New supramolecular host systems, 11. The stereoisomeric diaminobutanediol and dioxadiazadecalin systems: Synthesis, structure, stereoelectronics, and conformation - Theory vs. experiment

Article abstract of DOI:10.1002/(sici)1099-0690(199909)1999:9<2033::aid-ejoc2033>3.0.co;2-k

We present new approaches to the (C₂) chiral and meso 1,4-diamino-2,3- butanediol (1) and 2,3-diamino-1,4-butanediol (2) and derivatives. Reactions of these compounds with aldehydes to form the novel 1,5-dioxa-3,7- diazadecalin (DODAD) and 1,5-diaza-3,7-dioxadecalin (DADOD) classes of compounds (7, 9, 11-15) are also reported. These reactions are diastereospecific, i e, erythro (meso) or threo starting compounds lead to trans or cis products, respectively. The structural, conformational, and stereoelectronic aspects of these systems were probed experimentally and computationally and provided excellent insight into their properties and behaviour. Good agreement was observed between X-ray, NMR, and calculated results of the N,N'-dibenzyl derivatives of trans-DODAD (14) and trans-DADOD (15).

Full text of DOI:10.1002/(sici)1099-0690(199909)1999:9<2033::aid-ejoc2033>3.0.co;2-k

FULL PAPER
New Supramolecular Host Systems, 11[°]
The Stereoisomeric Diaminobutanediol and Dioxadiazadecalin Systems:
Synthesis, Structure, Stereoelectronics, and Conformation ؊ Theory
vs. Experiment
Alexander Star,[a] Israel Goldberg,[a] N. Gabriel Lemcoff,[a] and Benzion Fuchs*[a]
Keywords: Diaminobutanediol / Dioxadiazadecalin / Diazadioxadecalin / Conformation analysis / Stereoelectronic effects
We present new approaches to the (C2) chiral and meso 1,4-
diamino-2,3-butanediol (1) and 2,3-diamino-1,4-butanediol
(2) and derivatives. Reactions of these compounds with
aldehydes to form the novel 1,5-dioxa-3,7-diazadecalin
(DODAD) and 1,5-diaza-3,7-dioxadecalin (DADOD) classes
of compounds (7, 9, 11–15) are also reported. These reactions
are diastereospecific, i.e., erythro (meso) or threo starting
compounds lead to trans or cis products, respectively. The
structural, conformational, and stereoelectronic aspects of
these systems were probed experimentally and
computationally and provided excellent insight into their
properties and behaviour. Good agreement was observed
between X-ray, NMR, and calculated results of the N,NЈ-
dibenzyl derivatives of trans-DODAD (14) and trans-
DADOD (15).
ling, the appropriate starting materials being the positional
and diastereoisomeric 1,4;2,3-diaminobutanediols.
Introduction
We have recently been conceiving and developing new
Over the past three decades the anticancer drug proper-
hosts, based on the diastereomeric 1,3,5,7-tetraheterodeca- ties of the 1,2,3,4-diaminobutanediols 1, 2, and their deriva-
lin (THD) systems (Scheme 1), which can be prepared from tives have been examined.[4] For example, the platinum
suitable 1,2,3,4-tetraheterobutanes and aldehydes. Having complexes of threo-1,4-diamino-2,3-O-isopropylidenebut-
gained experience with the tetraoxadecalin (X ϭ Y ϭ O)[2] anediol (Scheme 2) showed in vivo and in vitro antitumor
and the tetrazadecalin (X ϭ Y ϭ NH)[3] systems, the prep- activity and desirable properties as good as or better than
aration and investigation of dioxadiazadecalins (X ϭ O, cisplatin.[5] Complexes of threo-2,3-diamino-1,4-butanediol
Y ϭ NH; X ϭ NH, Y ϭ O) for these purposes was compel- (2) were also used as antitumor agents.[6] Recently, in the
Scheme 1. The 1,3,5,7-tetraheterodecalin (THD) system in all its diastereomeric forms
context of the axisymmetrical nature of human immunode-
ficency virus (HIV) protease, members of the above C2-
[°]
Part 10: Ref.[1a]
[a]
symmetric class of compounds, e.g. threo-1,4-diamino-2,3-
butanediol, were also proven to be potent and selective in-
hibitors of the protease.[7] Finding new synthetic strategies
and improving existing ones for the preparation of these
School of Chemistry (Raymond and Beverly Sackler Faculty of
Exact Sciences),
Tel-Aviv University, Ramat-Aviv, 69978 Tel-Aviv, Israel
Fax: (internat.) ϩ 972-3/ 640 9293
E-mail: bfuchs@post.tau.ac.il
Eur. J. Org. Chem. 1999, 2033Ϫ2043
WILEY-VCH Verlag GmbH, D-69451 Weinheim, 1999
1434Ϫ193X/99/0909Ϫ2033 $ 17.50ϩ.50/0
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A. Star, I. Goldberg, N. G. Lemcoff, B. Fuchs
FULL PAPER
Scheme 2. Synthesis of threo-1,4;2,3-diaminobutanediols 1 and 2: (a) (CH3)2C(OCH3)2, MeOH/PTSA, 75%; (b) NH3/MeOH, 90%; (c) 1.
LiAlH4, dry THF, 95%; 2. HCl, 90% ethanol, 67%; (d) 1. LiAlH4, dry THF, 82%; 2. NaH, PhCH2Br, PTC, THF, 100%; 3. Dowex 50
WX4/Hϩ, ethanol, 99%; (e) 1. Mesyl chloride,Py, 96%; 2. NaN3, DMF 110°C, 89%; (f) H2, Pd/C, HCl, 93%.
precursors seemed to us of additional importance to that of
securing the desired new bicyclic systems.
Results and Discussion
Synthesis
Optically pure -1,4-diamino-2,3-butanediol (1) was pre-
pared (Scheme 2; top) from -tartaric acid (via -2,3-O-iso-
propylidenedimethyltartarate, amidation,[8] then LAH re-
duction[5a] and deprotection). This was also the starting
material for optically pure -2,3-diamino-1,4-butanediol
Scheme 3. Preparation of N,NЈ-dialkyl threo-1,4-diamino-2,3-buta-
(2), based on a series of reactions worked out by Feit et
nediols: (a) benzylation of 1: (i) benzyl bromide/K2CO3 aq.; (ii) H2,
al.[4b] but with certain significant improvements (Scheme 2;
Pd/C, HCl. (b) from threo-1,2;3,4-diepoxybutane
bottom). In the last step, hydrogenolysis of the O-benzyl
group, was problematic, due to the inhibitory effect of am-
ines on the catalytic hydrogenolysis.[9] Benzyl ethers had
been cleaved in burdensome procedures, by high-pressure
hydrogenolysis using stoichiometric quantities of Pd/C 10%
and a large excess of HCl.[10][11] Feit et al.[4b] had obviated
this by converting 2,3-diazido-1,4-dibenzyloxybutane to 2
in four costly steps: catalytic hydrogenation of the azide
groups, N-acetylation, hydrogenolysis of O-benzyl groups,
and deacetylation. We found, however, that -2,3-diazido-
1,4-dibenzyloxybutane underwent one-pot azide reduction
and benzyl hydrogenolysis to -2,3-diamino-1,4-butanediol,
using a catalytic amount of Pd/C ( 5Ϫ10%) and 1.5 equiv. of
HCl, at atmospheric pressure. This made possible the ef-
ficient and economic synthesis of -2,3-diamino-1,4-but-
anediol (2) and we suggest this as a general approach.
Since the need for N-alkyl, especially benzyl, derivatives
of 1 and 2 also arose (vide infra), we attempted direct alky-
lations, but only with partial success. Thus (Scheme 3a),
threo-1,4-bis(benzylamino)-2,3-butanediol (1-Bn2) was ob-
tained from the selective, partial hydrogenolysis of 1-Bn4,
which had been prepared by exhaustive N-benzylation of
threo-1,4-diamino-2,3-butanediol (1). We developed, how-
ever, a new, general and better approach (Scheme 3b) to the
preparation of N,NЈ-dialkyl-1,4-diamino-2,3-butanediols,
by aminolytic ring opening of threo-diepoxybutane, which
proceeded regioselectively and smoothly with aqueous am-
ine solutions,[12] to give, e.g. 1-Me2 or 1-Bn2 (Scheme 3b).
