Stereospecific Construction of Quaternary Carbon Stereocenters from Quaternary Carbon Stereocenters.

Organoaluminum species promote a smooth nucleophilic substitution at the quaternary carbon stereocenter of stereodefined polysubstituted cyclopropyl methyl phosphate with a complete inversion of configuration, even when more reactive functional groups are present. The regio- and diastereoselectivity of the substitution is attributed to the existence of a bicyclobutonium intermediate.

The stereospecific synthesis of quaternary carbon stereocenter A, a molecular fragment found in many natural products,[1] has constantly aroused the curiosity of organic chemists, leading in the past decade to numerous efficient strategies.[2] However, if one needs to add an additional vicinal stereocenter next to the quaternary, the proximity of these bulky alkyl chains induces distorted geometries and the diastereocontrol of the overall spatial arrangement of these two stereocenters in acyclic systems becomes more difficult.[3] Even more challenging is the preparation of vicinal stereocenter B that is only constituted of carbons and hydrogen atoms (hydrocarbon chains) and therefore devoid of polar functions (Scheme ),[4] which are usually required as a chemical handle to perform selective transformations, eliminating most of the synthetically powerful [3,3]-sigmatropic rearrangements[5] and enolate approaches.[6] While the nucleophilic substitution reaction at primary, secondary,[7] and even at tertiary stereocenters[8] are well explored with carbon nucleophiles, nucleophilic substitution at quaternary carbon stereocenter with carbon nucleophile has never been considered since the amount of energy required to break a C–C single bond is too high (bond energy 348 kJ/mol). Is, nevertheless, the nucleophilic substitution at a quaternary carbon center a conceivable process? Could we promote a carbon–carbon bond cleavage at a quaternary carbon center with pure inversion of configuration? Could it be used for the preparation of regio-, diastereo-, and even enantiomerically enriched products possessing vicinal stereocenters including a quaternary carbon stereocenter? If the C–C bond is the least reactive functional group, how could a C–C bond cleavage be performed under mild conditions that would allow the presence of more sensitive functional groups? Thrilled by these fundamental questions, we have recently reported a contra-intuitive approach, where nucleophilic substitution at the quaternary carbon stereocenter was indeed a viable concept to create tertiary alcohol and halides with a complete inversion of configuration (Scheme ).[9] Actually, cyclopropyl carbinol derivatives could undergo a regio- and stereoselective nucleophilic substitution at the quaternary carbon center C1, with pure inversion of configuration, to provide the acyclic products as a single diastereoisomer. The selectivity of the substitution was attributed to the existence of a bicyclobutonium species,[10] reacting at the most substituted carbon center. Spurred by this remarkable transformation, we implemented this discovery in a newly devised strategy to address the highly challenging and selective preparation of three-dimensional hydrocarbon chains possessing vicinal and congested sp3 centers. In this communication, we wish to report the results of this overall synthetic approach, ultimately representing a modular route to efficiently prepare acyclic hydrocarbon chains featuring vicinal congested quaternary and tertiary carbon stereocenters.

Scheme 1

Vicinal Stereocenters and Nucleophilic Substitution at Quaternary Carbon Stereocenter

Based on the selective metal-catalyzed ring opening of cyclopropylcarbinol with heteroatoms,[9] we recognized the unique potential of these three-membered rings to serve as a central platform to promote highly selective nucleophilic substitution with carbon nucleophiles. Accordingly, a modular and efficient preparation of these starting polysubstituted cyclopropyl carbinols was easily achieved by a diastereoselective copper-catalyzed carbomagnesiation reaction of achiral cyclopropenes (Scheme a).[11] After reaction with CO2 and subsequent reduction, the corresponding polysubstituted cyclopropyl carbinols 2a–k were obtained in excellent diastereomeric ratios even when spiro-cyclic products were formed (Scheme a).[11] Among all tested leaving groups, phosphates 3 displayed the right compromise between stability and reactivity.[10]

