CHAPTER-I, Section-A

1. INTRODUCTION:

Natural product chemistry has undergone an explosive growth during the last century.
Substances from natural products display various pharmacological activities like antibiotic,
antitumor, immunostimulants affecting cardiovascular and central nervous system, analgesics,
etc. Thus, the synthesis of natural products having biological activity is always a fascinating
subject which excited the synthetic organic chemists worldwide.

6-Substituted-5,6-dihydro-2H-pyran-2-ones, 11 also called ,-unsaturated--lactones are

important structural subunits in many biologically important natural products. These units are
important for a wide variety of biological activities, such as insect growth inhibition and insect
antifeedent, antifungal, and antitumor properties. The pyrone units are widely distributed in all
parts of various plants (Lamiaceae, Piperaceae, Lauraceae, and Annonaceae families) including
leaves, stems, flowers, and fruits. Various kinds of substitutions have been found at the C-6
position of the ring such as polyacetoxy alkane, polyhydroxy alkane, a combination of both, or
even a simple alkane. Due to their structural complexities and biological activities, the synthesis
of these type of molecules in optically pure form attracted several total syntheses.
O

O1 2 3
4
R 6
5
1
General structure of 5,6-dihydro-2H-pyran-2-one

Some important natural products containing 5,6-dihydro-2H-pyran-2-one core unit having

vital medicinal properties are described below.

(+)-Boronolide

The (+)-Boronolide 2a was isolated from the bark and branches of Tetradenia fruticosa
and from the leaves of Tetradenia barbere,2 and has been used as local folk medicine in
Madagascar and southern Africa. (+)-Deacetylboronolide 2b and (+)-Acetylboronolide 2c were
obtained from Tetradenia riparia,3 a cental African species widely used as a tribal medicine.

1
 CHAPTER-I, Section-A

O
2a : R = R' = OAc (+)-Boronolide
OR O
2b : R = R' = H (+)-Deacetylboronolide

OR' OR 2c : R = H, R' = OAc Acetylboronolide

Medicinal properties of boronolides have been exploited for a long time in crude form. Zulu
used roots of these plants as an emetic, and infusion of leaves has been reported to be effective
against malaria.4

Tarchonanthuslactone

Tarchonanthuslactone 3, was isolated by Bohlmann et al from Tarchonanthustrilobus

compositae,5 a simple syn-1,3-diol contain 5,6-dihydropyran-2-one moiety. Hsu et al 6
have
reported that Tarchonanthuslactone 3, lowers plasma glucose in diabetic rats as an important
biological activity. Cryptocarya diacetate 4 and Cryptocarya triacetate 5 are more complex
examples having similar structural motifs of 3.

O O O
HO
O O OAc OAc O

HO

3. Tarchonanthus lactone 4. Cryptocarya diacetate

OAc OAc OAc O

5. Cryptocarya triacetate

Passifloricin A

Passifloricin A 6,7 is a polyketide-type -pyrone was isolated from the resin of Passiflora
foetida var, hispida, a species from the family Passifloraceae that grows in tropical zones of
America. It was found to be active in the Artemia salina test.

2
 CHAPTER-I, Section-A

OH OH OH O

( )n

6. Passifloricin A, n = 14

Kurzilactone

Kurzilactone 7,8 a new ,-unsaturated--lactone, has been isolated from the leaves of
Cryptocarya kurzii. The structure of kurzilactone was determined by spectroscopic methods.
Kurzilactone exhibits marked cytotoxicity against KB cells with IC50 = 1 g ml-1.
O

O OH O

7. Kurzilactone

Argentilactone and Massoia lactone

Massoia lactone 89 first isolated from the bark oil of Cryptocarya massoia by Abe in
1937. This lactone has been used for many centuries as a constituent of native medicines. Ruveda
et al reported the isolation of Argentilactone 910 from Aristolochia argentina (Aristolochiaceae).
Later, natural pyranone was also isolated from Chorisia crispflora and Annona haematantha.
Argentilactone 9 was shown to have antileishmanial and cytotoxic activities.

O O

O O

8. (R)-Massoia lactone 9. (R)-Argentilactone

3
 CHAPTER-I, Section-A

Strictifolione
Strictifolione 1011 was isolated from Cryptocarya stritctifolia and has shown to display
antifungal activity.
O

OH OH O

10. (+)-Strictifolione

(-)-Ratjadone

Ratjadone 11, a polyketide was isolated in 1994 from Sorangium cellulosum strain
Soce36012 collected as a soil sample at Cala Ratjada (Mallorea, Spain). Ratjadone displays
potent in vitro antifungal activity with MIC values in the range from 0.004 to 0.6g/mL for
Mucor hiemalis, Phythophthora drechsleri, Ceratocystis ulmi, and Monilia brunnea.
Additionally, significant cytotoxicity in mammalian L929 cell lines (IC50 = 0.05 ng/mL) and
HeLa cell line KB3.1 (IC50 = 0.04 ng/mL) has been demonstrated.13

OH

O
OH
O O
11. (+)-Ratjadone

Fostriecin
Fostriecin 12, is a phosphate ester metabolite produced by Streptomyces pulveraceus.14 It
displays potent in vitro activiy against a broad range of cancer cell lines and inhibitory activity
against protein serine/threonine phosphatases.
O ONa
O
P
HO OH
OH O O

HO

12. Fostriecin

4
 CHAPTER-I, Section-A

(-)-Callystatin A

(-)-Callystatin A 13 is a polyketide-based natural product isolated in 1997 by Kobayashi

et al from the marine sponge Callyspongia truncata. It exhibits remarkable cytotoxicity with an
IC50 value of 10pg/mL against KB cell lines and 20 pg/mL against L1210 cells.15

OH O O

13. Callystatin A

Spicigerolide
(+)-Spicigerolide 14,16 (+)-Hyptolide 15,17 (-)-Synrotolide 1618 and (+)-Anamarine 1719
are the various ,-unsaturated -lactones isolated from several Hyptis species and other
botanically related genera. These compounds contain a polyoxygenated chain connected with an
,-unsaturated six memberted lactone and have been found to show a range of pharmacological
properties, such as cytotoxicity against human tumor cells, antimicrobial or antifungal activity,
etc. (+)-Spicigerolide, for instance, has been found to exhibit cytotoxicity with ED50 =1.5 g/mL
in the human nasopharyngeal carcinoma (KB) assay system. Other structurally similar lactones
‘Synrolide’, ‘Hypotolide’ and ‘Anamarine’ from Hyptis and taxonomically related species have
been found to be antimicrobial.20
O O

OAc OAc O OAc OAc O

OAc OAc OAc

14. (-)-Spicigerolide 15. Hypotolide

O O

OH OAc O OAc OAc O

OAc OH OAc OAc

16. (-)-Synrotolide 17. (+)-Anamarine

5
 CHAPTER-I, Section-A

Hostettman et al has recently isolated an α,β-unsaturated lactone (6S)-5,6-dihydro-6-

[(2R)-2-hdroxy-6-phenylhexyl]-2H-pyran-2-one 18 from Ravensara crassifolia, a tree growing
up to 18-20m long in the eastern region of Madagascar. After preliminary screenings compound
1821, was found to show antifungal activity against the phytopathogenic fungus Cladosporium
cucumerinum in a bioautographic TLC assay.
O
1 2
OH O 3
6"
1" 4
5" 6' 4' 2' 6
5' 3' 1' 5
4" 2"
3"

18. (6S)-5,6-dihydro-6-[(2R)-2-hydroxy-6-

phenylhexyl]-2H-pyran-2-one

The minimum amount of compound 18 required to inhibit C. cucumerimum fungal growth on

TLC plates was 1 g. These amounts were comparable to the minimum quantities in the same
assays of miconazole (1 g) and propiconazole (0.1 g), as reference antifungal compounds.

In 2007, J.M. Coustard et al22 isolated an α,β-unsaturated lactone Dodoneine 19, namely
[(R)-6-[(S)-2-hydroxy-4-(4-hydroxyphenyl)butyl]-5,6-di-hydropyran-2-one],from the methanolic
extract of hemi plant parasite, Tapinanthus dodoneifolius DC Danser (also known as African
mistletoe) found on a sheanut tree in Loumbila, West Africa. The structure of [(R)-6-[(S)-2-
hydroxy-4-(4-hydroxyphenyl)butyl]-5,6-di-hydropyran-2-one 19 was determined from
spectroscopic and X-ray crystallographic analysis of its camphor sulphonate derivative. (+)-
Dodoneine 19 exhibited relaxing effect on preconstricted rat arotic rings (IC50 of 81.4 ± 0.9 µM).

O
1 2
OH O 3
2"
1" 4
3" 4' 2' 6
3' 1' 5
4"
6"
HO
5"

19. Dodoneine

6
 CHAPTER-I, Section-A

In view its potential biological activities, Dodoneine 19 is considered challenging for its
total synthesis. The various previous synthetic approaches described in literature for Dodoneine
19 are given below.

7
 CHAPTER-I, Section-A

2. PREVIOUS SYNTHETIC APPROACH:

Srihari et al approach:
CHO COOEt
a b O c
HO TBSO TBSO
20 21 22

OH O S OTBS O S

N diastereomer d N
S + S
TBSO TBSO
syn syn:anti anti
Ph 72:13 Ph

23 24
23a

OTBS OTBS OH O S

CHO f N g
e S

TBSO TBSO
syn Ph
anti syn:anti
25 26a + 26b 68:13

O O
OTBS OMOM OTBS OMOM
CHO
N S h i

TBSO TBSO
Ph
27 28
O
OTBS OMOM
OH O
CO2CH3 j

TBSO
29 OH
19
O
+
H O
Scheme 1 O H
H
OH
30

8
 CHAPTER-I, Section-A

Reagents and conditions: (a) (i) Ph3PCHCO2Et, DCM, 12 h (ii) TBSCl, imidazole, 2 h, r.t, 98%. (b)
(i) LAH, THF, reflux, 30 min. (ii) PCC, DCM, 0 oC- r.t, 1 h, 86%. (c) (S)-1-(4-benzyl-2-
thioxothiazolidin-3-yl)ethanone, TiCl4, DIPEA, DCM, -78 oC, 85%. (d) TBSCl, 2,6-lutidine, DMF, r.t,
4 h, 98%. (e) DIBAL-H, DCM, -78 oC, 5 min., 93%. (f) (S)-1-(4-benzyl-2-thioxothiazolidin-3-
yl)ethanone, TiCl4, DIPEA, DCM, -78 oC, 81%. (g) MOMCl, DIPEA, DCM, - 78 oC, 76%. (h)
DIBAL-H, DCM, -78 oC, 5 min., 93%. (i) (CF3CH2O)2 P(O)CH2COOCH3, NaH, THF, -78 oC, 82%.
(j) 3 mol% HCl.
Srihari et al23 has reported the first linear stereoselective total synthesis of (+)-
dodoneine [(R)-6-[(S)-2-hydroxy-4-(4-hydroxyphenyl)butyl]-5,6-di-hydropyran-2-one] 19
involving Crimmins aldol and a Horner-Wadsworth-Emmons olefination as the key steps
(Scheme 1). The synthesis started with 2C-Witting homologation of p-hydroxybenzaldehyde 20
with (carboethoxymethylene)triphenylphosphorane). Compound 21, resulted after TBS
protection, was reduced with LiAlH4 and then oxidized with PCC to afford aldehyde 22. It was
treated with (S)-1-(4-benzyl-2-thioxothiazolidin-3-yl)ethanone in the presence of titanium
chloride using the Crimmins protocol to give diastereomers of β-hydroxy amide. Compound 23,
with required stereochemistry was protected with TBSCl and with DIBAL-H to give an
aldehyde 25. Repeating Crimmins aldol reaction on 25 using (S)-1-(4-benzyl-2-
thioxothiazolidin-3-yl)ethanone, gave seperable diastereomers 26a and 26b. The free hydroxyl
group in compound 26a was masked with MOMCl followed by treatment with DIBAL-H to
provide aldehyde 28. Horner-Wadsworth-Emmons olefination reaction on compound 28
employing bis(2,2,2-trifluoromethyl)(methoxycarbonylmethyl)phosphonate gave the cis-olefinic
ester 29. It was then treated with 3 mol% HCl to give the target molecule Dodoneine 19 as a
major isomer along with bicyclic lactone 30 as minor isomer.
J. Cossy et al approach:
J. Cossy et al24 achieved (+)-Dodoneine 19 starting from methyl-3-(4-
hydroxyphenyl)propionate 31 (Scheme 2). Compound 31, protected with TBSCl, and then ester
was reduced with DIBAL-H to give aldehyde 22. The aldehyde 22 was directly reacted with a
face-selective allyltitanium complex(S,S)-Ti-I (Et2O, -78 oC, 3 h) to furnish the optically active
homoallylic alcohol 32.

