F3N3O6 (Mꢀ+ꢀH) : m/z
718.3104. Found: m/z 718.3098.
Glucuronide 18
Glucuronide 14
Donor 16 (202 mg, 0.29 mmol) and acceptor 17 (140 mg, 0.19 mmol)
were dissolved in anhydrous CH2Cl2 (10 mL). Freshly activated 4-Å
molecular sieves (500 mg) were added and the mixture was stirred
at room temperature for 1 h under nitrogen. The mixture was
cooled to 0°C and TMSOTf (32 μL, 0.176 mmol) was added dropwise.
After stirring at 0°C for 1h, additional TMSOTf (11 μL, 0.06 mmol)
was added. The mixture was stirred for another 30 min, treated
with a saturated solution of NaHCO3, extracted with ethyl acetate
and the extract was concentrated under reduced pressure. Flash
chromatography on silica gel (gradient 0–65%, ethyl acetate/
Donor 16 (81 mg, 0.12 mmol) and acceptor 9 (48 mg, 0.08 mmol)
were dissolved in anhydrous CH2Cl2 (4 mL). Freshly activated 4-Å
molecular sieves (170 mg) were added, and the mixture was stirred
at room temperature for 1 h under nitrogen. The mixture was cooled
to 0°C and TMSOTf (12 μL, 0.9 eq) was added dropwise. After stir-
ring at 0°C for 1 h, the mixture was treated with a saturated solution
of NaHCO3, extracted with ethyl acetate and the extract was concen-
trated under reduced pressure. Flash chromatography on silica gel
(gradient 0–25%, ethyl acetate/hexanes) afforded 14 (51 mg, 47%). 1H
NMR (600 MHz, CDCl3): δ 8.00–7.94 (m, 4H), 7.89 (d, Jꢀ=ꢀ8.0 Hz, 2H),
7.57–7.50 (m, 2H), 7.47 (t, Jꢀ=ꢀ7.4 Hz, 1H), 7.43–7.30 (m, 11H), 7.06–6.71
(m, 6H), 5.95 (t, Jꢀ=ꢀ9.5 Hz, 1H), 5.72 (t, Jꢀ=ꢀ9.5 Hz, 1H), 5.62–5.54 (m,
1H), 5.22–5.05 (m, 2H), 4.92 (d, Jꢀ=ꢀ7.5 Hz, 1H), 4.43–4.32 (m, 3H),
4.18–4.06 (m, 3H), 4.04–3.91 (m, 1H), 3.77–3.68 (m, 4H), 3.62–3.40 (m,
5H), 3.36–3.27 (m, 1H), 2.93–2.67 (m, 3H), 2.61–2.49 (m, 1H), 2.02–1.87
(m, 2H), 1.27 (s, 3H); 13C NMR (150 MHz, CDCl3): δ 167.3, 165.6, 165.2,
165.0, 156.4 and 155.5 (rotamers), 151.7 and 151.6 (rotamers), 149.3 and
149.1 (rotamers), 147.2 and 147.1 (rotamers), 136.7 and 136.4 (rotamers),
133.5, 133.4, 132.8 and 132.8, 131.2, 129.8, 129.8, 129.3 and 129.3 (rotam-
ers), 129.2, 128.8, 128.8, 128.6, 128.5, 128.4, 128.2, 128.1, 128.1, 127.9,
127.4 and 127.2 (rotamers), 123.9, 123.9, 123.5 (q, Jꢀ=ꢀ278 Hz), 121.5, 121.2,
116.9, 116.8, 113.9, 113.7, 101.2, 87.2, 72.9, 72.2, 71.7, 70.3, 67.8, 67.53 (q,
