Synopsis
ABSTRACT
The thesis entitled “Bromosulfonamides Formation from Alkenes mediated by
Sulfilimine moiety as the Nucleophile: Formal Synthesis of Balanol and Nelfinavir” has
been divided into three chapters.
Chapter-I comprises of three sections A, B and C. Section A describes a brief
introduction to sulfilimines, its preparation and uses in stereoselective organic synthesis.
Section B deals with the preparation of bromosulfonamides from acyclic olefins using
S,S-dimethyl-N-Ts sulfilimine as the nucleophile. Section C deals with the use of an
intramolecular sulfilimine for the regio- and stereoselective functionalisation of olefins.
Chapter-II deals with a brief introduction to previous synthetic approaches to
Balanol, an inhibitor of protein kinase C (PKC) and the present work directed at the
stereoselective synthesis of the hexahydroazepine core of balanol.
Chapter-III summarizes previous synthetic approaches to nelfinavir and the
present work aimed at the stereoselective formal synthesis of nelfinavir.
CHAPTER-I:
Bromosulfonamide
formation
from
olefins
mediated
by
sulfilimine moiety as the nucleophile
Chapter-I summarizes the chemistry of sulfilimines, which remain less explored as
synthetic reagents, as compared to the isomeric sulfoxides, which have found broad use in
the area of stereoselective synthesis. The introduction, section A, covers the bonding and
configuration, preparation of enantiomerically enriched sulfilimines from chiral and
achiral starting materials and applications of chiral sulfilimines in stereoselective
synthesis, including stereospecific conversion to the other chiral compounds,
stereospecific electrocyclic reactions, diastereoselective and enantioselective reactions.
I
Synopsis
In all the chemistry of sulfilimines reported so far, the sulfilimine moiety (S=NR)
does not participate in the reaction. It is therefore of interest to develop chemistry where
the sulfilimine moiety participation in the reaction and does not function as a chiral
auxiliary alone. In this context sulfilimines have been employed as inter- and
intramolecular nucleophiles to functionalize acyclic olefins.
Section B: Sulfilimine moiety as nucleophile in intermolecular reactions:
The vicinal halo amine functionality is a structural unit of importance in synthetic
organic chemistry. A number of synthetic approaches have been developed to secure this
functionality from alkenes. Nevertheless, the study of highly regio- and stereoselcetive
aminohalogenation of olefins still remains important and challenging.
Drawing a parallel with the reactivity of dimethyl sulfoxide with alkenes by NBS,
it was decided to explore the reaction of alkenes with NBS using S,S-dimethyl-N-(ptoluenesulfonyl) sulfilimine 1, as the nucleophile (Scheme 1).
Scheme 1
R1
R2
NHTs
NTs
S
Me Me
1
NBS, CH2Cl2
R2
R1
Br
The reagent, dimethyl-N-Ts-sulfilimine 1 was prepared from dimethylsulfide and
chloramine-T by Mann-Pope reaction. Triacetyl-D-glucal 2 on treatment with dimethyl-NTs-sulfilimine and NBS in dichloromethane afforded product 3 as the only
bromosulfonamide, while related substrate 4, yielded sulfonamides 5 and 6 in a 2:1 ratio.
Dihydropyran 7 afforded the isomers 8 and 9. Indene and stilbene afford products regioand stereoselectively, resulting from trans addition of bromonium and sulfilimine across
the alkene.
II
Synopsis
The rate of the reaction and the yield varied with the substrates. The electron rich
substrates 2, 4, 7, and 10 afforded products in high yield and the reaction proceeded
within minutes at ice-salt temperature while the stilbene and the styrenes react slowly and
furnish products in low yields and the reaction proceeded in a couple of hours at ambient
temperature (Table 1).