Scheme 2

Diastereoselective Preparation of Polysubstituted Cyclopropyl Methyl Phosphates

To further extend the nature of potential groups present on the three-membered rings, we also developed an alternative approach to cyclopropyl methyl phosphates through the copper-catalyzed carbomagnesiation reaction of cyclopropenyl esters 4a–4h,[12] easily prepared by a [2 + 1]-cycloaddition of Rh-carbene with alkynes,[13] followed by reaction with various electrophiles (2l–ac, Scheme b).[14] By a simple reduction of the ester and protection of the resulting alcohol, the substrates bearing the phosphate leaving group (3l–3ac, Scheme b) were easily obtained with excellent diastereomeric ratios in overall yields ranging from 40% to 60%. In this case, the nature of the R3 groups originates from the electrophiles and not from the nucleophilic addition as previously discussed in Scheme a. It should be noted that, for 3f, 3t, 3w, and 3x, an additional chemical step was used to transform the alkenyl moieties into their respective functionalized products whereas the Simmons–Smith cyclopropenation reaction[15] of geraniol was used to prepare 3n (see Supporting Information). The advantage of the latter strategy (Scheme b) is that the electrophile (i.e., allyl bromide) could easily be transformed into valuable functionalized groups; see 3w and 3x, Scheme b. As a result of these two well-coordinated strategies, a variety of bench-stable diversely polysubstituted cyclopropyl methyl phosphates 3a–ac were quickly assembled, in high stereoisomeric purities. Keys to the success of our strategies were that enantioselective catalytic copper-carbomagnesiation of achiral cyclopropenes (Scheme a)[16] and the enantioselective catalytic [2 + 1] cycloaddition reaction leading to enantiomerically enriched cyclopropenyl ester (Scheme b)[13] have been successfully reported. With these straightforward and general methods for the preparation of 3 in hand, we focused on probing the feasibility of nucleophilic substitution at the quaternary carbon stereocenter with carbon nucleophiles. Following a thorough optimization (see the Supporting Information for all details), it became rapidly clear that a Lewis acid was necessary to promote the reaction while a nucleophile was needed to perform the substitution at the quaternary carbon stereocenter of the cyclopropyl ring. Organoaluminum compound R3Al possessing not only a polar C–Al bond but also a high Lewis acidity property was the perfect candidate to perform this transformation (Scheme ).[17] Under the optimal conditions, when 3a was treated with Me3Al at low temperature, 5a was obtained in an excellent yield (90%) and diastereomeric ratio (dr 94:06, specificity sp 96:04). It is important to note that the nucleophilic substitution occurs exclusively at the quaternary carbon stereocenter, as no trace of substitution was detected at either the primary C4 [CH2OPO(OEt)2] or tertiary C2[C–CHR3–C] carbon centers. The relative configuration was determined by X-ray analysis of derivatized 5u,[18] and all other configurations were assigned by analogy. Considering the configurations of the starting materials,[11−14] the nucleophilic substitution at the quaternary carbon center proceeds with a complete inversion of configuration. The nature of the R3 group on C2 could be varied as longer or branched alkyl chains, and terminus phenyl or alkenyl groups are tolerated (5b–5e, Scheme ). More sophisticated molecular backbones in the starting materials possessing spiro moieties such as 3i–k are compatible and proceed selectively at the rather bulky quaternary carbon stereocenter to provide 5k–m in excellent yields and selectivities (Scheme ). The two diastereomers at the quaternary carbon C1 can easily be accessed by simply permuting the nature of the two substituents (5n and 5o, Scheme ). Interestingly, when 3f or 3x, possessing a terminal reactive epoxide functionality, is treated with Me3Al, the nucleophilic substitution still proceeds at the quaternary carbon stereocenter without any traces of ring opening to the epoxide (5f and 5u, Scheme ). This chemoselective transformation (selective carbon–carbon bond cleavage in the presence of an epoxide) illustrates the power of the exclusive formation of the bicyclobutonium species as a reactive intermediate. In this context, 3w possessing a second cyclopropyl ring on the same molecular backbone but unable to provide the bicyclobutonium remains untouched under this reaction condition (formation of 5v, Scheme ). The nature of the two substituents at C1 could be successfully varied, and in all cases, hydrocarbon chains possessing the desired quaternary and tertiary stereocenters are obtained with very high stereospecificity (Scheme ), even when functional groups are present (5w, Scheme ).

