SYNOPSIS
SYNOPSIS
The thesis entitled “ Stereoselective Total Synthesis of (+) Membrenone C And
Studies Directed Towards The Total Synthesis Of Siphonarin B” is divided into three
chapters.
CHAPTER I : Chapter I is further classified into two sections.
SECTION A: This section of thesis contains the general introduction and the earlier
synthetic approaches to Membrenone C.
SECTION B: This section concerns with the stereoselective total synthesis of (+)
Membrenone C and its 7-epimer.
CHAPTER II : This chapter is further organized into two sections.
SECTION A: This sections deals with the introduction and earlier synthetic approaches
to Siphonarin B.
SECTION B: This section deals with the present work done for the stereoselective
synthesis of C3 – C8 and C9 – C21 fragments of Siphonarin B.
CHAPTER III: This chapter describes the development of novel methodologies.
SECTION A : LPDE catalyzed intramolecular Aza – Diels – Alder reaction : A Facile
synthesis of Tetrahydrochromanoquinolines.
SECTION B : Synthesis of 4-Chlorotetrahydropyrans under microwave irradiation.
I
SYNOPSIS
CHAPTER I :
STEREOSELECTIVE TOTAL SYNTHESIS (+) MEMBRENONE C :
Naturally occurring polyketides and polypropionates have attracted a lot of
attention during the past 50 years, and a great deal of research has been concerned with
their isolation, biological activity, biogenesis and total synthesis. Much is known about
these compounds from a biological perspective including a detailed understanding of their
biosynthesis, which gives rise to endless chemical diversity and results in rich biological
activity.
Opisthobranchs are marine molluscs scarcely protected by a shell that, generally is
reduced fragile and sometimes, completely absent. Many studies have strongly supported
that opisthobranchs are frequently protected against predators by chemicals which are
either concentrated in anatomical parts more exposed to predators or released into
defensive mucous secretions. Three compounds Membrenones A, B & C were isolated in
1993 from the skin of the marine mollusc pleurobranchus membrane.ceus. There is an
apparent error in the sign of the optical rotation reported for natural Membrenone C in the
original isolation paper as concluded by recent reports.
O
O
O
O
1
(+) Membrenone C
Authors envisaged that the total synthesis of natural membrenone C not only would
help to solve the sign of the optical rotation ambiguity but also add a route to synthesize it.
This chapter deals with the total synthesis of natural (+) Membrenone C and its 7- epimer
utilizing desymmetrization approach.
II
SYNOPSIS
Restrosynthetically, (+) Membrenone C 1 can be obtained via tetrone 2. The
construction of tetrone was based on a disconnection between the C4-C5 & C11-C12
bonds via double aldol. The sequence of five contiguous stereogenic centres C6 to C10 in
3 was envisaged from the chiral bicyclic lactone 5 which was generated from bicyclic
ketone 6.
Restrosynthetic strategy of (+) membrenone C :
O
O
O
O
O
O
O
O
O
O
Si
2
(+) Membrenone C
1
H
H
+
O
O
O
2
O
Si
O
4
3
O
O
O
H3 C
O
4
O
O
6
OPMB
SCHEME 1
III
5
SYNOPSIS
The synthesis of (+) Membrenone C starts with the common bicyclic ketone 6. The
bicyclic ketone 6 was prepared by employing a (3+4) cycloaddition reaction of oxyallyl
cation and furan as reported by Hoffmann and co-workers.
The acid catalysed
dibromination of 3-pentanone 7 afforded the dibromo compound 8.
The dibromo
compound 8 when treated with furan 9 in the presence of Zn-Cu couple underwent (3+4)
cycloaddition reaction to afford 2,4-dimethyl-8-oxabicyclo[3.2.1]oct-6-ene-3-ones 6, 10
and 11 in the ratio 8:1:1. These bicyclic ketones on selective reduction with DIBAL-H
gave the corresponding alcohols (Scheme 2).
