Syntheses of hapalosin analogs by solid-phase assembly of acyclic precursors

Article abstract of DOI:10.1016/S0040-4020(01)00903-6

The paper details the synthesis of hapalosin analogs 4 (cyclic depsipeptides) using solid-phase chemistry. Key building blocks were the Fmoc-protected γ-amino-β-hydroxy acid 11 and the THP-protected syn-β-hydroxy acids 18. The amino acid 11 was fashioned from the amine 6 which was obtained by an ADH-route. The protected amino acids 18 were prepared by Evans aldol reactions. Esterification of 18 with the Wang resin started the solid-phase assembly of the depsipeptides 25 containing all the building blocks. A final solution-phase deprotection of the amino group followed by macrolactamization completed the synthesis of the analogs 4. In one instance (compound 4aaa) the conformation was studied using ROESY NMR spectroscopy and MD simulation. This revealed an almost complete (93:7) preference for the s-cis-rotamer.

Full text of DOI:10.1016/S0040-4020(01)00903-6

TETRAHEDRON
Pergamon
Tetrahedron 57 (2001) 8999±9010
Syntheses of hapalosin analogs by solid-phase assembly of
acyclic precursors
Christoph Hermann,a Chiara Giammasi,a Armin Geyerb and Martin E. Maiera,p
a
È È
Institut fur Organische Chemie, Universitat Tubingen, Auf der Morgenstelle 18, D-72076 Tubingen, Germany
Institut fur Organische Chemie, Universitat Regensburg, D-93040 Regensburg, Germany
È
È
b
È
È
Received 15 June 2001;revised 27 August 2001;accepted 5 September 2001
AbstractÐThe paper details the synthesis of hapalosin analogs 4 (cyclic depsipeptides) using solid-phase chemistry. Key building blocks
were the Fmoc-protected g-amino-b-hydroxy acid 11 and the THP-protected syn-b-hydroxy acids 18. The amino acid 11 was fashioned from
the amine 6 which was obtained by an ADH-route. The protected amino acids 18 were prepared by Evans aldol reactions. Esteri®cation of 18
with the Wang resin started the solid-phase assembly of the depsipeptides 25 containing all the building blocks. A ®nal solution-phase
deprotection of the amino group followed by macrolactamization completed the synthesis of the analogs 4. In one instance (compound 4aaa)
the conformation was studied using ROESY NMR spectroscopy and MD simulation. This revealed an almost complete (93:7) preference for
the s-cis-rotamer. q 2001 Elsevier Science Ltd. All rights reserved.
1. Introduction
didemnin,8 sanglifehrin A,9 the AM-toxins I±III,7 the
cryptophycins (1),10 jasplakinolide (2),11 and hapalosin (3)
(Fig. 1).12
The importance of natural products for biochemistry and
medicine is undisputed. Quite often natural products serve
as biochemical tools or they lead to the discovery of a
hitherto unknown biochemical pathway or molecular target.
Nevertheless, in the context of the human genome project it
was speculated that there might not be enough natural
products to probe the functions of all genes via selective
interaction of natural products with the corresponding
proteins.1 On the other hand natural products offer
structurally interesting platforms, that might be used to
produce natural product-like molecules. This way the
chances of discovering novel modes of biological activity
might be higher. With a view towards applying parallel or
combinatorial synthesis strategies, natural products that are
characterized by a modular built are obvious starting
points.2 Some representative examples include the indo-
lactam library of Waldmann et al.,3 the prostaglandin library
of Janda,4 the muscone library of Nicolaou,5 or the
carpanone library of Shair.6 In this regard we have targeted
the class of cyclic depsipeptides.7 In these compounds one
or more amide bonds are replaced with ester bonds. Very
often depsipeptides contain unusual hydroxy acids or amino
acids that pose a certain challenge from a synthetic point of
view. Among the depsipeptides one might point out
In making these compounds even more peptide-like, some
of the ester bonds could be replaced by amide bonds.
Guided by the above-mentioned reasoning we became
interested in the depsipeptide hapalosin (3). This natural
compound is able to reverse multidrug resistance (MDR)
in tumor cells. The phenomenon of MDR is caused by
over-expression of the MDR1 gene that encodes for a
170 kDa P-glycoprotein. By virtue of its ability to block
this transmembrane protein, hapalosin is an interesting
lead compound for the development of drugs that can
cope with resistant tumor cells. In fact, several syntheses
of the natural product as well as some analogs have been
reported.13 Our own work in this area has resulted in two
syntheses for the g-amino-b-hydroxy acid B, whereby the
®rst one is based on an Evans aldol/Curtius combination14
and in the second route a Sharpless asymmetric dihydroxyl-
ation of an allylic chloride came to use.15 In addition, we
had reported the synthesis of hapalosin itself and some
ring expanded analogs.16 Due to its molecular structure
hapalosin appears as a promising macrocycle for modi®ca-
tions in a parallel fashion. Taking into consideration our
experience in the hapalosin area we decided to follow a
strategy as shown in Fig. 2.
Thus, we planned to prepare some b-hydroxy acids A using
an Evans aldol reaction. Also, we planned to replace the
a-hydroxy acids with a range of a-amino acids C. While
the syntheses of the g-amino-b-hydroxy acid B would allow
Keywords: conformation;depsipeptides;macrocycles;NMR;peptide
analogues;solid-phase synthesis.
Corresponding author. Tel.: 149-7071-29-75247;fax: 149-7071-29-
5137;e-mail: martin.e.maier@uni-tuebingen.de
p
0040±4020/01/$ - see front matter q 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(01)00903-6

9000
C. Hermann et al. / Tetrahedron 5702001) 8999±9010
Figure 1. Structure of some representative cyclic depsipeptides.
Figure 2. Design of hapalosin analogs suitable for parallel synthesis. The a-hydroxy acid is replaced by an a-amino acid.
for modi®cations at position 9, in the present study we
restricted ourselves to the benzyl group. Another issue
concerns the macrocycle bond formation. In principle, the
synthesis of cyclic ring systems can be approached using
various strategies,17 such as the classical solution phase
head-to-tail cyclization, the solid phase cyclorelease
strategy18 or on-support cyclization using backbone or side-
chain attachment,19 respectively. We opted for the solid
phase assembly of the cyclization precursor. This approach
would also allow to probe a cyclorelease macrolactamiza-
tion. In the case of hapalosin, generally the amide bond is
being formed. However, due to the secondary amine, the
yields for the cyclization are moderate. By replacing the
a-hydroxy acid with an amino acid the corresponding
amide bond presents itself for the site of the ®nal macro-
cyclization. At the same time, this choice determines the
component that will be attached at ®rst onto the solid
phase. With an ester bond present, the ®nal cleavage of an
assembled cyclization precursor cannot be done by trans-
esteri®cation, but rather has to be done under acidic
conditions, therefore the choice of the Wang resin. Because
of the nature of the resin, the use of the boc protecting group
would also not be optimal, since in the assembly process,
cleavage of a boc group under strong acidic conditions
could harm the Wang ester bond. Therefore, we opted for
a combination of the tetrahydropyranyl- and Fmoc
protective groups.
2. Results and discussion
2.1. Synthesis of the Fmoc-amino acid 11
The solid-phase assembly on the Wang resin required the
synthesis of the Fmoc-protected g-amino-b-hydroxy acid
11. This compound was prepared by branching from our
previously described route (Scheme 1). Thus, the amine 6,
available via an asymmetric dihydroxylation route,15 was
converted to the formamide 7. Hydride reduction of the
amide 7 provided the N-methylamine 8 in good yield.
After removal of the benzyl protecting group by transfer
hydrogenation, treatment of the amino alcohol 9 with
9-¯uorenylmethylchloroformate gave the Fmoc protected
amine 10. A ®nal oxidation step with sodium hypochlorite
delivered the desired amino acid 11.
2.2. Synthesis of b-hydroxy acids by Evans aldol reaction
As another prelude to the solid-phase chemistry a few THP-
protected b-hydroxy acids 18 were fashioned by Evans
aldol reaction.20 Starting with the known oxazolidinone
12,21 the sequence of deprotonation with n-butyllithium
followed by treatment with the acid chlorides 13a and 13b
or with the mixed anhydride of 13c gave the acylated
oxazolidinones 14a±14c (Scheme 2). The chiral amide
derivatives were then converted to the b-hydroxy carbonyl

C. Hermann et al. / Tetrahedron 5702001) 8999±9010
9001
Scheme 1. Synthesis of the Fmoc-protected N-methyl amino acid 11.
Scheme 2. Synthesis of the THP-protected hydroxy acids 18 by Evans aldol reaction.
Scheme 3. Assembly of the acyclic depispeptide 24 by solid-phase synthesis.

