Asymmetric Total Synthesis of (−)-(3R)-Inthomycin C

Abstract

A short (10 step) and efficient (15% overall yield) synthesis of the natural product (-)-(3 R)-inthomycin C is reported. The key steps comprise three C-C bond-forming reactions: (i) a vinylogous Mukaiyama aldol, (ii) an olefin cross-metathesis reaction, and (iii) an asymmetric Mukaiyama-Kiyooka aldol. This route is notable for its brevity and has the advantage of lacking stoichiometric tin-promoted cross-coupling reactions present in previous approaches. Initial investigations on the biological activity of (-)-(3 R)-inthomycin C and structural analogues on human cancer cell lines are also described for the first time.

Progress in the total synthesis of inthomycins

“…Utilizing the same sequence as applied to the synthesis of inthomycin As ((+)-1) and B ((+)-2) from (+)-146a and (+)-146b, respectively (see Scheme 25), the triene (+)-146c was successfully converted into an 8:1 mixture of inthomycin C ((−)-3) and another minor isomer in good overall yield after the final step (Scheme 26). The spectroscopic data and specific rotation values of the three inthomycins A-C ((+)-1, (+)-2, and (−)-3) were consistent with those reported previously [8,23,57]. The absolute configurations of inthomycins A-C ((+)-1, (+)-2, and (−)-3) were reconfirmed as 3R by assigning the (R)-stereochemical descriptor for the common intermediate (−)-140, which supports the recent work of Hale and Hatakeyama [57].…”

“…Inthomycins were reported to possess many interesting biological properties, which include the specific inhibition of the cellular biosynthesis [1,4], in vitro antimicrobial activity [4,5], and anticancer activity against human prostate cancer cell lines [6,7]. A recent study suggested that the close analogue (+)-11 of inthomycin C was found to exhibit proteasome inhibition activity [8]. The skeletal structures of inthomycins A-C (1-3) are embodied in several other naturally occurring compounds, such as neooxazolomycin (4), oxazolomycins A-C (5, 6) [9][10][11][12][13][14], curromycins (7) [15], and KSM-2690 (8) [16] (Figure 1).…”

“…A recent study suggested that the close analogue (+)-11 of inthomycin C was found to exhibit proteasome inhibition activity [8]. The skeletal structures of inthomycins A-C (1-3) are embodied in several other naturally occurring compounds, such as neooxazolomycin (4), oxazolomycins A-C (5, 6) [9][10][11][12][13][14], curromycins (7) [15], and KSM-2690 (8) [16] (Figure 1). Owing to their various biological activities and characteristic closely related structural motifs, they have generated immense interest among the chemists.…”

Short, Tin‐Free Synthesis of All Three Inthomycins

“…In 2010, Ryu reported an enantioselective synthesis of inthomycin C 3 which was followed by Hale's reports on the enantioselective synthesis of 3 . Very recently the Donohoe group published an enantioselective synthesis of inthomycin C 3 . All of the syntheses of the inthomycins bar one, feature a Stille cross‐coupling as a key step with the inherent problems associated with the toxicity and disposal of stoichiometric organotin waste.…”

“…We envisaged that inthomycins A-C (1-3), could all be prepared throughc ross-coupling of the (E)-or (Z)-alkenyl iodides 5 with the (E,E)-or (E,Z)-dienylboronic esters 4 ( Figure 2). The dienylboronic esters 4 were to be prepared by syn or anti hydroboration of the enyne oxazole 6 with the enyne oxazole 6 being prepared from alkylation of oxazole 8 with an electrophile derived from commerciallya vailable( E)-pent-2-en-4-yn-1ol (7). The iodides 5 were to be prepared using an enantiose-lectiveK iyooka aldol reaction [14] between the silylketene acetal 9 and the known (E)-or (Z)-iodoaldehydes 10,w hich can be readily prepared from propargyl alcohol 11.T his modular route allowed the ready synthesis of all three inthomycins A-C 1-3.…”