A new strategy for the synthesis of substituted dihydropyrones and tetrahydropyrones via palladium-catalyzed coupling of thioesters

Article abstract of DOI:10.1016/j.tet.2011.03.114

In this paper, we describe a new strategy for the synthesis of substituted dihydropyrones and tetrahydropyrones. By exploiting palladium-catalyzed coupling of thioesters with terminal alkynes or alkenylboronic acids, a variety of β-hydroxy ynones or enones, respectively, could be prepared in an efficient manner under mild conditions. AgOTf-promoted intramolecular oxa-conjugate cyclization of β-hydroxy ynones provided 2,6-substituted dihydropyrones in excellent yields. On the other hand, acid-catalyzed cyclization of β-hydroxy enones caused racemization of the product 2,6-substituted tetrahydropyrones due to its reversible nature. Eventually, stereoselective hydrogenation of substituted dihydropyrones was found to be a solid and efficient approach for the synthesis of 2,6-cis-substituted tetrahydropyrone derivatives.

Full text of DOI:10.1016/j.tet.2011.03.114

Tetrahedron 67 (2011) 4995e5010
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
A new strategy for the synthesis of substituted dihydropyrones and
tetrahydropyrones via palladium-catalyzed coupling of thioesters
*
Haruhiko Fuwa , Kana Mizunuma, Seiji Matsukida, Makoto Sasaki
Graduate School of Life Sciences, Tohoku University, 2-1-1 Katahira, Aoba-ku, Sendai 980-8577, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
In this paper, we describe a new strategy for the synthesis of substituted dihydropyrones and tetrahy-
dropyrones. By exploiting palladium-catalyzed coupling of thioesters with terminal alkynes or alke-
Received 20 January 2011
Received in revised form 22 March 2011
Accepted 29 March 2011
Available online 8 April 2011
nylboronic acids, a variety of
manner under mild conditions. AgOTf-promoted intramolecular oxa-conjugate cyclization of
ynones provided 2,6-substituted dihydropyrones in excellent yields. On the other hand, acid-catalyzed
cyclization of -hydroxy enones caused racemization of the product 2,6-substituted tetrahydropyrones
b
-hydroxy ynones or enones, respectively, could be prepared in an efficient
b
-hydroxy
b
Keywords:
Dihydropyrones
Tetrahydropyrones
Palladium-catalyzed coupling
Thioesters
due to its reversible nature. Eventually, stereoselective hydrogenation of substituted dihydropyrones was
found to be a solid and efficient approach for the synthesis of 2,6-cis-substituted tetrahydropyrone
derivatives.
Ó 2011 Elsevier Ltd. All rights reserved.
Intramolecular oxa-conjugate cyclization
1. Introduction
6-exo cyclization
(a)
Due to their abundant presence in a plethora of naturally
occurring biologically active substances, substituted tetrahy-
dropyrans have been for a long time important synthetic targets
and provide excellent opportunities for the synthetic community
to develop new chemistry. Although less frequently encountered
in the structure of natural substances, substituted dihydropyrans
represent valuable synthetic precursors for tetrahydropyran de-
rivatives via transformation of the double bond. Consequently,
a number of methodologies for the synthesis of substituted tet-
rahydropyrans and dihydropyrans are currently available and
have been reviewed elsewhere.1
One of the renowned methods for the stereoselective synthesisof
substituted tetrahydropyran derivatives is an intramolecular oxa-
conjugate cyclization2 (Scheme 1a). This reaction has been most
commonly applied to hydroxy enones and enoates under basic
conditions to deliver 2,6-cis- or 2,6-trans-substituted tetrahy-
dropyran derivatives via 6-exo-trig ring closure (generally repre-
sented by the transformation of 1 into 2).3 It has also been reported
that acid-catalyzed intramolecular oxa-conjugate cyclization of
hydroxy enones provides substituted tetrahydropyrans.4 The ste-
reochemical outcome depends on the local structure of the sub-
strates and the reaction conditions (i.e., kinetic vs thermodynamic).5
Importantly, a recent biosynthetic study on the bryostatins has
suggested that the tetrahydropyran ring of this family of natural
EWG
HO
O
base or acid
EWG
[6-exo-trig]
1
2
(b)
6-endo cyclizations (this work)
O
HO
base or acid
[6-endo-trig]
O
5
O
3
HO
O
base or acid
[6-endo-dig]
O
4
O
6
Scheme 1. Synthesis of substituted tetrahydropyrans and dihydropyrans via intra-
molecular oxa-conjugate cyclization.
products would be formed via intramolecular oxa-conjugate cycli-
zation of an intermediary a,b-unsaturated thioester on a polyketide
synthase, and it has been proposed that ‘pyran synthase’ would be
* Corresponding author. E-mail address: hfuwa@bios.tohoku.ac.jp (H. Fuwa).
responsible for the cyclization.6 Thus, intramolecular oxa-conjugate
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.03.114

4996
H. Fuwa et al. / Tetrahedron 67 (2011) 4995e5010
cyclization mayrepresent a ‘biomimetic’ strategyfor the synthesis of
tetrahydropyran derivatives.7 With this in mind, we have imple-
mented intramolecular oxa-conjugate cyclization in our recent total
syntheses of (þ)-neopeltolide,8 (ꢀ)-aspergillides A and B,9 (ꢀ)-exi-
guolide,10 and (ꢁ)-centrolobine.11
(ꢁ)-14 led to the corresponding carboxylic acid (ꢁ)-15. Finally,
coupling with an appropriate thiol using DCC/DMAP or EDC/DMAP
afforded thioesters (ꢁ)-16aed.
MgCl
OH
BnO
BnO
CHO
In contrast, there are only limited reports on the intramolecular
THF, 0 °C
81%
oxa-conjugate cyclization of b-hydroxy enones 3 or ynones 4 via
( )-13
12
6-endo closure to provide the respective substituted tetrahy-
dropyrones 5 or dihydropyrones 6,12,13 although these products are
potentially useful for the synthesis of tetrahydropyran-containing
natural products (Scheme 1b). One plausible reason for this may
2. OsO4, NMO;
then NaIO4
1. MPMCl, KOt-Bu
n-Bu4NI, DMF, rt
THF/H2O, rt
88% (2 steps)
be the difficulty in the synthesis of acid and base sensitive
b-hy-
NaClO2
droxy enones and ynones. In recent years, -hydroxy enones have
b
NaH2PO4
OMPM
OH
OMPM
H
been synthesized via elongation of simple enones via aldol cou-
pling14 or olefin cross-metathesis,15 but multistep synthetic trans-
formations would be necessary for the preparation of the
substrates utilized in these approaches. On the other hand, it is well
Me2C=CHMe
BnO
BnO
t-BuOH/H2O, rt
99%
( )-15
RSH
( )-14
O
O
accepted that b-hydroxy ynones could be prepared by means of
anion coupling of carbonyl compounds and terminal alkynes.
However, the coupling might be problematic when enolizable
carbonyl compounds were used as the substrate.16
DCC or EDC
DMAP
CH2Cl2, rt
Herein, we describe in detail a new strategy for the synthesis of
substituted dihydropyrones and tetrahydropyrones via palladium-
catalyzed reactions of thioesters.17e19 We envisioned that
palladium-catalyzed coupling of thioesters 7 with terminal alkynes
OMPM
SR
( )-16a: R = Et (85%)
( )-16b: R = Ph (90%)
( )-16c: R = p-MeC6H4 (95%)
( )-16d: R = p-NO2C6H4 (85%)
BnO
O
would provide
sequent intramolecular oxa-conjugate cyclization would afford 2,6-
substituted dihydropyrones 10. similar strategy involving
b
-alkoxy ynones 8 (Scheme 2, Tol¼p-tolyl). Sub-
Scheme 3. Preparation of thioesters (ꢁ)-16aed.
A
palladium-catalyzed coupling of thioesters 7 with alkenylboronic
acids would be applicable to the synthesis of 2,6-substituted tet-
rahydropyrones 11 via b-alkoxy enones 9. Meanwhile, we envis-
aged that hydrogenation of 2,6-substituted dihydropyrones 10
would also afford the corresponding tetrahydropyrones 11.
Initially, we attempted coupling of S-ethyl thioester (ꢁ)-16a with
terminal alkyne 17 under the conditions reported by Fukuyama
et al.,20 giving ynone (ꢁ)-18, albeit in 39% yield (Table 1, entry 1). The
reaction proceeded only slowly and prolonged reaction time was
necessary for complete consumption of (ꢁ)-16a, during which time
1,4-addition of ethanethiol to the product ynone (ꢁ)-18 was ob-
served as a side reaction and lowered the product yield. We also
observed competitive homocoupling of terminal alkyne 17 under
these conditions. To overcome these problems, we examined vari-
ous reaction parameters, including bases (i-Pr2NEt, 2,6-lutidine),
additives (CuTC,22 CuDPP23), and solvents (CH3CN, THF, 1,4-di-
oxane), but all of these attempts turned out to be fruitless. However,
wewere delighted tofindthat S-arylthioesters (ꢁ)-16bed displayed
muchhigherreactivitythan(ꢁ)-16a undertheFukuyama conditions
(entries 2e4). Especially, coupling of S-(p-tolyl)thioester (ꢁ)-16c
with terminal alkyne 17 was complete within 4 h to give ynone
R2
R1
O
O
R2
Pd(0)/ligand
R1 OMPM
R2
DDQ
CuI, Et3N
6-endo
O
8
10
cyclization
R1 OMPM
STol
H2, Pd/C
O
7
R1 OMPM
R1
O
O
R2
DDQ
R2
(HO)2B
R2
6-endo
cyclization
Pd(0)/ligand
CuTC
O
9
11
Table 1
Scheme 2. Synthesis of substituted dihydropyrones and tetrahydropyrones via
palladium-catalyzed coupling of thioesters and intramolecular oxa-conjugate cycliza-
tion. Tol¼p-tolyl.
Screening of the reaction conditions
OMPM
BnO
BnO
17
OMPM
OMPM
SR
(2.0 equiv)
OMPM
2. Results and discussion
Pd catalyst/ligand
CuI (1.7 equiv)
DMF/Et N (5:1), 50 °C
O
O
2.1. Synthesis of
coupling of thioesters with terminal alkynes
b-alkoxy ynones via palladium-catalyzed
( )-16a: R = Et
( )-16b: R = Ph
( )-18
( )-16c: R = p-MeC H
( )-16d: R = p-NO C H
We first investigated the synthesis of
cursor to substituted dihydropyrones. Because of their lability un-
der acidic or basic conditions, we planned to prepare -alkoxy
b-alkoxy ynones as a pre-
b
Entry Thioester Pd catalyst, ligand
Yield (%)
ynones via palladium-catalyzed coupling of thioesters and terminal
alkynes, which has already been reported by Fukuyama et al.20
The preparation of thioesters (ꢁ)-16aed, illustrated in Scheme 3,
started with allylation of 4-(benzyloxy)butylaldehyde (12) to give
homoallylic alcohol (ꢁ)-13.21 After protection of the hydroxy group
as its MPM ether, the double bond was oxidatively cleaved (OsO4,
NMO; then NaIO4) to provide aldehyde (ꢁ)-14. NaClO2 oxidation of
1
2
3
4
(ꢁ)-16a PdCl2(dppf)$CH2Cl2 (10 mol %), (2-furyl)3P (25 mol %) 39
(ꢁ)-16b PdCl2(dppf)$CH2Cl2 (10 mol %), (2-furyl)3P (25 mol %) 70
(ꢁ)-16c PdCl2(dppf)$CH2Cl2 (10 mol %), (2-furyl)3P (25 mol %) 73
(ꢁ)-16d PdCl2(dppf)$CH2Cl2 (10 mol %), (2-furyl)3P (25 mol %) 65
5
(ꢁ)-16c Pd2(dba)3$CHCl3 (5 mol %), (2-furyl)3P (40 mol %)
(ꢁ)-16c Pd2(dba)3$CHCl3 (5 mol %), (2-furyl)3P (40 mol %)
77
80
6a
a
Reaction performed at room temperature.

