Concise syntheses of γ-oxo-β,β-difluorinated amino acids via chelated [3,3]-rearrangement of difluoroallylic alcohols

Full text of DOI:10.1021/jo981119h

J . Org. Chem. 1998, 63, 8049-8051
8049
Sch em e 1
Con cise Syn th eses of
γ-Oxo-â,â-d iflu or in a ted Am in o Acid s via
Ch ela ted [3,3]-Rea r r a n gem en t of
Diflu or oa llylic Alcoh ols
J onathan M. Percy* and Michael E. Prime
School of Chemistry, University of Birmingham,
Edgbaston, Birmingham B15 2TT, United Kingdom
Michael J . Broadhurst
Roche Discovery Welwyn, 40 Broadwater Way,
Welwyn Garden City,
Hertfordshire AL7 3AY, United Kingdom
Received J une 11, 1998
Nonproteinogenic amino acids continue to attract the
attention of synthetic chemists, not the least from those
within the organofluorine community.1 Inspired by the
work of Kazmaier2 (and subsequent approaches to the
morphine skeleton by the Hudlicky group)3 and consis-
tent with our interest in sigmatropic rearrangements4 of
trifluoroethanol-derived fluorinated building blocks,5 we
decided to investigate the possibility of generating γ-oxo-
â,â-difluorinated amino acids by a chelated [3,3]-rear-
rangement of protected glycinate esters of readily avail-
able difluoroallylic alcohols. Release of the masked
carbonyl group would afford amino acid products in which
the side chain contained a ketonic carbonyl group flanked
by a CF2 center (Scheme 1). The unusual hydration
properties of this array are well known;6 indeed, they
have found a number of applications in the area of
protease inhibition. Though the array is usually located
as a backbone modification in short peptides,7 C-terminal
modifications are also well tried.8 The title compounds
containing modified side chains are novel and may have
interesting properties; herein we wish to report a short
route to the title compounds from trifluoroethanol (Scheme
1).
Exposure of the glycinate esters to modified Kazmaier
conditions (3.0 equiv of LDA, THF, -78 °C and then
ZnCl2, THF) followed by acidic workup afforded acids
1
4a -e and 5a -e (Table 1). Analysis by both 19F and H
NMR spectroscopy revealed that the rearranged acid was
the only product of the reaction in each case, with yields
of up to 99%. Whereas Kazmaier used the less reactive
lithium hexamethyldisilazide to form the chelated eno-
lates, we found that LDA was quite suitable for forming
the chelated lithium enolates.
Attempted release of the masked ketone at the acid
stage resulted in complete decomposition of the crude
(7) (a) Schirlin, D.; Rondeau, J . M.; Podlogar, B.; Tardif, C.; Tarnus,
C.; Vandorsselaer, V.; Farr, R. ACS Symp. Ser. 1996, 639, 169. (b)
Schirlin, D.; Baltzer, S.; Altenburger, J . M.; Tarnus, C.; Remy, J . M.
Tetrahedron 1996, 52, 305. (c) Sham, H. L. ACS Symp. Ser. 1996, 639,
184. (d) Skiles, J . W.; Fuchs, V.; Miao, C.; Sorcek, R.; Grozinger, K.
G.; Mauldin, S. C.; Vitous, J .; Mui, P. W.; J acober, S.; Chow, G.; Matteo,
M.; Skoog, M.; Weldon, S. M.; Possanza, G.; Keirns, J .; Letts, G.;
Rosenthal, A. S. J . Med. Chem. 1992, 35, 641. (e) Angelastro, M. R.;
Bet, P.; Mehdi, S.; Peet, N. P. Bioorg. Med. Chem. Lett. 1992, 2, 1235.
