A new chiral route to 5- and 6-substituted hydropyran-2-ones utilizing enantiopure 4-cumyloxy-2-cyclopenten-1-one

Article abstract of DOI:10.1016/S0040-4039(01)00303-3

Starting from enantiopure 4-cumyloxy-2-cyclopenten-1-one, a route to 5- and 6-substituted hyropyran-2-ones has been developed. The method has achieved the synthesis of 4,5-cis- and 4,5-trans-5-ethyl-4-hydroxytetrahydropyran-2-ones assigned to marine natural products simplactones. A and B to disprove the former and revise the latter of the proposed structures.

Full text of DOI:10.1016/S0040-4039(01)00303-3

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 2833–2837
A new chiral route to 5- and 6-substituted hydropyran-2-ones
utilizing enantiopure 4-cumyloxy-2-cyclopenten-1-one
Masayuki Sato, Hiromi Nakashima, Keisuke Hanada, Masato Hayashi, Masatoshi Honzumi,
Takahiko Taniguchi and Kunio Ogasawara*
Pharmaceutical Institute, Tohoku University, Aobayama, Sendai 980-8578, Japan
Received 21 February 2001
Abstract—Starting from enantiopure 4-cumyloxy-2-cyclopenten-1-one, a route to 5- and 6-substituted hyropyran-2-ones has been
developed. The method has achieved the synthesis of 4,5-cis- and 4,5-trans-5-ethyl-4-hydroxytetrahydropyran-2-ones assigned to
marine natural products simplactones A and B to disprove the former and revise the latter of the proposed structures. © 2001
Elsevier Science Ltd. All rights reserved.
Although a number of synthetic procedures for the
construction of 6-substituted hydropyran-2-one deriva-
tives have been reported so far, there is no efficient
general route to 5-substituted hydropyran-2-one deriva-
tives.1 We report here a new route to 5- and 6-substi-
tuted hydropyran-3-ones 1–4 utilizing enantiopure
4-cumyloxy-2-cyclopenten-1-one 5 whose efficient syn-
thesis in both enantiomeric forms has been established
recently2 (Fig. 1). We explored a route to 5-substituted
hydropyran-2-one derivatives from 5 targeting a natu-
rally occurring 5-substituted hydropyran-2-ones, (−)-
simplactone A3 1 and (−)-simplactone B3 2, along with
structurally defined compounds, 3a,4 b5 and 4a,6 b,5
having a 6-substituted hydropyran-2-one structure on
the basis of the same methodology to confirm the
absolute configuration of the target natural products.
Simplactones A 1 and B 2 were isolated from the
Caribbean sponge; Plakortis simplex; their structures
were proposed based on spectroscopic analyses and
assigned as 4R,5S-5-ethyl-4-hydroxytetrahydropyran-2-
one for the former and as 4R,5R-5-ethyl-4-hydroxytet-
rahydropyran-2-one for the latter.3
The basis of the present study utilizing 5 is a
diastereoselective 1,4-addition placing an incoming
nucleophile opposite the cumyloxy functionality. If an
OH
OH
OCum
R
O
O
O
O
R
O
O
O
(–)-massoialactone
4a:R=C5H11
(confirmed)
(–)-simplactone A 1
(–)-3a:R=C5H11
(–)-5
(proposed)
(confirmed)
OH
OCum
OH
R
O
O
R
O
O
O
O
O
(+)-4b:R=C11H23
(–)-simplactone B 2
(+)-3b:R=C11H23
(+)-5
(confirmed)
(proposed)
(confirmed)
Figure 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)00303-3

