Synthesis of Salvinorin A
347
1683s, 1438m, 1379w, 1261m, 1197m, 1164m, 1106s. δH (300 MHz;
CDCl3) 6.00 (1H, s, H3), 4.05 (1H, dd, 1J 13.5, 2J 5.5, H5), 3.75 (3H,
s, H9), 3.55 (1H, m, H1), 2.52 (1H, dt, 1J 13.4, 2J 5.5, H6A), 2.07 (1H,
apparent q, J 13.4, H6B), 1.98 (3H, s, H8). δC (75 MHz; CDCl3) 198.4
(C4), 172.0 (C7), 158.9 (C2), 125.9 (C3), 71.2 (C5), 52.7 (C9), 47.4
(C1), 34.4 (C6), 22.2 (C10). m/z 184 (M+•, 1.4%), 140 (72.5), 112 (100),
109 (7.2), 97 (66.7), 95 (9.4), 67 (8.7), 53 (11.6), 41 (13.0). (HR-ESI-
MS: Found: [M+•], 207.0627. C9H12O4Na [M+•] requires 207.0633.)
132.5 (C3), 132.5 (C3), 123.2 (C3ꢀꢀ), 123.2 (C3ꢀꢀ), 120.6 (C4), 120.6
(C4), 108.6 (C4ꢀꢀ), 108.6 (C4ꢀꢀ), 66.3 (C1ꢀ), 66.2 (C1ꢀ), 48.0 (C2ꢀ), 47.9
(C2ꢀ), 45.4 (C2), 45.3 (C2), 30.5 (C4ꢀ), 30.5 (C4ꢀ). m/z 302 (1.0%), 300
(M+•, 1.0), 221 (4.6), 161 (6.1), 155 (3.8), 154 (50.0), 153 (30.0), 149
(4.6), 147 (4.6), 137 (9.2), 136 (9.2), 121 (22.3), 119 (15.4), 112 (7.7),
111 (7.7), 96 (6.9), 95 (46.2), 94 (72.3), 93 (12.3), 68 (21.5), 65 (9.2),
43 (100), 38 (20.8).
Preparation of 22
Preparation of 17
A solution of 21 (1.0 g, 6.0 mmol) in dryTHF (40 mL) was cooled to
0◦C and Rieke zinc (120 mg, 18.0 mmol) suspension in THF (2.5 mL)
was added in one portion. The solution was heated to reflux for 5 h
then cooled before quenching in HCl (30 mL, 2 M) and allowed to stir
for 1 h. Distilled H2O (50 mL) was added and the solution extracted
with Et2O (3 × 50 mL). The combined organic extracts were dried
over Na2SO4 then concentrated to leave 6-(furan-3-yl)-5,6-dihydro-4-
methyl-3-vinylpyran-2-one 22 (1.4 g, 92% yield, GC-MS) as a deep
yellow resin. νmax (neat)/cm−1 3147w, 2972w, 2933w, 1713s, 1629s,
1505m, 1430m, 1376m, 1260s, 1162s, 1122m, 1098m, 1061m, 1034s.
δH (300 MHz; CDCl3) 7.49 (1H, arom. m, H5ꢀ), 7.42 (1H, arom. m,
H2ꢀ), 6.55 (1H, dd, 1J 17.7, 2J 11.5, H7), 6.45 (1H, arom. m, H4ꢀ), 5.72
(1H, d, J 17.7, H8A), 5.47 (1H, d, J 11.5, H8B), 5.35 (1H, dd, 1J 11.5,
2J 3.8, H6), 2.78 (1H, dd, 1J 18.2, 2J 11.5, H5A), 2.54 (1H, dd, 1J 18.2,
2J 3.8, H5B), 2.11 (3H, s, H9). δC (75 MHz; CDCl3) 164.2 (C2), 150.3
(C4), 143.9 (C5ꢀ), 140.2 (C2ꢀ), 128.9 (C7), 125.4 (C3), 124.1 (C3ꢀ),
121.0 (C4), 108.8 (C4ꢀ), 70.8 (C6), 37.7 (C5), 21.1 (C9). m/z (EI-MS,
relative intensity) 204 (M+, 41.5), 189 (46.2), 160 (9.2), 159 (33.1),
158 (13.8), 145 (13.8), 131 (25.4), 129 (20.0), 128 (8.5), 127 (10.0),
117 (18.5), 116 (13.1), 115 (29.2), 95 (20.8), 94 (22.3), 93 (7.7), 91
(30.0), 82 (13.1), 81 (88.5), 80 (42.3), 79 (100), 78 (6.1), 77 (27.7), 75
(7.7), 67 (7.7), 66 (17.7), 65 (27.7), 63 (11.5), 53 (13.8), 51 (13.1), 41
(8.5), 40 (10.8), 39 (36.2). (HR-ESI-MS: Found [M + Na]+•, 227.0677.
C12H12O3Na [M + Na]+• requires 227.0684.)
To a racemic solution of 12b (75 mg, 0.41 mmol) in dry DCM
(100 mL) at −1◦C was added BBr3 (0.3 mL, 0.30 mmol, 1 M in DCM)
at once under dry N2. The solution was stirred at −1◦C for 10 min,
then immediately poured into a well stirred quenching solution of col-
lidine (3 g) in DCM (25 mL, LR). The solution was stirred at ambient
temperature for 35 min then acetyl chloride (2 mL) was added and the
mixture stirred for an additional 35 min.The solution was then extracted
with HCl (3 × 75 mL, 1 M) and the organic layer evaporated to leave
a brown viscous resin. The sample was purified by semi-preparative
HPLC (tR 7.2 min, λmax 235 nm) to afford (1R,5S)/(1S,5R)-methyl 5-
acetoxy-2-methyl-4-oxocyclohex-2-enecarboxylate 17 as a pale yellow
oil (37 mg, 40% yield). νmax (neat)/cm−1 2925m, 2857w, 1742s, 1692s,
1634m, 1442m, 1379m, 1222s, 1169s, 1078s. δH (300 MHz; CDCl3)
6.02 (1H, s, H3), 5.32 (1H, dd, 1J 11.1, 2J 6.2, H5), 3.77 (3H, s, H11),
3.58 (1H, m, H1), 2.44 (2H, m, H6), 2.17 (3H, s, H11), 1.98 (3H, s, H10).
