The thesis entitled “Total synthesis of Chapter I deals with the historical and
bistramide A” is divided into three biological background of bistramides,
chapters. CHAPTER-I:
including their isolations, structural
elucidation and previous synthetic
approaches.
CHAPTER-II:
Chapter II deals with the synthesis of
C19-C40
spiroketal fragment
of
bistramide A.
CHAPTER-III:
This chapter is further divided into two
sections.
SECTION A:
Section A deals with the synthesis of
C1-C13 pyran fragment of bistramide
A.
SECTION B:
Section B deals with the synthesis of
C14-C18 γ-amino acid fragment and
completion of the synthesis of
bistramide A.
Bistramide A-D and K, constitute a novel class of bioactive marine natural products,
isolated from the marine ascidian Lissoclinum bistratum. They exhibit high cytotoxicity and
significant effects on cell cycle regulation. Bistramide A displays an IC of 0.03-0.32 μg/mL
50
+
for the P388/dox, B16, HT29, and NSCLC-N6 cell lines, inhibits Na conductance and is
selective towards the activation of a single protein kinase C (PKC) isotype δ. It is also
believed that bistramide A can inhibit nucleotide exchange by stabilizing the closed actin
conformation. These promising biological activities of bistramide A have manifested it as a
potential candidate for cancer therapy.
Bistramide A skeleton consists of a substituted tetrahydropyran and spiroketal
subunit connected by a central γ-amino acid linker. Initially the Hawkins group from the
University of Queensland, Australia suggested a 19-membered macrocyclic lactum
structure for bistramide A. After three years the Ireland group from the University of Utah
revised the macrocyclic structure of Bistramide A and proposed the acylic structure without
assigning the absolute stereochemistry. The first synthesis of bistramide A was reported
by Kozmin and co-workers in 2004 confirming the assigned stereochemistry and
structure as illustrated in Fig 1. After Kozmin, Crimmins and Panek have reported the
synthesis of this molecule using different strategies. Additionally Wipf et al reported the
synthesis of bistramide C which is structurally related with bistramide A. Intrigued by its
excellent biological activity and interesting molecular architecture, we became interested in
the total synthesis of bistramide A.
CHAPTER-II: Synthesis of C19-C40 fragment of bistramide A.
Retrosynthetic analysis:
Figure 1 depicts the disconnection of bistramide A (1) at C13 and C18 amide linkages to
afford spiroketal fragment 2 (C19-C40), γ-amino acid fragment 3 (C14-C18) and pyran
fragment 4 (C1-C13).
The spyroketal fragment 2 could be obtained via HWE olefination of aldehyde 5
with phosphonate 6. The aldehyde 5 was envisioned to be derived via spiroketalization of
dialkylated product 7, which in turn could be
obtained via alkylation of TosMIC 8 with iodo compounds 9 and 10. The iodo
compound 9 was anticipated to be prepared from dithiane 11 and epoxide 12, which could
be easily synthesized from ester 13 and olefin 14 respectively. Another iodo compound 10
could be obtained from lactone 15. The lactone 15 could also be prepared from allyl alcohol
16 which could be easily synthesized from 1,4-butane diol 17 through routine course of
reactions.
Synthesis of iodo compound 9:
Alcohol 14 was first protected as its benzyl ether with benzyl bromide and then treated
with m-CPBA in CH Cl to afford epoxide 18 (Scheme 1). This racemic epoxide was then
2
2
resoluted hydrolytically in presence of (S,S)-cobalt salen complex to get chiral epoxide 12
(96% ee).
Scheme 1
Commercially available alcohol 13 was first converted into its TBS ether 19 on
treatment with TBSCl and imidazole. DIBAL reduction of 19 followed by treatment with
1,3-propane dithiol in presence of BF .OEt
3
2
afforded dithiane 20 with concomitant deprotection of silyl group. The free hydroxyl
group of 20 was further protected as its TBDPS ether to afford compound 11. Lithiation of
11 with n-BuLi followed by treatment with epoxide 12 gave alcohol 21. Alcohol 21 was
further converted into its TBS ether 22. Treatment of 22 with Raney-nickel under H
2
atmosphere in EtOH afforded a primary alcohol via a concomitant debenzylation, which
was further converted into corresponding iodo compound 9.
Synthesis of iodo compound 10:
Synthesis of the iodo compound 10 is depicted in scheme 2. The 1,4-butanediol 17
was first protected as its mono benzyl ether 23 and the free
hydroxyl group was then oxidized under Swern conditions to afford an aldehyde which on
Wittig olefination produced trans α,β-unsaturated ester 24. Allane reduction of the ester
group of compound 24 furnished allyl alcohol 25. Sharpless asymmetric epoxidation of this
allyl alcohol using D-(–)-DIPT gave chiral epoxy alcohol 26 (93% ee). The epoxy alcohol was
then transformed into the corresponding iodo compound 27, which on treatment with Zn
and NaI gave chiral secondary allyl alcohol 16. Compound 16 was then treated with NBS
and ethyl vinyl ether to form bromo acetal 28. Treatment of this bromo acetal with nBu SnH in presence of catalytic AIBN led to stereoselective formation of product 29 (98%
3
de), which was further converted into lactone 15 via Jones oxidation. Reductive opening of
the lactone gave diol 30. The primary hydroxyl group of the diol was protected as pivalate
ester 31 and the secondary hydroxyl group was protected as its TBS ether 32. Deprotection
of the pivalate group by DIBAL reduction afforded the alcohol 33, which was further
converted into iodo compound 10.
