SAMP addition

The use of hydrazone or enamine derivatives of ketones or aldehydes offers the advantage of stcreocontrol via chelated azaenolates. Extremely useful synthetic methodology, with consistently high anti selectivity, has been developed using azaenolates based on (S)- or (R)-l-amino-2-(methoxymethyl)pyrrolidine (SAMP or RAMP)51 58 (Enders method, see Section 1.5.2.4.2.2.3.). An example which illustrates the efficiency of this type of Michael addition is the addition of the lithium azaenolate of (5 )-l-amino-2-(methoxymethyl)pyrrolidine (SAMP) hydrazone of propanal (R = II) to methyl (E )-2-butenoate to give the nub-isomer (an 1 adduct) in 80% yield with a diastereomeric ratio > 98 2,... 

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. 

Thus, the lithiated SAMP hydrazones of various methyl ketones on addition to 2-(aryl-methylene)- , 3-propanedionates and propanedinitriles provide, after the removal of the auxiliary, (R)-2-( l-aryl-3-oxobutyl)-1,3-propanedioates and -propanedinitriles with high enantiomeric excess (> 95%) in 50 82% yield (sec Table 6) 195,197. Using similar methods optically active (5-lactones (90% to > 96% ee) are obtained198. 

Table 6. 5-Oxoalkanoates by Addition of Aldehyde or Ketone SAMP I tydra/ones to F.nones...

The addition of the lithium azaenolate of the SAMP hydrazone of propanal to methyl (E)-2-butenoate to furnish the (S,S,S)-adduct in 58% yield with > 96% ee and de is illustrative for the efficiency of this asymmetric Michael addition10°. Only the anti-isomer (an / adduct) is found. This methodology was used in the synthesis of pheromones of the small forest and red wood ant200. 

The Enders method has also been used as a key step in the synthesis of optically active Ar-heterocycles. The use of cyclic 1,3-diketones for the preparation of the SAMP or RAMP lithium azaenolates is shown by the synthesis of substituted 4,6,7,8-tetrahydro-2,5(l//,3//)-quinolinediones 2. Michael addition of 1 with, for example, benzylidene propanedioates followed by removal of the auxiliary and lactamization gives 2 with > 98% ee201. 

Additions of stabilized carbanions to imines and hydrazones, respectively, have been used to initiate domino 1,2-addition/cyclization reactions. Thus, as described by Benetti and coworkers, 2-subshtuted 3-nitropyrrolidines are accessible via a nitro-Mannich (aza-Henry)/SN-type process [165]. Enders research group established a 1,2-addition/lactamization sequence using their well-known SAMP/ RAMP-hydrazones 2-308 and lithiated o-toluamides 2-307 as substrates to afford the lactams 2-309 in excellent diastereoselectivity (Scheme 2.72) [166]. These compounds can be further transformed into valuable, almost enantiopure, dihydro-2H-isoquinolin-l-ones, as well as dihydro- and tetrahydroisoquinolines. 

The addition of a-lithiomethoxyallene 144 [55] to benzaldehyde dimethylhydra-zone 145 (Eq. 13.48) leads to a mixture of pyrroline 146 and dihydroazete 147 [56]. The cydization in this case, which takes place in the same operation as the addition to the hydrazone, follows two distinct pathways, with attack of the nitrogen atom taking place at the inner, in addition to the terminal, carbon atom of the allene. A similar reaction of 144 with SAMP-hydrazone 148 (Eq. 13.49) leads to 3-pyrroline 149 in 88% yield and excellent diastereoselectivity [57]. Cleavage of the chiral auxiliary group from 149 takes place in two steps (1, methyl chloroformate 2, Raney nickel, 50 bar, 50 °C) in 74% overall yield. When the addition of 144 to 148 is conducted in diethyl ether, cydization of the adduct does not take place. Surprisingly, the hydrazones of aliphatic aldehydes react with 144 in poor yield in THF, but react quantitatively and diastereoselectively in diethyl ether to give the (uncyclized) allenyl hydrazone products. 

A solution of 1.05 equiv of butyllithium in hexane (1.6 M) are added dropwise via syringe to a solution of 1.05 equiv of diisopropylaminc in diethyl ether (0.25-0.5 M) under argon at O C and stirred for 15 min lo generate a solution of 1.05 equiv of lithium diisopropylamide. After dropwise addition of 1.0 equiv of the SAMP-hydrazone, the mixture is stirred at 0 °C for 4 h, cooled to — 110 °C, and 1.05 equiv of the electrophile... 

In addition to the standard alkylation procedure, a,tx -dialkylated products are obtained by double alkylation of symmetrical SAMP-hydrazones20. 

During our investigations on asymmetric C—C bond formation reactions via conjugate addition of SAMP hydrazones to various a,(3-unsaturated Michael acceptors, it occurred to us to use the chiral hydrazine auxiliary S AM P as a nitrogen nucleophile and a chiral equivalent of ammonia in aza-Michael additions. Thus, we developed diastereo- and enantioselective 1,4-additions for the synthesis of P-amino acids and P-aminosulfonates [14, 15]. 

Sulfones have become increasingly important in organic synthesis in recent years and a, P-unsaturated sulfones especially are known to be excellent Michael acceptors. Following our concept of using SAMP derivatives as chiral equivalents of ammonia, the enantioselective aza-Michael addition has been investigated in order to provide a new method for the synthesis of P-aminosulfones [15]. 

