Lithium Enolate with a Lithium-Alkyne Interaction in the Enantioselective Construction of Quaternary Carbon Centers: Concise Synthesis of (+)-Goniomitine

Abstract

We report a method for direct enantioselective alkylation of 3-alkynoic and 2,3-alkendioic acids that form quaternary stereogenic centers, and application of this method to the total enantioselective synthesis of a complex alkaloid (+)-goniomitine. The methods were effective in the alkylation of both 3-alkynoic acids, 2,3-alkendioic acids substrates with a broad range of heterocyclic and functionalized alkyl group substituents. Accompanying crystallographic studies provide mechanistic insight into the structure of well-defined chiral aggregates, highlighting cation-π interactions between lithium and alkyne groups.

Graphical Abstract

We report a method for direct enantioselective alkylation of 3-alkynoic acids and 2,3-alkendioic acids that form quaternary stereogenic centers, and application of this method to the total enantioselective synthesis of complex alkaloid (+)-goniomitine. Crystallographic studies highlighted cation-π interactions between lithium and alkyne groups in the chiral lithium aggregate intermediate.

Introduction

Quaternary stereogenic centers are important structural motifs in natural products and biologically active compounds, and present some of the most challenging constructs in organic synthesis.^[1–4] The enantioselective construction of quaternary stereocenters in acyclic systems is particularly difficult.^[5]

The alkynyl group is an important functional group because it can be utilized in a broad array of cross-coupling reactions and functional group transformations.^[6,7] Consequently, the enantioselective construction of alkyne-substituted quaternary carbon stereocenters coupled with subsequent functionalization of the alkyne group enables access to intricately functionalized quaternary stereocenters.^[8]

Several distinct approaches have been recently developed for the asymmetric assembly of acyclic alkyne-substituted quaternary carbon centers (Scheme 1). The pioneering work by Maruoka and co-workers reported a phase transfer catalyzed alkylation of α–alkynyl esters.^[9] The groups of Nishibayashi and Jacobsen have reported copper- or organocatalyzed propargylic substitution methods to access acyclic quaternary carbon stereocenters, respectively.^[10,11] Hoveyda and co-workers have developed a highly enantioselective Cu-catalyzed allylic substitution reaction of allylic phosphates with alkynyl aluminum reagents.^[12] The Li group has achieved Ir-catalyzed asymmetric hydroalkynylation of trisubstituted alkenes with triisopropyl-silylacetylene.^[13] Very recently, Liu and co-workers reported an enantioconvergent Cu-catalyzed C(sp³)-C(sp) cross-coupling of tertiary electrophiles with terminal alkynes.^[14] Some of the limitation of these notable methods include nucleophile scope and, in some cases, multistep preparation of catalysts and starting materials. A highly enantioselective, practical, and scalable technique for the assembly of alkynyl-substituted quaternary centers would further expand this valuable methodology. ^[15,16]

Scheme 1.

Construction of acyclic alkyne substituted quaternary carbon stereocenters.

Chiral lithium amides (CLAs) have emerged as a powerful class of reagents for asymmetric functionalization of a diverse group of carbanions.^[17] Previously, we demonstrated that CLAs enable highly effective enantioselective alkylations of arylacetic acids, α-alkyl-α-methoxyacetic acids and 2-alkylpyridines.^[18,19] The common feature of these transformations is the intermediacy of structurally well-defined lithium aggregates formed between the substrate anions and CLAs, providing the chiral environment for subsequent functionalizations.^[18d,20] To date, these lithium aggregate-mediated alkylation reactions have been mostly confined to the formation of tertiary carbon stereocenters.^[18e] Asymmetric construction of quaternary stereogenic carbon centers with practical levels of stereocontrol can improve the versatility of this methodology. We focused our effort on alkylation of α-alkynyl carboxylic acids, as well as α-alkylallenoic acids as a complementary set of substrates.

