Total synthesis of hapalosin and two ring expanded analogs

Article abstract of DOI:10.1016/S0040-4020(00)00772-9

The macrocyclic depsipeptide hapalosin was assembled from three subunits. Beginning with the condensation of a protected β-hydroxy acid 13 with the α-hydroxy ester 14, the hydroxy diester 16 was produced. This compound, in turn, was condensed with the γ-amino-β-hydroxy acid 17. Macrocyclization was performed on the fully deprotected amino acid 20. In a similar manner, a cyclization substrate 28 was prepared that contains valine instead of the α-hydroxy acid. In this case, however, the cyclization with the Shioiri reagent induced a Curtius rearrangement prior to the cyclization reaction. As a result the two ring expanded hapalosin analogs 29 and 30 were formed. The conformations of the three macrocycles were studied by 2D NMR spectroscopy and molecular dynamics simulation. It was found that in DMSO-d₆ all of them prefer the s-trans-amide rotamer around the tertiary amide. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4020(00)00772-9

TETRAHEDRON
Pergamon
Tetrahedron 56 (2000) 8461±8471
Total Synthesis of Hapalosin and Two Ring Expanded Analogs
a
Christoph Hermann, Godwin C. G. Pais, Armin Geyer, Sven M. Kuhnert and
a
b
a
È
Martin E. Maiera,
*
a
È È È È
Institut fur Organische Chemie, Universitat Tubingen, Auf der Morgenstelle 18, D-72076 Tubingen, Germany
b
È
È
È
Fakultat fur Chemie, Universitat Konstanz, D-78457 Konstanz, Germany
Dedicated to Professor Dr Richard R. Schmidt on the occasion of his 65th birthday
Received 21 August 2000; accepted 29 August 2000
AbstractÐThe macrocyclic depsipeptide hapalosin was assembled from three subunits. Beginning with the condensation of a protected
b-hydroxy acid 13 with the a-hydroxy ester 14, the hydroxy diester 16 was produced. This compound, in turn, was condensed with the
g-amino-b-hydroxy acid 17. Macrocyclization was performed on the fully deprotected amino acid 20. In a similar manner, a cyclization
substrate 28 was prepared that contains valine instead of the a-hydroxy acid. In this case, however, the cyclization with the Shioiri reagent
induced a Curtius rearrangement prior to the cyclization reaction. As a result the two ring expanded hapalosin analogs 29 and 30 were formed.
The conformations of the three macrocycles were studied by 2D NMR spectroscopy and molecular dynamics simulation. It was found that in
DMSO-d6 all of them prefer the s-trans-amide rotamer around the tertiary amide. q 2000 Elsevier Science Ltd. All rights reserved.
Introduction
methyl-hapalosin 2,6 8-deoxy-hapalosin 3,13 and the
triamide analog 4.6
For the chemotherapy of cancer a large number of cytotoxic
compounds that attack cells at various locations are in use.
However, chemotherapy still is associated with a lot of
problems due to toxic side effects and the phenomenon of
resistance. In many cases resistance is caused by over-
expression of the MDR 1 gene that encodes for a 170 kDa
p-glycoprotein.1 This membrane protein functions as a drug
ef¯ux pump thereby making drugs essentially ineffective. In
order to make resistant cells susceptible for cytotoxic drugs,
inhibitors of this p-glycoprotein are necessary. In fact,
several natural and synthetic compounds are known to
antagonize MDR caused by the p-glycoprotein.2,3 Among
these compounds, the natural product hapalosin (1) has
aroused a great deal of interest (Fig. 1). Structurally,
hapalosin is a depsipeptide consisting of three subunits, a
b-hydroxy acid A, a g-amino-b-hydroxy acid B and an
a-hydroxy acid C.
While hapalosin and verapamil (as a control) have similar
activity in reversing MDR, the triamide 4 is less active. The
8-deoxy-hapalosin is devoid of any activity. Also the non-
Me-analog 2 was found to be substantially weaker. This was
attributed to a change of the major conformation from the
s-cis- to the s-trans amide rotamer. In order to restrain the
conformation around the secondary amide, the group of
Armstrong designed four proline analogs of hapalosin.11
Among them, compounds 5 and 6 turned out to surpass
hapalosin in the biological activity. The most recent paper
concerning the synthesis of hapalosin analogs was published
by Schwartz et al. as illustrated with compounds 7±9.14
Due to its biological activity and structure hapalosin has
triggered a lot of synthetic activity. For example, since the
disclosure of the hapalosin structure,4 several syntheses of
the natural product have been published.5±14 Moreover, with
a view to establish a structure±activity correlation and to
improve upon the activity of hapalosin, some hapalosin
analogs were prepared (Fig. 2). These include non-N-
Keywords: conformation; depsipeptides; macrocycles; NMR; peptide
analogs; rearrangements.
* Corresponding author. Tel.: 149-7071-29-75247; fax: 149-707-129-
5137; e-mail: martin.e.maier@uni-tuebingen.de
Figure 1. Structure and building blocks for hapalosin (1).
0040±4020/00/$ - see front matter q 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(00)00772-9

8462
C. Hermann et al. / Tetrahedron 56 (2000) 8461±8471
Figure 2. Structure of some hapalosin analogs from the literature.
activity. As illustrated above hapalosin can be modi®ed by
rational design but with its modular structure it is particu-
larly suited for variations in a more random, respectively
combinatorial manner.15,16 This way it might even be pos-
sible to generate other kinds of biological activity. Our plan
for a combinatorial variation is illustrated in Fig. 3.
Thus, a number of b-hydroxy acids A could easily be
prepared by an Evans aldol reaction.17,18 In order to install
different side-chains in the unusual amino acid B, we
developed two ¯exible syntheses that allow for the replace-
ment of the phenyl group. Finally, we planned to replace the
a-hydroxy acid C with a range of a-amino acids. In this
paper we report the synthesis of hapalosin (1) and an
interesting observation during the attempted synthesis of a
molecule of type 10.
Figure 3. Design of hapalosin analogs suitable for parallel synthesis. The
a-hydroxy acid is replaced by an a-amino acid.
These authors reported on variations at positions 12, 3, 4 and
8 (hapalosin numbering). Some substituent modi®cations
resulted in lower cytotoxicities, but most structural changes
were either detrimental or did not alter the MDR-reversing
Synthesis of Hapalosin
A crucial step in the synthesis of hapalosin is obviously the
macrocyclization reaction. Most of the known syntheses
Scheme 1. Assembly of the protected acyclic precursor 18 by condensation reactions.

C. Hermann et al. / Tetrahedron 56 (2000) 8461±8471
8463
with the b-hydroxy acid derivative 11 which was prepared
by an Evans aldol reaction (Scheme 1).13 After protection of
the hydroxyl group as its tetrahydropyranyl ether 12, the
chiral auxiliary was removed under basic conditions to
provide the known acid 13.8 Subsequently, the acid 13
was condensed with the a-hydroxy benzyl ester6 14 using
the Yamaguchi reagent (2,4,6-trichlorobenzoyl chloride) as
an activating agent. Following removal of the THP-
protecting group, the alcohol 16 was acylated with the
amino acid 17. Again, the use of the Yamaguchi reagent
secured a high yield in the coupling step. The synthesis of
the O- and N-protected g-amino-b-hydroxy acid 17 has
been described elsewhere.19,20 One of our routes is based
on an Aldol/Curtius combination whereas the other route
features an asymmetric dihydroxylation, an epoxide
opening and a Mitsunobu reaction as key steps.
The next steps which are basically protecting group
manipulations required some careful optimizations
(Scheme 2). After some trials, the methoxymethyl group
could be selectively removed with the combination of
trimethylsilyl chloride and tetrabutylammonium bromide
giving rise to the triester 19. Subsequent reductive removal
of the benzyl group gave the carboxylic acid 20. This was
followed by acid-induced cleavage of the N-boc protecting
group providing the cyclization substrate 21. The
subsequent cyclization proved to be quite dif®cult. Using
well-established reaction conditions, that is, the use of
diphenylphosphoryl azide,21,22 diisopropylethylamine in
DMF under high dilution conditions, a yield of 23% for 1
could be realized. This way, suf®cient material for
spectroscopic studies could be secured. The structure was
determined by mass spectrometry and NMR spectroscopy.
