Total synthesis of (-)-salviasperanol

Article abstract of DOI:10.1021/ol701743c

The achiral enynone shown cyclized to produce a tricyclic dienone that was converted in six steps to (-)-salviasperanol.

Full text of DOI:10.1021/ol701743c

ORGANIC
LETTERS
Total Synthesis of (−
)-Salviasperanol§
2008
Vol. 10, No. 1
85-87
George Majetich,* Ge Zou, and Jeremy Grove
Department of Chemistry, UniVersity of Georgia, Athens, Georgia 30602
majetich@chem.uga.edu
Received July 21, 2007
ABSTRACT
The achiral enynone shown cyclized to produce a tricyclic dienone that was converted in six steps to (−)-salviasperanol.
More than five hundred species of SalVia are found world-
wide, and they have been widely used as folk medicines since
ancient times.1 The two subgenera of Salvia, SalVia and
Sclarea, contain mostly rearranged abietane-type diterpenes,
such as barbatusol (1),2,3 salvicanol (2),4 salviasperanol (3),5,6
and komaroviquinone (4)7,8 (Scheme 1). We have synthesized
several icetexane diterpenoids by using an intramolecular
Friedel-Crafts, or cyclialkylation strategy,9 to efficiently
assemble the carbocyclic skeleton.10 Here we report a
modification of our cyclialkylation strategy that facilitates
the first total synthesis of (-)-salviasperanol (3).11
Scheme 1
§ Presented at the 233rd National Meeting of the American Chemical
Society, Chicago, IL, March 2007; Paper ORGN #376.
(1) (a) Fujita, E.; Node, M. Prog. Chem. Org. Nat. Prod. 1986, 46, 77-
157. (b) Chopra, R. N.; Nayar, S. L.; Chopra, I. C. Glossary of Indian
Medicinal Plants; CSIR: New Delhi, India, 1956; p 189. (c) Kirtikar, K.
R.; Basu, B. D. Indian Medicinal Plants; Indian Press: Allahabad, India,
1918; p 1031.
(2) For a cyclialkylation-based synthesis of (()-barbatusol, see: Majetich,
G.; Zhang, Y.; Feltman, T. L.; Duncan, S., Jr. Tetrahedron Lett. 1993, 34,
445-448.
(3) For the synthesis of (+)-barbatusol, (+)-demethylsalvicanol, (+)-
brussonol, and (+)-grandione, see: Majetich, G.; Zou, G. Org. Lett. 2008,
10, 81-84.
(4) For the isolation of salvicanol, see: Bruno, M.; Savona, G.; Piozzi,
F.; De la Torre, M. C.; Rodriguez, B.; Marlier, M. Phytochem. 1991, 30,
2339-2343.
In our synthesis of komaroviquinone we found that
treatment of enone 57,8 with Aren’s reagent, the anion of
ethoxyacetylene (cf. 6),12 produced enynone 7 (Scheme 2).
While direct cyclization of enynone 7 to dienone 10 might
be envisioned, analysis of Dreiding models of 7 indicated
that the linear nature of the alkyne prevented the “6” carbon
(5) For the isolation of salviasperanol, see: Esquivel, B.; Flores, M.;
Hernandez-Ortega, S.; Toscano, R. A.; Ramamoorthy, T. P. Phytochemistry
1995, 39, 139-143.
(6) For the first synthesis of (()-salviasperanol, see: Simmons, E. R.;
Sarpong, R. Org. Lett. 2006, 8, 2883-2886.
(7) For our synthesis of (()-komaroviquinone, see: Majetich, G.; Li,
Y.; Zou, G. Hetereocycles 2007, 73, 217-225.
(8) For our synthesis of (+)-komaroviquinone, see: Majetich, G.; Yu,
J.; Li, Y. Hetereocycles 2007, 73, 227-235.
(11) The spectroscopic data obtained for all new compounds were fully
consistent with the assigned structures. Reaction conditions have not been
optimized. All yields are isolated yields.
(12) (a) Jacobs, T. L.; Cramer, R.; Hanson, J. E. J. Am. Chem. Soc. 1942,
64, 233-235. (b) Raucher, S.; Bray, B. L. J. Org. Chem. 1987, 52, 2332-
2333.
(9) Brunson, H. A.; Kroeger, J. W. J. Am. Chem. Soc. 1940, 62, 36-44.
(10) (a) For our synthesis of (()-perovskone, see: Majetich, G.; Zhang,
Y. J. Am. Chem. Soc. 1994, 116, 4979-4980. (b) For the synthesis of (+)-
salvadione-A, see: Majetich, G.; Wang, Y.; Li, Y.; Vohs, J. K.; Robinson,
G. H. Org. Lett. 2003, 5, 3847-3850.
10.1021/ol701743c CCC: $40.75
© 2008 American Chemical Society
Published on Web 12/04/2007

