Addition of 2-lithiothiazoles to ROPHy/SOPHy aldoximes: Asymmetric synthesis of 1-(2-thiazolyl)ethylamines

Article abstract of DOI:10.1055/s-1999-3109

A new asymmetric synthesis of 1-(2-thiazolyl)ethylamines is described in which the key step is the diastereoselective addition of 2-lithiothiazoles to O-(1-phenylbutyl) aidoximes.

Full text of DOI:10.1055/s-1999-3109

984
LETTER
Addition of 2-Lithiothiazoles to ROPHy/SOPHy Aldoximes: Asymmetric
Synthesis of 1-(2-Thiazolyl)ethylamines
Christopher J. Moody, James C. A. Hunt
School of Chemistry, University of Exeter, Stocker Road, Exeter, EX4 4QD, UK
Fax +44(1392)263434, E-mail: c.j.moody@exeter.ac.uk
Received 8 February 1999
Dedicated with respect and affection to Professor Albert Eschenmoser in recognition of his outstanding contributions to organic
chemistry
droxylamine (ROPHy) with the appropriate aldehyde;10 in
Abstract: A new asymmetric synthesis of 1-(2-thiazolyl)ethyl-
all cases the Z-oxime ether was also formed (17-50%) but
amines is described in which the key step is the diastereoselective
was readily separated by chromatography.11 However the
acetaldehyde oxime ether 1c was formed as a 1:1 mixture
of geometric isomers; separation by chromatography only
addition of 2-lithiothiazoles to O-(1-phenylbutyl) aldoximes.
Key words: oxime ether, hydroxylamine, thiazole
gave a low yield of the E-oxime ether (22%). Oxime
ethers 1a-d were treated with 2-lithiothiazole (prepared
by reaction of thiazole with n-butyllithium in ether at -78
Thiazole containing peptides often show interesting bio-
logical activity. For example, the potent antineoplastic
°C) in the presence of boron trifluoride etherate to give
agents dolastatin 10 and the virenamides are both linear
hydroxylamines 2 in excellent yield (Table).12 Determina-
peptides containing 1-(2-thiazolyl)ethylamine units.1,2
tion of the diastereoselectivity by 1H NMR showed the de
Nostocyclamide and promothiocin A, on the other hand,
are macrocyclic peptides containing 1-(4-carboxy-2-thia-
to be greater than 85% in all cases except the acetaldehyde
oxime ether 1c, where a low de, thought to be caused by
facile isomerisation of the E-oxime ether under the reac-
tion conditions, was obtained. Addition of 2-lithio-4-me-
thylthiazole (obtained from reaction of 4-methylthiazole
with n-butyllithium) proceeded in a similar fashion to the
2-lithiothiazole analogue giving a high yield and excellent
de (Table). The stereochemical outcome of the addition
zolyl)ethylamine units. In continuation of our interest in
the synthesis of biologically active thiazoles,3 we have re-
cently reported the synthesis of both these macrocyclic
peptides, using a modified Hantzsch reaction to prepare
the chiral 2,4-disubstituted thiazoles.4,5 In these two cases
the source of chirality was the starting a-amino acid deriv-
ative, but other approaches to the asymmetric synthesis of
1-(2-thiazolyl)ethylamines have also been reported.
These include the addition of 2-lithiothiazoles to carbo-
hydrate derived nitrones,6 the addition of Grignard re-
agents to 2-thiazolyl nitrones,7 and the alkylation of
imines derived from 2-(aminomethyl)thiazole.8
reactions was assumed to be as indicated based on our pre-
vious results.10
Table Preparation of oxime ethers 1 and their addition reactions with
2-lithiothiazoles to give hydroxylamines 2
Our own work in this area initially involved the addition
of Grignard reagents to (S)-O-(1-phenylbutyl)-2-thiaz-
olylcarboxaldehyde aldoxime; however the yield was low
and the diastereoselectivity poor (20%).9 Therefore an al-
ternative was sought, and we now report an asymmetric
synthesis of 1-(2-thiazolyl)ethylamines, including N-pro-
tected dolaphenine, the C-terminal unit of dolastatin 10,