Jꢀ=ꢀ35 Hz), 67.08, 67.03, 55.55, 53.49, 52.90, 44.7, 40.4, 39.6, 27.9, 27.2, 18.7
1
hexanes) afforded 18 (200 mg, 85%). H NMR (600 MHz, CDCl3):
δ 7.99–7.94 (m, 4H), 7.89 (d, Jꢀ=ꢀ7.8 Hz, 2H), 7.79 (t, Jꢀ=ꢀ6.3 Hz, 1H), 7.70
(d, Jꢀ=ꢀ5.0 Hz, 1H), 7.63–7.44 (m, 5H), 7.42–7.25 (m, 10H), 7.07–6.88 (m,
5H), 6.68–6.59 (m, 1H), 5.96 (t, Jꢀ=ꢀ9.5 Hz, 1H), 5.71 (t, Jꢀ=ꢀ9.5 Hz, 1H),
5.56 (dd, Jꢀ=ꢀ16.5 Hz and 7.8 Hz, 1H), 4.86 (d, Jꢀ=ꢀ7.3 Hz, 1H), 4.70–4.55
(m, 1H), 4.54–4.45 (m, 1H), 4.40–4.31 (m, 3H), 4.27–4.14 (m, 2H),,
4.04–3.92 (m, 2H), 3.70 (s, 3H), 3.57 (d, Jꢀ=ꢀ5.6 Hz, 2H), 3.50 (d, Jꢀ=ꢀ23 Hz,
1H), 3.31–3.17 (m, 3H), 3.08–2.95 (m, 2H), 2.89–2.62 (m, 3H), 2.50–2.26
(m, 1H), 1.87–1.69 (m, 2H), 1.21 (d, Jꢀ=ꢀ6.6 Hz, 1.5 H, rotamer), 0.96 (d,
Jꢀ=ꢀ5.2 Hz, 1.5 H, rotamer); 13C NMR (150 MHz, CDCl3): δ 169.77 and
169.7 (rotamers), 167.5, 165.7, 165.2, 165.0, 156.7 and 155.7 (rotamers),
149.6 and 149.4 (rotamers), 147.1, 144.1 and 143.9 (rotamers), 141.5 and
141.4 (rotamers), 134.4 and 134.2 (rotamers), 133.5, 133.4, 130.7 and
130.6 (rotamers), 129.8, 129.8, 129.2, 128.8, 128.7, 128.5, 128.4, 128.4,
127.8, 127.6, 127.2, 127.1 and 124.7 (rotamers), 124.0 and 123.9 (rotam-
ers), 123.6 (q, Jꢀ=ꢀ279.3 Hz), 121.3, 121.1, 120.1 and 120.1 (rotamers),
119.9, 118.9 and 118.8 (rotamers), 117.2, 113.9 and 113.7 (rotamers),
101.1, 72.8, 72.1, 71.2, 70.2, 68.2, 67.7 (q, Jꢀ=ꢀ35 Hz), 67.0 and 66.7 (rota-
mers), 66.7 and 66.6 (rotamers), 552, 53.4, 52.9, 51.2 and 50.9 (rota-
mers), 47.5, 47.4, 43.7, 40.0, 28.3, 28.0 and 27.9 (rotamers), 18.4 and
18.0 (rotamers); 19F NMR (377 MHz, CDCl3): δ −73.97 (d, Jꢀ=ꢀ11.4 Hz).
+
and 17.9 (rotamers). ESI-HRMS. Calcd for C61H59F3N3O14 (Mꢀ+ꢀH) : m/z
1114.3949. Found: m/z 1114.3981.
(R)-(9H-Fluoren-9-yl)methyl (1-(7-carbamoyl-1-(3-
hydroxypropyl)indolin-5-yl)propan-2-yl)(2-(2-(2,2,2-tri-
fluoroethoxy)phenoxy)ethyl)carbamate (17)
+
ESI-HRMS. Calcd for C68H65F3N3O15 (Mꢀ+ꢀH) : m/z 1220.4368. Found:
To a solution of 1 (100 mg, 0.20 mmol) in CH2Cl2 (3 mL) was added
DIEPA (105 μL, 0.60 mmol), and the mixture was stirred for 20 min
at 0°C under nitrogen. Then a solution of FmocCl (63 mg, 0.24 mmol)
in CH2Cl2 (3 mL) was added over 20 min. The mixture was warmed to
room temperature, stirred for 12 h, then concentrated and the residue
was purified by flash chromatography on silica gel (gradient 0–60%,
m/z 1220.4338.
