Abstract

1

The thesis entitled “Formal synthesis of (+)-neopeltolide and studies directed towards

the total synthesis of carolacton” is devided into three chapters.

Chapter I: Formal synthesis of (+)-neopeltolide

(+)-Neopeltolide (1), a 14-membered marine macrolide, was isolated by Wright et

al.1 in 2007 from a deep-water sponge of the family Neopeltidae off the north coast of

Jamaica. The interesting structural features of 1 are: a trisubstituted 2,6-cis tetrahydropyran

moiety within the macro-lactone ring, 6-chiral carbons (3R, 5R, 7R, 9S, 11S, 13S), besides

the presence of an unsaturated oxazole-containing side chain at C5. It exhibited significant

and highly potent in vitro toxicity towards several cancer cell lines (A549 human lung

adenocarcinoma, NCI/ADR-RES ovarian carcinoma and P388 murine leukemia cell lines)

with excellent IC50 values of 1.2, 5.1 and 0.56 nM. respectively. It has also exhibited potent

antifungal (Candida albicans) and cytostatic activities (PANC-1 pancreate and DLD-1

colorectal adenocarcinoma cell lines) besides targeting cytochrome bc1 complex. The

biological activity coupled with structural complexity of 1 attracted several groups for its

total and formal synthesis2. This chapter describes formal synthesis of 1 by accomplishing

the synthesis of 2, through a transannular cyclization as key step in the construction of 2,6-

cis-disubstituted tetrahydropyran ring.

Retrosynthetic analysis (Scheme 1) of 1 revealed that the macrolactone 2 is late

stage intermediate, which could be synthesized from 3, that in turn could be realized from

bis-olefin 4. Ester 4 could be obtained from alcohol fragment 5 and acid fragment 6, which

in turn could be envisaged from L-malic acid as a common staring material. Thus, the key

synthetic strategy is to construct the macrolide ring through macrocyclization using RCM

protocol and finally formation of the tetrahydropyran ring through mercuric triflouroacetate-

mediated cyclization within the macrolide ring.

O

O

H H

O

O

O

N

O

HN

O

OCH3

(+)-neopeltolide (1)

1

35

7

9

11

13 OMe

Abstract

2

The synthesis of the acid fragment 6 was achieved from L-malic acid derived allylic

alcohol 83b

(Scheme 2). Accordingly, Sharpless asymmetric epoxidation of alcohol 8 with (-

)-DIPT, cumene hydroperoxide and Ti(OiPr)4 gave epoxy alcohol 9 (85%). Epoxide 9 on

regioselective reductive opening with Red-Al4 at 0 °C in THF and subsequent cleavage of

the 1,2-diol (side product) with NaIO4 afforded 1,3-diol 10 (80%). Diol 10 on treatment

with p-anisaldehyde dimethyl acetal and PPTS furnished 11 (79%), which on subsequent

regioselective reaction with DIBAL-H at 0 °C to room temparature for 4 h effected ring

opening and afforded alcohol 12 in 86% yield. Alcohol 12 on reaction with TBDPSCl and

imidazole gave silyl ether 13 (92%), which on reaction with CuCl2.2H2O furnished diol5 14

(79%). Diol 14 on a regioselective tosylation6 gave 15 in 95% yield, which, on further

reaction with K2CO3 in methanol furnished epoxide 16 (83%).

O

O

H HO

OH OMe

HO

OPMB OMOMO

+

OH

O

O

H H

O

O

O

N

O

HN

O

OCH3

O

OPMB

O

OMe

OMOM

OO

OMOM

1: neopeltolide

23

46

7

OH

1

35

7

9

11

13

Retrosynthetic strategy of neopeltolide 1

OMeOMe OMe

L-malic acid

5

Scheme 1

Abstract

3

Treatment of epoxide 16 with vinylmagnesium bromide in the presence of CuI7 in

THF at -20 °C gave homoallylic alcohol 17 in 82% yield, which on protection with MOM-

Cl and iPr2NEt afforded 18 (92%). Desilylation of 18 with TBAF in THF furnished alcohol

19 (85%), which on subsequent oxidation with TEMPO and BAIB8 gave acid 6 in 70%

yield.

