Biomedical Frontiers of Fluorine Chemistry - American Chemical Society

Chapter 5

Asymmetric Synthesis of Functionalized Fluorinated Cyclopropanes and Its Application to Fluoromethano Amino Acids Takeo Taguchi, Akira Shibuya, and Tsutomu Morikawa

Downloaded by UNIV LAVAL on July 12, 2016 | http://pubs.acs.org Publication Date: August 13, 1996 | doi: 10.1021/bk-1996-0639.ch005

Tokyo College of Pharmacy, 1432-1 Horinouchi, Hachioji, Tokyo 192-03, Japan

Asymmetric syntheses of functionalized fluorinated cyclopropanes developed in our group are described. These are 1) the SimmonsSmith reaction of fluoroallyl alcohol derivatives, 2) difluorocarbene addition to chiral olefins, and 3) utilization of 4-bromo-4,4-difluoro crotonate as a building block. As an application, synthesis of 2-fluoro2,3-methano-GABA and 3,4-(difluoromethano)glutamic acid is also described. The cyclopropane subunit can be found in a number of natural and unnatural substrates, and some of these have attracted attention due to their interesting biological effects (1). Introduction of the cyclopropane moiety into biologically active substances has been recognized as one of the important chemical modifications owing to conformational rigidity and potential chemical reactivity brought about by this modification (1-4). For example, conformationally restricted analogs of glutamic acid having the cyclopropane moiety were studied so as to elucidate the conformational requirements (extended and folded forms) for the receptor subtype specificity (5, 6). For such chemically modified substances, the introduction of fluorine atom(s) onto the cyclopropane ring would lead to interesting results in consideration of characteristic features of fluorinated compounds based on both steric and electronic effects (7). In general, chirality at the asymmetric center in the molecule is quite important with respect to its biological response. For this, it should be needed to develop an efficient method for the preparation of suitably functionalized fluorinated cyclopropanes in a stereo- and enantioselective manner. In this review, some asymmetric syntheses of monofluoro- and difluorocyclopropanes mainly developed in our group are described

Simmons-Smith Reaction of Fluoroallyl Alcohol Derivative. The Simmons-Smith reaction is extensively used in the synthesis of cyclopropanes from oleflnes (8). Functional groups on the double bond influence the reactivity of cyclopropanation of alkenes; electron-donating groups activate and electron-with-

0097-6156/96/0639-0073$15.00/0 © 1996 American Chemical Society

Ojima et al.; Biomedical Frontiers of Fluorine Chemistry ACS Symposium Series; American Chemical Society: Washington, DC, 1996.

74

BIOMEDICAL FRONTIERS OF FLUORINE CHEMISTRY


drawing groups deactivate the methylene-transfer reaction from the zinc reagent to alkenes. A fluorine-substituted double bond is regarded as a deactivated substrate for the Simmons-Smith reaction due to the electron-withdrawing nature of the fluorine substituent. Since in the Simmons-Smith reaction, allylic oxygen functionality accelerates the reaction rate (8, 9), a fluorinated double bond having an allylic oxygen functionality would be expected to show enhanced reactivity toward the zinc reagent. Typical examples using fluoroallyl alcohol 1 and its benzyl ether 3 are summarized in Scheme 1 (10). To obtain the cyclopropane in reasonable yield, excess amount of the zinc reagent (5-15 eq) is required. Since with hydroxyl free substrate 1, scrambling at the hydroxyl group of cyclopropane by the formation of the mixture of acetal derivatives (e.g. formaldehyde acetal derivatives) occurs extensively, acidic hydrolysis of die crude reaction mixture is needed to obtain the cyclopropane compound 2. The complete stereospecificity (cis addition) is also confirmed with both (£)- and (Z)-fluoroallyl alcohol derivatives. 5eq. Zn-Cu, 5eq. CH l2

