Cycloadditions of chiral carbonyl ylides with imine dipolarophiles as a route to enantiomerically pure α-amino-β-hydroxy acids

Article abstract of DOI:10.1016/j.tetasy.2009.02.029

The preparation of enantiomerically pure threo-β-amino-α-hydroxy acids via 1,3-dipolar cycloadditions of imine dipolarophiles with the chiral isomuenchnone derived from (5R)-5-phenylmorpholin-3-one 1 is described. The cycloadducts were obtained with excellent diastereofacial- and exo-selectivity. Subsequent hydrolysis and chemoselective exocyclic amide cleavage afforded the threo-β-amino-α-hydroxy acids with recovery of the initial chiral auxiliary.

Full text of DOI:10.1016/j.tetasy.2009.02.029

Tetrahedron: Asymmetry 20 (2009) 723–725
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Cycloadditions of chiral carbonyl ylides with imine dipolarophiles as a route
to enantiomerically pure
a
-amino-b-hydroxy acids
a
b
b,à
Yu Gan a, , Laurence M. Harwood a, , Simon C. Richards , Ian E. D. Smith , Victoria Vinader
*
a Department of Chemistry, University of Reading, Whiteknights, Reading RG6 6AD, UK
b GlaxoSmithKline, Gunnels Wood Road, Stevenage Herts SG1 2NY, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
The preparation of enantiomerically pure threo-b-amino-
of imine dipolarophiles with the chiral isomünchnone derived from (5R)-5-phenylmorpholin-3-one 1
is described. The cycloadducts were obtained with excellent diastereofacial- and exo-selectivity. Subse-
a
-hydroxy acids via 1,3-dipolar cycloadditions
Received 27 January 2009
Accepted 23 February 2009
Available online 3 April 2009
quent hydrolysis and chemoselective exocyclic amide cleavage afforded the threo-b-amino-a-hydroxy
acids with recovery of the initial chiral auxiliary.
This paper is dedicated to Professor George
Fleet, on the occasion of his 65th birthday
Ó 2009 Published by Elsevier Ltd.
1. Introduction
polystyrene-bound benzenesulfonyl azide,14 for ease of purification,
giving the diazo adduct 4 in a reproducible 91% yield. Finally, deacet-
ylation15 of 4 was achieved using pyrrolidine, to afford carbonyl
ylide precursor 2 in 87% yield (Scheme 1). This synthesis represents
a significant improvement over our earlier methodology.
Cycloadditions with the isomünchnone, derived from the rho-
dium-catalysed decomposition of 2, with the imine dipolarophile
5a were initially studied in order to optimise conditions. A range
of solvents, temperatures and addition protocols for this cycloaddi-
tion were surveyed and it was found that use of nitromethane as
solvent proved to be a key element, affording 6a in 43% purified
yield (Table 1).16 Inspection of the crude reaction material revealed
no other cycloadduct to be present. X-ray crystallographic analysis
of 6a showed cycloaddition to have occurred on the face of the car-
bonyl ylide anti to the phenyl substituent with the anisyl group in
an exo-configuration (Fig. 1).17
Following this optimisation study, the scope of this conversion
was studied using aromatic imine dipolarophiles bearing both
electron-withdrawing and electron-donating substituents on the
aromatic ring (Scheme 2). The highest yield was obtained for the
reaction between 2 and the imine derived from benzaldehyde
and benzylamine 6c and all cycloadditions occurred with the same
excellent diastereofacial- and exo-selectivity (Table 2), with only
one diastereoisomer being identified in the crude material in all
cases. Comparison of the NMR spectroscopic data for these cyc-
loadducts with those of 6a,16 indicated that the additions had all
occurred in the same anti-exo manner.
