A formal [3,3]-sigmatropic rearrangement route to quaternary α-vinyl amino acids: Use of allylic N-PMP trifluoroacetimidates

Article abstract of DOI:10.1021/ol060019s

Pd(II)-mediated rearrangement of allylic N-PMP (p-methoxyphenyl) trifluoroacetimidates provides the first formal sigmatropic route to quaternary, α-vinylic amino acids, potential suicide substrates for PLP enzymes. The amino acid side chains enter via tra

Full text of DOI:10.1021/ol060019s

ORGANIC
LETTERS
2006
Vol. 8, No. 5
971-974
A Formal [3,3]-Sigmatropic
Rearrangement Route to Quaternary
r
-Vinyl Amino Acids: Use of Allylic
N-PMP Trifluoroacetimidates
David B. Berkowitz,* Bin Wu, and Huijie Li
Department of Chemistry, UniVersity of Nebraska, Lincoln, Nebraska 68588-0304
dbb@unlserVe.unl.edu
Received January 4, 2006
ABSTRACT
Pd(II)-mediated rearrangement of allylic N-PMP (p-methoxyphenyl) trifluoroacetimidates provides the first formal sigmatropic route to quaternary,
-vinylic amino acids, potential suicide substrates for PLP enzymes. The amino acid side chains enter via transition-metal-mediated C
bond constructions, including (i) Cu(I)-mediated conjugate addition (Ala); (ii) Pd(0)/AsPh3-mediated Stille coupling (allyl-Gly, Phe, DOPA, m-Tyr);
r
−C
and (iii) Pd(0)/Pt-Bu3-mediated Negishi coupling (Leu). In the synthesis of the DOPA decarboxylase inactivator,
N-PMP trifluoroacetimidate rearranges much more efficiently than the corresponding trichloroacetimidate.
r-vinyl-m-tyrosine, the new
Placing an unsubstituted vinyl group alpha to the amino
group in an amino acid is an effective strategy for the suicide
inactivation of some pyridoxal phosphate (PLP) enzymes.
Examples include R-vinylglycine (naturally occurring) and
vigabatrin (γ-vinyl-GABA), a synthetic antiepileptic drug,
with exciting new potential for the treatment of substance
abuse.1 The principal mechanism by which the vinylic trigger
is actuated, leading to an active site-directed Michael
acceptor, is now established for both vinylglycine2 and
vigabatrin.3 These precedents continue to motivate the
synthesis and testing of quaternary, R-vinyl amino acids as
candidates for the inactivation of amino acid decarboxylases
(AADC’s).4
The replacement of the R-hydrogen with a vinyl group
builds specificity into the design, as it prevents PLP-
dependent racemase, transaminase, and â- or γ-eliminase/
replacement enzymes from actuating the trigger, yet allows
for inclusion of the usual side chain for AADC recognition.
The R-vinyl branch can subsequently be elaborated into
halovinyl5 or oxiranyl6 groups, as potential triggering func-
tionalities.
(1) (a) Brodie, J. D.; Figueroa, E.; Laska, E. M.; Dewey, S. L. Synapse
2005, 55, 122-125. (b) Brodie, J. D.; Figueroa, E.; Dewey, S. L. Synapse
2003, 50, 261-265.
(2) Capitani, G.; Tschopp, M.; Eliot, A. C.; Kirsch, J. F.; Gruetter, M.
G. FEBS Lett. 2005, 579, 2458-2462.
(3) (a) Czapinski, P.; Blaszczyk, B.; Czuczwar, S. J. Curr. Top. Med.
Chem. 2005, 5, 3-14. (b) Storici, P.; De Biase, D.; Bossa, F.; Bruno, S.;
Mozzarelli, A.; Peneff, C.; Silverman, R. B.; Schirmer, T. J. Biol. Chem.
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Soc. 1991, 113, 9341-9349. (d) De Biase, D.; Barra, D.; Bossa, F.; Pucci,
P.; John, R. A. J. Biol. Chem. 1991, 266, 20056-20061.
Quaternary amino acids are also noteworthy targets for
their ability to confer stability to proteases,7 promote helical
10.1021/ol060019s CCC: $33.50
© 2006 American Chemical Society
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structure,8 and serve as substrates for unnatural amino acid
mutagenesis.9 The incorporation of unsaturation adds syn-
thetic value.10 Given this, several synthetic approaches to
quaternary, R-vinyl AA’s have appeared, most using alky-
lative disconnections at the CR-vinylic11 or CR-side chain12
junctions.
