Synopsis
SYNOPSIS
Synopsis of the thesis entitled “Heterofunctionalization of Di- and Tri-substituted
Olefins Mediated by Pendant Sulfoxide: Application to the Synthesis of (+)Lentiginosine, (4S,5R,6S,17S)-Aspicilin, 2-C-Methyl-D-Erythritol 4-Phosphate and
C7-C11 Fragment of Fostriecin” is divided in to three chapters.
Chapter-I: Novel and Stereoselective Synthesis of (+)-Lentiginosine
This chapter deals with a brief account of the applications of sulfoxides in
asymmetric synthesis, brief account of the work carried out by the various research
groups toward the synthesis of lentiginosine and a detailed account of the present work.
Many natural products pose considerable synthetic challenge because of their
stereochemical complexity. The development of new and efficient methods for the regioand stereoselective synthesis of biologically active compounds is an active area of
research. The sulfoxide group is widely used as a chiral auxiliary in numerous
asymmetric transformations. The efficacy of the sulfoxide group in the stereoselective
auxiliary induced reactions is mainly due to steric and stereoelectronic diffrerences
between the substituents of the chiral sulfur atom: a lone pair of electrons, an oxygen
atom and two different carbon ligands.
Indolizidine alkaloids having nitrogen-fused bicyclic ring systems have been the
target of the many synthetic efforts due to their interesting and potent biological activities
including antiviral, antitumor, and glucosidase inhibitors. A large number of
polyhydroxylated indolizidine such as lentiginosine 1, swainsonine 2, castanospermine 3,
(Figure-1) isolated from natural sources are powerful and specific inhibitors of α or βglycosidases.
Figure 1
H
OH
OH
H
OH
OH
OH
OH
OH
N
N
I-1
I-2
1
OH
H
N
I-3
OH
Synopsis
As a part of the programme aimed at the synthesis of biologically active
molecules, it was decided to synthesize (+)-Lentiginosine. The retrosynthetic analysis is
depicted below (Scheme-1).
Scheme 1
OH
HO
H
OH
O
TsO
OH
Br
S
HO
Tol
TFAH2N
N
OH
OBn
I-4
I-1
I-5
OTs
O
Tol
OH
S
OBn
I-6
The synthesis of Lentiginosine commemced with the condensation of the lithium
anion derived from (R)-methyl p-tolyl sulfoxide 11 with unsaturated ester 10 in THF at 0
C to afford -keto sulfoxide 12. The ester was prepared from 1,5-pentane diol 7 in three
o
steps. The -hydroxy sulfoxide 6 obtained by diastereoselective reduction of -keto
sulfoxide 12. On treatment with NBS in toluene in the presence of water afforded the
bromodiol 5 (Scheme-2)
Scheme 2
HO
OH
a
BnO
b
OH
T ol
c
O
BnO
I-9
O
I-8
I-7
O
BnO
S
O
Me
I-11
T ol
O
T ol
O
S
d
OEt
e
H
I-12
OH
O
S
f
I-6
T ol
OH
Br
S
OH
OBn
OBn
I-5
OBn
Reaction conditions: (a) NaH, THF, 70 oC, rt, 30 min, then BnBr, 12 h, 60% (b) (COCl)2, DMSO, CH2Cl2, -78 oC, 45 min,
Et3N, 80% (c) PPh3CHCO2Et, benzene, rt, 6 h, 85% (d) LDA, THF, -78 oC, 11, 30 min, then 10 at -78 oC, 2 h, 60% (e) DIBAL,
ZnCl2,THF, -78 oC, 1 h, 91% (f) NBS, toluene, H2O, rt, 30 min, 85%
2
Synopsis
It was required to introduce an amino group in the place of bromine with retention
of configuration and this was achieved by two successive inversions. Thus subjecting the
epoxide 13, obtained from bromohydrin 5 by treatment with potassium carbonate, to
treatment with NaN3 in the presence of NH4Cl according to the Sharpless protocol
afforded regio- and stereoselectively azido diol 14. The azido diol was converted into
acetonide 15 with 2,2-DMP in presence of cat. amount of CSA in CH2Cl2. Treatment of
15 with TFAA in the presence of Et3N in CH2Cl2 afforded Pummerer intermediate, which
without isolation was treated with satd. aq. NaHCO3 solution and NaBH4 to yield alcohol
16 (Scheme-3).
