SAMP/RAMP chiral auxiliaries synthesis

In continuation of our efforts to explore the utility of the SAMP/RAMP hydra-zone methodology, we developed the first asymmetric synthesis of a-phosphino ketones via formation of a carbon-phosphorus bond in the a-position to the carbonyl group [70]. The key step of this asymmetric C—P bond formation is the electrophilic phosphinylation of the ketone SAMP hydrazone 87, giving rise to the borane-adduct of the phosphino hydrazone 88 with excellent diastereoselectiv-ity (de = 95-98%). Since these phosphane-borane adducts are stable with respect to oxidation, the chemoselective cleavage of the chiral auxiliary by ozonolysis leading to the a-phosphino ketones (R)-89 could be accomplished with virtually no racemization. Using RAMP as a chiral auxiliary, the synthesis of the enantiomer (S)-89 was possible (Scheme 1.1.25). 

Many chiral auxiliaries are derived from 1,2-amino alcohols.7 These include oxazolidinones (l),7-9 oxazolines (2),10 11 bis-oxazolines (3),1213 oxazinones (4),14 and oxazaborolidines (5).15-17 Even the 1,2-amino alcohol itself can be used as a chiral auxiliary.18-22 Other chiral auxiliaries examples include camphorsultams (6),23 piperazinediones (7),24 SAMP [(S)-l-amino-2-methoxy-methylpyrrolidine] (8) and RAMP (ent-8),25 chiral boranes such as isopinocampheylborane (9),26 and tartaric acid esters (10). For examples of terpenes as chiral auxiliaries, see Chapter 5. Some of these auxiliaries have been used as ligands in reagents (e.g., Chapters 17 and 24), such as 3 and 5, whereas others have only been used at laboratory scale (e.g., 6 and 7). It should be noted that some auxiliaries may be used to synthesize starting materials, such as an unnatural amino acid, for a drug synthesis, and these may not have been reported in the primary literature. 

The synthesis of (-)-Cio-desmethyl arteannuin B, a structural analog of the antimalarial artemisinin, was developed by D. Little et a. In their approach, the absolute stereochemistry was introduced early in the synthesis utilizing the Enders SAMP/RAMP hydrazone alkylation method. The sequence begins with the conversion of 3-methylcyclohexenone to the corresponding (S)-(-)-1-amino-2-(methoxymethyl)pyrrolidine (SAMP) hydrazone. Deprotonation with lithium diisopropylamide, followed by alkylation in the presence of lithium chloride at -95 °C afforded the product as a single diastereomer. The SAMP chiral auxiliary was removed by ozonolysis. 

Application of the Enders SAMP/RAMP hydrazone alkylation method on 1,3-dioxan-5-one derivatives leads to versatile C3 building blocks. To demonstrate the usefulness of the above method, the research group of D. Enders applied it during the first asymmetric total synthesis of both enantiomers of streptenol A. " To obtain the natural isomer, the RAMP hydrazone of 2,2-dimethyl-1,3-dioxan-5-one was used as starting material. This compound was deprotonated with f-butyllithium and alkylated with 2-bromo-1-fert-butyldimethylsilyloxyethane. The chiral auxiliary could be hydrolyzed under mildly acidic conditions to provide the ketone in excellent yield and enantioselectivity. 

Chiral a-sulfinyl dimethylhydrazones form stabilized carbanions that can be used in enantioselective aldol reactions. A typical example is shown in equation (21).55 36 Removal of the chiral sulfur auxiliary is accomplished by reductive desulfurization. Under these conditions recovery and reuse of the sulfur moiety is impossible. Synthetic and optical yields reponed for these aldol reactions are modest in most cases. However, in a direct comparison to the SAMP/RAMP methodology, Annunziata has prepared (-)-(/ )-[6]-gingerol in 60% eeP Enders prior synthesis had yielded this aldol product in 36% eeP... 

