A Convergent Synthesis of Enantiopure Open-Chain, Cyclic, and Fluorinated α-Amino Acids

Article abstract of DOI:10.1021/acs.orglett.6b00656

A radical based synthesis of a broad variety of protected enantiopure α-amino acids, including fluorinated derivatives, is described. The radical addition furnishes naturally latent mercapto-α-amino acids ideally equipped for native chemical ligation.

Full text of DOI:10.1021/acs.orglett.6b00656

Letter
pubs.acs.org/OrgLett
A Convergent Synthesis of Enantiopure Open-Chain, Cyclic, and
Fluorinated α‑Amino Acids
Shi-Guang Li, Fernando Portela-Cubillo, and Samir Z. Zard*
̀
Laboratoire de Synthese Organique, CNRS UMR 7652 Ecole Polytechnique, 91128 Palaiseau, Cedex, France
S
* Supporting Information
ABSTRACT: A radical based synthesis of a broad variety of
protected enantiopure α-amino acids, including fluorinated
derivatives, is described. The radical addition furnishes
naturally latent mercapto-α-amino acids ideally equipped for
native chemical ligation.
atural and unnatural α-amino acids are extensively used
Scheme 2. Xanthate Addition to Protected Vinyl Glycine
N
in various sectors of the agrochemical and pharmaceutical
industries, and as structural units or chiral catalysts in organic
synthesis and in ligand design.1 Not surprisingly, great efforts
for the development of synthetic routes to this critically
important class of compounds have spanned more than a
century and have involved all types of chemical reactions. One
approach, which has received almost no attention, is the radical
addition to vinyl glycine. While protected vinyl glycine has
occasionally served as a starting material for synthesis, the few
reports of radical additions concern mainly the addition of
phosphorus centered radicals,2 with only one report of addition
of thiols,2g and another of stannanes.2c There appears to be a
single case of addition of a carbon radical, namely the copper-
mediated addition of ethyl difluoroiodoacetate to derivative 1
described by Taguchi in 1990 (Scheme 1).3a This reaction was
appear as paradoxical constraints, namely considerably
extending the lifetime of the intermediate radicals even in a
concentrated medium, yet avoiding unwanted radical−radical
interactions, and thus provides a convenient solution to the
longstanding problem of intermolecular C−C bond formation
on unactivated alkenes.4 In case of success, this strategy could
also be used to access either natural or unnatural protected β-
mercapto-α-amino acids 8. These would be ideal substrates for
the so-called native chemical ligation, an ingenious process for
the coupling of α-amino acids and peptides in an aqueous
medium.5
Protected vinyl glycine 1 is readily prepared in good yield in
a straightforward manner starting from L-methionine (Scheme
2). In our hands, diphenyl ether proved a more reliable medium
for the thermolysis of sulfoxide 4, allowing the obtention of
protected vinyl glycine 1 in reproducible yield and quality. In
the event, we were pleased to find that the radical addition of
various xanthates 5a−j proceeded smoothly with essentially no
complications from the labile tertiary hydrogen atom, as
demonstrated by the examples displayed in Scheme 3.
The corresponding adducts 6a−j were reductively dexanthy-
lated into sulfur-free protected α-amino acids 7a−j using
Barton’s hypophosphorus based method.6 This operation also
simplified the spectroscopic characterization by removing one
chiral center. That no serious complications were encountered
Scheme 1. Radical Addition to Protected Vinyl Glycine
reexamined later by Hallinan at Pfizer, who could only secure a
32% yield of reduced adduct 2 and had to use ultrapure DMF
as the solvent. To quote from their article: “This reaction is
somewhat capricious and the yields are variable. Burton
chemistry was attempted with results similar to that described
for Taguchi chemistry.”
The main difficulty is the presence of a labile hydrogen,
highlighted in red in structure 1, which is simultaneously
tertiary, allylic, and geminal to both an ester and a carbamate
nitrogen. Its abstraction by a radical species in the medium
would generate a highly stabilized capto-dative carbon radical 3,
which can evolve into a number of unwanted side products and
act as a chain breaker in the case of a radical chain.
With these apprehensions in mind, we decided to test the
xanthate addition to derivative 1 as a possible route to
protected enantiopure α-amino acids 7 via adducts 6 (Scheme
2), as well as to cyclic and fluorinated congeners. The
degenerate xanthate addition−transfer satisfies what may
Received: March 7, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b00656
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Letter
first, oxazolone 12, was prepared according to the procedure of
Scheme 3. Radical Additions to Protected Vinyl Glycine 1
Williams (Scheme 5).9 No racemization can take place in this
Scheme 5. Synthesis of Protected Proline Derivatives
from untoward abstraction of the normally labile tertiary
hydrogen in vinyl glycine 1 to give radical 3 is remarkable and
presumably due to steric shielding from any incoming radical
by the surrounding groups. Steric repulsions between these
same groups could also prevent the molecule from adopting the
conformation that provides radical 3 with maximum stabiliza-
tion, which is simultaneous and complete overlap of the SOMO
of the carbon radical with both π-orbitals of the vinyl group and
the carbonyl of the ester as well as with the nonbonding orbital
of the nitrogen.
