Expedient Synthesis of Furo[2,3-d][1,3]thiazinamines and Pyrano[2,3-d][1,3]thiazinamines from Enones and Thiourea

Article abstract of DOI:10.1021/acs.joc.5b02705

Michael addition of thiourea to enones with subsequent intramolecular aminal ether formation provided easy access to furo[2,3-d]thiazinamines and pyrano[2,3-d][1,3]thiazin-2-amines. These amines served as versatile intermediates to a variety of beta-amyloid cleaving enzyme-1 (BACE1) inhibitors.

Full text of DOI:10.1021/acs.joc.5b02705

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Note
An Expedient Synthesis of Furo[2,3-d][1,3]thiazinamines and
Pyrano[2,3-d][1,3]thiazinamines from Enones and Thiourea
Yong-Jin Wu, Jason Guernon, Hyunsoo Park, and Lorin A. Thompson
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.5b02705 • Publication Date (Web): 22 Mar 2016
Downloaded from http://pubs.acs.org on March 23, 2016
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An Expedient Synthesis of Furo[2,3-d][1,3]thiazinamines and Pyrano[2,3-d][1,3]thiazinamines from
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Enones and Thiourea
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YongꢀJin Wu,* Jason Guernon, Hyunsoo Park, Lorin A. Thompson
Research and Development, Bristol-Myers Squibb Company, 5 Research Parkway, Wallingford, CT 06492, USA
RECEIVED DATE (will be automatically inserted after manuscript is accepted).
ABSTRACT: Michael addition of thiourea to enones with subsequent intramolecular aminal ether formation provided easy
access to furo[2,3ꢀd]thiazinamines and pyrano[2,3ꢀd][1,3]thiazinꢀ2ꢀamines. These amines served as versatile intermediates
to a variety of betaꢀamyloid cleaving enzymeꢀ1 (BACE1) inhibitors.
There is substantial evidence to suggest that βꢀamyloid (Aβ) peptide, particularly the longer 42 amino acid form, Aβ42, plays a
critical role in the progression of Alzheimer’s disease (AD).1ꢀ4 Aβ is derived from the βꢀamyloid precursor protein (APP) by
proteolysis. Cleavage of APP by βꢀsite APP cleaving enzymeꢀ1 (BACE1) results in shedding of the APP ectodomain, and the
remaining membrane bound Cꢀterminal fragment, C99, is further processed by γꢀsecretase to produce Aβ. Thus, inhibition of
BACE1 to reduce Aβ production is a promising approach to test the amyloid hypothesis.5ꢀ7 Recently, scientists from Eli Lilly
reported the discovery of tetrahydroꢀ4Hꢀfuro[3,4ꢀd][1,3]thiazinꢀ2ꢀamine 1 (LY2886721, Figure 1), a potent BACE1 inhibitor that
reached phase II clinical trials in mild congitive impairmente.8 The fused bicyclic ring system was constructed through a stepswise
process: intramolecular nitrile oxideꢀolefin cycloaddition to form the furan ring and intramolecular Mitsunobu reaction of the Nꢀ
benzoylthiourea intermediate 5 to form the 6ꢀmembered thiazinamine ring (Scheme 1).9 As part of our continuous efforts in the
discovery of BACE1 inhibitors, we sought to design close analogs of 1 where the fused bicyclic ring system can be assembled more
efficiently in one single operation. An Xꢀray coꢀcrystal structure of 1 bound in the BACE1 active site indicates no particular
interaction with the furan oxygen,8 and therefore relocation of the furan oxygen to the adjacient position as shown in 2 (Figure 1)
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would be expected to have marginal impact on activity. Retrosynthetically, the furo[2,3ꢀd]thiazinamine intermediates 7a/b could
be assembled from 4ꢀhydroxybutyl carbamimidothioate ketones 8a/b via an intramolecular aminal ether formation. Compounds
8a/b can be visualized from the Michael addition of enones 9a/b with thiourea (Scheme 2). This report describes our endeavors in
this area.
