Selective N-acylation and N-alkylation of biotin

Article abstract of DOI:10.1021/jo201615j

Simple and efficient methodology is presented for the selective acylation and alkylation of biotin at its 3′-nitrogen.

Full text of DOI:10.1021/jo201615j

Note
pubs.acs.org/joc
Selective N-Acylation and N-Alkylation of Biotin
Ashok D. Pehere and Andrew D. Abell*
School of Chemistry & Physics, The University of Adelaide, North Terrace, Adelaide SA 5005, Australia
S
* Supporting Information
ABSTRACT: Simple and efficient methodology is presented for the
selective acylation and alkylation of biotin at its 3′-nitrogen.
and nonsymmetrical analogues of 3 and other biotin
derivatives.
iotin (1, Figure 1) is a water-soluble B vitamin that
Bfunctions as a prosthetic group for the biotin-dependent
Our approach to this problem is simple but effective. We
react biotin with 4,4′-dimethoxytrityl chloride (DMTrCl) to
introduce a trityl protecting group at the 1′ nitrogen and then
acylate or alkylate at the 3′-nitrogen. Removal of the protecting
group gives the desired 3′-substituted product in good yield; see
Schemes 1 and Tables 1 and 2 for examples. The methodology
Scheme 1. Selective 3′-Alkylation of Biotin
Figure 1. Biotin and its derivatives.
carboxylases, key metabolic enzymes found in all organisms.1
For this and other reasons, biotin and its derivatives attract
considerable synthetic and biochemical interest.1−4 For
example, N1′-substututed derivative 2 is reported to be an
inhibitor of biotin CoA carboxylase,5 3 is an inhibitor of HIV
protease,6 and N3′-substituted 4 is a substrate for biotin protein
ligase.7 To date, the HIV proteases of type 3 are limited to
structures having the same substituents at both N1′ and N3′. In
addition, the interaction of biotin with the receptor streptavidin
is one of the strongest protein ligand interactions known with a
Ka ≈ 1015 M−1.8 The key interaction here involves hydrogen
bonding between the protein and the ureido nitrogens of
biotin. For all these reasons, there is a need for simple and
selective methods for functionalizing the two ureido nitrogens
of biotin. However, there are relatively few such reports,6 with a
solution being to simply functionalize at both nitrogens and to
then separate the resulting isomers by exhaustive HPLC.7
What we do know is that the 3′-nitrogen of biotin is
significantly more sterically hindered than the 1′-nitrogen due
to presence of the 4-carboxybutyl substituent.9 In addition, the
1′-nitrogen is significantly more nucleophilic than the 3′-
nitrogen due to twisted conformation of the bicyclic ring
system.2,10 As such, N-acylation or alkylation of biotin, when it
occurs, preferentially takes place at the 1′-nitrogen. This has
been put to good effect with the preparation of structures such
as 2.5 However, to our knowledge, there are no specific reports
on selective acylation or alkylation at the 3′-nitrogen, despite
the need for such methodology to prepare derivatives of type 47
is simple and generally applicable, while avoiding the current
practice7 of carrying out extensive chromatography to separate
isomers.
The sequence is shown in Scheme 1 for the preparation of
the known7 derivative 4. The methyl ester of biotin (5,
prepared as shown) was treated with a pyridine solution of
DMTrCl containing Et3N11 to give 6 in 81% after purification
by flash chromatography, without evidence of any N3′-
substituted product. Alkylation at N1′ was confirmed by
1
characteristic H−1H ROESY correlations between the NH
resonance at 4.67 ppm and 1 proton resonance at 4.35−4.31
(SCHCH) and the multiplet at 1.71−1.56 ppm (SCHCH2).
Further characteristic correlations were observed between the
Received: August 29, 2011
Published: October 17, 2011
© 2011 American Chemical Society
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Note
a
The conditions shown in Scheme 1 are suitable for reaction
of 6 with a variety of electrophiles to give a range of derivatives
as shown in Tables 1 and 2. Derivative 13 is particularly
significant in that the 1′- and 3′-nitrogens of biotin are
differentially protected with trityl and benzyloxycarbonyl
(Cbz), respectively. The trityl protecting groups of 11−16
were removed on treatment with TFA to give 17−22 as
summarized in Table 2. Biotin derivative 19, derived from 13, is
significant in that its 3′-nitrogen is selectively protected with a
Cbz group. The protection of biotin at this position is
otherwise difficult to achieve. As for the preparation of 4, the
methyl esters were removed under the conditions to give 18
and 21 possibly due to extended time on the rotatory
evaporator during workup.
