Acyclic Remote 1,5- and 1,4,5-Stereocontrol in the Catalytic

Article Cite This: J. Org. Chem. 2018, 83, 14527−14552

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Acyclic Remote 1,5- and 1,4,5-Stereocontrol in the Catalytic Stereoselective Reactions of β‑Lactams with Aldehydes: The Effect of the N‑Methylimidazole Ligand Paulina Plata, Urszula Klimczak, and Bartosz K. Zambroń* Institute of Organic Chemistry, Polish Academy of Sciences, Kasprzaka 44/52, Warsaw 01-224, Poland

J. Org. Chem. 2018.83:14527-14552. Downloaded from pubs.acs.org by UNIV OF OTAGO on 12/18/18. For personal use only.

S Supporting Information *

ABSTRACT: The application of the N-methylimidazole (N-MI) ligand in the Pd(0)/InI-promoted allylations of aldehydes with β-lactam-derived organoindiums enables the reaction of azetidin-2-ones with diversely substituted allyl moieties, inert under previously reported conditions. As a result, allylations and crotylations of a variety of aromatic and aliphatic aldehydes with previously unavailable chiral ε-amido-allylindiums bearing α-, β-, or γ-substituted allyl fragments were developed. The reactions occur under thermodynamic control with a highly efficient remote 1,5- or 1,4,5-stereocontrol to afford a diversity of (3Z)-2,5-anti-2,6-syn- or (3Z)2,5-syn-2,6-anti-substituted enediols, aminoalcohols, and homoallylic alcohols in moderate to high yields and with an excellent diastereoselectivity. A detailed study on the effect of the β-lactam and aldehyde structures and chirality on the yield and stereochemistry in the products was carried out.

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INTRODUCTION The reaction of allylmetal reagents with carbonyl compounds is one of the most effective C−C bond formation methods in organic synthesis.1 Among many reagents, the nontoxic, watertolerant allylindiums generated in situ by reductive transmetalation of π-allylpalladium(II) complexes, providing high yields and often an excellent selectivity under mild reaction conditions, constitute a very interesting alternative.2 Recently, we have demonstrated that readily available 4-vinylazetidin-2ones bearing strongly electron-withdrawing groups attached to the nitrogen atom can undergo “umpolung” upon treatment with InI and catalytic amounts of a Pd(0) catalyst.3 As a result of this process, nucleophilic ε-amido-allylindiums are generated, which are able to react regio- and stereoselectively with a variety of aromatic and aliphatic aldehydes to afford semiprotected (3Z)-2,6-anti-enediols or homoallylic alcohols in a high yield with a very efficient acyclic remote 1,5stereocontrol.3a Due to the presence of numerous functional groups in their structure, including an easily modifiable N-Tscarboxamide function4 and internal (3Z)-substituted double bond, enediols obtained in this manner could serve in the asymmetric synthesis of a variety of heterocycles, as well as linear derivatives such as challenging 1,5-polyols subunits.5 It should be pointed out that achieving high levels of remote asymmetric induction remains a nontrivial task in current organic synthesis and that developing methodology for new stereoselective entries to linear and cyclic organic compounds with distant stereogenic centers is of high importance.6 Due to the well-known antibiotic activity of β-lactams, a great number of successful methods for their asymmetric © 2018 American Chemical Society

synthesis have been developed, which makes them readily available in both enantiomeric forms in an excellent optical purity.7 Thus, these reactive four-membered azacycles are widely used intermediates for the asymmetric synthesis of diverse classes of organic compounds such as α- and β-amino acids or biologically active alkaloids.8 It is noteworthy that the vast majority of reports concerning the application of β-lactams as building blocks deal with stereoselective ring-opening reactions upon treatment with various types of nucleophiles. In contrast, the reactions of β-lactams with electrophiles, including their umpolung by Pd(0)/InI methodology to enable the reaction with aldehydes developed by our group, are rare.3,8,9 Since our previous study was limited to only cis-substituted β-lactams bearing bulky substituents (OTIPS, i-Pr) at the C3 carbon of the azetidin-2-one ring,3 further elaboration of the chemistry presented and advanced study of the effect of the βlactam structure and configuration on the reaction outcome was a matter of interest. Importantly, in the course of our previous study, it appeared that the developed reaction conditions could be applied only to β-lactams bearing an unsubstituted vinyl moiety, which constituted a serious limitation for their general use. Bearing in mind that the possibility of application of the substrates with an elaborated allyl fragment might lead to desired enediols or homoallylic alcohols with an additional stereogenic center, substituents or functional groups in their structure led us to a deeper Received: September 10, 2018 Published: November 9, 2018 14527

DOI: 10.1021/acs.joc.8b02333 J. Org. Chem. 2018, 83, 14527−14552

Article

The Journal of Organic Chemistry

Table 1. Pd(PPh3)4/InI-Mediated Crotylation of Benzaldehyde with β-Lactam 1-Derived ε-Amido-allylindium: Optimization of the Reaction Conditions

entry

solvent

1 2 3 4 5 6 7 8

THF/HMPA (3:1) THF THFc THFf THFh THF/EtOH (9:1)j THF/EtOH (9:1)j THF/HMPA (9:1)j

a

additive (x equiv)

N-MIi (2) N-MIi (2) N-MIi (2)

time (h)

conversion (%)

2a yielda (%) (dr)b

2b yielda (%) (dr)b

24 24 1d 3 3 1 24 24

99% ee according to chiral HPLC) was applied. dDetermined by chiral HPLC analysis. eAdditionally, 30% of β-elimination products according to the crude 1H NMR integration.

a

hydrazones, with organoindiums derived from allyl boronates. 14 Although we observed an increased rate of disproportionation of InI in the presence of N-methylimidazole, especially in the THF/HMPA mixtures, the generated in situ complex proved to be stable enough to enable an overall crotylation process to proceed when THF or a THF/EtOH mixture was employed. To further explore our methodology, a variety of aromatic and aliphatic aldehydes were subjected to the reaction with βlactam 1 under optimized conditions, in order to determine the aldehyde effect on the crotylation outcome (Scheme 2). All of the reactions involving aromatic aldehydes, electron-rich or

due to its altered aggregation state in solution and/or increased nucleophilicity of the attached allylic ligand in the presence of the coordinated electron-donating N-MI (Scheme 1). However, the effect of N-methylimidazole on the stereochemical course of the process resulting in a significantly higher (Z)selectivity remains unclear, which is detailed in further paragraphs. In most reports on coordination chemistry of indium(I), reactions of indium(I) halides with bases (ligands) cause its redox disproportionation.11,13 However, besides the number of reports on quite stable achiral In(I) complexes with no synthetic application,13 there are remarkable examples of InI complexes able to catalyze allylations and crotylations of 14529


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Scheme 3. Pd(PPh3)4/InI/N-MI-Mediated Crotylation of Benzaldehyde with β-Lactam 1- and 15−17-Derived ε-Amidoallylindiums: The Effect of β-Lactam Configuration

a

Isolated yield. bAssayed by 1H NMR integration.

compounds 18a and 18b in the mixtures obtained from substrates 1 and 15, and analogously compounds 2a and 2b in the mixtures resulting from reactions of β-lactams 16−17 (Figure 1). However, these seem to be the products of the

-deficient, including heteroaromatic furfural and thiophene-2carbaldehyde afforded (3Z)-enediols as major products in high 77−87% yields and with an excellent, ≥95:5, 2,5-syn-2,6antiselectivity (Scheme 2, structures 2a, (−)-2a, 3−7). Also reactions with aliphatic aldehydes, primary or secondary including 4-hydroxybutyric aldehyde containing an unprotected hydroxyl group, proceeded very effectively, delivering the corresponding products in a high yield and with the same highly efficient remote 1,4,5-asymmetric induction (68−81% yield, ≥95:5 dr Scheme 2, structures 8−12). Only in the case of tertiary pivalaldehyde, the yield of the corresponding (3Z)2,5-syn-2,6-antienediol 13 was significantly reduced, most likely due to severe steric hindrance. The rate of the reaction and the stereoselectivity remained high (43% yield, dr 95:5, Scheme 2, structure 13). Even in the case of α,β-unsaturated 3-methylbut2-enal,3a which was incompatible in our previous study, the corresponding adduct was obtained in a good yield with the same excellent level of diastereoselectivity (74% yield, 95:5 dr, Scheme 2, structure 14). Importantly, when the enantioenriched N-Ts-4-(E)-propenylazetidin-2-one (−)-1 (>99% ee according to HPLC10) was combined with benzaldehyde or isobutyric aldehyde under our standard conditions, the corresponding (3Z)-2,5-syn-2,6-antienediols (−)-2a and (−)-11a were obtained in high yields with the same excellent enantiomeric excess, which was proved by chiral HPLC analysis.10 These examples demonstrate that the developed method can be applied in asymmetric synthesis, since a variety of β-lactams are readily available in both enantiomeric forms in an excellent optical purity.7 Next, a series of experiments using cis- and trans-substituted 4-propenylazetidin-2-ones 1 and 15−17 differing in the relative double CC bond configuration were conducted in order to determine the effect of β-lactam chirality on the reaction outcome, which led to very interesting observations (Scheme 3). Surprisingly, the application of trans-azetidin-2-one 15 bearing (Z)-propenyl provided nearly the same mixture of products 2a and 2b as previously used cis-4-(E)-propenyl-βlactam 1, while the use of trans-(E)- and cis-(Z)-substituted isomers 16−17 afforded compounds 18−18b of completely different configurations and ratios. However, almost equal sets of products were obtained in both cases. Slight differences visible in the 1H NMR spectra of the crude reaction mixtures arise from the presence of small but not equal quantities of

Figure 1. 1H NMR study of Pd(PPh3)4/InI/N-MI-mediated crotylation of benzaldehyde with β-lactam 1- and 15−17-derived εamido-allylindiums.

reactions of the geometrical isomers of the starting β-lactams 1 and 15−17 present in their samples in small but not equal amounts (dr (Z/E) = 95:5, 91:9, 98:2, and 96:4 for 1, 15, 16, and 17, respectively), which is detailed in the further paragraphs. The obtained results indicate a high stereoselectivity of the formation of the configurationally stable εamido-organoindium intermediates reacting with benzaldehyde in the subsequent crotylation step.15 Furthermore, obtaining the almost identical sets of products 2a−2b or 18a−18b from the differently configured pairs of substrates 1, 15, or 16−17, respectively, clearly shows that the presented allylations occur under thermodynamic control, where the equilibration of the initially formed organoindiums is significantly faster than their subsequent addition to the electrophile. Thus, the scope of the isomeric enediols potentially available from β-lactams 1 and 15−17 is reduced, although the two isomers of the starting β-lactam can be applied to obtain the desired product, depending on its relative availability in the individual cases. 14530


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The Journal of Organic Chemistry Scheme 4. Pd(PPh3)4/InI/N-MI-Mediated Crotylation of Benzaldehyde with β-Lactam 1- and 15-Derived ε-Amidoallylindiums: Possible Reaction Pathway

Scheme 5. Pd(PPh3)4/InI/N-MI-Mediated Crotylation of Benzaldehyde with β-Lactam 16- and 17-Derived ε-Amidoallylindiums: Possible Reaction Pathway

bond of azetidin-2-one ring with inversion of configuration, followed by reductive transmetalation of the transient πallylpalladium(II) species with the active InI·N-MI complex, retaining the stereochemistry. Subsequent fast equilibration via a sequence of rapid 1,3-rearrangements delivers different pairs

The plausible reaction pathway of the above transformations, based on the observed regio- and stereoselectivity, is depicted in Schemes 4 and 5. In all cases, the initial step consists of a stereoselective C4−N β-lactam bond cleavage by Pd(PPh3)4 attack occurring from the opposite side of the C−N 14531


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Scheme 6. Pd(PPh3)4/InI/N-MI-Mediated Crotylation of Benzaldehyde with β-Lactam 19-, (+)-19-, 20-, and (−)-20-Derived ε-Amido-allylindiums

a

Isolated yields. bAssayed by 1H NMR integration. cDetrermined by chiral HPLC analysis. dAssayed by 19F NMR integration.

of isomeric chiral ε-amido-allylindiums, depending on whether β-lactam 1, 15, or 16−17 was applied.15 In all generated allylindiums, the metal atom is situated in the γ position as a consequence of the coordination of indium to the N-Tscarboxamide group. Thus, the reactions take place on the other carbon of the allyl system, bearing a methyl substituent, which explains the observed rare high α-regioselectivity of the process.1−3 Due to a significant disparity in energy between trans-(E)- and cis-(Z)-organoindiums generated from β-lactam 1 or 15, the equilibrium is shifted far toward the thermodynamically favored trans-(E)-isomer in this case (Scheme 4). Conversely, similarly stable trans-(Z) and cis(E)-isomers formed from β-lactam 16 or 17 are present at comparable concentrations, which results in a reduced stereoselectivity (Scheme 5). Assuming the addition step occurs via bicyclic, rigid transition states, ts-1-ts-4 or ts-5-ts-8, depending on the substrate used, different ratios of enediols may be produced. In the first case, thermodynamically favored trans-(E)-ε-amido-allylindium reacts with benzaldehyde via transition states ts-1 and ts-2, affording the corresponding enediols 2a and 2b (Scheme 4). However, due to the strong preference of ts-1, in which the group next to the indium adopts the axial position, compound 2a is formed in great predominance. It should be pointed out that the preference of the transition structure ts-1, leading to the (Z)-substituted product over ts-2, is not general and strongly depends on the applied reaction conditions, which have been discussed in our previous study.3a In contrast, due to a severe 1,3-diaxial strain existing in transition state ts-3, minor cis-(Z)-ε-amidoallylindium reacts with the aldehyde only via transition state ts-4, giving (E)-substituted enediol 2b′ exclusively. As a consequence, compound 2a arises in a high yield with a nearly perfect stereoselectivity (98:2 dr), while the (E)-enediols result in minor amounts as the inseparable mixture of isomers 2b and 2b′ additionally contaminated by comparable quantities of

isomers 18a and 18b resulting from the moderately (E)stereoselective reactions of 16 or 17, present in the samples of substrates 1 and 15 in small amounts, as depicted in Scheme 5 (dr (E/Z) = 95:5 and dr (Z/E) = 91:9 for 1 and 15, respectively). In the case of reactions of β-lactam 16 or 17, involving a pair of ε-amido-allylindiums, cis-(E) and trans-(Z), the addition occurs analogously, except that these intermediates would exist in comparable concentrations, probably due to their similar energies (Scheme 5). The cis-(E)-ε-amido-allylindium reacts with benzaldehyde via transition states ts-5 and ts-6, affording the corresponding enediols 18a and 18b′ in 33% and 12% yields, respectively (45% overall). In contrast, due to a severe 1,3-diaxial strain existing in transition state ts-7, ε-amidoallylindium trans-(Z) reacts exclusively via transition state ts-8, giving (E)-substituted enediol 18b in 47% yield. Conversely to the former example, where the obtained (E)-endiols 2b and 2b′ were contaminated by small amounts of isomers 18b and 18b′, in this case, (Z)-enediol 18a is contaminated with small amounts of compound 2a, resulting from the highly (Z)stereoselective allylation involving small amounts of compound 1 or 15 present in the samples of β-lactams 16 and 17, as depicted in Scheme 4 (dr (Z/E) = 92:8 and dr (Z/E) = 96:4 for 16 and 17, respectively). However, in both cases, incomplete stereoselectivity of the presented processes cannot be fully discounted either. Additional experiments involving racemic and enantioenriched β-lactams 19−20, (−)-19, and (+)-20 with an unsubstituted C3 position of the azetidinone ring confirmed the configurational stability of the generated in situ ε-amidoallylindiums and the occurrence of the reaction under thermodynamic control (Scheme 6). As expected, the treatment of racemic substrates 19 and 20 differing in the geometry of the CC double bond in the propenyl substituent with benzaldehyde under optimized reaction 14532


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Scheme 7. Pd(PPh3)4/InI/N-MI-Mediated Crotylation of Benzaldehyde with β-Lactam 1- and 24−31-Derived ε-Amidoallylindiums: The Effect of Allyl Moiety Substitution

a

Isolated yield. bAssayed by 1H NMR integration. cReactions were carried out with 2 equiv of benzaldehyde, 2 equiv of InI, and 5 mol % Pd(PPh3)4 in a 3:1 THF/HMPA mixture at 25 °C. dcis-Substituted β-lactam 30 was applied. A mixture of (3E)-enediols 38b was also formed (28% yield, 54:46 dr). etrans-Substituted β-lactam 31 was applied. A mixture of (3E)-enediols 38b was also formed (30% yield, 51:49 dr). fcis-Substituted β-lactam 30 was applied. A mixture of (3E)-enediols 38b was also formed (13% yield, 52:48 dr); 63% of β-lactam 30 was recovered.

33 and 34). To our delight, the use of azetidin-2-one 27 bearing a methyl group in the β position resulted in the formation of the triply substituted enediol 35 in a high 85% yield with an excellent 95:5 diastereoselectivity. However, the use of analogous substrate 28 with an acetoxy group in the β position as well as β-lactam 29 bearing two methyl substituents in the α and β positions failed, since no conversion was observed in both cases within 24 h. Most likely, the inertness of these substrates under our reaction conditions results from insufficient electrophilicity of the CC double bond, caused by the presence of the strongly electron-donating acetoxy group in 28 and two moderately electron-donating methyl substituents in 29, which result in an insufficient reactivity with the nucleophilic Pd(PPh3)4 catalyst. Although an increased steric hindrance in 28 and 29 in comparison with 27 and 1, respectively, as the reason for the reduced reactivity cannot be fully excluded, in the light of the formerly presented results, it seems to play a minor role. The application of cis-substituted βlactam 30, bearing a methyl substituent at quaternary C4 of the azetidin-2-one ring, led to the formation of triply substituted enediol 38a in a moderate 46% yield, but with the same excellent 1,5-asymmetric induction (>98:2). In this case, the (Z/E)-selectivity of the reaction appeared reduced since 28% of (E)-enediol 44b was also formed as a mixture of two diastereomers in a 54:46 ratio. Interestingly, the use of the trans-substituted isomer of β-lactam 30, i.e., azetidin-2-one 31, in sharp contrast to the analogous reactions of pairs of cis- and trans-substituted 4-(E)-propenyl-β-lactams 1, 15, and 16−17 described in former paragraphs (Schemes 3, 4, and 5), led to the formation of exactly the same set of products in almost equal amounts and stereoselectivities. While in apparent opposition, the obtained results stay in line with previous observations. The difference results from the lack of the transor cis-oriented methyl group at the α position of the vinyl substituent, which causes the stereochemical information

conditions resulted in the formation of the same (Z)substituted homoallylic alcohol 21 in similar yields and the same high diastereoselectivity (57 and 60% yields, respectively, >98:2 dr). The experiments with the use of analogous enantioenriched substrates bearing a stereogenic center of the same absolute configuration, in turn, delivered the enantiomers (−)-21 and (+)-21 with the er fully corresponding to the dr of the starting β-lactams (+)-19 and (−)-20, which was proved by a 19F NMR study of Mosher’s esters 28 and 29.10 Notably, the absence of substituent at C3 of the βlactam ring in compounds 19−20, (−)-19, and (+)-20 did not affected the selectivity of the process since, in all cases, (Z)substituted adducts were obtained in great predominance with a high diastereomeric excess. However, the chemical yield of the reaction suffered due to the significantly faster (with regard to allylation involving C3-substituted substrates) competitive β-elimination. Next, a number of β-lactams differing in double CC bond substitution (positions α and β) or with an additional methyl substituent at C4 of the azetidin-2-one ring (position γ) were subjected to the reaction with benzaldehyde in order to investigate the effect of the allyl moiety substitution on the reaction outcome (Scheme 7). Application of β-lactam 24, bearing an (E)-oriented i-Pr substituent at the α position of the vinyl fragment, delivered the expected product with a somewhat lower yield, but with the same high diastereoselectivity, showing that the substrates with larger aliphatic substituents can be applied likewise (74% yield, 98:2 dr, Scheme 7, structure 32). Also β-lactams bearing aromatic substituents or additional functional groups at the α position, such as phenyl in compound 25 or ethyl ester in azetidin-2-one 26, were tolerated and the desired (Z)-substituted enediols 33−34 were obtained in high yields and excellent 2,5-syn-2,6anti-selectivities, indicating a broad applicability of the asymmetric allylation under examination (Scheme 7, structures 14533


Article

The Journal of Organic Chemistry Scheme 8. Pd(PPh3)4/InI/N-MI-Mediated Crotylation of Benzaldehyde with β-Lactam 30- and 31-Derived ε-Amidoallylindiums: Possible Reaction Pathway

Reaction was carried out with benzaldehyde (2 equiv), InI (2 equiv), and Pd(PPh3)4 (5 mol %) in a 3:1 THF/HMPA mixture at 25 °C.

a

Scheme 9. Pd(PPh3)4/InI/N-MI-Mediated Allylation of Benzaldehyde with β-Lactam 39−43-Derived ε-Amido-allylindiums: The Effect of C3 β-Lactam Substitution

Condition A: PhCHO (2 equiv), InI (3 equiv), N-MI (2 equiv), Pd(PPh3)4 (5 mol %), THF/EtOH (9:1), 25 °C. Condition B: PhCHO (2 equiv), InI (2 equiv), Pd(PPh3)4 (5 mol%), THF/HMPA (3:1), 25 °C. bIsolated yield. cAssayed by 1H NMR integration. dtrans-Substituted βlactam 42 was applied.

a

coming from the β-lactam relative configuration to be lost during the fast equilibration preceding the addition step (Scheme 8). Further studies confirmed that this is always the case when the azetidin-2-ones without a substituent at the vinyl α position are applied. Additionally, comparative experiments applying previously developed conditions (2 equiv of benzaldehyde, 2 equiv of InI, and 5 mol % of Pd(PPh3)4 in a 3:1 THF/HMPA mixture at 25 °C)3a were conducted using β-lactams 27 and 30. Similarly to the reaction of β-lactam 1, application of azetidin-2-one 27 under these conditions failed as only ∼5% of conversion was observed within 24 h at 25 °C. The use of β-lactam 30, in turn, resulted in less than 30% of its conversion within 1 h, whereas no further progress was

observed in the next 23 h. The obtained results emphasize the advantage of the newly developed protocol over the previously reported method for β-lactams with a substituted allyl moiety. In order to investigate the effect of C3 substitution of the βlactam ring on the reaction outcome, 4-vinyl-azetidin-2-ones 39−43 were synthesized10 and subjected to the reaction with benzaldehyde under newly developed and previously reported3a reaction conditions (Scheme 9, Conditions A and B, respectively). As in the case of azetidin-2-one 39 bearing an OTIPS substituent, also cis- and trans-substituted β-lactams 41 and 42 with an i-Pr group, as well as the β-lactam 40 with a methyl substituent at C3 of β-lactam ring delivered the desired (Z)-enediols in good yields and with high 2,6-anti-stereo14534


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Next, a series of experiments with the use of 4-vinyl-βlactams with Ts, Ms, Boc, and PMP groups attached to the nitrogen atom were conducted under Conditions A and B in order to verify the possibility of the use of other more common protective groups and their influence on the reaction outcome (Scheme 11). However, only N-Ts- or N-Ms-substituted azetidin-2-ones 39 and 50 proved to be suitable substrates for the method under development. Using these substrates, corresponding (Z)-enediols 44a and 53a were obtained in high yields and, especially under Condition B, an excellent 2,6anti-stereoselectivity. As in our previous study,3a Boc- and PMP-protected β-lactams 51 and 52 appeared inert also under the newly developed conditions, confirming that a strongly electron-withdrawing group attached to the nitrogen atom of the azetidin-2-one ring is necessary. Finally, in order to verify if the stereochemical course of the addition of the β-lactam-derived chiral ε-amido-allyindiums to aldehydes is determined by the chirality in the reagent or in the aldehyde, the enantiomeric azetidin-2-ones (+)-1 and (−)-1 were subjected to the reaction with (R)-(+)-glyceraldehyde acetonide under our standard reaction conditions (Scheme 12). Interestingly, no matching and mismatching was observed, since in both cases the reaction proceeded with the same rate and the products (−)-56 and (+)-57 were obtained in nearly equal yields with the same excellent 2,5-syn-2,6-anti-stereoselectivity. The obtained results clearly show that the presented crotylations are strongly reagent-controlled and chirality in the aldehyde does not affect the course of the process. A number of methods were used to determine the configuration of obtained enediols, aminoalcohols, and homoallylic alcohols. The (Z/E)-configuration of compounds bearing double substituted CC bonds was easily assigned by an analysis of coupling constants of the olefin protons in the 1 H NMR spectra (J ∼ 10 Hz for (Z)- and J ∼ 15 Hz for (E)isomers). In the case of enediols 35 and 38a−38b with the triply substituted CC bond, the (Z/E)-configurations were assigned by NOE measurements.10 Also, the dr of all (3Z)- and (3E)-products was established using 1H NMR spectroscopy. The relative configurations of enediols 2a, 2b, 2b′, 18a, 18b, and 18b′ were assigned by NOE measurements in

selectivities, especially when Condition B was applied showing that the substrates with smaller substituents at this position are just as viable (Scheme 10, structures 44a−46a and 44b−46b). Scheme 10. Synhesis of (3Z)-2,5-syn-2,6-anti-Aminoalcohol 49 via Pd(PPh3)4/InI/N-MI-Mediated Crotylation of Benzaldehyde with β-Lactam 48-Derived ε-Amidoallylindiums

a


Interestingly, the application of the more classical azetidin-2one 43 with a phthalimide-protected amino group at the C3 position of the β-lactam ring delivered the expected (Z)-2,6anti-aminoalcohol in a similarly high yield and with an excellent stereoselectivity (75% yield, 88:12 dr (Condition A), 74% yield, 98:2 dr (Condition B), Scheme 9, structures 47a−47b). Applying Condition A to azetidin-2-one 48 bearing an (E)-propenyl substituent at C4 of the β-lactam ring, in turn, delivered the related 2,5-syn-2,6-anti-(Z)-aminoalcohol 49 with a somewhat lower yield, but with the same excellent remote 1,4,5-stereocontol, showing that the methodology under development can also serve in the asymmetric synthesis of this class of highly desirable organic compounds (63% yield, >98:2 dr, Scheme 10).16 It is noteworthy that although the desired (Z)-adducts were obtained in great predominance in comparable yields using both protocols, under Condition B, noticeably higher 2,6-anti-stereoselectivities were obtained in all conducted experiments, showing this procedure to be superior for β-lactams with an unsubstituted 4-vinyl group. Since the application of Condition A enables the reactions of azetidin-2-ones with a differently substituted allyl moiety, both protocols appear to be complementary.

