Enzymatic- and iridium-catalyzed asymmetric synthesis of a benzothiazepinylphosphonate bile acid transporter inhibitor

Article abstract of DOI:10.1021/jo402311e

A synthesis of the benzothiazepine phosphonic acid 3, employing both enzymatic and transition metal catalysis, is described. The quaternary chiral center of 3 was obtained by resolution of ethyl (2-ethyl)norleucinate (4) with porcine liver esterase (PLE) immobilized on Sepabeads. The resulting (R)-amino acid (5) was converted in two steps to aminosulfate 7, which was used for construction of the benzothiazepine ring. Benzophenone 15, prepared in four steps from trimethylhydroquinone 11, enabled sequential incorporation of phosphorus (Arbuzov chemistry) and sulfur (Pd(0)-catalyzed thiol coupling) leading to mercaptan intermediate 18. S-Alkylation of 18 with aminosulfate 7 followed by cyclodehydration afforded dihydrobenzothiazepine 20. Iridium-catalyzed asymmetric hydrogenation of 20 with the complex of [Ir(COD)₂BArF] (26) and Taniaphos ligand P afforded the (3R,5R)-tetrahydrobenzothiazepine 30 following flash chromatography. Oxidation of 30 to sulfone 31 and phosphonate hydrolysis completed the synthesis of 3 in 12 steps and 13% overall yield.

Full text of DOI:10.1021/jo402311e

Article
pubs.acs.org/joc
Enzymatic- and Iridium-Catalyzed Asymmetric Synthesis of a
Benzothiazepinylphosphonate Bile Acid Transporter Inhibitor
David J. Cowan,† Jon L. Collins,† Mark B. Mitchell,† John A. Ray,† Peter W. Sutton,§ Amy A. Sarjeant,‡
and Eric E. Boros*,†
†GlaxoSmithKline Research & Development, Five Moore Drive, Research Triangle Park, North Carolina 27709, United States
§GlaxoSmithKline Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire, SG1 2NY, United Kingdom
‡Department of Chemistry, Northwestern University, 2145 Sheridan Road, Evanston, Illinois 60208, United States
S
* Supporting Information
ABSTRACT: A synthesis of the benzothiazepine phosphonic acid 3, employing both enzymatic and transition metal catalysis, is
described. The quaternary chiral center of 3 was obtained by resolution of ethyl (2-ethyl)norleucinate (4) with porcine liver
esterase (PLE) immobilized on Sepabeads. The resulting (R)-amino acid (5) was converted in two steps to aminosulfate 7, which
was used for construction of the benzothiazepine ring. Benzophenone 15, prepared in four steps from trimethylhydroquinone 11,
enabled sequential incorporation of phosphorus (Arbuzov chemistry) and sulfur (Pd(0)-catalyzed thiol coupling) leading to
mercaptan intermediate 18. S-Alkylation of 18 with aminosulfate 7 followed by cyclodehydration afforded dihydrobenzo-
thiazepine 20. Iridium-catalyzed asymmetric hydrogenation of 20 with the complex of [Ir(COD)2BArF] (26) and Taniaphos
ligand P afforded the (3R,5R)-tetrahydrobenzothiazepine 30 following flash chromatography. Oxidation of 30 to sulfone 31 and
phosphonate hydrolysis completed the synthesis of 3 in 12 steps and 13% overall yield.
(IC50 = 23 nM), good aqueous solubility (≥200 μg/mL), and
low permeability (MDCK Papp = 7 nm/s).
INTRODUCTION
■
The apical sodium-dependent bile acid transporter (ASBT) is a
protein highly expressed in the distal ileum of the gastrointestinal
tract that helps maintain an enterohepatic balance of bile salts
and cholesterol.1−3 ASBT inhibitors promote conversion of
cholesterol to bile acids in the liver and may serve as viable
therapeutic agents for the treatment of hyperlipidemia.4−6
Moreover, elevated intestinal levels of bile acids are known to
induce secretion of gut hormone peptide GLP-1,7 suggesting that
a clinical ASBT inhibitor may ameliorate both blood glucose and
cholesterol levels in humans. The goal of our ASBT inhibitor
discovery program was to identify a potent, nonabsorbable ASBT
inhibitor for treatment of type 2 diabetes.8,9 Soluble and
nonabsorbable ASBT10,11 inhibitors were of particular interest
because they localize the drug in the intestine (the locus of drug
action) and minimize systemic side effects.
The original synthesis of 3 (Scheme 1) and its congeners relied
heavily on multikilogram stores of 1. Nonselective mono-O-
demethylation of 1 (AlCl3/HCl) afforded a 1:1 mixture of 7-
hydroxy-8-methoxy and 8-hydroxy-7-methoxy regioisomers
from which the desired 8-hydroxy isomer was isolated by
preparative chiral HPLC and converted to triflate 2.8,9 A five-step
process starting with methoxy carbonylation of 2, and ending
with phosphonate hydrolysis, afforded the lead inhibitor 3. In
addition to the finite supply of 1, the eight-step linear sequence
used for installation of the phosphonic acid moiety (1 → 3),
including a nonselective demethylation of 1, was inefficient. The
lead status of 3 at the time of this work prompted the team to
investigate an alternative synthesis.
We initiated a medicinal chemistry effort targeting non-
systemic analogs of the clinical ASBT inhibitor 264W9412,13 (1).
Structure−activity work showed that acidic moieties joined by a
methylene group to C-8 produced potent, soluble inhibitors with
restricted absorption and good intestinal stability. These
compounds were generally prepared from triflate intermediate
2 using in-house supplies of 1 as starting material. During the
course of this work, phosphonic acid congener 3 emerged as a
potential drug candidate, with potent ASBT inhibition activity
RESULTS AND DISCUSSION
■
The second generation approach to 3 is outlined in Figure 1.
Formally, the route entailed reductive cyclo-condensation of a 2-
mercaptobenzophenone with an (R)-(2-ethyl)norleucine deriv-
ative. Asymmetric imine reduction of the resulting dihydro-
Received: October 16, 2013
© XXXX American Chemical Society
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Scheme 1. First-Generation Synthesis of Phosphonic Acid 3 from ASBT Inhibitor 1
Figure 1. Key features of the second-generation pathway to 3.
benzothiazepine, followed by sulfur oxidation and phosphonate
hydrolysis, respectively would complete the synthesis.
enzymatic resolution performed with Sepabead PLE was with
1.73 kg of 4 (9.21 mol) which afforded 4 mol of 5.
The quaternary C3 stereocenter in 3 was derived by porcine
liver esterase (PLE) resolution of ( )-ethyl (2-ethyl)-
norleucinate (4) as previously described for the synthesis of 1
(Scheme 2).12,14 PLE hydrolysis of 4 on the 10 g scale gave a 43%
Reduction of amino acid 5 with LAH gave (R)-(2-ethyl)-
norleucinol (6) which was treated with chlorosulfonic acid to
afford aminosulfate 7.12 More than 600 g of 7 were prepared in
order to support ongoing medicinal chemistry studies and
synthetic development work.
Scheme 2. Enzymatic Hydrolysis of 4 and Synthesis of
Aminosulfate 7
Enantiopurities of 7 were established by derivatization with the
commercial aromatic mercaptan 8 followed by chiral SFC
analysis. This reaction proceeds with retention of configuration
through aziridine18,19 intermediate 9 and afforded chiral
aminosulfide 10 as an oil in good yield (eq 1). Chiral SFC
analyses of 10 prepared from Sepabead PLE hydrolysis of 4 on
the 50 g scale (37% substrate conversion) and 1.73 kg scale (42%
substrate conversion) showed 94% ee and 88% ee, respectively.
