Application of dimedone enamines as dienophiles: stereoselective synthesis of amino enols of fused uracils containing a sugar moiety by hetero-Diels-Alder reactions of barbituric acid 5-ylidene alditols with dimedone enamines

Article abstract of DOI:10.1016/j.tet.2015.09.065

Dimedone enamines were applied for the first time as new dienophiles in hetero-Diels-Alder reactions with inverse electron demand. Cycloadditions of barbituric acid 5-ylidene alditols with dimedone enamines were performed in dichloromethane at room temperature for 3 days and fused uracils-chromeno[2,3-d]pyrimidine-2,4-diones were obtained in good 73-87% yields. Only one enantiomerically pure stereoisomer was obtained in each studied cycloaddition. Analysis of ¹H NMR and 2D NMR spectra allowed for the determination that cycloadducts exist in solution as mixture of the neutral form and dipolar ion. The prepared fused uracils contain both amine and enol functional groups, so share amphiprotic properties and they are zwitterions in solid state. The new class of compounds-amino enols was synthesized, which similarly to amino acids exists as zwitterions. In obtained cycloadducts amino groups and sugar moieties are close each other and they both are in cis configuration and in axial position. It was also shown that different alkenes can be used as dienophiles towards barbituric acid 5-ylidene alditols, for example, styrene or 1-amino-2-thiocarbamoyl-cyclopent-1-ene.

Full text of DOI:10.1016/j.tet.2015.09.065

Accepted Manuscript
Application of dimedone enamines as dienophiles: Stereoselective synthesis of amino
enols of fused uracils containing a sugar moiety by hetero-Diels-Alder reactions of
barbituric acid 5-ylidene alditols with dimedone enamines
Aleksandra Pałasz, Dariusz Cież, Bogdan Musielak, Justyna Kalinowska-Tłuścik
PII:
S0040-4020(15)30093-4
10.1016/j.tet.2015.09.065
TET 27162
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 31 July 2015
Revised Date: 14 September 2015
Accepted Date: 25 September 2015
Please cite this article as: Pałasz A, Cież D, Musielak B, Kalinowska-Tłuścik J, Application of dimedone
enamines as dienophiles: Stereoselective synthesis of amino enols of fused uracils containing a sugar
moiety by hetero-Diels-Alder reactions of barbituric acid 5-ylidene alditols with dimedone enamines,
Tetrahedron (2015), doi: 10.1016/j.tet.2015.09.065.
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ACCEPTED MANUSCRIPT
O
O
alditol
O
L-(+)-Arabinose
L-(-)-Xylose
D-(+)-Glucose
D-(+)-Galactose
X
O
O
X
Na sugar
X
N
Na
CO
N
N
2
3
o
Ac O, ZnCl
2
2
H
2
O, 80 C
r.t.
stirring
alditol
alditol O
OH
Y
O
N
X
O
O
N
X
O
O
N
X
O
O
X
X
CH
2
Cl
2
N
N
C-glycosides
r.t.
O
O
N
X
O
N
O
N
X
O
N
H
p-TSA
H
Y
Y-NH
2
H
EtOH, reflux
H
amino enols
zwitterion
O
N
Y
Application of dimedone enamines as dienophiles: Stereoselective synthesis of
amino enols of fused uracils containing a sugar moiety by hetero-Diels-Alder
reactions of barbituric acid 5-ylidene alditols with dimedone enamines
a*
a
a
b
Aleksandra Pałasz , Dariusz Cież , Bogdan Musielak , Justyna Kalinowska-Tłuścik
a
Department of Organic Chemistry, Faculty of Chemistry, Jagiellonian University, Ingardena
3
St, 30-060 Kraków, Poland, e-mail: palasz@chemia.uj.edu.pl, ciez@chemia.uj.edu.pl,
musielak@chemia.uj.edu.pl
b
Department of Crystal Chemistry and Crystal Physics, Faculty of Chemistry, Jagiellonian
University, Ingardena 3 St, 30-060 Kraków, Poland, e-mail: kalinow@chemia.uj.edu.pl
ABSTRACT
Dimedone enamines were applied for the first time as new dienophiles in hetero-Diels-Alder
reactions with inverse electron demand. Cycloadditions of barbituric acid 5-ylidene alditols
with dimedone enamines were performed in dichloromethane at room temperature for 3 days
and fused uracils - chromeno[2,3-d]pyrimidine-2,4-diones were obtained in good 73–87%
yields. Only one enantiomerically pure stereoisomer was obtained in each studied
1
cycloaddition. Analysis of H NMR and 2D NMR spectra allowed for the determination that
cycloadducts exist in solution as mixture of the neutral form and dipolar ion. The prepared
fused uracils contain both amine and enol functional groups, so share amphiprotic properties
and they are zwitterions in solid state. The new class of compounds – amino enols was
synthesized, which similarly to amino acids exists as zwitterions. In obtained cycloadducts
amino groups and sugar moieties are close each other and they both are in cis configuration
and in axial position. It was also shown that different alkenes can be used as dienophiles
1

ACCEPTED MANUSCRIPT
towards barbituric acid 5-ylidene alditols, for example styrene or 1-amino-2-thiocarbamoyl-
cyclopent-1-ene.
Keywords: Hetero Diels-Alder reactions, Enamines, Unprotected sugars, 1-Oxa-1,3-
butadienes, Uracils
1
. Introduction
Cycloaddition reactions provide rapid and elegant methods for the construction of
mono- and polycyclic systems. The development of new cycloreactants is a continuous
challenge in the field of pericyclic reactions. The use of hetero-substituted diene and
dienophiles is of specific interest for the application of Diels-Alder cycloadditions towards
natural and biologically active product synthesis. Hetero-Diels-Alder reactions of
α,β-
unsaturated carbonyl compounds representing an 1-oxa-1,3-butadiene system with electron
rich alkenes is an efficient method for 3,4-dihydro-2H-pyran derivatives which are valuable
precursors for the synthesis of many natural products such as carbohydrates, alkaloids and
1
antibiotics. These reactions have been classified as cycloadditions with inverse electron
2
demand. The reactivity of
α,β-unsaturated carbonyl compounds in hetero-Diels-Alder
3
4
reactions is generally low and the reactions require high temperature or high pressure. The
reactivity can be enhanced by introducing electron-withdrawing substituents into the 1-oxa-
5
1
,3-butadiene system and the application of dienophiles possessing electron-donating groups.
Aza-substituted dienophiles have been used more rarely than their oxygenated counterparts in
the current literature. Enamines participate in Diels-Alder reactions with inverse electron
demand with different classes of dienes, providing entry to highly complex molecular
6
frameworks. Electron-rich enamines have found use in inverse electron demand [4 + 2]
cycloadditions, but none have reported the use of weaker dienophiles such as enamines of
2

ACCEPTED MANUSCRIPT
dimedone. The first example of using dimedone enamines as the dienophile in inverse
electron demand heterocycloaddition is described in this paper.
Pyran derivatives are common structural subunits in a variety of important natural
products, including carbohydrates, alkaloids, polyether antibiotics, pheromones, and
1
a,1b
iridoids.
Uracils are considered as privileged structures in drug discovery with a wide
array of biological activities, synthetic accessibility and ability to confer druglike properties to
1
3
5
6
7
the compound libraries appended on them at N , N , C and C positions. Antiviral and anti-
8
tumor are the two most widely reported activities of uracil analogs ; however they also
9
possess herbicidal, insecticidal and bactericidal activities. Fused uracils, such as pyrano[2,3-
d]pyrimidines, pyrido[2,3-d]pyrimidines, pyrazo[3,4-d]pyrimidines or pyrimido[4,5-
d]pyrimidines are reported to have a wide range of biological activities such as antiallergic,
1
0
antihypertensive, cardiotonic, bronchodilator, antibronchitic or antitumor activity. The
preparation of the aforementioned compounds containing a pyran and an uracil ring poses a
significant synthetic challenge.
We have shown in our recent papers that intermolecular and intramolecular hetero-
Diels-Alder reactions are a powerful tool in 2H-pyran and policyclic 2H-pyran derivatives
1
1
synthesis. We described convenient and efficient procedures for the preparation of fused
uracils - pyrano[2,3-d]pyrimidine derivatives. It was shown that pyrano[2,3-d]pyrimidines
with an aryl substituent at carbon C(5) in the ring system can be efficiently synthesized by
1
1i
hetero-Diels-Alder reactions of 5-arylidene derivatives of barbituric acids with enol ethers.
It was also examined that, three-component one-pot reactions of barbituric acid, aromatic and
heteroaromatic aldehydes, and enol ethers in the presence of piperidine gave uracils in very
1
1i
good yields. Moreover, solvent-free hetero-Diels-Alder reactions of 5-arylidene derivatives
of barbituric acids with vinyl ethers were investigated at room temperature and pyrano[2,3-
1
1j
d]pyrimidines were obtained in excellent yields. Three-component one-pot syntheses of
3

ACCEPTED MANUSCRIPT
1
1j
fused uracils were also performed in aqueous suspensions. In our recent work we developed
a convenient and efficient procedure for the preparation of fused uracils containing a sugar
1
1m
moiety.
The reaction sequence was: Knoevenagel condensation of unprotected sugars and
N,N-dimethylbarbituric acid, acetylation of C-glycosides and hetero-Diels-Alder reaction.
Solvent-free hetero-Diels-Alder cycloadditions of O-acetylated pyrimidin-5-ylidene alditols
with enol ethers and cyclic enol ether were investigated at room temperature. Introducing a
sugar moiety instead of an aryl group at the C(5) position of pyrano[2,3-d]pyrimidine can
increase the potential pharmacological activity of the fused uracil. There have been several
advances in coupling of unprotected sugars with malonate-derived nucleophiles such as
1
2
13
barbituric derivatives or Meldrum’s acid. The use of water-soluble unprotected
carbohydrates allows the synthesis of compounds without a protection-deprotection protocol.
The Knoevenagel condensation under aqueous conditions is a very convenient method for the
1
4
preparation of pure β-C-glycosidic ketones in one step directly from an unprotected sugar.
Thus, reports in the area of hetero-Diels-Alder cycloadditions mainly concern the use
of vinyl ethers or simple enamines, but none have reported the use of cyclic enamines
possessing carbonyl function in position alpha to the ene. The 5-ylidene derivatives of
barbituric acids containing different sugar moieties seem to be excellent heterodienes in
hetero-Diels-Alder reactions. The efficiency of cycloadditions with enol ethers prompted us
to extend these reactions to cycloadditions with dimedone enamines.
2
. Results and discussion
Development of new cycloreactants is a continuous challenge in the field of pericyclic
reactions, thus efforts were undertaken to find new dienophiles for hetero-Diels-Alder
reactions with inverse electron demand which could concomitantly introduce important
functional groups such as amino or carbonyl groups into the prepared compounds. The aim of
the study was to investigate if different enamines of dimedone - 5,5-dimethyl-3-amino-
4

