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Synlett 2006(7): 1119-1121  
DOI: 10.1055/s-2006-939690
LETTER
© Georg Thieme Verlag Stuttgart · New York

An Efficient Asymmetric Synthesis of Cascarillic Acid

Matt Cheeseman, Steven D. Bull*
Department of Chemistry, University of Bath, Bath BA2 7AY, UK
Fax: +44(1225)386231; e-Mail: s.d.bull@bath.ac.uk;
Further Information

Publication History

Received 19 January 2006
Publication Date:
24 April 2006 (online)

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Abstract

An efficient six-step asymmetric synthesis of the cyclopropane containing natural product cascarillic acid in 41% overall yield is described. The key synthetic steps involve the use of a temporary stereogenic hydroxyl group to control the facial selectivity of a directed cyclopropanation reaction and its subsequent removal via a retro-aldol reaction.

Key words

cascarillic acid - cyclopropane - aldol - retro-aldol - temporary stereocentre

    References and Notes

  • 1a Motl O. Sedmera P. Amin AM. Phytochemistry  1972,  11:  407 
    CrossrefSearch in Google Scholar
  • 1b Wilson SR. Prodan KA. Tetrahedron Lett.  1976,  17:  4231 
    CrossrefSearch in Google Scholar
  • For example:
  • 2a Lactobacillic acid: Coxon GD. Al Dulayymi JR. Baird MS. Knobl S. Roberts E. Minnikin DE. Tetrahedron: Asymmetry  2003,  14:  1211 
    CrossrefSearch in Google Scholar
  • 2b Methyl dihydrosterculate: Stuart LJ. Buist PH. Tetrahedron: Asymmetry  2004,  15:  401 
    CrossrefSearch in Google Scholar
  • 3 Roberts IO. Baird MS. Liu Y. Tetrahedron Lett.  2004,  45:  8685 
    CrossrefSearch in Google Scholar
  • 4 Cheeseman M. Feuillet FJP. Johnson AL. Bull SD. Chem. Commun.  2005,  2372 
    Crossref
  • 5 Green R. Cheeseman M. Duffill S. Merritt A. Bull SD. Tetrahedron Lett.  2005,  46:  7931 
    CrossrefSearch in Google Scholar
  • Also see:
  • 6a Dixon DJ. Scott MS. Luckhurst CA. Synlett  2005,  2420 
    Crossref
  • 6b Scott MS. Luckhurst CA. Dixon DJ. Org. Lett.  2005,  7:  5813 
    CrossrefSearch in Google Scholar
  • 7a Jones PF. Lappert MF. J. Chem. Soc., Chem. Commun.  1972,  526 
    Crossref
  • 7b Corey EJ. Markl G. Tetrahedron Lett.  1967,  8:  3201 
    CrossrefSearch in Google Scholar
  • 8 For a previous example where this methodology has been used for the oxidative C-1 homolgation of aldehydes to their corresponding acids see: Kametani T. Tsubuki M. Tatsuzaki Y. Honda T. J. Chem. Soc., Perkin Trans. 1  1990,  639 
    Crossref
  • For a discussion of the potential benefits of using 5,5-dimethyl-oxazolidin-2-ones (SuperQuats) for asymmetric synthesis see:
  • 9a Bull SD. Davies SG. Jones S. Sanganee HJ. J. Chem. Soc., Perkin Trans. 1  1999,  387 
    Crossref
  • 9b Bull SD. Davies SG. Nicholson RL. Sanganee HJ. Smith AD. Tetrahedron: Asymmetry  2000,  387 
    Crossref
  • 9c Bull SD. Davies SG. Key MS. Savory ED. Chem. Commun.  2000,  1721 
    Crossref
  • 10 Bull SD. Davies SG. Jones S. Polywka MEC. Prasad RC. Sanganee HJ. Synlett  1998,  519 
    Thieme Connect
  • These conditions have been used previously for the preparation of racemic and chiral syn-aldols derived from N-acyl-oxazolidin-2-ones, see:
  • 11a

