Palladium-catalysed enantio- and regioselective (3 + 2) cycloaddition reactions of sulfamidate imine-derived 1-azadienes towards spirocyclic cyclopentanes

Abstract

An enantio- and diastereoselective Pd-catalysed (3 + 2) cycloaddition of bis(trifluoroethyl) 2-vinyl-cyclopropane-1,1-dicarboxylate (VCP) with cyclic sulfamidate imine-derived 1-azadienes (SDAs) has been developed. These reactions provide highly functionalized spiroheterocycles having three contiguous stereocentres, including a tetrasubstituted carbon bearing an oxygen functionality. The two geminal trifluoroethyl ester moieties can be manipulated in a facially selective manner to afford more diversely decorated spirocycles with four contiguous stereocentres. In addition, diastereoselective reduction of the imine moiety can also afford a fourth stereocentre and exposes the important 1,2-amino alcohol functionality.

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Introduction

The sterically congested and highly functionalised cyclopentane scaffold is among the most encountered architectural features in natural products, bioactive compounds, and medicinally relevant molecules (Fig. 1).^1–3 Due to their importance, synthetic protocols enabling efficient access to this privileged motif with high stereocontrol are indispensable and highly sought after. Among these, a commonly employed strategy concerns the use of donor–acceptor cyclopropanes (DACs) as C3 synthons in (3 + 2) cycloaddditions, which allow the effective construction of these five-membered carbocycles^4–8 as well as their heterocyclic counterparts^9–13 in a stereoselective and atom economical fashion. Within the array of structurally diverse DACs lies the vinylcyclopropane (VCP) scaffold, which readily ring-open in the presence of a transition metal catalyst such as palladium to afford a metal-bound zwitterionic π-allyl dipole that can undergo (3 + 2) cycloaddition with an array of dipolarophiles to furnish five-membered rings bearing a synthetically valuable vinyl handle.^14–20

Fig. 1 Selected examples of naturally occurring and medicinally relevant compounds containing a densely functionalized cyclopentane core.

A wide range of dipolarophiles have been utilised in conjunction with VCP-derived 1,3-dipoles,^21–43 enabling the synthesis of fused-^{23–26,30,43} and spirocyclic cyclopentanes and 5-membered heterocycles via (3 + 2) cycloaddition reactions.^{33,37,39,41,42} Among these, benzofuran-derived azadienes (BDAs) are an intriguing potential class of dipolarophiles for Pd-catalysed (3 + 2) reactions for cyclopentane synthesis.^31,34 However, BDAs often act as four-atom synthons in (4 + n) cycloadditions to give larger ring systems via an aromatic benzofuran intermediate I (Fig. 2a).^44–55 In comparison, their employment as two-atom synthons has been scarcer,^31,34,47,50 among which there are only two examples of (3 + 2) cycloaddition reactions with BDAs known, with chemoselectivity for C=N versus C=C addition being a potential challenge.^31,34 The preference for (4 + n) reactions of BDAs is due to the favoured attack of the intermediate sulfonamide anion on the pendant Pd-allyl complex to preserve the aromatic benzofuran moiety (highlighted in grey). We therefore designed a new azadiene dipolarophile that would completely preclude (4 + n) reactivity and enable reliable (3 + 2) processes with VCPs to be realised. From our experience with cyclic sulfamidate imines,⁵⁶ we envisaged that sulfamidate imine-derived azadienes (SDAs) would be an intriguing alternative to the BDA system that would completely preclude the (4 + n) reaction mode and give highly functionalised cyclopentanes (Fig. 2b).^57,58 Such (3 + 2) cycloadditions would proceed via a non-aromatic intermediate II, where attack by the nitrogen on the pendant π-allyl palladium complex would be unlikely as it would result in a strained bicyclic product. Furthermore, in contrast to BDA cycloaddition products, the oxygen substituent in the SDA-derived cyclopentanes would not be attached to an aromatic ring. We envision that this method will open up new (3 + 2) reaction manifolds for aza-dienes and find wide application in target synthesis of densely functionalised bioactive cyclopentanes.

