Download Microsoft Word

Synopsis
SYNOPSIS
The thesis entitled “Utilization of the nucleophilic potential of the sulfinyl group for the
stereoselective synthesis of (+)–zoapatanol, stereotriads from cyclopropylcarbinols and
enantioselective synthesis of tamiflu” consists of three chapters.
Chapter-I
Total Synthesis of (+)-(2’S,3’R)-Zoapatanol
In this chapter a brief account of the applications of sulfoxides in asymmetric synthesis,
an account of the work carried out by various research groups toward the synthesis of (+)zoapatanol and an elaborate account of the present work is described.
Zoapatanol 1 is among the many diterpenoid oxepanes isolated from the leaves of the
plant Montanoa tomentosa. Investigators have suggested a potential use of zoapatanol and its
bicyclic analogs as anti–fertility agents. Due to its biological activity and novel structure several
groups have disclosed the total synthesis of racemic and natural zoapatanol. The issues to be
addressed in an efficient synthesis of zoapatanol include, a) the stereocontrolled preparation of
the oxepane ring, b) the geometrical isomerism of the allylic system and c) the relative and
absolute stereochemistry of the two stereogenic centers on the ring.
Figure 1
OR'
HO
R
3'
2'
O
O
1
2
3
4
R = (CH3)2C=CHCH2-, R' = H Zoapatanol
R = (CH3)2CHC(CH3)=CH-, R' = H Montanol
R = H2C=C(CH3)CH(CH3)CH2-, R' = H Tomentanol
R = (CH3)2C(OH)CH=CH-, R' = Ac Tomentol
By retrosynthetic analysis (Scheme 1) 1 was envisioned to be derived from retron 5 by
oxidation of the primary hydroxyl to an acid followed by prenyllithium addition. The oxepane 5
was envisaged to be obtained by a Williamson-type ether synthesis from 6. Compound 6 was
envisioned to be obtained by a B-alkyl Suzuki reaction of the organoborane derived from
terminal alkene 7 with the iodoalkene 8. The triol derivative 7 was envisaged to be obtained from
-hydroxy sulfoxide 9. The iodo compound 8 can be obtained from propargylic alcohol 10.
1
Synopsis
Scheme 1
HO
P'O
OH
PO
O
O
OP'
O
5
1
PO
OP
P'O
PO
OP
OP'
OP'
OH
6
I
OP'
8
7
X
P, P' =Protecting group
X = Leaving group
O
S
Tol
OPMB
OH
HO
10
OP
9
The synthesis commenced with the reaction of 9-BBN dimer with PMB ether 14 to
afford the trialkylborane that was subjected to Suzuki-cross coupling with (Z)-vinyl triflate 17 in
the presence of Pd(PPh3)4 and K3PO4 to furnish the α,β-unsaturated ester 15. The compound 14
obtained from propionic acid 11 in three steps and (Z)-vinyl triflate 17 was obtained from ethyl
acetoacetate 16 following procedures reported in the literature.
Scheme 2
LAH, THF, 0 oC-rt
NaH, DIPA, nBuLi, THF
COOH
11
COOH
Allylbromide, 0 0C-rt, 4 h, 93%
12
13
O
9-BBN-H, THF, 0 oC
NaH, PMB-Br, TBAI, THF
OH
12 h, 91%
OEt
OPMB
OPMB
o
0 C-rt, 92%
14
O
O
17, K3PO4, Pd(PPh3)4,
1.4-Dioxane, 85 oC, 8h, 74%
15
NaH, DCM, Tf2O
OEt
0 oC-rt, 2h, 89%
16
TfO
OEt
O
17
The addition of lithium anion of (R)-methyl p-tolyl sulfoxide to unsaturated ester 15 in
THF at 0 oC afforded -keto sulfoxide 18. Diastereoselective reduction of the keto carbonyl in 18
using DIBAL-H in THF exploiting the sulfinyl group as an intramolecular chiral auxiliary
yielded the -hydroxy sulfoxide 9 (dr >95:<5), which on treatment with freshly recrystallized Nbromosuccinimide (NBS) afforded bromohydrin 19 as a single isomer regio- and
stereoselectively. To transform bromohydrin 19 to alkene 7 it was required to replace the
2
Synopsis
bromine by hydroxy group with inversion of configuration. This called for the chemoselective
participation of the secondary hydroxyl group in epoxide formation which on treatment with NaHg would suffer reductive elimination to yield alkene 7 (P = P1 = H). In the event, treatment of
bromohydrin 19 with K2CO3 in methanol or acetonitrile yielded epoxide 21 via participation of
the tertiary hydroxy group and none of the expected epoxide 20 via participation of the
secondary hydroxy group. Further, attempts to protect both the hydroxy groups and subsequently
deprotect to reveal the secondary hydroxy group did not meet with success. Therefore the hydroxy sulfoxide 9 was protected as its TBS ether 22 Scheme 4.
