Stereoselective reactions of a (-)-quinic acid-derived enone: Application to the synthesis of the core of scyphostatin

Article abstract of DOI:10.1021/ol034521d

(Matrix presented) A (-)-quinic acid-derived enone, with the trans-1, 2-diol protected as a 2,3-dimethoxybutanediyldioxy ketal, provides an excellent template for further highly stereoselective elaboration as exemplified by its conversion into the core of

Full text of DOI:10.1021/ol034521d

ORGANIC
LETTERS
2003
Vol. 5, No. 11
1943-1946
Stereoselective Reactions of a
(−)-Quinic Acid-Derived Enone:
Application to the Synthesis of the Core
of Scyphostatin
Lynne M. Murray, Peter O’Brien,* and Richard J. K. Taylor
Department of Chemistry, UniVersity of York, Heslington, York YO10 5DD, UK
paob1@york.ac.uk
Received March 25, 2003
ABSTRACT
A (−)-quinic acid-derived enone, with the trans-1,2-diol protected as a 2,3-dimethoxybutanediyldioxy ketal, provides an excellent template for
further highly stereoselective elaboration as exemplified by its conversion into the core of scyphostatin, a potent inhibitor of neutral
sphingomyelinase.
The conformationally rigid cyclohexenone 1, with the trans-
1,2-diol protected as a 2,3-dimethoxybutanediyldioxy ketal,
appears to be ideally suited to further stereoselective elabora-
tion and therefore should prove to be a useful synthetic
building block. Given our continued interest in the prepara-
tion of cyclohexane-based natural products,1,2 we have
explored the use of enone 1 in synthesis.
There are two published syntheses of enone 1. In 2000,
we reported the synthesis of racemic 1:3 LDA-mediated
diastereoselectiVe rearrangement of chiral (but racemic)
epoxide 3 (prepared in three steps from 1,4-cyclohexadiene)
gave allylic alcohol 2 (as a single diastereomer), and
subsequent oxidation afforded enone 1 (Scheme 1). Maycock
et al. then reported an efficient four-step synthesis of enone
(4R,5R)-1 starting from (-)-quinic acid4, and it is this route
to 1 that we have utilized in the present work.
In this paper, we describe a range of stereoselective
reactions of enone (4R,5R)-1 and its corresponding trimeth-
ylsilyl enol ether. With both enone (4R,5R)-1 and its enol
ether, there is very little steric bias on either face for
controlling stereoselective reactions of the π-systems. Indeed,
we invoke subtle stereoelectronic effects to explain the highly
stereoselective processes that are observed. Furthermore, to
exemplify enone (4R,5R)-1 as a useful synthetic building
block, its use in the synthesis of the core of scyphostatin is
also described. Scyphostatin5 is a cyclohexenone-based
naturally occurring inhibitor of neutral sphingomyelinase and
has attracted significant synthetic interest of late.2a,6
Scheme 1
(1) de Sousa, S. E.; O’Brien, P.; Pilgram, C. D. Tetrahedron 2002, 58,
4643.
(2) (a) Runcie, K.; Taylor, R. J. K. Org. Lett. 2001, 3, 3237. (b) Alcaraz,
L.; Macdonald, G.; Ragot, J. P.; Taylor, R. J. K. J. Org. Chem. 1998, 63,
3526.
(3) Kee, A.; O’Brien, P.; Pilgram, C. D.; Watson, S. T. Chem. Commun.
2000, 1521.
(4) Barros, M. T.; Maycock, C. D.; Ventura, M. R. J. Chem. Soc., Perkin
Trans. 1 2001, 166.
10.1021/ol034521d CCC: $25.00 © 2003 American Chemical Society
Published on Web 05/08/2003

