Sequential Enyne-Metathesis/Diels–Alder Strategy: Rapid Access to Sugar–Oxasteroid–Quinone Hybrids

Article abstract of DOI:10.1002/ejoc.201700599

A sequential enyne-metathesis/Diels–Alder strategy is reported for the synthesis of a new class of sugar–oxasteroid–quinone hybrid molecules. 1,2:5,6-Di-O-isopropylidine-d-glucose was chosen as a chiral-pool starting material. Various sugar-derived enynes were synthesised from the common starting material. Dienes derived from these enynes were treated with various quinone dienophiles under Diels–Alder reaction conditions to give a library of sugar–oxasteroid–quinone hybrids.

Full text of DOI:10.1002/ejoc.201700599

A Journal of
Accepted Article
Title: A Sequential Enyne-Metathesis/Diels-Alder Strategy to Sugar-
Oxasteroid-Quinone Hybrids
Authors: Krishna Pillai Kaliappan and Ashik Sayyad
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201700599
Link to VoR: http://dx.doi.org/10.1002/ejoc.201700599
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10.1002/ejoc.201700599
European Journal of Organic Chemistry
FULL PAPER
Sequential Enyne-Metathesis/Diels-Alder Strategy: Rapid Access
to the Novel Sugar-oxasteroid-quinone Hybrids
Ashik A. Sayyad and Krishna P. Kaliappan*
Abstract Sequential enyne metathesis/Diels-Alder strategy is herein
reported to synthesize a novel class of sugar-oxasteroid-quinone
hybrid molecules. For the synthesis of series of sugar-oxasteroid-
quinone hybrid analogues, 1,2,5,6-diisopropylidine-D-glucose was
chosen as the chiral pool starting material. Varieties of sugar derived
enynes are synthesized from common starting precursor and their
treatment with various quinone dienophiles in Diels-Alder reaction
have been reported for the synthesis of different types of steroid
hybrids.4,5 Treatment of inflammatory diseases (Rheumatoid
arthritis, COPD and related autoimmune diseases) has been
achieved with powerful glucocorticoids such as dexamethasone,
prednisolone, fluticasone (Fig. 1) etc. However, prolonged use of
Glucocorticoids in the treatment of chronic conditions causes
various serious side effects including diabetes and
conditions resulted in the library of sugar-oxasteroid-quinone hybrids. osteoporosis.6,7 Therefore, there is a great need to synthesize
steroid-like molecules with desired biological activity and lacking
the serious side-effects. Quinones are ubiquitous in nature and
constitute of natural and synthetic compounds that have several
beneficial as well as toxicological effects.8a-f Anthracycline
antibiotics consists of quinone unit are well known for their
important antineoplastic activity. Out of the various
anthracyclines daunorubicin and doxorubicin (Fig. 2) were
initially isolated from Streptomyces peucetius and were found to
exhibit the widest spectrum of antitumor activity against human
cancers.8g-j Because of the promising anticancer activity of these
molecules, there has been a lot of interest in chemically
modifying them to minimize their cardiotoxic side effects.
Introduction
Nature has been the main source of structurally diverse and
complex natural products from long time; some of these natural
products are found to exhibit interesting biological activities.1 It
has long been recognized that natural product structures
possess high chemical diversity and biological specificity that
makes them favourable as lead structures for drug discovery.
Steroids represent an important class of natural products, which
plays critical role in
a
number of disorders, including
O
OH
O
O
OH
O
malignancies like prostate cancer, where steroid production
inside and outside the tumor promotes cancer cell
aggressiveness.2
OH
OH
O
OH
O
O
OH
O
O
O
OH
O
OH
O
O
HO
O
OH
OH
HO
OH
H2N
NH2
H
H
H
H
H
H
H
H
H
Doxorubicin
Daunorubicin
O
O
O
F
Testosterone
Cortisol
Projesterone
OH
OH
Fig. 2 Daunorubicin and Doxorubicin
S
O
O
O
HO
H
OH
HO
OH
HO
H
OH
H
The chemical synthesis of hybrid natural product provides rapid
access to structurally diverse chemical substances for
pharmacological testing in short span of time. The novel class of
hybrid natural products, which are potentially bioactive, can be
designed by combining structural units of two or more classes of
natural products. As a part of our research programme aimed at
the synthesis of biologically active compounds,9 we earlier
reported our preliminary attempts towards design and synthesis
of new class of sugar–oxasteroid–quinone hybrids with the
purpose of combining the reactivity of the acetal moiety of
furanose and the quinone unit with the steroidal backbone, as
outlined in Scheme 1.10 Our strategy consists of sequential
enyne metathesis and Diels–Alder reaction11 of an enyne 1
derived from a sugar unit with a variety of 1,4-quinones to
provide hybrid molecule 3 as outlined in Scheme 1. Herein, we
disclose a comprehensive account on our endeavours for the
F
H
H
H
H
H
O
O
O
F
Dexamethasone
Prednisolone
Fluticasone
Fig.1 Glucocorticoids
Synthetic steroid hybrids have attracted significant attention for
the purpose of drug development.3 A few interesting strategies
[a]
[b]
Department of Chemistry, Indian Institute of Technology Bombay,
Mumbai, 400 076, India.
E-mail: ashik_sayyad@chem.iitb.ac.in
Department of Chemistry, Indian Institute of Technology Bombay,
Mumbai, 400 076, India.
synthesis of sugar–oxasteroid–quinone hybrids through
a
E-mail: kpk@chem.iitb.ac.in
sequential intramolecular enyne metathesis/Diels–Alder11
/aromatization reaction strategy (Scheme 1).
URL: http://www.chem.iitb.ac.in/~kpk
Supporting information for this article is given via a link at the end of
the document
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10.1002/ejoc.201700599
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The major difference in these scaffolds is in the A-B and B-C
ring fusion with respect to the steroidal backbone, thus providing
the access to array of hybrids with significant variety in the ring
fusion of the steroid skeleton (Scaffold I-III, Fig. 3). To test our
planned strategy, we designed a set of dienes (17-21) that could
be synthesised from the common starting precursor 1,2,5,6-
diisopropylidine-D-glucose 4 by using enyne metathesis. Later,
these dienes could be used in the Diels–Alder reaction11 with 1,
4-naphthoquinone (11), 5, 8-dihydroxy-1,4-naphthoquinone (12),
1,4-anthraquinone (13), 5-hydroxy-1,4-naphthoquinone (14), 5-
nitro-1,4-naphthoquinone (15),13a and DMAD (16) as dienophiles
(Fig.4) for the synthesis of respective sugar oxasteroid-quinone
hybrids.
O
O
Sugar
Sugar
Sugar
I. Diels-Alder
EM
ii. Aromatization
R
1
2
3
Scheme 1. General enyne metathesis/Diels-Alder/aromatization strategy
The diversity for the synthesis of various sugar–oxasteroid–
quinone hybrids could be accomplished by treating different
dienes derived from carbohydrate precursor with a variety of
dienophiles in the Diels–Alder reaction. 1,2,5,6-diisopropylidine-
D-glucose 4 was used as the chiral pool starting material.10b
OH
O
NO2
O
O
OH
O
O
COOMe
COOMe
O
R
O
O
R
O
OH
O
O
O
EM
O
O
O
O
O
15
16
14
12
13
11
O
H
O
O
O
O
O
O
H
Me
Ph
H
H
O
O
O
O
5
O
O
O
6
O
O
HO
O
O
O
O
O
O
H
O
O
R
H
O
H
H
H
O
O
21
EM
O
O
20
18
19
O
17
O
O
O
H
O
H
H
4
7
Figure 4. Various dienes and quinone dienophiles
8
O
Wittig
O
O
Results and Discussion
H
O
O
9
O
10
Synthesis of sugar-oxasteroid-quinone hybrids
The building blocks for the synthesis of sugar-oxasteroid-
quinone hybrids are enynes, which were derived from the
secondary alcohol 4 (Scheme 3). Our synthetic journey towards
the sugar–oxasteroid–quinone hybrid molecules was started
with the synthesis of diene 17 in a convergent manner from the
1,2,5,6-diisopropylidine-D-glucose 4. Allylation of precursor 4
resulted in to the allyl ether 22 in good yield. Selective
deprotection of the more exposed 5,6-O-isopropylidene group of
22 afforded a diol, which was subsequently cleaved by silica gel
supported NaIO4 to provide the aldehyde 23.13b-c
Scheme 2. Diversity in the synthesis of dienes
Varieties of enynes were synthesized in few steps from common
starting precursor 4. Treatment of these various enynes with
Grubb’s first generation catalyst afforded reactive dienes
(Scheme 2). These dienes on treatment with various quinone
dienophiles12 resulted in a library of sugar–oxasteroid–quinone
hybrids with different scaffolds as shown in the Figure 3.
O
O
12
O
13
O
HO
O
17
16
15
i. 90 % aq. AcOH
rt, 12 h, 88%
R1
H
NaH, cat. TBAI
11
O
O
O
allylbromide, THF
C
8
O
O
D
1
O
9
O
10
5
O
reflux, 12 h, 78%
ii. Silica gel supp.
