Synthesis of new chiral mixed cis-tetraheterodecalines by highly selective cyclization of N,N′-bisalkyl 2,3-diaminobutanediols

Article abstract of DOI:10.1055/s-2006-926389

Chiral secondary vic-diamines of diaminobutanediols have been efficiently prepared from L-tartaric acid. Their selective cyclization led to cis-tetraheterodecalines having a (1S,6S)-2,7-diaza-4,9-dioxa[4.4.0]decane core system. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2006-926389

PAPER
1093
Synthesis of New Chiral Mixed cis-Tetraheterodecalines by Highly Selective
Cyclization of N,N¢-Bisalkyl 2,3-Diaminobutanediols
Synthesis
e
of Chiral
M
a
ixed cis-T
e
n
traheterodec
-
alines Louis Gras,* Eric Taulier
Université P. Cézanne-AIX-MARSEILLE III, CNRS-UMR 6178 SymBio, Laboratoire RéSo, Faculté des Sciences St Jérôme - D12, 13397
Marseille Cedex 20, France
Fax +33(4)9128 8841; E-mail: jean-louis.gras@univ.u-3mrs.fr
Received 10 October 2005
and bioxazolidinones 4,9 useful for asymmetric hydrosilyl-
Abstract: Chiral secondary vic-diamines of diaminobutanediols
ation and allylic substitution.10
have been efficiently prepared from L-tartaric acid. Their selective
cyclization led to cis-tetraheterodecalines having a (1S,6S)-2,7-di-
aza-4,9-dioxa[4.4.0]decane core system.
Our continuing interest in utilizing tartaric acid as a chiral
source for the synthesis of optically active products11 led
Key words: amino alcohols, fused-ring systems, heterocycles, ring us to investigate an efficient construction of polyfunction-
closure
alized, N-substituted compounds 5 and of the correspond-
ing N,O-formacetals 6 (Figure 2). These C2-symmetric
cis-tetraheterodecalines have two chelating oxygen at-
oms, plus two nitrogen atoms that can be substituted.12
Enantiomerically pure vicinal diamines occur commonly
These compounds bearing chirality on their backbone
could be related to (–)-sparteine (7), a natural polycyclic
diamine used in asymmetric synthesis, for instance in the
deprotonation of carbamates.13 The cavity defined by the
concave shape of the cis-decaline configuration could be
useful for metal binding.14 The basic acyclic diaminobu-
tanediol skeleton has been prepared by various groups and
the cyclic heterodecalines have been obtained recently by
Fuchs and co-workers.15 Probably due to synthetic draw-
backs no N,N¢-bisalkyl derivative has been reported yet,
except a formally parent 2,3-substituted DABCO deriva-
tive.16
in nature, with many of them having biological properties.
Some of them and several synthetic vic-diamines are used
as medicinal agents.1 In the laboratory vic-diamines have
found widespread use as chiral ligands in asymmetric re-
actions, especially C2-symmetric vic-diamines with their
symmetry element added.2 Moreover, with the degree of
conformational freedom of chiral complexes with a tran-
sition metal being reduced in cyclic derivatives, only a
few such chiral vic-diamines have been designed. For ex-
ample bipyrrolidines 1 were used in the asymmetric dihy-
droxylation of alkenes3 and the ligand activity of
bioxazoles 2, where the two oxazoline rings are directly
bonded, has been reported in Cu, Rh, Ir catalyzed asym-
metric hydrosilylation of ketones,4 cyclopropanation of
olefins,5 and transfer hydrogenation of ketones
(Figure 1).6
OH
H
N
R
O
N
RNH
N
H
N
O
NHR
OH
R
5
6
7
O
O
Figure 2 Optically active N-substituted compounds 5–7
N
R
N
R
N
N
R
O
R
O
2
4
1
Therefore, we report here an efficient and selective syn-
thesis of N,N¢-bisalkyl-2,3-diaminodiols 5 and N,N¢-sub-
stituted (1S,6S)-2,7-diaza-4,9-dioxabicyclo[4.4.0]decanes
6, starting from L-tartaric acid. The enantiomeric tetrahet-
erodecalines could be similarly obtained starting from D-
tartaric acid.
O
O
O
O
N
N
N
N
R
R
3
Figure 1 Chiral vic-diamines 1–4
The synthesis of chiral diaminodiols 5 was achieved from
tartaric acid as the free (R = H) or carbamate protected
primary amine, via a 1,4-protected threitol. Preparing N-
alkyl vic-diamines was a critical step. The secondary ami-
no groups could not be introduced by direct Mitsunobu
amination of diol 8 to form secondary amines 11. More-
over, SN2 displacement of the corresponding sulfonyl es-
ter by a primary amine mostly led to olefin 10 after b-
elimination (Scheme 1).
Several reports show the biological importance of diami-
nobutanediols. Indeed, drugs based on 1,2,3,4-diamino-
butanediols and derivatives showed anticancer properties,
and complexes of threo-2,3-diaminobutane-1,4-diol de-
rived from mannitol were used as antitumor agents.7
These compounds are also the precursors of bioxazoles 38
SYNTHESIS 2006, No. 7, pp 1093–1098
x
x
.
x
x
.2
0
0
6
Advanced online publication: 08.03.2006
DOI: 10.1055/s-2006-926389; Art ID: P16005SS
© Georg Thieme Verlag Stuttgart · New York
However vicinal primary amine 11a was easily synthe-
sized in seven steps,17 and could become a convenient

1094
J.-L. Gras, E. Taulier
PAPER
R
O
R
O
O
HO
MsO
MsO
OBn
OBn
OBn
OBn
ii
HN
HN
OH
OH
OBn
H
2, Pd/C
HO
8
9
MeOH, r.t.
