InI-mediated reactions

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Diastereoselectivity switch in the Pd(0)/InI-mediated reactions of #-lactams with aldehydes. An entry into nonracemic semi-protected (3E)-2,6-enediols. Sylwia Domin, Paulina Plata, and Bartosz K. Zambro# J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b01471 • Publication Date (Web): 06 Sep 2019 Downloaded from pubs.acs.org on September 6, 2019

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The Journal of Organic Chemistry

Diastereoselectivity switch in the Pd(0)/InI-mediated reactions of βlactams with aldehydes. An entry into nonracemic semi-protected (3E)-2,6-enediols. Sylwia Domin, Paulina Plata, and Bartosz K. Zambroń

*

Institute of Organic Chemistry, Polish Academy of Sciences, Kasprzaka 44/52, 01-224 Warsaw, Poland

e-mail: [email protected]

ABSTRACT The switch from N-methylimidazole (N-MI) to Et3N N-ligand efficiently alters diastereoselectivity in Pd(0)/InI-mediated allylations of aldehydes with β-lactam-derived organoindiums. As a result, (3E)selective allylations and crotylations of a variety of aliphatic and (hetero)aromatic aldehydes with differently substituted chiral -amido-allylindiums were developed. Depending on relative β-lactam configuration, the reactions occur under kinetic or thermodynamic control, with effective remote 1,5- or 1,4,5-asymmetric induction to afford a diversity of previously unavailable (3E)-2,5-syn-2,6-anti-, (3E)-2,5anti-2,6-anti-, and (3E)-2,5-anti-2,6-syn-substituted enediols, amino alcohols, and homoallylic alcohols in modest to high yields and with moderate to excellent diastereoselectivity. The effect of the N-ligand as well as β-lactam and aldehyde structures on the yield and stereoselectivity was investigated. Keywords: stereoselective crotylation, β-lactams, palladium, indium(I) iodide, chiral organoindium compounds INTRODUCTION Allylations of carbonyl compounds with organometal reagents constitute one of the most efficient 1 transformations in synthetic organic chemistry. Among many reagents, air and moisture tolerant, nontoxic and easy to handle allylindiums, giving high yields and often excellent levels of stereocontrol 2 constitute a widely used option. Recently, we have shown that nucleophilic -amido-allylindiums generated from N-Ts- or N-Ms-4-vinylazetidin-2-ones in the presence of InI and catalytic amounts of a Pd(0) catalyst can react with a variety of aromatic and aliphatic aldehydes regio- and stereoselectively to afford highly functionalized (3Z)-2,5-anti-2,6-syn- or (3Z)-2,5-syn-2,6-anti-enediols and amino alcohols 3 in high yield with very efficient remote 1,5- or 1,4,5- asymmetric induction. Highly functionalized products of the above transformation, with an internal (3Z)-substituted double bond and active N-Ts-carboxamide 4 function , constitute useful building blocks for the asymmetric synthesis of a variety of derivatives, such as 5 challenging 1,5-polyol subunits or different types of heterocycles. It is noteworthy that due to the limited 6 number of methods for the synthesis of linear organic compounds bearing distant stereogenic centers, the development of new types of acyclic remote stereocontrol is very important. Furthermore, we have

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shown that the regioselectivity of these reactions may be effectively reversed by the addition of CF 3CO2H, which leads to trisubstituted γ-butyrolactones via spontaneous cyclization of the initially formed 1,33b diols. During our study, we have observed that carrying out the allylation in some solvents, and especially in the presence of certain N-ligands, in contrast to reactions carried out in the absence of N3a 3c ligand in THF:HMPA mixture or with addition of N-MI in 9:1 THF:EtOH solution, favors the formation of isomeric enediols bearing (3E)-configured double bond and altered configuration of the stereogenic center at the C6 carbon atom. The notion that the possibility of selective synthesis of such alternatively configured enediols, amino alcohols, and homoallylic alcohols would greatly expand the scope of these desirable compounds from β-lactams prompted us to examine more deeply this potentially useful variant of the transformation. Indeed, further study confirmed that the diastereoselectivity of the allylations and crotylations of aldehydes with β-lactam-derived -amido-allylindiums can be effectively altered by a ligand switch, providing (3E)-2,5-syn-2,6-anti-, (3E)-2,5-anti-2,6-anti-, and (3E)-2,5-anti-2,6-syn-substituted enediols, amino alcohols, and homoallylic alcohols in high yields and with moderate to excellent diastereoselectivity. It should be pointed out that, while stereoselectivity control by a N-ligand switch in the related Pd(0)/InI-induced allenylations of aldehydes with 4-ethynyl-β-lactams leading to chiral 2,67 allenediols has been recently reported by our group, to the best of our knowledge, examples of analogous possibility in the Pd/InI mediated allylations and crotylations have not been reported so far. It is noteworthy that although active azetidin-2-ones are relatively often used as chiral building blocks for the synthesis of different types of organic compounds, in the majority of reports in this field, the 8 stereoselective reactions of electrophilic β-lactams with different classes of nucleophiles are applied. In contrast, the reactions of azetidin-2-ones with electrophilic partners, including the method of their 3,7,8-9 umpolung with InI in the presence of a Pd(0) catalyst developed by our group, are seldom reported. RESULTS AND DISCUSSION Racemic N-Ts-4-(E)-propenylazetidin-2-one 1, readily accessible from commercially available 3c substrates was chosen as a model β-lactam and benzaldehyde was used as a model electrophile. As reported, the application of 2 equiv. of benzaldehyde, 2 equiv. of InI and 5 mol% Pd(PPh3)4 in THF at ° 25 C to β-lactam 1 leads to only partial conversion of 1, low yield and inefficient (Z)/(E)-selectivity (51%, (Z):(E) = 43:57, Table 1, entry 1). However, the addition of 2 equiv. of N-MI ligand efficiently accelerates the reaction, allowing full conversion within 3 h and a noticeable increase in diastereoselectivity in favor of 3c (3Z)-substituted enediol 2b (76%, (Z):(E) = 84:16, Table 1, entry 2). In order to ascertain whether it possible to alter the (Z)/(E)–selectivity of the model reaction by a proper change in the reaction conditions, a series of experiments using a variety of simple N-ligands were carried out. The most significant of the obtained results are collected in Table 1, entries 3-9. Similarly to N-MI, the use of other heteroaromatic N-ligands, i.e. pyridine and isoquinoline favored the formation of (Z)-substituted 2,6enediol 2b (Table 1, entries 4 and 5). Quinoline, whose application delivered desired (3E)-enediol 2a as a major product in 69% yield, with high 2,5-syn-2,6-anti-diastereoselectivity (92:8 d.r., Table 1, entry 5), was an exception. However, in this case the product was contaminated with 8% of inseparable 58:42 mixture of two C5-epimers, probably as a result of partial epimerization of the intermediate -amido-allylindium under these conditions. On the other hand, the use of aliphatic tertiary amines in every case led to preferable formation of the desired (3E)-enediol 2a (Table 1, entries 6-8). Among these, the application of 2 equiv. of Et3N with respect to the β-lactam appeared most efficient. Under these conditions, full conversion of azetidin-2-one 1 occurred within 1 hour and the desired (3E)-2,5-syn-2,6-anti-enediol 2a was delivered in 75% yield, high 84:16 (E):(Z)-selectivity, and very efficient remote 1,4,5-asymmetric induction (d.r. (E) = 95:5, Table 1, entry 6). While the use of DIPEA gave comparable results (Table 1, entry 7), the application of quinuclidine appeared ineffective, since only partial conversion of β-lactam 1 was observed within 24 h and the isolated product was contaminated with 8% of additional two C5epimers in 70:30 ratio (Table 1, entry 8). Further experiments involving Et3N in a number of solvents,


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including NMP and 3:1 THF:DMPU mixture which appeared to enhance (3E)-selectivity in our previous 3a investigation as well as 9:1 THF:EtOH mixture which proved optimal for the previously reported 3c synthesis of (3Z)-enediols failed since in all cases noticeable reduction in yield and/or selectivity was observed (Table 1, entries 9-11). Finally, a series of reactions using different InI and Et3N quantity and ratio let us establish that the addition of 3 equiv. of InI and the same amount of Et3N with respect to the βlactam is optimal. Using this method, the desired (3E)-substituted enediol 2a was obtained in 81% yield, with high (3E)- and excellent 2,5-syn-2,6-anti-stereoselectivity ((E):(Z) = 91:9, d.r (E) = 95:5, Table 1, entry 12). On the other hand, competitive (Z)-enediol 2b was formed only in 8% yield as virtually single 1 diastereomer. Since further study revealed that the formation of small quantities (4-9% according to H NMR of crude reaction mixtures) of (3Z)-substituted enediols corresponding to their (3E)-isomers is 3a,3c general and all of these compounds were fully characterized during our previous study, in the further investigation these compounds were not isolated nor characterized. It should be pointed out that in every case, compound 2a and all other (E)-enediols obtained from β-lactam 1 presented in this study contained about 4-5% of additional two C5-epimers as a consequence of incomplete diastereomeric purity of this substrate (95:5 d.r.), which is detailed in further paragraphs. Importantly, in all conducted experiments, isomers of products varying in the double C-C bond configuration could be separated through column chromatography; this wasn’t the case with diastereomers differing only in the configuration of the newly formed stereogenic centers at C-5 and/or C-6. Table 1. Pd(PPh3)4/InI-mediated crotylation of benzaldehyde with β-lactam 1-derived -amidoallylindium. Optimization of the reaction conditions.

entry

Solvent

additive

time [h]

conversion [%]

2a yielda,b [%]; (d.r.)c

2b yielda [%]; (d.r.)c

1 2 3 4 5 6 7 8 9 10 11 12

THF THF THF THF THF THF THF THF NMPg 3:1 THF:DMPUg 9:1 THF:EtOHg THFg,h

--N-MId pyridine isoquinoline quinoline Et3N DIPEA quinuclidine Et3N Et3N Et3N Et3N

24 3 3 3 6 1 1 24 1 1 1 1

53 100 100 100 100 100 100 44 100 100 100 100

29 (88:12) 12 (72:28) 26 (90:10) 21 (87:13) 69e (92:8) 75 (95:5) 73 (94:6) 30f (93:7) 66 (92:8) 69 (95:5) 76 (89:11) 81 (95:5)

22 (≥ 97:3) 64 (≥ 97:3) 64 (≥ 97:3) 63 (≥ 97:3) 22 (≥ 97:3) 8 (≥ 97:3) 8 (≥ 97:3) 11 (≥ 97:3) 26 (≥ 97:3) 25 (≥ 97:3) 16 (≥ 97:3) 8 (≥ 97:3)

a

Isolated yield. b Containing 4-5% of two C5-epimers according to 1H NMR. c Assayed by 1H NMR integration. d N-Methylimidazole. Containing 8% of two C5-epimers (58:42 d.r.) according to 1H NMR. f Containing 8% of two C5-epimers (70:30 d.r.) according to 1H NMR. g 3 equiv. of InI was used. h 3 equiv. of Et3N was used. e


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Scheme 1. Pd(PPh3)4/InI/Et3N-mediated crotylation of aromatic and aliphatic aldehydes with βlactam 1-derived -amido-allylindium. The effect of aldehyde structure.

