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Enantioselective Synthesis of r-Fluoro-β -amino Esters: Synthesis of Enantiopure, Orthogonally Protected r-Fluoro-β -lysine
Enantioselective Synthesis of r-Fluoro-β -amino Esters: Synthesis of Enantiopure, Orthogonally Protected r-Fluoro-β -lysine
org/joc
peter.duggan@csiro.au
Received August 20, 2010
DOI: 10.1021/jo101600c Published on Web 10/08/2010 J. Org. Chem. 2010, 75, 7365–7372 7365
r 2010 American Chemical Society
JOC Article Duggan et al.
a
NFSI added at -78 °C for 5a,b,d, -60 °C for 5e, -50 °C for 5c, and -45 °C for 5f. b>99:1 dr. cAfter chromatography. dDetermined from the crude
reaction mixture by integration of 1H NMR resonances due to R-protons. eMcWhorter reported an equivalent yield for this reaction.14 fDavies reported
an equivalent yield for this reaction.15 gFrom ref 11.
SCHEME 3. Stepwise Conjugate Addition-fluorination Involving Deprotonation of Isolated (2S)-β3-Amino Esters 4b and 4c Followed
by Fluorination with NFSI
gives the anti-compound as the major product; the 2S,3S,RS >99:1 dr while the 2S diastereomer of 5e was purified to
diastereomer in the case of 5. This was previously confirmed to a dr of 98:2.
be the case for the reaction of the enolate 3b with NFSI by An alternative to the one-pot sequence shown in Scheme 1 is
X-ray crystallography performed on 5b.11 It was also con- a stepwise procedure (Scheme 3). In order to compare these
firmed for the reaction that produced the ethyl ester analogue sequences, two β-amino esters 4b and 4c were deprotonated
of 5a. NMR-based similarities between these previously pub- with LDA and quenched with NFSI at -78 °C. While yields of
lished compounds and 5a,c-f suggest that the anti-product or the fluorides 5b and 5c were equivalent to those obtained with
the 2S,3S,RS diastereomer is also the major product produced the tandem method (quantitative and 93% respectively), the
here. X-ray crystallography performed on a single crystal of 5c dr’s were inferior. The reaction with 4c was also repeated with
(see the Supporting Information) supports this conclusion. the NFSI quench performed at -55 °C, but the result was
The dr’s for the fluorination step were optimized by varia- equivalent to that obtained at -78 °C. These findings are in
tion of the temperature of the NFSI addition and range from accord with the stereoselectivities recently reported for the
moderate (Table 1, entry 3) to very high (Table 1, entry 6). stepwise fluorination of amide and Boc-protected forms of 4b
Using standard chromatographic and recrystallization tech- performed under very similar reaction conditions.9a
niques the 2S diastereomers of 5a,c,d,f could be obtained in Three attempts to prepare an epimeric or (2R,3S,RS)-R-
fluoro-β3-amino ester, 5-syn were made. In the first, the 2-
(14) Fleck, T. J.; McWhorter, W. W., Jr.; DeKam, R. N.; Pearlman, B. A. fluorocinnamate 916 was treated with the lithium amide 2 then
J. Org. Chem. 2003, 68, 9612.
(15) Bull, S. D.; Davies, S. G.; Roberts, P. M.; Savory, E. D.; Smith, A. D.
Tetrahedron 2002, 58, 4629. (16) Elkik, E.; Imbeaux-Oudotte, M. Bull. Soc. Chim. Fr. 1987, 861.
CDCl3) δ 168.4 (d, J = 24.4 Hz), 142.1, 141.7, 128.2, 128.1, 128.0, 126.6, 90.1 (d, J = 190.0 Hz), 82.4, 82.0, 58.1 (d, J = 4.6 Hz),
127.9, 127.0, 126.5, 90.0 (d, J = 188.8 Hz), 82.2, 63.0, 58.1, 57.9, 57.6, 50.8, 46.5, 28.04, 27.97, 27.2, 24.6, 19.9; 19F NMR (282
50.7 (d, J = 4.5 Hz), 30.6, 27.9, 25.9, 23.4 (d, J = 5.2 Hz), 20.0, MHz, CDCl3) δ -199.1 (dd, J = 51.8, 32.3 Hz); HRMS calcd for
18.2, -5.36, -5.38. 19F NMR (282 MHz, CDCl3) δ -200.0 (dd, C35H51FN2NaO6 637.3623, found 637.3645 [M þ Na]þ.
