The synthesis of AraBOX, a new 4,4′-bis(oxazoline), from novel pentitol-derived bis-β-amino alcohols

Article abstract of DOI:10.1055/s-0029-1216731

The preparation of a novel phenyl 4,4′-bis(oxazoline) [AraBOX] is described. The novel ligand is prepared in two efficient steps from a bis-[(O-silyl)β-amino alcohol], via conversion into an intermediate bis(benzamide) followed by a one-pot deprotection-a

Full text of DOI:10.1055/s-0029-1216731

LETTER
1261
The Synthesis of AraBOX, a New 4,4¢-Bis(oxazoline), from Novel Pentitol-
Derived Bis-b-amino Alcohols
David Frain,a Fiona Kirby,a Patrick McArdle,b Patrick O’Leary*a
a
School of Chemistry, SMACT (Synthetic Methods: Asymmetric Catalytic Transformations), National University of Ireland,
Galway, Ireland
Fax +353(91)525700; E-mail: patrick.oleary@nuigalway.ie
School of Chemistry, National University of Ireland, Galway, Ireland
b
Received 5 February 2009
This letter is dedicated to Professor Richard N. Butler on the occasion of his 65th birthday.
Abstract: The preparation of a novel phenyl 4,4¢-bis(oxazoline)
O
O
[AraBOX] is described. The novel ligand is prepared in two effi-
cient steps from a bis-[(O-silyl)b-amino alcohol], via conversion
into an intermediate bis(benzamide) followed by a one-pot depro-
tection–activation–ring closure (DARC) oxazoline formation. To
our knowledge, this is the first reported synthesis of an oxazoline
ring via this DARC method. The synthesis of two precursor bis-b-
amino alcohols, (2R,4R)- and meso-2,4-diaminopentane-1,5-diol,
derived from D-(+)-arabitol and xylitol, respectively, is also de-
scribed.
O
O
N
N
N
N
1
Ph
Ph
Ph
Ph
novel
established
phenyl-2,2'-BOX
DARC
reaction
phenyl-4,4'-BOX
OTBS
O
TBSO
O
NH HN
Ph
OH
Key words: asymmetric synthesis, ligand, catalysis, oxazoline,
chiral pool
Ph
OH
OH
HO
HO
OH
OH
NH2 NH2
The design of new asymmetric ligands remains an active
area of chemical research.1 These ligands have found use,
generally as their metal complexes, as enantioselective
catalysts for key synthetic transformations.2 Many differ-
ent ligand types have been reported, for example phos-
phines,3 salens,4 Binols,5 BOXs (including Sasai’s
spiroBOXs which are the closest relative to the ligands
described herein),6 etc. Our recent research has focused on
N-donor-based ligands including BOX and PYBOX
ligands and their catalytically active metal complexes.7
During the course of this work we became interested in al-
tering the traditional BOX motif with the aim of address-
ing a problem which arises in the case of traditional BOX
ligands with a methylene bridge.
Scheme 1 Retrosynthetic analysis of the AraBOX 1 ligand
such a ligand is also likely to have more general applica-
tion.
Chiral b-amino alcohols are often key components in the
synthesis of oxazoline-based ligands and are commonly
derived from amino acids such as phenylglycine or va-
line.9 The AraBOX ligand synthesis would require the
preparation of a new type of bis b-amino alcohol
(Scheme 1). These bis-b-amino alcohols could be access-
ed from the widely available sugar-derived pentitols.
The preparation of novel bis-b-amino alcohols is of syn-
thetic interest due to their potential application here, but
also in a number of other contexts. Chiral amino alcohols,
chiral amino diols and their derivatives have been report-
ed as asymmetric catalysts for a number of reactions.10
Amino diols are also a common structural motif in drug
therapy.11 They have also been used widely as starting
materials for the synthesis of bioactive natural products.12
In addition, structurally similar bisamino acids have been
shown to have a useful cross-linking property which is of
enormous potential for an application in the design and
synthesis of conformationally constrained cyclic pep-
tides.13 The bis-b-amino alcohols in this study could be
similarly applied.