Alcohol fragment 5 was synthesized from L-malic acid derived aldehyde 203a

(Scheme 3). Accordingly, 20 on reaction with n-propylmagnesium bromide in THF

afforded diasteromeric mixture of carbinols 21 (1.5:1) in 70% yield, which on oxidation

under Swern reaction conditions gave ketone 22. Chelation controlled reduction of ketone

22 with LiAlH4 and LiI furnished the syn alcohol 23 in 81% yield (95% de),9 which on

silylation with TBDPSCl and imidazole afforded ether 24 (82%). Acetonide deprotection in

24 with CuCl2.2H2O gave diol6 25 in 75% yield. Regioselective protection of primary

alcohol in 25 with benzoyl chloride7 furnished 26 in 94% yield, which on further reaction

with p-TsCl and Et3N afforded 27. Reaction of 27 with K2CO3 in methanol led to the

hydrolysis of the benzoyl ester in 27, which on concomitant ring closure furnished epoxide

28 in 83% yield (for two steps). Epoxide 28 on alkynylation with alkynyl borane reagent

that was generated in situ at -78 °C by the reaction of 29 with n-BuLi and BF3.OEt210

in

THF afforded alcohol 30 in 67% yield.

OR

OH

TBDPSO

TBDPSO

O

a b, c d

g, h i

8 9 10

12 R = H13 R = TBDPS

14 R = H15 R = Ts

16

PMBO

PMBO

HO

OMOM

HOOC

OMOM

TBDPSO

OH

TBDPSO

OMOM

j k

m

17 18

19 6

l

BMPO

BMPO

BMPO

BMPO

O

OOH

O

OOH

O

OOH

OH

H

OH

O

OOR

OPMBO

O

OO

PMP

e, f

11

(a) (-)-DIPT, Ti(OiPr)4, Cumene hydroperoxide, 4 Å molecular sieves, CH2Cl2, -20 °C; (b) Red-Al, THF, 0 °C-rt; (c) NaIO4, sat.

NaHCO3, CH2Cl2, 0 °C-rt; (d) p -anisaldehyde dimethyl acetal, PPTS, CH2Cl2, 0 °C-rt; (e) DIBAL-H, CH2Cl2, 0 °C-rt; (f )

TBDPSCl, imidazole, CH2Cl2, 0 °C-rt; (g) CuCl2.2H2O, CH3CN, 0 °C-rt; (h) p -TsCl, Bu2SnO, Et3N, CH2Cl2; (i) K2CO3, MeOH, 0

°C-rt; (j) vinylmagnesium bromide, CuI, THF, -20 °C; (k) MOMCl, DIPEA, DMAP, 0 °C-rt; (l) TBAF, THF, 0 °C-rt; (m) TEMPO,

BAIB, CH2Cl2:H2O (1:1).

Scheme 2

Abstract

4

Alkylation of 30 with MeI in the presence of NaH gave ether 31 in 82% yield, which

on treatment with PPTS in methanol furnished 32 in 75% yield. Stereospecific reduction of

acetylenic group in alcohol 32 with Red-Al11

gave (E)-allylic alcohol 33 (94%), which on

Sharpless asymmetric epoxidation afforded the epoxy alcohol 34 in 75% yield. Epoxide 34

on regioselective opening with Me3Al12

in hexane at 0 °C furnished 1,2-diol 35 in 85%

yield, which on subsequent reaction with Ph3P, imidazole and I2 gave olefin

13 36 (70%).

Finally, ether 36 on reaction with TBAF underwent desilylation to afford alcohol 5 in 84%

yield.

To establish the relative configuration in 26, it was treated with TBAF to give 26a

(Scheme 3), which on further reaction with 2,2-dimethoxy propane and p-TsOH (cat.) in

CH2Cl2 furnished acetonide 26b. The 13

C NMR of 26b revealed the presence of two peaks

corresponding to the two methyl groups of the acetonide: at 19.7 ppm and 30.1 ppm,

charecterstic of a syn-1,3-diol derivative. 14

OBz

OH

OO

OBzH

H

1

234

5 6

q

26b

RO

p26 R = TBDPS

26a R = H

TBDPSO OHOTHP

TBDPSO OMeOR

TBDPSO OMe

OH

TBDPSO OMe

OH

OH

H

TBDPSO OMe

OH

OH

OH OMe

OTHP

TBDPSO OMe

iTBDPSO OR'

OR

TBDPSOO

29

b

d e, f , g h

j , k l

m n o

p

21 23

24 25 R = R' = H28

30 31 R = THP32 R = H

33

34 35 36

5

O

O

OH O

O

OH

O

O

OTBDPS

CHO

O

O

20

a O

O

O c

22

(a) n-propyl bromide, Mg, THF, 0 °C-rt; (b) (COCl)2, DMSO, Et3N, CH2Cl2, -78 °C; (c) LiAlH4, LiI, -40 to -100 °C; (d)

