I
Synopsis
Synopsis
The thesis entitled “Synthetic efforts towards FR901483, Microsclerodermin
A&B and development of new methodologies in poly(ethylene glycol)” has been
divided into three chapters.
Chapter I: Chapter I deals with the brief introduction to immunosuppressants and
synthetic efforts on FR901483.
Chapter II: Chapter II describes the stereoselective synthesis of the C1-C20 segment of
microsclerodermin A&B.
Chapter III: This chapter deals with introduction to alternative solvents and poly
(ethylene glycol) (PEG) as a reusable solvent for organic reactions. This
chapter is further subdivided into two sections.
Section A: Section A deals with poly(ethylene glycol) (PEG) as reusable solvent for the
Heck reaction.
Section B: This section describes poly(ethylene glycol) (PEG) as rapid and reusable
solvent for OsO4 catalyzed dihydroxylation reactions.
Chapter I: This chapter deals with the brief introduction to immunosuppressants and
synthetic efforts on FR901483.
INTRODUCTION:
Organ transplant recipients can attribute survival, in part, to the discovery of the
immunosuppressive agents cyclosporin A and FK-506 (tacrolimus). However, these
compounds are toxic at high doses and, consequently, the identification of additional
immunosuppressants which function by mechanisms of actions different from these two
drugs remains an ongoing concern. To that end, the Fujisawa Company screened a
number of microbial culture broths for the inhibition of 12-O-tetradecanoylphorbol 13acetate stimulated T-cell proliferation in the presence of exogenous IL-2, conditions
which suppress the antiproliferative activity of tacrolimus. An attractive compound,
FR901483 (1), was isolated from the fermentation broth of Cladobotrym sp. No. 11231
that was retrieved from litter collected at Iwaki, Japan.
II
Synopsis
Experimental results suggest that FR901483 is likely to operate through an
antimetabolite effect on immunocompetent cells by interfering with the enzymes
adenylosuccinate synthetase and/or adenylosuccinase. Further information concerning the
biological activity of this compound has not been forthcoming. However, one can
speculate that the activity may result from FR901483 serving as a competitive inhibitor
for inositol monophosphate (IMP) or an analogue of IMP. It was further demonstrated
that FR901483 significantly prolongs graft survival time in the rat skin allograft model,
and moreover, evidence was obtained which is suggestive of a different mechanism of
action, namely, inhibition of purine nucleotide biosynthesis. The promising biological
activity and structural novelty have elicited substantial interest in 1 at synthetic chemical
level.
MeHN
OP(O)(OH)2
A
N
C
B
MeO
OH
FR901483 (1)
Retrosynthetically, FR901483 (1) can be disconnected into two subunits
azabicyclic amine 3 and -bromo ester 6. We envisioned that the azabicyclic amine 3
could be accessed via ‘Robinson annulation’ type reaction of the functionalized
pyrrolidine carboxaldehyde 4, which in turn would be synthesized from commercially
available trans-4-hydroxy-L-proline 5. The other subunit -bromo ester 6 would be
synthesized from the Wittig product of anisaldehyde 8, after the Sharpless asymmetric
dihydroxylation and regioselective deoxygenation. The retrosynthetic analysis is
represented in scheme 1.
III
Synopsis
Me
HN
A
N
FR901483 1
MeO
2
C
O
B
OH
Me
TsN
MeO
O
O
N
H
Br
CO2Me
+
6
3
Me
O
TsN
OMe
N
Boc
MeO
CHO
4
HO
OH
7
CHO
N
H
COOH
MeO
8
5
trans-4-hydroxy-L-proline
Scheme 1
Our first goal was to devise an efficient route to azabicyclic amine 3. Accordingly
initial modification of trans-4-hydroxy-L-proline 5 was done by sequential esterification
and protection of amine as its tert-butylcarbamate to give 9 in 95% yield. The next step
of the synthesis was the transformation of the hydroxyl group in 9 to the corresponding
azide 10. For this purpose, a two-step sequence was used. The mesylation of the hydroxy
function of 9, followed by azidation furnished the azido compound 10 in 90% yield
(scheme 2).
