Studies towards the synthesis of bicyclomycin precursors: Synthesis of N,N′-disubstituted 2,5-diketopiperazines in solution and on solid phase

Article abstract of DOI:10.1002/jhet.5570450321

(Chemical Equation Presented) The synthesis of 3-(hydroxyalkyl)-N,N′- disubstituted 2,5-diketopiperazine derivatives - compounds required for the bicyclomycin analogues preparation - has been studied. The use of various oxo components in the Ugi multicomp

Full text of DOI:10.1002/jhet.5570450321

May-Jun 2008
765
Studies Towards The Synthesis Of Bicyclomycin Precursors:
Synthesis of N,N'-Disubstituted 2,5-Diketopiperazines In Solution
And On Solid Phase
Anna Fryszkowska and Ryszard Ostaszewski*
Institute of Organic Chemistry, Polish Academy of Sciences, Kasprzaka 44/52, 01-224 Warsaw, Poland; Fax:
++48 22 632 66 81; Tel: ++48 22 343 21 20; E-mail: rysza@icho.edu.pl
Received June 26, 2007
RO
(
)
n
O
or
or
R
N
O
HO
O
O
OR
(
)
n
O
N
R
H3C
(
)
O
n
The synthesis of 3-(hydroxyalkyl)-N,N'-disubstituted 2,5-diketopiperazine derivatives - compounds
required for the bicyclomycin analogues preparation - has been studied. The use of various oxo
components in the Ugi multicomponent reaction (U-MCR) has been evaluated. The first example of an
semicyclic O,O-acetal employed as an aldehyde equivalent in the U-MCR has been reported. The
preparation and the synthetic application of Wang resin-bound aliphatic aldehydes in the synthesis of 2,5-
diketopiperazine skeleton has also been described.
J. Heterocyclic Chem., 45, 765 (2008).
INTRODUCTION
In our research we focused on the synthesis of 3-(ω-
hydroxy-alkyl)-N,N'-disubstituted 2,5-diketopiperazines
of structure 5 (Scheme 2) required as precursors for
bicyclomycin analogues synthesis [15,18]. The aim of this
study was to develop a novel and practical approach,
which would allow a synthetically feasible method of
introducing structural variations within the substituents at
N,N'-positions. The latter would be especially valuable for
combinatorial library synthesis. Here, we report the
results of our studies on the synthesis of these derivatives
based on U-MCR, both in solution and in solid phase.
The 2,5-diketopiperazines (DKPs) are cyclic head-to-
tail dipeptides, found as a structural motif in many natural
products [1,2]. 3-Substituted 2,5-DKPs (A, Scheme 1)
represent peptidomimetics with interesting biological
activity [3-7] and they may serve as precursors to the
other versatile classes of compounds including: amino
acids [8,9], bicyclic derivatives [5,10-12] or piperazines
[12-14]. Moreover, they serve as synthons in the course of
synthesis of very important antibiotics like bicyclomycin
(B, Scheme 1) [15] or quinocarcin [16].
Numerous synthetic studies have been devoted to the
RESULTS AND DISCUSSION
Synthesis in solution. The retrosynthetic analysis of 3-
(ω-hydroxy-alkyl)-N,N'-disubstituted 2,5-DKPs (5)
showed that ω-acetoxy-alkyl aldehydes 2 could be used as
an oxo component in Ugi reaction (Scheme 2), whilst the
required structural diversity could be easily achieved via
amine and isocyanide component variations.
The aldehydes 2a-b were prepared from α,ω-diols 1a-b
via a monoacylation reaction, followed by a PCC-
catalysed oxidation, as previously published [19,20],
giving overall yields of 23-30%. Subsequently, the Ugi
condensation of chloroacetic acid, benzyl isocyanide,
respective amine and aldehydes 2a-b furnished
N-chloroacetyl-aminoamide derivatives 3a-d in good
yields (62-85%). At this stage we used 2 different amines
as amino component in U-MCR, namely benzyl amine
and (S)-phenylethyl amine. The precedents in the
literature suggested that the use of chiral, sterically
Scheme 1
3-Alkyl-2,5-diketopiperazines as bicyclomycin precursors.
CH2
1
R
O
OH
O
N
O
HN
O
N
HO
HO
H
H
3
O
N
R
R
Me
2
OH
A
B, Bicyclomycin
construction of 2,5-DKP skeleton and the recent
development in their synthesis was summarised in an
excellent review by Dinsmore [2]. A wide variety of 2,5-
DKP scaffolds is accessible via isocyanide-based
multicomponent reactions (I-MCRs), in particular via Ugi
reaction (U-MCR) [17].

766
A. Fryszkowska and R. Ostaszewski
Vol 45
Scheme 2
Scheme 3
Synthesis of 2,5-diketopiperazines 4 and 5 in solution from diols
1a-b.
2,3-Dihydropyran (6) as an aldehyde (8) [24,25] and imine
(10) [26,27] equivalent.
H+
a-b
HO
AcO
(
)
n
OH
(
)
n
O
H2O
2a, n = 1
2b, n = 2
1a, n = 1
1b, n = 2
OH
O
N
O
O
OH
7
9
8
O
c
6
H+
Bn
R
R
N
OH
O
N
RNH2
H
10
d
OAc
NHBn
O
( )
n
(
)
n
O
N
35-92%
Cl
OAc
N
Ph
R
ester hydrolysis in methanol solution in 42-92% yield
(Scheme 2).
O
Ph
R
4a-d
Tetrahydropyran-2-ol as oxo component. The
previously presented approach required non-commercially
available aldehydes 2 as starting materials. In order to
avoid the low-yield and laborious preparation of the
aldehydes 2 from the diols 1 we searched for more
efficient building blocks, which could be used as an oxo
component in U-MCR.
It is well known that the Ugi reaction mechanism
proceeds via imine formation [22]. The substitution of the
oxo and amine compounds by the corresponding imine is
known as Joullié 3-component variant of U-MCR [23].
On the basis of this observation, our attention was drawn
by 2,3-dihydropyran (6) and its easily accessible
semicyclic X,O-acetal derivatives 7 and 9 (Scheme 3).
Tetrahydropyran-2-ol (7) exists in an equilibrium with
5-hydroxypentanal (8), thus could be used as an aldehyde
equivalent [24,25]. Similarly, semicyclic N,O-acetals (9)
exists in an equilibrium with imines 10 and as the imines
can be functionalised to the respective linear products,
e.g. amino-alcohols [26,27].
Initially, we envisaged that 2,3-dihydropyran (6) could
be directly employed as an oxo component in U-MCR.
