Fluorine-Containing Synthons - American Chemical Society

Chapter 23

The Role of Fluorine-Containing Methyl Groups toward Diastereofacial Selection 1,2,3

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Takashi Yamazaki , Satoshi Takei , Tatsuro Ichige , Seiji Kawashita , Toshio Kubota , and Tomoya Kitazume Downloaded by FUDAN UNIV on April 12, 2017 | http://pubs.acs.org Publication Date: July 21, 2005 | doi: 10.1021/bk-2005-0911.ch023

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Graduate School of Bioscience and Biotechnology, Tokyo Institute of Technology, 4259 Nagatsuta, Midori-ku, Yokohama 226-8501, Japan Department of Materials Science, Ibaraki University, 4-12-1 Nakanarusawa, Hitachi 316-8511, Japan Current address: Department of Applied Chemistry, Tokyo University of Agriculture and Technology, 2-24-16 Nakamachi, Koganei 184-8588, Japan 2

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Michael addition reactions of enolates derived from the selected ketone, ester, and amide to γ-CH F -α,β-unsaturated ketones (n=1~3) were proved to smoothly furnish the desired 1,4-adducts with high level of diastereofacial selectivity, which monotonously decreased by reduction in a number of fluorine involved. Although the Felkin-Anh model can accommodate the stereochemical outcome when E-acceptors were employed, the opposite stereoisomer was obtained from the corresponding trifluorinated Z-isomer. The hyperconjugative stabilization of transition states by electron donation from the proximate allylic substituents (the Cieplak rule) successfully explains the observed π-facial preference of both E- and Z-acceptors. 3-n

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© 2005 American Chemical Society

Soloshonok; Fluorine-Containing Synthons ACS Symposium Series; American Chemical Society: Washington, DC, 2005.

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Downloaded by FUDAN UNIV on April 12, 2017 | http://pubs.acs.org Publication Date: July 21, 2005 | doi: 10.1021/bk-2005-0911.ch023

Introduction It is well documented (2-4) that introduction of a trifluoromethyl moiety into organic molecules gave rise to significant change in their physical properties which is due in part to its strong electron-withdrawing nature making the proximate bonds shorter and stronger. When this group directly attaches to π systems, electrophilicity is extraordinarily enhanced by decreasing the molecular orbital, especially LUMO energy levels (5,6). On the other hand, because of threefluorineatoms and each of which possessing three lone pairs, this moiety behaves like a mass of electrons which effectively prevents the access of appropriate nucleophiles. Previously, we have reported (7) that £-4,4,4-trifluorocrotonate 1 readily underwent Michael addition reactions (8-10) with enolates derived from acylated oxazolidinones, and the intermediates trapped as ketene silyl acetals were found to follow highly stereoselective Ireland-Claisen rearrangements in the presence of a Pd catalyst, controlling three consecutive stereocenters in the product 2 (Scheme 1). The smooth conjugate addition at the first stage (5,11,12) would be elucidated in consequence of the significant stabilization of the Michael intermediates due to intramolecular F-Li chelation (5,11), and the stereochemical outcome of the Ireland-Claisen procedure (13) at the next step would be understood by the different steric requirement between the both π faces, allowing the rearrangement to occur from the re-face where the smaller CF group occupies (compare TS-re and -si in Scheme 1). However, the results for the simplified derivative 3 was totally opposite to our expectation. Thus, in spite of closer steric bulkiness of i-Pr and CF groups (14-16), good selectivity of ca. 9:1 was attained by the preferential rearrangement again occurring from the same re-face. This fact clearly demonstrated that the different electrostatic circumstance of the two π faces would be responsible for realization of this good 3

3

Scheme 1 Sequential Michael and Ireland-Claisen rearrangement OLi

Ο

0

CF

3

o F C;

*>AOx

ο

3

as

ii)TMSCI iii) PdCl (PhCN) 2

2

v

R'

iA

2 (single isomer) Ο CF

CF

3

3

4 74% yield, 88% 5ΚΛ


401 Scheme 2 Preparation of the trifluorinated acceptors E- and Z-6a Ο

Z-6a

Z-7

5

£-6a

a) (EtO) P(0)CH C(0)Bu"', w-BuLi/Et 0; b) ( P h O ) P ( 0 ) C H C 0 E t , NaH/THF; 2

2

2

2

c) N a O H / T H F - H 0 ; d) AcCl, E t N / C H C l ; e) 2

3

2

2

2

2

te/Z-BuMgCl/THF.