NaIO4, DCM
rt, 2 h, 79%
2
3
H
O
14
H
O
O
A
B
O
22
4
7
4
6
R2
Steroid Backbone
PCy3
Scaffold I
O
O
P
Cl
Ph
OMe
OMe
O
R1
Ru
O
R2
Cl
O
N2
26
PCy3
25
O
O
O
O
O
H
O
O
H
H
O
O
O
O
25
, K2CO3
O
O
26, DCM, 40 oC
O
O
MeOH, rt
4h, 73%
O
O
O
O
O
OHC
11 h, 77%
H
H
Scaffold III
17
Scaffold II
R2
23
24
Scheme 3. Synthesis of diene 17
Figure 3. Various scaffolds of oxasteroid-quinone hybrids
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The aldehyde 23 was then easily converted into the key enyne
precursor 24 by Ohira-Bestmann’s protocol14 in a single step by
treating aldehyde 23 with the diazo compound 25 in presence of
K2CO3 in MeOH in 73% yield. The synthesis of enyne 24
allowed us to attempt the key enyne metathesis reaction. As
planned, the enyne 24 underwent a smooth intramolecular
enyne metathesis15 with the Grubbs’ first generation catalyst 26
to yield the diene 17 in good yield. However, synthesis of dienes
18 and 19 were commenced with the ketone 27 which could be
obtained from precursor 4 (Scheme 4) by PDC oxidation.16
Addition of phenyl17 and methyl magnesium bromide10
separately to the ketone 27 resulted in respective tertiary
alcohols in moderate yields. Allylation of resulting tertiary
alcohols yielded allyl ethers 28a and 28b, which on cleavage of
more exposed 5,6-O-isopropylidene group furnished respective
diols10 in quantitative yields, further treatment with silica
supported NaIO4 afforded aldehydes 29a and 29b. Aldehydes
were converted into desired enynes 30a and 30b in single step
by using Ohira-Bestmann’s protocol14 (Scheme 4).
Scheme 5. Diels-Alder/aromatization strategy
This sequence was then repeated with 5,8-dihydroxy 1,4-naph
thoquinone 12, 1,4-anthraquinone 13, 5-hydroxy 1,4-
napthoquinone 14 and 5-nitro 1,4-napthoquinone 15 to obtain
the respective hybrid molecules 32, 33, 34 and 35 with scaffold-
I structure (Table 1) in moderate to good overall yields. As
expected mixture of inseparable regeoisomers was obtained in
case of substituted quinones 14 and 15. We were sceptical
about reactivity of our sugar dienes with dienophiles other than
quinone and hence we treated diene 17 with DMAD. Unlike
quinone dienophiles Diels-Alder adducts, the adduct with DMAD
was reluctant to undergo aromatization with triethyl amine/
O
i. RMgX in Et2O, THF
0 oC to rt, 2h
O
PDC, Ac2O
O
O
HO
O
Et3N, CH2Cl2
18
O
basified silica gel, however treatment with oxidant MnO2 in
O
78% 40 oC, 4 h
ii. NaH, allylbromide
cat. TBAI, THF
reflux, 12 h
O
refluxing toluene resulted in the desired aromatised product 36
in 73% yield. In similar manner diene 18 and 19 were subjected
to Diels–Alder reaction/aromatization10 reaction sequence with
quinone dienophiles 11 to 15 as well as DMAD, reactions
proceeded smoothly and the respective aromatization reactions
led to the corresponding sugar–oxasteroid–quinone hybrids 37-
48 in 62-89% yields (Table 1). Synthesis of diene 2019 was
commenced with propargylation of precursor 4 followed by
selective deprotection of the more exposed 5,6-O-isopropylidene
group of 55 to give diol in quantitative yield, which on treatment
with silica supported NaIO4 resulted in aldehyde 56 in 79% yield
(Scheme 6). Further treatment of aldehyde with methyl triphenyl
phosphonium bromide in basic condition furnished enyne 57 in
73% yield. The treatment of enyne 57 with Grubbs’ first
generation catalyst 26 afforded diene 20.19
O
O
H
O
H
27
4
O
R
O
O
R
H
i. 90% aq. AcOH
rt, 12 h
O
O
OHC
O
25, K2CO3
O
ii. Silica gel supp.
NaIO4, DCM
rt, 2 h
MeOH, rt, 4h
H
O
O
O
28
28a, R= Ph, 74%
29a, R= Ph, 70%
29b
28b
, R= Me, 62%
, R= Me, 75%
O
O
R
R
O
O
O
26
O
, CH2Cl2
O
O
reflux, 11 h
H
H
30a
30b
19
, R= Ph, 80%
18
, R= Me, 74%
, R= Ph, 71%
, R= Me, 74%
Scheme 4. Synthesis of diene 18 and 19
Finally enyne metathesis15 of above enynes with Grubbs’ first
generation catalyst 26 yielded dienes 19 and 18 in good yields.
After synthesizing the dienes 17, 18 and 19, the stage was set to
carry out the intermolecular Diels–Alder reaction11 with 1,4-
quinones as dienophiles to generate sugar-oxasteroid quinone
hybrids. As expected and based on our earlier experience10
Diels-alder reaction of diene 17 with 1,4-napthoquinone
underwent smoothly under thermal conditions. However, the
cycloadduct seemed to be unstable and found to undergo
aromatization/oxidation on a silica gel column without any
oxidizing agent. Thus we treated the crude cycloaddition product
immediately with triethylamine10 and silica gel without
purification which resulted in the aromatised product 31 in 68%
yield (Scheme 5).
Scheme 6. Synthesis of diene 20
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Table 1. Synthesis of sugar-oxasteroid quinone hybrids. [a,b,c,d,e]
by aromatization with basic (Et3N) silica in CHCl3 at RT. (c) Overall yield for
two steps. (d) Mixture of regioisomers was obtained. (e) Yields are given in
parenthesis.
(a) The dienes were synthesised from the respective alkynes by using Grubbs’
first-generation catalyst (7 mol%) under an Ar atmosphere in CH2Cl2 at 40 oC.
(b) All the Diels–Alder reactions were carried out in toluene at 80oC followed
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In this event, the Diels–Alder reaction11 of the diene 20
proceeded smoothly with dienophiles 11-16, and the respective
aromatization reactions led to the corresponding sugar-
oxasteroid-quinone hybrids 49-54 with scaffold-II in good yields
(Table 1), where symmetric quinones yielded single product but
in case of substituted quinones (14 and 15) inseparable mixture
of regeoisomers (52 and 53 respectively) were obtained. The
synthetic journey towards diene 21 was commenced with same
with new scaffold III. Surprisingly, diene 21 was found to be less
reactive towards the Diels–Alder reaction11 with 1,4 quinones
than the diene 17-20 and required longer time for completion of
the reaction, however after refluxing the diene 21 with 1,4-
naphthoquinone for 48 to 72 hours in toluene, desired hybrid 61
with scaffold-III (Fig. 3) was obtained in 64% yield (Table 2). The
reaction of diene 21 with 5,8-dihydroxy-1,4 naphthoquinone
effortlesssely yielded hybrid 62 in 52% yield. However, Diels
Alder reactions with 5-hydroxy, 1,4-naphthoquinone, 5-nitro 1,4-
naphthoquinone and DMAD were not clean and only traces of
product formed, which could be attributed to the low reactivity of
diene 21 towards Diels-Alder reaction.
precursor
4 4 was
by using known protocol.20 Precursor
subjected to mesylation condition to obtain mesyl ether 58. The
selective deprotection of more exposed 5,6-O-isopropylidene
group of 58 with dil. H2SO4 afforded a diol, which was further
cleaved by silica gel supported NaIO4 to provide the aldehyde
59. Treatment of aldehyde 59 with pyridine in refluxing
conditions afforded aldehyde 60 in 93% yield. Finally aldehyde
60 was treated with methyl triphenyl phosphonium bromide in
basic condition furnished diene 21 (Scheme 7) in 73% yield.
The diene 21 is structurally different from the other dienes of 6
Conclusion
We have disclosed a simple, versatile and efficient strategy for
the synthesis of a novel class of sugar–oxa–steroid quinone
hybrids. The choice of different types of sugar dienes derived
from the common precursor on Diels-Alder/aromatization
reaction sequence has led us to novel sugar oxa-steroid quinone
hybrids with three different steroidal scaffolds. During this
course, Diels-alder/aromatization strategy for six different
dienophiles against five different dienes was investigated. Also,
these sugar derived dienes undergo smooth reaction with
DMAD, this proves scope of our methodology is not only limited
to quinone dienophiles but could be extended to non-quinone
dienophiles as well. Thus, library of hybrid molecules which has
steroid-like backbone (scaffold-I) and modified steroidal
backbone (scaffold II and III) can be synthesized by using this
methodology, which provides a rapid access to number of
steroid hybrids.
and
8
types. Also the Diels-Alder/aromatization10 reaction
sequence in this case of diene 21 will essentially lead to the
sugar oxa-steroid quinone hybrids
Experimental Section
Scheme 7. Synthesis of diene 21
General: All starting materials and reagents were obtained from
commercial suppliers and used after further purification as
detailed below. All solvents for routine isolation of products and
chromatography were reagent-grade and glass-distilled.
Reaction flasks were dried in oven at 130 °C for 12 h. Air and
moisture-sensitive reactions were performed under an
argon/UHP nitrogen atmosphere. Column chromatography was
performed using silica gel (100−200 mesh size) with indicated
solvents. Thin-layer chromatography (TLC) was conducted with
silica gel 60 F254 precoated plates (0.25 mm) and visualized with
UV, potassium permanganate, ceric ammonium molybdate, or
iodine staining as appropriate. All 1H NMR spectra were
recorded on 400 and 500 MHz spectrometers and have been
reported in ppm using solvents as internal standards (CDCl3 at
7.26 ppm). All proton-decoupled 13C NMR spectra were
recorded at 100 and 125 MHz and have been reported in ppm
using solvents as internal standards (CDCl3 at 77.2 ppm).