Scheme 3
O
OEt
OPMB Tol
Tol
Me
Tol
LDA, THF,
-40-0 oC, 55%
15
O
S
O
S
O
S
O
DIBAL-H, THF
OPMB
18
NBS, H2O, Toluene
OH
OPMB
Tol
rt, 2 h, 76%
X
Tol
OH
K2CO3, MeOH
rt, 2 h, (or)
K2CO3, AcCN
rt, 12 h
PMBO
O
Tol
OH
OH
PMBO
OH
OP
20
O
S
O
S
Br
19
9
O
S
1 h, -78 oC, 81%
PMBO
7
OH
O
21
PMBO
Treatment of silyl ether 22 with freshly recrystallized N-bromosuccinimide (NBS) in
toluene at ambient temperature in the presence of water afforded bromohydrin 23 as a single
regio- and stereoisomer. The tertiary hydroxy group in bromohydrin 23 was protected as an
acetal 24 by treatment with ethyl vinyl ether in the presence of cat CSA in CH2Cl2. Treatment of
24 with TBAF afforded 1,2–diol derivative 26 via three transformations in one pot including
silyl deprotection followed by epoxide formation under basic conditions and further –
elimination.
3
Synopsis
Scheme 4
Tol
O
S
OH
TBS-Cl, Imidazole
OPMB
Tol
DCM, 1 h, rt, 93%
O
S
OPMB
rt, 2 h, 76%
22
9
Tol
O
S
NBS, H2O, Toluene
OTBS
OTBSOH
Cat CSA,
Br
O
Tol
O
S
OTBSOEE
0 oC, 1 h, 88%
PMBO
PMBO
Br
24
23
O
TBAF, THF
rt, 30 min, 86%
Tol
PMBO
O
S
Tol
OEE
H
O
S
OEE
OH
PMBO
26
25
Oxidation of vinyl sulfoxide 26 using mCPBA in CH2Cl2 afforded the sulfone 27 that on
treatment with Mg-Hg in methanol afforded terminal alkene 28. Protection of hydroxy group as
its acetate yielded compound 7, Scheme 5.
Scheme 5
Tol
O
S
O
S
Tol
O
OEE
mCPBA, DCM
OH
PMBO
0 oC-rt, 30 min, 92%
OEE
OH
Mg, HgCl2, MeOH
PMBO
0 oC-rt, 4 h, 76%
27
26
OEE
OEE
Ac2O, Et3N, cat DMAP, DCM
OH
28
PMBO
0 oC-rt, 1 h, 94%
OAc
7
PMBO
The iodo alkene 8 was prepared as detailed here under. Monoprotection of the
commercially available diol 10 as its silyl ether using sodium hydride and TBS-Cl in THF
afforded 29. Propargylic alcohol on treatment with Red-Al in THF followed by quenching the
intermediate with iodine in THF afforded iodo compound 30 that on acetylation furnished iodo
alkene 8.
4
Synopsis
Scheme 6
HO
TBS-Cl, NaH, THF
OH
10
TBSO
0 C-rt, 14 h, 72%
H
I
Red-Al, THF, I2
HO
o
Ac2O, Et3N, Cat DMAP, DCM
OH
29
OTBS
TBSO
H
I
0 oC-rt, 1 h, 97%
30
-78 oC, 2 h, 78%
OAc
8
Hydroboration of alkene 7 with 9-BBN dimer in THF afforded organoborane
intermediate 31 that was coupled with iodo compound 8 using Suzuki reaction in the presence of
K3PO4 and Pd(PPh3)4 in 1,4-dioxane to furnish trisubstituted alkene 32 with concomitant
deprotection of acetal group under reaction conditions (Scheme 7). The primary TBS ether in 32
was selectively deprotected using catalytic amount of PPTS in methanol to furnish the diol 6.
With the diol 6 becoming available the stage was set to attempt the crucial Williamson-type ether
reaction. Thus treatment of 6 with triflic anhydride in the presence 2,6-lutidine in CH2Cl2
afforded the oxepane 5 cleanly (Scheme 7). The 4-methoxybenzyl group of compound 5 was
deprotected with the use of DDQ in aq dichloromethane to afford the alcohol 33.
