regiodivergent conjugate addition controlled by rhodium(i) and … · 2017-09-25 · ieved by...

Regiodivergent Conjugate Addition Controlled by Rhodium(I)and Palladium(II) Catalysts: A Combined Computational andExperimental Study

Hoimin Jung,+a,c Ansoo Lee,+c Jin Kim,c Hyunwoo Kim,b,c,* and Mu-Hyun Baika,c,*a Center for Catalytic Hydrocarbon Functionalizations, Institute for Basic Science (IBS), Daejeon 34141, South Korea

Fax: (++82)-42-350-2810; phone: (++ 82)-42-350-2820; e-mail: [email protected] Center for Nanomaterials and Chemical Reactions, Institute for Basic Science (IBS), Daejeon 34141, South Korea

Fax: (++82)-42-350-2810; phone: (++ 82)-42-350-2816; e-mail: [email protected] Department of Chemistry, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 34141, South Korea+ These authors contributed equally to this work.

Received: May 18, 2017; Revised: July 22, 2017; Published online: September 7, 2017

Supporting information for this article can be found under https://doi.org/10.1002/adsc.201700628.

Abstract: A new divergent catalytic method for the1,4- and 1,6-selective conjugate additions of arylbor-onic acids to a,b,g,d-unsaturated imino esters medi-ated by two different transition metal systems wasdeveloped. The rhodium complex carrying briphos, anew bicyclic, bridgehead phosphoramidite ligand,showed excellent regioselectivity towards 1,4-addi-tion with product ratios of >50:1, whereas the palla-dium catalyst Pd(OPiv)2 reversed the regiochemistryto afford the 1,6-product with mild levels of selectivi-ty of &1:7. Both theoretical and experimental studieswere utilized to understand the catalytic systems andto elucidate the molecular level mechanism leadingto the selective reactions. Since Rh(I) and Pd(II) are

both d8-complexes, their electronic structures andbinding behaviours can be compared. Our calcula-tions suggest that the outcome of the catalysis in theRh(I) system is under kinetic control, where the mi-gratory insertion of the alkene is the step that deter-mines the regiochemistry. When the Pd(II) catalyst isused, the regiochemistry is under thermodynamiccontrol where the relative stability of the h3-p-allyl-over the h3-aza-p-allyl-intermediate dictates the se-lectivity at the 1,6-migratory insertion step.

Keywords: arylation; density functional calculations;palladium; regioselectivity; rhodium

Introduction

Divergent catalytic methods of synthesis that arestereo- and/or regioselective are very desirable, inpart, as they allow for quickly assembling a highly di-versified library of chemical stocks that are structural-ly similar, but are chemically different enough to beuseful for screening applications.[2] Nature uses ananalogous strategy to elegantly prepare a largenumber of natural products with various biological ac-tivities.[3] In the laboratory, such a task is often ach-ieved by reagent controlled reactions, which are ofteninefficient and laborious.[4] In principle, it is more effi-cient to control reactions with catalysts, such that avariety of molecules can be prepared simply byadding different catalysts.

Conjugate additions of arylboronic acids to carbon-yls or imines catalyzed by transition metal complexes

are ideal for implementing such a divergent strategy.[5]

Imine,[6] carbonyl[7] and electron-deficient olefin[8]

groups are particularly interesting in the substrates, asthey may engage in one of the most robust C–Arbond forming reactions known. Although the aryla-tions of conjugated carbonyl and olefin compoundswith high regioselectivities are well established, thereare only a few examples of regiodivergent reactionswith them. Cs#ke and co-workers have reported sub-strate controlled divergent 1,4- and 1,6-conjugate ary-lations (Scheme 1a),[9] and Zhou and Liao devised1,2- and 1,4-arylation reactions controlled by a combi-nation of substrates and ligands (Scheme 1b).[10] Hay-ashi showed that catalyst-controlled 1,4- and 1,6-ary-lation reactions of conjugated carbonyl compoundsare possible, but saw only a very moderate 1,4-selec-tivity of 55:34 (Scheme 1c).[11]

Adv. Synth. Catal. 2017, 359, 3160 – 3175 V 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim3160

FULL PAPERS DOI: 10.1002/adsc.201700628

https://doi.org/10.1002/adsc.201700628

The divergent conjugate arylation of imines withextended p-systems is unknown to date. These areparticularly challenging substrates to utilize in thisstrategy because there are constitutional isomers thatmay be formed from 1,2-, 1,4- and 1,6-additions, aswell as (E)- and (Z)-products. Designing a set of cata-lysts that can produce this variety of possible productsselectively is daunting. For example, 1,4- and 1,6-addi-tion to a,b,g,d-unsaturated imino esters (1) provideg,g-aryl,alkenyl-a,b-dehydroamino esters (3) and e,e-diaryl-a,b,g,d-dehydroamino esters (4), respectively,as highlighted in Scheme 1d. Many of these dehydroa-mino ester derivatives are biologically active, and aredrug candidates.[12] Therefore, selective syntheticmethods for this type of imines are highly desirable.Here, we report the transition metal-controlled regio-divergent conjugate addition of arylboronic acids toa,b,g,d-unsaturated imino esters.

We recently developed a bicyclic bridgehead phos-phoramidite ligand (briphos) as a new class of ligandsthat shows high p-accepting characteristics.[13] Severalconjugate additions using Rh(I)-briphos catalystswere previously reported and we found that usingchiral briphos, the 1,4-addition reaction of arylboronicacid to a,b-unsaturated imino esters could be carriedout in excellent yields and high enantioselectivities.[14]

Also, asymmetric 1,2- and 1,4-additions on N-tosylketimines were investigated with chiral bri-phos.[15] These previous results suggested that weshould be able to develop regiodivergent conjugateadditions of arylboronic acids to a,b,g,d-unsaturatedN,N-dimethylsulfamoyl imino ester (1a), which can

undergo either 1,4- or 1,6-addition under catalyst con-trol. Interestingly, we found that the regiochemistrycan be controlled by using Rh(I)-briphos or a Pd(II)catalyst, as shown in Scheme 1d. To understand themechanism that leads to these regioselectivities, weused computational molecular modeling techniquesbased on density functional theory (DFT).[16]

Results and Discussion

Experimental Findings

In order to design a divergent reaction, we chose toinvestigate the conjugate addition of 4-methoxyphe-nylboronic acid (2a) to a,b,g,d-unsaturated N,N-dime-thylsulfamoyl imino ester (1a) catalyzed by a Rh anda Pd catalyst. Initial screening efforts indicated thatthese metals may display different regiochemical out-comes under similar, if not identical conditions.Whereas we had no mechanistic rationale for thisfinding initially, we decided to first optimize the reac-tion conditions to obtain robust and reliable resultsthat are reproducible. A series of ligands were testedand the results are enumerated in Table 1. Amongthem Rh(acac)(C2H4)2-L1 showed an excellent yieldof 95% and a regioselectivity of >50:1 for the 1,4-ad-dition product (Z,E)-3aa over the 1,6-addition alter-native (Z,E)-4aa (entry 1) under relatively mild con-ditions, clearly outperforming many other phospho-rus-based ligands including monophos (L2), binap(L3), P(OPh)3, PPh3, and P(C6F5)3 (entries 2–6). Verylow yields were observed, if any, when these ligandswere used. Here [Rh(cod)OH]2 showed good reactivi-ty (entry 7), but due to the poor 1,4-/1,6- and E/Z se-lectivities, the yield of 3aa was lower than in reactionswith Rh(acac)(C2H4)-L1. Interestingly, using variousPd(II) catalysts instead of Rh(I)-briphos we were ableto switch the regiochemistry and obtain (Z,E)-4aa,the 1,6-addition product from reactant 1a, as themajor product (entry 8). Best results were obtainedwith Pd(OPiv)2, which displays a ratio of (Z,E)-3aa :4aa of 1:7.2 and a yield of 62% in dioxane. Otherpalladium catalysts or solvent systems for the reaction(entries 9–13) as well as using additional ligands likeL1, L4, and PPh3 (entries 14–16) did not improve theresults. Although the yield and selectivity are modest,this system allows for answering the fundamentalquestion posed above; namely, how we may be ableto design two different catalytic systems that take theidentical set of substrates and obtain two differentoutcomes by changing the catalyst. Which feature ofthe catalysts can be exploited in this fashion?

Scheme 1. Strategies for regiodivergent arylations.


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Catalytic Cycle

Intrigued by the regiochemistry described above, wewished to construct complete catalytic cycles of boththe Rh(I)- and Pd(II)-catalyzed reactions to preciselyunderstand the reason for the regiochemical outcomeof these reactions. The general mechanistic featuresof transition metal-catalyzed conjugate additions arewell established,[17] and we expect both the Rh(I)- andPd(II)-catalyzed reactions to roughly follow thismechanism. As summarized in Figure 1, there arethree distinctive sequential steps: (i) transmetalationof the boronic acid to generate the active catalyst car-rying the aryl substrate, (ii) alkene coordination fol-lowed by migratory insertion, which formally consti-tutes the addition of the aryl to the alkene and (iii)protonation and release of the product.

