Enantio- and diastereoselective syntheses of orthogonally protected anti-2-amino-1,3,4-butanetriols from an achiral β-ketoester

Article abstract of DOI:10.1055/s-2005-871954

An efficient enantio- and diastereoselective synthesis of orthogonally protected anti-2-amino-1,3,4-butanetriols from an achiral source is described. The anti relationship between the two adjacent aminated and hydroxylated carbons was controlled by sequen

Full text of DOI:10.1055/s-2005-871954

2086
LETTER
Enantio- and Diastereoselective Syntheses of Orthogonally Protected
anti-2-Amino-1,3,4-butanetriols from an Achiral b-Ketoester
S
ynthese
s
of Ortho
a
gonally
P
ro
n
tected anti-2
n
-Amino-1,3,4-buta
B
netriols ourdreux, Bruno Drouillat, Christine Greck*
Laboratoire SIRCOB, UMR 8086, Université de Versailles Saint-Quentin-en-Yvelines, 45 avenue des Etats-Unis,
78035 Versailles Cédex, France
Fax +33(1)39254452; E-mail: greck@chimie.uvsq.fr
Received 15 April 2005
In recent years, several approaches to the synthesis of
anti-ABTs have been developed. Most of these syntheses
started from naturally occurring compounds already pos-
sessing one or two of the stereogenic centers.1a,2a,4 To our
Abstract: An efficient enantio- and diastereoselective synthesis of
orthogonally protected anti-2-amino-1,3,4-butanetriols from an
achiral source is described. The anti relationship between the two
adjacent aminated and hydroxylated carbons was controlled by se-
quential hydrogenation of a b-ketoester in the presence of a chiral knowledge, only a few syntheses of anti-ABTs using
ruthenium catalyst and electrophilic amination of the resulting b-
hydroxyester.
achiral sources as precursors have been described in the
literature. The first relied on the asymmetric Sharpless ep-
Key words: aminobutanetriols, asymmetric synthesis, chiral ruthe-
nium catalyst, electrophilic amination, orthogonal protecting
groups
oxidation reaction of allylic alcohols followed by ring-
opening reactions of the resulting 2,3-epoxyalcohols by
nucleophilic nitrogen equivalents.5 The second involved
catalyzed hydration of chlorofumaric acid to L-threo-
chloromalic acid by a fumarase before introducing the ni-
trogen atom by intramolecular nucleophilic substitution.6
The third installed the syn-vicinal amino alcohol function-
ality by the regioselective aminohydroxylation of trans-
ethyl 4-(4-methoxyphenoxy)crotonate before inverting
the C2 hydroxy group stereochemistry.7 In order to make
possible regioselective transformations to targeted mole-
cules, the protecting groups used should be orthogonal
with one another.
Enantiomerically
pure
2-amino-1,3,4-butanetriols
(ABTs) are highly functionalized compounds that are in-
teresting key intermediates for the production of natural
products. ABTs and ABT equivalents have been used in
protected and unprotected forms for the production of bi-
ologically important compounds including sphingosines,1
the ribosyldiazepanone core of liposidomycins2 and
glycomimetics3 (Scheme 1).
In connection with our work on the asymmetric synthesis
of a-amino-b-hydroxy acids,8 we proposed a diastereose-
lective synthesis of orthogonally protected anti-2-amino-
1,3,4-butanetriols 9a and 9b starting from a prochiral ma-
terial. These compounds were derived from the a-hydrazi-
OH
HO
N
O
OMe
HO2C
N
O
O
O
ribosyldiazepanone core
of the liposidomycins
no-b-hydroxyester 3 obtained with excellent anti
stereoselectivity at C2-C3 from the corresponding b-ke-
toester 1 by catalytic hydrogenation followed by electro-
philic amination of the resulting b-hydroxyester
(Scheme 2).