J = 50.7, 31.2 Hz); HRMS calcd for C31H49FNO3Si 530.3460, (2S,3S,rS)-tert-Butyl 6-(4,4-Diphenyl-1-aza-4-silacyclohex-
found 530.3465 [M þ H]þ. 1-yl)-3-(N-benzyl-r-methylbenzylamino)-2-fluorohexanoate, 5f.
(2S,3S,rS)-tert-Butyl 3-(N-Benzyl-r-methylbenzylamino)-2- The fluoroamino hexanoate 5f was prepared from 1f (136 mg,
fluorobutanoate, 5a. The fluoroaminobutanoate 5a was pre- 0.32 mmol) according to representative procedure B, with the
pared from (E)-tert-butyl crotonate 1a (134 mg, 0.94 mmol) following variation: NFSI was added at -45 °C, and after 2 h the
according to representative procedure B, with the following varia- reaction mixture was allowed to warm to -10 °C over 45 min
tion: after NFSI addition, stirring was continued at -78 °C for 1 h, before being quenched. After a standard workup, the sulfoni-
and then the reaction mixture was allowed to warm to -30 °C over mide byproducts were removed by filtration through a plug of
1.5 h before being quenched. Analysis of the crude product by 1H silica (1:2 diethyl ether/hexane), and the filtrate was concen-
NMR showed dr = 92:8. Column chromatography (3:7 diethyl trated in vacuo. The residue was redissolved in dry DCM (2 mL),
ether/hexane) gave a mixture of the C2 epimers as a colorless oil and phenyl isocyanate (22 μL, 0.20 mmol) was added in order to
(217 mg, 62%). Recrystallization from hexane gave the 2S-fluoride remove excess (S)-N-benzyl-N-(R-methylbenzyl)amine. After
5a-anti (195 mg, 56%) as white needles: mp 82.5-84 °C; [R]20D = being stirred under N2 for 3.5 h, the mixture was concentrated
þ22 (c = 1.0, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.45 (d, J = in vacuo and subjected to column chromatography (5:44:1 diethyl
7.6 Hz, 2H), 7.36-7.20 (m, 8 H), 4.65 (dd, J = 50.4, 2.0 Hz, 1H), ether/hexane/Et3N) to give 5f-anti as a colorless gum (107 mg,
3.99 (q, J = 6.8 Hz, 1H), 3.98 (d, J =14.8 Hz, 1H), 3.84 (d, J =14.8 51%, dr > 99:1): [R]20D = þ13 (c = 1.0, CHCl3); 1H NMR (400
Hz, 1H), 3.47-3.33(m, 1H), 1.38 (s, 9H), 1.34 (d, J = 6.8 Hz, 3H), MHz, CDCl3) δ 7.56-7.54 (m, 4H), 7.45-7.23 (m, 16H), 4.50 (d,
1.15 (dd, J = 7.2, 0.8 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ J = 50.4 Hz, 1H), 4.16 (d, J = 15.8 Hz, 1H), 3.94 (q, J = 6.8 Hz,
168.4 (d, J = 24.8 Hz), 143.6, 141.9, 128.23, 128.18, 128.1, 127.7, 1H), 3.66 (d, J = 15.8 Hz, 1H), 3.37 (ddd, J = 30.8, 10.0, 3.6 Hz,
126.8, 126.6, 92.3 (d, J = 188.0 Hz), 82.1, 58.1, 53.4 (d, J = 18.8 1H), 2.81 (t, J = 6.0 Hz, 4H), 2.42-2.30 (m, 2H), 1.85-1.75 (m,
Hz), 50.6 (d, J = 4.0 Hz), 27.9, 17.2, 12.2 (d, J = 5.7 Hz); 19F NMR 1H), 1.70-1.59 (m, 1H), 1.53-1.40 (m, 10H), 1.40-1.27 (m, 8H);
(282 MHz, CDCl3) δ -202.5 (dd, J = 49.7, 30.2 Hz); HRMS calcd 13
