Amino acids RAMP

For a facial selective assembly ofthe stereogenic centers and the introduction of the amino functionality, chiral nitrogen-containing reagents, such as benzyl(2-pheny-lethyl)amine (2-19) and trimethylsilyl RAMP derivative 2-24 were applied. Treatment of diacrylates 2-18, 2-21, and 2-23 with 2-19 and 2-24, respectively, gave the protected amino acids 2-20, 2-22, and 2-25 in good yields as single isomers. 

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 synthetic utility of the SAMP/RAMP hydrazone method is demonstrated in particular in the stereoselective alkylation of aldehyde and ketone SAMP/RAMP hydrazones. A great number of natural products have been synthesized using this method, like the principal alarm pheromone of the leaf cutting ant Atta texana (eq 1), the C(l)-C(15) segment of FK 506 (eq 2) the amino acid MeBMT (eq 3), and (-)-methyl kolavenate (eq 4). ... 

The basic concept, although most likely not the detailed mechanism, of the Enders asymmetric induction follows from the chelation-controlled asymmetric alkylation of imine anions introduced by Meyers and Whitesell. The hydrazones derived from either the (5)- or the (/ )-enantiomer of iV-amino-2-methoxymethylpyrrolidine (SAMP and RAMP, derived from the amino acid proline) can be converted to anions that undergo reaction with a variety of electrophiles. After hydrolysis of the product hydrazones, the alkylated ketones can be obtained with good to excellent levels of optical purity (Scheme 19). 

The asymmetric Strecker reaction Chiral Enolates from Imines of Aldehydes SAMP and RAMP Chiral Enolates from Amino Acids... 

The Oppolzer sultam 35-1 (Scheme 35, reaction (101) [84] reacts with even higher stereoselectivies and is easier to remove. The main domains of the Oppolzer sultam are conjugate 1,4-additions or simple double bond additions [Scheme 35, reactions (102) and (103)] [85], which show diastereoselectivities of >95% in most cases. Scheme 36 presents examples of persistent, restorable and selfimmolative auxiliaries which are all based on amino acids or amino alcohols, finders RAMP-SAMP [86] is attached to ketones or aldehydes in form of a hydrazone 36-1 which is used for highly stereoselective electrophilic a-alkyla-tions. After the reaction the auxihary is removed via ozonolysis which generates the nitrosamine 36-2 first. In an ensuing step this is reduced to the original auxiliary. In Schollkopf s bislactim ether alkylations [Scheme 36, reaction (105)]... 

FIGURE 5.1 Human PXR crystal structures, (a) Diagrams of the crystal structures of the apo, ligand-bound, and coactivator-bound human PXR LBD. A rainbow ramp color code of blue to red is used to trace the amino acid chain from the N terminus to the C terminus. 

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 ... 

RAMP (R)-l-Amino-2-methoxyraethylpyrrolidine 1-Pyrrolidinamine, 2-(methoxyraethyl)-, (R)- 65, 173, 183 REDUCTION OF CARBOXYLIC ACIDS TO ALDEHYDES. 66, 121 RING EXPANSION, 65, 17... 

The (R)-enantiomer of (242) has also been prepared and used as a chiral auxiliary in an enantioselective aldol synthesis of (+)-(S )-gingerol (79CB3703). (R )-Glutamic acid (246) was thus converted into (i )-pyroglutamic acid by simply heating in water. Conversion of (247) to its methyl ester and LAH reduction delivered alcohol (248). Ethyl nitrite treatment of (248) gave nitrosoamine (249), which was methylated to furnish (250). Exposure of (250) to LAH completed the synthesis of the required chiral auxiliary RAMP [(R)- l-amino-2-(methoxymethyl)pyrrolidine]. The hydrazone (252), derived from RAMP and acetone, was... 

This method was recently used in the synthesis of different natural products, like the ladybug defence alkaloid harmonine, a- and p-amino acetals and acids (eq 14), and both enantiomers of the hemlock alkaloid coniine, utilizing the nucleophilic 1,2-addition of organolithium and -lanthanoid reagents to SAMP/RAMP hydrazones. 

Commercial (S)- and (R)-1 -amino-2-methoxypyrrolidines (SAMP and RAMP) can be synthesized from either prolines or glutamic acids. They are widely used for the stereoselective a-alkylation of aldehydes. One first forms the hydrazone with SAMP or RAMP and then alkylates in the presence of lithiu-mamide at low temperature. The optical purity is usually in the order of 90%, but enantiomeric excesses of 95% may also be obtained with large alkylbromides (Scheme 9.4.14) (Coppola and Schuster, 1987). 

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. 

Pr, n-Propyl Py, Pyridine PROPHOS, 1,2-Bis(diphenylphosphino)propane PTA, l,3,5-Triaza-7-phosphaadamantane PTC, Phase-transfer catalyst PTSA, p-Toluenesulfonic acid R, An organic group RAMP, R-(-l-)-Amino-2-(methoxymethyOpyrrolidine Rf, Perfluoroalkyl... 

In the late 1970s, Enders pioneered an elegant method for ketone and aldehyde alkylation involving the use of metalated chiral hydrazones [92, 93). Extensive studies with the (S)-l-amino-2-methoxymethylpyrrolidine (SAMP, 150, Scheme 3.24) auxiliary and its enantiomer RAMP established these as superb chiral auxiliaries with numerous applications. In a typical alkylation sequence, a RAMP/SAMP hydrazine is condensed with an aldehyde or a ketone to form the corresponding hydrazone, such as 152. This can subsequently be deprotonated and the resulting enolate trapped with a variety of electrophilic reagents including alkyl halides, aldehydes, Michael acceptors, silyl triflates, and disulfides. The RAMP/SAMP hydrazine auxiliary may be removed by acidic hydrolysis or ozonolysis to reveal the alkylated... 

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