To start with, gram quantities of enone (4R,5R)-1 were
prepared from (-)-quinic acid using minor modifications to
the literature route reported by Maycock et al.4 (Scheme 2).
Scheme 3
Scheme 2
alkylation of the lithium enolate of 1 with allyl halides under
a variety of conditions met with complete failure. Therefore,
our attention switched to reactions of silyl enol ether 6.
Two very useful transformations of silyl enol ether 6 were
found: reaction with m-CBPA (Rubottom oxidation9) fol-
lowed by treatment with TBAF gave 7 (92% yield), and
reaction with NBS gave 8 (66% yield), both as single
diastereomers (Scheme 4). In both adducts 7 and 8, the
Scheme 4
In a one-step process (reported as unpublished work in a
review article7), (-)-quinic acid was converted into bis-ketal
4 with concomitant methyl ester formation (99% yield). The
2,3-dimethoxybutanediyldioxy ketal group, introduced by
Ley and co-workers,7,8 selectively protects the trans-1,2-diol
and provides a conformational lock in enone (4R,5R)-1.
Conversion of bis-ketal 4 into ketone 5 via ester reduction
and subsequent cleavage of the 1,2-diol following the
published procedure proved to be problematic in our hands.
Eventually, reproducible yields of 75% over the two steps
were obtained using a modified workup procedure after the
DIBAL-H step (see Supporting Information for full details).
Elimination of the hydroxyl group in ketone 5 proceeded
uneventfully to furnish enone (4R,5R)-1.
relative stereochemistry was assigned on the basis of the
small J coupling constant of 3.0-3.5 Hz between H-5
(known axial orientation due to the bis-ketal protecting
group) and H-6.
3
The exclusive axial attack on silyl enol ether 6 using
m-CPBA and NBS as electrophiles is noteworthy. High levels
of stereoselectivity using these types of reactions are usually
governed by steric factors, and in previously reported
reactions of conformationally locked but sterically unbiased
silyl enol ethers with m-CPBA10 or NBS,11 the sense and
degree of stereoselectivity is quite varied and not predictable.
The complete stereocontrol exhibited by electrophilic attack
on silyl enol ether 6 (which has no obvious steric bias) is a
consequence of the conformational rigidity imparted by the
trans-diequatorial-protected 1,2-diol and the stereoelectronic
preference for axial attack on the electron-rich C-6 (avoiding
a twist boat conformation12).
Initially, we envisaged exploring R-functionalization of
enone (4R,5R)-1 via its enolate. To demonstrate that the
enolate could be formed without elimination of the â-alkoxyl
group, enone (4R,5R)-1 was deprotonated with LHMDS in
THF at -78 °C for 30 min and then reacted with Me3SiCl.
1
After workup, analysis by H NMR spectroscopy indicated
quantitative formation of silyl enol ether 6 (62% isolated
yield after chromatography; Scheme 3). Satisfied that the
enolate could be generated without â-elimination, we inves-
tigated alkylation reactions of the lithium enolate. Direct
(5) Tanaka, M.; Nara, F.; Suzuki-Konagai, K.; Ogita, T. J. Am. Chem.
Soc. 1997, 119, 7871.
(6) (a) Takagi, R.; Miyanaga, W.; Yukiko, T.; Ohkata, K. Chem.
Commun. 2002, 2096. (b) Fujioka, H.; Kotoku, N.; Sawama, Y.; Nagatomi,
Y.; Kita, Y. Tetrahedron Lett. 2002, 43, 4825. (c) Izuhara, T.; Yokota, W.;
Inoue, M.; Katoh, T. Heterocycles 2002, 56, 553. (d) Izuhara, T.; Katoh,
T. Org. Lett. 2001, 3, 1653. (e) Izuhara, T.; Katoh, T. Tetrahedron Lett.
2000, 41, 7651. (f) Gurjar, M. K.; Hotha, S. Heterocycles 2000, 53, 1885.
(g) Hoye, T. R.; Tennakoon, M. A. Org. Lett. 2000, 2, 1481. (h) Saito, S.;
Tanaka, N.; Fujimoto, K.; Kogen, H. Org. Lett. 2000, 2, 505.
(7) Ley, S. V.; Baeschlin, D. K.; Dixon, D. J.; Foster, A. C.; Ince, S. J.;
Priepke, H. W. M.; Reynolds, D. J. Chem. ReV. 2001, 101, 53.
(8) Hense, A.; Ley, S. V.; Osborn, H. M. I.; Owen, D. R.; Poisson,
J.-F.; Warriner, S. L.; Wesson, K. E. J. Chem. Soc., Perkin Trans. 1 1997,
2023.
(9) Rubottom, G. M.; Gruber, J. M.; Juve, H. D.; Charleson, D. A. Org.
Synth. 1986, 64, 118.
(10) (a) Jones, T. K.; Denmark, S. E. J. Org. Chem. 1985, 50, 4037. (b)
Baudouy, R.; Maliverney, C. Tetrahedron 1988, 44, 471. (c) Cain, C. M.;
Cousins, R. P. C.; Coumbarides, G.; Simpkins, N. S. Tetrahedron 1990,
46, 523. (d) Majewski, M.; Irvine, N. M.; MacKinnon, J. Tetrahedron:
Asymmetry 1995, 6, 1837. (e) Minor, K. P.; Overman, L. E .Tetrahedron
1997, 53, 8927.
(11) (a) Parker, K. A.; Dermatakis, A. J. Org. Chem. 1997, 62, 6692.
(b) Kreiser, W.; Ko¨rner HelV. Chim. Acta 1999, 82, 1610. (c) Paquette, L.
A.; Wang, X. J. Org. Chem. 1994, 59, 2052.
1944
Org. Lett., Vol. 5, No. 11, 2003