Next, a variety of aliphatic and (hetero)aromatic aldehydes were subjected to the reaction with βlactam 1 under optimized conditions in order to determine the aldehyde effect on the crotylation outcome (Scheme 1). All of the reactions involving aromatic aldehydes, electron-rich or deficient, afforded the desired (3E)-enediols as major products in high 79 – 82% yields and with excellent, ≥ 94:6, 2,5-syn-2,6anti-selectivity (Scheme 2, structures 2a, 3-5). Also reactions with heteroaromatic furfural and thiophene2-carbaldehyde proceeded efficiently, affording the corresponding products in good yield and with very effective remote 1,4,5-asymmetric induction (68-74 %, ≥93:7 d.r. Scheme 2, structures 6-7). Although the application of primary and secondary aliphatic aldehydes delivered the desired products in high 84-88% yield as well, only in the case of the secondary ones the high 2,5-syn-2,6-anti-selectivity was retained (≥96:4 d.r., Scheme 1, structures 10-11). In the cases of the primary propionaldehyde and especially dihydrocinnamaldehyde, the 2,6-anti-diastereoselctivity was significantly reduced (70:30 d.r., Scheme 1, structures 8-9). An attempt to improve it in the former example through the replacement of Et3N with more bulky DIPEA was unsuccessful since only further decrease in selectivity was found (55:45 d.r.; Scheme 1, structure 8). The application of tertiary pivalaldehyde, in turn, delivered the expected enediol 12 in only moderate 55% yield, although with quite effective 1,4,5-stereocontrol (90:10 d.r., Scheme 1, structure 12). Unfortunately, the product was contaminated with 13% of an inseparable mixture of two C5-epimers in 68:32 ratio, indicating partial epimerization of the -amido-allylindium intermediate in this case, most likely due to reduced addition rate caused by severe steric hindrance of the t-Bu substituent. On the other hand, the use of α,β-unsaturated 3-methylbut-2-enal delivered the corresponding adduct in high yield and with a useful level of diastereoselectivity (82%, 85:15 d.r, Scheme 1, structure 13). What is important, the subjection of the enantioenriched β-lactam (+)-1 (99% ee according to HPLC) to the reaction with benzaldehyde or isobutyric aldehyde under optimized conditions delivered the expected (E)-enediols (+)2a and (+)-10a in comparable yield and with the same excellent optical purity, which was proved by


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a F{ H} NMR study of Mosher’s esters derived from them. Since a broad range of chiral azetidin-2-ones 10 are readily available in both enantiomeric forms, these examples shows that the presented method can be used in asymmetric synthesis. Scheme 2. Pd(PPh3)4/InI/Et3N-mediated crotylation of benzaldehyde with β-lactam 1, 14-16 derived -amido-allylindiums. The effect of β-lactam configuration.

In order to determine the influence of β-lactam chirality on the reaction outcome, a number of reactions applying cis- and trans-substituted 4-propenylazetidin-2-ones 1 and 14-16 differing in relative double C=C bond configuration were conducted, which led to quite surprising results (Scheme 2). Although the application of β-lactams 1 and 14 provided a mixture of epimeric (3E)-enediols 2a and 2a’ with the former one in predominance, as expected, in contrast to previously disclosed analogous allylations conducted in 3c the presence of N-MI ligand leading to (3Z)-enediols, different product ratios were obtained from each substrate (Scheme 2, Figure 1). This disparity proved even more vivid in the case of reactions of a pair of β-lactams 15-16 where different C6-epimers 17 and 17’ were obtained as major products in each case 3c 1 (Scheme 2, Figure 1). Analogously to our previous study, careful H NMR spectra analysis of the obtained products showed that there are slight but not equal quantities of isomers 17 and 17’ visible in the spectra of compounds 2 and 2a’ obtained from substrates 1 and 14, and analogously compounds 2a and 2a’ in the mixtures of products 17 and 17’, resulting from reactions of β-lactams 15-16 (Figure 1). However, these apparently are the products of the reactions of the geometrical isomers of the starting βlactams 1 and 14-16 present in the samples in small but not equal amounts (d.r. (Z):(E) = 95:5, 91:9, 96:4 and 98:2 for 1, 14, 15, and 16, respectively), since their quantities virtually correspond to each other. 3c Thus, similarly to the previous account, also the results presented above point towards highly stereoselective formation of two different pairs of configurationally stable isomeric -amido-allylindiums from the corresponding two pairs of substrates, reacting with benzaldehyde in the subsequent crotylation 11 step. However, obtaining (3E)-enediols 2a-2a’ or 17-17’ in a different ratio using differently configured pairs of substrates 1, 15 or 16-17, respectively, shows that the equilibration between the initially formed pairs of organoindiums is faster only in the former case and noticeably slower in the latter one, than their subsequent addition to the aldehyde. This stays in sharp contrast to disclosed previously analogous (3Z)3c selective reactions, which proceed under thermodynamic control exclusively. In consequence, the scope of the isomeric (3E)-enediols potentially available from β-lactams 1, 15-17 is substantially broader in 3c comparison to their (3Z)-isomers.


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Figure 1. H NMR study of Pd(PPh3)4/InI/Et3N-mediated crotylation of benzaldehyde with β-lactam 1, 14-16-derived -amido-allylindiums. Scheme 3. Pd(PPh3)4/InI/Et3N-mediated crotylation of benzaldehyde with β-lactam 1 and 14-16derived -amido-allylindiums. Possible reaction pathway.

A mechanistic rationale of the above reactions, based on the observed regio- and stereoselectivity in the products, is depicted in Scheme 3. In the first step, Pd(PPh3)4-initiated stereoselective C4-N azetidin-2one bond cleavage occurs with inversion of configuration to deliver transient π-allylpalladium(II) complex which, via subsequent reductive transmetalation with active InI-Et3N species proceeding with retention of 3c the stereochemistry, results in the formation of four isomeric chiral -amido-allylindiums trans-(E), cis(Z), cis-(E), and trans-(Z), depending on whether β-lactams 1 or 14-16 were used. The chelation of 12 indium with the N-Ts-carboxamide function locates the metal atom in the γ position in all cases. As a consequence, the addition occurs on the other terminus of the allyl system, which is revealed in the 1-3 unusual α-regioselectivity of the transformation. Assuming the addition of these four isomeric intermediates occurs via corresponding bicyclic, rigid transition states ts-1-ts-4, in which the group next to 13 the indium adopts the equatorial position, depending on the substrate used, four different enediols may be formed. However, due to relatively fast equilibration between trans-(E) and cis-(Z) cyclic -amidoallylindiums generated from β-lactam 1 and 14, respectively, under the reaction conditions, and significant


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disparity in energy between these two intermediates, the equilibrium is shifted towards the thermodynamically favored trans-(E) isomer in these cases. Thus, (3E)-2,5-syn-2,6-anti-enediol 2a is formed via ts-1 transition state as major product regardless of whether -lactam 1 or 14 is applied, albeit only with moderate diastereoselectivity from the latter one. In the case of reactions of β-lactams 15 and 16, in turn, the apparently slower equilibration between the corresponding pair of -amido-allylindiums cis-(E) and trans-(Z) with regard to addition to aldehyde rate causes one of the two different products to be formed in predominance, depending on which β-lactam was applied. Scheme 4 Pd(PPh3)4/InI/Et3N-mediated crotylation of benzaldehyde with β-lactam 1 and 18-25derived -amido-allylindiums. The effect of allyl moiety substitution.

Next, the effect of the allyl moiety substitution on the allylation result was investigated. For this purpose, a number of azetidin-2-ones differing in double C-C bond substitution (positions α and β) or with additional methyl substituent at C4 of the azetidin-2-one ring (position γ) were synthesized and combined with benzaldehyde under optimized reaction conditions (Scheme 4). When azetidin-2-one 18, with an (E)oriented i-Pr group at the α position of the vinyl moiety was used, the desired (3E)-enediol 26 was obtained in noticeably lower yield, but with exceptionally efficient diastereoselectivity. This example shows that -lactams with larger aliphatic groups can be applied as well (60%, 98:2 d.r., Scheme 4, structure 26). Also azetidin-2-one 19 with an (E)-oriented phenyl group at the same location was tolerated since the expected product 27 was obtained in good yield, although with somewhat reduced 2,5-syn-2,6anti-selectivity (68%, 74:26 d.r., Scheme 4, structure 27). On the other hand, β-lactam 20 with ethyl ester in the same position appeared incompatible with the developed reaction conditions, since the expected product 28 was isolated in only 21% yield with 82:18 2,5-syn-2,6-anti-selectivity (Scheme 4, structure 28). Also the application of azetidin-2-one 21 bearing a methyl group in the β position appeared moderately successful since the desired triply substituted (3E)-enediol 29 was obtained in only 51% yield and with modest 75:25 2,6-anti-selectivity (Scheme 4, structure 29). As in our previous study on the synthesis of 3c (3Z)-substituted enediols, substrate 22 with an acetoxy group in the β position as well as β-lactam 23 bearing two methyl substituents in the α and β positions proved inert under our reaction conditions, most likely due to insufficient electrophilicity of the C=C double bond in these compounds, caused by the presence of strongly electron-donating acetoxy group in 22 and two moderately electron-donating methyl substituents in 23, which result in insufficient reactivity toward the nucleophilic Pd(PPh3)4 catalyst. On the


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other hand, the application of cis- and trans-substituted β-lactams 24 and 25 bearing a methyl substituent at the quaternary C-4 of the azetidin-2-one ring (γ-position) led to the formation of the desired triply substituted enediol 32 in high >80% yield and good >80:20 2,6-anti-selectivity in both cases (Scheme 4, structure 32). It should be pointed out that in contrast to the analogous reactions of pairs of cis- and transsubstituted 4-(E)-propenyl-β-lactams 1, 15 and 14, 16 described in previous paragraphs (Schemes 2 and 3, Figure 1), reactions of compounds 24 and 25 led to the formation of exactly the same products in comparable yields and selectivities. The disparity is due to the lack of (Z)- or (E)-oriented methyl substituents at the α position of the vinyl moiety, which results in the loss of stereochemical information coming from the β-lactam relative configuration in the course of the seemingly quick equilibration preceding the addition step (Scheme 5). Further investigation showed that this is always the case when β-lactams unsubstituted at the vinyl α position are used. It is noteworthy that, due to very high (> 98:2 d.r.) diastereomeric purity of the starting β-lactams 18-20, in contrast to β-lactams 1 and 14-16-derived (E)enediols 2a, 3-13, 17 and 17’, compounds 26-28 are not contaminated with the corresponding mixture of two C5-isomers. This further confirms the high stereoselectivity of formation and configurational stability of intermediate -amido-allylindiums under the developed reaction conditions, which was discussed in previous paragraphs. Scheme 5. Pd(PPh3)4/InI/Et3N-mediated allylation of benzaldehyde with β-lactam 24 and 25-derived -amido-allylindiums. Possible reaction pathway.

Scheme 6. Pd(PPh3)4/InI/Et3N-mediated allylation of benzaldehyde with β-lactam 33-40-derived amido-allylindiums. The effect of protective group at nitrogen atom and C3 β-lactam substitution.


