The conjugate addition of enantiopure lithium
N-benzyl-
N-(α-methylbenzyl)amide to α,β-unsaturated esters and amides displays high diastereoselectivity with extremely wide substrate scope and thus this process has been recognized as one of the most robust and reliable methods to prepare β-amino acid derivatives. The stereochemical outcome of this process is predictable in most cases and is rationalised by a transition state mnemonic.
2 This methodology has found numerous applications, including in the areas of target synthesis and molecular recognition phenomenα, and was comprehensively reviewed in 2005,
3 2012,
4 and 2017.
5
Lithium Amide Family and Selective Deprotection Strategies
In addition to the most commonly employed lithium amide reagent, lithium
N-benzyl-
N-(α-methylbenzyl)amide, more than 20 analogues which incorporate allyl, various substituted benzyl, haloalkyl, and methylheteroaryl groups have been developed for conjugate addition. Enantiomerically pure lithium amides
18 and
21 as a chiral "hydroxylamine equivalent" and a chiral "aniline equivalent", respectively, have also been developed. Conjugate additions of some representative members of the lithium amide family are presented below and the conjugate addition products
7,
10,
13,
16,
19 and
22 were isolated as single diastereoisomers (Scheme 1).
Scheme 1. Conjugate additions of representative lithium amides [PMP = 4-methoxyphenyl; TDBMS = tert-butyldimethylsilyl]6,7,8,9,10,11
Several chemoselective deprotection methods for removal of the
N-protecting groups have been developed. For example, treatment of
23 with ceric ammonium nitrate (CAN) in MeCN/H
2O at rt for 2 h
12 gave selectively mono-debenzylated β-amino ester
24 in 60% yield.
13 Oxidative removal of the
N-3,4-dimethoxybenzyl group within
25 with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) gave
26 in 98% yield.
14 The
p-methoxy variant, incorporating an
N -α-methyl-
p-methoxybenyl group, can be removed under various acidic conditions; for example: treatment of
10 with HCO
2H and Et
3SiH gave
27 in 81% yield.
7 Treatment of
28 with a Pd catalyst and
N,
N-dimethylbarbituric acid
29 smoothly removed the
N-allyl group to give
30 in 97% yield (Scheme 2).
15
Scheme 2. Representative chemoselective N-deprotections [PMP = 4-methoxyphenyl; TDBMS = tert-butyldimethylsilyl]
α-Functionalisation of β-Amino Acid Derivatives
In order to expand the structural diversity of the accessible β-amino acid derivatives, α-functionalisation of the β-amino ester has been investigated. α-Functionalisation of the β-amino acid derivatives can be achieved via elaboration of the intermediate enolate resulting from conjugate addition of a lithium amide reagent to an α,β-unsaturated ester with an electrophile (tandem manner). Alternatively, α-functionalisation can be achieved upon formation of the corresponding β-amino enolate upon deprotonation of a β-amino ester with a strong base (e.g., LDA, NaHMDS etc) followed by treatment with an electrophile (stepwise manner). The stereochemical outcome and diastereoselectivity of these processes depends on the nature of the substrate and the electrophile.
16 For example, "tandem" conjugate addition/alkylation upon reaction of (
S)-
32 and α,β-unsaturated ester
31 followed by the addition of allyl bromide to the intermediate lithium (Z)-β-amino enolate (
Z)-
33 gave
34 in 60% yield as an 85:15 mixture of C(2)-epimers,
17 while treatment of β-amino ester
35 with LiTMP to form the corresponding enolate (
E)-
36 in situ and addition of acrolein
37 gave
38 in 96% yield as a single diastereoisomeric product (Scheme 3).
18
Scheme 3. "Tandem" and "stepwise" α-functionalisation strategies
Treatment of β-amino enolates, derived from the conjugate addition of an enantiopure lithium amide
40 to an α,β-unsaturated ester
39, with various electrophiles facilitated the preparation of a range of α-fluoro,
α-mercapto, and α-hydroxy-β-amino acid derivatives
41. For example, Duggan and co-workers reported the tandem conjugate addition/fluorination of α,β-unsaturated ester using the electrophilic fluorinating agent
N-fluorobenzenesulfonimide (NFSI), which gave
anti-α-fluoro-β-amino ester
42 in 77% yield.
19 Similarly,
anti-α-
tert-butylthio-β-amino ester
43 was obtained in 88% yield as a single diastereoisomer by in situ enolate trapping with TsS
tBu.
