A diels-alder approach to (-)-ovalicin

Article abstract of DOI:10.1002/anie.200604781

A round at the Oval: The antiangiogenic activity of the natural product ovalicin has sparked significant interest. A highly efficient enantio- and diastereoselective total synthesis of ovalicin proved successful in which the key step involved an endo sele

Full text of DOI:10.1002/anie.200604781

Communications
DOI: 10.1002/anie.200604781
Natural Product Synthesis
A Diels–Alder Approach to (À)-Ovalicin**
Konrad Tiefenbacher, Vladimir B. Arion, and Johann Mulzer*
Dedicated to Professor Lutz F. Tietze on the occasion of his 65th birthday
A fascinating aspect of the Diels–Alder reaction is its endo
selectivity. This endo preference is much less pronounced in
intermolecular cases compared with the intramolecular and
transannular Diels–Alder (IMDA and TADA) reactions.[1]
Nevertheless, high endo selectivity is observed in the Diels–
Alder additions of (E)-1-O-substituted dienes catalyzed by
Lewis acids that lead to cis-1,6-disubstituted cyclohexene
systems of type I (Scheme 1).[2] Compounds of type I could be
Scheme 2. Natural products with antiangiogenic activity.
sparked scientific interest because of their potent antiangio-
genic activity.[4] In addition, 1 is a promising agent against
microsporidiosis.[5]
Although a Diels–Alder reaction was employed in two of
the reported total syntheses of fumagillin (2),[6] it has not been
used in the reported syntheses of ovalicin (1).[7] From our
retrosynthetic plan, 3 and 4 emerged as key intermediates that
could originate from the Diels–Alder reaction between 5 and
6 (Scheme 3).
Scheme 1. Strategy to reach highly functionalized cyclohexane deriva-
tives. EWG=electron-withdrawing group, FGI=functional-group inter-
conversion, X=SiR3, acyl, alkyl.
used as a temporary means to control the stereogenic centers
at C2 and C3. For example, the substituent at C1 in I and II
should direct additions to the opposite face of the ring to give
III selectively. Subsequently, the substitution at C1 may be
transformed to give the desired substitution pattern IV.
We chose ovalicin (1), a sesquiterpene alkaloid first
isolated from cultures of the fungus Pseudorotium ovalis
Stolk as a target for this strategy.[3] Compound 1 and the
structurally closely related fumagillin (2) (Scheme 2) have
Scheme 3. Retrosynthetic analysis of ovalicin (1). PG=protecting
group.
Several attempts to develop a catalytic enantioselective
Diels–Alder reaction of 5 and various derivatives of 6, such as
1,3-butadienyl benzoate (7), tert-butyldimethylsiloxy-1,3-
butadiene (8), or para-methoxybenzyl-oxy-1,3-butadiene
(9), failed to produce results with reasonable enantioselectiv-
ities (Table 1). The best results were obtained from reactions
of the titanium-based Keck (A) and Mikami (B) catalysts[8,9]
(Scheme 4) with diene 7 (Table 1, entries 1 and 3; 56 and
45% ee, respectively). No selectivity was observed using
diene 8 even at À788C (entry 2). Diene 9 proved to be
unstable towards the Keck and Mikami catalysts, even at
À788C. Use of the Corey (S)-tryptophan-derived oxazabor-
olidine[10] (C) failed to give selectivities with diene 8 and 9
(entries 4 and 5). Diene 7 did not react in the presence of C,
and was recovered from the reaction. Also the imidazolidi-
none catalyst (D) reported by MacMillan et al.[11] showed only
negligible selectivity with 7 (entry 6). Thus the electron-rich
dienes 8 and 9 are too reactive to need catalysis. The electron-
poor (“slow”) diene 7 does react under catalysis, although
without much induction of asymmetry.
[*] Dipl.-Ing. K. Tiefenbacher, Prof. Dr. J. Mulzer
Institut für Organische Chemie
Universität Wien
Währingerstrasse 38, 1090 Vienna (Austria)
Fax: (+43)1-4277-52189
E-mail: johann.mulzer@univie.ac.at
Homepage: http://www.univie.ac.at/rg_mulzer/
Prof. Dr. V. B. Arion
Institut für Anorganische Chemie
Universität Wien
Währingerstrasse 42, 1090 Vienna (Austria)
[**] Financial support for K. Tiefenbacher by the Austrian Academy of
Sciences (DOC scholarship) is gratefully acknowledged. We are also
thankful to A. Roller for X-ray analyses.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
2690
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2007, 46, 2690 –2693