We assumed that 2,3-dihydropyran could be reacted with
an amine to form a semicyclic N,O-acetal, and then, as its
imine form 10 would follow Ugi reaction mechanism
[22]. This approach would considerably simplify the
process and it would open a new route toward 2,5-DKP
derivatives. Unfortunately, the reaction of chloroacetic
acid, benzyl amine, benzyl isocyanide and 2,3-dihydro-
pyran (6) in methanol resulted in a complex mixture and
no expected aminoamide product was isolated. This
apparently arose from the presence of the other nucleo-
philes in the solution (both from the reactants and
3a, R = H, n = 1
3b, R = H, n = 2
3c, R = Me, n = 1
3d, R = Me, n = 2
e, 74-99%
Bn
N
O
f
(
)
n
O
N
a: 42%
b: 92%
OH
Ph
R
5a-d
Reagents and conditions: [a] Ac2O, CH2Cl2, rt, 5h; [b] PCC,
CH2Cl2, 4 Å mol. sieves, 0 °C→rt, 5h, 23-30% overall yield;
[c] ClCH2COOH, Ph(CH)RNH2, BnNC, MeOH, 5 d, rt, 62-85%;
[d] Cs2CO3, MeCN, 2 h, rt, 35-92%; [e] KOH, sonication, 20 min, rt,
74-99%; [f] NaOH, MeOH, H2O, 9 h, rt, 42-92%.
hindered amines as substrates in U-MCR may lead to
stereodiscrimation of a newly formed stereogenic centre
[21], which would facilitate the synthesis optically pure
bicyclomycin analogues. However, when (S)-phenylethyl
amine was used as amino component in the synthesis
compounds 3c-d (Scheme 2), no diastereoselectivity was
observed. The U-MCR reaction resulted in a mixture of
the diastereoisomers in approx. 50:50 ratio, which was
evident from the 1H NMR spectrum.
In the next step, Cs2CO3-catalysed cyclisation of N-
chloroacetyl-aminoamides 3a-d led to 3-(acetoxyalkyl)-
2,5-DKP derivatives 4, without the concomitant acyl ester
hydrolysis (Scheme 2). The reaction proceeded in very
good yields for the benzylamine derivatives 4a-b (75-
92%). The yields obtained for diastereoisomeric
derivatives 4c-d were significantly lower (35-47%). This
can be attributed to the difficulties in the chromatographic
purification of the latter. Subsequent ester group
hydrolysis of the derivatives 4a-d with KOH, enhanced
by sonication, led to the respective 3-(hydroxy-alkyl)-2,5-
DKP derivatives 5 in good or in very good yields
(Scheme 2).
methanol used as
a solvent), which reacted with
2,3-dihydropyran (6) under Ugi reaction conditions.
However, when tetrahydropyran-2-ol (7) was used as
the oxo component, a respective product 11 was formed
in 74% yield (Scheme 4). Subsequent Cs2CO3-catalysed
cyclisation of amide 11 yielded a respective butanol
2,5-DKP derivative 5b in 50% yield (Scheme 4).
Contrarily, the dipeptides 3a-b were transformed into
their respective hydroxyalkyl derivatives 5a-b in one step.
This was accomplished via NaOH-catalysed cyclisation/

May-Jun 2008
Synthesis of Bicyclomycin Precursors In Solution And On Solid Phase
767
determination of the nitrogen content in the resins 17
(elemental analysis) allowed determination of the
aldehyde 16 loading at the level of 0.50-0.59 mmol/g.
The Ugi reaction with the aldehydes 16a-b was
performed in methylene chloride: methanol (2:1) mixture
in order to ensure resin swelling (Scheme 6 and Table 1).
The Ugi reaction of haloacetic acid, benzylamine and
benzyl isocyanide resulted in respective Ugi products
bound to the resin (18a-d, Scheme 6).
Scheme 4
Synthesis of aminoamides 11 from tetrahydropyran-2-ol (7) in
U-MCR and their further functionalisation.
THPO
OH
a
O
O
+
Cl
NHBn
NHBn
Cl
O
OH
N
N
7
Bn
O
Bn
O
12, 6%
11, 74%
Scheme 5
b or c
Synthesis of Wang resin-bound aliphatic aldehydes 16.
d-e
Bn
N
NH
O
a
b
OH
H3C
O
CCl3
(
)
n
H3C
O
13
O
N
OH
1.00 mmol.g-1
14
15a, n = 1
15b, n = 2
Bn
5b
c
Reagents and conditions: [a] ClCH2COOH, BnNH2, BnNC, MeOH,
5 d, rt; [b] Cs2CO3, MeCN, 2 h, rt, 50%; [c] NaOH, MeOH, H2O,
16 h, rt, 55%; [d] p-TsOH, MeOH, 2 h, rt; [e] Cs2CO3, MeCN, 2 h,
rt; 54% for 2 steps.
d
O
N-NH-Ph
(
)
n
H3C
O
H3C
O
( )
n
17a, n = 1
17b, n = 2
16a, n = 1, 0.59 mmol.g-1
16b, n = 2, 0.50 mmol.g-1
It is noteworthy, that small amount (6%) of the
respective tetrahydropyranyl aminoamide derivative 12
was isolated as well, which can be explained by the
presence of a tetrahydropyran-2-ol dimer in the starting
material. Nevertheless, we also demonstrated that the side
product 12 could be converted to 2,5-DKP 5b in a
convenient way (Scheme 4). p-TsOH-catalysed
Reagents and conditions: [a] Cl3CCN, DBU, 0 °C, 40 min; [b] diol 1 (10
eq), BF3⋅OEt2, cyclohexane, CH2Cl2 rt, 20 min; [c] DMSO, Et3N,
Py⋅SO3, rt, 3.5 h (2 times); [d] PhNH-NH2, EtOHanh., ΔT, 4 h (2 times).
Scheme 6
Synthesis of 2,5-diketopiperazine 5 derivatives on solid phase.
deprotection of
a THP group, followed by basic
cyclisation, which led to the product 5b 55% overall
yield.
In this manner, we demonstrated the synthetic use of
tetrahydropyranol (7) and thus-obtained Ugi products in
the synthesis of bicyclomycin precursors.
H3C O (
)
n
Bn
N
Bn
O
OH
N
O
a
b-c
NH
Bn
16a-b
(
)
n
O
X
O
N
Bn
Solid-phase synthesis of 2,5-diketopiperazines. In
order to simplify the product purification, we decided to
extend our synthetic methodology to the solid phase
approach. We envisaged that the oxo component - an
aliphatic aldehyde bearing hydroxyl group - could be
bound to a resin (Scheme 5). Thus, 1,4-butanediol (1a)
and 1,5-pentanediol (1b) were bound to the Wang benzyl
resin (13, loading 1.00 mmol.g-1), employing the
methodology proposed before [28]. An activated Wang
resin (14) was treated with 10 equivalents of the
respective diol 1a-b to yield alcohols 15a-b bound to the
resins, which was demonstrated by the disappearance of
C=N stretching band (1663 cm-1) and the appearance of a
strong OH band around 3500 cm-1. Py⋅SO3 mediated
oxidation of the free hydroxyl groups of 15a-b gave
aldehydes 16a-b (IR data showed presence of a new C=O
stretching band at 1722 cm-1). At this point the loading of
the resin was estimated by transforming the aldehyde
resins (16) into phenylhydrazine derivatives 17a-b. The
5a, n = 1
5b, n = 2
18a-d, n = 1,2
X = Cl, Br, I
d
(
)
(
HO
)
CF3CO2
2
2
Bn
Bn
N
N
+
NH
Bn
NH
O
O
Cl
Bn
O
O
Cl
3e
11
Reagents and conditions: [a] XCH2CO2H (10eq), BnNH2 (10 eq), BnNC
(10 eq), CH2Cl2:MeOH, 2:1, rt, 5 d; [b] 10% TFA, CH2Cl2, 2-5 h; [c]
NaOH, THF, H2O, 16 h, 4-32%; [d] 10% TFA, CH2Cl2, rt, 4 h, 3e: 17%.