ACCEPTED MANUSCRIPT
cyclohex-2-en-1-one can act as active dienophiles in hetero-Diels-Alder reaction with inverse
electron demand. We also wanted to determinate the influence of substituents on the amino
group on reactivity and diastereoselectivity of cycloadditions.
The 5-ylidene derivatives of barbituric acids containing different sugar moieties were
chosen to act as heterodienes in hetero-Diels-Alder reactions because they react with enol
ethers and their use in cycloadditions allows the preparation of enantiomerically pure
1
1m
diastereoisomers of fused uracils - pyrano[2,3-d]pyrimidines.
First, barbituric acid 5-
ylidene alditols and different enamines of dimedone were synthesized. In the second step their
reactions were conducted. A convenient procedure for Knoevenagel condensation of
1
2a
barbituric acids and unprotected sugars in water was described by Gonzalez et al. The
Knoevenagel condensations of L-(+)-arabinose 1a, L-(-)-xylose 1b, D-(+)-glucose 1c and D-
(+)-galactose 1d with N,N’-dimethylbarbituric acid 2a or barbituric acid 2b in water solution
o
in the presence of sodium carbonate were performed at 80 C for 5 hours (Scheme 1).
X
X
N
R5
R5
R7
O
N
O
X
O
O
X
7
R
Na CO3
1O
2
R6
O
R
R6
1
o
R
H O, 80
C
R3
N
N
2
R3
OH
R2
R2
Na
4
4
O
R
O
R
3
a-e
2
a, 2b
2a: X=Me
b: X=H
c: D-(+)-Glucose, R =R =R =H, R =R =R =OH, R =CH OH
1
a-d 1
4
6
7
2
3
5
Ac O, ZnCl2
1
1
1
1
a: L-(+)-Arabinose, R =R =R =R =H, R =R =R =OH
2
1
4
5
2
3
6
7
2
r.t.
stirring
b: L-(-)-Xylose, R =R =R =OH, R =R =R =R =H
1
4
5
2
3
6
7
2
1
4
6
2
3
5
7
d: D-(+)-Galactose, R =R =R =H, R =R =R =OH, R =CH OH
2
7
1
4
6
7
2
3
5
R
3
3
3
3
3
a: L-(+)-Arabinose, R =R =R =R =H, R =R =R =OH, X=Me
R9
6
R8
1
4
5
2
3
6
7
b: L-(-)-Xylose, R =R =R =OH, R =R =R =R =H, X=Me
1
4
5
2
3
6
7
5
c: D-(+)-Glucose, R =R =R =H, R =R =R =OH, R =CH OH, X=Me
R
R
2
1
4
5
2
3
6
7
4
3
d: D-(+)-Glucose, R =R =R =H, R =R =R =OH, R =CH OH, X=H
R
R
R1
2
1
4
6
2
3
5
7
R2
e: D-(+)-Galactose, R =R =R =H, R =R =R =OH, R =CH OH, X=Me
2
O
1
4
6
7
9
2
3
5
8
X
4
4
4
4
4
a: L-Arabino, R =R =R =R =R =H, R =R =R =R =OAc, X=Me
N
1
4
5
8
2
3
6
7
9
b: L-Xylo, R =R =R =R =OAc, R =R =R =R =R =H, X=Me
1
4
5
8
2
3
6
9
7
c: D-Gluco, R =R =R =R =H, R =R =R =R =OAc, R =CH OAc, X=Me
2
O
N
X
O
1
4
5
8
2
3
6
9
7
d: D-Gluco, R =R =R =R =H, R =R =R =R =OAc, R =CH OAc, X=H
2
1
4
6
8
2
3
5
9
7
e: D-Galacto, R =R =R =R =H, R =R =R =R =OAc, R =CH OAc, X=Me
4a-e
2
Scheme 1. Knoevenagel condensations of sugars 1a-d with barbituric acids 2 and acetylation
reaction of C-glycosides 3a-e.
5

ACCEPTED MANUSCRIPT
Sodium 5-glycopyranosylbarbiturates 3a-e as condensation products, didn’t represent an 1-
oxa-1,3-diene system. However, as it is described that treatment of compounds 3a-e with
acetic anhydride and a large excess of zinc chloride gave the O-acetylated 2,4,6-trioxo-
1
2a
pyrimidin-5-ylidene derivatives 4a-e. Therefore, the mixture of anhydrous zinc chloride in
acetic anhydride and 3a-e was stirred at room temperature and compounds 4a-e were obtained
in good yields 75-89% after 24h ( Scheme 1).
The condensations of cyclic β-dicarbonyl compounds and amines have been widely
1
5
described in literature. Compounds 7a-i were synthesized by condensation of dimedone 5
with the appropriate amine 6a-i by refluxing in ethanol for 3-5 hours in the presence of p-
toluenesulfonic acid as catalyst (76-85% yield, Scheme 2, Table 1).
O
O
p-TSA
Y-NH2
EtOH, reflux
H
O
N
Y
5
6a-i
7a-i
Scheme 2. Condensations of dimedone 5 with aromatic or chiral aliphatic amines 6a-i.
Table 1. Synthesis of enaminones 7a-i by condensations of dimedone 5 with amines 6a-i
amine
Y-NH2
-NH
-NH
-NH
dimedone enamine
reaction time /h
yield/%
85
6a
C
6
H
5
2
7a
7b
7c
7d
7e
3
3
3
3
5
6b
4-MeC
4-MeOC
4-NO -C
6
H
4
2
83
82
81
78
6c
6
H
4
2
6d
2
NH2
6
H
4
-NH
2
6e
Me
Me
NH
2
6
f
7f
5
5
84
76
Me
Me
Me
Me
Me
NH
2
6g
7g
Me
Me
Me
6

ACCEPTED MANUSCRIPT
NH
2
6
h
7h
5
3
82
82
OH
6
i
7i
O
N H
The cycloaddition reactions of O-acetylated 2,4,6-trioxo-pyrimidin-5-ylidene
derivatives 4a-e with dimedone enamines 7a-i were performed in dichloromethane at room
temperature for 3 days and chromeno[2,3-d]pyrimidine-2,4-diones 8a-m were obtained in
good 73-87 % yields (Scheme 3, Table 2).
R7
R7
R7
R9
R6
R4
R2
R8
R5
R3
R9
R6
R4
R2
R8
R5
R3
R1
R9
R6
R4
R2
R8
R5
R3
1
1
R O
R OH
O
O
O
O
X
X
X
N
N
N
CH Cl
2
2
+
H
r. t.
O
N
X
O
H
O
N
X
O
O
N
X
O
N
Y
N
N
Y
H
Y
H
4a-e
7a-i
8a-m NF
8a-m
8a-m DI
Scheme 3. Hetero-Diels-Alder reactions of O-acetylated 2,4,6-trioxo-pyrimidin-5-ylidene
alditols 4a-e with dimedone enamines 7a-i.
Table 2. Synthesis of chromeno[2,3-d]pyrimidine-2,4-diones 8a-m by hetero-Diels-Alder
reaction of alditols 4a-e with enaminones 7a-i. The enaminones 7d and 7i didn’t react with
heterodienes 4
entry
4
sugar
X
7
Y-NH
cycloadduct
yield/%
8
1
2
3
4
5
6
7
8
9
4a
4e
4b
4c
4d
4e
4d
4e
4a
L-arabino
D-galacto
L-xylo
D-gluco
D-gluco
D-galacto
D-gluco
D-galacto
L-arabino
Me
Me
Me
Me
H
Me
H
Me
Me
7a
7a
7b
7b
7b
7b
7c
7c
7e
C H -NH
8a
8b
8c
8d
8e
8f
8g
8h
8i
82
84
81
78
79
83
75
83
86
6
5
C H -NH
6
5
4-MeC H -NH
6
4
4-MeC H -NH
6 4
4-MeC H -NH
6
4
4-MeC H -NH
6 4
4-MeOC H -NH
6
4
4-MeOC H -NH
6
4
NH
Me
Me
NH
1
0
1
4d
4e
D-gluco
H
7f
7f
8j
77
84
Me
Me
Me
Me
NH
1
D-galacto
Me
8k
Me
Me
Me
Me
7

