Asymmetric 1,2-Carbamoyl Rearrangement of Lithiated Chiral Oxazolidine Carbamates and Diastereoselective synthesis of α-Hydroxy Amides

Abstract

Asymmetric 1,2-carbamoyl rearrangement of lithiated 2-alkenyl carbamates has been investigated. Deprotonation of chiral 2-alkenyl oxazolidine carbamates with sec-butyllithium in ether at −78 °C followed by warming of the resulting 1-lithio-2-alkenyl derivatives to room temperature resulted in 1,2-carbamoyl rearrangement to provide α-hydroxy amides. The rearrangement proceeded with excellent diastereoselectivity and in good to excellent isolated yield of the α-hydroxy amide derivatives. The substrate scope of the reaction was investigated with a variety of 2-alkenyl and benzyl oxazolidine carbamates. A stereochemical model is provided to explain the stereochemical outcome associated with the rearrangement. Acid-catalyzed removal of the chiral oxazolidine afforded α-hydroxy acid in high optical purity.

Graphical Abstract

We have investigated asymmetric 1,2-carbamoyl rearrangement of chiral 2-alkenyl oxazolidine carbamates. These rearrangements provided α-hydroxy amide derivatives with excellent diastereoselectivity and in good to excellent isolated yields. The substrate scope of the reaction was examined with a variety of 2-alkenyl and benzyl oxazolidine carbamates. The observed high degree of diastereoselectivity was rationalized using a stereochemical model.

Introduction

In a series of seminal works in the early 1980s, Hoppe and co-workers developed a number of powerful asymmetric carbon-carbon bond forming reactions involving alkyl and 2-alkenyl N,N-dialkyl carbamates.^[1,2] In particular, it has been shown that treatment of (E)-2-butenyl carbamate 1 with n-BuLi in the presence of TMEDA at −78 °C in ether/hexane resulted in a smooth deprotonation and generated 1-lithio-2-alkenyl carbamates (Figure 1).^[3] The reaction of the resulting oxyallyl anion with aldehydes or ketones provided δ-hydroxy enolcarbamates 2 (eq 1).^[4,5] These allylmetal derivatives so formed, provided access to a variety of compounds in a diastereoselective manner.^[6] Hoppe and co-workers also demonstrated that the deprotonation of the prochiral heptyl carbamate 3 with sec-butyllithium in the presence of (−)-sparteine provided chiral lithium-sparteine carbanions. Reaction of the carbanion with a variety of electrophiles resulted in various enantioenriched products like 4 which have been utilized in synthesis (eq 2).^[7,8] These lithiated allyl carbamates have been shown to exhibit properties typical of allyl anions and covalent allyl metal type derivatives.^[9,10]

Figure 1.

Prior work on lithiation of carbamates and reactions.

Over the years, other directed lithiation, alkylation of N-Boc-pyrrolidines and N-Boc benzyl amines resulted in a variety of heterocyclic derivatives. Meyer et al.^[11] and Beak et al.^[8,12] developed n-BuLi and TMEDA promoted rapid deprotection of Boc-amine derivatives. Enantioselective deprotonation and alkylation of piperidines and indoline derivatives have been extensively utilized in synthesis.^[8,11,12] Corey and co-workers reported deprotonation of α-nitrogen protons of Boc-protected amines using sec-BuLi and sparteine and developed enantioselective homo coupling reactions.¹⁴ Agarwal et al. promoted chelation-controlled deprotonation and effectively utilized in cross-coupling reactions.^15–18 More recently, Baudoin and co-workers reported interesting enantioselective arylation reactions involving directed metallation and Negishi cross-coupling reaction.^19,20

