ABSTRACT
CHAPTER I: This chapter describes introduction of Prins cyclisation,
CHAPTER II: This chapter describes the stereoselective total
synthesis of Brevisamide.
Brevisamide is a marine cyclic ether alkaloid isolated from karenia
brevis. The dinoflagellate Karenia brevisis known to produce polycyclic
ethers such as the brevetoxins and brevenal. The brevetoxins are
known to exhibit potent neurotoxicity, which causes massive killing of
fish and marine animals such as dolphins and manatees along the
Florida coast. The brevenals have an antagonistic activity against the
brevetoxins. Brevisamide (1) was recently isolated by Wright’s group
(Center for Marine Science at University of North Carolina) while
conducting experiments aimed at the identification of new metabolites
from K. brevis. Chemistry, biology and scarcity of the natural
abundance of brevisamide attracted our attention to its synthesis.
Herein, we disclosed an asymmetric total synthesis of brevisamide.
O
OH
O
O
OH
H
N
O
O
O
O
O
O
Brevisamide (1)
OH
Brevinal (2)
Figure I
Scheme 1 discribes our retrosynthetic analysis of brevisamide (1)
providing
a
convergent
synthetic
stratagy.
The
functionalized
tetrahydropyran ring moiety (3) was constructed from compound 3a
1
via intramolecular SN2 cyclisation. Compound 3a was obtained from
(R)-2,3-O-isopropylideneglyceraldehyde 5. The phosponate ester 6 was
obtained from acetoin. The target molecule was achieved from
compound 3 and compound 6 by using a Horner-Emmons-wodsworth
reaction.
Scheme1: Retrosynthesis of brevisamide.
The synthesis of tetrahydropyran ring moiety 3 was began with readily
available
(R)-2,3-O-isopropylideneglyceraldehyde
5.
Allylation
of
aldehyde 5 using Zn and allyl bromide in THF produced compound 7
in 92% yield. Compound 7 subjected to benzylation using NaH, BnBr
in THF afforded compound 8 in 90% yield. Compound 8 which was
subjected to Ozonalysis then followed by Wittig olefination with stable
ylide
(ethoxycarbonylmethylene)
triphenylphosphorane
2
in
CH2Cl2
produced α, β-unsaturated ester 9 in 78% yeild. Reduction of
unsaturated ester 9 to allylic alcohol with DIBAL-H in CH2Cl2
produced compound 10 in 92% yield.
Scheme 2
Sharpless asymmetric epoxidation of allylic alcohol 10 using (-) DIPT,
Ti(OiPr)4 and TBHP in CH2Cl2 furnished epoxide 11 in 88% yield.
Benzylation of epoxide 11 as Benzyl ether with BnBr, NaH in THF
afforded compound 12 in 90% yield. Tretement of benzyl protected
epoxide 12 with lithium dimethylcuprate in ether at -30
oC
was
afforded a mixture of diastereomeric alcohols 4a and 4b (7:1) in 86%
yield, which were easily separated by simple column chromotography.
Scheme 3
3
The functionalized tetrahydropyran ring 15 was obtained from
compound 4a. Mesylation of compound 4a using MsCl, TEA in CH2Cl2
followed by deprotection of acetonide using p-TSA in MeOH produced
compound 14. The intramolecular SN2 cyclisation of mesylated diol
with NaH in THF afforded key tetrahydropyran ring 15 in 75% yield
for three steps. Protection of primary hydroxyl group in compound 15
as TBDMS ether using TBSOTf, 2,6 lutidine in CH2Cl2 followed by
deprotection of two benzyl groups of 16 using Li/Napthalene in THF
afforded diol 17 in 75% yield.
Scheme 4
Selective oxidation of primary alcohol of diol 17 with TEMPO-BIAB in
CH2Cl2
followed
by
Wittig
olefination
(ethoxycarbonylmethylene)triphenylphosphorane
with
stable
gave
α,
ylide
β-
unsaturated ester 18 in single step in 86% yield. Reduction of ester
double bond with PtO2 in ethyl acetate followed by protection of
secondary hydroxyl group as TBDMS ether using TBSOTf, 2,6 lutidine
in CH2Cl2 afforded compound 20 in 96% yield for the two steps.
