Natural product synthesis Amphidinolide

The utility of these reagents for natural product synthesis is very well documented as shown in few recent representative examples such as cochleamycin 39, amphidinolide 40, azithromycin 41, brevisamide 42 (Figure 25.5). ... 

The amphidinolides are a class of structurally diverse and physiologically potent natural products. The key step in the total synthesis of enantiomerically-pure amphidinolide T l 3 recently reported (J. Am. Chem. Soc. 2004,126,998) by Timothy Jamison of , the Ni-mediated cyclization of 1 to 2, clearly illustrates the power of organometallic C-C bond formation in organic synthesis. 

Corey s asymmetric allylation methodology was utilized in the total synthesis of amphidinolide T3 (95), a marine natural product that exhibits significant antitumor properties37 (Scheme 3.1gg). The asymmetric allylation of the aldehyde 96 was carried out successfully with chiral allylborane reagent generated in situ from allyltributylstannane and (R,R)-82 to furnish the homoallylic alcohol desired (97) in 85% yield with excellent diastereoselectivity. Subsequent conversion of the alcohol to the tosylate ester followed by treatment with potassium hydroxide resulted in formation of the trisubstituted tetrahydrofuran 98. 

The synthesis of the 36-membered macrolide dermostatin A (42), carried out by Rychnovsky, is remarkable for the complexity of this natural product and its acid- and light-sensitivity (Scheme 5.4.10). i Several approaches to the synthesis of amphidinolides also make use of alkenyl-alkenyl Stille coupling... 

The amphidinolide family of marine natural products has attracted a great deal of interest from the synthetic community due to their structural diversity as well as their potent biological activity. In the synthesis of amphidinoUde T1 (Scheme 8.43) and amphidinohde T4 (Scheme 8.44), late-stage nickel-catalyzed... 

In the enantioselective synthesis of the C-l-C-28 portion of cytotoxic marine natural product amphidinolide B1217, Lee [47] developed a strategy using the key steps of the Evans oxazohdinone alkylation, Sharpless epoxidation and orthoester Claisen rearrangement AUylic alcohol 218 as a mixture of diastereomers gave rise after treatment with triethyl orthoacetate under acidic catalysis to ester 219 in 66% yield (Scheme 6.34). This result exemplifies the potency of the orthoester rearrangement even with such probably sensitive epoxyallylic alcohol. 

The ( )-crotylboronate 2 was used by Lee and co-workers in their total synthesis of the cytotoxic 18-membered macrolide, amphidinolide Crotylation of the advanced aldehyde 74 provided stereotetrad 75 with 16 1 diastereoselectivity. This intermediate was elaborated to enoate 76, which underwent a diastereoselective radical cyclization to efficiently provide the c/ -tetrahydrofuran 77, which was converted to the natural product via several additional transformations. 

In the total synthesis of the related natural product amphidinolide H (8) [34], Fiirstner et al. also utilized the late stage alkene RCM strategy for the challenging... 

Similarly, Lee and coworkers reported the total synthesis of amphidinolide X (11) through the key alkene RCM using Grubbs second generation catalyst to provide the desired natural product (11) in 74% yield, accompanied by the Z isomer byproduct in 11% yield (Fig. 4) [35]. 

Amphidinolide V 38 is a 14-membered macrocycbc structure belonging to the same family of marine natural products that presents an epoxide functional group and seven C=C double bonds. To epoxidize one double bond selectively and leave unaffected the others, a Sharpless asymmetric epoxidation of an allyl alcohol 39 residue was introduced in the synthesis of the intermediate molecule 40 (Scheme 34.11). In detail, the reaction was performed with Ti(IV) and (+)-l-DET as chiral ligand under classic experimental conditions leading to the formation of the epoxide 41 in 77% yield (ee not reported). 

Other examples of the use of this technique include 2,6-dimethylheptyl sulfate, 89.1 (see Figure 89), which was isolated from marine ascidians and its configuration at C-2 was inferred as R, from the application of the same method to its desulfated derivative 89.2. Kobayashi et al. also used this technique on a variety of marine metabolites such as the ecdysteroids palythoalones A (89.3) and B (89.4) and the amphidinolides T (89.5) and E (89.6) In these latter cases, the absolute configuration was deduced after degradation of the natural product (89.7, 89.8, 89.9, and 89.10), subsequent derivatization with MTPA, and the use of compounds with known absolute configuration, obtained by synthesis, as models for comparison of the NMR spectra. 

Allyl epoxides are produced by the acclaimed Sharpless asymmetric epoxidation reaction [75], and are important intermediates and products. For example, an allyl epoxide is a vital part of the structure of amphidinolides, a series of unique macrolides isolated from dinoflagellates (Amphidinium sp.). Amphidinolide H (AmpH) is a potent cytotoxic 26-membered macrolide with potent cytotoxicity for several carcinoma cell lines [76]. An allyl epoxide is involved in the total synthesis of prostaglandin A2 with a cuprate reagent [77]. Allyl epoxides derived from Sharpless chemistry are a practical method for construction of polypropionate structures by Lewis acid-induced rearrangement [78,79]. Other allyl epoxides such as l,2-epoxy-3-methyl-3-butanol are useful organic intermediates for the production of a-hydroxyketones, which are used for the synthesis of various natural... 

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