Fluorine-Containing Synthons - American Chemical Society

Chapter 25

Optically Active gem-Difluorocyclopropanes: Synthesis and Application for Novel Molecular Materials

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Toshiyuki Itoh Department of Materials Science, Faculty of Engineering, Tottori University, 4-101 Koyama Minami, Tottori 680-8552, Japan

Chemo-enzymatic syntheses of a variety of novel gem-difluorocyclopropanes have been accomplished. Important aspects of the synthetic procedure include optical resolution based on lipase-catalyzed ester hydrolysis, difluorocarbene addition, and olefin metatheses. Several types of optically active multi-gem -diflurocyclopropane derivatives were prepared.

Introduction The cyclopropyl group is a structural element present in a wide range of naturally occurring biologically active compounds found in both plants and microorganisms (7). Since substitution of two fluorine atoms on the cyclopropane ring is expected to alter both chemical reactivity and biological activity due to the strong electron-withdrawing nature of fluorine, gemdifluorocyclopropanes are expected to display unique biological and physical properties (2,3). To the best of our knowledge, the first synthesis of gemdifluorocyclopropane was reported by Sargeant in 1970 (4). Since then, a great deal of attention has been paid to the chemistry and unique properties of gemdifluorocyclopropanes (5-12). Numerous types of ge/w-difluorocyclopropanes have been synthesized such as biologically active compounds (6-9), liquid crystalline compounds (11), and even polymeric compounds (12). We have been interested in the unique properties of chiral bis- and multi-gemdifluorocyclopropanes. For example, we found the shape of 1,6bis(hydroxymethyl)-2,2,5,5-tetrafluorobicyclopropane (1) (9b) to be slightly

430

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431

different from that of the simple bicyclopropane (2). MO calculation suggested a kinked form of two difluorocyclopropane groups for compound 1, while no such twisted form was indicated for bicyclopropane 2. The results of these calculation were confirmed by results of CD spectroscopic analysis of optically active 2 in that a large CD spectral change on the Cotton effect was observed (9b). The computational chemistry suggested a highly helical shape for petakis- gem-difluorocyclopropane 3, as shown in Figure 1. Optically active multi-gemdifluorocyclopropanes are Figure I. Result ofMO(PM3) calculation of challenging targets for synthetic bis- and pentakis-gem-difluorocyclopropanes organic chemists. However, little attention has been paid to the chemistry of this material and when we undertook the present project, only two methods have been reported for the synthesis of optically active ge/w-difluoro- cycloropanes, both from the Taguchi group (7,8). The first synthesis of optically active gew-difluorocyclopropane was accomplished in 1994. Diastereoselective 1,4-addition of the enolate 4 with 4bromodifluorobutanoate and subsequent oxidative cyclopropanation gave gemdifluorocyclopropane 5 with high diastereoselecivity (Eq. 1) (7). The second synthesis was based on the addition of difluorocarbene to the optically active olefin 6 and subsequent separation of the resulting two diastereo-isomers 7 using HPLC (Eq. 2)(7). Ό R- A

Ο A

1) L D A / D M F P

h

h-* ^2

4

s

2) B r F a C ^ o R :CF

^rV^V

N

R0

Et B,0 3

H

2

*

1

R

(1)

2

2

B n o ' ^ Y ^ O

• 7

Taguchi (1994)

H

6>

{S,R,R>7

H H h

(2)

(S,S,Sh7

These two methods are excellent but are difficult to apply for large-scale preparation. For this reason, we developed a synthetic methodology for preparing optically active gem-difluorocyclopropanes using lipase technology

432 (9,11b). We review here the details of our synthesis project of optically active multi-gem-difluorocyclopropanes.


1. Preparation of optically active ge/#f-difluorocyclopropanes The lipase-catalyzed reaction protocol was used as the key process of our asymmetric synthesis for chiral ge/w-difluorocyclopropanes (9,11b). The value of an enzymatic reaction in organic synthesis is now well respected for its broad applicability and environmentally friendly nature. In particular, lipase-catalyzed enantioselective acetylation or deacetylation is known to be a useful means of preparing optically active alcohols (13).