Scheme 11. Pd(PPh3)4/InI/N-MI-Mediated Allylation of Benzaldehyde with β-Lactam 39- and 50−52-Derived ε-Amidoallylindiums: The Effect of a Protective Group at the Nitrogen Atom of the Azetidin-2-one Ring

Condition A: PhCHO (2 equiv), InI (3 equiv), N-MI (2 equiv), Pd(PPh3)4 (5 mol %), THF/EtOH (9:1), 25 °C. Condition B: PhCHO (2 equiv), Pd(PPh3)4 (5 mol %), THF/HMPA (3:1), 25 °C. bIsolated yield. cAssayed by 1H NMR integration.

a

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Scheme 12. Pd(PPh3)4/InI/N-MI-Mediated Allylation of (R)-(+)-Glyceraldehyde Acetonide with Enantioenriched β-Lactam (+)-1- and (−)-1-Derived ε-Amido-allylindiums: The Effect of Chirality in the Organoindium Reagent and Aldehyde

a

Determined by chiral HPLC analysis. bIsolated yield. cAssayed by 1H NMR integration.

Scheme 13. Synthesis of 3,6,7-Trisubstituted Caprolactones 61−63: Determination of the Relative Configuration of (3Z)- and (3E)-2,6-Enediols 2a−2b and 18a−18b

Isolated yield. bAssayed by 1H NMR integration. cObtained in 58% yield from β-lactam 1 and benzaldehyde during optimization using InI (3 equiv) and Pd(PPh3)4 (10 mol %) in anhydrous THF at 25 °C. a

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Scheme 14. Synthesis of (4Z)-3,6-syn-3,7-anti-Caprolactones (−)-65 and (+)-67 from (3Z)-2,5-syn-2,6-anti-Enediols (−)-56 and (+)-57

a


purity.7 The utility of the obtained enediols was exemplified in the preparation of highly substituted chiral caprolactones with three stereogenic centers in the ring. Further elaboration of the chemistry presented and its application in asymmetric synthesis of other types of heterocycles and selected natural products is currently in progress.

caprolactones 61−63 derived from them, using wellestablished methods (Scheme 13).10 In the cases of enediol 2a and caprolactone 62a, the assignments were further confirmed by X-ray analysis.10 Also relative configuration of enediol 13 was established using X-ray diffractometry.10 Relative configurations of (Z)-enediols (−)-56 and (+)-57 in turn were determined by X-ray analysis of caprolactones (−)-65 and (+)-67 derived from them in two steps using standard procedures (Scheme 14).10 The configurations of other enediols, amino alcohols, and homoallylic alcohols were assigned by analogy. It is noteworthy that although caprolactones 61−63, (−)-65, and (+)-67 depicted in Schemes 13 and 14 were synthesized to determine the relative configuration of obtained adducts, they also constitute a simple example of the application of β-lactam-derived enediols in asymmetric synthesis of this type of highly desirable chiral heterocycles.17

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EXPERIMENTAL SECTION

General Experimental Methods. 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 CaH2 (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 aluminum plates (Merck, Darmstadt). Indication was achieved with UV light (λ = 254 nm) and common dip stains (potassium permanganate or cerium ammonium molybdate). NMR spectra were recorded on Varian Mercury 400 MHz, Bruker DRX 500 Avance, or Varian VNMRS 600 MHz spectrometer in a CDCl3, MeOH-d4, or acetone-d6 solution. Chemical shifts are quoted on the δ scale, ppm, and are calibrated using the following residual solvents signals: 1H NMR CDCl3 7.26 ppm, MeOH-d4 3.31 ppm, acetone-d6 2.05 ppm; 13C{1H} NMR CDCl3 77.16 ppm, MeOH-d4 49.00 ppm, acetone-d6 29.84 ppm. Multiplicities for 1H 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 (IR) were measured on a FT-IR-1600-PerkinElmer spectrophotometer and are reported in cm−1. The samples were prepared as thin films. High-resolution mass spectra (HRMS) were obtained on an ESI-TOF Mariner spectrometer (Perspective Biosystem) and are given in m/z. Melting points (mp) were determined with a melting point meter MPM-H2 apparatus and are uncorrected. Optical rotations [α] were measured on a Jasco P-2000 Polarimeter in a quartz glass cuvette at λ = 589 nm (Na D line). Concentrations [c] are given in g/100 mL. Analytical highperformance liquid chromatography (HPLC) was performed using a Knauer HPLC system (WellChrom K-1001 pump, WellChrom K2501 UV detector, WellChrom K-2301 RI detector) outfitted with a Daicel Chiralpak ASH (250 mm × 4.6 mm, 5 μm) column. Operating procedures and retention times were reported with the corresponding chromatograms. (1E,2E)-N-(4-Methoxyphenyl)-3-phenylprop-2-en-1imine (v),18 (1E,2Z)-N1,N2-bis(4-methoxyphenyl)propane-1,2-diimine (xviii),19 β-lactams (3R*,4R*)-3-isopropyl-1-(4-methoxyphenyl)-4-((E)-styryl)azetidin-2-one (xxi),20 (2R*,3R*)-1-(4-methoxyphenyl)-3-methyl-4-oxoazetidine-2-carbaldehyde (xxvi), 2 1 (2R*,3R*)-3-(1,3-dioxoisoindolin-2-yl)-1-(4-methoxyphenyl)-4-oxoa-

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CONCLUSIONS We demonstrated that the application of an N-methylimidazole (N-MI) ligand in the Pd(0)/InI-promoted allylations of aldehydes with β-lactam-derived organoindiums enables the use of azetidin-2-ones with a diversely substituted allyl moiety, inert under our previously developed conditions,3a for the first time. At this stage, we assume that the in situ formation of the reactive InI·N-MI complex in the course of the process is responsible for the observed beneficial effect of the Nmethylimidazole on the rate, yield, and stereoselectivity of the process. As a result, efficient entry to a broad range of previously unavailable configurationally stable chiral ε-amidoallylindiums bearing an α-, β-, or γ-substituted allyl fragment was developed. We showed that the additions of these particular cyclic intermediates to the aldehydes are strongly reagent-controlled and proceed under thermodynamic control with atypical allylindium reagent α-regioselectivity1−3 and a very efficient remote 1,5- or 1,4,5-asymmetric induction. The resulting semiprotected (3Z)-substituted enediols, aminoalcohols, or homoallylic alcohols are obtained in a modest or high yield with an excellent 2,5-syn-2,6-anti- or 2,5-anti-2,6anti-selectivity depending on the β-lactam relative configuration used. Importantly, when enantioenriched substrates were applied, no racemization was observed, demonstrating that the developed methodology can be successively applied in asymmetric synthesis, since a variety of β-lactams are readily available in both enantiomeric forms in an excellent optical 14537


Article


(101 MHz, CDCl3) δ 169.5, 161.7, 156.6, 131.2, 128.9, 127.4, 118.4, 114.5, 75.8, 64.3, 55.6, 20.5, 13.7, 12.7; IR (film) v 2935, 2837, 1754, 1667, 1585, 1514, 1442, 1373, 1248, 1226, 1113, 1032, 830 cm−1; HRMS (ESI-TOF) m/z calcd for C16H19NNaO4 [M + Na+] 312.1212, found 312.1199. Preparation of β-Lactams (−)-i and (+)-i.25 To a vigorously stirred suspension of racemic β-lactam i (11.012 g, 40 mmol) in 0.2 M sodium phosphate buffer (pH 7.5, 450 mL)26 and acetonitrile (50 mL) was added Amano Lipase PS (10 g, immobilized on diatomite) in one portion at 50 °C. After 36 h at the same temperature (ca. 55% conversion according to 1H NMR of the crude reaction mixture), the mixture was cooled to 25 °C, filtered through a pad of Celite, and extracted with CH2Cl2 (3 × 100 mL). The combined extracts were dried over MgSO4 and concentrated under reduced pressure, and the resulting enantioenriched β-lactams (−)-i (4.567 g, >98% ee) and (−)-vii (3.438 g, 92% ee) were separated by column chromatography on silica gel using an ethyl acetate/hexane mixture as an eluent. 3OH-β-Lactam (−)-vii was then dissolved in an anhydrous 50% vinyl acetate/hexane mixture (80 mL), and to this solution were added PS Amano Lipase (3 g, immobilized on diatomite) and 4 Å molecular sieves (2 g) sequentially both in one portion at 25 °C under an atmosphere of argon. The resulting mixture was heated to 50 °C for 30 min (ca. 90% conversion according to 1H NMR of the crude reaction mixture). After the mixture was cooled to 25 °C, the mixture was filtered through a pad of Celite, washed with EtOAc (25 mL), and concentrated under reduced pressure. Purification of the crude product by column chromatography on silica gel using an ethyl acetate/hexane mixture as an eluent afforded enantioenriched βlactam (+)-i (3.788 g, >99% ee) as colorless crystals. (3R,4S)-1-(4-Methoxyphenyl)-2-oxo-4-((E)-prop-1-en-1-yl)azetidin-3-yl Acetate ((−)-i): 4.567 g (42% yield); colorless crystals; mp 110.5−111.2 °C; Rf (30% AcOEt/hexane) 0.60; [α]24 D −6.3 (c 0.83, CHCl3); >98% ee; NMR and IR spectra were consistent with those recorded for the racemate; HRMS (ESI-TOF) m/z calcd for C15H17NNaO4 [M + Na+] 298.1055, found 298.1049. (3S,4R)-1-(4-Methoxyphenyl)-2-oxo-4-((E)-prop-1-en-1-yl)azetidin-3-yl Acetate ((+)-i): 3.788 g (34% yield); colorless crystals; mp 111.1−111.5 °C; Rf (30% AcOEt/hexane) 0.60; [α]24 D +6.0 (c 0.82, CHCl3); >99% ee; NMR and IR spectra were consistent with those recorded for the racemate; HRMS (ESI-TOF) m/z calcd for C15H17NNaO4 [M + Na+] 298.1055, found 298.1046. Preparation of β-Lactam vi. To a vigorously stirred solution of (1E,2E)-N-(4-Methoxyphenyl)-3-phenylprop-2-en-1-imine (v), (2.373 g, 10 mmol) and NEt3 (2.091 mL, 15 mmol) in anhydrous CH2Cl2 (25 mL), acetoxyacetyl chloride (1.290 mL, 12 mmol) was added dropwise over 15 min at −78 °C under an atmosphere of argon. The mixture was stirred for an additional hour at the same temperature and then was allowed to warm to 25 °C slowly overnight. At the end of this time, the reaction was quenched with 5% aqueous HCl solution (25 mL), poured into water and extracted with CH2Cl2 (2 × 25 mL). Combined extracts were washed successively with 5% aqueous HCl solution (25 mL), saturated solution of NaHCO3 (25 mL) and water (25 mL), dried over MgSO4 and concentrated. Purification of the crude product by column chromatography on silica gel using an acetone/hexane mixture as an eluent afforded β-lactam vi as colorless crystals. (3R*,4S*)-1-(4-Methoxyphenyl)-2-oxo-4-((E)-styryl)azetidin-3-yl acetate (vi): 3.273 g (97% yield); colorless crystals; Rf (30% acetone/ hexane) 0.45. Analytical data were consistent with previously reported values.27 Preparation of β-Lactams vii, (+)-vii, and (−)-vii. To a vigorously stirred solution of β-lactam i, (−)-i, or (+)-i (5.506 g, 20 mmol) in MeOH (250 mL) was added a solution of K2CO3 (5.528 g, 40 mmol) in water (125 mL) in one portion at 25 °C, and the mixture was stirred for 5 min at the same temperature. The reaction was then quenched with an aqueous saturated NH4Cl solution (100 mL), poured into water, and extracted with EtOAc (3 × 100 mL). The combined extracts were successively washed with water (200 mL), a saturated solution of NaHCO3 (100 mL) and brine (100 mL), dried over anhydrous MgSO4, and concentrated under reduced pressure.

zetidine-2-carbaldehyde (xxviii),22 2-((3R*,4S*)-1-(4-methoxyphenyl)-2-oxo-4-((E)-prop-1-en-1-yl)azetidin-3-yl)isoindoline-1,3-dione (xxxii),23 (3R*,4S*)-1-tosyl-3-((triisopropylsilyl)oxy)-4-vinylazetidin2-one (39),3a (3R*,4S*)-3-isopropyl-1-tosyl-4-vinylazetidin-2-one (41),3a (3R*,4S*)-1-(methylsulfonyl)-3-((triisopropylsilyl)oxy)-4-vinylazetidin-2-one (50), 3 b tert-butyl (3R*,4S*)-2-oxo-3((triisopropylsilyl)oxy)-4-vinylazetidine-1-carboxylate (51),24 and (3R*,4S*)-1-(4-methoxyphenyl)-3-((triisopropylsilyl)oxy)-4-vinylazetidin-2-one (52)24 were prepared following the previously reported procedures, and their analytical data were consistent with those published in the literature. Preparation of β-Lactams i−iv. To a vigorously stirred solution of crotonaldehyde were added (E)-4-methylpent-2-enal, methacrolein, or tiglic aldehyde (66 mmol) and p-anisidine (7.389 g, 60 mmol) in anhydrous CH2Cl2 (75 mL), and Na2SO4 (42.612 g, 300 mmol) at 25 °C in one portion under an atmosphere of argon. After 3 h at the same temperature, Na2SO4 was filtered off and the solvent was removed under reduced pressure. Resulting crude imines were then dissolved in anhydrous CH2Cl2 (150 mL) and cooled to −78 °C under an atmosphere of argon. NEt3 (12.544 mL, 90 mmol) was added in one portion followed by the addition of acetoxyacetyl chloride (7.74 mL,72 mmol) dropwise over 15 min. The mixture was stirred for an additional hour at −78 °C and then allowed to warm to 25 °C slowly overnight. At the end of this time, the reaction was quenched with 5% aqueous HCl solution (100 mL), poured into water, and extracted with CH2Cl2 (2 × 100 mL). Combined extracts were washed successively with 5% aqueous HCl solution (100 mL), saturated solution of NaHCO3 (100 mL), and water (100 mL), dried over MgSO4, and concentrated. Purification of the crude product by column chromatography on silica gel using an ethyl acetate/hexane mixture as an eluent afforded β-lactams i−iv as colorless crystals. (3R*,4S*)-1-(4-Methoxyphenyl)-2-oxo-4-((E)-prop-1-en-1-yl)azetidin-3-yl Acetate (i): 5.844 g (25% yield); colorless crystals; mp 94.3−95.8 °C; Rf (30% AcOEt/hexane) 0.60; 1H NMR (400 MHz, CDCl3) δ 7.42−7.31 (m, 2H), 6.90−6.81 (m, 2H), 5.96 (dqd, J = 15.5, 6.5, 0.8, 1H), 5.80 (d, J = 4.9, 1H), 5.44 (ddq, J = 15.5, 8.1, 1.7, 1H), 4.72 (dd, J = 8.1, 4.9, 1H), 3.78 (s, 3H), 2.13 (s, 3H), 1.76 (dd, J = 6.5, 1.7, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 169.6, 161.4, 156.7, 134. 7, 131.0, 123.6, 118.9, 114.5, 76.2, 60.1, 55.6, 20.5, 18.2; IR (film) v 2938, 2838, 1753, 1670, 1513, 1442, 1391, 1246, 1224, 1112, 1033, 830 cm −1 ; HRMS (ESI-TOF) m/z calcd for C15H17NNaO4 [M + Na+] 298.1055, found 298.1046. (2S*,3R*)-1-(4-Methoxyphenyl)-2-((E)-3-methylbut-1-en-1-yl)-4oxoazetidin-3-yl Acetate (ii): 12.013 g (66% yield); colorless crystals; mp 87.1−88.2 °C; Rf (25% AcOEt/hexane) 0.50; 1H NMR (400 MHz, CDCl3) δ 7.41−7.32 (m, 2H), 6.90−6.81 (m, 2H), 5.92 (ddd, J = 15.7, 6.7, 0.8, 1H), 5.78 (d, J = 4.9, 1H), 5.36 (ddd, J = 15.7, 8.0, 1.4, 1H), 4.71 (ddd, J = 8.0, 4.9, 0.8, 1H), 3.78 (s, 3H), 2.45−2.27 (m, 1H), 2.11 (s, 3H), 0.99 (d, J = 6.8, 3H), 0.98 (d, J = 6.8, 3H); 13 C{1H} NMR (101 MHz, CDCl3) δ 169.5, 161.4, 156.6, 146.7, 131.0, 119.4, 118.9, 114.4, 76.2, 60.1, 55.6, 31.2, 22.2, 22.1, 20.5; IR (film) v 3943, 2960, 2839, 1757, 1666, 1514, 1464, 1390, 1373, 1246, 1225, 1104, 1035, 831 cm−1; HRMS (ESI-TOF) m/z calcd for C17H21NNaO4 [M + Na+] 326.1368, found 326.1359. (3R*,4S*)-1-(4-Methoxyphenyl)-2-oxo-4-(prop-1-en-2-yl)azetidin-3-yl Acetate (iii): 13.049 g (79% yield); colorless crystals; mp 128.9−130.2 °C; Rf (30% AcOEt/hexane) 0.45; 1H NMR (400 MHz, CDCl3) δ 7.39−7.29 (m, 2H), 6.91−6.80 (m, 2H), 5.93 (d, J = 5.2, 1H), 5.20−5.18 (m, 1H), 5.14−5.11 (m, 1H), 4.72 (d, J = 5.2, 1H), 3.77 (s, 3H), 2.11 (s, 3H), 1.74 (s, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 169.5, 161.5, 156.8, 138.2, 131.0, 118.4, 117.7, 114.6, 75.5, 62.6, 55.6, 20.6, 19.1; IR (film) v 2980, 2943, 2844, 1749, 1514, 1465, 1370, 1248, 1221, 1111, 1015, 831 cm−1; HRMS (ESI-TOF) m/z calcd for C15H17NNaO4 [M + Na+] 298.1055, found 298.1045. (2S*,3R*)-2-((E)-But-2-en-2-yl)-1-(4-methoxyphenyl)-4-oxoazetidin-3-yl Acetate (iv): 11.110 g (64% yield); colorless crystals; mp 120.1−120.4 °C; Rf (30% AcOEt/hexane) 0.60; 1H NMR (400 MHz, CDCl3) δ 7.37−7.28 (m, 2H), 6.88−6.79 (m, 2H), 5.89 (d, J = 5.1, 1H), 5.73−5.62 (m, 1H), 4.67 (d, J = 5.1, 1H), 3.77 (s, 3H), 2.08 (s, 3H), 1.68 (dd, J = 6.8, 1.2, 3H), 1.63−1.57 (m, 3H); 13C{1H} NMR 14538


Article

The Journal of Organic Chemistry Crystallization of the crude product from ethyl acetate/hexane mixture afforded β-lactams vii, (+)-vii, and (−)-vii as colorless crystals. (3R*,4S*)-3-Hydroxy-1-(4-methoxyphenyl)-4-((E)-prop-1-en-1yl)azetidin-2-one (vii): 4.265 g (91% yield); colorless crystals; mp 139.2−139.7 °C; Rf (30% AcOEt/hexane) 0.20; 1H NMR (400 MHz, CDCl3) δ 7.42−7.31 (m, 2H), 6.89−6.79 (m, 2H), 6.04−5.90 (m, 1H), 5.60 (ddq, J = 15.5, 7.6, 1.7, 1H), 5.01 (dd, J = 7.8, 5.2, 1H), 4.64 (dd, J = 7.6, 5.2, 1H), 3.78 (s, 3H), 3.02 (d, J = 7.8, 1H), 1.82 (dd, J = 6.6, 1.7, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 166.4, 156.5, 133.9, 131.1, 124.8, 119.0, 114.4, 76.8, 61.3, 55.6, 18.3; IR (film) v 3346, 2924, 2836, 1878, 1721, 1672, 1518, 1445, 1396, 1255, 1128, 1034, 965, 827 cm−1; HRMS (ESI-TOF) m/z calcd for C13H15NNaO3 [M + Na+] 256.0950, found 256.0941. (3R,4S)-3-Hydroxy-1-(4-methoxyphenyl)-4-((E)-prop-1-en-1-yl)azetidin-2-one ((+)-vii): 3.640 g (78% yield); colorless crystals; mp 134.5−135.1 °C; Rf (30% AcOEt/hexane) 0.20; [α]25 D +152.9 (c 0.94, CHCl3); >99% ee; NMR and IR spectra were consistent with those recorded for the racemate; HRMS (ESI-TOF) m/z calcd for C13H15NNaO3 [M + Na+] 256.0950, found 256.0944. (3S,4R)-3-Hydroxy-1-(4-methoxyphenyl)-4-((E)-prop-1-en-1-yl)azetidin-2-one ((−)-vii): 3.956 g (85% yield); colorless crystals; mp 134.2−134.8 °C; Rf (30% AcOEt/hexane) 0.20; [α]25 D −153.5 (c 1.13, CHCl3); >99% ee; NMR and IR spectra were consistent with those recorded for the racemate; HRMS (ESI-TOF) m/z calcd for C13H15NNaO3 [M + Na+] 256.0950, found 256.0941. Preparation of β-Lactams viii, (+)-viii, and (−)-viii. To a stirred solution of β-lactam vii, (+)-vii, or (−)-vii (2.333 g, 10 mmol) and imidazole (1.702 g, 25 mmol) in anhydrous DMF (10 mL) was added TIPSCl (2.247 mL, 10.5 mmol) in one portion at 0 °C under an atmosphere of argon, and the mixture was stirred for 15 min at the same temperature. Then the cooling bath was removed, and the stirring was continued at 25 °C overnight. At the end of this time, the reaction mixture was poured into water and extracted with EtOAc (3 × 50 mL). Combined extracts were washed with a 5% aqueous solution of HCl (150 mL), saturated solution of NaHCO3 (50 mL) and brine (50 mL), dried over anhydrous MgSO4, and concentrated under reduced pressure. Purification of the crude product by column chromatography on silica gel using an ethyl acetate/hexane mixture as an eluent afforded β-lactams viii, (+)-viii, and (−)-viii as colorless crystals. (3R*,4S*)-1-(4-Methoxyphenyl)-4-((E)-prop-1-en-1-yl)-3((triisopropylsilyl)oxy)azetidin-2-one (viii): 3.701 g (95% yield); colorless crystals; mp 76.6−77.8 °C; Rf (30% AcOEt/hexane) 0.90; 1 H NMR (400 MHz, CDCl3) δ 7.42−7.34 (m, 2H), 6.88−6.79 (m, 2H), 5.92 (dqd, J = 15.4, 6.4, 0.6, 1H), 5.61 (ddq, J = 15.4, 8.7, 1.7, 1H), 5.05 (d, J = 5.0, 1H), 4.53 (dd, J = 8.7, 5.0, 1H), 3.77 (s, 3H), 1.77 (dd, J = 6.4, 1.7, 3H), 1.24−0.98 (m, 21H); 13C{1H} NMR (101 MHz, CDCl3) δ 165.6, 156.2, 132.7, 131.8, 126.8, 118.7, 114.4, 77.8, 62.1, 55.6, 18.1, 17.84, 17.79, 12.1; IR (film) v 2943, 2866, 1751, 1671, 1513, 1464, 1387, 1246, 1181, 1128, 1036, 966, 829 cm−1; HRMS (ESI-TOF) m/z calcd for C22H35NNaO3Si [M + Na+] 412.2284, found 412.2269. (3R,4S)-1-(4-Methoxyphenyl)-4-((E)-prop-1-en-1-yl)-3((triisopropylsilyl)oxy)azetidin-2-one ((+)-viii): 3.818 g (98% yield); colorless crystals; mp 75.4−76.3 °C; Rf (30% AcOEt/hexane) 0.90; [α]25 D +73.5 (c 2.36, CHCl3); NMR and IR spectra were consistent with those recorded for the racemate; HRMS (ESI-TOF) m/z calcd for C22H35NNaO3Si [M + Na+] 412.2284, found 412.2273. (3S,4R)-1-(4-Methoxyphenyl)-4-((E)-prop-1-en-1-yl)-3((triisopropylsilyl)oxy)azetidin-2-one ((−)-viii): 3.779 g (97% yield); colorless crystals; mp 76.1−76.9 °C; Rf (30% AcOEt/hexane) 0.90; [α]25 D −77.1 (c 1.58, CHCl3); NMR and IR spectra were consistent with those recorded for the racemate; HRMS (ESI-TOF) m/z calcd for C22H35NNaO3Si [M + Na+] 412.2284, found 412.2267. Preparation of β-Lactams ix and x. To a solution of β-lactam vii (2.333 g, 10 mmol), DMAP (122 mg, 1 mmol), and NEt3 (5.575 mL, 40 mmol) in anhydrous CH2Cl2 (100 mL) was added methanesulfonyl chloride (1.548 mL, 20 mmol) dropwise at 0 °C under an atmosphere of argon, and the mixture was stirred for 15 min