2834
M. Sato et al. / Tetrahedron Letters 42 (2001) 2833–2837
enolate intermediate 6 could be trapped as an enol
ether 7, it would afford a 5-substituted 3-hydroxy tetra-
hydropyran-2-one 8 on sequential oxidative cleavage of
the enol double bond, chemoselective reduction of the
formyl carbonyl and removal of the cumyl functional-
ity. On the other hand, if an enolate 6 could be isolated
as a ketone 9, it could be transformed into a cyclopen-
tanol 10 on sequential stereospecific reduction, O-pro-
tection, and decumylation. On further sequential
oxidation, Baeyer–Villiger reaction, and deprotection,
oxide and 4-methylmorphorine N-oxide (NMO) in
aqueous THF to give the acyloin 13 as an epimeric
mixture. Ketone transposition affording the isomeric
acyloin did not take place under these conditions. Peri-
odate cleavage of 13 yielded the g-formyl ester 14, [h]D29
+75.3 (c 1.3, CHCl3), after workup with diazomethane,
which was then reduced with sodium borohydride to
give the 4,5-disubstituted tetrahydropyran-2-one 15, mp
49–50°C, [h]2D9 −37.8 (c 1.1, CHCl3), by concurrent
lactonization. Finally, the cumyl functionality was
removed by hydrogenolysis to afford (−)-simplactone B
2. However, the product, obtained in 38% overall yield
from the starting (−)-5, was found to be different from
our target; its spectroscopic data (IR, 1H and 13C
NMR) were not identical with those reported for (−)-
simplactone B 2, but with those of (−)-simplactone A 1
assigned to have 4,5-cis-configuration though the syn-
thetic material had much higher optical rotation value,
[h]D28 −23.9 (c 0.8, CHCl3) {lit.:3 [h]2D5 −3 (c 0.002,
CHCl3)}. Thus, this concluded that the originally
assigned 4%R,5%S-4,5-cis-structure for (−)-simplactone B
2% should be corrected as 4%R,5%R-4,5-trans-structure
originally assigned for (−)-simplactone % A 1% (Scheme
2).
10 could furnish
a 6-substituted 3-hydroxytetra-
hydropyran-2-one 11 isomeric to 8 (Scheme 1).
To realize the enol ether route, we first examined the
synthesis of (−)-simplactone B 2 having 4R,5R-4,5-
trans-stereochemistry as its stereocontrol seemed much
easier than the cis-counterpart simplactone A 1. Thus,
(−)-5, [h]2D5 −62.7 (c 3.9, CHCl3) (>99% ee), was treated
with a cuprate generated from ethylmagnesium bro-
mide in THF containing HMPA followed by tert-
butyldimethylsilyl chloride (TBS-Cl) in the same flask7
to give the TBS-enol ether 12, [h]2D6 −88.3 (c 1.3,
CHCl3), in good yield. The TBS-ether 12 obtained was
then dihydroxylated with a catalytic amount of Os(IV)
OH
OCum
Nu
OCum
Nu
OCum
1) O3 then NaBH4
acid workup
*
Nu
*
*
*
Nu–
O-protection
2) hydrogenolysis
O
O
O–
OP
O
8
7
6
(–)-5
Cum = cumyl, P = protecting group
H+
OCum
Nu
OH
OH
Nu
*
*
1) stereospecific reduction
1) oxidation
2) O-protection
2) Baeyer-Villiger
3) deprotection
*
Nu
O
O
O
3) hydrogenolysis
OP
11
9
10
Scheme 1.
OCum
*
OCum
*
OCum
*
EtMgBr, CuI
OsO4(cat.)
NaIO4, aq.MeOH
then CH2N2
NMO
50% aq.THF
HO
TBS-Cl, HMPA
THF
O
OTBS
(69%)
O
(90%)
(77%)
13
12
(–)-5
OH
*
OCum
OCum
*
H2, Pd(OH)2
NaBH4
*
MeOH
(88%)
O
AcOEt
(90%)
O
O
OMe
O
O
O
(–)-simplactone B 2
"proposed"
15
14
(not identical, but identical with
proposed (–)-simplactone A 1)
Cum = cumyl
Scheme 2.