ACCEPTED MANUSCRIPT
NH
1
2
3
4b
4a
L-xylo
Me
7g
8l
87
73
Me
Me
Me
Me
NH
1
L-arabino
Me
7h
8m
OH
1
1
1
4
5
6
4a
4c
4b
L-arabino
D-gluco
L-xylo
Me
Me
Me
7d
7d
7i
p-NO C H -NH
-
-
-
-
-
-
2
6
4
p-NO C H -NH
2
6
4
O
O
N
N
1
7
4e
D-galacto
Me
7i
-
-
It is worth noting that enaminones 7d and 7i didn’t react with heterodienes 4 (entry 14-17). In
case of 7d, it may be due to the electrono-withdrawing - NO group in para position of
2
phenyl group. In contrast to 7d, enaminones 7a, 7b and 7c poses respectively H, CH or
3
OCH groups in para position which are electrono-donating. The fact, that dienophile 7i
3
didn’t create cycloadducts with heterodienes 4, may be explained by the electronic nature of
the substituent and steric interactions. For hetero-Diels-Alder reactions of heterodienes 4a-e
and heterodienophiles 7a-i we should expect cycloadducts 8a-m possessing structure for
example 8c-A as it is depictured on Scheme 4 for reaction of compounds 4b and 7b.
4
'
4'
4'
CH
2
OAc
CH
'
2
OAc
CH
2
OAc
CH
2
OAc
3
3'
3'
H
OAc
H
OAc
H
OAc
H
OAc
2
'
2'
1'
2'
1'
AcO
H
AcO
H
AcO
H
AcO
H
1
'
H
O
OAc
H
O
OAc
O
H
O
OAc
H
O
OAc
O
O
OH
Me
O
Me
O
Me
O
Me
O
5
6
5
6
5
6
N
N
3 4
5a
7
8
N
2
3
4
N3
2
4
CH
2
Cl
2
7
8
7
8
+
2
1
O
0
r. t.
1
N
9
1
10
O
1
10
O
H
9
9
N
O
N
N
N
N
N
N
Me
Me
H
Me
H
Me
H
H
4b
7b
8c-A
8c-NF
8c-DI
Me
Me
CH2 OAc
OAc
Me
CH
2
OAc
Me
H
OAc
H
AcO
H
AcO
H
H
O
OAc
O
H
OAc
O
OH
Me
O
Me
O
N
N
N
O
N
N
O
N
Me
Me
H
H
8
c-B
8c-C
4
'
Me
Me
4'
CH
'
2
OAc
4'
CH
2
OAc
CH
2
OAc
3
H
OAc
3'
H
OAc
3'
H
OAc
2
1
'
Me
AcO
H
2'
1'
CH3
AcO
H
2'
1'
Me
AcO
H
'
H
OAc
NH
6
O
H
O
OAc
H
O
OAc
Me
O
NH
NH
2
N
3 4
5
Me
O
5
6
Me
O
5
a
7
N3
2
4
5
6
7
8
N3
2
4
5a
2
9a
8
5a
7
8
10
1
9
10
N
O
1
N
9
1
N
10
O
9
O
Me
O
Me
OH
8
c-D
Me
O
8c-E
8c-F
8

ACCEPTED MANUSCRIPT
Scheme 4. Hetero-Diels-Alder reactions of barbituric acid 5-ylidene derivative 4b with
enaminone 7b. Cycloadduct 8c does not exist in 8c-A form. Compound exists as mixture of
the neutral form NF / dipolar ion DI (ratio of 8c-NF / 8c-DI 0.6 : 0.4 = 1.5 : 1).
Expected cycloadduct 8c-A has three stereocenters, so eight stereoisomers can be formed.
Only one enantiomerically pure stereoisomer was obtained in each studied cycloaddition of
compounds 4a-e, 7a-c and 7e-h so examined cycloadditions are completely stereoselective.
1
The structure of cycloadducts 8a-m is discussed using 8c as an example. In the H NMR
spectrum of 8c there is characteristic for enol proton OH singlet at
δ = 16.91 ppm. The proton
5
a-H in structure 8c-A is acidic and cycloadduct 8c exists as tautomeric enol form 8c-NF
1
(
Scheme 4). Analysis of H NMR of compounds 8a-m and 2D NMR spectra of compound 8c
allowed us to determinate that cycloadducts 8a-m exist as mixture of the neutral form 8a-m
NF and dipolar ion 8a-m DI (Scheme 3, Table 3). The ratios of the NF/DI of 8a-m were
1
determined on basis of analysis of integrations for the signals of 5-H and 1’-H protons in H
1
NMR spectra. In the H NMR spectra of the compounds 8a-m, the proton attached to C-5
3
give rise to a doublet with coupling constant J = 8.4-10.2 Hz at
δ = 4.14-5.22 ppm due to
coupling with proton at C-1’ (Table 3). Thus, on the basis of the signals of proton 5-H
analysis we can determinate that compounds 8a-m don’t exist in form like 8c-A because in
1
the H NMR spectrum of 8c-A the signal of 5-H should appear as a doublet of doublet due to
coupling with protons 1’-H and 5a-H (Scheme 4). The ratio of the neutral form NF and
dipolar ion DI change in the range from NF/DI 0.65:0.35 = 1.86:1 for cycloadduct 8j to
NF/DI 0.4:0.6 = 1:1.5 for compound 8e.
Table 3. The ratios of the neutral form NF / dipolar ion DI of the chromeno[2,3-
1
d]pyrimidine-2,4-diones 8a-m. Signals of proton 5-H both forms NF and DI in H NMR
spectra of 8a-m
8
sugar
X
Y-NH
ratio
NF:DI
0.6 : 0.4
0.5 : 0.5
0.6 : 0.4
doublet 5-H ΝF/DI
ΝF
=4.37, J1’,5 =9.6 /
=4.29, J1’,5 =10.2 / =4.43, J1’,5 =10.2
=4.41, J1’,5 =9.6 / δ =4.55, J1’,5 =10.2
δ
(ppm), J1’,5 (Hz)
a
/
DI
8a
L-arabino Me
D-galacto Me
L-xylo
C
C
6
6
H -NH
5
H -NH
5
6
δ
δ
δ
δ =4.50, J1’,5 =10.2
δ
8b
8c
Me
4-MeC
H
4
-NH
9

ACCEPTED MANUSCRIPT
8
8
8
8
8
8
d
e
f
g
h
i
D-gluco
D-gluco
D-galacto Me
D-gluco
D-galacto Me
L-arabino Me
Me
H
4-MeC
4-MeC
4-MeC
4-MeOC
4-MeOC
NH
6
6
6
H
H
H
4
4
4
-NH
-NH
-NH
0.55 : 0.45
0.4 : 0.6
0.6 : 0.4
0.4 : 0.6
0.5 : 0.5
0.6 : 0.4
δ
δ
δ
δ
δ
δ
=4.39, J1’,5 =10.2 / δ =4.53, J1’,5 =10.2
=5.22, J1’,5 =8.4 /
=4.29, J1’,5 =9.6 /
=4.38, J1’,5 =9.0 /
=4.28, J1’,5 =9.6 /
δ
=5.28, J1’,5 =8.4
=4.44, J1’,5 =10.2
=4.49, J1’,5 =9.0
=4.44, J1’,5 =10.2
δ
δ
δ
H
H
H
-NH
-NH
6
4
6
4
=4.14, J1’,5 =10.2 / =4.48, J1’,5 =10.2
δ
Me
Me
8
j
D-gluco
H
NH
0.65 : 0.35
0.5 : 0.5
δ
δ
δ
δ
=4.48, J1’,5 =10.2 / δ =4.70, J1’,5 =10.2
Me
Me
Me
Me
Me
Me
8k
D-galacto Me
NH
=4.15, J1’,5 =9.6 /
=4.27, J1’,5 =10.2 /
=4.32, J1’,5 =10.2 /
δ =4.49, J1’,5 =10.2
Me
Me
Me
8
l
L-xylo
Me
NH
0.6 : 0.4
δ
=4.57, J1’,5 =10.2
Me
Me
Me
NH
8
m L-arabino Me
0.55 : 0.45
δ =4.56, J1’,5 =10.2
OH
a
The ratios of the NF/DI of 8a-m determined on the basis of analysis the signals of proton 5-
1
H and 1’-H in H NMR spectra.
All compounds 8a-m contain amino and enol functional groups, they share amphiprotic
1
properties. On base H NMR spectra (CDCl ) we determinate that for compounds 8a, 8c, 8d,
3
8
f, 8i, 8j, 8l and 8m, the predominant form have a neutral hydroxyl group and neutral amino
group. Dipolar ion form of compounds 8e and 8g is a major species in CDCl solution. For
3
compounds 8b, 8h and 8k equimolar amounts of both forms exist in CDCl . We can also
3
1
deduce that compound 8c is a cycloadduct and not a Michael adduct 8c-B because in the H
NMR spectrum of 8c-B the signal of proton at carbon connecting barbituric acid, sugar and
amine moiety should appeared as a doublet of doublets (Scheme 4). To confirm that
1
cycloadducts 8a-m exist as mixture of the neutral form NF and dipolar ion DI, the H NMR
spectrum of compound 8c in CDCl with drop of triethylamine was measured (Figure 1).
3
1
Extensively discussion and comparison of H NMR spectra of 8c without and with
triethylamine there is in Supplementary data.
1
0

ACCEPTED MANUSCRIPT
1
1
Fig. 1. Part of H NMR spectrum of 8c without triethylamine (top) and part of H NMR
spectrum of 8c with triethylamine (bottom).
It is worth noting that in IR spectra of compounds 8a-m the characteristic bands for O-H and
N-H groups aren’t present (Supplementary data). It suggests that cyloadducts 8a-m exist as
zwitterions in solid state.
1
1

ACCEPTED MANUSCRIPT
On the basis of analysis of HMBC spectrum of compound 8c we can confirm that this
compound isn’t the enol form 8c-C of Michael adduct (Scheme 4). In the HMBC spectrum of
cycloadduct 8c, there are cross peaks between signals of enol carbons (
δ
= 194.9 ppm,
= 2.10-2.50
δ
= 192.3 ppm) and signals of protons of methylene groups C(7)-H and C(9)-H (
δ
ppm) (Figure 2). This correlation can’t be observed for 8c-C form because in this form enol
carbon and protons of methylene groups are separated by six bonds.
Fig. 2 Part of HMBC spectrum of compound 8c recorded in CDCl . Cross peaks for signals of
3
enol carbons (
δ
= 194.9 ppm,
δ = 192.3 ppm) and signals of protons of methylene groups
C(7)-H and C(9)-H (
δ
= 2.10-2.50 ppm).
According to regioselectivity of hetero-Diels-Alder reactions of 1-oxa-1,3-dienes with enol
1
1m
ethers we can deduced that regioisomer 8c-A should be the only product (Scheme 4).
However, in studied cycloadditions we should take into account the possibility of creation of
1
regioisomer 8c-D. In the H NMR spectrum of 8c-D the signal of proton C(9a) should be a
1
singlet at
δ
= 5-6 ppm. There isn’t signal like this in H NMR spectrum of 8c. On the basis of
analysis of NOESY spectrum of compound 8c we can also determine that this compound isn’t
enol form 8c-E of regioisomer 8c-D (Scheme 4). In the NOESY spectrum of cycloadduct 8c,
1
2