OBn
HN
HN
R
NH2
R
NH2
i
iii
13, 14
R
O
R
15
R
NH
OBn
OBn
OBn
OBn
BH3⋅SMe2
THF, reflux
MsO
R
NH
11
16 R'
R'
a
b
c
d
e
f
Me
Et
Bn
10
HN
OH
11a
Scheme 1 Reagents and conditions: i) DEAD, Ph3P, THF, r.t.; ii)
MsCl, Et3N, CH2Cl2; iii) R = Bn or t-Bu, base: Na2CO3, K2CO3 or
Cs2CO3, with/without 18-CE-6, MeCN, reflux.
2-PyCH2
OH
Ts
H
HN
R'
Scheme 3
building block. The synthesis of 11a was performed in
55% overall yield, without purification of the intermedi-
ates. Crude diamine 11a was purified via the correspond-
ing dihydrochloride. Williamson-type alkylation of 11a
could not be controlled and hence was of no practical use.
Condensation of n-butanal to give the diimine led only to
imidazolidine 12, formed by intramolecular condensation
from the intermediate monoimine (Scheme 2).
be clearly superior in that case. Refluxing dibenzyl ether
derivative 13d with cyclohexene in ethyl acetate–metha-
nol (1:1) in the presence of Pd(OH)2/C for 16 hours af-
forded 15d in 72% yield. Compound 16a could not be
cleanly obtained because of solubility problems with 15a
(R = H).
The amides were conveniently reduced by borane/dimeth-
yl sulfide complex in refluxing THF, a better reagent than
lithium aluminum hydride in this case, to give the corre-
sponding new secondary alkylamines 16. These vic-di-
amines should behave differently because of their
nitrogen atoms being more nucleophilic than the known
compound 16f (R¢ = H).
R
R
NH
NH
OBn
OBn
R
hal
H2N
H2N
OBn
OBn
OBn
OBn
N
N
n-butanal
MgSO4, 0 °C
41%
The cyclization of amines 16 to heterodecalines 6 with
their 6 member rings was another critical step, most cy-
clizations in this area leading to five-membered rings. Cy-
clization under basic conditions of diaminobutanediol 16f
having the amino groups protected as carbamates or by an
acyl group like in 15c and 15d, led to bioxazoles 311 and
bisoxazolidinones 4,10 i.e. compounds having only five-
membered rings. Cyclization of 16f with aqueous formal-
dehyde under required strong acidic conditions gave a
moderate yield of 6a, as a 1:2 mixture with the five-mem-
bered oxazolidine rings.18 DL-2,3-Dianilinobutane-1,4-
diol as well reacted with aqueous formaldehyde forming a
dioxazolidine.19
11a
12
Scheme 2
Pure vicinal diamine 11a was efficiently converted into
diacylated derivatives 13 under experimental conditions
specific to each case, followed by a standard work-up and
chromatographic purification (Scheme 3). Bistosylamine
14 was obtained using TsCl (Table 1).
Debenzylation of 13 and 14 was efficiently accomplished
under an atmospheric pressure of H2 using Pd/C in meth-
anol at room temperature, to provide 15b, 15c and 16e.
However, alcohol 15d was obtained in only 39% yield un-
der these standard conditions, the pyridyl moiety probably
poisoning the catalyst. Pearlman’s catalyst was found to
Eventually, reaction of 16c with aqueous formaldehyde at
room temperature gave a kinetic product in 43% yield,
identified as the imidazoline 17. In this reaction catalysis
Table 1 Acylation and Sulfonation of Primary Amine 11a
R
Product
13a
Reagent
Reaction conditions
THF, r.t.
Yield (%)
60
H
HCO2H/Ac2O
Ac2O/Et3N/DMAP
PhCOCl
Me
13b
13c
CH2Cl2, 0 °C
CH2Cl2, 0 °C
CH2Cl2, 0 °C/r.t.
CH2Cl2, 0 °C
ca. 100
90
Ph
2-Py
13d
14
2-PyCO2H/DCC/DMAP
TsCl
ca. 100
88
RCO = Ts
Synthesis 2006, No. 7, 1093–1098 © Thieme Stuttgart · New York

PAPER
Synthesis of New Chiral Mixed cis-Tetraheterodecalines
1095
Table 2 MM2 Calculated Conformations of Amino Alcohol 16b
and Iminium Ions 18 Leading to the Oxazine (A) and Oxazoline (B)
Isomersa
by TsOH was not necessary. The desired tetraheterodeca-
line 6c was isolated in 71% yield using paraformaldehyde
as the source of methylene, under acidic conditions and
refluxing dichloromethane for 4 days. At higher tempera-
ture, such as refluxing chloroform, 6c was obtained in 16
hours only and in 86% yield. The tetraheterodecaline ap-
peared thus to be the thermodynamic product. This was
confirmed by the conversion of imidazoline 17 to decaline
6c in 60% yield and under the same conditions
(Scheme 4). The bis(2-pyridinylmethyl)- and bis(eth-
yl)tetraheterodecalines 6d and 6b were also synthesized
under the same conditions in 34% and 70% yields from
16d and 16b, respectively.