The basic meso-diaminobutanediols 4 and 6 were acces-
tives were secured as follows: meso-1,4-bis(benzylamino)-
2,3-butanediol (4-Bn2) was prepared by selective tosylation
of the terminal hydroxy groups in erythritol, followed by
nucleophilic substitution of erythritol-1,4-ditosylate (3-Ts)
(Scheme 4). Meso-2,3-Bis(benzylamino)-1,4-butanediol
(6-Bn2) was obtained by esterification of dibenzylaminosuc-
cinic acid (5) and reduction of the diethyl ester 5-Et2 with
LiAlH4.[4b] We found that the esterification of 5 in ethanolic
HCl is very temperature sensitive and occurs only in a short
range around 60°C.
Scheme 4. The preparation of the N,NЈ-dibenzyl derivatives of
meso-diaminobutanediols (4, 6): (a) (i) TsCl/Py, Ϫ10°C; (ii) ben-
zylamine. (b) (i) EtOH/HCl, 60°C; (ii) LAH.
Another goal of this work, was the preparation and study
sible by known procedures.[4b,8b] The N-benzylated deriva- of the hitherto unknown diastereomeric 1,5-dioxa-3,7-diaz-
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Eur. J. Org. Chem. 1999, 2033Ϫ2043

New Supramolecular Host Systems, 11
FULL PAPER
adecalin (DODAD) and 1,5-diaza-3,7-dioxadecalin (DA- 50Ϫ60°C and at very low pH (< 1). Highest conversion
DOD) systems, by condensation of the starting tetrafunc- (75%) was achieved by using an excess (3 mol-equiv.) of for-
tionalized butanes (e.g. 1, 2) with aldehydes. The only maldehyde (37% aq.), which gave a II/9 ratio of 1:2. Reaction
known related system was 1,3,5-trioxa-7-aza-cis-decalin[13a] at natural pH of the dihydrochloride of 2 or higher, gave
and 1,5-dioxa-4,8-diazadecalin.[13b]
exclusively the tricyclic product (10) (Scheme 6), i.e., the
The reaction of 1 and 2 with formaldehyde gave the bi- methylene bridged bi(oxazolidinyl) (IV) (Scheme 7). Also, on
cyclic cis-1,5-dioxa-3,7-diazadecalin (cis-DODAD, 7) and adding base to the above reaction mixture and extraction
cis-1,5-diaza-3,7-dioxadecalin (cis-DADOD, 9) products, with chloroform, a 1:1 mixture of 9 and 10 was isolated.
respectively (Schemes 5 and 6). These are formed via the
Similar attempts to produce the trans-DODAD and
corresponding monocyclic intermediates I and II; in prin- trans-DADOD molecules from the corresponding meso-
ciple, additional corresponding bi(oxazolidinyl), aminal 1,4;2,3-diaminobutanediols, were largely unsuccessful.
and/or acetal by-products, viz., III or IIIЈ in the DODAD
cis-DODAD (and even more so cis-DADOD) undergoes
series and IV or IVЈ in the DADOD one (Scheme 7) (and hydrolysis in aqueous solution and transacetalation in al-
their monocyclic intermediates) are possible, but were not cohols, leading to starting materials. cis-DODAD could,
observed. These are pH dependent reactions, the nitrogen however, be stored for a long time in the desiccator in pres-
atoms being the most reactive centres in these systems.
ence of POM, whose unzipping and release of formal-
dehyde has a stabilizing effect on cis-DODAD. Both cis-
DODAD and cis-DADOD were, therefore, used and
probed only as obtained in their crude form, but their N,NЈ-
substituted (see below) or 2,6-substituted derivatives could
be further purified and characterized. The latter have been
probed and discussed,[1] in particular the 2,6-aryl-substi-
tuted compounds, in the context of their formation via
Schiff base intermediates and the ring-chain tautomerism
associated with this process.[1a]
Scheme 5. Reaction of -threo-1,4-diamino-2,3-butanediol (1)
with formaldehyde
In N-acylation attempts, acetylation of cis-DODAD pro-
ceeded smoothly to give 3,7-diacetyl-cis-DODAD (11); 3,7-
dinitroso-cis-DODAD (12) was prepared by nitrosation of
crude cis-DODAD followed by crystallization. In contrast
to these, no good acylation procedures could be worked out
for cis-DADOD; the isolated mixtures of diacetyl deriva-
tives were difficult to separate and 1,5-dinitroso-cis-DA-
DOD was obtained in low yield.
Scheme 6. Reaction of -threo-2,3-diamino-1,4-butanediol (2)
with formaldehyde
1
Using the H-NMR C4Hax,eqϪC10H (3J) couplings cri-
terion, both 11 and 12 exist predominantly in the N,O-in-
side form (Scheme 1), similar to cis-DODAD itself and its
1
derivatives (vide infra). The H- and 13C-NMR spectra of
both indicated the occurrence of a relatively slow dynamic
process in its solution at room temperature. In the diacetyl
compound (11) two main dynamic processes are possible,
Scheme 7. Possible alternative reaction products of formaldehyde
with 1 (III, IIIЈ) and 2 (IV, IVЈ)
Best results for 1 Ǟ 7 were obtained in the temperature amide rotation and ring inversion, in order of decreasing
range of 50Ϫ60°C and at pH 5, of the dihydrochloride of energies of activation (nitrogen inversion is too fast to be
1, which decreased to pH ϭ 3 during the reaction (this low counted).
pH precluded formation of undesired aminal systems).
3,7-diacetyl-cis-DODAD exists in three possible confor-
Complete conversion was achieved by using an excess (5 mational isomers related by amide double-bond rotation:
mol-equiv.) of formaldehyde (37% aq.), which gave a I/7 ϭ two symmetric (11aa, 11ss) and one asymmetric rotameric
1:4 ratio and concentration of this solution brought about (11as) forms (Scheme 8; a and s stand for an anti or syn
complete conversion of I to 7 and ca. 10% by products, in direction of the carbonyl to the acetal moiety). A variable-
addition to polyoxymethylene (POM), formed from an ex- temperature 1H-NMR study in [D8]toluene solution showed
cess of formaldehyde (in a polymerization process known[14] coalescence to occur at 76°C, the resulting activation free
to be initiated inter alia, by ammonium salts). On making energy, ∆GÐ ϭ 16.9 kcal molϪ1, being typical for amide
the above reaction mixture basic, and extraction with rotation barriers.[15] All three rotamers were observed and
chloroform, cis-DODAD (7) became the minor product relative populations could be evaluated, using chemical shift
and the tricyclic product (8) (Scheme 5) was isolated, which and NOE criteria, as follows: 11aa/11ss/11as ϭ 2:1:2.
is formally the methylene bridged bi(oxazolidinyl) (III)
species (Scheme 7).
Study of the dinitroso derivative (12), relied on the
extensive H-NMR spectroscopic documentation for deter-
1
A similar procedure was used for cis-DADOD (9) and best mination of the stereochemistry and barriers of rotation in
results for 2 Ǟ 9 were obtained in the temperature range of N-nitrosamines.[16] The shielding effect of the nitrosamino
Eur. J. Org. Chem. 1999, 2033Ϫ2043
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A. Star, I. Goldberg, N. G. Lemcoff, B. Fuchs
FULL PAPER
Scheme 10. The reaction products of N,NЈ-dibenzyl--threo-1,4-di-
amino-2,3-butanediol (1-Alk2) with formaldehyde
Scheme 8. The observed forms of 3,7-diacetyl-cis-DODAD (11)
(a ϭ anti, s ϭ syn indicate directionality of CϭO with C2)
group on differently oriented vicinal protons is seen in the
1
wide separation (over 2 ppm) of the H-NMR signals: δ4eq
Ϫ δ4ax in 3,7-dinitroso-cis-DODAD (12) is 2.2 ppm, as
compared to 0.13 ppm in cis-DODAD. It is known that the
proton syn to the nitroso oxygen (and nearly coplanar with
the NNO group), resonates at lower frequency than the one
anti to the oxygen.[17a] The axial protons are located deeper
in the shielding zone of the NNO group and therefore res-
onate appreciably upfield from the corresponding equa-
torial ones. Hence, we deal with the 12aa rotamer, ac-
companied by ca. 15% of other rotamers.
