A stereoselective synthesis of (2R,3S)-2-amino-3,4-dihydroxybutyric acid using an ether directed aza-Claisen rearrangement

Article abstract of DOI:10.1016/j.tetlet.2007.03.161

A new approach for the stereoselective synthesis of (2R,3S)-2-amino-3,4-dihydroxybutyric acid, an α-amino acid from Lyophyllum ulmarium, has been accomplished using an ether directed aza-Claisen rearrangement. On investigation of optimal conditions for th

Full text of DOI:10.1016/j.tetlet.2007.03.161

Tetrahedron Letters 48 (2007) 3771–3773
A stereoselective synthesis of (2R,3S)-2-amino-3,4-dihydroxy-
butyric acid using an ether directed aza-Claisen rearrangement
Michael D. Swift and Andrew Sutherland*
WestChem, Department of Chemistry, The Joseph Black Building, University of Glasgow, Glasgow G12 8QQ, UK
Received 19 February 2007; revised 7 March 2007; accepted 30 March 2007
Available online 4 April 2007
Abstract—A new approach for the stereoselective synthesis of (2R,3S)-2-amino-3,4-dihydroxybutyric acid, an a-amino acid from
Lyophyllum ulmarium, has been accomplished using an ether directed aza-Claisen rearrangement. On investigation of optimal con-
ditions for this key step it was shown for the first time that Au(I) can be used to catalyse this transformation.
Ó 2007 Elsevier Ltd. All rights reserved.
b-Hydroxy-a-amino acids are widely prevalent in Nat-
ure occurring as structural components in many biolog-
ically active peptides and natural products.1 Due to their
importance, many different approaches have been devel-
oped for their stereoselective synthesis2 including asym-
metric aldol additions of benzophenone glycinates,3
Sharpless epoxidation of allylic alcohols,4 Strecker syn-
thesis of protected glyceraldehydes5 and threonine aldol-
ase mediated reactions with glycine.6
tuted allylic acetimidate which has been used to com-
plete a stereoselective synthesis of (2R,3S)-2-amino-
3,4-dihydroxybutyric acid 1. We also show for the first
We have recently developed an ether directed, palla-
dium(II)-catalysed, aza-Claisen rearrangement of allylic
trichloroacetimidates7 which, when carried out in non-
coordinating solvents such as toluene, produces the
corresponding allylic amides in good yields and in high
diastereoselectivity (up to 15:1).8 Oxidation of the allylic
amides followed by deprotection then gave direct access
to a range of erythro-b-hydroxy-a-amino acids with sim-
ple alkyl side chains (Scheme 1).9 Having established an
efficient synthesis of these compounds we sought to
expand the scope of this ether directed rearrangement
for the stereoselective preparation of more complex b-
hydroxy-a-amino acids and other natural products.
Our initial target was (2R,3S)-2-amino-3,4-dihydroxy-
butyric acid 1,
a
dihydroxylated a-amino acid
which has been isolated from the edible mushroom,
Lyophyllum ulmarium.10 In this Letter, we now report
the ether directed rearrangement of a novel 4,5-disubsti-
Keywords: b-Hydroxy-a-amino acid; Natural product; Rearrangement;
Stereoselective synthesis; Palladium catalysis.
*
Scheme 1. Synthesis of b-hydroxy-a-amino acids via an ether directed
Corresponding author. Tel.: +44 141 330 5936; fax: +44 141 330
aza-Claisen rearrangement.
4888; e-mail: andrews@chem.gla.ac.uk
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.03.161

