Retro-aldol disconnection

As shown in Scheme 4.16, the retrosynthetic process proceeds as follows i) FGI (substitution of the unconjugated aldehyde by an acetal group and the conjugated double bond by an OH group) ii) retro-aldol disconnection of the 1,3-C system iii) "reconnection" of the resulting 1,6-D system to a 6-membered ring iv) FGI (substitution of the double bond by an OH group and the acetal by a carbonyl... 

The retrosynthetic process (Scheme 6.2) involves the following operations i) substitution of the conjugated double bond by an OH group ii) retro-aldol disconnection of the 1,3-C system, and iii) disconnection at the a-position of the resulting 1,4-D system which leads to 2-methylcyclopentane-l,3-dione and an umpoled three-carbon atom fragment. This retrosynthetic process offers, however, only a theoretical scheme which, in practice, presents some difficulties. For example. Table 5.1 gives 2-nitropropene (3) as a possible equivalent of the umpoled C3 fragment, in which case the process in the synthetic direction would be as... 

This is a typical retro-aldol disconnection using the enolate as an equivalent of the carbanion and a carbonyl electrophile (Scheme 2.37). 

The first two FGIs interconvert two amino groups into their precursors in TM 2.18a next FGA introduces the double C=C bond in TM 2.18b, enabling retro-aldol disconnection of nitromethane and TM 2.18c. Cyano-aldehyde TM 2.18c affords acrylonitrile and stabilized carbanion of isobutyraldehyde on rc/ro-Michael disconnection. 

Retro-aldol disconnection of a,P-unsaturated ketone leads to 1,4-diketone TM 5.19a. By disconnection of the central C-C bond, we generate two synthons, a-carbanion of cyclohexanone and a-carbocation in acetone. Synthetic equivalents for two synthons are the enamine of cyclohexanone TM 5.19b and a-chloroacetone TM 5.19c (Scheme 5.45). 

First, retro-aldol disconnection gready simplifies the stmcture of TM 9.2b to benzaldehyde and 2-nitroethanol, amenable to a second retro-aldol disconnection to nitromethane and formaldehyde. 

The recognition of consonant bifunctional relationships in the target molecule allows their disconnection by a retro-Claisen, a retro-aldol or a retro-Mannich condensation or by retro-Michael addition [equivalent, according to Corey s formalisation, to the application of the corresponding transforms (= operators) to the appropriate retrons]. 

The usefulness of FGI operations is easily understood considering a very simple example. 1,3-Butanediol, notwithstanding being a 1,3-C system, does not offer a reasonable disconnection mechanism. However, if the primary hydroxyl group is converted to a carbonyl group, the resulting product can be then disconnected into two stable identical molecules of acetaldehyde, according to a reasonable retro-aldol mechanism, and the whole process represents a simple solution in accordance with the criterium of maximum simplicity. 

Bifunctional systems In the case of bifunctional systems (or molecules) only two alternatives are possible the bifunctional relationships are either "consonant" or "dissonant" (apart from molecules or systems with functional groups of type A to which we have referred to as "assonant"). In the first case, the synthetic problem will have been solved, in principle, in applying the "heuristic principle" HP-2 that is to say, the molecule will be disconnected according to a retro-Claisen, a retro-aldol or a retro-Mannich condensation, or a retro-Michael addition, proceeding if necessary by a prior adjustment of the heteroatom oxidation level (FGI). 

The synthetic method (a) is the regioselective reduction of an a,/ -unsaturated aldehyde or ketone (Section 5.18.2, p. 798), which is most conveniently effected by the Meerwein-Ponndorf-Verley procedure (Section 5.4.1, p. 520). The further disconnection shown of the a, -carbonyl compound is a retro-aldol condensation (Section 5.18.2, p. 799) however it should be emphasised that other routes to the unsaturated carbonyl compound, such as the Horner-Emmons reaction (Section 5.18.2, p. 799), may also be feasible. 

An example of the Knorr pyrrole synthesis is provided by the formation of 3,5-diethoxycarbonyl-2,4-dimethylpyrrole (55). Overall ring construction in this case may be related to (46) above. A retrosynthetic analysis involving disconnection of the N—C2 bond, appropriate prototropic shifts, and finally a retro-aldol reaction to effect disconnection of the C3—C4 bond, reveals ethyl acetoacetate and ethyl a-aminoacetoacetate (ethyl 2-amino-3-oxo-butanoate) (56) as reagents. An FGI transform on this latter compound generates the corresponding nitroso (oximino) compound which may also be derived from ethyl acetoacetate. 

In the case of (11), retrosynthetic functional group interconversion into the aldol followed by disconnection of the a, /J-bond gives the dipolar synthon (15), of which the reagent equivalent is the 1,4-dicarbonyl compound, hexane-2,5-dione (i.e. a retro-aldol condensation). The action of base on this diketone effects the forward aldol reaction followed by spontaneous dehydration (see Expt 7.4 for formulation). 

