Synthesis of all distinct α-methyl-substituted isomers of amino bis(2,2'-ethanoic acid) diethyl ester and ethylene diamine tetraacetic acid tetraethyl ester scaffolds

Article abstract of DOI:10.1016/S0040-4020(00)00103-4

The syntheses of three dialkylated and six tetraalkylated ethylene diamine tetraacetic acid tetraesters is described. The dialkylated derivatives were synthesized by a convergent non-racemizing route to yield three enantiomerically and diastereomerically

Full text of DOI:10.1016/S0040-4020(00)00103-4

TETRAHEDRON
Pergamon
Tetrahedron 56 (2000) 2359–2367
Synthesis of All Distinct a-Methyl-Substituted Isomers of Amino
Bis(2,20-Ethanoic Acid) Diethyl Ester and Ethylene Diamine
Tetraacetic Acid Tetraethyl Ester Scaffolds
,†
Shabana S. Insaf and Donald T. Witiak‡
*
Division of Medicinal Chemistry, School of Pharmacy, University of Wisconsin at Madison, Madison, WI 53706, USA
Received 17 December 1998; revised 7 January 2000; accepted 1 February 2000
Abstract—The syntheses of three dialkylated and six tetraalkylated ethylene diamine tetraacetic acid tetraesters is described. The dialky-
lated derivatives were synthesized by a convergent non-racemizing route to yield three enantiomerically and diastereomerically pure
tetraesters (SS)-3a, (RR)-3b and (RءSء)-3c in 55–57% yields from alanine ethyl ester 1. Enantiomerically and diastereomerically pure
tetraalkylated derivatives (SSSS)-8a, (RRRR)-8b, (2Rء,20Sء,200Rء,2000Sء)-8c, (2Rء,20Rء,200Sء,2000Sء)-8d, (2R,20R,200R,2000S)-8e and
(2S,20S,200S,2000R)-8f were synthesized in two to five steps and 22–49% overall yields from alanine ethyl ester 1. ᭧ 2000 Elsevier Science
Ltd. All rights reserved.
Amino acid derivatives capable of mimicking peptide
segments are becoming increasingly important in the design
of enzyme-inhibitors. Enantiomerically pure scaffolds of
amino bis(2,20-ethanoic acid) constitute a part of many
important drugs such as Enalapril, Enalkiren, Captopril,
etc.1 They are also useful synthetic intermediates in the
formation of analeptics,2 natural products,3 anxiolytic
agents,4 antipsychotic agents,5 and enantiomerically pure
vicinal diamine scaffolds such as ethylene diamine tetra-
acetic acid tetraesters (EDTA tetraesters) described in this
paper (Fig. 1). Vicinal diamino tetraester scaffolds are
useful in medicinal chemistry,6 polyazamacrocyclic and
cryptate chemistry7 and in the formation of heterocyclic
rings.8 EDTA derivatives, in particular, are important for
studying metal chelation9 and form synthetic intermediates
for the preparation of bimolanes which prevent chlorosis in
plants,10 and topoisomerase II inhibitors which have anti-
cancer properties.11 A convenient synthesis for the enantio-
merically pure derivatives possessing the EDTA scaffold is
highly desirable, since their ultimate use in combinatorial
solid phase syntheses could lead to the production of
numerous biologically important libraries. This paper
describes the synthetic design of nine EDTA tetraesters
(Fig. 2) which have two or four methyl groups on the
ethanoic acid branches of the molecules.
Upon examination, it is evident that some EDTA tetraesters
with two or four chiral centers possess planes of symmetry.
EDTA tetraesters (3c, 8c, 8d) are symmetric along plane I
passing through the ethylene linker. Tetra(a-methyl) EDTA
analog (8c; R0ˆMe) also exhibits symmetry along a second
plane (plane II) perpendicular to plane I. This reduces the
theoretically possible four (R0ˆH) and sixteen (R0ˆMe)
isomers to three and six isomers, respectively. Thus,
di(a-methyl) EDTA scaffolds (3a–3c, Fig. 2) exist in
three stereoisomeric forms, whereas tetra(a-methyl)
EDTA scaffolds (8a–8f) exist in six distinct stereoisomeric
forms.
Synthetic Details
Keywords: alkylation; amines; stereoisomerism.
* Corresponding author. Tel.: ϩ1-609-655-6912; fax: ϩ1-609-655-6930;
e-mail: sinsaf@irl.incara.com
Di-alkylated amines 3a and 3b were synthesized (Scheme 1)
in 57% overall yields from (S)- and (R)-alanine ethyl ester
hydrochlorides (1a and 1b), respectively. Intermediate
diesters (S)-2a or (R)-2b were prepared as previously
described.12 No dialkylation was observed during the
†
Current address: Incara Research Laboratories, 8 Cedar Brook Drive,
Cranbury, NJ 08512.
‡
Deceased.
0040–4020/00/$ - see front matter ᭧ 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(00)00103-4

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S. S. Insaf, D. T. Witiak / Tetrahedron 56 (2000) 2359–2367
Figure 1. Synthetic applications of a-methyl-substituted isomers of amino bis(2,20-ethanoic acid) diethyl ester and ethylene diamine tetraacetic acid tetraethyl
ester scaffolds.
preparation of (S)-2a or (R)-2b. Bis(coupling) of diesters
(S)-2a or (R)-2b was expected to yield 1,2-ethanediyl
bridged (S,S)-3a and (RR)-3b. There is little precedence
for N-alkylations in electronically deactivated and hindered
systems.13 After numerous attempts, success was finally
achieved by utilization of a combination of ethylene glycol
di-p-tosylate and pentamethylpiperidine (PMP) in refluxing
toluene. This non-racemizing reaction likely proceeds
through the intermediacy of a highly reactive aziridinium
ion.14 The formation of such aziridinium salts from
2-haloethylamines and their high lability in the presence
of nucleophiles is well precedented.14 Both optically active
compounds (S,S)-3a and (RR)-3b were found to be enantio-
merically pure by proton and 13C NMR spectroscopy; both
rotated a plane of polarized light equally, but in opposite
directions.
tetraester derivatives S,S-3a, R,R-3b and (RءSء)-3c. This
mixture of racemic and meso tetraesters was found to be
inseparable by distillation, column chromatography or
crystallization with chiral acids (mandelic acid) and thus
was of no synthetic utility. Alternatively, alkylated
S-alanine derivative 2a was treated with a 3-fold excess of
ethylene glycol di-p-tosylate in the hope of obtaining mono-
tosylate 6. However, the method only generated tetraester
S,S-3a without detectable quantities of derivative 6. This
may be a function of a highly reactive aziridinium inter-
mediate.14 Thus, unsymmetrically 1,2-substituted-ethyl
tetraester (RءSء)-3c is derived by stepwise coupling of
constitutive monomeric units as depicted in Scheme 2.
The meso diastereomer (RءSء)-3c was prepared by N-alky-
lation of diester (S)-2a with benzyloxy ethylene monotosy-
late15,16 to furnish intermediate (S)-4 (92%) which was
subsequently hydrogenated to produce diester-alcohol
(S)-5 in quantitative yields (Scheme 2). Alcohol (S)-5 was
prone to lactonization and was immediately taken to the
next step. Tosylation generated an unstable ß-aminotosylate
To synthesize the meso isomer Rء,Sء-3c (see Scheme 2),
racemic alanine ethyl ester was alkylated with ethyl
a-bromopropionate and coupled with 1,2-ethylene glycol
di-p-tosylate to afford a mixture of meso and racemic alanyl

S. S. Insaf, D. T. Witiak / Tetrahedron 56 (2000) 2359–2367
2361
Figure 2. Ethylene diamine tetraacetic acid tetraethyl ester scaffolds showing the planes of symmetry.