TBDPSCl, imidazole, CH2Cl2, 0 °C-rt; (e) CuCl2.2H2O, CH3CN, 0 °C-rt; (f ) BzCl, Bu2SnO, Et3N, CH2Cl2; (g) p -TsCl,

DMAP, Et3N, CH2Cl2, 0 °C-rt; (h) K2CO3, MeOH, 0 °C-rt; (i) n-BuLi, BF3.Et2O, THF, -78 °C; (j) MeI, NaH, THF, 0 °C-rt;

(k) PPTs, MeOH, 0 °C-rt; (l) Red-Al, Diethyl Ether, -20 °C; (m) (-)-DIPT, Ti(OiPr)4, Cumene hydroperoxide, 4 Å molecular

seives, CH2Cl2, -20 °C; (n) Me3Al, Hexane, 0 °C-rt; (o) Ph3P, I2, imidazole, CH2Cl2, 0 °C-rt; (p) TBAF, THF, 0 °C-rt; (q)

Me2C(OMe)2, p -TsOH, CH2Cl2, 0 °C-rt.

27 R = Bz, R' = Ts

26 R = Bz, R' = H

Scheme 3

Abstract

5

Having synthesized both the fragments 5 and 6, the study was then extended to the

synthesis of lactone 3 and then to lactone - pyran 2. Accordingly, esterification of 6 with

alcohol 5 (Scheme 4) using DCC and DMAP gave ester 4 in 67% yield. Ester 4 on ring

closing metathesis (RCM) under high dilution conditions with 10 mol% of Grubb’s second

generation catalyst afforded the 14-membered macrolactone 37 in 65% yield,15

which on

oxidative deprotection of PMB ether with DDQ gave δ-hydroxy alkene 3 in 90% yield.

With the completion of the synthesis of macrolactone 3, the attention was directed to

construct the 2,6-cis-tetrahydropyran ring by transannular cyclization.16

Accordingly, 3 was

subjected to iodocyclization17

with iodine in acetonitrile to give a mixture of isomers 38/38a

with the desired 2,6-cis-tetrahydropyran 38 as minor product, along with the major 2,6-

trans isomer 38a in 60% overall yield (38/38a = 15:85). In a further study, the attempted

OO

OMOM

OMe

CH3 OO

OMOM

OMe

CH3

OPMB

OO

OMOM

OMe

CH3

OH

OO

OMOM

OMe

CH3

OX

H H

OO

OMOM

OMe

CH3

OX

H H

a b

4 37

3

c

+d

38 X = I39 X = HgBr

OO

OMOM

OMe

CH3

OHgBr

H H

OO

OMOM

OMe

CH3

OH H

OO

OH

OMe

CH3

OH H

e f

39 40 2

(a) 5, DCC, DMAP, CH2Cl2, 0 °C-rt; (b) Grubb`s 2nd generation catalyst, CH2Cl2, rt; (c) DDQ,

CH2Cl2:H2O (19:1); (d) I2, CH3CN, -40 °C-0 °C (or) NIS, CH2Cl2, 0 °C-rt (or) Hg(CF3COO)2, CH2Cl2, 0 °C,

aq. KBr, rt; (e) n-Bu3SnH, AIBN, Toulene, ref lux; (f) con. HCl, MeOH, 0 °C-rt.

6

38a X = I39a X = HgBr

OPMB

Scheme 4

Abstract

6

cyclization of 3 with NIS in CH2Cl2 at 0 °C resulted in a moderate increase in the isomer

ratio (38/38a = 30:70) in 78% yield. However, oxymercuration18

of alcohol 3 with

Hg(CF3OO)2 in dry CH2Cl2 at 0 °C and treatment of the resultant organomercurial acetate

with saturated aq. KBr solution gave the 2,6-cis-tetrahydropyran 39 as a single product in

84% yield. The above results on the formation of a mixture of 38/38a on iodoetherification

and exclusive formation of 39 on oxymercuration can be rationalized based on the

conformational and steric factors respectively, as evidenced from literature.19

The structures of 38, 38a and 39 were established by 1H NMR (500 MHz, CDCl3)

data and assignments were made with the help of TOCSY and NOESY experiments. The

characteristic nOe between C3H/C7H in 39 (Figure 1) suggested that both the protons are on

the same face. This was further supported by nOe correlations between C7H/C9H and

C8H/C11H, confirming the structure of 39 [Figure 1(a)]. The energy minimized structure as

shown in Figure 1(b) is also in agreement with the assigned structure from NMR data.

a b

Figure 1: (a) NOESY spectrum (in CDCl3) of 39 (The nOes C3H/C7H, C7H/C9H and

C8H/C11H are marked as 1, 2 and 3 respectively), (b) Energy minimized structure of 39.

