LETTER
An Efficient Asymmetric Synthesis of Cascarillic Acid
1121
6.5 Hz, COCH), 3.09 (1 H, dd, J = 14.5, 4.0 Hz, CHAHBPh),
2.81 (1 H, dd, J = 14.5, 10.0 Hz, CHAHBPh), 2.04–1.88 [4 H,
obs. m, OH, CH=CHCH2 and CH(CH3)2], 1.35–1.12 [8 H,
m, (CH2)4], 1.24 [6 H, app. s, (CH3)2C], 0.90 [3 H, d, J = 7.0
Hz, CH(CH3)CH3], 0.82 [3 H, obs. d, J = 7.0 Hz,
CH(CH3)CH3], 0.80 (3 H, obs. t, J = 7.0 Hz, CH2CH3).
13C NMR (75 MHz, CDCl3): d = 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)-[(1R,2R)-2-hexylcyclo-
propyl](hydroxy)methyl]-3-methylbutanoyl}-5,5-
dimethyl-1,3-oxazolidin-2-one (13): [a]D25 –21.0 (c 0.62,
MeOH). 1H NMR (300 MHz, CDCl3): d = 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, CHAHBPh), 2.86
(1 H, dd, J = 14.5, 10.0 Hz, CHACHBPh), 2.31 [1 H, m,
(CH3)2CH], 1.85 (1 H, br s, OH), 1.44–1.20 [10 H m,
(CH2)5], 1.34 [3 H, s, (CH3)C(CH3)], 1.33 [3 H, s,
(CH3)C(CH3)], 1.02 [3 H, d, J = 7.0 Hz, CH(CH3)CH3], 1.00
(1 H, obs. m, cyc-CH), 0.93 [3 H, d, J = 7.0 Hz,
References and Notes
(1) (a) Motl, O.; Sedmera, P.; Amin, A. M. Phytochemistry
1972, 11, 407. (b) Wilson, S. R.; Prodan, K. A. Tetrahedron
Lett. 1976, 17, 4231.
(2) For example: (a) Lactobacillic acid: Coxon, G. D.; Al
Dulayymi, J. R.; Baird, M. S.; Knobl, S.; Roberts, E.;
Minnikin, D. E. Tetrahedron: Asymmetry 2003, 14, 1211.
(b) Methyl dihydrosterculate: Stuart, L. J.; Buist, P. H.
Tetrahedron: Asymmetry 2004, 15, 401.
(3) Roberts, I. O.; Baird, M. S.; Liu, Y. Tetrahedron Lett. 2004,
45, 8685.
(4) Cheeseman, M.; Feuillet, F. J. P.; Johnson, A. L.; Bull, S. D.
Chem. Commun. 2005, 2372.
(5) Green, R.; Cheeseman, M.; Duffill, S.; Merritt, A.; Bull, S.
D. Tetrahedron Lett. 2005, 46, 7931.
(6) Also see: (a) Dixon, D. J.; Scott, M. S.; Luckhurst, C. A.
Synlett 2005, 2420. (b) Scott, M. S.; Luckhurst, C. A.;
Dixon, D. J. Org. Lett. 2005, 7, 5813.
(7) (a) Jones, P. F.; Lappert, M. F. J. Chem. Soc., Chem.
Commun. 1972, 526. (b) Corey, E. J.; 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.
(9) For a discussion of the potential benefits of using 5,5-
dimethyl-oxazolidin-2-ones (SuperQuats) for asymmetric
synthesis see: (a) Bull, S. D.; Davies, S. G.; Jones, S.;
Sanganee, H. J. J. Chem. Soc., Perkin Trans. 1 1999, 387.
(b) Bull, S. D.; Davies, S. G.; Nicholson, R. L.; Sanganee, H.
J.; Smith, A. D. Tetrahedron: Asymmetry 2000, 387.
(c) Bull, S. D.; Davies, S. G.; Key, M. S.; Savory, E. D.
Chem. Commun. 2000, 1721.