at the same temperature. Then the cooling bath was removed, and the stirring was continued for an additional 30 min at 25 °C. At the end of this time, the reaction was poured into water and extracted with CH2Cl2 (2 × 50 mL). The combined extracts were washed successively with a 5% aqueous solution of HCl (50 mL), saturated solution of NaHCO3 (50 mL) and water (50 mL), dried over anhydrous MgSO4, and concentrated under reduced pressure. Purification of the crude product by column chromatography on silica gel using an ethyl acetate/hexane mixture as an eluent afforded β-lactam ix as colorless crystals. β-Lactam ix (2.74 g, 8.8 mmol) and anhydrous sodium acetate (3.609 g, 44 mmol) were dissolved in anhydrous DMSO (110 mL), and the mixture was stirred at 130 °C for 24 h under an atmosphere of argon. After being cooled to 25 °C, the mixture was poured into water and extracted with ethyl acetate (3 × 75 mL). The combined extracts were washed with a 5% aqueous solution of HCl (200 mL), water (4 × 200 mL), and brine (100 mL), dried over anhydrous MgSO4, and concentrated under reduced pressure. The residue was dissolved in MeOH (100 mL), and the solution of K2CO3 (2.433 g, 17.6 mmol) in water (50 mL) was added in one portion at 25 °C. After 5 min of stirring at the same temperature, the reaction was quenched with an aqueous saturated NH4Cl solution (100 mL), poured into water, and extracted with EtOAc (3 × 50 mL). The combined extracts were successively washed with water (100 mL), a saturated solution of NaHCO3 (50 mL), and brine (50 mL), dried over anhydrous MgSO4, and concentrated under reduced pressure. Filtration of the residue through a pad of silica gel with ethyl acetate/ hexane afforded the crude alcohol, which was then dissolved in anhydrous DMF (10 mL), and imidazole (1.498 g, 22 mmol) and TIPSCl (1.977 mL, 9.24 mmol) were sequentially added in one portion at 0 °C under an atmosphere of argon. The mixture was stirred for 15 min at the same temperature. Then the cooling bath was removed, and the stirring was continued at 25 °C overnight. Then the reaction mixture was poured into water and extracted with ethyl acetate (3 × 50 mL). Combined extracts were washed with a 5% aqueous solution of HCl (150 mL), saturated solution of NaHCO3 (50 mL), and brine (50 mL), dried over anhydrous MgSO4, and concentrated under reduced pressure. Purification of the crude product by column chromatography on silica gel using an ethyl acetate/hexane mixture as an eluent afforded β-lactam x as colorless crystals. (3R*,4S*)-1-(4-Methoxyphenyl)-2-oxo-4-((E)-prop-1-en-1-yl)azetidin-3-yl Methanesulfonate (ix): 2.740 g (88% yield); colorless crystals; mp 110.3−111.7 °C; Rf (30% AcOEt/hexane) 0.30; 1H NMR (400 MHz, CDCl3) δ 7.40−7.31 (m, 2H), 6.91−6.82 (m, 2H), 6.05 (ddd, J = 15.4, 6.6, 0.7, 1H), 5.64 (d, J = 5.2, 1H), 5.54 (ddd, J = 15.4, 8.5, 1.7, 1H), 4.77 (dd, J = 8.5, 5.2, 1H), 3.78 (s, 3H), 3.24 (s, 3H), 1.81 (dd, J = 6.6, 1.7, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 159.8, 157.0, 135.7, 130.5, 123.5, 119.0, 114.6, 79.8, 60.3, 55.6, 39.4, 18.2; IR (film) v 3018, 2937, 2838, 1756, 1671, 1585, 1514, 1442, 1365, 1248, 1179, 1081, 890, 831 cm−1; HRMS (ESI-TOF) m/z calcd for C14H17NNaO5S [M + Na+] 334.0725, found 334.0713. (3S*,4S*)-1-(4-Methoxyphenyl)-4-((E)-prop-1-en-1-yl)-3((triisopropylsilyl)oxy)azetidin-2-one (x): 1.851 g (54% yield); colorless crystals; mp 86.1−86.6 °C; Rf (30% AcOEt/hexane) 0.90; 1 H NMR (400 MHz, CDCl3) δ 7.41−7.30 (m, 2H), 6.89−6.79 (m, 2H), 5.95 (dq, J = 15.4, 6.5, 1H), 5.52 (ddq, J = 15.4, 8.6, 1.7, 1H), 4.66 (d, J = 1.6, 1H), 4.23 (dd, J = 8.6, 1.6, 1H), 3.77 (s, 3H), 1.76 (dd, J = 6.5, 1.7, 3H), 1.21−1.05 (m, 21H); 13C{1H} NMR (101 MHz, CDCl3) δ 165.2, 156.2, 131.7, 131.6, 127.7, 118.9, 114.4, 82.6, 65.5, 55.6, 18.0, 17.8, 12.1; IR (film) v 2943, 2867, 1756, 1670, 1513, 1464, 1386, 1247, 1151, 1035, 830, 687 cm−1; HRMS (ESI-TOF) m/ z calcd for C22H35NNaO3Si [M + Na+] 412.2284, found 412.2274. Preparation of β-Lactams xi and (+)-xi. To a solution of βlactam vii or (+)-vii (2.333 g, 10 mmol) and CBr4 (8.291 g, 25 mmol) in anhydrous THF (150 mL) was added a solution of PPh3 (6.557 g, 25 mmol) in anhydrous THF (150 mL) dropwise at 25 °C under an atmosphere of argon. The mixture was stirred for 15 min at the same temperature and then refluxed for an additional 30 min. After being cooled to 25 °C, the mixture was diluted with MTBE (300 14539


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The Journal of Organic Chemistry mL) and filtered through a pad of Celite. Removal of solvents under reduced pressure and filtration of the residue through a pad of silica gel using CH2Cl2 afforded the crude bromide, which was then dissolved in THF (100 mL) with the addition of acetic acid (10 mL). To this mixture was added Zn dust (6.516 mg, 100 mmol) portionwise at 25 °C under an atmosphere of argon. After an additional 15 min at the same temperature, reaction mixture was poured carefully into a vigorously stirred saturated solution of NaHCO3 (100 mL) and extracted with AcOEt (3 × 75 mL). Combined extracts were washed with water (100 mL) and brine (100 mL) and dried over anhydrous MgSO4. Solvents were then removed under reduced pressure, and the crude product was purified by column chromatography on silica gel using an acetone/hexane mixture as an eluent to afford β-lactam xi or (+)-xi. (R*,E)-1-(4-Methoxyphenyl)-4-(prop-1-en-1-yl)azetidin-2-one (xi): 1.086 g (50% yield); colorless oil; Rf (15% acetone/hexane) 0.45. Analytical data were consistent with previously reported values.28 (R,E)-1-(4-Methoxyphenyl)-4-(prop-1-en-1-yl)azetidin-2-one ((+)-xi): 1.108 g (51% yield); colorless oil; Rf (15% acetone/hexane) 0.45; [α]25 D +61.1 (c 1.35, CHCl3); NMR and IR spectra were consistent with those recorded for the racemate; HRMS (ESI-TOF) m/z calcd for C13H15NNaO2 [M + Na+] 240.1000, found 240.0994. Preparation of β-Lactams xii−xv. To a solution of β-lactam ii− iv or vi (5 mmol) in MeOH (70 mL) was added a solution of K2CO3 (1.382 g, 10 mmol) in water (35 mL) in one portion at 25 °C, and the mixture was stirred for 5 min at the same temperature. The reaction was then quenched with an aqueous saturated NH4Cl solution (50 mL), poured into water, and extracted with EtOAc (3 × 50 mL). The combined extracts were washed successively with water (100 mL), a saturated solution of NaHCO3 (50 mL), and brine (50 mL), dried over anhydrous MgSO4, and concentrated under reduced pressure. The obtained crude alcohols were dissolved in anhydrous DMF (5 mL), and imidazole (851 mg, 12.5 mmol) and TIPSCl (1.121 mL, 5.25 mmol) were sequentially added both in one portion at 0 °C under an atmosphere of argon. The mixture was stirred for 15 min at the same temperature. Then the cooling bath was removed, and the stirring was continued at 25 °C overnight. At the end of this time, the reaction mixture was poured into water and extracted with ethyl acetate (3 × 50 mL). Combined extracts were washed with a 5% aqueous solution of HCl (100 mL), saturated solution of NaHCO3 (50 mL), and brine (50 mL), dried over anhydrous MgSO4, and concentrated under reduced pressure. Purification of the crude product by column chromatography on silica gel using an ethyl acetate/hexane mixture as an eluent afforded β-lactams xii−xv as colorless crystals. (3R*,4S*)-1-(4-Methoxyphenyl)-4-((E)-3-methylbut-1-en-1-yl)-3((triisopropylsilyl)oxy)azetidin-2-one (xii): 2.067 g (99% yield); colorless crystals; mp 97.9−98.4 °C; Rf (15% AcOEt/hexane) 0.70; 1 H NMR (400 MHz, CDCl3) δ 7.43−7.34 (m, 2H), 6.89−6.77 (m, 2H), 5.91 (dd, J = 15.6, 6.4, 1H), 5.55 (ddd, J = 15.6, 8.8, 1.4, 1H), 5.05 (d, J = 5.0, 1H), 4.52 (dd, J = 8.8, 5.0, 1H), 3.77 (s, 3H), 2.37 (dheptd, J = 13.5, 6.7, 1.4, 1H), 1.19−1.06 (m, 21H), 1.02 (dd, J = 6.7, 0.9, 6H); 13C{1H} NMR (101 MHz, CDCl3) δ 165.6, 156.2, 145.2, 131.9, 122.4, 118.6, 114.3, 77.7, 62.4, 55.6, 31.2, 22.1, 21.9, 17.89, 17.86, 12.0; IR (film) v 3073, 2957, 2867, 1877, 1749, 1663, 1515, 1463, 1386, 1248, 1129, 1033, 839, 688 cm−1; HRMS (ESITOF) m/z calcd for C24H39NNaO3Si [M + Na+] 440.2597, found 440.2592. (3R*,4S*)-1-(4-Methoxyphenyl)-4-(prop-1-en-2-yl)-3((triisopropylsilyl)oxy)azetidin-2-one (xiii): 1.868 g (96% yield); colorless crystals; mp 81.7−82.9 °C; Rf (30% AcOEt/hexane) 0.80; 1 H NMR (400 MHz, CDCl3) δ 7.41−7.31 (m, 2H), 6.88−6.79 (m, 2H), 5.17 (p, J = 1.6, 1H), 5.13 (dt, J = 1.6, 0.8, 1H), 5.11 (d, J = 5.2, 1H), 4.58 (d, J = 5.2, 1H), 3.77 (s, 3H), 1.80−1.77 (m, 3H), 1.21− 1.07 (m, 21H); 13C{1H} NMR (101 MHz, CDCl3) δ 165.7, 156.3, 141.1, 131.9, 118.2, 116.6, 114.5, 77.7, 64.7, 55.6, 19.1, 17.9, 17.8, 12.1; IR (film) v 3078, 2944, 2867, 1753, 1583, 1513, 1464, 1388, 1248, 1183, 1127, 1036, 881, 830, 685 cm−1; HRMS (ESI-TOF) m/z calcd for C22H35NNaO3Si [M + Na+] 412.2284, found 412.2279.

(3R*,4S*)-4-((E)-But-2-en-2-yl)-1-(4-methoxyphenyl)-3((triisopropylsilyl)oxy)azetidin-2-one (xiv): 1.978 g (98% yield); colorless crystals; mp 93.5−94.7 °C; Rf (15% AcOEt/hexane) 0.70; 1 H NMR (400 MHz, CDCl3) δ 7.39−7.31 (m, 2H), 6.88−6.77 (m, 2H), 5.72−5.61 (m, 1H), 5.06 (d, J = 5.1, 1H), 4.52 (d, J = 5.1, 1H), 3.76 (s, 3H), 1.70 (dd, J = 6.7, 1.2, 3H), 1.64 (t, J = 1.2, 3H), 1.18− 1.04 (m, 21H); 13C{1H} NMR (101 MHz, CDCl3) δ 166.0, 156.2, 132.1, 131.9, 125.8, 118.2, 114.4, 77.8, 66.4, 55.5, 17.8, 17.7, 13.6, 12.9, 12.0; IR (film) v 2943, 2867, 1751, 1514, 1465, 1384, 1248, 1182, 1128, 829, 686 cm−1; HRMS (ESI-TOF) m/z calcd for C23H37NNaO3Si [M + Na+] 426.2440, found 426.2426. (3R*,4S*)-1-(4-Methoxyphenyl)-4-((E)-styryl)-3((triisopropylsilyl)oxy)azetidin-2-one (xv): 2.213 g (98% yield); Rf (15% AcOEt/hexane) 0.60. Analytical data were consistent with previously reported values.29 Preparation of Chloride xvi. To a vigorously stirred solution of methyl {[tri(propan-2-yl)silyl]oxy}acetate (12.321 g, 50 mmol) in THF (30 mL) cooled to −10 °C, KOH (2.973 g, 52.5 mmol) dissolved in 30% MeOH/water mixture (18 mL) was added carefully so that the reaction temperature did not exceed −5 °C. Then the reaction was warmed to 5 °C and stirring was continued for additional 30 min. At the end of this time the mixture was diluted with water (200 mL), washed with Et2O (100 mL) and phases were separated. Aqueous layer was cooled to 0 °C, acidified by addition of 10% aqueous solution o HCl (20 mL) and extracted with Et2O (3 × 100 mL). Combined extracts were washed with water (200 mL) and brine (100 mL), dried over anhydrous MgSO4 and concentrated under reduced pressure. The resulting crude acid was dissolved in anhydrous toluene (60 mL) and oxalyl chloride (6.542 mL, 75 mmol) was added dropwise at 25 °C under an atmosphere of argon. Then the reaction was heated to reflux until evolution of gaseous side products stopped (about 30−40 min) and the solvents and oxalyl chloride excess were distilled off to give chloride xvi as colorless oil. 2-((Triisopropylsilyl)oxy)acetyl chloride (xvi): 10.661 g (85% yield); colorless oil; analytical data were consistent with previously reported values;30 1H NMR (400 MHz, CDCl3) δ 4.62 (s, 2H), 1.18− 1.03 (m, 21H); 13C{1H} NMR (101 MHz, CDCl3) δ 172.9, 70.3. Preparation of β-Lactam xvii. To a vigorously stirred solution of (E)-4-oxo-2-butenoic acid ethyl ester (2.819 g, 22 mmol) and panisidine (2.463 g, 20 mmol) in anhydrous CH2Cl2 (25 mL) was added Na2SO4 (14.204 g, 100 mmol) in one portion at 25 °C under an atmosphere of argon. After the mixture was stirred for 3 h at the same temperature, Na2SO4 was filtered off and the solvent was removed under reduced pressure. The resulting crude imine was dissolved in anhydrous toluene (300 mL), and NEt3 (4.181 mL, 30 mmol) was added followed by chloride xvi (6.02 g, 24 mmol) both in one portion at 25 °C under an atmosphere of argon. Then the reaction was heated to 80 °C for 2.5 h. After being cooled to 25 °C, the mixture was poured into the water and the layers were separated. The water layer was extracted with a portion of toluene (50 mL), and the combined extracts were washed with a 5% aqueous HCl solution (300 mL), saturated solution of NaHCO3 (300 mL), and brine (300 mL), dried over MgSO4, and concentrated. Purification of the crude product by column chromatography on silica gel using an ethyl acetate/hexane mixture as an eluent afforded β-lactam xvii as colorless crystals. Ethyl (E)-3-((2S*,3R*)-1-(4-methoxyphenyl)-4-oxo-3((triisopropylsilyl)oxy)azetidin-2-yl)acrylate (xvii): 5.909 g (66% yield); colorless crystals; mp 49.7−50.9 °C; Rf (15% AcOEt/hexane) 0.65; 1H NMR (400 MHz, CDCl3) δ 7.36−7.27 (m, 2H), 7.00 (dd, J = 15.8, 7.6, 1H), 6.89−6.79 (m, 2H), 6.13 (dd, J = 15.8, 0.9, 1H), 5.19 (d, J = 5.1, 1H), 4.71 (ddd, J = 7.6, 5.1, 0.9, 1H), 4.19 (qq, J = 10.9, 7.1, 1H), 3.78 (s, 3H), 1.27 (t, J = 7.1, 3H), 1.21−1.02 (m, 21H); 13C{1H} NMR (101 MHz, CDCl3) δ 165.2, 164.8, 142.7, 126.5, 118.5, 114.6, 78.6, 60.8, 60.1, 55.6, 17.9, 17.8, 14.3, 12.0; IR (film) v 2944, 2867, 1757, 1722, 1659, 1584, 1514, 1465, 1388, 1249, 1179, 1122, 1037, 882, 830, 688 cm−1; HRMS (ESI-TOF) m/z calcd for C24H37NNaO5Si [M + Na]+ 470.2339, found 470.2325. Preparation of β-Lactams xix and xxa−xxb. To a solution of (1E,2Z)-N1,N2-bis(4-methoxyphenyl)propane-1,2-diimine (xviii) 14540


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formylazetidinon-2-ones, which were used in the next step without further purification. To a vigorously stirred suspension of methyltriphenylphosphonium bromide (4.644 g, 13 mmol) or ethyltriphenylphosphonium bromide (4.826 g, 13 mmol) in anhydrous THF (200 mL) was added a 2.5 M solution of n-butyllithium in hexanes (5.2 mL, 13 mmol) dropwise at −78 °C under an atmosphere of argon, and the mixture was stirred for 10 min at the same temperature. Then the cooling bath was removed, and the stirring was continued for 30 min at 25 °C. After the mixture was cooled to −78 °C, the generated in situ ylide was transferred via cannula to the vigorously stirred solution of the previously prepared crude 4-formylazetidinon-2-ones in anhydrous THF (150 mL), cooled to −78 °C under an atmosphere of argon. The mixture was stirred for an additional hour at the same temperature and then allowed to warm to 25 °C slowly overnight. The reaction was quenched with a saturated aqueous NH4Cl solution (100 mL), poured into water, and extracted with EtOAc (3 × 100 mL). Combined extracts were successively washed with water (100 mL), a saturated solution of NaHCO3 (50 mL), and brine (50 mL), dried over anhydrous MgSO4, and concentrated under reduced pressure. Purification of the crude product by column chromatography on silica gel using an ethyl acetate/hexane or acetone/hexane mixture as an eluent afforded β-lactams xxii−xxiv, (−)-xxiv, and xxv as colorless crystals. (3R*,4S*)-1-(4-Methoxyphenyl)-4-((Z)-prop-1-en-1-yl)-3((triisopropylsilyl)oxy)azetidin-2-one (xxii): 2.805 mg (72% yield); Z/E = 86:14, colorless crystals; mp 120.1−121.3 °C; Rf (15% AcOEt/ hexane) 0.75; 1H NMR (400 MHz, CDCl3) δ (major) 7.37−7.28 (m, 2H), 6.88−6.79 (m, 2H), 5.91 (dqd, J = 11.3, 7.1, 1.0, 1H), 5.57 (ddq, J = 11.3, 10.0, 1.8, 1H), 5.08 (d, J = 4.9, 1H), 4.90 (ddd, J = 10.0, 4.9, 1.0, 1H), 3.77 (s, 3H), 1.86 (dd, J = 7.1, 1.8, 3H), 1.22− 1.01 (m, 21H); 13C{1H} NMR (101 MHz, CDCl3) δ (major): 165.6, 156.3, 131.6, 131.1, 125.8, 118.5, 114.4, 77.6, 56.2, 55.6, 17.84, 17.80, 13.6, 12.1; IR (film) v 2943, 2866, 1745, 1658, 1514, 1460, 1383, 1249, 1127, 1032, 903, 837, 694 cm−1; HRMS (ESI-TOF) m/z calcd for C22H35NNaO3Si [M + Na]+ 412.2284, found 412.2273. (3S*,4S*)-1-(4-Methoxyphenyl)-4-((Z)-prop-1-en-1-yl)-3((triisopropylsilyl)oxy)azetidin-2-one (xxiii): 2.883 g (74% yield), Z/ E = 82:18; after crystallization from MeOH 1.831 g (47% yield), Z/E = 95:5, colorless crystals; mp 97.1−97.5 °C; Rf (15% AcOEt/hexane) 0.75; 1H NMR (400 MHz, CDCl3) δ 7.36−7.28 (m, 2H), 6.88−6.80 (m, 2H), 5.85 (dqd, J = 10.9, 7.0, 1.0, 1H), 5.49−5.37 (m, 1H), 4.69 (d, J = 1.7, 1H), 4.61 (ddd, J = 10.2, 1.7, 1.0, 1H), 3.77 (s, 3H), 1.89 (dd, J = 7.0, 1.8, 3H), 1.22−1.06 (m, 21H); 13C{1H} NMR (101 MHz, CDCl3) δ 165.2, 156.3, 131.5, 130.7, 127.2, 118.6, 114.4, 82.5, 60.2, 55.6, 17.8, 13.8, 12.1; IR (film) v 2943, 2867, 1757, 1657, 1586, 1513, 1465, 1386, 1248, 1152, 1037, 941, 830, 716 cm−1; HRMS (ESI-TOF) m/z calcd for C22H35NNaO3Si [M + Na]+ 412.2284, found 412.2276. (R*,Z)-1-(4-Methoxyphenyl)-4-(prop-1-en-1-yl)azetidin-2-one (xxiv): 891 mg (41% yield), Z/E = 78:22, colorless crystals; mp 63.5− 64.6 °C; Rf (25% AcOEt/hexane) 0.50; 1H NMR (400 MHz, CDCl3) δ (major) 7.31−7.25 (m, 2H), 6.86−6.80 (m, 2H), 5.78 (dqd, J = 11.0, 7.0, 1.0, 1H), 5.52−5.43 (m, 1H), 4.75 (dddd, J = 9.3, 5.5, 2.6, 1.0, 1H), 3.75 (s), 3.31 (dd, J = 15.0, 5.5, 1H), 2.76 (dd, J = 15.0, 2.6, 1H), 1.84 (dd, J = 7.0, 1.8, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 163.9, 156.0, 131.9, 129.8, 128.9, 117.9, 114.4, 55.5, 47.7, 43.7, 13.5; IR (film) v 2997, 2951, 2836, 1745, 1658, 1583, 1512, 1442, 1379, 1245, 1140, 1036, 830, 517 cm−1; HRMS (ESI-TOF) m/z calcd for C13H15NNaO2 [M + Na]+ 240.1000, found 240.0994. (R,Z)-1-(4-Methoxyphenyl)-4-(prop-1-en-1-yl)azetidin-2-one ((−)-xxiv): 1.029 g (47% yield), Z/E = 76:24, colorless oil; Rf (25% AcOEt/hexane) 0.50; [α]25 D −20.9 (c 0.70, CHCl3); NMR and IR spectra were consistent with those recorded for the racemate; HRMS (ESI-TOF) m/z calcd for C13H15NNaO2 [M + Na]+ 240.1000, found 240.0996. (3R*,4R*)-3-Isopropyl-1-(4-methoxyphenyl)-4-vinylazetidin-2one (xxv): 1.662 g (81% yield); colorless wax; Rf (20% acetone/ hexane) 0.75; 1H NMR (400 MHz, CDCl3) δ 7.40−7.30 (m, 2H), 6.88−6.79 (m, 2H), 5.93 (ddd, J = 17.1, 10.3, 8.0, 1H), 5.44 (dt, J =