To achieve this goal, several conditions have to be met. First, a stable mixed aggregation between the enediolate and the chiral lithium amide must be feasible, providing a chiral environment for subsequent alkylation. Second, this complex lithium aggregate must overcome significant steric hindrance in reactivity required for the formation of quaternary carbon stereocenter. Third, the lithium aggregate must exert regiocontrol because the alkylation could also occur at the γ-position.^[21,22]

Herein, we report a successful development of a highly enantioselective alkylation of both α-alkynyl carboxylic acids and α-alkylallenoic acids forming all-carbon quaternary centers. Chiral lithium amides were used as noncovalent stereodirecting auxiliaries and could be efficiently recovered by acid-base extraction. This strategy provided a direct, enantioselective, regioselective, and practical synthetic approach to α-alkynyl carboxylic acids with acyclic quaternary carbon stereocenters. For deeper insight into the reaction mechanism, we carried out the structural characterization of the mixed aggregate, revealing a cation-π-interaction between lithium and alkyne groups. To demonstrate its broader utility, this method was applied to the concise enantioselective total synthesis of Aspidosperma alkaloid (+)-goniomitine.

Results and Discussion

Reaction development.

As we found in the course of our studies, both α-alkynyl carboxylic acids and α-alkylallenoic acids are suitable substrates and can be used interchangeably. Because α-alkylallenoic acid are typically thermodynamically preferred and thus more synthetically accessible, we chose to explore alkylation of α-alkylallenoic acids first. The alkylation of 2-methyl-4-phenylbuta-2,3-dienoic acid 1a with benzyl bromide was evaluated in the presence of a variety of chiral amines. The C₂-symmetric tetraamines ¹TA and ²TA, shown in Table 1, gave clean, high-yielding reactions with excellent enantioselectivity. Other structurally modified chiral tetraamines such as azepane type tetramine ³TA or morpholine type tetramine ⁴TA showed lower enantioselectivity. THF was found to be the best solvent, which was consistent with our prior observations in asymmetric alkylation of aryl acetic acids. DME produced a decreased ee, while other common alkylation solvents (Et₂O, toluene) resulted in low conversions. Interestingly, a 10:1 mixture of Et₂O:THF resulted in excellent ee, which indicated that THF was an essential constituent of the reactive aggregate.

Table 1.

Selective optimization of reaction conditions.

^[a]Reaction conditions: All reactions were carried out on a 0.15 mmol scale unless otherwise noted.

^[b]Conversions and yields were determined by analysis of ¹H NMR spectra of crude product mixtures using 1,3,5-trimethoxybenzene as the internal standard.

^[c]Enantiomeric excess (ee) were determined by high performance liquid chromatography (HPLC) analysis. All results normalized to bases with the R configuration.

^[d]Isolated yield.

^[e]Methyl ester as the product. See supporting information for details.

Addition of HMPA resulted in a reduced enantioselectivity, presumably due to the disruption of the aggregate. Replacing tetramine ¹TA with its N,N’-diethylated version decreased the ee to 7%. Using less equivalents of n-BuLi, or more equivalents of ¹TA also delivered inferior enantioselectivity. Replacing the acid 1a with its methyl ester also gave low enantioselectivity. Loss of enantioselectivity in these experiments is presumably due to disrupting the structure of the key reactive lithium aggregate.

Substrate scope.

Having optimized the reaction conditions, the scope of this alkylation reaction was examined next (Table 2). Varying the alkylating reagents first, high yield and enantioselectivity were observed for a variety of benzylic bromides (2b-2d), irrespective of the electronic nature and substituent pattern on the phenyl ring. Heteroaromatic benzylic bromides, such as 2-thienyl bromide, reacted rapidly to form 2f in good yield and enantioselectivity. Excellent levels of enantioselectivity were attained in the reactions involving a range of allylic halides: allyl bromide, methallyl bromide, and cinnamyl bromide (2g, 2h and 2i). Alkylation with 3-(trimethylsilyl)propargyl bromide delivered the 1,5-diyne (2j) in 93% ee. For unactivated alkyl halides (ethyl iodide, 2k), the pyrrolidine type tetramine (R)-²TA and a slightly higher temperature (−55 °C) were required to ensure full conversion while maintaining satisfactory enantioselectivity.

