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Synopsis
Synopsis
The thesis entitled, “Preparation, Application of Sulfilimines as
Intramolecular Nucleophiles in the Synthesis of AHDA, AHPBA, (+)Desoxoprosophylline and (-)-Deoxocassine” is divided into three chapters.
Chapter-I comprises two sections, ‘A’ and ‘B’. Section A concerns with a
brief introduction to sulfilimines, its preparation and use in stereoselective
organic synthesis. Section ‘B’ deals with a brief account of the work carried out
by various research groups toward the synthesis of α-hydroxy-β-amino acid
derivatives and a detailed account on the stereoselective synthesis of AHDA
and AHPBA, two representatives of the α-hydroxy-β-amino acid class of
compounds.
Chapter-II comprises two sections, ‘A’ and ‘B’. Section A briefly
introduces Burgess reagent, its applications in organic synthesis and a detailed
account of the present work that pertains to the preparation of sulfilimines from
sulfoxides using the Burgess reagent. Section ‘B’ deals with a brief introduction
to earlier reported synthetic approaches to piperidine alkaloids and the present
work directed toward the stereoselective synthesis of the (-)-Deoxocassine and
(+)-Desoxoprosophylline, which are representatives of the piperidine alkaloid
family.
Chapter-III summarizes previous synthetic approaches to 1,2- and 1,3aminoalcohols, haloamine building blocks and gives details of the present work
aimed at a versatile route to -hydroxy-,-cis-and trans-disubstituted
sulfilimines and their haloamidation reaction.
Chapter-I:
Sulfilimines remain less explored as synthetic reagents as compared to
the isomeric sulfoxides, which have found broad use in the area of
stereoselective synthesis. Section ‘A’ covers introduction, bonding and
configuration, preparation of enantiomerically enriched sulfilimines from
I
Synopsis
chiral/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.
Many natural products pose considerable synthetic challenge because of
their stereochemical complexity. The development of new and efficient
methods for the regio- and stereoselective synthesis of biologically active
compounds is an active area of research.
Over the past sixty years, many unusual aminoacids have been isolated
from natural sources. Among them, 3-hydroxy-2-amino acids and 2-hydroxy-3amino acids represent an important class of compounds. The latter occur in
diverse natural and synthetic molecules possessing significant biological
activity. (2S,3R)-3-Amino-2-hydroxydecanoic acid ((2S,3R)- AHDA), is the Nterminal moiety of a marine natural product Microginin, a linear pentapeptide
isolated from the cultured fresh water blue-green algae Microcystis aeruginosa
and exhibits an inhibitory activity toward the angiotensin-converting enzyme
(ACE). (2S,3R)-3-Amino-2-hydroxy-4-phenylbutanoic acid ((2S,3R)-AHPBA) is
a non-proteinogenic constituent of the dipeptide N-(2S,3R)-3-amino-2-hydroxy4-phenylbutanoyl)-L-leucine, known as Bestatin isolated from Streptomyces
olivoreticuli with antitumor and antibacterial activities (Scheme-1).
Scheme-1
O
Val-Val-Asp-OH
R
H2N
O
OH
H
N
N
Amastatine
1
O
N
H
O
O
OH
2, KRI-1230, R = i-Pr:
3, KRI-1314, R = c-Hex:
HN
N
II
CO2i-Pr
Synopsis
NH2
O
OH
O
NH
OH
NH2
O
O
H
N
HN
N
H
CO2H
N
Me
OH
O
OH
O
Bestatin
5
Microginin
4
OH
OH
OH
HO2C
HO2C
AHDA
NH2
Ph
AHPBA
7
6
NH2
As a part of the programme aimed at the synthesis of biologically active
molecules, it was decided to synthesize (2S,3R) AHDA and (2S,3R) AHPBA.
The retrosynthetic analysis is depicted below (Scheme-2).
Scheme-2
OH
O
MeO2C
O
OP
S
S
R
p-Tol
NHP
8, R = Hex
9, R = Ph
R
10, R=Hex
11, R =Ph
CbzN
p-Tol
OP
Br
12
NHP
NHP
O
S
S
p-Tol
OP
p-Tol
13
Me
P = Protecting group
14
The syntheses of the derivative of AHDA and AHPBA commenced from
the β-hydroxy sulfoxide 17, obtained in the two steps from (R)-methyl p-tolyl
sulfoxide 14. The condensation of the lithium anion of sulfoxide 14 with 1imidazolyl-2-propen-1-one 15 afforded β-ketosulfoxide 16, which on reduction
with
i-Bu2AlH
(DIBAL)
in
THF
stereoselectively (Scheme-3).
