DOI: 10.1002/chem.201403357

Full Paper

& Asymmetric Catalysis

Catalytic Enantioselective Amide Allylation of Isatins and Its Application in the Synthesis of 2-Oxindole Derivatives SpiroFused to the a-Methylene-g-Butyrolactone Functionality Masaki Takahashi,[a] Yusuke Murata,[b] Fumitoshi Yagishita,[c] Masami Sakamoto,[c] Tetsuya Sengoku,[a] and Hidemi Yoda*[a, b]

Abstract: This article is a full account of the work exploring the potential utility of catalytic enantioselective amide allylation of various isatins using indium-based chiral catalysts. A survey of various isatin substrates and NH-containing stannylated reagents revealed that the reaction has a remarkably wide scope to result in extremely high yields and enantioselectivities (up to > 99 %, 99 % ee) of variously substituted homoallylic alcohols. Several mechanistic investigations demonstrated that the substrate–reagent hydrogen-bond inter-

action plays a critical role in the formation of the key transition states to result in enhanced catalytic reaction. The success of this approach allowed convenient access to chiral 2-oxindoles spiro-fused to the a-methylene-g-butyrolactone functionality and their halogenated derivatives in almost enantiopure forms, thus highlighting the general utility of this synthetic method to deliver a large variety of antineoplastic drug candidates and pharmaceutically meaningful compounds.

Introduction The enantioselective allylation of carbonyl compounds using b-carbonyl allylstannanes is a reaction of fundamental significance in the synthesis of key homoallylic alcohol intermediates to deliver a large variety of biologically attractive compounds.[1–3] Among several examples of such entities,[4] chiral a-methylene-g-butyrolactones, accessible by means of a twostep reaction sequence that involves amide allylation followed by acid-promoted lactonization (Scheme 1a), have proven particularly appealing owing to their profound impact on the development of new potential drugs and chemotherapeutic agents for the treatment of a wide range of human diseases including bacterial infections and various cancers.[5, 6] The greater importance of this application has been exemplified by our recent work[7] on the synthesis of antineoplastic 2-oxindole [a] Dr. M. Takahashi, Dr. T. Sengoku, Prof. Dr. H. Yoda Department of Applied Chemistry Graduate School of Engineering, Shizuoka University 3-5-1 Johoku, Naka-ku, Hamamatsu 432-8561 (Japan) Fax: (+ 81) 53-478-1150 E-mail: [email protected] [b] Y. Murata, Prof. Dr. H. Yoda Graduate School of Science and Technology Shizuoka University, 3-5-1 Johoku, Naka-ku Hamamatsu 432-8561 (Japan) [c] Dr. F. Yagishita, Prof. Dr. M. Sakamoto Department of Applied Chemistry and Biotechnology Graduate School of Engineering, Chiba University 1-33 Yayoi-cho, Inage-ku, Chiba 263-8522 (Japan) Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/chem.201403357. Chem. Eur. J. 2014, 20, 11091 – 11100

Scheme 1. Examples of enantioselective allylation.

derivatives spiro-fused to the a-methylene-g-butyrolactone functionality,[8–10] which was achieved with perfect enantioselectivity (> 99 %, 99 % ee) by means of indium-catalyzed amide allylation of N-methyl isatin (1 a; Scheme 1b). Despite the inherent benefits of this protocol, which offers efficient short-step syntheses of the cytotoxic antineoplastic drug candidates in almost enantiopure forms, our current success with these molecular systems has been limited to just one particular isatin substrate and the mechanistic foundation for the extremely high enantioselectivity remained poorly understood. Accordingly, the principal objective of the present work is to extend the scope and potential application of the enantioselective amide allylation of various isatins and stannylated reagents, and to provide a detailed mechanistic picture of this transformation. Herein, we report a full account of our efforts in exploring the potential utility of our synthetic methodology

11091

 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper to access a variety of enantiomerically enriched 2-oxindole derivatives, in addition to understanding the origin of the stereocontrol induced by the local molecular environment of the transition states for the indium-mediated nucleophilic processes.

shortened dramatically to around 3 h. This phenomenon was also observed for (S)-1,1’-bi(2-naphthol) L2 and (S,S)-phenylpybox L3, whereas sterically more congested (S,R)-indapybox L4 was less effective but still substantial in accelerating the reaction (Table 1, entries 4–6). The above kinetic effects of the chiral ligands to favor the amide allylation is therefore indicative of the possible involvement of these species, which interResults and Discussion act considerably with the reacting components, in the transition states required to accomplish the highly efficient processAs in our earlier studies of the amide allylation of N-methyl es. Thus, these reaction systems were suggested to achieve isatin (1 a) with N-phenyl-b-amido allyltributylstannane (2 a), significant levels of asymmetric induction on the stereochemiindium(III) triflate (In(OTf)3) has been demonstrated to be the cal courses of the nucleophilic additions under steric influences best-performing catalyst among the Lewis acids examined, inof the chiral ligands, as has been shown in a series of the precluding scandium(III) triflate, samarium(III) triflate, and indiumceding reports by Franz and co-workers on enantioselective re(III) chloride.[7] At the same time, we noticed that the use of actions onto isatins.[12–14] This expectation could be observed Lewis acids is essential to drive the reaction smoothly, in view experimentally by chiral HPLC analyses of the isolated products of the fact that only a sluggish and incomplete reaction took on a Chiralpak IC chiral stationary phase; high levels of enanplace in the absence of any catalyst source (Table 1, entry 1). tioselectivity (84–97 % ee) were obtained in each case with the series of the pybox ligands, but failed in the Table 1. Reactivity of amide allylation.[a] one with L2 (7 % ee; Table 1, entries 3–6). Given that L3 proved to be the most effective by providing up to 99 % yield and 97 % ee, as shown in Table 1, further investigations on the model reaction of converting 1 a to 3 a are being pursued intensively with the [In(L3)(OTf)3] catalyst system based on stoichiometric mixtures of components 1 a and 2 a. Once the proper catalyst was selected, a systematic screening of different parameters was undertaken to find the optimal conditions for producing the most prominent enhancement in either reactivity or enantioseee[c] Entry Catalyst Chiral ligand t Yield[b] lectivity. Beginning with a search for the optimum [%] [%] [mol %] [h] amount of catalyst loading, practically identical re1 0 – 139 47[d] 0 sults were obtained in cases at catalyst loadings 2 10 – 24 63 0 ranging from 5 to 20 mol % (Table 2, entries 1–3), 3 10 L1 3 97 84 whereas a catalyst loading as low as 1 mol % was 4 10 L2 1 90 7 found ineffective for promoting the reaction (Table 2, 5 10 L3 3 99 97 6 10 L4 18 99 88 entry 4). Thus, the results would suggest that 10 mol % catalyst loading is needed to ensure a quali[a] The absolute configuration of the major enantiomer was assigned on the basis of ty product. In continuing the efforts to improve the further X-ray diffraction works (discussed later). [b] Isolated yields. [c] The ee values were determined by HPLC analysis with a Daicel Chiralpak IC. [d] A large amount of level of reaction efficiency and asymmetric induction, the starting material was recovered intact. we turned to the use of different solvents for comparison. On replacing the solvent by 1,2-dichloroFor these reasons, a series of experiments were designed to operate with indium(III) triflate to further test the efficiency of the amide allylation process. Initially, we attempted the reaction of 1 a with 1.2 equiv of 2 a in the presence of 10 mol % of In(OTf)3 and activated 4  molecular sieves (MS4) in dichloromethane (CH2Cl2) at RT. Under these conditions, the reaction proceeded up to its completion after a period of 24 h, and racemic allylated adduct 3 a was obtained in 63 % isolated yield as the predominant product (Table 1, entry 2). For this transformation, a catalytic amount of 2,6-bis[4’-(S)-isopropyloxazolin-2yl]pyridine ((S,S)-isopropylpybox; L1)[11] can markedly increase the reaction rate and enable a high yield of the desired product (Table 1, entry 3). Indeed, the addition of this chiral ligand resulted in reduction of the entire reaction period, which was Chem. Eur. J. 2014, 20, 11091 – 11100