(S)-6, which decomposed on silica gel and proved difficult
to purify by neutral alumina column chromatography. Use
of potassium hydrogen sulphate as a milder substitute for
aqueous HCl in the work up yielded 93% of tosylate not
requiring further purification. Reaction of (S)-6 with diester
(R)-2b yielded the coupled tetraester (RءSء)-3c in 90% yield.
pure diastereomers were coupled with ethylene glycol di-p-
tosylate to yield tetraesters (2Rء,20Sء,200Rء,2000Sء)-8c,
(S,S,S,S)-8a and (R,R,R,R)-8b. Tetraesters (S,S,S,S)-8a and
(R,R,R,R)-8b exhibited equal and opposite rotations of
polarized light ([a]2D2ˆϪ93.69 (0.555, DMF) and
[a]2D4ˆϩ95.65 (0.735, DMF), respectively), whereas
(2Rء,20Sء,200Rء,2000Sء)-8c did not rotate the plane of polarized
The diastereomeric mixture of (RءSء)-7c and (S,S)-7a
(Scheme 3) is known.12,17 Reaction of (S)- or (R)-alanine
ethyl ester HCl with ethyl bromopropionate yielded a dia-
stereomeric mixture of (RءSء)-7c with (S,S)-7a or (RءSء)-7c
with (R,R)-7b, respectively. The diastereomers were
successfully separated by simple column chromatographic
techniques (1:4 ethyl acetate–hexanes) over silica gel. The
light under the same conditions. Additionally, H and 13C
1
NMR spectra were in accordance with the assigned struc-
tures. The tetraester (2Rء,20Sء,200Rء,2000Sء)-8c shows a singlet
at d 2.87 for equivalent methylene protons of the linker,
whereas both (S,S,S,S)-8a and (R,R,R,R)-8b show a multi-
plet d (2.99–2.78) for the linker methylene protons which
are magnetically non equivalent.
For tetraesters [(2S,20S,200S,2000R)-8f, (2R,20R,200R,2000S)-8e
and (2Rء,20Rء,200Sء,2000Sء)-8d], either (Rء,Sء)-7c or (S,S)-7a
were treated with silyl protected ethylene glycol mono-
tosylate or benzyl protected ethylene glycol monotosy-
late15,16 to yield the corresponding protected ethoxy
derivatives 9a–9d (in 65–87% yields) as depicted in
Scheme 4. TBDMS-protected compounds 9a and 9c
racemized when deprotected with HF-pyridine or acetic
acid and methanol. Therefore, hydroxyethyl compounds
(Rء,Sء)-10b and (S,S)-10a were prepared by hydrogenation
of benzyloxy derivatives (Rء,Sء)-9d and (S,S)-9b, respec-
tively, in 99ϩ% yields. Both (Rء,Sء)-10b and (S,S)-10a
were prone to lactonization on standing and were immedi-
ately taken to the next step. Reaction of p-TsCl with
alcohols (Rء,Sء)-10b and (S,S)-10a yielded the corre-
sponding tosylates (Rء,Sء)-11b and (S,S)-11a in 93–95%
yields. Reaction of ß-aminotosylates (Rء,Sء)-11b and
(S,S)-11a with diesters (S,S)-7a and (R,R)-7b yielded the
Scheme 1.

2362
S. S. Insaf, D. T. Witiak / Tetrahedron 56 (2000) 2359–2367
yields from alanine ethyl ester 1. Enantiomerically and
diastereomerically pure tetraalkylated derivatives (SSSS)-
8a, (RRRR)-8b, (2Rء,20Sء,200Rء,2000Sء)-8c, (2Rء,20Rء,200Sء,2000
Sء)-8d, (2R,20R,200R,2000S)-8e and (2S,20S,200S,2000R)-8f were
synthesized in two to five steps and 22–49% overall yields
from alanine ethyl ester 1.
Experimental
(S)-N-(Carboxymethyl)alanine, diethyl ester12 (2a).
l-Alanine ethyl ester hydrochloride (1.54 g, 10 mmol),
K2CO3 (4.15 g, 30 mmol) and ethyl bromoacetate (1.67 g,
10 mmol) in 10 mL of dry dimethylformamide were
refluxed under Ar for 16 h. After cooling the suspended
solids were filtered and washed with ethanol. The filtrate
was concentrated in vacuo and the residue chromatographed
(3:2 hexanes–ethyl acetate) to yield 1.42 g (72%) of a color-
less liquid. [a]2D3ˆϪ25.92 (2.014, CH3OH); IR (Neat) 3368,
3000, 2956, 2928, 2896, 1748, 1457, 1380, 1205, 1165,
1030 cmϪ1
;
1H NMR (300 MHz, CDCl3) d 4.15 (q,
Jˆ7.1 Hz, 4 H), 3.41 (d AB pattern, Jˆ17.2 Hz, 1 H),
3.33 (d AB pattern, Jˆ17.2 Hz, 1 H), 3.36 (q, Jˆ7.0 Hz, 1
H), 2.01 (s, 1 H), 1.30 (d, Jˆ7.0 Hz, 3 H), 1.24 (t, Jˆ7.1 Hz,
3 H), 1.23 (t, Jˆ7.1 Hz, 3 H); 13C NMR (75 MHz, CDCl3) d
174.7 (C), 171.7 (C), 60.9 (CH2), 55.9 (CH), 48.9 (CH2),
18.7 (CH3), 14.2 (CH3), 14.2 (CH3); Anal. Calcd for
C9H17NO4: C, 53.17; H, 8.44; N, 6.89. Found: C, 52.92;
H, 8.38; N, 6.80.
Scheme 2.
unsymmetrically substituted tetraesters 8d–8f in 64–77%
yields. (2S,20S,200S,2000R)-8f and (2R,20R,200R,2000S)-8e are
enantiomers and yielded similar spectral data but opposite
rotations. The methylene protons of the central linker
chain are magnetically non-equivalent, yielding a complex
multiplet. (2Rء,20Rء,200Sء,2000Sء)-8d did not rotate the
plane of polarized light and showed a distinctly different
spectrum when compared to (2S,20S,200S,2000R)-8f and
(2R,20R,200R,2000S)-8e. The central linker protons appear as
a singlet at d 2.91.
(R)-N-(Carboxymethyl)alanine, diethyl ester12 (2b). R-2b
was prepared from d-Alanine ethyl ester hydrochloride
(Indofine Chemicals) in similar yield as for S-2a.
[a]2D3ˆϩ25.12 (1.27, CH3OH).
(S,S)-N,N0-Ethylenebis[N-(carboxymethyl)alanine], tetra-
ethyl ester (3a). A mixture of diester 2a (1.02 g, 5 mmol),
ethylene glycol di-p-tosylate (0.93 g 2.5 mmol) and
1,2,2,6,6-pentamethylpiperidine (0.78 g, 5 mmol) in 2 mL
of dry toluene was refluxed under Ar for 2 days. After
Thus, the syntheses of the three enantiomerically and
diastereomerically pure dialkylated tetraesters (S,S)-3a,
(RR)-3b and (RءSء)-3c was achieved in 55–57% overall
Scheme 3.