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Finally, in order to explore the influence of the substitution of the azetidin-2-one ring on the allylation result, β-lactams 33-40, differing in nitrogen atom and C3 substitution were synthesized and combined with benzaldehyde under the developed reaction conditions (Scheme 6). As expected, among substrates with Ms, Ts, PMP, and Boc activating/protective groups, only the first two proved to be sufficiently active under our reaction conditions. Using these substrates, the expected (3E)-2,6-anti-enediols 41 and 42 were obtained in good yields as well as, especially in the case of product 41, with acceptable level of 2,6anti-selectivity (≥ 68%, ≥ 73:27 d.r., Scheme 6, structures 41-42). In contrast to the above, Boc- and 3 PMP-protected azetidin-2-ones 35 and 36, similarly as in our previous study, appeared inert also under the newly developed conditions. This confirms that the presence of a strongly electron-withdrawing function at the nitrogen atom of the β-lactam ring is crucial. Similarly to substrate 33 with an OTIPS group, also cis- and trans-substituted azetidin-2-ones 38 and 40 bearing an i-Pr substituent at C3 of azetidin-2one ring afforded the expected (3E)-enediols in high yields and with high 2,6-anti-stereoselectivities. This shows that β-lactams with other bulky substituents at this position are just as useful (≥ 71%, ≥ 90:10 d.r. Scheme 6, structure 46). On the other hand, the use of β-lactam 37 with smaller methyl substituent, due to significantly faster competitive β-elimination, delivered the desired product 45 in low 43% yield and with reduced 70:30 2,6-anti-selectivity (Scheme 6, structure 45). Importantly, the application of azetidin-2-one 39 with C-3 phthalimide-protected amino group delivered the expected (3E)-2,6-anti-amino alcohol 47 in moderate 54% yield and with good 86:14 2,6-anti-diastereoselectivity. This result exhibits the potential of the method in the asymmetric synthesis of this type of organic features difficult to prepare in another 14 manner (Scheme 6, Structure 47). Scheme 7. Synthesis of 1,5-diols 48-49 and 3,6,7-trisubstituted caprolactones 50-51.

Semi-protected differently configurated enediols, amino alcohols, and homoallylic alcohols with 4 internal (3E)-substituted double bond and readily modifiable N-Ts-carboxamide function could serve in the asymmetric synthesis of a variety of linear derivatives as well as carba- and heterocyclic compounds of different ring size and substitution pattern. As a simple example of application of enediol 2a and 17’ in 15 synthesis, chiral caprolactones 50-51 with three stereogenic centers in the ring were prepared using 3c a previously reported method (Scheme 7). Such heterocycles constitute an important structural motif found in a range of natural products, as well as their synthetic analogues exhibiting interesting 16 pharmacological activity, which makes them highly desirable. Catalytic hydrogenation of double C=C bond in enediols 2a and 17 delivered epimeric 1,5-diols 48-49 in high yield. Subsequent chemoselective


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methylation of the amide function in these compounds under PTC conditions followed by cyclization 17 involving an alkoxide generated in situ afforded the desired caproactones 50-51 in 71% and 57% yield, respectively. It should be pointed out that compounds 50-51 are the isomers of caprolactone 52 derived from the corresponding (3Z)-enediol 2b obtained according to the previously reported protocol involving 3c N-MI, which emphases the complementarity of both procedures. Different methods were used to establish the configuration of the obtained products. The (Z)- and (E)configured isomers with disubstituted C=C bonds were easily distinguished by an analysis of coupling 1 constants of the olefin protons in H NMR spectra (J~10 Hz for (Z)- and J~15 Hz for (E)-isomers). Configuration of (3E)-enediols bearing the triply substituted C=C bond were assigned according to NOE 18 1 measurements. Also d.r. of all obtained allylation/crotylation products was determined using H NMR spectroscopy. The relative configurations of enediols 2a, 17, 32, amino alcohol 47, homoallylic alcohols 1 13 1 41-42, 45-46, diols 48-49 and caprolactones 50-51 were assigned by H NMR and C{ H} NMR spectra 3a,3c comparison with previously reported data. The relative configuration of enediol 12 was established 18 directly using X-ray diffractometry. The relative configurations of other (3E)-enediols were assigned by analogy. CONCLUSIONS We demonstrated that the switch from N-MI to Et3N N-ligand in the Pd(0)/InI promoted allylations and crotylations of aldehydes with β-lactam-derived -amido-allylindiums effectively alters the diastereoselectivity in these transformations. In contrast to previously disclosed (3Z)-selective processes, 3c which proved to proceed under thermodynamic control, the newly developed (3E)-selective variant delivers kinetic or thermodynamic products depending on the relative configuration of the β-lactam applied. As a result, efficient entry to a range of previously unavailable (3E)-2,5-syn-2,6-anti-, (3E)-2,5anti-2,6-syn- and (3E)-2,5-anti-2,6-anti-enediols, amino alcohols, and homoallylic alcohols has been opened. The products are obtained in modest to high yield and with moderate to excellent diastereoselectivities depending on β-lactam structure and aldehyde type used. What is important, the use of the enantioenriched azetidin-2-ones under the developed reaction conditions delivered the desired products with the same excellent optical purity. This shows that the developed method may find application in asymmetric synthesis, since a broad range of chiral azetidin-2-ones are readily available in 10 both enantiomeric forms. The synthetic potential of the obtained highly functionalized isomeric (3E)enediols in the stereodivergent synthesis was exhibited in the preparation of differently configured chiral caprolactones bearing three stereogenic centers in the ring, unavailable from the corresponding (3Z)3c enediol prepared according to the previously reported protocol. Further elaboration of the methodology presented and its application in asymmetric synthesis of other types of heterocycles and selected natural compounds is currently in progress.

EXPERIMENTAL SECTION General remarks. InI was purchased from Sigma Aldrich and powdered in a mortar prior to use. Other reagents were purchased from ABCR, Acros, Alfa Aesar or Sigma Aldrich and used as received. Dry solvents were obtained by distillation over Na/benzophenone (THF) or CaH 2 (CH2Cl2). Air- and moisture-sensitive reactions were conducted in oven-dried glassware under an atmosphere of argon. Column chromatography was carried out using Kiesel gel (230-400 mesh). Analytical TLC was performed on Silica gel 60 F254 aluminium plates (Merck, Darmstadt). Indication was achieved with UV light (λ =254


10

Page 11 of 21 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


nm) and common dip stains (potassium permanganate or cerium ammonium molybdate). NMR spectra were recorded on Varian Mercury 400 MHz or Varian VNMRS 500 MHz spectrometers in CDCl3, C6D6 or MeOH-d4 solutions. Chemical shifts are quoted on the δ scale, ppm, and are calibrated using residual 1 13 1 solvents signals ( H NMR: CDCl3: 7.26 ppm, C6D6: 7.16 ppm, MeOH-d4 3.31 ppm; C { H} NMR: CDCl3: 1 77.16 ppm, C6D6: 128.06 ppm; MeOH-d4 49.00 ppm). Multiplicities for H NMR signals are described using the following abbreviations: s = singlet, d = doublet, t = triplet, q = quartet, quint = quintet, sep = septet, m = multiplet, br = broad signal. Coupling constants, J, are given in Hertz (Hz). Infrared spectra -1 (IR) were measured on a FT-IR-1600-Perkin Elmer spectrophotometer and are reported in cm . The samples were prepared as thin films using solutions in CH 2Cl2. High resolution mass spectra (HRMS) were obtained on ESI-TOF Mariner spectrometer (Perspective Biosystem) and are given in m/z. Melting points (m.p.) were determined with Melting Point Meter MPM-H2 apparatus and are uncorrected. Optical rotations [α] were measured on Jasco P-2000 Polarimeter in a quartz glass cuvette at λ = 589 nm (Na D3c 3c 3c 3c 3a 3b line). Concentrations [c] are given in g/100 mL. β-Lactams 1 , (+)-1 , 14-16 , 18-25 , 33 , 34 , 3519 3c 36 , 37-40 were prepared following the previously reported procedures and their analytical data were consistent with those published in the literature. Pd/InI/Et3N promoted additions of β-lactams to aldehydes. Syntheses of (3E)-enediols 2a, (+)2a, 3-10, (+)-10, 11-13, 17, 17’, 26-29, 32, 41-42, (3E)-homoallylic alcohols 45-46 and aminoalcohol 47. General procedure. To a vigorously stirred mixture of N-Ts- or N-Ms-β-lactam (0.125 mmol), aldehyde (0.25 mmol) and InI (90.7 mg, 0.375 mmol) in anhydrous THF (2 mL), Et3N (52 µL, 0.375 mmol) and Pd(PPh3)4 (7.2 mg, 6.25 ° µmol) were sequentially added in one portion at 25 C under an argon atmosphere. The stirring was continued at the same temperature until full conversion of the starting β-lactam was observed (TLC monitoring, 1-12 hours). Reaction was then quenched with 1M aqueous HCl solution (2 mL), poured into water and extracted with EtOAc (3 x 10 mL). The combined extracts were washed successively with water (30 mL), saturated solution of NaHCO3 (30 mL) and brine (30 mL), dried over anhydrous MgSO 4 and concentrated under reduced pressure. Purification of the crude product by column chromatography 20 on silica gel using acetone/hexane, ethyl acetate/hexane with addition of 0.5% v/v HCO 2H or 20 MTBE/hexane with addition of 0.5% v/v HCO2H mixture as eluent afforded desired enediol, homoallylic alcohol or amino alcohol as colorless crystals or colorless wax. (2R*,5R*,6R*,E)-6-hydroxy-5-methyl-6-phenyl-N-tosyl-2-((triisopropylsilyl)oxy)hex-3-enamide (2a). 21 22 Starting from 1: Yield: 55.3 mg (81%) ; 96:4 d.r.; Starting from 16: Yield 51.2 mg (75 %) , 67:33 d.r.; colorless wax; Rf (25% acetone/hexane) 0.60; Analytical data were consistent with previously reported 1 values. (2R,5R,6R,E)-6-hydroxy-5-methyl-6-phenyl-N-tosyl-2-((triisopropylsilyl)oxy)hex-3-enamide ((+)-2a). Yield: 22 49.8 mg (73%); 93:7 d.r.; colorless wax; Rf (25% acetone/hexane) 0.60; [α]D = + 74.8 (c = 0.94, CHCl3); >98% ee; NMR and IR spectra were consistent with those recorded for the racemate. HRMS (ESI-TOF) m/z + calcd for C29H43NNaO5SSi [M + Na ] 568.2529. Found 568.2513. (2R*,5R*,6R*,E)-6-hydroxy-6-(4-methoxyphenyl)-5-methyl-N-tosyl-2-((triisopropylsilyl)oxy)hex-3-enamide 21 1 (3). Yield: 59.0 mg (82 %) ; 94:6 d.r; colorless wax; Rf (30% acetone/hexane) 0.60; H NMR (400 MHz, CDCl3) δ: 9.03 (br s, 1H), 8.07 – 7.76 (m, 2H), 7.39 – 7.27 (m, 2H), 7.23 – 7.14 (m, 2H), 6.93 – 6.83 (m, 2H), 5.80 (dd, J = 15.5, 8.2 Hz, 1H), 5.47 (dd, J = 15.5, 6.2 Hz, 1H), 4.58 (d, J = 6.2 Hz, 1H), 4.30 (d, J = 7.5 Hz, 1H), 3.80 (s, 3H), 2.49 – 2.38 (m, 1H), 2.42 (s, 3H), 2.00 (br s, 1H), 1.13 – 0.97 (m, 21H), 0.82 (d, 13 1 J = 6.8 Hz, 3H); C{ H} NMR (101 MHz, CDCl3) δ: 169.8, 159.3, 145.3, 137.4, 135.6, 134.5, 129.6, 128.5, 128.1, 128.0, 113.8, 77.8, 75.4, 55.4, 44.7, 21.8, 17.94, 17.88, 16.4, 12.1; IR (film) v: 3520, 3354,