2 3~syn selectivity, not by the steric bulkiness of the two substituents occupied the both faces {17). Because this type of phenomenon has not been reported yet, we have decided to prepare the variously fluorinated substrates for the clarification of the role of C H _ F groups for controlling the π-facial selectivity.


9

3

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Preparation of the Starting Materials The Michael acceptor with a C F group, £"-6a, was synthesized from the commercially available aldehyde 5 and the Horner-Wadsworth-Emmons (HWE) reagent derived from bromopinacolone (Scheme 2). On the other hand, the corresponding Z-isomer, Z-6a, was obtained by the literature method (18) using the H W E reagent with a phenoxy group on the phosphorus atom, enabling the selective formation of Ζ-α,β-unsaturated acid Z-7 by the successive hydrolytic treatment. Its further conversion to the desired Z-acceptor was not clean and satisfactory yields have not been attained yet in spite of our extensive investigation of reaction conditions. Condensation of (PhO) P(0)CH C(0)Bu"' and 5 were also carried out as the directly accessible process to the target Z-6a, but the product was formed only in 30% yield in an unexpected Ε selective (£:Z~8:2) manner. At the next stage, the monofluorinated acceptor E-6c was prepared from 3hydroxyisobutyrate 8 which was at first fluorinated (19) by the Ishikawa's reagent (20) and its "half reduction by DIBAL, followed by the olefination with the bromopinacolone-based H W E reagent (21-25) (Scheme 3). Our initial plan was to construct E-6c via the intermediate E-10 by taking into account the low boiling point and high volatility of the compound 9, but it turned out that the final fluorination yielded the unexpected product ΕΊΙ. This type of reaction was sometimes observed when allylic alcohols were treated with this type of reagents (26). The present homoallylic alcohol transformation allowed entry of fluorine to the most stable and least congested intermediary cation Int-3 following to the S 1 type mechanism. The difluorinated acceptor was considered to be the most difficult to 3

2

2

N


402

Scheme 3 Preparation of the monofluorinated acceptor E~6c

a

Me^C0 Me

Me^CC^Me

2

7

HOH C

0

%

FH C

2

3

%

M e

.0

Bu

£-6c

,

HOH C

^ ^

2

9 (λ

v

FH C

2

8

F

Ο

29% (2 steps)

2


b,c ^ 4

£-10

I Int-1

Int-2

+

a) Et NCF2CHFCF3/CH Cl2; b) D I B A L / E t 0 ; c) (EtO) P(0)CH C(0)Bu"', « - B u L i / E t 0 ; d) H . 2

2

2

2

2

2

construct among three acceptors required here from the standpoint of the availability of starting materials and/or limited preparation methods. Under such a circumstance, we have devised the synthetic sequences as shown in Scheme 4. Readily available trifluoromethacrylic acid 12 was first converted into the corresponding acid chloride whose esterification with 2-phenylethanol and further smooth hydrogenolysis yielded trifluorinated isobutyrate 13 in Scheme 4 Preparation of the difluorinated acceptor E-6b

^,C0

2

H

x^COsiR

CF3

v^CC^R

d

CF3

12

CF

13

2

14 Ο ,-f

6O0/0

J

H

F

69o/

2

0

ρ

2

η

τ

(2 steps)

15

£-6b

a ) C H ( C O C I ) ; b) R O H , pyridine/CH Cl ; c) 10% Pd/C/MeOH; d) L D A / T H F ; 6

