A novel one-pot procedure for the stereoselective synthesis of α-hydroxy esters from ortho esters

Article abstract of DOI:10.1021/ol901214n

A novel one-pot procedure for the stereoselective synthesis of a-hydroxy esters from ortho esters was developed. Key steps were multiheteroatom Cope rearrangements of O-acylated N-hydroxy-L-tert-leucinol-derived oxazoline N-oxides leading to a-acyloxy oxazolines and, after methanolysis, to the target molecules in 67-80% yield and 94-98% ee.

Full text of DOI:10.1021/ol901214n

ORGANIC
LETTERS
2009
Vol. 11, No. 18
4032-4035
A Novel One-Pot Procedure for the
Stereoselective Synthesis of r-Hydroxy
Esters from Ortho Esters
Matthias Breuning,* Tobias Ha¨user, and Eva-Maria Tanzer
UniVersita¨t Wu¨rzburg, Institut fu¨r Organische Chemie, Am Hubland, 97074 Wu¨rzburg,
Germany
breuning@chemie.uni-wuerzburg.de
Received May 29, 2009
ABSTRACT
A novel one-pot procedure for the stereoselective synthesis of r-hydroxy esters from ortho esters was developed. Key steps were multi-
heteroatom Cope rearrangements of O-acylated N-hydroxy-L-tert-leucinol-derived oxazoline N-oxides leading to r-acyloxy oxazolines and,
after methanolysis, to the target molecules in 67-80% yield and 94-98% ee.
Enantiomerically pure R-hydroxy acids and esters are
important synthetic building blocks.1 Only a few methods
are currently known for the stereoselective preparation of
such compounds from the corresponding acid derivatives.
The R-oxidation of methyl esters with the enzyme extract
of peas gives R-configured R-hydroxy esters with excellent
stereocontrol (>99% ee),2 but this biocatalytic transformation
is often hampered by low yields. The stereoselective R-hy-
droxylation of enolates with oxaziridines is well studied.3
While enantioselective variants of this reaction, usually with
(+)- or (-)-(camphorylsulfonyl)oxaziridine as the chiral
oxygen source, suffer from moderate stereocontrol,4 good
to excellent asymmetric inductions are achieved in diaste-
reoselective R-oxidations of chirally modified amide or ester
enolates.5 Disadvantages of the latter method are the
incompatibility of the oxaziridine with some functional
groups6 and the additional steps required to attach and
remove the chiral auxiliary.
A first step toward a conceptually different approach7 that
does not rely on an electrophilic oxygen source was presented
in 1998 by Dalko and Langlois (Scheme 1):8 Condensation
of the N-hydroxyisoborneol 1 with ortho esters afforded the
oxazoline N-oxides 2, which upon O-acylation underwent
[3,3]-sigmatropic rearrangements leading to the R-acyloxy
oxazolines 3 in 41-67% yield and high 92-95% de. The
(5) (a) Raghavan, S.; Ganapathy Subramanian, S.; Tony, K. A. Tetra-
hedron Lett. 2008, 49, 1601. (b) Gaich, T.; Karig, G.; Martin, H. J.; Mulzer,
J. Eur. J. Org. Chem. 2006, 3372. (c) Williams, D. R.; Nold, A. N.; Mullins,
R. J. J. Org. Chem. 2004, 69, 5374. (d) Wei, Y.; Bakthavatchalam, R.; Jin,
X.-M.; Murphy, C. K.; Davis, F. A. Tetrahedron Lett. 1993, 34, 3715. (e)
Gamboni, R.; Tamm, C. HelV. Chim. Acta 1986, 69, 615.
(1) Coppola, G. M.; Schuster, H. F. R-Hydroxy Acids in EnantioselectiVe
Synthesis; VCH: Weinheim, 1997.
(2) (a) Adam, W.; Boland, W.; Hartmann-Schreier, J.; Humpf, H.-U.;
Lazarus, M.; Saffert, A.; Saha-Mo¨ller, C. R.; Schreier, P. J. Am. Chem.
Soc. 1998, 120, 11044. (b) Adam, W.; Lazarus, M.; Saha-Mo¨ller, C. R.;
Schreier, P. Tetrahedron: Asymmetry 1996, 7, 2287.
(6) Alkenes, for example, react with oxaziridines to give epoxides; see:
(a) Michaelis, D. J.; Ischay, M. A.; Yoon, T. P. J. Am. Chem. Soc. 2008,
130, 6610. (b) Armstrong, A.; Edmonds, I. D.; Swarbrick, A. E. Tetrahedron
Lett. 2005, 46, 2207.
(3) Davis, F. A.; Chen, B.-C. Chem. ReV. 1992, 92, 919.
(4) (a) Chen, B.-C.; Weismiller, M. C.; Davis, F. A. Tetrahedron 1991,
47, 173. (b) Davis, F. A.; Weismiller, M. C. J. Org. Chem. 1990, 55, 3715.
(c) Davis, F. A.; Serajul Haque, M.; Ulatowski, T. G.; Towson, J. C. J.
Org. Chem. 1986, 51, 2402. (d) Boschelli, D.; Smith, A. B. Tetrahedron
Lett. 1981, 22, 4385.
(7) For a two-step sequence that includes an asymmetric Sharpless
dihydroxylation of ketene O,O- or S,O-acetals, see: (a) Kirschning, A.;
Dra¨ger, G.; Jung, A. Angew. Chem., Int. Ed. Engl. 1997, 36, 253. (b)
Monenschein, H.; Dra¨ger, G.; Jung, A.; Kirschning, A. Chem.sEur. J. 1999,
5, 2270.
(8) Dalko, P. I.; Langlois, Y. Tetrahedron Lett. 1998, 39, 2107.
10.1021/ol901214n CCC: $40.75
Published on Web 08/19/2009
 2009 American Chemical Society