Glucuronide 2
1
A solution of 18 (80 mg, 0.07 mmol) in a mixed solvent of MeOH/H2O
(5/1, 2.6 mL) and THF (1 mL) was stirred at 0°C under nitrogen and
treated with 3M NaOH (0.87 mL). The mixture was warmed to room
temperature, stirred overnight, quenched with acetic acid (205 μL)
and concentrated. Flash chromatography on a reversed-phase C18
column (gradient 0–70%, acetonitrile/water) afforded 2 (31 mg, 71%).
1H NMR (400 MHz, MeOD): δ 7.17–6.96 (m, 6H), 4.57 (q, Jꢀ=ꢀ8.6 Hz,
2H), 4.40–4.20 (m, 3H), 4.07–3.91 (m, 1H), 3.67–3.57 (m, 2H), 3.57–3.48
(m, 3H), 3.44 (dd, Jꢀ=ꢀ17.2 Hz and 8.6 Hz, 3H), 3.35–3.21 (m, 4H), 3.06
(dd, Jꢀ=ꢀ13.6 Hz and 5.1 Hz, 1H), 2.99–2.85 (m, 2H), 2.77–2.66 (m, 1H),
acetone/hexanes) to afford 17 (144 mg, 99%). H NMR (600 MHz,
CDCl3): δ 7.80–7.67 (m, 2H), 7.63–7.43 (m, 2H), 7.43–7.24 (m, 4H), 7.19 (s,
0.5 H, rotamers), 7.08–6.88 (m, 4H), 6.84 (s, 0.5 H, rotamers), 6.77 (d,
Jꢀ=ꢀ27 Hz, 1H), 6.70–6.60 (m, 1H), 6.46 (s, 1H), 4.59 (dd, Jꢀ=ꢀ10.7 Hz and
5.3 Hz, 1H), 4.51–4.26 (m, 3H), 4.18–4.05 (m, 1H), 4.02–3.86 (m, 1H),
3.79–3.43 (m, 5H), 3.44–3.32 (m, 1H), 3.30–3.05 (m, 3H), 3.03–2.60 (m,
4H), 2.48–2.27 (m, 1H), 1.79–1.65 (m, 2H), 1.22 (d, Jꢀ=ꢀ6.7 Hz, 1.5 H, rota-
mers), 1.02 (d, Jꢀ=ꢀ5.3 Hz, 1.5 H, rotamers); 13C NMR (150 MHz, CDCl3):
δ 171.7 and 171.6 (rotamers), 157.0, 155.8, 149.8 and 149.6 (rotamers),
149.3 and 149.2(rotamers), 147.0, 144.2 and 144.1 (rotamers), 143.9 and
Brought to you by | New York University
Authenticated
Download Date | 7/3/17 9:22 AM

ꢀꢀꢀꢁ
8ꢀ ꢀJ. Zhou et al.: Synthesis of silodosin glucuronide and its deuterated counterpart
1.94–1.78 (m, 2H), 1.30 (d, Jꢀ=ꢀ6.4 Hz, 3H); 13C NMR (100 MHz, MeOD): concentrated under reduced pressure. Flash chromatography on sil-
δ 173.0, 149.0, 148.2, 147.6, 133.9, 128.0, 127.0, 125.3, 124.5 (q, Jꢀ=ꢀ278 Hz), ica gel (gradient 0–10%, MeOH/CH2Cl2) afforded 21 (93 mg, 93%). 1H
123.3, 122.3, 118.0, 115.7, 115.3, 103.2, 76.4, 74.9, 73.6, 72.4, 67.3, 66.6 (q, NMR (400 MHz, CDCl3): δ 7.17 (s, 1H), 7.07–6.93 (m, 4H), 6.93–6.80 (m,
Jꢀ=ꢀ35 Hz), 65.5, 53.1, 48.3, 44.1, 38.5, 27.7, 27.1, 14.9; 19F NMR (377 MHz, 3H), 4.30 (q, Jꢀ=ꢀ8.5 Hz, 2H), 3.69 (t, Jꢀ=ꢀ5.5 Hz, 2H), 3.37 (t, Jꢀ=ꢀ8.5 Hz,
+
MeOD): δ −75.38. ESI-HRMS. Calcd for C31H41F3N3O10 (Mꢀ+ꢀH) : m/z 2H), 3.21–3.09 (m, 3H), 3.02–2.86 (m, 3H), 2.68 (dd, Jꢀ=ꢀ13.5 Hz and
