Nicolaou’s synthesis

Scheme 19. The Sonogashira coupling in Nicolaou s synthesis of (12S)-HETE (78).

Scheme 28. Nicolaou s synthesis of (5S,6fi)-diHETE methyl ester (115).

Nicolaou s Synthesis. Nicolaou s synthesis also involves a B-ring closure to connect the A and C rings.33 The retro synthetic approach is depicted in Scheme 7-59. 

Although the asymmetric total syntheses developed by Nicolaou and by Shair provide easy routes to enantiomerically pure CP compounds, the target molecules (+)-CP-263,114 (ent-1) and (—)-CP-225,917 (ent-2) are only the enantiomers of the natural occurring phomoidrides. After the establishment of the absolute configuration of the CP molecules by chemical synthesis, the focus of synthetic interest is the asymmetric total syntheses of (—)-CP-263,114 (1) and (-l-)-CP-225,917 (2). The first total synthesis furnishing (—)-CP-263,114 (1) as the correct enantiomer has recently been reported by Fukuyama et al. [23]. As the stereoselectivitydetermining step, an intramolecular Diels-Alder reaction was chosen, similar to that in Nicolaou s synthesis (Figure 11). The Diels-Alder precursor 42 is prepared in four easy... 

Paquette et al. start with the bis-vinylogation of the same compound 29 [14], by Wittig-Horner reaction, reduction, and oxidation (Scheme 5). For the formation of the C17-C16 bond, the onti-aldol 41 (ds not reported) is obtained by treatment of the aldehyde 39 with the (Z)-boron enolate 40, bearing a dithioketal moiety that is later to be the C51-C54 side chain. 3-Hydroxy-assisted, diastereoselective reduction of the keto group at C15 gives 41, which is converted into intermediate 42 in five more steps. The dethioketalization of 41 is achieved with phenyliodine(m) bis(trifluoroacetate) [16], As in Nicolaou s synthesis, the N12-C13 amide bond is formed first, followed by a low-yielding (21%, even at a concentration of 1 him) macrolactonization to 3. Table 1 summarizes the benchmark data of the two total syntheses of sanglifehrin A (1). 

SCHEME 12.2 Nicolaou s synthesis of Gb3Cer. DMAP, 4-dimethylaminopyridine NBS, A-bromosuccinimide TBAF, tetrabutylammonium fluoride. 

Key step of Nicolaou s synthesis is the stereoselective hydrogenation of the unsaturated cyclo-dodecanone 17 which was obtained via intramolecular acetylide-aldehyde condensation of 6. The intermediate (Z)-olefm immediately rearranges to the tricyclic dihydrofuran 18 (Scheme 2). Solely the hydroxyl group at the quaternary carbon atom... 

To underscore the fact that the rate of deprotection is widely variable and very structure dependent, we cite an example in which a hindered trimethysilyl ether was surprisingly robust. In Nicolaou s synthesis of Zaragozic Acid A [Scheme 4.5] 4 treatment of 5.1 with 50 equivalents of trifluoroacetic acid in dichloro-... 

There is sufficient latitude in the rates for selective removal of a 3,4-dimethoxy-benzyl ether in the presence of an adjacent p-methoxybenzyl ether as illustrated in Scheme 4T74, taken from Smith s synthesis of Zampanolide,247 324 For other examples of the beneficial lability of 3,4-dimethoxybenzyl ethers, see Smith s synthesis of Phorboxazole131 and Nicolaou s synthesis of Apoptoli-dine.325... 

To show how this is done in practice, we will examine Nicolaou s synthesis of zoopatenol 212, a biologically active natural diterpenoid (Scheme 2.91). A retrosynthetic analysis of this structure envisions the disconnection of bonds a, b, and c, to lead to rather simple precursors, the bromo ketone 213 and the triol 214. A formal pathway for the assemblage of 212 from these precursors involves several steps, as outlined in Scheme 2.91. This plan appears strategically... 

Nicolaou s synthesis [7] of the Sialyl-Lewis tetrasaccharide is discussed in detail as an example of the stepwise route (Scheme 5.4). 

A vinylogous Mukaiyama reaction, similar to that utilized in our synthesis, was employed to introduce the C-, stereocenter in Nicolaou s synthesis and also in the synthesis of preswinholide A reported by the Nakata group I53k One notable reaction in Nakata s synthesis of preswinholide A was the auxiliary-controlled aldol reaction shown in Scheme 9-31. Here the Evans auxiliary is used to couple two relatively complex fragments 91 and 92 to give 93. Unusually, this reaction was best performed using the lithium enolate of imide 91. 

Even if the only difference between the two alkenes is the number of substituents, that can be enough for some reactions. If the substituents are simple alkyl or aryl groups, then the more highly substituted alkene will be the more nucleophilic. This is enough to allow the epoxidation of the trisubstituted alkene in citronellene2 28 while leaving the monosubstituted alkene intact and provide a source of the optically active acid 31 for Nicolaou s synthesis of rapamycin.3... 

Only Nicolaou s synthesis [143a,c] is described in this section (Scheme 82), because the results of olefin metathesis at the Cl2 and C13 positions, the key reaction of this strategy, are almost the same. The Cl-Cl 2 acid 573 was synthesized as the coupling partner. The Brown asymmetric allylboration of p-keto aldehyde 569 followed by TBS protection furnished 570, which was oxidized... 

An alternative method for the formation of an a,(3-unsaturated carbonyl compound is the elimination of an initially formed Mannich product. The procedure is particularly effective for the formation of (3,(3-bis(unsubstituted) a, -unsaturated carbonyl compounds. The Mannich product 11 can be formed in the presence of a secondary amine and a non-enolizable aldehyde such as formaldehyde (2.12). The Mannich reaction is a useful carbon-carbon bond-forming reaction and the products have found application in the synthesis of, in particular, alkaloid ring systems. The Mannich product may eliminate under the reaction conditions, or can be alkylated to form the quaternary ammonium salt in order to induce elimination. A convenient variation of this method is the use of Eschenmoser s salt, H2C=NMe2 X. For example, Nicolaou s synthesis of hemibrevetoxin B used this salt in order to introduce the required methylene unit a- to the aldehyde 12 (2.13). The same transformation with the corresponding methyl ester, which is less acidic, requires prior enolization with a strong base (e.g. NaN(SiMe3)2) and subsequent quatemization of the tertiary amine with iodomethane and elimination using DBU. 

SCHEME 2 (A) Nicolaou s synthesis of the bicyclic lactone using an intramolecular Michael addition of an acetoxy dienone. (B) Failed cyclization of our... 

Scheme 11. Nicolaou s synthesis of A-ring amino acid building block 42.

---