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Title:
C-H Functionalization Approach for the Synthesis of Chiral C 2 Symmetric 1,5-Cyclooctadiene Ligands

Paper sections:

<p>1,5-Cyclooctadiene (COD) is widely used as a ligand in transition metal complexes. 1 Metal-COD complexes are useful because many are sufficiently stable to be isolated and easily handled, often more robust than the related ethylene complexes because of chelation. Even though the metal-COD complexes were initially considered as stable precursors to active catalysts, it became clear in many instances that the COD ligand was not lost and was an integral part of the catalytic cycle. [2][3][4] Consequently, there became interest in designing chiral COD ligands for chiral catalysis. The Chiral COD ligands 1 and 2 have shown considerable promise but their synthesis requires a multistep synthesis and a resolution. 4b This has led to the synthesis of other skipped cyclic dienes as chiral ligands, [4][5][6] including a number of C2 symmetric ligands 3-6. However, all require a multistep synthesis and most involve a racemic synthesis followed by resolution 4-6 (Scheme 1). In this paper we describe an enantioselective C-H functionalization method for the direct synthesis of C2 symmetric COD derivatives 7, with four stereogenic centers. Furthermore, we describe their derivatization to other C2 symmetric COD derivatives 8 and their initial evaluation as chiral ligands for rhodium-catalyzed conjugate addition.</p><p>The motivation for this study was the realization that COD would be an intriguing substrate to challenge catalystcontrolled C-H functionalization by rhodium-stabilized donor/acceptor carbenes (Scheme 2). 7,8 We have recently shown that dirhodium catalysts of defined shapes are capable of selecting between primary, secondary and tertiary unactivated</p>

Scheme 1 Chiral cyclic diene ligands
<p>C-H bonds. 8a-e We have also shown that catalysts can be designed that would select between different secondary C-H bonds. 8c,f,g COD was considered to be an interesting substrate because even though the methylene sites are allylic and relatively activated, the cis alkene would be expected to be a competing site for cyclopropanation. Therefore, we would need to identify a catalyst that would lead to selective C-H functionalization instead of cyclopropanation. Then, ideally once the mono C-H functionalization has occurred, the catalyst would select the C5 site for a second C-H functionalization, over the two other allylic methylene sites at C3 and C6 to generate the COD derivative 9. For the overall</p><p>(1 mol %)</p><p>scheme to be useful we would need to be able to control the stereochemistry of the four newly formed stereogenic centers so that the C2-symmetric form of 7 is generated.</p>

Scheme 2. Synthetic Challenge
<p>The first stage of the study focused on the mono-C-H functionalization reactions using the most promising catalysts in our tool box for selective reactions at methylene sites (Scheme 3). Rh2(S-DOSP)4 (10) is our original catalyst and has been shown to be broadly applicable for functionalization of activated methylene sites. 7b Rh2(S-PTAD)4 ( 11) is an uncrowded catalyst that can give different stereochemical results to Rh2(S-DOSP)4 at methylene C-H functionalization. 7b Rh2(R-TPPTTL)4 (12) has shown remarkable site selectivity for C3 over C4 C-H functionalization of alkylcyclohexanes. 8f The triphenylcyclopropanecarboxylates (TPCP) derivatives generate the most sterically crowded dirhodium tetracarboxylate catalysts. Rh2(R-p-BrTPCP)4 ( 13) was the first member of this class and preferentially reacts at less crowded C-H bonds. 8a,b Rh2(R-3,5-(p-t BuC6H4)TPCP)4 ( 14) and Rh2(R-2-Cl-5-BrTPCP)4 ( 15) selectively react at the most accessible unactivated methylene site in linear alkanes. 8c,g We have recently found that C-H functionalization with donor/acceptor carbenes tend to proceed in higher yields when the acceptor group is a trihaloethyl derivative. 8b Therefore, the test reaction was initially conducted with the trichloroethyl aryldiazoacetate 16 and 2.5 equiv of COD. Most of the catalysts gave an undefined mixture of products, consisting of cyclopropanation, diastereomeric monoinsertion and likely diastereomeric and/or regioisomeric diinsertion products (see supplementary information for details). In contrast, the Rh2(R-2-Cl-5-BrTPCP)4-catalyzed reaction was relatively clean and the desired mono C-H functionalization product 17 could be isolated in 72% yield, >30:1 dr and 91% ee.</p>

Scheme 3 Catalyst screening
<p>The scope of the reaction was then examined with a range of aryldiazoacetates as summarized in Scheme 4. The first three systems examined the influence of the ester functionality. The methyl ester gave the C-H functionalization product 18 with lower diastereoselectivity and enantioselectivity compared to the trichloroethyl ester 17, further underscoring the advantage of the trihaloethyl esters in C-H functionalization reactions. The trifluoroethyl derivative 19 was formed with the highest yield and enantioselectivity and retained the high diastereoselectivity. Therefore, the further studies focused on the trifluoroethyl derivatives. A series of p-substituted aryl (20-24) and a pyridyl derivative (25) were prepared and they were formed in high yield and dr, with the asymmetric induction in the range of 79-95% ee. The reaction with a metasubstituted aryldiazoacetate gave the mono-insertion product 26 but with decreased enantioselectivity (63% ee). We also examined the reaction with the styryldiazoacetate and it similarly gave an effective reaction to form 27 in 67% yield, >30:1 dr, 88% ee.</p>