Parameters
En (kcal)
9.48
2.77
2.31
10.64
2.72
2.41
N(1)–OH (Å)
N(1)–HO (Å)
R'
R'
OH
OH
HN
N
N
OH
OH
aq HCHO
CH2Cl2, r.t.
HN
R'
R'
17
(HCHO)n
p-TsOH,
CHCl3, reflux
16
R' = Bn
16b: R = Et
16c: R = Bn
16d: R = 2-PyCH2
O
R'
N
O
(HCHO)n
p-TsOH, CHCl3, reflux
N
R'
6
N+CH2–OH (Å) 2.95
3.01
6b: R = Et, 6c: R = Bn, 6d: R = 2-PyCH2
a Some hydrogen atoms are omitted.
Scheme 4
The pre-organized conformation 16A was confirmed by
NMR spectroscopy. The diaminobutanediols gave more
splitting than the corresponding amides. The methylene
protons in the OCH2CHN fragment resonated as two well
separated ABX signals in 16b (JAB = 11.3) and AB signals
in 16c (JAB = 9.3). The methine proton gave only a broad-
ened singlet. These data were consistent with a pre-orga-
nized chair conformation of a pseudo six-membered ring.
The ring closure occurred via the intramolecular addition
of the hydroxyl group onto the iminium ion, easily formed
by reaction of the nucleophilic secondary amine on form-
aldehyde and stabilized by the donor effect of R¢ group. In
this process, in compliance with Baldwin’s rules the 6-
endo-trig type ring closure seemed to be favored over the
5-endo-trig type (Scheme 5).20
O
Debenzylation of 6c using Pd/C in methanol under an at-
mospheric pressure of hydrogen gave the unsubstituted
tetraheterodecaline 6a in 94% yield. This indirect ap-
proach to 6a was more efficient than the direct cyclization
of primary amine 16f (Scheme 6).
5-endo-trig unfavored
R'
N
N
'
R
N
R'
+
O
oxazolidine
OH
HO
oxazine
R'
6
N
O
N
+
N
R'
O
N
Bn
18
O
H2, Pd/C
N
O
HN
O
6-endo-trig favored
O
R'
NH
MeOH, r.t.
Bn
Scheme 5 Ring closure according to Baldwin rules
6c
6a
Scheme 6
MM2 calculations on the diaminobutanediols 16, illustrat-
ed by 16b (R¢ = Et), indicated that the conformation of
lowest energy was a pseudo cis-fused bicyclic structure
16bA precursor of the oxazine (Table 2). This conforma-
tion is favored by a N---HO hydrogen bond, stronger
within a six-membered ring than within the five-mem-
bered ring 16bB that would give the oxazolidine: albeit
the N1–O2 atoms are closer to each other in 16bB, atoms
N1 and H3 are closer in 16bA. In the corresponding imi-
nium ions 18, O2 is closer to the Csp2 C4 in 18A than in
18B.
Tetraheterodecalines 6 were fully and unambiguously
characterized by usual spectroscopic methods. The N,O-
methylene acetal protons resonated as an AB pattern typ-
ical of six-membered rings. The coupling constant (J =
10.6 to 11.3 Hz) indicated that there is no nitrogen inver-
sion, but rather an axial configuration for the NR and NH
substituents.21
In conclusion, we have reported the efficient synthesis of
enantiomerically pure new C2-symmetric vicinal second-
Synthesis 2006, No. 7, 1093–1098 © Thieme Stuttgart · New York

1096
J.-L. Gras, E. Taulier
PAPER
The solvent was evaporated and the residue was chromatographed
on silica gel to give 13a (65 mg, 60%) as a solid; mp 145–146 °C.
oxabicyclo[4.4.0]decane core. The different chemical be- IR (CHCl3): 3010, 2990, 1680, 1210, 1060 cm–1.
ary amines in diaminobutanediols, that cyclized to mixed
tetraheterodecalines having a (1S,6S)-2,7-diaza-4,9-di-
1H NMR: d = 8.10 (s, 2 H), 7.37–7.21 (m, 10 H), 6.35 (br s, 2 H),
4.45 (d, J = 12 Hz, 2 H), 4.35 (d, J = 12 Hz, 2 H), 3.46 (m, 4 H), 4.40
(m, 2 H).
13C NMR: d = 161.6, 137.4, 128.4, 127.9, 127.6, 73.4, 68.6, 49.0.
havior of the secondary diamines when compared to
diaminobutanediols having primary or deactivated amino
groups, should result in different bio and chemical prop-
erties for their derivatives.
Studies on the potential of this kind of ligands for metal-
catalyzed asymmetric reactions are in progress.
(2S,3S)-1,4-Dibenzyloxy-2,3-bis(acetamino)butane (13b)
Ac2O (660 mL, 6.99 mmol) was added to a solution of diamine 11a
(1 g, 3.33 mmol), Et3N (965 mL, 6.99 mol) and N,N-dimethylami-
nopyridine (8 mg, 0.06 mmol) in CH2Cl2 (13 mL) at 0 °C. The re-
action was instantaneous. The mixture was quenched by addition of
H2O (20 mL) and extracted with CH2Cl2. The combined organic
layers were washed with brine and dried (MgSO4). Chromatogra-
phy on silica gel with 0.5% and 1% MeOH in CH2Cl2 as eluent af-
forded diacetamide 13b as a white solid (1.27 g, 99%); mp 134–
136 °C.