We describe here a new entry into this unnatural AA class;
namely, we disconnect at the CR-N bond via a formal [3,3]-
sigmatropic process (Scheme 1). To our knowledge, no
olefin to a monosubstituted and sterically encumbered,
quaternary vinyl group. Specifically, the Pd(II)-mediated
allylic imidate rearrangement appeared attractive, as it
proceeds under mild conditions and asymmetric variants have
appeared, largely through the work of Overman.15 We are
pleased to report that the N-PMP (p-methoxyphenyl) tri-
fluoroacetimidate is particularly well suited for this trans-
formation.16,17
One distinguishing feature of a sigmatropic rearrangement
approach to these unnatural AA’s lies in the mode of side
chain attachment. Previous approaches from our laboratory12a-c
and others12d,e have used vinylglycine-derived AA enolates
as the vehicles for side chain introduction. This chemistry
usually requires strictly anhydrous conditions and low
temperature.
Scheme 1. New Disconnection toward Quaternary, R-Vinyl
AA’s
Scheme 2. Introduction of the Ala and Leu Side Chains via
Cuprate and Negishi Couplings
examples of sigmatropic routes to quaternary R-vinyl AA’s
have previously appeared, though a high temperature, thermal
allylic imidate rearrangement gives vinylglycinol.13,14 We had
hoped to tap into the favorable O-CdN to OdC-N
enthalpics to overcome the transformation of a trisubstituted
(4) Berkowitz, D. B.; Jahng, W.-J.; Pedersen, M. L. Bioorg. Med. Chem.
Lett. 1996, 6, 2151-2156 and references therein.
As is illustrated in Schemes 2 and 3, the formal sigmat-
ropic approach exploits transition-metal-mediated C-C
(5) (a) Berkowitz, D. B.; de la Salud-Bea, R.; Jahng, W.-J. Org. Lett.
2004, 6, 1821-1824. (b) Berkowitz, D. B.; Pedersen, M. L.; Jahng, W.-J.
Tetrahedron Lett. 1996, 37, 4309-4312.
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5369.
(7) Khosla, M. C.; Stachowiak, K.; Smeby, R. R.; Bumpus, F. M.; Piriou,
F.; Lintner, K.; Fermandjian, S. Proc. Natl. Acad. Sci. U.S.A. 1981, 78,
757-60.
(14) For examples of thermal rearrangements (typically refluxing toluene
for days) of allylic trichloroacetimidates to access quaternary centers in
the lactacystin class of natural products, see: (a) Sato, H.; Maeba, T.;
Yanase, R.; Yamaji-Hasegawa, A.; Kobayashi, T.; Chida, N. J. Antibiot.
2005, 58, 37-49. (b) Oishi, T.; Ando, K.; Inomiya, K.; Sato, H.; Iida, M.;
Chida, N. Org. Lett. 2002, 4, 151-154. (c) Chida, N.; Takeoka, J.; Ando,
K.; Tsutsumi, N.; Ogawa, S. Tetrahedron 1997, 53, 16287-16298.
(15) (a) Anderson, C. E.; Overman, L. E. J. Am. Chem. Soc. 2003, 125,
12412-12413. (b) Kang, J.; Yew, K. H.; Kim, T. H.; Choi, D. H.
Tetrahedron Lett. 2002, 43, 9509-9512. (c) Donde, Y.; Overman, L. E. J.
Am. Chem. Soc. 1999, 121, 2933-2934. (d) Uozumi, Y.; Kato, K.; Hayashi,
T. Tetrahedron: Asymmetry 1998, 9, 1065-1072. (e) Calter, M.; Hollis;
Keith, T.; Overman, L. E.; Ziller, J.; Zipp, G. G. J. Org. Chem. 1997, 62,
1449-1456.
(16) For preliminary descriptions of the behavior of the new allylic
N-PMP trifluoroacetimidates and their application to the synthesis of
quaternary, R-vinyl AA’s via Pd(II)-mediated rearrangement, see: (a)
Berkowitz, D. B. Abstract No. 68, 36th Midwest Regional American
Chemical Society Meeting, 2001. (b) Li, H. A New Approach to Quaternary
Beta,Gamma-Unsaturated Amino Acids via a Formal [3,3]-Sigmatropic
Rearrangement. M.S. Thesis, University of Nebraska, 2001.
