An efficient method for preparation of chiral macrocyclic bisamides starting from diol derivatives of D-mannitol and L-tartaric acid

Article abstract of DOI:10.1055/s-1999-6054

Starting from various 1,2- and 1,4-diol derivatives of D-mannitol and L- tartaric acid, eight chiral macrocyclic bisamides were obtained via C₂- elongation of diols with tert-butyl bromoacetate followed by macrocyclization of the resultant diesters with primary α,ω-diamines.

Full text of DOI:10.1055/s-1999-6054

336
PAPER
An Efficient Method for Preparation of Chiral Macrocyclic Bisamides Starting
from Diol Derivatives of D-Mannitol and L-Tartaric Acid
Daniel T. Gryko,a Piotr Piaþtek,b Janusz Jurczak*ab
a Institute of Organic Chemistry, Polish Academy of Sciences, 01-224 Warsaw, Poland
b Department of Chemistry, University of Warsaw, 02-093 Warsaw, Poland
Fax +48(22)6326681; E-mail jurczak@ichf.edu.pl
Received 2 April 1998; revised 17 July 1998
the methyl esters immediately by elongation of the respec-
Abstract: Starting from various 1,2- and 1,4-diol derivatives of D-
tive diols with methyl bromoacetate. In spite of testing
mannitol and L-tartaric acid, eight chiral macrocyclic bisamides
various reaction conditions, we did not obtain the desired
were obtained via C2-elongation of diols with tert-butyl bromoace-
compounds. In this situation, we decided to apply the two-
phase method of C2-elongation of diols using tert-butyl
bromoacetate, previously described by us,11 to obtain es-
ters 5, 6, 15, and 16. After slight modification of the reac-
tion conditions, we obtained tert-butyl esters 5, 6, 15, and
16 in very good yield (Schemes 1 and 2, Table 2). The
main advantages of this method are: one-stage reaction,
use of relatively safe reactants, short reaction time, easy
workup, high yield, and crystallizable products. Prolonga-
tion of the reaction time results in reduction of yield. It is
noteworthy that substitution of BrCH2CO2t-Bu with
ClCH2CO2t-Bu proved unsuccessful. Similarly, applica-
tion of methyl or ethyl bromoacetate did not lead to the de-
sired products.
tate followed by macrocyclization of the resultant diesters with pri-
mary a,w-diamines.
Key words: chiral diazacoronands, cyclic bisamides, macrocycli-
sation, high pressure, transesterification
The strategies of preparation of highly elaborated macro-
cyclic compounds are based on elongation of the selected
starting material with the successive, usually two-carbon
fragments. To achieve this, reactions with allyl bromide
followed by reductive ozonolysis,1, 2 as well as reactions
with chloroacetic3, 4 or bromoacetic5, 6 acid are applied.
Recently, we have reported that dimethyl a,w-dicarboxy-
lates react with primary a,w-diamines in methanol at
room temperature with no need for using the high-dilution
technique.7Ð10 Obviously, to obtain the more complex di-
azacoronand derivatives by our method, it would be ad-
vantageous to elongate the diol with the -CH2CO2Me unit
within one step. Such an increase in performance of the
proposed strategy is particularly significant in the case of
the optically active compounds. This results from the
presence of various, often unstable functional or protec-
tive groups as well as from the expense of diols, which are
often prepared from tartaric acid or sugars in several
stages.
The synthesis of macrocyclic bisamides was initially per-
formed using methyl esters 3 and 4. These esters react
with amines 7 and 8 under normal conditions to give bisa-
mides 9, 10, 11, and 12, although, as expected, the yields
are lower than in the case of dimethyl 3,6-dioxaoctano-
dioate,9 the unsubstituted analogue of esters 3 and 4
(Scheme 1, Table 1). It would seem reasonable that bulky,
labile benzyl groups disorder the preorganization much
more than the more rigid dioxolanes, but the yields of the
respective bisamides do not differ markedly each other.
We knew from the previous studies12 that tert-butyl esters
did not react with a,w-diamines under normal conditions.
