Total synthesis of 20-norsalvinorin A. 1. Preparation of a key intermediate

Article abstract of DOI:10.1021/jo802623n

The key tricylic intermediate 3a, for the total synthesis of the C ₂₀-nor analogue of salvinorin A, was prepared in seven steps from 3-furaldehyde. Key steps involved a highly regioand diastereoselective Lewis acid assisted Diels-Alder reaction

Full text of DOI:10.1021/jo802623n

Total Synthesis of 20-Norsalvinorin A. 1.
Preparation of a Key Intermediate
Ylva E. Bergman,† Roger Mulder,‡ and Patrick Perlmutter*,†
School of Chemistry, Monash UniVersity, PO Box 23,
Victoria 3800, Australia, and CSIRO Molecular and Health
Technologies, Bag 10 Clayton South, Victoria 3169, Australia
patrick.perlmutter@sci.monash.edu.au
ReceiVed December 14, 2008
FIGURE 1. Summary of the outcomes of SAR studies on salvinorin
A (1).
SCHEME 1. Retrosynthetic Analysis of 20-Norsalvinorin
Analogue Including the Target Intermediate 3a
The key tricylic intermediate 3a, for the total synthesis of
the C20-nor analogue of salvinorin A, was prepared in seven
steps from 3-furaldehyde. Key steps involved a highly regio-
and diastereoselective Lewis acid assisted Diels-Alder
reaction followed by base-promoted epimerization and a
completely stereoselective conjugate reduction.
Salvinorin A (1) is a highly potent and selective κ-opioid
receptor (KOR) agonist, both in vivo and in vitro, with no
significant affinity for any other opioid receptor subtype.1 It was
originally isolated in 1982 from the perennial herb SalVia
diVinorum by Ortega2 and independently by Valde´s.3 Two total
syntheses of salvinorin A have been reported. One by Evans4
in 29 steps via a transannular Michael reaction cascade and the
other by Hagiwara5 in 20 steps from enantiomerically pure
Wieland-Miescher ketone. In addition, partial syntheses have
been disclosed by Hu¨gel6 and Forsyth.7
phore. The rapidly expanding library of salvinorin A analogues
includes modifications at the C1, C2, C4, C17, and C8 position
(Figure 1).8 To date no studies have evaluated the importance,
if any, of the C20-methyl group. From its location on the
salvinorin skeleton modification of C20 is clearly very difficult.
Hence we decided to prepare the C20-nor analogue of salvinorin
A through total synthesis. Herein we describe a short, expedi-
tious, synthesis of key intermediate 3a (Scheme 1).
From the retrosynthesis shown in Scheme 1, the key step is
an endo-syn selective intermolecular Diels-Alder addition of
a semicyclic dihydropyran-based diene (4a). It is envisaged that
the C18-methoxycarbonyl group will be introduced via Pd-
catalyzed carbonylation of the enoltriflate of 3a.9 A sequence
of conjugate reduction of the unsaturated ester followed by
allylic oxidation and Evans4 conjugate reduction of the resulting
unsaturated lactone would provide the 20-norsalvinorin A
skeleton. Demethylation followed by acetylation completes the
synthesis of 2.
Because of the remarkable affinity for the KOR, the functional
groups of salvinorin A have been extensively modified, and
subsequent SAR studies have begun to clarify the pharmaco-
† Monash University.
‡ CSIRO Molecular and Health Technologies.
(1) Roth, B. L.; Baner, K.; Westkaemper, R.; Siebert, D.; Rice, K. C.;
Steinberg, S.; Ernsberger, P.; Rothman, R. B. Proc. Nat. Acad. Sci. U.S.A. 2002,
99, 11934–11939.
(2) Ortega, A.; Blount, J. F. J. Chem. Soc., Perkin Trans. 1 1982, 2505–
2508.
(3) Valde´s, I.; Leander, J.; Butler, W. M.; Hatfield, G. M.; Paul, A. G.;
Koreeda, M. J. Org. Chem. 1984, 49, 4716–4720.
(4) Scheerer, J. R.; Lawrence, J. F.; Wang, G. C.; Evans, D. A. J. Am. Chem.
Soc. 2007, 129, 8968–8969.
(5) Nozawa, M.; Suka, Y.; Hoshi, T.; Suzuki, T.; Hagiwara, H. Org. Lett.
