Stereoselective Synthesis of Cyclohexanes via an Iridium Catalyzed (5 + 1) Annulation Strategy

: An iridium catalyzed method for the synthesis of functionalized cyclohexanes from methyl ketones and 1,5-diols is described. This process operates by two sequential hydrogen borrowing reactions, providing direct access to multisubstituted cyclic products with high levels of stereocontrol. This methodology represents a novel (5 + 1) strategy for the stereoselective construction of the cyclohexane core.

T he substituted cyclohexane motif is encountered in a wide range of natural products, pharmaceutical agents, and materials. 1 Consequently, methods which target the synthesis of this scaffold, particularly those in which the regio-and stereochemistry of the product can be controlled, are of great importance. 2 Previous approaches to substituted cyclohexanes have primarily been based upon (6 + 0) or (4 + 2) strategies involving hydrogenation of an aromatic precursor or Diels− Alder cycloaddition followed by reduction (Scheme 1A). 3 Several elegant (3 + 3) approaches based on cyclodimerization of donor−acceptor cyclopropanes have also been reported. 4 All of these strategies rely on the availability of appropriately substituted precursors, and as a result new methods targeting multisubstituted cyclohexanes are of great interest. A complementary (5 + 1) strategy would involve double alkylation of a C-1 building block with a C-5 bis-electrophile. However, very few such examples have been reported in the literature. 5 Typically, multistep sequences such as malonate alkylation/decarboxylation are required, and consequently, this methodology has not been widely employed. 6 We have recently reported that pentamethylphenyl (Ph*) ketones can be alkylated with alcohols via hydrogen borrowing catalysis (Scheme 1B). 7 This process is mediated by an iridium catalyst, which abstracts hydrogen from an alcohol to generate the corresponding carbonyl compound in situ. 8 After aldol condensation with the aryl ketone, the catalyst "returns" the abstracted hydrogen to provide the C−C coupled product and complete the catalytic cycle. We wondered whether a related approach could be used to construct substituted cyclohexane rings by double alkylation of Ph* ketones with 1,5-diols (Scheme 1C). 9 This approach would form two new C−C bonds in a direct manner, enabling the synthesis of a diverse range of cyclohexane products due to the widespread availability of functionalized 1,5-diols. However, we recognized that, for this approach to prove fruitful, several challenges must be addressed: (i) to identify conditions which favor cyclization over competing oligomerization of the 1,5-diol; (ii) to control the stereochemistry at each of the newly formed stereogenic centers; (iii) straightforward conversion of the Ph* ketone to a range of functional groups without loss of stereochemistry.
We commenced our study by investigating the reaction between ketone 1 and unsubstituted pentanediol 2a. In the presence of catalytic [IrCp*Cl 2 ] 2 and KOH in toluene at 105°C, we were pleased to isolate the desired cyclohexane product 3a in 44% yield (Table 1, entry 1). We investigated various bases and found that KO t Bu provided similar results, while other bases (NaOH, LiOH, K 3 PO 4 ) afforded 3a in reduced yields (entries 2−5). With an increased amount of base (4 equiv) we obtained 3a in a higher yield of 58%, but a further increase to 5 equiv did not provide any further improvement (entries 6−7). When the temperature was raised by 10°C, 3a was obtained in an improved 66% yield (entry 8). Increasing the amount of diol to 2 equiv did not result in any further enhancement (entry 9). We then applied these conditions to a diol bearing an α-methyl substituent (2b). In this case, the desired product 3b was isolated in 61% yield as an 85:15 mixture of diastereoisomers (entry 10). We were delighted to find that increasing the loading of diol to 2.0 equiv resulted in a significant increase in yield and 3b was isolated in 80% yield (entry 11). Moreover, 3b was formed as a single diastereomer. As expected, an experiment conducted in the absence of [IrCp*Cl 2 ] 2 gave only unreacted starting materials (entry 12). Finally, when 1 was replaced by acetophenone a complex mixture of products was obtained (entry 13), which confirms the key role that the Ph* group plays in minimizing undesired side reactions.
With optimal conditions for double alkylation of Ph* ketones in hand, we set out to investigate the generality of this process (Table 2). We were pleased to find that diols substituted with a geminal dimethyl group cyclized cleanly to afford cyclohexanes 4 and 5 in 79% and 83% yield, respectively. We were also able to access spirocyclic products 6 and 7 in excellent yields. The enhanced yields obtained with geminally disubstituted diols are likely a consequence of the Thorpe−Ingold effect which favors the desired cyclization pathway. 10 An α-phenyl substituted diol cyclized efficiently to afford 8 in 78% yield as a single diastereoisomer. In both NaOH (3) 2a (