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Figure 1. Structures of BACEꢀ1 inhibitors
Scheme 1. Synthesis of furo[3,4ꢀd][1,3]thiazinꢀ2ꢀamine 1
Scheme 2. Retroynthesis of furo[2,3-d][1,3]thiazinamine 2
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Our synthesis started with vinyl bromide 1010 which was readily prepared from commercially availble 3ꢀbromobutꢀ3ꢀenꢀ1ꢀol
under standard silylation conditions (Scheme 3). Lithiumꢀhalogen exchange of 10 with tertꢀbutyllithium provided the vinyl lithium
reagent which was added to 2ꢀfluoroꢀ5ꢀnitrobenzaldehyde to furnish allylic alcohol 11 in 31% yield. This alcohol was converted to
enone 9a by Swern oxidation or upon treatment with manganese dioxide. This enone was treated with thiourea in acetic acid at
room temperature. LCMS analysis of the crude product using TFA as a solvent modifier showed clean conversion, while a similar
analysis using a mildly basic ammonium acetate modifier showed evidence of instability through retroꢀMichael addition. Efforts to
purify the Michael adduct 12 by either silica gel chromatograhy or recrystallization failed again due to retroꢀMichael addition. For
this reason, the crude reaction mixture in acetic acid was treated with tetrabutylammonium fluoride (TBAF). As the deprotection
was somewhat sluggish at room temperature, the reaction mixture was then warmed to 70 ºC, and the tertꢀbutylsilyl ether was
cleaved within 10 min. Heating this crude reaction mixture at 70 ºC for 10 h resulted in smooth ring closure to 7a as shown by
LC/MS analysis. For our medicinal chemistry program, we desired to have enantiomerically pure intermediates. Thus, we
attempted preparative chiral HPLC separation of racemic 7a without success. Therefore, the crude 7a was subjected to Boc
protection to give (±)ꢀ13. Chiral supercritical fluid chromatography (SFC) on (±)ꢀ13 gave (R,R)ꢀ13 and (S,S)ꢀ13 in 14% and 19%
yield, respectively from 9a on a 11 g scale. Assuming an 85% yield for the Boc protection reaction, the threeꢀstep, oneꢀpot process
proceeds in 40% yield. This throughput was more than sufficient for analoging. The absolute configurations of both enantiomers
were confirmed by singleꢀcrystal Xꢀray diffraction analysis (Figure 2).11
Scheme 3. Synthesis of furo[2,3-d][1,3]thiazinamine 7a
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OTBS
OTBS
t-BuLi, -78 °C;
2-fluoro-5-nitro-
benzaldehyde
(COCl)2,
DMSO;
Et3N, 80%
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HO
OTBS
O
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F
or MnO2
82%
F
31%
Br
O2N
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O2N
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9a
OTBS
O
OH
TBAF,
70 °C
thiourea,
HOAc
S
NH
O
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NH
NH2
F
NH2
F
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O2N
8a
12
H
H
S
S
Boc2O,
NaHCO3
O
O
H2N
BocHN
N
N
F
F
chiral
HPLC
O2N
O2N
7a
(R,R)-13
9a
)
(14% from
(S,S)-13 (19% from 9a)
Figure 2. Thermal ellipsoid plots (50% ellipsoids) of (S,S)ꢀ13 (left) and (R,R)ꢀ13 (right).
Enone 9b was converted to the bicyclic compound 7b in the same fashion as 9a was converted to 7a (Scheme 4). In this case, we
were able to carry out preparative chiral HPLC separation of (±)ꢀ7b, and the two enantiomers of 7b were obtained independently in
a combined yield of 48%.
Scheme 4. Synthesis of furo[2,3-d][1,3]thiazinamine 7b
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In order to probe the impact of the fluorine substitution on both BACE1 inhibitory activity and pharmaceutical properties, we
also prepared furo[2,3ꢀd]thiazinamines with fluorine substitution of the phenyl ring at the para position (15) from enone 14
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(Scheme 5). This reaction was run only once, and the yield shown was not optimized.
Scheme 5. Synthesis of furo[2,3-d][1,3]thiazinamines 15
This methodology was extended to the synthesis of pyrano[2,3ꢀd][1,3]thiazinꢀ2ꢀamines. For example, treatment of enone 16 with
thiourea followed by TBAF and heating under typical conditiones provided a single fused bicyclic compound 17 in 33% yield. The
cisꢀfused stereochemistry was assigned based on the nOe effect observed between the angular hydrogen and the hydrogen attached
to the difluorophenyl ring (Scheme 6). More studies are required to understand the high stereoselectivity observed in the
intramolecular aminal ether formation.
Scheme 6. Synthesis of pyrano[2,3ꢀd][1,3]thiazinamine 17
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In summary, we have developed an operationally simple threeꢀstep, one pot procedure for the synthesis of furo[2,3-
d][1,3]thiazinamines and pyrano[2,3ꢀd][1,3]thiazinamines. These amines were incorporated into a variety of BACE1 inhibitors,
and the biological data for these compounds will be reported in due course.
EXPERIMENTAL SECTION
General. All nonꢀaqueous reactions were carried out under an argon or nitrogen atmosphere at room temperature, unless
otherwise noted. All commercial reagents and anhydrous solvents were purchased from commercial sources and were used without
further purification or distillation, unless otherwise stated. Analytical thin layer chromatography (tlc) was performed on silica gel
60 F254 (0.25 mm). Compounds were visualized by UV light and/or stained with either pꢀanisaldehyde, potassium permanganate,
or cerium molybdate solutions followed by heating. Flash column chromatography was performed using SiO2 columns of the
appropriate sizes, with gradients of solvents as indicated. Analytical high pressure liquid chromatography (HPLC) and LCꢀMS
analyses were conducted using a single piston pump and a UVꢀvis detector set at 220 nm or 254 nm with MS detection performed
with a LC spectrometer. Chiral LC/Analytical SFC conditions: Column: LuxꢀCelluloseꢀ2 (0.46 x 25cm), Mobile phase: 10%
methanol in CO2, Flow rate: 3 mL/min, wavelength: 220 nm; Temp.: 35 °C. Preparative SFC chromatography: LuxꢀCelluloseꢀ2 (3
x 25cm), 8% methanol in CO2, 140 mL/min at 220 nm and 35°C; Sample in methanol, conc. = 70 mg/mL, Stack injection: 0.5
mL/9.2min. Fractions containing product were concentrated, and dried overnight under vacuum to provide desired compounds.
High resolution mass spectrometry (HRMS) analyses were performed on a Fourier Transform Orbitrap mass spectrometer in
positive or negative electrospray ionization mode (ESI) operating at 100,000 resolution (full width at half height maximum,
FWHM). The instrument was daily calibrated according to manufacturer's specifications resulting in mass accuracy of or better than
5 ppm. NMR (1H and 13C) spectra were recorded on 500 MHz or 400 MHz spectrometers and calibrated using an internal
reference.