Scheme 3
O
OH
Br
O
a
S
O
OH
b
S
Tol
Tol
Tol
O
OH
OBn
O
O
O
O
S
d
Tol
I-15
OBn
I-14
O
O
TolS
CF3C(O)O
N3
N3
OH
OBn
I-13
I-5
c
OH
S
O
HO
N3
N3
I-16
OBn
OBn
OBn
Reaction conditions: (a) K2CO3, MeOH, 0 oC-rt , 1 h. 45 min, 83% (b) NaN3, NH4Cl, MeOH/H2O (8:1), reflux, 6 h, 85% (c)
2,2-DMP, CH2Cl2, cat. CSA, rt, 1 h, 87% (d) TFAA, Et3N, CH2Cl2, 0 oC, then aq NaHCO3, NaBH4, 75% for two steps
Three transformations were effected in a one-pot operation, by treatment of
alcohol 16 with Pd(OH)2/C in methanol in the presence of di-tert-butyldicarbonate under
an atmosphere of hydrogen to yield the acetonidediol 17. Treatment of 17 with ptoluenesulfonyl chloride in the presence of Et3N in CH2Cl2 afforded the the ditosyl
derivative 18. The ditosyl derivative 18, on treatment with TFA/H2O (95:5) overnight
afforded the ammonium salt 4, which without isolation was subjected to treatment with
excess triethylamine in dichloromethane to afford (+)-Lentiginosine 1. The physical
characteristics of (+)-lentiginosine were in excellent agreement to those reported in the
literature (Scheme-4).
3
Synopsis
Scheme 4
O
O
O
a
HO
O
O
b
HO
I-17
I-16
I-18
OH
OBn
OH
c
BocHN
BocHN
N3
OH
O
TsO
HO
TsO
OTs
H
d
HO
TFA +H3N
N
I-1
I-4
OTs
Reaction condition: (a) H2, Pd(OH)2, (Boc)2O, ethanol, rt, 16 h, 82% (b) TsCl, Et3N, cat. DMAP, CH2Cl2,
rt, 1 h, 75% (c) TFA/H2O (95:5), CH2Cl2, 0 oC to rt, 16 h (d) Et3N, CH2Cl2, rt,6 h, 70% for two steps
In conclusion a novel synthesis of lentiginosine, in 12 steps and 10.7 overall yield
that exploits the potential of the sulfinyl group as a nucleophile to functionalize an olefin
stereo- and regioselectively was developed.
Chapter-II: Stereoselective Total Synthesis of (4S,5R,6S,17S)-Aspicilin
This chapter deals with a brief account of the reported synthesis of (+)-aspicilin
by various research groups and an elaborate account of the present work. (+)-Aspicilin 1,
an 18-memberd macrolide was first isolated in 1900 by Hesse from various lichens of the
Lecanoraceae family. Although no unique biological activity has been attributed thus far
to aspicilin, this natural product has attracted attention from synthetic chemists because
of its challenging architecture having an 18-memberd-macrolide structure with three
contiguous chiral centers (Figure-1).
Figure 1
OH
OH
O
OH
O
II-1
As a part of the programme aimed at the synthesis of biologically active molecules,
it was decided to synthesize aspicilin. The retrosynthetic analysis is depicted below
4
Synopsis
(Scheme-1). 1 can be derived from the fully protected compound 2, which can be derived
from phosphonate ester 3, which in turn can be derived from sulfoxide 4 and alkene 5 by
a Pummerer ene reaction. Compound 4 in turn can be obtained from bromohydrin 6,
which in turn can be traced back to the unsaturated sulfoxide 7.
Scheme 1
O
OTBS
O
OTBS
O
OH
OEt
II-1
O
O
Me
O
Me
O
P
O
II-3
II-2
O
Tol
O
OTBS
O
OBn
S
O
II-4
Tol
+
O
OH
Br
S
OBn
O
P
O
OEt
Tol
OH
S
OBn
OH
OEt
Me
OEt
O
II-6
II-7
O
II-5
The synthesis of aspicilin commenced with the condensation of the lithium anion
derived from (R)-methyl p-tolyl sulfoxide 11 with unsaturated ester 10 in THF at 0 oC to
afford -keto sulfoxide 12. The ester was prepared from 1,4-butenediol 8 in three steps.
The -hydroxy sulfoxide 7 obtained by diastereoselective reduction of -keto sulfoxide
12 with DIBAL/ZnCl2. Treatment of alcohol with NBS in toluene in the presence of
water afforded the bromodiol 6 (Scheme-2).
