DOI: 10.3987/COM-13-S(S)27 DIASTEREOSELECTIVE SYNTHESIS...

HETEROCYCLES Vol 88 No 1 2014 pp 331 - 346 copy 2014 The Japan Institute of Heterocyclic Chemistry Received 6th June 2013 Accepted 4th July 2013 Published online 16th July 2013 DOI 103987COM-13-S(S)27

DIASTEREOSELECTIVE SYNTHESIS OF 3-FLUORO-2-SUBSTITUTED

PIPERIDINES AND PYRROLIDINESdagger

Paul N Gichuhi Masami Kuriyama and Osamu Onomura

Graduate School of Biomedical Sciences Nagasaki University 1-14 Bunkyo-

machi Nagasaki 852-8521 Japan Email onomuranagasaki-uacjp

Abstract ndash A facile procedure for synthesis of trans-3-fluoro-2-substituted

piperidines by utilizing electrophilic fluorination of cyclic enamines and Lewis

acid mediated nucleophilic substitution has been developed Also optically active

trans-2-allyl-3-fluorinated pyrrolidines have been prepared by utilizing

nucleophilic fluorination of hydroxyl group of trans-hydroxy-L-proline and Lewis

acid mediated diastereoselective allylation as key steps

INTRODUCTION

N-Heterocycles such as substituted piperidine or pyrrolidines are vast substructures in a great number of

biologically active natural products and small molecule pharmaceuticals1 Since fluorinated compounds

exhibit distinctive biological and physical properties fluorinated N-heterocycles are of great interest in

areas such as material science agrochemicals and pharmaceuticals (Figure 1)2 To date both

electrophilic and nucleophilic fluorination methods have been developed to furnish fluorinated N-

heterocycles34

N

F

NC O

F

FNH2

NN

H

F

O

O F

Cl

NH

SO2Cl

NH

NBn

F

N

NN

N

F

HN

N

O

CN

F

F

Denaglipti(dipeptidyl aminopeptidase IV inhibitor)

Profluazol (herbicide) (selective 5-HT1D agonist) (iNOS selective inhibitor)

Figure 1 Some examples of fluorinated N-heterocycles

dagger Dedicated to Professor Dr Victor Snieckus on his 77th birthday

HETEROCYCLES Vol 88 No 1 2014 331

In addition the nucleophilic additions to N-acyliminium ions are powerful methods for synthesis of

biologically active N-heterocycles5 Also a large number of methods containing diastereoselective

reactions to furnish substituted piperidines and pyrrolidines have been developed6 An example of such

addition reaction to N-acyliminium ion in which a fluorine atom present on the ring influences the

stereochemistry of the adducts is uniquely important Hence the synthesis of stereo defined fluorinated

cyclic amine derivatives with nucleophilic addition to N-acyliminium ion has not yet been reported

Herein we describe a facile synthesis using an electrophilic fluorinating reagent SelectfluorTM 17 utilizing

N-acyliminium ion precursors to furnish 3-fluorinated derivatives where the fluorine atom on the ring

influences the diastereoselectivities of adducts The significance of this method is threefold (Step 1)

Preparation of N-protected cyclic enamines 4 from corresponding amines 2 using the electrochemical

oxidation method8 and demethoxylation of 39 (Step 2) Electrophilic fluorination of 4 using 1 which is

safe non-toxic and easy to handle (Eq 1)1011 (Step 3) Lewis acid mediated nucleophilic substitution of

5 to give trans-substituted derivatives 6 or 7 (Eq 2)

N

PG

N

PG

OMeN

PG

N

PG

Nu

F

N

PG

Nu

F

N

PG

OMe

F

2e

100 oC

Nucleophiles

Lewis acid

5

+

3 4

n n n n

n n

trans-6 or 7 (major) cis-6 or 7 (minor)

(1)

(2)

2

1

5

MeOH

up to 58 de

(Step 1) (Step 2)

(Step 3)

NN F 2BF4Cl

MeOH

NH4Cl

In addition a nucleophilic fluorination with XtalFluor-ETM 812 of N-Cbz-trans-4-hydroxy-L-prolinate 9

afforded cis-fluoro-L-prolinate 10 which was electrochemically transformed into methoxylated derivative

11 Successive diastereoselective allylation of 11 afforded optically active allylated derivative 12 which

was easily transformed into 2R-allyl-3S-fluoropyrrolidine 13 (Eq 3)13

N

F

Cbz

CO2Me N

F

Cbz

S

S

R R

S

12 13 (82 de)

N

HO

CO2Me

Cbz

N SF2

Me

MeBF4

S

S

N

F

CO2Me

Cbz MeOH

S

N

F

CO2Me

CbzMeO

SSiMe3

9

8

10

2e

11

(3)

Lewis acid

332 HETEROCYCLES Vol 88 No 1 2014

RESULTS AND DISCUSSION

Preparation of N-protected enamines 4a-f from the respective N-protected piperidines and pyrrolidines

was achieved according to Shono method which consists of electrochemical methoxylation and

successive removal of methanol with up to 97 yield89 Next electrophilic fluorination of substrates 4a-f

using SelectfluorTM 1 afforded 3-fluoro-2-methoxy-N-protected piperidine and pyrrolidine derivatives710

Namely addition of 1 to a solution of 4 in acetonitrilemethanol gave 5a-f in good yields (Table 1)

Table 1 Fluoromethoxylation of cyclic enamines 4a-f

N

PG

N

PG

F

OMe

(11 equiv)

MeOHMeCN=11+

5a-f4a-f

n n

0 oC to rt

3 h1

NN F2BF4Cl

Entry PG n Substrate Product Yield () 1 CO2Me 2 4a 5a 72 2 CO2Ph 2 4b 5b 74 3 CO2Ph 1 4c 5c 64 4 Cbz 2 4d 5d 79 5 Cbz 1 4e 5e 72 6 Bz 2 4f 5f 65

We envisaged that upon treatment of 5 with some Lewis acids the N-acyliminium ions was generated and

readily trapped by the carbon nucleophiles resulting to the desired products with fluorine atom

influencing the diastereoselectivities1314 To our delight when compounds 5 were treated with some

Lewis acids in CH2Cl2 the allylation using allyltrimethylsilane proceeded satisfactorily to give allylated

products 6 in good yields (Table 2) TiCl4 or BF3OEt2 mediated allylation of 3-fluoro-2-methoxy-N-

methoxycarbonylpiperidine 5a smoothly proceeded to afford the allylated product 6a in high yields with

moderate diastereoselectivities (entries 1 and 2) For allylation of N-phenyloxycarbonylated piperidine 5b

the higher diastereoselectivity was achieved by using TiCl4 affording 58 de and 81 yield compared

with BF3OEt2 (entries 3 and 4) Although TiCl4 did not result to the allylated product for N-

benzyloxycarbonylated piperidine 5d using BF3OEt2 gave 58 de and 87 yield (entries 6 and 7)15 On

the other hand SnCl4 did not lead to any improvement on the de value of 6d (entry 8) In addition

BF3OEt2 mediated allylation of pyrrolidine derivatives 5ce proceeded to afford substituted products 6ce

in high yields with low diastereoselectivities (entries 5 and 9)

Next we focused on cyanation of 5 When compounds 5abd were treated with trimethylsilyl cyanide in

the presence of TiCl4 the desired product was formed in high yields and moderate diastereoselectivities

as shown in Table 3 (entries 1-3) Also 2-cyano-3-fluoro-N-benzyloxycarbonylpiperidine 7d was formed

with a higher de of 58 and yield of 84 when mediated by BF3OEt2 as the Lewis acid of choice (entry

4) SnCl4 did not lead to an improvement of the de and the yield of 7d (entry 5)


Table 2 Synthesis of 2-allyl-3-fluoropiperidine derivatives 6

Lewis acid (11 equiv)

in CH2Cl278 oC to rt 3 h

+

trans-6 (major) cis-6 (minor)5

+ SiMe3

(30 equiv)N

PG

F

OMen

N

PG

F

n

N

PG

F

n

Entry PG n Lewis acid Product Yield () De ()a 1 CO2Me 2 TiCl4 6a 89 44 2 CO2Me 2 BF3OEt2 6a 76 40 3 CO2Ph 2 TiCl4 6b 81 58 4 CO2Ph 2 BF3OEt2 6b 69 42 5 CO2Ph 1 BF3OEt2 6c 82 14 6 Cbz 2 TiCl4 6d 0 - 7 Cbz 2 BF3OEt2 6d 87 58 8 Cbz 2 SnCl4 6d 68 48 9 Cbz 1 BF3OEt2 6e 79 26 a Determined by 1H NMR andor 19F NMR at 50 oC

Table 3 Synthesis of 2-cyano-3-fluoropiperidine derivatives 7

N

PG

F

OMe N

PG

F

CN N

PG

F

CNLewis acid (11 equiv)

in CH2Cl2

Me3SiCN (30 equiv)

78 oC to rt 3 h

+

trans-7 cis-75

Entry PG Lewis acid Product Yield () De ()a 1 CO2Me TiCl4 7a 89 48 2 CO2Ph TiCl4 7b 83 50 3 Cbz TiCl4 7d 76 50 4 Cbz BF3OEt2 7d 84 58 5 Cbz SnCl4 7d 62 34

a Determined by 1H NMR andor 19F NMR at 50 oC

Relative stereoconfigurations for 6 and 7 were speculated by the NOESY studies for 6d and the HMBC

studies16 for 7d Diastereomers of 6d or 7d were separable by silica gel PTLC to afford major isomer and

minor isomer respectively The NOESY spectroscopy for major isomer of 6d showed correlations while

the NOESY spectroscopy for minor isomer of 6d did not show the correlation Accordingly it was

determined that major isomer was trans-6d and minor isomer was cis-6d Similarly separated major

isomer for 7d was determined as trans configuration (Figure 2)

N

Cbz

FH

H

HHH

HMBC

N

Cbz

FH

H

HHH

N

Cbz

F

CN

H

HN

Cbz

F

CN

H

H

timestimestimes

NOESY

trans-7d (major isomer)

cis-7d(minor isomer)


cis-6d (minor isomer)

Figure 2 NOESY for 6d and HMBC for 7d


We next focused on the synthesis of optically active 2-allyl-3-fluoropyrrolidine starting from N-Cbz-

trans-4-hydroxy-L-prolinate 917 Deoxofluorination of 9 was achieved by utilizing XtalFluor-ETM 8 as the

reagent of choice12 The fluorination of the hydroxyl group at the 4-position proceeded in an inversion

manner to give the desired compound 10 in 82 yield1218 Electrochemical oxidation of 10 afforded 4-

fluoro-5-methoxy-L-proline derivative 11 in 74 yield (Eq 4)

CH2Cl2

MeOHDBU (15 equiv)

27 Fmol 2e

0 oC78 oC to rt

N

HO

CO2Me

Cbz

N SF2

Me

MeBF4

S

S

N CO2Me

Cbz

FS

N

F

CO2Me

Cbz

MeOS8 (15 equiv)

9 10 82 11 74

(4)

The allylation of 11 using 20 equiv of Lewis acids19 was successfully achieved affording compound 12

(Eq 5)13 In the case of N-benzyloxycarbonylprolinate 11 the allylation mediated by TiCl4 resulted to

good yield and de Using BF3OEt2 afforded 12 in higher yield and de (entry 2) while the use of SnCl4

afforded low yield and de of 12

TiCl4

BF3-OEt2SnCl4

52 (62 de)