Scheme 2
of the aryl ring and C(7) of the alkyne from ever becoming
faciliate the introduction of the C(10) and C(7) asymmetric
centers (Scheme 3). 1,2-Reduction of 10 using Corey’s CBS
protocol gave alcohol (1R)-14 in 91% yield and excellent
enantioselectivity.14 The final steps of our (-)-salviasperanol
synthesis benefitted from Simmons and Sarpong’s observa-
tion6 that epoxide 17 isomerizes to dihydrofuran 18 under
acidic conditions. We expected that the C(1) hydroxyl group
would direct the epoxidation to only the C(5), C(10)-double
bond,15 and that the subsequent rearrangement of epoxide
15 would produce dihydrofuran 16 with the desired config-
uration at C(7) and C(10). Indeed, treatment of dienol 14
with m-CPBA in CH2Cl2 at 0 °C in the presence of NaHCO3
for 1 h furnished only epoxy alcohol (1R)-15 in good yield.
spatially close enough to react. Not surprisingly, the cy-
clialkylation of 7 was unsuccessful. In contrast, Lindlar
hydrogenation13 of the triple bond in 7 cleanly gave cy-
clialkylation precursor 8, which upon treatment with excess
TiCl4 first formed intermediate 9, which subsequently lost
ethanol to give dienone 10 in 66% isolated yield.
Scheme 3
Scheme 4
1,2-Addition of lithium acetylide to ketone 5, followed
by mild acid hydrolysis, produced enynone 11 in 92% yield.
Stirring 11 with excess BF3-etherate and a 10% stoichio-
metric quantity of ethanethiol in CH2Cl2 at room temperature
for 12 h gave dienone 10 in 94% yield. Under these
conditions, vinyl sulfide 12 was formed rapidly (<1 h). If
an aliquot of the reaction mixture was worked up intermedi-
ate 12 could be isolated and characterized; however, longer
reaction times permitted the cyclialklyation of 12 to give
the seven-membered ring, and subsequent elimination of
ethanethiol from intermediate 13. This two-step sequence
represents a more efficient way to functionalize the central
carbocyclic ring in comparison with the Aren’s reagent/
reduction/and cyclialkylation route.
Epoxy alcohol (1R)-15, however, was acid sensitive preclud-
ing its acid-promoted isomerization. This dictated that the
C(1) hydroxyl group must either be protected or removed
before attempting to rearrange the C(5), C(10) epoxide.
Asymmetric reduction of the C(1) carbonyl would create
enantiomerically enriched allylic alcohol 14, which would
(13) (a) For experimental conditions, see: Overman, L. E.; Thompson,
A. S. J. Am. Chem. Soc. 1988, 110, 2248-2256. (b) Lipshutz, B. H.; Tirado,
R. J. Org. Chem. 1994, 59, 8307-8311.
(14) Corey, E. J.; Helal, C. J. Angew. Chem., Int. Ed. 1998, 37, 1986-
2012.
(15) Henbest, H. B.; Wilson, R. A. L. J. Chem. Soc. 1957, 1958-1965.
86
Org. Lett., Vol. 10, No. 1, 2008

In contrast, O-thiocarbamate 19 could be rearranged to
21 using trifluoroacetic acid (Scheme 5).6 The removal of
the thiocarbamate moiety was achieved by heating a toluene
solution of (1R)-21, with a catalytic amount of AIBN and
excess tri-n-butyltin hydride at 110 °C for a 30-min period.
These conditions provided salviasperanol dimethyl ether 18
in 76% yield from epoxide 19. Treatment of 18 with excess
sodium ethanethiolate in hot DMF cleaved the C(11) and
C(12) methyl ethers to furnish (-)-salviasperanol (3) in 86%
Scheme 5
1
yield. Our synthetic 3 displays H and 13C NMR, IR, and
MS spectra identical to those reported for the natural
sample.5 The application of this modified cyclialkylation
strategy to synthesize other icetexane natural products is
underway.18,19
Acknowledgment. We thank the National Science Foun-
dation for support of this research (Grant CHE-0506486).
Instead of using a common protecting group for the C(1)
hydroxyl group, crude 15 was treated with 1,1-thiocar-
bonyldiimidazole to give O-thiocarbamate 19 which could
be chromatographed and characterized (Scheme 4).16 Free
radical deoxygenation of 19, followed by isomerization of
vinyl epoxide 17 using catalytic trifluoroacetic acid (TFA),
produced salviasperanol dimethyl ether 18, but in low overall
yield. The isomerization of vinyl epoxides to dihydrofurans,
via a π-allyl copper intermediate, such as 20, is known even
in the presence of ethers and esters.17 However, treatment
of vinyl epoxide 19 with copper bis-hexafluoroacetylaceto-
nate [Cu(hfacac)2] only cleaved the O-thiocarbamate.
Supporting Information Available: Detailed experi-
mental procedures for the transformations described herein
and the spectroscopic data for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL701743C
(17) Batory, L. A.; McInnis, C. E.; Njardarso, J. T. J. Am. Chem. Soc.
2006, 128, 16054-16055.
(18) Grove, J. L.; Majetich, G. Presented at the 233rd National Meeting
of the American Chemical Society, Chicago, IL, March 2007; Paper ORGN
No. 375.
(16) RajanBabu, T. V.; Fukunaga, T.; Reddy, G. S. J. Am. Chem. Soc.
1989, 111, 1759-1769.
(19) For the synthesis of (+)-komarovispirone, see: Majetich, G.; Yu,
J. Org. Lett. 2008, 10, 89-92.
Org. Lett., Vol. 10, No. 1, 2008
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