2008, 10, 1365–1368.
(6) Lingham, A. R.; Hu¨gel, H. M.; Rook, T. J. Aust. J. Chem. 2006, 59,
340–348.
(7) Burns, A. C.; Forsyth, C. J. Org. Lett. 2008, 10, 97–100.
(8) Prisinzano, T. E.; Rothman, R. B. Chem. ReV. 2008, 108, 1732–1743.
(9) Hagiwara, H.; Hamano, K.; Nozawa, M.; Hoshi, T.; Suzuki, T.; Kido, F.
J. Org. Chem. 2005, 70, 2250–2255.
10.1021/jo802623n CCC: $40.75
Published on Web 02/20/2009
2009 American Chemical Society
J. Org. Chem. 2009, 74, 2589–2591 2589

SCHEME 2. Stannic Chloride Mediated Diels-Alder
Reactions of Diene 4b with 2-Methoxy-5-methyl-1,4-
benzoquinone (6)
SCHEME 4. Epimerization of Adduct 7a To Adjust the
Stereochemistry at C10
SCHEME 5. Attempted Conjugate Reduction of Epimerized
Adduct 8b
SCHEME 3. Titanium-tetrachloride Mediated Diels-Alder
Reactions of Diene 4a with 2-Methoxy-5-methyl-1,4-
benzoquinone (6)
-78 °C in dichloromethane gave a 1:1 mixture of two adducts.
Changing the solvent to toluene gave no reaction at -78 °C.
However, at -45 °C a 1:1 ratio of adducts was again obtained,
providing the desired endo-syn product 7a in 37% isolated yield.
Although yields were modest (37% and 51% for 7a and 7b,
respectively), the major product in each case was formed with
full regiocontrol with the three newly created stereogenic centers
(at C5, C9, and C10) in the same orientation as the natural product.
Significantly, the relative stereochemistry between C5 and C12
in 7a is also correct for the natural product. Interestingly a small
amount (∼10%) of 8a (vide infra) was also present in the
product. Thus, some epimerization of the adduct had occurred
after cycloaddition.
With 7a and 7b in hand, it remained for us to adjust the
relative stereochemistry at C10 and introduce the correct stere-
ochemistry at C2 (Scheme 4). Thus treatment of 7a with DBU
at room temperature in dichloromethane for 1 h gave smooth
conversion to a single product, 8a (adduct 7b behaved similarly,
cleanly epimerizing to 8b).
A variety of conditions were explored in order to effect
reduction of 8a and 8b. All attempts to achieve this transforma-
tion with copper-14 and zinc-based15 reagents led to mixtures
of 1,2-reduction products. In the case of L-Selectride16 smooth
conversion to a single 1,2-reduction product, 9b, was observed
(Scheme 5).
Finally, alkaline dithionite was employed as the reducing
system.17 Unlike previous reductions, this led to exclusive
conjugate reduction installing the correct relative stereochemistry
at C2 without loss of OMe. Similar results were obtained for
both 8a and 8b (Scheme 6). A crystal structure for 3b was
obtained that confirmed our assignments of relative stereochem-
istry (see Supporting Information).
Model studies of the Diels-Alder reaction were carried out
with a phenyl-substituted diene 4b (prepared in three steps10
from benzaldehyde) with 2-methoxy-5-methyl-1,4-benzoqui-
none11 (6). By analogy with the work of Carren˜o, it was
anticipated that a mixture of endo-anti and endo-syn adducts
would be obtained.12 However, unlike Carren˜o’s dienophiles,
which reacted completely after 16 h at room temperature, no
reaction was observed between 4b and 6 after 3 days at 80 °C.
In order to increase the reactivity of 4b, we turned to
precomplexation of the methoxyquinone with metal salts.
Thus, employing the method of Reusch,13 4b was added to
a precomplexed mixture of 6 and SnCl4 at low temperature.
Reaction was found to commence upon warming to ap-
proximately -45 °C. After 4 h at this temperature, the reaction
was quenched, and an inseparable mixture of two products was
obtained. However, allowing the reaction mixture to warm to
0 °C produced the desired adduct 7b in 51% yield (Scheme 2).
Apparently at this higher temperature the second product either
is converted to 7b via a retro-Diels-Alder pathway or simply
decomposes under the conditions.