68 (82 de)

18 (10 de)

S

N

F

CO2Me

Cbz

MeOS

SiMe3

Lewis acid (20 equiv)S

N

F

CO2Me

Cbz

S

11

in CH2Cl278 oC to rt

+

(30 equiv)

12

(5)

Hydrolysis successive decarboxylative methoxylation and reductive demethoxylation13 of 12 prepared

by using BF3OEt2 proceeded smoothly without purification of intermediate 14 to give 2-allyl-3S-

fluoropyrrolidine 13 (Eq 6)

2) 2eMeOH

1) NaOH

N

F

Cbz

OMe N

F

Cbz

12

14

(6)

78 oC to rt

13 (82 de)

CH2Cl2

Et3SiH

MeSO3H

58 from 12

S S

R

Comparing HPLC pattern of 13 with that of 6e (transcis=6337) showed that the relative

stereoconfiguration of 13 was majorly trans (82 de) and its absolute stereoconfiguration was 2R3S

CONCLUSION

In conclusion a facile procedure for synthesis of trans-3-fluoro-2-substituted piperidines and optically

active trans-2-allyl-3-fluorinated pyrrolidine which can be used as precursors for new drugs in

pharmaceuticals has been developed This was achieved by utilizing facile electrochemical oxidation and

electrophilic or nucleophilic fluorination Additionally mild conditions and practical convenience will

make this method a valuable synthetic tool in organic chemistry


EXPERIMENTAL

General All commercial materials reagents and solvents were used without further purification unless

otherwise stated Electrochemical reactions were carried out by the use of DC power supply (GP 050-2)

of Takasago Seikakusho in an undivided glass cell by using platinum plate electrodes (10 x 20 mm)

graphite electrodes (50 x 12 x 2 mm) 1H NMR spectra were measured at 500 and 400 MHz with TMS as

an internal standard at 50 oC 19F NMR spectra were measured at 376 MHz with CFCl3 used as the

internal standard at 50 oC 13C NMR spectra were measured at 100MHz on JEOL JNM-AL 400MHZ IR

spectra were obtained on Shimadzu FTIR-8100A High resolution mass spectra were recorded on a JEOL

JMS-700N instrument using electron ionization (EI) mass spectrometry Melting points were measured

with micro melting point apparatus (Yanaco) Flash column chromatography was performed using silica

gel 60 (230-400 mesh Nacalai tesque) with the indicated solvents Thin-layer chromatography was

performed using 025 mm silica gel plates (Merck) Specific optical rotations were recorded on JASCO

DIP-1000 digital polarimeter

General procedure for the preparation of N-protected enamines 4a-f

The substrates 4a-i were prepared from the respective N-protected piperidine and pyrrolidines according

to previously reported methods89 Compounds 4a8 4b20 4c21 4d22 4e9 and 4f23 are known compounds

and their spectroscopic data is available in literature

General procedure for the fluorination of N-protected enamines 4a-i using Selectfluor

To the substrates 4a-f (10 mmol) dissolved in 3 mL of MeCNMeOH (11) under a nitrogen atmosphere

Selectfluor (11 mmol) was added at 0 oC stirring the mixture for 1 h The temperature of the mixture was

then gradually allowed to rise to room temperature and the reaction was monitored using TLC for over 2

h Water (5 mL) was added and the mixture extracted using CH2Cl2 (5 x 10 mL) The combined organic

layer was dried by anhydrous Na2SO4 The crude product was purified by column chromatography on

silica gel (n-hexaneEtOAc 41) to give the desired product 5a-f

3-Fluoro-2-methoxy-N-methoxycarbonylpiperidine (5a)

Colorless oil 1H NMR (CDCl3) 142-165 (m 1H) 173-203 (m 3H) 285-299 (m 1H) 330 and 336

(2s 3H) 374 and 375 (2s 3H) 381-403 (m 1H) 435-452 and 461 (m and d J=464 Hz 1H) 520-

555 (m 1H) 13C NMR (CDCl3) 187 and 232 (2s) 241 and 242 (2s) 373 and 379 (2s) 524 and

525 (2s) 546 and 551 (2s) 822 and 825 (2s) 858 and 886 (2d J=1706 and 1839 Hz) 1567 and

1559 (2s) 19F NMR (CDCl3)1912 (br s 067F) 1835 (d J=473 Hz 033F) IR (neat) 2953 1701

1440 1412 1369 1261 1163 1086 962 770 cm1 HR-MS [EI (+)] mz calcd for C8H14FNO3 [M+]

1910958 found 1910941

3-Fluoro-2-methoxy-N-phenyloxycarbonylpiperidine (5b)


Mp 76-78 oC 1H NMR (CDCl3) 152-168 (m 1H) 175-207 (m 3H) 305 (br s 1H) 331-353 (m

3H) 396-410 (m 1H) 453 and 467 (br d and d J=476 and 476 Hz 1H) 551-562 (m 1H) 709-736

(m 5H) 13C NMR (CDCl3) 2382-2438 (m) 2550 (br s) 3819 (br s) 5275-5604 (m) 8298 (br s)

8488-8679 (m) 12106-12176 (m 2C) 12467-12560 (m) 12875-12940 (m 2C) 15089-15135 (m)

15361 (s) 19F NMR (CDCl3) 19157 (t J=451 Hz 040F) 1838 (t J=471 Hz 060F) IR (neat)

2945 1717 1495 1410 1381 1369 1260 1198 1161 1069 1024 968 748 cm1 HR-MS [EI (+)] mz

calcd for C13H16FNO3 [M+] 2531114 found 2531127

3-Fluoro-2-methoxy-N-phenyloxycarbonylpyrrolidine (5c)

Colorless oil 1H NMR (CDCl3) 220-231 (m 2H) 348 and 358 (2s 3H) 373-381 (m 2H) 489-

504 (m 1H) 524-533 (m 1H) 713-725 (m 3H) 734-738 (m 2H) 13C NMR (CDCl3) 2817-2996

(m) 4137-4630 (m) 5604-5797 (m) 8639 (s) 9149-9559 (m) 12192 (br s) 12587 (s 2C) 12966

(s 2C) 15101 (2s) 15302-15484 (m) 19F NMR (CDCl3) 2003- 2015 (m 037F)1869- 1882

(m 063F) IR (neat) 2936 1721 1593 1495 1456 1387 1371 1204 1163 1099 1042 957 731 cm1

HR-MS [EI (+)] mz calcd for C12H14FNO3 [M+] 2390958 found 2390958

N-Benzyloxycarbonyl-3-fluoro-2-methoxypiperidine (5d)

Colorless oil 1H NMR (CDCl3) 140-154 (m 1H) 169-205 (m 3H) 289-295 (m 1H) 325-362 (m

3H) 368-400 (m 1H) 433-450 and 459 (m and d J=481 Hz 1H) 506-527 (m 2H) 546 (br s 1H)

723-741 (m 5H) 13C NMR (CDCl3) 189 and 233 (2s) 242 and 244 (2s) 375 and 381 (2s) 548

and 551 (2s) 672 and 674 (2s) 823 and 826 (2s) 859 and 887 (2s) 1279 (s) 1281 (s) 1280 (s)

1283 (s) 1285 and 1286 (2s) 1362 and 1365 (2s) 1552 and 1559 (2s) 19F NMR (CDCl3)

(s 050F) 18367 (s 050F) IR (neat) 2947 1697 1447 1418 1258 1070 962 cm1 HR-MS

[EI (+)] mz calcd for C14H18FNO3 [M+] 2671271 found 2671257

N-Benzyloxycarbonyl-3-fluoro-2-methoxypyrrolidine (5e)

Colorless oil 1H NMR (CDCl3) 203-215 (m 2H) 318-347 (m 4H) 357 (br s 1H) 468-488 and

481 (m and d J=524 Hz 1H) 495-525 (m 3H) 719-728 (m 5H) 13C NMR (CDCl3) 2982 (s)

4155 (s) 4371 and 4562 (2s) 5560 and 5616 (2s) 8655 (s) 9165 (s) 12772-12858 (m 5C) 13619-

13635 (m) 15517-15579 (m) 19F NMR (CDCl3) 20125 and 20032 (2d J=410 519 Hz 019F)

18803 and 18710 (2s 081F) IR (neat) 2947 1705 1449 1404 1341 1279 1213 1177 1096 1076

959 772 cm1 HR-MS [EI (+)] mz calcd for C13H16FNO3 [M+] 2531114 found 2531120

N-Benzoyl-3-fluoro-2-methoxypiperidine (5f)


5H) 13C NMR (CDCl3) 1931 (br s) 2462-2503 (m) 3622 (m) 5485 and 556 (2s) 8574-8801 (m)


8987 (br s) 12723-12780 (m 2C) 12868-12889 (m 2C) 13003 and 13042 (2s) 13555 and 13576

(2s) 17165 and 17238 (2s) 19F NMR (CDCl3) 19124 (br s 029F) 18323 and 18409 (2br s

071F) IR (neat) 2945 1641 1412 1352 1301 1273 1069 1045 968 702 cm1 HR-MS [EI (+)] mz


General procedure for the preparation of 2-allyl-3-fluoro-N-protected cyclic amine derivatives 6a-e

The substrate compound 5 (10 mmol) and allyltrimethylsilane (30 mmol) were dissolved in dry CH2Cl2

(3 mL) at 78 oC under nitrogen atmosphere 1M TiCl4 in CH2Cl2 (11 mmol) was added dropwise via

syringe The reaction was allowed to warm to room temperature over 3 h progress monitored by TLC

After completion the reaction mixture was quenched with (5 mL) of saturated aqueous NaHCO3 solution

The aqueous layer was extracted with CH2Cl2 (3 x 5 mL) and the combined organic layer washed with

saturated aqueous NaCl (10 mL) and dried over anhydrous Na2SO4 The organic layer was evaporated in

vacuo which was further purified by column chromatography on silica gel (n-hexaneEtOAc 81) as

eluent giving a mixture of diastereoisomers compound 6

2-Allyl-3-fluoro-N-methoxycarbonylpiperidine (6a) (44 de)


2H) 268 (td J=134 31 Hz 072H) 278-283 (m 028H) 348-372 (m 3H) 387 (d J=122 Hz

072H) 401 (d J=98 Hz 028H) 445-451 (m 1H) 457-463 (m 1H) 494-505 (m 2H) 561-572

(m 1H) 13C NMR (CDCl3) 1965 (s) 2496-2524 (m) 2590 (s) 3363 and 3372 (2s) 3809 and 3915

(2s) 5301-5412 (m) 8798 and 8974 (2d J=1840 and 1705 Hz) 11772 and 11824 (2s) 13429 and

13472 (2s) 15695 and 15727 (2s) 19F NMR (CDCl3) 18245 (br s 028F)18151 (d J=488 Hz

072F) IR (neat) 2953 1694 1449 1408 1366 1310 1190 1152 1034 959 916 766 cm1 HR-MS [EI

(+)] mz calcd for C10H16FNO2 [M+] 2011165 found 2011163

2-Allyl-3-fluoro-N-phenyloxycarbonylpiperidine (6b) (58 de)

Mp 80-81 oC 1H NMR (CDCl3) 157-172 (m 2H) 173-191 (m 1H) 187-215 (m 1H) 234-258 (m