4

2

2

2

e) D I B A L / E t 0 ; f) (EtO) P(0)CH C(0)Bu', « - B u L i / E t 0 2

2

2

2

(R: PhCH CH -> 2

2


403 excellent yield. During this study, we have found (27) that LDA effected the clean formal dehydrofluorination of 13 to furnish terminally difluorinated methacrylate 14. The key to success of this transformation was to slowly add a small excess amount of LDA to keep the reaction temperature almost constant at-78 °C, which seemed to effectively retard the delivery of fluoride from the resultant enolate species. Otherwise the highly electrophilic olefinic carbon atom with two fluorine atoms (28,29) would accept the quite facile nucleophilic attack by this strong base. This inverse addition method eventually improved the yield of the product 14 to 86% from 25% when 13 was added to a solution of LDA. Hydrogénation of 14 required positive pressure of H for conversion with an acceptable reaction rate (10 mol% of a Pd catalyst under 5 atm of H ) which was in sharp contrast to the case of 12, which was quite readily transformed into 13 in the presence of only a 1/20 amount (0.5 mol%) of the catalyst under atmospheric pressure of H . This method opened a new route to introduce a CHF group at the 2 position of appropriate carbonyl compounds by way of trifluoromethylation of their ketene or enol silyl acetals (30) at the first step. 2


2

2

2

Table 1 Reaction of Enolates with E-6 or Z-6a

19-21 Accpt.

a)

R

1

R

5

Yield

Pro.

b)

c;

Diastereoselectivity

(%)

£-6a Ph E-6b E-6c Z-6a E-6a EtO E-6b E-6c Z-6a E-6a Me N E-6b E-6c Z-6a 2

Me

MeS

Me

95.0 80.5 76.3 0 quant 86.0 76.3 45.9 87.5 74.4 78.8 87.6

19a 19b 19c

2.8 . 97.2 92.4 7.6 82.4 17.6

20a 20b 20c 20a 21a 21b 21c 21a

7.7 15.1 30.9 99.0 5.1 13.8 16.3 16.6

: : : :

[99.0] 83.3] 73.7]

30.4 30.9 34.0 28.4

60.9 50.3 34.1 52.8

a) Acceptor, b) Product, c) In the bracket was shown the diastereomeric ratio after removal of the MeS group.


404

Michael Addition Reactions of Enolates As described above, we have obtained all Michael acceptors E-6 and Z-6a with CH . F groups (n=l-3) which were subjected to the reactions with enolates from propiophenone 16, ethyl (methylthio)acetate 17, and N,Ndimethyl-propionamide 18 (Table 1). As we expected, these donors experienced facile conjugate addition to yield stereoisomeric mixtures 19-21 in every instance. In principle, four diastereomers could be formed but this was the case only when the amide donor 18 was employed. The enolates from the ketone 16 and ester 17 selectively afforded two stereoisomers. Their chemical yields were generally increased in proportion to the number of fluorine involved in the acceptors 6. Stereochemistry of the adducts with a CF group was determined as follows. First of all, the major diastereomer of 21a from 18 and 2s-6a was successfully purified and separated by simple column chromatography and gave suitable crystal for X-ray crystallographic analysis which unambiguously manifested its relative stereochemistry as 2i?*,3i?*,5S* (Figure 1). On the other hand, when the compound 20a was treated with «-Bu SnH, a facile elimination of a MeS group occurred to furnish a single isomer 22a (Scheme 5). This result indicated that two stereoisomers of 20a stemmed from the epimer at 2 position. 22a was further treated with an excess amount of LDA and the trapping of the resultant bisenolate by Mel realized the regioselective methylation at the 2 position. It was clarified from the *H as well as F NMR analyses that 23a consisted of a 26:74 mixture and its ester group was independently converted into phenyl ketone and iV,iV-dimethylamide to produce 24a and 25a, respectively, basically with retention of stereochemical integrity. The major and minor isomers of the latter amide 25a were analytically proved to be the same as the ones obtained as the most and the second predominant stereoisomers of the amide Michael adduct


3

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3

3

l9

Figure 1 3D Structure of the Most Predominant Diastereomer of21a by Crystallographic Analysis (some hydrogen atoms are omittedfor clarity


