Letter pubs.acs.org/OrgLett
Rh-Catalyzed Conjugate Addition of Aryl and Alkenyl Boronic Acids to α‑Methylene-β-lactones: Stereoselective Synthesis of trans-3,4Disubstituted β‑Lactones Christian A. Malapit,† Irungu K. Luvaga, Donald R. Caldwell, Nicholas K. Schipper, and Amy R. Howell* Department of Chemistry, University of Connecticut, Storrs, Connecticut 06269-3060 United States S Supporting Information *
ABSTRACT: A one-step preparation of 3,4-disubstituted βlactones through Rh-catalyzed conjugate addition of aryl or alkenyl boronic acids to α-methylene-β-lactones is described. The operationally simple, stereoselective transformation provides a broad range of β-lactones from individual αmethylene-β-lactone templates. This methodology allowed for a direct, final-step C-3 diversification of nocardiolactone, an antimicrobial natural product. reduction to access the generally more biologically active trans βlactones suffers from modest diasteroselectivities and yields. We hypothesized that β-lactones 2 could be directly accessed from 1 via conjugate addition, in particular, with organoboron reagents under Rh catalysis (Figure 1b). Rh-catalyzed conjugate additions of organoboron reagents to a wide range of activated alkenes have emerged as one of the most powerful approaches to this type of reaction.9 There are significant advantages in comparison to other traditional methods, such as organocuprate chemistry. Only catalytic amounts of the metal are used; indeed, catalytic loadings as low as 0.5 mol % have been reported. The reactions can be carried out in water or water/organic solvent mixtures. In addition, more and more aryl and alkenyl boronic acids and esters are commercially available, or they can be readily synthesized. Significantly for us, substrates containing γ- and δlactones and -lactams have been utilized and tolerated.10 We recognized, however, two critical challenges. First, β-lactones may not be compatible with the most commonly reported basic/ aqueous conditions due to facile ring-opening of the starting material or products.7 Second, the propensity toward β-hydride elimination11 of the anticipated intermediate A, giving Heck-type product 3 (Figure 1b), could result. Here, we report an efficient, stereoselective, one-step synthesis of 3,4-disubstituted β-lactones via Rh-catalyzed conjugate addition of organoboron reagents to α-methylene-β-lactones. Initial studies examined the reaction of α-methylene-β-lactone 1a with phenylboronic acid in 3:1 toluene/H2O at 80 °C (Table 1, entry 1) using Wilkinson’s catalyst and K2CO3 as base. Although complete conversion was observed after 24 h, a 1:1 mixture of conjugate addition 4 and Heck-type product 5 resulted. In addition, there was extensive material decomposition. Lowering the temperature to 60 °C resulted in a very low conversion (entry 2). However, switching the catalyst to
β-Lactones are an important class of heterocycles found in many synthetic and natural products of biological interest.1 They have been explored for antiobesity,2 anticancer,3 and antibacterial4 applications and have been utilized as probes in activity-based protein profiling (ABPP).1b,5,6 β-Lactones are also versatile intermediates in organic synthesis with a broad range of reactivities.7 We recently showed that α-methylene-β-lactones 1 could be used for the synthesis of structurally diverse 3,4disubstituted β-lactones 2 via cross-metathesis (CM)8 to 3 and subsequent reduction (Figure 1a).6 While this methodology is attractive for assembling focused libraries of 3,4-disubstituted βlactones, there are limitations. First, the CM reaction typically requires high catalyst loading (5−10 mol %). Second, the 1,4-
Figure 1. Syntheses of 3,4-disubstituted β-lactones 2 from α-methyleneβ-lactones 1. © 2017 American Chemical Society
Received: June 30, 2017 Published: August 15, 2017 4460
DOI: 10.1021/acs.orglett.7b01994 Org. Lett. 2017, 19, 4460−4463
Letter
Organic Letters