Because of its inconvenience, we discarded the two-stage
process, i.e., transesterification followed by macrocy-
clization under normal conditions. We found that tert-bu-
tyl esters 5, 6, 15, and 16 reacted with a,w-diamines in
methanol under pressure of 12 kbar to afford optically ac-
tive bisamides 9, 10, 12, 18, and 19 in 47Ð80% yield
(Schemes 1 and 2, Table 1). It seems that the high-pres-
sure macrocyclization proceeds in two stages. Transester-
ification is the first stage, and the resulting dimethyl ester
reacts with a,w-diamine in the second stage. To verify this
hypothesis, we performed two experiments. In the first
one, we reacted ester 3 with amine 8 under pressure of 12
kbar. The respective bisamide 10 was obtained in 48%
yield, almost identical as in case of the reaction of tert-bu-
tyl ester 5 under pressure of 12 kbar. Next, tert-butyl ester
6 was transesterified in methanol under normal pressure.
In spite of prolonged reaction time (72 h), only traces of
As a part of our extensive studies on methodology of the
synthesis of chiral macrocyclic bisamides being the con-
venient precursors of the respective diazacoronands, we
decided to prepare the series of chiral compounds 9Ð12
and 18Ð21, differing in the ring size, starting from D-man-
nitol and L-tartaric acid. According to the strategy adopted
from the literature, the substrate esters 3Ð6 and 15Ð17
should be prepared by elongation of the respective diols
with bromoacetic acid and then esterification of the result-
ant acids. This method was verified for two diols, 1 and 2
(Scheme 1). Unfortunately, in the case of ester 3, the yield
was merely 8%, in spite of the application of a very mild
method of esterification. A much better yield (49%) was
achieved in the synthesis of ester 4, but here some prob-
lems with purification of the product occurred.
Being aware of disadvantages of this two-step procedure
recommended in the literature, we attempted to prepare
Synthesis 1999, No. 2, 336Ð340 ISSN 0039-7881 © Thieme Stuttgart á New York

PAPER
An Efficient Method for Preparation of Chiral Macrocyclic Bisamides
337
Scheme 1 a) NaH, THF, BrCH2CO2H, reflux; b) ClO2Me, NMM, MeOH, r.t.; c) BrCH2CO2t-Bu, NaOHaq, (Bu)4NCl, PhMe, r.t.; d) Et3N,
MeOH, r.t., 12 kbar; e) 7 or 8, MeOH, r.t.; f) 7 or 8, MeOH, r.t., 12 kbar; g) 7 or 8, DBU, MeOH, r.t.; h) 8, DBU, LiBr, MeOH, r.t.
products 4 were observed. Then we modified the reaction Having in perspective the necessity for preparation of di-
conditions by adding catalytic amounts of triethylamine azacoronands in multigram scale, we looked for a catalyst
(Scheme 1). Now dimethyl ester 4 was isolated in 91% which could enable amidation of tert-butyl esters under
yield. This allows conclusion that primary amines 7 and 8 normal pressure. We needed the transesterification cata-
are both transesterification catalysts and substrates in the lyst to be simultaneously a strong base and a weak nucleo-
macrocyclization reaction.
phile. Unlike the acid catalyst, such a compound would
not inactivate the amine and would accelerate the amida-
tion reaction itself, which is catalyzed by bases.13 Our
choice was 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU),
which was already used for transesterification in the syn-
thesis of various esters.14Ð16 Thus, we performed reaction
of tert-butyl ester 5 and amine 8 in methanol in the pres-
ence of 20 mol% DBU at room temperature. After three
weeks, we isolated cyclic bisamide 10 in 52% yield
(Scheme 1). It is noteworthy that unlike DBU, triethy-
lamine, 1,4-diazabicyclo[2.2.2]octane (DABCO), or 4-
dimethylaminopyridine (DMAP) are not effective cata-
lysts in this reaction.
