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Polypropionate Synthesis Essay

Synthetic strategy

Our synthetic design follows the formation of the seven-membered lactone 1, harbouring three to four stereocentres (Fig. 2). The embedded oxygen functionalities at C4 and C6 positions of lactone 1 can be traced back to cyclohexanone 2 by Baeyer–Villiger oxidation. Analysis of compound 2 shows possible access from a pivotal Diels–Alder cycloaddition of silyloxydiene 3 and dienophile 4. Previous studies have demonstrated the strong effect of the terminal substitution of dienes and dienophiles in the exo- and endo-stereochemical outcome of the Diels–Alder reaction20, 21. Thus, we anticipate a favourable control of stereoselectivity during the formation of the cycloadduct. Finally, the required dienes, and in certain cases, the dienophiles could be afforded from the commercially or readily available enone 5. This synthetic approach benefits from the inherent flexibility of the Diels–Alder reaction and the ready availability of various dienes and dienophiles, with the potential option to grow the polypropionate chains having the desired diastereomeric relationships. In addition, the transformations of the diene 3 and dienophile 4 towards the lactone 1, that is, the Diels–Alder/Baeyer–Villiger relay process, could be performed using compatible reagents to permit not only stepwise handling but also one-pot operation. Furthermore, with synthetically versatile groups at the terminal positions of the corresponding open form of the lactone 1, it is, in principle, possible to reiterate the process through compound 6 carrying the familiar enone structure.

Evaluation of the Diels–Alder/Baeyer–Villiger relay process

To examine the proposed relay concept, we first applied the designed procedure to the prototypical enones 7 and 9 in a stepwise manner (Fig. 3a). Deprotonation of enone 7 with lithium hexamethyldisilazide followed by silyl trapping supplied the silylenol ether 8 in 89% yield ((Z,E)/(E,E) = 86/14). Alternatively, use of triethylamine as base to permit the same reaction led to lower yield (82%) and diastereoselectivity for the desired (Z,E)-isomer (85/15). The cycloaddition of diene 8 and dienophile 9 is expected to produce the exo-adduct based on the methyl substitution at C1 of 8 and Cβ of 921 (for the carbon designations of dienes and dienophiles used in this paper, refer to Fig. 2). Thus, the boron trifluoride-catalysed Diels–Alder reaction effectively provided the product 10 in excellent yield and exo-selectivity. Other Lewis acid catalysts, such as copper(II) triflate, scandium(III) triflate, trimethylsilyl triflate, dimethylaluminum chloride and tin tetrachloride, also gave similar exo-preference, but only in moderate-to-good yields (Supplementary Table 1). Notably, the supposed Diels–Alder cycloadduct between the (E,E)-isomer of 8 and the enone 9 was not observed in these cases. The desilylation of 10 could be achieved by tetrabutylammonium fluoride (TBAF), but acid hydrolysis offers better compatibility with Baeyer–Villiger oxidation in light of our desire for a one-pot operation. Consequently, treatment with trifluoroacetic acid (TFA) for 20 min delivered the corresponding dione, which was directly treated with meta-chloroperoxybenzoic acid (mCPBA) for the double oxygen insertion to afford the expected ε-lactone 11 carrying a polypropionate syn,syn,syn-stereotetrad in 75% yield (two steps, one pot). The structure of 11 was unambiguously confirmed by X-ray crystallographic analysis (Fig. 3b, Supplementary Table 2, Supplementary Data 1) and further characterized by nuclear magnetic resonance (NMR) spectroscopy (Supplementary Methods). Curiously, the exposure of compound 10 to TBAF led to a complete epimerization at the α-carbon leading to compound 12 (77%) as a single diastereomer, providing a possible point of access to another stereotetrad structure.

Treatment of the lactone 11 with catalytic sodium methoxide in methanol resulted in deacetylation and transesterification, supplying the γ-lactone 13 (96%). This cyclic system should offer more stability than the initial seven-membered ring structure and could serve as key intermediate with various potential for further manipulation. With the intent to explore the possibility of reiterating the tandem Diels–Alder/Baeyer–Villiger reaction process, we examined the elaboration of compound 13 to further generate an advanced enone structure. The operation started from the silyl group protection of the free hydroxy group (97%), followed by nucleophilic addition to the carbonyl using allylmagnesium chloride. Subsequent base-promoted double bond isomerization ultimately afforded the desired enone 14 (78% in two steps). This and similar compounds offer prospective applications for the assembly of longer and more complex polypropionate chains.