4
Selective deprotection of TBDMS group of compound 20 with
catalytic Camphorsulphonic acid in CH2Cl2:MeOH (4:1) produced
primary alcohol 21 in 90% yeild. Primary alcohol was substituted with
Scheme 5
azide using TPP, DPPA, DIAD in THF under Mistunobu conditions
afforded azide 22 in 76% yeild. Reduction of azide in the presence of
Pd/C in MeOH:THF followed by acetylation of primary amine afforded
the acetyl amide 23 in 88% yield for the two steps. Reduction of acetyl
amide ester with DIBAL-H in CH2Cl2 afford aldehyde 3 in 86% yield.
Wittig
olefination
of
acetoin
24
with
(ethoxycarbonylmethylene)triphenylphosphorane
stable
gave
α,
ylide
β-
unsaturated ester 25 in 95% yield. Bromination of secondary alcohol
was carried out by using TPP, CBr4, Imidazole in CH2Cl2 produced
bromoester 26 in 76% yield. Reaction of bromoester with triethyl
phosphate afforded phosponate ester 27 in 95% yield.
5
Scheme 6
The Horner-Wadsworth-Emmons reaction between the fragment 3 and
Scheme 7
the fragment 6 produced 3,4-dimethyl-2,4-dienal moiety 28 in 78%
yield (Scheme 7). DIBAL-H reduction of the ester to the corresponding
allylic alcohol followed by deprotection of the secondary TBS ether
using TBAF delivered 30, the direct precursor to Brevisamide, in 71%
yield for the two steps. A final MnO2 oxidation of the allylic alcohol
produced the natural product Brevisamide (1) in 74% yield. The
synthetic brevisamide 1 exhibited identical physical and spectroscopic
data to that of the natural Brevisamide and that of the previously
prepared synthetic Brevisamide.
6
Chapter III: Stereoselective total synthesis of (-)-Colletol via Prins
cyclisation.
(-)-Colletol (III), a 14-membered bis-macrolactone, was isolated from
the fermentation broth of the plant pathogen Colletotrichium capsici
along with other bis-macrolactones (II-V) (fig.1) in the year 1973.
Although, no biological activity was reported for these macrolactones,
interest in these compounds was stimulated when isolation of
grahamimycin A1 was reported which showed potent activity against
bacteria, algae and fungi. Being a fascinated bis-macrolactone having
1,3 diol system for which we have recently established a method via
Prins cyclisation, Colletol has inspired us to investigate its synthesis.
Before the synthetic venture, a careful examination was made on
retrosynthetic analysis as depicted in (Scheme 8). It was envisaged
that
the
target
molecule
could
be
obtained
via
Yamaguchi
macrolactonization of 13, which is viewed as being obtained from
Mitsunobu reaction between the two compounds 32 and 36 could be
easily drawn from pyran 34, by a reductive opening followed by
homologation and in turn pyranyl methanol 34 would be obtained via
Prins cyclisation of known homoallylic alcohol 35 and acetaldehyde
7
following our recently developed methodology. Compound 36 would be
obtained from known homoallyl alcohol after simple chemical
modifications.
Scheme 8: Retrosynthesis of (-)-Colletol
Our synthesis of alcohol fragment 32 of colletol as described in
Scheme 9, commenced from Prins cyclisation between known homo
allylic alcohol 35 and acetaldehyde in the presence of TFA was
afforded trifluoroacetate of 34 which was further treated with K2CO3
8
in MeOH produced tetrahydropyran diol 34 as an only isolable isomer
in 55% yield.
Scheme 9
Primary hydroxyl group in 34 was protected as tosylate using 1.1
equivalent of tosylchloride and triethylamine, and protection of
secondary hydroxyl group as methoxy methyl ether using methoxy
methyl chloride and N,N-diisopropylethylamine in CH2Cl2 resulted in
intermediate 37 in 90% yield. Substitution of tosylate with iodo using
sodium
iodide
in
acetone
followed
by
reductive
opening
of
iodomethylpyran 38 produced alcohol 33 with anti-1, 3- diol system.
