s), 3.13 (1H, d, 18.5), 3.90 (1H, m), 2.88 (1H, d, 14.5), 2.59 (1H,
m), 2.49 (1H, m), 2.36 (3H, s), 2.13 (1H, dt, 5.5, 13.0), 2.30 (1H,
m), 1.96 (1H, m), 1.68 (2H, m), 1.47 (1H, d, 14.5). 13C NMR δ
146.7, 142.1, 135.5, 131.3, 119.6, 114.3, 93.6, 67.7, 62.9, 58.2,
56.9, 51.9, 45.8, 44.7, 43.7, 40.9, 37.0, 35.5, 30.6, 21.9, 21.7. MS
(LCMS) m/z 388.4 (M + 1). The signal for C-6 was not present,
and it is assumed to be masked by signals from CHCl3.
12 may be forming in the initial benzylation reaction, or
the benzyl group may be transferred between the 20- and
18-hydroxyls during treatment with the Dess-Martin
reagent. No suitable crystal could be generated; however,
COSY, TOCSY, and HMBC NMR analysis of the benzyl-
ation product confirmed that 12 is indeed the product
formed from the treatment of 8 with benzyl bromide. A
full analysis of the 2D NMR spectra is included in the
Supporting Information.
The reason the apparently more hindered alcohol of 8
was selectively benzylated was not clear, although it was
considered that initial benzylation of the 20-hydroxyl
followed by an intramolecular benzyl group transfer to
the 18-hydroxyl would account for 12. Previous stud-
ies14,15 have shown that such intramolecular transfers are
disfavored, and this was also shown to be the case in the
current studies through quantum mechanical determi-
nation of the transition state. Results, discussed in detail
in the Supporting Information, revealed the barrier for
transfer to be approximately 60 kcal/mol, and that the
orientation of the groups is not consistent with an SN2
process.
7r-Benzyloxymethyl-4,5r-epoxy-19S-hydroxy-3-methoxy-
17-methyl-6r,14r-ethano-isomorphinan (10). NaH (62 mg,
95%, 2.5 mmol) was added to a solution of 9 (0.43 g, 1.2 mmol)
in DMF (8 mL) and the resulting mixture was stirred for 1 h at
room temperature. After cooling to -78 °C, benzyl bromide (0.18
mL, 1.5 mmol) was added and the suspension was stirred for
10 min. The mixture was warmed to -60 °C and stirred for an
additional 1 h. Saturated NH4Cl (8 mL) was added and extracted
with diethyl ether (4 × 15 mL). The ether extracts were washed
with brine (2 × 5 mL) and dried (Na2SO4), and 10 was purified
by preparative TLC (Silica, CHCl3:MeOH, 97:3) after removal
of the ether (0.24 g, 45%). 1H NMR δ 7.34 (5H, m), 6.69 (1H, d,
8.5), 6.57 (1H, d, 8.54), 4.61 (1H, d, 10.0), 4.50 (1H, d, 10.0), 4.40
(1H, s), 3.94 (1H, dd, 2.0, 9.0), 3.86 (3H, s), 3.49 (1H, m), 3.40
(1H, m), 3.37 (3H, s), 3.11 (2h, m), 2.80 (1H, m), 2.60 (1H, m),
2.45 (1H, m), 2.37-2.31 (4H, m), 2.11 (1H, dt, 5.5, 12.5), 2.02
(1H, dd, 6.0, 14.0), 1.88 (1H, m), 1.68 (1H, m), 1.55 (1H, d, 15.1).
13C NMR δ 146.7, 141.9, 137.4, 131.5, 129.1, 128.7, 128.3, 128.2,
119.5, 114.1, 92.5, 75.1, 74.0, 69.2, 67.9, 58.4, 56.8, 50.9, 45.8,
44.4, 43.7, 41.0, 35.7, 34.8, 31.7, 21.7, 21.6. MS (LCMS) m/z 478.3
(M + 1). (See the Supporting Information for X-ray crystal data.)
In conclusion, the 6,14-bridge of the thevinones can be
hydroxylated to give both 18- and 19-hydroxylated prod-
ucts. The fact that benzylation of 8 leads to selective
protection of the 18-hydroxyl, and benzylation of 9 leads
to the selective protection of the 20-hydroxyl, provides a
method to differentiate between the alcohols and facili-
tates the use of both 8 and 9 as intermediates in the
synthesis of novel analogues of the orvinols.
7r-Benzyloxymethyl-4,5r-epoxy-3-methoxy-17-methyl-
19-oxo-6r,14r-ethano-isomorphinan (11). Dess-Martin salt
(DMP, 0.1 g) was added to a solution of 10 (45 mg, 0.09 mmol)
in CH2Cl2 (10 mL). To that solution was added wet CH2Cl2 (4
mL shake with 100 µL of water) dropwise over 1 h. The mixture
was stirred for an additional 2 h as the solution became cloudy.
A mixure of 10% Na2S2O3 and saturated Na2CO3 (1:1, 4 mL)
was added, and the organic layer was separated. The aqueous
layer was extracted with CH2Cl2 (3 × 3 mL) and the organic
layers were combined and dried (Na2SO4). Removal of the solvent
Experimental Section
4,5r-Epoxy-18R-hydroxy-7r-hydroxymethyl-3-methoxy-
17-methyl-6r,14r-ethano-isomorphinan (8) and 4,5r-Epoxy-
19S-hydroxy-7r-hydroxymethyl-3-methoxy-17-methyl-6r,-
14r-ethano-isomorphinan (9). BH3‚Me2S (2M, THF, 35 mL,
70 mmol) was added dropwise with vigorous stirring to a solution
of 712 (1.80 g, 4.5 mmol) in THF (5 mL) at room temperature.
