Janine Cossy

Matthew Popkin

Samir BouzBouz

Comptes Rendus Chimie

Account / RevueStereo- and enantioselective reactions. Application to the synthesisof biologically active compoundsJanine Cossy *, Samir BouzBouz, Matthew PopkinLaboratoire de chimie organique, associé au CNRS, ESPCI, 10, rue Vauquelin, 75231 Paris cedex 05, FranceReceived 23 December 2002; accepted 11 April 2003AbstractEnantioselective allyltitanation as reactions as well as ring closing metathesis reaction have been used to synthesizebiologically active compounds.To cite this article: J. Cossy et al., C. R. Chimie 6 (2003).© 2003 Académie des sciences. Published by Éditions scientifiques et médicales Elsevier SAS. All rights reserved.RésuméDes allyltitanations énantiosélectives et de fermeture de cycle par métathèse ont été mises au point pour synthétiser desproduits biologiquement actifs.Pour citer cet article : J. Cossy et al., C. R. Chimie 6 (2003).© 2003 Académie des sciences. Published by Éditions scientifiques et médicales Elsevier SAS. All rights reserved.Keywords: allyltitanation; enantioselectivity; metathesis; passifloricin A; staurosporine; discodermolideMots clés : allylation ; énantiosélectivité ; métathèse ; passifloricine A ; staurosporine ; discodermolideOne of the major challenges in synthetic organicchemistry is the design and execution of concise ap-proaches and strategies to complex molecules by usingreactions that rapidly lead to their carbon skeleton. Inthis context, we have explored the construction ofmolecules having diol and polypropionate units bytuning up regio-, chemo-, stereo- and enantioselectivereactions.Asymmetric C–C bond formation is an attractivesynthetic strategy, as the connectivity of a carbonframework and its configuration are established simul-taneously. The allylmetallation of aldehydes and ke-tones, leading to products with a maximum of two newstereocentres and versatile functionalities for furthertransformations is an important method for acyclicstereocontrol[1–5]. Efficient chirality transfer fromallyl moieties has been obtained with chiral allylmetalreagents[6–13]. In the 1980s, organotitanium reagentsopened new perspectives for high selectivity, as theirstructural variability allows the necessary adjustmentsfor reactivity[14–19]. Duthaler and Hafner prepared avariety of such chiral organotitanium reagents andamong them, chiral cyclopentadienyldialkoxytitanium(IV) complexes[20, 21]. They screened them for enan-tioselective allyltitanations and crotyltitanations and* Corresponding author.E-mail address: janine.cossy@espci.fr (J. Cossy).C. R. Chimie 6 (2003) 547–552© 2003 Académie des sciences. Published by Éditions scientifiques et médicales Elsevier SAS. All rights reserved.doi:10.1016/S1631-0748(03)00082-1they discovered that the presence of the (R,R)-tartrateligand in complex (R,R)-I and (R,R)-II allows thetransfer of allyl and crotyl groups to aldehydes withhigh si face selectivity and that the presence of the(S,S)-tartrate ligand in complex (S,S)-I and (S,S)-IIallows the transfer of allyl and crotyl groups to alde-hydes with high re face selectivity [22, 23]. A widerange of homoallylic alcohols with high enantiomericexcess was obtained by using these complexes (Fig. 1).Nevertheless, it was desired to develop methodolo-gies for the stereocontrolled obtention of 1,2- or 1,3-diol units as well as polypropionate units to preparebiologically active compounds such as LY 33 35 31,passifloricin A and discodermolide (Fig. 2).The first product that we became interested in wasLY 33 35 31 related to the naturally occurring stauro-sporine, which is a Protein Kinase C inhibitor. Thiscompound was obtained by others with alkylation of 1with bis-mesylate 2, which was synthesized from theexpensive (R)-1-chloro-2,3-propanediol 3 with anoverall yield of 45–55% and an enantiomeric excess of98% [24–26] (Fig. 3).By using an enantioselective allyltitanation, wewere able to transform the cheap allylic alcohol 4 to thebis-mesylate 2 in six steps, in good yield (66%) andwith good enantiomeric excess (98%) (Fig. 4) [27].If 1,2-diols are found in a great number of biologi-cally active compounds, the 1,3-diol functionality is ofgreat importance for the biological activity of manypharmaceutical products. Therefore, it is not surprisingthat numerous strategies have been developed for thestereoselective synthesis of compounds containing1,3-diol units [28–30].Fig. 1. Enantioselective allyl- and crotyltitanium complexes.Fig. 2. Biologically active compounds.Fig. 3. Retrosynthetic analysis of staurosporine.Fig. 4. Synthesis of the precursor of LY 33 35 31.548 