Inversion strategy

Figure 10.22 Synthetic approaches to DAHP and KDO by a backbone inversion strategy using FruA cataiysis.

In using the "reactivity inversion" strategy, three different approaches may be considered the simple, the reversible and the use of "inversion operators". 

Efficient Carbohydrate Synthesis by Controlled Inversion Strategies... 

Hai Dong Efficient Carbohydrate Synthesis by Controlled Inversion Strategies Organic Chemistry, KTH Chemistry, Royal Institnte of Technology, S-10044 Stockholm, Sweden. 

Using the same initial step for the double serial inversion strategy, from methyl glucoside 37, the 2,4-tiiflate intermediates 50 could be produced via a Inflation process (Scheme 15). The 4-triflates of these intermediates were subsequently inversed to the corresponding 4-0-acetyl intermediates 51 by substitution with tetrabutylammonium acetate, followed by inversion of the 2-position by tetrabutylammonium nitrite, to yield a mixture of methyl... 

In addition, due to the fact that methyl glucoside 3 was produced in a lower yield (70%) than methyl galactoside 1 (90%), following the double serial inversion strategy, an... 

Scheme 17. Alternative double serial inversion strategy to intermediate 50...

In order to overcome the problem, the inverse strategy was followed. Chromium-Reformatsky reaction between 76-derived C8 aldehyde and a 68-derived ester afforded all four possible C6,C7-diastereomers, which can be independently processed to epothilone D5 diastereomers (including the natural one) by the macrolactonization route. 

The obvious disconnection in cyclopeptide alkaloids and indeed the strategy employed in most total syntheses of this type of compound is the formation of the aryl ether bond. Many groups chose to form the macrocyclic aryl ether by S Ar reaction. We decided to follow the inverse strategy, i.e., displacement of an allylic leaving group by a phenolate. In case of the natural cyclopeptide alkaloids, this would involve activation of yS-hydroxy-a-amino acids, which is likely to be accompanied by extensive elimination. Elimination is not possible when a-methylene- -hydroxy acids are used. Additionally, the double bond activates the leaving group and provides a handle for a possible later side chain attachment. 

Activated A-alkoxycarbonyl amino acid derivatives, on the other hand, do not cyclize as readily as A -acyl amino acids, and therefore racemize more slowly. Accordingly, solid-phase peptide synthesis is generally performed by acylation of support-bound amines with activated A -alkoxycarbonyl amino acids. Examples of the preparation of peptides by the inverse strategy (first amino acid linked to the support via its amino group as carbamate activation of support-bound AAacylamino acids) have, nevertheless, been reported [13-16]. 

Being restricted to DHAP as the nucleophile, aldol additions will only generate ketoses and derivatives from which aldose isomers may be obtained by biocatalytic ketol isomerization (cf. Sect. 7.1) [306]. For a more direct entry to aldoses the inversion strategy may be followed (Scheme 19) [290] which utilizes monoprotected dialdehydes. After aldolization and stereoselective chemical or enzymatic ketone reduction, the remaining masked aldehyde function is deprotected to provide the free aldose. Further examples of the directed, stereodivergent synthesis of sugars and related compounds such as aza- or thiosugars are collected in Sect. 7. 

Scheme 5. Inversion strategy and further functionalizations for the diversity oriented synthesis of carbohydrate derivatives...

The stereoselective reduction of the ketone function of 9 leads to a direct entry to selectively protected aldopentoses ( inversion strategy ) (Borysenko et al. 1989), which greatly expand the potential of this new protocol (Scheme 5). Following Evans protocol the tetramethylammo-nium triacetoxyborohydride-mediated reduction provides the yyn-diol 15 constituting a protected D-ribose (95%, >96% de). The anti-selective reduction to 17 was obtained after silyl protection of the free hydroxyl group of 9 to the OTBS-ether 16 using L-selectride. The aldopentose 18 was then accessible via chemoselective acetal cleavage followed by in situ cyclization (47% over two steps, >96% de). 

An alternate approach, the inversion strategy, is useful for the transformation of ketose to aldose products.35 In this procedure mono-protected dialdehydes were allowed to react with DHAP in the presence of an aldolase to generate ketoses. The ketones are then reduced either chemically or enzymatically. When the aldehyde-protecting group is removed, the aldose is revealed.27 36... 

The scheme of classical peptide SPS is shown in Fig. 2.1. The first step is the attachment of the first amino acid onto the resin, usually via the carboxylic group with both the amino and the side-chain functions of the a-amino acid protected (step 1). The inverse strategy, where the amino group would be linked to the resin and the carboxyl would be protected, has seldom been used because extensive racemization occurs during repeated resin-bound carboxylate activations (3) this limits the accessibility of C-terminal modified peptides that are biologically relevant. However, several recent reports (4-7) describe the SP modification of the peptide C-terminus using the more reliable C-to-N direction for peptide synthesis. 

Figure 14.1-9. Use of the "inversion strategy to synthesize L-xylose and 2-deOxy-D-orafamo-hexose.

Scheme 3. The Inversion Strategy. P = phosphate PG = protecting group.

Polymer-Supported Stannanes and Fluorous Stannane. Some interesting procedures are being developed to make the present protocol more useful as a synthetic tool. Directed toward combinatorial synthesis, solid-phase syntheses have currently been under development using polymer-supported stannanes.t t In these cases trialkyltin halide is released during the course of the reactions. More recently, a new version was developed with inversed strategy. In this process, the stannyl group remains on the polystyrene support and could be recovered for reuse. ... 

Hoge G (2004) Stereoselective cyclization and pyramidal inversion strategies for P-chirogenic phospholane synthesis. J Am Chem Soc 126 9920-9921... 

The scope and synthetic usefulness of reactions catalyzed by DHAP aldolases may be further illustrated by exemplary syntheses of some interesting compounds that comprise functionalities and skeletons of a different nature. Aldol additions of 22 will typically generate ketose derivatives from which aldose isomers may be obtained by biocatalytic ketol isomerization [130]. For an alternative entry to aldoses, the inversion strategy [131] utilizes monoprotected dialdehydes for adolization which, after stereoselective ketone reduction, provide free aldoses from deprotection of the masked aldehyde function. 

DAHP, 64) [135], an intermediate of the shikimic acid pathway, have been synthesized from corresponding aldehyde precursors. Several cychtols (e.g., 71-73) could be made from aldol products by radical or nucleophilic cyclization reactions [136-138]. An intermediate was also found to be a correctly configurated precursor to the spirocyclic Strep-tomyces metabolite sphydrofuran 69 [139]. In an approach resembling the inversion strategy an a-C-mannoside 68 has been prepared from D-ribose 5-phosphate [140]. 

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