Scheme 7
OEE
OEE
9-BBN, THF
OAc
PMBO
TBSO
H
NBB
OAc
3 h, 0 oC
7
I
PMBO
OAc
8
31
OAc
OAc
K3PO4, Pd(PPh3)4, 1,4-dioxane
OH
8 h, 85 oC, 66%
rt, 30 min, 86%
OTBS
OAc
OH
cat PPTS, MeOH
PMBO
OH
OAc
6
32
AcO
PMBO
AcO
OAc
Tf2O, 2,6-Lutidine
OAc
DDQ, DCM:H2O (19:1)
O
DCM, -78 oC, 6 h, 68%
OPMB
0 oC,30 min, 91%
5
O
OH
33
Oxidation of the alcohol 33 using TEMPO in the presence of PhI(OAc)2 in aq acetonitrile
afforded the acid 34. Following the precedent of Chen, reaction of prenyl lithium with acid 34 in
a mixture of THF and ether afforded (+)-zoapatanol in only 40% yield. In an attempt to improve
the yield the acid was converted to Weinreb amide 35 by treatment with MeNHOMe.HCl,
iPr2NEt and EDCI in CH2Cl2. Reaction of prenyl lithium with Weinreb amide 35 in a mixture of
5
Synopsis
THF and diethyl ether (1:1) at -78 oC furnished the (+)-zoapatanol by concomitant deprotection
of both acetyl groups in 72% yield. The yield was much better using Weinreb amide.
Scheme 8
AcO
OAc
AcO
PhI(OAc)2, TEMPO, aq CH3CN
OH
HO
O
rt, 4 h, 93%
O
O
33
AcO
H
MeNOMe.HCl,
EDCI, cat DMAP
iPr2NEt, DCM,
Me
0 oC-rt, 12 h, 82%
OMe
N
O
O
35
34
HO
Li
AcO
OAc
THF:Ether (1:1)
-78-0 oC, 2 h, 72%
OH
O
O
1
In conclusion, a short stereoselective efficient synthesis of zoapatanol (2.8% overall yield in 20
steps) was achieved. The key steps include the stereo– and regioselective functionalization of a
trisubstituted alkene to create a quaternary stereogenic center, a B–alkyl Suzuki coupling
reaction to create trisubstituted alkenes stereoselectively. Another interesting feature of the
synthesis is the one-pot transformation of compound 24 to 26. Also the methodology can be
applied in the synthesis of other oxepane diterpenoids and analogs of zoapatanol.
Chapter-II
Regio-
and
stereoselective
cyclopropylcarbinols
activated
preparation
by
of
mercuric
stereotriads
and
tetrads
from
trifluoroacetate
via
sulfinyl
group
participation.
This chapter deals with the preparation of stereotriads and tetrads consisting of
alternating hydroxyl and methyl groups from cyclopropylcarbinols. Alternating hydroxy and
methyl substituted subunits are a characteristic feature of polypropionate derived natural
products. The importance of these natural products as antibiotics, antifungals, antitumors,
antiparasitics and immunosuppressants together with their structural and stereochemical
complexity has led to the design and development of several unique methodologies to prepare
these structures. A common strategy has been the disconnection of the polypropionate chain into
smaller subunits containing alternating methyl and hydroxy groups and uniting them by coupling
reactions. In an abiding interest in utilizing the sulfinyl group as an intramolecular nucleophile,
the oxymercuration–demercuration of cyclopropylcarbinols was investigated with the aim of
obtaining products possessing alternating hydroxy and methyl groups as observed in
6
Synopsis
polypropionate derived natural products. This chapter includes the regio- and stereospecific
opening of cyclopropylcarbinols by an intramolecular sulfinyl group promoted by mercuric
trifluoroacetate to furnish stereotriads and stereotetrad, Scheme 9.
Scheme 9
Tol
O
S
OH
1. Hg(OCOCF3)2, HgO, 1.2-DCE
R2
3
R
2. Aq KBr
3. nBu3SnH, cat Et3B, O2, DCM
R1
Tol
O
S
OHHO 2
R
R3
R1
The cyclopropylcarbinols were prepared from the corresponding allylic alcohols using
the Furukawa’s protocol. The trans di- and trisubstituted allylic alcohols were prepared as
depicted in Scheme 10. The -keto sulfoxides 38 a-d were prepared by reaction of the lithium
anion of the (S)-methyl-p-tolylsulfoxide 36 with trans unsaturated esters 37 a-d following the
protocol reported by Solladie and co-workers.
Scheme 10
O
Tol
O
S
36
R1
LDA,THF
EtO
Me
2
R
R
37 a-d
-40 oC-0 oC
Tol
O
S
R1
O
DIBAL-H
R
38 a-d
a: R = R1 = H, R2 = CH2Ph
b: R = R1 = H, R2 = OBn
c: R = Me, R1 = H, R2 = (CH2)4Me
d: R = H, R1 = Me, R2 = OBn
R
2
ZnCl2, THF
Tol
O
S
OH
R
R1
R2
39 a-d
(E)--Hydroxy-,-unsaturated sulfoxides 39 a-d were prepared by diastereoselective
reduction of ketones 38 a-d respectively using DIBAL-H in the presence of ZnCl2 in THF with
(>95:<5) diastereoselectivity, Scheme 10.