www.chemeurj.org

11092

Table 2. Optimization for amide allylation of 1 a with 2 a. Entry

[In(L3)(OTf)3] [mol %]

Solvent

t [h]

Yield[a] [%]

ee[b] [%]

1 2 3 4 5 6 7

10 20 5 1 10 10 10

CH2Cl2[c] CH2Cl2[c] CH2Cl2[c] CH2Cl2[c] DCE[c] toluene[c] MeCN[d]

3 2 4 44 3 19 3

99 99 98 67 99 89 100

97 97 96 41 97 92 98

[a] Isolated yields. [b] The ee values were determined by HPLC analysis with a Daicel Chiralpak IC. [c] Reactions performed with MS4. [d] Reactions performed with MS3.

 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper ethane (DCE), there was no dramatic change in the reaction outcome (Table 2, entry 5). In a nonpolar solvent, toluene, the reaction proceeded sluggishly to completion in 19 h and gave 89 % yield of the product with a slight diminution in enantioselectivity (Table 2, entry 6). In contrast, the use of MeCN as solvent, together with activated MS3 as a substitute for MS4, produced a further substantial improvement with regard to reaction time in addition to excellent isolated yield and enantioselectivity (100 %, 98 % ee; Table 2, entry 7). Consequently, we could identify the optimal conditions for the most efficient protocol, which involve the use of 10 mol % of [In(L3)(OTf)3] in MeCN. With the optimal conditions in hand, the scope of the catalytic amide allylation was next explored to demonstrate the general utility of this protocol, and the results are compiled in Tables 3 and 4. By applying the conditions used for 2 a

Table 3. Scope of amide allylation of 1 a.[a]

Entry 1 2 3 4 5 6 7

Reagent 2a 2b 2c 2d 2e 2f 2g

R NHPh NHC5H11 NH(tBu) NH(1-naph) NH(p-tolyl) NH(p-tBuPh) NMePh

t [h] 3 4 8 4 3 17 72

Product 3a 3b 3c 3d 3e 3f 3g

Yield[b] [%] 100 88 91 95 99 92 37[d]

ee[c] [%]

thus indicating that the constituent molecules crystallizes in the monoclinic P21 space group and adopts a twisted conformation (see Figure S1 in the Supporting Information), with the S absolute configuration in the new stereogenic carbon atom as assigned on the basis of further X-ray diffraction work that will be discussed later. The behavior of N-methyl-N-phenyl-bamido-functionalized allylstannane 2 g that lacks the N H hydrogen atom, in contrast, is fundamentally different from those stated above. The amide allylation with this stannylated reagent proceeded at an impractically slow rate to result in incomplete consumption of the starting material even after 72 h, and rather poor enantioselectivity was observed with the reaction product 3 g (Table 3, entry 7). This is most likely due to the difference of the mechanism that operated in the transition state, despite the close steric similarity of this reagent to the others. On the basis of the above observation that highlights the importance of the secondary amide functionality in the stannylated reagent, we sought to encompass a broader substrate scope to ensure reliability of this catalytic system, with the use of the most promising reagent 2 e as a representative selection. To this end, a variety of N-substituted isatin analogues— 1 b–e, nonsubstituted isatin 1 f, and C5-halogenated N-methyl derivatives 1 g–i—were subjected to the amide allylation conditions. The results are summarized in Table 4. It can be noted

98 95 90 98 99 94 66

Table 4. Scope of amide allylation with 2 e.[a]

[a] The absolute configurations of major enantiomers were assigned on the basis of further X-ray diffraction works (discussed later). [b] Isolated yields. [c] The ee values were determined by HPLC analysis with Daicel Chiralpaks IC (for 3 a, 3 b, 3 c, 3 e, and 3 f), IE (for 3 g), and IF (for 3 d). [d] A large amount of the starting material was recovered intact after prolonged reaction times.

Entry

(Table 3, entry 1), all the new stannylated reagents that bore N H groups, 2 b–f, allowed for good to excellent yields (88– 99 %) and enantioselectivities (90–99 % ee) of the corresponding products 3 b–f, respectively, upon reaction of 1 a (Table 3, entries 2–6), although negligible reactivity attenuation was observed for sterically more demanding analogues such as 2 c and 2 f (Table 3, entries 3 and 6). Thus, one can see that the electronic and steric properties of aryl rings and alkyl chains in the stannylated reagents have little influence on the mechanism of the reaction, and that the protocol is characterized by broad functional-group tolerance with respect to the secondary amides. Among the results obtained, we placed particular emphasis on the case of using 2 e since the enantioselectivity reached up to the highest value of 99 % ee with a quantitative isolated yield (Table 3, entry 5). This example allowed us to confirm the geometric structure of the allylated adduct 3 e unambiguously from single-crystal X-ray diffraction analysis,[15] Chem. Eur. J. 2014, 20, 11091 – 11100

www.chemeurj.org

1 2 3 4 5 6 7 8 9

Substrate 1a 1b 1c 1d 1e 1f 1g 1h 1i

R

X Me nBu iBu Bn Ph H Me Me Me

t [h] H H H H H H I Br Cl

3 2 3 3 2 2 2 2 2

Product 3e 4b 4c 4d 4e 4f 4g 4h 4i

Yield[b] [%] 99 95 99 100 97 99 99 99 99

ee[c] [%] 99 99 98 98 98 96 97 97 98

[a] The absolute configurations of major enantiomers were assigned on the basis of further X-ray diffraction works (discussed later). [b] Isolated yields. [c] The ee values were determined by HPLC analysis with Daicel Chiralpaks IC (for 3 e, 4 b, 4 c, 4 d, and 4 g–i) and IF (for 4 e and 4 f).

