Formal synthesis

As with i -substituted allyl alcohols, 2,i -substituted allyl alcohols are epoxidized in excellent enantioselectivity. Examples of AE reactions of this class of substrate are shown below. Epoxide 23 was utilized to prepare chiral allene oxides, which were ring opened with TBAF to provide chiral a-fluoroketones. Epoxide 24 was used to prepare 5,8-disubstituted indolizidines and epoxide 25 was utilized in the formal synthesis of macrosphelide A. Epoxide 26 represents an AE reaction on the very electron deficient 2-cyanoallylic alcohols and epoxide 27 was an intermediate in the total synthesis of (+)-varantmycin. 

In a formal synthesis of fasicularin, the critical spirocyclic ketone intermediate 183 was obtained by use of the rearrangement reaction of the silyloxy epoxide 182, derived from the unsaturated alcohol 180. Alkene 180 was epoxidized with DMDO to produce epoxy alcohol 181 as a single diastereoisomer, which was transformed into the trimethyl silyl ether derivative 182. Treatment of 182 with HCU resulted in smooth ring-expansion to produce spiro compound 183, which was subsequently elaborated to the desired natural product (Scheme 8.46) [88]. 

Conjugated dienes can be epoxidized to provide vinylepoxides. Cyclic substrates react with Katsuki s catalyst to give vinylepoxides with high ees and moderate yields [17], whereas Jacobsen s catalyst gives good yields but moderate enantiose-lectivities [18]. Acyclic substrates were found to isomerize upon epoxidation (Z, )-conjugated dienes reacted selectively at the (Z)-alkene to give trans-vinylepoxides (Scheme 9.4a) [19]. This feature was utilized in the formal synthesis of leuko-triene A4 methyl ester (Scheme 9.4b) [19]. 

Bromoethylvinylarylsulfones as versatile dienophiles a formal synthesis of epibati-dine [156]... 

Treatment of 69 with oxahc acid and subsequently with base yields benzofuran 70. This constitutes a new formal synthesis of lycoramine 71 <96TL6283>. 

Allylsilane additions were used in a formal synthesis of roflamycoin [51] (Eq. 24). A one-pot, three-component sequential coupling of bis-allylsilane 138 with 4-acetoxy-l,3-dioxanes 137 and 139 provided the C11-C22 polyol chain (140) in moderate yield. 

NHC-catalysed homoenolate generation has been applied by Bode and Struble in the formal synthesis of the natural product salinosporamide A [77], The key step in the synthesis is a late-stage NHC-catalysed intramolecular lactonisation step of intermediate 186. When this reaction was attempted with an achiral triazolium-derived NHC, a 4 1 diastereomeric ratio of products was obtained in preference for the undesired product 189. In order to circumvent this, chiral triazolium salt 187 was employed, giving an approximately 1 1 mixture of desired undesired diastereoisomers (Scheme 12.41). 

Imanishi, T., Shin, H., Yagi, N., Hanaoka, M. (1980) l,6-Dihydro-3(2H)-Pyridinones as Symmetric Intermediates. Formal Synthesis of ( )-Tabersonine and ( )-Catharanthine. Tetrahedron Letters, 21, 3285-3288. 

Parker, K.A. Fokas, D. (2006) Enantioselective Synthesis of (—)-Dihydrocodeinone A Short Formal Synthesis of (—)-Morphine. Journal of Organic Chemistry, 71,449 55. 

Mehta, G. Reddy, D.S. (2000) A Formal Synthesis of Reserpine Hydrindane Approach to the Woodward s Ring-E Precursor. Journal of the Chemical Society Perkin Transactions J, 1399-1404. 

Sparks, S.M., Gutierrez, A.J., Shea, K.f (2003) Preparation of Perhydroisoquinolines Via the Intramolecular Diels-Alder Reaction of N-3,5-Hexadienoyl Ethyl Acrylimidates A Formal Synthesis of ( )-Reserpine. Journal of Organic Chemistry, 68, 5274-5285. 

Similar reactions were applied to the syntheses of rf/-ep/-pyroangolen-solide, i/-pyroangoensolide (Eq. 12.29)88 and the formal synthesis of the Inhoffen-Lythgoe diol (Eq. 12.30).89 The key step in the formal synthesis of the Inhoffen-Lythgoe diol is the aqueous Diels-Alder reaction between the sodium salt of the diene and methacrolein to form the cycloadduct, which then undergoes subsequent reactions to form the known hydrin-dan. Sodium (E)-4, 6, 7-octatrienoate reacted smoothly with a variety of dienophiles to give conjugated diene products.90... 

The approach also allows the synthesis of furans by employing ethoxymethylene malonate, followed by an eliminative decarboxylation. This method was used by Balme for a formal synthesis of the antitumor lignan burseran (6/1-294), starting from 6/1-290,6/1-291 and 6/1-292 via the furan 6/1-293 (Scheme 6/1.78) [139], Furans as 6/1-298 can also be obtained by Pd-catalyzed reaction of 2-propynyl-l,3-dicarbonyls 6/1-295 with aryl halides 6/1-296 in DMF, using potassium carbonate as base, as shown by Arcadi, Cacchi and coworkers (Scheme 6/1.79) [140]. 