9002
C. Hermann et al. / Tetrahedron 5702001) 8999±9010
compounds 18aa, 18ba, 18cb, 18ca under standard condi-
tions. Thus, conversion of 14a±14c to the corresponding
boron enolates followed by addition of an aldehyde (15a,
15b, respectively) and oxidative work-up gave the syn-aldol
products 16aa, 16ba, 16cb, 16ca in high yield. The main
diastereomer accounted for greater than 95% of the isolated
product. Protection of the hydroxy group with dihydro-
pyran22 followed by removal of the chiral auxiliary under
basic conditions provided the THP-protected hydroxy acids
18aa, 18ba, 18cb, 18ca. It should be noted that the Evans
aldol reaction has been used recently to generate a collection
of chiral 1,3-diols that were channeled into a library of
tetrahydrooxazepines.23
by GC±MS through observation of the peak at m/zˆ116
which corresponds to 2-methoxytetrahydro-2H-pyran.25
While this method is quite ef®cient a chromophoric THP-
derivative would be an useful alternative. The assembly was
continued by adding the Fmoc-protected amino acid 11
(3 equiv.) and MSNT to the resin mixture. At this stage
the loading could be estimated via monitoring the release
of the Fmoc group upon addition of piperidine. It turned out
that longer reaction times (30 min) caused some cleavage of
the ester bond between 20 and 11, possibly via lactam
formation or b-elimination. In experiments where R2 was
a vinylic group even complete hydrolysis of the ester group
occurred.
With the Fmoc group removed, an amide bond was estab-
lished by reacting the N-methylamine 22 with Fmoc-
protected a-amino acids 23a±c. Knowing that the coupling
of N-methyl amino groups is rather dif®cult we relied on the
use of bromo-tris-pyrrolidino-phosphonium hexa¯uoro-
phosphate (PyBroP) in combination with diisopropylethyl-
amine.26 In some cases these couplings were run twice in
order to drive them to completion. As could be judged
from the deprotections of aliquots, these coupling went
with high ef®ciency. A summary of the coupling ef®ciencies
for all compounds and a series of steps is depicted in
Table 1.
2.3. Solid-phase assembly
With all the building blocks in hand, we undertook the
parallel synthesis of hapalosin analogs (Scheme 3). The hy-
droxy acids 18 were esteri®ed with the Wang resin (capaci-
tyˆ1.3 mmol/g) using 1-mesitylene-2-sulfonyl)-3-nitro-
1H-1,2,4-triazole (MSNT) in the presence of methylimida-
zole.24 The acids 18aa, 18ba, 18cb, 18ca and the other
reagents were used in a three-fold excess. In order to
achieve good swelling of the resin, the deprotection of the
THP group was done in a mixture of methanol/dichloro-
methane. The progress of the deprotection was monitored
Table 1. Coupling yields for the condensation reactions yielding to the hapalosin analogs 4
Substitution
pattern
Wang resin
(mmol)
Yield of
resin 21
(%)a
Yield of
resin 24
(%)a
Yield of
amino acid 25
(%, mmol)
Yield of
macrocycle 4
(%, mmol)b
aaa
aab
aac
baa
cba
caa
0.10
0.20
0.20
0.20
0.20
0.20
60
100c
85e
33, 0.02
82, 0.14f
90, 0.18f
30, 0.036
21, 0.028
53, 0.10
60, 0.012
33, 0.046
44, 0.080
64, 0.023
43, 0.012
57, 0.057
100d
100d
100d
100
100e
60c
65c
100
95e
a
Yields were estimated spectrophotometrically by measurement of the Fmoc group, released from the resin by treatment with 20% piperidine in DMF (for
details see Section 5).
The yield is based on compounds 25.
Deprotection of the amino group before coupling with amino acid 23 was executed with a cleavage time of 30 min. This resulted in lower yields because of
hydrolysis of the ester bound between building block 20 and 11. In experiments where R2 was a vinylic group complete hydrolysis of the ester group
occurred.
The calculation in these cases suggests a higher initial loading.
Deprotection of the amino group before coupling with amino acid 23 was executed with a cleavage time of 5 min.
Yield of the crude product which was used without further puri®cation for subsequent deprotection and cyclization.
b
c
d
e
f
Scheme 4. Synthesis of the cyclization substrate 5 and the solution phase macrocyclization to the hapalosin analogs 4.

C. Hermann et al. / Tetrahedron 5702001) 8999±9010
9003
Table 2. Peak assignments for the 1H and 13C NMR spectra of 4aaa
measured in DMSO-d6
Preliminary experiments showed that the sequence of Fmoc
deprotection and acid treatment resulting in the amino acid
5aaa is not optimal since this amino acid is dif®cult to purify
by chromatography. Unfortunately, the Fmoc deprotection
did not lead to cleavage from the resin in a cyclorelease
amide formation. Therefore, cleavage from the resin was
done prior to the removal of the Fmoc protecting group.
Under the conditions used (TFA/CH2Cl2) the MOM protect-
ing group was also cleaved. The Fmoc-protected amino
acids 25 proved to be quite pure, thus demonstrating the
ef®ciency of the solid-phase assembly. They were charac-
terized by NMR spectroscopy and mass spectrometry. After
chromatographic puri®cation, treatment of the amino acids
25 with diethylamine in THF followed by concentration in
vacuo to remove the ¯uorenylamine adduct gave the amino
acids 5 (Scheme 4).
C/H-number
13C shift
1H shift
2
3
5
6
9
10
11
75.29
40.45
±
53.43
59.67
69.53
40.06
4.816
2.834
8.079
3.471
3.924
3.962
2.601 (HProS
)
)
2.391 (HProR
13
14
15±18
27.34
25.12
22.08
28.42
31.17
13.92
12.52
19.05
18.01
28.41
33.28
2.02211.506
1.39811.137
1.265
1.265
1.250
0.857
0.935
0.124
0.473
19
20
22
23
24
25
The crucial macrocyclization reactions were run under high
dilution (cˆ1 mmol/l) in DMF as solvent and 2-(1H-benzo-
triazole-1-yl)-1,1,3,3-tetramethyluronium tetra¯uoroborate
as condensing agent. Gratifyingly, the macrolactamization
reaction proved to be quite ef®cient, with yields for the
macrocycles 4 ranging from 33 to 64%. The structures for
the hapalosin analogs were secured by high resolution mass
spectra and by NMR spectrometry. In one instance (4aaa)
the conformational situation in the macrocyclic ring was
further examined by homo- and heteronuclear NMR
methods.
2.790
3.021 (HProS
)
)
2.681 (HProR
4/7/12
CvO
171.82
170.17
169.65
±
10-OH
5.244
distances of this average conformation of 4aaa are listed
in the column MD distance of Table 3.
The prochiral assignments of the diastereotopic methylene
groups CH2-11 and CH2-25 are based on the combined data
of the NOE intensities and the 3JH,H coupling constants. For
methylene group CH2-11 NOE correlations were observed
3. Conformational studies
on the one hand between H-11ProS and H-9 (distance ,3 A)
Ê
Due to isomerism about the tertiary amide bond hapalosin
(3) exists at room temperature as a mixture of s-cis and
s-trans rotamer which leads to a doubled signal set in
NMR spectra. The cis rotamer is the dominating conformer
in CDCl3 (cis/trans 3:1)12 while it is the minor conformer in
DMSO-d6 (cis/trans 1:3).16 The hapalosin analog 4aaa
shows two signal sets, both in the 1H and 13C NMR spectra.
However, the ratio suggests a stronger preference of one
conformer (93:7 in DMSO-d6). The corresponding peak
assignments are shown in Table 2.
and on the other hand between H-11ProR and OH (distance
Ê
,3 A). Coupling constants indicate an antiperiplanar
orientation of H-11ProS and H-10 (3JH11,H10ˆ10.1 Hz) and a
synclinal orientation of H-11ProR and H-10 (3JH11,H10,2 Hz).
In the case of the benzylic methylene group CH2-25, NOE
correlations were found between H-25ProS and H-9 (,2.5 A)
Ê
and also between H-25ProS and H-10 (distance ,3 A). The
Ê
proton H-25ProR exhibits correlations to H-9 (distance
Ê
Ê
Ê
,3 A), H-10 (distance .3 A) and H3-24 (distance ,3 A).
Coupling constants indicate an antiperiplanar orientation of
To elucidate the solution conformation of the analog 4aaa,
homo- and heteronuclear NMR spectra were measured in
DMSO-d6. Compensated ROESY27 spectra (O1ˆ2.1 ppm,
4 kHz pulsed spin lock, 200 ms mixing time) show an
intense NOE correlation between H-6 and H-9, which
proves the s-cis-conformation of the tertiary amide bond.
Ê
Table 3. Experimental interproton distances (A) obtained from a compen-
sated ROESY spectrum and the corresponding theoretical results from
molecular dynamics simulation of 4aaa. The torsional restraints for the
MD simulation are listed above
H±H
NOE distance
MD distance
Ê
Table 3 contains the average interproton distances (A)
5±3
5±6
5±9
5±10
5±21
2±3
6±9
2.05
2.95
3.1
3.5
2.9
2.24
3.00
3.16
3.68
2.85
2.35
2.10
obtained from the cross signal intensities in the ROESY
spectrum of 4aaa. Under the experimental conditions spin
diffusion is neglectable and the volume integral of each
cross-peak correlates with a single interproton distance
(two-spin approximation).28 The proton±proton distances
were calculated according to the r26-dependance (rˆinter-
proton distance) of the NOE.29 The NOE distances served as
weak distance restraints for a 100 ps molecular dynamics
simulation. Additional weak torsional restraints were
included for the benzylic side chain and the C10±C11
bond. Averaging of 10 snapshots was followed by energy
minimization without distance constraints. Interproton
2.2
2.1
Torsion
(8)
C6±C(O)ÐN±C9
0
H9±C9±C25ÐH25proR
H9±C9±C25ÐH25proS
H10±C10±C11±H11proR
H10±C10±C11±H11proS
180
260
260
180

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C. Hermann et al. / Tetrahedron 5702001) 8999±9010
402. ES-FT-ICR-MS: Bruker Daltonic APEX II. HPLC:
Hewlett Packard HP 1100. Flash chromatography: J. T.