C NMR (100 MHz, CDCl3) δ 168.4 (d, J = 25.0 Hz), 142.4,
for C23H31FNO2 372.2333, found 372.2336 [M þ H]þ. 141.8, 135.6, 134.6, 129.3, 128.2, 128.1, 128.0, 127.9, 127.8, 127.1,
(2S,3S,rS)-tert-Butyl 5-(tert-Butyldimethylsilyloxy)-3-(N-ben- 126.5, 89.9 (d, J = 189.0 Hz), 82.2, 58.3, 58.1 (d, J = 19.0 Hz),
zyl-r-methylbenzylamino)-2-fluoropentanoate, 5c. The fluoroamino 57.9, 52.0, 50.7 (d, J = 5.0 Hz), 27.9, 25.2 (d, J = 5.0 Hz), 24.4,
pentanoate 5c was prepared from (E)-tert-butyl 5-(tert- 20.3, 11.0; 19F NMR (282 MHz, CDCl3) δ -200 (bs); HRMS
butyldimethylsilyloxy)pent-2-enoate 1c (105 mg, 0.37 mmol) ac- calcd for C41H52FN2O2Si 651.3777, found 651.3777 [M þ H]þ.
cording to representative procedure B, with the following varia- Representative Procedure C-Stepwise Fluorination. Fluorina-
tion: NFSI was added at -50 °C, and stirring was continued for tion of 4c. Fluorination at -55 °C: To a solution of diisopropy-
1 h, after which time the solution was quenched and allowed to lamine (0.034 mL, 0.24 mmol) in dry THF (2 mL) at 0 °C was
warm to 0 °C. The product was obtained as a colorless oil which added nBuLi (1.6 M in hexanes, 0.16 mL, 0.24 mmol) and the
crystallized on standing (171 mg, 90%, dr 80:20). Recrystalliza- solution stirred for 20 min, after which time it was cooled to -78 °C.
tion from acetone (slow evaporation) gave the major isomer 2S- The amino ester 4c (96 mg, 0.19 mmol) in THF (1.5 mL) was
fluoride 5c-anti as white needles (118 mg, 62%): mp 109-110 °C; added dropwise and the solution stirred for another 1 h before
[R]20D = þ4 (c = 1.0, CHCl3); 1H NMR (400 MHz, CDCl3) δ being warmed to -55 °C. A solution of NFSI (89 mg, 0.28 mmol)
7.43-7.24 (m, 10H), 4.26 (dd, J = 50.4, 0.8 Hz, 1H), 4.12 (d, J = in THF (1.5 mL) was added and stirring continued at -55 °C for
14.4 Hz, 1H), 3.94-3.86 (m, 2H), 3.83-3.71 (m, 2H), 3.65 (dd, 3 h followed by warming to 0 °C over a further 1 h before quench-
J = 15.2, 1.6 Hz, 1H), 1.86-1.78 (m, 1H), 1.55-1.48 (m, 1H), 1.49 ing with saturated aq NH 4Cl (4 mL). Ether (25 mL) and H2O
(s, 9H), 1.38 (d, J = 7.2 Hz, 3H), 0.93 (s, 9H), 0.09 (s, 3H), 0.08 (25 mL) were added and the layers separated. The ether layer was
(s, 3H); 13C NMR (100 MHz, CDCl3) δ 168.4 (d, J = 24.7 Hz), washed with H2O (25 mL) and brine (25 mL) and then dried
141.3, 141.2, 128.4, 128.3, 128.2, 128.1, 127.2, 126.7, 90.7 (d, J = (Na2SO4) and concentrated in vacuo. Crude 1H NMR showed a
187.3 Hz), 82.3, 59.7, 57.0, 53.6 (d, J = 18.7 Hz), 50.7, 30.3 (d, J = 69:31 mixture of anti/syn isomers. Passage through a plug of silica
4.9 Hz), 28.0, 26.1, 19.4, 18.4, -5.2, -5.3; 19F NMR (282 MHz, (1:9 ether/hexane) gave a white solid (93 mg, 93%), which was
