An enantiocontrolled approach for the synthesis of chiral 3,5-disubstituted 2(1H)-pyridinones

Article abstract of DOI:10.3987/com-05-s(t)70

An enantioselective route for the convergent synthesis of chiral, nonracemic 5-substituted 3-acyl-2(1H)-pyridinones is reported. Claisen rearrangement provides direct access to the α-branched 2-[4-(tert-butyldimethylsilanoxy)cyclohex-2-enyl]-3-hydroxypropionaldehyde as a key intermediate. The application of mild oxidation conditions facilitates the preparation of a series of 3,5-disubstituted 2(1H)-pyridinones.

Full text of DOI:10.3987/com-05-s(t)70

HETEROCYCLES, Vol. 67, No. 2, 2006
555
HETEROCYCLES, Vol. 67, No. 2, 2006, pp. 555 - 559. © The Japan Institute of Heterocyclic Chemistry
Received, 11th August, 2005, Accepted, 29th September, 2005, Published online, 30th September, 2005. COM-05-S(T)70
AN ENANTIOCONTROLLED APPROACH FOR THE SYNTHESIS OF
CHIRAL 3,5-DISUBSTITUTED 2(1H)-PYRIDINONES†
David R. Williams,* David C. Kammler, and William R. F. Goundry
Indiana University, Department of Chemistry, 800 East Kirkwood Avenue,
Bloomington, Indiana 47405-7102, U.S.A.
Email: williamd@indiana.edu
Abstract – An enantioselective route for the convergent synthesis of chiral,
nonracemic 5-substituted 3-acyl-2(1H)-pyridinones is reported.
Claisen
rearrangement provides direct access to the α-branched 2-[4-(tert-
butyldimethylsilanoxy)cyclohex-2-enyl]-3-hydroxypropionaldehyde as a key
intermediate. The application of mild oxidation conditions facilitates the
preparation of a series of 3,5-disubstituted 2(1H)-pyridinones.
Our recent studies toward the synthesis of naturally occurring pyridinones, such as apiosporamide (1),1
YM-215343 (2),2 fischerin (3),3 and oxysporidinone (4)4 have focused on the development of a
convergent, enantiocontrolled strategy which provides rapid access to C-1' deoxy derivatives of these
novel 2(1H)-pyridinone systems. Significant antibacterial, antifungal and cytotoxic properties associated
with the natural metabolites are difficult to assess owing to their relative instability.
R
N
1
OH
OH
O
CH3
H
O
H
HO 6
H
8
12
2
CH3
9
7
O
5'
HO
H
O
H
4
1'
2'
X
H
4'
OH
O
17
N
H
O
H3C
Y
CH3
H
4 (Oxysporidinone)
1 (Apiosporamide): X = OH; Y = H; R = H
2 (YM-215343): X = Y = O; R = H
3 (Fischerin): X = OH; Y = H; R = OH
The presence of the C-1' tertiary hydroxyl group in these structures is postulated to contribute to the
observed labile behavior. Facile synthesis of the corresponding deoxy compounds provides an
opportunity for studies of biological activity as well as a platform for late-stage oxidation for introduction
†
Dedicated to Professor Barry M. Trost in celebration of his 65th birthday.