H. Fuwa et al. / Tetrahedron 67 (2011) 4995e5010
4997
(ꢁ)-18 in 73% yield (entry3). Examinationof severalcatalyst systems
(PdCl2(dppf)$CH2Cl2/Ph3As, Pd2(dba)3/(2-furyl)3P, Pd2(dba)3$
tolerated under the optimized conditions (5 mol
%
of
Pd2(dba)3$CHCl3, 40 mol % of (2-furyl)3P, 1.7 equiv of CuI, DMF/Et3N
CHCl3/(2-furyl)3P) revealed that Pd2(dba)3$CHCl3 was the optimal
source of palladium (entry 5). In addition, we were able to isolate
(ꢁ)-18 in 80% yield when the reaction was performed at room
temperature, although longer reaction time (22 h) was necessary in
this case (entry 6).
(5:1), 50 ꢂC) to deliver
b
-alkoxy ynones in good yields (73e93%). In
the case of (ꢀ)-20, however, we isolated -alkoxy ynone (ꢀ)-34 as
b
an inseparable 1.3:1 mixture of diastereomers, indicating that
a significant degree of epimerization of the stereogenic center next
to the carbonyl group occurred under the reaction conditions (entry
Encouraged by the optimization study, we next investigated the
8). The palladium-catalyzed coupling of b-[(benzyloxycarbonyl)
synthesis of a series of
b
-alkoxy ynones, as summarized in Table 2.
amino]thioester (ꢁ)-21 with alkyne 23 also proceeded cleanly to
Various combinations of thioesters24 and terminal alkynes were
afford ynone (ꢁ)-35 in high yield (entry 9).
Table 2
Application to a variety of substratesa
Entry
Thioester
Alkyne
Product (Yield %)
BnO
BnO
BnO
BnO
BnO
BnO
OMPM
STol
OMPM
Me
Me
1b
22
O
O
( )-27 (80%)
( )-16c
BnO
OMPM
STol
O
OMPM
OTBDPS
OTBDPS
2c
3b
4b
5c
6c
7b
23
O
( )-28 (80%)
( )-16c
BnO
OMPM
STol
O
OMPM
O
24
( )-29 (82%)
( )-16c
BnO
OMPM
STol
O
OMPM
O
25
( )-30 (75%)
( )-16c
BnO
MPM
O
Me Me
OMPM
STol
O
Me Me
OBn
OBn
26
O
( )-31 (82%)
( )-16c
OMPM
STol
OMPM
OTBDPS
OTBDPS
23
O
O
( )-19
( )-32 (80%)
OMPM
STol
O
OMPM
O
24
( )-19
( )-33 (73%)
(continued on next page)

4998
H. Fuwa et al. / Tetrahedron 67 (2011) 4995e5010
Table 2 (continued )
Entry
Thioester
Alkyne
Product (Yield %)
BnO
BnO
BnO
BnO
OMPM
OMPM
STol
OTBDPS
OTBDPS
OTBDPS
8c
Me
(–)-20
Me
23
O
O
(–)-34 (83%, dr 1.3:1)
NHCbz
NHCbz
STol
O
OTBDPS
9c
23
O
( )-21
( )-35 (93%)
a
All reactions were performed using Pd2(dba)3$CHCl3 (5 mol %), (2-furyl)3P (40 mol %), and CuI (1.7 equiv) in DMF/Et3N (5:1) at 50 ꢂC.
Alkyne (2.0 equiv) was used.
Alkyne (1.5 equiv) was used.
b
c
2.2. Synthesis of substituted dihydropyrones via
intramolecular oxa-conjugate cyclization
corresponding
(Table 3). Treatment of the resultant
b
-hydroxy ynones in good yields without incident
b
-hydroxy ynones with AgOTf
in CH2Cl2 at room temperature12c,d furnished the respective dihy-
dropyrones in excellent yields (Table 3). This reaction could be
performed under either catalytic or stoichiometric conditions
without affecting the product yield (see entry 2), but the latter
conditions proceeded more rapidly. On the other hand, CSA, TMSOTf
or KOt-Bu were completely ineffective for the cyclization and caused
With a facile access to a series of b-alkoxy ynones established, we
put our efforts on their intramolecular oxa-conjugate cyclization to
synthesize dihydropyrone derivatives. Toward this end, depro-
tection of the MPM group in b-alkoxy ynones 27e34 was carried out
using DDQ (pH 7 buffer/CH2Cl2, room temperature) to give the
Table 3
Deprotection and 6-endo cyclization
R1 OMPM
R1 OH
R1
O
O
R2
R2
R2
AgOTf
DDQ
CH2Cl2, rt
pH 7 buffer
CH2Cl2, rt
O
O
Entry
Ynone
Product
Yield step 1 (%)
Yield step 2 (%)
BnO
O
Me
1
(ꢁ)-27
85
96a
O
( )-36
BnO
O
OTBDPS
98a
98b
2
(ꢁ)-28
92
O
( )-37
BnO
O
3
(ꢁ)-29
(ꢁ)-30
90
97a
O
( )-38
BnO
O
4
100
100a
O
( )-39

H. Fuwa et al. / Tetrahedron 67 (2011) 4995e5010
4999
Table 3 (continued )
Entry
Ynone
Product
Yield step 1 (%)
Yield step 2 (%)
BnO
BnO
O
OMPM
5
94
100a
O
O
(+)-30
(+)-39 (98%ee)
BnO
Me Me
O
OBn
6
7
(ꢁ)-31
(ꢁ)-32
96
88
98a
O
( )-40
O
O
OTBDPS
98b
( )-41
O
8
(ꢁ)-33
88
94a
O
( )-42
BnO
H
O
OTBDPS
X
Y
9
(ꢀ)-34
96
100a
O
(+)-43a: X = H, Y = Me
(+)-43b: X = Me, Y = H
[(+)-43a:(+)-43b = 1.3:1]
a
Cyclization was performed using 1.1 equiv of AgOTf.
Cyclization was performed using 0.1 equiv of AgOTf.
b
material decomposition. Notably, our strategyenabled the synthesis
of optically active dihydropyrone (þ)-39 (entry 5). The enantiomeric
excess of (þ)-39 was determined to be 98% ee on the basis of chiral
HPLC analysis, which matched that of the starting material (i.e.,
2.3. Synthesis of
coupling of S-(p-tolyl)thioesters with alkenylboronic acids
b-hydroxy enones via palladium-catalyzed
We envisioned that b-hydroxy enones would be accessible in an
(ꢀ)-16c25). Furthermore, the cyclization could also be applied to
b
-
efficient manner via palladium-catalyzed coupling of S-(p-tolyl)
thioesters with alkenylboronic acids, the reaction originally dis-
covered by Liebeskind and Srogl.26 In the event, we were pleased to
find that the coupling reaction of S-(p-tolyl)thioesters and alke-
nylboronic acids proceeded smoothly under the influence of
Pd2(dba)3$CHCl3 (5 mol %), (2-furyl)3P (40 mol %), and CuTC
(1.5 equiv) in THF at 50 ꢂC (Table 4).27 After removal of the MPM
[(benzyloxycarbonyl)amino]ynone (ꢁ)-35 to give N-Cbz protected
dihydropyridin-4-one (ꢁ)-44, albeit in 50% yield (64% yield based on
recovered starting material) (Scheme 4).
BnO
NHCbz
OTBDPS
group, the desired b-hydroxy enones were isolated in good overall
yields from the respective thioesters.
O
( )-35
2.4. Synthesis of substituted tetrahydropyrones via
intramolecular oxa-conjugate cyclization
AgOTf
N
BnO
Cbz
N
t-Bu
t-Bu
OTBDPS
Having synthesized a series of
attention to the construction of substituted tetrahydropyrone de-
rivatives. We chose optically active
b-hydroxy enones, we turned our
ClCH2CH2Cl
60 °C
50% (64% brsm)
b
-hydroxy enone (ꢀ)-48 (97% ee,
O
determined by chiral HPLC analysis) as a model substrate to in-
vestigate its ring closure under various conditions (Table 5). We
quickly recognized that the desired cyclization could not be
( )-44
Scheme 4. Synthesis of 2,6-disubstituted dihydropyridin-4-one (ꢁ)-44.

5000
H. Fuwa et al. / Tetrahedron 67 (2011) 4995e5010
Table 4
Synthesis of b
-hydroxy enonesa
R1 OMPM
(HO)2B
R1 OH
R2
DDQ
R2
STol
O
pH 7 buffer
CH2Cl2, rt
Pd2(dba)3•CHCl3
(2-furyl)3P, CuTC
THF, 50 °C
O
Entry
Thioester
Boronic acid
Product (Yield %)
BnO
BnO
BnO
BnO
OMPM
STol
O
OH
(HO)2B
1
45
O
(–)-16c
(–)-48 (71%)
BnO
OMPM
STol
O
OH
(HO)2B
Me
2
Me
46
O
(–)-16c
(–)-49 (66%)
BnO
OMPM
STol
O
OH
(HO)2B
Me
3
Me
47
O
( )-16c
( )-50 (53%)
OMPM
STol
OH
(HO)2B
Me
Me
4
47
O
O
( )-19
( )-51 (64%)
a
All coupling reactions were performed using alkenylboronic acid (1.1 equiv), Pd2(dba)3$CHCl3 (5 mol %), (2-furyl)3P (40 mol %), and CuTC (1.5 equiv) in THF at 50 ꢂC.
achieved under basic conditions; exposure of (ꢀ)-48 to a strong base
such as KOt-Bu or NaH gave only a complex mixture of unidentified
products (entries 1 and 2). Treatment of (ꢀ)-48 with CSA in CH2Cl2 at
room temperature resulted in dehydration and did not give tetra-
hydropyrone (þ)-52 at all (entry 3). In contrast, tri-
fluoromethanesulfonic acid (TfOH) promoted the cyclization of
(ꢀ)-48 to give (þ)-52 in 92% yield with moderate diaster-
eoselectivity (cis/trans¼7:1) (entry 4). In line with the previous ob-
servation by Gouverneur et al.,12b (ꢀ)-48 cyclized cleanly upon
exposure to AmberlystÒ 15 to afford tetrahydropyrone (þ)-52 in 95%
yield (cis/trans¼3:1) (entry 5). AgOTf also facilitated the cyclization
smoothly to afford tetrahydropyrone (þ)-52 in 94% yield as a 6:1
mixture of cis/trans isomers (entry 6). Prompted by this result, we
examined the use of several Lewis acids, such as BF3$OEt2, TMSOTf,
and [Pd(MeCN)4](BF4)2, and found that all of these Lewis acids fa-
cilitated the cyclization of (ꢀ)-48 to deliver (þ)-52 in moderate to
good yields, although the diastereoselectivity depended on Lewis
acid used and varied significantly, ranging from3:1 to >20:1 (entries
assigned to be 2,6-trans isomer on the basis of the diagnostic 3JH,H
values as shown. The relative stereochemistry of 53e55 was
assigned in a similar manner.
At this stage, we thought that the observed deviations in
diastereoselectivity would be, at least in part, ascribed to isom-
erization of the thermodynamically less favored 2,6-trans isomer
to the more favored 2,6-cis isomer via a ring-opening/cyclization
sequence. This possibility was easily confirmed by treatment of
tetrahydropyrone (þ)-52 (cis/trans¼ca. 3:1) with TMSOTf (CH2Cl2,
room temperature), which gave (þ)-52 as a single stereoisomer
(cis/trans >20:1). Thus, TMSOTf was found to promote not only
cyclization of (ꢀ)-48 but also thermodynamic equilibration of
a kinetically formed mixture of 2,6-cis and 2,6-trans isomers.
However, these results suggested that a serious problem would
arise when enantiomerically pure b-hydroxy enones were used as
substrates. On the basis of the ring-opening/cyclization mecha-
nism, racemization of the stereogenic center of the cyclization
precursor would occur as the reaction proceeds and result in
a loss of enantiomeric purity of the product (Scheme 5).12c
To ascertain the above racemization problem, we assessed the
optical purity of the products (þ)-52 and (þ)-53 by chiral HPLC
(Table 5). Not surprisingly, the use of TMSOTf as a Lewis acid
resulted in complete racemization (0% ee, entry 8), and a partial
racemization was observed for the product synthesized by the
reaction with TfOH, AmberlystÒ 15, AgOTf or BF3$OEt2 (entries
4e7). In contrast, cyclization of (ꢀ)-48 with [Pd(MeCN)4](BF4)2
delivered (þ)-52 in 95% ee, albeit in moderate yield (entry 9).
7e9). We also examined AgOTf-promoted cyclization of b-hydroxy
enones (ꢀ)-49, (ꢁ)-50, and (ꢁ)-51, which afforded tetrahydropyr-
ones(þ)-53, (ꢁ)-54, and(ꢁ)-55, respectively, withmoderatetogood
diastereoselectivity (entries 10e12). The relative stereochemistry of
each product was established on the basis of an NOE experiment or
3JH,H analysis. For example, the major isomer of (þ)-52 was assigned
to be 2,6-cis isomer since an NOE enhancement was observed be-
tween the two axial oxymethine protons flanking the cyclic ether
oxygen (Fig. 1). On the other hand, the minor isomer of (þ)-52 was