Scheme 2. Deprotection of 18 and macrocyclization of 21 to give hapalosin
(1).
rely on the formation of the amide bond from a suitable
precursor. These reactions are dif®cult because
a
12-membered ring has to be formed and the amide is a
tertiary one. This way moderate yields for 1 can be realized.
As it turned out, however, formation of the ester bond
between O5 and C6 is even less ef®cient.6 The major
difference between the various total syntheses are related
to the choice of protecting groups. Our synthesis is patterned
along similar lines. We began the synthesis of hapalosin (1)
Scheme 3. Assembly of the analog precursor 28 and its cyclization to the ring expanded analogs 29 and 30.

8464
C. Hermann et al. / Tetrahedron 56 (2000) 8461±8471
Figure 4. ROESY spectrum of the macrocycle 29 (600 MHz, 300 K). Average distances (pm) were calculated from the cross peak intensities by the two-spin
approximation.

C. Hermann et al. / Tetrahedron 56 (2000) 8461±8471
8465
Synthesis of the Ring Expanded Analogs
tion, compounds 1, 29 and 30 were studied by homo- and
1
heteronuclear NMR methods. H and 13C resonance signal
Replacing the a-hydroxy acid with an a-amino acid should
allow for the easy variation at that position. According to the
order of events which we had established for hapalosin, the
synthesis of the analog 10 was approached (Scheme 3).
Thus, the para-toluenesulfonic acid salt of the valine benzyl
ester 22 was condensed with the carboxylic acid 13 in the
presence of benzotriazol-1-yloxy-tris(dimethylamino)-
phosphoniumhexa¯uorophosphate (BOP) to provide the
amide 23. After liberation of the hydroxyl group using
p-TsOH in MeOH, esteri®cation of the resulting 24 with
the amino acid 17 delivered compound 25. As for the
synthesis of hapalosin, all protecting groups were removed
prior to the macrocyclization reaction. First, trimethylsilyl
bromide caused cleavage of the MOM-protecting group
providing the alcohol 26. Subsequent hydrogenolytic
removal of the benzyl group led to the amino acid 27.
This was followed by the hydrolysis of the boc-protecting
group to yield the cyclization substrate 28. The crucial
macrocyclization of 28 was attempted under similar con-
ditions as for the production of hapalosin 1. Running the
cyclization reaction for 3 days at room temperature
produced two new products that showed the expected
assignments of 1, 29, and 30 were performed in DMSO-d6
where hapalosin shows a doubled signal set due to isomer-
ism about the tertiary amide bond. The two isomers of 1
were distinguished by the strong NOE between H-6 and
H-10 which can be observed only for the cis-isomer. The
trans-isomer is the dominating isomer in DMSO-d6 (75%)
while it is the less populated isomer in CDCl3. The solution
structure of the trans-isomer of Hapalosin was not solved
before.6 Since it closely resembles the two ring-expanded
analogs 29 and 30, we include the structural analysis of
trans-1 here. A structure of the s-trans rotamer of hapalosin
obtained by MM2p force ®eld calculations differs from our
one in the area C2±O1±C12.13 The gradient-selected
HMBC spectrum of the ring-expanded analog 29 proved
the Curtius rearrangement and the ring closure by the
heteronuclear scalar couplings between C-8 (d 157.3) and
H-7 (2JC,H), H-6 (3JC,H), and H3-25 (3JC,H). The resonance
signal assignments were performed from DQF-COSY,
TOCSY and HMQC spectra. Compensated ROESY23±25
spectra (O1ˆ2.1 ppm, 4 kHz pulsed spin lock, 200 ms
mixing time) were acquired, an expansion is shown in
Fig. 4. Spin diffusion is neglectable under these experimen-
tal conditions and the volume integral of each cross-peak
correlates with a single interproton distance (two-spin
approximation).26 The macrocyclic rings effectively
constrain the solution conformations of 29 and 30 to a single
minimum which are characterized by well-separated NOE
intensities.
1
polarity on TLC. Compared to the H NMR spectrum of
hapalosin, the two spectra showed same characteristic
differences. First, each of them was devoid of rotamers. In
addition, the signal that corresponds to H-9 of hapalosin was
shifted down®eld from dˆ3.73 to around dˆ4.55 in 29 and
4.52 in 30. A signi®cant shift, although less pronounced was
seen for H-12 (CHiPr), which appears at dˆ4.30 in 1, at
4.46 in 29 and 4.12 in 30. Particularly revealing were the
mass spectra for the two macrocycles 29 and 30. They
showed masses which are by 14 amu higher than expected.
Based on this and additional NMR data the structures of
these macrocycles could be assigned to the cyclic dia-
cylamines 29 and 30. Their molecular formula were
supported by high resolution mass spectra using a FT-
ICR-mass spectrometer.
The prochiral assignments of the diastereotopic methylene
groups CH2-12 and CH2-17 are based on the combined data
of the NOE intensities and the JH,H coupling constants.
3
Even the con®gurational assignment of C-6 was possible
by NMR spectroscopy. In isomer 29, an intense NOE corre-
lation was observed between H-7 and H-6 (Fig. 4) and an
antiperiplanar orientation of H-5 and H-6 (3JH5,H6ˆ11 Hz).
30 Exhibits an intense correlation between H-7 and H-22
and an antiperiplanar orientation of H-6 and H-7
(3JH5,H6ˆ10 Hz). The cross signal intensities in the
ROESY spectra of 1, 29 and 30 were integrated and
offset-corrected. The proton±proton distances of 29 listed
in Table 1 were calculated according to the r26-dependence
Conformational Studies
To further elucidate the molecular structure and conforma-
Ê
Table 1. Interproton distances (A) obtained from a compensated ROESY spectrum served as weak distance restraints for a 100 ms molecular dynamics
simulation of 29; averaging of ten snapshots was followed by energy minimization without distance restraints; interproton distances of this average
conformation are listed in the column MD distance; deviations between experimental and calculated average distances are below 10% for short distances
Ê
Ê
(,2.5 A), and below 20% for distances above 2.5 A; deviations above 10% are indicated
H±H
Experimental
MD distance
H±H
Experimental
MD distance
2±3
5±6
5±21
5±22
5±24
6±7
6±22
7±10
7±22
10-OH
10±12proR
10±12proS
10±26proS
11±12proR
2.3
3.05
2.5
2.4
3.0
2.2
3.0
3.15
3.2
3.35
2.95
2.3
2.5
2.95
2.55
2.5
3.15
2.25
3.05
4.35 (28%)
3.70 (15%)
3.55
3.6
2.4
11±12proS
11±26proR
11±26proS
11-OH
3.2
2.5
3
2.55
2.8
3.1
2.65
3.3
2.25 (11%)
2.35 (18%)
12proR-OH
H±CH3
6±23proR
6±24proS
7±24proS
7±25
2.7
2.7
3.1
2.4
3.2
2.5
2.7
2.7
2.8
3.35
2.55
3.45
2.95 (15%)
2.9
10±25
11±25
2.45
2.5
2.4
2.65
26proR±25

8466
C. Hermann et al. / Tetrahedron 56 (2000) 8461±8471
Figure 5. Energy-minimized average conformations of 1 (trans-conformer), 30, and 29. To simplify the calculation, the side-chains were shortened by two
atoms.
(rˆinterproton distance) of the NOE.27 The average
distances served as restraints in a molecular dynamics simu-
lation. An additional weak torsional restraint was included
for the dominating -gauche rotamer around the benzylic side
chain. The interproton distances taken from an averaged and
energy-minimized computer model of 29 are also listed in
Table 1. A single conformational minimum of 29 ful®lls the
network of 26 NOEs. The conformational homogeneity
being a requirement for the direct quanti®cation of
NOEs.28 The structures of 30 and trans-1 were determined
the same way, they are also shown in Fig. 5.
according to literature procedures: (4S)-4-benzyl-3-propionyl-
1,3-oxazolidin-2-one,38 (S)-(1)-2-hydroxy-3-methylbutyric
acid benzyl ester 14,6 the amino acid 17,20 l-valine benzyl
ester toluene-4-sulfonate 22.39±41
Hapalosin (1). To a solution of amino acid 21 (0.065 g,
0.128 mmol) in DMF (128 ml) were added diphenyl-
phosphoryl azide DPPA (0.083 ml, 0.385 mmol) and
iPr2NEt (0.130 ml, 0.765 mmol) at 08C. The mixture was
stirred at this temperature for 3 h, then at room temperature
for 4 days. The resulting mixture was partitioned between
ethyl acetate and water. The organic layer was washed with
brine, dried (Na2SO4), ®ltered and evaporated. Puri®cation
of the residue by ¯ash chromatography (petroleum ether/
ethyl acetate, 6:4) gave 14 mg of hapalosin (1).
