A convenient enantioselective synthesis of (S)-α- trifluoromethylisoserine

Article abstract of DOI:10.1021/jo0505371

This report describes two straightforward synthetic methodologies to obtain α-CF₃-isoserine, a new α,α-disubstituted β-amino acid, from α-(trifluoromethyl)acrylic acid. The routes involve the synthesis of five-membered cyclic sulfates (using su

Full text of DOI:10.1021/jo0505371

A Convenient Enantioselective Synthesis of
(
S)-r-Trifluoromethylisoserine
Alberto Avenoza,* Jes u´ s H. Busto,
Gonzalo Jim e´ nez-Os e´ s, and Jes u´ s M. Peregrina*
Departamento de Qu ı´ mica, Universidad de La Rioja,
Grupo de S ı´ ntesis Qu ı´ mica de La Rioja, U.A.-C.S.I.C.,
E-26006 Logro n˜ o, Spain
FIGURE 1. The R- and â-trifluoromethylated hydroxy amino
acids.
3
2
â- or R-substituted â-AA (â - or â -AA) represent an
important class of compounds because these substituents
favor folded conformations in â-peptides.4 Several
alberto.avenoza@dq.unirioja.es
Received March 16, 2005
c,5
3
synthetic approaches have been described for â -AA, but
2
very few routes have been reported for â -AA and even
fewer on the synthesis of chiral geminally R,R-disubsti-
tuted â-AA (â2 -AA). Consequently, the development of
practical methods for the synthesis of â-AA bearing a
chiral quaternary center in the R-position would be
exceedingly valuable, particularly in cases that bear a
,2
6
CF
3
substituent.7
In connection with our project on restricted hydroxy
8
This report describes two straightforward synthetic meth-
odologies to obtain R-CF3-isoserine, a new R,R-disubstituted
â-amino acid, from R-(trifluoromethyl)acrylic acid. The
routes involve the synthesis of five-membered cyclic sulfates
amino acids, and with the aim of combining the two
aforementioned aspects, we focused our attention on the
synthesis of R-CF -â-AA. Our specific aim was to syn-
thesize derivatives of isoserine due to their implications
as peptidomimetic units and as important targets in the
synthesis of â-lactams and of Taxol analogues (taxoids).
In the case of serine, the asymmetric synthesis of R-CF
Ser11 and of syn- and anti-â-CF
-Ser have been previously
reported. Regarding isoserine, only the asymmetric
3
(
using sulfuryl chloride) or sulfamidates (using the Burgess
9
reagent) from the corresponding chiral diols, which are
obtained by a catalytic asymmetric dihydroxylation (AD)
reaction.
10
3
-
3
12
3
synthesis of both enantiomers of syn- and anti-â-CF -
In recent years, the synthesis of fluorinated organic
compounds (FOC) has emerged as an important field in
organic chemistry because the unique properties of the
isoserine has been published.13 To cover this gap, we
1
report here the enantioselective synthesis of R-CF3-
isoserine 1. Moreover, to the best of our knowledge, there
fluorine atom give rise to certain general characteristics
in FOC. Moreover, it is well known that optically active
FOC exhibit high physiological activity and remarkable
are only two references concerning the introduction of a
CF
A very short method to obtain enantiomerically pure
R-CF -isoserine 1 could make use of the Sharpless
3
group in the R-position of a â-AA14 (Figure 1).
1
physical properties. Among such FOC, trifluorometh-
ylated (CF ) products constitute an important family
3
3
because of the lipophilicity associated with this substitu-
2
(4) (a) Cheng, R. P.; Gellman, S. H.; DeGrado, W. F. Chem. Rev.
001, 101, 3219-3232. (b) Liu, M.; Sibi, M. P. Tetrahedron 2002, 58,
991-8035. (c) Seebach, D.; Beck, A. K.; Bierbaum, D. J. Chem.
ent.
2
In this context, fluorinated analogues of naturally
occurring amino acids have proved to be of great interest.
7
3
Biodiversity 2004, 1, 1111-1239. (d) Seebach, D.; Kimmerlin, T.;
Sebesta, R.; Campo, M. A.; Beck A. K. Tetrahedron 2004, 60, 7455-
7
In the field of amino acids, the study of â-amino acids
506.
