organic synthesis

Review ArticleSynthesis and Reactivity of

N-Protected-�-Amino AldehydesDOROTA GRYKO,1 JOANNA CHAŁKO,2 AND JANUSZ JURCZAK1,2*

1Institute of Organic Chemistry, The Polish Academy of Science, Warsaw, Poland2Department of Chemistry, Warsaw University, Warsaw, Poland

ABSTRACT During the last decade �-amino aldehydes have attracted widespreadattention as the important natural source of chiral substrates useful in stereocontrolledorganic synthesis. They are of special interest due to their ready availability in bothenantiomeric forms from natural sources, as well as their pronounced versatility, due tothe presence of both the formyl group and suitably protected amino functionality in themolecule. These bifunctional compounds exhibit a valuable dual reactivity, which hasbeen utilized in a broad range of synthetic applications. Chirality 15:514–541, 2003.© 2003 Wiley-Liss, Inc.

KEY WORDS: �-amino aldehydes; metalloorganic additions; aldol; Wittig; Diels-Alderreactions; cyclization

The synthesis of enantiomerically pure organic com-pounds from chiral substrates is very advantageous, as itenables the precise programming and efficient realizationof a synthetic pathway. During recent years this approachto organic synthesis has greatly contributed to the prog-ress in the directed introduction of various functionalitiesand in the closely controlled formation of new stereogeniccenters.1 Many monosaccharides and their readily avail-able derivatives are versatile substrates for the synthesis ofoptically active target molecules.2 �-Amino acids are thenext important natural source of chiral starting materials,useful in stereocontrolled organic synthesis.3 One of themost frequently used strategies based on �-amino acidsconsists of their transformation into N-protected �-aminoaldehydes. These chiral substrates are of special interestdue to their ready availability in both enantiomeric formsand to their pronounced versatility due to the presence ofboth the formyl group and suitably protected amino func-tionality in the molecule.4–6

Very recently, two comprehensive reviews on the ap-plication of N,N-dibenzyl L-�-amino aldehydes (A)5 and(S)-1,1-dimethyl-4-formyl-2,2-dimethyloxazolisine-3-car-boxylate (so-called Garner’s aldehyde, B)6 in organic syn-thesis have been published. However, the important groupof �-amino aldehydes, protected in a different way, such asN-monoprotected and nonsymmetrically N,N-diprotectedderivatives of type C (Fig. 1) is of growing interest. Ourformer review,4 in which we surveyed applications of thelatter compounds, is not sufficiently up to date since it waspublished 13 years ago. Therefore, we resolved to gatherand present the current knowledge concerning the use ofthese �-amino aldehydes in stereocontrolled organic syn-thesis.

In the present review we focus our attention mainly onnew methods of preparing enantiomerically pure protected

�-amino aldehydes of type C as well as on reactions usingthe carbonyl group of protected �-amino aldehydes to forma new stereogenic center.

SYNTHESIS OF �-AMINO ALDEHYDESReductive Methods

One of the most widely used methods for the prepara-tion of �-amino aldehydes is the reduction of the respective�-amino acid derivatives with various reducing agents; theprocedures in use before 1989 were described in the com-prehensive review by Jurczak and Gołe�biowski.4 The mostcommon method used is the reduction of carboxylic acidmethyl or ethyl ester by diisobutylaluminum hydride(DIBAL),7 but in many cases overreduction of the respec-tive alcohol7,8 and/or racemization9 is observed. Because�-amino aldehydes are known to racemize upon a chro-

Contract grant sponsor: The State Committee for Scientific Research, War-saw, Poland; Contract grant number: PBZ 6.05/T09/1999.*Correspondence to: Prof. Janusz Jurczak, Institute of Organic Chemistry,The Polish Academy of Science, Kasprzaka 44/52, 01-224 Warsaw, Poland.E-mail: [email protected] for publication 21 October 2002; Accepted 11 February 2003

Fig. 1.

CHIRALITY 15:514–541 (2003)

© 2003 Wiley-Liss, Inc.

matographic purification and storing, the alcohol formationis a real drawback in this method. Since that time, a lot ofwork has been done in order to avoid the undesired alcoholformation or racemization process, mainly focusing on theapplication of other derivatives of �-amino acid and otherreducing agents. Procedures based on this approach(Scheme 1) are listed in Table 1.

Zlatoidsky10 demonstrated that the reduction of phenylesters, easily prepared by the DCC method, with LiAl(t-BuO)3H allowed synthesization of a broad range of�-amino aldehydes with the N-Boc and/or N-Cbz protect-ing group with good yield. The author measured opticalrotations of the aldehydes but did not comment their opti-cal purity. The hydride reduction is unsuitable for the syn-thesis of multifunctional compounds, such as N-acylaminoaspartyl aldehyde, as the carboxylic functionality does notsurvive under these conditions. However, the use of benzylthioester was found to be a suitable derivative to the tri-ethylsilane reduction to give the respective aldehyde,11 andas it was shown for N-Fmoc-protected aldehydes that theracemization did not occur. A practical one-pot synthesisstarting from a protected �-amino acid was presented byTaddei and co-workers.12 The activated ester of N-Boc-amino acids with 2-chloro-4,6-dimethoxy[1,3,5]triazine canbe reduced with H2-Pd/C to afford the corresponding al-dehyde with no significant racemization and in good yield.Another approach, which avoids racemization of N-protected �-amino aldehydes, was discovered by Hyun andKim,13 who decided to change the carbonyl group into thesaturated cyclic hemiacetal group. The procedure involvesthe synthesis of cyclic derivative 2, followed by the reduc-tion with DIBAL, giving optically pure and configuration-ally stable hemiacetal 3 (Scheme 2).

Reduction of mixed anhydrides of N-Boc-amino acids,commonly used in peptide chemistry as activating agents,with LiAl(t-BuO)3H gave respective aldehydes with theyield in the range of 70–80% and with negligible racemiza-tion.14 The results were obtained with the use of pivaloylchloride as a reagent for the anhydride formation, so, afterthe reduction, pivalic acid can be removed by extraction,which is not the case for the commonly used diphenylace-tic acid.

Since the first report on the preparation of �-amino al-dehydes by the reduction of Weinreb amide (WA), thismethod has gained increasing importance due to the factthat overreduction and racemization do not occur. An ex-cellent example came from the Parke-Davis Laboratory,where Schwindt et al.15 prepared 6 on a kilogram scale andsuccessfully reduced it to the corresponding aldehyde 7with sodium bis-(2-methoxyethoxy)aluminum hydride (Vit-ride) (Scheme 3).

This method can also be applied to the synthesis of N-Fmoc-protected �-amino aldehydes using LiAlH4 as a re-ducing agent.16 Martinez and co-workers17 have shownthat WA derivatives of protected aspartic and glutamic acidcan be reduced to the corresponding aldehydes with LiAl(t-BuO)3H and lithium tris[(3-ethyl-3-phenyl)oxy]aluminumhydride (LTEPA). N-Cbz and N-Boc protecting groups aswell as cyclohexyl and t-butyl ester groups of aspartic andglutamic acids are stable under these conditions. Becauseof the high cost of N,O-dimethylhydroxamate hydrochlo-ride, used for the preparation of WA, N-protected �-aminomorpholine amides18 present an interesting alternative.They are reduced to aldehydes with LiAlH4 within 15–25min and, as the authors claim, without racemization. Thismethod is compatible with most of the commonly usedN-protecting groups.

Most �-amino acid derivatives have to be preparedthrough acid chlorides; Zlatoidsky19 has undertaken thechallenge to find a method for the direct reduction of thesecompounds. He showed that by using LiAl(t-BuO)3H as areducing agent, N-Boc- or N-Cbz-�-amino acid fluoridesand N-Fmoc-amino acid chlorides are reduced to corre-sponding �-amino aldehydes. Unfortunately, this method isnot free from racemization, and yields are usually ∼60%.Another, even simpler method was proposed by Ohmoriand co-workers20—the direct electrochemical reduction of

Scheme 1.

Scheme 2.

Scheme 3.

N-PROTECTED-�-AMINO ALDEHYDES 515

N-protected �-amino acids gave aldehydes with good opti-cal purity and in high yields. The method, however, hasone major drawback—it requires special apparatus for theelectrolysis, which is not standard equipment in organicchemistry laboratories.

Oxidative Methods

A common approach to obtain aldehydes is in fact theoxidation of primary alcohols and this is also true in thecase of �-amino aldehydes of type C. The synthesis in-volves the reduction of a suitably protected �-amino acid or�-amino acid ester to the corresponding alcohol, followedby the selective oxidation.

The N-protected �-amino alcohols are easily prepared bythe reduction of the corresponding amino acid with, forexample benzotriazol-1-yloxytris(dimethylamino)phos-phonium hexafluorophosphate(BOP-reagent)/DIPEA/NaBH4,

21 BH3·SMe2/BF3·OEt2,22 NaBH4/BF3,23 NaBH4/H2SO4,24 NaBH4/Me3SiCl,25 LiBH4/Me3SiCl,25 cyanuricchloride/NaBH4,26 or by the reduction of �-amino acid es-ter, usually methyl or ethyl, with NaBH4/LiCl,27 NaBH4/CaCl2,28 LiBH4,9 NaBH4/AcOH,29 or LiAlH4.28

The final oxidation step can be carried out using a widevariety of methods.4–6 Keeping in mind that �-amino alde-hydes are notoriously prone to racemize, it is not surpris-ing that a great deal of work has been done to find condi-tions under which the aldehydes can be obtained with high

optical purity. Among these oxidation methods, the mostwidely used is the Swern procedure.30 It was found to bevery useful in the preparation of N,O-protected-L-serinals31

with very high yield, but as shown later by the same re-search group, the optical purity of these aldehydes wasvery low.9 However, the method worked well for L-alaninals, which were obtained with good enantiomeric ex-cess.9 The simple replacement of NEt3 with diisopropyl-ethylamine (Hunig’s base),32 caused by the N-Boc-L-cyclohexylalaninal (7), was obtained with ee >95% at–20°C, whereas under standard conditions, even at –70°C,the optical purity was lower, as presented by Krysan et al.29

Another efficient alternative to the classical Swern methodwas proposed by the Giacomelli group,33 who used 2,4,6-trichloro[1,3,5]-triazine (TCT) instead of moisture-sensitive oxalyl chloride, assuring in this way milder reac-tion conditions. While the oxidation of simple aliphatic al-cohols gave aldehydes with high yield, �-amino aldehydeswere obtained with low to moderate yield, although with-out significant racemization. The authors29 showed that thesame high level of optical purity could be achieved whenthe modified Parikh-Doering procedure was used.

The success of the Swern method requires the use oflow temperature and strict adherence to the documentedreaction conditions in order to avoid racemization. More-over, the coproduction of SMe2 (stench) and toxic gaseousside products ((COCl)2 and CO) additionally limits its use

TABLE 1. Preparation of N-protected �-amino aldehydes by reductive methods (Scheme 1)

X PG1 PG2 R [H] Yield [%] Ref.

