Stereodivergent Approach to β-Hydroxy α-Amino Acids from C2-Symmetrical Alk-2-yne-1,4-diols

Article abstract of DOI:10.1021/ol0270428

(Matrix Presented) A new stereodivergent route to erythro- and threo-β-substituted serines from a common C₂-symmetrical alk-2-yne-1,4-diol is described. Stereocontrol in such an acyclic system is achieved by taking advantage of symmetry. Stereo

Full text of DOI:10.1021/ol0270428

ORGANIC
LETTERS
2002
Vol. 4, No. 25
4511-4514
Stereodivergent Approach to â-Hydroxy
r-Amino Acids from C -Symmetrical
2
Alk-2-yne-1,4-diols
Marta Amador, Xavier Ariza,* Jordi Garcia,* and Sara Sevilla
Departament de Qu´ımica Orga`nica, UniVersitat de Barcelona, Mart´ı i Franque`s 1,
08028 Barcelona, Catalonia, Spain
xariza@qo.ub.es
Received October 7, 2002
ABSTRACT
A new stereodivergent route to erythro- and threo-â-substituted serines from a common C -symmetrical alk-2-yne-1,4-diol is described.
2
Stereocontrol in such an acyclic system is achieved by taking advantage of symmetry. Stereoselective alkyne reduction to either (Z)- or
(E)-olefin allows selection of the stereochemistry of r-carbon in the final amino acid by using a Pd(0)-catalyzed process. This strategy has
been applied to the synthesis of (2S,3S)-3-hydroxyleucine.
â-Hydroxy R-amino acids are structural components of many
complex natural products with interesting pharmacological
properties.1 For example, some of them are found in peptides
possessing antibiotic or immunosuppressant activities.2 Fur-
thermore, these functionalized amino acids have also been
used as intermediates in asymmetric synthesis of numerous
compounds,3 including â-lactames.4 As a result of their major
significance in biological systems, a number of elegant
stereoselective approaches have been described for their
preparation.5 These strategies include some catalytic pro-
cesses (viz. Sharpless AD and AE,6 aldol reactions,7 catalytic
hydrogenations,8 or enzymatic methods9).
Although most of these catalytic methods afford threo-
â-hydroxy R-amino acids in good yields and selectivity,
reliable procedures that lead to either erythro or threo isomers
proved to be elusive.10 Herein, we report an efficient method
for a selective preparation of both diastereoisomers from a
common precursor, a C2-symmetrical alk-2-yne-1,4-diol (1).
As we have recently reported, such diols can be readily
available by stereoselective reduction of the parent acetylenic
diketones11 or by stereoselective addition of alk-1-yn-3-ols
to aldehydes.12
The key features of our synthesis (Scheme 1) are (i) a
selective transformation to the corresponding (E)- or (Z)-
allylic dicarbamates (4 or 5); (ii) desymmetrization and
stereoselective conversion to either trans- or cis-oxazolidi-
nones (6 and 7, respectively) by a Pd(0)-catalyzed allylic
alkylation; and (iii) oxidative cleavage of the double bond
and final deprotection to afford the selected â-substituted
serines. As far as the stereoselectivity is concerned, the
configuration of the starting diols would determine the
â-carbon configuration of the final product. On the other
(1) Barrett G. C. Chemistry and Biochemistry of Amino Acids; Chapman
and Hall: London, 1985.
(2) (a) Nagarajan, R. Glycopeptide Antibiotics; Marcel-Dekker: New
York, 1994. (b) See also ref 2 in: Blaskovich, M. A.; Evindar, G.; Rose,
N. G. W.; Wilkinson, S.; Lou, Y.; Lajoie, G. A. J. Org. Chem. 1998, 63,
3631-3646.
(3) Coppola, G. M.; Schuster, H. F. Asymmetric Synthesis. Construction
of Chiral Molecules Using Amino Acids. Wiley: New York, 1987.
(4) (a) Miller, M. J. Acc. Chem. Res. 1986, 19, 49-56. (b) Labia, R.;
Morin, C. J. Antibiot. 1984, 37, 1103-1129. (c) Floyd, D. M.; Fritz, A.
W.; Pluscec, J.; Weaver, E. R.; Cimarusti, C. M. J. Org. Chem. 1982, 47,
5160-5167.
(5) (a) Williams, R. M. Synthesis of Optically ActiVe R-Amino Acids;
Pergamon Press: Oxford, 1989. (b) Duthaler, R. O. Tetrahedron 1994, 50,
1539-1650. (c) Chapter 8 in ref 1.
10.1021/ol0270428 CCC: $22.00 © 2002 American Chemical Society
Published on Web 11/20/2002