[a]2D5ˆ241.7 (c 0.078, CH2Cl2); TLC (ethyl acetate/
petroleum ether, 4:6): Rfˆ0.43; IR (neat): 3420, 1733,
The solution conformation of the ring-expanded hapalosin-
analog 30 closely resembles the trans-isomer of 1. Both
have a very similar arrangement of peptidic side-chains
with the structural differences restricted to the macrolide
backbone.
;
1635, 1489, 1456, 1187 cm21 1H NMR (400 MHz,
It is interesting to note that the presence of the amide bond
in compound 28 seemingly favors the Curtius rearrange-
ment of the intermediate acyl azide.29±37 The Curtius
rearrangement of acyl azides followed by trapping of the
intermediate isocyanates with nucleophiles has been
occasionally described in the context of the synthesis of
peptide mimetics. Alternatively, gem-diamino derivatives
can be accessed via this route. The current strategy might
be very useful for the synthesis of other cyclic urea
derivatives.
CDCl3): d (major isomer)ˆ0.21 (d, Jˆ6.6 Hz, 3H,
CH3(iPr)), 0.54 (d, Jˆ7.8 Hz, 3H, CH3(iPr)), 0.85±0.89
(m, 3H, CH3), 1.16 (d, Jˆ7.1 Hz, 3H, Me), 1.23±1.38 (m,
10H, (CH2)5), 1.62±1.93 (m, 2H, CH2),1.95±2.04 (m, 1H,
CH(iPr)), 2.56±2.68 (m, 2H, CH2C(O), CH2Ph), 2.83 (s, 3H,
NCH3), 2.91 (dd, Jˆ17.7, 4.9 Hz, 1H, CH2C(O)), 3.21 (t,
Jˆ6.6 Hz, 1H, CH2Ph), 3.39 (dd, Jˆ13.7, 2.2 Hz, 1H,
CH2Ph), 3.66±3.72 (m, 1H, CHN), 3.78±3.85 (m, 1H,
CHOH), 4.30 (d, Jˆ8.4 Hz, 1H, CHiPr), 5.06±5.14 (m,
1H, CHOC(O)), 7.16±7.35 (m, 5H); 13C NMR
(100.6 MHz, CDCl3): dˆ12.1, 14.1, 17.6, 18.3, 22.6, 26.1,
28.1, 28.8, 29.0, 29.1, 29.2, 29.3, 31.7, 36.5, 37.1, 40.7,
61.5, 70.2, 73.9, 76.4, 127.1, 128.4, 128.9, 129.7, 137.4,
168.5, 168.7, 172.7; HRMS (ESI): calcd for 490.31632,
found 490.31649.
Experimental
General
1H and 13C NMR: Bruker AC 250, Bruker AMX 400, Bruker
DRX 600; all spectra were recorded in CDCl3 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. EI-MS: AMD Intectra
GmbH AMD 402. ES-FT-ICR-MS: Bruker Daltonic APEX
II. HPLC: Hewlett±Packard HP 1100. Flash chroma-
tography: 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 of 35±
658C was used. The following compounds were prepared
(4S)-4-Benzyl-3-[(2S,3R)-3-hydroxy-2-methyldecanoyl]-
1,3-oxazolidin-2-one (11).13 To a solution of (4S)-4-benzyl-
3-propionyl-1,3-oxazolidin-2-one (3.11 g, 13.3 mmol) and
triethylamine (2.34 ml, 16.8 mmol) in CH2Cl2 (70 ml) was
added n-Bu2BOTf (1 M in CH2Cl2, 15.4 ml, 15.4 mmol) in
a dropwise fashion at 08C. The mixture was stirred at the
same temperature for 30 min, and then cooled to 2788C
before octanal (2.3 ml, 14.7 mmol) was added dropwise at
2788C. The solution was stirred at 2788C for 1 h and at
room temperature for 2 h. After quenching of the reaction
with phosphate buffer (pH 7.0, 70 ml), the mixture was
extracted with CH2Cl2 (3£70 ml). The organic extracts

C. Hermann et al. / Tetrahedron 56 (2000) 8461±8471
8467
were combined, dried (Na2SO4), ®ltered and concentrated in
vacuo. The residue was dissolved in MeOH (70 ml), and
30% aqueous H2O2 (42 ml) was added at 08C. After being
stirred at 08C for 1 h, the reaction was quenched by the
addition of 10% aqueous NaHSO4. The mixture was
extracted with ethyl acetate (3£70 ml), and the organic
extracts were washed with saturated aqueous NaHCO3 and
brine, dried (Na2SO4), ®ltered and concentrated in vacuo.
The residue was puri®ed by ¯ash chromatography (25%
EtOAc in petroleum ether as eluent) to yield 4.35 g (90%)
of 11 as colorless oil. [a]2D1ˆ142.6 (c 1.4, CHCl3); TLC
(petroleum ether/ethyl acetate, 3:1): Rfˆ0.43; IR (neat):
3854 (s), 3087 (w), 2927 (s), 1779 (s), 1698 (s), 1386 (s),
room temperature, the excess H2O2 was quenched by the
addition of sodium sul®te (2.12 g, 16.8 mmol) in distilled
water (10 ml). The bulk of the tetrahydrofuran was removed
by rotary evaporation at a bath temperature of 25±308C, and
the remainder was extracted with dichloromethane
(3£20 ml) to remove the oxazolidinone auxiliary. The
aqueous layer was cooled in an ice bath, acidi®ed to pH 2
with aqueous 1N hydrochloric acid, and the resulting cloudy
solution was then extracted with diethyl ether (5£20 ml).
The combined ether extracts were dried (Na2SO4), ®ltered,
and concentrated. The residue was puri®ed by ¯ash chro-
matography (petroleum ether/ethyl acetate, 7:3) to give
0.81 g (84%) of 13 as a colorless oil. [a]2D3ˆ144.7 (c 1.2,
CHCl3); TLC (petroleum ether/ethyl acetate, 7:3): Rfˆ0.63;
1209 (s), 971 (s), 702 (s) cm21 1H NMR (250 MHz,
;
CDCl3): dˆ0.86 (t, Jˆ6.5 Hz, 3H, CH3), 1.21±1.27 (m,
13H, (CH2)5, Me), 1.33±1.58 (m, 2H, CH2), 2.77 (dd,
Jˆ13.4, 9.5 Hz, 1H, CH2Ph), 3.23 (dd, Jˆ13.4, 3.3 Hz,
1H, CH2Ph), 3.75 (qd, Jˆ4.6, 2.5 Hz, 1H, CHMe), 3.90±
3.96 (m, 1H, CHOH), 4.16±4.25 (m, 2H, CH2O), 4.66±4.73
(m, 1H, CHN), 7.17±7.21 (m, 2H), 7.23±7.36 (m, 3H); 13C
NMR (CDCl3): dˆ10.4, 14.1, 22.7, 26.1, 29.3, 29.6, 31.9,
33.9, 37.8, 42.1, 55.2, 66.2, 71.6, 127.5, 129.0, 129.5, 135.1,
153.1, 177.6; MS (EI): m/z (%)ˆ361 (4) [M1], 343 (5), 233
(8), 178 (9), 134 (11), 86 (100); HRMS (EI): calcd for
361.22529, found 361.22922.