IV
HO
Synopsis
HO
COOH
N
H
Boc2O, iPr2EtN,THF
95%
6
COOMe
N
N3
a. MsCl, DIPEA
CH2Cl2, 95%
CH3COCl, MeOH, reflux
Boc
COOMe
N
b. NaN3, DMF, 90%
9
Boc
10
Scheme 2
The obtained azide 10 was subjected to ‘Staudinger reaction’ using TPP in
THF/H2O at room temperature to afford the corresponding amine 11 in 86% yield. The
tosylation of amine with TsCl, DIPEA followed by methylation using CH3I, K2CO3
furnished the tosyl protected methylamino compound 13 in 88% yield. The construction
of the pyrrolidine carboxaldehyde 4 was now investigated from 13. After reduction of the
carboxylic ester in 13 with LiAlH4 in diehyl ether, the resulting primary alcohol 14 was
oxidized to the requisite aldehyde 4 utilizing CrO3 in quantitative yield (scheme 3).
N3
H2 N
TsHN
Ph3P, THF,H2O
N
Boc
COOMe
TsCl, DIPEA
r.t. 86%
COOMe
N
Boc
10
N
COOMe
-10
82%
12
Me
TsN
CrO3, pyridine
LiAlH4, ether
oC,
COOMe
Boc
Me
TsN
K2CO3, MeI
N
11
Me
TsN
Acetone, r.t. 88%
CH2Cl2, r.t. 90 %
Acetone, r.t. 90%
N
N
CHO
Boc
4
OH
Boc
Boc
13
14
Scheme 3
The azaspiro-ring system could be assembled by Michael addition followed by
aldol condensation. Accordingly, the conjugate addition of pyrrolidine carboxaldehyde 4
to methyl vinyl ketone in the presence of K2CO3, and catalytic amount of tetra-n-butyl
ammonium bromide provided 15 as a diastereometic mixture which was subjected to the
intramolecular aldol condensation induced under the alkaline condition using catalytic
amount of alcoholic KOH yielded enone 16 in 78% yield along with small amount of
hydroxy ketone 16a. Mesylation of 16a with methanesulfonyl chloride, TEA followed by
column chromatography on silica gel, gave enone 16 after elimination (scheme 4).
V
Me
TsN
Synopsis
O
N
CHO
Boc
4
Me
TsN
N
K2CO3, nBu4NBr
Toluene, r.t. to-10 oC 48%
Me
TsN
O
15
KOH, Et2O, r.t. 78%
O
+
N
OH
16a
CHO
Boc
Me
TsN
N
H
O
Boc
16
MsCl, TEA
Scheme 4
The resulting enone 16 was subjected to catalytic hydrogenation using 20%
Pd(OH)2/C in benzene to afford the ketone 17 in 96% yield. Subsequent ketalization of
17 with ethylene glycol under acid catalyzed process by the azeotropic removal of water
provided the compound 18 in 85% yield. In the final transformation, deprotection of the
N-Boc group of 18 was accomplished by treatment with TFA:CH2Cl2(1:1) leading to free
amine 3 (scheme 5).
Me
TsN
Me
TsN
O
Benzene, r.t. 96%
N
Boc
Pd(OH)2, H2
16
(CH2OH)2, pTSA
Benzene, r.t. 85%
N
17
Boc
Me
TsN
Me
TsN
O
O
N
Boc
O
O
TFA:CH2Cl2
r.t. 70%
18
O
N
H
3
Scheme 5
At this juncture, we were positioned to synthesize -bromo ester 6 that
commenced with the preparation of methyl cinnamate 19, which was easily obtained as a
VI
Synopsis
single isomer in 95% yield via Wittig reaction of aldehyde 8 with a stabilized Wittig
reagent (MeO2CCH=PPh3). Next, Sharpless asymmetric dihydroxylation using AD-mix-
 was explored to incorporate the vicinal dihydroxy group followed by selective
hydrogenolytic removal of the benzylic hydroxy group furnished the -hydroxy ester 7 in
82% yield. The hydroxy functional group of compound 7 was converted to bromo ester 6
in two steps. Accordingly, 7 was treated with MsCl and DIPEA to furnish mesylate.
Displacement of mesylate with LiBr proceeded with complete inversion to provide the
desired compound 6 in 90% yield (scheme 6).