5
Synopsis
Scheme 2
O
a
OH
HO
OBn
BnO
BnO
II-8
Tol
O
b
II-9
OEt
II-10
O
O
S
OBn
d
Tol
Tol
OH
e
Tol
OBn
S
Me
II-11
c
O
O
S
OH
Br
OBn
S
OH
II-6
II-7
II-12
Reaction conditions: (a) NaH, n-Bu4NI, THF, 0 oC, rt, 30 min, then BnBr, 70 oC, 12 h, 88% (b) (i) O3, CH2Cl2,
-78 oC, 30 min then Me2S, 30 min at -78 oC then rt, 8 h (ii) PPh3CHCO2Et, benzene, rt, 6 h, 82% (for two steps)
(c) LDA, THF, -78 oC, 11, 30 min, then 10 at 0 oC, 1 h, 60% (d) DIBAL, ZnCl2, THF, -78 oC, 2 h, 91% (e)
NBS, toluene, H2O, rt, 82%
The anti, syn-triol motif present in aspicilin, required the replacement of bromine
by a hydroxy group with retention of configuration and this was achieved by two
successive inversions. Thus treatment of diol 6 with anhydrous potassium carbonate in
methanol afforded the epoxide 13 as a single diastereomer. Initially opening of epoxide
13 was attempted using sodium acetate in presence of titanium tetraisopropoxide in
dichloromethane following the Sharpless protocol no desired product was obtained and
starting material being recovered. Attempted opening of the epoxide in the presence of
titanium tetraisopropoxide using both the ammonium acetate and p-methoxy benzyl
alcohol gave a complex mixture of products (Scheme-3).
Scheme 3
b
O
Tol
O
OH
OH
Br
S
OBn
a
Tol
c
S
OBn
Rec. S. M.
Complex
product mixture
O
OH
II-13
II-6
d
Complex
product mixture
Reaction conditions: (a) K2CO3, MeOH, 0 oC-rt, 1 h, 90% (b) CH3CO2Na, Ti(OiPr)4, CH2Cl2 (c) PMB-OH,
Ti(OiPr)4, CH2Cl2, 0 oC-rt (d) CH3COONH4, Ti(OiPr)4,CH2Cl2, rt, 1 h
Subjecting the epoxide 13 to treatment with aq. 5% H2SO4 in dioxane afforded the
triol 14, which was converted into acetonide 15 by reaction with 2,2-dimethoxypropane
in the presence of cat. amounts of camphor-10-sulfonic acid (CSA). The 13C spectrum of
6
Synopsis
15 revealed signals for the methyl groups of the acetonide at  19.3, 29.1 and for
the quaternary carbon of the acetonide at  100.0 proving beyond doubt the 1,3-syn
disposition of the hydroxy groups. Based on this result, a mechanism involving the
participation of sulfinyl group was proposed (Scheme-4).
Scheme 4
..
OH
..
+S
H2O
O
Tol
OH
Tol
a
S
OBn
O
OBn
O
H
O
II-13
O
O
OH
OH
S
b
OBn
Tol
Tol
II-14
O
O
OBn
S
OH
II-15
OH
Reaction conditions: (a) 5% H2SO4, dioxane, 0 oC, 10 min, 85% (b) 2,2-DMP, acetone, cat CSA, rt, 2 h, 89%
Subjecting the epoxide 13 to treatment with benzoicacid in the presence of
titanium tetraisopropoxide in dichloromethane afforded regio- and stereoselectively diol
benzoate 16, which was converted to acetonide 17 with 2,2-DMP in presence of cat.
amount of CSA in CH2Cl2. The 13C spectrum of 17 revealed signals for the methyl’s of
the acetonide at  26.8,  27.2 and for the quaternary carbon of the acetonide at  110.4
proving beyond doubt the 1,2-syn disposition of the hydroxy groups. Deprotection of
benzoate 17 was carried out using DIBAL-H in toluene at –78 oC to afford the alcohol
18, which was protected as its silyl ether 4 (Scheme-5).
Scheme 5
O
O
Tol
OH
a
S
OBn
II-13
OCOPh
S
OBn
b
Tol
Tol
O
OBn
II-17
II-16
O
c
O
O
OH
S
d
OBn
II-18
Tol
O
S
OC(O)Ph
S
OH
O
Tol
O
OH
O
OTBS
OBn
II-4 O
O
Reaction conditions: (a) Ti(OiPr)4, PhCOOH, CH2Cl2, 3 h, rt, 55% (b) 2,2-DMP, acetone, cat CSA, rt, 2 h, 88% (c)
DIBAL-H, toluene, -78 oC, 45 min, 91% (d) TBDMSCl, imidazole, CH2Cl2, rt,1 h, 90%
7
Synopsis
Silyl ether 4 was treated with trifluoroacetic anhydride in CH2Cl2, the resulting
intermediate 19, without isolation was reacted with the terminal alkene 5 and tin
tetrachloride to afford the homoallylsulfide 20. Hydrogenolysis of 20 using Raney-Ni in
ethanol afforded alcohol 3. Oxidation of the primary hydroxy group using Dess-Martin
periodinane in CH2Cl2 and intramolecular Wadsworth-Emmons reaction of the resulting
aldehyde 21 with the phosphonate ester in acetonitrile employing Masamune-Roush
conditions yielded fully protected aspicilin 2. Smooth deprotection of 2 was achieved
with cat. amounts of PPTS in methanol to provide the aspicilin 22 (Scheme-5).