HCI

2

MeOH

Et 0, refl., 20 h 2

OH 2a R = PhCH CH 2b R « P h 2

7.5eq. Et Zn, 15eq. CH I 2

-OBn

2

2

77% 78%

Jr

2

hexane, -23 °C., 6 h then 0°C., 16 h 4a R = PhCH CH 4b R = Ph 2

2

70 % 34%

Scheme 1 A competitive cyclopropanation reaction with fluorinated and non-fluorinated substrates (3b and 5, respectively) shows a considerable decrease in reactivity by the fluorine substituent (Scheme 2). ρ

P

\=/

+

H

\=s

-OBn ^-O Bn

5eq. Zn-Cu, 5eq. CH I 2

^-OBn

2

Et 0, refl.,15 h 2

3b

(1:1)

5 PI

Ph V\-OBn 4b (17%)

V\-oBn

3a (83%)

6 (quant)

Scheme 2 A diastereoselective Simmons-Smith reaction was conducted using a C 2 symmetric acetal 7 and the benzyl ether 9 derived from (#)-2,3-0-isopropylideneglyceraldehyde (Scheme 3) (11). While moderate diastereoselectivity was observed in the cycloropanation reaction of 7, extremely high chiral induction was realized


5.

TAGUCHI ET AL.

75

Functionalized Fluorinated Cyclopropanes


with the enantio pure allylic alcohol derivative 9 under both Zn-Cu/CH2l2 and Et2Zn/CH2l2 conditions. The absolute stereochemistry of the cyclopropane 10 was confirmed to be (1/?, 2S, YS). Highly diastereoselective cyclopropanations of nonfluorinated chiral allyl alcohol derivatives structurally similar to 9 were also demonstrated and it was proposed that the specific coordination of the zinc reagent to the allylic oxygen (0-1) of the dioxolane ring would be crucial for the stereocontrol (12). The cyclopropane 10 may be a versatile synthetic intermediate due to its functionality. Preparation of fluoromethano-GABA 11 is illustrated (Scheme 4).

Zn-Cu, CH I , Et 0, refl., 20 h EtZn, CH I , hexane, 0 °C., 3.5 d 2 2

2

34 % (44 %de) 63 % (46 %de)

2

2 2

10

Zn-Cu, CH I , Et 0, refl., 6 h EtZn, CH I , hexane, 0 °C., 3.5 d 2 2

2

2

2 2

38 % (>98 %de) 50 % (>98 %de)

Scheme 3

Boc

^^yOoBn

A

BocNH

yv

10

.COOH 11

a) HCI, MeOH; b) Nal0 ; c) NaBhU; d) MsCI, Et N; e) NaN ; f)SnCI; g) Boc 0, NaHCOa; h) H , Pd-C.; i) Cr0 - H S0 ; j)CF COOH; k)1N-HCI 4

2

2

3

2

3

3

2

4

3

Scheme 4 Difluorocarbene Addition to a Chiral Olefin. Difluorocarbene addition to an olefin is a fundamental reaction for the preparation of difluorocyclopropane derivatives (13). Reaction of the allylic alcohol derivatives, Eisomer 12 and Z-isomer 15, derived from (/?)-2,3-0-isopropylideneglyceraldehyde with difluorocarbene generated by thermal decarboxylation of sodium chlorodifluoroacetate, proceeds in stereospecific manner to give the difluorocyclopropanes; 13,14 from 12 and 16,17 from 15, respectively (14,15). In both cases, (^stereoselectivities are low; 2.6:1 for E-isomer 12 and 1.4:1 forZisomer 15 (Scheme 5). The rrarts-difluorocyclopropanes 13 and 14, were easily separable by column chromatography, and can serve as precursors for the preparation of 3 ,3 -difluoro-2 carboxycyclopropylglycines (3',3'-F2CCGs) as shown in Scheme 6 (16). From the f

f


f

76


Ο Ô


12

77

13

OH

N

NH · HCI L-3\3'- FCCG-I (2S, VS, 2'S)