b-Amino-a-hydroxy acids are typically prepared by methods
that utilise asymmetric epoxidation,1 Sharpless asymmetric
dihydroxylation,2 and chiral auxiliary-based strategies.3,4 They
are an important component in many biologically active com-
pounds,5–8 in particular TaxolÒ and TaxotereÒ.9,10 Previous work
within the group has developed a carbonyl ylide system11 based
on the chiral auxiliary 5-phenylmorpholin-3-one 1. Cycloadditions
of this system with selected aldehyde dipolarophiles have been
shown to afford cycloadducts with excellent diastereoselectivities,
although the scope of the reaction was limited to electron-deficient
aldehydes. Subsequent manipulation of the cycloadducts afforded
enantiomerically pure
a,b-dihydroxyacids, allowing the recovery
of the initial chiral material.12
Herein, we report a significantly more reproducible and effi-
cient synthesis of the key carbonyl ylide precursor 2, its highly dia-
stereoselective cycloadditions with
dipolarophiles to afford cycloadducts in moderate to good yields
and their subsequent efficient conversion into enantiomerically
pure threo-b-amino-a-hydroxy acids.
a
variety of imine
2. Results and discussion
The carbonyl ylide precursor 2 was synthesised from auxiliary 1
via diamide 3 prepared in 84% yield following Sato’s diketene
methodology.13 Compound
3 was subsequently treated with
Cycloadducts 6a–e were subjected to mild acid hydrolysis,
using a THF/water mixture and p-toluenesulfonic acid catalyst
(1 mol %). The hydrolysis products 7a–e could not be purified by
chromatography, as they appeared to exist as an equilibrium
mixture of ring-chain tautomers; therefore the crude hydrolysis
products 7a–e were subjected to selective exocyclic amide bond
* Corresponding author. Tel.: +44 (0) 118 378 7417; fax: +44 (0) 118 378 6121.
E-mail address: l.m.harwood@reading.ac.uk (L.M. Harwood).
Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1Ez, UK.
Institute of Cancer Therapeutics, School of Life Sciences, University of Bradford,
à
West Yorkshire BD7 1DP, UK.
0957-4166/$ - see front matter Ó 2009 Published by Elsevier Ltd.
doi:10.1016/j.tetasy.2009.02.029

724
Y. Gan et al. / Tetrahedron: Asymmetry 20 (2009) 723–725
O
O
O
O
O
O
(2 equiv)
H
N
N2
O
O
O
Ph
O
N2
O
PsTsN3 (1.1 equiv)
O
pyrrolidine (5 equiv)
CH2Cl2, -78°C, 10 min
87%
Ph
N
Ph
N
Ph
N
xylene, reflux, 2h
84%
CH2Cl2, r.t., 15 h
91%
O
O
O
O
1
3
4
2
Scheme 1.
Table 1
Effect of temperature and solvent on cycloaddition
Table 2
Yields of cycloadducts
Solvent
Temperature
Yield (%)
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
THF
ꢀ78 °C
0 °C
rt
Reflux
rt
Reflux
rt
rt
0
7
12
10
3
0
0
2
0
Entry
R
Yield (%)
Diastereoisomer
6a
6b
6c
6d
6e
OMe
NMe2
H
NO2
Cl
43
21
70
47
30
exo-I
exo-I
exo-I
exo-I
exo-I
THF
EtOAc
CHCl3
MeOH
CH3NO2
rt
rt
43
cleavage with lithium hydroperoxide following the methodology of
Evans (Scheme 3).18 Purification of products 8a–e and recovery of
the initial chiral auxiliary 1 were achieved through column chro-
matography.17 The pure chiral auxiliary 1 was recovered in good
to excellent yields, and the desired threo-b-amino-a-hydroxy acids
were isolated in reasonable to good yields over the two-step
sequence (Table 3). It is worth noting that both the methyl ester
Table 3
The preparation of b-amino-a-hydroxy acids and the recovery of the chiral auxiliary
Cycloadduct
R
Yield of 8 (%)
Recovery of 2 (%)
6a
6b
6c
6d
6e
OMe
NMe2
H
NO2
Cl
59
32
80
65
61
90
84
95
71
83
Figure 1. X-ray crystal structure of 6a.
BnN
(2 equiv)
R
a
: R=OMe
b: R=N(Me)2
c: R=H
d: R=NO2
R
O
O
H
5a-e
N2
O
Rh2(OAc)4 (2 mol%)
3Å molecular sieves
Ph
N
O
Ph
N
O
e: R=Cl
NBn
CH3NO2, r.t., 1 h
O
2
6a-e
Scheme 2.
R
HO
O
H
R
HO
NHBn
NHBn
H
LiOH (2 equiv)
H2O2 (6 equiv)
R
O
H
p -TSA (1 mol%)
THF/H2O, r.t.