Baker silica gel 30±60 mm. Thin-layer chromatography:
Merck Si 60 F254. Solvents were distilled prior to use;
petroleum ether with a boiling range 35±658C was used.
The following compounds were prepared according to
literature procedures: 2-amino-5-O-benzyl-1,2,4-trideoxy-
3-O-(methoxymethyl)-1-phenyl-d-threo-pentitol (6),15 (4S)-
4-benzyl-3-propionyl-1,3-oxazolidin-2-one (12),21 (S)-4-
benzyl-3-propionyl-2-oxazolidinone (14a),21 (S)-4-benzyl-
3-(3-phenylpropionyl)-2-oxazolidinone (14b)30. Manual
assembling of the linear depsipeptides was performed in a
polypropylene column (isolute SPE column from Roland
Vetter, Germany) ®tted with a porous polyethylene frit
(20 mm porosity) using an IKA Vibrax-VXR for agitation.
Wang resin (100±200 mesh, loading capacity 1.3 mmol/g),
the condensation reagents PyBroP and TBTU and the Fmoc
protected amino acids were purchased from Novabiochem.
Figure 3. Energy-minimized average conformations of 4aaa (cis-confor-
mer). To simplify the calculation, the side-chain was shortened by two
atoms.
H-25ProR and H-9 (3JH25,H9ˆ11 Hz) and a synclinal orienta-
tion of H-25ProS and H-9 (3JH25,H9ˆ2.5 Hz). The averaged
and energy-minimized conformation of 4aaa that is shown
in Fig. 3 ful®lls all NOE data.
5.1.1. 5-O-Benzyl-1,2,4-trideoxy-2-.N-formylamino)-3-
O-.methoxymethyl)-1-phenyl-erythro-d-pentitol .7). A
solution of amine 6 (3.45 g, 10.5 mmol) in ethyl formate
(20 ml) was heated at re¯ux for 26 h. After removal of the
excess ethyl formate under reduced pressure, the residue
was puri®ed by ¯ash chromatography (20% petroleum
ether in ethyl acetate) to give formamide 7 (3.43 g, 91%)
As determined in a previous study, the cis/trans ratio for
hapalosin in the same solvent was 25:75.16 Thus, the
replacement of an ester- with an amide bond seems to
enhance the cis/trans-ratio.
as a light yellow oil. [a]25 ˆ229.1 (c 0.8, CH2Cl2);TLC
D
(petroleum ether/ethyl acetate, 2:8): Rfˆ0.46;IR (neat):
1
3291 (m), 1687 (s) cm21; H NMR (250 MHz, CDCl3): d
(both rotamers)ˆ1.82±1.93 (m, 2H, CH2), 2.58 (dd,
Jˆ10.6, 14.2 Hz, 1H, minor, CH2Ph), 2.70 (dd, Jˆ9.5,
14.2 Hz, 1H, major, CH2Ph), 2.88±2.99 (m (,2£dd,
Jˆ5.2, 14.2 Hz), 1H, CH2Ph), 3.39, 3.40 (s, 3H, OCH3),
3.54±3.64 (m, .2H, CH2OBn, CHN (minor)), 3.76±3.82
(m, 1H, CHOMOM), 4.44±4.51 (m, ,3H, OCH2Ph, CHN
(major)), 4.57±4.68 (m (,2£d, Jˆ6.9 Hz), 2H, CH2OMe),
6.48 (d, br., 1H, minor, NH), 6.55 (d, br., 1H, major, NH),
7.03±7.07 (m, ,1H, aryl H), 7.14±7.37 (m, .9H, aryl H),
7.47 (d, Jˆ11.8 Hz, 1H, minor, CHO), 7.98 (d, Jˆ1.3 Hz,
1H, major, CHO); 13C NMR (62.9 MHz, CDCl3): d (both
rotamers)ˆ31.7, 32.4, 35.5, 36.7, 51.4, 55.9, 57.6, 66.1,
66.4, 73.2, 73.3, 79.6, 79.9, 97.5, 97.7, 126.4, 126.7,
127.7, 127.9, 128.0, 128.4, 128.5, 128.7, 129.2, 129.4,
137.7, 138.0, 138.1, 138.2, 160.5, 164.2.
4. Conclusion
In this paper we illustrate the synthesis of a small library of
analogs of the depsipeptide hapalosin. The analogs are
characterized by one ester and two amide bonds. The
three building blocks consist of b-hydroxy acids 18,
a-amino acids 23 and the unusual g-amino-b-hydroxy
acid 11. As protecting groups the Fmoc for the amino
function, and the THP-group for the hydroxy function
proved to be advantageous. With a view towards generating
structural variability the aldol reaction holds great potential.
The corresponding building blocks, carboxylic acids and
aldehydes are available in large number. In addition, the
aldol products can be converted to many interesting building
blocks, for example to 1,2-amino alcohols by Curtius
rearrangement. We believe that the general strategy outlined
here should work as well for other depsipeptides. Studies
along these lines are underway in our laboratory.
5.1.2. 5-O-Benzyl-1,2,4-trideoxy-3-O-.methoxymethyl)-
2-.N-methylamino)-1-phenyl-erythro-d-pentitol .8).
A
solution of formamide 7 (3.4 g, 9.5 mmol) in diethyl ether
(30 ml) was added dropwise at room temperature to a stirred
suspension of LiAlH4 (0.72 g, 19.0 mmol) in dry diethyl
ether (100 ml). The reaction mixture was stirred at re¯ux
for 24 h and then cooled in an ice bath. Water (120 ml) was
added carefully to destroy the excess of LiAlH4 followed by
the addition of diethyl ether (70 ml). The layers were
separated and the aqueous layer was extracted with Et2O
(3£150 ml). The combined organic layers were washed
with brine (150 ml), dried (MgSO4), ®ltered and concen-
trated in vacuo to give crude the amine 8 (3.05 g, 93%) as
a yellow oil which was used in the next step without further
5. Experimental
5.1. General
1H and 13C NMR: Bruker AC 250, Bruker AMX 400, Bruker
DRX 600;all spectra were recorded in CDCl 3 unless noted
otherwise;chemical shifts are calibrated to residual proton
resonances in CDCl3 (7.24 ppm) and DMSO-d6 (2.49 ppm),
respectively. Optical rotations: JASCO P-1020 polarimeter.
IR: Jasco FT/IR-430 spectrometer. UV: Shimadzu 240-1PC
UV±VIS recording spectrophotometer. GC±MS: HP 6890
Series GC System with 5973 mass selective detector and
7683 Series injector. EI-MS: AMD Intectra GmbH AMD
puri®cation. [a]25 ˆ124.4 (c 0.54, CH2Cl2);TLC (ethyl
D
1
acetate/MeOH, 8:2): Rfˆ0.29±0.34; H NMR (250 MHz,
CDCl3): dˆ1.58 (s, br., 1H, NH), 1.80±1.88 (m, 2H,
CH2), 2.31 (s, 3H, NCH3), 2.63±2.66 (m, 2H, CHN,

C. Hermann et al. / Tetrahedron 5702001) 8999±9010
9005
CH2Ph), 2.77±2.83 (m, 1H, CH2Ph), 3.26 (s, 3H, OCH3),
3.44±3.57 (m, 2H, CH2OBn), 3.69±3.76 (m, 1H, CHOMOM),
4.47, 4.52 (2 d, Jˆ12.0 Hz, 2H, OCH2Ph), 4.49, 4.58 (2 d,
Jˆ6.7 Hz, 2H, CH2OMe), 7.06±7.27 (m, 10H, aryl H); 13C
NMR (62.9 MHz, CDCl3): dˆ30.7, 35.1, 36.7, 55.7, 64.6,
67.2, 73.0, 76.3, 96.9, 126.2, 127.6, 127.7, 128.4, 128.5,
129.2, 138.6, 139.6;MS (EI), m/z (%) 344 [M111] (1.8).
