Addition diastereoselective

The highly regio- and diastereoselective addition of an alkyl and an arylthio group to an olefinic double bond ( carbosulfenylation ) is achieved with arenesulfenyl chlorides and alkyl-chloro-titanium(IV) species (Reetz reagent, from R2Zn/TiCU 5 1 M. T. Reetz, 1987, 1989), Use of the more bulky 2,4,6-triisopropylbenzenesulfenyl chloride improves the yield of the highly versatile alkyl aryl sulfide products. 

The key step to this first reported case of the highly diastereoselective addition of a fluorinated enolate in an aldol process is the selective formation of the enolate a,a-Difluonnated enolates prepared by a metallation process employing either a zinc-copper couple [S] or reduced titanium species [9] undergo aldol condensation smoothly (equation 9) (Table 5)... 

Although the true nature of the interaction leading to predominant axial attack remains a point of discussion and awaits final clarification, there is nevertheless a vast body of experimental results indicating the possibilities and limitations of diastereoselective addition to cyclic ketones. 

An analogous solvent effect was observed upon treatment of the chiral a-alkoxy aldehyde 11 with 2-lithio-4-methylfuran in the presence of zinc bromide. This highly diastereoselective addition reaction was the key step in a synthesis of the enantiomcrically pure C-10-C-20 fragment of the immunosuppressant KK 506139. 

One of the first examples of this type of reaction, using a chiral alcohol as an auxiliary, was the asymmetric synthesis of 2-hydroxy-2-phenylpropanoic acid (atrolactic acid, 3, R1 =C6H5 R3 = CH3) by diastereoselective addition of methyl magnesium iodide to the men-thyl ester of phcnylglyoxylie acid4,5 (Table 22). 

Another chiral auxiliary used in diastereoselective addition reactions is the 1,3-oxazine derivative 4a which shows a close structural resemblance to the 1,3-oxathiane 16 (vide supra). However, in contrast to the oxathiane, 4a cannot be readily acylatcd in the 2-position. Therefore, the benzoyl derivative 4b was prepared by condensing amino alcohol 3 with phenylglyoxal. 

Besides simple alkyl-substituted sulfoxides, (a-chloroalkyl)sulfoxides have been used as reagents for diastereoselective addition reactions. Thus, a synthesis of enantiomerically pure 2-hydroxy carboxylates is based on the addition of (-)-l-[(l-chlorobutyl)sulfinyl]-4-methyl-benzene (10) to aldehydes433. The sulfoxide, optically pure with respect to the sulfoxide chirality but a mixture of diastereomers with respect to the a-sulfinyl carbon, can be readily deprotonated at — 55 °C. Subsequent addition to aldehydes afforded a mixture of the diastereomers 11A and 11B. Although the diastereoselectivity of the addition reaction is very low, the diastereomers are easily separated by flash chromatography. Thermal elimination of the sulfinyl group in refluxing xylene cleanly afforded the vinyl chlorides 12 A/12B in high chemical yield as a mixture of E- and Z-isomers. After ozonolysis in ethanol, followed by reductive workup, enantiomerically pure ethyl a-hydroxycarboxylates were obtained. 

For diastereoselective addition of pcrfluoroalkyl lithium generated in situ to imines and %-alkoxy imines in the presence of BF, OEt2. see refs 13 and 14. 

For diastereoselective addition of organometallic agents to imines attached to arene tricar-bonylchromium or ferrocenyl moieties, see refs 26 28 and Section 1.4.1.1.2.2. 

In order to synthesize 1,3-diphenyl-l, 3-diamines 3 containing a C2 axis of symmetry, which can be employed as auxiliaries and controller groups in asymmetric syntheses, the diastereoselective addition of organometallic reagents to racemic pyrazolines 2, prepared from cinnamaldehyde (l)23, was investigated. 

Deacetylanisomycin (4) is synthesized using L-tartaric acid (1) as a precursor in 12% overall yield16. The key step is the diastereoselective addition of (4-methoxybenzyl)magnesium chloride to the C — N double bond of nitrone 2 at 0°C in the presence of 1 equivalent of ethylmagncsium-bromide diethyl ether complex in dichloromethane. This procedure affords a chromatograph-ically separable mixture of the hydroxylamines 3 a and 3 b in a diastereomeric ratio [(2R,35,4R)/ (25,35,47 )] 70 30 and 60% yield from 2. 

The addition of boron enolates to imincs is useful for the construction of anti-fi-amino acid derivatives8. On the other hand, it is possible to control the direction of the diastereoselective addition of enolates from (A)-phenyl alkanethioates with imines9. 