III
afforded
β-hydroxy
sulfoxide
17
Synopsis
Scheme-3
O
O
LDA, THF
S
p-Tol
Me
DIBAL-H, THF
S
OH
S
p-Tol
p-Tol
O
14
O
O
17
16
N
N
15
Protection of 17 as its silyl ether 18 by treatment with TBS-Cl followed
by reaction with N-sulfinyl benzylcarbamate (CbzNSO) in acetonitrile afforded
a 7:3 mixture of diastereomeric sulfilimines 19anti and 19syn respectively, in
75% yield along with the corresponding sulfide 20 (10%) that were separated by
column chromatography on silica gel. The major isomer possessed an inverted
sulfur configuration relative to the sulfoxide. The isomer 19anti eluted first
during column chromatography followed by the isomer 19syn (Scheme-4).
Scheme-4
O
OH
O
OTBS
CbzNSO
18
CH3CN, 75%
TBS-Cl, Imid.,
S
p-Tol
S
DCM, 90%
17
CbzN
p-Tol
CbzN
OTBS
+
S
OTBS
S
p-Tol
p-Tol
19anti
OTBS
+
S
p-Tol
19syn
20
7:3
The reaction of 18 with CbzNSO was attempted in different solvents to
determine the stereoselectivity and acetonitrile was found to be the best in
terms of yield and diastereoselectivity. The results are tabulated in Table-1. It
can be seen that sulfilimine formation proceeds with moderate or no selectivity.
IV
Synopsis
Table-1 Stereoselectivity of sulfilimine formation
Entry
Sulfoxide
1
O
Solvent
Stereoselectivity
Inversion:Retention
Yield
DCM
1:1
50%
THF
1:1
20%
PhH
1:1
20%
CH3CN
3:2
75%
CH3CN
1:1
70%
CH3CN
1:1
70%
OTBS
S
p-Tol
18
2
O
OTBS
S
p-Tol
18
3
O
OTBS
S
p-Tol
18
4
O
OTBS
S
p-Tol
21
5
O
OTBS
S
p-Tol
22
6
O
OTBS
S
p-Tol
OBn
23
Deprotection of the silyl group in 19syn by treatment with ntetrabutylammonium fluoride (TBAF) furnished the allyl alcohol 24syn. The
reaction of 24syn with freshly recrystallized NBS proceeded regio- and
stereoselectively to yield bromocarbamate 25anti, which served as the common
advanced intermediate for the preparation of both AHDA and AHPBA
(Scheme-5).
Scheme-5
CbzN
O
OP
NBS, H2O
S
Toluene, 85%
p-Tol
OH
S
p-Tol
Br
25anti
19syn, P = TBS
TBAF,
THF, 93%
24syn, P = H
V
NHCbz
Synopsis
Bromocarbamate 25anti was used to synthesize different hydroxy amino
acid precursors by displacing the bromide ion with variety of carbon
nucleophiles. This strategy obviates the necessity of starting from different
(amino acid) precursors to synthesize 1,2-amino alcohols and is versatile for its
flexibility for the introduction of various carbon side chains or heteroatoms at a
later stage in the synthesis on an advanced intermediate like 25anti.
Displacement of bromine using an excess of cuprate reagents like Me2CuLi,
Bu2CuLi, Hex2CuLi and Ph2CuLi yielded different intermediates for the
preparation of different 2-hydroxy-3-amino acids (Scheme-6).
Scheme-6
O
O
OH
S
p-Tol
Br
R2CuLi, THF
OH
S
p-Tol
R
NHCbz
25anti NHCbz
26a, R = Me, 92%; 26b, R = Bu, 95%
26c, R = Hex, 92%; 26d, R = Ph, 85%
Compound 26c was transformed into AHDA as depicted in Scheme-7.
Since the Pummerer reaction could not be carried out on an unprotected amino
alcohol 26c, it was converted to acetonide 27 by treatment with 2,2dimethoxypropane and cat. CSA. Acetonide 27 was subjected to treatment with
trifluroacetic anhydride (TFAA) to afford the intermediate 28 which without
isolation was hydrolyzed by the treatment with aq. NaHCO3 to furnish
aldehyde 29, which without purification was used directly in the next step.
Attempted purification of the aldehyde 29 led to its disintegration. Thus,
oxidation of the aldehyde 29 by the Pinnick protocol yielded an acid which was
transformed to the corresponding methyl ester 30 using ethereal diazomethane
in ethylacetate. Deprotection of acetonide functionality of 30 with cat. amounts
of CSA in methanol afforded the AHDA derivative 31 (95%, 25% overall yield
from 19 in 10 steps), Scheme-7.