(8) (a) Yokum, T. S.; Gauthier, T. J.; Hammer, R. P.; McLaughlin, M.
L. J. Am. Chem. Soc. 1997, 119, 1167-1168. (b) Jaun, B.; Tanaka, M.;
Seiler, P.; Kuhnle, F. N. M.; Braun, C.; Seebach, D. Liebigs Annalen/Recueil
1997, 1697-1710. (c) Aubry, A.; Bayeul, D.; Precigoux, G.; Pantano, M.;
Formaggio, F.; Crisma, M.; Toniolo, C.; Boesten, W. H. J.; Schoemaker,
H. E.; Kamphuis, J. J. Chem. Soc., Perkin Trans. 2 1994, 525-529.
(9) Mendel, D.; Ellman, J.; Schultz, P. G. J. Am. Chem. Soc. 1993, 115,
4359-4360.
(10) Kaiser, J.; Kinderman, S. S.; van Esseveldt, B. C. J.; van Delft, F.
L.; Schoemaker, H. E.; Blaauw, R. H.; Rutjes, F. P. J. T. Org. Biomol.
Chem. 2005, 3, 3435-3467.
(11) (a) Ma, D.; Zhu, W. J. Org. Chem. 2001, 66, 348-350. (b) Petasis,
N. A.; Zavialov, I. A. J. Am. Chem. Soc. 1997, 119, 445-446. (c) Pedersen,
M. L.; Berkowitz, D. B. J. Org. Chem. 1993, 58, 6966-6975. (d) Groth,
U.; Schoellkopf, U.; Chiang, Y. C. Synthesis 1982, 864-866.
(12) (a) Berkowitz, D. B.; Chisowa, E.; McFadden, J. M. Tetrahedron
2001, 57, 6329-6343. (b) Berkowitz, D. B.; McFadden, J. M.; Sloss, M.
K. J. Org. Chem. 2000, 65, 2907-2918. (c) Berkowitz, D. B.; McFadden,
J. M.; Chisowa, E.; Semerad, C. L. J. Am. Chem. Soc. 2000, 122, 11031-
11032. (d) Colson, P. J.; Hegedus, L. S. J. Org. Chem. 1993, 58, 5918-
5924. (e) Seebach, D.; Buerger, H. M.; Schickli, C. P. Liebigs Ann. Chem.
1991, 669-684.
(17) Subsequently, Overman and co-workers reported asymmetric, Pd-
(II) rearrangements of N-PMP trifluoroacetimidates in nonquaternary model
systems: (a) Overman, L. E.; Owen, C. E.; Pavan, M. M.; Richards, C. J.
Org. Lett. 2003, 5, 1809-1812. (b) Anderson, C. E.; Donde, Y.; Douglas,
C. J.; Overman, L. E. J. Org. Chem. 2005, 70, 648-657. (c) Prasad, R. S.;
Anderson, C. E.; Richards, C. J.; Overman, L. E. Organometallics 2005,
24, 77-81.
(13) Vyas, D. M.; Chiang, Y.; Doyle, T. W. J. Org. Chem. 1984, 49,
2037-2039.
972
Org. Lett., Vol. 8, No. 5, 2006

fluoroacetimidoyl chloride is readily accessible24 and
provides for an exceedingly mild and efficient method for
the introduction of the title imidate at -78 °C (Table 1).
Scheme 3. Side Chain Introduction via Modified Stille
Couplings
Table 1. Allylic N-PMP Trifluoroacetimidate Installation/
Rearrangementa
entry
R
AA
Ala
Phe
m-Tyr
Leu
yield of 9/10b
a
b
c
d
e
f
Me
CH2Ph
88/92%c
95/98%d
95/83%d,e
98/83%c
82/96%d
82/(70%)c,f
CH2(3′-OTBS)C6H4
CH2CHMe2
CH2(3′,4′-bis-OTBS)C6H3
CH2CHdCH2
bond forming processes, at sp2- or sp-centers, for side
chain installation. On one hand, for R-vinylalanine, the side
chain (Me) is carried in directly as part of a cuprate, thereby
adding to the activated sp-center in 1, under conditions
described recently by Joullie´.18 Alternatively, advantage
was taken of higher order stannylcuprate chemistry pioneered
by Lipshutz,19 again emanating from 1, to access vinylstan-
nanes 3 and 7 and lay the foundation for Stille-based
chemistry.
DOPA
All-Gly
a Procedure: Imidate installations were initiated at -78 °C in dry THF.