(3-Bromobut-3-enyloxy)(tert-butyl)dimethylsilane (10).10 To a solution of 3ꢀbromobutꢀ3ꢀenꢀ1ꢀol (5.2 g, 34.4 mmol) in
dichloromethane (69 mL) at rt was added tertꢀbutyldimethylsilyl trifluoromethanesulfonate (10 g. 37.9 mmol) and Hunig's base
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(7.22 mL, 41.3 mmol), and the mixture was stirred at rt for 30 min. Water was added, the aqueous layer was extracted with
dichloromethane (x3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and then
filtered. The filtrate was evaporated in vacuo, and the resulting crude product was purified by silica gel chromatography eluting
with 5ꢀ30% ethyl acetate/hexanes to give 10 as a colorless liquid (8.72 g, 95%). 1H NMR (400 MHz, CDCl3): δ 5.66 (1H, s), 5.48
(1H, s), 3.81 (2H, t, J = 6.0 Hz), 2.64 (2H, t, J = 6.0 Hz), 0.91 (9H, s), and 0.09 (6H, s).
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4-(tert-Butyldimethylsilyloxy)-1-(2-fluoro-5-nitrophenyl)-2-methylenebutan-1-ol (11). To a solution of 10 (3.14 g, 11.83
mmol) in THF (10 mL) at ꢀ78 °C was added tertꢀbutyllithium (14.8 mL, 23.7 mmol, 1.7 M solution in hexanes) dropwise over a
period of 5 min, and the reaction mixture was stirred at ꢀ78 °C for 10 min. The resulting lithium reagent was added dropwise to a
solution of 2ꢀfluoroꢀ5ꢀnitrobenzaldehyde (2 g, 11.8 mmol) in THF (10 mL) at ꢀ78 °C, and the reaction mixture was stirred at ꢀ78 °C
for 30 min. Water was added, the aqueous layer was extracted with ethyl acetate (x3). The combined organic layers were washed
with brine, dried over anhydrous sodium sulfate, and then filtered. The filtrate was evaporated in vacuo, and the resulting crude
product was purified by silica gel chromatography eluting with 0ꢀ25% ethyl acetate//hexanes to give 11 as a colorless oil (1.3 g,
31% yield). 1H NMR (500 MHz, CDCl3): δ 8.57 (1H, m), 8.18 (1H, m), 7.15 (1H, m), 5.52 (1H, br. s), 5.16 (1H, s), 5.09 (1H, s),
4.96 (1H, m), 3.7ꢀ3.9 (2H, m), 2.20ꢀ2.35 (2H, m), 0.97 (9H, s), 0.17 (3H) and 0.15 (3H, s). 13C NMR (125 MHz, CDCl3): δ
(attached protons) ꢀ5.5 (2C, 3), 18.4 (0), 25.9 (3C, 3), 34.6 (2), 64.7 (2), 70.5 (1), 116.1 (1) (d, J = 25.1 Hz). 116.2 (2), 124.3 (1) (d,
J = 7.5 Hz), 124.5 (1) (d, J = 10.1 Hz), 132.7 (0) (d, J = 14.7 Hz), 144.4 (0), 147.2 (0), and 163.3 (0) (d, J = 258.3 Hz). LCMS m/z:
338.2 (M + H)+. HRMS m/z (ESI) calcd for C17H25O3NFSi (M + H – H2O)+ 338.1587, found 338.1582.
4-(tert-Butyldimethylsilyloxy)-1-(2-fluoro-5-nitrophenyl)-2-methylenebutan-1-one (9a). Method 1: To a solution of oxalyl
chloride (1.1 mL, 12.7 mmol) in DCM (30 mL) at ꢀ78°C was added DMSO (0.9 mL, 12.7 mmol), and the reaction mixture was
stirred at ꢀ78°C for 20 min. A solution of 11 (3 g, 8.4 mmol) in DCM (30 mL) was added, and the reaction mixture was stirred at
ꢀ78°C for 20 min. Triethylamine (5.9 mL, 42.2 mmol) was added, and the reaction mixture was warmed up to RT and stirred at RT
for 30 min. Water was added and the aqueous layer was extracted with ethyl acetate (x3). The combined organic layers were
washed with brine, dried over anhydrous sodium sulfate, and filtered, and the filtrate was evaporated in vacuo to give the crude
product. The crude product was purified by silica gel chromatography eluting with 0ꢀ10% ethyl acetate/hexanes to give 9a (2.4 g,
80%). Method 2: To a solution of 11 (0.94 g, 2.64 mmol) in chloroform (88 mL) was added manganese dioxide (3.45 g, 39.7
mmol), and the reaction mixture was heated under reflux for 24 h. The reaction mixture was filtered through a pad of Celite, and
the filtrate was evaporated in vacuo. The residue was purified by silica gel chromatography eluting with 5ꢀ10% ethyl
acetate/hexanes to give 9a as a colorless oil (0.77 g, 82% yield). 1H NMR (500 MHz, CDCl3): δ 8.35 (1H, m), 7.35 (1H, m), 6.18
(1H, s), 5.76 (1H, s), 3.83 (2H, t, J = 6.0 Hz), 2.72 (2H, t, J = 6.0 Hz), 0.90 (9H, s), and 0.08 (6H, s). 13C NMR (125 MHz,
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CDCl3): δ (attached protons) ꢀ5.4 (2C, 3), 18.3 (0), 25.9 (3C, 3), 34.2 (2), 61.4 (2), 117.4 (1) (d, J = 24.4 Hz), 126.2 (1) (d, J = 5.3
Hz), 127.7 (1) (d, J = 10.3 Hz), 128.3 (0) (d, J = 18.0 Hz), 131.7 (2), 143.9 (0), 145.8 (0), 162.5 (0) (d, J = 262.6 Hz), 192.1 (0).