Further, treatment of 39 with Bu3SnH and AIBN in toluene at reflux afforded 40

(Scheme 4) in 93% yield, which on reaction with con. HCl in MeOH underwent MOM-

ether deprotection to give 2 in 86% yield. The spectral and analytical data of 2 is in

accordance with the data reported earlier.2k

O

O

O

O

O

H H

H

H g B r

H

O H

3 9

1

3

5

7

9

1 1 1 3

H

F1 (ppm)

2.02.42.83.23.64.0

F2

(ppm)

2.4

2.6

2.8

3.0

3.2

3.4

3.6

3.8

4.0

4.2

F1 (ppm)

2.02.42.83.23.64.0

F2

(ppm)

2.4

2.6

2.8

3.0

3.2

3.4

3.6

3.8

4.0

4.2

2.0

3.0

4.0

4.0 3.0 2.0

/ppm

/ppm

2

1

3

Abstract

7

Chapter II: Studies directed towards the total synthesis of carolacton by cross

metathesis (CM) strategy: Synthesis of C1-C7 fragment and macrolactone core (C7-

C19)

Carolacton 1 was discovered by Kirschning and Muller in the extract of a

Sorangium cellulosum strain So ce9620

in 2010. It exhibited activity against the antibiotic-

sensitive E. coli strain tolC, with MIC value of 0.06 μg/mL, 1 besides minor antifungal

activity21

and other applications.22

Carolacton 1 is a 12-membered macrolactone with 8-

stereogenic centers (3R, 4R, 6R, 9S, 10S, 14R, 17R, 18R). It has a 1,2-diol moiety, a trans

double bond in the lactone ring and a trisubstituted olefin with E-configuration, besides a

side chain containing keto carbonic acid. Schmidt and Kirschning23

reported the first total

synthesis of carolacton.

Retrosynthetic analysis of 1 as shown in Scheme 5, indicated that the cross

metathesis (CM) of olefins 2 (C8-C19) and 3 (C1-C7) would give macrolide 1.

Macrolactone 2 which is the late stage intermediate, could be synthesized from bis-olefin 4,

which in turn could be prepared from acid 5 and alcohol 6.

O

OH

OH

O OMeO

OH

O

OO

OH

1,5 Pentane diol

D-ribose

Carolacton (1)

68

+

2

OO

O

O

OHO

O

O

4

3

57

OH

OPMB

9

OH

Retrosynthetic analysis of Carolacton 1

OH

OMe

OPMB

TBSO

2+

3 HO

OMe

OPMBO N

OO

Bn1011

12

34

5

78

910

14

1618

Scheme 5

Abstract

8

Acid fragment 5 was planned from D-ribose 7, while alcohol 6 could be envisaged

from 1,5-pentane diol 9, through 8. Synthesis of 3 began from Evan’s chiral auxiliary 11.

Thus, the key synthetic strategy is to construct the macrolide ring through macrocyclization

using RCM protocol followed by the CM to accomplish the total synthesis of 1.

Synthesis of alcohol fragment 6 was intiated from the known allylic alcohol 9a24

(Scheme 6). Accordingly, Sharpless asymmetric epoxidation of alcohol 9a with (-)-DIPT,

cumene hydroperoxide and Ti(OiPr)4 gave epoxy alcohol 12 in 87% yield. Epoxide 12 on

regioselective opening with Me3Al in hexane at 0 °C furnished 1,2-diol 13 in 80% yield.

Oxidative cleavage of 13 with NaIO4 followed by Wittig reaction of aldehyde with

Ph3P=C(Me)CO2Et25

in toluene gave ester 14 in 88% yield. DIBAL-H reduction of 14

afforded the allylic alcohol 15 (85%), which on Sharpless asymmetric epoxidation with (-)-

DIPT, cumene hydroperoxide and Ti(OiPr)4 furnished epoxy alcohol 16 in 96% yield.

Further, epoxy alcohol 16 on treatment with imidazole, Ph3P and iodine in THF afforded

iodide 16a, which on reaction with NaI and zinc dust in MeOH furnished allylic alcohol

1726

in 88% yield. Reaction of 17 with NaH and PMBBr gave ether 18 in 88% yield.