We briefly investigated the effect of the leaving group on
the U-MCR on the solid phase, by using chloro-, bromo-
and iodoacetic acids as carboxylic components (Scheme 6).

768
A. Fryszkowska and R. Ostaszewski
Vol 45
Furthermore, tetrahydropyran-2-ol (7) was found to be a
useful and easily accessible building block in the
synthesis of the target compound. According to our
knowledge, this is the first example of the use of a
semicyclic O,O-acetal as an equivalent of the oxo
component in U-MCR. Finally, we extended our studies
to the solid phase approach, which simplified the product
purification and allowed the preparation of required
products in good purity and in good overall yield.
Table 1
Synthesis of 1,4-dibenzyl-3-(ω-hydroxy-alkyl)-piperazine-
2,5-diones 5a-b on the solid support.
entry Loading
of 16
n
18
X
t
Yield of
5
Yield Purity
of 5 [b] [c]
(days) 18 [a]
(mmol.g-1)
1
2
3
16a (0.59)
16b (0.50)
16b (0.50)
1
2
2
18a Cl
18b Cl
18c Br
5
5
7
71%
100%
5a 8%
nd
5b 32% 96%
94% [d] 5b 4%
65% [d] 5b 8%
19%
45%
4
16b (0.50)
2
18d
I
5
[a] percent yield in respect to the loading of 16, on the basis of N%
incorporation determined by EA; [b] for 2 steps, in respect of the
aldehydes 16; [c] by HPLC; [d] halogens were incorporated into
the resin 18 in higher amounts then stoichiometric (by EA).
EXPERIMENTAL
NMR spectra were recorded in CDCl3 with TMS as an
internal standard using a 200 MHz Varian Gemini 200
spectrometer. Chemical shifts are reported in ppm and coupling
constants (J) are given in hertz (Hz). MS spectra were recorded
on an API - 365 (SCIEX) apparatus. IR spectra were recorded in
KBr with a Perkin Elmer FT-IR Spectrum 2000 apparatus.
Optical rotations of separated diastereoisomers were measured
in a 1-dm cell of 1.2 mL capacity using a Jasco DIP-360
polarimeter operating at 589 nm. HPLC analysis was performed
using a Kromasil, Si 60 column, (4 mm φ × 250 mm), using a
LC-6A Shimadzu apparatus with a UV SPD-6A detector and a
Chromatopac C-R6A analyzer. Elemental analyses were
performed using a CHN Perkin-Elmer 240 apparatus. All
reactions in solution were monitored by TLC on Merck silica gel
60 F254 plates. Column chromatography was performed on
Merck silica gel 60/230-400 mesh. Melting points are
uncorrected. All the chemicals were obtained from common
suppliers.
The reaction yields were determined by elemental
analysis, based on nitrogen content in the resin 18.
Comparison of the reaction yields and product purities
with various haloacetic acids (entries 2-4, Table 1) proved
that the use of chloroacetic acid (entry 2, Table 1) was
beneficial to the course of the reaction and it enabled us to
obtain 96% pure compound 5b in a good overall yield.
Significantly lower yields were obtained, when bromo-
and iodoacetic acids were used (4% and 8%,
respectively). Moreover, the elemental analysis showed
that halogen incorporation into the resin was higher than
stoichiometric (Entries 3-4, Table 2), which may suggest
the possible occurrence of side reactions. Low nitrogen
incorporation leads to the conclusion that the product
cleavage might have occurred, however, this problem was
not analysed in detail.
The last step of this synthetic strategy was the cleavage
of the final product from the resin. Typically, the cleavage
of the polymer-bound benzyl ethers, i.e. Wang resin, is
effected by treatment of the resin in a solution of 1% TFA
in methylene chloride [28]. It was reported in the
literature that for polymer-bound benzyl-alkyl ethers
higher concentration of TFA (up to 10%) led to
quantitative recovery of aliphatic alcohol derivatives [28].
However, in our hands, treatment of the resin 18b with
10% TFA solution resulted mainly in the formation of the
respective trifluoroacetic ester 3e (17% yield) and only
traces of the expected hydroxy-alkyl product 11 were
isolated (Scheme 6). Therefore, in order to simplify the
overall procedure, the TFA-catalysed cleavage was
followed by the NaOH cyclisation/ ester hydrolysis. This
easy procedure led directly to the desired 3-(ω-hydroxy-
alkyl) 2,5-DKP derivatives 5a-b (Scheme 6).
Synthesis in solution.
Synthesis of aldehydes 2. The aldehydes 2a-b were prepared
from 1,4-butanediol (1a) and 1,5-pentanediol (1b), respectively,
according to published procedure [19,20].
4-Acetoxy-1-butanal (2a). Overall yield 23%: colourless oil;
1
Rf = 0.50 (hexane:EtOAc, 6:4); H NMR (CDCl3, 200 MHz) δ
1.88-1.99 (m, 2H), 2.02 (s, 3H), 2.53 (dt, J = 1.1 Hz, J = 7.1 Hz,
2H), 4.07 (t, J = 6.4 Hz, 2H), 9.77 (t, J = 1.3 Hz, 1H); 13C NMR
(CDCl3, 50 MHz) δ 21.5, 25.5, 40.7, 63.7, 171.9, 179.0.
5-Acetoxy-1-pentanal (2b). Overall yield 30%: colourless
oil; Rf = 0.40 (hexane:EtOAc, 6:4); 1H NMR (CDCl3, 200 MHz)
δ 1.60-1.80 (m, 4H), 2.05 (s, 3H), 2.50 (dt, J = 1.5 Hz,
J = 6.3 Hz, 2H), 4.08 (t, J = 6.0 Hz, 2H), 9.78 (t, J = 1.5 Hz,
1H); 13C NMR (CDCl3, 50 MHz) δ 21.4, 21.7, 28.5, 33.9, 64.5,
171.7, 179.6.
Synthesis of N-acyl aminoamide derivatives 3. General
procedure 1. To a solution of the aldehyde 2 (6.0 mmol) in
methanol (5 mL) at 0 °C, amine (6.0 mmol), isocyanide (6.0
mmol) and acid (5.0 mmol) were added sequentially within
15 min intervals. The mixture was stirred for 5 days at rt. The
solvent was evaporated in vacuo and the resulting slurry was
dissolved in EtOAc (50 mL) and washed with NaOHaq (1 M, 30
mL), HClaq (1 M, 30 mL) and brine (30 mL). The organic phase
was dried (MgSO4) prior to the solvent being evaporated in
vacuo. The resulting residue was purified on a silica gel column.
Products 3a-b were recrystallised from EtOAc/hexane.
