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J. P. Bequette et al. / Tetrahedron Letters 50 (2009) 6963–6964
O2
S
References and notes
O2
S
DIBALH
COOEt
O
O
OH
1. John, J. P.; Novikov, A. V. Org. Lett. 2007, 9, 61.
CH2Cl2
0oC, 1 h
96%
2. Mehta, G.; Nayak, U. R.; Dev, S. Tetrahedron Lett. 1966, 4561.
3. Wolckenhauer, S. A.; Devlin, A. S.; Du Bois, J. Org. Lett. 2007, 9, 4363.
4. Jungong, C. S.; John, J. P.; Bequette, J. B.; Novikov, A. V. Heterocycles 2009, 78,
2531.
5. Metz, P.; Cramer, E. Tetrahedron Lett. 1993, 34, 6371.
6. Bremner, J.; Julia, M.; Launay, M.; Stacino, J.-P. Tetrahedron Lett. 1982, 23, 3265.
7. Fabre, J.-L.; Julia, M. Tetrahedron Lett. 1983, 40, 4311.
8. Masaski, Y.; Iwata, I.; Imaeda, T.; Oda, H.; Nagashima, H. Chem. Pharm. Bull.
1988, 36, 1241.
3
4
MsCl, Et3N;
DBU
95%
O2
S
Bu3SnLi, THF
85%
OH
O
9. Ochiai, M.; Ukita, T.; Fujita, E. J. Chem. Soc., Chem. Commun. 1983, 619.
10. Chen, H.; Du, X.; Tang, W.; Zhou, Y.; Zuo, J.; Feng, H.; Li, Y. Bioorg. Med. Chem.
2008, 16, 2403.
6
5
11. Candruff, J.; Miller, J. A. J. Chem. Soc. (C) 1968, 2671.
12. Specific rotations for optically pure compounds: Ethyl (3S),2-[[(3,7-dimethyl-
Scheme 2. Conversion of the sultone to the key intermediate.
6-octen-1-yl)oxy]sulfonyl]-acetate (1): ½a D20
¼ ꢀ2:0 (1.2, CHCl3).Ethyl (3S)-2-
ꢂ
diazo-2-[[(3,7-dimethyl-6-octen-1-yl)oxy]sulfonyl]-acetate (2): ½a D20
¼ ꢀ35:6
ꢂ
—44:6 (1.2, CHCl3). Constant rapid oscillation in the specified range was
observed for undetermined reasons.(4R)-3-Carbethoxy-4-methyl-4-(4-
methylpent-3-enyl)-1,2-oxathiane-2,2-dioxide (3): Less polar isomer:
OH
OH
1) TPAP, NMO
a 2D0
ꢂ
¼ þ48:3 (1.1, CHCl3). More polar isomer: ½a D20
¼ ꢀ52:7 (1.2, CHCl3).
ꢂ
2) PMPMgBr
½
or PMPLi
6
13. Physical data for (4R)-3-hydroxymethyl-4-methyl-4-(4-methylpent-3-enyl)-
1,2-oxathiane-2,2-dioxide (4).Less polar isomer: colorless oil. Rf 0.44 (1:2
MeO
1) POCl3, Py
2) MeMgI, 180oC
EtOAc/hexanes). ½a D20
ꢂ
¼ ꢀ11:6 (1.0, CHCl3). 1H NMR (500 MHz, CDCl3): d 5.07
80%
(t, J = 7 Hz, 1H), 4.66 (td, J = 11.5, 2.5 Hz, 1H), 4.50 (dt, J = 11.5, 4 Hz, 1H), 4.16–
4.22 (m, 1H), 4.01–4.07 (m, 1H), 3.21 (dd, J = 8, 3 Hz, 1H), 2.34 (dd, J = 9.5,
4.5 Hz, 1H), 1.95–2.05 (m, 3H), 1.70 (s, 3H), 1.63–1.69 (m, 2H), 1.62 (s, 3H),
1.44–1.52 (m, 1H), 1.22 (s, 3H). 13C NMR (CDCl3, 125 MHz): d 133.0 (C), 123.1
(CH), 69.5 (CH2), 68.0 (CH), 58.2 (CH2), 41.3 (CH2), 38.4 (C), 35.8 (CH2), 25.9
(CH3), 22.0 (CH2), 20.5 (CH3), 17.9 (CH3). HRMS (ESI) calcd for C12H26NO4S
[M+NH4] 280.1583, found 280.1583. IR (neat, cmꢀ1): 3527, 2971, 2919, 1461,
1348, 1172.More polar isomer: colorless oil. Rf 0.38 (1:2 EtOAc/hexanes).
HO
½ ꢂ
a 2D0 ¼ þ23:4 (0.55, CHCl3). 1H NMR (500 MHz, CDCl3): d 5.07 (t, J = 7 Hz, 1H),
Scheme 3. Preparation of Bakuchiol.