Scheme 6
O
O
T ol
O
a
OBn
S
OT BS
O
OT BS
S
p-T ol
II-4
OBn
OEt
Bn
O
P OEt
O
II-20
O
OT BS
OT BS
O
OH
Me
O
OEt
c
OEt
b
O
O
O
II-19
O
Me
O
CF3(O)CO
O
T ol
O
OT BS
S
P OEt
O
Me
O
O
O
O
d
P OEt
O
II-21
II-3
O
OT BS
OH
,
OH
O
O
e
O
O
Me
OH
O
Me
II-22
II-2
Reactions conditions: (a)TFAA, CH2Cl2, 0 oC, 30 min, then 5, SnCl4, 65% (b) Raney-Ni, H2, EtOH, 60 oC, 6 h,
80% (c) DMP, CH2Cl2, 0 oC, 30 min, 90% (d) DBU, LiCl, CH3CN, rt, 30 min, 60% (e) PPTS, methanol rt, 60%
Note: Kindly note that while the β-ketosulfoxide 12 should have been reduced with
DIBAL-H to get allyl alcohol 7, DIBAL-H/ZnCl2 was used. Further reactions were
carried out with 7 and we ended up preparing the (4S,5R,6S,17S)-epimer of aspicilin and
not aspicilin itself as originally intended. This error was unfortunately discovered after
publishing the results.
In conclusion, a stereoselective synthesis of the (4S,5R,6S,17S)-aspicilin has
achieved using bromodiol 6, readily obtained from (R)-methyl p-tolylsulfoxide. The key
8
Synopsis
steps
include
nucleophilic
sulfinyl
group
participation,
ene
reaction
and
macrolactonization using mild conditions.
Chapter-III: This chapter has been divided into three sections.
Section A: Stereoselective Synthesis of Chiral Tertiary Alcohol Building Blocks via
Neighbouring Group Participation from Trisubstituted Olefins.
This sections deals with the preparation of bromohydrins from trisubstituted allylic alcohols.
A number of natural products and compounds with pharmaceutical and biological
interest contain a chiral tertiary alcohol moiety. Stereoselective construction of this
quaternary carbon center usually represents a major challenge in the synthetic chemistry.
It is well known that sulfoxide participates as neighbouring group in a number of
reactions. Sulfoxide group participation in halohydrin formation from cyclic and simple
acyclic olefins has been demonstrated, but its potential to produce higly functionalized
products with stereochemical control at two adjacent centers in substituted acyclic olefins
remained unexplored, here we have described the formation halohydrins from trisubstituted olefins. It was therefore interesting to study the regio- and stereoselectivity of
bromohydrin formation from tri-substituted allylic alcohols. The tri-substituted
unsaturated -hydroxy sulfoxide precursors were prepared as an epimeric mixture in
equimolar proportion and in good yield by condensing the lithium anion of (R)-methyl ptolylsulfoxide 1 with the appropriate aldehydes 2, 3, 4 and 5. (Scheme-1).
Scheme 1
O
Tol
S
CH3
III-1
O
R2
O
a
+
R
3
R1
III-2, 3, 4, 5
Tol
OH
S
R3
Sc
Rs
O
R2
R1
III-6a, 7a, 8a, 9a
+
OH
R2
S
Tol Rs
R3
Rc
R
1
III-6s, 7s, 8s, 9s
2, 6: R1 = H, R2 = CH2OPMB, R3 = Me
3, 7: R1 = Me, R2 = CH2OBPS, R3 = H
4, 8: R1 = H, R2 = Me, R3 = CH2OPMB
5, 9: R1 = Me, R2 = H, R3 = CH2OBPS
Reaction conditions: (a) LDA, THF, -78 oC, then III-1, 30 min, then III-2/III-3/ III-4/III-5, ,30 min-1 h,
80-90%
9
Synopsis
The isomeric -hydroxy sulfoxides 6, 7, 8 and 9 [(Rs,Sc) and (Rs,Rc)] were
purified by column chromatography and their configuration assigned unambiguously by
comparison of coupling constants for the methylene protons attached to the carbon of the
-hydroxy sulfinyl moiety.