3

2

t

2

b

13

FF J H H

FF C ,

Α

Χ H

Γ OTBS OH

H

14

FF HOOC X H

f

v

nu u n NH · HCI D-3',3'- F^CG-II (2R, r s , ZS) M

3

SX/H t V

HOOC

>- y COOH N

1 A 1

2

F- F a,c,d . ΗΟΟθΛ(

3

-d

d

i OTBS N

HF a

14

%

> H

4

H

Η

NH · HCI Z.-3\3 - F^CG-II {2S,VR,ZF)

?-%ΧΟΟΗ

NH · HCI - F^CG-I (2R,VR,2R)

2

2

a) I) HCI / M e OH, ii) TBDMS-CI, Imidazole; b) 0 PhCOOH, DEAD, Pr^P, ii) "OH; c) (PhO)P(0)N, DEAD, Ph P; d) i) H , Pd-C., ii) BocfeO, NaHC0 , iii) HCI / MeOH, iv) RuCI, Nal0 then CH N , v) H , Pd-C., vi) RuCI, Nal0 then C H ^ , vil) Ti(OBn), BnOH, viii) H , Pd-C., ix) HCI / H 0 2

3

3

4

4

3

2

2

2

3

2

2

3

4

2

Scheme 6


5. TAGUCHI ET AL.


77

study of conformational requirement of L-glutamic acid to receptor subtypespecificity using CCGs, it was proposed that the extended form of L-glutamic acid, which corresponds to fra/w-isomers of 3,4-methano analogs (CCG-I and CCG-Π), is possibly an active conformation to the metabotropic glutamate receptors. In particular, L-CCG-I was reported to be a highly potent and specific agonist to the metabotropic receptors (17). As a preliminary result of pharmacological activity of thesefluorinatedCCGs, it would be noteworthy that L-3',3'-F2CCG-I was found to be a more potent agonist than L-CCG-I.


R e g i o - a n d Stereoselective Synthesis o f F u n c t i o n a l i z e d D i f l u o r o c y c l o p r o p a n e Using Bromodifluorocrotonate.

4-Bromo-4,4-difluorocrotonate 18 was shown to be an efficient building block for the preparation of functionalized difluorocyclopropane 19 (18). Thus, reaction of 18 with lithium enolate of ester or amide in the presence of triethylborane (Et3B) provides the rratts-difluorocyclopropane 19 inregio-and stereoselective manner (Scheme 7). The reaction pathway involves the sequential Michael addition of enolate to 18 and the intramolecular substitution, in which Et3B acts as a radical initiator (19) to cleave the CF2-Br bond as shown in Scheme 8.

1

2

1

2

R -R «H

R-R-CH

3

1

X-Oteu X-Cfeu 2

R «2-Propenyl, R « H

47% 73% X - N^jNPh

75 %

TMP « 2,4,6-trimethylphenyl DMI - 1,3-dimethyl-2-imidazolidinone Scheme 7 Bromodifluorocrotonate 18 shows a high reactivity as a Michael acceptor against active methylene compounds. Reaction of 18 with sodium salt of malonate provides the Michael adduct 21 and/or the difluorocyclopropane 20 depending on the reaction conditions (Scheme 9). In the case of non-fluorinated crotonate, ethyl 4bromocrotonate, only direct Stfl displacement occurred with malonate anion (20). Asymmetric synthesis of difluorocyclopropanes was studied as an extension of the above mentioned methodology using a chiral Michael donor (14) or acceptor (15). According to the reaction pathway (Scheme 8), the enantiomeric purity of the difluorocyclopropane would depend on the degree of chiral induction of the Michael addition step. As a chiral Michael donor, N-acylimidazolidinone 21 provided a good result (Scheme 10). When the chiral auxiliary has S-configuration, the major transdifluorocyclopropane 22a or 22b, obtained by the sequential Michael addition and Et3B-mediated substitution reaction, has (2fl,17?,27?)-configuration (Scheme 10). The observed diastereoselectivity may be explained by considering the transition state model A, in which the reaction at the re-face of the (Z)-enolate of 21 (R^=OBn) with the crotonate 18 proceeds preferentially when 18 approaches in a way to minimize steric interaction between TMP ester part and the imidazolidinone part as illustrated in Scheme 11.