ACCEPTED MANUSCRIPT
there is cross peak between signal of enol proton at
δ
= 16.91 ppm and signal of proton 1’-H
at
δ
= 6.49 ppm (0.6H, dd, J 1.8, 9.6 Hz) (Figure 3). This correlation can’t be observed for
8
c-E form because in this form enol proton and 1’-H proton are far from each other in space.
Fig. 3 NOESY spectrum recorded in CDCl for compound 8c. Highlighted signals correspond
3
to key NOE correlations. In blue and red boxes are shown respectively the correlations of enol
proton OH with 5-H and 1’-H. In magenta and green boxes are marked the correlations of the
sugar chain protons 1’-H and 4’-H with ammonium group protons which confirm the cis
axial-axial conformation of both substituents.
To unambiguously determine the R, S configuration at stereogenic centeres C(5) and
C(9a), the crystal structures of compounds 8a-m should be studied. Obtaining of crystals
suitable for X-ray analysis was problematic. Crystallization was unsuccessful. However, on
basis of analysis of NOESY spectrum of cycloadduct 8c and analysis of molecule 8c model
we can determinate that this compound has (5R, 9aR) or (5S, 9aS) relative configurations at
stereogenic centeres. Cross peaks which there are in NOESY spectrum of compound 8c can
1
3

ACCEPTED MANUSCRIPT
be observed only for stereoisomers with configurations (5R, 9aR) or (5S, 9aS) in which sugar
moiety and amino moiety are close each other and they both are axial (Figure 4).
OAc
H
4
'
H
AcO
H
H
H
HO
AcO
H
HO
1
'
AcOH
AcO H
Me
H
O
N
O
O
N
O
5
R
5
S
N
1
'
Me
Me
AcO
9
aR
O H
9aS
Me
Me
O
H
Me
Me
Me
AcO
N
H
N
H
N
NF
Me AcO
H
Me
4
'
NF
H
AcO
OAc
H
4
'
O
H
H
AcO
H
O
H
5
R
H
1
'
O
Me
AcO
1
'
AcO
Me
AcO
H
9
aR
H
O H
O
N
O
H
Me N
O
H
Me
Me
AcO
AcO H
5
S
N
N
H
H
Me
N
H
9aS
Me AcO
H
Me
O
Me
4
'
H
AcO
N
DI
DI
(5S,9aS)-8c
Me
(
5R, 9aR) - 8c
Fig.4. Key NOE correlations of neutral form NF and dipolar ion DI of cycloadduct 8c.
In case of equatorial orientation of sugar substituent or amino group, appropriate cross peaks
can’t be observed in NOESY spectrum because hydrogen atoms for which we observe cross
peaks are too far each other. In NOESY spectrum of 8c there is cross peak for correlation of
enol proton of neutral form NF of 8c (
δ = 16.91 ppm) and 5-H proton (δ = 4.55 ppm) (Figure
3
). On basis of analysis of 8c model we can see that this correlation can be observed only for
equatorial orientation of 5-H because axial 5-H is too far from OH attached to enol carbon
2
with sp hybridization. The cross peak is also observed for signal of enol proton
δ
= 16.91
ppm and signal of 1’-H
δ = 6.48 ppm (Figure 3). In NOESY spectrum of 8c there are two
cross peaks which are important for determination of compound configuration and its
conformation. First of them presents correlation of one from two protons of ammonium group
1
4

ACCEPTED MANUSCRIPT
+
NH -C H -CH (
δ
= 12.32 ppm) and 1’-H proton (
correlation with the second proton of the ammonium group (
= 4.42 ppm) (Figure 3). It means that ammonium group and sugar moiety are close each
δ
= 6.56 ppm) and second of them shows
2
6
4
3
δ
= 10.94 ppm) and 4’-H proton
(
δ
other and it is possible only for conformation in which they both are in axial position. In
consequence the relative configuration at stereogenic centers must be (5R, 9aR) or (5S, 9aS).
The same configurations at the C-5, C-9a stereogenic centers and relative cis configuration of
sugar and ammonium substituents for remaining compounds 8a-b and 8d-m were assigned
(Figure 5). It was made on basis of comparison of chemical shifts and coupling constant
values of the protons attached to C-5, C-1’ of compound 8c with coupling constants values of
the protons 5-H and 1’-H of remaining compounds 8.
HO
alditol HO
H
O
N
O
O
N
O
H
5
R
5S
NHY
Me
Me
Me
Me
alditol
O
9
aR
9
aS
X
X
O
NHY
N
N
X
X
O
alditol
O
H
O
N
O
O
N
O
H
5
R
5S
NH Y
2
Me
Me
Me
Me
alditol
O
9
aR
9
aS
X
X
O
NH Y
2
N
N
X
5R, 9aR) - 8a-m
X
(5S,9aS)-8a-m
(
Fig. 5. Preferred cis configurations and axial-axial conformations of cycloadducts 8a-m based
on the NOESY analysis.
The 5-ylidene derivatives of barbituric acids 4 containing different sugar moieties are
1
1m
active heterodienes in hetero-Diels-Alder reactions with inverse electron demand. The high
reactivity of molecules of heterodienes 4 follows the fact that each hydroxyl group of sugar
chain is protected by electrono-withdrawing acetyl group. The results of mentioned
cycloadditions prompted us to extend these reactions to cycloadditions with another
heterodienes. Bellow we present the result of a preliminary test-reaction with styrene as
1
5

ACCEPTED MANUSCRIPT
dienophile and one example of trial reaction with 1-amino-2-thiocarbamoyl-cyclopent-1-ene
as dienophile. Styrenes are known as efficient dienophiles in conventional Diels-Alder
cycloadditions, however in cycloadditions with inverse electron demand they react
1
1d
reluctantly.
The cycloaddition reaction of pyrimidin-5-ylidene-L-arabinitol 4a with α-
methylstyrene 9 was performed in dichloromethane at room temperature for 3 days and
pyrano[2,3-d]pyrimidine-2,4-diones 10a and 10b were obtained in good 82% yields (Scheme
5
).
CH OAc
2
CH OAc
CH OAc
2
2
H
H
OAc
OAc
H
H
H
OAc
OAc
H
H
H
OAc
OAc
H
AcO
O
AcO
O
AcO
O
Me
H
H
Me
O
Me
O
N
CH Cl
5R
5R
2
2
N
N
+
+
r. t.
Me
Me
O
N
O
Me
N
O
N
O
Me
Me
Me
4
a
9
10a major
10b minor
Scheme 5. Hetero-Diels-Alder reaction of pyrimidin-5-ylidene-L-arabinitol 4a with styrene 9.
Four different diastereoisomers can be formed in the hetero-Diels-Alder reactions of
compounds 4a and 9. Only two diastereoisomers were obtained in studied cycloaddition.
Thus, the examined reaction characterized by high diastereoselectivity which resulted in two
enantiomerically pure diastereoisomers. The ratio of 10a major/10b minor 2:1 was
1
determined on the basis of H NMR spectrum of crude product, analyzing the signals of
protons 5-H or 1’-H. Two diastereoisomers of 10 were separated by column chromatography.
1
Analysis of H NMR spectra of compounds 10 do not allow the configuration R, S to be
1
assigned with certainty. The compounds 10 are oils, so X-ray analysis is impossible. In the H
NMR spectrum of the major diastereoisomer 10a the signal of 5-H appeared as a multiplet at
1
δ
= 3.30 ppm. The H NMR spectrum of 10a reveal the signals of protons 6-H as a doublet of
3
3
doublets at
δ = 2.19 ppm with coupling constant J = 11.4 Hz and J = 14.4 Hz, and at δ =
1
6

ACCEPTED MANUSCRIPT
3
3
3
2
1
.34 ppm with coupling constant J = 7.2 Hz and J = 14.4 Hz. The coupling constant J =
3
3
4.4 Hz corresponds to 6-H protons geminal coupling and the values J = 7.2 Hz / J = 11.4
Hz relate to coupling with 5-H. Thus, on the basis of the coupling constants analysis, 5-H is
axial and the sugar moiety occupies the equatorial position (Figure 6).
alditol
alditol
alditol
alditol
O
5
R
O
O
5
R
5R
O
Me
or
5R
Ph
Ph
Me
H
7S
H
7R
H
7R
H
7S
Ph
Me
Me
Ph
Minor 10b
Major 10a
Minor 10b
Major 10a
1
Fig. 6. Preferred configurations and conformations of cycloadducts 10 based on the H NMR
analysis.
For the minor diastereoisomer 10b the proton attached to C-5 give rise to a doublet of doublet
3
3
of doublets with coupling constants J = 1.2 Hz, J = 6.6 Hz and 10.8 Hz at
δ = 2.79 ppm.
3
The first value of constant J = 1.2 Hz refers to coupling with 1’-H. Two large coupling
constants related with 6-H protons coupling indicate that 5-H is axial and the alditol moiety
occupies the equatorial position (Figure 6). Diastereoisomers 10a and 10b differ of
orientation of methyl and phenyl groups at C-7.
Next, we tested the cycloaddition reaction of pyrimidin-5-ylidene-L-arabinitol 4a with
1
-anilino-2-phenylthiocarbamoyl-cyclopent-1-ene 11 as dienophile. Compound 11 was
1
6
prepared according to the method described in the literature from N-cyclopentylidene-
aniline and phenylisothiocyanate. Potential dienophile 11 possess an enamine system and
additionally thiocarbamoyl group. Reaction was performed in dichloromethane at room
temperature for 3 days and cyclopentano[6,5]pyrano[2,3-d]pyrimidine-2,4-dione 12 was
prepared with 76% yields (Scheme 6). This test-reaction also reveals high reactivity of
compounds 4 in hetero-Diels-Alder reactions with different dienophiles. Probably, not only
derivatives of N-cyclopentylidene-amine and phenylisothiocyanate 11 can be used as
dienophiles, also N-cyclohexylidene or N-cycloheptylidene-amine and phenylisothiocyanate
1
7