Herein we report the synthesis of novel 4,4¢-methyl-
enebis[(4R)-2-phenyl-2-oxazoline] 1 with the methylene
bridgehead of the ligand bound to the chiral sp3-hybri-
dised 4-position of the oxazoline rings. This ligand is a
regioisomer of a standard 2,2¢-BOX ligand and is syn-
thesised from arabitol so we use the acronym (AraBOX).
Regulating the electron density of the oxazoline rings in
standard BOX ligands is difficult because of the potential
for migration of the double bonds into conjugation.8 This
factor has traditionally limited the use of methylene-
bridged BOXs and led to the use of gem-dimethyl-substi-
tuted bridges. The AraBOX ligand cannot undergo such a
migration, which is a significant advantage. Obviously
We envisaged that the bis-b-amino alcohol shown could
be elaborated to the AraBOX ligand (Scheme 1). The key
step in the synthesis of the ligand would be a one-pot dou-
ble deprotection–activation–ring-closure (DARC) reac-
tion. This transformation would provide a facile synthetic
route to our desired phenyl-AraBOX ligand.
SYNLETT 2009, No. 8, pp 1261–1264
x
x.
x
x.
2
0
0
9
Advanced online publication: 17.04.2009
DOI: 10.1055/s-0029-1216731; Art ID: G05009ST
© Georg Thieme Verlag Stuttgart · New York

1262
D. Frain et al.
LETTER
We initially studied the synthesis of the precursor bis-b- Conversion of the secondary alcohols to amines could be
amino alcohols. A suitable starting point for the synthesis achieved by activation as sulfonyl groups followed by SN2
was identified as tetraol 5 (Scheme 2), which would pro- reaction involving azide transfer and reduction to amines
vide the appropriate structural and stereochemical basis leading to 10 (Scheme 3). The key transformation re-
with overall C2-symmetry. The preparation of 5 was quired to allow this to take place was selective protection
achieved from D-(+)-arabitol 2 in four steps through a pro- of the primary hydroxyl groups of 5. This was achieved by
cedure modified from that of Linclau.14 This process was conversion to primary silyl ethers using tert-butyldimeth-
also applied to xylitol 6, yielding the meso diastereomer of ylsilyl chloride, triethylamine, and dimethylaminopyri-
the tetraol 7. The main discussion will focus on the syn- dine in CH2Cl2 over a 40-hour period.
thetic results of the chiral compounds. The meso synthesis
is documented in Scheme 2 and Scheme 3.
(i)
HO
OH
TBSO
OTBS
OH OH
OH OH
S
5
8
SMe
(ii)
O
OH
(iii)
(i)
O
O
O
HO
OH
OTBS
OTBS
TBSO
TBSO
O
O
O
OH OH
NH2 NH2
OMs OMs
2
3
10
9
(ii)
(iv)
O
(iii)
HO
OH
HO
HO
OH
OH
O
NH2 NH2
⋅2HCl
OH OH
4
11
5
OH
(i)–(iii)
(i)–(iv)
HO
OH
HO
OH
HO
OH
NH2 NH2
12
OH OH
⋅2HCl
OH OH
OH OH
7
7
6
Scheme 3 Synthesis of bis-b-amino alcohol 11. Reagents and con-
ditions: (i) Et3N, DMAP, TBSCl, CH2Cl2, –15 °C to r.t., 40 h, 65%;
(ii) Et3N, MsCl, CH2Cl2, 0 °C to r.t., 4 h, 99%; (iii) (a) NaN3, DMF,
85 °C, 16 h; (b) H2 (5 bar), 10% Pd/C, MeOH, 4 d, 76%; (iv) 1% HCl–
MeOH, 4 h, 87%. Bis-b-amino alcohol 12 (i) 54%; (ii) 83%; (iii)
43%; (iv) 92%.
Scheme 2 Synthesis of tetraol. Reagents and conditions: arabitol 2
conversion into tetraol 5 (i) as ref. 14, 68%; (ii) ACN, Bu3SnH, tolue-
ne, reflux, 4 h, 95%; (iii) AcOH–H2O–THF (3:2:1), 80 °C, 4 h, 90%.