2H) 409 (d J=137 Hz 079H) 422 (d J=122 Hz 021H) 456-487 (m 2H) 499-525 (m 2H) 515-

566 (m 1H) 570-595 (m 1H) 701-713 (m 2H) 713-721 (m 1H) 727-739 (m 2H) 13C NMR

(CDCl3) 1924 (s) 2479 and 2457 (2s) 3324 and 3333 (2s) 3808 (br s) 5384 (br s) 8672 and

8871 (2s) 11573 (s) 1180 (br s) 11908 (s) 12173 (s) 12515 (s) 12919 (s) 13356 (s) 15161 (s)

15423 (s) 19F NMR (CDCl3) 17891 and 17955 (2b s 1F) IR (neat) 2949 1709 1643 1593 1495

1412 1356 1310 1240 1196 1161 1140 1040 1024 991 957 743 cm1 HR-MS [EI (+)] mz calcd

for C15H18FNO2 [M+] 2631322 found 2631324

2-Allyl-3-fluoro-N-phenyloxycarbonylpyrrolidine (6c) (14 de)

Colorless oil 1H NMR (CDCl3) 179-267 (m 4H) 281 and 342-428 (br s and m 3H) 483-526 (m


3H) 568-587 (m 1H) 706-717 (m 3H) 727-735 (m 2H) 13C NMR (CDCl3) 2854-3162 (m)

3572 and 3678 (2br s) 4465 (s) 6211 and 6399 (2br s) 9186-9426 (m) 11788 (s) 11815 (br s)

12158 (s) 12519 (s) 12911 and 12919 (2s) 13348 (br s) 13414 and 13416 (2s) 15133 and 15135

(2s) 15309 and 15317 (2s) 19F NMR (CDCl3) 19317 and 19384 (2br s 057F) 17621- 17520

(m 043F) IR (neat) 2949 1717 1641 1593 1494 1389 1192 1070 1022 918 754 739 cm1 HR-MS


2-Allyl-N-benzyloxycarbonyl-3-fluoropiperidine (6d) (58 de)


2H) 278 (t J=134 Hz 079H) 288 (t J=132 Hz 021H) 400 (br d J=139 Hz 079H) 414 (br d

J=132 Hz 021H) 450-472 (m 2H) 495-520 (m 4H) 562-578 (m 1H) 733 (s 5H) 13C NMR

(CDCl3) 2371 (s) 2559 and 2578 (2s) 2888 (s) 3796 and 3901 (2s) 5367 and 5392 (2s) 6746

and 6764 (2s) 8825 and 9006 (2s) 11763 and 11811 (2s) 1281-2892 (m 5C) 13405 and 13459

(2s) 13714 and 13740 (2s) 15607 (s) 19F NMR (CDCl3) 18148 (d J=489 Hz 1F) IR (neat) 2949

1692 1423 1350 1248 1148 1069 1028 1001 959 733 cm1 HR-MS [EI (+)] mz calcd for

C16H20FNO2 [M+] 2771478 found 2771458

Further purification of a mixture of cis- and trans-6d by PTLC afforded cis-6d and trans-6d

cis-2-Allyl-N-benzyloxycarbonyl-3-fluoropiperidine (cis-6d) (less polar)


2H) 288 (t J=134 Hz 1H) 414 (d J=137 Hz 1H) 452-471 (m 2H) 509 (br s 1H) 499-503 (m

1H) 510-517 (m 2H) 57 (d J=73 Hz 1H) 727-738 (m 5H) 13C NMR (CDCl3) 2366 and 2376

(2s) 2482 and 2504 (2s) 2888 (s) 3796 (s) 5367 and 5392 (2s) 6746 and 6764 (2s) 8825 and

9006 (2s) 11763 and 11811 (2s) 12815-12886 (m 5C) 13405 and 13459 (2s) 13714 and 13740

(2s) 15607 (s) 19F NMR (CDCl3) 18078 (d J=457 Hz 1F)

trans-2-Allyl-N-benzyloxycarbonyl-3-fluoropiperidine (trans-6d) (polar)


2H) 277 (t J=133 1H) 399 (d J=137 Hz 1H) 455 (dt J=109 53 Hz 1H) 451-459 (m 1H) 461-

470 (m 1H) 498 (d J=100 Hz 1H) 506 (d J=173 Hz 1H) 509-516 (m 2H) 570 (d J=732 Hz

1H) 733 (m 5H) 13C NMR (CDCl3) 2371 (s) 2568 (s) 2888 (s) 3796 (s) 5367 and 5392 (2s)

6746 and 6764 (2s) 8825 and 9006 (2s) 11763 and 11811 (2s) 12611-13061 (m 5C) 13310 (s)

13636 (s) 15607 (s) 19F NMR (CDCl3) 18152 (d J=489 Hz 1F)

2-Allyl-N-benzyloxycarbonyl-3-fluoropyrrolidine (6e) (26 de)

Colorless oil 1H NMR (CDCl3) 162-240 (m 4H) 316-410 (m 3H) 483 (dd J=524 22 Hz 063H)

487 (dd J=528 28 Hz 037H) 496 and 500 (2d J=34 and 34 Hz 1H) 502-511 (m 1H) 512-521


(m 2H) 562-592 (m 1H) 727-738 (m 5H) 13C NMR (CDCl3) 2902 and 3005 (2br s) 3108 and

3130 (2s) 4450 and 4452 (2s) 6153 and 6369 (2br s) 6688 (s) 9034 and 9186 (2s) 11760 (s)

11796 (s) 12778 (s) 12789 and 12795 (2s) 12842 and 12844 (2s) 13355 (s) 13429 and13431 (2s)

13679 (s) 15457 and 15468 (2s) 19F NMR (CDCl3) 18696 and 18789 (2br s 063F)17607 and

17546 (2br s 037F) IR (neat) 2953 1701 1447 1406 1340 1279 1211 1179 1098 1078 1053

959 735 cm1 HR-MS [EI (+)] mz calcd for C15H18FNO2 [M+] 2631322 found 2631313 HPLC

YMC-Pack SIL column 150 mm x 46 mm n-hexane2-propanol 501 wavelength 254 nm flow rate 10

mLmin retention time 38 min (37) 56 min (63)

General procedure for the preparation of 2-cyano-3-fluoro-N-protected cyclic amine derivatives 7a-d

The substrate compound 5 (10 mmol) and trimethylsilyl cyanide (30 mmol) were dissolved in dry

CH2Cl2 (3 mL) at 78 oC under nitrogen atmosphere 1M TiCl4 in CH2Cl2 (11 mmol) was added drop-

wise via syringe The reaction was allowed to warm to room temperature then quenched with saturated

aqueous NaHCO3 (5 mL) The aqueous layer was extracted with CH2Cl2 (3 x 5 mL) and the combined

organic layer washed with saturated aqueous NaCl (10 mL) and dried over anhydrous Na2SO4 The

organic layer was evaporated in vacuo which was further purified by column chromatography on silica

gel (n-hexaneEtOAc 81) as eluent giving a mixture of diastereoisomers compound 7 The same

procedure was repeated for BF3OEt2 and SnCl4

2-Cyano-3-fluoro-N-methyloxycarbonylpiperidine (7a) (48 de)

Colorless oil 1H NMR (CDCl3) 151-154 (m 1H) 183-192 (m 2H) 210-230 (m 1H) 296 (td

J=134 27 Hz 074H) 305 (br t J=134 Hz 026H) 377 (s 3H) 406 (br d J=129 Hz 074H) 419

(br d J=112 Hz 026H) 442-460 (m 074H) 485 (br d J=462 Hz 026H) 543 and 553 (2br s 1H) 13C NMR (CDCl3) 2231 (s) 2545 and 2700 (2s) 4034 (s) 4833 and 4861 (2s) 5345 (s) 8580 and

8763 (2s) 11421 (s) 15486 (s) 19F NMR (CDCl3) 18645 (br s 026F) 17876 (d J=473 Hz

074F) IR (neat) 2959 1707 1447 1404 1366 1306 1261 1202 1109 1042 980 932 903 869 733

702 cm1 HR-MS [EI (+)] mz calcd for C8H11FN2O2 [M+] 1860805 found 1860802

2-Cyano-3-fluoro-N-phenyloxycarbonylpiperidine (7b) (50 de)

Mp 79-81oC 1H NMR (CDCl3) 155-170 (m 1H) 190-205 (m 2H) 215-235 (m 1H) 312 and 320

(2br s 1H) 422 and 434 (2d J=129 and 139 Hz 1H) 454-472 (m 075H) 493 (d J=454 Hz

025H) 556 (d J=104 Hz 025H) 565 (d J=56 Hz 075H) 710-717 (m 2H) 722-729 (m 1H)

736-733 (m 2H) 13C NMR (CDCl3) 2546 and 2566 (2s) 2703 and 2721 (2s) 4111 (br s) 4872

(br s) 8469 and 8656 (2s) 11439 (s) 12143-12177 (m 2C) 12597-12625 (m) 12946-12972 (m

2C) 15106 and 15119 (2s) 15204 (s) 19F NMR (CDCl3) 18620 and 18619 (2s 025F) 17965

(br d J=456 Hz 075F) IR (neat) 2959 1717 1593 1494 1456 1408 1348 1252 1196 1070 1026


974 872 733 cm1 HR-MS [EI (+)] mz calcd for C13H13FN2O2 [M+] 2480961 found 2480960

N-Benzyloxycabonyl-2-cyano-3-fluoropiperidine (7d) (50 de)

Colorless oil 1H NMR (CDCl3) 143-204 (m 4H) 308 (t J=135 Hz 025H) 316 (t J=108 Hz

075H) 383 (d J=129 Hz 025H) 394 (d J=125 Hz 075H) 445-455 (m 025H) 466 (d J=468 Hz

075H) 514 (s 2H) 577 (d J=28 Hz 075H) 591 (s 025H) 734 (s 5H) 13C NMR (CDCl3) 1860

(s) 2281 and 2373 (2s) 3793 (s) 3859 (s) 6755 and 6769 (2s) 8585 and 8756 (2s) 12798 (s 2C)

12807 (s) 12823 and 12831 (2s) 12864 (s 2C) 13632 and 13643 (2s) 15489 (s) 19F NMR (CDCl3)

18983 (t J=488 Hz 075F) 18346 (d J=443 Hz 025F) IR (neat) 2959 1701 1414 1344 1312

1254 1155 1047 974 874 731 cm1 HR-MS [EI (+)] mz calcd for C14H15FN2O2 [M+] 2621118 found

2621120


cis-N-Benzyloxycabonyl-2-cyano-3-fluoropiperidine (cis-7d) (less polar)


J=133 27 Hz 1H) 409 (br d J=132 Hz 1H) 442-460 (m 1 H) 517 (s 2H) 555 (br s 1H) 732-

738 (m 5H) 13C NMR (CDCl3) 1962 (s) 2776 (s) 3545 (s) 3930 (s) 5808 and 5863 (2s) 6787

(s) 8757 (s) 11862 (s) 12849 (s 2C) 12860 (s) 12916 (s) 13437 and 13776 (2s) 15679 (s) 19F

NMR (CDCl3) 18340 (d J=470 Hz 1F)

trans-N-Benzyloxycabonyl-2-cyano-3-fluoropiperidine (trans-7d) (polar)

