Total synthesis of (-)-PA-48153C (pironetin) utilising L-quebrachitol as a chiral building block

Article abstract of DOI:10.1039/a701404j

The chiral and stereoselective synthesis of (-)-PA-48153C (pironetin) 1, a novel immunosuppressant, is described; the acyclic portion possessing four contiguous chiral centres in 1 was constructed stereoselectively from L-quebrachitol and the 2-pyranone m

Full text of DOI:10.1039/a701404j

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Total synthesis of (2)-PA-48153C (pironetin) utilising l-quebrachitol as a
chiral building block
Noritaka Chida,* Mitsukane Yoshinaga, Takahiko Tobe and Seiichiro Ogawa
Department of Applied Chemistry, Faculty of Science and Technology, Keio University, Hiyoshi, Kohoku-ku, Yokohama 223,
Japan
The chiral and stereoselective synthesis of (2)-PA-48153C
(pironetin) 1, a novel immunosuppressant, is described; the
acyclic portion possessing four contiguous chiral centres in 1
was constructed stereoselectively from L-quebrachitol and
the 2-pyranone moiety was prepared from L-malic acid.
89% isolated yield. Treatment of 16 under the conditions of
Mitsunobu9 furnished the acyclic moiety, epoxide 17 in 71%
yield.
The synthesis of the precursor of the 2-pyranone portion in 1
commenced with known (2S,3S)-2-ethyl-3,4-isopropyl-
idenedioxypropan-1-ol 18, obtained from l-malic acid in 6
PA-48153C (pironetin) 1 is a novel 2-pyranone derivative
isolated from the culture broth of Streptomyces1,2 and is
reported to show a potent immunosuppressive,1 cytotoxic1 and
plant growth regulator activities.2a Its interesting mode of
action, its suppressive effect on the responses of both T and B
lymphocytes to mitogens1 as well as its unique structure1,2b has
attracted much synthetic interest and three total syntheses of 1
have been reported to date.3 Recently, reports on the synthesis
and the structure–activity relationship study of the analogues of
1 have appeared.4 Here we report an alternative approach to 1,
which utilises l-quebrachitol 2, an optically active cyclitol
obtained in a large quantity from the serum of the rubber tree5,6
as a chiral building block.
OMe
OH
ii
5
2
6
1
O
OR
O
3 R = H
4 R = Ts
ii
iii
OMe
OMe
Me
OR
iv
vi
O
O
OMe
O
v
O
HO
HO
OH
OH
OMe OH
O
O
O
6 R = H
7 R = Bz
5
OH
OMe
PA-48153C (pironetin) 1
L-quebrachitol 2
7%
3%
OMe
5
The known 1d-(1,2,3,5/4,6)-1,2-O-isopropylidene-3-methyl-
4-O-methylcyclohexane-1,2,4,5,6-pentol 3,6a prepared stereo-
selectively from 2 in five steps, was chosen as the starting
material for the preparation of the acyclic moiety in 1. Reaction
of 3 with dibutyltin oxide7 followed by treatment with
p-toluenesulfonyl chloride (TsCl) afforded 4 in 82% yield.†
Base treatment of 4 provided a-epoxide 5 in 93% yield.
Reaction of 5 with trimethylaluminium in CH2Cl2–hexane at
room temp. caused the trans-diaxial opening of the epoxide ring
with the methyl group to afford 6, which was isolated after
O-benzoylation to provide 7 in 56% yield from 5. The observed
coupling constants and NOE of 7 clearly supported the assigned
structure. The O-isopropylidene group in 7 was removed to give
8 (96%). The cyclohexane ring in 8 was cleaved by periodate
oxidation to provide acyclic diformyl derivative, which, without
isolation, was reduced with NaBH4 to afford diol 9 in 90%
yield. Removal of the O-benzoyl group in 9 and protection of
the resulting 1,2-diol moiety gave 11 (89% yield from 9), which
was converted into the nitrile derivative 13 via O-tosylate 12
(97% for two steps). Reduction of the nitrile function in 13 with
DIBAL-H, followed by acidic work-up provide 14. Wittig
olefination of 14 with Ph3PNCHMe, followed by photo-induced
isomerization, showed low E-selectivity and gave an insepara-
ble mixture of 15 and its Z-isomer in a ratio of 3:1 (61% yield
from 13). Fortunately, better results were obtained when 14 was
reacted with MeCHI2 in the presence of CrCl2 (Takai reaction)8
to provide 15 as the major product (E:Z = 11:1, 74% yield
from 13).‡ Acid hydrolysis of the mixture, followed by
chromatographic separation afforded geometrically pure 16 in
H
J1,2 = 3.7 Hz
J1,6 = 9.2 Hz
J5,6 = 7.0 Hz
HO
OBz
1
2
O
R
H
6
Me
H
OH
8
6%
H
O
BzO
9% NOE
vii
OMe OR
OMe
O
viii
O
OH
HO
11 R = OH
9 R = Bz
ix
iii
12 R = OTs
13 R = CN
14 R = CHO
10 R = H
x
xi
xii
OMe OR
OMe
O
OR
xiv
17
15 R = acetonide
16 R = H
xiii
Scheme 1 Ts = SO2C6H4(p-Me) Reagents and conditions: i, see ref. 6(a);
ii, Bu2SnO, MeOH, reflux, then TsCl, DMAP, 1,4-dioxane, room temp.; iii,
MeONa, MeOH; iv, Me3Al (10 equiv.), CH2Cl2–hexanes (1:1), room
temp.; v, BzCl, pyridine, DMAP, room temp.; vi, 10-camphorsulfonic acid
(CSA, 0.2 equiv.), MeOH, room temp.; vii, NaIO4, acetone–H2O (1:1),
0 °C, then NaBH4, MeOH, 0 °C; viii, acetone, CSA, 0 °C; ix, TsCl, pyridine;
x, NaCN, 15-crown-5, DMF 60 °C; xi, DIBAL-H, CH2Cl2, 278°C, then 5%
aqueous H2SO4–CH2Cl2, 0 °C, 40 min.; xii, MeCHI2 (2 equiv.), CrCl2 (8
equiv.), THF, room temp., 3 h; xiii, CSA, MeOH, 60 °C; xiv, Ph3P, diethyl
azodicarboxylate, toluene, reflux, 36 h
Chem. Commun., 1997
1043

