s n & f 0 ( p s i s SYNOPSIS

SYNOPSIS

The thesis entitled “ Synthetic Studies Directed Towards the Total Synthesis of (+)-Discodermolide” is divided into two chapters.

CH A PTER I: Towards the total synthesis of (+)-Discodermolide

SECTIO N A: This section deals with the biological importance of discodermolide and earlier synthetic approaches cited in the literature.

SECTIO N B: This chapter includes the stereoselective synthesis of C1-C7 and C8-C15 fragments o f the (+)-discodermolide.

CHAPTER II: LiC 104 catalyzed 1,3-dipolar cycloaddition reactions as well as Domino-

Knoevenagel hetero-Diels-Alder reactions.

SECTION A: A facile synthesis of cw-fused chromano[4,3-c]isoxazoles: LiC 104 accelerated 1,3-dipolar cycloaddition reactions.

SECTIO N B: A stereoselective synthesis of sugar fused furo[3,2-^)]pyrano[4,3-flTlpyran derivatives: Domino Knoevenagel hetero-Diels-Alder reactions.

C H A P T E R I:

SECTIO N A: This section describes the biological importance and earlier synthetic strategies of (+)-Discodermolide.

SECTIO N B: This chapter deals with the stereoselective synthesis of C1-C7 and C8-C15 fragments of (+)-discodermolide.

Discodermolide is a unique cytotoxic polyketide isolated by Gunasekara and co­ workers at the Harbor Branch Oceanographic Institute in 1990 from the extracts of rare

Caribbean deep sea sponge Discodermia dissoluta.^ Structurally, it bears 13 stereogenic n SYNOPSIS

centers, a tetrasubstituted 8-lactone (C1-C5), one di- and one trisubstituted (Z)-double

bond, a pendant carbamate moiety (C19), and a terminal (Z)-diene (C21-C24).

Discodermolide displays both potent cytotoxic activity against a wide variety of human

tumor cell lines and significant in vivo antitumor activity. The mode of action, similar to

that of paclitaxel, comprises binding and stabilization of microtubules leading to mitotic

arrest and cell death. Discodermolide is currently undergoing phase-I clinical trials.

The biological data obtained to date indicate that (+)-discodermolide holds great promise as a new chemotherapeutic agent for the treatment of cancer. Unfortunately, the supply of 1 is severely limited; the reported isolation yield is only 0 .002% (w/w from

frozen sponge), resulting in the acquisition of only 7 mg of natural product from 434 g of

sponge.' Thus, synthesis of (+)-discodermolide is an attractive, to date, the only

economical means of producing the quantities of 1 required for further biological

evaluation. To satisfy this we explored a highly convergent approach to (+)-

discodermolide 1 disconnecting the carbon backbone at C (7-8) and C (15-16) thus called

for construction of three advanced subtargets 2, 3, and 4 from a common precursor 5

possessing the triad o f stereogenicity that appears in each subtarget. Ill SYNOPSIS

RETROSYNTHETIC STRATEGY:

HO, OH O^NH,

, 0 H

^ o 1 (+)-DISCODERMOLIDE

O O ^ N H , .O P v Y ' 4 O HO,,

3 c + Hv^O 7 .xOH OBn

O S ch e m e - 1 2 FURAN

The synthesis of C1-C7 fragment of (+)-discodermolide began with the preparation of bicyclic alcohol 7 from bicyclic ketone 6 in a three step sequence using (-) - Ipc2B H asymmetric hydroboration^ as a key step. PCC oxidation of the bicyclic alcohol 7 gave the keto compound 8 . Baeyer-Vllliger oxidation of the resulting ketone 8 yielded the lactone 5 (Scheme-2). The lactone 5 so obtained was utilized as further common precursor for both the key fragments 2 & 3. IV SYNOPSIS

Sch em e - 2

The bicylic lactone 5 was opened with LiAlH 4 to obtain the triol 9. The primary

hydroxyl groups of the triol 9 were selectively protected using TBDPS-Cl and imidazole

to get the corresponding TBDPS ether 10 (Scheme-3).

L A H . T H F TBDPS-Cl, Imid.

O “C - R .T O OH OBn OH OH CHjClj, R.T -pB^PSO OBn OH OTBDPS O B n 9 10

Scheme - 3

Inversion of the hydroxyl group configuration at C-5 centre of compound 10

using Mitsunobu protocol^ failed. Alternatively we explored the oxidation reduction

strategy. Oxidation of compound 10 using Dess-Martin periodinane'’ followed by

reduction using NaBH 4 in MeOH/THF (4.1) afforded the required a-isomer 12 as the

major product. Gratifyingly, the desired a-isomer could be isolated by flash

chromatography. V SYNOPSIS

Dess-Martin Periodinane NaBH. 10 f'fii r i"^ CH 2CI2 OR OBn O OR MeOHATHF OR OBn OH OR 0 °C - R .T R=TBDPS R=TBDPS

11 12 9 :1 Scheme -4

T he B u 4NF-mediated desilylation of TBDPS groups gave the corresponding triol

13, which was further treated with 2,2-DMP and (cat) PTSA to give the acetonide

compound 14 (Scheme-5).

