Synopsis
SYNOPSIS
The thesis entitled “Stereoselective total syntheses of (-)-tetrahydrolipstatin and
development of novel synthetic methodologies” is divided into three chapters.
Chapter-I: This chapter deals with an introduction to anti-obesity drugs, containing
-lactone moieties and various approaches cited in the literature for the total
synthesis of (-)-tetrahydrolipstatin.
Chapter-II: This chapter describes the two efficient approaches for the total
synthesis of (-)-tetrahydrolipstatin, which is further divided into two sections.
Section-A:
This
section
describes
an
efficient
total
synthesis
of
(-)-
tetrahydrolipstatin via stereoselective radical cyclization.
Section-B: This section describes the Chiron approach to stereoselective total
synthesis of (-)-tetrahydrolipstatin from tri-o-acetyl D-glucal.
Chapter-III: This chapter describes the development of novel synthetic
methodologies, which is further divided into two sections.
Section-A: This section describes the InBr3-catalyzed novel cyclization of glycals
with aromatic amines.
Section-B: This section describes the synthesis of trans-fused pyrano [3,2-c]
benzopyrans through [4+2] cycloaddition of o-quinonemethides.
CHAPTER-I: An attempt is made to provide an introduction to anti-obesity drugs,
containing -lactone moieties and the earlier approaches cited in the literature for
the total synthesis of (-)-tetrahydrolipstatin.
CHAPTER-II:
Section A: Total synthesis of (-)-tetrahydrolipstatin via stereo selective radical
cyclization based strategy
(-)-Tetrahydrolipstatin 2, a -lactone, a potent and irreversible inhibitor of
pancreatic lipase is the saturated analogue of lipstatin 1 isolated from streptomyces
toxytricini in 1987.
I
Synopsis
Recently, it has been marketed in several countries as anti-obesity agent
under the name Xenical. The key to the biological activity of the lipstatins is the lactone moiety, featuring anti-stereochemistry about the ring. The lactone has been
shown to bind irreversibly to an active site serine of pancreatic lipase.
NHCHO
O
O
NHCHO
O
O
O
n-C6H13
O
O
O
n-C11H23
Lipstatin (1)
n-C6H13
Tetrahydrolipstatin (2)
Figure: 1
Due to its biological properties, (-)-tetrahydrolipstatin 2 has been the subject
of profound synthetic activity since its isolation. The retrosynthetic analysis is
outlined in Scheme 1.
n-C10H21
O
n-C6H13
O
O
O
n-C6H13
n-C10H21
COOH
OBn OH
22
NHCHO
(-)-THL
n-C6H13
n-C10H21
n-C10H21
n-C5H11
OBn O
OBn O
19
OH
17
n-C5H11
HOOC
n-C10H2
1
14b
Br
OEt
COOH
OH
3
OBn OH
Scheme: 1
II
Synopsis
(-)-Tetrahydrolipstatin 2 could be obtained in a three-step sequence from the
known β-hydroxy acid 22. It is envisioned that the degradation of compound 19
could be effected by water elimination and ozonolysis sequence. The lactol would
be obtained from the propargylic alcohol 14b through bromoacetal formation and
stereoselective radical cyclization, which is the key step for the success of this
approach. The propargylic alcohol 14b in turn was obtained from commercially
available S-Malic acid 3 by carbon extension on one end and Grignard addition on
other.
COOH
HOOC
3
OH
OH
OH OH
5
MeOH, BF3.OEt2 ,
CO2Me
MeO2 C
OH
0 oC-r.t., 12 h, 85%
4
BH3.SMe2, THF,
0 oC-r.t., 2 h, 90%
OH
PhCH(OMe)2, p-TSA,
toluene, reflux, 6 h, 80%
O
O
Ph
6
Scheme: 2
Key starting material 1, 3-benzylidine protected triol 6 was obtained from
commercially available S-malic acid 3 in three steps. Thus S-malic acid 3 was
converted to its dimethyl ester derivative 4 by using methanol, borantrifluoride
diethyl ether (BF3.Et2O), which on treatment with borane dimethylsulfide
(BH3.DMS) and a very small quantity of sodium borohydride (NaBH4) in THF
afforded 1,2,4-butane triol 5 in 90% yield (Scheme 2).
