Diels–Alder reaction of two green chiral precursors. Approach to natural product like structures

Article abstract of DOI:10.1016/j.tetlet.2016.09.031

Diels–Alder cycloaddition between an enantiomerically pure protected cis-cyclohexadiene diol metabolite and optically pure levoglucosenone derived from cellulose gave rise to complex pentacyclic natural product like structures in a chemically succinct pro

Full text of DOI:10.1016/j.tetlet.2016.09.031

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Accepted Manuscript
Diels-Alder reaction of two green chiral precursors. Approach to natural product
like structures
Gonzalo Carrau, Nicolas Veiga, Leopoldo Suescun, Germán F. Giri, Alejandra
G. Suárez, Rolando Spanevello, David González
PII:
S0040-4039(16)31188-1
DOI:
http://dx.doi.org/10.1016/j.tetlet.2016.09.031
TETL 48101
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
21 July 2016
29 August 2016
7 September 2016
Please cite this article as: Carrau, G., Veiga, N., Suescun, L., Giri, G.F., Suárez, A.G., Spanevello, R., González,
D., Diels-Alder reaction of two green chiral precursors. Approach to natural product like structures, Tetrahedron
Letters (2016), doi: http://dx.doi.org/10.1016/j.tetlet.2016.09.031
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Diels-Alder reaction of two green chiral precursors.
Approach to natural product like structures.
Gonzalo Carrau,a Nicolas Veiga,b Leopoldo Suescun,c Germán F. Giri,d Alejandra
G. Suárez,d Rolando Spanevello,d and David González*a
a) Departamento de Química Orgánica, Fac. de Química, UdelaR, Montevideo -
Uruguay.
b) Departamento Estrella Campos, Fac. de Química, UdelaR, Montevideo -
Uruguay.
c) Cryssmat-Lab, Cátedra de Física, DETEMA, Fac. de Química, UdelaR,
Montevideo - Uruguay.
d) IQUIR, UNR, Rosario – Argentina.
Corresponding author’s e-mail address: davidg@fq.edu.uy
Abstract: Diels-Alder cycloaddition between an enantiomerically pure protected
cis-ciclohexadienediol metabolite and optically pure levoglucosenone derived from
cellulose gave rise to complex pentacyclic natural product like structures in a
chemically succinct process. The adducts were fully characterized and the
observed results were in accord with theoretical calculations performed on the
possible course of the reaction.

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Introduction
The quest for strategies to rapidly build structural diversity, often targeting complex
chiral molecules that resemble natural products, has emerged as route for the
discovery of new bioactive molecules.1 These structures are often called natural
product like (NPL) compounds and typically comprise molecules with several rings
and stereochemically defined chiral centers and double bonds. The interest in NPL
compounds becomes relevant when they are constructed by short synthetic
sequences. In that fashion, NPL compounds could incorporate the advantages of
natural products such as complexity and diversity, along with the benefits of typical
synthetic pharmaceutical molecules, such as the ease of preparation and structural
modification.2 In addition, the gain of considering NPL compounds among
potential drug candidates is increased when they are accessible via green routes
or renewable starting materials.3
Our groups have a tradition of working in green chemistry and biocatalysis. The
Uruguayan group has a tradition in biocatalysis and the exploitation in synthesis of
homochiral cyclohexadiene diols like compound 1 (Scheme 1) obtained by
microbial oxidation of aromatics.4 These metabolites have been utilized worldwide
for the synthesis of alkaloids, inositols, prostaglandins, and a wide array of natural
products and unnatural analogues. The results of these efforts have been reviewed
extensively,5 and to date cyclohexadiene diols are considered among the most
versatile chiral precursors.
The group in Argentina has made several contributions to synthetic methodology
working in the preparation and modification of levoglucosenone (compound 3,
Scheme 1), a chiral starting material obtainable from pyrolysis of cellulose. The
pyrolytic conversion of biomass into useful chemicals,6 has resulted in synthetic
applications of levoglucosenone (1,2-anhydro-3,4-dideoxy-β-D-glycero-hex-3-
enopyranos-2-ulose, 3) as a chiral building block for the development of new
methods for asymmetric synthesis.7 This versatile and easily available synthon
from the carbohydrate family can be produced in enantiomeric pure form by

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conventional pyrolysis of cellulose containing materials,8 such as waste paper, but
also by microwave (MW) irradiation of microcrystalline cellulose.9
The Diels-Alder reaction has been widely applied to the total syntheses of natural
products. The reaction itself has become a valuable tool in the development of
synthetic, mechanistic, and theoretical concepts, and this important role could be
attributed to its remarkable regio- and stereoselectivities.10 This versatility provides
a powerful means to challenge the construction of complex molecules.11 Both
levoglucosenone and cyclohexadiene diols are superb partners in Diels-Alder
reactions. Levoglucosenone has been studied as dienophile and cyclohexadiene
diol derivatives have been used in DA and hetero DA reactions as relevant
dienes.12 Interestingly, diol derivatives can also react as dienophiles as it can be
noted in the rapid dimerization of the corresponding acetonides.12c, 13 Along these
lines we decided to joint efforts and test the Diels-Alder reaction of
levoglucosenone (3) and the acetonide derivative 2 obtained from (1S,2R)-3-
methylcyclohexa-3,5-diene-1,2-diol (1), by reaction with dimethoxypropane in the
presence of a catalytic amount of p-toluenesulfonic acid.
Results and discussion
Chemical reactions
The presence of four chiral centers and a distinguished high degree of face
selectivity in both partners (2 and 3) suggested that they might render adducts of
elevated molecular complexity with a good degree of stereoselectivity. In fact, this
Diels-Alder reaction could afford up to eight stereoisomers depending on the facial
approach and orientation of the partners. Therefore, we can have endo and exo
products, ortho and meta Diels-Alder adducts, and finally  and β approaches (
refers to the approach of levoglucosenone from the α face of the diene) (Scheme
1).