Total Syntheses of Amphidinolide H and G

Abstract

General. NMR spectra were recorded with a Bruker DPX 300, AV 400, or DMX 600 spectrometer in the solvents indicated; chemical shifts (δ) are given in ppm relative to TMS, coupling constants (J) in Hertz. The solvent signals were used as references and the chemical shifts converted to the TMS scale (CDCl 3 : δ C = 77.0 ppm; residual CHCl 3 in CDCl 3 : δ H = 7.24 ppm; CD 2 Cl 2 : δ C = 53.8 ppm; residual CH 2 Cl 2 in CD 2 Cl 2 : δ H = 5.32 ppm). Where indicated, the signal assignments are unambiguous; the numbering scheme is arbitrary and is shown in the inserts. The assignments are based upon 1D and 2D spectra recorded using the following pulse sequences from the Bruker standard pulse program library: DEPT; COSY (cosygs and Negishi carboalumination: Preparation of vinyl iodide 25.A solution of AlMe 3 (2.0 M in heptane, 21.2 mL, 42.4 mmol) was added to a suspension of Cp 2 ZrCl 2 (4.64 g, 15.9 mmol) in 1,2-dichloroethane (70 mL). After stirring for 0.5 h, a solution of alkyne 24 (3.56 g, 10.57 mmol) in 1,2-dichloroethane (15 mL) was added dropwise. The resulting yellow solution was stirred for 24 h at ambient temperature before the mixture was cooled to −20°C and a solution of iodine (16.10 g, 63.5 mmol) in THF (60 mL) was slowly added. After stirring for 20 min at −20°C and 30 min at 0°C, the reaction was carefully quenched with water (10 mL). A sat. aq. Na 2 SO 3 solution was then added and the layers were separated. The aqueous phase was extracted twice with CH 2 Cl 2 (40 mL each), the combined organic extracts were washed with brine, dried over MgSO 4 and evaporated. .7, 135.7, 134.0, 129.7, 127.8, 75.4, 61.8, 39.9, 37.7, 27.0, 20.5, 19.6, 19.3 was added dropwise to a solution of epoxide 7 (7.6 g, 30.84 mmol) in toluene (25 mL) at −78°C over the course of 1 h. The temperature was then raised to −40°C and stirring continued for 4 h before the reaction was carefully quenched at −60°C with a solution of tBuOH in THF (1:1, 25 mL). The resulting mixture was poured into an icecold solution of Rochelle's salt (85g in 250 mL water) and vigorously stirred for 2 h until a clear separation of the phases was reached. The aqueous layer was extracted with tert-butyl methyl ether, the combined organic phases were dried over Na 2 SO 4 and evaporated, and the residue was purified by flash chromatography (hexanes:EtOAc, 1:1) to give product 8 as a

Amphidinolides and Its Related Macrolides from Marine Dinoflagellates

“…The absolute stereochemistry of amphidinolide H (8) was assigned by comparison of the 1 H-NMR data of the tris-(S)-MTPA ester of the C-22ϳC-26 segment derived from natural 8 with those of tris-(S)-and -(R)-MTPA esters of the C-22ϳC-26 segment synthesized from methyl (2S)-3-hydroxy-2-methyl-propionate [26]. Recently, Fürstner and co-workers synthesized amphidinolide H (8) using ring closing metathesis of 53 through sp 2 -sp 2 Stille coupling reaction between 54 and 55 derived from 56 and 57, respectively, via aldol reaction (Scheme 3) [31]. …”

Gram‐Scale Synthesis of Iejimalide B

“…In practical terms, the preparation of the chromium carbenoid derived from CHI 3 and the TEMPO oxidation of alcohol 51 were best performed in parallel; since the oxidation (15 min) as well as the olefination step (30 min) both proceed rapidly, significant amounts of material can be quickly brought through, even though the largest batch of 53 produced in this way was restricted to one gram of product. As expected, the reaction of this iodide with stannane 41, using again the three-component cocktail (Pd 0 , CuTC, Ph 2 PO 2 NBu 4 ) previously described by our group, [40,41] proceeded smoothly, as did the final saponification of the ethyl ester in 55 under standard conditions. Overall, the modifications outlined above secured an excellent supply of the acid perimeter 56 as required for the gram scale total synthesis of iejimalide B.…”

“…RT, then 33, À78 8C, 81 %; m) pinacolborane, 9-H-9-BBN (10 mol %), THF, 45 8C, 56 %; TEMPO = 2,2,6,6-tetramethyl-1-piperinyloxy; NCS = N-chlorosuccinimide. oped by our group for challenging cases, [40][41][42] secured gram amounts of the fully functional Southern sector 36 in well reproducible 87 % yield (1.3 g, single largest batch) (Scheme 6). This result clearly exceeds the outcome of the competing Suzuki reaction [43] between boronate 34 and iodide 22, which delivered the same product in only 66 % yield, even though the conditions had previously been carefully optimized.…”

“…[10] We tentatively ascribe the superior performance of the Stille coupling to the fact that the used cocktail of catalytic [PdA C H T U N G T R E N N U N G (PPh 3 ) 4 ], copper thiophenecarboxylate (CuTC), and Ph 2 PO 2 NBu 4 in DMF ensures particularly mild and essentially neutral conditions, and is therefore well suited for delicate bond-forming reactions as is the case with the heat-and base-sensitive polyene 36. [40,41] The fluoridefree and essentially neutral conditions ensure compatibility of this method with the primary -OTBS ether and preclude epimerization of the racemization-prone N-formyl serine residue.…”

Molecular Editing and Assessment of the Cytotoxic Properties of Iejimalide and Progeny

“…[13] Treatment with Et 4 NF in MeCN [22] furnished the corresponding amine, which was reacted with the desired amino acid derivative under standard peptide coupling conditions. The subsequent Stille reaction with stannane 18 under the neutral conditions developed in this laboratory, [23,24] esterification of the resulting products with the acid sector 20, [13] followed by ring-closing metathesis (RCM) [25] were carried out according to the protocols developed for the large scale synthesis of iejimalide B itself. [13] Although not fully optimized for all individual compounds, this sequence was invariably high yielding (see Table 1), furnishing the targeted analogues 8, [12] 9 [12] and 29 a-e in good overall yields; several hundred milligrams of products were prepared by this route.…”