Angewandte
Chemie
Table 1: Selection of the attempted enantioselective Diels–Alder cyclo-
additions of 5 with various dienes.
Entry Catalyst[a] Diene[b]
T, t
Yield [%][c] ee [%][d]
1
2
3
4
5
6
A
A
B
C
C
D
48C, 18 h
42
56
<10
45
À788C, 1.5 h 73
48C, 18 h
41
44
58
74
À788C, 6 h
<10
<10
<10
À308C, 5 h
208C, 12 h
48C, 18 h
[a] A=Keck catalyst;[8] B=Mikami catalyst;[9] C=Corey catalyst derived
from (S)-tryptophan;[10] D=MacMillan imidazolidinone;[11] [b] Bz=ben-
zoyl, PMB=para-methoxybenzyl, TBS=tert-butyldimethylsilyl; [c] yields
of isolated product; [d] determined by HPLC analysis on a chiral
stationary phase and by analysis of 250 MHz 1H NMR spectra using the
chiral shift reagent europium tris[3-(heptafluoropropylhydroxymeth-
ylene)-(+)-camphorate]
Scheme 5. Synthesis of the core fragment. CSA=(Æ)-camphor-10-
sulfonic acid, DIBAL-H=diisobutylaluminum hydride, NMO=4-meth-
ylmorpholine N-oxide, DDQ=2,3-dicyano-5,6-dichloro-parabenzoqui-
none, DMP=Dess–Martin periodinane.
methoxybenzylidene acetal and reduced to the PMB-alcohol
13 with DIBAL-H. The epoxide was formed from 13 using an
intramolecular SN2-type substitution in excellent yield. Sub-
sequent dihydroxylation afforded the diol 14 in high diaste-
reoselectivity. The NMR coupling constants indicated that the
hydroxy group at C3 in 14 occupies an equatorial position and
should therefore be more reactive. Nevertheless, since the
hydroxy function at C3 is sterically encumbered by the vicinal
OPMB group, we were able to protect selectively the axial
hydroxy group at C4 with TBSCl. Use of the less bulky
triethylsilyl chloride led mainly to 3,4 disilylation. After
methylation and removal of the PMB group, the crystalline
alcohol 15 was isolated and characterized by X-ray analysis.[16]
Interestingly the bulky TBS group was found to still occupy
the axial position. Oxidation with Dess–Martin periodinane
produced the core fragment 16.
Scheme 4. Chiral catalysts tested for the enantioselective Diels–Alder
reaction.
Instead of screening a library of chiral catalysts, we turned
to chiral auxiliaries, and very soon found that butadiene 10
reported by Trost et al.[12] gave adduct 11 with good endo
selectivity (d.r. 8:1) in 75% yield after chromatographic
separation (Scheme 5). The stereochemical implications of
Diels–Alder additions with the Trost diene have been
discussed in detail previously.[13]
As a result of the lability of the ester group in 11 under
reductive and nucleophilic conditions, it was necessary to
introduce a stable protecting group. Classical saponification
conditions (K2CO3 in MeOH) led to rapid decomposition of
the starting material 11. Therefore, we decided to convert 11
into diol 12 and to selectively protect the secondary alcohol by
using the para-methoxybenzylidene acetal formation and
reduction procedure.[14] Reduction of 11 with DIBAL-H gave
only low yields of 12. We overcame this problem by using an
excess of borane ammonia complex, thus affording diol 12 in
89% yield. At this stage, 90% of the chiral auxiliary was
recovered in form of the alcohol and could be recycled in one
step by oxidation.[15] Diol 12 was converted into the para-
We next turned to the synthesis of side chain 17.
Surprisingly, even after numerous repetitions and modifica-
tions, the published route[6b] only gave an inseparable (ca. 4:1)
mixture of 17 and its isomer 18 (Scheme 6). For this reason,
we had to develop an alternative route.
Scheme 6. Products formed following the published route.[6b]
Angew. Chem. Int. Ed. 2007, 46, 2690 –2693
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
2691