S. S. Insaf, D. T. Witiak / Tetrahedron 56 (2000) 2359–2367
2363
Scheme 4.
cooling to room temperature, the mixture was diluted with
ether and filtered. The filtrate was evaporated and the resi-
due chromatographed (3:2 hexanes–ethyl acetate) to yield
798 mg (79%) of a light yellow liquid. [a]2D7ˆϪ47.82
(1.125, DMF); IR (Neat) 3000, 2960, 2928, 2890, 1740,
NMR (300 MHz, CDCl3) d 7.37–7.23 (m, 5 H), 4.49 (s, 2
H), 4.13 (q, Jˆ7.1 Hz, 2 H), 4.11 (q, Jˆ7.1 Hz, 2 H), 3.68
(q, Jˆ7.2 Hz, 2 H), 3.60 (t, Jˆ5.8 Hz, 2 H), 3.57 (d AB
pattern, Jˆ17.7 Hz, 1 H), 3.53 (d AB pattern, Jˆ17.7 Hz,
1 H), 2.97 (t, Jˆ5.7 Hz, 1 H), 2.96 (t, Jˆ5.9 Hz, 1 H), 1.33
(d, Jˆ7.2 Hz, 3 H), 1.25 (t, Jˆ7.1 Hz, 3 H), 1.22 (t,
Jˆ7.2 Hz, 3 H); 13C NMR (75 MHz, CDCl3) d 174.0 (C),
172.2 (C), 138.4 (C), 128.3 (CH), 127.5 (CH), 127.5 (CH),
73.0 (CH2), 70.0 (CH2), 60.4 (CH), 53.0 (CH2), 52.4 (CH2),
16.4 (CH3), 14.3 (CH3), 14.2 (CH3). Anal. Calcd for
C18H27NO5: C, 64.06; H, 8.07; N, 4.15. Found: C, 63.79;
H, 8.21; N, 3.73.
1470, 1455, 1380, 1190, 1160, 1035 cmϪ1 1H NMR
;
(300 MHz, CDCl3) d 4.15 (q, Jˆ7.2 Hz, 8 H), 3.67 (q,
Jˆ7.2 Hz, 2 H), 3.58 (d, JABˆ17.6 Hz, 2 H), 3.48 (d,
JABˆ17.6 Hz, 2 H), 2.81 (s, 4 H), 1.30 (d, Jˆ7.2 Hz, 6
H), 1.27 (t, Jˆ7.1 Hz, 6 H), 1.26 (t, Jˆ7.1 Hz, 6 H); 13C
NMR (75 MHz, CDCl3) d 173.8 (C), 172.1 (C), 60.4 (CH2),
60.3 (CH2), 59.6 (CH), 52.8 (CH2), 51.8 (CH2), 16.1 (CH3),
14.3 (CH3), 14.2 (CH3); Anal. Calcd for C20H36N2O8: C,
55.52; H, 8.39; N, 6.48. Found: C, 55.28; H, 8.67; N, 6.34.
(S)-N-(Carboxymethyl)-N-[2-hydroxyethyl]alanine, di-
ethyl ester (5). Diester 4 (1.01 g, 3 mmol), 0.45 g of
Pd(OH)2 (20% on C, 50% H2O) in 20 mL of ethyl acetate
was hydrogenated at 1 atm of H2 for 3 h. The catalyst was
filtered, thoroughly washed, and the solution evaporated to
yield 739 mg (100%) of a light yellow liquid. [a]2D7ˆϪ32.81
(0.82, DMF); IR (Neat) 3500, 3000, 2960, 2923, 2896,
1742, 1470, 1460, 1382, 1304, 1100, 1070, 1035,
(R,R)-N,N0-Ethylenebis[N-(carboxymethyl)alanine], tetra-
ethyl ester (3b). RR-3b was prepared from R-2b in similar
yield as for SS-3a. [a]2D3ˆϩ50.2 (1.02, DMF).
(S)-N-[2-(Benzyloxy)ethyl]-N-(carboxymethyl)alanine, di-
ethyl ester (4). A mixture of tetraester 2a (7.11 g, 35 mmol),
1-O-benzyl-2-O-p-toluenesulfonyl glycol (10.72 g, 35 mmol)
and 1,2,2,6,6-pentamethylpiperidine (5.44 g, 35 mmol) in
28 mL of dry toluene was refluxed under Ar for 4 days.
After cooling to room temperature, the mixture was diluted
with ether and filtered. The filtrate was evaporated and the
residue chromatographed (1:4 ethyl acetate–hexanes) to
;
865 cmϪ1 1H NMR (300 MHz, CDCl3) d 4.19 (q,
Jˆ7.0 Hz, 2 H), 4.17 (q, Jˆ7.0 Hz, 2 H), 3.71 (br s, 1 H),
3.59 (q, Jˆ7.6 Hz, 1 H), 3.59–3.46 (m, 2 H), 3.58 (d AB
pattern, Jˆ18.3 Hz, 1 H), 3.44 (d AB pattern, Jˆ18.3 Hz, 1
H), 2.87 (t, Jˆ5.0 Hz, 2 H), 1.34 (d, Jˆ7.3 Hz, 3 H), 1.28 (t,
Jˆ7.1 Hz, 6 H); 13C NMR (75 MHz, CDCl3) d 173.8 (C),
173.4 (C), 61.0 (CH2), 60.6 (CH2), 60.2 (CH), 59.2 (CH2),
56.0 (CH2), 52.3 (CH2), 16.2 (CH3), 14.3 (CH3), 14.1 (CH3);
Anal. Calcd for C11H21NO5: C, 53.43; H, 8.56; N, 5.66.
Found: C, 53.84; H, 8.64; N, 5.27.
yield 10.86 g (92%) of
a
light yellow liquid.
[a]2D4ˆϪ28.33 (1.08, DMF); IR (Neat) 3110, 3086, 3052,
3000, 2960, 2923, 2880, 1760, 1745, 1507, 1462, 1380,
1255, 1180, 1100, 1036, 930, 865, 742, 704 cmϪ1 1H
;

2364
S. S. Insaf, D. T. Witiak / Tetrahedron 56 (2000) 2359–2367
(S)-N-(Carboxymethyl)-N-(2-hydroxyethyl)alanine, di-
ethyl ester, p-toluenesulfonate (6). To a solution of
p-toluenesulfonyl chloride (458 mg, 2.4 mmol) in 0.5 mL
of pyridine at Ϫ5ЊC was added a solution of 5 (494 mg,
2 mmol) in 2 mL of pyridine in a dropwise manner. The
resulting mixture was stirred at Ϫ5ЊC for 3 h and refriger-
ated for 16–18 h. Subsequently, 2 mL of H2O was added
and the aqueous mixture was extracted with ether (20 mL).
The ether layer was washed with 1 M KHSO4 solution
(3×20 mL) and brine (1×20 mL), dried over Na2SO4 and
concentrated in vacuo to yield 750 mg (93%)of a pale
yellow liquid. [a]2D7ˆϪ19.9 (1.00, DMF); IR (Neat) 3000,
2960, 2922, 2892, 1747, 1610, 1505, 1455, 1370, 1300,
1260, 1182, 1106, 1035, 970, 915, 823, 776, 670,
60.8 (CH2), 54.3 (CH),18.8 (CH3), 14.2 (CH3); Anal. Calcd
for C10H19NO4: C, 55.27; H, 8.82; N, 6.45. Found: C, 55.56;
H, 8.54; N, 6.24. 7a [a]2D1ˆϪ59.54 (1.295, CH3OH);
[a]2D4ˆϪ63.07 (1.205, DMF); IR (Neat) 3360, 3000, 2960,
2912, 2894, 1740, 1460, 1380, 1305, 1265, 1175, 1100
1
cmϪ1; H NMR (300 MHz, CDCl3) d 4.19 (q, Jˆ7.2 Hz, 2
H), 4.18 (q, Jˆ7.1 Hz, 2 H), 3.38 (q, Jˆ7.0 Hz, 2 H), 1.33
(d, Jˆ7.0 Hz, 6 H), 1.28 (t, Jˆ7.1 Hz, 3 H); 13C NMR
(75 MHz, CDCl3): d 175.3 (C), 60.8 (CH2), 55.2 (CH),
19.4 (CH3), 14.2 (CH3); Anal. Calcd for C10H19NO4:
C, 55.27; H, 8.82; N, 6.45. Found: C, 54.92; H, 8.89; N,
6.35.
