Diastereoselection in the Formation of Spirocyclic Oxindoles by the Intramolecular Heck Reaction

Abstract

Diastereoselective double Heck cyclizations of cyclohexene diamides 1 and 3 form contiguous quaternary stereocenters, with diastereoselection being controlled by the trans diol-protecting group. In this, the first in a series of two papers, the origin of diastereoselection in the first ring closure step of these reactions is examined. Nine simplified analogues of 1 and 3 were synthesized and cyclized to discern what structural features are required to realize high diastereoselection in the first intramolecular Heck reaction. These studies show that high stereoselection (>20:1) does not arise from a single structural feature: it is seen only in substrates that contain both a trans acetonide and a tertiary amide substituent at C2. Two subtle factors appear to be involved: (1) Avoidance of eclipsing interactions between the forming C–C bond and the pseudoaxial hydrogen atom at C6, and between the pseudoequatorial hydrogen atom at C6 and the carbonyl carbon of the forming spirooxindole; (2) The vinylic amide substituent that is not involved in the insertion event, preferentially adopts a perpendicular conformation placing the sterically bulky NR₂ over the alkene π-bond. Syn-pentane-like interactions between this substituent and C3 of the cyclohexene are avoided in the favored insertion topography. These two effects, when combined, produce a highly diastereoselective process.

Introduction

Diastereoselective Heck cyclizations that form spirocyclic products without the use of chiral additives are rare.¹ In the context of total syntheses of meso- and (−)-chimonanthine, this research group described recently the diastereoselective sequential double Heck cyclization of C₂-symmetric diiodides 1a and 3a to provide spirocyclic dioxindoles 2 and 4 (Scheme 1).² These cyclizations are exceptional in their ability to establish vicinal quaternary carbon stereocenters by a catalytic reaction.^3,4 Remarkably, the relative configuration of the products was dependent upon the group used to protect the trans diol, a functional group that is remote from the site of the Heck cyclizations. In the case of acetonide-protected diiodide 1a, dioxindole 2 having a trans relationship of its spirooxindole fragments was formed in 90% yield as a single diastereoisomer. On the other hand, cyclization of trans disiloxy substrate 3a produced preferentially dioxindole 4 (isolated in 64% yield) having a cis relationship of its spirooxindole units; additional minor products were observed in the unpurified reaction mixture formed upon cyclization of 3a.² Although not disclosed previously, the related ditriflate substrates 1b and 3b provided nearly identical product mixtures when cyclized under the same conditions.⁵

SCHEME 1^a.

^a Key: (a) 20 mol% Pd(PPh₃)₂Cl₂, 10 equiv Et₃N, N,N-dimethylacetamide (DMA), 100 °C, 24 h.

The cyclization reactions described in Scheme 1 are unique in terms of their diastereoselectivity, the role played by the diol protecting groups, and their ability to construct contiguous quaternary carbon stereocenters. Thus, we sought to better understand these transformations. We chose to pursue this objective by synthesis and subsequent Heck cyclization of simplified analogues of 1 and 3, hoping to discern the structural features required to realize high diastereoselection. In this paper we disclose our investigations of the factors controlling stereoselection in the first cyclization event. These studies show that the origin of diastereoselection in these systems is subtle, resulting from several cooperative factors. In the following paper, we describe related studies directed at understanding the second ring closure event in the sequential double Heck cyclizations of 1 and 3.⁶

Results

Diastereoselection in the Cyclization of Disiloxy Substrates 3

We began our study by more thoroughly defining the product mixture produced upon cyclization of disiloxy substrate 3. Unlike acetonide 1, which cyclizes to provide a single product (as determined by NMR analysis), precursor 3 provides a mixture of products upon Heck cyclization. One epimer of dioxindole 4 (isolated in 64% yield) was the major product reported from cyclization of diiodide 3a; the configuration of the allylic siloxy substituent in this product was not determined at the time of the previous report.² In addition, minor products formed alongside 4 were not characterized in our earlier study.² At the time the present study began, aryltriflates had emerged in our laboratories as preferred substrates in Heck cyclization routes to synthesize pyrrolidinoindoline alkaloids.⁵ Therefore, we elected to study in detail the Heck cyclization of disiloxy ditriflate 3b.

Heck cyclization substrates 1b and 3b are available in only a few synthetic steps (Scheme 2). Amination of diacyl dichloride 5 with N-benzyl-2-(triethylsiloxy)aniline (6) provided the corresponding diamide. Installation of the triflate groups was accomplished in two routine steps to provide 7 in 65% overall yield. The disubstituted alkene then was converted to the corresponding trans diol by reaction with m-chloroperbenzoic acid (m-CPBA), followed by acid hydrolysis of the resultant epoxide. Treatment of this diol with 2,2-dimethoxypropane (2,2-DMP) and catalytic camphorsulfonic acid (CSA) in acetone provided the acetonide ditriflate 1b in 74% yield over three steps. Alternatively, protection of the diol by reaction with excess TBDMSOTf in the presence of 2,6-lutidine provided disiloxy ditriflate 3b in 76% yield over three steps.

SCHEME 2^a.

^a Key: (a) 6, 2,6-lutidine, Et₂O; (b) TBAF; (c) PhNTf₂, Cs₂CO₃; (d) m-CPBA; (e) cat. TFA, H₂O, 80 °C; (f) 2,2-DMP, CSA; (g) TBDMSOTf, 2,6-lutidine.

Cyclizations of acetonide ditriflate 1b and disiloxy ditriflate 3b were investigated using the reaction conditions summarized in Scheme 1. Similar to diiodide 1a, acetonide-protected ditriflate 1b underwent double Heck cyclization cleanly to provide trans dioxindole 2 in 87% yield as the single detectable product (by ¹H NMR analysis). In contrast, subjection of disiloxy ditriflate 3b to the same conditions resulted in a more complex mixture of products. Analysis of this mixture by ¹H NMR showed that it was similar to that obtained in the cyclization of disiloxy diiodide 3a.⁷ Purification of the crude reaction product by column chromatography provided 4 in 56% yield, together with shunt reduction product 10 (10% yield), and a 10% yield of an equimolar mixture of two additional products 11 and 12.

The relative configuration of the major product 4 was rigorously defined. After extensive efforts, we found that diffusion of n-hexane into a solution of dioxindole 4 in ca. 3:1 Et₂O–EtOAc resulted in crystals suitable for X-ray diffraction analysis. This study, although unable to provide exact metric data because of disorder in the silyl groups, clearly demonstrated the all-cis relationship of the aryl fragments of the spirooxindoles and the allylic siloxy substituent.⁸

Structures of the minor products formed upon Heck cyclization of 3b were determined as follows. The relative configuration of shunt reduction product 10 was assigned by comparison of its ¹H NMR spectrum with those of related compounds of established configuration (see below). Although attempts to separate the two additional products led only to their decomposition, the relative configurations of 11 and 12 could be assigned by comparison of the ¹H NMR spectrum of a mixture of these compounds to ¹H NMR spectra of authentic samples of each material.⁹ Each of these products has a trans relationship of its spirooxindole groups. C₂-symmetric 11 arises from a cyclization process terminated by reduction, a transformation that is discussed further in the accompanying article.

The ratio of products 4:10:11:12 (65:11:11:13, determined by ¹H NMR analysis of the crude cyclization product mixture) generated from Heck cyclization of 3b suggests that the first spirocyclization in the disiloxy series occurred with moderate diastereoselection, generating an approximate 86:14 mixture of mono-cyclization products 8 and 9. Intermediate 8 then partitions to pentacyclic products 4 and 11 and shunt product 10, whereas intermediate triflate 9 cyclizes to provide pentacyclic product 12.

Synthesis of Model Substrates

To study the origins of diastereoselection in the first spirocyclization step, a number of monoaryl triflates were synthesized and studied. These model compounds contained various structural features of the C₂-symmetric substrates 1 and 3. Cyclization of these model substrates was then undertaken to study the consequence of each substructure on diastereoselection of the first Heck cyclization.

To begin, mono triflates 16a and 16b, in which the cyclohexene double bond is trisubstituted, were prepared. Cyclohexadienoic acid 13¹⁰ was coupled to aniline 6 using 2-chloro-1-methylpyridinium iodide (Mukaiyama's salt)¹¹ to provide the corresponding anilide (Scheme 4). The triethylsilyl protecting group was removed, and the triflate was installed to provide diene 14. The disubstituted alkene was then converted to trans diol 15,¹² which was in turn protected as either an acetonide or a disilyl derivative giving substrate 16a or 16b.

SCHEME 4^a.

^a Key: (a) 6, Mukaiyama's salt, 2,4,6-collidine, PhMe, 80 °C; (b) K₂CO₃, H₂O; (c) PhNTf₂, Cs₂CO₃; (d) m-CPBA; (e) cat. TFA, H₂O, 80 °C; (f) 2,2-DMP, CSA; (g) TBDMSOTf, 2,6-lutidine.