O
8a-e
OH
O
O
THF/H2O
Ph
N
+
Ph
N
NBn
H
N
Ph
O
O
O
b
a
: R=N(Me)2
: R=OMe
6a-e
c: R=H
e: R=Cl
d: R=NO2
7a-e
O
1
Scheme 3.

Y. Gan et al. / Tetrahedron: Asymmetry 20 (2009) 723–725
725
removed in vacuo and purification by gradient column chromatography
eluting with diethyl ether/petroleum ether (30–40 °C) and triethylamine (2%)
afforded 6a–e.
and the free amine derivatives of 8c have been used to access the
C-13 side chain of TaxolÒ.19
General cycloadduct degradation procedure: To a 0.05 M solution 6a–e of in THF/
water (3:1) was added p-TSA (1 mol %). The reaction was monitored by TLC
analysis and, when the cycloadduct was no longer observed, the solvents were
removed in vacuo. The crude hydrolysis product was dissolved in THF/water
(3:1) to make a 0.05 M solution, cooled to 0 °C and a hydrogen peroxide
solution (30% w/w) (6 equiv) was added, followed by solid lithium hydroxide
monohydrate (2 equiv). The solution was warmed to room temperature over
2 h and left to stir until the hydrolysis product was no longer present by TLC
analysis. The reaction mixture was recooled to 0 °C and quenched by addition
of a 1.5 M aqueous sodium thiosulfate solution (6.6 equiv). The solution was
adjusted to pH 8 with 4 M aqueous hydrochloric acid and the solvents were
removed in vacuo. Purification by gradient column chromatography eluting
with chloroform/ethanol, gave 1 and 8a–e.
3. Conclusion
In conclusion, we have developed a highly diastereocontrolled
synthesis of enantiopure b-amino-a-hydroxy acids, via the cyc-
loadditions of imines with the carbonyl ylide derived from chiral
precursor 1. After cleavage, the chiral auxiliary 1 was recovered
in excellent yield, with the b-amino-a-hydroxy acids 8a–e isolated
in reasonable to good yields. Optimisation studies of the carbonyl
ylide generation/cycloaddition step demonstrated the dramatic
effect of the use of nitromethane as a solvent.
Compound 6a: mp 124–125 °C; m/z C27H26N2O4 requires 442.1893, found
442.1899;
dH (400 MHz, CDCl3) 7.41–6.65 (14H, m, ArH), 4.97 (1H, dd, J 5.0, J0 9.5 Hz, 10
H), 4.72 (1H, d, J 13.0 Hz, NCHHPh), 4.60 (1H, d, J 12.5 Hz, 7
(1H, s, 3-H), 4.32 (1H, d, J 12.5 Hz, 7
-H or 7b-H), 4.08 (1H, dd, J 5.0, J0 12.0 Hz,
-H or 9b-H), 3.73, (3H, s, CH3), 3.68 (1H, d, J 13.0 Hz, NCHHPh), 3.59 (1H, s,
4H) and 3.54 (1H, dd, J 10.0, J0 12.0 Hz, 9
-H or 9b-H); dC (101 MHz, CDCl3)
m
max (thin film) 1728, 1609, 1511, 1454, 1421, 1336 and 1244 cmꢀ1
;
a-
a
-H or 7b-H), 4.48
Acknowledgements
a
9a
S.C.R thanks GlaxoSmithKline and the University of Reading
(R.E.T.F) for financial support.