6
TsCl, TEA, CH2Cl2,
0 oC-r.t., 92%
OTs
O
O
n-C10H21MgBr, CuBr,
THF, 0 oC-r.t., 76%
Ph
7
O
O
Ph
8
Scheme: 3
III
n-C10H21
Synopsis
Selective protection of 2 and 4 hydroxy functions of the triol 5 with
benzaldehyde dimethyl acetal, p-TSA in CH2Cl2 gave the acetal 6. The primary
alcohol was transformed to tosylate 7, which on copper mediated C-C bond
formation with Grignard reagent, n-decylmagnesiumbromide resulted in coupled
product 8. The same was achieved by converting the alcohol 6 to corresponding
triflate and copper mediated Grignard addition (Scheme 3).
n-C10H21
Ph3CHCO2Et, CH2Cl2,
CHO
n-C10H21
CO2Et
9
r.t., 12 h, 82%
DIBAL-H, CH2Cl2,
-78 oC, 2 h,
n-C10H21
OH
n-C10H21
MS 4 Ao , TBHP, -20 oC,
83%
10
O
OH
D(-)-DET, Ti(iOPr)4,
(i) Red-Al, THF, 0 oC-r.t., 12 h,
(ii) PhCH(OMe)2, pTSA, CH2Cl2,
reflux, 6 h, 79%
11
O
n-C10H21
O
Ph
8
Scheme: 4
Compound 8 can also be obtained in 3-step sequence from dodecanal 9 via
Sharpless asymmetric epoxidation. Accordingly dodecanal on Wittig olefination
with stable ylide ethoxycarbonylmethylenetriphenylphosphorane in benzene
8
DIBAL-H, CH2Cl2,
(COCl)2, DMSO,TEA,
CH2Cl2, -78 oC, 2 h
n-C10H21
OBn OH
-78 oC, 3 h, 69%
13
Then n-C7H12MgBr,
0 oC-r.t., 5 h, 82%
n-C5H11
n-C5H11
n-C10H21
+
n-C10H21
OBn OH
14a
DEAD, TPP, p-NBA,
THF, 0 oC, 88%
Scheme: 5
IV
OBn OH
14b
Synopsis
yielded - unsaturated ester 10, which on reduction with DIBAL-H in CH2Cl2 gave
allyl alcohol 11. Allyl alcohol 11 on Sharpless epoxidation with D (-) DET gave
epoxy alcohol 12 which on reductive and regioselective opening with Red-Al gave
1, 3-diol, followed by protection with benzaldehyde dimethyl acetal yielded 8
(Scheme 4).
Reductive and regioselective opening of benzylidine acetal 8 was easily
carried out using DIBAL-H to produce 13. Oxidation of 13 under Swern conditions
followed by heptynyl Grignard addition resulted in cis and trans propargylic
alcohols 14a and 14b in 1:1 ratio. The unrequired diastereomer 14a was converted to
14b under standard Mitsunobu conditions to obtain 14b in 72 % overall yield
(Scheme 5).
n-C5H11
n-C10H21
n-C5H11
n-C10H21
+
OBn OH
OBn OH
14b
(i) LiAlH4, THF, 0 oC-r.t.
14a
(i) LiAlH4, THF, 0 oC-r.t.
(ii) Li-liq.NH3, -33 oC
(ii) Li-liq.NH3, -33 oC
(iii) 2,2-DMP, p-TSA,
(iii) 2,2-DMP, p-TSA,
acetone, 0 oC-r.t.
acetone, 0
n-C5H11
n-C10H21
O
Me
30.3
oC-r.t.
15a
O
Me
n-C5H11
n-C10H21
19.9
98.3
25.3
O
Me
15b
O
Me
24.8
100.1
Scheme: 6
The stereochemistry was assigned by converting both the isomers to the
corresponding acetonides 15a and 15b in a three-step sequence. Reduction of
propargylic to allylic system with LiAlH4 in THF and debenzylation with Li in Liq.
NH3 generated 1, 3-diols which on treatment with 2, 2-DMP in acetone produced
V
Synopsis
acetonides 15a and 15b. The
13C
Analysis of these acetonides clearly revealed the
stereochemistry of the diastereomers (Scheme 6).
LiAlH4, THF,
14b
0 oC-r.t., 85%
OBn O
17
0 oC-r.t., 90%
OBn OH
16
n-C5H11
n-C10H21
NBS, EVE, CH2Cl2,
n-C5H11
n-C10H21
Br
n-C6H13
AIBN, n-Bu3SnH, dry toluene,
n-C10H21
reflux, 2 h, 92%
OEt
OBn O
18
OEt
Scheme: 7
Reduction of propargyl alcohol 14b with LiAlH4 in THF resulted in trans
allyl alcohol 16, which on treatment with NBS and ethyl vinyl ether yielded
bromoacetal 17 as an epimeric mixture at newly created acetal centre. The key step,
stereo controlled radical cyclization, was easily effected by treating the bromoacetal
17 with refluxing mixture of n-Bu3SnH and catalytic AIBN in toluene to produce
thermodynamically stable isomer 18 (Scheme 7).