H. Fuwa et al. / Tetrahedron 67 (2011) 4995e5010
5001
Table 5
Intramolecular oxa-conjugate cyclization of
b
-hydroxy enones
R1 OH
R1
O
O
R2
R2
O
Entry
b
-Hydroxy enone
Reagents and conditions
Product
Yield (%)
dra
ee (%)b
BnO
O
1
(ꢀ)-48
KOt-Bu, THF, 0 ꢂC
0
N/A
N/A
O
(+)-52
2
3
4
5
6
7
8
9
(ꢀ)-48
(ꢀ)-48
(ꢀ)-48
(ꢀ)-48
(ꢀ)-48
(ꢀ)-48
(ꢀ)-48
(ꢀ)-48
NaH, THF, rt
CSA, CH2Cl2, rt
TfOH, CH2Cl2, 0 ꢂC to rt
AmberlystÒ 15, CH2Cl2, rt
AgOTf, CH2Cl2, rt
BF3ꢃOEt2, CH2Cl2, rt
TMSOTf, CH2Cl2, 0 ꢂC to rt
[Pd(MeCN)4](BF4)2, CH2Cl2, rt
(þ)-52
(þ)-52
(þ)-52
(þ)-52
(þ)-52
(þ)-52
(þ)-52
(þ)-52
0
0
N/A
N/A
7:1
3:1
6:1
3:1
>20:1
3:1
N/A
N/A
79
81
81
86
0
92
95
94
80
51
54
95
BnO
O
O
Me
10
(ꢀ)-49
(ꢁ)-50
(ꢁ)-51
AgOTf, CH2Cl2, rt
AgOTf, CH2Cl2, rt
AgOTf, CH2Cl2, rt
89
3:1
92
(+)-53
BnO
O
Me
11
87
10:1
N/A
O
( )-54
O
O
Me
12
100
3:1
N/A
( )-55
a
Diastereomer ratio was determined by 600 MHz 1H NMR analysis of a purified mixture of cis/trans isomers.
Enantiomeric excess (ee) of 2,6-cis isomers was determined by chiral HPLC analysis.
b
The optical purity of (þ)-53 was determined to be 92% ee, in-
dicating that only a slight racemization occurred in this case
(entry 10).
5.1 Hz
5.5 Hz
H
H
H
H
O
O
2.5. Synthesis of substituted tetrahydropyrones via
stereoselecive hydrogenation of dihydropyrones
H
O
H
O
8.6 Hz
H
H
Although intramolecular oxa-conjugate cyclization of b-hydroxy
NOE
4.1 Hz
minor (2,6-trans isomer)
enones 48e51 could afford 2,6-substituted tetrahydropyrone de-
rivatives 52e55 in good yields, the racemization problem of this
process makes it synthetically incompetent. Accordingly, as
summarized in Table 6, we investigated the synthesis of 2,6-cis-
major (2,6-cis isomer)
Fig. 1. Stereochemical assignment of the cyclization product (þ)-52.

5002
H. Fuwa et al. / Tetrahedron 67 (2011) 4995e5010
BnO
BnO
BnO
BnO
OH
O
HO
O
O
O
O
acid
acid
acid
O
(–)-52
acid
acid
BnO
BnO
BnO
BnO
O
O
OH
O
O
HO
O
acid
acid
acid
O
(+)-52
Scheme 5. Racemization via ring-opening/cyclization mechanism.
substituted tetrahydropyrones from the corresponding dihy-
dropyrones via hydrogenation (H2, Pd/C, Et3N, EtOAc or EtOH, room
temperature) and found it feasible.28 Thus, a series of tetrahy-
dropyrones (þ)-52, (ꢁ)-56e(ꢁ)-60 could be synthesized in good to
excellent yields. Importantly, hydrogenation of (þ)-39 proceeded to
give (þ)-52 without any loss of its optical purity (98% ee by chiral
HPLC analysis). The relative stereochemistry of each product was
established on the basis of an NOE enhancement observed between
the two oxymethine protons flanking the oxygen. Thus, stereo-
selective hydrogenation of 2,6-substituted dihydropyrones serves
as a solid and efficient method for the synthesis of 2,6-cis-
substituted tetrahydropyrones.
chemicals were purchased at the highest commercial grade and
used directly. Analytical thin-layer chromatography (TLC) was
performed using E. Merck silica gel 60 F254 plates (0.25-mm
thickness). Flash column chromatography was carried out using
Kanto chemical silica gel 60 N (40e100 mesh, spherical, neutral) or
Fuji Silysia silica gel BW-300 (200e400 mesh). Optical rotations
were recorded on a JASCO P-1020 digital polarimeter. IR spectra
were recorded on a JASCO FT/IR-4100 spectrometer. 1H and 13C
NMR spectra were recorded on a JEOL JNM ECA-600 or a Varian
Unity INOVA 500 spectrometer, and chemical shift values are
reported in parts per million (d) downfield from tetramethylsilane
with reference to internal solvent [1H NMR, CHCl3 (7.24), C6HD5
(7.15); 13C NMR, CDCl3 (77.0), C6D6 (128.0)] unless otherwise noted.
Coupling constants (J) are reported in hertz (Hz). The following
abbreviations were used to designate the multiplicities: s¼singlet;
d¼doublet; t¼triplet; m¼multiplet; br¼broad. EI and FAB mass
spectra were recorded on a JEOL JMS-700 spectrometer and ESI-TOF
3. Conclusion
We have shown that b-hydroxy ynones and enones could be
synthesized in an efficient manner by means of palladium-
catalyzed coupling of S-(p-tolyl)thioesters. Intramolecular oxa-
mass spectra were measured on
spectrometer.
a Bruker microTOFfocus
conjugate cyclization of b-hydroxy ynones could be achieved by
treatment with AgOTf to provide substituted dihydropyrone de-
rivatives in high yields. On the other hand, several Brønsted and
Lewis acids were found to facilitate intramolecular oxa-conjugate
4.2. Synthesis of thioesters ( )-16aed
cyclization of b-hydroxy enones. However, as a result of the re-
4.2.1. 7-Benzyloxy-1-heptene-4-ol (ꢁ)-13. To a solution of 4-(ben-
zyloxy)butylaldehyde (1.25 g, 7.01 mmol) in THF (25 mL) cooled to
0 ꢂC was added allylmagnesium chloride (2.0 M solution in THF,
4.21 mL, 8.42 mmol), and the resultant solution was stirred at 0 ꢂC
for 2 h. The reaction was quenched with saturated aqueous NH4Cl
solution. The resultant mixture was extracted with EtOAc, and the
organic layer was washed with brine, dried (Na2SO4), filtered, and
concentrated under reduced pressure. Purification of the residue by
flash chromatography on silica gel (5e20% EtOAc/hexanes) gave the
known title compound (ꢁ)-1321 (1.25 g, 81%) as a yellow oil: 1H NMR
versible nature of the cyclization, racemization of the product was
observed under these conditions. Finally, we found that stereo-
selective hydrogenation of substituted dihydropyrones represents
a
solid and efficient approach for the synthesis of 2,6-cis-
substituted tetrahydropyrone derivatives.
4. Experimental
4.1. General remarks
(500 MHz, CDCl3)
d 7.34e7.31 (m, 3H), 7.28e7.23 (m, 2H), 5.82 (m,
All reactions sensitive to moisture and/or air were carried out
under an atmosphere of argon in dry, freshly distilled solvents
under anhydrous conditions using oven-dried glassware unless
otherwise noted. Anhydrous dichloromethane (CH2Cl2) was pur-
chased from Kanto Chemical Co. Inc. and used directly without
further drying. Anhydrous tetrahydrofuran and toluene were pur-
chased from Wako Pure Chemical Industries, Ltd. and further pu-
rified by a Glass Contour solvent purification system under an
atmosphere of argon immediately prior to use. Diisopropylethyl-
amine, triethylamine, 2,6-lutidine, and acetonitrile (CH3CN) were
distilled from calcium hydride under an atmosphere of argon. N,N-
Dimethylformamide (DMF) and dimethyl sulfoxide (DMSO) were
distilled from magnesium sulfate under reduced pressure. All other
1H), 5.12e5.08 (m, 2H), 4.50 (s, 2H), 3.63 (m, 1H), 3.50 (t, J¼6.0 Hz,
2H), 2.36 (br s, 1H), 2.28e2.14 (m, 2H), 1.78e1.60 (m, 3H), 1.48
(m, 1H).
4.2.2. 6-Benzyloxy-3-(4-methoxybenzyloxy)-1-hexanal (ꢁ)-14. To
a solution of homoallylic alcohol (ꢁ)-13 (1.24 g, 5.63 mmol) in DMF
(28 mL) cooled to 0 ꢂC was added KOt-Bu (1.26 g, 11.3 mmol). After
being stirred at 0 ꢂC for 10 min, MPMCl (1.14 mL, 8.44 mmol), and
n-Bu4NI (0.42 g, 1.13 mmol) were added to the solution at 0 ꢂC. The
resultant mixture was stirred at room temperature for 1.5 h. The
reaction was quenched with saturated aqueous NH4Cl solution at
0 ꢂC. The resultant mixture was extracted with diethyl ether. The
organic layer was washed with brine, dried (MgSO4), filtered, and