Scheme 3

Nucleophilic Substitution at Quaternary Carbon Stereocenters

Remarkably, even when the nucleophilic substitution reaction might have two competitive sites of reaction such as an unsubstituted cyclopropyl carbon center (C2) and a fully substituted carbon center (C1), the transformation exclusively proceeds on C1 to give the products 5x–z in excellent yields.

The reaction is not limited to the addition of Me3Al, and the higher Et3Al homologue could also be used (5h, 5z, and 5aa, Scheme ). Finally, the presence of an additional substituent on C3 (R4 = Ph) does not impede the reaction to proceed, as the skipped dienes 5ab and 5ac were obtained with excellent stereospecificities (Scheme ). When the copper-catalyzed carbomagnesiation of achiral cyclopropenes 1a (R1 = Ph, R2 = Et) and 1d (R1, R2 = −C6H4–(CH2)3−) were performed with H2C=CH–(CH2)3MgBr in the presence of Cu(CH3CN)4PF6 (5 mol %) and (R,S)-Josiphos (7.5 mol %) as a chiral ligand,[16e] the corresponding cyclopropanes 3e and 3k were obtained with moderate enantiomeric ratios of 80:20 and 90:10, respectively.[13] However, the subsequent addition of Me3Al promotes the nucleophilic substitution at the quaternary carbon stereocenter in excellent yield and stereospecificities to give the corresponding two products 5e and 5m with the same enantiomeric ratios. It should be noted that the two enantiomers could not be separated by classical HPLC due to their nonpolar nature and lack of functional groups. Hence, the enantiomeric ratios of 5e and 5m were determined after subsequent transformation of the less sterically hindered terminal alkene into alcohols using a hydroboration–oxidation sequence (See the Supporting Information).[19] Based on the observations above, the reaction is both highly enantiospecific (>99%) and diastereoselective, implying that the reaction proceeds without racemization.

To have additional insight on the reaction mechanism, two secondary cyclopropyl phosphates 3ad and 3ae were prepared as a mixture of two diastereomers at the secondary protected alcohol moiety C4 (Scheme ).

Scheme 4

Nucleophilic Substitution of Secondary Cyclopropyl Phosphate

Upon addition of Me3Al, two pure E-stereodefined hydrocarbon derivatives 5ad and 5ae were obtained with excellent stereospecificities. In both cases, direct nucleophilic addition on C4 was also observed in 40% and 10% yields respectively. As expected, the nucleophilic substitution proceeding at the most substituted carbon center is independent of the stereochemistry at the starting carbinol center C4 suggesting that the reaction proceeds through the formation of an initial cyclopropyl carbocation, best represented as the hybrid bicyclobutonium form (Scheme ). The addition occurs at the carbon center possessing the highest positive charge and therefore proceeds selectively at the initial quaternary carbon center with a complete inversion of configuration. The unique feature of this bicyclobutonium species is that one face of the transient carbocation is shielded by the molecular backbone, and although it relates to the substitution at the level of intimate ion-pairs, the selectivity of the substitution is therefore easier to control.

In conclusion, organoaluminum species promote smooth nucleophilic substitution at quaternary carbon stereocenters with a complete inversion of configuration, even when more reactive functional groups are present such as epoxides or alkyl halides. The regio- and diastereoselectivity of the substitution is attributed to the existence of a bicyclobutonium intermediate. As a result, otherwise difficult to access, acyclic hydrocarbons are easily prepared from readily available starting materials.