78


Scheme 8

+ BrCF ^ ^ 2

18

NaCH(COOEt)

2

"OTMP FF MeOOC^^v S A . îη MeOOC^ÔTMP THF,0°C,3h THF, refl.,2h THF-DMI, rt, 29 h

BrCF Ο — >^ ν -OTMP Μβα>ο > ΧΛ ( MeOOC 2

•

+

20

21

0% 64% 66 %

71% 10% 8%

Scheme 9


5. TAGUCHI ET AL.

1

,

9

> 2)

9

LDA

BrCF

"ΝΛ^Ρ

oF F XX H9 v

^COOTMP

Ρ0

THF, -78 °C 1

)— R 21

9

Λ

Λ

™ ^>| Ν ΝΡΗ 1

3) Et3B-0, THF-DMI, -20 °C

R

2

2

)—' 2

R 22a-c 1


79


2

22a R= OBn R= /^Pr 22b R=OBn R=Bn 22c R= H R= Bn 1

2

1

2

51 % 92 %de 48% 76%de 61 % 80 %de

Scheme 10

2

A (favorable)

Β (unfavorable)

1

I

1TJL1 4

Ph

NPh

W

OBn

TMPO 4

ΟΒΠ

yJ 2

R

2

R

2,3-syn

2,3-anti

I

t (2J?,177,271) isomer of 22

(2R,VS,ZS) isomer of 22

Scheme 11


80


As an alternative method, in particular for the preparation of 3,4-(difluoromethano) glutamic acid, the use of the chiral Michael acceptor, iV-(4 -bromo-4 ,4 -difluoro crotonoyl)oxazolidinone 23, provided exellent diastereoselectivity (15). Thus, the reaction of (5)-imide 23 with lithium enolate of ^-(diphenylmethylidene)glycinate in DMF gave (2/?,17?,27?)-24 as an almost single isomer (Scheme 12). Conversion of 24 to 3,4-(difluoromethano)glutamic acid 26 is readily achieved by titanium isopropoxide-catalyzed ester exchange reaction with benzyl alcohol followed by hydrogenolysis (Scheme 13).


,

THF DMF

,

,

24

25

54 % (>95 %de)

93%(>95%de) 16 % (>95 %de)

Scheme 12 F, F 2 4

Ti(0/-Pr)4 BnOH

B

ÂîcOOBn g

X

Ph-^Ph

H , Pd-C 2

HOOcJC *H H

>^VCOOH

NH

2

26

Scheme 13

Acknowledgements We thank the contribution of our coworkers whose names are shown as co-authors in published papers, in particular the essential part due to Mr. H. Sasaki. We are grateful to Dr. M. Shiro of Rigaku Corporation for X-ray analyses, and to Dr. H. Shinozaki of the Tokyo Metropolitan Institute of Medical Science for pharmacological study of F2CCGs. References 1. (a) Lin, H. W.; Walsh, C. T. Biochemistry of the Cyclopropyl Group; In 'The



