A practical synthesis of the lipophilic side chain of the polyoxypeptins

Article abstract of DOI:10.1016/S0040-4039(01)00205-2

The lipophilic side chain of the cyclic depsipeptide polyoxypeptin A (1) and B (2), strong apoptosis inducers, has been synthesised as an ester of mixed methyl ketal 18. The key step is an asymmetric anti-aldol reaction of the designed 2-(N-2-methylbenzyl

Full text of DOI:10.1016/S0040-4039(01)00205-2

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 2431–2434
A practical synthesis of the lipophilic side chain of the
polyoxypeptins
Miguel Lorca and Michio Kurosu*
Department of Chemistry, The Florida State University, Tallahassee, FL 32306, USA
Received 25 January 2001; accepted 6 February 2001
Abstract—The lipophilic side chain of the cyclic depsipeptide polyoxypeptin A (1) and B (2), strong apoptosis inducers, has been
synthesised as an ester of mixed methyl ketal 18. The key step is an asymmetric anti-aldol reaction of the designed
2-(N-2-methylbenzyl-N-2,4,6-trimethylbenzyl) amino-1-phenylpropyl ester 8 by means of a combination of LDA–Cp2ZrCl2 (0.3
equiv.) for enolation and transmetallation into the zirconium enolate for aldolization. By using a non-boron associated anti-aldol
reaction, 10 g of the key lactone 6 were synthesised in six steps from 8 and in 48% overall yield. © 2001 Published by Elsevier
Science Ltd.
Anticancer agents which induce apoptosis (pro-
grammed cell death) have a significant advantage over
those which induce necrosis (accidental death caused by
anticancer drugs). Thus, specific apoptosis inducers in
cells expressing oncogenes will be useful for treating
certain types of tumors. Polyoxypeptin A (1) and B (2),
natural products isolated from the culture of broth of
Streptomyces sp., induce apoptotic cell death in human
pancreatic adenocarcinoma AsPC-1 cells, an apoptosis-
resistant cell line, with ED50 values of 80 and 170
ng/mL, respectively. The relative and absolute stereo-
chemistries of polyoxypeptin A were unambiguously
determined through X-ray analysis and amino acids
analyses. Polyoxypeptin A and B are 19-membered
depsipeptides containing a lipophilic side chain, differ
in the structure of the piperazic acid moiety (Scheme
1).1
While the side chain of polyoxypeptin is similar to that
of antibiotic L-156602, the difference is the structure of
the alkyl substituent on the tetrahydropyran ring (R2=
Me in the structure 3).2 Because of its important biolog-
Me
H
O
Me
Me
Me
H
R2
O
H
O
O
H
R2
O
tBu
H
Me
Me
HO
O
O
Me
H
O
R1O
O
Me
H
Me
HO
Me
3
H
H 5
Me
H
HO
1
OH
Me
O
NH
N
O
Me
Me
OH
known for
R2=Me
Me
H
H
N
3 : R1=H, R2=Et
4 : R1=Me, R2=Et
6
O
OH
O
N
H
O
N
Ph
O
H
OTBS
Me
O
N
H
O
Me
OH
Me
Me
+ C2
anti-aldol
Mes
N
Me
TsO
R
N
Me
H
NH
Me
H
O
Polyoxypeptin A (1): R=OH
Polyoxypeptin B (2) : R=H
Me
8
7
Scheme 1. The structure of polyoxypeptins and retrosynthesis of their lipophilic side chain 3.
* Corresponding author. E-mail: kurosu@chem.fsu.edu
0040-4039/01/$ - see front matter © 2001 Published by Elsevier Science Ltd.
PII: S0040-4039(01)00205-2