(
â-AA) is a topic of constant attention due to the applica-
(
5) Seebach, D.; Abele, S.; Gademann, K.; Guichard, G.; Hintermann,
tions of such compounds in medicinal and peptide chem-
istry as well as molecular recognition. In this respect,
T.; Jaun, B.; Matthews, J. L.; Schreiber, J. V.; Oberer, L.; Hommel,
4
U.; Widmer, H. Helv. Chim. Acta 1998, 81, 932-982.
(
(
6) Abele, S.; Seebach, D. Eur. J. Org. Chem. 2000, 1-15.
7) Kimura, M.; Yamazaki, T.; Kitazume, T.; Kubota, T. Org. Lett.
*
To whom correspondence should be addressed. Fax: +34 941
99655.
1) (a) Ma, J.-A.; Cahard, D. Chem. Rev. 2004, 104, 6119-6146 and
references therein. (b) Mikami, K.; Itoh, Y.; Yamanaka, M. Chem. Rev.
2004, 6, 4651-4654.
2
(8) Avenoza, A.; Busto, J. H.; Cativiela, C.; Corzana, F.; Peregrina,
J. M.; Sucunza, D.; Zurbano, M. M. In Targets in Heterocyclic Systems;
Attanasi, O. A., Spinelli, D., Eds.; Italian Society of Chemistry: Italy,
2002; pp 231-244.
(
2
5
6
004, 104, 1-16. (c) Special issue: ChemBioChem 2004, 5, 557-726.
2) Special issue: Gladysz, J. A.; Curran, D. P. Tetrahedron 2002,
8, 3823-4131.
3) (a) Qiu, X.-L.; Meng, W.-D.; Qing, F.-L. Tetrahedron 2004, 60,
711-6745 and references therein. (b) Kukhar, V. P.; Soloshonok, V.
(
(9) Volonteiro, A.; Bravo, P.; Zanda, M. Org. Lett. 2000, 2, 1827-
1830.
(
(10) Kuznetsova, L.; Ungureanu, I. M.; Pepe, A.; Zanardi, I.; Wu,
X.; Ojima, I. J. Fluorine Chem. 2004, 125, 487-500.
A. Fluorine Containing Amino Acids: Synthesis and Properties;
Wiley: New York, 1995. (c) Horng, J. C.; Raleigh, D. P. J. Am. Chem.
Soc. 2003, 125, 9286-9287. (d) Bravo, P.; Bruch e´ , L.; Pesenti, C.; Viani,
F.; Volonteiro, A.; Zanda, M. J. Fluorine Chem. 2001, 112, 153-162.
3
(11) Synthesis of R-CF -Ser: (a) Bravo, P.; Viani, F.; Zanda, M.;
Soloshonok, V. Gazz. Chim. Ital. 1995, 125, 149-150. (b) Bravo, P.;
Zanda, M.; Zappal a` , C. Tetrahedron Lett. 1996, 37, 6005-6006.
3
(12) Synthesis of â-CF -Ser: Jiang, Z.-X.; Qin, Y.-Y.; Qing, F.-L. J.
(
e) Koksch, B.; Sewald, N.; Hofmann, H.-J.; Burger, K.; Jakubke, H.-
Org. Chem. 2003, 68, 7544-7547 and references therein.
(13) Synthesis of â-CF -isoserine: Jiang, Z.-X.; Qing, F.-L. J. Org.
D. J. Pept. Sci. 1997, 3, 157-167. (f) Koksch, B.; Dahl, C.; Radics, G.;
Vocks, A.; Arnold, K.; Arnhold, J.; Sieler, J.; Burger, K. J. Pept. Sci.
3
Chem. 2004, 69, 5486-5489 and references therein.
(14) (a) Haddad, M.; Vakselman, C. J. Fluorine Chem. 1995, 73, 57-
59. (b) Sekiguchi, T.; Sato, K.; Ishihara, T.; Konno, T.; Yamanaka, H.
Chem. Lett. 2004, 33, 666-667.
2
004, 10, 67-81. (g) Koksch, B.; Quaedflieg, P. J. L. M.; Michel, T.;
Burger, K.; Broxterman, Q. B.; Schoemaker, H. E. Tetrahedron:
Asymmetry 2004, 15, 1401-1407.