HRMS m/z (ESI) calcd for C17H25O4NFSi (M + H)+ 354.1537, found 354.1531.
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(4aRS,7aRS)-7a-(2-Fluoro-5-nitrophenyl)-4a,5,6,7a-tetrahydro-4H-furo[2,3-d][1,3]thiazin-2-amine ((±)-7a). To a solution
of 9a (11 g, 31.1 mmol) in acetic acid (110 mL) was added thiourea (9.5 g, 124 mmol) at rt, and the reaction mixture was stirred
at rt for 5 h. TBAF (1 M in THF ) (46.7 mL, 46.7 mmol) was added, and the reaction mixture was heated at 70 °C for 12 h.
Acetic acid was removed under reduced pressure, saturated sodium bicarbonate was added, and the aqueous layer was extracted
with ethyl acetate (x3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and then
filtered. The filtrate was evaporated to give 11 g of the crude product, which was used directly for the Boc protection reaction. A
small fraction of the crude product was purified by preparatibe TLC eluting with 90% DCM/9% MeOH/1% NH3•H2O to give (±)ꢀ
7a as colorless oil for analytical data. 1H NMR (500 MHz, CDCl3): δ 8.56 (dd, J = 6.8, 3.0 Hz, 1H), 8.26 ꢀ 8.14 (m, 1H), 7.19 (dd,
J = 10.2, 8.9 Hz, 1H), 4.11 (t, J = 7.2 Hz, 2H), 3.16 ꢀ 3.08 (m, 1H), 3.05 ꢀ 2.93 (m, 1H), 2.78 ꢀ 2.67 (m, 1H), 2.30 ꢀ 2.13 (m, 2H).
13C NMR (100 MHz, CDCl3) (attached protons) δ 163.1 (0) (d, J = 258 Hz), 153.0 (0), 143.7 (0) (d, J = 2.0 Hz), 133.5 (0) (d, J
= 12 Hz), 125.0 (1) (d, J = 9.0 Hz), 124.2 (1) (d, J = 5.0 Hz), 117.1 (1) (d, J = 26 Hz), 92.8 (0), 64.5 (2), 36.9 (1), 29.1 (2) and
27.1 (2). HRMS m/z (ESI) calcd for C12H13O3N3FS (M + H)+ 298.0655, found 298.0656.
(R,R)- and (S,S)-tert-Butyl 7a-(2-fluoro-5-nitrophenyl)-4a,5,6,7a-tetrahydro-4H-furo[2,3-d][1,3]thiazin-2-ylcarbamate
((R,R)-13 and (S,S)-13). The crude (±)ꢀ7a (11 g) obtained from above was dissolved in dioxane (100 mL), and diꢀtertꢀbutyl
dicarbonate (9.4 g, 42.9 mmol), saturated sodium bicarbonate (100 mL) and water (10 mL) were added. The reaction mixture was
stirred at rt for 12 h. Water was added, the aqueous layer was extracted with ethyl acetate (x3). The combined organic layers were
washed with brine, dried over anhydrous sodium sulfate, and then filtered. The filtrate was evaporated in vacuo, and the resulting
crude product was purified by chiral supercritical fluid chromatography (AD column) to give (S,S)ꢀ13 (2.2 g, 19% yield) as a white
solid and (R,R)ꢀ13 (1.6 g, 14% yield) as a white solid. (S,S)ꢀ13: retention time: 2.1 min; HRMS m/z (ESI) calcd for C17H21O5N3FS
(M + H)+ 398.1185, found 398.1180. (R,R)ꢀ13: retention time: 3.5 min; (chiral ADꢀH 250x4.6 mm, CO2 flow rate: 2.8 mL/min, coꢀ
solvent flow rate: 1.2 mL/min, coꢀsolvent: 0.3% Et2NH in methanol, coꢀsolvent% : 30, total running time: 14 min). 1HNMR (500
MHz, CDCl3): δ 8.51 (1H, m), 8.25 (1H, m), 7.24 (1H, t, J = 9.0 Hz), 4.14 (2H, t, J = 8.5 Hz), 3.23 (1H, m), 2.90 (2H, m), 2.40
(1H, m), 2.20 (1H, m), and 1.50 (9H, s). 13C NMR (100 MHz, CDCl3): δ 26.8, 28.1, 28.9, 65.3, 91.7, 117.8 (d, J = 25.4 Hz), ,
124.6, 126.1, 144.1, 163.5 (d, J = 258.7 Hz). LCMS m/z: 398.1 (M + H)+. HRMS m/z (ESI) calcd for C17H21O5N3FS (M + H)+
398.1185, found 398.1180.