Protection of secondary hydroxyl group in 33 as TBDMS ether using
TBSCl, imidazole in CH2Cl2 furnished 39 in 85% yield. Ozonolytic
cleavage of olefinic bond of 39 followed by Wittig olefination with
stable
ylide
(ethoxycarbonylmethylene)
triphenylphosphorane
in
benzene gave α, β-unsaturated ester 40. Deprotection of TBS was
carried out using NH4F, MeOH produced compound 32 in 86 % yield.
9
Scheme 10
Synthesis of compound 41 commenced from commercially available
optically active homoallyl alcohol 42 as shown in scheme 11.
Protection of (R)-penten-ol 42 as TBS ether using TBSCl, imidazole in
Scheme 11
CH2Cl2 produced compound 43 in 99% yield. Ozonalysis followed by
wittig olefination of compound 43 gave ester 44 in 86% yield. The
ester 44 on hydrolysis using 2N NaOH, MeOH:H2O afforded the
required acid 41 in 90% yield.
After constructing the two fragments 32 and 41, both were coupled
under Mitsnobu conditions. Thus, acid 41 when treated with alcohol
32 under standard Mitsnobu conditions (TPP, DEAD, THF) smoothly
resulted in ester 44. The TBS group was deprotected followed by
10
hydrolysis of ester group to form conjugated hydroxy acid 46 in 80%
yield.
Scheme 12
The obtained secoacid 46 was macrolactonized under the Yamaguchi’s
conditions afforded the macrolactone 31 which was after treatment
with HCl afforded (-)-colletol (III) in 70 % yield. The spectral and
analytical data (1H NMR,
13C
NMR, IR, Rf and D for the synthetic
compound were in accordance with the data reported in the literature.
Chapter IV: Stereoselective total synthesis of Stagonolide –C via
Prins cyclisation:
Naturally occurring 10-membered lactones from fungal metabolites
present a wide variety of potent biological properties. Among them
stagonolides A-I (Fig. 3) represent a novel family isolated recently from
Stagonosporacirsii, a fungal pathogen of Cirsiumarvense causing
necrotic lesions on leaves, with interesting phytotoxic properties.
When tested by a leaf disk puncture assay at a concentration of
11
1mg/ml, stagonolide B-I showed no toxicity to C. arvense and
Sonchusarvensis,
whereas
stagonolide
A
was
highly
toxic.
Stagonolides A-I possess interesting structural features, as they are
compact, bearing properly placed olefin moieties with well defined
geometry and, therefore they become attractive synthetic targets.
In continuation of our ongoing program towards synthesis of
biologically active compounds, we showed interest in developing a
simple and flexible route to the total synthesis of stagonolide C (46).
Our group has made a significant effort to explore the utility of the
Prins cyclisation in the synthesis of various polyketide intermediates
as well as for the synthesis of some complex natural products. As a
part of this program, we now accomplished a stereoselective total
synthesis of stagonolide C.
The retrosynthetic analysis delineated in Scheme 13 indicated that
stagonolide C (46) could be synthesized by utilizing a ring closing
12
metathesis (RCM) protocol from bis-olefin 47, which in turn could be
prepared from esterification of acid 50 with alcohol 48 .We anticipated
that alcohol 48 would be derived from 2H-pyran-2-methanol 49,
which in turn could be easily constructed via Prins cyclisation, in
analogy to our previous approach. The second fragment, acid 50,
could easily be derived from L-(+)-diethyl tartarate 51.
Scheme 13
Prins cyclisation (Scheme 14) between the known homoallylic alcohol
52 and acetaldehyde in the presence of Trifluoroacetic acid resulted in
the trifluoroacetate salt of 49, which on treatment with K2CO3 in
MeOH gave tetrahydro-4-hydroxy-2H-pyran-2-methanol 49 as the
only isolable diastereoisomer in 55% yield.