J. Cossy et al. / C. R. Chimie 6 (2003) 547–552We have synthesized syn- as well as anti-1,3 diols oftype D from aldehyde of type A with good to excellentenantiomeric excess by using the allyltitanium com-plexes (R,R)-I and (S,S)-I (Fig. 5). For example, 1,3-diols 14–17 were obtained in good yield (67–72%) andgood enantiomeric excess (93%) from aldehyde 9 [31].After the allyltitanation of aldehyde 9 by using (R,R)-Ior (S,S)-I, the obtained homoallylic alcohols 10 and 11were oxidatively cleaved (OsO4/NMO; NaIO4) and theunstable b-hydroxy aldehydes 12 and 13 were treateddirectly with the allyltitanium complexes. When thenon-protected b-hydroxy aldehydes 12 and 13 weretreated respectively with (R,R)-I and (S,S)-I, the syn-1,3-diols 14 and 17 were respectively obtained in highyield (79–85%) and with a diastereomeric excess supe-rior to 95%. When b-hydroxy aldehydes 12 and 13were treated respectively with (S,S)-I and (R,R)-I, theanti-1,3-diols 15 and 16 were isolated in high yield(79–83%) and with a diastereomeric excess superior to95%. The formation of syn- or anti-1,3-diols fromnon-protected b-hydroxy aldehydes of type C by using(R,R)-I or (S,S)-I is very general. The most importantfeature in these allyltitanations is that 1,3-diols can beobtained without any protective or deprotective steps,which enhances the synthetic potential of this organo-metallic allylation reaction (Fig. 5). We have also dem-onstrated that acid-sensitive (silyl ether, trityl ether) orbase-sensitive (benzoyl) protecting groups can be tol-erated in these allyltitanations [31].Non-protected 1,3-diols are interesting intermedi-ates, which offer an efficient entry to the synthesis ofnatural products such as passifloricin A, an antifungalagent recently isolated, for which the absolute configu-ration of the stereogenic centres has to be confirmed bysynthesis, as two different structures E and F have beenreported in the literature (Fig. 6) [32].We chose to synthesize structure E. The synthesis ofE has been achieved from hexadecanal 18. As thereagents (R,R)-I and (S,S)-I are highly face-selective,the stereogenic centres were controlled by adding(R,R)-I and (S,S)-I to the corresponding aldehydesFig. 5. Synthesis of 1,3-diols syn and anti.Fig. 6. Possible structures for passifloricin A.549J. Cossy et al. / C. R. Chimie 6 (2003) 547–552(Fig. 7). Compound 19 was obtained by this processand transformed into compound E in a three-step se-quence. Unfortunately, the spectroscopic data do notcorrespond to those of passifloricin A. This leads tosuspect that passifloricin A has structure F (Fig. 7).The polypropionates (chains with alternatingmethyl-hydroxy-methyl substituents) [33] represent animportant class of natural products such as the iono-phores, the lactones and the macrolides [34–37]. Asso-ciated with a broad spectrum of biological activity,these structures encompass a large diversity of molecu-lar architecture.In looking for routes to prepare (+)-discodermolide,our interest was drawn to build up stereotetrads andstereopentads as these units are present in this com-pound. We have synthesized stereotetrads from meso-dialdehydes with good dia- and enantioselectivities.For example, when meso-dialdehyde 21 was treatedwith (R,R)-I, lactol 22 was obtained and reduced withNaBH4 to furnish compound 23 in 49% overall yield[38] (Fig. 8). It is worth noting that (R,R)-I discrimi-nates the pro(S) face of the aldehyde. Furthermore, theallyltitanations have been shown to closely follow aFelkin–Anh transition state [38].The stereotetrads have also been synthesized fromaldehyde of type A with good to excellent diastereose-lectivity and enantioselectivity by using the crotyltita-nium complexes (R,R)-II and (S,S)-II. For example,stereotetrads 26 have been obtained from aldehyde 24by using two crotyltitanations [39]. After treatment ofaldehyde 24 with (R,R)-II, the obtained homoallylicalcohol 25 was oxidatively cleaved (OsO4/NMO,NaIO4) and the b-hydroxyaldehyde 26 was treateddirectly with the crotyltitanium complexes. When 26was treated with (R,R)-II, the stereotetrads 26 and 27were respectively obtained in high diastereoselectivity(> 95%) and enantioselectivity (Fig. 8) [39]. As in thecase of the allyltitanium complexes, the crotyltitaniumcomplexes are highly face-selective.Stereopentads can be obtained from meso-dialdehydes by treatment with (R,R)-II and (S,S)-II.For example, when meso-dialdehydes 21 and 30 weretreated with (R,R)-II, the stereopentads 29 and 32 wereisolated after reduction of the intermediate lactols 28and 31 with NaBH4 (Fig. 9) [40]. It is worth noting thatcompound 32 corresponds to the