An Efficient Asymmetric Synthesis of Cascarillic Acid

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.

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

References and Notes

1a Motl O. Sedmera P. Amin AM. Phytochemistry  1972,  11:  407 

1b Wilson SR. Prodan KA. Tetrahedron Lett.  1976,  17:  4231 

For example:

2a Lactobacillic acid: Coxon GD. Al Dulayymi JR. Baird MS. Knobl S. Roberts E. Minnikin DE. Tetrahedron: Asymmetry  2003,  14:  1211 

2b Methyl dihydrosterculate: Stuart LJ. Buist PH. Tetrahedron: Asymmetry  2004,  15:  401 

3 Roberts IO. Baird MS. Liu Y. Tetrahedron Lett.  2004,  45:  8685 

4 Cheeseman M. Feuillet FJP. Johnson AL. Bull SD. Chem. Commun.  2005,  2372 

5 Green R. Cheeseman M. Duffill S. Merritt A. Bull SD. Tetrahedron Lett.  2005,  46:  7931 

Also see:

6a Dixon DJ. Scott MS. Luckhurst CA. Synlett  2005,  2420 

6b Scott MS. Luckhurst CA. Dixon DJ. Org. Lett.  2005,  7:  5813 

7a Jones PF. Lappert MF. J. Chem. Soc., Chem. Commun.  1972,  526 

7b Corey EJ. Markl G. Tetrahedron Lett.  1967,  8:  3201 

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 

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 

9b Bull SD. Davies SG. Nicholson RL. Sanganee HJ. Smith AD. Tetrahedron: Asymmetry  2000,  387 

9c Bull SD. Davies SG. Key MS. Savory ED. Chem. Commun.  2000,  1721 

10 Bull SD. Davies SG. Jones S. Polywka MEC. Prasad RC. Sanganee HJ. Synlett  1998,  519 

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.

11b Feuillet FJP. Robinson DEJE. Bull SD. Chem. Commun.  2003,  2184 

11c Feuillet FJP. Cheeseman M. Mahon MF. Bull SD. Org. Biomol. Chem.  2005,  2976 

11d Feuillet FJP. Niyadurupola DG. Green R. Cheeseman M. Bull SD. Synlett  2005,  1090 

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 

13 Charette AB. Lebel H. J. Org. Chem.  1995,  60:  2966 

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 

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 _AH_BPh), 2.81 (1 H, dd, J = 14.5, 10.0 Hz, CH_A 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=O_ox), 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 _AH_BPh), 2.86 (1 H, dd, J = 14.5, 10.0 Hz, CH_ACH _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 _AH_B), 0.28 (1 H, app. dt, J = 8.5, 5.0 Hz, cyc-CH_A 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=O_ox), 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.