Synthetic studies on a cyclic hexadepsipeptide GE3: Stereoselective construction of the acyl side chain segment

Article abstract of DOI:10.1055/s-2002-22724

Stereoselective synthesis of the acyl side chain segment 2 of GE3 (1), a potent inhibitor of cell progression of the cell cycle from the G1 to S phase, has been achieved by using Sharpless' asymmetric dihydroxylation and Evans' and Paterson's stereoselective aldol methodologies.

Full text of DOI:10.1055/s-2002-22724

LETTER
613
Synthetic Studies on a Cyclic Hexadepsipeptide GE3: Stereoselective
Construction of the Acyl Side Chain Segment
Synthetic Studies
o
n a Cyclic
z
H
exadepsip
u
eptide GE
3
ishi Makino, Yoshiaki Henmi, Yasumasa Hamada*
Graduate School of Pharmaceutical Sciences, Chiba University, Yayoi-cho, Inage-ku, Chiba 263-8522, Japan
Fax +81(43)2902987; E-mail: hamada@p.chiba-u.ac.jp
Received 10 December 2001
stereocontrolled synthesis of the acyl side chain segment
Abstract: Stereoselective synthesis of the acyl side chain segment
2 of GE3 (1), a potent inhibitor of cell progression of the cell cycle
from the G1 to S phase, has been achieved by using Sharpless’
asymmetric dihydroxylation and Evans’ and Paterson’s stereoselec-
tive aldol methodologies.
2 of GE3.12
Our strategy for the synthesis of the acyl side chain seg-
ment 2 of GE3 is shown in Scheme 1. Disconnection be-
tween the acyl side chain and the cyclodepsipeptide
segment gives the C1-C14 fragment 3 masked as an inter-
nal hemiacetal, which would be further disconnected at
the C4-C5 bond to afford the C1-C4 fragment 4 and C5-
C14 fragment 5. The quaternary asymmetric center at C2
in C1-C4 fragment 4 could be conveniently installed by
the Sharpless’ asymmetric dihydroxylation13 of the tiglic
ester. The C5-C14 fragment 5 would be constructed by the
diastereoselective syn and anti aldol condensations with
chiral auxiliaries developed by Evans14 and Paterson,15 re-
spectively.
Key words: GE3, hexadepsipeptide, asymmetric dihydroxylation,
asymmetric aldol reaction, antitumor activity
GE3 (1),1 a member of novel cyclic hexadepsipeptides in-
cluding citropeptin,2 azinothricin,3 A83586C,4 variapep-
tin,5 L156,602,6 verucopeptin,7 IC101,8 aurantimycins9
and polyoxypeptin,10 was isolated from the culture broth
of a Streptomyces sp. by Kyowa Hakko Kogyo’s group in
1997 (Scheme 1). GE3 shows potent antitumor activity
against human pancreatic carcinoma, PSN-1, in addition
to antibacterial activities. Also, GE3 exhibits inhibitory
activity against cell progression of the cell cycle from G1
to S.1a,c The relative and absolute stereostructures of GE3
were deduced by the structural similarity and comparison
of 13C chemical shift values with the known cyclodep-
sipeptide azinothricin and A83586C as well as by degra-
dation studies.1b But the stereochemical assignments of
both piperazic acids and N-methyl leucine residue re-
mained to be confirmed clearly.11 The novel molecular
structure and potent antitumor activity of GE3 led us to in-
vestigate its total synthesis. Here we wish to describe the
An expeditious synthesis of the C1-C4 fragment is out-
lined in Scheme 2. The enantiocontrolled Sharpless’
dihydroxylation13 of benzyl tiglate 6 with AD-mix-
(88% yield, 93% ee), followed by selective oxidation of
the secondary alcohol with sulfur trioxide-pyridine com-
plex in dimethyl sulfoxide afforded ketone 8 in 96% yield,
which was subjected to subsequent protection of the ter-
tiary alcohol as a trimethyl silyl (TMS) ether to furnish the
C1-C4 fragment 4 ([ ]D24 = –9.5 (c 1.25, CHCl3)) in 94%
yield.16
6
OH
11
O
OH
3
7
OH
3
7
10
O
14
11
O
(R)-Pip
2
H
1
OH
O
14
OH
H
1
(S)-N-OH Ala
HO
BnO
NHNH
O
acyl side chain segment (2)
N
N
(2S, 3S)-β-OH Leu
O
1
O
OTBDMS OTBDMS
5
O
O
O
4
O
2
14
O
NMe
3
7
BnO
(2R, 3S)-Thr
O
OTMS
O
3
HN
(R)-N-Me Leu
O
N
OH
O
2
O
5
OTBDMS
OTBDMS
HN
O
2
4
14
BnO
1
GE3 (1)
BnO
H
(S)-Pip
OTMS
6
4
5
Scheme 1
Synlett 2002, No. 4, 29 03 2002. Article Identifier:
1437-2096,E;2002,0,04,0613,0615,ftx,en;Y25101ST.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0936-5214