Fig. 2 (a) Prior work on the different reaction modes of BDAs as dipolarophiles in Pd-catalysed cycloadditions. (b) This work: SDA scaffolds as dipolarophiles in Pd-catalysed (3 + 2) cycloadditions with VCP-derived 1,3-dipoles.

Herein, we report this new class of dipolarophiles successfully undergoing chemo- and enantioselective (3 + 2) cycloaddition with the exocyclic C=C bond to give exclusively stereodefined and densely functionalised spirocyclic cyclopentanes containing three-contiguous stereogenic centres. In addition, we can demonstrate that these cycloadducts—having a structurally rigid skeleton decorated with useful synthetic handles such as the imine, vinyl, and geminal diester moieties—can undergo further stereoselective transformations to create an additional stereogenic centre.

Results and discussion

A preliminary optimisation, carried out using VCP 1a⁵⁹ and cyclic 1-azadiene 2a as model substrates, identified toluene as the solvent of choice (see the ESI† for full optimisation details). Azadiene 2a was readily accessible from the corresponding C5-unsubstituted cyclic sulfamidate imine via a Knoevenagel condensation.⁶⁰ A selection of C₂ symmetric chiral ligands were then screened in toluene (Table 1). BINAP analogues L2 and L3 both performed well, furnishing the product in high yields and drs, but slightly lower ers compared to L1 (entries 1–3). Among the three SEGPHOS-type ligands L4–6 tested (entries 4–6), (S)-DM-SEGPHOS L5 was found to be the most suitable candidate, affording the desired product in high yield, good dr and high er (entry 5). Encouraged by the results obtained with L5, further fine tuning of other reaction conditions was attempted with this ligand. Performing the transformation at 0 °C or −10 °C led to a significant decline in dr, er and yield (entries 7 and 8). The diastereoselectivity of the reaction was found to be concentration-dependent: performing the reaction at a higher concentration resulted in a significant decline in dr (entry 9), whereas a lower reaction concentration allowed for better diastereocontrol (entry 10). Gratifyingly, a slight increase in the amount of VCP (from 1.2 to 1.5 equivalents), to account for any potential polymerisation, allowed the reaction to achieve near quantitative yield (entry 11). The results obtained by variations of the Pd⁰ source and catalytic loadings were all inferior to that outlined in entry 11 (see the ESI†).

Table 1 Ligand screen of the Pd-catalysed (3 + 2) cycloaddition reaction of VCP 1a with 1-azadiene 2a with toluene as solvent^a

Entry	Ligand	Yield^b	dr^c	er^d
a Reaction conditions: 1a (0.15 mmol, 1.2 equiv.), 2a (0.1 mmol, 1.0 equiv.), Pd2dba3·CHCl3 (2.5 mol%), ligand (7.5 mol%), PhMe (0.067 M w.r.t. 2a), rt, 24 h. b Calculated yields are provided in parentheses and were determined by ^1H NMR integration against an internal standard (1,3,5-trimethoxybenzene). c Determined by ^1H NMR analysis of the crude reaction mixture. d Enantiomeric ratio was determined by chiral HPLC. e Reaction was carried out at 0 °C. f Reaction was carried out at −10 °C. g Reaction concentration was doubled (0.134 M w.r.t. 2a). h Reaction concentration was halved (0.034 M w.r.t. 2a). i 1.5 Equiv. of 1a used.
1	L1	36% (71%)	7.2 : 1	7 : 93
2	L2	81% (87%)	8.7 : 1	11 : 89
3	L3	74% (91%)	7.1 : 1	12 : 88
4	L4	76% (80%)	7.1 : 1	90 : 10
5	L5	84% (98%)	7.3 : 1	94 : 6
6	L6	34% (31%)	1 : 1.2	94 : 6
7^e	L5	92% (84%)	3.8 : 1	90 : 10
8^f	L5	85% (81%)	2.7 : 1	81 : 91
9^g	L5	84% (88%)	5.4 : 1	93 : 7
10^h	L5	77% (83%)	8.5 : 1	94 : 6
11^h^,^i	L5	99% (99%)	8.0 : 1	95 : 5

