The Nicolaou Synthesis

The Nicolaou group published a preliminary account of their synthesis in early 1994 (429) and followed this up with a series of full papers in 1995 430-433). The synthesis is of the form A+C— A-C ABC ABCD, and it is thus a convergent synthesis as opposed to the linear approach adopted by Holton. The C ring was prepared by a Diels-Alder reaction between diene 14.2.2 and dienophile 14.2.1, using phenylboronic acid as a tether to hold the reactants together. Elaboration of the adduct 14.2.3 then gave the protected ring C synthon 14.2.8. 

The A-ring was also prepared by a Diels-Alder reaction this time between diene 14.2.9 and dienophile 14.2.10 to give 14.2.11. Adduct 

11 was hydrolyzed and protected to give 14.2.12, which was then converted to the sulfonylhydrazone 14.2.13. 

With the ABC ring system and much of the required functionality in place, intermediate 14.2.17 was efficiently converted to baccatin III by the sequence 14.2.17— 14.2.24. 

---

A distinguishing feature of the Nicolaou synthesis of rapamycin is the use of a palladium-mediated tandem inter-/intramolecular Stille coupling to construct rapamycin s 31-membered macrolide ring and conjugated triene moiety. This maneuver was unprecedented in the macrolide field,9 and it can be applied to a fully deprotected seco substrate (vide infra). 

Construction of the segments was similar to the Nicolaou synthesis of leucomycin... 

The six reported syntheses are described in the following sections in order of their completion. The Holton and Nicolaou syntheses were published within days of each other, with the Nicolaou synthesis appearing first. The Holton synthesis is described first on the basis of the earlier submission date of the manuscript describing the work. 

As with the Nicolaou synthesis of 13, these concluding operations began with the union of the two advanced intermediates through peptide coupling, and, as shown in Scheme 37, 49 and 50 were neatly combined into 144 under the influence of EDC and HOBt in 86% yield. The success of this operation then paved the way for the final S Ar macrocyclization event. Unlike the triazene-dri-ven macrocyclization discussed earlier, which led to a disappointing distribution of products, the use of CsF and DMSO at ambient temperature in this case afforded a satisfying 5 1 mixture of atropi-somers (145 and 146) in favor of the desired isomer in a total combined yield of 95 %. 

Different Strategies with Aldol Reactions The Nicolaou Synthesis of Epothilone A Using an Unselective Aldol Reaction... 

Enantioselective Organocatalytic Construction of Carbocycles The Nicolaou Synthesis of Biyouyanagin A... 

Key steps (Figure 3.3, Scheme 3.2) in the Nicolaou synthesis of ABJ879 (10) are the formation of the C12-C13 double bond via a selective Wittig reaction between phosphorane 11 and aldehyde 12, the stereoselective aldol reaction of ot-chiral aldehyde 13 and ketone 14, macrolactonization of seco acid 16, stereoselective Sharpless epoxidation, to afford the C12-C13 epoxide, and introduction of the heterocycle by means of Stille coupling. ... 

Through a display of a series of electrocyclization reactions, the Nicolaou group demonstrated the biomimetic , one-step synthesis of the endiandric acids involving the cascade of reactions proposed by Black. The polyunsaturated compounds 37 and 38 (Scheme 7) were designed for their relative stability and potential to serve as... 

Our general survey of palladium in organic synthesis must now come to an end. At the very least, we hope that our brief foray into this fascinating area conveys some of the vitality that characterizes research in this area. The remainder of this chapter will address the first total synthesis of rapamycin by the Nicolaou group. This work is predicated on a novel variant of the Stille reaction. 

An unusual cationic domino transformation has been observed by Nicolaou and coworkers during their studies on the total synthesis of the natural product azadirachtin (1-105) [30]. Thus, exposure of the substrate 1-106 to sulfuric acid in CHjClj at 0°C led to the smooth production of diketone 1-109 in 80% yield (Scheme 1.27). The reaction is initiated by proto nation of the olefinic bond in 1-106, affording the tertiary carbocation 1-107, which undergoes a 1,5-hydride shift with concomitant disconnection of the oxygen bridge between the two domains of the molecule. Subsequent hydrolysis of the formed oxenium ion 1-108 yielded the diketone 1-109. 

The total synthesis of calicheamicin y/ by the research group of K. C. Nicolaou (The Scripps Research Institute, University of California, San Diego) represents a stunning achievement in synthetic organic chemistry. 

Uemura, T., Zhang, X.Y., Matsumura, K., Sayo, N., Kumobayashi, H., Ohta, T., Nozaki, K. and Takaya, H. J. Org. Chem., 1996, 61, 5510 a classical example is the Monsanto synthesis of (l)-DOPA using ruthenium complexed with the diphosphine DIPAMP, see Classics in Total Synthesis, Nicolaou, K.C. and Sorensen, E.J. VCH, Weinheim, 1996. 

As an example of the usefulness of the Sharpless asymmetric epoxidation the enantioselective synthesis of (-)-swainsonine and an early note by Nicolaou on the stereocontrolled synthesis of 1, 3, 5...(2n + 1) polyols, undertaken in connection with a programme directed towards the total synthesis of polyene macrolide antibiotics, such as amphotericin B and nystatin Aj, will be discussed. 

The semisynthesis of taxol [1], as well as the synthesis of taxoid model systems have been the focus of extensive research efforts in many laboratories, all over the world, which have greatly simplified the total synthesis of taxol itself. An excellent review by Nicolaou et al. has recently been published in Angewandte Chemie [2]. 

The strategy followed by Nicolaou and his group for the total synthesis of taxol was based on a retrosynthetic analysis already devised by the author in 1992 [6], which implies a convergent synthesis (Scheme 13.6.1). 

Nicolaou and co-workers recently published a formal synthesis of ( )-platen-simycin utilizing Stetter methodology [102], Aldehyde 162 was treated with achiral A-pentafluorophenyl pre-catalyst 164 and readily underwent cyclization to yield 163 as a single diastereomer (Scheme 26). After an additional seven steps late stage intermediate 165 was formed to complete the formal synthesis. 

The group of K. C. Nicolaou at Scripps Research Institute has developed two synthetic routes to epothilone A. Because the 16-membered lactone ring is quite flexible, it is not likely to impose strong stereoselectivity. Instead, the stereoselective synthesis of epothilone A requires building the correct stereochemistry into acyclic precursors which are closed later in the synthesis. One of the Nicolaou syntheses involves closure of the lactone ring as a late step. This synthesis is shown in Scheme 13.48. Two enantiomerically... 

The second Nicolaou synthesis is shown in Scheme 13.49. Stereoselective aldol additions are used to construct the fragments which are brought together by esterification at step D. The synthesis uses an olefin metathesis reaction to construct the 16-membered ring (step E). 

Based on that methodology, Oppolzer [551] and Nicolaou [552] devised procedures for the total synthesis of aromatic steroids as (+)-estradiol and ( )-estra-l,3,5(10)-triene-17-one. In this latter case, experimental conditions for the pyrolytic step are given. 

---