Diastereoselectivity is also observed in reactions of carbanions derived from imines and hydrazones, when those species contain a chiral center or a chiral auxiliary (sec. 9.4.F). Asymmetric imines can be used, and chiral oxazoline derivatives have also been prepared and used in the alkylation sequence (sec. 9.3.A). Meyers showed that chiral oxazoline 478 could be alkylated to give the ethyl derivative, 479. A second alkylation generated the diastereomeric product 480, and hydrolysis provided the chiral lactone (481) in 58% yield and with a selectivity of 70% ee for the (R) enantiomer. 53 As pointed out in Section 9.4.F.ii, hydrazone carbanions can be used for alkylation or condensation reactions. In a synthesis of laurencin. Holmes -l prepared the asymmetric hydrazone 483 (prepared by Enders by reaction of cycloheptanone and the chiral hydrazine derivative called SAMP, 482-A-amino-(2S)-(methoxymethyl)pyrrolidine)- - and showed that treatment with LDA and reaction with iodomethane gave an 87% yield of the 2-ethyl derivative in >96% de. Ozonolysis cleaved the SAMP group to give (/ )-2-ethylcycloheptane (484) in 69% yield. The enantiomer of 482 is also known (it is called RAMP, A-amino-(27 )-(methoxymethyl)pyrrolidine). 

The designation chiral pool was introduced to denote an available source of enantiomerically pure natural products. These include the (5)-amino acids, as well as (iS)-lactic acid, (5)-malic acid, (RJl)-tartaric acid and / -D-glucose. How the knowledge of their chirality can be utilized for asymmetric syntheses is demonstrated by an example of the chiral auxiliaries S) and (i )-l-amino-2-(methoxymethyl)pyrrolidine developed by Enders and abbreviated as SAMP (2) and RAMP [61]. They are synthesized from (5)- or (R)-proline in several steps [62]. The enantioselective synthesis of the insect pheromone (5)-4-methylheptan-3-one 8 by alkylation of pentan-3-one 1 serves as an example for the use of these chiral auxiliaries ... 

Alkylation of lithiated hydrazones forms the basis of an efficient method for the asymmetric alkylation of aldehydes and ketones, using the optically active hydrazines (5)-l-amino-2-(methoxymethyl)pyrroUdine (SAMP) 59 and its enantiomer (RAMP) as chiral auxiliaries. Deprotonation of the optically active hydra-zones, alkylation and removal of the chiral auxiliary under mild conditions (ozonol-ysis or acid hydrolysis of the A-methyl salt) gives the alkylated aldehyde or ketone with, generally, greater than 95% optical purity. This procedure has been exploited in the asymmetric synthesis of several natural products. Thus, (S)-4-methyl-3-heptanone, the principal alarm pheromone of the leaf-cutting ant Am texana, was prepared from 3-pentanone in very high optical purity as shown in Scheme 1.74. 

The easiest way to make oxidizable silanes is by condensation of an organolithium with the inexpensive dimethyldimethoxysilane. If enolates have to be silylated, it may be preferable to use the more reactive chlorodimethylalkoxysilanes. Introduced by Dieter Enders, a-lithiated RAMP- and SAMP-hydrazones (e.g., 78) are enolate-like species having an impressive track record for stereocontrolled synthesis. The chiral auxiliary enables the stereoselective introduction of the silicon substituent. Having oxidatively cleaved the hydrazone to restore the original carbonyl function, the latter may be diastereoselective reduced to either an (/ )- or (5)-alcohoI. The ultimate silicon/oxygen displacement thus produces either a meso- or a dl-Aio (Scheme 1-55). ... 

Auxiliary Synthesis Synthesis of the SAMP chiral auxiliary can be achieved in six steps, and in 57% overall yield, beginning with (5)-proline 3 using the procedure outlined in Scheme 7.1A. " An alternative four-step procedure is available (Scheme 7.IB) however, it is less desirable as it proceeds through a highly toxic nitrosoamine intermediate 8. The RAMP auxiliary, on the other hand, may be obtained in six steps and 35% overall yield starting from (R)-glu-tamic acid (10, Scheme 7.1C). Purification of each auxiliary is achieved by distillation, and the enantiomeric purity can be established by either optical rotation or by chiral gas chromatography (GC) measurement. 

One of the most successful classes of chiral auxiliaries for asymmetric synthesis is that of Enders proline-based hydrazines, namely (S)-l-amino-2-methoxymethylpyrrolidine (SAMP, 74) and its (R)-enantiomer RAMP (Scheme 11.11) [68]. Enders has reported that chiral hydrazones such as 75 undergo diastereoselective additions with organolithium reagents. The facile removal of the auxiliary by reductive cleavage of the N-N bond enables it as a versatile tool for the synthesis of a wide range of chiral secondary amines [69, 70]. As shown in Scheme 11.11, the secondary amine 77 was thus prepared in 73 % overall yield and 93 % ee [69]. 

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