Table 1 Yields (%) of Bisamides 9Ð12 and 18Ð21
Bisamide From
From
Dimethyl Esters tert-Butyl Esters
7 daysa
12 kbar, 72 h,a DBU, 21 days,a
(Method B)
(Method A)
(Method C)
9
10
11
12
18
19
20
21
30
39
34
35
Ð
Ð
Ð
Ð
57
48
Ð
64
65
80
Ð
42
52
56
59
57
62
41
33
In absence of primary amine, the tert-butyl esters undergo
conversion to the dimethyl esters, e.g., ester 16 can be
converted directly to dimethyl ester 17 in 90% yield
(Scheme 2). The same conversion can be effected by heat-
ing the ester with one equivalent of DBU at reflux for 8 h.
Ð
a MeOH, r.t.
Synthesis 1999, No. 2, 336–340 ISSN 0039-7881 © Thieme Stuttgart · New York

338
D. T. Gryko et al.
PAPER
Melting points were taken on a Kofler type (Boetius) hot-stage ap-
paratus and are not corrected. Optical rotations were measured using
a JASCO DIP-360 polarimeter with thermally jacketed 10 cm cell.
1H NMR spectra were recorded with a Varian Gemini (200 MHz)
and/or a Bruker AM500 (500 MHz) spectrometer in CDCl3 using
TMS as an internal standard. 13C NMR spectra were recorded using
also a Varian Gemini (50 MHz) and/or a Bruker AM500 (125 MHz)
spectrometers. All chemical shifts are quoted in parts per million
relative to TMS (d = 0.00 ppm), and coupling constants (J) are mea-
sured in Hertz. HRMS experiments were performed on an AMD-
604 Intectra instrument using the electron impact (EI) technique.
Column chromatography was carried out on silica gel (Kieselgel-
60, 200Ð400 mesh). Methanol was freshly distilled from Mg/I2 un-
der Ar. THF was freshly distilled from Na under Ar. LiBr was dried
at 180°C under high vacuum and stored in a desiccator over P2O5.
18
a,w-Diamine 8 was purchased from Fluka. a,w-Diamine 7 and
diols 1,19 2,20 1321,22 and 1420 were prepared according to the litera-
ture procedures.
Dimethyl Esters (3 and 4); General Procedure
A solution of diol (19 mmol) in THF (50 mL) was dropwise added
to a vigorously stirred suspension of NaH, (1.83 g, 76 mmol) in
THF (400 mL), and the mixture was refluxed over a period of 1 h.
Then a solution of bromoacetic acid (5.35 g, 38 mmol) in THF (100
mL) was dropwise added over a period of 4 h, and the mixture was
refluxed over a period of 8 h. After cooling, H2O (30 mL) was add-
ed, THF was evaporated, and the residue was carefully acidified to
pH = 6.9Ð7.0, using diluted HClaq. Then water was evaporated at
30°C, and the residue was suspended in MeOH (100 mL). N-Meth-
ylmorpholine (NMM, 4.1 g, 40 mmol) was added, and the suspen-
sion was cooled down to 0¡C. To the vigorously stirred suspension,
methyl chloroformate (3.6 g, 40 mmol) was dropwise added, and
the mixture was left standing at r.t. for a period of 12 h. Then MeOH
Scheme 2 a) BrCH2CO2t-Bu, NaOHaq, (Bu)4NCl, PhMe, r.t.; b)
MeOH, DBU, reflux; c) 7 or 8, MeOH, r.t., 12 kbar; d) 7 or 8, DBU,
MeOH, r.t.
was evaporated, sat. NaHCO (40 mL) was added to the residue,
3
and the aqueous suspension was extracted with CHCl3 (4 × 50 mL).
The combined extracts were washed with H2O (50 mL) and dried
(Na2SO4). The filtrate was evaporated to leave the diester as an oil.
Crude diester 5 was then recrystallized from MeOH, while crude di-
ester 6 was then chromatographed on a silica gel column using hex-
ane/EtOAc as an eluent (Table 2).
The successful experiment of preparation of bisamide 10
from ester 5 in the presence of DBU prompted us to pre-
pare other bisamides in this way. Table 1 shows the results
of reaction of the tert-butyl esters with amines in the pres-
ence of DBU. The yields are in the range of 40% to 60%.