1.8 mmol), acetone (14 ml) and aqueous 5% NaHCO3
(5 ml) were added KBr (0.21 g, 0.18 mmol) and TEMPO
(0.29 g, 1.86 mmol) at 08C. An aqueous NaOCl solution
(,1.9 M, 5.5 ml, ,10.5 mmol) was then added dropwise,
while the mixture was vigorously stirred at 08C. After 1 h
additional NaOCl (2 ml, ,3.8 mmol) was added, and
stirring was continued at 08C for another hour followed by
the addition of saturated aqueous NaHCO3 (35 ml). The
acetone was then removed in vacuo, and the resulting
aqueous mixture extracted with diethyl ether (2£30 ml) to
remove TEMPO impurities and then acidi®ed to pH 5±6
with 10% aqueous citric acid. After extraction of the
aqueous layer with ethyl acetate (3£60 ml) the combined
ethyl acetate layers were dried (MgSO4), ®ltered and
concentrated in vacuo to give the pure acid 11 (0.82 g,
5.1.3. 1,2,4-Trideoxy-2-.N-methylamino)-3-O-.methoxy-
methyl)-1-phenyl-erythro-d-pentitol .9). A solution of
crude benzyl ether 8 (0.8 g, 2.3 mmol) in EtOH/cyclo-
hexene 2:1 (15 ml) was stirred in the presence of Pd(OH)2
(0.2 g) at re¯ux for 16 h. The reaction mixture was ®ltered
through a pad of Celite, and the ®ltrate evaporated in vacuo
to leave the crude amino alcohol 9 as a yellow oil which was
1
used directly in the subsequent step. H NMR (250 MHz,
93%). [a]28 ˆ246.2 (c 0.64, CH2Cl2);TLC (ethyl ace-
D
CDCl3): dˆ1.75±1.87, 1.92±1.97 (2 m, 2H, CH2), 2.42 (s,
3H, NCH3), 2.72 (dd, Jˆ7.5, 13.9 Hz, 1H, CH2Ph), 2.86 (dd,
Jˆ7.2, 13.9 Hz, 1H, CH2Ph), 2.99±3.07 (m, 1H, CHN),
3.34 (s, 3H, OCH3), 3.53±3.60 (m, 1H, CHOMOM),
3.69±3.79 (m, 2H, CH2OH), 4.58, 4.62 (d, Jˆ6.8 Hz, 2H,
CH2OMe), 7.17±7.33 (m, 5H, aryl H); 13C NMR
(62.9 MHz, CDCl3): dˆ32.8, 34.5, 36.2, 55.7, 57.1, 63.5,
77.4, 95.9, 126.5, 128.7, 129.0, 138.5.
tate/petroleum ether, 8:2): Rfˆ0.20±0.23;IR (neat):
;
1H NMR
3600±2500 (br), 1736 (s), 1703 (s) cm21
(250 MHz, CDCl3): d (both rotamers)ˆ2.06±2.15 (m, 1H,
CH2CO), 2.4±2.68 (m, 4H, CH2O, NCH3), 2.79±2.95
(m, ,1H, CH2Ph), 3.22±3.28 (m, ,1H, CH2Ph), 3.33,
3.40 (2 s, 3H, OCH3), 4.06±4.15 (m, ,2H, CH, CH(Fmoc)),
4.22±4.40 (m, ,3H, CH, CH2(Fmoc)), 4.39±4.66 (m, br.,
,1H, CH2OMe), 4.70, 4.77 (2 d, Jˆ6.8 Hz, 1H, CH2OMe),
6.75 (s, br., ,1H, aryl H), 7.10±7.53 (m, 10H, aryl H),
7.69±7.78 (m, 2H, aryl H); 13C NMR (62.9 MHz, CDCl3):
d (both rotamers)ˆ34.4, 38.0, 47.3, 56.0, 56.2, 67.3,
97.2, 119.9, 120.2, 124.5, 125.1, 126.3, 126.5, 127.0,
127.1, 127.3, 127.6, 127.7, 128.4, 128.5, 128.8, 128.9,
138.4, 141.3, 141.4, 141.5, 143.8, 144.0, 144.3, 156.3,
156.6, 175.6, 175.8;MS (FD), m/z (%) 488.8 [M121]
(100).
5.1.4. 1,2,4-Trideoxy-2-[N-.9-¯uorenylmethoxycarbonyl)-
N-methylamino]-3-O-.methoxymethyl)-1-phenyl-erythro-
d-pentitol .10). To a cooled (08C) solution of FmocCl
(0.78 g, 3.0 mmol) in toluene (30 ml) was added dropwise
a solution of the crude amino alcohol 9 (2.3 mmol) in
toluene (20 ml) followed by the addition of saturated
aqueous NaHCO3 (10 ml). The resulting mixture was
vigorously stirred at 08C for 20 min and for 1 h at room
temperature. Water (20 ml) was added and the layers were
separated. After extraction of the water layer with ethyl
acetate (40 ml), the organic layers were combined, washed
with brine (40 ml), dried (MgSO4), ®ltered, and concen-
trated in vacuo. Puri®cation of the residue by ¯ash chroma-
tography (30% petroleum ether in ethyl acetate) gave 10
5.1.6. .4S)-4-Benzyl-3-dodecanoyl-2-oxazolidinone .14c).
A stirred solution of dodecanoic acid (2.60 g, 13.1 mmol) in
dry THF (60 ml) was treated with Et3N (3.6 ml, 26.1 mmol)
and pivaloyl chloride (1.7 g, 14.1 mmol) at 2158C. After
warming slowly to 08C, the resulting mixture was cooled to
2788C. In a separate ¯ask, a solution of auxiliary 12
(2.50 g, 14.1 mmol) in dry THF (40 ml) was treated with
n-BuLi (2.7 M in heptane, 5.3 ml, 14.3 mmol) at 2788C.
The solution of the lithiated oxazolidinone was stirred at
2788C for 10 min before it was transferred to the cooled
(2788C) reaction mixture of the mixed anhydride. The
resulting mixture was allowed to warm to 2208C within
1 h and stirred at this temperature for 30 min. After addition
of aqueous NaHSO4 (1 M, 40 ml), the bulk of THF was
removed by rotary evaporation, and the remainder extracted
with ethyl acetate (2£60 ml). The combined organic layers
were washed with 5% aqueous Na2CO3 and brine, dried
(Na2SO4), ®ltered and concentrated in vacuo. The residue
was puri®ed by ¯ash chromatography (10 and 20% ethyl
acetate in petroleum ether) to give 14c (4.64 g, 99%) as a
colorless crystalline solid. mp 478C;TLC (petroleum ether/
(0.89 g, 81%). [a]26 ˆ218.7 (c 0.18, CH2Cl2);TLC
D
(ethyl acetate/petroleum ether, 6:4): Rfˆ0.22;IR (neat):
1
3461 (m), 1695 (s) cm21; H NMR (250 MHz, CDCl3): d
(both rotamers)ˆ1.17±1.31, 1.40±1.56 (2 m, br., 2H, minor,
CH2), 1.60±1.69, 1.79±1.87 (2 m, 2H, major, CH2), 2.45±
2.65 (m, br.) and 2.61 (s, 3H, NCH3), 2.78±2.92 (m, 1H,
CH2Ph), 3.18 (dd, Jˆ4.1, 14.4 Hz, 1H, CH2Ph), 3.39, 3.44
(s, 3H, OCH3), 3.40±3.68 (m, 2H, minor, CH2OH), 3.72±
3.82 (m, 2H, major, CH2OH), 3.90±4.01 (m, ,1H,
CHOMOM), 4.03±4.15 (m, ,2H, CHN, CH(Fmoc)), 4.21
(dd, Jˆ7.1, 10.5 Hz, 1H, CH2(Fmoc)), 4.35 (dd, Jˆ6.5,
10.5 Hz, CH2(Fmoc)), 4.3±4.45, 4.46±4.59 (2 m, br.,
minor, CH2OMe), 4.71, 4.75 (2 d, Jˆ6.7 Hz, major,
CH2OMe), 6.7±6.85 (m, ,1H, aryl H), 7.10±7.58 (m,
10H, aryl H), 7.70±7.83 (m, .2H, aryl H); 13C NMR
(62.9 MHz, CDCl3): d (both rotamers)ˆ34.0, 34.3, 47.3,
56.3, 58.9, 59.0, 67.2, 78.3, 97.6, 97.8, 119.9, 120.1, 124.5,
125.0, 125.1, 126.2, 126.4, 127.0, 127.2, 127.7, 128.4, 128.5,
128.8, 138.4, 141.3, 141.4, 141.6, 142.8, 144.2, 144.3, 155.2,
156.6;MS (FD), m/z (%) 474.7 [M1-1] (100).
1
ethyl acetate, 8:2): Rfˆ0.60; H NMR (250 MHz, CDCl3):
dˆ0.87 (t, Jˆ6.4 Hz, 3H, CH3), 1.22±1.40 (m, 16H), 1.62±
1.71 (m, 2H), 2.76 (dd, Jˆ9.6, 13.3 Hz, 1H, CH2Ph), 2.81±
3.03 (m, 2H, CH2C(O)), 3.29 (dd, Jˆ3.3, 13.3 Hz, 1H,
CH2Ph), 4.11±4.23 (m, 2H, CH2O), 4.62±4.71 (m, 1H,
CHN), 7.18±7.36 (m, 5H, aryl H); 13C NMR (62.9 MHz,
CDCl3): dˆ14.1, 22.7, 24.3, 29.2, 29.4, 29.5, 29.7, 31.9,
35.6, 38.0, 55.2, 66.2, 127.4, 129.0, 129.5, 135.4, 153.5,
173.5.
5.1.5.