(f) Doherty, A. M.; Sircar, I.; Kornberg, B. E.; Quin, J .; Winters, R. T.;
Kaltenbronn, J . S.; Taylor, M. D.; Batley, B. L.; Rapundalo, S. R.; Ryan,
M. J .; Painchaud, C. A. J . Med. Chem. 1992, 35, 2. (g) Robinson, R. P.;
Donahue, K. M. J . Org. Chem. 1992, 57, 7309. (h) Yamamoto, T.;
Ishibuchi, S.; Ishizuka, T.; Haratake, M.; Kunieda, T. J . Org. Chem.
1993, 58, 1997. (I) Bernstein, P. R.; Kosmider, B. J .; Vacek, E. P.; Veale,
C. A.; Gomes, B. C. Bioorg. Med. Chem. Lett. 1994, 4, 2175.
(8) (a) Peet, N. P.; Burkhart, J . P.; Angelastro, M. R.; Giroux, E. L.;
Mehdi, S.; Bey, P.; Kolb, M.; Neises, B.; Schirlin, D. J . Med. Chem.
1990, 33, 394. (b) Angelastro, M. R.; Burkhart, J . P.; Bey, P.; Peet, N.
P. Tetrahedron Lett. 1992, 33, 3265. (c) Angelastro, M. R.; Baugh, L.
E.; Bey, P.; Burkhart, J . P.; Chen, T. M.; Durham, S. L.; Hare, C. M.;
Huber, E. W.; J anusz, M. J .; Koehl, J . R.; Marquart, A. L.; Mehdi, S.;
Peet, N. P. J . Med. Chem. 1994, 37, 4538. (d) J anusz, M. J .; Durham,
S. L.; Hare, C. M.; Geary, J . L.; Mandagere, A. K.; Poole, J . C.;
Thompson, T. N.; Xu, D.; Angelastro, M. R.; Burkhart, J . P.; Chen, T.
M.; Marquart, A. L.; Peet, N. P.; Hwang, K. K. J . Pharmacol. Exp.
Ther. 1995, 275, 1233. (e) Hornsperger, J . M.; Collard, J . N.; Heydt, J .
G.; Giacobini, E.; Funes, S.; Dow, J .; Schirlin, D. Biochem. Soc. Trans.
1994, 22, 758.
Difluoroallylic alcohols 1a -f were synthesized accord-
ing to our published procedure.9 Glycinate esters 2a -e
and 3a -e were prepared from the alcohols 1a -e and
commercial Boc- or Z-glycine in excellent yield according
to standard procedures (EDC, DMAP, DCM, 0 °C, 18 h).
(1) (a) Kukhar, V. P.; Soloshonok, V. A. Fluorine-containing Amino
Acids; J ohn Wiley and Sons: New York, 1995. (b) Kukhar, V. P. J .
Fluorine Chem. 1994, 69, 199. (c) Hudlicky, M., Pavlath, A. E., Eds.
Chemistry of Organic Fluorine Compounds II: A Critical Review; ACS
Monograph 187; American Chemical Society: Washington, DC, 1995.
(2) For recent examples, see: (a) Kazmaier, U. J . Org. Chem. 1996,
61, 3694. (b) Kazmaier, U. Synlett 1995, 1138.
(3) Gonzalez, D.; Schapiro, V.; Seoane, G.; Hudlicky, T.; Abboud, K.
J . Org. Chem. 1997, 62, 1194. For a more general description of
chelation-controlled [3,3]-rearrangements, see: Frauenrath, H. In
Stereoselective Synthesis; Helmchen, G.; Hoffmann, R. W., Mulzer, J .,
Schaumann, E., Eds.; Georg Thieme Verlag: Stuttgart, 1996; E21,
D.1.6, 3420. For a recent review of chelated [3,3]-rearrangements,
see: Kazmaier, U. Liebigs. Ann./ Recl. 1997, 285.
(4) For chelated [3,3]-rearrangements of difluoroallylic alkoxy-
acetates, see: Broadhurst, M. J .; Percy, J . M.; Prime, M. E. Tetrahedron
Lett. 1997, 38, 5903. [2,3]-Wittig rearrangements have also been
described Patel, S. T.; Percy, J . M.; Wilkes, R. D. J . Org. Chem. 1996,
61, 166.