Construction of the requisite dihydrobenzothiazepine is
illustrated in Scheme 3. Trimethylhydroquinone 11 was selected
as the benzophenone synthon for the second-generation
synthesis of 3. This material was inexpensive and well-suited
for Friedel−Crafts reaction with benzoyl chloride. The goal, at an
appropriate point in the synthesis, was to convert the aryl methyl
substituent in 11 to a dialkyl phosphonomethyl group through a
sequential free radical bromination and Arbuzov20 reaction
sequence.
yield of 5 with 93% ee based on the aminosulfate derivatization
sequence shown in eq 1. In our hands, filtration of the PLE
Reaction of 11 with benzoyl chloride in the presence of AlCl3
proceeded in good yield to afford benzophenone 12.
Regioselective demethylation of the methoxyl group ortho to
the ketone in 12 with BCl3 gave the corresponding 2-
hydroxybenzophenone 13 (72% overall yield). Boron complex-
ation with the carbonyl oxygen in 12 directs the regioselectivity
in this reaction.21
Synthesis of triflate 14 from phenol 13 was straightforward and
set the stage for palladium-catalyzed coupling of a suitably
protected thiol ortho to the carbonyl group. However, to avoid
oxidative NBS conditions in the presence of divalent sulfur, the
radical bromination and Arbuzov reactions were performed prior
to the thiol coupling with the triflate functionality in place. We
were pleased to find that NBS bromination of 14 proceeded
smoothly to give bromomethyl intermediate 15 in good yield.
reaction mixture during workup could be slow owing to filter
blockage by the enzyme and passage of fine particles into the
filtrate. For this reason, the possibility of linking the PLE to a
solid support was explored.
Enzyme immobilization was achieved in two steps by reacting
powdered PLE with Sepabeads EC-EP15−17 followed by
deactivation of the remaining epoxy units on the polymer with
glycine. Reaction times for Sepabead PLE hydrolysis of 4 to 37−
42% substrate conversion were about 24 h, and removal of the
immobilized enzyme by filtration was facile. The largest scale
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Scheme 3. Synthesis of Phosphonomethylbenzothiazepine 20
Scheme 4. Synthesis and Asymmetric Reduction of Bromobenzothiazepine 22
Benzylic bromide 15 was a pivotal intermediate in the
synthesis of 3. Its trifunctionality (benzylic bromide, triflate,
and ketone) allowed sequential incorporation of phosphorus and
sulfur and subsequent thiazepine ring closure. It is worth noting
that reaction of 15 with other nucleophiles (e.g., amines, thiols,
phenols, etc.) may afford access to additional 8-methylene-linked
congeners in this family of ASBT inhibitors.
presence of Xantphos, Pd2(dba)3, and Hunig’s base.22 This
procedure was performed successfully on a 79 g scale and
afforded 17 in 83% yield following crystallization. Removal of the
PMB group in 17 with TFA/anisole afforded the corresponding
thiol 18 which was used immediately in the next step without
purification. S-Alkylation of 18 with aminosulfate 7 (prepared
from the 1.725 kg scale resolution of 4) afforded aminosulfide 19
which showed a 93:7 ratio of enantiomers by chiral normal phase
HPLC/MS analysis.
Cyclodehydration of 19 under Dean−Stark conditions gave
dihydrobenzothiazepine 20 in 38% overall yield (three steps)
from 17. We considered the synthesis of aminomercaptan 21 (R
= Et; R′ = Bu)23 which (if coupled to 16) would improve
Treatment of 15 with triethylphosphite at 115 °C afforded
phosphonate 16. The crude material was initially an oil and did
not crystallize despite considerable efforts. Flash chromatog-
raphy of 16 did afford crystalline material (mp 53−56 °C) after
storage for several weeks at 10−15 °C.
Introduction of the protected thiol group was accomplished by
coupling 16 with p-methoxybenzyl mercaptan (PMBSH) in the
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Figure 2. Structures of bidentate phosphines (A−V) and monodentate phosphoramidites (W−Z) screened in combination with [Ir(COD)2]BArF (26)
for asymmetric hydrogenation of 22.
synthetic convergence, but development priorities24 precluded
this investigation.
sample of the cis/trans mixture 27/28 (∼1:1) was prepared by
borane reduction of 22, and an analytical sample of the desired
trans-product (28) was isolated by silica gel chromatography.
The relative stereochemistry of 28 was established by two-
dimensional NOESY NMR experiments.
A number of the ligands shown in Figure 2, in combination
with iridium complex 26, quantitatively reduced the imine
functionality of 22 under 30 bar (gauge) H2, including biphenyl
bis-phospine B, Walphos ligands K−N, Mandyphos ligand R,
catASium ligand V, and Monophos Z. Of these catalysts,
Walphos ligands K−M gave 60−70% selectivity for the trans-
product (28). More significantly, complexes derived from 26 and
Taniaphos ligands O and P, Monophos Y, and ROPhos ligand T
all gave complete imine reduction with 85−90% diastereose-
lectivity.
Asymmetric imine reduction of 20 was initially scoped with
traditional Noyori ruthenium catalysts, including transfer
hydrogenation with (S,S)-pTsDPEN-Ru(p-cymene)Cl25 and
hydrogenation in the presence of RuCl2(R)-BINAP-(S,S)-
DPEN.26 None of the expected reduction products were
observed, presumably owing to low catalytic reactivity with the
substrate.
We next screened the effectiveness of cationic iridium
complexes27 for dihydrobenzothiazepine reduction, but to
avoid the consumption of more phosphonate 20, in-house stores
of the bromo substrate 22 were employed. The synthesis of 22
and its asymmetric reduction are outlined in Scheme 4. Briefly,
hydrolysis of the known thiocarbamate 238 with KOH/EtOH
afforded 2-mercaptobenzophenone 24. S-Alkylation of 24 with
aminosulfate 7 and cyclization of the resulting product (25)
afforded benzothiazepine 22.
Taniaphos28,29 ligand P (Cy = cyclohexyl), in combination
with 26, gave 100% reduction of 22 with 90% trans product (28).
It is important to note that the same reaction with Taniaphos
ligand O (the enantiomer of P) gave 100% reduction and 88%
cis-product (27). This indicates that the stereoselectivity of the
reduction is controlled by the Re/Si-face of the imine substrate
and is not significantly influenced by the quaternary stereocenter.
Consequently, a silica gel chromatographic separation of the cis/
trans-products following reduction will significantly enhance the
enantiopurity of the desired trans-product.
Rophos30 ligand T also gave 90% cis-product 27, and the
Monophos31 ligand Y, which can offer cost of goods savings
compared to chiral phosphines, gave clean imine reduction with
85% trans-product 28. Because the antipode of Rophos ligand T
Asymmetric hydrogenation of 22 was examined with a series of
chiral cationic iridium complexes generated in situ from chiral
ligands A−Z (Figure 2) and [Ir(COD)2BArF] (26). The results
of these experiments are shown in Table 1. An HPLC reference
D
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a
time) under 4 bar (gauge) H2 (95% imine reduction; trans/cis
ratio 9:1). Separation of the unwanted cis-isomer by flash
chromatography on silica gel afforded the pure diastereomer 30
in 73−85% yields. The desired syn orientation of the diaryl
methine proton and n-butyl side chain in 30 was supported by a
combination of NOE measurements and two-dimensional
HMBC spectroscopy.
Oxidation of 30 with H2O2/TFA afforded sulfone 31. The
relative and absolute stereochemistry of 31 were confirmed by X-
ray crystallography (Figure 3). In the solid state, the exocyclic
phenyl substituent of 31, although trans to the n-butyl side chain,
is oriented slightly above the plane of the benzo ring which
directs the benzylic methine proton toward the pro-(S) sulfonyl
oxygen (O6 in Figure 3). The crystal structure of 31 also revealed
an intermolecular hydrogen bond between the pro-(R) sulfonyl
oxygen and the N−H proton of a neighboring molecule.
