Received: 26 November 2020
DOI: 10.1002/jhet.4286
Revised: 21 April 2021
Accepted: 3 May 2021
C O M M U N I C A T I O N
Catalytic Sc(OTf)3 mediated direct asymmetric aldol
reaction of (À)-menthyl isothiocyanatoacetate with
aldehydes by using (À)-menthol as chiral auxiliary
Dattatraya N. Bhangare1,2 | Rohit G. Shinde1 | Pushpalata D. Pawar1
Milind D. Nikalje1 | Mahendra N. Lokhande3
|
1Department of Chemistry, Savitribai
Abstract
Phule Pune University, Pune, India
2Department of Chemistry, Government
of Maharashtra's Ismail Yusuf College
Jogeshwari(E), Mumbai, India
3Department of Chemistry, Avvaiyar
Government College for Women Karaikal,
Puducherry (U.T.), India
This method involves the direct asymmetric aldol reaction of (À)-menthyl iso-
thiocyanatoacetate 5 with a variety of substituted aromatic aldehydes, which
offers a convenient method for the synthesis of intermediate containing biolog-
ically relevant α-amino β-hydroxyl groups in oxazolidine ring. In this method-
ology, the products show remarkable diastereoselectivity using Sc(OTf)3 as a
catalyst and easily accessible (À)-menthol as a chiral auxiliary. This approach
includes some important aspects such as mild reaction conditions, high yields,
and excellent diastereoselectivity with a number of substituted aromatic alde-
hydes. The optimization and effect of different catalysts were studied at differ-
ent reaction conditions and it is found that Sc(OTf)3 shows excellent
diastereoselectivity at À45ꢀC.
Correspondence
Milind D. Nikalje, Department of
Chemistry, Savitribai Phule Pune
University, Ganeshkhind, Pune 411007,
India.
Mahendra N. Lokhande, Department of
Chemistry, Avvaiyar Government College
for Women Karaikal, Puducherry (U.T.)
609602, India.
α-Amino acids (α-AAs) constitute one of the most impor-
tant families of natural products and are essential mole-
cules in a biological system and other scientific endeavor.1
Many natural and unnatural amino acids were synthesized
by diastereoselective addition of chiral auxiliary substituted
enolate over aldehyde. The previous method involves the
reaction of aldehyde with α-isothiocyanato imide or ester.2
In recent year the reaction which involves the formation of
C C bond by aldol reaction has gained much interest via
enolate or direct aldol adducts formation.3 In other reports
of related aldol reaction includes the organocatalytic
approach,4 metal enolate,5 and stoichiometric catalytic
Lewis acid and catalytic Lewis bases.6 Herein, we report
the diastereoselective aldol reaction for the synthesis of
α-amino β-hydroxyl using a catalytic amount of Sc(OTf)3.
Stability of Sc(OTf)3 toward water and moisture is a
unique feature inconsistent to that of the other Lewis acids
reported in the literature.7 In other method naturally
occurring (À)-menthol is used as a chiral auxiliary in the
form of (À)-menthyl isothiocyanatoacetate for direct aldol
reaction.8 In current methodology (Scheme 1), chiral
auxilary based reagent (À)-menthyl isothiocyanatoacetate
5 was prepared by three step sequential reaction of the
(À)-menthol 1 with chloroacetyl chloride 2 in presence
pyridine at 0ꢀC to afford compound 3 which on treatment
with sodium azide in DMF displaced chlorine by azido
functionality at 40ꢀC to get azido functionality 4 which
was then finally transferred to desired key intermediate
isothiocyanatoacetate 5 through aza-wittig reaction in CS2
as solvent at room temperature.9
In a typical experiment (Scheme 2), we tried asym-
metric aldol reaction of a chiral (À)-menthyl iso-
thiocyanatoacetate 5 with 4-nitrobenzaldehyde 6 in the
presence of scandium triflate as Lewis acid and the
diisopropylethylamine (Hünig Base) as a base to afford
product 7.
J Heterocyclic Chem. 2021;1–5.
© 2021 Wiley Periodicals LLC.
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