via addition of 2-lithiothiazoles to a range of (R)- and (S)-
O-(1-phenylbutyl) oxime ethers (ROPHy and SOPHy al-
doximes).
The E-oxime ethers 1 were prepared by our conventional
method of condensation of (R)-O-(1-phenylbutyl) hy-
Synlett 1999, S1, 984–986 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Asymmetric Synthesis of 1-(2-Thiazolyl)ethylamines
985
(6) Merchan, F. L.; Merino, P.; Rojo, I.; Tejero, T. Tetrahedron:
Asymmetry 1995, 6, 2145; see also: Tomioka, K,; Satoh, M.;
Taniyama, D.; Kanai, M. Iida, A. Heterocycles 1998, 47, 77.
(7) Merchan, F. L.; Merino, P.; Rojo, I.; Tejero, T.; Dondoni, A.;
Tetrahedron: Asymmetry 1996, 7, 667.
(8) Dondoni, A.; Merchan, F. L.; Merino, P.; Rojo, I.; Tejero, T.
Synthesis 1996, 641; for a recent review of Dondoni’s
contributions in this area, see: Dondoni, A. Synthesis 1998,
1681.
Hydroxylamines 2a and 2b were subsequently converted
into the t-butoxycarbonyl protected amines 3a and 3b.
The conversion was effected by N-O bond cleavage of the
chiral auxiliary using the zinc/acetic acid/ultrasound
method,13 immediately followed by nitrogen protection
with di-tert-butyl dicarbonate.14,15 In both cases the corre-
sponding racemates were also prepared for comparison by
HPLC on a chiral stationary phase, thereby confirming the
enantiomeric purity of 3a and 3b as 83 and 92% ee respec-
tively.16 In the case of amine 3a ((S)-dolaphenine) the ab-
solute configuration was confirmed by comparison of the
optical rotation to literature values.1b-d N-Protected amine
3b, the constituent 1-(2-thiazolyl)ethylamine in the linear
peptides virenamides A and B, was assigned (S)-stere-
ochemistry by analogy.
(9) Hunt, J. C. A.; Lloyd, C.; Moody, C. J.; Slawin, A. M. Z.;
Takle, A. K. submitted for publication.
(10) Gallagher, P. T.; Hunt, J. C. A.; Lightfoot, A. P.; Moody, C. J.
J. Chem. Soc., Perkin Trans. 1 1997, 2633; Moody, C. J.;
Lightfoot, A. P.; Gallagher, P. T. J. Org. Chem. 1997, 62, 746;
Moody, C. J.; Lightfoot, A. P.; Gallagher, P. T. Synlett 1997,
659.
(11) Selected data
Oxime 1a, oil, [a]21D = -20.7 (c 1.0, CH2Cl2); dH (300 MHz;
CDCl3) 7.58 (1H, t, J 6.5, CHN), 7.33 (8H, m, ArH), 7.18 (2H,
m, ArH), 5.16 (1H, t, J 7.0, OCH), 3.51 (2H, d, J 6.5, CH2Ph),
1.99 (1H, m, CHH), 1.79 (1H, m, CHH), 1.51-1.38 (2H, m,
CH2), 0.99 (3H, t, J 7.3, Me)
Oxime 1b, oil, [a]20D = +9.9 (c 0.95, CH2Cl2); dH (300 MHz;
CDCl3) 7.47-7.24 (6H, m, CHN, ArH), 5.06 (1H, t, J 6.8,
OCH), 2.48 (1H, m, CHMe2), 1.95 (1H, m, CHH), 1.75 (1H,
m, CHH), 1.46-1.32 (2H, m, CH2), 1.07 (3H, d, J 6.8, Me),
1.04 (3H, d, J 6.8, Me), 0.96 (3H, t, J 7.3, Me).
Oxime 1c, oil, [a]18D = +7.8 (c 1.8, CH2Cl2); dH (300 MHz;
CDCl3) 7.50 (1H, t, J 5.9, CHN), 7.39-7.26 (5H, m, ArH), 5.06
(1H, t, J 6.8, OCH), 1.95-1.89 (1H, m, CHH), 1.81 (3H, t, J
5.8, MeCN), 1.78-1.69 (1H, m, CHH), 1.48-1.31 (2H, m,
CH2), 0.96 (3H, t, J 7.3, Me).
In summary, we have established a simple and
efficient method for the asymmetric synthesis of 1-
(2-thiazolyl)ethylamines, which has the potential for
application in the synthesis of the chiral thiazole units
found in a range of natural products.
Oxime 1d, oil, [a]21D = +7.6 (c 1.7, CH2Cl2); dH (300 MHz;
CDCl3) 7.49 (1H, t, J 6.6, CHN), 7.39-7.24 (5H, m, ArH), 5.10
(1H, t, J 6.7, OCH), 2.06 (2H, dt, J 2.9, 6.8, CH2CN), 2.01
(1H, m, CHH), 1.84-1.72 (2H, m, CHH, CHMe2), 0.97 (3H, t,
J 7.4, Me), 0.94 (3H, d, J 7.4, CMe), 0.90 (3H, d, J 6.6, CMe).
(12) Thiazole (0.85 mL, 12 mmol) was dissolved in ether (5.5 mL)
under nitrogen and cooled to -78 °C. n-Butyllithium (2.5 M;
4.8 mL, 12 mmol) was added dropwise to the solution over 15
min. The mixture turned pale yellow. The mixture was stirred
for a further 30 min, then added dropwise to a pre-formed