(2R,20R)-diethyl 2,20-iminodipropionate (7b). RR-7b was
prepared from d-alanine ethyl ester hydrochloride (Indofine
Chemicals) in similar yield as for SS-7a. [a]2D7ˆϩ59.89
(0.915, DMF).
557 cmϪ1
;
1H NMR (300 MHz, CDCl3) d 7.79 (d,
Jˆ8.3 Hz, 2 H), 7.34 (d, Jˆ8.0 Hz, 2 H), 4.25–4.08 (m, 2
H), 4.10 (q, Jˆ6.2 Hz, 4 H), 3.54 (q, Jˆ7.2 Hz, 1 H), 3.48
(s, 2 H), 3.13–3.01 (m, 2 H), 2.45 (s, 3 H), 1.27 (d,
Jˆ7.6 Hz, 3 H), 1.25 (t, Jˆ7.2 Hz, 3 H), 1.24 (t, Jˆ
7.2 Hz, 3 H); 13C NMR (75 MHz, CDCl3) d 173.5 (C),
171.6 (C), 144.7 (C), 133.1 (C), 129.8 (CH), 127.9 (CH),
69.3 (CH2), 60.6 (CH2), 60.3 (CH), 53.3 (CH2), 51.2 (CH2),
21.6 (CH3), 16.4 (CH3), 14.3 (CH3), 14.2 (CH3); Anal. Calcd
for C18H27NO7S: C, 53.85; H, 6.78; N, 3.49. Found: C,
53.68; H, 6.57; N, 3.28.
(2S,20S,200S,2000S)-Tetraethyl 2,20,200,2000-(ethylene-dinitrilo)-
tetra-propionate (8a). A mixture of 7a (1.09 g, 5 mmol),
ethylene glycol di-p-tosylate (0.93 g 2.5 mmol) and
1,2,2,6,6-pentamethylpiperidine (0.78 g, 5 mmol) in 4 mL
of dry toluene was heated at reflux under Ar for 7 days.
After cooling to room temperature, the mixture was diluted
with ether and filtered. The filtrate was evaporated and the
residue chromatographed (6:1 hexanes–ethyl acetate) to
(Rء,Sء)-N,N0-ethylenebis[N-(carboxymethyl)alanine], tetra-
ethyl ester (3c). A mixture of 2b (244 mg, 1.2 mmol), 6
(402 mg, 1 mmol) and 1,2,2,6,6-pentamethylpiperidine
(160 mg, 1 mmol) in 2 mL of dry toluene was heated at
reflux under Ar for 2 days. After cooling to room tempera-
ture, the mixture was diluted with ether and filtered. The
filtrate was evaporated and the residue chromatographed
(4:1 dichloromethane–ether) to yield 389 mg (90%) of a
yellow liquid. [a]2D7ˆϪ0.00 (0.81, DMF); IR (Neat) 3000,
2960, 2928, 2896, 1740, 1470, 1455, 1380, 1190, 1160,
yield 550 mg (48%) of
a
pale yellow liquid.
[a]2D2ˆϪ93.69 (0.555, DMF); IR (Neat) 3000, 2958, 2915,
2892, 1744, 1455, 1380, 1337, 1305, 1260, 1185, 1160,
1110, 1060, 1030, 960, 864, 795, 750 cmϪ1 1H NMR
;
(300 MHz, CDCl3) d 4.10 (q, Jˆ7.1 Hz, 8 H), 3.64 (q,
Jˆ7.2 Hz, 4 H), 2.99–2.78 (m, 4 H), 1.28 (d, Jˆ7.2 Hz,
12 H), 1.26 (t, Jˆ7.1 Hz, 12 H); 13C NMR (75 MHz,
CDCl3) d 174.0 (C), 60.1 (CH2), 56.4 (CH), 47.7 (CH2),
17.4 (CH3), 14.2 (CH3); Anal. Calcd for C22H40N2O8:
C, 57.36; H, 8.76; N, 6.08. Found: C, 57.06; H, 8.81; N,
6.42.
1
1035 cmϪ1; H NMR (300 MHz, CDCl3) d 4.14 (q, Jˆ
7.1 Hz, 8 H), 3.65 (q, Jˆ7.2 Hz, 2 H), 3.56 (d AB pattern,
Jˆ17.59 Hz, 2 H), 3.51 (d AB pattern, Jˆ17.58 Hz, 2 H),
2.81 (qd, Jˆ10.4, 2.4 Hz, 4 H), 1.30 (d, Jˆ7.2 Hz, 6 H),
1.27 (t, Jˆ7.1 Hz, 6 H), 1.26 (t, Jˆ7.2 Hz, 6 H); 13C NMR
(75 MHz, CDCl3) d 173.8 (C), 172.1 (C), 60.2 (CH2), 60.3
(CH2), 59.7 (CH), 52.9 (CH2), 51.8 (CH2), 16.1 (CH3), 14.3
(CH3), 14.2 (CH3); Anal. Calcd for C20H36N2O8: C, 55.52;
H, 8.39; N, 6.48. Found: C, 55.44; H, 8.02; N, 6.17.
(2R,20R,200R,2000R)-Tetraethyl 2,20,200,2000-(ethylene-dinitrilo)-
tetra-propionate (8b). RRRR-8a was prepared from RR-7b
in similar yield as for SSSS-8a. [a]2D4ˆϩ95.65 (0.735,
DMF).
(2Rء,20Sء,200Rء,2000Sء)-Tetraethyl 2,20,200,2000-(ethylene-dini-
trilo)tetra-propionate (8c). A mixture of 7c (1.085 g,
5 mmol), ethylene glycol di-p-tosylate (0.93 g, 2.5 mmol)
and 1,2,2,6,6-pentamethylpiperidine (0.78 g, 5 mmol) in
4 mL of dry toluene was heated at reflux under Ar for
7 days. After cooling to room temperature, the mixture
was diluted with ether and filtered. The filtrate was evapo-
rated and the residue chromatographed (6:1 hexanes–ethyl
acetate) to yield 327 mg (28%) of a white crystalline solid.
(2S,20S)-Diethyl 2,20-iminodipropionate (7a) and
(2Sء,20Rء)-diethyl 2,20-iminodipropionate (7c). A mixture
of l-alanine ethyl ester hydrochloride (1.54 g, 10 mmol),
potassium carbonate (4.15 g, 30 mmol) and ethyl bromo-
propionate (1.67 g, 10 mmol) in 10 mL of dry dimethyl-
formamide was heated at refluxed under Ar for 12 h. After
cooling the suspended solids were filtered and washed with
ethanol. The filtrate was concentrated in vacuo and the resi-
due chromatographed (4:1 hexane–ethyl acetate) to first
elute 0.75 g (35%) of a yellow liquid (7c) followed by
0.6 g (28%) of 7a as a light yellow liquid.7c [a]2D1ˆϪ0.07
(1.462, CH3OH); IR (Neat) 3358, 3000, 2958, 2912, 2892,
1830, 1747, 1456, 1420, 1384, 1308, 1260, 1210, 1165,
1
[a]2D7ˆϪ0.27 (0.73, DMF); H NMR (300 MHz, CDCl3) d
4.12 (q, Jˆ7.1 Hz, 8 H), 3.64 (q, Jˆ7.1 Hz, 4 H), 2.87 (s, 4
H), 1.28 (d, Jˆ7.1 Hz, 12 H), 1.26 (t, Jˆ7.1 Hz, 12 H); 13C
NMR (300 MHz, CDCl3) d 174.6 (C), 60.2 (CH2), 57.6
(CH), 48.1 (CH2), 16.2 (CH3), 14.2 (CH3); Anal. Calcd for
C22H40N2O8: C, 57.36; H, 8.76; N, 6.08. Found: C, 57.24; H,
8.54; N, 5.98.