that all of these compounds underwent an analogous reaction, regardless of any functionalization on the nitrogen atom, thereby allowing for smooth conversion to the desired products 4 b–i with extremely high isolated yields (95–100 %) and enantioselectivities (96–99 % ee; Table 4, entries 2–9), comparable to those found in 3 e (Table 4, entry 1). During the course of our investigation on the scope of the enantioselective amide allylation of isatins, we realized that the

11093

 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper use of stannylated reagents functionalized with secondary amide moieties should be the key requirement for the success of the reaction. To confirm this hypothesis, nonsubstituted allyltributylstannane 2 h was used as a nucleophilic species. When this reagent was subjected to the typical amide allylation conditions (10 mol % of [In(L3)(OTf)3], MS3, MeCN, RT) with 1 a, the corresponding allylated adduct 3 h was smoothly produced in 99 % isolated yield within 1 h. The composition analysis of 3 h by the chiral HPLC method on the Chiralpak IC showed that the reaction is much less enantioselective than those with the NH-containing ones to give an unsatisfactory ee value of 25 % (Table 5, entry 1).[16] With identical purpose, we

to result in exclusive formation of 3 i with an isolated yield of 45 % as a virtually racemic product (5 % ee; Table 5, entry 6). The main features of the results presented above can be summarized as follows: 1) the non-NH-functionalized types of stannylated reagents such as 2 g, 2 h, and 2 i lose their propensity to interact with chiral ligand/indium/substrate complexes and hence fail to facilitate highly efficient and fully stereocontrolled processes; 2) the NH moieties are therefore critically important elements to direct the stannylated reagents toward the catalytically active centers; and 3) the homoallylic alcohol 3 i is acidlabile and very likely to cyclize to 5 a under the conditions employed.[3, 10b] In a series of pioneering contributions, Franz and co-workers Table 5. Allylation with non-NH-functionalized stannylated reagents.[a] have established an important method for highly stereoselective catalytic allylation of isatins, wherein allylsilanes act as an efficient nucleophile and allow for asymmetric [3+2] annulation to access enantiomerically enriched spirocyclic 2-oxindoles.[4c, 13] The [b] [b] Yield of 5 a Entry Reagent Lewis Chiral Solvent t Yield of 3 [c] [c] success of the work prompted [%] (ee [%]) [%] (ee [%]) acid ligand [h] us to examine whether structur[d] 1 2h In(OTf)3 L3 MeCN 1 99 (25) 0 (–) ally related allylsilanes could be L3 MeCN[d] 72 0 (–) 46 (83) 2 2i In(OTf)3 L1 CH2Cl2[e] 44 0 (–) 52 (38) 3 2i In(OTf)3 used for the present system, and L2 CH2Cl2[e] 45 40 (10) 37 (10) 4 2i In(OTf)3 the results are summarized in L1 CH2Cl2[e] 72 0 (–) 0 (–) 5 2i InCl3 Table 6. Despite repeated efforts [e] L2 CH2Cl2 64 45 (5) 0 (–) 6 2i InCl3 in this direction, our results [a] The absolute configuration of major enantiomer for 3 h was assigned by comparison with the reported clearly show that two typical value of optical rotation (see Ref. [13b]), and that of 3 i was assigned on the basis of further X-ray diffraction sets of silyl reagents 2 j and 2 k works (discussed later). [b] Isolated yields. [c] The ee values were determined by HPLC analysis with Daicel Chirfail to initiate the reaction even alpaks IC (for 3 h and 3 i) and IB (for 5 a). [d] Reactions performed with MS3. [e] Reactions performed with MS4. in the presence of trimethylsilyl

next examined whether b-methoxycarbonyl allylstannane 2 i can conduct reactions with high levels of stereocontrol. Under the same conditions, substrate 1 a was treated with this reagent much more slowly to give incomplete conversion even after 72 h with exclusive formation of spirocyclic lactone 5 a, instead of the expected product 3 i, in only low isolated yield (46 %) and moderate enantioselectivity (83 % ee) (Table 5, entry 2). This set of results was reproduced using analogous conditions that involved the use of the chiral ligand L1 and CH2Cl2 solvent. In this case, the reaction appeared relatively fast and afforded exclusively a comparable isolated yield (52 %) of 5 a after a reaction time of 44 h, albeit with only modest enantioselectivity (38 % ee; Table 5, entry 3). A further modification, replacement of the chiral ligand with L2, led to a considerable change in the reaction outcome, thus giving a certain amount (40 % isolated yield) of 3 i together with a nearly equal amount (37 % isolated yield) of 5 a over a long period of time (45 h), but obtained in almost racemic (10 % ee) forms (Table 5, entry 4). When the catalyst of choice was [In(L1)Cl3], no reaction was observed, even after a prolonged reaction time (> 72 h) (Table 5, entry 5). By using the chiral catalyst [In(L2)Cl3], only a sluggish and incomplete reaction took place over 64 h Chem. Eur. J. 2014, 20, 11091 – 11100

www.chemeurj.org

Table 6. Allylation with allylsilanes.[a]

Entry 1 2 3 4

Reagent 2j 2k 2k 2k

Chiral catalyst [In(L1)(OTf)3] [In(L1)(OTf)3] [In(L3)(OTf)3] [In(L3)(OTf)3]

Additive – – – TMSCl[d]

Solvent [b]

CH2Cl2 CH2Cl2[b] MeCN[c] MeCN[c]

t [h] 91 121 72 72

[a] NR (no reaction). [b] Reactions performed with MS4. [c] Reactions performed with MS3. [d] A stoichiometric amount (1.2 equiv) was added to the reaction mixture.

chloride (TMSCl), which would serve as a Lewis acid promoter,[13, 17] to result in complete recovery of unchanged starting isatin 1 a in all cases (Table 6, entries 1–4). Thus, the silyl reagents prove to be totally ineffective in our catalytic systems, even though they include the N H group in their structures.

11094

 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper With the objective of determining the mechanistic origins of the asymmetric induction during the catalytic amide allylation, a further discussion should be given of the structural requirements for substrates to be used. To address this issue, we tested the utility of propiophenone substrate S1 as a monoketone analogue of isatin. Subjection of this material to the most favorable conditions that involve the use of 10 mol % of [In(L3)(OTf)3] in MeCN ultimately resulted in no reaction over a period of 72 h upon treatment with the stannylated reagent 2 e (Scheme 2a). In contrast, N-phenyl benzoylformamide S2, Figure 1. Proposed transition-state models.