Table 1: Bromosulfonamide from olefins
________________________________________________________________________
S. No
Substrate
Temp (Time)
Product
Yield %
________________________________________________________________________
O
AcO
OAc
Br
O
-150C
(30 min)
1
75
AcO
AcO
AcO
NHTs
OAc
2
3
O
BnO
-150C
(30 min)
2
BnO
OBn
Br
O
OBn
O
BnO
BnO
BnO
BnO
5
OBn
4
3
O
O
65b
NHTs
Br
Br
9
8
7
55a
6
NHTs
O
-150C
(30 min)
NHTs
Br
NHTs
NHTs
r. t
(3 h)
4
Br
60
11
10
NHTs
Ph
5
Ph
Ph
r. t
(24 h)
40
Ph
13
12
Br
NHTs
Br
r. t
(24 h)
6
30
15
14
________________________________________________________________________
a
Products formed in a 2:1 ratio. b Products formed in a 1:2 ratio
III
Synopsis
Section C: Sulfilimine moiety as nucleophile in intramolecular reactions:
Earlier studies in the lab had demonstrated the nucleophilic potential of an
intramolecular sulfinyl group to functionalize acyclic olefins stereo- and regioselectively.
It was of interest therefore to prepare and investigate the reactivity of β–hydroxy
(silyloxy), γ, δ-unsaturated sulfilimines to secure amino alcohol derivatives.
An efficient, novel and general method for the preparation of aminoalcohol
derivatives from β-hydroxy(silyloxy)-γ, δ-unsaturated sulfilimines via intramolecular
nucleophilic assistance, by the sulfilimine group is described (Scheme 2).
Scheme 2
NTs
OP
R1
O
NBS
S
R2
Ph
OP
R1
S
R2
Ph
16
Br
17
NHTs
P= H, SiR
R1= H, Alkyl
R2= H, Alkyl, Aryl
The sulfides 20a, 20d and 20e were obtained by condensation of phenylthiomethyl
lithium with acrolein, cinnamaldehyde and 4-benzyloxy-2-butenal
respectively.
Subsequent protection of the hydroxy group as its t-butyldiphenylsilyl ether was 21b, 21d,
and 21e accomplished by treating with TBDPSCl and imidazole in DCM. The
sulfilimines 22 were synthesized as a diastereomeric mixture in nearly equimolar
quantities from the sulfide 21 by treatment with chloramine-T in dry acetonitrile and
separated by column chromatography (Scheme 3). On the other hand the β-hydroxy
sulfides on treatment with chloramine-T in acetonitrile gave sulfilimines along with
IV
Synopsis
diastereomeric sulfoxides (30%). The β-hydroxy sulfilimines 22a, 22e were therefore
prepared by deprotection of the corresponding silyl ethers using TBAF.
Scheme 3
R1
O
Ph
S
Me +
18
OH
Ph
S
20
19
OP
Ph
DABCO
n-BuLi
2
R THF
60-70%
S
R1
R2
NaNTsCl
CH3CN
80-95%
Ph
NTs OP
S
R1
OP
TBDPS-Cl
S
R2 Imidazole Ph
DCM
90-95%
R1
R2
+
Ph
R2
21
NTs OP
S
22a
21
R1
R1
R2
22s
a, P = R1 = R2 = H
b, P = TBDPS, R1 = R2 = H
c, P = TBDPS, R1 = n-Bu, R2 = H
d, P = TBDPS, R1 = H, R2 = Ph
e, P = R1 = H, R2 = CH2OBn
The sulfide 21c was elaborated in a short sequence of high yielding reactions from
1-hexyne (Scheme 4). Thus addition reaction of the Grignard reagent prepared from 1hexyne to aldehyde 25 in THF at room temperature yielded 26. Treatment of 26 with
Lindlar’s catalyst under an atmosphere of hydrogen in ethyl acetate afforded the cis-olefin
27. Allyl alcohol 27 on deprotection of the THP using PPTS in ethanol at 70oC afforded
the diol 28, which was subjected to selective monotosylation with tosyl chloride in the
presence of Bu2SnO in dichloromethane to afford 29, in 82% yield. The reaction of 29
with thiophenol and DBU in toluene yielded sulfide 30. Treatment of sulfide 30 with
TBDPS-Cl and imidazole in dichloromethane at room temperature yielded the silylether
21c (Scheme 4).