O
CHO
OMe
Ph3P=CHCO2Me
Benzene, r.t. 95%
MeO
MeO
AD-mix-
tBuOH-H
19
2O,
0 oC, 86%
8
OH
O
O
OH
MeO
OMe
Pd(OH)2, H2
OMe
MeOH, Methanolic-HCl(cat)
r.t. 82%
20
OH
MeO
7
O
MsCl, DIPEA, DCM
LiBr, acetone
reflux, 90%
OMe
Br
MeO
6
Scheme 6
Now the two fully functionalized fragments, azabicyclic amine 3 and -bromo
ester 6 are ready to couple to get the tricyclic core of the target molecule 1 via 21 which
is being pursued in our research group (scheme 7).
Me
TsN
Me
TsN
O
O
N
H
O
DIPEA, DCM, 6
r.t.
N
MeO
3
O
CO2Me
21
Scheme 7
1
VII
Synopsis
Chapter II: Chapter II describes the stereoselective synthesis of the C1-C20 segment of
Microsclerodermin A&B.
Studies of sponges of the order Lithistida have provided many bioactive
metabolites, most of which are peptides that contain unusual amino acids. Detailed
studies of the metabolites of different populations of lithistid sponges are valuable in both
the structure activity and chemotaxonomic arenas. The microsclerodermins are a growing
family of cyclic peptides. Faulkner et al., reported the isolation and structural elucidation
of two new cyclic peptides microsclerodermin A and B from a deep-water sponge and
commented on the nature of the symbiotic filamentous bacterium associated with the
sponge. The crude aqueous extract showed antifungal activity against Botrytis cinerea,
Candida albicans, Fusarium oxysporum, Helminthosporium sativum, and Pyricularia
oryzae.
The basic structural motif of the microsclerodermins consists of a 23-membered
ring constructed from six amino acid residues three of which namely glycine, N-methyl
glycine and (3R)-4-amino-3-hydroxybutyric acid (GABOB), are common to all members
of the family. The variable units are a modifieded tryptophan residue, an unusual 3aminopyrrolidone-4-acetic acid
moiety and
various ω-aromatic
3-amino-2,4,5-
trihydroxyacids.
As a continuation of our studies on the synthesis of structurally novel and
challenging natural products, we have attempted the total synthesis of these unique cyclic
peptides. This chapter describes an efficient synthesis of the C1-C20 fragment of this
potent natural product.
37
H
N
O
30
COOH
32
H
N
N
28
O
O
NH
26
H
N
R
O HN
40
O
42
OH N
H
OH O
21
O
22
R=OH: Microsclerodermin A
R=H: Microsclerodermin B
47
N
H
1
20
OH
OH
3
OMe
18
11
5
HO
14
19
VIII
Synopsis
Our retrosynthetic analysis envisioned the late installment of the four
contiguous stereocenters of 23 through the application of an iterative asymmetric
dihydroxylation on diene ester 26. This inturn could be obtained by deoxygenative
rearrangrment of alkynol 27 which was further synthesized from commercially available
S-(-)-citronellol 28 (scheme 8).
37
H
N
O
30
COOH
40
N
28
O
R=OH: Microsclerodermin A
R=H: Microsclerodermin B
R
O HN
H
N
32
47
O
NH
26
H
N
42
OH
N
H
21
O
O
OH N
H
O
22
1
OH
OH
20
OMe
18
3
11
5
HO
14
19
OMOM
O
O
O
OH
O
O
O
NHBoc
HO
23
MeO
NHBoc
24
+ PPh3 Cl
+
MeO
25
OH
OH
BnO
OEt
BnO
27
CO2 Et
26
O
28
(S)-(-)- Citronellol
Scheme 8
We initially investigated the synthesis of diene ester 26 from S-citronellol 28. The
S-(-)-citronellol 28 was protected as its tetrahydropyranyl ether 29. The compound 29
was subjected to ozonolysis to furnish aldehyde, which was elaborated to unsaturated
ester 30 by Wittig olefination (scheme 9).