18
80% AcOH in H2O,
n-C6H13
n-C10H21
MsCl, TEA, CH2Cl2,
reflux, 6 h, 78%
OBn O
n-C6H13
n-C10H21
OBn O
20
NaClO2-H2O, 10% NaOH,
CH3CN, 0 oC-r.t., 86%
-22 oC-r.t.-reflux, 92%
OH
19
n-C6H13
O3, Ph3P, CH2Cl2,
n-C10H21
-78 oC-r.t., 76%
n-C6H13
n-C10H21
OBn OH
22
Scheme: 8
VI
CO2H
CHO
OBn OCHO
21
Synopsis
Cyclic ethyl acetal 18, when treated with 80% AcOH in H2O resulted in lactol
19. Mesylation of lactol 19 and insitu elimination was achieved by treating lactol 19
with mesyl chloride and TEA in CH2Cl2 under reflux conditions to yield cyclic vinyl
ether 20. Cyclic vinyl ether 20 on ozonolytic oxidative cleavage produced aldehyde
21, which as a crude was subjected to oxidation with NaClO2 and 10 % NaOH
solution to furnish β-hydroxy acid 22 (Scheme 8).
22
OBn O
0 oC-r.t., 12 h, 78%
OH O
24
23
n-C6H13
n-C10H21
n-C6H13
n-C10H21
PhSO2Cl, pyridine,
O
O
H2-Pd/C, THF, r.t.,
4 h, 90%
DEAD, Ph3P, (S)- N-formyl leucine,
0
oC-r.t.,
(-)-THL 2
2 h, 65%
Scheme: 9
The β-lactone ring was formed using PhSO2Cl in pyridine, followed by
debenzylation and esterification with S-N-formyl leucine under Mitsunobu
conditions furnished (-)-Tetrahydrolipstatin 2 (Scheme 9).
Section B: Total synthesis of (-)-tetrahydrolipstatin via Chiron approach
The synthetic route depicted in Scheme 1 is based on the retrosynthetic
analysis. Thus THL 2 could be obtained from a three-step sequence from the βhydroxy acid 42.
VII
Synopsis
NH-CHO
O
O
O
n-C11H23
OH
MOMO
O
n-C11H23
n-C11H23
n-C6H13
36
O
n-C6H13
42
(-)-Tetrahydrolipstatin 2
n-C11H23
OMe
O
CO2H
O
TBSO
OMe
OBn
O
AcO
AcO
33
OBn
38
O
25
OBn
OAc
Scheme: 10 Retrosynthetic analysis
The synthetic approach begins with C-glycosidation of tri-o-acetyl D-glucal
25 by adding methanol and using CeCl3.7H2O-NaI in acetonitrile, to afford methyl
acetal 26. The methyl acetal 26 was subjected to methanolysis and subsequent
selective protection of 1,3-diol part to furnish 28 in 70% overall yield.
O
AcO
AcO
25
O
AcO
CH3CN, Reflux, 3.5 h, 87%
OAc
O
HO
CeCl3.7H2O, NaI, MeOH,
AcO
OMe
NaOMe, MeOH,
0 oC-r.t., 2 h, 85%
26
OAc
OMe
HO
27
OH
Scheme: 11
The hydroxy function of compound 28 was protected as benzyl ether 29 and
acetal cleavage of benzyl ether 29 was effected with p-TSA in MeOH to afford 1,3diol 30, which was selectively protected with a TBS group at the primary hydroxy
group 31 and the secondary hydroxy group was protected as its xanthate ester to
afford 32 in 70% yield for three steps.
VIII
Synopsis
27
CH2Cl2, 0 0C-r.t., 82%
O
O
PhCH(OMe)2, p-TSA,
Ph
OMe
NaH, BnBr, n-Bu4NI,
O
THF, reflux, 4 h, 78%
OH
28
O
O
Ph
OMe
O
OMe
HO
r.t., 3 h, 79%
OBn
O
HO
p-TSA, MeOH,
OBn
29
30
Scheme: 12
Compound 32 was treated with n-Bu3SnH and catalytic AIBN in dry toluene
under reflux conditions to afford the deoxygenated compound 33.