405

Scheme 5 Determination of relative stereochemistry

86% EtO'

BLT

SMe 20a (7.7:92.3)

2

22a (single isomer)

23a (26:74 at C )


d,e,f 66
99% syn

Previously, Reetz and his coworkers reported (38) the 1,2-oxazolidin-5-one formation via conjugate addition (Scheme 6). 3,4-Syn stereochemistry was constructed in a ratio of syn\anti being 90:10 from 26a, while the diastereomeric awn'-isomer became predominant for 26b (R = C 0 E t ) . This sharp difference in the π-facial selection, highly dependent on the structure of the acceptors employed, would be explained by the TS model FA-4 for the former but AS-1 for the latter. On the other hand, Yamamoto et al found (39) examples showing high level of syn selectivity even when substrates possess cis substituents like 28b. The methoxy group played a pivotal role in this instance by forming chelation with the incoming nucleophiles which definitely determined the face where Michael addition really occurred (AS-2). 2

As shown in Table 1 and Scheme 5, both E- and Z-6a predominantly furnished the Felkin-Anh type products and high affinity of fluorine with metals was considered to determine the latter stereoselection like the case of Yamamoto et al Thus, these two Michael acceptors could be considered to follow FA-4 and AS-2, respectively. However, on the basis of our recent results (40), this does not seem to be the case. Esters 30 with fluorine-containing auxiliaries were benzylated in a re-face selective fashion by construction of the rigid bicyclo[3.3.1] type intermediates which allowed the phenyl and methyl moieties in the auxiliaries to effectively cover the opposite si face. As shown in Scheme 7, existence of fluorine seems to be responsible for fixing the conformation and the diastereoselectivity of the products 31 is almost constant although the chemical yields varied to some extent. It is interesting to note that the absence of fluorine is responsible to the apparent decrease of the de values, indicating the important role of this atom's inherent electronic characteristics. However, Table 1 exhibits


408

Scheme 7 Diastereoselective alkylation of 30 Ο

Ο R V

O^A

Me*/ Ph

(

BnBr

KHMDS OMe Me' Ph

30

Ph

Bn

31

X:HorF


a: R=CF , 79% yield, 80% de; b: R=CHF ,45% yield, 84% de; c: R=CH F, 41% yield, 84% de; d: R=CH , 31% yield, 48% de; 3

2

2

3

clear dependence of diastereomeric selection on the number of fluorine, which made us suspicious for considering the chelation-controlled reaction and eventually we have excluded the possibility of this chelation mechanism. Then, what can properly rationalize how our stereoselectivity was attained? Eventually, we have reached the conclusion that it is Cieplak rule (41,42) which can consistently explain the present stereochemical outcome. This rule is summarized as the hyperconjugative stabilization effect by electron donation from adjacent bonds to an incipient bond and thus reactions occur from the side opposite to the best electron donating substituent. With this définition in mind, this rule is applied to our system. First of all, the //-C-C=C part of the stable conformation would keep planarity for minimizing allylic 1,3-strain especially in the case of R not being H (Int-4 in Figure 4). However, when a nucleophile approaches from the top side, the stereogenic center rotates clockwise so that the CF group at the TS occupies the anil position to the incoming Nu and the incipient bond σ*ψ orbital is able to accept electron donation from the neighboring OC-CF3 bond (C-1). On the other hand, C-2 is the TS model where Nu attacks from the bottom side and, in this case, the C H moiety is located on the other side of the nucleophile and the similar electrostatic interaction would occur between a c - c m Φ orbitals. Considering the strongly electronwithdrawing nature of a CF group, it is quite apparent that electrostatic stabilization should be more pronounced for C-2 rather than C-1, leading to predominant acceptance of nucleophilic reagents 2