In addition to the results described, enantioselective access to 2-phosphino alcohols could be accomplished, too [71]. Starting from a borane-protected a-phosphino aldehyde hydrazone 91 as the key intermediate and available by two different approaches, the enantioselective synthesis of the desired 2-phosphino alcohols 93 could be accomplished. Thus, the electrophilic phosphinylation of aldehyde hydrazones 90 (via route I with the chlorodiphenylphosphine-borane adduct or via route II with chlorophosphines and subsequent phosphorus-boron bond formation) and the alkylation of phosphino acetaldehyde-SAMP hydrazones 92 (route III) was carried out (Scheme 1.1.26). 

As shown in Scheme 1.2.12, the aldehyde or ketone SAMP hydrazones 50 were metallated using LDA to generate the desired azaenolate, and then TMEDA was added. Subsequent Michael addition with methyl-2-cyclopentenone carboxylate (51) resulted in a clean 1,4-addition leading to the desired adducts 52 in good yields. 

In our group the diastereoselective 1,2-addition of organometallic reagents to aldehyde SAMP hydrazones was employed in the synthesis of several alkaloids and we have now extended our method to the efficient asymmetric synthesis of the poison-dart-frog indolizidine alkaloids 2091 and 223J and their enantiomers via a common late-stage intermediate amino nitrile (5R,8R,8aS)-63 [45]. This amino nitrile chemistry had previously been used by Polniaszek and Belmont in the first enantioselective total syntheses of 5,8-disubstituted indolizidine alkaloids [46]. They were able to prepare the indolizidines 205A (65) from 64 in one or two steps (Scheme 1.2.15). 

By contrast with the above examples which involve activated olefins, the addition of zinc enolates to unactivated alkenes is much more difficult to achieve. Although ethylene seems to be an acceptable partner for such additions, the reactions have to be carried out under pressure and require relatively long reaction times. Thus, the butylzinc aza-enolate generated from the SAMP hydrazone of cyclohexanone 452 reacted slowly with ethylene... 

A highly selective method for the preparation of optically active 3-substituted or 3, y-disubstituted-S-keto esters and related compounds is based on asymmetric Michael additions of chiral hydrazones (156), derived from (5)-l-amino-2-methoxymethylpyrrolidine (SAMP) or its enantiomer (RAMP), to unsaturated esters (154).167-172 Overall, a carbonyl compound (153) is converted to the Michael adduct (155) as outlined in Scheme 55. The actual asymmetric 1,4-addition of the lithiated hydrazone affords the adduct (157) with virtually complete diastereoselection in a variety of cases (Table 3). Some of the products were used for the synthesis of pheromones,169 others were converted to 8-lactones.170 The Michael acceptor (158) also reacts selectively with SAMP hydrazones.171 Tetrahydroquinolindiones of type (159) are prepared from cyclic 1,3-diketones via SAMP derivatives like (160), as indicated in Scheme 56.172... 

Asymmetric synthesis of primary amines by nucleophilic 1,2-addition of alkyl-lithiums to aldehyde SAMP/RAMP hydrazones has been reported in detail.105 On reaction with a range of lithium alkyls, 1,3,5-triazinc has been found to form 1,4-adducts which yield 1,4-dihydrotriazines on hydrolysis 106 in contrast LiNR2 or LiCR3(thf)2 promote 1,3,5-triazine ring-opening reactions. 

F. (S)-(-)-l-Amino-3-methoxymethylpyrrolidine (SAMP). A 4-L, threenecked flask containing the crude urea is cooled to -5°C (internal temperature) by means of an ice-salt bath and treated with a chilled (-5°C) solution of 168 g of potassium hydroxide in 150 mL of water. After addition of 685 mL (1.3 mol) of 1.9 N potassium hypochlorite solution (Note 15), precooled to -6°C, the temperature rises within 10 min to 30-40°C and the cooling bath is removed after the mixture reaches room temperature (Note 16). Stirring is... 

Obtained by addition of butyllithium to benzaldehyde-SAMP-hydrazone, followed by N-N bond cleavage. 

An efficient asymmetric synthesis of the 3-substituted /3-sultams 163 has been reported. The key step of the synthesis is the Lewis acid-catalyzed aza-Michael addition of the enantiopure hydrazines (A)-l-amino-2-methoxy-methylpyrrolidine (SAMP) or CR,l ,l )-2-amino-3-methoxymethyl-2-azabicyclo[3.3.0]octane (RAMBO) to the alke-nylsulfonyl sulfonates 176. /3-Hydrazino sulfonates were obtained in good yield and excellent enantioselectivity. Cleavage of the sulfonates followed by chlorination resulted in the corresponding sulfonyl chlorides 177. The (A)-3-substituted /3-sultams 163 have been obtained in moderate to good yields and high enantioselectivity over two steps, an acidic N-deprotection followed by in situ cyclization promoted by triethylamine (Scheme 55) <2002TL5109, 2003S1856>. 

Beyond the scope discussed so far, Michael additions also include additions of stoichio-metrically generated enolates of ketones, SAMP or RAMP hydrazones, or esters to the C=C double bond of ,/Tun saturated ketones and a,/Tunsaturated esters. These Michael additions convert one kind of enolate into another. The driving force stems from the C—C bond formation, not from differential stabilities of the enolates. It is important that the addition of the preformed enolate to the Michael acceptor is faster than the addition of the resulting enolate to another molecule of the Michael acceptor. If that reactivity order were not true, an anionic polymerization of the Michael acceptor would occur. In many Michael additions, however, the enolate created is more hindered sterically than the enolate employed as the starting material, and in these cases Michael additions are possible without polymerization. 

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