    Ref. 4.
    Thieme Connect
  • 11b Feuillet FJP. Robinson DEJE. Bull SD. Chem. Commun.  2003,  2184 
    Thieme Connect
  • 11c Feuillet FJP. Cheeseman M. Mahon MF. Bull SD. Org. Biomol. Chem.  2005,  2976 
    Thieme Connect
  • 11d Feuillet FJP. Niyadurupola DG. Green R. Cheeseman M. Bull SD. Synlett  2005,  1090 
    Thieme Connect
  • 12 anti-α-Alkyl-β-hydroxy-N-acyl-oxazolidin-2-ones normally exhibit J ( 2 ′ ,3 ′ ) coupling constants of ³7.0 Hz see: Evans DA. Tedrow JS. Shaw JT. Downey CW. J. Am. Chem. Soc.  2002,  124:  392 
    CrossrefSearch in Google Scholar
  • 13 Charette AB. Lebel H. J. Org. Chem.  1995,  60:  2966 
    CrossrefSearch in Google Scholar
  • 14 For a discussion on the mechanism of directed cyclopropanation reactions of allylic alcohols, see: Nakamura M. Hirai A. Nakamura E. J. Am. Chem. Soc.  2003,  125:  2341 
    CrossrefSearch in Google Scholar
15

All new compounds were fully characterised. Selected data for new compounds:
( R )-4-Benzyl-3-[( E )-(2 R ,3 S )-3-hydroxy-2-isopropyl-undec-4-enoyl]-5,5-dimethyl-1,3-oxazolidin-2-one ( 12): [α]D 25 +22.0 (c 0.85, CH2Cl2). 1H NMR (300 MHz, CDCl3): δ = 7.27-7.11 (5 H, m, Ph), 5.54-5.71 (2 H, m, CH=CHCH2 and CH=CHCH2), 4.53 (1 H, dd, J = 10.0, 4.0 Hz, CHN), 4.36 (1 H, app. t, J = 6.5 Hz, CHOH), 4.09 (1 H, dd, J = 9.0, 6.5 Hz, COCH), 3.09 (1 H, dd, J = 14.5, 4.0 Hz, CH AHBPh), 2.81 (1 H, dd, J = 14.5, 10.0 Hz, CHA H BPh), 2.04-1.88 [4 H, obs. m, OH, CH=CHCH 2 and CH(CH3)2], 1.35-1.12 [8 H, m, (CH 2)4], 1.24 [6 H, app. s, (CH 3)2C], 0.90 [3 H, d, J = 7.0 Hz, CH(CH 3)CH3], 0.82 [3 H, obs. d, J = 7.0 Hz, CH(CH3)CH 3], 0.80 (3 H, obs. t, J = 7.0 Hz, CH2CH 3). 13C NMR (75 MHz, CDCl3): δ = 174.7, 153.9, 137.4, 135.8, 129.5, 129.1, 128.9, 127.2, 82.4, 73.8, 64.3, 54.1, 35.9, 32.7, 32.1, 29.5, 29.3, 28.7, 28.6, 23.0, 22.6, 21.0, 20.4, 14.5. IR (film): 3501 (br OH), 1778 (C=Oox), 1693 (C=O) cm-1. HRMS (ES): m/z calcd [M + NH4]+: 447.3217; found: 447.3213.
( R )-4-Benzyl-3-{( R )-2-[( S )-[(1 R ,2 R )-2-hexylcyclo-propyl](hydroxy)methyl]-3-methylbutanoyl}-5,5-dimethyl-1,3-oxazolidin-2-one ( 13): [α]D 25 -21.0 (c 0.62, MeOH). 