One can easily note that the yields for the tert-butyl esters
and DBU are in each case at least by 10% higher than the
yields for the methyl esters. The most probable explana-
tion is overlapping of two factors. The first of them is the
increase of conversion to 100% using DBU. The second
one is the quasi-high-dilution condition caused by slow
transesterification of the tert-butyl esters during the reac-
tion course.
Di-tert-butyl Esters (5, 6, 15 and 16); General Procedure
A solution containing diol (16.6 mmol) and tetrabutylammonium
chloride (10.8 mmol) in toluene (250 mL) was added to solution of
aq NaOH (35%, 250 mL). The mixture was cooled to 10¡C, under
vigorous stirring. Then tert-butyl bromoacetate (51 mmol) was add-
ed in one portion. The water bath was removed and mixture was
very vigorously stirred for 30 min. Next, H2O (100 mL) and hexane
(100 mL) were added and the mixture was stirred for another 5 min-
utes. Phases were separated and organic phase was dried (Na2SO4).
The filtrate was evaporated to leave the diester as a pale yellow oil.
Crude product was then chromatographed on a silica gel column us-
ing hexane/EtOAc as an eluent (Table 2).
The disadvantage of this method is long reaction time. It
was avoided by us via addition of anhydrous LiBr. The
DBU/LiBr system has been used as a strong basic trans-
esterification catalyst by Seebach et al.17 Thus, an addition
of DBU/LiBr to the mixture of di-tert-butyl ester and di-
amine in methanol should accelerate both reaction steps.
Thanks to the use of the DBU/LiBr system, we shorten the
reaction time from three weeks to 24 hours. The reaction
of di-tert-butyl ester 5 with diamine 8 in anhydrous meth-
anol in the presence of one equivalent of DBU and 10
equivalents of LiBr afforded bisamide 10 in the yield of
61% (the highest from among all methods).
Bisamides (9Ð12 and 18Ð21); General Procedures
Method A (standard conditions): An equimolar 0.1 M methanolic
solution (1.5 mmol) of a,w-diamine and dimethyl a,w-dicarboxy-
late was left at ambient temperature over a period of 7 days. Then
the solvent was evaporated and the residue was chromatographed
on a silica gel column using 0.5Ð3% mixtures of MeOH in CHCl3.
Method B (under high pressure): An equimolar solution of the di-
methyl a,w-dicarboxylate (0.5 mmol) and the appropriate a,w-di-
amine (0.5 mmol) in 5 mL of MeOH was filled into a Teflon am-
poule, placed in a high-pressure vessel filled with ligroin as a trans-
mission medium and compressed (12 kbar) at r.t. for 48 h.8,23 After
decompression, the mixture was transferred quantitatively to a
The method presented here enables two-stage transforma-
tion of diols to macrocyclic bisamides in the average total
yield of about 40%.