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1-(5-Bromo-2-fluorophenyl)-4-((tert-butyldimethylsilyl)oxy)-2-methylenebutan-1-one (9b). Step A: To a solution of 10
(1.57 g, 5.91 mmol) in THF (16 mL) at ꢀ78 °C was added tertꢀbutyllithium (6.9 mL, 11.8 mmol, 1.7 M solution in hexanes)
dropwise over a period of 5 min, and the reaction mixture was stirred at ꢀ78 °C for 10 min. The resulting lithium reagent was added
dropwise to a solution of 5ꢀbromoꢀ2ꢀfluorobenzaldehyde (1 g, 4.9 mmol) in THF (2 mL) at ꢀ78 °C, and the reaction mixture was
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stirred at ꢀ78 °C for 30 min. Water was added, the aqueous layer was extracted with ethyl acetate (x3). The combined organic
layers were washed with brine, dried over anhydrous sodium sulfate, and then filtered. The filtrate was evaporated in vacuo, and
the resulting crude product was purified by silica gel chromatography eluting with 0ꢀ5% ethyl acetate//hexanes to give 1ꢀ(5ꢀbromoꢀ
2ꢀfluorophenyl)ꢀ4ꢀ((tertꢀbutyldimethylsilyl)oxy)ꢀ2ꢀmethylenebutanꢀ1ꢀol (923 mg, 48% yield). 1H NMR (500 MHz, CDCl3) δ 7.79 ꢀ
7.65 (m, 1H), 7.35 (ddd, J = 8.7, 4.5, 2.7 Hz, 1H), 6.89 (dd, J = 9.8, 8.7 Hz, 1H), 5.45 (br. s., 1H), 5.15 (d, J = 0.9 Hz, 1H), 5.04 (s,
1H), 4.48 (d, J = 3.5 Hz, 1H), 3.86 ꢀ 3.79 (m, 1H), 3.73 (ddd, J = 9.6, 8.4, 4.3 Hz, 1H), 2.37 ꢀ 2.17 (m, 2H), 1.01 ꢀ 0.93 (s, 9H), 0.14
(3H, s) and 0.13 (3H, s). 13C NMR (125 MHz, CDCl3): δ (attached protons) ꢀ5.5 (2C, 3), 18.4 (0), 25.9 (3C, 3), 34.8 (2), 64.5 (2),
70.5 (1), 115.3 (2), 117.0 (1) (d, J = 23.1 Hz), 116.7 (0), 131.0 (1) (d, J = 4.5 Hz), 131.4 (1) (d, J = 8.2 Hz), 132.6 (0) (d, J = 14.3
Hz), 147.6 (0), 159.0 (0) (d, J = 247.4 Hz). HRMS m/z (ESI) calcd for C17H25OBrFSi (M + H – H2O)+ 371.0844, found 371.0837.
Step B: A mixture of 1ꢀ(5ꢀbromoꢀ2ꢀfluorophenyl)ꢀ4ꢀ((tertꢀbutyldimethylsilyl)oxy)ꢀ2ꢀmethylenebutanꢀ1ꢀol (923 mg, 2.37 mmol)
and manganese dioxide (3.1 g, 35.6 mmol) in chloroform (119 mL) was heated under reflux for 12 h, and then filtered through a
pad of Celite. The filtrate was evaporated in vacuo and the residue was purified by silica gel chromatography eluting with 0ꢀ5%
ethyl acetate//hexanes to give 9b (706 mg, 77%) as colorless oil. 1H NMR (500 MHz, CDCl3) δ 7.62 ꢀ 7.50 (m, 1H), 7.03 (t, J = 8.8
Hz, 1H), 6.10 (s, 1H), 5.78 (d, J = 1.5 Hz, 1H), 3.80 (t, J = 6.4 Hz, 2H), 2.68 (td, J = 6.3, 0.8 Hz, 2H), 0.90 (s, 9H), 0.07 (s, 6H).
13C NMR (125 MHz, CDCl3): δ (attached protons) ꢀ5.4 (2C, 3), 18.3 (0), 25.9 (3C, 3), 34.2 (2), 61.5 (2), 116.6 (0) (d, J = 3.6 Hz),
118.0 (1) (d, J = 23.3 Hz), 129.1 (0) (d, J = 17.1 Hz), 131.1 (2), 132.9 (1) (d, J = 3.1 Hz), 135.1 (1) (d, J = 8.4 Hz), 145.8 (0), 158.7
(0) (d, J = 251.9 Hz), 193,2 (0). HRMS m/z (ESI) calcd for C17H25O2BrFSi (M + H)+ 387.0792, found 387.0786.