(5) Percy, J . M. Top. Curr. Chem. 1997, 193, 131.
(6) Neder, K. M.; French, S. A.; Miller, S. P. F. Tetrahedron 1994,
50, 9847.
(9) Patel, S. T.; Percy, J . M.; Wilkes, R. D. Tetrahedron 1995, 51,
9201.
10.1021/jo981119h CCC: $15.00 © 1998 American Chemical Society
Published on Web 10/02/1998

8050 J . Org. Chem., Vol. 63, No. 22, 1998
Ta ble 1. P r ep a r a tion a n d [3,3]-Rea r r a n gem en ts of Diflu or oa llylic Glycin a tes
Notes
Ta ble 2. Ester ifica tion a n d Dep r otection of [3,3]-Rea r r a n gem en t P r od u cts
products.10 Attempts to prepare methyl esters on a small
scale using diazomethane in diethyl ether led to complete
decomposition of the crude acids. Instead, the crude
acids were converted to the methyl esters (EDC, excess
MeOH, DMAP, DCM, 0 °C, 18 h) 6a -e and 7a -e without
purification. Other alcohols could be used; for example,
4d coupled with benzyl alcohol in a satisfactory (58%)
yield to afford 10d . Coupling procedures using DCC (1.1
occurred and the latent ketone functionality was re-
vealed, affording 8c and 9b-e in good yields (Table 2).
Given the acid lability of the Boc protecting group, we
were not too surprised to isolate 11d as a side product
in one instance; however, the Z-protected amino acids
were stable under the methanolysis conditions. In one
case, we also detected the presence of an unstable
dehydrofluorination product which displayed spectra
consistent with structure 12b.
In conclusion, a facile route to γ-oxo-â,â-difluorinated
amino acids has been established using chelated rear-
rangement technology and smooth deprotection chemis-
try. Given the potential for asymmetric [3,3]-rearrange-
ment in the presence of optically pure N,O-ligands,11 we
believe this may be a promising route to enantiomerically
enriched or pure, novel, difluorinated materials.12
equiv DMAP, DCM) gave unsatisfactory results (typically
,50% yield). Upon exposure of methyl esters 6c and
7b-e to thionyl chloride in a mixture of chloroform and
methanol (9:1), methanolysis of the enol acetal group
Exp er im en ta l Section
Gen er a l Meth od s. All difluoroallylic alcohols were prepared
according to our published procedure.9 Boc- and Z-glycine are
available commercially and were used without further purifica-
tion. All rearrangements were performed in THF dried over and
freshly distilled from sodium and benzophenone and collected
by syringe as required. All esterifications were performed in
DCM which had been distilled from calcium hydride. NMR
(10) We described previously (ref 4a) a mild enol acetal hydrolysis,
that occurred during an attempted esterification following a recent
protocol: Hosangadi, B. D.; Dave, R. H. Tetrahedron Lett. 1996, 37,
6375. Lewis acid-mediated cleavage of MEM acetals is a considerably
more widely used procedure; see: (a) Guindon, Y.; Yoakim, C.; Morton,
H. E. J . Org. Chem. 1984, 49, 3912. (b) Herbert, J . M.; Knight, J . G.;
Sexton, B. Tetrahedron 1996, 52, 15257. The only example, to our
knowledge, of a MEM enol acetal cleavage was reported by Magnus
and co-workers; see: Magnus, P.; Carter, P.; Elliott, J .; Lewis, R.;
Harling, J .; Pitterna, T.; Bauta, W. E.; Fortt, S. J . Am. Chem. Soc.
1992, 114, 2544.
(11) Kazmaier, U.; Krebs, A. Tetrahedron Lett. 1996, 37, 7945.