OH Cbz H Bn electrochemical reduction 83 20Cbz H MeSCH2CH2 84 20Cbz proline 81 20

OPh Boc H Me LiAl(t-BuO)3H 76 10Boc H MeSCH2CH2 82 10

SBn Fmoc H Bn Et3SiH, Pd/C 70 11Fmoc H BocNH(CH2)4 75 11Fmoc H t-BuOCOCH2 75 11

BocH Me H2, Pd/C 79 12

Boc H BnOCOCH2 72 12Cl Fmoc H i-Pr LiAl(t-BuO)3H ca 60 19F Boc H Bn LiAl(t-BuO)3H ca 60 19

Cbz H Bn ca 60 19t-BuOCOO Boc H Me LiAl(t-BuO)3H 76 14

Boc H MeSCH2CH2 82 14

BocH Me LiAlH4 75 18

Boc H BnOCH2 48 18Cbz H Bn 53 18Fmoc H Bn 50 18

FmocH i-Pr LiAlH4 80 16

Fmoc H MeSCH2 89 16Fmoc H BuOCH2 85 16Cbz H Asp(Ot-Bu) LTEPA 54 17Cbz H Glu(Ot-Bu) 54 17

LTEPA–lithium tris[(3-ethyl-3-pentyl)oxy]aluminium hydride.

516 GRYKO ET AL.

on an industrial scale. In 1992 Leanna et al.34 described thefirst application of oxoammonium-promoted oxidation of�-amino alcohols to �-amino aldehydes in the presence ofa catalytic amount of 2,2,6,6-tetramethyl-1-piperidinyloxyfree radical (TEMPO). N-Mono and N,N-diprotected alde-hydes were obtained with good yield and high optical pu-rity. This method was further developed by our group9 andwe have shown that the TEMPO oxidation is a very effec-tive procedure for the preparation of optically active, vari-ously protected �-amino and �-amino-�-hydroxy alde-hydes, practically without racemization. This appears to bemore efficient than the routes previously used for the syn-thesis of these compounds. The comparison between theTEMPO [A] or Swern [B] oxidation and DIBAL reduction[C] for several aldehydes is presented in Table 2.

Recently, Giacomelli and co-workers35 improved theTEMPO oxidation method. They found that the efficientoxidation of alcohols to corresponding aldehydes could becarried out at room temperature in CH2Cl2 as a solvent,using cynauric chloride instead of NaOCl in the presenceof a catalytic amount of TEMPO radical. The main advan-tage of doing so is the time of the reaction (usually 20 min)and the lack of overoxidation process. The procedure iscompatible with the N-Boc-, N-Cbz-, and N-Fmoc-protectinggroups.

In the course of studies directed toward the synthesis ofsaframycin A, Myers et al.36 were led to prepare a series of�-amino aldehydes with the base-labile N-Fmoc protectinggroup. In all cases examined the Dess-Martin oxidationprocedure proved to be highly efficient and proceeded with

minimal epimerization of the �-stereocenter. The summaryof their study is presented in Table 3.

While this procedure is the best choice for the oxidationof N-Fmoc-protected amino alcohols, it does not work wellfor N-Boc-protected counterparts. These aldehydes are ob-tained with good yield but the optical purity ranges fromlow to very high for N-Boc-L-phenylalaninal.37

Preparation of �-Amino Aldehyde Acetals and Aminals

The above-presented syntheses of N-protected �-aminoaldehydes are limited to the naturally occurring �-aminoacids. Recently, stereoselective methods for the synthesisof these carbonyl compounds have started to play an in-creasingly important role. One of the most frequently ap-plied methods in this respect is the addition of organome-tallic compounds to CN double bond.

In 1989 the Bringmann group38 reported the chiral pool-independent synthesis of alaninal acetals essentially in twosteps: formation of imines of 1,1-dialkoxy-2-propanone with(R)- or (S)-1-phenylenethylamine and the subsequentasymmetric catalytic reduction. Yields were usually highand the diastereoisomeric excess (de) value reached 96%.

A milestone in the synthesis of a broad variety of�-amino aldehyde acetals was set by Katritzky et al.,39 whoused glyoxal monoacetal 8 as a starting material. The con-densation of 8, benzotriazole, and a primary or secondaryamine gave an intermediate which, treated with Grignardreagents and followed by acidic hydrolysis, afforded race-mic �-amino aldehydes with high yield. The asymmetricversion of this concept uses a chiral acetal as a protectivegroup and the transformation of the free aldehyde intohydrazone 10, which is subjected to reactions with variousorganometallic reagents (Scheme 4).40,41

TABLE 2. Optical purity of aldehydes obtained using theTEMPO [A] or Swern [B] oxidation and DIBAL reduction

[C] methods9

RCHO

Method

Aee [%]

Bee [%]

Cee [%]

100 100 96

98 — 82

100 98 72

100 76 —

88 38 —

96 24 —

TABLE 3. Optical purity of aldehydes obtained using theDess-Martin [A] or Swern [B] oxidation and DIBAL

reduction [C] methods36

RCHO

Method

Aee [%]

B*ee [%]

Cee [%]

99 50 95

99 68 —

96 81 90

90 45 —

*i-Pr2NEt was used as a base.


As chiral auxiliary acetals 10a,b,c, derived from diolsprepared from malic acid, and 10d from an appropriatesugar have been tested. The best diastereoselectivity ob-tained upon the addition of RLi was observed for the steri-cally demanding substituted acetal 10d. However, thehydrolysis of the chiral acetals was difficult and only oxi-dative cleavage was successful, leading to �-amino acidsinstead of �-amino aldehydes.

Alternatively, the Alexakis group42–44 has used aminalsas chiral auxiliaries as well as a protection of the formylgroup (Scheme 5). Since aminal 13 gave very poor resultsupon the addition of MeLi as compared to aminal 14, mostextensive research was carried out using the latter anddifferent organometallic reagents. Aminal 14 reacted withMeLi42,44 in THF with very high selectivity (99% de) andvery similar results were obtained when Me3Ce42,44 wasused (Table 4). Furthermore, primary, secondary, and ter-tiary alkyllithium as well as phenyl- and alkenyllithium de-rivatives all gave a single, detectable diastereoisomer whenTHF was used as a solvent. Cuprate reagents turned out tobe unreactive under a variety of reaction conditions, whilethe reaction of Grignard reagents43,44 with 14 in THF ledto the recovery of the substrate only. However, the samereaction carried out in toluene proceeded extremely well.The most striking aspect of the reaction involving thesereagents concerns the diastereoselectivity, which is the op-posite of that observed for organolithium and organoce-rium derivatives. To complete the synthesis of �-amino

aldehydes, the N-N bond was cleaved upon the hydroge-nation with no epimerization.

Another approach to the synthesis of �-amino aldehydeacetals was independently published by Enders et al.45

and Denmark and Nicaise.46 Both groups utilized chiralhydrazone acetal �-SAMP 15 to which an organoceriumreagent was added (Scheme 6). Applying different reac-tion conditions to the addition of RLi or RMgBr in thepresence of CeCl3 to hydrazone 15, the Enders group45

obtained better diastereoselectivity and yield than theDenmark group.46 The best de value reached 98% in theEtMgBr/CeCl3 case. Unfortunately, removal of the chiralauxiliary resulted in some epimerization of �-amino alde-hyde, as observed by both groups.

TABLE 4. Addition of organometallic reagents toaminal 1442–44

RM Solvent de (%) Yield [%]

MeLi, LiBr THF >99 (S) 74Me3Ce, 3LiCl THF >99 (S) 76MeMgBr toluene/Et2O 88 (R) 85PrMgCl toluene/Et2O >99 (R) 89t-BuMgCl toluene/Et2O >99 (R) 67Me2C=CHMgBr CH2Cl2* 92 (R) 78PhLi, LiBr THF >99 (S) 78Me2C=CHLi, LiBr THF >99 (S) 62

*1 equiv. of TiCl4 was added.

Scheme 4.

Scheme 5. Scheme 6.

518 GRYKO ET AL.

Pridgen and co-workers47 have shown that the additionof organometallic reagents to chiral 1,3-oxazolidine 17gave acetal 20 with only slight epimerization (Scheme 7).In this case the addition of t-BuMgCl proceeded muchbetter (96% de) than the addition of t-BuLi in the presenceof CeCl3 (75% de). The major drawback of this procedurewas the conversion of cyclic acetal 19 to aldehyde 21,which could not be accomplished directly. The cyclic acetal19 had to be converted into the dimethyl acetal 20, whichupon hydrolysis afforded the �-amino aldehyde 21.

Miscellaneous Methods

Kunieda and co-workers48 reported that (+)- and (–)-4,5-dialkoxy-2-oxazolidinones 25 are versatile chirons for thesynthesis of optically pure �-amino aldehydes. They arereadily accessible from simple 2-oxazolone 22 by regio-and stereoselective electrophilic addition which was ac-complished with NBS in methanol, followed by treatmentwith benzyl alcohol (Scheme 8). Subsequent optical reso-lution afforded the desired 4,5-dialkoxy derivatives 25aand 25b, which were treated with organo cuprates in thepresence of BF3·OEt2, resulting in the regioselective re-placement of the 4-methoxy group with alkyl or aryl groupwith complete retention of configuration. Eleven opticallypure N-Boc-�-amino aldehydes were synthesized in thisway with good yields.

Braun et al.49 described the synthesis of �-amino acidsand N-protected �-amino aldehydes from chiral dibro-moolefin 29 and sulfonylimine 30 (Scheme 9). Lithiumderivative of bromoolefin 29 reacted with a sulfonyliminegiving adduct 31 in moderate yield with 95% de. After

chromatographic purification, diastereoisomer 31 wasagain lithiated and then protonated to yield Z-alkene 32whose ozonolysis, after workup with DMSO, afforded N-protected aldehyde 33 together with MEM-protected lac-talaldehyde 34, which can be easily removed.

The diastereoselective conjugate addition of N-benzyl,N-�-methylbenzylamide to �,�-unsaturated esters and sub-sequent enolate hydroxylation, followed by reduction andoxidative cleavage, provides a facile route to N,N-diprotected-�-amino aldehydes.50

An interesting application of thermal rearrangement ofthe imidates derived from the stereochemically pure mono-

Scheme 7.

Scheme 8.

Scheme 9.


protected allylic diols was presented by the Larchevequegroup (Scheme 10).51 Allylic alcohols 36, obtained by thereaction of O-protected �-hydroxy aldehydes 35 with vi-nylic organometallic compounds 36, were reacted withtrichloroacetonitrile to give product 37. Thermal rear-rangement of imidate 37 afforded compound 38, whichafter ozonolysis in the presence of DMSO gave N-protected�-amino aldehyde 39 in excellent yield and >98% ee.

Ito and co-workers52 described a method for the synthe-sis of N,O-protected �-hydroxy-�-amino aldehydes and N-Boc-L-phenylalaninal (47), starting from oxazoline 44(Scheme 11). The Weinreb amide (WA) derived from N-Cbz-glycine (40) was transformed into formamide 42,which upon dehydratation gave �-isocyano Weinreb amide43. The aldol reaction of 43 with aliphatic or aromaticaldehydes, in the presence of a chiral gold catalyst, gavealmost optically pure (96%) oxazoline 44 with good yield.The oxazoline 44 can be easily transformed into desired�-amino aldehydes, e.g., 47, as shown in Scheme 11.