(10) Bull, S. D.; Davies, S. G.; Jones, S.; Polywka, M. E. C.;
Prasad, R. C.; Sanganee, H. J. Synlett 1998, 519.
(11) These conditions have been used previously for the
preparation of racemic and chiral syn-aldols derived from N-
acyl-oxazolidin-2-ones, see: (a) Ref. 4. (b) Feuillet, F. J. P.;
Robinson, D. E. J. E.; Bull, S. D. Chem. Commun. 2003,
2184. (c) Feuillet, F. J. P.; Cheeseman, M.; Mahon, M. F.;
Bull, S. D. Org. Biomol. Chem. 2005, 2976. (d) Feuillet, F.
J. P.; Niyadurupola, D. G.; Green, R.; Cheeseman, M.; Bull,
S. D. Synlett 2005, 1090.
(12) anti-a-Alkyl-b-hydroxy-N-acyl-oxazolidin-2-onesnormally
exhibit J(2¢,3¢) coupling constants of ≥7.0 Hz see: Evans, D.
A.; Tedrow, J. S.; Shaw, J. T.; Downey, C. W. J. Am. Chem.
Soc. 2002, 124, 392.
(13) Charette, A. B.; 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.
CH(CH3)CH3], 0.88 (3 H, t, J = 7.0 Hz, CH2CH3), 0.76 (1 H,
m, cyc-CH), 0.43 (1 H, app. dt, J = 8.5, 4.5 Hz, cyc-CHAHB),
0.28 (1 H, app. dt, J = 8.5, 5.0 Hz, cyc-CHAHB). 13C NMR
(75 MHz, CDCl3): d = 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.
25
(R,R)-2-Hexylcyclopropanecarbaldehyde (9): [a]D
–26.0 (c 0.35, CH2Cl2). 1H NMR (300 MHz, CDCl3): d =
8.98 (1 H, d, J = 5.5 Hz, CHO), 1.61 (1 H, m, C1H), 1.51–
1.20 [11 H, m, C2H and (CH2)5], 0.96–0.83 (5 H, m, cyc-CH2
and CH3). 13C NMR (75 MHz, CDCl3): d = 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): [a]D25 –20.0 (c 0.30, CH2Cl2). 1H NMR (300 MHz,
CDCl3): d = 5.42 (1 H, d, J = 10.0 Hz, C=CH), 2.91 (4 H, m,
2 × SCH2), 2.22–2.13 (2 H, m, SCH2CH2), 1.58 (1 H, m,
C=CHCH), 1.41–1.20 [10 H, m, (CH2)5], 0.88 (3 H, t, J = 7.0
Hz, CH2CH3), 0.79 (1 H, m, cyc-CH), 0.65–0.56 (2 H, m,
cyc-CH2). 13C NMR (75 MHz, CDCl3): d = 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-[(1S,2R)-2-Hexylcyclopropyl]acetic acid [(3S,4R)-
cascarillic acid] (2): [a]D25 –11.0 (c 0.41, CHCl3); lit. 1a:
[a]D25 –10.5 (c 0.553, CHCl3). 1H NMR (300 MHz, CDCl3):
d = 2.26 (2 H, app. d, J = 7.0 Hz, CH2CO2H), 1.41–1.18 [10
H, m, (CH2)5], 0.88 (3 H, t, J = 7.0 Hz, CH2CH3), 0.77 (1 H,
m, C1H), 0.56 (1 H, m, C2H), 0.33 (2 H, m, cyc-CH2).
13C NMR (75 MHz, CDCl3): d = 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.
(15) All new compounds were fully characterised. Selected data
for new compounds:
(R)-4-Benzyl-3-[(E)-(2R,3S)-3-hydroxy-2-isopropyl-
undec-4-enoyl]-5,5-dimethyl-1,3-oxazolidin-2-one (12):
[a]D25 +22.0 (c 0.85, CH2Cl2). 1H NMR (300 MHz, CDCl3):
d = 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,
Synlett 2006, No. 7, 1119–1121 © Thieme Stuttgart · New York