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HETEROCYCLES, Vol. 67, No. 2, 2006
of the C-1' hydroxyl moiety. We and others have previously reported studies of total syntheses of 5-aryl-
2-pyridone representatives of this family, including tenellin,5 ilicicolin H,6 sambutoxin,7 and leporin A,8
and pyridovericin.9 However, the stereochemical complexities of structures (1–4) display two independent
components, as exhibited by the cyclohexanediol and the trans-decalin unit which are joined by the
planar pyridone ring in 1. A convergent synthesis approach is required to address these concerns. Herein
we describe an enantioselective route featuring a useful Claisen rearrangement for preparation of chiral,
nonracemic 4-substituted 2-cyclohexen-1-ols and the highly efficient transformation to yield 5-substituted
2-pyridinones.
Preparation of the optically active cyclohexenyl component is summarized in Scheme 1. Beginning with
2-bromocyclohex-2-en-1-one, the Corey CBS asymmetric reduction10 with 6 results in 91% yield of 7
with high enantioselectivity (91–95% ee). Surprisingly, the reductive removal of the 2-bromo substituent
proved more difficult than anticipated.11 Reactions of 7 with excess lithium metal in a mixture of THF
and tert-butanol (5:1 by volume) proceeded very slowly, requiring more than 24 h at reflux for complete
consumption of starting material. While a number of other techniques proved to be less advantageous,
this dissolving metal reduction consistently gave 56% yield of (R)-2-cyclohexen-1-ol (8) and some over-
reduction to cyclohexanol (approximately 10%).
Scheme 1.
Ph
H
Ph
O
1)
Br
X
N
B
3) TBS–Cl, imid.
CH2Cl2 (84%)
N
Li
O
O
R O
H
TBS O
H
6
CH
3
BH3•DMS, THF
91% (95% ee)
2) Li°, t-C4H9OH
THF, reflux (56%)
then MCPBA
NaHCO3
CH2Cl2 at 0 °C (63%)
PhH:Hex (2:1)
0 °C → rt
5
7 R = H; X = Br
8 R = H; X = H
9 R = TBS; X = H
10
TBS O
O
OR
OH
O
H
COOCH
3
1)
TBS O
TBS O
H
2
(C4H9)3P; CH2Cl2
toluene; 180 °C
H
H
H
H
H
22 °C for 5 min
(87%)
2) DIBAL/tol (86%)
O R
TES–Cl
imid.
CH2Cl2 (97%)
12 (R = H)
11
13 (R = H; 56%)
15 (R = TES; 93%)
14 (R = TES)
Silylation and subsequent epoxidation of 9 with buffered meta-chloroperbenzoic acid gave a 78% yield of
a 4:1 mixture of epoxides which were readily separated by flash chromatography affording 10. Base-
induced isomerization12 gave allylic alcohol (11), and facile conjugate addition with methyl propiolate,
catalyzed by tri-n-butylphosphine, yielded the (E)-α,β-unsaturated ester (87%) for subsequent DIBAL
reduction to provide allylic alcohol (12) (86%). Claisen rearrangement of 12 proceeded in a resealable
Carius tube at 180 °C to give the β-hydroxy aldehyde (13) (56% yield) with high diastereoselectivity at C-2
(dr 13:1). However, the thermal rearrangement of the triethylsilyl ether (14) provided a superior yield of 15
(93%; dr 8:1 at C-2) as well as small amounts of the β-elimination product (2.5%). A rationale for the

HETEROCYCLES, Vol. 67, No. 2, 2006
557
observed stereoselectivity of the concerted [3,3]-process is illustrated by analysis of the chair-like and
boat-like arrangements of A and B (Figure 1), respectively. The conformation in A, leading to the 2(S)-
diastereomer (16), reveals a nonbonded steric interaction of the vinylic hydrogen HA with remaining axial
hydrogen of the cyclohexenyl ring. This destabilizing interaction is avoided in B which yields 2(R)-15 as
the major product.
Figure 1.
TESO
HA
OTES
TBSO
TBSO
HA
H
H
O
O
O
O
H
H
H
H
H
H
H
H
OTBS
OTBS
OTES
OTES
15
16
A
B
Convergent construction of the pyridone ring system is illustrated in Scheme 2. Amino alcohol (17) is
readily produced in two steps from aldehyde (15) via reductive amination of the corresponding oximino
ether derived from 4-methoxybenzyloxylamine (70–75% yield for 2 steps). Acylation using benzotriazol-
1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP reagent) for activation of β-
ketocarboxylic acids (18a, 18b, and 18c) gave the expected amides (19a, 19b, and 19c) with minimal
byproducts of O-acylation.13 Swern oxidation14 of the primary alcohol provides the expected aldehyde in
high yield, however, attempted purification by silica gel chromatography effected an undesired cyclization
to yield the 5,6-dihydropyridones (20a and 20b). Alternatively, the use of Dess–Martin
Scheme 2.
1) PMBO–NH2
CH2Cl2
TBSO
TBSO
OH
OH
O
BOP Reagent
15
R
O
O
H
H
PPTs, rt
N–H
O
N
O
O
17
HO
R
4Å sieves (97%)
2) NaCNBH3, AcOH
10 °C (75%)
PMB
PMB
18abc
19a (75%)
19b (95%)
19c (56%)
1) Dess–Martin
periodinane
NaHCO3; CH2Cl2
2) NaClO2; NaH2PO4
(COCl)2; DMSO; –78 °C
(C2H5)3N, CH2Cl2
aqu. CH3CN;
t-C4H9OH; 0 °C
O
3)
TBSO
TBSO
N
N
OH
O
O
O
O
N
N
5
5
R
R
DMF; rt
then NaH
H
H
N
O
N
CH
3
PMB
PMB
O
H
H
21a (40%)
21b (30%)
21c (58%)
Key: (a) R = OC2H5; (b) R = cyclohexyl; (c) R =
H C
20a
20b
H
3
periodinane15 allows for isolation of crude aldehyde without the need for flash chromatography, and this
material may be oxidized with sodium chlorite under buffered conditions16 to yield carboxylic acids.
Treatment of the crude carboxylic acids with 1,1'-carbonyldiimidazole and sodium hydride gave the 5,6-