Inspection of the examples in Scheme 3 provides an idea of
the broad variety of functional groups that can be introduced,
from the naked tert-butyl group in 7c to the reactive α-
chloroketone in 7g. Addition products 7f and 7i contain a
masked α-keto aldehyde and a protected α-amino ketone motif
respectively (PhthN = phthalimide). Compound 6j is a masked
β-mercapto derivative of ornithine suitable for native chemical
ligation; it undergoes reductive dexanthylation to furnish 7j, a
protected form of ornithine itself.
case, and the desired additions proceeded smoothly (Scheme
5). Nevertheless, we were fortunate that the trichloromethyl
group did not interfere with the radical process. Polyhalo-
genated compounds can undergo halide atom transfers (e.g.,
the Kharasch reaction), but chlorine atom transfer in this case
must be significantly slower than the exchange of the xanthate
group. We tested the deprotection on product 14d. Thus,
reaction with NaOMe destroyed the aminal ring and furnished
N-formyl intermediate 15 through expulsion of a chloroform
molecule. Exposure to methanolic HCl then delivered proline
derivative 16 in 62% overall yield.
The second approach started with Boc protected allyl proline
18, prepared in a straightforward manner from compound 12
(Scheme 6). This more conventionally protected proline based
alkene also reacted cleanly with a similar assortment of
xanthates to give the corresponding adducts as well as the
desulfurized derivatives (Scheme 6). It is worth pointing out
Even though the neutral conditions of the radical addition
more or less ensures that no unwanted racemization at the α-
amino acid carbon would take place, this key aspect of our
approach was confirmed by preparing the Mosher amide 10
from protected ornithine derivative 7j and comparing its NMR
spectrum with that of the corresponding Mosher amide
obtained from commercial racemic ornithine (Scheme 4;
Scheme 6. Synthesis of Boc-Protected Proline Derivatives
Scheme 4. Determination of the Enantiomeric Purity
MTPA = α-methyl-α-trifluoromethyl phenylacetic acid).7 This
clearly demonstrated that no loss of enantiomeric purity had
occurred, neither in the radical addition nor in the subsequent
ionic transformations leading to Mosher amide 10 (ee = 94%;
see Supporting Information for details).
Among the essential amino acids, proline occupies a very
special position. Its rigid structure has important implications
on the tertiary and quaternary structures of proteins and on
their biological activity.8 We approached the synthesis of
proline derivatives using two related olefinic substrates. The
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compound 20e, an unusual protected hybrid of proline and lysine.
Another product of interest is adduct 20g, a masked form of
aldehyde 21.
Finally, we exploited the addition of xanthates to access
fluorinated amino acids. These have gained widespread
importance as building blocks with improved biophysical,
chemical, and biological properties,10 and as reporter units in
the analysis of peptides and proteins by 19F NMR spectrosco-
py.11 In this respect, 5,5,5-trifluoronorvaline 22 and 6,6,6-
trifluoronorleucine 23 (Scheme 7) were found to be useful
(S)-α-Tfm-amino acids (Tfm = trifluoromethyl), a class of
fluorinated amino acids that is rapidly gaining in importance.19
The series of examples assembled in Scheme 8 confirms the
viability of this approach.
Scheme 8. Synthesis of α-Tfm α-Amino Acids
Scheme 7. Synthesis of Trifluoromethyl-Substituted α-
Amino Acids
One particularly important case is that of compound 37d,
which is in fact a masked (S)-α-Tfm-lysine. This modified
amino acid has not been reported in open literature, but
racemic carboxamide 38 has been described twice as an
intermediate in the synthesis of α-Tfm-ornithine 39 (Scheme
9) through a Hoffmann-type degradation of the carboxamide
Scheme 9. A 6,6,6-Trifluoro-α-Tfm-Norleucine Analog
modifiers of biologically active peptides.12 Both of these
compounds are commercially available but are exceedingly
expensive, reflecting complex multistep syntheses.13 The
present modular approach allows the easy introduction of
fluorinated groups, either on the xanthate or on the amino acid
alkene partner, or on both. This opens up vast possibilities,
especially that the fluorinated amino acids can be equipped with
the necessary auxiliary mercapto group needed for the native
chemical ligation if so desired.
As shown in Scheme 7, addition of xanthate 24 to alkenes
1,14 12, and 18 furnished the corresponding adducts 25, 27,
and 29, which were then reductively dexanthylated. In the case
of xanthate 27, the reduced material 28 was heavily
contaminated with 1-octadecanol arising from the normal
hydrolytic decomposition of the labile phosphorus xanthate
coproduced under the Barton reduction. We therefore resorted
to another method involving the use of stoichiometric amounts
of lauroyl peroxide in isopropanol as solvent and reductant.15
No octadecanol is formed under these conditions, and the
desired reduced product 28 could be isolated pure in 66% yield.
