Hexafluoroacetone as a protecting and activating reagent: 5,5-difluoro- and trans-5-fluoropipecolic acids from glutamic acid

Article abstract of DOI:10.1016/j.tetlet.2003.12.038

Starting from hexafluoroacetone-protected (S)-glutamic acid, trans-5-fluoropipecolic and 5,5-difluoropipecolic acid have been synthesized. The piperidine ring was constructed by an intramolecular metal carbenoid NH insertion.

Full text of DOI:10.1016/j.tetlet.2003.12.038

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 1445–1447
Hexafluoroacetone as a protecting and activating reagent:
5,5-difluoro- and trans-5-fluoropipecolic acids from glutamic acid
Alexander S. Golubev,a,b Hartmut Schedel,a Gabor Radics,a Marco Fioroni,a,c
Sven Thusta and Klaus Burgera,*
aDepartment of Organic Chemistry, University of Leipzig, Johannisallee 29, D-04103Leipzig, Germany
bInstitute of Organoelement Compounds, Russian Academy of Sciences, Vavilov str. 28, GSP-1, V-334 Rus-117813 Moscow, Russia
cDepartment of Chemistry, Technical University of Eindhoven, Helix Building, Eindhoven, The Netherlands
Received 14 November 2003; revised 5 December 2003; accepted 9 December 2003
Dedicated to Professor Dr. M. Lozinsky on the occasion of his 70th birthday
Abstract—Starting from hexafluoroacetone-protected (S)-glutamic acid, trans-5-fluoropipecolic and 5,5-difluoropipecolic acid have
been synthesized. The piperidine ring was constructed by an intramolecular metal carbenoid NH insertion.
Ó 2003 Elsevier Ltd. All rights reserved.
The application of substituted pipecolic acids as building
blocks in drug design is steadily growing.1;2 Furthermore,
fluorine-containing proline3 and pipecolic acid deriva-
tives4 represent valuable tools for the investigation of the
cis–trans isomerization of the peptide bond5 and for the
investigation of peptide and protein folding.6 Recently,
we reported on the synthesis of 4-fluoro-substituted
pipecolic acids.4 In an extension of our studies we now
disclose a preparatively simple route to the virtually
unknown 5-fluoro-substituted pipecolic acids.
advantages of this strategy7;8 with the advantages of the
new hexafluoroacetone concept.
Glutamic acid 1 and hexafluoroacetone react at room
temperature in DMSO or DMF to give 2,2-bis(trifluo-
romethyl)-1,3-oxazolidin-5-one 2.10 In one-step, protec-
tion of the a-amino group and the adjacent carboxy
group has been achieved, while the x-carboxy group
remains unaffected and can be derivatized regioselec-
tively after separate activation.11 When we tried to
activate the x-carboxy group of 2 by treatment with
thionyl chloride we obtained the HFA-protected pGlu 3
in almost quantitative yield.12 However, when milder
activation strategies were applied, the intramolecular
ring closure to give a lactam could be avoided. The
mixed anhydride, formed on treatment of 2 with
isobutyl chloroformate at )15 °C in the presence of
N-methyl morpholine, was reacted directly with an
excess of diazomethane (>3 equiv) at 0 °C to give
diazoketone 4 in 61% yield (Scheme 1).
Based on recently published results, we thought that a
suitably protected 5-oxopipecolic acid could serve as a
key precursor in the synthesis of 5-hydroxy-, 5,5-diflu-
oro- and 5-fluoropipecolic acids. Concise synthetic
approaches to enantiomerically pure 5-oxo-7 and
5-hydroxy-pipecolic8 acids starting from suitably
protected glutamic acid derivatives have been described.
Construction9 of the piperidine ring was achieved via x-
carboxy group activation and diazoketone formation,
followed by a metal carbenoid NH insertion. This route
attracted our interest, because it is preparatively simple,
and both enantiomeric forms of glutamic acid are cheap
and commercially available. We decided to combine the
Compound 4 was subjected to a dirhodium tetraacetate
catalyzed decomposition.13 The reaction proceeds via an
electrophilic Fischer-type carbene complex, surpressing
the Wolff-type rearrangement completely in favour of an
intramolecular metal carbenoid NH insertion.14 The
best yields (70–80%15) of the bicyclic compound 5 were
obtained when a solution of 4 in chloroform was added
dropwise to a vigorously stirred suspension of dirho-
dium tetraacetate in refluxing chloroform (Scheme 2).