11


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-1

2944, 288, 1732, 1612, 1513, 1408, 1249, 1177, 1088, 882, 663, 549 cm ; HRMS (ESI-TOF) m/z calcd + for C30H45NNaO6SSi [M + Na ] 598.2635. Found 598.2625. (2R,5R,6R,E)-6-(4-cyanophenyl)-6-hydroxy-5-methyl-N-tosyl-2-((triisopropylsilyl)oxy)hex-3-enamide (4). 21 ° Yield: 56.4 mg (79%) ; 94:6 d.r.; colorless crystals; mp = 149.3-151.9 C; Rf (30% acetone/hexane) 0.60; 1 H NMR (400 MHz, CDCl3) δ: 8.98 (br s, 1H), 7.98 – 7.87 (m, 2H), 7.63 – 7.57 (m, 2H), 7.41 – 7.36 (m, 2H), 7.35 – 7.30 (m, 2H), 5.72 (ddd, J = 15.4, 8.3, 1.3 Hz, 1H), 5.43 (ddd, J = 15.4, 6.2, 0.9 Hz, 1H), 4.54 (dd, J = 6.2, 1.3 Hz, 1H), 4.47 (d, J = 6.6 Hz, 1H), 2.50-2.38 (m, 1H), 2.43 (s, 3H), 1.10 – 0.94 (m, 21H), 13 1 0.90 (d, J = 6.8 Hz, 3H); C{ H} NMR (101 MHz, CDCl3) δ: 169.7, 147.7, 145.4, 135.8, 135.5, 132.2, 129.7, 129.0, 128.5, 127.5, 118.9, 111.5, 77.2, 75.3, 44.6, 21.8, 17.9, 16.3, 12.0; IR (film) v: 3505, 3353, -1 2944, 2868, 2228, 1730, 1461, 1408, 1352, 1176, 1160, 1089, 881, 816, 661, 549 cm ; HRMS (ESI-TOF) + m/z calcd for C30H42N2NaO5SSi [M + Na ] 593.2481. Found 593.2470. (2R*,5R*,6R*,E)-6-Hydroxy-5-methyl-6-(naphthalen-2-yl)-N-tosyl-2-((triisopropylsilyl)oxy)hex-3-enamide 21 1 (5). Yield: 59.6 mg (80%) ; 95:5 d.r.; colorless wax; Rf (30% acetone/hexane) 0.60; H NMR (400 MHz, CDCl3) δ: 9.02 (br s, 1H), 8.00 – 7.90 (m, 2H), 7.88 – 7.78 (m, 3H), 7.76 – 7.69 (m, 1H), 7.50 – 7.46 (m, 2H), 7.44 – 7.41 (m, 1H), 7.33 – 7.28 (m, 2H), 5.84 (ddd, J = 15.5, 8.1, 1.4 Hz, 1H), 5.53 (ddd, J = 15.5, 6.2, 1.0 Hz, 1H), 4.59 (dd, J = 6.2, 1.4 Hz, 1H), 4.53 (d, J = 7.5 Hz, 1H), 2.66 – 2.52 (m, 1H), 2.42 (s, 3H), 1 13 2.12 (br s, 1H), 1.14 – 0.93 (m, 21H), 0.87 (d, J = 6.9 Hz, 3H); C{ H} NMR (101 MHz, CDCl3) δ: 169.8, 145.3, 139.8, 137.0, 135.6, 133.32, 133.28, 129.7, 128.5, 128.4, 128.3, 128.1, 127.8, 126.3, 126.0, 125.9, 124.6, 78.3, 75.4, 44.5, 21.8, 17.9, 17.8, 16.5, 12.1; IR (film) v: 3538, 3353, 2944, 2867, 1731, 1599, -1 1462, 1407, 1352, 1177, 1089, 881, 817, 662, 549 cm ; HRMS (ESI-TOF) m/z calcd for C33H45NNaO5SSi + [M + Na ] 618.2685. Found 618.2660. (2R*,5R*,6R*,E)-6-(Furan-2-yl)-6-hydroxy-5-methyl-N-tosyl-2-((triisopropylsilyl)oxy)hex-3-enamide (6). 21 1 Yield: 45.5 mg (68%) ; 93:7 d.r.; colorless wax; Rf (30% acetone/hexane) 0.50; H NMR (400 MHz, CDCl3) δ: 8.97 (br s, 1H), 7.99 – 7.85 (m, 2H), 7.35 (d, J = 1.8 Hz, 1H), 7.34 – 7.28 (m, 2H), 6.31 (dd, J = 3.2, 1.8 Hz, 1H), 6.22 (d, J = 3.2 Hz, 1H), 5.82 (ddd, J = 15.5, 8.0, 1.4 Hz, 1H), 5.50 (ddd, J = 15.5, 6.0, 1.0 Hz, 1H), 4.58 (dd, J = 6.0, 1.4 Hz, 1H), 4.41 (dd, J = 7.3, 3.6 Hz, 1H), 2.75 – 2.61 (m, 1H), 2.43 (s, 13 1 3H), 1.99 (br d, J = 3.6 Hz, 1H), 1.17 – 0.95 (m, 21H), 0.92 (d, J = 6.8 Hz, 3H); C{ H} NMR (101 MHz, CDCl3) δ: 169.8, 155.0, 145.3, 142.1, 136.3, 135.6, 129.7, 128.5, 128.4, 110.3, 107.4, 75.3, 71.7, 42.2, 21.8, 17.94, 17.91, 16.1, 12.1; IR (film) v: 3527, 3355, 2944, 2868, 1731, 1462, 1408, 1352, 1177, 1152, -1 + 1089, 882, 663, 549 cm ; HRMS (ESI-TOF) m/z calcd for C27H41NNaO6SSi [M + Na ] 558.2322. Found 558.2323. (2R*,5R*,6R*,E)-6-Hydroxy-5-methyl-6-(thiophen-2-yl)-N-tosyl-2-((triisopropylsilyl)oxy)hex-3-enamide (7). 21 1 Yield: 51.0 mg (74%) ; 94:6 d.r.; colorless wax; Rf (30% acetone/hexane) 0.50; H NMR (400 MHz, CDCl3) δ: 8.99 (br s, 1H), 8.01 – 7.84 (m, 2H), 7.35 – 7.28 (m, 2H), 7.24 (dd, J = 4.8, 1.5 Hz, 1H), 6.97 – 6.91 (m, 2H), 5.82 (ddd, J = 15.5, 8.1, 1.3 Hz, 1H), 5.52 (ddd, J = 15.5, 6.1, 1.0 Hz, 1H), 4.64 (dd, J = 7.5, 2.4 Hz, 1H), 4.59 (dd, J = 6.1, 1.3 Hz, 1H), 2.59 – 2.47 (m, 1H), 2.43 (s, 3H), 2.16 (br d, J = 2.4 Hz, 1H), 13 1 1.15 – 0.94 (m, 21H), 0.92 (d, J = 6.8 Hz, 3H); C{ H} NMR (101 MHz, CDCl3) δ: 169.7, 146.2, 145.3, 136.4, 135.6, 129.7, 128.7, 128.5, 126.6, 125.0, 124.9, 75.3, 74.1, 45.1, 21.8, 17.9, 16.4, 12.1; IR (film) v: -1 3534, 3355, 2944, 2867, 1731, 1461, 1408, 1352, 1177, 1159, 1089, 882, 690, 549 cm ; HRMS (ESI+ TOF) m/z calcd for C27H41NNaO5S2Si [M + Na ] 574.2093. Found 574.2083. (2R*,5R*,6S*,E)-6-Hydroxy-5-methyl-N-tosyl-2-((triisopropylsilyl)oxy)oct-3-enamide (8). Yield: 52.3 mg 21 21 (84%) ; 70:30 d.r. (8:8‘); Yield: 52.9 mg (85%, i-Pr2NEt was applied instead of Et3N); 55:45 d.r. (8:8‘); 1 colorless wax; Rf (30% acetone/hexane) 0.55; H NMR (400 MHz, CDCl3) δ: 8.98 (br s, 1H), 8.95 (br s, ‘ 1H ), 8.02 – 7.86 (m, 2H+2H‘), 7.37 – 7.28 (m, 2H+2H‘), 5.79 – 5.69 (m, 1H+1H‘), 5.47 – 5.37 (m,