Scheme 11. The reaction products of N,NЈ-dibenzyl-meso-diamino-
butanediols with formaldehyde
(4-Bn2) or with erythro-2,3-bis(benzylamino)-1,4-butanediol
(6-Bn2), respectively. In the latter case, the major product
was actually the isomeric imidazolidine (16).
The difference in the geminal (2J) coupling constant of
the α-methylene protons may also serve as a valuable diag-
nostic tool for configurational assignment[17a] and arises
probably from the interaction of the oxygen 2p component
of the πNNO molecular orbital with the neighboring 2-syn
CϪH bond. In 3,7-dinitroso-cis-DODAD (12) the 2J coup-
Conformational Analysis of Diaminobutanediols
The different behaviour of N,NЈ-substituted threo-1,4-di-
amino-2,3-butanediols in protic and aprotic solutions, as
manifested in the 1H-NMR signals of their C1H2ϪC2H
protons (Table 1), is interesting. In aprotic (e.g. CHCl3)
solution, two well-separated and differently split AB pat-
terns were registered, evidently due to a fixed conformation.
The calculated dihedral angles[18] related to vicinal coupling
suggest pseudobicyclic structures stabilized by intramolecu-
lar hydrogen bonds (Table 1). In the case of free rotation
around the C1ϪC2 bond, the coupling constants would be
averaged to 6 Hz. This is exactly what is observed in D2O
solution of 1-Me2, where no intramolecular hydrogen bond-
ing can operate.
2
lings of the α-methylene protons are J(C2H2) ϭ 10.3 Hz
and 2J(C4H2) ϭ 14.8 Hz, while the long-range coupling
4Jee ϭ 1.8 Hz is due to the defined W arrangement of bonds
in the HCN(NO)CH moiety (Scheme 9) (in cis-DODAD
they are 10.4 Hz, 14.5 Hz and 1 Hz, respectively).
Scheme 9. N,NЈ-Dinitroso-cis-DODAD (12)
Table 1. 1H-NMR coupling constants (3J1,2) and derived dihedral
angles in the H2CϪCH moiety of N-substituted threo-1,4-diamino-
2,3-butanediols (see Scheme 3)
N-Alkylation attempts were largely discouraging in both
series. Various methylations of cis-DODAD, viz., with
methyl iodide, methyl iodide with silver oxide, dimethyl sul-
fate, use of sodium hydride, were fruitless and benzylation
with benzyl bromide and potassium carbonate lead to 3,7-
dibenzyl-cis-DODAD (13-Bn2) in low yield. However, hav-
ing secured the N,NЈ-dialkylated threo-1,4-diamino-2,3-but-
anediols (1-R2) (Scheme 3), we were able to attain the corre-
sponding 3,7-disubstituted cis-DODAD systems, among
them 13-Bn2, in good yields by reactions of the former with
formaldehyde (Scheme 10).
By the same approach (Scheme 11), trans-3,7-dibenzyl-
DODAD (14), and trans-1,5-dibenzyl-DADOD (15) were
readily isolated from the condensation reactions of formal-
[a] The H2CϪCH dihedral angles: [b] calculated by Haasnoot equa-
[c]
tion;[18]
calculated (MM3) lowest energy conformation of 1-
dehyde with erythro-1,4-bis(benzylamino)-2,3-butanediol Me2.
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New Supramolecular Host Systems, 11
FULL PAPER
Similar observations have been reported[17b] for 2- tems. In OϪCϪN [Figure 1(i)] the anomeric effect is out-
hydroxymethylcyclohexylamine and 2-aminomethylcy- standing, since it has a good N lone-pair donor adjacent
clohexanol, but in our 1,4-diamino-2,3-butanediol cases, and anti to an excellent CϪO σ* acceptor, to mix in-
there is no structural preorganisation, so the double amine/ to.[13b,22] This is illustrated for the gϩa and gϪa forms of
alcohol hydrogen bond may be the main driving force to the RϪOϪCϪN lone pair moiety [Figure 1(ii)], including
attain the pseudobicyclic structures.
the structural manifestations of this phenomenon, viz., con-
MM3 calculations of 1-Me2 showed that its most stable traction of the NϪC bond and elongation of the CϪO
conformation includes six-membered OH---N and NH---O bond and, an upright gauche NϪH (dictated by the anti N
hydrogen-bonded modes and the C1/C2 hydrogens have di- lone pair). The gϪa form is, evidently, the one occurring in
hedral angles of 60°, consistent with the observed vicinal the 1,3-oxazane chair and, implicitly in the DODAD [Fig-
coupling constants (Table 1). In all calculated confor- ure 1(iii)] and DADOD bicyclic systems, with all the above
mations of 1-Me2 the N-Me group is anti to the C1ϪC2 structural implications.
bond, so replacing the methyl groups with benzyl, should
As to the gauche effect (i.e. the lessening of the preference
have no significant effect on the conformation of the mol- of anti over gauche forms), we have recently reviewed[23] it
ecule. The NMR data of 1-Bn2 (Table 1) indicate indeed and studied it in OϪCϪCϪO systems, where we concluded
that it exists in aprotic solution in a similar conformation. from available experimental and computational results that
For 1-Bn4, the calculated structure has the bulky tertiary it is smaller than previously thought. The gauche effect in
dibenzylamino groups buttressed against the hydroxyl other XϪCϪCϪY moieties is less well documented, but
groups and reinforced by five-membered OϪH···N hydro- very recent computational studies made possible the re-
gen bonds (Table 1).
Conformational Analysis of 1,5-Dioxa-3,7-diaza-and 1,5- NϪCϪCϪO,[24] and NϪCϪCϪN.[24a,25] The values were
diaza-3,7-dioxadecalins ( DODAD & DADOD) taken in particular from the most recent and detailed paper
evaluation of the gauche effect in OϪCϪCϪO,[24a]
In the diastereomeric tetraheterodecalin (THD) series of Y.-P. Chang et. al.,[24a] namely, results of high-level ab
(Scheme 1), cis-THD exist in two chair conformations, X- initio [MP2/6-311ϩG(2d,p)] calculations of 1,2-ethanediol,
inside and X-outside, which, in contrast to the fixed trans 1,2-diaminoethane, and 2-aminoethanol in their various
isomer, may interconvert by conformational ring inversion conformations (see Figure 2 for selected viable NϪCϪCϪO
or by chemical (acid-catalysed) isomerization. The cis/trans conformations). Also included was a conformational energy
relative stabilities and the equilibrium distribution between decomposition scheme, which allowed the evaluation of the
cis-THD X-inside and X-outside chairϪchair forms depend intrinsic gauche effect and of the hydrogen-bonding contri-
on a combination of steric and stereoelectronic effects, due butions (MM3 calculations were included as well). Thus,
to their fragment components, e.g. in the dioxadiazadecal- we adopted their[24a] values for the antiϪgauche differences
ins, CϪCϪCϪC in the centre and CϪO(N)ϪCϪC in the due to the intrinsic gauche effect in OϪCϪCϪO (Erel(aϪg) ϭ
flanks, OϪCϪN units (with their anomeric effect) in each 0.8 kcal molϪ1), NϪCϪCϪN, (Erel(aϪg) ϭ Ϫ0.5 kcal
ring, OϪCϪCϪO in DODAD and NϪCϪCϪN in molϪ1) and NϪCϪCϪO (Erel(aϪg) ϭ 0.4 kcal molϪ1), along
DADOD, as well as OϪCϪCϪN in both (with their gau- with that of the intramolecular NϪH---O hydrogen bond
che effect).
(0.8 kcal molϪ1).
This enabled us to carry out a fragment analysis[26] (Table
The well-known anomeric effect[19] has been investigated
in our group, both experimentally and theoretically, in 2) for the DODAD and DADOD series, following their mo-
OϪCϪO,[20] NϪCϪN [21] and OϪCϪN [22] containing sys- lecular composition of CϪCϪCϪC (butane), OϪCϪN
Figure 1. The anomeric effect: (i) in the prototypal RϪOϪCϪNϪRЈ moiety (uniquely defined by the N lone pair and OR termini); (ii)
with MO visualization of its geometrical consequences; (iii) in the 1,3-oxazane system of trans-and cis-DODAD
Eur. J. Org. Chem. 1999, 2033Ϫ2043
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A. Star, I. Goldberg, N. G. Lemcoff, B. Fuchs
FULL PAPER
Figure 2. Selected conformations of the NϪCϪCϪO moiety, uniquely defined by the N lone pair and OR termini
(oxymethylamine), OϪCϪCϪO (dioxyethane), NϪCϪ lead to the final estimation of relative stabilities of the
CϪN (diaminoethane), and OϪCϪCϪN (1-oxy-2-amino- DODAD and DADOD diastereomers.
ethane) described above, as well as CϪOϪCϪC (methyl-
ethyl ether) (Erel(aϪg) and if not in magnitude, with those of molecular mechanics cal-
1.5 kcal molϪ1 [26a,b]
CϪNϪCϪC (methylethyl amine) (Erel(aϪg) ϭ 1.1 kcal culations, using the MM3(92) force field,[27] given in Table
The results of the fragment analysis agree well in order,
ϭ
)
mol
)
Ϫ1 [26a,c] fragments.