2432
M. Lorca, M. Kurosu / Tetrahedron Letters 42 (2001) 2431–2434
ical activity and unique structural features, we wanted
to synthesize a relatively large quantity of such a
molecule.3
diastereomers.7 From a practical point of view, the
anti-aldol reaction demonstrated herein has several
advantages: (1) the high degree of diastereofacial selec-
tivity; (2) all reagents for this chemistry are commer-
cially available; (3) easy purification of anti and syn
diastereomers; (4) quantitative recovery of the auxil-
iary. Because the structure of auxiliary 9 is similar to
Masamune ester 14, we applied the ester 8 to the
Masamune’s boron mediated aldol reaction condition.8
By using (c-Hex)2BOTf (2.4 equiv. as a monomer)9 and
3 equiv. of Et3N the aldol reaction of 8 with propi-
onaldehyde afforded, after oxidative work-up, exclu-
sively the anti-aldol product in 90% yield with greater
than 98% ds (Scheme 3). For the reasons described
above, we conducted the anti-aldol reaction of 8 on a
17 g scale using LDA–Cp2ZrCl2.
The transformation of lactone 6 (R2=Me) into 3 (R2=
Me) with Seebach ester 5 has already been described by
Caldwell and co-workers,4 and it would be the shortest
method for creating the C1–C3 chiral centres of the side
chain. Therefore our strategy to access 3 (Scheme 1)
required an efficient method to synthesize lactone 6
(R2=Et). We realised that an asymmetric anti-aldol
reaction would be the most effective means for produc-
ing intermediate 7 (Scheme 1). We have recently devel-
oped a non-boron associated diastereselective anti-aldol
reaction using a readily synthesized chiral template,
2-(N-2-methylbenzyl-N-2,4,6-trimethylbenzyl) amino-1-
phenylpropyl ester.5 Herein we report a practical syn-
thesis of the lipophilic side chain of polyoxypeptins.
Protection of 11 as its TBS ether and reductive cleavage
of the ester moiety yielded 12 in 95% yield, and auxil-
iary 9 was recovered almost quantitatively. For C2
elongation, the primary alcohol of 12 was activated as
its tosylate.10 The cesium malonate anion addition to
tosylate 7 proceeded smoothly at 70°C in DMF within
5 h. The malonate adduct 13 could be transformed into
the lactone 6 from 13 through the intermediate lactone–
carboxylic acid in 90% yield by treatment with 80%
AcOH at 90°C for 24 h. Thus, we were able to obtain
more than 10 g of lactone 6 starting from 17 g of ester
8 in 43% overall yield.
The synthesis of the key intermediate lactone 6 com-
menced with the known chiral carboxylic acid 106
(Scheme 2). For use in the diastereselective anti-aldol
reaction, alcohol 9 was converted into its ester 8 by
reaction with water-soluble carbodiimide and DMAP.
Selective generation of the E-enolate of 8 using LDA–
Cp2ZrCl2 (0.3 equiv.), followed by transmetallation
with Cp2ZrCl2 (2–3 equiv.) and aldolization with propi-
onaldehyde afforded anti-aldol 9 in 85–90% yield with
98% ds (determined by HPLC).5 Interestingly, the iso-
lated syn-aldol product was
a
1.5:1 mixture of
LDA (2.5 equiv)-
Cp2ZrCl2 (0.3 equiv)
then Cp2ZrCl2,
O
OH
Ph
Ph
O
Ph
O
Me
Me
Me
Me
HO
Me
O
O
Me
OH
propionaldehyde
Me
10
Mes
N
Mes
N
Me
Mes
N
Me
THF
EDCI•HCl, DMAP
Me
Me
Me
CH2Cl2
85-90 %
(ds : 10-15 : 1)
98 %
Me
11
9
8
OTBS
OTBS
TsCl, Me3N•HCl (cat.)
Et3N / Toluene
dimethylmalonate, NaH
CsI / DMF
1) TBSCl, imidazole
DMF
Me
Me
HO
TsO
Me
Me
Me
70 °C
2) DIBAl-H
CH2Cl2
89 %
94 %
95 % overall
Me
12
7
Me
Me
O
OTBS
H
Me
AcOH-H2O
(4 : 1)
H
O
Me
Me
MeO
MeO
Me
H
O
90 °C
O
Me
H
Me
Me
O
O
90 % overall
HO
O
13
6
Scheme 2. Synthesis of the lactone 6.

