I Synopsis

SYNOPSIS
The thesis entitled Synthetic efforts towards Phorboxazole A, Nuphar alkaloids and development of new methodologies using TaCl5 as catalyst has been divided into four chapters. Chapter-I: This chapter deals with an introduction to cancer and the approaches cited in the literature towards the synthesis of phorboxazole-A, including the total syntheses. Chapter-II: This chapter deals with the chiron approach to phorboxazole A: Stereoselective synthesis of the C2-C16 bis-oxane fragment of the phorboxazole macrolide from D-glucose. Chapter-III: This chapter describes an efficient synthesis of advanced intermediate of Nuphar alkaloids from natural amino acid L-serine. Chapter-IV: This chapter describes the development of new methodologies using TaCl5SiO2 as catalyst, which is further divided into two sections. Section-A: This section describes with the three component coupling catalyzed by TaCl5SiO2: Synthesis of -amino phosphonates. Section-B: This section describes the cleavage of epoxides with aromatic amines catalyzed by TaCl5-SiO2. CHAPTER-I: An introduction to cancer and the approaches cited in the literature towards the synthesis of phorboxazole-A, including the total syntheses. CHAPTER-II: Chiron approach to phorboxazole A: Stereoselective synthesis of the C2C16 bis-oxane fragment of the phorboxazole macrolide from D-glucose. Phorboxazole A 1a and its C13 epimer phorboxazole B 1b are unique oxaneoxazole based macrolides isolated in 1995 by Searle and Molinski from the Indian ocean sponge Phorbas sp. These compounds show an exceptional cytostatic activity and antifungal activity. Phorboxazole A and B were tested against 60 tumor cell lines of the

II Synopsis U.S. National Cancer Institute (NCI), and they effected in vitro inhibition of cell growth with mean GI50 values of <1.6x10-9 M. Phorboxazole A arrests the cell cycle during Sphase. Together with the spongistatins, phorboxazoles are the most potent naturally The impressive biological activity and the unique structure of phorboxazoles have led to efforts directed toward the synthesis of these compounds. The first total synthesis of phorboxazole A was reported in 1998 by Forsyth and co-workers and subsequently by some other groups.
O 19 N OMe OMe Br 46 Me O 39 O OH OH 31 N O Me O Me 24 O 1 Me O 5 O 13 Y X

occurring cytotoxic agents discovered so far (Figure 1).

Phorboxazole A (1a) : X = OH, Y = H Phorboxazole B (1b) : X = H, Y = OH Figure 1

Our retrosynthetic analysis involved disconnections of the structure at the C(3146), the C(19-20) and the C(1-24) bonds, which led to the key building blocks 2, 3 and 4 respectively. The convergent synthesis of C31-C46 fragment 2 has been reported by our group. In continuation of our program on the total synthesis of phorboxazole A, herein we describe the synthesis of the C2-C16 bis-oxane portion 5 of phorboxazole A. Our synthetic strategy to the C2-C16 fragment 5 involves the chiron approach using D-glucose 6 as a replenishable starting material. The strategy for constructing the bis-oxane skeleton 5 is retrosynthetically outlined in scheme 1.

III Synopsis
Phorboxazole A (1a)

CHO OMe OMe Br Me H OMe 2 OBn O OMe O OEt HO O + H2N Me 3 Me Me OH +

O N

O 4

O MeO O

OBn

OBn

HO

O 5

MOMO

O 26

OBn O O OBn OH 20 OH MOMO O 22 O O

O O

D-Glucose
6

12

Scheme 1: Retrosynthetic analysis

1,2-5,6-Di-O-isopropylidene-glucofuranose 7 was prepared from D-glucose 6 by a well documented procedure. Diacetone-D-glucose 7 was converted into its

IV Synopsis corresponding xanthate 8 by treating with sodium hydride, carbon disulphide and methyl iodide in dry THF at 0 0C in 91% yield (Scheme 2). The xanthate 8 was then deoxygenated under Barton-McCombie protocol using tri-n-butyltin hydride and catalytic amount of azobisisobutyronitrile as radical initiator in dry toluene at reflux temperature to afford the 3-deoxyglucose 9 in 75% yield. Regioselective monohydrolysis of 5,6-Oisopropylidene group of 3-deoxyglucose 9 with 60% aqueous acetic acid at ambient temperature afforded the diol 10 in 75% yield. The diol 10 was transformed to 5,6-ene derivative 12 following the two-step procedure. Thus the diol 10 was converted to its dimesylate ester 11 under standard conditions using methane sulphonyl chloride and triethylamine in dichloromethane at 5 0C in 92% yield. Exposure of dimesylate ester 11 to excess NaI in butanone, smoothly effected the elimination to give the desired ene 12 in 70% yield (Scheme 2).

