Practical Asymmetric Synthesis of a γ-Secretase Inhibitor Exploiting Substrate-Controlled Intramolecular Nitrile Oxide-Olefin Cycloaddition Jeremy P. Scott,*,† Steven F. Oliver,*,† Karel M. J. Brands,† Sarah E. Brewer,† Antony J. Davies,† Andrew D. Gibb,† David Hands,† Stephen P. Keen,† Faye J. Sheen,† Robert A. Reamer,‡ Robert D. Wilson,† and Ulf-H. Dolling‡ Department of Process Research, Merck Sharp & Dohme Research Laboratories, Hertford Road, Hoddesdon, Hertfordshire EN11 9BU, United Kingdom, and Department of Process Research, Merck Research Laboratories, P.O. Box 2000, Rahway, New Jersey 07065
[email protected];
[email protected] ReceiVed January 6, 2006
A practical asymmetric synthesis of the γ-secretase inhibitor (-)-1 is described. As the key transformation, a highly diastereoselective intramolecular nitrile oxide cycloaddition forms the hexahydrobenzisoxazole core of 3 in four operations. Other aspects of the route include a highly stereoselective reduction of an isoxazole to form a cis-γ-amino alcohol, an efficient chemical resolution, a dianion cyclization to construct a sultam ring, and the R-alkylation of a sultam with excellent diastereoselectivity. In each instance, the relative stereochemistry was evolved by way of substrate-based induction with g96% ds. Kilogram quantities of the targeted drug candidate (-)-1 were obtained, without recourse to chromatography, by way of 10 isolated intermediates and in 13% overall yield.
Introduction Alzheimer’s disease (AD) is a progressive and chronic neurodegenerative disease that leads to loss of intellect and memory in those afflicted. AD affects around 4.5 million people in the U.S. and 18 million people worldwide, and with the limited therapies currently available, this represents a major unmet medical need. One of the main pathological characteristics of this disease is the production of the 40-42 amino acid amyloid-β (Aβ) peptide,1 in which the protease enzyme γ-secretase plays a critical role through cleavage of the β-amyloid precursor protein (βAPP). γ-Secretase, therefore, represents a potential target for AD therapeutic intervention, and as part of a program at Merck directed toward the identification of inhibitors of this enzyme,2 (-)-1 was selected for further † ‡
Merck Sharp & Dohme Research Laboratories. Merck Research Laboratories.
(1) (a) Jhee, S.; Shiovitz, T.; Crawford, A. W.; Cutler, N. R. Expert Opin. InVest. Drugs 2001, 10, 593-605. (b) Sambamurti, K.; Grieg, N. H.; Lahiri, D. K. NeuroMol. Med. 2002, 1, 1-31. (c) Hardy, J.; Higgins, G. A. Science 1992, 256, 184-185. (d) Tsai, J.-Y.; Wolfe, M. S.; Xia, W. Curr. Med. Chem. 2002, 9, 1087-1106.
development. We report herein an efficient and practical asymmetric synthesis of 1 that is amenable to multikilogram operation.
Results and Discussion Retrosynthetic Analysis. γ-Secretase inhibitor 1 represents a significant synthetic challenge (Scheme 1). Key structural elements include a trisubstituted octahydro-1H-2,1-benzothiazine-2,2-dioxide core and an uncommon, sulfone-bearing carbon as one of four stereogenic centers. Our approach to the synthesis sought to exploit the tertiary sulfone stereocenter to control all relative stereochemistry in the molecule (Scheme 1). 10.1021/jo060033i CCC: $33.50 © 2006 American Chemical Society
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J. Org. Chem. 2006, 71, 3086-3092
Published on Web 03/11/2006
Synthesis of a γ-Secretase Inhibitor SCHEME 1.
Retrosynthetic Analysisa
SCHEME 2
a
°C.
a
Conditions: (a) 2 M NaOH, EtOH, T e 15 °C. (b) H2O2, AcOH, 40
SCHEME 3 a
a
Ar1 ) 4-trifluoromethylphenyl; Ar2 ) 2,5-difluorophenyl.