Methyl ester congeners 20a and 20b were prepared in a similar fashion. Low temperature addition of methoxide to anhydride 17¹³ provided the corresponding methyl ester (Scheme 5).¹⁴ This mono acid was converted to the corresponding anilide by in situ formation of the acid chloride and subsequent coupling of this intermediate with aniline 6.^15,16 The resultant aryl silyl ether was then converted directly to triflate 18 in 59% overall yield from anhydride 17 by treatment with CsF and PhNTf₂. The syntheses of esters 20a and 20b were completed by installation of the trans ether functionalities, using a sequence similar to the one described previously.

SCHEME 5^a.

^a Key: (a) NaOMe/MeOH, −78 °C; (b) (COCl)₂, CH₂Cl₂, then 6, 2,6-lutidine, Et₂O; (c) PhNTf₂, CsF; (d) m-CPBA; (e) cat. TFA, H₂O, 80 °C; (f) 2,2-DMP, CSA; (g) TBDMSOTf, 2,6-lutidine.

We wished also to study substrates such as 23 having amide substituents at C2. Initially, we hoped to access these materials from esters 20a or 20b. Unfortunately, all attempts to carry out these transformations failed. For example, as shown in Figure 1, we were unable to hydrolyze ester 21 to give acid 22 using a variety of reagents (LiOH, KOTMS, etc.). We believe that cleavage of the ester occurred smoothly, but the resultant carboxylate engaged the C7 anilide, ejecting N-benzylaniline and providing a pathway for further decomposition.

FIGURE 1.

Failed strategy for preparing diamide 23.

As earlier studies had shown that metal mediated methods¹⁷ for the direct conversion of esters to tertiary ortho-alkoxyanilides were not effective in these systems,¹⁸ an alternative route to the diamide substrates was devised. This sequence, which installed both acylamino groups prior to formation of the cyclohexene ring, is shown in Scheme 6. Lithiation of propiolic acid anilide 24a,¹⁹ followed by quenching with CO₂ provided the corresponding acid. Subsequent coupling of this acid with N-benzyl-2-(tert-butyldimethylsiloxy)aniline (25) promoted by 1-ethyl-3-(3'-dimethylaminopropyl)carbodiimide hydrochloride (EDCI) resulted in the formation of dianilide 26a.²⁰ Attempts to carry out the cycloaddition of 26a and 1,3-butadiene thermally were not successful. At 150 °C Diels–Alder products were observed, but extensive polymerization of 1,3-butadiene at this temperature made the reaction impractical. After screening several Lewis acids, the desired cyclohexadiene was obtained in high yield by the reaction of 26a and 1,3-butadiene at room temperature in the presence of excess EtAlCl₂.²¹ The cyclohexadiene product was converted easily to triflate 27a. Acetonide 29a and disilyl ether 29b then were obtained by processing triflate 27a by a standard sequence of steps. Beginning with N,N-dimethylpropynamide (24b), the preparation of dimethyl amide 29c proceeded in similar fashion to that of anilides 29a and 29b.²²

SCHEME 6^a.

^a Key: (a) n-BuLi or LiHMDS, then CO₂, −78 °C; (b) EDCI, 25; (c) 1,3-butadiene, EtAlCl₂, 2,6-di-tert-butyl-4-methylpyridine (DTBMP), PhMe, rt, 48 h; (d) PhNTf₂, CsF; (e) m-CPBA; (f) cat. TFA, H₂O, 80 °C; (h) 2,2-DMP, CSA; (i) TBDMSOTf, 2,6-lutidine.

Two additional substrates lacking oxidation at C4 and C5 were synthesized also (Scheme 7). tert-Butyl-substituted substrate 31 was assembled in two steps from the known triflate 30.²³ In the first step, the anilide was constructed by palladium-catalyzed carbonylation of 30 in the presence of aniline 25.²⁴ The TBDMS group was then exchanged for triflate by reaction with CsF, Cs₂CO₃ and PhNTf₂ to provide 31 in 66% overall yield. Octalin 33, and its double bond isomer 34, were prepared in 56% combined yield by a similar two-step sequence from the known mixture of alkene isomers of triflate 32,²⁵ and were separated by preparative HPLC.

SCHEME 7^a.

^a Key: (a) 5–10 mol% Pd(PPh₃)₂Cl₂, 25, CO (1 atm), Bu₃N, 100 °C; (b) PhNTf₂, CsF, Cs₂CO₃.

Heck Cyclizations

Intramolecular Heck reactions of model substrates were carried out in identical fashion [20 mol% Pd(PPh₃)₂Cl₂, 10 equiv of Et₃N, DMA, 100 °C, 24 h], with product ratios being determined by analysis of the ¹H NMR spectra of unpurified reaction products. We began by studying the cyclization of acetonide diamide 29a and disiloxy diamide 29b, substrates that contain the dianilide framework of the C₂-symmetric double Heck precursors 1 and 3, but lack one triflate functional group. Similar to its C₂-symmetric counter part, acetonide-protected substrate 29a cyclized to provide spirooxindole 35 as a single detectable isomer (96% yield). The relative configuration of this product was determined by observation of a 4% NOE for the aromatic hydrogen atom at C12 upon irradiation of the methine hydrogen atom at C5.⁸ On the other hand, cyclization of disiloxy analogue 29b provided a mixture of three products. The two major products, spirooxindoles 10 and 36, were formed in a 2:1 ratio. These products differ in relative configuration at their spiro stereocenters as determined by comparison of ¹H NMR spectra of these materials with those of the two products produced upon cyclization of disiloxy congener 16b (vide infra), with the signals for the C6 hydrogen atoms being particularly diagnostic. The relative configuration of the enoxysilane 37 was assigned by observation of a series of NOE enhancements, including a 1.7% enhancement for the C2 methine hydrogen atom upon irradiation of the pseudoaxial hydrogen atom at C6 and a 1.8% enhancement for the C12 hydrogen atom upon irradiation of the C2 methine hydrogen atom.⁸ Presumably, enoxysilane 37 arose from the palladium hydride complex of the major Heck product 10 by double bond migration. Thus, the overall diastereoselectivity of the Heck cyclization of disiloxy mono triflate 29b was 72:28, favoring formation of the spirooxindole isomer having the aryl fragment cis to the C5 siloxy substituent.

Results obtained from cyclizations of aryl triflate substrates 16a and 16b, which have no substituent at C2, are summarized in Scheme 9. Cyclization of acetonide precursor 16a gave rise to an 80:20 mixture of epimeric spirooxindoles 38 and 39. Conversely, cyclization of the disiloxy congener 16b occurred with no stereoselection to give an equal mixture of epimeric spirooxindoles 40 and 41. Relative configurations of products 38–41 were established by removal of their respective protecting groups to provide the corresponding diols. The relative configuration of the diol derived from disiloxy product 41 was then determined by X-ray crystallography.⁸

SCHEME 9^a.

^a Key: (a) 20 mol% Pd(PPh₃)₂Cl₂, 10 equiv Et₃N, DMA, 100 °C, 24 h.

Substrates that lacked oxidation at C4 and C5 were studied to see if there was any intrinsic preference for forming an axial C–C bond. A small preference of this type was seen with octalin 33, which cyclized to provide a 70:24:6 mixture of spirooxindoles 42, 43 and 44 in 72% yield (Scheme 10). The relative configurations of the two major products 42 and 43, which are epimeric at the C1 spiro stereocenter, were defined by X-ray crystallographic analysis of 42.⁸ A series of NOE studies showed that the minor product 44 had the same relative configuration as 42; diagnostic signals included a 1.7% enhancement for the C12 aryl hydrogen atom and a 1.0% enhancement for the pseudoaxial C6 hydrogen atom upon irradiation of the pseudoaxial C2 hydrogen atom.

SCHEME 10^a.

^a Key: (a) 20 mol% Pd(PPh₃)₂Cl₂, 10 equiv Et₃N, DMA, 100 °C, 24 h.

Little axial preference was seen in the cyclization of the related substrate 31 in which the cyclohexene ring was anchored with a tert-butyl group. Thus, three spirooxindoles 45, 46 and 47 were formed in a ratio of 50:40:10 and 93% combined yield.²⁶ The relative configurations of epimers 45 and 46 were determined by observation of a 2.2% NOE enhancement for the C12 aryl hydrogen atom and a 2.4% NOE enhancement for the hydrogen atom at C4 upon irradiation of the pseudoaxial hydrogen atom at C6 in compound 46. This NOE correlation establishes a trans relationship between the tert-butyl group and the aryl fragment of the spirooxindole in compound 46. Alkene isomer 47 must arise by double bond isomerization; however, as the initial C4 stereocenter of substrate 31 is destroyed in this process, it is not possible to establish how 47 was formed.²⁷

As the presence of an amide substituent at C2 enhances cyclization diastereoselection in both the acetonide and disiloxy series, we investigated whether or not a simple methyl ester substituent would have a similar effect. Acetonide ester 20a cyclized with low selectivity, providing a 45:21:34 mixture of spirocyclic products 48, 49 and 50 in 86% combined yield (Scheme 11). Again the relative configuration of these products could be assigned by ¹H NMR NOE analysis. The major product 48 displayed a 4.6% NOE enhancement for the C12 aryl hydrogen atom when the C5 methine hydrogen atom was irradiated, indicative of an axial orientation of the aryl portion of the spirooxindole. Conversely, irradiation of the pseudoaxial C6 hydrogen atom of compound 49 resulted in a 4.3% enhancement for the C4 hydrogen atom, and importantly, a 1.5% enhancement for the C12 aryl hydrogen atom, confirming the pseudoequatorial disposition of the aryl fragment of the oxindole in this epimer. The aryl portion of the oxindole was also pseudoaxial in the enol ether product 50 as signaled by the observation of a 4.6% NOE enhancement of the C12 aryl hydrogen atom upon irradiation of the C5 hydrogen atom. Irradiation of the C2 methine hydrogen atom of enol ether 50 resulted in a 1.4% NOE of the pseudoaxial C6 hydrogen atom, establishing that methyl ester substituent is pseudoequatorial. Thus in the acetonide series, the overall diastereoselection in forming the spirooxindole was 79:21 favoring the product in which the aryl fragment of the oxindole is pseudoaxial. As observed with other model substrates, disiloxy congener 20b cyclized with lower diastereoselection, providing in this case a 59:41 mixture of spirooxindoles 51 and 52 in high yield. Diagnostic signals for the C6 hydrogen atoms (at approximately 2 ppm) were similar to those seen in the ¹H NMR spectra of spirooxindoles 40 and 41, thus allowing the relative configuration of products 51 and 52 to be specified.