12

Page 13 of 21 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


1H+1H‘), 4.58 – 4.52 (m, 1H+1H‘), 3.47 – 3.18 (m, 1H+1H‘), 2.43 (s, 3H+3H‘), 2.31 – 2.09 (m, 1H+1H‘), 1.53 – 1.39 (m, 1H+1H‘), 1.36 – 1.25 (m, 1H+1H‘), 1.13 – 0.96 (m, 24H+24H‘), 0.91 (t, J = 7.4 Hz, 13 1 3H+3H‘); C{ H} NMR (101 MHz, CDCl3) δ 169.9, 169.8, 145.3, 137.7, 137.0, 135.6, 129.7, 129.6, 128.5, 127.8, 126.9, 76.5, 76.4, 75.38, 75.36, 42.4, 42.2, 27.3, 21.8, 17.94, 17.93, 16.4, 14.7, 12.1, 10.3, 10.1; -1 IR (film) v: 3454, 3356, 2943, 2868, 1733, 1462, 1408, 1352, 1177, 1161, 1089, 880, 814, 662, 549 cm ; + HRMS (ESI-TOF) m/z calcd for C25H43NNaO5SSi [M + Na ] 520.2529. Found 520.2501. (2R*,5R*,6S*,E)-6-Hydroxy-5-methyl-8-phenyl-N-tosyl-2-((triisopropylsilyl)oxy)oct-3-enamide (9) and (2R*,5R*,6R*,E)-6-Hydroxy-5-methyl-8-phenyl-N-tosyl-2-((triisopropylsilyl)oxy)oct-3-enamide (9‘). 21 Inseparable mixture. Yield: 63.1 mg (88%) ; 50:50 d.r. (9:9’); colorless wax; Rf (30% acetone/hexane) 1 0.60; H NMR (400 MHz, CDCl3) δ: 8.99 (br s, 1H), 8.95 (br s, 1H‘), 8.01 – 7.87 (m, 2H+2H‘), 7.33 – 7.26 (m, 4H+4H‘), 7.22 – 7.15 (m, 3H+3H‘), 5.80 – 5.67 (m, 1H+1H‘), 5.51 – 5.37 (m, 1H+1H‘), 4.61 – 4.52 (m, 1H+1H‘), 3.55 – 3.24 (m, 1H+1H‘), 2.95 – 2.72 (m, 1H+1H‘), 2.70 – 2.55 (m, 1H+1H‘), 2.42 (s, 3H+3H‘), 2.30 – 2.14 (m, 1H+1H‘), 1.85 – 1.69 (m, 1H+1H‘), 1.69 – 1.56 (m, 1H+1H‘), 1.18 – 0.94 (m, 24H+24H‘). 13 1 C{ H} NMR (101 MHz, CDCl3) δ 169.9, 169.8, 145.3, 142.2, 142.1, 137.3, 136.9, 135.6, 129.7, 129.6, 128.59, 128.57, 128.56, 128.54, 128.48, 128.0, 127.2, 125.99, 125.96, 75.4, 75.3, 74.4, 74.2, 43.0, 42.7, 36.14, 36.08, 32.5, 32.2, 21.8, 17.94, 17.92, 16.3, 14.9, 12.1; IR (film) v: 3355, 2944, 2867, 1732, 1456, -1 1407, 1352, 1177, 1160, 1089, 881, 663, 549 cm ; HRMS (ESI-TOF) m/z calcd for C31H47NNaO5SSi [M + + Na ] 596.2842. Found 596.2817. (2R*,5R*,6S*,E)-6-hydroxy-5,7-dimethyl-N-tosyl-2-((triisopropylsilyl)oxy)oct-3-enamide (10). Yield: 53.7 21 1 mg (84 %) ; 95:5 d.r.; colorless wax; Rf (30% acetone/hexane) 0.50; H NMR (400 MHz, CDCl3) δ: 8.99 (br s, 1H), 8.08 – 7.79 (m, 2H), 7.33 – 7.28 (m, 2H), 5.78 (ddd, J = 15.5, 8.7, 1.3 Hz, 1H), 5.43 (ddd, J = 15.5, 6.3, 0.9 Hz, 1H), 4.56 (dd, J = 6.3, 1.3 Hz, 1H), 3.04 (t, J = 5.8 Hz, 1H), 2.43 (s, 3H), 2.34 – 2.23 (m, 1H), 1.70 – 1.56 (m, 1H), 1.14 – 0.99 (m, 21H), 0.97 (d, J = 6.8 Hz, 3H), 0.88 (d, J = 6.7 Hz, 3H), 0.88 (d, 13 1 J = 6.7 Hz, 3H); C{ H} NMR (101 MHz, CDCl3) δ 169.9, 145.2, 137.2, 135.6, 129.6, 128.5, 127.7, 79.8, 75.4, 40.1, 30.7, 21.8, 19.8, 17.9, 17.2, 16.7, 12.1; IR (film) v: 3357, 2959, 2868, 1733, 1463, 1408, 1353, -1 + 1176, 1158, 1089, 993, 882, 661, 549 cm ; HRMS (ESI-TOF) m/z calcd for C26H45NNaO5SSi [M + Na ] 534.2685. Found 534.2652. (2R,5R,6S,E)-6-Hydroxy-5,7-dimethyl-N-tosyl-2-((triisopropylsilyl)oxy)oct-3-enamide ((+)-10). Yield: 48.6 22 mg (76%); 93:7 d.r.; >98% ee; colorless wax; Rf (30% acetone/hexane) 0.50; [α]D = 34.8 (c = 1.35, CHCl3); NMR and IR spectra were consistent with those recorded for racemate; HRMS (ESI-TOF) m/z + calcd for C26H45NNaO5SSi [M + Na ] 534.2685. Found 534.2687. (2R*,5R*,6S*,E)-6-Cyclopentyl-6-hydroxy-5-methyl-N-tosyl-2-((triisopropylsilyl)oxy)hex-3-enamide (11). 21 1 Yield: 57.8 mg (86%) ; 96:4 d.r.; colorless wax; Rf (30% acetone/hexane) 0.55; H NMR (400 MHz, CDCl3) δ: 8.96 (br s, 1H), 8.07 – 7.80 (m, 2H), 7.35 – 7.28 (m, 2H), 5.83 (ddd, J = 15.5, 8.7, 1.3 Hz, 1H), 5.42 (ddd, J = 15.5, 6.1, 0.9 Hz, 1H), 4.56 (dd, J = 6.1, 1.4 Hz, 1H), 3.32 – 2.92 (m, 1H), 2.43 (s, 3H), 2.31 – 2.18 (m, 1H), 1.91 – 1.76 (m, 1H), 1.76 – 1.66 (m, 1H), 1.65 – 1.52 (m, 4H), 1.52 – 1.44 (m, 1H), 13 1 1.38 – 1.29 (m, 1H), 1.22 – 1.14 (m, 1H), 1.14 – 0.94 (m, 24H); C{ H} NMR (101 MHz, CDCl3) δ: 169.9, 145.2, 136.5, 135.6, 129.6, 128.5, 127.5, 79.4, 75.4, 43.9, 41.3, 29.2, 28.6, 25.8, 25.7, 21.8, 17.9, 17.5, -1 12.1; IR (film) v: 3357, 2946, 2868, 1734, 1461, 1408, 1353, 1177, 1159, 1089, 990, 881, 661, 549 cm ; + HRMS (ESI-TOF) m/z calcd for C28H47NNaO5SSi [M + Na ] 560.2842. Found 560.2842. (2R*,5R*,6R*,E)-6-Hydroxy-5,7,7-trimethyl-N-tosyl-2-((triisopropylsilyl)oxy)oct-3-enamide (12). Yield: 36.2 23 ° mg (55%) ; 90:10 d.r.; (97:3 d.r. after crystallization from hexane); colorless crystals; mp = 96.7-98.5 C; 1 Rf (30% acetone/hexane) 0.65; H NMR (400 MHz, CDCl3) δ: 8.96 (br s, 1H), 8.08 – 7.87 (m, 2H), 7.45 – 7.28 (m, 2H), 5.93 (ddd, J = 15.6, 8.8, 1.3 Hz, 1H), 5.31 (ddd, J = 15.6, 6.5, 0.9 Hz, 1H), 4.55 (dd, J = 6.5,


13


Page 14 of 21

1.3 Hz, 1H), 3.12 (d, J = 2.3 Hz, 1H), 2.62 – 2.46 (m, 1H), 2.43 (s, 3H), 1.16 – 0.96 (m, 24H), 0.84 (s, 9H); 1 C{ H} NMR (101 MHz, CDCl3) δ: 169.6, 145.2, 137.4, 135.7, 129.6, 128.5, 126.5, 83.2, 75.7, 38.3, 35.9, 26.7, 21.8, 21.1, 18.0, 12.1; IR (film) v: 3572, 3358, 2948, 2868, 1733, 1463, 1407, 1353, 1177, 1158, -1 + 1089, 990, 880, 662, 548 cm ; HRMS (ESI-TOF) m/z calcd for C27H48NO5SSi [M + H ] 526.3022. Found 526.3036. 13

(2R*,5R*,6R*,E)-6-Hydroxy-5,8-dimethyl-N-tosyl-2-((triisopropylsilyl)oxy)nona-3,7-dienamide (13). Yield: 21 1 53.7 mg (82%) ; 85:15 d.r.; colorless wax; Rf (30% acetone/hexane) 0.65; H NMR (400 MHz, CDCl3) δ (major C6-epimer): 9.03 (br s, 1H), 7.97 – 7.84 (m, 2H), 7.39 – 7.28 (m, 2H), 5.77 (ddd, J = 15.4, 8.3, 1.3 Hz, 1H), 5.46 (ddd, J = 15.4, 6.2, 1.0 Hz, 1H), 5.13 – 5.08 (m, 1H), 4.57 (dd, J = 6.2, 1.3 Hz, 1H), 4.06 (dd, J = 9.0, 7.1 Hz, 1H), 2.43 (s, 3H), 2.25 – 2.14 (m, 1H), 1.72 (d, J = 1.4 Hz, 3H), 1.67 (d, J = 1.4 Hz, 13 1 3H), 1.14 – 0.97 (m, 21H), 0.92 (d, J = 6.9 Hz, 3H); C{ H} NMR (101 MHz, CDCl3) δ (major C6-epimer): 169.9, 145.2, 137.4, 136.8, 135.6, 129.6, 128.5, 127.8, 125.6, 75.4, 71.8, 43.6, 26.0, 21.8, 18.6, 17.93, 17.86, 15.9, 12.1. IR (film) v: 3357, 2944, 2868, 1733, 1461, 1408, 1352, 1177, 1162, 1089, 882, 682, -1 + 661, 549 cm ; HRMS (ESI-TOF) m/z calcd for C27H45NNaO5SSi [M + Na ] 546.2685. Found 546.2687. (2R*,5S*,6S*,E)-6-hydroxy-5-methyl-6-phenyl-N-tosyl-2-((triisopropylsilyl)oxy)hex-3-enamide (17). 24 Starting from 15: Yield 52.3 mg (77 %) , 66:34 d.r. (17:17‘); colorless wax; Rf (25% acetone/hexane) 1 0.60; H NMR (400 MHz, CDCl3) δ (major C6-epimer): 8.97 (br s, 1H), 8.02 – 7.76 (m, 2H), 7.39 – 7.16 (m, 7H), 5.89 (ddd, J = 15.6, 7.7, 1.5 Hz, 1H), 5.48 (ddd, J = 15.6, 5.5, 1.1 Hz, 1H), 4.57 (dd, J = 5.5, 1.5 Hz, 1H), 4.39 (d, J = 6.9 Hz, 1H), 2.55 – 2.47 (m, 1H), 2.42 (s, 3H), 2.08 (br s, 1H), 1.13 – 0.91 (m, 21H), 13 1 0.85 (d, J = 6.8 Hz, 3H); C{ H} NMR (101 MHz, CDCl3) δ (major C6-epimer): 169.7, 145.2, 142.6, 136.3, 135.6, 129.6, 128.5, 128.4, 127.8, 127.7, 126.6, 78.1, 75.1, 44.0, 21.8, 17.9, 16.3, 12.0; IR (film) v: -1 3544, 3356, 2944, 2868, 1731, 1455, 1407, 1352, 1191, 1177, 1159, 1089, 881, 702, 662, 548 cm ; + HRMS (ESI-TOF) m/z calcd for C29H43NNaO5SSi [M + Na ] 568.2529. Found 568.2518. (2R*,5S*,6R*,E)-6-hydroxy-5-methyl-6-phenyl-N-tosyl-2-((triisopropylsilyl)oxy)hex-3-enamide (17‘). Starting from 16: Yield 51.2 mg (75 %), 70:30 d.r. (17‘:17); colorless wax; Rf (25% acetone/hexane) 0.60; 3c Analytical data were consistent with previously reported values. (2R*,5R*,E)-5-((R*)-hydroxy(phenyl)methyl)-6-methyl-N-tosyl-2-((triisopropylsilyl)oxy)hept-3-enamide 1 (26). Yield 43.0 mg (60 %), 98:2 d.r.; colorless wax; Rf (20% acetone/hexane) 0.40; H NMR (400 MHz, CDCl3) δ: 9.07 (br s, 1H), 7.98 – 7.91 (m, 2H), 7.38 – 7.24 (m, 7H), 5.82 (ddd, J = 15.5, 10.0, 1.4 Hz, 1H), 5.42 (dd, J = 15.5, 6.1 Hz, 1H), 4.63 (dd, J = 6.1, 1.4 Hz, 1H), 4.62 (d, J = 7.6 Hz, 1H), 2.42 (s, 3H), 2.12 (ddd, J = 10.0, 7.6, 4.6 Hz, 1H), 1.93 (br s, 1H), 1.59 – 1.46 (m, 1H), 1.20 – 0.98 (m, 21H), 0.80 (d, J = 13 1 6.8 Hz, 3H), 0.77 (d, J = 6.8 Hz, 3H); C{ H} NMR (101 MHz, CDCl3) δ: 169.8, 145.2, 142.8, 135.6, 132.4, 131.3, 129.7, 128.52, 128.50, 127.8, 126.8, 75.4, 75.1, 57.2, 28.2, 22.0, 21.8, 18.0, 12.1; IR (film) -1 v: 3527, 3357, 2956, 2868, 1732, 1462, 1408, 1353, 1191, 1177, 1157, 1088, 882, 702, 662, 549 cm ; + HRMS (ESI-TOF) m/z calcd for C31H47NNaO5SSi [M + Na ] 596.2842. Found 596.2839. (2R*,5S*,6R*,E)-6-hydroxy-5,6-diphenyl-N-tosyl-2-((triisopropylsilyl)oxy)hex-3-enamide (27). Yield: 51.7 ° mg (68%); 74:26 d.r. (27:27’); colorless crystals; mp = 116.5-118.7 C; Rf (30% MTBE/hexane + 0.5% 1 HCO2H) 0.40; H NMR (400 MHz, CDCl3) δ: 8.98 (br s, 1H), 8.75 (br s, 1H‘), 7.97 – 7.80 (m, 2H+2H‘), 7.38 – 7.13 (m, 8H+8H‘), 7.12 – 7.09 (m, 2H), 7.03 – 6.97 (m, 2H), 6.24 (ddd, J = 15.4, 8.7, 1.4 Hz, 1H), 5.88 (ddd, J = 15.5, 7.3, 1.5 Hz, 1H‘), 5.44 (ddd, J = 15.4, 6.1, 1.0 Hz, 1H), 5.15 (ddd, J = 15.5, 5.5, 1.4 Hz, 1H‘), 4.90 – 4.77 (m, 1H+1H‘), 4.60 (dd, J = 6.1, 1.4 Hz, 1H), 4.50 – 4.37 (m, 1H‘), 3.73 – 3.56 (m, 1H‘), 3.56 – 3.48 (m, 1H), 2.43 (s, 3H‘), 2.42 (s, 3H), 2.13 – 1.83 (br m, 1H+1H‘), 1.12 – 0.87 (m, 13 1 21H+21H‘); C{ H} NMR (101 MHz, CDCl3) δ: 169.6, 169.4, 145.2, 141.9, 141.6, 140.3, 139.5, 135.5, 134.2, 134.0, 129.64, 129.61, 129.59, 129.0, 128.90, 128.88, 128.53, 128.48, 128.46, 128.4, 128.1,