Xylitol 6 conversion into tetraol 7 (i) as ref. 14, 32%; (ii) 81%; (iii)
0.5 M H2SO4, EtOH, reflux, 4 h, 85%.
Mesylation of 8 gave 9, in 99% yield, which could be car-
ried through to the next step without purification. The
treatment of 9 with sodium azide in N,N-dimethylforma-
mide was seen to give complete displacement of sulfonate
groups after 16 hours at 85 °C by 1H NMR. The resultant
diazido compound was not isolated but instead used in its
crude form in the next step. Hydrogenation of the diazido
compound gave diamine 10 after four days at 5 bar H2 in
the presence of 10% palladium on activated carbon.
Kinetic acid-catalysed acetalisation of arabitol 2 with 3,3-
dimethoxypentane yielded 1,2:4,5-bisacetalised arabitol
as the major product. Sodium hydride mediated genera-
tion of the alkoxide at the 3-O-position in the presence of
carbon disulfide and subsequent methylation using
iodomethane provided xanthate 3 in high yield, as report-
ed. Radical deoxygenation of 3 with tributyltin hydride
was first attempted using AIBN as a radical initiator, but
an increase in yield was observed when 1,1-azobis(cyclo-
hexane-carbonitrile) (ACN) was used to initiate single
electron transfer. Since 3 and 4 proved difficult to separate
chromatographically, this increased yield in turn facilitat-
ed the process of column chromatography, given that less
starting material needed to be separated from deoxygenat-
ed product 4. Hydrolysis of both acetals occurred in a
mixture of acetic acid, water, and tetrahydrofuran at 80 °C
over four hours to yield desired 5. The synthesis com-
mencing from xylitol 6 was conducted in a similar fash-
ion. The yield in the acetalisation reaction was found to be
low (35%) in this case leading to a lower yield of the cor-
responding xanthate (32%).
Desilylation of 10 by treatment with 1% hydrochloric acid
in methanol solution gave (2R,4R)-2,4-diaminopentane-
1,5-diol 11 as the crystalline dihydrochloride salt which
was suitable for X-ray crystal-structure determination.15
The compound was optically active as expected. The ab-
solute structure was determined in this case and the Flack
parameter was –0.02(5). The X-ray crystal structure of a
dication of meso-2,4-diaminopentane-1,5-diol 1216 was
also determined.
Our attention then turned to the conversion of hydrogena-
tion product 10 into novel ligand target 1. Conventional
oxazoline synthesis involves reaction between an acid
Synlett 2009, No. 8, 1261–1264 © Thieme Stuttgart · New York

LETTER
AraBOX, a New 4,4′-Bis(oxazoline)
1263
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TBSO
Ph
OTBS
Ph
(i)
TBSO
OTBS
NH HN
NH2 NH2
10
O
O
(ii)
13
O
O
(5) Brunel, J. M. Chem. Rev. 2007, 107, PR1.
N
N
(6) (a) Palomo, C.; Oiarbide, M.; Laso, A. Eur. J. Org. Chem.
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Asymmetry 2008, 19, 391.
Ph
Ph
1
Scheme 4 Synthesis of phenyl 4,4¢-bis(oxazoline) 1. Reagents and
conditions: (i) Et3N, BzCl, 0 °C, 4 h, 76%; (ii) TsF, DBU, MeCN,
reflux, 16 h, 75%.
chloride and an amino alcohol to yield a hydroxyamide,
followed by activation with tosyl chloride, and subsequent
base-promoted cyclisation. Hampering this approach with
relation to 10 was the need to carry out desilylation of any
resultant amide-type product prior to tosyl activation.
DBU is known to catalyse the conversion of a TBS group
into a tosyl group with p-toluenesulfonyl fluoride in re-
fluxing MeCN.17 We hoped that as well as catalysing the
conversion from O-silyl to O-tosyl, employing a stoichio-
metric quantity of DBU would perhaps drive the reaction
further, cyclising to the desired oxazoline.
(8) Pellissier, H. Tetrahedron 2008, 64, 7041.
(9) (a) Denmark, S. E.; Nakajima, N.; Nicaise, O. J. C.; Faucher,
A. M.; Edwards, J. P. J. Org. Chem. 1995, 60, 4884.
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64, 1034. (b) Pedrosa, R.; Andrés, C.; Mendiguchía, P.
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Asymmetry 2002, 13, 1477.
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Lavallée, P.; Wernic, D. J. Org. Chem. 1999, 64, 6622.