Colorless oil 1H NMR (CDCl3) 149-159 (m 2H) 187-204 (m 2H) 307 (t J=125 Hz 1H) 421 (br

d J=122 Hz 1H) 486 (d J=454 Hz 1H) 520 (s 2H) 547 (br s 1H) 735 (s 5H) 13C NMR (CDCl3)

1829 (s) 2078-2617 (m 2C) 2854-2897 (m) 3565-4083 (m) 6701-6752 (m) 8556 (s) 12531-

13134 (m 5C) 13393-13802 (m) 15289-15742 (m) 19F NMR (CDCl3) 18884 (d J=473 Hz 1F)

Preparation of methyl N-benzyloxycarbonyl-cis-4-fluoro-L-prolinate (10)

N-Benzyloxycarbonyl-trans-4-hydroxy-L-prolinate (9) was prepared from trans-4-hydroxy-L-proline

according to literature method in quantitative yield1724 Compound 9 was transformed into N-

benzyloxycarbonyl-cis-4-fluoro-L-prolinate 10 according to literature method using XtalFluor-E 8 in 82

yield25

Methyl N-benzyloxycarbonyl-cis-4-fluoro-L-prolinate (10)

[α]D27 450 (c 178 CH2Cl2)

Procedure for electrochemical oxidation of 10

The substrate (10mmol) and Et4NBF4 (01 mmol) were placed in a beaker type cell containing a stirring

bar MeOH and MeCN (14) were added and the mixture stirred at 0 oC The graphite anode and platinum

cathodes were fitted and 27 Fmol-1 of current was passed through The reaction mixture was evaporated


to eliminate methanol Water was added and the mixture was then extracted with EtOAc and the

combined organic layer dried using anhydrous MgSO4 and filtered The solvent was removed in vacuo

and the resulting concentrate purified by silica gel chromatography to afford 4-fluoro-5-methoxy-L-

prolinate 11 in 74 yield

Methyl (2S4S)-N-benzyloxycarbonyl-4-fluoro-5-methoxy-L-prolinate (11)

Yellow oil 1H NMR (CDCl3) 223-246 (m 1H) 252 (dd J=187 150 Hz 1H) 327-395 (m 6H)

450-466 (m 1H) 514 (t J=43 Hz 1H) 516-523 (m 2H) 527 (t J=43 Hz 1H) 719-735 (m 5H) 13C NMR (CDCl3) 2932 and 2967 (2s) 3634-3787 (m) 5180 (s) 5229-5383 (m) 5763 and 5783

(2s) 6732 and 6754 (2s) 9108 and 9232 (2d J=3562 and 3560 Hz) 12793-12882 (m 5C) 13655

(s) 15457 (br s) 17173 (br s) 19F NMR (CDCl3) 17368 (br s 1F) IR (neat) 2955 1755 1703 1414

1348 1263 1206 1167 1113 1003 957 916 735 cm1 HR-MS [EI (+)] mz calcd for C15H18FNO5

[M+] 3111169 found 3051167

Preparation of methyl N-benzyloxycarbonyl -5-allyl-4-fluoro-L-prolinate (12)

To a mixture of 11 (10 mmol) and allyltrimethylsilane (30 mmol) in dry CH2Cl2 (3 mL) was added

dropwise BF3OEt2 (20 mmol) at 78 oC under nitrogen atmosphere The reaction was allowed to warm

to room temperature over 12 h The reaction mixture was quenched with saturated aqueous NaHCO3 (5

mL) The aqueous layer was extracted with CH2Cl2 (3 x 5 mL) and the combined organic layer washed

with saturated aqueous NaCl (10 mL) and dried over anhydrous Na2SO4 The organic layer was

evaporated in vacuo which was further purified by column chromatography on silica gel (n-

hexaneEtOAc 21) as eluent giving 12

Methyl (2S4S)-5-allyl-N-benzyloxycarbonyl-4-fluoro-L- prolinate (12)


3H) 518 (d J=118 Hz 1H) 535 (d J=134 Hz 1H) 568-590 (m 1H) 722-747 (m 5H) 13C NMR

(CDCl3) 2966 and 3176 (2s) 5148 and 5178 (2s) 5210 (s) 5817 (s) 6717 (s) 6967-7019 (m)

10973-11075 (m) 11682-12124 (m) 12743-12889 (m 5C) 13410 (s) 13650 (s) 16084 (s) 17185

(s) 19F NMR (CDCl3) 17363 (br s 1F) IR (neat) 2953 1757 1709 1436 1354 1213 1175 957

756 cm1 HR-MS [EI (+)] mz calcd for C17H20FNO4 [M+] 3221376 found 3221361

Demethoxycarbonylation of 12

2N NaOH (1mmol) was added to a solution of 12 (10 mmol) in MeOH (10 mL) and the mixture refluxed

for 2 h MeOH was removed in vacuo and the pH was adjusted to 1 with 3N HCl The resulting

suspension was extracted using EtOAc (3x 5 mL) The combined organic layer was dried using

anhydrous Na2SO4 and evaporated to give the corresponding acid which was further dissolved in MeOH

(7 mL) The resulting mixture was placed in a beaker type cell stirring at 0 oC Then graphite anode and


platinum cathode were fitted and 26-lutidine (12 mmol) was added and a constant current of 20 Fmol-1

was passed through The solvent was evaporated followed by addition of aqueous NaCl (7 mL) The

mixture was extracted with EtOAc 3 times and the combined organic layer dried over anhydrous MgSO4

and filtered The solvent was removed under vacuo to give the corresponding methoxylated compound 14

Triethylsilane (075 mmol) was added to a stirred solution of 14 (050 mmol) dissolved in dry CH2Cl2 (3

mL) at 78 oC under nitrogen atmosphere The reaction was allowed to warm to 0 oC for 1 h

Methanesulfonic acid (060 mmol) was then added drop wise and the mixture was stirred over 30 min at

room temperature Water (20 mL) was added and the solution was extracted with CHCl3 (3 x 10 mL) The

combined organic layer was dried over anhydrous MgSO4 and filtered The organic layer was evaporated

in vacuo and the concentrate was purified by using silica-gel column chromatography (n-hexaneEtOAc

21) as eluent giving 13 in 58 yield

(2R3S)-2-Allyl-N-benzyloxycarbonyl-3-fluoropyrrolidine (13)


4H) 562-592 (m 1H) 732-738 (m 5H) 13C NMR (CDCl3) 2928 and 3005 (2br s) 3152 (s) 4451

and 4453 (2s) 6155 and 6302 (2br d) 6691 (s) 8991-9287 (m) 11759 (s) 11793 (s) 12780 (s)

12790 and 12795 (2s) 12842 (s) 13333 (br s) 13432 (s) 13681 (s) 15490 (s) 19F NMR (CDCl3)

18761 and 18668 (2br s) IR (neat) 2953 1701 1447 1406 1340 1279 1211 1179 1098 1078

1053 959 735 cm1 HR-MS [EI (+)] mz calcd for C15H18FNO2 [M+] 2631322 found 2631313 HPLC


mLmin retention time 38 min (2S 9) 56 min (2R 91)

ACKNOWLEDGEMENTS

This research was supported by a Grant-in-Aid for Scientific Research on Innovative Areas (23105539)

from The Ministry of Education Culture Sports Science and Technology a Grant-in-Aid for Scientific

Research (C) (24590012) from The Japan Society for the Promotion of Science Research Grant for

Pharmaceutical Sciences from Takeda Science Foundation and the Presidentrsquos Discretion Fund of

Nagasaki University

REFERENCES AND NOTES

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Kane and D R Borcherding Tetrahedron 2003 59 2953 M G Buffat Tetrahedron 2004 60

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2 J L Castro I Collins M G N Russell A P Watt B Sohal D Rathbone M S Beer and J A

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635 P T Nyffeler G D Sergio D B Michael P V Stephanne and W Chi-Huey Agnew Chem

Int Ed 2005 44 192 L Riyuan D Shentao S Zhuangzhi and J Ning Org Lett 2011 13

4498 C Walpole Z Liu E E Lee F Zhou N Mackintosh M Sjogren D Taylor J Shen and R

A Batey Tetrahedron Lett 2012 53 2942

3 D C Lankin N S Chandrakumar S N Rao D P Spangler and J P Synder J Am Chem Soc

1993 115 3356 L Demange A Meacutenez and C Dugave Tetrahedron Lett 1998 39 1169 J P

Synder N S Chandrakumar H Sato and D C Lankin J Am Chem Soc 2000 122 544 S A

Golubev S Hartmut R Gabor M Fioroni S Thust and B Burger Tetrahedron Lett 2004 45

1445 J P Synder K Hardcastle A Sun and D C Lankin Chem Eur J 2005 11 1579 G

Verniest R Surmont E Van Hende A Deweweire D Frederik J W Thuring and N D Kimpe J

Org Chem 2008 73 5458 P K Mykhailiuk S V Shishkina O V Shishkin O A Zaporozhets

and I V Komarov Tetrahedron 2011 67 3091 P S Rajendra and T Umemoto J Org Chem

2011 76 3113

4 I Nowak L M Roger D R Rogers and S J Thrasher J Fluorine Chem 1999 99 73 P S

Rajendra and M S Jeanrsquone Acc Chem Res 2004 37 31 A Togni and H Ibrahim Chem

Commun 2004 1147 J Cossy P D Gomez and I Dechamps Synlett 2007 263 L K Kirk Org

Proc Res Dev 2008 12 305 L Hunter Beil J Org Chem 2010 6 38 T Furuya A S Kamlet

and T Ritter Nature 2011 473 470 D Chopra Cryst Growth Des 2012 12 541

5 Some representative reviews J M Moolenaar and N W Speckamp Tetrahedron 2000 56 3817

A Yazici and S G Pyne Synthesis 2009 339 A Yazici and S G Pyne Synthesis 2009 513

6 T Shono Y Matsumura K Tsubata and K Uchida J Org Chem 1986 51 2590 M Skrinjar

and L-G Wistrand Tetrahedron Lett 1990 31 1775 T Shono T Fujita and Y Matsumura

Chem Lett 1991 81 A Rouchaud and J-C Braekman Eur J Org Chem 2011 12 2346 O

Onomura Heterocycles 2012 85 2111

7 R E Banks J Fluorine Chem 1998 87 1 Y Takeuchi T Suzuki A Satoh T Shiragami and N

Shibata J Org Chem 1999 64 5708 A J Poss and G A Shia Tetrahedron Lett 1999 40

2673 D Cahard and C Audouard Org Lett 2000 2 3699 B Greedy and V Gouverneur Chem

Commun 2001 233 S Mizuta and O Onomura RSC Adv 2012 2 2266 S Singh C-M

Martinz S Calvet-Vitale A K Prasad T Prangeacute P I Dalko and H Dhimane Synlett 2012 23

2421


8 T Shono H Hamaguchi and Y Matsumura J Am Chem Soc 1975 97 4264

9 T Shono Y Matsumura T Tsubata Y Sugihara S Yamane T Kanazawa and T Aoki J Am

Chem Soc 1982 104 6697

10 Electrophilic chlorination and bromination of 4 T Shono Y Matsumura O Onomura M Ogaki

and T Kanazawa J Org Chem 1987 52 536

11 A Alix C Lalli P Retailleau and G Masson J Am Chem Soc 2012 134 10389

12 For deoxofluorination R P Singh and J M Shreeve Synthesis 2002 2561 F Beaulieu L-P

Beauregard G Courchesne M Couturier F Laflamme and A LrsquoHeureux Org Lett 2009 11