A variety of aryl boronic acids were examined next. As summarized in Scheme 1, both electron-rich and electron-poor aryl boronic acids reacted efficiently with α-methylene-βlactones. More importantly, diverse functional groups were tolerated, including aryl chlorides (13), benzyl/phenyl ethers (14−16), phenol (18), and styrene (19). Heterocycliccontaining aryl boronic acids (20, 21) also underwent conjugate addition in good yields. Moreover, alkenyl boronic acids were suitable coupling partners, providing C-3 allylated β-lactones (22, 23) in good yields. Notably, the alkene geometry of the boronic acid is preserved in the lactone product. Under similar conditions, α-methylene-γ-lactone also underwent conjugate addition to yield α-substituted γ-lactones (24, 25) in excellent yields. Nocardiolactone (Scheme 1), a trans-3,4-disubstituted βlactone, is a natural product isolated from pathogenic Nocardia strains and has been found to exhibit antimicrobial activities.6b,16,17 Using the developed Rh-catalyzed conjugate addition of boronic acids to a single substrate, a direct, final-stage diversification at C-3 of nocardiolactone was achieved. Nocardiolactone analogues (26−28) were obtained in excellent yields. Having achieved control of conjugate addition vs Heck reaction, future efforts will focus on control of relative and absolute stereochemistry. Catalysts, ligands, and bases have all been used to influence both diastereo- and enantiostereoselectivity in Rh-catalyzed conjugated additions.9,10 In our studies, a 2:1 trans/cis ratio of 4 was seen under all conditions explored using the catalysts noted for the reaction of 1a and phenylboronic acid. (See entries 1, 4, 5, 9, and 10 in Table 1. In addition, the same ratio was seen with other bases/reaction conditions not included here.) We also determined that this outcome was not dependent on equilibration subsequent to product formation. A 1:1 mixture of trans/cis-4 was subjected to the optimized reaction conditions and was recovered unchanged. A broader range of Rh catalysts and associated ligands will be explored to enhance control of relative stereochemistry. The preparation of enantioenriched α-methylene-β-lactones has been previously reported, and these methods can be used to access enantioenriched 3,4-disubstituted β-lactones.18 We view α-methylene-β-lactones as masked Morita−Baylis− Hillman (MBH) adducts.8,19 Not only are these lactones readily prepared from and returned to MBH products, but α-methyleneβ-lactones also undergo reactions that MBH products do not. For example, whether the allylic OH is protected or not, MBH adducts do not readily undergo CM reactions, while αmethylene-β-lactones (and -lactams) have been shown to be superior CM partners.8 Navarre et al.20 reported that, when MBH adducts were treated with aryl boronic acids under conditions similar to ours, in sharp contrast to our results, trisubstituted alkenes were obtained (see Scheme 2), an outcome that persisted with different rhodium catalysts, solvents, and types of organoboron reagents. When the acetate of a MBH adduct was used, lower reactivity was observed, but the result was the same. We confirmed that, under conditions that gave conjugate addition for α-methylene-β-lactones, MBH adduct 29 reacted with phenylboronic acid to give exclusively trisubstituted (E)-alkene 30 in 90% yield (Scheme 2). Thus, while conjugate addition products from MBH adducts appear to be inaccessible under Rh catalysis, such products would result from transesterification of the β-lactone products obtained from Rhcatalyzed conjugate addition of boronic acids to α-methylene-βlactones.
Table 1. Optimization of Rh-Catalyzed Conjugate Addition (CA) of Phenylboronic Acid to 1aa
entry
Rh catalyst
base (equiv)
conv (%),b time (h)
1d 2 3 4 5 6 7 8 9 10
RhCl(PPh3)3 RhCl(PPh3)3 [Rh(cod)Cl]2 [Rh(cod)Cl]2 [Rh(cod)Cl]2 [Rh(cod)Cl]2 [Rh(cod)Cl]2 [Rh(cod)Cl]2 RhCl(PPh3)3 [Rh(nbd)Cl]2
K2CO3 (2) K2CO3 (2) K2CO3 (2) KOH (2) KOH (1) KOH (0.5) KOH (0.1) none KOH (1) KOH (1)
100, 24
