Enantioselective synthesis of 5-epi-citreoviral using ruthenium-catalyzed asymmetric ring-closing metathesis

Article abstract of DOI:10.1021/ol901853t

Chiral ruthenium olefin metathesis catalysts can perform asymmetric ring-closing reactions in ≥90% ee with low catalyst loadings. To illustrate the practicality of these reactions and the products they form, an enantioselective total synthesis of 5-epi-ci

Full text of DOI:10.1021/ol901853t

ORGANIC
LETTERS
2009
Vol. 11, No. 21
4998-5001
Enantioselective Synthesis of
5-epi-Citreoviral Using
Ruthenium-Catalyzed Asymmetric
Ring-Closing Metathesis
Timothy W. Funk*
The Arnold and Mabel Beckman Laboratory of Chemical Synthesis, DiVision of
Chemistry and Chemical Engineering, California Institute of Technology,
Pasadena, California 91125, and the Department of Chemistry, Gettysburg College,
Gettysburg, PennsylVania 17325
tfunk@gettysburg.edu
Received August 10, 2009
ABSTRACT
Chiral ruthenium olefin metathesis catalysts can perform asymmetric ring-closing reactions in g90% ee with low catalyst loadings. To illustrate
the practicality of these reactions and the products they form, an enantioselective total synthesis of 5-epi-citreoviral was completed by using
an asymmetric ring-closing olefin metathesis reaction as a key step early in the synthesis. All of the stereocenters in the final compound were
set by using the chiral center generated by asymmetric olefin metathesis.
Asymmetric olefin metathesis has been extensively explored
since its initial report more than a decade ago.1 While most
of the focus has been on using high oxidation-state molyb-
denum alkylidene complexes,2 chiral ruthenium alkylidenes
(Figure 1) have been shown to catalyze asymmetric olefin
metathesis reactions efficiently and in g90% ee.3 Considering
the volume of work on asymmetric olefin metathesis there
have been very few applications of either molybdenum- or
ruthenium-catalyzed asymmetric olefin metathesis catalysts
in the synthesis of complex, biologically relevant com-
pounds.4 The air and moisture stability of ruthenium alky-
lidenes makes them attractive for use in complex molecule
synthesis. To illustrate the practicality of asymmetric olefin
metathesis and the utility of the products formed in these
(3) (a) Seiders, T. J.; Ward, D. W.; Grubbs, R. H. Org. Lett. 2001, 3,
3225–3228. (b) Van Veldhuizen, J. J.; Garber, S. B.; Kingsbury, J. S.;
Hoveyda, A. H. J. Am. Chem. Soc. 2002, 124, 4954–4955. (c) Van
Veldhuizen, J. J.; Gillingham, D. G.; Garber, S. B.; Kataoka, O.; Hoveyda,
A. H. J. Am. Chem. Soc. 2003, 125, 12502–12508. (d) Gillingham, D. G.;
Kataoka, O.; Garber, S. B.; Hoveyda, A. H. J. Am. Chem. Soc. 2004, 126,
12288–12290. (e) Van Veldhuizen, J. J.; Campbell, J. E.; Guidici, R. E.;
Hoveyda, A. H. J. Am. Chem. Soc. 2005, 127, 6877–6882. (f) Funk, T. W.;
Berlin, J. M.; Grubbs, R. H. J. Am. Chem. Soc. 2006, 128, 1840–1846. (g)
Berlin, J. M.; Goldberg, S. D.; Grubbs, R. H. Angew. Chem., Int. Ed. 2006,
45, 7591–7595.
(1) Fujimura, O.; Grubbs, R. H. J. Am. Chem. Soc. 1996, 118, 2499–
2500.
(2) For reviews on asymmetric olefin metathesis, see: (a) Schrock, R. R.;
Hoveyda, A. H. Angew. Chem., Int. Ed. 2003, 42, 4592–4633. (b) Hoveyda,
A. H. In Handbook of Metathesis; Grubbs, R. H., Ed.; Wiley-VCH:
Weinheim, Germany, 2003; Chapter 2.3. (c) Hoveyda, A. H.; Schrock, R. R.
Chem.sEur. J. 2001, 7, 945–950. For other examples, see: (d) Malcolmson,
S. J.; Meek, S. J.; Sattely, E. S.; Schrock, R. R.; Hoveyda, A. H. Nature
2008, 465, 933–937.
(4) (a) Burke, S. D.; Muller, N.; Beudry, C. M. Org. Lett. 1999, 1, 1827–
1829. (b) Weatherhead, G. S.; Cortez, G. A.; Schrock, R. R.; Hoveyda,
A. H. Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 5805–5809. (c) Gillingham,
D. G.; Hoveyda, A. H. Angew. Chem., Int. Ed. 2007, 46, 3860–3864. (d)
Sattely, E. S.; Meek, S. J.; Malcolmson, S. J.; Schrock, R. R.; Hoveyda,
A. H. J. Am. Chem. Soc. 2009, 131, 943–953.
10.1021/ol901853t CCC: $40.75
Published on Web 09/28/2009
 2009 American Chemical Society