V
Synopsis
Scheme 4
O
OH
OTHP
MeMgBr,
THPO
25
a
1-hexyne
26
OH
b
OH
c
THPO
HO
28
27
OH
OH
d
e
TsO
29
PhS
30
OTBDPS
f
PhS
21c
Reaction conditions: (a) EtMgBr, aldehyde, r.t, 1h, 80% ; (b) H2, Pd/CaCO3, cat.quinoline, EtOAc, r.t, 1h,
95%; (c )PPTS, EtOH, 70oC, 2h, 90%; (d) TsCl, Bu2SnO, Et3N, DCM, 1h, 82%; (e) PhSH, DBU, Toluene,
r.t, 30 min, 98%; (f) TBDPS-Cl, imidazole, DCM, r.t, 1 h, 92%.
The sulfilimines 22 were reacted at ambient temperature in toluene in the presence
of water and NBS to yield the bromosulfonamides 23 (Table 2). Inspection of Table 2
reveals the following: 1) The sulfilimine moiety of the starting material is
stereospecifically transformed into a sulfoxide with an inverted configuration in going to
the product. 2) The reaction is general for a variety of substrates with different olefinic
substitution patterns. 3) The reaction proceeds regioselectively affording products arising
from a 5-exo nucleophilic attack by the sulfilimine group except for 22d which yields
products resulting from 6-endo nucleophilic attack. This can be rationalized by the ability
of the phenyl group to stabilize a partial positive charge at C4 leading to the nucleophilic
VI
Synopsis
attack at C4 in accordance with the Markonokov’s rule. 4) The reaction proceeds to afford
the products with good to high stereoselectivity. 5) The regio- and stereoselectivity of the
reaction is influenced by the nature of the substituent R at C4, the olefin geometry and the
relative configurations of sulfur and C2. 6) The reaction proceeds to afford the products
with good to high stereoselectivity. The reaction probably proceeds via the bromonium
ion complexed to the olefin, which on nucleophilic attack by the sulfilimine (pathway a or
b) would afford the salts I or II, from the anti and the syn sulfilimines respectively.
Further hydrolysis of the salts by the attack of water at the sulfur atom would yield the
inverted sulfoxide and the 1,2- (pathway a) or the 1,3-aminoalcohol derivatives (pathway
b, Scheme 5).
Scheme 5
VII
Synopsis
The isomeric nature of the products 23as and 23aa was proven by oxidation
individually, to yield an identical sulfone. A similar exercise proved the isomeric
character of sulfoxides 23bs/23ba, 23cs/23ca, 23ds/23da and 23es/23ea. The structure of
22da with an anti orientation of the sulfilimine moiety and the silyloxy group was
confirmed by single crystal X-ray diffraction. The structure of sulfilimines 22aa, 22ba,
22ca and 22ea were assigned by comparison which revealed similarities in the chemical
shifts of C1, C2 protons to those in 22da. The sulfilimines 22as-22es also revealed
similarities in their 1H NMR spectra. The difference in chemical shifts () between the
methylene protons is lesser and the methine proton resonates downfield in 22aa-22ea
compared to 22as-22es.
The structure of the bromosulfonamide 23ds was secured by X-ray
crystallography. The X-ray structure established beyond doubt the inversion of sulfur
configuration in going from the starting material to the product and also relative
configuration at C2, C3 and C4. The structure of the product from 22ca was deduced by
X-ray crystallography on the derived sulfone. The syn disposition of the hydroxy and
sulfonamido groups in 23aa was confirmed by nOe studies on the derived acetonide. The
structures assigned to 23bs and 23ba were confirmed by deprotection to yield 23as and
23aa respectively. The structure assigned to 23es was confirmed by transformation to the
corresponding acetonide which revealed a value of 2.9 Hz for the coupling between C2H
and C3H indicating the trans orientation of these protons in the acetonide.
VIII
Synopsis
Nearly single diastereomerically pure sulfilimines were prepared from β-hydroxy
sulfoxides by following the Cram’s protocol. The β-hydroxy sulfoxides can be obtained
diastereomerically pure from β-keto sulfoxides following Solladie’s protocol. Thus
sulfoxides 24a and 24s were readily transformed using the TsNCO and t-BuSMe in dry
acetonitrile as solvent to yield 22bs and 22ba respectively (Scheme 6). Thus it should be
possible to prepare optically sulfilimines from the corresponding optically active
sulfoxides which can be readily prepared.