CONCLUSIONS
In conclusion, in our studies we demonstrated three
various approaches based on U-MCR towards N,N'-disub-
stituted 3-ω-hydroxyalkyl-piperazine-2,5-diones 5. The
use of acyl-protected aldehydes 2 as oxo component was
proven to be an effective, yet laborious synthetic route.
4-Benzylcarbamoyl-4-[benzyl-(2-chloroacetyl)-amino]-
butyl acetate (3a). The product was prepared according to
general procedure 1 in 65% yield: white crystals; mp 88-90 °C

May-Jun 2008
Synthesis of Bicyclomycin Precursors In Solution And On Solid Phase
769
(EtOAc/hexane); Rf = 0.36 (hexane:EtOAc, 6:4); 1H NMR
(CDCl3, 200 MHz) δ 1.50-1.80 (m, 4H), 2.06 (s, 3H), 4.02 (s,
2H), 4.05 (t, J = 6.3 Hz, 2H), 4.44 (d, J = 5.8 Hz, 2H), 4.76 (s,
2H), 5.01-5.08 (m, 1H), 6.95 (t, J = 5.6 Hz, 1H), 7.08-7.40 (m,
10H); 13C NMR (CDCl3, 50 MHz) δ 21.0, 25.2, 25.5, 41.9, 43.6,
48.5, 58.1, 63.8, 125.9, 127.6, 127.8, 127.9, 128.7, 128.8, 129.2,
136.6, 137.9, 169.0, 169.4, 171.1; Anal. Calcd for
C23H27ClN2O4: C, 64.11; H, 6.32; N, 6.50; Found: C, 64.11; H,
6.35; N, 6.44.
164.2, 166.0, 171.1; ESI-MS: m/z = 395 ([M+H]+, 4%), 417
([M+Na]+, 100%); ESI-MS HR: m/z calcd for [M+Na]+,
C23H26N2O4Na: 417.1785; Found: 417.1812; Anal. Calcd for
C23H26N2O4: C, 70.03; H, 6.64; N, 7.10; Found: C, 69.85; H,
6.64; N, 6.86.
1,4-Dibenzyl-3-(4-acetoxybutyl)-piperazine-2,5-dione (4b).
The product was prepared according to general procedure 2 in
75% yield: white crystals; mp 56-58 °C (EtOAc/hexane);
1
Rf = 0.37 (hexane:EtOAc, 6:4); H NMR (CDCl3, 200 MHz) δ
5-Benzylcarbamoyl-5-[benzyl-(2-chloroacetyl)-amino]-
pentyl acetate (3b). The product was prepared according to
1.20-1.45 (m, 2H), 1.46-1.70 (m, 2H), 1.71-2.00 (m, 2H), 2.10
(s, 3H), 3.96-4.07 (m, 5H), 4.12 (d, J = 14.6 Hz, 1H), 4.42 (d,
J = 14.4 Hz, 1H), 4.89 (d, J = 14.4 Hz, 1H), 5.17 (d,
J = 14.9 Hz, 1H), 7.20-7.60 (m, 10H); 13C NMR (CDCl3,
50 MHz) δ 20.8, 20.9 28.2, 31.5, 47.4, 49.1, 49.5, 59.3, 63.7,
128.1, 128.2, 128.4, 128.9, 135.2, 135.5, 164.1, 166.1, 171.0;
Anal. Calcd for C24H28N2O4: C, 70.57; H, 6.91; N, 6.86; Found:
C, 70.44; H, 6.87; N, 6.82.
1-Benzyl-3-(3-acetoxypropyl)-4-((1'S)-1-phenylethyl)-
piperazine-2,5-dione ((1'S,3RS)-4c). The product was prepared
according to general procedure 2 in 47% yield as mixture of
distereomeres: Dr 50:50 (NMR); white crystals; mp 94-95 °C
(Et2O/hexane); Rf = 0.30 (hexane:EtOAc, 6:4); 1H NMR (CDCl3,
200 MHz) δ 0.80-1.80 (m, 8H), 1.59 (d, J = 7.1 Hz, 3H), 1.63 (d,
J = 7.1 Hz, 3H), 1.95 (s, 3H), 2.04 (s, 3H), 3.70-4.15 (m, 10H),
4.29 (d, J = 14.5 Hz, 1H), 4.38 (d, J = 14.4 Hz, 1H), 4.71 (d,
J = 14.5 Hz, 1H), 4.86 (d, J = 14.5 Hz, 1H), 5.79 (q, J = 7.1 Hz,
1H), 5.92 (q, J = 7.1 Hz, 1H), 7.17-7.50 (m, 20H); 13C NMR
(CDCl3, 50 MHz) δ 16.2, 17.6, 21.0, 24.4, 29.6, 30.7, 49.5, 49.6,
49.9, 51.4, 52.6, 56.8, 57.0, 63.4, 127.3, 128.1, 128.2, 128.3,
128.4, 128.8, 129.1, 135.5, 138.8, 139.4, 164.5, 164.8, 166.4,
166.7, 170.8, 171.7; UV-VIS λmax (ε; MeCN): 257 (490), 208
(25 500); Anal. Calcd for C24H28N2O4: C, 70.55; H, 6.91; N,
6.86; Found: C, 70.45; H, 7.02; N, 6.83.
1-Benzyl-3-(4-acetoxybutyl)-4-((1'S)-1-phenylethyl)-piper-
azine-2,5-dione ((1'S,3RS)-4d). The product was prepared
according to general procedure 2 in 35% yield as mixture of
distereomeres: Dr 50:50 (NMR); colourless oil, purified by
PHPLC (hexane:EtOAc, 6:4); Rf = 0.35 (hexane:EtOAc, 6:4);
1H NMR (CDCl3, 200 MHz) δ 0.80-2.10 (m, 12H), 1.59 (d,
J = 7.3 Hz, 3H), 1.63 (d, J = 7.3 Hz, 3H), 2.00 (s, 3H), 2.04 (s,
3H), 3.70-4.15 (m, 10H), 4.29 (d, J = 14.5 Hz, 1H), 4.39 (d,
J = 14.4 Hz, 1H), 4.70 (d, J = 14.5 Hz, 1H), 4.84 (d,
J = 14.5 Hz, 1H), 5.78 (q, J = 7.1 Hz, 1H), 5.90 (q, J = 7.1 Hz,
1H), 7.17-7.50 (m, 20H); 13C NMR (CDCl3, 50 MHz) δ 16.2,
17.7, 21.1, 21.5, 28.3, 28.6, 33.9, 42.2, 43.3, 49.5, 52.6, 57.4,
63.9, 64.1, 126.9, 127.3, 127.7, 127.8, 128.2, 128.3, 128.6,
128.8, 129.0, 135.5, 138.9, 164.5, 164.8, 166.4, 166.7, 171.7,
174.1; ESI-MS: m/z = 445 ([M+Na]+, 100%), 446 (3%); ESI-MS
HR: m/z calcd for [M+Na]+, C25H30N2O4Na: 445.2103; Found:
445.2078.
Synthesis of 3-(hydroxyalkyl)-2,5-DKP derivatives 5.