The final step in the synthesis of 3 entailed phosphonate
hydrolysis of 31 in refluxing 6 N HCl. Evaparation of the solvent
afforded the hydrochloride salt of the title compound as an
amorphous solid (3·HCl) in 97% yield.
Table 1. Percent Conversion and Products for
b
Hydrogenation of 22 to 27/28 with Chiral Iridium Catalysts
Prepared in situ from [Ir(COD)2]BArF (26) and Bidentate
Phosphines (A−V) or Monodentate Phosphoramidites (W−
c
c
Z)
ligand
% conversion (27 + 28)
% 27 (cis)
% 28 (trans)
A
B
C
D
E
73
100
73
43
45
38
12
26
34
10
34
44
5.8
30
31
40
47
88
10
53
54
26
90
14
68
48
2.5
15
65
30
55
35
12
52
44
13
44
41
5.5
70
69
60
53
12
90
38
46
22
10
11
32
39
2.1
85
35
24
76
F
78
G
H
I
23
78
85
J
11
K
L
100
100
100
100
100
100
91
M
N
O
P
CONCLUSION
■
A convergent 12 step synthesis of benzothiazepinylphosphonic
acid 3 was achieved through an unusual trifunctional
benzophenone intermediate (15). The title synthesis represents
a unique asymmetric pathway to this family of nonabsorbable
ASBT inhibitors. Chemistry highlights included a Sepabead PLE-
catalyzed synthesis of (R)-aminosulfate 7 and its two-step
cyclocondensation with 2-mercapto-4-phosphonobenzophe-
none 18. The synthesis culminated with an iridium-catalyzed
asymmetric hydrogenation of dihydrothiazepine 20 followed by
flash chromatography which afforded the desired (3R,5R)-
diastereomer 30. Absolute and relative stereochemistries of the
title compound were confirmed by X-ray crystallographic
analysis of the penultimate diethylphosphonate product (31).
In addition, some synthetic convergence was achieved by
incorporating the two stereocenters late in the pathway (after
construction of the fully functionalized mercaptobenzophenone
18). The medicinal chemistry and structure−activity relation-
ships of 3 and related analogs are reported elsewhere.9
Q
R
S
100
48
T
U
V
W
X
Y
100
25
100
87
4.6
100
Z
100
a
b
c
Determined by HPLC. See Experimental Section. See Figure 2 for
structures of ligands A−Z.
was not commercially available, we employed Taniaphos ligand P
for asymmetric synthesis of 3.
Anchimeric assistance by the divalent sulfur during iridium-
catalyzed reduction of 22 does not explain the observed
stereoselectivity, but is an intriguing possibility (see generalized
transition structure 29).32 In fact, attempts to hydrogenate the
sulfone derivative of 22 with the complex of 26 and ligand P
failed to produce any imine reduction product, which is
consistent with this hypothesis.
The final three steps in the synthesis of 3 are shown in Scheme
5. As anticipated, asymmetric hydrogenation of 20 with
[Ir(COD)2BArF] (26) and ligand P under 30 bar (gauge) H2
gave predominantly trans-isomer 30 (100% conversion; trans/cis
ratio 9:1), a result identical to that observed with the 8-bromo
substrate (22). This reaction went to completion in 2 h (1−4 g
scale of 18) and also proceeded at a slower rate (24 h reaction
EXPERIMENTAL SECTION
■
Sepabead-Immobilized Porcine Liver Esterase. A fixed glass
reactor equipped with a mechanical stirrer was charged with 1 M pH 7
sodium phosphate buffer (8.2 L, 8.2 mol). EC-EP Sepabeads (1646 g)
and porcine liver esterase lyophilized powder (17 units/mg protein, 99
g) were added, and the mixture was stirred gently for 3 d at rt. The beads
were collected by filtration. The reactor was cleaned and charged with a
3 M solution of aqueous glycine (8.2 L, 24.6 mol). This solution was
charged with the beads from the filter and stirred gently for 3 d. The
beads again were collected by filtration and air-dried on the filter for 30
min to afford the Sepabead-immobilized PLE (1622 g).
Scheme 5. Asymmetric Reduction of 20 and Conversion to ASBT Inhibitor 3
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Figure 3. A view of the X-ray crystal structure of 31 showing the numbering scheme employed. Anisotropic atomic displacement ellipsoids for the non-
hydrogen atoms are shown at the 50% probability level. Hydrogen atoms are displayed with an arbitrarily small radius.
2-Ethyl-D-norleucine (5). A fixed glass reactor equipped with a
mechanical stirrer, pH stat, and metered 2 M NaOH pump was charged
with racemic ethyl (2-ethyl)norleucinate (4) (1.725 kg, 9.211 mol) and
water (8 L). To this stirred mixture was added the Sepabead-
immobilized PLE (570 g), and the reaction mixture was stirred for 28
h at rt; the pH of the reaction mixture was maintained between 9.4 and
9.8 by automated pH stat addition of NaOH. PLE hydrolysis of 4 was
8 (567 mg, 3.33 mmol), water (4 mL), and toluene (4 mL) was purged
with N2 and then heated to reflux. A solution of NaOH (355 mg, 8.88
mmol) in water (4 mL) was added dropwise over 2 h. The reaction
mixture was heated at reflux an additional 3 h and then stirred at 45 °C
overnight. The layers were separated, and the toluene phase was washed
with 1 N NaOH, dried over MgSO4, and concentrated to an oil. This
material was partitioned between 1 N HCl (7.5 mL) and Et2O (10 mL)
and stirred for 15 min to remove residual disulfide byproduct. The
aqueous phase was cooled in an ice bath, basified with 1 N NaOH, and
extracted with Et2O. The organic phase was dried over MgSO4, filtered,
and concentrated to afford 10 (505 mg, 77% yield) as a colorless oil.
Samples of 10 derived from the 50 g scale Sepabead PLE resolution of 4
and 1.725 kg scale Sepabead PLE resolution of 4 showed 94% ee and
88% ee, respectively, by chiral SFC: chiral AD-H column, 10% MeOH/
CO2/0.5% diethylamine, 140 bar, 40 °C, flow rate 2 mL/min. Spectral
data for ( )-10: 1H NMR (CDCl3, 400 MHz) δ 7.01 (dd, J = 8, 2 Hz,
1H), 6.98 (d, J = 2 Hz, 1H), 6.79 (d, J = 8 Hz, 1H), 3.87 (s, 3H), 3.86 (s,
3H), 2.95 (s, 2H), 1.55−1.15 (m, 10H), 0.88 (t, J = 7 Hz, 3H), 0.84 (t, J
= 7 Hz, 3H); 13C NMR (CDCl3, 100 MHz) δ 148.8, 148.0, 128.2, 123.8,
114.7, 111.4, 55.7, 54.6, 47.6, 38.4, 31.6, 25.6, 23.1, 13.9, 7.8; HRMS
(TOF ES+) C16H28NO2S calcd 298.1841, found 298.1843.
(2,5-Dimethoxy-4-methylphenyl)(phenyl)methanone (12). A
round bottomed flask equipped with an overhead stirrer was charged
with AlCl3 (60.7 g, 455 mmol) and CH2Cl2 (300 mL). The stirred
mixture was cooled in an ice bath, and a solution of benzoyl chloride (64
g, 455 mmol) in CH2Cl2 (300 mL) was added dropwise over 20 min.