ACCEPTED MANUSCRIPT
or phenylisocyanate derivatives can be applied. The hetero-Diels-Alder reactions of
compounds 4 with different dienophiles allow rapid access to a number of fused uracils
containing sugar moiety and pyran ring condensed with rings consisting of five, six or seven
atoms.
CH OAc
CH OAc
2
2
H
H
OAc
OAc
H
H
H
OAc
OAc
AcO
O
NHPh
AcO
O
H
CSNHPh
Me
O
S
C
Me
O
N
CH Cl2
N
2
+
r. t.
H
N
O
N
O
N
NHPh
Me
Me
Ph
12
4
a
1
1
Scheme 6. Hetero-Diels-Alder reaction of pyrimidin-5-ylidene-L-arabinitol 4a with 1-anilino-
-phenylthiocarbamoyl-cyclopent-1-ene 11.
2
Eight different diastereoisomers can be formed in the hetero-Diels-Alder reactions of
compounds 4a and 11. The studied reaction is completely stereoselective because only one
1
diastereoisomer was obtained. Unfortunately, on the base of simple analysis of H NMR
spectrum of compounds 12 we can only determinate its structure as it is show on Scheme 6.
The NMR analysis doesn’t allow to determinate the stereochemistry this compound. Crystal
structure determination was also impossible because compound 12 is a gel. Our plan was to
show high reactivity of dienophiles 4 and indicate of directions of future research. In our
opinion determination of absolute configurations and conformations of compounds 10a, 10b
and 12 goes beyond this paper.
At the end, we hint that obtaining of crystals suitable for X-ray analysis was
problematic. However, it is worth noting that some crystals of compound 13 (Figure 7)
suitable for X-ray analysis were unexpectedly obtained in trace amounts as the result of
crystal preparing of compound 8c. Prepared crystals of compound 13 represent an oxirane
1
8

ACCEPTED MANUSCRIPT
structure. We studied if preparing of compound 13 is possible by refluxing for a long time
(1h) of cycloadduct 8c in solvents which were used for crystallization. Compound 8c did not
subject to decomposition to compound 13. Formation of unexpected side product –
spiro[pyrimidine-5,2’-oxirane] 13 can be explained as the result of oxidation of compound 4b
in the presence of zinc chloride during of synthesis of 4b from 3b (Scheme 1). The compound
4
b was substratum for synthesis of 8c (Scheme 3) and therefore crystals of oxirane 13 were
prepared during of compound 8c crystallization.
2
CH OAc
H
OAc
H
AcO
H
O
OAc
H
Me
N
S
O
13
O
N
O
Me
Fig. 7. Structure of side product – spiro[pyrimidine-5,2’-oxirane] 13. Molecular geometry
observed in the crystal structures of compound 13 showing the atom labelling scheme.
Displacement ellipsoids of non-hydrogen atoms are drawn at the 30% probability level. H
atoms are presented as small spheres with an arbitrary radius.
As it is shown on the perspective view of molecule 13 the absolute configuration at C-7 is S
(Figure 7).
3
. Conclusion
1
9

ACCEPTED MANUSCRIPT
In summary, a convenient and efficient methods for the synthesis of fused uracils,
namely chromeno[2,3-d]pyrimidine-2,4-diones containing different sugar moieties, enol
moiety and different amino groups of potential pharmacological activity, were described.
Dimedone enamines were used for the first time as dienophiles in hetero-Diels-Alder
reactions. The new procedure of enaminones synthesis was used: condensation of dimedone
with aromatic or chiral aliphatic amine by refluxing in ethanol in the presence of p-
toluenesulfonic acid as catalyst. The cycloaddition reactions of O-acetylated 1,3-dimethyl-
2
,4,6-trioxo-pyrimidin-5-ylidene alditols, representing a 1-oxa-1,3-butadiene system, with
dimedone enamines were performed in dichloromethane at room temperature for 3 days and
only one enantiomerically pure cis diastereoisomer of chromeno[2,3-d]pyrimidine-2,4-diones
was obtained in each reaction in good 73-87 % yields. Analysis of NMR spectra allowed the
determination that prepared fused uracils containing amino and enol functional groups exist
as mixture of the neutral form and zwitterions. It was also showed that different enes can be
used as dienophiles towards barbituric acid 5-ylidene alditols. These studies show that
different enamines of dimedone can act as active dienophiles in hetero-Diels-Alder reaction
with inverse electron demand. By this simple hetero-Diels-Alder reaction we can introduce
into fused uracil systems such important for biological interaction groups as: different sugar
moieties, enol moiety and different amino groups.
4
4
. Experimental
.1. General
Melting points were determined on a Boetius hot stage apparatus. IR spectra: Nicolet IR 200
FT-IR Thermo Scientific (with diamond stand) as film or powder. All NMR experiments were
performed with a 600 MHz spectrometer. Chemical shifts (
δ
in ppm) are referenced to the
1
13
solvent CDCl (
δ = 7.26 ppm for H and 77.0 ppm for C NMR). Optical rotations were
3
2
0

ACCEPTED MANUSCRIPT
measured with a P-2000 Jasco polarimeter. Microanalyses were performed with Euro EA
3
000 Elemental Analyzer.
4
.2. Materials
Sugars: L-(+)-arabinose 1a, L-(-)-xylose 1b, D-(+)-glucose 1c, D-(+)-galactose 1d, N,N’-
dimethylbarbituric acid 2a, barbituric acid 2b, acetic anhydride, anhydrous ZnCl , dimedone
2
5
, amines 6a-i and
α-methylstyrene 9 were commercially available. Sodium 5-
glycopyranosyl-1,3-dimethylbarbiturates 3a-e were obtained according to the procedure
1
2a
described in the literature.
1-Anilino-2-phenylthiocarbamoyl-cyclopent-1-ene 11 was
1
6
prepared according to the method described in the literature.
4
.3 General procedure for acetylation
To a solution of anhydrous zinc chloride (10.0 g, 73.5 mmol) in acetic anhydride (50 mL) was
added the sodium 5-glycopyranosylbarbiturate 3a-e (4 mmol). The mixture was stirred for 1h
and next it was kept for 24 h at room temperature. The solution was then poured in to ice-
water. After that, the mixture was extracted with chloroform. The combined organic layers
were dried over MgSO and the solvent was evaporated under reduced pressure. The oily
4
residue was purified by crystallization from ethanol to give 4a-e with yields 75-89%.
4
.3.1. 2,3,4,5,6-Penta-O-acetyl-1-deoxy-1-(2,4,6-trioxo-1H,3H,5H-pyrimidin-5-ylidene)-D-
o
glucitol (4d). White solid (1.460 g, 73%); m.p. 183–185 C; R (20:1 CHCl /MeOH) 0.35;
f
3
2
7
[
α]D +7.2 (c 0.39, CHCl ); IR (neat) ν 3281, 3208, 3112, 3029, 2780, 1782, 1741, 1700,
3
-
1 1
1
8
2
3
625, 1520, 1463, 1444, 1379, 1360, 1249, 1207, 1032 cm ; H NMR (600 MHz, CDCl ) δ
3
.41 (1H, s, N-H), 8.34 (1H, s, N-H), 7.47 (1H, d, J 7.2 Hz, 1’-H), 6.50 (1H, dd, J 3.0, 7.2 Hz,
’-H), 5.63 (1H, dd, J 3.0, 6.0 Hz, 3’-H), 5.58 (1H, dd, J 5.4, 6.0 Hz, 4’-H), 5.13 (1H, ddd, J
.0, 5.4, 7.2 Hz, 5’-H), 4.41 (1H, dd, J 3.0, 12.6 Hz, 6’-H), 4.22 (1H, dd, J 6.6, 12.6 Hz, 6’-
2
1

ACCEPTED MANUSCRIPT
H), 2.20 (3H, s, COCH ), 2.10 (3H, s, COCH ), 2.07 (3H, s, COCH ), 2.06 (3H, s, COCH ),
3
3
3
3
1
3
2
.04 (3H, s, COCH3); C NMR (151 MHz, CDCl3)
δ 170.7, 169.9, 169.7, 160.3, 160.2,
1
48.0, 120.7, 70.4, 70.1, 69.4, 69.1, 61.5, 20.8, 20.7, 20.6, 20.4; Anal. Calcd for C H N O :
2
0
24
2
13
C, 48.00; H, 4.83; N, 5.60. Found: C, 48.34; H, 5.05; N, 5.32.
4
.4 General procedure for synthesis of enaminones 7a-i
To a solution of dimedone 5 (2.8 g, 20 mmol) in 50 mL of ethanol was added amine 6a-i (21
mmol) and catalytic amount of p-toluenesulfonic acid and the mixture was refluxed for 3-5 h.
The progress of the reactions was monitored by TLC (20:1 CHCl /MeOH). Evaporation of the
3
mixture to dryness and two crystallizations from: 7a-d, 7i (ethanol), 7f, 7g (n-hexane), 7h
(ethanol/n-hexane 1:2) provided products 7a-i with 76-85 % yields listed in Table 1.
.
4
.4.1. 5,5-dimethyl-3-(N-2’S-hexanoyl)-cyclohex-2-en-1-on (7e). Yellow oil; (3.48 g, 78%);
2
D
7
R (20:1 CHCl /MeOH) 0.41; [α]
-21.9 (c 0.28, CHCl ); IR (neat) ν 3241, 3063, 2955,
3
f
3
-
1 1
2
928, 2863, 1531, 1456, 1374, 1270, 1250, 1149 cm ; H NMR (600 MHz, CDCl )
δ
5.09
1H, s, 2-H), 4.49 (1H, d J 6.0 Hz, N-H), 3.43 (1H, m, CH), 2.15 (2H, s, 6-H), 2.14 (2H, s, 4-
H), 1.50 (1H, m, CH ), 1.41 (1H, m, CH ), 1.21-1.31 (4H, m, CH ), 1.14 (3H, d, J 6.0 Hz,
3
(
2
2
2
1
3
CH ), 1.04 (6H, s, 5-CH ), 0.86 (3H, t, J 7.2 Hz, CH ); C NMR (151 MHz, CDCl )
δ
196.5,
61.7, 95.4, 50.2, 48.3, 44.1, 36.3, 32.7, 31.6, 28.3, 28.2, 25.6, 22.5, 20.1, 13.9; Anal. Calcd
for C H NO: C, 75.28; H, 11.28; N, 6.27. Found: C, 75.44; H, 11.59; N, 6.45.
3
3
3
3
1
1
4
25
4
.4.2. 5,5-dimethyl-3-(N-2’S-(3’,3’-dimethybutyl))-cyclohex-2-en-1-on (7f). Yellow solid
o
27
(
3.30 g, 74%); m.p. 178–180 C; R (20:1 CHCl /MeOH) 0.45; [α] -342.1 (c 0.14, CHCl3);
f 3 D
IR (neat) ν 3266, 3228, 3058, 2956, 2926, 2871, 1591, 1527, 1460, 1374, 1270, 1248, 1150,
-1 1
1
128 cm ; H NMR (600 MHz, CDCl ) δ 5.15 (1H, s, 2-H), 4.37 (1H, br, N-H), 3.27 (1H,
3
2
2

