ABSTRACT
The title of the thesis is “Application of Prins cyclisation to the synthesis of
(+) - Crocacin C, (-) - Basiliskamide A and B”. The quantum of thesis work carried out
is divided into three chapters.
Chapter I: This chapter describes introduction of Prins cyclisation, previous approaches
to the key intermediate 1,3 diols and its application in the synthesis of polyketide
natural products.
Chapter II: In this chapter the work is presented into two sections A and B.
Section A: This section includes introduction and previous synthetic approaches of (+)Crocacin C.
Section B: This section describes stereoselective formal synthesis of (+)-Crocacin C via
prins cyclisation.
Chapter III: The work carried out under this chapter is also depicted in two sections A
and B.
Section A: This section describes introduction, known synthetic approaches of
(-)-Basiliskamide A and B.
Section B: This section elaborates the stereoselective synthesis of (-)-Basiliskamide A
and B via prins cyclisation.
Chapter I:
This chapter describes introduction of Prins cyclisation, previous
approaches to the versatile intermediate 1,3 diols and its application in the synthesis of
polyketide natural products. The acid catalyzed condensation of olefins with aldehydes,
known as the Prins reaction. Scope of the prins cyclisation in the
synthesis of
multisubstituted tetrahydropyrans from aldehydes and homo allylic alcohols, is
expanded. A new approach for the stereoselective synthesis of polyketide precursors
containing 1, 3-diol units, flanked by divergent alkyl branches with different functional
groups..Polyketide
natural
products
pharmacologically
important
are
activities
known
including
to
possess
a
antimicrobial,
wealth
of
antifungal,
antiparasitic, antitumor and agrochemical properties. These metabolites are ubiquitous
in distribution and have been reported from organisms as diverse as bacteria, fungi,
plants, insects, dinoflagellates, mollusks and sponges.
Chapter II:
The Crocacins A (1), B (2), C (3), and D (4) are isolated from myxobacteria
belonging to the Chondromyces genus (Chondromyces crocatus and Chondromyces
pediulatus) and represent a second novel group of modified peptides from C. crocatus.
Crocacins are a group of electron transport inhibitors, which moderately inhibit the
growth of a few Gram-positive bacteria and are potent inhibitors of animal cell cultures
and several yeasts and fungi. Crocacin D(4) shows higher biological activity against
Saccharomyces cerevisiae as well as higher toxicity in L929 mouse fibroblast cell culture
when Compared to A(1), B(2) and C(3).
NH
OMe OMe
O
OR
N
H
O
O
R=Me:Crocacin B (2)
R=H : Crocacin A (1)
NH2
OMe OMe
O
Crocacin C (3)
NH
OMe OMe
O
O
N
H
OMe
O
Crocacin D (4)
Figure 1
These unusual linear dipeptides contain a reactive N-acyl enamine or enamide
functionality, which is present in a number of other myxobacteria metabolites as well as
natural products, isolated from marine sponges. Jansen and co-workers by means of
molecular modeling studies and NOE experiments proposed the relative configuration
of Crocacin A-D. The relative and absolute configuration was confirmed by its first total
synthesis as being 6S, 7S, 8R, and 9S. Crocacin C (3) is a structural fragment of Crocacin
A (1), B (2) and D (4). In order to provide sufficient material for more extensive
biological evaluation along with access to novel analogues, the thesis work is aimed to
synthesize the polyketide Crocacin C.
The Prins cyclisation has been emerged as a powerful synthetic tool for the
construction of multisubstituted tetrahydropyran systems and has been utilized in the
synthesis of several natural products. Recently at our institute Prins cyclisation is
extensively applied in the synthesis of various polyketide intermediates and explored
its application in the synthesis of some natural products. Taking leadsfrom such
pioneering work the synthesis of Crocacin C through Prins cyclisation is attempted,
succeded and the work carried out is presented in this chapter.
Retrosynthetical analysis (scheme 1) has envisaged that the crocacin C would be
easily constructed from aldehyde 6 and sulfone 7 . Aldehyde 6 was thought to be
elaborated from suitably substituted pyran system 8 with all required stereogenic
OMe OMe
centers along with a
Pyran
cyclisation
8
3
was
from
hydroxy methyl group at C-6
NH2
which would be
ring.