Scheme 6
O
OTBDPS
a
S
OTBDPS
S
Ph
Ph
21b
O
24
OTBDPS
NTs
OTBDPS
b
S
S
Ph
Ph
24a
O
22bs
OTBDPS
NTs
OTBDPS
b
S
S
Ph
Ph
24s
22ba
Reaction conditions: (a) NaIO4, MeOH/H2O, 0oC-r.t, overnight, 90%; (b) TsNCO,
t-BuSMe, CH3CN, r.t, 70-75%.
IX
Synopsis
Table 2: Preparation of bromosulfonamides from unsaturated sulfilimines
S. No
Sulfilimine
1
Ph
2
Ph
3
Ph
Bromosulfonamide
NTs OTBDPS
S
O
Ph
22ba
OTBDPS
S
Br
OTBDPS
S
Ph
80
>95:<5
23bs NHTs
O
NTs OTBDPS
S
Yield %
C2-C3
(Syn:Anti)
Br
22bs
82
>95:<5
23ba NHTs
NTs OTBDPS
S
O
90
<5:>95
S
Ph
22ca
OTBDPS
Br
23cs NHTs
4
Ph
5
Ph
NTs OTBDPS
O
S
S
Ph
22cs
NTs OTBDPS
S
OTBDPS
Br
23ca NHTs
O
S
Ph
Ph
OTBDPS
NHTs
Ph
22da
6
Ph
NTs OTBDPS
S
22ds
7
Ph
23ds
O
Ph
Ph
9
Ph
Ph
OH
S
Ph
Br
86
>95:<5
23as NHTs
O
NTs OH
S
OH
S
Ph
22as
NTs OH
S
82
<5:>95
Ph
O
Br
85
>95:<5
23aa NHTs
O
OBn
Ph
22ea
10
OTBDPS
NHTs
23da Br
NTs OH
S
NTs OH
S
86
1:3[b],[c]
Br
S
Ph
22aa
8
85
1:2[b],[c],[d]
OH
Br
S
OBn
90
>95:<5
23es NHTs
Ph
OBn
O
S
OH
Br
OBn
86
3:1[b],[c],[d]
23ea NHTs
22es
[a] All reactions were done on 0.5 mmol scale in toluene as the solvent in the presence of 1.3 eq. of NBS
and 1.2 eq. of H2O. [b] The yield refers to the combined yield of both the products. [c] The major product is
depicted. [d] The isomers are inseparable.
X
Synopsis
CHAPTER-II: Stereoselective Synthesis of the Hexahydro Azepine Core of (-)Balanol
Protien Kinase-C (PKC) is a family of phospholipids dependent serine/threonine
specific protein kinases that mediate a wide range of signal transduction processes in
cells. Human PKC enzyme consists of at least eight isoforms, which play important roles
in cellular growth control, regulation and differentiation. Since activation of PKC enzyme
has been implicated in the progression of a wide variety of diseases, such as cancer,
cardiovascular disorders, asthma, diabetes, central nervous system dysfunction,
inflammation, rheumatoid arthritis and HIV infection, a selective inhibitor of PKC
enzymes might have a wide range of therapeutic potential.
(-)-Balanol 31, a fungal metabolite, was isolated independently by Kulanthaivel et
al. from Verticillium balanoides and by Ohshima et al. from Fusarium merismoides. The
unique structure and the biological activity of balanol have attracted the attention of
synthetic chemists and a number of reports have disclosed the total synthesis or the
synthesis of fragments. Balanol consists of the hexahydroazepine and the benzophenone
fragment.
Figure 1
HO
O
O
COOH O
HOOC
OH
OH
O
OH
OH
N
H
(-)-Balanol
H
N
NH2
OH
N
H
O
Hexahydroazepine fragment
32
31
XI
O
OH OH
OH
Benzophenone fragment
33
Synopsis
An efficient route to the hexahydro azepine core of balanol has been developed.
