Intramolecular [2+2] Photocycloaddition Reactions as an Entry to the 2‐Oxatricyclo[4.2.1.0^4, 9]nonan‐3‐one Skeleton of Lactiflorin

Abstract

Two [2+2] photocycloaddition routes were evaluated as possible ways to access the tricyclic core structure found in the terpene monoglycoside lactiflorin. While the first route via γ-substituted cyclopentenones was quickly discarded, the reactions of racemic (5R*)-3-benzyloxy-5-but-3'-enyl-4-methoxycarbonylfuran-2(5H)-ones proceeded in high yields and with perfect diastereoselectivity. However, it turned out that the regioselectivity was strongly dependent on the substitution pattern within the but-3'-enyl chain, which connects the terminal olefinic double bond to the photoexcited butenolide chromophor. If the chain was unsubstituted or if a tert-butyldimethylsilyloxy group was placed at the 2' position in a syn-relationship to the existing stereogenic center (5R*,2'S*), the crossed product prevailed with regioselectivities of 89:11 to 69:31. If the tert-butyldimethylsilyloxy group was positioned at 2' in an anti-relationship to the existing stereogenic center (5R*,2'R*), the desired straight products were obtained in regioselectivities of 74:24 to 55:45 (61-83% yield). Following this route, the aglycon part of lactiflorin was obtained by an intramolecular [2+2] photocycloaddition and a subsequent hydrogenolysis in 53% yield. Its further conversion into the natural product after glycosylation included a methyl addition to the lactone carbonyl group, which was optimized to give the desired key intermediate in a yield of 70%. The further conversion to lactiflorin was achieved in four steps and with an overall yield of 49%.

Recent Advances in the Synthesis of Cyclobutanes by Olefin [2 + 2] Photocycloaddition Reactions

“…Alcohol 365 was obtained as a single product and served as the aglycon in the synthesis of the terpene glycoside (+)-lactiflorin. 657 , 658 …”

Chemoenzymatic Synthesis towards the Active Agent Travoprost

“…Tremendous effort has been invested in the enantiomerically pure synthesis of 4‐hydroxy‐2‐cyclopentenones and their O ‐silyl‐derivatives, such as building block A , owing to it being a valuable synthetic intermediate for the synthesis of prostaglandins . These building blocks also function as cornerstones in the synthesis of numerous other natural compounds, including alkaloids, terpenes, and many more …”

“…Tremendous effort has been invested in the enantiomerically pure synthesis of 4-hydroxy-2-cyclopentenones and their Osilyl-derivatives, such as buildingb lock A,o wing to it being av aluable synthetic intermediate for the synthesis of prostaglandins. [6, 14b, 19-21] These building blocks also functiona sc ornerstones in the synthesis of numerouso ther natural compounds, includinga lkaloids, [22][23][24][25] terpenes, [26,27] and many more. [28][29][30][31] Althought here are several approaches for the preparation of A,m ost of them are based on the meso-diol 4 or the diacylated molecule 5.I na ni nitial investigation, we started our endeavor towards (R)-4-hydroxyketone 6 by using these commercially available materials that can also be readily prepared by established methodsf rom cyclopentadiene.…”

“…In addition, access to (R)-4-hydroxy-2-cyclopentenone (6)c ould notably be provided in terms of high enantioselectivity and yield by an oxidative desymmetrization step utilizingt he alcohol dehydrogenase RasADH. This enantiopure building block is not only valuable in the synthesis of prostaglandins and derivatives, it is ah ighly functionalized synthon for av ast variety of natural compounds, [26][27][28][29][30][31][32][33][34][35] implementing at remendous interest for organic chemistry.…”

Photo-Induced Cycloaddition Reactions of α-Diketones and Transformations of the Photocycloadducts

“…Photo-induced cycloaddition reactions combined with subsequent transformations of the photocycloadducts have played important roles in building diverse organic frameworks [1,2,3,4]. The application of photocycloaddition as the key step in the synthesis of natural products [5,6,7,8,9] and other novel frameworks is of current research interest [10,11,12,13,14,15]. The photo-induced [2 + 2] cycloaddition of carbonyl groups with C=C or C≡C groups, also known as the Paterno-Büchi reaction, is the most common photocycloaddition reactions of carbonyl compounds [16].…”