Short, Tin‐Free Synthesis of All Three Inthomycins

Abstract

The inthomycins are a family of structurally and biologically rich natural products isolated from Streptomyces species. Herein the implementation of a modular synthetic route is reported that has enabled the enantioselective synthesis of all three inthomycins. Key steps include Suzuki and Sonogashira cross‐couplings and an enantioselective Kiyooka aldol reaction.

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 3 R by assigning the ( R )-stereochemical descriptor for the common intermediate (−)- 140 , which supports the recent work of Hale and Hatakeyama [ 57 ].…”

“…Various stereoselective cross-coupling reactions such as Stille, Suzuki, or Sonogashira or Suzuki–Miyaura have been utilized to construct the geometrically distinctive polyene systems of inthomycins A–C ( 1 – 3 ). The elegant work of R. J. K. Taylor [ 21 , 43 ], Ryu [ 50 ], Donohoe [ 57 ], and Burton [ 23 ] demonstrated the power of the Mukaiyama−Kiyooka aldol reactions to install the asymmetric center of inthomycins. Alternatively, Hatakeyama and Kim’s groups employed an asymmetric β-lactone synthesis and an asymmetric ynone reduction protocol for the construction of the stereogenic center of inthomycins, respectively [ 22 , 24 ].…”

“…Since the pioneering works of Henaff and Whiting [19,20], several racemic and asymmetric total syntheses of inthomycins A-C (1-3) have been carried out in many research groups (Figure 2). However, only four synthetic strategies that lead to the total synthesis of all three members of inthomycins A-C (1-3) are available ( Figure 2, route b, d, h, and i) [21][22][23][24].…”

Asymmetric Total Synthesis of (+)‐Neooxazolomycin Using a Chirality‐Transfer Strategy

“…[12] We envisaged that the Z,Z,E-configured triene unit of 2 could be constructed from the Z-unsaturated aldehyde 4.T he Z configuration of the trisubstituted double bond in 4 was expected to be installed by a1 ,4-addition of methyl cuprate to the alkynoic ester 5.I nt urn, 5 would be accessible from hydroxypivalic acid. An obvious disconnection of the amide linkage of 1 gave two fragments, 2 and 3.T he amide form of 2 is an aturally occurring compound named inthomycin A.…”

Oxazolomycins produced by Streptomyces glaucus and their cytotoxic activity

“…In addition, several synthesis method to establish the different structural segments of oxazolomycins have been reported. [23][24][25][26][27] In our continuous search for bioactive natural compounds from microbial sources, the secondary metabolites of a soil-borne Streptomyces glaucus (YIM 33872) were investigated. Streptomyces glaucus was isolated from the soil sample collected from the rainforest of Xishuangbanna, Yunnan, China.…”