O
utilized in the opening of pyran
envisioned to be assembled through Prins
homoallylic
alcohol 9 and aldehyde 10 which in turn
OMe OMe
could be obtained
O
through
the
well
OEt
literature.
5
OMe OMe
O
O
N O O
S
S
7
+
6
OEt
OH
Me
HO
+
HO
O
8
OH
OBn
Me
9
O
OBn
Me
10
established
Scheme 1: The retrosynthetic analysis of Crocacin C.
Synthesis commenced from S-benzyl glycidyl ether 12. The Jacobsen resolution
of compound 11 using (R,R)-(salen)cobalt(II) precatalyst, aceticacid (AcOH) and H2O
(0.51 equiv) for 22 hours resulted in (S)-benzyl glycidyl ether 12 in 46% yield. Opening
of the epoxide 12 with propynyllithium, formed on treatment of condensed propyne
gas with n-BuLi, in the presence of boron trifluoride diethyl ether (BF 3.OEt2 ) in
tetrahydrofuran (THF) at –78oC resulted in homopropargyl alcohol 13. Birch reduction
of 13 using Na in liquid NH3 furnished trans homoallylic alcohol 9 in 6 hours in 86%
yield.
BnO
O
11
CH3CCH, n-BuLi
BF3.OEt2, THF
(R,R) Co-(salen)
AcOH,H2O, THF
BnO
O
12
0 oC-rt, 22 h
Na, liq. NH3
BnO
-78 oC, 2 h, 86%
OH
-33 oC, 6 h, 86%
13
OH
OCOCF3
10,TFA, CH2Cl2
0 oC-rt, 3 h
K2CO3, MeOH
OH
OH
O
9
HO
OBn
OBn
O
Me 10
HO
O
30 min, rt, 55%
8
14
OMe
OH
TBSCl, imid, CH2Cl2
TBSO
0 oC-rt, 6 h, 86%
NaH, MeI, THF
O
15
TBSO
10 min,
-33 oC,
88%
TBSO
O
OBn
OBn
16
0 oC-rt, 6 h, 90%
OMe
Na, liq. NH3, THF
OBn
OMe
MOMCl, DIPEA
CH2Cl2
O
OH
TBSO
rt, 6 h, 94%
17
O
OMOM
18
OMe
TBAF, THF
HO
rt, 4 h, 94%
O
19
OMOM
Scheme 2
Subjection of homoallylic alcohol 9 to crucial Prins cyclisation with aldehyde 10
using trifluoroacetic acid (TFA) in CH2Cl2 resulted in tetrasubstituted pyran 8 in 55%
yield after hydrolysis of corresponding trifluoroacetate 14 using potassium carbonate
(K2CO3 ) in methanol. Stereochemistry was assumed to be in anticipated line as it was
well examined and established previously. Primary hydroxy group of 8 was selectively
protected as TBS ether using 1.1 equivalents of tert-butyl dimethylsilyl chloride (TBSCl)
and imidazole to give 15. Secondary hydroxy group in Compound 15 was transformed
into methyl ether using sodium hydride (NaH) and methyl iodide (MeI) to produce
fully protected 16. Debenzylation of 16 under Birch conditions provided corresponding
1o alcohol 17, which on protection using methoxy methylchloride (MOMCl) and N,N-
Diisopropylethylamine
(DIPEA)
in
CH2Cl2
resulted
compound
18.
Tetra-n-
butylammonium fluoride (TBAF) mediated cleavage of pyran silyl ether in 18 resulted
in 6- pyranyl methanol 19 in 94 % yield.
OMe
OMe
HO
b) TPP, I2, imidazole
benzene, rt
O
19
I
OMOM
2h, 95%
20
OMe
OMe
silica
rearrangement
NaH, DMF
rt, 12 h
OMOM
O
O
21
OMOM
83%
O
22
OMOM
Scheme 3
Compound 19 on treatment with triphenyl phosphine (TPP), iodine and
imidazole in benzene yielded corresponding iodo compound 20. Elimination of HI from
20 using NaH in N,N-dimethylformamide (DMF) produced enolic exo olefin 21 which
on column chromatography revealed rearranged product 22. In fact, it is anticipated
that rearranging the exo-olefin 21 to the more stable endo-olefin 22 in an acidic medium
but rearrangement occurred on silica gel during flash chromatography. To confirm that
the elimination reaction itself did not result in rearranged product, the crude product of
elimination reaction is analysed for its protan
nuclear magnetic spectroscopy (1H
NMR) which clearly revealed the presence of two doublets at d = 4.33 and 4.09 ppm (J =
2.2 Hz, geminal coupling) and absence of any characteristic signal regarding rearranged
product.