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steps.10 Oxidation of 18 with pyridinium chlorochromate (PCC)
on alumina,11 followed by treatment with propane-1,3-dithiol in
the presence of BF3·OEt2 gave diol 19 in 63% yield. Glycol
cleavage and subsequent modified Wittig–Horner reaction12
gave desired Z-alkene 20 (63% yield) along with its E-isomer
(14%). DIBAL-H reduction of 20 followed by protection of the
resulting alcohol function provided 2-pyranone precursor 22 in
68% yield from 20.
26 to furnish 1 in 87% yield. The spectroscopic (1H and 13C
NMR) data for synthetic 1 were identical with those of natural
PA-48153C, and the physical properties of 1 [mp, 74–76 °C;
21
27
[a]D 2 141 (c 0.18, CHCl3); lit.1,2b mp, 78–79 °C; [a]D
,
2143.71 (c 0.5, CHCl3); 2136.62b (c 1, CHCl3)] showed a good
accord with those reported for the natural product.
We thank Dr Kenji Kawada (Shionogi & Co., Ltd., Osaka,
Japan) for providing us with natural PA-48153C. We also thank
Yokohama Rubber Co. Ltd., (Tokyo, Japan) for the gift of
l-quebrachitol. Financial support of the Moritani Scholarship
Foundation is gratefully acknowledged.
Deprotonation of 22 with tert-butyllithium in the presence of
hexamethylphosphoramide (HMPA),13 followed by addition of
epoxide 17 afforded the coupling product 23 in 56% yield.
Deprotection of the dithioacetal function in 23 was achieved by
14a
treatment with N-chlorosuccinimide (NCS) and AgNO3
in
Footnotes
the presence of 2,4,6-collidine14b§ to give 24 quantitatively.
Reduction of the ketone carbonyl in 24 with NaBH(OAc)315 in
MeCN–AcOH afforded anti-diol 25 as the major product in
65% isolated yield (syn isomer 25% yield). Removal of the
O-silyl protecting group in 25 afforded triol 26 in 82% yield.
The final step was successfully achieved by MnO2 oxidation of
* E-mail: chida@applc.keio.ac.jp
† When this reaction was carried out with TsCl and DMAP in pyridine at
50 °C, compound 4 and its positional isomer (5-O-tosylate) were obtained
in 37 and 22 isolated yield, respectively.
‡ Reaction of 12 (or its corresponding O-triflate derivative) with prop-
1-enyllithium in the presence of CuI salts directly afforded 15, however, the
yield of 15 was low (less than 10%).
§ In the absence of collidine, the formation of cyclic hemi-ketal derivative,
which arose from undesired deprotection of O-silyl group, was observed.
O
i
O
L-malic acid
HO
References
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18
ii
R
iii
S
OH
S
OH
S
S
19
20 R = CO2Me
iv
v
21 R = CH2OH
22 R = CH2OSiMe2But
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Scheme 2 Reagents and conditions: i, see ref. 10(a); ii, PCC, Al2O3,
CH2Cl2, room temp., then 1,3-propanedithiol (1.5 equiv.), BF3·OEt2 (0.3
equiv.), CH2Cl2, room temp.; iii, Pb(OAc)4, K2CO3, benzene, room temp.,
then (CF3CH2O)2P(O)CH2CO2Me, KN(SiMe3)2, 18-crown-6, THF,
278 °C; iv, DIBAL-H CH2Cl2, 278 °C; v, tert-butyldimethylsilyl
trifluoromethanesulfonate, 2,6-lutidine, CH2Cl2, 0 °C
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OSiMe2But
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OMe OH
X
i
22
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D. Wasmuth, D. Arigoni and D. Seebach, Helv. Chim. Acta, 1982, 65,
344.
23 X = S[CH2]3S
24 X = O
ii
iii
OR
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OMe OH OH
v
1
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25 R = SiMe2But
26 R = H
iv
Scheme 3 Reagents and conditions: i, ButLi, HMPA, THF, 278 °C, 10 min,
then THF solution of 17, 278 °C, 30 min; ii, NCS (4 equiv.), AgNO3 (4.5
equiv.), 2,4,6-collidine (8 equiv.), MeCN–H2O (4:1), 0 °C, 1 min; iii,
NaBH(OAc)3, MeCN–AcOH (2:1), 0 °C, 5 h; iv, tetrabutylammonium
fluoride, THF, room temp.; v, MnO2, CH2Cl2, room temp., 3 h
Received in Cambridge, UK, 28th February 1997; Com.
7/01404J
1044
Chem. Commun., 1997