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Total Synthesis of the CP-Molecules (CP-263,114 and CP-225,917, Phomoidrides B and A)

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Total Synthesis of the CP-Molecules (CP-263,114 and CP-225,917, Phomoidrides B and A) Published on Web 02/16/2002 Total Synthesis of the CP-Molecules (CP-263,114 and CP-225,917, Phomoidrides B and A). 3. Completion and Synthesis of Advanced Analogues K. C. Nicolaou,* Y.-L. Zhong, P. S. Baran, J. Jung, H.-S. Choi, and W. H. Yoon Contribution from the Department of Chemistry and The Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, and Department of Chemistry and Biochemistry, UniVersity of California, San Diego, 9500 Gilman DriVe, La Jolla, California 92093 Received August 20, 2001 Abstract: The completion of the total syntheses of the CP-molecules is reported. Several strategies and tactics, including the use of amide-based protecting groups for the homologated C-29 carboxylic acid and the use of an internal pyran protecting group scheme, are discussed. The endeavors leading to the design of new methods for the homologation of hindered aldehydes and to the isolation of a polycyclic byproduct (23), which inspired the development of a new series of reactions based on iodine(V) reagents, are described. In addition, the discovery and development of the LiOH-mediated conversion of CP-263,114 (1)toCP- 225,917 (2) is described, and a mechanistic rationale is presented. Finally, a synthetic route to complex analogues of the CP-molecules harboring a maleimide moiety in place of the maleic anhydride is presented. Introduction Scheme 1. Second-Generation Strategy for the Total Synthesis of 1 and 2 In the preceding paper in this issue,1 basic strategies for the installation of the maleic anhydride, γ-hydroxylactone, and remote stereocenter at C-7 (“upper” side chain) of the CP- molecules (1 and 2, Scheme 1) were devised and carried out. In addition, a first generation synthetic route to the natural products was tested employing these new methodologies. Central to our synthetic plan was the premise that the advanced key intermediate 5 (Scheme 1) would eventually lead to the target structures. Arrival at this “checkpoint” in the synthetic “laby- rinth” permitted a systematic investigation of the timing of the individual steps in the final stages. Specifically, the correct order for the installation of the γ-hydroxylactone and the one-carbon homologation of the “lower” side chain (C-28 f C-29) remained to be addressed. Whether to first target CP-263,114 (1)orCP- 225,917 (2) was also a lingering question in our minds. In this paper, second- and third-generation strategies toward the CP- molecules are delineated. Most importantly, the design and discovery of new cascade reactions and synthetic technologies en route to 1 and 2, and designed analogues thereof, are described. Results and Discussion 1. Second-Generation Retrosynthetic Analysis. During our first-generation1 approach to 1 and 2, we attempted to install Scheme 2. Thus, if we were to perform the one-carbon the C-29 carbon after the construction of the γ-hydroxylactone homologation of C-28 prior to the γ-hydroxylactone formation, and failed, due to the frailty of the precursors. The only dilemma the latter operation would require the presence of a free 1,4- associated with inverting the order of these events is shown in diol such as the one generated from 7 upon hydrolysis of the acetal protecting group. In the event, the primary alcohol of * To whom correspondence should be addressed at the Department of that diol, when generated by acid catalysis, spontaneously Chemistry, The Scripps Research Institute. (1) Nicolaou, K. C.; Baran, P. S.; Zhong, Y.-L.; Fong, K. C.; Choi, H.-S. J. cyclized onto the proximate ester to furnish lactone 8 (see Am. Chem. Soc. 2002, 124, 2190-2201. Scheme 2), a stop that proved to be a dead end. Due to the 2202 VOL. 124, NO. 10, 2002 9 J. AM. CHEM. SOC. 10.1021/ja0120126 CCC: $22.00 © 2002 American Chemical Society Total Synthesis of the CP-Molecules. 3 ARTICLES Scheme 2. Conformationally Locked γ-Lactone 8 Resulting from Scheme 3. Construction of Benzyl Amide 17a Cyclization of 7 in the Presence of Acida a Reagents and conditions: (a) CSA (0.2 equiv), MeOH, 25 °C,1h, 90%. conformational rigidity in this system, and the sensitivity of neighboring functionalities, we were unable to open lactone 8. Efforts to reduce the C-29 carbon to the alcohol stage were complicated by protecting group incompatibilities. To circum- vent this problem, the reigning theme of our second-generation strategy (Scheme 1), which provided a potential solution to this roadblock, involved the enlistment of an amide functionality to disguise and deactivate the electrophilic center at C-29. In doing so, we could avoid the problems associated with the late-stage homologation of the first-generation strategy,1 lockup structures, and, subsequently, only face what we perceived to be the comparably facile task of amide hydrolysis. As shown in the retrosynthetic blueprint in Scheme 1, an intermediate of type 3 was targeted as a potential precursor to 2. Intermediate 3 was envisioned to arise from homologated intermediate 4 by employing the DMP-mediated cascade for γ-hydroxylactol construction described in the preceding paper.1 Retrohomolo- gation and protecting group manipulations led to the previously synthesized advanced key intermediate 5. 