Melting points are uncorrected. IR spectra were recorded on a Per-
1
kin-Elmer IR FT-1605 spectrophotometer. The H NMR spectra
and the 13C NMR spectra were recorded on an AC 200 Bruker in-
strument, in CDCl3 as internal reference for chemical shifts at 7.24
ppm and 77.1 ppm, respectively, and are expressed as d values in
ppm. Coupling constants are in Hz. Optical rotations were measured
on a Perkin-Elmer 341 polarimeter at the sodium D line, at the des-
ignated concentration in g per mL. Chromatography was carried out
on columns packed with Merck silica gel 60 (70–230 mesh).
IR (CHCl3): 3420, 2990, 2900, 2880, 1640, 1530, 1460, 1100, 1050
cm–1.
1H NMR: d = 7.34–7.21 (m, 10 H), 6.27 (m, 2 H), 4.44 (d, J = 12
Hz, 2 H), 4.35 (d, J = 12 Hz, 2 H), 4.25 (m, 2 H), 3.43 (m, 4 H), 1.89
(s, 6 H).
13C NMR: d = 170.5, 137.5, 128.3, 127.7, 127.3, 73.1, 68.7, 50.4,
23.1.
All reactions were performed under argon. THF was distilled from
sodium benzophenone ketyl under argon, and CH2Cl2 and CHCl3
were distilled from P2O5. DMF was distilled from BaO and MeOH
from CaH2. Petroleum ether used refers to the fraction boiling at 40–
65 °C. Reagents were used as received or were purified by standard
methods.22
(2S,3S)-1,4-Dibenzyloxy-2,3-bis(benzoylamino)butane (13c)
Benzoyl chloride (810 mL, 6.99 mmol) was added to a solution of
diamine 11a (1 g, 3.33 mmol), Et3N (965 mL, 6.99 mmol) in CH2Cl2
(13 mL) at 0 °C. The reaction was instantaneous. The mixture was
quenched by addition of H2O (20 mL) and extracted with CH2Cl2.
The combined organic layers were washed with brine and dried
(MgSO4). Chromatography on silica gel with 0.5% and 1% MeOH
in CH2Cl2 as eluent afforded dibenzoylamide 13c as a white solid
(1.52 g, 90%); mp 113–114 °C.
IR (CHCl3): 3460, 3020, 2990, 1660, 1530, 1220, 1090 cm–1.
1H NMR: d = 7.63–7.46 (m, 4 H), 7.43–7.26 (m, 16 H), 4.64 (m, 2
H), 4.48 (br s, 4 H), 3.68 (m, 4 H), 1.61 (br s, 2 H).
Methanesulfonic Acid (E)-3-Benzyloxy-1-benzyloxymethylpro-
penyl Ester (10)
To a solution of dimesylate 9 (114 mg, 0.249 mmol) in MeCN (2.5
mL) were added Na2CO3 or K2CO3 or Cs2CO3 (0.6 mmol), benzyl-
or tert-butylamine (0.6 mmol). The mixture was stirred at various
temperatures until total conversion of 9. The solvent was evaporat-
ed under vacuum and the residue was filtered through Celite with
the help of CH2Cl2, then chromatographed on silica gel to give 10
(65 mg, 72%) as a colorless oil.
IR (film): 3030, 2920, 2870, 1360, 1180, 1100, 1060 cm–1.
1H NMR: d = 7.33 (m, 10 H), 5.72 (t, J = 6.1 Hz, 1 H), 4.51 (d,
J = 3.4 Hz, 4 H), 4.25 (d, J = 6.1 Hz, 2 H), 4.12 (s, 2 H), 3.11 (s, 3
13C NMR: d = 167.5, 137.4, 133.9, 131.4, 128.5, 128.42, 128.4,
128.0, 126.9, 73.5, 68.9, 50.9.
H).
13C NMR: d = 145.1, 137.8, 137.2, 127.8–128.5 (10 C), 121.6, 72.8,
72.1, 69.4, 64.3, 38.9.
(2S,3S)-1,4-Dibenzyloxy-2,3-bis(2-pyridinoylamino)butane
(13d)
(4S,5S)-4,5-Bis(benzyloxymethyl)-2-propylimidazolidine (12)
To a solution of diamine 11a (150 mg, 0.5 mmol) in THF (2 mL)
cooled to 0 °C were added MgSO4 (30 mg, 0.25 mmol) and n-buta-
nal (112.5 mL, 1.25 mmol). After total conversion of 11, the mixture
was filtered through silica gel with the help of Et2O containing Et3N
(1%). Chromatography on silica gel afforded 12 (72 mg, 41%) as a
colorless oil.
Piconilic acid (775 mg, 6.3 mmol) was added to a solution of di-
amine 11a (900 mg, 3 mmol), dicyclohexylcarbodiimide (1.32 g,
6.3 moles) and N,N-dimethylaminopyridine (36 mg, 0.3 mmol) in
CH2Cl2 (12 mL) at 0 °C. The reaction was monitored by TLC. Et2O
(10 mL) was added and the crystalline urea was filtered off over sil-
ica gel using Et2O as eluent. Concentration gave 13d as a white sol-
id (1.53 g, 99%); mp 86–88 °C.