With the above precedence of a wide range of protocols for lithiation of carbamates and their applications, we sought to generate a relatively stable oxyallyl anion bearing a chiral oxazolidine template and investigate its ability to promote 1,2-carbamoyl rearrangement. Interestingly, such direct diastereoselective deprotonation of carbamates has not been previously investigated. We presume that diastereoselective deprotonation will lead to the corresponding α-hydroxyamide derivatives stereoselectively. Prior work in this area includes the report of Sibi and Snieckus in 1993.^[21,22] Ortho-lithiation of O-aryl carbamate 5 at low temperature followed by warming of the resulting lithiated derivatives to room temperature promoted 1,3-acyl migration, leading to salicylamide 6 (Figure 2). Hoppe and co-workers reported that lithiation of carbamate 7 with sec-BuLi in THF or DME led to α-alkoxy amide 8.^[23] However, product yield, diastereoselectivity, and the reaction conditions have not been reported. Nakai and co-workers reported lithiation of alkyl N,N’-diisopropyl carbamate 9 using sec-butyllithium and (−)-sparteine at −78 °C.^[24] The resulting lithiated derivative when warmed to room temperature, resulted in 1,2-carbamoyl migration. The α-hydroxy amide 10 was isolated in 46% yield and >95% ee with complete retention of configuration at the Li-bearing carbanion center. Herein, we report the results of our investigation where we lithiated various chiral alkenyl carbamates and promoted 1,2-carbamoyl rearrangement to provide α-hydroxy amides with high diastereofacial selectivity and good to excellent isolated yields. Hydrolytic removal of the chiral oxazolidine group provided optically active α-hydroxy acids which are important structural features of important bioactive compounds.^[25–27]

Figure 2.

Prior work on lithiation of carbamates and 1,2-carbamoyl rearrangement.

Results and Discussion

Our tentative plan for the asymmetric 1,2-carbamoyl rearrangement of lithiated chiral 2-alkenyl carbamates is shown in Scheme 1. We planned to synthesize various chiral carbamates 11 and examine various base catalyzed rearrangements. The intriguing question is whether the deprotonation would result from the conformer 13A or the conformer 13B. We presume that directed lithiation would be highly diastereoselective as the H_B proton is more accessible and the lithiated derivative 14A would form over 14B. This is due to competing non-bonded interactions between the allyl side chain and the isopropyl group on the rigid oxazolidine ring. Subsequent 1,2-carbamoyl rearrangement of 14A would provide α-hydroxy amide 12 as the major isomer with depicted stereochemistry. The size of the R-group may also influence diastereoselectivity and we planned to investigate varying R-groups.

Scheme 1.

Asymmetric 1,2-carbamoyl rearrangement of chiral alkenyl carbamates.

We investigated asymmetric 1,2-carbamoyl rearrangement of various alkenyl-(S)-4-isopropyl carbamates 11a-h shown in Scheme 2. Syntheses of these carbamates were carried out conveniently in a one-pot operation. Reaction of various allylic alcohols with triphosgene and K₂CO₃ in toluene at 0 °C to 23 °C for 2 h followed by reaction of the resulting chloro carbonate with known^[28] (S)-4-isopropyl oxazolidine in the presence of Na₂CO₃ in CH₂Cl₂ at 0 °C to 23 °C for 8 h provided carbamate derivatives 11a-11h in good yields.

Scheme 2.

Synthesis of chiral alkenyl carbamates 11a-h

First, we examined lithiation and 1,2-carbamoyl rearrangement of chiral crotyloxazolidine carbamate 11a with various bases. The results are shown in Table 1. Initially, we attempted lithiation with n-BuLi in ether at −78 °C to 23 °C, however no product was detected and starting materials were mostly recovered (entry 1). We then explored lithiation in combination with TMEDA, DIPEA, and KO^tBu in ether at −78 °C to 23 °C (entries 2–4). Reaction of 11a with 1.2 equiv of n-BuLi and 1.2 equiv of TMEDA at −78 °C to 23 °C for 4 h provided α-hydroxy amide 12a in 50% yield as a single isomer (by ¹H-NMR analysis of the crude reaction product). We have further analyzed diastereomeric ratios by chiral HPLC analysis of the corresponding p-bromobenzoate derivative of 12a and p-bromobenzoate of a mixture of diastereomers of 12a (please see supporting materials for details).^[29] Reactions in combination with DIPEA or KO^tBu did not provide any rearrangement product. Reactions with LiHMDS did not provide any detectable α-hydroxy amide product (entry 5). However, reaction of 11a with LDA provided small amount (10% yield) of α-hydroxy amide 12a, unreacted starting material was recovered (entry 6). We then examined lithiation with sec-BuLi in ether at −78 °C and then warmed to 23 °C for 2 h. This condition provided α-hydroxy amide 12a as a single diastereomer (by ¹H-NMR 500 MHz analysis) in 75% yield (entry 7). Reaction of 11a with sec-BuLi and 1.2 equiv of TMEDA also resulted in 12a in comparable yield (entry 8). Reaction of 11a in the presence of DIPEA (2 equiv) or with (−)-sparteine resulted in α-hydroxy amide 12a in 55% and 62% yield, respectively (entries 9, 10).