ACO-X-OAC Η

Η

L

Î

P

a

S

e

Q

-

L

0

buffer (pH7.2),35 C

H

°-\k^OAc Η

(

3

)

Ή

(SS ,) ψ ψ AcO->^( Η H

N-OAC

(transH±)~S

Lipase SL O R L I P A S E Q

L

H V-OAc (trans)-(+)-9 (4)

pH72, 35°C, 1 h E*>11 (irtmsH-yS

>99%ee

Initially we tested lipase-catalyzed enantioselective hydrolysis of diacetate (cis)-8. Twenty-eight commercially available lipases were screened for their activity and lipase QL (Meito) from Alcaligems sp. provided the corresponding monoacetate (cis)-9 in the highest enantiomeric excess (Eq 3) (9a,9f). The diacetate of (trans)-8 is not a prochiral but a racemic form, so that optical resolution of (±)-(trans)-8 was performed using the lipase-catalyzed reaction (Eq 4). The enzymatic reactions were tentatively evaluated by the E * value" which was calculated by the results of enantiomeric excesses of the monoacetate (transy(S,S)-(+)-9 and unreacted (trans)-(R,R)-(-y8 according to the same method of the "E value" (14), although it was the combined results of two enantioselective enzymatic reactions, the initial hydrolysis of (trans)-(±)-8 and subsequent hydrolysis of the corresponding monoacetate 9. In this reaction, the best result was recorded when trans)'(±)-8 was reacted with lipase SL (Pseudomonas cepacia SL-25, Meito), and the diacetate (trans)-(R,R)-(-)-% remaining was obtained with >99% ee (Eq. 4) (9a,9J). Chiral (im«5,/raw5)-l,6-bishydroxylmethyl-2,2,5,5-tetrafluorobicyclopropane (1) is an inviting target for synthetic organic chemists because computational chemistry suggests a kinked form of two ge/w-difluorocyclopropane groups for 1. However, no example of the synthesis of even the racemic form of 1 had been reported when we undertook this project (9b). The dibenzylether of M

433

bisdifluorocyclopropane (transtrans)-\ was directly synthesized in 66% overall yield from (Ε,Ε)-1,8-dibenzyloxy-2,4-hexadiene using 5 eq. of difluorocarbene, produced by the thermolysis of sodium chlorodifluoroacetate. Subsequent hydrogenolysis of the benzyl group produced 1 (9b,9j). In the first step of difluorocyclopropanation, the benzyl protecting group was essential in order to achieve difluorocyclopropanation in acceptable yield (9b). The optical resolution of the diacetate, (trans,trans)~lQ which is a mixture of the dl and meso forms, was very successfully accomplished by the lipase SL-catalyzed reaction. We found that the dibenzyl ether of meso-1 was preferentially crystallized from hexane. The rf/-rich dibenzylether (dhmeso = 7:3) was obtained by removing the iweso-isomer by a single recrystallization from hexane, and this mixture was converted to the corresponding rf/-rich-diacetate 10 and subjected to lipase-catalyzed hydrolysis. The lipase SL-catalyzed hydrolysis of therf/-rich-diacetate10 (dhmeso = 7:3) gave the diol (S,R R,S)-(+)1 in 30% yield with 99% ee, and the unreacted diacetate (R,S,S,R)-(-)-lù in 24% yield with >99% ee. The meso-isomer was obtained as the monoacetate 11 in 30% yield. We thus succeeded in preparing both enantiomers of bis-gemdifluorocyclopropane 1 with sufficient optical purity (Eq. 5). This was the first example of the synthesis of a bis-gew-difluorocyclopropane in optically active form. t


9

9f

f

(5)

meso-10

Recently two groups also reported efficient preparation of optically active gemdifluorocyclopropanes using lipase-catalyzed reaction as a key technology. Kirihara reported that enantioselective monohydrolysis of diacetate 12 gave the monoacetate 13 with excellent optical purity and this was converted to the novel cyclopropane amino acid 14 (Eq. 6)(10). Meijere and colleagues accomplished the synthesis of a unique spiro type gem-difluorcyclopropane 17 using lipase technology. The chiral spirobicyclopropane 16 was prepared by the optical resolution of lipase-catalyzed reaction and subsequent conversion by the addition of difluorocarbene to afford gem-difluoroeyclopropane 17. This was used as the core molecule for the liquid crystal compound 18 (Eq.7) (11a).

