A stereoselective oxy-Michael route to protected β-aryl-β- hydroxy-α-amino acids

Article abstract of DOI:10.1055/s-2006-950434

The stereoselective oxy-Michael addition of the 'naked' anion of (5)-6-methyl tetrahydropyran-2-ol to α-nitro-α,β-unsaturated esters followed by reduction and in situ protection of the corresponding amine provides a new and efficient route to protected β-

Full text of DOI:10.1055/s-2006-950434

LETTER
2673
A Stereoselective Oxy-Michael Route to Protected b-Aryl-b-Hydroxy-a-Amino
Acids
R
a
oute to Prote
e
cted
b
-Ary
l
l-
b
-Hyd
i
roxy-
a
x
-
Amino
A
cids A. Hernandez-Juan,a Robert D. Richardson,a Darren J. Dixon*b
Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK
b
School of Chemistry, The University of Manchester, Oxford Road, Manchester M13 9PL, UK
Fax +44(161)2754939; E-mail: Darren.Dixon@manchester.ac.uk
Received 1 May 2006
devised over the years. Recent methods include stereo-
selective ring opening of phenyl-substituted aziridines,7
Sharpless AA of unsaturated carboxylic acids8 and
cinnamates.9 Additionally, asymmetric syntheses using
sulfinimides,10 Rapoport’s serine derivatives,11 Evans’
oxazolidinones,12 Garner’s aldehyde,13 Lewis acid catal-
ized aldol reactions14 have been reported.
Abstract: The stereoselective oxy-Michael addition of the ‘naked’
anion of (S)-6-methyl tetrahydropyran-2-ol to a-nitro-a,b-unsatur-
ated esters followed by reduction and in situ protection of the corre-
sponding amine provides a new and efficient route to protected b-
aryl-b-hydroxy-a-amino acids.
Key words: oxy-Michael addition, (S)-6-methyl tetrahydropyran-
2-ol, b-hydroxy-a-amino acids, stereoselectivity
In this paper we wish to report a short and efficient ste-
reoselective synthesis of protected b-aryl-b-hydroxy-a-
amino acids via a stereoselective oxy-Michael addition of
(S)-6-methyl tetrahydropyran-2-ol 1 to Michael acceptors
derived from nitro acetates (Scheme 1). Our group and
others15 have been involved with the development of
chiral water equivalents for the addition to reactive
Michael acceptors and to this end the highly diastereose-
lective oxy-Michael addition of the ‘naked’ anions of
enantiopure delta lactols has been described. We recently
found that the addition of the ‘naked’ anion of (S)-6-
methyl tetrahydropyran-2-ol (1) to b-substituted nitro ole-
fins proceeded with high diastereoselectivities and
yields16 and this methodology has been successfully
applied to other Michael acceptors such as malonate
derivatives,17 a,b-disubstituted nitro olefins,18 a,b-un-
saturated methylsulfone-derived acceptors19 and in the
synthesis of bioactive compounds.20 We believed that an
extension of this methodology to encompass the synthesis
of protected b-aryl-b-hydroxy-a-amino acids would
further highlight the power of this work.