General procedure 3. A solution of the acetate 4 (0.15 mmol)
in MeOH:H2O (9:1, 8 mL) was treated with KOH (0.30 mmol,
18 mg). The reaction mixture was sonicated for 20 min at rt,
then brine (5 mL) was added and the residue was extracted with
CH2Cl2 (3 × 10 mL). The combined organic phases were washed
with brine (30 mL), dried (MgSO4) and the solvent evaporated
in vacuo. The product 5 was purified on a silica gel column
(hexane:i-PrOH, 8:2).
general procedure
1 in 62% yield: white crystals; mp
1
100-102 °C; Rf = 0.37 (hexane:EtOAc, 6:4); H NMR (CDCl3,
200 MHz) δ 1.20-1.40 (m, 2H), 1.41-1.70 (m, 4H), 2.00 (s, 3H),
3.90 (s, 2H), 3.95 (t, J = 6.3 Hz, 2H), 4.35 (dd, J = 2.0 Hz,
J = 5.6 Hz, 2H), 4.67 (s, 2H), 4.93 (dd, J = 2.3 Hz, J = 6.0 Hz,
1H), 6.80 (t, J = 5.6 Hz, 1H), 7.08-7.40 (m, 10H); 13C NMR
(CDCl3, 50 MHz) δ 21.1, 23.0, 28.2, 28.4, 41.9, 43.6, 48.5, 58.4,
64.1, 125.9, 127.6, 127.8, 127.9, 128.8, 129.2, 136.7, 138.0,
168.9, 169.6, 171.1; IR (KBr) νmax: 3309 (C−Cl), 1727 (C=O),
1674 (C=O), 1640 (C=O) cm-1; UV-VIS λmax (ε; MeCN): 210
(19 400); Anal. Calcd for C24H29ClN2O4: C, 64.78; H, 6.57; N,
6.30; Found: C, 64.69; H, 6.61; N, 6.18.
4-Benzylcarbamoyl-4-[(2-chloroacetyl)-((S)-1-phenylethyl)-
amino]-butyl acetate (3c). The product was prepared according
to general procedure 1 in 78% yield as mixture of distereomeres:
Dr 50:50 (NMR); colourless oil; Rf = 0.34 (hexane:EtOAc, 6:4);
1H NMR (CDCl3, 200 MHz) δ 0.80-2.10 (m, 8H), 1.99 (s, 3H),
2.10 (s, 3H), 3.78 (t, J = 6.1 Hz, 4H), 4.00-4.30 (m, 12H), 4.47
(d, J = 5.3 Hz, 2H), 4.52 (d, J = 5.5 Hz, 2H), 4.80-5.20 (m, 2H),
7.00 (brs, 1H), 7.17-7.50 (m, 20H), 7.80 (brs, 1H); ESI-MS:
m/z = 467 ([M+Na]+, 100%), 469 (20%); ESI-MS HR: m/z calcd
for [M+Na]+, C24H29ClN2O4Na: 467.1713; Found: 467.1696.
5-Benzylcarbamoyl-5-[(2-chloroacetyl)-((S)-1-phenylethyl)-
amino]-pentyl acetate (3d). The product was prepared
according to general procedure 1 in 85% yield as mixture of
distereomeres: Dr 50:50 (NMR); colourless oil; Rf = 0.32
1
(hexane:EtOAc, 6:4); H NMR (CDCl3, 200 MHz) δ 0.80-2.10
(m, 12H), 1.99 (s, 3H), 2.10 (s, 3H), 3.78 (t, J = 6.1 Hz, 4H),
4.00 – 4.30 (m, 12H), 4.47 (d, J = 5.3 Hz, 2H), 4.52 (d,
J = 5.5 Hz, 2H), 4.80-5.20 (m, 2H), 7.00 (brs, 1H), 7.1-7.50 (m,
20H), 7.80 (brs, 1H); ESI-MS: m/z = 481 ([M+Na]+, 100%), 483
(30%); ESI-MS HR: m/z calcd for [M+Na]+, C25H31ClN2O4Na:
481.1870; Found: 481.1888.
Synthesis of 2,5-DKP acetate derivatives 4. General
procedure 2. Cs2CO3 (8.00 mmol, 3.540 g) was added to a
solution of the aminoamide 3 (3.90 mmol) in MeCN (50 mL).
After stirring at rt for 2 h, the solution was acidified with 2 M
HClaq to pH = 5 and the solvent was evaporated in vacuo. The
resulting residue was extracted with CH2Cl2 (3 × 30 mL) and the
combined organic layers were dried (MgSO4). The solvent was
evaporated in vacuo and product 4 was purified on a silica gel
column (hexane:EtOAc, 6:4).
1,4-Dibenzyl-3-(3-acetoxypropyl)-piperazine-2,5-dione (4a).
The product was prepared according to general procedure 2 in
92% yield: white crystals; mp 95-96 °C (EtOAc/hexane);
1
Rf = 0.37 (hexane:EtOAc, 6:4); H NMR (CDCl3, 200 MHz) δ
1.51-1.70 (m, 2H), 1.71-2.00 (m, 2H), 2.10 (s, 3H), 3.80-4.18
(m, 5H), 4.15 (d, J = 15.0 Hz, 1H), 4.45 (d, J = 14.4 Hz, 1H),
4.88 (d, J = 14.4 Hz, 1H), 5.26 (d, J = 14.9 Hz, 1H), 7.20-7.50
(m, 10H); 13C NMR (CDCl3, 50 MHz) δ 21.1, 24.0, 28.7, 47.6,
49.2, 40.7, 59.2, 63.5, 128.3, 128.4, 128.5, 129.1, 135.3, 135.5,
1,4-Dibenzyl-3-(3-hydroxy-propyl)-piperazine-2,5-dione (5a).
The product was prepared according to general procedure 3 in
74% yield: colourless oil; Rf = 0.32 (hexane:i-PrOH, 8:2);

770
A. Fryszkowska and R. Ostaszewski
Vol 45
1H NMR (CDCl3, 200 MHz) δ 1.20-1.60 (m, 2H), 1.70-2.00 (m,
2H), 2.50 (brs, 1H), 3.47 (t, J = 6.0 Hz, 2H), 3.71-3.98 (m, 3H),
3.97 (d, J = 14.7 Hz, 1H), 4.30 (d, J = 14.4 Hz, 1H), 4.70 (d,
J = 14.4 Hz, 1H), 5.12 (d, J = 14.9 Hz, 1H), 7.14-7.40 (m, 10H);
13C NMR (CDCl3, 50 MHz) δ 27.4, 28.6, 47.4, 49.1, 59.6, 59.1,
61.8, 128.1, 128.3, 128.4, 129.0, 129.1, 135.1, 135.5, 164.2,
166.5; ESI-MS: m/z = 353 ([M+H]+, 40%), 375 ([M+Na]+,
100%), 376 (8%); ESI-MS HR: m/z calcd for [M+Na]+,
C21H24N2O3Na: 375.1684; Found: 375.1699; UV-VIS λmax (ε;
MeCN): 257 (420), 209 (16 500); Anal. Calcd for
C21H24N2O3·0.4H2O: C, 70.13; H, 6.95; N, 7.79; Found:
C, 70.80; H, 6.80; N, 7.31.