Synthesis 1999, No. 2, 336–340 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
An Efficient Method for Preparation of Chiral Macrocyclic Bisamides
339
Table 2 Compounds 3Ð6, 9Ð12 and 15Ð21 Prepareda,b
Pro- Yieldc mp
[a]D23
1H NMR (CDCl3/TMS)
(c, CHCl3) d, J (Hz)
13C NMR (CDCl3/TMS)
d
HRMS
m/z
duct (%)
(ûC)
3
4
5
8.4
111
+ 10.1
(1.3)
1.31 (s, 6 H), 1.4 (s, 6 H), 3.7 (s, 6 H), 3.7Ð 24.9, 26.5, 51.7, 65.9, 69.1, Calcd for C18H31O10 (M
4.3 (m, 8 H), 4.34 (s, 2 H), 4.37 (s, 2 H)
76.4, 80.7, 108.4, 170.6
+ H)+ 407.1917 Found
407.1908
49.0d,e colour- + 8.5
3.6Ð3.9 (m, 6 H), 3.70 (s, 6 H), 4.35 (s, 4 H), 51.7, 68.3, 70.6, 73.5, 80.0, Calcd for C24H31O8 (M
4.51 (s, 2 H), 4.52 (s, 2 H), 7.2Ð2.4 (m, 10 127.7, 127.8, 128.4, 138.2, + H)+ 447.2019 Found
91.0f
less oil
(2.5)
H)
171.2
447.2015
79.2
83Ð86
+ 7.1
(1.05)
1.35 (s, 6 H), 1.42 (s, 6 H), 1.47 (s, 18 H), 25.0, 26.5, 28.1, 66.2, 69.8, Calcd for C23H39O10
3.7Ð3.9 (m, 2 H), 4.0Ð4.2 (m, 4 H), 4.17 (d, 76.3, 80.6, 81.4, 108.3, 169.2 (M Ð CH3)+ 475.2543
AB/2, 2 H, J = 16.2), 4.28 (d AB/2, 2 H, J =
Found 475.2542
16.2), 4.3Ð4.5 (m, 2 H)
6
9
38.5
56Ð58
+ 3.1
(1.0)
1.45 (s, 18 H), 3.5Ð3.9 (m, 6 H), 4.20 (d AB/ 28.3, 69.3, 70.7, 73.6, 79.0, Calcd. for C30H42O8Na
2, 2 H, J = 16.5), 4.24 (d AB/2, 2 H, J = 16.5), 81.5, 127.6, 127.9, 128.5, (M + Na)+ 553.2777
4.46 (d, AB/2, 2 H, J = 11.8), 4.55 (d AB/2, 2 138.4, 170.2
H, J = 11.8), 7.2Ð7.4 (m, 10 H)
Found 553.2771
g
colour- Ð14.9 (1.0) 1.34 (s, 6 H), 1.40 (s, 6H), 3.4Ð3.7 (m, 8 H), 25.2, 26.7, 38.2, 69.8, 70.6, Calcd. for C20H35N2O9
less oil
3.7Ð3.9 (m, 4 H), 4.0Ð4.1 (m, 4 H), 4.16 (d 74.7, 78.6, 109.5, 168.8
AB/2, 2 H, J = 14.8), 4.20 (d, AB/2, 2 H, J =
14.8), 7.23 (br t, 2 H)
(M + H)+ 447.2343
Found 447.2338
g
10
66Ð68
+ 2.2
(1.0)
1.33 (s, 6 H), 1.39 (s, 6 H), 3.55 (s, 8 H), 25.0, 26.6, 38.3, 66.8, 69.7, Calcd. for C22H38N2O10
3.6Ð3.7 (m, 8 H), 3.9Ð4.0 (m, 2 H), 4.1Ð4.2 70.6, 72.0, 74.9, 80.3, 109.1, (M)+ 490.2526 Found
(m, 2 H), 4.17 (d AB/2, 2 H, J = 14.8), 4.21 168.7
(d AB/2, 2 H, J = 14.8), 7.09 (br t, 2 H)
490.2528
g
g
11
12
colour- + 54.5
less oil (0.95)
3.3Ð3.8 (m, 14 H), 3.93 (d AB/2, 2 H, J = 38.0, 68.1, 68.8, 69.3, 73.6, Calcd. for C26H34N2O7
15.0), 4.20 (d AB/2, 2 H, J = 15.0), 4.47 (s, 78.6, 127.9, 128.0, 128.5, (M)+ 486.2366 Found
4 H), 7.19 (br t, 2 H), 7.2Ð7.4 (m, 10 H)
137.3, 169.3
486.2368
colour- + 4.3