VI
Synopsis
Scheme-7
O
OMe
OH
O
p-Tol
p-Tol
5
26c
TFAA, DCM
27
Cat. CSA, DCM
NHCbz
NCbz
S
OMe
S
O
5
O
O
NCbz
S
Aq. NaHCO3
NCbz
p-Tol
NaClO2,
OHC
NaH2PO4, t-BuOH
F3C(O)CO
28
5
29
O
5
then CH2N2, ether
OH
NCbz
Cat. CSA
MeO2C
MeOH
MeO2C
5
31
30
NHCbz
5
A similar sequence of reactions starting from 26d gave AHPBA
derivative (Scheme-8). The treatment of compound 26d with excess 2,2dimethoxypropane in the presence of cat. amounts of CSA yielded acetonide 32
in 83%. Subjecting 32 to Pummerer reaction using TFAA led to formation of
intermediate 33 which without isolation was hydrolyzed by the treatment with
aq. NaHCO3 to furnish aldehyde 34. Pinnick oxidation of 34 afforded the acid
which was characterized as its methyl ester 35. Deprotection of acetonide
functionality of 35 with cat. amounts of CSA in methanol afforded the AHPBA
derivative 36 (18.6% overall yield from 19 in 10 steps), Scheme-8.
Scheme-8
O
OMe
OH
O
p-Tol
Ph
26d
NHCbz
NCbz
S
OMe
S
p-Tol
O
32
Cat. CSA, DCM
VII
Ph
TFAA, DCM
Synopsis
O
O
NCbz
S
Aq. NaHCO3
NCbz
p-Tol
NaH2PO4, t-BuOH
F3C(O)CO
33
Ph
34
O
Ph
then CH2N2, ether
OH
NCbz
MeO2C
Cat. CSA
MeOH
35
NaClO2,
OHC
Ph
MeO2C
Ph
36
NHCbz
In conclusion, a route to optically active sulfilimines from the
corresponding sulfoxides has been developed though non stereoselectively. The
diastereomeric sulfilimines behave in a stereoconvergent fashion and afford
products with the same configuration at carbon. An efficient route to αhydroxy-β-amino acid derivatives AHDA and AHPBA was developed using a
common advanced intermediate. The methodology provides aminoalcohol
derivatives with a Cbz group on nitrogen that can be deprotected under mild
reaction conditions.
Chapter-II: This chapter is divided into two sections
Section-A:
Methyl N-(triethylammoniumsulphonyl)carbamate (37b), also known as
Burgess reagent is a mild and selective dehydrating agent has been successfully
utilized for the preparation of alkenes from alcohols. It went into oblivion for
nearly a decade soon after its discovery by E. M. Burgess in 1968. It was Peter
Wipf who brought it to the attention of organic chemists through its extensive
use in the formation of 5-membered heterocycles from their acyclic precursors.
The inner salt 37 is prepared from three readily available chemicals, i.e.
chlorosulfonyl isocyanate, triethylamine and an alcohol via a two-step sequence
as outlined in Scheme-9.
VIII
Synopsis
Scheme-9
O
Cl
S
O
O
ROH, PhH
NCO
Cl
O 38
S
O
O
R
N
H
Et3N, PhH
O
S
O
Et3N
39
R
N
O
O
37a, R = Bn; 37b, R = Me
37c, R = allyl; 37d, R = 2,2,2-trichloroethyl
It was of interest to explore the reaction of sulfoxides with the Burgess
reagent. Racemic methyl p-tolyl sulfoxide 40a was reacted with Burgess reagent
37a in anhydrous THF (0.2 M) at 60 oC. After 2 h, the polar sulfilimine 41a was
isolated in 30% yield along with unreacted sulfoxide 40a and methyl p-tolyl
sulfide 42a. The use of excess of Burgess reagent 37a (2 eq) relative to 40a led to
the consumption of the latter in about 1.5 h to furnish the sulfilimine 41a in
72% yield along with methyl p-tolyl sulfide 42a (Scheme-10).
Scheme-10
O
O
S
S
p-Tol
NCO2Bn
dry. THF
Me
40a
O
+ Et N
3
Bn
N
O
O
o
60 C
+
S
p-Tol
S
Me
Me
41a
37a
p-Tol
42a
In order to optimize the reaction, sulfoxide 40a was reacted with Burgess
reagent 37a at rt in different solvents. In acetonitrile and dichloromethane, an
excess of 37a was required for completion of the reaction over a 5-7 h period.
Interestingly, when the reaction was carried out in benzene, conversion to 40a
was observed at 0 oC and complete conversion was observed in 7 h to yield 41a
in 80% yield. The same reaction at rt was completed within a 2 h period
affording 41a in 85% yield. The reaction was performed using 1-2 equivalents of
Burgess reagent in different solvents and the results are tabulated in Table-2.
Inspection of Table-2 reveals that for total consumption of starting material, 2
equiv of Burgess reagent is required and benzene is found to be the best solvent
in terms of yield and mild conditions.
