Synthesis of the C15-C35 segment of chivosazole A

Article abstract of DOI:10.1055/s-2007-991049

The synthesis of the C15-C35 segment of chivosazole A is reported using a convergent approach that incorporates an E-selective Wittig olefination for joining both subunits of this fragment. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2007-991049

LETTER
2667
Synthesis of the C15–C35 Segment of Chivosazole A
S
ynthesis of the C1
o
5–C35 Segm
m
ent of Chivosazole
iA nic Janssen, Markus Kalesse*
Institut für Organische Chemie, Leibniz-Universität Hannover, Schneiderberg 1B, 30167 Hannover, Germany
Fax +49(511)7623011; E-mail: Markus.Kalesse@oci.uni-hannover.de
Received 21 August 2007
synthesizing this segment. In order to independently
confirm the proposed stereochemistry of the remaining
structural motifs and to access derivatives for structure–
activity investigations we initiated a program that aims at
the synthesis of chivosazole A (1).
Abstract: The synthesis of the C15–C35 segment of chivosazole A
is reported using a convergent approach that incorporates an E-se-
lective Wittig olefination for joining both subunits of this fragment.
Key words: chivosazole, natural product, antibiotic, myxobacteria
chivosazole A (1)
Chivosazole A (Table 1) belongs to a family of 31-mem-
bered macrolide glycosides isolated at the Helmholtz
Centre for Infection Research (HZI, formerly GBF) in
1997 from S. cellulosum So ce12.1 They are active against
yeasts and filamentous fungi and they are highly cytotoxic
against mammalian cell cultures (IC50 9 ng/mL L 929 and
HeLa). Except for chivosazole F (7), all natural variants
possess a 6-desoxyglucopyranose (chinovose) at C11.
25
MeO
26
35
30
O
OH
O
N
OH OH
15
O
macro-
lactonization
O
MeO
O
OH
OMe
olefination
MeO
Table 1 Chivosazoles
21
Wittig olefination
R1O
40
28
25
26
OH
39
35
O
38
35
N
7
O
OH OH
30
OTBS
O
37
1
8
O
N
OH
O
O
36
TBS TBS
13
OH
OR2
O
R2a
=
O
OH
R3O
OR4
BrBu3P
O
R
2b = H
9
OTBS
Chivosazoles R1
R2
R3
Me
Me
Me
H
R4
Me
Me
Me
H
R2a
R2a
R2a
R2a
R2a
R2a
R2b
Nagao
aldol reaction
1
A
Me
Ando olefination
2
3
4
5
6
7
A1 (6,7-E)
Me
H
MeO
CHO BrBu3P
B
C
D
E
F
OH
O
Me
H
N
O
O
O
PMB TBS TBS
H
Me
H
Masamune
10 aldol reaction
11
O
OMe
H
H
Scheme 1 Retrosynthetic disconnection of chivosazole
Me
–
–
We envisioned constructing chivosazole A (1) from the
two equally complex fragments 8 and 9 via olefination at
carbons C14 and C15 followed by macrolactone forma-
tion (Scheme 1). In synthetic direction the northern hemi-
sphere 8 can be constructed from aldehyde 10 and Wittig
reagent 11. This segment contains already eight out of the
ten stereocenters of the aglycon of chivosazole A (1). The
synthesis of 11 commenced with the construction of the
C28–C35 segment 12 which was synthesized according to
our strategy used for the structural elucidation. An anti-
The stereochemistry of chivosazole A (1) was solved by
chemical degradation, NMR studies, and analysis of the
polyketide reductase gene cluster.2 Finally, an additional
confirmation of the configurational assignment of the
segment obtained from ozonolysis was obtained by re-
SYNLETT 2007, No. 17, pp 2667–2670
1
6
.1
0
.
2
0
0
7
Advanced online publication: 25.09.2007
DOI: 10.1055/s-2007-991049; Art ID: G27407ST
© Georg Thieme Verlag Stuttgart · New York

2668
D. Janssen, M. Kalesse
LETTER
S
O
Felkin selective Mukaiyama aldol reaction and an anti-
selective reduction of the so-obtained hydroxyl ketone
were used as the pivotal transformations for this segment.2
Reductive opening of the PMP acetal and subsequent
Swern oxidation provided compound 13. In the sub-
sequent olefination the Ando protocol3 installing the Z-
configured double bond provided higher yields and selec-
tivities compared to the Still–Gennari4 reaction (Z/E =
20:1, 58%). The so-obtained ester 15 was reduced and
transformed to the corresponding bromide,5 which was
subsequently reacted with PBu3 to generate Wittig salt 166
(Scheme 2).