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The optimum VCP was then examined (Scheme 1). The styryl derivative 1b was found to have comparable reactivity to 1a, affording the product in excellent yield, although in significantly poorer dr and er. The reaction of the diethyl malonate substrate 1c was remarkably lower yielding compared to its bis(trifluoro)ethyl counterparts 1a and 1b, affording 3ca in a modest 43% yield, 2.3 : 1 dr and 82 : 12 er. Interestingly, when the malononitrile derivative 1d was tested, the trans-diastereoisomer 3da′ was formed preferentially.⁵⁹ Among the three spirocyclic VCPs 1e–g subjected to the optimised reaction conditions, only 1e reacted to afford the desired product (3ea) but in moderate yield, poor dr, and modest er. No reaction took place when either 1f or 1g was employed as the reactant, and the decomposition of these VCPs was noted in both cases. These results highlight the VCP as the optimum reactant.

Scheme 1 Screening of various VCPs. ^aReaction conditions: (i) 1a (0.15 mmol, 1.5 equiv.), 2a (0.1 mmol, 1.0 equiv.), Pd₂dba₃·CHCl₃ (2.5 mol%), L5 (7.5 mol%), PhMe (0.034 M w.r.t. 2a), rt, 24 h. Calculated yields are provided in parentheses and were determined by ¹H NMR integration against an internal standard (1,2,3-trimethoxybenzene). The diastereomeric ratio was determined by ¹H NMR analysis of the crude reaction mixture. The enantiomeric ratio was determined by chiral HPLC. ^bThe two diastereoisomers are separable by chromatography. ^cLowest estimation due to HPLC traces of the two diastereoisomers being undistinguishable.

With the optimised conditions and VCP in hand, the scope of cyclic sulfamidate imine-derived 1-azadiene was next investigated (Scheme 2). 1-Azadienes with electronically diverse aryl substituents at the C4 position (R¹) were first examined, and were generally well tolerated. Almost all of these substrates (with the exception of 2f) furnished the desired (3 + 2) cycloaddition product in lower drs compared to the parent substrate 2a. While electron rich 1-azadiene 2b reacted smoothly under the optimised reaction conditions, the reactions of 2c and 2d—each bearing an electron deficient C4 aryl moiety—were both sluggish at rt; therefore, heating under reflux conditions was required. In stark contrast to the low reactivity of 2d, the reactions of its analogues 2e and 2f were significantly more efficient, furnishing the desired products in good yields, drs, and ers. The excellent diastereocontrol achieved with substrate 2f was particularly remarkable, which is hypothesised to be due to the sterically demanding ortho-bromophenyl moiety being twisted out of the plane with the cyclic sulfamidate imine ring, exerting additional facial selectivity that favours the formation of the major diastereoisomer. A single 4-alkyl substrate, the tert-butyl derivative 2g was tested and was poorly tolerated under the optimised reaction conditions, as shown by the poor dr and er of the product 3ag.

Scheme 2 Substrate scope of cyclic 1-azadienes. ^aReaction conditions: (i) 1a (0.15 mmol, 1.5 equiv.), 2a (0.1 mmol, 1.0 equiv.), Pd₂dba₃·CHCl₃ (2.5 mol%), L5 (7.5 mol%), PhMe (0.034 M w.r.t. 2a), rt, 24 h. Calculated yields are provided in parentheses and were determined by ¹H NMR integration against an internal standard 1,2,3-trimethoxybenzene. The diastereomeric ratio was determined by ¹H NMR analysis of the crude reaction mixture. The enantiomeric ratio was determined by chiral HPLC. ^bReaction was carried out at reflux. ^cDiastereomeric ratio was determined by ¹H NMR analysis of the purified product.