1
0.1021/jo0505371 CCC: $30.25 © 2005 American Chemical Society
Published on Web 06/15/2005
J. Org. Chem. 2005, 70, 5721-5724
5721

SCHEME 1. Synthesis of Olefins 2b,c and a
Asymmetric Aminohydroxylation Reaction
SCHEME 2. Sharpless AD Reaction on Olefins
2b,ca
a
t
(
a) AD-mix R, MeSO2NH2, BuOH/H2O (1:1), 0 °C, 24 h, 87%,
ee ) 66% of (R)-4b, 90% of (R)-4c, ee ) 90%; (b) conditions of (a)
with AD-mix â, 87%, ee ) 66% of (S)-4b, 90% of (S)-4c, ee ) 90%.
aminohydroxylation on olefin 2c, we decided to use the
sulfamidate and sulfate protocols to achieve the target
3
R-CF -isoserine. Therefore, the key step in our synthetic
a
(
a) BnOH/TEA or HCl‚HN(OMe)Me/DIEA, Mukaiyama’s re-
routes will involve the Sharpless AD on olefins 2b,c.
As outlined in Scheme 2, olefins 2b,c were subjected
to Sharpless dihydroxylation conditions using AD-mix R
or â to give the mixture of compounds (S)-4b,c and (R)-
agent, CH2Cl2, reflux, 16 h; (b) BnOH or HCl‚HN(OMe)Me, DIEA,
DCC, CH2Cl2, 0 °C, 16 h; (c) (i) phthaloyl chloride, 140 °C; (ii)
HCl‚HN(OMe)Me, Py, CH2Cl2, -20 °C, 4 h; (d) (i) PCl5, CH2Cl2,
5 °C; (ii) HCl‚HN(OMe)Me, Py, CH2Cl2, 0 °C, 2 h; (e) LiOH‚H2O,
K2OsO4‚2H2O (5%), (DHQD)2PHAL (5%), AcNHBr, BuOH/H2O
1.5:1), 0 °C, 24 h, 84%.
2
t
4
b,c in good yields (87% from 2b and 90% from 2c).
(
Nevertheless, the enantioselectivity achieved from 2c
2
1
asymmetric aminohydroxylation15 of 2-(trifluoromethyl)-
acrylic acid derivatives as a key step. We therefore
synthesized two derivatives of commercially available
(90% ee) was better than that from 2b (66% ee).
We
observed that the reactivity or the degree and sense of
the enantioselectivity did not differ from those of similar
nonfluorinated substrates (2-methylacrylic acid deriva-
tives).20 These results are very important, because a
recent review concerning asymmetric catalytic reactions
2
-(trifluoromethyl)acrylic acid (2a) as prochiral fluorine-
containing starting materials: compounds 2b and 2c.
Several coupling methods were tested, and it was found
that the best conditions for the synthesis of olefin 2b
involved the use of Mukaiyama’s reagent (N-methyl-2-
chloropyridinium iodide). This approach gave a yield of
1
b
on fluorinated carbonyl and olefinic compounds de-
scribes several enantioselective reductions, but only one
example of the catalytic enantioselective oxidation of
prochiral fluorine-containing carbonyl compounds or ole-
fins.22 Likewise, these AD reactions on olefins 2b,c
constitute the first examples of non-Michael-type func-
tionalization of these types of substrate, which have been
described as excellent Michael acceptors.23
3
4% accompanied by a 15% yield of racemic Michael
coupling product 3b. In contrast, compound 2c was
obtained in 83% yield along with 8% of racemic Michael
coupling product 3c when DCC was used as the coupling
agent (Scheme 1). We proceeded to attempt the asym-
metric aminohydroxylation reaction on olefin 2c using
the conditions shown in Scheme 1. Under these condi-
tions, all of the starting material was consumed but
aminohydroxylation products were not detected. A mix-
ture of two compounds was obtained: dihydroxylation
product (10%) and the corresponding racemic compound
2
4
Treatment of diol (S)-4c with Burgess reagent gave
the corresponding sulfamidate (S)-5 as a single regio-
isomer25 in 34% yield when the reaction was carried out
at rt. This yield could be improved (51%) by carrying out
the reaction under reflux. Sulfamidate (S)-5 was quan-
3
titatively hydrolyzed in an acidic medium to give R-CF -
isoserine (S)-1 in its hydrochloride form (Scheme 3). In
this way, (S)-1‚HCl was obtained from olefin 2a in four
3
d, which is formed by Michael addition of acetamide on
olefin 2c (Scheme 1).
