Stereocenters, quaternary carbon

The previous section discussed chelation enforced intra-annular chirality transfer in the asymmetric synthesis of substituted carbonyl compounds. These compounds can be used as building blocks in the asymmetric synthesis of important chiral ligands or biologically active natural compounds. Asymmetric synthesis of chiral quaternary carbon centers has been of significant interest because several types of natural products with bioactivity possess a quaternary stereocenter, so the synthesis of such compounds raises the challenge of enantiomer construction. This applies especially to the asymmetric synthesis of amino group-substituted carboxylic acids with quaternary chiral centers. 

Since the first synthesis of ketone 2 was reported by Rapoport et al. in 1977 [15], four research groups including our group have reported the synthesis of ketone 2 [ 16-19]. These syntheses will be described in the following sections. The structural feature of ketone 2 is the frans-decahydroisoquinoline skeleton possessing a quaternary carbon stereocenter at the bridgehead position. The key step is the construction of this characteristic structure. 

With the procedure for constructing the quaternary carbon stereocenter in hand, the conversion of the ris-form to the trans form was explored in accordance with the synthetic plan shown in Scheme 9. The ketone moiety of the 1,4-conjugated adduct 61 was protected by an acetal group, followed by decarboxylation of compound 65 using sodium ethylthiolate to yield lactam trans-62 and cis-62 as an 8 1 diastereomixture [31]. The reason why the lactam trans-62 was obtained as a major product is that the subsequent protonation after decarboxylation proceeded kinetically. This assertion is supported by experimental results in which the trans- and cis-lactam diastereomixture (8 1) in ethanol was refluxed in the presence of potassium hydroxide to afford a 1 5 mixture [15,32,33]. The mixture of the lactam trans-62 and cis-62 was reduced with DIBALH, followed by treatment with sodium hydroxide to give bicyclic enamine 63. The kinetic iminium salt prepared from bicyclic enamine 63 with hydrochloric acid was reduced with sodium cyanoborohydride, leading to the frans-decahydroisoquinoline structure [22], The acetal moiety of the resultant 67 was removed to provide the objective ketones 68a and 2c. This method enabled the construction of the tra s-decahydroisoquinoline structure without an intermediate resembling the neurotoxic MPTP, and in fewer steps. 

Silylene transfer to a,j3-unsaturated carbonyl compounds has been shown to provide a stereoselective method for the synthesis of compounds possessing quaternary carbon stereocenters (Scheme 36).61... 

Silylene transfer to a -unsaturated esters produces oxasilacyclopentenes and provides a new method for regio- and stereo-selective formation of enolate that can undergo facile and selective Ireland-Claisen rearrangements and aldol addition reactions to provide products with multiple contiguous stereocenters and quaternary carbon centers (Scheme 37). 

Similar TiCl4-promoted coupling reactions of pyruvates 467 with 3,4-dihydro-2//-pyran 455 provided quaternary carbon stereocenters stereoselectively (Scheme 83) <2000TL8425>. The use of (2-trimethylsilyl)ethyl pymvate in this transformation results in a one-pot addition sequence to deliver functionalized [2,3-Z4pyran derivatives, for example 468, in good yields <2003SL1491>. 

Intramolecular Heck reactions for building up complex oxacyclic skeletons are a common theme in the synthesis of natural products. These reactions are exceptionally valuable for the installation of quaternary carbon stereocenters. In the morphine total syntheses by Overman <1994PAC1423> and Trost et al., intramolecular Heck reactions to form dihydrobenzofurans served as strategic key steps (Equation 138) <2005JA14785>. Asymmetric variants of intramolecular Heck reactions based on BINAP ligands to yield dihydrobenzofurans have also been investigated <1998T4579>. 

Formation of Chiral Quaternary Carbon. Birch reduction-alkylation of benzoic acids and esters establishes quaternary carbon centers. Neighboring stereocenters will influence the stereochemical outcome of the tandem reaction sequence. The following example illustrates how a chiral auxiliary (derived from prolinol) controls the stereoselection in the Birch reduction-alkylation step. ... 

Sugars have also been used as chiral auxiliaries in acetal formation for diaste-reoselective radical cyclizations [52]. In Eq. (13.40) a chiral acetal is utilized to control the stereochemistry of a 5-exo-dig cyclization resulting in the formation of quaternary carbon-based stereocenters. Product 129 is formed as a single diaste-reomer in 35% yield. An allylic strain model is proposed to account for the stereochemical outcome of this reaction. 