The synthetic approach to the azepine segment includes the bromosulfonamidation of an
olefin using the intramolecular sulfilimine group as the nucleophile and the Pummerer ene
reaction as the key steps. The synthesis began with the allyl alcohol which was obtained
in three steps from cis-2-butenediol 34 by a known literature procedure. Compound
alcohol 37 on treatment with thiophenol in the presence of DBU afforded the sulfide 39.
The sulfide 39 on treatment with Chloramine-T in the presence of Cu(II)triflate (5 mole%)
afforded an equimolar mixture of sulfilimines 40s and 40a. Treatment of the unsaturated
sulfilimines with N-bromosuccinimide in toluene in the presence of water at ambient
temperature yielded the bromosulfonamides 41a and 41s. The reaction probably proceeds
via the intermediacy of salts I and II, formed by 5-exo nucleophilic attack of the
sulfilimine on the olefin -complexed to the bromonium ion, and subsequent hydrolysis
by the attack of water at sulfur (Scheme 7). Here the relative configuration of the
sulfilimine group did not influence the stereoselectivity of new stereogenic center being
generated. The isomeric nature of the products 41s and 41a was proven by oxidation of
sulfoxides individually with m-CPBA to afford the sulfone 42 (Scheme 7).
Protection of 41 by subjecting it to treatment with 2,2-dimethoxypropane (2,2DMP) in the presence of catalytic amounts of CSA yieleded the acetonide 43.
Displacement of the bromide by azide by treatment with NaN3 in DMSO at 80oC gave 44
which on treatment with trifluoroacetic anhydride yielded the Pummerer intermediate 45,
which without isolation was subjected to reaction with 1-hexene in the presence of SnCl4
to afford the ene product 46. The configuration at the newly created stereogenic center
was not established since it was to be removed in the subsequent step.
XII
Synopsis
Scheme 7
OH
a
HO
OH
b
HO
OH
TsO
34
35
OH
OH
c
+
TsO
TsO
OH
d
NTs OH
PhS
e
PhS
TsO
37
O
38
37
OH
36
H2O
f
40s
Ph
S N SO 2Ar
OH
NTs OH
PhS
H2O
f
40a
O
PhS
OH
g
Br
41a
NHTs
O
PhS
O
Br
41a
I
O
PhS
S N SO 2Ar
Br
OH
NHTs
OH
Br
NHTs
41s
II
O
PhS
OH
Br
Ph
OH
40a
NTs OH
PhS
40s
39
NTs OH
PhS
+
g
O
PhS
OH
Br
Br
42 NHTs
NHTs
41s
Reaction conditions: (a) HgSO4, H2SO4, H2O, 80oC, 1 h, 65%. (b) TsCl, Pyridine, CHCl 3, r.t, 1 h, 90%. (c)
L-DIPT, Ti(OPr)4, TBHP, DCM, -10oC, 48 h, 47%.(d) PhSH, DBU, toluene, r.t, 30 min, 90%. (e)
Chloramine-T, CuOTf (5 mole%), CH3CN, r.t, 2 h, 80%. (f) NBS, H2O, toluene, r.t, 30 min, 80%. (g) mCPBA, DCM, 0oC, 30 min, 90%.
Compound 46 was subjected to ozonolysis reaction at -78oC in dry DCM followed
by quenching with dimethyl sulfide to afford the α,β -unsaturated aldehyde 47. Aldehyde
47 was subjected to reductive amination by treatment with palladium over carbon in ethyl
acetate under an atmosphere of hydrogen atmosphere to afford 32. This reaction proved to
XIII
Synopsis
irreproducible. Therefore the hexahydroazepine fragment 52 was elaborated from 47 in a
step wise manner.