Diene 4a, prepared according to Snapper’s protocol in three
steps from 3-furaldehyde,10 was then added to 6 under condi-
tions similar to those just described for 4b (Scheme 3). Only
decomposition was observed when the reaction was warmed to
0 °C. At lower temperatures very poor conversion was obtained
with a highest yield of only ∼20%. Switching to the use of
TiCl4 gave decomposition at -45 °C. Running the reaction at
(10) Cheung, A. K.; Murelli, R.; Snapper, M. L. J. Org. Chem. 2004, 69,
5712–5719.
(11) Takizawa, Y.; Iwasa, Y.; Suzuki, T.; Miyaji, H. Chem. Lett. 1993, 1863–
1864.
(14) Rainka, M. P.; Aye, Y.; Buchwald, S. L. Proc. Nat. Acad. Sci. U.S.A.
2004, 101, 5821–5823.
(12) Carren˜o, C. M.; Urbano, A.; Di Vitta, C. J. Org. Chem. 1998, 63, 8320–
8330.
(13) Tou, J. S.; Reusch, W. J. Org. Chem. 1980, 45, 5012–5014.
(15) Marchand, A. P.; Reddy, M. Synthesis 1991, 198–200.
(16) Comins, D. L.; Dehghani, A. Tetrahedron Lett. 1992, 33, 6299–6302.
(17) de Vries, J. G.; Kellogg, R. M. J. Org. Chem. 1980, 45, 4126–4129.
2590 J. Org. Chem. Vol. 74, No. 6, 2009

SCHEME 6. Successful Conjugate Reduction of Epimerized
Adducts 8a and 8b
1.6 Hz), 7.32 (1H, m), 6.32 (1H, m), 5.83 (1H, s), 5.58 (1H, m),
4.39 (1H, dd, J ) 11.0, 1.7 Hz), 4.24 (1H, d, J ) 12.5 Hz), 4.08
(1H, dm, J ) 12.5), 3.76 (3H, s), 3.16 (1H, d, J ) 6.7 Hz),
2.74-2.86 (2H, m), 2.04 (1H, q, J ) 23.7, 12.4 Hz), 1.80 (1H, dq,
J ) 17.8, 5.6, 2.8 Hz), 1.57 (1H, ddd, J ) 12.4 Hz, 4.3, 2.0 Hz),
1.33 (3H, s). 13C NMR (100 MHz, CDCl3): δ 200.7, 195.6, 162.4,
143.2, 139.1, 133.3, 126.6, 119.4, 109.5, 108.7, 73.4, 72.5, 56.6,
55.6, 47.8, 37.1, 36.3, 31.9, 26.5. IR (neat): ν 3065w, 2945m,
2840m, 1711m, 1661s, 1609s cm-1. ESI-MS: m/z 351.2 [M + Na]+.
ESI-HRMS Calcd for [M + Na]+ (C19H20NaO5): m/z 351.1208,
found 351.1205.
rac-(2S,6aR,10aR,10bR)-2-(Furan-3-yl)-9-methoxy-6a-methyl-
6,6a,10a,10b-tetrahydro-1H-benzo[f]isochromene-7,10(2H,4H)-
dione (8a). To a stirring solution of 7a (63 mg, 0.19 mmol) in dry
CH2Cl2 (3 mL) under an atmosphere of argon was added DBU
(2.8 µL, 0.019 mmol), and the resulting solution was stirred for
1 h at room temperature. The solvent was evaporated, and the brown
residue was immediately purified on a short plug of silica gel (2:3
With a short route to intermediate 3a now developed, studies
directed toward the synthesis of 2 and evaluation of its KOR
selectivity are underway in our laboratories and will be published
in due course.
Experimental Section
1
EtOAc/hexanes) to yield 8a (55 mg, 87%) as an yellow gum. H
rac-(2S,6aR,10aS,10bR)-9-Methoxy-6a-methyl-2-phenyl-
6,6a,10a,10b-tetrahydro-1H-benzo[f]isochromene-7,10(2H,4H)-
dione (7b). To a stirring solution of 2-methoxy-5-methyl-1,4-
benzoquinone (6) (2.50 g, 16.43 mmol) in dry CH2Cl2 (120 mL)
under an atmosphere of argon was added a 1.0 M solution of SnCl4
in CH2Cl2 (13.1 mL, 13.1 mmol), dropwise at -78 °C. Stirring
was continued at this temperature for 1 h, after which a solution of
diene 4b (1.84 g, 9.86 mmol) in CH2Cl2 (30 mL) was added slowly.
