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.

Application of the Dipeptidyl Peptidase IV (DPPIV/CD26) Based Prodrug Approach to Different Amine-Containing Drugs

“…Similar to that observed with cytidine dipeptide prodrugs, N-deprotection of dipeptide conjugate 26 with 20% piperidine showed that parent nucleoside ara-A was spontaneously released with concomitant formation of the known DKP 10 whereas the tetrapeptide prodrug was much more stable. The Cbz-tetrapeptide conjugate derivative 27 was first subjected to TBAF-promoted TBS removal in THF.…”

Application of the Dipeptidyl Peptidase IV (DPPIV/CD26) Based Prodrug Approach to Different Amine-Containing Drugs

“…Similar to that observed with cytidine dipeptide prodrugs, N-deprotection of dipeptide conjugate 26 with 20% piperidine showed that parent nucleoside ara-A was spontaneously released with concomitant formation of the known DKP 10 whereas the tetrapeptide prodrug was much more stable. The Cbz-tetrapeptide conjugate derivative 27 was first subjected to TBAF-promoted TBS removal in THF.…”

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).…”

New Chlorinated 2,5-Diketopiperazines from Marine-Derived Bacteria Isolated from Sediments of the Eastern Mediterranean Sea

“…The organic extracts of five marine-derived bacterial strains, specifically Bacillus endophyticus BI0327, Streptomyces albidoflavus BI0383, Nocardiopsis aegyptia BI0618, Streptomyces smyrnaeus BI0918, and Bacillus subtilis BI0980, isolated from marine sediments collected in the Aegean and Ionian seas, were subjected to repetitive chromatographic fractionations to yield three new natural products, namely cis-cyclo(Pro-3-chloro-Tyr) (15), trans-cyclo(Pro-3-chloro-Tyr) (16), and cis-cyclo(3-chloro-Tyr-Ile) (31), and 29 previously reported metabolites, which were identified as cyclo(Pro-Gly) (1) [24,25], cis-cyclo(Pro-Ala) (2) [26,27], cis-cyclo(Pro-Val) (3) [28][29][30], cis-cyclo(Pro-Leu) (4) [25,29,31,32], trans-cyclo(Pro-Leu) (5) [31,33], cis-cyclo(trans-4-Hyp-Leu) (6) [34], trans-cyclo(cis-4-Hyp-Leu) (7) [35], cis-cyclo(Pro-Ile) (8) [28,31,36], trans-cyclo(Pro-Ile) (9) [36,37], cis-cyclo(Pro-OMet) (10) [38], cis-cyclo(Pro-Phe) (11) [28,30,31,39,40], trans-cyclo(Pro-Phe) (12) [33,36,40], cis-cyclo(trans-4-Hyp-Phe) (13) [36,41], cis-cyclo(Pro-Tyr) (14) [42,43], cis-cyclo(Pro-Trp) (17) [44,45], cyclo(Leu-Gly) (18) [46]…”

Application of the Dipeptidyl Peptidase IV (DPPIV/CD26) Based Prodrug Approach to Different Amine-Containing Drugs

“…Similar to that observed with cytidine dipeptide prodrugs, N-deprotection of dipeptide conjugate 26 with 20% piperidine showed that parent nucleoside ara-A was spontaneously released with concomitant formation of the known DKP 10 whereas the tetrapeptide prodrug was much more stable. The Cbz-tetrapeptide conjugate derivative 27 was first subjected to TBAF-promoted TBS removal in THF.…”

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).…”

New Chlorinated 2,5-Diketopiperazines from Marine-Derived Bacteria Isolated from Sediments of the Eastern Mediterranean Sea

“…The organic extracts of five marine-derived bacterial strains, specifically Bacillus endophyticus BI0327, Streptomyces albidoflavus BI0383, Nocardiopsis aegyptia BI0618, Streptomyces smyrnaeus BI0918, and Bacillus subtilis BI0980, isolated from marine sediments collected in the Aegean and Ionian seas, were subjected to repetitive chromatographic fractionations to yield three new natural products, namely cis-cyclo(Pro-3-chloro-Tyr) (15), trans-cyclo(Pro-3-chloro-Tyr) (16), and cis-cyclo(3-chloro-Tyr-Ile) (31), and 29 previously reported metabolites, which were identified as cyclo(Pro-Gly) (1) [24,25], cis-cyclo(Pro-Ala) (2) [26,27], cis-cyclo(Pro-Val) (3) [28][29][30], cis-cyclo(Pro-Leu) (4) [25,29,31,32], trans-cyclo(Pro-Leu) (5) [31,33], cis-cyclo(trans-4-Hyp-Leu) (6) [34], trans-cyclo(cis-4-Hyp-Leu) (7) [35], cis-cyclo(Pro-Ile) (8) [28,31,36], trans-cyclo(Pro-Ile) (9) [36,37], cis-cyclo(Pro-OMet) (10) [38], cis-cyclo(Pro-Phe) (11) [28,30,31,39,40], trans-cyclo(Pro-Phe) (12) [33,36,40], cis-cyclo(trans-4-Hyp-Phe) (13) [36,41], cis-cyclo(Pro-Tyr) (14) [42,43], cis-cyclo(Pro-Trp) (17) [44,45], cyclo(Leu-Gly) (18) [46]…”

Application of the Dipeptidyl Peptidase IV (DPPIV/CD26) Based Prodrug Approach to Different Amine-Containing Drugs

“…Similar to that observed with cytidine dipeptide prodrugs, N-deprotection of dipeptide conjugate 26 with 20% piperidine showed that parent nucleoside ara-A was spontaneously released with concomitant formation of the known DKP 10 whereas the tetrapeptide prodrug was much more stable. The Cbz-tetrapeptide conjugate derivative 27 was first subjected to TBAF-promoted TBS removal in THF.…”

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).…”

New Chlorinated 2,5-Diketopiperazines from Marine-Derived Bacteria Isolated from Sediments of the Eastern Mediterranean Sea

“…The organic extracts of five marine-derived bacterial strains, specifically Bacillus endophyticus BI0327, Streptomyces albidoflavus BI0383, Nocardiopsis aegyptia BI0618, Streptomyces smyrnaeus BI0918, and Bacillus subtilis BI0980, isolated from marine sediments collected in the Aegean and Ionian seas, were subjected to repetitive chromatographic fractionations to yield three new natural products, namely cis-cyclo(Pro-3-chloro-Tyr) (15), trans-cyclo(Pro-3-chloro-Tyr) (16), and cis-cyclo(3-chloro-Tyr-Ile) (31), and 29 previously reported metabolites, which were identified as cyclo(Pro-Gly) (1) [24,25], cis-cyclo(Pro-Ala) (2) [26,27], cis-cyclo(Pro-Val) (3) [28][29][30], cis-cyclo(Pro-Leu) (4) [25,29,31,32], trans-cyclo(Pro-Leu) (5) [31,33], cis-cyclo(trans-4-Hyp-Leu) (6) [34], trans-cyclo(cis-4-Hyp-Leu) (7) [35], cis-cyclo(Pro-Ile) (8) [28,31,36], trans-cyclo(Pro-Ile) (9) [36,37], cis-cyclo(Pro-OMet) (10) [38], cis-cyclo(Pro-Phe) (11) [28,30,31,39,40], trans-cyclo(Pro-Phe) (12) [33,36,40], cis-cyclo(trans-4-Hyp-Phe) (13) [36,41], cis-cyclo(Pro-Tyr) (14) [42,43], cis-cyclo(Pro-Trp) (17) [44,45], cyclo(Leu-Gly) (18) [46]…”