Short and efficient route to the fully functionalized polar core of scyphostatin

Article abstract of DOI:10.1021/ol0506359

(Chemical Equation Presented) Diastereoselective oxidative dearomatization of benzopyran 5 to the corresponding p-quinol 9b allows a fast, efficient, and versatile entry to scyphostatin's polar epoxycyclohexenone moiety as demonstrated by the preparation

Full text of DOI:10.1021/ol0506359

ORGANIC
LETTERS
2005
Vol. 7, No. 11
2245-2248
Short and Efficient Route to the Fully
Functionalized Polar Core of
Scyphostatin
Emmanuel N. Pitsinos* and Ana Cruz
Laboratory of Natural Products Synthesis and Bioorganic Chemistry,
Institute of Physical Chemistry, NCSR “Demokritos”, P.O. Box 60228,
GR-153 10 Aghia ParaskeVi, Athens, Greece
pitsinos@chem.demokritos.gr
Received March 24, 2005
ABSTRACT
Diastereoselective oxidative dearomatization of benzopyran 5 to the corresponding p-quinol 9b allows a fast, efficient, and versatile entry to
scyphostatin’s polar epoxycyclohexenone moiety as demonstrated by the preparation of its palmitoyl analogue 16 (R (CH2)14CH3).
)
Neutral sphingomyelinase (N-SMase) has emerged as a
promising pharmacological target for the treatment of
inflammation and immunological and neurological disorders.1
Among the many low molecular weight N-SMase inhibitors
of natural2 or synthetic origin3 known to date, scyphostatin
(1, Scheme 1) stands out as the most potent and specific
one. This natural product was isolated in 1997 by Ogita and
co-workers from a culture broth of Dasyscyphus mollisimus
SANK-13892 and features a novel, aminopropanol-substi-
tuted, epoxycyclohexenone polar core and a polyunsaturated
fatty acid moiety.4 Inhibitory activity was mainly attributed
to the polar moiety of the molecule, while the fatty side chain
was blamed for its short half-life in the solid state, even when
stored at -20 °C. Interestingly and in order to elucidate the
(3) (a) Hakogi, T.; Monden, Y.; Iwama, S.; Katsumura, S. Org. Lett.
2000, 2, 2627-2630. (b) Arenz, C.; Giannis, A. Angew. Chem., Int. Ed.
2000, 39, 1440-1442. (c) Arenz, C.; Gartner, M.; Wascholowski, V.;
Giannis, A. Bioorg. Med. Chem. 2001, 9, 2901-2904. (d) Arenz, C.;
Giannis, A. Eur. J. Org. Chem. 2001, 137-140. (e) Yokomatsu, T.; Takechi,
H.; Akiyama, T.; Shibuya, S.; Kominato, T.; Soeda, S.; Shimeno, H. Bioorg.
Med. Chem. Lett. 2001, 11, 1277-1280. (f) Hakogi, T.; Monden, Y.; Taichi,
M.; Iwama, S.; Fujii, S.; Ikeda, K.; Katsumura, S. J. Org. Chem. 2002, 67,
4839-4846. (g) Lindsey, C. C.; Gomez-Diaz, C.; Villalba, J. M.; Pettus,
T. R. R. Tetrahedron 2002, 58, 4559-4565. (h) Pitsinos, E. N.; Wascholow-
ski, V.; Karaliota, S.; Rigou, C.; Couladouros, E. A.; Giannis, A.
ChemBioChem 2003, 4, 1223-1225. (i) Yokomatsu, T.; Murano, T.;
Akiyama, T.; Koizumi, J.; Shibuya, S.; Tsuji, Y.; Soeda, S.; Shimeno, H.
Bioorg. Med. Chem. Lett. 2003, 13, 229-236. (j) Taguchi, M.; Sugimoto,
K.; Goda, K.-i.; Akama, T.; Yamamoto, K.; Suzuki, T.; Tomishima, Y.;
Nishiguchi, M.; Arai, K.; Takahashi, K.; Kobori, T. Bioorg. Med. Chem.