Rearrangements were run in PhH at room temperature, until complete
conversion to 10 was evident by TLC. 9a-f designate the N-PMP allylic
trifluoroacetimidates. b Isolated yields of purified rearrangement products
[as THP diastereomers]. c R′ ) Ph. d R′ ) Me. e In this case, the reaction
is more rapid for the benzonitrile-based catalyst (see Figure 1). f This yield
is corrected for recovery of starting imidate (27%). Product 10f itself was
isolated in 51% yield.
Stannane 3 also serves to provide a complementary vinyl
iodide 4,20 for cross-couplings with the opposite sense of
polarity. Indeed, the leucine side chain, as the isobutylzinc
reagent, enters efficiently (73%) via Negishi-type coupling
on this system. Best results were obtained with the Pd(Pt-
Bu3)2 catalyst, under the Fu conditions.21 Cl2Pd(dppf) was
much less effective. Formation of the isobutylzinc reagent,
via halogen-metal exchange from i-BuI, under the condi-
tions recently disclosed by Smith (3 equiv of t-BuLi,
ZnCl2),22 led to successful Negishi coupling, albeit in lower
yields (30-35%). For benzylic and allylic side chains, a
modified Pd-mediated Stille cross-coupling reaction23 on
ester 7 or alcohol 3 proceeded smoothly. In our hands,
use of the AsPh3 ligand generally gave very good results,
though the DOPA system proved to be more difficult to
handle.
This is to be contrasted with the typical procedure for imi-
date installation by alcohol condensation with a nitrile
in the presence of base (e.g., NaH, DBU) at room temper-
ature.14
The N-PMP trifluoroacetimidate functionality was found
to lead to clean rearrangement to the desired quaternary,
protected R-amino alcohols, under Pd(II) catalysis, with all
AA side chains examined (Table 1). Among Pd(II) catalyst
candidates examined, phosphine-coordinated complexes, such
as Cl2Pd(PPh3)2 or Cl2Pd(dppf), gave little to no product.
Provided that reactions were carried out in MeCN, Pd(OAc)2
and PdCl2 catalysts gave the desired formal [3,3]-sigmatropic
rearrangement products. However, best results were obtained
by starting from the preformed nitrile complex, either Cl2-
Pd(NCMe)2 or Cl2Pd(NCPh)2, in benzene solvent, whereby
the latter complex generally produced more rapid conversion.
The title imidate appears especially well suited to the
construction of these hindered quaternary centers. Thus, in
the important m-tyrosine system, direct NMR comparison
(benzene-d6) revealed that the allylic N-PMP trifluoroace-
timidate rearranges completely within 1 h, whereas the
corresponding trichloroacetimidate gives little to no product
(Figure 1).
With all six targeted AA side chains installed, the desired
imidate rearrangement could be investigated. N-PMP-tri-
(18) Leonard, M. S.; Carroll, P. J.; Joullie, M. M. J. Org. Chem. 2004,
69, 2526-2531.
(19) (a) Reginato, G.; Capperucci, A.; Degl’Innocenti, A.; Mordini, A.;
Pecchi, S. Tetrahedron 1995, 51, 2129-2136. (b) Lipshutz, B. H.; Ellsworth,
E. L.; Dimock, S. H.; Reuter, D. C. Tetrahedron Lett. 1989, 30, 2065-
2068.
(20) Thibonnet, J.; Launay, V.; Abarbri, M.; Duchene, A.; Parrain, J.-L.
Tetrahedron Lett. 1998, 39, 4277-4280.
In these transformations, it proved auspicious to mask the
latent R-carboxyl group as a THP ether. This protecting group
is stable to the cuprate, Negishi or Stille side chain-couplings
employed early, and leads to successful Pd(II) rearrangement.
(21) Dai, C.; Fu, G. C. J. Am. Chem. Soc. 2001, 123, 2719-2724.
(22) Smith, A. B., III; Beauchamp, T. J.; LaMarche, M. J.; Kaufman,
M. D.; Qiu, Y.; Arimoto, H.; Jones, D. R.; Kobayashi, K. J. Am. Chem.
Soc. 2000, 122, 8654-8664.
(23) (a) Sheffy, F. K.; Godschalx, J. P.; Stille, J. K. J. Am. Chem. Soc.
1984, 106, 4833-4840. (b) Milstein, D.; Stille, J. K. J. Am. Chem. Soc.
1979, 101, 4992-4998.