(R,R)- and (S,S)-tert-Butyl 7a-(2-fluoro-5-bromophenyl)-4a,5,6,7a-tetrahydro-4H-furo[2,3-d][1,3]thiazin-2-ylcarbamate
(7b). To a solution of 9b (27 g, 69.7 mmol) in acetic acid (225 mL) was added thiourea (15.92 g, 209 mmol) at rt, and the reaction
mixture was stirred at rt for 12 h. TBAF (1 M in THF ) (105 mL, 105 mmol) was added, and the reaction mixture was heated at
70 °C for 6 h. Acetic acid was removed under reduced pressure, saturated sodium bicarbonate was added, and the aqueous layer
was extracted with ethyl acetate (x3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate,
and then filtered. The filtrate was evaporated in vacuo, and the resulting crude product was purified by chiral supercritical fluid
chromatography (AD column) to give one enantiomer (A) of 7b (5 g, 22% yield) as a white solid and the other enantiomer (B) of
7b (4 g, 17% yield) as a white solid. Enantiomer A: retention time: 4.6 min; Enantiomer B: retention time: 7.3 min; (chiral ADꢀH
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250x4.6 mm, CO2 flow rate: 2.0 mL/min, coꢀsolvent flow rate: 1.0 mL/min, coꢀsolvent: 0.5% Et2NH in methanol, coꢀsolvent% :
30, total running time: 25 min). 1H NMR (500 MHz, CDCl3): δ 7.72 (dd, J = 7.0, 2.4 Hz, 1H), 7.37 (ddd, J = 8.6, 4.2, 2.7 Hz,
1H), 6.91 (dd, J = 11.0, 8.5 Hz, 1H), 4.12 ꢀ 3.96 (m, 2H), 3.09 (dd, J = 13.1, 4.0 Hz, 1H), 2.93 (ddd, J = 12.9, 7.6, 1.8 Hz, 1H),
2.76 ꢀ 2.63 (m, 1H), 2.22 ꢀ 2.05 (m, 2H). 13C NMR (125 MHz, CDCl3): δ (attached protons) 159.0 (0) (d, J = 246.2 Hz), 153.2 (0),
134.0 (0) (d, J = 12.2 Hz), 132.4 (1) (d, J = 8.6 Hz), 131.2 (1) (d, J = 3.4 Hz), 118.3 (1) (d, J = 24.1 Hz), 116.7 (0) (d, J = 2.1
Hz), 93.3 (0) (d, J = 2.5 Hz), 64.7 (2), 37.4 (1), 29.4 (2), and 27.6 (2). Enantiomer A: LCMS m/z: 331.0 (M + H)+. HRMS m/z
(ESI) calcd for C12H13BrFN2OS (M + H)+ 330.9911, found 330.9899. Enantiomer B: LCMS m/z: 331.0 (M + H)+. HRMS m/z (ESI)
calcd for C12H13BrFN2OS (M + H)+ 330.9911, found 330.9900.
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1-(3-Bromo-4-fluorophenyl)-4-((tert-butyldimethylsilyl)oxy)-2-methylenebutan-1-one (14). Step A: Step A: To a solution of
10 (3.14 g, 11.82 mmol) in THF (32 mL) at ꢀ78 °C was added tertꢀbutyllithium (13.9 mL, 23.8 mmol, 1.7 M solution in hexanes)
dropwise over a period of 5 min, and the reaction mixture was stirred at ꢀ78 °C for 10 min. The resulting lithium reagent was added
dropwise to a solution of 3ꢀbromoꢀ4ꢀfluorobenzaldehyde (2 g, 9.8 mmol) in THF (2 mL) at ꢀ78 °C, and the reaction mixture was
stirred at ꢀ78 °C for 30 min. Water was added, the aqueous layer was extracted with ethyl acetate (x3). The combined organic
layers were washed with brine, dried over anhydrous sodium sulfate, and then filtered. The filtrate was evaporated in vacuo, and
the resulting crude product was purified by silica gel chromatography eluting with 0ꢀ5% ethyl acetate//hexanes to give 1ꢀ(3ꢀbromoꢀ
4ꢀfluorophenyl)ꢀ4ꢀ(tertꢀbutyldimethylsilyloxy)ꢀ2ꢀmethylenebutanꢀ1ꢀol (1.32 g, 34% yield). 1H NMR (500 MHz, CDCl3) δ 7.69 ꢀ
7.60 (m, 1H), 7.34 ꢀ 7.29 (m, 1H), 7.08 (t, J = 8.5 Hz, 1H), 5.19 (d, J = 13.6 Hz, 2H), 5.07 (d, J = 0.8 Hz, 1H), 4.46 (br. s., 1H),
3.85 ꢀ 3.79 (m, 1H), 3.68 (ddd, J = 9.7, 7.0, 6.1 Hz, 1H), 2.17 (t, J = 5.9 Hz, 2H), 0.94 (s, 9H), 0.12 (s, 6H). 13C NMR (125 MHz,
CDCl3): δ (attached protons) ꢀ5.5 (2C, 3), 18.4 (0), 25.9 (3C, 3), 34.3 (2), 64.4 (2), 76.0 (1), 108.7 (0) (d, J = 21.1 Hz), 115.5 (2),
115.9 (1) (d, J = 22.2 Hz), 126.7 (1) (d, J = 7.5 Hz), 131.2 (1), 140.5 (0) (d, J = 3.3 Hz), 148.9 (0), 158.1 (0, d, J = 246.1 Hz).