Scheme 1
hand, we expected that the configuration of the R-carbon
π-allyl complex (III and IV, respectively). Then, the
intramolecular cyclization would afford preferentially two
diastereoisomers: the observed (E)-trans-oxazolidinone 6
and the isomeric (Z)-cis-oxazolidinone 8. In general, the (E)-
trans isomer seems to be favored by sterical interactions not
only on the π-allyl complexes but also on the ionization or
cyclization transition state. However, when R is a smaller
group (i.e., methyl), such interactions are less important, and
in fact, a mixture of 6d and 8d is obtained (Table 1, entry
4).
could be selected by an appropriate stereoselective alkyne
reduction.13 Thus, (E)-unsaturated diols (4) would afford
trans-oxazolidinones (6), whereas (Z)-olefins (5) would give
access to cis-oxazolidinones (7), which are direct precursors
of the â-substituted serines.
Our first efforts were directed to the cyclization of (E)-
allylic alcohols. Thus, diol 2a was treated with 2.5 equiva-
lents of tosyl isocyanate in THF at room temperature to
afford the transient dicarbamate 4a, which was converted in
situ to the oxazolidine 6a in a Pd(0)-catalyzed process (Pd2-
dba3‚CHCl3/(iPrO)3P).14 As expected, only the (E)-trans-
oxazolidine 6a isomer was detected.15 The same behavior
was observed for other diols, which also afforded a single
diastereoisomer (6)16 (Table 1, entries 1-3).
Scheme 2
Table 1. Pd(0)-Catalyzed Cyclization of Diols 2 and 3a
entry
diol
R
yieldb
product
dr (%)c
1
2
3
4
5d,e
6e,f
7d
2a
2b
2c
2d
3b
3c
3d
cyclohexyl
isopropyl
pentyl
methyl
isopropyl
pentyl
70%
85%
75%
93%
70%
75%
89%
6a
6b
6c
6d
7b
7c
7d
>95:5
>95:5
>95:5
58:42
>95.5
>95:5
90:10
methyl
a Typical conditions: 2.5 equiv of TsNCO, 4 mol % Pd2dba3‚CHCl3,
24 mol % P(OiPr)3. b Isolated yield. c Determined by 1H NMR analysis.
d Dicarbamates 5b and 5d were first isolated and then cyclized in CH3CN.17
e Catalyst load: 6-12 mol % Pd2dba3‚CHCl3 and 36-72 mol % P(OiPr)3.
f Performed in 1:1 THF/CH3CN.
The origin of such a remarkable acyclic stereoselection is
based on the symmetry properties of the substrate (Scheme
2). Pd can be complexed unequally to both diastereotopical
faces of the olefin (complexes I or II), but when these
complexes ionize, each one can form initially18 a single
4512
Org. Lett., Vol. 4, No. 25, 2002