Recently, we achieved excellent results in the synthesis
of several enantiopure â2 -AA from two kinds of chiral
building blocks. These precursors were five-membered
(
19) (a) Kolb, H. C.; VanNiewenhze, M. S.; Sharpless, K. B. Chem.
,2
Rev. 1994, 94, 2483-2547. (b) Berrisford, D. J.; Bolm, C.; Sharpless,
K. B. Angew. Chem., Int. Ed. Engl. 1995, 34, 1059-1070. (c) Johnson,
R. A.; Sharpless, K. B. In Catalytic Asymmetric Synthesis; Ojima, I.,
Ed.; VCH Publishers: New York, 1993; pp 227-272.
1
6
cyclic R-methylisoserine-derived sulfamidates and R-
methyl-R,â-dihydroxypropanoic acid-derived sulfates.1
These compounds were obtained from chiral 1,2-diols,
which in turn were synthesized by a Sharpless asym-
7,18
(
20) (a) Avenoza, A.; Cativiela, C.; Corzana, F.; Peregrina, J. M.;
Sucunza, D.; Zurbano, M. M. Tetrahedron: Asymmetry 2001, 12, 949-
9
2
53. (b) Bennani, Y. L.; Sharpless K. B. Tetrahedron Lett. 1993, 34,
079-2082.
19
metric dihydroxylation (AD) on the corresponding olefin
using AD-mix R or â.20 Taking into account these facts,
and considering the previous results of asymmetric
(
21) The yield was calculated after column chromatography, and the
enantiomeric excess (ee) was determined by GC-MS (see Supporting
Information).
(
22) Bennani, Y. L.; Vanhessche, K. P. M.; Sharpless, B. Tetrahe-
dron: Asymmetry 1994, 5, 1473-1476.
(15) (a) Sharpless, K. B.; Bruncko, M.; Schlingloff, G. Angew. Chem.,
(23) (a) Colantoni, D.; Fioravanti, S.; Pellacani, L.; Tardella, P. A.
Org. Lett. 2004, 6, 197-200. (b) Sani, M.; Bruch e´ , L.; Chiva, G.;
Fustero, S.; Piera, J.; Volonteiro, A.; Zanda, M. Angew. Chem., Int.
Ed. 2003, 42, 2060-2063.
Int. Ed. Engl. 1997, 36, 1483-1486. (b) Sharpless, K. B.; Tao, B.;
Schlingloff, G. Tetrahedron Lett. 1998, 39, 2507-2510. (c) Song, C. E.;
Oh, C. R.; Roh, E. J.; Lee, S.; Choi, J. H. Tetrahedron: Asymmetry
1
999, 10, 671-674. (d) O’Brien, P. Angew. Chem., Int. Ed. 1999, 38,
(24) (a) Atkins, G. M.; Burgess, E. M. J. Am. Chem. Soc. 1972, 94,
6135-6141. (b) Nicolaou, K. C.; Huang, X.; Snyder, S. A.; Rao, P. B.;
Bella, M.; Reddy, M. V. Angew. Chem., Int. Ed. 2002, 41, 834-838. (c)
Nicolaou, K. C.; Snyder, S. A.; Longbottom, D. A.; Nalbandian, A. Z.;
Huang, X. Chem.-Eur. J. 2004, 10, 5581-5606. (d) Bower, J. F.;
Svenda, J.; Williams, A. J.; Charmant, J. P. H.; Lawrence, R. M.; Szeto,
P.; Gallagher, T. Org. Lett. 2004, 6, 4727-4730.
3
26-329.
(16) Avenoza, A.; Busto, J. H.; Corzana, F.; Jim e´ nez-Os e´ s, G.;
Peregrina, J. M. Chem. Commun. 2004, 980-981.
(17) Avenoza, A.; Busto, J. H.; Corzana, F.; Jim e´ nez-Os e´ s, G.; Par ´ı s,
M.; Peregrina, J. M.; Sucunza, D.; Zurbano, M. M. Tetrahedron:
Asymmetry 2004, 15, 131-137.