With late-stage construction of the sultam ring and substratecontrolled installation of the pendant ethyl substituent, γ-amino alcohol derivative 2 was identified as a key intermediate. This γ-amino alcohol enables an intramolecular [3+2] nitrile oxideolefin cycloaddition (INOC)3 disconnection by way of isoxazoline 3, generated from oximes 4. These in turn would be accessible from the dioxolane-bearing tertiary sulfone 5, itself available by sequential alkylations of benzylaryl sulfone 6. In the forward sense, analysis of the likely stereochemical outcome of the three key diastereoselective transformations (INOC, isoxazoline reduction, and ethylation) led us to expect the desired stereochemistry to evolve with substrate control relative to the tertiary sulfone in 5. The enantioselective synthesis of 1 would, therefore, require either the preparation of a single enantiomer of 5 or a classical resolution. Construction of the Cycloaddition Precursor. Our synthesis began with the alkylation of commercially available 4-trifluoromethylthiophenol with 2,5-difluorobenzyl bromide (Scheme 2). A highly practical procedure involving the generation of the sodium thiolate with NaOH in aqueous EtOH and the addition of the bromide led to the desired sulfide 7 in excellent yield (99%). Oxidation to the corresponding sulfone 6, using H2O2 (2) (a) Shaw, D. E.; Best, J. D.; Dinnell, J.; Nadin, A.; Shearman, M. S.; Pattison, C.; Peachey, J.; Reilly, M. A.; Williams, B. J.; Wrigley, J. D. J.; Harrison, T. Biorg. Med. Chem. Lett. Submitted for publication. (b) Churcher, I.; Beher, D.; Best, J. D.; Castro, J. L.; Clarke, E. E.; Gentry, A.; Harrison, T.; Hitzel, L.; Kay, E.; Kerrad, S.; Lewis, H. W.; MorentinGutierrez, P.; Mortishire-Smith, R.; Oakley, P. J.; Reilly, M.; Shaw, D. E.; Shearman, M. S.; Teall, M. R.; Williams, S.; Wrigley, J. D. J. Biorg. Med. Chem. Lett. 2006, 16, 280-284. (c) Teall, M.; Oakley, P.; Harrison, T.; Shaw, D.; Kay, E.; Elliot. J.; Gerhard, U.; Castro, J. L.; Shearman, M.; Ball, R. G.; Tsou, N. N. Biorg. Med. Chem. Lett. 2005, 15, 2685-2688. (d) Churcher, I.; Ashton, K.; Butcher, J. W.; Clarke, E. E.; Harrison, T.; Lewis, H. D.; Owens, A. P.; Teall, M. R.; Williams, S.; Wrigley, J. D. J. Biorg. Med. Chem. Lett. 2003, 13, 179-183. (e) Churcher, I.; Williams, S.; Kerrad, S.; Harrison, T.; Castro, J. L.; Shearman, M. S.; Lewis, H. D.; Clarke, E. E.; Wrigley, J. D. J.; Beher, D.; Tang, Y. S.; Liu, W. J. Med. Chem. 2003, 46, 2275-2278. (3) Reviews: (a) Jager, V.; Colinas, P. A. In Synthetic Applications of 1,3-Dipolar Cycloaddition Chemistry Towards Heterocycles and Natural Products; Padwa, A., Pearson, W. H., Eds.; John Wiley & Sons: New Jersey, 2003; Chapter 6. (b) Kozikowski, A. P. Acc. Chem. Res. 1984, 17, 410-416. (c) Kanemasa, S.; Tsuge, O. Heterocycles 1990, 30, 719-736.
a Conditions: (a) KOt-Bu, 2-(2-bromoethyl)-1,3-dioxolane, DMSO, T < 20 °C. (b) KOt-Bu, allyl bromide, DMSO, T < 25 °C. Ar1 ) 4-trifluoromethylphenyl; Ar2 ) 2,5-difluorophenyl.
