A short and efficient route to novel scyphostatin analogues

Article abstract of DOI:10.1021/ol0164132

Equation presented Several novel scyphostatin analogues have been prepared in up to 18% yield over five steps from commercially available 4-bromoguaiacol, utilizing an organometallic addition to afford the desired syn-hydroxy-epoxides.

Full text of DOI:10.1021/ol0164132

ORGANIC
LETTERS
2
001
Vol. 3, No. 21
237-3239
A Short and Efficient Route to Novel
Scyphostatin Analogues
3
Karen A. Runcie and Richard J. K. Taylor*
Department of Chemistry, UniVersity of York, Heslington, York, YO10 5DD, U.K.
rjkt1@york.ac.uk
Received July 10, 2001
ABSTRACT
Several novel scyphostatin analogues have been prepared in up to 18% yield over five steps from commercially available 4-bromoguaiacol,
utilizing an organometallic addition to afford the desired syn-hydroxy-epoxides.
Scyphostatin (1) was first isolated in 1997 from a mycelial
extract of the microorganism Dasyscyphus mollissimus
SANK-13892 by Ogita et al. It was found to exhibit
selective inhibitory activity against the enzyme neutral
sphingomyelinase (N-SMase) and to date remains the most
potent of the few known inhibitors of this enzyme. It is
believed that inhibition of N-SMase may lead to treatments
for inflammatory and autoimmune disorders because cer-
amide, a product of sphingomyelin hydrolysis by N-SMase,
plays a key role in these disease pathways.2
synthesis and its stereochemistry unambiguously confirmed.4
The highly functionalized epoxycyclohexenone nucleus of
scyphostatin is noteworthy from a structural and synthetic
viewpoint. Several papers have recently been published
1
The structure of scyphostatin (1, Figure 1) was determined
by extensive spectroscopic and derivatization studies, al-
though the stereochemistry of the side chain methyl groups
was not initially assigned. Subsequent degradation studies
established the absolute configuration of scyphostatin and
3
revealed the 14′R,10′S,8′R configuration of the side chain.
The side chain unit was successfully prepared by total
(1) Tanaka, M.; Nara, F.; Suzuki-Konagai, K.; Hosoya, T.; Ogita, T. J.
Am. Chem. Soc. 1997, 119, 7871-7872.
(
2) Kolesnick, R.; Golde, D. W. Cell 1994, 77, 325-328. For recent
advances, see: Arnez, C.; Thutewohl, M.; Block, O.; Waldmann, H.;
Altenbach, H.-J.; Giannis, A. Chembiochem 2001, 141-143.
Figure 1. Structure of scyphostatin (1) and cyclohexenone
analogues 2 and 3.
(
3) Saito, S.; Tanaka, N.; Fujimoto, K.; Kogen, H. Org. Lett. 2000, 2,
5
05-506.
(
4) Hoye, T. R.; Tennakoon, M. A. Org. Lett. 2000, 2, 1481-1483.
1
0.1021/ol0164132 CCC: $20.00 © 2001 American Chemical Society
Published on Web 09/26/2001