5. TAGUCHI ET AL.


81

Chemistry of the Cyclopropyl Group'; Patai, S.; Rappoport, Z., Eds.; Wiley, New York, 1987; Chapter 16. (b) Suckling, C. J. Angew. Chem. Int. Ed. Engl. 1988, 27, 537-552. (c) Wong, H. N. C.; Hon, M.-Y.; Tse, C.-W.; Yip, Y.-C.; Takano, J. Chem. Rev. 1989, 89, 165-198. (d) Salaun, J. Chem. Rev. 1989, 89, 1247-1270. 2. (a) Stammer, C. H. Tetrahedron 1990, 46, 2231-2254. (b) Shimohigashi, Y.; Costa, T.; Pfeiffer, Α.; Herz, Α.; Kimura, H.; Stammer, C. H. FEBS Lett. 1987, 222, 71-74. (c) Pirrug, M. C.; Dunlup, S. E.; Trinks, U. P. Helv. Chim. Acta 1989, 1301-1310. (d) Burgess, Κ.; Ho, K.-K. J. Org. Chem. 1992, 57, 5931-5936. (e) Burgess, K.; Ho, K.-K. Pettitt, Β. M. J. Am. Chem. Soc. 1994, 116, 799-800. (f) Kodama, H.; Shimohigashi, Y. J. Syn. Org. Chem. Jpn. 1994, 52, 180-191. 3. Tamura, O.; Hashimoto, M.; Kobayashi, Y.; Katoh, T.; Nakatani, K.; Hayata, I.; Akiba, T.; Terashima, S. Tetrahedron Lett. 1992, 33, 3483-3486 and 3487-3490. 4. (a) Paech, C.; Salach, J. L.; Singer, T. P.; J. Biol. Chem. 1980, 255, 2700-1704. (b) Silvermann, R. B.; Hoffmann, S. J.; Catus, II, W. B. J. Am. Chem. Soc. 1980, 102, 7120-7128. (c) MacDonald, T. L.; Zirvi, K.; Burka, L. T.; Peyman, P.; Guengrich, F. P. J. Am. Chem. Soc. 1982, 104, 2050-2052. 5. (a) Yamanoi, K.; Ohfune, Y.; Watanabe, K.; Li, P.-N.; Takeuchi, H. Tetrahedron Lett. 1988, 29, 1181-1184. (b) Shimamoto, K.; Ishida, M.; Shinozaki, H.; Ohfune, Y. J. Org. Chem. 1991, 56, 4167-4176. (c) Raghavan, S.; Ishida, M.; Shinozaki, H.; Nakanishi, K.; Ohfune, Y. Tetrahedron Lett. 1993, 34, 5765-5768. (d) Pellicciari, R.; Natalini, B.; Marinizzi, M.; Monahan, J. B.; Snyder, J. P. Tetrahedron Lett. 1990, 31, 139-142. 6. (a) Shinozaki, H.; Ishida, M.; Shimamoto, K.; Ohfune, Y. Brain Res. 1989, 480, 355-359. (b) Shinozaki, H.; Ishida, M.; Shimamoto, K.; Ohfune, Y. Br. J. Pharmacol. 1989, 98, 1213-1224. (c) Kawai, M.; Horikawa, Y.; Ishihara, T.; Shimamoto, K.; Ohfune, Y. Eur. J. Pharmac. 1992, 211, 195-202. 7. (a) Welch, J. T. Tetrahedron 1987, 43, 3123-3197. (b) Kirk. K. L. "FluorineSubstituted Neuroactive Amines". In 'Selective Fluorination in Organic and Bioorganic Chemistry'; Welch, J. T. Ed.; ACS Symposium Series 456, Washington DC, 1991; pp136-155. 8. (a) Simmons, H. E.; Cairns, T. L.; Vladuchick, S. Α.; Hoiness, C. M. Org. React. 1973, 20, 1-131. (b) Furukawa, J.; Kawabata, N.; Nishimura, J. Tetrahedron 1968, 24, 53-58. 9. (a) Poulter, C. D.; Friedrich, Ε. C.; Winstein, S. J. Am. Chem. Soc. 1969, 91, 6892-6894. (b) Molander, G. Α.; Hairing, L. S. J. Org Chem. 1989, 54, 35253532. (c) Denmark, S. E.; Edwards, J. P.; Wilson, S. R. J. Am. Chem. Soc. 1991, 113, 723-725. 10. Morikawa, T.; Sasaki, H.; Mori, K.; Shiro, M.; Taguchi, T. Chem. Pharm. Bull. 1992, 40, 3189-3193. 11.Forrecentexamples of asymmetric Simmons-Smith reactions: (a) Mori, Α.; Arai, I.; Yamamoto, H. Tetrahedron 1986, 42, 6447-6458. (b) Mash, Ε. Α.; Torek, D. S. J. Org. Chem. 1989, 54, 250-253. (c) Frutos, M. P.; Fernandez, M. D.; Alvarez, E. F.; Bernarbe, M. Tetrahedron Lett. 1991, 32, 541-542. (d) Charette, A. B.; Cote, B.; Marcoux, J.-F. J. Am. Chem. Soc. 1991, 113, 8166-8167. (e) Ukaji, Y.; Nishimura, M.; Fujisawa, T. Chem. Lett. 1992, 61-64. (g) Takahashi, H.; Yoshioka, M.; Ohno, M.; Kobayashi, S. Tetrahedron Lett. 1992, 33, 25752578. 12.Morikawa, T.; Sasaki, H.; Hanai, R.; Shibuya, Α.; Taguchi, T. J. Org. Chem. 1994, 59, 97-103. 13. (a) Burton, D. J.; Hahnfeld, J. C. Fluorine Chemistry Reviews; Tarant, P., Ed.; Marcell Dekker Inc.; New York, 1977, Vol 8, pp 153-179. (b) Dolbier, Jr., W. R.; Wojtowicz, H.; Burkholder, C. R. J. Org. Chem. 1990, 55, 5420-5422. 14.Taguchi, T.; Shibuya, Α.; Sasaki, H.; Endo, J.; Morikawa, T.; Shiro, M. Tetrahedron: Asymmetry 1994, 5, 1423-1426. 15.Shibuya, Α.; Kurishita, M.; Ago, C.; Taguchi, T. Tetrahedron 1996, 52, 271-278.