in AcOH, proceeded in high yield (98%). In both of these processes, the crystalline product is filtered directly from the reaction mixture without extractive workup. The screening of solvent, base, and reagent stoichiometry led to the rapid definition of a practical one-pot procedure for the preparation of rac-5 (Scheme 3). Exposing benzylaryl sulfone 6 to KOt-Bu in DMSO at ambient temperature, followed by the addition of 2-(2-bromoethyl)-1,3-dioxolane, afforded monoalkylated 8. This intermediate was not isolated but was directly alkylated further by the formation of the anion with KOt-Bu in DMSO and quenching with allyl bromide. On addition of water, the desired rac-5 could be crystallized directly from the reaction mixture in 79% overall yield. A reverseaddition protocol for the allylation step minimized the formation of the diene byproduct 9, which was otherwise significant (up to 35%). Symmetrical dialkylated products 10 and 11 were only formed at low levels (99% ee). 1H NMR (400 MHz, DMSO-d6, 80 °C) δ 7.89 (d, J ) 8.4 Hz, 2H), 7.67 (d, J ) 8.4 Hz, 2H), 7.28 (m, 1H), 7.15 (d, J ) 7.3 Hz, 1H), 7.10 (m, 2H), 3.68 (m, 1H), 3.62 (dd, J ) 6.6, 10.1 Hz, 1H), 3.52 (br t, J ) 8.2 Hz, 1H), 2.97 (s, 3H), 2.79 (br m, 1H), 2.60 (br m, 1H), 2.45 (m, 1H), 2.22 (t, J ) 13.5 Hz, 1H), 2.03 (m, 1H), 1.82 (m, 1H), 1.43 (m, 1H);13C NMR (100 MHz, DMF-d7, 5 °C) δ 158.9 (dd, J ) 2.8, 247.5 Hz), 158.6 (dd, J ) 2.0, 239.5 Hz), 138.9 (m), 134.5 (q, J ) 33.0 Hz), 131.5, 126.3 (m), 123.6 (q, J ) 273.1), 120.7 (m), 118.9 (3C, m), 70.9 (d, J ) 3.9 Hz), 49.9, 40.6, 39.7, 35.4, 28.6 (m), 24.2, 23.9 (m); mp 200201 °C; [R]20D -26.9 (c 1.0, MeOH, >99% ee); Anal. Calcd for C21H21BrF5N04S2: C, 42.72; H, 3.59; N, 2.37. Found: C, 42.81; H, 3.55; N, 2.24. The separation of the enantiomers was accomplished by HPLC analysis (Chiralpak AD, 2.0 mL/min, 90% hexane, 10% EtOH, tR ) 13.2, 17.9 min). (4aS,6S,8aR)-6-(2,5-Difluorophenyl)-1-(4-methoxybenzyl)-6{[4-(trifluoromethyl)phenyl]sulfonyl}octahydro-1H-2,1-benzothiazine 2,2-Dioxide (22). THF (14.7 kg) was cooled to less than -60 °C, and hexyllithium (5.2 kg of a 2.28 M solution in hexane, 16.8 mol) was added at T < -20 °C. Diisopropylamine (1.78 kg, 17.6 mol) was then added while maintaining T < -20 °C. The resultant solution was cooled to -60 °C, and then a solution of 16 (3.22 kg, 5.45 mol) in THF (4.8 kg) was added while maintaining T < -45 °C. The resultant solution was aged for 3 h, and then water (0.11 kg, 6.15 mol) was added while maintaining T < -40 °C. The solution was allowed to warm to -20 °C, and a solution of NaI (0.42 kg, 2.80 mol) in DMAc (8.66 kg) was added, followed by para-methoxybenzyl chloride (1.58 kg, 10.1 mol). The mixture was warmed to room temperature and aged to reach full conversion. A solution of HCl [1.64 L of concentrated HCl (specific gravity 1.18) diluted with 17 L of water, 19.4 mol] was added while maintaining T < 50 °C. Toluene (44.3 kg) was added, and the layers were separated. The organic layer was washed with water (3 × 8.9 kg) and then distilled to reach a volume of 22.5 L, adding toluene as necessary to reach a residual THF content of 99% ee). 