After stirring an additional 10 min, a solution of 11 (63 g, 414 mmol) in
CH2Cl2 (300 mL) was added over 20 min. The resulting dark red
reaction mixture was stirred for 1 h at ice bath temperature and then
quenched by slow dropwise addition of conc. HCl (150 mL) with very
slow mechanical stirring. The supernatant was decanted, and the
remaining gum was triturated with CH2Cl2 (3 × 150 mL). The
combined supernatants were washed with satd. NaHCO3, dried over
MgSO4, filtered, and concentrated. The resulting material was triturated
with heptane, and 12 was collected by filtration as a white solid (95 g,
90% yield): Mp 117−119 °C; 1H NMR (CDCl3, 400 MHz) δ 7.82 (dd, J
= 7.5, 1 Hz, 2H), 7.55 (t, J = 8 Hz, 1H), 7.43 (t, J = 7.5 Hz, 2H), 6.90 (s,
1H), 6.82 (s, 1H), 3.80 (s, 3H), 3.65 (s, 3H), 2.30 (s, 3H); 13C NMR
(CDCl3, 100 MHz) δ 196.1, 151.5, 151.2, 138.1, 132.5, 131.0, 129.5,
127.9, 126.0, 114.8, 111.2, 56.1, 55.7, 16.6; ES+ MS 257 (M + 1, 100);
Anal. Calcd for C16H16O3: C, 74.98; H, 6.29. Found: C, 75.10; H, 6.36.
(2-Hydroxy-5-methoxy-4-methylphenyl)(phenyl)methanone
(13). A stirred solution of BCl3 in CH2Cl2 (1 M, 351 mL, 351 mmol) was
cooled to −15 °C, and a solution of 12 (72 g, 281 mmol) in CH2Cl2
(300 mL) was added dropwise. The resulting dark red reaction mixture
1
monitored by H NMR (CD3OD) for production of EtOH in the
organic phase. The immobilized enzyme was removed by filtration, and
the filtrate was extracted with Et2O (2 × 1.5 L). The combined ether
layers were dried over MgSO4, filtered, and concentrated to afford
unreacted ester. The aqueous phase was neutralized to pH 6.8 with 2 M
HCl and concentrated to a solid by rotovap. This material was further
dried to a constant weight in a vacuum oven at 80 °C to afford 700 g of a
white solid containing 5 (∼640 g, 4.02 mol) and NaCl (∼60 g, 1.5 mol).
This material was used without further purification: 1H NMR (D2O, 400
MHz) δ 1.86−1.58 (m, 4H), 1.30−1.17 (m, 3H), 1.13−1.03 (m, 1H),
0.82 (t, J = 7.6 Hz, 3H), 0.78 (t, J = 7.2 Hz, 3H).
(R)-2-Amino-2-ethylhexan-1-ol (6). A 1 M solution of LAH in
THF (3.24 L, 3.24 mol) was added dropwise over 2.5 h to a mechanically
stirred slurry of 5 (400 g, 2.11 mol, ∼8 wt % NaCl) in THF while the
reaction temperature was maintained at around 5 °C. Following the
addition, the reaction mixture was allowed to warm to rt over 1 h and
then slowly heated to reflux. Reflux was maintained for 3 h, and the
reaction mixture was allowed to cool to rt overnight. After the mixture
was cooled to 5 °C, water (125 mL) followed by 15% NaOH (123 mL)
and then water (369 mL) were added slowly dropwise while maintaining
an internal temperature below 13 °C. The resulting slurry was stirred for
1 h at 5 °C, and the solids were removed by filtration. Rotary evaporation
of the filtrate afforded 6 as a light yellow oil (334 g, 99% yield). This
material was used without further purification: 1H NMR (CDCl3, 400
MHz) δ 3.30 (s, 2H), 1.89 (br, 3H), 1.50−1.16 (m, 8H), 0.90 (t, J = 7.0
Hz, 3H), 0.84 (t, J = 7.6 Hz, 3H).
(R)-2-Ammonio-2-ethylhexyl sulfate (7). Chlorosulfonic acid
(254 mL, 3.79 mol) was added dropwise over 1 h to a stirred solution of
6 (500.5 g, 3.45 mol) in EtOAc (3 L). Some external cooling was applied
during the chlorosulfonic acid addition to maintain the reaction
temperature at or below 35 °C. The reaction mixture was maintained at
40 °C for 2 h and then cooled to 18 °C. Compound 7 was collected by
filtration as a white solid and dried to a constant weight in a vacuum oven
at rt (624 g, 80%): 1H NMR (D2O, 400 MHz) δ 4.02 (s, 2H), 1.72−1.56
(m, 4H), 1.32−1.18 (m, 4H), 0.88 (t, J = 7.4 Hz, 3H), 0.83 (t, J = 7.0 Hz,
3H).
(R)-3-(((3,4-Dimethoxyphenyl)thio)methyl)heptan-3-amine
(10). In a typical procedure, a stirred mixture of 7 (500 mg, 2.22 mmol),
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was allowed to warm to rt over 30 min and was then quenched by slow
addition of MeOH (300 mL) followed by 1 M HCl (300 mL). The
layers were separated, and the CH2Cl2 was washed with water, dried
over MgSO4, filtered, and concentrated to afford a yellow oil which was
triturated with heptane. The product (13) was collected by filtration as a
yellow crystalline solid (54 g, 80%): Mp 65−67 °C; 1H NMR (CDCl3,
400 MHz) δ 11.85 (s, 1H), 7.71 (dd, J = 8, 1 Hz, 2H), 7.60 (br t, J = 7.4
Hz, 1H), 7.52 (t, J = 8 Hz, 2H), 6.93 (s, 1H), 6.90 (s, 1H), 3.67 (s, 3H),
2.28 (s, 3H); 13C NMR (CDCl3, 100 MHz) δ 200.5, 157.8, 149.9, 138.2,
138.1, 131.6, 128.8, 128.2, 120.0, 116.2, 112.4, 55.6, 16.8; ES+ MS 243
(M + 1, 100); Anal. Calcd for C15H14O3: C, 74.36; H, 5.82. Found: C,
74.65; H, 5.87.
2-Benzoyl-4-methoxy-5-methylphenyl Trifluoromethane-
sulfonate (14). A solution of 13 (54 g, 223 mmol) in CH2Cl2 (400
mL) and DIEA (49 mL, 280 mmol) was cooled in an ice bath, and neat
triflic anhydride (41 mL, 245 mmol) was added dropwise. The reaction
mixture was stirred at ice-bath temperature for 1 h and then diluted with
EtOAc (400 mL). The mixture was washed with 0.1 M NaOH and twice
with 1 M HCl, dried over MgSO4, filtered, and concentrated to afford 14
as a dark amber oil (78 g, 93%): 1H NMR (CDCl3, 400 MHz) δ 7.83
(dd, J = 7.8, 1.3 Hz, 2H), 7.62 (t, J ≈ 7.5 Hz, 1H), 7.49 (t, J = 7.8 Hz, 2H),
7.16 (s, 1H), 6.96 (s, 1H), 3.84 (s, 3H), 2.32 (s, 3H); 13C NMR (CDCl3,
100 MHz) δ 192.6, 156.6, 139.4, 136.6, 133.5, 132.3, 130.3, 129.9, 128.3,
124.0, 118.3 (q, JCF = 320 Hz), 111.4, 55.7, 16.2; ES+ MS 375 (M + 1,
100); Anal. Calcd for C16H13F3O5S: C, 51.34; H, 3.50. Found: C, 51.18;
H, 3.56.
2-Benzoyl-5-(bromomethyl)-4-methoxyphenyl Trifluoro-
methanesulfonate (15). A solution of 14 (71 g, 190 mmol) in 1,2-
dichloroethane (600 mL) was charged with NBS (44g, 247 mmol) and
benzoyl peroxide (1.2 g, 4.95 mmol), and the stirred reaction mixture
was heated at reflux for 20 h. The solution was allowed to cool to rt,
washed once with 10% Na2SO3 and once with 10% NaHCO3, dried over
MgSO4, filtered, and concentrated to afford crude 15 (89 g, >100%
theoretical) as a dark amber oil which was used without purification.