OMe
OMe OAc
O3, TPP, CH2Cl2
then TPPCH2, tBuOK
OMOM
O
K2CO3, MeOH
OMOM
THF, -78 oC- 0 oC, 74%
23
22
styrene, Grubbs-II cat.
benzene, 50 oC, 12 h, 82%
or
OMe OMe
OMe OH
OMOM
rt, 2 h, 96%
NaH, MeI, THF
OMOM
0 oC-rt, 6 h, 90%
25
24
PhI, Pd(OAc)2 TPP, TEA
DMF, 100 oC, 8 h, 65%
OMe OMe
OMe OMe
OMOM
TFA:CH2Cl2 (3:1)
OH
rt, 6 h, 90%
26
27
OMe OMe
Dess-Martin reagent
CH2Cl2, rt, 2 h, 88%
O
6
Scheme 4.
The substrate 22 was subjected to ozonolysis to obtain corresponding acetoxy
aldehyde, which without purification was treated with one carbon ylide to furnish open
chain olefin product 23. Hydrolysis of acetate group in 23 using K2CO3 in MeOH
resulted 2o alcohol 24, followed by etherification of resulting 2o alcohol with NaH and
MeI in THF afforded methyl ether 25. For the remaining task of inserting phenyl group
on olefin function in an anti fashion, we explored two different methods. First, we
opted cross metathesis with styrene using Grubb’s II catalyst to obtain 26 in 82% yield.
Next, we tested Heck coupling of 25 with iodobenzene using Pd(OAc)2, Ph3P, triethyl
amine (TEA) in DMF to obtain 26 in 65% yield. Deprotection of MOM ether group in 26
using TFA in CH2Cl2 furnished alcohol 27 which in all respects was identical with the
reported one. Oxidation of alcohol 27 with Dess-Martin reagent yielded corresponding
aldehyde 6.
O
N
SH + Cl
S
28
N
r,t , 5h, 92%
S
O
S
OEt
S
PPh3=CHCO2Et
S
benzene, reflux, 68%
29
Oxone
(THF,H2O,MeOH=2:1:1)
O
N
Et3N, THF
12h, 90%
30
N O O
S
S
7
O
OEt
Scheme 5
The
sulfone
7
required
for
coupling
was
synthesized
from
mercaptobenzolthiazole 28 which on treating with chloroacetone in the presence of
triethylamine in THF provided 29. Wittig reaction of β-keto sulphide 29 with stabilized
yilide provided conjugated ester 30. Followed by oxidation of sulfide with oxone
yielded sulfone 7 in 90%.
OMe OMe
OMe OMe
O
6
OEt
7, LiHMDS, -78 oC
THF, 1 h, 56%
O
5
Crocacin C
Scheme 6
Ultimately the aldehyde 6 was treated with sulfone 7 in the presence of
lithiumhexamethyldisilazane (LiHMDS) in THF at -78 oC, was resulted the E-olefin
ester 5 in 56% yield, the spectral and physical data of 5 were in good agreement with
those reported.
The compound 5 was already converted to the final target crocacin C by furthur
one step, this advanced intermediate 5 has been utilized for the synthesis of all the
crocacins (A, C, D). Thus formal total synthesis of Crocacin C was achieved.
Chapter III:
Basiliskamides A (1) and B (2) were co-isolated by Andersen and co-workers in
2002 from the marine bacterium PNG-276 off the coast of Papua New Guinea. Initial
biological studies showed that both basiliskamide A and B showed the antifungal
activity against Candida albicans and Aspergillus fumigatus. Basiliskamides A and B are
structurally identical in every respect except for the position of the cinnamate ester: C9
in basiliskamide A and C7 in basiliskamide B. The same authors elucidated the
structures after rigorous analysis of spectral and comparative data. Inspired by the
biological properties and structural closeness to other biologically active polyketides
natural products like crocacins, YM-47522 and pironetin. The synthesis of
basiliskamides A and B via Prins cyclisation is aimed in this thesis work. A
stereoselective total synthesis of basiliskamide A and B via
Prins cyclisation and
reductive opening sequence is systametically executed.