IX
Synopsis
aTable
2: Reaction of 40a with 37a in different solvents
O
O
S
p-Tol
Me
+
O
S
Et3N
40a
NCO2Bn
Solvent
Bn
N
O
S
Temperature
O
p-Tol
Me
41a
37a
S. No
Eq of 37a
Solvent
Yieldb%
THF
Temp. in oC,
(Time in h)
RT
1
1
2
1
THF
60, (2)
30c
3
2
THF
60, (1.5)
72d
4
1
CH3CN
RT, (6)
32c
5
2
CH3CN
RT, (5)
68d
6
1
CH2Cl2
RT, (7)
30c
7
2
CH2Cl2
RT, (6)
65d
8
1
PhH
0 to RT, (7)
30c
9
2
PhH
0 to RT, (5)
80
10
2
PhH
RT, (2)
85
No Rxn
a: All reactions were run using 0.5 mmol of 4a, 0.2 M in solvent. b: Yield refers to isolated yield. c: Starting
material (ca. 60% was recovered). d: 10-15% of sulfide isolated.
Having standardized the reaction conditions, the generality of the
reaction was examined, on a variety of aryl alkyl and di-alkyl sulfoxides (Table
3). A perusal of Table 3 reveals that the reaction is general, high yielding and
proceeds under mild conditions. The reaction proceeds with equal facility on
sulfoxides with electron donating (entry 2, 4 & 9), electron withdrawing
substituents (entry 3, 6 & 12), o-substituted sulfoxides (entry 4). Also the
reaction is general for a variety of Burgess reagents 37b-d thus furnishing
sulfilimines with different protecting groups on nitrogen.
X
Synopsis
aTable-3:
Reaction of sulfoxides with Burgess reagent
O
O
S
R1
R2
+
O
S
Et3N
NCO2R3
Benzene
N
R3
O
S
rt
R1
O
R2
41
40
37a, R3 = Bn; 37b, R3 = Me
37c, R3 = Allyl; 37d, R3 = CH2CCl3
Entry
Burgess
reagent
Sulfoxide
Sulfilimine
NCO2Bn
O
1
S
37a
S
p-Tol
Me
p-Tol
40a
NCO2Bn
S
S
37a
Me
40b
MeO
Me
NCO2Bn
Me
Me
40c
Br
4
S
S
37a
NCO2Bn
S
S
Me
Me
40dOMe
41d
S
S
37a
41e
NCO2Bn
O
S
S
37a
Me
Me
40f
O2N
O2N
NCO2Bn
S
S
37a
Me
Me
Me
40g
37a
41g
NCO2Bn
S
S
MeO
Me
MeO
40h
Me
NCO2Me
S
S
37b
Me
Me
40b
MeO
37c
NCO2Allyl
S
S
p-Tol
78
41i
MeO
O
10
70
41h
O
9
90
Me
O
8
82
41f
O
7
85
Me
Me
40e
6
70
OMe
NCO2Bn
O
5
82
41c
Br
O
37a
80
41b
MeO
O
3
85
Me
41a
O
2
Yieldb%
Me
p-Tol
Me
41j
40a
XI
85
Synopsis
O
37c
11
NCO2Allyl
S
MeO
S
Me
MeO
O
NCO2CH2CCl3
S
37d
12
S
Me
Br
76
Me
41k
40h
70
Me
41l
40c
Br
a: All reactions were run using 0.5 mmol of 4, 2 eq of 1, 0.2 M in solvent. b: Yield refers to isolated yield.
Optically pure 14 was reacted with 37a under standard conditions in
benzene at 0 oC to rt, only to obtain racemic 41a. Chiral HPLC after 30 min
revealed the presence of 20% & 28% of (+)- & (-)-14 respectively along with 17%
& 22% of enantiomers of 41a. Chiral HPLC after 1 h revealed the presence of
both enatiomers of 41a in equimolar quantity (32% each) along with
enantiomers of 14 in equal amounts (11% each). It can be inferred that 14 is
getting epimerized by 37a faster than its reaction with 37a to afford 41a. The
outcome of the reaction 14 with 1a in other solvents such as dichloromethane,
acetonitrile and THF was no better (Scheme-11).
Scheme-11
O
Me
O
O
S
S
p-Tol
Me
14
+
Et3N
O
O
S
N
O
O
NCO2Bn
S
Me O
S
O
S
p-Tol
Me
+ 37a
O
37a
Bn
p-Tol
p-Tol
ent-14
43
In conclusion, a novel and mild method has been developed for the
preparation of a variety of sulfilimines with different protecting groups on
nitrogen from the corresponding sulfoxides, using the Burgess reagent. The
protecting groups (Cbz, carbomethoxy, Alloc, Troc) on nitrogen are orthogonal
by nature and can be removed selectively using mild reaction conditions of
choice without affecting other sensitive functional groups.
