Efficient enantioselective synthesis of α-hydroxy-β-amino acids using the Claisen and Curtius rearrangements

Article abstract of DOI:10.1055/s-2005-922793

Highly enantioselective and facile synthesis of α-hydroxy-β- amino acids has been achieved using the Claisen and Curtius rearrangements as key reactions. Chiral allylic alcohols were employed, which can be prepared by asymmetric catalysis in both E- and Z

Full text of DOI:10.1055/s-2005-922793

86
LETTER
Efficient Enantioselective Synthesis of a-Hydroxy-b-amino Acids Using the
Claisen and Curtius Rearrangements
Synthesis of
a
-Hyd
o
roxy-
b
-
amin
o
o Aci ds Young Jung, Sol Kang, Sukbok Chang,* Yong Hae Kim*
Center for Molecular Design and Synthesis, School of Molecular Science (BK-21), Korea Advanced Institute of Science and Technology,
373-1 Guseong Dong, Yuseong Gu, Taejon, 305-701, Korea
Fax +82(42)8695818; E-mail: kimyh@kaist.ac.kr
Received 31 August 2005
O
Abstract: Highly enantioselective and facile synthesis of a-hy-
droxy-b-amino acids has been achieved using the Claisen and
Ph
NH
O
NH2
O
Curtius rearrangements as key reactions. Chiral allylic alcohols
were employed, which can be prepared by asymmetric catalysis in
both E- and Z-forms; both anti- and syn-a-hydroxy-b-amino acids
have been synthesized.
OMe
N
H
CO2H
OH
OH
Taxol side chain
O
Bestatin
S
Key words: amino alcohols, amino acids, enantioselective synthe-
sis, Claisen rearrangement, Curtius rearrangement
S
N
O
OH
H
H
N
N
N
N
H
O
Ph
O
O
a-Hydroxy-b-amino acids are common structural units
found in many biologically active compounds, including
both naturally occurring and synthetic pharmaceuticals.1
As one can see in Figure 1, a-hydroxy-b-amino acids or
their derivatives reside in key structural elements of bio-
logically active molecules, including Taxol,2 a potent an-
titumor agent; bestatin,3 an aminopeptidase inhibitor; and
KNI-272,4 a highly potent HIV-protease inhibitor. Due to
their widespread occurrence in biologically active mole-
cules, much synthetic effort has been devoted to the devel-
opment of efficient stereoselective routes to prepare
enantiopure a-hydroxy-b-amino acids.5–8 Traditional syn-
thetic methods toward these molecules have depended
heavily on the use of chiral pools, such as amino acids or
carbohydrates. In these types of syntheses, diastereoselec-
tive addition of nucleophiles to a-aminocarbonyl or a-hy-
droxyimino compounds is typical. In these syntheses,
however, it was hard to obtain both syn- and anti-a-hy-
droxy-b-amino acids and thus Mitsunobu inversion of a
secondary alcohol was required to obtain both forms of a-
hydroxy-b-amino acids.5 There are some good methods to
synthesize a-hydroxy-b-amino acids through asymmetric
synthesis. However, in these cases, expensive chiral aux-
iliaries are needed to obtain enantioenriched products.6
Recently, some methods employing asymmetric catalysis
were reported,7,8 they include well-known examples of
nucleophilic epoxide ring-opening reactions7 and asym-
metric aminohydroxylations.8 However, in these catalytic
systems, substrates that can be used or the stereochemistry
of products are quite limited. Also, in the case of amino-
hydroxylations, the regioselectivity is sometimes prob-
lematic. Thus, the development of efficient synthetic
routes to a-hydroxy-b-amino acids, which can give prod-
KNI-272
Figure 1
ucts with well-defined stereochemistry (R/S and syn/anti)
in high yields is urgently needed.