1,4-Dibenzyl-3-(4-hydroxy-butyl)-piperazine-2,5-dione (5b).
The product was prepared according to general procedure 3 in
92% yield: colourless oil; Rf = 0.34 (hexane:i-PrOH, 8:2);
1H NMR (CDCl3, 200 MHz) δ 1.20-2.00 (m, 6H), 3.52 (t,
J = 6.0 Hz, 2H), 3.79-4.00 (m, 3H), 4.05 (d, J = 14.7 Hz, 1H),
4.34 (d, J = 14.4 Hz, 1H), 4.80 (d, J = 14.4 Hz, 1H), 5.17 (d,
J = 14.9 Hz, 1H), 7.20-7.60 (m, 10H); 13C NMR (CDCl3,
50 MHz) δ 20.7, 31.7, 32.1, 47.4, 49.2, 49.6, 59.5, 62.0, 127.8,
128.2, 128.3, 128.5, 128.7, 129.0, 129.1, 135.2, 135.2, 125.6,
164.3, 166.4; ESI-MS: m/z = 367 ([M+H]+, 40%), 389
([M+Na]+, 100%); ESI-MS HR: m/z calcd for [M+Na]+,
C22H26N2O3Na: 389.1836; Found: 389.1838; UV-VIS λmax
(ε; MeCN): 258 (420), 209 (21 700).
colourless oil: [α]D26 = –4.0 (c 0.93, CH2Cl2); Rf = 0.14
[
!
]
1
(hexane:i-PrOH, 8:2); H NMR (CDCl3, 200 MHz) δ 0.80-2.00
(m, 6H), 1.63 (d, J = 7.1 Hz, 3H), 3.58 (t, J = 6.0 Hz, 2H), 3.73
(dd, J = 4.1 Hz, J = 8.7 Hz, 1H), 3.78 (d, J = 17.4 Hz, 1H), 4.00
(d, J = 17.2 Hz, 1H), 4.38 (d, J = 14.4 Hz, 1H), 4.71 (d,
J = 14.5 Hz, 1H), 5.78 (q, J = 7.1 Hz, 1H), 7.10-7.40 (m, 10H);
13C NMR (CDCl3, 50 MHz) δ 17.7, 21.3, 32.3, 34.1, 49.5, 49.7,
52.6, 57.4, 62.3, 127.3, 128.1, 128.2, 128.3, 128.8, 129.0, 135.5,
138.9, 164.9, 166.9; ESI-MS: m/z = 381 ([M+H]+, 28%), 403
([M+Na]+, 100%), 783 ([2M+Na]+, 25%); ESI-MS HR: m/z
calcd for [M+Na]+, C23H28N2O3Na: 403.1997; Found: 403.2012.
One step cyclisation and hydrolysis of N-chloroacetyl
aminoamide derivatives 3 to alcohols 5. General procedure
4. NaOH (5.20 mmol, 291 mg) was added to a solution of
aminoamide 3 (1.70 mmol) in MeOH:H2O (9:1, 45 mL). The
reaction mixture was stirred at rt until completed as determined
by TLC analysis. Brine (5 mL) was added and the reaction
mixture was extracted with CH2Cl2 (3 × 10 mL). The combined
organic phases were washed with brine (30 mL), dried (MgSO4)
and the solvent was evaporated in vacuo. Product 5 was purified
on a silica gel column (hexane:i-PrOH, 8:2). Yields are given in
Scheme 2.
Solution phase synthesis of 2,5-DKPs from tetrahydropyran-
2-ol (7).
1-Benzyl-3-(3-hydroxy-propyl)-4-((1'S)-1-phenylethyl)-
piperazine-2,5-dione ((1'S,3RS)-5c). The product was prepared
according to general procedure 3 in 99% yield: colourless oil; Dr
50:50 (NMR); Rf1 = 0.24; Rf2 = 0.15 (hexane:i-PrOH, 8:2);
1H NMR (CDCl3, 200 MHz) δ 0.80-2.00 (m, 8H), 1.59 (d,
J = 7.1 Hz, 3H), 1.64 (d, J = 7.2 Hz, 3H), 2.2 (s, 2H), 3.21 (t,
J = 6.0 Hz, 2H), 3.56 (t, J = 5.2 Hz, 2H), 3.75 (d, J = 17.1 Hz,
1H), 3.80 (d, J = 17.2 Hz, 1H), 3.92 (d, J = 17.2 Hz, 1H), 3.82
(dd, J = 4.0 Hz, J = 9.3 Hz, 1H), 4.01 (d, J = 17.4 Hz, 1H), 4.12
(dd, J = 3.6 Hz, J = 9.0 Hz, 1H), 4.30 (d, J = 14.5 Hz, 1H), 4.41
(d, J = 14.5 Hz, 1H), 4.67 (d, J = 14.5 Hz, 1H), 4.81 (d,
J = 14.4 Hz, 1H), 5.79 (q, J = 7.1 Hz, 1H), 5.88 (q, J = 7.1 Hz,
1H ), 7.16-7.50 (m, 20H); 13C NMR (CDCl3, 50 MHz) δ 16.2,
17.6, 27.9, 28.0, 29.7, 30.9, 49.5, 49.6, 49.7, 49.8, 51.5, 52.5,
56.9, 57.0, 61.9, 62.0, 127.2, 127.3, 128.2, 128.3, 128.4, 128.7,
128.8, 129.0, 129.1, 135.3, 135.5, 139.1, 139.3, 164.4, 164.9,
167.1, 167.2; UV-VIS λmax (ε; MeCN): 257 (380), 210 (17 600);
Anal. Calcd for C22H26N2O3⋅1H2O: C, 68.73; H, 7.34; N, 7.29;
Found: C, 69.15; H, 7.40; N, 7.08.
Tetrahydropyran-2-ol
2,3-dihydropyran in 85% yield, according to the published
procedure [25].
(7)
was
obtained
from
Synthesis of chloroacetyl aminoamides 11 and 12. To a
solution of tetrahydropyran-2-ol (7, 2.00 mmol, 202 mg) in
methanol (8 mL) at 0 °C, benzylamine (1.00 mmol, 110 µl),
benzyl isocyanide (1.00 mmol, 117 mg) and chloroacetic acid (1.0
mmol, 95 mg) were added sequentially within 15 min intervals.
The mixture was stirred at rt for 5 days. Then the solvent was
evaporated, and the resulting slurry was dissolved in EtOAc (50
mL) and washed with NaOHaq (1 M, 30 mL), HClaq (1 M, 30 mL)
and brine (30 mL). The organic phase was dried (MgSO4) and the
solvent was evaporated in vacuo. The resulting residue was
purified on a silica gel column to give two fractions: a THP-
derivative 12 in 6% yield (hexane:EtOAc, 8:2 → 6:4) and a
respective alcohol 11 in 74% yield (CHCl3:MeOH, 95:5 → 8:2).