HO

OH O HO OH OH CuSO4, Acetone Conc. H2SO4 (cat.), 52% O

O O HO O O NaH, CS2, MeI THF, 0 0C-r.t., 1 h, 91%

6 D-Glucose O O

O S CH3S HO

O O

n-Bu3SnH, AIBN (cat.) Toluene, reflux, 8 h, 75%

O O O O 60% aq. CH3CO2H r.t., 12 h, 75%

O 8 OH O 10 O O O O

9 OMs O 11 O

TEA, MsCl CH2Cl2, -5

0C,

MsO

1 h, 92%

NaI, butanone reflux, 12 h, 70%

12

Scheme 2

The ene 12 was treated with 50% aqueous acetic acid and catalytic amount of conc. sulphuric acid to afford the lactol 13. The crude lactol 13 was reduced to triol 14 in

V Synopsis 67% overall yield using sodium borohydride in methanol at 0 0C (Scheme 3). The triol 14 was converted to fully protected form 16, employing selective protections. Initially, selective protection of triol 14 on treatment with catalytic amount of paratoluenesulphonic acid in acetone at room temperature afforded the 1,2-acetonide 15 in 76% yield. The secondary hydroxyl group in compound 15 was protected as its benzyl ether using sodium hydride and benzyl bromide in anhydrous THF at reflux temperature to afford 16 in 96% yield (Scheme 3).
O O

O O

50% aq. CH3CO2H Conc. H2SO4 (cat.) 50 0C, 2 h 13

OH OH

NaBH4, MeOH 0 0C - r.t., 1 h (67% overall yield)

12

OH OH 14 OH

PTSA (cat.) Acetone, r.t., 3 h, 76% O OH 15 O

NaH, BnBr, THF reflux, 8 h, 96%

O OBn 16 Scheme 3 O

Fully protected ene 16 was subjected to hydroboration conditions using BH3.DMS in dry THF followed by quenching the boron complex using 3N NaOH and H2O2 to afford the alcohol 17 in 80% yield (Scheme 4). The primary alcohol 17 was oxidized to aldehyde using iodoxybenzoic acid in DMSO/THF to afford the aldehyde 18 in 83% yield. The aldehyde 18 was further subjected to two carbon extension by Wittig olefination protocol using ethoxycarbonylmethylene triphenylphosphorane in benzene at room temperature to afford the ,-unsaturated ester 19 in 89% yield. The conjugated ester 19 was subjected to hydrolysis using catalytic amount of camphor sulphonic acid in methanol at room temperature to afford the diol 20 in 91% yield. The 7-hydroxy unsaturated ester 20 underwent a smooth and selective intramolecular oxy-anion Michael-reaction in the presence of NaH at 78 0C leading to the cis-oxane 21a in 82% yield (Scheme 4). A small

VI Synopsis amount (< 5%) of the corresponding trans-oxane 21b was also produced concurrently and was easily separated using silica gel column chromatography.

O OBn 16 O

i) BH3.DMS, THF, 0 0C ii) NaOH, H 2O2, 0 0C, 80%

HO OBn 17 O

IBX, DMSO, THF 2 h, r.t., 83%

OHC OBn 18 O

Ph3P=CH-CO 2Et, benzene O r.t., 12 h, 89%

O O 19 OBn O

CSA (cat.), MeOH r.t., 2 h, 91%

O O 20 OBn OH

OH

NaH, THF, -78 0C 4 h, 82%

OBn O HO O 21a cis O (20:1) +

OBn O HO trans O 21b O

Scheme 4

The free hydroxyl group of oxane 21a was masked as methoxymethyl ether using MOMCl and N,N-diisopropylethylamine in dichloromethane to afford 22 in 90% yield (Scheme 5). The ester 22 was subjected to partial reduction using DIBAL-H in dichloromethane at 78 0C to afford the aldehyde 23 in 86% yield.
OBn O HO O 21a OBn DIBAL-H, CH 2Cl2 -78 0C, 1 h, 86% MOMO O 23 Scheme 5 CHO O
iPr 2NEt,