SCHEME 11^a.

^a Key: (a) 20 mol% Pd(PPh₃)₂Cl₂, 10 equiv Et₃N, DMA, 100 °C, 24 h.

The presence of a methyl ester or N-benzylanilide substituent at C2 had quite different effects on cyclization diastereoselectivity. Thus, we examined Heck cyclization of the N,N-dimethylamide congener 29c, which in size would be more similar to the methyl ester (equation 1). Like the dianilide substrates 1b and 29a (Scheme 1 and Scheme 8), amide 29c cyclized with high stereoselectivity to provide a single spirooxindole 53, isolated in 76% yield. The observation of a 3.1% NOE for the C12 hydrogen atom upon irradiation of the C5 hydrogen atom allowed the relative configuration of 53 to be specified.

(1)

SCHEME 8^a.

^a Key: (a) 20 mol% Pd(PPh₃)₂Cl₂, 10 equiv Et₃N, DMA, 100 °C, 24 h.

Discussion

Two trends are apparent in the diastereoselective Heck cyclizations examined in the present study. First, substrates containing a trans C4,C5 acetonide undergo Heck cyclization with higher diastereoselectivity (>20–4:1; Scheme 1, Scheme 8, Scheme 9 and Scheme 11, and equation 1) than congeners having the trans C4,C5 diol protected with TBDMS groups (diastereoselectivity = 6–1:1; Scheme 3, Scheme 8, Scheme 11). In the acetonide series, the relative configuration of the spirooxindole in the major product is the same as that of the "first-formed" spirooxindole unit in the cyclization of acetonide ditriflate 1a → 2 (Scheme 1): an axial C–C bond is formed preferentially upon insertion. When modest stereoselectivity is seen in the disiloxy series, the relative configuration of the newly formed spirooxindole is the opposite: the aryl fragment of the spirooxindole is cis to the C5 siloxy substituent. Second, the presence of a tertiary amide substituent at C2 significantly enhances diastereoselection in the acetonide-protected substrates compared to substrates lacking this functionality. These two substitution effects are reinforcing; only substrates that contain both a trans C4,C5 acetonide and a C2 tertiary amide substituent (1, 29a and 29c) cyclize with high levels (>20:1) of diastereoselection.

SCHEME 3^a.

^a Key: (a) 20 mol% Pd(PPh₃)₂Cl₂, 10 equiv Et₃N, DMA, 100 °C, 30 h.

Diastereoselection in the acetonide series

Several potential models for interpreting diastereoselection are easily dismissed. First, diastereoselection in the acetonide series does not reflect the thermodynamic stability of the Heck products as the relative configuration of the spirooxindole of the major product places the larger aryl portion of the oxindole axial and the smaller carbonyl group pseudoequatorial.²⁸ Second, arguments based on the notion that syn insertion would take place preferentially to form the most stable chair conformation of the cyclohexylpalladium intermediate also are not consistent with the observed results. Because of conformational constraints, only two chair intermediates are possible in the acetonide series (Figure 2): in A, which would lead to the observed predominant stereoisomer of the Heck product, the new C–C bond is axial, whereas in B, the C–Pd bond is axial. As the R group at C2 would experience two destabilizing 1,3-diaxial interactions in intermediate A, the observation that stereoselection does not decrease as the size of the C2 substituent R increases is not consistent with this model.³⁰

FIGURE 2.

Chair conformations of the two possible products resulting from syn insertion and tabulated Heck insertion diastereoselectivity as a function of the C2 alkenyl substituent; the product resulting from intermediate A is produced predominantly.

Consideration of the transition structures for migratory insertion to the alkene faces of the acetonide substrates provides a rationale for the observed diastereoselection (Figure 3). Because of the rigid half-chair conformation of the cyclohexene, the C6 methylene hydrogen atoms are in distinct environments. The same is true for the methylene hydrogen atoms at C3. In the transition structure leading to the minor products, disfavored transition structure 54a, two major destabilizing interactions result from the C6 hydrogen atoms. First, as migratory insertion occurs to the alkene face proximate to the pseudoaxial C6 hydrogen atom, formation of the new C–C σ bond at C1 results in a developing eclipsed interaction between this new bond and the axial C6–H bond. Second, as migratory insertion occurs, C1 and C2 undergo rehybridization from sp² to sp³. As a result, the alkene substituents move away from the incoming palladium arene. In the disfavored transition structure 54a, this motion results in an eclipsing interaction between the C1–C7 σbond and the pseudoequatorial C6–H bond. These destabilizing interactions are illustrated in the modified Newman projection of the disfavored transition structure 54b.

FIGURE 3.

Representation of the two syn insertion pathways in the acetonide series. Destabilizing eclipsing interactions are avoided in insertion topography 55.

On the other hand, in the transition structure leading to the major product (55a, Figure 3), migratory insertion to the alkene face opposite the axial C6 hydrogen atom avoids eclipsing interactions between the C1 and C6 substituents (see 55b). Here, the developing eclipsing interactions are predicted to occur between the C2 and C3 substituents. One of these interactions involves the developing long Pd–C σbond and the axial C3–H bond, and the second involves the interaction of two C–H bonds. Both of these interactions should be less energetically costly than the two C–C/C–H bond interactions in 54a.

Although the energy differences imparted by these competing eclipsing interactions are not large, only small energy differences between diastereomeric transition structures are required to rationalize stereoselection in Heck cyclizations of substrates lacking amide substituents at C2.

In order to gain support for our explanation of the observed diastereoselection in the acetonide series in the absence of a C2 substituent, DFT calculations of the two competing transition states for migratory insertion were performed using a slightly simplified model structure.^31,32,33,34 As shown in Figure 4, the energies of the calculated transition states 56 and 57 predict the formation of the observed diastereomer with a calculated ΔΔG^‡_373K = 1.45 kcal/mol. This free energy difference is roughly consistent with the observed 4:1 ratio of diasteromeric products (corresponding to a ΔΔG^‡ _373K = 1.02 kcal/mol) in the cyclization of acetonide triflate 16a, which lacks a C2 substituent. In the higher energy transition state 57, the calculated dihedral angle between the pseudoequatorial C6-H bond and the C1–C7 σ bond is 6.4°. Likewise, the calculated dihedral angle between the forming C–C σ bond and the pseudoaxial C6–H bond is 14.3°. These calculations support the hypothesis that avoidance of developing eclipsing interactions in the competing transition states controls face selectivity in the Heck cyclization.

FIGURE 4.

Calculated (DFT) transition states for competing syn insertion pathways in substrates lacking the C2 amide.

As noted previously, diastereoselection is strongly dependent upon the nature of the C2 alkene substituent (summarized in Figure 2). The high diastereoselectivity observed in Heck cyclizations of acetonide triflates 29a and 29c demonstrates that the C2 anilide substituent is critical for realizing high diastereoselectivity in the sequential double Heck cyclization of acetonide ditriflates 1. The similar diastereoselectivities observed in Heck cyclizations of methyl ester 20a (Scheme 11) and trisubstituted alkene 16a (Scheme 9) demonstrate that a simple electronic effect is not the origin of the enhanced diastereoselectivity seen with substrates having C2 amide substituents.

Insight into the role of a C2 amide substituent is gained by examination of the structures of the Heck cyclization substrates obtained from X-ray crystallographic studies. Figure 5 shows the solid-state structure of methyl ester 20a and dimethyl amide 29c.³⁵ Whereas the carbomethoxy of 20a adopts a conformation in which the carbonyl and alkene π-bonds are coplanar, the acyl group of amide 29c is nearly perpendicular to the π-system of the alkene. In both structures, the triflato anilide substituent adopts a similar conformation placing the carbonyl group perpendicular to the alkene.³⁶ Molecular mechanics minimizations and dihedral driving experiments show that the favored conformations of the amide substituents results from steric interactions between the s-trans R substituent of the amide and the adjacent methylene fragment of the cyclohexene ring (see 59, Figure 6). This interaction destabilizes the conjugated conformation by about 5.5 kcal/mol.⁸ No analogous destabilizing steric interaction is present in the coplanar conformation of the s-trans methyl ester (see 58, Figure 6). The favored perpendicular conformation of the amide places the steric bulk of the NR₂ fragment either above or below the alkene π-bond.