IR (neat): 3500±2500 (br), 1708 (s) cm21 1H NMR
;
(250 MHz, CDCl3): dˆ0.81 (t, Jˆ7.0 Hz, 3H, CH3), 1.10
(dd, Jˆ1.5, 7.0 Hz, 3H, Me), 1.14±1.35 (m, 10H, (CH2)5),
1.36±1.72 (m, 8H, CH2, 3£CH2(THP)), 2.57±2.75 (m, 1H,
CHMe), 3.39±3.45 (m, 1H, CHOTHP), 3.79±3.92 (m, 2H,
CH2O), 4.57±4.65 (m, 1H, CH(THP)), 10.87 (s, br., 1H);
13C NMR: dˆ10.9, 11.7, 14.1, 19.8, 20.1, 22.7, 25.2, 25.4,
25.6, 25.7, 29.2, 29.6, 30.9, 31.1, 31.3, 31.8, 32.7, 42.3, 43.6,
62.8, 63.3, 78.6, 79.0, 99.1, 99.3, 179.3, 180.6; MS (EI): m/z
(%)ˆ287 (16) [M111], 203 (30), 185 (46), 101 (77), 85 (100).
(1S)-1-[(Benzyloxy)carbonyl]-2-methylpropyl (2S,3R)-2-
methyl-3-(tetrahydro-2H-pyran-2-yloxy)decanoate (15).8
To a solution of the carboxylic acid 13 (100 mg,
0.349 mmol) and triethylamine (58 ml, 0.419 mmol) in
THF (1 ml) was added the Yamaguchi reagent (568 ml,
0.349 mmol) followed by stirring of the reaction mixture
at room temperature for 30 min. The amine hydrochloride
salt was ®ltered off under argon and the ®ltrate concentrated
under reduced pressure. The residue was redissolved in
benzene (1 ml), the hydroxy compound 14 in benzene
(1 ml) was added dropwise to the mixed anhydride solution,
and ®nally dimethylaminopyridine (DMAP) (85 mg,
0.699 mmol) was added. The solution turns cloudy. After
stirring the reaction mixture at room temperature for
90 min it was diluted with diethyl ether, washed succes-
sively with 3% HCl, water, saturated aqueous NaHCO3
and water. The organic layer was dried (Na2SO4), ®ltered,
and concentrated. The residue was puri®ed by ¯ash chro-
matography (petroleum ether/ethyl acetate, 9:1) to provide
0.140 g (87%) of 15 as a colorless oil. [a]2D3ˆ29.2 (c 1.0,
CHCl3); TLC: Rfˆ0.44 (petroleum ether/ethyl acetate, 9:1);
(4S)-4-Benzyl-3-[(2S,3R)-2-methyl-3-(tetrahydro-2H-pyran-
2-yloxy)decanoyl]-1,3-oxazolidin-2-one (12). A solution
of 11 (2.80 g, 7.76 mmol) and dihydropyran (1.30 g,
15.5 mmol) in dry dichloromethane (20 ml) containing pyri-
dinium-p-toluene sulfonate (PPTS) (0.097 g, 0.388 mmol)
was stirred overnight at room temperature. Then the solu-
tion was diluted with dichloromethane and washed once
with half-saturated brine to remove the acid catalyst. Drying
of the combined organic layers (Na2SO4), ®ltration and
evaporation of the solvent provided the crude product
which was puri®ed by ¯ash chromatography (10% EtOAc
in petroleum ether) to yield 3.04 g (88%) of 12 as a colorless
oil. TLC (petroleum ether/ethyl acetate, 9:1): Rfˆ0.46; IR
(neat): 3063 (m), 3028 (m), 2928 (s), 2855 (s), 1782 (s),
1
1699 (s), 1209 (s), 702 (s) cm21; H NMR (250 MHz,
CDCl3): dˆ0.80 (dd, Jˆ0.9, 5.5 Hz, 3H), 1.13±1.35 (m,
13H, (CH2)5, Me), 1.40±1.97 (m, 8H, CH2, 3£CH2(THP)),
2.70 (dd, Jˆ3.4, 9.9 Hz, 1H, CH2Ph), 3.20±3.43 (m, 2H,
CH2Ph, CHOTHP), 3.68±4.02 (m, 3H, CHMe,
CH2O(THP)), 4.06±4.11 (m, 2H, CH2O), 4.42±4.59 (m,
2H, CHN, CH(THP)), 7.29±7.36 (m, 5H); 13C NMR
(CDCl3): dˆ10.7, 12.1, 14.1, 19.9, 20.4, 22.7, 25.5, 25.9,
29.3, 29.7, 29.8, 30.8, 31.2, 31.85, 31.9, 32.5, 33.4, 37.8,
37.9, 41.1, 42.1, 55.97, 56.3, 62.96, 63.6, 66.1, 66.2, 77.6,
78.4, 98.8, 98.9, 127.3, 127.4, 128.9, 129.5, 135.4, 135.8,
153.2, 153.5, 174.9, 175.6; MS (EI): m/z (%)ˆ446 (14)
[M111], 344 (7), 233 (41.3), 178 (14), 85 (100); HRMS
(EI): calcd for 445.28280, found 445.28537.
1
IR (neat): 1742 (s) cm21; H NMR (250 MHz, CDCl3):
dˆ0.80 (t, Jˆ6.9 Hz, 3H, CH3), 0.84±0.95 (m, 6H,
2£CH3(iPr)), 1.12 (dd, Jˆ7.2, 1.4 Hz, 3H, Me), 1.16±1.33
(m, 10H, (CH2)5), 1.38±1.75 (m, 8H, CH2, 3£CH2(THP)),
2.16±2.21 (m, 1H, CH(iPr)), 2.63±2.68 (m, 1H, CHMe),
3.31±3.45 (m, 1H, CHOTHP), 3.79±3.91 (m, 2H, CH2O),
4.55, 4.61 (2£m, 1H, CH(THP)), 4.78 (dd, Jˆ2.8, 1.8 Hz,
1H, CHiPr), 5.15 (d, Jˆ1.5 Hz, 2H, CH2(Bn)), 7.22±7.33
(m, 5H); 13C NMR (CDCl3): dˆ11.2, 12.9, 14.1, 17.3, 18.8,
19.9, 20.1, 22.7, 24.99, 25.5, 29.3, 29.7, 30.2, 31.0, 31.7,
31.9, 33.3, 42.8, 44.1, 62.7, 62.98, 66.7, 66.95, 76.3, 76.7,
79.0, 97.8, 99.9, 128.3, 128.5, 128.6, 135.8, 169.5, 174.6;
MS (EI): m/z (%)ˆ477 (10.4) [M111], 393 (100), 375 (19),
239 (6), 85 (27).
(2S,3R)-2-Methyl-3-(tetrahydro-2H-pyran-2-yloxy)de-
canoic acid (13).8 To a solution of oxazolidinone 13
(1.50 g, 3.37 mmol) in tetrahydrofuran-distilled water (3:1
v/v, 67 ml) was added H2O2 (30% aqueous solution, 2.3 ml,
16.85 mmol) at 08C via syringe over a 5-min period. This
was followed by the addition of LiOH (0.283 g, 6.74 mmol),
dissolved in water (6.7 ml). Some gas evolved from the
clear solution. After stirring for 1 h at 08C and for 2.5 h at
(1S)-1-[(Benzyloxy)carbonyl]-2-methylpropyl (2S,3R)-3-
hydroxy-2-methyldecanoate (16). A solution of the diester

8468
C. Hermann et al. / Tetrahedron 56 (2000) 8461±8471
15 (0.20 g, 0.42 mmol) and a small amount of p-TsOH
(8 mg, 0.042 mmol) in MeOH (6 ml) was stirred at room
temperature for 1 h and then quenched by the addition of
aqueous 2N NaHCO3 solution (5 ml). Most of the MeOH
was removed under reduced pressure and the resulting
slurry extracted with diethyl ether (3£20 ml). The combined
organic layers were dried (Na2SO4), ®ltered and concen-
trated. The crude product was puri®ed by ¯ash chromato-
graphy (petroleum/ethyl acetate, 8:2) to yield 0.153 g (93%)
of 16 as a colorless oil (petroleum ether/ethyl acetate, 8:2).
TLC (petroleum ether/ethyl acetate, 7:3): Rfˆ0.62;
[a]2D1ˆ212.2 (c 1.76, CHCl3); IR (neat): 3544 (s), 1743
(EI): calcd for C35H56NO10 [M12PhCH2] 650.390423,
found 650.38698.