OBn MOMCl MOMO O 22 O O

CH2Cl2, 0 0C, 6 h, 90%

VII Synopsis The aldehyde 23 was subjected to chiral allylation using (+)-allyl

diisopinocampheylborane to afford homoallyl alcohol 24 in 78% yield with a 9:1 diasteriomeric ratio (Scheme 6). We then planned to construct the lactone moiety 26 by ring closing metathesis (RCM) approach, for which initially homo allylic alcohol 24 was subjected to esterification using acryloyl chloride and diisopropylethylamine in dichloromethane at 0 0C resulting the unsaturated ester 25, which is required for the ring closing metathesis (RCM), in 93% yield. The ring closing metathesis (RCM) of the unsaturated ester 25 has been successfully achieved to reach the lactone moiety 26 in 94% yield (Scheme 6).
OBn (+)-allyldiisopinocampheylborane MOMO O 23 OBn
iPr 2NEt,

OBn

CHO

Et3N, H2O2, -78 0C, 1h, 78%

MOMO

O 24

OH

acryloyl chloride MOMO O 25 OBn O O

Grubb's catalyst, Ti(iOPr)4 CH2Cl2, 60 0C, 6 h, 94%

CH2Cl2, 0 0C-r.t., 4 h, 93%

MOMO

O 26

O Scheme 6

It was now planned for the construction of C5-C9 trans-pyran ring using 5 the following sequential reactions. The lactone 26 was subjected to partial reduction using DIBAL-H in dichloromethane at 78 0C resulting in lactol, which was converted as ethyl glycoside 27 using catalytic amount of camphor sulphonic acid in ethanol at room temperature in 86% yield. Reaction of ethyl acetal 27 with allyltrimethylsilane and catalytic amount of TMSOTf as a Lewis acid catalyst in dichloromethane at 0 0C temperature afforded the corresponding allyl substituted trans dihydropyran 5 as a single

VIII Synopsis isomer in 85% yield. Under these reaction conditions MOM group has got deprotected (Scheme 7).
OBn DIBAL-H, CH2Cl2, -78 0C, 30 min O 26 OBn allyltrimethyl silane TMSOTf, CH2Cl2, 0 0C, 1 h, 85% HO O 5 Scheme 7 O O then CSA, EtOH, 86% MOMO OBn

MOMO

O 27

OEt

In conclusion, we have successfully envisaged and executed the synthesis of C2C16 bis-oxane fragment of phorboxazole A 1a in a highly stereocontrolled manner starting with abundantly available precursor D-glucose employing advanced synthetic strategies like oxy-anion Michael addition, Browns chiral allylation and Grubbs ring closing metathesis. CHAPTER-III: An efficient synthesis of advanced intermediate of Nuphar alkaloids from natural amino acid L-serine. The six membered ring containing one nitrogen atom is a common structural feature among the known alkaloids. As a consequence, a central problem in alkaloid total synthesis has been concerned with the preparation and modification of piperidine derivatives. All Nuphar alkaloids are characterized by the presence of one or more furan rings and almost all display a quinolizidine core. Nuphar alkaloids could be prepared from advanced intermediate 42 after opening of aziridine with nucleophiles followed by cyclization reaction. Therefore, quinolozidinone would represent a late-stage intermediate, which could be transformed into a variety of Nuphar alkaloids after few steps. Some of the nuphar alkaloids are shown in figure 2.

IX Synopsis

Me OH N

Me H N 29 O (-)-Castoramine Me H N Me OH

Me H N OH 30 O (-)-Nupharolutine

28 O (-)-Nupharamine Me H N

31 O 7-Epideoxynupharidine

32 O (-)-Deoxynupharidine Figure 2

In retrosynthetic analysis chiral aziridine intermediate 42, was synthesized from naturally available L-serine. In the key step, hydroboration reaction produced chiral methyl center (anti with respect to amine group) with high diastereoselectvity (Scheme 8).

R NR

MPMO N 42 Boc

O NUPHAR ALKALOIDS O HO 33 NH2 L-Serine Scheme 8 OH O Boc N

38

X Synopsis Accordingly L-serine methyl ester hydrochloride 34 was prepared from L-serine 33, by a well documented procedure. L-serine methyl ester hydrochloride 34 was converted to Boc protected amine 35 using triethylamine and (Boc)2O in THF at 0 0C in quantitative yield (Scheme 9). The Boc protected amine 35 was converted to oxazolidine ester 36 using 2,2-dimethoxy propane and catalytic amount of BF3.OEt2 in dichloromethane at room temperature in 98% yield. The oxazolidine ester 36 was The transformed to isopropylidene derivative 38 following the two step procedure.

oxazolidine ester 36 was subjected to Grignard reaction using MeMgI in anhydrous ether at 0 0C for 30 minutes to afford the tertiary alcohol 37 in 96% yield. The tertiary alcohol 37 was subjected to mesylation using methane sulphonyl chloride and triethylamine in CH2Cl2 at 10 0C to yield the isopropylidene derivative 38 in 76% yield (Scheme 9).