In conclusion, we report a simple and efficient sequence for
the selective functionalization of biotin at the 3′-nitrogen. The
methodology involves the selective tritylation at the 1′-nitrogen,
followed by reaction with the appropriate electrophile and
removal of the trityl group. The reported chemistry is
significant in that it provides access to the known derivative
47 and also 17−22 in good yields. Thus biotin can be
selectively protected at the 1′-nitrogen (6), 3′-nitrogen (19),
and also differentially at both sites (13). The methodology
presented should be amenable to the preparation of a wide
range of otherwise inaccessible biotin analogues.
Table 1. 3′-Substitution of Biotin
a
product
electrophile
ClCH2COCl
R
yield (%)
b
11
12
13
14
15
16
ClCH2CO
59
b
CH2CH(CH2)8COCl
PhCH2OCOCl
PO(OEt)2Cl
TsCl
CH2CH(CH2)8CO
PhCH2OCO
PO(OEt)2
Ts
60
80
58
b
28
PhCH2Br
PhCH2
76
a
Isolated yield after flash column chromatography on silica gel.
Contains 20% DMTrOH by H NMR
b
1
Table 2. Cleavage of N1′-DMTr
a
product
R1
ClCH2CO
R2
yield (%)
17
18
19
20
21
22
Me
H
84
b
CH2CH(CH2)8CO
PhCH2OCO
PO(OEt)2
Ts
∼68
90
Me
Me
H
64
EXPERIMENTAL SECTION
b
■
∼58
90
NMR spectra were recorded in the specified solvent at 300 or 600
MHz (1H), 151 MHz (13C), and 121 MHz (31P); chemical shifts are
quoted on the δ scale (ppm) with TMS or the solvent signal as the
internal standard (1H NMR: CDCl3, TMS = 0.00 ppm and DMSO-d6,
2.50 ppm; 13C NMR; CDCl3 77.00 ppm and DMSO-d6 39.5 ppm.
Thin-layer chromatography (TLC) was carried out on commercially
available precoated aluminum plates (Merck 60F254) with visual-
ization under 254 nm light or by developing with vanillin or
permanganate dip. Flash column chromatography was carried out
using Merck Kieselgel 60 (230−400 mesh). Melting points were
measured on a microscope hot-stage melting point apparatus and are
uncorrected. All yields reported refer to isolated material judged to be
homogeneous by TLC and NMR spectroscopy. Oven-dried glassware
was used in all reactions carried out under an inert atmosphere (either
dry nitrogen or argon). All starting materials and reagents were
obtained commercially unless otherwise stated. Removal of solvents
“under reduced pressure” refers to the process of bulk solvent removal
by rotary evaporation (low vacuum pump) followed by application of
high vacuum pump (oil pump) for a minimum of 30 min.
PhCH2
Me
a
b
Isolated yield after flash column chromatography on silica gel. >90%
1
purity based on H NMR
DMTr resonance and the resonances at 4.42−4.37 ppm
(SCH2CH) and 2.47 (SCHACH). This material was then
treated with sodium hydride in DMF, followed by the addition
of propargyl bromide, to give the disubstituted derivative 7 in
85%. Treatment with 5.0 equiv of TFA in dichloromethane
then gave the desired derivative 4 in 90% yield.
It is also possible to prepare the 1′-isomer 10 and the doubly
alkyated product 9 under the appropriate reaction conditions as
shown in Scheme 2. In particular, alkylation of the methyl ester
Scheme 2. Alkylation Alkylation and Dialkylation of Biotin
General Procedure A. Reaction 6 with an Electrophile. A
suspension of sodium hydride (60% dispersion in oil, 5.0 equiv) in dry
DMF (4 mL/mmol) was cooled in an ice bath and stirred for 15 min
under a nitrogen atmosphere. A solution of 6 (1.0 equiv) in dry DMF
(4 mL/mmol) was added dropwise over 30 min, followed by addition
of TBAI (0.5 equiv) and dropwise addition of the electrophile (1.2
equiv). The reaction mixture was warmed to rt and stirred for an
additional 3 h. The reaction was then quenched by the slow addition
of water (20 mL), and the volatiles were removed under reduced
pressure. Further water (40 mL) was added, and the aqueous phase
was acidified to pH 2 (universal indicator paper) with the addition of
aqueous KHSO4. The mixture was extracted with ethyl acetate (3 × 40
mL), and the organic layers were combined, dried over anhydrous
Na2SO4, filtered, and evaporated under reduced pressure to give a
yellow oil that was purified by chromatography on silica gel (1%
CH3OH in CH2Cl2). See the individual experiments for details.