Scheme 2. Mechanistic studies.

an acyclic ketoamide derivative, was shown to achieve a considerable degree of asymmetric induction to afford the corresponding homoallylic alcohol P2 with an ee value of 67 %, although the reaction ended with incomplete conversion and a moderate isolated yield of 72 % (Scheme 2a).[18] The observed differences in both the reactivity and enantioselectivity emphasize the importance of functional-group compatibility of the substrates with the chiral catalyst–reagent association. Therefore, it is reasonable to assume that the ketoamide structural motif of isatins is responsible for the precise control over enantiotopic differentiation of two faces of the carbonyl moieties through the N-C=O···H-N-C=O hydrogen-bond interactions between the catalyst-bound substrates 1 and reagents 2. This situation likely arises when the related elements assemble around the six-coordinate indium(III) ion, thus connecting to three nitrogen atoms of L3, two oxygen atoms of 1, and one oxygen atom of 2 into a highly ordered structure with a well-defined chiral environment. In view of this structural description, a mechanistic possibility of engaging another reagent molecule in the transition state must be taken into consideration as illustrated in Figure 1a, because the substrate–reagent complexes adopt a conformation with the nucleophilic residues away from the keto carbonyl carbon atoms, which is clearly unfavorable for facilitating the nucleophilic processes between these two reacting centers. In fact, this transitionstate model provides mechanistically reasonable reaction pathways that avoid the Si-face attack of nucleophiles owing to the steric repulsion from the phenyl group of the chiral ligand L3 and rather assist the strong preference for the Re-face attack Chem. Eur. J. 2014, 20, 11091 – 11100

www.chemeurj.org

from the sterically allowed spaces. It is of interest to note that our current rationale for the Re-face attack enables proper prediction of the stereochemical courses that lead to predominant formation of the S enantiomers, which is in good agreement with further evidence for the absolute stereochemistry assignments on the basis of X-ray analyses that will be described later. Within the framework of the proposed model, one may design a modified method for enantioselective catalysis of the amide allylation with the stannylated reagent 2 g (Figure 1b). This reaction has met with unsatisfactory outcomes (37 %, 66 % ee) in the foregoing experiments (Table 3, entry 7), and one might see whether this synthetic operation could be aided by the addition of the chemically inert but equally effective hydrogen-bond donor, allylsilane 2 k, to reflect any real change in product-forming behavior. To examine effects of the modification and validity of our proposed mechanistic model, we attempted to treat a reaction mixture that contained 1 a (c: 0.5 m), 2 k (1.2 equiv), and [In(L3)(OTf)3] (10 mol %) with 2 g (1.2 equiv) in MeCN. It is remarkable that this reaction took place at an appreciably increased rate relative to the performance under the original conditions and led to preferential formation of the desired product 3 g with much improved isolated yield (98 %) and enantioselectivity (90 % ee) after a period of 12 h for reaction completion (Scheme 2b). Furthermore, similar but much more distinct behavior was observed in another attempt made with the use of N-phenyl methacrylamide 2 l, which represents a structurally simplified alternative to 2 k. In this case, the catalyst was found to be much more active and accelerated the reaction with approximately sixfold rate enhancement to result in a clean and full conversion in 2 h to 3 g with quantitative isolated yield and comparably high ee value of 90 %. Besides, N-phenyl acetamide (2 m), N-phenyl benzamide (2 n), and even ethyl N-phenylcarbamate (2 o) still afforded enhanced isolated yields and enantioselectivities (93 %, 93 % ee; 98 %, 93 % ee; and 98 %, 91 % ee, respectively) in short reaction times of 5, 2, and 2 h, respectively, thereby suggesting that the conjugated C=C double bonds have little involvement in the rate- and stereochemistry-determining steps.[19] These dramatically enhanced effects of the chemically inert additives on the catalytic activity strongly support our conclusion that the mechanistic origin of the highly efficient and enantioselective amide allylation lies in the precise control over the spatial

11095

 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper arrangement and orientation of the molecular constituents imparted by the catalyst system. The O=C-NH-containing species play a key role in activating the chiral transition states through the hydrogen-bond interactions with the substrates.[20] Having successfully established a reasonably efficient protocol for the production of nearly enantiopure forms of the homoallylic alcohols with a full understanding of the mechanistic course, we directed our attention to the application of these compounds to the synthesis of spiro-fused bicyclic a-methylene-g-butyrolactones, which are of great pharmaceutical interest.[8, 10] As the first step towards this goal, we explored an approach upon acidic treatment to cyclize the substrates to the spirocyclic lactones, as indicated by previous results.[2, 3] Our major concern was to identify optimal conditions that would satisfy a primary requirement to maintain the original level of the stereochemical integrity. The results listed in Table 7 imply

siderably long times necessary to complete the processes (Table 7, entries 3 and 4). In continuation of our efforts, it was noted that an approach with the use of PTSA offered the most effective and rapid access to a diverse set of spirocyclic lactones, 5 a–f, 6 a, 7 a, and 8 a, of the highest quality (Ree = 100 %) in sufficiently high isolated yields (91–100 %) for all ten substrates investigated (Table 7, entries 5–14). A particularly noteworthy feature of this approach is the perfectly controlled formation of 5 a as the essentially enantiopure form with up to 99 % ee, starting from 3 e (Table 7, entry 6). Thus we obtained single crystals of this compound from a chloroform/hexane mixture and determined its structure by means of X-ray analysis (see Figure S2 in the Supporting Information).[21] The structure was solved in the orthorhombic chiral space group P212121, attributable to the chirality of the molecular constituents, and thus provided the most conclusive evidence for the successful construction of the rigid spirocyclic Table 7. Lactonization of homoallylic alcohols.[a] framework with complete retention of the configuration. It is interesting to remark that despite unsatisfactory Flack parameter value of 0.1 (3),[22] the configurational assignment of this structure composed entirely of light Ree[c, d] Entry Substrate R1 R2 X Reagent Solvent t Product Yield[b] atomic elements was found to [%] [%] [h] be valid, in good accord with 1 3a Ph Me H TfOH CH2Cl2 123 5a 62 22 the results unambiguously seCH2Cl2 97 5a 94 87 2 3a Ph Me H BF3·OEt2 cured by more reliable X-ray dif3 3a Ph Me H HCl (concd) 1,4-dioxane 139 5a 88 100 fraction studies conducted on its 44 5a 98 100 4 3a Ph Me H TFA CH2Cl2 11 5a 98 100 5 3a Ph Me H PTSA CH2Cl2 halogenated derivatives, thereby 11 5a 96 100 6 3e p-tolyl Me H PTSA CH2Cl2 assuring the S configurations as 9 5b 91 100 7 4b p-tolyl nBu H PTSA CH2Cl2 reported in our earlier work.[7] 7 5c 97 100 8 4c p-tolyl iBu H PTSA CH2Cl2 Given that the straightforward 9 5d 99 100 9 4d p-tolyl Bn H PTSA CH2Cl2 10 5e 96 100 10 4e p-tolyl Ph H PTSA CH2Cl2 cyclization is guaranteed to 24 5f 95 100 11 4f p-tolyl H H PTSA CH2Cl2 work, we envisaged that the ab[e] CH2Cl2 61 6a 99 100 12 4g p-tolyl Me I PTSA solute configurations of 3 a–d, [e] CH2Cl2 24 7a 99 100 13 4h p-tolyl Me Br PTSA 3 f, and 3 g could be established CH2Cl2 63 8a 100 100 14 4i p-tolyl Me Cl PTSA[e] by distinct correlations with the [a] The absolute configurations of major enantiomers were assigned on the basis of further X-ray diffraction chiral HPLC analyses of the corworks (discussed later). [b] Isolated yields. [c] Retention of enantiomeric purities (Ree = 100 {ee [%] (substrate) ee [%] (product)}). [d] The product enantioselectivities were determined by HPLC analysis with Daicel Chirresponding cyclization products alpaks IB (for 5 a, 5 d, 5 e, 6 a, 7 a, and 8 a), IE (for 5 f), and IF (for 5 b and 5 c). [e] 2.0 equiv of the reagent was with that of the authentic employed. sample of (S)-5 a. Upon subjection of each to the lactonization conditions, smooth conversion that solutions of triflic acid (TfOH) and BF3·OEt2 in CH2Cl2 are was observed, and similar yields of 5 a could be obtained with enantiomeric excesses exactly identical to those of their presynthetically useless in causing serious and significant decreascursors. All these isolated products exhibited HPLC profiles, in es in the ee values, respectively, possibly due to comparatively qualitative agreement with the result obtained for the enantiofast racemization of the substrate taking place at RT in the merically pure (S)-5 a, thus leading to a conclusion that all the acid-promoted processes (Table 7, entries 1 and 2). The milder absolute configurations of 3 a–d, 3 f, and 3 g should be asBrønsted acids, such as concentrated HCl (solution in 1,4-dioxsigned as S. ane), trifluoroacetic acid (TFA), and p-toluenesulfonic acid Concerning the biological impact of the spirocyclic lactones (PTSA; solution in CH2Cl2), can likely be utilized to address the as potential drug candidates, an early report by Heindel indiabove issues. Indeed, the use of the former two acids was cated that C5-iodinated N-methyl 2-oxindole of the spirocyclic found to promote the formation of the desired product with lactone is more attractive than the nonsubstituted one owing no detectable degradation of enantiomeric purity under analoto the potent antineoplastic activity against cells derived from gous reaction conditions, but to be impractical owing to con-