Rh(I)-Catalyzed Conjugate Additions

The catalytic mechanisms leading to the 1,4- or 1,6-addition products are compared using the Rh(I)(L1)2

catalyst in Figure 2. The catalytic cycle starts with thetransmetalation of the pre-complex ofRh(I)(L1)2(OH) and p-methoxyphenylboronic acid.Traversing the transition state Rh-1-TS at 5.8 kcalmol@1, the aryl-rhodium complex Rh-2 at @9.8 kcalmol@1 is obtained. Next, the a,b,g,d-unsaturated iminoester 1a binds to the aryl-rhodium complex Rh-3. Be-cause 1a has two binding sites for the metal, there aretwo regioisomeric reactant complexes Rh-4a and Rh-4b with very similar binding free energies. The transi-tion states for the migratory insertion of the aryl-moiety Rh-4a-TS and Rh-4b-TS were readily locatedat @6.7 and @4.6 kcalmol@1, respectively, and the

Table 1. Optimization of the conjugate addition to a,b,g,d-unsaturated imino ester 1a.[a]

Entry [M] Ligand[b] Solvent Ratio of 3aa :4aa[c] Yield [%][d]

1 Rh(acac)(C2H4)2 L1 toluene >50:1 3aa, 95(92)2 Rh(acac)(C2H4)2 L2 toluene n.d. 203 Rh(acac)(C2H4)2 L3 toluene – n.r.4 Rh(acac)(C2H4)2 P(OPh)3 toluene n.d. 3aa, <35 Rh(acac)(C2H4)2 PPh3 toluene n.d. n.r.6 Rh(acac)(C2H4)2 P(C6F5)3 toluene n.d. trace7 [Rh(cod)(OH)]2 – toluene 4.0:1 3aa, 478 Pd(OPiv)2 – dioxane 1:7.2 4aa, 62(55)9 Pd(TFA)2 – dioxane 1:3.8 4aa, 5010 Pd(OAc)2 – dioxane 1:7.4 4aa, 1511 Pd(OPiv)2 – MeOH 1:8.0 4aa, 5512 Pd(OPiv)2 – toluene 1:5.0 4aa, 4813 Pd(OPiv)2 – DCM 1:3.4 4aa, 3614 Pd(OPiv)2 L1 dioxane 1:6.5 4aa, 3515 Pd(OPiv)2 L4 dioxane n.d. 4aa, 216 Pd(OPiv)2 PPh3 dioxane 1:5.7 4aa, 19

[a] Conditions: 1a (0.2 mmol), 2a (0.6 mmol), and [M] (5 mol%) were stirred in solvent (2.0 mL) at 30 88C for 20 h.[b] Monodentate ligands (12.5 mol%) and bidentate ligands (6 mol%) were used.[c] Determined by crude 1H NMR spectroscopy.[d] The yields are determined by 1H NMR with N,N-dimethyl sulfone as internal standard. Isolated yields are listed in paren-

thesis.




&2 kcal mol@1 energy difference leads to the regiose-lective 1,4-addition. Note that the general transitionstates for the loss and uptake of the molecules werenot located, since they are dominated by entropy.[18]

The insertion products Rh-5a, Rh-5b proceed toform the p-allyl complexes Rh-6a and Rh-6b, whichdisplay quite different energies of @26.5 [email protected] kcal mol@1, respectively. As illustrated inFigure 1, Rh-6a is an h3-aza-p-allyl complex, whereasRh-6b is a classical h3-p-allyl complex and this energydifference is puzzling, as will be discussed below. Pro-tonation by boronic acid completes the catalytic cycle.The boric acid coordinations to give Rh-7a and Rh-7bwere found at @15.1 and @26.7 kcal mol@1. Then, eachpathway traverses the transition states Rh-7a-TS andRh-7b-TS, which were located at @13.0 [email protected] kcal mol@1, respectively. The final product p-complexes Rh-8a and Rh-8b will release the productand the metal-complex, which can then reenter thecatalytic cycle.

Pd(II)-Catalyzed Conjugate Additions

The mechanism of the catalytic 1,6- and 1,4-additionsusing the Pd(II)-catalyst is shown in Figure 3. Com-plex Pd-1 underwent transmetalation to give the aryl-palladium complexes Pd-2 and Pd-3 with a barrier of10.5 kcal mol@1. Addition of 1a affords the reactantcomplexes Pd-4a and Pd-4b, at @36.8 and @35.4 kcalmol@1, respectively. Next, the coordinated ene func-tionalities undergo migratory insertion into the Pd-aryl carbon bond via Pd-4a-TS and Pd-4b-TS both [email protected] kcal mol@1. Given the analogous character ofthese two steps, it is not surprising that these barriersare identical. Up to this point in the catalytic cycle,our calculations do not suggest any discrimination ofthe two regioisomers. The direct insertion productsare intermediates Pd-5a and Pd-5b at @44.9 [email protected] kcal mol@1, respectively. It is at this juncturewhere a divergence in the mechanism dictates the re-giochemistry. Intermediate Pd-5b may expose a p-allyl moiety to form the Pd-h3-allyl complex Pd-6b to

Figure 1. Proposed catalytic cycle of the transition metal-catalyzed 1,4- and 1,6-addition reactions. Ar=p-methoxyphenyl,R1 = SO2NMe2 and R2 =CO2Et.




gain 12.6 kcalmol@1 in energy. Intermediate Pd-5a,however, can only form an isomeric structure with theimine to make the Pd-h3-aza-p-allyl complex Pd-6a,which does not differ much in energy from Pd-5a. Tocomplete the catalytic cycle, the product complexesmust be protonated in order to regeneratePd(OH)(OPiv), which may be accomplished using acoordinated boric acid, as illustrated in Figure 3.

The reaction energy profiles highlight that the bar-riers for migratory insertion are nearly identical forthe 1,4- and 1,6-pathways, and thus, there is no kineticpreference for the experimentally observed major 1,6-product. This is puzzling at first. Interestingly, the se-lectivity for the 1,6-product is calculated to be underthermodynamic control, as Pd-6b, the Pd-h3-allyl com-plex, is 11.5 kcal mol@1 lower in energy than Pd-6a.Because Pd-6a is practically isoenergetic with Pd-5a,the 1,4-insertion is reversible with the backward reac-tion barrier being only &23 kcal mol@1. The lowenergy of the intermediate Pd-6b, however, renders

the insertion irreversible with the corresponding back-ward reaction barrier being 34.8 kcal mol@1. Thus, in-termediate Pd-6b serves as a thermodynamic sink,from which protonation will afford the final product.Thus, it is the relative ratio of Pd-6a :Pd-6b that deter-mines the regiochemical outcome of the reaction inthis case.

As the final product formation is energeticallyuphill from the intermediates Pd-6a and Pd-6b andboth pathways are again similar in energetic demandimposing no kinetic control, regioselectivity is neces-sarily inefficient and only modest levels of 1,6-selec-tivity can be expected: Although the thermodynamicpreference of Pd-6b over Pd-6a is substantial atnearly 12 kcal mol@1, it cannot be turned into a deci-sive thermodynamic control of the regioselectivity, asthe kinetic barriers leading to and proceeding awayfrom them are nearly identical. Thus, our calculationsindicate that the modest regiocontrol with Pd(II) issystemic and cannot be overcome by minor variations

Figure 2. Computed free energy profiles[1] for Rh(I)-catalyzed 1,4- and 1,6-additions. L1=briphos, Ar=p-methoxyphenyl,R1 = SO2NMe2, and R2 = CO2Et; black: 1,4-addition; blue: 1,6-addition; plain: favoured; dashed: disfavoured.




of the ligand composition. Instead, the protonationstep must be optimized to be less energetically de-manding – ideally downhill.

Stability of h3-p-Complexes

Both the Rh- and Pd-catalyzed reactions feature a re-markable energy difference between the h3-p-allyl-complexes 6a and 6b that must be understood indetail. The energies can be dissected by partitioningthe h3-p-complexes into chemically meaningful frag-ments and calculating their individual energies.[19] Inthis context, the electronic energy is most importantbecause other free energy components are nearlyidentical. Figure 4 summarizes the fragment electronicenergies allowing for partitioning the overall energy

difference into substrate distortions, metal-fragmentdistortions and the interaction between the metal andthe substrate. Although the h3-p-allyl isomer 6b ispreferred over the h3-aza-p-allyl analogue 6a in bothmetal systems, as illustrated by the black dotted linein Figure 4, the origin of the energy difference is verydifferent. The interaction energies between the Rh(I)fragment and the p-allyl substrates are comparable [email protected] and @167.5 kcal mol@1 in Rh-6b and Rh-6a, re-spectively. The Rh(I)(L1)2 fragments are practicallyisoenergetic, leaving the difference in p-allyl distor-tion energy of 7.1 kcalmol@1 as being responsible formore than half of the overall energy difference. Incomparison, the Pd(II)-system shows a much strongermetal-substrate interaction of @280.7 kcalmol@1 inPd-6b. In the h3-aza-p-allyl analogue Pd-6a, this inter-action is 55.0 kcal mol@1 less favourable at @225.7 kcal

Figure 3. Computed free energy profiles[1] for Pd(II)-catalyzed 1,4- and 1,6-additions. Ar= p-methoxyphenyl, R1 =SO2NMe2,

and R2 =CO2Et; black: 1,4-addition; blue: 1,6-addition; plain: favoured; dashed: disfavoured.




mol@1, which goes hand in hand with a smaller distor-tion energy in the metal fragment to recover 46.3 kcalmol@1 in favour of Pd-6a. The substrate distortions ac-count for 2.8 kcal mol@1 in favour of Pd-6b. Thus, inthe Pd(II) system the energetic preference is dominat-ed by the metal-substrate interaction energy.

Whereas these dramatically different energy de-composition results may be surprising at first, theyare relatively easy to understand. The nearly 100 kcalmol@1 stronger electronic interaction displayed byPd(II) over the Rh(I) analogue is a direct conse-quence of (i) the higher oxidation state of Pd(II) com-pared to the isoelectronic d8-Rh(I), which strengthensthe electrostatic interaction, and (ii) Pd(II) is smallerand is therefore a harder Lewis acid than Rh(I),giving rise to a better Lewis acid/base pairing with thep-allylic and aza-p-allylic ligand, where the negativecharge is confined to a three-atom center. Note, thatwe categorize Pd(II) as a harder Lewis acid thanRh(I) in comparison. On an absolute scale, Pd(II) isof course not considered a hard Lewis acid.