Communications
Vinyl stannane 19,[17] which was prepared in one step from
Keywords: asymmetric synthesis · cycloaddition · inhibitors ·
natural products · total synthesis
.
2,3-dihydrofuran, was brominated with NBS and then oxi-
dized to the labile aldehyde 20 (Scheme 7). Wittig olefination
of 20 failed, but the Julia–Kocienski[18] reaction with sulfone
21 furnished the isomerically pure (E)-vinylbromide 17 in
good overall yield.
[1]See for example: E. Marsault, A. Toro, P. Nowak, P. Deslong-
champs, Tetrahedron 2001, 57, 4243; K.-i. Takao, R. Munakata,
K.-i. Tadano, Chem. Rev. 2005, 105, 4779; W. R. Roush, K.
Koyama, M. L. Curtin, K. J. Moriarty, J. Am. Chem. Soc. 1996,
118, 7502.
[2]For a review, see: J. Jurczak, T. Bauer, C. Chapuis in Houben-
Weyl, Methods of Organic Synthesis, Vol. E21c, Stereoselective
Synthesis (Eds.: G. Helmchen, R. W. Hoffmann, J. Mulzer, E.
Schaumann), Thieme, Stuttgart, 1995, pp. 2779 – 2798.
[3]a) H. Sigg, H. Weber, Helv. Chim. Acta 1968, 51, 1395; b) P.
Bollinger, H. Sigg, H. Weber, Helv. Chim. Acta 1973, 56, 819.
[4]a) J. Folkman, N. Engl. J. Med. 1971, 285, 1182; b) J. Folkman, D.
Ingber, T. Fujita, S. Kishimoto, K. Sudo, T. Kanamaru, H. Brem,
J. Folkman, Nature 1990, 348, 555; c) W. Auerbach, R. Auerbach,
Pharmacol. Ther. 1994, 63, 265; d) J. Folkman, Nat. Med. 1995, 1,
27; e) A. Giannis, F. Rübsam, Angew. Chem. 1997, 109, 606;
Angew. Chem. Int. Ed. Engl. 1997, 36, 588; f) D. Powell, J.
Skotnicki, J. Upeslacis, Annu. Rep. Med. Chem. 1997, 32, 161.
[5]P. Didier, J. Phillips, D. Kuebler, M. Nasr, P. Brindley, M. Stovall,
L. Bowers, E. Didier, Antimicrob. Agents Chemother. 2006, 50,
2146.
Scheme 7. Synthesis of the side chain. NBS=N-bromosuccinimide,
LHMDS=lithium hexamethyldisilazide.
Freshly prepared vinylbromide 17 was lithiated with tert-
butyllithium and coupled to the core fragment 16 to yield
alcohol 22 stereoselectively (Scheme 8). Removal of the TBS
group proceeded smoothly with tetra-n-butylammonium
[6]a) E. J. Corey, B. B. Snider, J. Am. Chem. Soc. 1972, 94, 2549;
b) D. Vosburg, S. Weiler, E. Sorensen, Chirality 2003, 15, 156.
[7]a) E. J. Corey, A. Guzman-Perez, M. C. Noe, J. Am. Chem. Soc.
1994, 116, 12109; E. J. Corey, J. P. Dittami, J. Am. Chem. Soc.
1985, 107, 256; b) S. Bath, D. C. Billington, S. D. Gero, B.
Quiclet-Sire, M. Samadi, J. Chem. Soc. Chem. Commun. 1994,
1495; D. H. R. Barton, S. Bath, D. C. Billington, S. D. Gero, B.
Quiclet-Sire, M. Samadi, J. Chem. Soc. Perkin Trans. 1 1995,
1551; c) S. Takahashi, N. Hishinuma, H. Koshino, T. Nakata, J.
Org. Chem. 2005, 70, 10162; d) J. Yamaguchi, M. Toyoshima, M.
Shoji, H. Kakeya, H. Osada, Y. Hayashi, Angew. Chem. 2006,
118, 803; Angew. Chem. Int. Ed. 2006, 45, 789; Formal synthesis:
A. Barco, S. Benetti, C. De Risi, P. Marchetti, G. P. Pollini, V.
Zanirato, Tetrahedron: Asymmetry 1998, 9, 2857; for an incom-
plete synthesis, see: K. M. Brummond, J. M. McCabe, Tetrahe-
dron 2006, 62, 10541.
[8]G. Keck, D. Krishnamurthy, Synth. Commun. 1996, 26, 367.
[9]K. Mikami, Y. Motoyama, M. Terada, J. Am. Chem. Soc. 1994,
116, 2812.
[10]E. J. Corey, T. P. Loh, J. Am. Chem. Soc. 1991, 113, 8966.
[11]D. MacMillan, K. Ahrendt, C. Borths, J. Am. Chem. Soc. 2000,
122, 4243.
[12]Diene 10 was prepared by using a variation of the published
procedure (B. Trost, L. Chupak, T. Lübbers, J. Org. Chem. 1997,
62, 736) in which acyl fluoride instead of chloride was used. This
modification improved the ease of preparation and yield
significantly (see the Supporting Information).
[13]C. Siegel, E. R. Thornton, Tetrahedron: Asymmetry 1991, 2,
1413.
[14]For a related use of this procedure, see: M. Takano, A. Umino,
M. Nakada, Org. Lett. 2004, 6, 4897.
Scheme 8. Completion of total synthesis. TBAF=tetra-n-butylammo-
nium fluoride, [VO(acac)2]=vanadyl acetylacetonate.
fluoride at 08C to deliver the known diol 23.[7c] Oxidation
with Dess–Martin periodinane and stereoselective epoxida-
tion[7a,c] yielded (À)-ovalicin (1), of which the analytical data
were fully in accord with those of natural ovalicin. See the
Supporting Information.
In summary, ovalicin was prepared in 15 linear steps
enantio-, diastereo-, and regioselectively with an overall yield
of 15%. The efficiency of the synthesis depended on the
excellent endo selectivity of the initial Diels–Alder reaction
that paved the way for all the equally selective transforma-
tions to follow.
[15]F. J. Moreno-Dorado, F. M. Guerra, M. J. Ortega, E. Zubia,
G. M. Massanet, Tetrahedron: Asymmetry 2003, 14, 503.
[16]The crystal was obtained from an earlier racemic synthesis.
Crystal data for (Æ )-15: C14H28O4Si, Mr = 288.45, monoclinic,
space group P21/c, a = 12.2625(3), b = 11.9960(4), c =
11.3541(3) Š, b = 97.638(2)8, V= 1655.38(8) Š3, Z = 4, 1calcd
=
1.157 gcmÀ3, MoKa radiation (l = 0.71073 Š, m = 0.149 mmÀ1),
T= 100 K, R = 0.0345 (F2 > 2s), Rw = 0.0959 (for 4848 data and
176 refined parameters). Data were collected on a Bruker
X8APEX II CCD difractometer. Single crystals were placed at
40 mm from the detector and 2286 frames were measured, each
Received: November 24, 2006
Revised: January 17, 2007
Published online: March 1, 2007
2692 www.angewandte.org
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2007, 46, 2690 –2693