TBDPSO OH

O

H

TBDPSO OH

OH

OPMB

O

MeO

OPMB

HO

OH

H

H

OPMB

HO

OH

a b

c, d

e

a) (-)-DIPT, Ti(OiPr)4, Cumene hydroperoxide, 4 Å molecular sieves, CH2Cl2, -20 °C; b) Me3Al, Hexane, 0 °C - rt; c) NaIO4,

aq. NaHCO3, CH2Cl2, 0 °C-rt; d) Ph3P=C(Me)COOEt, Benzene, ref lux; e) DIBAL-H, CH2Cl2, 0 °C-rt; f ) (+)-DIPT, Ti(OiPr)4,

Cumene hydroperoxide, 4 Å molecular seives, CH2Cl2, -20 °C; g) PPh3, imidazole, Iodine, THF, 0 oC-rt; h) NaI, Zinc dust,

MeOH reflux; i) NaH, PMB-Br, THF, 0 °C-rt; j ) TBAF, THF, 0 °C-rt; k) (COCl)2, DMSO, Et3N, -78 °C; l) Ph3P=CHCO2Me,

benzene, 80 °C; m) DDQ, CH2Cl

2:H

2O (19:1), 0 °C-rt.

f

g

OPMB

m6

TBDPSO OH

TBDPSOOEt

TBDPSOR

ORO

OPMB

f , g

h

k, l

9a 12 13

16 R = OH16a R = I

1920

2122

TBDPSOOH

O

e

TBDPSO

OH

i, j

18 R = TBDPS8 R = H

14 15

17

OPMB

HO

b

23

Scheme 6

Abstract

9

Desilylation of 18 with TBAF in THF furnished alcohol 18 (86%), which on Swern

oxidation followed by Wittig reaction afforded α,β-unsaturated ester 19 (93%) with E-

configuration. Reduction of 19 with DIBAL-H afforded allylic alcohol 20 (91%), which on

Sharpless asymmetric epoxidation with (-)-DIPT, cumene hydroperoxide and Ti(OiPr)4 gave

21 in 90% yield. Regioselective opening of 21 with Me3Al in hexane at 0 °C furnished 1,2-

diol 22 (79%), which on subsequent reaction with Ph3P, imidazole and I2 gave olefin 23 in

63% yield. Finally, treatment of PMB ether with DDQ afforded alcohol 6 in 60% yield.

In a further study on the synthesis of 2, esterification of the known acid 527

with

alcohol 6 under Yamaguchi conditions28

(Scheme 7) gave ester 4 in 69% yield. RCM

reaction of 4 with 10 mol% of Grubb’s second generation catalyst in toluene at reflux met

with failure and starting material remained as such. Attributing such a failure to get 24 from

4, it was planned to remove the acetonide protection. Accordingly, reaction of 4 with

trifluoro acetic acid29

gave diol 25 (73%), which on RCM with 10 mol% of Grubb’s second

generation catalyst in toluene at reflux afforded the 12-membered macrolactone 2 in 67%

yield, the specific optical rotation of 2 is []D25

-54.2 (c 0.57, CHCl3).

Having synthesized lactone 2, it was aimed at the synthesis of the other olefin 3

(Scheme 8). Accordingly, known alcohol 26,30

prepared from 11 (Scheme 8), on oxidation

under Swern conditions and subsequent Wittig reaction in benzene for 4 h afforded ester 27

in 93% yield. Reduction of 27 with DIBALH in CH2Cl2 at 0 oC for 4 h gave the allylic

alcohol 28 in 82% yield. Sharpless asymmetric epoxidation of allylic alcohol 28 with (+)-

DIPT, Ti(OiPr)4 and cumenehydroperoxide at -20

oC for 12 h furnished epoxide 29 in 81%

OOH

O O+

OH

OO

O

O

6

54

2OO

OH

OH

a) 2,4,6-trichlorobenzoyl chloride, Et3N, DMAP. toluene; b) Grubb`s 2nd generation catalyst, toulene, reflux; c) CF3COOH,

CH2Cl2, 0 °C-rt.

a

O O

O

O

22

23

c b

Xb

4

Scheme 7

Abstract

10

yield. Alcohol 29 on reaction with imidazole, Ph3P and I2 in THF at 0 oC-room temparature

for 15 min gave the corresponding iodide 29a in 88% yield, which on treatment with NaI

and zinc dust in MeOH at reflux for 2 h afforded 30 in 79% yield. Reaction of 30 with MeI

and NaH in THF at 0 °C to room temperature for 4 h furnished ether 31 in 91% yield.

