Novel Stereocontrolled Approach to syn‐ and anti‐Oxepene–Cyclogeranyl trans‐Fused Polycyclic Systems: Asymmetric Total Synthesis of (−)‐Aplysistatin, (+)‐Palisadin A, (+)‐Palisadin B, (+)‐12‐Hydroxy‐Palisadin B, and the AB Ring System of Adociasulfate‐2 and Toxicol A

Abstract

A new stereocontrolled method for the formation of trans-anti cyclogeranyl-oxepene systems is described. The demanding stereochemistry is secured by stereoselective coupling of a cyclogeranyl tertiary alcohol with a 1,2-unsymmetrically substituted epoxide, while the formation of the highly strained oxepene is achieved employing ring-closing metathesis. Since the stereochemistry of the trans-fused 6,7-ring system is determined by the epoxide, the method also allows the construction of trans-syn 6,7-ring systems. This approach leads to the synthesis of the AB fragment of Adociasulfate-2 and Toxicol A, for the first time. The flexibility and efficiency of the presented strategy is demonstrated by the total asymmetric synthesis of (-)-Aplysistatin, (+)-Palisadin A, (+)-12-hydroxy-Palisadin B, and (+)-Palisadin B, employing two similar key intermediates.

Total Synthesis of (+)-Greek Tobacco Lactone

“…12,13 The X-ray crystal structure of diol 7, 14 shown as an inset in Scheme 4, confirmed the relative stereochemistry of this intermediate and, given the stereochemical reliability of the Sharpless dihydroxylation, the absolute configuration of 7. 15 Cyclization of diol 7 was readily achieved under the conditions described above (NaH, THF) to give the 6-exo-tet cyclization product 9 exclusively.…”

Control of the Regio‐ and Diastereoselectivity for the Preparation of Highly Functionalized Terpenic Cyclopentanes through Radical Cyclization

“…Compound 16 was obtained with low diastereoselectivity as a mixture of four diastereomers (2ЈS,3ЈS), (2ЈR,3ЈS), (2ЈS,3ЈR), and (2ЈR,3ЈR), which could be separated by column chromatography and HPLC in a ratio of 28:29:14:29 (Scheme 6; Table 1 In the light of the excellent yields obtained for the closure of the cyclopentane ring of these C15 precursors, and because of the absence of stereoselectivity, we focused our efforts on studying the outcome of the radical 5-exo-trig cyclization by using C10 epoxy-polyprenes derived from commercial geraniol (17)(18)(19)(20)(21) (Table 2).…”

An Enantiospecific Polyene Cyclization Initiated by an Enantiomerically Pure Bromonium Ion

“…An enantiomerically pure bromonium ion was generated in the formation of a vicinal bromochloride in the total synthesis of (+)‐intricatetraol . Lewis acid‐mediated carbocyclizations of (racemic) 1,2‐bromohydrins (3˚ alcohol and/or esterified derivatives, 2˚ bromide) have been demonstrated previously, and a cyclization of an enantiopure 1,2‐bromohydrin (3˚ alcohol, 2˚ bromide) to an enantiopure 1‐bromo‐2,2,4‐trimethylcyclohexane has been reported, but bromonium ions were not invoked. Herein, as an extension of our previous work, we report the formation of an enantiopure bromonium ion at the terminus of a polyene by suitable activation of an enantiopure bromohydrin, thereby initiating polyene cyclization to produce tricyclic carbocycles with the characteristic α‐bromo‐β,β‐dimethylcyclohexane motif of (poly)cyclic naturally occurring terpenoids.…”

“…Following the method of Couladouros and Vidali, to a solution of ( S )‐epoxide 4 (200 mg, 0.73 mmol) in N ‐methyl‐2‐pyrrolidone (0.22 mL) was added LiBr (99 mg, 0.95 mmol) and PPTS (183 mg, 0.73 mmol) and stirred at room temperature for 4 h. The reaction was quenched with saturated aqueous NaHCO 3 solution (15 mL), extracted with EtOAc (2 × 15 mL), washed with brine (30 mL), dried over Na 2 SO 4 , concentrated under reduced pressure, and chromatographed (1:9‐1:4 EtOAc:PE) to yield first ( E )‐9‐(4‐methoxyphenyl)‐2,6‐dimethylnon‐6‐en‐3‐one (10 mg, 5%) as a colorless oil, second bromohydrin 5a (66 mg, 25%) as a colorless oil, and third, bromohydrin 5b (119 mg, 46%) as a colorless oil. Bromohydrin 5a : R f = 0.32 (1:9 EtOAc:PE); [α] D 24 ‐10.6 ( c 1.3, CH 2 Cl 2 ); IR ν max 3600‐3200, 2958, 2926, 2855, 2835, 1612 cm ‐1 ; 1 H NMR (400 MHz, CDCl 3 ) δ 7.14 (d, J = 8.6 Hz, 2H), 6.86 (d, J = 8.6 Hz, 2H), 5.27 (tq, J = 6.8, 1.4 Hz, 1H), 3.82 (s, 3H), 3.40 (dd, J = 10.1, 3.0 Hz, 1H), 2.63 (t, J = 7.5 Hz 2H), 2.37‐2.25 (m, 3H), 2.17‐2.05 (m, 2H), 1.82 (s, 3H), 1.81‐1.72 (m, 1H), 1.75 (s, 3H), 1.59 (s, 3H), 1.49 (dddd, J = 14.0, 10.3, 8.8, 5.2 Hz, 1H) ppm; 13 C NMR (100 MHz, CDCl 3 ) δ 157.7, 135.1, 134.4, 129.4, 124.6, 113.7, 79.0, 75.4, 55.3, 36.4, 35.1, 31.1, 30.1 (×2), 28.9, 16.0 ppm; MS (CI + , NH 3 ) m/z 374, 372 [M + NH 4 ] + ; HRMS (CI + , NH 3 ) calcd.…”