3772
M. D. Swift, A. Sutherland / Tetrahedron Letters 48 (2007) 3771–3773
time that an Au(I)-catalyst can be used to effect ether
directed rearrangements.
jected to a thermal rearrangement in refluxing p-xylene
(entry 1).11,12 While this gave the corresponding allylic
amides 7a and 7b in good yield over the two steps from
allylic alcohol 6, the reaction time was excessively long
(120 h) and more importantly, the transformation was
not selective for the desired diastereomer, 7a. Allylic
trichloroacetimidate 2 was then subjected to Pd(II)-
catalysis using both bis(acetonitrile)- and bis(benzonit-
rile)-palladium(II) chloride under standard conditions
(entries 2 and 3).13 These reactions were complete in
only 12 h and although the yields were only 32% and
30%, respectively, from 6, the reaction was now selective
for diastereomer 7a. In our studies on the ether directed
rearrangement of allylic trichloroacetimidates, we have
found that using non-coordinating solvents such as tol-
uene not only results in a more selective rearrangement
but that the reactions are cleaner giving the allylic tri-
chloroamides in higher yields.8b,14 It has also been
shown that the rearrangement of allylic trichloroacet-
imidates can also be catalysed using platinum and gold
complexes.8b,15 Thus, allylic trichloroacetimidate 2 was
treated with platinum(II)-, gold(III)- and gold(I)-cata-
lysts in toluene. These were all able to catalyse this
transformation (entries 4–6), and for the gold catalysts,
in higher yield than previous metal catalysed conditions.
Moreover, the use of gold(I) chloride represents the first
example of an Au(I)-catalyst to effect an ether directed
rearrangement. The reaction was also repeated using a
Pd(II)-catalyst in toluene (entry 7) and this gave an
excellent yield of the allylic amides (68% over the two
steps) and with a 4:1 ratio of diastereomers. Our previ-
ous work9 on MOM-ether directed rearrangements
using less complex substrates has produced allylic tri-
chloroamides with diastereoselective ratios of at least
9:1 and thus, the modest selectivities observed here are
surprising. It is likely that the steric bulk of the tert-
butyldiphenylsilyl ether while not completely preventing
coordination of the catalyst to the MOM-ether does hin-
der the effectiveness of the directing effect.
OH
HO
CO2H
NH2
1
The initial stage of this project involved the efficient
preparation of the rearrangement substrate 2, which
was achieved in five steps from commercially available
a,b-unsaturated ester 3 (Scheme 2). We have shown that
ether directed rearrangements are most effective when
the MOM-ether group is used to direct the metal cata-
lyst.8 Thus, acid mediated hydrolysis of the acetonide
protecting group of 3 gave the corresponding diol 4 in
94% yield. Subsequent protection of the primary alcohol
as the tert-butyldiphenylsilyl ether and the secondary
alcohol as the required MOM-ether both under stan-
dard conditions, gave 5 in excellent overall yield. Reduc-
tion of 5 using 2.2 equiv of DIBAL-H gave allylic
alcohol 6 in 70% overall yield from the commercially
available starting material 3. Finally, reaction with
DBU and trichloroacetonitrile gave the desired rear-
rangement substrate 2.
With allylic trichloroacetimidate 2 in hand, a series of
reactions were carried out to find the optimal conditions
for the rearrangement (Table 1). Initially, 2 was sub-
O
OH
a
O
HO
CO2Et
CO2Et
4
3
Nevertheless, using this approach does give allylic
amides 7a and 7b in only six steps, and in 48% overall
yield from commercially available starting material 3.
At this stage 7a was easily separated from 7b using flash
column chromatography. Ruthenium(III) trichloride
catalysed oxidation16 of allylic amide 7a gave the corre-
sponding carboxylic acid 8 in 71% yield (Scheme 3).
Removal of the silyl ether using TBAF and acid medi-
ated deprotection of the other functional groups gave
(2R,3S)-2-amino-3,4-dihydroxybutyric acid 1 in 44%
yield over the two steps.17
b, c
OMOM
OMOM
d
TBDPSO
TBDPSO
CO2Et
OH
5
6
e
In conclusion, we have developed a direct, novel
approach for the synthesis of (2R,3S)-2-amino-3,4-
dihydroxybutyric acid 1 using an MOM-ether directed
rearrangement of an allylic trichloroacetimidate to effect
the key step. As well as using Pd(II), Pt(II) and Au(III)
for this transformation, we have also shown for the first
time that an Au(I)-catalyst can be used during an ether
directed rearrangement. Further studies are currently
underway to expand the scope of directed rearrange-
ments of highly substituted allylic acetimidate for natu-
ral product synthesis.
OMOM
HN
TBDPSO
O
CCl3
2
Scheme 2. Reagents and conditions: (a) 2 M HCl, 94%; (b) TBDPSCl,
imidazole, THF, 100%; (c) MOMBr, EtN(iPr)2, CH2Cl2, 86%; (d)
DIBAL-H (2.2 equiv), Et2O, ꢀ78 °C to rt, 86%; (e) Cl3CCN, DBU,
CH2Cl2.