5050 A LrsquoHeureux F Beaulieu C Bennet D R Bill S Clayton F Laflamme M Mirmehrabi S

Tadayon D Tovell and M Couturier J Org Chem 2010 75 3401

13 O Onomura P G Kirira T Tanaka S Tsukada Y Matsumura and Y Demizu Tetrahedron

2008 64 7498 P G Kirira M Kuriyama and O Onomura Chem Eur J 2010 16 3970 S

Hirata M Kuriyama and O Onomura Tetrahedron 2011 67 9411

14 C Bucher C Sparr W B Schweizer and R Gilmour Chem Eur J 2009 15 7637 L E Zimmer

C Sparr and R Gilmour Angew Chem Int Ed 2011 50 2

15 BF3OEt2 mediated allylation of 3-chloro-2-methoxy-N-benzyloxycarbonylpiperidine gave 2-allyl-3-

chloro-N-benzyloxypiperidine in 87 de and 74 yield

2-Allyl-3-chloro-N-benzyloxypiperidine Colorless oil 1H NMR (CDCl3) 145-151 (m 1 H)

190-199 (m 1H) 203-209 (m 2H) 229-234 (m 1H) 239-246 (m 1H) 287 (br t J=132 Hz

1H) 415-421 (m 2H) 457 (br t J=77 Hz 1H) 503-510 (m 2H) 515 (s 2H) 565-578 (m

1H) 728-735 (m 5H) 13C NMR (CDCl3) 1899 (s) 2713 (s) 3481 (s) 3864 (s) 5332 (s)

5741 and 5795 (2s) 6718 (s) 11787 (s) 12772 12784 and 12840 (3s 5C) 13360 (s) 13698

(s) 15599 (s) IR (neat) 2951 1692 1423 1348 1246 1186 1123 1026 916 733 cm1 HR-MS

[EI (+)] mz calcd for C16H20ClNO2 [M+] 2931183 found 2931174 HPLC YMC-Pack SIL

column 150 mm x 46 mm n-hexane2-propanol 501 wavelength 254 nm flow rate 10 mLmin

retention time 27 min (63) 35 min (937)

16 M Koumlck J Junker and T Lindel Org Lett 1999 1 2041 M Perez-Trujillo P Nolis and T

Parella Org Lett 2007 9 29

17 J E Baldwin S J Bamford A M Fryer and M E Wood Tetrahedron Lett 1995 36 4869 J E

Baldwin S J Bamford A M Fryer M P W Rudolph and M E Wood Tetrahedron 1997 53

5233

18 Some literature for fluorinated cyclic amines L Demange J Cluzeau A Meacutenez and C Dugave

Tetrahedron Lett 2001 42 651 A S Golubev H Schedel G Radics M Fioroni S Thust and K


Burger Tetrahedron Lett 2004 45 1445

19 Using 11 equiv of Lewis acids lowered the yields of allylated products 12 and 13

20 L Franck C Sylvain B Pascal and G Courdet Tetrahedron 2001 57 6969

21 L E Burgess K M G Elizabeth and J Jurka Tetrahedron Lett 1996 37 3255

22 O Okitsu R Suzuki and S Kobayashi J Org Chem 2001 66 809

23 S Furukubo N Moriyama O Onomura and Y Matsumura Tetrahedron Lett 2004 45 8177

24 W Maison E Arce P Renold R J Kennedy and D S Kemp J Am Chem Soc 2001 123

10245

25 R P Singh and T Umemoto J Org Chem 2011 76 3113


In addition the nucleophilic additions to N-acyliminium ions are powerful methods for synthesis of

biologically active N-heterocycles5 Also a large number of methods containing diastereoselective

reactions to furnish substituted piperidines and pyrrolidines have been developed6 An example of such

addition reaction to N-acyliminium ion in which a fluorine atom present on the ring influences the

stereochemistry of the adducts is uniquely important Hence the synthesis of stereo defined fluorinated

cyclic amine derivatives with nucleophilic addition to N-acyliminium ion has not yet been reported

Herein we describe a facile synthesis using an electrophilic fluorinating reagent SelectfluorTM 17 utilizing

N-acyliminium ion precursors to furnish 3-fluorinated derivatives where the fluorine atom on the ring

influences the diastereoselectivities of adducts The significance of this method is threefold (Step 1)

Preparation of N-protected cyclic enamines 4 from corresponding amines 2 using the electrochemical

oxidation method8 and demethoxylation of 39 (Step 2) Electrophilic fluorination of 4 using 1 which is

safe non-toxic and easy to handle (Eq 1)1011 (Step 3) Lewis acid mediated nucleophilic substitution of

5 to give trans-substituted derivatives 6 or 7 (Eq 2)

N

PG

N

PG

OMeN

PG

N

PG

Nu

F

N

PG

Nu

F

N

PG

OMe

F

2e

100 oC

Nucleophiles

Lewis acid

5

+

3 4

n n n n

n n

trans-6 or 7 (major) cis-6 or 7 (minor)

(1)

(2)

2

1

5

MeOH

up to 58 de

(Step 1) (Step 2)

(Step 3)

NN F 2BF4Cl

MeOH

NH4Cl

In addition a nucleophilic fluorination with XtalFluor-ETM 812 of N-Cbz-trans-4-hydroxy-L-prolinate 9

afforded cis-fluoro-L-prolinate 10 which was electrochemically transformed into methoxylated derivative

11 Successive diastereoselective allylation of 11 afforded optically active allylated derivative 12 which

was easily transformed into 2R-allyl-3S-fluoropyrrolidine 13 (Eq 3)13

N

F

Cbz

CO2Me N

F

Cbz

S

S

R R

S

12 13 (82 de)

N

HO

CO2Me

Cbz

N SF2

Me

MeBF4

S

S

N

F

CO2Me

Cbz MeOH

S

N

F

CO2Me

CbzMeO

SSiMe3

9

8

10

2e

11

(3)

Lewis acid









N

PG

N

PG

F

OMe

(11 equiv)

MeOHMeCN=11+

5a-f4a-f

n n

0 oC to rt

3 h1

NN F2BF4Cl
























+


+ SiMe3

(30 equiv)N

PG

F

OMen

N

PG

F

n

N

PG

F

n



N

PG

F

OMe N

PG

F

CN N

PG

F


in CH2Cl2

Me3SiCN (30 equiv)

78 oC to rt 3 h

+

trans-7 cis-75









N

Cbz

FH

H

HHH

HMBC

N

Cbz

FH

H

HHH

N

Cbz

F

CN

H

HN

Cbz

F

CN

H

H

timestimestimes

NOESY












CH2Cl2

MeOHDBU (15 equiv)

27 Fmol 2e

0 oC78 oC to rt

N

HO

CO2Me

Cbz

N SF2

Me

MeBF4

S

S

N CO2Me

Cbz

FS

N

F

CO2Me

Cbz

MeOS8 (15 equiv)

9 10 82 11 74

(4)





TiCl4

BF3-OEt2SnCl4

52 (62 de)

68 (82 de)

18 (10 de)

S

N

F

CO2Me

Cbz

MeOS

SiMe3


N

F

CO2Me

Cbz

S

11


+

(30 equiv)

12

(5)




2) 2eMeOH

1) NaOH

N

F

Cbz

OMe N

F

Cbz

12

14

(6)

78 oC to rt

13 (82 de)

CH2Cl2

Et3SiH

MeSO3H

58 from 12

S S

R



CONCLUSION







EXPERIMENTAL































1910958 found 1910941






8488-8679 (m) 12106-12176 (m 2C) 12467-12560 (m) 12875-12940 (m 2C) 15089-15135 (m)


2945 1717 1495 1410 1381 1369 1260 1198 1161 1069 1024 968 748 cm1 HR-MS [EI (+)] mz





(m) 4137-4630 (m) 5604-5797 (m) 8639 (s) 9149-9559 (m) 12192 (br s) 12587 (s 2C) 12966

(s 2C) 15101 (2s) 15302-15484 (m) 19F NMR (CDCl3) 2003- 2015 (m 037F)1869- 1882

(m 063F) IR (neat) 2936 1721 1593 1495 1456 1387 1371 1204 1163 1099 1042 957 731 cm1













4155 (s) 4371 and 4562 (2s) 5560 and 5616 (2s) 8655 (s) 9165 (s) 12772-12858 (m 5C) 13619-


18803 and 18710 (2s 081F) IR (neat) 2947 1705 1449 1404 1341 1279 1213 1177 1096 1076






8987 (br s) 12723-12780 (m 2C) 12868-12889 (m 2C) 13003 and 13042 (2s) 13555 and 13576
















072H) 401 (d J=98 Hz 028H) 445-451 (m 1H) 457-463 (m 1H) 494-505 (m 2H) 561-572









566 (m 1H) 570-595 (m 1H) 701-713 (m 2H) 713-721 (m 1H) 727-739 (m 2H) 13C NMR


8871 (2s) 11573 (s) 1180 (br s) 11908 (s) 12173 (s) 12515 (s) 12919 (s) 13356 (s) 15161 (s)



for C15H18FNO2 [M+] 2631322 found 2631324








(m 043F) IR (neat) 2949 1717 1641 1593 1494 1389 1192 1070 1022 918 754 739 cm1 HR-MS










C16H20FNO2 [M+] 2771478 found 2771458







9006 (2s) 11763 and 11811 (2s) 12815-12886 (m 5C) 13405 and 13459 (2s) 13714 and 13740

















17546 (2br s 037F) IR (neat) 2953 1701 1447 1406 1340 1279 1211 1179 1098 1078 1053


















074F) IR (neat) 2959 1707 1447 1404 1366 1306 1261 1202 1109 1042 980 932 903 869 733







(br s) 8469 and 8656 (2s) 11439 (s) 12143-12177 (m 2C) 12597-12625 (m) 12946-12972 (m


(br d J=456 Hz 075F) IR (neat) 2959 1717 1593 1494 1456 1408 1348 1252 1196 1070 1026











2621120






(s) 8757 (s) 11862 (s) 12849 (s 2C) 12860 (s) 12916 (s) 13437 and 13776 (2s) 15679 (s) 19F

NMR (CDCl3) 18340 (d J=470 Hz 1F)




1829 (s) 2078-2617 (m 2C) 2854-2897 (m) 3565-4083 (m) 6701-6752 (m) 8556 (s) 12531-






yield25


[α]D27 450 (c 178 CH2Cl2)
















[M+] 3111169 found 3051167













10973-11075 (m) 11682-12124 (m) 12743-12889 (m 5C) 13410 (s) 13650 (s) 16084 (s) 17185


























18761 and 18668 (2br s) IR (neat) 2953 1701 1447 1406 1340 1279 1211 1179 1098 1078




ACKNOWLEDGEMENTS





Nagasaki University








1701















2011 76 3113

















2421




Chem Soc 1982 104 6697
















190-199 (m 1H) 203-209 (m 2H) 229-234 (m 1H) 239-246 (m 1H) 287 (br t J=132 Hz



5741 and 5795 (2s) 6718 (s) 11787 (s) 12772 12784 and 12840 (3s 5C) 13360 (s) 13698