(1R)-1-[(1S)-2-({(1S)-1-[(Benzyloxy)carbonyl]-2-methyl-
propyl}oxy)-1-methyl-2-oxoethyl]octyl 4-[(tert-butoxy-
carbonyl)(methyl)amino]-2,4,5-trideoxy-5-phenyl-l-
erythro-pentonate (19). A mixture of the MOM ether 18
(200 mg, 0.27 mmol) and tetrabutylammonium bromide
(435 mg, 1.35 mmol) in dichloromethane (10 ml) was
treated with trimethylsilyl chloride (171 ml, 1.35 mmol) at
08C. Stirring was continued for 36 h at room temperature.
Thereafter, the reaction was quenched by the addition of
saturated aqueous NaHCO3 at 08C. The mixture was
extracted with diethyl ether (3£15 ml) and the organic
layers were dried (Na2SO4), ®ltered, and concentrated.
The crude product was puri®ed by ¯ash chromatography
(petroleum ether/ethyl acetate, 85:15) to give 0.15 g
(79%) of 19 as a colorless oil. TLC (petroleum ether/ethyl
acetate, 8:2): Rfˆ0.39; IR (neat): 3501 (m), 1741 (s), 1694
1
(s), 1464 (m) cm21; H NMR (250 MHz, CDCl3): dˆ0.80
(t, Jˆ6.9 Hz, 3H, CH3), 0.85, 0.94 (2 d, Jˆ6.8 Hz, 6H,
2£CH3(iPr)), 1.10 (d, Jˆ7.0 Hz, 3H, Me), 1.18±1.29 (m,
10H, (CH2)5), 1.30±1.42 (m, 2H, CH2), 2.14±2.29 (m, 1H,
CH(iPr)), 2.62±2.75 (m, 1H, CHMe), 2.83 (dd, Jˆ6.1,
5.2 Hz, 1H, OH), 3.95±4.08 (m, 1H, CHOH), 4.87±4.93
(m, 1H, CHiPr), 5.11 (dd, Jˆ13.7, 12.3 Hz, 2H, CH2(Bn)),
7.22±7.33 (m, 5H); 13C NMR (CDCl3): dˆ9.6, 14.1, 17.0,
18.7, 22.7, 26.3, 29.3, 29.6, 30.0, 31.9, 33.5, 44.5, 67.3,
72.0, 76.4, 128.5, 128.6, 128.7, 135.1, 170.3, 175.2.
1
(s) cm21; H NMR (250 MHz, CDCl3): (both rotamers)
dˆ0.81 (t, Jˆ5.8 Hz, 3H, CH3), 0.88 (d, Jˆ6.8 Hz, 3H,
CH3(iPr)), 0.91 (d, Jˆ6.8 Hz, 3H, CH3(iPr)), 1.14±1.66
(m, 24H, Me, 3£CH3(Boc), (CH2)6), 2.10±2.83 (m, 8H,
CH(iPr), NCH3, CH2C(O), CH2Ph, CHMe), 3.08±3.24 (m,
1H, CH2Ph), 3.80±4.20 (m, 3H, CHN, CHOH), 4.79 (d,
Jˆ4.3 Hz, 1H, CHiPr), 5.08±5.12 (m, 2H, CH2(Bn)),
5.13±5.22 (m, 1H, CHOC(O)), 7.07±7.29 (m, 10H); 13C
HMR (CDCl3): (both rotamers) dˆ11.6, 11.9, 14.1, 17.2,
18.8, 22.7, 25.7, 28.2, 28.3, 29.2, 29.3, 30.1, 31.2, 31.5,
31.8, 33.3, 34.9, 39.5, 42.3, 42.6, 67.0, 67.1, 70.1, 74.4,
77.01, 79.6, 126.1, 126.2, 128.4, 128.5, 128.6, 129.1,
135.3, 139.0, 156.2, 169.3, 169.6, 171.9, 173.7; HRMS
(ESI): calcd for 698.42626 (MH1), found 698.4228.
(1R)-1-[(1S)-2-({(1S)-1-[(Benzyloxy)carbonyl]-2-methyl-
propyl}oxy)-1-methyl-2-oxoethyl]octyl 4-[(tert-butoxy-
carbonyl)(methyl)amino]-2,4,5-trideoxy-3-O-(methoxy-
methyl)-5-phenyl-l-erythro-pentonate (18). To a solution
of the amino acid 17 (0.140 g, 0.383 mmol) in THF (2 ml)
and triethylamine (0.064 ml, 0.459 mmol) was added the
Yamaguchi reagent in a dropwise fashion at room tempera-
ture (0.063 ml, 0.383 mmol). The resulting mixture was stir-
red at room temperature for 1 h. The amine hydrochloride
salt was ®ltered off under argon and the ®ltrate concentrated
under argon. To the residue, dissolved in dry benzene (2 ml)
was added a solution of the alcohol 16 (0.180 g,
0.459 mmol) in benzene (2 ml) dropwise. Finally DMAP
(0.094 g, 0.753 mmol) was added and the reaction mixture
stirred at room temperature for 2 h. Afterwards, the reaction
mixture was diluted with diethyl ether, washed successively
with 2N HCl, water, saturated aqueous NaHCO3, water, and
®nally with brine. The combined organic layers were dried
(Na2SO4), ®ltered, and concentrated. The residue was puri-
®ed by ¯ash chromatography (petroleum ether/ethyl acetate,
85:15) to yield 0.224 g (79%) of 18 as a colorless oil.
[a]2D1ˆ228.6 (c 1.0, CHCl3); TLC (petroleum ether/ethyl
(1R)-1-((1S)-2-{[(1S)-1-Carboxy-2-methylpropyl]oxy}-1-
methyl-2-oxoethyl)octyl 4-[(tert-butoxycarbonyl)(methyl)-
amino]-2,4,5-trideoxy-5-phenyl-l-erythro-pentonate (20).
The hydroxy ester 19 (0.11 g, 0.157 mmol), dissolved in
MeOH (7 ml) was hydrogenated over Pd(OH)2 (0.150 g)
at 5 bar pressure in an autoclave (Parr apparatus) at room
temperature for 24 h. The mixture was passed through a
Celite pad, washed thoroughly with MeOH, the ®ltrate
was dried (Na2SO4), ®ltered and concentrated. The residue
was puri®ed by ¯ash chromatography (CHCl3/MeOH, 10:1)
to provide 20 as a colorless oil (90 mg, 94%). [a]2D4ˆ225.5
(c 1.3, CHCl3); TLC (CHCl3/MeOH, 10:1): Rfˆ0.71; IR
(neat): 3479 (br), 1739 (s), 1699 (s), 1652 (s), 1634 (s)
acetate, 85:15): Rfˆ0.32; IR (neat): 1742 (s), 1694 (s) cm21
;
1H NMR (250 MHz, CDCl3): (both rotamers) dˆ0.87 (t,
Jˆ7.1 Hz, 3H, CH3), 0.92 (d, Jˆ6.7 Hz, 3H, CH3(iPr)),
0.96 (d, Jˆ7.1 Hz, 3H, CH3(iPr)), 1.19 (d, Jˆ7.3 Hz, 3H,
Me), 1.25±1.29 (m, 19H, 3£CH3(Boc), (CH2)5), 1.60 (s, br.,
2H, CH2), 2.17±2.28 (m, 1H, CH(iPr)), 2.42±2.81 (m, 7H,
NCH3, CH2C(O), CH2Ph, CHMe), 3.17±3.22 (m, 1H,
CH2Ph), 3.39 (minor, s, 3H, CH3(MOM)), 3.40 (major, s,
3H, CH3(MOM)), 4.1±4.3 (m, 2H, CHN, CHOMOM),
4.68±4.81 (m, 2H, CH2(MOM)), 4.85 (d, Jˆ4.3 Hz, 1H,
CHiPr), 5.14±5.21 (m, 3H, CH2(Bn), CHOC(O)), 7.13±
7.23 (m, 5H), 7.33±7.34 (m, 5H); 13C HMR (CDCl3):
(both rotamers) dˆ12.5, 12.8, 14.1, 15.3, 17.2, 18.6, 18.8,
21.0, 22.6, 25.4, 28.2, 28.3, 29.2, 29.4, 30.1, 31.8, 31.95,
34.5, 37.9, 42.9, 43.2, 56.1, 56.3, 65.8, 66.8, 66.96, 74.4,
74.5, 76.6, 76.7, 97.3, 97.5, 126.1, 126.2, 128.3, 128.4,
128.6, 129.1, 135.4, 139.0, 155.5, 155.8, 169.1, 171.0,
173.3; MS (EI): m/z (%)ˆ650 (9) [M12PhCH2]; HRMS
cm21
;
1H NMR (250 MHz, CDCl3): (both rotamers)
dˆ0.80 (t, Jˆ6.8 Hz, 3H, CH3), 0.83±0.88 (m, 6H,
2£CH3(iPr)), 1.09 (d, Jˆ6.4 Hz, 3H, Me), 1.17±1.62 (m,
21H, 3£CH3(Boc), (CH2)6), 2.35±2.65 (m, 8H, CH(iPr),
NCH3, CH2C(O), CHMe, CH2Ph), 3.13±3.22 (m, 1H,
CH2Ph), 3.38 (s, br., 1H), 4.01±4.22 (m, 2H, CHN,
CHOH), 4.64 (d, Jˆ3.6 Hz, 1H, CHiPr), 5.31 (s, br., 1H,
CHOC(O)), 7.05±7.18 (m, 5H); 13C NMR (CDCl3): (both
rotamers) dˆ10.3, 14.1, 17.3, 19.4, 22.6, 25.7, 28.3, 29.2,
29.3, 29.5, 29.8, 31.8, 32.1, 33.8, 39.5, 42.2, 50.5, 53.9,
69.8, 74.5, 79.6, 126.1, 128.2, 128.3, 129.05, 129.1, 138.9,
156.1, 172.97, 174.6, 176.6; HRMS (ESI): calcd for
608.3793 (MH1), found 608.3785.