14

Page 15 of 21 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


127.6, 127.4, 127.1, 126.9, 126.7, 77.58, 77.55, 75.3, 75.0, 57.2, 56.8, 21.8, 17.91, 17.89, 17.86, 12.1, 12.0; IR (film) v: 3535, 3354, 2925, 2867, 1730, 1454, 1407, 1352, 1177, 1157, 1089, 881, 865, 700, 664, -1 + 549 cm ; HRMS (ESI-TOF) m/z calcd for C34H45NNaO5SSi [M + Na ] 630.2685. Found 630.2673. (2R*,5R*,E)-ethyl 2-((R*)-hydroxy(phenyl)methyl)-6-(4-methylphenylsulfonamido)-6-oxo-5((triisopropylsilyl)oxy)hex-3-enoate (28). Yield: 15.9 mg (21%); 82:18 d.r.; colorless wax; Rf (30% 1 AcOEt/hexane + 0.5% HCO2H) 0.50; H NMR (400 MHz, CDCl3) δ (major C6-epimer) : 8.89 (br s, 1H), 8.05 – 7.91 (m, 2H), 7.41 – 7.20 (m, 7H), 5.97 (ddd, J = 15.6, 9.0, 1.5 Hz, 1H), 5.46 (ddd, J = 15.6, 5.8, 0.9 Hz, 1H), 5.00 (d, J = 5.4 Hz, 1H), 4.56 (dd, J = 5.8, 1.5 Hz, 1H), 4.05 (q, J = 7.1 Hz, 2H), 3.30 (ddd, J 13 1 = 9.0, 5.4, 0.9 Hz, 1H), 2.43 (s, 3H), 1.12 (t, J = 7.1 Hz, 3H), 1.07 – 0.94 (m, 21H); C{ H} NMR (101 MHz, CDCl3) δ (major C6-epimer): 172.2, 169.2, 145.3, 140.5, 135.6, 131.8, 129.7, 128.5, 128.4, 128.0, 128.01, 127.96, 75.1, 74.0, 61.3, 56.5, 21.8, 17.9, 14.1, 12.0; IR (film) v: 3519, 3357, 2944, 2868, 1731, -1 1409, 1353, 1177, 1158, 1089, 881, 663, 549 cm ; HRMS (ESI-TOF) m/z calcd for C31H45NNaO7SSi [M + + Na ] 626.2584. Found 626.2555. (2R*,6R*,E)-6-hydroxy-4-methyl-6-phenyl-N-tosyl-2-((triisopropylsilyl)oxy)hex-3-enamide (29). Yield: 34.8 1 mg (51%); 75:25 d.r. (29:29‘); colorless wax; Rf (20% acetone/hexane) 0.40; H NMR (400 MHz, CDCl3) δ: 9.12 (br s, 1H), 8.98 (br s, 1H‘), 7.99 – 7.89 (m, 2H+2H‘), 7.43 – 7.21 (m, 7H+7H‘), 5.23 – 5.15 (m, 1H), 5.12 – 5.07 (m, 1H‘), 4.84 (d, J = 8.3 Hz, 1H), 4.81 (d, J = 8.2 Hz, 1H‘), 4.78 – 4.72 (m, 1H+1H‘), 2.43 (s, 3H+3H‘), 2.41 – 2.35 (m, 2H+2H‘), 1.91 (br s, 1H+1H‘), 1.77 (s, 3H+3H‘), 1.10 – 0.93 (m, 21H+21H‘); 13 1 C{ H} NMR (101 MHz, CDCl3) δ: 170.2, 169.9, 145.3, 145.2, 143.9, 139.2, 139.1, 135.7, 135.6, 129.69, 129.66, 128.61, 128.59, 128.48, 128.47, 127.8, 127.7, 125.9, 125.84, 125.80, 125.7, 72.3, 72.10, 72.07, 72.0, 49.9, 49.6, 21.80, 21.79, 17.91, 17.88, 17.83, 17.79, 12.04, 12.02; IR (film) v: 3529, 3355, 2944, -1 2867, 1732, 1455, 1406, 1351, 1191, 1177, 1090, 1062, 879, 663, 549 cm ; HRMS (ESI-TOF) m/z calcd + for C29H43NNaO5SSi [M + Na ] 568.2529. Found 568.2521. (2R*,6R*,E)-6-hydroxy-3-methyl-6-phenyl-N-tosyl-2-((triisopropylsilyl)oxy)hex-3-enamide (32). Starting from 24: Yield 59.4 mg (87 %), 80:20 d.r.; Starting from 25: Yield 55.3 mg (81 %), 82:18 d.r.; colorless 1 wax; Rf (30% acetone/hexane) 0.40; H NMR (400 MHz, CDCl3) δ (major): 8.97 (br s, 1H), 7.91 – 7.75 (m, 2H), 7.37 – 7.12 (m, 7H), 5.57 – 5.52 (m, 1H), 4.62 (dd, J = 7.5, 5.7 Hz, 1H), 4.34 (s, 1H), 2.51 – 2.38 (m, 13 1 2H), 2.37 (s, 3H), 1.41 (s, 3H), 1.02 – 0.85 (m, 21H); C{ H} NMR (101 MHz, CDCl3) δ (major): 169.9, 145.2, 143.8, 135.6, 134.9, 129.6, 128.6, 128.5, 127.8, 126.3, 125.9, 79.5, 73.8, 37.7, 21.8, 17.91, 17.87, -1 12.1, 12.0; IR (film) v: 3354, 2944, 2867, 1730, 1458, 1405, 1351, 1177, 1088, 880, 701, 663, 549 cm ; + HRMS (ESI-TOF) m/z calcd for C29H43NNaO5SSi [M + Na ] 568.2529. Found 568.2520. (2R*,6R*,E)-6-hydroxy-6-phenyl-N-tosyl-2-((triisopropylsilyl)oxy)hex-3-enamide (41). Yield: 45.2 mg (68 %); d.r. = 81:19; colorless wax; Rf (20% acetone/hexane) 0.40; Analytical data were consistent with 3a previously reported values. (2R*,6R*,E)-6-Hydroxy-N-(methylsulfonyl)-6-phenyl-2-((triisopropylsilyl)oxy)hex-3-enamide (42). Yield: 51.8 mg (91 %); d.r. = 73:27; colorless wax; Rf (30% acetone/hexane) 0.40; Analytical data were 3c consistent with previously reported values. (2R*,6R*,E)-6-Hydroxy-2-methyl-6-phenyl-N-tosylhex-3-enamide (45). Yield: 20.1 mg (43 %); 70:30 d.r.; colorless wax; Rf (30% acetone/hexane) 0.45; Analytical data were consistent with previously reported 3c values.


15


Page 16 of 21

(2R*,6R*,E)-6-hydroxy-2-isopropyl-6-phenyl-N-tosylhex-3-enamide (46). Starting from 38: Yield: 35.6 mg (71%), 91:9 d.r.; Starting from 40: Yield: 37.1 mg (74%), 90:10 d.r.; colorless wax; Rf (30% 3a acetone/hexane) 0.40; Analytical data were consistent with previously reported values. (2R*,6R*,E)-2-(1,3-Dioxoisoindolin-2-yl)-6-hydroxy-6-phenyl-N-tosylhex-3-enamide (47). Yield: 34.1 mg (54%); 86:14 d.r.; colorless wax; Rf (45% AcOEt/hexane + 0.5% HCO2H) 0.50; Analytical data were 3c consistent with previously reported values. Reduction of (3E)-enediols 2a and 17. To a solution of 2,6-enediol 2a or 17’ (109.6 mg, 0.2 mmol) in toluene (5 mL), PtO2 (6.8 mg, 0.03 o mmol) was added in one portion at 25 C and the resulting suspension was saturated with H2. After 24 h at the same temperature reaction mixture was diluted with toluene (5 mL) and filtered through a pad of Celite. Removal of solvent under reduced pressure and purification of the crude product by column chromatography on silica gel using an acetone/hexane mixture as an eluent afforded saturated 2,6-diols 48 - 49 as colorless oils. (2R*,5R*,6R*)-6-Hydroxy-5-methyl-6-phenyl-N-tosyl-2-((triisopropylsilyl)oxy)hexanamide (48). Yield: 88.7 mg (79%, starting from 2a), 95:5 d.r.; colorless oil; Rf (25% acetone/hexane) 0.60; Analytical data were 3c consistent with previously reported values. (2R*,5S*,6R*)-6-Hydroxy-5-methyl-6-phenyl-N-tosyl-2-((triisopropylsilyl)oxy)hexanamide (49). Yield: 93.2 mg (83%, starting from 17’); 70:30 d.r.; colorless oil; Rf (25% acetone/hexane) 0.60; Analytical data were 3c consistent with previously reported values. . Synthesis of 3,6,7-trisubstituted caprolactones 50-51. To a vigorously stirred solution of 2,6-diol 48-49 (110 mg, 0.2 mmol) and TBAB (32 mg, 0.1 mmol) in o MeI (2.5 mL), K2CO3 (1 g) was added in one portion at 25 C. After 12 h at the same temperature excess of K2CO3 was filtered off, washed with CH2Cl2 (25 mL), and the combined filtrates were concentrated under reduced pressure. Filtration of the residue through a pad of silica gel with acetone/hexane mixture afforded crude products which were subsequently, without further purification, dissolved in anhydrous THF (50 mL). To this mixture 2M NaHMDS solution in THF (100 µL, 0.2 mmol) was added dropwise at o 50 C under argon atmosphere and stirring was continued for 10 min at the same temperature. Then the reaction was quenched with saturated solution of NH4Cl (50 mL), poured into water and extracted with EtOAc (3 x 25 mL). The combined extracts were washed successively with water (50 mL), saturated solution of NaHCO3 (50 mL) and brine (50 mL), dried over anhydrous MgSO 4 and concentrated under reduced pressure. Purification of the crude product by column chromatography on silica gel using an MTBE/hexane mixture as an eluent afforded lactones 50-51 as colorless crystals or colorless oil. (3R*,6R*,7R*)-6-Methyl-7-phenyl-3-((triisopropylsilyl)oxy)oxepan-2-one (50). Yield: 53.5 mg (71%, starting o from 48); d.r. > 98:2; colorless crystals; mp = 92.9-93.8 C; Rf (15% MTBE/hexane) 0.60; Analytical data 3c were consistent with previously reported values. (3R*,6S*,7R*)-6-Methyl-7-phenyl-3-((triisopropylsilyl)oxy)oxepan-2-one (51). Yield: 43.0 mg (57%, starting from 49 (70:30 d.r.), additionally 16.6 mg (22%) of 52 resulting from epimer of 49 was isolated); d.r. > 98:2; colorless oil; Rf (15% MTBE/hexane) 0.65; Analytical data were consistent with previously reported 3c values.