TBSCl, imidazole,
30
TBSO
O
OMe
HO
CH2Cl2, 0 0C-r.t., 83%
NaH, CS2, MeI, THF,
0 0C-r.t., 12 h, 78%
OBn
31
TBSO
O
S
H3 CS
O
OMe
n-Bu3SnH, AIBN, PhMe,
TBSO
O
OMe
reflux, 6 h, 79%
OBn
OBn
32
33
Scheme: 13
The TBS group of compound 33 was removed and the resulting alcohol 34
was treated with TsCl and TEA in CH2Cl2 to afford the corresponding tosylate 35,
which was treated with n-decylmagnesiumbromide and catalytic CuBr to obtain the
coupled product 36. The compound 36 could also be obtained from alcohol 34 via
conversion
to
the
corresponding
triflate
displacement.
IX
and
copper-mediated
Grignard
Synopsis
TBAF, THF,
33
O
HO
0 oC-r.t., 98%
O
TsO
OMe
OBn
OMe
TsCl, TEA, CH2Cl2,
0 oC-r.t., 92%
OBn
34
n-C11H23
n-C10H21MgBr, CuBr,
0 oC-r.t., 76%
O
OMe
OBn
36
35
Scheme: 14
The methyl acetal of 36 was converted to lactol 37 by treating with 80%
aq.acetic acid, which in turn was subjected to oxidation with Dess-Martin period
inane to yield lactone 38. Methanol addition to the lactone 38 was carried out in
36
80% aq.AcOH,
n-C11H23
O
OH
reflux, 4 h, 72%
Dess-Martin periodinane,
CH2Cl2, 0 oC-r.t., 79%
OBn
37
n-C11H23
O
OBn
38
O
TEA, MeOH, 0 oC-r.t., then
MOMCl, DIPEA, CH2Cl2
0 oC-r.t., 71%
OBn
MOMO
CO2Me
n-C11H23
39
Scheme: 15
presence of TEA in MeOH resulted in corresponding -hydroxy ester, which
without workup, on removal of MeOH under reduced pressure was protected as its
MOM ether 39 in presence of DIPEA and MOMCl in CH2Cl2. Attempts made to
isolate MeOH addition product, hydroxy ester, were unsuccessful as it cyclized
back to lactone 38.
X
Synopsis
39
n-C11H23
r.t.,12 h, 94%
MOMO
CO2Me
MOMO
PhSO2Cl, py,
0
12 h, 78%
CO2Me
40
n-C11H23
43
LiOH.H2O,
THF, 0 oC-r.t., 88%
n-C6H13
41
OH
LDA, n- C6H13I, HMPA,
THF, -50 oC, 75%
MOMO
OH
n-C11H23
oC,
MOMO
Pd(OH)2, EtOAc,
CO2H
n-C11H23
42
O
(i) BF3Et2O, EtSH, THF,
0 oC-r.t., 88%
O
OH
n-C6H13
(-)-THL 2
n-C6H13 (ii) DIAD, TPP, S-N-formyl
leucine, THF, 0 oC-r.t., 90%
Scheme: 16
The methyl ester was hydrogenated with Pd(OH)
2
in EtOAc to afford
-hydroxy ester 40. The key step, stereocontrolled alkylation, was effected by
treating the -hydroxy ester 40 with LDA in THF, followed by addition of n-hexyl
iodide to the dianion to give 41 as the major diastereomer in 77% yield after a flash
column chromatography. The crude product of the reaction revealed ~2% of the
other diastereomer.
Hydroxy ester 41 was converted to -lactone 43 by hydrolysis of ester group
with LiOH followed by exposure of acid 42 to PhSO2Cl in pyridine. Deprotection of
MOM ether of -lactone with BF3.OEt2 and ethane dithiol in CH2Cl2 produced
alcohol 24 which on esterification with (S)-N-formylleucine under Mitsunobu
conditions furnished (-)-Tetrahydrolipstatin 2.