Sugars offer a great opportunity for the synthesis of�-amino aldehydes. A new diastereoselective synthesis ofN-Boc-L-serinal from D-glucosamine hydrochloride (48)was developed by Giannis and Henk (Scheme 12).53 Thethree-step procedure involves protection of the amino func-tionality with Boc2O, reduction of 49 with excess NaBH4,followed by NaIO4 oxidation of D-glucosamine derivatives50. The multigram synthesis afforded analytically pure N-Boc-L-serinal (51).

Another example of the synthesis of �-amino aldehydes,starting from a sugar derivative, namely D-mannitol, wasdescribed by a French group.54 This approach involved asa key step the nucleophilic opening of suitably protected

bisaziridines 52 (Scheme 13). Symmetrical, regioselectiveopening of chiral bisaziridines 52, followed by deprotec-tion of diol 53, and subsequent NaIO4 oxidation of 54,gave N-protected �-amino aldehyde 55. The ring openingwas influenced by the nature of the N-protecting group andthe nucleophile as well as by a Lewis acid. A wide range oforganometallic reagents was checked, including alkyl-, vi-nyl-, and allyllithium cuprates.

Scheme 10.

Scheme 11.

Scheme 12.

520 GRYKO ET AL.

Two groups independently discovered the same proline-catalyzed direct asymmetric �-amination of unmodified al-dehydes, using azodicarboxylate reagents (Scheme14).55,56 �-Hydrazino aldehydes 56 produced are versatileprecursors for diverse �-amino aldehydes and other aminoacid derivatives.

The List group55 has used dibenzyl azodicarboxylates asaminating agents; regardless of the simple aldehyde used,�-hydrazino aldehydes were obtained with ee higher than95% and in the yield exceeding 93% (Table 5, entries 1–4).The authors pointed out that other azodicarboxylates werealso efficient in this reaction. The Danish group56 synthe-sized a larger variety of �-hydrazino aldehydes (entries5–8) and showed that the reaction could also be performedon a gram scale with similar high yield and enantioselec-tivity.

An efficient five-step synthesis of optically pure �,�-disubstituted-�-amino aldehydes was achieved featuring adiastereoselective alkylation of N-allylic oxazolidinone.57

The addition of Grignard reagents to N-benzyl-2,3-O-isopropylidene-D-glyceraldehyde nitrone gave syn- or anti-hydroxylamine predominantly, depending on the condi-tions used.58 Subsequent acetylation and oxidation withperiodic acid afforded, respectively, D- or L-N-OAc,N-Bn-�-amino aldehydes with good yield and optical purity.

Four unnatural racemic �-amino aldehydes were synthe-sized using Weinreb resin.59 The approach should be ofgreat importance following the development of an asym-metric version of this method as it allows production oflarge libraries of compounds in good to excellent yieldsand purities.

A multistep synthesis of two interesting �-amino alde-hydes was reported by Jung et al.60 The key step involvedstereospecific rearrangement of optically active tertiary al-lylic epoxides to optically active quaternary aldehydes inthe presence of BF3·OEt2. The resulting aldehyde wastransformed in four steps into an N-Cbz-�-amino aldehyde.

BASIC TRANSFORMATIONS OF N-PROTECTED�-AMINO ALDEHYDES

Additions of Organometallic Reagents

Reactions of metalloorganic reagents with various chiralaldehydes are of great interest from the point of view ofasymmetric synthesis. This type of reaction with N-protected �-amino aldehydes was often used in the synthe-sis of amino sugars, peptide isosteres, etc. As a result oforganometallic addition to �-amino aldehydes, syn- andanti-adducts are formed (Scheme 15) and the diastereoiso-meric ratio is influenced by many factors, such as: thenature of the organometallic reagent, N-protecting group,solvent, temperature, additives, etc. The formation of syn-adduct results from the chelation control, whereas anti-diastereoisomer constitutes the nonchelation controlledproduct.

Allyl addition. Among metalloorganic reactions withN-protected �-amino aldehydes, the allyl addition has beenone of most widely studied. Simple addition of allylmagne-sium halide to N-Ts-61 and N-Boc-L-alaninal62 resulted inthe low syn-diastereoselectivity, whereas the same additionto N-benzyl-N-tosyl-L-alaninal predominantly gave the anti-isomer. The experimental results showed that addition tothe re face of the N,N-diprotected aldehyde is in line withthe Felkin-Anh model63,64 when the protected amino groupis considered as the largest one. To rationalize the additionto N-monoprotected derivative, the chelation-controlledmodel should operate. The diastereoselectivity was im-

TABLE 5. Proline-catalyzed direct asymmetric�-amination of aldehydes

Entry R1 R2 Yield [%] ee [%] Ref.

1 i-Pr Bn 99a 96 552 Pr Bn 93a >95 553 Me Bn 97a >95 554 Bn Bn 95a >95 555 Et Et 77b 90 566 i-Pr Et 83b 93 567 i-Pr Bn 70b 91 568 Allyl Et 92b 93 56

aReaction was carried out in CH3CN.bReaction was carried out in CH2Cl2.

Scheme 13.

Scheme 14.

Scheme 15.


proved to 84:16 in favor of the adduct syn-61 by treatmentof lactol 59 obtained from protected amino acid 57 by atwo-step sequence (Scheme 16).65 The level of asymmetricinduction was slightly influenced by the R group present inthe amino side chain. Since the yield of the process was notgiven by the authors,65 it is difficult to discuss the useful-ness of this approach.

Another example of an allylation reaction with enhancedsyn-diastereoselectivity was given by the Kano group;66 itrelied on a one-pot conversion of N-Cbz-�-amino acid estersto chiral �-amino alcohols via �-amino aldehydes. Reduc-tion of N-Cbz-L-leucine methyl ester with DIBAL, followedby allylation with allylmagnesium bromide (60), afforded amixture of allylic adducts in 83% yield and with the ratio ofsyn:anti equal to 75:25.

The reaction of allylsilanes with N-protected �-amino al-dehydes in the presence of a Lewis acid to produce ho-moallylic amino alcohols has been the subject of broadinterest. As part of a stereoselective synthesis of hydroxy-ethylene dipeptide isosteres, Vara Prasad and Rich62 re-ported that N-monoprotected �-amino aldehydes reactedwith allyltrimethylsilane in the presence of TiCl4 or SnCl4to give the desired homoallylic products (Table 6, entries 1,2) with a preference for the syn-adduct. The course of thereaction is in agreement with the chelation-controlledmodel;67 it was observed that an increase in the steric bulkof the protective group gave better stereochemical results(entries 2, 3).

More detailed research of the above-mentioned problemhas recently been conducted by our group.68 For this pur-pose variously N-protected L-alaninals were chosen asmodel systems. The results of these studies are presentedin Table 6 (entries 4–9). Addition of allyltrimethylsilane(63) to L-alaninals strongly depended on the Lewis acidused. In the case of the reaction of N,N-diprotected alde-hydes with 63, mediated by SnCl4, no diastereoselectivitywas observed, contrary to the reaction of N-monoprotected

aldehydes for which Rich and colleague62 observed thehighest de. When BF3·OEt2 was used anti-diastereoselec-tivity was noted (entries 4, 5). Surprisingly, this was not thecase for TiCl4; the reaction with N-Bn-N-Cbz-L-alaninal gaverise mainly to the syn-isomer, whereas with N-Bn-N-Ts-L-alaninal, to the anti-isomer. For rationalization of the ste-reochemical course of the reaction of N,N-diprotected�-amino aldehydes with 63 it was proposed that the reac-tion proceed through the Felkin-Anh model. The unusualdirection of asymmetric induction in the case of N-Bn-N-Cbz-L-alaninal can be explained by the seven-memberedring formation as a result of the coordination of titanium bytwo oxygen atoms (Fig. 2).

Although the addition of allyltrimethylsilane (63) toN-Boc-�-amino aldehydes in the presence of BF3·OEt2 af-forded the expected allylic derivatives, the reaction of N-Cbz-L-alaninal (62) produced the corresponding homoal-lylic alcohol 65 with moderate syn-diastereoselectivity,along with the cyclic compound 64, which was proved tobe cis-2,3,5-trisubstituted pyrrolidine (Scheme 17).69 Theyield of the pyrrolidine 64 was considerably improvedwhen a catalytic amount (0.2 equiv.) of the Lewis acid wasused at –10°C. The relative stereochemistry at the C-2 andC-5 positions of the pyrrolidine 64 corresponded to syn-relation in the homoallylic alcohol 65. This result suggeststhat a chelation controlled C-C bond formation took place.

Furthermore, the influence of the �-hydroxy group pres-ent in a serinal molecule was studied (Table 7).68,70 Theaddition of allyltrimethylsilane (63) to N-Cbz-O-TBS-L-serinal (66), regardless of the Lewis acid used, gave pre-dominantly product syn-70 (Scheme 18), which means thatin the case of chelating Lewis acids (TiCl4, SnCl4, ZnBr2)the direction of asymmetric induction can be explained bythe cyclic-Cram model. Surprisingly, in the case of

TABLE 6. Addition of allyltrimethylsilane (63) toN-protected �-amino aldehydes (see Scheme 15)

Entry PG1 PG2 R1 Lewis acid Yield [%] syn:anti Ref.

1 H Cbz n-Bu TiCl4 not given 77:23 622 H Cbz n-Bu SnCl4 77 87:13 623 H Boc n-Bu SnCl4 80 92:8 624 Bn Cbz Me BF3OEt2 83 12:88 685 Bn Ts Me BF3OEt2 85 7:93 686 Bn Cbz Me SnCl4 96 50:50 687 Bn Ts Me SnCl4 34 34:66 688 Bn Cbz Me TiCl4 62 84:16 689 Bn Ts Me TiCl4 87 32:68 68

Scheme 16.

Fig. 2.

522 GRYKO ET AL.

BF3·OEt2 the same product formed predominantly as aconsequence of H-bonding between the NH and carbonylgroup. When the TBS group was replaced by the BOMgroup, the formation of both �- and �-chelates were pos-sible since the latter one did not strongly influence thecoordination by the etheral oxygen atom. The reaction me-diated by SnCl4 proceeded via �-chelate giving rise to syn-diastereoselectivity while the reaction in the presence ofTiCl4 led to product anti-71, formed as a consequence ofthe six-membered �-chelate formation between the Lewisacid and etheral oxygen atom. The most interesting resultof these studies was observed for the addition of 63 toN-Bn-N-Cbz-O-TBS-L-serinal 68, namely, adduct syn-72was mainly formed with TiCl4 (Scheme 18). We proposedan explanation that a titanium atom is coordinated by twocarbonyl oxygen atoms (CHO and COOBn). In all cases ofthe allylic addition to protected L-serinal 69, the majorproduct anti-73 results from the �-chelation-controlled re-action. The results presented by our group clearly indicatethat by means of changing the protective group, one couldinfluence the stereochemical course of the reaction.