Compounds were analyzed for HRMS on an ESI-QTOF mass
spectrometer using electrospray ionization in the positive ion
mode. IR spectra were recorded with KBr on an FT-IR
Table 2. Synthesis of sugar-oxasteroid-quinone hybrids with scaffold III[a,b,c,]
(a) All the Diels–Alder reactions were carried out in toluene at 80 oC followed
by aromatization with basic (Et3N) silica in CHCl3 at RT. (b) Overall yield for
two steps. (c) Yields are given in parenthesis.
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10.1002/ejoc.201700599
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spectrometer and have been reported in wavenumber (cm−1).
For all the solid compounds melting points were measured on a
Buchi micromelting point apparatus. A few general procedures
were followed during the course of reactions, and they are
explained later. Splitting patterns are designated as s, singlet; d,
doublet; dd, doublet of doublet; t, triplet; q, quartet; quin, quintet;
m, multiplet. Optical rotations were measured at 25 oC on
Autopol IV polarimeter.
(3aR,5R,6R,6aR)-6-(allyloxy)-5-((R)-2,2-dimethyl-1,3-dioxolan-4-yl)-
2,2-dimethyl-6-phenyltetrahydrofuro[3,2-d][1,3]dioxole (28a)
:
A
solution of PhMgBr (7.2 g, 42.8 mmol) in ether (50 mL) was added to a
solution of the ketone 27 (3 g, 10.7 mmol) in THF (60 mL) at 0 oC. Stirring
was continued for 2 h at 0 oC and then at room temperature for 12 h. The
reaction mixture was quenched with saturated NH4Cl and extracted with
ethyl acetate (3 x 50 mL). Organic layer was concentrated and the crude
product (2.7 g) was used for next step without purification. To a
suspension of sodium hydride (0.45 g, 18.6 mmol, 60% dispersion in
mineral oil) in dry THF (35 mL) was added a solution of alcohol (2.5 g,
7.44 mmol) in THF (17 mL) drop wise at 0 oC and the mixture was stirred
for 15 min., then at room temperature for 30 min. To this mixture allyl
bromide (2.9 g, 18.6 mmol) was added drop wise followed by a catalytic
General procedure for Diels-Alder reaction and aromatization
o
amount of TBAI and the reaction mixture was stirred at 0 C for 10 min.,
Method A: To a solution of quinone (0.65 mmol, 1.2 equiv) in dry
toluene (10 mL) was added a solution of diene (0.5 mmol, 1 equiv) in
toluene (3 mL) at RT and then refluxed till the complete disappearance of
diene. Then the solvent was removed under vacuum. The crude product
was dissolved in minimum amount of CHCl3. To this solution silica gel (2
g) purged in triethylamine (0.6 mL) was added and stirred till the
complete conversion to product was observed. Then the solvent was
removed in rotavapor and purified by a silica gel column chromatography
to afford the corresponding aromatized hybrid.
and then refluxed for 12 h. The reaction mixture was quenched with
saturated NH4Cl solution and extracted with ethyl acetate (3 x 50 mL).
The organic layer was washed with brine, dried over anhydrous Na2SO4,
concentrated and purified by silica gel column chromatography (25%
EtOAc/hexane) yielded 2 g of 28a as colourless syrup in 74% yield over
two steps. Rf = 0.6 (40% EtOAc/hexane); [α]25 = +106.0 (c 1.2, CHCl3);
D
IR (neat) 3017, 1646, 1496, 1427, 1373, 1219, 1023 cm−1; 1H NMR (500
MHz, CDCl3) δ 7.32–7.42 (m, 3H), 7.25–7.22 (m, 2H), 6.11 (d, J = 3.8 Hz,
1H), 6.25– 5.91 (m,1H), 5.38 (dd, J = 17.2, 1.9 Hz, 1H), 5.18 (dd, J = 7.7,
1.6 Hz, 1H), 4.75 (d, J = 3.8 Hz, 1H), 4.44 (d, J = 4.2 Hz, 1H), 4.17–4.13
(m, 1H), 3.87 (ddt, J = 12.4, 7.2, 1.7 Hz, 1H), 3.77–3.73 (m, 1H), 3.24,
(dd, J = 8.4, 6.4 Hz, 1H), 1.66 (s, 3H), 1.41 (s, 3H), 1.37 (s, 3H) , 1.22 (s,
3H); 13C NMR (100 MHz, CDCl3) δ 137.2, 134.9 128.7, 128.5, 126.9,
115.9, 112.7, 108.4, 105.3, 86.7, 83.2, 82.3, 74.2, 66.2, 64.5, 27, 26.8,
26.6, 25.5; HRMS (ESI) calcd. for C21H28O6Na (M+Na)+ 399.1784, found
399.1782.
Method B: A solution of diene (1 mmol) in dry toluene (10 mL) was
treated with DMAD (1.2 mmol) at RT and then heated at 80 oC until the
complete conversion of the diene to product was observed. The solvent
was removed under reduced pressure and the crude product was
dissolved in CH2Cl2 (20 mL) and treated with MnO2 (10 mmol) under
refluxing conditions. After 12 h, the reaction mixture was passed through
a small pad of Celite and the filtrate was concentrated and purified by
column chromatography to afford the corresponding aromatized adducts.
Note: For experimental details and spectral data of compounds 28b-18
and 37, 39 see reference (10).
(3aR,5R,6R,6aR)-6-(allyloxy)-2,2-dimethyl-6-phenyltetrahydrofuro
[3,2-d][1,3]dioxole-5 carbaldehyde (29a): The allyl ether 28a (2 g, 5.31
mmol) was stirred with 35 mL of 90% aqueous AcOH for 12 h at room
temperature. The reaction mixture was concentrated azeotropically to
provide a diol (1.4 g) as syrup in 70% yield. The resultant diol was
dissolved in DCM (5 mL) and added to a stirred suspension of silica
supported NaIO4 in DCM (10 mL). The stirring was continued at room
Compound 17: A solution of enyne 24 (0.23 g, 1.03 mmol) was
dissolved in dry CH2Cl2 (30 mL) under argon and the solution was
degassed. To this mixture a solution of 26 (0.059 g, 7 mol%) in CH2Cl2 (5
mL) was added dropwise and refluxed for 12 h. The reaction mixture was
cooled to room temperature and DMSO (0.36 mL, 5.15 mmol) was added
to quench the excess of catalyst and stirred for 6 h at room temperature.
Evaporation of solvent and purification by silica gel column
chromatography (5% ethyl acetate in hexanes) gave the cyclized
compound 17 (0.17 g) as colourless syrup in 77% yield. Rf = 0.6 (15%
EtOAc/hexane); [α]25D = +1.58 (c 2.4, CHCl3); IR (neat) 3030, 1671, 1629,
1454, 1376, 1216, 1091 cm−1; 1H NMR (400 MHz, CDCl3) δ 6.36 (dd, J =
17.7, 10.8 Hz, 1H), 5.98 (d, J = 3.7 Hz, 1H), 5.95–5.94 (m, 1H), 5.50 (d, J
= 17.5 Hz, 1H), 5.18 (d, J = 10.8 Hz, 1H), 4.60–4.58 (m, 2H), 4.29 (dd, J
= 17.7 , 4.1 Hz, 1H), 4.19 (d, J = 17.7 Hz, 1H), 3.97 (d, J = 2.4 Hz, 1H),
1.53 (s, 3H), 1.33 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 135.7, 131.7,
129.2, 114.7, 111.5, 105.3, 83.7, 79.0, 70.8, 64.8, 26.9, 26.2; HRMS
(ESI) calc. for C12H16O4Na (M+Na)+ 247.0946, found 247.0949.
temperature for
8 h. The solid was filtered off. The filtrate was
concentrated to afford the aldehyde 29a in quantitative yield. Rf = 0.5
(20% EtOAc/hexane); [α]25D = +87.2 (c 1.0, CHCl3); IR (neat) 3021, 2927,
;
2857, 1728, 1671, 1591, 1278, 1216, 1021 cm−1 1H NMR (400 MHz,
CDCl3) δ 9.19 (s, 1H), 7.42–7.36 (m, 2H), 7.36–7.31 (m, 1H), 7.24–7.15
(m, 1H), 6.22 (d, J = 3.6 Hz, 1H), 6.04–5.92 (m, 1H), 5.37 (dq, J = 17.2,
1.7 Hz, 1H), 5.21 (dq, J = 10.4, 1.6 Hz, 1H), 4.83 (d, J = 3.5 Hz, 1H), 4.71
(d, J = 1.5 Hz, 1H), 4.14 (ddt, J = 12.0, 5.5, 1.5 Hz, 1H), 3.92 (ddt, J =
12.0, 5.5, 1.5 Hz, 1H), 2.86 (dd, J = 8.4, 6.5 Hz, 1H), 1.66 (s, 3H), 1.44 (s,
3H); 13C NMR (100 MHz, CDCl3) δ 197.9, 135.6, 134.3, 129.1, 128.9,
126.6, 116.9, 113.5, 105.9, 87.9, 85.9, 83.4, 66.6, 27.1, 26.8; HRMS
(ESI) calcd. for C17H20O5Na (M+Na)+ 327.1208, found 327.1221.