Our synthetic routes are based on both highly stereoselec-
tive Claisen rearrangements9 and stereospecific Curtius
rearrangements10 as shown in Scheme 1. Both E-and Z-
chiral allylic alcohols are starting materials for our syn-
thesis. These allylic alcohols are well-known and easily
prepared by various methods including catalytic reac-
tions.11,12 The stereochemistry of a-hydroxy-b-amino
acids will be established through the Claisen rearrange-
ment.9b Curtius rearrangement of carboxylic acids is
known to introduce nitrogen functionality in a stereospe-
cific manner from carboxylic acids with retention of the
stereochemistry of the carboxylic acid, and as a result, the
Curtius rearrangement has been employed in the stereo-
selective synthesis of amino acids.10a–c
The starting allylic esters can be easily prepared from sim-
ple starting materials in high ee by asymmetric catalysis
(Scheme 2). The Z-allylic esters were prepared in three
steps by initial asymmetric alkynylation developed by
Carreira et al.,11 followed by Lindlar hydrogenation, and
subsequent acylation with commercially available benzyl-
oxyacetyl chloride. The E-allylic esters were prepared in
two steps through the enantioselective addition of a di-
ethyl zinc reagent to a,b-unsaturated aldehydes catalyzed
by (1S,2R)-dibutylnorephedrine,12 followed by acylation
with benzyloxyacetyl chloride. Starting from the corre-
sponding aldehydes, E/Z-allylic esters can be prepared in
high optical purity (Table 1, up to 96% ee) and good
yields (>70% in every case).
SYNLETT 2006, No. 1, pp 0086–0090
0
5.
0
1.
2
0
0
6
Advanced online publication: 16.12.2005
DOI: 10.1055/s-2005-922793; Art ID: U26705ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
Synthesis of a-Hydroxy-b-amino Acids
87
Then, the allylic esters were treated with a strong base
such as LDA and quenched with TMSCl to induce a
Claisen rearrangement. The Claisen rearrangement took
place in high yields with excellent diastereoselectivity. In
each case, only one diastereomer could be observed. Also,
the enantiopurity of the starting allylic ester was main-
tained in every case. This is in accordance with previous
reports which showed that the Claisen rearrangement of
allylic esters, containing chelating elements such as
oxygen, gave g,d-unsaturated esters almost stereospecifi-
cally.9 The Claisen rearrangement of allylic esters 1a and
1c containing a phenyl group directly attached to a double
bond gave the best results when a mixture of 1a or 1c and
TMSCl were treated with an excess amount of KHMDS.
Alternatively, when 1b and 1d were employed, the best
results were obtained when the allylic esters were treated
with 1.1 equivalents of LDA and 1.5 equivalents of
TMSCl (Table 2). The crude carboxylic acids were treat-
ed with TMS–diazomethane to give methyl esters 2a–d,
which were purified by silica gel column chromatogra-
phy. This reaction proceeded uneventfully to give 2a–d in
good yields with excellent stereoselectivity.13 Their abso-
lute and relative stereochemistries were determined by
comparison with the reported data of known compounds.
OBn
R
OCH3
O
O
OBn
R
O
Claisen
Rearrangement
R
OBn
OCH3
O
O
OBn
R
O
OBn
R
R
CO2Me
NHCbz
Oxidation/
Curtius Rearrangement
OBn
CO2Me
NHCbz
syn- and anti-α-hydroxy-
β-amino acids
Scheme 1
R
R
H
(a)
(b)
+
OH
H
To synthesize a-hydroxy-b-amino acids from these g,d-
unsaturated esters, the double bonds could be cleaved to
give carboxylic acids, which could then be converted to
the amino acids stereospecifically using the Curtius
rearrangement. Although various methods to cleave the
double bond in 2 were tested, ozonolysis followed by
NaClO2 oxidation proved to be optimal to give the car-
boxylic acid in excellent yields with high purity with no
purification required before the final Curtius rearrange-
ment. Using a variant of the Curtius rearrangement devel-
oped by Shioiri,10d,e 3 was converted to a-hydroxy-b-
amino acid 4 in a stereospecific manner (Scheme 3,
Table 3).
O
OH
(c)
R
O
R
OBn
O
1a,b
R
O
R
(d)
(c)
O
OBn
1c,d
R
OH
O
Scheme 2 Preparations of E- and Z-allylic esters. Reagents and con-
ditions: (a) Zn(OTf)2, (–)-N-methylephedrine, Et3N, toluene, 25 °C,
(b) Lindlar catalyst (5 wt%), quinoline (45 wt%), H2 (1 atm), MeOH,
25 °C, (c) BnOCH2COCl (1.1 equiv), pyridine (3 equiv), THF, 25 °C,
(d) Et2Zn (3 equiv), (1S,2R)-dibutylnorephedrine (5 mol%), hexane,
0 °C.