The p-allylic anion is a much stronger Lewis basethan the aza-p-allylic anion, since the higher electro-negativity of nitrogen renders the aza-fragment lessnucleophilic than the carbon analogue. Thus, our cal-culations show consistently that the p-allyl binding ispreferred. The extent of this preference depends onthe energy and overlap of the orbitals of the metaland substrate fragments. Another important factorthat exacerbates the substrate binding energy differ-

ence is the steric demand that the briphos ligandexerts on the ligand binding. As highlighted inFigure 5, the two phenyl rings on L1 and substrateclash into each other in Rh-6a. The geometrical ar-rangement in Rh-6b is much better and shows well-

Figure 4. Graph of interaction energies for h3-p-complexes Rh-6a, Rh-6b and Pd-6a, Pd-6b. Bidirectional arrows indicate theenergy for structural changes, and the unidirectional arrows show the metal-substrate interactions. Dotted lines represent thedifference between the two intermediates. Red: metal fragment; blue: substrate fragment; green: interaction between thetwo fragments.

Figure 5. Optimized structures of Rh-6a, Rh-6b, Pd-6a andPd-6b.




aligned phenyl rings avoiding unfavourable steric in-teractions. Due to the small size of the acetate ligandon Pd(II), no such steric discrimination is possible.

Kinetic Control by Rh-briphos

As discussed above, the 1,4-selectivity seen with theRh-briphos catalyst originates from the transitionstate Rh-4a-TS being 2.1 kcal mol@1 lower in energythan Rh-4b-TS, suggesting kinetic control of the re-gioselectivity. Given the structural complexity of thebriphos ligand, steric factors that may discriminatethe migratory insertion leading to the 1,6-productmay be suspected. A close inspection of the computedtransition state structures does not reveal any suchsteric clash in Rh-4b-TS, however. Therefore, weagain applied the fragmentation method to preciselyelucidate the origin of the transition state energy dif-ference. Both reactant complexes Rh-4a, Rh-4b andthe transition states Rh-4a-TS, Rh-4b-TS were dividedinto two fragments, as illustrated in Figure 6. Interest-

ingly, Rh-4a-TS and Rh-4b-TS show very similar totaldistortion energies with 26.4 and 25.8 kcal mol@1, re-spectively. Hence, the interaction energies of @16.6and @14.0 kcalmol@1 for Rh-4a-TS and Rh-4b-TS, re-spectively, are therefore ultimately responsible for the&2 kcal mol@1 energy difference.

Substrate Scope

Having established a mechanistic understanding ofhow divergent, catalyst-controlled conjugate additionsmay be carried out, we sought to confirm that ourprototype reaction can be applied to a variety of sub-strates. We explored the scope of arylboronic acidswith the imino ester 1a using Rh(acac)(C2H4)2-L1 andPd(OPiv)2, respectively, as summarized in Scheme 2.For the Rh(I) system, arylboronic acids with electron-donating groups on meta- and para- positions and 2-naphthyl group (3aa to 3af) gave the products 3 and 4in a regioselectivity ratio of >50:1 in high yields of78–94%, but ortho-substituted arylboronic acids and1-naphthylboronic acid (2g) gave no product. Thephenyl- and p-fluorophenylboronic acids reacted at50 88C with moderate to good yields of 75–80% andgood selectivities (>38:1 for 3 :4).

Pd(OPiv)2 reverses the regioselectivity, but thelevel of selectivity and yield are relatively low, as ex-plained above. All arylboronic acid substrates showedmoderate yields of 41–62% and 3 :4 product ratios of1:4.3 to 1:7.6. Unlike the Rh(I)-L1 system, the ortho-substituted boronic acids and 1-naphthylboronic acid(2g) provided the desired products 4ag in 41% yield,while the 1,4-adduct 3ag could not be obtained fromthe reaction of 1a to 2g using Rh-L1. The 1,6-additionof 1a with phenylboronic acid and 4-fluorophenylbor-onic acid, 2h and 2i, provided the products 4ah and4ai with decreased yields (44–54%) and similar selec-tivities (1:6.4 to 1:6.7).

Next, the conjugate addition of p-methoxyphenyl-boronic acid 2a to several functionalized variants ofthe a,b,g,d-unsaturated imino ester 1 was explored(Scheme 3). Namely, the Me- and i-Pr-imino esters 1band 1c, the conjugated imines with MeO (1d), Cl (1e),and F (1f) substituents at the para-position of the aro-matic ring were used to test the scope of the reaction.Reactant 1b gave products 3ba and 4ba with some-what reduced yields of 77% and 42%, respectively,under both conditions. The Rh-L1 promoted reactionsproceeded well with these substrates to afford 3ca–3fa with good yields of 85–92% and 3 :4 selectivitiesas high as >38:1, while the use of Pd(OPiv)2 gave thedesired products 4ca–4fa with moderate yields of 55–63% and 3 :4 selectivities in the range of 1:4.2 to 1:5.9.The identities of the final major products were con-firmed by the X-ray crystal structure analysis of 3caand 4ah (Figure 7).[20]

Preparation of Unnatural a-Amino Esters

To demonstrate the synthetic utility, we attempted toprepare unnatural a-amino esters from the corre-sponding dehydroamino esters, as shown in Scheme 4.The a-amino esters 5 and 6 were prepared from 1a in

Figure 6. Distortion/interaction model of migratory insertionstep in Rh system. L1=briphos, Ar=p-methoxyphenyl.




two-steps without isolating the conjugate additionproduct. After Rh(I)-L1-catalyzed conjugate additionof 2a to 1a, hydrogenation of the mixture providedthe a-amino ester 5 in 84% overall yield and 1.2:1diastereomeric ratio. Also, the a-amino ester 6 wasprepared in 61% yield by hydrogenating the Pd(II)-catalyzed conjugate addition mixture. Unsurprisingly,the hydrogenation is not diastereoselective and a rac-emic mixture of products is obtained. These reactionshighlight how our divergent synthetic method can beutilized to construct g,e-diaryl or e,e-diaryl-a-aminoacid derivatives with unprecedented ease.

Conclusions

We have developed a divergent conjugate addition re-action, where the selectivity towards either the 1,4- or1,6-addition is controlled by the identity of the cata-lyst, using nearly identical conditions. Computational

modeling of the mechanism suggests that the Rh-cata-lyzed 1,4-conjugate addition is under kinetic control,where the transition state of the migratory insertionleading to the 1,4-product is &2 kcal mol@1 lower inenergy than the alternative that would afford the 1,6-product. Thermodynamically, the 1,6-conjugate addi-tion is preferable, as it leads to the h3-p-allyl-rhodiumintermediate, which is nearly 12 kcal mol@1 lower inenergy than the h3-aza-p-allyl-rhodium complex.When Pd(II) without any sterically encumberingligand is used, the kinetic control is lost, becausePd(II) is a stronger and harder Lewis acid than Rh(I)and it is not sensitive to the subtle electronic differen-ces of the conjugated ene fragment. Regiochemistrybecomes determined by the energetic preference ofthe h3-p-allyl-palladium complex over the h3-aza-p-allyl-palladium. Whereas the degree of regioselectivi-ty is relatively low in the Pd-catalyzed reactions andmay be improved with a more elaborate liganddesign, the principles of turning the kinetically con-

Scheme 2. Substrate scope of Rh-L1 and Pd-catalyzed conjugate addition to 1a.[a] Conditions for 1,4-addition: 1a (0.2 mmol), 2 (0.6 mmol), Rh(acac)(C2H4)2 (5 mol%), and L1 (12.5 mol%) were stirred intoluene (2.0 mL) at 30 88C for 20 h. Yield of isolated product. Conditions for 1,6-addition: 1a (0.2 mmol), 2 (0.6 mmol), andPd(OPiv)2 (5 mol%) were stirred in dioxane (2.0 mL) at 30 88C for 20 h. The yields are determined by 1H NMR with N,N-di-methyl sulfone as internal standard. The isolated yields are in parenthesis.[b] Determined by crude 1H NMR spectroscopy.[c] Reaction conducted for 40 h.[d] Reaction conducted for 50 h.[e] Reaction conducted at 50 88C.




trolled 1,4-conjugate addition to a thermodynamicallycontrolled 1,6-conjugate addition is clearly demon-strated.

Experimental Section

Experimental Details

Commercially available compounds were used without fur-ther purification or drying. The 1H NMR (400 MHz),13C NMR (100 MHz), 19F NMR (376 MHz) and 31P NMR(162 MHz) spectra were recorded on a Bruker Avance IIIHD spectrometer. All coupling constants (J values) are re-ported in Hertz (Hz). Mass spectra were obtained using aBruker Daltonik micrOTOF-Q II high-resolution mass spec-trometer (ESI) at the KAIST Analyst Center for ResearchAdvancement.

General Procedure for Synthesis of a,b,g,d-Unsaturated Imino Esters (1)[21]

A solution of the corresponding keto ester (2.0 mmol), N,N-dimethylsulfamide (248.3 mg, 2 mmol), and triethylamine(0.84 mL, 6 mmol) in 1.2-dichloromethane (DCM) (7 mL)was cooled to 0 88C. To this mixture was slowly added a solu-tion of TiCl4 (1.0 M in CH2Cl2, 2.0 mL, 2 mmol) under N2

and then stirred at ambient temperature for 2 h. The solu-tion was filtered over a pad of silica (5 cm) with ethyl ace-tate and then concentrated under reduced pressure. The res-idue was purified by silica gel column chromatography withdiethyl ether/hexane (1:1) to give the corresponding a,b,g,d-unsaturated N,N-dimethylsulfamoyl imino esters 1 (54–73%yield) as a yellow or orange solids. The E/Z isomers of theimine group exist in a ratio of 7:3.[14,22]

Scheme 3. Substrate scope of Rh-L1 and Pd-catalyzed conjugate addition to various imino esters 1.[a] Conditions for 1,4-addition: 1 (0.2 mmol), 2 (0.6 mmol), Rh(acac)(C2H4)2 (5 mol%), and L1 (12.5 mol%) were stirred intoluene (2.0 mL) at 30 88C for 20 h. Yield of isolated product. Conditions for 1,6-addition: 1 (0.2 mmol), 2 (0.6 mmol), andPd(OPiv)2 (5 mol%) were stirred in dioxane (2.0 mL) at 30 88C for 20 h. The yields are determined by 1H NMR with N,N-di-methyl sulfone as internal standard. The isolated yields are in parenthesis.[b] Determined by crude 1H NMR spectroscopy.