IX
OH
Dihydropyran
p-TSA (5 mol%)
OTHP
Synopsis
O3, -78oC,
CH2Cl2, 30 min
Ph3P=CHCO2Me
benzene, r.t. 84%
CH2Cl2, r.t. 2h, 98%
28
MeO2 C
OTHP
30
29
Scheme 9
The stepwise reduction of 30 with Mg-MeOH caused the selective reduction of
olefin to give saturated ester 31 followed by ester reduction to primary alcohol 32 was
achieved using LiAlH4. The primary alcohol group in 32 was protected as its benzyl ether
33 by treatment with NaH and benzyl bromide in 90% yield. The selective release of one
of the primary alcohols was achieved by using p-TSA in MeOH to realize 34 (scheme
10). This allowed us to extend the right side of the fragment.
MeO2 C
30
LiAlH4, THF
0
oC-r.t.
OTHP
Mg/MeOH
r.t. 12h, 86%
MeO2 C
HO
96%
32
BnO
33
OTHP
p-TSA (5 mol%)
MeOH, r.t. 2h, 93%
OTHP
OTHP
31
NaH, BnBr
THF, 0 oC- r.t. 90%
BnO
34
OH
Scheme 10
The oxidation of 34 using IBX furnished the aldehyde 35, which was immediately
exposed to lithiated ethylpropiolate to realize the formation of hydroxy alkynoate 27 as a
diastereomeric mixture, which was unseparated. The critical diene ester intermediate 26
has been obtained from hydroxy alkynoate 27 by triphenylphosphine mediated
deoxygenative rearrangement via allene. This rearrangement allowed us to obtain the
diene ester ready for the incorporation of stereoselective hydroxy groups via iterative
Sharpless asymmetric dihydroxylation (scheme 11).
X
Synopsis
H
IBX
BnO
34
BnO
OH
O
DMSO-THF, r.t. 95%
35
LiHMDS, -78 oC
CO2 Et
THF, 86%
BnO
26
CO2 Et
OH
Ph3P
BnO
benzene, r.t. 90%
27
CO2 Et
Scheme 11
At a first glance Sharpless asymmetric dihydroxylation followed by Sharpless
asymmetric aminohydroxylation reaction seemed to be an apparent option to establish the
required four stereogenic centers at C2-3, C4-5 in 23. The enantio and regioselective
Sharpless asymmetric dihydroxylation of diene ester 26 with AD mix- in tBuOH:H2O
(1:1) provided the diol 36 which was masked as its acetonide 37 using 2,2-dimethoxy
propane and catalytic camphorsulfonic acid (CSA) in 85% yield (for two steps) with 96%
de. The major isomer was separated by column chromatography (scheme 12).
OH
BnO
26
CO2 Et
AD mix-
HO
CO2 Et
BnO
tBuOH-H
o
2O, 0 C,
MeSO2NH2, 24 h
36
O
O
2,2 DMP, CSA (5 mol%),
DCM, r.t. 2 h, 85%
CO2 Et
BnO
37
Scheme 12
The regioselective incorporation of cis-aminohydroxyl group was planned in
next step by Sharpless asymmetric aminohydroxylation. However this method was
unsuccessful. Thus we envisaged that, this issue could be well addressed by another
asymmetric dihydroxylation-double inversion (at C-3) sequence. Thus we changed the
strategy to a second Sharpless asymmetric dihydroxylation on 37, with a
diastereomerically matched chiral reagent AD mix- in tBuOH-H2O at 0 oC to afford the
XI
Synopsis
diol 38 in 87% yield with excellent diastereoselectivity (10:1) (scheme 13). Efforts to
introduce the amine functionality at C-3 always ended up with the elimination product.
O
OH
O
O
CO2 Et
BnO
AD mix-
tBuOH-H
2O, 0
24 h, 87%
37
O
CO2 Et
oC,
BnO
OH
38
Scheme 13
To avoid the competitive elimination reaction, the dihydroxy ester 38 was
reduced to triol 39 with LiAlH4 in THF. Then, the triol 39 was subjected to regioselective
1,2-acetonide protection using 2,2-DMP in DCM under acid catalyst p-TSA to give 40 in
85% yield. Treatment of the diacetonide 40 with Tf2O in the presence of pyridine gave
triflate 41. The sequential displacement of the triflate 41 by bromide ion (Bu4NBr)
followed by azide ion (NaN3) provided the nitrogen function with retention of
configuration at C-3. The required five contiguous asymmetric centers at C2-C6 for the
key building block 23 are now been established by the synthesis of azido compound 43
(scheme 14).