1H NMR (400 MHz, DMSO-d6, 85 °C) δ 7.85 (d, J ) 8.2 Hz, 2H), 7.57 (d, J ) 8.1 Hz, 2H), 7.37 (d, J ) 8.4 Hz, 2H), 7.307.23 (m, 1H), 7.13-7.05 (m, 2H), 6.92 (d, J ) 8.5 Hz, 2H), 4.53 (d, J ) 16.6 Hz, 1H), 4.11 (d, J ) 16.6 Hz, 1H), 3.82 (s, 3H), 3.50 (br s, 1H), 3.35 (dt, J ) 3.7, 13.7 Hz, 1H), 3.25-3.18 (m, 1H), 2.69-2.60 (m, 1H), 2.48-2.40 (m, 1H), 2.38-2.25 (m, 1H), 2.212.11 (m, 2H), 2.10-2.01 (m, 1H), 1.79-1.68 (m, 2H), 1.40-1.28 (m, 1H); 13C NMR (100 MHz, DMSO-d6, 85 °C) δ 159.2 (d, J ) 247 Hz), 159.1, 158.7 (d, J ) 240 Hz), 139.5, 134.5 (q, J ) 32 Hz), 131.3, 130.8, 129.4, 126.2 (q, J ) 3.0 Hz), 123.8 (q, J ) 272 Hz), 121.5 (dd, J ) 7.0, 12.0 Hz), 119.5-118.6 (3C, overlapping resonances), 114.5, 71.8, 58.3, 55.8, 45.5, 44.9, 32.4, 28.7 (d, J ) 7.0 Hz), 28.1, 25.3, 24.5; mp 230-231 °C; [R]20D -7.58 (c 1.0, CH3CN, >99% ee); Anal. Calcd for C29H28F5N05S2: C, 55.32; H, 4.48; N, 2.22. Found: C, 55.20; H, 4.48; N, 2.15. Separation of enantiomers was accomplished by HPLC analysis (Chiralpak AD, 1.0 mL/min, 60% hexane, 40% EtOH, tR ) 9.8, 16.9 min). (3R,4aS,6S,8aR)-6-(2,5-Difluorophenyl)-3-ethyl-1-(4-methoxybenzyl)-6-{[4-(trifluoromethyl)phenyl]sulfonyl}octahydro-1H2,1-benzothiazine 2,2-Dioxide (24). A solution of 22 (2.97 kg, 4.7 mol) and ethyl iodide (1.03 kg, 6.60 mol) in THF (26.3 kg) was cooled to -5 °C. Sodium bis(trimethylsilylamide) (1.0 M in THF, 5.97 kg, 6.60 mol) was then added while maintaining T < 1 °C. The mixture was aged for 80 min, and then an aqueous citric acid solution (0.55 kg citric acid, 2.84 mol in 28.3 kg water) was added while maintaining T < 8 °C. Methyl tert-butyl ether (22 kg) was added, and the layers were allowed to settle. The organic layer was washed with water (8.91 kg) and then distilled at atmospheric pressure to a volume of 34 L. The mixture was further distilled, adding 2-propanol (80.2 kg) to reach a final volume of 34 L. The resultant slurry was cooled and filtered, and the solid was washed with 2-propanol (2.70 kg). Drying in vacuo furnished the title compound as a white solid (2.74 kg, 90%, >99% ee). 1H NMR (400 MHz, DMSO-d6, 85 °C) δ 7.87 (d, J ) 8.0 Hz, 2H), 7.56 (d, J ) 7.2 Hz, 2H), 7.40 (d, J ) 8.0 Hz, 2H), 7.31-7.25 (m, 1H), 7.18-7.03 (m, 2H), 6.94-6.90 (d, J ) 8.0 Hz, 2H), 4.55 (d, J ) 17.2 Hz, 1H), 4.17 (d, J ) 16.8 Hz, 1H), 3.81 (s, 3H), 3.49-3.48 (m, 1H), 3.28-3.19 (m, 1H), 2.70-2.61 (m, 1H), 2.52-2.43 (m, 1H), 2.20-1.92 (m, 5H), 1.75-1.67 (m, 2H), 1.60-1.49 (m, 1H), 1.38-1.28 (m, 1H), 1.10 (t, J ) 7.2 Hz, 3H); 13C NMR (100 MHz, DMSO-d6, 85 °C) δ 159.2 (d, J ) 245 Hz), 159.1, 158.7 (d, J ) 241 Hz), 139.5, 134.5 (q, J ) 32.0 Hz), 131.3, 130.9, 129.4, 126.3 (d, J ) 3.0 Hz), 123.8 (q, J ) 272 Hz), 121.4 (dd, J ) 12.0, 20.0 Hz), 119.5-118.5 (3C, overlapping resonances), 114.5, 71.9, 57.7, 56.2, 55.8, 45.0, 34.0, 33.0, 29.0 (d, J ) 6.1 Hz), 25.3, 24.5, 21.7, 11.0; mp 188-189 °C; [R]20D -23.9 (c 1.0, MeOH, >99% ee);
3092 J. Org. Chem., Vol. 71, No. 8, 2006
Anal. Calcd for C31H32F5N05S2: C, 56.61; H, 4.90; N, 2.13. Found: C, 56.50; H, 4.89; N, 2.06. Separation of enantiomers was accomplished by HPLC analysis (Chiralpak AD, 0.7 mL/min, 60% hexane, 40% EtOH, tR ) 10.5, 14.5 min). (3R,4aS,6S,8aR)-6-(2,5-Difluorophenyl)-3-ethyl-6-{[4(trifluoromethyl)phenyl]sulfonyl}octahydro-1H-2,1-benzothia-zine 2,2-Dioxide (1). To a stirred solution of 24 (2.74 kg, 4.16 mol) in CH2Cl2 (18 L) at 0 °C was added thioglycolic acid (1.53 kg,16.6 mol). A solution of methanesulfonic acid (1.21 kg, 12.5 mol) in CH2Cl2 (2 L) was added while maintaining T < 5 °C. The reaction was then aged 30 min, and then a 2 M NaOH solution (18 L, 36 mol) was added while maintaining T < 10 °C. The lower organic layer was diluted with IPAc (35 L), and the combined organic layers were washed sequentially with 2 M NaOH (18 L, 36 mol) and water (17 L). The organic layer was distilled to a volume of 15 L, and further IPAc (20 L) was added. The solution was again distilled to a volume of 15 L, and then heptane (12.5 L) was added to crystallize the product. The solid was isolated by filtration and washed with a 2:1 heptane/IPAc mixture (5 L). Drying in vacuo furnished the title compound as a white solid (1.97 kg, 89%, >99 wt %, >99% ee). 1H NMR (400 MHz, DMSO-d6, 85 °C) δ 7.88 (2H, d, J ) 7.9 Hz), 7.65 (d, J ) 7.6 Hz, 2H), 7.307.23 (m, 1H), 7.22-7.05 (m, 2H), 7.00-6.95 (m, 1H), 3.48-3.40 (m, 1H), 2.96-2.89 (m, 1H), 2.63-2.38 (m, 4H), 2.10-1.95 (m, 1H), 1.90-1.79 (m, 3H), 1.65-1.35 (m, 3H), 1.05 (t, J ) 7.6 Hz, 3H); 13C NMR (100 MHz, DMSO-d6, 85 °C) δ 159.2 (d, J ) 248 Hz), 158.4 (d, J ) 240 Hz), 139.6, 134.5 (q, J ) 32.0 Hz), 131.3, 126.3 (q, J ) 3.0 Hz), 123.8 (q, J ) 272 Hz), 121.3 (dd, J ) 7.0, 90 Hz), 119.5-118.5 (3C, overlapping resonances), 72.3 (d, J ) 4.0 Hz), 55.7, 52.1, 35.1, 31.9, 38.0 (d, J ) 7.0 Hz), 26.6, 24.0, 21.9, 11.2; mp 247-248 °C; [R]20D -52.6 (c 1.0, MeOH, >99% ee); Anal. Calcd for C23H24F5N04S2: C, 51.39; H, 4.50; N, 2.61. Found: C, 51.28; H, 4.47; N, 2.54. Separation of enantiomers was accomplished by HPLC analysis (Chiralpak AD, 1.5 mL/min, 60% hexane, 40% EtOH, tR ) 4.3, 10.4 min). Acknowledgment. We thank Andrew Kirtley, Sophie Aillaud, Mirlinda Biba, Jennifer Chilenski, Arlene McKeown, Jimmy Dasilva, Christopher J. Welch, and Peter Yehl for technical support. We thank Mike S. Ashwood, Khateeta M. Emerson, John S. Edwards, and Adrian Goodyear for pilot plant support. Supporting Information Available: Details of the stereochemical assignment of 3 and the X-ray structure of 1. This material is available free of charge via the Internet at http://pubs.asc.org. JO060033I
