(38) Synthesis of the diiodoaryl alcohol involves protection of the dibromo-diol as bis(methoxymethyl)ether, metal-halogen exchange (n-BuLi) followed by treatment with I2, removal of the MOM groups and installation of a TBS group.
We then examined transformations of oxabicyclic olefins of different stereochemical identities that contain varying protecting groups at their alkoxy substituent, and the results of our investigations are summarized in Table 1.6. When exo oxabicycle 1.74 is subjected to 1.1 equivalents of n-butylvinyl ether 1.88a (entry 1, Table 1.6) or p-methoxyphenyl vinyl ether 1.88b in the presence of 1.69c (entry 3, Table 1.6), ROCM processes proceed readily to >98%
conversion with complete Z selectivity; however, in stark contrast with the endo oxabicycle 1.66 (cf. Table 1.5), there is hardly any enantioselectivity (52:48 er for 1.94a and 57:43 for 1.94b).
Subsequent studies, further discussed in section 1.4.d, allowed us to establish that when larger amounts of enol ether 1.88a–b are employed, as the results in entries 2 and 4 of Table 1.6 indicate, the desired Z enol ether ROCM products are formed in high enantioselectivity (95:5 er for 1.94a and 92:8 er for 1.94b).
The ROCM data (entries 5–10, table 1.6) of oxabicyclic benzyl ethers 1.78 and 1.80 illustrate that the requirement of excess enol ether cross partner for obtaining high degree of enantioselectivity is particular to exo oxabicycle substrates. When endo oxabicyclic benzyl ether 1.78 is utilized in ROCM with 1.1 equivalents of cross partner, pyrans 1.95a and 1.95b are obtained in good efficiency (75% and 80% yield, respectively) and excellent enantioselectivity (97:3 er in both instances, entries 5 and 6, Table 1.6). With exo isomer of the oxabicycle, 30 equivalents of enol ether are necessary for attaining an optimal enantioselectivity (95:5 for 1.96a and 97:3 for 1.96b, entries 8 and 10, Table 1.6), otherwise, enantioselectivity of the pyrans drops significantly, especially when 1.1 equivalents of enol ether are utilized (58:42 for 1.96a and 82:18 for 1.96b, entries 7 and 9, Table 1.6). But it should be noted that pyran products 1.95a–b as well as 1.96a–b are generated with >98% Z selectivity regardless of the conditions used.
entry ROCM Product vinyl ether
equiv conv (%);b yield (%)c
1 1.1 >98; 53 52:48 >98:<2 Table 1.6: Z- and Enantioselective ROCM Reactions Promoted by Stereogenic-at-Mo Complex 1.69ca
a Reactions were carried out in benzene at 22 oC under an atmosphere of nitrogen gas with 1.69c generated in situ from reaction of 1.0 mol % of the bispyrrolide and enantiomerically pure aryl alcohol; reaction time = 30 min.. b Conversion and Z:E ratios were determined by analysis of 400 MHz 1H NMR of unpurified mixtures. c Yields of purified products. d Enantiomer ratios were determined by HPLC analysis.
Z:Eb 1.97 with p-methoxyphenyl vinyl ether 1.88b deliver 2,4,6-trisubstituted piperidine 1.98b.
Though the transformation is significantly less efficient than with oxabicycles, particularly when lower amounts of the enol ether cross partner are employed, ROCM in the presence of 20 equivalents cross partner generates the desired product in 90% yield and 91:9 er, and enol ether
olefin is formed with 92% Z selectivity. The relatively diminished preference for the Z alkene compared to the reactions involving oxabicyclic substrates might be partly because of the requisite elevated temperature (60 oC vs 22 oC) for attaining a higher conversion. The reactivity differential between azabicycle 1.97 and oxabicycles is likely the reason for the necessity of a higher catalyst loading (5.0 vs 1.0 mol %) as well as the need for excess enol ether cross partner.
Another attribute of the reactions with 1.97, unlike those with oxabicycles, relates to lower Z selectivity when fewer equivalents of cross partner are involved. It is possible that such a difference in Z selectivity partly comes from catalyst-induced alkene isomerization at elevated temperature: when the reaction in entry 1 of Table 1.7 is analyzed after 30 minutes, an 85:15 mixture of Z and E isomers of 1.98b is observed (vs 75:25 after 3 h). Mechanistic models that explain the dependence of stereo- and enantioselectivity on enol ether concentration will be addressed in the later sections of this chapter.
1.82 Table 1.7: Z- and Enantioselective ROCM Reactions of Enol Ethers with an Azabicycle, Cyclobutenes, and a Cyclopropene Promoted by Stereogenic-at-Mo Complex 1.69ca
a-d See Table 1.6. oxabicycles, 1.0 mol % of the catalyst is sufficient for achieving complete conversion; however, the requirement for excess cross partner to achieve high enantioselectivity (cf. entries 4 vs 5 and entries 6 vs 7, Table 1.7) is reminiscent of the exo oxabicyclic alkenes. Gratifyingly, in the presence of 10 equivalents of enol ether 1.88a–b, ROCM products 1.99a–b are obtained with good efficiency (90% yield in both cases) and enantioselectivity (>85:15 er, entries 5 and 7, Table 1.7). With bis-benzyl ether cyclobutene 1.84 as the cyclic olefin substrate (entries 8 and 9, Table 1.7), reactions are significantly slower at 22 oC, in spite of the smaller size of benzyloxy
groups (vs OTBS in 1.82). The difference in reactivity is possibly due to the internal chelation between the metal center and the sterically accessible and Lewis basic alkoxy group, as discussed in 1.3.b, leading to the lowering of reaction rate. Consequently, as shown in entries 8 and 9 of Table 1.7, elevated temperature (60 vs 22 oC in ROCM of 1.84) is necessary for attaining complete conversion to diene 1.100a–b; diene products are formed in 85:15 er and isolated in 61% and 73% yield, respectively. It is noteworthy that the Z selectivity in the synthesis of 1.100a is lower than all other examples, which is likely the result of elevated temperature required for an efficient transformation, causing Mo-catalyzed isomerization of the kinetically preferred Z-enol ether. Such isomerization of the sterically more hindered 1,2-disubstituted enol ether in 1.100b probably occurs less readily (98% Z, entry 9, Table 1.7).
Catalytic enantioselective ROCM of cyclopropene 1.86 (entries 10 and 11, Table 1.7) proceeds to complete conversion within 30 minutes, delivering 1,4-dienes 1.111a–b, containing an all-carbon quaternary stereogenic center. ROCM products are obtained in 79% and 71% yield, and 95:5 and 97:3 er, respectively. It should be noted that the newly formed disubstituted enol ethers are generated with >98% Z selectivity, like most of the other examples. Comparing with the stereochemical outcomes of ROCM with cyclobutenes 1.82 and 1.84 (entries 4–9, Table 1.7), the relatively higher enantioselectivity observed with cyclopropene arises from the higher degree of steric differentiation between the two faces of the cyclic alkene, whereas the oxygen atoms of 1.82 and 1.84 reduce the effective size of the silyl and benzyl ether units.