Highly diasteroselective intermolecular 1,3-dipolar cycloaddition reactions of carbonyl ylides with aldimines to afford sterically disfavored cis-oxazolidines

Abstract

Rhodium acetate and AgSbF₆ co-catalyzed highly diastereoselective 1,3-dipolar cycloaddition reactions of carbonyl ylides with aldimines have been carried out to afford sterically disfavored oxazolidines via a [3 + 2] exo-addition process. Subsequent hydrolysis gave trans-β-amino-α-hydroxyl ester derivatives in high yields.

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Carbonyl ylide dipoles are highly reactive and are important intermediates for 1,3-dipolar cycloadditions. They find widespread use in heterocyclic chemistry.¹ These ylides are typically generated in situ from carbonyl compounds and metallocarbenoids. The bimolecular version of cycloaddition has been applied with great success in natural product synthesis.² However, the cycloaddition of an intermolecularly generated carbonyl ylide with various dipolarophiles is still a challenge in terms of efficiency and selectivity.

The 1,3-dipolar cycloaddition reaction between carbonyl ylides and imines is one of the most useful protocols that have been used for the preparation of oxazolidines.³ Subsequent hydrolysis of the N,O-acetal ultimately yields β-amino alcohols, which are found in a vast array of biologically important compounds and are frequently used as building blocks in natural product synthesis.⁴ Surprisingly, very limited examples of cycloadditions involving imines and intermolecularly generated carbonyl ylide dipoles have been reported,³ although the analogous reactions of carbonyl ylide dipoles with aldehydes,⁵ alkynes, or alkenes⁶ have been extensively studied. The reported 1,3-dipolar cycloaddition of carbonyl ylides with benzylimines to give trans-4,5-oxazolidines (Scheme 1, Path A),³ was believed to arise from a sterically preferred metal-free endo-transition state (TS).⁷ It is worth noting that in this study, imines derived from aromatic amines were inactive dipolarophiles. Presumably, the conjugate resonance of the aromatic ring with the imine double bond stabilizes the imine moiety toward the reaction. It was also reported that Lewis acid additives disrupted the diastereoselectivity of the reaction.^3e Here, we wish to report our continuing study on the cooperative-catalysis strategy,⁸ which facilitates the highly diastereoselective [3 + 2] exo-addition process of carbonyl ylides with imines (Path B).

Scheme 1 Rhodium-catalyzed 1,3-dipolar cycloaddition of carbonyl ylide dipoles with imines.

In recent years, cooperative catalysis has gained much attention owing to its ability to enhance both selectivity and reactivity in organic reactions.⁹ In some cases of multi-component reactions (MCRs) in which three or more components are involved in one transition state (TS) to generate two or more chemical bonds simultaneously, cooperative catalysis provides an opportunity to control the reaction selectivity of the multi-bond formation process, as the appropriate combination of compatible co-catalysts can affect the intrinsic reaction kinetics in a designed manner by separately activating the desired component(s).⁸ In the transition-metal-catalyzed three-component reaction of a diazo compound, which comprises an aldehyde and an aldimine, there are possible side reactions, including aziridination,¹⁰ epoxidation,¹¹ Mannich-type addition to the imine,¹² aldol-type addition to the aldehyde,¹³ other carbonyl ylide or azomethine ylide cycloadditions with aldehydes or imines, respectively (Scheme 2),¹⁴ and others,¹⁵ that may compete with the desired cycloaddition of the carbonyl ylide with the aldimine. We envisioned that the complexity of this reaction system provides us with an opportunity to carry out the co-catalyzed multi-component strategy. In the current situation (Scheme 2), Rh₂(OAc)₄ is the catalyst of choice to generate the active carbonyl ylide dipole, and it should be possible to find a compatible co-catalyst to activate the aldimine substrate so as to achieve control of chemo- and diastereoselectivity.

Scheme 2 Possible [3 + 2] cycloaddition reactions of diazo compounds with aldehydes and imines.