(24) Tamura, K.; Mizukami, H.; Maeda, K.; Watanabe, H.; Uneyama,
K. J. Org. Chem. 1993, 58, 32-35.
Org. Lett., Vol. 8, No. 5, 2006
973

Table 2. Protecting Group Interchange/Oxidationa
entry
R
AA
Ala
Phe
11b
12c
13
14
a
b
c
Me
CH2Ph
83%
51%d 79%
96% 63% 41%
90%
76%
CH2(3′-OTBS)C6H4 m-Tyr 87%e 67% 78%
CH2CHMe2
d
Leu
67%
54%d 73%
a Isolated yields of purified products are reported. 11a-d denote the
products of trifluoroacetamide deprotection. 12a-d are the products of
simultaneous N-PMP and THP deprotection. 13a-d designate the N-FMOC-
protected amino alcohols. b These reactions typically involve addition of 5
equiv of NaBH4 in EtOH, at 0 °C, in portions, followed by warming to
room temperature. c Yields here reflect cleavage of both the OTHP and
N-PMP protecting groups. d In these cases, the crude amino alcohol was
protected with FMOC-OSu, so a two-step yield is given. e This yield
reflects the installation of a more robust TIPS silyl protecting group (TBAF,
then TIPSCl, imidazole), following rearrangement, in addition to trifluo-
roacetamide cleavage.
Figure 1. Allylic imidate rearrangement, as monitored by 1H NMR
(benzene-d6). Panels a and b show allylic N-PMP trifluoroacetimi-
date 9c and trichloroacetimidate 16c, respectively, at t ) 0. Panels
c and d show NMR spectra of the same samples at t ) 1 h, after
exposure to 10 mol % of PdCl2(PhCN)2. In going from panel a to
c, the imidate methine proton in 9c (br t, 6.0 ppm) is converted to
the methine proton of the emerging vinyl group (dd, 5.8 ppm) in
10c. Simultaneously, the allylic ether methylene in 9c (2 H, 4.8
ppm) splits out into the cis (d, 1 H, 4.95 ppm) and trans (d, 1 H,
5.16 ppm) terminal vinylic protons of 10c. These spectral snapshots
attest to the efficiency with which the new quaternary center in
the R-vinyl-m-tyrosine system is assembled, when the N-PMP
trifluoroacetimidate is employed.
interesting N-PMP trifluoroacetimidate to the installation of
quaternary centers bearing nitrogen.
Scheme 4. Joint FMOC/TIPS Deprotection to R-Vinyl-m-Tyr
Moreover, immediately thereafter, we find that one can
simultaneously cleave both the THP ether and the N-PMP
group (CAN, MeCN, H2O), following reductive (NaBH4)
removal of the trifluoroacetamide functionality (Table 2).
This quickly yields R-vinyl amino alcohols, good vehicles
for the introduction of FMOC functionality. To our knowl-
edge, this is first synthesis of quaternary R-vinyl AA’s that
outfits them with FMOC protection.
Finally, Jones oxidation serves to complete the synthesis
of the targeted N-FMOC R-vinyl AA’s, in a form appropriate
for future peptide synthesis. Alternatively, should one wish
to unveil the corresponding free R-vinyl AA’s for study with
PLP enzymes, one can cleave the FMOC groups, by
subjection to mildly basic conditions (TBAF at room
temperature). We were particularly pleased to find that, for
14c, both the side chain OTIPS protecting group and the
N-FMOC group could be cleaved simultaneously in this way
(Scheme 4), providing a novel synthesis of the known DOPA
decarboxylase suicide substrate, 15c. This work serves as
proof of principle for a new allylic imidate rearrangement
entry into quaternary R-vinyl amino acids, in the racemic
series, and sets the stage for potential asymmetric variants
of the approach, as well as for further applications of the
Acknowledgment. We thank the NSF (CHE-0317083)
and NIH (CA 62034) for support of our research program.
Assistance from Kannan Karukurichi, Weijun Shen, Xiang
Shi, and Sonia Bironneau-Gouault is acknowledged. This
research was facilitated by shared instrumentation grants
(NIH SIG-1-510-RR-06301, NSF CHE-0091975, NSF MRI-
0079750).
1
Supporting Information Available: Copies of H and
13C NMR spectra, as well as experimental procedures and
characterization data for all new compounds. This material
is available free of charge via the Internet at http://pubs.acs.org.
OL060019S
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Org. Lett., Vol. 8, No. 5, 2006