OR2
H
N
Catalytic hydrogenation of 1 conducted in methanol at
40 °C under a pressure of 10 bar of hydrogen in the pres-
ence of 2 mol% of (R)-BinapRuBr2 afforded the b-hy-
R3O
HO
HO
OR1
NHR4
OH
ABTs
OH
1-deoxyiminosugars
OH
OBn
TIPSO
CO2Me
NCbz
TIPSO
OR
NHBoc
OH
CbzHN
9a R = Bz
9b R = PMP
OH
3
11
NH2
sphingosines
O
Scheme 1
TIPSO
CO2Me
SYNLETT 2005, No. 13, pp 2086–2088
Advanced online publication: 12.07.2005
1
9
.0
8
.2
0
0
5
1
DOI: 10.1055/s-2005-871954; Art ID: D10205ST
© Georg Thieme Verlag Stuttgart · New York
Scheme 2 Retrosynthetic analysis.

LETTER
Syntheses of Orthogonally Protected anti-2-Amino-1,3,4-butanetriols
2087
droxyester 2 in quantitative yield. The hydrogenation was Ni to the reaction mixture. Protection of the amine by the
totally enantioselective as confirmed by europium NMR tert-butoxycarbonyl group afforded 5 in 93% yield. The
studies. Noyori described the catalyzed hydrogenation of ester function of 5 was reduced with calcium borohydride
ethyl 4-(triisopropyloxy)-3-oxopentanoate in the presence at –20 °C to room temperature and the primary alcohol 6
of previously isolated (S)-BinapRuBr2 in similar yield and was obtained in 99% yield.
enantioselectivity.9
To obtain an orthogonally protected triol, we envisaged
The use of 2 mol% (S)-BinapRuBr2 yielded only the R- the introduction of a benzyl ether on the free alcohol
enantiomer of 2. In our case, each catalyst was prepared in group of 6. Treatment of 6 with sodium hydride and ben-
situ from commercially available Ru(Cod)(2-methylal- zyl bromide in DMF resulted in the migration of the tert-
lyl)2.10
butyldimethylsilyl group to the primary alcohol and sub-
sequent benzylation of the secondary alcohol in 80%
yield. Proton NMR of the crude product showed that a
small amount of 6 was benzylated on the primary alcohol.
Regioselective cleavage of the tert-butyldimethylsilyl
ether of 7 using 0.1 equivalent of PPTS in THF–EtOH af-
forded 8 in 86% yield.12
OH
b
a
TIPSO
CO2Me
1
3
2
Scheme 3 Reagents and conditions: (a) H2 (10 bar), (R)-Binap
RuBr2 (2 mol%), MeOH, 40 °C, 16 h (quantitative yield, ee > 95%);
(b) 1. MeZnBr (1.1 equiv) THF, 1 h, 0 °C; 2. LDA (2.2 equiv), THF,
1 h, –78 °C; 3. CbzN=NCbz (2 equiv), THF, 1.5 h, –78 °C; 4. sat. aq
NH4Cl (52%, de = 95%).
Benzoylation of 8 gave orthogonally protected ABT 9a in
98% yield. Treatment of 8 with para-methoxyphenyl al-
cohol under Mitsunobu conditions13 successfully fur-
nished the desired orthogonally protected ABT 9b in 70%
yield (Scheme 4).
The electrophilic amination of the zinc enolate of 2 was
performed at –78 °C with dibenzyl azodicarboxylate to
produce the anti diastereoisomer 3 in 52% yield and 95%
diastereomeric excess. Starting material 2 was recovered
in 34% yield (Scheme 3). Our result is in contrast with
that of Guanti who showed that the electrophilic amina-
tion of the lithium enolate of methyl 4-(tert-butyldi-
phenylsilyloxy)-3-oxopentanoate with di-tert-butylazo-
dicarboxylate led to only a moderate selectivity of 2:1 fa-
voring the anti diastereoisomer even at low temperature.11
Finally, the orthogonality of the protection strategy em-
ployed in the synthesis was confirmed by regioselective
unmasking of each O-protecting group. As expected the
benzoyl, PMP, TIPS, and benzyl groups could be selec-
tively removed by PhLi or NaOH, CAN, TBAF, and H2 in
presence of Pd/C, respectively, as shown in Scheme 5.
This synthetic route provides an efficient and general
method for obtaining orthogonally protected anti-ABTs
by coupling two sequential reactions: catalytic hydroge-
nation and electrophilic amination. The same key steps
could be applied to prepare the enantiomers of 9a and 9b14
from the same prochiral b-keto ester. The anti-ABTs syn-
thesized in this work are valuable building blocks for the
preparation of other types of natural products.