Finally, the addition of xanthate 3116 to protected vinyl glycine
1 highlights the convenient access to trifluoromethyl ketone 33,
which could then be exploited in a short route to trifluoro-
methylpipecolate 34 that compares favorably with the earlier
literature synthesis.17
function.20 Interestingly, racemic difluoromethyl-ornithine 40
(eflornithine) is currently in clinical use for the treatment of
sleeping sickness.21 This actual application further underscores
the vast therapeutic potential of fluorinated amino acids. The
reaction of S-trifluoromethyl xanthate 41 with allylmor-
pholinone 35 pictured in Scheme 9 represents an example of
a fluorinated xanthate undergoing addition to a fluorinated
alkene partner. Adduct 42 corresponds to a masked form of
6,6,6-trifluoro-α-Tfm-γ-mercaptonorleucine 44, whereas its
reduced parent derivative 43 is protected 6,6,6-trifluoro-α-
Tfm-norleucine 45. Both are so far unknown substances that
correspond to α-trifluoromethyl analogs of 6,6,6-trifluoro-
norleucine, reported by Ojima in 1989.13
In summary, we have described a modular, flexible, and
cheap synthesis of a variety of enantiopure α-amino acids. They
represent a potentially large pool of readily available chiral,
nonracemic, building blocks for use in the synthesis of natural
products (especially alkaloids), for the introduction of diversity
in medicinal chemistry, and for the construction of ligands for
transition metals. The intermolecular radical addition to
To illustrate the variant where the alkene is the fluorine-
bearing partner, we prepared allylmorpholinone 35 from
commercially available D-2-phenylglycine according to the
procedure of Brigaud.18 Radical additions to this olefin lead to
C
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protected vinyl glycine 1 without complications from the labile
tertiary hydrogen is indeed remarkable. The radical addition
leads naturally to precursors of mercapto amino acids, which
are key substrates in the native chemical ligation technology.
ASSOCIATED CONTENT
* Supporting Information
■
S
(8) Sewald, N.; Jakubke, H.-D. Peptides: Chemistry and Biology; Wiley-
VCH: Weinheim, 2002.
(9) Artman, G. D.; Rafferty, R. J.; Williams, R. M. Org. Synth. 2009,
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b00656.
86, 262.
Experimental procedures, full spectroscopic data, and
(10) For selected reviews, see: (a) Fluorine Containing Amino Acids -
Synthesis and Properties; Kukhar, V. P., Soloshonok, V. A., Eds.; Wiley:
Chichester, 1995. (b) Purser, S.; Moore, P. R.; Swallow, S.;
Gouverneur, V. Chem. Soc. Rev. 2008, 37, 320. (c) Smits, R.;
Cadicamo, C. D.; Burger, K.; Koksch, B. Chem. Soc. Rev. 2008, 37,
1727. (d) Nie, J.; Guo, H.-C.; Cahard, D.; Ma, J.-A. Chem. Rev. 2011,
111, 455. (e) Acena, J. L.; Sorochinsky, A. E.; Soloshonok, V. A.
Synthesis 2012, 44, 1591. (f) Ojima, I. J. Org. Chem. 2013, 78, 6358.
(11) (a) Salwiczek, M.; Nyakatura, E. K.; Gerling, U. I. M.; Ye, S.;
Koksch, B. Chem. Soc. Rev. 2012, 41, 2135. (b) Marsh, E. N. G. Acc.
Chem. Res. 2014, 47, 2878.
1
copies of H and 13C NMR for all new compounds
(PDF)
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: samir.zard@polytechnique.edu.
Notes
The authors declare no competing financial interest.
(12) Fluorine in Medicinal Chemistry and Chemical Biology; Ojima, I.,
Ed.; Wiley-Blackwell: Chichester, 2009; p 411.
ACKNOWLEDGMENTS
■
(13) Ojima, I.; Kato, K.; Nakahashi, K. J. Org. Chem. 1989, 54, 4511.
The catalog prices for racemic 5,5,5-trifluoronorvaline are in excess of
400$/g; for racemic 6,6,6-trifluoro-norleucine, the prices are in excess
of 200$/g.
(14) Li, S.-G.; Zard, S. Z. Org. Lett. 2013, 15, 5898.
(15) Liard, A.; Quiclet-Sire, B.; Zard, S. Z. Tetrahedron Lett. 1996, 37,
We thank the China Scholarship Council and Ecole
Polytechnique for scholarships to S.-G. L. and F. P.-C.,
respectively, and Nicolas Legrand and Juan-Carlos Ortiz-Lara
(Ecole Polytechnique) for preliminary experiments.
5877.
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