S
N
OH
1) PMBCl, NaH
CH2Cl2, 60 °C
OPMB
19
2) MnO2, CH2Cl2,
81% two steps
TiCl4, i-Pr2NEt,
CH2Cl2, –78 °C
95:5, 97%
OHC
OH 17
18
1) TBSOTf, 2,6-lutidine
CH2Cl2, –30 °C, 92%
OPMB
S
N
20
O
2) DIBAL-H, toluene,
–78 °C, 70%
24
S
OH
Ph
O
20
O
OPMB
22
N
Bn
SO2Mes
20
O
1) DIBAL-H
OHC
c-Hex2BOTf,
Et3N, CH2Cl2
–78 °C, 95:5,
99%
24
CH2Cl2, –78 °C,
74%
H
OTBS
21
34
34
O
29
29
2) (COCl)2,
DMSO, Et3N,
CH2Cl2, –78 °C,
88%
O
O
O
O
O
O
TBS TBS
PMB TBS TBS
OPMB
12
13
PMP
OPMB
20
HO
20
MeO
24
1) MeI, Ag2O,
3 Å MS, CH2Cl2,
89%
Ph
O
OTBS
24
EtO2C
2
O
P
OTBS
EtO2C
1) DIBAL-H, CH2Cl2,
–78 °C, 91%
O
34
O
O
23
29
N
14
2) LiAlH4, THF,
Bn
SO2Mes
OH
24
0 °C, 80%
O
O
2) PPh3, CBr4,
CH2Cl2, 84%
NaH, CH2Cl2, –78 °C,
15
PMB TBS TBS
Z/E = 30:1, 69%
1) SerOMe,
EDC, HOBt,
i-Pr2NEt, 78%
1) (COCl)2, DMSO,
Et3N, CH2Cl2,
–78 °C
OPMB
3) PBu3, MeCN
BrBu3P
20
MeO
HO
24
34
2) NaClO2, NaH2PO4
t-BuOH, 91%,
two steps
OTBS
2) DAST, CH2Cl2,
DBU, BrCCl3,
CH2Cl2, 0 °C,
29
16
O
O
O
25
O
PMB TBS TBS
70%, two steps
O
OPMB
Scheme 2 Synthesis of segment 16
20
20
MeO
MeO
24
24
OTBS
OTBS
The synthesis of the C15–C25 segment 10 began with
PMB protection and oxidation of diol 17. For the required
enantioselective aldol reaction the Nagao protocol7 pro-
vided high yields and selectivity (90% ee, 97%). After
TBS protection and transformation of the amide to the
corresponding aldehyde the anti-aldol reaction according
to Masamune8 gave superior results compared to the
Evans or Paterson anti-aldol reactions and provided aldol
product 23 with three configurations established. Methy-
lation of the so-generated secondary alcohol was achieved
by treatment with MeI and Ag2O9 and for cleaving the
chiral auxiliary reduction with LiAlH4 was mandatory.
Re-oxidation to acid 25 was accomplished via a two-step
Swern10 and Pinnick11 oxidation sequence. Finally, the
oxazole moiety was introduced under standard condi-
tions.12 In order to liberate the aldehyde carbonyl group
necessary for coupling, the PMB group was removed us-
ing DDQ and the alcohol oxidized with MnO2 to provide
segment 27 (Scheme 3).
O
N
O
1) DDQ
CH2Cl2/H2O
N
2) MnO2, CH2Cl2,
76%, two steps
26
27
O
O
OMe
OMe
Scheme 3 Synthesis of segment 27
OPMB
OPMB
HF-py
THF–pyridine
1:1, 56%
MeO
HO
MeO
OTBS
O
25
28
O
O
O
Ha
O
MeO
OPMB
H19–H20 = 4.6 Hz
H20–H21a = 4.6 Hz
H20–H21b = 6.8 Hz
H21a–H22 = 11.2 Hz
H21b–H22 = 4.4 Hz
Me
20 21
19
22
H
Hb
H
H
NOE
Scheme 4 Configurational assignment of lactone 28
Even though the Nagao and Masamune protocols are
known as reliable and widely applicable methods in aldol
chemistry we independently confirmed the relative con-
figuration of compound 25 through analyzing the H–H
coupling constants of lactone 28, obtained by treatment of
25 with HF in pyridine (Scheme 4).13
The observed NOE contacts and the coupling constants
clearly support the configurations expected from these
aldol reactions. The boat conformation on which the
configurational analysis was performed was deduced
from coupling constants and computational analysis of the
lactone.