M. Lorca, M. Kurosu / Tetrahedron Letters 42 (2001) 2431–2434
2433
O
OH
Ph
O
Ph
O
Ph
Me
Me
Me
O
Me
O
Me
Bn
1) [(c-Hex)2BOTf]2, Et3N
CH2Cl2, -78 °C
then
O
Mes
N
Me
Mes
N
Me
N
Me
Me
SO2Mes
Me
propionaldehyde
Masamune ester 14
2) H2O2, buffer (pH 7.0)
8
11
90 % (ds : > 98%)
"no detectable syn diastereomers"
Scheme 3. The anti-aldol reaction of 8 via Masamune’s condition.
O
1)
Me
O
O
OTBS
Me
O
O
OTBS
1) DIBAl-H, CH2Cl2
2) ethylenedithiol,
BF3•OEt2 / CH2Cl2
3) TBSCl, DMF
tBu
O
Me
LDA / THF
5
-100-95 °C
O
tBu
H
Me
O
Me
Me
6
Me
Me
2) (COCl)2, DMSO
Et3N
H
4) MeI / acetone-H2O
65 - 80 %
74 % overall
16
15
Me
H
Me
H
Me
Me
Me
O
O MeO
O
O MeO
H
NaOMe / MeOH
Me
H
1) 49 % HF / CH3CN
2) HCl / MeOH
85 %
O
MeO
tBu
O
Me
HO
Me
95 %
H
18
17
Scheme 4.
In our hands, introduction of a three-carbon unit by
addition of lithium enolate of Seebach ester 5 to lactone
6 could not be reproducible. We have never obtained
the coupling product under the condition described by
Seebach.11 In order to facilitate the coupling reaction
with 5, lactone 6 was converted into the acyclic alde-
hyde 15 via standard procedures (Scheme 4). Coupling
of 15 with lithium enolate of 5 generated at −100 to
−95°C followed by Swern oxidation gave b-keto ester
16. Treatment of 16 with 49% HF in CH3CN afforded
hemiketal, which was then transformed into mixed
methyl ketal 17.12 The transesterification of 17 with
NaOMe in absolute MeOH yielded the stable com-
pound 18.13
References
1. Umezawa, K.; Nakazawa, K.; Ikeda, Y.; Nakagawa, H.;
Kondo, S. J. Org. Chem. 1999, 64, 3034.
2. Hensens, O. D.; Springer, J. P.; Cadwell, C. G.; Zink, D.
L.; Homnick, C. F. J. Antibiot. 1991, 44, 249.
3. For synthetic work from another group, see: Noguchi,
Y.; Yamada, T.; Uchiro, H.; Kobayashi, S. Tetrahedron
Lett. 2000, 41, 7499.
4. Caldwell, C. G.; Rupprecht, K. M.; Bondy, S. S.; Davis,
A. A. J. Org. Chem. 1990, 55, 2355.
5. Kurosu, M.; Lorca, M. J. Org. Chem. 2001, in press.
6. For example (S)-4-methylhexanoic acid (10) was utilised
in Heathcock’s zaragozic acid synthesis, see: Stoermer,
D.; Caron, S.; Heathcock, C. H. J. Org. Chem. 1996, 61,
9115. Since in many cases the overall yield in the synthe-
sis of 10 starting from commercially available (S)-2-
methyl-1-butanol (i) was low and required multiple
chromatographic purification, we developed a practical
method for preparing 10 which does not require a silica
gel purification. The procedure is the following. (1) For
tosylation of i via Tanabe’s condition (see Ref. 10): The
reaction mixture was filtered through a glass-filter, and
the crude mixture was distilled at 140°C/1 mmHg. (2)
The cesium malonate addition to tosylate at 70°C: All
volatiles were evaporated, and the crude mixture was
distilled at 150°C/1 mmHg. (3) Saponification by NaOH
in aqueous MeOH: The reaction mixture was acidified
In summary, the side chain of the polyoxypeptins has
been synthesized very efficiently as a mixed methyl
ketal ester 18 via a highly diastereoselective anti-aldol
reaction as a key step.
Acknowledgements
This work was supported by a grant from The Florida
State University. Dr. Alan Marshall is gratefully
acknowledged for the high-resolution mass spectral
measurements.