.3R,4S)-4-[N-.9-Fluorenylmethoxycarbonyl)-N-
methylamino]-3-.methoxymethoxy)-5-phenylpentanoic
acid .11). To a stirred heterogeneous mixture of 10 (0.85 g,

9006
C. Hermann et al. / Tetrahedron 5702001) 8999±9010
5.2. Preparation of the aldol products 16aa, 16ba, 16cb,
16ca
¯ash chromatography: 20% ethyl acetate in petroleum
ether, yield: 92%. TLC (petroleum ether/ethyl acetate,
1
8:2): Rfˆ0.38; H NMR (250 MHz, CDCl3): dˆ0.86 (m,
3H, CH3), 1.16±1.35 (m, 16H, (CH2)8), 1.50±1.70 (m, 1H,
CH2), 1.7±1.96 (m, 3H, CH2, CH2Bn), 2.59±2.73 (m, 2H,
CH2Ph(auxiliary), CH2Ph), 2.78±2.96 (m, 1H, CH2Ph), 3.34
(dd, Jˆ3.2, 13.2 Hz, 1H, CH2Ph(auxiliary)), 3.85±3.92 (m,
1H, CH), 4.04±4.10, 4.10±4.19 (m, 3H, CH, CH2O), 4.68±
4.74 (m, 1H, CHN), 7.14±7.37 (m, 10H, aryl H); 13C NMR
(62.9 MHz, CDCl3): dˆ14.1, 22.7, 27.3, 27.6, 29.3, 29.4,
29.6, 29.8, 31.9, 32.3, 35.4, 38.1, 47.8, 55.6, 66.0, 71.8,
125.9, 127.4, 128.4, 128.5, 129.0, 129.4, 135.2, 141.9,
153.7, 176.1.
To a stirred solution of the oxazolidinone 14 in dry CH2Cl2
(0.5 M) was added n-Bu2BOTf (1 M in CH2Cl2, 1.3 equiv.)
dropwise at 08C followed by the dropwise addition of diiso-
propylethylamine (1.3 equiv.). After stirring for 1 h at 08C,
the solution was cooled to 2788C, and the aldehyde 15
(1.4 equiv.) was added at this temperature. The resulting
mixture was stirred for 1 h at 2788C, then allowed to
warm to room temperature in 1 h and kept at room tempera-
ture for 2 h. After quenching the reaction with phosphate
buffer (pH 7.0, 3 ml/mmol of 14), the layers were separated,
and the aqueous layer was extracted with CH2Cl2 (2£). The
combined organic layers were washed with brine, dried
(Na2SO4), ®ltered and evaporated in vacuo to leave an oil
which was dissolved in MeOH (3 ml/mmol 14). After cool-
ing to 08C, the solution was treated dropwise with 30%
aqueous H2O2 (1 ml/mmol of 14) and stirred for 1 h at
08C. The reaction was quenched by the addition of 10%
aqueous NaHSO4 (same volume as MeOH), and after warm-
ing to room temperature, the resulting mixture was extracted
with ethyl acetate (3£). The ethyl acetate layers were
combined, washed with saturated aqueous NaHCO3 and
brine, dried (Na2SO4), ®ltered and concentrated in vacuo.
Puri®cation of the residue by ¯ash chromatography gave the
pure aldol product 16 as a colorless oil.
5.2.4. .4S)-4-Benzyl-3-{.2S)-2-[.1R)-1-hydroxyoctyl]do-
decanoyl}-2-oxazolidinone .16ca). Eluents for ¯ash chro-
matography: 10, 15 and 20% ethyl acetate in petroleum
ether, yield: 88%. TLC (petroleum ether/ethyl acetate,
1
8:2): Rfˆ0.37; H NMR (250 MHz, CDCl3): dˆ0.83±0.88
(m, 6H, 2£CH3), 1.2±1.4 (m, 26H, (CH2)8, (CH2)5), 1.42±
1.55 (m, 2H, CH2), 1.50±1.70, 1.78±1.96, (2 m, 2H, CH2),
2.69 (dd, Jˆ10.0, 13.2 Hz, 1H, CH2Ph), 3.35 (dd, Jˆ3.3,
13.2 Hz, 1H, CH2Ph), 3.84±3.89 (m, 1H, CH), 4.02±4.07
(m, 1H, CH), 4.13±4.22 (m, 2H, CH2O), 4.67±4.77 (m, 1H,
CHN), 7.21±7.37 (m, 5H, aryl H); 13C NMR (62.9 MHz,
CDCl3): dˆ14.1, 22.7, 26.2, 27.0, 27.6, 29.3, 29.4, 29.5,
29.6, 29.9, 31.9, 33.9, 38.1, 47.8, 55.6, 66.0, 72.6, 127.4,
129.0, 129.4, 135.3, 153.6, 176.2.
5.2.1. .4S)-4-Benzyl-3-[.2S,3R)-3-hydroxy-2-methylde-
canoyl]-2-oxazolidinone .16aa). Eluents for ¯ash chroma-
tography: 20 and 30% ethyl acetate in petroleum ether,
5.3. Preparation of the THP protected b-hydroxy acids
18aa, 18ba, 18cb, 18ca
yield: 80%. [a]21 ˆ142.6 (c 1.4, CHCl3);TLC (petroleum
D
ether/ethyl acetate, 7:3): Rfˆ0.44; 1H NMR (250 MHz,
CDCl3): dˆ0.87 (m, 3H, CH3), 1.2±1.6 (m, 15H, (CH2)6,
CH3), 2.44 (s, br., 1H, OH), 2.78 (dd, Jˆ9.4, 13.4 Hz, 1H,
CH2Ph), 3.24 (dd, Jˆ3.3, 13.4 Hz, 1H, CH2Ph), 3.75 (dq,
Jˆ2.7, 7.0 Hz, 1H, CHMe), 3.90±3.95 (m, 1H, CHOH),
4.15±4.26 (m, 2H, CH2O), 4.65±4.73 (m, 1H, CHN),
7.17±7.21, 7.23±7.36 (m, 5H, aryl H); 13C NMR
(62.9 MHz, CDCl3): dˆ10.4, 14.1, 22.7, 26.1, 29.3, 29.6,
31.9, 33.9, 34.9, 37.9, 42.1, 55.2, 66.2, 71.5, 127.5, 129.0,
129.5, 135.1, 153.1, 177.6;HRMS (EI): calcd for
C21H31NO4 361.22529, found 361.22922.
After addition of pyridinium para-toluenesulfonate (PPTS,
0.1 equiv.) to a solution of b-hydroxy compound 16 and 3,4-
dihydro-2H-pyran (1.5 equiv.) in dry CH2Cl2 (0.15 M), the
resulting solution was stirred for 12 h at room temperature.
The reaction solution was diluted with CH2Cl2 and then
washed once with half-saturated brine to remove PPTS.
After drying (MgSO4) and ®ltration, the CH2Cl2 solution
was evaporated in vacuo to leave the crude product 17 as
a light yellow oil which was used as such in the subsequent
cleavage of the auxiliary.
The crude product 17 was dissolved in THF/H2O 3:1
(0.05 M) and cooled to 08C. To the cooled and stirred solu-
tion was added dropwise 30% aqueous H2O2 (0.6 ml/mmol,
,6 equiv.) followed by the addition of LiOH monohydrate
(2 equiv.). The resulting mixture was stirred for 20 min at
08C and then at room temperature for 8 h. After quenching
with aqueous Na2SO3 (1.5 M, 7 ml/ml H2O2) at 08C, most of
the THF was removed under reduced pressure. The
remainder was diluted with CH2Cl2 before acidifying
the cooled (08C) mixture to pH 6 with aqueous 1N HCl.
The layers were separated, and after extraction of the
aqueous layer with CH2Cl2 (2£), the organic layers were
combined, washed with aqueous HCl (1N) and brine,
dried (Na2SO4), ®ltered and concentrated in vacuo. The
residue was puri®ed by ¯ash chromatography to give the
product 18 as a colorless oil.
5.2.2. .4S)-4-Benzyl-3-[.2S,3R)-2-benzyl-3-hydroxydeca-
noyl]-2-oxazolidinone .16ba). Eluents for ¯ash chromato-
graphy: 20 and 30% ethyl acetate in petroleum ether, yield:
81%. [a]25 ˆ136.9 (c 0.976, CH2Cl2);TLC (petroleum
D
ether/ethyl acetate, 7:3): Rfˆ0.51; 1H NMR (250 MHz,
CDCl3): dˆ0.88 (m, 3H, CH3), 1.22±1.40 (m, 10H),
1.45±1.66 (m, 2H), 2.17 (dd, Jˆ9.4, 13.5 Hz, 1H,
CH2Ph(auxiliary)), 2.84 (dd, Jˆ3.2, 13.5 Hz, 1H,
CH2Ph(auxiliary)), 3.03 (dd, Jˆ5.2, 13.4 Hz, 1H, CH2Ph),
3.14 (dd, Jˆ10.5, 13.4 Hz, 1H, CH2Ph), 3.91±4.01 (m, 1H,
CH), 3.98 (dd, Jˆ3.0, 9.1 Hz, 1H, CH2O), 4.07 (dd, Jˆ7.8,
9.1 Hz, 1H, CH2O), 4.52±4.65 (m, 2H, CHN, CH), 6.91±
6.94 (m, 2H, aryl H), 7.16±7.28 (m, 8H, aryl H); 13C NMR
(62.9 MHz, CDCl3): dˆ14.1, 22.7, 26.1, 29.3, 29.5, 31.9,
33.1, 34.0, 37.3, 49.3, 55.0, 65.7, 72.5, 126.5, 127.3, 128.5,
128.9, 129.3, 129.5, 135.1, 138.8, 153.4, 175.2.