The cis disubstituted allylic alcohols were prepared by selective reduction of propargylic
alcohols. The aldehyde 40 upon subjecting to the Corey–Fuchs reaction afforded dibromo
compound 41, that on further treatment with nBuLi in THF and quenching with acetaldehyde
provided an inseparable mixture of propargylic alcohols 42 & 43 in equimolar amounts. The
propargylic alcohols 45 & 46 were prepared as an epimeric mixture in equimolar proportion and
good yield by condensing the lithium anion of the sulfoxide 36 with the aldehyde 44, Scheme 12.
7
Synopsis
Scheme 11
Ph
S
H
O
40
Ph
Ph
Br
S
0 oC, 1h, 95%
S
Ph
42
Tol
CBr4, TPP, DCM
S
43
OH
OH
LDA, THF
+
Me
44
36
-78 oC, 1h, 80%
Br
41
O
O
S
n-BuLi, CH3CHO, THF
( )Me
5
Tol
-40--78 oC, 1h, 86%
O
S
O
S
OH
Tol
46
( )
5
45
OH
( )
5
The inseparable mixture of propargylic alcohols 42 & 43 were subjected to reduction with
nickel boride to afford an equimolar ratio of separable allylic alcohols 47 & 48. In a similar
fashion propargylic alcohols 45 & 46 were also transformed into an equimolar ratio of separable
allylic alcohols 49 & 50.
Scheme 12
Ph
OH
S
Ni(OAc)2.4H2O, NaBH4,
42 & 43
Tol
O
S
Ph
Ethanol, Ethylenediamine
rt, 8h, 85%
OH
Ph
Ni(OAc)2.4H2O, NaBH4,
O
S
Tol
Ethanol, Ethylenediamine
rt, 8h, 89%
( )
5
S
47
OH
45 & 46
OH
S
48
OH
( )
5
Tol
O
S
49
OH
( )
5
50
The epimeric inseparable mixture of sulfoxides 51 & 52 were prepared by subjecting both
the sulfides 47 & 48 to treatment with mCPBA in CH2Cl2 Scheme 13.
Scheme 13
OH
Ph
S
OH
Ph
Ph
O
S
1h, 92%
47
S
mCPBA, CH2Cl2, -40 oC
51
o
mCPBA, CH2Cl2, -40 C
1h, 90%
48
8
OH
Ph
O
S
OH
52
Synopsis
Preparation of cyclopropylcarbinols.
Cyclopropylcarbinols 53-60 were prepared from the corresponding allylic carbinols using
Furukawa’s protocol in yields ranging from 83-92%, Scheme 14.
Scheme 14
O
S
Tol
OH
R1
R2
Tol
DCM, 0 oC - rt
R
39 a-d
O
S
Et2Zn, CH2I2, 1,2-DME
R1
OH
R2
R
53-56
R1, R2 = H, Me
R3 = alkyl, OBn
Isomeric cyclopropylcarbinols were prepared by oxidation followed by diastereoselective
reduction of some cyclopropylcarbinols to study the influence of relative stereochemistry of
sulfoxide and carbinol centre on product formation. Thus cyclopropylcarbinols 53, 55-58 were
converted to cyclopropylketones 61-65 under mild conditions by treatment with Dess-Martin
periodinane (DMP) in CH2Cl2 in good yield, Scheme 15.
Scheme 15
Tol
O
S
OH
R1
R2
R
53, 55, 56
Tol
O
S
OH
DMP, DCM
0 oC - rt, 30 min
Tol
O
S
R2
R
61-63
R1, R2 = H, Me
R3 = alkyl, OBn
DMP, DCM
0 oC - rt, 30 min, 89%
R1
O
Tol
O
S
O
57
Tol
O
S
OH
64
DMP, DCM
0 oC - rt, 30 min, 91%
Tol
O
S
O
65
58
Diastereoselective reduction of ketones 61-63 & 65 using DIBAL–H in THF yielded
cyclopropylcarbinols 66-68 & 70. In a similar manner diastereoselective reduction of 64 using
DIBAL-H in the presence of anhydrous ZnCl2 furnished alcohol 69.