XII
Synopsis
Section-B:
Piperidine alkaloids possessing a 2,3- or 2,3,6-substitution, particularly a
hydroxy group at C3 position occur widely in nature. The hydroxylated
piperidines display a wide range of biological activities such as antibiotic,
anesthetic and CNS stimulating properties since they mimic carbohydrates in
enzymatic processes.
Numerous compounds possessing either the 2,6-cis or 2,6-trans
substitution pattern have been discovered, in addition to ones with 3- and 3configurations; typical representatives of this class of compounds include (+)spectaline 44, (+)-azimic acid 45, (+)-carpamic acid 46, (-)-prosafrinine 47 and
(-)-cassine
48,
(-)-deoxocassine
49,
(+)-prosophylline
50,
(+)-
desoxoprosophylline 51, (-)-prosopinine 52 (Scheme-12).
Scheme-12
OH
OH
R
N
H
R
Me
44: R = -(CH2)12COCH3
45: R = -(CH2)5CO2H
46: R = -(CH2)7CO2H
N
H
47: R = -(CH2)9COCH3
48: R = -(CH2)10COCH3
49: R = -(CH2)11CH3
OH
R
N
H
Me
OH
CH2OH
R
50: R = -(CH2)9COC2H5
51: R = -(CH2)11CH3
N
H
CH2OH
52: R = -(CH2)9COCH3
Members of this class occur among the alkaloids of various species of the
plant genera Cassia and Prosopis. Not surprisingly, because of their medical
potential and interesting structural features, the piperidine alkaloids have been
popular synthetic targets to showcase the potential of new synthetic
methodologies
XIII
Synopsis
Synthesis of (-)-Deoxocassine
Retrosynthetic analysis revealed that deoxocassine 49 could be obtained
from unsaturated carbamate 53 by a stereoselective amidomercuration.
Carbamate 53 can be traced to aminoalcohol derivative 54 which can readily be
obtained from sulfoxide 55 (Scheme-13).
Scheme-13
STol-p
OP
OH
O
OP
S
11
p-Tol
HN
N
H
49
10
O
Br
NHP
P
54
53
OTBS
P = Protecting group
S
p-Tol
18
The synthesis began with β-siloxy sulfoxide 18. Treatment of sulfoxide 18
with Burgess reagent 37a in anhydrous benzene at rt yielded sulfilimines 19anti
and 19syn in equimolar amounts. Bromocarbamate 25 was prepared from
sulfilimine 19 as depicted in scheme-5.
Protection of 25 as its N,O-acetonide using 2,2-dimethoxypropane and
cat. amounts of CSA yielded acetonide 55. Subjecting 55 to an one-pot
Pummerer followed by the ene reaction furnished homoallyl sulfide 57 cleanly
as a single isomer. The Pummerer intermediate 56 without isolation was reacted
with 1-tetradecene in the presence of stoichiometric amounts of SnCl4 at 0 oC for
30 min to yield 57. The configuration at the newly introduced stereogenic centre
in 57 was not assigned till after amidomercuration, vide infra, Scheme 14. The
entire carbon framework was introduced and it only remained to cyclize the
unsaturated carbamate to form the piperidine ring.
XIV
Synopsis
Scheme-14
O
OTBS
S
CbzN
Et3NSO2NCbz 37a
S
PhH, 0 oC to rt
p-Tol
CbzN
OTBS
+
p-Tol
OTBS
S
p-Tol
19syn
19anti
18
R1 R2
OMe
OH
R1
OMe
S
p-Tol
R2
O
NCbz
S
p-Tol
Br
Cat. CSA, DCM
Br
NHCbz
25syn, R1 = O, R2 =
55syn, R1 = O, R2 =
25anti, R2 = O, R1 =
55anti, R2 = O, R1 =
O
TFAA, DCM
O
NCbz
11
S
p-Tol
F3C(O)CO
Br
SnCl4
NCbz
S
p-Tol
Br
57
56
10
Toward this end, debromination of 57 was effected by treatment with ntributyltin hydride in refluxing benzene in the presence of cat. amounts of
AIBN to furnish acetonide 58. Deprotection of the acetonide using cat. CSA in
methanol proceeded cleanly to yield alcohol 59 which was protected as its
acetate 60 to chemoselectively involve the carbamate in the amidomercuration
reaction. Treatment of 60 with mercuric trifluoroacetate in DCM at rt overnight
followed by reductive demercuration using LiBH4 at low temperature and
gradual warming furnished 2,6-cis di-substituted piperidine derivative 61 by
concomitant deacetylation. The structure of 61 was proven unambiguously by
nOe experiments. The structure of 61 also helped to assign the configuration of
the newly established stereogenic centre in 57 as depicted. The synthesis of
deoxocassine was completed by subjecting 61 to hydrogenolysis using Ra-Ni in
ethanol, Scheme 15. Synthetic deoxocassine had physical properties in excellent
agreement to those reported in the literature.
