Letter pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Total Synthesis of Pactalactam, an Imidazolidinone-Type Pactamycin Analogue Taejung Kim,†,‡ Shohei Matsushita,† So Matsudaira,† Tsuyoshi Doi,† Shinji Hirota,† Young-Tae Park,‡ Masayuki Igarashi,§ Masaki Hatano,§ Noriko Ikeda,§ Jungyeob Ham,*,‡ Masaya Nakata,*,† and Yoko Saikawa*,†
Downloaded via NOTTINGHAM TRENT UNIV on May 6, 2019 at 18:30:51 (UTC). See https://pubs.acs.org/sharingguidelines for options on how to legitimately share published articles.
†
Department of Applied Chemistry, Faculty of Science and Technology, Keio University, 3-14-1 Hiyoshi, Kohoku-ku, Yokohama 223-8522, Japan ‡ Natural Products Research Institute, Korea Institute of Science and Technology (KIST), 679 Saimdang-ro, Gangneung 25451, Republic of Korea § Institute of Microbial Chemistry (BIKAKEN), 3-14-23 Kamiosaki, Shinagawa-ku, Tokyo 141-0021, Japan S Supporting Information *
ABSTRACT: The first total synthesis of pactalactam was accomplished using substrate-controlled stereoselective aziridination and regioselective aziridine ring-opening to construct three continuous amino groups on an octasubstituted cyclopentane core. The cyclopentane framework was obtained by ring-closing metathesis and aldol coupling using a Lthreonine-derived oxazoline compound. Cyclic urea formation, m-acetylphenyl group introduction by Chan−Lam coupling, and primary alcohol-selective acylation yielded the reported pactalactam structure. The presence of pactalactam in the fermentation broth of pactamycin-producing bacteria was also confirmed.
P
Pactalactam (2) was reported in a review paper published in 1980 by Rinehart et al. as a minor component of the metabolite of the same genus culture broth as that of 1, but no data were available to confirm its structure (Figure 1).2b,e Its reported structure formula is similar to that of 1, except for the imidazolidinone moiety; it is also analogous to that of pactamycate, an oxazolidinone derivative obtained by the acidic treatment of 1 where the 7-hydroxy group attacked the carbamoyl group.7 Although 2 and pactamycate were reported to be inactive against bacteria, these shelved analogues deserve reexamination regarding their structures and coexistence in the culture broth. Herein, we report the synthesis of the reported structure of 2 and reveal its existence in nature. Despite the presence of many reports8 regarding synthetic studies toward 1, the first total synthesis by Hanessian’s group9 and a concise total synthesis by Johnson’s group10 are the only two reported total syntheses of 1 to date. Notably, the aforementioned pactamycin analogues have not been synthesized yet. Thus, we envisioned devising a strategy to access cyclopentane core 3, which might be applicable to access other pactamycin analogues (Scheme 1). For the synthesis of 2, we envisioned late-stage formation of cyclic urea, m-acetylphenyl group introduction by Chan−Lam coupling,11 and primary alcohol-selective acylation using Hanessian’s procedure9 to yield 2 from core 3. Azidoamine 3 would be constructed by a regioselective aziridine-opening reaction with an azide group
actamycin (1) is a representative bioactive aminocyclopentitol isolated from the culture broth of Streptomyces pactum var. pactum (Figure 1).1 Its attractive
Figure 1. Chemical structures of pactamycin (1) and pactalactam (2).