Keywords: Glutamic acid; Hexafluoroacetone; Diazo ketones; Metal
carbenoid NH insertion; DAST fluorination.
* Corresponding author. Tel.: +49-341-8622866; fax: +49-341-97365-
99; e-mail: burger@organik.chemie.uni-leipzig.de
0040-4039/$ - see front matter Ó 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2003.12.038

1446
A. S. Golubev et al. / Tetrahedron Letters 45 (2004) 1445–1447
H
O
b
92%
N
O
O
O
H
N
O
F3C CF3
3
HO2C
CO2H
NH2
a
HO
O
H
76%
H
O
H
F3C CF3
2
O
1
c,d
N2
N
H
O
61%
F3C CF3
4
Scheme 1. Reagents and conditions: (a) hexafluoroacetone, DMSO; (b) SOCl2; (c) ClOCO-i-Bu, N-methyl morpholine; (d) CH2N2.
H
H
O
O
H
CO2H
a
b
c,d
F
F
4
O
N
O
N
O
F
N
44%
59%
61%
H
F
F3C CF3
5
F3C CF3
6
7
Scheme 2. Reagents and conditions: (a) Rh2(O2CCH3)4, CHCl3; (b) DAST in CH2Cl2; (c) aq HCl in dioxane; (d) propene oxide.
H
H
H
O
O
O
TfO
H
HO
H
a
b
O
N
O
N
O
N
O
92%
F3C CF3
5
F3C CF3
9
F3C CF3
8
H
H
O
d,e
O
CO2H
H
c
H
N
N
F
47%
5
8%
H
F
F3C CF3
10
11
Scheme 3. Reagents and conditions: (a) BH3ÆTHF; (b) (CF3SO2)2O; (c) 3HFÆEt3N, 30 MS (d) aq HCl in dioxane; (e) propene oxide.
Next, DAST (diethylaminosulfur trifluoride) fluoro-
deoxygenation16 of compound 5 was performed in
solution in methylene chloride on adding 2 equiv of
DAST at )78 °C to give the HFA-protected difluoro-
pipecolic acid 6. Transformation of 6 into the unpro-
(1:1) at room temperature followed by treatment with
propene oxide. Compounds 6 and 10 are carboxy-acti-
vated species and can be directly applied to peptide
coupling.
tected 5,5-difluoro-L
-pipecolic acid 717 was achieved on
stirring with aqueous HCl in dioxane (1:1) at room
temperature followed by treatment with propene oxide
to trap the HCl.
Acknowledgements
This work was supported by Stiftung Volkswagenwerk,
Hannover.
Reduction of the carbonyl group of 5 to give a hydroxy
group was achieved on reaction with BH3ÆTHF at
)78 °C18 with excellent regio- and stereo-selectivity in
92% yield. The reason for the high selectivity is the
concave geometry of the bicyclic system,19 which
favours exo-attack of the hydride ion to the carbonyl
group to give exclusively the cis-hydroxy derivative 8
(Scheme 3).