434 F F

F.F

Lipase Q L

V

^ O A c

F

0

buffer (pH7.2)

12

F

V i-nnw

H

NHJJ/HCI

(Ryi3

>99%ee

14

/(,

Kirihara(1999)i > Lipase Q L (7) *~OH

-OAc

vinyl acetate

K

M -OH


^< 19

Scheme 1

H

F

H

H" \ - 0 B n

8

%

U

3


435 Therefore we examined a second strategy for the synthesis of multi-gewdiflurocyelopropanes. This was based on a ruthenium complex catalyzed-olefin methathesis reaction protocol (Scheme 2). Olefin metathesis has been extensively studied and procedures leading to remarkably broad applicability have been developed (19). We first investigated the reaction of vinylcyclopropane 24 as a model compound using the Grubbs catalyst A (19). However, the coupling product was obtained in only 15 % yield in the presence of 15 mol % of the catalyst. Nonetheless, the newly formed olefin had perfect (E)-stereochemistry. We tested four solvent systems: dichloromethane, toluene, benzene and THF, and the desired product 25 was obtained only when the reaction was carried out in dichloromethane at room temperature. We then used a total of 1.0 equivalent of the catalyst by adding 20 mol% of the dichloromethane solution dropwise five times at 12 h intervals. This increased the chemical yield and we obtained the desired coupling product 25 in 35% yield. It is assumed that decomposition of a metallacyclobutane intermediate in this reaction releases ethylene gas and regenerates the ruthenium carbene complex to complete the catalytic cycle. In the present reaction, however, the retro decomposition of metallacyclobutene to vinylcyclopropane also seemed to occur due to the strong electron withdrawing nature of difluoromethylene moiety and this stopped the catalytic cycle. Though, another explanation of the poor results may be possible (9c). Second generation ruthenium-based olefin metathesis catalysts have been reported (20). F F BnOnQ^H V