A similar analysis for (Z)-allylic dicarbamates 5 (Scheme
3) can be performed. In contrast to the (E)-isomer, in this
lead to two possible π-allyl intermediates (VI or VII) where
again one could be favored over the other by sterical
constraints. Interestingly, the expected preferred isomer
would be the (E)-cis-oxazolidinone 7. According to this
prediction, when dicarbamate 5b was submitted to our
conditions, only the desired isomer (7b) was obtained (entry
5).19 Similarly, dicarbamate 5c afforded stereoselectively the
expected (E)-cis-oxazolidinone (7c). Only when the sterically
less hindered dicarbamate 5d was used, was the minor isomer
9d detected in a 90:10 ratio.
Scheme 3
The methodology can also be applied to meso-diols 10
and 11 (Table 2) in good yields and with high diastereo-
Table 2. Pd(0)-Catalyzed Cyclization of meso-Diolsa
entry
diol
R
yield
product
dr (%)b
1c
2c
3c
4
5
6
10a
10c
10d
11a
11c
11d
cyclohexyl
pentyl
methyl
cyclohexyl
pentyl
methyl
82%
68%
86%
96%
69%
84%
7a
7c
7d
6a
6c
6d
>95:5
>95:5
90:10d
>95.5
>95:5
93:7e
a Typical conditions: 2.5 equiv of TsNCO, 4 mol % Pd2dba3‚CHCl3,
24 mol % P(OiPr)3. b Determined by 1H NMR analysis. c Dicarbamate was
first isolated and then cyclized in CH3CN. d Minor isomer 9d. e Minor
isomer 8d.
selectivities. In the case of diols 10 (entries 1-3), both faces
are enantiotopical and the diastereoselection occurs after the
complexation step. As a result, oxazolidinones 7 were
obtained as the major diastereoisomers. Obviously, as achiral
palladium ligands are used, a racemic product is obtained.
Alternatively, diols 11 afforded (E)-trans-oxazolidinones 6
(entries 4-6) through a mechanism where we assumed that
the complexation is now the diastereoselective process,
whereas ionization is an enantioselective one.
Transformation of oxazolidinones 6 and 7 into acids 12
and 13, respectively, was successfully accomplished by
ozonolysis followed by oxidation of the crude aldehyde with
NaClO220 without loss of stereochemical purity (Scheme 4).
This two-step process gave better yields than direct olefin
cleavage with RuCl3.21
case only a single olefin complex (V) is possible since both
alkene faces are homotopical. The ionization process could
(6) See, for example: (a) Shao, H.; Goodman, M. J. Org. Chem. 1996,
61, 2582-2583. (b) Jung, M. E.; Jung, Y. H. Tetrahedron Lett. 1989, 30,
6637-6640. (c) Schmidt, U.; Respondek, M.; Lieberknecht, A.; Werner,
J.; Fischer, P. Synthesis 1989, 256-261.
(7) (a) MacMillan, J. B.; Molinski, T. F. Org. Lett. 2002, 4, 1883-1886.
(b) Horikawa, M.; Busch-Petersen, J.; Corey, E. J. Tetrahedron Lett. 1999,
40, 3843-3846. (c) Ito, Y.; Sawamura, M.; Hayashi, T. J. Am. Chem. Soc.
1986, 108, 6405-6406.
(8) (a) Noyori, R.; Ikeda, T.; Ohkuma, T.; Widhalm, M.; Kitamura, M.;
Takaya, H.; Akutagawa, S.; Sayo, N.; Saito, T.; Taketomi, T.; Kumobayashi,
H.; J. Am. Chem. Soc. 1989, 111, 9134-9135. (b) Genet, J. P.; Pinel, C.;
Mallart, S.; Juge, S.; Thorimbert, S.; Laffitte, J. A. Tetrahedron: Asymmetry
1991, 2, 555-567.
(9) Kimura, T., Vassilev, V. P.; Shen, G.-J.; Wong, C.-H. J. Am. Chem.
Soc. 1997, 119, 11734-11742.
(10) Some remarkable exceptions are: (a) Evans, D. A.; Janey, J. M.;
Magomedov, N.; Tedrow, J. S. Angew. Chem., Int. Ed. 2001, 40, 1884-
1888. (b) Kuwano, R.; Okuda, S.; Ito, Y. J. Org. Chem. 1998, 63, 3499-
3503. (c) Sunazuka, T.; Nagamitsu, T.; Tanaka H.; Omura, S.; Sprengeler,
P. A.; Smith A. B. III. Tetrahedron Lett. 1993, 34, 4447-4448.
(11) Bach, J.; Berenguer, R.; Garcia, J.; Loscertales, T.; Manzanal, J.;
Vilarrasa, J. Tetrahedron Lett. 1997, 38, 1091-1094.
(12) Amador, M.; Ariza, X.; Garcia, J.; Ortiz, J. Tetrahedron Lett. 2002,
43, 2691-2694.
(13) Allylic diols 2 and 3 were easily obtained from acetylenic diols 1
by LiAlH4 reduction and partial hydrogenation (H2, Lindlar catalyst, EtOAc),
respectively.
(15) The stereochemistry was assigned by NOE experiments and spectral
data comparison with similar oxazolidinones: Kimura, M.; Tanaka, S.;
Tamaru, Y. Bull. Chem. Soc. Jpn. 1995, 68, 1689-1705.
(16) HPLC analysis of 6b derived from 2b (>99% ee) showed a single
stereoisomer on a chiral column (Chiralcel OD-H, 9:1 hexane/2-propanol,
0.5 mL/min, t(-) ) 12.7 min, t(+) ) 16.3 min).
(17) Acetonitrile improved the reaction rates and stereoselectivity.
(18) Both π-allyl complexes are amenable to π-σ-π isomerization.
(19) HPLC analysis of 7b on a Chiralcel OD-H column showed a single
enantiomer (9:1 hexane/2-propanol, 0.5 mL/min, t(+) ) 16.6 min, t(-) )
21.1 min).
(14) For related cyclizations, see: (a) Hayashi, T.; Yamamoto, A.; Ito,
Y. Tetrahedron Lett. 1987, 28, 4837-4840. (b) Trost, B. M.; Van Vranken,
D. L. J. Am. Chem. Soc. 1990, 112, 1261-1263.
(20) Dalcanale, E.; Montanari, F. J. Org. Chem. 1986, 51, 567-569.
Org. Lett., Vol. 4, No. 25, 2002
4513