9
Synopsis
Scheme 16
Tol
O
S
R1
O
R2
R
61-63
Tol
O
S
DIBAL-H, THF
Tol
-78 oC, 1 h
O
S
R1
OH
R2
R
66-68
R1, R2 = H, Me
R3 = alkyl, OBn
O
DIBAL-H, ZnCl2, THF
Tol
O
S
OH
-78 oC, 1 h, 90%
69
64
Tol
O
S
O
DIBAL-H, THF
Tol
-78 oC, 1 h, 86%
O
S
OH
65
70
Oxymercuration–Demercuration of Cyclopropylcarbinols
Treatment of cyclopropane 57 with 2 eq of mercuric trifluoroacetate in the presence of 0.5
eq of mercuric oxide, 1.3 eq of water in 1,2-dichloroethane as the solvent in the dark overnight,
afforded organomercurial 71 after treatment with aq potassium bromide. Demercuration of 71
using lithium borohydride yielded 1,3-diol 72 as the sole product.
Scheme 17
XHg
Tol
O
S
OH
Hg(OTFA)2, HgO
57
Tol
O
S
OH
OH
HO
S O
H
H2O, 1,2-DCE, 16 h, rt, 89% 2O
Tol
I
LiBH4, THF, -78 oC
1 h, 85%
HgBr
71
Tol
O
S
OH
5
OH
72
While compound 71 was characterized, the organomercuric bromides resulting from other
cyclopropylcarbinols were not characterized and directly subjected to demercuration using n–
tributyltin hydride in the presence of catalytic amounts of triethylborane in an oxygen
atmosphere. Demercuration using LiBH4 afforded trace amounts of sulfide via sulfoxide
reduction, and this side reaction could be avoided using tributyltin hydride for demercuration.
10
Synopsis
The results are collected in Table 1. An examination of the Table 1 reveals that the
reaction is general in nature and proceeds with equal facility on di– and trisubstituted
cyclopropylcarbinols. The reaction proceeds highly regioselectively and the outcome can be
rationalized by the destabilizing inductive effect of the hydroxy/stabilizing inductive effect of the
methyl groups. The reaction proceeds with clean inversion of configuration at the electrophilic
carbon and sulfur atoms.
Table-1: Mercuric Trifluoroacetate Promoted Sulfinyl Group Opening of
Cyclopropylcarbinols
S. No
1.
O
S
Tol
OH
Tol
O
S
OH
2.
Tol
72
OH
Tol
O
S
OH
3.
Tol
73
OH
Tol
O
S
OH
4.
5.
Tol
Tol
74
OH
Tol
O
S
O
S
OH
6.
Tol
75
70
OH
Ph
Tol
O
S
OH
7.
Tol
OH
78%
Ph
76
OH
Tol
Ph
O
S
66
O
S
OH
75%
53
O
S
OH
82%
69
O
S
OH
84%
58
O
S
OH
85%
57
O
S
Yield
Product
Cyclopropylcarbinol
OH
OH
Ph
73%
77
OH
OBn
Tol
54
O
S
OH
OBn
78
11
OH
76%
Synopsis
8.
O
S
Tol
OH
( )5
O
S
Tol
OH
OH
67
9.
O
S
Tol
70
OH
( )5
O
S
Tol
10.
Tol
OH
OBn
Tol
O
S
56
11.
Tol
O
S
OH
OH
( )5
74%
80
55
O
S
72%
( )5
OH
OH
OBn
76%
81
OH
OBn
Recovery of Starting Material
68
12.
Ph
O
S
OH
Recovery of Starting Material
59
13.
Ph
O
S
OH
Ph
O
S
83%
OH
82
60
BocN
14.
Tol
OH
OH
S
Recovery of Starting Material
Ph
83
BocN
15.
Tol
OH
S
5
Recovery of Starting Material
84
The regio- & stereochemical outcome of the reaction of 57 with Hg(OCOCF3)2 entry 1,
Table 1 can be rationalized by invoking intermediate I, resulting from 6-endo nucleophilic attack
by the sulfinyl moiety on the cyclopropane ring Scheme 17.
As Table 1 indicates, the reaction is general in nature and proceeds with equal facility on
di– and trisubstituted cyclopropylcarbinols. The structure of diol 76, obtained from 53, was
12
Synopsis
proven by X-ray crystallography. The structure of the other products were assigned based on
analogy and further confirmed by 1H NMR–NOE analysis of the acetonides derived from the
diols.
In conclsion, a highly regio– and stereoselective synthesis of diastereomeric stereotriads and
tetrads by oxymercuration–demercuration of cyclopropylcarbinols employing an intramolecular
sulfinyl group as the nucleophile has been disclosed. The reaction proceeds with equal facility on
di– and trisubstituted alkenes to furnish products possessing tertiary and quaternary stereogenic
centres. The reaction can be considered to be complimentary to other routes to
stereotriads/stereotetrads such as the two step epoxidation followed by dimethyl cuprate opening
of allylic alcohols, hydroboration and hydrosilylation reactions.