General Procedure B. DMTr Cleavage. To a solution of
disubstituted derivative of biotin (1.0 equiv) in CH2Cl2 (20 mL)
was added (5.0 equiv) TFA, and the reaction mixture was stirred under
argon for 1 h at rt. The solution was concentrated in vacuo, and the
of biotin (5), with propargyl bromide, gave the dialkylated
material 9 in 89% yield after hydrolysis of the methyl ester with
LiOH. The choice of solvent in the alkylation step is critical,
with the use of THF (in place of DMF) under literature
conditions,7 giving a mixture of 4 and its 1′-isomer 10 (2:3,
based on 1H NMR) under otherwise identical conditions.
These two isomers were separated by reversed-phase HPLC to
give 10 and 4 in 30% and 20% yields, respectively.
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Note
residue purified by chromatography on silica gel (1% CH3OH in
CH2Cl2). See the individual experiments for details.
warmed to rt and stirred for an additional 3 h. The reaction mixture
was quenched by the slow addition of water (10 mL), and the solvents
were removed under reduced pressure. Further water (30 mL) was
added, and the aqueous phase was acidified to pH 2 (universal
indicator paper) with the addition of aqueous KHSO4. The mixture
was extracted with ethyl acetate (3 × 30 mL), and the combined
organic layers were dried over anhydrous Na2SO4, filtered, and
evaporated under reduced pressure to give 8 as a yellow oil that was
not purified further (0.67 g). This material (0.6 g) was dissolved in
THF (1.5 mL) and the solution cooled in an ice bath. Methanol (1.5
mL) followed by a solution of lithium hydroxide (0.06 g 2.66 mmol) in
water (4.2 mL) were added. The reaction mixture was stirred for 3 h,
allowed to warm to rt, and then concentrated in vacuo. The residue
was purified by chromatography on a column of silica gel (1% CH3OH
5-((3aS,4S,6aR)-2-Oxo-3-(prop-2-ynyl)hexahydro-1H-thieno-
[3,4-d]imidazol-4-yl)pentanoic Acid (4).7 A solution of 7 (0.50 g,
0.83 mmol) in CH2Cl2 (20 mL) was treated with TFA according to
general method B to give 4 as a white solid (0.21 g, 90%): mp 170−
1
175 °C; H NMR (DMSO-d6, 600 MHz) δ 12.01 (bs, 1H), 6.98 (s,
1H), 4.20−4.34 (m, 3H), 3.60 (dd, J = 17.9, 2.0, 1H), 3.22−3.28 (m,
2H), 2.86 (dd, J = 12.7, 5.3, 1H), 2.60 (d, J = 12.2, 1H), 2.21 (t, J =
7.2, 2H), 1.30−1.81 (m, 6H); 13C NMR (DMSO-d6, 151 MHz) 174.5,
161.2, 79.4, 75.2, 64.1, 57.3, 55.9, 34.0, 33.5, 28.9, 28.2, 24.4; HRMS
(ESI, [M + Na]+) calcd for C13H18N2O3SNa 305.0936, found
305.0926.