Scheme 1
.
Multiheteroatom Cope Rearrangements of Chiral
Scheme 3. General Scheme for the Preparation and
Multiheteroatom Cope Rearrangement of Chiral Oxazoline
Oxazoline N-Oxides According to Dalko and Langlois8
N-Oxides
possibility to convert 3 into R-hydroxy esters was also
demonstrated on one example (R ) Bn, R′ ) Me: three steps,
42% yield). Variations of the chiral auxiliary and further
attempts to optimize the hydrolysis of 3 were not done, even
though this sequence might allow a versatile alternative
access to chiral R-hydroxy esters. Herein we report on a
highly efficient method for the one-pot transformation of
ortho esters into R-hydroxy methyl esters of g94% ee that
includes a multiheteroatom Cope rearrangement9 of an
O-acylated N-hydroxy-L-tert-leucinol-derived oxazoline N-
oxide as the stereochemical key step.
enantiomerically and analytically pure form and 50-60%
overall yield.
Initial screening experiments on the condensation-acylation-
rearrangement sequence were performed with the ortho ester
7a as the model substrate (Scheme 3). Reaction of 3 equiv of
7a with 6 in the presence of TFA and evaporation quantitatively
afforded the protonated oxazoline N-oxides 8, as determined
by 1H NMR. Subsequent treatment of 8 with an acid chloride
or anhydride and triethylamine in CH2Cl2 at -78 °C led to the
O-acylated intermediates 9 and, after loss of a proton, to the
ketene N,O-acetals 10, which smoothly underwent [3,3]-
sigmatropic multiheteroatom Cope rearrangements to give the
S-configured13 R-acyloxy oxazolines 11.
Scheme 2.
Preparation of the N-Hydroxy ꢀ-Amino Alcohols 6a
For high yields of 11 it was crucial to remove the methanol
freed in the initial preparation of the oxazoline N-oxide 8.
Otherwise, it will add to the acylated intermediate 9 to give
methanol adducts of type 12 (Figure 1) in varying amounts,
1
as evidenced from H NMR investigations of the crude
reaction mixtures. These compounds were stable under basic
conditions, thus inhibiting the formation of the required Cope
systems 10, but usually decomposed or partially rearranged
upon aqueous workup. In the reaction of 7a with 6a and
AcCl, for example, the intermediate 12a was found as the
sole primary product. In contrast to all other derivatives of
12, 12a possessed a decent stability and was isolated as a
single diastereomer in 43% yield after chromatography.
The diastereomeric excess in the products 11 strongly
depended on the steric demand of the substituent R of the
a PMP ) 4-MeOPh; m-CPBA ) m-chloroperoxybenzoic acid.
Since the preparation of the isoborneol derivative 1
requires expensive camphorquinone as the starting material,
we explored whether the structurally simpler, nonbicyclic
N-hydroxy ꢀ-amino alcohols of type 6 (Scheme 2) are also
suited as chiral auxiliaries and induce highly diastereose-
lective rearrangements. The synthesis of 6a-d (R ) Ph, Bn,
i-Pr, t-Bu)11 was straightforward from the commercially
available ꢀ-amino alcohols 4a-d using a slightly modified
variant of a known three-step procedure.12 Simple extraction
with diethyl ether in the last step furnished 6a-d in
(11) The N-hydroxy ꢀ-amino alcohol 6a and the HCl salt of 6c are
known compounds; see: (a) Tamura, O.; Gotanda, K.; Yoshino, J.; Morita,
Y.; Terashima, R.; Kikuchi, M.; Miyawaki, T.; Mita, N.; Yamashita, M.;
Ishibashi, H.; Sakamoto, M. J. Org. Chem. 2000, 65, 8544. (b) Aurich,
H. G.; Biesemeier, F.; Geiger, M.; Harms, K. Liebigs Ann. Org. Bioorg.
Chem. 1997, 423.
(9) For reviews about asymmetric Cope and Claisen rearrangements,
see: (a) Castro, A. M. M. Chem. ReV. 2004, 104, 2939. (b) Nubbemeyer,
U. Synthesis 2003, 961.
(12) (a) Wovkulich, P. M.; Uskokoviæ, M. R. Tetrahedron 1985, 41,
3455. (b) Połon˜ski, T.; Chimiak, A. Tetrahedron Lett. 1974, 28, 2453. (c)
See also ref 11b.
(10) (a) Dirat, O.; Kouklovsky, C.; Mauduit, M.; Langlois, Y. Pure Appl.
Chem. 2000, 72, 1721. (b) Baldwin, S. W.; McFadyen, R. B.; Aube´, J.;
Wilson, J. D. Tetrahedron Lett. 1991, 32, 4431.
(13) The S-configuration of the products 15a,b,e,f and 16 was established
from the sign of their known optical rotations or by comparison with the
known retention times on HPLC on chiral phase.
Org. Lett., Vol. 11, No. 18, 2009
4033