CDCl3) δ -199.1 (dd, J = 51.8, 32.3 Hz); HRMS calcd for recrystallized from acetone to give 5c-anti (59 mg, 59%) as white
C30H47FNO3Si 516.3304, found 516.3306 [M þ H]þ. needles. Fluorination at -78 °C: To a solution of diisopropyla-
(2S,3S,rS)-tert-Butyl 6-(N,N-Di-tert-butylcarbonyloxy)amino- mine (0.033 mL, 0.23 mmol) in dry THF (2 mL) at 0 °C was added
n
(N-benzyl-r-methylbenzylamino)-2-fluorohexanoate, 5e. The fluor- BuLi (1.5 M in hexanes, 0.15 mL, 0.23 mmol) and the solution
oamino hexanoate 5e was prepared from (E)-tert-butyl 6-(N,N-di- stirred for 20 min, after which time it was cooled to -78 °C. The
tert-butylcarbonyloxy)aminohex-2-enoate 1e (130 mg, 0.34 mmol) amino ester 4c (94 mg, 0.19 mmol) in THF (1.5 mL) was added
according to representative procedure B, with the following varia- dropwise and the solution stirred for another 1 h. A solution of
tion: NFSI was added at -60 °C, and after 1.5 h the reaction was NFSI (86 mg, 0.27 mmol) in THF (1.5 mL) was added dropwise
allowed to warm to -35 °C over 30 min before quenching. Analysis with stirring continued at -78 °C for 3 h, after which the solu-
of the crude mixture by 1H NMR showed a dr of 88:12. Column tion was allowed to warm to -35 °C over 1.5 h and then quenched
chromatography (1:9 to 1:3 diethyl ether/hexane) gave a colorless with saturated aq NH4Cl (4 mL). Ether (25 mL) and H2O (25 mL)
oil as a mixture of isomers (277 mg, 48%, dr 93:7). A portion of this were added and the layers separated. The ether layer was washed
was further purified by chromatography (1:9 diethyl ether/hexane) with H2O (25 mL) and brine (25 mL) and then dried (Na2SO4)
to give a sample with a dr of 98:2: [R]20D = þ5 (c = 1.0, CHCl3); and concentrated in vacuo. A 1H NMR spectrum of the crude
1
H NMR (400 MHz, CDCl3) δ 7.43(d, J = 7.6 Hz, 2H), 7.36-7.23 reaction mixture showed 5c as a 72:28 mixture of anti/syn isomers.
(m, 8H), 4.36 (d, J = 50.0 Hz, 1H), 4.12 (d, J = 14.4 Hz, 1H), 3.91 The product was not further purified.
(q, J = 6.8 Hz, 1H), 3.64 (d, J = 16.4 Hz, 1H), 3.62-3.53 (m, 2H), Treatment of (Z)-tert-Butyl-r-fluorocinnamate 9 with Lithium
3.40 (ddd, J = 31.5, 9.6, 3.2 Hz, 1H), 2.03-1.92 (m, 1H), 1.70- (S)-N-Benzyl-N-(R-methylbenzyl)amide, 2. To a stirred solution
1.58 (m, 1H), 1.57-1.40 (m, 2H), 1.50 (s, 18H), 1.44 (s, 9H), 1.33 of (S)-N-benzyl-N-(R-methylbenzyl)amine (0.11 mL, 0.54 mmol)
(d, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 168.0 (d, J = in THF (2 mL) at -78 °C, under N2, was added nBuLi (1.5 M
25.0 Hz), 152.60, 152.55, 141.9, 128.3, 128.2, 128.13, 128.06, 127.2, in hexanes, 0.36 mL, 0.54 mmol). After 20 min, a solution of