614
K. Makino et al.
LETTER
O
1
O
O
O
O
O
OH
3
a
c
2
b
2
4
2
BnO
3
BnO
BnO
BnO
94 %
88 %, 93 %ee
96 %
OTMS
OH
OH
4
6
8
7
Scheme 2 a) AD-mix- , MeSO2NH2, t-BuOH, H2O, 32 h, 4 °C, 88%, 93% ee; b) SO3 Py (Py = pyridine), DMSO, 10 °C to r.t., 24 h, 96%; c)
TMSOTf, 2,6-lutidine, CH2Cl2, –78 to –10 °C, 5 h, 94%.
The synthesis of C5-C14 fragment 5 was initiated by em-
ploying Evans’ aldol methodology17 as shown in
Scheme 3. Condensation of the boron enolate derived
from N-propionyl-2-oxazolidone 9 with tiglic aldehyde
gave the diastereometically pure aldol adduct 10 in 48%
yield. The unexpected low yield was improved by em-
ploying the titanium enolate prepared from titanium tet-
rachloride and diisopropylethylamine, which afforded
the desired syn adduct 10 along with its diastereomer in a
ratio of 13:1 and 92% yield. Protection of the C11 alcohol
with a tert-butyldimethylsilyl (TBDMS) group of 10 and
removal of the oxazolidinone auxiliary with lithium
ethanethiolate afforded thiol ester 12 in 85%. After re-
duction of the thiol ester to an aldehyde according to
Fukuyama’s method,18 treatment of ethyl 2-(triphenyl-
phophoranyldiene)propionate gave the (E)- , -unsatur-
ated ester 13 in 86% yield. Adjustment of the oxidation
state through a sequence of reduction with DIBALH and
oxidation with active MnO219 afforded the aldehyde 15 in
94% yield. The stereocontrolled construction of C6 and
C7 was achieved by Paterson’s anti aldol condensation15
using lactate-derived ketone 16 with the aldehyde 15 via
its dicyclohexylborinate in 99% yield as the sole product.
Protection of the C7 hydroxyl group as a TBDMS ether
followed by reduction of the carbonyl function with lith-
ium aluminum hydride gave the diol 19 in 82% yield. Ox-
idative cleavage of vic-diol with NaIO4 furnished the
fragment 5 ([ ]D24 = +4.7 (c 0.97, CHCl3)) in 93% yield.
synthesize the acyl side chain segment 2 by alkylation of
the enolate derived from 4 with the corresponding iodide.
The reaction, however, failed to give the product. Next,
we turned our attention to the coupling of 4 and 5 using
aldol condensation. Fragment coupling of 4 and 5 using
aldol condensation with LDA-ZnCl2 in THF20 provided
the aldol adducts 20 as a 4:1 mixture of diastereomers at
C5. Successive mesylation at the C5 hydroxy group and
elimination in the presence of excess triethylamine (MsCl
4.1 equiv, Et3N 12.3 equiv, CH2Cl2, 0 °C to r.t., 2 h) gave
the labile (E)- , -unsaturated ketone 3 in moderate yield
along with recovery of the aldol adducts 20 (3: 44%, 20:
47%). The use of Burgess reagent21 as a dehydrating re-
agent, however, afforded the ketone 3 in good yield
(75%). Treatment of the unsaturated ketone 3 with Stryk-
er’s reagent [(Ph3P)CuH]622 and subsequent deprotection
of the TMS ether produced the alcohol 21 in 54% yield.
Hemiacetal formation concurrent with removal of the
TBDMS ether at C7 and C11 completed the synthesis of
the acyl side chain segment 223 in 49% yield.
In conclusion, we have achieved the first synthesis of the
acyl side chain segment 2 of GE3 using Sharpless’ asym-