This material crystallized on standing, and an analytical sample was
obtained by trituration with heptane: Mp 91−94 °C; 1H NMR (CDCl3,
400 MHz) δ 7.84 (d, J = 7.4 Hz, 2H), 7.65 (t, J = 7.4 Hz, 1H), 7.51 (t, J =
7.61 Hz, 2H), 7.39 (s, 1H), 7.04 (s, 1H), 4.55 (s, 2H), 3.92 (s, 3H); 13C
NMR (CDCl3, 100 MHz) δ 192.1, 156.2, 139.3, 136.2, 134.0, 133.4,
130.7, 130.1, 128.6, 124.5, 118.3 (q, JCF = 321 Hz), 112.7, 56.4, 26.1;
HRMS (TOF ES+) Calcd for C16H13(79Br)F3O5S: 452.9619 (M + 1).
Found: 452.9619; Anal. Calcd for C16H12BrF3O5S: C, 42.40; H, 2.67; S,
7.07. Found: C, 42.33; H, 2.54; S, 7.07.
at reflux for 18 h at which point HPLC showed 96% conversion.
Additional PMBSH (9 g, 58 mmol) was added, and reflux was continued
for 6 h. At this point, HPLC showed 98% conversion. The reaction
mixture was allowed to cool to rt and diluted with 1 M HCl (500 mL)
with rapid stirring. The mixture was filtered through Celite, and the
filtrate layers were separated. The toluene phase was washed
sequentially with 1 M HCl, 1 M NaOH, and 10% NaHCO3, then
dried over MgSO4, filtered, and partially concentrated by rotovap until
most of the toluene was removed. EtOAc (500 mL) was added, and
about one-third of the solvent was removed by rotovap until
crystallization ensued. The mixture was diluted with heptane (1 L)
and cooled in an ice bath. The product (17) was collected by filtration as
1
a pale orange solid (65 g, 82% yield): Mp 111−114 °C; H NMR
(CDCl3, 400 MHz) δ 7.71 (dd, J = 8, 1 Hz, 2H), 7.57 (t, J = 8 Hz, 1H),
7.46−7.40 (m, 3H), 7.02 (d, J = 9 Hz, 2H), 6.81 (s, 1H), 6.71 (d, J = 9
Hz, 2H), 4.07 (m, 4H), 3.89 (s, 2H), 3.81 (s, 3H), 3.76 (s, 3H), 3.24 (d,
JHP = 22 Hz, 2H), 1.29 (t, J = 7 Hz, 6H); 13C NMR (CDCl3, 100 MHz) δ
196.4, 158.4, 156.1 (d, 3JCP = 7 Hz), 142.5 (d, 5JCP = 4 Hz), 137.1, 136.5
(d, 3JCP = 6 Hz), 133.0, 129.9, 129.7, 129.0, 128.2, 124.2 (d, 4JCP = 4 Hz),
122.9 (d, 2JCP = 10 Hz), 113.4, 110.0 (d, 4JCP = 3 Hz), 61.8 (d, 2JCP = 7
Hz), 55.6, 55.0, 40.5, 26.4 (d, 1JCP = 139 Hz), 16.2 (d, 3JCP = 6 Hz); ES+
MS 515 (M + 1, 100); Anal. Calcd for C27H31O6PS: C, 63.02; H, 6.07.
Found: C, 62.77; H, 6.07.
Diethyl 4-Benzoyl-5-mercapto-2-methoxybenzyl-
phosphonate (18). Compound 17 (20 g, 38.9 mmol) was dissolved
in anisole (60 mL), and N2 was passed through the solution
continuously. Neat TFA (125 mL) was added dropwise over 15 min,
and the reaction mixture was heated at reflux for 4 h. The TFA was
removed by rotovap, and the remaining dark solution was diluted with
TBME (400 mL) and washed with water (2 × 200 mL) and then
extracted with previously degassed 2 M NaOH (4 × 75 mL). The
combined NaOH layers were washed with TBME (2 × 200 mL) and
filtered. The NaOH filtrate was cooled in an ice bath, and N2 was
bubbled through the solution continuously while acidifying with conc.
HCl (60 mL). The aqueous mixture was extracted with TBME (2 × 200
mL), and the combined TBME layers were washed with pH 7.2
phosphate buffer (2 × 200 mL), dried over MgSO4, filtered, and
concentrated to afford thiol 18 (10.5 g, 69% crude yield) as a light amber
oil which was used immediately without further purification: 1H NMR
(CDCl3, 400 MHz) δ 10.97 (br s, 1H), 7.81 (dd, J = 8.4, 1.4 Hz, 2H),
7.62 (br t, J = 7.6 Hz, 1H), 7.50 (t, J = 8.0 Hz, 2H), 7.36 (d, JHP = 3 Hz,
1H), 6.94 (s, 1H), 4.12 (dq, JHP = 8, J = 7 Hz, 4H), 3.75 (s, 3H), 3.30 (d,
JHP = 22 Hz, 2H), 1.31 (t, J = 7 Hz, 6H); ES+ MS 395 (M + 1, 100).
(R)-Diethyl 5-((2-Amino-2-ethylhexyl)thio)-4-benzoyl-2-
methoxybenzylphosphonate (19). Crude 18 (10.5 g) was dissolved
in toluene (40 mL) and degassed with N2, and the aminosulfate 7 (6.57
g, 29.1 mmol) and water (9 mL) were added. The stirred mixture was
heated to reflux, and 50% NaOH (5.5 mL, 104 mmol) was added
dropwise over 1.5 h. Reflux was maintained for 30 min following the
addition. Upon cooling to rt, the reaction mixture was extracted with
TBME (2 × 100 mL) and the combined organic layers were washed with
10% NaHCO3, dried over MgSO4, filtered, and concentrated to afford
19 as an amber oil (11.6 g, 84% yield) which was used without further
purification. An analytical sample was obtained as a light amber oil by
flash chromatography on silica gel eluting with 0 → 20% EtOH/EtOAc:
86% ee by normal phase chiral HPLC (enantiomer ratio 93:7),
Chiralpak IC column, hexane (0.1% dimethylaminoethanol)/EtOH
eluent, flow rate 1 mL/min; [α]25D = −1.16° (c = 0.9, CDCl3); 1H NMR
(CDCl3, 400 MHz) δ 7.79 (d, J = 8 Hz, 2H), 7.59 (t, J = 8 Hz, 1H), 7.54
(br d, JHP = 3 Hz, 1H), 7.46 (t, J = 8 Hz, 2H), 6.82 (s, 1H), 4.09 (m, 4H),
3.82 (s, 3H), 3.27 (d, JHP = 22 Hz, 2H), 2.81 (s, 2H), 1.37−1.17 (m, 6H),
1.30 (t, J = 7 Hz, 6H), 1.12 (m, 2H), 0.85 (t, J = 7 Hz, 3H), 0.74 (t, J = 8
Hz, 3H); 13C NMR (CDCl3, 100 MHz) δ 196.8, 156.3 (d, 3JCP = 7 Hz),
142.6 (d, 5JCP = 4 Hz), 137.3, 136.6 (d, 3JCP = 6 Hz), 133.3, 129.9, 128.5,
125.3 (d, 4JCP = 4 Hz), 123.3 (d, 2JCP = 10 Hz), 110.1 (d, 4JCP = 3 Hz),
62.0 (d, 2JCP = 6 Hz), 55.8, 54.5, 48.9, 38.4, 31.6, 26.6 (d, 1JCP = 139 Hz),
2-Benzoyl-5-((diethoxyphosphoryl)methyl)-4-methoxy-
phenyl Trifluoromethanesulfonate (16). A solution of 15 (89 g,
assumed 190 mmol) in triethyl phosphite (77 g, 463 mmol) was heated
in a 115 °C sand bath for 3 h. The solution was cooled to rt, diluted with
CH2Cl2 (100 mL), and applied to a 600 g silica gel column. Nonpolar
impurities were washed off the column with hexanes, and the eluent was
switched to EtOAc to elute 16. Desired EtOAc fractions were combined
and washed with 1 M HCl and 10% NaHCO3, dried over MgSO4,
filtered, and concentrated to afford 16 (80 g, 80% yield) as an oil which
crystallized on standing to a light orange solid: Mp 53−56 °C; 1H NMR
(CDCl3, 400 MHz) δ 7.82 (d, J = 8 Hz, 2H), 7.63 (t, J = 8 Hz, 1H), 7.49
(t, J = 8 Hz, 2H), 7.38 (d, JHP = 3 Hz, 1H), 7.02 (s, 1H), 4.10 (m, 4H),
3.86 (s, 3H), 3.31 (d, JHP = 22 Hz, 2H), 1.30 (t, J = 7 Hz, 6H); 13C NMR
(100 MHz, CDCl3) δ 192.3, 156.1 (d, 3JCP = 7 Hz), 139.3 (d, 5JCP = 4
Hz), 136.2, 133.7, 131.6 (d, 3JCP = 4 Hz), 129.9, 128.4, 125.9 (d, 2JCP
=
10 Hz), 124.8 (d, 4JCP = 5 Hz), 118.2 (q, JCF = 320 Hz), 112.1 (d,4JCP = 3
Hz), 62.1 (d, 2JCP = 7 Hz), 56.1, 26.6 (d, 1JCP = 140 Hz), 16.1 (d, 3JCP = 6
Hz); ES+ MS 511 (M + 1, 100); Anal. Calcd for C20H22F3O8PS: C,
47.06; H, 4.34. Found: C, 46.97; H, 4.44.