(s) 15599 (s) IR (neat) 2951 1692 1423 1348 1246 1186 1123 1026 916 733 cm1 HR-MS








5233











10245










N

PG

N

PG

F

OMe

(11 equiv)

MeOHMeCN=11+

5a-f4a-f

n n

0 oC to rt

3 h1

NN F2BF4Cl
























+


+ SiMe3

(30 equiv)N

PG

F

OMen

N

PG

F

n

N

PG

F

n



N

PG

F

OMe N

PG

F

CN N

PG

F


in CH2Cl2

Me3SiCN (30 equiv)

78 oC to rt 3 h

+

trans-7 cis-75









N

Cbz

FH

H

HHH

HMBC

N

Cbz

FH

H

HHH

N

Cbz

F

CN

H

HN

Cbz

F

CN

H

H

timestimestimes

NOESY












CH2Cl2

MeOHDBU (15 equiv)

27 Fmol 2e

0 oC78 oC to rt

N

HO

CO2Me

Cbz

N SF2

Me

MeBF4

S

S

N CO2Me

Cbz

FS

N

F

CO2Me

Cbz

MeOS8 (15 equiv)

9 10 82 11 74

(4)





TiCl4

BF3-OEt2SnCl4

52 (62 de)

68 (82 de)

18 (10 de)

S

N

F

CO2Me

Cbz

MeOS

SiMe3


N

F

CO2Me

Cbz

S

11


+

(30 equiv)

12

(5)




2) 2eMeOH

1) NaOH

N

F

Cbz

OMe N

F

Cbz

12

14

(6)

78 oC to rt

13 (82 de)

CH2Cl2

Et3SiH

MeSO3H

58 from 12

S S

R



CONCLUSION







EXPERIMENTAL































1910958 found 1910941






8488-8679 (m) 12106-12176 (m 2C) 12467-12560 (m) 12875-12940 (m 2C) 15089-15135 (m)


2945 1717 1495 1410 1381 1369 1260 1198 1161 1069 1024 968 748 cm1 HR-MS [EI (+)] mz





(m) 4137-4630 (m) 5604-5797 (m) 8639 (s) 9149-9559 (m) 12192 (br s) 12587 (s 2C) 12966

(s 2C) 15101 (2s) 15302-15484 (m) 19F NMR (CDCl3) 2003- 2015 (m 037F)1869- 1882

(m 063F) IR (neat) 2936 1721 1593 1495 1456 1387 1371 1204 1163 1099 1042 957 731 cm1













4155 (s) 4371 and 4562 (2s) 5560 and 5616 (2s) 8655 (s) 9165 (s) 12772-12858 (m 5C) 13619-


18803 and 18710 (2s 081F) IR (neat) 2947 1705 1449 1404 1341 1279 1213 1177 1096 1076






8987 (br s) 12723-12780 (m 2C) 12868-12889 (m 2C) 13003 and 13042 (2s) 13555 and 13576
















072H) 401 (d J=98 Hz 028H) 445-451 (m 1H) 457-463 (m 1H) 494-505 (m 2H) 561-572









566 (m 1H) 570-595 (m 1H) 701-713 (m 2H) 713-721 (m 1H) 727-739 (m 2H) 13C NMR


8871 (2s) 11573 (s) 1180 (br s) 11908 (s) 12173 (s) 12515 (s) 12919 (s) 13356 (s) 15161 (s)



for C15H18FNO2 [M+] 2631322 found 2631324








(m 043F) IR (neat) 2949 1717 1641 1593 1494 1389 1192 1070 1022 918 754 739 cm1 HR-MS










C16H20FNO2 [M+] 2771478 found 2771458







9006 (2s) 11763 and 11811 (2s) 12815-12886 (m 5C) 13405 and 13459 (2s) 13714 and 13740

















17546 (2br s 037F) IR (neat) 2953 1701 1447 1406 1340 1279 1211 1179 1098 1078 1053


















074F) IR (neat) 2959 1707 1447 1404 1366 1306 1261 1202 1109 1042 980 932 903 869 733







(br s) 8469 and 8656 (2s) 11439 (s) 12143-12177 (m 2C) 12597-12625 (m) 12946-12972 (m


(br d J=456 Hz 075F) IR (neat) 2959 1717 1593 1494 1456 1408 1348 1252 1196 1070 1026











2621120






(s) 8757 (s) 11862 (s) 12849 (s 2C) 12860 (s) 12916 (s) 13437 and 13776 (2s) 15679 (s) 19F

NMR (CDCl3) 18340 (d J=470 Hz 1F)




1829 (s) 2078-2617 (m 2C) 2854-2897 (m) 3565-4083 (m) 6701-6752 (m) 8556 (s) 12531-






yield25


[α]D27 450 (c 178 CH2Cl2)
















[M+] 3111169 found 3051167













10973-11075 (m) 11682-12124 (m) 12743-12889 (m 5C) 13410 (s) 13650 (s) 16084 (s) 17185


























18761 and 18668 (2br s) IR (neat) 2953 1701 1447 1406 1340 1279 1211 1179 1098 1078




ACKNOWLEDGEMENTS





Nagasaki University








1701















2011 76 3113

















2421




Chem Soc 1982 104 6697
















190-199 (m 1H) 203-209 (m 2H) 229-234 (m 1H) 239-246 (m 1H) 287 (br t J=132 Hz



5741 and 5795 (2s) 6718 (s) 11787 (s) 12772 12784 and 12840 (3s 5C) 13360 (s) 13698

(s) 15599 (s) IR (neat) 2951 1692 1423 1348 1246 1186 1123 1026 916 733 cm1 HR-MS








5233











10245






+


+ SiMe3

(30 equiv)N

PG

F

OMen

N

PG

F

n

N

PG

F

n



N

PG

F

OMe N

PG

F

CN N

PG

F


in CH2Cl2

Me3SiCN (30 equiv)

78 oC to rt 3 h

+

trans-7 cis-75









N

Cbz

FH

H

HHH

HMBC

N

Cbz

FH

H

HHH

N

Cbz

F

CN

H

HN

Cbz

F

CN

H

H

timestimestimes

NOESY












CH2Cl2

MeOHDBU (15 equiv)

27 Fmol 2e

0 oC78 oC to rt

N

HO

CO2Me

Cbz

N SF2

Me

MeBF4

S

S

N CO2Me

Cbz

FS

N

F

CO2Me

Cbz

MeOS8 (15 equiv)

9 10 82 11 74

(4)





TiCl4

BF3-OEt2SnCl4

52 (62 de)

68 (82 de)

18 (10 de)

S

N

F

CO2Me

Cbz

MeOS

SiMe3


N

F

CO2Me

Cbz

S

11


+

(30 equiv)

12

(5)




2) 2eMeOH

1) NaOH

N

F

Cbz

OMe N

F

Cbz

12

14

(6)

78 oC to rt

13 (82 de)

CH2Cl2

Et3SiH

MeSO3H

58 from 12

S S

R



CONCLUSION







EXPERIMENTAL































1910958 found 1910941






8488-8679 (m) 12106-12176 (m 2C) 12467-12560 (m) 12875-12940 (m 2C) 15089-15135 (m)


2945 1717 1495 1410 1381 1369 1260 1198 1161 1069 1024 968 748 cm1 HR-MS [EI (+)] mz





(m) 4137-4630 (m) 5604-5797 (m) 8639 (s) 9149-9559 (m) 12192 (br s) 12587 (s 2C) 12966

(s 2C) 15101 (2s) 15302-15484 (m) 19F NMR (CDCl3) 2003- 2015 (m 037F)1869- 1882

(m 063F) IR (neat) 2936 1721 1593 1495 1456 1387 1371 1204 1163 1099 1042 957 731 cm1













4155 (s) 4371 and 4562 (2s) 5560 and 5616 (2s) 8655 (s) 9165 (s) 12772-12858 (m 5C) 13619-


18803 and 18710 (2s 081F) IR (neat) 2947 1705 1449 1404 1341 1279 1213 1177 1096 1076






8987 (br s) 12723-12780 (m 2C) 12868-12889 (m 2C) 13003 and 13042 (2s) 13555 and 13576
















072H) 401 (d J=98 Hz 028H) 445-451 (m 1H) 457-463 (m 1H) 494-505 (m 2H) 561-572









566 (m 1H) 570-595 (m 1H) 701-713 (m 2H) 713-721 (m 1H) 727-739 (m 2H) 13C NMR


8871 (2s) 11573 (s) 1180 (br s) 11908 (s) 12173 (s) 12515 (s) 12919 (s) 13356 (s) 15161 (s)



for C15H18FNO2 [M+] 2631322 found 2631324








(m 043F) IR (neat) 2949 1717 1641 1593 1494 1389 1192 1070 1022 918 754 739 cm1 HR-MS










C16H20FNO2 [M+] 2771478 found 2771458







9006 (2s) 11763 and 11811 (2s) 12815-12886 (m 5C) 13405 and 13459 (2s) 13714 and 13740

















17546 (2br s 037F) IR (neat) 2953 1701 1447 1406 1340 1279 1211 1179 1098 1078 1053


















074F) IR (neat) 2959 1707 1447 1404 1366 1306 1261 1202 1109 1042 980 932 903 869 733







(br s) 8469 and 8656 (2s) 11439 (s) 12143-12177 (m 2C) 12597-12625 (m) 12946-12972 (m


(br d J=456 Hz 075F) IR (neat) 2959 1717 1593 1494 1456 1408 1348 1252 1196 1070 1026











2621120






(s) 8757 (s) 11862 (s) 12849 (s 2C) 12860 (s) 12916 (s) 13437 and 13776 (2s) 15679 (s) 19F

NMR (CDCl3) 18340 (d J=470 Hz 1F)




1829 (s) 2078-2617 (m 2C) 2854-2897 (m) 3565-4083 (m) 6701-6752 (m) 8556 (s) 12531-






yield25


[α]D27 450 (c 178 CH2Cl2)
















[M+] 3111169 found 3051167













10973-11075 (m) 11682-12124 (m) 12743-12889 (m 5C) 13410 (s) 13650 (s) 16084 (s) 17185


























18761 and 18668 (2br s) IR (neat) 2953 1701 1447 1406 1340 1279 1211 1179 1098 1078




ACKNOWLEDGEMENTS





Nagasaki University








1701















2011 76 3113

















2421




Chem Soc 1982 104 6697
















190-199 (m 1H) 203-209 (m 2H) 229-234 (m 1H) 239-246 (m 1H) 287 (br t J=132 Hz



5741 and 5795 (2s) 6718 (s) 11787 (s) 12772 12784 and 12840 (3s 5C) 13360 (s) 13698

(s) 15599 (s) IR (neat) 2951 1692 1423 1348 1246 1186 1123 1026 916 733 cm1 HR-MS








5233











10245








CH2Cl2

MeOHDBU (15 equiv)

27 Fmol 2e

0 oC78 oC to rt

N

HO

CO2Me

Cbz

N SF2

Me

MeBF4

S

S

N CO2Me

Cbz

FS

N

F

CO2Me

Cbz

MeOS8 (15 equiv)

9 10 82 11 74

(4)





TiCl4

BF3-OEt2SnCl4

52 (62 de)

68 (82 de)

18 (10 de)

S

N

F

CO2Me

Cbz

MeOS

SiMe3


N

F

CO2Me

Cbz

S

11


+

(30 equiv)

12

(5)