2. Explorations To Implement the Second-Generation Strategy. The attempted execution of the newly designed second-generation strategy toward the CP-molecules began with the advanced key intermediate 5 as shown in Scheme 3. Thus, removal of the isopropylidene group from 5 using aqueous AcOH furnished the diol 9 in 85% yield. DDQ-mediated formation2 of the seven-membered benzylidene acetal 10 (57% yield) followed by stepwise oxidation of the remaining hydroxyl a Reagents and conditions: (a) 90% aqueous AcOH, 25 °C, 5 h, 85%; (b) DDQ (2.0 equiv), fluorobenzene, 25 °C, 2.5 h, 57%; (c) DMP (3.0 group with DMP (90% yield) and then NaClO2 led to carboxylic equiv), NaHCO3 (10 equiv), CH2Cl2,25°C, 1 h, 90%; (d) NaClO2 (3.0 acid 12 in 78% yield via the intermediate aldehyde 11. equiv), NaH2PO4 (1.5 equiv), 2-methyl-2-butene (50 equiv), t-BuOH/H2O ° Optimization studies of the DDQ-mediated cyclization (see (2:1), 25 C, 20 min, 78%; (e) MsCl (5.0 equiv), Et3N (10 equiv), THF, ° f ° Table 1) led to the identification of fluorobenzene as a superior 0 C, 5 min; (f) CH2N2 (excess), Et2O/THF, 0 25 C, 1 h; (g) Ag2O (5.0 equiv), DMF/H2O (2:1), 120 °C, 1 min, 43% overall from 12; (h) PhCH2NH2 solvent for this transformation. (1.5 equiv), EDC (3.0 equiv), 4-DMAP (1.0 equiv), CH2Cl2,25°C,1h, To execute the planned Arndt-Eistert homologation protocol3 85%; (i) 80% aqueous AcOH, 25 °C, 1.5 h, 77%. TFA ) trifluoroacetic on carboxylic acid 12, we required a mild method for the acid;4-DMAP)4-(N,N-dimethylamino)pyridine;EDC)1-(3-(dimethylamino)- ) activation of hindered carboxylic acids since acid chloride propyl)-3-ethylcarbodiimide hydrochloride; PMP p-methoxyphenyl. formation with this system and others related to it was extremely to the highly hindered nature of the CP-skeleton. Specifically, inefficient or did not work at all. As we had done with the maleic we took advantage of the reactive and compact nature of the anhydride construction, we designed a method which responded acyl mesylate species to activate these sterically blocked systems (2) Oikawa, Y.; Yoshioka, T.; Yonemitsu, O. Tetrahedron Lett. 1982, 23, 889. for attack by diazomethane, a small reagent itself. The developed (3) (a) Arndt, F.; Eistert, B.; Partale, W. Ber. Dtsch. Chem. Ges. 1927, 60, method4 is extremely mild, requiring only low temperatures 1364. (b) Arndt, F.; Amende, J. Ber. Dtsch. Chem. Ges. 1928, 61, 1122. (c) Arndt, F.; Eistert, B. Ber. Dtsch. Chem. Ges. 1935, 68B, 200. See also: Smith, A. B., III; Toder, B. H.; Branca, S. J. J. Am. Chem. Soc. 1984, 106, (4) Nicolaou, K. C.; Baran, P. S.; Zhong, Y.-L.; Choi, H.-S.; Fong, K. C.; He, 3995. Y.; Yoon, W. H. Org. Lett. 1999, 1, 883. J. AM. CHEM. SOC. 9 VOL. 124, NO. 10, 2002 2203 ARTICLES Nicolaou et al. Table 1. Optimization of the DDQ-Mediated Benzylidene Scheme 4. Attempted Hydrolysis of Benzyl Amide 20a Formation a Reagents and conditions: (a) DMP (5.0 equiv), benzene, 80 °C, 8 min, 35%; (b) TEMPO (10 equiv), PhI(OAc)2 (10 equiv), CH3CN, 25 °C,2h, 70%. Table 2. Optimization of the Wolff Rearrangement Leading to Carboxylic Acid 15 Scheme 5. Use of the Martin Sulfurane for the Conversion of Anilides to Esters and Carboxylic Acidsa a See ref 7. leading to diol 17. The latter compound was found to be resistant to cyclization as predicted. With diol 17 in hand, the stage was now set for the application of the DMP cascade oxidation sequence to install the γ-hydroxy- lactone functionality (Scheme 4). Thus, treatment of 17 with DMP in refluxing benzene led to the γ-hydroxylactol 19 in 35% yield. TEMPO-mediated conversion of 19 to the lactone 20 proceeded smoothly in 70% yield. However, and despite for rapid activation. Thus, carboxylic acid 12 was smoothly encouraging model studies,6 amide 20 resisted hydrolysis under transformed into diazo ketone 14 via the acyl mesylate 13 upon conditions required for the survival of the parent structures. This ° treatment with MsCl/Et3Nat0 C followed by addition of excess time, we had successfully constructed the entire CP skeleton CH2N2 as a dried ethereal solution. The generality of this with correct oxidation states at all centers only to be frustrated protocol and relevant mechanistic studies have been reported by one protecting group which refused to dismantle as expected.
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