This three-step sequence worked remarkably well regard-
less of the nature of R (R = Ph, CH2Ph) or the relative
stereochemistry (syn or anti) of the substrates. Thus, in
every case examined, yields were excellent (total yield
>67%, 3 steps) and there was no reduction of either dia-
stereopurity or enantiopurity, giving stereochemically
pure a-hydroxy-b-amino acids 4a–d efficiently.
Table 1 Preparation of E- and Z-Allylic Esters
Entry
Product
1a
Configuration (R/S)
Configuration (E/Z)
R
Yield (%)a
ee (%)b
95
1
2
3
4
S
S
S
S
Z
Z
E
E
Ph
74
71
83
86
1b
CH2Ph
Ph
94
1c
96
1d
CH2Ph
95
a Isolated yields based on starting aldehydes.
b Determined by chiral HPLC analysis by DAICEL OD-H column.
Synlett 2006, No. 1, 86–90 © Thieme Stuttgart · New York

88
D. Y. Jung et al.
LETTER
Table 2 Claisen Rearrangement of Allylic Esters
R1
R3
OBn
R3
OMe
R2
OBn
A or B
O
R1
R2
O
O
1a–d
2a–d
Substrate
Product
R1
R2
R3
Conditionsa Yield (%)b
dr (syn/ anti)c
1:99
ee (%)c
95
1a
1b
1c
1d
2a
2b
2c
2d
H
Ph
i-Pr
i-Pr
Et
A
B
A
B
81
79
86
77
H
CH2Ph
H
1:99
94
Ph
99:1
96
CH2Ph
H
Et
99:1
95
a Conditions A: TMSCl (4.5 equiv) was added to a solution of 1 in THF at –78 °C. Then, KHMDS (4 equiv) was added and stirred for 10 min.
The mixture was allowed to warm to r.t. and stirred for an additional 2 h. Conditions B: LDA (1.1 equiv) was added to a THF solution of 1 at
–78 °C. After 3 min, TMSCl (2.0 equiv) was added and then allowed to warm to r.t. After work-up, the crude carboxylic acids were treated
with TMS–diazomethane to give the corresponding methyl esters.
b Isolated yields.
c Determined by HPLC analysis with a chiral AD-H column (DAICEL).
OBn
Table 3 Stereoselective Synthesis of a-Hydroxy-b-amino Acids
Et
(a), (b)
OBn
CO2Me
Product
R
Yield
(%)a
dr
(syn/anti)b tionc
Configura- ee (%)d
R
2a,b
4a
4b
4c
4d
Ph
71
67
73
68
99:1
99:1
1:99
1:99
(S,S)
(S,S)
(R,S)
(R,S)
>95
>95
>95
>95
OBn
CO2Me
OBn
CO2Me
CH2Ph
Ph
R
HO2C
R
=
CO2Me
(c)
CO2H
R
NHCbz
4a,b
3a,b
CH2Ph
a Isolated yields over 2 steps.
OBn
CO2Me
b Determined from derivatives 5a–d prepared by a known proce-
dure.5a
i-Pr
(a), (b)
OBn
c Determined from derivatives 5a–d.
d Determined from derivatives 5c, 5d, ent-5c, and ent-5d prepared by
a known procedure.5a,15
R
2c,d
OBn
CO2Me
OBn
R
HO2C
R
=
CO2Me
(c)
CO2Me
CO2H
R
NHCbz
4c,d
OBn
CO2Me
OH
3c,d
R
R
R
R
CO2Me
Scheme 3 Reagents and conditions: (a) O3, CH2Cl2–MeOH, –78 °C,
then Me2S; (b) NaClO2, 2-methyl-2-butene, t-BuOH–H2O (pH 7
buffer); (c) (i) dppa, Et3N, toluene, 25 °C, 30 min, then reflux 3 h;
(ii) BnOH (3 equiv), reflux 2 d.