-Hydroxy sulfoxides prepared by the condensation of the lithiated anion of
sulfoxide with the aldehyde with benzyl ether protecting group gave inseparable mixture
of diastereomers. Hence the keto sulfoxide was prepared by reaction of the lithium anion
of the (R)-methyl-p-tolylsulfoxide 1 with ethyl ester 10. The individual diastereomers
were prepared by stereoselective reduction of the -ketosulfoxide 11 (Scheme 2).
Scheme 2
O
OH
Me
S
Tol
OBn
b
O
S
Tol
O
CH3
Me
a
OBn
+
EtO
O
O
Me
S
III-12a
OBn
Tol
c
O
OH
Me
S
III-1
III-10
OBn
Tol
III- 11
III-12s
o
o
Reaction conditions: (a) LDA, THF, -40 C, then III-1, 30 min, 0 C then III-10, 30 min 60% (b) DIBAL, THF,
-78 oC, 2 h, 80-90% (c) DIBAL, ZnCl2, THF, -78 oC, 3 h, 80-90%
The unsaturated -hydroxysulfoxides were reacted with N-bromosuccinimide
(NBS) and water in toluene at ambient temperature to afford the bromohydrins in
moderate to high stereoselectivity and in good yields. The regio- and stereoselectivity of
the reaction can be rationalized by the intermediacy of the sulfoxonium salt formed by
the nucleophilic attack of the sulfinyl group on to the olefin - complexed to the
bromonium ion and subsequent hydrolysis by attack of water at sulfur (Scheme 3).
Hence in effect the configuration at sulfur gets inverted.
Scheme 3
O
HO
S
OPMB
Tol
Me
Tol
OPMB
..
H2O
S
O
+
O
Br
HO
Me
HO
HO
Me
OPMB
S
Tol
Br
III-6a
III-15
As Table-1 indicates, the reaction is general for a variety of ,-unsaturated
sulfoxides. The stereochemical assignments to the products were made by 1H NMR and
10
Synopsis
nOe
analysis of the spectra of the acetonides derived from the bromohydrins by
treatment of the bromohydrins with 2,2-dimethyoxypropane, dimethyl acetal of
anisaldehydes in the presence of catalytic amounts of CSA.
Table-1: Regio- and stereoselectivity of bromohydrin formation
Product
Olefin
O
1)
OH
Anti (C-2/C-3)
O
OPMB
HO
OPMB
O
Tol
OH
O
OPMB
Tol
S
HO
Tol
O
HO Me
S
OPMB
3)
HO
O
4)
Me
Tol
OPMB
OH
72 (2:1)
OPMB
HO Me
S
Tol
OPMB
83(1:4)
Br
Br
III-19
OTBS
OH
S
O TBSO
Me
S
III-13a
80(
<5:>95)
III-18 Br
Tol
S
Tol
O TBSO
OPMB
OPMB
III-16
III-17 Br
OTBS
HO Me
Br
III-6s
O
HO
S
Br
III-15
III-6a
2)
OH
S
Anti:Syn
Syn (C-2/C-3)
O
Me
Tol
S
Tol
Yield(%)
III-20
OPMB
Inseparable mixture of three compounds
S
Tol
III-13s
O
5)
Tol
OH
Tol
S
III-7a
O
6)
Tol
O
OH
S
III-14s Me
O
Br
OBPS
Tol
OBPS
OBPS
Tol
OBPS
Me
S
OH
85
(<5:>95)
III-26
OBPS
O
Br
OBPS
HO
Br
S
OH
OBPS
Tol
78 (1:2)
OH
O
S
O
Br
OBPS
Me
III-25
OBPS
OH
III-24
Br
Me
78 (1:1)
Me
S
OBPS
O
OBPS
HO
HO
Me
O
Tol
Me
III-23
OBPS
Br
III-22
S
Tol
OBPS
Tol
OBPS
OH
S
Me
Me
S
III-14a
8)
OBPS
Tol
OBPS
O
Br
OH
III-21
S
O
Tol
OH
S
Me
OH
III-7s
7)
O
OBPS
Tol
Br
S
OBPS
HO
Me
III-28
III-27
11
Me
83 (1:3)
Synopsis
Table-1: Regio- and stereoselectivity of bromohydrin formation
Yield(%)
Product
Olefin
O
9)
Anti (C-2/C-3)
OH
S
Tol
O
Me
OBn
HO
Tol
OBn
OH
Me
S
OBn
Tol
HO
Tol
OBn
OH
O
Me
S
OPMB
HO
Me
Me
S
OPMB
Tol
O
HO
HO
Me
OPMB
HO Me
O
OPMB
HO HO
O
OH
OPMB
Tol
III-36
OH
OBPS
Tol
OBPS
O
OH
OBPS
Tol
OH
O
Br
OBPS
HO
Me
Br
OBPS
84 (<5:>95)
OBPS
83 (<5:>95)
Me
III-38
S
S
Tol
OH
OH
III-37
III-9a
III-9s
Tol
78 (>95:<5)
Br
S
HO
Me
Me
O
O
Br
S
S
Tol
Me
S
Br
O
75 (>95:<5)
Br
III-34
III-35
III-8s