(-)-citreoviridinol (8) have been isolated.8 The complexity
of the tetrahydrofuran and 2,6-dioxabicyclo[3.2.1]octane
rings have made these families of compounds attractive
synthetic targets, and citreoviral, which has been used as an
intermediate in syntheses of the more complex metabolites,
has been generated in racemic and enantioenriched forms.9
Unnatural (()-3-epi-citreoviral10 and (()-5-epi-citreoviral11
have also been made and could be used as synthetic
intermediates to access unnatural diastereomers of citreovir-
din and citreoviridinol. Of all of the syntheses of citreoviral
and its unnatural isomers, there has been only one report
that used asymmetric catalysis.12
It was suspected that (-)-5-epi-citreoviral ((-)-6) could
be generated from intermediate 11, which is easily accessible
by using ruthenium-catalyzed asymmetric ring-closing me-
tathesis (ARCM) (Scheme 1).3f The highly substituted
Figure 1. Chiral ruthenium olefin metathesis catalysts.
Scheme 1. Retrosynthesis of (-)-5-epi-Citreoviral ((-)-6)
reactions, an enantioselective synthesis of 5-epi-citreoviral
was undertaken.
(+)-Citreoviral (5) was isolated from Penicillium citre-
oViride in 1984 (Figure 2).5 Other structurally similar
tetrahydrofuran 9 was to be made from a Payne rearrange-
ment/epoxide opening sequence of bis-epoxide 10. Ideally
10 could be formed by using a substrate-directed bis-
epoxidation that would use the stereocenter generated by
ARCM.
The synthesis commenced as shown in Scheme 2. As
previously reported, gram quantities of 11 in 92% ee were
available from silyl ether 12 by using 0.75-0.8 mol % of
catalyst 2.3f Tamao-Fleming oxidation of 11 afforded 13
in 64% over two steps.13 It has been reported that a one-pot
olefin metathesis/Tamao-Fleming oxidation process is pos-
sible,14 but attempts to oxidize 11 to 13 without removing
the ruthenium byproduct by flash chromatography resulted
in an exothermic decomposition of hydrogen peroxide and
Figure 2. Citreoviral and related compounds.
metabolites were isolated from the same fungus (7 and 8),6
and most have been found to be potent inhibitors of
mitochondrial ATPase and oxidative phosphorylation.7 Ad-
ditionally, a number of naturally occurring stereoisomers of
(8) (a) Nishiyama, S.; Shizuri, Y.; Imai, D.; Yamamura, S. Tetrahedron
Lett. 1985, 26, 3243–3246. (b) Nishiyama, S.; Toshima, H.; Yamamura, S.
Chem. Lett. 1986, 1973–1976. (c) Nishiyama, S.; Shizuri, Y.; Toshima,
H.; Ozaki, M.; Yamamura, S.; Kawai, K.; Kawai, N.; Furukawa, K. Chem.
Lett. 1987, 515–518. (d) Lai, S.; Matsunaga, K.; Shizuri, Y.; Yamamura,
S. Tetrahedron Lett. 1990, 31, 5503–5506.
(5) (a) Shizuri, Y.; Nishiyama, S.; Imai, D.; Yamamura, S. Tetrahedron
Lett. 1984, 25, 4771–4774. (b) Nishiyama, S.; Shizuri, Y.; Yamamura, S.
Tetrahedron Lett. 1985, 26, 231–234.
(9) Murata, Y.; Kamino, T.; Aoki, T.; Hosokawa, S.; Kobayashi, S.
Angew. Chem., Int. Ed. 2004, 43, 3175–3177, and references cited therein.
(10) Williams, D. R.; White, F. H. J. Org. Chem. 1987, 52, 5067–5079.
(11) Peng, Z.-H.; Woerpel, K. A. Org. Lett. 2002, 4, 2945–2948.
(12) Trost, B. M.; Lynch, J. K.; Angle, S. R. Tetrahedron Lett. 1987,
28, 375–378.
(6) Sakabe, N.; Goto, T.; Hirata, Y. Tetrahedron 1977, 33, 3077–3081.
(7) (a) Boyer, P. D.; Chance, B.; Ernster, L.; Mitchell, P.; Racker, E.;
Slater, E. C. Annu. ReV. Biochem. 1977, 46, 955–1026. (b) Muller, J. L. M.;
Rosing, J.; Slater, E. C. Biochim. Biophys. Acta 1977, 462, 422–437. (c)
Gause, E. M.; Buck, M. A.; Douglas, M. G. J. Biol. Chem. 1981, 256,
557–559.
(13) Tamao, K.; Ishida, N.; Ito, Y.; Kumada, M. Org. Synth. 1990, 69,
96–102.
(14) Yao, Q. Org. Lett. 2001, 3, 2069–2072.
Org. Lett., Vol. 11, No. 21, 2009
4999