Methyl 5-((3aS,4S,6aR)-1-(Bis(4-methoxyphenyl)(phenyl)-
methyl)-2-oxohexahydro-1H-thieno[3,4-d]imidazol-4-yl)-
pentanoate (6). To a solution of (+)-biotin methyl ester 5 (3.0 g,
11.6 mmol), rendered anhydrous by coevaporation with dry pyridine
(three times), in dry pyridine (65 mL) were added 4,4′-
dimethoxytrityl chloride (11.8 g, 34.0 mmol), triethylamine (1.95
mL, 13.9 mmol), and DMAP (0.35 g, 2.8 mmol). The mixture was
heated to 75 °C, stirred at this temperature for 4 h, and then diluted
with CHCl3. The CHCl3 phase was separated and washed three times
with 5% aqueous sodium citrate. The organic layer was collected, dried
over Na2SO4, filtered, and evaporated under reduced pressure. The
residue was purified by silica gel chromatography (2% CH3OH in
CH2Cl2) to 6 as a yellow foam (5.27 g, 81%): mp 68−71 °C; 1H NMR
(600 MHz, CDCl3): δ 7.33−7.23 (m, 5H), 7.21−7.13 (m, 4H), 6.85−
6.79 (m, 4H), 4.67 (s, 1H), 4.42−4.37 (m, 1H), 4.35−4.31 (m, 1H),
3.80 (s, 6H), 3.67 (s, 3H), 3.15−3.10 (m, 1H), 2.47 (dd, J = 13.0, 1.8
Hz, 1H), 2.34−2.24 (m, 3H), 1.71−1.56 (m, 4H), 1.50−1.33 (m, 2H);
13C NMR (151 MHz, CDCl3): δ 173.8, 160.9, 158.4, 143.7, 139.5,
135.8, 135.7, 131.3, 129.7, 129.1, 127.6, 127.1, 126.9, 112.8, 72.8, 65.6,
59.7, 55.22, 55.20, 53.9, 51.5, 39.0, 33.6, 28.8, 28.2, 24.6; HRMS (ESI,
[M + Na]+) calcd for C32H36N2O5SNa 583.2243, found 583.2239.
Methyl 5-((3aS,4S,6aR)-1-(Bis(4-methoxyphenyl)(phenyl)-
methyl)-2-oxo-3-(prop-2-ynyl)hexahydro-1H-thieno[3,4-d]-
imidazol-4-yl)pentanoate (7). A suspension of sodium hydride
(0.38 g of a 60% dispersion in oil, 16.6 mmol) in dry DMF (15 mL)
was cooled in an ice bath and stirred for 15 min under a nitrogen
atmosphere. A solution of 6 (2.0 g, 3.5 mmol) in dry DMF (20 mL)
was added dropwise over 30 min, followed by addition of TBAI (0.65
g, 1.7 mmol) and dropwise addition propargyl bromide (0.37 mL of
80% solution in toluene, 4.2 mmol). The reaction mixture was warmed
to rt and stirred for an additional 3 h. Water (20 mL) was added
slowly, and the volatiles were removed under reduced pressure.
Further water (40 mL) was added, and the aqueous phase was
acidified to pH 2 (universal indicator paper) with the addition of
aqueous KHSO4. The mixture was extracted with ethyl acetate (3 × 40
mL), and the organic layers were combined, dried over anhydrous
Na2SO4, filtered, and evaporated under reduced pressure to give a
yellow oil which was purified by chromatography on silica gel (1%
CH3OH in CH2Cl2) to give 7 as a low melting white solid (1.81 g,
85%): mp 63−67 °C; 1H NMR (600 MHz, CDCl3) δ 7.34 −7.09 (m,
9H), 6.85−6.79 (m, 4H), 4.61 (dd, J = 17.8, 2.4 Hz, 1H), 4.53−4.45
(m, 1H), 3.80 (s, 6H), 3.67 (s, 3H), 3.55 (dd, J = 17.8, 2.2 Hz, 1H),
3.24−3.19 (m, 1H), 2.37 (t, J = 2.3 Hz, 1H), 2.31−2.34 (m, 2H),
2.26−2.24 (dd, J = 4.2,4.0 Hz, 1H), 1.89 (dd, J = 12.9, 6.0 Hz, 1H),
1.75−1.36 (m, 7H); 13C NMR (151) MHz, CDCl3) δ 173.9, 160.9,
158.5, 143.1, 139.5, 135.2, 131.5, 131.3, 129.8, 129.1, 127.9, 127.7,
127.0, 112.9, 78.5, 73.3, 72.8, 63.1, 62.3, 55.24, 55.22 54.2, 51.6, 37.7,
35.0, 33.9, 28.9, 28.5, 24.7; HRMS (ESI, [M + Na]+) calcd for
C35H38N2O5SNa 621.2399, found 621.2395.