3.3Ð3.7 (m, 16 H), 3.73 (m, 2 H), 4.01 (d 38.4, 68.7, 69.7, 70.4, 70.8, Calcd for C28H38N2O8
less oil
(1.0)j
AB/2, 2 H, J = 15.3), 4.17 (d AB/2, 2 H, J = 73.5, 78.8, 127.7, 127.9, (M)+ 530.2641 Found
15.3), 4.48 (d AB/2, 2 H, J = 11.9), 4.51 (d 128.5, 137.5, 169.4
AB/2, 2 H, J = 11.9), 7.2Ð7.4 (m, 10 H), 7.23
(t, 2 H, J = 5.1)
530.2641
15
16
17
18
84.5
85.7
65Ð67
+ 1.4
(1.05)
1.47 (s, 9 H), 1.48 (s, 9 H), 3.81 (d, 4 H, J = 28.1, 69.0, 71.4, 77.5, 78.0, Calcd for C23H34O8
4.4), 4.06 (d, 4 H, J = 4.5), 4.4Ð4.8 (m, 2 H), 81.7, 104.1, 126.8, 128.3, (M)+ 438.2254 Found
5.98 (s, 1 H), 7.2Ð7.6 (m, 5 H)
129.3, 137.4, 169.4
438.2248
colour- Ð 9.6
less oil (1.2)
1.43 (s, 6 H), 1.48 (s, 18 H), 3.6Ð3.8 (m, 4 26.9, 28.0, 69.2, 71.6, 77.1, Calcd for C18H31O8
H), 4.04 (s, 4 H), 4.0Ð4.2 (m, 2 H)
81.5, 109.7, 169.3
(M Ð CH3)+ 375.2019
Found 375.2014
90.0h
92.5i
colour- Ð9.8
less oil (1.0)
1.42 (s, 6 H), 3.75 (s, 6 H), 3.7Ð3.8 (m, 4 H), 26.9, 51.8, 68.7, 71.8, 77.0, Calcd. for C16H22O6 (M
4.0Ð4.1 (m, 2 H), 4.19 (s, 4 H)
109.8, 170.6
+ H)+ 307.1393 Found
307.1390
g
colour- + 30.0
less oil (0.9)
3.4Ð3.8 (m, 12 H), 4.04 (d AB/2, 2 H, J = 38.5, 38.5, 69.5, 69.6, 70.9, Calcd for C19H26N2O7
15.2), 4.10 (d AB/2, 2 H, J = 15.2), 4.35 (m, 71.1, 71.9, 77.2, 77.4, 103.9, (M)+ 394.1740 Found
2 H), 5.98 (s, 1 H), 6.86 (br t, 2 H), 7.3Ð7.5 126.3, 128.4, 129.6, 137.1, 394.1734
(m, 5 H)
168.7, 168.8
g
19
colour- Ð 2.0
3.4Ð3.7 (m, 12 H), 3.80 (m, 4 H), 4.09 (s, 2 36.6, 38.7, 70.1, 70.2, 70.6, Calcd for C21H30N2O8
H), 4.12 (d AB/2, 2 H, J = 15.0), 4.29 (m, 2 70.7, 71.2, 71.4, 71.4, 77.3, (M)+ 438.2002 Found
H), 5.97 (s, 1 H), 7.16 (br t, 1 H), 7.19 (br t, 78.0, 104.1, 126.5, 128.4, 438.2003
less oil
(1.0)
1 H), 7.3Ð7.5 (m, 5 H)
129.6, 136.9, 169.2, 169.2
g
g
20
21
105Ð
108
+ 34.3
(1.0)
1.41 (s, 6 H), 3.4Ð3.6 (m, 8 H), 3.70 (m, 4 27.2, 38.4, 69.4, 71.0, 72.0, Calcd for C14H23N2O7
H), 4.06 (s, 4 H), 4.12 (m, 2 H), 6.88 (br t, 2 77.1, 109.8, 168.9
H)
(M Ð CH3)+ 331.1505
Found 331.1510
colour- Ð14.9 (1.1) 1.41 (s, 6 H), 3.4Ð3.6 (m, 8 H), 3.63 (s, 4 H), 26.8, 38.6, 70.1, 70.6, 71.3, Calcd for C17H31N2O8
less oil
3.6Ð3.8 (m, 4 H), 4.0Ð4.1 (m, 2 H), 4.09 (d 71.4, 77.2, 109.8, 169.2
AB/2, 4 H, J = 15.1), 7.06 (br t, 2 H)
(M + H)+ 391.2080
Found 391.2079
a
e
All compounds are hygroscopic and many of them are labile oils
available only in small quantities.
The yield of crude product.