Br2 /AcOH
O
O
Br
Br
O
O 9
H2 O
O
Zn-Cu Couple
DME ,-10 0 C
+
O
O
6
7
O
+
O
10
11
8
DIBAL-H
THF
,-10 0 C
O
+Mixture of isomers.
OH
(Major)
12
SCHEME 2
The required major alcohol 12 was separated from the other isomers using column
chromatography and the structure was confirmed by spectral studies.
The hydroxyl group of compound 12 was protected as its 4-methoxybenzyl
(PMB) ether 13 using NaH and 4-methoxybenzyl bromide.
IV
Asymmetric hydroboration of
SYNOPSIS
olefin 13 using (+) - Diisopinocampheylborane (IPC2BH) proceeded smoothly to give the
alcohol 14 with high enantiomeric purity. The alcohol 14 was converted into the lactone
16 by a two step sequence. PCC oxidation of alcohol 14 followed by Baeyer-Villiger
oxidation of the resulting ketone 15 afforded lactone 16. Alkylation of lactone 16 using
LHMDS and methyl iodide gave 5. Reductive opening of bicyclic lactone 5 with LAH
afforded the triol 17 (Scheme 3).
O
O
O
(+) IPC2BH
NaH, PMB Br
TBAI, THF, reflux
OPMB
OH
NaOH, H2O2
13
12
HO
OPMB
14
O
O
O
m-CPBA, NaHCO3 O O
PCC
DCM, 25oC
LHMDS, MeI
DCM, 25 oC
-78oc ,THF
OPMB
OPMB
16
15
O
O
O
LAH
OPMB
THF, 25 oC
OH OPMBOH
OH
17
5
SCHEME 3
Triol 17 was selectively protected as its di silyl ether 18 using TBDMSCl and
imidazole. Acetyl protection of alcohol 18 using acetic anhydride ,TEA and DMAP
V
SYNOPSIS
afforded 19. Deprotection of PMB ether of 19 in presence of DDQ in aq. DCM afforded
compound 20 which was oxidised with Dess-Martin periodinane to give ketone 21
(Scheme 4).
Ac2 O/ Et3 N/ DMAP
TBSCl (2 eq)/ Imidazole
OH
OPMBOH OH
DCM, rt
OTBSOPMBOH OTBS
DCM, rt
18
17
DDQ
OTBSOPMBOAc OTBS
Dess-Martin Periodinane
DCM : H2 O, 19:1
00 C,
OTBS OH
OAc OTBS
DCM
15 min
19
20
OTBS O
OAc OTBS
SCHEME 4
21
Next attention was directed towards one pot deprotection of 21 and
diastereoselective 1,3 syn selective reduction . Reaction of 21 with DIBAL-H in dry ether
at -100º C afforded the undesired product 23 as the major isomer with high
diastereoselectivity (Scheme 5).
DIBAL, 6 eq
OTBSO
OAc OTBS
Et2O , -1000 C
OH
OTBSOH
21
22
SCHEME 5
VI
+
OTBS
OTBS OH
OH
23
OTBS
SYNOPSIS
The stereochemistry of 23 was assigned by the total synthesis of final product. The diol of
major isomer 23 was protected as di tert-butylsilylene 24 using di tert-butyl
trifluoromethane sulfonate and 2,6 lutidine. Treatment of silylether 24 with 2 eq. of PPTS
in methanolic DCM produced 25, which was subjected to PCC (8 eq.) oxidation to give
stable dialdehyde 26 (Scheme 6).
) Si(OTf)2
2
PPTS
OTBSOH OH OTBS 2,6- lutidine, DCM OTBSO
O
OTBS
24
H
DCM
O
OH
Si
Si
23
PCC(8eqv.)
OH O
DCM, MeOH; 3:1
25
H
O
O
O
O
Si
26
SCHEME 6
Next the two directional chain extending double aldol was achieved by treating 26
with Ti (IV) enolate of diethyl ketone in DCM at -78º C to afford the double aldol product
27. Since the stereo centres produced in formation 27 are not present in final product, we
proceeded with diastereomeric mixture. Double Swern oxidation of diol 27 using oxalyl
chloride, DMSO and triethylamine readily provided tetraone 28. Di tert-butyl silylene
group of tetraone 28 was removed by treatment with HF-pyridine buffered with excess
pyridine giving a mixture of diols and hemiacetals. Rapid acid catalyzed cyclisation
dehydration was achieved by treatment with TFA giving a single product 29 (Scheme 7).