M. D. Swift, A. Sutherland / Tetrahedron Letters 48 (2007) 3771–3773
3773
Table 1.
OMOM
HN
OMOM
HN
TBDPSO
TBDPSO
+
2
O
O
CCl3
CCl3
7a
7b
Entry
Reaction conditionsa
Reaction time (h)
Yieldb (%)
Ratioc (7a/7b)
1
2
3
4
5
6
7
D, p-Xylene
120
12
12
168
48
168
12
61
32
30
25
49
40
68
1:1
4:1
4:1
4:1
2:1
3:1
4:1
PdCl2(MeCN)2, THF
PdCl2(PhCN)2, THF
PtCl2, toluene
HAuCl4Æ3H2O, toluene
AuCl, toluene
PdCl2(MeCN)2, toluene
a All reactions using a catalyst were carried out at room temperature.
b Isolated combined yields of 7a and 7b from E-allylic alcohol 6.
c Ratio in crude reaction mixture.
2. For a range of general examples see: (a) Blaskovich, M.
A.; Evinder, G.; Rose, N. G. W.; Wilkinson, S.; Luo, Y.;
Lajoie, G. A. J. Org. Chem. 1998, 63, 3631–3646; (b)
MacMillan, J. B.; Molinski, T. F. Org. Lett. 2002, 4, 1883–
1886; (c) Mettath, S.; Srikanth, G. S. C.; Dangerfield, B.
S.; Castle, S. L. J. Org. Chem. 2004, 69, 6489–6492.
3. O’Donnell, M. J. Aldrichim. Acta 2001, 34, 3–15, and
references cited therein.
4. Nagamitsu, T.; Sunazuka, T.; Tanaka, H.; Omura, S.;
Sprengler, P. A.; Smith, A. B., III. J. Am. Chem. Soc.
1996, 118, 3584–3590.
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´
5. Cativiela, C.; Dıaz-de-Villegas, M. D.; Galvez, J. A.;
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Garcıa, J. I. Tetrahedron 1996, 52, 9563–9574.
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J. Am. Chem. Soc. 1997, 119, 11734–11742.
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2005, 3, 735–736; (b) Jamieson, A. G.; Sutherland, A. Org.
Biomol. Chem. 2006, 4, 2932–2937; (c) Jamieson, A. G.;
Sutherland, A. Tetrahedron 2007, 63, 2123–2131.
9. Fanning, K. N.; Jamieson, A. G.; Sutherland, A. Org.
Biomol. Chem. 2005, 3, 3749–3756.
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Scheme 3. Reagents and conditions: (a) RuCl3ÆxH2O, NaIO4, CCl4,
MeCN, H2O, 71%; (b) TBAF, THF; (c) 6 M HCl, D, 44% over two
steps.
Acknowledgements
The authors gratefully acknowledge the EPSRC (stu-
dentship to M.D.S.) and the University of Glasgow
for financial support.
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References and notes
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24
17. Optical rotation for 1: ½aꢁD +10.6 (c 0.5, H2O); lit.5 +11.3
(c 7.0, H2O). Spectroscopic data were entirely consistent
with that published for (2R,3S)-2-amino-3,4-dihydroxy-
butyric acid 1.5