U

Catalyst A:Y=* 15% Catalyst B:Y= 31%

CH C1 ,RT 2

2

24 Catalyst A:Y=* 8%

BnO

Catalyst B:Y= 35%

CH C1 ,RT 2

2

26

OBn F^F,

Catalyst A : Y « 86%

H^^-OBn F F

CH CI ,RT 2

2

28

(E:Z)«4:1

PCy

T F D A , catNaF, 3

Mes-N^N-Mes

toluene 1 0 5 ° C , Y = 72%

;Ru=\

Cr I Ph PCy 3

Catalyst A

Catalyst Β

3 Scheme 2

^ 30

F

>


436

We found that use of catalyst Β indeed gave better results than A and the metathesis product could be obtained in 31 % yield even when 15 mol% of the catalyst was used. The most dramatic increase in chemical yield was recorded when bisdiflurocyclopropane 26 was subjected to the metathesis reaction. The desired tetrakisdifluorocylopropane derivative 27 was obtained in 35 % yield using catalyst B, while the chemical yield of the metathesis product was only 8% when a total of 1.0 equivalent of catalyst A was used (five additions of 20 mol% of the catalyst at 12 h intervals). In contrast, the olefin metathesis reaction of allylic ether 28 proceeded smoothly to give the coupling product 29 in excellent yield of 86 % using 15 mol% of the commercial catalyst A (9c 9d). Since compound 29 possess an olefinic unit between difluorocyclopropane moieties, we were able to add one more difluorocyclopropane group to the structure. Thus, trisdifluorocyclopropane (trans,trans,trans)-30 was synthesized in 54% yield from 29 using excess amounts of difluoroearbene (50 eq.), produced by the thermolysis of sodium chlorodifluoroacetate (8 M in a diglyme solution) (Pc). Recently, trimethylsilyl fluorosulfonyldifluoroacetate (TFDA) was developed as a good difluoroearbene source by the Dolbier group (5/). This reagent was applicable to our compound, and the desired tris-gemdifluorocyclopropane 30 was obtained in 72% yield using 10 eq. of the carbene source. Dolbier's procedure thus was found to be useful for preparation of polydifluorocyclopropanes possessing an odd number of difluorocyclopropane moieties (Scheme 2) (9d). Eight types of multi-gew-difluorinated cyclopropane derivatives have now been synthesized via this olefin metathesis reaction methodology (9d). As noted above, the products obtained by the olefin methathesis reaction protocol possess olefinic parts between the difluorocyclopropane moieties. This is an important advantage since this allows the addition of another difluorocyclopropane group or of a variety of other functional groups. t

(SMS^U

CH

97%ee

2

C,

*

rt

Y

a

e

6

1

%

32

H

-_ Bn 0

(E/Z = 6:l) N CHC02Et 2

Cu(acac) (15 mol%)

B n3 O - ^ F ^ HH

2

C

"W*-

2

CH C1 ,40°C, lh

COOEt 0 0 E t c

ρ

Y=38%

2

H

33

l)LiOH,THF/H 0(5:l)

' - °

Β

"

2

rt,24h,Y=88%

c F BnO— v

2)

/

^

°

n

-

η ° - ~

υ

H

Η 3

EDC,DMAP CH Cl , t

40°c,24h

2

,Y=65%

2

'

Scheme 3

4

ι/ H

-

t

" " °

B

n


437 We are considering various applications of our multi-gem-difluorocyclopropanes. For example, tetrakis-gem-difluorocyclopropane 32 was easily prepared by the homo coupling reaction of (S,R,R,S)-31 in optically active form starting from 97% ee of (S,R,R,S)-1 in 47% overall yield (three steps) using the olefin methathesis protocol. This was treated with ethyl diazoacetate in the presence of 15 mol% of copper acetoacetate in CH2CI2 at 40°C to give pentakis-cyclopropane 33 in 38% yield (21). Hydrolysis and subsequent esterification with pyrenylmethanol using EDC in the presence of DMAP afforded pyrenyl ester 34 in 65% yield (Scheme 3). Since compound 34 is actually a mixture of diastereomers, we are now attempting to purify each isomer. We are hoping that the compound will become a unique sensitive marking agent for DNA.

Conclusions We have carried out chemo-enzymatic syntheses of optically active multi-ge/wdifluorocyclopropane using lipase-catalyzed ester hydrolysis, difluoroearbene addition, and olefin methatheses as key reactions. We first accomplished the synthesis of (tram)-% and (trans,trans)A in optically active form. These compounds were used as the core molecules for synthesizing novel multi-gewdifluorocyclopropane derivatives, 30, 21,34. We are now able to prepare chiral gew-difluorocyclopropanes on a multi-gram scale. Since our building blocks have hydroxymethyl groups at each terminus, it should be emphasized that they are extremely versatile intermediates. We thus plan to synthesize various types of multi-gem-difluorocyclopropanes such as amino acids, carboxylic acids, polymeric compounds and hybrid types of difluorocyclopropanes using these versatile building blocks we have prepared. Acknowledgments This work was supported by a Grant-in-Aid for Scientific Research on Priority Areas (No. 283, "Innovative Synthetic Reactions") from The Ministry of Education, Science, Sports, Culture and Technology of Japan. The author is grateful to Professor Kenji Uneyama of Okayama University for the helpful discussions throughout this work. The author also gratefully acknowledges and his students, in particular, Dr. Koichi Mitsukura and Miss Nanane Ishida who helped to complete this study. References 1. For reviews see: a) "Cyclopropanes and Related Rings", Chem. Rev. 2003, 103, 931-1648. (b) Tozer, M . J.; Herpin, T. F. Tetrahedron, 1996, 52, 8619-

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2.