OH
Tol
Br
S
Tol
77 (>95:<5)
S
OPMB
III-33
OH
OBn
Me
Tol
OH
Tol
O
O
75 (>95:<5)
III-32
S
III-8a
OBn
Br
11)
14)
HO HO
S
III-31
Tol
13)
O
HO Me
Br
O
OH
Br
III-30
S
III-12s
12)
Tol
Me
S
Br
III-29
O
10)
HO
OH
S
III-12a
O
O
Me
Anti:Syn
Syn (C-2/C-3)
Me
OH
Br
S
Tol
Me
OH
III-40
III-39
By an appropriate choice of anti/syn isomers or suitably protecting the allylic
hydroxy group the reaction course can be directed to obtain a single stereoisomer, almost
exclusively.
12
Synopsis
Section B: Novel and Stereoselective Synthesis of 2-C-Methyl-D-erythritol 4Phosphate:
This section deals with a brief account of synthesis of 2-C-Methyl D-erythritol 4phosphate carried out by the various research groups and an elaborate account of the
present work.
MEP is a key intermediate of the newly discovered mevalonate-independent pathway
for isoprenoid biosynthesis in bacteria, plant chloroplasts and algae. MEP and a plethora
of natural products and compounds with pharmaceutical and biological interest contain a
chiral tertiary alcohol moiety. Stereoselective construction of this quaternary carbon
center represents a major challenge in the synthetic chemistry.
As a part of the programme aimed at the synthesis of biologically active molecules,
it was decided to synthesize MEP. The retrosynthetic analysis is depicted below (Scheme
4).
The synthesis of MEP commenced from the -hydroxy sulfoxide 6a obtained
by condensation of lithium anion of the (R)-methyl-p-tolylsulfoxide 1 with Z-trisubstituted olefin aldehyde 2 ( as illustrated in this chapter, section-A). Treatment of the
-hydroxy sulfoxide 6a with NBS in toluene in the presence of water afforded the
bromodiol 15. The bromodiol 15 on treatment with DDQ in the presence of 4 Å MS
yielded the 1,2-acetonide 43 as a mixture of epimers (Scheme 5).
13
Synopsis
The required replacement of bromine by hydroxy group with inversion of
configuration was achieved by three successive reactions. Thus treatment of bromohydrin
43 with anhydrous potassium carbonate in acetonitrile afforded the epoxide 44, oxidation
to sulfone using mCPBA in CH2Cl2 and reductive elimination using Na-Hg in methanol
under buffered reaction condition yielded allylic alcohol 46. The allylic alcohol 46 was
protected as the benzyl ether 42 using NaH as the base and benzyl bromide as alkylating
agent (Scheme 6).
Scheme 6
PMP
O Me
OH
O
O
a
O
S
b
S
O
Tol
Tol
O
O
Me
PMP
III-44
O
Me
HO
d
O
O
O
Me
O
PMP
III-45
PMP
PMP
c
Tol
O
Br
III-43
O
S
O
Me
O
BnO
III-42
III-46
Reaction condition: (a) K2CO3, CH3CN, rt, 48 h, 91% (b) mCPBA, CH2Cl2, 0 oC, 15 min, 89% (c) Na-Hg, Na2HPO4,
MeOH, -20 oC-0 oC, 15 min, 70% (d) NaH, BnBr, THF, 0 oC-rt, 5 h, 90%
Oxidative cleavage of olefin followed by reduction of the resulting aldehyde to
alcohol was achieved in a one pot operation. Thus reacting the olefin 42 with OsO4,
NaIO4 in presence of 2,6-lutidine gave an aldehyde which on treatment with NaBH4 in
the same pot afforded primary alcohol 47. Phosphorylation was achieved using benzyl
14
Synopsis
chlorophosphoridate using n-BuLi as a base at –78 oC in THF. Finally hydrogenolysis
using Pd(OH)2 under an atmosphere of hydrogen in ethanol yielded MEP 41 (Scheme 7).
