A-ring precursors

Wittig-Horaer reaction to give vitamin D2. The unique feature of this synthesis is the synthesis and preservation of the Z-geometry of C-5,6 double bond while the final step of the Wittig-Homer reaction allows the selective formation of J -geometry for the C-7,8 olefin. 

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Posner G. H., Anjeh T. E. N., Carry J. C., French A. N. A New and Efficient Asymmetric Synthesis of an A-Ring Precursor to Physiologically Active 1-a-Hydroxyvitamin D3 Steroids Proc. - NOBCChE 1994 21 383-389 Keywords inverse electron-demand Diels-Alder cycloadditions, (S)-lactate and Lewis acids (-)-Pr(hfc)3 with benzyl vinyl ether... 

Ferrero, M., Fernandez, S. and Gotor, V., Selective alkoxycarbonylation of A-ring precursors of vitamin D using enzymes in organic solvents. Chemoenzymatic synthesis of lo ,25-dihydroxyvi-tamin D3 C-5 A-ring carbamate derivatives. J. Org. Chem., 1997, 62, 4358. 

The first diastereoselective total synthesis of ( )-guanacastepene A (rac-187) was published in a series of papers by Danishefsky and co-workers [107-110]. The tricyclic carbon framework was assembled by interplay of enolate alkylations and ring-closing carbon/carbon double bond forming reactions (Fig. 19). Commercially available cyclopentenone 90 was utilized as the A-ring precursor. 

Frohlich, L. and Torsten, L. (2004) Simple and diastereoselective synthesis of an A-ring precursor of dihydroxyvitamin D3 (caldtriol) by photooxygenation. Syrdett, (15), 2725-2727. 

An auxiliary-directed asymmetric Simmons-Smith reaction was used by a Hoff-mann-La Roche group88 for the synthesis of an ethynyl cyclopropane that served as the A-ring precursor to Vitamin D derivatives [Scheme 2.41]. High diastereoselectivity was achieved with the aid of the dioxolane ring prepared from (/ft/f)-(-)-butane-2,3-diol. The acid conditions for hydrolysis of the dioxolane ring were mild enough to leave the cyclopropane ring unperturbed. Dia-stereoselective cyclopropanation of acetals derived from 1,2-di-O-benzyl-L-threi-tol have also been reported 90... 

Posner and Kinter have demonstrated MAD-promoted highly stereoselective [4 + 2] cycloaddition under mild conditions in the asymmetric total synthesis of an A-ring precursor 171 to hormonally active la,25-dihydroxyvitamin D3 [172]. Reaction of a pyrone sulfone 168 and an enantiomerically pure vinyl ether 169 under the influence of MAD in toluene-CH2Cl2 at -45 °C for 12 h afforded cycloadduct 170 in 93 % isolated yield as a 98 2 ratio of the endo diastereomers. From 170, the synthesis of 171 required 13 steps and proceeded in 34.6 % overall yield as indicated in Sch. 133. 

Pepperman et al (14) prepared and tested 30 strigol precursors, analogs, and fragments for germination stimulation activity in witchweed. Seven of these compounds were A-ring precursors, of which four were active. The data for the active compounds are summarized in Table 4 (Insert Table 4), and the structures are given in Figure 6... 

Cycloaddition of 2-pyrones 5 to vinyl ethers 6 serves a key reaction in the synthesis of the important chiron 9, being an A-ring precursor to la-hydroxyvitamin D3. The best diastereose-lectivities were obtained when the appropriate chiral auxiliary was used in the diene component22 or a stereochemically matched pair of chiral diene and chiral catalyst was applied22. 

Among the very few reported possibilities offered by transannular cycle contraction of cyclododecenyl radicals to construct 9,5-, 8,6- or 7,7-bicyclic systems, the radical tandem approach to the taxanes planned by Pattenden, from the substituted A-ring precursor 134, introduces a new conceptual strategy, described as E in Scheme 29. First, a 12-e Jo-dig macrocyclization involving alkyl radical 135 occurs easily on the triple bond of the ynone moiety. The produced vinyl radical (major conformer is presented) 136 cyclizes in a 6- n-endo)-exol - n-exo)-endo transannular manner to assemble the unusual tricyclo[9.3.1.0 ]pentadecane framework 137 as a 6 1 ratio of diastereomers (Scheme 38) [55]. 