IR (film): 3300, 3050, 3020, 2980, 1450, 1200, 1090 cm–1.
IR (CHCl3): 3020, 2960, 1680, 1560, 1280, 1260, 1110, 1050 cm–1.
1H NMR: d = 7.35–7.28 (m, 10 H), 4.50 (s, 4 H), 3.85 (t, J = 5.5 Hz,
1 H), 3.69–3.33 (m, 4 H), 3.10 (m, 2 H), 1.95 (br s, 2 H), 1.63–1.36
(m, 4 H), 0.90 (t, J = 7.2 Hz, 3 H).
13C NMR: d = 138.2, 127.6–128.4 (10 C), 74.8, 73.8 (2 C), 72.4 (2
C), 59.1 (2 C), 37.6, 19.7, 14.8.
1H NMR: d = 8.71 (m, 2 H), 8.45 (m, 2 H), 8.08 (m, 2 H), 7.74 (m,
2 H), 7.37–7.23 (m, 12 H), 4.71 (m, 2 H), 4.51 (s, 4 H), 3.69 (m, 4
H).
13C NMR: d = 164.5, 149.7, 148.2, 137.8, 137.0, 128.3, 127.8,
127.7, 126.0, 122.1 73.4, 69.4, 50.3.
(2S,3S)-1,4-Dibenzyloxy-2,3-bis(formylamino)butane (13a)
Ac2O (159 mL, 1.56 mmol) and formic acid (72 mL, 1.92 mmol)
were heated at 60 °C for 2 h. The mixture was cooled to 0 °C and
diluted with THF (1 mL) before the addition of diamine 11a (100
mg, 0.3 mmol) in THF (1 mL). The mixture was stirred for 3 h at r.t.
(2S,3S)-1,4-Dibenzyloxy-2,3-bis(O-tosylamino)butane (14)
To a solution of diamine 11a (103 mg, 0.5 mmol) in CH2Cl2 (2 mL)
at 0 °C was added tosyl chloride (458 mg, 1.2 mmol); Et3N (166 mL,
1.2 mmol) and DMAP (1.2 mg, 0.01 mmol). After 30 min, the mix-
ture was acidified with 5% HCl (5 mL). The organic layer was
washed with aq NaHCO3 (5 mL) and distilled H2O (5 mL), and
Synthesis 2006, No. 7, 1093–1098 © Thieme Stuttgart · New York

PAPER
Synthesis of New Chiral Mixed cis-Tetraheterodecalines
1097
dried (MgSO4). Chromatography on silica gel afforded 14 as a
1H NMR: d = 3.85 (dd, J = 11.3, 3.1 Hz, 2 H), 3.76 (dd, J = 11.3, 3.1
Hz, 2 H), 3.65 (m, 4 H), 2.85 (dq, J = 11.3, 7.2 Hz, 2 H), 2.66 (br s,
2 H), 1.09 (t, J = 7.2 Hz, 3 H).
20
white solid (226 mg, 88%); mp 121–123 °C; [a]D –34.2 (c
25 × 10–3, CHCl3).
IR (CHCl3): 3390, 3050, 3000, 2900, 1530, 1460, 1350, 1180, 1100,
13C NMR: d = 63.4, 61.3, 41.9, 15.5.
1020 cm–1.
(2S,3S)-2,3-Dibenzylaminobutane-1,4-diol (16c)
1H NMR: d = 7.64 (d, J = 8.2 Hz, 4 H), 7.33–7.10 (m, 10 H), 7.30
(d, J = 8.2 Hz, 4 H), 5.08 (d, J = 6.1 Hz, 2 H), 4.23 (s, 4 H), 3.52 (br
s, 2 H), 3.38–3.22 (m, 4 H), 2.38 (s, 6 H).
13C NMR: d = 143.2, 137.5, 137.0, 129.5–127.6 (18 C), 72.8, 68.4,
53.5, 21.4.
To a solution of dibenzylamide 15c (950 mg, 2.89 mmol) in THF
(86 mL) was added borane dimethyl sulfide complex (1.21 mL,
12.72 mmol) at 0 °C. The mixture was refluxed for 16 h, then 6 N
HCl (965 mL, 5.78 mmol) was added at 0 °C. The mixture was re-
fluxed for 1 h, then basified by addition of 6 N NaOH (1.447 mL,
8.67 mmol) at 0 °C, then distilled H2O (20 mL) was added. The
mixture was extracted with CH2Cl2, the organic extracts were dried
(Na2SO4) and the solvent was evaporated to give crude 16c (870
mg, 99%) as a white solid; mp 82–84 °C.
(2S,3S)-2,3-Bis(acetamino)butane-1,4-diol (15b)
To a solution of dibenzyl ether 13b (1.273 g, 3.31 mmol) in anhyd
MeOH (33 mL) was added 10% Pd/C (382 mg). The mixture was
vigorously stirred under an atmospheric pressure of H2 and was
monitored by TLC. The catalyst was removed by filtration over
Celite with MeOH–CH2Cl2 (1:1) as eluent. Concentration gave 15b
(662 mg, 98%) as a white solid; mp 160–162 °C.
IR (CHCl3): 3440, 3040, 2990, 2900, 1660, 1050 cm–1.
