The Danishefsky Synthesis

The synthesis started with the well-known Wieland-Miescher ketone 14.3.1, which was converted in several steps to the triol 14.3.5 and thence to the oxetane 14.3.7. Cleavage of the A-ring of 14.3.7 and adjustment of oxidation levels gave the aldehyde 14.3.10, which was 

The key cyclization to give tetracyclic product was achieved by the Heck reaction. The vinyl triflate 14.3.15 underwent cyclization in the presence of Pd(PPh3)4 to give the product 14.3.16 in 49% yield. Subsequent elaboration of 14.3.16 gave the protected baccatin III 

with the introduction of the C-9 ketone using the procedure developed by Holton and the conversion of 14.3.21 to baccatin III following Nicolaou s procedure. 

The Danishevsky synthesis, as noted earlier, is unique in its early incorporation of the oxetane ring. It also makes effective use of the starting Wieland-Miescher ketone, since this is available in enantio-merically pure form and all the stereochemistry of baccatin III derives from the chiral center of this ketone. 

---

The two syntheses in Schemes 8.12 and 8.13 are essentially linear. They have rather different bond-sets, yet they have the same number of steps and the same number of bonds in the bond-sets (Scheme 13.33). Accordingly, the difference in the ratio between skeletal bond-forming steps and refunctionalization steps is minimal, arising solely from differences in the polycyclization cascades. Note that step (4) in the Danishefsky synthesis counts as a refunctionalization step, because the skeleton is only temporarily extended. 

Danishefsky s synthesis reaches a high level of complexity by the middle of the synthesis sequence (step (6)), whereas in the Curran synthesis high complexity is reached in the final step of the sequence. In terms of the robustness of the plan, the Danishefsky synthesis has substantial potential for variation. Curran s synthesis has two key steps, (3) and (8), on which failure or success depends. To have such a step as the last one of a synthesis is quite daring. 

Different Strategies with Aldol Reactions The Danishefsky Synthesis of Epothilone A Relying on Intramolecular Aldol Reaction... 

T. M. Kamenecka and S. J. Danishefsky, The Total Synthesis of Himastatin Confirmation of the Revised Stereostructure, Angew. Chem., Int. Ed. Engl., 37, 2995 (1998). We thank Professor Danishefsky for providing us with preprints of the himastatin communications here and in ref. 31(d). 

A series of chiral binaphthyl ligands in combination with AlMe3 has been used for the cycloaddition reaction of enamide aldehydes with Danishefsky s diene for the enantioselective synthesis of a chiral amino dihydroxy molecule [15]. The cycloaddition reaction, which was found to proceed via a Mukaiyama aldol condensation followed by a cyclization, gives the cycloaddition product in up to 60% yield and 78% ee. 

Node and co-workers have found that the Diels-Alder reaction of nitroalkenes v/ith 1-methoxy-3-trimethylsilyloxy-l,3-butadiene (Danishefsky s dienesi exhibit abnormal exo-se-lecdvity Electrostadc repulsion between the nitro and the silyloxy group of the diene induces this abnormal exc-selecdvity (Tq 8 10 This selecdve reacdon has been used for the asymmetric synthesis of various naniral products as shovm in Scheme 8 6... 

Node and coworkers have used this aromadzadon strategy for the synthesis of (-) aphanor-phineThe Diels-Alder reacdon of chiral nitroalkene, prepared by the asymmecdc nitrooleft-nation reacdon of ct-methyl-o-valerolactone, with the Danishefsky s diene followed by aromadzadon is used as a key step for this total synthesis, as shown in Scheme 8 6... 

During the course of an elegant synthesis of the multifunctional FR-900482 molecule [( )-43, Scheme 9], the Danishefsky group accomplished the assembly of tetracycle 42 using an intramolecular Heck arylation as a key step.24 In the crucial C-C bond forming reaction, exposure of aryl iodide 41 to a catalytic amount of tetra-kis(triphenylphosphine)palladium(o) and triethylamine in acetonitrile at 80 °C effects the desired Heck arylation, affording 42 in an excellent yield of 93 %. The impressive success of this cyclization reaction is noteworthy in view of the potentially sensitive functionality contained within 41. 

Bicyclic 2-pyridones fused over the nitrogen is another important heterocyclic scaffold. In the quest towards the total synthesis of Camptothecin, Danishefsky and co-workers developed a method where a vinylogous urethane was reacted with 1,3-dicarboxymethoxyallene generated in situ from dimethyl 3-chloroglutaconate to a bicyclic 2-pyridone intermediate [31-34]. This method has later been successfully applied in the synthesis of other... 

En route to the total synthesis oftashironin (7-114a) and the debenzoylated compound 7-114b, which shows an interesting promotion of neurite growth, Danishefsky and coworkers have developed a domino oxidative dearomatization/trans-annular Diels-Alder reaction [54]. In this line, treatment of 7-115 with phenyl-iodine(III) diacetate (PIDA) led to an intermediate 7-116, which immediately underwent a transannular Diels-Alder reaction to furnish the complex cycloadducts 7-117 in good yields (Scheme 7.31). 