Scheme 7
PMP
O
Me
PMP
PMP
Me
O
b
BnO
BnO
HO
BnO
BnO
III-42
c
III-47
HO
HO
P
Me
O
O
BnO
III-48
OH
O
P
O
O
O
a
O
Me
OH
O
HO
III-41
Reaction conditions: (a) OsO4, NaIO4, 2,6-Lutidine, dioxane:water, 16 h, then NaBH4, 70%, (b) (OBn)2POCl, THF, n-BuLi,
-78 oC, 30 min, 70%
In conclusion an enantioselective synthesis of the 2-C-methyl D-erythritol 4phosphate was achieved using bromodiol 15 readily obtained from (R)-methyl ptolylsulfoxide. The key steps include nucleophilic sulfinyl group participation to generate
chiral quaternary center, one pot oxidative cleavage followed by reduction.
Section C: Synthesis of C7-C11 fragment of Fostriecin:
This section deals with a brief account of the work carried out by the various
research groups and present work toward the synthesis of fostriecin.
Fostriecin 49 is a structurally novel phosphate ester produced by Streptomyces
pulveraceus that is active in vitro against leukemia, lung cancer, breast cancer, ovarian
cancer and exhibits efficacious in vivo antitumor activity (Figure-1).
Figure 1
H2O3PO
O
O
OH
OH
HO
III-49
Earlier investigations have demonstrated the merit of the sulfinyl moiety as an
internal nucleophile to functionalize tri-substituted olefins regio- and stereoselectively.
The present work illustrates the potential of this methodology to access chiral quaternary
15
Synopsis
center toward the synthesis of fostriecin. Due to its unique structure and potent
bioactivity, fostriecin has attracted the attention of synthetic chemists. Almost all the
reported synthesis utilize chiral pool starting materials.
The retrosynthetic analysis revealed that fostriecin 49 could be derived by
coupling the subunits 50, 51and 52. Subunit 51 is commercially available and subunit 52
is known compound. Subunit 50 can be derived from aldehyde 53 and sulfone 54 which
in turn can be obtained from bromohydrin 35 (Scheme 8).
Scheme 8
H2O3PO
O
OH
O
OH
HO
III-49
PO
O
O
TMS
+
+
OP
O
PO
III-51
III-50
OP
N
+
S
O
O
S
O
III-52
OP
PO
III-54
III-53
Tol
O
S
OH
OH
P = Protecting group
OP
Br
III-35
Bromo hydrin 31 was obtained as disclosed in section-A. It was required to
replace the bromine by hydroxy group with inversion of configuration. This necessitated
chemoselective participation of the secondary alcohol during epoxide formation followed
by reductive elimination of toluenesulfinate using Na-Hg. In the event treatment of
bromohydrin 31 with K2CO3 in methanol yielded epoxide 55 the regioisomer arising via
participation of the tertiary hydroxy group. The reaction when carried out in a variety of
solvents like isopropanol, 2o-butanol, aprotic solvent MeCN still led to the formation of
epoxide 55 (Scheme 9).
16
Synopsis
Scheme 9
a
b
O
HO
HO
O
Me
OBn
S
Tol
c
Tol
OH
O
Me
S
OBn
Br
III-55
d
III-31
Reaction conditions: (a) K2CO3, MeOH, 0 oC, 15 min (b) K2CO3, isopropanol, (c) 2o -butanol, K2CO3, rt (d)
MeCN, K2CO3, 0 oC
To get desired epoxide it was therefore necessary to protect the tertiary alcohol. The
bromohydrin 31 on treatment with DDQ in presence of 4 Å molecular sieves in CH2Cl2
led mostly to recovery of starting material and desired 1,2 acetonide 56 in 10% yield.
Reaction of 31 with DDQ in 1,2-dichloro ethane also gave poor yield of the 1,2-acetonide
56 and mostly un reacted starting material was recovered (Scheme 10).
Scheme 10
a
O
HO
HO
O
b
OBn
S
O
HO
Tol
Ph
Rec. S.M
+
O
S
Tol
Br
Br
c
III-56
III-31
Reaction conditions: (a) DDQ, 4 oA MS, CH2Cl2, 10% (b) DDQ, 4 oA.MS, ClCH2CH2Cl2 (c) DDQ, CH2Cl2, hv
Instead of the benzyl ether the substrate with the p-methoxy benzyl group was
prepared and subjected to treatment with DDQ proceeded cleanly to afford the 1,3acetonide 57 (Scheme 11).