Figure 7. Crystal structures of (a) 3ca and (b) 4ah.

Scheme 4. Synthesis of unnatural a-amino esters.




Spectroscopic Data of a,b,g,d-Unsaturated IminoEsters (1a–1f)

Ethyl (3E,5E)-2-[(N,N-dimethylsulfamoyl)imino]-6-phenyl-hexa-3,5-dienoate (1a): yellow solid; yield: 465.0 mg (69%).1H NMR (400 MHz, CDCl3): d=7.49 (d, J= 6.7 Hz, 2 H),7.42–7.30 (m, 3 H), 7.24–7.07 (m, 1.3 H), 7.03–6.88 (m, 2 H),6.43 (d, J=15.6 Hz, 0.7 H), 4.55–4.35 (m, 2 H), 2.88 (d, J=5.4 Hz, 6 H), 1.41 (t, J=7.1 Hz, 3 H); 13C NMR (100 MHz,CDCl3): (major): d =168.2, 164.7, 148.6, 143.4, 135.6, 130.0,129.1, 127.8, 126.7, 126.7, 63.1, 38.5, 14.0; (minor): d= 168.6,163.8, 149.6, 144.7, 135.6, 130.2, 129.1, 127.9, 127.3, 121.8,62.7, 38.8, 14.2; HR-MS (ESI): m/z= 359.1044, calculatedfor C16H20N2O4S [M++Na]++: 359.1041.

Methyl (3E,5E)-2-[(N,N-dimethylsulfamoyl)imino]-6-phe-nylhexa-3,5-dienoate (1b): orange solid; yield: 472.0 mg(73%). 1H NMR (400 MHz, CDCl3): d=7.57–7.43 (m, 2 H),7.43–7.31 (m, 3 H), 7.23–7.08 (m, 1.3 H), 7.03–6.93 (m, 2 H),6.43 (d, J= 15.6 Hz, 0.7 H), 3.96 (d, J=4.6 Hz, 3 H), 2.88 (d,J=6.7 Hz, 6 H); 13C NMR (100 MHz, CDCl3): (major): d =167.9, 165.1, 148.8, 143.6, 135.6, 130.1, 129.1, 127.8, 126.7,126.5, 53.5, 38.5; (minor): d =168.3, 164.2, 149.8, 144.8,135.7, 130.2, 129.1, 127.9, 127.3, 121.7, 53.3, 38.7; HR-MS(ESI): m/z =345.0891, calculated for C15H18N2O4S [M++Na]++: 345.0885.

Isopropyl (3E,5E)-2-[(N,N-dimethylsulfamoyl)imino]-6-phenylhexa-3,5-dienoate (1c): yellow solid; yield: 405.8 mg(58%). 1H NMR (400 MHz, CDCl3): d=7.57–7.43 (m, 2 H),7.44–7.31 (m, 3 H), 7.21–7.08 (m, 1.3 H), 7.07–6.89 (m, 2 H),6.42 (d, J= 15.6 Hz, 0.7 H), 5.31 (tp, J=12.9, 6.5 Hz, 1 H),2.87 (d, J= 3.4 Hz, 6 H), 1.49–1.27 (m, 6 H); 13C NMR(100 MHz, CDCl3): (major): d=168.3, 164.1, 148.3, 143.2,135.7, 130.0, 129.1, 127.8, 126.9, 126.8, 71.4, 38.5, 21.8;(minor): d =168.9, 163.4, 149.4, 144.5, 135.6, 130.2, 129.1,127.9, 127.4, 121.9, 70.9, 38.8, 21.9; HR-MS (ESI): m/z=373.1198 calculated for C17H22N2O4S [M++Na]++: 373.1189.

Ethyl (3E,5E)-2-[(N,N-dimethylsulfamoyl)imino]-6-(4-me-thoxyphenyl)hexa-3,5-dienoate (1d): yellow solid; yield:445.6 mg (61%). 1H NMR (400 MHz, CDCl3): d =7.44 (d,J=8.7 Hz, 2 H), 7.21–7.08 (m, 1.3 H), 7.03–6.74 (m, 4 H),6.37 (d, J= 15.6 Hz, 0.7 H), 4.42 (p, J= 7.4 Hz, 2 H), 3.84 (s,3 H), 2.87 (d, J=5.3 Hz, 6 H), 1.41 (t, J= 7.2 Hz, 3 H);13C NMR (100 MHz, CDCl3): (major): d =168.3, 164.8,161.4, 149.3, 143.4, 129.5, 128.5, 125.4, 124.7, 114.6, 63.0,55.6, 38.6, 14.1; (minor): d=168.8, 164.0, 161.5, 150.3, 144.7,129.7, 128.9, 125.3, 120.7, 114.6, 62.6, 55.6, 38.8, 14.3; HR-MS (ESI): m/z= 389.1146, calculated for C17H22N2O5S [M++Na]++: 389.1147.

Ethyl (3E,5E)-6-(4-chlorophenyl)-2-[(N,N-dimethylsulfa-moyl)imino]hexa-3,5-dienoate (1e): orange solid; yield:399.8 mg (54%). 1H NMR (400 MHz, CDCl3): d= 7.48–7.31(m, 4 H), 7.21–7.06 (m, 1.3 H), 6.94 (m, 2 H), 6.43 (d, J=15.6 Hz, 0.7 H), 4.43 (p, J=7.2 Hz, 2 H), 2.88 (d, J= 5.7 Hz,6 H), 1.41 (t, J=7.2 Hz, 3 H); 13C NMR (100 MHz, CDCl3):(major): d =168.0, 164.6, 148.0, 141.7, 135.8, 134.2, 129.4,128.9, 127.2, 127.2, 63.1, 38.5, 14.0; (minor): d =168.4, 163.7,149.0, 142.9, 136.0, 134.1, 129.4, 129.0, 127.8, 122.3, 62.8,38.8, 14.3; HR-MS (ESI): m/z=393.0661, calculated forC16H19ClN2O4S [M++Na]++: 393.0652.

Ethyl (3E,5E)-2-[(N,N-dimethylsulfamoyl)imino]-6-(4-flu-orophenyl)hexa-3,5-dienoate (1f): yellow solid; yield:455.0 mg (64%). 1H NMR (400 MHz, CDCl3): d= 7.53–7.42

(m, 2 H), 7.20–7.02 (m, 3.3 H), 6.99–6.81 (m, 2 H), 6.41 (d,J=15.6 Hz, 0.7 H), 4.43 (p, J=7.2 Hz, 2 H), 2.88 (d, J=5.4 Hz, 6 H), 1.41 (t, J=7.2 Hz, 3 H); 13C NMR (100 MHz,CDCl3): (major ++minor): d= 168.1, 165.0, 164.7, 163.8,162.5, 149.3, 148.3, 143.1, 141.9, 132.0, 131.9, 129.7, 129.7,129.6, 129.5, 127.1, 127.1, 127.1, 126.8, 126.5, 126.5, 121.9,116.4, 116.2, 63.1, 62.7, 38.8, 38.5, 14.2, 14.0; 19F NMR(376 MHz, CDCl3): (minor): [email protected], (major): [email protected]; HR-MS (ESI): m/z =377.0941, calculated forC16H19FN2O4S [M++Na]++: 377.0947.

General Procedure for Rh(I)-Catalyzed 1,4-Additionof Arylboronic Acids to a,b,g,d-Unsaturated N,N-Dimethylsulfamoyl Imino Esters

A 25-mL flask was flushed with nitrogen and charged withL1 (0.025 mmol, 12.5 mol%), Rh(acac)(C2H4)2 (2.6 mg,0.01 mmol, 5 mol%) and 2.0 mL of degassed toluene. Themixture was stirred for 10 min at ambient temperature. Thereaction mixture was mixed with arylboronic acid(0.6 mmol) and then a,b,g,d-unsaturated N,N-dimethylsulfa-moyl imino ester (0.2 mmol) was added. After being stirredat 30 88C for 20 h, the reaction mixture was passed through apad of silica gel with ethyl acetate and the solvent was re-moved under vacuum. The residue was purified by silica gelcolumn chromatography (ethyl acetate/hexane=1/3).

Spectroscopic Data of Compounds (3aa–3ai and 3ba–3fa)

Ethyl (2Z,5E)-2-[(N,N-dimethylsulfamoyl)amino]-4-(4-me-thoxyphenyl)-6-phenylhexa-2,5-dienoate (3aa): pale yellowsolid; yield: 81.7 mg (92%). 1H NMR (400 MHz, CDCl3):d= 7.40–7.35 (m, 2 H), 7.33–7.26 (m, 4 H), 7.25–7.19 (m,1 H), 6.99 (d, J=10.7 Hz, 1 H), 6.93–6.86 (m, 2 H), 6.57–6.45(m, 1 H), 6.35 (dd, J=16.0, 6.7 Hz, 1 H), 6.04 (s, 1 H), 5.15(dd, J= 10.5, 6.7 Hz, 1 H), 4.29 (qd, J=7.1, 2.6 Hz, 2 H), 3.80(s, 3 H), 2.84 (s, 6 H), 1.35 (t, J= 7.1 Hz, 3 H); 13C NMR(100 MHz, CDCl3): d= 165.5, 158.7, 142.2, 137.2, 133.2,131.5, 130.0, 129.1, 128.7, 127.6, 126.4, 124.7, 114.3, 62.3,55.4, 45.6, 38.3, 14.4; HR-MS (ESI): m/z =467.1619, calculat-ed for C23H28N2O5S [M++ Na]++: 467.1617.