Table 2.

Substrate scope of alkylation reagents.^[a]

^[a]Reaction conditions: All reactions were carried out on a 0.15 mmol scale unless otherwise noted. Isolated yields are shown. Enantiomeric excess (ee) were determined by high performance liquid chromatography (HPLC) analysis.

^[b]Reaction was carried out at −55 °C. (R)-²TA was used instead of (R)-¹TA.

This alkylation conditions were applicable to both α-allenoic acids and α-alkynyl acids. Comparable results were obtained when 2-methyl-2-(phenyl)ethynyl acid 3a was used in place of 1a (Table 3). A 3 mmol scale alkylation reaction was also conducted, resulting in a comparable 85% yield and 92% ee. In this larger-scale reaction, chiral tetraamine ¹TA was recovered in 92% yield after an acid-base extraction. After comparing reported optical rotation values, the newly formed quaternary center was determined to have an S configuration.^[23] To investigate the tolerance of the other α-alkyl groups, 2-ethyl- and 2-allylbuta-2,3-dienoic acids (4b, 4c) were subjected to the alkylation conditions and expected products were formed in satisfactory yields and ee. Alkylations of 4-arylbuta-2,3-dienoic acid with different steric and electronic properties also performed very efficiently (4d, 4e and 4f). Furthermore, this method was applicable to a variety 2-methyl-2-(alkyl)ethynyl acids (4g, 4h, 4i and 4j). A trimethylsilyl group at the acetylene terminus was also well tolerated (4k), which allowed for further transformations and opened up the synthetic application of this method. A silyl ether was also compatible with these reaction conditions (4l). During the preparation of our acid starting materials, in many cases an inseparable mixture of α-alkynyl acids and α-allenoic acids was formed.^[24] Given that this mixture would be expected to form identical lithium enediolate intermediates, a mixture of α-alkynyl acid and corresponding α-allenoic acid was employed in the alkylation reaction (4h, 4i and 4j). The resulting excellent yield and enantioselectivities confirmed applicability of the alkylation protocol to both α-alkynyl acids and α-allenoic acids, which alleviated the need for separation of substrate acids.

Table 3.

Substrate scope of α-allenoic acids and α-alkynyl acids.^[a]

^[a]Reaction conditions: All reactions were carried out on a 0.15 mmol scale unless otherwise noted. Isolated yields are shown. Enantiomeric excess (ee) were determined by high performance liquid chromatography (HPLC) analysis.

^[b]The corresponding α-alkynyl acids were used instead.

^[c]A mixture of a-alkynyl acids and α-allenoic acids were used.

^[d]3.0 mmol reaction scale.

^[e]Allyl iodide was used as the electrophile.

^[f]Methyl iodide was used as the electrophile. See supporting information for details.

In addition to the abovementioned electrophiles, iodomethane also proved to be a good alkylation reagent with a variety of 2-alkyl-4-phenylbuta-2,3-dienoic acids. Product acids (R)-2k, (R)-2g and (R)-2a were prepared by methylation of the corresponding 2-ethyl-, 2-allyl-, and 2-benzylbuta-2,3-dienoic acids in good yields and ee. In addition to constructing quaternary carbon centers, our alkylation method could be extended to preparing α-chiral alkynyl acid with tertiary carbon centers (Table 4). Using 4-trimethylsilyl-3-butyonic acid 5a as the nucleophile, a variety of electrophiles, including different benzylic bromides (6a, 6b, 6c) and cinnamyl bromide (6d), delivered excellent yield and enantioselectivity. As for the nucleophile part, a variety of silyl, alkenyl or aryl ethynyl acetic acids (6e, 6f, 6g, 6h) were tested and all resulted in practically useful outcomes.

Table 4.

Construction of α-alkynyl acids with tertiary carbon stereocenters.^[a]

^[a]Reaction conditions: All reactions were carried out on a 0.15 mmol scale unless otherwise noted. Isolated yields are shown. Enantiomeric excess (ee) were determined by high performance liquid chromatography (HPLC) analysis.

Crystallographic studies.