(12) For a recent asymmetric synthesis of â-difluorinated amino
acids from L-isoascorbic acid, see: Li, K.; Leriche, C.; Liu, H.-W. Bioorg.
Med. Chem. Lett. 1998, 8, 1097.

Notes
J . Org. Chem., Vol. 63, No. 22, 1998 8051
spectra were obtained at 75 (13C), 282 (19F), or 300 (1H) MHz in
CDCl3 using residual CHCl3 as internal reference.
0.40 (40:60 diethyl ether/hexanes); 1H NMR δ 1.15 (s, 9H), 1.43
(s, 9H), 3.38 (s, 3H), 3.55-3.62 (m, 2H), 3.76 (s, 3H), 3.82-3.93
(m, 2H), 4.92-5.13 (m, 3H), 5.38 (d, J ) 10.3 Hz, 1H), 5.44 (s,
1H); 19F NMR δ -106.6 (dd, J ) 247.9 Hz, J ) 14.0 Hz, 1F),
-107.5 (dd, J ) 247.9 Hz, J ) 11.4 Hz, 1F); 13C NMR δ 28.2,
30.2, 31.9, 52.6, 56.4 (t, J ) 28.4 Hz), 58.9, 68.9, 71.5, 80.3, 117.1
(t, J ) 252.9 Hz), 130.3, 142.4 (t, J ) 24.3 Hz), 154.6, 167.8.
Anal. Calcd for C19H33O7NF2: C, 53.64; H, 7.82; N, 3.29.
Found: C, 53.83; H, 7.82; N, 3.11.
Met h yl-2-[N-b en zyloxyca r b on yl]a m in o-3,3-d iflu or o-4-
([m et h oxyet h oxy]m et h oxy)p en t -4-en oa t e (7a ): Rf ) 0.50
(40:60 diethyl ether/hexanes); 1H NMR δ 3.38 (s, 3H), 3.49-3.55
(m, 2H), 3.62-3.80 (m, 5H), 4.78 (s, 2H), 4.96-5.21 (m, 5H), 5.60
(d, J ) 9.56 Hz, 1H), 7.31-7.40 (m, 5H); 19F NMR δ -110.1 (dd,
J ) 252.7 Hz, J ) 11.00 Hz, 1F), -110.8 (dd, J ) 252.7 Hz, J )
13.2 Hz, 1F); 13C NMR δ 53.0, 56.4 (t, J ) 168.5 Hz), 59.0, 67.5,
68.1, 71.4, 90.5, 93.8, 115.5 (t, J ) 251.0 Hz), 128.2, 128.4, 128.6,
128.8, 135.9, 151.0 (t, J ) 29.4 Hz), 155.3, 167.2; HRMS calcd
for C18H24NO7F2 404.152084, found 404.152005.
Gen er a l P r oced u r e for th e En ol Aceta l Hyd r olysis of
th e Meth yl Ester s. Thionyl chloride (2.2 mmol) was added
dropwise to a cooled solution of the methyl ester 6 or 7 (2 mmol)
in a 9:1 chloroform/methanol mixture (15 mL) at 0 °C. The
reaction mixture was allowed to warm to room temperature
overnight, after which time the reaction was stopped by the
addition of water (10 mL) the mixture was extracted with DCM
(3 × 20 mL), and the organic extracts were combined, dried
(MgSO4), and concentrated in vacuo to yield the ketoester 8 or
9 as an oil. Purification of these ketoesters was achieved by
flash column chromatography.
Gen er a l P r oced u r e for t h e P r ep a r a t ion of Boc- or
Z-Glycin a tes. EDC (11 mmol), was added in one portion to a
cooled solution of difluoroallylic alcohol 1 (10 mmol), Boc- or
Z-glycine (11 mmol) and DMAP (4 mmol) in DCM (50 mL) at 0
°C. After 5 min of stirring at 0 °C, the reaction mixture was
concentrated in vacuo and the residue was taken up in ethyl
acetate and washed consecutively with HCl (1 M, 15 mL), water
(15 mL), saturated sodium bicarbonate (15 mL), and brine (15
mL). The organic layer was dried (MgSO4), filtered, and
concentrated in vacuo to yield the glycinates 2 or 3 as oils.