Table 2. Substrate Scope
Figure 1. Methanol adducts 12 and 12a.
entry
7
puritya (%)
R
13 yieldb (%) dec (%)
1
2
3
4
5
6
7
8
9
bd
cd
d
e
45
100
100
40
82
52
>90
100
53
CH2Bn
Me
n-Pr
n-Pent
(CH2)10Me
(CH2)11Me
(CH2)2OBn
(CH2)4Br
(CH2)4Br
b
c
d
e
f
g
h
i
76
74
71
80
83
77
74
77
70
97
97
97
97
97
96
97
96
96
chiral N-hydroxy ꢀ-amino alcohol 6 (Table 1, entries 1-4).
Only moderate 62-83% de’s were achieved with 6a-c (R
) Ph, Bn, i-Pr), whereas excellent 96% de were obtained
with the L-tert-leucinol-derived auxiliary 6d possessing the
bulky tert-butyl group. Thus, the use of bicyclic N-hydroxy
ꢀ-amino alcohols like 1 is not required for a highly
diastereoselective rearrangement step.
The influence of the acylating reagent as studied on the
reaction of 7a with 6d is small (Table 1, entries 4-7). With
Ac2O, AcCl, BzCl, and PivCl, the products 11d-f were
isolated in good 78-88% yield and 95-98% de. No rearrange-
ment occurred with the less reactive Boc2O (entry 8).
f
g
h
i
i
i
a Contaminated by the corresponding ester. b Isolated yields refer to
the limiting reagent 6d; the ortho esters 7 were used in a 2-fold excess.
Determined by H NMR. d The triethyl orthoate was used.
c
1
which the bulky tert-butyl group induces a transient stereo-
genic center at the nitrogen atom that, in turn, defines the
chairlike conformation of the Cope system. The alternative
arrangement 14B is strongly disfavored due to the repulsion
of the tert-butyl group with the oxygen atom of the N-O
moiety.
Table 1. Influence of the Chiral N-Hydroxy ꢀ-Amino Alcohol 6
and the Acylating Reagent on the Transformation of 7a into 11
entry
6
R
R′COCl/(R′CO)2O 11
R′
yielda (%) deb(%)
1
2
3
4
5
6
7
8
a
b
c
d
d
d
d
d
Ph
Bn
AcCl
AcCl
AcCl
AcCl
Ac2O
BzCl
PivCl
Boc2O
a
b
c
d
d
e
f
Me
Me
Me
Me
Me
Ph
t-Bu
Ot-Bu
68
48
59
78
80
88
86
0
83
62
63
96
96
95
98
i-Pr
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
g
a Isolated yields refer to the limiting reagent 6; the ortho ester 7a was
used in a 2-fold excess. Determined by H NMR.
b
Figure 2. Proposed transition states.
1
The primary goal of our investigations, the one-pot
conversion of ortho esters into chiral R-hydroxy methyl
esters, was achieved by an additional methanolysis step
(Table 3). Thus, condensation of 7a,b,e-i with 6d, evapora-
tion, acetylation followed by the multiheteroatom Cope
rearrangement, and final methanolysis delivered the products
15a,b,e-i in good 67-80% yield and excellent 94-98%
ee. Any significant racemization at the newly formed
stereogenic center in R-position was not observed, as was
obvious from the high enantiopurities of 15. The fatty acid
derivatives 15e and 15g are the methyl esters of the natural
products (S)-2-hydroxyonanthic acid and (S)-2-hydroxy-
myristic acid.
The substrate scope of this transformation was evaluated
next (Table 2). Condensation of 6d with the ortho esters 7b-i
and subsequent rearrangement upon addition of acetyl
chloride provided the R-acetoxy oxazolines 13b-i in good
70-83% yield and g96% de. It should be noted that a
contamination of 7 with even large amounts of the corre-
sponding methyl or ethyl esters, which are usually formed
as side products in the preparation of ortho esters from
nitriles, has no negative effect on the outcome of the reaction.
For example, similar results were obtained with analytically
pure 7i and with a 53:47 mixture of 7i and the corresponding
methyl ester (entries 7 and 8). A time-consuming purification
of 7 is thus not necessary.
The highly preferential formation of the (S)-configured13
products 13 suggests that the rearrangement is a concerted
process14 via the Z-ketene N,O-acetal 14A (Figure 2), in
By the same procedure, but with a final hydrolysis step in
6 N HCl, the corresponding R-hydroxy acids are in principle
available, as exemplarily demonstrated on the one-pot
transformation of 7a into L-phenyllactic acid (16, 81% yield,
97% ee, Scheme 4).
(14) The high stereoselectivities obtained strongly support a concerted
[3,3]-sigmatropic rearrangement. Non-concerted processes involving short-
lived radicals or ionic species, however, cannot fully be excluded; see also:
Cummins, C. H.; Coates, R. M. J. Org. Chem. 1983, 48, 2070.
In summary, we developed a novel one-pot procedure for
the conversion of ortho esters into highly enantioenriched
4034
Org. Lett., Vol. 11, No. 18, 2009