Hydrboration of olefin 31 with 9-BBN in THF gave the alcohol 32 (72%), which on

treatment with PMBBr and NaH in THF for 6 h afforded 33 in 80% yield. Desilylation of

33 using TBAF at 0 °C to room temperature for 3 h furnished alcohol 10 in 78% yield,

which on oxidation under Swern conditions gave aldehyde 10a. Aldehyde 10a was

subjected to Roush crotylation31

reaction using (E)-crotyl boronate 34, generated from

trans-2-butene, KOt-Bu, n-BuLi, B(OiPr)3 and (-)-DIPT, to furnish the alcohol 35

exclusively in 84% yield. Silylation of 35 on reaction with TBSOTf and 2,6-lutidine in

CH2Cl2 for 2 h afforded ether 3 in 91% yield.

TBDPSO OH TBDPSO OMe

O

26 27

a) (COCl)2, DMSO, Et3N, CH2Cl2, -78 oC; b) Ph3P=CHCOOMe, Benzene, reflux; c) DIBAL-H, CH2Cl2, 0 oC-rt; d) (+)-

DIPT, Ti(OiPr)4, cumenehydroperoxide, 4 Å molecular seives, CH

2Cl

2, -20 oC; e) Imidazole, Ph

3P, I

2, 0 oC-rt, THF; f )

NaI, Zinc dust, MeOH, ref lux; g) MeI, NaH, THF, 0 °C-rt; h) 9-BBN, 4N NaOH, 30% H2O

2, THF, 0 °C-rt; i) NaH,

PMBBr, THF, 0 oC-rt; j) TBAF, THF, 0 oC-rt; k) 34, 4 Å molecular seives, toulene, -78 oC; l) TBSOTf , 2,6-lutidine, 0 oC-

rt.

TBDPSO OH

28

TBDPSO R

OH

H

29 R = OH29a R = I

TBDPSO

OH

30

TBDPSO

OMe

31

TBDPSO

OMe

OH

32

TBDPSO

OMe

OPMB33

R

OMe

OPMB

OMe

OPMB

OH

35

OMe

OPMB

TBSO

3

a, b c

d, e f g

h i j, a

k l

10 R = CH2OH

10a R = CHO

BCH3O

O

CO2iPr

CO2iPr

34

Scheme 8

Abstract

11

According to retrosynthetic strategy, lactone 2 and olefin 3 were subjected to cross

metathesis reaction32

(Scheme 9) using Grubb’s II catalyst in CH2Cl2 at room temperature

as well as at reflux. The reaction met with failure to give 36, while, olefins 2 or 3 or their

homo-dimerized products, also were not detected in the reaction.

Having met with failure in realizing the target by cross metathesis reaction of 2 and

3, it was proposed first to build the entire carbon skeleton by CM reaction of 39 and 3 and

subject it to esterification with 5 and macrocyclization. Accordingly, it was planned to

prepare 1 from 5 and 38 (C1-C16 fragment) by esterification and RCM reaction, while,

olefin 38 in turn could be synthesized from 39 and 3. Further 39 was envisaged from 22

(Scheme 10).

N N

Ru

PCy3Cl

Cl

Ph

MesMes

37

OMe

OPMB

TBSO

+O

OH

OH

O

OMe

OPMB

TBSOO

OH

OH

O

Grubb's II catalyst

XCH

2Cl

2, Ref lux

Scheme 9

2

3

36

OH OMe

OPMB

TBSO O

OH

O

O

+

+

O

O

OPMB OMe

OPMB

TBSO D (-) Ribose

Carolacton (1)

5

38

393

6

Retrosynthetic analysis of Carolacton 1

Scheme 10

22

Abstract

12

Thus, diol 22 on reaction with 2,2-dimethoxy propane and PTSA (cat.) in CH2Cl2

furnished acetonide 39 in 88% yield (Scheme 11). Treatment of 39 with DDQ gave the

allylic alcohol 40 in 79% yield. The cross metathesis reaction of 39 with 3 (Scheme 11)

using Grubb’s II generation catalyst 37 or Hoveyda Grubb’s II catalyst 41 in CH2Cl2 or

toluene at room temperature/reflux conditions gave the homo dimer 43 instead of giving

required 42. Similarly, the attempted CM of 3 with 40 gave 43 as an exclusive product,

while the expected product 42 could not be obtained.

From the above two synthetic sequences, where in both the coupling of 2 and 3 to

give 1; synthesis of C1-C16 fragment 38 from 39 and 3, it was amply evident that the

introduction of trisubstituted olefin (C7-C8) by CM is not feasible in the present study.

OPMB

HO

OH OPMBO

O

22 39

a) Me2C(OMe)2, p -TsOH, CH2Cl2, 0 °C-rt; b) DDQ, CH2Cl2:H2O (19:1), 0 °C-rt; c) 3, Grubb`s 2nd generation

catalyst (or) Hoveyda Grubb's 2nd generation catalyst, CH2Cl2 (or) Toulene, rt (or) ref lux.