3. In the case of DODAD, which contains an OϪCϪCϪO
unit, we used MM3-GE,[23] that is, MM3(92) reparame-
trized for the gauche effect in OϪCϪCϪO containing sys-
tems (we have not yet done the same for NϪCϪCϪN and
OϪCϪCϪN systems). In these calculations, the cis-N,O-
outside conformations were found 10 to 12 kcal molϪ1 less
stable than their inside counterparts (and were, therefore,
not included in the display) and axial NϪH bonds were
clearly preferred. Also, among the two most stable confor-
mations, cis-DADOD was calculated to be slightly (0.4 kcal
molϪ1) more stable than cis-DODAD in the O,N-inside
forms. The discrepancy in the magnitude of the (cis-N,O-
outside vs. cis-N,O-inside vs. trans) energy differences could
be understood after having appreciated the substantial dis-
parity between the ab initio and MM3 calculated[24a] anti-
gauche differences for the NϪCϪCϪN and NϪCϪCϪO
basic units.
Table 2. Relative energies (kcal molϪ1) of the DODAD and
DADOD diastereomers as obtained by fragment analysis
Table 3. Various conformations of cis-O,N-inside and trans-DO-
DAD and DADOD, and their relative energies (kcal molϪ1) as cal-
culated by MM3-GE[a]
In both the DODAD and DADOD series of dia-
stereomers, the CϪOϪCϪNϪC fragments are intraannular
and conformationally constant, except that conformers hav-
ing an N lone pair antiperiplanar to the adjacent CϪO
bond (NϪH axial) gain special stability, due to delocalis-
ation of the N lone pair into the adjacent σ*CϪO orbital
[e.g. Figure 1(iii)]. Therefore, Table 2 presents the fragment
analysis of and comparison between the (NϪH) diaxial
forms in each series.
In contrast, all the CϪCϪCϪC, OϪCϪCϪO,
OϪCϪCϪN, NϪCϪCϪN, CϪOϪCϪC, and CϪNϪCϪC
fragments are interannular and vary with each, trans-, cis-
N,O-inside and cis-N,O-outside form. Finally, intramolecu-
lar hydrogen bonding of NϪH---O type is possible only in
the cis-N,O-inside isomer [Figure 1(iii)]. The quantification
of all these contributions within the same frame of refer-
[a] The O,N-outside were omitted since they are all higher by 10Ϫ12
[b]
kcal/mol then their O,N-inside counterparts. Ϫ
DADOD is
slightly (0.4 kcal/mol) more stable than DODAD in the O,N-in-
side form.
We had observed (X-ray diffraction) all axial NϪH
ence[24a] and the summation of these differences (Table 2), bonds in 2,6-dinitrophenyl-cis-DODAD and -cis-DA-
2038
Eur. J. Org. Chem. 1999, 2033Ϫ2043

New Supramolecular Host Systems, 11
FULL PAPER
Table 4. Selected conformations of 3,7-dimethyl-trans- and -cis- DODAD and DADOD systems in solution (Table 5), we
DODAD (13), as well as 1,5-dibenzyl-trans-DADOD (15) and their
could assert that 3,7-dimethyl-cis-DODAD exists predomi-
nantly with diaxial N-Me groups and this preference in-
MM3-GE relative energies (kcal molϪ1) and dipole moments
creases with decreasing solvent polarity (Table 5). All cis-
DODAD systems examined in (polar and nonpolar) solu-
tion are by far more stable in the inside form. MM3-
GE[23][27] calculations of 3,7-dimethyl-cis-and trans-DO-
DAD (Table 4) indeed revealed high preference of the N,O-
inside form and, interestingly, slight preference of the N-Me
diaxial conformations in both the cis and trans series, in
good accord with the experimental (NMR) results.
An even more detailed and enlightening analysis was pos-
sible for the N,NЈ-dibenzyl-trans-DODAD and DADOD
(14, 15) compounds. According to NMR 2J criteria, 3,7-
dibenzyl-trans-DODAD (14) exists in solution (CDCl3)
mostly as the diaxial conformer (2J ϭ 10 Hz). At the same
time, 1,5-dibenzyl-trans-DADOD (15) exhibits 2J ϭ 9.2 Hz,
which indicates some equatorial character of the N-sub-
stituent. (Table 5). MM3-GE calculations (Table 4 last col-
umn) showed indeed that while, similarly to 3,7-dimethyl-
trans-DODAD, the diaxial form of the 3,7-dibenzyl deriva-
tive (14) is the most stable one, 1,5-dibenzyl-trans-DADOD
(15) slightly prefers the axial/equatorial conformation.
For a decisive answer, we were able to secure single crys-
DOD [1] and interpreted it as a result of the strong NϪCϪO
anomeric effect, reinforced by intramolecular NϪH---O hy-
drogen bonding. Notwithstanding the fact that MM3[27]
had been parametrized for the anomeric effect in OϪCϪO
systems but not beyond that, our calculations reproduced tals of both N,NЈ-dibenzyl derivatives and to subject them
the axial positioning of the amine hydrogens. This is most to X-ray diffraction analysis. The observed structures con-
probably due to the strong effect of the intramolecular firmed that we deal with diaxial N,NЈ-dibenzyl-trans-DO-
NϪH---O bonding mentioned above, along with dipoleϪdi- DAD (14) and axial-equatorial N,NЈ-dibenzyl-trans-DA-
pole interactions and the alleviation of steric interactions.
DOD (15) (Figure 3), as concluded from NMR 2J criteria
The effect of the relative orientation of the lone pair and (Table 5) and from the molecular mechanics calculation
N-substituents on the geminal coupling constants in tetra- (Table 4). The structural parameters (Table 6) substantiate
hydro-1,3-oxazines has been thoroughly studied.[28] The ge- the existence of strong NϪCϪO anomeric effects in the N-
minal coupling constant of the methylene protons at C2 axially substituted rings, namely, short NϪC bonds and
changes from 7.5 Hz for equatorial to 10.5 Hz for axial long CϪO bonds. Careful comparison of the X-ray and cal-
NϪR. Using this effect for conformational analysis of culated structures shows that the MM3 forcefield,[27] which
Figure 3. ORTEP drawings of 3,7-dibenzyl-trans-DODAD (14) and 1,5-dibenzyl-trans-DADOD (15). Molecular packing of 14 is projected
down the b-axis (frames of two, and content of three, unit cells are shown) and of 15 down the a-axis (two unit cells)
Eur. J. Org. Chem. 1999, 2033Ϫ2043
2039

A. Star, I. Goldberg, N. G. Lemcoff, B. Fuchs
FULL PAPER
has not been parametrized for the NϪCϪO anomeric effect, achieved from experimental and computational probes.
does not reproduce these geometrical features (Table 6; ital- Good agreement was observed between X-ray, NMR, and
ics). Clearly, MM3 needs additional parametrization, to be calculated results of the N,NЈ-dibenzyl derivatives of trans-
able to reproduce faithfully large systems endowed with DODAD (14) and trans-DADOD (15). We anticipate sig-
such stereoelectronic effects.
nificant use of these findings and of the insight gained, both
in the area of C2-dissymetric drug design and in the supra-
molecular field (functionalized derivatives of 7 already
Table 5. NMR spectral data of DODAD and DADOD systems
showed good heavy-ion complexation[29]
)
Experimental Section
General: Melting points were recorded on a capillary melting-point
apparatus and are uncorrected. Ϫ The NMR spectra were obtained
on a AC 200, AMX 360, or ARX 500 Bruker spectrometer. All 1H
chemical shifts are in ppm and δ values are relative to TMS as
internal standard. 13C chemical shifts are reported in ppm relative
to CDCl3 (centre of triplet δ ϭ 77.0) except for those taken in D2O
which are reported in ppm relative to TMS salt as internal stand-
ard. Ϫ Mass spectra (DEI-MS, DCI-MS, and FAB) were recorded
on a VG Autospec 250 mass-spectrometer. Ϫ Elemental analysis
were performed at the Microanalytical Laboratory of the Hebrew
University, Jerusalem. Ϫ IR spectra were measured on a Nicolet
205 FTIR instrument in potassium bromide pellets (solids), sodium
chloride cells (solutions), or sodium chloride pellets (neat). UV
spectra were taken on a Unikon 931 spectrophotometer.