Dias et al.71 reported the first example of allylsilane ad-ditions to chiral dipeptide aldehydes. Treatment of allyl-silanes with SnCl4 afforded allyltrichlorostannane interme-diates that reacted with dipeptide aldehydes to give 1,2-syn-homoallylic alcohols with moderate diastereoselectivityand good yield. Following their interest in the synthesis ofhydroxyethylene dipeptide isosteres, the Taddei group72,73

suggested that these compounds could be obtained by theelaboration of the allylic chloride 76a being the result ofthe reaction of N-Boc-L-alaninal (74) with allyl reagent 75a(Scheme 19).

The allylation reaction was mediated by BF3·OEt2 andcarried out in CHCl3 giving rise to a single adduct, syn-76a, contaminated with 3–5% of the other isomer, irrespec-tive of the aldehyde used. Intrigued by the very high dia-stereoselectivity in the above-mentioned reaction, thesame group73 investigated the influence of the steric bulkof the substituents attached to the double bond in allylsi-

TABLE 7. Addition of allyltrimethylsilane (63) toN,O-protected-L-serinals68,70

RCHO Lewis acid Yield [%] syn:anti

66 SnCl4 88 98:266 TiCl4 90 72:2866 BF3�OEt2 52 79:2166 ZnBr2 63 85:1567 SnCl4 68 82:1867 TiCl4 82 2:9867 BF3�OEt2 65 89:1168 SnCl4 75 45:5568 TiCl4 79 97:368 BF3�OEt2 72 25:7568 ZnBr2 34 52:4869 SnCl4 73 21:7969 TiCl4 72 18:8269 BF3�OEt2 25 27:7369 ZnCl2 23 24:76

Scheme 17.

Scheme 18.

Scheme 19.


lane 75 and/or the influence of the Lewis acid used(Scheme 19). The diastereoisomeric composition of a prod-uct mixture was influenced by the nature of substituentsattached to the allylsilane 75. The rank order observedwas 75a > 75b > 75c, and it was independent of the�-amino aldehyde used. The authors73 suggested that2-(chloromethyl)-3-(trimethylsilyl)-1-propene (75a) re-acted with aldehydes as an electron-rich olefin. In this case,75a stereoselectively gave the product coming from an“ene” reaction, whereas the remaining two allylsilanes,75b and 75c, reacted by the mechanism of nucleophilicdisplacement of the silicon via an acyclic transition state.

The application of chiral crotylsilane 77 offered the op-portunity for the asymmetric construction of more elabo-rated homoallylic alcohols. In 1997, Panek and Liu74

reported that a Lewis acid promoted double-stereodiffer-entiating crotylation reactions of (E)-crotylsilane (R)-77 or(S)-77 with �-amino aldehydes provided amino alcohols78 with useful levels of selectivity (Scheme 20). The reac-tion of (R)-77 with N-Boc-L-alaninal (74) led to anti,anti-vicinal amino alcohol 78 (30:1), whereas enantiomer (S)-77 gave rise to syn,anti-adduct 78, albeit in lower diaste-reoselectivity (3:1). The results indicate that in the case ofcrotylation reactions the absolute configuration of both themethyl and hydroxy groups bearing stereogenic centersare dependent on the absolute configuration of the C-SiR3center in a silane reaction, although the chirality of thealdehyde influences the stereochemical outcome of the re-action, which is reflected by the level of diastereoselectivityof the addition.

Another example of double stereodifferentiating allyla-tion reaction was presented by Dias and Meira.75 Chiralallylsilane 7976 reacted with (S)-74 in the presence ofSnCl4, favoring syn,syn-adduct 80, the product of amatched reaction (Scheme 21).75 Under the same condi-tions, the reaction of 79 with (R)-74 gave a mixture ofsyn,anti-80 and anti,syn-80 (34:66) being the mismatchedpair.

In 2000 we published77 several examples of the additionof allyltrichlorosilane to N-mono- and N,N-diprotected-L-alaninals. For N-monoprotected-L-alaninals, regardless ofthe protecting group, the ratio of syn- to anti-adduct was75:25 favoring syn-diastereoselectivity, whereas for N,N-diprotected L-alaninals diastereoselectivity remained at thelevel 95:5 in favor of anti-product.

The Barbier type allylation has held increasing attention,principally as it is environmentally friendly and because theuse of aqueous media for this reaction offers a number ofconsiderable advantages, e.g., the direct use of H2O-soluble compounds without derivatization and the generalavoidance of anhydrous solvent. In the light of this trend,several experiments using the zinc-mediated Barbier typeallylation procedure were carried out at our labora-tory.61,77,78 The results of these studies are shown in Ta-ble 8.

Addition of allylbromide to N-monoprotected L-alaninalsin the presence of Zn did not give any diastereoisomericinduction (Table 8, entries 1–3), whereas moderate anti-diastereoselectivity and high yield were observed in thecase of N,N-diprotected L-alaninals (entries 4–6).61,77 At-tack by allyl reagent occurs from the less hindered side ofthe Felkin-Anh model, leading to anti-diastereoselection.Under the same reaction conditions, addition of allylbro-mide to fully protected L-serinals led to the same level ofdiastereoselection favoring anti-isomer (entries 7, 8).78 Atthe same time, Giannis and co-workers79 reported a Bar-bier type addition to �-hydroxy-�-amino aldehydes. Theyfound that the stereochemical outcome depended on themetal used (Zn vs. Sn) (entries 9, 10) as well as on thenature of the allylic halide. Most interestingly, the ratio ofisomers changed in favor of the anti-diastereoisomer byusing prenyl bromide and tin instead of zinc, but this effectwas not observed for unsubstituted allyl bromide. More-over, the influence of the nature of allylic halide was evenmore strongly underlined when cyclohexenyl bromide wasused. Regardless of the metal used, the formation of theanti-isomer was favored. Indium-mediated allylation of N-monoprotected �-amino aldehydes was largely unselec-tive.80 The reaction with N,N-dibenzyl-�-amino aldehydes

Scheme 20.

TABLE 8. Zinc-mediated Barbier type allylation ofL-alaninals and L-serinals

Entry R PG1 PG2 Yield [%] syn:anti Ref.

1 Me H Boc 88 50:50 772 Me H Cbz 93 50:50 773 Me H Ts 66 50:50 614 Me Bn Boc 99 20:80 775 Me Bn Cbz 99 10:90 776 Me Bn Ts 71 14:86 617 CH2OTBS Bn Cbz 96 18:82 788 CH2OTBS Bn Ts 78 15:85 789 CH2OHa H Boc 62 83:17 79

10 CH2OHb H Boc 56 17:83 79

aPrenyl bromide was used (4-bromo-2-methyl-2-butene).bSn and prenyl bromide were used.

524 GRYKO ET AL.

of type A proceeded with moderate anti-selectivity,whereas N,N-dimethyl derivative resulted in allyl adductwith high syn-selectivity.

The Barbier type addition opens the way to the synthesisof �-methylene-�-butyrolactones starting from �-amino al-dehydes and 2-(bromomethyl)acrylates. During the courseof the synthesis of this type of compounds, Steurer andPodlech81 found that the reaction of 2-(bromomethyl)acry-lates with N-Cbz-�-amino aldehydes in the presence of in-dium in an ethanol/water mixture gave the same resultswhen carried out in a THF/water mixture. The presence ofwater appeared to be essential for a clean and fast reaction.The diastereoselectivity was strongly dependent on thebulk of the amino acid sidechain, while the ester function-ality did not influence the asymmetric induction, as shownby applying t-butyl 2-(bromomethyl)acrylate. Additionally,they proved that during the addition racemization of�-amino aldehydes did not occur.

In ongoing studies on the use of sulfoxides as chiralauxiliaries, Delgado and colleagues82 described the doublediastereodifferentiating allylation of �-amino aldehydeswith (Ss)-3-chloro-2-(p-tolylsulfinyl)-1-propene (81)(Scheme 22). Through the proper choice of the starting�-amino aldehyde configuration, a matched double asym-metric induction could be achieved. It was shown that a“matched” pair is formed when L-amino aldehydes wereused. Regardless of the protecting groups (one or two)anti-isomer 83 was formed as the major product. However,N-monoprotected aldehydes afforded lower diastereoiso-meric ratio (d.r.) (25:75) due to the fact that the reactioncould proceed through both the chelation and nonchela-tion transition states.

In search of a chemoselective method for the formationof a new carbon–carbon bond in oligopeptides, the Taddeigroup83,84 found that the Hiyama reaction is a very efficientmethod to prepare peptides containing hydroxyethyleneisosteres. N-Boc-�-amino aldehydes reacted with allyl bro-mide or ethyl 2-(bromomethyl)acrylate in the presence ofCrCl2 with low diastereoselectivity and acceptable yield,whereas the same reaction with crotyl bromide affordedsyn-isomer as a major product. Better yield and de’s wereobserved with N,N-diprotected aldehydes, but in this casethe direction of asymmetric induction was reversed.

In 2000 McCluskey et al.85 reported an allylation processwith high atom efficiency. Reactions of N-Pht or N-Bn pro-tected �-amino aldehydes with 25 mol% of tetrallylstannaneregardless of the solvent used (Bmim[BF4], MeOH) af-forded homoallylic alcohols with moderate syn-diastereo-selectivity.

Vinyl addition. Organometallic vinyl addition to�-amino aldehydes (Scheme 23) is a very important pro-cess in the synthesis of dipeptide isosteres, although itsbroad application has not been very extensively studied.Most of the work has been conducted on the reaction ofvinylmagnesium bromide 84b with N-Boc-�-amino alde-hydes. Table 9 shows the results.

Scheme 21.

Scheme 22.

Scheme 23.


The reaction of N-Boc-L-alaninal (74) with vinylmagne-sium chloride (84a)86 at low temperature gave a mixtureof syn and anti vinyl alcohols 85 (7:3) in 53% overall yield(Table 9, entry 1). The diastereoselectivity observed couldbe explained by the Cram chelation-controlled cyclic modelbeing the consequence of the coordination of magnesiumby the oxygen (CHO) and the nitrogen (NHBoc) atoms.The diastereoselectivity of this reaction increased whenthe respective amino ester was successively treated withDIBAL and vinylmagnesium chloride (84a) in a one-potreaction to predominantly yield syn-adduct 85, presumablydue to the coordination of aluminum in the same way asmagnesium (entry 2). Two research groups87,88 haveshown independently that the reaction of vinylmagnesiumbromide (84b) with N-Boc-L-alaninal 74 afforded vinyl ad-ducts 85 in high yield, but the diastereoselectivity of theprocess decreased (entry 3). After replacing the Boc pro-tective group with the Cbz-group, the syn:anti ratio in-creased.

Although the application of alkylmanganese compoundsusually improved diastereoselectivity in chelation-controlled reactions, this was not the case for the vinyl-typeaddition.88 An appreciable improvement was achieved byThompson et al.,89 who used vinylzinc chloride. The de-sired adducts 85 formed with 60% yield and with the 88:12syn:anti ratio.

The tandem Swern oxidation-vinyl addition was em-ployed by Greene and colleagues90 for the synthesis oftaxol and taxotere sidechains. They found that by usingthis sequence N-Boc-phenylglycinol was transformed intorespective vinyl-adducts 85 with 80% de and 62% yield;unfortunately, they were racemic. Surprisingly, it wasenough to change the order of reagents added, namely, toadd the reaction mixture after the Swern oxidation to vi-nylmagnesium bromide (84b) to obtain enantiomericallypure products. In the course of the synthesis of polyoxamicacid, protected statine, and norstatine, Veeresa andDatta91,92 used the same procedure, although they addedthe vinylmagnesium bromide (84b) to the Swern oxida-

tion mixture. They did not mention enantiomeric purity atall.