The yield obtained from 6 via transesterefication
Yields are given in Table 1.
The yield obtained from 16 via transesterification in method I
The yield obtained from 16 via transesterification in method II
[a]D23 = + 4.3 (1.3, CHCl3)5
f
b
g
h
i
The chemical purity of all compounds was confirmed by 1H and 13
NMR spectra.
C
c
All yields were based on isolated product.
The yield obtained via elongation using bromoacetic acid.
d
j
Synthesis 1999, No. 2, 336–340 ISSN 0039-7881 © Thieme Stuttgart · New York

340
D. T. Gryko et al.
PAPER
round-bottomed flask and the solvent was evaporated. The residue
was chromatographed on a silica gel column using 0.5Ð3% mixtures
of MeOH in CHCl3.
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Method C (with DBU): An equimolar 0.1 M methanolic solution
(1.5 mmol) of a,w-diamine and dimethyl a,w-dicarboxylate con-
taining DBU (20 mol%) was left at ambient temperature over a pe-
riod of 21 days. Then the solvent was evaporated and the residue
was chromatographed on a silica gel column using 0.5Ð3% mixtures
of MeOH in CHCl3.
(6) Rastetter, W.H.; Phillion, D.P. J. Org. Chem. 1981, 46, 3204.
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solution (1.5 mmol) of a,w-diamine and dimethyl a,w-dicarboxy-
late containing DBU (100 mol%) and anhyd LiBr (1000 mol%) was
left at ambient temperature over a period of 24 h. Then the solvent
was evaporated and the residue was chromatographed on a silica gel
column using 0.5Ð3 % mixtures of MeOH in CHCl3.
(8) Jurczak, J.; Kasprzyk, S.; SaΩanski, P.; Stankiewicz, T. High
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Transesterification Procedures
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Methyl 2-[((4S,5S)-2,2-Dimethyl-5-{[(methyloxycarbonyl)-
methoxy]methyl}-1,3-dioxolan-4-yl)methoxy]acetate (17)
Method I: A reaction mixture containing di-tert-butyl ester 16
(390 mg, 1 mmol), DBU (610 mg, 4 mmol) and MeOH (100 mL)
was allowed to stand at r.t. for 4 weeks. Then MeOH was removed
under reduced pressure and oily residue was chromatographed on a
silica gel column using CHCl3. Method II: A mixture containing di-
tert-butyl ester 16 (390 mg, 1 mmol), DBU (610 mg, 4 mmol) and
MeOH (100 mL) was refluxed for 8 h. Then MeOH was removed
under reduced pressure and oily residue was chromatographed un-
der above-mentioned conditions (Table 2).
(16) Ishikawa, T.; Ohsumi,Y.; Kawai, T. Bull. Chem. Soc. Jpn.
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[(methyloxycarbonyl)methoxy]propylo}oxy)acetate (4)
1969, 10, 2885.
Di-tert-butyl ester 6 (530 mg, 1 mmol), Et3N (10 mg, 0.2 mmol) and
MeOH (5 mL) was filled into a Teflon ampoule, placed in a high-
pressure vessel filled with ligroin as a transmission medium and
compressed (12 kbar) at r.t. for 72 h. After decompression, the mix-
ture was transferred quantitatively to a round-bottomed flask and
the solvent was evaporated. The residue was chromatographed on a
silica gel column using CHCl3 as an eluent (Table 2).
(19) Kierstead, R.W.; Faraone, A.; Mennona, F.; Mullin, J.;
Guthrie, R.W.; Crowley, H.; Simko, B.; Blaber, L.C. J. Med.
Chem. 1983, 26, 1561.
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Chem. Soc., Perkin Trans. 1 1977, 1756.
(23) Jurczak, J.; Chmielewski, M.; Filipek, S. Synthesis 1979, 41
Acknowledgement
This work was supported by the State Committee for ScientiÞc
Research (Project 3T09A13409) and by Warsaw University (BST-
562/18/97).
Synthesis 1999, No. 2, 336–340 ISSN 0039-7881 © Thieme Stuttgart · New York