1
1105, 1060, 1027, 864, 758 cmϪ1; H NMR (300 MHz,
CDCl3): d(4.17 (q, Jˆ7.0 Hz, 4 H), 3.38 (q, Jˆ6.9 Hz, 2
H), 1.31 (d, Jˆ7.0 Hz, 6 H), 1.28 (t, Jˆ7.1 Hz, 3 H), 1.27 (t,
Jˆ7.1 Hz, 3 H); 13C NMR (75 MHz, CDCl3): d 174.8 (C),
(2S,20S)-Diethyl 2,20-[tert-butyldimethylsiloxy ethyl-
imino]-dipropionate (9a). A mixture of 7a (217 mg,
1 mmol), tert-butyldimethylsilyl protected ethylene glycol

S. S. Insaf, D. T. Witiak / Tetrahedron 56 (2000) 2359–2367
2365
mono-p-tosylate (330 mg, 1 mmol) and 1,2,2,6,6-penta-
methylpiperidine (160 mg, 1 mmol) in 1 mL of dry toluene
was heated at reflux under Ar for 2 days. After cooling to
room temperature, the mixture was diluted with ether and
filtered. The filtrate was evaporated and the residue
chromatographed (2% ethanol in 1:5:4 ether–hexanes–
dichloromethane) to yield 321 mg (86%) of a light yellow
liquid. [a]2D3ˆϪ49.4 (0.50, DMF); IR (Neat) 3000, 2972,
2948, 2911, 2872, 1747, 1472, 1395, 1380, 1264, 1162,
After cooling to room temperature, the mixture was diluted
with ether and filtered. The filtrate was evaporated and the
residue chromatographed (1:6 ethyl acetate–hexanes) to
yield 1.5 g (85%) of a light yellow liquid. [a]2D7ˆϪ0.00
(0.51, DMF); IR (Neat) 3040, 3026, 3000, 2960, 2920,
2880, 1744, 1505, 1460, 1392, 1375, 1308, 1260, 1210,
1172, 1105, 1030, 865, 742, 704 cmϪ1
;
1H NMR
(300 MHz, CDCl3) d 7.36–7.24 (m, 5 H), 4.51 (s, 2 H),
4.10 (q, Jˆ7.1 Hz, 4 H), 3.70 (q, Jˆ7.2 Hz, 2 H), 3.50 (t,
Jˆ6.6 Hz, 2 H), 3.10 (t, Jˆ6.5 Hz, 2 H) 1.29 (d, Jˆ7.2 Hz, 6
H), 1.24 (t, Jˆ7.1 Hz, 6 H); 13C NMR (75 MHz, CDCl3)
d 174.8 (C), 138.6 (C), 128.3 (CH), 127.5 (CH), 127.5
(CH), 73.1 (CH2), 71.3 (CH2), 60.3 (CH2), 57.9 (CH),
47.1 (CH2), 16.3 (CH3), 14.2 (CH3); Anal. Calcd for
C19H29NO5: C, 64.92; H, 8.32; N, 3.99. Found: C, 65.48;
H, 8.44; N, 3.93.
1107, 1030, 930, 842, 782 cmϪ1 1H NMR (300 MHz,
;
CDCl3) d 4.04 (q, Jˆ7.2 Hz, 4 H), 3.62 (q, Jˆ7.2 Hz, 2
H), 3.51 (t, Jˆ6.7 Hz, 2 H), 2.97 (t, Jˆ6.7 Hz, 2 H), 1.23
(d, Jˆ7.2 Hz, 6 H), 1.20 (t, Jˆ7.2 Hz, 6 H), 0.84 (s, 9 H),
0.00 (s, 6 H); 13C NMR (75 MHz, CDCl3) d 174.1 (C), 63.9
(CH2), 60.1 (CH2), 58.9 (CH), 49.5 (CH2), 25.9 (CH3), 18.3
(C), 17.4 (CH3), 14.2 (CH3).
(2S,20S)-Diethyl 2,20-[2-(benzyloxy)ethylimino]-dipro-
pionate (9b). A mixture of 7a (4.34 g, 20 mmol), 1-O-
benzyl-2-O-p-toluenesulfonyl glycol (6.13 g, 20 mmol)
and 1,2,2,6,6-pentamethylpiperidine (3.11 g, 20 mmol) in
15 mL of dry toluene was heated at reflux under Ar for
7 days. After cooling to room temperature, the mixture
was diluted with ether and filtered. The filtrate was evapo-
rated and the residue chromatographed (1:6 ethyl acetate–
hexanes) to yield 4.53 g (65%) of a light yellow liquid.
[a]2D7ˆϪ53.67 (0.885, DMF); IR (Neat) 3040, 3025, 3000,
2960, 2920, 2880, 1745, 1505, 1462, 1380, 1340, 1308,
(2S,20S)-Diethyl 2,20-[2-hydroxyethylimino]dipropionate
(10a). Dipropionate 9b (351 mg, 1 mmol) and 20%
Pd(OH2) on carbon (150 mg) in 10 mL of ethyl acetate
was hydrogenated under 1 atm of H2 at ambient temperature
for 24 h. The solution was filtered over celite to yield
260 mg (100%) of a light yellow liquid. [a]2D6ˆϪ61.35
(1.115, DMF); IR (Neat) 3478, 3000, 2960, 2926, 2895,
1740, 1464, 1385, 1338, 1305, 1650, 1105, 1030,
;
864 cmϪ1 1H NMR (300 MHz, CDCl3) d 4.14 (q,
Jˆ7.1 Hz, 4 H), 3.67 (q, Jˆ7.2 Hz, 2 H), 3.60–3.45 (m, 2
H), 3.18–2.88 (m, 2 H), 1.33 (d, Jˆ7.2 Hz, 6 H), 1.27 (t,
Jˆ7.1 Hz, 6 H); 13C NMR (75 MHz, CDCl3) d 174.2 (C),
60.7 (CH2), 59.6 (CH2), 57.1 (CH), 48.4 (CH2), 16.1 (CH3),
14.2 (CH3); Anal. Calcd for C12H23NO5: C, 55.14; H, 8.88;
N, 5.36. Found: C, 55.46; H, 8.96; N, 5.01.
1
1255, 1162, 1110, 1030, 865, 740, 704 cmϪ1; H NMR
(300 MHz, CDCl3) d 7.38–7.23 (m, 5 H), 4.52 (s, 2 H),
4.09 (q, Jˆ7.1 Hz, 4 H), 3.70 (q, Jˆ7.2 Hz, 2 H), 3.48 (t,
Jˆ6.1 Hz, 2 H), 3.15 (t, Jˆ6.2 Hz, 2 H) 1.29 (d, Jˆ7.2 Hz, 6
H), 1.24 (t, Jˆ7.1 Hz, 6 H); 13C NMR (75 MHz, CDCl3) d
174.1 (C), 138.6 (C), 128.3 (CH), 127.5 (CH), 73.0 (CH2),
71.1 (CH2), 60.2 (CH2), 56.9 (CH), 46.8 (CH2), 17.3 (CH3),
14.2 (CH3); Anal. Calcd for C19H29NO5: C, 64.92; H, 8.32;
N, 3.99. Found: C, 65.15; H, 8.26; N, 3.74.