O
O
CO2 Et
BnO
OH
LiAlH4, THF
BnO
DCM, r.t. 1 h, 85%
39
OH
-10 oC, 15 min
40
O
O
nBu
OTf
BnO
O
O
O
O
O
NaN3, DMF,
BnO
Br
42
65 oC, 4 h, 82%
N3
BnO
Scheme 14
43
4NBr,
DCM
r.t. 8 h, 86%
41
O
O
O
O
O
O
Tf2O, Py, CH2Cl2
2,2-DMP, p-TSA (cat)
OH
O
O
OH
BnO
0 oC-r.t. 2 h, 80%
38
O
OH
O
OH
O
XII
Synopsis
At this point a one-pot deprotection-reduction-protection strategy was
utilized. The azide 43 was subjected to Pd(OH)2/C catalyzed hydrogenation in presence
of (Boc)2O effected the benzyl ether deprotection, azide reduction and Boc-protection of
the resulting amine to afford the compound 24 in 92% overall yield.The alcohol 24 was
oxidized with IBX to furnish the desired aldehyde, which was subjected to Wittig
olefination with (4-methoxy-phenylmethylene) triphenylphosphorane in THF was used to
provide 44 as a mixture of E/Z isomers in a ratio of 3:2 in 70% yield. Treatment of the
mixture of E/Z isomers with catalytic amount of Pd(CH3CN)2Cl2 in 0.5 M DCM at room
temperature caused the isomerization of the double bond and afforded the isomerically
pure E-isomer 45 in 92% yield (scheme 15).
O
O
O
O
O
Pd(OH)2/C, H2
N3
BnO
O
a. IBX, THF:DMSO
(Boc)2O, MeOH HO
r.t. 5 h, 92%
43
O
O
NHBoc
24
27
b. BuLi, THF, r.t., 70%
O
O
O
O
O
O
O
O
NHBoc
44
NHBoc
Pd(CH3CN)2Cl2, DCM
r.t. 12 h, 92%
MeO
45
MeO
Scheme 15
The terminal acetonide in 45 was selectively deprotected under mildly acidic
conditions (PPTS in MeOH) to give the diol 46. The two liberated hydroxyl groups were
protected selectively. The TBS group was introduced regioselectively at the primary
hydroxyl group to yield 47. The introduction of methoxy methyl protection at the
remaining free hydroxyl group was achieved by the reaction of 47 with MOMCl and
diisopropylethylamine in DCM to obtain 48 in 90% yield. The conditions for the
regioselective removal of protecting group from 48 were investigated next. It was
possible to remove the TBS protecting group utilizing TBAF in THF to provide the key
fragment 23, which could be oxidized at a later stage (scheme 16). All these
transformations completed the stereoselective synthesis of C1-C20 segment of
microsclerodermins A and B.
XIII
Synopsis
NHBoc
OH
O
O
O
OH
O
O
O
PPTS, MeOH, 75%
NHBoc
46
45 oC
45
MeO
MeO
O
OH
OTBS
O
NHBoc
TBSCl, imidazole
O
O
DCM, 1 h, 90%
47
DMAP (3 mol%),
MeO
DCM, r.t. 12 h, 85%
MOMCl, DIPEA,
O
OMOM
OTBS
O
TBAF, THF
NHBoc
NHBoc
r.t. 1 h, 70%
48
23
MeO
MeO
Scheme 16
OMOM
OH
C1-C20 segment
XIV
Synopsis
Chapter III: Introduction to alternative solvents
Solvents are widely used in commercial manufacturing and service industries.
Despite abundant precaution, they have inevitably contaminated our air, land and water
because they are difficult to contain and recycle. Researchers have therefore focused on
reducing solvent use through the development “solvent alternatives” like, supercritical
fluids, ionic liquids or fluorous phases. However, these approaches have their limitations.