H. Fuwa et al. / Tetrahedron 67 (2011) 4995e5010
5003
Table 6
Stereoselective hydrogenation of 2,6-substituted dihydropyrones
R1
O
O
R2
R1 OH
R2
O
Entry
Dihydropyrone
Product (Yield %)
BnO
O
O
1a
(þ)-39
(+)-52 (91%, 98% ee)
BnO
O
Me
4b
3a
5b
2a
(ꢁ)-36
(ꢁ)-37
(ꢁ)-38
(ꢁ)-40
O
( )-56 (95%)
BnO
O
OTBDPS
O
( )-57 (100%)
BnO
O
O
( )-58 (52%)
BnO
Me Me
O
OBn
O
( )-59 (96%)
O
OTBDPS
6a
(ꢁ)-41
O
( )-60 (96%)
a
Performed in EtOAc at room temperature.
Performed in EtOH at room temperature.
b
concentrated under reduced pressure. Purification of the residue by
flash chromatography on silica gel (5% EtOAc/hexanes) gave an
MPM ether (1.92 g), which was contaminated with some impurities
and used in the next reaction without further purification.
Toa solution of the aboveMPMether (1.92 g) inTHF/H2O (1:1, v/v,
28 mL) were added NMO (4.8 M solution in H2O, 3.52 mL,
16.9 mmol) and OsO4 (1.0 g in 100 mL of t-BuOH, 7.2 mL,
0.28 mmol), and the resultant solution was stirred at room tem-
perature overnight. To this solution was added NaIO4 (1.81 g,
8.46 mmol), and the resultant suspension was stirred at room
temperature for 1 h. The mixture was diluted with EtOAc and
washed successively with H2O, saturated aqueous Na2SO3 solution,
and brine, dried (Na2SO4), filtered, and concentrated under reduced
pressure. Purification of the residue by flash chromatography on
silica gel (5e20% EtOAc/hexanes) gave the title compound (ꢁ)-14
(1.70 g, 88% for the two steps) as a pale yellow oil: IR (film) 2937,
2856, 1717, 1513, 1247, 1031 cmꢀ1; 1H NMR (600 MHz, CDCl3)
d 9.75
(ddd, J¼9.6, 2.4, 1.7 Hz, 1H), 7.33e7.20 (m, 7H), 6.84 (ddd, J¼8.9, 2.8,
2.0 Hz, 2H), 4.47 (s, 2H), 4.45 (d, J¼11.0 Hz, 1H), 4.42 (d, J¼11.0 Hz,
1H), 3.94 (m, 1H), 3.78 (s, 3H), 3.47e3.45 (m, 2H), 2.25 (ddd, J¼16.5,
7.2, 2.4 Hz,1H), 2.53 (ddd, J¼16.5, 4.8,1.7 Hz,1H),1.73e1.65 (m, 4H);
13C NMR (150 MHz, CDCl3)
d 201.5, 159.2, 138.4, 130.2, 129.3 (2C),

5004
H. Fuwa et al. / Tetrahedron 67 (2011) 4995e5010
128.3 (2C), 127.6 (2C), 127.5, 113.8 (2C), 73.6, 72.9, 70.8, 70.0, 55.2,
48.2, 30.9, 25.3; HRMS (ESI) calcd for C21H26O4Na [(MþNa)þ]
365.1723, found 365.1732.
4.2.6. S-(4-Methylphenyl) 6-benzyloxy-3-(4-methoxybenzyloxy)-1-
hexanethioate (ꢁ)-16c. Using the procedure described for (ꢁ)-16b,
carboxylic acid 15 (1.46 g, 4.07 mmol) was reacted with p-toluene-
thiol (0.61 g, 4.9 mmol), DCC (1.01 g, 4.89 mmol), and DMAP
(24.9 mg, 0.20 mmol) in CH2Cl2 (21 mL) to give the title compound
(ꢁ)-16c (1.80 g, 95%); IR (film) 2932, 2863, 1698, 1512, 1247,
4.2.3. 6-Benzyloxy-3-(4-methoxybenzyloxy)-1-hexanoicacid(ꢁ)-15. To
a solution of aldehyde (ꢁ)-14 (1.61 g, 4.70 mmol), 2-methyl-2-butene
(2.49 mL, 23.5 mmol), and NaH2PO4 (0.62 g, 5.17 mmol) in t-BuOH/
H2O (4:1, v/v, 25 mL) cooled to 0 ꢂC was added NaClO2 (1.49 g,
16.5 mmol), and the resultant mixture was stirred at room tempera-
ture for 50 min. The reaction mixture was diluted with H2O, cooled to
0 ꢂC, and acidified with 0.5 M aqueous HCl. The resultant mixture was
extracted with EtOAc, dried (Na2SO4), filtered, and concentrated under
reduced pressure. Purification of the residue by flash chromatography
on silica gel (10e30% EtOAc/hexanes) gave the title compound (ꢁ)-15
(1.66 g, 99%) as a colorless oil: IR (film) 2935, 2861, 1708, 1513, 1247,
1033 cmꢀ1; 1H NMR (600 MHz, CDCl3)
d 7.35e7.20 (m,12H), 6.84 (d,
J¼9.0 Hz, 2H), 4.49 (d, J¼10.8 Hz,1H), 4.47 (s, 2H), 4.42 (d, J¼10.8 Hz,
1H), 3.94 (m, 1H), 3.78 (s, 3H), 3.47e3.41 (m, 2H), 2.95 (dd, J¼14.4,
7.2 Hz, 1H), 2.74 (dd, J¼14.4, 5.4 Hz, 1H), 2.36 (s, 3H), 1.74e1.65 (m,
3H); 13C NMR (150 MHz, CDCl3)
d 196.1, 159.2, 139.7, 138.5, 134.4
(2C), 130.4, 130.0 (2C), 129.4 (2C), 128.3 (2C), 127.6 (2C), 127.5, 124.2,
113.7 (2C), 75.6, 72.8, 71.5, 70.1, 55.2, 48.6, 31.2, 25.5, 21.3; HRMS
(ESI) calcd for C28H32O4SNa [(MþNa)þ] 487.1914, found 487.1915.
1033 cmꢀ1
;
1H NMR (600 MHz, CDCl3)
d
7.34e7.31 (m, 4H), 7.27 (m,
4.2.7. S-(4-Nitrophenyl)
6-benzyloxy-3-(4-methoxybenzyloxy)-1-
1H), 7.24e7.21 (m, 2H), 6.84 (ddd, J¼8.9, 2.8, 2.0 Hz, 2H), 4.49 (d,
J¼11.3 Hz,1H), 4.48 (s, 2H), 4.46 (d, J¼11.3 Hz,1H), 3.88 (m,1H), 3.77 (s,
3H), 3.47e3.44 (m, 2H), 2.62 (dd, J¼15.4, 7.2 Hz, 1H), 2.52 (dd, J¼15.4,
5.5 Hz, 1H), 1.72e1.65 (m, 4H) (one proton missing due to H/D ex-
hexanethioate (ꢁ)-16d. Using the procedure described for (ꢁ)-16b,
carboxylic acid 15 (0.51 g, 1.4 mmol) was reacted with p-nitro-
benzenethiol (0.26 g, 1.7 mmol), DCC (0.35 g, 1.7 mmol), and DMAP
(8.7 mg, 0.071 mmol) in CH2Cl2 (14 mL) to give the title compound
(ꢁ)-16d (0.60 g, 85%) as a pale yellow oil: IR (film) 2935, 2857, 1710,
1517, 1343, 1248, 1092, 1033, 852 cmꢀ1; 1H NMR (600 MHz, CDCl3)
change); 13C NMR (150 MHz, CDCl3)
d 176.8, 159.2, 138.4, 130.1, 129.5
(2C), 128.3 (2C), 127.6 (2C), 127.5, 113.8 (2C), 75.0, 72.8, 71.2, 70.0, 55.2,
39.4, 30.8, 25.3; HRMS (ESI) calcd for C21H25O5 [(MꢀH)ꢀ] 357.1707,
found 357.1698.
d
8.21 (d, J¼8.9 Hz, 2H), 7.54 (ddd, J¼8.9, 2.4, 2.4 Hz, 2H), 7.36e7.31
(m, 5H), 7.25 (d, J¼7.6 Hz, 2H), 6.87 (d, J¼8.3 Hz, 2H), 4.51 (s, 2H),