Cyclic sulfamidate 1-azadienes with a range of electronically and sterically diverse phenyl and heteroaryl groups at the olefinic terminal (2h–o) were next subjected to the optimised reaction conditions (Scheme 2). Gratifyingly, all the tested substrates underwent the transformation efficiently, affording the desired (3 + 2) products in good to high yields and in high ers, suggesting that the impact of either electronic or steric effects on both the efficiency and the enantioselectivity of the transformation was minor. The diastereocontrol of the reaction seemed to be more prone to these variations in the electronic and steric properties of the substrate, as illustrated by the minimal erosion in diastereoselectivity observed for substrates with electron deficient aryl groups (2k and 2m), as well as the notable increase in dr noted with substrates bearing more sterically demanding aryl moieties (2j and 2l). The alkynyl substituted 1-azadienyne 2p was found to be a competent substrate, furnishing the desired product 3ap in respectable yield, dr, and er. In comparison, the reaction of its saturated analogue 2q gave the product 3aq in poor yield, but in slightly higher dr and er.

The absolute configuration of the major diastereomeric cycloadduct was determined via X-ray crystallographic analysis of the enantiopure crystal of 3ao, which allowed the absolute configuration of other substrates to be assigned by analogy.

To demonstrate the synthetic viability of our optimised protocol, the reaction of VCP 1a and 1-azadiene 2a was carried out on a 1 mmol scale (Scheme 3a). Delightfully, the cycloadduct 3aa was obtained in comparably high yield and enantioselectivity to that observed on a smaller scale, although a significant decline in dr was observed. Although direct manipulation of a diastereo-enriched mixture of 3aa/3aa′ was possible, it was soon realised that the resulting diastereomeric mixture—which would likely consist of more than two species—might pose a significant analytical challenge. Aiming to avoid the challenging task of analysing these complex mixtures, cycloadduct 3aa was first converted to its styryl analogue via olefin cross-metathesis, allowing the major diastereomer 3ba to be isolated in 72% isolated yield without any erosion in er. With a substantial amount of 3ba in hand, several post-synthetic transformations were then attempted to illustrate the versatility of this scaffold (Scheme 3b).

Scheme 3 Scale up and derivatisation of products 3aa and 3ba. ^aReaction conditions: (i) 1a (0.15 mmol, 1.5 equiv.), 2a (0.1 mmol, 1.0 equiv.), Pd₂dba₃·CHCl₃ (2.5 mol%), L5 (7.5 mol%), PhMe (0.034 M w.r.t. 2a), rt, 24 h. (ii) Styrene (200 equiv.), Grubbs catalyst 2nd generation (3.5 mol%), CH₂Cl₂, reflux, overnight. (iii) NH₃ (7 N in MeOH), 40 °C, 88 h. (iv) BnNH₂ (1.9 equiv.), THF, reflux, 24 h. (v) K₂CO₃ (3.1 equiv.), allyl alcohol, rt, 66 h. (vi) Na_(s) (2.4 equiv.), MeOH, rt, 23 h. (vii) NaBH₃CN (8.4 equiv.), 1 : 1 MeOH/CH₂Cl₂, rt, 65 h.

The distinction in the reactivity of the geminal esters provided opportunities for some chemoselective reactions to be conducted and allowed a fourth stereogenic centre to be readily created. Treatment of spirocyclic cyclic imine 3ba with ammonia in methanol allowed a double transesterification to take place, followed by a regioselective amidation of the more reactive ester moiety trans- to the SO₂ bridge, furnishing amide 4 in high yield and dr (relative configuration of 4 was determined by 2D NOESY, see the ESI†). These differences in reactivity of the two ester moieties of 3ba were further exploited for the preparation of amide 5 and diester 6—via chemoselective amidation and transesterification, respectively. These reactions occurred in moderate to high yields and good to high drs, with that of 5 being diminished relative to that of 4, presumably due to the higher reaction temperature (reflux in THF). In addition to the selective functionalisation of the gem diesters, construction of an additional stereogenic centre could be otherwise achieved via the functionalisation of the reactive imine moiety. Reduction of 7—readily obtained by a double transesterification of 3ba with NaOMe—by NaBH₃CN afforded cyclic sulfamidate 8 in moderate yield and dr (relative stereochemistry of the major diastereoisomer was established by 2D NOESY analysis, see the ESI†). Attempts to subject 3ba to a variety of other common hydride reducing agents were complicated by the highly reactive nature of the bis(trifluoroethyl) diester moieties.

The stereochemical outcomes of the transformation can be rationalised using a quadrant analysis, generated based on X-ray data for analogous Pd–Segphos complexes (Fig. 3).^61,62 Ionisation of the racemic VCP by the chiral [(S)-DM-Segphos]Pd⁰ complex can afford either diastereomeric complex A or B, which can interconvert via π–σ–π isomerisation. Of these two, complex A is likely more favoured due to the lower steric interaction between the dipole fragment and the equatorial xylyl group from the ligand. In line with established literature, the Michael addition of the dipole to the dipolarophile is likely a reversible process, whereas the ring-closure occurs irreversibly and under the control of the ligand to determine the configuration [stereochemistry] of the cycloadduct. Specifically, addition of A to the Re-face of 1-azadiene viaC should form the pre-cyclisation conformer E—where the R² moiety is placed in the pseudo-equatorial position—followed by irreversible ring closure to furnish the major diastereomeric product with the observed absolute configuration. In contrast, addition of A to the Si face of 1-azadiene viaD gives pre-cyclisation conformer F—with the R² substituent similarly occupying the pseudo-equatorial position—and then ring closure of F provides an enantiomer of the minor diastereomeric product. For pre-cyclised conformer E, it is likely that the more favourable disposition of a significant portion of the intermediate in the open quadrant of the chiral ligand space may have allowed the cyclisation to proceed faster than that of F, thus leading to high stereocontrol.

Fig. 3 Rationalisation of the observed stereochemical outcomes using a quadrant analysis. For clarity, in complexes A–F, the chiral ligand scaffold is omitted and the cationic metal centre is represented by the light grey circle.

Conclusions

In conclusion, SDAs have been demonstrated to be competent partners in stereo- and regioselective Pd-catalysed (3 + 2) cycloaddition reactions with vinylcyclopropane derived 1,3-dipoles. The ability of this dipolarophile to avoid (4 + n) reaction manifolds has implications for reactions with a myriad of other Pd-stabilised dipoles and in organocatalysed processes,^63,64 which can also be utilised with BDAs but are far less explored, with no (3 + 2) processes known. The cycloaddition provides a rapid assembly of highly substituted and stereodefined cyclopentanes as part of a spirocyclic system, with sp³-rich systems being privileged structures in pharmaceutical development. The transformation is scalable and post-synthetic modifications targeting different functional handles demonstrate the synthetic utility of the cycloadduct. Many of these transformations allow an additional stereocentre to be readily installed via either chemoselective manipulations of geminal diester functionalities or via diastereoselective reduction of the imine moiety.

Data availability

Data for all compounds reported in this manuscript are available in the ESI,† which includes experimental details, characterisation, copies of ¹H and ¹³C NMR spectra as well as HPLC traces. Crystallographic data for compounds has been deposited at the CCDC under CCDC 2224300.

Author contributions

HP, CH, and SP conceptualised the project. CH and SP were involved with supervision, funding acquisition and writing – reviewing and editing. HP carried out the investigation and formal analysis of the data and was involved with writing the original draft of the manuscript. AT was involved in writing – reviewing and editing and formal analysis of data. MGG and CR carried out the X-ray crystallography.

Conflicts of interest

There are no conflicts to declare.

Acknowledgements

The authors acknowledge Australian Research Council Discovery Grant DP180101332 for funding of this research. QHP is the recipient of a UOW UPA and IPTA PhD Scholarship.

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Footnote

† Electronic supplementary information (ESI) available. CCDC 2224300. For ESI and crystallographic data in CIF or other electronic format see DOI: https://doi.org/10.1039/d3sc01510f

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