FIGURE 5.

ORTEP representation of the X-ray model of methyl ester 20a and dimethyl amide 29c.

FIGURE 6.

Coplanar conformations of cyclization substrates having a methyl ester or tertiary amide substituent at the C2 vinylic carbon showing the destabilizing steric interactions present in the latter.

Although not shown in Figure 5, X-ray crystallographic studies suggest that the C2 amide substituents could adopt either of the two possible perpendicular conformations with respect to the C1–C2 alkene during the insertion step (Figure 7).³⁵ The steric bulk of the s-trans nitrogen substituent in these conformations would shield approach to the alkene face that is proximal to the NR₂ group. Thus, favored conformations for migratory insertion would be 60 and 61 in which the organometallic fragment approaches the alkene from the face of the carbonyl group of the C2 amide substituent.³⁷

FIGURE 7.

Representation of the four syn insertion pathways in the acetonide series for substrates having a perpendicularly oriented amide substituent at C2. Destabilizing steric interactions between the cis amide substituent and the arylpalladium fragment are avoided in insertion topographies 60 and 61.

Further analysis of potential transition structures 60 and 61 provides a reasonable explanation for the role of the C2 amide substituent in augmenting face diastereoselectivity of the insertion step. As migratory insertion involves the rehybridization of the alkene carbons to sp³, the original alkene substituents would be deflected away from the incoming palladium arene fragments in transition structures 60 and 61 (depicted in more detail in Figure 8).³⁸ Of these two possible insertion topographies, 61 would experience a developing syn-pentane-like steric interaction between the s-trans substituent of the amide and the pseudo-axial hydrogen atom at C3. This destabilizing interaction is avoided in the favored diastereomeric transition structure 60.^39,40

FIGURE 8.

More detailed representation of syn insertion topographies 60 and 61. Syn-pentane-like interactions between the cis amide substituent and C3 of the cyclohexene are avoided in the favored insertion topography 60.

Again, in order to further explore the role played by the C2 amide, we undertook a DFT study of the two completing transition states for migratory insertion in a substrate that contained the C2 dimethyl amide.^31,32,33 Although multiple rotatmers of the C2 amide were investigated computationally, structures 62 and 63 were the only transition states located (Figure 9). As predicted, the calculated transition states place the bulky NR₂ group over the cyclohexene ring in order to avoid steric interactions of this group with the palladium atom and its ligands and the C3 methylene. These calculations largely confirm the model for increased diastereoselection by the C2 amide advanced above. The lower energy transition state 62 leads to the observed diastereomer of the cyclization product. The calculated ΔΔG^‡_373K value (2.16 kcal/mol) corresponds to higher calculated diastereoselection than in the cases lacking the C2 amide substituent. As predicted, in the higher energy transition state 63 the s-trans methyl group of the dimethyl amide is forced into close proximity (2.4 Å) to the axial hydrogen atoms at C3. There is also a close contact (2.5 Å) between this methyl group and the C5 hydrogen atom. Evidently, this interaction with the C3 hydrogen atom is sufficiently severe to cause rotation of the amide group towards C5. On the other hand, in the lower energy transition state 62, the s-trans methyl group of the C2 amide abuts the hydrogen atom at C4 with a H–H distance of 2.2 Å. Although this latter interaction is the closest contact calculated in either pathway, it appears the energetic cost is less severe than the sum of the two interactions in the opposing diastereomeric transition state. When these steric interactions are combined with the eclipsing interactions also present in the transition state (vide infra), a highly diastereoselective transformation results.

FIGURE 9.

Calculated (DFT) transition states for competing syn insertion pathways in substrates containing the C2 amide.

Diastereoselection in the disiloxy series

As expected from the stereoselectivity of the double Heck cyclization of the C₂-symmetric disiloxy ditriflate 3b, little diastereoselection was observed in the Heck cyclizations of model disiloxy substrates. Of these substrates, disiloxy diamide 29b having the dianilide framework of 3b but lacking one triflate functional group, cyclized with highest diastereoselectivity provided a 2.6:1 mixture of diastereomeric products. In this case, as in the cyclization of C₂-symmetric disiloxy ditriflate 3b, the sense of diastereoselection is opposite to that seen in the acetonide series. Because of the low levels of diastereoselection observed in the disiloxy series, ΔΔG^‡ = 0.7 kcal/mol in the case of Heck cyclization of 29b, and the fact that these substrates are not conformationally fixed, no convincing rationalization can be provided.⁴¹

Conclusion

The intramolecular Heck reaction remains among the most powerful reactions available for assembling complex polycyclic organic compounds, particularly those that contain congested all-carbon quaternary stereocenters. This study investigated the origin of stereoselectivity in the first ring-closing event in sequential Heck cyclizations of C₂-symmetric ditriflates 1b and 3b that construct complex hexacyclic products containing vicinal all-carbon quaternary stereocenters. The former substrate, in which the trans C3,C4 diol is masked as an acetonide, undergoes a remarkably stereoselective transformation to provide hexacyclic product 2 in nearly quantitative yield. By examining diastereoselection in Heck cyclizations of simpler congeners in the acetonide series, and by consideration of both computational and crystallographic models, we established that the high diastereoselectivity of the first cyclization step (likely >20:1) derives from two subtle factors: (1) Avoidance of eclipsing interactions between the forming C–C bond and the pseudoaxial hydrogen atom at C6 and between the pseudoequatorial hydrogen atom at C6 and the carbonyl carbon of the forming spirooxindole leads to a moderate preference for insertion from the alkene face proximate to the pseudoequatorial hydrogen atom at C6. (2) The vinylic amide substituent that is not involved in the insertion event, preferentially adopts a perpendicular conformation placing the sterically bulky NR₂ over the alkene π-bond. Syn-pentane-like interactions between this substituent and C3 of the cyclohexene are avoided in the favored insertion topography. These two effects, when combined, produce a highly diastereoselective process.

In contrast, substrates in which the trans C3,C4 diol is protected with TBDMS groups cyclize with much lower levels of diastereoselection. In the following paper, studies directed at understanding the second ring closure event in sequential double Heck cyclizations of 1 and 3 are described.⁶

Experimental Section⁴²

General Procedure for Heck Reactions

In a glovebox under a nitrogen atmosphere the triflate substrate, Pd(PPh₃)₂Cl₂, Et₃N and DMA were combined in a base-washed, glass vial containing a magnetic stir bar. The vial was sealed with a Teflon-lined cap and placed in a 100 °C aluminum heating-block (bored to the diameter of the vial) atop a magnetic stir plate. The reaction was maintained with stirring for 24 h during which time the initial yellow suspension became a deep red, homogenous solution. On occasion, precipitous Pd-black was observed toward the end of the reaction. At the end of the indicated time, the reaction was cooled to room temperature, removed from the glovebox, opened to the atmosphere and diluted with Et₂O. The resultant solution was washed with water twice and once with brine, dried over MgSO₄ and concentrated in vacuo. ¹H NMR analysis of the crude reaction mixture was then used to determine the diastereomeric ratio of the products formed.

Heck Cyclization of Ditriflate 1b

According to the general procedure, triflate 1b (313 mg, 360 µmol), Pd(PPh₃)₂Cl₂ (101 mg, 144 µmol), Et₃N (546 mg, 0.75 mL, 540 mmol) and DMA (4.7 mL) were heated to give dioxindole 2 as a single detectable isomer. Column chromatography (80:20 hexanes–EtOAc) provided 180 mg (87%) of dioxindole 2 as a colorless solid. Data for 2 matched that previously reported.²

Heck Cyclization of Ditriflate 3b

Using a modification of general procedure, triflate 3b (196 mg, 185 µmol), Pd(PPh₃)₂Cl₂ (26.9 mg, 37.0 µmol), Et₃N (188 mg, 0.26 mL, 1.85 mmol) and DMA (1.9 mL) were heated for 30 h to give an approximate 65:11:11:13 mixture of 4, 10, 11 and 12. Due to the complexity of the spectrum, precise integrations of the species present was not possible. Column chromatography (90:10 to 70:30 hexanes–Et₂O) allowed for isolation of 78.5 mg (56%) of 4 as a colorless oil, 13.3 mg (10%) 10 as an off-white solid and 14.8 mg (10%) of an inseparable, approximate equimolar mixture of 11 and 12 as a white solid. Pure samples of 11 and 12 were independently prepared and characterized, see accompanying article.⁶ Slow diffusion of hexanes into a EtOAc–Et₂O solution of 4 provided crystals suitable for X-ray crystallographic analysis.