4.49 (s, 2H), 4.00 (m, 1H), 3.79 (s, 3H), 3.49 (t, J¼5.9 Hz, 2H), 3.00
(dd, J¼14.8, 7.3 Hz, 1H), 2.84 (dd, J¼14.8, 4.9 Hz, 1H), 1.78e1.68 (m,
4.2.4. S-Ethyl 6-benzyloxy-3-(4-methoxybenzyloxy)-1-hexanethioate
(ꢁ)-16a. To
a
solution of carboxylic acid (ꢁ)-15 (1.02 g,
4H); 13C NMR (150 MHz, CDCl3)
d 193.2, 159.1, 147.9, 138.3, 136.1,
2.85 mmol), DMAP (17.4 mg, 0.14 mmol), and ethanethiol
(0.85 mL, 11 mmol) in CH2Cl2 (29 mL) cooled to 0 ꢂC was added
EDC$HCl (0.82 g, 4.3 mmol), and the mixture was stirred at room
temperature for 1 h. The reaction mixture was diluted with
EtOAc, washed successively with saturated aqueous NH4Cl solu-
tion, saturated aqueous NaHCO3 solution, and brine, dried
(Na2SO4), filtered, and concentrated under reduced pressure.
Purification of the residue by flash chromatography on silica gel
(0e10% EtOAc/hexanes) gave the title compound (ꢁ)-16a (0.97 g,
85%) as a yellow oil: IR (film) 2931, 2858, 1682, 1613, 1513, 1454,
134.4 (2C), 130.0, 129.3 (2C), 128.2 (2C), 127.5 (2C), 124.3, 123.7 (2C),
113.6 (2C), 75.4, 72.7, 71.3, 69.8, 55.1, 48.9, 30.9, 25.2; HRMS (ESI)
calcd for C27H29NO6SNa [(MþNa)þ] 518.1608, found 518.1597.
4.3. General procedure for the palladium-catalyzed coupling
of thioesters and terminal alkynes
General procedure (GP-1): To a mixture of Pd2(dba)3$CHCl3
(13.2 mg, 0.0128 mmol), CuI (82.7 mg, 0.434 mmol), and (2-furyl)3P
(23.7 mg, 0.102 mmol) in degassed DMF (1.1 mL) was added a so-
lution of thioester (ꢁ)-16c (118.7 mg, 0.255 mmol) in degassed
DMF (1.1 mL), 1-hexyne (0.059 mL, 0.51 mmol), and Et3N
(0.430 mL). The resultant mixture was stirred at 50 ꢂC for 4.4 h.
After being cooled to room temperature, the reaction mixture was
diluted with H2O (10 mL) and extracted with diethyl ether (30 mL).
The organic layer was washed with brine (20 mLꢄ2), dried
(MgSO4), filtered, and concentrated under reduced pressure. Puri-
fication of the residue by flash chromatography on silica gel (5e10%
EtOAc/hexanes) gave ynone (ꢁ)-27 (86.7 mg, 80%) as a yellow oil.
1301, 1173, 1097, 821 cmꢀ1
;
1H NMR (600 MHz, CDCl3)
d
7.36e7.34 (m, 5H), 7.25 (d, J¼8.2 Hz, 2H), 6.86 (d, J¼8.6 Hz, 2H),
4.50 (d, J¼11.0 Hz, 1H), 4.49 (s, 2H), 4.42 (d, J¼11.0 Hz, 1H), 3.93
(m, 1H), 3.78 (s, 3H), 3.46e3.44 (m, 2H), 2.94e2.86 (m, 3H), 2.67
(dd, J¼14.8, 5.5 Hz, 1H), 1.78e1.63 (m, 4H), 1.26 (t, J¼7.6 Hz, 3H);
13C NMR (150 MHz, CDCl3)
d 197.5, 159.0, 138.5, 130.3, 129.3 (2C),
128.2 (2C), 127.5 (2C), 127.4, 113.6 (2C), 75.5, 72.7, 71.2, 70.0, 55.1,
49.0, 31.1, 25.4, 23.3, 14.6; HRMS (ESI) calcd for C23H30O4SNa
[(MþNa)þ] 425.1757, found 425.1760.
4.2.5. S-Phenyl 6-benzyloxy-3-(4-methoxybenzyloxy)-1-hexanethi-
oate (ꢁ)-16b. To a solution of carboxylic acid (ꢁ)-15 (0.56 g,
1.56 mmol), DMAP (9.5 mg, 0.078 mmol), and benzenethiol
(0.190 mL, 1.87 mmol) in CH2Cl2 (15.6 mL) cooled to 0 ꢂC was added
DCC (0.39 g, 1.87 mmol), and the resultant mixture was stirred at
room temperature for 1 h. Insoluble materials were filtered off, and
the filtrate was concentrated under reduced pressure. Purification
of the residue by flash chromatography on silica gel (5e10% EtOAc/
hexanes) gave the title compound (ꢁ)-16b (0.63 g, 90%) as a color-
4.3.1. 1-Benzyloxy-4-(4-methoxybenzyloxy)-7-dodecyn-6-one
(ꢁ)-27. IR (film) 2930, 2210, 1670, 1513, 1455, 1247, 1095,
698 cmꢀ1 1H NMR (500 MHz, CDCl3)
; d 7.32e7.26 (m, 5H), 7.21 (d,
J¼8.0 Hz, 2H), 6.83 (d, J¼8.5 Hz, 2H), 4.47e4.37 (m, 4H), 4.00 (m,
1H), 3.77 (s, 3H), 3.44 (t, J¼5.0 Hz, 2H), 2.86 (dd, J¼15.5, 7.5 Hz, 1H),
2.63 (dd, J¼15.5, 4.5 Hz, 1H), 2.36e2.29 (m, 2H), 1.74e1.60 (m, 4H),
1.58e1.50 (m, 2H), 1.49e1.36 (m, 2H), 0.89 (t, J¼7.5 Hz, 3H); 13C
NMR (125 MHz, CDCl3)
d 186.1, 159.1, 138.4, 130.4, 129.3 (2C), 128.3
(2C), 127.5 (2C), 127.4, 113.6 (2C), 94.9, 81.2, 74.7, 72.8, 71.1, 70.1,
55.2, 50.6, 31.0, 29.6, 25.4, 21.9, 18.6, 13.4; HRMS (ESI) calcd for
C27H34O4Na [(MþNa)þ] 445.2349, found 445.2365.
less oil: IR (film) 2934, 2857, 1702, 1513, 1247, 1096 cmꢀ1
;
1H NMR
(600 MHz, CDCl3)
d 7.40e7.33 (m, 5H) (s, 5H), 7.39e7.36 (m, 5H),
7.30 (d, J¼8.9 Hz, 2H), 6.90 (d, J¼8.6 Hz, 2H), 4.54 (d, J¼11.0 Hz, 1H),
4.52 (s, 2H), 4.48 (d, J¼11.0 Hz, 1H), 4.01 (m, 1H), 3.80 (s, 3H),
3.51e3.47 (m, 2H), 3.01 (dd, J¼15.1, 7.2 Hz, 1H), 2.81 (dd, J¼15.1,
4.3.2. 1-Benzyloxy-4,11-bis(4-methoxybenzyloxy)-7-undecyn-6-one
(ꢁ)-18. According to GP-1, thioester (ꢁ)-16c (65.6 mg, 0.141 mmol)
was reacted with alkyne 17 (57.7 mg, 0.282 mmol) in the presence of
Pd2(dba)3$CHCl3 (7.3 mg, 0.0071 mmol), (2-furyl)3P (13.1 mg,
0.0565 mmol), and CuI (45.6 mg, 0.240 mmol) in DMF/Et3N (5:1, v/v,
0.70 mL) to give the title compound (ꢁ)-18 (58.8 mg, 77%) as a yel-
low oil: IR (film) 2857, 2210, 1670, 1612, 1512, 1246, 1172, 1100, 1033,
5.2 Hz, 1H), 1.80e1.70 (m, 4H); 13C NMR (150 MHz, CDCl3)
d 195.4,
159.1, 138.4, 134.3 (2C), 130.3, 129.3 (2C), 129.2, 129.1 (2C), 128.2
(2C), 128.1, 127.5 (2C), 127.4, 113.6 (2C), 75.5, 72.3, 71.4, 69.9, 55.1,
48.6, 31.1, 25.3; HRMS (ESI) calcd for C27H30O4SNa [(MþNa)þ]
473.1757, found 473.1774.