1H NMR (300 MHz, CDCl3): δ = 7.34-7.18 (5 H, m, Ph), 4.56 (1 H, dd, J = 10.0, 3.5 Hz, CHN), 4.22 (1 H, dd, J = 8.5, 6.0 Hz, COCH), 3.39 (1 H, dd, J = 8.5, 6.0 Hz, CHOH), 3.23 (1 H, dd, J = 14.5, 3.5 Hz, CH AHBPh), 2.86 (1 H, dd, J = 14.5, 10.0 Hz, CHACH BPh), 2.31 [1 H, m, (CH3)2CH], 1.85 (1 H, br s, OH), 1.44-1.20 [10 H m, (CH 2)5], 1.34 [3 H, s, (CH 3)C(CH3)], 1.33 [3 H, s, (CH3)C(CH 3)], 1.02 [3 H, d, J = 7.0 Hz, CH(CH 3)CH3], 1.00 (1 H, obs. m, cyc-CH), 0.93 [3 H, d, J = 7.0 Hz, CH(CH3)CH 3], 0.88 (3 H, t, J = 7.0 Hz, CH2CH 3), 0.76 (1 H, m, cyc-CH), 0.43 (1 H, app. dt, J = 8.5, 4.5 Hz, cyc-CH AHB), 0.28 (1 H, app. dt, J = 8.5, 5.0 Hz, cyc-CHA H B). 13C NMR (75 MHz, CDCl3): δ = 175.1, 153.7, 137.5, 129.4, 129.1, 127.2, 82.2, 75.5, 64.4, 54.5, 35.8, 34.2, 32.3, 29.6, 29.5, 28.8, 28.6, 23.1, 22.8, 22.2, 21.4, 21.1, 18.8, 14.5, 9.6. IR (film): 3516 (br OH), 1778 (C=Oox), 1693 (C=O) cm-1. HRMS (ES): m/z calcd [M + NH4]+: 461.3374; found: 461.3370.
( R , R )-2-Hexylcyclopropanecarbaldehyde ( 9): [α]D 25
-26.0 (c 0.35, CH2Cl2). 1H NMR (300 MHz, CDCl3): δ = 8.98 (1 H, d, J = 5.5 Hz, CHO), 1.61 (1 H, m, C1 H), 1.51-1.20 [11 H, m, C2 H and (CH 2)5], 0.96-0.83 (5 H, m, cyc-CH 2 and CH 3). 13C NMR (75 MHz, CDCl3): δ = 201.2, 32.6, 31.7, 30.6, 29.0, 28.9, 22.7, 22.6, 14.9, 14.1. IR (film): 1713 (C=O) cm-1. HRMS (ES): m/z calcd [M + NH4]+: 172.1696; found: 172.1696. 2-{[( R , R )-2-Hexylcyclopropyl]methylene}-1,3-dithiane ( 14): [α]D 25 -20.0 (c 0.30, CH2Cl2). 1H NMR (300 MHz, CDCl3): δ = 5.42 (1 H, d, J = 10.0 Hz, C=CH), 2.91 (4 H, m, 2 × SCH 2), 2.22-2.13 (2 H, m, SCH2CH 2), 1.58 (1 H, m, C=CHCH), 1.41-1.20 [10 H, m, (CH 2)5], 0.88 (3 H, t, J = 7.0 Hz, CH2CH 3), 0.79 (1 H, m, cyc-CH), 0.65-0.56 (2 H, m, cyc-CH 2). 13C NMR (75 MHz, CDCl3): δ = 140.4, 121.6, 34.1, 32.3, 31.3, 30.5, 29.7, 29.5, 26.0, 23.1, 22.2, 20.3, 15.2, 14.5. IR (film):1678 (C=C) cm- 1. HRMS (ES): m/z calcd [M + H]+: 257.1392; found: 257.1393.
2-[(1 S ,2 R )-2-Hexylcyclopropyl]acetic acid [(3 S ,4 R )-cascarillic acid] ( 2): [α]D 25 -11.0 (c 0.41, CHCl3); lit. 1a: [α]D 25 -10.5 (c 0.553, CHCl3). 1H NMR (300 MHz, CDCl3): δ = 2.26 (2 H, app. d, J = 7.0 Hz, CH 2CO2H), 1.41-1.18 [10 H, m, (CH 2)5], 0.88 (3 H, t, J = 7.0 Hz, CH2CH 3), 0.77 (1 H, m, C1 H), 0.56 (1 H, m, C2 H), 0.33 (2 H, m, cyc-CH 2). 13C NMR (75 MHz, CDCl3): δ = 176.6, 37.5, 32.8, 30.9, 28.3, 28.1, 21.6, 17.7, 13.1, 13.0, 10.6. IR (film): 1711 (C=O) cm-1. HRMS (EI): m/z calcd [M]+: 184.1458; found: 184.1458.