A diastereocontrolled route to the tetrahydropyran nucleus of pseudomonic acids

Article abstract of DOI:10.1016/S0040-4039(01)00440-3

A diastereocontrolled synthesis of the tetrahydropyran nucleus of pseudomonic acids has been achieved starting from a chiral building block, which we have developed. The key step is a convex-face reduction of the block having a biased framework which allo

Full text of DOI:10.1016/S0040-4039(01)00440-3

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 3359–3361
A diastereocontrolled route to the tetrahydropyran nucleus of
pseudomonic acids
Takahiko Taniguchi and Kunio Ogasawara*
Pharmaceutical Institute, Tohoku University, Aobayama, Sendai 980-8578, Japan
Received 14 March 2001; revised 15 March 2001; accepted 16 March 2001
Abstract—A diastereocontrolled synthesis of the tetrahydropyran nucleus of pseudomonic acids has been achieved starting from
a chiral building block, which we have developed. The key step is a convex-face reduction of the block having a biased framework
which allowed assemblage of the most important core in a completely diastereoselective manner. © 2001 Elsevier Science Ltd. All
rights reserved.
The pseudomonic acids 1–4 are a family of C-glycopy-
ranoside antibiotics produced by Pseudomonas fluores-
cens and are potent inhibitors of gram-positive aerobic
bacteria.1,2 All four pseudomonic acids are structurally
related and three of them contained a common tetra-
hydropyran ring flanked by a-cis side chains at C-5 and
C-8 as well as b-cis side chains at C-6 and C-7. Due to
their unusual structure and potent biological activity, a
number of racemic and non-racemic syntheses have
been reported to date.1 However, few have accom-
plished the construction of the most important common
tetrahydropyran nucleus responsible for inhibitory
activity of the three pseudomonic acids in complete
diastereoselection with the proper absolute configura-
tion. Here, we report a diastereocontrolled route to the
most important tetrahydropyran nucleus3 5, which was
previously obtained from D-arabinose and used as the
key intermediate of pseudomonic acids A 1 C 3 by
Fleet and coworkers,3 in enantiopure forms starting
from the chiral building block 6. Although the basic
concept employed in the present synthesis is rather
common, complete diastereocontrol could be attained
on the basis of inherent diastereoselective nature of
the chiral building block which we have developed for
the sugar synthesis4,5 by employing either catalytic
asymmetric synthesis6 or enzymatic resolution7
(Scheme 1).
Thus, the reaction of enantiopure enone (−)-6 with
sodium borohydride in the presence of cerium (III)
chloride8 afforded single endo-allyl alcohol 7, [h]2D8 +2.9
(c 1.0, CHCl3), diastereoselectively by reduction from
OH
4'
HO
O
7
6
CO2H
5
5'
10
8
O
O
pseudomonic acid A 1: R=H
O
R
11
pseudomonic acid B 2: R=OH
pseudomonic acid C 3: R=H, C-10/C-11 E-alkene
pseudomonic acid D 4: R=H, C-4'/C-5' E-alkene
OH
O
O
ref. 3
present study
O
O
O
O
TBSO
O
TBDPSO
(–)-6
5
Scheme 1.
* Corresponding author. E-mail: konol@mail.cc.tohoku.ac.jp
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)00440-3