Table 6. Observed (X-ray) vs. calculated (MM3) selected structural
parameters of trans-3,7-dibenzyl-DODAD (14) trans-1,5-dibenzyl-
DADOD (15)[a]
L
-1,4-Diamino-2,3-butanediol (1): Prepared from -2,3-O-isopropyl-
idenedimethyl tartarate[8a] by amidation with methanolic am-
monia,[8b] then reduction with lithium aluminium hydride[5a] and
finally the solution of acetonide 3.6 g (22.5 mmol) in ethanol (90%)
60 mL, saturated with HCl was refluxed for 1 h and then left at
room temperature overnight. Filtration gave a white dihydrochlo-
ride salt 2.9 g (67%), m.p. 210°C. Ϫ 1H NMR (D2O): δ ϭ 3.94 (dd,
J ϭ 4.0, 7.0 H2), 3.16 (m, 2 H1); Ϫ 13C NMR (D2O): δ ϭ 71 (d,
C2), 45 (t, C1). Ϫ C4H14Cl2N2O2 (193.07).
1,5-Dioxa-3,7-diazadecalin (cis-DODAD) (7): To -1,4-diamino-
2,3-butanediol dihydrochloride (1:2HCl) (0.40 g, 2 mmol) in 10 mL
of water, formaldehyde (37% aq.) (0.8 mL, 10 mmol) was added at
room temperature. The reaction mixture was heated at 60°C for
2 h. According to NMR, 7 was the major product (72%). 1H NMR
(D2O, pH ϭ 3): δ ϭ 5.16 (d, 2J ϭ 9.3, 1 H2eq), 4.74 (d, 2J ϭ 9.3,
1 H2ax), 4.31 (brs, 1 H9), 3.69 (m, 2 H4); Ϫ 13C NMR (D2O, pH ϭ
3): δ ϭ 78 (t, C2), 70 (d, C9), 48 (t, C4). Ϫ The minor product (18%)
at these reaction conditions was 5-hydroxy-6-aminometyltetrahydro-
1
1,3-oxazine (I): H NMR (D2O, pH ϭ 3): δ ϭ 5.16 (d, 2J ϭ 9.3,
2
3
3
1 H2eq), 4.74 (d, J ϭ 9.3, 1 H2ax), 4.20 (m, J6,7 ϭ 5, J4,5 ϭ 1.7,
3
3
2 H5,6), 3.57 (d, J4,5 ϭ 1.7, 2 H4), 3.33 (d, J6,7 ϭ 5, 2 H7); Ϫ
13C NMR (D2O, pH ϭ 3): δ ϭ 78 (t, C2), 77 (d, C6), 64 (d, C5), 51
(t, C4), 43 (t, C7). Ϫ Adding base (sodium carbonate) to the reac-
tion mixture and extraction with chloroform gave 7. H NMR
(CDCl3): δ ϭ 4.63 (dd, 2J2,2Ј ϭ 10.4, 4J2,4 ϭ 1, H2), 4.32 (d, 2J2Ј,2 ϭ
[a] See formulae and numbering in Scheme 11. Ϫ MM3 repara-
[b]
metrized for the gauche effect in OCCO systems.
2
3
4
10.4, H2Ј), 3.08 (ddd, J4,4Ј ϭ 14.5, J4,9 ϭ 1.5, J2,4 ϭ 1, H4), 2.95
2
3
3
3
Conclusions
(dd, J4Ј,4 ϭ 14.5, J4Ј,9 ϭ 2, H4Ј), 3.38 (dd, J9,4Ј ϭ 2, J9,4 ϭ 1.5,
H9); Ϫ 13C NMR (CDCl3): δ ϭ 79.2 (t, C2), 70.1 (d, C9), 49.3 (t,
C4). Ϫ C6H12N2O2 (144.17). Since ultimate purification was practi-
cally impossible, elemental analysis was performed on its deriva-
tives.
New and improved approaches to the chiral and meso
1,4-diamino-2,3-butanediol (1) and 2,3-diamino-1,4-but-
anediol (2) and derivatives have been developed. Their dia-
stereospecific reactions with aldehydes provided the novel
1,5-dioxa-3,7-diazadecalin (DODAD) and 1,5-diaza-3,7-di-
oxadecalin (DADOD) classes of compounds (7, 9, 11؊15).
Thorough understanding of the structural, conformational,
3,3Ј-Methylene-5,5Ј-bi(oxazolidinyl) (8): Obtained according to the
method described for 7, but extraction of the reaction mixture
(pH ϭ 3) with chloroform was done in the presence of Amberlite
(IR-4B, weakly basic) overnight. Evaporation of chloroform gave
and stereoelectronic properties of these systems was exclusively 8 which was purified by column chromatography
2040 Eur. J. Org. Chem. 1999, 2033Ϫ2043

New Supramolecular Host Systems, 11
FULL PAPER
2
2
3
(MeOH washed SiO2, EtOAc). Yield 0.09 g (30%). Ϫ 1H NMR
3.66 (s) (ss), 3.47 (d, J ϭ 14.5) (ss and as), 2.96 (dd, J ϭ 14, J ϭ
1.5) (aa and as), 2.17 (s) (aa and as), 2.12 (s) (ss), 2.10 (s) (as). Ϫ
2
2
4
(CDCl3): δ ϭ 4.70 (d, J2 ϭ 9.2, H2), 4.63 (dd, J2 ϭ 9.2, J2,4
ϭ
1.7, H2), 4.23 (m, H5), 4.14 (s, H6), 3.35 (dm, J4 ϭ 15, H4), 3.13 13C NMR (CDCl3): δ ϭ 170.5, 170.3, 169.9, 169.7 (s), 77.2 (t), 72.7
2
(dd, J4 ϭ 15, J4,2 ϭ 1.7, H4); Ϫ 13C NMR (CDCl3): δ ϭ 83.0 (t,
C2), 80.0 (t, C6), 71.3 (d, C5), 49.4 (t, C4). Ϫ FAB MS; m/z: 157.0 UV: λmax ϭ 199 nm (acetonitrile). Ϫ DEI MS; m/z (%): 228 (45.4)
[MH]ϩ. Ϫ EI-MS; m/z (%): 157 (23.9) [M]ϩ, 156 (61.2), 127 (26.4), [Mϩ·], 168 (19.6), 141 (56.5), 128 (61.8), 111 (42.6), 98 (37.6), 85
114 (21.9), 98 (100), 86 (45.5), 85 (77.5), 84 (37.2), 72 (39.7), 57 (91.3), 72 (100). Ϫ C10H16N2O4 (228.25): calcd. C 52.61, H 7.07,
(t), 71.9(d), 71.3(d), 70.9 (d), 49.4 (t), 44.7 (t), 21.3 (q), 21.0 (q). Ϫ
2
4
(80). Ϫ C7H12N2O2 (156.0): calcd. C 53.82, H 7.75, N 17.94; found
N 12.28; found C 52.20, H 7.30, N 12.10.
C 53.64, H 8.04, N 17.81.
VT-NMR measurements of conformational equilibria of 11 were
taken at 360 MHz. The temperature was checked using an ethylene
glycol solution.[30]
D
-2,3-Diamino-1,4-butanediol (2): To a solution of -2,3-diazido-
1,4-dibenzyloxybutane [prepared by FeitЈs procedure[2b] from -1,4-
dibenzyloxy-2,3-butanediol (Aldrich)] (3.52 g, 10 mmol) in 30 mL
of ethanol, Pd/C (10%) (0.352 g) was added, followed by slow ad-
dition of conc. HCl (3 mL, 30 mmol). The resulting solution was
stirred under hydrogen at atmospheric pressure for 48 hours. The
catalyst was filtered out and evaporation provided -2,3-diamino-
1,4-butanediol dihydrochloride (2 · 2 HCl) (1.8 g, 93%). Ϫ 1H
NMR (D2O): δ ϭ 4.00 (m, 2 H1), 3.86 (m, H2); Ϫ 13C NMR (D2O):
δ ϭ 61.4 (t, C1), 54.6 (d, C2). Ϫ C4H14Cl2N2O2 (193.07).
