Synthesis of Macrolactam Marine Natural Products Using Fluorous

Chapter 14

Downloaded by UNIV MASSACHUSETTS AMHERST on September 27, 2012 | http://pubs.acs.org Publication Date: January 11, 2007 | doi: 10.1021/bk-2007-0949.ch014

Synthesis of Macrolactam Marine Natural Products Using Fluorous Protecting Groups Yutaka Nakamura and Seiji Takeuchi* Niigata University of Pharmacy and Applied Life Sciences, 265-1 Higashijima, Niigata 956-8603, Japan

Marine natural products, bistratamides, were synthesized by using heavyfluorousprotecting group, Teoc or light fluorous one, Boc. The intermediates of both methods were easily isolated by fluorous liquid phase extraction and solid phase extraction, respectively. Precursors of bistratamide H and its unnatural diastereomer were simultaneously prepared by quasi-racemic mixture synthesis. Each component of the mixture was cleanly separated by fluorous flash column chromatography. F

F

Bistratamides (1,2) and didmolamides (5) were isolated from ascidians Lissoclinum bistratum and Didemnum molle, respectively, while tenuecyclamides (4) were isolated from cyanobacterium Nostoc spongiaeforme var. tenue. They are macrolactams of amino acids that include thiazole, oxazole or oxazoline (Figure 1). The unique structures and their bioactivities such as moderate cytotoxic activity, anti-drug resistance and antimicrobial properties and 244

© 2007 American Chemical Society

In Current Fluoroorganic Chemistry; Soloshonok, V., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2007.


245

δ

I

I §

j

•I

ι



246 inhibition of the division of sea urchin embryos have attracted synthetic organic chemists' interest. Among them, Kelly's and Shin's groups have recently reported syntheses of bistratamides according to their own methodologies of thiazole amino acid synthesis. Kelly stated in his reports that "Construction of the thiazoles in these macrolactams is central to their total synthesis" and discovered a facile and efficient biomimetic synthesis of thiazoles. The construction was accomplished by treating N-acylated cysteine with bis(triphenyl)oxodiphosphonium trifluoromethanesulfonate followed by oxidation of the thiazolines employing activated M n O . Utilizing this method, Kelly's group has synthesized most of bistratamides (5), didmolamides (6) and tenuecyclamides (7). Shin and his coworkers have synthesized bistratamide G in a high total yield by a modified Hantzsch's method using thioamide and bromoacyl derivatives of an oxazole amino acid as intermediates. The intermediates were prepared by a unique strategy via dehydropeptides (8). Coupling the thioamide and bromoacyl moieties of the intermediates led to the thiazole amino acid part of bistratamide G . These interesting works prompted us to employ fluorous technologies for an expeditious synthesis of the macrolactams owing to the following reasons. Firstly, Kelly's group synthesized didmolamides and tenuecyclamides by solid phase assemblies of thiazole-containing amino acids. However they prepared the amino acids by the above biomimetic synthetic methods without using the solid support. Secondly, a modified Hantzsch's method used by Shin's group includes thiocarbonylation of a-amino acid amide with Lawesson's reagent. In the reac tion, it is very hard to separate the products from unbearably bad smelling by products by silica gel column chromatography. Partial racemization of the products during the reactions is another serious problem of this method. 2

Unlike Kelly's solid support synthesis, fluorous protecting groups can be used from the beginning of the modified Hantzsch's route for protecting amino groups of a-amino acids. If the fluorine atom content of the intermediates of the route is enough high (>60wt %), the fluorous intermediates can be clearly separated from organic by-products including the bad smelling ones by liquid phase extraction with fluorous and organic solvents (9). In the case of lower fluorine atom contents than 40 wt%, fluorous intermediates are separated from the organic by-products by solid phase extraction with a fluorous reverse phase silica gel column (10). Optimization of the reaction conditions is accomplished by checking the enantiomeric purity of the fluorous intermediates by H P L C with a chiral column to avoid the racemization of the intermediates. A n excellent method using fluorous supports such as HfBz and HfBn has already been reported by Inazu and his coworkers for oligopeptide and ologosaccharide syntheses (11,12). However, we wanted to synthesize the macrolactams by using fluorous protecting groups in order to apply our method also to a fluorous mixture synthesis (13,14).