Chapter-III
Enantioselective Synthesis of Tamiflu
In this chapter a brief account of the synthesis of tamiflu by selected research groups is
described followed by and an elaborate account of the present work. Oseltamivir phosphate
(Tamiflu) 85, is an approved orally effective neuraminidase inhibitor used for the treatment of
human influenza and H5N1 avian flu. Numerous people have fallen victim to human influenza
and H5N1 avian flu and it still continues to be a threat. A ready stock of Tamiflu is desirable to
protect people from a future outbreak. Currently, tamiflu is manufactured from (–)-shikimic acid
or (–)-quinic acid, however the limited availability of raw material, low overall yield and long
synthetic sequences have propelled synthetic chemists worldwide to design alternate routes from
non-natural readily available chemicals. An enantioselective synthesis of tamiflu taking
advantage of the Diels–Alder reaction is described herein.
Figure 2
COOEt
O
AcHN
NH2
85
Oseltamivir
By a retrosynthetic analysis, shown in Scheme 18, tamiflu 85 was envisioned to be
derived from the unsaturated ketone 86 which can be obtained from the aziridine 87 by
13
Synopsis
regioselective opening followed by oxidation. The aziridine 87 was envisaged to be obtained
from the epoxycarbamate 88. The epoxidation was planned to be carried out stereoselectively by
taking advantage of the directing ability of the precursor allylic carbamate. The carbamate itself
was prepared by asymmetric palladium catalyzed reaction of allylic acetate with a nitrogen
nucleophile derived from hydroxyl ester 89 with retention of configuration. The hydroxyl ester
89 can be readily obtained from cyclohexene carboxylic acid 90.
Scheme 18
CO2Et
O
CO2Et
O
CO2Et
CO2Et
AcN
AcHN
O
AcHN
NH2.H3PO4
85
NHBoc
NHBoc
NHBoc
86
87
88
CO2Et
COOH
90
OH
89
To begin with, to standardize reactions racemic substrates were employed.
Commercially available cyclohexene carboxylic acid 90 on iodolactonization by treatment with
sodium bicarbonate, iodine and KI in the presence of water afforded iodolactone 91. Iodolactone
91 was subjected to dehydroiodination using DBU as a base to yield unsaturated lactone 92. Base
promoted opening of unsaturated lactone 92 with K2CO3 in ethanol furnished allylic alcohol 89
that upon treatment with acetic anhydride, triethylamine in presence of CH2Cl2 yielded acetate
93. Allylic substitution of the acetate in ester 93 using Pd2(dba)3, dppb and sodium azide in
mixture of THF:H2O mixture afforded allylic azide 94 with the retention of stereochemistry.
Scheme 19
O
O
OH
I2, NaHCO3, KI, H2O
rt, 6 h, 110 oC, 97%
DBU, Toluene
O
91
90
K2CO3, EtOH
5 h, rt, 90%
20 h, 98%
I
OH
O
O
92
N3
OAc
Ac2O, Et3N, Cat. DMAP, DCM
NaN3, Pd2(dba)3.CHCl3
0 oC - rt, 1 h, 96%
93
CO2Et
dppb, THF:H2O (9:1)
80 oC, 6 h, 78%
14
CO2Et
89
CO2Et
94
Synopsis
Azide 94 was chemoselectively reduced using Lindlar’s catalyst to afford free amine
which was protected with (Boc)2O under basic conditions to afford carbamate 95. Stereoselective
epoxidation directed by the carbamate moiety using mCPBA in dichloromethane furnished the
epoxide 88. Epoxide 88 was converted to azido alcohol 96 by using ammonium azide in aq
ethanol. The azido group in 96 was reduced to the corresponding primary amine using Pd/C in
EtOAc under hydrogen atmosphere, and further converted to acetamide 97 under standard
conditions. The next objective was to prepare aziridine 87 from amide 97 and subject it to
regioselective opening with an oxygen nucleophile. To this end the carbinol 97 was converted to
mesylate, subsequent treatment with sodium hydride furnished aziridine 87. With aziridine 87 in
hand, the stage was set to carry out the crucial opening with water under Lewis acid conditions.
Aziridine 87 on treatment with BF3.OEt2 in CH2Cl2 in the presence of water as the nucleophile
afforded amino alcohol 97 instead of 98.