3,7-Dinitroso-cis-DODAD (12): To a cold solution (0Ϫ5°C) of
crude cis-DODAD (7) (1.5 mmol) and NaNO2 (0.22 g) in water,
concentrated HCl (0.3 mL) was added. The reaction mixture was
stirred for 1 h, and allowed to stand overnight in the refrigerator.
NaOH was added to neutralize the HCl and the product was ex-
tracted with CHCl3. The solvent was removed in vacuo to give solid
1
product 12 (0.30 g, 99%), m.p. 197°C (CH3CN/H2O). Ϫ H NMR
2
4
(CDCl3): δ ϭ 6.11 (dd, J2,2Ј ϭ 10.3, J2,4 ϭ 1.8, H2), 5.23 (d,
2J2Ј,2 ϭ 10.3,H2Ј), 5.21 (dd, 2J4,4Ј ϭ 14.8, 4J4,2 ϭ 1.8, H4), 4.01 (brs,
3,7-Dioxa-1,5-diazadecalin (cis-DADOD, 1,5-diaza-3,7-dioxadeca-
lin, 9): -2,3-diamino-1,4-butanediol dihydrochloride (2 · 2 HCl)
(0.35 g, 1.8 mmol) in 10 mL HCl (0.8 ) was treated with formal-
dehyde (37% aq.) (0.5 mL, 6 mmol) by dropwise addition at room
temperature. The reaction mixture was heated at 60°C for 4 h. Ac-
cording to NMR spectrscopy, 9 was the major product (75%). Ϫ
1H NMR (D2O, pH ϭ 0): δ ϭ 5.14 (d, J ϭ 9.5, H2), 4.7 (d, J ϭ
9.5, H2), 4.22 (d, 2J ϭ 14, H4), 4.11 (d, 2J ϭ 14, H4), 4.10 (br. s,
H9). Ϫ 13C NMR (D2O, pH ϭ 0): δ ϭ 79.0 (t, C2), 69.8 (t, C4),
50.9 (d, C9). Ϫ 5-Amino-4-hydroxymethyl-1,3-oxazane (II) was ob-
tained as a by-product (30%) under these reaction conditions. Ϫ
2
3
H9), 3.01 (dd, J4,4Ј ϭ 14.8, J4Ј,9 ϭ 2.7, H4Ј) (in addition there are
low (ca. 15%) signals at 6.16 (dd), 5.34 (d), 5.06 (dd), 4.04 (d)); Ϫ
13C NMR (CDCl3): δ ϭ 79.1 (t, C2), 71.8 (d, C9), 41.6 (t, C4). Ϫ
IR: ν˜ ϭ 2850 cmϪ1 (med.), 1450 (strong), 1360 (strong), 1051
(strong). Ϫ EI MS; m/z (%): 202 (100) [Mϩ·], 149 (34), 142 (28),
114 (38), 113 (25), 101 (53, Mϩ·/2). Ϫ C6H10N4O4 (202.07): calcd.
C 35.63, H 4.99, N 27.72; found C 35.85, H 5.00, N 27.43.
2
2
1,5-Dinitroso-cis-DADOD: Prepared as described for 12, from
crude cis-DADOD (9). Ϫ Yield: 90 mg, (30%); Ϫ m.p. 229°C (dec.)
1
(EtOH/H2O). Ϫ H NMR (CDCl3): δ ϭ 6.02 (d, 2J ϭ 11.0, H2),
1H NMR (D2O, pH ϭ 0): δ ϭ 5.13 (d, J ϭ 9.5, H2), 4.7 (d, J ϭ
9.5, H2), 3.92 (m), other signals overlap. Ϫ 13C NMR (D2O, pH ϭ
0): δ ϭ 79.1 (t, C2), 71.1 (t, C6), 62.1 (t, CH2OH), 56.7 (d, C5),
49.7 (d, C4). Adding base (sodium carbonate) to the reaction mix-
ture and extraction with chloroform gave 9 and 10 in a 1:1 ratio.
Ϫ 3,7-Dioxa-1,5-diazadecalin (cis-DADOD, 1,5-diaza-3,7-dioxade-
2
2
2
5.33 (d, J ϭ 11.0, H2) 5.2 (bm, H9), 4.0 (m, H4), 3.85 (m, H4); Ϫ
13C NMR (CDCl3): δ ϭ 77.5 (C2), 61.4 (C4), 42.3 (C9). Ϫ EI MS;
m/z: 202.1 [M]ϩ·, 172.1 [M Ϫ NO], 142.1 [M Ϫ 2 NO]. Ϫ
HRCIMS: calcd for C6H11N4O4 [MH]ϩ 203.1018, observed m/z
203.1018.
1
2
calin, 9): H NMR (CDCl3): δ ϭ 4.58 (d, J ϭ 10.6, H2), 4.22 (d,
General Procedure for the Preparation of threo-1,4-Diamino-2,3-but-
anediols: threo-1,2,3,4-Diepoxybutane (0.4 mL, 5 mmol) was added
dropwise with good stirring to a cold (0Ϫ5°C) aq. solution of pri-
mary amine (25Ϫ30%) (10 mL). The reaction mixture was stirred
overnight at room temperature. threo-1,4-Bis(methylamino)-2,3-but-
anediol (1-Me2) was prepared from methylamine.[12] Evaporation
gave solid product (0.74 g, quantitative yield); m.p. 142°C (iPrOH),
2
2
2J ϭ 10.6, H2), 3.88 (d, J ഠ 8, H4); 3.81 (d, J ഠ 8, H4); 2.72 (s,
H9); Ϫ 13C NMR (CD3Cl): δ ϭ 79.2 (t, C2), 71.0 (t, C4), 49.8 (d,
C9). Ϫ FAB MS; m/z: 145.1 [MH]ϩ. C6H12N2O2 (144.17).
3,3Ј-Methylene-4,4Ј-bi(oxazolidinyl) (10): 1H NMR (CDCl3): δ ϭ
4.49 (d, 2J ϭ 6, H2), 4.3 (d, 2J ϭ 6, H2); 3.92 (s, H6), 3.86 (dd, 2J ϭ
3
2
3
3
8.3, J ϭ 7.0, H5); 3.77 (dd, J ϭ 8.3, J ϭ 4.3, H5), 3.57 (dd, J ϭ
7.0, 4.3, H4); Ϫ 13C NMR (CD3CN): δ ϭ 86.2(t, C2), 76.0(t, C6)
(hidden in CDCl3), 69.9(t, C5), 68.2(d, C4). Ϫ EI MS; m/z (%):
156.2 (7) [M]ϩ·, 85.1 (100). Ϫ HREIMS: calcd for C7H12N2O2
[M]ϩ· 156.0899, observed m/z ϭ 156.0907.
1
144°C (MeOH)[12]. Ϫ H NMR (CDCl3): δ ϭ 3.84 (dd, 3J ϭ 3.5,
2
3
2
3
2, H2), 3.07 (dd, J ϭ 12, J ϭ 3.5, H1), 2.65 (dd, J ϭ 12, J ϭ 2,
H1), 2.42 (s, CH3); 1H NMR (D2O): δ ϭ 3.61 (m, H2), 3.57 (m,
2 H1), 2.27 (s, CH3); Ϫ 13C NMR (D2O): δ ϭ 73.7 (d, C2), 55.3 (t,
C1), 37.3 (q, CH3). Ϫ DEI MS; m/z (%): 104 (40) [M
Ϫ
3,7-Diacetyl-cis-DODAD (11): The crude cis-DODAD hydrochlo-
ride (7 · 2 HCl) (prepared from 1 (1 mmol) was dissolved in pyri-
dine (5 mL) / acetic anhydride (15 mL) mixture and heated at
50Ϫ60°C overnight. The excess of acetic anhydride was removed
in vacuo and the residue was dissolved in CH2Cl2, washed with
CH2NHCH3]ϩ·, 86 (63), 74 (23), 57 (17), 45 (24), 44 (100); DCI
MS: 149.1 (25) [MH]ϩ, 118.1 (100), 104.1 (20), 86.1 (20). Ϫ
HRCIMS: calcd for C6H17N2O2 [MH]ϩ 149.1290, observed m/z
149.1301.