Purification was achieved by flash column chromatography.
3-[(N-ter t-Bu t yloxyca r b on yl)glycin oyl]-1,1-d iflu or o-2-
[(m eth oxyeth oxy)m eth oxy]-4-m eth ylp en t-1-en e: Rf ) 0.57
1
(50:50 diethyl ether/hexanes); H NMR δ 0.88 (d, J ) 6.62 Hz,
3H), 0.92 (d, J ) 6.62 Hz, 3H), 1.40 (s, 9H), 2.06-2.20 (m, 1H),
3.35 (s, 3H), 3.50-3.58 (m, 2H), 3.76-3.80 (m, 2H), 3.87-3.92
(m, 2H), 4.85 (d, J ) 6.25 Hz, 1H), 4.98 (d, J ) 6.25 Hz, 1H),
5.03-5.11 (m, 1H), 5.20-5.30 (m, 1H); 19F NMR δ -97.4 (d, J )
55.9 Hz, 1F), -105.7 (d, J ) 55.9 Hz, 1F); 13C NMR δ 18.2, 18.8,
28.3, 29.0, 42.5, 58.9, 68.4, 71.6, 75.9, 79.8, 97.1, 112.4 (dd, J )
14.7 Hz), 113.0 (d, J ) 14.7 Hz) 155.8 (t, J ) 296.1 Hz), 169.6;
HRMS calcd for C17H29NO7F2Na 420.180979, found 420.181458.
3-[(N-Ben zyloxyca r bon yl)glycin oyl]-1,1-d iflu or o-4,4-d i-
m eth yl-2-([m eth oxyeth oxy)m eth oxy]p en t-1-en e: Rf ) 0.45
(50:50 diethyl ether/hexanes); 1H NMR δ 1.00 (s, 9H), 3.35 (s,
3H), 3.51-3.58 (m, 2H), 3.67-3.90 (m, 2H), 4.00 (d, J ) 5.52
Hz, 2H), 4.81 (d, J ) 6.25 Hz, 1H), 4.96 (d, J ) 6.25 Hz, 1H),
5.00-5.22 (m, 3H), 5.66 (t, J ) 5.52 Hz, 1H), 7.35 (s, 5H); 19F
NMR δ -97.8 (d, J ) 55.9 Hz, 1F), -100.5 (d, J ) 55.9 Hz, 1F);
13C NMR δ 26.1, 35.1, 42.8, 58.8, 66.9, 68.6, 71.6, 76.6, 97.8, 112.9
(d, J ) 14.6 Hz), 113.0 (d, J ) 14.6 Hz), 128.0, 128.4, 136.2,
156.4 (t, J ) 288.8 Hz, 1C); HRMS calcd for C21H30NO7F2
446.199034, found 446.199397.
Meth yl-2-[N-ter t-bu tyloxyca r bon yl]a m in o-3,3-d iflu or o-
4-oxooct-4-en oa te (8c): Rf ) 0.76 (50:50 diethyl ether/hex-
1
anes); H NMR δ 0.92 (d, J ) 6.62 Hz, 6H), 1.41 (s, 9H), 2.08-
2.23 (m, 1H), 2.55 (d, J ) 6.61 Hz, 2H), 3.70 (s, 3H), 5.01-5.18
(m, 1H), 5.35 (d, J ) 9.93 Hz, 1H); 19F NMR δ -111.0 (dd, J )
273.4 Hz, J ) 10.2 Hz, 1F), -115.8 (dd, J ) 273.4 Hz, J ) 14.0
Hz, 1F); 13C NMR δ 22.1, 23.2, 27.9, 45.2, 52.9, 55.1 (t, J ) 24.87
Hz), 80.9, 113.7 (t, J ) 260.5 Hz), 154.7, 166.8, 198.6 (t, J )
29.4 Hz). Anal. Calcd for C14H23NO5F2: C, 52.01; H, 7.17; N,
4.33. Found: C, 52.06; H, 7.26; N, 4.25.
Gen er a l P r oced u r e for th e Ch ela ted Rea r r a n gem en ts.