9
 CHAPTER-I, Section-A

O O OH
OMe a H b
HO TBSO TBSO
31 22 32
Ph
OH O
O O O
c OEt d OEt
TBSO
TBSO
33 34

Ph Ph
O O O O O
e H f g

TBSO EtO2C
TBSO
35 36
O

OH O

HO
19 Scheme 2

Reagents and conditions: (a) (i) TBSCl, imidazole, CH2Cl2 (ii) DIBAL-H, toluene, -78 oC, 88%. (b)
(S,S)-Ti-1, Et2O, -78 oC, 3 h, 97%. (c) Ethyl acrylate, HG-II (5 mol%), CH2Cl2, r.t., 2 d, 80%. (d)
o o
PhCHO, t-BuOK, THF, 0 C, 2 h, 68%. (e) DIBAL-H, toluene, -78 C, 94%. (f)
(CF3CH2O)2P(O)CH2COOEt, KHMDS, 18-C-6, THF, -78 C, 2 h, 70%. (g) aq AcOH, 60 oC, 24 h,
o

70%.
Further, on reaction with ethyl acrylate in the presence of the Grubbs-second generation catalyst
HG-II (5 mol %) (CH2Cl2, r.t., 2.5 d) leads to an unsaturated ester 33. With benzaldehyde under
basic conditions, 33 was then transformed to the protected 1,3-diol 34, with syn/anti ratio of
98:2. Aldehyde 35, obtained after DIBAL-H reduction was converted to the desired unsaturated
ester 36 with Z/E ratio of 90:10 by Horner-Wadsworth-Emmons reaction using Still-Gennari
o
reagent (KHMDS, 18-crown-6, THF, -78 C, 2 h). Finally, deprotection followed by

10
 CHAPTER-I, Section-A

lactonization in one-pot sequence using aqueous AcOH, at 60 oC for 24 hours gave the target
molecule 19.
Marco et al approach:
OH OTBS
COOH
a b
HO TBSO TBSO
37 32 38

OTBS OTBS OH
c e
O d

TBSO TBSO
25 39

O O

OTBS O OTBS O
f g

TBSO TBSO
40 O 41

OH O

HO
19

Scheme 3

Reagents and conditions: (a) (i) MeOH, cat. H+, heating. (ii) TBSCl, imidazole, 12 h, r.t. (iii)
DIBAL-H, 0 oC, (iv) Swern Oxidation (v) allyltri-n-butyltin, ( R)-BINOL, Ti(OiPr)4 (~60% overall).
(b) TBSOTf, base, r.t., 2 h, 85%. (c) Ozonolysis. (d) (+)-Ipc2BCl, allylMgBr, -90 oC, 2 h, 65%. (e)
acryloyl choride, iPr2NEt, -78 oC, 62%. (f) 10% Grubbs Ru-I, CH2Cl2, 4 h, 84%. (g) aq. HF, MeCN,
r.t., 16 h, 89%.
Marco et al25 achieved the target molecule 19 from dihydro-p-coumaric acid 37. The
homoallyl alcohol 32 was prepared from 37, by following asymmetric Keck allylation of an
intermediate silylated dihydro-p-coumaraldehyde (Scheme 3). Silylation of 32 to 38 using
TBSCl and ozonolytic cleavage of the olefinic bond in 38 yielded aldehyde 25. It was then

11
 CHAPTER-I, Section-A

allylated using asymmetric allylboration with (+)-Ipc2BCl/allylmagnesium bromide to homoallyl

alcohol 39.
The single diastereomer isolated was subjected to sequential acylation with acryloyl chloride and
ring-closing olefin metathesis of the resulting acrylate 40 using Grubbs’ first-generation catalyst
Ru-I furnished pyranone 41. Cleavage of two silyl groups in 41 using aqueous HF yielded target
molecule 19.
G. Hall et al approach:
G. Hall et al26 achieved the synthesis of 19 from known aldehyde25 22 (Scheme 4). The
procedures used here is essentially similar to the previously reported by Marco and Cossy et al
protocols. However a newly developed catalyst namely P-F-Vivol.SnCl4 (Fig. 1) is employed for
highly enantioselective allyl boration steps (ee > 98%).

F F

HO OH
Sn
Cl4

p-F-vivol.SnCl4, Catalyst

Fig. 1

12
 CHAPTER-I, Section-A

O OH

H a b

TBSO TBSO
22 32

OTBS OTBS O

c H d

TBSO TBSO
38 25

OTBS OH OTBS O
e

TBSO TBSO
39 40
O O

f OTBS O g OH O

TBSO HO
41 19

Scheme 4

Reagents and conditions: (a) allylboration using (R,R)-p-F-vivol (5 mol%), SnCl4 (3.8 mol%),
Na2CO3, 4Ao ms, toluene, [1.3 M], -78 oC, (99%, 97%ee). (b) TBSOTf, 2,6-lutidine, CH2Cl2, 95%. (c)
O3, PPh3, CH2Cl2, 75%. (d) allylboration using (R,R)-p-F-vivol (5 mol%), SnCl4 (3.8 mol%),
Na2CO3, 4 oA ms, toluene, [1.3 M], -78 oC, (96%, 99:1 dr). (e) acryloyl chloride, Et3N, CH2Cl2, 82%.
(f)
10% Grubbs Ru-I, CH2Cl2, 95%. (g) HF-pyridine, 100%.

13
 CHAPTER-I, Section-A

Das et al approach:
CHO COOEt
a OH
b
HO BnO BnO
20 42 43

c OH d OH e
O
BnO BnO
44 45
OH OTBS
f CHO g
OH

BnO BnO
46 47

OTBS X Y OTBS O
h
i
BnO 49
BnO 48
O

OTBS OH OTBS O
j k

BnO BnO
50 51
O O

OTBS O OH O

BnO HO
52 19

Scheme 5

Reagents and conditions: (a) (i) NaH, BnBr, THF, 0 oC to r.t, 4 h, 82%. (ii) PPh3CHCOOEt,
CH2Cl2, r.t, 6 h, 80%. (iii) LiBH4, H2O, Et2O, 0 oC, 24 h, 91%. (b) (i) (COCl)2, DMSO, Et3N, CH2Cl2,
-78 oC, 0.5 h, 82%. (ii) PPh3CHCOOEt, CH2Cl2, r.t, 24 h, 81%. (c) DIBAL-H, CH2Cl2, -78 oC to -10
o
C, 0.5 h, 79%. (d) Ti (iOPr)4 (1.0 equiv), (+)-DIPT (1.1 equiv), TBHP (2.5 equiv), CH2Cl2, -20 oC, 12
h, 92%. (e) Red-Al (3.0 equiv), THF, 0 oC, 0.5 h, 82%. (f) (i) TBSCl, imidazole, DMF, r.t, 12 h, 88%.
(ii) PTSA (0.05 equiv), MeOH, 0 oC, 81%. (ii) (COCl)2, DMSO, Et3N, CH2Cl2, -78 oC, 0.5 h, 82%.
(g) Allyl MgBr, Et2O, 0 oC, 1 h, 74%. (h) DMP, NaHCO3, CH2Cl2, 0 oC to r.t, 1 h, 88%. (i) LiAlH4-

14
 CHAPTER-I, Section-A

LiI, Et2O, -100 oC, 30 min, 94%. (j) acryloyl chloride, Et3N, 0 oC to r.t, 30 min, 96%. (k) Grubb’s first
generation catalyst, CH2Cl2, 50 oC, 24 h, 85%. (l) TiCl4, DCM, 0 oC, 89%.

Das et al27 reported the synthesis of target molecule 19 from p-hydroxybenzaldehyde,

involving Sharpless asymmetric epoxidation, 1,3-syn diastereoselective reduction and Grubb’s
ring-closing metathesis as key steps (Scheme 5). O-benzyllation of compound 20 followed by
2C-Witting homologation with (carboethoxymethylene)triphenyl phosphorane and reduction of
the resulting ester with LiAlH4 to form alcohol 42. Swern oxidation of this primary alcohol,
followed by 2C-Witting homologation produced ester 43. 44 were obtained after DIBAL-H
reduction, which underwent epoxidation under Sharpless asymmetric epoxidation conditions
using (+)-DIPT to furnish epoxy alcohol 45. Then unprotected hydroxyl group of compound 46
was converted into aldehyde by using Swern oxidation to afford aldehyde 47. It was treated with
allyl magnesium bromide to provide a diastereomeric mixture (syn:anti 42:58) of a homoallylic
alcohol 48, which in turn was oxidized with Dess-Martin periodinane reagent to form allyl
ketone 49. The diastereoselective reduction of ketone 49, using LiAlH4-LiI at -100 oC gave
product 50 (a ratio of syn: anti- isomers 94:6). Acylation of secondary alcohol with acrolyl
chloride followed by intramolecular metathesis reaction, in the presence of 5 mol% Grubbs’ 1st
generation catalyst yielded the α, β-unsaturated unsaturated lactone 52. Finally deprotection of
the TBS and benzyl groups by using TiCl4, CH2Cl2, 0 oC gave the target molecule 19.

15
 CHAPTER-I, Section-A

3. PRESENT WORK

Many natural products possessing α,β-unsaturated δ-lactone moiety exhibit various

biological activities such as antitumor, antibacterial, antifungal and immunosuppressive
properties. Dodoneine 19, an α,β-unsaturated δ-lactone, isolated in 2007 by J.M. Coustard22 et al
from Tapinanthus dodoneifolius. T. dodoneifolius is used as a remedy to treat wounds,
stomachache, diarrhea, cholera, nervous confusion, and cardiovascular and respiratory diseases.
The basic structure of α -pyrone 19 is a syn 1,3-diol unit with one hydroxyl group involved in
α,β-unsaturated lactone, and the other one is free hydroxyl group. Thus the pyrone 19 possesses a
noncoplanar six membered α,β-unsaturated lactone chromophore, in addition to a disubstituted
benzene ring with a two carbon distance from the chirality center C(2′). Inspired by this type of
lactones we have undertaken the synthesis of Dodoneine 19.
O
1 2
OH O 3
2"
1" 4
3" 4' 2' 6
3' 1' 5
4"
6"
HO
5"

19. Dodoneine

[(R)-6-[(S)-2-hydroxy-4-(4-hydroxy phenyl) butyl]-5,6-di-hydropyran-2-one]

Here we described an efficient and enantioselective formal synthesis of α-pyrone 19,

from p-hydroxybenzaldehyde 20. Sharpless asymmetric dihydroxylation and regioselective
nucleophilic opening of cyclic sulfate are the key steps involved in our synthesis. The
retrosynthetic analysis for Dodoneine 19, [(R)-6-[(S)-2-hydroxy-4-(4-hydroxy phenyl)butyl]-5,6-
di-hydropyran-2-one] presented in Scheme 6.