VII
SYNOPSIS
H
O
H
O
O
O
O
(COCl)2 , DMSO
TiCl4 / i-Pr2 NEt
Si
O
OH O
O
OH O
26
27
1. HF-Py, Pyridine, THF
O
Et3 N, -780 C
Si
DCM, -780 C
O
O
O
Si
O
O
O
O
O
O
2. TFA, DCM
29
28
SCHEME 7
After comparision of optical rotation and 1H NMR data of synthetic 29 and that of natural
1, we realized that the synthetic compound was the 7-epimer of (+) Membrenone C. It was
reasoned that 1,3 syn selectivity was not observed in case of DIBAL-H reduction of
compound 21 (Scheme 5). Probably because DIBAL-H was not chelating with the oxygen
when the hydroxyl was protected as acetate in 21. Deprotection of acetate of 21 under
various experiments led to eliminated or cleaved products.(Scheme 8)
VIII
SYNOPSIS
LiOH
Undesired Product
MeOH/THF 00 C
K2 CO3 /MeOH
Undesired Product
NaOMe (cat.)
Undesired Product
MeOH
Acetate
deprotection
Mg(OMe)2
Undesired Product
MeOH
OTBS
O
OAc
OTBS
H2 O2 /NaHCO3
Undesired Product
21
CRL/ PH 7 Buffer
No Reaction
PPL/ PH 7 Buffer
No Reaction
SCHEME 8
Since the acetate deprotection failed, protecting groups strategey was changed. The
two primary hydroxyl of triol 17 were protected as di benzylether 30, which was further
subjected to silylation using TBSOTf and 2,6 lutidine to afford 31. Deprotection of PMB
ether 31 using DDQ in aq. DCM afforded 32, which was subjected to Dess Martin
oxidation to give ketone 33. Treatment of 33 with 2 eq.. of PTSA in methanolic DCM
afforded hydroxyl ketone 34 (Scheme 9).
IX
SYNOPSIS
NaH, BnBr
OH OPMBOH OH
THF, 250 C
TBSOTf
2,6-lutidine, 250 C
OBn OPMBOH OBn
17
OBn OPMB
OBn
OTBS
30
31
Dess-Martin Periodinane
DDQ
OTBSOBn
OBn O
DCM, H2 O; 19:1
OBn OH
DCM
OTBSOBn
33
32
PTSA
DCM, MeOH; 1:3
OBn O
OH OBn
34
SCHEME 9
Diastereoselective reduction of 34 using DIBAL-H in ether at -100º C afforded syn diol 35
as the major isomer with high diastereoselectivity (Scheme 10)
DIBAL, 4 eq
OBn O
OH OBn
Et2 O, -1000 C
OBn OH OH OBn
34
35
+
OBn OH OH OBn
36
SCHEME 10
Di tert butyl silylene protection of the diol 35 using di tert butyl trifluoromethane
sulfonate and 2,6 lutidine afforded compound 36. Debenzylation of 36 under catalytic
X
SYNOPSIS
(Pd/C) hydrogenolysis afforded diol 37, which was subjected to PCC oxidation to give
dialdehyde 3 (Scheme 11)
) Si(OTf)2
2
H2 / Pd- C
OBn O
2,6- lutidine, DCM
OBn OH OH OBn
EtOH
OBn
O
Si
35
36
H
H
PCC, DCM
OH O
O
O
OH
25 0 C
Si
O
O
O
Si
3
37
SCHEME 11
Next, the double aldol was achieved by treating 3 with the Ti (IV) enolate of
diethyl ketone 4 in DCM at -78º C to afford 38. Double Swern oxidation of double aldol
product 38, using oxalylchloride, DMSO and triethylamine afforded tetraone 2. Di tert
butyl silylene group of tetraone 2 was removed by treatment with HF-pyridine buffered
with
excess
pyridine
to
afford
mixture
of
diols
and
hemiacetals.