3360
T. Taniguchi, K. Ogasawara / Tetrahedron Letters 42 (2001) 3359–3361
Having installed the four functionalities in a completely
diastereoselective manner on the tetrahydropyran ring
in the proper configuration, we next carried out the
conversion of 19 into the known intermediate3 5, which
has been used for the synthesis of pseudomonic acids A
1 and C 3, to confirm the structure of the synthetic
product. Thus, primary alcohol 19, was first dehydrated
by employing Grieco conditions14 to give terminal
olefin 21, [h]2D8 −2.8 (c 0.5, CHCl3), which was then
reduced with lithium triethylborohydride to convert the
amide functionality into the primary hydroxy
functionality15 in one step to give 22, [h]2D1 −16.0 (c 1.4,
CHCl3). After silylation, resulting silyl ether 23, [h]D25
−3.3 (c 2.3, CHCl3), was subjected to the Wacker
oxidation under the Tsuji conditions16,17 to give the
target ketone 5 without difficulty. Thus, on stirring with
copper(I) chloride (1 equiv.) in aqueous DMF (60%) in
the presence of a catalytic amount of palladium(II)
chloride (10 mol%) under oxygen at room temperature,
23 furnished 5, [h]2D7 −1.0 (c 1.5, CHCl3), in 89% yield.
Since its specific rotation value was not reported, the
product 5 obtained was hydrolyzed with ethanolic
hydrochloric acid18 so as to obtain the known diol 24,
[h]D26 +19.1 (c 0.7, CHCl3) {lit.:3 [h]2D0 +18.6 (c 2.0,
CHCl3)}. The key pyran nucleus 5 of pseudomonic
acids was thus obtained from the chiral building block
(−)-6 with complete diastereoselection in 16% yield in
18 steps (Scheme 3).
the convex-face of the molecule. After hydrogenation of
7, the resulting 8, [h]2D9 +16.5 (c 1.0, CHCl3), was
transformed into allyl ether 9, [h]2D6 +1.8 (c 1.6, CHCl3),
which was further transformed into iodide 11, [h]D27
−18.6 (c 1.2, CHCl3), via primary alcohol 10, [h]D29
+45.0 (c 1.5, CHCl3), by sequential desilylation and
iodination.9 Upon exposure to zinc in methanol con-
taining acetic acid4,5 at room temperature, 11 furnished
hemiacetal 12, by reductive cleavage of the iodo–ether
linkage, which was further reduced with sodium boro-
hydride to afford the diol 13, [h]2D8 −4.8 (c 1.0, CHCl3),
having a 1,7-diene system. Overall yield of 13 from the
chiral building block (−)-6 was 47% in seven steps. The
most important stage for the construction of the target
molecule has been virtually done at this stage (Scheme
2).
Conversion of the diene 13 into the pyran ring was
carried out in a straightforward manner employing
standard ring-closing metathesis reaction.10,11 The reac-
tion took place very easily when 0.02 M solution of 13
in dichloromethane was refluxed in the presence of 10
mol% of Grubbs’ catalyst12 to furnish the diol 14 in
nearly quantitative yield. After selective protection of
the primary hydroxy functionality of 14 as a silyl ether,
the resulting 15, [h]D26 +85.0 (c 1.1, CHCl3), was heated
with dimethylacetamide dimethylacetal in diphenyl
ether at 280°C to initiate the Eschenmoser–Claisen
rearrangement13 to give rise to the cis-2,5-disubstituted
dihydropyran 16, [h]D24 −19.2 (c 1.2, CHCl3). Among the
solvents tested, the rearrangement reaction proceeded
best in refluxing diphenyl ether. As expected, dihydroxy-
lation of 16 under standard conditions1 proceeded
diastereoselectively from the opposite face of the 2,5-
substituents to furnish the single diol 17, [h]2D3 +1.3
(c1.7, CHCl3), which was transformed into primary
alcohol 19, via 18, [h]D23 −4.1 (c 1.3, CHCl3), by seqen-
tial ketalization and desilylation. Overall yield of 19,
[h]2D1 −4.4 (c 1.2, CHCl3), from diene 13 was 76% in six
steps.
In summary, we report a diastereocontrolled route to
the tetrahydropyran nucleus of pseudomonic acids in
enantiopure forms utilizing a chiral building block orig-
inally developed for the construction of sugar
molecules. Although the present synthesis connects to
the known intermediate to complete a formal synthesis
of pseudomonic acids A and C, the methodology
employed may be shortened and improved in more
ways for the synthesis of the pseudomonic acids as well
as medicinally interesting unnatural pseudomonic acid
derivatives19 in diastereselectively in enantiopure forms.
NaH
allyl bromide
5
O
O
NaBH4-CeCl3
4
(–)-6
OH
O
O
O
MeOH
(95%)
THF-DMF (1:1)
(91%)
TBSO
X
9: X=OTBS
10: X=OH
7: ∆4,5
TBAF
THF
I2 , PPh3
imidazole
toluene
H2, PtO2
AcOEt
(95%)
8
11: X=I
(72%, 2 steps)
OH
OH
HO
O
Zn, AcOH
NaBH4
O
EtOH
(96%)
O
MeOH
(83%)
13
12
Scheme 2.

T. Taniguchi, K. Ogasawara / Tetrahedron Letters 42 (2001) 3359–3361
3361
OH
OR
OR
OsO4 (cat.)
MeC(OMe)2NMe2
Grubbs' catalyst
13
O
O
Ph2O, reflux
(87%)
NMO
aq. THF
(100%)
CH2Cl2
(99%)
CONMe2
16
TBDPSCl
14: R=H
imidazole
15: R=TBDPS
DMF
(100%)
R
O
O
OH
OTBDPS
O
O
30% H2O2
THF
HO
cyclohexanone
O
O
O
PPTS
benzene, reflux
(75%, 2 steps)
CONMe2
TBAF
CONMe2
CONMe2
(94%)
18: R=OTBDPS
17
21
THF (95%)
19: R=OH
o-(NO2)C6H4SeCN
20: R=SeC6H4(NO2)-o
Bu3P, THF
O
O
O2, CuCl
OH
O
PdCl2(cat.)
3N HCl
LiEt3BH
HO
5
O
aq. DMF
(89%)
THF
EtOH
O
(75%)
(79%)
OR
TBDPSO
TBDPS-Cl
imidazole
24
22:R=H
DMF (90%)
23: R=TBDPS
Scheme 3.
9. Garegg, P. J.; Samuelsson, B. J. Chem. Soc., Perkin
Trans. 1 1980, 2866.
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