Table 3. One-Pot Synthesis of the R-Hydroxy Methyl Esters 15
Scheme 4. One-Pot Procedure for the Synthesis of
L-Phenyllactic Acid (16) from the Ortho Ester 7a
entry
7
puritya (%)
R
15 yieldb (%) ee (%)
a Determined by HPLC on chiral phase after conversion of 16 into 15a.
1
2
3
4
5
6
7
a
100
45
40
82
52
Bn
CH2Bn
n-Pent
(CH2)10Me
(CH2)11Me
(CH2)2OBn
(CH2)4Br
a
b
e
f
g
h
i
80
72
75
71
73
67
70
96c
96e
94e
98e
96e
98e
97e,f
bd
e
f
L-tert-leucinol-derived oxazoline N-oxide intermediate. Fur-
ther extension of this method toward the preparation of chiral
R-amino acids is in progress.
g
h
i
>90
53
a Contaminated by the corresponding ester. b Isolated yields refer to
the limiting reagent 6d; the ortho esters 7 were used in a 2-fold excess.
c Determined by HPLC on chiral phase. d The triethyl orthoate was used.
e Determined by 1H NMR of the Mosher ester. f Ac2O was used in the
acylation step and HBr in MeOH for hydrolysis to avoid a Cl/Br exchange.
Acknowledgment. This work was supported by the
Deutsche Forschungsgemeinschaft DFG.
Supporting Information Available: Full experimental
1
procedures, characterization data, and copies of H NMR
and 13C NMR spectra. This material is available free of
charge via the Internet at http://pubs.acs.org.
(94-98% ee) R-hydroxy esters and acids. The stereochemical
information in the R-position was introduced via a multi-
heteroatom Cope rearrangement of an O-acylated N-hydroxy-
OL901214N
Org. Lett., Vol. 11, No. 18, 2009
4035