H2O, and dried with MgSO4. The solvent was evaporated to give threo-1,4-Bis(benzylamino)-2,3-butanediol (1-Bn2): Prepared from
the crude product 11 which was purified by flash chromatography
(SiO2, CH2Cl2/MeOH, 96:4). Ϫ Yield 0.18 g (64%). NOE (OCMe)
benzylamine. The solid product was filtered in vacuo, thoroughly
washed with water and dried in a vacuum desicator o.n. Ϫ Yield
measurements and chemical shifts (below) show a composition of 1.5 g (quant.), m.p. 107°C (CH3CN). Ϫ 1H NMR (CDCl3): δ ϭ
11aa (40%), 11ss (20%), and 11as (40%). 1H NMR (CDCl3): δ ϭ
7.28 (m, Ph), 3.83 (dd, 3J ϭ 3.5, 2.2, H2), 3.82 (d, 2J ϭ 13, CH2Ph),
2
4
2
4
6.02 (dd, J ϭ 10.2, J ϭ 2.2) (ss and as), 5.30 (dd, J ϭ 11, J ϭ 3.72 (d, 2J ϭ 13, CH2Ph), 3.08 (dd, 2J ϭ 12, 3J ϭ 3.5, H1), 2.72
2
4
2
3
2), 5.28 (dd, J ϭ 11, J ϭ 2) (aa), 4.84 (ddd, J ϭ 14.5, J ϭ 1.4,
(dd, 2J ϭ 12, 3J ϭ 2.2, H1); Ϫ 13C NMR (CDCl3): δ ϭ 139.8 (s,
Ph), 129.1, 128.9, 127.8 (d, Ph),73.2 (d, C2), 54.3 (t), 53.5 (t). Ϫ
FAB MS; m/z: 301 [MH]ϩ. Ϫ C18H24N2O2 (300.40): calcd. C 71.97,
H 8.05, N 9.33; found C 72.20, H 7.94, N 9.25.
4J ϭ 2) (aa), 4.80 (ddd, J ϭ 14.1, J ϭ 1.4, J ϭ 2) (as), 4.66 (m),
2
3
4
4.62 (d, 2J ϭ 11) (aa), 4.10 (d, 2J ϭ 10.2) (ss and as), 3.97 (dd,
2J ϭ 14.5, J ϭ 2.2) (ss and as), 3.64Ϫ3.71 (m) (as), 3.71 (s) (aa),
4
Eur. J. Org. Chem. 1999, 2033Ϫ2043
2041

A. Star, I. Goldberg, N. G. Lemcoff, B. Fuchs
FULL PAPER
4
2
L
-1,4-Bis(dibenzylamino)-2,3-butanediol (1-Bn4): To
a
refluxing
10.4, J2,4eq ϭ 1.3, H2), 4.28 (d, J2Ј,2 ϭ 10.4, H2Ј), 4.31 (d, 2J ϭ
2
ethanol/ water (1:1) (20 mL) solution of -1,4-diamino-2,3-butane-
13.2, CHHPh), 4.19 (d, J ϭ 13.2, CHHPh), 3.50 (s, H9), 3.15 (d,
diol (1) (1 mmol) and K2CO3, benzyl bromide (0.5 mL, 4 mmol) 2J ϭ 14.5, H4eq), 3.07 (d, 2J ϭ 14.5, 3J ϭ 2, H4ax). Ϫ 13C NMR
was added and after reflux for 1 hour the solution was stirred over-
night. Filtration of water-insoluble solids gave tetrabenzyl 1-Bn4
(0.23 g, 48%), m.p. 120°C. Ϫ 1H NMR (CDCl3): δ ϭ 7.27 (m,
(CDCl3): δ ϭ 129.3, 128.3, 127.1 (d, Ph), 83.0 (t, C2), 72.7 (d, C9),
57.7 (t, C4), 53.5 (t, CH2Ph). Ϫ DEI MS; m/z (%) 324.3 (2) [M]ϩ·
294.3 (8), 233.2 (6), 187.2 (7), 176.2 (26), 175.2 (32), 174.2 (24),
162.0 (7) [M/2], 146.2 (12), 120.2 (26), 91.0 (100). Ϫ HRCIMS:
calcd for C20H25N2O2 [MH]ϩ 325.1916, observed m/z 325.1917.
,
2
3
2 Ph), 4.39 (brs, OH), 3.76 (d, J ϭ 13.3, CH2Ph), 3.61 (dd, J ϭ
2
2
3
6.3, 5.1, H2), 3.44 (d, J ϭ 13.3, CH2Ph), 2.65 (dd, J ϭ 13.2, J ϭ
6.3, H1), 2.52 (dd, J ϭ 13.2, J ϭ 5.1, H1); Ϫ 13C NMR (CDCl3):
δ ϭ 139.1 (s, Ph), 129.9, 129.1, 128.0 (d, Ph), 70.2 (d, C2), 59.7(t),
57.2 (t). Ϫ FAB-MS; m/z: 481.3 [Mϩ]. C32H36N2O2 (480.65).
2
3
trans-3,7-Dibenzyl-DODAD (14): Prepared from meso-1,4-bis(ben-
zylamino)-2,3-butanediol (4-Bn2). Yield: 0.31 g, (95%); m.p. 107°C
(petroleum ether). Ϫ 1H NMR (CDCl3): δ ϭ 7.30 (m, Ph), 4.44
2
4
2
2
The extraction of filtrate with CHCl3 gave 1-Bn4 and other benzyl-
ated products (0.24 g, 51%). The crude benzylated products were
hydrogenolyzed (30 ψ, Pd/C (5%), HCl, MeOH) for 2 h. Filtration
of catalyst, evaporation of solvent, treatment with aq. NaOH, and
extraction with CHCl3 gave 1,4-bis(benzylamino)-2,3-butanediol
(1-Bn2) (0.08 g, 27% from 1).
(dd, J ϭ 10, J ϭ 1.5, H2eq), 4.30 (d, J ϭ 10, H2ax), 3.96 (d, J ϭ
13.4, CHHPh), 3.87 (d, 2J ϭ 13.4, CHHPh), 3.56 (m, H9), 3.10
(ddd, J ϭ 12.5, J ϭ 2.2, J ϭ 1.5, H4eq), 2.80 (m, 2J ϭ 12.5, J ϭ
10.3, H4ax) (non-equiv. magn.). Ϫ 13C NMR (CDCl3): 138.9 (s, Ph),
129.5, 129.1, 128.0 (d, Ph), 85.0 (d, C2), 74.1 (d, C9), 57.6 (t, C4),
53.7 (t, CH2Ph). Ϫ DCI MS; m/z (%): 325.2 (100) [MH]ϩ, 134.1
(46) [C8H8NO], 91.0 (23) [C7H7]. Ϫ C20H24N2O2 (324.42).
2
3
4
3
Erythritol-1,4-ditosylate (3-Ts2): To a cooled (Ϫ10°C) solution of
meso-erythritol (2.2 g, 18 mmol) in dry pyridine (40 mL) freshly
recrystallysed tosyl chloride (7.0 g, 37 mmol) in CH2Cl2 was added
dropwise at such a rate that the temperature did not exceed 5°C at
the start, then 10°C. After an additional one hour, the cooling bath
was removed and the resulting green-yellow solution was stirred
overnight. The reaction mixture was poured onto ice/HCl, ex-
tracted with CH2Cl2, and dried with MgSO4. The crude product
was used without further purification. Yield 3.13 g (63%).
trans-1,5-Dibenzyl-DADOD (15) and aminal 16 (1:4.5) were ob-
tained from meso-2,3-bis(benzylamino)-1,4-butanediol (6-Bn2).