(3aR,5R,6R,6aR)-6-(allyloxy)-5-ethynyl-2,2-dimethyl-6-phenyltetra
hydrofuro[3,2 d][1,3] dioxole (30a): To a solution of aldehyde 29a (0.3
g, 0.98 mmol) in dry methanol (21 mL) was added anhydrous K2CO3
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10.1002/ejoc.201700599
European Journal of Organic Chemistry
FULL PAPER
(0.34 g). To this mixture dimethyl-1-diazo-2-oxopropylphosphonate 25
was added at room temperature and stirred for 4 h. The reaction mixture
was diluted with 35 mL of ether, washed with 5% of aqueous NaHCO3
and the organic layer was concentrated. The crude product was purified
by a silica gel column chromatography (5% EtOAc/hexane) to afford the
30a (0.2 g) as a white gummy solid in 71% yield. Rf =0.7 (10%
aromatized adduct 32 in 67% yield as a brown solid after silica gel
column chromatography (8% EtOAc/hexane) : mp = 186–188 oC ; Rf =
0.5 (15% EtOAc/hexane); [α ]25 = +142 (c 0.8, CHCl3); IR (neat) 3469,
D
1
2924, 1617, 1418, 1352, 1218, 1094 cm−1; H NMR (400 MHz, CDCl3) δ
12.84 (s, 2H), 8.39, (d, J = 8.0 Hz, 1H), 7.97 (d, J = 8.0 Hz, 1H), 7.31 (s,
2H), 6.04 (d, J = 4.0 Hz, 1H), 5.68 (d, J = 17.6 Hz, 1H), 5.08 (d, J = 17.6
Hz, 1H), 5.06 (d, J = 2.0 Hz, 1H), 4.81 (d, J = 4.0 Hz, 1H), 4.22 (d, J =
2.4 Hz, 1H), 1.62 (s, 3H), 1.40 (s, 3H); 13C NMR (100 MHz, CDCl3) δ
188.9, 186.6, 139.9, 157.5, 136.9, 134.8, 129.9, 129.7, 129.3, 126.3,
112.4, 112.3, 105.4, 84.8, 78.7, 73.8, 68.1, 29.9, 27.0, 26.3; HRMS (ESI)
calcl. For C22H19O8 (M+H)+ 411.1080, found 411.1100.
EtOAc/hexane); [α]25 = +64.5 (c 0.78, CHCl3); IR (neat) 3019, 2400,
D
1
1522, 1425, 1219, 1097, 1018 cm−1; H NMR (400 MHz, CDCl3) δ 7.52–
5.48 (m, 2H), 7.44–7.33 (m, 3H), 6.03–5.94 (m, 1H), 5.93 (d, J = 3.7 Hz,
1H), 5.33 (dq, J = 17.2, 1.7Hz, 1H), 5.21 (dq, J = 17.2, 1.7 Hz, 1H), 5.11
(d, J = 2.3 Hz, 1H), 4.71 (d, J = 3.6 Hz, 1H), 4.12 (ddt, J = 12.0, 5.6, 1.4
Hz, 1H), 3.92 (ddt, J = 12.0, 5.6, 1.4 Hz, 1H), 2.40 (s, 1 H), 1.65 (s, 3H),
1.38 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 136.6, 134.6, 128.6, 127.6,
117.0, 113.4, 104.6, 87.5, 83.5, 78.4, 78.3, 73.3, 67.0, 27.1, 26.6; HRMS
(ESI) calcd. for C18H20O4Na (M+Na)+ 323.1259, found 323.1266.
Hybrid compound 33 : Following the general procedure (method A) for
Diels-Alder reaction between the diene 17 (0.112 g, 0.5 mmol) and 1,4-
dihydroxy naphthoquinone 13 (0.135 g, 0.65mmol) afforded 0.150 g of
the aromatized adduct 33 in 71% yield as a brown solid after silica gel
column chromatography (8% EtOAc/hexane) : mp = 179–181 oC; Rf = 0.5
Compound 19: A solution of enyne 30a (0.3 g, 1.05 mmol) in dry CH2Cl2
(340 mL) under Argon was degassed and to this mixture a solution of
Grubbs’ catalyst 26 (0.052 g, 7 mol %) in CH2Cl2 (5 mL) was added drop
wise and refluxed for 11 h. The reaction mixture was cooled to room
temperature and DMSO (5.9 mmol) was added to quench the catalyst
and stirred for 6 h at room temperature. Evaporation of the solvent and
purification by silica gel column chromatography (8% EtOAc/hexane)
gave 19 (0.24 g) as a white gummy solid in 80% yield. Rf =0.7 (10%
(15% EtOAc/hexane); [α ]25 = –87.17 (c 0.39, CHCl3); IR (neat) 3464,
D
3020, 1732, 1645, 1375, 1215, 1094 cm−1;1H NMR (400 MHz, CDCl3) δ
8.80 (s, 1H), 8.77, (s,1H), 8.41 (d, J = 8.0 Hz, 1H), 8.11–8.06 (m, 2H),
7.94 (d, J = 8.0 Hz, 1H), 7.67–7.30 (m, 2H), 6.03 (d, J = 3.8 Hz, 1H), 5.65
(d, J = 17.5 Hz, 1H), 5.11 (d, J = 17.5 Hz, 1H), 5.05 (d, J = 2.0 Hz, 1H),
4.80 (d, J = 3.5 Hz, 1H), 4.24 (d, J = 2.2 Hz, 1H), 1.62 (s, 3H), 1.40 (s,
3H); 13C NMR (100 MHz, CDCl3) δ 184.6, 182.7, 139.5, 136.9, 136.4,
135.7, 135.4, 135.1, 130.8, 130.3, 130.2, 130.2, 129.7, 129.6, 129.4,
128.9, 126.7, 112.2, 105.4, 84.8, 78.7, 73.8, 68.2, 27.0, 26.3; HRMS
(ESI) calcl. For C26H21O6 (M+H)+ 429.1338, found 429.1331.
EtOAc/hexane); [α ]25 = +265.9 (c 0.46, CHCl3); IR (neat) 2939, 1657,
D
1451, 1376, 1215, 1090 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.65–7.59 (m,
2H), 7.36–7.24 (m, 3H), 6.30 (dd, J = 17.5, 11.1 Hz, 1H,), 5.90 (d, 17.4
Hz, 1H), 5.71 (d, J = 3.3 Hz, 1H), 5.31–5.21 (m, 3H), 4.52 (d, J = 3.3 Hz,
1H), 4.43 (d, J = 18.6 Hz, 1H), 3.97 (d, J = 2.5 Hz, 1H), 1.67 (s, 3 H),
1.33 (s, 3 H); 13C NMR (100 MHz, CDCl3) δ 138.2, 136.8, 134.3, 134.2,
128.5, 128.2, 127.9, 123.6, 117.5, 117.4, 114.1, 106.0, 83.0, 75.2, 65.7,
26.8, 26.3; HRMS (ESI) calcd. for C18H20O4Na (M+Na)+ 323.1259, found
323.1264.
Hybrid compound 34 : Following the general procedure (method A) for
Diels-Alder reaction between the diene 17 (0.112 g, 0.5 mmol) and 5-
hydroxy 1,4-naphthoquinone 14 (0.113 g, 0.65 mmol) afforded 0.164 g of
the aromatized adduct 34 in 80% yield (inseparable mixture of
diastereomers (d.r = 2.2:1)) as a brown solid after silica gel column
o
chromatography (8% EtOAc/hexane) : mp = 187–189 C ; Rf = 0.6 (15%
EtOAc/hexane); [α ]25 = –89.9 (c 1.3, CHCl3); IR (neat) 3472, 2927,
;
2854, 1966, 1732, 1673, 1636, 1456, 1313, 1216, 1096 cm−1 1H NMR
Hybrid compound 31 : Following the general procedure (method A) for
Diels-Alder reaction between the diene 17 (0.112 g, 0.5 mmol) and 1, 4-
naphthoquinone 11 (0.102 g, 0.65 mmol) afforded 0.128 g of the
aromatized adduct 31 in 68% yield as a yellow solid after silica gel
column chromatography (8% EtOAc/hexane): mp = 172–174 oC; Rf = 0.6
D
(500 MHz, CDCl3) δ 12.46 (s, 0.65H), 12.39 (s, 0.3H), 8.28–8.25 (m, 1H),
7.93–7.87 (m,1H), 7.78 (dd, J = 7.4, 1.1 Hz, 0.7H), 7.69 (dd, J = 7.5, 1.2
Hz, 0.3H), 7.66–7.63 (m, 1H), 7.29–7.25 (m, 1H), 6.02–6.01 (m, 1H),
5.59–5.49 (m, 1H), 4.99–4.98 (m, 2H), 4.78 (d, J = 3.6 Hz, 1H), 4.18 (s,
1H), 1.62 (s, 3H), 1.40 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 190.4,
187.9, 183.8, 181.9, 162.3, 161.1, 139.4, 137.9, 136.9, 136.8, 136.6,
136.2, 134.5, 134.1, 133.8, 132.4, 129.6, 129.1, 126.4, 125.9, 124.6,
123.9, 119.4, 119.2, 116.4,115.3, 112, 105.2, 84.5, 78.5, 78.4, 73.6, 73.5,
67.8, 67.7, 26.8, 26.1; HRMS (ESI) calcl. For C22H18O7Na (M+Na)+
417.0950, found 417.0931.