4.55 (t, J = 5.5 Hz, 2H), 4.14–4.21 (m, 1H), 4.02–4.07 (m, 1H), 3.11 (dd, J = 8,
2,5 Hz, 1H), 2.52 (dd, J = 10, 4 Hz, 1H), 1.84–1.96 (m, 4H), 1.69 (s, 3H), 1.62–
1.66 (m, 1H), 1.61 (s, 3H), 1.34–1.40 (m, 1H), 1.33 (s, 3H). 13C NMR (CDCl3,
125 MHz): d 132.8 (C), 123.3 (CH), 70.3 (CH), 69.5 (CH2), 58.5 (CH2), 38.7 (C),
35.7 (CH2), 34.8 (CH2), 25.9 (CH3), 25.6 (CH3), 21.9 (CH2), 17.9 (CH3). HRMS
(ESI) calcd for C12H26NO4S [M+NH4] 280.1583, found 280.1584. IR (neat, cmꢀ1):
3527, 2970, 2924, 1459, 1344, 1172.
of R-acetylmandelic ester of alcohol 6 (and its independently pre-
pared racemic form) confirmed that no detectable loss of optical
purity took place.
The obtained alcohol was oxidized to the aldehyde,16 and con-
verted to Bakuchiol using the described method (Scheme 3),10,11
via addition of p-methoxyphenyl magnesium bromide or lithium
reagents (the latter was obtained by metal–halogen exchange be-
tween p-bromomethoxybenzene and n-butyllithium), elimination
and demethylation. The synthetic compound matched the natural
product by spectral data and specific rotation.
14. Physical data for 3-methylene-4-methyl-4-(4-methylpent-3-enyl)-1,2-oxa-
thiane-2,2-dioxide (5): Colorless oil. Rf 0.49 (1:5 EtOAc/hexanes).
½
a 2D0
ꢂ
¼ ꢀ52:7 (0.70, CHCl3). 1H NMR (500 MHz, CDCl3): d 6.29 (s, 1H), 5.68 (s,
1H), 5.11 (t, J = 7 Hz, 1H), 4.79 (td, J = 11.5, 2.5 Hz, 1H), 4.45 (dt, J = 11.5, 4 Hz,
1H), 2.12–2.18 (m, 1H), 2.00 (ddd, J = 15.5, 11, 4.5 Hz, 1H), 1.89–1.95 (m, 2H),
1.73 (ddd, J = 14, 4, 2.5 Hz, 1H), 1.69 (s, 3H), 1.61 (s, 3H), 1.38–1.45 (m, 1H),
1.33 (s, 3H). 13C NMR (CDCl3, 125 MHz): d 150.5 (C), 132.6 (C), 123.5 (CH),
121.4 (CH2), 68.8 (CH2), 41.8 (C), 39.0 (CH2), 37.5 (CH2), 25.9 (CH3), 23.1
(CH2), 17.8 (CH3). 13C NMR (C6D6, 125 MHz): d 151.1 (C), 132.4 (C), 124.5 (CH),
121.0 (CH2), 68.4 (CH2), 41.7 (C), 39.2 (CH2), 37.8 (CH2), 26.2 (CH3), 25.7
(CH3), 23.7 (CH2), 18.0 (CH3). HRMS (ESI) calcd for C12H24NO3S [M+NH4]+
262.1477, found 262.1490. IR (neat, cmꢀ1): 2970, 2918, 2857 1456, 1353, 1185.
There is 1 less signal in 13C spectrum of the compound due to accidental
equivalence of chemical shifts of two methyl signals. It is consistent with the
increased height of the signal and confirmed by a 13C spectrum in C6D6, where
these two carbons show separately.
Thus, synthesis of Bakuchiol was achieved using diazosulfonate
C–H insertion to install the quaternary center, demonstrating the
utility of this methodology. Further studies on synthetic applica-
tions of this modification of C–H insertion are being performed
and will be reported in due course.
Acknowledgments
15. Although alcohol 6 was previously reported in the literature (in racemic form),
no complete set of physical data was provided. Data for (R)-3,7-dimethyl-3-
vinyloct-6-en-1-ol (6):Colorless oil. Rf 0.42 (1:5 EtOAc/hexanes). ½a D20
¼ ꢀ20:6
ꢂ
This work was supported by the American Chemical Society
Petroleum Research Fund under Grant No. PRF#46278-G1 and Na-
tional Institutes of Health under Grant No. GM085645. We thank
Alena Kubatova for HRMS analyses. The work on TOF MS was sup-
ported by the National Foundation under Grant No. CHE-0216038.
(0.35, CHCl3). 1H NMR (500 MHz, CDCl3): d 5.79 (dd, J = 17.5, 10.5 Hz, 1H), 5.09
(t, J = 7 Hz, 1H), 5.04 (dd, J = 10.5, 1 Hz, 1H), 4.96 (dd, J = 17.5, 1 Hz, 1H), 3.62–
3.70 (m, 2H), 1.86–1.94 (m, 2H), 1.57–1.70 (m, 8H), 1.68 (s), 1.59 (s), 1.42 (br s,
1H), 1.32 (dd, J = 9.5, 8 Hz, 2H), 1.03 (s, 3H). 13C NMR (CDCl3, 125 MHz): d 147.2
(CH), 131.5 (C), 124.9 (CH), 112.3 (CH2), 60.1 (CH2), 43.6 (CH2), 41.7 (CH2),
38.9 (C), 25.9 (CH3), 22.8 (CH2), 22.6 (CH3), 17.8 (CH3). HRMS (ESI) calcd for
C12H26NO [M+NH4]+ 200.2014, found 200.2018. IR (neat, cmꢀ1): 3337, 3082,
2967, 2926, 1636 1453, 1376, 1048.
Supplementary data
16. (R)-3,7-Dimethyl-3-vinyloct-6-enal: ½a D20
¼ ꢀ25:0 (0.5, CHCl3).
ꢂ
Supplementary data associated with this article can be found, in