Stereochemical Courses and Mechanisms of Ring-opening Cyclization of Donor–Acceptor Cyclopropylcarbinols and Cyclization of 7-Benzyloxy Dibenzyl Lignan Lactones

Abstract

Lewis acid-mediated ring-opening cyclization of trans-and cis-cyclopropanes 1a and 1b afforded the same trans-dihydronaphthalene 2a. Moreover, Lewis acid-mediated cyclization of 7R-and 7S-benzyloxy dibenzyl lignan lactones 5a and 5b furnished trans-tetralin 6a with high diastereomeric and enantiomeric excess. Based on these results, we rationalized the mechanisms of the cyclizations via trans-selective intramolecular FriedelCrafts alkylation/cyclization, via the S N 1 pathway.Keywords: Ring-opening cyclization | Cyclopropane | Friedel-Crafts reactionCyclization reactions of donoracceptor (DA) cyclopropanes are recognized as versatile protocols for the syntheses of carbocyclic and heterocyclic scaffolds.1,2 As part of a program of synthetic studies using cyclopropropane moieties, 3,4 we achieved the first asymmetric total synthesis of (+)-podophillic aldehydes using the highly stereoselective Lewis acid-mediated ring-opening cyclization of DA cyclopropylcarbinols to afford 1-aryl-1,2-dihydronaphthalene with retention of stereochemistry and high enantiomeric excess (Scheme 1). 4fRecentry, France and co-workers improved our method by using a catalytic amount of Ca(NTf 2 ) 2 instead of a stoichiometric amount of BF 3 ¢OEt 2 or Sc(OTf ) 3 .5 Although the modified method can provide a variety of cyclic compounds, this method deals with racemic substrates. Meanwhile, the mechanism of the reaction has not been revealed, and two plausible mechanisms can be proposed. One is the FriedelCrafts-type attack of the aromatic ring to the benzyl cation to furnish the trans-product based on the neighboring chiral center (trans-selective S N 1 pathway via cation A). The other is the pericyclic reaction-like 6 mechanism via transition state B with retention of stereochemistry of the cyclopropane. In France's report, a substrate bearing cyclic cis-2,3-disubstituents was employed to investigate the diastereoselectivity and it afforded the cis-substituted tetracyclic product (Scheme 2). This result seems to support the pericyclic reaction-like mechanism. However, a cyclic cation can prevent the construction of the tetracyclic trans-cyclopentene product due to the high strain (on the basis of our calculation using Spartan 09 using B3LYP/6-31G(d), the energy of cis-product is 6.6 kcal mol ¹1 lower than that of trans-product). Here, we report the diastereoselectivities of the ring-opening cyclization of trans-and cis-cyclopropanes 1a and 1b along with similar cyclizations of 7-benzyloxy dibenzyl lignan lactones 4a and 4b. Based on those results, we elucidate the reaction mechanism.Investigation of the diastereoselectivities of the ringopening cyclizations of 1a and 1b is key to reveal the reaction mechanism (Scheme 3). Following our previously reported transformation 4a of dichlorocyclopropane, the desired substrates 1a and 1b were obtained in good yields. However, cyclopropanations of (E)-and (Z)-1-phenyl-1-propenes using α,α-diazo-β-ketoester in the presence of the Rh 2 (esp) 2

Asymmetric Total Synthesis of a Bioactive Lignanamide Using a 5‐endo‐tet‐Type Cyclization of Activated Cyclopropylcarbinols and Synthetic Support for the Reaction Mechanism

“…Namely, the formal 5‐ endo ‐ tet ‐type cyclization of cyclopropylcarbinols 19 a and 19 b , which bear a benzoyl group, proceeds predominantly via a highly trans ‐selective S N 1‐like mechanism with no participation of the neighboring benzoyloxymethyl group [20] (Scheme 11). The steric hindrance of the neighboring substituent is the driving force that promotes the trans ‐selective Friedel–Crafts alkylation [4e,19] . This result is consistent with that of substrate 16 b , which bears a methyl group instead of a benzoyloxymethyl group [4e] .…”

Modular Access to Chiral 2,3-Dihydrofurans and 3,4-Dihydro-2H-pyrans by Stereospecific Activation of Formylcyclopropanes through Combination of Organocatalytic Reductive Coupling and Lewis-Acid-Catalyzed Annulative Ring-Opening Reactions

“…Compounds 7 and 8 are prevalent structural motifs found in many natural products and pharmaceuticals with diverse biological activities as shown in Figure (Figure S2, see Supporting Information-1 for more information). , As both electrophilic and nucleophilic groups are present in the chiral cyclopropanes 5 , it is inspiring to investigate the reactivity and selectivity pattern of these functional groups on the cyclopropane ring under acid/base catalysis as shown in Scheme . We thought that the coordination of BF 3 ·OEt 2 to the carbonyls of tethered diesters of cyclopropane 5 would render this unit more reactive by polarizing the cyclopropane C–C bond and thus facilitate the intramolecular nucleophilic ring opening by the cyclic-1,3-diketone group with inversion at the cyclopropane site . Surprisingly, the treatment of (−)- 5ha with 1 equiv of BF 3 ·OEt 2 in DCM at 25 °C for 2 h gave only one product the dihydropyran (−)- 7ha in 82% yield and >98% de with inversion of configuration at the cyclopropane ring-opening center, and similar results were obtained with 30 mol % of catalyst also (Table ).…”

“…Synthesis and study of the cyclopropane ring, which is widely present as a key structural motif in many natural and pharmaceutically active compounds, is a challenging task due to its stereoelectronic factors and intrinsic ring strain. − Over the past two decades, the domain of donor–acceptor cyclopropanes (D–A cyclopropanes) has experienced an exponential growth since the seminal work by Wenkert, Danishefsky, and Reissig . Chemist’s interest in D–A cyclopropanes has increased, as they are predisposed to provide ready access to multifunctionalized intermediates and key building blocks, for the synthesis of natural products and biologically active molecules through various ring-opening strategies. − The ring opening has been largely realized through activation by Lewis-acid , and transition-metal catalysis in both achiral and chiral versions. In addition, D–A cyclopropanes are transformed into various cyclic compounds by Brønsted-acid- and base- induced nucleophilic addition, ring expansion, and cycloaddition reactions.…”

Stereochemistry of Dichlorocarbene Addition to Alkenes: A Collaborative, Discovery-Based Experiment for the Organic Chemistry Laboratory

“…The first week of the experiment is devoted to synthesizing the cyclopropane adducts of dichlorocarbene with Z - and E -β-methylstyrenes using benzyltriethylammonium chloride (TEBAC) as a phase transfer catalyst , and performing calculations on the singlet and triplet states of the carbene. Analysis of the products by GC-MS and 1 H NMR is carried out the following week.…”