247 In an early stage of this work, we confirmed that Curran's light fluorous Boc-protecting group (15) and Bannwarth type heavy fluorous Cbz-protecting group (16) were really effective for a synthesis of thiazole amino acid derivative by a modified Hantzsch's method. However, the light fluorous Boc-protecting group is more practical for a small scale synthesis and especially for a mixture synthesis. We thought that a heavy fluorous protecting group was more suitable for establishing a long synthetic route as expeditiously as possible because the liquid phase extraction procedure was simpler and quicker than that of the solid phase one. Even i f the fluorous solid phase extraction is needed in a later stage of the synthetic route, the heavy fluorous protecting group is considered to be more practical at least until the step. The heavy fluorous Cbz-protecting group, however, resisted being removed by hydrogenation over palladium on charcoal because of inactivation of the catalyst by sulfur atom of thiazole ring. Therefore we tried to prepare a new type of protecting group suitable for a modified Hantzsch's method and finally reached 2-tri(perfluorodecyl)silyl]ethoxycarbonyl ( Teoc) group, a fluorous version of 2-(trimethylsilyl)ethoxycarbonyl group (17). The fluorous protecting group has a simple structure and thus high fluorine atom content and can be deprotected by tetrabutylammonium fluoride (TBAF). In this paper, we would like to describe an expeditious synthesis of bistratamide H using the heavy fluorous protecting group Teoc preparation of bistratamide H and C using the light fluorous Boc-protecting groups and an attempt of a mixture synthesis of precursors of bistratamide H and its unnatural diastereomer. F

F

F

Synthesis of bistratamide H using heavy fluorous protecting group, Teoc Fluorous protecting agent, 2-[tris(perfluorodecyl)silyl]ethoxycarbonyl-0succimide ( Teoc-OSu) was prepared as shown in Scheme 1. Fluorous hydrosilane (1) was reacted with bromine in FC-72 (perfluorohexane) and then the silylbromide (2) was reacted with vinyl magnesium chloride to give vinylsilane (3) in 87% yield via the two steps. The vinylsilane 3 was reacted with 9-borabicyclo[3,3,l]nonane (9-BBN) and then treated with hydrogen peroxide to give fluorous silylethanol (4) in 84% yield (18). The silylethanol 4 was treated with triphosgene and then reacted with Nhydroxysuccimide. After purification of the crude product by silica gel column chromatography, the fluorous protecting agent Teoc-OSu (5) was obtained in 97% yield as white solid. The overall yield from the hydrosilane 1 was about 70%. By using Teoc-OSu 5, thiazole amino acid derivative 10 was prepared from valine by a modified Hantzsch's method (Scheme 2). F

F

F


248

Br

^

2

(C F CH CH ) SiH 8

l7

2

2

*

3

MgCl

(C„F, CH CH ) SiBr 7

2

2

^

3


FC-72

(C^nOÔ^Si

^

Et 0 2

1

2

3 87% (2 sicps)

1)9-BBN/Et2p

I) Triphosgene/THF

84%

O

97%

C T F

4

5: TeocOSu

Scheme 1. Preparation of fluorous protecting agent Teoc-OSu F

F

> T

Teoc-OSuS,Bt N

in THF

3

H N-*Y° 0

H

K

THF-H 0 »t, 2 h

2

2

TeocHN' Y

O H

Y

2)NH OH

^

4

o

extracted with FC-72 (andCHjCN)

6

A

-

>TeocHN'\'^ O

filteredDCUrea extracted with FC-72

'

quant

8

98% DKHCO, ^ Y C O E i 0

r

i

n

2

Lawesson's reagent — THF extracted with FC-72 (andCHjCN)

F

TeocHNX.HH, » 9

D

M

E

°

^

" W « ^ N r \

2) TFAA, pyridine in D M E

C0 El 2

evaporated DME orfroeta/ wftA FC-72(and CH CN) purified by Si0 column

1 0

3

9

5

%

2

80%(99%ee) F

Scheme 2. Preparation ofN- Teoc-thiazole amino acid ester from valine.