M. Sato et al. / Tetrahedron Letters 42 (2001) 2833–2837
2835
1
To obtain the ‘proposed’ (−)-simplactone A 1 having
4R,5S-4,5-cis-configuration, the above TBS-ether 12
was treated under Saegusa8–Larock9 conditions using a
catalytic amount of palladium(II) acetate (10 mol%) in
DMSO under an oxygen atmosphere to give cyclopen-
tenone 16 in 90% yield. Although diastereocontrolled
hydrogenation could not be attained, 16 furnished a
separable 1:1 mixture of keto-alcohols, cis-17 and
trans-18, with concomitant removal of the cumyl func-
tionality on catalytic hydrogenation. As hydroxy-
directed regioselective Baeyer–Villiger oxidation of a
3-hydroxycyclopentanone was reported,10 we treated
these two with m-chloroperbenzoic acid in
dichloromethane. Though the reaction proceeded very
slowly, 17 furnished an inseparable 4.5:1 mixture con-
taining ‘proposed’ simplactone A 1 as the major com-
ponent and its regio-isomer as the minor component.
On the other hand, the trans-18 furnished the trans-lac-
tone identical with ‘proposed’ simplactone B 2 as the
sole product. The major component of the mixture
obtained from 17 showed virtually the same H NMR
spectrum, but its 13C NMR spectrum was significantly
different from the reported one for ‘proposed’ simplac-
tone A 1. Thus, we cannot help concluding the pro-
posed structure of (−)-simplactone
1 should be
corrected though the proper structure could not be
determined (Scheme 3, Table 1).
Since there are some precedents11 exhibiting syn-selec-
tive 1,4-addition in the related cyclopentenone deriva-
tives, we explored the synthesis of structure-defined
compounds having a 4,6-disubstituted tetrahydropyran-
1-one structure to ascertain the anti-selective 1,4-addi-
tion of our cyclopentenone 5 by employing the ketone
route. Targeting the naturally occurring 3a and the key
intermediate 3b of (−)-tetrahydrolipstatin 23, (−)-5 was
reacted with a cuprate prepared in situ from pentylmag-
nesium bromide in the presence of TMS-Cl in ether
containing HMPA to furnish diastereoselectively the
ketone 19a, [h]2D9 −65.8 (c 0.9, CHCl3), as a single
OH
OH
*
*
m-CPBA
CH2Cl2
O
O
(–)-simplactone A 1
"proposed"
OCum
*
O
17
Pd(OAc)2
H2, Pd(OH)2
(not identical)
12
+
O2, DMSO
(90%)
AcOEt
OH
*
O
OH
*
m-CPBA
CH2Cl2
16
Cum = cumyl
O
O
O
(–)-simplactone B 2
18
"proposed"
(not identical, but identical with
proposed (–)-simplactone A 1)
Scheme 3.
Table 1. 1H and 13C NMR spectra of naturala and syntheticb simplactones A and B
Simplactone A
Simplactone B
Synthetic
Simplactone B
Natural
Simplactone A
Synthetic
Natural
13C
1H
13C
1H
13C
1H
13C
1H
1
5
170.2
171.6
170.3
170.1
69.0 4.49 (1H, dd, J=11.4,
4.4 Hz) 3.98 (1H,
69.3 4.49 (1H, dd, J=11.5,
68.5 4.36 (1H, dd, J=11.2,
10.5 Hz) 4.25 (1H, dd,
J=11.2, 4.6 Hz)
68.9 4.36 (1H, dd, J=10.8,
10.8 Hz) 4.25 (1H, dd,
J=11.3, 4.5 Hz)
4.6 Hz)
overlapped)
3
2
68.1 3.97 (1H, overlapped)
67.7 3.98 (2H, dd, J=11.5,
8.0 Hz)
42.3 2.86 (1H, dd, J=17.6,
5.8 Hz) 2.55 (1H, dd,
J=17.6, 5.8 Hz)
67.1 4.21 (1H, t, J=10.1 Hz)
64.6 4.21 (1H, br s)
42.4 2.88 (1H, dd, J=17.5,
5.8 Hz) 2.55 (1H, dd,
J=17.5, 5.5 Hz)
42.4 2.72 (1H, overlapped)
2.71 (1H, overlapped)
39.4 2.71 (2H, t, J=4.1 Hz)
4
6
38.2 1.78 (1H, m)
21.6 1.65 (1H, m)1.36 (1H, m)
38.0 1.79 (1H, m)
21.6 1.64 (1H, m) 1.36 (1H,
m)
37.5 1.87 (1H, m)
20.6 1.47 (1H, m) 1.36 (1H, m) 19.6 1.46 (1H, m) 1.36 (1H, m)
39.2 1.87 (1H, m)
7
OH
11.2 1.01 (3H, t, J=7.5 Hz)
1.84 (1H, br d, J=4.1 Hz)
11.1 1.01 (3H, t, J=7.6 Hz) 11.8 1.00 (3H, t, J=7.3 Hz)
11.2 1.00 (3H, t, J=7.3 Hz)
2.60 (1H, br s)
1.68 (1H, br.d, J=2.8 Hz)
2.41 (1H, br s)
a NMR spectra were measured in CDCl3
b NMR spectra were measured in CDCl3
(
(
13C: 125 MHz and 1H: 500 MHz).3
13C: 75 MHz and 1H: 300 MHz).