2434
M. Lorca, M. Kurosu / Tetrahedron Letters 42 (2001) 2431–2434
and extracted with Et2O, and the crude product was
This was stored as a toluene solution (0.8 M).
10. Yoshida, Y.; Sakakura, Y.; Aso, N.; Okada, S.; Tanabe,
Y. Tetrahedron 1999, 55, 2183.
11. Seebach, D.; Naef, R.; Calderari, G. Tetrahedron 1984,
40, 1313.
subjected to the next reaction. (4) Decarboxylation at
130°C: The reaction mixture was acidified and extracted
with Et2O. (S)-4-Methylhexanoic acid (10) was distilled
at 92°C/1 mmHg.
7. This poor selectivity for syn diastereomers would be
attributed to a boat-like transition structure that can
accommodate two possible orientations of propionalde-
hyde.
8. Abiko, A.; Liu, J.-F.; Masamune, S. J. Am. Chem. Soc.
1997, 119, 2586. For application of this chemistry to
natural product synthesis, see: Yoshimitsu, T.; Song, J. J.;
Wang, G.-Q.; Masamune, S. J. Org. Chem. 1997, 62,
8978.
9. (c-Hex)2BOTf was prepared from cyclohexene and
BH3·NEt3 followed by TfOH treatment. Procedure: (1) A
mixture of BH3·NEt3 (35 mL) and cyclohexene (95 mL, 4
equiv.) was stirred at 80°C for 24 h and at 100°C for 12
h. All volatiles (cyclohexene and NEt3) were distilled off
at 150°C and (c-Hex)3B (very air sensitive) was distilled
at 110°C at 1 mmHg. (c-Hex)3B was then reacted with
TfOH (15 mL) under Ar for 1 h. The reaction mixture
was distilled at 118–120°C at 0.2 mmHg to afford (c-
Hex)2BOTf (39.5 g, ca. 60% overall) as a yellow solid.
12. Data for 17: 1H NMR (300 MHz, CDCl3): 5.25 ppm
(1H, s), 3.37 (3H, s), 3.17 (1H, m), 1.86 (2H, td, J=
13.5, 4.8 Hz), 1.74–1.53 (7H, m), 1.03–0.97 (6H, m),
0.93 (9H, s), 0.88 (3H, d, J=2.7 Hz), 0.82 (6H, t, J=6.0
Hz). 13C NMR (75 MHz, CDCl3): 174.5 ppm, 108.3,
101.2, 84.9, 77.6, 50.2, 38.4, 36.0, 34.1, 30.9, 28.4, 25.6,
24.1, 18.8, 18.6, 11.5, 9.2. IR (neat): 2960 cm−1
,
2870, 1790, HRMS (ESI) C21H38O5 (M+Li+) calcd
377.19948, found 377.20020. [h]D=+72.0 (c 0.2, CHCl3 at
25°C).
13. Compounds 3 and 4 are extremely sensitive to acids and
strong bases. Side chain 3 was isolated and characterised
as its protected form 18. Data for 18: 1H NMR (300
MHz, CDCl3): 3.78 ppm (3H, s), 3.76 (1H, s), 3.49 (3H,
s), 3.47 (1H, m), 1.86 (2H, td, J=13.2, 4.8 Hz), 1.77–1.52
(2H, m), 1.44–1.11 (2H, m), 1.37 (9H, m), 1.09–0.78 (9H,
m). IR (neat): 2970 cm−1, 2880, 1780. HRMS (ESI)
C17H32O5 (M+Li+) calcd 323.18542, found 323.18531.
[h]D=+82.0 (c 0.1, CHCl3 at 25°C).
.