1H NMR (CD3OD): d = 4.09 (m, 2 H), 3.54 (m, 4 H), 1.97 (s, 6 H).
13C NMR (CD3OD): d = 173.8, 62.3, 52.9, 22.7.
IR (CHCl3): 3320, 3040, 2940, 2880, 1460, 1100, 1070 cm–1.
1H NMR: d = 7.29 (m, 10 H), 3.91 (d, J = 12.6 Hz, 2 H), 3.89 (d,
J = 9.4 Hz, 2 H), 3.68 (d, J = 12.6 Hz, 2 H), 3.66 (d, J = 9.4 Hz, 2
H), 2.73 (br s, 2 H).
13C NMR: d = 139, 128.6, 128.4, 127.4, 62.5, 60.4, 51.5.
(2S,3S)-2,3-Bis(2-pyridinylamino)butane-1,4-diol (16d)
Prepared from 15d (157 mg, 0.476 mmol) following the procedure
used for 16c. Crude product without purification (74 mg, 51%).
(2S,3S)-2,3-Bis(benzoylamino)butane-1,4-diol (15c)
To a solution of dibenzyl ether 13c (1.52 g, 2.99 mmol) in anhyd
MeOH (30 mL) was added 10% Pd/C (380 mg). The mixture was
vigorously stirred under an atmospheric pressure of H2 and was
monitored by TLC. The catalyst was removed by filtration over
Celite with MeOH in CH2Cl2 (1:1) as eluent. Concentration gave
15c (947 mg, 97%) as a white solid; mp 174–176 °C.
IR (CCl4): 3420, 3010, 2980, 1490, 1220, 1090 cm–1.
1H NMR (CD3OD): d = 7.84–7.78 (m, 4 H), 7.56–7.38 (m, 6 H),
4.49 (m, 2 H), 3.82 (m, 4 H).
1H NMR: complex unresolved multiplets.
13C NMR: d = 149.1, 148.3, 136.9, 122.5, 122.3, 60.7, 52.6.
(2S,3S)-2,3-Bis(tosylamino)butane-1,4-diol (16e)
Prepared from 14 (561 mg, 1.09 mmol) following the procedure
used for 15b and 15c; yield: 341 mg (93%); white solid; mp 171–
173 °C; [a]D20 –42.6 (c 21 × 10–3, CHCl3).
IR (CHCl3): 3400, 3040, 2990, 1530, 1480, 1430, 1060 cm–1.
1H NMR (CD3OD): d = 7.78 (d, J = 6.5 Hz, 4 H), 7.39 (d, J = 6.5
Hz, 4 H), 3.38–3.22 (m, 4 H), 3.29–3.18 (m, 2 H), 2.47 (s, 6 H).
13C NMR (CD3OD): d = 170.9, 135.5, 132.7, 129.5, 128.4, 62.4,
54.0.
(1S,6S)-2,7-Di(N-benzyl)aza-4,9-dioxabicyclo[4.4.0]decane (6c)
To a solution of 16c (300 mg, 1 mmol) in CHCl3 (6 mL) were added
anhyd paraformaldehyde (120 mg, 4 mmol) and p-TsOH (9 mg,
0.05 mmol). The mixture was refluxed for 16 h, then cooled to r.t.
before addition of H2O (5 mL) and K2CO3. After extraction with
CH2Cl2, the organic layer was dried (Na2SO4) and concentrated.
Chromatography on silica gel with Et2O in petroleum ether (3:7 to
1:1) as eluent afforded tetraheterodecalin 6c as a white solid (279
mg, 86%); mp 54–55 °C; [a]D20 +61.6 (c 24 × 10–3, CHCl3).
(2S,3S)-2,3-Bis(2-pyridinoylamino)butane-1,4-diol (15d)
To a solution of dibenzyl ether 13d (255 mg, 0.5 mmol) in anhyd
MeOH (1.5 mL) was added 20% Pd(OH)2/C (80 mg) and cyclohex-
ene (1.3 mL, 13 mmol). The mixture was vigorously stirred under
reflux for 16 h. The catalyst was removed by filtration over Celite
with EtOAc as eluent. Concentration and chromatography on silica
gel using 1% Et3N in 5% MeOH–CH2Cl2 as starting eluent, then
MeOH–CH2Cl2 (1:1) gave 15d (120 mg, 72%) as a white solid; mp
144–145 °C.
IR (CHCl3): 3000, 2960, 2900, 1480, 1220, 1110, 1060, 1010 cm–1.
IR (CHCl3): 3380, 3040, 2910, 1680, 1530, 1440, 1060 cm–1.
1H NMR: d = 7.35–7.25 (m, 10 H), 4.41 (d, J = 11.3 Hz, 2 H), 4.17
(d, J = 11.3 Hz, 2 H), 3.95 (dd, J = 11.3, 11.0 Hz, 2 H), 3.91 (br s, 4
H), 3.80 (dd, J = 11.3, 5.6 Hz, 2 H), 3.26 (m, 2 H).
13C NMR: d = 138.9, 128.7, 128.6, 127.4, 80.1, 64.9, 57.4, 46.8.
