RAMP/SAMP hydrazone chiral auxiliary

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). 

One-carbon Homologations. SEM-Cl can be used as a formaldehyde equivalent, which upon alkylation affords, directly, a protected hydroxyl. SEM-Cl does not suffer from some of the handling liabilities of formaldehyde (e.g., the need for cracking or the use of aqueous solutions) and as such has shown specific promise in the area of asymmetric alkylations. Asymmetric alkylations of enolates have been accomplished via the employment of chiral auxiliaries including oxazolidinones (eq 26) and RAMP/SAMP hydrazones. Furthermore, Schultz and co-workers have utilized SEM-Cl to trap chiral enolates derived from Birch reductions (eq 27). ... 

An excellent synthetic method for asymmetric C—C-bond formation which gives consistently high enantioselectivity has been developed using azaenolates based on chiral hydrazones. (S)-or (/ )-2-(methoxymethyl)-1 -pyrrolidinamine (SAMP or RAMP) are chiral hydrazines, easily prepared from proline, which on reaction with various aldehydes and ketones yield optically active hydrazones. After the asymmetric 1,4-addition to a Michael acceptor, the chiral auxiliary is removed by ozonolysis to restore the ketone or aldehyde functionality. The enolates are normally prepared by deprotonation with lithium diisopropylamide. 

It has been reported that the cleavage of SAMP hydrazones can proceed smoothly with a saturated aqueous oxalic acid, and this allows the efficient recovery of the expensive and acid-sensitive chiral auxiliaries SAMP and RAMP. No racemization of the chiral ketones occurs during the weak acid oxalic acid treatment, so this method is essential for compounds sensitive to oxidative cleavage.393... 

In contrast to the variety of chiral auxiliaries which have been used in the asymmetric alkylation of imine-derived azaenolates (see Section 1.1.1.4.1Table 7), alkylations of the hydrazone analogues employ mainly (-)-(S)-l-amino-2-methoxymethylpyrrolidine (SAMP) and its opti-cal antipode (RAMP). r A oCH, O ... 

The three-step procedure described here, using inexpensive, commercially available starting materials and the chiral auxiliary SAMP, Illustrates the synthetic utility of the "SAMP-/RAMP-hydrazone method".18 It is remarkable that the classical electrophilic substitution of a conformationally flexible, acyclic ketone 1 (S)-4 occurs with virtually complete asymmetric... 

Alkyl- E21a, 1010 (Cleavage of Alkylated SAMP/RAMP-Hydrazones) 1010 (Recovery of the Chiral Auxiliary by Cleavage of Alkylated SAMP/ RAMP-Hydrazones) a-(Phenylthio-methyl)- E21a, 720 (Phenylthio-alkylation)... 

A, A -Dialkylhydrazones are often converted into the carbonyl form by a variety of oxidative methods. The respective compounds (like 100) shown in Scheme 93, derived from proline-based systems (RAMP and SAMP), are widely used as potent chiral auxiliaries and have provided a very versatile method for the diastereoselective a-alkylation of ketones. SAMP and RAMP hydrazones can be cleaved with O3, by reductive techniques and by hydrolysis with strong acids. 

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. 

The use of hydrazines as chiral auxiliaries was initiated by Enders and coworkers [315]. They have developed the chemistry of hydrazones derived from epimeric 1 -amino-2-methoxymethylpyrrolidines 1.76, Samp and Ramp [161, 169, 253, 261, 315, 316], These compounds are commercially available, or they can easily be prepared from (S)-prolinol 1.64 (R = CH2OH) or (R)-glutamic add [261]. Hydrazones have some advantages over their related imine derivatives. First, they are formed in quantitative yield even from sterically hindered ketones. Second, their derived anions are often more reactive than the related aldehyde or ketone enolates. 

Acylations of lithium enolates of JV-acyloxazolidinones 5.30 and 5.31 by acetyl or benzoyl chloride at -78°C are highly diastereoselective (de > 90%) [167]. Such is also the case for reactions of Samp or Ramp 1.76 hydrazone enolates with CICOOMe [1077] or MeNCS [1078], Sodium enolates of iV-acyloxazolidinones 5.30 and 5.31 can be oxidized on the least hindered face at -78°C by an oxaziridine [741], After cleavage of the chiral auxiliary by magnesium methoxide, a-hydro-xyesters are obtained with an excellent enantiomeric excess [742] (Figure 5.39). Similar results are obtained from Samp and Ramp 1.76 hydrazone enolates [742] (Figure 539). Oppolzer and coworkers [147] carried out the stereoselective... 