Data for 4: IR (film) 2954, 2929, 2858, 1719, 1652, 1611, 1360 1250, 1171 cm⁻¹; ¹H NMR (500 MHz, C₆D₆, rt) δ 8.43 (bs, 1H), 7.29 (bs, 2H), 7.05 (bs, 2H), 6.82–6.70 (m, 7H), 6.76 (bs, 1H), 6.15–6.43 (m, 5H), 4.93–5.10 (m, 3H), 4.64–4.80 (m, 2H), 4.26 (bs, 1H), 3.80 (bd, J = 15.0 Hz, 1H), 2.01 (bd, J = 13.0 Hz, 1H), 1.02 (s, 9H), 0.89 (s, 9H), 0.15–0.25 (m, 9H), −0.14 (bs, 3H); ¹³C NMR (125 MHz, C₆D₆, rt) δ 177.1, 176.4, 156.5, 144.6, 143.7, 137.2, 136.3, 131.3, 130.6, 130.1, 129.3, 129.2, 129.1, 129.0, 128.7, 127.7, 127.4, 126.8, 125.9, 122.2, 121.8, 109.7, 109.4, 106.4, 67.1, 55.1, 52.0, 45.0, 43.7, 37.2, 26.6, 26.4, 19.1, 18.5, −3.3, −3.4, −3.9, −4.2; LRMS (ESI) m/z 757.73 (M+H)⁺, 779.7 (M+Na)⁺; HRMS (ESI) m/z calcd for C₄₆H₅₆N₂O₄Si₂ 779.3676 (M+Na)⁺; found: 779.3684. The ¹H NMR spectrum was also recorded in d₈-toluene at 100 °C and CDCl₃ at room temperature, see Supporting Information for details.

Data for 10: IR (film) 2930, 2856, 1714, 1629, 1100 cm⁻¹; ¹H NMR (500 MHz, C₆D₆) δ 7.37 (d, J = 7.5 Hz, 2H). 7.13–7.16 (m, 2H), 6.86–7.07 (m, 10H), 6.84–6.80 (m, 2H), 6.70–6.75 (m, 2H) 6.57 (d, J = 7.8 Hz, 1H), 5.88 (d, J = 1.8 Hz 1H), 5.27 (d, J = 16.0 Hz, 1H), 5.13 (d, J = 14.8 Hz, 1H), 5.07 (ddd, J = 11.4, 7.7, 3.6 Hz, 1H), 4.57 (d, J = 15.7 Hz, 1H), 4.14 (d, J = 14.8 Hz, 1H), 4.04 (dd, J = 7.7, 1.7 Hz, 1H), 2.06 (dd, J = 13.7, 3.7 Hz, 1H) 1.94 (t, J = 11.8 Hz, 1H), 0.96 (s, 18H), 0.19 (s, 3H), 0.18 (s, 3H), 0.12 (s, 3H), −0.11 (s, 3H); ¹³C NMR (125 MHz, C₆D₆) δ 178.5, 167.2, 145.1, 144.4, 143.2, 138.3, 137.7, 133.1, 129.8, 129.2, 129.0, 128.9, 128.8, 128.72, 128.68, 128.1, 127.8, 127.6, 127.5, 123.4, 121.9, 110.0, 74.1, 69.2, 54.4, 53.3, 44.8, 41.2, 26.68, 26.66, 18.7, 18.4, −3.46, −3.49, −4.2 (b); LRMS (ESI) m/z 759.59 (M+H)⁺, 781.58 (M+Na)⁺; HRMS (ESI) Calcd for C₄₆H₅₈N₂O₄Si₂ m/z 781.3833 (M+Na)⁺; found: 781.3857.

Heck Cyclization of Triflate 29a

According to the general procedure, triflate 29a (104 mg, 184 µmol), Pd(PPh₃)₂Cl₂ (20.3 mg, 29.0 µmol), Et₃N (146 mg, 0.20 mL, 1.46 mmol) and DMA (1.5 mL) were heated to give spirooxindole 35 as a single detectable isomer. Column chromatography (50:50 hexanes–Et₂O) provided 79.3 mg (96%) of 35 as a colorless oil: IR (film) 3035, 2985, 1717, 1646, 1613, 1495, 1227 1073 cm⁻¹; ¹H NMR (500 MHz, C₆D₆) δ 7.39 (d, J = 7.4 Hz, 2H), 7.10–7.14 (m, 5H), 6.78–7.04 (m, 11H), 6.56 (d, J = 7.6 Hz, 1H), 6.22 (d, J = 1.2 Hz, 1H), 5.03 (d, J = 14.7 Hz, 1H), 4.96 (d, J = 16.1 Hz, 1H), 4.87 (d, J = 16.1 Hz, 1H), 4.37 (dd, J = 8.3, 1.7 Hz, 1H), 4.31 (d, J = 14.7 Hz, 1H), 3.90 (ddd, J = 12.6, 8.3, 4.1 Hz, 1H), 2.69 (t, J = 12.1 Hz, 1H), 2.18 (dd, J = 11.9, 4.1 Hz, 1H), 1.29 (s, 3H), 1.27 (s, 3H); ¹³C NMR (125 MHz, C₆D₆) δ 179.0, 166.8, 144.3, 144.2, 138.2, 137.7, 137.1, 135.4, 133.8, 129.5, 129.2, 128.9, 128.84, 128.81, 128.76, 128.0, 127.8, 127.64, 127.60; 123.6, 122.2, 112.5, 110.2, 78.2, 75.7, 54.8, 54.4, 45.0, 37.9, 27.3, 27.1; LRMS (ESI) m/z 571.28 (M+H)⁺, 593.27 (M+Na)⁺; HRMS (ESI) Calcd for C₃₇H₃₄N₂O₄ m/z 593.2416 (M+Na)⁺; found: 593.2412.

Heck Cyclization of Triflate 29b

According to the general procedure, triflate 29b (280 mg, 0.308 mmol), Pd(PPh₃)₂Cl₂ (43.2 mg, 55.6 µmol), Et₃N (310 mg, 0.43 mL, 3.08 mmol) and DMA (3.1 mL) were heated to give a 60:28:12 mixture of spirooxindoles 10, 36 and 37. Column chromatography (90:10 hexanes–EtOAc) allowed for partial separation of the isomers giving a combined yield of 470 mg (73%) of the mixture of isomers. Preparative HPLC (95:4.5:0.5 hexanes–EtOAc–Et₃N, 30 mL/min, 300 × 50 mm, 5 µm silica gel column) provided analytically pure samples of 10, 36 and 37 each as colorless oils. Data for 10 matched that reported above.

Data for 36: IR (film) 2930, 2856, 1710, 1633, 1104 cm⁻¹; ¹H NMR (500 MHz, C₆D₆) δ 7.46 (bs, 1H), 7.34–7.40 (m, 3H), 7.13–7.16 (m, 3H), 7.10 (t, J = 7.8 Hz, 2H), 6.95–7.02 (m, 5H), 6.87–6.92 (m, 2H), 6.77–6.84 (m, 2H) 6.48 (d, J = 7.7 Hz, 1H), 5.01 (d, J = 2.5 Hz 1H), 5.03–5.13 (m, 2H), 4.52–4.61 (m, 2H), 4.46 (ddd, J = 11.8, 7.4, 3.7 Hz, 1H), 4.18 (dd, J = 7.5, 2.5 Hz, 1H), 2.67 (t, J = 12.5 Hz, 1H), 1.95 (dd, J = 12.6, 3.7 Hz, 1H), 0.97 (s, 9H), 0.84 (s, 9H), 0.09 (s, 6H), −0.13 (s, 3H), −0.15 (s, 3H); ¹³C NMR (125 MHz, C₆D₆) δ179.4, 168.2, 145.3, 143.2, 143.0, 138.2, 136.7, 135.6, 132.6, 129.8, 129.3, 128.9, 128.7, 128.4, 127.8, 127.6 (b), 123.7, 122.5, 110.4, 74.8, 71.0, 54.7, 54.2, 44.2, 42.5, 26.7, 26.4, 18.6, 18.4, −3.4, −3.7, −4.2, −4.3; LRMS (ESI) m/z 759.61 (M+H)⁺, 781.60 (M+Na)⁺; HRMS (ESI) Calcd for C₄₆H₅₈N₂O₄Si₂ m/z 759.4014 (M+H)⁺; found: 759.3994.

Data for 37: IR (film) 2930, 2856, 1718, 1664, 1613, 1494, 1085 cm⁻¹; ¹H NMR (500 MHz, C₆D₆) δ 7.38 (d, J = 7.4 Hz, 2H), 7.09 (t, J = 7.5 Hz, 2H), 6.97–7.03 (m, 4H), 6.85–9.95 (m, 4H), 6.76–6.84 (m, 6H), 6.50 (d, J = 7.8 Hz, 1H), 5.24–5.28 (m, 1H), 5.11 (d, J = 2.0 Hz, 1H), 4.93 (d, J = 15.9 Hz, 1H), 4.87 (d, J = 15.9 Hz, 1H), 4.62 (d, J = 15.9 Hz, 1H), 4.56 (d, J = 15.9 Hz, 1H), 4.18 (t, J = 2.3 Hz, 1H), 2.34 (dd, J = 13.4, 6.7 Hz, 1H), 2.17 (dd, J = 13.5, 8.8 Hz, 1H), 1.12 (s, 9H), 0.91 (s, 9H), 0.41 (s, 3H), 0.40 (s, 3H), 0.10 (s, 3H), 0.01 (s, 3H); ¹³C NMR (125 MHz, C₆D₆) δ 178.1, 170.8, 154.2, 144.4, 143.1, 138.7, 137.7, 132.7, 130.0, 129.1 (b), 129.0 (b), 128.8, 128.7, 127.7, 122.8,121.8, 109.6, 101.6, 68.0, 53.7, 50.2, 48.6, 44.4, 42.3, 26.9, 26.5, 19.3, 26.5, 19.3, 18.7, −3.1, −3.2, −3.7, −4.1; LRMS (ESI) m/z 759.59 (M+H)⁺, 781.58 (M+Na)⁺; HRMS (ESI) Calcd for C₄₆H₅₈N₂O₄Si₂ m/z 781.3833 (M+Na)⁺; found: 781.3849.