H. Fuwa et al. / Tetrahedron 67 (2011) 4995e5010
5005
819 cmꢀ1; 1H NMR (500 MHz, CDCl3)
d
7.35e7.28 (m, 5H), 7.23e7.21
(1.01 g, 2.17 mmol) was reacted with alkyne 26 (0.61 g, 3.26 mmol)
in the presence of Pd2(dba)3$CHCl3 (99.5 mg, 0.109 mmol), (2-fur-
yl)3P (0.20 g, 0.87 mmol), and CuI (0.70 g, 3.70 mmol) in DMF/Et3N
(5:1, v/v, 22 mL) to give the title compound (ꢁ)-31 (0.94 g, 82%) as
a yellow oil: IR (film) 2858, 2361, 2208, 1671, 1612, 1513, 1454, 1360,
(m, 4H), 6.86 (d, J¼9.0 Hz, 2H), 6.84 (d, J¼8.5 Hz, 2H), 4.48 (s, 2H),
4.44 (d, J¼9.5 Hz, 2H), 4.41 (s, 2H), 4.01 (m, 1H), 3.78 (s, 3H), 3.77 (s,
3H), 3.49 (t, J¼5.5 Hz, 2H), 3.45 (t, J¼ 5.5 Hz, 2H), 2.85 (dd, J¼15.5,
7.5 Hz, 1H), 2.62 (dd, J¼15.5, 5.0 Hz, 1H), 2.45 (t, J¼6.5 Hz, 2H),
1.85e1.80 (m, 2H), 1.75e1.62 (m, 4H); 13C NMR (125 MHz, CDCl3);
1247, 1173, 1098 cmꢀ1 1H NMR (500 MHz, CDCl3)
; d 7.34e7.26 (m,
d
186.0, 159.2, 159.1, 138.5, 130.4, 130.2, 129.4 (2C), 129.2 (2C), 128.3
10H), 7.21 (d, J¼9.0 Hz, 2H), 6.82 (d, J¼8.5 Hz, 2H), 4.55 (s, 2H), 4.47
(s, 2H), 4.46e4.41 (m, 2H), 4.00 (m,1H), 3.76 (s, 3H), 3.43 (t, J¼5.0 Hz,
2H), 3.32 (s, 2H), 2.86 (dd, J¼15.5, 7.5 Hz,1H), 2.63 (dd, J¼15.5, 5.5 Hz,
1H), 1.72e1.63 (m, 4H), 1.25 (s, 6H); 13C NMR (125 MHz, CDCl3)
(2C),127.6 (2C),127.5 (2C),113.8 (2C),113.7 (2C), 94.2, 81.3, 74.7, 72.8,
72.6, 71.1, 70.1, 68.0, 55.2, 50.6, 31.0, 27.9, 25.4,15.9; HRMS (ESI) calcd
for C34H40O6Na [(MþNa)þ] 567.2717, found 567.2716.
d
186.1, 159.1, 138.5, 138.1, 130.5, 129.4 (2C), 128.4 (2C), 128.3 (2C),
4.3.3. 1-Benzyloxy-11-(tert-butyldiphenylsilyloxy)-4-(4-methox-
ybenzyloxy)-7-undecyn-6-one (ꢁ)-28. According to GP-1, thioester
(ꢁ)-16c (411 mg, 0.885 mmol) was reacted with alkyne 23 (428 mg,
1.33 mmol) in the presence of Pd2(dba)3$CHCl3 (46.0 mg,
0.0442 mmol), (2-furyl)3P (82.0 mg, 0.354 mmol), and CuI (286 mg,
1.50 mmol) in DMF/Et3N (5:1, v/v, 8.8 mL) to give the title compound
(ꢁ)-28 (385 mg, 80%) as a yellow oil: IR (film) 2857, 2211, 1671, 1513,
127.6 (2C), 127.5, 127.4 (2C), 113.7 (2C), 109.7, 99.4, 80.8, 77.3, 74.8,
73.3, 72.9, 71.2, 70.1, 55.2, 50.7, 32.9, 31.0, 25.5, 25.2 (2C); HRMS (ESI)
calcd for C34H40O5Na [(MþNa)þ] 551.2768, found 551.2755.
4.3.7. 8-(tert-Butyldiphenylsilyloxy)-1-cyclohexyl-1-(4-methox-
ybenzyloxy)oct-4-yn-3-one (ꢁ)-32. According to GP-1, thioester
(ꢁ)-19 (155.1 mg, 0.374 mmol) was reacted with alkyne 23
(181.0 mg, 0.561 mmol) in the presence of Pd2(dba)3$CHCl3
(19.4 mg, 0.0187 mmol), (2-furyl)3P (34.7 mg, 0.150 mmol), and CuI
(121.1 mg, 0.636 mmol) in DMF/Et3N (5:1, v/v, 3.7 mL) to give the
title compound (ꢁ)-32 (177.8 mg, 80%) as a yellow oil: IR (film) 2928,
1428, 1247, 1109, 822 cmꢀ1 1H NMR (500 MHz, CDCl3)
; d 7.63e7.62
(m, 4H), 7.40e7.30 (m, 11H), 7.20 (d, J¼8.5 Hz, 2H), 6.81 (d, J¼8.0 Hz,
2H), 4.46 (s, 2H), 4.45e4.36 (m, 2H), 3.98 (m,1H), 3.75 (s, 3H), 3.69 (t,
J¼5.5 Hz, 2H), 3.43e3.42 (m, 2H), 2.83 (dd, J¼15.5, 7.5 Hz, 1H), 2.59
(dd, J¼15.5, 5.0 Hz, 1H), 2.49 (t, J¼6.5 Hz, 2H), 1.79e1.74 (m, 2H),
2854, 2361, 1671, 1612, 1513, 1247, 1109 cmꢀ1 1H NMR (600 MHz,
;
1.70e1.62 (m, 4H), 1.02 (s, 9H); 13C NMR (125 MHz, CDCl3)
d
186.0,
CDCl3)
d
7.55 (d, J¼6.6 Hz, 4H), 7.32e7.26 (m, 6H), 7.13 (d, J¼8.4 Hz,
159.1,138.5,135.5,135.5 (4C),133.5,130.4,129.7(2C),129.4(2C),128.3
(2C),128.3,127.7 (4C),127.6 (2C),113.7 (2C), 94.4, 81.2, 74.6, 72.8, 71.1,
70.1, 62.0, 55.2, 50.5, 31.0, 30.6, 26.8 (3C), 25.4,19.2,15.6; HRMS (ESI)
calcd for C42H50O5SiNa [(MþNa)þ] 685.3320, found 685.3342.
2H), 6.73 (d, J¼8.4 Hz, 2H), 4.35 (q, J¼14.5 Hz, 2H), 3.72 (m, 1H),
3.64 (s, 3H), 3.62 (t, J¼5.4 Hz, 2H), 2.68 (dd, J¼15.6, 7.8 Hz, 1H), 2.53
(dd, J¼15.6, 4.2 Hz, 1H), 2.41 (t, J¼7.8 Hz, 2H), 1.70e1.63 (m, 5H),
1.57 (m, 1H), 1.50e1.43 (m, 2H), 1.16e0.99 (m, 3H), 0.96 (s, 9H),
0.93e0.87 (m, 2H); 13C NMR (150 MHz, CDCl3)
d 186.6, 159.0, 135.4
4.3.4. 8-Benzyloxy-5-(4-methoxybenzyloxy)-1-phenyl-1-octyn-3-
one (ꢁ)-29. According to GP-1, thioester (ꢁ)-16c (132.8 mg,
0.286 mmol) was reacted with ethynylbenzene (0.063 mL,
0.57 mmol) in the presence of Pd2(dba)3$CHCl3 (14.8 mg,
0.0143 mmol), (2-furyl)3P (26.5 mg, 0.114 mmol), and CuI (92.5 mg,
0.486 mmol) in DMF/Et3N (5:1, v/v, 2.9 mL) to give the title com-
pound (ꢁ)-29 (103.6 mg, 82%) as a yellow oil: IR (film); 2856, 2202,
(4C), 133.4, 130.6, 129.6 (2C), 129.3 (2C), 128.2, 127.6 (4C), 113.6 (2C),
94.2, 81.3, 79.2, 71.9, 62.0, 55.1, 48.0, 41.7, 30.6, 28.6, 28.5, 26.8 (3C),
26.5, 26.2 (2C), 19.1, 15.5; HRMS (ESI) calcd for C38H48O4SiNa
[(MþNa)þ] 619.3214, found 619.3235.
4.3.8. 1-Cyclohexyl-1-(4-methoxybenzyloxy)-5-phenyl-4-pentyn-
3-one (ꢁ)-33. According to GP-1, thioester (ꢁ)-19 (138.1 mg,
0.333 mmol) was reacted with ethynylbenzene (0.073 mL,
0.67 mmol) in the presence of Pd2(dba)3$CHCl3 (17.2 mg,
0.0167 mmol), (2-furyl)3P (30.9 mg, 0.133 mmol), and CuI (107.9 mg,
0.566 mmol) in DMF/Et3N (5:1, v/v, 3.3 mL) to give the title compound
(ꢁ)-33 (91.0 mg, 73%) as a yellow oil: IR (film) 2926, 2852,1668,1512,
1665, 1612, 1512, 1454, 1246, 1070, 820 cmꢀ1 1H NMR (500 MHz,
;
CDCl3)
d
7.52e7.25 (m, 10H), 7.23 (d, J¼8.5 Hz, 2H), 6.80 (d,
J¼8.0 Hz, 2H), 4.48 (dd, J¼12.0, 11.5 Hz, 2H), 4.47 (s, 2H), 4.10e4.07
(m, 1H), 3.74 (s, 3H), 3.47e3.46 (m, 2H), 2.98 (dd, J¼7.5, 7.0 Hz, 1H),
2.76 (dd, J¼5.5, 5.0 Hz, 1H), 1.76e1.66 (m, 4H); 13C NMR (125 MHz,
CDCl3)
d
185.9, 159.0, 138.4, 133.0, 130.7, 130.2 (2C), 129.5, 129.4,
1247,1070, 821 cmꢀ1; 1H NMR (600 MHz, CDCl3)
d 7.53e7.52 (m, 2H),
128.6, 128.5, 128.3, 127.5, 127.4, 119.7, 113.6 (4C), 91.2, 88.1, 74.6,
72.8, 71.1, 70.0, 55.1, 50.5, 30.9, 25.4; HRMS (ESI) calcd for
C29H30O4Na [(MþNa)þ] 465.2036, found 465.2037.
7.43 (m, 1H), 7.37e7.35 (m, 2H), 7.25 (d, J¼9.6 Hz, 2H), 6.81 (d,
J¼8.4 Hz, 2H), 4.50 (dd, J¼15.6, 7.8 Hz,1H), 3.91 (m,1H), 3.73 (m,1H),
2.93 (dd, J¼15.6, 7.8 Hz, 4H), 2.79 (dd, J¼15.6, 4.2 Hz, 1H), 1.83e1.61
(m, 6H),1.27e1.01 (m, 5H); 13C NMR (150 MHz, CDCl3)
d 186.6, 159.0,
4.3.5. 8-Benzyloxy-1-cyclohexyl-5-(4-methoxybenzyloxy)oct-1-yn-
3-one (ꢁ)-30. According to GP-1, thioester (ꢁ)-16c (145.1 mg,
0.312 mmol) was reacted with cyclohexylacetylene (0.080 mL,
0.63 mmol) in the presence of Pd2(dba)3$CHCl3 (16.2 mg,
0.0156 mmol), (2-furyl)3P (29.0 mg, 0.125 mmol), and CuI (101 mg,
0.531 mmol) in DMF/Et3N (5:1, v/v, 3.2 mL) to give the title com-
pound (ꢁ)-30 (104.4 mg, 75%) as a yellow oil: IR (film) 2931, 2854,
132.9 (2C), 130.6, 130.5, 129.3 (2C), 128.5 (2C), 119.8, 113.6 (2C), 91.0,
88.2, 79.3, 71.9, 55.1, 48.0, 41.6, 28.7, 28.4, 26.4, 26.2, 26.1; HRMS (ESI)
calcd for C25H28O3Na [(MþNa)þ] 399.1931, found 399.1941.
4.3.9. (4R,5S)-1-Benzyloxy-11-(tert-butyldiphenylsilyloxy)-4-(4-me-
thoxybenzyloxy)-5-methyl-7-undecyn-6-one and (4R,5R)-1-benzyloxy-
11-(tert-butyldiphenylsilyloxy)-4-(4-methoxybenzyloxy)-5-methyl-7-
undecyn-6-one (ꢀ)-34. AccordingtoGP-1, thioester(ꢀ)-20(156.2 mg,
0.326 mmol) was reacted with alkyne 23 (157.8 mg, 0.490 mmol) in
the presence of Pd2(dba)3$CHCl3 (16.9 mg, 0.0163 mmol), (2-furyl)3P
(30.3 mg, 0.131 mmol), and CuI (106.2 mg, 0.555 mmol) in DMF/Et3N
(5:1, v/v, 3.3 mL) to give the title compounds 34 (184.0 mg, 83%) as an
2205, 1670, 1613, 1513, 1451, 1247, 1172, 1096, 820 cmꢀ1 1H NMR
;
(500 MHz, CDCl3)
d
7.32e7.30 (m, 5H), 7.22 (d, J¼8.0 Hz, 2H), 6.83
(d, J¼8.0 Hz, 2H), 4.47 (s, 2H), 4.46e4.42 (m, 2H), 4.02 (m, 1H), 3.77
(s, 3H), 3.44 (t, J¼5.0 Hz, 2H), 2.86 (dd, J¼15.5, 7.0 Hz, 1H), 2.63 (dd,
J¼15.5, 5.0 Hz, 1H), 2.50 (m, 1H), 1.78 (br s, 2H), 1.74e1.64 (m, 6H),
1.48e1.41 (m, 3H), 1.30e1.23 (m, 3H); 13C NMR (125 MHz, CDCl3)
inseparable 1.3:1 mixture of diastereomers: ½a D30
ꢀ4.6 (c 1.00, CHCl3);
ꢅ
d
186.2, 159.0, 138.4, 130.3, 129.3 (2C), 128.2 (2C), 127.5 (2C), 127.4,
IR (film) 2932, 2857, 2209, 1671, 1612, 1513, 1455, 1428, 1360, 1301,
113.6 (2C), 98.4, 81.0, 74.7, 72.7, 71.0, 70.0, 65.7, 55.1, 50.6, 31.4, 30.9,
29.0, 25.49, 25.42, 24.5, 15.2; HRMS (ESI) calcd for C29H36O4Na
[(MþNa)þ] 471.2506, found 471.2494.
1247, 1175, 1109 cmꢀ1; 1H NMR (600 MHz, C6D6)
d 7.73e7.71 (m, 4H),
7.32e7.30 (m, 6H), 7.23e7.11 (m, 5H), 7.11e7.09(m, 2H), 6.79e6.75(m,
2H), 4.43 (q, J¼4.8 Hz, 2H), 4.31 (d, J¼9.6 Hz, 2H), 4.09 (m, 0.43H), 4.01
(m, 0.57H), 3.55 (q, J¼4.2 Hz,2H), 3.28(d, J¼3.0 Hz,3H), 3.27e3.25(m,
2H), 2.98 (m, 0.57H), 2.64 (m, 0.43H), 2.19e2.16 (m, 2H),1.84e1.78 (m,
2H), 1.66e1.57 (m, 2H),1.51e1.46 (m, 2H),1.29 (d, J¼7.2 Hz, 1.3H), 1.13
4.3.6. 1,10-Bis(benzyloxy)-7-(4-methoxybenzyloxy)-2,2-dime-
thyldec-3-yn-5-one (ꢁ)-31. According to GP-1, thioester (ꢁ)-16c