XV
Synopsis
Scheme-15
STol-p
O
NCbz
S
n-BuSnH, AIBN
OP
Cat. CSA
p-Tol
57
MeOH
PhH
HN
58
10
10
Ac2O, Et3N,
DMAP, CH2Cl2
STol-p
LiBH4
59, P = H
60, P = OAc
OH
OH
Hg(OTFA)2, CH2Cl2
Cbz
Ra-Ni, H2, EtOH
N
11 H
N
11 Cbz
49, (-)-deoxocassine
61
Synthesis of (+)-Desoxoprosophylline
The interesting structural features and the varied biological activity of
(+)-desoxoprosophylline 51 has attracted the attention of synthetic chemists and
several reports detail its synthesis. Many among them rely on chiral pool
starting materials and there are only a handful of reports on asymmetric
syntheses. The synthesis of 51 commenced from homoallyl sulfide 57 which on
treatment with excess sodium nitrite in DMF yielded the alcohol 62.
Deprotection of the acetonide using cat. CSA and protection of the resulting
diol 63 as its silyl ether using TBS-OTf in the presence of 2,6-lutidine furnished
64 cleanly. Amidomercuration of 64 using mercuric trifluoroacetate followed by
demercuration using LiBH4 furnished the oxazolidinone 65 via concomitant
desilylation under the reaction conditions, Scheme-16. The structure of alcohol
65 was confirmed by nOe studies on the acetate derivative 66. The p-tolyl thio
group was removed by hydrogenolysis by treatment with Ra-Ni to furnish
alcohol 67. Attempted Mitsunobu reaction on 67 using chloroacetic acid as the
acid partner only returned unreacted starting material. Therefore an oxidation-
XVI
Synopsis
reduction sequence was resorted to prepare the inverted alcohol. In the event,
treatment of 67 with IBX in refluxing ethyl acetate furnished the corresponding
ketone 68 which was not stable to column chromatography on silica gel. The
crude product was reduced with NaBH4 to yield alcohol 69 as the sole product.
Scheme-16
PO
O
p-TolS
NCbz
OP
S
NaNO2, DMF
p-Tol
Cat. CSA, MeOH
57
HN
Cbz
OH
62
10
10
63, P = H
64, P = TBS
X
R2
OP
Hg(OC(O)CF3)2, DCM
11
N
11
N
O
O
Ra-Ni, EtOH
R1
IBX, EtOAc
then LiBH4
Ac2O, Et3N,
DMAP, CH2Cl2
TBS-OTf,
2,6-Lutidine,
DCM
O
O
65, P = H, X = STol-p
66, P = Ac, X = STol-p
67, P = X = H
NaBH4,
MeOH
68, R1, R2 = O
69, R1 = OH, R2 = H
OH
8N KOH, EtOH
N
11 H
OH
51, (+)-desoxoprosophylline
Deprotection of the oxazolidinone was achieved by base promoted
hydrolysis to afford (+)-desoxoprosophylline 51 with physical characteristics
that were in excellent agreement with those reported in the literature, Scheme16.
In conclusion, a novel asymmetric synthesis of (-)-deoxocassine and (+)desoxoprosophylline using a sulfilimine as an intramolecular nucleophile has
been developed. The sulfilimine was readily obtained from the corresponding
sulfoxide using the Burgess reagent as the source of the carbamate moiety. The
XVII
Synopsis
route disclosed is suitable for the synthesis of several related natural products
by a) varying the nucleophile used for bromide displacement (C-heteroatom
and C-C bonds can be made); b) varying the chain length of the alkene
employed
in
the
Pummerer
ene
reaction;
c)
the
conditions
of
amidomercuration, using kinetic rather than thermodynamic conditions to
prepare 2,6-trans di-substituted piperidine derivatives.
Chapter-III:
Vicinal haloamines, obtained by the addition of amine and halogen
moieties across carbon-carbon double bonds, are useful building blocks in
organic synthesis and medicinal chemistry. Halolamines have been obtained by
a) aminohalogenation via an aziridinium intermediate followed by attack of a
halogen nucleophile or b) haloamination which involves a source of halonium
ion and nitrogen nucleophiles.
In an effort to prepare optically active haloamine derivative with easily
removable protecting groups on nitrogen and develop a common route to both
cis and trans alkene precursors, chiral propargyl alcohols were considered to be
suitable starting materials. Initial consideration was to prepare propargyl
alcohols by introducing chirality simultaneously with carbon-carbon bond
formation. Using Pu’s protocol the propargyl alcohol 78a prepared from phenyl
acetylene 71a and tolylthio acetaldehyde 70 was obtained in only moderate
enantimeric excess, Scheme-17.