Synthesis of spiroketal fragment 2:
After synthesizing the iodo compounds 9 and 10 we proceeded to complete the synthesis of
fragment 2 (Scheme 3). TosMIC 8 was first alkylated with iodo compound 10 in presence of n-BuLi
to afford mono alkylated product 34. Further alkylation of the anion generated from 34 with iodo
compound 9 gave dialkylated product 7, which on treatment with aq. HF in MeOH/THF afforded
spiroketal 35. Swern oxidation of alcohol 35 followed by Horner-Wadsworth-Emmons olefination
using 1-methyl-2-oxopropyl phosphonate provided an α,β-unsaturated ketone 36 (E:Z 10:1).
Reduction of the ketone 36 with Corey’s chiral oxazaborolidine yielded alcohol 37 (94% de, 93%
yield). The alcohol 37 was further protected as its TBS ether 38. Birch reduction of compound 38
gave an alcohol which was further converted into its corresponding azide 39 under Mitsunobu
conditions. Finally azide 39 was converted into 2 by treating with Me P in THF/H O.
3
2
Scheme 3
CHAPTER III, Section A: Synthesis of C1-C13 fragment of bistramide A
Retrosynthetic analysis of C1-C13 fragment:
The retrosynthetic analysis of C1-C13 fragment 4 is depicted in Figure 3. The trans C6 and
C11 geometry of fragment 4 could be easily obtained from acetate 40 via C-glycosidation with silyl
enol ether of ketone 41. Acetate 40 was envisioned to be derived from lactone 42, which in turn
could be obtained from the hydroxy ester 43 via lactonization. The C9 and C11 syn geometry
hydroxy ester 43 could also be obtained from nucleophilic opening of cis epoxide 44 with methyl
nucleophile. Compound 44 could in turn be obtained from alcohol 46 via epoxide 45 through a
routine course of reactions
Synthesis of pyran fragment 4 (C1-C13):
Synthesis of pyran fragment 4 is depicted in scheme 4. Alcohol 46 was first protected as its
benzyl ether 47 with BnBr. Formylation of compound 47 in the terminal acetylenic carbon
afforded alcohol 48. Catalytic hydrogenation of 48 in presence of Lindlar catalyst gave cis
olefin 49. Sharpless asymmetric epoxidation of 49 using (-)-DIPT afforded epoxy alcohol 45
(92% ee). The free hydroxyl group was then oxidized under Swern conditions to afford an
aldehyde which on Wittig olefination produced trans α,β-unsaturated ester 44. Treatment of
ester 44 with Me Al in presence of water following Miyashita’s protocol furnished regio3
and streoselectively the syn product 43. One-pot olefin reduction and benzyl ether
deprotection with Raney-nickel gave a mixture of hydroxy ester and lactone, which on
treatment with PPTS in refluxing CH Cl afforded the lactone 50 exclusively. The free
2
2
hydroxyl group of lactone 50 was protected as its TBS ether 42. Reductive acylation of 42
following Rychnovsky’s protocol produced acetate 40, which was treated with silyl enol
ether derived from ketone 41 in presence of TMSOTf to afford
exclusively alcohol 51. Alcohol 51 was further oxidized with H IO /CrO to yield
5
6
3
pyran fragment 4.
Synthesis of γ-amino acid fragment 3 (C14-C18):
After synthesizing the pyran fragment 4 we further proceeded to synthesize the γ-amino
acid fragment 3 (Scheme 5). Anti-aldol reaction of magnesium enolate of 52 with aldehyde
53, followed by treatment of the adduct with HCl afforded 54 with 90% de. The adduct 54
was converted into its Weinreb amide 55 on treatment with MeO(Me)NH.HCl. The free
hydroxyl group was protected as its TBS ether 56 with TBSOTf. Ozonolysis followed by
reductive workup gave alcohol 57, which was converted into its azide 58 under Mitsunobu
t
conditions. The amide group was hydrolyzed with KO Bu in THF/H O to afford acid 59. Acid was
2
then protected as its TIPS ester 60 and was converted into γ-amino acid fragment 3 via catalytic
hydrogenation.
Scheme 5
Completion of the synthesis of bistramide A:
Having synthesized all the three fragments 2, 3 and 4, we further proceeded to complete
the synthesis of bistramide A (Scheme 6). Coupling of tetrahydropyran subunit 4 and amine 3 in
presence of PyBOP furnished a TIPS ester, which was selectively deprotected with TBAF to yield acid
61. The final peptide coupling of acid 61 with amine 2 led to the formation of complete carbon
skeleton. Removal of the silyl protecting groups with PPTS completed the synthesis of bistramide A
(1). The synthetic compound was found to be identical with that reported earlier based on the
1
13
comparison of H NMR, C NMR, HRMS and optical rotation data.
Scheme 6
Thus we have accomplished a highly convergent and stereoselective synthesis of bistramide
A.