1H NMR: d = 8.51 (m, 2 H), 8.24 (m, 2 H), 8.16 (m, 2 H), 7.89–7.40
(m, 2 H), 7.46–7.23 (m, 2 H), 4.53 (d, J = 7.9 Hz, 2 H), 4.04 (m, 2
H), 3.87 (dd, J = 11.6, 4.1 Hz, 2 H), 3.66 (dd, J = 11.6, 4.1 Hz, 2 H).
13C NMR: d = 165.9, 148.8, 148.3, 137.5, 126.7, 122.6, 62.0, 51.6.
Anal. Calcd for C20H24N2O2: C, 74.04; H, 7.46; N, 8.63. Found: C,
74.03; H, 7.45; N, 8.59.
(2S,3S)-2,3-Diethylaminobutane-1,4-diol (16b)
To a solution of diacetamide 15b (676 mg, 3.31 mmol) in THF (165
mL) was added borane dimethyl sulfide complex (1.88 mL, 19.88
mmol) at 0 °C. The mixture was refluxed for 2 d, then quenched
with H2O (20 mL) at 0 °C. The aqueous layer was washed with
CH2Cl2, acidified with 35% HCl (6 mL) and refluxed for 16 h. The
pH of the mixture was adjusted to 9 by addition of solid NaOH at
0 °C. The mixture was extracted with CH2Cl2, the organic extracts
were dried (Na2SO4) and the solvent was evaporated to give crude
16b (553 mg, 95%) as a colorless liquid.
(1S,6S)-2,7-Di(N-ethyl)aza-4,9-dioxabicyclo[4.4.0]decane (6b)
Prepared from 16b in a similar manner to 6c; yield: 70%; colorless
liquid; [a]D20 +1.8 (c 60 × 10–3, CHCl3).
IR (CHCl3): 2990, 2960, 2900, 1480, 1400, 1230, 1100, 1050 cm–1.
1H NMR: d = 4.32 (d, J = 11.3 Hz, 2 H), 4.21 (d, J = 11.3 Hz, 2 H),
3.89 (dd, J = 11.3, 10.9 Hz, 2 H), 3.80 (dd, J = 11.3, 6.3 Hz, 2 H),
3.25 (m, 2 H), 2.90 (dq, J = 12.7, 7.2 Hz, 2 H), 2.80 (dq, J = 12.7,
7.2 Hz, 2 H), 2.07 (t, J = 7.2 Hz, 6 H).
IR (film): 3300, 2980, 2920, 1260, 1050 cm–1.
13C NMR: d = 79.2, 64.7, 48.1, 47.5, 14.1.
Synthesis 2006, No. 7, 1093–1098 © Thieme Stuttgart · New York

1098
J.-L. Gras, E. Taulier
PAPER
Anal. Calcd for C10H20N2O2: C, 59.97; H, 10.07; N, 13.99. Found:
C, 59.89; H, 10.10; N, 13.90.
References
(1) Lucet, D.; Le Gall, T.; Mioskowski, C. Angew. Chem. Int.
Ed. 1998, 37, 2580.
(2) Reviews for C2-symmetric ligands: (a) Whitesell, J. K.
Chem. Rev. 1989, 89, 1581. (b) Ghosh, A. K.; Mathivanan,
P.; Cappiello, J. Tetrahedron: Asymmetry 1998, 9, 1.
(3) Hirama, M.; Oishi, T.; Itô, S. J. Chem. Soc., Chem. Commun.
1989, 665.
(4) Helmchen, G.; Krotz, A.; Ganz, K.-T.; Hansen, D. Synlett
1991, 257.
(5) Evans, D. A.; Woerpel, K. A.; Hinman, M. M.; Faul, M. M.
J. Am. Chem. Soc. 1991, 113, 726.
(1S,6S)-2,7-Bis[N-(2-pyridinylmethyl)]-4,9-dioxabicy-
clo[4.4.0]decane (6d)
Prepared from 16d in a similar manner to 6c. The crude product was
purified by chromatography on silica gel using 1% Et3N in 1 to 5%
MeOH–CH2Cl2 to give 6d; yield: 34%; white solid.; mp 97–99 °C;
[a]D20 +47.7 (c 13 × 10–3, CHCl3).
IR (CHCl3): 3000, 2950, 2920, 1470, 1220, 1100, 1040 cm–1.
1H NMR: d = 8.52 (d, J = 4.8 Hz, 2 H), 7.63 (d, J = 7.8 Hz, 2 H),
7.34 (d, J = 7.8 Hz, 2 H), 7.18–6.96 (m, 2 H), 4.45 (d, J = 11.3 Hz,
2 H), 4.20 (d, J = 11.3 Hz, 2 H), 4.11–3.92 (m, 2 H), 4.07 (d, J = 4.1
Hz, 2 H), 3.29 (m, 2 H).
(6) Muller, D.; Umbricht, G.; Pfaltz, A. Helv. Chim. Acta 1991,
74, 232.
(7) (a) Feit, P. W.; Nielsen, O. T. J. Med. Chem. 1967, 10, 697.
(b) Feit, P. W.; Nielsen, O. T. J. Med. Chem. 1970, 13, 447.
(c) Haines, A. H.; Morley, C.; Murrer, B. A. J. Med. Chem.
1989, 32, 742. (d) Hanessian, S.; Gauthier, J.-Y.; Okamoto,
K.; Beauchamp, A. L.; Theophanides, T. Can. J. Chem.
1993, 71, 880.
(8) Lee, S.-g.; Lim, C. W.; Song, C. E.; Okim, I.; Jun, C.-H.