TBAF/THF 2,2-DMP

OH OBn OH OH (cat) PTSA, acetone OH OBn 0 ^ -0

1 3 14

S ch em e -5

Transformation of primary alcohol 14 to aldehyde 15 was achieved by treatment with IBX. The aldehyde 15 was then treated with NaC 102 and N aH 2?04 to yield corresponding acid 16. Treatment of crude acid 16 with catalytic amount of CSA in

MeOH cleanly promoted the lactonization to give the 8-lactone 17. IBX oxidation of the compound 17 gave the aldehyde 2 (Scheme-6). VI SYNOPSIS

,0 H N aC lO , (cat) C S A O O B n N a H 2P 04,H 202 O O B n M e O H

O B n 15 16 17

IBX/DMSO 0 ^ 0 ,

O B n 2

Schem e -6

After successful completion of C1-C7 fragment of (+)-discodermolide, we next turned our attention to the construction of C8-C15 fragment. The bicyclic lactone 18 obtained from bicyclic ketone 6 in a three step sequence using (+) - IpC2BH asymmetric hydroboration as a key step was alkylated using lithiumdiisopropylamide (LDA) and methyl iodide in dry THF at -78 °C to get the compound 19 (Scheme-7).

o O O. O L D A , M e l LiAlH^, THF \ THF, -78 °C 0 ‘>C-25 °C, 4h OH OBn OH OH

O B n O B n 18 19 20

2,2-Diemthoxypropane^

(cat) P T SA , Acetone OH OBn 0 ^ 0 21

Scheme - 7 VII SYNOPSIS

Reductive opening of the methylated bicyclic lactone 19 with LiAlH 4 liberated the triol

20. The triol 20 was further treated with 2, 2-DMP and (cat) PTSA in acetone to give acetonide compound 21 (Scheme-7).

IB X , D M S O NaClOj.NaH^PO,

OH OBn 0 ^ 0 O O B n 0 ^ 0

21 22

HO, (cat) C S A

O O B n 0 ^ 0 M e O H O B n 23 24

Scheme - 8

Oxidation of primary alcohol of compound 21 with IBX gave aldehyde 22; subjection of the resultant aldehyde to NaC 102 and N aH 2P 04 reliably delivered carboxylic acid 23. The crude acid 23 upon lactonization using catalytic amount of CSA in methanol gave the corresponding 5-lactone 24 (Scheme-8).

The free hydroxyl group of the 5-lactone 24 was protected as its TBDPS ether 25.

Removal of benzyl group of compound 25 was found to be unexpectedly troublesome. A wide range of reducing agents were screened including Pd/C, Pd (OH) 2/C and TiCU

However, all these experiments resulted in either poor yields or no reaction. Pleasingly, this benzyl ether was cleaved oxidatively on treatment with DDQ, to afford the corresponding alcohol 26 in 86% yield. The hydroxyl group was mesylated using VIII SYNOPSIS methanesulfonyl chloride and triethylamine to give the compound 27. Treatment of mesylated compound 27 with DBU resulted the a, p- unsaturated lactone 28 (Scheme 9).

HO. TBDPSO. TBDPSO^^^A^O^O T B D P S C l DDQ

Imidazole D C M : H^O ; 2 OH O B n O B n

24 25 26

TBDPSO. , 0 ^ 0 MsCI, EtjN TBDPSG^^^A^O v ^ O DBU (cat) D M A P CHjCl^

O M s

27 28

Schem e - 9

The a, P-unsaturated lactone 28 was converted to the allylalcohol 30 by reduction with DIBAL-H at -78 °C followed by reduction of the subsequent lactol 29 using NaBH 4_

CeCb (cat.) in MeOH at 0 °C. Protection of this allylic alcohol 30 as a pivaloyl ester

(PivCl, Triethylamine, 25 °C) followed by protection of the secondary hydroxyl group with TBSO Tf (2, 6 lutidine, 0 °C) led to compound 32 (Scheme-10). IX SYNOPSIS

D IB A L - H T B D P S O ^ ^ - ^ v ^ O ^ O H N aBH ,, (cat) CeCl, CH^Cij, -78 °C M e O H

28 29

O Piv PivCl, EtjN TBDPSO TBDPSO (cat) Pyridine, C H 2CI2

O Piv T B S O T f TBDPSO 2,6 - lutidine, 0 “C -R.T

S ch em e - 1 0

Selective removal of the less sterically encumbered TBDPS ether 32 was then achieved by using NH 4F to provide alcohol 33. IBX oxidation of the free hydroxyl functionality at C9 gave the aldehyde 24 in good yield (Schem e-11).

O P iv O P iv NH,F TBDPSO M eO H 60 “C

,O P iv

IB X , D M SO H

CHjCl^ O O T B S

34

Scheme -11 ^ SYNOPSIS

The aldehyde 34 was further elaborated to the acetylene compound 3 using Corey and Fuchs homologation method^ (Scheme-12). Further work is under progress in our laboratory to utilize these fragments in the total synthesis of (+)-Discodermolide.