672.2744. Found: m/z 672.2785.
6.4 Hz, 1H), 2.51 (dd, Jꢀ=ꢀ13.5Hz and 6.9 Hz, 1H), 1.86–1.69 (m, 2H),
1.06 (d, Jꢀ=ꢀ6.2 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ 171.6, 149.8, 149.6,
147.4, 133.9, 130.2, 128.2, 128.0, 124.3, 123.6 (q, Jꢀ=ꢀ278 Hz), 121.5, 118.3,
118.1, 114.7, 68.0 (q, Jꢀ=ꢀ35 Hz), 59.4, 54.4, 53.6, 50.8, 42.5, 21.0, 28.2,
Compound 19
+
19.8. ESI-HRMS. Calcd for C25H29D4F3N3O4 (Mꢀ+ꢀH) : m/z 500.2674.
Found: m/z 500.2659.
To a solution of 6 (1.0 g, 5.2 mmol) and 7D (3.0 g, 15.6 mmol) in CH3CN
(20 mL) was added K2CO3 (1.44 g, 10.4 mmol) under nitrogen. The
mixture was heated under reflux for 16 h, then filtered and concen-
trated. Flash chromatography on silica gel (gradient 0–10%, ethyl
acetate/hexanes) afforded 19 (1.14 g, 73%). 1H NMR (600 MHz, CDCl3):
Compound 22
δ 7.11–7.04 (m, 2H), 7.02–6.94 (m, 2H), 4.46 (q, Jꢀ=ꢀ8.4 Hz, 2H); 13C NMR To a solution of 21 (400 mg, 0.80 mmol) in CH2Cl2 (12 mL) was added
(151 MHz, CDCl3): δ 149.1, 147.7, 124.4, 123.6 (q, Jꢀ=ꢀ279 Hz), 122.4, 118.9, DIEPA (418 μL, 0.24 mmol) and the mixture was stirred at 0°C under
+
115.4, 68.5 (q, Jꢀ=ꢀ35 Hz). ESI-HRMS. Calcd for C10H7D4BrF3O2 (Mꢀ+ꢀH) : nitrogen. Then a solution of FmocCl (224 mg, 0.84 mmol) in CH2Cl2
m/z 303.0146. Found: m/z 303.0137.