Rapid
cyclisation/dehydration of the mixture using TFA afforded the solid product 1 (Scheme
12)
XI
SYNOPSIS
H
H
O
O
O
O
4
O
(COCl)2 , DMSO
TiCl4 / DIPEA
Si
O
OH O
O
DCM, -780 C
Et3 N, -780 C
38
3
1. HF-Py, Pyridine, THF
O
OH O
Si
O
O
O
O
O
2. TFA, DCM
O
O
O
O
Si
(+) Membrenone C
2
1
SCHEME 12
The spectral and optical properties for 1 were in agreement with those reported
earlier and we have prepared for the first time (+)7-epi-Membrenone C 29.
DIRECT SYNTHESIS OF (+)7-epi-MEMBRENONE C :
Synthesis (+)7-epi Membrenone C 29 was achieved directly from the dibenzyl
ether 30, without using oxidation/reduction strategy. Removal of PMB group of 30 using
TFA/anisole in DCM afforded diol 39, which was protected as di tert butyl silylene to give
40. Treatment of 40 with catalytic amount of Pd/C under H2 atmosphere gave the known
diol 25 (Scheme 13). Further treatment of 25 to 29 following same steps as depicted in
Scheme 6 & 7.
XII
SYNOPSIS
) Si(OTf)2
2
TFA
OBn O
OBn OPMBOH OBn
anisole, DCM
OBn OH
30
OH OBn 2,6- lutidine, DCM
39
H2 / Pd- C
EtOH
O
Si
40
O
OH O
O
OH
7
9
O
O
O
Si
1
1
(+) 7-epi Membrenone C
29
25
SCHEME 13
XIII
OBn
SYNOPSIS
CHAPTER II :
STUDIES DIRECTED TOWARDS THE TOTAL SYNTHESIS OF SIPHONARIN B
In 1984, Faulkner, Ireland and co-workers first reported isolation of unusual γpyrone polypropionate, containing a characteristic spiroacetal ring system, siphonarin B 41
from the marine molluscs , Siphonaria zelandica and S. atra, collected on the coast of New
South wales, Australia, Siphonarin B was found to possess anti-microbial activity.
O
3
5
O
O
OH
O
O
15
13
9
O
19
OH
21
41
SIPHONARIN B
The architecturally complex structure, biological activity and scarcity of Siphonarin
B make it an attractive target for total synthesis. As part of our studies towards the total
synthesis of Siphonarin B, we chose to adopt a highly stereoconvergent strategy,
disconnecting the carbon back bone at C2-C3 via Kishi-Nozaki coupling, reveals two sub
units 44 and 45. Further disconnection of acyclic precursor 44 at C8-C9 via aldol
coupling leads to subunits 46 and 47. The synthesis of 46 and 47 are envisaged from
common precursor triol 51, which was generated from the known bicyclic ketone 6.
XIV
SYNOPSIS
RETROSYNTHETICANALYSIS OF SIPHONARIN B :
O
3
5
O O OH
O
O
15
13
9
O
3
O
O
19
O
O
O
OH
OPMB
O
+
O
I
44
21
45
21
43
H
8
3
O
O
O
9
21
+
O
O
OPMBOMOM
O
47
46
C3-C8 fragment
C9-C21 fragment
H
OH
OH
O
OBn OPMB
OMOM
OPMBOH
49
48
OH
OPMB OH
OH
51
O
O
6
SCHEME 14
XV
+
O
O
50
SYNOPSIS
Synthesis of Intermediate triol 51 :
Asymmetric hydroboration of known olefin 13 using (-)-Diisopinocampheylborane
(Ipc2BH) proceeded smoothly to give the alcohol 52 with high enantiomeric purity. The
alcohol was converted into the ketone 53 by PCC oxidation. Baeyer-Villiger oxidation of
the resulting ketone 53 gave the lactone 54 which on treatment with methyl iodide and
O
O
(-)IPC2 BH
,48h
-20 to 0 0 c,
3N, NaOH,
OPMB
30% H2 O2
rt,6 hrs.