Scheme 8
O
PhS
OH
O
PhS
a
Br
41 NHTs
O
O
NTs
PhS
NTs
CF 3(O)CO
X
43, X = Br
b
c (i)
45
N3
44, X = N3
O
c (ii)
PhS
NTs
d
O
N3
H
46
O
O
Ph
S
NTs
NTs
CHO
OHC
N3
47
2
O
e
NTs
O
O
f
NTs
h
49, R = NHBoc; X = OH
i
NHTs
N
Boc
N
Boc
51
52
X
48
OH
NTs
R
N3
OH
N3
g
50, R = NHBoc; X = OMs
Reaction conditions: (a) 2,2-DMP, acetone, CSA (Cat), 70oC, 6 h, 80%. (b) NaN3, DMSO, 80oC, 6 h, 90%.
(c) (i) TFAA, DCM, 0oC, 30 min (ii) 1-Hexene, SnCl4, 0oC, 10 min, 70% for two steps. (d) O3, DMS, DCM,
-78oC, 30 min, 75%. (e) NaBH4, CeCl3, MeOH, 0oC, 30 min, 70%. (f) H 2, Pd/C, (Boc)2O, r.t, 6h, 90%. (g)
MsCl, Et3N, DCM, 0oC, 30 min, 90%. (h) KOBut, THF, r.t, 1 h, 70%. (i) PPTS, EtOH, 80 oC, 1 h, 85%.
The reduction of the aldehyde 47 with sodium borohydride in the presence of
CeCl3 in methanol at 0oC afforded the allyl alcohol 48. Treatment of 48 with Pd/C in the
presence of di-tert-butyldicarbonate under an atmosphere of hydrogen in EtOAc as the
solvent afforded the carbamate 49. Mesylation of the alcohol yielded cleanly the mesylate
50 which on treatment with potassium tert-butoxide as the base in anhydrous THF cleanly
XIV
Synopsis
afforded 51. Finally, the acetonide protecting group in 51 was removed by treatment with
PPTS in ethanol furnished the chiral azepine alcohol 52 (Scheme 8).
In conclusion, a highly stereoselective route to the hexahydro azepine core of
balanol has been developed.
CHAPTER-III: Stereoselective Synthesis of the HIV-Protease Inhibitor Nelfinavir
The human immunodeficiency virus protease (HIVPr) has emerged as a promising
therapeutic target for the treatment of AIDS due to the essential role this enzyme plays in
virus maturation. Inhibitors of HIVPr are presently being used in therapy for the treatment
of AIDS. Nelfinavir mesylate 53 is a potent, orally active inhibitor of HIV protease and has
recently been approved by the US FDA as a treatment for HIV infection.
Figure 2
CH3
HO
SPh
O
CONH-t-Bu
N
X
N
H
OH
H
H
53
Viracept ( Nelfinavir Mesylate, AG 1343)
X=MeSO3H
It
comprises
three
retrosynthetic
components:
a
chiral
C4
unit,
a
perhydroisoquinoline derivative unit, and a benzoic acid derivative unit. The preparation of
the perhydroisoquinoline derivative has been previously addressed in the literature, and the
substituted benzoic acid derivative can be prepared using well-known chemistry. The chiral
four-carbon backbone has attracted the attention of synthetic chemists. Disclose herein is a
stereoselective synthesis of the C4 amino alcohol unit using a bromosulfonamide as the
intermediate.
XV
Synopsis
The synthesis began with the allyl alcohol 54 which on treatment with thiophenol
in the presence of DBU in toluene at room temperature afforded the sulfide 55. Treatment
of sulfide 55 with chloramine-T and dry acetonitrile in the presence of catalytic amounts
of Cu(II) triflate at room temperature afforded an equimolar mixture of sulfilimines 56a &
56s. The mixture of sulfilimines 56 was subjected to treatment with NBS in the presence
of water in toluene at ambient temperature to afford the bromo sulfonamides (57s & 57a)
regio- and stereoselectively (Scheme 9).
Scheme 9
OH
OH
a
TsO
NTs
b
S
OH
O
c
S
56s
O
OH
S
Br
Ph
56
Ph
56a
55
OH
S
Ph
54
Ph
NTs
S
Ph
NTs
OH
57s NHTs
Ph
OH
S
Br
57a NHTs
Reaction conditions: (a) PhSH, DBU, Toluene, rt, 1h, 82%. (b) Chloramine-T, CH3CN, CuOTf (5
mole%), rt, 30 min, 90%.(c) NBS, H2O, Toluene, 1h, 85%.