OHO

O

a b

40

OMe

OPMB

TBSOO

O

OR

OMe

OPMB

TBSO

OMe

PMBO

OTBS

42

43

N N

RuCl

Cl

MesMes

O

41

+

c

c

Scheme 11

Abstract

13

Chapter III: Studies directed towards the total synthesis of carolacton by ring closing

metathesis (RCM) strategy: Synthesis of C1-C19 fragment of carolacton

Having observed that it is difficult to create the tri-substituted olefin C7-C8 by cross

metathesis, it was proposed first to create a segment with tri-substituted double bond (C7-

C8) by RCM reaction. Thus, in the new retro analysis, it was planned to have two iterative

esterifications and RCM reactions. Thus, 1 was envisaged from 44 by RCM, which in turn

would come from 45 and 5. Compound 45 with the tri-substituted C7-C8 double bond was

envisaged from 46, which in turn could be realised from 47 and 48 by esterification and

RCM. 47 in turn was planned from 3 (Scheme 12).

OMe

OMe

D (-) Ribose

6

OOO

O

O

OHO

O

O

5

TBSO

O

O OMe

OTBS

OMe

OH

TBSO O

+

44

47

BzO

OMe

OMe

OOH TBSO

OPMBOH

HO

OMe

OPMB

TBSO

+

Retrosynthetic analysis of Carolacton 1

45

46

3

22

Scheme 12

O

OH

OH

O OMeO

OH

O

Carolacton (1)

12

34

5

78

910

14

1618

Abstract

14

Accordingly, diol 22 was subjected to benzoylation with benzoyl chloride and Et3N

in CH2Cl2 at room temperature for 4 h to furnish benzoate 48 in 81% yield (Scheme 13).

For the synthesis of 47, compound 3 was treated with DDQ in CH2Cl2:H2O (19:1) at room

temperature for 2 h to afford alcohol 49 in 97% yield, which on oxidation using TEMPO

and BAIB in CH2Cl2:H2O (1:1) at room temperature for 1.5 h furnished acid 47 in 74%

yield. Further, esterification of acid 47 and alcohol 48 with DCC and DMAP in CH2Cl2 at

room temperature for 12 h afforded the ester 50 in 69% yield.

However, bis-olefin 50 on treatment either with Grubb’s II33

generation catalyst 37

in CH2Cl2 at reflux for 12 h or with Hoveyda Grubb’s II generation catalyst 41 in toluene at

reflux failed to give the required lactone 46. The above observations, led us to conclude that

the creation of a tri-substituted olefinic moiety is challenging in its reactivity and may be

abstructing both the CM and RCM reactions. Since both the earlier approaches, the

formation of double bond at C7-C8 position either by CM or RCM was difficult, to

circumvent the problems it was proposed to introduce the tri-substituted (C7-C8) olefin of

carolacton 1 by a Wittig reaction and extend the segment.

According to the modified retroanalysis, 1 could be obtained from 38, while 38

could be realized from the lactone 51. Esterification of 52 with 53 and RCM of ester would

give 51, while, 52 and 53 would be made from 11 and 3 respectively (Scheme 14).

OPMBOH

HO

OPMBOH

BzO

22 48

a) BzCl, Bu2SnO, Et

3N, CH

2Cl

2, rt; b) DDQ, CH

2Cl

2:H

2O (19:1), 0 °C-rt; c) TEMPO, BAIB, CH

2Cl

2:H

2O (1:1), 0 oC-rt;

d) 48, DCC, DMAP, CH2Cl2, 0 °C-rt; e) Grubb`s 2nd generation catalyst, CH2Cl2, ref lux or

Hoveyda Grubb`s 2nd generation catalyst, toulene, ref lux.

OMe

COOH

TBSO

47

OMe

OPMB

TBSO OMe

OH

TBSO

3 49

a

b c

BzO

O OPMBOTBSOMe

O

50

O

O OMe

OTBSBzO

X

46

d e

Scheme 13

Abstract

15

Accordingly, olefin 3 was subjected to ozonolysis in CH2Cl2 at -78 C for 15 min to

give the corresponding aldehyde, which on subsequent treatment with Ph3P=C(Me)CO2Et

in benzene at reflux for 2 h afforded 54 in 90% yield (Scheme 15). Reduction of ester 54 on

treatment with DIBAL-H in dry CH2Cl2 at 0 C for 1 h furnished allylic alcohol 55 in 87%

yield, which on further oxidation under Swern conditions gave aldehyde 55a. Roush

crotylation reaction of 55a using (E)-crotyl boronate 56, generated from trans-2-butene,

KOt-Bu, n-BuLi, B(OiPr)3 and (+)-DIPT, afforded the alcohol 53 in 67% yield.