(5.647 g, 20 mmol) in anhydrous toluene (300 mL) were added NEt3 (4.181 mL, 30 mmol) and chloride xvi (6.02 g, 24 mmol) sequentially both in one portion at 25 °C under an atmosphere of argon, and the reaction was heated at 80 °C for 3 h. After the mixture cooled to 25 °C, a 5% aqueous solution of HCl was added in one portion (300 mL) and stirring was continued for an additional 1 h. At the end of this time, the phases were separated and the aqueous one was extracted with toluene (2 × 100 mL). Combined extracts were washed with a 5% aqueous HCl solution (2 × 100 mL), saturated solution of NaHCO3 (100 mL), and brine (100 mL), dried over MgSO4, and concentrated. Purification of the crude product by column chromatography on silica gel using CH2Cl2 as an eluent afforded β-lactam xix as colorless crystals. To a vigorously stirred solution of β-lactam xix (3.916 g, 10 mmol) in anhydrous toluene (400 mL) was added 0.6 M Tebbe reagent solution in toluene (16.667 mL, 10 mmol) dropwise at 0 °C under an atmosphere of argon, and stirring was continued for 15 min at the same temperature. At the end of this time, the reaction was quenched with a 5% aqueous HCl solution (200 mL), poured into water, and extracted with toluene (2 × 100 mL). Combined extracts were washed successively with a 5% aqueous HCl solution (100 mL), saturated solution of NaHCO3 (100 mL), and brine (100 mL), dried over MgSO4, and concentrated. Purification of the crude product by column chromatography on silica gel using an ethyl acetate/hexane mixture as an eluent afforded β-lactams xxa and xxb as colorless crystals. (2R*,3R*)-1-(4-Methoxyphenyl)-2-methyl-4-oxo-3((triisopropylsilyl)oxy)azetidine-2-carbaldehyde (xix): 4.229 g (54% yield), white solid; mp 97.8−99.1 °C; Rf (1% MeOH/CH2Cl2) 0.65; 1 H NMR (400 MHz, CDCl3) δ 9.87 (s, 1H), 7.26−7.18 (m, 2H), 6.88−6.82 (m, 2H), 4.82 (s, 1H), 3.77 (s, 3H), 1.62 (s, 3H), 1.20− 1.02 (m, 21H); 13C{1H} NMR (101 MHz, CDCl3) δ 201.7, 164.5, 157.1, 129.6, 119.2, 114.8, 114.8, 86.0, 70.3, 55.6, 17.7, 17.7, 14.9, 11.9; IR (film) v 2945, 2868, 2718, 1763, 1612, 1584, 1513, 1464, 1380, 1250, 1150, 1036, 832, 688 cm−1; HRMS (ESI-TOF) m/z calcd for C21H33NNaO4Si [M + Na+] 414.2077, found 414.2065. (3R*,4S*)-1-(4-Methoxyphenyl)-4-methyl-3-((triisopropylsilyl)oxy)-4-vinylazetidin-2-one (xxa): 740 mg (19% yield); colorless crystals; mp 69.3−70.2 °C; Rf (15% AcOEt/hexane) 0.70; relative configuration was assigned by NOE measurements; 1H NMR (400 MHz, CDCl3) δ 7.46−7.37 (m, 2H), 6.88−6.78 (m, 2H), 6.15 (dd, J = 17.6, 10.9, 1H), 5.45 (dd, J = 10.9, 0.9, 1H), 5.40 (dd, J = 17.6, 0.9, 1H), 4.68 (s, 1H), 1.67 (s, 3H), 1.24−0.99 (m, 21H); 13C{1H} NMR (101 MHz, CDCl3) δ 165.1, 156.3, 138.0, 130.7, 119.5, 118.5, 114.4, 84.9, 66.9, 55.6, 19.6, 17.9, 17.8, 12.1; IR (film) v 3087, 2944, 2867, 1751, 1583, 1513, 1464, 1378, 1247, 1155, 1038, 829, 685 cm−1; HRMS (ESI-TOF) m/z calcd for C22H35NNaO3Si [M + Na]+ 412.2284, found 412.2268. (3R*,4R*)-1-(4-Methoxyphenyl)-4-methyl-3-((triisopropylsilyl)oxy)-4-vinylazetidin-2-one (xxb): 234 mg (6% yield); colorless crystals; mp 52.8−53.9 °C; Rf (15% AcOEt/hexane) 0.75; relative configuration was assigned by NOE measurements; 1H NMR (400 MHz, CDCl3) δ 7.49−7.40 (m, 2H), 6.87−6.78 (m, 2H), 6.07 (dd, J = 17.5, 10.8, 1H), 5.33 (d, J = 17.5, 2H), 5.32 (d, J = 10.8, 1H), 4.65 (s, 1H), 3.77 (s, 3H), 1.63 (s, 3H), 1.22−1.03 (m, 21H); 13C{1H} NMR (101 MHz, CDCl3) δ 165.4, 156.1, 139.9, 130.9, 119.2, 117.0, 114.3, 83.9, 66.6, 55.6, 18.0,17.9, 17.8, 16.5, 12.1; IR (film) v 2944, 2867, 1753, 1513, 1464, 1377, 1247, 1156, 1039, 829, 686 cm−1; HRMS (ESI-TOF) m/z calcd for C22H35NNaO3Si [M + Na]+ 412.2284, found 412.2271. Preparation of β-Lactams xxii−xxiv, (−)-xxiv, and xxv. A mixture of β-lactam viii, x, xi, (+)-xi or xxi (10 mmol) and saturated ethanolic solution of ozonizable dye Sudan red 7B (0.2 mL) in anhydrous CH2Cl2 (50 mL) was cooled to −78 °C, and ozone was bubbled through it until the deep red color of the reaction mixture turned to pale yellow. Then dimethyl sulfide (2.5 mL) was added in one portion; the cooling bath was removed, and the stirring was continued for 3 h at 25 °C. At the end of this time, the solvents were removed under reduced pressure and the residue was filtered through a pad silica gel using a MeOH/CH2Cl2 mixture to afford crude 414541


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The Journal of Organic Chemistry 17.1, 0.9, 1H), 5.30 (dt, J = 10.3, 0.9, 1H), 4.16 (dd, J = 8.0, 2.4, 1H), 3.76 (s, 3H), 2.79 (dd, J = 8.3, 2.4, 1H), 2.19−2.02 (m, 1H), 1.12 (d, J = 6.7, 3H), 1.03 (d, J = 6.7, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 166.4, 156.0, 136.8, 131.9, 118.7, 118.2, 114.4, 64.0, 58.4, 55.6, 28.5, 20.3, 20.2; IR (film) v 3081, 2958, 2873, 1742, 1641, 1584, 1513, 1465, 1386, 1246, 1147, 1032, 928, 830, 522 cm−1; HRMS (ESI-TOF) m/z calcd for C15H19NNaO2 [M + Na]+ 268.1313, found 268.1302. Preparation of β-Lactam xxvii. To a vigorously stirred suspension of methyltriphenylphosphonium bromide (4.644 g, 13 mmol) in anhydrous THF (200 mL) was added a 2.5 M solution of nbutyllithium in hexanes (5.2 mL, 13 mmol) dropwise over 15 min at −78 °C under an atmosphere of argon, and the mixture was stirred for 10 min at the same temperature. Then the cooling bath was removed, and the stirring was continued for 30 min at 25 °C. After the mixture cooled to −78 °C, the generated in situ ylide was transferred via cannula to the vigorously stirred solution of 4-formylazetidinon-2-one xxvi (10 mmol) in anhydrous THF (150 mL), cooled to −78 °C under an atmosphere of argon. The mixture was stirred for an additional hour at the same temperature and then allowed to warm to 25 °C slowly overnight. The reaction was quenched with an aqueous saturated NH4Cl solution (100 mL), poured into water, and extracted with EtOAc (3 × 100 mL). The combined extracts were washed successively with water (100 mL), a saturated solution of NaHCO3 (50 mL), and brine (50 mL), dried over anhydrous MgSO4, and concentrated under reduced pressure. Purification of the crude product by column chromatography on silica gel using an ethyl acetate/hexane mixture as an eluent afforded β-lactam xxvii as colorless crystals. (3R*,4S*)-1-(4-Methoxyphenyl)-3-methyl-4-vinylazetidin-2-one (xxvii): 1.890 g (87% yield); colorless crystals; mp 78.1−78.5 °C; Rf (30% AcOEt/hexane) 0.65; 1H NMR (400 MHz, CDCl3) δ 7.37− 7.28 (m, 2H), 6.86−6.77 (m, 2H), 5.84 (ddd, J = 17.6, 10.2, 7.6, 1H), 5.46−5.36 (m, 2H), 4.52 (ddt, J = 7.6, 5.8, 0.9, 1H), 3.75 (s, 3H), 3.47 (qd, J = 7.6, 5.8, 1H), 1.19 (d, J = 7.6, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 167.8, 156.0, 133.6, 131.9, 120.7, 118.2, 114.3, 57.4, 55.5, 48.3, 9.7; IR (film) v 3081, 2971, 2933, 2836, 1863, 1741, 1642, 1584, 1513, 1443, 1388, 1246, 1159, 1032, 931, 831, 526 cm−1; HRMS (ESI-TOF) m/z calcd for C13H15NNaO2 [M + Na]+ 240.1000, found 240.0992. Preparation of β-Lactam xxix. To a vigorously stirred suspension of methyltriphenylphosphonium bromide (3.929 g, 11 mmol) in anhydrous THF (200 mL) was added a 2.5 M solution of nbutyllithium in hexanes (4.4 mL, 11 mmol) dropwise at −78 °C under an atmosphere of argon, and the mixture was stirred for 10 min at the same temperature. Then the cooling bath was removed, and the stirring was continued for 30 min at 25 °C. After the mixture cooled to −78 °C, the generated in situ ylide was transferred via cannula to a vigorously stirred solution of 4-formylazetidinon-2-one xxviii (3.503 g, 10 mmol) in anhydrous THF (700 mL),31 cooled to −78 °C under an atmosphere of argon. The reaction mixture was stirred for 30 min at the same temperature; then the cooling bath was removed, and stirring was continued until the reaction mixture reached 25 °C. Then an aqueous saturated NH4Cl solution (150 mL) was added, and THF was carefully distilled off under reduced pressure without separating phases. The concentrated reaction mixture was diluted with water (300 mL) and extracted with CH2Cl2 (3 × 150 mL). The combined extracts were successively washed with water (250 mL) and a saturated solution of NaHCO3 (150 mL), dried over anhydrous MgSO4, and concentrated under reduced pressure. Purification of the crude product by column chromatography on silica gel using an acetone/hexane mixture as an eluent afforded β-lactam xxix as colorless crystals. 2-((3R*,4S*)-1-(4-Methoxyphenyl)-2-oxo-4-vinylazetidin-3-yl)isoindoline-1,3-dione (xxix): 2.264 g (65% yield); colorless crystals; mp 161.4−161.8 °C; Rf (30% acetone/hexane) 0.5; 1H NMR (400 MHz, CDCl3) δ 7.92−7.79 (m, 2H), 7.79−7.69 (m, 2H), 7.47−7.38 (m, 2H), 6.92−6.83 (m, 2H), 5.92 (dt, J = 17.6, 10.4, 8.1, 1H), 5.59 (d, J = 5.5, 1H), 5.50 (d, J = 17.6, 1H), 5.34 (d, J = 10.4, 1H), 4.84 (t, J = 8.1, 5.5, 1H), 3.78 (s, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ

167.2, 160.5, 156.6, 134.6, 132.0, 131.7, 131.3, 123.8, 123.2, 118.6, 114.5, 60.8, 57.6, 55.6; IR (film) v 2957, 2837, 1756, 1721, 1612, 1586, 1513, 1466, 1388, 1247, 1131, 1032, 945, 830, 714 cm−1; HRMS (ESI-TOF) m/z calcd for C20H16N2NaO4 [M + Na]+ 371.1008, found 371.1003. Preparation of β-Lactams xxx and xxxi. A mixture of xiv (4.036 g, 10 mmol) and saturated ethanolic solution of ozonizable dye Sudan red 7B (0.2 mL) in anhydrous CH2Cl2 (40 mL) was cooled to −78 °C, and ozone was bubbled through it until the deep red color of the reaction mixture turned to pale yellow. Then a dimethyl sulfide (4 mL) was added in one portion; the cooling bath was removed, and stirring was continued for an additional 3 h at 25 °C. At the end of this time, the reaction mixture was concentrated under reduced pressure and the resulting crude product was purified by column chromatography on silica gel using an ethyl acetate/hexane mixture as an eluent to afford β-lactam xxx as colorless crystals. To a vigorously stirred solution of β-lactam xxx (3.916 g, 10 mmol) in anhydrous THF (40 mL), a mixture of NaHMDS (3.668 g, 20 mmol) and TMEDA (2.998 mL, 20 mmol) in anhydrous THF (80 mL) was added dropwise at 0 °C under an argon atmosphere and the cooling bath was removed. The stirring was continued at 25 °C for an additional 30 min, and the mixture was transferred via cannula to a vigorously stirred solution of acetyl chloride (1.422 mL, 20 mmol) in anhydrous THF (80 mL) at 25 °C under an argon atmosphere. After the next 30 min at the same temperature, the reaction was quenched with an aqueous saturated NH4Cl solution (200 mL), poured into water, and extracted with EtOAc (3 × 100 mL). The combined extracts were washed successively with water (200 mL), a saturated solution of NaHCO3 (100 mL), and brine (100 mL), dried over anhydrous MgSO4, and concentrated under reduced pressure. Filtration of the residue through a pad of silica gel with CH2Cl2 afforded the crude intermediate vinyl acetate accompanied by unreacted β-lactam xxx, which were without further purification dissolved in the mixture of acetonitrile (400 mL) and water (80 mL) and cooled to −10 °C. Then a solution of CAN (19.188 g, 35 mmol) in water (320 mL) was added dropwise within 15 min, and the reaction was stirred at the same temperature for 3.5 h. At the end of this time, the reaction was quenched with a saturated aqueous Na2S2O3 solution (100 mL), poured into water, and extracted with ethyl acetate (3 × 150 mL). Combined extracts were washed with water (500 mL), a saturated aqueous solution of NaHCO3 (300 mL), and brine (300 mL), dried over MgSO4, and concentrated under reduced pressure. Purification of the crude product by column chromatography on silica gel using a MTBE/hexane mixture as an eluent afforded β-lactam xxxi as colorless crystals (3R*,4R*)-4-Acetyl-1-(4-methoxyphenyl)-3-((triisopropylsilyl)oxy)azetidin-2-one (xxx): 2.858 g (73% yield); colorless crystals; mp 105.1−106.2 °C; Rf (15% AcOEt/hexane) 0.55; 1H NMR (400 MHz, CDCl3) δ 7.26−7.21 (m, 2H), 6.88−6.83 (m, 2H), 5.25 (d, J = 5.5, 1H), 4.51 (d, J = 5.5, 1H), 3.77 (s, 3H), 2.20 (s, 3H), 1.23−1.04 (m, 21H); 13C{1H} NMR (101 MHz, CDCl3) δ 205.8, 164.7, 156.9, 130.8, 118.0, 114.8, 78.0, 66.0, 55.6, 27.8, 17.8, 17.7, 12.0; IR (film) v 3004, 2944, 2867, 1877, 1756, 1721, 1517, 1463, 1298, 1251, 1185, 1123, 1031, 962, 830, 683 cm−1; HRMS (ESI-TOF) m/z calcd for C21H33NNaO4Si [M + Na+] 414.2077, found 414.2069. 1-((2R*,3R*)-4-Oxo-3-((triisopropylsilyl)oxy)azetidin-2-yl)vinyl Acetate (xxxi): 754 mg (23% yield); colorless crystals; mp 77.8−78.7 °C; Rf (30% MTBE/hexane) 0.7; 1H NMR (400 MHz, CDCl3) δ 6.24 (br s, 1H), 5.10 (s, 2H), 5.03 (dd, J = 4.8, 2.2, 1H), 4.25 (d, J = 4.8, 1H), 2.13 (s, 3H), 1.18−1.01 (m, 21H); 13C{1H} NMR (101 MHz, CDCl3) δ 169.7, 169.3, 151.3, 105.5, 79.6, 57.3, 21.1, 17.8, 17.7, 12.0; IR (film) v 2941, 2865, 1760, 1674, 1462, 1370, 1228, 1178, 1040, 881, 686 cm −1 ; HRMS (ESI-TOF) m/z calcd for C16H29NNaO4Si [M + Na+] 350.1764, found 350.1751. Synthesis of N-Ts-Azetidin-2-ones 1, (+)-1, (−)-1, 15−17, 19, (+)-19, 20, (−)-20, 24−31, 40, 42−43, and 48: General Procedures. Method A. To a solution of N-PMP-azetidin-2-one (5 mmol) in acetonitrile (200 mL) and water (40 mL) cooled to −10 °C was added a solution of CAN (9.594 g, 17.5 mmol) in water (160 mL) dropwise within 15 min, and the reaction was stirred at the same 14542


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NaHCO3 (50 mL), dried over anhydrous MgSO4, and concentrated under reduced pressure. Purification of the crude product by column chromatography on silica gel using an ethyl acetate/hexane mixture as an eluent afforded the desired N-Ts-azetidin-2-one as colorless crystals. (3R*,4S*)-4-((E)-Prop-1-en-1-yl)-1-tosyl-3-((triisopropylsilyl)oxy)azetidin-2-one (1): Method A; 1.576 g (72% yield); E/Z = 95:5, colorless crystals; mp 122.7−124.5 °C; Rf (15% AcOEt/hexane) 0.5; 1 H NMR (400 MHz, CDCl3) δ 7.87−7.78 (m, 2H), 7.36−7.30 (m, 2H), 5.90 (dq, J = 15.4, 6.6, 1H), 5.29 (ddq, J = 15.4, 9.2, 1.7, 1H), 5.00 (d, J = 5.7, 1H), 4.63 (dd, J = 9.2, 5.7, 1H), 2.44 (s, 3H), 1.70 (dd, J = 6.6, 1.7, 3H), 1.14−0.93 (m, 21H); 13C{1H} NMR (101 MHz, CDCl3) δ 165.0, 145.2, 136.6, 134.7, 129.9, 127.8, 124.0, 77.7, 64.5, 21.8, 18.0, 17.6, 17.6, 11.8; IR (film) v 2945, 2868, 1800, 1464, 1366, 1171, 1091, 728 cm−1; HRMS (ESI-TOF) m/z calcd for C22H35NNaO4SSi [M + Na+] 460.1954, found 460.1941. (3S,4R)-4-((E)-Prop-1-en-1-yl)-1-tosyl-3-((triisopropylsilyl)oxy)azetidin-2-one ((−)-1): Method A; 1.707 g (78% yield); E/Z = 98:2; ee > 99%; colorless crystals; mp 98.2−98.8 °C; Rf (15% AcOEt/ hexane) 0.5; [α]23 D −43.9 (c 0.89, CHCl3); NMR and IR spectra were consistent with those recorded for the racemate; HRMS (ESI-TOF) m/z calcd for C22H35NNaO4SSi [M + Na+] 460.1954, found 460.1945. (3R,4S)-4-((E)-Prop-1-en-1-yl)-1-tosyl-3-((triisopropylsilyl)oxy)azetidin-2-one ((+)-1): Method A; 1.751 g (80% yield); E/Z = 95:5; ee > 99%; colorless crystals; mp 98.7−99.9 °C; Rf (15% AcOEt/ hexane) 0.5; [α]23 D +41.5 (c 0.63, CHCl3); NMR and IR spectra were consistent with those recorded for the racemate; HRMS (ESI-TOF) m/z calcd for C22H35NNaO4SSi [M + Na+] 460.1954, found 460.1946. (3R*,4R*)-4-((Z)-Prop-1-en-1-yl)-1-tosyl-3-((triisopropylsilyl)oxy)azetidin-2-one (15): Method A; 1.510 g (69% yield); Z/E = 91:9, colorless crystals; mp 79.6−80.7 °C; Rf (20% Et2O/hexane) 0.55; 1H NMR (400 MHz, CDCl3) δ 7.87−7.79 (m, 2H), 7.37−7.30 (m, 2H), 5.87 (dqd, J = 10.8, 7.0, 0.9, 1H), 5.40−5.28 (m, 1H), 4.61 (ddd, J = 9.8, 2.6, 0.9, 1H), 4.57 (d, J = 2.6, 1H), 2.44 (s, 3H), 1.80 (dd, J = 7.0, 1.8, 3H), 1.12−0.96 (m, 21H); 13C{1H} NMR (101 MHz, CDCl3) δ 165.0, 145.3, 136.2, 132.5, 130.0, 127.7, 125.2, 82.2, 62.3, 21.8, 17.6, 17.6, 13.6, 11.9; IR (film) v 2945, 2868, 1803, 1464, 1368, 1171, 1090, 720 cm−1; HRMS (ESI-TOF) m/z calcd for C22H35NNaO4SSi [M + Na+] 460.1954, found 460.1941. (3R*,4S*)-4-((Z)-Prop-1-en-1-yl)-1-tosyl-3-((triisopropylsilyl)oxy)azetidin-2-one (16): Method A; 1.795 g (82% yield); Z/E = 76:24; 897 mg (41% yield), Z/E = 98:2 after an additional column eluting with a MTBE/hexane mixture; colorless crystals; mp 82.8−83.5 °C; (20% Et2O/hexane) 0.55; 1H NMR (400 MHz, CDCl3) δ 7.88−7.79 (m, 2H), 7.35−7.28 (m, 2H), 5.88 (dq, J = 10.9, 7.0, 1H), 5.38−5.25 (m, 1H), 5.11−5.00 (m, 2H), 2.43 (s, 3H), 1.81 (dd, J = 7.0, 1.8, 3H), 1.13−0.96 (m, 21H); 13C{1H} NMR (101 MHz, CDCl3) δ 165.0, 145.2, 136.6, 133.3, 129.9, 127.7, 122.7, 77.6, 58.4, 21.8, 17.7, 17.6, 13.4, 11.9; IR (film) v 2945, 2893, 2868, 1801, 1464, 1365, 1170, 1091, 896, 608 cm−1; HRMS (ESI-TOF) m/z calcd for C22H35NNaO4SSi [M + Na+] 460.1954, found 460.1942. (3R*,4R*)-4-((E)-Prop-1-en-1-yl)-1-tosyl-3-((triisopropylsilyl)oxy)azetidin-2-one (17): Method A; 1.444 g (66% yield); E/Z = 96:4, colorless crystals; mp 107.8−108.3 °C; Rf (20% Et2O/hexane) 0.55; 1 H NMR (400 MHz, CDCl3) δ 7.82 (m, 2H), 7.33 (m, 2H), 5.94 (dq, J = 15.2, 6.5, 1H), 5.38 (ddq, J = 15.2, 8.9, 1.7, 1H), 4.56 (d, J = 2.6, 1H), 4.20 (dd, J = 8.9, 2.6, 1H), 2.44 (s, 3H), 1.75 (dd, J = 6.5, 1.7, 3H), 1.09−0.97 (m, 21H); 13C{1H} NMR (101 MHz, CDCl3) δ 165.0, 145.3, 136.2, 133.6, 130.0, 127.7, 126.0, 82.1, 67.8, 21.8, 17.9, 17.6, 11.9; IR (film) v 2945, 2893, 2868, 1803, 1464, 1171, 1092, 882, 719 cm−1; HRMS (ESI-TOF) m/z calcd for C22H35NNaO4SSi [M + Na+] 460.1954, found 460.1946. (R*,E)-4-(Prop-1-en-1-yl)-1-tosylazetidin-2-one (19): Method C; 637 mg (48% yield);32 E/Z = 95:5; colorless oil; Rf (30% AcOEt/ hexane) 0.60; 1H NMR (400 MHz, CDCl3) δ 7.91−7.76 (m, 2H), 7.41−7.29 (m, 2H), 5.91 (dq, J = 15.2, 6.6, 1H), 5.34 (ddt, J = 15.2, 8.8, 1.7, 1H), 4.50 (ddd, J = 8.8, 6.1, 3.3, 1H), 3.20 (dd, J = 16.0, 6.1, 1H), 2.72 (dd, J = 16.0, 3.3, 1H), 2.44 (s, 3H), 1.71 (dd, J = 6.6, 1.7,

temperature for 3.5 h. At the end of this time, the reaction was quenched with a saturated aqueous Na2S2O3 solution (50 mL), poured into water (500 mL), and extracted with ethyl acetate (3 × 100 mL). The combined extracts were washed with water (300 mL), a saturated aqueous solution of NaHCO3 (300 mL), and brine (300 mL), dried over MgSO4, and concentrated under reduced pressure. Filtration of the residue through a pad of silica gel with CH2Cl2 (to remove quinone formed as the byproduct) and then an ethyl acetate/ hexane mixture afforded the crude NH-β-lactam, which was then dissolved in toluene (25 mL) and added in one portion to a vigorously stirred mixture of TsCl (4.766 g, 25 mmol), TBAB (161 mg, 0.5 mmol), and solid NaOH (15 g) in toluene (275 mL) at 25 °C. After 15 min at the same temperature, an excess of NaOH was filtered off and washed with a portion of toluene (50 mL). Combined filtrates were then washed with water (300 mL), a saturated aqueous solution of NH4Cl (100 mL), and a saturated aqueous solution of NaHCO3 (100 mL), dried over MgSO4, and concentrated. Purification of the crude product by column chromatography on silica gel using an ethyl acetate/hexane, acetone/hexane, or Et2O/ hexane mixture as an eluent afforded the desired N-Ts-azetidin-2-one as colorless crystals. Method B. To a solution of N-PMP-azetidin-2-one (5 mmol) in acetonitrile (200 mL) and water (40 mL) cooled to −10 °C was added a solution of CAN (9.594 g, 17.5 mmol) in water (160 mL) dropwise within 15 min, and the reaction was stirred at the same temperature for 3.5 h. At the end of this time, the reaction was quenched with a saturated aqueous Na2S2O3 solution (50 mL), poured into water (500 mL), and extracted with ethyl acetate (3 × 100 mL). The combined extracts were washed with water (300 mL), a saturated aqueous solution of NaHCO3, and brine (300 mL), dried over MgSO4, and concentrated under reduced pressure. Filtration of the residue through a pad silica gel with CH2Cl2 (to remove quinone formed as the byproduct) and then an ethyl acetate/hexane mixture afforded the crude NH-β-lactam, which was then dissolved in anhydrous THF (200 mL). To this mixture was added 2 M NaHMDS solution in THF (2.5 mL, 5 mmol) dropwise at −78 °C under an argon atmosphere. The stirring was continued for 30 min at the same temperature, and the mixture was transferred via cannula to the vigorously stirred solution of tosyl chloride in anhydrous THF (100 mL) at −78 °C under an argon atmosphere. After the next 30 min at the same temperature, the cooling bath was removed, and once warmed to 25 °C, the reaction was quenched with an aqueous saturated NH4Cl solution (100 mL), poured into water, and extracted with EtOAc (3 × 75 mL). The combined extracts were washed successively with water (100 mL), a saturated solution of NaHCO3 (50 mL), and brine (50 mL), dried over anhydrous MgSO4, and concentrated under reduced pressure. Purification of the crude product by column chromatography on silica gel using an ethyl acetate/hexane, acetone/hexane, or Et2O/hexane mixture as an eluent afforded the corresponding N-Ts-azetidin-2-one as colorless crystals. Method C. To a solution of N-PMP-azetidin-2-one (5 mmol) in acetonitrile (200 mL) and water (40 mL) cooled to −10 °C was added a solution of CAN (9.594 g, 17.5 mmol) in water (160 mL) dropwise within 15 min, and the reaction was stirred at the same temperature for 3.5 h. At the end of this time, the reaction was quenched with a saturated aqueous Na2S2O3 solution (50 mL), poured into water (500 mL), and extracted with ethyl acetate (3 × 100 mL). The combined extracts were washed with water (300 mL), a saturated aqueous solution of NaHCO3, and brine (300 mL), dried over MgSO4, and concentrated under reduced pressure. Filtration of the residue through a pad of silica gel with CH2Cl2 (to remove quinone formed as the byproduct) and then an ethyl acetate/hexane mixture afforded the crude NH-β-lactam, which was then dissolved in anhydrous CH2Cl2 (35 mL). To this mixture were sequentially added NEt3 (2.788 mL, 20 mmol), DMAP (61 mg, 0.5 mmol), and Ts2O (6.528 g, 20 mmol) all in one portion at 0 °C under an argon atmosphere, and the cooling bath was removed. After 24 h at 25 °C, the reaction mixture was poured into water and extracted with CH2Cl2 (3 × 25 mL). The combined extracts were washed successively with water (100 mL) and a saturated solution of 14543