In Holton s and Wender s work, the total synthesis was achieved by sequentially forming the AB ring through the fragmentation of epoxy alcohols derived from (—)-camphor and a-pinene. Nicolau s, Danishefsky s, and Kuwa-jima s total syntheses involved B ring closure connecting the A and C rings, whereas in Mukaiyama s synthesis, the aldol reaction was extensively applied to construct the polycyclic system. 

Hybrid materials [Ln(fod) (THF)y] MCM-41.28o [Ln = Sc (18F), Y (19F) and La (26F)] and [Y(fod)3] MCM-41.28o (6) were used under standard conditions as catalysts for the Danishefsky transformation (Table 12.9). In these reactions 1.1 equivalents of benzaldehyde (Sj) were allowed to react with trans-l-methoxy-3-trimethylsilyloxy-1,3-butadiene (Si) in n-hexane at ambient temperature. The outcome of the reaction was highly dependent on the synthesis procedure used for the Ln-fod surface complexes. For materials [Ln(fod) ,(THF)y] MCM-41.28o. obtained by secondary ligand exchange from silylamide surface complexes 18,19 and 27 (via route C in Scheme 12.3 see also Table 12.3 and Scheme 12.8), the... 

The formal total synthesis of racemic guanacastepene (rac-187) from Snider and co-workers (Fig. 20) was submitted six months later than the completed synthesis of Danishefsky s group [116-118]. The shortest sequence developed by the Snider group utilized the sequential cuprate addition/enolate alkylation of 2-methylcyclopent-2-enone 90 previously exploited by Piers, Williams and Danishefsky (Schemes 15 and 31). As outlined in Figs. 19 and 20, the strategies of Danishefsky and Snider are closely related. Both rely on stepwise annulations to build up the tricyclic ring system. They differ only in respect to the particular reactions that converted the monocyclic starting material (90) via bicyclic hydroazulenes (207 vs 227) into the desired tricyclic 5-7-6-system (224). 

Figure 12. The Danishefsky-Hungate synthesis of octosyl acid A.

J. ApSimon, ed., The Total Synthesis of Natural Products, Vols. 1—9, Wiley-Interscience, New York, 1973—1992. S. Danishefsky and S. E. Danishefsky, Progress in Total Synthesis, Meredith, New York, 1971. 

Interest in the total synthesis of the Aspergillus terreus derived quadrone fi06), an antitumor agent has been very intense. Success was first realized in Danishefsky s laboratory Once 601 was reached, its sidechain was elaborated and ring closure effected (Scheme LII). Condensation of 602 with 1-tert-butoxy-l-tcrt-butyl-dimethylsiloxyethylene in the presence of titanium tetrachloride and subsequent desilylation resulted in introduction of an angular acetic acid moiety. The two sidechains were next connected by intramolecular alkylation and the resulting keto add was subjected to selenenylation in order to produce 603. The a, P-unsaturated double bond was used to force enolization to the a position. Indeed, 604 was... 

Ring closure to an episulfide is a feasible reaction for thiocarbonyl ylides. In most cases, the sulfur is further extruded under the reaction conditions to afford an olefin as the final product. This cascade transformation has been utilized by Danishefsky and co-workers in their total synthesis of ( )-indolizomycin (Scheme 16)." In the Danishefsky s approach, diazo ketone 137 is treated with a catalytic amount of Rh2(OAc)4 to generate thiocarbonyl ylide 138, which cyclizes to give episulfide 139. This episulfide isomerizes to mercaptan 140, which is then desulfurized by partially deactivated W-2 Raney nickel. 

Other alkcnes in the substrate, and especially other alkynes, will react with the Ru catalyst. Samuel Danishefsky, of Columbia University and Sloan-Kettering Institute, recently completed (Organic Lett. 2004,6,413) the total synthesis of the antimalarial and antitumor agent aigialomycin D. For the Ru-mediated macrocyclization of 4 to 5, the alkyne in the molecule was protected as the dicobalt octacarbonyl adduct. After the cyclization, the alkyne was deprotected by brief exposure to ceric ammonium nitrate. 

The aza-Diels-Alder reaction of Danishefsky s diene with imines provides a convenient method for the synthesis of 2-substituted 2,3-dihydro-4-pyridones, a compound class that has important synthetic applications. Kobayashi and co-workers have studied the reaction in detail using ytterbium (III) triflate as the Lewis acid30. Although the reaction is often run at low temperature (—78°C to 0°C) for a number of hours, we have found that the reaction also worked well at elevated temperatures (150°C) in the microwave for a few minutes (J. Westman and A. Hurynowics, unpublished results) (see Scheme 5.15). The imines could either be preformed prior to the addition of the Danishefsky s diene or the reaction could be performed as a multi-component protocol, where all components were added at once. 

The Danishefsky group reported the use of an organocatalytic intramolecular aldol reaction in the synthesis of a key intermediate, 108, for preparation of optically active estrone and commercially relevant 19-norsteroids [118, 119]. In the presence... 

---