Chem. Eur. J. 2014, 20, 11091 – 11100

www.chemeurj.org

11096

 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper human carcinoma of the nasopharynx (KB).[8] The pharmaceutical importance of the C5-halogenated analogue, along with the additional advantage of making it possible to determine the absolute stereochemistry of the spirocyclic systems, stimulated our continuing interest in exploring an efficient approach to install halogen atoms at the C5 positions of the parent spirocyclic lactones 5.[23] In the beginning, we treated a mixture of 5 a and TFA (1.0 equiv) in MeCN with N-iodosuccinimide (NIS; 2.0 equiv) at RT to attempt a straightforward derivatization by using a procedure reported by Colobert and co-workers.[24] Fortunately, the acid-promoted substitution of the aromatic protons took place smoothly at the desired C5 position over a period of 15 h at RT to afford the iodinated derivative 6 a in 98 % isolated yield as an exclusive product (Table 8, entry 1). Initially, the relatively

Figure 2. The aromatic regions of 1H NMR spectra (300 MHz, CDCl3) of 5 e (top) and 6 e (bottom).

give simple patterns of downfield- and upfield-shifted signals for the C4, C6, and C7 aromatic protons, respectively, as the reaction progressed, whereas the other aromatic resonances remained almost unchanged, as demonstrated by a clear example from entry 5 of Table 8 (Figure 2). With such success in obtaining several examples of the iodinated products, we applied this approach to reagent-guided chemical functionalization to prepare ee[c] [%] Entry Substrate R Reagent t Product X Yield[b] the other halogenated derivatives, such as brominat[%] [h] (Ree[d] [%]) ed and chlorinated spirocyclic lactones. This is exem1 5a Me NIS 15 6a I 98 99 (100) plified by the reactions of 5 a, which were performed 2 5b nBu NIS 15 6b I 93 99 (100) under analogous conditions using N-bromosuccini3 5c iBu NIS 16 6c I 90 98 (100) mide (NBS) and N-chlorosuccinimide (NCS) as the 4 5d Bn NIS 19 6d I 94 98 (100) electrophilic halogen sources. Our attempts to effect 5 5e Ph NIS 19 6e I 91 98 (100) 6 5f H NIS 25 6f I 99 96 (100) the individual transformations also met with equally 7 5a Me NBS 14 7a Br 98 99 (100) satisfactory outcomes, thereby affording excellent 8 5a Me NCS 10 8a Cl 99 99 (100) yields (> 98 %) of the brominated and chlorinated de[a] The absolute configurations were assigned on the basis of further X-ray diffraction rivatives 7 a and 8 a, respectively, with complete reworks (discussed later). [b] Isolated yields. [c] The product enantioselectivities were detention of the enantiopurities (Table 8, entries 7 and termined by HPLC analysis with Daicel Chiralpaks IB (for 6 a, 6 e, 7 a, and 8 a), IC (for 8). Thus, the above method was demonstrated to 6 f), IE (for 6 d), and IF (for 6 b and 6 c). [d] Retention of enantiomeric purities (Ree = 100 {ee [%] (substrate) ee [%] (product)}). have appreciable tolerance for variations in the substrates and reagents, thereby offering convenient access to a large diversity of the C5-halogenated 2harsh conditions required for this operation led to some conoxindoles in high yields without degradation of the pre-existcern with regard to potential detrimental effects on the stereoing labile a-methylene-g-butyrolactone moieties. chemical outcome. However, the very high level of the enanAt the final stage of our research, we undertook comprehentiomeric purity was completely retained in the product with sive X-ray studies to reveal the unspecified absolute stereochethe ee value of 99 % as confirmed by chiral HPLC analysis. This mistries of the halogenated compounds.[25–31] The selected transformation could be effected on all the other spirocyclic crystallographic data obtained from the X-ray results are lactones 5 b–f, which underwent clean reactions only at the shown in Table 9. Accordingly, all the structures were solved in relevant C5 positions to result in very high isolated yields (> the chiral space groups commonly attributed to one-handed90 %) of the corresponding iodinated analogues 6 b–f with ness, established in crystallization of the enantiopure molecomplete retention of the stereochemistry, respectively cules and thoroughly refined to allow for high accuracy, with (Table 8, entries 2–6). Of particular interest is the fact that the the final R1 and wR2 values being less than 0.0716 and 0.1939, cases of entries 4 and 5 of Table 8, in which R contains an aryl respectively. As seen in the case of 5 a, the given structures (benzyl and phenyl) group, maintain structural integrity of the show the rigid conformations owing to geometric constraints aromatic substituents during the course of the reaction. In this imposed by the cross-linked bicyclic systems (see Figures S3– regard, 1H NMR spectroscopy allowed us to follow the reaction 10 in the Supporting Information). It deserves to be mentioned here that all the absolute configurations in the C3-stereogenic trajectories of the individual molecules; the characteristic resocenters are assigned as S with satisfactory Flack parameter nances assignable to the C5 aromatic protons disappeared to Table 8. Halogenation of spirocyclic lactones.[a]