1
in CH2Cl2) to give 9 as colorless oil (0.50 g, 89%): H NMR (600
MHz, DMSO-d6) δ 12.00 (s, 1H), 4.41 (m, 1H), 4.31−4.20 (m, 2H),
4.13 (dd, J = 17.9, 1.2 Hz, 1H), 3.86 (dd, J = 17.9, 1.0 Hz, 1H), 3.72
(dd, J = 18.0, 0.9 Hz, 1H), 3.31−3.18 (m, 3H), 3.02 (d, J = 12.8 Hz,
1H), 2.85 (dd, J = 12.8, 5.3 Hz, 1H), 2.26−2.18 (m, 2H), 1.81 − 1.72
(m, 1H), 1.60−1.48 (m, 2H), 1.48−1.30 (m, 3H); 13C NMR (151
MHz, DMSO-d6) δ 174.3, 159.8, 79.1, 79.0, 75.2, 74.6, 62.4, 61.3, 55.1,
34.5, 34.3, 33.4, 31.2, 28.6, 28.0, 24.2; HRMS (ESI, [M + Na]+) calcd
for C16H20N2O3SNa 343.1092, found 343.1089.
(3aR,6S,6aS)-Benzyl 3-(bis(4-methoxyphenyl)(phenyl)-
methyl)-6-(5-methoxy-5-oxopentyl)-2-oxohexahydro-1H-
thieno[3,4-d]imidazole-1-carboxylate (13). Compound 6 (100
mg, 1.0 equiv) and benzyl chloroformate (36 mg, 1.2 equiv) were
reacted according to general procedure A to give 13 as a low-melting
1
solid (95 mg, 80%): H NMR (600 MHz, CDCl3) δ 7.40−7.09 (m,
14H), 6.81 (dd, J = 9.0, 2.1 Hz, 4H), 5.40 (d, J = 12.3 Hz, 1H), 5.13
(d, J = 12.2 Hz, 1H), 4.75 (m, 2H), 4.38 (m, 1H), 3.81 (s, 6H), 3.74
(s, 3H), 3.44−3.37 (m, 1H), 2.44−2.36 (m, 1H), 2.26 (t, J = 6.7 Hz,
2H), 1.66−1.38 (m, 4H), 1.31−1.13 (m, 2H); 13C NMR (151 MHz,
CDCl3) δ 173.9, 158.6, 158.5, 153.0, 152.1, 142.4, 135.7, 134.6, 134.4,
131.5, 131.3, 129.7, 128.6, 128.4, 127.8, 127.6, 127.2, 127.0, 113.1,
73.7, 68.0, 61.4, 61.2, 55.3, 55.2, 51.9, 51.5, 37.0, 33.9, 27.6, 27.4,
24.41; HRMS (ESI, [M + Na]+) calcd for C40H42N2O7SNa 717.2610,
found 717.2610.
Methyl 5-((3aS,4S,6aR)-1-(Bis(4-methoxyphenyl)(phenyl)-
methyl)-3-(diethoxyphosphoryl)-2-oxohexahydro-1H-thieno-
[3,4-d]imidazol-4-yl)pentanoate (14). Compound 6 (120 mg,
0.26 mmol, 1.0 equiv) and diethyl phosphoryl chloride (44 mg, 1.2
equiv) were reacted according to general procedure A to give 14 as a
colorless oil (85 mg, 58%): 1H NMR (300 MHz, CDCl3) δ 7.37−7.06
(m, 9H), 6.89−6.75 (m, 4H), 4.78−4.61 (m, 1H), 4.57−4.30 (m, 1H),
4.27−4.07 (m, 4H), 3.79 (s, 6H), 3.67 (s, 3H), 3.41 (m, 1H), 2.56−
2.23 (m, 4H), 1.65−1.23 (m, 12H); 13C NMR (75 MHz, CDCl3) δ
174.2, 161.2, 158.7, 158.5, 143.9, 142.8, 135.0, 134.8, 131.7, 131.5,
129.8, 127.7, 127.2, 113.1, 73.5, 65.0 (d, J = 7.0 Hz), 64.1 (d, J = 6.4
Hz), 63.7 (d, J = 7.9 Hz), 63.0 (d, J = 3.0 Hz), 55.4, 52.7, 51.7, 37.0,
34.1, 27.8, 27.5, 24.8, 16.4 (m); 31P NMR (122 MHz, CDCl3) δ
−0.93; HRMS (ESI, [M + Na]+) calcd for C36H45N2O8PSNa
719.2532, found 719.2533.
