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.
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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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tert-Butyl (1R,2R)-2-[(2R,6S)-Tetrahydro-6-methyl-2H-
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.
HRMS (EI): m/z calcd for [M + Na]+: 430.2206; found:
430.2221.
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Synlett 2006, No. 16, 2673–2675 © Thieme Stuttgart · New York