Tandem aldol reaction

Figure 14.12 Asymmetric tandem aldol reaction using 2-deoxyribose-5-phosphate aldolase (DERA) and its application for production of Atorvastatin...

Tandem aldol reaction/siloxy-Cope rearrangement equivalent 181... 

In contrast to transketolase and the DHAP-dependent aldolases, deoxyribose aldolase (DERA) catalyzes the aldol reaction with the simple aldehyde, acetaldehyde. In vivo it catalyzes the formation of 2-deoxyribose-5-phosphate, the building block of DNA, from acetaldehyde and D-glyceraldehyde-3-phosphate, but in vitro it can catalyze the aldol reaction of acetaldehyde with other non-phosphorylated aldehydes. The example shown in Scheme 6.28 involves a tandem aldol reaction... 

The key step in the synthetic routes described in Section 6.4.1 is the DERA-cata-lyzed tandem aldol reaction of chloroacetaldehyde (CIAA) with two equivalents of acetaldehyde (AA) to lactol 1 proceeding via a monoaldol intermediate (S)-4-chloro-3-hydroxybutanal 7 and the open form of lactol 1 6-chloro-(3R,5S)-dihydroxyhex-anal (8) (Scheme 6.4). 

Scheme 6.4 DERA-catalyzed stereoselective tandem aldol reaction, using chloroacetaldehyde and 2 equivalents of acetaldehyde, yielding (3R,5S)-6-chloro-2,4,6-trideoxyhexapyranoside (1).

Claisen condensation equivalent, 10, 174 Claisen rearrangement equivalent, 10, 176 enolate alkylation equivalent, 10, 171 Mannich reaction equivalent, 10, 174 as strategic reaction, 10, 171 intermolecular carbene insertion, C-H activation-Cope rearrangement characteristics, 10, 177 as strategic reaction, 10, 178 tandem aldol reaction-siloxy-Cope rearrangement equivalent, 10, 181... 

To make the DERA-catalyzed process commercially attractive, improvements were required in catalyst load, reaction time, and volumetric productivity. We undertook an enzyme discovery program, using a combination of activity- and sequence-based screening, and discovered 15 DERAs that are active in the previously mentioned process. Several of these enzymes had improved catalyst load relative to the benchmark DERA from E. coli. In the first step of our process, our new DERA enzymes catalyze the enantioselective tandem aldol reaction of two equivalents of acetaldehyde with one equivalent of chloroacetaldehyde (Scheme 20.6). Thus, in 1 step a 6-carbon lactol with two stereogenic centers is formed from achiral 2-carbon starting materials. In the second step, the lactol is oxidized to the corresponding lactone 7 with sodium hypochlorite in acetic acid, which is crystallized to an exceptionally high level of purity (99.9% ee, 99.8% de). 

The tandem aldol reaction simply involves adding an aldehyde to the lithium enolate before work-up. Since it is a Z-enolate we can expect a syn aldol. The Z -enolate 90 is indeed formed (we are drawing the molecules in a different way to make the aldol stereochemistry clearer) and it does give a syn-aldol with the added advantage that only one of the two possible. vyn-aldols 90 predominates. The two benzylic groups can be removed, the first with CAN , ceric ammonium nitrate, Ce(IV)(NH4)2(N03)6 and the second by reduction, to give one enantiomer of 95. 

A synthesis of the -lactone of (2Z,5 S, 7iS, 9R,l lR)-tetrahydroxyhexacos-2- enoic acid (589), a natural product isolated from the aerial parts of Eupatorium pilosum, employs a strategically similar approach of coupling two chiral aldehyde pieces via a tandem aldol reaction (Scheme 85) [146]. Aldehyde 584 is prepared from 303 in 4 steps (1 -Ci4H29MgBr/CuI 2 DHP, CSA 3 BU4NF 4 PCC) in 73% overall yield. 

An unexpected result from the same series of work as above by Perumal et al was obtained when cycloalkenones were used as dienophiles [187]. Instead of the imino Diels-Alder product, azabicyclic ketones were obtained (Figure 8.79). The authors proposed a novel Diels-Alder reaction between In-dienolate ions as dienes, and the imines as dienophiles. Another possibility brought up by the authors was that the products were the result of a tandem aldol reaction on the imine, followed by a Michael-type cyclization reaction. 

Bidirectional chain extension of dihydroxy dialdehydes gives rise to carbon-linked disaccharide mimetics (e.g., 43, 45, 46) by simple one-pot operations [115,117]. The latter may be obtained as single diastereomers in good overall yield even from racemic precursors (especially cycloolefins), if the tandem aldolization reactions are conducted under conditions of thermodynamic control (Fig. 19). Typically, the thermodynamic advantage favors the trans (43) and equatorial attachments (45, 47) of the sugar ring by far, so that the... 