Environmental advantage alone probably will not enable alternative solvents to achieve
widespread applicability. The pollution prevention technologies must include not only
environmental or “green” advantages, but also advantages related to performance, health
and cost. To addresses some of these issues, we initiated a new program to identify any
liquid polymer or low melting polymer can be used as reusable reaction medium and we
have found that poly (ethylene glycol) (PEG) is an efficient reusable reaction medium for
organic reactions.
Poly (ethylene glycol) (PEG) was used as solvent medium for very few reactions in
the literature, but not extensively studied. The complete toxicological profiles are
available for a range of PEG molecular weights. Their low-toxicity, low volatility, and
biodegradability represent important environmentally benign characteristics, which are
particularly attractive when combined with their relatively low cost as a bulk commodity
chemical. This material is widely used in food and beverages and medical purposes,
which is a testament to its benign character. In addition, aqueous PEG solutions may
often substitute for expensive and often toxic PTCs. The developed state of knowledge
with regard to the toxicological properties of PEG is of considerable current advantage
compared to the paucity of knowledge for many other potential alternative solvent
systems.
Considering all these attractive “green” advantages, we explored the PEG as a
potential alternative solvent medium and here we described the Heck reaction and
dihydroxylation reactions.
XV
Synopsis
Section A: Section A deals with a poly(ethylene glycol) (PEG) as reusable solvent for
the Heck reaction.
Palladium catalyzed arylation and vinylation of olefins called as the Heck
reaction. Heck reaction is normally carried out in the presence of phosphine ligand and
base under inert atmosphere. However, the relatively high price of the palladium complex
has greatly limited the industrial application of the Heck reaction, and some of the
phosphine ligands are sensitive to air and moisture.
In view of the economy of the reaction, the recovery as well as recycling of the
expensive palladium catalyst is required. In addition, phosphine-freed reaction conditions
are highly desired due to the environmental effects associated with phosphine.
Here, we
report poly(ethylene glycol) (PEG) is an efficient reusable reaction medium for the Heck
reaction (scheme 17). We have noticed the following advantages.
The Heck reaction proceeded without phosphine ligands, which are expensive,
toxic, and contaminates the products. The stereo and regioselectivities are also different
from those with conventional solvents and ionic liquids. The reaction works very well for
electron-deficient and electron-rich olefins, with equal ease and with high regio and
stereoselectivities. One major advantage of the present protocol is that the catalyst is
easily reusable up to five runs without loss activity even after fifth run we could obtain
product in 70% yield. Benign character of PEG as well as easy operation makes the
present Heck reaction attractive.
Br
R
+
X
X = Ph, COOEt
R = Cl, OMe
OBu
methylenedioxy
Pd(OAc)2 (3 mol%)
Triethylamine
PEG(2000), 80 oC
Scheme 17
X
R
+
R
Time = 8-16 h
Yields = 82-95%
X
XVI
Synopsis
Table 1. Pd catalysed Heck reaction of and electron deficient and electron rich olefins in PEG
Ethyacrylate
time, %yield
Substrate
S. No
Styrene
time, %yield
nButylvinyl
ether
time, %yield (E:Z)
O
Br
OBu
OEt
1
+
10 h, 93%
8 h, 90%
O
OBu
Br
+
OEt
2
MeO
MeO
MeO
3
O
O
OBu
O
OEt
OBu
O
+
O
O
O
MeO
16 h, 82%, 70:30
12 h, 85%
O
Br
70:30
MeO
12 h, 91%
O
OBu
12 h, 88%, 80:20
O
OBu
O
12 h, 95%
15 h, 80%, 75:25
13 h, 89%
O
Br
OBu
OEt
4
+
Cl
Cl
8 h, 90%
9 h, 89%
O
5
Br
OBu
14 h, 90%, 100:00
OBu
OEt
10 h, 89%
Cl
Cl
Cl
+
12 h, 90%
OBu
15 h, 87%, 75:25
Section B: This section describes poly(ethylene glycol) (PEG) as rapid and reusable
solvent for OsO4 catalyzed dihydroxylation reactions.