Ethyl (2Z,5E)-2-[(N,N-dimethylsulfamoyl)amino]-4-(3-methoxyphenyl)-6-phenylhexa-2,5-dienoate (3ab): yellowsticky oil; yield: 69.5 mg (78%). 1H NMR (400 MHz,CDCl3): d =7.40–7.36 (m, 2 H), 7.33–7.26 (m, 3 H), 7.25–7.20(m, 1 H), 7.00 (d, J=10.6 Hz, 1 H), 6.96–6.92 (m, 1 H), 6.92–6.90 (m, 1 H), 6.80 (ddd, J= 8.2, 2.6, 0.8 Hz, 1 H), 6.59–6.47(m, 1 H), 6.35 (dd, J=16.0, 6.9 Hz, 1 H), 6.02 (s, 1 H), 5.17(dd, J= 10.8, 6.8 Hz, 1 H), 4.29 (qd, J=7.1, 2.9 Hz, 2 H), 3.81(s, 3 H), 2.84 (s, 6 H), 1.34 (t, J= 7.1 Hz, 3 H); 13C NMR(100 MHz, CDCl3): d= 165.5, 160.0, 142.9, 141.8, 137.1,131.8, 129.9, 129.5, 128.7, 127.7, 126.5, 125.1, 120.4, 114.2,112.3, 62.4, 55.4, 46.4, 38.3, 14.4; HR-MS (ESI): m/z=467.1629, calculated for C23H28N2O5S [M++Na]++: 467.1617.

Ethyl (2Z,5E)-2-[(N,N-dimethylsulfamoyl)amino]-6-phenyl-4-(p-tolyl)hexa-2,5-dienoate (3ac): pale yellow stickyoil; yield: 77.3 mg (90%). 1H NMR (400 MHz, CDCl3): d =7.38 (m, 2 H), 7.33–7.27 (m, 2 H), 7.27–7.19 (m, 3 H), 7.16 (d,J=7.9 Hz, 2 H), 7.01 (d, J=10.7 Hz, 1 H), 6.53 (dd, J=16.0,0.9 Hz, 1 H), 6.36 (dd, J=16.0, 6.8 Hz, 1 H), 6.02 (s, 1 H),5.17 (dd, J=10.8, 6.8 Hz, 1 H), 4.28 (qd, J= 7.1, 2.9 Hz, 2 H),




2.84 (s, 6 H), 2.34 (s, 3 H), 1.34 (t, J=7.1 Hz, 3 H); 13C NMR(100 MHz, CDCl3): d= 165.5, 142.1, 138.2, 137.2, 136.8,131.5, 129.9, 129.6, 128.7, 128.0, 127.6, 126.5, 124.9, 62.3,46.1, 38.3, 21.2, 14.4; HR-MS (ESI): m/z =451.1662, calculat-ed for C23H28N2O4S [M++ Na]++: 451.1667.

Ethyl (2Z,5E)-2-[(N,N-dimethylsulfamoyl)amino]-6-phenyl-4-(m-tolyl)hexa-2,5-dienoate (3ad): pale yellowsticky oil; yield: 73.4 mg (86%). 1H NMR (400 MHz,CDCl3): d =7.41–7.36 (m, 2 H), 7.33–7.28 (m, 2 H), 7.25–7.20(m, 2 H), 7.17–7.13 (m, 2 H), 7.10–7.06 (m, 1 H), 7.02 (d, J=10.6 Hz, 1 H), 6.59–6.48 (m, 1 H), 6.36 (dd, J=16.0, 6.8 Hz,1 H), 6.00 (s, 1 H), 5.16 (dd, J=11.0, 6.7 Hz, 1 H), 4.29 (qd,J=7.1, 4.2 Hz, 2 H), 2.84 (s, 6 H), 2.35 (s, 3 H), 1.35 (t, J=7.1 Hz, 3 H); 13C NMR (100 MHz, CDCl3): d =165.5, 142.1,141.2, 138.6, 137.2, 131.6, 129.8, 128.9, 128.8, 128.7, 128.0,127.7, 126.5, 125.1, 124.9, 62.3, 46.4, 38.3, 21.6, 14.4; HR-MS(ESI): m/z =451.1665, calculated for C23H28N2O4S [M++Na]++: 451.1667.

Ethyl (2Z,5E)-4-[4-(tert-butyl)phenyl]-2-[(N,N-dimethyl-sulfamoyl)amino]-6-phenylhexa-2,5-dienoate (3ae): yellowsolid; yield: 75.6 mg (80%). 1H NMR (400 MHz, CDCl3):d= 7.40–7.34 (m, 4 H), 7.32–7.26 (m, 4 H), 7.25–7.19 (m,1 H), 7.02 (d, J=10.6 Hz, 1 H), 6.58–6.50 (m, 1 H), 6.36 (dd,J=16.0, 6.9 Hz, 1 H), 5.99 (s, 1 H), 5.17 (dd, J=10.5, 7.0 Hz,1 H), 4.28 (qd, J=7.1, 3.3 Hz, 2 H), 2.85 (s, 6 H), 1.34 (t, J=7.1 Hz, 3 H), 1.32 (s, 9 H); 13C NMR (100 MHz, CDCl3): d=165.6, 150.1, 142.2, 138.2, 137.2, 131.6, 129.8, 128.7, 127.8,127.6, 126.5, 125.9, 124.9, 62.3, 46.0, 38.3, 34.6, 31.5, 14.4;HR-MS (ESI): m/z =493.2137, calculated for C26H34N2O4S[M++Na]++: 493.2137.

Ethyl (2Z,5E)-2-[(N,N-dimethylsulfamoyl)amino]-4-(naphthalen-2-yl)-6-phenylhexa-2,5-dienoate (3af): brownsolid; yield: 87.5 mg (94%). 1H NMR (400 MHz, CDCl3):d= 7.91–7.75 (m, 4 H), 7.54–7.45 (m, 3 H), 7.43–7.39 (m,2 H), 7.36–7.29 (m, 2 H), 7.28–7.21 (m, 1 H), 7.13 (d, J=10.6 Hz, 1 H), 6.60 (d, J= 16.0 Hz, 1 H), 6.47 (dd, J= 16.0,6.6 Hz, 1 H), 6.11 (s, 1 H), 5.39 (dd, J=10.6, 6.7 Hz, 1 H),4.31 (qq, J= 7.1, 3.7 Hz, 2 H), 2.86 (s, 6 H), 1.36 (t, J=7.1 Hz, 3 H); 13C NMR (100 MHz, CDCl3): d =165.5, 141.6,138.7, 137.1, 133.7, 132.6, 132.0, 129.6, 128.7, 128.6, 127.9,127.8, 127.7, 126.6, 126.5, 126.5, 126.3, 126.0, 125.2, 62.4,46.5, 38.3, 14.4; HR-MS (ESI): m/z= 487.1677, calculatedfor C26H28N2O4S [M++Na]++: 487.1667.

Ethyl (2Z,5E)-2-[(N,N-dimethylsulfamoyl)amino]-4,6-di-phenylhexa-2,5-dienoate (3ah): pale yellow sticky oil; yield:66.5 mg (80%). 1H NMR (400 MHz, CDCl3): d= 7.41–7.27(m, 9 H), 7.25–7.19 (m, 1 H), 7.02 (d, J= 10.6 Hz, 1 H), 6.58–6.49 (m, 1 H), 6.36 (dd, J= 16.0, 6.8 Hz, 1 H), 6.02 (s, 1 H),5.20 (ddd, J=10.6, 6.9, 1.2 Hz, 1 H), 2.84 (s, 6 H), 1.35 (t, J=7.1 Hz, 3 H); 13C NMR (100 MHz, CDCl3): d =165.5, 141.9,141.3, 137.2, 131.8, 129.7, 128.9, 128.7, 128.2, 127.7, 127.2,126.5, 125.1, 62.4, 46.4, 38.3, 14.4; HR-MS (ESI): m/z =437.1515, calculated for C22H26N2O4S [M++Na]++: 437.1511.

Ethyl (2Z,5E)-2-[(N,N-dimethylsulfamoyl)amino]-4-(4-flu-orophenyl)-6-phenylhexa-2,5-dienoate (3ai): yellow stickyoil; yield: 64.5 mg (75%). 1H NMR (400 MHz, CDCl3): d =7.40–7.35 (m, 2 H), 7.35–7.28 (m, 4 H), 7.25–7.20 (m, 1 H),7.07–7.00 (m, 2 H), 6.96 (d, J= 10.6 Hz, 1 H), 6.51 (dd, J=16.0, 0.9 Hz, 1 H), 6.32 (dd, J=15.9, 6.9 Hz, 1 H), 6.05 (s,1 H), 5.19 (dd, J= 10.5, 6.9 Hz, 1 H), 4.30 (qd, J=7.1, 1.8 Hz,2 H), 2.84 (s, 6 H), 1.35 (t, J= 7.1 Hz, 3 H); 13C NMR(100 MHz, CDCl3): d= 165.4, 162.0 (d, J= 245.5 Hz), 141.5,

137.0, 137.0 (d, J= 3.3 Hz), 131.9, 129.7 (d, J= 8.0 Hz), 129.5,128.7, 127.8, 126.5, 125.2, 115.7 (d, J=21.3 Hz), 62.4, 45.7,38.3, 14.4; 19F NMR (376 MHz, CDCl3): [email protected]; HR-MS(ESI): m/z =455.1410, calculated for C22H25FN2O4S [M++Na]++: 455.1417.

Methyl (2Z,5E)-2-[(N,N-dimethylsulfamoyl)amino]-4-(4-methoxyphenyl)-6-phenylhexa-2,5-dienoate (3ba): yellowsolid; yield: 66.6 mg (77%). 1H NMR (400 MHz, CDCl3):d= 7.41–7.34 (m, 2 H), 7.33–7.26 (m, 3 H), 7.26–7.19 (m,2 H), 7.00 (d, J=10.7 Hz, 1 H), 6.92–6.83 (m, 2 H), 6.55–6.46(m, 1 H), 6.34 (dd, J= 16.0, 6.6 Hz,1 H), 5.99 (s, 1 H), 5.13(dd, J=10.1, 6.7 Hz, 1 H), 3.83 (s, 3 H), 3.80 (s, 3 H), 2.84 (s,6 H); 13C NMR (100 MHz, CDCl3): d =166.0, 158.8, 142.6,137.2, 133.1, 131.5, 129.9, 129.1, 128.7, 127.6, 126.5, 124.5,114.3, 55.4, 53.0, 45.6, 38.3; HR-MS (ESI): m/z= 453.1474,calculated for C22H26N2O5S [M++Na]++: 453.1460.