Through the synthetic analysis (scheme 7), it is envisaged that the core part of
both the molecules could be easily drawn from pyranyl methanol 3 via Mitsunobu
inversion. Pyranyl methanol 3, however, could be easily constructed via Prins
cyclisation from homo allylic alcohol 4 and (S)- 2 methyl 1- butanal 5.
O
O
OH
Ph
Ph
O
O
OH
H2N
H2N
O
O
Basiliskamide B (2)
Basiliskamide A (1)
OH
HO
Prins
cyclisation
O
3
+
OH
OH 4
O
Me
5
Scheme 7: The retrosynthetic analysis of Basiliskamide A and B.
Synthesis of Basiliskamide A :
Synthesis of Basiliskamide A is outlined in Scheme 8. Synthesis started from
opening of (R)-benzyl glycidyl ether 6 with propynyllithium, formed on treatment of
condensed propyne gas with n-BuLi, in the presence of BF3.OEt2 in THF at –78 oC
resulted in homopropargyl alcohol 7. Birch reduction of 7 using Na in liquid NH3
furnished trans homoallylic alcohol 4 in 6 hours in 86% yield. Prins cyclisation between
homo allylic alcohol 4 and (S)- 2 methyl 1- butanal 5 in the presence of TFA resulted in
ttrifluoroacetate 8, which as a crude on treatment with K2CO3 in MeOH gave
tetrahydropyran diol 3 in 50 % yield.
CH3CCH, n-BuLi
BF3.OEt2, THF
BnO
6
O
oC,
-78
Na, liq. NH3
BnO
7
2 h, 86%
OH
-33 oC, 5 h, 86%
OH
OH 4
OH
OCOCF3
5,TFA, CH2Cl2,rt, 3 h,
K2CO3, MeOH
4
HO
O
Me
5
HO
rt, 30min, 50%
O
3
8
OH
OH
TBSCl, imidazole
CH2Cl2
0 oC-rt,
O
TBSO
3 h, 85%
DEAD, PNB, TPP
THF, 0 oC-rt, 30min,
O
9
TBSO
O
then K2CO3, MeOH
rt,30min, 80%
10
OTIPS
OTIPS
TIPS(OTf )2,
2,6-lutidine
0
oC-rt,
TBSO
95%
CSA, MeOH,CH2Cl2 (7:1)
O
11
HO
O
0 oC-rt,10min, 92%
12
OTIPS
OTIPSOH
TPP, I2, imidazole
benzene, rt, 2h, 95%
I
Zn, EtOH, NaHCO3,
O
13
reflux, 2 h, 92%
14
Scheme 8
Protection of prins compound 3 as TBS ether 9 and inversion of secondary hydroxyl
group by using Mitsunobu's protocol produced pyranol 10 in 68 % over all yield. Protection of
inverted alcohol as triisopropylsilyl (TIPS) ether 11 and deprotection of TBS group resulted in
pyranyl methanol 12 in 87 % over two steps. Hydroxyl group in 12 was converted to iodo using
Ph3P, imidazole and iodine to give 13 which on reductive opening using Zn in EtOH furnished
homoallylic alcohol 14 in 87 % combined yield. Esterification of resulting alcohol with transcinnamic acid using dicyclohexylcarbodimide (DCC) and 4-dimethylaminopyridine (DMAP)
yielded 15 in 90 %.