Synlett 2007, No. 17, 2667–2670 © Thieme Stuttgart · New York

LETTER
Synthesis of the C15–C35 Segment of Chivosazole A
2669
(12) (a) Phillips, A. J.; Uto, Y.; Wipf, P.; Reno, M. J.; Williams,
D. R. Org. Lett. 2000, 2, 1165. (b) Williams, D. R.; Lowder,
P. D.; Gu, Y.-G.; Brooks, D. A. Tetrahedron Lett. 1997, 38,
331.
(13) Nicolaou, K. C.; Seitz, S. P.; Pavia, M. R. J. Am. Chem. Soc.
1982, 104, 2030.
The final coupling of both segments could then be
obtained in toluene at 0 °C with KOt-Bu as the base with
gratifying yields and the E-configured double bond as the
only detectable isomer (Scheme 5).14 Even though the 1H
NMR spectrum of the C24–C28 segment was of higher
order and confirmation of the E-configuration was there-
fore not accessible through analysis of the coupling
constants, a Win-Dyna simulation clearly confirmed the
expected E-configured double bond.
(14) Synthesis of Alkene 15
Reagent 14 (14 mg, 44 mmol) was dissolved in THF (1 mL)
and cooled to 0 °C. Then, NaH (2.5 mg, 62 mmol, 60%
dispersion on mineral oil) was added, the solution stirred for
15 min at 0 °C, and then cooled to –78 °C. Aldehyde 13 (27
mg, 49 mmol) was added and the mixture was warmed over
2 h to 0 °C and then quenched with sat. NH4Cl solution (5
mL). The layers were separated and the aqueous layer was
extracted with EtOAc (3 × 5 mL). The combined organic
layers were washed with brine (1 × 10 mL) and dried over
MgSO4. The solvent was removed under reduced pressure
and the residue was purified via flash chromatography. The
reaction yielded 21 mg of the Z-olefin (0.03 mmol, 69%).
Rf = 0.29 (EtOAc–hexane, 1:30); [a]D23 +6.5 (c 1.07,
CHCl3). 1H NMR (400 MHz, CDCl3): d = 7.29 (d, J = 8.5
Hz, 2 H), 6.87 (d, J = 8.5 Hz, 2 H), 6.40 (dd, J = 11.6, 10.2
Hz, 1 H), 5.82 (d, J = 11.6 Hz, 1 H), 4.57 (d, J = 10.6 Hz, 1
H), 4.52 (d, J = 10.6 Hz, 1 H), 4.15 (q, J = 7.1 Hz, 2 H),
3.95–3.90 (m, 1 H), 3.88–3.83 (m, 1 H), 3.80 (s, 3 H), 3.23
(dd, J = 5.8, 3.8 Hz, 1 H), 1.77–1.73 (m, 2 H), 1.57 (ddd,
J = 14.0, 8.0, 1.9 Hz, 1 H), 1.41 (ddd, J = 13.7, 9.1, 4.1 Hz,
1 H), 1.28 (t, J = 7.2 Hz, 3 H), 1.15 (d, J = 6.2 Hz, 3 H), 1.11
(d, J = 6.8 Hz, 3 H), 0.95 (d, J = 6.8 Hz, 3 H), 0.90 (s, 9 H),
0.87 (s, 9 H), 0.10 (s, 3 H), 0.09 (s, 3 H), 0.02 (s, 3 H), –0.01
(s, 3 H). 13C NMR (100 MHz, CDCl3): d = 195.6, 166.1,
159.1, 156.3, 152.4, 131.4, 129.4, 119.8, 113.8, 83.8, 74.3,
72.2, 66.9, 59.8, 55.4, 43.7, 37.1, 26.2, 26.1, 25.4, 18.2, 17.7,
14.4, 9.5, –3.6, –3.8, –4.3, –4.3. ESI-HRMS: m/z calcd for
C33H62O6NaSi2: 645.3983 [M + Na+]; found: 645.3975.