16
 CHAPTER-I, Section-A

OH O OTBS
CHO

HO 19 TBSO
25

O O
CHO
OEt
O
HO TBSO S
O O
20 59

Scheme 6. Retro synthetic route to (+)-dodoneine.

The key intermediate aldehyde 25 was visualized as an ultimate precursor for the target
molecule 19, which could be obtained from the hydride opening of cyclic sulfate 59 and
subsequent hydrolysis. The cyclic sulfate 59 could be derived from commercially available p-
hydroxybenzaldehyde 20 through series of reactions comprising double 2C Wittig olefinations
and Sharpless asymmetric dihydroxylation (As the source of chirality). The salient feature of our
synthetic strategy was on the presumption that regioselective nucleophilic opening of cyclic
sulfate would occur at the α-carbon.
O
TBS-Cl CHO
CHO
Imidazole Ph3PCHCO2Et OEt
dry CH2Cl2 TBSO benzene
HO
o oC, 1.5 h, 96% reflux, 6.5 h TBSO
20 53 92% 21

Scheme 7

Our approach starts from p-hydroxybenzaldehyde 20, as it is an inexpensive and readily

available starting material. The phenolic hydroxyl group of compound 20 was protected as tert-
butyldimethylsilyl (TBS)-ether by using TBS-Cl and imidazole in dichloromethane at 0 oC to
room temperature afforded compound 53 in 96% yield (Scheme 7). 1H NMR spectrum of
compound 53 showed signals at 0.99 (9H),  0.24 (6H) as singlets conforming the structure 53.

17
 CHAPTER-I, Section-A

The other protons of compound 53 resonated at their expected chemical shift values. It was
further conformed by its ESI mass spectrum that showed peat at m/z 259 (M++Na). Witting
olefination of 4-(tert-Butyldimethylsilyloxy)benzaldehyde 53 with Ethyl
(triphenylphosphornylidene)acetate in dry benzene under reflux conditions for 6.5 h gave trans-
olefin 21 in 92% yield. Compound 21 was characterized from 1H NMR spectrum by appearance
of doublets at  6.77 and  6.21 for trans-olefinic protons and also from disappearance of
aldehydic proton. The structure of the compound 21 was also confirmed by its ESI mass
spectrum at m/z 329 (M++Na).
O O
OEt H2, 10% Pd/C OEt LiAlH4, THF

TBSO EtOAC, overnight TBSO 0 oC, 1.5 h, 91%

21 92% 54

OH

TBSO
55

Scheme 8

Reduction of trans-olefinic ester 21 using LiAlH4 at room temperature gave mixture of

products along with low yield of desired alcohol 55. In order to obtain the best yield of alcohol
compound 55, a two step procedure (Scheme 8) was devised involving catalytic hydrogenation
using Pd/C and then LiAlH4. Reduction of olefinic functionality by using 10% Pd/C in ethyl
acetate at 25 oC under H2 for 12 h resulted the saturated ester 54 in 92% yield. Appearance of
triplets at  2.84 and  2.53 confirms the reduction of olefinic functionality, IR spectrum showed
absorption at 1736 cm-1 for C=O stretching and a peak at m/z 309 (M++H) in ESI mass spectrum
confirmed the structure of the compound 54.

The reduction of ester group with LiAlH4 in dry THF at 0 oC for 1.5 h gave the desired
alcohol 55 in 91% yield. The conversion of ester to alcohol was confirmed by the 1H NMR
spectrum, disappreance of ester protons triplet at  2.53 and quartet at  4.08. It was also assisted
by IR spectrum appearing absorbance at 3416 cm-1. Further the structure of compound 55 was
confirmed by its ESI mass spectrum at m/z 267 (M++H).

18
 CHAPTER-I, Section-A

CHO
OH
(COCl)2, DMSO
TBSO Et3N, CH2Cl2, -78 oC TBSO
55 30 min, 94% 22

O
Ph3PCHCO2Et
OEt
benzene, reflux
8 h, 91% TBSO
56

Scheme 9

Oxidation of the alcohol functionality in compound 55 using oxalyl chloride, DMSO in

dichloromethane at -78 oC under Swern oxidation conditions gave the aldehyde 22 in 94% yield
after silica gel flash column chromatography (Scheme 9). The formation of aldehyde was
evident from 1H NMR spectrum by the appearance of characteristic aldehyde proton at  9.78 as
a singlet, carbonyl carbon at  201.8 in 13C NMR spectrum and an absorption band at 1721 cm-1
in IR spectrum. The 2C-Witting reaction on compound 22 using ethyl
(triphenylphosphornylidine) acetate in dry benzene under reflux conditions produced α, β-
unsaturated ester 56 in 91% yield. The formation of α, β-unsaturated ester 56 was revealed from
1
H NMR spectrum, disappreance of aldehyde proton and displayed signals at  6.91 and  5.76
as doublets. In 13C NMR spectrum the ester carbonyl carbon appeared at  166.5. A absorption
band at 1721 cm-1 in the IR spectrum for the ester group and a peak at m/z 352 (M++NH4) in
mass spectrum confirmed the formation of α, β-unsaturated ester 56.

In recent years, AD reaction has become indispensible and reliable tool for the
introduction of enantioselective hydroxyls at olefinic carbons. The reaction has been used as
powerful method for developing enantioselective syntheses of naturally occurring lactones, the
Sharpless asymmetric dihydroxylation was envisaged as powerful tool offering considerable
further opportunities for synthetic manipulations28. According to the recent reports,23-27 achieved
chirality at C(2′) carbon using various reagents. We therefore visined to use Sharpless
asymmetric dihyxroxylation using AD-mix- α as source of chirality at C(2′) carbon.

19
 CHAPTER-I, Section-A

O OH O
OEt AD-mix-, MeSO2NH2 OEt
TBSO t-BuOH:H2O (1:1) OH
TBSO
0 oC, Overnight
56 57
85%

Scheme 10

The dihydroxylation of trans-olefinic ester 56 with AD-mix-α, methane sulfonamide in

tert-BuOH:H2O (1:1) at 0 oC under the Sharpless asymmetric dihydroxylation conditions gave
diol 57 in 85% yield and 96% ee after the purification of column chromatography (Scheme 10).
The formation of diol is established from its spectral data. The 1H NMR spectrum showed
signals at  4.01-3.99 and  3.85-3.77 as a multiplets. The IR spectrum showed absorption band
at 3432 cm-1 indicates the formation of hydroxyl group. Molecular ion peak at m/z 391 (M++Na),
in the mass spectrum confirms the formation of compound 57.

OH O O O

OEt SOCl2, Et3N OEt

OH O
TBSO CH2Cl2, 0 oC TBSO S
30 min, 94% O
57 58

O O
RuCl3, NaIO4
CCl4-MeCN-H2O (1:1:1.5) OEt
O
0 oC, 30 min, 92% TBSO S
O O

59

Scheme 11

Sharpless and co-workers have also observed29 that vicinal diol cyclic sulfates are “like
epoxides only more reactive”. With this clue, the diol 57 was treated with thionyl chloride in the
presence of triethyl amine in dichloromethane at 0 oC to give isomeric cyclic sulfite 58 in 94%
yield (Scheme 11) after purification of flash column chromatography. The compound 58 was

20
 CHAPTER-I, Section-A

characterized from 1H NMR spectrum by the shift of signals from  4.01-3.99 and  3.85-3.77 to
 5.11-4.96 and  4.58-4.43 respectively as multiplets. Compound 58 also confirmed by its mass
spectrum, which showed a peak at m/z 437(M++Na). Oxidation of compound 58 to Cyclic
sulfate compound 59 using Ruthenium chloride-sodiumperiodate in CCl4:CH3CN:H2O (1:1:1.5)
mixture at 0 oC gave the desired compound in 92% yield after purification of column
chromatography. The conversion of cyclic sulfite to cyclic sulfate was confirmed by the
spectroscopic data. The 1H NMR spectrum of the compound 59 showed peaks at  4.87-4.83 as a
multiplet and  4.75 (d, J=7.8Hz, 1H) as a doublet. The structure of the compound 59 was
unambiguously confirmed by its ESI mass spectrum which showed a peak at m/z 453(M++Na).

The essential feature of our synthetic strategy shown in the Scheme 12 was observed on
the presumption that the nucleophilic opening of the cyclic sulfate 59 would occur in the
regiospecific manner at the α-position. Reduction of cyclic sulfates to mono alcohols with
sodium borohydride in dimethyl acetamide was originally recommended.29a

The intermediate sulfate esters 59a were then hydrolyzed in a 20% aqueous H2SO4-ether
system. Alternatively, hydrolysis could be affected with a catalytic amount of concentrated
sulfuric acid and 0.5-1.0 equiv of water in THF.30

O O O
OSO3-
OEt NaBH4, DMF, 15 min OEt
O
TBSO S TBSO
O O

59 59a

OH O

THF, cat.Conc.H2SO4 OEt

cat. H2O, 20 min, 90% TBSO

60

Scheme 12

We have observed that, hydrolysis (with catalytic amount of sulfuric acid and water) of
intermediate sulfate ester, obtained from cyclic sulfate 59 after treatment with sodium
borohydride in DMF at 25 oC, was sluggish and gave the desired product alcohol 60 in low

21
 CHAPTER-I, Section-A

yields (<10%). Conducting both the stages of reaction at 0 oC for longer hours (2-3 h each)
improved the formation of alcohol 60 (52% yield), but α, β-unsaturated ester 56 was also
obtained as side product in substantial amount (~35%). After series of experiments, we have
established that treatment of cyclic sulfate 59 with sodium borohydride in DMF for 15 minutes at
0 oC, followed by hydrolysis with catalytic amount of concentrated sulfuric acid and 0.35 equiv
of water in THF at 0 oC for 20 min afforded the desired alcohol 60 in quantitative yield (90%)
after purification of the column chromatography. The choice of reaction conditions (reaction
temperature and time) is crucial for the successful yield of the desired compound 60 (Scheme
12). In 1H NMR spectrum the disappearance of  4.87-4.83 as a multiplet and  4.75 (d,
J=7.8Hz, 1H) as a doublet and appearance of multiplet at  3.96-3.91. It was also assisted by IR
spectrum appearing absorbance at 3451 cm-1. Mass spectrum shows molecular ion peak at m/z
353(M++H) confirms the formation of required alcohol compound 60.

OH O OTBS O
TBSCl, imidazole
OEt CH2Cl2, 0 oC-25 oC OEt

TBSO overnight, 95% TBSO

60 61

Scheme 13

The secondary hydroxyl group of compound 60 was protected as tert-butyldimethylsilyl

(TBS) ether by using TBS-Cl and imidazole in dichloromethane at 0 oC to afford the compound
61 in 95% yield (Scheme 13). The formation of compound was confirmed by 1H NMR spectrum
showed signals at  0.17,  0.06 and  0.03 as a singlets and Mass spectrum showed a molecular
ion peak at m/z 467 (M++H).

OTBS O OTBS
CHO
OEt DIBAL-H, CH2Cl2
TBSO -78 oC, 10 min TBSO
61 25
88%
ref. 26
25 (+)-Dodoneine
Scheme 14

22
 CHAPTER-I, Section-A

The ester functional group in compound 61 was reduced by using DIBAL-H in dry
dichloromethane at -78 oC to afford the our target intermediate aldehyde 25 in 88% yield after
column purification (Scheme 14). The formation of absolute stereo chemistry of the product

aldehyde (S)-25 was ascertained by comparing all the analytical (specific rotation, [α]D25 = +5.54
(c 2.1, CHCl3), Lit26 [α]D25 = + 5.57) and 1H and 13C NMR spectral data with recently reported
literature values.26 The 1H NMR spectrum of compound 25 showed aldehyde proton at  9.80
(1H, t, J= 1.9HZ), aromatic protons at  6.99 and  6.73 as a doublets (2H, d, J= 8.7HZ),
secondary alcohol attached proton appears at  4.24-4.19 as multiplet, benzylic and carbonyl
attached methylene protons at  2.60-2.55 as multiplet and aliphatic CH2 protons at  1.85-1.80
as multiplet and 2-TBS protons at  0.98,  0.89,  0.18,  0.07 as singlets. It also further
confirmed through its 13C NMR spectrum showed signal at  202.0.