NHCbz
4a,b
NHBz
5a,b
(i) Pd(OH)2, H2 (1 atm)
MeOH, 25 °C
(ii) Bz-Cl (1.1 equiv)
Py (3 equiv)
THF, 0 °C
OBn
OH
CO2Me
CO2Me
To determine the absolute configurations of 4a–d and
examine the applicability of this route to a practical syn-
thesis, 4a–d were converted to benzoylated a-hydroxy-b-
amino acids 5a–d. Thus, 4a–d were debenzylated by
hydrogenolysis and carefully benzoylated to give N-
benzoyl-a-hydroxy-b-amino acids 5a–d.14 Among these
compounds, 5a is the enantiomer of the side chain of
Taxol, one of the most famous, a-hydroxy-b-amino acids
(Scheme 4). This method can be applied to the preparation
of the Taxol side chain.
NHCbz
4c,d
NHBz
5c,d
5a: R = Ph, 81%, >95% ee
5b: R = CH2Ph, 86%, >95% ee
5c: R = Ph, 83%, >95% ee
5d: R = CH2Ph, 87%, >95% ee
Scheme 4 Deprotection and derivatization
Synlett 2006, No. 1, 86–90 © Thieme Stuttgart · New York

LETTER
Synthesis of a-Hydroxy-b-amino Acids
89
(11) Frantz, D. E.; Fassler, R.; Carreira, E. M. J. Am. Chem. Soc.
2000, 122, 1806.
(12) Soai, K.; Yokoyama, S.; Hayasaka, T. J. Org. Chem. 1991,
56, 4264.
(13) Claisen Rearrangement of Allylic Esters 1c; Typical
Procedure
In conclusion, we have developed new routes for the high-
ly enantioselective synthesis of a-hydroxy-b-amino acids,
including the unnatural enantiomer of the Taxol side
chain. Starting from allylic alcohols, a-hydroxy-b-amino
acids can be prepared in four steps in better than 45% total
yield. The enantiopurity of allylic alcohols are thoroughly
reflected in the enantiopurity of the resulting products.
There are a lot more E- and Z-allylic alcohols that can be
prepared in high enantiopurity, this newly developed
route can be applied to the synthesis of a diverse range of
a-hydroxy-b-amino acids.
To a cooled solution of 1c (1 mmol) in THF at –78 °C, was
added TMSCl (0.576 mL, 4.5 mmol). The solution was
stirred for 5 min and a solution of KHMDS (0.5 M soln in
toluene; 8.0 mL) was added rapidly by syringe. The reaction
was stirred for 10 min at –78 °C and allowed to warm to r.t.
over 1 h. The reaction was quenched with HCl (1 N) and
diluted with Et2O. The resulting mixture was partitioned and
the resulting aqueous layer was extracted with Et2O (× 2).
The combined organic layers were dried over MgSO4,
filtered, and the solvent was removed to give the crude
carboxylic acid. The crude carboxylic acid was dissolve in
MeOH–benzene (1:1, 4 mL). TMS–diazomethane (2.0 M
solution in hexane, 1.0 mL, 2.0 mmol) was added dropwise
and the solution was stirred for 30 min and then the solvent
was removed in vacuo. The crude thus obtained was purified
by silica gel column chromatography (EtOAc–hexane, 1:10)
to give pure 2c in 86% yield. HPLC (Chiracel AD column,
i-PrOH–hexane, 2:98, 1 mL/min) tR 14.1 min, 18.7 min. For
anti-isomers, 2a, tR 17.1 min, 23.2 min. 1H NMR (300 MHz,
CDCl3): d = 0.91 (t, 3 H), 1.96 (m, 2 H), 3.63 (m, 1 H), 3.67
(s, 3 H), 4.10 (d, 1 H), 4.26 (d, 1 H), 4.58 (d, 1 H), 5.56 (m,
2 H), 7.21 (m, 10 H). 13C NMR (75 MHz, CDCl3): d = 14.0,
26.4, 51.5, 53.3, 73.3, 86.2, 125.7, 127.6, 127.7, 127.9,
128.4, 128.7, 129.1, 129.3, 137.2, 140.2, 172.0. MS (EI):
m/z calcd for C21H24O3: 324.1725; found: 323.19.