After being stirred for 30 min at room temperature, the mixture
was heated at 65-70 °C for 5 h. After cooling, water (3 mL) was
added and the mixture was stirred at room temperature to 30
min to quench excess borane. Aqueous NaOH (15%, 30 mL) and
hydrogen peroxide (30%, 40 mL) were added successively, and
the mixture was stirred overnight, poured into an aqueous
NaOH solution, and then extracted into CHCl3 (3 × 50 mL). The
organic extracts were washed successively with aqueous NaOH
(100 mL) and brine (100 mL). After removal of the solvent, the
two products were isolated by preparative TLC (Silica, CH2Cl2:
MeOH:NH4OH 96:4:0.1) after successive developments.
The higher running product was shown to be 18-hydroxyl
isomer 8 (0.81 g, 46%). 1H NMR δ 6.71 (1H, d, 8.5), 6.62 (1H, d,
8.5), 4.55 (1H, s), 4.06 (1H, s, br), 3.88 (1H, m), 3.86 (3H, s),
3.72 (1H, m), 3.49 (1H, m), 3.45 (3H, s), 3.12 (1H, d, 18.5), 2.92
(1H, s, br), 2.79-2.73 (2H, m), 2.46 (1H, dd, 5.5, 12.0), 1.2.34-
2.29 (5H, m), 2.09 (1H, dt, 5.0, 13.0), 2.03 (1H, m), 1.80 (1H, dd,
7.0, 13.0), 1.70 (1H, d, 10.0), 1.30 (1H, m), 1.08 (1H, dd, 5.5, 13.5).
13C NMR δ 146.5, 142.1, 132.4, 128.6, 119.8, 113.7, 91.2, 78.4
65.1, 61.2, 59.7, 56.7, 50.8, 45.6, 45.5, 43.7, 38.6, 26.5, 35.9, 35.3,
28.5, 22.1. MS (LCMS) m/z 388.3 (M + 1). (See the Supporting
Information for X-ray crystal data.)
1
gave 11 (37 mg, 82%). H NMR δ 7.34-7.24 (5H, m), 6.68 (1H,
d, 8.2), 6.56 (1H, d, 8.2), 4.65 (1H, s), 4.49 (2H, s), 3.77 (3H, s),
3.56 (1H, dd, 3.9, 9.1), 3.43 (1H, dd, 7.4, 9.0), 3.36 (3H, s), 3.29
(1H, m), 2.98 (2H, m), 2.60 (1H, dd, 6.7, 18.1), 2.45 (1H, m), 2.35-
2.23 (5H, m), 2.19 (1H, m), 2.07 (2H, m), 1.76 (1H, dd, 2.4, 13.0),
1.45 (1H, dd, 6.6, 14.6). MS (LCMS) m/z 476.5 (M + 1).
18R-Benzyloxy-4,5r-epoxy-7r-hydroxymethyl-3-methoxy-
17-methyl-6r,14r-ethano-isomorphinan (12). 8 (110 mg, 0.3
mmol) was treated with NaH and benzyl bromide as for 9 above
to yield the benzyl ether 12 (44 mg 31%) and recovered 8 (42
1
mg). H NMR δ 7.29-7.16 (5H, m), 6.72 (1H, d, 8.1), 6.61 (1H,
d, 8.1), 4.52/4.46 (s, 1H (2/1), 4.50/4.43 (1H, s, 2/1), 3.89 (1H, d,
11.5), 3.86 (s, 3H), 3.64 (2H, m), 3.49 (3H, s), 3.13 (1H, d, 18.5),
2.76 (2H, m), 2.46 (1H, dd, 5.1, 11.8), 2.31-2.24 (5H, m), 2.06
(1H, dt, 5.5, 12.8), 1.97 (1H, m), 1.69-1.63 (2H, m), 1,30-1.26
(1H, m), 1.15 (1H, dd, 4.8, 13.5). 13C NMR δ 146.5, 142.0, 137.8,
132.4, 128.6, 128.4, 127.7, 127.7, 119.6, 114.2, 94.0, 79.1, 77.4,
77.2, 76.9, 72.7, 71.1, 61.0, 61.0, 56.8, 51.5, 45.3, 45.3, 43.6, 39.0,
37.8, 36.6, 35.1, 28.6, 22.0. MS (LCMS) m/z 478.3 (M + 1).
18R-Benzyloxy-7r-carboxaldehydo-4,5r-epoxy-3-meth-
oxy-17-methyl-6r,14r-ethano-isomorphinan (13). 12 (47 mg,
0.1 mmol) was treated with DMP (0.1 g) following a similar
procedure to 10 above to give aldehyde 13 (35 mg 78%). MS +
1
1+, 476.4. The H and 13C NMR spectra indicated an aldehyde
group exisiting as two rotamers, with chemical shifts at 10.18
(H), 205.8 (C) and 9.98 (H), 202 (C), respectively. See the
Supporting Information for a copy of the NMR spectra.
The lower running spot was shown to be the 19-hydroxyl
isomer 9 (0.76 g, 43%). 1H NMR δ 6.71 (1H, d, 8.5), 6.59 (1H, d,
8.5), 4.44 (1H, s), 3.87 (3H, s), 3.80 (2H, dd, 6.0, 14.0), 3.45 (3H,
Acknowledgment. The authors with to thank the
National Institute on Drug Abuse, National Institutes
of Health (NIDA, NIH) for financial support of this work
(DA-13583), and also the University of Maryland Com-
(14) Tenud, L.; Farooq, S.; Seibl, J.; Eschenmoser, A. Helv. Chim.
Acta 1970, 53, 2059.
(15) King, J. F.; McGarrity, M. J. J. Chem. Soc., Chem. Commun.
1979, 24, 1140.
J. Org. Chem, Vol. 70, No. 5, 2005 1909