Heck Cyclization of Triflate 16a

According to the general procedure, triflate 16a (109 mg, 0.213 mmol), Pd(PPh₃)₂Cl₂ (29.9 mg, 42.6 µmol), Et₃N (0.22 mL) and DMA (1.5 mL) were heated to give a 80:20 mixture of diastereomers 38 and 39. Purification by column chromatography (90:10 hexanes-acetone) afforded 65.0 mg (84%) of 38 and 39 as an inseparable mixture. Spiroxindoles 38 and 39 were characterized as the corresponding diols upon removal of the acetonides, see supporting information for details.

Heck Cyclization of Triflate 16b

According to the general procedure, triflate 16b (1.24 g, 1.77 mmol), Pd(PPh₃)₂Cl₂ (250 mg, 0.355 mmol), Et₃N (1.35g, 13.3 mmol, 1.85 mL) and DMA (10 mL) were heated to give a 50:50 mixture of diastereomers 40 and 41. Column chromatography (90:10 hexanes-Et₂O) afforded 940 mg (96%) of a mixture 40 and 41. Further chromatography by MPLC partially separated these diastereomers, yielding 350 mg of 40 and 400 mg of 41, which were diastereomerically pure by ¹H NMR analysis.

Data for 40: IR (film) 2928, 2856, 1715, 1098, 832 cm⁻¹; ¹H NMR (500 MHz, CDCl₃) δ 7.31–7.37 (m, 5H), 7.21–7.24 (m, 2H), 7.08 (td, J = 7.8, 1.0 Hz, 1H), 6.80 (d, J = 7.6 Hz, 1H), 5.94 (dd, J = 9.8. 1.9 Hz, 1H), 5.29 (dt, J = 8.0, 1.9 Hz, 1H), 5.06 (d, J = 15.5 Hz, 1H), 4.84 (d, J = 15.5 Hz, 1H), 4.64–4.66 (m, 1H), 4.31 (dt, J = 7.2, 2.0, 1H), 2.00–2.08 (m, 2H), 1.02 (s, 9H), 0.95 (s, 9H), 0.23 (s, 3H), 0.22 (s, 3H), 0.20 (s, 3H), 0.18 (s, 3H); ¹³C NMR (125 MHz, CDCl₃) δ 178.1, 142.1, 136.0, 135.6, 133.3, 128.8, 128.3, 127.6, 127.3, 125.5, 123.7, 122.8, 108.9, 73.2, 69.8, 51.7, 43.7, 39.4, 26.0 (b), 18.1, 18.0, −4.1 (b), −4.6, −4.8; LRMS (ESI) m/z 550.29 (M+H)⁺, 572.27 (M+Na)⁺; HRMS (ESI) Calcd for C₃₂H₄₇NO₃Si₂ m/z 572.2992 (M+H)⁺. Found: 572.2985.

Data for 41: IR (film) 2928, 2856, 1719, 1610, 1100, 836 cm⁻¹; ¹H NMR (500 MHz, CDCl₃) δ 7.26–7.36 (m, 6H), 7.21 (td, J = 7.8, 1.2 Hz, 1H), 7.18 (td, J = 7.6, 1.0 Hz, 1H), 6.78 (d, J = 7.8 Hz, 1H), 5.89 (dd, J = 9.9, 1.7 Hz, 1H), 5.25 (dt, J = 9.8, 1.9 Hz, 1H), 5.03 (d, J = 15.7 Hz, 1H), 4.89 (d, J = 15.7 Hz, 1H), 2.80 (dt, J = 7.6, 1.9, 1H), 4.12–4.17 (m, 1H), 2.37 (t, J = 12.5, 1H), 1.76–1.82 (m, 1H), 1.00 (s, 9H), 0.88 (s, 9H), 0.21 (s, 3H), 0.19 (s, 3H), 0.12 (s, 3H), −0.01 (s, 3H); ¹³C NMR (125 MHz, CDCl₃) δ 178.7, 141.7, 135.8, 135.3, 133.2, 128.8, 128.3, 127.7, 127.2, 124.8, 124.2, 122.7, 109.3, 73.3, 71.2, 52.6, 43.9, 39.0, 26.0, 25.9, 18.2, 17.9, 18.2, 17.9, −39, −4.0, −4.7 (b); LRMS (ESI) m/z 550.29 (M+H)⁺, 572.28 (M+Na)⁺; HRMS (ESI) Calcd for C₃₂H₄₇NO₃Si₂ m/z 572.2992 (M+H)⁺. Found: 572.2998.

Heck Cyclization of Triflate 33

According to the general procedure, triflate 33 (142 mg, 288 µmol), Pd(PPh₃)₂Cl₂ (40.3 mg, 58.1 µmol), Et₃N (290 mg, 0.40 mL, 2.87 mmol) and DMA (2.8 mL) were heated to give a 70:24:6 mixture of isomers 42, 43 and 44 for an overall diastereoselection of 70:30. Column chromatography (93:7 hexanes–Et₂O) allowed for isolation of 56.1 mg (57%) of 42 as a colorless solid and 15.1 mg (15%) of a mixture of 43 and 44. Crystallization of a small sample of 42 from hot n-heptane gave crystals suitable for X-ray crystallographic analysis. Preparative HPLC (40 mL/min 97.5:2.5 hexanes–EtOAc, 300 × 50 mm, 5 µm silica gel column) allowed for the separation of 43 and 44. By this process, 43 could be obtained as an analytically pure colorless oil. The alkene isomer 44 was obtained at ca. 90% purity as colorless oil.

Data for 42: IR (film) 2921, 2852, 1711, 1609, 1486, 1347 cm⁻¹; ¹H NMR (500 MHz, C₆D₆) δ 7.29–7.38 (m, 6H), 7.21 (td, J = 7.7, 1.0 Hz, 1H), 7.07 (t, J = 7.3 Hz, 1H), 6.78 (d, J = 7.8 Hz, 1H), 5.97 (dd, J = 9.7, 1.1 Hz, 1H), 5.31 (d, J = 9.7 Hz, 1H), 5.06 (d, J = 15.7 Hz, 1H), 4.92 (d, J = 15.7 Hz, 1H), 2.13 (t, J = 13.3 Hz, 1H), 2.01 (t, J = 10.4 Hz, 1H), 1.84–1.97 (m, 2H), 1.64–1.72 (m, 2H), 1.41–1.53 (m, 2H), 1.18–1.32 (m, 4 H) ; ¹³C NMR (125 MHz, C₆D₆) δ 180.3, 141.7, 136.6, 135.9, 134.9, 128.7, 127.8, 127.5, 127.1, 124.2, 123.8, 122.4, 109.0, 51.6, 43.7, 41.3, 39.3, 37.5, 32.9, 32.8, 29.7, 26.7, 26.6; LRMS (ESI) m/z 344.11 (M+H)⁺, 366.08 (M+Na)⁺; HRMS (ESI) Calcd for C₂₄H₂₅NO 344.2014 (M+H)⁺; found 344.2005.

Data for 43: IR (film) 2921, 2850, 1710, 1609, 1488, 1345 cm⁻¹; ¹H NMR (500 MHz, C₆D₆) δ 7.28–7.33 (m, 4H), 7.23–7.27 (m, 1H), 7.13 (m, 2H), 7.00 (td, J = 7.6, 1.0 Hz, 1H), 6.71 (d, J = 7.3 Hz, 1H), 5.93 (d, J = 10.6 Hz, 1H), 5.22 (ddd, J = 9.3, 2.5, 1.5 Hz, 1H), 4.92 (d, J = 15.6 Hz, 1H), 4.87 (d, J = 15.6 Hz, 1H), 2.10–2.24 (m, 1H), 1.64–1.84 (m, 7H), 1.26–1.50 (3H), 1.02–1.10 (m, 1H); ¹³C NMR (125 MHz, C₆D₆) δ 179.4, 142.2, 137.3, 136.1, 134.9, 128.7, 127.8, 127.5, 127.3, 124.4, 123.3, 122.7, 108.8, 50.5, 43.7, 41.8, 39.8, 36.2, 32.9, 32.5, 27.0, 26.4; LRMS (ESI) m/z 344.11 (M+H)⁺, 366.10 (M+Na)⁺; HRMS (ESI) Calcd for C₂₄H₂₅NO 366.1834 (M+H)⁺; found: 366.1826.