Scheme-17
O
p-TolS
H
70
OH
Et2Zn, Ti(OiPr)4
Ph
+
71a
p-TolS
(R)-Binol,
Toluene, HMPA
78a 50% ee
Ph
Therefore catalytic asymmetric reduction of ynones 75 was considered.
The ynones were prepared as depicted in Scheme-18. Thus chloroacetyl
chloride 72 was reacted with N,O-dimethylhydroxylamine hydrochloride 73 to
XVIII
Synopsis
furnish amide 74. Further reaction of amide 74 with lithium acetylides derived
from alkynes 71a-d afforded ynone 75 after quenching the reaction mixture
with aq. HCl. Chiral Rh hydrogenation catalysts have been reported to
efficiently convert -halogenated ketones to optically active alcohols though in
moderate ee. Ikariya and co-workers have reported highly efficient asymmetric
transfer hydrogenation of -chloro acetophenones using a well defined chiral
Rh-complex. The catalyst however, when used for the reduction of -chloro
ketones possessing conjugated double or triple bonds gave the corresponding
products with only moderate ee ranging from 58-68%. The ynone 75a has been
reduced by Ikariya via transfer hydrogenation using a Rh catalyst under
optimized conditions to afford propargylic alcohol 77a in 68% ee. In this context
it was very pleasant to note that the transfer hydrogenation of ketones 75 using
2.5 mol% of Noyori’s catalyst, CpRuCl[(S,S)-Tsdpen] 76 in the presence of
formic acid-triethylamine azeotrope in dichloromethane as solvent at rt
furnished propargylic alcohols 77 in good yield (70-80%) and enantioselectivity
(er 94-97 to 6-3), Scheme-18.
Scheme-18
HCl. HNMeOMe
O
O
Li
73
Cl
Cl
Cl
72
N
2,6-Lutidine, CH2Cl2,
0 oC to rt, 90%
74
THF, 0 oC
Me
Ts
N
Ru
N Cl
H2
OH
O
CpRuCl[(S,S)-Tsdpen
Cl
76
75
R
OMe
R
Cl
77
HCO2H, Et3N,
CH2Cl2
R
76
a; R = Ph, b; R = (CH2)4Me
c; R = (CH2)2OBPS, d; R = CH2OPMB
A mixture of formic acid/triethylamine was found to be an optimal
hydrogen source as no reduction was observed using 2-propanol. The catalyst
XIX
Synopsis
was prepared in situ and dichloromethane was found to be the solvent of
choice, Scheme-18.
Incidentally, the chloropropargylic alcohols are useful synthons and can
be converted directly or via the corresponding epoxides into chiral functionalized alkynes, heterocycles, allenes, and subjected to nucleophilic
displacement. Proceeding further, the chlorine was displaced by treatment of 77
with thiocresol in the presence of DBU in toluene to furnish sulfide 78.
Scheme-19
OH
X
pTolSH, DBU,
Toluene
77; X = Cl
78; X =STolp
Ni(OAc)2.6H2O,
Ethylenediamine,
NaBH4, EtOH
R
Red-Al, THF
OH
OH
pTolS
pTolS
R
R
79
80
NaNCbzCl,
CH3CN
CbzN
CbzN
OH
pTolS
R
+
NaNCbzCl,
CH3CN
OH
pTolS
R
syn81
anti81
CbzN
OH
CbzN
+
R
pTolS
anti82
OH
pTolS
R
syn82
a; R = Ph, b; R = (CH2)4Me
c; R = (CH2)2OBPS, d; R = CH2OPMB
Reduction of the triple bond using nickel-boride and Red-Al afforded
cleanly cis- and trans-allylalcohols 79 and 80 respectively. Further treatment of
the sulfide with N-Chloro-N-sodio-benzylcarbamate (NaNCbzCl) in acetonitrile
XX
Synopsis
as the solvent yielded an equimolar mixture of separable anti- and syn
sulfilimines, Scheme-19.
Diastereoselective imination using a chiral metal complex would furnish
either anti- or syn sulfilimines selectively if not exclusively. It is noteworthy that
selective oxidation of sulfides 79 and 80 using sodium metaperiodate or metachloroperoxybenzoic acid at low temperatures would afford the corresponding
-hydroxy-,-disubstituted sulfoxides.
Having prepared the unsaturated sulfilimines, their regio- and
stereoselective bromoamidation was next investigated. An inspection of Table 4
reveals that the intramolecular transfer of the N-Cbz group from sulfur to
carbon is highly regioselective affording 5-exo opening products in all cases
except the styrene derivatives 81a and 82a which afford 6-endo opening
products, both modes of opening being in accordance with Markovnikov’s rule.