Undoubtedly, the dihydroxylation of olefins using catalytic amounts of OsO4 is
the most sought after method for the preparation of vicinal diols. The importance of this
reaction has been enhanced substantially through the use of cinchona alkaloids, which
result in chiral vicinal diols as reported by Sharpless et al. Even though the products of
dihydroxylation have a prominent role in pharmaceuticals and fine chemicals, the cost of
osmium and chiral ligands as well as the high toxicity and volatility of the osmium
component has restricted its use in industry. To addresses this issue several groups
investigated this reaction in reusable solvents. We intended to apply our procedure to Oscatalysis (scheme 18) to attempt all the above-mentioned issues and found very
interesting observations.
XVII
Synopsis
OsO4 in PEG not only as a recoverable and reusable system for dihydroxylation
but also as a medium where reaction is rapid (2h) and high yielding at very low
concentrations (0.5 mol%) of OsO4. All the reported protocols require 1–5 mol% catalyst
and 12–48 hours time for completion for a similar result. Reusability of the solvent and
the catalyst have been achieved up to five runs without loss of activity even after fifth run
we could isolate diol in 90% yield.
OsO4, 0.5 mol%
NMO.H2O, (1.3 eq.)
R'
R
OH
R = alkyl, aryl
R' =H, alkyl, aryl
R'
R
PEG (400), r.t
OH
2-3 h
Yields = 88-97%
Scheme 18
Encouraged by these results, then we attempted the asymmetric dihydroxylation
of olefins according to the Sharpless procedure and we have observed very interesting
results (scheme 19). Conventionally, this reaction required longer reaction times (up to 24
h) and addition of 1 equivalent of methanesulfonamide is required for dihydroxylation of
internal olefin. In our method the reaction is quite rapid (2 h) and no additional reagent
like metanesulfonamide is required.
R
R'
R = alkyl, aryl
R' =H, alkyl, aryl
OsO4, 0.5 mol%
(DHQD)2 PHAL, 2mol%
NMO.H2O, (1.3 eq.)
PEG (400), r.t
2-3 h
OH
R
R'
OH
Yields = 88-97%
ee = 44-96%
Scheme 19
Reusability: To check the reusability of OsO4 and possibly ligand as well as
trans-stilbene was subjected to asymmetric dihydroxylation (table 3). After 2 h, the
product was separated by ether extraction and fresh trans-stilbene was added. To our
great surprise, in the second run diol was obtained with more than 80% ee. Further
addition of 0.5-mol% ligand helped us to obtain diol with more than 90% ee (Table 2).
XVIII
Synopsis
Table 2: Reusability of OsO4 and (DHQD)2PHAL in PEG
Run
ee (%)a
94
92(81)a
95(83)a
92(80)a
90(65)a
95
91
92
92
91
2
2
2
2
2
1
2
3
4
5
aee's
Yield (%)
Time(h)
in paranthesis obtained without adding an additional ligand
Table 3. Dihydroxylation of olefins using OsO 4 in PEG
S. No
Olefin
Proudct
Time/Yield(%)a
OH
OH
2h, 94
1
OH
OH
2h, 97
2
OH
2h, 95
3
OH
OH
4
3h, 90
OH
O
5
OEt
2h, 93
OEt
2h, 95
OEt
OH
OH O
O
6
O
OH
OEt
OH
MeO
MeO
OH
7
3h, 92
OH
8
OH
3h, 89
OH
9
OH
2h, 95
9
9
NBoc
10
OEt
O
NBoc OH
3h, 92b
OEt
O
O
O
11
BnO
OH
O
3h, 88c
OH
HO
O
bde
O
O
O
BnO
aYields
OH
based on isolation of chromatographically homogeneous products
55% (by NMR). c de 91% (by NMR)
O
XIX
Synopsis
Table 4. Asymmetric dihydroxylation using (DHQD) 2 PHAL, OsO4 and NMO.H2O in PEG
S. No
Time/Yield/ee (%)a
Product
Olefin
OH
2h, 95%, 94% ee
1
OH
OEt
OEt
2
OH
O
OEt
OEt
3
4
n
n
n=9
2h, 94%, 96% ee
OH
MeO
MeO
2h, 92%, 91% ee
OH
O
aThe
O
OH
O
n=9
OH
OH
products ee was determined by chiral GC analysis (Cyclosil-B)
2h, 96%, 44% ee