(18) Avenoza, A.; Busto, J. H.; Corzana, F.; Garc ´ı a, J. I.; Peregrina,
(25) Mel e´ ndez, R. E.; Lubell, W. D. Tetrahedron 2003, 59, 2581-
2616.
J. M. J. Org. Chem. 2003, 68, 4506-4513.
5722 J. Org. Chem., Vol. 70, No. 14, 2005

SCHEME 3. aSynthesis of r-CF
3
-Isoserine (S)-1 via
Sulfamidate
a
(
a) Burgess reagent, THF, reflux, 1 h, 51%; (b) 6 N HCl (aq),
1
00 °C, 12 h, 90%.
SCHEME 4. Synthesis of r-CF
3
-Isoserine (S)-1 via
a
Sulfates
FIGURE 2. Lowest energy TS calculated with (S)-6c and (S)-
d and azide anion.
6
SCHEME 5. Determination of Absolute
Configuration of â2 -AA
,2
a
a
(a) (i) LiOH‚H2O, H2O/MeOH (1:3), 25 °C, 2 h; (ii) AcCl, MeOH,
reflux, 12 h, 85%; (b) SO2Cl2, TEA, CH2Cl2, -20 °C, 1 h, 81% of
c, 78% of 6d; (c) (i) NaN3, DMF, 70 °C, 12 h, (ii) 20% H2SO4 (aq)/
6
CH2Cl2 (1:1), 25 °C, 10 h, 99% of 7c, 90% of 7d; (d) (i) LiOH‚H2O,
H2O/MeOH (1:3), 25 °C, 2 h; (ii) H2, Pd-C, MeOH, 25 °C, 48 h,
a
(
a) (i) AcCl, MeOH, reflux, 10 h; (ii) N-(tosyl)phenylalaninyl
9
5% from 7c.
chloride, DIEA, CH2Cl2, 25 °C, 14 h, 88%.
steps in 34% yield. This moderate overall yield is mainly
due to the modest yield of the sulfamidate generation and
led us to develop a new synthetic strategy involving the
use of chiral sulfates as building blocks followed by
regioselective nucleophilic opening with the azide ion.
The use of sulfuryl chloride allowed the preparation
with good yields of two chiral gem-disubstituted sulfates
ion. All ground state and transition state (TS) geometries
were located using hybrid DFT (B3LYP)26 and the
2
7
6-31+G(d) basis sets implemented in Gaussian 98.
Solvent effects were taken into account through single
28
point energy calculations with the IPCM method at the
B3LYP/6-31+G(d) level using the dielectric permittivity
of DMF (38.25), which was the solvent used in the
experiments.
[(S)-6c,d] from diols (S)-4c,d (Scheme 4). This last chiral
diol [(S)-4d] was obtained by basic hydrolysis of the
amide group in diol (S)-4c and subsequent esterification
with acetyl chloride in MeOH. Furthermore, the ring-
opening reaction of these sulfates with sodium azide in
DMF and subsequent acid hydrolysis surprisingly gave,
in both cases, an exclusive regioisomer: the â-azido
R-alcohols (S)-7c,d. These surprising results regarding
Two competitive S 2 pathways were examined: azide
attack at the “free” (f) secondary position and at the
N
“hindered” (h) quaternary position. Each TS was located
in the two possible carbonyl conformations, syn (s) and
anti (a) with regard to the CF group. This led to four
3
possible TS for each sulfate, and these are denoted as
TSc-d_af, TSc-d_ah, TSc-d_sf, and TSc-d_sh, respec-
tively. Several geometrical features of the minimum
energy TS are shown in Figure 2. As far as substrates
(S)-6c and (S)-6d are concerned, the TS obtained for the
17
our previous work agree with those reported by Jiang
1
2,13
and Qing’s
and are probably due to the effect of the
CF group. Compounds (S)-7c,d were subjected to hy-
3
drolysis in a basic medium to give the corresponding
carboxylic acid derivatives after neutralization. Subse-
quent hydrogenation using MeOH as solvent and Pd/C
S 2 reaction on the “free” position (TSc_sf and TSd_sf,
N
respectively) were considerably lower in energy (4.82 and
5.94 kcal/mol more stable) than those resulting from
as a catalyst quantitatively provided R-CF
S)-1 (seven steps, 51% from 2a) (Scheme 4).
