Design and Synthesis of Medium-Ring Lactam Libraries Inspired by Octalactin A. A Convergent−Divergent Approach

Abstract

Small molecule compound libraries based on medium rings 1 are virtually unknown. 2 This critical gap in the literature is probably caused by two main factors. First, medium ring natural products are themselves uncommon and therefore less likely to be the object of total synthesis efforts. 3 Second, there is a widely held view that medium rings remain the most challenging and difficult systems to synthesize. 4 As part of a program to identify interesting chemotypes for library development, we examined several medium-ring natural products. One system in particular, namely, octalactin A (1) (Figure 1), 5 continues to attract intense interest because of its fascinating architecture and potent antitumor profile. 6 The rare, saturated eight-membered lactone core appeared to be an attractive feature on which to base a new library template. Our previous experience with the total synthesis of the octalactins7 and of other eight-membered lactone natural products 8 by means of a facile direct lactonization from the saturated seco acid ("zip-up" approach) and via an equally efficient ringclosing metathesis to afford oxocenes from the diene ester ("zip-down" approach), 9 provided the enabling technology for this project and prompted us to proceed with this scaffold.Because it was desirable for us to have the flexibility to introduce additional functionality that could later be easily modified, we settled on a convergent-divergent strategy of constructing lactam rather than lactone libraries via RCM (Scheme 1).In the convergent phase, three simple, commercially available building blocks served as sources of diversity for the scaffold: protected L-amino acids, benzaldehydes, and benzyl amines. Once the desired frameworks were in hand, diversification at the secondary amine R 2 N was carried out in parallel fashion (divergent phase) to afford compound libraries of amines, amides, sulfonamides, carbamates, and ureas. As a guiding principle for the creation of molecules most likely to have druglike properties, all of the entries were screened in silico prior to synthesis to comport with Lipinski's Rules. 10 We are now pleased to report a 163-member demonstration library, the first based on a monocyclic medium-ring platform. The synthesis of the scaffold began with the commercially available t-butyl ester hydrochloride salts of the amino acids glycine, alanine, and phenylalanine (Scheme 2). The salts were allylated by a modified one-pot literature procedure (CH 2 =CHCH 2 Br, NaHCO 3 , LiI), 11 and then protected with the Fmoc group to afford the Nallyl esters 12-14 in 53-81% yield. Attempts at unmasking the carboxylic acid using conventional ester hydrolysis protocols proved unsuccessful and resulted in significant racemization with the two chiral amino acids. However, the use of Et 3 SiH in TFA/CH 2 Cl 2 (1:1) 12 produced the desired acids 15-17.To maximize the number compounds available for biological screening with a minimum of synthetic effort, we decided to employ a single racemic coupling partner. The secondary allylic amin...

Novel synthetic inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase activity that inhibit tumor cell proliferation and are structurally unrelated to existing statins

“…The synthesis of the 10-member sublibrary of novel unsaturated eight-membered lactam compounds used in this study (DL-II-D4 and DL-II-D7; GG-II-Ala29, GG-II-G3-cis, and GG-II-G7; NB-IX-Gly27, NB-IX-Gly35, NB-IX-Gly38, NB-IX-Gly44 and NB-IX-Gly46) was performed in the convergent-divergent manner described previously (3,4). In general, ring-closing metathesis (RCM) of a collection of diene amides (prepared from the carboxylic acids and the fluorinated secondary allyl amine), was followed, after deprotection, by parallel derivatization of the resulting cyclic secondary amine scaffold (Scheme 1).…”

“…Eight-membered and medium-ring lactones are rare and their therapeutic properties largely unknown (1–4). A synthetic analog of the natural marine product, octalactin A (1), was previously shown to inhibit L1210 tumor cell proliferation without altering the rates of DNA, RNA and protein syntheses (2).…”

“…But this compound inhibited the polymerization of purified tubulin, suggesting that microtubule de-stabilization might be involved in its cytostatic action (2). Pilot-scale libraries of 2nd and 3rd generation 8-membered medium-ring lactams (MRLs) inspired by octalactin A were then synthesized for optimization studies and screened for bioactivity in hyperplastic tumor cell systems in vitro (3,4). Several MRLs inhibited, in a concentration- and time-dependent manner, tumor cell proliferation in the low μ M range after 2 and 4 days in culture and were effective across a spectrum of leukemic (L1210 and HL-60), pancreatic (Pan02) and mammary (SK-BR-3) tumor cell lines.…”

A New Synthesis of Sulfur‐, Nitrogen‐ and Oxygen‐Containing Eight‐Membered Ring Lactams

“…We considered β-oxo esters with a tetrahydrothiophene ring (5), pyrrolidine ring (6) or tetrahydrofuran ring (7) to be appropriate starting materials for the synthesis of nitrogen, sulfur or oxygen containing eight-membered ring lactams 8, 9 and 10 (Scheme 2). Whereas benzo-and dibenzoannulated 1,4-diazocanes, [3] 1,4-thiazocanes [4] and 1,4-oxazocanes [5] frequently appeared in the literature, only very few synthetic pathways to monocyclic 1,4-diazocanes, [6] 1,4-thiazocanes [7] and 1,4-oxazocanes [8] have been reported so far.…”

“…Whereas benzo-and dibenzoannulated 1,4-diazocanes, [3] 1,4-thiazocanes [4] and 1,4-oxazocanes [5] frequently appeared in the literature, only very few synthetic pathways to monocyclic 1,4-diazocanes, [6] 1,4-thiazocanes [7] and 1,4-oxazocanes [8] have been reported so far. Therefore, the Bi(NO 3 ) 3 -catalyzed ring expanding reaction is interesting as it allows a straightforward access to these rare eight-membered heterocycles.…”