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437. (b) Mishra, R. K.; Coates, C. M.; Revell, K. D.; Turos,
E. Org. Lett. 2007, 9, 575.
The TBS protected b-amino alcohol 10 reacted with ben-
zoyl chloride in high yield to give bis (O-silyl) benzamide
13 (Scheme 4).18 The TsF-mediated double deprotection–
activation–ring-closure reaction was then explored. We
were pleased to find that bis (O-silyl) benzamide 13
refluxed overnight with 2.2 equivalents of both TsF and
DBU in dry MeCN gave the desired double cyclisation
product, phenyl 4,4¢-BOX 1,19 in good yield (75%,
Scheme 4). Recrystallisation from hot petroleum ether
gave crystals suitable for crystallographic analysis.
In conclusion we have reported the synthesis of the first
member of a new family of 4,4¢-BOX ligands. The final
step involved a TsF-mediated double deprotection–
activation–ring-closure reaction which lead to the prepa-
ration of the ligand in high yield. We have also prepared
novel bis-b-amino alcohols, which are of considerable
synthetic interest. We will report in due course on the met-
al complexes of ligand 1 and their catalytic activity.
(13) (a) Taylor, S. M.; Yamada, T.; Ueki, H.; Soloshonok, V. A.
Tetrahedron Lett. 2004, 45, 9159. (b) Soloshonok, V. A.;
Yamada, T.; Ueki, H.; Moore, A. M.; Cook, T. K.; Arbogast,
K. L.; Soloshonok, A. V.; Martin, C. H.; Ohfune, Y.
Tetrahedron 2006, 62, 6412.
(14) (a) Boydell, A. J.; Jeffery, M. J.; Burkstummer, E.; Linclau,
B. J. Org. Chem. 2003, 68, 8252. (b) Linclau, B.; Boydell,
A. J.; Clarke, P. J.; Horan, R.; Jacquet, C. J. Org. Chem.
2003, 68, 1821.
Acknowledgment
This publication has emanated from research conducted with the fi-
nancial support of Science Foundation Ireland (RFP).
(15) (2R,4R)-2,4-Diaminopentane-1,5-diol Dihydrochloride
(11)
References and Notes
1H NMR (400 MHz, D2O): d = 3.86 (2 H, dd, J = 12.4, 3.7
Hz 2 × one of CH2OH), 3.71 (2 H, dd, J = 12.4, 6.0 Hz,
2 × one of CH2OH), 3.56–3.50 (2 H, m, 2 × CHNH2), 2.05 (2
H, t, J = 7.1 Hz, CHCH2CH). 13C NMR (100 MHz, CDCl3):
d = 60.2 (2 × CH2OH), 49.4 (2 × CHN), 28.8 (CHCH2CH)
ppm. IR: 3512, 3333, 3048 (br), 2907, 1490, 1036 cm–1.
Anal. Calcd for C5H16Cl2N2O2: C, 29.00; H, 7.79; N, 13.53.
Found C, 29.17; H, 7.63; N, 13.71. [a]D22 –46.5 (c 0.7,
MeOH). The CIF file for this compound has been deposited
(1) (a) Guiry, P. J.; Saunders, C. P. Adv. Synth. Catal. 2004, 346,
497. (b) McManus, H. A.; Guiry, P. J. Chem. Rev. 2004, 104,
4151. (c) Goudriaan, P. E.; van Leeuwen, P. W. N. M.;
Birkholtz, M.-N.; Reek, J. N. H. Eur. J. Inorg. Chem. 2008,
2939.
(2) (a) Christoffers, J.; Koripelly, G.; Rosiak, A.; Rossle, M.
Synthesis 2007, 1279. (b) Trost, B. M.; Jiang, C. H.
Synthesis 2006, 369.
Synlett 2009, No. 8, 1261–1264 © Thieme Stuttgart · New York

1264
D. Frain et al.
LETTER
1629, 1536, 1102, 777, 691 cm–1. Anal. Calcd for
with the The Cambridge Crystallographic Data Centre
(deposition number 719095).