The sulfonamide 57 represents the four carbon unit for the synthesis of nelfinavir
intermediate. The next step in synthesis was the protection of 57 which was accomplished
by treatment with 2,2-DMP in the presence catalytic amounts of CSA in acetone at 70oC
to afford the acetonide 58. Displacement of bromide 58 by treatment with thiophenol in
the presence of DBU at room temperature in toluene as solvent afforded the inseparable
mixture of sulfides 59. The compound 59 on Pummerer reaction treatment by with TFAA
and triethylamine in dichloromethane as the solvent at 0oC afforded the intermediate 60,
XVI
Synopsis
which upon hydrolysis and reduction by treatment with an saturated aqueous sodium
bicarbonate and sodium borohydride yielded the primary alcohol 61.
Scheme 10
O
OH
O
S
Ph
a
Br
57
S
NHTs
NTs
58
S
Ph
NTs
59
SPh
O
NTs
SPh
d
O
O
f
SPh
BOC-NTs
63
SPh
SPh
61
62
60
O
S
Br
HO
Ph
e
O
O
NTs
OCOCF3
b
Ph
O
c
O
O
O
OH
g
HO
O
SPh
SPh
64
NHBOC
NHTs
65
NHBOC
Reaction conditions: (a) 2,2-DMP, Cat. CSA, Acetone, 70oC, 75%. (b) PhSH, DBU, Toluene, rt, 1h,
80%.(c) TFAA, Et3N, DCM, 0oC, 30 min then NaBH4, NaHCO3, 30 min, 70%. (d) 2,2-DMP,
Cat.CSA, rt, 1h, 90%.(e) (Boc)2O, TEA, Cat.DMAP, DCM, rt, 2h, 80%. (f) Mg, MeOH, ultrasound,
6h, 80%. (g) p-TSA, MeOH, rt, 1h, 90%.
Treatment of 61 with 2,2-DMP in the presence of CSA in DCM at room
temperature afforded the migrated acetonide product 62. Compound 62 on treatment with
(Boc)2O and triethylamine in the presence of catalytic DMAP in DCM at room
temperature afforded 63. Compound 63 was subjected to the detosylation by treatment
with magnesium in methanol using ultra sound to afford the carbamate 64. The acetonide
protection was removed by treatment of 64 with p-TSA in methanol at room temperature
to afford the diol 65 (Scheme 10).
XVII
Synopsis
Since transformation of 65 into epoxide 68 required inversion of the secondary
hydroxy group of 65, the secondary hydroxy group was converted to a mesylate treatment
with methanesulfonyl chloride after protection of the primary hydroxy group with
pivaloyl chloride in the presence of pyridine. Finally treatment of 67 with potassium
carbonate in methanol promoted the hydrolysis of pivaloyl group and spontaneous ring
closer to afford 68, in 80% yield. Compound 68 has been converted to nelfinavir 53 in
three steps and thus this completes a formal synthesis of nelfinavir (Scheme 11).
Scheme 11
OH
OH
a
HO
OMs
PivO
b
SPh
SPh
NHBOC
NHBOC
SPh
67
66
65
PivO
O
3 steps
c
SPh
Nelfinavir
53
NHBOC
68
Reaction conditions: (a) Piv-Cl, Py, DCM, rt, 30 min, 90%.(b) MsCl, Et3N, DCM, 0oC, 30 min.
(c) K2CO3, MeOH, rt, 1 h, 80%.
XVIII
NHBOC
Synopsis
Bromosulfonamides Formation from Alkenes mediated by Sulfilimine
moiety as the Nucleophile: Formal Synthesis of Balanol and Nelfinavir
ABSTRACT
Submitted to Osmania University
For the degree of
Doctor of Philosophy
(in Chemistry)
By
CH. Naveen Kumar
Organic Division -I
Indian Institute of Chemical Technology
Hyderabad 500 007, India
August 2004
XIX