Table 1.

Conditions used on the Crotyl derivative for optimization

Entry	Base	Activator	Solvents	Yields (dr)[a],[b]
1	n-BuLi	none	Ether	No Product
2	n-BuLi	TMEDA	Ether	50% (>20:1)
3	n-BuLi	DIPEA (2eq.)	Ether	No Product
4	n-BuLi	KOtBu	THF	No Product
5	LiHMDS	None	Ether	No Product
6	LDA	None	Ether	10% (>20:1)
7	s-BuLi	none	Ether	75% (>20:1)
8	s-BuLi	TMEDA	Ether	77% (>20:1)
9	s-BuLi	DIPEA (2eq.)	Ether	55% (>20:1)
10	s-BuLi	(-)-sparteine	Ether	62% (>20:1)

^[a]All reactions were carried out at −78 °C to 23 °C.

^[b]Diastereomeric ratios were determined via ¹H NMR of crude reaction mixture.

Besides dimethyl oxazolidine chiral auxiliary, we have also investigated sterically hindered cyclopentyl and cyclohexyl substituents on the chiral auxiliaries. Synthesis of these carbamates and their 1,2-rearrangements are shown in Scheme 3. Reaction of crotyl alcohol with triphosgene in the presence of K₂CO₃ at 0 °C to 23 °C for 2 h followed by reaction of the resulting chlorocarbonate with L-valinol provided amide derivative 16 in 88% yield. Reaction of 16 with cyclopentanone and cyclohexanone in the presence of catalytic amount of p-TSA in toluene at reflux, afforded carbamates 17a and 17b in 40% and 35% yields, respectively. Both carbamates 17a and 17b were then reacted with sec-BuLi in ether at −78 °C to 23 °C similar to conditions in entry 7. These conditions resulted in 1,2-carbamoyl rearrangement products 18a and 18b as a single diastereomer in 65% and 62% yields, respectively. Thus, bulkier oxazolidine did not provide any advantage over dimethyl oxazolidine derivatives.

Scheme 3.

Synthesis of carbamates 17 and their 1,2-carbamoyl rearrangements.

We then conducted 1,2-carbamoyl rearrangement of various other substrates using sec-BuLi in ether at −78 °C to 23 °C as shown in entry 7 (Table 1) and the results are shown in Table 2. We investigated allyl carbamate to probe the scope of chirality transfer and the effect of alkene subsitution on the substrate. Reaction of 11b with sec-BuLi provided rearrangement product 12b in 75% yield. The diastereofacial selectivity was similar to crotyl carbamate 11a in entry 1 (>20:1 dr). The stereochemical outcome of 1,2-carbamoyl rearrangement was unambigously confirmed by X-ray crystal structure determination of α-hydroxy amide derivative obtained from (S)-oxazolidine carbamate. As shown in Scheme 4, α-hydroxy amide 12a was reacted with p-bromobenzoyl chloride and triethylamine in the presence of a catalytic amount of DMAP

Table 2.

Substrate scope for the carbamates.

Entry	Starting Materials	Product	Yield % (diastereomeric ratio)
1			75% (>20:1)
2			75% (>20:1)
3			72% (>20:1)
4			62% (>20:1)
5			68% (>20:1)
6			48% (>20:1)
7			73% (>20:1)
8			52% (>20:1)

Scheme 4.

Synthesis of p-bromobenzoate ester, X-ray structure of 19 and synthesis of acid 20.

in CH₂Cl₂ at 23 °C for 12 h to provide benzoate ester 19 in 86% yield. Standard recrystalization in a mixture of ethyl acetate and hexanes (4:1 mixture, 23 °C for 2 days) provided suitable single crystal for X-ray analysis. The ORTEP drawing of 19 is shown and the structure supported the relative and absolute stereochemical assignment.^[30,31] The results show that the stereochemical course of lithiation and subseqent 1,2-carbamoyl rearrangement can be directed by the existing chirality on the oxazolidine ring. The absolute conformation of the new asymmetric center was further confirmed after removal of the chiral oxazolidine ring. As shown in Scheme 4, treatment of α-hydroxy amide 12a with 4N aqueous HCl in 1,4-dioxane at 90 °C for 2 h, furnished α-hydroxy acid 20 in 82% yield. The observed optical rotation of 20 [α]_D²⁰ −90 (c 0.67, CHCl₃) is higher than the reported literature value [α]_D²⁰ −42 (c 0.14, CHCl₃).^[32]