Lett. 2003, 13, 1963-1966. (k) Taguchi, M.; Goda, K.-i.; Sugimoto, K.;
Akama, T.; Yamamoto, K.; Suzuki, T.; Tomishima, Y.; Nishiguchi, M.;
Arai, K.; Takahashi, K.; Kobori, T. Bioorg. Med. Chem. Lett. 2003, 13,
3681-3684. (l) Deigner, H.-P. (Biofrontera Pharmaceuticals GmbH). U.S.
Patent US6790992B2, 2004.
(1) Wascholowski, V.; Giannis, A. Drug News Perspect. 2001, 14, 581-
590.
(2) (a) Uchida, R.; Tomoda, H.; Dong, Y.; Omura, S. J. Antibiot. 1999,
52, 572-574. (b) Tanaka, M.; Nara, F.; Yamasato, Y.; Masuda-Inoue, S.;
Doi-Yoshioka, H.; Kumakura, S.; Enokita, R.; Ogita, T. J. Antibiot. 1999,
52, 670-673. (c) Tanaka, M.; Nara, F.; Yamasato, Y.; Ono, Y.; Ogita, T.
J. Antibiot. 1999, 52, 827-830. (d) Arenz, C.; Thutewohl, M.; Block, O.;
Waldmann, H.; Altenbach, H.-J.; Giannis, A. ChemBioChem 2001, 2, 141-
143. (e) Uchida, R.; Tomoda, H.; Arai, M.; Omura, S. J. Antibiot. 2001,
54, 882-889.
10.1021/ol0506359 CCC: $30.25
© 2005 American Chemical Society
Published on Web 04/28/2005

Scheme 1. Transformation of Scyphostatin (1) to Ketal 3 by
Scheme 2. Retrosynthetic Plan for Scyphostatin’s Polar Corea
Ogita and Co-workers
a PIFA ) [bis(trifluoroacetoxy)iodo]benzene.
absolute stereochemistry of the hydrophilic head moiety,
Ogita and co-workers have succeeded in converting scy-
phostatin to hemiketal 2 and ketal 3.4a
different conjugation, would exhibit different reactivity, thus
allowing regioselective epoxidation. Concerning the stereo-
selectivity of this transformation, we planned to exploit the
directing effect of the tertiary hydroxyl group at C4. This
left us with the challenge of controlling the stereochemistry
of 4, hopefully by diastereoselective oxidative dearomati-
zation8 of benzopyran 5. Such benzopyranes can be easily
prepared from 2,4-dihydroxybenzaldehyde (6).9
Thus, the required aminobenzopyrane 8a (R1 ) Bn,
Scheme 3) was easily prepared, in analogy with the known
aminobenzopyrane 8b (R1 ) Me),9 in three steps and 61%
overall yield from 4-benzyloxy-2-hydroxy-benzaldehyde
(7).10 To explore the feasibility of our strategy, we chose
palmitic acid as a surrogate for the fatty side chain of
scyphostatin and decided to utilize racemic aminobenzopy-
rane 8a.11 Hence, coupling of amine 8a with palmitic acid
and subsequent hydrogenolysis of the benzyl protective group
furnished phenol 5 in 83% yield.
Attempted oxidation of this substrate, employing [bis-
(trifluoroacetoxy)iodo]benzene (PIFA) in wet acetonitrile,12
was disappointing in that an almost equimolar, yet at least
separable, mixture of diastereomeric quinols 9a and 9b was
formed in 43% combined yield. The relative stereochemistry
of the two isomers was initially assigned on the basis of the
comparative analysis of their 1H NMR and NOESY spectra.13
Not satisfied with the observed lack of diastereoselectivity,
In light of its significant biological activity and structural
novelty, it is not surprising that scyphostatin, and in particular
its polar moiety,5 has attracted considerable attention either
as a target for synthetic studies6 or as a prototype for the
design of novel N-SMase inhibitors.3b-d,h Recently, an elegant
total synthesis of (+)-scyphostatin has been disclosed by
Katoh and co-workers.6k However, more than 20 synthetic
steps were required to establish the fully functionalized core
starting from D-arabinose. This prompted us to disclose herein
an alternative, shorter approach to the fully functionalized
polar core of scyphostatin.
Key to the conception of our retrosynthetic plan was the
realization that the transformations of scyphostatin to hemiket-
al 2 and ketal 3 are in principle reversible. Thus, ketal 3
(Scheme 2) could serve as an advanced key intermediate.