2836
M. Sato et al. / Tetrahedron Letters 42 (2001) 2833–2837
product. Although extensive examination was made,
diastereoselective reduction of the ketone 19a could not
be attained, and the reduction product obtained as a
mixture of two diastereomers was transformed into a
mixture of the tert-butyldimethylsilyl (TBS) ether 20a
by sequential silylation and catalytic de-O-cumylation.
Oxidation of 20a followed by the Baeyer–Villiger oxida-
tion of the resulting ketone 21a afforded the 4,6-disub-
stituted tetrahydropyran-1-one 22a as an inseparable
mixture of two C4-epimers. The mixture was refluxed in
benzene with a catalytic amount of p-toluenesulfonic
acid to give (−)-massoialactone 4a, [h]2D8 −109.7 (c 3.9,
CHCl3){lit.12: [h]D29 −107.52 (c 1.07, CHCl3)}, isolated
from the bark of Cryptocrya massoia and having 6R
configuration. The product obtained as a single product
had the same characteristics as those of an authentic
material prepared by a completely different procedure12
to support the anti-1,4-addition pathway as well as to
support our product above having 4-hydroxy-5-
ethyltetrahydropyran-2-one as trans-4,5 with 4R,5R-
configuration proposed to (−)-simplactone B 2 though
it possessed the spectroscopic data assigned to (−)-sim-
plactone A 1 having the cis-4,5-4S,5R-structure. Over-
all yield of (−)-4a from (−)-5 was 43% in seven steps.
This synthesis constitutes a formal acquisition of (−)-4a
as it has been previously prepared diastereoselectively
from (−)-3a1b,12,13 (Scheme 4).
The anti-1,4 addition pathway was further supported
by reaction using the enantiomeric starting material.
Thus, the reaction of (+)-5, [h]2D6 +62.9 (c 1.9, CHCl3)
(>99% ee), with a cuprate generated from dodecylmag-
nesium bromide under the same conditions above gave
the single (+)-ketone 19b, [h]2D5 +54.8 (c 2.4, CHCl3),
excellently, which was transformed into 6S-dodecyl-5,6-
dihydropyran-2- one (+)-4b, mp 45–47°C, [h]2D6 +74.4 (c
1.8, CHCl3) {lit.:14 [h]D26 +75.38 (c 6.54, CHCl3)}, by
employing exactly the same procedure above via a
diastereomeric mixture of the cyclopentanol 20b,
cyclopentanone 21b, and d-lactone 22b. As (+)-4b was
obtained by a completely different procedure5 and was
transformed into (+)-tetrahydrolipstatin5 23 after
diastereocontrolled conversion into 4S,6S-6-dodecyl-4-
hydroxytetrahydropyran-2-one (+)-3b, the present syn-
thesis constitutes a formal alternative synthesis of 23.
Overall yield of (+)-4b from (+)-enone 5 was 45% in
seven steps (Scheme 5).
In conclusion, we have developed a new diastereocon-
trolled route to both enantiomeric 5- and 6-substituted
4-hydroxytetrahydropyran-2-one
derivatives
using
enantiopure 4-cumyloxy-2-cyclopenten-2-one as the chi-
ral building block. Although direct stereocontrolled
introduction of a 3-hydroxy functionality in 6-substi-
tuted tetrahydropyran-2-ones could not be accom-
OCum
C5H11
OH
C5H11
OCum
*
*
*
1) NaBH4, MeOH
2) TBS-Cl
imidazole, DMF
3) H2, 10%Pd-C
C5H11MgBr
CuI,TMS-Cl
HMPA, Et2O
(85%)
PCC
CH2Cl2
O
OTBS
(89%)
O
(–)-5
19a
(77%)
20a
Cum = cumyl
OTBS
C5H11
O
*
m-CPBA
p-TsOH
benzene
reflux
known
(–)-3a
*
NaHCO3
CH2Cl2
(88%)
*
C5H11
O
O
C5H11
O
O
OTBS
21a
(84%)
(–)-massoialactone 4a
22a
Scheme 4.
OCum
C11H23
OCum
C
11H23
OH
C11H23
O
*
*
C11H23MgBr
*
1) NaBH4, MeOH
m-CPBA
PCC
*
2) TBS-Cl
imidazole, DMF
3)H2, 10%Pd-C
CuI, TMS-Cl
HMPA, Et2O
(87%)
NaHCO3
CH2Cl2
CH2Cl2
(86%)
O
O
OTBS
20b
OTBS
21b
(85%)
AcOEt
(85%)
(+)-5
19b
Cum = cumyl
OTBS
NHCHO
p-TsOH
ref. 6
ref. 6
O
(+)-3b
*
O
O
O
benzene
reflux
*
C11H23
O
O
C11H23
O
O
C11H23
C6H11
(83%)
(+)-4b
22b
(–)-tetrahydrolipstatin 23
Scheme 5.

M. Sato et al. / Tetrahedron Letters 42 (2001) 2833–2837
2837
plished, a convenient route to rather less accessible
4-hydroxy-5-substituted tetrahydropyran-2-one deriva-
tives has been established using the same chiral starting
material.
W.; Fenton, G. J. Chem. Soc., Perkin Trans. 1 1991,
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We thank Professor Arun K. Ghosh, Department of
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