Tin(Il) shows considerable affinity towards nitrogen, therefore is expected to activate the imino group. The diastereoselective addition of tin(II) enolates derived from thioesters 1 to x-imino-esters 2 is reported12. This reaction proceeds smoothly to afford. vi w-/j-amino acid derivatives 3 (d.r. 95 5) in good yields. Lithium, magnesium, and zinc enolates do not react while titanium enolates give the adducts in low yield with preferential formation of the anti-isomer. 

The quantitative and diastereoselective addition of the sodium enolate of te/7-buty] 5-methyl-3-oxohexanoate to the Michael acceptor 2 was used in the synthesis of 0-methyl pisiferic acid280. 

The diastereoselective addition of [(S)-3-alkoxy-l-octenyl]lithium to an enantiomerically pure cyclic y-(rer/-butyldimethylsilyloxy)-o(,/S-unsaturated sulfone was employed in the synthesis of ( )-prostaglandin E219, with addition occurring exclusively anti to the sterically demand-... 

Diastereoselective addition has been carried out with achiral reagents and chiral substrates, similar to the reduction shown on page. 1201, but because the attacking atom in this case is carbon, not hydrogen, it is also possible to get diastereoselective addition with an achiral substrate and an optically active reagent. Use of suitable reactants creates, in the most general case, two new chiral centers, so the product can exist as two pairs of enantiomers ... 

Scheme 13 Diastereoselective addition of a-nitrocarbanions to chiral imines...

Scheme 25 Diastereoselective addition of organometallic reagents to chiral a-amino hydrazones...

On the other hand, following the same sequences from the differently protected serine-derived nitrone 168, through the formation of hydroxylamines 169, C2 epimers of carboxylic acid and aldehydes are obtained, i.e., (2S,3R)-170 and (2S,3R)-171. Moreover, the syn adducts 164 were exclusively obtained in the addition of Grignard reagents to the nitrone 163, whereas the same reactions on nitrone 168 occurred with a partial loss of diastereoselectivity [80]. Q, j6-Diamino acids (2R,3S)- and (2R,3R)-167 can also be prepared from the a-amino hydroxylamines 164 and 169 by reduction, deprotection and oxidation steps. The diastereoselective addition of acetylide anion to N,N-dibenzyl L-serine phenyhmine has been also described [81]. 

Scheme 40 Diastereoselective addition of y-substituted allyllithium and allylzinc reagents to a chiral diimine...

Metal-catalyzed asymmetric addition of dialkyl phosphites to aldehydes (Pudovik reaction) has been extensively developed since the initial reports in 1993 by Shibuya. Scheme 5-25 illustrates the use of TiCh to promote diastereoselective addition of diethyl phosphite to an a-amino aldehyde. 

Diastereoselective addition of a wide range of Grignard reagents to C -alkyl and C-aryl-A-[a.-phenyl- or u-methyl-j3-(benzyloxy)ethyl nitrones is determined by the presence of a stereogenic A -substituent (136, 137). High diastereoselectiv-ity in the addition of organometalic compounds to A-(( i-methoxyalkyl) nitrones can be explained by a simple chelation model (Scheme 2.132) (136). 

As in all cases already mentioned, diastereoselective addition of Grignard reagents to j3-amino nitrones (a-aminoalkyl nitrones) is a key step in the stereo-controlled syntheses of O.,j3-diamino acids (Scheme 2.141) (565, 566), of unsym-metrical a-amino hydroxylamines and 1,2-diamines (Scheme 2.142) (209, 567). 

Table 2.15 Diastereoselective addition of vinyl reagents to nitrone BIGN 292...

The reaction of nitrones with terminal alkynes proceeds in excellent yields and high purity, in the presence of stoichiometric quantities of diethylzinc and zinc triflate (219, 661-663). To optimize the process of diastereoselective addition of terminal alkynes to chiral nitrones, ZnCl2 and NEt3 in toluene were used. This reaction protocol is facile to perform, cost-effective and environmental friendly (664). 

Although there are some examples of diastereoselective addition of allylic stannanes to substituted 1,3-oxazolidi-nones (Scheme 52),141 these reactions have still not been applied to asymmetric synthesis. 

Recent developments of aldol-type reactions with titanium enolates include the a- and /3-C-glycosidation of glycals73 and the diastereoselective addition to 2-acetoxytetrahydrofurans.74 Mukaiyama and co-workers have developed a one-pot procedure for the preparation of unsymmetrical double aldols.75... 

Titanium enolates of various carbonyl compounds play an increasingly important role in Mannich-type reactions with different electrophiles. Recently, Liotta and co-workers reported a novel diastereoselective addition of chloro-titanium enolate 80 of iV-acylthiazolidinethione to various types of O-methyl oximes to afford the desired anti-azetines, precursors of a,/3-disubstituted /3-amino carbonyl derivatives 82 (Scheme 32).109... 