We then investigated the effect of alkyl substitution on other allylic alcohols. Methallyl carbamate 11c afforded comparable yield and diastereoselectivity as allyl and crotyl carbamates (entry 3). Similarly, 2-hexenyl carbamate 11d and cyclohexylallyl carbamate 11e furnished α-hydroxy amides 12d and 12e with high diastereoselectivity (entries 4, 5). We examined sterically bulky t-butylallyl carbamate 11f which provided high diastereoselectivity however, reaction yield was reduced (entry 6). Furthermore, 2-methyl-2-butenyl carbamate 11g also provided excellent diastereoselectivity and isolated yield (entry 7). Benzyl carbamate 11h also furnished α-hydroxy amide derivative 12h with high diastereoselectivity (entry 8).

Sparteine-controlled asymmetric deprotonation has been well precedented.^[4–8] The streochemical outcome for this reaction was extensively discussed by three limiting classes of mechanisms proposed by Beak and co-workders^[8] which involve either asymmetric lithiation, diastereoselective formation of one of the two interconverting RLi species due to equilibration, or diastereoselective rearrangement from the more rapidly reacting of the two interconverting RLi species. However, in our current work, a covalently attached chiral auxiliary directed the carbamate asymmetric lithiation reactions which were not explored previously. To explain the stereochemical outcome of the asymmetric 1,2-carbamoyl rearrangement of chiral oxazolidine-derived carbamates, we proposed stereochemical models shown in Figure 3. The observed high degree of diastereoselectivity is presumably due to the specific orientation of the carbamate functionality with respect to the ring chirality of the oxazolidine. Carbamate 11 is the lowest energy conformer based upon the optimization done by DFT calculations using B3LYP hybrid functional with the basis set 6–31+G (d,p).^[33] Deprotonation of the chiral carbamate can occur from the favored conformation 11a and unfavored conformation 11b with sec-BuLi which would lead to two lithiated intermediates 21 and 22. However, deprotonation of H_B proton leading to chelated intermediate 21 is favored over 22 due to fact that deprotonation of the diastereotopic protons H_A and H_B is influenced by the stereochemistry of the isopropyl group on the oxazolidine ring. Similar facial selectivity was reported by Meyers and coworkers.^[13] Addition of sec-BuLi occurs from the face farthest from the isopropyl group thus leading to the abstraction of the proton, H_B, which is anti to the isopropyl group. In transition state 21, deprotonation of H_A proton seems unlikely due to close proximity to the isopropyl group. Lithiated intermediate 21 can form an alkoxy-oxirane intermediate 23 via an intramolecular addition of lithium-bearing carbon to the carbamoyl carbonyl group with complete retention of configuration at the Li-bearing center. The opening of the strained oxirane ring will occur leading to α-hydroxy amide 12 with depicted stereochemistry.

Figure 3.

Representations of transition states of lithiated chiral oxazolidine carbamates and their 1,2-rearrangement.

Conclusion

In summary, we investigated asymmetric 1,2-carbamoyl rearrangement of lithiated 2-alkenyl carbamates containing a chiral oxazolidine ring. Deprotonation of these alkenyl carbamates with sec-BuLi in ether −78 °C followed by warming of the resulting lithium salt resulted in 1,2-carbamoyl rearrangement and furnished α-hydroxy amides with high diastereoselectivity and isolated yield. The stereoelectronic effect of the chiral oxazolidine ring and the carbonyl group of the carbamate functionality directed asymmetric deprotonation of O-alkenyl carbamates. Such chiral oxazolidine-based directed asymmetric lithiation has been reported previously. The stereochemical outcome of the 1,2-carbamoyl rearrangement was rationalized using a stereochemical model. The assigned stereochemistry was supported by X-ray crystal structural analysis of the rearranged α-hydroxy amide product. Acid-catalyzed hydrolytic removal of the oxazolidine ring provided optically active α-hydroxy acid. Further application of this new asymmetric-1,2-carbamoyl rearrangements in the synthesis of bioactive compounds is in progress.

Data Availability Statement

The data that support the findings of this study are available in the supplementary material of this article.