It has recently been demonstrated that alkylation of allyl acetate and symmetrical allylic carbonates with a 3-ketoester is an efficient route to products containing a quaternary carbon center and one or two new stereocenters, respectively [129]. The best ee for the alkylation of 2-carboethoxycyclohexanone was 86% using toluene (75% ee in CH2CI2) as the solvent, N,N,N, N -tetramethylgaa-nidinium ion as the cation, and 49 as the ligand (Scheme 46). The product was used as a key intermediate in the synthesis of the spiroalkaloid (-)-nitramine. 

When a quaternary carbon atom is produced in the acylation process, racemization is not possible and the stereochemical outcome can be affected by the presence of an adjacent stereocenter. Treatment of the chiral lactone (168) with LDA and acetyl cyanide gave the diastereomeric products (169) and (170) in the ratio 60 1 (equation 44). ... 

An important utility of the Krapcho reaction is not necessarily the decarboxylation step itself. Rather, the fact that the decarboxylation can be made to occur allows several reactions that require malonates or their derivatives to find general synthetic utility. For example, elegant work in the area of rhodium carbenoid chemistry relies on diazomalonates to generate the carbenoid. As utilized by Wee,20 diazomalonate 14 is treated with Rh20Ac4 to generate the carbenoid which inserts into the stereochemically defined tertiary C—H bond. The reaction proceeds exclusively with retention of configuration in forming the new quaternary carbon stereocenter. Decarboxylation of 15 under Krapcho s conditions provides lactone 16, a key intermediate in the synthesis of (-)-ebumamonine. 

Strecker reaction to establish a new stereocenter is subject to asymmetric induction, capable of creating either a tertiary" or quaternary carbon atom in the presence of 59. The peptido-imine 60 proves to be an excellent ligand for the Ti(IV)-mediated cyanation of aldimines. On catalysis of the bicyclic guanidine 61 the addition of HCN to A-benzhydrylaldimines affords a-amino nitrile derivatives with moderate to good ee. ... 

Reserpine a challenge for total s5mthesis of natural products 05CRV4671. Stereo-controlled construction of quaternary carbon stereocenters in total synthesis of complex cydotiyptamine alkaloids 07AG(E)5488. S5mtheses of morphine and codeine (1992-2002) 06COS99. 

Diara et al. carried out interesting applications of the cyclopentanone formation. Stereoselective synthesis of a-substituted cyclopentanone 54 with a quaternary carbon stereocenter was carried out by the reaction of the allenylcyclobutanol 52 with 4-iodoanisole (53) [9]. Intramolecular reactions of the stereoisomers 55 and 57 in the presence of silver salt in toluene afforded different products depending on their stereochemistry. The macrocyclic dimeric product 56 was obtained from... 

Nemoto and Hamada [50] has described the development of a new class of chiral phosphorus ligand - aspartic acid-derived P-chirogenic diaminophosphine oxides, DIAPHOXs - and their application to several Pd-catalyzed asymmetric allylic substitution reactions. Pd-catalyzed asymmetric allylic alkylation was initially examined in detail using diaminophosphine oxides 77, resulting in the highly enantioselective construction of quaternary stereocenters. With the use of the Pd-DIAPHOX catalyst system, asymmetric allylic alkylation, asymmetric allylic amination, and enantioselective construction of quaternary carbons were achieved with high ee (up to 97-99% in many cases) (Scheme 24). 

With the formation of the entire colombiasin skeleton accomplished through the successful generation of 40 (Scheme 7), including the two quaternary carbon atoms and the additional three stereocenters present in the target molecule, only a few minor details remained before arriving at colombiasin A (1). First, the extraneous hydroxyl group at C-5 was reductively removed through the use of the Barton—McCombie protocol in which the initial for-... 

The enantioselective intramolecular [2+2+2] cycloaddition of 1,4-dienynes 429 gave the bicyclo[2.2,l]heptene skeleton 430, accompanied by a small amormt of 431 (Scheme 2-43). For Ais reaction, dienynes cormecting the alkyne and the other alkene components with 1,1-disubstituted alkene moieties were employed. For this reaction, dienynes connecting the alkyne and the other alkene components with 1,1-disubstituted alkene moieties were employed. Each product of this reaction represents a unique class of cycloadducts that possess two quaternary carbon stereocenters. 

Overman, L.E. and Watson, D.A. (2006) Diastereoselection in the formation of contiguous quaternary carbon stereocenters by the intramolecular Heck reaction. J. Org. Chem., 71, 2600-8. 

This work presents the first catalytic enantioselective cyclization strategy for accessing steroidal and terpenoidal frameworks using organocatalysis. It should be pointed out that the present domino cycHzation could be conducted at room temperature. The asymmetric construction of multiple C-C bonds and contiguous stereocenters using substrate 263 in the presence of the chiral imidazolidinone 259 resulted in the formation of 264 with four new C-C bonds, seven stereogenic centers, and three quaternary carbon centers with about 90% yield for each chemical bond formation and over 90% ee. 

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