Chem. Eur. J. 2014, 20, 11091 – 11100

www.chemeurj.org

11097

 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper Experimental Section

Table 9. Selected crystallographic data. Compound Empirical formula

Crystal system

Space group

6 a[a] 6b 6c 6d 6e 6f 7a 8a

monoclinic orthorhombic orthorhombic orthorhombic orthorhombic hexagonal monoclinic monoclinic

C2 P212121 P212121 P212121 P212121 P63 P21 P21

C13H10INO3 C16H16INO3 C16H16INO3 C19H14INO3 C18H12INO3 C12H8INO3 C13H10BrNO3 C13H10ClNO3

Absolute Flack R1 configuration parameter S S S S S S S S

0.098(16) 0.020(12) 0.028(18) 0.049(6) 0.02(2) 0.09(2) 0.064(8) 0.065(5)

wR2

0.0716 0.0301 0.0307 0.0311 0.0469 0.0387 0.0216 0.0412

All the experiments for the asymmetric amide allylations were carried out as described in the following typical procedure. For example, the reaction of isatin 1 a with stannylated reagent 2 c to generate homoallylic alcohol 3 c (entry 3 in Table 3) was exemplified as follows.

Synthesis of homoallylic alcohol 3 c

[a] See Ref. [7].

values less than 0.098, which would be attributed to the possible heavy atom effects of the halogen atoms.[22] From an assessment of the stereochemical correlations, these results allow us to unambiguously assign the S absolute configurations to all the related chiral intermediates 3–5.[32] The observed general preference for the S enantiomers appears to be in agreement with our predictions on the basis of the aforementioned transition state model for the stereochemical course of the catalytic amide allylation with the NH-containing stannylated reagents, thus yielding definitive proof of the suitability of the foregoing mechanistic interpretation.

Conclusion We have demonstrated that the indium-catalyzed amide allylation presented here represents an attractive and powerful means to achieve extremely high levels of enantioselectivity and exhibits a remarkably wide scope in a variety of isatins and NH-containing stannylated reagents to provide the homoallylic alcohols in almost enantiopure forms. Also worthy of note is that the successful synthesis of these chiral compounds allows the straightforward and rapid construction of a diverse set of the spirocyclic lactones and their halogenated derivatives under the perfect stereocontrol, with an operational convenience that would make this method adaptable to largescale synthesis. Several mechanistic investigations have shown that the substrate–reagent hydrogen-bond interaction plays a critical role in the formation of the key transition states that give rise to emergence of the high catalytic activity and enantioselectivity. This finding further inspired the employment of the hydrogen-bond donors, which led to a striking discovery that the externally added O=C NH-containing species can be effective as a catalyst activator to achieve high levels of enantiocontrol in the amide allylation processes. Therefore, the results of our studies can offer not only potential synthetic advantages to deliver a large variety of antineoplastic drug candidates and pharmaceutically meaningful compounds, but also many attractive opportunities to design and create new catalytic systems.

Chem. Eur. J. 2014, 20, 11091 – 11100

0.1939 0.0706 0.0636 0.0740 0.1052 0.1031 0.0563 0.1076

General procedure for asymmetric amide allylations

www.chemeurj.org

Under a nitrogen atmosphere, (S,S)-Ph-pybox (9.4 mg, 0.025 mmol) was added at RT to the suspension of In(OTf)3 (10.5 mg, 0.0187 mmol) and MS3 (93.5 mg, 0.5 g mmol 1) in anhydrous MeCN (0.37 mL), which was degassed by at least three freeze/pump/thaw cycles. After stirring for 1 h, compound 1 a (30.1 mg, 0.187 mmol) was added, and the resulting mixture was stirred for 0.5 h. Compound 2 c (96.6 mg, 0.224 mmol) was added at the same temperature to this mixture, and the resulting mixture was stirred for 8 h. The reaction was then quenched by the addition of saturated aqueous NaHCO3 (5.0 mL), extracted with ethyl acetate (30 mL), washed with 3 % w/w aqueous HCl (10 mL) and brine (10 mL), dried over Na2SO4, filtered, and concentrated under vacuum to provide a crude residue. Purification of the residue by column chromatography on 10 % w/ w anhydrous K2CO3/silica gel[33] (eluent: hexane/AcOEt 1:1) gave 3 c (51.6 mg, 91 %, 90 % ee) as a white solid. CCDC-976630 (3 e), CCDC-976631 (5 a), CCDC-976632 (7 a), CCDC976633 (8 a), CCDC-976951 (6 b), CCDC-976952 (6 c), CCDC-976954 (6 e), CCDC-976956 (6 f), and CCDC-977774 (6 d) contain the supplementary crystallographic data for this paper. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.

Acknowledgements This work was supported in part by a Grant-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology, Japan. The authors are grateful to Mr. Takashi Yamada for assistance with NMR spectroscopic measurements and Prof. Vadim A. Soloshonok (University of the Basque Country) for his valuable suggestions and comments on a possibility of self-disproportionation of enantiomers (SDE). Keywords: allylation · antitumor agents catalysis · lactones · spiro compounds

·

asymmetric

[1] a) Y. Yamamoto, N. Asao, Chem. Rev. 1993, 93, 2207 – 2293; b) Y. Yamamoto, Acc. Chem. Res. 1987, 20, 243 – 249. [2] a) K. Tanaka, H. Yoda, Y. Isobe, A. Kaji, J. Org. Chem. 1986, 51, 1856 – 1866; b) K. Tanaka, H. Yoda, Y. Isobe, A. Kaji, Tetrahedron Lett. 1985, 26, 1337 – 1340. [3] a) T. Suzuki, J. Atsumi, T. Sengoku, M. Takahashi, H. Yoda, J. Organomet. Chem. 2010, 695, 128 – 136; b) T. Suzuki, T. Sengoku, M. Takahashi, H. Yoda, Tetrahedron Lett. 2008, 49, 4701 – 4703. [4] a) D. L. Silverio, S. Torker, T. Pilyugina, E. M. Vieira, M. L. Snapper, F. Haeffner, A. H. Hoveyda, Nature 2013, 494, 216 – 221; b) J. Itoh, S. B. Han, M. J. Krische, Angew. Chem. 2009, 121, 6431 – 6434; Angew. Chem. Int. Ed. 2009, 48, 6313 – 6316; c) A. K. Franz, P. D. Dreyfuss, S. L. Schreiber, J. Am. Chem. Soc. 2007, 129, 1020 – 1021; d) B. M. Trost, M. U. Frederiksen,