13
PCC,DCM
HO
rt,3 hrs.
OPMB
52
O
O
m-CPBA
O
OPMB
LHMDS,MeI
NaHCO3 DCM
rt,10 hrs.
O
53
THF -78 0 C
O
OPMB
54
O
LAH,THF
OH
O
O
OPMB
0 0 C - rt,
4 hrs.
55
OH
OH
OPMB
51
SCHEME 15
lithiumhexamethyl disilazide (LHMDS) at -78º C furnished compound 55. Reductive
opening of bicyclic lactone 55 with LAH afforded the triol 51 (Scheme 15 ), which was
employed as a common precursor for the synthesis of both the key fragments.
XVI
SYNOPSIS
Synthesis of C3-C8 fragment :
The synthesis of C3-C8 fragment 46 was started from triol intermediate which has
five contiguous stereogenic centers. The two primary hydroxyl groups of triol 51 were
selectively protected as their tert-butyldimethyl silyl ether 56 (Scheme 16 ). Inversion of
the hydroxyl group configuration at C-5 center of compound 56 was achieved by oxidation
reduction strategy. Oxidation of compound 56 using Dess-Martin periodinane followed by
reduction using DIBAL-H afforded the required isomer 58 as the major product.
Compound 58 was then converted into the triol 48 by desilylation with TBAF (Scheme
16).
OH
OH
OH
OPMB
TBDMSCl
Imidazole
00 C-rt ,2 hrs.
OTBS Dess-martin
OTBSOH
Periodane
DCM
rt, 2hrs.
OPMB
OTBS
56
51
Et2 O
-1000 C
57
OTBS
DIBAL-H
OTBS OH
OPMB
OPMB
OTBS O
OH
TBAF
THF
00 C-rt ,1 h.
OH
OH
OPMB
4 hrs.
48
58
SCHEME 16
The triol 48 was subjected to 2,2 dimethoxy propane and CSA (cat.) to give the
acetonide product 59. The hydroxyl group of compound 59 was protected as the tertbutyldimethyl silyl group followed by the deprotection of PMB ether using DDQ afforded
XVII
SYNOPSIS
the compound 61.
Oxidation of 61 using Dess-Martin periodinane followed by
desilylation with TBAF to give the hydroxy ketone 63 (Scheme 17).
MeO
OMe
TBDMSCl
OH
OH
OPMBOH
CSA(Cat)
O
DCM; Et2 O
9:1, 1 h
OPMBOH Imidazole O
DCM
00 C -rt, 1 h
O
48
O
59
DDQ
60
TBAF
Dess-martin
DCM; H2 O
19:1
0
0 C 15 min.
O
O
OH
OPMBOTBS
Periodane
OTBS
rt,2 hrs.
O
O
O
THF
OTBS 00 C -rt
30 min.
62
61
:
H
O
O
O
OH
63
O
O
O
64
O
O
O
O
46
SCHEME 17
Now we focused on decarbonylation of β-keto aldehyde 64 through retero-Aldol
pathway. Under various oxidation conditions we failed to get the β-keto aldehyde. Further
attempts to complete the synthesis of C3-C8 fragment and total syntheis of Siphonarin B
are still under progress.
XVIII
SYNOPSIS
Synthesis of C9-C21 Fragment :
The triol 51 was subjected to 2,2 dimethoxypropane and CSA (Cat.) to give the
acetonide product 65. The alcohol 65 was protected as benzyl ether using NaH and BnBr
followed by deacetonization with aq.2N HCl to afford the diol 67.The primary alcohol of
67 was selectively protected as its benzoate ester 68 (Scheme 18 ).
OMe
MeO
NaH,BnBr
OH
OPMB OH
OH
CSA(Cat
)
DCM:Et2 O
OH
OPMB O
O
9 :1,rt,1
h
OBn
OPMB O
O
66
65
51
BzCl,Et3 N
aq.2N HCl
THF,25 0 C
5 hrs.
