Synthetic Approaches to α,β‐Unsaturated δ‐Lactones and Lactols

Abstract

The synthesis of six‐membered unsaturated δ‐lactones has generated considerable interest, due to their occurrence in a large number of natural products possessing potent biological activities. This microreview attempts to illustrate the different strategies used to obtain such compounds, with a special emphasis on catalytic and asymmetric approaches. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2007)

Total Synthesis of (+)-Cryptocaryol A Using a Prins Cyclization/Reductive Cleavage Sequence

“…2) Li 2 Having aldehyde 1 and the optically active homoallylic alcohol 2 in hand, a first Prins cyclization 19 was performed between these two compounds using TFA (26 equiv, CH 2 Cl 2 , rt, 3 h) 20 to produce, via the formation of intermediates F and G and after neutralization, a diastereomeric mixture of tetrahydropyranyl alcohols 5 and 5' (5/5' = 25:75) in favor of the undesired 2,4,6-cis,cis-isomer 5' 20 (Scheme 3). To convert 5' into 5, the mixture of 5 and 5' was oxidized (DMP, CH 2 Cl 2 , rt, 2.5 h) to the corresponding tetrahydropyranone 6 (70% overall yield from 1 and 2) and then diastereoselectively reduced.…”

“…1 Due to their important biological activities, these latter compounds have attracted considerable synthetic interest. 2 Our group has previously reported the synthesis of some members of this family, including passifloricin, 3 (-)-pironetin, 4 strictifolione, 5 and fostriecin, 6 and more recently, we became interested in the synthesis of (+)-cryptocaryol A. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 7 These compounds have been reported to act as Pdcd4 (programmed cell death 4) stabilizers with EC 50 values between 1.3 and 4.9 µM, Pdcd4 being a tumorgenesis and invasion suppressor protein, 8,9,10,11 whose expression is down-regulated in several cancers.…”

Anticancer Agents from the Australian Tropical Rainforest: Spiroacetals EBC‐23, 24, 25, 72, 73, 75 and 76

“…[12] In consideration of the above postulated biosynthetic origin retrosynthetic analysis was best initiated by ring opening of the spiroacetal moiety arriving at a straight chain polyketide 13. Keto functionality seen in 13 serves as a point of fusion, as shown in 14, via an acyl equivalent (15). A Tietze [13] -Smith [14] linchpin convergence strategy with epoxides 16 and 17 would satisfy this criteria, although subsequent ring-closing metathesis would be required to install the lactone.…”

“…A Tietze [13] -Smith [14] linchpin convergence strategy with epoxides 16 and 17 would satisfy this criteria, although subsequent ring-closing metathesis would be required to install the lactone. [15] A slight deviation of this approach could directly utilize the fully constructed, and suitably substituted, lactone (18) as the right-hand fragment. The synthetic approach to the left-hand fragment 16 must contain sufficient stereochemical flexibility in the event that the relative stereochemical assignment of 1 is incorrect, or structure-activity studies (SAR) are required.…”

N‐Heterocyclic Carbene‐Catalyzed Cyclization of Unsaturated Acyl Chlorides and Ketones

“…[15] However, the enantioselective synthesis of optically active 5,6-dihydropyran-2-ones is still limited. [16] In view of the wide application of fluorinated compounds in pharmaceuticals, agrochemistry, and materials, [17] trifluoromethyl ketones [18,19] were firstly explored as the substrates for the synthesis of 6-trifluoroA C H T U N G T R E N N U N G methyl-5,6-dihydropyran-2-ones.…”