Scheme 20
N3
NHBoc
NHBoc
0 oC-20 oC, 91%
CO2Et (Boc)2O, Et3N, DCM, rt, 1 h, 87%
94
95
CO2Et
CO2Et
CO2Et
aq EtOH, 70 oC, 72%
88
HO
H2, Pd/C, 1 h, EtOAc
N3
O
NHBoc
NHBoc
NHBoc
HO
NaN3, NH4Cl
mCPBA, DCM
H2, Pd-BaSO4, EtOAc, rt, 5 h,
Ac2O, Et3N, DCM, rt, 1h, 76%
1. Ms-Cl, Et3N, DCM
AcHN
CO2Et
97
96
AcN
2. NaH, THF
CO2Et
87
NHBoc
HO
AcHN
BF3.OEt2, H2O,
CO2Et
97
DCM, -24 oC
NHBoc
AcHN
HO
CO2Et
98
Having been unsuccessful in opening the aziridine regioselectively to secure 98, an
alternate route was designed for the synthesis of tamiflu 85. The revised strategy was based on
exploiting the Mitsunobu reaction to introduce the amino group with inversion of carbinol
configuration. The retrosynthesis is depicted in Scheme 21. Tamiflu 85 was envisioned to be
obtained by regioselective opening of aziridine 99. Compound 99 can be obtained from azido
15
Synopsis
alcohol 100 which inturn was envisaged to be obtained by regioselective opening of epoxy
carbamate 101. Carbamate 101 was traced to Diels-Alder adduct 103.
Scheme 21
CO2Et
O
CO2Et
CO2Et
HO
CO2Et
O
AcN
AcHN
N3
NH2.H3PO4
NHBoc
NHBoc
85
NHBoc
101
100
99
CO2Et
O
O
OH
O
102
O
103
The synthesis of Diels-Alder adduct 103 began with (S)-pantolactone 104 that was
subjected to treatment with propenoylchloride in the presence of triethylamine in anhydrous
CH2Cl2 to afford acrylate ester 105. Treatment of 105 with an excess of butadiene in presence of
TiCl4 in anhydrous CH2Cl2 following Helmchen’s protocol afforded the Diels-Alder adduct 103.
Basic hydrolysis of Diels-Alder adduct 103 using LiOH.H2O in THF/H2O mixture yielded
carboxylic acid 106. The acid 106 was subjected to iodolactonization afforded the iodolactone
107. Iodolactone 107 on dehydroiodination using DBU as a base yielded unsaturated lactone
108.
Scheme 22
O
Cl
OH
O
O
104
O
O
DCM, -24 oC, 6 h, 85%
O
105
-20 oC, 48 h, 72%
O
O
103
O
O
OH
O
DBU, Toluene
NaHCO3, I2, KI
H2O, rt, 20 h, 98%
THF:H2O, rt, 26 h, 97%
O
O
O
O
LiOH.H2O,
O
TiCl4, DCM: Hexane
, Et3N
106
105 oC, 6 h, 97%
I
107
108
Unsaturated lactone 108 was converted to hydroxyl ester 102 using K2CO3 in ethanol.
Treatment of 102 with BocNHNS-p, TPP and DEAD in toluene afforded sulfonamide 109. The
sulfonamide 109 was deprotected by treatment with 2-mercapto ethanol and DBU in acetone to
afford the carbamate 110. Carbamate 110 was subjected to stereoselective epoxidation using
16
Synopsis
mCPBA directed by the carbamate moiety in dichloromethane to afford the epoxide 101.
Epoxide 101 on treatment with TMSN3 in the presence of Ti(OiPr)4 in benzene afforded the
regioisomeric azido alcohols 100 & 111 in a 3:1 ratio respectively.
Scheme 23
p-Ns
O
O
OH
K2CO3, EtOH
rt, 5 h, 90%
CO2Et
DBU, 2-Mercaptoethanol
Acetone, rt, 3 h, 90%
CO2Et
PPh3, Toluene, -24 oC, 6 h, 85%
102
108
109
NHBoc
NHBoc
mCPBA, DCM
CO2Et
0 oC, 6 h, 83%
NHBoc
Ti-(iOPr)4, TMSN3
O
NHBoc
N3
HO
o
Benzene, 5 C-rt, 2 h, 86%
CO2Et
101
110
Boc
N
H
BocN-NS-p, DEAD
HO
CO2Et N3
100
CO2Et
111
:
3
1
Initially azido alcohol 100 was taken ahead. It was planned to oxidize the alcohol and
dehydrogenate the resulting ketone using Nicolaou’s protocol. Thus azidoalcohol 100 on
treatment with IBX (2.5 eq) in toluene/DMSO mixture afforded a complex mixture of products,
Scheme 24. Attempted dehydrogenation in the presence of 4-methoxy pyridine N- oxide and
IBX also failed to afford 112 cleanly. It was therefore decided to protect the azidoalcohol 100 as
its trimethylsilyl ether and proceed further.