mixture of the oxime ether 1 (4 mmol) and boron trifluoride
etherate (12 mmol) in toluene (9 mL) under nitrogen at -78 °C.
The mixture was stirred until all starting material was consu-
med (typically 2-12 hours). The reaction mixture was quen-
ched at -78 °C with saturated ammonium chloride solution,
allowed to warm to room temperature, and extracted with
ether (3 x 15 mL). The extracts were combined, dried
(Na2SO4), filtered and evaporated. The residue was purified
by flash chromatography on silica gel using ethyl acetate-light
petroleum (1:4) as eluent to give the hydroxylamine 2.
(13) Enders, D.; Kempen, H. Synlett 1994, 969.
Acknowledgement
This work was supported by the EPSRC. We thank Dr Mark Bagley
for helpful discussions, and the EPSRC Mass Spectrometry service
at Swansea for mass spectra.
References and Notes
(1) For accounts of the isolation, structure determination and
synthesis of dolastatin 10, see: (a) Pettit, G. R.; Kamano, Y.;
Herald, C. L.; Tuinman, A. A.; Boettner, F. E., Kizu, H.;
Schmidt, J. M.; Baczynkyj, L.; Tomer, K. B.; Bontems, R. J.
J. Am. Chem. Soc. 1987, 109, 6883; (b) Pettit, G. R.; Singh, S.
B.; Hogan, F.; Lloyd-Williams, P.; Herald, D. L.; Burkett, D.
D.; Clewlow, P. J. J. Am. Chem. Soc. 1989, 111, 5463. For the
synthesis of the chiral thiazole, dolaphenine, see:
(c) Bredenkamp, M. W.; Holzapfel, C. W.; Snyman, R. M.;
van Zyl, W. J. Synth. Commun. 1992, 22, 3029; (d) Irako, N.;
Hamada, Y.; Shioiri, T. Tetrahedron Lett. 1992, 48, 7265.
(2) For an account of the isolation and structure determination of
the virenamides A-C, see: Carroll, A. R.; Feng, Y.; Bowden,
B. F.; Coll, J. C. J. Org. Chem. 1996, 61, 4059.
(3) Moody, C. J.; Swann, E. J. Chem. Soc., Perkin Trans. 1, 1993,
2561; Moody, C. J.; Swann, E.; Houlbrook, S.; Stephens, M.
A.; Stratford, I. J. J. Med. Chem., 1995, 38, 1039; Moody, C.
J.; Roffey, J. R. A.; Stephens, M. A.; Stratford, I. J. Anti-
Cancer Drugs, 1997, 8, 489.
(4) Moody, C. J.; Bagley, M. C. J. Chem. Soc., Perkin Trans. 1
1998, 601.
(5) Moody, C. J.; Bagley, M. C. Chem. Commun. 1998, 2049.
(14) Zinc dust (40 mmol) was added to a mixture of hydroxylamine
2 (1 mmol) in acetic acid : water (1 : 1; 6.5 mL). The mixture
was placed in a sonic bath at 40 °C and the reaction followed
by TLC until completion (typically 2-6 h). The zinc was
filtered and washed with ether. The filtrate was basified with
sodium hydrogen carbonate solution (sat.) and the aqueous
layer exhaustively extracted with dichloromethane (8 x 15
mL). The extracts were combined, dried (Na2SO4), filtered
and evaporated. The residue was dissolved in dichlorometha-
ne (7 mL) and di-tert-butyl dicarbonate (4 mmol) and DMAP
(cat.). The mixture was stirred at room temperature for 12 h.
Saturated aqueous sodium bicarbonate (10 mL) was added
and the mixture stirred for 10 min. The mixture was extracted
with dichloromethane (4 x 10 mL), the organic extracts were
Synlett 1999, S1, 984–986 ISSN 0936-5214 © Thieme Stuttgart · New York

986
C. J. Moody, J. C. A. Hunt
LETTER
combined, dried (Na2SO4), filtered and evaporated. The resi-
due was purified by flash chromatography on silica gel, elu-
ting with ethyl acetate : light petroleum to give the t-Boc
amine 3.
(16) For 3a: Chiralpak AD column using hexane/2-propanol as sol-
vent (88 : 12); for 3b: Chiralcel OD column using hexane/2-
propanol as solvent (90 : 10).
(15) Selected data
N-Boc amine 3a, mp 89-90 °C (from n-hexane), (lit.1d mp
Article Identifier:
1437-2096,E;1999,0,S1,0984,0986,ftx,en;W06799ST.pdf
91-92 °C), [a]20D = -26.6 (c 0.6, CHCl3), (lit.1d [a]24.5D = -25.5
(c 0.6, CHCl3).
N-Boc amine 3b [a]21D = -33.6 (c 1.1, CHCl3).
Synlett 1999, S1, 984–986 ISSN 0936-5214 © Thieme Stuttgart · New York