The resulting a-hydrazino-b-hydroxyester 3 was protect-
ed as a tert-butyldimethylsilyl ether in 93% yield. One-pot
hydrogenolysis of the benzylcarbamates of 4 was accom-
plished and gave the resulting a-amino ester in 75% yield.
The hydrazine was first deprotected using Pd/C as catalyst
and the N–N bond was then cleaved by addition of Raney-
OTBDMS
OTBDMS
CO2Me
OTBDMS
a
b, c
d
TIPSO
CO2Me
TIPSO
TIPSO
3
OH
NCbz
NHBoc
NHBoc
CbzHN
4
5
6
e
OBn
g
TIPSO
OBz
NHBoc
OBn
OBn
9a
f
TIPSO
TIPSO
OTBDMS
OH
NHBoc
NHBoc
OBn
7
8
h
TIPSO
OPMP
NHBoc
9b
Scheme 4 Reagents and conditions: (a) TBDMSOTf (1.5 equiv), 2,6-lutidine (2 equiv), CH2Cl2, 2 h, –78 °C (93%); (b) 1. H2 (1 atm), Pd/C,
MeOH, 1 h; 2. H2 (1 atm), Raney-Ni, MeOH, 1 h (75%); (c) Boc2O (1.1 equiv), EtOAc, 2 h (93%); (d) Ca(BH4)2 (6 equiv), THF–EtOH 1:1.2,
–20 °C (15 min) to r.t., 1 h (99%); (e) NaH (1.3 equiv), BnBr (2 equiv), DMF, 0 °C to r.t., 12 h (80%); (f) PPTS (0.1 equiv), THF–EtOH 2:1,
5 d (86%); (g) BzCl (1.3 equiv), pyridine, r.t., 12 h (98%); (h) PPh3 (1.3 equiv), DEAD (1.3 equiv), PMPOH (3 equiv), THF, 80 °C, 4 h (70%).
Synlett 2005, No. 13, 2086–2088 © Thieme Stuttgart · New York

2088
Y. Bourdreux et al.
LETTER
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5696. (b) Roush, W. R.; Adam, M. A. J. Org. Chem. 1985,
50, 3752.
(6) Findeis, M. A.; Whitesides, G. M. J. Org. Chem. 1987, 52,
2838.
a
(for 9a)
8
b
(for 9b)
(7) Singh, O. V.; Han, H. Tetrahedron Lett. 2003, 44, 5289.
(8) (a) Greck, C.; Drouillat, B.; Thomassigny, C. Eur. J. Org.
Chem. 2004, 1377. (b) Greck, C.; Genêt, J. P. Synlett 1997,
741. (c) Genêt, J. P.; Greck, C.; Lavergne, D. Modern
Amination Methods; Ricci, A., Ed.; Wiley-VCH: Weinheim,
2000, 65.
OBn
OBn
c
TIPSO
HO
OR
NHBoc
OR
NHBoc
10a
10b
9a R = Bz
9b R = PMP
(9) Kitamura, M.; Ohkuma, S.; Inoue, S.; Sayo, N.;
Kumabayashi, H.; Akutagawa, S.; Ohta, T.; Tabaya, H.;
Noyori, R. J. Am. Chem. Soc. 1988, 110, 629.
(10) (a) Genêt, J. P.; Ratovelomanana-Vidal, V.; Cano de
Andrade, M. C.; Pfister, X.; Guerreiro, P.; Lenoir, J. Y.
Tetrahedron Lett. 1995, 36, 4801. (b) Ratovelomanana-
Vidal, V.; Genêt, J. P. Organomet. Chem. 1998, 567, 163.
(11) Guanti, G.; Banfi, L.; Narisano, E. Tetrahedron Lett. 1989,
30, 5507.
(12) Nicolaou, K. C.; Mitchell, H. J.; Fylaktakidou, K. C.;
Rodriguez, R. M.; Suzuki, H. Chem.–Eur. J. 2000, 6, 3116.
(13) Fukuyama, T.; Laird, A. A.; Hotchkiss, L. M. Tetrahedron
Lett. 1985, 26, 6291.