3.

4. 5.

6.

7. 8.

9.

8683. b) Wong, Η. Ν. C.; Hon, M-Y.; Tse, C-H.; Yip, Y-C. Chem. Rev. 1989, 89, 165-198. For reviews, see. (a) Welch, J. T. Tetrahedron, 1987, 43, 3123-3197. (b) Resnati, G. Tetrahedron,1993, 49, 9385-9445. (c) "Enantiocontrolled Synthesis of Fluororganic Compounds: Stereochemical Challenges and Biomedicinal Targets", Ed. Soloshonok, V . Α., Wiley, Chichester, U K (1999). (a) Dolbier, Jr. W. R.; Battiste, M . A . Chem. Rev. 2003, 103, 1071-1098. (b) Fedory'nski, M . Chem. Rev. 2003, 103, 1099-1132. and references cited therein. Sargeant, P. B. J. Org. Chem. 1970, 35, 678-682. Unique physical and chemical properties have been reported for gem -difluorocyclopropanes.(a) Seyferth, D.; Hopper, S. P. J. Org. Chem. 1972, 37, 4070-4075. (b) Schlosser, M . ; Chau, L-V.; Bojana, S. Helv. Chim. Acta, 1975, 58, 2575-2585. (c) Schlosser, M . ; Spahi'c; B.; Chau, L-V. Helv. Chim. Acta, 1975, 58, 2586-2604. (d) Schlosser, M . ; Bessard, Y . Tetrahedron, 1990, 46, 5222-5229. (e) Morikawa, T.; Uejima. M . ; Kobayashi, Y . Chem. Lett. 1988, 1407-1710. (f) Bessard, Y . ; Müller, U . ; Schlosser, M. Tetrahedron, 1990, 46, 5213-5221. (g) Schlosser, M . ; Bessard, Y . Tetrahedron, 1990, 46, 5222-5229. (h) Tian, F.; Battiste, Μ. Α.; Dolbier, Jr. W. R. Org. Lett. 1999, 1, 193-195. (i) Tian, F.; Kruger, V.; Bautista, O.; Duan, J-X.; Li, A-R.; Dolbier, Jr. W. R.; Chen, Q-Y. Org. Lett. 2000, 2, 563-564. Biological activities were reported for difluorocyclopropane derivatives. (a) Boger, D. L.; Jenkins, T. J. J. Am. Chem. Soc. 1996, 118, 8860-8870. (b) Koizumi, N . ; Takrgawa, S.; Mieda, M . ; Shibata, K . Chem. Pharm. Bull. 1996, 44, 2162-2164. (c) Taguchi, T.; Kurishita, M . ; Shibuya, Α., Aso, K . Tetrahedron, 1997, 53, 9497-9508. (d) Pechacek, J. T.; Bargar, T. M . ; Sabol, M . R. Bioorg. Med. Chem. Lett. 1997, 7, 2665-2668. (e) Csuk, R.; Eversmann, L . Tetrahedron, 1998, 54, 6445-6459. (f) Csuk, R.; Thiede, G. Tetrahedron, 1999, 55, 739-750. Taguchi, T.; Shibuya, Α.; Sasaki, H.; Endo, J-i.; Morikawa, T. ; Shiro, M . Tetrahedron: Asymmetry, 1994, 5, 1423-1426. (a) Shibuya, Α.; Kurishita, M . ; Ago, C.; Taguchi, T. Tetrahedron, 1996, 52, 271-278. (b) Taguchi, T.; Kurishita, M . ; Shibuya, Α.; Aso, K. Tetrahedron, 1997, 53, 9497-9508. (c) Shibuya, Α.; Sato, Α.; Taguchi, T. Bioorganic & Medicinal Chem. Lett. 1998, 8, 1979-1984. (d) Shibuya, Α.; Okada, M . ; Nakamura, Y.; Kibashi, M . ; Horikawa, H.; Taguchi, T. Tetrahedron, 1999, 55, 10325-10340. (a) Itoh, T.; Mitsukura, K.; Furutani, M . Chem. Lett. 1998, 903-904. (b) Mitsukura, K.; Korekiyo, S.; Itoh, T. Tetrahedron Lett. 1999, 40, 5739-5742. (c) Itoh, T.; Mitsukura, K.; Ishida, N . ; Uneyama, K . Org. Lett. 2000, 2, 1431-1434. (d) Itoh, T. J. Synth. Org. Chem. Jpn. 2000, 58, 316-326. (e)