a
171.5, 158.8, 137.2, 135.7, 132.4, 128.8, 128.7, 128.4, 128.0, 127.2, 127.0, 113.2,
101.0, 86.0, 73.1, 69.5, 65.6, 58.5, 55.2 and 55.1; ½a D20
¼ ꢀ204:3 (c 0.5 CHCl3);
ꢂ
Anal. Calcd for C27H26N2O4: C, 73.29; H, 5.92; N, 6.33. Found: C, 73.14; H, 5.99;
N, 6.35. Compound 6c: m/z C26H24N2O3 requires 412.1787, found 412.1787;
mmax (thin film) 1728, 1496, 1457, 1423, 1336 and 1071 cmꢀ1; dH (250 MHz,
References
CDCl3) 7.44–7.05 (15H, m, ArH), 4.97 (1H, dd, J 4.5, J0 9.5 Hz, 10
a
-H), 4.74 (1H,
-H or 7b-H), 4.50 (1H, s, 3-H),
-H or 7b-H), 4.06 (1H, dd, J 4.5, J0 12.0 Hz, 9
-H or 9b-
H), 3.68 (1H, d, J 13.0 Hz, NCHHPh), 3.62 (1H, s, 4H) and 3.53 (1H, dd, J 9.5, J0
12.0 Hz, 9 -H or 9b-H); dC (62.8 MHz, CDCl3) 171.9, 140.6, 137.5, 136.1, 129.4,
129.2, 129.1, 128.9, 128.5, 128.4, 128.3, 127.7, 127.0, 101.5, 86.4, 73.5, 69.9,
66.6, 58.9 and 55.7; [
D = ꢀ175.2 (c 0.4 CHCl3). Compound 8a: mp 204–207 °C;
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d, J 13.0 Hz, NCHHPh), 4.62 (1H, d, J 12.5 Hz, 7
4.32 (1H, d, J 12.5 Hz, 7
a
a
a
a
a
]
m/z C17H19NO4 requires 302.1392, found 302.1387; mmax (thin film) 3389, 2918,
1602, 1507, 1247, 1177, 1113 and 1026 cmꢀ1; dH (400 MHz, D2O); 7.56–7.10
(9H, m, ArH), 4.25 (1H, d, J 6.5 Hz N–CH), 4.14 (1H, d, J 6.5 Hz, O–CH), 3.95 (1H,
d, J 13.5 Hz, NCHHPh), 3.94 (3H, s, OCH3) and 3.84 (1H, d, J 13.5 Hz, NCHHPh);
dC (101 MHz, D20); 180.4, 161.7, 132.5, 131.9, 131.8, 131.6, 131.4, 130.9, 116.9,
77.1, 66.1, 58.1 and 51.6; ½a D20
¼ ꢀ31:7 (c 1.0 MeOH). Compound 8c: mp 146–
ꢂ
149 °C; m/z C16H17NO3 requires 272.1286, found 272.1276; mmax (thin film)
3399, 3058, 2845, 1600, 1454, 1369, 1124 and 697 cmꢀ1; dH (400 MHz, D2O/
MeOD); 7.44–7.10 (10H, m, ArH), 4.14 (1H, d, J 5.5 Hz N–CH), 4.10 (1H, d, J
5.5 Hz, O–CH), 3.92 (1H, d, J 13.5 Hz, NCHHPh) and 3.85 (1H, d, J 13.5 Hz,
NCHHPh); dC (101 MHz, D2O/MeOD); 178.9, 135.1, 134.2, 132.3, 132.1, 131.9,
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16. All novel compounds isolated gave spectroscopic data in accordance with their
assigned structures. General experimental and selected data for key products
are given below.
131.4, 130.7, 127.9, 75.4, 66.3 and 51.6; ½a D20
¼ ꢀ51:9 (c 0.95 MeOH).
ꢂ
17. Crystal data for 6a: C27H26N2O4 M = 442.5, orthorhombic, P212121, a = 9.5588(2),
b = 10.2099(3), c = 22.1559(4) Å, V = 2162.29(9) Å3, Z = 4, D = 1.359 g cmꢀ3
,
F(000) = 936. 3712 Independent reflections were collected on an Oxford
Gemini S Ultra Image Plate System. The structures were solved by direct
methods and refined on F2 using SHELX97. Final R = 0.0417, weighted R = 0.1327.
CCDC 717010 contains the supplementary crystallographic data for this paper.
These data can be obtained free of charge from The Cambridge Crystallographic
Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
General cycloaddition procedure: To Rh2(OAc)4 (2 mol %) and 3 Å molecular
sieves in nitromethane (1 mL) under an inert atmosphere, was added a 0.81 M
solution of 5a–e in nitromethane followed by the dropwise addition of a
0.27 M solution of 2 in nitromethane. The reaction was left to stir until TLC
analysis showed no evidence of the ylide precursor. The molecular sieves were
removed by filtration and washed with DCM (3 ꢁ 5 mL), the solvent was
18. Evans, D. A.; Britton, T. C.; Ellman, J. A. Tetrahedron Lett. 1987, 28, 6141.
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