Acknowledgment
This work was financially supported by grant No. R02-2002-000-
00097-0 from the Korea Science & Engineering Foundation and
Center for Molecular Design and Synthesis.
References and Notes
(1) Bergmeier, S. C. Tetrahedron 2000, 56, 2561.
(2) (a) Kingston, D. G. I.; Jagtap, P. G.; Yuan, H.; Samala, L. In
Progress in the Chemistry of Organic Natural Products,
Vol. 84; Herz, W.; Falk, H.; Kirby, G. W., Eds.; Springer:
Vienna, New York, 2002, 53–225. (b) Nicolaou, K. C.; Dai,
W. M.; Guy, R. K. Angew. Chem., Int. Ed. Engl. 1994, 33,
15.
(3) Umezawa, H.; Aoyagi, H.; Suda, H.; Kojima, F.; Hamada,
M.; Takeuchi, T. J. Antibiot. 1976, 29, 97.
(14) a-Hydroxy-b-amino Acids 5a; Typical Procedure
To a cooled solution of 2a in CH2Cl2–MeOH (1:1) at –78 °C,
O3 was bubbled until the color of the solution changed to a
purple color and the bubbling was continued for another 10
min. Then, O3 bubbling was stopped and a stream of
nitrogen was applied to the reaction mixture to drive off any
residual O3 until the solution became colorless. Then, excess
Me2S was added to quench the reaction and the resulting
mixture was left to warm to r.t. The solvent was removed in
vacuo and the crude mixture was dissolved in t-BuOH and 2-
methyl-2-butene (1:1 mixture). To the above solution, a
solution of NaH2PO4 (3 equiv) was added followed by
dropwise addition of NaClO2 (2 equiv). After 30 min at r.t.,
the reaction mixture was diluted with EtOAc and acidified
with HCl (1 N). The aqueous layer was extracted again with
EtOAc (× 2). The resulting organic layer was washed with a
sat. aq solution of Na2SO3, dried over MgSO4, filtered, and
evaporated in vacuo to give crude 3a. Then 3a was dissolved
in toluene, dppa (1.5 equiv), and Et3N (3 equiv) were added,
the resulting mixture was stirred for 30 min at r.t., and then
heated to reflux. After 3 h, benzyl alcohol (3 equiv) was
added and heating was continued for 2 d. The reaction
mixture was cooled to r.t. and quenched with an aq solution
of NH4Cl. The resulting mixture was extracted with EtOAc
(× 3). The resulting organic layer was dried over MgSO4,
filtered, and evaporated in vacuo to give crude 4a, which
was purified by silica gel column chromatography (EtOAc–
hexane, 1:6) to give pure 4a in 71% yield. To confirm the
structure and enantiopurity, 4a was converted to the known
compound 5a, which was converted to ent-5c. Firstly, it was
hydrogenolyzed over Pd(OH)2 under 1 atm of H2. The crude
mixture was dissolved in THF, cooled to 0 °C, treated with
pyridine (3 equiv), and benzoyl chloride (1.1 equiv) was
added dropwise. After 1 h, the reaction was quenched with
HCl (1 N) and extracted with EtOAc. The organic layer was
dried over MgSO4, filtered, and evaporated in vacuo to give
(4) Mimoto, T.; Imai, J.; Kisanuki, S.; Enomoto, H.; Hattori, N.;
Akaji, K.; Kiso, Y. Chem. Pharm. Bull. 1992, 40, 2251.
(5) (a) Lee, J. M.; Lim, H. S.; Seo, K. C.; Chung, S. K.
Tetrahedron: Asymmetry 2003, 14, 3639. (b) Hamamoto,
H.; Mamedov, V. A.; Kitamoto, M.; Hayashi, N. O.; Tsuboi,
S. Tetrahedron: Asymmetry 2000, 11, 4485. (c) Kayser, M.
M.; Mihovilovic, M. D.; Kearns, J.; Feicht, A.; Stewart, J. D.
J. Org. Chem. 1999, 64, 6603. (d) Kang, S. H.; Kim, C. M.;
Youn, J. H. Tetrahedron Lett. 1999, 40, 3581. (e) Jost, J.;
Gimbert, Y.; Greene, A. E. J. Org. Chem. 1997, 62, 6672.