HRMS m/z (ESI) calcd for C17H25OBrFSi (M + H – H2O)+ 371.0844, found 371.0837. Step B: A mixture of 1ꢀ(3ꢀbromoꢀ4ꢀ
fluorophenyl)ꢀ4ꢀ(tertꢀbutyldimethylsilyloxy)ꢀ2ꢀmethylenebutanꢀ1ꢀol (1.32 g, 3,39 mmol) and manganese dioxide (4.4 g, 50.9
mmol) in chloroform (113 mL) was heated under reflux for 12 h, and then filtered through a pad of Celite. The filtrate was
evaporated in vacuo and the residue was purified by silica gel chromatography eluting with 0ꢀ5% ethyl acetate//hexanes to give 14
(1.25 g, 95%) as colorless oil. 1H NMR (500 MHz, CDCl3) δ 8.04 (dd, J = 6.8, 2.0 Hz, 1H), 7.77 (ddd, J = 8.4, 4.8, 2.1 Hz, 1H),
7.19 (t, J = 8.4 Hz, 1H), 5.94 (d, J = 1.0 Hz, 1H), 5.61 (s, 1H), 3.79 (t, J = 6.1 Hz, 2H), 2.70 (td, J = 6.2, 0.9 Hz, 2H), 0.87 (s, 9H),
0.03 (s, 6H). 13C NMR (100 MHz, CDCl3): δ (attached protons) ꢀ5.8 (2C, 3), 17.9 (0), 25.5 (3C, 3), 35.8 (2), 61.2 (2), 108.7 (0) (d,
J = 21.0 Hz), 115.8 (1) (d, J = 23.0 Hz), 130.4 (1) (d, J = 9.0 Hz), 134.8 (0) (d, J = 8.0 Hz), 135.1 (1), 145.0 (0), 161.1 (0) (d, J =
253.0 Hz), and 195.0 (0). HRMS m/z (ESI) calcd for C17H25O2BrFSi (M + H)+ 387.0791, found 387.0786.
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(4aSR,7aSR)-7a-(3-Bromo-4-fluorophenyl)-4a,5,6,7a-tetrahydro-4H-furo[2,3-d][1,3]thiazin-2-amine (15). To a solution of
14 (1.25 g, 3.23 mmol) in acetic acid (11 mL) was added thiourea (0.73 g, 9.6 mmol) at rt, and the reaction mixture was stirred at
rt for 12 h. TBAF (1 M in THF ) (4.5 mL, 4.5 mmol) was added, and the reaction mixture was heated at 70 °C for 6 h. Acetic
acid was removed under reduced pressure, saturated sodium bicarbonate was added, and the aqueous layer was extracted with ethyl
acetate (x3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and then filtered. The
filtrate was evaporated in vacuo, and the resulting crude product was purified by preparatibe TLC eluting with 90% DCM/9%
MeOH/1% NH3•H2O to give 15 (460 mg, 43% yiled) as a white solid. 1H NMR (500 MHz, CDCl3): δ 7.66 (dd, J = 6.7, 2.4 Hz,
1H), 7.34 (ddd, J = 8.6, 4.7, 2.3 Hz, 1H), 7.09 (t, J = 8.4 Hz, 1H), 4.15 ꢀ 3.93 (m, 2H), 3.13 (dd, J = 13.3, 3.8 Hz, 1H), 2.93
(dd, J = 13.3, 5.0 Hz, 1H), 2.38 (tdd, J = 8.5, 4.9, 4.0 Hz, 1H), 2.25 (dtd, J = 12.4, 8.6, 6.4 Hz, 1H), 2.19 ꢀ 2.07 (m, 1H). 13C
NMR (125 MHz, CDCl3) (attached protons) δ 158.6 (0) (d, J = 246 Hz), 151.9 (0), 141.9 (0) (d, J = 3.5 Hz), 131.1 (1), 126.6 (1)
(d, J = 7.5 Hz), 116.1 (1) (d, J = 22.1 Hz), 108.9 (1) (d, J = 21.0 Hz), 93.4 (0), 65.3 (2), 38.8 (1), 28.1 (2) and 26.2 (2). LCMS
m/z: 332.98 (M + H)+. HRMS m/z (ESI) calcd for C12H13BrFN2OS (M + H)+ 330.9911, found 330.9900.
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5-((tert-Butyldimethylsilyl)oxy)-1-(2,4-difluoro-5-(pyrimidin-5-yl)phenyl)-2-methylenepentan-1-one (16). A solution of
((4ꢀbromopentꢀ4ꢀenꢀ1ꢀyl)oxy)(tertꢀbutyl)dimethylsilane12 (3.30 g, 11.81 mmol) in THF (25 mL) was added to a flask filled with
magnesium (0.574 g, 23.62 mmol) and iodine (0.092 g, 0.363 mmol), and the resulting dark brown suspension was stirred at rt for
15 min and then heated under reflux for 45 min. The color of iodine faded 10 min under reflux, and eventually, the reaction
mixture turned to grey. This regent was cooled to rt and then added to a suspension of 2,4ꢀdifluoroꢀ5ꢀ(pyrimidinꢀ5ꢀ
yl)benzaldehyde13 (2 g, 9.08 mmol) in THF (14 mL), and the reaction mixture was stirred at rt for 12 h. Water was added and the
aqueous layer was extracted with ethyl acetate (x3). The combined organic layers were washed with brine, dried over anhydrous
sodium sulfate, and filtered, and the filtrate was evaporated in vacuo to give the crude product. The crude product was purified by
silica gel chromatography eluting with 0ꢀ35% ethyl acetate/hexanes to give 5ꢀ((tertꢀbutyldimethylsilyl)oxy)ꢀ1ꢀ(2,4ꢀdifluoroꢀ5ꢀ