As presented for organometallic addition, a nonchelate-controlled product was observed when N,N-diprotected al-dehydes were used as substrates. It was shown byHeneghan and Procter93 that the reaction of N-Bn-N-Ts-L-phenylalaninal with vinylmagnesium bromide (84b) af-forded anti-adduct exclusively. The authors claim that, pre-sumably, the bulky nitrogen substituent is effective atblocking one of the faces of the carbonyl group and inrestricting conformational mobility of the formyl group.Indeed, the addition of allyl reagent to N-Bn-N-Ts-L-alaninal87 gave lower de. One can conclude that the asym-metric induction is also influenced by the nature of thesidechain present in amino acids. Replacement of the N-Tsgroup with the Boc or Cbz groups did not improve the levelof diastereoselection.87

During work on a cyclopropenone-containing inhibitor ofpapin, Ando et al.94 showed that elaborated lithium deriva-tive of vinyl reagent 86 added to N-Boc-L-valinal (87) ob-tained a 2:1 mixture of diastereoisomeric vinyl alcohols 88with syn-selectivity (Scheme 24).

Since the diastereoselectivity was not satisfactory, theNakamura group95 undertook the effort to find conditionsfor the addition of the metalated cyclopropenone acetal toN-protected �-amino aldehydes yielding adducts with bet-ter selectivity. As a result of their studies it was found thatthe reaction of N-Boc-L-valinal (87) with metalated cyclo-propenone acetal, performed in the presence of ceriumchloride, gave predominantly syn-diastereoisomer (77:23).

The Cram chelation-controlled product of vinylation ofthe carbonyl group could be obtained in the reaction of�-amino aldehydes with 2-trimethylsilylethylidentri-phenylphosphorane 89 (Scheme 25).96 The reaction of�-silylphosphorus ylides proceeds through the migrationof the silyl group to the oxygen and elimination of triphe-nylphosphine.

TABLE 9. Addition of vinyl magnesium halides toN-Boc-�-amino aldehydes

Entry R Conditions Yield [%] syn:anti Ref.

1 Me 84a 53 70:30 862 Me 84aa 60 94:6 863 Me 84b 90 (77) 58:42 87, 884 Me 84b, ZnCl2 60 88:12 895 Me 84b, MnBr2 62 66:34 886 Ph 84bb 62 90:10 907 Ph 84bc 55 90:10 918 i-Bu 84bc 59 90:10 92

a84a was added to the reaction mixture directly after DIBAL reduction.bThe reaction mixture after Swern oxidation was added to the solution of84b.c84b was added to the reaction mixture directly after Swern oxidation.

Scheme 24.

526 GRYKO ET AL.

Other organometallic additions. A great deal of re-search has been done by Reetz et al.88 aiming to find ageneral method for chelation-controlled addition to N-monoprotected �-amino aldehydes. It was found that thetransmetallation of organolithium compounds with copperand manganese salts provided reagents which added toaldehydes with good syn-selectivity up to 90% de. Thesereagents are efficient when alkylorganometallics are used,not vinyl or phenyl derivatives.

An efficient synthesis of chiral uloses, amino sugar pre-cursors, was achieved via addition of furyllithium (90) toN-protected �-amino aldehydes of type C (Scheme 26).

N-Monoprotected D-alaninals were unstable towardsfuryllithium (90). Therefore, our group97,98 turned its at-tention to N,N-diprotected derivatives. Addition of furyl-lithium (91) to N-Me- or N-Bn- and N-Boc-, N-Cbz- or N-Ts-D-alaninals afforded adducts 92 with high anti-stereoselec-tivity up to >95% and good yield. These were transformedinto the corresponding amino sugar precursors 92. Simi-lar results were obtained for the addition of 2-methylfuryl-lithium.98,99 For more complex amino aldehydes, such asthreoninals and allo-threoninals, it has been shown thatprotective groups and reaction conditions strongly influ-ence the level of asymmetric induction (Table 10).98,100

Dondoni et al.101,102 presented the synthesis of anotheruseful unit, �-amino-�-hydroxy aldehyde, in the context ofsynthetic strategies directed towards the construction ofamino sugars. The strategy involves the addition of theformyl anion synthon equivalent to title aldehydes. For thispurpose 2-(trimethylsilyl)thiazole (2-TST, 94) was found tobe the reagent of choice (Scheme 27). The reaction be-tween 2-TST (94) and N-mono- and N,N-diprotected alde-hydes occurred smoothly at room temperature or below to

give, after in situ desilylation of the resulting adducts withTBAF, the corresponding amino alcohols 95. The reactionwith N-monoprotected compounds afforded adducts syn-95, whereas N,N-diprotected derivatives gave predomi-nantly adducts anti-95, with the level of asymmetric induc-tion hovering around 80:20. It was observed that the dia-stereoselectivity decreased substantially by carrying outthe reaction in THF instead of CH2Cl2, as the consequenceof competition between the THF oxygen atom and the for-myl group for hydrogen bonding to the NH group.

TABLE 10. Addition of 2-methylfuryllithium to threoninalsand allo-threoninals

RCHO Reaction conditionsYield[%] anti:syn Ref.

THF, −78°C, 0.5 h 54 66:34 98

THF, −78→−40°C, 10 h 59 94:6 98

THF, −78→−40°C, 3 h 81 99:1 98

THF, −78→−40°C, 10 h 88 94:6 98

Et2O, 0°C→ rt, ZnBr2 78 14:86 100

Et2O, −70°C 90 81:19 100

glyme, −70°C 89 7:93 100

Scheme 25.

Scheme 26.

Scheme 27.


Aldol Condensation and Related Reactions

Aldol condensation is a very important transformationfrom the point of view of natural product synthesis. Unfor-tunately, the reaction with N-protected �-amino aldehydesis characterized by relatively low diastereoselectivity. Since1989 a lot of work has been done in this field, yet most ofit deals with N,N-Bn2-�-amino aldehydes A or Garner’s al-dehyde B. There are only a few examples where aldoladducts were obtained with very high stereocontrol. Thenonchelation reaction of N,N-Bn2-L-isoleucinal with alithium enolate afforded anti,anti-adduct exclusively. Thiscompound had the appropriate relative configuration toserve as a building block in the synthesis of dolastatin-10.5The same direction of asymmetric induction was observedwhen Garner’s aldehyde B was used in BF3·OEt2-assistedMukaiyama-aldol reaction.6

During work on the synthesis of (3S,4S)-statine, the Ter-ashima group103 found that the aldol reaction of O-methyl-O-trimethylsilyl ketene acetal (98) with N-isopropylcar-bonyloxy-L-leucinal (97) occurred in a highly stereoselec-tive manner, giving rise to a mixture of addition products99 in which syn-compound predominated (94:6) (Scheme28). Similar results were reported by Mikami et al.,104 whoobtained syn-aldol from the enol silane and N-Boc-L-leucinalin the presence of SnCl4.

In 1991 Ibuka et al.86 published a one-pot procedure forvinyl addition to aldehydes generated in situ via DIBALreduction. Following their approach, the Kiyooka group105

presented an effective one-pot aldol reaction using the alu-minum acetals from N-protected �-amino acid esters. AfterDIBAL reduction, intermediates of N-protected �-aminoacid esters were treated with TiCl2(O-iPr)2 and silyl keteneacetals affording the corresponding �-hydroxy esters ingood yield and syn-stereoselectivity. Other Lewis acidswere checked but TiCl2(O-iPr)2 gave the best results.

Very good results in chelation-controlled aldol reactionwere produced in the reaction of titanium homoenolate100 with N-Boc-L-phenylalaninal (47)(Scheme 29).106 Thestudies showed that the stereoselectivity of the aldol reac-tion was strongly dependent on the titanium ligands andthat the increase in the amount of chlorine atoms bound tothe titanium atom caused an increase in the diastereoselec-tivity. Interestingly, the reaction failed when three chlorineatoms were present in the titanium homoenolates. At-tempts to increase the diastereoselectivity of the reactionby precomplexing the N-Boc-L-phenylalaninal (47) withZnBr2 prior to the addition of homoenolate led to lower de.

Rapoport and co-workers107 noticed that the steric bulkof the ester functionality present in titanium homoenolate100 influenced the aldol reaction. Thus, it was found thatwhen t-Bu-ester was used in the reaction with N-Pht-O-Bn-D-serinal only a mixture of anti:syn lactones, formed fromthe corresponding aldol products, was isolated. Presum-ably, each of the initially formed alkoxy esters had lac-tonized during the course of the reaction.

As a highly convergent approach to protected hy-droxyethylene dipeptide isosteres 103, the Armstronggroup108,109 studied the addition of titanium indanolamidehomoenolates 102 to N-Boc-L-phenylalaninal (47)(Scheme 30).

Scheme 28.

Scheme 29.

Scheme 30.

528 GRYKO ET AL.

The reaction afforded anti-103 as the sole diastereoiso-mer representing a nonchelation-controlled case. It wasproved that the stereochemistry of the aminoindanol andthe C-2 benzyl substituents had a dramatic effect on thestereochemistry and reactivity of the titanium homoenolate102. The unsubstituted titanium enolate 102a gave ex-clusively adduct anti-103a; similarly, homoenolate withthe Bn group at C-2 position 102b afforded only diaste-reoisomer anti-103b, whereas the diastereoisomer 102cfailed to give any aldol product. Another approach to thediastereoselective aldol reaction with the use of �-aminoaldehydes was investigated by Shioiri and colleagues,110

who used the Evans chiral auxiliary. They observed a dra-matic change in the stereochemical course of the reactiondue to the addition order of NEt3 and n-Bu2BOTF to themixture of 104 and 105 (Scheme 31).

The reaction of N-Boc-L-prolinal (104) with chiral boronenolate generated from N-propionyloxazolidinone 105 bythe addition of n-Bu2BOTf and then NEt3, affordedanti,anti-aldol 106 accompanied by small amounts ofanti,syn-106. The latter (anti,syn) became the major prod-uct of this reaction when boron enolate was generated bythe reversed addition, i.e., NEt3 followed by n-Bu2BOTf.They proved111 that when NEt3 was used in excess overn-Bu2BOTf only anti,syn-adduct 106 was formed, whereasan excess of n-Bu2BOTf caused anti,anti-adduct 106 topredominate. However, the order of the addition of re-agents did not affect the product ratio. The methodologywas extended to other aldehydes such as N-Boc-L-valinal,N-Boc-N-Me-L-valinal, and N-Boc-L-leucinal; these alde-hydes always afforded anti,syn-diastereoisomer as the ma-jor product, even when an excess of n-Bu2BOTf was used.