Scheme 11
PMP
O
Tol
OH
OH
S
Me
O
d
OPMB
Tol
Br
O
O
S
OH
Br
III-35
III-57
Reaction conditions: (a) DDQ, CH2Cl2, 0 oC, 15 min, 75%
17
Me
Synopsis
The revised strategy necessitated protection of the allylic hydroxy group.
Protection and similar transformations as detailed for the free hydroxy group, yielded
bromohydrin 59. Treatment with DDQ gave the 1,2-acetonide 60 cleanly. Deprotection of
the silyl ether with TBAF bufferd with acetic acid yielded bromohydrin 61. Epoxidation
and reductive elimination with Na-Hg in methanol under buffered conditions yielded
allyl alcohol 64 (Scheme 12).
Scheme 12
O
OH
Me
O
S
Tol
OPMB
a
O
OTBS Me
S
Tol
b
OPMB
OTBS Me OH
S
Tol
OPMB
Br
III-8s
O
c
Tol
III-59
III-58
PMP
OTBS Me O
S
O
d
O
OH Me
S
Tol
e
O
S
O
Tol
III-62
PMP
PMP
O Me
O
g
Me
O
S
PMP
O
Br
III-61
III-60
O
Me
O
Br
f
O
PMP
O
O
Tol
O
O
HO
III-64
III-63
Reaction conditions:(a) TBDMSCl, imidazole, CH2Cl2, rt, 1 h, 90% (b) NBS, H2O, toluene, rt, 30 min, 75% (c)
DDQ, CH2Cl2, 0 oC, 15 min, 75% (d) TBAF:AcOH (1:2), THF, rt, 30 h, 90% (e) K2CO3, CH3CN, rt, 2 h, 91% (f)
mCPBA, CH2Cl2, 0 oC, 15 min, 89% (g) Na-Hg, Na2HPO4, MeOH, -20 oC-0 oC, 30 min, 70%
It is worthwhile to note that the reductive elimination of the epoxysulfone
proceeded in better yields than the epoxy sulfoxide. Protection as the silyl ether and
reduction of 1,2-acetonide gave a mixture of alcohols 66 and 67 in a ratio 9:1 (Scheme
13).
Scheme 13
PMP
O
Me
PMP
a
O
O
Me
O
b
III-64
OPMB
OH
OTBDPS
OTBDPS
HO
Me
III-66
III-65
OH
Me
OPMB
+
OTBDPS
III-67
Reaction conditions: (a) TBDPSCl, imidazole, rt, 1 h, 92% (b) DIBAL-H, toluene, 0 oC, 30 min, 70%
The -silyloxy sulfone 54 was prepared as depicted below (Scheme-13). Thiol 68
was reacted with bromoethanol 69 to afford 70. Oxidation of the hydroxy group using
Dess-Martin periodinane in CH2Cl2 followed by Keck allylation of the resulting aldehyde
18
Synopsis
71 afforded the homoallyl alcohol 72. Protection of hydroxy group as its silylether
followed by oxidation of sulfide 73 yielded sulfone 54 (Scheme 14).
Scheme 14
OH
N
SH
N
a
III-69
III-68
S
OH
S
S
c
N
b
S
+ Br
O
S
III-70
III-71
TBSO
HO
N
N
d
N
e
S
S
S
S
S
OTBS
III-54
III-73
III-72
O
S
O
Reaction conditions: (a) Et3N, CH2Cl2, 0 oC-rt, 1 h, 90% (b) DMP, CH2Cl2, 0 oC, 30 min, 92% (c) Allyl tributyl
stannane, R-Binol, Ti(OiPr)4, 0 oC, 12 h, 70% (d) TBSCl, imidazole, CH2Cl2, 0 oC-rt, 3 h, 94% (e) (NH4)6Mo7O24, H2O2,
dioxane:water, 80%
Oxidation of the primary hydroxy group of compound 66 gave the corresponding
aldehyde 53. The reaction of anion generated from -silyloxy sulfone 54 with the
aldehyde 53 gave triene 75 and none of the expected alkene 74. Elimination of the OTBS
was observed under the reaction condition. Changing the bases used for generating the
anion, mode of addition of aldehyde and temperature variation failed to yield the desired
product (Scheme 15).
Scheme 15
OPMB
Me
Me
OPMB
OH
a
Me
OPMB
O
OTBDPS
b
X
III-74
b
OTBDPS
III-66
OTBDPS
OTBS
OPMB
Me
III-53
III-75
OTBDPS
Reaction conditions: (a) 2,2-DMP, CH2Cl2, 0 oC, (b) III- 54, NaHMDS, -78 oC
Presently efforts are in progress to prepare fostriecin by another route.
19