Isopropyl (2Z,5E)-2-[(N,N-dimethylsulfamoyl)amino]-4-(4-methoxyphenyl)-6-phenylhexa-2,5-dienoate (3ca): paleyellow solid; yield: 77.5 mg (85%). 1H NMR (400 MHz,CDCl3): d =7.42–7.36 (m, 2 H), 7.34–7.26 (m, 5 H), 7.25–7.20(m, 1 H), 6.96 (d, J=10.7 Hz, 1 H), 6.93–6.87 (m, 2 H), 6.55–6.46 (m, 1 H), 6.35 (dd, J= 15.9, 6.8 Hz, 1 H), 6.04 (s, 1 H),5.20–5.01 (m, 2 H), 3.81 (s, 3 H), 2.85 (s, 6 H), 1.33 (t, J=6.2 Hz, 6 H); 13C NMR (100 MHz, CDCl3): d =165.1, 158.7,141.8, 137.2, 133.3, 131.5, 130.1, 129.2, 128.7, 127.6, 126.5,125.1, 114.3, 70.2, 55.4, 45.6, 38.3, 22.0; HR-MS (ESI): m/z=481.1788, calculated for C24H30N2O5S [M++Na]++: 481.1773.

Ethyl (2Z,5E)-2-[(N,N-dimethylsulfamoyl)amino]-4,6-bis(4-methoxyphenyl)hexa-2,5-dienoate (3da): yellow solid;yield: 85.8 mg (90%). 1H NMR (400 MHz, CDCl3): d= 7.37–7.22 (m, 4 H), 6.98 (d, J= 10.7 Hz, 1 H), 6.92–6.80 (m, 4 H),6.51–6.35 (m, 1 H), 6.19 (dd, J=15.9, 6.9 Hz, 1 H), 6.02 (s,1 H), 5.11 (dd, J= 10.9, 6.9 Hz, 1 H), 4.28 (qd, J=7.1, 2.1 Hz,2 H), 3.80 (s, 3 H), 3.80 (s, 3 H), 2.84 (s, 6 H), 1.34 (t, J=7.1 Hz, 3 H); 13C NMR (100 MHz, CDCl3): d =165.6, 159.3,158.7, 142.5, 133.4, 130.9, 130.0, 129.1, 127.7, 127.6, 124.6,114.3, 114.1, 62.3, 55.4, 45.6, 38.3, 14.4; HR-MS (ESI): m/z=497.1748, calculated for C24H30N2O6S [M++Na]++: 497.1722.

Ethyl (2Z,5E)-6-(4-chlorophenyl)-2-[(N,N-dimethylsulfa-moyl)amino]-4-(4-methoxyphenyl)hexa-2,5-dienoate (3ea):yellow solid; yield: 88.4 mg (92%). 1H NMR (400 MHz,CDCl3): d =7.33–7.22 (m, 6 H), 6.97 (d, J= 10.7 Hz, 1 H),6.91–6.86 (m, 2 H), 6.45 (dd, J= 16.0, 0.9 Hz, 1 H), 6.32 (dd,J=16.0, 6.6 Hz, 1 H), 6.02 (s, 1 H), 5.13 (dd, J=10.4, 6.7 Hz,1 H), 4.28 (qd, J=7.1, 2.3 Hz, 2 H), 3.80 (s, 3 H), 2.84 (s,6 H), 1.34 (t, J=7.1 Hz, 3 H); 13C NMR (100 MHz, CDCl3):d= 165.5, 158.8, 141.9, 135.7, 133.2, 133.0, 130.7, 130.3, 129.1,128.8, 127.7, 124.8, 114.4, 62.4, 55.4, 45.6, 38.3, 14.4; HR-MS(ESI): m/z =501.1220, calculated for C23H27ClN2O5S [M++Na]++: 501.1227.

Ethyl (2Z,5E)-2-[(N,N-dimethylsulfamoyl)amino]-6-(4-flu-orophenyl)-4-(4-methoxyphenyl)hexa-2,5-dienoate (3fa):brown sticky oil; yield: 82.9 mg (90%). 1H NMR (400 MHz,CDCl3): d =7.39–7.30 (m, 2 H), 7.29–7.21 (m, 2 H), 7.02–6.94(m, 3 H), 6.92–6.85 (m, 2 H), 6.46 (dd, J= 16.0, 1.0 Hz, 1 H),6.26 (dd, J=16.0, 7.0 Hz, 1 H), 6.02 (s, 1 H), 5.13 (dd, J=10.6, 7.3 Hz, 1 H), 4.28 (qd, J= 7.1, 2.3 Hz, 2 H), 3.80 (s, 3 H),2.84 (s, 6 H), 1.34 (t, J=7.1 Hz, 3 H); 13C NMR (100 MHz,CDCl3): d=165.5, 162.4 (d, J=246.6 Hz), 158.8, 142.1, 133.4(d, J= 3.3 Hz), 133.1, 130.3, 129.8 (d, J=2.2 Hz), 129.1,128.0, 127.9, 124.8, 115.5 (d, J= 21.6 Hz), 114.3, 62.3, 55.4,45.6, 38.3, 14.4; 19F NMR (376 MHz, CDCl3): d [email protected];




HR-MS (ESI) m/z= 485.1514,: calculated for C23H27FN2O5S[M++Na]++: 485.1522.

General Procedure for Pd(II)-Catalyzed 1,6-Additionof Arylboronic Acids to a,b,g,d-Unsaturated N,N-Dimethylsulfamoyl Imino Esters

A 25-mL flask was flushed with nitrogen and charged withPd(OPiv)2 (3.1 mg, 0.01 mmol, 5 mol%) and 2.0 mL of de-gassed toluene. The reaction mixture was mixed with aryl-boronic acid (0.6 mmol) and then a,b,g,d-unsaturated N,N-dimethylsulfamoyl imino ester (0.2 mmol) was added. Afterbeing stirred at 30 88C for 20 h, the reaction mixture waspassed through a pad of silica gel with ethyl acetate and thesolvent was removed under vacuum. Due to the difficulty incolumn chromatography, the yields were determined by1H NMR with N,N-dimethyl sulfone (18.8 mg, 0.2 mmol) asinternal standard. The residue was purified by silica gelcolumn chromatography (diethyl ether/hexane= 1/3).

Spectroscopic Data of Compounds (4aa-4ai and 4ba–4fa)

Ethyl (2Z,4E)-2-[(N,N-dimethylsulfamoyl)amino]-6-(4-me-thoxyphenyl)-6-phenylhexa-2,4-dienoate (4aa): yellow solid;yield: 48.7 mg (55%). 1H NMR (400 MHz, CDCl3): d= 7.33–7.27 (m, 2 H), 7.24–7.16 (m, 4 H), 7.14–7.07 (m, 2 H), 6.88–6.78 (m, 2 H), 6.71 (ddd, J= 15.2, 10.9, 1.0 Hz, 1 H), 6.59 (dd,J=15.3, 7.5 Hz, 1 H), 5.97 (s, 1 H), 4.87 (d, J=7.5 Hz, 1 H),4.28 (q, J=7.1 Hz, 2 H), 3.78 (s, 3 H), 2.75 (s, 6 H), 1.33 (t,J=7.1 Hz, 3 H); 13C NMR (100 MHz, CDCl3): d= 165.8,158.5, 146.6, 142.8, 136.8, 134.6, 129.7, 128.7, 128.7, 126.8,126.8, 123.0, 114.2, 62.1, 55.4, 53.8, 38.2, 14.4; HR-MS (ESI):m/z= 467.1614, calculated for C23H28N2O5S [M++ Na]++:467.1617.

Ethyl (2Z,4E)-2-[(N,N-dimethylsulfamoyl)amino]-6-(3-methoxyphenyl)-6-phenylhexa-2,4-dienoate (4ab): yellowsticky oil; yield: 35.6 mg (40%). 1H NMR (400 MHz,CDCl3): d =7.35–7.28 (m, 2 H), 7.26–7.18 (m, 5 H), 6.81–6.68(m, 4 H), 6.60 (dd, J=15.3, 7.8 Hz, 1 H), 6.00 (s, 1 H), 4.89(d, J=7.8 Hz, 1 H), 4.28 (q, J=7.1 Hz, 2 H), 3.77 (s, 3 H),2.75 (s, 6 H), 1.33 (t, J=7.1 Hz, 3 H); 13C NMR (100 MHz,CDCl3): d=165.8, 159.9, 146.0, 144.1, 142.3, 136.7, 129.7,128.8, 128.7, 127.1, 126.9, 123.1, 121.1, 114.7, 112.0, 62.1,55.3, 54.6, 38.2, 14.4; HR-MS (ESI): m/z =467.1615, calculat-ed for C23H28N2O5S [M++ Na]++: 467.1617.

Ethyl (2Z,4E)-2-[(N,N-dimethylsulfamoyl)amino]-6-phenyl-6-(p-tolyl)hexa-2,4-dienoate (4ac): yellow solid;yield: 41.9 mg (49%). 1H NMR (400 MHz, CDCl3): d= 7.34–7.26 (m, 2 H), 7.25–7.16 (m, 4 H), 7.10 (q, J= 8.2 Hz, 4 H),6.71 (ddd, J=15.3, 10.8, 0.9 Hz, 1 H), 6.60 (dd, J= 15.3,7.6 Hz, 1 H), 5.98 (s, 1 H), 4.88 (d, J=7.5 Hz, 1 H), 4.28 (q,J=7.1 Hz, 2 H), 2.74 (s, 6 H), 2.32 (s, 3 H), 1.33 (t, J= 7.1 Hz,3 H); 13C NMR (100 MHz, CDCl3): d =165.8, 146.5, 142.7,139.5, 136.8, 136.5, 129.4, 128.7, 128.7, 128.6, 126.9, 126.8,122.9, 62.1, 54.2, 38.1, 21.2, 14.4; HR-MS (ESI): m/z=451.1670, calculated for C23H28N2O4S [M++Na]++: 451.1667.