C15–C21 fragment of(+)-discodermolide (Fig. 10). The desymmetrizationof meso-dialdehydes by using chiral titanium com-plexes allows a short and efficient synthesis of polypro-pionates.As the chiral allyl- and crotyltitanium complexescan tolerate a great number of functionalities, they canbe used efficiently in the synthesis of biologically ac-tive natural products. For our part, we choose to syn-thesize (+)-discodermolide as we have already ob-tained the C15–C21 fragment. (+)-Discodermolide is aunique polyketide isolated from the Caribbean deep-sea sponge Discodermia Dissoluta [41, 42]. Its struc-ture was determined by extensive spectroscopic studiesand the relative stereochemistry was assigned by singlecrystal X-ray crystallography. Structurally, it bears13 stereogenic centres, a tetrasubstituted c-lactone(C1-C5), one di- and one trisubstituted (Z)-doublebond, a pendant carbamate moiety (C19) and a termi-nal (Z)-diene (C1-C24). (+)-Discodermolide was ini-tially found to be a potent immunosuppressive agent,both in vivo and in vitro, as well as displaying antifun-gal activity. It inhibited T-cell proliferation with anIC50 of 9 nM and graft versus host disease in trans-planted mice. Further biological screening of this com-Fig. 7. Synthesis of an analogue of passifloricin A.Fig. 8. Synthesis of stereotetrads.550 J. Cossy et al. / C. R. Chimie 6 (2003) 547–552pound revealed cytotoxicity, causing cell cycle arrestin the G2/M phase in a variety of human and murinecell lines [43]. (+)-Discodermolide has been recog-nized as one of the most potent tubulin polymerisingagents presently known. The highly encouraging bio-logical profile of (+)-discodermolide makes it a prom-ising candidate for clinical development as a chemo-therapeutic agent for taxol-resistant breast, ovarian andcolon cancer and other multidrug-resistant cancers.Clinical development is severely hampered by the ex-tremely scarce supply of (+)-discodermolide (0.0002%w/w frozen sponge) from the natural source. Thus,total synthesis presently provides the only viable routeto useful quantities of this novel cytotoxic polyketide.Consequently, there has been considerable syntheticeffort toward (+)-discodermolide.Our approach to (+)-discodermolide is based onsynthesis of two fragments G and H by using allylti-tanations. Connection of G and H will then have to becarried out with the help of a palladium-catalyzedcoupling reaction (Fig. 10).The synthesis of fragment C15–C24 was achievedfrom meso-dialdehyde 30, which was transformed toiodide 33 in 8 steps via stereopentad 32. The synthesisof the C1–C13 fragment was achieved in 18 steps fromthe commercially available methyl (+)-3-hydroxy-2-methyl propionate 35, the stereogenic centre of whichcorresponds to C12 of (+)-discodermolide. All the ste-reogenic centres were controlled by using (R,R)-I (C7)and (R,R)-II (C2, C3, C4, C5, C11, C12) (Fig. 11).The transformation of 33 to the boronate 34 and thecoupling of this later compound with the vinyl iodideof type G, prepared from 45, will lead to the C1-C24fragment of (+)-discodermolide. The stereocontrolledsynthesis of compounds 33 and 45 demonstrates thatFig. 9. Synthesis of stereopentads by desymmetrization of meso dialdehydes.Fig. 10. Retrosynthetic analysis of (+)-discodermolide.Fig. 11. Synthesis of the C1-C13 and C15-C24 fragments of(+)-discodermolide.551J. Cossy et al. / C. R. Chimie 6 (2003) 547–552the highly face selective allyltitanium complexes areuseful reagents for achieving remote stereocontrol inacyclic systems. Furthermore, by using these reagents,protection-deprotection sequences can be avoided aspolar groups are tolerated, which increases the effi-ciency of the syntheses.AcknowledgementsThe COST program D13/001/00 is acknowledgedfor support and Eli-Lilly (Indianapolis, IN) as well asPPG-Sipsy are acknowledged for financial support.References[1] R.W. Hoffmann, Angew. Chem., Int. Ed. Engl. 21 (1982) 555.[2] Y. Yamamoto, K. Maruyama, Heterocycles 18 (1982) 357.[3] R.W. Hoffmann, Angew. Chem., Int. Ed. Engl. 26 (1987) 489.[4] D. Hoppe, Angew. Chem., Int. Ed. Engl. 23 (1984) 932.[5] J. Mulzer, L. Kattner, A.R. Strecker, C.H. Schröder, J. Busch-mann, C.H. Lehmann, P. Luger, J. Am. Chem. Soc. 113 (1991)4218.[6] Y. Yamamoto, N. Asao, Chem. 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Stereo- and enantioselective reactions. Application to the synthesis of biologically active compounds

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Stereo- and enantioselective reactions. Application to the synthesis of biologically active compounds

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