Separation by column chromatography (SiO2 (methanol washed),
petroleum ether/EtOAc, gradient) gave compound 15, yield: 6 mg
(2%), m.p. 108°C (petroleum ether). Ϫ TLC (SiO2:petroleum ether/
EtOAc, 1:1) Rf ϭ 0.7. Ϫ 1H NMR (CDCl3): δ ϭ 7.30 (m, Ph), 4.34
(d, 2J ϭ 9.2, H2), 4.17 (dd, 2J ϭ 10.5, 3J ϭ 3.5, H4eq), 3.98 (d, 2J ϭ
9.2, H2), 3.89 (d, 2J ϭ 14, CHHPh), 3.48 (d, 2J ϭ 14, CHHPh),
2
3
3
3.51 (m, J ϭ 10.5, J ϭ 10, H4ax), 3.06 (m, J ϭ 3.5, 10, H9) (non
equiv. magn.). Ϫ 13C NMR (CDCl3): δ ϭ 139.0 (s, Ph), 129.1, 127.9
(d, Ph), 85.5 (t, C2), 70.4 (t, C4), 58.7 (d, C9), 52.3 (t, CH2Ph). DCI
MS; m/z (%): 325.2 (100) [MH]ϩ, 233.1 (21) [M Ϫ C7H7], 162.1
(12) [M/2], 91.0 (35) [C7H7]. Ϫ C20H24N2O2 (324.42). Ϫ 1,3-Di-
benzyl-4,5-dihydroxyethylimidazolidine (16): Isolated (35%) at
higher polarity. Yield (oil): 0.123 g, (44%). TLC (SiO2:petroleum
ether/EtOAc, 1:1) Rf ϭ 0.2. Ϫ 1H NMR (CDCl3): δ ϭ 7.25 (m,
Ph), 3.90 (d, 2J ϭ 13, CHHPh), 3.44 (d, 2J ϭ 13, CHHPh), 3.81
(d, 2J ϭ 4.2, H2), 3.8 (brs, OH), 3.73 (dd, 2J ϭ 11.4, 3J ϭ 6.2,
ϪCHHOH), 3.64 (d, 2J ϭ 11.4, ϪCHHOH), 2.99 (brs, 3J ϭ 6.2,
meso-1,4-Bis(benzylamino)-2,3-butanediol (4-Bn2): Prepared in the
reaction of 3-Ts2 (0.5 g, 1.16 mmol) with benzylamine (aq. 30%)
(4.6 mL, 13 mmol) at 0°C for half an hour and then at room tem-
perature for an additional two hours. Ϫ Yield 0.1 g (30%), m.p.
1
2
160°C. Ϫ H NMR (CD3OD): δ ϭ 7.52 (m, Ph), 3.99 (d, J ϭ 13,
3
CHHPh), 3.84 d (2J ϭ 13, CHHPh), 3.75 (dd, J ϭ 7.6, 3.5, H2),
2
3
2
3
3.02 (dd, J ϭ 12, J ϭ 3.5, H1), 2.(dd, J ϭ 12, J ϭ 7.6, H1); Ϫ
13C NMR (CD3OD): 140.5 (s, Ph), 129.9, 128.7 (d, Ph), 73.6 (d,
C2), 54.7 (t), 53.2 (t). Ϫ CI MS; m/z (%): 301 (100) [MH]ϩ, 194
(28) [M Ϫ C7H8N]ϩ, 91 (88) [C7H7]ϩ. C18H24N2O2 (300.18).
meso-2,3-Bis(benzylamino)-1,4-butanediol (6-Bn2): Prepared by
FeitЈs method,[4b] m.p. 76°C (EtOH). Ϫ 1H NMR (CDCl3): δ ϭ
7.28 (m, Ph), 3.7 (m, CH2Ph and 2 H1), 2.69 dd (3J ϭ 2.8, H2); Ϫ
13C NMR (50.3 MHz, CDCl3): 139 s, 128 d, 128 d, 127 d (Ph); 63
t, 60 t, 52 (d, C2). Ϫ DCI MS; m/z (%): 301 (100) [MH]ϩ, 283 (10)
[M Ϫ OH]ϩ, 194 (18) [M Ϫ C7H8N]ϩ, 150 (27) [M/2]ϩ, 91 (29)
[C7H7]ϩ. Ϫ C18H24N2O2 (300.18).
2
H4), 2.89 (d, J ϭ 4.2, H2); Ϫ 13C NMR (CDCl3): δ ϭ 138 (s, Ph),
129.2, 129.0, 127.9 (d, Ph), 76.5 (t, C2), 66 (d, C4), 60 (t), 58 (t).
DCI MS; m/z (%): 313.2 [MH]ϩ, 295.2 (25) [M Ϫ OH], 281.2 (47)
[M Ϫ CH3O], 91.0 (32) [C7H7]. Ϫ C19H24N2O2 (312.41).
cis-3,7-Dibenzyl-DODAD (13-Bn2): To the refluxing ethanol/water
(1:1) (20 mL) solution of cis-DODAD (7) (1 mmol) and K2CO3,
benzylbromide (0.25 mL, 2 mmol) was added and the solution was
refluxed for 1.5 h. Extraction with CHCl3 gave after drying with
K2CO3 and evaporation a pale oil (0.09 g, 28%). The crude 13-Bn2
was purified by column chromatography [SiO2 (methanol washed),
petroleum ether/EtOAc, gradient]. Ϫ Yield: 48 mg (15%).
General Procedure for the Preparation of N,NЈ-Disubstituted Diox-
adiazadecalins (13): To an aqueous solution of diaminobutanediols
(1 mmol) formadehyde (aq. 37% or paraformaldehyde) (2 mmol)
was added and the solution was heated in an ultrasonic bath for 2
h. The reaction solutions were extracted with CHCl3.
Crystal Structure Determination: The X-ray diffraction measure-
ments were carried out at ca. 295 K on an automated CAD4 dif-
fractometer equipped with a graphite monochromator, using Mo-
cis-3,7-Dimethyl-DODAD (13-Me2): Prepared from threo-1,4-bis-
(methylamino)-2,3-butanediol (1-Me2). Yield (oil): 0.15 g, (90%). Ϫ
1H NMR (CDCl3): δ ϭ 4.51 (dd, J ϭ 9.3, J ϭ 2, H2eq), 4.03 (d,
2J ϭ 9.3, H2ax), 3.44 (dd, 3J ϭ 2.4, 3J ϭ 1, H9), 3.08 (ddd, 2J ϭ
13.9, 4J ϭ 2, 3J ϭ 1, H4eq), 2.79 (dd, 2J ϭ 13.9, 3J ϭ 2.4, H4ax),
2.55 (s, NCH3). Ϫ 13C NMR (CDCl3): δ ϭ 85.7 (t, C2), 71.6 (d,
C9), 56.0 (t, C4), 41.5 (q, NCH3). Ϫ FAB MS; m/z: 173 [MH]ϩ; CI
MS; m/z (%): 173.1 (100) [MH]ϩ, 142.1 (14), 111.1 (20), 99.1 (44),
83.0 (17), 71.1 (36). Ϫ HRCIMS: calcd for C8H17N2O2 [MH]ϩ
173.1290, observed m/z ϭ 172.1310.
2
4
˚
Kα (λ ϭ 0.7107 A) radiation. Diffraction data were measured to
2θmax ϭ 50° with a constant scan rate of 4° minϪ1. Intensity data
were collected using the ωϪ2θ scan mode. Possible deterioration of
the analyzed crystal was tested by detecting periodically the inten-
sities of three reference reflections from different zones of the re-
ciprocal space, and was found to be negligible during the experi-
ment. No corrections for absorption or secondary extinction effects
were applied. The structure was solved by direct methods
(SHELXS-86[31]), and refined by full-matrix least-squares
(SHELXL-97[32]). Non-hydrogen atoms were treated aniso-
tropically. The hydrogen atoms were located in calculated positions.
cis-3,7-Dibenzyl-DODAD (13-Bn2): Prepared from threo-1,4-
bis(benzylamino)-2,3-butanediol (1-Bn2). Yield (pale oil): 0.30 g,
1
2
(92%). Ϫ H NMR (CDCl3): δ ϭ 7.33 (m, Ph), 4.56 (dd, J2Ј,2
ϭ
2042
Eur. J. Org. Chem. 1999, 2033Ϫ2043

New Supramolecular Host Systems, 11
FULL PAPER
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trans-3,7-dibenzyl-DODAD (14) and trans-1,5-dibenzyl-DADOD
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14: C20H24N2O2, formula weight 324.42, monoclinic, space group
˚
P21/c, a ϭ 8.541(2), b ϭ 5.782(1), c ϭ 18.094(5) A, β ϭ 102.77(2)°,
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3
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˚
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Eur. J. Org. Chem. 1999, 2033Ϫ2043
2043