The primary hydroxyl group present in 49 was transformed to its
tosylate 53 with TsCl and Et3N in anhydrous CH2Cl2, and the
secondary hydroxyl group was protected as its Methoxymethylether
with
CH3OCH2Cl
and
N,N-Diisopropylethylamine
(iPr2EtN)
in
anhydrous CH2Cl2 produced compound 54. The tosylate group of 54
was substituted by an Iodo on treatment with NaI produced 55, and
subsequent elimination of HI in compound 55 by using NaH in DMF
13
afforded the exocyclic alkene 56, which on column chromatography
revealed the rearranged product 57 in 72% yield. To confirm that the
HI elimination did not result in the rearranged product, we analyzed
the 1H NMR spectrum of the crude product of the elimination reaction,
which clearly revealed the presence of two doublets at δ = 4.33 and
4.09 (J = 2.2 Hz, geminal coupling) and the absence of any
characteristic signal for the rearranged product.
Scheme 14
The substrate 57 was then subjected to ozonolysis to obtain the
corresponding acetoxy substituted aldehyde, which on treatment with
methylenetriphenylphosphorane
furnished
the
open-chain
olefinic acetate 58. Hydrolysis of the acetate group in 58 with K2CO3
in MeOH provided the corresponding key alcohol 48.
14
Scheme 15
The synthesis of the other key fragment, acid 3 was synthesized from
commercially available (+)-Dimethyl tartrate 51. Acetonide protection
of (+)-Dimethyl tartrate using 2,2 DMP, catalytic p-TSA in bezene gave
compound 59 in 92% yield. Compound 59 subjected to reduction with
LiAlH4 in THF produced diol 60 in 94% yield. Selective benzylation of
diol 60 using NaH, BnBr in THF produced compound 61 in 82% yield.
Oxidation of alcohol 61 with (COCl)2, DMSO in CH2Cl2 followed by
wittig
olefination
with
stable
yilide
(ethoxycarbonylmethylene)triphenylphosphorane produced ester 62 in
78% yield in two steps.
Scheme 16
15
Deprotection of the benzyl ether and reduction of the double bond of
62 was achieved with Pd/C in the presence of H2 furnished hydroxyl
ester 63 in 90% yield. Its primary alcohol group was successfully
converted
into
an
iodo
group
64,
and
subsequent
reductive
elimination was promoted by Zn/EtOH afforded secondary alcohol
derivative 65. The free OH group of 65 was protected as its MOM
ether 66, and subsequent saponification of the ester group with 2N
NaOH and MeOH afforded acid 50 in 85% yield.
Scheme 17
The synthesis of the target compound was successfully completed by
combining the two fragments 48 and 50 in a three step sequence
Scheme 3. In analogy to alcohol 48 was acylated with acid 50 in the
Scheme 18
16
presence of Dicyclohexylcarbodimide/4-N,N-dimethyl pyridin-4-amine
(DCC/DMAP) obtained ester 47 in 80% yield. Ester 47 underwent ring
closing metathesis with Grubbs 2nd generation catalyst in boiling
CH2Cl2 to yield E-diastereoisomer 67 in 60% yield, which was
characterized by the usual spectroscopic techniques. The coupling
constant of 15.6 Hz between H−C(5) and H−C(6) clearly demonstrated
the (E)-configuration of the C=C bond. Deprotection of both MOM
ether moieties were carried out with Me3SiBr in CH2Cl2 afforded the
natural product stagonolide C (46). The spectroscopic (1H and
13C-
NMR) and analytical data were in good agreement with those of the
natural product.
Chapter V: Stereoselective synthesis of Spiroketal fragment of
(-)-Ushikulide via Prins cyclisation.