3

3

- 0

3

Figure 4 Explanation of Stereoselectivity by the Cieplak Models

t t

Nu

sHs^ Int-4

C-1

·

R>

f£

s

C-2


409 from the same olefinic face where a bulkier CF group occupies. As a consequence, the TS model C-2 leads to the production of the relative stereochemical relationship between C and C as shown in Scheme 5. Such experimental results could be alternatively understood by Felkin-Anh model in the case of /s-6a (ca 120° counterclockwise rotation of the allylic chiral carbon in C-2 gives rise to the identical conformation to FA-4 as described in Figure 3), which appears to expect the access of Nu from the same π-face. However, as mentioned above, Felkin-Anh model cannot account for the correct stereoisomers when Z-acceptors are used. We believe this is also the case for E6A because Int-4 type conformation is most abundant too in the case of Eacceptors (43). This is the reason why we adapt the Cieplak rule because it is only the Cieplak rule at present which has led to the consistent explanation for the obtained diastereofacial selectivity irrespective of the stereochemistry of Michael acceptors, and there are such examples whose selectivity is explained on the basis of this theory (44-48). 3


3

5

As described above, we have successfully clarified the role of CH _ F groups at the γ position of α,β-unsaturated ketones for diastereoselective enolate-Michael addition reactions. Their electron-withdrawing effect allowed the incoming nucleophiles to readily discriminate the two different π-faces. This phenomena were consistently explained by adapting the Cieplak rule for not only E-6 but also the corresponding Z-isomer. 3

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References and Notes

1. This manuscript is translated and reconstructed on the basis of the article already published. Yamazaki, T. J. Synth. Org. Chem. Jpn. 2004, 62, 911918. 2. Smart, Β. E. J. Fluorine Chem. 2001, 109, 3-11. 3. Hiyama, T. "Organofluorine Compounds Chemistry and Application" Springer, Berlin, 2000. 4. Kitazume, T.; Yamazaki, T. "Experimental Methods in Organic Fluorine Chemistry" Kodansha, Tokyo, 1998. 5. Shinohara, N.; Haga, J.; Yamazaki, T.; Kitazume, T.; Nakamura, S. J. Org. Chem. 1995, 60, 4363-4374. 6. Linderman, R. J.; Jamois, E. A. J. Fluorine Chem. 1991, 53, 79-91. 7. Yamazaki, T.; Shinohara, N.; Kitazume, T.; Sato, S. J. Org. Chem. 1995, 60, 8140-8141. 8. Perlmutter, P. "Conjugate Addition Reactions in Organic Synthesis" Pergamon, New York, 1992. 9. Oare, D. Α.; Heathcock, C. H. Top. Stereochem. 1989, 19, 227-407.