Article

The Journal of Organic Chemistry 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 163.6, 145.2, 136.5, 133.0, 130.0, 127.7, 127.4, 56.3, 43.8, 21.8, 17.8; IR (film) v 2998, 2951, 2920, 1793, 1598, 1450, 1362, 1169, 1091, 962, 678 cm−1; HRMS (ESI-TOF) m/z calcd for C13H15NNaO3S [M + Na+] 288.0670, found 288.0661. (R,E)-4-(Prop-1-en-1-yl)-1-tosylazetidin-2-one ((+)-19): Method C; 742 mg (56% yield);32 E/Z = 93:7; ee > 99%; colorless crystals; mp 100.2−101.9 °C; Rf (30% AcOEt/hexane) 0.60; [α]25 D +20.1 (c 1.48, CHCl3); NMR and IR spectra were consistent with those recorded for the racemate; HRMS (ESI-TOF) m/z calcd for C13H15NNaO3S [M + Na+] 288.0670, found 288.0663. (R*,Z)-4-(Prop-1-en-1-yl)-1-tosylazetidin-2-one (20): Method C; 387 mg (29% yield);33 Z/E = 60:40; 93 mg (7% yield ), Z/E = 83:17, after crystallization from DCM/hexane mixture; colorless crystals; mp 86.2−87.6 °C; Rf (30% AcOEt/hexane) 0.60; 1H NMR (400 MHz, CDCl3) δ (major) 7.89−7.78 (m, 2H), 7.39−7.30 (m, 2H), 5.80 (dqd, J = 10.8, 7.0, 1.0, 1H), 5.35−5.27 (m, 1H), 4.90 (dddd, J = 9.5, 6.2, 3.3, 1.0, 1H), 3.26 (dd, J = 15.9, 6.2, 1H), 2.72 (dd, J = 16.0, 3.3, 1H(19)), 2.70 (dd, J = 15.9, 3.3, 1H), 2.44 (s, 3H), 1.80 (dd, J = 7.0, 1.8, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 163.6, 145.2, 136.4, 132.0, 130.0, 127.5, 126.6, 50.6, 43.9, 21.7, 13.4; IR (film) v 3021, 2953, 2923, 2864, 1793, 1597, 1449, 1362, 1169, 1091, 962, 816, 678 cm−1; HRMS (ESI-TOF) m/z calcd for C13H15NNaO3S [M + Na+] 288.0670, found 288.0659. (R,Z)-4-(Prop-1-en-1-yl)-1-tosylazetidin-2-one ((−)-20): Method C; 398 mg (30% yield);33 Z/E = 60:40; ee > 99%; colorless crystals; mp 78.7−79.4 °C; Rf (30% AcOEt/hexane) 0.60; [α]24 D −10.2 (c 1.00, CHCl3); NMR and IR spectra were consistent with those recorded for the racemate; HRMS (ESI-TOF) m/z calcd for C13H15NNaO3S [M + Na+] 288.0670, found 288.0659. (3R*,4S*)-4-((E)-3-Methylbut-1-en-1-yl)-1-tosyl-3((triisopropylsilyl)oxy)azetidin-2-one (24): Method A; 1.797 g (76% yield); E/Z > 98:2, colorless crystals; mp 156.1−156.7 °C; Rf (15% AcOEt/hexane) 0.55; 1H NMR (400 MHz, CDCl3) δ 7.87−7.79 (m, 2H), 7.37−7.28 (m, 2H), 5.88 (dd, J = 15.5, 6.2, 1H), 5.19 (ddd, J = 15.5, 9.3, 1.5, 1H), 5.03 (d, J = 5.7, 1H), 4.65 (dd, J = 9.3, 5.7, 1H), 2.44 (s, 3H), 2.35−2.21 (m, 1H), 1.14−0.97 (m, 21H), 0.94 (t, J = 6.5, 6H); 13C{1H} NMR (101 MHz, CDCl3) δ 165.0, 146.7, 145.2, 136.7, 129.9, 127.8, 119.7, 77.7, 64.8, 31.1, 21.8, 21.8, 21.6, 17.71, 17.67, 11.9; IR (film) v 3506, 2946, 2893, 2868, 1930, 1793, 1464, 1357, 1264, 1169, 1136, 733 cm−1; HRMS (ESI-TOF) m/z calcd for C24H39NNaO4SSi [M + Na+] 488.2267, found 488.2254. (3R*,4S*)-4-((E)-Styryl)-1-tosyl-3-((triisopropylsilyl)oxy)azetidin2-one (25): Method A; 700 mg (28% yield); E/Z = 98:2; colorless crystals; mp 119.2−119.7 °C; Rf (15% AcOEt/hexane) 0.65; 1H NMR (400 MHz, CDCl3) δ 7.83−7.78 (m, 2H), 7.35−7.19 (m, 7H), 6.73 (d, J = 15.9, 1H), 5.92 (dd, J = 15.9, 9.2, 1H), 5.13 (d, J = 5.7, 1H), 4.86 (dd, J = 9.2, 5.7, 1H), 2.38 (s, 3H), 1.14−0.93 (m, 21H); 13 C{1H} NMR (101 MHz, CDCl3) δ 164.8, 145.3, 137.8, 136.5, 135.9, 130.0, 128.70, 128.6, 127.8, 126.8, 121.5, 78.1, 64.6, 21.8, 17.7, 17.6, 11.8; IR (film) v 3029, 2945, 2893, 2867, 1798, 1464, 1367, 1243, 1170, 1120, 883, 671 cm−1; HRMS (ESI-TOF) m/z calcd for C27H37NNaO4SSi [M + Na+] 522.2110, found 522.2093. Ethyl (E)-3-((2S*,3R*)-4-Oxo-1-tosyl-3-((triisopropylsilyl)oxy)azetidin-2-yl)acrylate (26): Method C; 1.239 g (50% yield); E/Z > 98:2; colorless crystals; mp 84.8−86.6 °C; Rf (25% AcOEt/hexane) 0.75; 1H NMR (400 MHz, CDCl3) δ 7.88−7.80 (m, 2H), 7.39−7.30 (m, 2H), 6.70 (dd, J = 15.7, 8.5, 1H), 6.10 (dd, J = 15.7, 0.8, 1H), 5.11 (d, J = 5.7, 1H), 4.76 (ddd, J = 8.5, 5.7, 0.8, 1H), 4.27−4.10 (m, 2H), 2.44 (s, 3H), 1.26 (t, J = 7.1, 3H), 1.14−0.95 (m, 21H); 13 C{1H} NMR (101 MHz, CDCl3) δ 164.8, 164.0, 145.7, 139.5, 135.8, 130.2, 127.8, 127.7, 78.7, 62.1, 60.8, 21.8, 17.9, 17.6, 14.3, 11.8; IR (film) v 2945, 2894, 2868, 1804, 1723, 1597, 1464, 1369, 1264, 1171, 1090, 882, 669 cm−1; HRMS (ESI-TOF) m/z calcd for C24H37NNaO6SSi [M + Na+] 518.2009, found 518.1999. (3R*,4S*)-4-(Prop-1-en-2-yl)-1-tosyl-3-((triisopropylsilyl)oxy)azetidin-2-one (27): Method C; 1.532 g (70% yield); colorless crystals; mp 120.1−121.0 °C; Rf (15% AcOEt/hexane) 0.60; 1H NMR (400 MHz, CDCl3) δ 7.91−7.84 (m, 2H), 7.38−7.31 (m, 2H), 5.13−5.07 (m, 1H), 5.07 (br s, 1H), 5.05 (d, J = 6.1, 1H), 4.68 (d, J =

6.1, 1H), 2.44 (s, 3H), 1.57 (s, 3H), 1.12−0.95 (m, 21H); 13C{1H} NMR (101 MHz, CDCl3) δ 165.1, 145.4, 139.1, 135.9, 130.1, 127.7, 118.3, 78.0, 67.3, 21.8, 18.7, 17.7, 17.6, 11.9; IR (film) v 3082, 2945, 2893, 2868, 2730, 1931, 1801, 1598, 1464, 1366, 1243, 1171, 1139, 882, 725 cm−1; HRMS (ESI-TOF) m/z calcd for C22H35NNaO4SSi [M + Na+] 460.1954, found 460.1956. 1-((2R*,3R*)-4-Oxo-1-tosyl-3-((triisopropylsilyl)oxy)azetidin-2yl)vinyl Acetate (28): Modified Method C, isolated NH-azetidin-2one xxxi (2.5 mmol) subjected to the tosylation step directly; 795 mg (66% yield); colorless crystals; mp 125.6−126.9 °C; Rf (30% Et2O/ hexane) 0.45; 1H NMR (400 MHz, CDCl3) δ 7.93−7.86 (m, 2H), 7.37−7.30 (m, 2H), 5.45 (d, J = 2.4, 1H), 5.10 (d, J = 5.8, 1H), 5.08 (d, J = 2.4, 1H), 4.65 (d, J = 5.8, 1H), 2.44 (s, 3H), 1.71 (s, 3H), 1.13−0.97 (m, 21H); 13C{1H} NMR (101 MHz, CDCl3) δ 167.2, 164.9, 146.2, 145.4, 136.0, 129.9, 127.9, 106.9, 77.5, 63.5, 21.8, 21.1, 17.7, 17.6, 11.9; IR (film) v 2945, 2894, 2868, 1809, 1769, 1597, 1464, 1367, 1200, 1170, 1137, 884, 688 cm−1; HRMS (ESI-TOF) m/ z calcd for C23H35NNaO6SSi [M + Na+] 504.1852, found 504.1835. (3R*,4S*)-4-((E)-But-2-en-2-yl)-1-tosyl-3-((triisopropylsilyl)oxy)azetidin-2-one (29): Method A; 1.739 g (77% yield); E/Z = 98:2; colorless crystals; mp 145.7−146.5 °C; Rf (15% acetone/hexane) 0.55; 1H NMR (400 MHz, CDCl3) δ 7.88−7.81 (m, 2H), 7.37−7.29 (m, 2H), 5.61 (q, J = 6.7, 1H), 5.01 (d, J = 6.0, 1H), 4.63 (d, J = 6.0, 1H), 2.44 (s, 3H), 1.61 (d, J = 6.7, 3H), 1.34 (s, 3H), 1.13−0.95 (m, 21H); 13C{1H} NMR (101 MHz, CDCl3) δ 165.4, 145.2, 136.0, 130.0, 129.9, 128.3, 127.7, 78.0, 69.2, 21.8, 17.62, 17.55, 13.6, 12.6, 11.8; IR (film) v 2945, 2893, 2868, 1798, 1597, 1464, 1365, 1200, 1171, 1137, 883, 731 cm−1; HRMS (ESI-TOF) m/z calcd for C23H37NNaO4SSi [M + Na+] 474.2110, found 474.2103. (3R*,4S*)-4-Methyl-1-tosyl-3-((triisopropylsilyl)oxy)-4-vinylazetidin-2-one (30): Method B; 647 mg (74% yield, starting from 2 mmol of xxa); colorless crystals; mp 84.7−85.5 °C; Rf (25% Et2O/hexane) 0.55; 1H NMR (400 MHz, CDCl3) δ 7.91−7.84 (m, 2H), 7.36−7.29 (m, 2H), 5.79 (dd, J = 17.4, 10.8, 1H), 5.44 (d, J = 17.4, 1H), 5.38 (d, J = 10.8, 1H), 4.62 (s, 1H), 2.44 (s, 3H), 1.77 (s, 3H), 1.10−0.97 (m, 21H); 13C{1H} NMR (101 MHz, CDCl3) δ 165.1, 145.2, 136.9, 135.0, 129.9, 127.8, 119.5, 84.5, 71.6, 21.8, 21.4, 17.7, 17.6, 11.9; IR (film) v 2945, 2894, 2868, 1795, 1598, 1463, 1365, 1200, 1173, 1090, 882, 712 cm−1; HRMS (ESI-TOF) m/z calcd for C22H35NNaO4SSi [M + Na+] 460.1954, found 460.1936. (3R*,4R*)-4-Methyl-1-tosyl-3-((triisopropylsilyl)oxy)-4-vinylazetidin-2-one (31): Method B; 157 mg (55% yield, starting from 0.65 mmol of xxb); colorless crystals; mp 69.8−70.5 °C; Rf (25% Et2O/ hexane) 0.60; 1H NMR (400 MHz, CDCl3) δ 7.93−7.86 (m, 2H), 7.37−7.30 (m, 2H), 5.98 (dd, J = 17.3, 10.8, 1H), 5.38 (d, J = 17.3, 1H), 5.32 (d, J = 10.8, 1H), 4.62 (s, 1H), 2.44 (s, 3H), 1.58 (s, 3H), 1.13−0.97 (m, 21H); 13C{1H} NMR (101 MHz, CDCl3) δ 165.2, 145.2, 138.3, 137.1, 130.0, 127.7, 117.6, 83.2, 71.6, 21.8, 17.71, 17.67, 17.4, 11.9; IR (film) v 2945, 2893, 2868, 1792, 1598, 1463, 1365, 1200, 1171, 1090, 882, 673 cm−1; HRMS (ESI-TOF) m/z calcd for C22H35NNaO4SSi [M + Na+] 460.1954, found 460.1934. (3R*,4S*)-3-Methyl-1-tosyl-4-vinylazetidin-2-one (40): Method C; 438 mg (33% yield); colorless crystals; mp 55.2−56.1 °C; Rf (30% AcOEt/hexane) 0.65; 1H NMR (400 MHz, CDCl3) δ 7.91− 7.81 (m, 2H), 7.39−7.30 (m, 2H), 5.68 (ddd, J = 17.0, 10.3, 8.2, 1H), 5.45 (dd, J = 17.0, 0.9, 1H), 5.40 (dt, J = 10.3, 0.9, 1H), 4.58 (ddt, J = 8.2, 6.6, 0.8, 1H), 3.43 (qd, J = 7.7, 6.6, 1H), 2.45 (s, 3H), 1.12 (d, J = 7.7, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 167.4, 145.3, 136.3, 131.4, 130.1, 127.6, 122.1, 60.4, 49.1, 21.8, 9.4; IR (film) v 2978, 2936, 2877, 1792, 1598, 1454, 1362, 1248, 1170, 1090, 717, 602 cm−1; HRMS (ESI-TOF) m/z calcd for C13H15NNaO3S [M + Na+] 288.0670, found 288.0661. (3R*,4R*)-3-Isopropyl-1-tosyl-4-vinylazetidin-2-one (42): Method B; 719 mg (49% yield); colorless crystals; mp 59.9−61.8 °C; Rf (15% AcOEt/hexane) 0.45; 1H NMR (400 MHz, CDCl3) δ 7.89− 7.81 (m, 2H), 7.37−7.29 (m, 2H), 5.81 (ddd, J = 17.0, 10.2, 8.0, 1H), 5.43 (dt, J = 17.0, 0.9, 1H), 5.29 (dd, J = 10.2, 0.9, 1H), 4.20 (dd, J = 8.0, 3.3, 1H), 2.75 (dd, J = 8.1, 3.3, 1H), 2.43 (s, 3H), 2.04−1.87 (m, 1H), 0.95 (d, J = 6.7, 3H), 0.85 (d, J = 6.7, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 166.1, 145.2, 136.3, 134.7, 130.0, 127.6, 120.1, 63.4, 14544


Article


8.00−7.88 (m, 2H), 7.41−7.25 (m, 7H), 5.56 (td, J = 10.8, 1.2, 1H), 5.39 (dd, J = 10.8, 8.8, 1H), 5.05 (dd, J = 8.8, 1.2, 1H), 4.29 (d, J = 9.2, 1H), 3.63 (br s, 1H), 2.81−2.67 (m, 1H), 2.43 (s, 3H), 1.15− 1.00 (m, 21H), 0.72 (d, J = 6.6, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 170.5, 145.2, 142.6, 138.3, 135.7, 129.7, 128.6, 128.5, 128.1, 127.8, 127.1, 78.9, 70.7, 41.6, 21.8, 18.0, 17.9, 17.2, 12.2; IR (film) v 3475, 3349, 3066, 2944, 2867, 1740, 1598, 1459, 1176, 1124, 1088, 882, 724, 662 cm −1 ; HRMS (ESI-TOF) m/z calcd for C29H43NNaO5SSi [M + Na+] 568.2529, found 568.2523. (2R,5S,6S,Z)-6-Hydroxy-5-methyl-6-phenyl-N-tosyl-2((triisopropylsilyl)oxy)hex-3-enamide ((−)-2a): Method A, starting from 1, 53.9 mg (79% yield); dr = 98:2; ee > 99%; colorless wax; Rf (25% acetone/hexane) 0.65; [α]25 D −153.5 (c 1.51, CHCl3); 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 568.2523. (2R*,5R*,6R*,E)-6-Hydroxy-5-methyl-6-phenyl-N-tosyl-2((triisopropylsilyl)oxy)hex-3-enamide (2b). A sample was obtained from β-lactam 1 and benzaldehyde during the optimization of reaction conditions according to the modified Method B where anhydrous THF was used instead of a 25% HMPA/THF mixture and Pd(PPh3)4 loading was increased to 10 mol %: 36.8 mg (54% yield); dr = 81:10:5:4; colorless wax; Rf (25% acetone/hexane) 0.60; 1H NMR (400 MHz, CDCl3) δ (major) 9.96 (s, 1H), 8.00−7.88 (m, 2H), 7.41−7.25 (m, 7H), 5.56 (td, J = 10.8, 1.2, 1H), 5.39 (dd, J = 10.8, 8.8, 1H), 5.05 (dd, J = 8.8, 1.2, 1H), 4.29 (d, J = 9.2, 1H), 3.63 (br s, 1H), 2.81−2.67 (m, 1H), 2.43 (s, 3H), 1.15−1.00 (m, 21H), 0.72 (d, J = 6.6, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 170.5, 145.2, 142.6, 138.3, 135.7, 129.7, 128.6, 128.5, 128.1, 127.8, 127.1, 78.9, 70.7, 41.6, 21.8, 18.0, 17.9, 17.2, 12.2; IR (film) v 3490, 3356, 3063, 2944, 2867, 1734, 1598, 1457, 1408, 1352, 1176, 1122, 1088, 881, 662 cm−1; HRMS (ESI-TOF) m/z calcd for C29H43NNaO5SSi [M + Na+] 568.2529, found 568.2519. (2R*,5S*,6S*,Z)-6-Hydroxy-6-(4-methoxyphenyl)-5-methyl-Ntosyl-2-((triisopropylsilyl)oxy)hex-3-enamide (3): Method A; 61.9 mg (86% yield); dr = 98:2; colorless crystals; mp 135.1−136.2 °C; Rf (30% acetone/hexane) 0.65; 1H NMR (400 MHz, CDCl3) δ 10.05 (s, 1H), 7.95−7.88 (m, 2H), 7.33−7.27 (m, 2H), 7.27−7.23 (m, 2H), 6.91−6.87 (m, 2H), 5.55 (td, J = 10.8, 1.2, 1H), 5.37 (t, J = 10.8, 8.9, 1H), 5.04 (dd, J = 8.9, 1.2, 1H), 4.25 (dd, J = 9.3, 3.9, 1H), 3.81 (s, 3H), 3.45 (d, J = 3.9, 1H), 2.78−2.66 (m, 1H), 2.42 (s, 3H), 1.13− 0.98 (m, 21H), 0.70 (d, J = 6.5, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 170.4, 159.5, 145.1, 138.3, 135.8, 134.6, 129.7, 128.5, 128.2, 127.8, 114.0, 78.5, 70.7, 55.4, 41.6, 21.8, 17.98, 17.95, 17.2, 12.2; IR (film) v 3475, 3349, 3071, 2943, 2867, 1739, 1611, 1513, 1464, 1350, 1249, 1176, 1124, 1088, 882, 661 cm−1; HRMS (ESI-TOF) m/z calcd for C30H45NNaO6SSi [M + Na+] 598.2635, found 598.2626. (2R*,5S*,6S*,Z)-6-(4-Cyanophenyl)-6-hydroxy-5-methyl-N-tosyl2-((triisopropylsilyl)oxy)hex-3-enamide (4): Method A; 61.4 mg (86% yield); dr = 97:3; colorless crystals; mp 177.4−178.6 °C; Rf (30% acetone/hexane) 0.65; 1H NMR (400 MHz, CDCl3) δ 9.50 (s, 1H), 7.97−7.90 (m, 2H), 7.66−7.59 (m, 2H), 7.47−7.40 (m, 2H), 7.36−7.29 (m, 2H), 5.53 (dd, J = 10.9, 1.2, 1H), 5.40 (dd, J = 10.9, 8.3, 1H), 5.00 (dd, J = 8.3, 1.2, 1H), 4.32 (dd, J = 9.0, 5.0, 1H), 4.05 (d, J = 5.0, 1H), 2.74−2.59 (m, 1H), 2.44 (s, 3H), 1.13−1.01 (m, 21H), 0.71 (d, J = 6.6, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 171.1, 148.3, 145.6, 137.7, 135.3, 132.3, 129.8, 128.6, 128.4, 128.0, 111.7, 78.0, 71.1, 41.9, 21.9, 17.96, 17.92, 17.0, 12.1; IR (film) v 3457, 3344, 3071, 2943, 2867, 2228, 1738, 1598, 1463, 1412, 1349, 1175, 1123, 1088, 1017, 881, 661 cm−1; HRMS (ESI-TOF) m/z calcd for C30H42N2NaO5SSi [M + Na+] 593.2481, found 593.2477. (2R*,5S*,6S*,Z)-6-Hydroxy-5-methyl-6-(naphthalen-2-yl)-Ntosyl-2-((triisopropylsilyl)oxy)hex-3-enamide (5): Method A; 64.8 mg (87% yield); dr = 95:5; colorless crystals; mp 142.9−143.8 °C; Rf (30% acetone/hexane) 0.65; 1H NMR (400 MHz, CDCl3) δ 7.98− 7.91 (m, 2H), 7.89−7.80 (m, 3H), 7.77−7.72 (m, 1H), 7.54−7.45 (m, 3H), 7.34−7.27 (m, 2H), 5.61 (dd, J = 10.9, 1.2, 1H), 5.41 (t, J = 10.9, 8.8, 1H), 5.10 (dd, J = 8.8, 1.2, 1H), 4.46 (dd, J = 9.3, 3.1, 1H), 3.80−3.74 (m, 1H), 2.91−2.76 (m, 1H), 2.43 (s, 3H), 1.17−1.00 (m, 21H), 0.73 (d, J = 6.5, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ

60.7, 28.0, 21.8, 19.8, 19.7; IR (film) v 3564, 2963, 2875, 1790, 1597, 1466, 1365, 1170, 1089, 668, 547 cm−1; HRMS (ESI-TOF) m/z calcd for C15H19NNaO3S [M + Na+] 316.0983, found 316.0977. 2-((3R*,4S*)-2-Oxo-1-tosyl-4-vinylazetidin-3-yl)isoindoline-1,3dione (43): Method B; 1.130 g (57% yield); cis/trans = 89:11; colorless crystals; mp 159.5−161.8 °C; 1H NMR (400 MHz, CDCl3) δ (major) 8.00−7.91 (m, 2H), 7.87−7.79 (m, 2H), 7.78−7.70 (m, 2H), 7.46−7.38 (m, 2H), 5.63 (ddd, J = 17.3, 10.3, 8.5, 1H), 5.55 (d, J = 6.4, 1H), 5.43 (d, J = 17.3), 5.26 (d, J = 10.3, 1H), 4.93 (dd, J = 8.5, 6.4, 1H), 2.48 (s, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ (major): 166.7, 160.6, 145.7, 136.0, 134.9, 131.5, 130.2, 129.8, 127.8, 124.4, 124.1, 63.2, 57.5, 21.9; IR (film) v 3288, 3064, 2922, 1806, 1781, 1726, 1597, 1467, 1389, 1251, 1170, 1090, 712, 586 cm−1; HRMS (ESI-TOF) m/z calcd for C20H16N2NaO5S [M + Na+] 419.0678, found 419.0665. 2-((3R*,4S*)-2-Oxo-4-((E)-prop-1-en-1-yl)-1-tosylazetidin-3-yl)isoindoline-1,3-dione (48): Method B; 1.026 g (50% yield); E/Z = 93:7; colorless crystals; mp 205.2−205.5 °C; Rf (40% acetone/ hexane) 0.75; 1H NMR (400 MHz, CDCl3) δ 7.96−7.88 (m, 2H), 7.88−7.78 (m, 2H), 7.80−7.70 (m, 2H), 7.43−7.36 (m, 2H), 5.91 (dq, J = 15.4, 6.6, 1H), 5.52 (d, J = 6.3, 1H), 5.26−5.14 (m, 1H), 4.91 (dd, J = 9.2, 6.3, 1H), 2.48 (s, 3H), 1.55 (dd, J = 6.6, 1.7, 3H); 13 C{1H} NMR (101 MHz, CDCl3) δ 166.8, 160.8, 145.5, 137.1, 136.2, 134.8, 131.5, 130.0, 127.8, 124.1, 122.3, 63.4, 57.4, 21.9, 18.0; IR (film) v 2945, 1803, 1781, 1721, 1596, 1389, 1363, 1249, 1170, 1090, 881, 720, 672 cm−1; HRMS (ESI-TOF) m/z calcd for C21H18N2NaO5S [M + Na+] 433.0834, found 433.0828. Pd/InI- and Pd/InI/N-MI-Promoted Additions of N-Ts-βLactams to Aldehydes and Syntheses of Enediols 2a−2b, (−)-2a, 3−14, (−)-11, 18a−18b, 32−35, 38a−38b, 44a−47a, 44b−47b, 49, 53a−53b, (−)-56, (+)-57, Aminoalcohols 47, 49, and Homoallylic Alcohols 21 (−)-21, (+)-21, 45a−45b, 46a− 46b: General Procedures. Method A. To a vigorously stirred solution of N-Ts- or N-Ms-β-lactam (0.125 mmol) and aldehyde (0.25 mmol) in an anhydrous 10% EtOH/THF mixture (2 mL) were sequentially added N-methylimidazole (20 μL, 0.25 mmol) and the mixture of InI (90.7 mg, 0.375 mmol) and Pd(PPh3)4 (7.2 mg, 6.25 μmol) 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 h). The reaction was then quenched with 1 M aqueous HCl solution (2 mL), poured into water, and extracted with EtOAc (3 × 10 mL). The combined extracts were washed successively with water (30 mL), a saturated solution of NaHCO3 (30 mL), and brine (30 mL), dried over anhydrous MgSO4, and concentrated under reduced pressure. Purification of the crude product by column chromatography on silica gel using an ethyl acetate/hexane with addition of 0.5% v/v HCO2H34 or acetone/hexane mixture as an eluent afforded the desired compound as colorless crystals or a colorless wax. Method B. To a vigorously stirred solution of N-Ts- or N-Ms-βlactam (0.125 mmol) and aldehyde (0.25 mmol) in an anhydrous 25% HMPA/THF mixture (2 mL) was added InI (60.5 mg, 0.25 mmol) in one portion followed by Pd(PPh3)4 (7.2 mg, 6.25 μmol) 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 or no further progress in conversion was found (TLC monitoring, 30 min to 24 h). The reaction was then quenched with a 1 M aqueous HCl solution (2 mL), poured into water, and extracted with CH2Cl2 (3 × 10 mL). Combined extracts were then washed with water (3 × 30 mL) and a saturated solution of NaHCO3 (30 mL), dried over MgSO4, and concentrated. Purification of the crude product by column chromatography on silica gel using an ethyl acetate/hexane with addition of 0.5% v/v HCO2H,34 Et2O/hexane with addition of 0.5% v/v HCO2H34 or acetone/hexane mixture as an eluent afforded the desired products as colorless crystals or a colorless wax. (2R*,5S*,6S*,Z)-6-Hydroxy-5-methyl-6-phenyl-N-tosyl-2((triisopropylsilyl)oxy)hex-3-enamide (2a): Method A, starting from 1, 56.6 mg (83% yield), dr = 97:3; starting from 15, 55.3 mg (81% yield), dr = 97:3; colorless crystals; mp 129.1−130.0 °C; Rf (25% acetone/hexane) 0.65; 1H NMR (400 MHz, CDCl3) δ 9.96 (s, 1H), 14545


Article


(film) v 3512, 3349, 3068, 2943, 2867, 1737, 1598, 1463, 1411, 1350, 1176, 1124, 1089, 881, 661, 549 cm−1; HRMS (ESI-TOF) m/z calcd for C26H45NNaO6SSi [M + Na+] 550.2635, found 550.2629. (2R*,5S*,6R*,Z)-6-Hydroxy-5,7-dimethyl-N-tosyl-2((triisopropylsilyl)oxy)oct-3-enamide (11): Method A; 48.0 mg (75% yield); dr = 98:2; colorless wax; Rf (30% acetone/hexane) 0.55; 1H NMR (400 MHz, CDCl3) δ 9.81 (s, 1H), 7.94−7.87 (m, 2H), 7.33− 7.26 (m, 2H), 5.49 (dd, J = 10.9, 1.2, 1H), 5.29 (dd, J = 10.9, 9.0, 1H), 4.93 (dd, J = 9.0, 1.2, 1H), 3.20 (dd, J = 9.2, 2.3, 1H), 2.63−2.48 (m, 1H), 2.42 (s, 3H), 1.90−1.79 (m, 1H), 1.11−1.00 (m, 24H), 0.91 (d, J = 6.5, 3H), 0.87 (d, J = 6.8, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 170.4, 145.1, 139.1, 135.8, 129.7, 128.5, 126.8, 79.0, 70.7, 37.2, 29.4, 21.8, 20.6, 17.99, 17.96, 16.8, 13.9, 12.2; IR (film) v 3513, 3350, 3071, 2943, 2868, 1741, 1654, 1598, 1465, 1412, 1351, 1177, 1124, 1089, 882, 720, 662 cm−1; HRMS (ESI-TOF) m/z calcd for C26H45NNaO5SSi [M + Na+] 534.2685, found 534.2664. (2R,5S,6R,Z)-6-Hydroxy-5,7-dimethyl-N-tosyl-2((triisopropylsilyl)oxy)oct-3-enamide ((−)-11): Method A; 45.4 mg (71% yield); dr = 98:2; ee > 99%; colorless wax; Rf (30% acetone/ hexane) 0.55; [α]25 D −77.7 (c 1.78, CHCl3); NMR and IR spectra were consistent with those recorded for the racemate; HRMS (ESITOF) m/z calcd for C26H45NNaO5SSi [M + Na+] 534.2685, found 534.2670. (2R*,5S*,6R*,Z)-6-Cyclopentyl-6-hydroxy-5-methyl-N-tosyl-2((triisopropylsilyl)oxy)hex-3-enamide (12): Method A; 54.5 mg (81% yield); dr = 98:2; white solid; mp 106.0−106.6 °C; Rf (30% acetone/hexane) 0.60; 1H NMR (400 MHz, CDCl3) δ 9.71 (s, 1H), 7.95−7.88 (m, 2H), 7.34−7.26 (m, 2H), 5.51 (dd, J = 10.9, 1.2, 1H), 5.28 (t, J = 10.9, 8.9, 1H), 4.92 (dd, J = 8.9, 1.2, 1H), 3.37 (m, 1H), 2.64 (s, 1H), 2.57−2.46 (m, 1H), 2.42 (s, 3H), 2.08 (td, J = 8.4, 3.6, 1H), 1.73−1.43 (m, 8H), 1.14−0.99 (m, 21H), 0.95 (d, J = 6.6, 3H); 13 C{1H} NMR (101 MHz, CDCl3) δ 170.4, 145.1, 139.0, 135.8, 129.7, 128.5, 126.7, 76.9, 70.8, 42.3, 38.7, 29.6, 25.96, 25.95, 24.8, 21.8, 18.00, 17.97, 17.2, 12.2; IR (film) v 3515, 3351, 3069, 2945, 2867, 1739, 1598, 1463, 1411, 1351, 1176, 1123, 1088, 881, 661 cm−1; HRMS (ESI-TOF) m/z calcd for C28H47NNaO5SSi [M + Na+] 560.2842, found 560.2838. (2R*,5S*,6S*,Z)-6-Hydroxy-5,7,7-trimethyl-N-tosyl-2((triisopropylsilyl)oxy)oct-3-enamide (13): Method A; 28.3 mg (43% yield); dr = 96:4; colorless crystals; mp 108.4−109.2 °C; Rf (30% acetone/hexane) 0.70; 1H NMR (400 MHz, CDCl3) δ 9.40 (s, 1H), 7.96−7.88 (m, 2H), 7.33−7.26 (m, 2H), 5.67 (dd, J = 10.9, 1.3, 1H), 5.14 (ddd, J = 10.9, 8.4, 0.8, 1H), 4.89 (dd, J = 8.4, 1.3, 1H), 3.07 (d, J = 5.9, 1H), 2.85−2.71 (m, 1H), 1.12−0.99 (m, 24H), 0.90 (s, 9H); 13 C{1H} NMR (101 MHz, CDCl3) δ 170.0, 145.1, 138.8, 135.7, 129.6, 128.5, 124.8, 83.0, 71.2, 36.3, 35.2, 26.8, 21.8, 20.5, 17.99, 17.97, 12.2; IR (film) v 3528, 3357, 2946, 2868, 1732, 1598, 1464, 1408, 1351, 1177, 1156, 1088, 873, 662 cm−1; HRMS (ESI-TOF) m/ z calcd for C27H47NNaO5SSi [M + Na+] 548.2842, found 548.2837. (2R*,5S*,6S*,Z)-6-Hydroxy-5,8-dimethyl-N-tosyl-2((triisopropylsilyl)oxy)nona-3,7-dienamide (14): Method A; 48.5 mg (74% yield); dr = 95:5; colorless crystals; mp 92.3−93.4 °C; Rf (30% acetone/hexane) 0.70; 1H NMR (400 MHz, CDCl3) δ 10.19 (s, 1H), 7.93−7.86 (m, 2H), 7.28 (m, 2H), 5.48 (td, J = 10.9, 1.0, 1H), 5.33 (dd, J = 10.9, 9.1, 1H), 5.18 (dp, J = 9.2, 1.4, 1H), 4.94 (dd, J = 9.1, 1.0, 1H), 4.09 (t, J = 9.2, 1H), 2.78 (s, 1H), 2.52−2.43 (m, 1H), 2.41 (s, 3H), 1.76 (d, J = 1.4, 3H), 1.69 (d, J = 1.4, 3H), 1.10−0.99 (m, 21H), 0.86 (d, J = 6.6, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 170.1, 144.9, 138.0, 137.4, 135.9, 129.6, 128.5, 127.6, 126.0, 72.5, 70.4, 40.2, 26.0, 21.8, 18.6, 17.97, 17.95, 16.8, 12.2; IR (film) v 3480, 3354, 3070, 2927, 2867, 1740, 1598, 1465, 1407, 1348, 1176, 1124, 1089, 882, 730 cm −1 ; HRMS (ESI-TOF) m/z calcd for C27H45NNaO5SSi [M + Na+] 546.2685, found 546.2686. (2R*,5R*,6R*,Z)-6-Hydroxy-5-methyl-6-phenyl-N-tosyl-2((triisopropylsilyl)oxy)hex-3-enamide (18a): Method A, starting from 16, 22.5 mg (33% yield), dr = 87:13; starting from 17, 21.2 mg (31% yield), dr = 94:6; colorless wax; Rf (50% Et2O/hexane + 0.5% HCO2H) 0.60; 1H NMR (400 MHz, CDCl3) δ 7.96−7.88 (m, 2H), 7.37−7.25 (m, 7H), 5.62 (dd, J = 10.9, 1.5, 1H), 5.34 (dd, J = 10.9, 7.3, 1H), 4.88 (dd, J = 7.3, 1.5, 1H), 4.37 (d, J = 7.7, 1H), 3.05−

170.6, 145.2, 139.9, 138.4, 135.6, 133.4, 133.3, 129.7, 128.54, 128.45, 128.1, 120.0, 127.9, 126.5, 126.3, 126.1, 124.7, 79.1, 70.8, 41.6, 21.8, 18.01, 17.97, 17.3, 12.2; IR (film) v 3467, 3347, 3060, 2943, 2867, 1739, 1598, 1464, 1409, 1349, 1174, 1124, 1088, 880, 662 cm−1; HRMS (ESI-TOF) m/z calcd for C33H45NNaO5SSi [M + Na+] 618.2685, found 618.2681. (2R*,5S*,6S*,Z)-6-(Furan-2-yl)-6-hydroxy-5-methyl-N-tosyl-2((triisopropylsilyl)oxy)hex-3-enamide (6): Method A; 51.8 mg (77% yield); dr = 98:2; colorless wax; Rf (30% acetone/hexane) 0.55; 1H NMR (400 MHz, CDCl3) δ 9.67 (s, 1H), 7.96−7.87 (m, 2H), 7.42− 7.37 (m, 1H), 7.33−7.26 (m, 2H), 6.40−6.30 (m, 1H), 6.31−6.24 (m, 1H), 5.53 (dd, J = 10.9, 1.2, 1H), 5.39 (dd, J = 10.9, 8.7, 1H), 5.03 (dd, J = 8.7, 1.2, 1H), 4.33 (d, J = 9.5, 1H), 3.04−2.92 (m, 1H), 2.42 (s, 3H), 1.16−0.99 (m, 21H), 0.78 (d, J = 6.6, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 170.6, 145.2, 139.9, 138.4, 135.6, 133.4, 133.3, 129.7, 128.54, 128.45, 128.1, 128.0, 127.9, 126.5, 126.3, 126.1, 124.7, 79.1, 70.8, 41.6, 21.8, 18.01, 17.97, 17.3, 12.2; IR (film) v 3472, 3349, 3097, 2941, 2868, 1739, 1598, 1463, 1410, 1350, 1174, 1123, 1089, 1012, 879, 663 cm−1; HRMS (ESI-TOF) m/z calcd for C27H41NNaO6SSi [M + Na+] 558.2322, found 558.2300. (2R*,5S*,6S*,Z)-6-Hydroxy-5-methyl-6-(thiophen-2-yl)-N-tosyl2-((triisopropylsilyl)oxy)hex-3-enamide (7): Method A; 53.1 mg (77% yield); dr = 97:3; white solid; mp 83.9−84.7 °C; Rf (30% acetone/hexane) 0.55; 1H NMR (400 MHz, CDCl3) δ 9.78 (s, 1H), 8.07−7.74 (m, 2H), 7.42−7.24 (m, 4H), 6.97 (m, 2H), 5.54 (td, J = 10.9, 1.1, 1H), 5.40 (dd, J = 10.9, 8.8, 1H), 5.02 (dd, J = 8.8, 1.1, 1H), 4.60 (d, J = 9.1, 1H), 3.72 (s, 1H), 2.85−2.70 (m, 1H), 2.43 (s, 3H), 1.16−0.97 (m, 21H), 0.82 (d, J = 6.5, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 170.4, 146.3, 145.2, 137.8, 135.6, 129.7, 128.6, 128.2, 126.6, 125.4, 125.2, 74.3, 70.7, 42.3, 21.8, 17.99, 17.95, 17.4, 12.2; IR (film) v 3467, 3349, 3102, 2942, 2868, 1739, 1598, 1464, 1410, 1350, 1174, 1124, 1088, 879, 664 cm−1; HRMS (ESI-TOF) m/z calcd for C27H41NNaO5S2Si [M + Na+] 574.2093, found 574.2092. (2R*,5S*,6R*,Z)-6-Hydroxy-5-methyl-N-tosyl-2((triisopropylsilyl)oxy)oct-3-enamide (8): Method A; 44.8 mg (72% yield); dr = 98:2; colorless wax; Rf (30% acetone/hexane) 0.60; 1H NMR (400 MHz, CDCl3) δ 9.67 (s, 1H), 7.95−7.88 (m, 2H), 7.33− 7.26 (m, 2H), 5.49 (dd, J = 10.9, 1.2, 1H), 5.30 (t, J = 10.9, 8.9, 1H), 4.92 (d, J = 8.9, 1H), 3.32−3.24 (m, 1H), 2.54−2.39 (m, 4H), 1.74− 1.61 (m, 1H), 1.44−1.31 (m, 1H), 1.15−0.95 (m, 24H), 0.93 (d, J = 6.6, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 170.4, 146.3, 145.2, 137.8, 135.6, 129.7, 128.6, 128.2, 126.6, 125.4, 125.2, 74.3, 70.7, 42.3, 21.8, 17.99, 17.95, 17.4, 12.2; IR (film) v 3507, 3350, 3070, 2943, 2868, 1739, 1598, 1464, 1411, 1350, 1176, 1124, 1089, 881, 724, 661 cm−1; HRMS (ESI-TOF) m/z calcd for C25H43NNaO5SSi [M + Na+] 520.2529, found 520.2526. (2R*,5S*,6R*,Z)-6-Hydroxy-5-methyl-8-phenyl-N-tosyl-2((triisopropylsilyl)oxy)oct-3-enamide (9): Method A; 58.1 mg (81% yield); dr > 95:5; colorless wax; Rf (30% acetone/hexane) 0.65; 1H NMR (400 MHz, CDCl3) δ 9.48 (s, 1H), 7.97−7.90 (m, 2H), 7.37− 7.13 (m, 7H), 5.47 (d, J = 10.9, 1H), 5.31 (t, J = 10.9, 8.8, 1H), 4.93 (d, J = 8.8, 1H), 3.37−3.28 (m, 1H), 2.93−2.84 (m, 1H), 2.74−2.65 (m, 1H), 2.51−2.39 (m, 4H), 1.96−1.85 (m, 1H), 1.71−1.58 (m, 1H), 1.09−0.99 (m, 21H), 0.91 (d, J = 6.6, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 170.7, 145.3, 142.5, 138.8, 135.5, 129.7, 128.7, 128.53, 128.50, 127.0, 125.9, 74.2, 71.0, 40.2, 36.5, 31.9, 21.8, 17.98, 17.95, 17.0, 12.1; IR (film) v 3507, 3351, 3063, 2942, 2867, 1739, 1655, 1599, 1462, 1410, 1351, 1176, 1123, 1088, 881, 661 cm−1; HRMS (ESI-TOF) m/z calcd for C31H47NNaO5SSi [M + Na+] 596.2842, found 596.2834. (2R*,5S*,6R*,Z)-6,9-Dihydroxy-5-methyl-N-tosyl-2((triisopropylsilyl)oxy)non-3-enamide (10): Method A; 44.9 mg (68% yield); dr = 98:2; colorless wax; Rf (30% acetone/hexane) 0.60; 1 H NMR (400 MHz, CDCl3) δ 10.09 (s, 1H), 7.95−7.86 (m, 2H), 7.34−7.26 (m, 2H), 5.48 (dd, J = 10.9, 1.1, 1H), 5.30 (t, J = 10.9, 9.0, 1H), 4.92 (dd, J = 9.0, 1.1, 1H), 3.80−3.63 (m, 2H), 3.37 (td, J = 8.8, 2.3, 1H), 2.42 (s, 4H), 1.91−1.66 (m, 3H), 1.41 (ddt, J = 13.2, 8.8, 6.5, 1H), 1.13−0.98 (m, 21H), 0.95 (d, J = 6.5, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 170.5, 145.1, 138.4, 135.8, 129.7, 128.4, 127.0, 75.2, 70.7, 63.2, 39.9, 32.3, 29.14, 21.8, 17.98, 17.95, 17.1, 12.2; IR 14546


Article


7.03 (m, 2H), 6.91−6.84 (m, 2H), 6.17 (td, J = 10.8, 1.4, 1H), 5.43 (dd, J = 10.8, 8.4, 1H), 5.09 (dd, J = 8.4, 1.4, 1H), 4.76 (d, J = 9.1, 1H), 3.91 (t, J = 10.0, 1H), 3.58 (s, 1H), 2.45 (s, 3H), 0.97−0.85 (m, 21H); 13C{1H} NMR (101 MHz, CDCl3) δ 170.5, 145.3, 142.2, 139.5, 135.58, 135.57, 129.7, 128.6, 128.5, 128.4, 128.3, 128.0, 127.5, 126.9, 126.8, 78.7, 70.9, 54.1, 21.8, 17.9, 17.8, 12.0; IR (film) v 3466, 3347, 3063, 3031, 2944, 2867, 1739, 1598, 1457, 1411, 1351, 1176, 1088, 871, 669, 549 cm−1; HRMS (ESI-TOF) m/z calcd for C34H45NNaO5SSi [M + Na+] 630.2685, found 630.2681. Ethyl (2S*,5R*,Z)-2-((S)-Hydroxy(phenyl)methyl)-6-((4methylphenyl)sulfonamido)-6-oxo-5-((triisopropylsilyl)oxy)hex-3enoate (34): Method A; 48.3 mg (64% yield); dr = 98:2; white solid; mp 130.1−131.4 °C; Rf (30% AcOEt/hexane + 0.5% HCO2H) 0.55; 1 H NMR (400 MHz, CDCl3) δ 9.53 (s, 1H), 7.98−7.91 (m, 2H), 7.39−7.26 (m, 7H), 5.93 (td, J = 10.9, 1.3, 1H), 5.54 (dd, J = 10.9, 8.5, 1H), 5.03 (dd, J = 8.5, 1.3, 1H), 4.81 (d, J = 9.1, 1H), 3.88−3.75 (m, 2H), 3.69 (dd, J = 10.9, 9.1, 1H), 2.44 (s, 3H), 1.15−0.98 (m, 21H), 0.91 (t, J = 7.1, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 170.5, 170.4, 145.5, 141.3, 135.3, 131.0, 130.9, 129.9, 128.6, 128.5, 128.3, 126.8, 75.4, 70.9, 60.9, 55.2, 21.8, 18.0, 17.9, 13.9, 12.1; IR (film) v 3457, 3349, 3094, 3033, 2944, 2868, 1735, 1598, 1462, 1413, 1353, 1175, 1125, 1088, 879, 700, 663, 549 cm−1; HRMS (ESI-TOF) m/z calcd for C31H45NNaO7SSi [M + Na+] 626.2584, found 626.2571. ( 2 R*,6S *,Z) -6 - Hydro x y- 4- meth yl - 6- p he ny l -N -t os y l -2 ((triisopropylsilyl)oxy)hex-3-enamide (35): Method A; 58.0 mg (85% yield); dr = 95:5; white solid; mp 76.1−76.9 °C; Rf (20% acetone/hexane) 0.45; 1H NMR (400 MHz, CDCl3) δ 9.67 (s, 1H), 7.98−7.92 (m, 2H), 7.42−7.27 (m, 7H), 5.25 (d, J = 9.1, 1H), 4.93 (d, J = 9.1, 1H), 4.89−4.80 (m, 1H), 3.98 (s, 1H), 2.65 (dd, J = 13.6, 10.2, 1H), 2.45 (s, 3H), 2.24 (dd, J = 13.6, 2.7, 1H), 1.85 (s, 3H), 1.07−0.97 (m, 21H); 13C{1H} NMR (101 MHz, CDCl3) δ 171.4, 145.3, 144.9, 139.1, 135.5, 129.7, 128.6, 128.5, 127.5, 125.6, 125.5, 71.3, 71.1, 44.3, 23.7, 21.8, 17.9, 17.8, 12.1; IR (film) v 3470, 3345, 3066, 2943, 2867, 1739, 1663, 1598, 1462, 1412, 1352, 1175, 1123, 1089, 883, 662, 548 cm−1; HRMS (ESI-TOF) m/z calcd for C29H43NNaO5SSi [M + Na+] 568.2529, found 568.2519. ( 2 R*,6S *,Z) -6 - Hydro x y- 3- meth yl - 6- p he ny l -N -t os y l -2 ((triisopropylsilyl)oxy)hex-3-enamide (38a): Method A, starting from 30, 31.4 mg (46% yield), dr = 98:2; starting from 31, 32.8 mg (48% yield), dr = 98:2; white solid; mp 129.4−130.8 °C; Rf (30% acetone/hexane) 0.45; 1H NMR (400 MHz, CDCl3) δ 9.87 (s, 1H), 7.96−7.90 (m, 2H), 7.41−7.26 (m, 7H), 5.55 (dd, J = 10.6, 5.7, 1H), 5.09 (s, 1H), 4.73 (dd, J = 9.8, 2.9, 1H), 3.52 (s, 1H), 2.59−2.47 (m, 1H), 2.44 (s, 3H), 2.41−2.33 (m, 1H), 1.58 (s, 3H), 1.13−0.93 (m, 21H); 13C{1H} NMR (101 MHz, CDCl3) δ 170.7, 145.2, 144.3, 135.7, 135.6, 129.7, 128.7, 128.5, 127.74, 127.71, 125.7, 73.6, 71.7, 39.3, 21.8, 18.0, 17.9, 17.8, 12.2; IR (film) v 3477, 3350, 3065, 2944, 2867, 1739, 1598, 1464, 1408, 1350, 1176, 1122, 1088, 882, 661, 554 cm−1; HRMS (ESI-TOF) m/z calcd for C29H43NNaO5SSi [M + Na+] 568.2529, found 568.2527. ( 2R *,6R *,E)-6-Hydroxy-3-methyl-6-phe nyl-N-t osyl-2((triisopropylsilyl)oxy)hex-3-enamide (38b) and (2R*,6S*,E)-6Hydroxy-3-methyl-6-phenyl-N-tosyl-2-((triisopropylsilyl)oxy)hex-3enamide (38b′): Method A, starting from 30, 19.1 mg (28% yield), dr = 54:46; starting from 31, 20.5 mg (30% yield), dr = 51:49; colorless wax; Rf (30% acetone/hexane) 0.40; 1H NMR (400 MHz, CDCl3) δ = 9.04 (br s, 1H), 9.01 (br s, 1H′), 8.00−7.87 (m, 2H + 2H′), 7.45− 7.20 (br m, 7H + 7H′), 5.66−5.54 (m, 1H + 1 H′), 4.74−4.64 (m, 1H + 1 H′), 4.41 (s, 1H), 4.39 (s, 1H′), 2.60−2.36 (m, 2H + 2H′), 2.43 (s, 3H + 3H′), 2.06 (br s, 1H + 1H′), 1.48 (s, 3H + 3H′), 1.09− 0.91 (m, 21H + 21H′); 13C{1H} NMR (101 MHz, CDCl3) δ 169.86, 169.85, 145.2, 143.9, 143.8, 135.67, 134.9, 134.6, 129.6, 128.6, 128.5, 127.8, 126.3, 126.1, 125.9, 79.54, 79.50, 73.84, 73.80, 37.7, 37.5, 21.8, 17.91, 17.87, 12.1, 12.02; IR (film) v 3352, 3063, 2944, 2867, 2730, 1920, 1729, 1598, 1459, 1406, 1351, 1176, 1088, 881, 663, 550 cm−1; HRMS (ESI-TOF) m/z calcd for C29H43NNaO5SSi [M + Na+] 568.2529, found 568.2515. (2R*,6S*,Z)-6-Hydroxy-6-phenyl-N-tosyl-2-((triisopropylsilyl)oxy)hex-3-enamide (44a): Method A, 51.9 mg (78% yield), dr = 87:13; Method B, 58.5 mg (88% yield), dr = 95:5; colorless wax; Rf