Synthesis of Lactone 28
With a reliable and efficient route for the northern hemi-
sphere in hand we now aim for the construction of the
aglycon of chivosazole A (1).
O
MeO
BrBu3P
25
26
35
OTBS
O
N
O
O
O
PMB TBS TBS
27
KOt-Bu, toluene
O
0 °C, 57%
OMe
16
25
26
MeO
35
OTBS
O
N
O
O
O
PMB TBS TBS
29
O
OMe
Scheme 5 Coupling of segments 27 and 16 via Wittig reaction
Acknowledgment
Acid 25 (10 mg, 22.1 mmol) was dissolved in THF (0.25 mL)
and treated with pyridine (0.25 mL). A HF–pyridine
complex (ca. 70% HF, ca. 30% pyridine, 0.4 mL, 15.3
mmol) was added. The reaction mixture was stirred for 16 h
at r.t. and then poured into sat. NaHCO3 solution (10 mL).
The layers were separated and the aqueous layer was
extracted with MTBE (5 × 5 mL). The combined organic
layers were washed with sat. NH4Cl solution (5 mL) and
brine (5 mL) and dried over MgSO4. The solvent was
removed under reduced pressure and the residue purified via
flash chromatography. The reaction yielded 4 mg of lactone
We gratefully acknowledge Dr. R. Jansen (HZI) for support in the
isolation of natural chivosazole A.
References and Notes
(1) Jansen, R.; Irschik, H.; Reichenbach, H.; Höfle, G. Liebigs
Ann./Recl. 1997, 1725.
(2) Janssen, D.; Albert, D.; Jansen, R.; Müller, R.; Kalesse, M.
Angew. Chem. Int. Ed. 2007, 46, 4898; Angew. Chem. 2007,
119, 4985.
23
28 (12.5 mmol, 56%). Rf = (EtOAc–hexane, 1:4); [a]D
(3) Ando, K. J. Org. Chem. 1997, 62, 1934.
–14.2 (c 0.30, CHCl3). 1H NMR (400 MHz, CDCl3): d = 7.26
(d, J = 8.5 Hz, 2 H), 6.88 (d, J = 8.7 Hz, 2 H), 5.91 (dt,
J = 15.5, 5.2 Hz, 1 H), 5.82 (dd, J = 15.7, 6.0 Hz, 1 H), 4.75
(ddd, J = 10.6, 5.3, 5.3 Hz, 1 H), 4.46 (s, 2 H), 4.02 (d,
J = 5.0 Hz, 2 H), 3.81 (s, 3 H), 3.73 (ddd, J = 6.8, 4.6, 4.6 Hz,
1 H), 3.31 (s, 3 H), 2.75 (dq, J = 6.8, 4.6 Hz, 1 H), 2.25 (ddd,
J = 14.5, 6.9, 4.4 Hz, 1 H), 1.87 (ddd, J = 14.6, 11.2, 4.6 Hz,
1 H), 1.28 (d, J = 6.9 Hz, 3 H). 13C NMR (100 MHz, CDCl3):
d = 173.5, 159.4, 130.2, 130.1, 129.6, 129.5, 114.0, 76.2,
75.9, 72.3, 69.4, 56.8, 55.4, 39.6, 34.0, 11.5. ESI-HRMS:
m/z calcd for C18H24O5Na: 343.1521 [M + Na+]; found:
343.1533.
(4) Still, W. C.; Gennari, C. Tetrahedron Lett. 1983, 24, 4405.
(5) Appel, R. Angew. Chem., Int. Ed. Engl. 1975, 87, 801.
(6) Christmann, M.; Bhatt, U.; Quitschalle, M.; Claus, E.;
Kalesse, M. Angew. Chem. Int. Ed. 2000, 39, 4364; Angew.
Chem. 2000, 112, 4535.
(7) (a) Nagao, Y.; Yamada, S.; Kumagi, T.; Ochiai, M.; Fujita,
E. J. Chem. Soc., Chem. Commun. 1985, 1418. (b) Nagao,
Y.; Hagiwara, Y.; Kumagi, T.; Ochiai, M.; Inoue, T.;
Hashimoto, K.; Fujita, E. J. Org. Chem. 1986, 51, 2391.