(pyrimidinꢀ5ꢀyl)phenyl)ꢀ2ꢀmethylenepentanꢀ1ꢀol (1 g, 26 % yield) and 16 (0.95 g, 25 % yield). Treatment of 5ꢀ((tertꢀ
Butyldimethylsilyl)oxy)ꢀ1ꢀ(2,4ꢀdifluoroꢀ5ꢀ(pyrimidinꢀ5ꢀyl)phenyl)ꢀ2ꢀmethylenepentanꢀ1ꢀol (1 g, 2.38 mmol) with manganese
dioxide (3.1 g, 36 mmol) in chloroform (20 mL) under reflux for 12 h gave 16 (0.83 g, 83% yield). The overall yield of 16 from
2,4ꢀdifluoroꢀ5ꢀ(pyrimidinꢀ5ꢀyl)benzaldehyde is 47%. 1H NMR (500 MHz, CDCl3) d 9.27 (s, 1H), 8.93 (d, J = 1.4 Hz, 2H), 7.59
(dd, J = 8.2, 7.5 Hz, 1H), 7.07 (t, J = 9.6 Hz, 1H), 6.04 (s, 1H), 5.77 (d, J = 2.0 Hz, 1H), 3.70 (t, J = 6.3 Hz, 2H), 2.58 ꢀ 2.51 (m,
2H), 1.82 ꢀ 1.71 (m, 3H), 0.92 (9H, s), and 0.08 (6H, s). 13C NMR (125 MHz, CDCl3): δ (attached protons) ꢀ5.3 (2C, 3), 18.3 (0),
25.9 (3C, 3), 29.3 (2), 31.3 (2), 62.3 (2), 105.6 (1) (t, J = 26.4 Hz), 119.1 (0) (dd, J = 3.9, 14.5 Hz), 125.0 (0) (t, J = 4.4 Hz), 128.2
(0), 128.7 (2), 131.8 (1) (t, J = 4.8 Hz), 148.9 (0), 156.3 (2C, 1), 158.1 (1), 160.6 (0) (dd, J = 12.6, 257.7), 161.2 (0) (dd, J = 12.6,
257.7 Hz), 193.1 (0). HRMS m/z (ESI) calcd for C22H29N2F2O2Si (M + H)+ 419.1967, found 419.1961.
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(4aSR,8aSR)-8a-(2,4-Difluoro-5-(pyrimidin-5-yl)phenyl)-4,4a,5,6,7,8a-hexahydropyrano[2,3-d][1,3]thiazin-2-amine (17).
To a solution of 16 (606 mg, 1.45 mmol) in acetic acid (7.3 mL) was added thiourea (441 mg, 5.8 mmol) at rt, and the reaction
mixture was stirred at rt for 12 h. TBAF (1 M in THF ) (2.2 mL, 2.2 mmol) was added, and the reaction mixture was heated at 70
°C for 6 h. Acetic acid was removed under reduced pressure, saturated sodium bicarbonate was added, and the aqueous layer was
extracted with ethyl acetate (x3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and
then filtered. The filtrate was evaporated in vacuo, and the resulting crude product was purified by preparatibe TLC eluting with
90% DCM/9% MeOH/1% NH3•H2O to give 15 (170 mg, 34% yiled) as a white solid.. 1H NMR (500 MHz, CDCl3): δ 9.22 (s,
1H), 8.91 (d, J = 1.4 Hz, 2H), 7.43 (t, J = 8.5 Hz, 1H), 7.02 (dd, J = 10.8, 10.2 Hz, 1H), 5.0ꢀ4.5 (broad s, 2H), 4.00 ꢀ 3.92 (m,
1H), 3.88 ꢀ 3.80 (m, 1H), 2.95 (dd, J = 12.6, 4.0 Hz, 1H), 2.81 ꢀ 2.71 (m, 1H), 2.67 (dd, J = 12.6, 2.8 Hz, 1H), 2.01 ꢀ 1.83 (m,
2H), 1.75 ꢀ 1.57 (m, 2H). MS 363.03 (M + H)+. 13C NMR (125 MHz, CDCl3): δ (attached protons) 160.4 (0) (dd, J = 11.3, 255
Hz), 159.7 (0) (dd, J = 11.3, 255 Hz), 158.3 (1), 156.0 (2C, 1) (d, J = 3.8 Hz), 153.8 (0), 130.1 (1) (dd, J = 5.0, 10.0 Hz), 128.9
(0) (d, J = 2.5 Hz), 127.8 (0) (dd, J = 3.8, 11.3 Hz), 117.0 (0) (dd, J = 3.8, 8.9 Hz), 106.2 (1) (dd, J = 26.3, 28.8 Hz), 86.3 (0)
(d, J = 3.8 Hz), 61.3 (2), 30.5 (1) (d, J = 3.8 Hz), 29.9 (2), 24.9 (2) and 23.5 (2). LCMS m/z: 363.02 (M + H)+. HRMS m/z (ESI)
calcd for C17H17F2N4OS (M + H)+ 363.1081, found 363.1086.
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ASSOCIATED CONTENT
Supporting Information
This supporting information is available free of charge on the ACS Publication website at DOI:.
NMR spectra for all new compounds, analytical chiral HPLC data for 13 and 7b , and Xꢀray crystallographic data for (R,R)ꢀ13 and (S,S)ꢀ
13.
AUTHOR INFORMATION
Corresponding Author
* Tel: 203ꢀ677ꢀ7485. Eꢀmail: Yongꢀjin.wu@bms.com
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
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We thank Dr. John Macor for support and Dr. Nicholas Meanwell for critically reviewing this manuscript. We also thank P.N. Arunachalam,
Arumugam Arunachalam and Richard Rampulla for scaling up intermediates 7a/b. We also thank Dr. Xiaohua Huang for nOe data and Dr. Dieter
Drexler for HRMS data.
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