Scheme 2
.
Synthesis of Intermediate 10
Scheme 3. Proposed Mechanism of Formation of 19
opening generated intermediate 18, which, if protonated,
would have led to the expected 9. Instead intermediate 18
preferentially underwent a second intramolecular epoxide
opening, presumably through a puckered tetrahydrofuran ring
and a boat-like transition state, to afford 19. Interestingly,
compound 19 is a diastereomer of the 2,6-dioxabicyclo-
[3.2.1]octane core found in the citreoviridinols.6 This result
suggests that these compounds may be made efficiently by
using this methodology.
To access (-)-5-epi-citreoviral, the tetrahydropyran ring
of 19 needed to be cleaved. No simple, direct, ring-opening
process was available, so a modified approach to 5-epi-
citreoviral was taken. It was reasoned that if the epoxides in
intermediate 10 could be attacked by an internal nucleophile
at the less hindered positions under basic conditions (Scheme
3), then perhaps they could be opened at the more substituted
positions under acidic conditions.17 To test this theory, the
primary alcohol of 10 was oxidized in two steps to the
carboxylic acid (20), and upon exposure to p-toluenesulfonic
acid in benzene, compound 23 was isolated as a single
diastereomer in 68% yield over three steps (Scheme 4). No
purification was needed until after the cascade epoxide
opening, and no erosion of the absolute stereochemistry was
observed by chiral HPLC. Now instead of an ether (as in
19), a labile lactone was present in the ring that needed to
be cleaved. By using an acid-catalyzed epoxide opening in
place of the base-mediated approach initially envisioned, the
absolute stereochemistry of the tetrahydrofuran was the
opposite of that originally intended. Therefore, by making
no oxidation of silane 11. The primary alcohol of 13 was
selectively protected, and 14 was treated with MCPBA at 5
°C. Gratifyingly, the desired bis-epoxide (15) was isolated
as the major product in 44% yield over two steps.15 In this
single step, all of the remaining stereocenters needed to form
5-epi-citreoviral were installed. None of the starting alcohol
14 remained, and the only other compounds formed
were diastereomers of 15. When catalytic VO(acac)2 with
t-BuOOH as the stoichiometric oxidant was used, bis-epoxide
15 was isolated as a minor diastereomer in only 13% yield
over two steps. Finally, protection of the secondary alcohol
as a benzyl ether and removal of the silyl protecting group
afforded 10.
With compound 10 in hand, the crucial Payne rearrange-
ment/epoxide opening reaction was explored. Treatment of
10 with sodium hydroxide in aqueous tert-butyl alcohol at
75-80 °C led to complete consumption of the starting
material after 6 h. Instead of the expected substituted
tetrahydrofuran 9, 2,6-dioxabicyclo[3.2.1]octane 19 was
isolated as the only product in 87% yield. The structure of
19 is supported by two crosspeaks in the NOESY spectrum:
there is a through-space interaction between an axial
hydrogen on the tetrahydropyran methylene with a methine
hydrogen on the tetrahydrofuran ring and between the
tetrahydrofuran methyl doublet with the methine hydrogen
on the carbon bearing the benzyloxy group (Scheme 3).16
The formation of 19 can be rationalized as shown in Scheme
3. Payne rearrangement followed by a 5-endo-tet epoxide
(16) For a more detailed discussion of the structure of 19 and the
assignment of hydrogen atoms in the 1H NMR spectrum, see the Supporting
Information.
(17) For another example of an acid-catalyzed ring-opening of a bis-
epoxide in the synthesis of citreoviral and its stereoisomers see: Ebenezer,
W.; Pattenden, G. Tetrahedron Lett. 1992, 33, 4053–4056.
(15) For acyclic stereocontrol in allylic alcohol epoxidation, see: (a)
Sharpless, K. B.; Verhoeven, T. R. Aldrichim. Acta 1979, 12, 63–74. (b)
Rossiter, B. E.; Verhoeven, T. R.; Sharpless, K. B. Tetrahedron Lett. 1979,
20, 4733–4736. (c) Tomioka, H.; Suzuki, T.; Oshima, K.; Nozaki, H.
Tetrahedron Lett. 1982, 23, 3387–3390.
5000
Org. Lett., Vol. 11, No. 21, 2009

