Download PDF
Synlett 2008(13): 2036-2040  
DOI: 10.1055/s-2008-1077957
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

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

Zdenko Časar*
Lek Pharmaceuticals, d.d., Sandoz Development Center Slovenia, API Development, Organic Synthesis Department, Kolodvorska 27, 1234 Menge, Slovenia
Fax: +386(1)7237382; e-Mail: zdenko.casar@sandoz.com;
Further Information

Publication History

Received 29 April 2008
Publication Date:
15 July 2008 (online)

    Permissions and Reprints All articles of this category

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 
    Google Scholar
  • 2 Endo A. Kuroda M. Tsujita Y. J. Antibiot.  1976,  29:  1346 
    CrossrefGoogle Scholar
  • 3 Lahera V. Goicoechea M. de Vinuesa SG. Miana M. de las Heras N. Cachofeiro V. Luno J. Curr. Med. Chem.  2007,  14:  243 
    CrossrefGoogle Scholar
  • 4 Istvan ES. Deisenhofer J. Science  2001,  292:  1160 
    CrossrefGoogle Scholar
  • 5 Grabarkiewicz T. Grobelny P. Hoffmann M. Mielcarek J. Org. Biomol. Chem.  2006,  4:  4299 
    Google Scholar
  • 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 
    CrossrefGoogle Scholar
  • 7 For examples of synthesis, see: Fernandes RA. Kumar P. Eur. J. Org. Chem.  2002,  2921 ; and references cited therein
    CrossrefGoogle Scholar
  • 8a Reddy MVR. Brown HC. Ramachandran PV.
    J. Organomet. Chem.  2001,  624:  239 
    Google Scholar
  • 8b Ghosh AK. Le H. J. Org. Chem.  2002,  67:  8783 
    Google Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 10 Bennett F. Knight DW. Fenton G. J. Chem. Soc., Perkin Trans. 1  1991,  133 ; and references cited therein
    CrossrefGoogle Scholar
  • 11 Maddrell SJ. Turner NJ. Kerridge A. Willetts AJ. Crosby J. Tetrahedron Lett.  1996,  37:  6001 
    CrossrefGoogle Scholar
  • 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 
    CrossrefGoogle Scholar
  • 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 
    CrossrefGoogle Scholar
  • 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 
    Google Scholar
  • 14b Kalkote UR. Ghorpade SR. Chavan SP. Ravindranathan T. J. Org. Chem.  2001,  66:  8277 
    Google Scholar
  • 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
    CrossrefGoogle Scholar
  • 16 Hareau GP.-J. Koiwa M. Hikichi S. Sato F. J. Am. Chem. Soc.  1999,  121:  3640 
    CrossrefGoogle Scholar
  • 17 Yamada T. Iritani M. Minoura K. Numata A. Kobayashi Y. Wang Y.-G. J. Antibiot.  2002,  55:  147 
    CrossrefGoogle Scholar
  • 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 
    CrossrefGoogle Scholar
  • 19a Epstein WW. Sweat FW. Chem. Rev.  1967,  67:  247 ; and references cited therein
    Google Scholar
  • 19b Chandrasekhar S. Sridhar M. Tetrahedron Lett.  2000,  41:  5423 ; and references cited therein
    Google Scholar
  • 19c Das S. Panigrahi AK. Maikap GC. Tetrahedron Lett.  2003,  44:  1375 
    Google Scholar
  • 20a Bedford SB. Fenton G. Knight DW. Shaw D. Tetrahedron Lett.  1992,  33:  6505 
    Google Scholar
  • 20b Allevi P. Anastasia M. Tetrahedron: Asymmetry  2000,  11:  3151 
    Google Scholar
  • 21 Hutchins RD. Taffer IM. J. Org. Chem.  1983,  48:  1360 
    CrossrefGoogle Scholar
  • 22 Gammill RB. J. Org. Chem.  1984,  49:  5035 
    CrossrefGoogle Scholar
  • 23 Williams RM. Im MN. J. Am. Chem. Soc.  1991,  113:  9276 
    CrossrefGoogle Scholar
  • 25 Cowley BR. Humber DC. Laundon B. Long AG. Lynd AL. Tetrahedron  1983,  39:  461 
    CrossrefGoogle Scholar
  • 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
    Google Scholar
  • 28 Orita A. Hamada Y. Nakano T. Toyoshima S. Otera J. Chem. Eur. J.  2001,  7:  3321 
    CrossrefGoogle Scholar
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).