In a formal synthesis of quinolizidine 233A 296, the 2,6-m-disubstituted piperidine 292, as a mixture of dia-stereomers, was transformed into 293 by N-acylation with but-3-enoyl chloride. An RCM afforded 294, which was transformed into 295 by hydrogenation of the double bonds and hydride reduction of the lactam, thereby completing a formal synthesis <2000JOC8908> of quinolizidine 233A 296 (Scheme 65) <2004JA4100>. 

A recent formal synthesis of the alkaloid (—)-mitralactonine relied on a reaction that allowed the simultaneous creation of three new bonds, two of them a and one ft with respect to the quinolizine nitrogen. As shown in Scheme 112, treatment of triptamine with chiral aldehyde 480 in the presence of acid directly gave a mixture of diastereo-meric indoloquinolizidines 481 and 482 through a mechanism involving a Pictet-Spengler cyclization and a N-alkylation reaction <2007SL79>. 

A microwave assisted Comforth rearrangement of oxazole-4-carboxamides 106 efficiently afforded 5-aminooxazole-4-carboxylates 107. This procedure was applied to the formal synthesis of a natural antibiotic derived from pseudomonic acid <06TL4698>. 

As will be discussed later, the novel pentacyclic antitumor alkaloid roseophilin continues to attract much synthetic effort and several approaches relied on the venerable Paal-Knorr condensation for construction of the pyrrole moiety. For instance, Trost utilized this reaction upon diketone 1 to afford the tricyclic core 2 of roseophilin in a strategy featuring an enyne metathesis as a key step <00JA3801>, while another formal synthesis of this alkaloid utilized a radical macrocyclization to produce the ketopyrrole core <00JCS(P1)3389>. 

A formal synthesis of the antifungal agent alternaric acid was realized in the Trost group.95 The skipped diene portion of the natural product was obtained via a ruthenium-catalyzed intermolecular Alder-ene reaction (Scheme 36). Several attempts to produce 162 from the protected fragment 161 gave low yields and unremarkable regioselectivity. The diol (R = H), however, performed satisfactorily, allowing the reaction to be carried out at room temperature. The product 162 was obtained in 51% isolated yield as an 8.9 1 mixture of branched to linear isomers. 

This intramolecular etherification approach has successfully been applied to the syntheses136 of siccanin137 and clusifoliol,136 and a formal synthesis of morphine.138 Examples of tandem inter- and intramolecular etherification reactions have also been reported which convert catechol and o-aminophenol derivatives into benzodioxins (Equation (24)),139-141 benzodioxepines,142 and morpholines.139,140... 

A new formal synthesis of ( )-zizaene (136) via the fragmentation reaction is a typical example 45,46). When the enol acetate (132) was irradiated, the isolable photoadduct (133) was formed together with other isomers. Reduction and mesylation of which afforded the mesylate (134). Then, fragmentation reaction would yield an epimeric mixture of the alkenone (755) in the presence of NaOH in aqueous dioxane at 60 °C, thus formulated a total synthesis of (+)-zizaene (136) 45-46). 

The vinyl triflate of Komfeld s ketone has been subjected to Heck reactions with methyl acrylate, methyl methacrylate, and methyl 3-(Af-rerf-butoxycarbonyl-lV-methyl)amino-2-methylenepropionate leading to a formal synthesis of lysergic acid [259]. A similar Heck reaction between l-(phenylsulfonyl)indol-5-yl triflate and dehydroalanine methyl ester was described by this research group [260]. Chloropyrazines undergo Heck couplings with both indole and 1-tosylindole, and these reactions are discussed in the pyrazine Chapter [261], Rajeswaran and Srinivasan described an interesting arylation of bromomethyl indole 229 with arenes [262]. Subsequent desulfurization and hydrolysis furnishes 2-arylmethylindoles 230. Bis-indole 231 was also prepared in this study. 

The addition of a titanium homoenolate 115 to a proline derivative 114 proved to be a feasible approach for the formal synthesis of pumiliotoxin 251D. The addition proceeded with high stereoselectivity (Scheme 30) <1999JOC1410>. 

Anthracyclinone synthesis. Wulf and Xu1 have reported a high-yield formal synthesis of 11-deoxydaunomycinone (5) in which the first step is a benzannelation of the chromium carbene 1 with the acetylene 2 to provide the naphthol 3, which is not isolated but treated with TFA to induce cleavage of the /-butyl ester and to... 

Recently, Curran described a procedure using triethylborane for the synthesis of spirooxindoles and spirodihydroquinolones through intramolecular addition of aryl radicals at the ipso position 4-alkoxy-substituted aromatic rings [15]. The key step for a formal synthesis of the vasopressin inhibitor SR121463A is described in Scheme 5. The initiation was performed with Et3B in an open to air reaction vessel. 

Scheme 5 Silane mediated key cyclization for a formal synthesis of the vasopressin inhibitor SR121463A...

---