Showing papers on "Total synthesis published in 1995"

Total Synthesis of the Polyether Antibiotic Lonomycin A (Emericid)

Abstract: The first asymmetric synthesis of the polyether antibiotic lonomycin has been achieved. The skeleton is assembled through the synthesis and union of two subunits comprising the CI-CII and C12-C3o portions of the structure. These fragments were constructed utilizing auxiliary-based asymmetric aldol and acylation reactions to control the absolute stereochemical relationships in the structure. The majority of the 1 ,Zdioxygen relationships in the polyether portion of the molecule were established through a succession of epoxidation reactions which were transformed through intramolecular heterocyclization to establish rings D, E, and F. The major subunits were coupled through a highly diastereoselective aldol reaction to construct the C11 -C12 bond. Spiroketalization followed by selective methylation of the Cll hydroxyl provided the protected ionophore in high yield.

Total synthesis of rapamycin

Abstract: Details of the total synthesis of rapamycin (1) are reported. The synthesis required the preparation of intermediates 4 - 9 in nonracemic form; key coupling reactions included a chromium-mediated addition of vinyl iodide 8 to aldehyde 7 and an Evans aldol reaction to couple fragments 62 and 9. Intermediates 4 and 6 were joined through an amide bond formation to afford advanced intermediate 71. Swern oxidation of the diol in 71 was followed by a selective removal of the TES groups and a second Swern oxidation. Finally, removal of the remaining silyl protecting groups provided fully deprotected, penultimate intermediate 2 in which all carbons were in their proper oxidation state. Macrocyclization was achieved through a tandem inter/intramolecular palladium-mediated Stille coupling reaction between distannylethene 3 and bis(vinyl iodide) 2. This latter process accomplished in one step the installation of the remaining two carbons of the natural product and the completion of its total synthesis.

Total Synthesis of Brevetoxin B. 1. First Generation Strategies and New Approaches to Oxepane Systems

Abstract: The fust generation strategies toward the total synthesis of brevetoxin B (1) are presented and the syntheses of the key intermediates 3, 4, 5, 67, 83, and 94-98 required for the projected construction are described. The earliest and most convergent strategy required the application of the hydroxy epoxide cyclization and the intramolecular conjugate addition as key reactions for the construction of the fused tetrahydropyran ring systems (4) [ABC], (7) [FG], and (8) [UK]. The oxocene ring (H) was formed via a Wittig reaction followed by a hydroxy dithioketal cyclization to produce the hexacyclic fragment [FGHIJK] (6 5). The 12-membered dithionolactone 18 was envisioned as the precursor of the dioxepane system of the molecule via a projected bridging reaction, to construct simultaneously both oxepane rings. However, the dithionation of dilactone 17 proved unsuccessful. In a subsequently evolved strategy, a new photolytic approach toward the dioxepane region was developed, starting from the acyclic dithiono progenitor 20 (20 23). Application of this reaction to the brevetoxin B skeleton afforded the desired oxepene (96 97), which after deprotection produced oxepanone 98. A specifically designed reductive hydroxy ketone cyclization (98 99) was then employed in an attempt to close the remaining ring [E], but, again, without success. The novel rearrangement of hydroxy ketone 87 to the pentacyclic system 89 was observed in a less elaborate skeleton. The scope and generality of these silicon-induced reductive cyclizations are also described.

Total Synthesis of Brevetoxin B. 3. Final Strategy and Completion

Abstract: The final strategy for the total synthesis of brevetoxin B (1) according to the retro synthetic analysis shown in Scheme 1 is described. Starting with the tetracyclic ring system 8 (DEFG), the construction of the C ring was accomplished via an intramolecular conjugate addition (7 — 13). A hydroxy epoxide cyclization was then utilized for the formation of ring B (6 —^ 21). Ring A was introduced via an intramolecular phosphonate ester—ketone condensation (5 -*• 27) to produce, after side chain elaboration, the desired heptacyclic phosphonium iodide 4. Formation of the tricyclic aldehyde 3 (UK) starting from diol 34 is also described. Wittig coupling of 3 and 4 followed by selective deprotection, hydroxy dithioketal cyclization, and radical desulfurization produced the undecacyclic system 48 representing the complete brevetoxin B skeleton (46 — 2 — 47 — 48). Allylic oxidation of ring A (48 49) followed by side chain elaboration of the K ring side chain (49 — * 50 —■ 51 — * 52) led to the TBS protected brevetoxin B (52) which upon exposure to HF*pyridine treatment afforded natural brevetoxin B (1).