Ethyl (2Z,4E)-2-[(N,N-dimethylsulfamoyl)amino]-6-phenyl-6-(m-tolyl)hexa-2,4-dienoate (4ad): yellow sticky oil;yield: 43.8 mg (51%). 1H NMR (400 MHz, CDCl3): d= 7.35–7.28 (m, 2 H), 7.26–7.17 (m, 5 H), 7.08–6.95 (m, 3 H), 6.72(ddd, J=15.3, 10.8, 0.9 Hz, 1 H), 6.61 (dd, J=15.4, 7.6 Hz,

1 H), 5.99 (s, 1 H), 4.88 (d, J=7.5 Hz, 1 H), 4.28 (q, J=7.1 Hz, 2 H), 2.75 (s, 6 H), 2.32 (s, 3 H), 1.33 (t, J= 7.1 Hz,3 H); 13C NMR (100 MHz, CDCl3): d =165.8, 146.4, 142.6,142.4, 138.4, 136.7, 129.5, 128.7, 128.6, 127.6, 127.0, 126.8,125.8, 123.0, 62.1, 54.6, 38.1, 21.6, 14.4; HR-MS (ESI): m/z=451.1669, calculated for C23H28N2O4S [M++Na]++: 451.1667.

Ethyl (2Z,4E)-6-[4-(tert-butyl)phenyl]-2-[(N,N-dimethyl-sulfamoyl)amino]-6-phenylhexa-2,4-dienoate (4ae): yellowsticky oil; yield: 43.9 mg (47%). 1H NMR (400 MHz,CDCl3): d=7.31 (t, J=8.0 Hz, 4 H), 7.25–7.18 (m, 4 H), 7.12(d, J=8.3 Hz, 2 H), 6.71 (dd, J=15.6, 10.8 Hz, 1 H), 6.61 (dd,J=15.3, 7.5 Hz, 1 H), 5.97 (s, 1 H), 4.89 (d, J=7.5 Hz, 1 H),4.28 (q, J= 7.1 Hz, 2 H), 2.73 (s, 6 H), 1.33 (t, J= 7.1 Hz,3 H), 1.30 (s, 9 H); 13C NMR (100 MHz, CDCl3): d= 165.8,149.6, 146.6, 142.6, 139.4, 136.9, 128.7, 128.7, 128.3, 126.8,125.6, 122.9, 62.1, 54.2, 38.1, 34.6, 31.5, 14.4; HR-MS (ESI):m/z= 493.2138, calculated for C26H34N2O4S [M++ Na]++:493.2137.

Ethyl (2Z,4E)-2-[(N,N-dimethylsulfamoyl)amino]-6-(naphthalen-2-yl)-6-phenylhexa-2,4-dienoate (4af): yellowsolid; yield: 34.7 mg (37%). 1H NMR (400 MHz, CDCl3):d= 7.83–7.75 (m, 3 H), 7.71–7.63 (m, 1 H), 7.48–7.42 (m,2 H), 7.35–7.27 (m, 3 H), 7.26–7.21 (m, 4 H), 6.82–6.74 (m,1 H), 6.70 (dd, J= 15.3, 7.2 Hz, 1 H), 5.98 (s, 1 H), 5.09 (d,J=7.9 Hz, 1 H), 4.28 (q, J= 7.1 Hz, 2 H), 2.71 (s, 6 H), 1.33(t, J=7.1 Hz, 3 H); 13C NMR (100 MHz, CDCl3): d= 165.8,145.9, 142.4, 140.0, 136.6, 133.6, 132.5, 128.9, 128.8, 128.4,127.9, 127.7, 127.3, 127.2, 127.1, 126.9, 126.3, 125.9, 123.2,62.1, 54.6, 38.1, 14.4; HR-MS (ESI): m/z =487.1667, calculat-ed for C26H28N2O4S [M++ Na]++: 487.1667.

Ethyl (2Z,4E)-2-[(N,N-dimethylsulfamoyl)amino]-6-(naphthalen-1-yl)-6-phenylhexa-2,4-dienoate (4ag): yellowsolid; yield: 29.9 mg (32%). 1H NMR (400 MHz, CDCl3):d= 8.04–7.96 (m, 1 H), 7.89–7.82 (m, 1 H), 7.78 (d, J= 8.2 Hz,1 H), 7.49–7.38 (m, 3 H), 7.34–7.27 (m, 3 H), 7.25–7.19 (m,4 H), 6.80–6.72 (m, 1 H), 6.64 (ddd, J=15.3, 11.0, 1.1 Hz,1 H), 5.91 (s, 1 H), 5.68 (d, J=7.0 Hz, 1 H), 4.28 (q, J=7.1 Hz, 2 H), 2.62 (s, 6 H), 1.33 (t, J= 7.1 Hz, 3 H); 13C NMR(100 MHz, CDCl3): d= 165.8, 146.3, 142.1, 138.2, 136.5,134.2, 131.7, 129.0, 128.9, 128.8, 127.9, 127.4, 126.9, 126.5,126.4, 125.8, 125.5, 124.2, 123.2, 62.1, 50.6, 38.0, 14.4; HR-MS (ESI): m/z= 487.1668, calculated for C26H28N2O4S [M++Na]++: 487.1667.

Ethyl (2Z,4E)-2-[(N,N-dimethylsulfamoyl)amino]-6,6-di-phenylhexa-2,4-dienoate (4ah): pale yellow solid; yield:39.8 mg (48%). 1H NMR (400 MHz, CDCl3): d= 7.35–7.28(m, 4 H), 7.25–7.17 (m, 7 H), 6.72 (ddd, J= 15.3, 10.8, 0.9 Hz,1 H), 6.61 (dd, J= 15.3, 7.6 Hz, 1 H), 5.98 (s, 1 H), 4.92 (d,J=7.7 Hz, 1 H), 4.28 (q, J= 7.1 Hz, 2 H), 2.74 (s, 6 H), 1.33(t, J=7.1 Hz, 3 H); 13C NMR (100 MHz, CDCl3): d= 165.8,146.2, 142.5, 136.6, 128.7, 128.5, 127.1, 126.9, 123.1, 62.1,54.6, 38.1, 14.4; HR-MS (ESI): m/z= 437.1517, calculatedfor C22H26N2O4S [M++Na]++: 437.1511.

Ethyl (2Z,4E)-2-[(N,N-dimethylsulfamoyl)amino]-6-(4-flu-orophenyl)-6-phenylhexa-2,4-dienoate (4ai): yellow stickyoil; yield: 28.7 mg (33%). 1H NMR (400 MHz, CDCl3): d =7.35–7.29 (m, 2 H), 7.26–7.13 (m, 6 H), 7.04–6.96 (m, 2 H),6.73 (ddd, J=15.3, 11.0, 1.1 Hz, 1 H), 6.56 (ddd, J=15.3, 7.8,0.6 Hz, 1 H), 6.01 (s, 1 H), 4.90 (d, J=7.8 Hz, 1 H), 4.28 (q,J=7.1 Hz, 2 H), 2.77 (s, 6 H), 1.33 (t, J=7.1 Hz, 3 H);13C NMR (100 MHz, CDCl3): d= 165.7, 161.8 (d, J=245.4 Hz), 145.7, 142.4, 138.3 (d, J=3.2 Hz), 136.4, 130.2 (d,




J=8.0 Hz), 128.9, 128.7, 127.3, 127.0, 123.2, 115.6 (d, J=21.3 Hz), 62.2, 53.8, 38.2, 14.4; 19F NMR (376 MHz, CDCl3):[email protected]; HR-MS (ESI): m/z= 455.1411, calculated forC22H25FN2O4S [M++Na]++: 455.1417.

Methyl (2Z,4E)-2-[(N,N-dimethylsulfamoyl)amino]-6-(4-methoxyphenyl)-6-phenylhexa-2,4-dienoate (4ba): yellowsticky oil; yield: 30.4 mg (35%). 1H NMR (400 MHz,CDCl3): d =7.34–7.27 (m, 2 H), 7.25–7.16 (m, 4 H), 7.15–7.06(m, 2 H), 6.89–6.82 (m, 2 H), 6.69 (ddd, J= 15.3, 10.7, 0.9 Hz,1 H), 6.59 (dd, J= 15.3, 7.3 Hz, 1 H), 5.93 (s, 1 H), 4.87 (d,J=7.5 Hz, 1 H), 3.83 (s, 3 H), 3.78 (s, 3 H), 2.74 (s, 6 H);13C NMR (100 MHz, CDCl3): d =166.3, 158.5, 146.9, 142.7,137.3, 134.5, 129.7, 128.7, 128.7, 126.8, 126.8, 122.7, 114.1,55.4, 53.8, 52.9, 38.1; HR-MS (ESI): m/z=453.1465 calculat-ed for C22H26N2O5S [M++ Na]++: 453.1460.

Isopropyl (2Z,4E)-2-[(N,N-dimethylsulfamoyl)amino]-6-(4-methoxyphenyl)-6-phenylhexa-2,4-dienoate (4ca): yellowsticky oil; yield: 45.8 mg (50%). 1H NMR (400 MHz,CDCl3): d =7.36–7.30 (m, 2 H), 7.27–7.19 (m, 4 H), 7.16–7.12(m, 2 H), 6.90–6.85 (m, 2 H), 6.75 (ddd, J= 15.3, 11.0, 1.1 Hz,1 H), 6.60 (ddd, J= 15.2, 7.8, 0.5 Hz, 1 H), 6.04 (s, 1 H), 5.18–5.09 (m, 1 H), 4.89 (d, J=7.8 Hz, 1 H), 3.81 (s, 3 H), 2.78 (s,6 H), 1.33 (d, J=6.3 Hz, 6 H); 13C NMR (100 MHz, CDCl3):d= 165.3, 158.5, 146.3, 142.8, 136.4, 134.7, 129.7, 128.7, 128.7,126.9, 126.8, 123.3, 114.1, 69.9, 55.4, 53.8, 38.2, 22.0; HR-MS(ESI): m/z =481.1774, calculated for C24H30N2O5S [M++Na]++: 481.1773.