The b-aryl-b-hydroxy-a-amino acid motif is commonly
found in an array of naturally occurring biologically ac-
tive compounds. These range from the structurally simple
such as corynecin II,1 to the structurally complex such as
gymnangiamide,2 and the ‘drug of last resort’ antibiotic
Vancomycin (Figure 1) which boasts two such motifs,
one with anti and one with syn stereochemistry.3 b-Hy-
droxy-a-amino acids are also useful for the synthesis of b-
lactams6 and b-fluoro-a-amino acids,4 compounds that act
as mechanism-based irreversible inactivators of certain
enzymes and as blocking agents for important metabolic
pathways.5
HO
HO
HO
H2N
OH
O
O
O
O
Cl
O
O
O
H
H
HO
H
OH
Cl
OTHP*
O
O
FG manipulation
OTHP*
CO2Et
H
H
H
NHMe
H
N
H
CO2Et
N
N
R
N
N
H
R
R
H
H
H
O
H
O
3
NHP
O
O
NO2
NH
HO2C
NH2
O
OH
oxy-Michael
H
OH
OH
1
HO
CO2Et
NO2
CO2Et
NO2
+
condensation
R
O
Figure 1 Vancomycin – an example of a potent, biologically active
compound possessing the b-aryl-b-hydroxy-a-amino acid motif
2
Scheme 1 An oxy-Michael route to b-aryl-b-hydroxy-a-amino
acids
As a result of the abundance and the impressive biological
activities of this class of compounds, a number of elegant
strategies for their stereoselective syntheses have been
Thus a series of b-aryl-a-nitro-a,b-unsaturated ester
Michael acceptors were prepared by the literature proce-
dures.21 These compounds were then subjected to our
standard oxy-Michael conditions. Thus, deprotonation of
(S)-6-methyl tetrahydropyran-2-ol (1) with KHMDS in
SYNLETT 2006, No. 16, pp 2673–2675
0
4
.1
0
.2
0
0
6
Advanced online publication: 22.09.2006
DOI: 10.1055/s-2006-950434; Art ID: D12506ST
© Georg Thieme Verlag Stuttgart · New York

2674
F. A. Hernandez-Juan et al.
LETTER
THF at –78 °C and addition of 18-crown-6 (1.0 equiv) reduction was successfully achieved by treatment with
generated the ‘naked’ chiral lactol alkoxide nucleophile. Ra-Ni in EtOH. To assist in isolation and characterisation,
Addition of the Michael acceptors 2 (0.67 equiv) and the amine product was treated in situ with Boc2O to afford
stirring for 1 hour before quenching with acetic acid (2.0 the N-Boc amino acid product materials 4–11 (Table 1).
equiv) at –78 °C afforded, after aqueous work-up, the
Flash column chromatography of the crude material al-
crude oxy-Michael adducts 3 with high stereoselectivity
lowed the ready separation of the syn and anti diastereo-
at the b-centre (up to 94%), and, for the major diastereo-
isomers. The stereochemistry of syn-4, the major
isomer at the b-centre, moderate selectivity at the a-centre
diastereomeric product from addition to benzaldehyde-
derived Michael acceptor (Table 1, entry 1), was unam-
(syn/anti from 2.1:1 to 3:1; Table 1).22
The high facial selectivity on addition to the nitro olefin biguously determined by single crystal X-ray diffraction
acceptor is consistent with our previous observations;16–20 (Figure 2). The relative stereochemistry across the tet-
likewise the moderate syn/anti selectivity, in favour of the rahydropyranyl ring and at both of the b- and a-centres is
syn diastereoisomer, resulting from the acetic acid quench consistent with our previous observations. Accordingly,
of the reaction mixture has been observed previously.18 the stereochemistry of the other products in Table 1 are
Interestingly, the geometry of the double bond in the assigned by analogy. Taking into account the three-step
Michael acceptor has little-to-no bearing on the observed sequence, the reactions proceeded with good to excellent
stereoselectivity at the b-centre in the oxy-Michael addi- yields (49–77%).
tion; different ratios of Z/E isomers (Table 1, entries 2 vs.
3 and 9 vs. 10) lead to similar de (b) values.