2) 2eMeOH

1) NaOH

N

F

Cbz

OMe N

F

Cbz

12

14

(6)

78 oC to rt

13 (82 de)

CH2Cl2

Et3SiH

MeSO3H

58 from 12

S S

R



CONCLUSION







EXPERIMENTAL































1910958 found 1910941






8488-8679 (m) 12106-12176 (m 2C) 12467-12560 (m) 12875-12940 (m 2C) 15089-15135 (m)


2945 1717 1495 1410 1381 1369 1260 1198 1161 1069 1024 968 748 cm1 HR-MS [EI (+)] mz





(m) 4137-4630 (m) 5604-5797 (m) 8639 (s) 9149-9559 (m) 12192 (br s) 12587 (s 2C) 12966

(s 2C) 15101 (2s) 15302-15484 (m) 19F NMR (CDCl3) 2003- 2015 (m 037F)1869- 1882

(m 063F) IR (neat) 2936 1721 1593 1495 1456 1387 1371 1204 1163 1099 1042 957 731 cm1













4155 (s) 4371 and 4562 (2s) 5560 and 5616 (2s) 8655 (s) 9165 (s) 12772-12858 (m 5C) 13619-


18803 and 18710 (2s 081F) IR (neat) 2947 1705 1449 1404 1341 1279 1213 1177 1096 1076






8987 (br s) 12723-12780 (m 2C) 12868-12889 (m 2C) 13003 and 13042 (2s) 13555 and 13576
















072H) 401 (d J=98 Hz 028H) 445-451 (m 1H) 457-463 (m 1H) 494-505 (m 2H) 561-572









566 (m 1H) 570-595 (m 1H) 701-713 (m 2H) 713-721 (m 1H) 727-739 (m 2H) 13C NMR


8871 (2s) 11573 (s) 1180 (br s) 11908 (s) 12173 (s) 12515 (s) 12919 (s) 13356 (s) 15161 (s)



for C15H18FNO2 [M+] 2631322 found 2631324








(m 043F) IR (neat) 2949 1717 1641 1593 1494 1389 1192 1070 1022 918 754 739 cm1 HR-MS










C16H20FNO2 [M+] 2771478 found 2771458







9006 (2s) 11763 and 11811 (2s) 12815-12886 (m 5C) 13405 and 13459 (2s) 13714 and 13740

















17546 (2br s 037F) IR (neat) 2953 1701 1447 1406 1340 1279 1211 1179 1098 1078 1053


















074F) IR (neat) 2959 1707 1447 1404 1366 1306 1261 1202 1109 1042 980 932 903 869 733







(br s) 8469 and 8656 (2s) 11439 (s) 12143-12177 (m 2C) 12597-12625 (m) 12946-12972 (m


(br d J=456 Hz 075F) IR (neat) 2959 1717 1593 1494 1456 1408 1348 1252 1196 1070 1026











2621120






(s) 8757 (s) 11862 (s) 12849 (s 2C) 12860 (s) 12916 (s) 13437 and 13776 (2s) 15679 (s) 19F

NMR (CDCl3) 18340 (d J=470 Hz 1F)




1829 (s) 2078-2617 (m 2C) 2854-2897 (m) 3565-4083 (m) 6701-6752 (m) 8556 (s) 12531-






yield25


[α]D27 450 (c 178 CH2Cl2)
















[M+] 3111169 found 3051167













10973-11075 (m) 11682-12124 (m) 12743-12889 (m 5C) 13410 (s) 13650 (s) 16084 (s) 17185


























18761 and 18668 (2br s) IR (neat) 2953 1701 1447 1406 1340 1279 1211 1179 1098 1078




ACKNOWLEDGEMENTS





Nagasaki University








1701















2011 76 3113

















2421




Chem Soc 1982 104 6697
















190-199 (m 1H) 203-209 (m 2H) 229-234 (m 1H) 239-246 (m 1H) 287 (br t J=132 Hz



5741 and 5795 (2s) 6718 (s) 11787 (s) 12772 12784 and 12840 (3s 5C) 13360 (s) 13698

(s) 15599 (s) IR (neat) 2951 1692 1423 1348 1246 1186 1123 1026 916 733 cm1 HR-MS








5233











10245



EXPERIMENTAL































1910958 found 1910941






8488-8679 (m) 12106-12176 (m 2C) 12467-12560 (m) 12875-12940 (m 2C) 15089-15135 (m)


2945 1717 1495 1410 1381 1369 1260 1198 1161 1069 1024 968 748 cm1 HR-MS [EI (+)] mz





(m) 4137-4630 (m) 5604-5797 (m) 8639 (s) 9149-9559 (m) 12192 (br s) 12587 (s 2C) 12966

(s 2C) 15101 (2s) 15302-15484 (m) 19F NMR (CDCl3) 2003- 2015 (m 037F)1869- 1882

(m 063F) IR (neat) 2936 1721 1593 1495 1456 1387 1371 1204 1163 1099 1042 957 731 cm1













4155 (s) 4371 and 4562 (2s) 5560 and 5616 (2s) 8655 (s) 9165 (s) 12772-12858 (m 5C) 13619-


18803 and 18710 (2s 081F) IR (neat) 2947 1705 1449 1404 1341 1279 1213 1177 1096 1076






8987 (br s) 12723-12780 (m 2C) 12868-12889 (m 2C) 13003 and 13042 (2s) 13555 and 13576
















072H) 401 (d J=98 Hz 028H) 445-451 (m 1H) 457-463 (m 1H) 494-505 (m 2H) 561-572









566 (m 1H) 570-595 (m 1H) 701-713 (m 2H) 713-721 (m 1H) 727-739 (m 2H) 13C NMR


8871 (2s) 11573 (s) 1180 (br s) 11908 (s) 12173 (s) 12515 (s) 12919 (s) 13356 (s) 15161 (s)



for C15H18FNO2 [M+] 2631322 found 2631324








(m 043F) IR (neat) 2949 1717 1641 1593 1494 1389 1192 1070 1022 918 754 739 cm1 HR-MS










C16H20FNO2 [M+] 2771478 found 2771458







9006 (2s) 11763 and 11811 (2s) 12815-12886 (m 5C) 13405 and 13459 (2s) 13714 and 13740

















17546 (2br s 037F) IR (neat) 2953 1701 1447 1406 1340 1279 1211 1179 1098 1078 1053


















074F) IR (neat) 2959 1707 1447 1404 1366 1306 1261 1202 1109 1042 980 932 903 869 733







(br s) 8469 and 8656 (2s) 11439 (s) 12143-12177 (m 2C) 12597-12625 (m) 12946-12972 (m


(br d J=456 Hz 075F) IR (neat) 2959 1717 1593 1494 1456 1408 1348 1252 1196 1070 1026











2621120






(s) 8757 (s) 11862 (s) 12849 (s 2C) 12860 (s) 12916 (s) 13437 and 13776 (2s) 15679 (s) 19F

NMR (CDCl3) 18340 (d J=470 Hz 1F)




1829 (s) 2078-2617 (m 2C) 2854-2897 (m) 3565-4083 (m) 6701-6752 (m) 8556 (s) 12531-






yield25


[α]D27 450 (c 178 CH2Cl2)
















[M+] 3111169 found 3051167













10973-11075 (m) 11682-12124 (m) 12743-12889 (m 5C) 13410 (s) 13650 (s) 16084 (s) 17185


























18761 and 18668 (2br s) IR (neat) 2953 1701 1447 1406 1340 1279 1211 1179 1098 1078




ACKNOWLEDGEMENTS





Nagasaki University








1701















2011 76 3113

















2421




Chem Soc 1982 104 6697
















190-199 (m 1H) 203-209 (m 2H) 229-234 (m 1H) 239-246 (m 1H) 287 (br t J=132 Hz



5741 and 5795 (2s) 6718 (s) 11787 (s) 12772 12784 and 12840 (3s 5C) 13360 (s) 13698

(s) 15599 (s) IR (neat) 2951 1692 1423 1348 1246 1186 1123 1026 916 733 cm1 HR-MS








5233











10245






8488-8679 (m) 12106-12176 (m 2C) 12467-12560 (m) 12875-12940 (m 2C) 15089-15135 (m)


2945 1717 1495 1410 1381 1369 1260 1198 1161 1069 1024 968 748 cm1 HR-MS [EI (+)] mz





(m) 4137-4630 (m) 5604-5797 (m) 8639 (s) 9149-9559 (m) 12192 (br s) 12587 (s 2C) 12966

(s 2C) 15101 (2s) 15302-15484 (m) 19F NMR (CDCl3) 2003- 2015 (m 037F)1869- 1882

(m 063F) IR (neat) 2936 1721 1593 1495 1456 1387 1371 1204 1163 1099 1042 957 731 cm1













4155 (s) 4371 and 4562 (2s) 5560 and 5616 (2s) 8655 (s) 9165 (s) 12772-12858 (m 5C) 13619-


18803 and 18710 (2s 081F) IR (neat) 2947 1705 1449 1404 1341 1279 1213 1177 1096 1076






8987 (br s) 12723-12780 (m 2C) 12868-12889 (m 2C) 13003 and 13042 (2s) 13555 and 13576
















072H) 401 (d J=98 Hz 028H) 445-451 (m 1H) 457-463 (m 1H) 494-505 (m 2H) 561-572









566 (m 1H) 570-595 (m 1H) 701-713 (m 2H) 713-721 (m 1H) 727-739 (m 2H) 13C NMR


8871 (2s) 11573 (s) 1180 (br s) 11908 (s) 12173 (s) 12515 (s) 12919 (s) 13356 (s) 15161 (s)



for C15H18FNO2 [M+] 2631322 found 2631324








(m 043F) IR (neat) 2949 1717 1641 1593 1494 1389 1192 1070 1022 918 754 739 cm1 HR-MS










C16H20FNO2 [M+] 2771478 found 2771458







9006 (2s) 11763 and 11811 (2s) 12815-12886 (m 5C) 13405 and 13459 (2s) 13714 and 13740

















17546 (2br s 037F) IR (neat) 2953 1701 1447 1406 1340 1279 1211 1179 1098 1078 1053


















074F) IR (neat) 2959 1707 1447 1404 1366 1306 1261 1202 1109 1042 980 932 903 869 733







(br s) 8469 and 8656 (2s) 11439 (s) 12143-12177 (m 2C) 12597-12625 (m) 12946-12972 (m


(br d J=456 Hz 075F) IR (neat) 2959 1717 1593 1494 1456 1408 1348 1252 1196 1070 1026











2621120






(s) 8757 (s) 11862 (s) 12849 (s 2C) 12860 (s) 12916 (s) 13437 and 13776 (2s) 15679 (s) 19F

NMR (CDCl3) 18340 (d J=470 Hz 1F)




1829 (s) 2078-2617 (m 2C) 2854-2897 (m) 3565-4083 (m) 6701-6752 (m) 8556 (s) 12531-






yield25


[α]D27 450 (c 178 CH2Cl2)
















[M+] 3111169 found 3051167













10973-11075 (m) 11682-12124 (m) 12743-12889 (m 5C) 13410 (s) 13650 (s) 16084 (s) 17185


























18761 and 18668 (2br s) IR (neat) 2953 1701 1447 1406 1340 1279 1211 1179 1098 1078