Methyl 5-((3aS,4S,6aR)-3-Benzyl-1-(bis(4-methoxyphenyl)-
(phenyl)methyl)-2-oxohexahydro-1H-thieno[3,4-d]imidazol-4-
yl)pentanoate (16). Compound 6 (200 mg, 1.0 equiv) and benzyl
bromide (61 mg, 1.2 equiv) were reacted according to general
1
procedure A to give 16 as a colorless oil (175 mg, 76%): H NMR
(600 MHz, CDCl3) δ 7.43−6.82 (m, 14H), 6.82−6.75 (m, 4H), 5.06
(dd, J = 14.6, 5.6 Hz, 1H), 4.31−4.21 (m, 1H), 4.17−4.03 (m, 1H),
3.79 (s, 6H), 3.69 (s, 3H), 3.23−3.13 (m, 1H), 2.44−2.30 (m, 3H),
1.78−1.26 (m, 8H); 13C NMR (151 MHz, CDCl3) δ 173.9, 160.2,
158.4, 143.3, 136.6, 135.5, 135.4, 131.5, 131.3, 129.8, 129.2, 128.7,
128.6, 128.2, 127.9, 127.6, 126.9, 112.8, 72.9, 62.6, 61.8, 55.25, 55.20,
52.4, 51.5, 47.1, 37.4, 33.9, 28.3, 28.0, 24.6; HRMS (ESI, [M + Na]+)
calcd for C39H42N2O5SNa 673.2712, found 673.2713.
Methyl 5-((3aS,4S,6aR)-3-(2-Chloroacetyl)-2-oxohexahydro-
1H-thieno[3,4-d]imidazol-4-yl)pentanoate (17). Compound 6
(1.0 g, 1.0 equiv) and chloroacetyl chloride (0.16 mL, 1.2 equiv)
were reacted according to general procedure A to give 11 as oil (0.71
g, contains 20% DMTrOH, 59%) that was used without further
5-((3aS,4S,6aR)-2-Oxo-1,3-di(prop-2-ynyl)hexahydro-1H-
thieno[3,4-d]imidazol-4-yl)pentanoic Acid (9). A suspension of
sodium hydride (0.27 g of a 60% dispersion in oil, 11.6 mmol) in dry
DMF (10 mL), under a nitrogen atmosphere, was cooled in an ice
bath with stirring. After 15 min, a solution of biotin methyl ester 5
(0.60 g, 2.3 mmol) in DMF (10 mL) was added dropwise over 30 min,
followed by TBAI (0.42 g, 1.6 mmol) and propargyl bromide (0.41
mL of 80% solution in toluene, 4.6 mmol). The reaction mixture was
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Note
purification: 1H NMR (300 MHz, CDCl3) δ 7.45−7.38 (m, 5H), 7.25
(m, 4H), 6.93 (m, 4H), 4.80 (m, 2H), 4.66−4.32 (m, 2H), 3.79 (s,
6H), 3.66 (s, 3H), 2.55−2.22 (m, 3H), 1.83−1.47 (m, 3H), 1.47−1.07
(m, 3H), 1.01−0.74 (m, 2H); HRMS (ESI, [M + H]+) calcd for
C34H38ClN2O6S 637.2139, found 637.2133.
12.0, 6.6 Hz, 1H), 2.55 (s, 3H), 2.49−2.32 (m, 4H), 2.21−1.59 (m,
4H), 1.57−1.30 (m, 2H); HRMS (ESI, [M + H]+) calcd for
C39H42N2O7S2Na 737.2331, found 737.2355
Compound 15 (80 mg, 1.0 equiv) and TFA (63 mg, 5.0 equiv) were
reacted according to general procedure B to give 21 as a colorless oil
(26 mg, >90% pure by 1H NMR, ∼58%): 1H NMR (600 MHz,
DMSO-d6) δ 7.79 (d, J = 8.3 Hz, 2H), 7.74 (s, 1H), 7.39 (d, J = 8.1
Hz, 2H), 4.84 (dd, 1H), 4.34−4.29 (m, 1H), 3.14 (d, J = 5.2 Hz, 1H),
2.85 (dd, J = 12.6, 5.2 Hz, 1H), 2.64 (dd, 1H), 2.37 (s, 3H), 2.20−2.13
(m, 2H), 1.95−0.78 (m, 6H); 13C NMR (151 MHz, DMSO-d6) δ
174.3, 154.9, 144.4, 135.6, 129.5, 127.7, 65.7, 57.1, 54.4, 36.9, 33.4,
28.5, 28.4, 24.4, 21.0; HRMS (ESI, [M + H]+) calcd for
C17H22N2O5S2Na 421.0868, found 421.0866.