11098

 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper

[5]

[6]

[7] [8] [9]

[10]

[11]

[12]

[13]

[14]

[15]

[16]

[17]

[18]

[19]

Angew. Chem. 2005, 117, 312 – 314; Angew. Chem. Int. Ed. 2005, 44, 308 – 310. a) R. A. Kitson, A. Millemaggi, R. J. K. Taylor, Angew. Chem. 2009, 121, 9590 – 9615; Angew. Chem. Int. Ed. 2009, 48, 9426 – 9451; b) A. Bachelier, R. Mayer, C. D. Klein, Bioorg. Med. Chem. Lett. 2006, 16, 5605 – 5609; c) B. Siedle, A. J. Garca-PiÇeres, R. Murillo, J. Schulte-Mçnting, V. Castro, P. Rngeler, C. A. Klaas, F. B. Da Costa, W. Kisiel, I. Merfort, J. Med. Chem. 2004, 47, 6042 – 6054; d) P. Rngeler, V. Castro, G. Mora, N. Gçren, W. Vichnewski, H. L. Pahl, I. Merfort, T. J. Schmidt, Bioorg. Med. Chem. 1999, 7, 2343 – 2352. a) M. Takahashi, T. Sudo, Y. Murata, T. Sengoku, H. Yoda, Nat. Prod. Commun. 2013, 8, 889 – 896; b) M. Takahashi, J. Atsumi, T. Sengoku, H. Yoda, Synthesis 2010, 3282 – 3288. Y. Murata, M. Takahashi, F. Yagishita, M. Sakamoto, T. Sengoku, H. Yoda, Org. Lett. 2013, 15, 6182 – 6185. N. D. Heindel, J. A. Minatelli, J. Pharm. Sci. 1981, 70, 84 – 86. a) G. S. Singh, Z. Y. Desta, Chem. Rev. 2012, 112, 6104 – 6155; b) S. Kato, T. Yoshino, M. Shibasaki, M. Kanai, S. Matsunaga, Angew. Chem. 2012, 124, 7113 – 7116; Angew. Chem. Int. Ed. 2012, 51, 7007 – 7010; c) C. V. Galliford, K. A. Scheidt, Angew. Chem. 2007, 119, 8902 – 8912; Angew. Chem. Int. Ed. 2007, 46, 8748 – 8758; d) C. Marti, E. M. Carreira, Eur. J. Org. Chem. 2003, 2209 – 2219. a) Q.-L. Wang, L. Peng, F.-Y. Wang, M.-L. Zhang, L.-N. Jia, F. Tian, X.-Y. Xu, L.-X. Wang, Chem. Commun. 2013, 49, 9422 – 9424; b) S. Rana, A. Natarajan, Org. Biomol. Chem. 2013, 11, 244 – 247; c) P. Shanmugam, B. Viswambharan, Synlett 2008, 2763 – 2768; d) P. Shanmugam, V. Vaithiyanathan, Tetrahedron 2008, 64, 3322 – 3330. a) Y. Motoyama, O. Kurihara, K. Murata, K. Aoki, H. Nishiyama, Organometallics 2000, 19, 1025 – 1034; b) H. Nishiyama, H. Sakaguchi, T. Nakamura, M. Horihata, M. Kondo, K. Itoh, Organometallics 1989, 8, 846 – 848. a) N. R. Ball-Jones, J. J. Badillo, A. K. Franz, Org. Biomol. Chem. 2012, 10, 5165 – 5181; b) J. P. MacDonald, J. J. Badillo, G. E. Arevalo, A. Silva-Garca, A. K. Franz, ACS Comb. Sci. 2012, 14, 285 – 293; c) E. G. Gutierrez, C. J. Wong, A. H. Sahin, A. K. Franz, Org. Lett. 2011, 13, 5754 – 5757; d) J. J. Badillo, A. Silva-Garca, B. H. Shupe, J. C. Fettinger, A. K. Franz, Tetrahedron Lett. 2011, 52, 5550 – 5553; e) N. V. Hanhan, A. H. Sahin, T. W. Chang, J. C. Fettinger, A. K. Franz, Angew. Chem. Int. Ed. 2010, 49, 744 – 747. a) N. V. Hanhan, Y. C. Tang, N. T. Tran, A. K. Franz, Org. Lett. 2012, 14, 2218 – 2221; b) N. V. Hanhan, N. R. Ball-Jones, N. T. Tran, A. K. Franz, Angew. Chem. 2012, 124, 1013 – 1016; Angew. Chem. Int. Ed. 2012, 51, 989 – 992. a) B. H. Shupe, E. E. Allen, J. P. MacDonald, S. O. Wilson, A. K. Franz, Org. Lett. 2013, 15, 3218 – 3221; b) J. J. Badillo, G. E. Arevalo, J. C. Fettinger, A. K. Franz, Org. Lett. 2011, 13, 418 – 421. Crystal data for 3 e (recrystallized from solution in methanol): monoclinic, space group P21 (no. 4), a = 8.54669(13) , b = 4.98993(8) , c = 20.4302(3) , a = g = 908, b = 92.9900(7)8, V = 870.11(2) 3, Z = 2, 1 = 1.284 Mg m 3, m(CuKa) = 0.705 cm 1, T = 173 K. In the final least-squares refinement cycles on F2, the model converged at R1 = 0.0386 (I > 2s(I)), wR2 = 0.1116, GoF = 1.228, and Flack absolute structure parameter = 0.10(6) for 2582 reflections and 222 parameters. For the absolute stereochemistry of 3 h, the R configuration was assigned to the newly created stereogenic center by comparison of the optical rotation with that reported in the literature (see Ref. [13b]). The opposite stereochemical preference in addition to the observed very low enantioselectivity (25 % ee) can be interpreted in terms of inefficient chirality transfer from the chiral environment at the catalytic center. a) S. E. Denmark, J. Fu, Chem. Rev. 2003, 103, 2763 – 2794; b) C.-T. Chen, S.-D. Chao, J. Org. Chem. 1999, 64, 1090 – 1091; c) J. Beignet, L. R. Cox, Org. Lett. 2003, 5, 4231 – 4234; d) J. Lu, S.-J. Ji, Y.-C. Teo, T.-P. Loh, Org. Lett. 2005, 7, 159 – 161. The lower efficiency of the reaction than with the isatin substrates is probably responsible for intrinsic low reactivity of the acyclic ketoamide system, which would be attributed to the greater conformational flexibility. The ee value of P2 was determined by HPLC analysis with the Daicel Chiralpak IF. In the mechanistic studies with the hydrogen-containing additives, it was found that use of imidazole (1.2 equiv) had a detrimental effect on both the reactivity and enantioselectivity of the amide allylation to 3 g.

