Straightforward and Efficient Synthesis of (4R,6S)-4-(tert-Butyldimethyl­siloxy)-6-(hydroxymethyl)tetrahydropyran-2-one

Abstract

A novel synthetic approach to (4R,6S)-4-(tert-butyldi­methylsiloxy)-6-(hydroxymethyl)tetrahydropyran-2-one, a key precursor of statin side chain, is described. A prime feature of the presented strategy is the transformation of (4R,6S)-4-(tert-butyldimethylsiloxy)-6-(iodomethyl)tetrahydropyran-2-one to an acetate ester derivative and subsequent cleavage of an acetate protection by applying homogeneous tin catalysis. Iodolactone used in the study is accessible by a new route in five steps from (S)-ethyl 4-chloro-3-hydroxybutanoate. This method overcomes many of the drawbacks associated with previously reported approaches. It gives the title compound in 21% over seven steps, which is the highest attained overall yield yet. The disclosed approach was realized in convenient and economical manner suitable for industrial use.

Key words

drugs - lactones - stereoselective synthesis - homogeneous catalysis - tin

References and Notes

• 1a Tobert JA. Nat. Rev. Drug Discov.  2003,  2:  517 
• 2 Endo A. Kuroda M. Tsujita Y. J. Antibiot.  1976,  29:  1346 
• 3 Lahera V. Goicoechea M. de Vinuesa SG. Miana M. de las Heras N. Cachofeiro V. Luno J. Curr. Med. Chem.  2007,  14:  243 
• 4 Istvan ES. Deisenhofer J. Science  2001,  292:  1160 
• 5 Grabarkiewicz T. Grobelny P. Hoffmann M. Mielcarek J. Org. Biomol. Chem.  2006,  4:  4299 
• 6 Sit SY. Parker RA. Motoc I. Han W. Balasubramanian N. Catt JD. Brown PJ. Harte WE. Thompson MD. Wright JJ. J. Med. Chem.  1990,  33:  2982 
• 7 For examples of synthesis, see: Fernandes RA. Kumar P. Eur. J. Org. Chem.  2002,  2921 ; and references cited therein
• 8a Reddy MVR. Brown HC. Ramachandran PV.
  J. Organomet. Chem.  2001,  624:  239 
• 8b Ghosh AK. Le H. J. Org. Chem.  2002,  67:  8783 
• 9 Greenberg W. Varvak A. Hanson SR. Wong K. Huang H. Chen P. Burk MJ. Proc. Natl. Acad. Sci. U. S. A.  2004,  101:  5788 ; and references cited therein
• 10 Bennett F. Knight DW. Fenton G. J. Chem. Soc., Perkin Trans. 1  1991,  133 ; and references cited therein
• 11 Maddrell SJ. Turner NJ. Kerridge A. Willetts AJ. Crosby J. Tetrahedron Lett.  1996,  37:  6001 
• 12 Lactone 1 (P = TBS) with mp 74-75 ˚C was obtained in seven steps from (S)-malic acid ester via (S)-butane-1,2,4-triol in an overall yield of 2%: Rosen T. Taschner MJ. Heathcock CH. J. Org. Chem.  1984,  49:  3994 
• 13 Enantiomerically pure lactone 1 with [α]_D -7.5 and mp 72-74 ˚C was accessed in 10% overall yield by an eight-step convergent synthesis based on diastereoselective aldol condensation between enzymatically derived chiral sulfoxide auxiliary prepared in two steps and chiral building block derived from (S)-butane-1,2,4-triol: Tang J. Brackenridge I. Roberts SM. Beecher J. Willetts AJ. Tetrahedron  1995,  51:  13217 
• Method utilizes an enzymatically derived chiral 3-hydroxycyclohexane acetate derivative obtained from phloroglucitol which was then transformed via Baeyer-Villiger oxidation to lactone 1 (P = TBS) with [α]_D +1.9 and mp 95 ˚C in nine steps and in 13% overall yield:
• 14a Ghorpade SR. Kalkote UR. Chavan SP. Bhide SR. Ravindranathan T. Puranik VG. J. Org. Chem.  2001,  66:  6803 
• 14b Kalkote UR. Ghorpade SR. Chavan SP. Ravindranathan T. J. Org. Chem.  2001,  66:  8277 
• 15 The most efficient (S)-malic acid based approach provided lactone 1 (P = TBS) with [α]_D +0.33, mp 96-98 ˚C in seven steps in 16% overall yield: Tararov VI. Andrushko N. Andrushko V. König G. Spannenberg A. Börner A. Eur. J. Org. Chem.  2006,  5543 ; and references cited therein
• 16 Hareau GP.-J. Koiwa M. Hikichi S. Sato F. J. Am. Chem. Soc.  1999,  121:  3640 
• 17 Yamada T. Iritani M. Minoura K. Numata A. Kobayashi Y. Wang Y.-G. J. Antibiot.  2002,  55:  147 
• 18 A hint for the preparation of acid 8 from ester 7 with LiOH in 70% yield was given in: Kobayashi Y. Wang Y.-G. Tetrahedron Lett.  2002,  43:  4381 
• 19a Epstein WW. Sweat FW. Chem. Rev.  1967,  67:  247 ; and references cited therein
• 19b Chandrasekhar S. Sridhar M. Tetrahedron Lett.  2000,  41:  5423 ; and references cited therein
• 19c Das S. Panigrahi AK. Maikap GC. Tetrahedron Lett.  2003,  44:  1375 
• 20a Bedford SB. Fenton G. Knight DW. Shaw D. Tetrahedron Lett.  1992,  33:  6505 
• 20b Allevi P. Anastasia M. Tetrahedron: Asymmetry  2000,  11:  3151 
• 21 Hutchins RD. Taffer IM. J. Org. Chem.  1983,  48:  1360 
• 22 Gammill RB. J. Org. Chem.  1984,  49:  5035 
• 23 Williams RM. Im MN. J. Am. Chem. Soc.  1991,  113:  9276 
• 25 Cowley BR. Humber DC. Laundon B. Long AG. Lynd AL. Tetrahedron  1983,  39:  461 
• 27 Wuts PGM. Greene TW. Greene’s Protective Groups in Organic Synthesis   4th ed.:  John Wiley and Sons; New York: 2007.  p.223-239  ; and references cited therein
• 28 Orita A. Hamada Y. Nakano T. Toyoshima S. Otera J. Chem. Eur. J.  2001,  7:  3321 

24

Data for ( R )-4-( tert -Butyldimethylsiloxy)-6-methylene-tetrahydro-2 H -pyran-2-one (10)
IR (KBr): 2956, 2930, 2897, 2857, 1760, 1663, 1210, 1130, 1089 cm^-¹. ^¹H NMR (300 MHz, CDCl₃): δ = 4.75 (s, 1 H), 4.33 (s, 1 H), 4.21 (m, 1 H), 2.78-2.52 (m, 4 H), 0.87 (s, 9 H), 0.08, 0.08 (2 s, 6 H). ^¹³C NMR (75 MHz, CDCl₃): δ = 166.9, 152.2, 95.6, 62.7, 39.5, 35.6, 25.5, 17.7, -5.0. HRMS (EI): m/z calcd for C₁₂H₂₃O₃Si [M + H]⁺: 243.1416; found: 243.1414. [α]_D ^²0 -3.0 (c 1, CHCl₃).

26

Procedure for the Preparation of [(2 S ,4 R )-4-( tert -Butyldimethylsiloxy)-6-oxotetrahydro-2 H -pyran-2-yl]methyl Acetate (11)
To the solution of (4R,6S)-4-(tert-butyldimethylsiloxy)-6-(iodomethyl)-tetrahydropyran-2-one (2, 40.00 g, 108.0 mmol) in AcOH (660 mL) was added AgOAc (20.03 g, 118.8 mmol). The resultant mixture was then heated at 120-125 ˚C for 6 h. The reaction mixture was filtered through diatomite filter medium (Celite^®). The obtained filtrate was evaporated to afford the residue. To this residue EtOAc (500 mL) and H₂O (600 mL) were added. The organic layer was separated and the aqueous layer was washed again with EtOAc (5 × 150 mL). The combined organic layers were washed with H₂O (4 × 300 mL), brine (5 × 300 mL) and dried over anhyd MgSO₄, filtered, and concentrated under reduced pressure to afford 30.28 g (92.6%) of [(2S,4R)-4-(tert-butyldimethylsiloxy)-6-oxotetrahydro-2H-pyran-2-yl]methyl acetate (11) as a pale yellow oil (HPLC purity 98%). IR (liquid film): 2955, 2930, 2897, 2857, 1742, 1226, 1089 cm^-¹. ^¹H NMR (300 MHz, CDCl₃): δ = 4.93 (m, 1 H), 4.37 (m, 1 H), 4.30 (dd, J = 12, 3 Hz, 1 H), 4.21 (dd, J = 12, 5 Hz, 1 H), 2.62 (d, J = 4 Hz, 2 H), 2.11 (s, 3 H), 1.84-1.80 (m, 2 H), 0.89 (s, 9 H), 0.09, 0.09 (2 s, 6 H). ^¹³C NMR (75 MHz, CDCl₃): δ = 170.4, 169.1, 73.3, 65.5, 63.0, 38.9, 32.2, 20.5, 17.7, -5.1, -5.2. HRMS (EI): m/z calcd for C₁₄H₂₇O₅Si [M + H]⁺: 303.1628; found: 303.1629. [α]_D ^²0 +11.0 (c 1, CHCl₃).