Compound 11 (60 mg, 1.0 equiv) and TFA (0.53 mg, 5.0 equiv)
were reacted according to general procedure B to give 17 as a colorless
1
oil (0.25 g, 84%): H NMR (600 MHz, CDCl3) δ 5.74 (bs, 1H),
5.01−4.91 (m, 1H), 4.80 (d, J = 15.8 Hz, 1H), 4.72 (d, J = 15.8 Hz,
1H), 4.31−4.24 (m, 1H), 3.68 (s, 3H), 3.26−3.19 (m, 1H), 3.14 (d, J
= 13.8 Hz, 1H), 3.03 (dd, J = 13.8, 5.4 Hz, 1H), 2.36 (t, J = 7.2 Hz,
2H), 1.80−1.63 (m, 4H), 1.55−1.41 (m, 2H); 13C NMR (151 MHz,
CDCl3) δ 173.9, 166.2, 155.9, 62.3, 58.0, 54.9, 51.7, 44.1, 38.0, 33.3,
27.9, 27.8, 24.5; HRMS (ESI, [M + H]+) calcd for C13H19ClN2O4S
335.0832, found 335.0822.
Methyl 5-((3aS,4S,6aR)-2-Oxo-3-undec-10-enoylhexahydro-
1H-thieno[3,4-d]imidazol-4-yl)pentanoate (18). Compound 6
(150 mg, 1.0 equiv) and 10-undecenoyl chloride (64 mg, 1.2 equiv)
were reacted according to general procedure A to give 12 as a low-
melting solid (125 mg, contains 20% DMTrOH, 60%): 1H NMR (600
MHz, CDCl3) δ 7.36−7.06 (m, 9H), 6.86−6.79 (m, 4H), 5.87−5.76
(m, 1H), 5.03−4.90 (m, 2H), 4.43−4.33 (m, 1H), 3.80 (s, 6H), 3.66
(s, 3H), 3.17−3.11 (m, 1H), 2.92−2.76 (m, 1H), 2.44 (t, J = 10.5 Hz,
1H), 2.32 (t, J = 7.5 Hz, 4H), 2.08−1.99 (m, 2H), 1.76−1.53 (m, 6H),
1.42−1.19 (m, 12H); HRMS (ESI, [M + H]+) calcd for
C43H54N2O6SNa 749.3600, found 749.3607.
Methyl 5-((3aS,4S,6aR)-3-Benzyl-2-oxohexahydro-1H-
thieno[3,4-d]imidazol-4-yl)pentanoate (22). Compound 16 (80
mg, 1.0 equiv) and TFA (70 mg, 5.0 equiv) were reacted according to
1
general procedure B to give 22 as a colorless oil (38 mg, 90%): H
NMR (600 MHz, CDCl3) δ 7.40−7.24 (m, 5H), 5.55 (bs, 1H), 4.98
(dd, J = 15.2, 9.7 Hz, 1H), 4.39−4.30 (m, 1H), 4.03 (m, 1H), 3.93
(dd, J = 15.2, 6.2 Hz, 1H), 3.68 (s, 3H), 3.16−3.04 (m, 1H), 2.99−
2.89 (m, 1H), 2.83−2.75 (m, 1H), 2.40−2.28 (m, 2H), 1.75−1.50 (m,
5H), 1.40−1.30 (m, 1H); 13C NMR (151 MHz, CDCl3) δ 173.9,
162.7, 136.6, 128.8, 128.2, 127.8, 66.2, 65.0, 57.8, 54.4, 51.6, 47.4, 37.9,
33.9, 28.7, 24.6; HRMS (ESI, [M + H]+) calcd for C18H24N2O3SNa
371.1405, found 371.1401.