Shibasaki has also extended the use of LLB catalyst to tandem nitro-aldol reactions providing bicyclic adducts with 65% ee (Eq. 3.75).124... 

Combining, in tandem, the nitro-aldol reaction with the Michael addition using thiophenol is a good method for the preparation of P-nitro sulfides as shown in Eqs. 4.2 and 4.3. This reaction is applied to a total synthesis of tuberine. Tuberine is a simple enamide isolated from Streptomyces amakusaensis and has some structural resemblance to erbastatin, an enamide which has received much attention in recent years as an inhibitor of tyrosine-specific kinases. The reaction of p-anisaldehyde and nitromethane in the presence of thiophenol yields the requisite P-nitro sulfide, which is converted into tuberine via reduction, formylation, oxidation, and thermal elimination of... 

Allylic alcohols react with aldehydes, in the presence of catalytic amounts of Fe(CO)s under photochemical activation conditions, to give mainly aldol products (Scheme 11).33 This novel tandem iosmerization-aldolization reaction is a process with a perfect atom economy, proceeding under neutral conditions. 

Silyltitanation of 1,3-dienes with Cp2Ti(SiMe2Ph) selectively affords 4-silylated r 3-allyl-titanocenes, which can further react with carbonyl compounds, C02, or a proton source [26]. Hydrotitanation of acyclic and cyclic 1,3-dienes functionalized at C-2 with a silyloxy group has been achieved [27]. The complexes formed undergo highly stereoselective addition with aldehydes to produce, after basic work-up, anti diastereomeric (3-hydroxy enol silanes. These compounds have proved to be versatile building blocks for stereocontrolled polypropionate synthesis. Thus, the combination of allyltitanation and Mukayiama aldol or tandem aldol-Tishchenko reactions provides a short access to five- or six-carbon polypropionate stereosequences (Scheme 13.15) [28],... 

T. Arai, H. Sasai, K. Aoe, K. Okamura, T. Date, M. Shibasaki, A New Multifunctional Heterobimetallic Asymmetric Catalyst for Michael Additions and Tandem Michael-Aldol Reactions, Angew. Chem. Int. Ed Engl 1996, 35,104-106. 

Several attempts to take advantage of the intermediate boron enolate to achieve tandem conjugate addition-aldol reaction have been proposed [71]. Recently, Chandrasekhar [72] reported the addition of triethylborane to methyl vinyl ketone followed by the in situ trapping of the enolate by aromatic aldehyde (Scheme 26). 

Scheme 26 Tandem conjugate addition-aldol reaction...

Tandem processes mediated by triethylborane involving conjugate addition to enones followed by aldol reaction are reported (Scheme 52, Eq. 52a). More recently, a tandem process involving addition of an isopropyl radical to an o ,/3-unsaturated oxime ether afforded an azaenolate intermediate that reacts with benzaldehyde in the presence of trimethylaluminum. The aldol product cyclizes to afford an isopropyl substituted y-bulyroloaclonc in 61% overall yield (Scheme 52) [116]. In these reactions, triethylborane is acting as a chain transfer reagent that delivers a boron enolate or azaenolate necessary for the aldolization process. 

The aldol reaction is probably one of the most important reactions in organic synthesis. In many industrially important hydroformylation processes selfcondensation of aldehydes is observed. Sometimes this consecutive reaction is favored as in the production of 2-ethyl hexanol. But synthetic applications of tandem hydroformylation/aldol reactions seem to be limited due regiose-lectivity problems of a mixed aldol reaction (Scheme 28). However, various tandem hydroformylation/intramolecular mixed aldol reactions have been described. 

Although the saturated ketone can be obtained in nearly quantitative yields, the loss of synthetically valuable functionality is unfavorable and can be overcome by a modification of the tandem sequence. The use of the corresponding unsaturated silyl enol ethers in a tandem hydroformyla-tion/Mukaiyama aldol reaction gives the desired aldol adduct with complete... 

This method can also be applied to silyl enol ethers of homologous unsaturated ketones as well as of unsaturated aldehydes or esters [85-87]. While unmodified unsaturated esters give only the corresponding aldehydes without cyclization under tandem hydroformylation/aldol reaction conditions, the corresponding silylated ester enolates smoothly cyclize in a tandem hy-droformylation/ Mukaiyama aldol reaction (Scheme 32) [85-87]. 

Very recently, a tandem sequence consisting of enolboration/hydroform-ylation/aldol reaction has been described [88]. Here configuration of the enol boronate is transferred to the aldol product, allowing good to excellent di-astereoselectivities in the hydroformylation/aldol reaction. With this method, 5-7-membered rings are obtained in excellent yields (Scheme 35). 

Tandem addition-aldol reaction with methyl propiolate... 

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