Attempted purification of the crude oxy-Michael adducts
by flash column chromatography was unsuccessful owing
to their high instability with respect to retro oxy-Michael
addition. Accordingly, the crude reaction products were
taken directly to the next stage in the sequence – the nitro
group reduction. A number of initial studies were per-
formed to ascertain the optimum conditions for the reac-
tion. Our previous best conditions18 using nickel boride
(NiCl2·6H2O/NaBH4) were unsuccessful. Little success
was witnessed using Pd-C/H2, PtO2/H2 but finally the
Figure 2 X-ray crystal structure of product syn-4
Table 1 Scope of the Reaction Sequence23
1) KHMDS, 18-C-6
THF, –78 °C
1) Ra-Ni, EtOH
O
O
O
O
O
O
+
CO2Et
NO2
2)
R
CO2Et
NO2
2) Boc2O
O
OH
CO2Et
NHBoc
CO2Et
R
R
R
2
NHBoc
(syn)-4–11
3) AcOH
1
3
(anti)-4–11
Entry
R
Z/E
de (b)
dr (a)a
2.4:1
2.0:1
2.8:1
2.7:1
2.6:1
3:1
Product
Yield (%)b
1
2
Ph
1.6:1
99:1
1:1.7
26:1
2.9:1
36:1
8:1
92
94
92
88
72
92
86
88
90
90
4
5
77
66
ND
51
58
69
49
4¢-MeO-C6H4
3
4¢-MeO-C6H4
4¢-F-C6H4
3¢-Br-C6H4
3¢-Me-C6H4
4¢-Cl-C6H4
2-Furyl
5
4
6
5
7
6
8
7
2.1:1
2.2:1
2.3:1
2.1:1
9
c
8
1:23
99:1
1:2.3
10
10
11
–
c
9
2-Thienyl
2-Thienyl
–
10
ND
a The syn/anti ratio of the major diastereomeric product at the b-centre.22
b Yield (over three steps) of separated syn and anti products.
c Extensive decomposition was observed during the Raney nickel reduction.
Synlett 2006, No. 16, 2673–2675 © Thieme Stuttgart · New York

LETTER
Route to Protected b-Aryl-b-Hydroxy-a-Amino Acids
2675
(18) Buchanan, D. J.; Dixon, D. J.; Hernandez-Juan, F. A. Org.
Biomol. Chem. 2004, 2, 2932.
(19) Hernandez-Juan, F. A.; Xiong, X.; Brewer, S. E.; Buchanan,
D. J.; Dixon, D. J. Synthesis 2005, 3283.
(20) (a) Buchanan, D. J.; Dixon, D. J.; Looker, B. E. Synlett 2005,
1948. (b) Buchanan, D. J.; Dixon, D. J.; Scott, M. S.; Lainé,
D. I. Tetrahedron: Asymmetry 2004, 15, 195.
Interestingly, the lower yields found for entries 5 and 7 are
due to a partial hydrodehalogenation of the aromatic ring
in the Raney nickel reduction step. With the five ring
heterocycles as substituents at the b-position, none of the
desired product was isolated owing to extensive decom-
position in the reduction step (entries 8 and 9).
(21) Fornicola, R. S.; Oblinger, E.; Montgomery, J. J. Org. Chem.
1998, 63, 3528.
(22) In this and in all other oxy-Michael addition reactions using
6-methyl tetrahydropyran-2-ol (1) reported by us, only the
cis-THP* ether products are observed in the reaction
mixtures.
In conclusion, a three-step sequence to protected b-aryl-b-
hydroxy-a-amino acids via a key, stereoselective oxy-
Michael addition of (S)-6-methyl tetrahydropyran-2-ol (1)
to Michael acceptors derived from nitro acetates has been
developed. As both the d-lactol and the Michael acceptors
are easily prepared, this route should find use in total syn-
thesis programs. Further work in this field is ongoing and
the results will be reported in due course.
(23) General Experimental Procedure.
To a stirred solution of (S)-6-methyl tetrahydropyran-2-ol
(1, 116mg, 1 mmol) in THF (15 mL) at –78 °C was added
KHMDS (2 mL, 1 mmol, 0.5 M solution in toluene)
dropwise. The reaction mixture was then stirred for 10 min
at –78 °C before a toluene solution of 18-crown-6 (1 mmol)
was added via syringe. The reaction mixture was then stirred
for 15 min at –78 °C before a solution of the Michael
acceptor (0.67 mmol) in THF (5 mL) was added dropwise.