metric dihydroxylation and Evans’ and Paterson’s stere-
oselective aldol reaction. Further investigation directed
towards the total synthesis of GE3 is underway.
Acknowledgement
This work was financially supported in part by research grants from
the Ministry of Education, Culture, Sports, Science and Technolo-
gy, Japan (to Y.H.) and the Nagase Science and Technology Foun-
dation (to Y.H.).
With the C1-C4 and C5-C14 fragments in hand, the stage
was then set for elaboration of the acyl side chain segment
as depicted in Scheme 4. We first attempted to directly
O
O
O
OR
O
7
OTBDMS
O
O
9
OTBDMS
9
c
a
14
10
d, e
O
N
EtO
O
N
11
b
EtS
48%
or
93%
92 %
86 %
13
12
10:
11:
R = H
R = TBDMS (92%)
9
Bn
Bn
OTBDMS
O
OR
OTBDMS
O
OTBDMS
7
f
g
14
BzO
h
6
HO
7
5
98 %
96 %
H
7
99%
14
15
17:
18:
R = H
OH OTBDMS
OTBDMS
i
O
O
5
OTBDMS
OTBDMS
R = TBDMS (93%)
BzO
j
k
6
HO
6
7
14
5
88 %
H
5
93 %
16
19
5
Scheme 3 a) n-Bu2BOTf, Et3N, CH2Cl2, 0 °C, 45 min, then tiglic aldehyde, –78 °C to 0 °C, 7.5 h, 48% (single isomer); or TiCl4, i-Pr2NEt,
CH2Cl2, –78 °C, 1.5 h, then tiglic aldehyde, –78 °C, 11 h, 93% (13:1); b) TBDMSCl, imidazole, DMF, 80 °C, 17 h, 92%; c) EtSH, n-BuLi,
THF, 0 °C, 2.5 h, 92%; d) Et3SiH, Pd/C, acetone, r.t., 5.5 h; e) Ph3P=C(CH3)COOEt, PhH, reflux, 12 h, 86% (2 steps); f) DIBALH, CH2Cl2,
–78 °C, 3 h, 98%; g) MnO2, CH2Cl2, r.t., 5 h, 96%; h) 16, (c-hex)2BCl, Me2NEt, Et2O, –78 to –20 °C, 15 h, 99% (single isomer); i) TBDMSOTf,
2,6-lutidine, CH2Cl2, –78 °C to r.t., 12 h, 93%; j) LiAlH4, Et2O, –78 to 0 °C, 1 h, 88%; k) NaIO4, MeOH–phosphate buffer (5:1), r.t., 6 h, 93%.
Synlett 2002, No. 4, 613–615 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Synthetic Studies on a Cyclic Hexadepsipeptide GE3
615
O
1
O
O
1
O
OH OTBDMS
OTBDMS
a
b
4
4
BnO
BnO
5
83%
14
4
75%
OTBDMS
OTBDMS
20
4
O
1
O
OTBDMS
OTBDMS
O
O
OTBDMS
OTBDMS
5
c,d
4
5
3
BnO
7
1
BnO
14
54%
14
14
OH
OTBDMS
21
3
OH
OH
3
7
e
O
49%
OH
H
1
BnO
O
2
Scheme 4 a) 5, i-Pr2NH, n-BuLi, ZnCl2, THF, –78 to –50 °C,1 h, 83%; b) Et3NSO2NCO2Me, PhH, r.t., 2 h, 75%; c) [(Ph3P)CuH]6, H2, H2O,
PhH, r.t., 12 h; d) TBAF, HOAc, THF, r.t., 24 h, 54% (2 steps); e) HF, CH3CN, 0 °C, 1.5 h, 49%
References
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(23) Compound 2: [ ]D23 +20.5 (c 0.19, CHCl3); IR(neat): 3474,
2956, 2857, 1722, 1462, 1254 cm–1; 1H NMR (500 MHz,
C6D6): = 0.70 (d, J = 6.7 Hz, 3 H, C6-CH3), 1.01 (d, J = 6.8
Hz, 3 H, C10-CH3), 1.30–1.45 (m, 1 H, C6-H), 1.50–1.60
(m, 13 H, C2-CH3, C5-H, C8-CH3, C12-CH3, C14-H), 1.65–
1.80 (m, 2 H, C5-H, C4-H), 2.04 (dd, J = 12.8, 10.3 Hz, C4-
H), 2.64 (m, 1 H, C10-H), 3.25 (brs, 1 H, OH), 3.71 (d,
J = 6.7 Hz, 1 H, C11-H), 4.01 (d, J = 10.4 Hz, 1 H, C7-H),
4.45 (s, 1 H, OH), 5.01 (d, J = 12.2 Hz, 1 H, ArCH2), 5.09 (d,
J = 12.2 Hz, 1 H, ArCH2), 5.30 (d, J = 9.4 Hz, 1 H, C9-H),
5.37 (m, 1 H, C13-H), 7.10–7.20 (m, 5 H, Ar-H); 13C NMR
(125 MHz, C6D6): = 11.8, 12.1, 13.0, 16.5, 17.8, 20.0, 27.4,
27.7, 32.3, 36.3, 67.5, 79.4, 81.2, 83.4, 99.7, 120.5, 128.4,
128.6, 128.8, 132.2, 133.1, 135.7, 137.8, 176.0.
Synlett 2002, No. 4, 613–615 ISSN 0936-5214 © Thieme Stuttgart · New York