-

^

249 F

Valine (6) was reacted with Teoc-OSu 5 in the presence of triethylamine in aqueous T H F . After the reaction, the reaction mixture was acidified and then extracted with FC-72 and acetonitrile. Concentration of the FC-72 layer gave NTeoc-valine (7) in quantitative yield. The A^Teoc-valine 7 was reacted with D C C and 1-hydroxybenzotriazole (HOBt) in T H F and then treated with an aqueous ammonia solution. The reaction mixture was filtered to remove D C U and then the filtrate was extracted with FC-72. Concentration of the FC-72 layer gave N- Teoc-Val-amide (8) in 98% yield. The amide 8 was reacted with Lawesson's reagent in T H F and then the reaction mixture was extracted with FC-72 and acetonitrile. The bad smelling by-products and the reagent were com pletely partitioned into an organic layer. Therefore, N- Teoc-Val-thioamide (9) obtained from the FC-72 layer was almost odorless. The thioamide 9 was reacted with excess amount of ethyl bromopyruvate in D M E and then treated with trifluoroacetic anhydride and pyridine. After evaporating D M E , the reaction mixture was extracted with FC-72 and acetonitrile and the crude product obtained from FC-72 extract was purified by silica gel column chromatography to provide N- Teoc-thiazole amino acid ester (10) in 80% yield as waxy solid. The overall yield from valine was about 74%. Enantiomeric purity of the product 10 was determined to be higher than 99% ee by H P L C with a chiral column, D A C E L C H I R A L C E L OD-H. F


F

F

F

F

Similarly, other JV- Teoc-thiazole amino acid derivatives were prepared in good overall yields from alanine and phenylalanine as shown in Table 1. Another component of bistratamide H , oxazole amino acid methyl ester (14) was prepared from the N- Teoc-valine 7 via 4 step reactions, coupling with threonine methyl ester, cyclization using PEG-Burgess reagent (79), dehydrogenation with D B U and B r C C l (20) and deprotection with T B A F (Scheme 3). Similarly, another N- Teoc-oxazole amino acid derivative was prepared in moderate overall yield by coupling with serine as shown in Table 2. Finally bistratamide H was synthesized from the thiazole amino acid ester 10 and the oxazole amino acid methyl ester 14 (Scheme 4). At first, the N- Teoc-thiazole amino acid 10 was treated with T B A F in T H F to remove Teoc protecting group. After evaporating T H F , the residue was extracted with water, chloroform and FC-72. From chloroform layer, deprotected thiazole amino acid ester (15) was obtained in 82% yield. On the other hand, the thiazole amino acid ester 10 was treated with 1 M L i O H aqueous T H F solution and then the reaction mixture was acidified and extracted with FC-72. From the FC-72 extract, N- Teoc-thiazole amino acid (16) was obtained in 98% yield. The two thiazole amino acid derivatives 15 and 16 were coupled by using benzotriazol-1 -yl-oxy-trispyrrolidinophosphonium hexafluorophophate (PyBOP) and /-Pr NEt in THF. After the work-up, thiazole amino acid dipeptide ester (17) was obtained in 96% yield. The thiazole dipeptide ester 17 was treated with 1M F

3

F

F

F

F

2


250

Table 1. Preparation of N- Teoc-thiazole amino acid esters Amino Acid Val Ala Phe

Entry


1 2 3 a

Yield(%) 8 9 98 95 quant 93 98 87

7 quant quant quant

%ee oflff 99 92 95

Total Yield(%) 74 64 72

10 80 69 84

Determined by HPLC analysis using DAICEL CHIRALCEL OD-H.

Table 2. Preparation of N- Teoc-oxazole amino acid esters C-Terminus Amino Acid Thr Ser

Entry 1 2 a

Yield (%) // 12 quant 70 96 83

13 79 83

Total Yield (%) 55 66

%eeof 1? 95 N.D.*

Determined by HPLC analysis using DAICEL CHIRALCEL OD-H.

* N.D. = Not determined.