ACKNOWLEDGEMENTS





Nagasaki University








1701















2011 76 3113

















2421




Chem Soc 1982 104 6697
















190-199 (m 1H) 203-209 (m 2H) 229-234 (m 1H) 239-246 (m 1H) 287 (br t J=132 Hz



5741 and 5795 (2s) 6718 (s) 11787 (s) 12772 12784 and 12840 (3s 5C) 13360 (s) 13698

(s) 15599 (s) IR (neat) 2951 1692 1423 1348 1246 1186 1123 1026 916 733 cm1 HR-MS








5233











10245



8987 (br s) 12723-12780 (m 2C) 12868-12889 (m 2C) 13003 and 13042 (2s) 13555 and 13576
















072H) 401 (d J=98 Hz 028H) 445-451 (m 1H) 457-463 (m 1H) 494-505 (m 2H) 561-572









566 (m 1H) 570-595 (m 1H) 701-713 (m 2H) 713-721 (m 1H) 727-739 (m 2H) 13C NMR


8871 (2s) 11573 (s) 1180 (br s) 11908 (s) 12173 (s) 12515 (s) 12919 (s) 13356 (s) 15161 (s)



for C15H18FNO2 [M+] 2631322 found 2631324








(m 043F) IR (neat) 2949 1717 1641 1593 1494 1389 1192 1070 1022 918 754 739 cm1 HR-MS










C16H20FNO2 [M+] 2771478 found 2771458







9006 (2s) 11763 and 11811 (2s) 12815-12886 (m 5C) 13405 and 13459 (2s) 13714 and 13740

















17546 (2br s 037F) IR (neat) 2953 1701 1447 1406 1340 1279 1211 1179 1098 1078 1053


















074F) IR (neat) 2959 1707 1447 1404 1366 1306 1261 1202 1109 1042 980 932 903 869 733







(br s) 8469 and 8656 (2s) 11439 (s) 12143-12177 (m 2C) 12597-12625 (m) 12946-12972 (m


(br d J=456 Hz 075F) IR (neat) 2959 1717 1593 1494 1456 1408 1348 1252 1196 1070 1026











2621120






(s) 8757 (s) 11862 (s) 12849 (s 2C) 12860 (s) 12916 (s) 13437 and 13776 (2s) 15679 (s) 19F

NMR (CDCl3) 18340 (d J=470 Hz 1F)




1829 (s) 2078-2617 (m 2C) 2854-2897 (m) 3565-4083 (m) 6701-6752 (m) 8556 (s) 12531-






yield25


[α]D27 450 (c 178 CH2Cl2)
















[M+] 3111169 found 3051167













10973-11075 (m) 11682-12124 (m) 12743-12889 (m 5C) 13410 (s) 13650 (s) 16084 (s) 17185


























18761 and 18668 (2br s) IR (neat) 2953 1701 1447 1406 1340 1279 1211 1179 1098 1078




ACKNOWLEDGEMENTS





Nagasaki University








1701















2011 76 3113

















2421




Chem Soc 1982 104 6697
















190-199 (m 1H) 203-209 (m 2H) 229-234 (m 1H) 239-246 (m 1H) 287 (br t J=132 Hz



5741 and 5795 (2s) 6718 (s) 11787 (s) 12772 12784 and 12840 (3s 5C) 13360 (s) 13698

(s) 15599 (s) IR (neat) 2951 1692 1423 1348 1246 1186 1123 1026 916 733 cm1 HR-MS








5233











10245







(m 043F) IR (neat) 2949 1717 1641 1593 1494 1389 1192 1070 1022 918 754 739 cm1 HR-MS










C16H20FNO2 [M+] 2771478 found 2771458







9006 (2s) 11763 and 11811 (2s) 12815-12886 (m 5C) 13405 and 13459 (2s) 13714 and 13740

















17546 (2br s 037F) IR (neat) 2953 1701 1447 1406 1340 1279 1211 1179 1098 1078 1053


















074F) IR (neat) 2959 1707 1447 1404 1366 1306 1261 1202 1109 1042 980 932 903 869 733







(br s) 8469 and 8656 (2s) 11439 (s) 12143-12177 (m 2C) 12597-12625 (m) 12946-12972 (m


(br d J=456 Hz 075F) IR (neat) 2959 1717 1593 1494 1456 1408 1348 1252 1196 1070 1026











2621120






(s) 8757 (s) 11862 (s) 12849 (s 2C) 12860 (s) 12916 (s) 13437 and 13776 (2s) 15679 (s) 19F

NMR (CDCl3) 18340 (d J=470 Hz 1F)




1829 (s) 2078-2617 (m 2C) 2854-2897 (m) 3565-4083 (m) 6701-6752 (m) 8556 (s) 12531-






yield25


[α]D27 450 (c 178 CH2Cl2)
















[M+] 3111169 found 3051167













10973-11075 (m) 11682-12124 (m) 12743-12889 (m 5C) 13410 (s) 13650 (s) 16084 (s) 17185


























18761 and 18668 (2br s) IR (neat) 2953 1701 1447 1406 1340 1279 1211 1179 1098 1078




ACKNOWLEDGEMENTS





Nagasaki University








1701















2011 76 3113

















2421




Chem Soc 1982 104 6697
















190-199 (m 1H) 203-209 (m 2H) 229-234 (m 1H) 239-246 (m 1H) 287 (br t J=132 Hz



5741 and 5795 (2s) 6718 (s) 11787 (s) 12772 12784 and 12840 (3s 5C) 13360 (s) 13698

(s) 15599 (s) IR (neat) 2951 1692 1423 1348 1246 1186 1123 1026 916 733 cm1 HR-MS








5233











10245







17546 (2br s 037F) IR (neat) 2953 1701 1447 1406 1340 1279 1211 1179 1098 1078 1053


















074F) IR (neat) 2959 1707 1447 1404 1366 1306 1261 1202 1109 1042 980 932 903 869 733







(br s) 8469 and 8656 (2s) 11439 (s) 12143-12177 (m 2C) 12597-12625 (m) 12946-12972 (m


(br d J=456 Hz 075F) IR (neat) 2959 1717 1593 1494 1456 1408 1348 1252 1196 1070 1026











2621120






(s) 8757 (s) 11862 (s) 12849 (s 2C) 12860 (s) 12916 (s) 13437 and 13776 (2s) 15679 (s) 19F

NMR (CDCl3) 18340 (d J=470 Hz 1F)




1829 (s) 2078-2617 (m 2C) 2854-2897 (m) 3565-4083 (m) 6701-6752 (m) 8556 (s) 12531-






yield25


[α]D27 450 (c 178 CH2Cl2)
















[M+] 3111169 found 3051167













10973-11075 (m) 11682-12124 (m) 12743-12889 (m 5C) 13410 (s) 13650 (s) 16084 (s) 17185


























18761 and 18668 (2br s) IR (neat) 2953 1701 1447 1406 1340 1279 1211 1179 1098 1078




ACKNOWLEDGEMENTS





Nagasaki University








1701















2011 76 3113

















2421




Chem Soc 1982 104 6697
















190-199 (m 1H) 203-209 (m 2H) 229-234 (m 1H) 239-246 (m 1H) 287 (br t J=132 Hz



5741 and 5795 (2s) 6718 (s) 11787 (s) 12772 12784 and 12840 (3s 5C) 13360 (s) 13698

(s) 15599 (s) IR (neat) 2951 1692 1423 1348 1246 1186 1123 1026 916 733 cm1 HR-MS








5233











10245












2621120






(s) 8757 (s) 11862 (s) 12849 (s 2C) 12860 (s) 12916 (s) 13437 and 13776 (2s) 15679 (s) 19F

NMR (CDCl3) 18340 (d J=470 Hz 1F)




1829 (s) 2078-2617 (m 2C) 2854-2897 (m) 3565-4083 (m) 6701-6752 (m) 8556 (s) 12531-






yield25


[α]D27 450 (c 178 CH2Cl2)
















[M+] 3111169 found 3051167













10973-11075 (m) 11682-12124 (m) 12743-12889 (m 5C) 13410 (s) 13650 (s) 16084 (s) 17185


























18761 and 18668 (2br s) IR (neat) 2953 1701 1447 1406 1340 1279 1211 1179 1098 1078




ACKNOWLEDGEMENTS





Nagasaki University








1701















2011 76 3113

















2421




Chem Soc 1982 104 6697
















190-199 (m 1H) 203-209 (m 2H) 229-234 (m 1H) 239-246 (m 1H) 287 (br t J=132 Hz



5741 and 5795 (2s) 6718 (s) 11787 (s) 12772 12784 and 12840 (3s 5C) 13360 (s) 13698

(s) 15599 (s) IR (neat) 2951 1692 1423 1348 1246 1186 1123 1026 916 733 cm1 HR-MS








5233











10245













[M+] 3111169 found 3051167













10973-11075 (m) 11682-12124 (m) 12743-12889 (m 5C) 13410 (s) 13650 (s) 16084 (s) 17185


























18761 and 18668 (2br s) IR (neat) 2953 1701 1447 1406 1340 1279 1211 1179 1098 1078




ACKNOWLEDGEMENTS





Nagasaki University








1701















2011 76 3113

















2421




Chem Soc 1982 104 6697
















190-199 (m 1H) 203-209 (m 2H) 229-234 (m 1H) 239-246 (m 1H) 287 (br t J=132 Hz



5741 and 5795 (2s) 6718 (s) 11787 (s) 12772 12784 and 12840 (3s 5C) 13360 (s) 13698

(s) 15599 (s) IR (neat) 2951 1692 1423 1348 1246 1186 1123 1026 916 733 cm1 HR-MS








5233











10245



















18761 and 18668 (2br s) IR (neat) 2953 1701 1447 1406 1340 1279 1211 1179 1098 1078




ACKNOWLEDGEMENTS





Nagasaki University








1701















2011 76 3113

















2421




Chem Soc 1982 104 6697
















190-199 (m 1H) 203-209 (m 2H) 229-234 (m 1H) 239-246 (m 1H) 287 (br t J=132 Hz



5741 and 5795 (2s) 6718 (s) 11787 (s) 12772 12784 and 12840 (3s 5C) 13360 (s) 13698

(s) 15599 (s) IR (neat) 2951 1692 1423 1348 1246 1186 1123 1026 916 733 cm1 HR-MS








5233











10245




1701















2011 76 3113

















2421




Chem Soc 1982 104 6697
















190-199 (m 1H) 203-209 (m 2H) 229-234 (m 1H) 239-246 (m 1H) 287 (br t J=132 Hz



5741 and 5795 (2s) 6718 (s) 11787 (s) 12772 12784 and 12840 (3s 5C) 13360 (s) 13698

(s) 15599 (s) IR (neat) 2951 1692 1423 1348 1246 1186 1123 1026 916 733 cm1 HR-MS








5233











10245





Chem Soc 1982 104 6697
















190-199 (m 1H) 203-209 (m 2H) 229-234 (m 1H) 239-246 (m 1H) 287 (br t J=132 Hz



5741 and 5795 (2s) 6718 (s) 11787 (s) 12772 12784 and 12840 (3s 5C) 13360 (s) 13698

(s) 15599 (s) IR (neat) 2951 1692 1423 1348 1246 1186 1123 1026 916 733 cm1 HR-MS








5233











10245










10245



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DOI: 10.3987/COM-13-S(S)27 DIASTEREOSELECTIVE SYNTHESIS...

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