(12 mL) was added over 20 min. The mixture was warmed to room
temperature, stirred for an additional 12 h and concentrated. Flash
chromatography on silica gel (gradient 0–60%, acetone/hexanes)
1
afforded 22 (569 mg, 99%). H NMR (400 MHz, CDCl3): δ 7. 8 2–7.6 5
Compound 20
(m, 2H), 7.62–7.42 (m, 2H), 7.42–7.25 (m, 4H), 7.17 (s, 0.5 H, rotamor),
7.07–6.86 (m, 4H), 6.82 (s, 1H, rotamor), 6.78–6.59 (m, 2H), 6.24 (s,
1H), 4.64–4.54 (m, 1H), 4.45–4.25 (m, 3H), 4.17–4.00 (m, 1H), 3.70
(d, Jꢀ=ꢀ13.3 Hz, 2H), 3.49 (s, 1H), 3.44–3.30 (m, 1H), 3.25–3.03 (m, 2H),
2.97–2.61 (m, 4H), 2.48–2.27 (m, 1H), 1.98 (s, 1H), 1.80–1.63 (m, 2H),
1.26–1.16 (m, 1.5 H, rotamer), 1.03 (d, Jꢀ=ꢀ6.5 Hz, 1.5 H, rotamer); 13C
NMR (100 MHz, CDCl3): δ 171.6 and 171.5 (rotamers), 157.0 and 155.9
(rotamers), 149.8 and 149.6 (rotamers), 147.0 and 147.0 (rotamers),
144.2 and 144.1 (rotamers), 143.9 and 143.8 (rotamers), 141.5 and 141.4
(rotamers), 141.3, 133.6, 129.5 and 129.3 (rotamers), 128.0 and 127.9
(rotamers), 127.7, 127.8 and 127.6 (rotamers), 127.1, 127.1, 124.7 and 124.7
(rotamers), 124.8 and 124.6 (rotamers), 124.0 and 123.9 (rotamors),
123.5 (q, Jꢀ=ꢀ278 Hz), 121.3 and 121.2, 120.0 and 120.0 (rotamers), 119.9,
117.5, 117.1 and 117.0 (rotamers), 113.8 and 113.6 (rotamers), 67.7 (q,
Jꢀ=ꢀ35 Hz) and 67.7 (q, Jꢀ=ꢀ35 Hz) (rotamers), 66.8 and 66.7 (rotamers),
59.4, 54.5, 53.6, 50.2 and 50.0 (rotamers), 47.5 and 47.4 (rotamers), 39.9,
30.9 and 30.9 (rotamers), 28.1 and 28.1 (rotamers), 18.6 and 18.2 (rota-
To a solution of 8ꢀ·ꢀL-tartaric acid salt (200 mg, 0.39 mmol) in H2O
(10 mL) was added K2CO3 (412 mg, 3.89 mmol) to adjust the pH to 10.
The mixture was extracted with CH2Cl2. The extract was dried over
Na2SO4, filtered and concentrated to give free amine 8. To a solution
of crude 8 in acetonitrile (20 mL) were added 19 (130 mg, 0.43 mmol),
K2CO3 (108 mg, 0.78 mmol) and TBAI (7 mg, 0.02 mmol). The mixture
was heated at 80°C for 12 h and then cooled to room temperature. The
mixture was filtered, washed with CH2Cl2, dried over Na2SO4 and con-
centrated under reduced pressure. Flash chromatography on silica
gel (gradient 0–40%, acetone/hexanes) afforded 20 (145 mg, 64%).
1H NMR (600 MHz, CDCl3): δ 8.09 (d, Jꢀ=ꢀ7.5 Hz, 2H), 7.58 (t, Jꢀ=ꢀ7.5 Hz,
1H), 7.46 (t, Jꢀ=ꢀ7.5 Hz, 2H), 7.08–7.03 (m, 1H), 7.02–6.96 (m, 3H), 6.95–
6.90 (m, 2H), 4.50 (t, Jꢀ=ꢀ6.3 Hz, 2H), 4.34 (q, Jꢀ=ꢀ8.5 Hz, 2H), 3.77 (t,
Jꢀ=ꢀ7.2 Hz, 2H), 3.59 (t, Jꢀ=ꢀ8.5 Hz, 2H), 2.99–2.92 (m, 2H), 2.90 (dd,
Jꢀ=ꢀ12.8 Hz and 6.4 Hz, 1H), 2.63 (dd, Jꢀ=ꢀ13.6 Hz and 6.4 Hz, 1H), 2.45
(dd, Jꢀ=ꢀ13.6 Hz and 6.9 Hz, 1H), 2.21–2.14 (m, 2H), 1.07 (d, Jꢀ=ꢀ6.4 Hz,
3H); 13C NMR (150 MHz, CDCl3): δ 166.6, 151.6, 149.8, 147.5, 132.9, 132.6,
131.5, 130.2, 129.7, 128.4, 128.0, 124.3, 123.6 (q, Jꢀ=ꢀ279 Hz), 121.5, 119.5,
118.1, 114.7, 88.0, 68.1 (q, Jꢀ=ꢀ35 Hz), 62.6, 54.2, 53.4, 45.3, 42.4, 27.3,
+
mers). ESI-HRMS. Calcd for C40H39D4F3N3O6 (Mꢀ+ꢀH) : m/z 722.3355.