Stirring was maintained for 30 min at –78 °C. The reaction
was then quenched with glacial AcOH (0.12 mL, 3 mmol)
via syringe and the resulting mixture was allowed to warm
to r.t. Then, Et2O (15 mL) and H2O (15 mL) were added and
the aqueous layer separated and extracted with Et2O (3 × 15
mL). The combined organic layers were washed with brine
(15 mL), dried (MgSO4), filtered and concentrated in vacuo.
The reaction diastereoselectivity was determined by
inspection of the crude 500 MHz NMR. A solution of the
crude oxy-Michael product in EtOH was then added to a
suspension of Raney nickel in EtOH and stirred for 20 h at
r.t. The reaction mixture was filtered through Celite®,
partially concentrated in vacuo, and Boc2O (3 equiv) was
added. The reaction mixture was stirred for a further 20 h
before the solvent was removed in vacuo and the crude
product purified by column chromatography.
Acknowledgment
We gratefully acknowledge the EPSRC for funding (F.A.H.-J. and
R.D.R.). We are indebted to Dr. J. E. Davies for single-crystal X-ray
analysis, and EPSRC National Mass Spectrometry Service Centre,
Swansea for analysis.
References and Notes
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tert-Butyl (1S,2R)-2-[(2R,6S)-Tetrahydro-6-methyl-2H-
pyran-2-yloxy]-1-(ethoxycarbonyl)-2-phenylethyl-
carbamate [syn-4 (major)].
[a]D20 –10.0 (c 0.3, CHCl3). IR (film): nmax = 1719, 1498,
1366, 1160, 1069, 1031 cm–1. 1H NMR (500 MHz, CDCl3):
d = 7.42 (d, J = 7.7 Hz, 2 H), 7.32 (t, J = 7.2 Hz, 2 H), 7.26
(t, J = 7.2 Hz, 1 H), 5.44 (d, J = 9.1 Hz, 1 H), 5.24 (d, J = 3.0
Hz, 1 H), 4.54 (dd, J = 9.1, 3.0 Hz, 1 H), 4.47 (dd, J = 9.5,
2.1 Hz, 1 H), 4.21 (m, 2 H), 3.43 (ddd, J = 12.3, 6.1, 2.0 Hz,
1 H), 1.84–1.68 (m, 2 H), 1.47–1.10 (m, 4 H), 1.34 (s, 9 H),
1.27 (t, J = 7.1 Hz, 3 H), 1.12 (d, J = 6.1 Hz, 3 H). 13C NMR
(125 MHz, CDCl3): d = 170.7, 155.5, 138.8, 128.0, 127.6,
126.8, 102.0, 79.5, 78.7, 72.8, 61.4, 59.1, 32.1, 30.5, 28.2,
22.1, 21.5, 14.2. HRMS (EI): m/z calcd for [M + Na]+:
430.2206; found: 430.2205.
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pyran-2-yloxy]-1-(ethoxycarbonyl)-2-phenylethyl-
carbamate [anti-4 (minor)].
[a]D20 –25.0 (c 1.0, CHCl3). IR (film): nmax = 1717, 1503,
1367, 1163, 1071, 1028 cm–1. 1H NMR (500 MHz, CDCl3):
d = 7.35–7.25 (m, 5 H), 5.26 (d, J = 4.0 Hz, 1 H), 5.23 (d,
J = 9.1 Hz, 1 H), 4.78 (dd, J = 9.1, 4.0 Hz, 1 H), 4.73 (d,
J = 8.4 Hz, 1 H), 4.10 (m, 2 H), 3.56 (m, 1 H), 1.85–1.74 (m,
2 H), 1.59–1.10 (m, 4 H), 1.45 (s, 9 H), 1.17 (t, J = 7.1 Hz, 3
H), 1.16 (d, J = 7.2 Hz, 3 H). 13C NMR (125 MHz, CDCl3):
d = 170.1, 155.4, 138.2, 128.0, 127.7, 126.7, 100.5, 79.7,
72.6, 61.2, 57.3, 32.2, 30.3, 29.7, 28.3, 22.2, 21.5, 14.0.
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430.2221.
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Synlett 2006, No. 16, 2673–2675 © Thieme Stuttgart · New York