With the above goal, we began to study the three-component reactions using ethyl diazoacetate (1a, EDA), p-bromophenylaldehyde (2a), and an aniline-derived imine (3a) in the presence of Rh₂(OAc)₄ (2.0 mol%) to find that only epoxidation occurred (Table 1, entry 1). Next, a variety of Lewis acids were used as co-catalysts to activate the aldimine 3a. We found that in the presence of Yb(OTf)₃, the 1,3-dipolar cycloaddition occurred to afford oxazolidine 4a in a 27% isolated yield with very low diastereoselectivity (4,5-cis/4,5-trans = 60/40). This promising outcome, despite the low yield and limited selectivity, clearly demonstrated the activation of imine 3a towards the 1,3-carbonyl dipole by a Lewis acid, and the slight, though noticeable, inversion of diastereoselectivity is comparable to those obtained in the reported results.¹⁶

Table 1 Selected optimization conditions for the cycloaddition^a

Entry	Co-catalyst	Yield^b (%)	dr^c (cis : trans)
a Unless otherwise noted, the reaction was carried out by the addition of 1a (0.22 mmol) in CH2Cl2 (0.5 mL) to a mixture of 2a (0.22 mmol), 3a (0.20 mmol), 4 Å MS (0.1 g) Rh2(OAc)4 (2.0 mol%), and the co-catalyst (10.0 mol%) in 1.5 mL CH2Cl2 under an argon atmosphere for 1 h at 25 °C. b Isolated yield of 4a (based on limiting reagent 3a). c Determined by ^1H NMR spectroscopy of the unpurified reaction mixture. d Isolated yield of the corresponding epoxide. e The reaction was carried out at 0 °C. f The reaction was carried out in the absence of Rh2(OAc)4, and no desired product was detected.
1	—	71^d	—
2	Yb(OTf)3	27	60 : 40
3	Sc(OTf)3	33	63 : 37
4	Zn(OTf)2	38	55 : 45
5	AgOTf	69	67 : 33
6	AgBF4	51	90 : 10
7	AgPF6	73	86 : 14
8	AgSbF6	76	>95 : 5
9^e	AgSbF6	81	>95 : 5
10^e^,^f	AgSbF6	ND	ND

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Other Lewis acid co-catalysts were tested: Sc(OTf)₃ promoted the reaction in a similar manner to that of Yb(OTf)₃, and Zn(OTf)₂ effected a 10% improvement of the yield. When AgOTf was employed, a dramatic increase in the yield to 69% and a slight enhancement of the diastereomeric ratio (dr) to 67/33 (4,5-cis/4,5-trans) were observed. A further survey of a variety of silver salts revealed that AgSbF₆ was the optimum co-catalyst, affording 4a in a 76% yield and in a cis/trans ratio as high as 95/5 (entry 8). When the reaction was carried out at 0 °C, the yield was further improved to 81% and the high levels of diastereoselectivity were maintained (entry 9). A control reaction was also carried out under the optimal conditions, in the absence of Rh₂(OAc)₄, which recovered the three starting materials with no trace of 4a being detected (entry 10). These findings rule out the possibility that the silver metal complex alone participates in the metal carbenoid formation and the subsequent carbonyl dipole formations.

The scope of this AgSbF₆ and Rh₂(OAc)₄ co-catalyzed three-component cycloaddition was further explored with EDA and p-bromophenylaldehyde as the 1,3-carbonyl dipole precursor and various aldimines as dipolarophiles, using CH₂Cl₂ as a solvent and 4 Å MS as a water scavenger. The results are listed in Table 2. Imines containing both electron-poor and electron-rich arenes gave the corresponding products with excellent selectivity (dr > 95 : 5) and high yields (75–90%). Substrates with either an o or m substituent on Ar⁴ exhibit slightly decreased reactivity while keeping the same high levels of stereoselective control (entries 6, 7 and 8).

Table 2 Scope of the reaction using various imines^a

Entry	Ar^3/Ar^4 (3)	Yield^b (%)	dr^c
a Unless otherwise noted, the reaction was carried out by the addition of 1a (0.22 mmol) in CH2Cl2 (0.5 mL) to a mixture of 2a (0.22 mmol), 3 (0.20 mmol), 4 Å MS (0.1 g) Rh2(OAc)4 (2.0 mol%), and AgSbF6 (10.0 mol%) in 1.5 mL CH2Cl2 under an argon atmosphere for 1 h at 0 °C. b Isolated yield of 4. c Determined by ^1H NMR spectroscopy of the unpurified reaction mixture.
1	Ph/Ph (3a)	81 (4a)	>95 : 5
2	Ph/4-BrC6H4 (3b)	87 (4b)	>95 : 5
3	Ph/4-ClC6H4 (3c)	83 (4c)	>95 : 5
4	Ph/3,4-2ClC6H3 (3d)	82 (4d)	>95 : 5
5	4-ClC6H4/4-BrC6H4 (3e)	76 (4e)	>95 : 5
6	PMP/4-BrC6H4 (3f)	90 (4f)	>95 : 5
7	PMP/3-BrC6H4 (3g)	78 (4g)	>95 : 5
8	PMP/2-BrC6H4 (3h)	75 (4h)	>95 : 5
9	PMP/PMP (3i)	89 (4i)	>95 : 5
10	PMP/4-MeC6H4 (3j)	78 (4j)	>95 : 5

