Zhoulong
Fan
,
Xinpei
Cai
,
Tao
Sheng
and
Jin-Quan
Yu
*
Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA. E-mail: yu200@scripps.edu
First published on 29th April 2025
Bicyclo[3.2.0]heptane lactones represent an important scaffold in bioactive molecules. Herein, we report a diastereoselective synthetic disconnection to access bicyclo[3.2.0]heptane lactones from bicyclo[1.1.1]pentane carboxylic acids, which proceeds through palladium-catalyzed C–H activation and C–C cleavage processes. By using two different classes of ligands, MPAA and pyridone-amine, either all-syn arylated bicyclo[3.2.0]heptane lactones or non-arylated ones can be synthesized. The bicyclo[3.2.0]heptane lactone products were converted into multiple substituted cyclobutane, γ-lactone, and oxobicyclo[3.2.0]heptane derivatives to showcase the synthetic versatility of this method.
Bicyclo[3.2.0]heptane lactones are not only bioactive but also versatile precursors for diverse bicyclo[3.2.0]heptane scaffolds, such as azabicyclo[3.2.0]heptanes and oxobicyclo[3.2.0]heptanes. The previous method involves three steps starting from pre-assembled cyclobutane derivatives, including C–H arylation, Boc protection, and TBS deprotection (Fig. 1C).20 Inspired by our recent work on palladium-catalyzed C–C cleavage of bicyclo[1.1.1]pentanol to form functionalized cyclobutenes diastereoselectively,21 we began to develop a palladium-catalyzed C–H arylation and sequential C–C cleavage/lactonization of bicyclo[1.1.1]pentane carboxylic acids for the construction of arylated bicyclo[3.2.0]heptane lactones in a diastereoselective manner (Fig. 1D). This process is realized using a mono-N-protected amino acid (MPAA) ligand. Interestingly, in the absence of aryl iodides, the different products, bicyclo[3.2.0]heptane lactones, were also obtained by switching the bidentate ligands from Ac-L-Val-OH to pyridone-amine L14. Ring opening of such motifs to generate trisubstituted cyclobutanes and γ-lactones, as well as reduction to form arylated oxobicyclo[3.2.0]heptane demonstrates the synthetic utility of these scaffolds.
Entry | Deviation from standard conditions | 3a, yield (%) |
---|---|---|
a Reaction conditions: 1a (0.1 mmol), 2a (0.3 mmol), Pd(OAc)2 (10 mol%), Ac-L-Val-OH (20 mol%), AgTFA (4 equiv.), Na2HPO4 (1 equiv.), HFIP (2 mL), 110 °C, 20 h. b The yield of 3a was determined by 1H NMR analysis using 1,3,5-trimethoxybenzene as an internal standard. | ||
1 | None | 66 |
2 | w/o Ac-L-Val-OH | 18 |
3 | Ac-Gly-OH instead of Ac-L-Val-OH | 31 |
4 | Ac-L-Phe-OH instead of Ac-L-Val-OH | 39 |
5 | Boc-L-Val-OH instead of Ac-L-Val-OH | 30 |
6 | L1 instead of Ac-L-Val-OH | 31 |
7 | L2 instead of Ac-L-Val-OH | 38 |
8 | L3 instead of Ac-L-Val-OH | 54 |
9 | L4 instead of Ac-L-Val-OH | 46 |
10 | L5 instead of Ac-L-Val-OH | 21 |
11 | L6 instead of Ac-L-Val-OH | 33 |
12 | w/o Pd(OAc)2 | n.d. |
13 | Pd(TFA)2 instead of Pd(OAc)2 | 33 |
14 | w/o AgTFA | n.d. |
15 | AgOAc instead of AgTFA | 10 |
16 | Ag2CO3 instead of AgTFA | 9 |
17 | w/o Na2HPO4 | 25 |
18 | Na2CO3 instead of Na2HPO4 | 27 |
19 | NaOAc instead of Na2HPO4 | 45 |
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With the optimal reaction conditions in hand, we explored the reaction scope concerning aryl and heteroaryl iodides, and bicyclo[1.1.1]pentanes (Scheme 1). When treating 1a with a variety of phenyl iodides featuring both electron-rich and electron-poor functional groups, the corresponding syn-arylated bicyclo[3.2.0]heptane lactone products 3a–3n were obtained in moderate to good yields. To determine whether the chiral ligand produces an enantiopure product, we carried out the reaction using 4-iodobiphenyl (2d) as the coupling partner with either nonchiral Ac-β-Ala-OH or chiral Ac-L-Val-OH as the ligand. Chiral HPLC analysis of the arylated product 3d revealed a 50:
50 ratio of the two enantiomers, indicating that the chiral ligand does not induce enantioselectivity (see the ESI†). For 6-iododihydrobenzodioxine and 2-iodonaphthalene, increasing the concentration of HFIP from 0.05 M to 0.3 M led to the desired products 3o and 3p in moderate yields. Typically, heterocycle motifs pose challenges in C–H activation reactions due to the undesired coordination of heteroatoms with palladium, deactivating the catalyst. However, under the current reaction conditions, heteroaryl iodides could serve as coupling partners. Various substituted pyridines, thiophenes, and furans were introduced at the β position of bicyclo[3.2.0]heptane lactones in a syn fashion. Additionally, three substituted bicyclo[1.1.1]pentane carboxylic acids were subjected to the standard conditions, yielding highly functionalized bicyclo[3.2.0]heptane lactone derivatives 3x to 3z.