(15% EtOAc/hexane); [α]25 = +215 (c 1.1, CHCl3); IR (neat) 3021,
D
2929,1675, 1412, 1217, 1086, 1017 cm−1 1H NMR (400 MHz,CDCl3) δ
;
8.34, (d, J = 8.0 Hz, 1H), 8.29–8.26 (m, 1H), 8.25–8.10 (m, 1H), 7.93 (d,
J = 8.0 Hz, 1H), 7.84–7.77 (m, 2H), 6.02 (d, J = 3.7 Hz, 1H), 5.60 (d, J =
17.8 Hz, 1H), 5.07 (d, J = 17.8 Hz, 1H), 5.04 (s, 1H), 4.79 (d, J = 3.8 Hz,
1H), 4.22 (d, J = 2.3 Hz, 1H), 1.61 (s, 3H), 1.39 (s, 3H); 13C NMR (100
MHz, CDCl3) δ 184.0, 183.0, 139.4, 136.9, 136.4, 134.8, 134.5, 134.3,
134.2, 132.7, 129.8, 127.4, 127.1, 126.6, 112.2, 105.4, 84.8, 78.8, 73.8,
68.0, 27.0, 26.3; HRMS (ESI) calcd. for C22H19O6 (M+H)+ m/z 379.1182,
found 379.1167.
Hybrid compound 35 : Following the general procedure (method A) for
Diels-Alder reaction between the diene 17 (0.112 g, 0.5 mmol) and 4-
nitronaphthoquinone 15 (0.132 g, 0.65 mmol) afforded 0.164 g of the
aromatized adduct 35 in 75% yield as a yellow solid (inseparable mixture
of diastereomers (d.r = 6.3:1)) after silica gel column chromatography
(9% EtOAc/hexane): mp = 218–220 oC ; Rf = 0.4 (15% EtOAc/hexane);
Hybrid compound 32 : Following the general procedure (method A) for
Diels-Alder reaction between the diene 17 (0.112 g, 0.5 mmol) and 1,4-
dihydroxy naphthoquinone 12 (0.123, 0.65 mmol) afforded 0.137 g of the
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10.1002/ejoc.201700599
European Journal of Organic Chemistry
FULL PAPER
[α ]25D = –79.5 (c 0.27, CHCl3); IR (neat) 2923, 2858, 1631, 1546, 1528,
Hz, 1H), 5.16 (s, 1H), 4.54 (dd, J = 3.3, 1.6 Hz, 1H), 1.66 (s, 3H), 1.43
(s, 3H), 0.98 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 190.7, 188.3, 184.1,
182.4, 162.6, 162.3, 142.9, 142.4, 137.3, 137.0, 136.7, 134.2, 133.9,
133.5, 132.7, 129.8, 129.4, 129.3, 129.1, 127.2, 126.6, 124.8, 124.0,
119.3, 116.8, 115.6, 114.3, 106.8, 82.7, 75.0, 74.9, 67.6, 26.6, 26.2, 15.9,
15.8; HRMS (ESI) calcd. For C23H21O7 m/z (M+H)+ 409.1287, found
409.1271.
1376, 1211, 1094, 1015 cm−1 1H NMR (500 MHz, CDCl3) δ 8.43, (dd, J
;
= 7.9, 0.95 Hz, 1H), 8.26 (d, J = 8.0 Hz, 1H), 7.99–7.95 (m, 1H), 7.94–
7.89 (m, 1H), 7.76 (dd, J = 7.8, 1 Hz, 1H), 6.01 (d, J = 3.7 Hz, 1H), 5.55
(d, J = 17.6 Hz, 1H), 5.01–5.08 (m, 2H), 4.78 (d, J = 3.6 Hz, 1H), 4.21 (d,
J = 1.2 Hz, 1H), 1.60 (s, 3H), 1.39 (s, 3H); 13C NMR (125 MHz, CDCl3) δ
182.4, 179.7, 148.7, 139.6, 139.5, 137.6, 137.0, 136.8, 134.9, 134.8,
134.4, 134.2, 129.7, 129.5, 128.5, 128.1, 127.5, 126.8, 126.5, 123.9,
112.1, 112.0, 105.2, 84.5, 78.7, 78.6, 73.4, 67.6, 67.4, 26.8, 26.1; HRMS
(ESI) calcl. For C22H17NNaO8 (M+Na)+ 446.0846, found 446.0841.
Hybrid compound 41 : Following the general procedure ( method A) for
Diels-Alder reaction between the diene 18 (0.119 g, 0.5 mmol) and 5-
nitronaphthoquinone 15 (0.132 g, 0.65 mmol) afforded 0.183 g of the
aromatized adduct 41 in 81% yield as a yellow solid (as a mixture of
inseparable diastereomers d.r
=
3.1:1) after silica gel column
Hybrid compound 36 : Following the general procedure (method B) for
Diels-Alder reaction between the diene 17 (0.112 g, 0.5 mmol) and
DMAD 16 (0.092 g, 0.65 mmol) afforded 0.133 g of the aromatized
o
chromatography (8% EtOAc/hexane) : mp = 176–178 C , Rf = 0.6 (15%
EtOAc/hexane); [α ]25 = +5.3 (c 0.46, CHCl3); IR (neat) 2926, 2854,
D
1966, 1605, 1571, 1545, 1514, 1365, 1216, 1082 cm−1
;
1H NMR (400
adduct 36 in 73% yield as
a white solid after silica gel column
chromatography (30% EtOAc/hexane) : mp = 154–156 oC ; Rf = 0.6 (30%
MHz, CDCl3) δ 8.35 (d, J = 7.9 Hz, 1H), 7.45 (dd, J = 8.2 Hz, 1H), 6.95
(dd, J = 8.3,1.0 Hz, 1H), 5.97 (d, J = 3.3 Hz, 1H), 5.67 (d, J = 18.9 Hz,
1H), 5.53 (d, J = 18.8 Hz, 1H), 5.15 (s, 1H), 4.51 (d, J = 3.3 Hz, 1H),
1.65 (s, 3H), 1.41 (s, 3H), 0.95 (s, 3H); 13C NMR (100 MHz, CDCl3) δ
185.0, 184.7, 181.4, 150.7, 143.2, 140.9, 137.4, 136.3, 135.2, 135, 134.9,
134.4, 133.6, 132.6, 129.8, 129.5, 129, 128.9, 128, 127, 126.4, 122.6,
117.3, 114.3, 114.1, 113, 106.6, 82.6, 82.5, 74.9, 74.8,67.5, 67, 26.53,
26.1, 26, 15.8, 15.7; HRMS (ESI) calcl. For C23H19NNaO8 (M+Na)+
460.1003, found 409.1000.
EtOAc/hexane); [α ]25 = -155 (c 0.91, CHCl3); 1H NMR (400 MHz,
D
CDCl3) δ 7.90 (d, J = 8.0 Hz, 1H), 7.63 (d, J = 8.0 Hz, 1H), 5.98 (d, J =
3.8 Hz, 1H), 4.99 (d, J = 2.3 Hz, 1H), 4.81 (d, J = 15.6 Hz, 1H), 4.73 (d, J
= 3.8 Hz, 1H), 4.66 (d, J = 15.6 Hz, 1H), 4.17 (d, J = 2.4 Hz, 1H), 3.91 (s,
3H), 3.89 (s, 3H),1.59 (s, 3H), 1.37 (s, 3H); 13C NMR (100 MHz, CDCl3)
δ 168.3, 166.0, 134.6, 133.3, 132.1, 131.6, 128.9, 128.7, 112.1, 105.3,
84.7, 79.7, 73.0, 65.5, 52.9, 52.8, 26.9, 26.3; IR (neat) 3019, 2929, 1733,
1449, 1216, 1018 cm−1; HRMS (ESI) calcd. for C18H20O8Na (M+Na)+
387.1050 found 387.1049.
Hybrid compound 42 : Following the general procedure (method B) for
Diels-Alder reaction between the diene 18 (0.119 g, 0.5 mmol) and
DMAD (0.092 g, 0.65 mmol) afforded 0.130 g of the aromatized adduct
Hybrid compound 38 : Following the general procedure (method A) for
Diels-Alder reaction between the diene 18 (0.119 g, 0.5 mmol) and 5, 8-
dihydroxynaphthoquinone 12 (0.123 g, 0.65 mmol) afforded 0.131 g of
the aromatized adduct 38 in 62% yield as a red solid after silica gel
column chromatography (9% EtOAc/hexane) : mp = 192–194 oC; Rf =
42 in 61% yield as
a white yellow solid after silica gel column
chromatography (13% EtOAc/hexane) : mp = 162–164 oC ; Rf = 0.6 (25%
EtOAc/hexane); [α]25 = −50.4 (c 1.3, CHCl3); IR (neat) 2926, 1735,
D
1639, 1374, 1250, 1098, 1025, 945 cm−1 1H NMR (500 MHz, CDCl3) δ
;
0.65 (15% EtOAc/hexane); [α]25 = +36.1 (c 0.5, CHCl3); IR (KBr) 3413,
D
2930, 2862, 1967, 1616, 1455, 1248, 1217, 1090, 1038 cm−1 1H NMR
;
7.93 (d, J = 7.9 Hz, 1H), 7.52 (d, J = 7.9 Hz, 1H), 5.94 (d, J = 3.7 Hz, 1H),
5.04-5.12 (m, 2H), 4.93 (d, J = 16.2 Hz, 1H), 4.45 (d, J = 3.2 Hz, 1H),
3.91 (s, 3H), 3.88 (s, 3H), 1.62 (s, 3H), 1.39 (s, 3H), 0.87 (s, 3H);; 13C
NMR (100 MHz, CDCl3) δ 168.4, 165.8, 139.9, 137.2, 130.1, 127.9,
127.5, 125.7, 112.3, 105.3, 84.5, 80.1, 70.3, 67.4, 52.9, 52.8, 27.2, 26.7;
HRMS (ESI) calcl. For C19H22O8Na (M+Na)+ 401.1207, found 401.1207.