(2Sء,20Rء)-Diethyl 2,20-[2-hydroxyethyl imino]dipropion-
ate (10b). Dipropionate 9d (1.05 g, 3 mmol) and 20%
Pd(OH2) on carbon (450 mg) in 20 mL of ethyl acetate
was hydrogenated under 1 atm of H2 at room temperature
for 3 h. The solution was filtered through celite, and the
filtrate evaporated to yield 782 mg (100%) of a colorless
liquid. [a]2D6ˆϪ0.17 (0.66, DMF); IR (Neat) 3480, 3000,
2958, 2920, 2892, 1740, 1470, 1456, 1385, 1305, 1140,
(2Sء,20Rء)-Diethyl 2,20-[tert-butyldimethylsiloxy ethyl-
imino]di-propionate (9c). A mixture of 7c (217 mg,
1 mmol), tert-butyldimethylsilyl protected ethylene glycol
mono-p-tosylate (330 mg, 1 mmol) and 1,2,2,6,6-penta-
methylpiperidine (160 mg, 1 mmol) in 1 mL of dry toluene
was heated at reflux under Ar for 2 days. After cooling to
room temperature, the mixture was diluted with ether and
filtered. The filtrate was evaporated and the residue chro-
matographed (95:5 dichloromethane–ether) to yield 324 mg
(87%) of a light yellow liquid. [a]2D7ˆϩ0.00 (0.625, DMF);
IR (Neat) 3000, 2980, 2953, 2920, 2880, 1750, 1475, 1422,
1
1100, 1070 cmϪ1; H NMR (300 MHz, CDCl3) d 4.16 (q,
Jˆ7.1 Hz, 4 H), 3.67 (q, Jˆ7.2 Hz, 2 H), 3.53 (t, Jˆ5.2 Hz,
2 H), 3.00 (t, Jˆ5.2 Hz, 2 H), 1.32 (d, Jˆ7.2 Hz, 6 H), 1.28
(t, Jˆ7.2 Hz, 6 H); 13C NMR (75 MHz, CDCl3) d 175.2 (C),
60.8 (CH2), 59.3 (CH2), 56.4 (CH), 49.7 (CH2), 15.6 (CH3),
14.2 (CH3); Anal. Calcd for C12H23NO5: C, 55.14; H, 8.88;
N, 5.36. Found: C, 55.11; H, 8.65; N, 5.05.
1
1400, 1265, 1185, 1170, 1110, 1030, 845, 785 cmϪ1; H
(2S,20S)-Diethyl 2,20-[2-hydroxyethyl imino]-dipropion-
ate p-toluene-sulfonate (11a). To a solution of p-toluene-
sulfonyl chloride (458 mg, 2.4 mmol) in 0.5 mL of pyridine
at Ϫ5ЊC was added a solution of 10a (522 mg, 2 mmol) in
2 mL of pyridine in a dropwise manner. The resulting
mixture was stirred at Ϫ5ЊC for 3 h and refrigerated for
16–18 h. Subsequently, 2 mL of H2O was added and the
aqueous mixture was extracted with ether (20 mL). The
ether layer was washed with 1 M KHSO4 solution
(3×20 mL) and brine (1×20 mL), dried over Na2SO4 and
concentrated in vacuo to yield 786 mg (95%) of a pale
yellow liquid. [a]2D7ˆϪ40.87 (0.925, DMF); IR (Neat)
3000, 2957, 2920, 2890, 1745, 1608, 1465, 1370, 1197,
NMR (300 MHz, CDCl3) d(4.08 (q, Jˆ7.1 Hz, 4 H), 3.63
(q, Jˆ7.2 Hz, 2 H), 3.54 (t, Jˆ6.9 Hz, 2 H), 2.92 (t,
Jˆ6.9 Hz, 2 H), 1.24 (d, Jˆ7.1 Hz, 6 H), 1.22 (t,
Jˆ7.1 Hz, 6 H), 0.84 (s, 9 H), 0.00 (s, 6 H); 13C NMR
(75 MHz, CDCl3) d 174.7 (C), 64.0 (CH2), 60.2 (CH2),
58.0 (CH), 49.7 (CH2), 25.9 (CH3), 18.3 (C), 16.4 (CH3),
14.2 (CH3).
(2Sء,20Rء)-Diethyl 2,20-[2-(benzyloxy)ethyl imino]-dipro-
pionate (9d). A mixture of 7c (1.09 g, 5 mmol), 1-O-
benzyl-2-O-p-toluenesulfonyl glycol (1.53 g, 5 mmol) and
1,2,2,6,6-pentamethylpiperidine (777 mg, 5 mmol) in 4 mL
of dry toluene was heated at reflux under Ar for 7 days.
1
1184, 1104, 1026, 1010, 960, 910, 820 cmϪ1; H NMR

2366
S. S. Insaf, D. T. Witiak / Tetrahedron 56 (2000) 2359–2367
(300 MHz, CDCl3) d 7.79 (d, Jˆ8.3 Hz, 2 H), 7.34 (d,
Jˆ8.2 Hz, 2 H), 4.07 (q, Jˆ7.2 Hz, 4 H), 4.01–3.90 (m, 2
H), 3.57 (q, Jˆ7.2 Hz, 2 H), 3.31–3.14 (m, 2 H), 2.45 (s, 3
H), 1.23 (t, Jˆ7.0 Hz, 6 H), 1.22 (d, Jˆ7.1 Hz, 6 H); 13C
NMR (75 MHz, CDCl3) d 173.7 (C), 144.7 (C), 133.3 (C),
129.8 (CH), 127.9 (CH), 69.2 (CH2), 60.3 (CH2), 56.6 (CH),
46.0 (CH2), 21.6 (CH3), 17.3 (CH3), 14.2 (CH3); Anal. Calcd
for C19H29NO7S: C, 54.92; H, 7.04; N, 3.37. Found: C,
54.85; H, 6.89; N, 3.23.
4.12 (q, Jˆ7.3 Hz, 4 H), 4.09 (q, Jˆ7.3 Hz, 4 H), 3.64 (q,
Jˆ7.1 Hz, 4 H), 2.99–2.75 (m, 4 H), 1.33–1.21 (m, 24 H);
13C NMR (300 MHz, CDCl3) d 174.6 (C), 174.0 (C), 60.2
(CH2), 60.0 (CH2), 57.6 (CH), 57.5 (CH), 56.5 (CH), 48.0
(CH2), 47.8 (CH2), 17.3 (CH3), 16.2 (CH3), 14.2 (CH3);
Anal. Calcd for C22H40N2O8: C, 57.36; H, 8.76; N, 6.08.
Found: C, 57.66; H, 8.69; N, 5.93.