Natural product (+)-dodoneine 19 was finally obtained from aldehyde (S)-25 by

following a well described25-27 reaction sequence comprising asymmetric allylation with allyl
magnesium bromide, acylation with acryloyl chloride and Grubs ring closer metathesis (Scheme
14).

4. CONCLUSION:

Formal synthesis of (+)_dodoneine 19 has been accomplished by Sharpless asymmetric

dihydroxylation and regioselective nucleophilic opening of cyclic sulfate 59. The optimum
conditions for the key steps, nucleophilic opening of cyclic sulfate 59 with sodium borohydride
in regioselective manner at the α-position (0 oC / 15 min) and subsequent hydrolysis of sulfate
ester (0 oC / 20 min) is ascertained after series of experimentations.

23
 CHAPTER-I, Section-A

5. EXPERIMENTAL SECTION

All the reactions were monitored by TLC (recoated silica plates and visualizing under UV
light). Air-sensitive reagents were transferred by syringe or double-ended needle. Evaporation of
solvents was performed at reduced pressure on a Buchi rotary evaporator. 1H and 13
C NMR
spectra of samples in CDCl3 were recorded on Bruker UXNMR FT-300 MHz (Avance)
spectrometer and Varian FT-500MHz (Inova). Chemical shift reported are relative to an internal
standard TMS (δ=0.0). Mass spectra were recorded in EI conditions at 70 eV on an LC-MSD
(Agilent technologies) spectrometers. All high-resolution spectra were recorded on QSTAR XL
hybrid MS/MS system (Applied Biosystems/ MDS sciex, foster city, USA), equipped with an
ESI source (IICT, Hyderabad). Column chromatography was performed on silica gel (60-120
mesh) supplied by Acme Chemical Co., India. TLC was performed on Merck 60 F-254 silica gel
o
plates. Optical rotations were measured with JASCO DIP-370 Polarimeter at 25 C.
Commercially available anhydrous solvents CH2Cl2, THF, and EtOAc were used as such with
out further purification.

4-(tert-Butyldimethylsilyloxy)benzaldehyde, 53

To the stirred solution of p-hydroxybenzaldehyde 20 (6.0 g, 49.18 mmol) in anhydrous

CH2Cl2 (35 mL), imidazole (5.0 g, 73.77 mmol) followed by tert-butyldimethylsilyl chloride
(8.89 g, 59.01 mmol) were added at 0 oC under N2. After stirring the reaction mixture for 1.5 h,
at 25 oC, it was quenched with a saturated aqueous solution of NH4Cl and extracted with CH2Cl2
(6 x 30 mL). The combined organic extracts were washed with brine, dried over anhydrous
Na2SO4 and concentrated in vacuum. The residue was purified by flash column chromatography
over silica gel (ethyl acetate/hexane, 5:95) afforded 4-(tert-butyldimethylsilyloxy)benzaldehyde
53 (11.12 g, 96%) as colorless liquid.

Yield : 96%

IR (neat) : max2934, 2858, 1697, 1598, 1508, 1272, 1156, 908 cm-1.
1
H NMR (CDCl3, 300 MHz) : δ 9.86 (s, 1H), 7.74 (d, J=7.8Hz, 2H), 6.89 (d, J= 8.7Hz,
2H), 0.99 (s, 9H), 0.24 (s, 6H).
13
C NMR (CDCl3, 75 MHz) : δ 189.8, 161.2, 131.8, 120.4, 96.2, 25.7, 18.4, -4.1.

MS (ESI) : m/z 259 (M+ + Na)

24
 CHAPTER-I, Section-A

HRMS (ESI) (M+ + Na) : Calcd for C13H20O2NaSi: 259.1130; found: 259.1125

(E)-Ethyl 3-[4-(tertbutyldimethylsilyloxy)phenyl] acrylate, 21

Ethyl (triphenylphosphornylidene) acetate (18.2 g, 54.0 mmol) was added to a stirred solution of
4-(tert-butyl-dimethylsilyloxy)benzaldehyde 53 (8.5 g, 36.0 mmol) in dry benzene (80 mL). The
reaction mixture was refluxed for 6.5 h, and concentrated in vacuum. Crude residue thus
obtained was purified by column chromatography (ethyl acetate/hexane 1:9) afforded (E)-ethyl
3-(4-(tert-butyl dimethylsilyloxy)phenyl) acrylate 21 (10.13 g, 92%) as color less liquid.

Yield : 92%

IR (neat) : max 2934, 1713, 1601, 1509, 1263, 1167, 912 cm-1.
1
H NMR (CDCl3, 300 MHz) : δ 7.55 (d, J= 15.8Hz, 1H), 7.37 (d, J= 8.3Hz, 2H), 6.77 (d,
J=8.3Hz, 2H), 6.21 (d, J= 15.8Hz, 1H), 4.21 (q, J= 7.5Hz,
2H), 1.33 (t, J= 7.5Hz, 3H), 0.98(s, 9H), 0.21 (s, 6H).

MS (ESI) : m/z 329 (M++ Na)

HRMS (ESI) (M+ + Na) : Calcd for C17 H26O3NaSi: 329.1548; found; 329.1544.

3-(4-(tert-butyldimethylsilyloxy)phenyl)propionic acid ethyl ester, 54

A mixture of 21 (8.2 g, 26.77 mmol), 10% Pd/C in ethyl acetate (75 mL) was stirred at 25 oC
under H2 (1 atm) for 12 h. After completion of reaction (monitored by TLC), it was filtered
through a celite (ethyl acetate as eluent) and the solvent evaporated under vacuum to afford 3-(4-
(tert-butyldimethylsilyloxy)phenyl)propionic acid ethyl ester 54 (7.50 g, 92%) as colorless
liquid.

Yield : 92%

IR (neat) : max 2934, 1736, 1510, 1258, 1169, 916 cm-1.

1
H NMR (CDCl3, 500 MHz) : δ 6.99 (d, J= 7.8Hz, 2H), 6.68 (d, J= 7.8Hz, 2H), 4.08 (q,
J= 6.8Hz, 2H), 2.84 (t, J = 7.8Hz, 2H), 2.53 (t, J= 7.8Hz,
2H), 1.22 (t, J= 6.8Hz, 3H), 0.97 (s, 9H), 0.17 (s, 6H).

MS (ESI) : m/z 309 (M+ +H)

HRMS (ESI) (M+ + Na) : Calcd for C17 H28O3NaSi: 331.1705; found; 331.1716.

25
 CHAPTER-I, Section-A

3-(4-(tert-butyldimethylsilyloxy)phenyl)propan-1-ol, 55

To a stirred suspension of LiAlH4 (1.35 g, 35.55 mmol) in dry THF (30 mL), was added drop
wise 3-(4-(tert-butyldimethylsilyloxy)phenyl)propionic acid ethyl ester 54 (7.3 g, 23.70 mmol) in
dry THF (40 mL) at 0 oC. After 1.5 h at 0 oC, it was quenched with the addition of saturated
aqueous Na2SO4 solution, filtered through a celite pad (hot ethyl acetate as eluent). Residue
obtained after evaporating the combined solvent under vacuum was purified by column
chromatography (ethyl acetate/ hexane 15:85) to give 3-(4-(tert-
butyldimethylsilyloxy)phenyl)propan-1-ol, 55 (5.73 g, 91%) as color less liquid.

Yield : 91%

IR (neat) : max 3416, 2932, 1508, 1254, 1041, 914 cm-1

1
H NMR (CDCl3, 500 MHz) : δ 6.98 (d, J= 7.8Hz, 2H), 6.68 (d, J= 7.8Hz, 2H), 3.65-
3.60 (m, 2H), 2.62 (t, J=7.8Hz, 2H), 1.86-1.80 (m, 2H),
0.97 (s, 9H), 0.17 (s, 6H).
13
C NMR (CDCl3, 75 MHz) : δ 153.6, 134.3, 129.1, 119.8, 62.3, 34.3, 31.2, 25.6, 18.1.

3-(4-(tert-butyldimethylsilyloxy)phenyl)propanal, 22

To a solution of oxalyl chloride (16.9 mmol, 1.41 mL) in dry dichloromethane (20 mL) at -78 oC,
DMSO (3.2 mL, 45.08 mmol) was added drop wise with stirring under nitrogen atmosphere.
After 15 min, compound 55 (3 g, 11.27 mmol) was added into the reaction mixture and
subsequently after stirring for 30 min at -78 oC, Et3N (56.35mmol, 7.8 mL) was added and the
mixture was stirred for another 0.5 h at –78 oC and then for 0.5 h at 0 oC. The reaction mixture

was quenched with saturated NH4Cl solution (40 mL) at 0 oC and extracted with EtOAc (5x30
mL). The combined organic extracts were washed with brine, dried over anhydrous Na2SO4 and
concentrated in vacuum. The 3-(4-(tert-butyldimethylsilyloxy)phenyl) propanal 22 thus obtained
after flash column chromatography (2.79 g, 94%) was used directly for further reaction.

Yield : 94%
1
H NMR (CDCl3, 300 MHz) : δ 9.78 (s, 1H), 6.98 (d, J= 8.7Hz, 2H), 6.68 (d, J= 8.7Hz,
2H), 2.86 (t, J= 7.8Hz, 2H), 2.71 (t, J= 6.8Hz, 2H), 0.97
(s, 9H), 0.17 (s, 6H).

26
 CHAPTER-I, Section-A

(E)-ethyl 5-(4-(tert-butyldimethylsilyloxy)phenyl) pent-2-enoate, 56

A solution of 3-(4-(tert-butyldimethylsilyloxy) phenyl) propanal 22 (2.0 g, 7.57 mmol) and ethyl

(triphenyl phosphorrnylidene) acetate (3.84 g, 11.36 mmol) in benzene (20 mL), was refluxed for
8 h. After completion of reaction (by TLC), it was concentrated in vacuum and the residue was
purified by column chromatography (ethyl acetate/ hexane 5:95) to afford 56 (2.30 g, 91%) as a
colorless liquid.

Yield : 91%

IR (neat) : max 2932, 1721, 1509, 1259, 1192, 915 cm-1.

1
H NMR (CDCl3, 500 MHz) : δ 6.96 (d, J= 7.8Hz, 2H), 6.91 (d, J= 15.6 Hz, 1H), 6.89
(d, J= 7.8Hz, 2H), 5.76 (d, J= 15.6Hz, 1H), 4.14 (q, J=
6.8Hz, 2H), 2.69 (t, J= 7.8Hz, 2H), 2.46 (q, J= 7.8Hz, 2H),
1.28 (t, J = 6.8Hz, 3H), 0.97 (s, 9H), 0.17 (s, 6H).
13
C NMR (CDCl3, 75 MHz) : δ 166.5, 153.8, 148.1, 133.4, 129.1, 121.6, 119.9, 60.0,
34.0, 33.4, 25.4, 18.1, 14.1, -4.5.

MS (ESI) : m/z 335 (M+ + H)

HRMS (ESI) (M+ + Na) : C19H30O3NaSi: 357.1861; found: 357.1856.