(400 MHz, CDCl3) δ 12.89 (s, 2H), 8.43 (d, J = 8.0 Hz, 1H), 7.90 (d, J =
8.0 Hz, 1H), 7.31(s, 2 H), 5.98 (d, J = 3.2 Hz, 1H), 5.74 (d, J = 19.2 Hz,
1H), 5.58 (d, J = 19.2 Hz, 1H,), 5.17 (s, 1H), 4.53 (d, J = 3.3 Hz, 1H),
1.69 (s, 3H), 1.24 (s, 3H), 1.00 (s, 3H); 13C NMR (100 MHz, CDCl3) δ
188.9, 186.7, 157.9, 157.6, 142.8, 137.6, 133.8, 129.8, 129.7, 129.4,
129.1, 126.8, 114.4, 113.5, 112.4, 106.8, 82.7, 77.40, 75.0, 67.7, 26.7,
26.2, 15.8; HRMS (ESI) calcd. for C23H20O8 m/z (M+H)+ 425.1236, found
425.1240.
Hybrid compound 43 : Following the general procedure (method A) for
Diels-Alder reaction of the diene 19 (0.150 g, 0.5 mmol) and 1,4-
naphthoquinone 11 (0.101 g, 0.65 mmol) afforded 0.186 g of the
aromatized adduct 43 in 82% yield as a dark yellow solid after silica gel
column chromatography (8% EtOAc/hexane): mp = 186–188 oC; Rf = 0.5
(10% EtOAc/hexane); [α ]25D = −23.4 (c 1.6, CHCl3); IR (KBr) 2983, 1671,
Hybrid compound 40 : Following the general procedure ( method A) for
Diels-Alder reaction between the diene 18 (0.119 g, 0.5 mmol) and 5-
hydroxynaphthoquinone 14 (0.113 g, 0.65 mmol) afforded 0.171 g of the
aromatized adduct 40 in 84% yield as a yellow solid (mixture of
1591, 1566, 1449, 1375, 1322, 1215, 1094 cm−1 1H NMR (400 MHz,
;
CDCl3) δ 8.36, (d, J = 7.9 Hz, 1H), 8.17−8.23 (m, 1H), 8.08−8.15 (m, 1 H),
8.14 (dd, J = 7.9, 1 Hz, 1H), 7.68−7.75 (m, 2H), 7.48−7.53 (m, 2H),
7.10−7.22 (m, 3H), 5.90 (d, J = 3.1 Hz, 1H), 5.73 (d, J = 4.3 Hz, 1H),
5.69 (s, 1H), 5.16 (d, 1H, J = 18.8 Hz), 4.67 (d, J = 3.12 Hz, 1H), 1.72 (s,
3H), 1.42 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 184.6, 183.1, 143, 136.8,
136.6, 134.3, 134.1, 134, 133.6, 132.6, 129.3, 128.8, 128.7, 127.4, 127,
inseparable regioisomers d.r.
chromatography (13% EtOAc/hexane): mp = 183–185 oC; Rf = 0.6 (25%
=
2.2:1) after silica gel column
EtOAc/hexane); [α ]25 = +247 (c 0.75, CHCl3); IR (neat) 2923, 2853,
D
1669, 1634, 1455, 1374, 1216, 1087, 1049 cm−1;1H NMR (400 MHz,
CDCl3) δ 12.59 (s, 0.7H), 12.5 (s, 0.3H), 8.35 (d, J = 7.9 Hz, 1H), 7.86
(dd, J = 16.8, 0.9 Hz, 1H), 7.63–7.70 (m, 1H), 7.27–7.33 (m, 1H), 5.99 (d,
J = 3.3 Hz, 1H), 5.67 (dd, J = 19.1, 6.9 Hz, 1H), 5.56 (dd, J = 19.1, 8.9
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10.1002/ejoc.201700599
European Journal of Organic Chemistry
FULL PAPER
115.1, 107.0, 84.0, 81.1, 76.4, 68.4, 27.0, 26.4; HRMS (ESI) calcd. for
C28H22O6Na (M+Na)+ 455.1495, found 455.1496.
Hybrid compound 47 : Following the general procedure (method A) for
Diels-Alder reaction of the diene 19 (0.150 g, 0.5 mmol) and 5-nitro
naphthoquinone 15 (0.132 g, 0.65 mmol) afforded 0.216 g of the
aromatized adduct 47 in 84% yield as a yellow solid (as mixture of
inseparable diastereomers d.r.
= 1.7:1) after silica gel column
Hybrid compound 44 : Following the general procedure (method A) for
Diels-Alder reaction of the diene 19 (0.150 g, 0.5 mmol) and 5,8-
dihydroxynaphthoquinone 12 (0.12 g, 0.65 mmol) afforded 0.153 g of the
aromatized adduct 44 in 63% yield as a red solid after silica gel column
chromatography (6% EtOAc/hexane): mp = 228–230 oC; Rf = 0.7 (10%
chromatography (8% EtOAc/hexane), Rf = 0.6 (15% EtOAc/hexane): mp
= 196–198 oC; [α ]25 = −9.5 (c 0.9, CHCl3); IR (KBr) 2926, 1738, 1634,
D
–1
1605, 1570, 1544, 1457, 1376, 1322, 1275, 1259, 1095, 1015 cm
;
1H
NMR (500 MHz, CDCl3) δ 8.25–8.35 (m, 2H), 8.06 (dd, J = 7.8, 1 Hz, 1H),
7.66 (dd, J = 7.8, 0.95 Hz, 1H), 7.44–7.53 (m, 2H), 7.11–7.22 (m, 4H),
5.90 (m, 1H), 5.64–5.75 (m, 2H), 5.09−5.14 (m, 1H), 4.64−4.66 (m, 1H),
1.72 (s, 3 H), 1.39 (s, 3 H); 13C NMR (100 MHz, CDCl3) δ 184.7, 184.6,
182, 179.6, 150.5, 148.7, 143.7, 141.6, 137, 136.5, 136.1, 134.9, 134.8,
134.7, 134.5, 133.1, 129.7, 129.3, 128.8, 128.6, 128.4, 128.3, 128.2,
128.1, 128.0, 127.9, 127.4, 127.2, 126.2, 124.0, 122.4, 117.1, 114.9,
114.8, 106.9, 106.8, 83.9, 83.8, 81, 80.9, 76.2, 76.1, 68.2, 67.9, 26.7,
26.2; HRMS (ESI) calcd. for C28H21NNaO7 (M+Na)+ 522.1159, found
522.1158.
EtOAc/hexane); [α ]25 = –116.8 (c 1.3, CHCl3); IR (KBr) 3439, 2924,
D
1
2854, 1618, 1455, 1248, 1095, 1018 cm−1; H NMR (400 MHz, CDCl3) δ
12.85 (s, 1H), 12.77 (s, 1H), 8.41 (d, J = 7.96 Hz, 1H), 8.09 (d, J = 1.08
Hz, 1H), 7.50 (d, J = 1.56 Hz, 1H), 7.25 (s, 1H), 7.12–7.22 (m, 5H), 5.90
(d, J = 3.12 Hz, 1H), 5.73 (s, 1H), 5.72 (d, J = 18.9 Hz, 1H), 5.16, (d, J =
18.9 Hz, 1H), 4.67, (d, 3.16 Hz, 1H), 1.72 (s, 3H), 1.40 (s, 3H); 13C NMR
(100 MHz, CDCl3) δ 188.7, 186.6, 157.7, 143.6, 137.3, 136.4, 133.4,
129.6, 129.3, 129.2, 129.0, 128.7, 128.3, 128.2, 126.6, 115.1, 113.4,
112.2, 107.0, 84.1, 81.0, 68.3, 27.0, 26.3; HRMS (ESI) calcd. for
C28H23O8 m/z (M+H)+ 487.1393, found 487.1401.