Scheme 4a
Scheme 5a
a Reaction conditions: (i) Na/Naphthalene (5 equiv); (ii) ref 23b.
â-hydroxy R-amino acids series that takes advantage of the
C2-symmetrical properties of our starting material. Further-
more, we have demonstrated that cyclization of dicarbamates
derived from acyclic alk-2-ene-1,4-diols can be stereoselec-
tive. In this sense, it has been possible to force the cyclization
toward the more sterically congested cis-4,5-disubstituted
oxazolidinones.
a Reaction conditions: (i) O3/CH2Cl2; (ii) Me2S; (iii) NaClO2,
H2O2, NaH2PO4, CH3CN-H2O.
Finally, compound 13b was detosylated under reductive
conditions (Na/naphthalene)22 to afford a known compound
14b that can be hydrolyzed to the free â-hydroxyleucine23
(Scheme 5).
In summary, we have developed a new catalytic, stereo-
divergent approach to both erythro- and threo-protected
Acknowledgment. This work has been supported by the
Ministerio de Educacio´n y Cultura (PB98-1272, DGESIC)
and Direccio´n General de Recerca, Generalitat de Catalunya
(2000SGR00021). We also thank the Universitat de Barce-
lona for doctorate studentships to M.A. and J.O. and
Professor J. Vilarrasa for reading the draft.
(21) Carlsen, H. J.; Katsuki, T.; Martin, V. S.; Sharpless, K. B. J. Org.
Chem. 1981, 46, 3936-3938.
(22) Removal of tosyl group was successfully carried out in a number
of oxazolidinones 12 or 13 in 65-94%: Ji, S.; Gortler, L. B.; Waring, A.;
Battisti, A. J.; Bank, S.; Closson, W. D.; Wriede, P. A. J. Am. Chem. Soc.
1967, 89, 5311-5312.
(23) Spectral data fully agree with those reported: (a) Hale, K. J.;
Manaviazar, S.; Delliser, V. M. Tetrahedron 1994, 50, 9181-9188. (b)
La¨ıb, T.; Chastanet, J.; Zhu, J. J. Org. Chem. 1998, 63, 1709-1713.
Supporting Information Available: Experimental pro-
cedures and analytical data. This material is available free
of charge via the Internet at http://pubs.acs.org.
OL0270428
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Org. Lett., Vol. 4, No. 25, 2002