5006
H. Fuwa et al. / Tetrahedron 67 (2011) 4995e5010
(s, 9H),1.12 (d, J¼7.2 Hz, 1.7H); 13CNMR (150 MHz, C6D6)
d
189.2,188.9,
28.4, 25.3, 22.1, 13.7; HRMS (ESI) calcd for C19H27O3 [(MþH)þ]
159.6, 159.6, 139.4, 139.4, 135.9 (4C), 133.9 (2C), 131.2, 131.1, 130.1 (2C),
129.6, 129.5, 128.5 (4C), 128.5, 128.3, 128.1 (2C), 127.71, 127.69, 127.6,
127.5, 113.9 (2C), 93.7, 93.5, 81.5, 81.4, 79.3, 79.1, 72.9, 72.9, 71.9, 71.3,
70.4, 70.3, 62.2, 54.7, 52.5, 51.7, 30.9, 27.0 (3C), 26.4, 25.7, 19.4, 15.50,
15.49, 11.2, 10.6; HRMS (ESI) calcd for C43H52O5SiNa [(MþNa)þ]
699.3476, found 699.3484.
303.1955, found 303.1965.
4.4.2. 6-(3-Benzyloxypropyl)-2-[3-(tert-butyldiphenylsilyloxy)pro-
pyl]-5,6-dihydro-4H-pyran-4-one (ꢁ)-37. According to GP-2, treat-
ment of
b
-alkoxy ynone (ꢁ)-28 (302 mg, 0.456 mmol) with DDQ
(117 mg, 0.501 mmol) in CH2Cl2/pH 7 buffer (10:1, v/v, 4.6 mL) gave
-hydroxy ynone (228.8 mg, 92%) as a yellow oil: IR (film) 3443,
2930, 2857, 2212, 1670, 1428, 1361, 1159, 823 cmꢀ1 1H NMR
(500 MHz, CDCl3) 7.64e7.62 (m, 4H), 7.42e7.30 (m, 11H), 4.49 (s,
a
b
4.3.10. 1-Benzyloxy-4-(benzyloxycarbonylamino)-11-(tert-butyldi-
phenylsilyloxy)-7-undecyn-6-one (ꢁ)-35. According to GP-1, thio-
ester (ꢁ)-21 (51.1 mg, 0.107 mmol) was reacted with alkyne 23
(51.8 mg, 0.160 mmol) in the presence of Pd2(dba)3$CHCl3 (5.5 mg,
0.0054 mmol), (2-furyl)3P (9.9 mg, 0.043 mmol), and CuI (34.6 mg,
0.182 mmol) in DMF/Et3N (5:1, v/v,1.1 mL) to give the title compound
(ꢁ)-35 (67.0 mg, 93%) as a yellow oil: IR (film) 3325, 3068, 2930,
;
d
2H), 4.09 (m, 1H), 3.98 (m, 1H), 3.71 (t, J¼5.5 Hz, 2H), 3.49 (t,
J¼6.0 Hz, 2H), 2.65 (d, J¼5.5 Hz, 2H), 2.51 (t, J¼7.0 Hz, 2H),1.81e1.75
(m, 2H), 1.74e1.64 (m, 2H), 1.60e1.45 (m, 2H), 1.02 (s, 9H); 13C NMR
(125 MHz, CDCl3)
d 187.4, 138.2, 135.4 (4C), 133.5, 129.7 (2C), 128.4
(2C), 128.3, 127.7 (4C), 127.6 (2C), 127.6, 94.9, 81.0, 73.0, 70.1, 67.3,
62.0, 52.3, 33.5, 30.5, 26.8 (3C), 25.9, 19.2, 15.6; HRMS (ESI) calcd for
C34H42O4SiNa [(MþNa)þ] 565.2745, found 565.2724.
2856, 2366, 2210,1720,1669,1508,1427,1233,1108,1026, 823 cmꢀ1
;
1H NMR (600 MHz, CDCl3)
d 7.64e7.62 (m, 4H), 7.42e7.25 (m, 16H),
5.15 (d, J¼9.0 Hz, 1H), 5.05 (s, 2H), 4.46 (s, 2H), 4.01 (m, 1H), 3.69 (t,
J¼6.0 Hz, 2H), 3.45 (s, 2H), 2.78 (dd, J¼17.4, 5.4 Hz, 1H), 2.71 (dd,
J¼16.8, 5.4 Hz, 1H), 2.49 (t, J¼7.2 Hz, 2H), 1.80e1.75 (m, 2H),
According to GP-3, the above b-hydroxy ynone (85.1 mg,
0.157 mmol)was reactedwith AgOTf(4.0 mg, 0.0016 mmol)inCH2Cl2
(1.6 mL) to give the title compound (ꢁ)-37 (83.9 mg, 98%) as a yellow
1.67e1.58 (m, 4H), 1.03 (s, 9H); 13C NMR (150 MHz, CDCl3)
d
185.8,
oil: IR (film) 2857, 1667, 1605, 1428, 1398, 1108, 822 cmꢀ1 1H NMR
;
155.7,138.3,136.5,135.5 (4C),133.5 (2C),129.7 (2C),128.5 (2C),128.3
(2C),128.0 (2C),127.9 (2C),127.7 (4C),127.6 (2C), 94.9, 81.0, 72.9, 69.7,
66.6, 62.0, 49.6, 47.9, 31.1, 30.5, 26.8 (3C), 26.4,19.2,15.6; HRMS (ESI)
calcd for C42H49NO5SiNa [(MþNa)þ] 698.3272, found 698.3275.
(500 MHz, CDCl3) d 7.63e7.61 (m, 4H), 7.42e7.29 (m,11H), 5.29 (s,1H),
4.48 (s, 2H), 4.27 (m, 1H), 3.64 (t, J¼6.0 Hz, 2H), 3.51e3.46 (m, 2H),
2.37e2.30 (m, 4H),1.86e1.65 (m, 6H),1.03 (s, 9H); 13C NMR (125 MHz,
CDCl3)d193.0,177.3,138.3,135.5(2C),135.5(2C),133.6(2C),129.6(2C),
128.4 (2C), 127.64 (3C), 127.59 (2C), 104.1 (2C), 78.9, 77.2, 73.0, 69.6,
62.6, 62.6, 41.0, 31.3, 31.2, 29.2, 26.8 (3C), 25.2, 19.2; HRMS (ESI) calcd
for C34H43O4Si [(MþH)þ] 543.2925, found 543.2922.
4.4. General procedure for the deprotection and 6-endo-dig
cyclization of b-alkoxy ynones
Step 1: Deprotection of MPM group. General procedure (GP-2): To
a solution of
4.4.3. 6-(3-Benzyloxypropyl)-2-phenyl-5,6-dihydro-4H-pyran-4-one
b
-alkoxy ynone (ꢁ)-27 (79.4 mg, 0.188 mmol) in
(ꢁ)-38. According to GP-2, treatment of
(140.1 mg, 0.317 mmol) with DDQ (81.5 mg, 0.348 mmol) in CH2Cl2/
pH 7 buffer (10:1, v/v, 3.3 mL) gave a -hydroxy ynone (92.4 mg,
90%) as a yellow oil: IR (film); 3422, 2924, 2857, 2203, 1489, 1454,
1286, 1095, 1026 cmꢀ1 1H NMR (600 MHz, CDCl3)
7.49e7.47 (m,
b
-alkoxy ynone (ꢁ)-29
CH2Cl2/pH 7 buffer (10:1, v/v, 1.9 mL) cooled to 0 ꢂC was added DDQ
(48.4 mg, 0.207 mmol), and the resultant mixture was stirred at
room temperature for 1 h. The reaction was quenched with satu-
rated aqueous NaHCO3 solution. The whole mixture was filtered
through a pad of Celite, and the filtrate was extracted with EtOAc
(40 mL). The organic layer was washed with brine (30 mLꢄ2), dried
(Na2SO4), filtered, and concentrated under reduced pressure. Pu-
rification of the residue by flash chromatography on silica gel
b
;
d
2H), 7.37 (m, 1H), 7.31e7.25 (m, 5H), 7.20e7.17 (m, 2H), 4.43 (s, 2H),
4.14 (m, 1H), 3.44 (t, J¼5.4 Hz, 2H), 3.08 (br s, 1H), 2.77 (d, J¼6.6 Hz,
2H), 1.74e1.62 (m, 2H), 1.61e1.48 (m, 2H); 13C NMR (150 MHz,
CDCl3)
d 187.2, 138.1, 133.1 (2C), 130.9, 128.6 (2C), 128.4 (2C), 127.7
(10e30% EtOAc/hexanes) gave a
a pale yellow oil: IR (film): 3427, 2930, 2862, 2210,1669, 1455,1362,
1160, 1097 cmꢀ1 1H NMR (500 MHz, CDCl3)
7.33e7.25 (m, 5H),
b
-hydroxy ynone (48.5 mg, 85%) as
(2C), 127.6, 119.7, 91.6, 87.9, 73.0, 70.1, 67.4, 52.4, 33.7, 25.9; HRMS
(ESI) calcd for C21H22O3Na [(MþNa)þ] 345.1461, found 345.1470.
;
d
According to GP-3, the above b-hydroxy ynone (50.0 mg,
4.49 (s, 2H), 4.12 (m, 1H), 3.49 (t, J¼6.5 Hz, 2H), 3.06 (br s, 1H), 2.69
(d, J¼6.0 Hz, 2H), 2.35 (t, J¼7.5 Hz, 2H),1.79e1.67 (m, 2H),1.63e1.49
(m, 4H), 1.45e1.37 (m, 2H), 0.90 (t, J¼7.5 Hz, 3H); 13C NMR
0.155 mmol) was reacted with AgOTf (43.8 mg, 0.171 mmol) in
CH2Cl2 (16 mL) to give the title compound (ꢁ)-38 (48.5 mg, 97%) as
an orange oil: IR (film) 2857, 1660, 1594, 1570, 1492, 1449, 1385,
(125 MHz, CDCl3)
d
187.5, 138.2, 128.4 (2C), 127.6 (2C), 127.5, 95.5,
1338, 1294, 1099 cmꢀ1 1H NMR (500 MHz, CDCl3)
; d 7.71(d,
81.0, 72.9, 70.1, 67.3, 52.3, 33.5, 29.6, 25.9, 21.9, 18.6, 13.4; HRMS
(ESI) calcd for C19H26O3Na [(MþNa)þ] 325.1774, found 325.1770.
Step 2: AgOTf-mediated 6-endo-dig cyclization. General pro-
J¼7.5 Hz, 2H), 7.33e7.31 (m, 8H), 5.99 (s, 1H), 4.54 (m, 1H), 4.52 (s,
2H), 3.58e3.50 (m, 2H), 2.59e2.46 (m, 2H), 2.04e1.81 (m, 4H); 13C
NMR (125 MHz, CDCl3)
d 193.4, 170.1, 138.2, 131.6, 128.6 (2C), 128.4
cedure (GP-3): To a solution of the above
b
-hydroxy ynone
(2C), 128.3 (2C), 127.6 (2C), 126.5 (2C), 102.0, 79.3, 73.0, 69.6, 41.4,
31.4, 25.5; HRMS (ESI) calcd for C21H23O3 [(MþH)þ] 323.1642, found
323.1631.
(38.0 mg, 0.126 mmol) in CH2Cl2 (12.6 mL) was added AgOTf
(35.5 mg, 0.138 mmol), and the resultant mixture was stirred at
room temperature for 3.2 h under exclusion of light. The reaction
mixture was diluted with EtOAc (40 mL) and washed with brine
(30 mLꢄ2). The organic layer was dried (Na2SO4), filtered, and
concentrated under reduced pressure. Purification of the residue by
flash chromatography on silica gel (30% EtOAc/hexanes) gave
dihydropyrone (ꢁ)-36 (36.5 mg, 96%) as a yellow oil.
4.4.4. 6-(3-Benzyloxypropyl)-2-cyclohexyl-5,6-dihydro-4H-pyran-4-
one (ꢁ)-39. According to GP-2, treatment of
(83.2 mg, 0.185 mmol) with DDQ (47.7 mg, 0.204 mmol) in CH2Cl2/
pH 7 buffer (10:1, v/v, 1.9 mL) gave a -hydroxy ynone (60.5 mg,
100%) as an orange oil: IR (film) 3432, 2930, 2854, 2363, 2205, 1667,
1450, 1362, 1160, 1099 cmꢀ1; 1H NMR (500 MHz, CDCl3)
7.34e7.30
b
-alkoxy ynone (ꢁ)-30
b
d
4.4.1. 6-(3-Benzyloxypropyl)-2-butyl-5,6-dihydro-4H-pyran-4-one
(m, 5H), 4.49 (s, 2H), 4.13 (m, 1H), 3.50 (t, J¼5.5 Hz, 2H), 3.05 (br s,
1H), 2.70 (d, J¼6.0 Hz, 2H), 2.53 (m, 1H), 1.82e1.79 (m, 2H),
1.77e1.67 (m, 4H), 1.63e1.45 (m, 4H), 1.31e1.22 (m, 4H); 13C NMR
(ꢁ)-36. IR (film) 2955, 1666, 1604, 1398, 1099, 737 cmꢀ1
;
1H NMR
(500 MHz, CDCl3) d 7.35e7.30 (m, 5H), 5.29 (s, 1H), 4.49 (s, 2H), 4.31
(m, 1H), 3.50 (t, J¼5.0 Hz, 2H), 2.43e2.30 (m, 2H), 2.25e2.15 (m,
(125 MHz, CDCl3) d 187.6, 138.2, 128.3 (2C), 127.6 (2C), 127.5, 98.9,
2H), 1.87e1.68 (m, 4H), 1.53e1.46 (m, 2H), 1.35e1.28 (m, 2H), 0.89
80.8, 72.9, 70.1, 67.3, 52.4, 41.2, 38.8, 33.4, 31.4, 29.0, 25.8, 25.5, 24.5;
HRMS (ESI) calcd for C21H28O3Na [(MþNa)þ] 351.1931, found
351.1938.
(t, J¼7.5 Hz, 3H); 13C NMR (125 MHz, CDCl3)
d 193.4, 177.9, 138.3,
128.4 (2C), 127.6 (2C), 104.1, 104.0, 78.9, 73.0, 69.6, 41.0, 34.5, 31.3,

