Diastereoselective Alkylation of a Proline-Derived Bicyclic Lactim Ether

Abstract

Dedicated to Professor Dieter Hoppe on the occasion of his 65th birthday N-Boc-protected L-proline (6) was converted into the bicyclic lactim ether (8aS)-6,7,8,8a-tetrahydro-1-methoxypyrrolo[1,2-a]pyrazin-4(3H)-one (5) in four steps (Scheme 1). Deprotonation with LDA or LHMDS and subsequent alkylation resulted in the diastereoisomeric products cis-and trans-9. The diastereoselectivity was mainly dependent on the electrophile. Whereas small alkyl halides gave preferably cis-9, sterically more-demanding alkyl halides resulted in cis/trans mixtures. Electrophiles bearing a psystem favored the trans-products 9. Some isolated cis-and trans-lactim ethers 9 were converted to the corresponding diketopiperazines cis-and trans-10 by acid hydrolysis. The structures and configurations of several compounds were confirmed by NMR and NOE experiments, as well as by X-ray crystallography (Figs. 1 -4).Introduction. -In contrast to the well-known Schçllkopf bislactim-ether method for the synthesis of a-amino acids [1 -3], the alkylation of monolactim ethers has been rarely reported in the literature [4 -6]. Recently, we have published the preparation of tricyclic diketopiperazines with an annulated tetrahydroisoquinoline moiety via diastereoselective alkylation of the corresponding monolactim ethers and subsequent hydrolysis [7].Several secondary metabolites of microorganisms with interesting biological properties such as deoxybrevianamide E (1) [8], tryprostatins A and B (2a, b) [9], spirotryprostatin A (3) [10], and fumitremorgin C (4) [11] contain a proline-derived diketopiperazine as part of their molecular skeleton. Furthermore, this type of compound has been found in the bitter flavor of roasted coffee [12]. The diketopiperazine structural motif in these natural products was prepared in most cases by cyclocondensation [8 -11] [13] [14]. However, we were interested to synthesize related proline-based diketopiperazines via alkylation of the bicyclic lactim ether 5, followed by acidic hydrolysis. The results of our investigation are reported in this paper.

A Subdomain Swap Strategy for Reengineering Nonribosomal Peptides

“…Evaporation of solvent in vacuo yielded pure D-Val-L-Pro DKP as a white solid (88% yield) without further purification. The 1 H-NMR spectrum was in good agreement with a published reference (Hendea et al, 2006). 1 H-NMR (300 MHz, CD 3 OD): d 4.14 (dd, J = 9.9, 6.5 Hz, 1H), 3.50 (dd, J = 6.1, 0.8 Hz, 1H), 3.59-3.32 (m, 2H), 2.32-2.16 (m, 1H), 2.04 (dq, J = 13.6, 6.8 Hz, 1H), 1.96-1.68 (m, 3H), 0.91 (dd, J = 9.8, 6.8 Hz, 6H).…”

GPR12 Selections of the metabolites from an endophytic Streptomyces sp. Asociated with Cistanches deserticola

“…So, compound 5 was identified as cyclo-(Trp-Pro) (Ashnagar et al 2007). Similarly, further analysis of the 1 H-NMR spectra of 6-8 indicated four amino acid residues including Pro, Phe, Val and Ala, then 6 was identified as cyclo-(PhePro) (Hendea et al 2006), 7 was cyclo-(Phe-Val) (Stark et al, 2005), and 8 was cyclo-(Pro-Ala) (Stark et al, 2005), respectively.…”

A combined quantum mechanical and experimental approach towards chiral diketopiperazine hydroperoxides

“…The diketopiperazines 1a, [70] 6a, [71] 16, [72] 19, [73] and 20 [74,75] have been already described as well as the diketopiperazine hydroperoxides 1b, [21a] 1c [21a] and 6b.…”

“…The proline glycine diketopiperazine 6a as well as anthranilic acid 27 and the achiral side product 28 could be isolated after 48 hours (Scheme 6). It should be noted that the stereochemical assignment for pyrazinoquinazoline hydroperoxides was based on NMR-assignments and comparison with earlier work in our group [72] on diketopiperazine hydroperoxides where we obtained NMR-and XRay data for both cis-and trans-isomers. The configuration of the diketopiperazine hydroperoxides 1b, c could be determined by X-Ray crystal structure analysis (see supporting information).…”

“…The residue was stirred in formic acid (60 ml) at room temperature for 4 h. Then, water (100 ml) was added and the mixture was extracted with diethylether (3 x 40 ml [73] (1.66 g, 56 %) and 20 [74,75] To a solution of diketopiperazine 20 (0.792 g, 5 mmol) in dry dichloromethane (30 ml) triethyloxonium tetrafluoroborate (1.141 g, 6 mmol) was added. The reaction mixture was refluxed and after 12 h additional triethyloxonium tetrafluoroborate (1.140 g, 6 mmol) was added and stirred for further 12 h. The mixture was slowly poured into ice-cold saturated NaHCO 3 -solution (pH>8) (50 ml), the organic layer was separated and the aqueous layer was extracted with dichloromethane (3 x 20 ml The diketopiperazine lactim ethers 21, [72] 22, [72] 23, [73] 25, [73] and 26 [76] were prepared following the procedure above for lactim ether 24 and all were obtained as pale yellow oils. The spectroscopic data was according to the literature.…”