Although extensive work has been done to address the structure of allenyl/propargyllithium reagents, not much has been reported about the structure or reactivity of alkynyl/allenyl enediolates.^[21] Given the evidence of the strong correlation between stereocontrol and aggregation states in organolithium chemistry, crystallographic study was conducted to probe the structure of mixed aggregates as the key reactive species in the alkylation reaction. Crystals were obtained by mixing 1.0 equiv each of 1a and (R)-¹TA and 4.0 equiv of n-butyllithium in tetrahydrofuran at −25 °C. Crystals were analyzed by X-ray diffraction studies at 100 K and the structure is shown in Figure 1.^[25] The crystal structure revealed a predominately alkynyl lithium enediolate structure, which was supported by the short C₂-C₃ distance (1.204 Å) and a close-to-linear alignment of C₁, C₂, C₃ and C₄ carbons. Together with this alkynyl lithium enediolate, four lithium cations, four THF ligands and one doubly deprotonated chiral amide composed a chiral organolithium supramolecular assembly. An interesting feature of this lithium aggregate is that one lithium center exhibited cation-π interaction with the acetylene motif.^[26,27] Such interaction was supported by the distance between the lithium and two acetylene carbons (Li₁-C₂, 2.402 Å; Li₁-C₃, 2.523 Å). Similar Li-carbon distance could be found in other organolithium complexes bearing lithium-acetylene interactions (ref [26]: Li-C₁, 2.443 Å; Li-C₂, 2.749 Å). It was also noticed that enediolate phenyl group was slightly away from the acetylene axis in a direction opposite to Li (C₁-C₂-C₃, 178.4 deg; C₂-C₃-C₄, 172.7 deg). Such bending, along with the shortened C₁-C₂ bond length (1.405 Å) indicated a partial rehybridization of the carbon C₂ and C₃ from sp to sp² to a small degree.^[27c] This suggested that the overall structure of the lithium aggregate would be mostly alkynyl lithium enediolate with a moderate contribution of allenyl lithium carboxylate resonance structure.

Figure 1.

X-ray structure of the lithium amide-lithium enediolate aggregate from (R)-¹TA and 1a. Hydrogen atoms and four coordinating THF molecules are omitted for clarity. See the Supporting information for details. Selected distance (Å) and angles (deg): Li₁-C₂, 2.402(14); Li₁-C₃, 2.523(16); C₁-C₂, 1.405(11); C₂-C₃, 1.204(10); C₁-C₂-C₃, 178.4(8); C₂-C₃-C₄, 172.7(8).

The above-mentioned crystal structure of the chiral lithium aggregate helped elucidate its unique reactivity. We believe that the observed lithium-acetylene interaction further stabilized the lithium aggregate, which contributed to the high selectivity observed in its reactions. Besides enhancing reactivity, this interaction could differentiate the alkynyl side and the methyl/alkyl side of the prochiral enediolate, which prevented the undesired enediolate flip in lithium aggregate and improved the enantioselectivity in the alkylation step.^[18d] In terms of enantiocontrol, re-face of the alkynyl lithium enediolate was blocked by one of the piperidine rings in the chiral bisamide (drawn in grey). As a result, the si-face of the prochiral enediolate was better available to various electrophiles, which was consistent with the absolute configuration of alkylation products in our experimental results.

Synthetic applications.

Isolated in 1987, goniomitine is a unique member of the Aspidosperma alkaloid family with a rare octahydroindolo[1,2-a][1,8]naphthyridin scaffold.^[28,29] Substantial efforts have been directed at the total synthesis of goniomitine.^[30,31] In the asymmetric approaches to this molecule, the C20 quaternary carbon is not only a synthetic challenge but also a stereochemical linchpin that controls the remaining chiral centers. Elegant solutions for the construction of this chiral center with high enantioselectivity have been developed and applied to the synthesis of goniomitine.^[5h] In this study, we adopted enantioselective alkylation of α-alkynyl carboxylic acids to construct the quaternary stereogenic center of goniomitine and complete its concise total synthesis.