Ushikolide A and B are novel immunosuppresents, isolated from the
culture broth of Streptomyces sp. IUK-102. In 2005, Takahashi and
co-workers reported the isolation of Ushikulide A (68) from a culture
broth of Streptomyces sp. IUK-102. This compound exhibited potent
activity against murine splenic lymphocyte proliferation (IC50) 70 nM),
revealed that of the well-known cyclosporin A2 and FK506,
Figure 4: (-)-Ushikulide A
17
potent activity against murine splenic lymphocyte proliferation (IC50 )
70 nM), revealed that of the well-known cyclosporin A2 and FK506,
which
revolutionized
organ
transplant
therapy
by
suppressing
rejection. Takahashi’s structural assignment dealt with connectivity,
not stereochemistry, as analysis of 68 by X-ray diffraction proved
untenable in this particular case. Barry M. Trost and co-workers
reported the first synthesis of (-)-ushikulede A and confirmed its
absolute structure. Due to interesting biological activity and scarcity
of the natural abundance attracted our attention to its synthesis.
Herein, we disclose an asymmetric synthesis of spiroketal fragment of
(-)-Ushikulide A.
Scheme 19: Retrosynthesis of Spiroketal fragment of (-)-Ushikulide A
18
Scheme 19 discribes our retrosynthetic analysis of spiroketal of
Ushikulide A, providing a convergent synthetic strategy. It was
achieved
from
acid
catalysed
spiroketal
formation
of
tosmate
compound, which was prepared from coupling of two iodo compounds
71 and 73 with tosyl isocyanide produced 72. The two iodo
compounds were obtained from tetrahydropyran moity and which was
obtained from segment coupling prins cyclisation of α-actoxy ether.
The synthesis was began with known homo allylic alcohol 77, which
was prepared from (S)-Benzyl glycidal ether. TBDPS protection of
homo allylic alcohol 77 as TBDPS ether with TBDPSCl, imidazole in
CH2Cl2 produced compound 75 in 92% yield. The coupling of alcohol
75 and acid 76 with DCC, DMAP in CH2Cl2 gave compound 78 in 86%
yield. Reduction of ester followed acetylation with DIBAL-H, Py, DMAP
and Ac2O afforded acetoxy ether 79 in 92% yield. Prins cyclisation of
α-acetoxy
ether
79
using
BF3.OEt2,
tetrahydropyran moity 74 in 72% yield.
Scheme 20
19
AcOH
in
Hexane
gave
TBAF mediated deprotection of compound 74 in THF produced diol 80
in 92% yield. Tosylation of compound 80 using p-TSCl, TEA in CH2Cl2
produced compound 81 in 86% yield. Tosyl group in 81 was converted
into iodo using NaI in acetone produced compound 82 in 90% yield.
Reductive opening of iodo compound 82 with Zn/MeOH gave diol 83
in 92% yield. Acetonide protection of diol 83 with 2,2 DMP, p-TSCl in
CH2Cl2 followed by debenzylation using Li/napthelene produced
compound 85 in 86% yield for two steps. Iodonation of compound 85
with I2, TPP, Imidazole in THF afforded compound 71 in 88% yield.
Scheme 21
Protection of secondary alcohol in compound 81 as TBS ether with
TBSOTf, 2,6 lutidine in CH2Cl2 produced compound 86 in 96% yield.
Gilman’s reaction of tosyl compound 86 with dimethyl cuprates in
ether afforded compound 87 in 86% yield. Debenzylation of compound
87 using Li/Napthlene in THF produced alcohol 88 in 92% yield.
20
Iodination of primary alcohol 88 using I2, TPP, imidazole in THF
produced compound 89 in 86% yield. Reductive opening of iodo
compound 89 using Zn/MeOH furnished compound 90 in 82% yield.
Compound 90 reacted with NaH, BnBr in THF produced compound
91 in 82% yield. Hydroboration and followed by iodination of
compound 91 with 9-BBN, MeONa in THF produced compound 73 in
80% yield.
Scheme 22
On the other hand, Coupling of compound 71 with tosyl
isocyanate 72 using n-BuLi, HMPA in THF afforded compound 92 in
92% yield. Coupling of compound 92 and compound 73 with n-BuLi,
HMPA in THF produced compound 70 in 86% yield. Finally,
21
compound 70 was subjected to p-TSA, MeOH afforded the Spiroketal
fragment 69 of (-)-Ushikulide A in 88% yield.
Scheme 23
22