5.3.1. .2S,3R)-2-Methyl-3-.tetrahydropyran-2-yloxy)de-
canoic acid .18aa). Eluent for ¯ash chromatography: 35%
5.2.3. .4S)-4-Benzyl-3-{.2S)-2-[.1R)-1-hydroxy-3-phenyl-
propyl]dodecanoyl}-2-oxazolidinone .16cb). Eluent for
ethyl acetate in petroleum ether, yield: 93%. [a]23 ˆ144.7
D

C. Hermann et al. / Tetrahedron 5702001) 8999±9010
9007
(c 1.2, CHCl3);TLC (petroleum ether/ethyl acetate, 6:4):
4.62, 4.71±4.77, 4.91±4.96 (m, 1H, CH(THP)); 13C NMR
(62.9 MHz, CDCl3): d (both diastereomers)ˆ14.1, 19.7,
20.7, 22.7, 25.1, 25.5, 25.7, 26.0, 26.7, 27.7, 27.8, 28.0,
29.2, 29.3, 29.5, 29.6, 30.7, 31.2, 31.8, 31.9, 32.1, 34.1,
48.3, 50.0, 50.8, 62.8, 62.9, 64.4, 72.1, 79.9, 94.7, 97.9,
100.9, 176.3, 178.6, 180.0;MS (FAB), m/z (%) 413 (8)
[M11], 329 (42), 311 (100), 293 (28).
1
Rfˆ0.52;IR (neat): 3400±2650 (br), 1709 (s) cm 21; H
NMR (250 MHz, CDCl3): d (both diastereomers)ˆ0.86 (t,
Jˆ6.8 Hz, 3H, CH3), 1.14, 1.16 (d, Jˆ3.1 Hz, 3H, Me),
1.2±1.38 (m, 10H, (CH2)5), 1.40±1.90 (m, 8H, CH2,
(CH2)3(THP)), 2.65±2.73, 2.83±2.89 (m, 1H, CHMe),
3.45±3.53 (m, 1H, CH2O), 3.77±3.96 (m, 2H, CHOTHP,
CH2O), 4.60±4.65, 4.68±4.72, 4.91±4.97 (m, 1H,
CH(THP)); 13C NMR (62.9 MHz, CDCl3): d (both dia-
stereomers)ˆ11.2, 12.1, 14.0, 19.8, 20.5, 22.6, 25.4, 25.5,
25.7, 26.0, 29.2, 29.5, 29.6, 30.7, 30.8, 30.9, 31.2, 31.8,
32.5, 42.2, 43.6, 62.9, 64.1, 78.6, 79.9, 94.7, 98.8, 100.4,
176.9, 178.9;MS (EI), m/z (%) 287 (16) [M111], 203 (30),
185 (46), 101 (77), 85 (100).
5.4. Preparation of the Wang ester 19aa, 19ba, 19cb,
19ca
Wang resin (154 mg, 0.2 mmol) was suspended in dry
CH2Cl2 and left to swell for 30 min followed by ®ltration.
To a solution of acid 18 (0.6 mmol) and MeIm (0.142 ml,
1.8 mmol) in dry CH2Cl2 (3 ml) was added MSNT (178 mg,
0.6 mmol) at room temperature. The reaction solution was
immediately added to the resin, and the resulting mixture
agitated at room temperature for 12 h. Then Ac2O (0.09 ml,
0.9 mmol) and pyridine (0.07 ml, 0.9 mmol) were added,
and the mixture was agitated for 1 h to block any unreacted
hydroxyl groups on the resin. The resulting resin was
®ltered, washed successively with CH2Cl2 (2£), [MeOH
(2£), DMF (2£)]£2, CH2Cl2 (3£) and Et2O (2£) and dried
in vacuo. Each wash was carried out using 2 ml solvent and
agitating the resin suspension for 2 min.
5.3.2. .2S,3R)-2-Benzyl-3-.tetrahydropyran-2-yloxy)de-
canoic acid .18ba). Eluent for ¯ash chromatography: 25%
ethyl acetate in petroleum ether, yield: 64%. [a]25 ˆ161.3
D
(c 1.10, CH2Cl2);TLC (petroleum ether/ethyl acetate, 7:3):
1
Rfˆ0.66;IR (neat): 3450±2600 (br), 1708 (s) cm 21; H
NMR (250 MHz, CDCl3): d (both diastereomers)ˆ0.88
(m, 3H, CH3), 1.2±1.4 (m, 10H, (CH2)5), 1.4±1.9 (m, 8H,
CH2, (CH2)3(THP)), 2.73±2.87, 2.93±3.09, 3.14±3.21 (m,
3H, CHBn, CH2Ph), 3.42±3.58, 3.71±3.79, 3.81±4.0 (m,
3H, CH2O, CHOTHP), 4.51±4.54, 4.70±4.75, 4.90±4.98
(m, 1H, CH(THP)), 7.16±7.30 (m, 5H, aryl H); 13C NMR
(62.9 MHz, CDCl3): d (both diastereomers)ˆ14.1, 19.4,
20.7, 22.7, 25.1, 25.4, 25.5, 25.6, 25.7, 25.9, 29.2, 29.4,
29.6, 30.7, 31.2, 31.8, 32.3, 33.0, 33.5, 34.0, 50.4, 51.6,
52.9, 62.9, 64.5, 71.9, 79.3, 94.7, 98.2, 100.9, 126.3,
126.4, 128.5, 128.7, 128.8, 139.2, 139.5, 175.8, 177.8,
178.8;MS (FAB), m/z (%) 363 (20) [M11], 279 (100),
261 (63), 243 (45), 215 (38).
5.5. Removal of the THP protecting group to give the
hydroxy esters 20aa, 20ba, 20cb, 20ca
After swelling of loaded resin 19 in CH2Cl2 for 30 min and
subsequent ®ltration, the resin was suspended in CH2Cl2/
MeOH 1:1 (2 ml) (containing dioxane (0.06 ml)) and treated
with pTsOH (10 mg) for 7 h at room temperature. After
®ltration, the resulting resin 20 was washed with CH2Cl2
(3£), [MeOH, CH2Cl2]£2, CH2Cl2 (2£) and Et2O (2£)
and dried in vacuo. To monitor the deprotection progress,
aliquots (20 ml) of the deprotection solution were removed
in intervals of 1 h and diluted with CH2Cl2 (80 ml). A
sample of this solution (0.5 ml) was then injected into a
GC capillary column (30 m£0.32 mm£1 mm) at 508C. GC
was then performed using the following temperature
program: 2 min 508C, increase (rate 58C/min) to 708C,
1 min 708C. Deprotection was judged complete when the
ratio of the peak areas of methoxytetrahydropyran
(tRˆ5.8 min) and dioxane (as an internal standard,
tRˆ2.8 min) was constant.
5.3.3. .2R)-2-[.1S)-3-Phenyl-1-.tetrahydro-2H-pyran-2-
yloxy)propyl]dodecanoic acid .18cb). Eluent for ¯ash
chromatography: 20% ethyl acetate in petroleum ether,
yield: 87%. TLC (petroleum ether/ethyl acetate, 7:3):
Rfˆ0.56;IR (neat): 3500±2500 (br), 1783 (m), 1709 (s),
1666 (m) cm21 1H NMR (250 MHz, CDCl3): d (both
;
diastereomers)ˆ0.85±0.87 (m, 3H, CH3), 1.2±1.4 (m,
16H, (CH2)8), 1.48±1.98 (m, 10H, CH2, (CH2)3(THP),
CH2Bn), 2.46±2.98 (m, 3H, CH2Ph, CHC(O)), 3.45±3.6,
3.68±3.75, 3.8±4.1 (m, 3H, CH2O, CHOTHP), 4.54±4.60,
4.71±4.77, 4.92±4.98 (m, 1H, CH(THP)), 7.1±7.3 (m, 5H,
aryl H); 13C NMR (62.9 MHz, CDCl3): d (both dia-
stereomers)ˆ14.1, 19.9, 20.9, 22.7, 25.1, 25.4, 26.8, 27.8,
27.9, 28.1, 29.3, 29.4, 29.6, 30.9, 31.3, 31.8, 31.9, 32.1,
32.3, 34.4, 35.7, 48.6, 50.0, 50.8, 62.9, 63.1, 64.7, 71.3,
77.3, 79.4, 94.7, 98.3, 101.4, 125.8, 126.0, 128.3, 128.5,
141.6, 142.2, 176.5, 178.3, 180.1;MS (FAB), m/z (%) 419
(16) [M11], 335 (78), 317 (100), 299 (30), 271 (16).