H 0 ^

HjN^COjMc

• HCl

PEG-Burgess

BOP, i-Pr NEt 2

F

THF it.3 h

N

TeoeHN"" lf'

C

O

j

M

dioxane-THF

evaporated dioxane and THF extracted with FC-72 (andCHjCN)

quant

C0 Mc 2

12

70%

DBU. BrCCl 2

0

TeocHlv^Y '

85 °C, 4 h

evaporated THF extracted with FC-72 (andCHiCN)

CH C1

F

c

3

F

TBAF

TeocHN

THF

2

0 °C then it, 12 h 2

3

2

79%(95%cc)

CC^Me

2

13 evaporated CH Cl extracted with FC- 72 (and CH CN) purified by Si0 column 2

If"

• n o

C0 Mc evaporated THF CHfN-FC-72 purified by alumina column 61% F

Scheme 3. Preparation of methyloxazole amino acid ester from N- Teoc-valine.


251


•mmonium salt

IMLiOH

^TeocHN^Y\

F

T _ TeocHN'^Y '

evaporated THF

TBAF

N

CHCIj ^

THF

THF-HjO COjKt

COjH acidified with citric acid extracted with FC-72

IS

-

82%

10

FC-72

(CgFpCHjCH^vSiF 22 recovered quantitatively

COjEt

F

IMLiOH

TeocHN CO,H

THF-H 0 2

evaporated THF acidified with citric acid extracted with FC-72

evaporated THF extracted with FC-72 (and CHjCN)

17

18

F. 52.34%

F. 53.15%

14

PyBOP /-Pr,NEl

F

TeocHN »

COjMe

evaporated THF extracted with FC- 72 (and CH,CN)

19

it 12 b

O ^

evaporated THF acidified with citric acid extracted with FC-72

20 F, 48.37%

F,48 03%

PyBOP, DMAP DMF-CHCI 2

2

W

°yN V ^ N H

N—y HNÔ

evaporated THF dilute with MeOH washed with FC-72

Bistratamide H

Scheme 4. Preparation of bistratamide H.


252 L i O H aqueous solution in THF. After evaporating THF, the aqueous solution was acidified and extracted with FC-72. From the FC-72 layer thiazole dipeptide amino acid (18) was obtained in 92% yield. The thiazole dipeptide 18 was coupled with the oxazole amino acid methyl ester 14 by using PyBOP and /Pr NEt in THF. After the work-up, tripeptide methyl ester (19) was obtained in 88% yield as amorphous solid. The tripeptide methyl ester 19 was treated with 1M L i O H aqueous solution in THF. The reaction mixture was acidified, T H F was evaporated and then the residue was extracted with FC-72. From the FC-72 layer tripeptide acid (20) was obtained in 90% yield. The tripeptide acid 20 was treated with T B A F to remove Teoc protecting group in THF. After evaporating THF, the residue was extracted with FC-72 and methanol. AÔ-Deprotected linear tripeptide 21 obtained from the methanol layer was dissolved in D M F C H C 1 and the solution was added very slowly to a solution of PyBOP and D M A P in D M F - C H C 1 with maintaining high dilution conditions. The product was purified with a preparative T L C to give bistratamide H in 35% yield. The specific rotation, *H and C N M R spectra and M S analysis demonstrated that the product was the desired compound.


2

F

2

2

2

2

1 3

The fluorous product (22) obtained from FC-72 layer on deprotection of Teoc group with T B A F was reacted with vinyl magnesium chloride in ether to provide vinyl silane 3 in moderate yield (Scheme 5) (21,22). *H N M R of the vinyl silane product was the same as that of the sample obtained by the reaction of tris(perfluorodecyl)silylbromide 2 with vinyl magnesium chloride. F