CHAPTER-III:
Section-A: InBr3-catalyzed cyclization of glycals with aryl amines
Glycals are ambident electrophiles capable of reacting with various
nucleophiles such as alcohols, silyl nucleophiles and malonates under the influence
XI
Synopsis
of either acid catalysts or oxidants to produce 2,3-unsaturated glycosides. However,
there are no precedents on the aminoglycosidation of D-glycals with aryl amines
because of the intrinsic lower reactivity of amines towards glycals. In recent times,
indium halides have emerged as versatile Lewis acid catalysts imparting high regio, chemo- and diastereosectivity for a variety of organic transformations. Compared
to conventional Lewis acids, particularly, indium tribromide has advantages of low
catalyst loading, moisture stability and catalyst recycling. C-Glycosides bearing
carbon linked heterocycles have attracted great significance because of their potent
antiviral and antitumour behavior. Because of the fascinating antiviral and
antitumour properties of aryl glycosides, we have attempted C-glycosidation with
aryl amines to synthesize aryl C-glycosides with free amino functionality for further
derivatization. Interestingly, we observed for the first time an unusual formation of
oxa-azatricyclotrideca-trienyl acetate derivatives in the aminoglycosidation.
OAc
R
R1
R2
NH2
1a
R1
OAc
+
O
2a
OAc
R
R2
H H
N
H
O
OAc
OAc
3a
Scheme: 17
Initially, it is attempted to carry aminoglycosidation reaction of D-glucal
with aniline using 10-mol% Indium (III) bromide as novel glycosyl activator.
Interestingly, an unusal bicyclic adduct i.e. 11-methylcarbonyloxymethyl-12-oxa-8azatricyclo[7.3.1.0]trideca-2,4,6-trien-10-ylacetate was isolated in 85% yield with
high stereoselectivity (Scheme 17).
The product 3a thus obtained was extensively characterized by various NMR
experiments like double quantum filtered correlation spectroscopy (DQFCOSY),
Nuclear Over Hauser effect spectroscopy (NOESY), hetero nuclear single quantum
correlation spectroscopy (HSQC) and 3JCH optimized HMBC experiments.
XII
Synopsis
H
H H
15
14
13
H
12
16
2
H
H
N
11 H
H
3
1
O
HH
4
O1
5
H
O
6
9
O
H
H H
10 8
7
H
H
N
H
H
OAc
OAc
O
H
O
H
H
H
Figure: 2
NOE's, chemical structure and energy-minimized structure of 3a
These unexpected results encouraged to extend this process for various
glycals and aryl amines. Interestingly, -naphthyl amine and substituted aryl
amines such as electron-rich as well as electron-deficient aniline derivatives reacted
efficiently with D-glucal under similar conditions to produce the corresponding
cyclic adducts in fairly good yields. Similarly, L-rhamnal also underwent
cyclization
with
aryl
amine
to
produce
11-methyl-12-oxa-8-
azatricyclo[7.3.1.0]trideca-2,4,6-trien-10-ylacetate derivative (entry 3k, Table 1).
Under similar reaction conditions, D-xylal also underwent cyclization with aryl
amine to afford the corresponding cyclic adduct (entry 3m, Table 1).
The method is highly stereoselective to afford oxa-azatricyclodeca-trienyl
acetate derivatives under mild conditions and the results are presented in Table 1.
The efficacy of various Lewis acids such as InBr3, InCl3, CeCl3.7H2O, YCl3, and
YbCl3 was tested for this conversion. Indium tribromide was found to be the most
effective catalyst in terms of conversion and selectivity. For instance, treatment of
3,4,6-tri-O-acetyl-D-glucal with aniline in the presence of 10-mol% InBr3 and 10mol% InCl3 for 6 h afforded 85% and 72% yields respectively. However, in the
absence of InBr3 or InCl3, the reaction did not proceed even after a long reaction
time. The scope and generality of this process is illustrated with respect to various
glycals and aryl amines.
XIII
Synopsis
Table 1: Synthesis of oxaazatricyclotridecatrienyl derivatives from D-glucal and aryl amines (Scheme 17)
Entry
Aryl amine
1
Glycal
2
Producta
3
OAc
H H
N
NH2
a
OAc
O
H
OAc
Me
NH2
b
OAc
Me
H H
N
OAc
O
OAc
H
OAc
c
O
F
OAc
F
H
d
Cl
OAc
O
NH2
e
OAc
Cl
Me
H
Br
OAc
Br
O
H H
N
OAc
NH2
O
H H
N
OAc
NH2
O
H H
N
OAc
O
OAc
Me
H
OAc
NH2
O
OAc
O
H H
N
OAc
f
O
H
O
InBr3(10 mol%)
Time(h)
OAc
Yield(%)b
TMSOTf(1 eq)
Time(h) Yield(%)b
6.0
85
3.5
87
5.5
82
4.0
85
7.0
78
5.0
81
6.0
84
4.5
85
8.0
75
6.0
82
9.0
80
5.0
75
OAc
OAc
OAc
OAc
OAc
OAc
OAc
OAc
OAc
OAc
OAc
(a) Products were characterized by 1H NMR, 13C NMR, IR spectroscopy and mass spectroscopy.
