The Pinene Path to Taxanes. 6. A Concise Stereocontrolled Synthesis of Taxol

Abstract

In the preceding communication, 1 we described the synthesis of a potentially general precursor (2, Scheme 1) of the highly promising chemotherapeutic agent Taxol 2 (1, Scheme 2) and its analogues. Our strategy for the elaboration of this ABbicyclic precursor into the ABC-tricyclic core of the taxanes was predicated on the view 1b that epimerization of the C7 center of Taxol 3 proceeds through the intermediacy of the AB-bicyclic enolaldehyde or its ketone isomer, leading to the intriguing possibility that the C-ring of Taxol could self-assemble under exceptionally mild conditions from a considerably less complex AB-bicyclic ketoaldehyde precursor (e.g., 9). In this communication, the viability of this aldol cyclization strategy is demonstrated in a synthesis of Taxol (1), representing the shortest sequence yet reported for the preparation of this important natural product. 4,5 The elaboration of our general taxane precursor (2, Scheme 1) into Taxol started with its homologation with Ph 3 PC(H)-OMe (91%) 6 followed by a one-step hydrolysis of the enol ether and acetonide groups (HCl, NaI) to provide aldehyde 3 (94%). 7 Selective protection of the C9 hydroxyl was then accomplished in 92% yield with TESCl and pyridine. Dess-Martin periodinane oxidation 8 of the C10 alcohol and introduction of C20 with [Me 2 NCH 2 ]I (g0.1 M) 9 and Et 3 N (excess) was conducted in one operation to produce enal 4 in 97% yield. The remaining carbons of the taxane skeleton were then introduced through the addition of 4 to a solution of allylmagnesium bromide and ZnCl 2 (89%) 10 which after BOM (benzyloxymethyl) protection (N,N-diisopropylethylamine solvent) provided the ether 5 as a single diastereomer. 10c The presence of ZnCl 2 in the former reaction completely suppressed addition of the Grignard reagent to the cyclic carbonate. Removal of the C9 silyl group (NH 4 F, MeOH) 11 provided an unstable hydroxyketone (93% over two steps) which was reacted immediately with PhLi 12 to form the C2 benzoate providing, after in situ acetylation, the acetate 6 in 79% yield. Transposition of the acetoxyketone under kinetic 5a or equilibrating conditions (Et 2 NH, KOAc, DMF) 13 resulted in limited success. However, when the guanidinium base 7 14 was employed for this transposition, the desired acetoxyketone 8 and recyclable 6 were obtained in 80% as a 4:3 equilibrium mixture. The monosubstituted alkene in 8 was then cleaved through addition of an ozone solution to form aldehyde 9 in 86% yield.The viability of the key aldol cyclization was addressed at this point. Previous studies in our laboratory 1b,15 showed that ketoaldehydes similar to 9 but incorporating a C1-C2 cyclic carbonate did not undergo aldol cyclization, preferring instead

Comparative citation analysis of duplicate or highly related publications

“…The next synthesis was reported by Danishefsky et al (1996;table abbreviation Da). Then Wender et al (1997a, 1997b; table abbreviations W-1 and W-2, respectively) reported another synthesis in two back-to-back communications, similar to Holton, Somoza, et al and Holton, Kim, et al Morihira et al (1998;table abbreviation Mo) published a communication followed by a full paper table abbreviation Ku). Between the publication of these two papers, another synthesis by Mukaiyama et al (1999; Nicolaou, Yang, et al (1994) and Mukaiyama et al (1999) papers, were published in the same journal.…”

“…The Holton, Somoza, et al paper is cited more often than the Holton, Kim, et al paper, while the Wender et al (1997a) paper has received about only half the number of citations of Wender et al (1997b). One may expect that the Holton, Kim, et al paper would receive more citations than Holton, Somoza, et al because the completion of the synthesis is reported in Holton, Kim, et al There is also a difference concerning citing journals.…”

“…The citation numbers for Wender et al (1997a) 1994 32 26 20 18 26 1995 84 77 70 62 84 1996 70 59 61 43 69 7 1997 57 67 46 44 57 21 6 15 17 1998 43 61 36 29 50 23 14 31 32 1999 32 51 30 22 33 21 16 21 22 12 11 2000 23 37 22 22 31 15 9 18 18 22 23 2 2001 19 31 8 13 16 8 5 10 12 6 17 9 Note. N-Na ϭ Nicolaou, Yang, et al (1994); N-AC ϭ Nicolaou, Dai, and Guy (1994) (2000) and Wender et al (1997b) in the Journal of Organic Chemistry are almost identical, while there is a strong tendency of authors of Tetrahedron Letters papers to cite Wender et al (1997b) instead of Wender et al (1997a) (see Table 6). Such a difference does not exist for the Holton, Somoza, et al and Holton, Kim, et al papers.…”

Organic synthesis: the art and science of replicating the molecules of living nature and creating others like them in the laboratory

“…Besides our total synthesis, a number of other elegant total syntheses of Taxol have been reported by Holton et al [27], Danishefsky et al [28], Wender et al [29], Mukaiyama et al [30] and Kuwajima and co-workers [31]. Collectively, these accomplishments advanced the art and science of organic synthesis, enabled the design and synthesis of numerous analogues of Taxol, and facilitated biological investigations and drug discovery efforts in the area, including identification of biological tools and drug candidates.…”

Oxetanes as versatile building blocks in the total synthesis of natural products: An overview

“…To date, seven methods was used in description the total synthesis of taxol [94][95][96][97][98][99][100][101][102][103]. Nicolaou and his co-workers were reported total synthesis of taxol and in 1994 [104][105][106][107].…”