ACCEPTED MANUSCRIPT
dq, J 6.6, 9.6 Hz, CH), 2.17 (2H, s, 6-H), 2.16 (2H, s, 4-H), 1.07 (3H, d, J 6.6 Hz, CH ), 1.04
3
13
(
3H, s, 5-CH ), 1.05 (3H, s, 5-CH ), 0.9 (9H, s, CH ); C NMR (151 MHz, CDCl )
δ
196.6,
3
3
3
3
1
62.1, 95.4, 56.3, 50.2, 44.5, 34.4, 32.7, 29.6, 28.4, 27.9, 26.1, 15.4; Anal. Calcd for
C H NO: C, 75.28; H, 11.28; N, 6.27. Found: C, 75.51; H, 11.49; N, 6.56.
14
25
4
.4.3. 5,5-dimethyl-3-(N-2’R-(3’,3’-dimethybutyl))-cyclohex-2-en-1-on (7g). Yellow solid
o
27
D
(
3.39 g, 76%); m.p. 178–180 C; R (20:1 CHCl /MeOH) 0.45; [α]
+346.9 (c 0.04,
f
3
CHCl ); IR (neat) ν 3267, 3071, 2955, 2870, 1590, 1535, 1457, 1374, 1269, 1248, 1151, 1127
3
-1 1
cm ; H NMR (600 MHz, CDCl )
δ
5.17 (1H, s, 2-H), 4.18 (1H, br, N-H), 3.29 (1H, dq, J
3
7
.2, 9.6 Hz, CH), 2.18 (2H, s, 6-H), 2.16 (2H, s, 4-H), 1.07 (3H, d, J 6.6 Hz, CH ), 1.07 (3H,
3
1
3
s, 5-CH ), 1.06 (3H, s, 5-CH ), 0.9 (9H, s, CH ); C NMR (151 MHz, CDCl )
δ
196.7,
62.1, 95.5, 56.3, 50.2, 44.6, 34.4, 32.8, 28.4, 28.0, 26.2, 26.0, 15.5; Anal. Calcd for
C H NO: C, 75.28; H, 11.28; N, 6.27. Found: C, 75.55; H, 11.53; N, 6.48.
3
3
3
3
1
14
25
4
.4.4. 5,5-dimethyl-3-(N-1’R-(2’S-hydroxyindanolyl))-cyclohex-2-en-1-on (7h). Yellow solid
o
27
(
4.44 g, 82%); m.p. 153–155 C; R (20:1 CHCl /MeOH) 0.35; [α] -30.9 (c 0.29, CHCl3);
f 3 D
IR (neat) ν 3339, 3290, 3070, 2957, 2923, 2865, 1588, 1560, 1510, 1423, 1381, 1252, 1183,
-1 1
1
153, 1123, 1063 cm ; H NMR (600 MHz, CDCl )
δ
7.20-7.30 (4H, m, Ar-H), 5.43 (1H, s,
3
2
-H), 4.85 (1H, br, N-H), 4.69 (1H, dd, J 4.8, 4.8 Hz, 1’-H), 3.20 (1H, dd, J 4.8, 16.8 Hz, 2’-
H), 2.98 (1H, br, OH), 2.31 (2H, dd, J 4.8, 15.6 Hz, 3’-H), 2.22 (2H, s, 6-H), 2.17 (2H, s, 4-
1
3
H), 1.13 (3H, s, 5-CH ), 1.10 (3H, s, 5-CH ); C NMR (151 MHz, CDCl )
δ
197.0, 163.0,
40.3, 139.7, 128.5, 127.6, 125.6, 124.6, 96.4, 73.0, 60.3, 50.2, 40.1, 32.8, 30.9, 28.5, 28.1;
Anal. Calcd for C H NO : C, 75.25; H, 7.80; N, 5.16. Found: C, 75.49; H, 8.16; N, 5.43.
3
3
3
1
1
7
21
2
2
3

ACCEPTED MANUSCRIPT
4
.5 General procedure for synthesis of chromeno[2,3-d]pyrimidine-2,4-diones 8a-m by
hetero-Diels-Alder reactions
To a solution of alditols 4a-e (1 mmol) in dichloromethane (30 mL) was added enaminones
7
a-i (1 mmol). The mixture was stirred for 1h and next it was kept for 3 days at room
temperature. The progress of the reactions was monitored by TLC (20:1 CHCl /MeOH). The
3
solvent was evaporated and the crude product was purified by crystallization from tert-butyl
methyl ether/pet. ether 1:1 (8a, 8c-h, 8l, 8k, 8m) or isopropanol (8b, 8j). Chromeno[2,3-
d]pyrimidines 8a-m were prepared with 73-87% yields listed in Table 2.
4
.5.1.
(1’S,2’R,3’S)-5-(1’,2’,3’,4’,5’-Penta-O-acetyl-pentane-1’,2’,3’,4’,5’-pentaolyl)-6-
hydroxy-1,3,8,8-tetramethyl-9a-anilino-1,2,3,4,7,8,9,9a-octahydro-5H-chromeno[2,3-
o
d]pyrimidine-2,4-dione (8a). White solid
(0.551 g, 82%); m.p. 88–90 C; R (20:1
f
2
D
7
CHCl /MeOH) 0.55; [α] -32.1 (c 0.35, CHCl ); IR (neat) ν 2959, 2884, 1743, 1693, 1584,
3
3
-
1
1
1
1
1
5
444, 1368, 1210, 1044, 1022 cm ; H NMR (600 MHz, CDCl ) δ 16.89 (0.6H, s, OH),
3
+
+
2.45 (0.4H, s, N -H), 11.05 (0.4H, s, N -H), 7.44-7.09 (5H, m, Ar-H), 6.58 (0.4H, dd, J 1.8,
0.2 Hz, 1’-H), 6.49 (0.6H, dd, J 1.8, 10.2 Hz, 1’-H), 5.25 (0.6H, dd, J 1.8, 9.6 Hz, 2’-H),
.22 (0.4H, dd, J 1.8, 9.0 Hz, 2’-H), 5.05 (0.6H, ddd, J 3.0, 5.4, 9.6 Hz, 3’-H), 5.03 (0.4H,
ddd, J 3.0, 6.0, 9.0 Hz, 3’-H), 4.50 (0.4H, d, J 10.2 Hz, 5-H), 4.37 (0.6H, d, J 9.6 Hz, 5-H),
4
6
0
.14 (0.6H, dd, J 2.4, 12.0 Hz, 4’-H), 4.09 (0.4H, dd, J 2.4, 12.0 Hz, 4’-H), 3.96 (0.6H, dd, J
.0, 12.6 Hz, 4’-H), 3.94 (0.4H, dd, J 5.4, 12.6 Hz, 4’-H), 3.41-3.19 (6.6H, singlets, N-CH3,
1
3
.6 N-H), 2.53-1.87 (16H, singlets, COCH , CH ), 1.17-0.86 (6H, singlets, 8-CH ); C NMR
3
2
3
(151 MHz, CDCl3) δ 195.4, 192.6, 170.5, 170.2, 170.1, 170.05, 169.7, 169.6, 169.5, 169.1,
168.7, 165.9, 165.6, 163.3, 161.6, 151.3, 151.2, 137.9, 137.6, 129.6, 129.5, 129.5, 127.6,
126.8, 125.8, 124.9, 123.9, 110.1, 110.0, 89.3, 89.0, 69.1, 69.05, 69.0, 68.8, 68.7, 68.3, 62.25,
62.2, 48.2, 46.7, 40.9, 40.7, 33.0, 32.9, 32.1, 31.1, 29.3, 28.9, 28.8, 28.4, 28.3, 28.1, 27.6,
2
4

