Total Synthesis of the CP Molecules CP-225,917 and CP-263,114— Part 2: Evolution of the Final Strategy

Abstract

In the preceding communication [1] we described our findings from two unique strategies aimed at the total synthesis of the CP molecules 1 and 2. [2,3] The current retrosynthetic analysis (Scheme 1) is predicated on the basic strategic Scheme 1. Final retrosynthetic analysis of the CP molecules 1 and 2. TBS tert-butyldimethylsilyl, TES triethylsilyl.considerations and chemistry reported earlier from these laboratories. [1, 4,8] In addition, extensive model studies, whose disclosure will have to await the full account of this work, led us to conclude that a plan that targeted CP-263,114 (1) first would be most prudent. The virtues of such a scheme would include a decreased reliance on protecting group chemistry, greater stability and ease of handling intermediates with the pyran motif, [5] and a rare opportunity to attempt the rather daring challenge of converting the seemingly robust CP-263,114 (1) into its hydrated counterpart CP-225,917 (2). Indoline amide 14 was targeted as an ideal precursor for the CP molecules by virtue of its facile accessibility from 3[1] and because of the relative ease with which this special amide can be hydrolyzed in a two-step procedure. [6] Thus, sequential treatment of 3 with aqueous TFA/CH 2 Cl 2 to remove both silicon groups followed by exposure to CH 3 SO 3 H [2] in dry CHCl 3 led to pyranlactol 4 (Scheme 2; see Table 1 for selected physical data). A key observation was made during the selective oxidation of diol 4 to aldehyde 5. When diol 4 was oxidized with DMP [7] in CH 2 Cl 2 at ambient temperature the aldehyde lactol 5 was isolated as the major product along with significant quantities of lactone 6 (5:6 approximate ratio 2:1, 85 % combined yield). The fact that DMP was sufficient to effect this transformation, which was normally only possible using TEMPO, [1,8] indicated to us that not only was the lactolpyran behaving as a normal lactol but also that it would be plausible to employ the simple DMP protocol to reach the amide 14 (see below). Over the course of this work we have taken notice of the ability to fine-tune the reactivity of DMP by mere solvent alteration. Thus, the undesired, yet highly informative, lactonealdehyde 6 could essentially be eliminated (5:6 approximate ratio b 20:1, 90 % combined yield) by carrying out the oxidation in benzene at 25 8C.The lactol 5 was shielded from the ensuing homologation procedure (potential ring closure) by protection as the TBSether 7 (TBSOTf, 2,6-lutidine, 85 % yield). NaClO 2 oxidation of 7 proceeded smoothly to produce acid 8 in 90 % yield. The intimidating task of converting the sterically congested (neopentyl, concave face) carboxylic acid 8 into diazoketone 10 was easily accomplished via the acyl mesylate 9 (prepared in situ with MsCl/ Et 3 N at 0 8C) with excess CH 2 N 2 at 0 8C.[1] The diazoketone so obtained was immediately dissolved in DMF:H 2 O (2:1) and heated to 120 8C in the presence of excess Ag 2 O for one minute to generate the homologated acid 11 in 35 % overall yield from 8. Combining carboxylic acid 11 and i...

Ketene Chemistry after 100 Years: Ready for a New Century

“…The utility of the Wolff rearrangement has increased continually, and, for example, has found application in the synthesis of the CP molecules by silver‐ion‐catalyzed thermolysis of the extremely crowded diazo ketone 13 to give the unobserved ketene 14 and finally the acid 15 [Equation (7)] 4d,4e. This ketene reaction has been utilized for construction of the acetic acid side‐chain at the highly hindered C 7 position, just as was the case of generation of 9 [Equation (5)] 4d,4e …”

Natural-product-like chiral derivatives by solid-phase synthesis

“…During the course of a total synthesis of CP molecules [25,26], an unexpected cyclization mediated under oxidative conditions, was observed by Nicolaou and co-workers [27,28]. Discovery of this reaction led to development of new chemical processes for obtaining molecular diversity.…”

Total Synthesis Endeavors and Their Contributions to Science and Society: A Personal Account

“…The first category of structural elucidation by total synthesis in our laboratories are those of absolute configuration determination of natural products whose original structures were reported as racemic mixtures (e.g., 13, 14, 32, 119, Figure 14c,d,m). 49,50,[73][74][75][76][77][78][79][80][81][82] The second category is that of molecules synthesized before they were found in nature (e.g., 4, 22′, 115, 116, Figure 14a, b,g). 40,41,[83][84][85][86][87] The third category includes molecules whose originally reported structure was later challenged based on biosynthetic considerations 88 [e.g., maitotoxin (74), Figure 7, stereogenic centers within gold-colored oval] and later confirmed by us as the correct one.…”