C31H50N2O4Si2: C, 65.25; H, 8.83; N, 4.91. Found: C, 65.25;
(16) meso-2,4-Diaminopentane-1,5-diol Dihydrochloride (12)
1H NMR (400 MHz, D2O): d = 3.84 (2 H, dd, J = 12.4, 3.7
Hz 2 × one of CH2OH), 3.67 (2 H, dd, J = 12.6, 6.0 Hz,
2 × one of CH2OH), 3.52–3.47 (2 H, m, 2 × CHNH2), 2.08–
1.88 (2 H m, CHCH2CH). 13C NMR (100 MHz, CDCl3):
d = 60.5 (2 × CH2OH), 49.2 (2 × CHN), 28.9 (CHCH2CH).
IR: 3315 (br), 2927 (br), 1612, 1559, 1513 cm–1. Anal. Calcd
for C5H16Cl2N2O2: C, 29.00; H, 7.79; N, 13.53. Found C,
28.37; H, 7.3; N, 12.53. The CIF file for this compound has
been deposited with the The Cambridge Crystallographic
Data Centre (deposition number 719096).
H, 8.74; N, 4.77. [a]D22 +52.2 (c 0.9, MeCN).
(19) To a solution of 13 (300 mg, 0.525 mmol) and TsF (140mg,
1.155 mmol) in dry MeCN (5 mL) was added DBU (185 mL,
1.115 mmol). The mixture was stirred at reflux overnight,
cooled, and concentrated in vacuo. The residue was purified
by flash chromatography on SiO2 (PE–EtOAc, 80:20) to
yield desired bis(oxazoline) 1 (120 mg, 75%).
4,4¢-Methylenebis[(4R)-2-phenyl-2-oxazoline] (1)
1H NMR (400 MHz, CDCl3): d = 7.95 (4 H, d, J = 6.9 Hz,
4 × ortho ArH), 7.49–7.38 (6 H, m, 4 × meta ArH, 2 × para
ArH), 4.66 (2 H, app t, J = 8.5 Hz, 2 × one of CH2O), 4.61–
4.51 (2 H, m, 2 × CHN), 4.14 (2 H, app t, J = 8 Hz, 2 × one
of CH2O), 1.98 (2 H, t, J = 7 Hz, CHCH2CH). 13C NMR (100
MHz, CDCl3): d = 163.9 (2 × C=N), 131.4 (2 × para ArC),
128.4 (4 × ortho ArC), 128.3 (4 × meta ArC), 127.9
(2 × ArCCN), 73.7 (2 × CHO), 65.5 (2 × CHN), 43.3
(CHCH2CH). IR: 2924, 1720, 1642, 1080, 1025, 779, 688
cm–1. Anal. Calcd for C19H18N2O2: C, 74.49; H, 5.92; N,
9.14. Found: C, 74.15; H, 5.83; N, 8.75. [a]D23 +57.1 (c 0.7,
MeCN). The CIF file for this compound has been deposited
with the The Cambridge Crystallographic Data Centre
(deposition number 719094).
(17) Gembus, V.; Marsais, F.; Levacher, V. Synlett 2008, 1463.
(18) N,N¢-[(2R,4R)-1,5-Bis{[tert-butyl(dimethyl)silyl]oxy}-
pentane-2,4-diyl]benzamide (13)
1H NMR (400 MHz, CDCl3): d = 7.77 (4 H, d, J = 6.9 Hz,
4 × ortho ArH), 7.48–7.35 (6 H, m, 4 × meta ArH, 2 × para
ArH), 7.05 (2 H, d, J = 7.8 Hz, 2 × NH), 4.19–4.12 (2 H, m,
2 × CHN), 3.88–3.81 (4 H, m, 2 × CH2O), 2.07 (2 H, t, J = 6
Hz, CHCH2CH). 13C NMR (100 MHz, CDCl3): d = 167.5
(2 × HNC=O), 134.5 (2 × ArCC=O), 131.5 (2 × para ArC),
128.6 (4 × ortho ArC), 127.0 (4 × meta ArC), 64.9 (2 ×
CH2OSi), 49.2 (2 × CHNH2), 33.4 (CHCH2CH), 26.0
(6 × CH3), 18.3 (2 × C), –5.3 [2 × Si(CH3)2]. IR: 3279, 2928,
Synlett 2009, No. 8, 1261–1264 © Thieme Stuttgart · New York

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