20 In situ enolate oxidation with the requisite antipode of canmphorsulfonyloxaziridine (CSO) has been well-established as a powerful tool for asymmetric
anti-aminohydroxylation and has been frequently reported in the literature (>50 examples in the last 5 years). For example,
44 was obtained by conjugate addition of (
R)-
32 to the requisite α,β-unsaturated ester followed by enolate oxidation with (-)-CSO in 80% yield as a single diastereoisomer (Scheme 4).
21,22
Scheme 4. α-Functionalisation of β-amino enolates
The corresponding
syn-α-hydroxy-β-amino ester
47 can be prepared via an oxidation/diastereoselective reduction protocol.
23 For example, Swern oxidation of
anti-α-hydroxy-β-amino ester
45 gives the corresponding ketone
46, and reduction with either NaBH
4 in MeOH or DIBAL-H in THF gives typically a >90:10 mixture of
syn-
47 and
anti-
45, respectively, and the corresponding
syn-α-hydroxy-β-amino ester
47 can be isolated as a single diastereoisomer. Representative recent examples are shown below (Scheme 5).
22,24,25
Scheme 5. Preparation of syn-β-amino-α-hydroxy esters
Cyclic β-Amino Acid Syntheses
Preparations of enantiopure cyclic β-amino acids were also developed via conjugate addition of lithium
N-allyl-
N-(α-methylbenzyl)amide or lithium
N-but-3-enyl-
N-(α-methylbenzyl)amide to a suitable α,β-unsaturated ester followed by ring-closing metathesis as the key steps. For example, conjugate addition of lithium (
S)-
N-allyl-
N-(α-methylbenzyl)amide (
S)-
6 to α,β-unsaturated ester
51 (derived from sorbic acid) gave β-amino ester
52 in 78% yield. Ring-closing metathesis of
52 with Grubbs I catalyst gave the cyclic β-amino ester
53 in 77% yield. Stepwise hydrogenation of
53 in the presence of Wilkinson's catalyst and subsequent hydrogenolytic removal of the
N-protecting group gave amino ester
55 in 79% yield (from
53). Acid-mediated ester hydrolysis gave (
S)-homoproline
56 in 96% yield (Scheme 6).
26 Application of this methodology, involving the conjugate addition of an enantiopure lithium amide incorporating alkenyl functionality to the requisite α,β-unsaturated esters followed by ring-closing metathesis, provided key intermediates for a wide range of azacyclic scaffolds such as cyclic β-amino acids
57-
59, pyrrolidines,
27 piperidines,
28,29,30 and pyrrolizidines.
17,31,32
Scheme 6. Preparation of cyclic β-amino acids
Rearrangement towards α-Amino Acids
Synthetic routes to access natural and non-natural α-amino acid derivatives have also been developed via the aminohydroxylation of an α,β-unsaturated ester and stereospecific rearrangement via the corresponding aziridinium ion intermediate.
24,25 For example, aminohydroxylation of
1 with (
R)-
32 and (-)-CSO gave
anti-α-hydroxy-β-amino ester
60 in 56% yield and >99:1 dr. Treatment of
60 with Tf
2O and DTBMP
61 activates the hydroxy group within
60 as a triflate followed by formation of the corresponding aziridinium ion intermediate
62 upon displacement by the adjacent tertiary amino group. Subsequent regioselective ring-opening of
62 with H
2O gave β-hydroxy-α-amino ester
63 in 68% yield and >99:1 dr after purification. Deprotection of
63 via hydrogenolysis in the presence of a Pd catalyst followed by acid-mediated hydrolysis gave (
S,
S)-β-hydroxyleucine
64 in 69% yield and ≥96:4 dr over 2 steps (Scheme 7).
33 This rearrangement progresses via an aziridinium ion intermediate using other nucleophiles (such as fluoride and azide) allowed access to various β-functionalized α-amino acid derivatives in high diastereoisomeric purity.
34
Scheme 7. α-Amino acid synthesis via aziridinium rearrangement
In conclusion, the conjugate addition of enantiopure lithium amides to α,β-unsaturated carbonyl compounds has consistently been demonstrated in high chemical yield and excellent diastereoselectivity with a wide range of substrate scope. Significant development for the elaboration of the resultant β-amino ester products or β-amino enolates has been achieved in the past few years and this will continuously contribute not only to the area of amino acid/peptide chemistry but also in the areas of natural products and pharmaceutically important target syntheses.
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