Boc- or Z-glycinate 2 or 3 (1 mmol) was added to a cold (-78 °C)
stirred solution of freshly prepared LDA generated by the slow
addition of butyllithium (3 mmol of a 1.7 M solution in hexanes)
to diisopropylamine (3.3 mmol) in THF (20 mL) at -78 °C.
Approximately 5 min after the addition of the glycinate was
complete, zinc(II) chloride (1.2 mmol) in THF (2 mL) was added
in one portion and the reaction mixture was allowed to warm to
room temperature with stirring over 1 h. Dilute HCl (1 M, 10
mL) was added to the orange colored solution and the mixture
was extracted with diethyl ether (3 × 20 mL). The organic
extracts were combined, dried (MgSO4), filtered, and concen-
trated in vacuo to afford the crude amino acid as an orange oil.
The rearrangement products were used without further purifica-
tion.
Met h yl-2-[N-b en zyloxyca r b on yl]a m in o-3,3-d iflu or o-4-
oxo-5-p h en ylp en t-4-en oa te (9e): Rf ) 0.51 (30:70 diethyl
1
ether/hexanes); H NMR δ 3.70 (s, 3H), 4.10 (s, 2H), 5.15-5.27
(m, 1H), 5.72 (d, J ) 9.56 Hz, 1H), 7.37 (m, 10H); 19F NMR δ
-108.5 (dd, J ) 274.1 Hz, J ) 9.31 Hz, 1F), -115.9 (dd, J )
274.1 Hz, J ) 15.8 Hz, 1F); 13C NMR δ 43.5, 53.4, 56.5 (t, J )
26.1 Hz), 67.9, 114.4 (t, J ) 261.0 Hz), 127.5, 128.2, 128.4, 128.6,
128.7, 129.1, 129.9, 131.4, 135.7, 155.9, 166.8, 196.8 (t, J ) 28.6
Hz); HRMS calcd for C20H20NO5F2 392.130955, found
392.130641.
Gen er a l P r oced u r e for th e Ester ifica tion of th e Rea r -
r a n gem en t P r od u cts. EDC (5.5 mmol) was added in one
portion to a cooled solution of N-protected amino acid 4 or 5 (5
mmol), methanol (50 mmol) and DMAP (2 mmol) in DCM at 0
°C. After 5 min of stirring at 0 °C, the reaction mixture was
warmed to room temperature and stirred overnight. The
resulting reaction mixture was concentrated in vacuo, and the
residue was taken up in ethyl acetate and washed consecutively
with HCl (1 M, 15 mL), water (15 mL), saturated sodium
bicarbonate (15 mL), and brine (15 mL). The organic layer was
dried (MgSO4), filtered and concentrated in vacuo to yield the
methyl ester 6 or 7 as an oil.
Ack n ow led gm en t. The authors thank the EPSRC
(CASE Studentship to M.E.P.) and Roche Discovery
Welwyn for financial support.
Su p p or tin g In for m a tion Ava ila ble: 13C, 1H, and 19F
NMR data and mass spectra (43 pages). This material is
contained in libraries on microfiche, immediately follows this
article in the microfilm version of the journal, and can be
ordered from the ACS; see any current masthead page for
ordering information.
Meth yl-2-[N-ter t-bu tyloxyca r bon yl]a m in o-3,3-d iflu or o-
4-([m eth oxyeth oxy]m eth oxy)-(Z)-n on -4-en oa te (6d ): Rf )
J O981119H