We have already noted that Luche reduction (NaBH4/
CeCl3) of enone (4R,5R)-1 occurs via axial attack of hydride
on the CdO group to give the corresponding allylic alcohol.3
To further probe the stereoelectronic preferences in this
system, enone (4R,5R)-1 was subjected to a Diels-Alder
reaction. Thus, enone (4R,5R)-1 was converted into a single
diastereomer of Diels-Alder adduct 9 on reaction with
cyclopentadiene in the presence of Et2AlCl (82% isolated
yield; Scheme 5).13
Scheme 7
Scheme 5
(N-SMASE). To date, no total synthesis of scyphostatin has
been reported, although several approaches to core structures
have appeared recently.2a,6
Our strategy toward R-allyl scyphostatin model core 12
is outlined in Scheme 7. Two key features are (i) stereose-
lective R-hydroxylation of a silyl enol ether derived from
R-allyl enone 10 or 11 in which axial attack at C-6
(analogous to 6 f 7, see Scheme 4) would establish the
required R-hydroxyl relative stereochemistry in 12 and (ii)
use of the protected trans-1,2-diol functionality in 10 or 11
as a masked epoxide in which subsequent regioselective
activation of the less sterically hindered C-4 hydroxyl group
would lead to the required epoxide stereochemistry in 12.
Furthermore, the absolute stereochemistry of the core of
scyphostatin can be derived from that present in (-)-quinic
acid via this approach. Katoh et al. have also utilized (-)-
quinic acid as starting material in a different approach to
scyphostatin core compounds.6d,e
Adduct 9 was identified as the expected endo-diastereomer
by a 6.1% NOE between an alkene proton and H-5. Further
3
NOE analysis together with a J coupling constant of 8.0
Hz between H-3 and H-4 allowed assignment of the C-3/
C-4 stereochemistry. This highly stereoselective Diels-Alder
reaction also proceeds via a stereoelectronically preferred
axial attack on the electron-deficient C-3 carbon.
For our proposed scyphostatin studies (vide infra), we
wished to incorporate an R-allyl side chain onto enone
(4R,5R)-1, but as discussed, direct allylation of the lithium
enolate was not successful. Instead, we investigated Keck
allylation14 of R-bromo enone 8 using allyltributyltin and
AIBN. Additionally, this would provide a further test of the
preferential axial attack on the sp2 carbon R to the carbonyl
in enone (4R,5R)-1. Reaction of R-bromo enone 8 with
allyltributyltin at 80 °C in toluene (with AIBN) gave a 74%
isolated yield of an inseparable 90:10 mixture of R-allylated
The details of the successful and highly stereoselective
synthesis of scyphostatin model core 12 are outlined in
Scheme 8. First of all, we discovered that it was not possible
to convert the major R-allyl diastereomer 10 into a silyl enol
ether (e.g., 13) using either LHMDS/Me3SiCl or Et3N/R3-
SiX (R ) Me or Et; X ) Cl or OTf). Presumably, an axially
oriented proton at C-4 (equatorial allyl group as in 11) is
required to facilitate silyl enol ether formation, and so
conditions for epimerizing 10 into 11 (equatorial allyl group)
were sought. Some epimerization of 10 into 11 was observed
using NaOMe in methanol, but it was accompanied by
decomposition (probably via elimination of the â-alkoxyl
group). More success was obtained using DBU in toluene
at 80 °C, but after 16 h, epimerization was only partially
complete. Therefore, we attempted to directly form a
3
enones 10 and 11, identified by analysis of the J coupling
constants between H-5 and H-6 (Scheme 6). Thus, an sp2-
hybridized radical at C-6 undergoes preferential axial attack.
Scheme 6
(12) (a) Matthews, R. S.; Girgenti, S. J.; Folkers, E. A. J. Chem. Soc.,
Chem. Commun. 1970, 708. (b) House, H. O.; Umen, M. J. J. Org. Chem.
1973, 38, 1000. (c) Skaddan, M. B.; Wu¨st; Katzenellenbogen, J. A. J. Org.
Chem. 1999, 64, 8108.
(13) For examples of related Diels-Alder reactions, see: (a) Jeroncic,
L. O.; Cabal, M.-P.; Danishefsky, S. J.; Shulte, G. M. J. Org. Chem. 1991,
56, 387. (b) Millan, D. S.; Pham, T. T.; Lavers, J. A.; Fallis, A. G.
Tetrahedron Lett. 1997, 38, 795.
(14) (a) Keck, G. E.; Yates, J. B. J. Am. Chem. Soc. 1982, 104, 5829.
(b) Keck, G. E.; Enholm, E. J.; Yates, J. B.; Wiley, M. R. Tetrahedron
1985, 41, 4079. (c) Umehare, M.; Honnami, H.; Hishida, S.; Kawata, T.;
Ohba, S.; Zen, S. Bull. Chem. Soc. Jpn. 1993, 66, 562. (d) Bamford, S. J.;
Luker, T.; Speckamp, W. N.; Hiemstra, H. Org. Lett. 2000, 2, 1157.
To demonstrate the usefulness of these highly stereo-
selective reactions of enone (4R,5R)-1 in synthesis, we
identified the core of scyphostatin (Scheme 7) as a viable
target. Scyphostatin was isolated in 19975 from a mycelial
extract of Dasyscyphus mollisimus, and it remains the most
potent inhibitor of the enzyme neutral sphingomyelinase
Org. Lett., Vol. 5, No. 11, 2003
1945