(b) Yield refers to pure products after chromatography.
XIV
Synopsis
Table 1: (continued) Synthesis of oxaazatricyclotridecatrienyl derivatives from D-glucal and aryl amines
Entry
Aryl amine
1
Glycal
Producta
2
3
OAc
H H
N
NH2
g
Br
O
OAc
H
OAc
NH2
h
MeO
O
OAc MeO
O
OAc
H
j
Me
OAc
O
OAc
Me
H
OAc
k
NH2
OAc
H
OAc
O
O
H H
N
OAc
NH2
O
H H
N
OAc
O
l
O
H H
N
OAc
NH2
O
H H
N
OAc
NH2
i
H
Cl
OAc
Cl
O
H H
N
OAc
OAc
H
TMSOTf(1 eq)
Time(h) Yield(%)b Time(h) Yield(%)b
OAc
Br
InBr3(10 mol%)
OAc
7.5
82
4.5
84
7.0
78
4.0
78
6.0
80
5.0
83
5.5
85
4.5
89
5.0
87
5.0
85
6.0
89
3.5
82
OAc
OAc
OAc
OAc
OAc
OAc
OAc
OAc
Me
OAc
O
(a) Products were characterized by 1H NMR, 13C NMR, IR spectroscopy and mass spectroscopy.
(b) Yield refers to pure products after chromatography.
XV
Synopsis
Section-B:
Synthesis
of
trans-fused
pyrano[3,2-c]benzopyrans
through
(4+2)
cycloaddition of o-quinonemethides
o-Quinonemethides are useful intermediates for the synthesis of many
oxygenated heterocycles. Iodine has been employed as an efficient and reusable
Lewis acid for the synthesis of fused tetrahydropyrano [3,2-c] benzopyrans
involving intramolecular (4+2) cycloaddition of o-quinonemethides. The treatment
of o-hydroxybenzaldehydes with 5-methyl-4-hexen-1-ol and trimethyl orthoformate
in the presence of 5-mol% iodine in dichloromethane at ambient temperature gave
exclusively trans-fused pyrano [3, 2-c] benzopyrans 2 in high yields (Scheme 18).
O
R
H
HO
+
H
Iodine,TMOF
OH
CH2Cl2, r.t.
O
R
H
H
O
+
O
R
H
O
Scheme: 18
Only a single diastereomer was obtained in each reaction, the structure of
which was established by 1H,
13C
NMR and mass spectroscopy. The scope and
generality of this process is illustrated by reacting the substrates bearing electron
donating as well as electron withdrawing groups in the aromatic ring.
XVI
Synopsis
Table :2 Elemental iodine-catalyzed synthesis of pyrano[3,2-c]benzopyrans
Entry
o-Hydroxy benzaldehyde
(1)
Producta
(2)
Reaction
time (h)
Yield
(%)b
O
CHO
a
OH
92
1.0
90
1.5
88
1.0
90
1.5
87
2.0
85
O
O
CHO
b
1.5
OH
O
OMe
OMe
O
CHO
c
O
OH
OEt
OEt
O
d
BnO
CHO
BnO
O
OH
O
e
Me
CHO
Me
OH
f
PhO
CHO
O
O
PhO
OH
O
a All products were characterised by 1H, 13C NMR, IR and Mass spectroscopy.
b Isolated and unoptimised yields.
XVII
Synopsis
Table :2 (continued) Elemental iodine-catalyzed synthesis of pyrano[3,2-c]benzopyrans
Entry
o-Hydroxy benzaldehyde
(1)
Reaction
time (h)
Producta
(2)
Yield
(%)b
O
CHO
g
OH
82
2.0
85
1.0
90
2.5
80
2.0
83
1.0
92
1.5
85
O
CHO
O
OH
h
O
O
CHO
i
1.0
OH
O
O
CHO
Br
Br
j
OH
O
Br
k
Br
Br
CHO
O
Br
OH
O
O
l
O
CHO
O
OH
O
O
O
O
m
MeO
CHO
MeO
MeO
OH
MeO
O
a All products were characterised by 1H, 13C NMR, IR and Mass spectroscopy.
b Isolated and unoptimised yields.
XVIII