Preparation of bistratamide H and C using light fluorous Boc-protecting group F

The new fluorous protecting group, Teoc enabled us to prepare bistratamide H so expeditiously that the other macrolactams including didmolamides and tenuecyclamides were considered to be synthesized via a similar route to that of bistratamide H . Furthermore since the macrolactams have analogous structures, it was expected that they would be prepared simultaneously by using Curran's strategy of mixture synthesis. However, a mixture synthesis using the heavy fluorous protecting groups like Teoc may cause a problem. That is, a large difference in partition coefficients to fluorous and organic solvents between the fluorous intermediates that bear fluorous Teoc groups of different size will limit the use of fluorous liquid phase extraction. If we use Teoc protecting groups that have lower fluorine atom contents, we will have to use a fluorous solid phase extraction sooner or later. Therefore we thought that it was the best choice to use light fluorous Boc protecting groups for the mixture synthesis. F

F


253 In order to confirm a generality of the synthetic route established above for bistratamide H , bistratamide H and C were prepared via similar synthetic routes except that light fluorous Boc-protected intermediates were separated from by products by fluorous solid phase extraction with YluoroFlash column (FSPE) (Scheme 6, 7, and 8). Generally the FSPE was carried out by evaporating a solvent of a reaction, dissolving the residue in a fluorophobic solvent such as 80% aqueous methanol (H O:MeOH=20:80) and loading the solution onto the FluoroF/as/i column. The column was eluted first with 80% aqueous methanol to remove organic by products and remaining reagents and then washed with methanol to extract the fluorous product. In the case of thioamidation with Lawesson's reagent, however, the step of evaporation of the solvent was skipped to avoid scattering the unbearably bad smell over the laboratory and the building. In addition the amount of the solvent for the reaction was made as small as possible and 70% aqueous methanol was used as an eluting solvent to ensure the separation. The light fluorous thioamide ((5)-25a) was successfully obtained in extremely high yield without bad smell just as in the case of the fluorous liquid phase extraction of heavy fluorous Teoc thioamide 9. Ethyl chloroformate was used for the amidation step instead of D C C and HOBt for the amidation of Teoc valine 7. However, there was no substantial difference between the two reagents for the reaction. In this step, the product was extracted simply with ethyl acetate, because the amide ((S)-24a) crystallized too easily to be loaded onto the YluoroFlash column. However the product obtained by the extraction had enough high purity without further purification for the next reaction probably because of the quantitative yield. In the saponification step, the product ((S)-27a)) was also extracted with ethyl acetate after acidifying the reaction mixture. Since the reaction mixture was aqueous, the extraction was more adequate than FSPE in this case (Scheme 6). Methyloxazole methyl ester (30) was purified by silica gel column chromatography in the middle of the synthetic route. The purification was necessary to provide the next intermediate (31) in pure state, because the product on the oxidation step was very messy due to low yield. The compound 31 was coupled with the thiazole dipeptide (33) to give the framework of bistratamide H , so it was inevitable to purify the intermediate 30 (Scheme 7). The intermediate (35a) was also purified by silica gel column chromatography, because the compound was considered to be easier to purify with a silica gel column compared to the precursor of bistratamide H (36a). In the final step, the yield was dramatically increased to 81% compared to that in the final step of the route using Teoc protecting group. In the route using Teoc protecting group, the solution of the precursor 21 in D M F and C H C 1 was slowly added to the solution of PyBOP and D M A P in D M F and C H C 1 with maintaining high dilution conditions. In contrast, in this case the solution of BOP


2

F

F

F

F

2

2


2

2


254

(C F CH CH ) SiF 8

1 7

2

2

-

3

(C F CH CH )3Si^^ g

l 7

2

2

Et 0 2

22

reflux, 24 h

3

62% Scheme 5. Attempt to recycle the recoveredfluorous

c

r

C

' "

^ X j ^ U ^

F

F

Boc-ON

XCN

6 —

•

rt, 2 h* THF-HjO

T

f

OH '

_ B o c H N yo

extracted with EtOAc FSFE

A

r

''BocHN^Tf' * T H

DKHCOj ^COjEt 1

o rn *

C

I

C

_ 2)N1W

O H

W .

Y NH MH " _ O •HOCIIN'V™

Liwesson's reagent DME

:

5

extracted with EtOAc (SyUm

FSPE (A>M"

97"/.