Found: m/z 722.3360.
+
27.2, 20.0 . ESI-HRMS. Calcd for C32H31D4F3N3O4 (Mꢀ+ꢀH) : m/z 586.2831.
Compound 23
Found: m/z 586.2837.
Donor 16 (667 mg, 0.96 mmol) and acceptor 22 (464 mg, 0.643 mmol)
were dissolved in anhydrous CH2Cl2 (7 mL). Freshly activated 4-Å
molecular sieves (500 mg) were added and the mixture was stirred at
Compound 21
To a solution of 20 (118 mg, 0.20 mmol) in a mixed solvent of MeOH room temperature for 1 h under nitrogen. The mixture was cooled to
(3 mL) and THF (2 mL) was added NaOH (0.4 mL, 1M), and the mix- 0°C and TMSOTf (105 μL, 0.9 eq) was added dropwise. After stirring at
ture was stirred at room temperature. After completion as indicated 0°C for 1 h, additional TMSOTf (35 μL, 0.3 eq) was added. The mixture
by TLC analysis, the solvent was evaporated. The residue was diluted was stirred for another 30 min, treated with a saturated solution of
with water and extracted with ethyl acetate. The extract was dried NaHCO3, extracted with ethyl acetate and the extract was concen-
over Na2SO4, filtered and concentrated to give a residue that was used trated under reduced pressure. Flash chromatography on silica gel
1
for the next step without purification. The crude product was dis- (0–65% ethyl acetate/hexanes) afforded 23 (668 mg, 85%). H NMR
solved in DMSO (4 mL) at 0°C under nitrogen and treated with 5 M (400 MHz, CDCl3): δ 7.96 (d, Jꢀ=ꢀ7.5 Hz, 4H), 7.88 (d, Jꢀ=ꢀ7.5 Hz, 2H),
NaOH (121 μL) and 30% H2O2 (87 μL). The mixture was warmed to 7.81–7.74 (m, 1H), 7.70 (d, Jꢀ=ꢀ7.5 Hz, 1H), 7.60–7.24 (m, 15H), 7.07–6.86
room temperature, stirred for 24 h, diluted with water and extracted (m, 5H), 6.68–6.56 (m, 1H), 5.94 (t, Jꢀ=ꢀ9.5 Hz, 1H), 5.83 (s, 1H), 5.70 (t,
with ethyl acetate. The extract was dried over Na2SO4, filtered and Jꢀ=ꢀ9.5 Hz, 1H), 5.61–5.50 (m, 1H), 4.85 (d, Jꢀ=ꢀ7.5 Hz, 1H), 4.69–4.55 (m,
Brought to you by | New York University
Authenticated
Download Date | 7/3/17 9:22 AM

ꢁꢀꢀꢀ
ꢂ9
J. Zhou et al.: Synthesis of silodosin glucuronide and its deuterated counterpartꢂ
1H), 4.53–4.44 (m, 1H), 4.41–4.29 (m, 3H), 4.25–4.14 (m, 2H), 4.04–3.95
(m, 1H), 3.92–3.80 (m, 1H), 3.70 (s, 3H), 3.61–3.51 (m, 1H), 3.33–3.15 (m,
2H), 3.08–2.93 (m, 2H), 2.91–2.60 (m, 3H), 2.45–2.27 (m, 1H), 1.83–1.68
(m, 2H), 1.20 (d, Jꢀ=ꢀ6.5 Hz, 1.5H, rotamer), 0.96 (d, Jꢀ=ꢀ6.5 Hz, 1.5H,
rotamer); 13C NMR (100 MHz, CDCl3): δ 169.7 and 169.6 (rotamers),
167.4, 165.7, 165.2, 165.0, 156.7 and 155.7 (rotamers), 149.6 and 149.2
(rotamers), 149.4, 147.1, 144.2 and 144.1 (rotamers), 144.0 and 143.9