OH
d
TIPSO
OR
NHBoc
11a
11b
Scheme 5 Reagents and conditions: (a) PhLi (9 equiv), THF, –78 °C
(87%), or 1% NaOH–MeOH, r.t., 40 min, quantitative yield; (b)
CAN, MeCN–H2O 4:1, 10 min, 0 °C (94%); (c) TBAF (1.5 equiv),
THF, 0 °C, 30 min (92% of 10a; 91% of 10b); (d) H2 (1 atm), Pd/C,
MeOH, r.t., 1 h, (95% of 11a; 97% of 11b).
(14) Characterization of Selected New Compounds:
Compound 8: [a]D25 –13 (c 0.52, EtOH). 1H NMR (300
MHz, CDCl3): d = 7.36–7.33 (m, 5 H), 5.43 (d, 1 H, J = 6.4
Hz), 4.75 (d, 1 H, J = 11.7 Hz), 4.62 (d, 1 H, J = 11.7 Hz),
3.92–3.80 (m, 4 H), 3.71–3.63 (m, 2 H), 2.40 (s, 1 H), 1.43
(s, 9 H), 1.08, 1.07 (2 s, 21 H). 13C NMR (50 MHz, CDCl3):
d = 156.1, 138.0, 128.5, 127.9, 127.8, 80.3, 79.4, 72.9, 64.2,
63.1, 52.9, 28.3, 18.0, 11.8. Anal. Calcd for C25H45NO5Si: C,
64.20; H, 9.70; N, 2.99. Found: C, 64.43; H, 9.78; N, 2.85.
Compound 9a: [a]D25 –12 (c 0.81, EtOH). 1H NMR (300
MHz, CDCl3): d = 8.01 (m, 2 H), 7.61–7.52 (m, 1 H), 7.44–
7.41 (m, 2 H), 7.34–7.28 (m, 5 H), 5.24 (d, 1 H, J = 9.1 Hz),
4.78 (d, 1 H, J = 11.8 Hz), 4.62 (d, 1 H, J = 11.8 Hz), 4.49–
4.37 (m, 2 H), 4.34–4.21 (m, 1 H), 3.95 (m, 2 H), 3.72–3.66
(m, 1 H), 1.40 (s, 9 H), 1.09, 1.08 (2 s, 21 H). 13C NMR (75
MHz, CDCl3): d = 166.4, 155.5, 138.2, 133.5, 132.9, 130.1,
129.7, 128.4, 128.3, 127.9, 127.7, 79.3, 78.9, 72.8, 64.5,
64.2, 50.7, 28.3, 18.0, 11.8. Anal. Calcd for C32H49NO6Si: C,
67.21; H, 8.64; N, 2.45. Found: C, 67.41; H, 8.89; N, 2.41.
Compound 9b: [a]D25 –1.2 (c 0.50, EtOH). 1H NMR (300
MHz, CDCl3): d = 7.26 (s, 5 H), 6.83 (s, 4 H), 5.34 (d, 1 H,
J = 8.1 Hz), 4.78 (d, 1 H, J = 11.4 Hz), 4.71 (d, 1 H, J = 11.4
Hz), 4.18 (dd, 1 H, J = 9.2, 3.5 Hz), 4.15–4.04 (m, 1 H),
4.00–3.91 (m, 3 H), 3.78 (s, 3 H), 3.76–3.71 (m, 1 H), 1.43
(s, 9 H), 1.10, 1.08 (2 s, 21 H). 13C NMR (75 MHz, CDCl3):
d = 155.5, 154.0, 152.8, 138.5, 128.3, 127.9, 127.5, 115.5,
114.7, 79.3, 78.9, 73.1, 67.5, 65.2, 55.8, 51.0, 28.4, 18.0,
11.9. Anal. Calcd for C32H51NO6Si: C, 66.98; H, 8.96; N,
2.44. Found: C, 66.91; H, 8.84; N, 2.39.
Acknowledgment
Funding for this work was provided by the Ministère de la Re-
cherche through a grant to Y.B.
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Synlett 2005, No. 13, 2086–2088 © Thieme Stuttgart · New York