(1R)-1-((1S)-2-{[(1S)-1-Carboxy-2-methylpropyl]oxy}-1-
methyl-2-oxoethyl)octyl 2,4,5-trideoxy-4-(methylamino)-

C. Hermann et al. / Tetrahedron 56 (2000) 8461±8471
8469
5-phenyl-l-erythro-pentonate (21). A mixture of the
carboxylic acid 20 (90 mg, 0.148 mmol) and tri¯uoroacetic
acid (0.609 ml) in dichloromethane (3 ml) was stirred at
room temperature for 2 h. After removal of the volatile
materials, the residue was puri®ed by ¯ash chromatography
(CHCl3/MeOH, 10:1) to give 21 as a colorless oil (71 mg,
93%). [a]2D5ˆ22.3 (c 1.0, CHCl3); TLC (CHCl3/MeOH,
trated. Puri®cation of the residue by ¯ash chromatography
(petroleum ether/ethyl acetate, 7:3) gave 0.37 g (90%) of 24
as colorless crystals, mp 80.8±81.88C. [a]2D8ˆ110.2 (c 0.4,
CHCl3); IR (neat): 3293 (s), 1735 (s), 1642 (s), 1539 (s)
1
cm21; H NMR (250 MHz, CDCl3): dˆ0.79 (d, Jˆ7.1 Hz,
6H, CH3(iPr), CH3), 0.86 (d, Jˆ6.7 Hz, 3H, CH3(iPr)), 1.11
(d, Jˆ7.0 Hz, 3H, Me), 1.19±1.36 (m, 12H, (CH2)6), 2.07±
2.19 (m, 1H, CH(iPr)), 2.30±2.39 (m, 1H, CHMe), 3.72±
3.77 (m, 1H, CHOH), 4.54 (dd, Jˆ4.6, 4.3 Hz, 1H, CHiPr),
5.08 (dd, Jˆ9.4, 12.2 Hz, 2H, CH2(Bn)), 6.29 (d, Jˆ8.6 Hz,
1H, NH), 7.25±7.37 (m, 5H); 13C NMR (62.5 MHz, CDCl3):
dˆ11.4, 14.1, 17.6, 19.1, 22.7, 26.1, 29.3, 29.6, 31.1, 31.8,
33.3, 44.9, 56.8, 67.2, 72.3, 128.4, 128.5, 128.7, 135.3,
172.1, 176.3; MS (EI): m/zˆ392 (6) [M111]; HRMS
(EI): calcd for C23H37NO4 391.27225, found 391.27108.
1
10:1): Rfˆ0.21; H NMR (250 MHz, CDCl3): dˆ0.81 (t,
Jˆ6.4 Hz, 3H, CH3), 0.90 (d, Jˆ6.8 Hz, 3H, CH3(iPr)),
0.93 (d, Jˆ6.7 Hz, 3H, CH3(iPr)), 1.09 (d, Jˆ7.0 Hz, 3H,
Me), 1.16±1.21 (m, 10H, (CH2)5), 1.31±1.55, 1.56±1.81
(2£m, 2H, CH2), 2.14±2.21 (m, 1H, CH(iPr)), 2.36±2.42
(m, 2H, CH2C(O)), 2.56 (s, 3H, NCH3), 2.67±2.74 (m, 1H,
CHMe), 2.92±3.04 (m, 2H, CH2Ph), 3.4±3.5 (m, 1H, CHN),
4.38±4.42 (m, 1H, CHOH), 4.69 (d, Jˆ4.3 Hz, 1H, CHiPr),
5.21±5.25 (m, 1H, CHOC(O)), 7.18±7.29 (m, 5H), 8.44 (s,
br., 2H); 13C NMR (62.5 MHz, CDCl3): dˆ9.4, 14.1, 17.1,
18.8, 22.6, 25.6, 29.1, 29.3, 29.7, 30.9, 31.8, 32.1, 32.3,
38.9, 41.0, 64.7, 66.4, 75.1, 77.1, 127.5, 129.2, 135.7,
170.2, 172.4, 173.9; MS (FAB): m/z (%)ˆ508 (56%)
[M111], 408 (4), 224 (100), 206 (30).