Diethyl 4-Benzoyl-2-methoxy-5-((4-methoxybenzyl)thio)-
benzylphosphonate (17). A round-bottom flask equipped with an
overhead stirrer and reflux condenser was charged with 16 (78.8 g, 154
mmol) and toluene, and the stirred solution was degassed with N2 for 5
min and then charged with Xantphos (8.93 g, 15.44 mmol) and
Pd2(dba3) (7.1 g, 7.75 mmol). Degassing was continued for 5 min. 4-
Methoxybenzyl mercaptan (PMBSH) (30 g, 195 mmol) was added, and
the dark solution was degassed 5 min. The reaction mixture was heated
3
25.6, 23.2, 16.4 (d, JCP = 7 Hz), 14.0, 7.9; ES+ MS 521 (M+1, 100);
Anal. Calcd for C27H40NO5PS: C, 62.17; H, 7.73; N, 2.69. Found: C,
62.22; H, 8.04; N, 3.08.
G
dx.doi.org/10.1021/jo402311e | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
(R)-Diethyl ((3-Butyl-3-ethyl-7-methoxy-5-phenyl-2,3-
dihydrobenzo[f ][1,4]thiazepin-8-yl)methyl)phosphonate (20).
To a solution of 19 (11 g, 21.09 mmol) in toluene (200 mL) was added
citric acid (600 mg, 2.08 mmol), and the stirred solution was heated at
reflux for 7 h; during the course of the reaction, water was azeotropically
removed with the aid of a Dean−Stark trap. The reaction was allowed to
cool to rt, diluted with EtOAc (100 mL), and washed with 1:1 10%
NaHCO3/brine. The aqueous phase was backextracted with EtOAc
(100 mL), and the combined organic layers were dried over MgSO4,
filtered, and concentrated to afford an amber oil. This material was
dissolved in hot heptane (500 mL) and filtered hot to remove some
insoluble material. The filtrate was concentrated to about 100 mL, and
the resulting slurry was stirred at ice-bath temperature for 3 h; the
product (20) was collected by filtration as a white solid (5.8 g). The
filtrate was concentrated, and the resulting material was purified by flash
chromatography on silica gel eluting with 0−25% EtOAc/CH2Cl2 to
direct injection HPLC to determine conversion and % de. An RRHT
XDB C-18 4.6 mm × 50 mm 1.8 μm column was employed under the
following conditions: 34→90% CH3CN/water with 0.05% TFA; 5 min
run; 4.5 mL/min; 60 °C. Compound 27 eluted at 3.6 min, and the
desired trans-product (28) eluted at 3.8 min. Starting material (22)
eluted at 3.9 min. The results of these experiments are shown in Table 1.
(3R,5R)-8-Bromo-3-butyl-3-ethyl-7-methoxy-5-phenyl-
2,3,4,5-tetrahydrobenzo[f ][1,4]thiazepine (28). A 1 M solution of
BH3·THF (23 mL, 23 mmol) was added dropwise to a stirred solution of
22 (4.86 g, 11.24 mmol) in THF (25 mL) at rt. The reaction mixture was
stirred for 3 h and then cooled to −15 °C and quenched by dropwise
addition of MeOH (60 mL). The cold mixture was stirred for 15 min
and then warmed to rt and concentrated by rotovap to afford an ∼1:1
mixture of diastereomers 27 and 28 (4.9 g, 100% yield). An analytical
sample of the desired diastereomer (28) was obtained by flash
chromatography on silica gel eluting with 0−3% EtOAc/heptane
(compound 27 elutes after 28) and was obtained as a colorless oil (100
mg, 230 μmol): 1H NMR (CDCl3, 400 MHz) δ 7.77 (s, 1H), 7.46−7.35
(m, 4H), 7.30 (t, J = 7 Hz, 1H), 6.11 (s, 1H), 5.74 (s, 1H), 3.51 (s, 3H),
2.77 (d, J = 14 Hz, 1H), 2.50 (d, J = 14 Hz, 1H), 2.11−2.00 (m, 1H),
1.71−1.60 (m, 1H), 1.46−1.38 (m, 2H), 1.35−1.25 (m, 23H), 1.19−
1.09 (m, 2H), 0.88 (t, J = 8 Hz, 3H), 0.85 (t, J = 7 Hz, 3H); 13C NMR
(CDCl3, 100 MHz) δ 155.2, 151.1, 143.6, 136.7, 129.0, 128.2, 127.6,
126.9, 111.8, 108.4, 57.4, 56.6, 55.8, 43.4, 33.3, 31.2, 25.0, 23.2, 14.1, 7.7;
HRMS (TOF ES+) C22H29(79Br)NOS calcd 434.1153, found 434.1153.
Diethyl (((3R,5R)-3-Butyl-3-ethyl-7-methoxy-5-phenyl-
2,3,4,5-tetrahydrobenzo[f ][1,4]-thiazepin-8-yl)methyl)phos-
phonate (30). A mechanically stirred solution of 20 (1 g, 1.99 mmol),
[Ir(COD)2BArF] (26) (100 mg, 79 μmol), and Taniaphos ligand Z
(Table 1) (60 mg, 84 μmol) in CH2Cl2 (35 mL) was hydrogenated at 25
°C and 30 bar (gauge) H2 for 2 h (100% conversion, 80% de). The
solution was concentrated, and the crude material was purified by flash
chromatography on silica gel eluting with 0→30% EtOAc/CH2Cl2 to
afford 30 as an off-white solid (850 mg, 85% yield). Performing this
afford an additional 1.2 g of 20 (combined yield = 7 g, 66% yield): Mp
1
87−89 °C; [α]25 = +6.05° (c = 1.62, CDCl3); H NMR (d6-DMSO,
D
400 MHz) δ 7.50−7.35 (m, 6H), 6.64 (s, 1H), 3.95 (m, 4H), 3.62 (s,
3H), 3.23 (br d, JHP ≈ 20 Hz, 2H), 3.20 (s, 2H), 1.60 (m, 1H), 1.50 (m,
1H), 1.47−1.18 (m, 4H), 1.14 (t, J = 7 Hz, 3H), 1.16 (t, J = 7 Hz, 3H)
1.14−1.03 (m, 2H), 0.84 (t, J = 7 Hz, 3H), 0.79 (t, J = 7 Hz, 3H); 13C
NMR (CDCl3, 100 MHz) δ 163.7, 156.6 (d, 3JCP = 7 Hz), 142.4, 140.8
(d, 5JCP = 4 Hz), 135.0 (d, 3JCP = 6 Hz), 129.3, 128.8, 127.7, 127.6, 121.9
(d, 2JCP = 10 Hz), 112.7 (d, 4JCP = 3 Hz), 63.7, 61.9 (d, 2JCP = 7 Hz), 55.7,
48.9, 39.5, 33.1, 26.5 (d, 1JCP = 140 Hz), 25.9, 23.1, 16.2 (d, 3JCP = 6 Hz),
14.0, 8.4; ES+ MS 504 (M + 1, 100); Anal. Calcd for C27H38NO4PS: C,
64.39; H, 7.60; N, 2.78. Found: C, 64.55; H, 7.57; N, 2.81.