(rotamers), 141.5 and 141.4 (rotamers), 141.4 and 141.3 (rotamers),
134.4 and 134.2 (rotamers), 133.5, 133.4, 133.3, 130.7 and 130.6 (rotam-
ers), 129.8, 129.8, 129.2, 128.8, 128.7, 128.5, 128.4, 128.4, 128.2, 127.8,
127.7, 127.6, 127.1, 124.7, 124.0, 123.9, 123.58 (q, Jꢀ=ꢀ279 Hz), 121.2, 121.1,
120.1 and 120.1 (rotamers), 119.9, 119.0 and 118.8 (rotamers), 117.2,
113.8, 113.6, 101.1, 72.8, 72.1, 71.7, 70.2, 68.2, 67.7 (q, Jꢀ=ꢀ35 Hz), 66.7 and
66.6 (rotamers), 55.0, 53.4, 52.9, 51.2 and 50.9 (rotamers), 47.5 and 47.4
(rotamers), 40.0, 28.3, 28.0 and 28.0 (rotamers), 18.4 and 18.3 (rotam-
evaluation of indoline and indole derivatives as potent and
selective α1A-adrenoceptor antagonists. J. Med. Chem. 2016,
59, 3826−3839.
[2] Wang, Z.; Xiang, Q.; Cui, Y.; Zhao, X.; Zhou, Y. The influence
of UGT2B7, UGT1A8, MDR1, ALDH, ADH, CYP3A4 and CYP3A5
genetic polymorphisms on the pharmacokinetics of silodosin
in healthy Chinese volunteers. Drug Metab. Pharmacokinet.
2013, 28, 239–243.
[3] Arewång, C. J.; Lahmann, M.; Oscarson, S.; Tidén, A.-K. Syn-
thesis of urine drug metabolites: glucuronic acid glycosides of
phenol intermediates. Carbohydr. Res. 2007, 342, 970–974.
[4] Mydock, L. K.; Demchenko, A. V. Mechanism of chemical
O-glycosylation: from early studies to recent discoveries. Org.
Biomol. Chem. 2010, 8, 497–510.
[5] Yu, B.; Sun, J.; Yang, X. Assembly of naturally occurring glyco-
sides, evolved tactics, and glycosylation methods. Acc. Chem.
Res. 2012, 45, 1227–1236.
+
ers). ESI-HRMS. Calcd for for C68H61D4F3N3O15: m/z (Mꢀ+ꢀH) 1224.4619.
Found: m/z 1224.4610.
[6] Christensen, H. M.; Oscarson, S.; Jensen, H. H. Common side
reactions of the glycosyl donor in chemical glycosylation.
Carbohydr. Res. 2015, 408, 51−95.
[7] Brown, R. T.; Carter, N. E.; Mayalarp, S. P.; Scheinmann, F. Sim-
ple synthesis of morphine-3,6-di-β-d-glucuronide. Tetrahedron
2000, 56, 7591–7594.
[8] de Jong, A.; Hagen, B.; van der Ark, V.; Overkleeft, H. S.; Codée,
J. D. C.; Van der Marel, G. A. Exploring and exploiting the reactiv-
ity of glucuronic acid donors. J. Org. Chem. 2012, 77, 108–125.
[9] Chen, Y.; Li, Y.; Sugiarto, G.; Thon, V.; Hwang, Li.; Hie, L.; Chen,
X. Tailored design and synthesis of heparan sulfate oligosac-
charide analogues using sequential one-pot multienzyme
systems. Angew. Chem. Int. Ed. 2013, 52, 11852–1185.
[10] Zhou, J.; Lv, S.; Zhang, D.; Xia, F.; Hu, W. Deactivating influence
of 3-O-glycosyl substituent on anomeric reactivity of thioman-
noside observed in oligomannoside synthesis. J. Org. Chem.