,OPiv _ ^oPiv T P P / C B r ^

CH2CI2 O O T B S 34

n -B u Li

THF, -78 °C

Scheme - 12

CH APTER II: This chapter describes the development of novel methodologies and is divided into two sections.

S E C T IO N A ;

The construction of isoxazolidines by 1,3-dipolar cycloaddition reactions between nitrones and alkenes has been utilized by several groups in the total synthesis of alkaloids and many other nitrogen containing natural products.^ Owing to the labile nature of the

N'O bond under mild reducing conditions, isoxazolidines provide easy access to a variety of fascinating 1,3-difunctional aminoalcohols.^ Particularly, the intramolecular cycloaddition reaction is one of the most powerful synthetic methods for the construction of fused bicyclic isoxazolidine derivatives. In recent years, LiC 104 in diethyl ether XI SYNOPSIS

(LDPE) has evolved as a mild Lewis acid catalyst in promoting various organic transformations*. Organic solutions of lithium perchlorate provide a convenient reaction medium to perform reactions under neutral conditions. Furthermore, lithium perchlorate

in organic solutions is found to retain its activity even in the presence of amines. In this report, we wish to highlight our results on intramolecular nitrone cycloaddition reactions

in the presence of LiC 104 in acetonitrile to produce isoxazolidine derivatives in excellent yields.

Thus treatment of the 0-prenyl derivative of salicylaldehyde with phenyl hydroxylamine in the presence of 10 moI% lithium perchlorate in acetonitrile afforded the corresponding tetrahydrochromano[4,3-c]isoxazole in 90% yield with cf5-selectivity.

LiCjO^ R'-NHOH CH 3CN

Scheme -13

Similarly, benzyl hydroxylamine also reacted smoothly with citronellal to give the trans-

fused cycloadduct in 85% yield.

M e

,NHOH L iC lO ^ CHO CHjCN Me

Scheme - 14 XII SYNOPSIS

Table 1. LiClO^ catalyzed synthesis of tetrahydrochromanoisoxazoles

Entry Hydroxylamine Salicylaldehyde Product Time(h) Yield (%)

,CH a P h N H O H 6,5 90 'O La

b P h N H O H I A j “ 7.0 87

O M e Ph N ' O .

6.5 85

O E t Ph H ' ' - ‘5 d P h N H O H 6.0 90 'H P h O ^ 0 PhO^^^'O'^ P h C H „ N-0 . / ^ C H e PhCH,NHOH 7.5 85 fi 1 H O

P h C H ,, N-Q H 6.0 90 H V ^ o O M e Q N-Q 8.0 79 NHOH a O M e

NHOH 6.5 92

a: All products were characterised by 'H N M R , IR and Mass spectroscopy

b: Isolated and unoptimised yields XIII SYNOPSIS

SECTION B:

This section describes the synthesis of sugar fused furo[3,2-A] pyrano [4,3-i/] pyrans via domino knoevenagel hetero Diels-AIder reactions. Coumarin derivatives are widely distributed in Nature and are reported to have a wide range o f biological activities such as anti-coagulant, insecticidal, anthelmintic, hypnotic and anti-fungal activity.

Others are phytoalexins and are inhibitors of HIV protease.^’ The domino Knoevenagel intramolecular hetero-Diels-Alder reaction is one of the most powerful synthetic route for the synthesis of various heterocycles and natural products." Thus, treatment of 4- hydroxycoumarin with an 0 -prenyl derivative of a sugar aldehyde in the presence of sodium acetate in acetic acid at 80 °C resulted in the formation o f cw-fused pyrano[3,2-c] coum arin

AcOH, 80 °C

Scheme -15

Similarly acetyl acetone and methyl acetoacetate also reacted smoothly with sugar aldehyde to give the corresponding perhydrofuro[3,2-6]pyrano[4,3-c/]pyrans.

R' O O o ,"0 CH3C00Na R' H A c O H , 80 o c O O A h

1 f : R = R '= M e 3f; R=R'=Me Ig ; R=Me,R'=OMe 3g : R=Me,R'=OMe Scheme - 16 XIV SYNOPSIS

Table 1. Domino-Knoevenagel hetero-Diels-Alder reaction

E ntry 1,3- Dione Aldehyde Product Reaction Time (h) Yield (% )

6.5 82

\ OHC ' u 0 7 7.5 73

A "U h^ h\,„ o 5.0 80 o r

6.0 82

A h Me Me^ V V ! PT<'’Vx A 8.5 72 o ' N O > ^ P : v MeI o\ h

0 A Me 5.0 79 Me > ^ K V

O MeO^O MeOA 6.0 70 Me^'^O o-r

a: A ll products were characterised by ’H N M R , IR and Mass spectra, b: Isolated and unoptimised yields. XV SYNOPSIS

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