Y

)

silylfluoride.

quanl

Y

' 2) TFAA, pyridine in DME

y fi^/ jS^r ^

THF «•«

N

C

ST""""

98%

O

)

B

J N - ^

SEfcESa!?

85%

quant F

Scheme 6. Preparation of Boc-thiazole amino acid ester.


c

w

)

255

H N * X 0 M c • HC1 2

2

rt,3h

°HCT^


evaporated THF FSPE

N

85°C,1.5h passed through Si0 pad 2

2 8

* \ CCsMc jo

1

99%

DBU, B1CCI3 CH C! 2

F

t

0

B 0

cHN^Y V_

^

N - / ^

2

0 °C then rt, 12 h

A

T 7 A ' H

r

CH C1 2

2

N ^

CC^Me

evaporated CH2CI2 pur»/>tt/frySiO> column

3

0

0

^

N - ^

2

CC^Me evaporated CH,CI and TFA FSPE

3 1

2

48% (2 steps)

quant F

Scheme 7. Preparation of Boc-oxazole amino acid ester.

Scheme 8. Preparation of bistratamide H.


256 and /-Pr NEt in D M F was slowly added to the solution of the precursor 36a in D M F . However, it is not clear whether or not the difference in a way of addition is actually the reason to lead the different yields (Scheme 8). Bistratamide C was prepared by almost the same way from fluorous Boc protected alanine as the starting material.


2

Quasi-racemic mixture synthesis of the precursors of bistratamide H and its diastereomer Very recently Curran and Zhang have reported a fluorous mixture synthesis of all 16 stereoisomers of Pinesaw fly sex pheromone (14). Starting from four stereoisomers that bore fluorous tags of different size, the target 16 stereoisomers were prepared via four lines of split parallel reactions. Each of the four stereoisomers in the four products was demixed by fluorous H P L C with FluoroFlash column. In addition, Wilcox and Curran have found an amazing method to prepare all of 16 stereoisomer of Murisolin in one pot by combination of four different size each of fluorous and oligoethylene glycol (OEG) tags (23). The product that contained 16 stereoisomers was first separated into four fractions based on the properties of O E G tags and then each of the four fractions was further demixed by fluorous H P L C chromatography on a FluoroFlash PFC8 column. The simplest fluorous mixture synthesis of this kind is a quasiracemic mixture synthesis in which a pair of enantiomers are tagged with different fluorous tags. In an example to prepare L - and D-phenylalanine tetrahydroisoquinoline amides, each of the quasi-enantiomers that contained C H C H C F and C H C H C F i tags was separated by flash chromatography with standard fraction collection using FluoroFlash column (24). Since we had established the synthetic route of bistratamides H and C using the light fluorous protecting group Boc we decided to prepare the precursors of bistratamide H and its unnatural diastereomer by the quasi-racemic mixture synthesis (exactly speaking "by quasi-diastereomer synthesis") to establish a method to prepare the macrolactams by the mixture synthesis (Scheme 9). Starting from a mixture of C F -Boc-(S)-valine (S)-23a and C i F - B o c (/0-valine (CR)-23b) the precursor Boc tripeptide methyl esters (M-35ab) were prepared via the route for bistratamide H . The mixture of the precursor com pounds and the intermediates to the compounds all showed the same behaviors as those described in the literatures reported by Curran and Zhang. The mixtures M-35ab behaved as a single compound on a silica gel T L C but as a distinct mixture on a fluorous T L C as shown in Figure 2. The two components of the product were clearly separated not only by fluorous H P L C with FluoroF/asA H P L C column (Figure 3; the difference in 2

2

6

1 3

2

2

8

7

8

17

F


0

2I

257

(Sy23m w

.

V

C I J ' I I ^ T J

^T^


& K

™

I

OH

FSPE

2

S

0

BocHN^r \

1

Yi^f * *

A

M-32ab

bistratamide H

'"-

S

n

F < S P £

THF

88%

S

BocHN^Y >

F

"

evaporated THF

I i ^ \ M

quant

F

evaporaU evaporated THF FSPE

3 3

- «

82-,.

w-^N'îr \

F\uoroFlashcolumn C0

QA

quant

acidified with citric acid extracted with EtOAc

b

(

BocHN^>|f%

IM LiOH

N-^

^ V ^ V ^ S ^

^

b

PyBOP,i-PrjNEt

«

evaporated DME

t

M-25ab

PyBOP, t-PrNEt

M

2) TFAA pyridine in DME

90*/.