(2R,3S)-ethyl5-(4-(tert-butyldimethylsilyloxy)phenyl)-2,3-dihydroxypentanoate, 57

To a solution of AD mix-α (4.2 g) in t-BuOH: H2O (1:1, 20 mL), was added MeSO2NH2 (300
mg) and alkene 56 (1.0 g, 2.99 mmol) slowly at 0 oC and the mixture was stirred overnight at the
same temperature. After complete consumption of the starting material, sodium sulfite (4.5 g)
was added and the solution was warmed to room temperature and stirred for 90min. After which
the reaction mixture was poured in water (10 ml) and several times with ethyl acetate (4x100
mL). Combined organic extracts were washed with brine (2x100 mL), dried over Na2SO4 and
concentrated in vacuum. Crude residue was chromatographed over silica (ethyl acetate/hexane
30:70) afforded 57 (0.93 g, 85%) as colorless liquid.

Yield : 85%

[α] D25 : -7.0 (c 1.0, CHCl3).

IR (neat) : max 3432, 2933, 2858, 1736, 1509, 1257, 1118, 916 cm-1.

27
 CHAPTER-I, Section-A

1
H NMR (CDCl3, 300 MHz) : δ 7.00 (d, J= 8.3Hz, 2H), 6.68 (d, J= 8.3Hz, 2H), 4.25 (q,
J= 7.1Hz, 2H), 4.01-3.99 (m, 1H), 3.85- 3.77 (m, 1H),
3.01-2.95 (m, 1H), 2.79-2.57 (m, 2H), 1.92-1.79 (m, 3H),
1.31 (t, J= 7.1Hz, 3H), 0.97 (s, 9H), 0.17 (s, 6H).
13
C NMR (CDCl3, 75 MHz) : δ 173.4, 153.7, 134.0, 129.2, 119.9, 73.1, 71.7, 62.1, 35.5,
31.0, 25.6, 18.1, 14.1, -4.4.

MS (ESI) : m/z 391 (M+ + Na)

HRMS (ESI) (M+ + Na) : Calcd for C19H32O5NaSi: 391.1916; found: 391.1916. .

Cyclic Sulfite, 58

To a solution of the compound 57 (0.85 g, 2.30 mmol) in CH2Cl2 (20 mL) at 0 oC, was added
Et3N (0.64 mL, 4.61mmol) followed by freshly distilled thionyl chloride (0.2 mL, 2.77 mmol)
drop wise. It was stirred further for 45min at 0 oC and then quenched by adding H2O (20 mL).
The phases were separated, aqueous phase was extracted with CH2Cl2 (3 x 50 mL), combined
organic phases were dried with Na2SO4 and concentrated in vacuum. After flash column
chromatography this cyclic sulfite 58 (0.89 g, 94%) was used for the next reaction.

Cyclic Sulfate, 59

The cyclic sulfite 58 (0.70 g, 1.69 mmol) dissolved in CCl4 (10 mL) and CH3CN (10 mL) was
cooled in an ice bath and cold H2O (15 mL) followed by RuCl3.H2O (17 mg, 0.10 mmol) and
NaIO4 (0.72 g, 3.38mmol) were added at once. The reaction mixture was vigorously stirred at 0
o
C for 30 min, extracted with ether (3x50 mL); the organic layer was washed with brine, dried
over Na2SO4 and concentrated in vacuum. The crude residue was purified by column
chromatography to afford 59 (0.66 g, 92%) as violet color liquid.

Yield : 92%

[α] D25 : -46.2 (c 1.0, CHCl3).

IR (neat) : max 2933, 1768, 1510, 1398, 1259, 1209, 1018, 912 cm-1.
1
H NMR (CDCl3, 500 MHz) : δ 7.00 (d, J= 8.7Hz, 2H), 6.72 (d, J= 7.8Hz, 2H), 4.87-
4.83 (m, 1H), 4.75 (d, J= 7.8Hz, 1H), 4.29 (q, J= 6.8Hz,
2H), 2.87-2.82 (m, 1H), 2.74-2.68 (m, 1H), 2.30-2.19 (m,

28
 CHAPTER-I, Section-A

2H), 1.33 (t, J= 6.8Hz, 3H), 0.97 (s, 9H), 0.18 (s, 6H).
13
C NMR (CDCl3, 75 MHz) : δ = 164.5, 154.2, 131.4, 129.2, 120.2, 83.0, 79.6, 63.1,
34.7, 30.0, 25.5, 18.0, 13.8, -4.5.

MS (ESI) : m/z 453 (M+ + Na)

HRMS (ESI) (M+ + Na) : Calcd for C19H30O7NaSi: 453.1379; found: 453.1361.

(S)-ethyl 5-(4-(tert-butyldimethylsilyloxy)phenyl) -3-hydroxypentanoate, 60

To a stirred solution of cyclic sulfate 59 (0.30 g, 0.69 mmol) in dry DMF (5 mL) at 0 oC, was
added NaBH4 (52 mg, 1.39 mmol) under N2 atm. After 15 min of stirring, solvent was removed
under reduced pressure (0.2 mm Hg,) and the residue was suspended in dry THF (10 mL). At 0
o
C, conc.H2SO4 (35 μL) and H2O (15 μL) were added slowly with stirring for another 20 min and
excess sodium bicarbonate (200 mg) was added with stirring further for 20 min. Filtered through
a celite pad (hot ethyl acetate as eluent), filtrate was concentrated under reduced pressure and the
crude liquid was chromatographed (ethyl acetate/ hexane 20:80) to give (S)-ethyl5-(4-(tert-
butyldimethyl silyloxy)phenyl)-3-hydroxy pentanoate 60 (0.22 g, 90%) as a colorless liquid.

Yield : 90%

[α] D25 : -5.0 (c 1.0, CHCl3).

IR (neat) : max 3451, 2931, 2858, 1727, 1509, 1256, 1179, 915 cm-1..
1
H NMR (CDCl3, 500 MHz) : δ 6.99 (d, J= 8.1Hz, 2H), 6.67 (d, J= 8.1Hz, 2H), 4.14 (q,
J= 7.2Hz, 2H), 3.96-3.91 (m, 1H), 2.94 (d, J= 3.6Hz, 1H),
2.75-2.69 (m, 1H), 2.63-2.57 (m, 1H), 2.46-2.35 (m, 2H),
1.81-1.74 (m, 1H), 1.68-1.62 (m, 1H), 1.27 (d, J= 7.2Hz,
3H), 0.97 (s, 9H), 0.17 (s, 6H).
13
C NMR (CDCl3, 75 MHz) : δ 172.9, 153.6, 134.2, 129.1, 119.8, 67.1, 60.6, 41.2, 38.2,
30.8, 29.6, 25.6, 18.1, 14.1, -4.4.

MS (ESI) : m/z 353 (M+ + H)

HRMS (ESI) (M+ + Na) : Calcd for C19H32O4NaSi: 375.1967; found: 375.1981.

29
 CHAPTER-I, Section-A

(S)-ethyl3-(tert-butyldimethylsilyloxy)-5-(4-(tert-butyldimethylsilyloxy) phenyl pentanoate,

61

To compound 60 (0.15 g, 0.42 mmol) in dry CH2Cl2 (5 mL), imidazole (86 mg, 1.27 mmol)
followed by TBS-Cl (130 mg, 0.85 mmol) were added at 0 oC under nitrogen atmosphere. After
stirring the reaction mixture over night, it was quenched with a saturated solution of NH4Cl (3
mL) and extracted with CH2Cl2 (6x25 mL). The combined organic extracts were washed with
brine, dried over anhydrous Na2SO4 and concentrated in vacuum. The crude residue was flash
chromatographed (ethyl acetate/hexane 5:95) to afford (S)-ethyl 3-(tert-butyldimethylsilyloxy)-5-
(4-(tert-butyl dimethylsilyloxy)phenyl)pentanoate 61 (0.18g, 95%) as colorless liquid.

Yield : 95%

[α] D25 : +10.6 (c 1.0, CHCl3).

IR (neat) : max 2932, 2858, 1737, 1509, 1256, 1091, 916 cm-1.
1
H NMR (CDCl3, 300 MHz) : δ 7.00 (d, J= 8.3Hz, 2H), 6.73 (d, J= 8.3Hz, 2H), 4.20-
4.08 (m, 3H), 2.62-2.52 (m, 2H), 2.47 (t, J= 6.7Hz, 2H),
1.82-1.73 (m, 2H), 1.25 (t, J= 6.7Hz, 3H), 0.97 (s, 9H),
0.88 (s, 9H), 0.17 (s, 6H), 0.06 (s, 3H), 0.03 (s, 3H).
13
C NMR (CDCl3, 75 MHz) : δ 171.7, 153.5, 134.6, 129.0, 119.8, 68.9, 60.3, 42.5, 39.4,
30.4, 25.7, 25.6, 18.1, 14.1, -4.8, -4.5, -4.4.

MS (ESI) : m/z 467 (M+ + H)

HRMS (ESI) (M++ Na) : Calcd for C25H46O4NaSi2: 489.2832; found: 489.2853.

(S)-3-(tert-butyldimethylsilyloxy)-5-(4-(tert-butyl dimethylsilyloxy)phenyl)pentanal, 25

To a solution of (S)-ethyl3-(tert-butyldimethylsilyloxy)-5-(4-(tert-
butyldimethylsilyloxy)phenylpentanoate 61 (0.1 g, 0.21 mmol) in dry CH2Cl2 (2 mL), DIBAL-H
(1.0M, 0.23 mL, 0.23 mmol) was added drop wise at -78 oC and stirred for 10 min. The reaction
mixture was quenched with saturated aqueous sodium potassium tartrate (1 mL) at –78 oC,
stirred for 20 min and then brought to room temperature. The organic layer was separated and
aqueous layer was extracted with EtOAC (4x10 mL), combined organic extracts were dried over
anhydrous Na2SO4 and concentrated in vacuum. The crude residue thus obtained was purified by

30
 CHAPTER-I, Section-A

column chromatography (ethyl acetate/hexane 10:90) to afford (S)-3-(tert-

butyldimethylsilyloxy)-5-(4-(tert-butyldimethyl silyloxy) phenyl)pentanal 25 (0.078g, 88%) as a
colorless liquid.

Yield : 88%

[α] D25 : + 5.54 (c 2.1, CHCl3); Lit26 [α]D25 =+ 5.57).

1
H NMR (CDCl3, 500 MHz) : δ 9.80 (t, J= 1.9 Hz, 1H), 6.99 (d, J= 8.7Hz, 2H), 6.73 (d,
J= 8.7Hz, 2H), 4.22 (q, J= 5.8Hz, 1H), 2.60-2.55 (m, 4H),
1.85-1.80 (m, 2H), 0.98 (s, 9H), 0.89 (s, 9H), 0.18 (s, 6H),
0.07 (s, 3H), 0.04 (s, 3H).
13
C NMR (CDCl3, 75 MHz) : δ 202.0, 153.7, 134.2, 129.0, 119.9, 67.7, 50.7, 39.6, 30.6,
25.7, 18.1, 17.9, -4.4, -4.6.

