Diastereoselective hydroformylation

Diastereoselective hydroformylation can be achieved in special cases through passive substrate control in which conformational preferences are transferred in the corresponding selectivity-determining hydrometalation step [4-6]. A recent example is the highly diastereoselective hydroformylation of a kainic acid derivative (Scheme 17) [64], The selective formation of the major diastereomer has been explained via a reactive substrate conformation in which allylic 1,2-strain has been minimized. In this situation the czs-positioned methylene carbonylmethoxy group controls the catalyst attack to occur from the si face exclusively. 

Scheme 17 Diastereoselective hydroformylation of a kainic acid derivative relying on passive substrate control...

Alternatively, substrate control of diastereoselectivity can rely on attractive catalyst substrate interactions. This requires in general special functional groups which allow for a directed hydroformylation, which is summarized in Sect. 6 (vide infra). 

In a similar fashion, allylboronates can be used as allylation reagents under hydroformylation conditions. Thus condensed 1,5-oxazadecalin systems are achieved via tandem hydroformylation/allylboration/hydroformylation sequences starting from an N-allyl-y-amidoallylboronate (Scheme 23) [77,78]. The aldehyde obtained from a regioselective hydroformylation undergoes diastereoselective intramolecular allylboration to give an intermediate al-lylic alcohol derivative. The reaction does not stop at this stage, since this... 

Scheme 35 Enolboration/hydroformylation/aldol reaction - Diastereoselective access to cyclic aldols...

Since the discovery and development of highly efficient Rh catalysts with chiral diphosphites and phosphine-phosphites in the 1990s, the enantioselectivity of asymmetric hydroformylation has reached the equivalent level to that of asymmetric hydrogenation for several substrates. Nevertheless, there still exist substrates that require even further development of more efficient chiral ligands, catalyst systems, and reaction conditions. Diastereoselective hydroformylation is expected to find many applications in the total synthesis of complex natural products as well as the syntheses of biologically active compounds of medicinal and agrochemical interests in the near future. Advances in asymmetric hydrocarboxylation has been much slower than that of asymmetric hydroformylation in spite of its high potential in the syntheses of fine chemicals. 

Rhodium( I)-catalyzed hydroformylation of cyclic enol acetals 1 leads to acetal-protected syn-3,5-dihydroxyalkanals 2 with extraordinarily high levels (>50 1) of diastereoselectivity (Scheme 5.2) [2]. The diastereoselectivity cannot be ascribed to any obvious steric bias, and serves as a powerful demonstration that the hydroformylation reaction may be subject to exquisite stereoelectronic control. Indeed, while the addition of a pseudo-axial methyl group to the acetal carbon (as in acetonide 3) has a deleterious effect on the rate of the reaction, the sy -diastereomer 4 is still produced selectively, in what is surely a contra-steric hydroformylation reaction. 

Recently, and for the first time, it has been shown that high levels of diastereocontrol may be realized in the rhodium(l)-catalyzed hydroformylation of acychc alkenes. In one example, acetals 10 afford aldehydes 11 with superior diastereoselectivity (Scheme 5.4) [4]. This result was attributed to a strong conformational bias in the substrate, as shown. Evidence for this conformational bias was secured by 2D-NOESY NMR experiments and MM3 force field calculations. When the experiment was repeated with R=H, the diastereoselectivity was lost, lending further support to the model. 

An equally intriguing report concerned the rhodium(I)-catalyzed hydroformylation of C-glycoside alkenes 12 (Scheme 5.5) [5]. As depicted, aldehydes 13 were formed with excellent diastereoselectivity. It was proposed that the diastereoselectivity is due to a strong conformational bias favoring the depicted alkene conformation. 

In one remarkable example, Burke and Cobb employed a directed hydroformylation to functionahze regio- and diastereoselectively alkene 24 to provide aldehyde 25 as the major product of a 7.7 0.3 1 1 mixture in 69% yield (Scheme 5.10) [12]. When the ester-directing group was replaced with a tert-butyldimethylsilyl group, a nonselective and inefficient reaction resulted. Aldehyde 25 was converted to the target (-i-)-phyl-lanthocin in just a few additional steps. 

Hydroformylation reactions have been shown to be amenable to use in tandem or domino reaction sequences. In one elegant example, alkene 36 was subjected to rho-dium(I)-catalyzed hydroformylation, and the resulting aldehyde underwent smooth intramolecular allylboration (Scheme 5.14) [19]. This produced a new terminal alkene which underwent a second hydroformylation to provide, after workup,lactols 37 in 80% yield and with excellent diastereoselectivity. 

Aldehyde 11a, produced by diastereoselective hydroformylation (R=Me Scheme 5.4), has been employed in the synthesis of polyketide fragment 40, a key building block for the synthesis of bafilomycin Ai (Scheme 5.16) [21]. 

Diastereoselective hydroformylation for synthesis of natural products and pharmaceuticals 458... 

Breit reported a substrate-directed diastereoselective hydroformylation of acyclic methallylic and homomethallylic alcohols protected by 2-(diphenylphosphanyl)benzoyl group (63 and 64) using a P(OPh)3/Rh(acac)(GO)2 system and isolated the corresponding < ///-aldehydes in good diastereoselectivity (Table 11, up to 9614 = They... 

Table 11 Diastereoselective hydroformylation of methallylio and homomethallylic aloohols protected by diphenylphosphanyl benzoyl group...

Table 12 Diastereoselective hydroformylation of 4-methylene-1,3-dioxane derivatives r2 H2, CO d2...

Scheme 7 Synthesis of 72, a synthetic intermediate for Bafilomycin Ai 71, using the diastereoselective hydroformylation.

Diastereoselective hydroformylation will find many applications in the total synthesis of complex natural products as well as the syntheses of biologically active compounds of medicinal and agrochemical interests in the near future. The diastereoselectivity of such reactions can be improved by the use of a matched-pair combination of a chiral ligand and chirality in the substrate. 

Diaryltellurium oxides, characteristics, 9, 591 Diastereoselective hydroformylation, for natural products and... 

Figure 1.9 Examples of a chemoselectivity and diastereoselectivity in the oxidation of a-pinene, b regioselectivity in the hydroformylation of 1-octene, and cenantioselectivityin the hydrogenation of the prochiral isopropyl (2-methoxyisopropyl) imine ( indicates the asymmetric carbon atoms).

An example is the rhodium catalyzed hydroformylation reaction, which is an industrially important homogenous catalytic process [3]. In contrast, it is amazing that such an important transition-metal catalyzed C/C bond-forming process has been employed only rarely in organic synthesis [4]. Part of the reason stems from the difficulty in controlling stereoselectivity. Even though some recently developed chiral rhodium catalysts allow for enantio- and diastereoselective hydroformylation of certain specific classes of alkenes [5, 6], only little is known about the diastereoselective hydroformylation of acyclic olefins [7, 8]. 

The difficulty of this task became obvious in an attempt to achieve a diastereoselective hydroformylation of a simple methallylic alcohol system. It was expected that in analogy to the known substrate-directed rhodium-catalyzed hydrogenation reaction, substrate direction via the hydroxyl substituent would control diastereoselectivity in the course of the hydro-formylation reaction [9], However, a completely stereorandom hydroformylation product formation was observed (1—>3) [10, 11]. 

Scheme 3. Design of a catalyst-directing group for the control of diastereoselectivity upon hydroformylation of acyclic methallylic alcohols.

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