Journal of the American Chemical Society
Communication compounds 3b and 8 the trans-diastereoisomer was obtained as the major product which led us to speculate that the relative stereochemistry is established by base-mediated epimerization αto the carbonyl. In line with this hypothesis, when βsubstituted diols were subjected to our optimized conditions we isolated cyclohexanes 9 and 10 in good to excellent yields with high selectivity in favor of the cis-diastereoisomer. Pleasingly, γ-substituted diols also proved to be well tolerated and products 11 and 12 were obtained in 76% and 83% yields respectively, both as a single trans-diastereomer. We found that substituents on the aromatic ring were well tolerated, including electron-donating, electron-deficient, halogen-containing, and sterically encumbered groups (13−16).
We next turned our attention to the synthesis of more complex cyclohexanes from multiply substituted diols. Trisubstituted cyclohexanes 17, 18, and 19 were obtained in good yields as mixtures of diastereoisomers (the factors responsible for stereoselectivity are discussed later). 11 Incorporation of a phenyl substituent was tolerated, and arylated cyclohexane 20 was isolated in 72% yield and 70:30 d.r. Symmetrical diols also participated in the desired reaction providing products 21 and 22 in high yields with a preference in both cases for the formation of the C2-symmetrical diastereoisomer. When we evaluated an α,γ-substituted diol we were pleased to obtain trisubstituted cyclohexane 23 in 74% yield with high diastereoselectivity (93:5:2 d.r.). With this substitution pattern, we explored variation of the C2 and C4 substituents and found that cyclohexanes 24 and 25 could be obtained in good yields again with excellent levels of diastereoselectivity. A diol synthesized in two steps from thujone cyclized to provide 6,3-fused product 26 in 90% yield as a mixture of diastereoisomers, while a diol obtained by reduction of camphoric acid afforded bicyclic product 27 in 75% yield as a single diastereoisomer. Finally, we subjected a symmetrical triol to our optimized conditions and obtained cyclohexane 28, resulting from cyclization followed by exocyclic hydrogen borrowing alkylation in 74% yield with good diastereoselectivity.
Having established that the relative stereochemistry at the C1 position arises from equilibration, 12 we were interested to determine how the relative stereochemistry is controlled at each of the other positions around the newly formed cyclohexane. Therefore, we carried out cyclohexane formation with enantioenriched diols bearing a stereogenic center at the α-, β-, and γ-positions (Scheme 2). As expected, diol (+)-2b reacted to give racemic 3b, a result which is consistent with a mechanism involving oxidation of the alcohol to the corresponding ketone. Interestingly, β-substituted diol (−)-29 also cyclized to give cyclohexane 9 as a racemate. We hypothesize that, after oxidation to the aldehyde, racemization can occur under the basic reaction conditions. 13 Pleasingly, γ-substituted diol (−)-30 cyclized cleanly to provide (−)-25 without any erosion of enantioselectivity (76% yield, >99:1 e.r.). This result demonstrates that a single γ-stereocenter can serve as a reporter site, translating its chiral information to new stereogenic centers on the cyclohexane ring.
For nonsymmetrical diols, the chemoselectivity of the initial oxidation and aldol reaction governs the regiochemistry of the final enone intermediate and is therefore expected to play a significant role in determining the stereochemical outcome of the reaction. To investigate this, we carried out a competition reaction in which ketone 1 was alkylated with an equimolar excess of a primary and secondary alcohol under our optimized conditions (Scheme 2B). The major products obtained were 33 (73% yield) and 35 (18% yield) which both arise from selective reaction of 1 with the primary alcohol. By extension, we propose that diols which possess both primary and secondary sites undergo preferential C−C bond formation at the primary position.
Given these results, we propose that stereochemistry at each position is controlled in the following manner: (i) The stereochemistry at C1 is set under thermodynamic control by base mediated epimerization; (ii) the stereochemistry at C2 is dictated by the facial selectivity of attack on a cyclic enone intermediate by iridium hydride; (iii) C3 is able to epimerize after oxidation to the aldehyde; (iv) the stereochemistry at C4 is translated from the diol starting material with complete fidelity (Scheme 2C).

Journal of the American Chemical Society
Communication With a robust method in hand for the stereoselective synthesis of cyclohexanes, we set out to demonstrate the utility of the Ph* ketone substituted cyclohexane products by carrying out a series of derivatization reactions. It has previously been demonstrated that Ph* ketones can be cleaved to the corresponding acid bromide by a retro-Friedel−Crafts acylation with bromine. 7 However, we were uncertain if this process would preserve the stereochemical integrity of the cyclohexane products. We were delighted to find that upon treatment of 8 with bromine at −17°C followed by addition of n-butanol the corresponding butyl ester 36 was obtained in 94% yield as a single diastereoisomer (Scheme 3A). A representative series of reaction products were smoothly converted to the butyl esters (37−41), and in all cases no erosion of stereochemistry was observed. 14 Taking cyclohexane 12 as a representative example, a range of different functional group interconversions were investigated (Scheme 3B). After cleavage to the acid bromide, reduction with LiAlH 4 afforded cyclohexyl alcohol 42 in 95% yield as a single diastereomer. Alternatively, palladium catalyzed partial reduction provided aldehyde 43 in 88% yield without epimerization. 15 The acid bromide is a versatile intermediate, which could be hydrolyzed to the corresponding acid 44 (76% yield, >95:5 d.r.) or coupled with amine nucleophiles to afford amides 45 and 46. Finally, coupling with N-hydroxyphthalimide afforded useful NHP-ester 47 in 89% yield as a single diastereomer. 16 In conclusion, we have developed an efficient method for the synthesis of cyclohexanes by alkylation of ketones with diols via hydrogen borrowing catalysis. A series of multiply substituted cyclohexane products were obtained often with high levels of control over relative stereochemistry. Several control experiments were carried out, which established the factors responsible for stereocontrol at each of the positions around the newly formed cyclohexane ring. Finally, it was demonstrated that the Ph* ketone substituted cyclohexanes could be readily converted into a wide variety of functional groups without epimerization. Given the extensive availability of substituted diols, we believe that this methodology will find widespread use for the stereoselective synthesis of functionalized cyclohexanes.

* S Supporting Information
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/jacs.8b07776.
Detailed experimental procedures and characterization data for new compounds (PDF)