31
 CHAPTER-I, Section-A

6. REFERENCES:

1. a) Coleman, D. M. T.; Rivett, D. E .A. Fortschr. Chem. Org. Naturst. 1989, 55, 1. b)
Ohloff, G. Fortschr. Chem. Org. Naturst. 1978, 35, 431. c) Adityachaudhury, N.; Das, A.
K. J. Sci. Ind.l Res. (India) 1979, 38, 265. d) Siegel, S. M. Phytochemistry 1976, 15, 566.
(e) Marco, J.A.; Carda, M.; Murga, J.; Falomir, E. Tetrahedron, 2007, 63, 2929.
2. Franca, N. C.; Polonsky, J. C. R. Hebd. Seanes. Acad.l Sci., Paris C. 1971, 273, 439.
3. Coleman, D. M. T.; Rivett, D. E. A Phytochemistry 1987, 26, 3047.
4. Watt, J.M.; Brandwijk, M. G. B. The Medicinal and Poisonous Plants of Southern and
Eastern Africa; Livingston; Edinburgh, 1962; p 516.
5. a) Bohlmann, F.; Suwita, A. Phytochemistry 1979, 18, 677. b) Andrianaivoravelona, J.
O.; Sahpaz, S.; Terreaux, C.; Hostettmann, K.; Stoecki-Evans, H.; Rasolondramanitra, J.
Phytochemistry 1999, 52, 265. c) Echeverri, F.; Arango, V.; Quinones, W.; Tyorres, F.;
Escobar, G.; Rosero, Y.; Archbolde, R. Phytochemistry 2001, 56, 881.
6. Hsu, F. L.; Chen, Y. C.; Cheng J. T. Planta Med. 2000, 66, 228.
7. Ecgeverri, F.; Arango, V.; Quinones, W.; Torres, F.; Escobar, G.; Rosero, Y.; Archbold,
R. Phytochemistry 2001, 56, 881.
8. Fu, X.; Sevenet, T.; Hamid, A.; Hadi, A.; Remy, F.; Pais, M. Phytochemistry 1993, 33,
1272.
9. Abe, S. J. Chem. Soc. Japan. 1937, 58, 246.
10. a) Priestap, H. A.; Bonafede, J. D.; Ruveda, E. A. Phytochemistry 1977, 16, 1579. b)
Priestap, H. A.; Van Baren, C. M.; Lira, P. D. L.; Coussio, J. D.; Bandoni, A. L.
Phytochemistry 2003, 63, 221. c) Matsuda, M.; Endo,Y.; Fushiya, S.; Endo, T.; Nozoe, S.
Heterocycles 1994, 38,1229. d) Juliawaty, L. D.; Kitajima, M.; Takayama, H.; Achmad,
S. A.; Aimi, N. Chem Pharm, Bull. 2000, 48, 1726.
11. Juliawaty, L. D.; Kitajima, M.; Takayama, H.; Achmad, S. A.; Aimi, N. Phytochemistry
2000, 54, 989.
12. Schummer, D.; Gerth, K.; Reichenbach, H.; Hofle, G. Liebigs Ann. 1995, 685.
13. Gerthl, K.; Schummer, D.; Hofle, G.; Irschik, H,; Reichenbach, H. J. Antibiot. 1995, 48,
973.

32
 CHAPTER-I, Section-A

14. a) Tunac, J. B.; Graham, B. D.; Dobson, W. E. J. Antibiot. 1983, 36, 1595. b)
Stamplwala, S. S.; Bunge, R. H.; Hurley, T. R.; Willmer, N. E.; Brankiewicz, A. J.;
Steinman, C. E.; Smitka, T. A.; French, J. C. J. Antibiot. 1983, 36, 1601. c) Leopold, W.
R.; Shillis, J. L.; Mertus, A. E.; Nelson, J. M.; Roberts, B. J.; Jackson, R. C. Cancer Res.
1997, 44, 1928. (d) Lewy, D.S.; Gauss, C.M.; Soenen, D.R.; Boger, D.L. Curr. Med.
Chem. 2002, 9, 2005.
15. (a) Kobayashi, M.; Higuchi, K.; Murakami, N.; Tajima, H.; Aoki, S. Tetrahedron Lett.
1997, 38, 2859-2862. (b) For a discussion of biological activity of (-)-Callystatin A,
leptomycin and related compounds, see: Kalesse, M.; Christmann, M. Synthesis 2002,
981.
16. Pereda-Miranda, R.; Fragoso-Serrano, M.; Cerda-Garcia-Roja, C. M. Tetrahedron 2001,
57, 47.
17. Achmad, S. A.; Hoyer, T.; Kjaer, A.; Makmur, L.; Norrestam, R. Acta Chem. Scand.
1987, 41(B), 599.
18. Coleman, M. T. D., English, R. B.; Rivett, D. E. A. Phytochemistry 1997, 26, 1497.
19 . Allemany, A.; Marquez, C.; Pascual, C.; Valverde, S.; Martinez-Ripoll, M.; Fayos, J.;
Perales, A. Tetrahedron Lett. 1979, 20, 3583.
20. Pereda-Miranda, R.; Hernandez, L.; Villavicencio, M. J.; Novelo, M.; Ibarra, P.; Chai,
H.; Pezzuto, J. M. J. Nat. Prod. 1993, 56, 583.
22. Raoelison, G. E.; Terreaux, C.; Queiroz, E. F.; Zsila, F.; Simonyi, M.; Antus, S.;
Randriantsoa, A.; Hostettmann, K. Helv. Chim. Acta 2001, 84, 3470-3476.
23. Ouedraogo, M.; Carreyre, H.; Vandelrouck, C.; Bescound, J.; Raymond, G.; Guissou, I.-
P.; Cognard, C.; Becq, F.; Potreau, D.; Cousson, A.; Marrot, J.; Coustard, J.-M. J. Nat.
Prod. 2007, 70, 2006.
24. Srihari, P.; Rajender, G.; Rao, R.S.; Yadav, J.S. Tetrahedron Lett. 2008, 49, 5590.
25. Dittoo, A.; Bellosta, V.; Cossy, J. Synlett 2008, 16, 2459.
26. Alvarez-Bercedo, P.; Falomir, E.; Murga, J.; Carda, M.; Marco, J.A. Eur. J. Org. Chem.
2008, 4015.
27. Rauniyar, V.; Hall, D.G. J. Org. Chem. 2009, 74, 4236.

33
 CHAPTER-I, Section-A

28. Das, B.; Suneel, K.; Satyalakshmi, G.; Kumar, D.N. Tetrahedron: Asymmetry 2009, 20,
13, 1536.
29. (a) Byun, H-S.; He, L.; Bittman R. Tetrahedron 2000, 56, 7051; (b) Qin, D-G.; Zha, H-
Y.; Yao, Z-J. J.Org. Chem. 2002, 67, 1038; (c) Fernandes, R.A.; Kumar, P. Eur. J. Org.
Chem. 2002, 2921; (d) Gupta, P.; Naidu, S. V.; Kumar, P. Tetrahedron Lett. 2004, 45,
9641. (e) Jagdale, A.R.; Reddy, Sudalai, A. Org. Lett. 2009, 11, 803.
30. (a) Gao, Y.; Sharpless, K.B. J. Am. Chem. Soc., 1988, 110, 7538 (b) Lohray, B.B.
Synthesis, 1992, 1035.
31. Kim, B.M.; Sharpless, K.B. Tetrahedron Lett. 1989, 6, 655.

34
 CHAPTER-I, Section-B

1. INTRODUCTION

Among the thousands of modern drugs, about 40% of them are of natural origin. The
widest spectrum of pharmacological action is exhibited by alkaloids, especially isoquinoline
containing alkaloids.1 The term alkaloid is derived from the name vegetable alkali and in broad
sense alkaloids are nitrogenous bases that occur naturally in plants. They always contain nitrogen
as apart of heterocyclic system and are often quite complex in structure. A characteristic of true
alkaloid plant is that it contains more than one alkaloid, the main component being accompanied
by smaller quantities of a number of biogenetically related compounds. Although the structures
of well-known alkaloid drugs are known, study of synthetic analogues of alkaloids, search for
new alkaloids and their synthesis is a never ending process in the field of organic chemistry.
It is interesting to note that alkaloids containing the isoquinoline ring as such or as part of
a more complex ring system are very numerous and widely distributed2. These occur in plants
particularly which belong to families Papaveraceae (poppies), Papilionaceae (lupins),
Rananculaceae (acronites) and Solanaceae (tobacco, potato).3
In 1990 Sariyar et al.,4-5 have isolated quaternary alkaloids from the aerial parts of
Turkish papavers namely Papaver cylindricum cullen and Papaver pseudo-orientale (PPO)
Fedde (Medw). The crude extraction and fractionation of aerial parts of PPO resulted in the
isolation of Cotarnine 1 along with (-)-α-N-methopapaverberbine 2 and Cotarnoline 3 (Fig. 1).

O O
N N CH3
O CH3 O
H
H3CO OH H3CO OCH3
HO
H
OCH3
1 2

O O
N N
O CH3 O CH3
H3CO O H3CO

3 4
Fig. 1

Cotarnine 1 was known to show haemostatic activity.6 Before its identification as a

natural product, cotarnine 1 was obtained for the first time by the oxidative degradation of (3S)-

35
 CHAPTER-I, Section-B

6,7-dimethoxy-3-[(5R)-5,6,7,8-tetrahydro-4-methoxy-6-methyl-1,3-dioxolo[4,5-g]isoquinolin-5-
yl]phthalide 5 (commonly known as Noscapine)7, which is an isoquinoline alkaloid isolated from
opium and is of value in suppression of cough. Cotarnine 1 is a key component in the
preparation of alkaloid (3R)-7-amino-4,5,6-triethoxy-3-[(5S)-5,6,7,8-tetrahydro-4-methoxy-6-
methyl-1,3-dioxolo[4,5-g]isoquinolin-5-yl]phthalide 6 (commonly known as Tritoqualin)8 (Fig.
2). Tritoqualin 6 is clinically used as an antiallergic drug9 and also shows a preventive effect on
liver injury in rats induced by treatment with CCl4 and other biological activities 10.

O O
N CH3 N CH3
O O
H H
H3CO
H
H3CO H OC2H5
O OC2H5
O
OCH3
O OCH3 OC2H5
O NH2
5 6
Fig. 2

Benzo[c]phenanthridines are naturally occurring isoquinoline containing alkaloids,

isolated from the plants of Papaveraceous and Rutaceous with various biological activities.11
Sanguinarine 8a shows anitbacterial12 and antifungal13 activities, while nitidine 8b and
fagaronine 8c has been investigated as potential anti-tumor and antiviral agents.14, 7-
Hydroxynitidine 9, a modified benzo[c] phenanthridine alkaloid, was shown to have strong
cytotoxic acivity against HeLa S3 cells.16 The presence of the 7-hydroxy group enhances anti-
tumor activity. 6,7,8-trimethoxy tetrahydroisoquinoline 10 also called as Anhalinine was found
to act as a psychomimetic activity (Fig. 3).17

Takatonine 11 is a quarternary base isolated from the Japanese commercial crude drug “Takato-
gusa”, the dried leaves and stems of Thalictrum minus and later eventually characterized as
5,6,7-trimethoxy-1-(4-methoxybenzyl)isoquinoline methiodide (Fig. 3).18 Synthetic compounds
like Heterocyclic decamethylenebis(quaternary ammonium salts) 12 act as a neuromuscular
blocking agents and some of which possess greater curarising activity in rabbits (Fig. 3).19 Due to
its clinical consumption, Takatonine 11 and Heterocyclic decamethylenebis(quaternary
ammonium salts) 12 are currently in short supply.