O
OTIPSOH
trans-cinnamic acid
DCC, DMAP, CH2Cl2
Ph
OTIPSO
0 oC-rt, 6 h, 90%
14
15
O
i) AD-mix-alpha CH3SO2NH2
tBuOH: H O (1:1), 24 h
2
Ph
OTIPSO
CrCl2, CHI3
dioxane:THF (6:1)
O
ii) NaIO4, THF:H2O (2:1), 2 h
12 h, 85%
16
O
OTIPSO
O
Ph PdCl2(CH3CN)2
OTIPSO
DMF, rt, 36 h, 74%
I
17
H2N
O
18
SnBu3
Ph
H2N
O
19
O
OH
70%,HF-Pyridine
THF, rt, 12h, 75%
O
Ph
H2N
1
O
Basiliskamide A
Scheme 9
The terminal olefin group in 15 was selectively subjected to dihydroxylation
using AD-mix-α, followed by oxidative cleavage of resulting diol using NaIO 4 revealed
corresponding aldehyde 16, which on treatment with chromium(II)chloride (CrCl2 ) and
iodoform (CHI3 ) yielded trans vinyl iodide 17 in 60 % in 3 steps. The remaining formal
stille coupling of 17 with cis vinyl stannane 18 using PdCl2(CH3CN)2 produced 19 which
on cleavage of TIPS ether with hydrofluoric acid (HF) in pyridine furnished the natural
product Basiliskamide A 1 in 60% combined yield. Synthetic compound showed
spectral and analytical data (1H NMR, 13C NMR, IR, Rf and D) identical to the isolated
sample.
Synthesis of Basiliskamide B:
OH
OH
DEAD, TPP
trans-cinnamic acid
TsCl, TEA, CH2Cl2
HO
TsO
O
3
O
0 oC-rt, 6 h, 90%
THF, 0 oC-rt, 2h, 75%
20
O
O
Ph
O
TsO
NaI, acetone, reflux
Zn, EtOH, NaHCO3
I
O
24 h, 92%
21
O
22
reflux, 4 h, 85%
O
O
Ph
Ph
O
O
OH
MOMCl, DIPEA
DMAP, CH2Cl2
Ph
O
OMOM
0 oC-rt, 6h, 95%
24
23
Scheme 10
The synthesis of the other target basiliskamide B 2 is described in Scheme 11.
Although, the structures of the basiliskamides A & B are just differentiated by the
position of cinnamoyl moiety. Prins cyclisation product 3 was protected as tosylate
using tosyl chloride in triethylamine to give 20 in 90% yield. We observed that the 1H
NMR specturm of this compound was suitable for analysis where it showed clear
signals of H-2 (2.90, dd, 1H, J = 9.8, 1.5 Hz), H-4 (3.32, ddd, J = 12.0, 4.5, 2.2 Hz) and H-5
(1.94, ddd, 1H, J = 13.5, 9.8, 4.5 Hz) with coupling constants consistent with the
equatorial disposition of all the substituents on the ring. Thus, the 2o hydroxyl group in
20 was inverted with cinnamic acid, diethyl azodicarboxylate (DEAD) and Ph3P to give
the cinnamic ester 21 with the required configuration. Then the tosyl group in 21was
replaced by iodide in presence of NaI in acetone to yield 22 which on subsequent to
reductive elimination using Zinc in ethanol (EtOH) yielded the homoallylic alcohol 23
in 3 steps with a 58 % yield. Protection of the resulting alcohol as its MOM ether using
MOMCl, DIPEA and DMAP gave 24.
O
Ph
O
OMOM
i) ADmix-alpha, CH3SO2NH2
tBuOH:H O (1:1), 24 h
2
ii) NaIO4, THF:H2O (2:1), rt, 2 h
24
O
O
Ph
OMOM
I
iii) CrCl2, CHI3
dioxane:THF (6:1), 12 h, 83%
25
O
BCl3, CH2Cl2,
,
18 PdCl2(CH3CN)2
OH
O
Ph
I
-78 oC, 4h, 70%
DMF, rt, 24 h, 74%
26
O
O
Ph
OH
H2N
2
O
Basiliskamide B
Scheme 11
Selective dihydroxylation of the terminal olefinic compound 24 followed by
oxidative cleavage produced an aldehyde which on Takai,s iodoolefination gave trans
olefin 25 in 72% over all yield. Cleavage of MOM ether in 25 was achieved using
borantrichloride (BCl3 ) in CH2Cl2 at –78oC, the resulting hydroxy iodo olefin 26
underwent Stille coupling with 18 smoothly to furnish basiliskamide B 2 in 52 % yield
in 2 steps. The synthetic sample was identical in all respects (1H NMR, 13C NMR, IR, Rf
and D) to the isolated compound.