While working on the synthesis of N-Cbz-galantic acid,Kiyooka et al.112 studied the chiral oxazaborolidinone-promoted asymmetric aldol reaction applying �-amino al-dehydes as substrates. The reaction of N-Cbz-L-leucinal107 with silyl nucleophile 108 in the presence of ox-azaborolidinone 109 resulted in high syn-diastereoselec-tivity, while the reaction in the presence of (ent-109) gavemoderate anti-diastereoselectivity (Scheme 32). The most

important finding of this work was that the promoter-control could be observed even in the case of chiral alde-hydes having a nitrogen substituent.

The utilization of aldol condensation with the use of�-amino aldehydes for the synthesis of polysubstituted pyr-roles was presented by Cushman and co-workers113,114 andlater by Lagu et al.115

The Henry reaction has seen extensive use in organicsynthesis, providing ready access to a wide variety of func-tionalities generated from the resulting nitroaldol product.In 1996 Hanessian and Devasthale116 published a nitroaldolreaction of N,N-Bn2-�-amino aldehydes of type A with ni-troalkanes. The reaction was mediated by TBAF hydrateand resulted in a nonracemic nitroaldol product, in mostcases with high anti,anti-diastereoselectivity. The methodwas applied to the synthesis of HIV protease inhibitorsstarting from N-Boc-L-phenylalaninal (47).117

The reaction of (4-tolylthio)-nitromethane with N-Boc-�-amino aldehydes118 gave �-hydroxynitroalkanes with mod-erate yield. It was found that N-Boc-L-phenylglycinal race-mizes either during its preparation or during the subse-quent condensation reaction, while nitroaldol productsobtained from L-alanine and L-phenylalanine derivativeswere enantiomerically pure. Similar studies have been car-ried out with N-Cbz- and N-Fmoc-L-alaninal, -L-phenyl-alaninal, and -L-leucinal, but the level of asymmetric induc-tion has not been reported.119

Shibasaki and co-workers120 found that the use of therare earth-Li-(R)-BINOL catalyst facilitated the diastereos-elective nitroaldol reactions of N-Pht-, N-Cbz-, N-Boc-L-amino aldehydes giving products with high yield and goodanti-diastereoselectivity. Reaction of the L-aldehydes withnitromethane, using the La-Li-(S)-BINOL complex as cata-lyst, reduced diastereoselection. As a result of these stud-ies an intermediate for the HIV protease inhibitors KNI-227and KNI-272 was synthesized.

Wittig-Type Reactions

The Wittig reaction with chiral �-amino aldehydes leadsto vinyl amines, which are very useful building blocks inthe synthesis of dipeptide isosteres. During the course of

Scheme 31.

Scheme 32.


the reaction Z and E diastereoisomers can be formed.There are a number of general conclusions concerning theeffect of the type of Wittig reagent used and of the reactionconditions on Z/E selectivity that can lead to one diaste-reoisomer predominantly. For example, the application ofstabilized organophosphorus compounds in nonpolar sol-vents yields products predominantly with the E-configur-ation, whereas in alcohol-type solvents the Z-isomer pre-dominates. In the case of nonstabilized Wittig reagents,there is usually a predominance of the Z-isomer.

In the reaction with �-amino aldehydes, the stereogeniccenter seems not to play a part in the stereochemical out-come and it was shown that it was mainly influenced by thenature of ylide and the reaction conditions.4 Until 1989 thebest Z-selectivity (up to 70:1) was obtained when highlyelectrophilic �-trifluoroethyl phosphonates were used.More bulky phosphonate esters shift the product distribu-tion towards the thermodynamically preferred E-olefin.4

This vinyl amines can be obtained exclusively using�-substituted alkoxycarbonyl phosphoranes of type 111,as reported by Scholz et al.121 The reaction of ylide 111with N-Boc-L-phenylalaninal (47) gave the desired E-olefin112 with the same optical purity as the aldehyde had(Scheme 33). Unfortunately, N-Boc-L-pyridinylalaninal andN-Boc-O-Bn-L-serinal derivatives were obtained in a race-mic form.

However, when Ph3P=CH(Me)CO2Et was reacted withN-Bts-N-Me-L-valinal in refluxing THF, E-olefin was ob-tained predominantly (26:1) in 87% yield.122 The resultsmentioned above indicated that the presence of �-substitu-ent in organophosphorus reagent assures high E-selec-tivity.

Since some aldehydes121 can racemize under Wittig re-action conditions, the Kim team123 blocked the amino func-tionality in �-amino aldehydes with the N-hydroxymethylprotection which had been shown13 to stabilize the labilestereogenic center of �-carbon by shifting the equilibriumtowards the cyclic hemiacetal. The Wittig olefination withstabilized ylide afforded the desired E-�-amino-�,�-conjugated ester in excellent yield and selectivity, whichmeant that no Z-alkene was detected. Furthermore, by syn-thesizing the enantiomerically pure (–)-statine it wasproved that no racemization occurred during this reaction.

�-Bromo-�,�-unsaturated esters synthesized from the�-amino aldehydes and Ph3P=C(Br)CO2Me were trans-formed into enantiomerically pure 2-ethynylaziridines,showing the usefulness of the Wittig olefination.124

The Pollini group125 worked on the synthesis of sub-stituted pyrroles and pyrrolidines by intramolecular cy-clization. During their studies it was found that the Wittig

reaction of 4-[(4-methylphenyl)sulfonyl]-1-(triphenylphos-phoranylidene)butan-2-one (113) with various N-pro-tected �-amino aldehydes furnished N-protected �-amino-�,�-unsaturated keto sulfones 114 as single diastereoiso-mers, in most cases in optically pure form (Scheme 34).Various nitrogen-protecting groups were utilized so thatthey could be cleaved under different experimental condi-tions, and it was shown that they did not strongly influencethe course of the Wittig reaction.

A series of Z-allylic amines was prepared by the reactionof N-Boc-L or -D-leucinal with simple alkyltriphenylphos-phonium bromide using KN(SiMe3)2 as a base.126 Catalyticreduction of the Wittig product afforded aliphatic amines ofhigh optical purity.

Further developments in this field were made by Ro-tella,127 who presented a solid phase synthesis of olefin.Wittig olefination of N-linked �-amino aldehydes usingNaHMDS and methylene triphenylphosphonium bromidein THF at room temperature led to appropriate allylicamines. The methodology was extended to the Horner-Wadsworth-Emmons olefination. Another solid phase ole-fination relied on the reaction of N-Fmoc-L-valinal withphosphonoacetyl Wang resin in the presence of NEt3 andLiBr, giving E-olefin bound to the resin.128

Applying chiral phosphonates, Rein et al.129 demon-strated that dynamic kinetic resolution of N-Ts-N-Bn-�-amino aldehydes, in the presence of a slight excess of thebase, can be accomplished.

The Horner-Wadsworth-Emmons modification shows ahigh preference for the formation of the thermodynami-cally more stable E-olefins. To perform this reaction, usu-ally strong bases (KHMDS, BuLi, LDA, NaH) are needed,which would lead to racemization of �-amino aldehydes.Ghosez and co-workers130 showed that the Wittig-Hornerreaction of N-phenylacetamido-D-alaninal (115) proceededwith better E-diastereoselectivity when carried out withphosphonate 117b instead of phosphonate 117a (Scheme35). Further improvement was achieved by changing thebase from BuLi to NaH. The optimized conditions for E-

Scheme 33.

Scheme 34.

Scheme 35.

530 GRYKO ET AL.

olefination were as follows: use of phosphonate 117b andNaH as a base, regardless of the N-protecting group in the�-amino aldehyde, led to �-amino-�,�-unsaturated sulfo-nates 118 with very high diastereoselectivity and goodyields. This approach was successfully utilized for the syn-thesis of sulfonamido-peptides.131,132

In 1997 the Giannis group,133 following the procedureusing DBU, DIPEA, or NEt3 in the presence of lithium ormagnesium halides, succeeded in achieving the desiredZ-olefin 120 without racemization, accompanied by thelactone 121 (Scheme 36).

�-Amino aldehydes can be used in the synthesis of C-terminal peptide aldehydes on solid support. Martinez andco-workers134 reported the synthesis of peptide aldehydesbased on the use of �,�-unsaturated-�-amino acid as alinker to the solid support. This compound was synthe-sized by the Wittig reaction between the carboethoxymeth-ylene triphenylphosphorane and the N-protected �-aminoaldehydes. Later on they presented a new approach whichconsisted of anchoring the Wittig or Wittig-Horner reagenton resin, followed by the reaction with N-Boc-�-amino al-dehydes.135 Yao and Xu136 used 10,11-dihydroxyundeca-noic acid as a linker; the first amino aldehyde was attachedby acetal formation reaction.

Chiral propargylic amines can be obtained from N-pro-tected-�-amino aldehydes via the Corey-Fuchs proce-dure.137–140 An aldehyde was reacted with CBr4/Zn/PPh3giving the crude dibromide 122, which upon treatmentwith BuLi transformed into propalgylic amine 123, usuallywith moderate to high yield (Scheme 37). Unfortunately,the first step of the synthesis was not free from racemiza-tion, although Reetz et al.137 showed that the isolation ofdibromide derivative 122 allowed one to obtain enantio-merically pure amines.

Another approach to this type of compound involved theexposure of N-Boc-L-�-amino aldehyde of type 28 to di-methyl diazophosphonate.141,142 The one-pot reaction gaveblocked propargylic amines with moderate yield and withoptical purity identical to that of the aldehyde used. Thissuggests that the diazophosphonate addition proceededwithout racemization.

CYCLOADDITION REACTIONSDiels-Alder Reaction

The Diels-Alder reaction is one of the most powerfultools for the construction of six-membered rings, includingheterocyclic ones. The stereoselectivity of this reactionwith the use of �-amino aldehydes is controlled by thechelation or nonchelation transition states.4 It was foundthat the reaction of amino acid derivatives with active 1,3-dienes such as Danishefsky’s derivative afforded predomi-nately syn-cycloadducts when N-monoprotected substrateswere used, whereas anti-cycloadduct was formed in thecase of the application of N-Pht-aldehydes.4 Since that timemuch work has been done in order to generalize the influ-ence of N,O-protecting groups, Lewis acids, pressure, andother experimental variables.

Variously protected D-alaninals 124 were treated withDanishefsky’s diene 125, in the presence of ZnBr2, afford-ing a mixture of cycloadducts 126 (Scheme 38).143,144 The

results presented in Table 11 show that the stereoselectiv-ity is reversed for N,N-diprotected-D-alaninals when com-pared with N-monoprotected analogs. The anti-diastereo-selectivity was obtained with the doubly protected alaninalsand the reaction proceeds via the Felkin-Anh transitionstate. Additionally, for this type of aldehyde the diastere-oselectivity of the reaction rose with the steric hindrance ofthe protecting groups (Table 11, entries 4–6). A similaranti-selectivity was observed by Reetz5 for cycloaddition toN,N-Bn2-�-amino aldehydes of type A. syn-Cycloadductswere formed predominantly when N-monoprotected alde-hydes were used (Table 11, entries 1, 2), with the excep-tion of N-Ts-D-alaninal, which gave no selectivity at all (en-try 3). The authors explained that in the case of N-Ts-D-

Scheme 36.

Scheme 37.

Scheme 38.


alaninal the protecting group was an intermediate betweenthe chelating and the steric types and that the sulfonylgroup strongly deactivated the nitrogen center.