The introduction of additional oxygenation at C7 led us to
envision p-quinol 4 as a suitable precursor.7 We anticipated
that the two double bonds present in 4, by merit of their
(4) (a) Tanaka, M.; Nara, F.; Suzuki-Konagai, K.; Hosoya, T.; Ogita, T.
J. Am. Chem. Soc. 1997, 119, 7871-7872. (b) Nara, F.; Tanaka, M.; Hosoya,
T.; Suzuki-Konagai, K.; Ogita, T. J. Antibiot. 1999, 52, 525-530. (c) Nara,
F.; Tanaka, M.; Masuda-Inoue, S.; Yamasato, Y.; Doi-Yoshioka, H.; Suzuki-
Konagai, K.; Kumakura, S.; Ogita, T. J. Antibiot. 1999, 52, 531-535. (d)
Saito, S.; Tanaka, N.; Fujimoto, K.; Kogen, H. Org. Lett. 2000, 2, 505-
506.
(5) For syntheses of the scyphostatin side chain, see: (a) Hoye, T. R.;
Tennakoon, M. A. Org. Lett. 2000, 2, 1481-1483. (b) McAllister, G. D.;
Taylor, R. J. K. Tetrahedron Lett. 2004, 45, 2551-2554. (c) Tan, Z.;
Negishi, E.-i. Angew. Chem., Int. Ed. 2004, 43, 2911-2914.
Scheme 3. Preparation of Phenol 5
(6) (a) Izuhara, T.; Katoh, T. Tetrahedron Lett. 2000, 41, 7651-7656.
(b) Gurjar, M. K.; Hotha, S. Heterocycles 2000, 53, 1885-1889. (c) Izuhara,
T.; Katoh, T. Org. Lett. 2001, 3, 1653-1656. (d) Runcie, K. A.; Taylor, R.
J. K. Org. Lett. 2001, 3, 3237-3239. (e) Izuhara, T.; Yokota, W.; Inoue,
M.; Katoh, T. Heterocycles 2002, 56, 553-560. (f) Takagi, R.; Miyanaga,
W.; Tamura, Y.; Ohkata, K. Chem. Commun. 2002, 2096-2097. (g) Fujioka,
H.; Kotoku, N.; Sawama, Y.; Nagatomi, Y.; Kita, Y. Tetrahedron Lett. 2002,
43, 4825-4828. (h) Eipert, M.; Maichle-Mossmer, C.; Maier, M. E.
Tetrahedron 2003, 59, 7949-7960. (i) Murray, L. M.; O’Brien, P.; Taylor,
R. J. K. Org. Lett. 2003, 5, 1943-1946. (j) Kenworthy, M. N.; McAllister,
G. D.; Taylor, R. J. K. Tetrahedron Lett. 2004, 45, 6661-6664. (k) Inoue,
M.; Yokota, W.; Murugesh, M. G.; Izuhara, T.; Katoh, T. Angew. Chem.,
Int. Ed. 2004, 43, 4207-4209.
2246
Org. Lett., Vol. 7, No. 11, 2005

Scheme 4. Diastereoselective Oxidative Dearomatizationa
Scheme 5. Final Synthetic Steps to the Fully Functionalized
Polar Core of Scyphostatina
a R ) CH2(CH2)13CH3.
we decided to investigate the use of 2,2,2-trifluoroethanol,
a polar but not nucleophilic solvent,12 and were rewarded
by formation of 10. Treatment with pyridinium p-toluene-
sulfonate (PPTS) in wet THF at ambient temperature for 18
h followed by addition of powdered K2CO3 achieved the
hydrolysis of the oxazine ring of 10 to furnish quinol 9b in
37% overall yield. Thus, a diastereoselective route to this
key intermediate was secured, and at the same time our initial
assignment of the relative stereochemistry at C4 was
confirmed.
a R1 ) CH2(CH2)13CH3.