After successfully demonstrating stereotetrad formation via Diels–Alder cycloaddition and Baeyer–Villiger oxidation in stepwise manner, we then explored the feasibility of our envisioned one-pot operation (Table 1). Pleasingly, the Diels–Alder exo-adduct, formed in situ from compounds 8 and 9 by the catalytic assistance of boron trifluoride, was smoothly converted to the desired ε-lactone 11 in 63% yield upon successive treatment with TFA and mCPBA in the same vessel (entry 1). For cycloaddition with enone 15, we found that copper(II) triflate provided the best product yield and selectivity for the expected endo-adduct20 (Supplementary Table 1). Thus, the sequential Diels–Alder cycloaddition of 8 and 15, acid hydrolysis and Baeyer–Villiger oxidation supplied the ε-lactone 16 in 53% yield for the one-pot process (entry 2). Further application of the one-pot procedure to different diene and enone combinations all provided satisfactory results (entry 3–12). Curiously, when the phenyl-substituted 32 was employed as starting enone (entries 11 and 12), minor amounts of the separable corresponding γ-lactone (34 and 36), apparently resulting from acid-induced translactonization22, was acquired along with the expected ε-lactone (33 and 35). The structures of the duly formed lactones were confirmed by NMR spectroscopy as well as X-ray crystallographic analysis for compounds 16, 23, 29 and 34 (Supplementary Fig. 1, Supplementary Tables 3–6, Supplementary Data 2–5). Treatment of all the lactone products with sodium methoxide in methanol resulted into the corresponding γ-lactone akin to compound 13 with variously substituted stereogenic centres (Supplementary Table 7).

Preparation of the C1–C9 segment of etnangien

To demonstrate the utility of the tandem one-pot Diels–Alder/Baeyer–Villiger relay process for the assembly of polypropionates leading to more complex molecular architectures, we targeted the stereohexad structure present at the C1–C9 subunit of the macrolide etnangien (Fig. 1). Etnangien, an antibiotic isolated from the myxobacterium Sorangium cellulosum, is a potent inhibitor of the RNA polymerase of Gram-positive bacteria23. Our synthesis began with the Weinreb amidation (85%) of the commercially available (S)-3-phenylbutanoic acid (37) (Fig. 4a). Nucleophilic allyl addition to the amide, followed by double-bond isomerization established the familiar enone structure 38. Silylation of this enone fashioned the desired 1,4-disubstituted diene 39 in 82% yield ((Z,E)/(E,E) = 70/30).

With required diene 39 in hand, the formation of the target ε-lactone through the crucial relay process was first performed in a stepwise fashion. Thus, the Diels–Alder cycloaddition of the diene 39 and enone 9 employing the boron trifluoride-catalysed condition produced two exo- and two endo-cycloadduct diastereoisomers (exo/endo = 84/16) of which the desired silylenol ether and exo-adduct 40 was obtained as the major diastereomer in 65% yield; the other diastereomers were collectively afforded in 25% yield (see the Supplementary Methods for details). A preliminary X-ray analysis of the racemic version of 40 supported the structure of this major diastereomer (Supplementary Fig. 1, Supplementary Table 8, Supplementary Data 6). The facial selectivity of the Diels–Alder reaction towards 40 is perceived as a result of the asymmetric induction of the stereocentre attached to C1 of the diene (Supplementary Fig. 2). Having the desired stereochemistry and the necessary carbon atoms of the target subunit, the exo-adduct 40 was subjected to sequential hydrolysis and Baeyer–Villiger oxidation utilizing TFA and mCPBA, respectively, generating the required ε-lactone 41 in 75% yield as a single isomer. X-ray crystallography confirmed the structure of 41 with the prescribed relative configuration of the contiguous stereocentres on the seven-membered lactone ring (Fig. 4b, Supplementary Table 9, Supplementary Data 7). After the successful stepwise attempt, we next pursued the transformation in one pot. To our satisfaction, the three-step sequence also proceeded smoothly and provided the expected lactone 41 in 40% overall yield. Treatment of 41 with sodium methoxide resulted to deacetylation and subsequent conversion into the γ-lactone 42 (96%). Again, an X-ray analysis supported the structure and relative configuration of the stereopentad motif of the crystalline 42 (Fig. 4c, Supplementary Table 10, Supplementary Data 8).

With implicitly positioned terminal groups, 42 was further modified to form the more elaborated C1–C9 fragment of etnangien, particularly using a Birch reduction/ozonolytic cleavage sequence24. Thus, exposure of the alcohol 42 to lithium metal in the presence of ammonia25 reduced the lactone into a terminal alcohol and the phenyl group into a 1,4-cyclohexadiene structure. A side product of this reaction, with the phenyl group remaining unscathed, was further converted to 42 using the same Birch reduction in moderate yield (Supplementary Methods). Silylation of the alcohol groups led to compound 43. Ozonolysis transformed the 1,4-cyclohexadiene portion of 43 into the keto/cis-enol pair as verified by NMR spectroscopy of 44 with likely stabilization by hydrogen bonding. Treatment of 44 with hydrogen fluoride in pyridine provided for partial desilylation and subsequent enol ether formation via a lactol intermediate. Acetylation of the so-formed 45 followed by Luche reduction26 established the alcohol 47 as a single diastereosomer in excellent yield. Final silylation and oxidation provided the desired C1–C9 fragment of etnangien containing six stereocentres (48). This fragment possesses the synthetic versatility that would enable further elaboration towards etnangien and other more advanced molecules.

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