Ethyl (2Z,4E)-2-[(N,N-dimethylsulfamoyl)amino]-6,6-bis(4-methoxyphenyl)hexa-2,4-dienoate (4da): yellow stickyoil; yield: 47.5 mg (50%). 1H NMR (400 MHz, CDCl3): d =7.22 (d, J=11.0 Hz, 1 H), 7.13–7.06 (m, 4 H), 6.89–6.80 (m,4 H), 6.70 (ddd, J= 15.2, 11.0, 1.1 Hz, 1 H), 6.56 (ddd, J=15.2, 7.7, 0.4 Hz, 1 H), 6.01 (s, 1 H), 4.82 (d, J=7.7 Hz, 1 H),4.28 (q, J=7.1 Hz, 2 H), 3.78 (s, 6 H), 2.76 (s, 6 H), 1.33 (t,J=7.1 Hz, 3 H); 13C NMR (100 MHz, CDCl3): d= 165.8,158.4, 146.9, 137.0, 134.9, 129.6, 126.5, 122.8, 114.1, 62.1,55.4, 52.9, 38.2, 14.4; HR-MS (ESI): m/z =497.1723, calculat-ed for C24H30N2O6S [M++ Na]++: 497.1722.

Ethyl (2Z,4E)-6-(4-chlorophenyl)-2-[(N,N-dimethylsulfa-moyl)amino]-6-(4-methoxyphenyl)hexa-2,4-dienoate (4ea):yellow sticky oil; yield: 36.6 mg (38%). 1H NMR (400 MHz,CDCl3): d =7.29–7.26 (m, 2 H), 7.23–7.18 (m, 1 H), 7.15–7.04(m, 4 H), 6.87–6.83 (m, 2 H), 6.72 (ddd, J= 15.3, 11.1, 1.1 Hz,1 H), 6.52 (ddd, J= 15.3, 7.8, 0.6 Hz, 1 H), 6.02 (s, 1 H), 4.83(d, J=7.9 Hz, 1 H), 4.28 (q, J=7.1 Hz, 2 H), 3.79 (s, 3 H),2.77 (s, 6 H), 1.33 (t, J=7.1 Hz, 3 H); 13C NMR (100 MHz,CDCl3): d=165.7, 158.6, 145.6, 141.4, 136.4, 134.1, 132.6,130.0, 129.6, 128.8, 127.2, 123.2, 114.2, 62.2, 55.4, 53.1, 38.2,14.4; HR-MS (ESI): m/z= 501.1222, calculated forC23H27ClN2O5S [M++Na]++: 501.1227.

Ethyl (2Z,4E)-2-((N,N-dimethylsulfamoyl)amino)-6-(4-flu-orophenyl)-6-(4-methoxyphenyl)hexa-2,4-dienoate (4fa):yellow sticky oil; yield: 44.6 mg (48%). 1H NMR (400 MHz,CDCl3): d =7.21 (d, J=11.1 Hz, 1 H), 7.17–7.11 (m, 2 H),7.13–7.03 (m, 2 H), 7.03–6.94 (m, 2 H), 6.87–6.82 (m, 2 H),6.71 (ddd, J=15.3, 11.1, 1.1 Hz, 1 H), 6.53 (ddd, J=15.3, 7.8,0.6 Hz, 1 H), 6.02 (s, 1 H), 4.85 (d, J=7.8 Hz, 1 H), 4.28 (q,J=7.1 Hz, 2 H), 3.79 (s, 3 H), 2.77 (s, 6 H), 1.33 (t, J= 7.1 Hz,3 H); 13C NMR (100 MHz, CDCl3): d =165.8, 161.7 (d, J=245.1 Hz), 158.6, 146.1, 138.5 (d, J=3.2 Hz), 136.6, 134.4,130.1 (d, J=8.0 Hz), 129.6, 127.0, 123.1, 115.5 (d, J=21.3 Hz), 114.2, 62.2, 55.4, 53.0, 38.2, 14.4; 19F NMR

(376 MHz, CDCl3): d [email protected]; HR-MS (ESI): m/z =485.1527, calculated for C23H27FN2O5S [M++Na]++: 485.1522.

Synthesis of Unnatural a-Amino Ester 5

A 25-mL flask was flushed with nitrogen and charged withL1 (0.025 mmol, 12.5 mol%), Rh(acac)(C2H4)2 (2.6 mg,0.01 mmol, 5 mol%) and 2.0 mL of degassed toluene. Themixture was stirred for 10 min at ambient temperature. Thereaction mixture was mixed with arylboronic acid(0.6 mmol) and then a,b,g,d-unsaturated N,N-dimethylsulfa-moyl imino ester (0.2 mmol) was added. After being stirredat 30 88C for 20 h, the reaction mixture was passed through apad of silica gel with ethyl acetate and the solvent was re-moved under vacuum.

To an oven-dried glass liner capped with a septum wasadded the crude dehydroamino ester and Pd/C (42.6 mg,20%) in EtOH (5 mL). After the mixture had been stirredfor 10 min at room temperature under a nitrogen atmos-phere, the metal cylinder of a Parr bomb was assembled andequipped with the glass liner. The Parr bomb was chargedto 100 psi with H2 and vented (repeated 3 times). The bombwas then pressurized to 725 psi with H2 and the mixturestirred at 100 88C. After 12 h, the bomb was de-pressurized.The solution was passed through a pad of Celite with ethylacetate. The crude was purified by chromatography on silicagel (ethyl acetate/hexane =1/3) to give 5 as a colorless oil ;yield: 75.1 mg (84%, dr=1.2:1). 1H NMR (400 MHz,CDCl3): d =7.29–7.20 (m, 2 H), 7.20–7.13 (m, 2 H), 7.15–7.05(m, 3 H), 6.95–6.83 (m, 2 H), 4.90 (d, J= 8.5 Hz, 0.45 H,minor), 4.70 (d, J=9.7 Hz, 0.55 H, major), 4.20–4.08 (m,1 H), 4.08–3.89 (m, 1 H), 3.87–3.84 (m, 0.45 H, minor), 3.81(d, J=5.0 Hz, 3 H, major), 3.73–3.64 (m, 0.55 H), 2.87–2.72(m, 1 H), 2.66 (d, J=7.9 Hz, 6 H), 2.42 (q, J=7.1, 6.4 Hz,2 H), 2.11–1.94 (m, 2 H), 1.93–1.79 (m, 2 H), 1.29–1.15 (m,3 H); 13C NMR (100 MHz, CDCl3): d =173.3, 172.5, 158.5,158.4, 142.2, 142.1, 135.5, 135.0, 129.1, 129.0, 128.5, 128.5,128.4, 128.4, 125.9, 125.9, 114.1, 114.0, 61.8, 61.7, 55.4, 55.3,55.0, 54.6, 40.9, 40.8, 40.4, 39.2, 38.5, 38.0, 38.0, 33.7, 33.6,14.3, 14.1; HR-MS (ESI): m/z= 471.1942, calculated forC23H32N2O5S [M++Na]++: 471.1930.

Synthesis of Unnatural a-Amino Ester 6

A 25-mL flask was flushed with nitrogen and charged withPd(OPiv)2 (3.1 mg, 0.01 mmol, 5 mol%) and 2.0 mL of de-gassed toluene. The reaction mixture was mixed with aryl-boronic acid (0.6 mmol) and then a,b,g,d-unsaturated N,N-dimethylsulfamoyl imino ester (0.2 mmol) was added. Afterbeing stirred at 30 88C for 20 h, the reaction mixture waspassed through a pad of silica gel with ethyl acetate and thesolvent was removed under vacuum.

To an oven-dried glass liner capped with a septum wasadded crude dehydroamino ester and Pd/C (42.6 mg, 20%)in EtOH (5 mL). After the mixture had been stirred for10 min at room temperature under a nitrogen atmosphere,the metal cylinder of a Parr bomb was assembled andequipped with the glass liner. The Parr bomb was chargedto 100 psi with H2 and vented (repeated 3 times). The bombwas then pressurized to 725 psi with H2 and the mixturestirred at 100 88C. After 12 h, the bomb was de-pressurized.The solution was passed through a pad of Celite with ethylacetate. The crude was purified by chromatography on silica




gel (ethyl acetate/hexane =1/3) to give 6 as a colorless oil ;yield: 54.4 mg (61%, dr=1:1). 1H NMR (400 MHz, CDCl3):d= 7.30–7.23 (m, 2 H), 7.23–7.08 (m, 5 H), 6.81 (d, J= 8.6 Hz,2 H), 4.76 (d, J=9.0 Hz, 1 H), 4.16 (q, J= 7.1 Hz, 2 H), 3.95–3.87 (m, 1 H), 3.86–3.79 (m, 1 H), 3.76 (s, 3 H), 2.71 (s, 6 H),2.15–1.93 (m, 2 H), 1.86–1.73 (m, 1 H), 1.73–1.64 (m, 1 H),1.44–1.29 (m, 2 H), 1.22 (t, J=7.1 Hz, 3 H); 13C NMR(100 MHz, CDCl3): d= 172.7, 158.1, 145.2, 145.2, 137.0,136.9, 128.8, 128.8, 128.6, 127.8, 127.8, 126.3, 114.0, 61.9,56.2, 55.4, 50.3, 38.1, 35.3, 33.4, 23.7, 14.3; HR-MS (ESI): m/z=471.1947, calculated for C23H32N2O5S [M++Na]++:471.1930.

Acknowledgements

This work was supported by the Institute for Basic Science(IBS-R10-D1 and IBS-R004-D1) and the National ResearchFoundation of Korea (NRF-2017R1A2B4002650).

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[18] Standard quantum chemical methods that can onlyscan the electronic potential energy surface are funda-mentally unable to properly locate transition states fortranslational motions. These transition states are notexpected to change the mechanism in a non-trivial wayand are shown for illustration in Figure 2 and Figure 3.

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