δC (75 MHz; CDCl3) 192.2 (C1), 171.8 (C7), 170.3 (C8), 157.1 (C2),
127.7 (C3), 71.8 (C5), 52.8 (C11), 47.1 (C1), 31.7 (C6), 22.2 (C10), 21.0
(C9). m/z 226 (M+•, 0.1%), 153 (10.1), 151 (5.8), 141 (8.0), 140 (89.9),
123 (13.0), 112 (100), 109 (8.7), 97 (20.3), 95 (16.7), 79 (7.2), 67 (13.0),
43 (35.5). (HR-ESI-MS: Found: [M + Na]+•, 249.0734. C11H14O5Na
[M + Na]+• requires 249.0739.)
Preparation of Ring C
Preparation of 19
Acknowledgments
To a solution of 3-furaldehyde (1.0 g, 10.4 mmol) in acetone (18 mL)
was added a 1% NaOH solution (2.5 mL) dropwise between −6 and
−9◦C. Stirring was continued for 40 min, before neutralization with
0.5 M HCl.The solution was concentrated under vacuum and the residue
dissolved in water (100 mL) then extracted with ether (3 × 75 mL). The
combined organic extracts were dried with Na2SO4 and concentrated to
leave 4-(furan-3-yl)-4-hydroxybutan-2-one 19 as a colourless oil (1.55 g,
97% yield). m/z 154 (M+•, 16.9), 111 (16.2), 97 (53.1), 96 (56.9), 95
(28.5), 94 (15.4), 93 (10.8), 83 (6.1), 69 (64.6), 68 (12.3), 65 (10.0), 58
(15.4), 55 (9.2), 43 (100), 42 (18.5), 41 (51.5).
Financial support from the School ofApplied Science, RMIT
University, is acknowledged. We thank Dr Julie Niere, Dr
Peter McKay, and Dr GaryAmiet for their advice on synthetic
problems and NMR interpretation, and Britta Drevermann
for assistance with manuscript revisions. Technical assis-
tance from Paul Morrison, Daniel Diaz, Daniel Beck (ANU),
Dr Jo Cosgriff (CSIRO), and Dr Roger Mulder (CSIRO) is
gratefully acknowledged. We also thank Dr Jonathan White
(Melbourne University) for X-ray crystal structure data, Sally
Duck (Monash University) for high-resolution mass spec-
trometry analysis, and Dr John Zdysiewicz for assistance
with organic nomenclature. We also thank Dr Jim Pearson
(VFSC) for support throughout this project.
Preparation of 21[35]
Compound 19 (1.0 g, 6.5 mmol) was added to dry Et2O (6 mL) then
cooled to −78◦C in a dry ice/acetone bath under inert atmosphere
(N2). Dry triethylamine (2.1 g, 21 mmol) was then added, followed by
a solution of 20 (1.9 g, 10 mmol) in Et2O (3 mL) dropwise with over-
head stirring. An additional volume of Et2O (3 mL) was added then the
mixture was allowed to stir at −78◦C for 45 min followed by vacuum
filtration. The filter cake was washed with Et2O (2 × 25 mL, LR), and
the solution was allowed to stand until all precipitate had formed, then
filtered under suction once more.The ethereal solution was washed with
HCl (3 × 20 mL, 1 M), dried with Na2SO4, then evaporated to leave 1-
(furan-3-yl)-3-oxobutyl 2-bromobut-3-enoate 21 (1.8 g, 92% yield) as
a 10:1 mixture of β,γ- and α,β-unsaturated esters. The β,γ-ester was
present as a 1:1 mixture of diastereoisomers. νmax (neat)/cm−1 3136w,
2985w, 2917w, 1741s, 1724s, 1624m, 1504m, 1419m, 1369m, 1315m,
1289m, 1252s, 1201s, 1148s, 1092m, 1037s. δH (300 MHz; CDCl3)
7.48 (2H, arom. m, H5ꢀꢀ), 7.38 (2H, arom. m, H2ꢀꢀ), 6.40 (2H, arom. m,
H4ꢀꢀ), 6.26 (2H, dd, 1J 8.1, 2J 5.2, H1ꢀ), 6.10 (2H, m, H3), 5.37 (2H, dd,
1J 16.9, 2J 4.5, H4A), 5.27 (2H, dd, 1J 10.1, 2J 3.3, H4B), 4.73 (2H, d,
J 9.4, H2), 3.16 (2H, dd, 1J 16.9, 2J 8.1, H2ꢀA), 2.89 (1H, dd, 1J 16.9,
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2J 5.4, H2Bꢀ , isomer 1), 2.88 (1H, dd, J 16.9, 2J 5.2, H2ꢀB, isomer 2),
1
2.18 (6H, s, H4ꢀ). δC (75 MHz; CDCl3) 204.0 (C3ꢀ), 204.0 (C3ꢀ), 167.0
(C1), 166.9 (C1), 143.0 (C5ꢀꢀ), 143.0 (C5ꢀꢀ), 140.7 (C2ꢀꢀ), 140.6 (C2ꢀꢀ),