The reaction was stirred at -78 °C for 15 min and then at 0 °C for
5 h. Quenching of the reaction was done at -78 °C by the addition
of brine (20 mL), the mixture was warmed to room temperature,
and the layers were separated. The aqueous layer was extracted
with CH2Cl2 (2 × 30 mL), and the combined organic layers were
washed with brine (70 mL), dried over MgSO4, filtered, and
concentrated in vacuo to yield a brown residue. This residue was
subsequently stirred with aqueous sodium bisulfite (NaHSO3)
solution for 1 h and then extracted with CH2Cl2. The combined
organic layers were washed and dried in the same manner as above,
and the resulting brown foam was purified by flash chromatography
(2:3 EtOAc/hexanes) to afford 7b (1.70 g, 51%) as a pale orange
solid. Mp 144-146 °C. 1H NMR (400 MHz, CDCl3): δ 7.23-7.29
(5H, m), 5.80 (1H, s), 5.61 (1H, d, J ) 1.4 Hz), 4.39 (1H, dd, J )
11.0, 2.0 Hz), 4.31 (1H, d, J ) 12.4 Hz), 4.11 (1H, dq, J ) 12.5,
2.8, 1.4 Hz), 3.71 (3H, s), 3.17 (1H, d, J ) 7.2 Hz), 2.89 (1H, m),
2.81 (1H, ddt, J ) 17.9, 4.7, 1.6 Hz), 1.95 (1H, q, J ) 23.6, 12.6
Hz), 1.81 (1H, dq, J ) 17.9, 5.6, 2.3 Hz), 1.58 (1H, ddd, J ) 12.5,
4.2, 2.0 Hz), 1.34 (3H, s). 13C NMR (100 MHz, CDCl3): δ 200.8,
195.7, 162.3, 141.9, 133.5, 128.5, 127.7, 126.1, 119.4, 109.6, 80.7,
72.7, 56.6, 55.7, 47.7, 38.5, 36.9, 31.8, 26.9. IR (neat): ν 3063w,
3030w, 2937m, 2844m, 1708m, 1662s, 1606s cm-1. ESI-MS: m/z
361.2 [M + Na]+. ESI-HRMS calcd for [M + Na]+ (C21H22NaO4):
m/z 361.1416, found 361.1405. Anal. Calcd for C21H22O4: C 74.54,
H 6.55. Found: C 74.15, H 6.52.
rac-(2S,6aR,10aS,10bR)-2-(Furan-3-yl)-9-methoxy-6a-methyl-
6,6a,10a,10b-tetrahydro-1H-benzo[f]isochromene-7,10(2H,4H)-
dione (7a). To a stirring solution of 2-methoxy-5-methyl-1,4-
benzoquinone (6) (860 mg, 5.65 mmol) in dry toluene (45 mL)
under an atmosphere of argon was added a 1.0 M solution of TiCl4
in CH2Cl2 (4.52 mL, 4.52 mmol) dropwise at -78 °C. Stirring was
continued at this temperature for 1 h, after which a solution of diene
4a (598 mg, 3.39 mmol) in toluene (5 mL) was added slowly. The
reaction was stirred at -78 °C for 15 min and then at -45 °C for
5 h. Quenching of the reaction was done at -78 °C by the addition
of brine (10 mL), the mixture was warmed to room temperature,
and the layers were separated. The aqueous layer was extracted
with Et2O (2 × 15 mL), and the combined organic layers were
washed with brine (30 mL), dried over MgSO4, filtered, and
concentrated in vacuo. The crude residue was purified by flash
chromatography (2:3 EtOAc/hexanes) to afford 7a (411 mg, 37%)
as a yellow gum. 1H NMR (400 MHz, CDCl3): δ 7.33 (1H, t, J )
NMR (400 MHz, CDCl3): δ 7.37 (1H, m), 7.35 (1H, t, J ) 1.8
Hz), 6.37 (1H, m), 5.81 (1H, s), 5.62 (1H, m), 4.63 (1H, dd, J )
11.3, 1.6 Hz), 4.25 (1H, d, J ) 12.5 Hz), 4.16 (1H, dm, J ) 12.4
Hz), 3.79 (3H, s), 2.95 (1H, m), 2.78 (1H, d, J ) 9.8 Hz), 2.57
(1H, ddd, J ) 12.7, 4.6, 2.0 Hz), 2.51 (1H, dm, J ) 20.0 Hz), 2.28
(1H, ddt, J ) 18.5, 5.7, 2.0 Hz), 1.30 (1H, dt, J ) 12.7, 11.4 Hz),
1.14 (3H, s). 13C NMR (100 MHz, CDCl3): δ 202.4, 194.7, 163.1,
143.2, 139.1, 132.8, 126.7, 119.3, 109.1, 108.7, 72.4, 72.4, 56.5,
56.4, 48.2, 39.8, 33.1, 32.4, 21.1. IR (neat): ν 2962m, 2844m,
1711m, 1661s, 1605s cm-1. ESI-HRMS calcd for [M + Na]+
(C19H20NaO5): m/z 351.1208, found 351.1215.