Chem. Eur. J. 2014, 20, 11091 – 11100

www.chemeurj.org

[20]

[21]

[22] [23]

[24]

[25]

[26]

[27]

[28]

[29]

[30]

[31]

11099

In this case, only a sluggish and incomplete reaction took place over 72 h to result in the formation of 3 g with an isolated yield of 12 % as a completely racemic product. As for the complexation behavior, extensive 1H NMR spectroscopic studies allowed us to gain additional insight into the proposed transition-state structure. The details are given in the Supporting Information. Crystal data for 5 a (recrystallized from solution in chloroform/hexane): orthorhombic, space group P212121 (no. 19), a = 6.7665(2) , b = 10.5151(4) , c = 15.5503(5) , a = b = g = 908, V = 1106.41(6) 3, Z = 4, 1 = 1.376 Mg m 3, m(CuKa) = 0.817 cm 1, T = 173 K. In the final leastsquares refinement cycles on F2, the model converged at R1 = 0.0362 (I > 2s(I)), wR2 = 0.1120, GoF = 1.068, and Flack absolute structure parameter = 0.1(3) for 1984 reflections and 155 parameters. a) H. D. Flack, G. Bernardinelli, Acta Crystallogr. Sect. A 1999, 55, 908 – 915; b) H. D. Flack, Acta Crystallogr. Sect. A 1983, 39, 876 – 881. Clearly, one can see that these types of compounds will be more easily accessed by the available amide allylation/lactonization sequence from the respective C5-halogenated isatins. a) A.-S. Castanet, F. Colobert, P.-E. Broutin, Tetrahedron Lett. 2002, 43, 5047 – 5048; b) M. C. CarreÇo, J. L. Garuca Ruano, G. Sanz, M. A. Toledo, A. Urbano, Tetrahedron Lett. 1996, 37, 4081 – 4084. Crystal data for 6 b (recrystallized from solution in chloroform/hexane): orthorhombic, space group P212121 (no. 19), a = 5.1110(5) , b = 16.8944(17) , c = 18.6050(18) , a = b = g = 908, V = 1606.5(3) 3, Z = 4, 1 = 1.642 Mg m 3, m(MoKa) = 2.002 cm 1, T = 173 K. In the final leastsquares refinement cycles on F2, the model converged at R1 = 0.0301 (I > 2s(I)), wR2 = 0.0706, GoF = 1.062, and Flack absolute structure parameter = 0.020(12) for 3675 reflections and 191 parameters. Crystal data for 6 c (recrystallized from solution in chloroform/hexane): orthorhombic, space group P212121 (no. 19), a = 5.1577(5) , b = 17.4431(17) , c = 18.1558(17) , a = b = g = 908, V = 1633.4(3) 3, Z = 4, 1 = 1.615 Mg m 3, m(MoKa) = 1.969 cm 1, T = 173 K. In the final leastsquares refinement cycles on F2, the model converged at R1 = 0.0307 (I > 2s(I)), wR2 = 0.0636, GoF = 1.027, and Flack absolute structure parameter = 0.028(18) for 3715 reflections and 192 parameters. Crystal data for 6 d (recrystallized from solution in chloroform/hexane): orthorhombic, space group P212121 (no. 19), a = 5.3720(2) , b = 16.4015(5) , c = 18.8857(6) , a = b = g = 908, V = 1664.00(10) 3, Z = 4, 1 = 1.721 Mg m 3, m(CuKa) = 15.265 cm 1, T = 173 K. In the final leastsquares refinement cycles on F2, the model converged at R1 = 0.0311 (I > 2s(I)), wR2 = 0.0740, GoF = 1.031, and Flack absolute structure parameter = 0.049(6) for 2909 reflections and 217 parameters. Crystal data for 6 e (recrystallized from solution in chloroform/hexane): orthorhombic, space group P212121 (no. 19), a = 5.5595(6) , b = 13.5457(14) , c = 20.892(2) , a = b = g = 908, V = 1573.3(3) 3, Z = 4, 1 = 1.761 Mg m 3, m(MoKa) = 2.050 cm 1, T = 173 K. In the final leastsquares refinement cycles on F2, the model converged at R1 = 0.0469 (I > 2s(I)), wR2 = 0.1052, GoF = 1.005, and Flack absolute structure parameter = 0.02(2) for 3532 reflections and 208 parameters. Crystal data for 6 f (recrystallized from solution in chloroform/hexane): hexagonal, space group P63 (no. 173), a = 18.1986(15) , b = 18.1986(15) , c = 6.8251(7) , a = b = 908, g = 1208, V = 1957.6(4) 3, Z = 6, 1 = 1.939 Mg m 3, m(MoKa) = 2.658 cm 1, T = 173 K. In the final leastsquares refinement cycles on F2, the model converged at R1 = 0.0387 (I > 2s(I)), wR2 = 0.1031, GoF = 1.108, and Flack absolute structure parameter = 0.09(2) for 2988 reflections and 166 parameters. Crystal data for 7 a (recrystallized from solution in chloroform/hexane): monoclinic, space group P21 (no. 4), a = 5.9706(3) , b = 12.0484(6) , c = 8.7734(4) , a = g = 908, b = 103.9550(15)8, V = 612.50(5) 3, Z = 2, 1 = 1.671 Mg m 3, m(CuKa) = 4.591 cm 1, T = 173 K. In the final leastsquares refinement cycles on F2, the model converged at R1 = 0.0216 (I > 2s(I)), wR2 = 0.0563, GoF = 1.039, and Flack absolute structure parameter = 0.064(8) for 1717 reflections and 164 parameters. Crystal data for 8 a (recrystallized from solution in chloroform/hexane): monoclinic, space group P21 (no. 4), a = 5.9100(2) , b = 12.3070(5) , c = 8.5206(3) , a = g = 908, b = 103.2334(13)8, V = 603.28(4) 3, Z = 2, 1 = 1.452 Mg m 3, m(CuKa) = 2.818 cm 1, T = 173 K. In the final leastsquares refinement cycles on F2, the model converged at R1 = 0.0412 (I > 2s(I)), wR2 = 0.1076, GoF = 1.081, and Flack absolute structure parameter = 0.065(5) for 2109 reflections and 164 parameters.  2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper [32] On the basis of these results, the absolute configurations of 4 g–i, which were left unassigned, could be determined to be S by distinct correlations with the chiral HPLC analyses of the corresponding cyclization products with those of the authentic samples of (S)-6 a–8 a, respectively.

Chem. Eur. J. 2014, 20, 11091 – 11100

www.chemeurj.org

[33] D. C. Harrowven, D. P. Curran, S. L. Kostiuk, I. L. Wallis-Guy, S. Whiting, K. J. Stenning, B. Tang, E. Packard, L. Nanson, Chem. Commun. 2010, 46, 6335 – 6337. Received: May 28, 2014 Published online on July 22, 2014

11100

 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim