Stereoselective synthesis of perillaldehyde-based chiral β-amino acid derivatives through conjugate addition of lithium amides

Article abstract of DOI:10.3762/bjoc.10.289

The Michael addition of dibenzylamine to (+)- tert-butyl perillate ( 3) and to (+)- tert-butyl phellandrate (6), derived from ( S)-(-)-perillaldehyde (1 ), resulted in diastereomeric β-amino esters 7A-D in a moderately stereospecific reaction in a ratio of 76:17:6:1. After separation of the diastereoisomers, the major product, cis isomer 7A, was quantitatively isomerized to the minor component, trans-amino ester 7D. All four isomers were transformed to the corresponding β-amino acids 10A-D, which are promising building blocks for the synthesis of β-peptides and 1,3-heterocycles in three steps. The steric effects of the isopropyl group at position 4 and of the α-methyl substituent of (R)-N-benzyl-N-α-methylbenzylamine on the reactivity were also studied, upon application of a chiral amine, excellent stereoselectivity of the conjugate addition was observed. Amino ester 11 was obtained as a single product and transformed to the corresponding amino acids 10A and 10D in good yields on the gram scale.

Full text of DOI:10.3762/bjoc.10.289

Stereoselective synthesis of perillaldehyde-based chiral
β-amino acid derivatives through conjugate addition
of lithium amides
Zsolt Szakonyi1, Reijo Sillanpää2 and Ferenc Fülöp*1,3,§
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2014, 10, 2738–2742.
1Institute of Pharmaceutical Chemistry, University of Szeged, H-6720
Szeged, Eötvös utca 6, Hungary, 2Department of Chemistry,
University of Jyväskylä, POB 35, 40351 Jyväskylä, Finland and
3Stereochemistry Research Group of the Hungarian Academy of
Sciences, H-6720 Szeged, Eötvös u. 6, Hungary
doi:10.3762/bjoc.10.289
Received: 08 September 2014
Accepted: 14 November 2014
Published: 21 November 2014
Email:
Associate Editor: S. Bräse
Ferenc Fülöp* - fulop@pharm.u-szeged.hu
© 2014 Szakonyi et al; licensee Beilstein-Institut.
License and terms: see end of document.
* Corresponding author
§ Tel.: +36-62-545564; Fax: +36-62-545705
Keywords:
asymmetric synthesis; β-amino acid; chiral; Michael addition;
monoterpene
Abstract
The Michael addition of dibenzylamine to (+)-tert-butyl perillate (3) and to (+)-tert-butyl phellandrate (6), derived from (S)-(−)-
perillaldehyde (1), resulted in diastereomeric β-amino esters 7A–D in a moderately stereospecific reaction in a ratio of 76:17:6:1.
After separation of the diastereoisomers, the major product, cis isomer 7A, was quantitatively isomerized to the minor component,
trans-amino ester 7D. All four isomers were transformed to the corresponding β-amino acids 10A–D, which are promising building
blocks for the synthesis of β-peptides and 1,3-heterocycles in three steps. The steric effects of the isopropyl group at position 4 and
of the α-methyl substituent of (R)-N-benzyl-N-α-methylbenzylamine on the reactivity were also studied and, upon application of a
chiral amine, excellent stereoselectivity of the conjugate addition was observed. Amino ester 11 was obtained as a single product
and transformed to the corresponding amino acids 10A and 10D in good yields on the gram scale.
Introduction
In the past decade, cyclic β-amino acids proved to be versatile tional groups, well-defined β-helical (e.g., β-H12, β-H14, β-H16
building blocks both in pharmacological developments and or β-H18) or β-sheet structures can be prepared [9-13]. While it
asymmetric syntheses [1-8]. Alicyclic and bicyclic chiral is primarily the backbone stereochemistry that determines the
β-amino acids have played a key role in the synthesis of secondary structure of foldamers, the introduction of well-
β-peptide-type foldamers, where through the selection of an designed hydrophilic or hydrophobic substituents on the
appropriate alicyclic or bicyclic ring system, the backbone alicyclic ring of β-amino acids can modify the fine structure of
stereochemistry, stereochemical patterning or additional func- β-peptides.
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Beilstein J. Org. Chem. 2014, 10, 2738–2742.
There are several powerful synthetic methods through which
alicyclic or bicyclic β-amino acid enantiomers can be obtained.
These include the selective reduction of β-enamino ester enan-
tiomers [14], enzyme-catalyzed kinetic resolution [15], and a
variety of asymmetric syntheses, for example, the enantioselect-
ive syntheses of β-lactams followed by ring opening [16,17], or
the enantioselective desymmetrization of achiral anhydrides fol-
lowed by Curtius degradation [18-20].
The highly stereoselective Michael addition of lithium amide-
type nucleophiles to α,β-unsaturated esters also proved to be a
very efficient and useful method for the preparation of alicyclic
β-amino acids in homochiral form [21,22]. Generally, in these
transformations, the source of chirality is served by chiral
lithium amides, and there are only few examples where chiral
α,β-unsaturated esters are applied [23-27].
Scheme 1: Reagents and conditions: (i) 2-methyl-2-butene, t-BuOH,
NaClO2 (aq), NaH2PO4 (aq), yield: 60%; (ii) (CF3CO)2O, dry toluene,
t-BuOH, rt, yield: 53%; (iii) 5% Pt/C, 1 atm H2, n-hexane/EtOAc 1:1,
12 h, rt, yield: 77%; (iv) 2-methyl-2-butene, t-BuOH, NaClO2 (aq),
NaH2PO4 (aq), yield: 58%; (v) (CF3CO)2O, dry toluene, t-BuOH, rt,
yield: 48%.
Easily obtainable chiral monoterpenes, such as (+)-3-carene as
well as all the enantiomers of pulegone, α-pinene and
verbenone, have frequently been used as starting materials for
the preparation of chiral reagents and as unique synthons in
asymmetric syntheses of β-amino acids and 1,3-amino alcohols,
which in turn can be applied as chiral additives, catalysts or NMR study of the crude product demonstrated the good stereo-
building blocks [17,28-34]. From this aspect, chiral, monoter- selectivity of the addition. The 1H NMR measurements of the
pene-based α,β-unsaturated esters might be excellent starting crude product indicated that all four possible diastereosomers
materials, in which the natural monoterpene skeleton may serve are formed in a ratio 7A:7B:7C:7D = 76:17:6:1 (Scheme 2).
as the chiral origin for the stereoselective construction of the The diastereoisomers 7A–D could be successfully separated
β-amino acid moiety.
through a two-step chromatographic process, and their relative
configurations were determined by 2D NMR techniques.
Our present aim was the synthesis of new, limonene-based Remarkable nOe correlations were observed between C2-H and
chiral β-amino acid derivatives derived from commercially C9-Me (10A and 10D), between C1-H and C8-H (10A), and a
available (−)-perillaldehyde (1). These 4-isopropyl-substituted weak effect was found between C1-H and C8-H (10B) (see
analogues of ACHC (2-aminocyclohexanecarboxylic acid) Figure 1 for numbering).
might serve as promising building blocks for the synthesis of
chiral 1,3-heterocycles and foldamers [7,11,23,35].
Amino esters 7A–D were transformed to the appropriate amino
acids 10A–D in three steps. The selective reduction of the
isopropenyl double bond over a Pt/C catalyst resulted in 8A–D.
Results and Discussion
The key intermediate Michael acceptor, tert-butyl perillate (3), The subsequent removal of the benzyl groups by hydrogeno-
was prepared by a combination of literature protocols, starting lysis over palladium on carbon (Pd/C) in a 1:1 mixture of
from commercially available (−)-(4S)-perillaldehyde (1) in a n-hexane/EtOAc for 24 h gave primary amino esters 9A–D in
two-step reaction. First, oxidation of 1 led to perillic acid (2) excellent yields. The final hydrolysis of the ester groups under
[36], which was subsequently converted to the tert-butyl ester acidic conditions successfully led to amino acids 10A–D.
(3) [37]. In order to study the steric effect of the more bulky iso-
propyl group on the Michael addition, (4S)-tert-butyl phellan- In addition to the NOESY experiments, the relative configur-
drate (6) was prepared via (4S)-phellandral (4) and (4S)-phel- ation of 10D was determined by means of X-ray crystallog-
landric acid (5) (Scheme 1) [38-40].
raphy (Figure 1).
The asymmetric Michael addition was accomplished by the The Michael addition was also carried out on 6, the 7,8-dihydro
reaction of in situ generated achiral lithium dibenzylamide with analogue of tert-butyl perillate (3), however the saturation of
compound 3 following a published protocol [23], to exploit the the isopropenyl function at position 4 proved to have no effect
effect of the isopropenyl group on the cyclohexene ring. An on the stereoselectivity of the reaction (Scheme 3).
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Beilstein J. Org. Chem. 2014, 10, 2738–2742.
Scheme 2: Reagents and conditions: (i) 2.4 equiv LiNBn2, dry THF, −78 °C, 6 h, then NH4Cl (aq), overall yield: 87% (isomeric mixture), ratio
7A:7B:7C:7D = 76:17:6:1; (ii) 5% Pt/C, n-hexane/EtOAc 1:1, 1 atm. H2, rt, 16 h, yield: 90–92%; (iii) 5% Pd/C, n-hexane/EtOAc 1:1, 1 atm H2, rt, 24 h,
yield: 92–95%; (iv) 10% HCl (aq), rt, 24 h, yield: 90–94%.
Scheme 3: Reagents and conditions: (i) 2.4 equiv LiNBn2, dry THF,
−78 °C, 6 h, then NH4Cl (aq), overall yield: 85% (isomeric mixture).
yield (Scheme 4). In addition to the NOESY examinations, the
relative stereochemistry of 11 was also proven through its
Figure 1: Structure of 10D and an ORTEP plot of its configuration.
conversion to 9A in two steps.
When N-benzyl-N-α-methylbenzylamine was applied as a chiral Applying (S)-N-benzyl-N-α-methylbenzylamide as a chiral
nucleophile in the conjugate addition, the steric effect of the lithium amide, only formation of the mixture of diastereoiso-
α-methyl substituent could be investigated. The addition was mers with very low yield (ca. 10%) was observed.
proven highly stereoselective (de > 99%), based on the
1H NMR data of the crude product and cis-amino ester 11 as a Under alkaline conditions, cis-amino esters 7A and 11 under-
single product was obtained in gram-scale quantities and high went isomerization at the carboxylic function, resulting in
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Beilstein J. Org. Chem. 2014, 10, 2738–2742.
Conclusion
In conclusion, the highly stereoselective Michael addition of
lithium dibenzylamide and (R)-N-benzyl-N-α-methylbenzyl-
amide to tert-butyl perillate (3) proved to be an efficient method
for the preparation of limonene-based β-amino acids through
the three-step transformation of the resulting N,N-dialkyl
β-amino esters 7A–D and 11. The minor component, trans-
amino acid 10D, was successfully prepared on gram-scale quan-
tities through the facile isomerization of the cis-amino esters
under alkaline conditions. It appears likely that the resulting
new monomers 10A–D incorporated in a β-peptide sequence
will be able to force the formation of unique β-helix or β-sheet
structures, thereby affording a novel route to promising
β-peptides.
Supporting Information
Scheme 4: Reagents and conditions: (i) 2.4 equiv lithium (R)-N-
benzyl-N-α-methylbenzylamide, dry THF, −78 °C, 6 h, then NH4Cl
(aq), yield: 88%; (ii) 5% Pt/C, n-hexane/EtOAc 1:1, 1 atm H2, rt, 16 h,
yield: 91%; (iii) 5% Pd/C, n-hexane/EtOAc 1:1, 1 atm H2, rt, 16 h, yield:
90%.
Supporting Information File 1
General information, experimental details, characterization
data and copies of 1H and 13C NMR spectra.
[http://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-10-289-S1.pdf]
trans-amino esters 7D and 13 in excellent yields (Scheme 5).
The relative stereochemistry of 13 was proven through its
conversion to 9D in two steps. This rapid and quantitative
isomerization allows the gram-scale synthesis of the minor
component amino acid 10D (see Scheme 2).
Acknowledgements
We are grateful to the Hungarian Research Foundation (OTKA
NK81371 and K112442) for financial support.
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