(1R)-1-[(1S)-2-({(1S)-1-[(Benzyloxy)carbonyl]-2-methyl-
propyl}amino)-1-methyl-2-oxoethyl]octyl 4-[(tert-butoxy-
carbonyl)(methyl)amino]-2,4,5-trideoxy-3-O-(methoxy-
methyl)-5-phenyl-l-erythro-pentonate (25). To a solution
of the amino acid20 17 (0.34 g, 0.93 mmol) in THF (4 ml)
and triethylamine (0.156 ml, 1.12 mmol) was added the
Yamaguchi reagent (0.156 g, 0.93 mmol) in a dropwise
fashion at room temperature. The resulting mixture was
stirred at room temperature for 1 h. The amine hydro-
chloride salt was ®ltered off under argon and the ®ltrate
concentrated under argon. To the residue, dissolved in dry
benzene (4 ml) was added a solution of the alcohol 24
(0.439 g, 1.12 mmol) in benzene (4 ml) dropwise. Finally
DMAP (0.227 g, 1.86 mmol) was added and the reaction
mixture stirred at room temperature for 2 h. Afterwards,
the reaction mixture was diluted with diethyl ether, washed
successively with 2N HCl, water, saturated aqueous
NaHCO3, water, and ®nally with brine. The combined
organic layers were dried (Na2SO4), ®ltered, and concen-
trated. The residue was puri®ed by ¯ash chromatography
(petroleum ether/ethyl acetate, 8:2) to yield 0.48 g (70%)
of 25 as a colorless oil. [a]2D5ˆ18.6 (c 0.5, CHCl3); IR
(neat): 3333 (m), 1735 (s), 1696 (s), 1675 (s), 1667 (s)
Benzyl (2S)-3-methyl-2-{[(2S,3R)-2-methyl-3-(tetrahydro-
2H-pyran-2-yloxy)decanoyl]amino}butanoate (23). Di-
isopropylethylamine (0.84 ml, 4.97 mmol) was added drop-
wise to a stirred mixture of the p-TSA salt of the valine
benzyl ester 22 (0.957 g, 2.48 mmol), the carboxylic acid
13 (0.71 g, 2.48 mmol) and BOP (1.09 g, 2.48 mmol) in
anhydrous acetonitrile (8 ml) at room temperature under
argon. After 2 h, the reaction mixture was diluted with
brine and extracted with ethyl acetate (3£20 ml). The
combined organic layers were washed sequentially with
10% citric acid and brine, dried (Na2SO4), ®ltered, and
concentrated. The residue was puri®ed by ¯ash chromato-
graphy (petroleum ether/ethyl acetate, 85:15) to provide
0.68 g (70%) of 23 as a colorless oil. [a]2D5ˆ128.3 (c 0.5,
CHCl3); TLC (petroleum ether/ethyl acetate, 8:2): Rfˆ0.43;
1H NMR (250 MHz, CDCl3): dˆ0.78±0.88 (m, 9H,
2£CH3(iPr), CH3), 1.03 (dd, Jˆ3.0, 4.3 Hz, 3H, Me),
1.10±1.28 (m, 10H, (CH2)5), 1.30±1.80 (m, 8H, CH2,
3£CH2(THP)), 2.07±2.19 (m, 1H, CH(iPr)), 2.56±2.61,
2.82±2.86 (2m, 1H, CHMe), 3.40±3.50 (m, 1H, CHOTHP),
3.52±3.72 (m, 1H, CH2O), 3.82±3.89 (m, 1H, CHOTHP),
4.45±4.58 (m, .1H, CHiPr, CH(THP)), 4.68±4.71 (m,
,1H, CH(THP)), 5.09 (dd, Jˆ1.2, 0.9 Hz, 2H, CH2(Bn)),
6.84 (d, Jˆ8.2 Hz, 1H, NH), 7.23±7.29 (m, 5H); 13C NMR
(100 MHz, CDCl3): dˆ12.7, 12.9, 17.7, 18.9, 19.0, 19.5,
21.0, 22.6, 25.2, 25.3, 26.2, 26.3, 29.1, 29.4, 29.7, 30.6,
30.9, 31.1, 31.2, 31.8, 42.2, 43.6, 56.9, 57.2, 62.7, 64.5,
66.4, 66.7, 76.6, 76.9, 77.1, 77.3, 79.3, 81.3, 97.3, 101.2,
128.1, 128.2, 128.4, 128.5, 135.5, 171.7, 173.9; MS (EI):
m/z (%)ˆ476 (6) [M111], 392 (100); HRMS (EI): calcd for
C28H45NO5 475.329747, found 475.322658.
;
cm21 1H NMR (250 MHz, CDCl3): (both rotamers)
dˆ0.72±0.89 (m, 9H, 2£CH3(iPr), CH3), 1.11 (dd, Jˆ4.2,
2.8 Hz, 3H, Me), 1.17±1.29 (m, 19H, 3£CH3(Boc), (CH2)5),
1.40±1.69 (m, 2H, CH2), 2.03±2.16 (m, 1H, CH(iPr)),
2.33±2.90 (m, 7H, CH2C(O), NCH3, CHMe, CH2Ph),
3.04±3.16 (m, 1H, CH2Ph), 3.34 (s, 3H, minor, OCH3),
3.36 (s, 3H, major, OCH3), 4.24±4.33 (m, 2H, CHN,
CHOMOM), 4.56±4.66 (m, 2H, CHiPr, CH2(MOM)),
4.79±4.91 (m, 2H, CHOC(O), CH2(MOM)), 5.06 (dd,
Jˆ9.2, 3.1 Hz, 2H, minor, CH2(Bn)), 5.13 (dd, Jˆ12.2,
10.1 Hz, 2H, major, CH2(Bn)), 6.56 (d, Jˆ8.2 Hz, 1H,
major, NH), 6.63 (s, br., 1H, minor, NH), 7.07±7.30 (m,
10H); 13C NMR (both rotamers, CDCl3): dˆ14.1, 14.3,
14.5, 17.6, 19.0, 22.7, 26.1, 28.1, 28.3, 29.2, 29.3, 30.4,
31.4, 31.8, 34.4, 38.2, 44.4, 44.6, 56.3, 56.5, 56.7, 56.8,
66.9, 76.1, 76.6, 76.8, 77.3, 79.4, 79.8, 97.1, 97.4, 126.3,
128.15, 128.2, 128.4, 128.6, 129.1, 135.4, 138.9, 155.6,
171.3, 172.3, 172.9, 173.1; MS (EI): m/z (%)ˆ649 (yy)
[M12PhCH2]; HRMS (EI): calcd for C35H57N2O9
[M12PhCH2] 649.40640, found 649.40033.
Benzyl (2S)-2-{[(2S,3R)-3-hydroxy-2-methyldecanoyl]-
amino}-3-methylbutanoate (24).
A solution of the
protected amide 23 (0.50 g, 1.05 mmol) and a small amount
of p-TsOH (20 mg, 0.1 mmol) in MeOH (10 ml) was stirred
at room temperature for 2 h and then quenched by the addi-
tion of aqueous 2N KHCO3 solution. Most of the MeOH
was removed under reduced pressure and the resulting
slurry extracted with diethyl ether (3£20 ml). The combined
organic layers were dried (Na2SO4), ®ltered and concen-
(1R)-1-[(1S)-2-({(1S)-1-[(Benzyloxy)carbonyl]-2-methyl-
propyl}amino)-1-methyl-2-oxoethyl]octyl 4-[(tert-butoxy-
carbonyl)(methyl)amino]-2,4,5-trideoxy-5-phenyl-l-

8470
C. Hermann et al. / Tetrahedron 56 (2000) 8461±8471
erythro-pentonate (26). A solution of MOM ether 25
(0.47 g, 0.63 mmol) in CH2Cl2 (5 ml) was treated with
trimethylsilyl bromide (0.39 g, 2.5 mmol) at 2308C. After
being stirred for 1 h at 2308C, the mixture was allowed to
warm up to 08C and stirred at this temperature for 3 h. After
quenching with a saturated aqueous NaHCO3 solution
(6 ml) the layers were separated and the water layer
extracted with CH2Cl2 (2£10 ml). The combined organic
layers were dried (MgSO4), ®ltered and evaporated in
vacuo. The residue was puri®ed by ¯ash chromatography
on silica gel (25% ethyl acetate in petroleum ether) to yield
0.34 g (78%) of 26 as a colorless oil. [a]2D6ˆ25.7 (c 0.46,
CH2Cl2); TLC (petroleum ether/ethyl acetate, 8:2):
heptyl-11-hydroxy-6-isopropyl-3,9-dimethyl-1-oxa-5,7,9-
triazacyclotridecane-4,8,13-trione (30). To a solution of
amino acid 28 (90 mg, 0.178 mmol) in dry DMF (180 ml)
were added diphenylphosphoryl azide (DPPA, 100 mg,
0.36 mmol) and diisopropylethylamine (DIEA, 137 mg,
1.06 mmol) at 08C. The solution was stirred at this tempera-
ture for 3 h, then at room temperature for 4 days. The
reaction solution was partitioned between ethyl acetate
(250 ml) and water (200 ml). After extracting of the
water-DMF layer with ethyl acetate (2£80 ml), the
combined ethyl acetate layers were washed with brine
(100 ml), dried (MgSO4), ®ltered and evaporated in vacuo.
The residue was puri®ed by ¯ash chromatography on
silica gel (50% ethyl acetate in petroleum ether) to give
the cyclic products 29 and 30 (24 mg, 0.048 mmol, 27%)
in a ratio of 1:1.