Hybrid compound 48 : Following the general procedure (method B) for
Diels-Alder reaction of the diene 19 (0.150 g, 0.5 mmol) and DMAD
(0.092 g, 0.65 mmol) afforded 0.165 g of the aromatized adduct 48 in
75% yield as colourless solid after silica gel column chromatography
Hybrid compound 45 : Following the general procedure (method A) for
Diels-Alder reaction of the diene 19 (0.150 g, 0.5 mmol) and 1,4-
anthraquinone 13 (0.135 g, 0.65 mmol) afforded 0.224
g of the
o
(40% EtOAc/hexane). Rf = 0.52 (20% EtOAc/hexane): mp = 175–177 C
aromatized adduct 45 in 89% yield as a yellow solid after silica gel
column chromatography (9% EtOAc/hexane) : mp = 198–200 oC; Rf = 0.7
[α ]25 = −29.9 (c 1.5, CHCl3); IR (neat) 3020, 2929, 1733, 1449, 1216,
D
1018 cm−1 ; 1H NMR (400 MHz, CDCl3) δ 8.31, (d, J = 8.2 Hz, 1H), 7.92
(d, J = 8.2 Hz, 1H), 7.34–7.44 (m, 5H), 5.20 (d, J = 2.9 Hz, 1H), 4.90 (d,
J = 16.3 Hz, 1H), 4.80 (d, J = 16.3 Hz, 1H), 4.52 (d, J = 2.88 Hz, 1H),
3.91 (s, 3H), 3.90 (s, 3H), 1.29 (s, 3H), 1.28 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ 168.4, 166.2, 132.6, 129.5, 129.0, 128.9, 128.7, 127.6, 112.7,
104.3, 88.8, 60.8, 55.3, 53.2, 27.1, 27.0; HRMS (ESI) calcd. For
C24H25O8 (M+H)+ 441.1549, found 441.1537.
(15% EtOAc/hexane); [α ]25 = –46.16 (c 0.50, CHCl3); IR (KBr) 2930,
;
1672, 1619, 1588, 1458, 1297, 1206, 1093, 1048 cm−1 1H NMR (400
D
MHz, CDCl3) δ 8.75 (s, 1H), 8.65 (s, 1H), 8.45 (d, J = 7.9 Hz, 1H), 8.05–
8.12 (m, 3H), 7.63–7.66 (m, 2H), 7.52–7.54 (m, 2H), 7.10–7.22 (m, 3H),
5.92 (d, J = 3.1 Hz, 1H), 5.78 (d, J = 18.6 Hz, 1H), 5.74 (s, 1H), 5.22 (d,
J = 18.6 Hz, 1H), 4.68, (d, 3.1Hz, 1H), 1.73 (s, 3H), 1.41 (s, 3H); 13C
NMR (100 MHz, CDCl3) δ 184.5, 183, 142.9, 137, 136.6, 135.4, 135.1,
134.7, 130.4, 130.2, 129.8, 129.6, 129.2, 129, 128.8, 128.7, 128.2, 127.2,
115.0, 107.0, 84.2, 81.1, 68.5, 27.0, 26.4 ; HRMS (ESI) calcd. for
C32H24O6 (M+H)+ 505.1651, found 505.1661.
Hybrid compound 49 : Following the general procedure (method A) for
Diels-Alder reaction between the diene 20 (0.112 g, 0.5 mmol) and 1,4-
naphthoquinone 11 (0.102 g, 0.65 mmol) afforded 0.145 g of the
aromatized adduct 49 in 77% yield as a pale yellow solid after silica gel
column chromatography (11% EtOAc/hexane: mp = 152–154 oC; Rf = 0.6
(20% EtOAc/hexane); [α ]25D = +129 (c 1.2, CHCl3); IR (neat) 2926, 2854,
Hybrid compound 46 : Following the general procedure (method A) for
Diels-Alder reaction of the diene 19 (0.150 g, 0.5 mmol) and 5-hydroxy
1,4-naphthoquinone 14 (0.113 g, 0.65 mmol) afforded 0.172 g of the
aromatized adduct 46 in 71% yield as a yellow solid (mixture of
1674, 1592, 1324, 1286, 1217, 1164, 1069 cm−1 1H NMR (500 MHz,
;
CDCl3) δ 8.30−8.40 (m, 2H), 8.21−8.29 (m, 1H), 7.77−7.79 (m, 2H), 7.49
(d, J = 8.0 Hz, 1H), 6.22 (d, J = 2.0 Hz, 1H), 6.03 (d, J = 3.7 Hz, 1H),
4.91−4.96 (m, 1H), 4.82−4.88 (m, 1H), 4.68−4.77 (m, 1H), 4.24 (d, 1H, J
= 2.1 Hz), 1.82 (s, 3H), 1.43 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 184.0,
183.2, 142.3, 134.7, 134.5, 133.9, 132.5, 131.2, 130.2, 128.3, 128.2,
126.8, 112.6, 105.1, 84.3, 79.9, 70.8, 67.8, 27.35, 27.0; HRMS (ESI)
calcl. For C22H19O6 (M+H)+ 379.1182, found 379.1194.
inseparable regioisomers d.r.
=
2.1:1) after silica gel column
chromatography (8% EtOAc/hexane): mp = 204–206 oC; Rf = 0.75 (15%
EtOAc/hexane); [α]25 = – 85.5 (c 1.19, CHCl3); IR (KBr) 3429, 2933,
D
1966, 1669, 1636, 1586, 1454, 1277, 1217, 1095, 1014 cm –1 ;1H NMR
(500 MHz, CDCl3) δ 12.49, (d, 1H, J = 4.2 Hz), 8.20–8.39 (m, 1H), 8.05
(d, J = 8.0 Hz, 1H), 7.73 (d, J = 7.4 Hz, 1H), 7.66–7.76 (m, 1H), 7.48–
7.53 (m, 2 H), 7.12–7.25 (m, 4H), 5.90 (d, 1 H, J = 2.9 Hz), 5.64–5.75 (m,
2H), 5.14 (d, 1H, J = 18.6 Hz), 4.67 (d, 1H, J = 2.9 Hz), 1.72 (s, 3 H),
1.43 (s, 3 H); 13C NMR (100 MHz, CDCl3) δ 190.5, 182.4, 162.6, 143.2,
136.9, 136.7, 136.5, 136.3, 133.5, 132.5, 129.2, 128.9, 128.5, 128.1, 128,
126.9, 126.4, 124.5, 123.7, 119.4, 119, 116.6, 114.9, 107.07, 84.1, 81.09,
80.9, 76.2, 76.1, 68.1, 26.8, 26.2; HRMS (ES) calcd. for C28H23O7
(M+H)+ 471.1444, found 471.1440.
Hybrid compound 50 : Following the general procedure (method A) for
Diels-Alder reaction between the diene 20 (0.112 g, 0.5 mmol) and 1,4-
dihydroxy naphthoquinone 12 (0.123 g, 0.65 mmol) afforded 0.096 g of
the aromatized adduct 50 in 63% yield as a brown solid after silica gel
column chromatography (8% EtOAc/hexane): mp = 177–179 oC; Rf = 0.5
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201700599
European Journal of Organic Chemistry
FULL PAPER
(15% EtOAc/hexane); [α ]25 = +51.3 (c 0.37, CHCl3); IR (neat) 3432,
CDCl3) δ 8.52 (dd, J = 7.9, 1.0 Hz, 1H), 8.26 (d, J = 8.0 Hz, 1H), 7.89 (dd,
J = 7.9, 7.8 Hz, 1H), 7.72−7.74 (dd, J = 7.8, 0.8 Hz, 1H), 7.52 (d, J = 7.8
Hz, 1H), 6.10 (d, J = 1.8 Hz, 1H), 6.0 (d, J = 4 Hz, 1H), 4.94 (d, J = 12 Hz,
1H), 4.82 (d, J = 12 Hz, 1H), 4.72 (d, 1H, J = 3.70 Hz), 4.23 (d, 1H, J =
2.2 Hz), 1.78 (s, 3H), 1.42 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 182.5,
179.7, 148.9, 148.2 135.5, 134.6, 133.4 130.9, 130.8, 130.4, 128.9,
123.3, 122.8, 112.4, 104.2, 84.9, 79.7, 70.4, 67.6, 27.4, 26.8 ; HRMS
(ESI) calcl. For C22H17O8NNa (M+Na)+ 446.0850, found 446.0850.
D
2923, 2857, 1671, 1583, 1322, 1283, 1211, 1165, 1065 cm−1 1H NMR
;
(500 MHz, CDCl3) δ 13.02 (s, 1H), 12.9 (s, 1H), 8.42 (d, J = 8 Hz, 1H),
7.53 (d, J = 8.1 Hz, 1H), 7.28−7.33 (m, 2H), 6.2 (d, J = 1.3 Hz, 1H), 6.03
(d, J = 3.5 Hz, 1H), 4.96 (d, J = 16 Hz, 1H),4.87 (d, J = 16 Hz, 1H), 4.73
(d, 1H, J = 3.5 Hz), 4.23 (d, 1H, J = 1.5 Hz), 1.76 (s, 3H), 1.42 (s, 3H);
13C NMR (125 MHz, CDCl3) δ 188.2, 186.2, 158.0, 157.4, 134.8, 131.8,
131.5, 130.6, 130, 128.9, 127.8, 113.4, 112.6, 112.1, 104.9, 83.9, 79.5,
70.6, 67.7, 27.1, 26.8; HRMS (ESI) calcl. For C22H18NaO8 (M+Na)+
433.0894, found 433.0896.