16

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Synthesis of Mosher’s esters i , ii, i/i” and ii/ii’.

25

To a solution of (3E)-2,6-enediol 2a, (+)-2a, 10 or (+)-10, (0.02 mmol) in MeI (2 mL) TBAB (3.2 mg, 0.01 mmol) and K2CO3 (0.5 g) were sequentially added both in one portion at 25 °C and reaction mixture was vigorously stirred at the same temperature overnight. At the end of this time excess of K 2CO3 was filtered off, washed with CH2Cl2 (25 mL) and combined filtrates were concentrated under reduced pressure. Filtration of the residue through a pad of silica gel with acetone/hexane mixture afforded crude N-methylated (3E)-2,6-enediol diols which were subsequently, without further purification, dissolved in the anhydrous CH2Cl2 (1 mL). To this mixture DMAP (0.6 mg; 0.005 mmol) and Et 3N (5.6 µL, 0.04 mmol) were sequentially added both in one portion followed by 1M solution of (+)-MTPACl in CH2Cl2 (22 µL, 0.022 mmol) dropwise at 25 °C. After 3 h at the same temperature, reaction was quenched with saturated 5% aqueous solution of HCl (0.5 mL), poured into water (10 mL) and layers were separated. The aqueous layer was extracted with CH 2Cl2 (3 x 10 mL) and the combined extracts were washed with saturated aqueous solution of NaHCO3 (15 mL) and brine (15 mL), dried over MgSO4 and concentrated. Filtration of the crude product through a pad of silica gel with an ethyl acetate/hexane mixture afforded Mosher’s esters i, i/i’, ii or ii/ii’ as colorless waxes. ((S)-(1R,2R,5R,E)-6-(N,4-dimethylphenylsulfonamido)-2-methyl-6-oxo-1-phenyl-5((triisopropylsilyl)oxy)hex-3-en-1-yl 3,3,3-trifluoro-2-methoxy-2-phenylpropanoate (anti-i) and (S)(1S,2R,5R,E)-6-(N,4-dimethylphenylsulfonamido)-2-methyl-6-oxo-1-phenyl-5-((triisopropylsilyl)oxy)hex-3en-1-yl 3,3,3-trifluoro-2-methoxy-2-phenylpropanoate (syn-i). Inseparable mixture. Starting from (+)-2a: 19 1 Yield 11.2 mg (72%); anti-i:syn-i = 95:5; colorless wax; Rf (13% ethyl acetate/hexane) 0.50; F{ H} NMR (376 MHz, CDCl3) δ: -71.12 (anti-i), -71.40 (syn-i); HRMS (ESI-TOF) m/z calcd for C40H52F3NNaO7SSi [M + + Na ] 798.3084. Found 798.3067. ((S)-(1R,2R,5R,E)-6-(N,4-dimethylphenylsulfonamido)-2-methyl-6-oxo-1-phenyl-5((triisopropylsilyl)oxy)hex-3-en-1-yl 3,3,3-trifluoro-2-methoxy-2-phenylpropanoate (anti-i), ((S)(1S,2S,5S,E)-6-(N,4-dimethylphenylsulfonamido)-2-methyl-6-oxo-1-phenyl-5-((triisopropylsilyl)oxy)hex-3en-1-yl 3,3,3-trifluoro-2-methoxy-2-phenylpropanoate (anti-i‘), (S)-(1S,2R,5R,E)-6-(N,4dimethylphenylsulfonamido)-2-methyl-6-oxo-1-phenyl-5-((triisopropylsilyl)oxy)hex-3-en-1-yl 3,3,3-trifluoro2-methoxy-2-phenylpropanoate (syn-i) and (S)-(1R,2S,5S,E)-6-(N,4-dimethylphenylsulfonamido)-2methyl-6-oxo-1-phenyl-5-((triisopropylsilyl)oxy)hex-3-en-1-yl 3,3,3-trifluoro-2-methoxy-2phenylpropanoate (syn-i‘). Inseparable mixture. Starting from 2a: Yield: 10.2 mg (66%); i:i‘ = 50:50; anti19 1 i:syn-i = 93:7; anti-i’:syn-i’ = 93:7; colorless wax; Rf (13% ethyl acetate/hexane) 0.50; F{ H} NMR (376 MHz, CDCl3) δ: -71.11 (anti-i), -71.16 (syn-i‘), -71.37 (anti-i‘), -71.40 (syn-i); HRMS (ESI-TOF) m/z calcd + for C40H52F3NNaO7SSi [M + Na ] 798.3084. Found 798.3058. (S)-(3S,4R,7R,E)-8-(N,4-dimethylphenylsulfonamido)-2,4-dimethyl-8-oxo-7-((triisopropylsilyl)oxy)oct-5-en3-yl 3,3,3-trifluoro-2-methoxy-2-phenylpropanoate (anti-ii) and (S)-(3R,4R,7R,E)-8-(N,4dimethylphenylsulfonamido)-2,4-dimethyl-8-oxo-7-((triisopropylsilyl)oxy)oct-5-en-3-yl 3,3,3-trifluoro-2methoxy-2-phenylpropanoate (syn-ii). Inseparable mixture. Starting from (+)-10: Yield: 9.4 mg (63%); 19 1 anti-ii:syn-i = 94:6; colorless wax; Rf (13% ethyl acetate/hexane) 0.55; F{ H} NMR (376 MHz, C6D6) δ: + 70.62 (anti-ii), -70.70 (syn-ii); HRMS (ESI-TOF) m/z calcd for C37H54F3NNaO7SSi [M + Na ] 764.3240. Found 764.3220. (S)-(3S,4R,7R,E)-8-(N,4-dimethylphenylsulfonamido)-2,4-dimethyl-8-oxo-7-((triisopropylsilyl)oxy)oct-5-en3-yl 3,3,3-trifluoro-2-methoxy-2-phenylpropanoate (anti-ii), (S)-(3R,4S,7S,E)-8-(N,4dimethylphenylsulfonamido)-2,4-dimethyl-8-oxo-7-((triisopropylsilyl)oxy)oct-5-en-3-yl 3,3,3-trifluoro-2methoxy-2-phenylpropanoate (anti-ii‘), (S)-(3R,4R,7R,E)-8-(N,4-dimethylphenylsulfonamido)-2,4-


17


Page 18 of 21

dimethyl-8-oxo-7-((triisopropylsilyl)oxy)oct-5-en-3-yl 3,3,3-trifluoro-2-methoxy-2-phenylpropanoate (syn-ii) and (S)-(3S,4S,7S,E)-8-(N,4-dimethylphenylsulfonamido)-2,4-dimethyl-8-oxo-7-((triisopropylsilyl)oxy)oct5-en-3-yl 3,3,3-trifluoro-2-methoxy-2-phenylpropanoate (syn-ii‘). Inseparable mixture. Starting from 10: Yield: 9.9 mg (67%); ii:ii‘ = 50:50; anti-ii:syn-ii = 94:6; anti-ii’:syn-ii’ = 96:4; Rf (13% ethyl acetate/hexane) 19 1 0.55; F{ H} NMR (376 MHz, C6D6) δ: -70.61 (anti-ii), -70.70 (syn-ii), -70.77 (anti-ii‘), -70.91 (syn-ii’); + HRMS (ESI-TOF) m/z calcd for C37H54F3NNaO7SSi [M + Na ] 764.3240. Found 764.3226. SUPPORTING INFORMATION 1

13

1

H and C{ H} NMR spectra for all new and selected known compounds, Mosher’s esters and X-ray crystallographic data (PDF)

19

1

F{ H} NMR spectra for

X-ray crystal data for 12 (CIF) ACKNOWLEDGEMENTS We gratefully thank the National Science Centre for financial support, grant SONATA UMO2015/19/D/ST5/00713. REFERENCES AND ENDNOTES

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4. For examples of chemoselective derivatization of N-tosylcarboxamides see: (a) Cho, S. H.; Chang S. Rate‐Accelerated Nonconventional Amide Synthesis in Water: A Practical Catalytic Aldol‐Surrogate Reaction. Angew. Chem. Int. Ed. 2007, 46, 1897–1900. (b) Casadei, M. A.; Gessner, A.; lnesi, A.; Jugelt, W.; Moracci, F. M. Electrodic Cleavage of the N-S Bond in N-Tosylcarboxamides. A New Entry to N-Unsubstituted Lactams J. Chem. Soc., Perkin Trans. 1 1992, 2001-2004. (c) Nagashima, H.; Ozaki, N.; Washiyama, M.; Kenji I. Conjugate Addition of Organocopper Reagents to N-Tosylated α,βUnsaturated Amides. Tetrahedron Lett. 1985, 26, 657-660. (d) Bhunia, S.; Chang, C.-J.; Liu, R.-S. Platinum-Catalyzed Oxoarylations of Ynamides with Nitrones. Org. Lett., 2012, 14, 5522–5525. (e) Pan, F.; Li, X.-L.; Chen, X.-M.; Shu, C.; Ruan, P.-P.; Shen, C.-H.; Lu, X.; Ye, L.-W. Catalytic Ynamide Oxidation Strategy for the Preparation of α-Functionalized Amides. ACS Catalysis 2016, 6, 6055-6062. (f) Inamoto, Y.; Kaga, Y.; Nishimoto, Y.; Yasuda, M.; Baba A. Indium Triiodide Catalyzed Reductive Functionalization of Amides via the Single-Stage Treatment of Hydrosilanes and Organosilicon Nucleophiles. Org. Lett. 2013, 15, 3452-3455. (g) Knowles, H. S.; Parsons, A. F.; Pettifer, R. M.; Rickling, S. Desulfonylation of Amides Using Tributyltin Hydride, Samarium Diiodide or Zinc/Titanium Tetrachloride. A Comparison of Methods. Tetrahedron 2000, 56, 979-988. (h) Péron, F.; Fossey, C. Cailly, T.; Fabis, F. N-Tosylcarboxamide as a Transformable Directing Group for Pd-Catalyzed C-H Ortho-Arylation. Org. Lett. 2012, 14, 1827-1829. 5. (a) Friestad, G. K.; Sreenilayam G. 1,5-Polyols: Challenging Motifs for Configurational Assignment and Synthesis. Pure Appl. Chem. 2011, 83, 461–478 and references therein. (b) Friestad, G. K.; Sreenilayam, G. Versatile Configuration-Encoded Strategy for Rapid Synthesis of 1,5-Polyol Stereoisomers. Org. Lett. 2010, 12, 5016–5019. (c) BouzBouz, S.; Cossy, J. Chemoselective CrossMetathesis Reaction. Application to the Synthesis of the C1−C14 Fragment of Amphidinol 3. Org. Lett. 2001, 3, 1451-1454. (d) Flamme, E. M.; Roush, W. R. Enantioselective Synthesis of 1,5-anti- and 1,5syn-Diols Using a Highly Diastereoselective One-Pot Double Allylboration Reaction Sequence. J. Am. Chem. Soc. 2002, 124, 13644-13645. (e) Flamme, E. M.; Roush, W. R. Synthesis of the C(1)−C(25) Fragment of Amphidinol 3: Application of the Double-Allylboration Reaction for Synthesis of 1,5-Diols. Org. Lett. 2005, 7, 1411–1414. 6. For selected reviews, see: (a) Mikami, K.; Shimizu, M. 1,4- and 1,5-Remote Stereocontrol via Relative and Internal Asymmetric Induction. J. Synth. Org. Chem. Jpn. 1993, 51, 21-31. (b) Mikami, K.; Shimizu, M.; Zhang, H.-C.; Maryanoff, B. E. Acyclic Stereocontrol Between Remote Atom Centers via Intramolecular and Intermolecular Stereo-Communication. Tetrahedron 2001, 57, 2917-2951. (c) Thomas, E. J. Remote Stereocontrol Using Functionalized Allylmetal Reagents. Chem. Rec. 2007, 7, 115-124. (d) Jiang, H.; Albrecht, Ł.; Jørgensen, K. A. Aminocatalytic Remote Functionalization Strategies. Chem. Sci. 2013, 4, 2287-2300. 7. Domin, S.; Kędzierski, J.; Zambroń, B. K. Remote 1,5-Stereoselectivity Control by an N-Ligand Switch in the Pd(0)/InI-Promoted Reactions of 4-Ethynyl-β-lactams with Aldehydes. Org. Lett. 2019, 21, 39043908. 8. For selected reviews, see: (a) I. Ojima, In The Organic Chemistry of β-Lactams, Georg, G. I., Eds.; VCH: New York, 1993; p 197. (b) Ojima, I.; Delaloge, F. Asymmetric Synthesis of Building-Blocks for Peptides and Peptidomimetics by Means of the β-Lactam Synthon Method. Chem. Soc. Rev. 1997, 26, 377-386. (c) Deshmukh, A. R. A. S.; Bhawal, B. M.; Krishnaswamy, D.; Govande, V. V.; Shinkre, B. A.; Jayanthi, A. Azetidin-2-ones, Synthon for Biologically Important Compounds. Curr. Med. Chem. 2004, 11, 1889-1920. (d) Alcaide B.; Almendros P. Beta-lactams as Versatile Synthetic Intermediates for the Preparation of Heterocycles of Biological Interest. Curr. Med. Chem. 2004, 11, 1921-1949. (e) Alcaide, B.; Almendros, P.; Aragoncillo, C. β-Lactams: Versatile Building Blocks for the Stereoselective Synthesis of Non-β-Lactam Products. Chem. Rev. 2007, 107, 4437-4492. (f) Palomo, C.; Oiarbide, M. β-Lactam Ring Opening: A Useful Entry to Amino Acids and Relevant NitrogenContaining Compounds. Top. Heterocyc. Chem. 2010, 22, 211-258. (g) Delpiccolo, C. M. L.; MartinezAmezaga, M.; Mata, E. G. In Beta-Lactams. Novel Synthetic Pathways and Applications; Banik, B. K.,