2.90 (m, 1H), 2.42 (s, 3H), 1.08−0.96 (m, 21H), 0.82 (d, J = 6.8, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 169.5, 145.1, 142.6, 137.9, 135.8, 129.6, 128.5, 128.5, 128.0, 127.9, 126.8, 78.9, 72.8, 41.4, 21.8, 18.03, 18.01, 17.4, 12.1; IR (film) v 3548, 3351, 3063, 2943, 2867, 1731, 1598, 1461, 1407, 1351, 1160, 1087, 871, 665, 549 cm−1; HRMS (ESI-TOF) m/z calcd for C29H43NNaO5SSi [M + Na+] 568.2529, found 568.2529. (2R*,5S*,6R*,E)-6-Hydroxy-5-methyl-6-phenyl-N-tosyl-2((triisopropylsilyl)oxy)hex-3-enamide (18b) and (2R*,5S*,6S*,E)-6Hydroxy-5-methyl-6-phenyl-N-tosyl-2-((triisopropylsilyl)oxy)hex-3enamide (18b′): Method A, starting from 16, 40.3 mg (59% yield), 18b/18b′ = 79:21; starting from 17, 38.2 mg (56% yield), 18b/18b′ = 78:22; colorless wax; Rf (50% Et2O/hexane + 0.5% HCO2H) 0.50; 1 H NMR (400 MHz, CDCl3) δ 8.85 (br s, 1H + 1H′), 7.96−7.89 (m, 2H + 2H′), 7.37−7.20 (m, 5H + 5H′), 5.89 (ddd, J = 15.6, 7.7, 1.5, 1H′), 5.78 (ddd, J = 15.6, 7.2, 1.5, 1H), 5.49 (ddd, J = 15.6, 5.5, 1.1, 1H′), 5.39 (ddd, J = 15.6, 5.5, 1.3, 1H), 4.58 (dd, J = 5.5, 1.5, 1H′), 4.53−4.49 (m, 2H), 4.40 (d, J = 6.9, 1H′), 2.63−2.47 (m, 1H + 1H′), 2.43 (s, 3H + 3H′), 1.08−0.92 (m, 24H + 21H′), 0.86 (d, J = 6.9, 3H′); 13C{1H} NMR (101 MHz, CDCl3) δ 169.7, 145.3, 142.6, 142.4, 136.5, 136.3, 135.6, 129.6, 129.6, 128.49, 128.45, 128.4, 127.8, 127.80, 127.76, 127.0, 126.7, 126.5, 78.1, 75.2, 44.1, 43.4, 29.8, 21.8, 18.0, 17.94, 17.91, 16.4, 14.4, 12.1, 12.0; IR (film) v 3541, 3357, 3063, 2944, 2868, 1732, 1598, 1455, 1408, 1352, 1160, 1089, 881, 663, 548 cm−1; HRMS (ESI-TOF) m/z calcd for C29H43NNaO5SSi [M + Na+] 568.2529, found 568.2535. (5S*,6S*,Z)-6-Hydroxy-5-methyl-6-phenyl-N-tosylhex-3-enamide (21): Method A, starting from 25, 26.6 mg (57% yield), dr > 95:5; starting from 26, 28 mg (60% yield), dr > 95:5; white solid; mp 121.2−122.1 °C; Rf (30% acetone/hexane) 0.50; 1H NMR (400 MHz, CDCl3) δ 10.86 (s, 1H), 7.93−7.86 (m, 2H), 7.42−7.27 (m, 7H), 5.61 (t, J = 10.6, 1H), 5.50 (td, J = 10.9, 5.0, 1H), 4.36 (d, J = 9.5, 1H), 3.38 (dd, J = 14.8, 11.0, 1H), 3.12 (s, 1H), 2.83−2.67 (m, 2H), 2.43 (s, 3H), 0.70 (d, J = 6.7, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 169.1, 144.7, 142.0, 139.0, 136.3, 129.5, 128.8, 128.6, 128.4, 127.1, 121.3, 79.3, 39.7, 37.3, 21.8, 17.2; IR (film) v 3488, 3064, 2875, 1712, 1453, 1347, 1172, 1149, 1088, 860, 764, 703, 663, 549 cm−1; HRMS (ESI-TOF) m/z calcd for C15H17O3SiNa [M + Na+] 396.1245, found 396.1237. (5S,6S,Z)-6-Hydroxy-5-methyl-6-phenyl-N-tosylhex-3-enamide ((−)-21): Method A; 28.0 mg (60% yield); dr > 95:5; 86% ee (19F NMR analysis of Mosher’s ester 28); white solid; mp 127.2−128.9 °C; Rf (30% acetone/hexane) 0.50; [α]23 D −263.6 (c 1.66, CHCl3); NMR and IR spectra were consistent with those recorded for the racemate; HRMS (ESI-TOF) m/z calcd for C15H17O3SiNa [M + Na+] 396.1245, found 396.1235. (5R,6R,Z)-6-Hydroxy-5-methyl-6-phenyl-N-tosylhex-3-enamide ((+)-21): Method A; 8.5 mg (61% yield); dr > 95:5; 20% ee (19F NMR analysis of Mosher’s ester 29); colorless wax; Rf (30% acetone/ hexane) 0.50; [α]24 D +40.3 (c 1.86, CHCl3); NMR and IR spectra were consistent with those recorded for the racemate; HRMS (ESI-TOF) m/z calcd for C15H17O3SiNa [M + Na+] 396.1245, found 396.1242. (2R*,5S*,Z)-5-((S)-Hydroxy(phenyl)methyl)-6-methyl-N-tosyl-2((triisopropylsilyl)oxy)hept-3-enamide (32): Method A; 53.1 mg (74% yield); dr = 98:2; white solid; mp 126.4−127.7 °C; Rf (20% acetone/hexane) 0.45; 1H NMR (400 MHz, CDCl3) δ 9.88 (s, 1H), 7.98−7.91 (m, 2H), 7.41−7.28 (m, 7H), 5.74 (td, J = 11.3, 1.4, 1H), 5.55 (dd, J = 11.3, 8.0, 1H), 5.08 (dd, J = 8.0, 1.4, 1H), 4.46 (d, J = 10.0, 1H), 3.59 (s, 1H), 2.79−2.71 (m, 1H), 2.42 (s, 3H), 1.44−1.34 (m, 1H), 1.18−1.01 (m, 21H), 0.83 (d, J = 6.9, 3H), 0.75 (d, J = 6.9, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 171.1, 145.2, 143.4, 135.6, 133.2, 130.9, 129.7, 128.7, 128.5, 128.0, 127.1, 76.3, 71.4, 51.9, 28.2, 22.3, 21.8, 18.14, 18.11, 15.9, 12.4; IR (film) v 3469, 3351, 3066, 2956, 2868, 1738, 1598, 1463, 1412, 1350, 1175, 1127, 1088, 880, 663, 548 cm−1; HRMS (ESI-TOF) m/z calcd for C31H47NNaO5SSi [M + Na+] 596.2842, found 596.2833. (2R*,5R*,6S*,Z)-6-Hydroxy-5,6-diphenyl-N-tosyl-2((triisopropylsilyl)oxy)hex-3-enamide (33): Method A; 54.7 mg (72% yield); dr = 98:2; white solid; mp 134.9−136.0 °C; Rf (30% acetone/hexane) 0.65; 1H NMR (400 MHz, CDCl3) δ 9.66 (s, 1H), 8.02−7.95 (m, 2H), 7.40−7.32 (m, 2H), 7.18−7.09 (m, 6H), 7.08− 14547


Article


128.2, 127.0, 125.3, 124.4, 74.3, 56.7, 43.2, 21.6; IR (film) v 3512, 3245, 2922, 1777, 1718, 1597, 1434, 1387, 1351, 1176, 1147, 1088, 852, 721, 549 cm −1 ; HRMS (ESI-TOF) m/z calcd for C27H24N2NaO6S [M + Na+] 527.1253, found 527.1243. (2R*,5S*,6S*,Z)-2-(1,3-Dioxoisoindolin-2-yl)-6-hydroxy-5-methyl-6-phenyl-N-tosylhex-3-enamide (49): 40.8 mg (63% yield); dr = 91:1; colorless solid; mp 154.2−154.7 °C; Rf (40% acetone/hexane) 0.45; 1H NMR (400 MHz, acetone-d6) δ 11.47 (s, 1H), 7.94−7.86 (m, 2H), 7.55−7.48 (m, 2H), 7.47−7.30 (m, 5H), 6.23 (td, J = 10.6, 0.8, 1H), 5.99−5.87 (m, 2H), 4.54 (d, J = 9.6, 1H), 3.09 (td, J = 10.1, 6.6, 1H), 2.44 (s, 3H), 0.73 (d, J = 6.6, 3H); 13C{1H} NMR (101 MHz, acetone-d6) δ 167.8, 166.3, 145.5, 143.9, 142.3, 137.6, 135.4, 132.7, 130.2, 129.2, 129.1, 128.8, 128.2, 124.1, 121.9, 79.5, 52.5, 40.8, 21.5, 17.1; IR (film) v 3501, 2985, 2848, 2791, 1773, 1712, 1597, 1465, 1389, 1348, 1162, 1018, 849, 756, 551 cm−1; HRMS (ESITOF) m/z calcd for C28H26N2NaO6S [M + Na+] 541.1409, found 541.1396. (2R*,6S*,Z)-6-Hydroxy-N-(methylsulfonyl)-6-phenyl-2((triisopropylsilyl)oxy)hex-3-enamide (53a): Method A, 41.0 mg (72% yield), dr = 90:10; Method B, 9.3 mg (69% yield), dr = 94:6; white solid; mp 88.5−89.6 °C; Rf (30% acetone/hexane) 0.45; 1H NMR (400 MHz, CDCl3) δ 9.61 (s, 1H), 7.41−7.23 (m, 5H), 5.84 (td, J = 10.7, 6.2, 1H), 5.54 (t, J = 10.7, 8.8, 1H), 5.10 (dd, J = 8.8, 1.2, 1H), 4.78 (dd, J = 9.6, 3.6, 1H), 3.48−3.31 (m, 1H), 3.26 (s, 3H), 2.65 (dt, J = 14.3, 9.6, 1H), 2.56−2.46 (m, 1H), 1.17−0.95 (m, 21H); 13C{1H} NMR (101 MHz, CDCl3) δ 171.8, 144.2, 131.9, 129.7, 128.7, 127.8, 125.7, 73.3, 70.5, 41.5, 39.3, 18.0, 17.9, 12.1; IR (film) v 3480, 3355, 3064, 3030, 2944, 2867, 1733, 1657, 1463, 1397, 1346, 1181, 1120, 1068, 973, 881, 700, 518 cm−1; HRMS (ESI-TOF) m/z calcd for C22H37NNaO5SSi [M + Na+] 478.2059, found 478.2052. (2R*,6R*,E)-6-Hydroxy-N-(methylsulfonyl)-6-phenyl-2((triisopropylsilyl)oxy)hex-3-enamide (53b): Method A, 8.5 mg (15% yield), dr = 61:39; Method B, 10.8 mg (19% yield), dr = 87:13; colorless wax; Rf (30% acetone/hexane) 0.40; 1H NMR (400 MHz, CDCl3) δ 8.80 (s, 1H), 7.40−7.26 (m, 5H), 5.89 (dtd, J = 15.7, 7.2, 1.4, 1H), 5.59 (ddt, J = 15.4, 5.8, 1.4, 1H), 4.79−4.66 (m, 2H), 3.25 (s, 3H), 2.59−2.52 (m, 2H), 1.14−0.99 (m, 21H); 13C{1H} NMR (101 MHz, CDCl3) δ 171.16, 143.6, 131.1, 129.5, 128.7, 127.9, 126.0, 75.1, 73.6, 41.9, 41.5, 17.99, 17.96, 12.1; IR (film) v 3358, 3030, 2944, 2868, 1724, 1461, 1397, 1348, 1181, 1149, 1056, 972, 881, 688, 519 cm −1 ; HRMS (ESI-TOF) m/z calcd for C22H37NNaO5SSi [M + Na+] 478.2059, found 478.2046. (2R,5S,6S,Z)-6-((R)-2,2-Dimethyl-1,3-dioxolan-4-yl)-6-hydroxy-5methyl-N-tosyl-2-((triisopropylsilyl)oxy)hex-3-enamide ((−)-56): 48.4 mg (68% yield); dr > 98:2; colorless wax; Rf (20% acetone/ 1 hexane) 0.50; [α]25 D −60.9 (c 2.25, CHCl3); H NMR (400 MHz, CDCl3) δ 9.78 (s, 1H), 7.95−7.88 (m, 2H), 7.35−7.27 (m, 2H), 5.51 (t, J = 10.8, 1H), 5.31 (t, J = 9.9, 1H), 4.88 (d, J = 8.9, 1H), 4.16 (q, J = 6.2, 1H), 3.97 (t, J = 7.3, 1H), 3.89 (t, J = 7.6, 1H), 3.56 (t, J = 6.3, 1H), 2.92 (s, 1H), 2.62−2.47 (m, 1H), 2.42 (s, 3H), 1.43 (s, 3H), 1.36 (s, 3H), 1.13−0.97 (m, 21H); 13C{1H} NMR (101 MHz, CDCl3) δ 170.1, 145.1, 137.1, 135.8, 129.6, 128.4, 127.4, 109.3, 77.7, 74.9, 70.5, 65.4, 37.4, 26.7, 25.5, 21.8, 17.95, 17.94, 17.0, 12.2; IR (film) v 3511, 3355, 3110, 2943, 2868, 1737, 1598, 1462, 1406, 1351, 1176, 1121, 1087, 871, 661, 548 cm−1; HRMS (ESI-TOF) m/z calcd for C28H47NNaO7SSi [M + Na+] 592.2740, found 592.2739. (2S,5R,6R,Z)-6-((R)-2,2-Dimethyl-1,3-dioxolan-4-yl)-6-hydroxy-5methyl-N-tosyl-2-((triisopropylsilyl)oxy)hex-3-enamide ((+)-57): 47.0 mg (66% yield); dr > 98:2; colorless wax; Rf (20% acetone/ 1 hexane) 0.45; [α]25 D +61.3 (c 2.48, CHCl3); H NMR (400 MHz, CDCl3) δ 9.38 (s, 1H), 7.94−7.87 (m, 2H), 7.35−7.25 (m, 2H), 5.58 (td, J = 10.9, 1.4, 1H), 5.28 (dd, J = 10.9, 8.3, 1H), 4.89 (dd, J = 8.3, 1.4, 1H), 4.11−3.99 (m, 2H), 3.96−3.85 (m, 1H), 3.29−3.22 (m, 1H), 3.19−3.13 (m, 1H), 2.80−2.68 (m, 1H), 2.42 (s, 3H), 1.43 (s, 3H), 1.36 (s, 3H), 1.11−0.96 (m, 21H); 13C{1H} NMR (101 MHz, CDCl3) δ 170.0, 145.2, 137.3, 135.6, 129.6, 128.6, 127.2, 109.4, 76.3, 75.1, 71.1, 66.5, 36.3, 26.6, 25.5, 21.8, 18.0, 17.9, 17.1, 12.1; IR (film) v 3495, 3352, 3071, 2943, 2868, 1736, 1652, 1598, 1462, 1410, 1352,

(20% acetone/hexane) 0.45. Analytical data were consistent with previously reported values.7 (2R,6R,E)-6-Hydroxy-6-phenyl-N-tosyl-2-((triisopropylsilyl)oxy)hex-3-enamide (44b): Method A, 8.6 mg (13% yield), dr = 51:49; Method B, 10.0 mg (15% yield), dr = 92:8; colorless wax; Rf (20% acetone/hexane) 0.40. Analytical data were consistent with previously reported values.7 (2R*,6S*,Z)-6-Hydroxy-2-methyl-6-phenyl-N-tosylhex-3-enamide (45a): Method A, 37.4 mg (80% yield), dr = 91:9; Method B, 34.6 mg (74% yield), dr = 95:5; white solid; mp 125.8−126.7 °C; Rf (30% acetone/hexane) 0.50; 1H NMR (400 MHz, CDCl3) δ 10.97 (s, 1H), 7.93−7.86 (m, 2H), 7.42−7.27 (m, 7H), 5.74 (dd, J = 10.9, 5.3, 1H), 5.34 (d, J = 10.9, 1H), 4.82 (d, J = 10.8, 1H), 3.45 (dq, J = 10.9, 6.6, 1H), 3.30 (s, 1H), 2.68 (dt, J = 14.1, 11.1, 1H), 2.43 (s, 3H), 2.24 (ddt, J = 15.8, 5.4, 1.8, 1H), 1.09 (d, J = 6.6, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 171.6, 144.5, 143.8, 136.4, 131.5, 129.5, 129.4, 128.8, 128.3, 128.2, 125.6, 74.12, 39.4, 37.7, 21.8, 14.8; IR (film) v 3487, 3087, 2978, 2877, 1722, 1598, 1453, 1400, 1344, 1175, 1086, 849, 663, 569 cm −1 ; HRMS (ESI-TOF) m/z calcd for C20H23NNaO4S [M + Na+] 396.1245, found 396.1241. (2R*,6R*,E)-6-Hydroxy-2-methyl-6-phenyl-N-tosylhex-3-enamide (45b) and (2R*,6S*,E)-6-Hydroxy-2-methyl-6-phenyl-N-tosylhex-3-enamide (45b′): Method A, 1.9 mg (4% yield), 45b/45b′ = 53:47; Method B, 7.0 mg (15% yield), 45b/45b′ = 74:26; colorless wax; Rf (30% acetone/hexane) 0.45; 1H NMR (400 MHz, CDCl3) δ 9.56 (s, 1H + 1H′), 7.99−7.89 (m, 2H + 2H′), 7.43−7.23 (m, 7H + 7H′), 5.80−5.67 (m, 1H), 5.70−5.58 (m, 1H′), 5.58−5.49 (m, 1H′), 5.47 (ddt, J = 15.3, 9.2, 1.1, 1H), 4.87 (dd, J = 7.0, 4.8, 1H′), 4.80 (dd, J = 9.2, 4.1, 1H), 3.11−2.92 (m, 1H + 1H′), 2.60−2.32 (m, 4H + 4H′), 1.20 (d, J = 7.1, 3H′), 1.18 (d, J = 7.0, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 172.2, 172.1, 145.0, 144.9, 143.9, 143.7, 136.0, 135.9, 132.6, 132.3, 132.1, 131.0, 129.64, 129.62, 128.8, 128.7, 128.6, 128.1, 127.9, 125.8, 125.7, 73.6, 73.4, 45.2, 44.8, 42.3, 41.7, 21.8, 15.9, 15.7; IR (film) v 3506, 3249, 3063, 2979, 2931, 1717, 1597, 1453, 1342, 1173, 1087, 843, 661, 548 cm−1; HRMS (ESI-TOF) m/z calcd for C20H23NNaO4S [M + Na+] 396.1245, found 396.1230. (2R*,6S*,Z)-6-Hydroxy-2-isopropyl-6-phenyl-N-tosylhex-3-enamide (46a): Method A, starting from 41, 42.2 mg (84% yield), dr = 96:4; Method B, starting from 41, 38.1 mg (76% yield), dr = 98:2, starting from 42, 5.6 mg (71% yield), dr = 99:1; colorless wax; Rf (30% acetone/hexane) 0.45. Analytical data were consistent with previously reported values.3a (2R*,6R*,E)-6-Hydroxy-2-isopropyl-6-phenyl-N-tosylhex-3-enamide (46b): Method A, starting from 41, 3.5 mg (7% yield), dr = 86:14; Method B, starting from 41, 11.0 mg (22% yield), dr = 98:2, starting from 42, 11.0 mg (22% yield), dr = 89:11; colorless wax; Rf (30% acetone/hexane) 0.40. Analytical data were consistent with previously reported values.3a (2R*,6S*,Z)-2-(1,3-Dioxoisoindolin-2-yl)-6-hydroxy-6-phenyl-Ntosylhex-3-enamide (47a): Method A, 47.3 mg (75% yield), dr = 88:12; Method B, 46.7 mg (74% yield), dr = 98:2; colorless crystals; mp 201.3−202.1 °C; Rf (45% AcOEt/hexane + 0.5% HCO2H) 0.60; 1 H NMR (400 MHz, CDCl3) δ 11.04 (s, 1H), 7.96−7.86 (m, 2H), 7.85−7.74 (m, 2H), 7.73−7.64 (m, 2H), 7.48−7.25 (m, 7H), 6.37 (td, J = 10.7, 1.3, 1H), 6.05 (td, J = 11.2, 5.0, 1H), 5.79 (d, J = 10.7, 1H), 4.92 (dd, J = 11.0, 2.2, 1H), 3.32 (s, 1H), 2.88 (dd, J = 14.1, 11.2, 1H), 2.43 (s, 3H), 2.39−2.31 (m, 1H); 13C{1H} NMR (101 MHz, CDCl3) δ 167.3, 165.1, 145.0, 143.2, 135.8, 134.4, 134.3, 131.9, 129.7, 128.9, 128.5, 128.4, 125.8, 123.7, 74.0, 51.2, 37.5, 21.8; IR (film) v 3476, 3067, 2882, 1775, 1714, 1597, 1468, 1386, 1347, 1176, 1152, 1086, 853, 718, 546 cm−1; HRMS (ESI-TOF) m/z calcd for C27H24N2NaO6S [M + Na+] 527.1253, found 527.1251. (2R*,6R*,E)-2-(1,3-Dioxoisoindolin-2-yl)-6-hydroxy-6-phenyl-Ntosylhex-3-enamide (47b): Method A, 8.2 mg (13% yield), dr = 55:45; Method B, 8.2 mg (13% yield), dr = 90:10; colorless wax; Rf (45% AcOEt/hexane + 0.5% HCO2H) 0.50; 1H NMR (400 MHz, MeOH-d4) δ 7.88−7.80 (m, 6H), 7.41−7.33 (m, 2H), 7.27−7.19 (m, 2H), 7.19−7.09 (m, 2H), 7.08−6.98 (m, 1H), 5.90−5.72 (m, 2H), 5.23 (d, J = 7.3, 1H), 4.65 (dd, J = 7.5, 6.0, 1H), 2.60−2.47 (m, 1H), 2.47−2.35 (m, 4H); 13C{1H} NMR (101 MHz, MeOH-d4) δ 168.6, 168.3, 146.2, 145.4, 137.6, 136.5, 135.6, 133.2, 130.5, 129.3, 129.1, 14548