Total Synthesis of Rapamycin and Demethoxyrapamycin

Abstract: Rapamycin (1) and demethoxyrapamycin (2) have gained prominence as members of a growing family of macrocyclic natural products with marked immunosuppressive properties.' These targets have stimulated intensive synthetic activity, including three total syntheses of le2 Rapamycin and its structurallyrelated cousin FK506 both bind to the cytosolic immunophilin FKBP, a strict requirement for the observed physiological re~ponse.~ Although the specific role of 1 in signal transduction and immunosuppression remains unclear, it has been established that rapamycin interferes with a Ca2+-independent signaling pathway emanating from the IL-2 r e~ep to r .~ From the retrosynthetic perspective (Scheme l), we envisioned the elaboration of rapamycin and the 27-demethoxy congener via couplings of fully functionalized ABC fragments with a common DE element, all derived in turn from the building blocks A-E.5 Final assembly of the macrocycle could then be effected by intermolecular acylation at C(34) and intramolecular Pd(0)-catalyzed Stille coupling, or via initial formation of the triene seco acid followed by macrolactonization. Herein we report the application of the former strategem to the total syntheses of rapamycin (1) and demethoxyrapamycin (2). This f i s t successful route to 2 confirmed the proposed structure, which until now was assigned solely on the basis of spectral comparisons with l . l b Our highly convergent approach is also intended to permit the straightforward preparation of designed analogs. The ABC fragment of demethoxyrapamycin derived from the previously described AB acetonide (+)-3 (Scheme 2).5 Following ketal hydrolysis, standard manipulations provided a highly acid-labile terminal epoxide which was used without purification in coupling to dithiane (-)-CS5 Silylation of the resultant C(28) alcohol afforded (+)-4.6 To introduce the requisite C(27) oxygen in the analogous rapamycin ABC subunit (7, Scheme 3), we employed aldehyde (+)-66 as an electrophilic AB component. The aldehyde was assembled via lithiation of dithiane (+)-5,5 alkylation with primary iodide (-)-A,5 and acetal hydrolysis. Metalation of dithiane (-)-C and addition to 6 then furnished the epimeric

Total synthesis of tautomycin

Abstract: The first synthesis of the antifungal antibiotic tautomycin, a potent protein phosphatase inhibitor, has been achieved via aldol coupling of two large subunits, a right-hand C1-C21 ketone and a left-hand aldehyde (left from C22). The C1-C10 segment was synthesized through a remote stereochemical control process using a spiroketal template After joining with the C11-C18 segment, the spiroketal moiety was selectively constructed. Then the right-hand C1-C21 ketone was synthesized via Roush asymmetric crotylboration. The left-hand aldehyde was prepared by esterification of a C21-C26 segment and a dialkylmaleic anhydride segment. The C21-C26 segment was synthesized through a regioselective opening of an epoxy alcohol and the dialkylmaleic anhydride segment was through a diastereoselective olefination. Completely stereoselective assemblage of the two subunits, the right-hand and the left-hand, was achieved employing the Mukaiyama aldol reaction. Further functional group manipulations including desilylation, oxidation at C2, and deprotection of tert-butyl ester with concomitant anhydride formation provided tautomycin which was identical with the natural product. As a preliminary study, derivatizations and degradation of the natural product were also examined to support the total synthesis.

Total Synthesis of Brevetoxin-B .2. 2nd Generation Strategies and Construction of the Dioxepane Region [Defg]

Abstract: The second generation strategy for the total synthesis of brevetoxin B (1) is presented. According to this •strategy, the heptacyclic (ABCDEFG) phosphonium iodide 4 and the tricyclic (UK) aldehyde 3 were defined as the precursors for the brevetoxin B skeleton. The Yamaguchi lactonization was successfully applied for the formation of the (EFG) and (DEFG) lactones (15 -* 7) and (29 6), respectively. The required appendage on ring (E) was efficiently introduced via a Murai coupling, involving addition of a higher order organocuprate derived from iodide 20 to the lactone-derived enol triflate 16 (16 — 25). The minor epimer of the resulting product 6fi was then converted to the desired isomer 6 a via hydrogenation using an Ir(I) catalyst. A number of approaches were considered for further elaboration of lactone 6. Among them a convienient Cr/Ni-promoted coupling' reaction was developed and applied to the introduction of the side chain on ring D. The scope and generality of this reaction was examined with a variety of aldehydes (e.g., 39, 59, and 62). Construction of 38 was thus achieved from vinyl triflate 36 and the ring B aldehyde 39. However, the projected intramolecular Michael addition (41 — ■ 1 42) and reductive hydroxy ketone cyclization (47 48) failed to yield ring C. Fetizon cyclization afforded the pentacyclic lactone (CDEFG) (51 — * 52), which resisted further useful functionalization, Using the more elaborate aldehyde 62, the Cr/Ni coupling reaction afforded allylic alcohol 64, which then served as a precursor to the pentacyclic lactol 80. The latter compound also resisted advancement to more elaborate intermediates, leading to abandonment of this approach and the formulation of a new strategy.

Total Synthesis of (+)- and (-)-K252a

Abstract: The isolation and structural characterization of architecturally novel and biologically important natural products is often followed by a flurry of synthetic activity. The indolo[2,3-a]carbazoles K252a (1) and staurosporine (2)' have been no exception, and several papers describing possible synthetic routes and derivatizations of the natural material have ap~ e a r e d . ~ . ~ In addition, four approaches to the naturally occuning aglycon K252c (3a, also known as staurosporinone) have been Classified by the last covalent bond(s) formed, these approaches include cycloaromatization (A)? double nitrene C-H insertion (B,B'),4b nitrene C-H insertion (B'),k,d and maleimide reduction (C) (see Scheme l)!e-g In this communication we report the development of a unique approach to 3 wherein coupling of diazolactam 4' and 2,2'-biindole (5)* initiates cycloaromatization to form bond D.9 Application of this strategy allows efficient access to both the parent aglycon (3a) and the selectively protected derivative (3c) employed in the total synthesis reported herein. Overall, preparation of the enantioenriched furanose 6 and aglycon unit 3c and their conversion to 1 require only 11 synthetic operations with a longest linear sequence of seven steps. The feasibility of our carbenoid approach to 3 was initially assessed by reaction of 4a (1.0 equiv) with indole (3.0 equiv) in the presence of catalytic Rhz(OAc)4 (0.01 equiv, Scheme 2). After only 12 h, TLC analysis indicated complete consumption of 4, and standard workup and isolation procedures furnished 71° in 65% yield. Similar conditions proved ineffective for the coupling of 4a with 5, and it was only after considerable