Angewandte
Chemie
for 10s over a 18 scan width. The structure was solved by direct
methods and refined by full-matrix least-squares techniques. All
non-hydrogen atoms were refined with anisotropic displacement
parameters. The hydrogen atoms were placed at calculated
positions (except H9 which was localized from difference
Fourier syntheses) and refined as riding atoms. Structure
solution and refinement was performed with the SHELX
program SHELX-74 program (G.M. Sheldrick, Program for
crystal structure solution, Universität Göttingen, 1997; G.M.
Sheldrick, Program for crystal structure refinement, Universität
Göttingen, 1997). CCDC-627132 contains the supplementary
crystallographic data for this paper. These data can be obtained
free of charge from The Cambridge Crystallographic Data
Centre via www.ccdc.cam.ac.uk/data_request/cif.
[17]a) D. F. Taber, T. E. Christos, A. L. Rheingold, I. A. Guzei, J.
Am. Chem. Soc. 1999, 121, 5589; b) P. Le Mꢀnez, V. Fargeas, J.
Poisson, J. Ardisson, J.-Y. Lallemand, A. Pancrazi, Tetrahedron
Lett. 1994, 35, 7767.
[18]a) J. B. Baudin, G. Hareau, S. A. Julia, O. Ruel, Tetrahedron Lett.
1991, 32, 1175; b) P. R. Blakemore, W. J. Cole, P. J. Kocienski, A.
Morley, Synlett 1998, 26; c) P. J. Kocienski, A. Bell, P. R.
Blakemore, Synlett 2000, 365; The Julia-Kocienski reaction was
also used in the synthesis of fumagillin: O. Bedel, A. Haudrechy,
Y. Langlois, Eur. J. Org. Chem. 2004, 3813.
Angew. Chem. Int. Ed. 2007, 46, 2690 –2693
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org 2693