Data for 44 (ca. 90% purity): IR (film) 2923, 2854, 1711, 1613, 1490, 1466, 1358, 1169 cm⁻¹; ¹H NMR (500 MHz, CDCl₃) δ 7.23–7.33 (m, 5H), 7.18 (d, J = 6.6 Hz, 1H), 7.12 (td, J = 7.7, 1.2 Hz, 1H), 7.00 (td, J = 7.5, 1.0 Hz, 1H), 6.70 (d, J = 7.8 Hz, 1H), 5.43 (bs, 1H), 4.90 (d, J = 15.4 Hz, 1H), 4.84 (d, J = 15.4 Hz, 1H), 2.66 (bs, 1H), 2.49 (dq, J = 17.6, 2.6 Hz, 1H), 2.14–2.39 (m, 3H), 1.68–1.90 (m, 5H), 1.38–1.51 (m, 1 H), 1.23–1.31 (m, 1H), 1.04–1.14 (m, 1H); ¹³C NMR (125 MHz, C₆D₆) δ 179.8, 142.0, 141.1, 136.3, 135.3, 128.8, 127.54, 127.46, 127.3, 122.6, 122.3, 114.9, 108.7, 45.6, 43.3, 38.8, 34.8, 34.6, 33.7, 33.1, 27.5, 26.2; LRMS (ESI) m/z 344.12 (M+H)⁺, 366.11 (M+Na)⁺; HRMS (ESI) Calcd for C₂₄H₂₅NO 366.1834 (M+H)⁺; found: 366.1830.

Heck Cyclization of Triflate 31

According to the general procedure, triflate 31 (255 mg, 0.514 mmol), Pd(PPh₃)₂Cl₂ (72.0 mg, 103 µmol), Et₃N (521 mg, 5.15 mmol, 0.65 mL) and DMA (5 mL) were heated to give a 50:40:10 mixture of 45, 46 and 47. Column chromatography (95:5 hexanes-Et₂O) afforded 76 mg (43%) of 45 as a colorless foam, 73 mg (41%) of 46 as a colorless solid and 15 mg (8%) of 47 as a colorless foam (93% combined yield).

Data for 45: IR (film) 3031, 2958, 1710, 1609, 1364, 1179 cm⁻¹; ¹H NMR (500 MHz, CDCl₃) δ 7.20–7.30 (m, 6H), 7.12 (td, J = 7.7, 1.2 Hz, 1H), 6.97 (td, J = 7.6, 0.9 Hz, 1H), 6.69 (d, J = 7.7 Hz, 1H), 6.15 (d, J = 10.2 Hz, 1H), 5.41 (ddd, J = 10.1, 2.6, 1.8 Hz, 1H), 4.98 (d, J = 15.7 Hz, 1H), 4.83 (d, J = 15.7 Hz, 1H), 2.21 (td, J = 13.5, 3.0 Hz, 1H), 2.13–2.16 (m, 1H), 1.90–1.94 (m, 1H), 1.68–1.78 (m, 2H), 1.00 (s, 9H); ¹³C NMR (125 MHz, CDCl₃) δ 180.4, 141.9, 135.9, 134.5, 133.4, 128.7, 127.8, 127.5, 127.1, 125.2, 124.2, 122.3, 109.0, 50.0, 44.8, 43.7, 32.7, 32.5, 27.3, 20.3; LRMS (CI/NH₃) m/z 345.1 (M)⁺; HRMS (CI/NH₃) Calcd for C₂₄H₂₇NO m/z 345.2093 (M)⁺; found: 345.2099.

Data for 46: IR (film) 3029, 2960, 1711, 1611, 1345, 1167 cm⁻¹; ¹H NMR (500 MHz, CDCl₃) δ 7.19–7.28 (m, 5H), 7.09–7.12 (m, 2H), 6.98 (t, J = 7.5 Hz, 1H), 6.67 (d, J = 7.5 Hz, 1H), 6,15 (dd, J = 10.1, 1.1 Hz, 1H), 5.36 (dt, J = 10.1, 1.6 Hz, 1H), 4.93 (d, J = 15.7 Hz, 1H), 4.73 (d, J = 15.7 Hz, 1H), 2.26–2.37 (m, 1H), 2.02–2.06 (m, 1H), 1.95–2.00 (m, 1H), 1.86 (td, J = 13.3, 3.1 Hz, 1H), 1.74–1.77 (m, 1H), 0.98 (m, 9 H); ¹³C NMR (125 MHz, CDCl₃) δ 179.1, 142.3, 136.1, 135.2, 134.2, 128.7, 127.8, 127.5, 127.2, 126.0, 123.2, 122.5, 108.8, 48.9, 45.1, 43.6, 33.1, 32.9, 27.3, 19.8; LRMS (CI/NH₃) m/z 345.1 (M)⁺; HRMS (CI/NH₃) Calcd for C₂₄H₂₇NO m/z 345.2093 (M)⁺; found: 345.2096.

Data for 47: IR (film) 3054, 2962, 1710, 1613, 1486, 1360 cm⁻¹; ¹H NMR (500 MHz, CDCl₃) δ 7.27–7.36 (m, 5H), 7.22 (d, J = 7.4 Hz, 1H), 7.18 (t, J = 7.8 Hz, 1H), 7.00 (d, J = 7.5 Hz, 1H), 6.77 (d, J = 7.8 Hz, 1H), 5.71 (bs, 1H), 5.05 (d, J = 15.7 Hz, 1H), 4.88 (d, J = 15.7 Hz, 1H), 2.80 (d, J = 17.4, 1H), 2.31–2.48 (m, 2H), 2.08–2.18 (m, 2H), 1.65–1.71 (m, 1H), 1.19 (s, 9H); ¹³C NMR (125 MHz, CDCl₃) δ 181.2, 144.9, 141.8, 136.1, 134.7, 128.7, 127.48, 127.45, 127.1, 123.9, 122.2, 115.5, 108.9, 45.9, 43.6, 35.5, 32.4, 30.3, 29.1, 20.93; LRMS (CI/NH₃) m/z 345.1 (M)⁺; HRMS (CI/NH₃) Calcd for C₂₄H₂₇NO m/z 345.2093 (M)⁺; found: 345.2098.

Heck Cyclization of Triflate 20a

According to the general procedure, triflate 20a (166 mg, 291 µmol), Pd(PPh₃)₂Cl₂ (40.7 mg, 58.1 µmol), Et₃N (294 mg, 0.41 mL, 2.91 mmol) and DMA (2.9 mL) were heated to give a 45:21:34 mixture of isomers 48, 49 and 50 for an overall diastereoselection of 79:21. Column chromatography (75:25 hexanes–Et₂O) afforded 105 mg (86%) of a mixture of the three isomers as a slightly yellow oil. These isomers were further purified by preparative HPLC (40 mL/min, 65:35 hexanes–EtOAc, 300 × 50 mm, 5 µm silica gel column) to give analytically pure samples of each isomer each as colorless oils.

Data for 48: IR (film) 3035, 2952, 1717, 1611, 1358, 1167, 1071 cm⁻¹; ¹H NMR (500 MHz, C₆D₆) δ 7.59 (d, J = 1.6 Hz, 1H), 7.30–7.31 (m, 2H), 7.09–7.12 (m, 2H), 7.02 (t, J = 7.4 Hz, 1H), 6.83–6.87 (m, 2H), 6.66 (td, J = 7.6, 0.9 Hz, 1H), 6.48 (d, J = 7.8 Hz, 1H), 4.8 (s, 2H), 4.33 (dd, J = 8.5, 1.7 Hz, 1H), 4.11 (ddd, J = 12.5, 8.5, 3.5 Hz, 1H), 2.96 (s, 3H), 2.66 (t, J = 12.7 Hz, 1H), 2.11 (dd, J = 11.7, 3.6 Hz), 1.46 (s, 3H), 1.36 (s, 3H); ¹³C NMR (125 MHz, C₆D₆) δ 178.6, 164.6, 143.5, 141.3, 137.1, 135.7. 131.9, 129.3, 128.7, 128.1, 128.0, 122.69, 122.68, 112.6, 109.9, 78.5, 75.0, 54.0, 51.8, 44.7, 38.6, 27.4, 27.1; LRMS (ESI; this compound partially decomposed in MeCN, t_1/2 ~ 5 min, during MS analysis, resulting in a more complex spectrum) m/z 420.14 (M+H)⁺, 442.11 (M+Na)⁺; HRMS (ESI) Calcd for C₂₅H₂₅NO₃ 420.1811 (M+H)⁺; found: 420.1797.