THF,Reflux,
1h
h
DCM,DMAP(Cat)
OBn
OPMB OH
OH
OBn
OPMB OH
OBz
00 C -rt,3 hrs.
68
67
SCHEME 18
The secondary hydroxyl group of compound 68 was protected as methoxy methyl
ether using MOMCl and DIPEA to afford 69. Hydrolysis of benzoate ester 69 using aq 3N
KOH followed by the oxidation with IBX-DMSO afforded aldehyde 49.
XIX
SYNOPSIS
MOMCl
OBn OPMB OH
OBz
i-Pr2 NEt,DMAP
CH2 Cl 2
OBn
OPMB OMOMOBz
00 C-rt
12
hrs.
68
OBn
3N, aq. KOH
OPMB OMOMOH
69
MeOH:TH
F 1:1,
rt5
hrs.
H
IBX-DMS
O
DCM, rt
1 h.
OBn OPMB OMOMO
49
70
SCHEME 19
Addition of the titanium enolate of 3-pentanone to propanal provided
diastereomeric mixture 72 which was oxidized with Dess-Martin periodinane to yield
diketone 50.
Dess-martin
1M TiCl4
O
i-Pr2 NEt
DCM, -78 0 C
H
O
OH
Periodane
DCM, rt, 30 min.
O
O
O
71
72
SCHEME 20
XX
50
SYNOPSIS
Our subsequent task was the coupling of fragments 49 and 50 to construct the γpyrone moiety. The diketone 50 was converted to a dianion with 2.5 eq.. of LDA and the
dianion was reacted with the aldehyde 49 to afford the diastereomeric mixture of aldol
products 73. Rapid cyclization / dehydration of the mixture 73 (without purification) was
achieved by treatment with CSA (cat) to give the diastereomeric mixture of γdihydropyrone 74 which is not easily separable by column chromatography (Scheme 21 ).
H
OBn
O O
LDA-HMPA
50
THF,-780 C
1 h.
OPMB OMOMO
OBn
OPMB OMOMOH
O
O
73
49
+
Minor amount of hemiacetal of 73
CSA, DCM
rt, 30 min.
O
OBn
OPMB OMOM
O
74
SCHEME 21
Next attention was directed to bring the unsaturation between C16 and C15 of γdihydropyrone. Inorder to obtain that, γ-dihydropyrone 74 was subjected to various types
of reactions like dehydrogenation, halogenation-dehydrohalogenation, selenylationselenoxide elimination etc, under different experimental conditions as shown in the scheme
22. But to our extreme surprise, none of the approaches led to the desired product.
XXI
SYNOPSIS
O
O
OBn
OPMB OMOM
OBn
OPMB OMOM
O
74
O
75
Reaction conditions :
1) IBX / Fluorobenzene:DM SO, 600C
2) DDQ,Toluene, 900C
Ph
3) LDA,
-780C
N
Cl
4) LDA, CBr4, -780C
6) LDA, PhSeBr, -780C
SCHEME 22
Since the desired product could not be obtained from 74, the diastereomeric aldol
mixture 73 was immediately subjected to careful oxidation with DMP to give the triketone
76. The resulting β-triketone 76 without purification was directly cyclised by TPP-CCl4
system to form the required γ-pyrone 75 (Scheme 23).
Dess-martin
OBn
OPMB OMOMOH
O
Periodane
rt,30 min.
O
73
OPMB OMOMO
76
O
Ph3 P-CCl4
THF, rt, 12 hrs.
OBn
OBn
OPMB OMOM
O
75
SCHEME 23
XXII
O
O
SYNOPSIS
To our relief and extreme satisfaction this approach afforded the much desired
product. So we successfully completed the synthesis of C9-C21 fragment. Efforts are in
progress to couple the C3-C8 and C9-C21 fragments and total synthesis of Siphonarin B.
XXIII
SYNOPSIS
CHAPTER III
This Chapter is divided into two sections .Section ‘A’ deals with the synthesis of
Tetrahydrochromanoquinolines using LPDE catalysed intramolecular aza-Diels-Alder
reaction.