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HETEROCYCLES, Vol. 67, No. 2, 2006
dihydro-4-hydroxy-2-pyridones (21a, 21b and 21c) in 30–58% overall yields (over 3 steps). Proton NMR
spectroscopy provides evidence that pyridones (20 and 21) are mixtures of C-5 diastereomers.
Furthermore, the examples of 5,6-dihydro-4-hydroxy-2-pyridones (21) have been shown to exist as
mixtures of equilibrating enol and keto tautomers.
Finally, the parent heterocycles were obtained by mild oxidation of 21abc with bromotrichloromethane,
as based on previous studies from these laboratories,17 providing good yields of 22abc. Similarly,
treatment of 20ab under these oxidation conditions also gave the analogous 2(1H)-pyridones (60%).
Subsequent cleavage of the N–O bond is efficiently undertaken using SmI2 at –78 °C (95%). However,
we have recently observed an unexpected N–O cleavage of 22c in our attempts to selectively provoke an
asymmetric C-1' Karasch oxidation.18 Using tert-butylperoxy-4-nitrobenzoate in the presence of the
Scheme 3.
TBS
O
TBS O
HO
O
HO
O
BrCCl3; CH2Cl2
R
R
H
H
N
O
O
N
O
O
N
N
PMB
PMB
NH
22 °C
21
22a (70%)
22b (69%)
22c (76%)
CH
3
H
H
Key: (a) R = OC2H5; (b) R = cyclohexyl; (c) R =
H C
H
3
copper bis(oxazoline) complex derived from copper(I) triflate,19 pyridone (23) was immediately formed
as the major product without evidence of the expected allylic oxidation.20 Although additional efforts are
necessary to generalize and optimize conditions for this transformation, this unusual N–O cleavage under
oxidizing conditions has led to the isolation of desired 2(1H)-pyridone (24) for further studies.
O
O
R O
H
CH3
TBS O
H
CH3
O
HO
O
HO
O
H
H
H
H
O N
2
H
H
H
H
O
H3C
O
H3C
O
O
N
O
N
H
N
N
PMB
t-C H
4
C H -t
4 9
22c
9
23 (R = TBS)
24 (R = H)
HF/pyr
[CuOTf]2•C6H6
22 °C; acetone
(44%)
In summary, we have established a convergent route for the enantioselective preparation of chiral,
nonracemic 5-substituted 3-acyl-2(1H)-pyridinones. A novel Claisen rearrangement selectively affords a
chiral 3-hydroxypropionaldehyde derivative as a key building block for pyridone synthesis. An
unanticipated oxidative N–O bond cleavage reaction has been described.
ACKNOWLEDGEMENTS
We gratefully acknowledge the National Institutes of Health (GM-41560) for generous support.

HETEROCYCLES, Vol. 67, No. 2, 2006
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