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Ed.; Springer International Publishing AG, 2017; p 129. (h) Alcaide, B.; Almendros, P.; Aragoncillo, C. In Beta-Lactams. Novel Synthetic Pathways and Applications.; B. K., Banik, Eds.; Springer International Publishing AG, 2017; p 163. (i) Martín-Torres, I.; González-Muñiz, R. In Beta-Lactams. Novel Synthetic Pathways and Applications.; B. K., Banik, Eds.; Springer International Publishing AG, 2017; p 219. 9. Wang, C. Electrophilic Ring Opening of Small Heterocycles. Synthesis 2017, 49, 5307-5319. 10. For selected reviews, see: (a) Ternansky, R. J., Morin, J. M. Jr. In The Organic Chemistry of βLactams; Georg, G. I., Eds.; VCH: New York, 1993; p 257. (b) Brandi, A.; Cicchi, S.; Cordero, F. M. Novel Syntheses of Azetidines and Azetidinones. Chem. Rev. 2008, 108, 3988-4035. (c) Pitts, C. R.; Lectka, T. Chemical Synthesis of β-Lactams: Asymmetric Catalysis and Other Recent Advances. Chem. Rev. 2014, 114, 7930-7953. (d) Kamath, A.; Ojima, I. Advances in the Chemistry of β-Lactam and its Medicinal Applications. Tetrahedron 2012, 68, 10640-10664. (e) Magriotis, P. A. Progress in Asymmetric Organocatalytic Synthesis of β‐Lactams. Eur. J. Org. Chem. 2014, 2014, 2647-2657. (f) Fu, N.; Tidwell, T. T. Preparation of β-Lactams by [2+2] Cycloaddition of Ketenes and Imines. Tetrahedron 2008, 64, 10465-10496. (g) β-Lactams: Unique Structures of Distinction for Novel Molecules.; B. K., Banik, Eds.; Springer, Heidelberg, 2013. (h) Beta-Lactams. Novel Synthetic Pathways and Applications.; B. K., Banik, Eds.; Springer International Publishing AG, 2017. 11. Other examples of configurationally stable organoindiums generated via transmetalation undergoing rapid 1,3-rearangement even in the presence of aldehydes: (a) Donnelly, S.; Thomas, E. J.; Arnott, E. A. Remote Stereocontrol Using Allylstannanes: Reversal in Stereoselectivity Using Indium(III) and Bismuth(III) Halides as Promoters. Chem. Commun. 2003, 1460-1461. (b) Marshall, J. A.; Hinkle, K. W. Synthesis of anti-Homoallylic Alcohols and Monoprotected 1,2-Diols through InCl3-Promoted Addition of Allylic Stannanes to Aldehydes. J. Org. Chem. 1995, 60, 1920-1921. 12. Due to significant oxophilicity of indium (III), alternative structures of intermediate -amido-allylindiums trans-(E), cis-(Z), cis-(E) and trans-(Z) as well as transition states ts-1 – ts-4, where the amide oxygen binds the indium (III) atom instead of the nitrogen could also be possible. 13. In contrast to isomeric transition states leading to (3Z)-substituted products, in which the group next to the indium adopts the axial position; for details, see refs 3a and 3c. 14. (a) Xin, T.; Okamoto S.; Sato, F. 1,5-Asymmetric Induction in Addition Reaction of Aldehydes with Chiral Allyltitaniums Having an Amino Group at the Stereogenic Center. Synthesis of Optically Active 2,6-cis-Disubstituted Piperidines. Tetrahedron Lett. 1998, 39, 6927-6930. (b) Stanway, S. J.; Thomas, E. J. 1,5-Induction in Reactions Between 4-Aminoallylstannanes and Aldehydes Promoted by Lewis Acids J. Chem. Soc., Chem. Commun. 1994, 285-286. (c) Bradley, G. W.; Hallett, D. J.; Thomas, E. J. The Effect of a tert-Butyldimethylsilyl Substituent on the 1,5-Asymmetric Induction Found in Reactions of 4- and 5-Alkoxyallylstannanes with Aldehydes and Imines. Tetrahedron: Asymmetry 1995, 6, 25792582. (d) Stanway, S. J.; Thomas, E. J. 1,5-Stereocontrol in Tin(IV) Halide Mediated Reactions Between N- and S-Substituted Pent-2-enylstannanes and Aldehydes or Imines. Tetrahedron 2012, 68, 5998-6009. (e) Mahajan, V.; Gais, H. J. Ring‐Closing Metathesis of Sulfoximine‐Substituted N‐Tethered Trienes: Modular Asymmetric Synthesis of Medium‐Ring Nitrogen Heterocycles. Chem. Eur. J. 2011, 17, 6187-6195. (f) Kang, S. H.; Kim, J. S.; Youn, J. H. A Versatile Synthetic Route to Indolizidines, (+)-7-Deoxy-6-Epicastanospermine, (−)-7,8-Dideoxy-6-Epicastanospermine and (−)-NAcetylslaframine. Tetrahedron Lett. 1998, 39, 9047-9050. (g) Choi, J. R.; Han, S.; Cha, J. K. An Enantioselective Synthesis of (−)-Slaframine. Tetrahedron Lett. 1991, 32, 6469-6472. 15. The application of (3E)-2,5-anti-2,6-syn-enediol 17 (66:34 d.r.) would lead to caprolactone 52 available from compound 2b (98:2 d.r) in high yield, thus it was not executed. For details see ref. 3c 16. For selected examples of natural caprolactones, see: (a) Alphand, V.; Furstoss, R.; PedragosaMoreau, S.; Roberts, S. M.; Willetts, A. J. Comparison of Microbiologically and Enzymatically Mediated Baeyer–Villiger Oxidations: Synthesis of Optically Active Caprolactones. J. Chem. Soc., Perkin Trans. 1 1996, 1867-1872. (b) Pirkle, W. H.; Adams, P. E. Broad-Spectrum Synthesis of


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Enantiomerically Pure Lactones. 1. Synthesis of Sex Pheromones of the Carpenter Bee, Rove Beetle, Japanese Beetle, Black-Tailed Deer, and Oriental Hornet. J. Org. Chem. 1979, 44, 2169-2175. (c) Cai, J. Y.; Zhang, Y.; Luo, S. H.; Chen, D. Z.; Tang, G. H.; Yuan, C. M.; Di, Y. T.; Li, S. H.; Hao, X. J.; He, H. P. Aphanamixoid A, a Potent Defensive Limonoid, With a New Carbon Skeleton from Aphanamixis Polystachya. Org. Lett. 2012, 14, 2524-2527. (d) Tang, Y.-Q.; Sattler, I.; Thiericke, R.; Grabley, S.; Feng, X.-Z. Feigrisolides A, B, C and D, New Lactones with Antibacterial Activities from Streptomyces Griseus. J. Antibiot. 2000, 53, 934-943. (e) Stritzke, K.; Schulz, S.; Laatsch, H.; Helmke, E.; Beil, W. Novel Caprolactones from a Marine Streptomycete. J. Nat. Prod. 2004, 67, 395-401. (f) Guella, G.; Mancini, I.; Chiasera, G.; Pietra, F. Rogiolenyne D, the Likely Immediate Precursor of Rogiolenyne A and B, Branched C15 Acetogenins Isolated from the Red Seaweed Laurencia Microcladia of II Rogiolo. Conformation and Absolute Configuration in the Whole Series. Helv. Chim. Acta 1992, 75, 303-309. 17. In this case, additional 22% of caprolactone 52 derived from epimer 49' was isolated (>98:2 d.r.). 18. See Supporting Information for details. 19. Ojima, I.; Lin, S.; Inoue, T.; Miller, M. L.; Borella, C. P.; Geng, X.; Walsh, J. J. Macrocycle Formation by Ring-Closing Metathesis. Application to the Syntheses of Novel Macrocyclic Taxoids. J. Am.Chem. Soc. 2000, 122, 5343−5353. 20. In these cases, collected fractions were diluted with toluene (50% v/v) before removal of eluent under reduced pressure to avoid HCO2H concentration. 21. Containing ~ 4-5 % of two C5-epimers resulting from incomplete diastereomeric purity of the starting β–lactam 1 (95:5 d.r.). 22. Containing 10% of two C5-epimers (58:42 d.r.) resulting from incomplete diastereomeric purity of the starting β–lactam 14 (91:9 d.r.). 23. Containing ~ 13 % of two C5-epimers (68:32 d.r.) resulting from incomplete diastereomeric purity of the starting β–lactam 1 (95:5 d.r.) and partial isomerization of intermediate allylindium due to decreased addition step rate caused by severe steric hindrance of t-Bu substituent of aldehyde. 24. Containing ~ 4-5 % of two C5-epimers resulting from incomplete diastereomeric purity of the starting β–lactam 15 (96:4 d.r.). 25. Methylation of N-Ts-amido group prior to esterification is necessary since attempts of obtaining Mosher’s esters directly form (3E)-enediols 2a and 10 resulted in complex mixtures of products.


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InI-mediated reactions

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