O MeO NH2 33 L-serine O MeO OH

CH3COCl, MeOH reflux, 6 h

O MeO 34 O O N Boc 36 OH NH3+ Cl-

TEA, (Boc)2O THF, 0 0C - r.t., 8 h (quantitative yield)

MeO OH CH2Cl2, r.t., 4 h, 98% NHBoc 35

2,2-DMP, BF3.OEt2

MeMgI, Ether 0 0C, 30 min, 96%

HO O N Boc 37 Scheme 9 MsCl, TEA, CH2Cl2 -10 0C, 1 h, 76% Boc O N 38

XI Synopsis Isopropylidene derivative 38 was subjected to hydroboration conditions using BH3.DMS in dry THF followed by quenching the boron complex using 3N NaOH and H2O2 to afford the anti alcohol 39a in 87% yield (Scheme 10). A small amount of (< 5%) of the corresponding syn alcohol 39b was also produced concurrently and easily separated by silica gel column chromatography.

O N Boc 38

i) BH3.DMS, THF,0 0C, 8 h ii) 3N NaOH, H2O2, 87%, 3 h

HO N Boc 39a anti

O +

HO N Boc

O syn

(20:1)

39b

Scheme 10

The alcohol 39a thus obtained was protected as its p-methoxy benzyl ether using sodium hydride (60% w/v dispersion of oil) and p-methoxy benzyl bromide in anhydrous THF at reflux temperature to give 40 in 92% yield (Scheme 11). We now planned the construction of aziridine ring 42 using the sequential reactions. The MPM protected compound 40 was subjected to hydrolysis using 80% aqueous AcOH at room temperature to afford the amino alcohol 41 in 86% yield. The Boc protected amino alcohol 41 was subjected to Mitsunobu conditions in order to obtain aziridine intermediate 42 with anti stereochemistry. The amino alcohol 41 was treated with diethylazodicarboxylate and triphenylphosphine in THF at room temperature to afford aziridine 42 in 83% yield (Scheme 11).
HO Boc N NaH, PMB-Br THF, reflux, 8 h, 92% Boc 40 MPMO N O 80% aq.CH3CO2H r.t., 12 h, 86%

39a

MPMO

OH NHBoc 41

TPP, DEAD THF, 12 h, r.t., 83%

MPMO NBoc 42 Scheme 11

XII Synopsis In conclusion, we have successfully executed a novel route for the synthesis of chiral aziridine intermediate known for profound application in natural product chemistry starting from commercially available L-serine. CHAPTER-IV: Section-A: Three-component coupling catalyzed by TaCl5-SiO2: Synthesis of -amino phosphonates. The synthesis and use of -amino phosphonates have received attention as structural analogues of the corresponding -amino acids. Peptido mimetics made out of this class of compounds have shown promising pharmacological properties. They also play an important role in hapten design for antibody generation and enzyme inhibitors. Thus a variety of synthetic approaches are desired to synthesize -amino phosphonates. Of the methods available, the nucleophilic addition of phosphites to imines is a convenient and is usually activated by an alkali metal alkoxide and an acid. Lewis acids such as SnCl2, SnCl4 and BF3.OEt2, ZnCl2 and MgBr2 have also been used to promote the addition reaction, moreover no synthesis can proceed in one-pot from carbonyl compound, an amine and a phosphite. Herein, we disclose the TaCl5 catalyzed three-component coupling of carbonyl compounds, amines and diethyl phosphite to the synthesis of various -amino phosphonates (Scheme 12). We first investigated the reaction between p-tolualdehyde (entry 1, table 1), aniline and diethyl phosphite by stirring equimolar quantities in dichloromethane in the presence of TaCl5-SiO2 for 22 hours and isolated the desired amino phosphonate in 92% isolated yield. After this success, we specified several aldehydes, amines and diethyl NH2 R' + R'' + HO P OEt OEt TaCl5-SiO2 (10 mol%) CH2Cl2, r.t., 18-24 h HN R O P R' (OEt)2

O R

R''

R = alkyl, aryl R' = H, alkyl. R'' = H, NO2, OMe, OH, F.