(R)-8-Bromo-3-butyl-3-ethyl-7-methoxy-5-phenyl-2,3-
dihydrobenzo[f ][1,4]thiazepine (22). Powdered KOH (54.2 g, 966
mmol) was added to a stirred suspension of 238 (136 g, 322 mmol) in
EtOH (1 L) at rt. The reaction mixture was heated at reflux for 3 h and
then cooled to rt overnight. Most of the volatiles were removed by
rotovap, and the remaining material was diluted with water (1.5 L) and
extracted with Et2O. The aqueous phase was acidified with 2 M HCl and
extracted with TBME. The organic layer was dried over MgSO4, filtered,
and concentrated to afford 24 (89.5 g, 86% crude yield) as a dark oil.
This material was dissolved in toluene, a solution of 7 (56.7 g, 252
mmol) in water (440 mL) was added, and the biphasic mixture was
heated to reflux. A solution NaOH (6.25 M, 160 mL, 1 mol) was added
dropwise over 2 h. Reflux was maintained for an additional 3 h following
the NaOH addition. The reaction mixture was allowed to cool to rt and
stirred overnight. The layers were separated, and the toluene phase was
washed with 1 M NaOH, dried over MgSO4, filtered, and concentrated
by rotovap to afford 25 as an oil. This material was dissolved in Et2O
(300 mL), and 1 M HCl (450 mL, 450 mmol) was added dropwise over
2 h with stirring. The slurry was stirred overnight, and the product (25·
HCl) was collected by filtration as a tan solid (98.9 g, 81% yield). A 1 M
solution of NaOH (300 mL, 300 mmol) was added dropwise to a stirred
solution of 25·HCl (114.7 g, 236 mmol) in toluene (1.1 L), and the
mixture was stirred for 15 min. The layers were separated, citric acid
(905 mg, 4.71 mmol) was added to the toluene phase, and the reaction
mixture was heated at reflux for 20 h under Dean−Stark conditions.
After cooling to rt, the mixture was washed with satd. NaHCO3 solution,
dried, and concentrated to afford 22 as a viscous oil (91 g, 63% overall
yield from 23): 1H NMR (CDCl3, 400 MHz) δ 7.80 (s, 1H), 7.54 (br d, J
= 8 Hz, 2H), 7.42−7.31 (m, 3H), 6.60 (s, 1H), 3.71 (s, 3H), 3.22 (s,
2H), 1.70−1.59 (m, 2H), 1.60−1.50 (m, 2H), 1.35−1.17 (m, 4H), 0.89
(t, J = 7.3 Hz, 3H), 0.86 (t, J = 7.0 Hz, 3H); 13C NMR (CDCl3, 100
MHz) δ 163.0, 155.3, 142.4, 141.2, 136.7, 129.6, 129.5, 128.8, 127.8,
113.8, 112.2, 64.0, 56.4, 49.0, 39.9, 33.2, 26.0, 23.2, 14.1, 8.4; ES+ MS 432
(M + 1, 100), 434 (M + 1, 100); Anal. Calcd for C22H26BrNOS: C,
61.11; H, 6.06; N, 3.24. Found: C, 61.52; H, 6.11; N, 3.14.
reaction at 4 bar (gauge) H2 for 24 h effected 95% conversion with 80%
1
de: Mp 88−91 °C; [α]25 = −37.3° (c = 1.34, CDCl3); H NMR
D
(CDCl3, 400 MHz) δ 7.51 (d, J = 3 Hz, 1H), 7.45−7.34 (m, 4H), 7.29
(m, 1H), 6.06 (s, 1H), 5.74 (s, 1H), 4.04 (m, 4H), 3.45 (s, 3H), 3.17 (dd,
J = 20 Hz, JHP = 15 Hz, 1H), 3.11 (dd, J = 20 Hz, JHP = 15 Hz, 1H), 2.76
(d, J = 14 Hz, 1H), 2.47 (d, J = 14 Hz, 1H), 2.11−1.99 (m, 1H), 1.70−
1.60 (m, 2H), 1.44−1.36 (m, 2H), 1.34−1.24 (m, 2H), 1.27 (t, J = 7 Hz,
3H), 1.26 (t, J = 7 Hz, 3H), 1.18−1.10 (m, 2H), 0.87 (t, J = 7 Hz, 3H);
0.85 (t, J = 7 Hz, 3H); 13C NMR (CDCl3, 100 MHz) 156.3 (d, 3JCP = 7
Hz), 150.4, 143.8, 135.1 (d, 3JCP = 6 Hz), 127.9, 127.5, 127.0 (d, 4JCP = 4
Hz), 126.5, 117.8 (d, 2JCP = 10 Hz), 110.4 (d, 4JCP = 3 Hz), 61.6 (d, 2JCP
=
7 Hz), 56.4, 54.9, 43.2, 33.1, 30.9, 25.9 (d, 1JCP = 139 Hz), 24.8, 23.0,
16.1 (d, 3JCP = 7 Hz), 13.9, 7.6; MS (ES+) 506 (M + 1, 100); Anal. Calcd
for C27H40NO4PS: C, 64.13; H, 7.97; N, 2.77. Found: C, 63.84; H, 7.82;
N, 2.76.
Diethyl (((3R,5R)-3-Butyl-3-ethyl-7-methoxy-1,1-dioxido-5-
phenyl-2,3,4,5-tetrahydrobenzo[f ][1,4]thiazepin-8-yl)methyl)-
phosphonate (31). A solution of 30 (0.5 g, 989 μmol) in TFA (2 mL)
was cooled to −20 °C, and 30% H2O2 (1.5 mL) was added dropwise.
The reaction mixture was stirred at −15 to −20 °C for 3.75 h and at rt for
3 h. The reaction mixture was then stored at 15 °C for 3 d. The mixture
was partitioned between EtOAc (30 mL) and water (30 mL), and the
layers were separated. The organic phase was washed with 1 N NaOH
(40 mL), and the combined aqueous phases were back extracted with
EtOAc. The combined organic layers were washed with 10% Na2SO3,
dried over MgSO4, filtered, and concentrated to an oil which was
triturated with heptane. The resulting off-white solid (31) was collected
by filtration (421 mg, 79% yield): Mp 122−125 °C; [α]25D = −7.9° (c =
1.24, CDCl3); 1H NMR (CDCl3, 400 MHz) δ 8.00 (br d, JHP = 2.7 Hz,
1H), 7.45−7.37 (m, 4H), 7.36−7.30 (m, 1H), 6.16 (s, 1H), 6.06 (s, 1H),
4.08 (m, 4H), 3.53 (s, 3H), 3.43 (d, J = 15 Hz, 1H), 3.20 (d, JHP = 21.8
Hz, 2H), 3.01 (d, J = 15 Hz, 1H), 2.18 (br m, 1H), 1.86 (br m, 1H), 1.52
(m, 1H), 1.46 (m, 1H), 1.36−1.05 (m, 4H), 1.30 (t, J = 7 Hz, 3H), 1.29
(t, J = 7 Hz, 3H), 0.90 (t, J = 7.4 Hz, 3H), 0.83 (t, J = 7.2, 3H); 13C NMR
Screening Conditions for Asymmetric Hydrogenation of 22.