concerning the synthesis of scyphostatin analogues, but as
yet, the final target has remained elusive. Gurjar and Hotha
conditions developed in our laboratory12 to give 5 in an
excellent 81% yield. Bromo-epoxide 5 could be stored in
the freezer under nitrogen for 4-5 weeks without noticeable
decomposition (Scheme 2).
5
reported a preparation of dihydroxylated cyclohexenone 2
6
starting from glucose, and Katoh and Izuhara used quinic
7
acid to prepare benzyl analogue 3a. More recently, this
pathway was extended to the preparation of the potential
scyphostatin precursor 3b.
Scheme 2a
As part of our ongoing research into the preparation of
8
epoxycyclohexenone-based natural products, we were par-
ticularly interested in a total synthesis of scyphostatin. We
envisaged that the highly functionalized nature of the
cyclohexenone fragment 4 would provide a suitable challenge
to the organometallic methodology developed in our manu-
mycin synthesis8b and felt that the unsaturated side chain
could be prepared using our recently developed in situ
oxidation-Wittig procedure.9
a
3
Reagents and conditions: (a) iodosobenzene diacetate, CH OH,
0
2
°C, 90-98%; (b) tert-butylhydroperoxide, 1,3,4,6,7,8-hexahydro-
H-pyrimido[1,2-a]pyrimidine, 0 °C, 81%.
In view of the interest in scyphostatin analogues, we first
set out to establish an efficient racemic route to cyclo-
hexenone analogues of scyphostatin. This Letter outlines our
progress. The approach is shown in retrosynthetic form in
Scheme 1.
To demonstrate the generality of our approach, a range of
organometallic reagents was employed in the key addition
step (Table 1).
Scheme 1
Table 1. Organometallic Addition to Epoxyketone 5
The key intermediate is bromide 5 which, on the basis of
our manumycin studies,8b we anticipated would undergo
stereoselective epoxide-directed organometallic addition, with
subsequent functional group interconversion giving the
required target 4. We intended to prepare 5 by epoxidation
of the known10 bromide 6, which we felt should be readily
available by oxidation of 4-bromoguaiacol (7). We chose
the bromo-substituted dienone 6 since the corresponding
1
3
The additions proceeded smoothly, giving adducts 8a-d
unsubstituted compound is known to undergo facile dimer-
14
ization by a Diels-Alder pathway.11
as single diastereomers in modest to good yields, with polar
decomposition products making up the material balance. The
predicted syn-stereochemistry was confirmed for the allyl
adduct 8a by X-ray crystallographic analysis (Figure 2).15
Elaboration of the allyl side chain could provide access to
scyphostatin itself.
With these results in hand, the remaining steps in our
proposed route involved reductive debromination of vinyl
bromides 8a-d and ketal hydrolysis (Scheme 3).
Starting from commercially available 4-bromoguaiacol (7),
oxidation using iodosobenzene diacetate in the presence of
methanol gave rise to bromocyclohexa-2,4-dienone 6 in
excellent yield. The presence of the bromide atom does
indeed reduce the propensity for dimerization, although some
dimerization is observed on storage. Compound 6 was thus
prepared and immediately subjected to epoxidation under
(
(
(
(
5) Gurjar, M. K.; Hotha, S. Heterocycles 2000, 53, 1885-1889.
6) Katoh, T.; Izuhara, T. Tetrahedron Lett. 2000, 41, 7651-7655.
7) Katoh, T.; Izuhara, T. Org. Lett. 2001, 3, 1653-1656.
(12) Genski, T.; Macdonald, G.; Wei, X.; Lewis, N.; Taylor, R. J. K.
Synlett 1999, 795-797.
8) For examples, see: (a) McKillop, A.; McLaren, L.; Taylor, R. J. K.;
(13) When ethyl- and cyclopentylmagnesium bromide were employed,
the product (possibly the corresponding secondary alcohol resulting from
hydride addition) was exceptionally unstable and decomposed violently upon
concentration.
Watson, R. J.; Lewis, N. J. Chem. Soc., Perkin Trans. 1 1996, 1385-1393.
b) Alcaraz, L.; Macdonald, G.; Ragot, J.; Lewis, N. J.; Taylor, R. J. K.
Tetrahedron 1999, 55, 3707-3716.
(
(14) All new compounds were fully characterized by H and 13C NMR
1
(
(
(
9) Wei, X.; Taylor, R. J. K. Tetrahedron Lett. 1998, 39, 3815-3818.
10) Mitchell, A. S.; Russell, R. A. Tetrahedron 1997, 53, 4387-4410.
11) Gao, S.-Y.; Lin, Y.-L.;. Rao, P. D.; Liao, C.-C. Synlett 2000, 421-
spectroscopy and HRMS/microanalysis.
(15) Further confirmation of the syn-stereochemistry of the organometallic
adducts was obtained by X-ray analysis of 10d.
4
23 and references therein.
3238
Org. Lett., Vol. 3, No. 21, 2001

THF at reflux containing catalytic AIBN were subjected to
a very slow addition of tributyltin hydride (typically addition
over 6 h). This approach, while still unoptimized, proved
markedly more successful and the results are summarized
in Table 2.
Table 2. Reduction of Vinyl Bromides 8a-d Followed by
Ketal Hydrolysis
Figure 2. ORTEP drawing of 8a (50% probability thermal
ellipsoids; CCDC 165946).
Initial attempts focused on ketal hydrolysis followed by
debromination (path A). However, while ketal hydrolysis
16
proceeded smoothly using Montmorillonite K10 (typically
in yields of 65-70%), the resulting vinyl bromides 9a-d
proved almost completely resistant to reductive debromina-
tion, giving very low yields of impure products. Therefore,
we turned our attention to initial reduction of vinyl bromides
As can be seen from Table 2, reduction of vinyl bromides
a-d under standard conditions gave rise to adducts 10a-d
8
in good to excellent yields. Subsequent ketal hydrolysis
proceeded smoothly to furnish a range of scyphostatin
analogues (4a-d) with spectral data in accordance with that
8a-d using tributyltin hydride and subsequent ketal hy-
1
7
of the natural product.
drolysis (path B). Dilute solutions of compounds 8a-d in
In conclusion, we have developed a novel and extremely
concise route toward the highly functionalized cyclohexenone
nucleus of scyphostatin (1) utilizing organometallic addition
reactions as the key step. We have shown our synthesis to
be general, producing a range of novel analogues of
scyphostatin. We are currently working toward an asym-
metric version of our methodology as well as a total synthesis
of scyphostatin itself.
Scheme 3a
Acknowledgment. We thank the University of York for
financial support. Miss Phillipa Timmins is gratefully
acknowledged for assistance with X-ray crystallography as
is Dr. T. A. Dransfield for mass spectrometry services.
Supporting Information Available: Experimental pro-
cedures and analytical data for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL0164132
(16) Gautier, E. C. L.; Graham, A. E.; McKillop, A.; Standen, S. P.;
Taylor, R. J. K. Tetrahedron Lett. 1997, 38, 1881-1884.
a
Reagents and conditions: (a) Montmorillonite K10, CH
SnH, AIBN, THF, reflux.
2
Cl
2
,
13
1
(
17) C NMR data for cyclohexenone nucleus of scyphostatin: δC (CD3-
rt; (b) Bu
3
OD, 360 MHz) 49.8, 58.7, 78.0, 132.5, 146.6, 201.0. For compound 4a:
δC (CD3OD, 270 MHz) 48.4, 58.0, 78.1, 132.4, 146.7, 199.6.
Org. Lett., Vol. 3, No. 21, 2001
3239