(f) Cardillo, G.; Tomasini, C. Chem. Soc. Rev. 1996, 117.
(g) Ambroise, L.; Jackson, R. F. W. Tetrahedron Lett. 1996,
37, 2311. (h) Bunnage, M. E.; Davies, S. G.; Goodwin, C. J.
J. Chem. Soc., Perkin Trans. 1 1994, 2385.
(6) (a) Ojima, I.; Park, Y. H.; Sun, C. M.; Brigaud, T.; Zhao, M.
Tetrahedron Lett. 1992, 33, 5737. (b) Kanazawa, A. M.;
Denis, J.-N.; Greene, A. E. J. Org. Chem. 1994, 59, 1238.
(7) (a) Righi, G.; Rumboldt, G.; Bonini, C. J. Org. Chem. 1996,
61, 3557. (b) Aggarwal, V. K.; Vasse, J.-L. Org. Lett. 2003,
5, 3987.
(8) (a) Bruncko, M.; Schilingloff, G.; Sharpless, K. B. Angew.
Chem., Int. Ed. Engl. 1997, 36, 1483. (b) Han, H.; Yoon, J.;
Janda, K. D. J. Org. Chem. 1998, 63, 2045.
(9) (a) Castro, A. M. M. Chem. Rev. 2004, 104, 2939.
(b) Gould, T. J.; Balestra, M.; Wittman, M. D.; Gary, J. A.;
Rossano, L. T.; Kallmerten, J. J. Org. Chem. 1987, 52,
3889. (c) Ireland, R. E.; Mueller, R. H.; Willard, A. K. J. Am.
Chem. Soc. 1976, 98, 2868. (d) Sparks, M. A.; Panek, J. S. J.
Org. Chem. 1991, 56, 3431.
(10) (a) Spino, C.; Tremblay, M.-C.; Gobdout, C. Org. Lett. 2004,
6, 2801. (b) Spino, C.; Gobdout, C. J. Am. Chem. Soc. 2003,
125, 12106. (c) Evans, D. A.; Wu, L. D.; Wiener, J. J. M.;
Johnson, J. S.; Ripin, D. H. B.; Tedrow, J. S. J. Org. Chem.
1999, 64, 6411. (d) Ninomiya, K.; Shioiri, T.; Yamada, S.
Tetrahedron 1974, 30, 2151. (e) Ninomiya, K.; Shioiri, T.;
Yamada, S. Chem. Pharm. Bull. 1974, 22, 1398.
Synlett 2006, No. 1, 86–90 © Thieme Stuttgart · New York

90
D. Y. Jung et al.
LETTER
crude 5a, which was purified by silica gel column
1 h, the reaction mixture was filtered through a short pad of
silica gel to give the corresponding a-amino ketone. This
compound was treated with tetrabutylammonium
borohydride as reported previously15 to give ent-5c, whose
spectral data are identical to those of the known compound
5c. Then ent-5c was reacted with Mosher reagent as
described.5a The enantiomeric purity of 5c was determined
by 1H and 19F NMR spectroscopy.
chromatography (EtOAc–hexane, 1:2) to give pure 5a in
81% yield (overall yield from 3a: 58%) The spectra were in
accordance with the known compound. [a]D23 +47.1 (c 1.00,
MeOH) {lit.5b [a]D23 –50.2 (c 1.00, MeOH)}; 1H NMR (400
MHz, CD3OD): d = 3.26 (d, 1 H), 3.86 (s, 3 H), 4.65 (dd, 1
H), 5.75 (dd, 1 H), 6.97 (br d, 1 H), 7.28–7.55 (m, 8 H), 7.78
(d, 2 H). To check the enantiopurity of 5a, it was converted
to the ent-5c. To a CH2Cl2 solution of 5a, NMO (2.5 equiv)
was added, followed by TPAP (10 mol%). After stirring for
(15) Li, W.-S.; Thottathil, J. K. US Patent US 5602272 A
19970211, 1997.
Synlett 2006, No. 1, 86–90 © Thieme Stuttgart · New York