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Itoh, T.; Ishida, Ν.; Mitsukura, K.; Uneyama, Κ. J. Fluorine Chem. 2001, 112, 63-69. (f) Itoh, T.; Ishida, N . ; Mitsukura, K.; Hayase, S.; Ohashi, K. J. Fluorine Chem. 2004, 125, 775-783. 10. (a) Kirihara, M . ; Takuwa, T.; Kawasaki, M . ; Kakuda, H.; Hirokami, S-i.; Takahata, H. Chem. Lett. 1999, 405-406. 11. Liquid crystals that have gem-difluorcyclopropane moiety. (a) Miyazawa, K.; Yufit, D. S.; Howard, J. A. K.; de Meijere, A . Eur. J. Org. Chem. 2000, 4109-4117. (b) Itoh, T.; Ishida, N.; Ohashi, M . ; Asep, R.; Nohira, H . Chem. Lett. 2003, 32, 494-495. 12. Polymer that possesses gem-diflurocyclopropane moiety. (a) Reisinger, J. J.; Hillmyer, M . A . Prog. Polym. Sci. 2002, 27, 971-1005. (b) Ren, Y.; Lodge, T. P.; Hillmyer, M . A . J. Am. Chem. Soc. 1998, 120, 6830-6831. (c) Ren, Y.; Lodge, T. P.; Hillmyer, M . A . Macromolecules, 2000, 33, 866-876. 13. For reviews, see: (a) Wong, C. H.; Whitesides, G. M . "Enzymes in Synthetic Organic Chemistry", Tetrahedron Organic Chemistry Series, Vol. 12, Eds, Baldwin J. E.; Magnus, P. D. Pergamon, (1994). (b) Theil, F. Chem. Rev. 1995, 95, 2203-2227. (c) Itoh, T.; Takagi, Y.; Tsukube, H. J. Molecular Catalysis B: Enzymatic, 1997, 3, 259-270. (d) Theil, F. Tetrahedron, 2000, 56, 2905-2919. 14. Chen, C. -S.; Fujimoto, Y.; Girdauskas, G.; Sih, C. J. J. Am. Chem. Soc. 1982, 102, 7294-7299. 15. For a review see: Nozaki, H . "Organotin Chemistry", Organometallics in Synthesis, A Manual, Ed. Schlosser, M . John Wiley & Sons, Chichester, 535-578 (1994) 16. McDermott, T. S.; Mortlock, Α. Α.; Heathcock, C. H. J. Org. Chem. 1996, 61, 700-709. 17. Itoh, T.; Emoto, S.; Kondo, M . Tetrahedron, 1998, 54, 5225-5232. 18. Wodsworth, Jr. W. S., Organic Reaction, 1977, 25, 73-253. 19. For reviews see: (a) Grubbs, R. H.; Chang, S. Tetrahedron, 1998, 54, 44134450. (c) Ulman, M . ; Grubbs, R. H. J. Org. Chem. 1999, 64, 7207-7209. 20. Scholl, M . ; Ding, S.; Lee, C. W.; Grubbs, R. H . Org. Lett. 1999, 1, 953-956. 21. For a review see. Doyle, M . P. Chem. Rev. 1986, 86, 919-939.

Fluorine-Containing Synthons - American Chemical Society

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