rac-(2S,6aR,9S10aR,10bR)-2-(Furan-3-yl)-9-methoxy-6a-methyl-
6,6a,8,9,10a,10b-hexahydro-1H-benzo[f]isochromene-7,10(2H,4H)-
dione (3a). To a stirring solution of 8a (45 mg, 0.14 mmol) in
toluene (4.5 mL) was added Adogen 464 (20 µL) followed by a
solution containing NaHCO3 (184 mg, 42.7 mmol) and Na2S2O4
(tech, ∼85%) (280 mg, 26.7 mmol) in water (6 mL). The biphasic
system was stirred vigorously at room temperature under an
atmosphere of nitrogen for 7 h, after which a second portion of
Na2S2O4 (tech, ∼85%) (56 mg, 0.274 mmol) was added. Upon
stirring for another 7 h, the layers were separated, and the aqueous
layer was extracted with Et2O (2 × 10 mL). The combined organic
layers were washed with brine (10 mL), dried over MgSO4, filtered,
and concentrated in vacuo. The resulting yellow residue was purified
by flash chromatography (2:3 EtOAc/hexanes) to yield 3a (33 mg,
1
73%) as a white solid. Mp 142-145 °C. H NMR (400 MHz,
CDCl3): δ 7.37 (1H, m), 7.35 (1H, t, J ) 2.1 Hz), 6.37 (1H, m),
5.56 (1H, m), 4.60 (1H, dd, J ) 11.2, 1.8 Hz), 4.25 (1H, d, J )
12.6 Hz), 4.15 (1H, dm, J ) 12.6 Hz), 4.04 (1H, ddd, J ) 12.0,
7.6, 0.9 Hz), 3.47 (3H, s), 3.09 (1H, dd, J ) 14.8, 7.6 Hz), 3.02
(1H, m), 2.95 (1H, dd, J ) 14.8, 12.0 Hz), 2.58 (1H, dm, J ) 18.4
Hz), 2.44 (1H, d, J ) 9.9 Hz), 2.24 (1H, ddd, J ) 12.5, 4.8, 2.0
Hz), 2.05 (1H, ddt, J ) 18.4, 5.7, 2.0 Hz), 1.19 (1H, q, J ) 24.0,
11.5 Hz) 1.03 (3H, s). 13C NMR (100 MHz, CDCl3): δ 207.7, 205.8,
143.2, 139.1, 132.8, 126.7, 118.9, 108.7, 80.9, 72.4, 72.3, 58.5,
52.9, 49.2, 44.8, 39.5, 33.0, 31.3, 19.1. IR (neat): ν 2930m, 2907m,
1717s, 1684m, 1654w, 1636w, 1559m cm-1
.
Acknowledgment. Y.B. and P.P. thank the ARC Centre for
Green Chemistry for partial funding of this research.
Supporting Information Available: General experimental,
experimental procedures, and characterization data for com-
1
pounds 3b, 4a, 4b, 5a, 5b, 8b, and 9b and H NMR and 13C
NMR spectra for all new compounds, as well as the crystal
structure of 3b in CIF format. This material is available free of
charge via the Internet at http://pubs.acs.org.
JO802623N
J. Org. Chem. Vol. 74, No. 6, 2009 2591