^^'YV-CO.H

q«nt

0

». «

M-24ab

THF-MeOH

IJ

\ ^BocNH^^ S

quant

acidified with citnc acid extracted with EtOAc ^

O

Lawesson's reagent

extracted w,th EtOAc

o

IMLiOH

rV^F.. S

F

OCICOjEl. EljN

" "BocNH-Y"' °

N V

" (fl)-23b

'

Mtx

O V I 1

MC

=

M-35.b

£ 351,

CO,Me CO,M.

/

o^yV S

bistratamide analogue

Scheme 9. Quasi-racemic mixture synthesis of bistratamide H and its analogue.

Figure 2. TLC offluorous mixture intermediates 35a and 35b. Left: silica gel, developed with 50% ethyl acetate in hexane; Right: FluoroFlash™, developed with MeOH (top: 35a, bottom: 35b).


258 retention time was larger than 9 min) but also by flash chromatography with FluoroFlash cartridge column. The samples separated by the flash chromatography were almost pure and gave *H N M R spectra in which only methine proton on the chiral carbon of Nterminal valine part exhibited a small difference in chemical shift (Figure 4). The H N M R of the product that bore C F - B o c group was exactly the same as that of the intermediate of bistratamide H prepared above. Therefore, bistratamide H and its unnatural diastereomer will be simultaneously synthesized by this method. Natural tenuecyclamide A and B are real diastereomers in which the configurations of just one chiral center are different Therefore the quasi-racemic mixture synthesis is the best way for the simultaneous preparation of them and the work is now under way in our laboratory. l


8

17

Conclusion In conclusion, we synthesized bistratamide H expeditiously by using the new fluorous protecting group, Teoc. The separation of the fluorous inter mediates by fluorous liquid phase extraction was very easy and quick, although the fluorine atom content was just about 48% at the final stage. The product in thiocarbonylation was cleanly separated from the bad smelling by-products by the extraction. Optimization of the reactions was carried out as usual by monitoring the reactions with T L C . The enantiomeric purities of the fluorous intermediates were checked by H P L C with a chiral column to find optimal reaction conditions for a voiding racemization of the products. In addition, the fluorous fragment from the fluorous protecting group was demonstrated to be recycled. The synthetic route was applied to the preparation of bistratamide H and C using light fluorous protecting group, Boc. The fluorous intermediates were separated from by-products by fluorous solid phase extraction with FluoroFlash cartridge column. Fluorous quasi-racemic (quasi-diastereomer) mixture of the precursors of bistratamide H and its unnatural diastereomer was prepared by the same way as those of bistratamide H and C. The two fluorous diastereomers were easily separated by flash chromatography with a FluoroFlash column. F

F

Acknowledgement The authors would like to thank Prof. Dennis P. Curran, University of Pittsburgh and Prof. Willi Bannwarth, Albert-Ludwigs-Universitat Freiburg for their helpful suggestions. They also would like to thank Dr. Nobuto Hoshi,


259 35a


35b

20

30

Figure 3. HPLC analysis of fluorous mixture intermediates 35a and 35b. Conditions: FluoroFlash PF-C8 column (4.6 xSOmm) using a gradient from 70% CH CN in water to 100% CH CN in 30 min at 1.0 mL/min. 3

3

ppm

Figure 4. *HNMR supectra of fluorous mixture intermediates 35a and 35b in CDCl . (a) product 35a sample in Scheme 8. (b) 35a sample separatedfrom M3 Sab. (c) 35b sample separated from M-35ab. (d) mixture M-35ab sample. 3


260 Noguchi Research Institute and Dr. Naoto Takada, Central Glass International, Inc. for their valuable advices about the fluorous silylfluoride and Noguchi Research Institute for the Noguchi Fluorous Project's Fund. This work has been done as a part of the project.


References and Notes 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24.

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