Scheme 12

XIII Synopsis phosphite were examined in the presence of 10 mol% TaCl5-SiO2 in dichloromethane. The results are summarized in the Table 1. In this methodology, TaCl5-SiO2 co-ordinated with the nitrogen of the imine, facilitate the nucleophilic addition of diethyl phosphite to yield the -amino phosphonate. In all cases, the three-component coupling proceeded smoothly and the corresponding -amino phosphonates were isolated in good yields. The overall yield of this multi-component coupling was ranged from 8194% irrespective of the nature of the aldehyde or amine. The only limitation was noticed that aliphatic amines gave non characterisable products. In conclusion, we have demonstrated that TaCl5SiO2 is an efficient catalyst for the three-component coupling of a carbonyl compound, amine and diethyl phosphite to yield the -amino phosphonates, which can serve as a peptide mimetic. The advantages of this procedure are operational simplicity, general applicability to aldehydes and ketones at room temperature and high yields obtained. It was demonstrated for the first time that the TaCl5 has been found to be an efficient coordinating Lewis acid facilitating the nucleophilic addition of diethyl phosphite.

XIV Synopsis

Entry
1 2

Aldehyde/ketone
H3C CHO H2N

Amine

Time (h)
22 19

Yield (%)a
92

MeO

CHO

H2N

88

MeO

CHO

H2N

OMe

18

94

CHO

H2N

OMe

18

93

CHO

H2N

20

90

CHO OH

H2N

24

84

H3C

CHO

H2N

OMe

18

93

H3C

CHO

H2N

18

94

CHO

H2N

OMe

20 20

92 93

10

CHO Cl

H2N

11 Cl

CHO

H2N

OMe

18

88

Me 12 CHO H2N 20 92

13

CHO

H2N

22

85

14

O O

H2N

22

81

15

CH3

H2N

24

87

Isolated yield.

Table 1

XV Synopsis Section-B: Cleavage of epoxides with aromatic amines catalyzed by TaCl5-SiO2. Introduction of amino functionality into an organic molecule has highest prominence. This may be attributed to the fact that more than 75% of drugs and drug intermediates posses amino functionality. Of the several methods available in the literature for this transformation, epoxide opening with amines catalyzed by metal amides and triflates provides direct access to this class, while liberating a free hydroxyl group as an efficient handle for further manipulations. The resultant trans-1,2-amino alcohols play a major role as intermediates in the synthesis of unusual amino acids and chiral auxiliaries in asymmetric synthesis. Several clinically useful skeletons, which exhibit a broad range of activities as anti-obesity drugs and anti-hypertensive agents, also contain the 1,2-amino alcohol functionality. Interest in exploring the usefulness of TaCl5 as an efficient catalyst in organic synthesis en route to the total synthesis of clinically useful amino alcohols prompted us to explore the possibility of opening of epoxides with aromatic amines in the presence of TaCl5-SiO2 (scheme 13).
O + H2N 10 mol% TaCl5-SiO2 CH2Cl2, r.t. Scheme 13
(CH2)n

(CH2)n

OH N H R

n = 1, 2, 4

We first examined the reaction of cyclohexene oxide with aniline in the presence of TaCl5-SiO2 in anhydrous CH2Cl2 at ambient temperature to give the corresponding amino alcohol in 85% yield (entry1, Table 2). In conclusion, we have demonstrated a novel, mild and efficient method for the ring opening of epoxides with aromatic amines using TaCl5-SiO2 as a Lewis acid catalyst. This novel method is applicable to a wide range of substrates.

XVI Synopsis

Entry

Amino alcohols OH NRAr

Yield (%)a

1 2 3 4 5 6 7

R=H, Ar=Ph R=H, Ar=C6H4-p-OCH3 R=H, Ar=C6H4-oCH3 R=H, Ar=C6H4-o-COCH3 R=H, Ar=C6H4-p-Cl R=H, Ar=C6H4-p-Br R=Et, Ar=C6H5 OH NRAr R=H, Ar=Ph R=H, Ar=C6H4-p-OCH3 R=H, Ar=C6H4-o-CH3 R=H, Ar=C6H4-o-COCH3 R=H, Ar=C6H4-p-Cl R=H, Ar=C6H4-p-Br R=Et, Ar=C6H5 OH NRAr

85 82 79 78 75 77 73

8 9 10 11 12 13 14

83 80 76 76 74 75 72

15 16 a. Isolated yield.

R=H, Ar=Ph R=H, Ar=C6H4-p-OCH3

80 78

Table 2