In comparison with the platinum catalysts, rhodium catalysts are much more reactive to effect addition of bis(catecholato)diboron even to non-strained internal alkenes under mild reaction conditions (Equation (5)).53-55 This higher reactivity prompted trials on the asymmetric diboration of alkenes. Diastereoselective addition of optically active diboron derived from (li ,2i )-diphenylethanediol for />-methoxystyrene gives 60% de (Equation (6)).50 Furthermore, enantioselective diboration of alkenes with bis(catecolato)diboron has been achieved by using Rh(nbd)(acac)/(A)-QUINAP catalyst (Equation (7)).55,56 The reaction of internal (A)-alkenes with / //-butylethylene derivatives gives high enantioselectivities (up to 98% ee), whereas lower ee s are obtained in the reaction of internal (Z)-alkenes, styrene, and a-methylstyrene. 

Increasing interest is expressed in diastereoselective addition of organometallic reagents to the ON bond of chiral imines or their derivatives, as well as chiral catalyst-facilitated enantioselective addition of nucleophiles to pro-chiral imines.98 The imines frequently selected for investigation include N-masked imines such as oxime ethers, sulfenimines, and /V-trimcthylsilylimines (150-153). A variety of chiral modifiers, including chiral boron compounds, chiral diols, chiral hydroxy acids, A-sull onyl amino acids, and /V-sulfonyl amido alcohols 141-149, have been evaluated for their efficiency in enantioselective allylboration reactions.680... 

The enantioselectivity can be increased by changing the methyl group on nitrogen to an isopropyl group. Thus highly diastereoselective additions to cyclic enones are obtained with the phospholidine 3, prepared in several steps from norpseu-doephedrine.1... 

The diastereoselective addition to imines proceeds well with aromatic enolsi-lanes (249). Propiophenone- and tetralone-derived enolsilanes provide good levels of diastereoselectivity (>95 5) and excellent enantioselectivity (>98% ee) with selective formation of the anti diastereomer. Nonaromatic enolsilanes are somewhat less selective although cyclohexanone enolsilane still provides useful levels of diastereoselectivity and enantioselectivity (92 8 anti/syn and 88% ee at -78°C). A one-pot procedure using glyoxylate, sulfonamide, and enolsilane as coupling partners was developed subsequently, leading to the product in comparable yields and selectivities (250, 251). 

Similarly, diastereoselective addition of 42 to chiral a-ketoamides 65 afforded primary allene adducts 66 in moderate yields but with a high level of stereoselectivity (Scheme 8.18) [55],... 

The substrate-controlled diastereoselective addition of lithiated alkoxyallenes to chiral nitrones such as 123, 125 and 126 (Scheme 8.32) furnish allenylhydroxyl-amines as unstable products, which immediately cydize to give enantiopure mono-orbicyclic 1,2-oxazines (Eqs 8.25 and 8.26) [72, 76]. Starting with (R)-glyceraldehyde-derived nitrone 123, cydization products 124 were formed with excellent syn selectivity in tetrahydrofuran as solvent, whereas precomplexation of nitrone 123 with... 

The bromoallene (-)-kumausallene (62) was isolated in 1983 from the red alga Laurencia nipponica Yamada [64a], The synthesis of the racemic natural product by Overman and co-workers once again employed the SN2 -substitution of a propargyl mesylate with lithium dibromocuprate (Scheme 18.22) [79]. Thus, starting from the unsymmetrically substituted 2,6-dioxabicyclo[3.3.0]octane derivative 69, the first side chain was introduced by Swern oxidation and subsequent Sakurai reaction with the allylsilane 70. The resulting alcohol 71 was protected and the second side chain was attached via diastereoselective addition of a titanium acetylide. The synthesis was concluded by the introduction of two bromine atoms anti-selective S -substitution of the bulky propargyl mesylate 72 was followed by Appel bromination (tetrabromo-methane-triphenylphosphine) of the alcohol derived from deprotection of the bromoallene 73. 

These first examples of the catalytic asymmetric aldol reaction not only provided first results that could be utilized for such transformations but also highlighted the problems that had to be overcome in further elaborations of this general method. It was shown that truly catalytic systems were required to perform an enantioselective and diastereoselective vinylogous aldol reaction, and it became obvious that y-substituted dienolates that serve as propionate-acetate equivalents provide an additional challenge for diastereoselective additions. To date, the latter problem has only been solved for diastereoselective additions under Lewis acid catalysis (vide infra) (Scheme 4, Table 3). 

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