2-[Benzyl-(2-chloroacetyl)-amino]-6-hydroxy-hexanoic
acid benzylamide (11). 74% yield: colourless oil; Rf = 0.33
1
(CHCl3:MeOH, 8:2); H NMR (CDCl3, 200 MHz) δ 1.20-1.60
1-Benzyl-3-(4-hydroxy-butyl)-4-((1'S)-1-phenylethyl)-piper-
azine-2,5-dione ((1'S,3RS)-5d). The product was prepared
according to general procedure 3 in 92% yield: colourless oil; Dr
50:50 (NMR); Rf1 = 0.26; Rf2 = 0.14 (hexane:i-PrOH, 8:2); an
analytical sample was separated into diastereoisomers by PTLC
(hexane:i-PrOH, 85:15, developed 3 times). (1'S,3R)-5d:
colourless oil: [α]D26 = –137.4 (c 0.76, CH2Cl2); Rf = 0.26
(hexane:i-PrOH, 8:2); H NMR (CDCl3, 200 MHz) δ 0.80-1.80
(m, 6H), 1.59 (d, J = 7.1 Hz, 3H), 3.36 (t, J = 6.0 Hz, 2H), 3.76
(d, J = 17.2 Hz, 1H), 3.92 (d, J = 17.2 Hz, 1H), 3.99 (dd,
J = 3.8 Hz, J = 8.7 Hz, 1H), 4.29 (d, J = 14.5 Hz, 1H), 4.84 (d,
J = 14.4 Hz, 1H), 4.86 (d, J = 14.5 Hz, 1H), 5.91 (q, J = 7.1 Hz,
1H), 7.16-7.50 (m, 10H); 13C NMR (CDCl3, 50 MHz) δ 16.3,
21.0, 31.9, 49.6, 49.9, 51.4, 57.1, 62.3, 127.4, 128.2, 128.3,
128.4, 128.8, 128.9, 129.0, 135.6, 139.0, 164.6, 167.2; ESI-MS:
m/z = 381 ([M+H]+, 12%); 403 ([M+Na]+, 100%), 783
([2M+Na]+, 15%); ESI-MS HR: m/z calcd for [M+Na]+,
C23H28N2O3Na: 403.1997; Found: 403.2011. (1'S,3S)-5d:
(m, 5H), 1.80-2.00 (m, 1H), 2.45 (brs, 1H), 3.42 (t, J = 6.2 Hz,
2H), 3.81 (s, 2H), 4.27 (d, J = 5.6 Hz, 2H), 4.63 (s, 2H), 4.93
(dd, J = 2.3 Hz, J = 6.2 Hz, 1H), 7.00-7.30 (m, 11H); 13C NMR
(CDCl3, 50 MHz) δ 22.5, 28.4, 32.1, 42.0, 44.5, 48.4, 58.2, 62.1,
125.8, 127.3, 127.7, 128.6, 128.5, 129.0, 136.7, 137.9, 168.2,
168.7; ESI-MS: m/z = 403 ([M+H]+, 22%), 405 (4%), 425
([M+Na]+, 100%), 427 (15%); ESI-MS HR: m/z calcd for
[M+Na]+, C22H27ClN2O3Na: 425.1602; Found: 425.1630; Anal.
Calcd for C22H27ClN2O3·0.5H2O: C, 64.15; H, 6.85; N, 6.80;
Found: C, 64.38; H, 6.94; N, 6.51.
[
!
]
1
2-[Benzyl-(2-chloroacetyl)-amino]-6-(tetrahydropyran-2-
yloxy)-hexanoic acid benzylamide (12). 6% yield: colourless
1
oil; Rf = 0.71 (CHCl3:MeOH, 8:2); H NMR (CDCl3, 200 MHz)
δ 1.20-1.79 (m, 11H), 1.80-2.00 (m, 1H), 3.15-3.29 (m, 1H),
3.30-3.45 (m, 1H), 3.50-3.65 (m, 1H), 3.66-3.80 (m, 1H), 3.81
(s, 2H), 4.27 (d, J = 5.6 Hz, 2H), 4.51 (s, 1H), 4.63 (s, 2H), 4.91
(t, J = 7.1 Hz, 1H), 7.00-7.30 (m, 11H); 13C NMR (CDCl3,
50 MHz) δ 18.8, 23.1, 25.5, 28.5, 29.4, 21.8, 41.9, 43.4, 48.3,

May-Jun 2008
Synthesis of Bicyclomycin Precursors In Solution And On Solid Phase
771
Table 2
The analysis of resins 18.
Resin Composition
58.3, 62.4, 67.0, 98.7, 98.9, 125.7, 127.3, 127.6, 128.5, 128.9,
136.7, 137.9, 168.6, 169.6; ESI-MS: m/z = 509 ([M+Na]+,
100%), 511 (15%); ESI-MS HR: m/z calcd for [M+Na]+,
C27H35ClN2O4Na: 509.2183; Found: 509.2163.
Entry
IR [cm-1]
(C=O)
C
H
N
X
[%]
[%] [%] [%]
Synthesis of 1,4-dibenzyl-3-(4-hydroxy-butyl)-piperazine-
2,5-dione (5b) from chloroacetoxyamide 11. The product 5b
was synthesised from 11 according to general procedure 2 via
Cs2CO3–catalysed cyclisation in 50% yield or according to
general procedure 4 (NaOH–catalysed cyclisation) in 55% yield.
The spectroscopic data were identical to those described
previously.
Synthesis of 1,4-dibenzyl-3-(4-hydroxy-butyl)-piperazine-
2,5-dione (5b) from the aminoamide 12. A solution of the
amide 12 (0.26 mmol, 126 mg) and p-TsOH (cat.) in MeOH
(5 mL) was stirred at rt for 2 h until completion as determined
by TLC analysis. NaHCO3 (10 mg) and ethyl ether (25 mL)
were added. The resulting mixture was filtered through a celite
plug and the solvent was evaporated in vacuo. The crude product
11 was dissolved in MeCN (5 mL) and Cs2CO3 (0.62 mmol,
202 mg) was added. After stirring at rt for 2h, the solution was
acidified with 2M HClaq to pH = 5 and the solvent was
evaporated. The residue was extracted with CH2Cl2 (3 × 30 mL),
the combined organic phases were dried (MgSO4) and the
solvent was evaporated. The product 5b was purified on a silica
gel column (CHCl3:MeOH, 100:2) to give colourless oil in 54%
yield. The spectroscopic data were identical to those described
previously.
1
2
3
4
18a
18b
18c
18d
84.55 7.12 1.24 1.02 (Cl)
84.35 7.61 1.76 0.51 (Cl)
86.56 7.08 1.32 3.72 (Br)
83.64 6.98 1.55 2.46 (I)
1658 (br)
1656 (br)
1677, 1651
1672, 1660
Wang resin-bound 4-hydroxybutan-1-al (16a). The resin
was prepared according to general procedure 7. Anal. Found: C,
85.79; H, 7.59; N, 0.00; IR (KBr) νmax: 1722 (C=O) cm-1;
loading 0.59 mmol.g-1.
Wang resin-bound 5-hydroxypentan-1-al (16b). The resin
was prepared according to general procedure 7. Anal. Found: C,
84.85; H, 7.43; N, 0.22; IR (KBr) νmax: 1722 (C=O) cm-1;
loading 0.50 mmol.g-1.