(2S,20S,200S,2000R)-Tetraethyl 2,20,200,2000-(ethylene-dini-
trilo)tetra-propionate (8f). A mixture of 11b (208 mg,
0.5 mmol), 7a (132 mg, 0.6 mmol) and 1,2,2,6,6-penta-
methylpiperidine (80 mg, 0.5 mmol) in 1 mL of dry toluene
was heated at reflux under Ar for 2 days. After cooling to
room temperature, the mixture was diluted with ether and
filtered. The filtrate was evaporated and the residue chro-
matographed (9:1 dichloromethane–ether) to yield 146 mg
(64%) of a light yellow liquid. [a]2D7ˆϪ34.85 (0.835,
DMF); IR (Neat) 3000, 2960, 2920, 2900, 1745, 1455,
(2Sء,20Rء)-Diethyl 2,20-[2-hydroxyethyl imino]dipropion-
ate p-toluene-sulfonate (11b). To a solution of p-toluene-
sulfonyl chloride (458 mg, 2.4 mmol) in 0.5 mL of pyridine
at Ϫ5ЊC was added a solution of 10b (522 mg, 2 mmol) in
2 mL of pyridine in a dropwise manner. The resulting
mixture was stirred at Ϫ5ЊC for 3 h and refrigerated for
16–18 h. Subsequently, 2 mL of H2O was added and the
aqueous mixture was extracted with ether (20 mL). The
ether layer was washed with 1 M KHSO4 solution
(3×20 mL) and brine (1×20 mL), dried over Na2SO4 and
concentrated in vacuo to yield 774 mg (93%) of a pale
yellow liquid. [a]2D7ˆϪ0.24 (0.785, DMF); IR (Neat)
3000, 2960, 2922, 2892, 1744, 1609, 1460, 1370, 1182,
1
1420, 1380, 1160, 1110, 1060, 1030, 865 cmϪ1; H NMR
(300 MHz, CDCl3) d 4.12 (q, Jˆ7.2 Hz, 4 H), 4.09 (q,
Jˆ7.2 Hz, 4 H), 3.64 (q, Jˆ7.1 Hz, 4 H), 2.98–2.75 (m, 4
H), 1.33–1.21 (m, 24 H); 13C NMR (75 MHz, CDCl3)
d 174.6 (C), 174.0 (C), 60.2 (CH2), 60.1 (CH2), 57.6
(CH), 57.5 (CH), 56.5 (CH), 48.0 (CH2), 47.8 (CH2), 17.3
(CH3), 16.2 (CH3), 14.2 (CH3); Anal. Calcd for C22H40N2O8:
C, 57.36; H, 8.76; N, 6.08. Found: C, 57.06; H, 8.46; N,
5.89.
1
1104, 1058, 1027, 962, 913 cmϪ1; H NMR (300 MHz,
CDCl3) d 7.79 (d, Jˆ8.3 Hz, 2 H), 7.34 (d, Jˆ8.0 Hz, 2
H), 4.09 (q, Jˆ7.1 Hz, 4 H), 3.98 (t, Jˆ7.0 Hz, 2 H), 3.57
(q, Jˆ7.2 Hz, 2 H), 3.17 (t, Jˆ6.7 Hz, 2 H), 2.45 (s, 3 H),
1.24 (t, Jˆ7.1 Hz, 6 H), 1.24 (d, Jˆ7.2 Hz, 6 H); 13C NMR
(75 MHz, CDCl3) d 174.2 (C), 144.7 (C), 133.2 (C), 129.8
(CH), 127.9 (CH), 70.0 (CH2), 60.5 (CH2), 58.2 (CH), 46.1
(CH2), 21.6 (CH3), 16.5 (CH3), 14.1 (CH3); Anal. Calcd for
C19H29NO7S: C, 54.92; H, 7.04; N, 3.37. Found: C, 54.92;
H, 7.00; N, 3.32.
References
1. (a) Baker, W.; Fung, A.; Kleinert, H.; Stein, H.; Plattner, J.;
Armiger, Y.-L.; Condon, S.; Cohen, J.; Egan, D.; Barlow, J.;
Verburg, K.; Martin, D.; Young, G.; Polakowski, J.; Boyd, S.;
Perun, T. J. Med. Chem. 1992, 35, 1722–1734. (b) Barton, J.;
Piwinski, J.; Skiles, J. W.; Regan, J. R.; Menard, P. R.; Desai,
R.; Golec, F. S.; Reilly, L. W.; Goetzen, T.; Ueng, S.-N.; Warus,
J. D.; Schwab, A.; Samuels, A. I.; Neiss, E. S.; Suh, J. T. J. Med.
Chem. 1990, 33, 1600–1606. (c) Kogan, T. P.; Rawson, T. E.
Tetrahedron Lett. 1992, 33, 7089–7092.
(2Rء,20Rء,200Sء,2000Sء)-Tetraethyl 2,20,200,2000-(ethylenedini-
trilo)tetra-propionate (8d). A mixture of 11a (208 mg,
0.5 mmol), 7b (132 mg, 0.6 mmol) and 1,2,2,6,6-penta-
methylpiperidine (80 mg, 0.5 mmol) in 1 mL of dry toluene
was heated at reflux under Ar for 2 days. After cooling to
room temperature, the mixture was diluted with ether and
filtered. The filtrate was evaporated and the residue chro-
matographed (9:1 dichloromethane–ether) to yield 163 mg
(71%) of a light yellow liquid. [a]2D7ˆϪ0.12 (0.755, DMF);
IR (Neat) 3000, 2960, 2920, 2895, 1745, 1470, 1455, 1370,
2. Martin, H.; Gysin, H. US 2411662, 1946, pp 12.
3. Singh, B. S. Tetrahedron Lett. 1995, 36, 2009–2012.
4. Mickelson, J. W.; Belonga, K. L.; Jacobsen, E. J. J. Org. Chem.
1995, 60, 4177.
5. Harfenist, M.; Hoerr, D. C.; Crouch, R. J. Org. Chem. 1985, 50,
1356.
6. Kasina, S.; Fritzberg, A. R.; Johnson, D. L.; Eshima, D. J.
J. Med. Chem. 1986, 29, 1933.
7. Lehn, J.-M. Acc. Chem. Res. 1978, 11, 49.
1
1335, 1160, 1110, 1030, 860 cmϪ1; H NMR (300 MHz,
CDCl3) d 4.10 (q, Jˆ7.2 Hz, 4 H), 3.67 (q, Jˆ7.2 Hz, 2
H), 2.91 (s, 4 H), 1.29 (d, Jˆ7.2 Hz, 6 H), 1.25 (t,
Jˆ7.1 Hz, 6 H); 13C NMR (300 MHz, CDCl3) d 174.0
(C), 60.1 (CH2), 56.5 (CH), 47.8 (CH2), 17.3 (CH3), 14.2
(CH3); Anal. Calcd for C22H40N2O8: C, 57.36; H, 8.76; N,
6.08. Found: C, 57.61; H, 8.65; N, 5.84.
8. Popter, A. E. A. In Comprehensive Heterocyclic Chemistry,
Katritzky, A. R., Rees, C. W., Eds.; Pergamon: Oxford, 1984;
Vol. 3, p 179.
(2R,20R,200R,2000S)-Tetraethyl 2,20,200,2000-(ethylene-dini-
trilo)tetra-propionate (8e). A mixture of 11b (208 mg,
0.5 mmol), 7b (132 mg, 0.6 mmol) and 1,2,2,6,6-penta-
methylpiperidine (80 mg, 0.5 mmol) in 1 mL of dry toluene
was heated at reflux under Ar for 2 days. After cooling to
room temperature, the mixture was diluted with ether and
filtered. The filtrate was evaporated and the residue chro-
matographed (9:1 dichloromethane–ether) to yield 178 mg
(77%) of a light yellow liquid. [a]2D7ˆϩ41.05 (0.86, DMF);
IR (Neat) 3000, 2960, 2920, 2890, 1740, 1470, 1380, 1160,
1110, 1060, 1030, 865 cmϪ1; 1H NMR (300 MHz, CDCl3) d
9. (a) Mukkala, V.-M.; Kwiatkowski, M.; Kankare, J.; Takalo, H.