References and notes
1. (a) Partogyan-Halim, K.; Besson, L.; Aitken, D. J.;
Husson, H.-P. Eur. J. Org. Chem. 2003, 268–273; (b)
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Chaplin, D. A.; McCague, R. Org. Proc. Res. Dev. 2002, 6,
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Grenier, L.; Guse, I.; Lavallee, P. J. Org. Chem. 1996, 61,
Fluorodehydroxylation of 8 with DAST gave an insep-
arable mixture of compounds. Therefore, we trans-
formed the hydroxy group into the triflate 9. The latter
was converted into HFA-protected trans-fluoropipecolic
acid 10 on treatment with 3HFÆEt3N in the presence of
20
molecular sieves (3 A) in 60% yield.21 Transformation
of 10 into the unprotected trans-5-fluoro-L-pipecolic
acid 11 was achieved on stirring with HCl in dioxane
ꢀ

A. S. Golubev et al. / Tetrahedron Letters 45 (2004) 1445–1447
1447
2226–2231; (g) Skiles, J. W.; Giannousis, P. P.; Fales,
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15. Compound 6: colourless crystals; mp 34–35 °C;
22
½aŠ ¼ )14.9 (c 1 , CHCl2); IR (KBr): m 1842 cmÀ1
;
1H
2
D
NMR (600 MHz, CDCl3): d 1.84 (1H, br m, CH2CHN),
1.90 (1H, m, CH2CH2CHN), 2.20 (1H, br m, CH2CHN),
2.41H(1, m,
C
H2CH2CHN), 3.11 (1H, br dd,
3JHF ¼ 26:1Hz, 2J ¼ 12:4 Hz, CH2N), 3.62 (1H, br d,
3J ¼ 10:5 Hz, CHN), 3.68 (1H, br t, JHF;HH ¼ 11:6 Hz,
CH2N); 13C NMR (151 MHz, CDCl3):
d 23.75 (d,
3JCF ¼ 10:3 Hz, CH2CHN), 31.81 (dd, JCF ¼ 25:9 Hz,
2JCF ¼ 23:9 Hz, CH2CH2CHN), 50.77 (dd, 2JCF ¼ 38:8 Hz,
2JCF ¼ 27:1Hz, CH2N), 55.14 (CHN), 88.06 (dqq,
2
2JCF ¼ 34:4 Hz, JCF ¼ 32:4 Hz, JCF ¼ 2:0 Hz, C(CF3)2),
2
4
1
1
5
117.62 (ddq, JCF ¼ 247:9 Hz, JCF ¼ 241:9 Hz, JCF
¼
1
3
1Hz, CF2), 120.20 (qq, JCF ¼ 287:1Hz, JCF ¼ 1Hz,
1
CF3), 121.65 (q, JCF ¼ 293:7 Hz, CF3), 166.90 (d,
5JCF ¼ 1:8 Hz, C@O); 19F NMR (376 MHz, CDCl3 with-
out 1H decoupling): d À 75:62 (q, JFF ¼ 8:4 Hz, CF3),
4
4
6
)78.73 (dq, JFF ¼ 8:4 Hz, JFF ¼ 1:2 Hz, CF3), )102.86
2
2
(d, JFF ¼ 244:6 Hz, CF2), )104.40 (dq, JFF ¼ 244:6 Hz,
6JFF ¼ 1:2 Hz, CF2); MS (EI) m=z (%): 313 [M]þ (6), 266
(9), 244 (20), 216 (100), 196 (13), 176 (7), 100 (10), 69
(20).
3. Burger, K.; Rudolph, M.; Fehn, S.; Sewald, N. J. Fluorine
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16. (a) Hudlicky, M. Org. React. 1988, 34, 513–637; (b)
Chemistry of Organic Fluorine Compounds; Hudlicky, M.,
Pavlath, A. E., Eds.; ACS Monograph 187; American
Chemical Society: Washington, DC, 1995; pp 240–242.
and references cited therein.
€
Maison, W.; Lutzen, A.; Kosten, M.; Schlemminger, I.;
17. 5,5-Difluoro-(S)-pipecolic acid 7: white powder; mp
22
D
Westerhoff, O.; Saak, W.; Martens, J. J. Chem. Soc.,
Perkin Trans. 1 2000, 1867–1871; (c) Wu, W.-J.; Raleigh,
D. P. J. Org. Chem. 1998, 63, 6689–6698; (d) Kern, D.;
Schutkowski, M.; Drakenberg, T. J. Am. Chem. Soc. 1997,
119, 8403–8408.
250 °C (sealed tube); ½aŠ ¼ )9 (c 1 , HO); 1H NMR
2
(300 MHz, D2O): d 1.85–2.32 (m, 4H), 3.38 (ddd, J ¼ 23:5,
13.5, 5.5 Hz, 1H), 3.58 (m, 1H), 3.72 (dd, J ¼ 10:7, 2.8 Hz,
1H); 13C NMR (50.3 MHz, D2O): d 25.30 (t, J ¼ 5 Hz),
32.38 (t, J ¼ 23 Hz), 48.55 (t, J ¼ 32 Hz), 59.86, 120.92 (t,
J ¼ 242 Hz), 174.88 (t, J ¼ 5 Hz).
6. (a) Renner, C.; Alefelder, S.; Bae, J. H.; Budisa, N.;
Huber, R.; Moroder, L. Angew. Chem. 2001, 113, 949–
951; (b) Eberhardt, E. S.; Panasik, N., Jr.; Raines, R. T.