Aza-Diels-Alder rection is one of the most powerful synthetic routes for
construction
nitrogen
containing
six-membred
heterocycles.
The
tetrahydrochromanoquinoline derivatives are exhibit a vast range of biological activities
including psychotropic, anti-allergic, anti-inflammatory and estrogenic behaviour.
The recent surge in the use of LPDE medium as a mild Lewis acid prompted us to
disclose
a
simple
and
efficient
procedure
for
the
synthesis
of
tetrahydrochromanoquinolines. 5M LiClO4 in diethyl ether was found to be effective
Lewis acid in promoting intramolecular imino-Diels-Alder reaction of aldimines derived
from aromatic amines and O-prenyl derivatives of salicylaldehydes to produce the
corresponding tetrahydrochromanoquinoline derivatives (Scheme 24).
N
H
H
O
5M LPDE
R
O
R
R'
N
H H
1
2
SCHEME 24
XXIV
+
R'
O
R
N
H H
3
R'
SYNOPSIS
Table 1: 5 M LPDE Promoted Synthesis of Tetrahydrochromanoquinolines a
Entr
y
Salicylaldehy
dederivative
Anilin
e
NH2
a
6.5
85
4
7.0
90
4
8.0
83
4
6.0
87
4
6.5
85
4
8.0
78
7.5
80
8.5
75
6.0
87
7.0
85
6.5
90
7.5
84
4
NH2
Cl
OMe
c
H2 N
NH2
d
Me
e
H2 N
Me
f
MeO
NH2
Cl
g
NH2
Me
h
Yield
O
OHC
b
Time
O
Me
4
Br
i
NH2
NH2
O
Br
OHC
Me
NH2
j
OBn
OHC
4
Br
NH2
k
F
l
NH2
4
O
OHC
XXV
OMe
SYNOPSIS
SECTION ‘B’ deals with the synthesis of 4-chlorotetrahydropyrans under microwave
irradiation.
The tetrahydropyran ring is part of the back-bone of various important
carbohydrates and natural products such as avermectins, aplysiatoxin, oscillatoxins,
latrunculins, talaromycins and acutiphycins.
The acid catalyzed condensation of olefins with carbonyl compounds known as
Prins reaction, is an important carbon-carbon bond forming reaction. In this section a mild
and efficient procedure for the synthesis of 4-chloropyrans through the Prins type
cyclization reaction of homoallyl alcohols with aldehydes in the presence of BiCl3 is
described (Scheme 24).
In recent years microwave assisted organic reactions is an area of growing interest
because of distinct advantages like rapid reaction, easy work up and solvent free
conditions. The general Scheme to synthesize 4-chlorotetrahydropyrans is outlined below
and results are listed in Table 2.
Cl
O
OH
+
R
H
BiCl3
1
R
M.W.
R
1
2
SCHEME 25
XXVI
1
O
R
3
SYNOPSIS
Table : Microwave-promoted synthesis of 4-chlorotetrahydropyrans
Homoallylalcohol 1
Entry
Aldehyde
2
OH
CHO
a)
OH
OH
1.5
92
1.5
85
2.0
90
2.5
78
2.0
70
1.5
81
2.0
98
1.5
90
2.0
89
1.5
87
2.0
84
2.5
90
1.5
88
2.0
85
OPh
CHO
Cl
c)
Cl
OH
CHO
OH
e)
Yield c
(%)
CHO
b)
d)
Reaction
time b (min)
CHO
OH
NO2
CH=CH CHO
f)
OH
g)
Cl
Cl
Cl
Cl
OH
CHO
CHO
Cl
h)
i)
Cl
OH
Cl
j)
CHO
Cl
OH
OPh
Cl
H3C CH CH CHO
Cl
OH
CHO
Cl
k)
M eO
Cl
OH
l)
CHO
Cl
Me
Cl
OH
m)
( ) 2 CHO
CHO
n)
H 2C CH CH2CH2 OH
Me
XXVII
a