To our dismay, however, all attempts to introduce the
epoxide ring at this stage were met with complete failure,
making the question of the regio- and diastereoselectivity
of this transformation irrelevant. Thus, we were forced to
reconsider the timing of the planned transformations toward
3. The issue of epoxide introduction was postponed, and we
proceeded to reduce, employing Luche conditions, the keto
functionality of 9b.14 Diol 11 (Scheme 5) was obtained in
excellent yield as a 2:1 mixture of diastereomers, provided
any acid treatment was avoided during its preparation and
purification. The observed low diastereoselectivity was of
no consequence, since subsequent ketal formation was
accompanied by dehydration. Thus, treatment of the mixture
of diastereomers of diol 11 with PPTS in anhydrous methanol
furnished ketal 12a in 79% yield and as a sole diastereomer.
To achieve stereo- and regioselective epoxidation of diene
12a, we resorted to the use of tert-butylhydroperoxide
(TBHP) in the presence of catalytic amount of vanadyl
acetylacetonate, a reagent combination known to be best
suited for such transformations.15a Nonetheless, in our case,
although the regioselectivity was excellent, the observed
stereoselectivity was disappointingly low, and epoxides 13a
and 14a were obtained in 1:1 ratio and in 66% combined
yield.15b,16 Even more alarming, however, was our failure to
achieve final deprotection of epoxide 14a or 13a toward our
target. A variety of ketal deprotection conditions were tested,
but invariably epoxide ring opening was observed prior to
ketal hydrolysis, if any.17
(7) (a) In the course of our work, the potential utility of p-quinol
derivatives for the construction of scyphostatin’s polar core has been
postulated; see ref 6h and: Magdziak, D.; Meek, S. J.; Pettus, T. R. R.
Chem. ReV. 2004, 104, 1383-1429. (b) For other quinol-based approaches
to scyphostatin’s core, see refs 3h and 6f.
(8) (a) Rama Rao, A. V.; Gurjar, M. K.; Sharma, P. A. Tetrahedron
Lett. 1991, 32, 6613-6616. (b) McKillop, A.; McLaren, L.; Watson, R. J.;
Taylor, R. J. K.; Lewis, N. Tetrahedron Lett. 1993, 34, 5519-5522. (c)
Wipf, P.; Kim, Y. J. Org. Chem. 1993, 58, 1649-1650. (d) Mejorado, L.
H.; Hoarau, C.; Pettus, T. R. R. Org. Lett. 2004, 6, 1535-1538.
(9) Boye´, S.; Pfei, B.; Renard, P.; Rettori, M.-C.; Guillaumet, G.; Viaud,
M.-C. Bioorg. Med. Chem. 1999, 7, 335-341 and refs therein.
(10) Mendelson, W. L.; Holmes, M.; Dougherty, J. Synth. Comm. 1996,
26, 593-601.
In an attempt to circumvent this obstacle, we decided to
retrace our steps and replace methanol with 4-methoxy-
(11) Closely related aminobenzopyranes have been successfully re-
solved: Hammarberg, E.; Nordvall, G.; Leideborg, R.; Nylo¨f, M.; Hanson,
S.; Johansson, L.; Thorberg, S.-O.; Tolf, B.-R.; Jerning, E.; Svantesson, G.
T.; Mohell, N.; Ahlgren, C.; Westlind-Danielsson, A.; Cso¨regh, I.; Johans-
son, R. J. Med. Chem. 2000, 43, 2837-2850.
(15) (a) Sharpless, K. B.; Verhoeven, T. R. Aldrichim. Acta 1979, 12,
63-71. (b) For other examples where this methodology gave poor
diastereoselectivity, see: Hoveyda, A. H.; Evans, D. A.; Fu, G. C. Chem.
ReV. 1993, 93, 1307-1370 and references therein.
(16) The indicated relative stereochemistry was assigned to epoxide 14a
on the basis of analysis of its NOESY spectrum; cross-peak H-8, H-1ax
indicated that the NHCOR moiety is axial, while cross-peaks H-5, H-3eq
and H-5, H-3ax are in accordance with the indicated relative stereochemistry
of the oxirane ring.
(12) Kita, Y.; Tohma, H.; Kikuchi, K.; Inagaki, M.; Yakura, T. J. Org.
Chem. 1991, 56, 435-438.