2017, 82, 2599–2621.
Compound 3
A solution of 23 (1.14 g, 0.93 mmol) in a mixed solvent of MeOH/H2O
(5/1, 37 mL) and THF (14 mL) was stirred at 0°C under nitrogen, then
treated with 3M NaOH (8.3 mL). The mixture was warmed to room
temperature, stirred overnight, quenched with acetic acid and con-
centrated. Flash chromatography on a reversed-phase C18 column
1
(gradient 0–60%, CH3CN/H2O) afforded 3 (535 mg, 85%). H NMR
(400 MHz, MeOD): δ 7.14–7.00 (m, 6H), 4.58 (q, Jꢀ=ꢀ8.6 Hz, 2H), 4.26 (d,
Jꢀ=ꢀ7.8 Hz, 1H), 4.04–3.94 (m, 1H), 3.69–3.57 (m, 2H), 3.54 (d, Jꢀ=ꢀ9.4 Hz,
1H), 3.50–3.38 (m, 4H), 3.31–3.21 (m, 3H), 3.05 (dd, Jꢀ=ꢀ13.8 Hz and
5.4 Hz, 1H), 2.99–2.86 (m, 2H), 2.74 (dd, Jꢀ=ꢀ13.8 Hz and 8.6 Hz, 1H),
1.95–1.79 (m, 2H), 1.32 (d, Jꢀ=ꢀ6.5 Hz, 3H); 13C NMR (100 MHz, MeOD):
δ 175.5, 173.0, 149.0, 148.1, 147.6, 133.9, 128.0, 126.9, 125.0, 123.9 (q,
Jꢀ=ꢀ278 Hz), 123.3, 122.4, 118.0, 115.5, 115.2, 103.2, 76.4, 74.9, 73.6, 72.4,
67.3, 66.5 (q, Jꢀ=ꢀ35 Hz), 55.7, 53.0, 48.1, 38.3, 27.6, 27.0, 14.8; 19F NMR
(377 MHz, MeOD): δ −75.41. ESI-HRMS. Calcd for C31H37D4F3N3O10
(Mꢀ+ꢀH)+: m/z 676.2995. Found: m/z 676.2987.
[11] Liu, Y.; Wen, L.; Li, L.; Gadi, M. R.; Guan, W.; Huang, K.; Xiao,
Z.; Wei, M.; Ma, C.; Zhang, Q.; et al. A general chemoenzymatic
strategy for the synthesis of glycosphingolipids. Eur. J. Org.
Chem. 2016, 2016, 4315–4320.
[12] Caroline Coutant, C.; Jacquinet, J. C. 2-Deoxy-2-trichloro-
acetamido-D-glucopyranose derivatives in oligosaccharide
synthesis: from hyaluronic acid to chondroitin 4-sulfate
trisaccharides. J. Chem. Soc. Perkin. Trans. 1995, 1573–1581.
DOI:10.1039/P19950001573.
[13] Zhou, J.; Yang, L.; Hu, W. Stereoselective synthesis of a
sulfated tetrasaccharide corresponding to a rare sequence in
the galactofucan isolated from Sargassum polycystum. J. Org.
Chem. 2014, 79, 4718−4726.
[14] Yu, B.; Sun, J. S. Glycosylation with glycosyl N-phenyltrifluoro-
acetimidates (PTFAI) and a perspective of the future develop-
ment of new glycosylation methods. Chem. Commun. 2010, 46,
4668–4679.
Acknowledgments: We wish to thank the NIH (grants R01
GM085267 and R01 AI083754) and the National Natural
Science Foundation of China (Grant 21372130) for finan-
cial support.
References
[1] Zhao, F.; Li, J.; Chen, Y.; Tian, Y.; Wu, C.; Xie, Y.; Zhou, Y.;
Wang, J.; Xie, X.; Liu, H. Design, synthesis, and biological
Brought to you by | New York University
Authenticated
Download Date | 7/3/17 9:22 AM