J. Am. Chem. Soc. 1996, 118, 12261–12266.
18. Zaidlewicz, M.; Brown, H. C. In Encyclopedia of Reagents
for Organic Synthesis; Paquette, L. A., Ed.; Wiley:
Chichester, 1995; pp 638–644.
7. (a) See Ref. 2a; (b) Adams, D. R.; Bailey, P. D.; Collier,
I. D.; Heffernan, J. D.; Stokes, S. J. Chem. Soc., Chem.
Commun. 1996, 349–350; (c) Baldwin, J. E.; Adlington,
R. M.; Godfrey, C. R. A.; Gollins, D. W.; Vaughan, J. G.
J. Chem. Soc., Chem. Commun. 1993, 1434–1435.
8. (a) Marin, J.; Didierjean, C.; Aubry, A.; Briand, J.-P.;
Guichard, G. J. Org. Chem. 2002, 67, 8440–8449; (b)
Hoarau, S.; Fauchere, J. L.; Pappalardo, L.; Roumestant,
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2585–2593; (c) Herdeis, C.; Heller, E. Tetrahedron: Asym-
metry 1993, 4, 2085–2094; (d) Bailey, P. D.; Bryans, J. S.
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68, 5147–5152; (b) Burger, K.; Rudolph, M.; Fehn, S.
Angew. Chem., Int. Ed. Engl. 1993, 32, 285–287.
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99, 1461–1469.
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2001–2004; (b) See Ref. 9b.
20. Dmowski, W. Replacement of Oxygen by Fluorine. In
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graph 187; American Chemical Society: Washington, DC,
1995; p 213.
22
D
21. Compound 10: colourless crystals; mp 51 °C, ½aŠ ¼ )9 (c
1
1, CHCl3); H NMR (600 MHz, CDCl3): d 1.62 (1H, m,
CH2CH2CHN), 1.92 (1H, m, CH2CHN), 2.04 (1H, m,
CH2CHN), 2.33 (1H, m, CH2CH2CHN), 3.03 (1H, br dd,
J ¼ 13:4 Hz, JHF ¼ 35:5 Hz, CH2N), 3.54 (1H, br d,
J ¼ 11:5 Hz, CHN), 3.72 (1H, br t, J ¼ 12:7 Hz, CH2N),
4.78 (1H, br d, JHF ¼ 45:9 Hz, CHF); 13C NMR
(151 MHz, CDCl3):
d 22.02 (CH2CHN), 28.18 (d,
2
2JCF ¼ 22:2 Hz, CH2CH2CHN), 49.02 (d, JCF ¼ 20:8 Hz,
1
CH2N), 55.55 (CHN), 83.65 (d, JCF ¼ 179:2 Hz, CHF),
2
2
88.78 (qq, JCF ¼ 33:5 Hz, JCF ¼ 31:3 Hz, C(CF3)2),
120.28 (qq, 1JCF ¼ 287:1Hz, CF 3), 121.83 (q,
1JCF ¼ 294:2 Hz, CF3), 168.27 (C@O); 19F NMR
€
1996, 52, 14757–14776; (b) Bottcher, C.; Burger, K.
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1
€
12. Pumpor, K.; Bottcher, C.; Fehn, S.; Burger, K. Hetero-
cycles 2003, 61, 259–269.
(376 MHz, CDCl3 without H decoupling): d À 75:28 (br
4
4
q, JFF ¼ 8 Hz, CF3), )78.68 (br dq, JFF ¼ 8:4 Hz,
2
13. Ko, K.-Y.; Lee, K.-I.; Kim, W.-J. Tetrahedron Lett. 1992,
33, 6651–6652.
14. (a) Doyle, M. P. Chem. Rev. 1986, 86, 919–939; (b) Doyle,
M. P.; Mc Kervey, M. A.; Ye, T. Modern Catalytic
6JFF ¼ 1:3 Hz, CF3), )187.24 (br dttq, JHF ¼ 45:3 Hz,
3JHF ¼ 34:3 Hz, 3JHF ¼ 11:0 Hz, 6JFF ¼ 1:3 Hz, CHF); MS
(EI) m=z (%): 295 (7) [M]þ, 198 (25) [M)CF3CO]þ, 1 69
(15), 149 (14), 102 (82), 82 (36), 69 (62).