(13) The following cross-peaks appear in the NOESY spectra: 12a H-2,
H-3eq; 12b H-5, H-3eq and H-2, H-3ax. Furthermore, the amide proton
signal of 12b appears downfield (7.02 ppm) compared with that of 12a
(5.90 ppm), indicative of an intramolecular hydrogen bond.
(14) Wipf, P.; Kim, Y. J. Am. Chem. Soc. 1994, 116, 11678-11688.
(17) For example, treatment with montmorillonite K 10 led solely to
epoxide ring opening, while treatment with acidic (oxalic acid) silica led
to concomitant epoxide ring opening and ketal hydrolysis.
Org. Lett., Vol. 7, No. 11, 2005
2247

benzyl alcohol (PMBOH) as the nucleophile at the ketal-
ization step. Thus, treatment of the mixture of diastereomers
of diol 11 in dry THF with PPTS in the presence of 5 equiv
of PMBOH and powdered activated 4 Å molecular sieves
formed ketal 12b in 63% yield as a single diastereomer.
Subsequent epoxidation, in analogy to diene 12a, furnished
epoxides 13b and 14b as a 1:1 mixture of diastereomers and
in 86% combined yield.18 The formation of acetal 15, upon
treatment of ketal 14b with 2,3-dichloro-5,6-dicyano-1,4-
benzoquinone (DDQ), allowed assignment of the relative
stereochemistry of ketal 12b and paved the way for the final
deprotection step. Thus, further treatment of acetal 15 with
montmorillonite K 106d afforded in 55% yield the targeted,
fully functionalized, unprotected palmitoyl analogue of
scyphostatin 16. All NMR data for 16 and its acetyl
derivative 17 were in accordance with the corresponding data
reported in the literature for the polar core of scyphostatin4a
and its acetyl derivative.6k
Having established the viability of our approach toward
the fully functionalized polar core of scyphostatin, we turned
our attention to the problematic epoxidation step. Models
indicated that the rigid cis-fused bicyclic frame of 12b and
the differential steric requirements it imposes on the two
double bonds present might allow its regio- and diastereo-
selective conversion to the desired epoxide 14b by employing
an organic peracid. Indeed, upon treatment of 12b with a
slight excess of m-chloroperbenzoic acid (m-CPBA; 1.2
equiv) in the presence of Na2HPO4 at 0 °C, fast and exclusive
formation of epoxide 14b was accomplished (Scheme 6).19
Scheme 6. Diastereoselective Epoxidation of Compound 12ba
a R ) CH2(CH2)13CH3.
In conclusion, the presented synthetic route to scypho-
statin’s polar core provides a short and efficient entry to
scyphostatin analogues. Furthermore, it is flexible, since it
not only has the potential for producing analogues bearing
various fatty acid side chains but in addition is amenable to
the preparation of any desired enantiomer or diastereomer.
The preparation of additional analogues of scyphostatin
bearing various fatty acid side chains and the evaluation of
their biological activities are currently in progress, and our
results will be reported in due course.
Acknowledgment. This work was supported in part by
the program “Advanced Functional Materials” (1422/B1/
3.3.1/362/15.04.2002) cofunded by the General Secretariat
for Research and Technology of the Greek Ministry of
Development and the European Community. A.C. thanks
“ERASMUS” program for a scholarship (29191(06)233/
2001). The authors wish to acknowledge Dr. K. Yannako-
poulou for her assistance in two-dimensional NMR experi-
ments.
(18) The indicated relative stereochemistry was assigned to epoxide 14b
on the basis of analysis of its NOESY spectrum and its successful conversion
to compounds 16 and 17. Cross-peak H-8, H-1ax indicated that the NHCOR
moiety is axial, while cross-peaks H-5, H-3eq; H-5, H-3ax; and H-6, H-3ax
are in accordance with the indicated relative stereochemistry of the oxirane
ring.
(19) This experiment was performed while the manuscript was being
evaluated. Nonetheless, the authors wish to acknowledge and thank both
referees for suggesting it, among their other kind and useful remarks.
Supporting Information Available: Spectral data and
experimental procedures for compounds 5, 9, and 11-17.
This material is available free of charge via the Internet at
http://pubs.acs.org.
OL0506359
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Org. Lett., Vol. 7, No. 11, 2005