Tetrahedron: Asymmetry 1997, 8, 2927.
(9) Tanner, D.; Railton, C. J.; Pettersson, I.; Sotofte, I. Acta
Chem. Scand. 1999, 53, 703.
(10) Lee, S.-g.; Lim, C. W.; Song, C. E.; Kim, K. M.; Jun, C.-H.
J. Org. Chem. 1999, 64, 4445.
(11) (a) Gras, J.-L.; Pellisier, H.; Nouguier, R. J. Org. Chem.
1989, 54, 5675. (b) Gras, J.-L.; Pellisier, H. Tetrahedron
1991, 32, 7043. (c) Gras, J.-L.; Dulphy, H.; Lejon, T.
Tetrahedron 1996, 52, 8517. (d) Gras, J.-L.; Soto, T.; Viala,
J. Tetrahedron: Asymmetry 1997, 8, 3829.
13C NMR: d = 159.1, 149.5, 136.7, 122.4, 122.3, 80.6, 64.9, 59.6,
47.9.
Anal. Calcd for C18H22N4O2: C, 66.24; H, 6.79; N, 17.16. Found: C,
66.22; H, 6.79; N, 17.10.
(1S,6S)-2,7-Diaza-4,9-dioxabicyclo[4.4.0]decane (6a)
To a solution of tetraheterodecalin 6c (279 mg, 0.86 mmol) in
MeOH (10 mL) was added 10% Pd/C (139 mg). The mixture was
vigorously stirred under an atmospheric pressure of H2 and the re-
action was monitored by TLC. The catalyst was removed by filtra-
tion over Celite with MeOH in CH2Cl2 (1:1) as eluent.
Concentration gave 6a (117 mg, 94%) as a white solid; mp 108–
110 °C; [a]D20 +15.0 (c 20 × 10–3, MeOH).
IR (CCl4): 3400, 3040, 2980, 2900, 1460, 1240, 1050 cm–1.
1H NMR: d = 4.59 (d, J = 10.6 Hz, 2 H), 4.24 (d, J = 10.6 Hz, 2 H),
3.95 (d, J = 12 Hz, 2 H), 3.80 (d, J = 12 Hz, 2 H), 2.74 (br s, 2 H).
(12) Gras, J.-L.; Dulphy, H.; Lejon, T. Bull. Soc. Chim. Fr. 1994,
131, 418.
13C NMR: d = 78.9, 70.7, 49.5.
(13) Hoppe, D.; Hintze, F.; Tebben, P. Angew. Chem., Int. Ed.
Engl. 1990, 29, 1422.
(14) Li, X.; Schenkel, L. B.; Kozlowski, M. C. Org. Lett. 2000, 2,
Anal. Calcd for C6H12N2O2: C, 49.99; H, 8.39; N, 19.43. Found: C,
49.91; H, 8.41; N, 19.36.
875.
(4S,5S)-4,5-Dihydroxymethyl-1,2-di(N-benzyl)imidazolidine
(17)
(15) Star, A.; Lemcoff, G.; Goldberg, I.; Fuchs, B. Tetrahedron
Lett. 1997, 38, 3573.
(16) Oishi, T.; Hirama, M. Tetrahedron Lett. 1992, 33, 639.
(17) Scheuren, A.; Mosset, P.; Saalfranck, R. W. Tetrahedron:
Asymmetry 1999, 10, 3559.
To a solution of dialkylaminodiol 16c (59 mg, 0.196 mmol) in
CH2Cl2 (1.8 mL) was added 30% aq formaldehyde (42 mL, 0.413
mmol) or paraformaldehyde (12.5 mg, 0.413 mmol). The mixture
was stirred for 1.5 h, then distilled H2O (5 mL) was added. The mix-
ture was extracted with CH2Cl2 and the organic layer was dried
(Na2SO4) and concentrated. Chromatography on silica gel with 1 to
3% MeOH–CH2Cl2 as eluent afforded imidazolidine 17 (27 mg,
(18) Star, A.; Lemcoff, G.; Goldberg, I.; Lemcoff, N. G.; Fuchs,
B. Eur. J. Org. Chem. 1999, 2033.
(19) Roberts, J. J.; Ross, W. C. J. Chem. Soc. 1952, 4288.
(20) Agami, C.; Rizk, T. Tetrahedron 1985, 41, 537.
(21) Riddell, F. G.; Lehn, J.-M. J. Chem. Soc., B 1968, 1224.
(22) Perrin, D. D.; Armengo, W. L. F. Purification of Laboratory
Chemicals, 3rd ed.; Pergamon: Oxford, 1988.
20
43%) as a white solid; mp 70–72 °C; [a]D –24.59 (c 22 × 10–3,
CHCl3).
IR (film): 3380, 2920, 2820, 1420, 1050 cm–1.
1H NMR: d = 7.26 (m, 10 H), 3.86 (d, J = 13 Hz, 2 H), 3.55 (d,
J = 13 Hz, 2 H), 3.54 (s, 2 H), 3.43 (m, 4 H), 2.87 (br s, 2 H), 2.54
(br s, 2 H).
13C NMR: d = 138.8, 128.5, 127.4, 75.9, 67.3, 60.6, 58.3.
Synthesis 2006, No. 7, 1093–1098 © Thieme Stuttgart · New York