(8) (a) Abiko, A.; Liu, J.-F.; Masamune, S. J. Am. Chem. Soc.
1997, 119, 2586. (b) Inoue, T.; Liu, J. F.; Buske, D. C.;
Abiko, A. J. Org. Chem. 2002, 67, 5286.
(9) Tanis, S. P.; Robinson, E. D.; McMills, M. C.; Watt, W.
J. Am. Chem. Soc. 1992, 22, 8349.
(10) Omura, K.; Swern, D. Tetrahedron 1978, 34, 1651.
(11) Bal, B. S.; Childers, W. E. Jr.; Pinnick, H. W. Tetrahedron
1981, 37, 2091.
Synthesis of the C15–C35 Segment (29)
Wittig salt 16 (17 mg, 20 mmol) was dissolved in toluene (1
mL) and cooled to 0 °C. A solution of the aldehyde 27 (10
mg, 24 mmol) in toluene (0.2 mL) was added to the mixture.
The reaction mixture was then treated with a KOt-Bu
solution (18 mL, 28 mmol, 1 M solution in THF). After 30
min H2O (2 mL) was added, the layers separated, and the
Synlett 2007, No. 17, 2667–2670 © Thieme Stuttgart · New York

2670
D. Janssen, M. Kalesse
LETTER
aqueous layer was extracted with MTBE (2 × 5 mL). The
combined organic layers were dried over MgSO4. The
solvent was removed under reduced pressure and the residue
was purified via flash chromatography. The reaction yielded
11 mg of compound 29 (15 mmol, 57%). Rf = 0.32 (EtOAc–
hexane, 1:10); [a]D23 +3.9 (c 1.02, CHCl3). 1H NMR (400
MHz, CDCl3): d = 8.17 (s, 1 H), 7.29 (d, J = 8.5 Hz, 2 H),
6.85 (d, J = 8.9 Hz, 2 H), 6.42–6.36 (m, 1 H), 6.18–6.09 (m,
2 H), 6.04 (t, J = 11.1 Hz, 1 H), 5.62 (t, J = 10.4 Hz, 1 H),
5.59 (dd, J = 14.0, 8.2 Hz, 1 H), 5.32–5.54 (m, 2 H), 4.51 (s,
2 H), 4.32–4.27 (m, 1 H), 3.97–3.92 (m, 1 H), 3.91 (s, 3 H),
3.84–3.81 (m, 1 H), 3.79 (s, 3 H), 3.78–3.76 (m, 1 H), 3.42
(dq, J = 6.8, 5.0 Hz, 1 H), 3.37 (s, 3 H), 3.12 (dd, J = 6.5, 3.8
Hz, 1 H), 2.93–2.84 (m, 1 H), 1.86–1.79 (m, 1 H), 1.43–1.37
(m, 4 H), 1.34 (d, J = 6.8 Hz, 3 H), 1.16 (d, J = 5.8 Hz), 1.06
(d, J = 6.8 Hz, 3 H), 0.95 (d, J = 6.8 Hz, 3 H), 0.92 (s, 9 H),
0.86 (s, 9 H), 0.85 (s, 9 H), 0.10 (s, 6 H), 0.04 (s, 3 H), –0.01
(s, 3 H), –0.02 (s, 6 H). 13C NMR (100 MHz, CDCl3): d =
166.9, 162.0, 159.1, 144.1, 137.2, 134.6, 133.2, 132.6,
131.3, 130.0, 129.5, 128.9, 128.4, 113.8, 84.7, 79.1, 74.6,
71.7, 70.3, 66.7, 57.6, 55.4, 52.3, 43.1, 40.3, 36.2, 32.1, 29.9,
26.2, 26.1, 26.0, 25.6, 22.9, 18.8, 18.2, 14.3, 11.5, 9.2, 7.5,
1.2, –3.3, –3.5, –3.8, –4.1, –4.3, –4.8. ESI-HRMS: m/z calcd
for C52H91NO9Si3Na: 980.5899 [M + Na+]; found: 980.5900.
Synlett 2007, No. 17, 2667–2670 © Thieme Stuttgart · New York

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