Helv. Chim. Acta 1993, 76, 893–899. (b) Ruan, F.; Chen, Y.;
Hopkins, P. J. Am. Chem. Soc. 1990, 112, 9403–9404. (c) Ruan,
F.; Chen, Y.; Itoh, K.; Sasaki, T.; Hopkins, P. J. Org. Chem. 1991,
56, 4347–4354. (d) Martin, V.; Keanna, J. Synth. Commun. 1995,
25, 3625–3634. (e) Storrs, R.; Tropper, F.; Li, H.; Song, C.;
Kuniyoshi, J.; Sipkins, D.; Li, K.; Bednarski, M. J. Am. Chem.
Soc. 1995, 117, 7301–7306. (f) Xu, J.; Kullgren, B.; Durbin, P.;
Raymond, K. J. Med. Chem. 1995, 38, 2606–2614. (g) Sosnovsky,
G.; Rao, N.; Li, S.; Swartz, H. J. Org. Chem. 1989, 54, 3667–3674.
(h) Goetz, C.; Debbrecht, F. Iowa State Coll. J. Sci. 1959, 33,

S. S. Insaf, D. T. Witiak / Tetrahedron 56 (2000) 2359–2367
2367
267–277. (i) Eckelman, W.; Karesh, S.; Reba, R. J. Pharm. Sci.
1975, 64, 704–706. (j) Gutsche, C.; Mei, G. J. Am. Chem. Soc.
1985, 107, 7964. (k) Kahana, N.; Arad-Yellin, R.; Warshawsky, A.
J. Org. Chem. 1994, 59, 4832–4837.
10. Dazzi, J. Swiss Patent 569,405, 1975, pp 9; Chem. Abstr. 1975,
84, 120434a.
11. (a) Daeid, N.; Nolan, K. B.; Ryan, L. J. Chem. Soc., Dalton
Trans. 1991, 2301–2304. (b) Herman, E. H.; Witiak, D. T.;
Hellmann, K.; Waravdekar, V. S. Adv. Pharmacol. Chemother.
1982, 19, 249–290. (c) Roca, J.; Ishida, R.; Berger, J.;
Andoh, T.; Wang, J. C. Proc. Natl. Acad. Sci. USA 1994, 91,
1781–1785.
11, 518. (g) Evans, D. A.; Mitch, C. H. Tetrahedron Lett. 1982, 23,
285. (h) Trefonas, L. M.; Majeste, R. Tetrahedron 1963, 19, 929.
(i) Cohen, B.; Van Artsdalen, E. R.; Harris, J. J. Am. Chem. Soc.
1952, 8, 1875 and 1878. (j) Leonard, N. J.; Jann, K. J. Am. Chem.
Soc. 1962, 84, 4806. (k) Di Vona, M.; Illuminati, G.; Lillocci, C.
J. Chem. Soc., Chem. Commun. 1985, 7, 380. (l) Rosen, G.;
Ehrenpreis, S.; Mittag, T. J. Med. Chem. 1971, 14, 514. (m)
Cassinelli, A.; Angeli, P.; Giannella, M.; Gualtieri, F. Eur.
J. Med. Chem. 1987, 22, 5. (n) Hansen, B. Acta Chem. Scand.
1962, 16, 1945. (o) Hall, A. W.; Taylor, R.; Simmonds, S. H.;
Strange, P. G. J. Med. Chem. 1987, 30, 1879. (p) Ringdahl, B.;
Jenden, D. J. J. Med. Chem. 1987, 30, 852. (q) Cohen, S. A.;
Neumeyer, J. L. J. Med. Chem. 1983, 26, 1348. (r) Foley, P. J.;
Neale, R. J. Chem. Engng Data 1968, 13, 593. (s) Di Vona, M.;
Illuminati, G.; Lillocci, C. J. Chem. Soc., Perkin Trans. 2 1985,
1943. (t) Gamcsik, M.; Hamhill, T. G.; Colvin, M. J. Med. Chem.
1990, 33, 1009. (u) Ringdahl, B.; Mellin, C.; Ehlert, F.; Roch, M.;
Rice, K.; Jenden, D. J. J. Med. Chem. 1990, 33, 281. (v) Karton, Y.;
Bradbury, B.; Baumgold, J.; Paek, R.; Jacobson, K. J. Med. Chem.
1991, 34, 2133. (w) Golding, B.; Kebbell, M. J. J. Chem. Soc.,
Perkin Trans. 2 1987, 705. (x) Liu, Q.; Simms, M.; Boden, N.;
Rayner, C. M. J. Chem. Soc., Perkin Trans. 1 1994, 1363. (y)
Chapman, N.; James, J. J. Chem. Soc. 1954, 2103. (z) Hanby,
W.; Hartley, G.; Powell, E.; Rydon, H. J. Chem. Soc. 1947, 519.
15. Walkowiak, W.; Ndip, G. M.; Desai, D. H.; Lee, H.; Bartsch,
R. A. Anal. Chem. 1992, 64, 1685–1690.
12. Garrigues, B. Tetrahedron 1984, 40, 1151–1156.
13. (a) Mukkala, V.-M.; Kwiatkowski, M.; Kankare, J.; Takalo, H.
Helv. Chim. Acta 1993, 76, 893. (b) Wolf, L.; Holzapfel, H. Chem.
1962, 2, 374. (c) Shin, C.; Ohmatsu, H.; Sato, Y.; Yoshimura, J.
Chem. Lett. 1981, 701. (d) Kozikowski, A.; Tu¨ckmantel, W.; Liao,
Y.; Manev, H.; Ikonomovic, S.; Wroblewski, J. J. Med. Chem.
1993, 36, 2706. (e) Klutchko, S.; Blankley, J.; Fleming, R. W.;
Hinkley, J.; Werner, A.; Nordin, I.; Holmes, A.; Hoefle, M.; Cohen,
D.; Essenburg, A.; Kaplan, H. J. Med. Chem. 1986, 29, 1953. (f)
Johansen, J.; Christie, B.; Rapaport, H. J. Org. Chem. 1981, 46,
4914. (g) Prota, G.; Ponsiglione, E. Tetrahedron 1973, 29, 4271.
(h) Singh, S. B. Tetrahedron Lett. 1995, 36, 2009. (i) Insaf, S. S.;
Witiak, D. T. Synthesis 1999, 435.
14. (a) Lillocci, C. J. Org. Chem. 1988, 53, 1733. (b) Bottini, A.
T.; Sousa, L. R.; Dowden, B. F. J. Org. Chem. 1974, 39, 355. (c)
Huh, N.; Thompson, C. M. Tetrahedron 1995, 51, 5935. (d) Fry, E.
M. J. Org. Chem. 1965, 30, 2058. (e) Leonard, N. J.; Jann, K.;
Paukstelis, J. V.; Steinhardt, C. K. J. Org. Chem. 1963, 28, 1499.
(f) Golumbig, C.; Fruton, J. S.; Bergmann, M. J. Org. Chem. 1946,
16. Yokoyama, M.; Nakao, E.; Sujino, K.; Watanabe, S.; Togo, H.
Heterocycles 1990, 31, 1669–1685.
17. Another procedure for the syntheses of diastereomerically
enriched mixtures of 7aϩ7c and 7bϩ7c is reported by: Harfenist,
M., Hoerr, D. C., Crouch, R. J. Org. Chem. 1985, 50, 1356.