Data for 49: IR (film) 3035, 2987, 1713, 1613, 1360, 1067 cm⁻¹; ¹H NMR (500 MHz, C₆D₆) δ 7.64 (d, J = 1.8 Hz, 1H), 7.28–7.30 (m, 2H), 7.06–7.09 (m, 2H), 7.00 (t, J = 7.3 Hz, 1H), 6.86 (td, J = 7.6, 1.4, Hz, 1H), 6.75 (td, J = 7.4, 0.9 Hz, 1H), 6.71 (dd, J = 7.3, 1.2 Hz, 1H), 6.48 (d, J = 7.8 Hz, 1H), 4.76– 4.85 (m, 2H), 4.72 (d, J = 15.8 Hz, 1H), 4.24 (dd, J = 8.4, 1.6 Hz, 1H), 2.96 (s, 3H), 2.52 (dd, J = 12.6, 3.8 Hz), 1.97 (t, J = 12.6 Hz, 1H), 1.44 (s, 3H), 1.41 (s, 3H); ¹³C NMR (125 MHz, C₆D₆) δ 78.8, 164.9, 144.0, 141.9, 137.2, 134.6, 128.8, 128.7, 128.2, 127.9, 123.0, 122.8, 112.6, 109.8, 78.7, 74.6, 53.2, 51.8, 44.7, 38.0, 27.5, 27.1; LRMS (ESI; his compound partially decomposed in MeCN, t_1/2 ~ 5 min, during MS analysis, resulting in a more complex spectrum) m/z 420.14 (M+H)⁺, 442.12 (M+Na)⁺; HRMS (ESI) Calcd for C₂₅H₂₅NO₃ 420.1811 (M+H)⁺; found: 420.1802.

Data for 50: IR (film) 3035, 2989, 2939, 1740, 1713, 1611, 1196, 1127 cm⁻¹; ¹H NMR (500 MHz, C₆D₆) δ 7.26–7.27 (m, 2H), 7.15–7.17 (m, 1H), 7.05–7.08 (m, 2H), 7.00 (t, J = 7.4 Hz, 1H), 6.84 (td, J = 7.2, 1.2 Hz, 1H), 6.65 (td, J = 7.6, 1.0 Hz, 1H), 6.48 (d, J = 7.8 Hz, 1H), 5.25 (dd, 3.3, 1.7 Hz, 1H), 4.81 (d, 15.5 Hz, 1H), 4.69–4.73 (m, 1H), 4.58 (d, J = 15.5 Hz, 1H), 4.30 (t, J = 2.9 Hz, 1H), 2.4 (s, 3H), 2.47 (t, J = 11.4 Hz, 1H), 1.96 (dd, J = 11.6, 5.3 Hz, 1H), 1.41 (s, 3H), 1.27 (s, 3H); ¹³C NMR (125 MHz, C₆D₆) δ 179.0, 171.3, 152.6, 143.6, 137.1, 131.4, 129.2, 128.8, 128.7, 128.1, 125.1, 122.4, 112.3, 109.6, 91.2, 71.1, 51.4, 50.4, 47.3, 44.5, 38.0, 27.5, 25.2; LRMS (ESI, Note: This compound was found to decompose while in MeCN solution as required for MS analysis and resulted in a more complex spectrum, t_1/2 ~ 5 min) m/z 420.17 (M+H)⁺, 442.14 (M+Na)⁺; HRMS (ESI) Calcd for C₂₅H₂₅NO₃ 420.1811 (M+H)⁺; found: 420.1805.

Heck Cyclization of Triflate 20b

According to the general procedure, triflate 20b (211 mg, 0.278 mmol), Pd(PPh₃)₂Cl₂ (39.0 mg, 55.6 µmol), Et₃N (281 mg, 0.39 mL, 2.78 mmol) and DMA (2.8 mL) were heated to give a 59:41 mixture of diastereomers 51 and 52. Column chromatography (90:10 hexanes–Et₂O) allowed for partial separation of the isomers giving a combined yield of 149 mg (88%) of 51 as a colorless foam and 52 as a colorless oil.

Data for 51: IR (film) 2929, 2858, 1717, 1613, 1252, 1100 cm⁻¹; ¹H NMR (500 MHz, CDCl₃) δ 7.39 (d, J = 7.5 Hz, 2H), 7.32 (t, J = 7.3 Hz, 2H), 7.24–7.28 (m, 1H), 7.16 (t, J = 7.4 Hz, 1H), 7.02–7.03 (m, 2H), 6.96 (t, J = 7.5 Hz, 1H), 6.76 (d, J = 7.8 Hz, 1H), 5.08 (d, J = 15.6 Hz, 1H), 4.81 (d, J = 15.6 Hz, 1H), 4.50 (ddd, J = 11.1, 7.3, 4.0 Hz, 1H), 4.33 (dd, J = 7.3, 1.9 Hz, 1H), 3.40 (s, 3H), 1.90–1.99 (m, 2H), 0.97 (s, 9H), 0.86 (s, 9H), 0.21 (s, 3H), 0.17 (s, 3H), 0.11 (s, 3H), 0.07 (s, 3H); ¹³C NMR (125 MHz, CDCl₃) δ 178.0, 165.2, 147.0, 142.7, 136.3, 133.4, 129.5, 128.7, 128.1, 127.6, 127.5, 122.5, 122.3, 108.9, 73.2, 68.9, 51.8, 51.3, 44.0, 40.8, 26.0 (b), 19.1, 17.9, −4.1, −4.2, −4.6, −4.8; LRMS (ESI) m/z 608.14 (M+H)⁺, 630.12 (M+Na)⁺; HRMS (ESI) Calcd for C₃₄H₄₉NO₅Si₂ m/z 630.3047 (M+Na)⁺; found: 630.3039.

Data for 52: IR (film) 2931, 2858, 1719, 1611, 1254, 1115, 1092 cm⁻¹; ¹H NMR (500 MHz, CDCl₃) δ 7.39 (d, J = 7.2 Hz, 2H), 7.32 (t, J = 7.2 Hz, 2H), 7.24–7.27 (m, 1H), 7.14–7.18 (m, 2H), 7.05 (d, J = 2.0 Hz, 1H), 6.98 (t, J = 7.7 Hz, 1H), 6.74 (d, 7.7 Hz, 1H), 4.97 (m, 2H), 4.32 (dd, J = 7.2, 1.9 Hz, 1H), 4.09 (ddd, J = 11.4, 7.6, 3.5, 1H), 3.49 (s, 3H), 2.29 (t, J = 12.7, 1H), 1.65 (dd, 13.0, 3.6 Hz, 1H), 0.99 (s, 9H), 0.80 (s, 9H), 0.21 (s, 3H), 0.17 (s, 3H), 0.03 (s, 3H), −0.16 (s, 3H): ¹³C NMR (125 MHz, CDCl₃) δ 178.7, 164.5, 147.0, 142.3, 136.0, 133.2, 128.7, 128.2, 127.5, 127.4, 122.8, 122.1, 109.5, 73.6, 70.1, 52.1, 52.0, 44.1, 41.4, 26.0, 25.8, 18.2, 17.9, −4.0, −4.1, −4.7, −4.9; LRMS (ESI) m/z 608.11 (M+H)⁺, 630.10 (M+Na)⁺; HRMS (ESI) Calcd for C₃₄H₄₉NO₅Si₂ m/z 630.3047 (M+Na)⁺; found: 630.3057.

Heck Cyclization of Triflate 29c

According to the general procedure, triflate 29c (108 mg, 184 µmol), Pd(PPh₃)₂Cl₂ (25.9 mg, 36.9 µmol), Et₃N (187 mg, 0.24 mL, 1.85 mmol) and DMA (1.8 mL) were heated to give oxindole 53 as a single detectable isomer. Column chromatography (50:50 to 30:70 hexanes–EtOAc) provided 59.6 mg (76%) of 53 as a colorless oil: IR (film) 2827, 2856, 1717, 1644, 1611, 1355, 1160 cm⁻¹; ¹H NMR (500 MHz, C₆D₆) δ 7.30 (d, J = 7.4 Hz, 2H), 7.10 (t, J = 7.5 Hz, 2H), 6.96–7.03 (m, 2H), 6.72 (t, J = 6.7 Hz, 1H), 6.40 (d, J = 7.8 Hz, 1H), 6.23 (d, J = 1.5 Hz, 1H), 4.79 (m, 2H), 4.56 (dd, J = 8.2, 1.5 Hz, 1H), 4.15 (ddd, J = 12.7, 8.2, 4.3 Hz, 1H), 2.77 (t, J = 12.3 Hz, 1H), 2.32 (bs, 2H), 2.23 (dd, J = 12.0, 4.3, 1H), 1.54 (s, 3H), 1.42 (s, 3H); ¹³C NMR (125 MHz, C₆D₆) δ 178.2, 167.6, 143.9, 137.1, 134.7, 134.6, 131.5. 129.2. 128.9, 128.7, 128.0, 127.8, 123.3, 122.4, 112.7, 110.0, 77.9, 76.9, 54.4, 44.9, 37.7, 27.6, 27.2; LRMS (ESI) m/z 433.45 (M+H)⁺, 455.43 (M+Na)⁺; HRMS (ESI) Calcd for C₂₆H₂₈N₂O₄ m/z 433.2127 (M+Na)⁺; found: 433.2130.

Supplementary Material

1si20051110_08. Supporting Information Available.

Complete experimental details for preparation of substrates and chemical correlation of products, copies of ¹H and ¹³C NMR spectra of all new compounds, ¹H NMR spectra of unpurified Heck products used in assignment of diastereoselection and NOE data and used in assignment of configuration of products. This material is available free of charge via the Internet at http://pubs.acs.org.