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The relative stereochemistry of the major product was determined to be 2,5-trans and 4,5-cis via single-crystal X-ray analysis of 4f¹⁶ and the ¹H NMR coupling data of J(4,5) of the corresponding major product is consistent with the 4,5-cis relative stereochemistry.^17,18

Deprotection of the oxazolidines under acidic conditions offered the valuable trans-amino alcohol 5a in a high yield, substantiating a facile entry to this class of compounds.^18,19 In the meantime, the stereochemistry of the minor isomer was deduced as 4,5-trans, since a diastereomeric mixture of 4a gave a diastereomeric mixture of 5a in the same dr, indicating that the relative stereochemistry of 4a is derived only from the 4,5-position.¹⁸

Compared to the previously reported Lewis acid (LA)-free endo-TS-favored addition,³ the dominant products were exo-TS adducts in this LA co-catalyzed three-component reaction. It is proposed that the cationic silver pre-organizes the thermally stable trans rhodium-free ylide⁷ and its cycloaddition partner in an exo-TS assembly, as depicted in Scheme 3, through coordination with both the ester carbonyl oxygen and the imine nitrogen.²⁰ Thus, the ester group is brought to the same side of Ar⁴, and Ar² is spontaneously forced to the same side as Ar³, leading to the formation of the exo-cycloaddition product. The intriguing effects of the LA in this system were underscored by the inversion of the trans/cis selection as well as the activation of the otherwise inert dipolarophiles.

Scheme 3 Proposed effect of the co-catalyst in the addition process.

Chiral diazo compound 1b, derived from L-menthol, was employed to introduce the chirality in this system (Scheme 4). Its reactions with 2a and 3 furnished the chiral products 6a–c in good yields (62–73%). Only two diastereomers out of the eight possible isomers were observed in the cycloaddition reaction. In order to clarify the stereochemistry of the adducts, subsequent reduction and hydrolysis of a crude product mixture of 6a were carried out to yield the known amino alcohol 8 in 80% ee, as determined by chiral HPLC, indicating a 90 : 10 dr in the cycloaddition step.¹⁷ To ensure that no racemization occurred during the transformation, purified 6a was used to carry out the same transformation to give 8 in 100% ee. The physical and spectrometric data of 8 ([α]²⁰_D = +4.0°) agree with the data reported for (2S,3S)-8 {lit [α]²⁰_D = +4.0° for (2S,3S)-8 (c = 1, EtOH)}.²¹ Thus, the absolute configuration of the major isomer 6a was deduced as 2R,4S,5S, and the minor diastereomer of 6a from the cycloaddition as 2S,4R,5R. At this stage, by analogy with 6a, the absolute configurations of all the major cycloaddition products 6a–c were finally assigned, as shown in Scheme 4.

Scheme 4 Asymmetric cycloadditions and subsequent transformations.

In summary, we have presented intermolecular LA co-catalyzed highly diastereoselective 1,3-dipolar cycloadditions of carbonyl ylides with inert aldimines. This multi-component reaction allowed facile access to cis-oxazolidines and gave chiral α-hydroxyl-β-amino ester derivatives in good yields with a high level of control of the stereoselectivity. The otherwise sterically disfavored exo-TS operates in this system because of the effect of a cationic Lewis acid co-catalyst that presumably occurs through a dual functional mechanism of coordination and activation of [3 + 2] cycloaddition partners. Further work will focus on developing an enantioselective version of this methodology.

We are grateful for the financial support from the NSFC (21125209 and 21332003), the MOST of China (2011CB808600) and STCSM (12JC1403800), and support from Ministry of Education of China (20100076110005).

Notes and references

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Footnote

† Electronic supplementary information (ESI) available. CCDC 970866 (4f) and other spectra. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c3qo00040k

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