The reactions of lithiated anions of chiral hydrazones 1.76 (Samp, Ramp) with a,P unsaturated esters or sulfones are highly stereoselective at -78°C. By a sequence of 1,4-addition and removal of the chiral auxiliary with O3, Enders and coworkers [161, 1441, 1442, 1443] prepared 5-keto-3,4-dialkylesters and 5-keto-3-alkylsulfones with high selectivities (figure 7.60). When -bromo-a,P-un-saturated esters or sulfones are used as Michael acceptors, cyclic ketoesters or... 

Enders and coworkers reported studies in which the RAMP and SAMP chiral auxiliaries were employed in the aza-annulation process (Scheme 39).1,4 Condensation of 179 with RAMP provided a route to the optically active enamino hydrazone 473, which was then metalated with nBuLi to generate the corresponding anion. Aza-annulation of 473 with 474 produced intermediate 475, which could be cyclized slowly (2 d) at 60 °C to give 476. Alternatively, heterocycle formation could be facilitated by an increase in reaction temperature (toluene, heat). Removal of the chiral auxiliary gave 477 in 50-52% overall yield from 179 in >99 1 enantiomeric purity. Substituents on the aromatic ring did not have a measureable effect on the yield of the aza-annulation reaction. 

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). 

Good results are obtained from reactions of compounds containing chiral auxiliaries. Thus, 1,3-asymmetric induction in the addition of radicals to 30, 1,4-asymmetric induction by the isopropyl group of the dilactim derived from cyclo(Gly-Val) in the addition to conjugated sulfones, and 1,5-asymmetric induction for SAMP/RAMP hydrazones during the addition to alkenylphosphonate esters are adequate. 

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 ketone 18 forms a hydrazone 19 with SAMP. Due to asymmetric induction by the chiral auxiliary, the subsequent alkylation (a-metalation with lithium diisopropylamide in diethyl ether, followed by 1-iodopropane at —110°C) occurs stereoselectively with formation of the diastereomer 20. In the final step, the auxiliary SAMP is removed from 20 by hydrolysis and the a-alkylated ketone 21 is obtained with ee = 99.5%. The use of RAMP as auxihary produces the (R)-enantiomer of 21. 

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). ... 

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... 

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]. 

In independent studies, Denmark noted that the yields in additions of or-ganometallic species to enolizable SAMP-derived hydrazones such as 78 were generally improved by employing the less basic organocerium reagents (Equation 7) [71]. These findings further expand the scope for the use of SAMP and RAMP chiral auxiliaries in asymmetric C=N additions. 

Enders and coworicers have shown that deprotonation of chiral SAMP/RAMP hydrazones (or their substituted analogs) derived from ketones or aldehydes, followed by reaction with Davis oxaziridine reagent provides the a-hydroxy hydrazones in moderate yield but with high diastereoselectivity. Direct unmasking or protection followed by unmasking provides the corresponding a-hydroxy ketones or aldehydes respectively (Scheme 24). Both antipodes of the hydroxylated compounds are available by appropriate choice of (5)- or (R)-proline-deiived auxiliaries. The direction of induction is predictable, if not wholly uniform (R substitution alters the a-stereochemistry for aldehyde hydrazones). The process clearly provides a valuable approach to both systems. 

The SAMP/RAMP Method As early as 1976, azaenolates derived from A,A-dialkyl hydrazones were studied as an alternative to direct ketone and aldehyde enolate alkylations. These species were found to exhibit higher reactivity toward electrophiles, as well as better regioselectivity for C-alkylation than their parent carbonyl compounds. A,A-diaIkyl hydrazones are stable and are relatively easy to prepare, making them appealing from a practical point of view in comparison with imines and enamines, which can be difficult to form quantitatively and are hydrolytically unstable. Given these desirable attributes, Enders undertook the development of chiral nonrace-mic A,A-diaIkyl hydrazine auxiliaries for the asymmetric a-alkylation of ketones. The result of his efforts were (5)-and (R)-l-amino-2-methoxypyrrohdine hydrazine (1 and 2, respectively), now commonly known as the SAMP and RAMP auxiliaries, respectively (Figure 7.1). Over the years, the SAMP/RAMP method has come to be considered the state-of-the-art approach to asymmetric ketone... 

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