Iridium catalysts were made in situ by mixing 1.1 equiv of chiral bidentate
phosphine or 2.2 equiv of a chiral monodentate ligand (A−Z, Table 1)
with Ir(COD)2BArF (26) followed by addition of 22 (30 mg, 69 μmol)
and CH2Cl2 (500 μL) (using a Flexiweigh dispensing robot). Reactions
were performed in parallel using 2.5 mol % of preformed catalyst at 25
°C, 30 bar (gauge) H2 for 16 h. The reaction mixtures were analyzed by
3
5
(CDCl3, 100 MHz) δ 160.3 (d, JCP = 6 Hz), 146.4 (d, JCP = 4 Hz),
141.6, 131.4 (d, 4JCP = 3 Hz), 130.7 (d, 3JCP = 5 Hz), 128.2, 127.6, 127.2,
H
dx.doi.org/10.1021/jo402311e | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
118.9 (d, 2JCP = 8 Hz), 110.5 (d, 4JCP = 3 Hz), 63.6, 61.9 (d, 2JCP = 7 Hz),
61.8 (d, 2JCP = 7 Hz), 57.1, 55.3, 55.1, 33.9, 30.8, 26.1 (d, 1JCP = 140 Hz),
25.0, 22.7, 16.1 (d, 3JCP = 7 Hz), 13.8, 7.4; MS (ES+) 538 (M + 1, 100);
Anal. Calcd for C27H40NO6PS·(0.5 H2O): C, 59.32; H, 7.56; N, 2.56; S,
5.87. Found: C, 59.43; H, 7.51; N, 2.58; S, 5.77.
McIntyre, M. S.; Merrill, C. L.; Patterson, K. M.; Prescott, J. S.; Ray, J. A.;
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Jones, C.; Koeller, K. J.; Kolodziej, S. A.; Li, J.; Manning, R. E.; Mahoney,
M. W.; Miller, R. E.; Mischke, D. A.; Rath, N. P.; Fletcher, T.; Reinhard,
E. J.; Tollefson, M. B.; Vernier, W. F.; Wagner, G. M.; Rapp, S. R.;
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J.; Huang, W.; Jones, C.; Koeller, K. J.; Kolodziej, S. A.; Li, J.; Manning,
R. E.; Mahoney, M. W.; Miller, R. E.; Mischke, D. A.; Rath, N. P.;
Reinhard, E. J.; Tollefson, M. B.; Vernier, W. F.; Wagner, G. M.; Rapp, S.
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(((3R,5R)-3-Butyl-3-ethyl-7-methoxy-1,1-dioxido-5-phenyl-
2,3,4,5-tetrahydrobenzo[f ][1,4]thiazepin-8-yl)methyl)phos-
phonic Acid Hydrochloride (3·HCl). A solution of 31 (62 mg, 115
μmol) in 6 M HCl (2 mL) was heated at 120 °C in a sealed tube for 20 h.
The solution was concentrated by rotovap to afford 3·HCl as an
amorphous off-white solid (58 mg, 97% yield): [α]25 = +47.6° (c =
D
1.56, CH3OH); 1H NMR (CD3OD, 400 MHz) δ 8.15 (br d, J = 2 Hz,
1H), 7.71−7.60 (m, 4H), 6.62 (s, 1H), 6.54 (s, 1H), 4.04 (d, J = 16 Hz,
1H), 3.64 (s, 3H), 3.57 (d, J = 16 Hz, 1H), 3.30−3.15 (m, 2H), 2.88 (m,
1H), 2.23−2.12 (m, 2H), 1.72 (m, 1H), 1.52−1.41 (m, 3H), 1.03 (t, J =
7 Hz, 3H), 0.95 (t, J = 7 Hz, 3H); 13C NMR (CD3OD, 100 MHz) δ
162.8, 135.1, 134.6, 132.7, 132.2, 131.8, 131.0, 130.8, 125.3, 115.2, 66.7,
59.5, 59.4, 56.8, 31.8, 30.0, 28.9 (d, 1JCP = 138 Hz), 26.0, 23.8, 14.3, 8.3;
MS (ES+) 482 (M + 1, 100); HRMS (TOF ES+) C23H33NO6PS calcd
482.1766, found 482.1767; Anal. Calcd for C23H32NO6PS·(HCl)·(0.5
H2O): C, 52.42; H, 6.50; N, 2.66; S, 6.08. Found: C, 52.48; H, 6.90; N,
2.60; S, 5.80.
(13) Root, C.; Smith, C. D.; Sundseth, S. S.; Pink, H. M.; Wilson, J. G.;
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(14) Liu, W.; Ray, P.; Benezra, S. A. J. Chem. Soc., Perkin Trans. 1 1995,
553−559.
ASSOCIATED CONTENT
* Supporting Information
■
S
(15) Mateo, C.; Abian, O.; Fernan
Fernan
634.
́
dez-Lorente, G.; Pedroche, J.;
́
dez-Lafuente, R.; Guisan, J. M. Biotechnol. Prog. 2002, 18, 629−
NMR Spectra for compounds 3, 5−7, ( )-10, 14−20, 22, 28,
30−31 and X-ray crystal structure data for compound 31. This
material is available free of charge via the Internet at http://pubs.
acs.org.
(16) Hilterhaus, L.; Minow, B.; Muller, J.; Berheide, M.; Quitmann, H.;
̈
Katzer, M.; Thum, O.; Antranikian, G.; Zeng, A. P.; Liese, A. Bioprocess
Biosyst. Eng. 2008, 31, 163−171.
(17) Percent loading and reuse of Sepabead PLE were not evaluated.
(18) Li, X.; Chen, N.; Xu, J. Synthesis 2010, 3423−3428.
(19) Buckley, B. R.; Patel, A. P.; Wijayantha, K. G. U. J. Org. Chem.
2013, 78, 1289−1292.
AUTHOR INFORMATION
Corresponding Author
*E-mail: eric.e.boros@gsk.com.
Notes
■
(20) Bhattacharya, A. K.; Thyagarajan, G. Chem. Rev. 1981, 81, 415−
430.
The authors declare no competing financial interest.
(21) Nagaoka, H.; Schmid, G.; Iio, H.; Kishi, Y. Tetrahedron Lett. 1981,
22, 899−902.
ACKNOWLEDGMENTS
■
(22) Itoh, T.; Mase, T. Org. Lett. 2004, 6, 4587−4590.
(23) For the synthesis of aminomercaptan 23 (R = R′ = Me), see: Wu,
W. L.; Burnett, D. A.; Greenlee, W. J. Pyranochromene Derivatives as γ-
Secretase Inhibitors and Their Preparation and Use for the Treatment of
Neurodegenerative Diseases, International Patent WO 2012/138678
A1, 2012; Chem. Abstr. 2012, 157, 577330.
The authors thank Professor Scott E. Denmark (Department of
Chemistry, University of Illinois) for helpful discussions during
the course of this work. We also thank Douglas J. Minick,
Timothy D. Spitzer, Eric S. Wentz, and Yang Zhao for their
analytical support.
(24) During the course of this work a (3-amino)pentanedioic acid
analog of 3 (GSK2330672) was selected as a suitable clinical candidate.9
(25) Uematsu, N.; Fujii, A.; Hashiguchi, S.; Ikariya, T.; Noyori, R. J.
Am. Chem. Soc. 1996, 118, 4916−4917.
(26) Cobley, C. J.; Henschke, J. P. Adv. Synth. Catal. 2003, 345, 195−
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(27) Imamoto, T.; Iwadate, N.; Yoshida, K. Org. Lett. 2006, 8, 2289−
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(28) Tappe, K.; Knochel, P. Tetrahedron: Asymmetry 2004, 15, 91−
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