1
Rfˆ0.38; IR (neat): 3330 (s), 1741 (s), 1695 (s) cm21; H
NMR (250 MHz, CDCl3): (both rotamers) dˆ0.82±0.89
(m, 9H, 2£CH3(iPr), CH3), 1.15±1.32 (m, 22H, Me,
3£CH3(Boc), (CH2)5), 1.50±1.72 (m, 2H, CH2), 2.07±2.23
(m, 1H, CH(iPr)), 2.30±2.78 (m, 7H, CH2C(O), NCH3,
CHMe, CH2Ph), 2.85±3.33 (m, 1H, CH2Ph), 3.84±3.98,
4.05±4.28, 4.31±4.43 (3m, 2H, CHN, CHOH), 4.50±4.58
(m, 1H, CHiPr), 4.97±5.23 (m, 3H, CHOC(O), CH2(Bn)),
6.30 (d, Jˆ8.5 Hz, 1H, major, NH), 6.43 (d, Jˆ9.4 Hz, 1H,
minor, NH), 7.08±7.28 (m, 10H); 13C NMR (CDCl3): (both
rotamers) dˆ12.4, 12.9, 14.1, 17.8, 17.9, 18.9, 22.6, 25.9,
28.3, 29.2, 29.3, 30.6, 30.9, 31.3, 31.4, 31.8, 33.4, 40.1,
40.4, 43.9, 44.2, 44.9, 57.1, 67.1, 67.3, 70.1, 74.8, 75.4,
79.6, 126.2, 128.4, 128.5, 128.6, 129.1, 129.5, 135.2,
135.3, 139.0, 156.3, 171.4, 171.5, 172.3, 173.4, 173.7.
Data for 29: [a]2D5ˆ162.5 (c 0.079, CHCl3); TLC (ethyl
acetate/petroleum ether, 1:1): Rfˆ0.24; 1H NMR (400
MHz, DMSO-d6): dˆ0.72±0.78 (m, 6H, 2£CH3(iPr)),
0.84 (t, Jˆ6.8 Hz, 3H, CH3), 0.97 (d, Jˆ7.0 Hz, 3H, Me),
1.10±1.26 (m, 10H, (CH2)5), 1.28±1.36, 1.38±1.52 (2m,
2H, CH2), 2.05±2.16 (m, 1H, CH(iPr)), 2.32±2.40 (m, 5H,
CHMe, NCH3, CH2C(O)), 2.61±2.75 (m, 2H, CH2C(O),
CH2Ph), 3.18 (dd, Jˆ12, 2.7 Hz, 1H, CH2Ph), 3.85±3.91
(m, 1H, CHOH), 4.42±4.50 (m, 1H, CHiPr), 4.51±4.59
(m, 1H, CHN), 5.18 (d, Jˆ6.1 Hz, 2H, CHOC(O), OH),
5.84 (d, Jˆ10 Hz, 1H, NH), 7.10±7.28 (m, 5H), 7.91 (d,
Jˆ6.1 Hz, 1H, NH); 13C NMR (100.6 MHz, DMSO-d6):
dˆ8.5, 19.4, 19.9, 22.0, 24.9, 28.5, 28.8, 30.0, 30.8, 31.1,
34.2, 40.7, 42.4, 58.6, 66.2, 67.9, 74.3, 125.7, 128.0, 128.4,
129.6, 139.3, 158.3, 169.5, 172.5; HRMS (ESI): calcd for
C28H46N3O5 504.34191, found 504.34320.
(1R)-1-((1S)-2-{[(1S)-1-Carboxy-2-methylpropyl]amino}-
1-methyl-2-oxoethyl)octyl 4-[(tert-butoxycarbonyl)(methyl)-
amino]-2,4,5-trideoxy-5-phenyl-l-erythro-pentonate (27).
A solution of the benzyl ester 26 (70 mg, 100 mmol) in
MeOH (5 ml) was stirred in the presence of Pd(OH)2
(70 mg) at room temperature overnight under a hydrogen
balloon. The reaction mixture was ®ltered through a Celite
pad and the ®ltrate evaporated to give the carboxylic acid
which was used as such for the next step.
Data for 30: [a]2D5ˆ166.4 (c 0.136, CHCl3); TLC (ethyl
acetate/petroleum ether, 1:1): Rfˆ0.37; 1H NMR (600
MHz, DMSO-d6): dˆ0.63, 0.77 (2d, Jˆ6.5 Hz, 6H,
2£CH3(iPr)), 0.85 (t, Jˆ6.8 Hz, 3H, CH3), 1.06 (d,
Jˆ7.1 Hz, 3H, Me), 1.13±1.26 (m, 10H, (CH2)5), 1.39±
1.51 (m, 2H, CH2), 2.26 (s, 3H, NCH3), 2.38±2.47 (m,
3H, CHMe, CH(iPr), CH2C(O)), 2.60 (t(dd), Jˆ12.8 Hz,
1H, CH2Ph), 2.82 (dd, Jˆ16.9, 10.4 Hz, 1H, CH2C(O)),
3.20 (dd, Jˆ12.5, 6.0 Hz, 1H, CH2Ph), 3.83±3.86 (m, 1H,
CHOH), 4.10±4.14 (m, 1H, CHiPr), 4.50±4.54 (m, 1H,
CHN), 4.98±5.00 (m, 1H, CHOC(O)), 5.11 (d, Jˆ5.9 Hz,
1H, OH), 6.50 (d, Jˆ5.9 Hz, 1H, NH), 7.08±7.24
(m, 6H, Ph, NH); 13C NMR (100.6 MHz, DMSO-d6):
dˆ13.9, 19.2, 20.0, 22.0, 25.1, 28.4, 28.6, 28.8, 30.1,
31.1, 31.9, 33.9, 41.9, 44.1, 57.7, 64.5, 67.1, 73.6, 125.6,
127.8, 127.9, 128.2, 128.7, 139.2, 157.3, 169.3, 173.6;
HRMS (ESI): calcd for C28H46N3O5 504.34191, found
504.34320.
(1R)-1-((1S)-2-{[(1S)-1-Carboxy-2-methylpropyl]amino}-
1-methyl-2-oxoethyl)octyl 2,4,5-trideoxy-4-(methylamino)-
5-phenyl-l-erythro-pentonate (28). A mixture of the
carboxylic acid 27 and TFA (0.36 ml) in dichloromethane
(3 ml) was stirred at room temperature for 2 h. After
removal of volatile materials, the residue was puri®ed by
¯ash chromatography (CHCl3/MeOH, 10:1) to provide
47 mg (94%) of 28 as a colorless oil. TLC (CHCl3/MeOH,
10:1): Rfˆ0.17; 1H NMR (250 MHz, CDCl3): dˆ0.77±0.87
(m, 9H, 2£CH3(iPr), CH3), 1.01 (d, Jˆ6.9 Hz, 3H, Me),
1.14±1.28 (m, 10H, (CH2)5), 1.38±1.65 (m, 2H, CH2),
1.97±2.13 (m, 1H, CH(iPr)), 2.40±2.46 (m, 2H,
CH2C(O)), 2.50±2.65 (m, 4H, NCH3, CHMe), 3.0 (d,
Jˆ6.8 Hz, 2H, CH2Ph), 3.43 (s, br., 1H, CHN), 4.20±4.30
(m, 1H, CHiPr), 4.40±4.45 (m, 1H, CHOH), 5.0±5.08 (m,
1H, CHOC(O)), 6.8 (d, Jˆ7.9 Hz, 1H, NH), 7.0 (s, br., 1H),
7.19±7.27 (m, 5H), 8.83 (s, br., 1H); 13C NMR (62.5 MHz,
CDCl3): dˆ11.3, 14.1, 18.1, 19.1, 22.6, 25.8, 29.1, 29.4,
30.5, 30.7, 31.8, 32.3, 32.7, 38.3, 43.2, 53.4, 58.2, 65.0,
66.5, 75.7, 127.6, 129.0, 129.3, 135.7, 170.7, 174.4, 175.1.
Acknowledgements
Financial support by the Deutsche Forschungsgemeinschaft
and the Fonds der Chemischen Industrie is gratefully
acknowledged. G. C. G. Pais thanks the Alexander von
Humboldt foundation for a postdoctoral fellowship. We
are indebted to the group of Professor Jung for performing
the FT-ICR spectra and many helpful comments.
(2S,3R,6S,10R,11R)-10-Benzyl-2-heptyl-11-hydroxy-6-iso-
propyl-3,9-dimethyl-1-oxa-5,7,9-triazacyclotridecane-4,8,
13-trione (29) and (2S,3R,6R,10R,11R)-10-benzyl-2-

C. Hermann et al. / Tetrahedron 56 (2000) 8461±8471
8471
21. Shioiri, T.; Yamada, S.-i. Chem. Pharm. Bull. 1974, 22, 859±
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