Furthermore, the influence of the O-protecting group, ifpresent in �-position, in an aldehyde was studied by thesame team145 (Scheme 39). The stereochemical course ofthe reaction of N-Cbz-O-TBS- (127), N-Cbz-O-BOM-D-threoninal (128), N-Cbz-O-TBS- (132), or N-Cbz-O-BOM-D-allo-threoninal (133) with 1-O-Bn-2-O-TBDMS-4-O-Me-buta-1,3-diene (129) was strongly influenced by the con-figuration and the nature of the –OR group in �-position.

Regardless of the nature of the O-protecting group, allfour aldehydes showed a strong preference for �-chelationinteraction leading to the formation of syn,syn-pyrones asthe major diastereoisomers. However, the use of the -O-

BOM protecting group for D-allo-threoninals gave betterresults than the use of the –O-TBS group. Replacing the–O-TBS group with the more bulky one, namely, –O-TBDPS, did not improve the asymmetric induction.146 Theabove findings were found to be true for D-threoninals. Inthe case of –O-BOM-protected aldehyde 128 used as adienophile, all four diastereoisomeric adducts 131 wereformed and syn,anti-cycloadduct predominated. Cycload-ducts 131 and 135 can be readily transformed into thedihydro-2H-pyrans,147 which can serve as chirons for thesynthesis of sugars and other natural products.

TABLE 11. Influence of the N-protecting group on thestereochemical course of the reaction of aldehyde 124

with 125143,144

Entry PG1 PG2 Yield [%] syn:anti

1 H Boc 75 75:252 H Cbz 78 67:333 H Ts 74 50:504 Bn Bn 80 10:905 Bn Ts 91 9:916 Bn Boc 85 7:93

Scheme 39.

Scheme 40.

532 GRYKO ET AL.

Midland et al.148 showed that the [4+2]cycloaddition isinfluenced by the nature of a Lewis acid used. Regardlessof the N-protecting group used, the reaction of N-Cbz-L-alaninal (62) with 1,3-dimethoxy-1-(silyloxy)buta-1,3-diene(136) afforded a mixture of cycloadducts with syn-preference (Scheme 40, Table 12). The stereochemical re-sult was consistent with a chelation-control process.

The use of LiClO4 as a promoter of the cyclocondensa-tion of N-mono- and N,N-diprotected �-amino aldehydeswith 1-methoxy-3-[tert-butyl(dimethyl)silyloxy]-buta-1,3-diene resulted in high product syn-diastereoselectivity.149 Itis noteworthy that increased steric bulkiness of the alkylsubstituents at the �-carbon atom led to enhanced diaste-reoselectivity. In the case of L-serine-derived aldehydes,lower syn-diastereoselectivity was observed with N-Boc-O-Bn-L-serinal as compared with N-Boc-O-TBS-L-serinal,presumably due to competing �-control. The syn-diastereo-facial selectivity observed above could be reversed bychanging the nature of the protecting group (N,N-Bn2 in-stead of N-Boc); in this case, only anti-diastereoisomer wasdetected.

High-pressure [4+2]cycloaddition of 1-methoxy-buta-1,3-diene to variously protected �-amino aldehydes in the pres-ence of Eu(fod)3 was studied by Jurczak and col-leagues.144,150 The use of the catalyst did not influence thediastereoisomeric ratio but improved the yield in compari-son to the noncatalyzed reaction. The stereochemical re-sults obtained for N-monoprotected-D-alaninals were con-sistent with chelation-controlled [4+2]cycloaddition, lead-ing to predominantly syn,syn-product, but the level ofdiastereoselection was moderate. For N,N-diprotected�-amino aldehydes the direction of asymmetric inductionwas reversed. Moreover, a high-pressure reaction, withoutany catalyst, was carried out with N-Cbz-protected D-threoninals and D-allo-threoninals, and it was revealed thata change in the protection of �-hydroxy function (from thebulky –TBS group to the chelating –BOM group) caused asubstantial increase in the formation of the anti,anti-cycloadduct.

Other CycloadditionsAsymmetric 1,3-dipolar cycloaddition provides versatile

heterocyclic intermediates in optically active forms. Inthese reactions �-amino aldehydes serve as starting mate-rials for the preparation of 1,3-dipoles. Cycloaddition ofchiral nitrone 138, derived from N-Boc-L-valinal (87), withmethyl acrylate was carried out under different reactionconditions, such as refluxing toluene or under high pres-sure (10 kbar) at 60°C or at room temperature (Scheme

41).151 The reaction afforded isoxazolidines 139 as a mix-ture of four diastereoisomers in good overall yield, but withmoderate diastereoselectivity. Further studies revealedthat regardless of the N-protecting groups the diastereos-electivity remained at the same level. Surprisingly, therewas no difference in the direction of asymmetric inductionwhen N-mono- and N,N-diprotected �-amino aldehydeswere used as substrates.

An intramolecular version of the 1,3-dipolar cycloaddi-tion, using nitrones generated in situ from the correspond-ing sulfonylated �-amino aldehydes 140 affording isoxa-zolidine fused heterocycles 142, was presented by theYamamoto group152 (Scheme 42). Regardless of the�-amino aldehyde used, diastereoisomeric excess was al-ways higher than 96%. This was also observed by Abiko etal.,153 who used N-Ts-N-prenyl-�-amino aldoximes as sub-strates.

In a similar manner, isoxazolines can be obtained. Thechiral nitrile oxides 144 were generated in situ from thecorresponding oximes 143 using NBS in THF, in the pres-ence of a catalytic amount of pyridine. The cyclization wasthen performed in the presence of NEt3 in boiling tolueneto give diastereoisomerically pure isoxazoline derivatives145 in a good yield (Scheme 43).152

TABLE 12. Influence of a Lewis acid used on thecycloaddition of 62 to 136148

Lewis acid Yield [%] syn:anti

Eu(fod)3 83 80:20ZnCl2 30 70:30Et2AlCl 48 70:30MgBr2�Et2O 30 50:50

Scheme 41.

Scheme 42.


Asymmetric 1,3-dipolar cycloaddition of chiral nitrile ox-ide 144 to chiral dipolarophile, namely, N-acroyl (2R) or(2S)-bornane-10,2-sultam, provided a diastereoisomericmixture of 2-isoxazoline cycloadducts in a ratio of ∼9:1,with a preference for the product possessing (R)-configuration at the newly formed center, regardless of the�-amino aldehyde used.154,155

1,3-Dipolar cycloaddition has also been used for the syn-thesis of imidazole rings.156 The reaction of N-Boc-L-phenylalaninal (47) with primary amine 146 produced theimine which underwent cycloaddition with tosylisonitrile147 to deliver imidazole 148 in high yield with 96% ee(Scheme 44).

The chemical and stereochemical behavior of �-aminoaldehydes in [2+2]cycloaddition was reported by thePalomo group.157,158 The reaction of dichloroketene 149generated in situ from dichloroacetyl chloride with N-Boc-L-phenylalaninal (47) led exclusively to �-lactone 150 in44% yield (Scheme 45).

Baylis-Hillman ReactionThe Baylis-Hillman reaction has received much attention

as an effective method for C-C bond formation and givinghighly functionalized products. The asymmetric version of

this reaction can be envisaged with chiral �-amino alde-hydes. This approach was presented by the Roos159 andDrewes160 groups, who studied the influence of the N-protecting group on the overall reactivity of an aldehydeand on the coupling diastereoselectivity (Scheme 46). It

was found that aldehydes having an electron-withdrawingN-protecting group were more reactive towards methyl ac-rylate in the presence of DABCO than their N,N-dibenzylcounterparts (Table 13). The anti-diastereoselectivity maybe rationalized in terms of the Felkin-Anh model and wasobserved for the N,N-Bn2 and the N-Pht protecting groups.The reversed stereoselectivity gave the reaction of N-Boc-L-alaninal (74) with methyl acrylate catalyzed by DABCO,which can be explained by the Cram cyclic model when thehydrogen bond is involved (Table 13).

The addition of acrylamide to N-protected �-amino alde-hydes did not give Baylis-Hillman adducts. Bussolari etal.161 reported that the reaction of acrylamide with N-Cbz-L-phenylalaninal (152), catalyzed by DABCO, afforded N-acylhemiaminal 153 with 63% yield (Scheme 47). The gen-erality of this transformation was explored using a widevariety of �-amino aldehydes: in all the cases reactions

TABLE 13. Baylis-Hillman reaction of �-amino aldehydeswith methyl acrylate159,160

AldehydeTime

[days] Yield [%] anti:syn

20 71 72:28

3.5 30 55:45

7 85 86:14

1.5 76 29:71

Scheme 43.

Scheme 44.

Scheme 45.

Scheme 46.

534 GRYKO ET AL.

were fast as compared with the classic Baylis-Hillman pro-cess.

While working on the enantio- and diastereocontrolledsynthesis of epopromycin B, the Hatakeyama group162

found that the reaction of N-Fmoc-L-leucinal (154) with1,1,1,3,3,3-hexafluoroisopropyl acrylate (155) proceededsmoothly in the presence of a stoichiomertic amount ofcinchona alkaloid, even at very low temperature, to give a6:1 mixture of syn-ester 156 and dioxane derivative 157(Scheme 48). The same reaction with N-Fmoc-D-leucinal(ent-154) turned out to be sluggish and only a mixture ofdioxanones was obtained in low yield. Thus, it can be con-cluded that the (R)-selectivity of the chiral amine catalystmatches well with L-configuration of the substrate leadingto high syn-selectivity.

Cyanohydrin-Forming Reactions

Optically active cyanohydrins derived from �-amino al-dehydes are an important class of compounds in organicsynthesis since their hydrolysis leads to �-hydroxy-�-amino acids. The most common procedure is based ontrimethylsilylcyanide (TMSCN) addition. The work pub-lished by Reetz et al.163 showed that through the properchoice of a Lewis acid the reaction of N,N-Bn2-�-aminoaldehydes of type A with TMSCN afforded adducts with ahigh level of diastereoselectivity. Herranz et al.164 foundthat the use of N-Cbz-L-phenylalaninal (152) or L-leucinal(107) as substrates in this type of reaction led to the bestresult (80:20, syn-preference) when the reaction was car-ried out at elevated temperature without any Lewis acid

added (Scheme 49). The addition of SnCl4 did not increasethe syn:anti ratio, and addition of BF3·OEt2 led to a totalloss of stereoselectivity.

A high level of diastereoselectivity was observed whenN-Boc protected �-amino aldehydes were used in the pres-ence of Eu(fod)3.165 The remarkably enhanced syn-stereoselectivity observed with N,N-Bn2-L-leucinal provedto be of special value when compared with the N-Boc-analog. The replacement of TMSCN by the more reactivetributyltin cyanide strongly reduced the reaction time,while the diastereoselectivity and the overall yield re-mained unchanged.166

It is also possible to replace TMSCN by acetone cyano-hydrin, which has been claimed to be more practical. Thereaction of acetone cyanohydrin with N,N-Bn2-L-phenyla-lanine proceeded in a highly stereoselective manner in thepresence of alkylaluminum reagents, affording the corre-sponding anti-cyanohydrin as a major product.167 Thesame reagent was used for the preparation of C-terminalcomponent 160 of renin inhibitors, starting from N-Boc-L-phenylalanine (1) (Scheme 50).168 The desired syn-diastereoisomer 159 was produced with very high selec-tivity, but significant epimerization in solution was found.This could be avoided by the immediate isolation of cya-nohydrin 159.