Article

The Journal of Organic Chemistry 1177, 1122, 1088, 879, 661, 548 cm−1; HRMS (ESI-TOF) m/z calcd for C28H47NNaO7SSi [M + Na+] 592.2740, found 592.2728. Synthesis of Mosher’s Esters 22 and 23. To a solution of (Z)5,6-anti-enediol 21, (−)-21, or (+)-21 (7.5 mg, 0.02 mmol), DMAP (0.6 mg; 0.005 mmol), and Et3N (5.6 μL, 0.04 mmol) in anhydrous CH2Cl2 (0.65 mL) was added a 1 M solution of (+)-MTPACl in CH2Cl2 (22 μL, 0.022 mmol) dropwise at 25 °C. After 1 h at the same temperature, the reaction was quenched with a saturated aqueous solution of NH4Cl (0.5 mL), poured into water (10 mL), and extracted with CH2Cl2 (3 × 5 mL). Combined extracts were then washed with brine (15 mL), dried over MgSO4, and concentrated. Filtration of the crude product through a pad of silica gel with an acetone/hexane mixture afforded Mosher’s esters 22 and 23 as inseparable mixtures of diastereomers. (1S,2S,Z)-2-Methyl-6-((4-methylphenyl)sulfonamido)-6-oxo-1phenylhex-3-en-1-yl (S)-3,3,3-Trifluoro-2-methoxy-2-phenylpropanoate (22) and (1R,2R,Z)-2-Methyl-6-((4-methylphenyl)sulfonamido)-6-oxo-1-phenylhex-3-en-1-yl (S)-3,3,3-Trifluoro-2methoxy-2-phenylpropanoate (23): obtained according to a general procedure using 21; inseparable mixture; 7.2 mg (61% yield); 22/23 = 50:50; colorless oil; Rf (30% acetone/hexane) 0.45; 19F NMR (376 MHz, CDCl3) δ −71.14 (23), −71.20 (22); HRMS (ESI-TOF) m/z calcd for C30H30F3NNaO6SSi [M + Na+] 612.1644, found 612.1630. (1S,2S,Z)-2-Methyl-6-((4-methylphenyl)sulfonamido)-6-oxo-1phenylhex-3-en-1-yl (S)-3,3,3-Trifluoro-2-methoxy-2-phenylpropanoate (22): obtained according to a general procedure using (−)-21; 8.0 mg (68% yield); 22/23 = 97:3 (86% de); colorless oil; Rf (30% acetone/hexane) 0.45; 19F NMR (376 MHz, CDCl3) δ −71.14 (23), −71.20 (major signal 22); HRMS (ESI-TOF) m/z calcd for C30H30F3NNaO6SSi [M + Na+] 612.1644, found 612.1636. (1R,2R,Z)-2-Methyl-6-((4-methylphenyl)sulfonamido)-6-oxo-1phenylhex-3-en-1-yl (S)-3,3,3-Trifluoro-2-methoxy-2-phenylpropanoate (23): obtained according to a general procedure using (+)-21;7.0 mg (59% yield); 23/22 = 60:40 (20% de); colorless oil; Rf (30% acetone/hexane) 0.45; 19F NMR (376 MHz, CDCl3) δ −71.14 (major signal 23), −71.21 (22); HRMS (ESI-TOF) m/z calcd for C30H30F3NNaO6SSi [M + Na+] 612.1644, found 612.1631. Reduction of (3Z)- and (3E)-Enediols 2a−2b and 18a−18b. To a solution of 2,6-enediol 2a, 2b, 18a, or 18b (109.6 mg, 0.2 mmol) in toluene (5 mL) was added PtO2 (6.8 mg, 0.03 mmol) in one portion at 25 °C, and the resulting suspension was saturated with H2. After 24 h at the same temperature, the 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 58−60 as colorless oils. (2R*,5S*,6S*)-6-Hydroxy-5-methyl-6-phenyl-N-tosyl-2((triisopropylsilyl)oxy)hexanamide (58): 82.0 mg (73% yield); dr = 97:3; colorless oil; Rf (25% acetone/hexane) 0.60; 1H NMR (400 MHz, CDCl3) δ 8.95 (s, 1H), 7.99−7.92 (m, 2H), 7.35−7.19 (m, 7H), 4.30 (d, J = 7.2, 1H), 4.21 (t, J = 5.1, 1H), 2.41 (s, 3H), 1.83− 1.66 (m, 4H), 1.52−1.40 (m, 1H), 1.10−0.96 (m, 21H), 0.63 (d, J = 6.8, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 171.6, 145.2, 143.3, 135.7, 129.6, 128.5, 128.4, 127.7, 126.7, 78.8, 74.1, 39.9, 32.9, 26.4, 21.8, 17.99, 17.97, 15.8, 12.2; IR (film) v 3539, 3357, 3062, 2926, 2867, 1728, 1598, 1459, 1406, 1351, 1175, 1088, 880, 662, 549 cm−1; HRMS (ESI-TOF) m/z calcd for C29H45NNaO5SSi [M + Na+] 570.2685, found 570.2688. (2R*,5R*,6R*)-6-Hydroxy-5-methyl-6-phenyl-N-tosyl-2((triisopropylsilyl)oxy)hexanamide (59): starting from 2b, 93.3 mg (83% yield), dr = 81:10:5:4; starting from 18a, 79.8 mg (71% yield), dr = 95:5; colorless oil; Rf (25% acetone/hexane) 0.60; 1H NMR (400 MHz, CDCl3) δ 8.98 (s, 1H), 7.96−7.92 (m, 2H), 7.36−7.21 (m, 7H), 4.31 (d, J = 6.8, 1H), 4.22 (dd, J = 5.7, 3.6, 1H), 2.43 (s, 3H), 1.91−1.51 (m, 5H), 1.11−0.93 (m, 21H), 0.62 (d, J = 6.8, 3H); 13 C{1H} NMR (101 MHz, CDCl3) δ 171.6, 145.2, 143.5, 135.7, 129.6, 128.54, 128.50, 128.4, 127.6, 126.6, 78.8, 74.1, 40.2, 33.1, 25.6, 21.8, 17.99, 17.95, 15.9, 12.1; IR (film) v 3464, 3358, 3062, 2926, 2867, 1729, 1664, 1598, 1461, 1406, 1351, 1176, 1088, 881, 662, 549

cm−1; HRMS (ESI-TOF) m/z calcd for C29H45NNaO5SSi [M + Na+] 570.2685, found 570.2687. (2R*,5S*,6R*)-6-Hydroxy-5-methyl-6-phenyl-N-tosyl-2((triisopropylsilyl)oxy)hexanamide (60) and (2R*,5S*,6S*)-6-Hydroxy-5-methyl-6-phenyl-N-tosyl-2-((triisopropylsilyl)oxy)hexanamide (60′): inseparable mixture; 96.6 mg (86% yield); 60b/ 60b′ = 78:22; colorless oil; Rf (25% acetone/hexane) 0.60; 1H NMR (400 MHz, CDCl3) δ 8.92 (br s, 1H + 1H′), 7.97−7.91 (m, 2H + 2H′), 7.37−7.18 (m, 7H + 7′), 4.44 (d, J = 5.0, 1H), 4.31 (d, J = 7.2, 1H′), 4.22 (t, J = 5.2, 1H′), 4.16 (t, J = 5.1, 1H), 2.42 (s, 3H), 2.42 (s, 3H′), 1.82−1.56 (m, 4H + 4H′), 1.24−1.16 (m, 1H + 1H′), 1.08− 0.94 (m, 21H + 21H′), 0.79 (d, J = 6.7, 3H), 0.64 (d, J = 6.8, 3H′); 13 C{1H} NMR (101 MHz, CDCl3) δ 171.6, 145.3, 145.2, 143.5, 143.3, 135.7, 135.7, 129.6, 128.6, 128.41, 128.37, 127.7, 127.44, 126.8, 126.3, 78.8, 77.7, 74.1, 74.0, 40.2, 40.0, 33.3, 32.9, 27.2, 26.4, 21.8, 18.00, 17.97, 15.8, 14.0, 12.2, 12.2; IR (film) v 3548, 3357, 3062, 2944, 2868, 1728, 1598, 1460, 1406, 1352, 1176, 1088, 880, 662, 549 cm−1; HRMS (ESI-TOF) m/z calcd for C29H45NNaO5SSi [M + Na+] 570.2685, found 570.2694. Synthesis of 3,6,7-Trisubstituted Caprolactones 61−63. To a vigorously stirred solution of 2,6-diol 58−60 (110 mg, 0.2 mmol) and TBAB (32 mg, 0.1 mmol) in MeI (2.5 mL) was added K2CO3 (1 g) in one portion at 25 °C. After 12 h at the same temperature, excess of K2CO3 was filtered off and washed with CH2Cl2 (25 mL), and combined filtrates were concentrated under reduced pressure. Filtration of the residue through a pad of silica gel with an acetone/hexane mixture afforded crude products, which were subsequently, without further purification, dissolved in the anhydrous THF (50 mL). To this mixture was added 2 M NaHMDS solution in THF (100 μL, 0.2 mmol) dropwise at −50 °C under an argon atmosphere, and the stirring was continued for 10 min at the same temperature. Then the reaction was quenched with a saturated solution of NH4Cl (50 mL), poured into water, and extracted with EtOAc (3 × 25 mL). The combined extracts were washed successively with water (50 mL), a saturated solution of NaHCO3 (50 mL), and brine (50 mL), dried over anhydrous MgSO4, 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 61−63 as colorless crystals or a colorless wax. (3R*,6S*,7S*)-6-Methyl-7-phenyl-3-((triisopropylsilyl)oxy)oxepan-2-one (61): 52.0 mg (69% yield); dr > 98:2; colorless oil; Rf (15% MTBE/hexane) 0.45; 1H NMR (400 MHz, CDCl3) δ 7.37− 7.26 (m, 5H), 5.94 (d, J = 8.1, 1H), 4.77 (dd, J = 6.4, 1.7, 1H), 2.14− 1.86 (m, 4H), 1.82−1.74 (m, 1H), 1.24−1.05 (m, 21H), 0.57 (d, J = 6.3, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 172.8, 139.9, 128.6, 128.3, 127.4, 85.8, 74.4, 39.1, 31.2, 30.3, 20.3, 18.1, 18.0, 12.1; IR (film) v 3032, 2937, 2867, 1735, 1460, 1268, 1211, 1120, 1016, 880, 695 cm−1; HRMS (ESI-TOF) m/z calcd for C22H36NaO3Si [M + Na+] 399.2331, found 399.2329. (3R*,6R*,7R*)-6-Methyl-7-phenyl-3-((triisopropylsilyl)oxy)oxepan-2-one (62a): 52.7 mg (70% yield); dr > 98:2, colorless crystals; mp 92.9−93.8 °C; Rf (15% MTBE/hexane) 0.60; 1H NMR (400 MHz, CDCl3) δ 7.40−7.29 (m, 5H), 4.83−4.73 (m, 2H), 2.22− 1.97 (m, 4H), 1.70−1.59 (m, 1H), 1.22−1.04 (m, 21H), 0.66 (d, J = 6.7, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 173.5, 139.3, 128.6, 128.6, 127.3, 86.3, 70.5, 38.4, 34.1, 33.2, 18.8, 18.1, 12.4; IR (film) v 3065, 3035, 2942, 2866, 2724, 1880, 1748, 1459, 1384, 1196, 1144, 882, 699 cm−1; HRMS (ESI-TOF) m/z calcd for C22H36NaO3Si [M + Na+] 399.2331, found 399.2319. (3R*,6R*,7S*)-6-Methyl-7-phenyl-3-((triisopropylsilyl)oxy)oxepan-2-one (62b): 6.0 mg (8% yield); dr > 98:2; colorless oil; Rf (15% MTBE/hexane) 0.70; 1H NMR (400 MHz, CDCl3) δ 7.41− 7.32 (m, 4H), 7.30−7.24 (m, 1H), 6.46 (s, 1H), 4.80−4.74 (m, 1H), 2.57−2.44 (m, 1H), 2.28−2.15 (m, 1H), 2.01−1.89 (m, 2H), 1.63 (dq, J = 13.9, 3.8, 1H), 1.22−1.04 (m, 21H), 0.87 (d, J = 7.2, 3H); 13 C{1H} NMR (101 MHz, CDCl3) δ 172.8, 140.7, 128.3, 127.4, 125.8, 81.5, 74.7, 38.9, 28.7, 25.6, 18.1, 18.0, 12.1, 9.3; IR (film) v 3457, 3062, 3030, 2939, 2866, 1737, 1460, 1364, 1283, 1181, 1123, 14549


Article

The Journal of Organic Chemistry 999, 877, 694 cm−1; HRMS (ESI-TOF) m/z calcd for C22H36NaO3Si [M + Na+] 399.2331, found 399.2313. (3R*,6S*,7R*)-6-Methyl-7-phenyl-3-((triisopropylsilyl)oxy)oxepan-2-one (63): 50.5 mg (67% yield); colorless oil; Rf (15% MTBE/hexane) 0.65; 1H NMR (400 MHz, CDCl3) δ 7.45−7.32 (m, 4H), 7.33−7.24 (m, 1H), 5.44 (s, 1H), 4.66 (dd, J = 10.3, 3.2, 1H), 2.26−2.04 (m, 3H), 2.00−1.83 (m, 2H), 1.21−1.03 (m, 21H), 0.81 (d, J = 7.1, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 173.6, 139.8, 128.4, 127.7, 125.7, 81.7, 70.9, 37.9, 33.1, 29.9, 18.1, 12.4, 10.1; IR (film) v 3032, 2942, 2866, 1755, 1463, 1385, 1143, 883, 684 cm−1; HRMS (ESI-TOF) m/z calcd for C22H36NaO3Si [M + Na+] 399.2331, found 399.2321. Synthesis of Caprolactones (−)-64 and (+)-66. To a vigorously stirred solution of 2,6-syn-enediol (−)-56 or (+)-57 (204 mg, 0.35 mmol) and TBAB (56 mg, 0.175 mmol) in MeI (5 mL) was added K2CO3 (2 g) in one portion at 25 °C. After 12 h at the same temperature, an excess of K2CO3 was filtered off and washed with CH2Cl2 (25 mL), and combined filtrates were concentrated under reduced pressure. Filtration of the residue through a pad of silica gel with an acetone/hexane mixture afforded crude products, which without further purification were dissolved in the anhydrous THF (50 mL). To this mixture was added a 2 M NaHMDS solution in THF (175 μL, 0.35 mmol) dropwise at −50 °C under an argon atmosphere, and the stirring was continued for 10 min at the same temperature. Then the reaction was quenched with a cold saturated solution of NH4Cl (50 mL), poured into water, and extracted with EtOAc (3 × 30 mL). The combined extracts were washed successively with water (100 mL), a saturated solution of NaHCO3 (50 mL), and brine (50 mL), dried over anhydrous MgSO4, 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 (−)-64 and (+)-66 as colorless oils. (3R,6S,7S)-7-((R)-2,2-Dimethyl-1,3-dioxolan-4-yl)-6-methyl-3((triisopropylsilyl)oxy)-6,7-dihydrooxepin-2(3H)-one ((−)-64): 90.7 mg (65% yield); dr > 98:2; colorless oil; Rf (20% MTBE/hexane) 1 0.55; [α]25 D −2.8 (c 0.51, CHCl3); H NMR (400 MHz, CDCl3) δ 5.89−5.75 (m, 2H), 5.48 (dd, J = 10.4, 6.2, 1H), 4.78 (d, J = 7.1, 1H), 4.23−4.09 (m, 2H), 4.02−3.91 (m, 1H), 2.58−2.47 (m, 1H), 1.36 (d, J = 9.2, 6H), 1.19 (d, J = 7.3, 3H), 1.17−1.01 (m, 21H); 13C{1H} NMR (101 MHz, CDCl3) δ 170.1, 142.4, 122.9, 110.1, 79.7, 76.8, 71.1, 67.0, 39.4, 26.5, 26.0, 17.94, 17.90, 17.3, 12.0; IR (film) v 2943, 2868, 1746, 1650, 1462, 1255, 1064, 883, 688 cm−1; HRMS (ESITOF) m/z calcd for C21H38NaO5Si [M + Na+] 421.2386, found 421.2368. (3S,6R,7R)-7-((R)-2,2-Dimethyl-1,3-dioxolan-4-yl)-6-methyl-3((triisopropylsilyl)oxy)-6,7-dihydrooxepin-2(3H)-one ((+)-66): 87.9 mg (63% yield); dr > 98:2; ee > 99%; colorless oil; Rf (20% MTBE/ 1 hexane) 0.65; [α]25 D +54.2 (c 0.46, CHCl3); H NMR (400 MHz, CDCl3) δ 5.87−5.80 (m, 2H), 5.41 (dd, J = 10.3, 2.0, 1H), 4.83−4.75 (m, 1H), 4.32 (td, J = 7.2, 2.0, 1H), 4.05−3.96 (m, 2H), 2.86 (dq, J = 10.3, 7.2, 1H), 1.47 (s, 3H), 1.37 (s, 3H), 1.15 (d, J = 7.2, 3H), 1.12− 0.99 (m, 21H); 13C{1H} NMR (101 MHz, CDCl3) δ 170.3, 142.4, 123.0, 109.8, 76.8, 74.4, 71.1, 65.3, 36.9, 26.2, 26.0, 17.9, 17.9, 17.4, 12.0; IR (film) v 2943, 2868, 1744, 1650, 1463, 1370, 1264, 1085, 1063, 993, 885, 687 cm−1; HRMS (ESI-TOF) m/z calcd for C21H38NaO5Si [M + Na+] 421.2386, found 421.2375. Preparation of Caprolactones (−)-65 and (+)-67. The lactone (−)-64 or (+)-66 (100 mg, 0.25 mmol) dissolved in a 60% aqueous solution of AcOH (5 mL) was stirred for 24 h at 25 °C. Then the reaction mixture was diluted with toluene (25 mL), and the solvents were removed under reduced pressure. The residue was dissolved in toluene (25 mL) and again concentrated under reduced pressure to remove the remaining acetic acid and water. Purification of the crude product by column chromatography on silica gel using an MeOH/ CH2Cl2 mixture as an eluent afforded lactones (−)-65 or (+)-67 as colorless crystals. (3R,6S,7S)-7-((R)-1,2-Dihydroxyethyl)-6-methyl-3((triisopropylsilyl)oxy)-6,7-dihydrooxepin-2(3H)-one ((−)-65): 74.4 mg (83% yield); dr = 95:5; colorless crystals; mp 84.8−85.3 °C; Rf

1 (5% MeOH/CH2Cl2) 0.45; [α]25 D −33.4 (c 0.86, CHCl3); H NMR (400 MHz, CDCl3) δ 5.93−5.76 (m, 2H), 5.70 (dd, J = 10.9, 3.1, 1H), 4.80 (d, J = 7.4, 1H), 3.96−3.81 (m, 2H), 3.76 (dd, J = 11.2, 3.6, 1H), 2.70−2.44 (m, 2H), 2.27 (s, 1H), 1.21−0.94 (m, 24H); 13 C{1H} NMR (101 MHz, CDCl3) δ 170.6, 141.8, 123.3, 81.5, 71.5, 70.9, 61.9, 36.7, 17.94, 17.91, 17.2, 12.0; IR (film) v 3410, 3023, 2943, 2868, 1739, 1651, 1464, 1292, 1095, 1012, 882, 685 cm−1; HRMS (ESI-TOF) m/z calcd for C18H34NaO5Si [M + Na+] 381.2073, found 381.2065. (3S,6R,7R)-7-((R)-1,2-Dihydroxyethyl)-6-methyl-3((triisopropylsilyl)oxy)-6,7-dihydrooxepin-2(3H)-one ((+)-67): 69.9 mg (78% yield); dr = 95:5; colorless crystals; mp 135.1−136.2 °C; Rf 1 (5% MeOH/CH2Cl2) 0.45; [α]25 D +39.0 (c 1.26, CHCl3); H NMR (400 MHz, CDCl3) δ 5.92−5.79 (m, 2H), 5.45 (d, J = 10.5, 1H), 4.78 (dd, J = 6.8, 1.4, 1H), 3.94−3.85 (m, 2H), 3.68 (q, J = 7.7, 1H), 2.98−2.88 (m, 1H), 2.72 (s, 2H), 1.17−0.99 (m, 24H); 13C{1H} NMR (101 MHz, CDCl3) δ 170.7, 142.5, 122.6, 80.3, 71.0, 70.9, 64.9, 35.9, 17.9, 17.9, 17.3, 12.0; IR (film) v 3498, 3243, 3028, 2948, 2868, 1714, 1463, 1293, 1084, 1015, 881, 693 cm−1; HRMS (ESI-TOF) m/ z calcd for C18H34NaO5Si [M + Na+] 381.2073, found 381.2064.

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.8b02333. 1 H and 13C NMR spectra for all new and selected known compounds, 19F NMR spectra for Mosher’s esters, HPLC chromatograms, and X-ray crystallographic data (PDF) X-ray crystal data for 2a (CIF) X-ray crystal data for 13 (CIF) X-ray crystal data for 62a (CIF) X-ray crystal data for (−)-65 (CIF) X-ray crystal data for (+)-67 (CIF)

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Bartosz K. Zambroń: 0000-0002-7170-4174 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We gratefully thank the National Science Centre for financial support (SONATA UMO-2015/19/D/ST5/00713). REFERENCES

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(18) Bennett, J. S.; Charles, K. L.; Miner, M. R.; Heuberger, C. F.; Spina, E. J.; Bartels, M. F.; Foreman, T. Ethyl lactate as a tunable solvent for the synthesis of aryl aldimines. Green Chem. 2009, 11, 166−168. (19) Wang, Z.; Chen, N.; Xu, J. Selectivities in the reaction of vicinal diimines and acyl chlorides. Tetrahedron 2011, 67, 9690−9699. (20) Palomo, C.; Cossio, F. P.; Arrieta, A.; Odriozola, J. M.; Oiarbide, M.; Ontoria, J. M. The Reformatskii type reaction of Gilman and Speeter in the preparation of valuable β-lactams in carbapenem synthesis: scope and synthetic utility. J. Org. Chem. 1989, 54, 5736−5745. (21) Li, G.-Q.; Li, Y.; Dai, L.-X.; You, S.-L. N-Heterocyclic Carbene Catalyzed Ring Expansion of 4-Formyl-β-lactams: Synthesis of Succinimide Derivatives. Org. Lett. 2007, 9, 3519−3521. (22) Grigg, R.; Thornton-Pett, M.; Xu, J.; Xu, L.-H. Synthesis of novel 4-(5′-pyrrolidinyl)-β-lactams. Tetrahedron 1999, 55, 13841− 13866. (23) Ren, X. F.; Konaklieva, M. I.; Turos, E. Synthesis of InverselyFused Bicyclic β-Lactams. J. Org. Chem. 1995, 60, 4980−4981. (24) 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. (25) Compounds (−)-i and (+)-i were prepared according to the modified procedure reported previously: Kuznetsova, L.; Ungureanu, I. M.; Pepe, A.; Zanardi, I.; Wu, X.; Ojima, I. Trifluoromethyl- and difluoromethyl-β-lactams as useful building blocks for the synthesis of fluorinated amino acids, dipeptides, and fluoro-taxoids. J. Fluorine Chem. 2004, 125, 487−500. (26) A total of 1000 mL of 0.2 M phosphate buffer solution (pH 7.5) was prepared by dissolution of KH2PO4 (27.22 g) in water (930 mL), adjustment of pH to 7.5 with a 300 g/L aqueous solution of KOH, and dilution to 1000 mL of water. (27) Carr, J. A.; Al-Azemi, T. F.; Long, T. E.; Shim, J.-Y.; Coates, C. M.; Turos, E.; Bisht, K. S. Lipase-catalyzed resolution of 4-arylsubstituted β-lactams: effect of substitution on the 4-aryl ring. Tetrahedron 2003, 59, 9147−9160. (28) Manhas, M. S.; Hegde, V. R.; Wagle, D. R.; Bose, A. K. Studies on Lactams. Part 74. An Approach to the Total Synthesis of Amino Sugars via β-Lactams. J. Chem. Soc., Perkin Trans. 1 1985, 1, 2045− 2050. (29) Ojima, I.; Habus, I.; Zhao, M.; Zucco, M.; Park, Y. H.; Sun, C. M.; Brigaud, T. New and efficient approaches to the semisynthesis of taxol and its C-13 side chain analogs by means of β-lactam synthon method. Tetrahedron 1992, 48, 6985−7012. (30) Elliott, D. C.; Beutler, J. A.; Parker, K. A. Importance of a 4Alkyl Substituent for Activity in the Englerin Series. ACS Med. Chem. Lett. 2017, 8, 746−750. (31) The increased amount of solvent had to be used due to poor solubility of starting 4-formyloxy-azetidin-2-one xxviii in anhydrous THF. (32) The reduced yield is caused by the volatility of intermediate (E)-4-(prop-1-en-1-yl)azetidin-2-one. (33) The reduced yield is caused by the volatility of intermediate (Z)-4-(prop-1-en-1-yl)azetidin-2-one. (34) In these cases, collected fractions were diluted with toluene (50% v/v) before removal of eluent under reduced pressure to avoid HCO2H concentration.

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