5.6. Coupling of the Fmoc protected g-amino acid 11
with the hydroxy esters 20
Loaded resin 20 (0.2 mmol) was washed with dry CH2Cl2
(2£3 ml) and then left in dry CH2Cl2 (3 ml) to swell for
30 min followed by ®ltration. To a solution of amino acid
11 (0.29 g, 0.6 mmol) and MeIm (0.142 ml, 1.8 mmol) in
dry CH2Cl2 (3 ml) was added MSNT (0.178 g, 0.6 mmol) at
room temperature. The reaction solution was added
immediately to the resin, and the resulting mixture was
shaken for 12 h at room temperature. After removal of the
reactants by ®ltration, the resulting resin 21 was washed and
dried as described in the procedure for esteri®cation of the
resin OH groups. The ®ltrates of the reaction mixture and of
the CH2Cl2 washings were combined, washed with aqueous
HCl (1N) and water, dried (MgSO4) and evaporated in
5.3.4. .2S)-2-[.1R)-1-.Tetrahydropyran-2-yloxy)octyl]-
dodecanoic acid .18ca). Eluents for ¯ash chromatography:
10 and 20% ethyl acetate in petroleum ether, yield: 85%.
TLC (petroleum ether/ethyl acetate, 8:2): Rfˆ0.53;IR
;
1H NMR
(neat): 3400±2500 (br), 1707 (s) cm21
(250 MHz, CDCl3): d (both diastereomers)ˆ0.84±0.89
(m, 6H, 2£CH3), 1.18±1.4 (m, 26H, (CH2)8, (CH2)5), 1.4±
1.95 (m, 10H, 2£CH2, (CH2)3(THP)), 2.41±2.52, 2.60±
2.70, 2.73±2.82 (m, 1H, CHC(O)), 3.44±3.58, 3.70±3.78,
3.79±3.91, 3.92±4.05 (m, 3H, CH2O, CHOTHP), 4.58±

9008
C. Hermann et al. / Tetrahedron 5702001) 8999±9010
vacuo to give crude starting material 11. After puri®cation
of the residue by ¯ash chromatography (20 and 10%
petroleum ether in ethyl acetate), 50% of Fmoc protected
g-amino acid 11 could be recovered. To determine the
coupling yield, a weighed sample of the dry resin 21
(,1 mg) was treated with 20% piperidine in DMF
(0.5 ml) for 5 min to release the Fmoc group. After accurate
dilution with DMF to 5 ml, the UV absorption of the solu-
tion based on the formed dibenzofulvene-piperidine adduct
was measured at lˆ301 nm (e301ˆ7800) and 289 nm
(e289ˆ5800). The loading x (mmol Fmoc/g resin) was
then obtained from the equation: xˆElV/eldy with
Vˆ5 ml, dˆ1 cm, yˆweight of the resin sample in g.
Coupling yields are listed in Table 1.
5.10. Deprotection of the amino group and macro-
cyclization of the amino acids 5 to the hapalosin
analogs 4
To a solution of Fmoc protected amino acid 25 (for scale see
Table 1) in THF (1.5 ml) was added diethylamine (0.5 ml)
at 08C. The mixture was stirred at 08C for 10 min, then at
room temperature for 2 h and then concentrated in vacuo.
The residue was dissolved in DMF (1 l/mmol 25) and the
stirred solution was treated successively with TBTU
(3 equiv.), HOBt (3 equiv.) and DIEA (4 equiv.) at room
temperature. The resulting solution was stirred for 14 h
and then partitioned between ethyl acetate and water.
After separation of the layers and extraction of the water
layer with ethyl acetate (2£), the organic layers were
combined, washed successively with water, 5% aqueous
KHSO4, water, half-saturated aqueous NaHCO3 and brine,
dried (MgSO4), ®ltered, and concentrated in vacuo. The
pure macrocycles 4 were obtained by ¯ash chromatography.
5.7. Cleavage of the Fmoc protecting group from 21aa,
21ba, 21cb, 21ca to give the diesters 22aa, 22ba, 22cb,
22ca
Loaded resin 21 was suspended in DMF (3 ml) and allowed
to swell for 5 min. After removal of DMF by ®ltration, it
was treated with 20% piperidine in DMF (2 ml) for 5 min at
room temperature, then ®ltered, washed with DMF (2 ml)
and treated again with 20% piperidine in DMF (2 ml) for
2 min. Longer cleavage times are critical because of hydro-
lysis of the ester bond. After removal of the cleavage
solution by ®ltration, the resulting resin 22 was washed
with [DMF (2£), MeOH (2£)]£2, CH2Cl2 (4£) and Et2O
(2£) and dried in vacuo.
5.10.1. .2R,3S,6S,9S,10R)-9-Benzyl-2-heptyl-10-hydroxy-
6-isopropyl-3,8-dimethyl-1-oxa-5,8-diazacyclododecane-
4,7,12-trione .4aaa). Eluents for ¯ash chromatography: 50
and 40% petroleum ether in ethyl acetate, yield: 0.006 g
(60%, based on 25aaa). [a]24 ˆ221.2 (c 0.404, CH2Cl2);
D
TLC (petroleum ether/ethyl acetate, 1:1): Rfˆ0.27; 1H NMR
(250 MHz, CDCl3): dˆ0.04 (d, Jˆ6.5 Hz, 3H, CH3(iPr)),
0.53 (d, Jˆ6.8 Hz, 3H, CH3(iPr)), 0.81±0.86 (m, 3H, CH3),
1.09 (d, Jˆ7.1 Hz, 3H, CH3), 1.14±1.38 (m, 10H, (CH2)5),
1.60±1.76 (m, 2H, CH(iPr), CH2), 2.08±2.26 (m, 1H, CH2),
2.49±2.68 (m, 2H, CH2Ph, CH2C(O)), 2.80 (s, 3H, NCH3),
2.86 (dd, Jˆ5.2, 17.9 Hz, 1H, CH2C(O)), 3.03±3.08 (m, 1H,
CHC(O)), 3.41 (dd, Jˆ2.2, 13.9 Hz, 1H, CH2Ph), 3.58 (dd,
Jˆ9.4, 9.4 Hz, 1H, CHiPr), 3.74±3.82 (m, 1H, CHOH),
3.83±3.93 (m, 1H, CHN), 4.76±4.84 (m, 1H, CHOC(O)),
6.24 (d, Jˆ10.4 Hz, 1H, NH), 7.08±7.32 (m, 5H, aryl H);
13C NMR (62.9 MHz, CDCl3): dˆ13.0, 14.1, 17.7, 19.0,
22.6, 26.6, 27.9, 28.3, 29.1, 29.2, 29.9, 31.8, 36.0, 37.1,
41.7, 54.1, 60.7, 70.2, 78.8, 126.9, 128.8, 130.0, 137.6,
170.2, 171.7, 171.8;HRMS (EI): calcd for C 28H44N2O5
488.32499, found 488.32773.
5.8. Coupling of the Fmoc protected amino acids 23a±c
with the amino esters 22
Loaded resin 22 was washed with dry CH2Cl2 (2£3 ml),
then allowed to swell in dry CH2Cl2 (3 ml) for 30 min,
and ®nally ®ltered. To a mixture of Fmoc protected amino
acid 23 (3 equiv.) and PyBroP (3 equiv.) in dry CH2Cl2
(3 ml) was added DIEA (6 equiv.) at room temperature.
The reaction solution was added immediately to the resin,
and the resulting mixture was shaken at room temperature
for 12 h. After removal of the reactants by ®ltration, the
resulting resin 24 was washed with [DMF (2£), MeOH
(2£)]£2, CH2Cl2 (4£) and Et2O (2£) and dried in vacuo.
The coupling yield was estimated analogous to the pro-
cedure described above for loaded resin 21. The results
are listed in Table 1.
5.10.2. .2R,3S,6S,9S,10R)-9-Benzyl-2-heptyl-10-hydroxy-
3,6,8-trimethyl-1-oxa-5,8-diazacyclododecane-4,7,12-
trione .4aab). Eluent for ¯ash chromatography: 20%
petroleum ether in ethyl acetate, yield: 0.021 g (33%,
based on 25aab). [a]24 ˆ214.0 (c 0.436, CH2Cl2);TLC
D
(petroleum ether/ethyl acetate, 2:8): Rfˆ0.42; 1H NMR
(400 MHz, CDCl3): dˆ0.65 (d, Jˆ6.6 Hz, 3H, CH3
(6-Me)), 0.88 (m, 3H, CH3), 1.07 (d, Jˆ7.1 Hz, 3H, CH3
(3-Me)), 1.15±1.73 (m, 10H, (CH2)5), 1.61±1.73, 2.04±2.15
(m, 2H, CH2), 2.56 (dd, Jˆ1.4, 15.9 Hz, 1H, CH2C(O)),
2.65 (dd, Jˆ10.7, 13.7 Hz, 1H, CH2Ph), 2.86 (s, 3H,
NCH3), 2.83±2.92 (m, 1H, CH2C(O)), 2.99 (dq, Jˆ6.7,
7.1 Hz, 1H, CHC(O)), 3.36 (dd, Jˆ1.8, 13.7 Hz, 1H,
CH2Ph), 3.72±3.88 (m, 3H, CHMe, CHN, CHOH), 4.74±
4.81 (m, 1H, CHOC(O)), 6.16 (d, Jˆ9.7 Hz, 1H, NH),
7.13±7.27, 7.27±7.36 (m, 5H, aryl H); 13C NMR
(62.9 MHz, CDCl3): dˆ12.6, 14.1, 17.2, 22.6, 26.5, 27.8,
28.6, 29.2, 31.7, 35.5, 37.9, 41.5, 44.4, 61.3, 70.1,
78.9, 126.9, 128.7, 129.6, 137.5, 170.4, 170.9, 172.6;
HRMS (EI): calcd for C26H40N2O5 460.29369, found
460.29928.