ACCEPTED MANUSCRIPT
2
6.9, 26.8, 21.2, 21.0, 21.0, 20.95, 20.9, 20.7, 20.65, 20.6, 20.5, 20.3; Anal. Calcd for
C H N O : C, 59.01; H, 6.15; N, 6.26. Found: C, 59.37; H, 6.44; N, 6.47.
33
41
3
12
4
.5.2. (1’S,2’R,3’S,4’R)-5-(1’,2’,3’,4’,5’-Penta-O-acetyl-pentane-1’,2’,3’,4’,5’-pentaolyl)-6-
hydroxy-1,3,8,8-tetramethyl-9a-anilino-1,2,3,4,7,8,9,9a-octahydro-5H-chromeno[2,3-
d]pyrimidine-2,4-dione (8b). White solid (0.625 g, 84%); R (20:1 CHCl /MeOH) 0.58;
f
3
2
4
o
[
α]D –77.6 (c 1.31, CHCl ); m.p. 183–185 C; IR (neat) ν 2957, 2870, 1742, 1691, 1585,
3
-1
1
1
432, 1367, 1207, 1021 cm ; H NMR (600 MHz, CDCl ) δ 16.83 (0.5H, s, OH), 12.39
3
+
+
(
0.5H, s, N -H), 11.05 (0.5H, s, N -H), 7.44-7.07 (5H, m, Ar-H), 6.48 (0.5H, dd, J 1.8, 10.2
Hz, 1’-H), 6.40 (0.5H, dd, J 1.8, 9.6 Hz, 1’-H), 5.32 (0.5H, dd, J 1.8, 9.6 Hz, 2’-H), 5.27
0.5H, dd, J 1.8, 9.6 Hz, 2’-H), 5.18 (0.5H, dd, J 2.4, 9.0 Hz, 3’-H), 5.17 (0.5H, dd, J 2.4, 9.6
(
Hz, 3’-H), 4.96 (0.5H, ddd, J 1.8, 4.8, 6.6 Hz, 4’-H), 4.94 (0.5H, ddd, J 1.8, 4.8, 6.6 Hz, 4’-
H), 4.43 (0.5H, d, J 10.2 Hz, 5-H), 4.29 (0.5H, d, J 10.2 Hz, 5-H), 4.24 (0.5H, dd, J 4.8, 12.0
Hz, 5’-H), 4.21 (0.5H, dd, J 5.4, 11.4 Hz, 5’-H), 3.81 (0.5H, dd, J 6.6, 12.0 Hz 5’-H), 3.76
(
0.5H, dd, J 6.6, 12.0 Hz 5’-H), 3.41-3.29 (6.5H, singlets, N-CH , 0.5 N-H), 2.52-1.87 (19H,
3
1
3
singlets, COCH , CH ), 1.11-0.88 (6H, singlets, 8-CH );
C NMR (151 MHz,
3
2
3
CDCl3)
δ
195.6, 192.8, 170.7, 170.4, 170.35, 170.2, 170.2, 169.9, 169.3, 169.3, 169.1, 168.5,
1
66.0, 165.6, 163.2, 161.4, 151.3, 151.2, 138.0, 137.7, 129.6, 129.5, 127.6, 126.7, 125.7,
1
24.8, 110.1, 110.0, 89.6, 89.3, 69.2, 68.7, 68.25, 68.2, 67.8, 67.75, 67.6, 64.3, 62.1, 62.0,
8.3, 46.9, 40.9, 40.7, 33.3, 33.1, 32.4, 31.3, 29.1, 28.8, 28.8, 28.4, 28.1, 28.0, 27.95, 27.2,
5.3, 21.3, 21.1, 20.9, 20.7, 20.6, 20.5, 20.3; Anal. Calcd for C H N O : C, 58.14; H, 6.10;
4
2
3
6
45
3
14
N, 5.65. Found: C, 58.39; H, 6.36; N, 5.86.
4
1
.5.3.
(1’R,2’S,3’S)-5-(1’,2’,3’,4’-Tetra-O-acetyl-butane-1’,2’,3’,4’-tetraolyl)-6-hydroxy-
,3,8,8-tetramethyl-9a-(4-methyl-anilino)-1,2,3,4,7,8,9,9a-octahydro-5H-chromeno[2,3-
2
5

ACCEPTED MANUSCRIPT
d]pyrimidine-2,4-dione (8c). White solid (0.556 g, 81%); R (20:1 CHCl /MeOH) 0.49;
f
3
2
4
o
[
α]D +98.0 (c 0.27, CHCl ); m.p. 173–175 C; IR (neat) ν 2935, 2876, 1745, 1695, 1585,
3
-
1
1
1
1
1
514, 1458, 1369, 1209, 1018 cm ; H NMR (600 MHz, CDCl ) δ 16.91 (0.6H, s, OH),
3
+
+
2.32 (0.4H, s, N -H), 10.94 (0.5H, s, N -H), 7.23-6.97 (4H, m, Ar-H), 6.56 (0.4H, dd, J 1.8,
0.8 Hz, 1’-H), 6.49 (0.6H, dd, J 1.8, 9.6 Hz, 1’-H), 5.31 (0.6H, dd, J 1.8, 9.0 Hz, 2’-H), 5.26
(
0.4H, dd, J 1.8, 8.4 Hz, 2’-H), 5.12 (0.4H, ddd, J 2.4, 5.4, 9.0 Hz, 3’-H), 5.07 (0.6H, ddd, J
.4, 5.4, 9.0 Hz, 3’-H), 4.55 (0.4H, d, J 10.2 Hz, 5-H), 4.41 (0.6H, d, J 9.6 Hz, 5-H), 4.42
0.6H, dd, J 2.4, 12.6 Hz, 4’-H), 4.28 (0.4H, dd, J 2.4, 12.6 Hz, 4’-H), 4.08 (0.4H, dd, J 5.4,
2.6 Hz 4’-H), 4.05 (0.6H, dd, J 5.4, 12.6 Hz 4’-H), 3.39-3.29 (6.5H, singlets, N-CH , 0.5 N-
2
(
1
3
13
H), 2.49-1.95 (22H, singlets, COCH , CH , CH ), 1.18-0.93 (6H, singlets, 8-CH ); C NMR
3
2
3
3
(151 MHz, CDCl3)
δ 194.9, 192.3, 170.5, 170.4, 170.0, 169.95, 169.8, 169.5, 169.4, 169.2,
1
1
4
2
6
69.0, 165.95, 165.4, 163.4, 161.7, 151.4, 151.2, 137.6, 137.1, 135.2, 134.9, 130.2, 130.1,
25.65, 125.0, 109.6, 109.55, 89.2, 88.95, 70.7, 70.6, 69.8, 69.6, 69.0, 62.2, 62.1, 48.1, 46.8,
1.0, 40.7, 33.4, 33.2, 32.0, 31.2, 29.2, 28.9, 28.8, 28.4, 28.35, 28.1, 27.6, 27.0, 21.3, 21.2,
1.1, 21.0, 20.7, 20.65, 20.6, 20.55, 20.5, 20.3; Anal. Calcd for C H N O : C, 59.55; H,
3
4
43
3
12
.32; N, 6.13. Found: C, 59.78; H, 6.54; N, 6.39.
4
.5.4. (1’S,2’R,3’R,4’R)-5-(1’,2’,3’,4’,5’-Penta-O-acetyl-pentane-1’,2’,3’,4’,5’-pentaolyl)-6-
hydroxy-1,3,8,8-tetramethyl-9a-(4-methyl-anilino)-1,2,3,4,7,8,9,9a-octahydro-5H-
chromeno[2,3-d]pyrimidine-2,4-dione (8d). White solid (0.591 g, 78%); R (20:1
f
24
o
CHCl /MeOH) 0.62; [α]D –231.2 (c 0.82, CHCl ); m.p. 108–110 C; IR (neat) ν 2960,
3
3
-
1 1
2
1
876, 1744, 1692, 1583, 1453, 1368, 1209, 1044, 1022 cm ; H NMR (600 MHz, CDCl ) δ
3
+
+
7.10 (0.55H, s, OH), 12.33 (0.4H, s, N -H), 11.03 (0.45H, s, N -H), 7.22-6.97 (4H, m, Ar-
H), 6.58 (0.45H, dd, J 1.8, 10.2 Hz, 1’-H), 6.49 (0.55H, dd, J 1.8, 9.6 Hz, 1’-H), 5.37 (0.45H,
dd, J 4.2, 8.4 Hz, 3’-H), 5.32 (0.55H, dd, J 4.2, 8.4 Hz, 3’-H), 5.15 (1H, ddd, J 1.8, 8.4, 8.4
2
6

ACCEPTED MANUSCRIPT
Hz, 4’-H), 5.07 (1H, m, 2’-H), 4.53 (0.45H, d, J 10.2 Hz, 5-H), 4.39 (0.55H, d, J 10.2 Hz, 5-
H), 4.32 (1H, dd, J 2.4, 12.6 Hz, 5’-H), 4.25 (0.55H, dd, J 7.8, 13.2 Hz, 5’-H), 4.24 (0.45H,
dd, J 7.8, 12.6 Hz 5’-H), 3.39-3.29 (6.6H, singlets, N-CH , 0.6 N-H), 2.50-1.82 (22H,
3
1
3
singlets, COCH , CH , CH ), 1.02-0.92 (6H, singlets, 8-CH ); C NMR (151 MHz,
3
2
3
3
CDCl3)
δ
194.7, 192.0, 170.9, 170.6, 170.4, 170.1, 169.9, 169.8, 169.6, 169.5, 165.8, 165.6,
1
1
4
2
5
63.5, 161.9, 151.4, 151.3, 137.6, 137.1, 135.15, 134.95, 130.2, 130.0, 125.85, 124.9, 109.7,
09.6, 89.3, 88.9, 70.65, 70.4, 70.2, 70.0, 69.8, 69.75, 69.7, 69.0, 61.5, 61.15, 48.0, 46.7,
1.1, 40.75, 33.7, 33.35, 32.1, 31.2, 29.2, 28.85, 28.8, 28.3, 28.15, 27.7, 27.1, 21.4, 21.2,
1.1, 21.0, 20.75, 20.7, 20.65, 20.55, 20.5, 20.4, 20.35, 20.2; Anal. Calcd for C H N O : C,
3
7
47
3
14
8.64; H, 6.25; N, 5.55. Found: C, 58.82; H, 6.54; N, 5.25.
4
.5.5. (1’S,2’R,3’R,4’R)-5-(1’,2’,3’,4’,5’-Penta-O-acetyl-pentane-1’,2’,3’,4’,5’-pentaolyl)-6-
hydroxy-8,8-dimethyl-9a-(4-methyl-anilino)-1,2,3,4,7,8,9,9a-octahydro-5H-chromeno[2,3-
o
d]pyrimidine-2,4-dione (8e). White solid
(0.576 g, 79%); m.p. 148–150 C; R (20:1
f
27
CHCl /MeOH) 0.57; [α]D -238.3 (c 0.33, CHCl ); IR (neat) ν 3278, 3242, 3189, 3043,
3
3
-1
1
2
957, 2868, 1742, 1605, 1575, 1513, 1461, 1368, 1211, 1047, 1023 cm ; H NMR (600
+
+
MHz, CDCl3)
δ 16.93 (0.4H, br, OH), 12.19 (0.2H, N -H), 10.68 (0.3H, s, N -H) 8.82
(0.2H, br, N-H), 7.99 (0.4H, br, N-H), 7.21-6.98 (4H, m, Ar-H), 6.50 (0.5H, dd, J 1.2, 8.4 Hz,
1
’-H), 6.47 (0.5H, dd, J 1.2, 8.4 Hz, 1’-H), 6.19 (0.65H, s, N-H), 5.52 (0.65H, s, N-H), 5.40
(0.5H, dd, J 3.6, 8.4 Hz, 3’-H), 5.34 (0.5H, dd, J 4.8, 8.4 Hz, 3’-H), 5.28 (0.5H, d, J 8.4 Hz,
5
-H), 5.22 (0.5H, d, J 8.4 Hz, 5-H), 5.04 (1H, br, 2’-H), 4.60 (0.5H, br, 4’-H), 4.38 (0.5H, dd,
J 1.8, 12.6 Hz, 5’-H), 4.33 (0.5H, dd, J 3.0, 12.0 Hz, 5’-H), 4.28 (1H, dd, J 6.6, 12.6 Hz, 5’-
H), 4.25 (0.5H, m, 4’-H), 3.20 (0.9H, br, N-H), 2.79 (0.3H, br, N-H), 2.50-1.80 (22H,
1
3
singlets, COCH , CH , CH ), 1.18-0.94 (6H, singlets, CH ); C NMR (151 MHz,
3
2
3
3
CDCl3)
δ 197.7, 194.1, 170.9, 170.7, 170.3, 170.2, 170.1, 169.95, 169.9, 169.8, 169.65,
2
7