Scheme 4
.
Acid-Catalyzed Cascade Epoxide Opening
Scheme 5. Synthesis of (+)-5-epi-Citreoviral
this adjustment, (+)-5-epi-citreoviral would be formed
instead of the (-)-enantiomer. Conveniently, this modifica-
tion placed the benzyl protected secondary alcohol in the
correct stereochemical configuration found in 5-epi-citre-
oviral (6).
The final steps of the synthesis are shown in Scheme 5.
Intermediate 27 was accessible in three sequential steps in
an 80% yield from lactone 23 with no purification needed
until after the Wittig olefination. Compound 27 is a late-
stage intermediate in the synthesis of (()-5-epi-citreoviral
by the Woerpel group, and the final three steps used here
are slight modifications of those previously described.11,18
Compound (+)-6 was isolated in 3.7% yield over 15 steps,
substrate-directed bis-epoxidation and the acid-catalyzed
cascade epoxide-opening reaction used to generate the highly
substituted tetrahydrofuran ring. Additionally, a direct route
to a 2,6-dioxabicyclo[3.2.1]octane ring system was discov-
ered, which could be applied to the synthesis of more
complex, biologically relevant metabolites.
1
and the H and 13C NMR spectral data for (+)-6 matched
those published for (()-6.11
Acknowledgment. The author gratefully acknowledges
Prof. Robert H. Grubbs (Caltech) for support and encourage-
ment, Dr. Jacob Berlin (Rice University) for donating catalyst
2, and Prof. Tobias Ritter (Harvard University) for helpful
discussions.
In conclusion, ruthenium-catalyzed ARCM has been
applied to the synthesis of (+)-5-epi-citreoviral. The low
catalyst loading (<1 mol %), good yield, and high enantio-
meric excess made ARCM practical as an early step in the
process. All of the stereocenters in the final product were
set from the one chiral center generated in the ARCM
reaction. Other key steps in the synthesis were the acyclic,
Supporting Information Available: Complete experi-
mental procedures and product characterization. This material
is available free of charge via the Internet at http://pubs.acs.org.
(18) Attempts to improve the yield of the last step by using procedures
known to selectively oxidize a primary alcohol in the presence of a
secondary alcohol were unsuccessful.
OL901853T
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5001