Starting from component 161, the reaction with NaCNin the presence of Ac2O, under phase-transfer conditions,led to a mixture of cyanohydrin acetates with formation ofsyn-162 as a major diastereoisomer (6:1).169 In contrast, a1:1 mixture of cyanohydrine acetals 162 was obtainedwhen aldehyde 161 was first allowed to react with NaCNunder the same conditions and the formed cyanohydrinssyn-163, anti-163 were subsequently acetylated (Scheme51).

Scheme 47.

Scheme 48.

Scheme 49.

Scheme 50.


The addition of TMSCN to �-amino aldehydes pro-ceeded well with or without the addition of a Lewis acid.Recently, Pedrosa and colleagues170 used diethylaluminumcyanide (so-called Nagata’s reagent) as a cyanating agent,which also behaves as a Lewis acid with the possibility ofreacting after coordination to the heteroatom in the start-ing aldehyde, e.g., to the amino group. In the reaction ofN,N-Bn2-�-amino aldehydes of type A with Nagata’s re-agent, predominantly anti-adduct was obtained.

Furthermore, it was demonstrated that the enantiomeri-cally pure bifunctional (both Lewis acid and base) catalysts164–166 (Fig. 3) promoted cyanosilylation of �-aminoaldehydes in excellent yield and with high diastereoselec-tivity.171 It was found that higher de was obtained whencomplexes 165 and 166 were used instead of 164. Bothanti- and syn-isomers could be obtained, depending on thetype of N-protecting group. For N,N-diprotected �-aminoaldehydes, syn-product predominated, whereas anti-cyanohydrin was formed as a major diastereoisomer whenN-monoprotected substrates were used.

Myers et al.172–174 showed that cyanohydrins derivedfrom �-amino aldehydes can be regarded as C-protected�-amino aldehydes.

Other Reactions

In the search for a new class of potent inhibitors forrenin, the Patel group175,176 found an effective method forthe preparation of �-amino-�-hydroxy phosphonate com-

pounds. The reaction of N-Boc-L-cyclohexylalaninal (7)with dimethyl phosphite, in the presence of DBU in DMF,gave essentially an equimolar ratio of syn- and anti-isomers167 (Scheme 52). Replacement of DBU with other basesimproved the diastereoselectivity of the reaction and thebest result was obtained when potassium fluoride was em-ployed. Diastereoisomer syn-167 (the amino and hydroxygroups in syn-orientation) was obtained as a major product(92:8) with overall yield of 95%.

Similar results were obtained when diethyl phosphitewas reacted with N-Boc- or N-Cbz-L-phenylglycinal, in thepresence of NEt3 or KF as a base.177 Employing lithiumdiethyl phosphonate as a reagent caused a sudden drop inthe diastereoselectivity of the addition, although the yieldimproved.

A double stereodifferentiating process, with the use ofchiral phosphinic acid 168 in the addition to N-Cbz-L-phenylalaninal (152), led to a mixture of three major dia-stereoisomers 169 in a ratio of 56:28:16 in 47% overall yield(Scheme 53).178 The formation of the additional third dia-stereoisomer was explained by the partial racemization ofthe starting aldehyde 152.

Fig. 3.

Scheme 52.

Scheme 51.

536 GRYKO ET AL.

The reaction of �-amino aldehydes with alkyl phosphi-nate, carried out in the presence of a chiral promoter de-rived from binaphthoxide, strongly depended on the na-ture of the N-protecting group.179 For N-monoprotected(-Cbz or -Boc)-L-phenylalaninals, the reaction afforded�-amino-�-hydroxy-phosphonic acid in a very low yield.However, the use of N,N-Bn2-L-phenylalaninal led to betteryield and higher diastereoselectivity.

Amino sugars containing the 3-amino-1,2-diol subunitare important constituents of a variety of antibiotics. Nu-merous synthetic approaches have been presented, amongthem the reductive coupling of an �-amino aldehyde withanother aldehyde. A successful pinacol cross-coupling re-action reported by the Pedersen group180,181 generally re-quires slow addition of a chelating aldehyde (in this case an�-amino aldehyde) to a mixture of [V2Cl3(THF)6]2[Zn2Cl6]and a nonchelating aldehyde. N-Monoprotected �-aminoaldehydes were reacted with aliphatic aldehydes giving, inmost cases, syn,syn-3-[N-(alkoxycarbonyl)amino]-1,2-diols171 with very high diastereoselectivity and in good yield(Scheme 54). It was also found that the nature of the N-alkoxycarbonyl group strongly influences the yield of cou-pling and the authors proposed that the steric bulk of thealkyl group may affect the rate and stability of chelation,and therefore influence the yield.

Diastereoselectivity decreased with aldehydes such asN-Cbz-L-prolinal, N-Bn-N-Cbz-L-phenylalaninal, Garner’s al-dehyde (B), and N-Cbz-O-Bn-L-serinal. However, if theO-Bn protective group was replaced by the bulkier O-TBSgroup, the cross-coupling reaction with n-pentadecanalgave the syn,syn-product almost exclusively.

In the early 1990s the same group showed that pinacolhomocoupling reactions using N-Cbz-�-amino aldehydes172 could be done through the application of a vanadi-um(II) reagent leading to C2-symmetric 1,4-diamino-2,3-diols 173 with very high diastereoselectivity (Scheme55).182 Under these reaction conditions racemization of thestarting materials did not occur.

Three-component Passerini condensation offers accessto highly functionalized compounds and when �-amino al-dehydes are employed, �-amino-�-hydroxy acid derivativesare produced. In 1994 the Schmidt group183 first reportedthis type of condensation with the use of N-Cbz-L-alaninal(62), isonitrile 174, and benzoic acid 175 (Scheme 56).The reaction gave a mixture of diastereoisomers 176 with85% yield, but no asymmetric induction was observed. Thehydroxy group attached to the newly formed stereogeniccenter was further oxidized to the carbonyl group givingenantiomerically pure eurystatin A, a prolyl endopeptidaseinhibitor.

The methodology was independently further developedby Semple et al.184 and Banfi et al.185 The Semple groupshowed that the reaction could be carried out under mild,almost neutral conditions (namely, 2 equiv. of TFA and 4equiv. of pyridine), typically at 0°C to room temperature.�-Amino-�-hydroxy amide derivatives 178 were obtainedin moderate to high yield, yet without appreciable stereose-lectivity (∼1:1 to 3:1). To illustrate the scope and limitation ofthe method, the authors used a wide variety of protected�-amino aldehydes 170 and isonitriles 177. The represen-tative results are presented in Table 14 (Scheme 57).

TABLE 14. Passerini condensation of �-amino aldehydeswith isonitriles in the presence of TFA and pyridine184,185

PG R1 R2 Yield [%]

Boc Bn t-Bu 78Boc CH2SMe CH2CO2Me 62Boc Bn CH2CO2Allyl 67Cbz d-Bn (S)-CH(i-Bu)CO2Bn 65Fmoc Et CH2CO2Allyl 73Fmoc (CH2)4NHBoc CH2CO2Allyl 79

Scheme 53.

Scheme 54.

Scheme 55.

Scheme 56.

Scheme 57.


Banfi et al.185 showed additionally that various organicacids, including �-amino acids, could be used in the Pas-serini reaction. The yield of adducts were in the range of70–95% and, regardless of the N-Boc-�-amino aldehyde 28,the stereoselectivity was almost at the same level in allcases, ∼2:1. Treatment of the Passerini product with TFA,followed by NEt3, led to both the cleavage ot the protectinggroup and in situ acyl migration, which directly gave apeptide-like structure. The two-step procedure allowed aneasy combinatorial entry to the oligopeptides. The pre-sented methodology was applied by Semple and co-workers186 to the synthesis of eurystatin A.

The diastereoselectivity of the reaction did not improveeven when sterically bulky sugar-derived isonitriles wereused. The reaction of per-O-benzyl and per-O-acetyl-isocyanoglucoses with N-Boc-L-phenylalaninal (47) andwith acetic acid furnished Passerini adducts in yields of35% and 57%, respectively, with very low diastereoselectiv-ity.187

The same authors187 reported the Ugi reaction of gluco-syl isonitriles with N-Boc-L-phenylalaninal (47). The reac-tion was slow and gave the Ugi product in low yield and thediastereoselectivity was not determined. However, the Ugi

reaction with �-amino aldehydes could proceed in highyield, as presented by the Hulme group.188 EmployingN-Boc-�-amino aldehydes, for example 87, followed byacid-mediated cyclization allowed easy access to imidazo-line 183 (Scheme 58).

In the course of studies on the tyrosine hydroxylasegene. the Thal group189,190 investigated the stereochemicalcourse of the Pictet-Spengler reaction between tryptamine185 and variously protected �-amino aldehydes 184 de-rived from L-glutamic acid. They found that in the N-monoprotected series syn-carboline 186 was alwaysformed as the major diastereoisomer and that the size ofthe carbamate group provided little influence on the courseof the reaction’s diastereoselectivity. Carboline anti-186could be obtained exclusively when the pyrrole or phthal-imide groups were used as the N-protecting groups(Scheme 59).

Homologation of �-amino aldehydes using various for-myl anion equivalents can be used for the preparation ofmasked �-hydroxy-�-amino carboxylic acids or es-ters.192,193 The reaction of O-protected malononitrile 187with N-Cbz-D-phenylalaninal (152) in the presence of abase gave the desired product 188 accompanied by cya-nohydrin 189 (Scheme 60). Through the proper choice ofa base, 4-pyrrolidinopyridine, and a solvent, Et2O, product188 was obtained as a mixture of syn:anti diastereoiso-mers (79:21) in 86% yield.

The same product 188, but with a free hydroxy group,can be obtained by the reaction of an aldehyde with di-alkoxymethyl diphenyl phosphine oxide in the presence ofLDA at –110°C, followed by treatment with wet dichloro-methane.192 The syn/anti-diastereoselectivity was found tobe 88:12.

Derivatives of tris(2-aminoethyl)amine (TREN) are of in-terest due to their enhanced rigidity, necessary for exert-ing good stereocontrol in catalytic reactions. Raymond andco-workers193,194 showed that the reaction of N-protected-L-alaninal or -L-serinal with NH4OAc under reductive ami-nation conditions afforded protected chiral TREN deriva-tives with good yield.

CONCLUSIONS

The literature data presented in this review show thatvariously N-mono- and N,N-diprotected �-amino aldehydes

Scheme 58.

Scheme 59.

Scheme 60.

538 GRYKO ET AL.

can be prepared in enantiomerically pure form from�-amino acids or other precursors and that they offer greatopportunities for a wide variety of diastereoselective C-Cbond-forming reactions, most of them proceeding withvery high asymmetric induction. The success of these re-actions is based on the protective group tuning, since it isvery often the case that, depending on the N-protectinggroup (N-mono- or N,N-di) it is possible to obtain two dia-stereoisomers syn and anti in pure form.

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