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16.Taguchi, T.; Shibuya, Α.; Kurishita, M. 1995 International Chemical Congress of Pacific Basin Societies; Honolulu, HI, USA, Dec. 1995. Abstract No. 666. 17.(a) Ishida, M.; Akagi, H.; Shimamoto, K.; Ohfune, Y.; Shinozaki, H. Brain Res. 1990, 537, 311-314. (b) Nakagawa, Y.; Saito, K.; Ishihara, T.; Shinozaki, H.; Eur. J. Pharmac. 1990, 184, 205-206. (c) Hayashi, Y.; Tanaka, Y.; Aramori, I.; Masu, M.; Shimamoto, K.; Ohfune, Y.; Nakanishi, S. Br. J. Pharmacol. 1992, 107, 539-543. (d) Lombardi, G.; Alesiami, M.; Leonardi, P.; Chericci, G.; Pellicciari, R.; Moroni, F. Br. J. Pharmacol. 1993, 110, 1407-1412. (e) Costantino, G.; Natalini, B.; Pellicciari, R.; Moroni, F.; Lombordi, G. Bioorg. Med. Chem. 1993, 1, 259-265. 18.Taguchi, T.; Sasaki, H.; Shibuya, Α.; Morikawa, T. Tetrahedron Lett. 1994, 35, 913-916. 19.(a) Takeyama, Y.; Ichinose, Y.; Oshima, K.; Utimoto, K. Tetrahedron Lett. 1989, 30, 3159-3162. (b) Iseki, K.; Nagai, T.; Kobayashi, Y. Tetrahedron Lett. 1993, 34, 2169-2170. 20.(a) Prempee, P.; Radviroongit, S.; Thebtaranonth, Y. J. Org. Chem. 1983, 48, 3553-3556. (b) Yamaguchi, M.; Tsukamoto, M.; Hirano, I. Tetrahedron Lett. 1985, 26, 1723-1726.


Biomedical Frontiers of Fluorine Chemistry - American Chemical Society

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