36
 CHAPTER-I, Section-B

1.1. Analogue of Cotarnine.iodide salt (7) and it uses in alkaloid Synthesis:

R4

R1 8a Sanguinarine : R1=H; R2=R3=R4=R5= -O-CH2-O-

R5
N 8b Nitidine : R1=R2= -OCH3; R3=H; R4=R5= -O-CH2-O-
R2 +
R3 X- 8c Fagaronine : R1=R2= -OCH3; R3=H; R4= -OH; R5= -OCH3

O
H3CO
H3CO O
NH
N H3CO
H3CO + OCH3
-
OH HSO4

9. 7-Hydroxynitidine 10. Anhalinine

H3CO N CH3
O -
O
I H
H3CO H OC2H5
N CH3 N OC2H5
O H3CO + CH3
H H O
H3CO OCH3 OC2H5
O
O NH2
OCH3 7
O OCH3
6
5

H3CO
-
+I
N CH3
H3CO H3CO
OCH3
N CH3 [CH2]10
H3CO +
OCH3 I- +
H3CO N CH3

H3CO
OCH3
H3CO

11. Takatonine 12. Dacamethylenebis(quaternary ammonium salts)

Fig. 3

37
 CHAPTER-I, Section-B

In view of such wide variety of biological and pharmalogical activity, development an

efficient route for the synthesis of 6,7,8-trimethoxyisoquinoline.methiodide 7 is highly
desirable.
2. Retro synthetic route:

H3CO H3CO H3CO CHO

N+ NH2
H3CO I- CH3 H3CO H3CO
OCH3 OCH3 OCH3

7 24 26

3,4-dihydro-6,7,8-trimethoxy Mescaline

isoquinoline methiodide

Previous approaches for the formation of Mescaline 24 and 3,4-dihydro-6,7,8-trimethoxy

isoquinoline methiodide 7 is presented below:

3. Previous approaches of Mescaline (24):

The cactus alkaloid, Mescaline 24 [β-(3,4,5-trimethoxyphenyl)ethylamine] is a key

intermediate in drug active isoquinoline containing alkaloids and also in our target compound 7.
Mescaline, the active hallucinatory principle of the “mescal buttons” or “Pellote”, was isolated
by Heffter20a in 1896. Pellote (Anhalonium Lewinii Hennnings) contains upto 6% mescaline.
Herrero-Ducloux.20b has assumed that one of the bases extracted from Echinocactus gibbosus
D.C., (Gymnocalycium gibbosum Pfeiff.) was mescaline. Synthesis of mescaline was elustrated
below because of its interesting effects on the psychic states of human subjects.
Eid et al21 achieved mescaline. hydrochloride 18 from 2,6-dimethoxyphenol 13. It was
converted to 4-dimethylaminomethyl-2,6-dimethoxyphenol 14 using dimethylamine,
formaldehyde in the presence of methanol in 10 days. Quaternization of compound 14 by using
methyl iodide in absolute ethanol gave compound 15. It was converted to cyano compound 16 by
refluxing KCN in water for 2.5 h. 4-hydroxy cyano compound 16 was converted to 3,4,5-
trimethoxybenzyl cyanide 17 using methyl iodide, K2CO3 in dry acetone. The reduction of

38
 CHAPTER-I, Section-B

compound 17 with LAH in THF followed by addition of methonolic.HCl to gave mescaline.HCl

salt 18.

Eid A.I. et al approach:

OCH3 OCH3 OCH3

OH OH OH
a b c
OCH3 OCH3 OCH3
N N+ I-
13 14 15

H3CO N H3CO N H3CO

d e
NH2.HCl
HO H3CO H3CO
OCH3 OCH3 OCH3

16 17 18
Mescaline.HCl
Scheme 1

Reagents and conditions: (a) Dimethylamine, 35% formaldehyde, CH3OH, rt, 10 days. (b)
CH3I, Ethanol, 10 oC. (c) KCN, H2O, reflux, 2.5 h.(d) CH3I, dry acetone, K2CO3, reflux,20 h. (e)
LAH, THF, reflux, 3 h.

39
 CHAPTER-I, Section-B

Tsao et al approach:
COOH COOH COOCH3 CH2OH
a b c

HO OH H3CO OCH3 H3CO OCH3 H3CO OCH3

OH OCH3 OCH3 OCH3
19 20 21 22

CH2Cl CH2CN
e H3CO NH2
d f

H3CO OCH3 H3CO OCH3 H3CO

OCH3 OCH3 OCH3

23 17 24
Mescaline
Scheme 2

Reagents and conditions: (a) Dimethyl sulfate, NaOH, 5 oC to rt. (b) Methyl sulfate, NaOH,
Na2CO3. (c) LAH, anhydrous ether, 10% H2SO4. (d) con.HCl, 0 oC-5 oC, 4 h. (e) KCN,
H2O+CH3OH, 90 oC, 10 min. (f) LAH, anhydrous ether, 10% H2SO4.

Tsao et al22 has used gallic acid 19 as a starting material for the synthesis of mescaline. The
hydroxyl groups were methylated with dimethyl sulfate under basic conditions. Esterification of
acid 20 using methyl sulfate gave the compound 21. Methyl ester was reduced with LAH in
anhydrous ether at ice-water condition gave the compound 22. The benzylic alcohol 22 was
converted to the respective chloro compound 23 using con.HCl, at 5 oC. Further on treatment
with KCN and followed by LAH reduction gave the desired mescaline 24.

40
 CHAPTER-I, Section-B

Slotta et al approach:

COOH COOH COCl CHO

a b c

HO OH H3CO OCH3 H3CO OCH3 H3CO OCH3

OH OCH3 OCH3 OCH3
19 20 25 26

H3CO NO2 H3CO NH2

d e
H3CO H3CO
OCH3 OCH3

27 24

Scheme 3

Reagents and conditions: (a) Dimethyl sulfate, NaOH, 5 oC to rt. (b) Thionyl chloride, reflux,
2h. (c) Rosunmund’s catalyst (palladium/barium sulfate), xylene, 150 oC, Hydrogen stream (d)
Nitromethane, KOH, MeOH, 0 oC. (e) Electrolytic reduction, 12 h.
Slotta et al23 achieved mescaline from gallic acid 19. These hydroxyl groups are
methylated with dimethyl sulfate gave the 3,4,5-trimethoxy benzoic acid 20. The benzoic acid
converted to benzoyl compound using thionyl chloride. The aldehyde 26 was obtained from acid
chloride through Rosunmund’s reduction using palladium/barium sulfate, H2 in xylene at 150 oC.
The aldehyde 26 was condensed with nitromethane in KOH followed by electrolytic
reduction gave the desired compound mescaline 24.

41
 CHAPTER-I, Section-B

Kindler et al approach:

COOH COOH COCl CHO

a b c

HO OH H3CO OCH3 H3CO OCH3 H3CO OCH3

OH OCH3 OCH3 OCH3
19 20 25
26

H3CO N
H3CO NH2
d e
H3CO
O H3CO
H3CO O
OCH3

28 24

Scheme 4

Reagents and conditions: (a) Dimethyl sulfate, NaOH, 5 oC to rt. (b) Thionyl chloride, reflux,
2h. (c) Adam’s catalyst (palladium/barium sulfate), xylene, 150 oC, Hydrogen stream (d) KCN,
sodium bisulfate, Acetic anhydride. (e) Palladium block, H2, acetic acid+sulfuric acid, 2.5 h.
In Kindler et al24 approach, mescaline also achieved from gallic acid 19. Compound 26
treated with KCN followed by acetic anhydride gave the 3,4,5-trimethoxyacetylmandelonitrile
28. Compound 28 upon reduction with palladium block in glacial acetic acid gave mescaline 24.
4. Previous approaches of 3,4-dihydro-6,7,8-trimethoxyisoquinoline methiodide (7):

Chazerain et al approach:

H3CO H3CO H3CO

a b
I-
NH2
H3CO
HN H N+
H3CO H3CO CH3
OCH3 OCH3 O OCH3

24 29 7

Scheme 5

Reagents and conditions: (a) HCOOH, acetic anhydride, 3 h, 80 oC. (b) POCl3, 50 oC, 2 h,
CH3I, CH3COCH3

42
 CHAPTER-I, Section-B

Chazerain et al25 achieved desired analogue of cotarnine iodide salt 7 from Mescaline 24.
This amine was converted to N-formyl mescaline 29 by using formic acid and acetic anhydride
at 80 oC about 3 h. Bischler-Napieralski reaction of compound 29 with POCl3 followed by
treatment with methyl iodide in acetone gave desired analogue of cotarnine iodide salt 7.
Kametani et al approach:

COOCH3 CH2OH CH2Cl

a b c
H3CO OCH3 H3CO OCH3 H3CO OCH3
OCH3 OCH3 OCH3

21 22 23
CH2CN
H3CO H3CO
d e
NH2 HN H f
H3CO OCH3 H3CO H3CO
OCH3 OCH3 OCH3 O

17 24 29

H3CO H3CO H3CO

h
g N+
N N
H3CO HO HO CH3
I-
OCH3 OCH3 OCH3

30 31 32

Scheme 6

Reagents and conditions: (a) LAH, anhydrous ether, 10% H2SO4. (b) SOCl2, dimethylaniline, 2
h. (c) KCN, Me2SO, H2O. (d) NH3, EtOH, Raney-Ni, H2. (e) 98% HCOOH, 170 oC, 5 h. (f)
POCl3, 0 oC- 90 oC, 2 h. (g) Conc. HCl, 120 oC- 130 oC, 3 h. (h) CH3I, CH3OH.
Kametani et al26 synthesized analogue of substituted cotarnine iodide salt 32 from
compound 21. The methyl ester of 3,4,5-trimethyoxy benzoic acid 21 was reduced with LAH in
anhydrous ether at ice-water condition gave the compound 22. This benzyl alcohol converted to
3,4,5-trimethoxy benzyl chloride 23 using thionyl chloride. On treatment with KCN followed by
Raney Ni reduction in ethanol using H2 to give the mescaline 24. Formylation of compound 24
with 98% formic acid at 170 oC for 5 h gave N-formyl mescaline 29. Bischler-Napieralski
reaction of compound 29 with POCl3 gave isoquinoline 30. Compound 30 treated with conc.HCl

43
 CHAPTER-I, Section-B

to gave 7-hydroxy 6,8-dimethoxy isoquinoline 31 which on subsequent treatment with CH3I

afforded desired compound 32.
Taylor et al approach: Through Bischler-Napieralski reaction:

COOH COOH COCl CHO

a b c
HO OH H3CO OCH3 H3CO OCH3 H3CO OCH3
OH OCH3 OCH3 OCH3
19 20 25 26

H3CO H3CO H3CO

d e f
NH2 HN H
NO2 H3CO H3CO
H3CO
OCH3 OCH3 O
OCH3
27 24 29
H3CO
g
I-
N+
H3CO CH3
OCH3

7
Scheme 7

Reagents and conditions: (a) Dimethyl sulfate, NaOH, 5 oC to rt. (b) Thionyl chloride, reflux,
2h. (c) Adam’s catalyst (palladium/barium sulfate), xylene, 150 oC, Hydrogen stream (d)
Nitromethane, KOH, MeOH, 0 oC. (e) Electrolytic reduction, 12 h. (f) HCOOH, 170 oC, 5 h. (g)
POCl3, 0 oC- 90 oC, 2 h, CH3I, CH3OH.

Taylor et al19 achieved 3,4-dihydro-6,7,8-trimethoxy-2-methylisoquinoline iodide salt 12

from gallic acid 19. These hydroxyl groups are methylated with dimethyl sulfate gave the 3,4,5-
trimethoxy benzoic acid 20. The formation of aldehyde 26 was achieved under Rosunmund’s
reduction conditions. Aldehyde 26 was condensed with nitromethane in KOH. The nitrostyrene
27 was reduced to Mescaline 24 by following Slotta’s electrolytic reduction protocol.
Formylation of compound 24 with 98% formic acid at 170 oC about 5 h gave N-formyl
mescaline 29. Bischler-Napieralski reaction of compound 29 with POCl3, which on subsequent
treatment with CH3I afforded desired analogue of cotarnine iodide salt 7.
.

44
 CHAPTER-I, Section-B

5. PRESENT WORK

The main drawbacks of the methods reported by Kametani and Taylor are:
1) During the synthesis of Mescaline 24 from nitro-styrene 27 Electrolytic reduction was
observed.
2) Handling wise is it difficult. So it is not amicable in large-scale synthesis.
3) Synthesis of compound 7, number of steps involved from gallic acid or trimethoxy gallic acid
as a starting materials.
4) From starting materials Hazardous and cost effective (Palladium/barium sulfate) reagents are
used. It is not suitable in large scale synthesis.
These factors make the process undesirable from industrial considerations.
5) Moreover there is no substantial spectral analysis (1H, 13C NMR and Mass) and no detailed
experimental procedures available from the previously described methods.
In view of its importance as a key moiety in Takatonine 11, Heterocyclic
Decamethylenebis (quaternary ammonium salts) 12 and 7-Hydroxynitidine 9 there is a need to
develop a simple, practical process route for the synthesis of cotarnine iodide.salt 7.

