Synthesis of (+) and (‐)‐Streptomyces coelicolor Butanolide 5 (SCB‐5)

Abstract

Various 1-(1-hydroxyalkyl) paraconyl alcohols are important signaling molecules within antibiotics production in Streptomyces sp. Intending developing a flexible convergent chemical synthesis of such butanolides, a zwitterionic aza-Claisen rearrangement was chosen as reliable strategy generating the central stereotriad. Reaction of enantiopure N-allyl pyrrolidines and 4-phenylbutenoic acid fluoride delivered defined configured amides displaying the 2,3,1' stereotriads. The configuration was determined by the allyl alcohol moiety indicating a complete remote stereo control. Amide removal by iodolactonization and proceeding reductions, halocyclization and elimination gave key alkylidene tetrahydrofuran derivatives. Stepwise degradation of the olefins through ozonolysis, reductive workup and protecting group removal delivered both enantiomers of the target Streptomyces coelicolor butanolide 5.

Synthesis of (–)-Virginiae Butanolide A (VB-A)

“…IR (thin film): 3461 (m, br), 3077 (w), 3030 (w), 2955 (m), 2935 (m), 2927 (m), 2871 (m), 1727 (s), 1599 (w), 1480 (m), 1461 (m), 1398 (w), 1365 (w), 1285 (s), 1162 (vs), 1033 (m), 968 (m), 917 (m), 861 (w), 826 (w), 770 (w), 750 (s), 692 (s), 645 (w), 633 (w), 614 (m). 1 H NMR (CDCl3, 400 MHz): δ [ppm] = 7.35 -7.27 (m, 4H, H-16, H-17), 7.25 -7.20 (m, 1H, H-18), 6.43 (d, 3 J = 15.8 Hz, 1H, H-14), 6.07 (dd, 3 J = 15.8 Hz, 3 J = 9.4 Hz, 1H, H-13), 5.64 (ddd, 3 J = 17.0 Hz, 3 J = 10.2 Hz, 3 J = 10.1 Hz, 1H, H-19), 5.24 (dd, 3 J = 10.2 Hz, 2 J = 1.9 Hz, 1H, H-20a), 5.17 (dd, 3 J = 17.0 Hz, 2 J = 1.9 Hz, 1H, H-20b), 4.25 (dd, 2 J = 10.9 Hz, 3 J = 4.1 Hz, 1H, H-1a), 4.02 (dd, 2 J = 10.9 Hz, 3 J = 8.1 Hz, 1H, H-1b), 3.68 (ddd, 3 J = 9.6 Hz, 3 J = 6.1 Hz, 3 J = 1.7 Hz, 1H, H-4), 2.77 -2.66 (m, 1H, H-2), 2.40 -2.30 (m, 1H, H-3), 1.74 (s, 1H, H-21), 1.59 -1.44 (m, 3H, H-5a, H-6a, H-8), 1.34 -1.05 (m, 4H, H-5b, H-6b, H-7), 1.16 (s, 9H, H-12), 0.82 (d, 3 J = 6.6 Hz, 3H, H-9), 0.82 (d, 3 J = 6.6 Hz, 3H, H-9'). (2S,3R,4S)-4-(tert-Butyldimethylsilyloxy)-8-methyl-2-((E)-styryl)-3vinylnonyl pivalate (XI): Triethylamine (0.15 mL, 0.11 g, 1.1 mmol, 8.2 eq) and TBSOTf (0.18 mL, 0.21 g, 0.78 mmol, 6.0 eq) were added to a solution of alcohol 10 (51.0 mg, 0.132 mmol, 1.0 eq) in DCM (5 mL) at 0 °C.…”

“…Therefore, the amide 1 was converted into methyl ester 3 as described within the SCB-5 synthesis. 11a 16 Removal of the TBS protecting group of syn / anti ester 3 without subsequent γ-lactonization failed despite of broadly varied reaction conditions. 17 Furthermore, TBS ether cleavage and γ-butyrolactone cyclization with SOCl 2 /MeOH delivered a 1.4:1 mixture of epimer lactones 4a and 4b in 62% yield (Scheme 3 ).…”

“…Obviously, any α-equilibration had to be suppressed by reducing ester 3 to syn / anti carbinol 5 as described in the literature. 11a 19 Now, the primary OH function requires a suitable orthogonal protection before removing the TBS group releasing the secondary carbinol. Considering prospective OH-group inversions via direct nucleophilic substitutions with carboxylates, a trityl ether was chosen.…”

“…Bacteria of the genus Streptomyces are well known for producing a variety of highly bioactive secondary metabolites including antibiotics. 1 The production of such antibiotics is controlled by various physiological and environmental signals. 1 Focusing on the largest group of hormone-like small signaling molecules, the 2,3-disubstituted γ-butyrolactones (GBL), three types have been identified as active compounds even at nanomolecular concentrations.…”

“…1 The production of such antibiotics is controlled by various physiological and environmental signals. 1 Focusing on the largest group of hormone-like small signaling molecules, the 2,3-disubstituted γ-butyrolactones (GBL), three types have been identified as active compounds even at nanomolecular concentrations. 2 Only one of these GBLs (A-factor) displays a 2-(1'-oxoalkyl) side chain.…”