The ee (90%) and the absolute configuration of R-CF
3
-isoserine
(
(26) Becke, A. D. J. Chem. Phys. 1993, 98, 1372-1377.
(
27) Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.;
3
-
Robb, M. A.; Cheeseman, J. R.; Zakrzewski, V. G.; Montgomery, J. A.,
Jr.; Stratmann, R. E.; Burant, J. C.; Dapprich, S.; Millan, J. M.;
Daniels, A. D.; Kudin, K. N.; Strain, M. C.; Farkas, O.; Tomasi, J.;
Barone, V.; Cossi, M.; Cammi, R.; Mennucci, B.; Pomelli, C.; Adamo,
C.; Clifford, S.; Ochterski, J.; Petersson, G. A.; Ayala, P. Y.; Cui, Q.;
Morokuma, K.; Malick, D. K.; Rabuck, A. D.; Raghavachari, K.;
Foresman, J. B.; Cioslowski, J.; Ortiz, J. V.; Stefanov, B. B.; Liu, G.;
Liashenko, A.; Piskorz, P.; Komaroni, I.; Gomperts, R.; Martin, R. L.;
Fox, D. J.; Keith, T.; Al-Laham, M. A.; Peng, C. Y.; Nanayakkara, A.;
Gonz a´ lez, C.; Challacombe, M.; Gill, P. M. W.; Johnson, B.; Chen, W.;
Replogle, E. S.; Pople, J. A. Gaussian 98, revisions A.7 and A.11;
Gaussian, Inc.: Pittsburgh, PA, 1998.
isoserine (S)-1 was unambiguously determined by trans-
formation of the methyl ester derivative of this â2,2-AA,
obtained by esterification with acetyl chloride in MeOH,
into the dipeptide 8, a chiral derivative with two stereo-
genic centers, whose absolute configuration was found
to be (S,S) by X-ray analysis (see Supporting Information)
of the corresponding monocrystals (Scheme 5).
A theoretical study was undertaken in an effort to
understand the behavior of this kind of cyclic R-CF
3
-
(
28) Foresman, J. B.; Keith, T. A.; Wiberg, K. B.; Snoonian, J.;
sulfate in the ring-opening S 2 reaction with the azide
N
Frisch, M. J. J. Phys. Chem. 1996, 100, 16098-16104.
J. Org. Chem, Vol. 70, No. 14, 2005 5723

nucleophilic attack at the “hindered” position (TSc_ah
and TSd_ah, respectively). This situation is in agreement
with the experimentally observed regioselectivity. More-
over, these results confirm the conclusion established by
Uneyama et al. on the prevention of nucleophilic substi-
R-(trifluoromethyl)acrylic acid and combines the Sharp-
less AD reaction for the preparation of chiral diols with
the generation of cyclic sulfamidates or cyclic sulfates.
Acknowledgment. We thank the Ministerio de
Ciencia y Tecnolog ´ı a (project PPQ2001-1305), the Min-
isterio de Educaci o´ n y Ciencia (Ramon y Cajal contract
of J.H.B.), and the Universidad de La Rioja (project
API-04/02, doctoral fellowship of G.J.-O.).
3
tution in the R-position with respect to a CF group. This
effect was attributed to the negatively charged nature
of this group, which exhibits strong repulsive interactions
toward negatively charged nucleophiles.29
In summary, we have developed a simple methodology
2,2
to obtain a new class of optically active â -AA with a
CF -containing quaternary carbon center; R-CF -iso-
serine. The route starts from commercially available
Supporting Information Available: Experimental de-
tails, spectroscopic characterization of all compounds, crystal
structure data, as well as computational energy data and
coordinates for the structures. This material is available free
of charge via the Internet at http://pubs.acs.org.
3
3
(
29) (a) Katagiri, T.; Uneyama, K. Chirality 2003, 15, 4-9. (b)
Shimizu, M.; Hiyama, T. Angew. Chem., Int. Ed. 2005, 44, 214-231.
JO0505371
5724 J. Org. Chem., Vol. 70, No. 14, 2005