Compound 12 (60 mg, 1.0 equiv) and TFA (47 mg, 5.0 equiv) were
reacted according to general procedure B to give 18 as a low melting
ASSOCIATED CONTENT
■
S
* Supporting Information
1
1
solid (23 mg, >90% pure by H NMR, ∼68%): H NMR (600 MHz,
CDCl3) δ 5.86−5.77 (m, 1H), 5.65 (s, 1H), 4.99 (dd, J = 17.1, 1.7 Hz,
1H), 4.94−4.90 (m, 2H), 4.41−4.33 (m, 1H), 3.57−3.49 (m, 1H),
3.05−2.91 (m, 2H), 2.92−2.74 (m, 2H), 2.34 (t, J = 7.2 Hz, 2H),
2.08−2.00 (m, 2H), 1.73−1.50 (m, 6H), 1.43−1.23 (m, 13H); 13C
NMR (151 MHz, CDCl3) δ 177.2, 174.0, 156.5, 139.2, 114.1, 63.7,
55.9, 53.0, 36.8, 35.5, 33.8, 33.6, 29.4, 29.3, 29.1, 28.9, 28.2, 27.8, 24.7,
24.3; HRMS (ESI, [M + H]+) calcd for C21H34N2O4SNa 433.2137,
found 433.2134.
1H and 13C NMR spectra of all new compounds. This material
is available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: andrew.abell@adelaide.edu.au.
(3aR,6S,6aS)-Benzyl 6-(5-Methoxy-5-oxopentyl)-2-oxohexa-
hydro-1H-thieno[3,4-d]imidazole-1-carboxylate (19). Com-
pound 13 (60 mg, 1.0 equiv) and TFA (49 mg, 5.0 equiv) were
reacted according to general procedure B to give 19 as white solid (30
mg, 90%): mp 132−135 °C; 1H NMR (600 MHz, CDCl3) δ 7.42 (d, J
= 7.2 Hz, 2H), 7.37−7.30 (m, 3H), 6.08 (bs, 1H), 5.35 (d, J = 12.2 Hz,
1H), 5.22 (d, J = 12.2 Hz, 1H), 4.77 (dd, J = 9.2, 6.4 Hz, 1H), 4.39−
4.33 (m, 1H), 3.67 (s, 3H), 3.40−3.34 (m, 1H), 3.05−2.98 (m, 1H),
2.78 (dd, J = 12.5, 4.7 Hz, 1H), 2.27−2.19 (m, 2H), 1.60−1.42 (m,
4H), 1.35−1.18 (m, 2H); 13C NMR (151 MHz, CDCl3) δ 173.8,
155.4, 151.7, 135.3, 128.6, 128.5, 128.4, 68.1, 64.4, 55.9, 53.1, 51.5,
36.8, 33.9, 28.2, 27.6, 24.4; HRMS (ESI, [M + H]+) calcd for
C19H24N2O5SNa 415.1304, found 415.1302.
ACKNOWLEDGMENTS
■
This work was supported by the Australia Research Council,
University of Adelaide CAS award, and a AFSI scholarship
award to A.D.P.
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1
(26 mg, 64%): H NMR (300 MHz, CDCl3) δ 5.77 (bs, 1H), 4.68−
6.60 (m, 1H), 4.50−4.37 (m, 1H), 4.35−4.04 (m, 4H), 3.65 (s, 3H),
3.36−3.25 (m, 1H), 2.95 (dd, J = 12.5, 6.2 Hz, 1H), 2.77 (dd, J = 12.4,
3.8 Hz, 1H), 2.31 (t, J = 7.3 Hz, 2H), 2.10−1.96 (m, 1H), 1.77−1.52
(m, 3H), 1.45−1.28 (m, 8H); 13C NMR (75 MHz, CDCl3) δ 174.2,
159.3, 66.6 (d, J = 3.6 Hz), 64.8 (d, J = 6.2 Hz), 64.1 (d, J = 6.0 Hz),
58.3 (d, J = 7.7 Hz), 54.2, 51.7, 37.0, 34.1, 28.6, 28.0, 24.8, 16.6−16.1
(m).31P NMR (122 MHz, CDCl3) δ −0.30; HRMS (ESI, [M + H]+)
calcd for C15H27N2O6PSNa 417.1225, found 417.1228.
Methyl 5-((3aS,4S,6aR)-2-Oxo-3-tosylhexahydro-1H-thieno-
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5429.
1
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Hz, 1H), 4.36−4.27 (m, 1H), 3.81 (s, 6H), 3.65 (s, 3H), 3.54 (dd, J =
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