Hybrid compound 54 : Following the general procedure (method B) for
Diels-Alder reaction between the diene 20 (0.112 g, 0.5 mmol) and
DMAD (0.092 g, 0.65 mmol) afforded 0.138 g of the aromatized adduct
Hybrid compound 51 : Following the general procedure (method A) for
Diels-Alder reaction between the diene 20 (0.112 g, 0.5 mmol) and 1,4-
54 in 76% yield as
a pale yellow solid after silica gel column
anthraquinone 13 (0.135 g, 0.65 mmol) afforded 0.161
g
of the
chromatography (13% EtOAc/hexane): mp = 127–129 oC; Rf = 0.6 (25%
aromatized adduct 51 in 76% yield as a yellow solid after silica gel
column chromatography (10% EtOAc/hexane): mp = 166–168 oC; Rf =
EtOAc/hexane); [α ]25 = −210 (c 0.95, CHCl3); IR (neat) 2927, 1733,
D
1441, 1279, 1216, 1019, 701 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.93 (d,
J = 8.1 Hz, 1H), 7.20 (d, J = 8.2 Hz, 1H), 5.95 (d, J = 3.7 Hz, 1H), 5.18 (d,
J = 2.3 Hz, 1H), 4.85 (d, J = 15.1 Hz, 1H), 4.70 (d, J = 15.7 Hz, 1H), 4.67
(s, 1H), 4.16 (d, J = 2.4 Hz, 1H), 3.96 (s, 3H), 3.90 (s, 3H), 1.56 (s, 3H),
1.36 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 168.4, 165.8, 139.9, 137.2,
130.1, 127.9, 127.5, 125.7, 112.3, 105.3, 84.5, 80.1, 70.3, 67.4, 52.9,
52.8, 27.2, 26.7; HRMS (ESI) calcl. For C18H20O8Na (M+Na)+ 387.1056,
found 387.1075.
0.5 (15% EtOAc/hexane); [α ]25 = +89 (c 1.0, CHCl3); IR (neat) 2929,
D
2851, 1674, 1581, 1317, 1286, 1215, 1162, 1059 cm−1 1H NMR (500
;
MHz, CDCl3) δ 8.88 (s, 1H), 8.78 (s, 1H), 8.44 (d, J = 8 Hz, 1H),
8.07−8.08 (m, 2H), 7.68 (d, J = 3.2 Hz, 1H), 7.67 (d, J = 3.1 Hz, 1H), 7.49
(d, J = 8 Hz, 1H), 6.30 (s, 1H), 6.04 (d, J = 3.6 Hz, 1H), 4.96 (d, J = 15.7
Hz, 1H), 4.86 (d, J = 15.7 Hz, 1H), 4.74 (d, J = 3.6 Hz, 1H), 4.25 (d, 1H, J
= 1.6 Hz), 1.85 (s, 3H), 1.44 (s, 3H); 13C NMR (125 MHz, CDCl3) δ183.7,
182.6, 142.2, 135.4, 134.9, 132.7, 131.6, 130.3, 129.4, 129.3, 128.8,
128.3, 118.4, 104.9, 84.1, 79.8, 70.6, 67.7, 27.2, 26.8; HRMS (ESI) calcl.
For C26H20NaO6 (M+Na)+ 451.1158, found 451.1158.
Hybrid compound 61 : Following the general procedure (method A) for
Diels-Alder reaction between the diene 21 (0.084 g, 0.5 mmol) and 1,4-
naphthoquinone 11 (0.102 g, 0.64 mmol) afforded 0.122 g of the
aromatized adduct 61 in 64% yield as a pale orange solid after silica gel
column chromatography (5% EtOAc/hexane): mp = 117–119 oC; Rf = 0.5
Hybrid compound 52 : Following the general procedure (method A) for
Diels-Alder reaction between the diene 20 (0.112 g, 0.5 mmol) and 5-
hydroxynaphthoquinone (0.113 g, 0.65 mmol) afforded 0.147 g of the
aromatized adduct 52 in 72 % yield as a yellow solid (mixture of
regioisomers d. r. = 3.6:1) after silica gel column chromatography (12%
(10% EtOAc/hexane); [α ]25 = +308.5 (c 0.56, CHCl3); IR (KBr) 2929,
D
1669, 1587, 1450, 1340, 1329, 1293, 1214, 1103, 1057 cm−1 1H NMR
;
(400 MHz, CDCl3) δ 8.37 (d, J = 8.4 Hz, 1H), 8.08−8.28 (m, 2H),
7.76−7.86 (m, 2H), 7.23 (d, J = 8.4Hz, 1H), 6.47 (d, J = 4.7 Hz, 1H), 6.34
(d, J = 4.7 Hz, 1H), 1.58 (s, 3H), 1.26 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ 183.5, 181.9, 164.4, 134.4, 134.02, 133.6, 133.5, 132.6, 131.3,
128.2, 127.4, 127.3, 126.0, 116.1, 114.1, 109.3, 80.7, 28.0, 27.7; HRMS
(ESI) calcd. for C19H14O5 (M+H)+ 323.0919, found 323.0916.
EtOAc/hexane): mp = 164–166 oC; Rf = 0.6 (25% EtOAc/hexane); [α ]25
D
= +121 (c 1.1, CHCl3); IR (neat) IR (neat) 3490, 3021, 2929, 1669, 1217,
1099, 1021, 940 cm−1; 1H NMR (400 MHz, CDCl3) δ 12.1 (s, 1H), 8.34 (d,
J = 8.04 Hz, 1H), 7.78 (dd, J = 7.5, 1.2 Hz, 1H), 7.65 (m, 1H), 7.49 (d, J
= 8.0 Hz, 1H), 7.32 (dd, J =8.4, 1.2 Hz, 1H), 7.28 (d, J = 8.2 Hz, 1H), 6.12
(d, J = 2.0 Hz, 1H), 6.02 (d, J = 3.7 Hz, 1H), 4.94 (d, J = 15.9 Hz, 1H),
4.86 (d, J = 15.9 Hz, 1H), 4.73 (d, 1H, J = 3.70 Hz), 4.23 (d, 1H, J = 2.2
Hz), 1.77 (s, 3H), 1.43 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 190.1,
182.4, 162.8, 142.6, 136.6, 134.6, 132.5, 131.7, 131.5, 130.9, 128.4,
127.9, 125.1, 120.5, 119.2, 117.1, 112.7, 105.1, 84.2, 84.1, 79.7, 70.8,
70.7, 67.9, 27.3, 27.0; HRMS (ESI) calcl. For C22H18O8Na (M+Na)+
433.0899, found 433.0878.
Hybrid compound 62 : Following the general procedure (method A) for
Diels-Alder reaction between the diene 21 (0.084, 0.5 mmol) and 5,8-
dihydroxynaphthoquinone 12 (0.123 g, 0.65 mmol) afforded 0.109 g of
the aromatized adduct 62 in 52% yield as a red solid after silica gel
column chromatography (6-8% EtOAc/hexane): mp = 146–148 oC ; Rf =
0.6 (10% EtOAc/hexane); [α ]25 = +109 (c 2.5, CHCl3); IR (neat) 3447,
D
2927, 1966, 1673, 1618, 1458, 1292, 1215, 1093, 1023, 920 cm−1 1H
;
NMR (400 MHz, CDCl3) δ 12.98 (s, 1H), 8.40 (d, J = 8 Hz, 1H), 7.97 (d,
J = 8 Hz, 1H), 7.31 (s, 2H), 6.03 (d, 1H, J = 4 Hz), 5.68 (d, 1H, J = 17.6
Hz), 5.0−5.12 (m, 2H), 4.80 (d, J = 4 Hz, 1H), 1.62 (s, 3H), 1.40 (s, 3H);
13C NMR (100 MHz, CDCl3) δ 188.9, 186.5, 157.8, 157.7, 139.9, 137.5,
136.9, 134.7, 129.9, 129.7, 129.2, 126.3, 112.3, 112.2, 105.4, 84.8, 78.6,
73.8, 67.0, 27.0, 26.3; HRMS (ESI) calcd. for C19H15O7 (M+H)+ 355.0818,
found 355.0816.
Hybrid compound 53 : Following the general procedure (method A) for
Diels-Alder reaction between the diene 20 (0.112 g, 0.5 mmol) and 5-
nitronaphthoquinone (0.132, 0.65 mmol) afforded 0.138
g
the
aromatized adduct 53 in 63% yield as a yellow solid (mixture of
regioisomers d. r. = 2.6:1) after silica gel column chromatography (8%
EtOAc/hexane): mp = 142–144 oC; Rf = 0.6 (15% EtOAc/hexane); [α ]25
D
= +194 (c 1.2, CHCl3); IR (neat); IR (neat) 3024, 2925, 2851, 1774, 1678,
1601, 1570, 1515, 1456, 1215, 1085, 1024, 940 cm−1; 1H NMR (400 MHz,
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201700599
European Journal of Organic Chemistry
FULL PAPER
Acknowledgements
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New Delhi for a fellowship.
Keywords: Aromatization, Diels-Alder reaction, enyne
metathesis, Grignard addition, quinones, steroid hybrids, sugar-
oxasteroid-quinone hybrids.
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Key Topic*
R2
H
O
R2
H
O
26 examples of Sugar-oxasteroid-
quinone hybrids
Ashik A. Sayyad and Krishna P.
Kaliappan
O
O
O
O
O
O
i. toluene
O
110 oC, 12 h
O
O
Scalable
ii. Silica gel, Et3N
CHCl3, rt, 1 h
R1
R1
Sequential Enyne-Metathesis/ Diels-
Alder Strategy: Rapid Access to the
Novel Sugar-oxasteroid-quinone
Hybrids
62-89% isolated yields
O
R1 = H, OH, NO2
R2 = H, Me, Et
This article is protected by copyright. All rights reserved.