The first disconnection lib (reductive amination) takes no consideration of the chirality at all - we will worry about this later. We already have a six membered ring and it now contains all the chirality. The introduction of double bonds by FGA is used to considerable effect in this retro-synthesis. The first new alkene allows us to do an aldol disconnection 13 that not only removes a carbon chain but also reveals an electron-withdrawing group on the six-membered ring 14. This is, of course, one vital component of the Diels-Alder reaction. The next FGA puts in the double bond that allows us to do the retrosynthetic Diels-Alder step 15. 

Snider published the synthesis of desmethylamino FR901483 in 1998 [9] and one year later, the first total synthesis of natural (-)-FR901483 [2]. The disconnective analysis is outlined in Scheme 5. The key step in the retrosynthetic analysis is the disassembly of the azatricyclic structure of 1 by a retro-aldol process, which leads to aldehyde 6. In the forward sense, while this approach should provide efficient access to the ring system,... 

On the other hand, the C-C bond formation can be a good retrosynthetic strategy for the cyclization of the ansa-ring. Meyers disconnected the bond between the C2 and C3 positions which was based upon a retro aldol reaction with biogenetic interest. In fact, the corresponding aldol reaction was achieved at a later step in the first total synthesis of maytansinol [4]. The stereochemical course was not clear since a mixture of stereoisomers of 6 were cyclized at — 78 °C in THF. Meyers obtained a mixture of the cyclized products 7, one of which, after a few more steps, was finally identified as maytansinol [5]. 

Identification of the four-carbon methyl vinyl ketone unit within the cyclohex-enone TM leads to the appropriate disconnections. The first retrosynthetic step is a retro-aldol, so a disconnection is made between the alpha and beta carbons. The alpha carbon will be introduced as an enolate nucleophile the other carbon was a carbonyl electrophile. 

According to route II, the primary H2O addition to the furan C-2/C-3 bond may occur in the opposite direction to a, thus following the retroanalytical step d. This leads to the intermediate 55, whose bond disconnection O/C-2 (e) corresponds to the reversal of an O-alkylation leading to the y-halo-P-hydroxycarbonyl system 57. A retro aldol operation (g) provides the same starting materials 58/59 as those from route I. 

Finally, 2- or 4-methyl substituents in the quinolizinium ion exhibit side-chain reactivity (as in the pyridinium ion, cf. p. 359) and thus allow electrophilic C-C bond formation. Retrosynthesis of the quinolizinium ion is based on disconnections of the retro-aldol type I q I a/b, which suggest 12/13 or 14/15 as educts for synthesis [216]. ----- ... 

The Robinson annulation combines Michael addition to an a,/3-unsaturated ketone with intramoleeular aldol condensation (Section 18-11) to afford a cyclohexenone. Retrosynthetic analysis (Section 8-9) of the target molecule leads to the disconnection of two bonds in ring A the carbon-carhon double bond, by a retro-aldol condensation, and a single bond by a retro-Michael addition. The Rohinson annulation for the construction of ring A is closely related to the example in Section 18-11, which condenses 2-methylcyclohexanone with 3-buten-2-one. 

In 1998, Kawahara and Nagumo reported the first total synthesis of a member of the TAN1251 series [63] and five years later both authors revisited the TAN1251A alkaloid by means of a new enantioselective synthesis (see Section 5.6). The retro synthetic analysis of TAN 1251A is outlined in Scheme 37. The target compound could be obtained by aldol reaction of tricyclic lactam 119, whose disconnection at the amide bond led to the bicyclic amino acid 120, which could be prepared from azaspirocyclic compound 121 by means of alkylation of the secondary amine and Mitsunobu-type chemistry. Azabicycle 121 may be prepared by an intramolecular alkylation of 122, which in turn could be available from allyl derivative 123. The latter can be prepared from carboxylic acid 124 by alkylation and subsequent Curtius rearrangement. 

The final example illustrates yet another use of the biomimetic approach. Figure 10.9shows a retro-synthetic analysis for Masamune s synthesis of deoxyerythronolide B (213). The biosynthetic building blocks of this and other macrolide antibiotics are known to be acetate and/or propionate units combined head-to-tail, as seen in 213. 7 xhe stereocenters in 213 are clearly shown in the acyclic (seco acid) form of the macrolide 215. The specific biopathway is not utilized but rather modified to include the basic building blocks, seven propionate units (bold lines in 213).Seco acid 215 was constructed by sequential aldol condensation reactions (sec. 9.4.A) of propionaldehyde units, as shown by the disconnections in Figure 10.9. Asymmetric... 

Isobe et al. at Nagoya made a retro synthesis of the maytansine framework by disconnecting between N19-C1, C2-C3 and Cn-Ci2 so that the ansa-ring was planned to be cyclized from the seco acid-like precursor. An aldol reaction and a... 

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