NHBoc
Scheme 24
N3
NHBoc
N3
1. IBX , Toluene:DMSO (2:1), 75 oC, 3 h
HO
CO2Et
100
O
CO2Et
112
o
2. IBX, MPO, DMSO, rt 2h, 70 C 3 h
Complex Mixture
Thus azidoalcohol 100 was subjected to treatment with trimethylsilyl chloride and triethyl
amine in anhydrous DCM to afford the TMS ether 113 (Scheme 25). TMS ether 113 was
subjected to treatment with lithium diisopropylamide in THF followed by phenylselenyl bromide
to afford the selenyl compound 114. The selenyl compound 114 on treatment with hydrogen
peroxide and pyridine in dicloromethane afforded an inseparable mixture of regioisomeric
unsaturated esters 115 and 116 in a 2:3 ratio respectively. The mixture of unsaturated esters 115
and 116 were treated with catalytic amounts of DBU in toluene to afford the unsaturated ester
115. Unsaturated ester 115 was subjected to treatment with triphenylphosphine in toluene under
Staudinger’s condition to afford aziridine 117.
17
Synopsis
Scheme 25
NHBoc
NHBoc
NHBoc
TMS-Cl, Et3N, DCM
N3
LDA, PhSeBr, THF
N3
TMSO
CO2Et
SePh
CO2Et
-78 oC, 30 min, 74%
0 oC, 30 min, 95%
HO
N3
HO
CO2Et
114
113
100
NHBoc
NHBoc
N3
N3
H2O2, Py, DCM
rt, 30 min, 76%
HO
115
DBU, Toluene
HO
CO2Et
2 : 3
NHBoc Inseparable Mixture
TPP, Toluene
105 oC, 3 h, 85%
NHBoc
N3
116
CO2Et
24 h, rt, 65%
HO
115
CO2Et
HN
CO2Et
117
At this stage, the conversion of regioisomeric azido alcohol 111 to aziridine 117 was
explored. Azidoalcohol 111 on treatment with trimethylsilyl chloride and triethylamine in
anhydrous DCM afforded the TMS ether 118 (Scheme 26). TMS ether 118 was subjected to
treatment with lithium diisopropylamide in THF followed by phenylselenyl bromide to yield 119
as the sole product. The selenyl compound 119 on treatment with hydrogen peroxide and
pyridine in DCM afforded an inseparable mixture of regioisomeric unsaturated esters 120 and
121 in a 1:3 ratio respectively. The mixture was subjected to treatment with triphenylphosphine
in toluene to afford the aziridines 117 and 122. These could be separated by column
chromatography the aziridine 122 was isomerized using DBU to afford the required aziridine
117.
Scheme 26
NHBoc
NHBoc
TMS-Cl, Et3N, DCM
HO
N3
TMSO
0 oC, 30 min, 94%
CO2Et
N3
CO2Et
NHBoc
rt, 30 min, 76%
-78 oC, 30 min, 58%
HO
119
NHBoc
NHBoc
HO
N3
TPP, Toluene
CO2Et N3
CO2Et
121
120
SePh
CO2Et
N3
118
111
H2O2, Py, DCM
NHBoc
HO
LDA, PhSeBr, THF
1 : 3
105 oC, 3 h, 85%
NHBoc
HN
HN
117
CO2Et
122
Separable Mixture
DBU, Toluene
Inseparable Mixture
rt, 24 h, 58%
18
CO2Et
Synopsis
The aziridine 117 was protected as its acetate 99 by treatment with acetic anhydride and
triethylamine in DCM, Scheme 27. The compound 99 was transformed into 123 following
Shibasaki’s protocol. Thus treatment with 3-pentanol in the presence of BF3.OEt2 afforded ether
123. Finally deprotection of Boc group in 123 using trifluoroacetic acid in DCM afforded amine
as its trifluoroacetate salt which on treatment with a base and then with H3PO4 in ethanol
provided tamiflu 85. The physical data of 85 were in full agreement to those reported in the
literature.
Scheme 27
NHBoc
NHBoc
NHBoc
Ac2O, Et3N, DCM, Cat DMAP
HN
CO2Et
3-Pentanol, BF3.OEt2
AcN
0 oC - rt, 30 min, 87%
CO2Et
99
117
-20 oC, 30 min, 70%
AcHN
O
CO2Et
123
NH2.H3PO4
CF3COOH, DCM, rt
H3PO4, EtOH, 50 oC, 71%
AcHN
O
CO2Et
85
In conclusion, a new stereoselective synthesis of tamiflu was achieved from (-)-cyclohexene
carboxylic acid using an asymmetric Diels-Alder reaction. The regioisomeric azido alcohols 100
and 111 converged to yield the same aziridine 117. Attempts to introduce a double bond
regioselectively using IBX as an oxidant following Nicoloau’s protocol afforded a complex
mixture of products. The regioisomeric unsaturated esters could be prepared by selenenylation
followed by elimination of selenoxide to afford isomeric esters that were isomerized to the
desired product. The overall yield was 2.8%.
19