bioactivity and intriguing chemical structure based on a densely functionalized cyclopentane core drove the isolation of several related bioactive aminocyclitols, such as 7deoxypactamycin2 and 8″-hydroxypactamycin,2b−e as well as the recently isolated jogyamycin.3 Although the development of 1 as a clinical drug has been curtailed by its broad and potent cytotoxicity, these related analogues exhibit antimicrobial,4 antitumor,5 and antiprotozoal6 activities, among others. However, their structure−activity relationships are not completely understood. Thus, expanding the scope of pactamycin analogues may lead to the discovery of more acceptable safety profiles with well-characterized bioactivity. © XXXX American Chemical Society
Received: March 13, 2019
A
DOI: 10.1021/acs.orglett.9b00905 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters
center at C5 was conveniently isomerized to the desired stereoisomer 9 in 68% yield through oxidation by Dess− Martin periodinane (DMP) and subsequent NaBH4 reduction. The secondary alcohol of 9 was protected with TBSCl, giving silyl ether 10 in 99% yield. Next, the methyl ester was converted into a terminal olefin in three steps. The subsequent selective deprotection of the Tr group was achieved using a large excess of ZnBr2 in a CH2Cl2−MeOH (1:1) solvent system. Dess−Martin oxidation provided aldehyde 11; only one chromatographic separation was needed after the above five steps (from 10 to 11) at the scaled-up synthesis. After the Grignard reaction with vinylmagnesium bromide, the intermediate mixture of allylic alcohols (3:1 ratio by its 1H NMR spectrum) was subjected to RCM using a second-generation Grubbs catalyst to produce the separable cyclopentenols 12a and 12b in 74% and 19% yields, respectively, over two steps. The stereochemistries of the C-4 and C-5 positions having oxygen functional groups were determined on the basis of NOE experiments using 12a, 12b, and their C-5 diastereomers from 8.14 Finally, oxidation of the allylic alcohol furnished cyclopentenone 13. We next focused on stereoselective aziridination to construct the three continuous chiral centers with amino groups of core 3 via a Gabriel−Cromwell method15 starting from cyclopentenone 13 (Scheme 3). The conventional iodination16 of
Scheme 1. Synthetic Plan toward Pactalactam (2) and Core 3
and the sequential construction of two continuous tetrasubstituted carbons by dihydroxylation and addition of a methyl group. These could be conducted from the upper face of an idealized intermediate of pentenone 4, whose lower face would be shielded by the methyl group in the oxazoline ring. Stereoselective aziridination would be controlled by the rigid spirostructure and the 5R-alkoxy group (OP2), which would avoid conflict with the incoming aziridinating reagent. Finally, the preparation of 5 could be traced to L-threonine-derived oxazoline methyl ester 6, utilizing ring-closing metathesis (RCM) to construct the five-membered ring with a faceselective coupling reaction using a chiral oxazoline enolate. Stepwise construction of the potentially functionalized cyclopentenone 13 began with oxazoline methyl ester 6 (Scheme 2), derived from L-threonine in three known steps.12 The nitrogen-containing stereogenic carbon center was formed by face-selective coupling using the chiral oxazoline enolate with a known aldehyde 713 derived from glycerol in two steps. Our procedure yielded the separable adducts 8 (37%) and 9 (40%). Secondary alcohol 8 with the undesired stereogenic
Scheme 3. Stereoselective Aziridinations of Cyclopentenone 13 via a Gabriel−Cromwell Reaction
13 using iodine and pyridine in CCl4 proceeded smoothly to provide α-iodoenone 14 in 96% yield. Attempts at aziridine formation using p-methoxybenzylamine and Cs2CO3 in xylene according to Maycock’s conditions17 induced decomposition of the substrate upon heating (95 °C), whereas no reaction occurred at room temperature. To our delight, aziridination proceeded smoothly in DMF at room temperature to produce the desired N-PMB aziridine 16, through 15, as a single isomer in good yield (86%).18 Next, aziridine 16 was converted to the key intermediate 19 with three continuous stereogenic tetrasubstituted carbons and then to octasubstituted cyclopentane core 21 (Scheme 4). The Wittig reaction of 16 yielded exo-olefin 17, the stereochemistry of which was confirmed by X-ray crystallographic analysis. Substrate-dependent (the neighboring siloxy group and the methyl group on oxazoline) dihydroxylation of 17 using OsO4 without chiral ligands provided an inseparable mixture of two diols at the C-4 position. The diols were treated with 2,2dimethoxypropane to give acetonides. Removal of the TBS group, followed by oxidation of the secondary alcohol, produced separable ketone 18 in 72% yield along with its C4 diastereomer in 13% yield over four steps. The stereoselective addition of a methyl anion to 18 using MeLi gave 19 in low yield (