Determination of the loading of Wang resin-bound
aliphatic aldehydes (17). General procedure 8. The Wang
resin 16 (0.12 g) was washed carefully with anhydrous
ethanol, then ethanol (2.5 mL) and phenylhydrazine (2 mmol,
200 µl) were added. The mixture was refluxed for 4 h. The
solution was filtered and the resin was washed with ethanol,
CH2Cl2, ethyl ether, THF, then dried in vacuo. The entire
procedure was repeated to give resin 17. The loading of the
aldehyde 16 was determined on the basis of the nitrogen
composition in elemental analysis of 17.
General procedure for the Ugi reaction on solid phase.
Synthesis of the resin 18. General procedure 9. To a
suspension of the resin 16 (400 mg, ~0.20 mmol) in
Solid phase synthesis.
Wang resin (13) used for the solid phase synthesis: loading
~1 mmol.g-1; Anal. Found: C, 87.56; H, 7.36; N, 0.00; IR (KBr)
νmax: 3500 (O−H) cm-1).
CH2Cl2:MeOH (2:1,
6 mL) benzylamine (10 eq), benzyl
isocyanide (10 eq) and acid (10 eq) were added. The mixture
was stirred at rt for 5 days. The solution was filtered off and the
resin was washed with THF, methanol, CH2Cl2, ethyl ether,
THF, then dried in vacuo. The elemental analysis and IR bands
of the resulting resins 18 are given in Table 2. Yields were
estimated on the basis of the nitrogen composition (by EA) in
respect to the loading of the aldehydes 16.
The Wang trichloroacetimidate resin (14). The Wang
trichloroacetimidate resin (14) was prepared according to the
procedure described by Hanessian et al. [28]. Anal. Found: C,
77.32; H, 5.93; N, 1.31; IR (KBr) νmax: 1663 (C=NH) cm-1.
Synthesis of the Wang resin-bound α,ω-diols (15).
General procedure 6 [28]. The trichloroacetimidate resin (14,
0.90 g) was washed twice with anhydrous THF under an inert
gas atmosphere. The resin was suspended in anhydrous
cyclohexane (10 mL) and α,ω-diol (1, 9.00 mmol) in anhydrous
CH2Cl2 (10 mL) was added. After stirring for 5 min at rt
BF3⋅Et2O (125 µl) was added and the stirring was continued for
10 min. The resin 15 was washed with CH2Cl2, ethyl ether, THF,
then dried in vacuo.
Wang resin-bound 1,4-butanediol (15a). The resin was
prepared according to general procedure 6. Anal. Found:
C, 85.98; H, 7.55; N, 0.00; IR (KBr) νmax: 3444 (O−H) cm-1.
Wang resin-bound 1,5-pentanediol (15b). The resin was
prepared according to general procedure 6. Anal. Found: C,
84.74; H, 7.62; N, 0.35; IR (KBr) νmax: 3500 (O−H) cm-1.
Synthesis of the Wang resin-bound aliphatic aldehydes
(16). General procedure 7. The resin 15 (0.80 g) was purged
with argon for 30 min and anhydrous DMSO (5 mL) was added.
In another flask Py⋅SO3 complex (12.4 mmol, 1.97 g) was
purged with argon for 10 min and Et3N (7.5 mL) and anhydrous
DMSO (10 mL) were added. After stirring for 15 min, the
Py⋅SO3 solution was cannulated to a suspension of the resin 15
in DMSO. The resulting mixture was stirred for 3h at rt. The
reaction mixture was filtered off and the resin 16 was washed
with CH2Cl2, ethyl ether and THF. The entire procedure was
repeated.
Synthesis of 5-benzylcarbamoyl-5-[benzyl-(2-trifluoro-
acetyl)-amino]-pentyl acetate (3e). To a suspension of the resin
18b (450 mg, ~0.225 mmol) in CH2Cl2 a solution of 10% TFA
in anhydrous CH2Cl2 (8 mL) was added. The mixture was stirred
at rt for 4 h. Na2CO3 (100 mg) was added and the stirring was
continued for 30 min. The solution was filtered and the resin
was washed carefully with CH2Cl2, ethyl ether, THF. The
combined organic solution was concentrated in vacuo and the
product 3e was isolated on a silica gel column (hexane:EtOAc,
7:3). Yield 17%: colourless oil; Rf = 0.80 (CHCl3:MeOH,
1
85:15); H NMR (CDCl3, 200 MHz) δ 1.20-1.80 (m, 5H), 1.90-
2.10 (m, 1H), 3.96 (s, 2H), 4.25 (t, J = 6.4 Hz, 2H), 4.27 (d,
J = 5.0 Hz, 2H), 4.68 (s, 2H), 4.92 (dd, J = 1.8 Hz, J = 6.6 Hz,
1H), 6.81 (t, J = 6.0 Hz, 1H), 7.00-7.30 (m, 10H); 13C NMR
(CDCl3, 50 MHz) δ 22.5, 28.4, 32.1, 42.0, 44.5, 48.4, 58.2, 62.1,
125.8, 127.3, 127.7, 128.6, 128.5, 129.0, 136.7, 137.9, 168.2,
168.7; ESI-MS: m/z = 521 ([M+Na]+, 100%), 523 (20%);
ESI-MS HR: m/z calcd for [M+Na]+, C24H26F3ClN2O4Na:
521.1425; Found: 521.1438.
Synthesis of the 2,5-DKP alcohol derivatives 5. General
procedure 10. To a suspension of the resin 18 (180 mg, ~0.125
mmol) in CH2Cl2 a solution of 10% TFA in anhydrous CH2Cl2
(8 mL) was added. The mixture was stirred at rt for 4 h. Na2CO3
(100 mg) was added and the stirring was continued for 30 min.

772
A. Fryszkowska and R. Ostaszewski
Vol 45
[8] Williams, R. M. Synthesis of Optically Active a-Amino Acids;
Pergamon Press, Inc.: Oxford, 1989.
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6532-6536.
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The solution was filtered and the resin was washed carefully
with CH2Cl2, ethyl ether and THF. The combined organic
solution was concentrated in vacuo. The crude product was
dissolved in THF:H2O (6 mL, 2:1) and treated with NaOH
(0.300 mmol, 12 mg). The mixture was stirred at rt overnight
and then acidified with 10% HCl to pH = 5. The resulting
residue was extracted with CH2Cl2 (3 × 10 mL), the combined
organic phases were dried (MgSO4) and concentrated in vacuo.
The product 5 was filtered through a silica gel plug (CH2Cl2 →
CH2Cl2:MeOH, 9:1). The purity of the compounds 5 was
determined by HPLC using a Kromasil Si 60 column (4.6 mm φ
×
250 mm, Eka Chemical). HPLC analysis parameters:
MeCN:H2O, 4:7; λ = 207 nm, 1.0 mL/min; Rt = 8.7 min. Yields
and purities are given in Table 2. The analytical data of 5a-b
were the same as those described previously.
Acknowledgments. This work was supported Polish State
Committee for Scientific Research, Grant PBZ –KBN
126/T09/07.
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1730.
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