Our synthesis suggested a short sequence from the α-alkynyl acid 11 (Scheme 2). The aminal functionality was planned to be created by reductive cyclization of imide 7, which can be obtained by hydrogenation of alkyne 8. A Sonogashira cross-coupling was planned to combine the indole unit 9 with the alkyne unit 10.^[32] The amine functional group was planned to be installed by a formal anti-Markovnikov hydroamination of the terminal alkene in 11. The α-quaternary chiral center of acid 11 presents a good fit with the asymmetric alkylation method developed in this study.

Scheme 2.

Synthesis plan for goniomitine.

The synthesis of goniomitine commenced with the allylation of α-ethyl-α-(trimethylsilyl)ethynyl acid 12, which was prepared in one step from commercially available 4-trimethylsilyl-3-butynoic acid 5a (Scheme 3). Intermediate acid 11 was obtained in 91% yield and 86% ee on a 1.3 g scale. To obtain a satisfactory conversion and enantioselectivity, ²TA chiral amine and a longer reaction time (3 h) were required. It is noteworthy that the chiral amine ²TA could be prepared in one pot from commercially available (R)-styrene oxide in decagram scale without column purification and it could be recovered after the reaction in one simple acid-base extraction.^[33] The α-allyl ester 13 was obtained in 95% yield by methylation of acid 11 using (trimethylsilyl)diazomethane.

Scheme 3.

Synthesis of (+)-goniomitine.

With the requisite quaternary center established, we began investigating methods to achieve an anti-Markovnikov hydroamination of the terminal olefin of 13. The one-pot hydrozirconation/amination procedure failed to deliver the desired product.^[34,35] Other olefin functionalization methods, for example, Rh-catalyzed hydroboration/oxidation proved sluggish, probably due to presence of trimethylsilylalkyne. To our delight, the copper-hydride catalyzed hydroamination method reported by Buchwald and co-workers facilitated the desired amination, leaving the alkyne group intact.^[36,37] By treating with potassium carbonate in methanol, desilylation was achieved in the same pot to give amino alkyne 14 in a moderate yield.

Subsequent Sonogashira cross-coupling brought together terminal alkyne 14 with the indole unit 15.^[32] Hydrogenation of the alkyne in 16 and complete debenzylation of the amine were achieved in a single step. The resulting primary amine intermediate formed lactam 7 upon heating with DBU.

Attempts to form the aminal function by treating 7 with reducing reagents (diisobutylaluminum hydride or lithium aluminum hydride or Schwartz reagent) only resulted in amide overreduction to amine.^[31f] To that end, following Takano’s method, tetracyclic core was constructed by dehydration-cyclization of lactam 7 with POCl₃ followed by NaBH₄ reduction.^[30h] Reduction of ester 17 with diisobutylaluminum hydride merged the sequence back into Takano’s pioneering work, where the final acid-catalyzed epimerization of known intermediate 18 was carried out to give (+)-goniomitine. In brief, by applying our alkylation method, the enantioselective synthesis was completed in 9 steps and 15% overall yield from commercially available 4-trimethylsilyl-3-butynoic acid.

In summary, we demonstrated the feasibility of α-alkynyl acids and α-allenoic acids to undergo highly enantioselective alkylation reaction using chiral lithium amide as noncovalent stereodirecting auxiliaries. This method allows for the practical rapid construction of α-chiral alkynyl acid with quaternary centers at the α-position. The chiral amine can be readily recovered by an aqueous extraction. Crystallographic studies suggest that the enantioselectivity is controlled by a unique alkynyl enediolate lithium aggregate which features a lithium cation-π interaction with acetylene unit. These structural studies suggest the potential using lithium-acetylene interaction as a new mode of molecular recognition in the enantiocontrol. The utility of this alkylation method was demonstrated in the enantioselective total synthesis of (+)-goniomitine. Key steps of the synthesis involved construction of C20 quaternary centers via our asymmetric alkylation method and a CuH-catalyzed anti-Markovnikov hydroamination reaction. Application of the strategy in the context of alkaloid total synthesis is ongoing in our laboratory.