410

10. Yamazaki, T. In "Enantiocontrolled Synthesis of Fluoro-organic Compounds" V. A. Soloshonok, Ed., John Wiley & Sons, New York, 1999, p. 263-286. 11. Yamazaki, T.; Haga, J.; Kitazume, T.; Nakamura, S. Chem. Lett. 1991, 2171-2174. 12. Yamazaki, T.; Haga, J.; Kitazume, T. Chem. Lett. 1991, 2175-2178. 13. Ziegler, F. E. Chem. Rev. 1988, 88, 1423-1452. 14. MacPhee, J. Α.; Panaye, Α.; Dubois, J.-E. Tetrahedron 1978, 34, 35533562. 15. Bott, G.; Field, L. D.; Sternhell, S. J. Am. Chem. Soc. 1980, 102, 56185626. 16. Weseloh, G.; Wolf, C.; König, W. A. Chirality 1996, 8, 441-445. 17. Recently, Fleming et al. reported a similar type of rearrangement by substrates containing trialkylsilyl groups instead of a CF3 moiety. Betson, M. S.; Fleming, I. Org. Biomol. Chem. 2003, 1, 4005-4016. 18. Ando, K. J. Org. Chem. 1999, 64, 8406-8408. 19. O'Hagan, D. J. Fluorine Chem. 1989, 43, 371-377. 20. Takaoka, Α.; Iwakiri, H.; Ishikawa, N . Bull. Chem. Soc. Jpn. 1979, 52, 3377-3380. 21. Takacs, J. M.; Helle, Μ. Α.; Seely, F. L. Tetrahedron Lett. 1986, 27, 12571260. 22. Thenappan, Α.; Burton, D. J. J. Org. Chem. 1990, 55, 4639-4642. 23. Lanier, M.; Haddach, M . ; Pastor, R.; Reiss, J. G. Tetrahedron Lett. 1993, 34, 2469-2472. 24. Tsukamoto, T.; Kitazume, T. J. Chem. Soc. Perkin Trans. 1 1993, 11771181. 25. Haas, A. M.; Hägele, G. J. Fluorine Chem. 1996, 78, 75-82. 26. Legoupy, S.; Cévisy, C.; Guillemin, J.-C.; Grée, R. J. Fluorine Chem. 1999, 93, 171-173. 27. Yamazaki, T.; Ichige, T.; Kitazume, T. Collect. Czech. Chem. Commun., 2002, 67, 1479-1485. 28. Yamazaki, T.; Hiraoka, S.; Sakamoto, J.; Kitazume, T. J. Phys. Chem. A 1999, 103, 6820-6824. 29. Ichikawa, J.; Wada, Y.; Fujiwara, M.; Sakoda, K. Synthesis, 2002, 1917 1936. 30. Miura, K.; Takeyama, Y.; Oshima, K.; Utimoto, K. Bull. Chem. Soc. Jpn. 1991, 64, 1542-1553. 31. Chérest, M.; Felkin, H.; Prudent, Ν. Tetrahderon Lett. 1968, 2199-2204. 32. Chérest, M.; Felkin, H. Tetrahderon Lett. 1968, 2205-2208. 33. Anh, Ν. T. Top. Cur. Chem. 1980, 88, 146-162. 34. Smith, R. J.; Trzoss, M.; Bühl, M . ; Bienz, S. Eur. J. Org. Chem. 2002, 2770-2775.



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35. Mengel, Α.; Reiser, Ο. Chem. Rev., 1999, 99, 1191-1123. 36. Yamamoto, Y.; Chounan, Y.; Nishii, S.; Ibuka, T.; Kitahara, H. J. Am. Chem. Soc. 1992, 114, 7652-7660. 37. Hoffmann, R. W. Chem. Rev. 1989, 89, 1841-1860. 38. Reetz, M. T.; Röhrig, D.; Harms, K.; Frenking, G. Tetrahedron Lett. 1994, 35, 8765-8768. 39. Asao, N.; Shimada, T.; Sudo, T.; Tsukada, N.; Yazawa, K.; Gyoung, Y.-S.; Uyehara, T.; Yamamoto, Y. J. Org. Chem. 1997, 62, 6274-6282. 40. Yamazaki, T.; Ando, M.; Kitazume, T.; Kubota, T.; Omura, M. Org. Lett. 1999, 1, 905-908. 41. Cieplak, A. S. Chem. Rev. 1999, 99, 1265-1336. 42. Gung, B. W. Tetrahedron 1996, 52, 5263-5301. 43. Int-4 type conformation is calculated to exist in 94% probability at the reaction temperature -78 °C by ab initio calculation (Gaussian 03W at the B3LYP/6-31+G* basis set). 44. Coxon, J. M.; McDonald, D. Q. Tetrahedron 1992, 48, 3353-3364. 45. Tsai, T.-L.; Chen, W.-C.; Yu, C.-H.; le Noble, W. J.; Chung, W.-S. J. Org. Chem. 1999, 64, 1099-1107. 46. Yadav, V. K.; Jeyaraj, D. Α.; Parvez, M.; Yamdagni, R. J. Org. Chem. 1999, 64, 2928-29. 47.Ono,M.; Nishimura, K.; Nagaoka, Y.; Tomioka, K. Tetrahedron Lett. 1999, 40, 1509-1512. 48. Recently, Fleming et al. reported a similar type of Michael addition by substrates containing trialkylsilyl groups instead of a CF moiety. Betson, M. S.; Fleming, I.; Guzman, V. A. Org. Biomol. Chem. 2003, 1, 4017-4024. 3


Fluorine-Containing Synthons - American Chemical Society

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