Scheme 4. Mono C-H functionalization of COD
<p>With the vision of designing chiral COD ligands, we decided to explore whether a double C-H functionalization could be achieved because this could be a direct way for the synthesis of C2 symmetric ligands. At the onset of this work, it was considered to be a challenging C-H functionalization because a stereoselective reaction would be required at a specific allylic methylene site in the presence of two other allylic methylene sites and two cis-alkenes. Nevertheless, the double C-H functionalization turned out to be very effective (Scheme 5). The reaction was conducted using 3 equiv of the diazo compound at elevated temperature (40 °C), and under these conditions the bis C-H functionalization products 28-35 were formed in good yield. All the products are produced with very high levels of enantioselectivity (>99% ee) even though the enantiomeric purity of the mono C-H functionalization products was considerably lower (72-95% ee). This is because the minor enantiomer of the mono-insertion product is primarily transformed into the meso diastereomer of the final bis C-H insertion product during the second insertion. Also, imperfect asymmetric induction of the major enantiomer of the mono insertion product generates a diastereomer rather than an enantiomer of the final bis C-H insertion products. Consequently 28-35 are produced with very high enantioselectivity but with moderate diastereoselectivity. Fortunately, the desired major diastereomer is easily purified on silver-impregnated silica.</p>

Scheme 5. Double C-H functionalization of COD
<p>In order to understand the unprecedented site selectivity exhibited by COD, control experiments were conducted on related substrates using Rh2(2-Cl,5-BrTPCP)4 (15) as catalyst (Scheme 6). 1E,5E,9E-Cyclododecatriene (36) was found to be an effective substrate, forming the allylic C-H functionalization product 37 with poor diastereoselectivity but high enantioselectivity. The diastereomeric ratio could be altered slightly (2:1 -1:2) with different dirhodium catalysts, but no catalyst rendered the reaction highly diastereoselective. The reaction with cyclohexene gave a mixture of cyclopropanation (38) and C-H functionalization products (39), ranging from 1.27:1 to 1:2.85, and the diastereoselectivity was also poor ranging from 3.11:1 to 1:3.12 dr (see supporting information for details). The reaction with cis-cyclooctene, however, was very clean but the only product formed was the cyclopropane (40) (scheme 3). These results indicate that the structural features of COD are ideally suited for stereoselective allylic C-H functionalization, and other cycloalkenes can have a very different reactivity profile.</p>

Scheme 6. Evaluation of related cycloalkenes
<p>The bis C-H functionalization products can be further derivatized by either ester hydrolysis, ester reduction, or aryllithium addition, and the resulting alcohol products can be either methylated or silylated (See supporting information for details), leading to the formation of a variety of C2-symmetric chiral COD ligands (41-49). A preliminary exploratory study was conducted to determine if these chiral COD ligands were compatible with rhodium-catalyzed conjugate addition of phenylboronic acid to cyclohexenone (Scheme 7).</p><p>The reactions with all of the ligands, except for the aryl iodide derivative 31 resulted in the formation of conjugate addition product 50 in reasonable yield (32-84%) and variable levels of enantioselectivity (26-76% ee). Most of the direct double C-H insertion products gave about 30-40% ee but some of the ligands derived from the aryllithium addition gave higher levels of enantioselectivity. The most promising ligand to date has been 49, which resulted in the formation of 50 in 63% yield and 76% ee. In conclusion, a one-step enantioselective synthesis of C2symmetric chiral COD ligands was achieved by means of a double allylic C-H functionalization of COD. This transformation illustrates the capacity of C-H functionalization to rapidly generate synthetic complexity from a simple starting material. Initial evaluation of these chiral COD ligands along with their derivatives revealed they were effective in the rhodium-catalyzed asymmetric arylation of cyclohex-2enone.</p>

ASSOCIATED CONTENT
<p>Supporting Information. The Supporting Information is available free of charge on the ACS Publications website. Complete experimental procedures and compound characterization are available in the Supporting Information. (PDF) CIF file for 22 (CCDC 1960982), 35 (after reduction) (CCDC  1960983), 37 (major) (CCDC 1960993)</p>
Chiral cyclooctadiene (COD) derivatives are readily prepared by rhodium-catalyzed allylic C-H functionalization of COD. Either mono or difunctionalization of COD is possible generating the products in high yield, diastereoselectivity and enantioselectivity. The double C-H functionalization generates C2 symmetric COD derivatives with four new stereogenic centers in >99% ee, which can be readily converted to a series of chiral COD ligands. Preliminary evaluations revealed that the COD ligands can be used in rhodium-catalyzed asymmetric arylation of cyclohex-2-enone, leading to the conjugate addition products in up to 76% ee.