Stereocontrolled Total Synthesis of Apicularen A and Its Δ17,18 Z Isomer

Abstract

Apicularen A (1, Scheme 1) is a polyketide natural product with a novel molecular architecture and impressive antiproliferative properties against a series of human cancer cells including a drug-resistant line. [1,2] Recently isolated from various strains of the myxobacterial genus Chondromyces (i.e., C. apiculatus, C. lanuginosus, C. pediculatus, and C. robustus), [1] apicularen A possesses a structure characterized by a salicylic acid residue, a macrolide ring bridged by an oxygen atom in such a way as to form a tetrahydropyran system, and a 10-membered ring lactone bearing a side chain with a doubly unsaturated acylenamine moiety. Interestingly, biosynthetic studies revealed the incorporation of eleven intact acetate units into the molecule of apicularen A that account for the entire natural carbon skeleton of the molecule except for C-17 (which stems from glycine), C-18, and C-25 (which is derived from methionine). [2] Here we report a total synthesis [3] of apicularen A (1) and its D 17,18 Z isomer (2) inspired by its polyacetate-based biosynthesis.Scheme 1 traces retrosynthetically the origins of apicularen A (1) (and its isomer 2) to key building blocks 3, 4 a±c, and 5, all of which are readily available. [4±6] In this analysis, we equated the introduction of an acetate unit to a two-step procedure involving allylation followed by ozonolysis. The five projected reiterations of the allylation±ozonolysis sequence are indicated on the structure of 1 and were to be performed in the designated order ( 1 to 5 ). These steps not only would ™mimic∫ nature×s polyacetate biosynthetic pathway to 1, but also would have the potential of yielding the correct stereochemistry at each chiral center of the target molecule through the judicious choice of appropriate reagents and conditions. Thus, while the first planned allylation [7] with allyltributyltin and a palladium catalyst should provide the required extension from the salicylic acid residue, the second and third allylations with Brown×s reagent (Ipc 2 Ballyl) [5] should install the C-9 and C-11 hydroxy groups in their absolute stereochemistry through the use of the appropriate enantiomer. The fourth allylation calls upon allyltrimethylsilane as a reagent to further extend the growing chain with concomitant formation of the C-13 stereocenter in a diastereocontrolled manner. The fifth allylation would require, once more, the use of Brown©s reagent (Ipc 2 Ballyl) for the construction of the final chiral center in its absolute stereochemical configuration. This strategy left the required ringforming reactions and the stereoselective installment of the acylenamine side chain to be negotiated in the synthetic direction.Scheme 2 details the construction of advanced intermediate 14 from which both 1 and 2 would be derived. Acetonide triflate 3 [4] was coupled with allyltributyltin [7] under the influence of catalytic [Pd(PPh 3 ) 4 ] to afford allyl compound 6 (99 % yield) whose rupture with ozone led, upon reduction with PPh 3 , to aldehyde 7 (92 % yield). The addition of...

Overcoming the Inherent Alkylation Selectivity of 2,3-trans-3,4-cis-Trisubstituted Cyclopentanones

“…Volatiles were removed under reduced pressure, and the crude material was purified by column chromatography (25 mL silica gel, 5:1 hexane-EtOAc) to yield ketone 24 (615 mg, 1.76 mmol, 95%) as a pale yellow oil; R f = 0.47 (4:1 hexane-EtOAc, UV/CAM). 1 (d,J = 7.5 Hz,3 H,CH 3 ). 13 C NMR (50 MHz, CDCl 3 ): δ = 218.…”

“…An enriched aliquot of ether 11 was used for analysis. 1 90, 145.90, 145.77, 130.91, 128.96, 113.60, 109.89, 100.13, 94.82, 80.84, 76.39, 72.59, 71.85, 71.12, 62.72, 61.71, 55.24, 45.95, 45.82, 44.98, 44.90, 42.37, 37.33, 34.68, 31.13, 30.79, 25.65, 25.53, 23.91, 23.82, 19.89, 19.27, 14.93, 14.83 (d,J = 6.9 Hz,3 H,CH 3 ). 13 C NMR (50 MHz, CDCl 3 ): δ = 159.…”

“…1 H NMR signals were assigned by 1 H-1 H COSY. IR (neat): 3083, 2968, 2918, 2849, 1739, 1612, 1514, 1455, 1248, 1172: δ = 7.21 (d,J = 8.6 Hz,2 H,Ar),6.87 (d,J = 8.6 Hz,2 H,Ar),4.89 (s,1 H,C=CH), 4.69 (s, 1 H, C=CH), 4.38 (s, 2 H, CH 2 Ar), 3.80 (s, 3 H, OCH 3 ), 3.42 (dd, J 1 = 9.2 Hz, J 2 = 5. 9 Hz, 1 H, CH 2 OPMB), 3.36 (dd, J 1 = 9.2 Hz, J 2 = 5.…”

“…IR (neat): 3078, 2961, 2917, 2851, 1644, 1513, 1250, 1091, 1040: δ = 7.24 (d, J = 8. 6 Hz, 2 H, Ar), 6.86 (d,J = 8.6 Hz,2 H,Ar),4.79 (s,1 H,C=CH),4.74 (s,1 H,C=CH),1 H,TMSOC=CH),4.42 (d,J = 11.7 Hz,1 H,CH 2 Ar),4.34 (d,J = 11.7 Hz,1 H,CH 2 Ar), 3.80 (s,3 H,OCH 3 ),3 H,CH 2 OPMB,CHC=C),2.36 (pent,J = 6.8 Hz,1 H,CHMe),2.21 (pent,J = 7.2 Hz,1 H,CHCOPMB),1.68 (s,3 H,C=CCH 3 ), 1.08 (d,J = 6.8 Hz,3 H,CH 3 ),0.22 (s,9 H,TMS). 13 C NMR (50 MHz, CDCl 3 ): δ = 159.…”

Easy and regioselective access to dimethyl acetal-protected heterocycles and their efficient allylation reactions mediated by allylaluminum reagent

“…An interesting application for heterocycles with aldehyde moieties would be in the synthesis of homoallyl alcohols, which are usually obtained by an addition reaction of an allylic metal nucleophile with carbonyl compounds such as aldehydes or ketones. [17][18][19][20][21] Homoallyl alcohols are important building blocks or versatile synthons for many biologically active molecules such as macrolides, polyhydroxylated natural compounds, polyether antibiotics, [22][23][24][25][26][27] and functionalized tetrahydropyrans. [28][29][30] Thus, the aim of this paper is to report the synthesis of new trifluoromethylated heterocycles containing a dimethyl acetal-protected aldehyde function as a substituent from the reactions of 4,6,6-trimethoxy-1,1,1-trifluoro-3-en-2-one (1) with hydrazines, hydrazides, hydroxylamine, 1-acetylguanidine and 1,8-diaminonaphthalene, which furnishes examples of new and stable trifluoromethyl-substituted pyrazolines, pyrazoles, isoxazoline, pyrimidine and perimidine.…”