OPMB

OH TBSO OMe

53

OMe

OPMB

TBSO OMe

OPMB

TBSO

EtO

O

3 54

a, b

OMe

OPMB

TBSO

HO

55

OMe

OPMB

TBSO

O

55a

d

c

e

a) O3, CH2Cl2, Me2S, -78 °C; b) Ph3P=C(Me)CO2Et, benzene, ref lux; c) DIBAL-H, CH2Cl2, 0 °C; d) (COCl)2,

DMSO, Et3N, CH2Cl2, -78 oC; e) 56, 4 Å molecular seives, toulene, -78 oC.

BCH3O

O

CO2iPr

CO2iPr

56

Scheme 15

O

OH

OH

O OMeO

OH

O

Carolacton (1)

OMe

OPMB

OH TBSO

OPMB

TBSO OMeO

O

OPMB

OH TBSO OMe

OPMB

TBSO OMe

Retrosynthetic analysis of Carolacton 1

38

51

53

3

HO

O

+

52

NO

O

Bn

O

11

Scheme 14

O

O

OMeO

Abstract

16

The required acid fragment 5234

(Scheme 16) was prepared from N-

acyloxazolidinone 11, which on enolization with NaHMDS followed by alkylation with

allyl iodide in THF at -78 oC, under Evan’s conditions, gave 57 as the only diastereomer.

Hydrolysis of 57 with 30% H2O2 and LiOH in THF: H2O (1:1) afforded acid 52 in 71%

yield (Scheme 16).

OPMB

O TBSO OMe

O

OPMB

TBSO OMeO

O

OPMB

TBSO OMeO

O

OPMB

TBSO OMeOH

O OMeOO

OH

OH

OH

O

5851

59

61

c d e

f

a) NaHMDS, THF, -40 oC; b) LiOH, 30% H2O2, THF:H2O (1:1); 0 oC-rt. c) 53, DCC, DMAP, CH2Cl2, 0 oC-rt; d) Hoveyda

Grubb's 2nd Generation Catalyst, CH2Cl2, rt; e) 60, Et3N, 1,2-dichloro ethane, 60 oC; f ) DIBAL-H, CH2Cl2, -78 oC; g) PPh3-

CH3I, n-BuLi, THF, 0 oC-rt; h) 62, Grubb's 2nd Generation Catalyst, CH2Cl2, rt.

1

O N

O

Bn

O

I O N

O

Bn

O

HO

O

+

11 5752

a b S OO

HNNH2

60

Scheme 16

OPMB

TBSO OMeO

OH

g

59a

OMe

OPMB

OH TBSO

38

O

O

OMeO

h

OO

MeO O 62

Esterification of acid 52 with alcohol 53 using DCC and DMAP in CH2Cl2 at room

temperature for 12 h furnished the ester 58 in 91% yield. Bis-olefin 58 on treatment with

Hoveyda Grubb’s II generation catalyst 41 in toulene at reflux for 12 h afforded eight

membered lactone35

51 in 66% yield (Scheme 18). Selective reduction of disubstituted

olefin in the presence of a tri-substituted olefin in 51, with 2,4,6-

triisopropylbenzenesulphonyl hydrazide36

(60) as hydrogen source in the presence of Et3N

Abstract

17

in 1,2-dichloro ethane at 80 oC gave the expected product 59 in 65% yield, thus successfully

introducing the C7-C8 double bond. Next, to introduce the terminal olefin, lactone 59 was

subjected to reduction with 1 eq. of DIBAL-H in dry CH2Cl2 at -78 °C for 1 h to afford the

lactol37

59a (75%), which on reaction with (methylene)triphenyl phosphorane in THF at -20

°C for 9 h gave 61 in 55% yield. Olefin 61 on cross metathesis with 62 using Grubb’s II

generation catalyst in CH2Cl2 at room temperature furnished 38 in 73% yield.

Thus, the synthesis of 38 constitutes the synthesis of C1-C19 fragment of 1.

Macrocyclisation of 38 followed by deprotections would give the target molecule 1. Thus,

the present chapter described the synthesis of C1-C19 fragment 38 of carolacton 1 and

synthetic studies towards the total synthesis of carolacton 1 are ongoing in our laboratory.

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