3.2% NOE between the hydroxyl proton and H-4 and by
NOEs between H-5 and protons on the allyl side chain. The
conversion of R-hydroxy enone 14 into model core com-
pound 12 was carried out via three steps without isolation
of any of the intermediates. Deprotection of the bis-ketal
protecting group using TFA-water8 was followed by me-
sylation using 1 equiv of mesyl chloride. Finally, treatment
of the crude mesylate with 0.1 M aqueous NaOH (Katoh’s
conditions6d,e) gave epoxy enone 12 {[R]D +31.6 (c 0.35 in
CHCl3)} as the only isolable diastereomeric product in 55%
Scheme 8
1
yield over the three steps. The H NMR spectrum of 12 in
acetone-d6 was identical to that reported for racemic 12,2a
thus confirming the epoxide stereochemistry and establishing
that regioselective mesylation of the least hindered C-4
hydroxyl group in 15 must have occurred. Thus, a highly
stereoselective, 11-step synthesis of enantiomerically pure
scyphostatin core 12 starting from (-)-quinic acid has been
achieved.
In summary, we report a selection of highly stereoselective
reactions of enone (4R,5R)-1 (derived from (-)-quinic acid).
These include, R-hydroxylation, R-bromination, CdO reduc-
tion, Diels-Alder reaction with cyclopentadiene, and radical
R-allylation. In particular, enone (4R,5R)-1 can be converted
in just eight steps into a scyphostatin model core compound
12 in enantiomerically pure form. On the basis of our
findings, it seems likely that enone (4R,5R)-1 will be a useful
building block for future synthetic endeavors.
trimethylsilyl enol ether from the 90:10 mixture of 10 and
11 by reaction with DBU and Me3SiCl in toluene at 80 °C
for 18 h. To our surprise and delight, almost complete
epimerization was observed: we isolated a 93% yield of a
95:5 mixture of 11 and 10. Silyl enol ether formation was
never observed under these conditions.
Acknowledgment. We thank the BBSRC and Hoffman-
La-Roche for a CASE award (to L.M.M.) and Dr. Graeme
McAllister for carrying out the NOE experiments.
The remainder of the synthesis of scyphostatin core 12
proceeded as anticipated. Thus, the 95:5 mixture of 11 and
10 was converted into silyl enol ether 13 (64% isolated yield)
using Et3SiOTf/Et3N. Rubottom oxidation of 13 using the
same conditions as for 6 f 7 (see Scheme 4) furnished a
single diastereomer of R-hydroxy enone 14 (64% isolated
yield). The expected axial attack at C-6 was confirmed by a
Supporting Information Available: Full details on the
synthesis of enone (4R,5R)-1 and on the synthesis, charac-
terization, and 1H NMR spectra of all intermediates en route
to epoxy enone 12. This material is available free of charge
via the Internet at http://pubs.acs.org.
OL034521D
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Org. Lett., Vol. 5, No. 11, 2003