Having established the synthetic methods for accessing arylated bicyclo[3.2.0]heptane lactones, we then sought to investigate the possibility of generating bicyclo[3.2.0]heptane lactone scaffolds without the arylation step (Scheme 2). Initially, we conducted the reaction using Ac-L-Val-OH as a ligand under the standard conditions without aryl iodide. However, the starting material 1a was recovered, and no product 4a was observed, indicating that the MPAA ligand might be applicable for the cleavage of C–C bonds at benzylic positions. Considering the effectiveness of our recently developed bidentate pyridone ligands in palladium catalysis,29,30 we tested X,L-type quinoline–pyridone ligand L9 and X,X-type pyridone–pyridone ligand L10. Although these ligands provided product 4a, the yield was low. Encouraged by these results, we examined several imine–pyridone and amine–pyridone ligands (L11–L15).31 Significantly, when L14 was employed as the ligand, the product 4a was obtained in 68% yield. These conditions were identified as the optimal ones and used to explore the substrate scope. Various 1-substituted bicyclo[1.1.1]pentane-2-carboxylic acids were subjected to the conditions, leading to the corresponding bicyclo[3.2.0]heptane lactone derivatives in yields ranging from 39% to 65%. These previously inaccessible substitution patterns on bicylco[3.2.0]heptane lactones could prove beneficial in exploring the available chemical space in pharmaceutical campaign.
To elucidate the possible mechanism, we carried out the reaction in the presence of acetic acid-d4 and HFIP-d1 without the aryl iodide. The partially deuterated carboxylic acid [D]-1a was recovered in 53% yield, with 20% and 25% deuterium incorporation on the α-position and β-position, respectively (Scheme 3A). In addition, to rule out the possibility of non-directed C–H bond cleavage, we performed the reaction under standard conditions using 4-methylbenzyl bicyclo[1.1.1]pentane-2-carboxylate (1f) as the substrate. However, no deuteration was observed at the α- or β-positions, further verifying that the carboxylic acid directed C–H bond cleavage step occurred in the process (see the ESI†). A plausible mechanism is depicted in Scheme 3B. The β-C–H palladation intermediate II is first formed, followed by an oxidative addition and reductive elimination sequence to deliver the β-arylation intermediate IV. Subsequently, a strain-release C–C bond cleavage event takes place, generating the palladium species V. Then, this species undergoes lactonization and protodepalladation to afford product 3. In addition, we also proposed the mechanism in the absence of aryl iodides. The C–C cleavage occurs directly with the assistance of the pyridone–amine ligand, providing the intermediate III′. Then, the sequential lactonization and protodepalladation processes produce the non-arylated lactone 4.
To further illustrate the application of the current methods, we conducted extensive transformations of bicyclo[3.2.0]heptane lactone 3a. The ring-opening process of γ-lactone yielded the tri-substituted cyclobutane derivative 5 under sequential hydrolysis and substitution conditions. Notably, the cyclobutane ring of 3a was unexpectedly cleaved to produce γ-lactone 6 in the presence of BBr3, and the detailed mechanism remains unclear. In addition, the oxobicyclo[3.2.0]heptane scaffold 7 could be easily obtained through the sequential reduction of the ester and recyclization (Scheme 4A).20 To explore the potential utility of this bicyclic γ-lactone in chemical biology, we removed the Bn protecting group of 3f and coupled it with propargylamine, resulting in the generation of product 8 with an alkynyl group for protein labeling (Scheme 4B).
Footnote |
† Electronic supplementary information (ESI) available. CCDC 2204195 and 2252736. For ESI and crystallographic data in CIF or other electronic format see DOI: https://doi.org/10.1039/d5sc00711a |
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