H3CO CHO CH3NO2 H3CO NO2 H3CO

Piperidine.acetate LiAlH4, THF
H3CO Toluene, reflux H3CO NH2
24 h, 79% H3CO
OCH3 12 h, 86% OCH3 OCH3

26 27 24

Scheme 8

Our approach starts from 3,4,5-trimethoxy benzaldehyde 26, it is inexpensive and

commercially available starting material. The aldehyde group of compound 26 was condensed
with nitromethane in the presence of piperidine.acetate in Toluene at reflux temperature using
dean-stark water collector for 12 h to obtain trans- ω-nitrostyrene 27 in 86% as a yellow colored
solid. M.p. 120 oC-122 oC (Lit23 120 oC-121 oC) (Scheme 8). The formation of compound 27
was confirmed by 1HNMR spectrum showed signals at  7.90 (J=13.59Hz, 1H),  7.50
(J=13.59Hz, 1H) as doublets and disappearance of aldehyde proton. The compound was further
conformed by its Mass spectrum, which showed molecular ion peak at m/z 240 (M++H).

45
 CHAPTER-I, Section-B

Compound 27 was subjected to the reduction with LAH in dry THF at 0 oC for 1 h and
42 oC for 24 h to afford Mescaline 24 in 79% yield as a colorless liquid (Scheme 8). Compound
24 was characterized from 1H NMR spectrum by appearance of two methylene group protons at
δ 2.94(J= 6.79 Hz, 2H) and 2.65 (J = 6.79 Hz, 2H) as a triplets and also disappearance of styrene
protons. The compound is further conformed by its Mass spectrum, which showed molecular ion
peak at m/z 211 (M+).
Reduction of nitrostyrene was also attempted using Raney Ni catalyst under H2 pressure
at 60 oC for 6 h. The analysis of reaction mixture showed formation of several unidentified
compounds with low yield of (≈10%) of the desired product Mescaline 24. Modifications of
reaction conditions and containing the reaction of longer period did not give fruitful results. The
reduction of nitrostyrene 27 with LAH in dry THF was found to be superior condition in terms of
yield and purity of the product 24.

H3CO H3CO H3CO

HCOOEt POCl3
NH2 NHCHO N
H3CO reflux, 3h H3CO reflux, 12 h H3CO
OCH3 97.5% OCH3 78% OCH3

24 29 30

Scheme 9

Formylation of mescaline 24 using ethylformate at reflux temperature for 3 h yielded

amide 29 in 97.5% yield as a syrup (Scheme 9). The formation of formamide 29 was revealed
from 1H NMR spectrum, appreance of aldehyde proton at  8.11 as a singlet. In 13
C NMR
spectrum the carbonyl carbon appeared at  161.2. IR spectrum showed absorption band at 1666
cm-1 for the N-formyl group. A peak at m/z 240 (M++H) in the mass spectrum confirms the
formation of amide 29.
Cyclization of compound 29 using POCl3 under Bischler-Napieralski reaction conditions for 12 h
at reflux temperature afforded the desired isoquinoline compound 30 in 78% as a brown color
solid, m.p. 85 oC-86 oC. (Lit.19 91 oC-92 oC). The formation of compound 30 was confirmed
through 1H NMR spectrum by appearance of characteristic H-1 proton at  8.48 as a singlet. The
other protons of compound 30 resonated at their expected chemical shift values. The Mass
spectrum shows a peak at m/z 222 (M++H) confirms the formation of desired isoquinoline 30.

46
 CHAPTER-I, Section-B

Cyclization of compound 29 using PPA under reflux conditions (160 oC) for 22 h gave
mixture of products along with low yield (≈10%) of desired substituted isoquinoline compound
30. POCl3 is the best (yield, temperature and time) cyclizing agent than compared to PPA.

H3CO H3CO
CH3I, ether
N N+
H3CO 0 oC-RT H3CO I- CH3
OCH3 81.2% OCH3

30 7

Scheme 10

Further compound 30 was converted to methyl iodide.salt using methyl iodide as a

reagent and ether as a solvent at cooling condition and room temperature for 30 min to afford
desired analogue of cotarnine iodie.salt 7 in 81.2% yield as a brown color solid (Scheme 10).
This quaternary iodide salt was confirmed by 1H NMR spectrum disappearance of H-1 proton at
 8.48 as a singlet and appearance of  9.12 as a singlet. The Mass spectrum shows a peak at m/z
236 (M+-I) confirms the formation of analogue of cotarnine iodide.salt 7.

6. CONCLUSION:
Synthesis of natural products having biological activity is an important process in organic
chemistry. Analogue of Cotarnine iodide.salt 7 is a key constituent in the preparation in
Takatonine 11, Heterocyclic Decamethylenebis (quaternary ammonium salts) 12 and 7-Hydroxy
nitidine 9 as shown in Fig. 3.
A process route for the synthesis of 3,4-dihydro-6,7,8-trimethoxyisoquinoline methiodide
7 has been achieved starting from 3,4,5-trimethoxy benzaldehyde 26. The process described
herein for 7 is efficient, improved, and is amicable to large-scale synthesis.

47
 CHAPTER-I, Section-B

7. EXPERIMENTAL SECTION

3,4,5-Trimethoxy-ω-nitrostyrene (27):

To a Solution of 3,4,5-trimethoxy benzaldehyde 26 (200.0 g, 1.02 mol) in toluene (960

mL) was added piperidine.acetate 10 g [prepared by addition of glacial acetic acid (11mL) to
piperidine (18 mL) at 0 oC] and nitro methane (124.48 g, 2.04 mol). It was refluxed using dean-
stark water collector for 12 h. The reaction mixture was cooled to room temperature and the solid
precipitate obtained was filtered. It was then washed with 2-propanol (2x150 mL) and dried
under vaccum to obtain the compound ώ-nitrostyrene 27 (209.6 g, 86%) as yellow colored solid.
M.P. : 120 oC-122 oC (Lit.23 120 oC-121 oC)

IR (neat) : max 3110, 2938, 2837, 1631, 1583, 1500, 1418, 1321,
1251, 1122, 973 cm-1.
1
H NMR (CDCl3, 300 MHz) : δ 7.90 (d, J= 13.59Hz, 1H), 7.50 (d, J= 13.59Hz, 1H), 6.72
(s, 2H), 3.89 (s, 6H), 3.87 (s, 3H).
13
C NMR (CDCl3, 75 MHz) : δ 153.6, 139.2, 136.2, 125.2, 106.4, 60.9, 56.2.
MS (ESI) : m/z 240 (M+ + H)

2-(3,4,5-trimethoxyphenyl)ethanamine (24):

To a stirred solution of LiAlH4 (43.70 g, 1.15 mol) in dry THF (750 mL) at 0 oC was
added ώ-nitrostyrene 27 (50.0 g, 0.20 mol) slowly under nitrogen atmosphere. The mixture was
brought to room temperature and stirred 24 h. The contents were cooled to 0 oC, excess LiAlH4
was quenched with 1.5N H2SO4 (1.2 L). Aqueous layer was neutralized with sodium potassium
tartrate (450.0 g) and basified with 5% NaOH (300 mL). The aqueous layer extracted with
CH2Cl2 (3x500 mL), separated organic layer dried over Na2SO4 and evaporated. The crude
amine was transformed to its hydrochloride salt using IPA.HCl [HCl gas passed in IPA solvent]
Its salt m.p. 178 oC – 180 oC (Lit.21 180 oC- 181 oC).
The amine.hydrochloride salt basified with 10% NaOH and extracted into dichloromethane
(2x200 mL), dried over Na2SO4 and concentrated to afford pure amine (Mescaline) 24 (33.3 g,
79%) as a liquid.

48
 CHAPTER-I, Section-B

IR (neat) : max 3361, 2937, 1591, 1507, 1460, 1423, 1328, 1239,
1125, 1006 cm-1.
1
H NMR (CDCl3, 300 MHz) : δ 6.36 (s, 2H), 3.83 (s, 6H), 3.78 (s, 3H), 2.94 (t, J= 6.79
Hz, 2H), 2.65 (t, J= 6.79 Hz, 2H), 1.70 (brs, 2H).
13
C NMR (CDCl3, 75 MHz) : δ 153.1, 134.7, 105.6, 60.7, 56.0, 43.3, 42.8, 38.9.
MS (EI) : m/z 211 (M+)

N-(3,4,5-trimethoxyphenethyl)formamide (29):

A solution of amine 24 (11.58 g, 54.88 mmol) in ethyl formate (12.18 g, 164.6 mmol)
was heated to reflux for 3 h. After completion of reaction (TLC), the reaction mixture was
concentrated to give formamide 29 (12.78 g, 97.5 %) as a syrup. It was used in next step without
any further purification.
IR (neat) : max 2939, 1666, 1591, 1508, 1459, 1330, 1238, 1124,
1004 cm-1.
1
H NMR (CDCl3, 300 MHz) : δ 8.11 (s, 1H), 6.35 (s, 2H), 3.83 (s, 6H), 3.78 (s, 3H),
3.55 (q, J= 6.79 Hz, 2H), 2.75 (t, J= 6.79 Hz, 2H), 1.57
(brs, 1H).
13
C NMR (CDCl3, 75 MHz) : δ 161.2, 153.2, 134.1, 105.5, 60.7, 56.0, 43.0, 39.1, 35.7.
MS (ESI) : m/z 240 (M+ + H)

6,7,8-trimethoxy-3,4-dihydroisoquinoline (30):

A mixture of compound 29 (5.0 g, 20.92 mmol) in POCl3 (32.07 g, 209.20 mmol) was
refluxed for 12 h. It was cooled to 5 oC and added ice-coldwater (150 mL) and then 50%
aq.NaOH (100 mL). Aq.layer was extracted with DCM (4x150 mL), the organic layer was dried
over Na2SO4 and concentrated. Crude compound recrystalized from dichloromethane: Hexane
(2:1) to afford pure 6,7,8-trimethoxy-3,4-dihydroisoquinoline 30 (3.60 g, 78%) as a brown color
solid.
M.P. : 85 oC-86 oC (Lit.19 91 oC- 92 oC)
IR (neat) : max 2939, 1597, 1460, 1355, 1314, 1241, 1121,
1032 cm-1.

49
 CHAPTER-I, Section-B

1
H NMR (CDCl3, 200 MHz) : δ 8.48 (s, 1H), 6.39 (s, 1H), 3.94 (s, 3H), 3.87 (s, 3H),
3.81 (s, 3H), 3.65 (dt, J= 8.01Hz, 2.40 Hz, 2H), 2.59 (t, J=
8.01Hz, 2H).
MS (ESI) : m/z 222 (M+ + H)

Analogue of (3,4-dihydro-6,7,8-trimethoxyisoquinoline-methiodide) (7):

To a stirred solution of isoquinoline 30 (1.70 g, 7.69 mmol) in ether (28 mL) at 0 oC was
added CH3I (4.36 g, 30.76 mmol) and stirred for 20 min. It was then brought to room
temperature for 30 min. The precipitated brown colored solid was filtered and dried under
vaccum to afford the title compound 7 (2.26 g, 81.2%) as a brown color solid.
M.P. : 180 oC-182 oC (Lit.19 179 oC-180 oC)
IR (neat) : max 3421, 2939, 1596, 1503, 1455, 1397, 1317, 1249,
1128, 1084, 1032 cm-1.
1
H NMR (CDCl3, 200 MHz) : δ 9.12 (s, 1H), 6.82 (s, 1H), 4.12 (s, 3H), 4.01-3.99 (m,
5H), 3.84-3.81 (m, 6H), 3.25 (t, J= 7.43Hz, 2H) .
MS (ESI) : m/z 236 (M+-I)

50
 CHAPTER-I, Section-B

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