5.9. Cleavage of the Fmoc protected amino acids 25 from
the resin
After swelling of the loaded resin 24 in CH2Cl2 (3 ml) for
10 min and subsequent ®ltration, CH2Cl2/TFA 1:1 (2 ml)
was added to the resin, and the mixture agitated at room
temperature for 1 h resulting in a color change to dark
violet. After ®ltration and washing of the resin with
CH2Cl2 (4£3 ml), all ®ltrates were combined, diluted with
CH2Cl2 (10 ml), washed with water (2£10 ml) to remove
TFA, dried (Na2SO4) and concentrated in vacuo. Puri®ca-
tion of the residue by ¯ash chromatography gave the Fmoc
protected amino acids 25. Yields of the isolated products are
listed in Table 1.

C. Hermann et al. / Tetrahedron 5702001) 8999±9010
9009
5.10.3.
.2R,3S,6S,9S,10R)-6,9-Dibenzyl-2-heptyl-10-
(d, Jˆ10.4 Hz, 1H, NH), 7.10±7.35 (m, 10H, aryl H); 13C
NMR (62.9 MHz, CDCl3): dˆ14.1, 17.9, 19.1, 22.7, 28.1,
28.3, 29.3, 29.4, 29.5, 30.1, 31.9, 32.5, 36.0, 37.1, 48.3,
54.3, 60.7, 70.1, 126.3, 127.0, 128.4, 128.7, 128.9, 130.0,
137.6, 140.3, 169.9, 171.3, 171.7;HRMS (EI): calcd for
C38H56N2O5 620.41888, found 620.42180.
hydroxy-3,8-dimethyl-1-oxa-5,8-diazacyclododecane-4,
7,12-trione .4aac). Eluents for ¯ash chromatography: 50
and 40% petroleum ether in ethyl acetate, yield: 0.043 g
(44%, based on 25aac). [a]25 ˆ26.0 (c 0.764, CH2Cl2);
D
TLC (petroleum ether/ethyl acetate, 1:1): Rfˆ0.29; 1H
NMR (400 MHz, CDCl3): dˆ0.76 (d, Jˆ7.2 Hz, 3H, CH3
(3-Me)), 0.85 (t, Jˆ6.7 Hz, 3H, CH3), 1.10±1.33 (m, 10H,
(CH2)5), 1.52±1.61, 1.96±2.07 (m, 2H, CH2), 2.29 (dd,
Jˆ4.9, 13.9 Hz, 1H, CH2Ph(6-Bn)), 2.52±2.70 (m, 3H,
CH2C(O), CH2Ph(6-Bn), CH2Ph(9-Bn)), 2.84±2.94 (m,
2H, CH2C(O), CHC(O)), 2.89 (s, 3H, NCH3), 3.37 (dd,
Jˆ1.4, 13.3 Hz, 1H, CH2Ph(9-Bn)), 3.81±3.86 (m, 2H,
CHOH, CHN), 3.90±3.97 (m, 1H, CHBn), 4.65±4.73 (m,
1H, CHOC(O)), 6.24 (d, Jˆ10.3 Hz, 1H, NH), 6.77±6.83
(m, 2H, aryl H), 7.05±7.41 (m, 8H, aryl H); 13C NMR
(62.9 MHz, CDCl3): dˆ12.4, 14.0, 22.6, 26.5, 27.8, 28.7,
29.1, 29.2, 31.7, 35.3, 37.6, 37.7, 41.3, 49.5, 60.7, 70.1,
79.0, 126.2, 127.0, 127.7, 128.4, 128.8, 129.5, 129.8,
129.9, 137.0, 137.7, 170.5, 170.9, 172.0;HRMS (EI):
calcd for C32H44N2O5 536.32502, found 536.33003.
5.10.6. .2R,3S,6S,9S,10R)-9-Benzyl-3-decyl-2-heptyl-10-
hydroxy-6-isopropyl-8-methyl-1-oxa-5,8-diazacyclodo-
decane-4,7,12-trione .4caa). Eluents for ¯ash chromato-
graphy: 30 and 40% ethyl acetate in petroleum ether,
yield: 0.035 g (57%, based on 25caa). [a]25 ˆ24.2 (c
D
0.717, CH2Cl2);TLC (petroleum ether/ethyl acetate, 6:4):
Rfˆ0.32; 1H NMR (400 MHz, CDCl3): dˆ0.07 (d,
Jˆ6.6 Hz, 3H, CH3(iPr)), 0.59 (d, Jˆ7.1 Hz, 3H,
CH3(iPr)), 0.85 (m, 6H, 2£CH3), 1.08±1.41 (m, 27H,
(CH2)5, (CH2)8, CH2(decyl)), 1.68±1.77 (m, 3H, CH(iPr),
CH2(decyl), CH2(heptyl)), 2.18±2.30 (m, 1H, CH2(heptyl)),
2.52±2.71 (m, 2H, CH2C(O), CH2Ph), 2.83 (s, 3H, NCH3),
2.88 (dd, Jˆ5.3, 18.1 Hz, 1H, CH2C(O)), 2.96±3.03 (m, 1H,
CHC(O)), 3.44 (dd, Jˆ1.8, 13.7 Hz, 1H, CH2Ph), 3.68 (dd,
Jˆ9.3, 9.3 Hz, 1H, CHiPr), 3.76±3.82 (m, 1H, CHOH),
3.86±3.94 (m, 1H, CHN), 4.76±4.83 (m, 1H, CHOC(O)),
6.64 (d, Jˆ10.2 Hz, 1H, NH), 7.16±7.25, 7.26±7.33 (m, 5H,
aryl H); 13C NMR (62.9 MHz, CDCl3): dˆ14.1, 17.9, 19.1,
22.7, 26.7, 28.0, 28.1, 28.2, 28.3, 29.2, 29.3, 29.4, 29.6,
30.1, 31.8, 31.9, 35.7, 37.0, 48.1, 54.4, 60.6, 70.1, 78.7,
126.9, 128.8, 130.0, 137.6, 170.2, 171.5, 171.9;HRMS
(EI): calcd for C37H62N2O5 614.46583, found 614.46757.
5.10.4.
.2R,3S,6S,9S,10R)-3,9-Dibenzyl-2-heptyl-10-
hydroxy-6-isopropyl-8-methyl-1-oxa-5,8-diazacyclodo-
decane-4,7,12-trione .4baa). Eluents for ¯ash chromato-
graphy: 50 and 40% petroleum ether in ethyl acetate,
yield: 0.013 g (64%, based on 25baa). [a]24 ˆ235.3 (c
D
0.23, CH2Cl2);TLC (petroleum ether/ethyl acetate, 1:1):
Rfˆ0.29; 1H NMR (400 MHz, CDCl3): dˆ20.04 (d,
Jˆ6.7 Hz, 3H, CH3(iPr)), 0.10 (d, Jˆ6.7 Hz, 3H,
CH3(iPr)), 0.91 (m, 3H, CH3), 1.28±1.53 (m, 11H, (CH2)5,
CH(iPr)), 1.80±1.90 (m, 1H, CH2), 2.31±2.43 (m, 1H, CH2),
2.54 (dd, Jˆ1.3, 17.9 Hz, 1H, CH2C(O)), 2.64 (dd, Jˆ10.7,
13.9 Hz, 1H, CH2Ph(9-Bn)), 2.71 (dd, Jˆ4.1, 13.0 Hz, 1H,
CH2Ph(3-Bn)), 2.81 (s, 3H, NCH3), 2.92 (dd, Jˆ4.9,
17.9 Hz, 1H, CH2C(O)), 2.01 (dd, Jˆ11.2, 13.0 Hz, 1H,
CH2Ph(3-Bn)), 3.38 (ddd, Jˆ4.1, 6.8, 11.2 Hz, 1H,
CHC(O)), 3.46 (dd, Jˆ1.8, 13.9 Hz, 1H, CH2Ph(9-Bn)),
3.59 (dd, Jˆ7.6, 10.3 Hz, 1H, CHiPr), 3.78±3.91 (m, 2H,
CHN, CHOH), 4.81±4.95 (m, 1H, CHOC(O)), 5.84 (d,
Jˆ10.3 Hz, 1H, NH), 7.15±7.35 (m, 10H, aryl H); 13C
NMR (62.9 MHz, CDCl3): dˆ14.1, 17.1, 19.0, 22.7, 26.7,
28.2, 28.3, 29.2, 29.7, 31.8, 34.4, 35.8, 36.9, 50.1, 54.1,
60.7, 70.1, 78.5, 126.8, 126.9, 128.6, 128.8, 129.9, 137.6,
138.1, 170.3, 171.7;HRMS (EI): calcd for C 34H48N2O5
564.35628, found 564.35795.
Acknowledgements
Financial support by the Deutsche Forschungsgemeinschaft
and the Fonds der Chemischen Industrie is gratefully
acknowledged.
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