The anti- and syn sulfilimines behave stereoconvergently (compare entries 1,3
with 2,4 etc) to afford bromocarbamates with identical configuration at carbon
but differing at sulfur, which was proven by oxidation of the sulfinyl moiety in
the products individually to an identical sulfone. This therefore avoids the
necessity of having to prepare diastereomerically pure anti or syn -hydroxy
sulfilimines or, if prepared as a mixture to separate them. The reaction is
general and proceeds under mild reaction conditions.
aTable
Entry
4: Regio- and stereoselective preparation of bromocarbamates
Sulfilimine
CbzN
1
Bromocarbamateb
OH
pTolS
O
Ph
NHCbz
pTolS
Ph
anti81a
CbzN
2
OH
76% (>95:<5)
syn83 Br
O
OH
pTolS
Yield,c (dr)d
Ph
OH
NHCbz
pTolS
Ph
syn81a
anti83 Br
XXI
78% (>95:<5)
Synopsis
CbzN
3
OH
O
pTolS
Ph
pTolS
Ph
anti82a
CbzN
4
OH
O
Ph
pTolS
Ph
O
pTolS
5
5
OH
O
pTolS
5
OH
O
Br
5
OH
O
OBPS
Br
OBPS
pTolS
2
O
OH
Br
OBPS
pTolS
2
OBPS
O
OBPS
OH
OBPS
pTolS
2
O
OBPS
syn82c
OH
Br
OBPS
pTolS
2
82% (85:15)e
anti88
OH
O
pTolS
OPMB
anti81d
85% (>95:<5)
syn88 NHCbz
2
CbzN
75% (>95:<5)
Br
2
OH
pTolS
2
anti87 NHCbz
OH
anti82c
76% (>95:<5)
syn87 NHCbz
pTolS
CbzN
OH
2
OH
pTolS
80% (75:25)e
anti86 NHCbz
pTolS
CbzN
13
OH
pTolS
syn81c
82% (>95:<5)
syn86 NHCbz
5
CbzN
12
Br
pTolS
anti81c
11
OH
5
pTolS
CbzN
80 (>95:<5)
anti85 NHCbz
syn82b
10
Br
pTolS
anti82b
9
OH
5
CbzN
76% (>95:<5)
syn85 NHCbz
O
OH
pTolS
CbzN
8
Br
pTolS
syn81b
7
OH
5
CbzN
80% (>95:<5)
anti84 Br
OH
anti81b
6
NHCbz
OH
syn82a
5
78% (>95:<5)
syn84 Br
pTolS
CbzN
NHCbz
OH
NHCbz
OH Br
OPMB
pTolS
syn89
XXII
NHCbz
74% (>95:<5)
Synopsis
CbzN
14
O
OH
OH
pTolS
pTolS
OPMB
syn81d
Br
OPMB
80% (>95:<5)
anti89
NHCbz
a: All reactions were done using 0.5 mmol of the sulfilimine in the presence of 1.2 eq. of NBS and 1.5 eq. of
water in toluene (0.2 M) at rt. b: The structure of the sole or major product depicted. c: Yield refers to
isolated yields. d: Diastereoselectivity (at C3 relative to C2) is based on 1H NMR of crude reaction mixture.
e: The isomers were inseparable; structures could be unambiguously assigned to the major products only.
The structure of anti84 was unambiguously assigned by X-ray
crystallography. The structure of anti83 was assigned by debromination using
n-tributyltin hydride to afford an aminoalcohol derivative which was identical
to the debrominated product obtained from anti84. The structure of syn86 was
confirmed by debromination and relating it to a known compound.
Bromocarbamate anti89 was debrominated and further converted to an
acetonide. The nOe studies on the acetonide confirm the structure assigned to
anti89. The structures were assigned to products 85, 87 and 88 by analogy.
In conclusion, highly enantioselective -chloropropargylic alcohols have
been prepared by transfer hydrogenation using Noyori’s catalyst. In a highly
enantioselective fashion ,-cis and trans-disubstituted -hydroxysulfilimines
have been prepared from a common precursor by a straightforward sequence of
reactions in few steps from readily available starting materials. The sulfilimines
have been shown to be excellent intramolecular nucleophiles for the
preparation of bromocarbamates regio- and stereoselectively. The products
possess functional group handles for further manipulation and should serve as
synthons for natural product synthesis and other bioactive molecules. In
comparison to earlier methodology using N-Ts sulfilimine, the methodology
described herein has several advantages, in particular the stereoconvergent
behaviour of the diastereomeric sulfilimines and the nitrogen protecting group
that can be removed under mild conditions.
XXIII