Danishefsky s synthesis (Scheme 4) [7] started from the readily available Wieland-Mie-scher ketone (19) which, by a series of mainly protection and oxidation reactions, was transformed to the fully functionalized C ring precursor 21. The oxetane moiety was introduced very early on in the synthesis, from a corresponding triol, again by nucleophilic substitution at C5. Noteworthy is the selective protection or modification of primary versus secondary versus tertiary hydroxy groups for this purpose. The benzyl protected enolized form 20 then could be oxidized, cleaved oxidatively and processed to compound 21 which, apart from complete C/D rings, possesses the necessary handles (C2 and C9/10) to bind to the A ring precursor 22 and thus form the B ring. 

Stereochemical Control Element on the Dienophile. Pyrone sulfone 47 undergoes asymmetrical cycloaddition with a number of homochiral dienophiles at room temperature and gives modest to good diastereomeric excesses. The results, shown in Table 7, were best with benzylic vinyl ethers. This methodology was employed to synthesize (-)-methyl triacetyl-4-epishikimate and an A-ring precursor to la,25-dihydroxy vitamin Dj. ... 

Hydrogenolysis of vinyloxirane is regioselective to give homoallylic alcohol 435. Hydrogenolysis of the alkenyloxirane 436 is regio- and stereospecific and proceeds by overall inversion of configuration of the allylic C—O bond to afford the homoallylic alcohol 437 [167]. Sato applied the reaction to the synthesis of an A-ring precursor of vitamin D. The protected homoallylic alcohol 439 was obtained at room temperature from the alkenyloxirane 438 in 90% yield [168]. 

The A-ring precursor 999 of vitamin D has been prepared by selective alkoxy-carbonylation using enzymes in organic solvents. Candida antarctica lipase (CAL) is found to be the best catalyst in toluene solution. Other suitable enzymes are PSL and CVL, and alternative solvents are THE and 1,4-dioxane the yields of alkoxy-carbonylation products depend strongly on the conditions and amount to 17-100%. Regioselective alkoxycarbonylation occurs only at the C-5-(R) hydroxy group [719, 720]. 

Interestingly, no biogenetic studies have been carried out on these compounds, but one can speculate that cyclization of an A-ring precursor may occur on the ortho position of the hydroxyl function of tyrosine to give these skeletons. Further studies are needed to clarify this point. 

Mourino, A., Torneiro, M., Vitale, C., Fernandez, S., Perez-Sestelo, J., Anne, S. and Gregorio, C. (1997) Effident and versatile synthesis of A-ring precursors of la,25-dihydroxy-vitamin Dj and analogues. Application to the synthesis of Lythgoe-Roche phosphine oxide. Tetrahedron Letters, 38, 4713-4716. 

Herein, three syntheses of morphine or related alkaloids are discussed in detail, which utilize completely different protocols for the coupling of the ring motifs of the alkaloid. Rice published a biomimetic approach with an acid-mediated electrophilic cyclization strategy as key step [144]. Mulzer employed a Friedel-Crafts acylation and a Robinson annulation to construct the phenanthrenone ring system [145]. The D ring of the alkaloid was elaborated with a 1,4-cuprate addition as key step. In his most recent contribution to morphine research, Hudlicky employed a Diels-Alder cycloaddition reaction to construct the ABCE ring system of the natural product. The requisite diene was obtained after oxidative dearomatization of the A ring precursor [146]. 

Method D involves an A-ring precursor that is cross-coupled to 24,25-dihydroxy CD-ring sulfone synthon 195 (prepared through a chemoenzymatic synthesis from easily accessible diketone) leading directly to the la,25-dihydroxyvitamin D3 skeleton. 

Utilization of the optically pure compounds for the construction of optically active material is exemplified with the preparation of A-ring precursor 218 from alcohol (/ )-(+)-215, which reacts to form cyclopropane compound 217, which is then desilylated to A-ring synthon 218. 

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