ACCEPTED MANUSCRIPT
1
1
7
2
69.6, 167.2, 163.3, 160.5, 150.4, 149.8, 135.5, 135.4, 130.2, 130.2, 130.1, 129.95, 129.9,
25.95, 125.9, 125.9, 124.8, 124.0, 109.6, 98.6, 98.5, 89.3, 88.75, 87.8, 70.5, 70.4, 70.3, 70.1,
0.0, 69.95, 69.7, 69.7, 69.6, 69.3, 50.3, 43.6, 43.5, 41.2, 32.8, 32.0, 31.2, 28.4, 28.35, 28.3,
8.3, 28.2, 27.6, 21.1, 21.0, 20.9, 20.85, 20.8, 20.65, 20.6, 20.55, 20.5, 20.4, 20.3, 20.25;
Anal. Calcd for C H N O : C, 57.61; H, 5.94; N, 5.76. Found: C, 57.87; H, 5.85; N, 5.94.
3
5
43
3
14
4
.5.6. (1’S,2’R,3’S,4’R)-5-(1’,2’,3’,4’,5’-Penta-O-acetyl-pentane-1’,2’,3’,4’,5’-pentaolyl)-6-
hydroxy-1,3,8,8-tetramethyl-9a-(4-methyl-anilino)-1,2,3,4,7,8,9,9a-octahydro-5H-
chromeno[2,3-d]pyrimidine-2,4-dione (8f). White solid (0.629 g, 83%); R (20:1
f
24
o
CHCl /MeOH) 0.63; [α]D –131.4 (c 0.95, CHCl ); m.p. 108–110 C; IR (neat) ν 2957,
3
3
-1 1
2
870, 1742, 1691, 1585, 1432, 1367, 1207, 1021 cm ; H NMR (600 MHz, CDCl ) δ 16.98
3
+
+
(
0.6H, s, OH), 12.43 (0.45H, s, N -H), 11.04 (0.4H, s, N -H), 7.23-6.96 (4H, m, Ar-H), 6.47
(0.6H, dd, J 1.2, 10.2 Hz, 1’-H), 6.43 (0.4H, dd, J 1.8, 10.2 Hz, 1’-H), 5.32 (0.6H, dd, J 1.2,
1
0.2 Hz, 2’-H), 5.27 (0.4H, dd, J 1.8, 9.6 Hz, 2’-H), 5.18 (0.4H, dd, J 1.8, 9.6 Hz, 3’-H), 5.15
0.6H, dd, J 1.8, 9.6 Hz, 3’-H), 4.96 (0.6H, ddd, J 1.8, 4.8, 6.0 Hz, 4’-H), 4.94 (0.4H, ddd, J
.8, 4.8, 6.0 Hz, 4’-H), 4.44 (0.4H, d, J 10.2 Hz, 5-H), 4.29 (0.6H, d, J 9.6 Hz, 5-H), 4.25
0.6H, dd, J 4.8, 12.0 Hz, 5’-H), 4.21 (0.4H, dd, J 4.8, 12.0 Hz, 5’-H), 3.82 (0.6H, dd, J 6.6,
2.0 Hz 5’-H), 3.77 (0.4H, dd, J 6.6, 11.4 Hz 5’-H), 3.41-3.20 (6.5H, singlets, N-CH , 0.5 N-
(
1
(
1
3
13
H), 2.48-1.87 (22H, singlets, COCH , CH , CH ), 1.18-0.90 (6H, singlets, 8-CH ); C NMR
3
2
3
3
(151 MHz, CDCl3)
δ 194.8, 191.8, 170.8, 170.4, 170.35, 170.2, 170.2, 169.9, 169.6, 169.3,
1
1
4
2
69.1, 165.95, 165.5, 163.5, 161.7, 151.4, 151.3, 137.7, 136.95, 135.3, 135.0, 130.1, 125.5,
24.8, 109.95, 109.9, 89.5, 89.2, 69.2, 68.8, 68.3, 68.25, 67.95, 67.9, 67.8, 67.7, 62.2, 62.1,
8.1, 46.7, 41.0, 40.7, 33.3, 33.1, 32.2, 31.2, 29.2, 28.8, 28.7, 28.3, 28.2, 28.1, 27.85, 27.1,
7.0, 22.6, 21.4, 21.2, 21.1, 21.0, 20.9, 20.8, 20.7, 20.6, 20.55, 20.3; Anal. Calcd for
C H N O : C, 58.64; H, 6.25; N, 5.55. Found: C, 58.89; H, 6.51; N, 5.78.
37
47
3
14
2
8

ACCEPTED MANUSCRIPT
4
.5.7. (1’S,2’R,3’R,4’R)-5-(1’,2’,3’,4’,5’-Penta-O-acetyl-pentane-1’,2’,3’,4’,5’-pentaolyl)-6-
hydroxy-8,8-dimethyl-9a-(4-methoxy-anilino)-1,2,3,4,7,8,9,9a-octahydro-5H-chromeno[2,3-
o
d]pyrimidine-2,4-dione (8g). White solid
(0.560 g, 75%); m.p. 180–181 C; R (20:1
f
2
D
7
CHCl /MeOH) 0.54; [α] -27.0 (c 0.46, CHCl ); IR (neat) ν 2959, 1741, 1613, 1590, 1510,
3
3
-1 1
1
369, 1369, 1210, 1024 cm ; H NMR (600 MHz, CDCl ) δ 16.97 (0.35H, s, OH), 12.28
3
+
+
(
0.45H, s, N -H), 10.67 (0.45H, s, N -H), 9.23 (1.3H, br, N-H), 8.88 (0.3H, br, N-H), 8.21
(0.4H, br, N-H), 6.52 (0.5H, dd, J 1.2, 9.6 Hz, 1’-H), 6.47 (0.5H, dd, J 1.2, 9.6 Hz, 1’-H),
5
.38 (0.5H, dd, J 3.6, 8.4 Hz, 3’-H), 5.33 (0.5H, dd, J 4.8, 8.4 Hz, 3’-H), 5.26 (0.5H, dd, J
.2, 8.4 Hz, 2’-H), 5.21 (0.5H, dd, J 1.8, 8.4 Hz, 2’-H), 5.05 (0.5H, ddd, J 1.8, 3.6, 7.8 Hz, 4’-
1
H), 5.03 (0.5H, ddd, J 3.0, 4.8, 7.2 Hz, 4’-H), 4.49 (0.5H, d, J 9.0 Hz, 5-H), 4.38 (0.5H, d, J
.0 Hz, 5-H), 4.33 (0.5H, dd, J 1.8, 12.0 Hz, 5’-H), 4.27 (0.5H, dd, J 3.0, 12.0 Hz, 5’-H), 4.25
1H, dd, J 7.2, 12.0 Hz 5’-H), 3.81 (3.8H, s, OCH , 0.8 N-H), 2.45-1.82 (19H, singlets,
9
(
3
1
3
COCH , CH ), 1.18-0.84 (6H, singlets, 8-CH ); C NMR (151 MHz, CDCl )
δ 193.4, 189.6,
3
2
3
3
1
1
1
5
2
5
71.4, 171.0, 170.7, 170.3, 170.2, 170.1, 170.0, 169.9, 169.85, 169.8, 169.6, 167.2, 166.4,
65.6, 163.5, 159.1, 158.7, 150.45, 150.4, 150.1, 130.0, 129.9, 127.3, 126.5, 114.8, 114.6,
09.8, 109.3, 88.7, 88.0, 71.0, 70.4, 70.15, 69.9, 69.8, 69.6, 69.4, 68.8, 64.3, 61.2, 61.0,
5.51, 55.47, 47.4, 45.8, 41.2, 40.8, 32.3, 32.2, 31.7, 31.5, 31.0, 29.2, 28.5, 27.3, 26.9, 25.3,
2.6, 21.4, 21.2, 20.7, 20.65, 20.5, 20.45, 20.4, 20.35, 20.2; Anal. Calcd for C H N O : C,
35
43
3
15
6.37; H, 5.81; N, 5.63. Found: C, 56.55; H, 6.01; N, 5.84.
4
.5.8. (1’S,2’R,3’S,4’R)-5-(1’,2’,3’,4’,5’-Penta-O-acetyl-pentane-1’,2’,3’,4’,5’-pentaolyl)-6-
hydroxy-1,3,8,8-tetramethyl-9a-(4-methoxy-anilino)-1,2,3,4,7,8,9,9a-octahydro-5H-
chromeno[2,3-d]pyrimidine-2,4-dione (8h). White solid (0.642 g, 83%); m.p. 113–115 C;
o
2
D
4
R (20:1 CHCl /MeOH) 0.58; [α]
-46.4 (c 0.29, CHCl ); IR (neat) ν 2956, 2890, 2837,
3
f
3
2
9