H. Fuwa et al. / Tetrahedron 67 (2011) 4995e5010
5007
According to GP-3, the above
b
-hydroxy ynone (52.7 mg,
88%) as a yellow oil: IR (film) 3446, 2924, 2852, 2203, 1665, 1488,
1444, 1284, 1086 cmꢀ1 1H NMR (600 MHz, CDCl3)
7.55e7.54 (m,
0.160 mmol) was reacted with AgOTf (45.3 mg, 0.0176 mmol) in
CH2Cl2 (16 mL) to give the title compound (ꢁ)-39 (52.6 mg, 100%) as
a yellow oil: IR (film) 2929, 2854, 1666, 1599, 1451, 1396, 1338, 1243,
;
d
2H), 7.43 (m, 1H), 7.37e7.34 (m, 2H), 3.95 (m, 1H), 2.86 (m, 1H), 2.80
(dd, J¼17.4, 9.6 Hz, 1H), 2.64 (br s, 1H), 1.86 (d, J¼12.6 Hz, 1H),
1.77e1.74 (m, 2H), 1.69e1.64 (m, 2H), 1.40 (m, 1H), 1.26e0.98 (m,
1099, 1024 cmꢀ1 1H NMR (500 MHz, CDCl3)
; d 7.33e7.27 (m, 5H),
5.27 (s, 1H), 4.50 (s, 2H), 4.29 (m, 1H), 3.51e3.49 (m, 2H), 2.42e2.31
5H); 13C NMR (150 MHz, CDCl3)
d 187.9,133.0 (2C),130.8,128.6 (2C),
(m, 2H), 2.09 (m, 1H), 1.88e1.66 (m, 9H), 1.30e1.14 (m, 5H); 13C
119.6, 91.5, 87.9, 71.6, 49.6, 43.0, 28.8, 28.1, 26.3, 26.1, 26.0; HRMS
NMR (125 MHz, CDCl3)
d
193.5, 181.3, 138.2, 128.3 (2C), 128.2, 127.6
(ESI) calcd for C17H20O2Na [(MþNa)þ] 279.1356, found 279.1357.
(2C), 102.0, 78.8, 72.9, 69.6, 41.2, 41.1, 31.2, 30.0, 29.8, 25.8, 25.71,
25.69, 25.3; HRMS (ESI) calcd for C21H29O3 [(MþH)þ] 329.2111,
found 329.2101.
According to GP-3, the above b-hydroxy ynone (27.7 mg,
0.108 mmol) was reacted with AgOTf (30.5 mg, 0.119 mmol) in
CH2Cl2 (11 mL) to give the title compound (ꢁ)-42 (26.0 mg, 94%) as
a yellow oil: IR (film) 2927, 2853, 1664, 1595, 1571, 1492, 1449, 1386,
4.4.5. 2-(2-Benzyloxy-1,1-dimethylethyl)-6-(3-benzyloxypropyl)-5,6-
1337, 1054 cmꢀ1; 1H NMR (500 MHz, CDCl3)
d
7.72 (d, J¼8.0 Hz, 2H),
dihydro-4H-pyran-4-one (ꢁ)-40. According to GP-2, treatment of
7.48e7.40 (m, 3H), 5.98 (s,1H), 4.28 (m,1H), 2.58 (dd, J¼15.5, 7.5 Hz,
b
-alkoxy ynone (ꢁ)-31 (0.86 g, 1.63 mmol) with DDQ (0.42 g,
1H), 2.46 (dd, J¼15.5, 4.0 Hz, 1H), 2.06 (d, J¼12.0 Hz, 1H), 1.84e1.66
1.79 mmol) in CH2Cl2/pH 7 buffer (10:1, v/v,16 mL) gave a
b-hydroxy
(m, 5H), 1.34e1.14 (m, 5H); 13C NMR (125 MHz, CDCl3)
d 193.9,
ynone (0.64 g, 96%) as a yellow oil: IR (film) 3444, 2858, 2360, 2208,
170.3, 132.8, 128.6 (2C), 126.4 (2C), 101.8 (2C), 83.5, 41.6, 38.7, 28.4,
28.4, 26.2, 25.8, 25.7; HRMS (ESI) calcd for C17H21O2 [(MþH)þ]
257.1536, found 257.1542.
1669, 1454, 1361, 1295, 1099, 1027 cmꢀ1; 1H NMR (500 MHz, CDCl3)
d
7.34e7.26 (m,10H), 4.57 (s, 2H), 4.49 (s, 2H), 4.11 (m,1H), 3.50e3.47
(m, 2H), 3.33 (s, 2H), 3.11 (d, J¼3.5 Hz, 1H), 2.69 (d, J¼6.0 Hz, 1H),
1.78e1.64 (m, 2H), 1.61e1.49 (m, 2H), 1.26 (s, 6H), one proton
4.4.8. (5R,6R)-6-(3-Benzyloxypropyl)-2-[3-(tert-butyldiphenylsilyloxy)
propyl]-5-methyl-5,6-dihydro-4H-pyran-4-one (þ)-43a and (5S,6R)-6-
(3-benzyloxypropyl)-2-[3-(tert-butyldiphenylsilyloxy)propyl]-5-
methyl-5,6-dihydro-4H-pyran-4-one (þ)-43b. According to GP-2,
treatment of (ꢀ)-34 (70.9 mg, 0.105 mmol) with DDQ (27.2 mg,
missing due to H/D exchange; 13C NMR (125 MHz, CDCl3)
d 187.5,
138.2, 138.0, 128.4 (4C), 127.7 (2C), 127.6 (2C), 127.5 (2C), 99.9, 80.6,
73.3, 73.0, 70.1, 67.3, 52.4, 33.5, 32.9, 25.9, 25.1 (2C), ꢀ3.4; HRMS
(ESI) calcd for C26H32O4Na [(MþNa)þ] 431.2193, found 431.2200.
According to GP-3, the above
b
-hydroxy ynone (47.6 mg,
0.115 mmol) in CH2Cl2/pH 7 buffer (10:1, v/v, 1.1 mL) gave a
b-hy-
0.117 mmol) was reacted with AgOTf (32.9 mg, 0.128 mmol) in
CH2Cl2 (12 mL) to give the title compound (ꢁ)-40 (46.5 mg, 98%) as
a yellow oil: IR (film) 2857, 1495, 1478, 1454, 1383, 1360, 1291, 1242,
droxy ynone (56.0 mg, 96%) as a colorless oil: ½a D30
ꢅ
ꢀ1.2 (c 1.00,
CHCl3); IR (film) 3446, 3069, 2931, 2857, 2210,1668, 1428, 1184,1109,
970 cmꢀ1; 1H NMR (600 MHz, C6D6)
d 7.73e7.71 (m, 4H), 7.29e7.24
1208, 1027 cmꢀ1
;
1H NMR (500 MHz, CDCl3)
d
7.34e7.25 (m, 10H),
(m, 5H), 7.19e7.17 (m, 5H), 7.09 (m, 1H), 4.28 (s, 2H), 4.10 (m, 0.43H),
3.90 (m, 0.57H), 3.54 (q, J¼6.0 Hz, 2H), 3.28e3.24 (m, 2H), 2.80 (br s,
0.57H), 2.67e2.62 (m, 0.57H), 2.56 (br s, 0.43H), 2.44 (m, 0.43H),
2.17e2.14 (m, 2H), 1.78e1.70 (m, 2H), 1.66e1.51 (m, 2H), 1.50e1.38
(m, 2H), 1.30 (d, J¼7.2 Hz, 1.3H), 1.13 (s, 9H), 1.11 (d, J¼7.2 Hz, 1.7H);
5.44 (s, 1H), 4.46 (s, 4H), 4.25 (m, 1H), 3.50e3.43 (m, 2H), 3.37e3.33
(m, 2H), 2.42e2.31 (m, 2H), 1.84e1.63 (m, 4H), 1.13 (s, 6H); 13C NMR
(125 MHz, CDCl3)
d 193.6, 181.3, 138.2 (2C), 128.3 (2C), 128.2 (2C),
127.6 (2C), 127.4 (2C), 127.3 (2C), 102.9, 78.9, 76.4, 73.1, 72.9, 69.5,
41.2, 41.1, 31.2, 25.3, 22.92, 22.88; HRMS (ESI) calcd for C26H33O4
[(MþH)þ] 409.2373, found 409.2360.
13C NMR (150 MHz, C6D6)
d 190.5, 139.1, 135.9 (4C), 133.9 (2C), 130.1,
130.1, 128.6, 128.5 (2C), 128.1 (4C), 127.8, 127.7, 127.6, 94.0, 94.0, 81.4,
81.3, 73.0, 72.6, 71.1, 70.4, 70.4, 62.2, 54.9, 54.1, 32.3, 31.5, 30.79, 30.76,
27.0 (3C), 26.9, 26.4, 19.4, 15.47, 15.46, 13.0, 10.4; HRMS (ESI) calcd for
C35H44O4SiNa [(MþNa)þ] 579.2901, found 579.2892.
4.4.6. 2-[3-(tert-Butyldiphenylsilyloxy)propyl]-6-cyclohexyl-5,6-di-
hydro-4H-pyran-4-one (ꢁ)-41. According to GP-2, treatment of
b
-alkoxy ynone (ꢁ)-32 (177.3 mg, 0.290 mmol) with DDQ (74.7 mg,
According to GP-3, the above b-hydroxy ynone (16.2 mg,
0.319 mmol)inCH2Cl2/pH7buffer(10:1, v/v, 2.9 mL)gavea
ynone (122.1 mg, 88%) as a yellow oil: IR (film) 3481, 2927, 2854, 2212,
1670, 1427, 1109, 701 cmꢀ1; 1H NMR (500 MHz, CDCl3)
7.64e7.62 (m,
b-hydroxy
0.0291 mmol) was reacted with AgOTf (8.2 mg, 0.032 mmol) in
CH2Cl2 (2.9 mL) to give the title compounds (þ)-43a (8.8 mg, 54%)
d
and (þ)-43b (7.4 mg, 46%). Data for (D)-43a: ½a D29
þ47.0 (c 0.81,
ꢅ
4H), 7.43e7.35 (m, 6H), 3.85 (m, 1H), 3.71 (t, J¼5.5 Hz, 2H), 2.71e2.59
(m, 2H), 2.52 (t, J¼6.5 Hz, 2H), 1.82e1.73 (m, 3H), 1.66e1.56 (m, 5H),
1.35e1.10 (m, 5H), 1.03 (s, 9H), one proton missing due to H/D ex-
CHCl3); IR (film) 3069, 2930, 2857, 2357,1668,1606,1455,1428,1355,
1248,1109, 963, 822 cmꢀ1; 1H NMR (600 MHz, C6D6)
d 7.74e7.73 (m,
4H), 7.29e7.22 (m, 5H), 7.20e7.16 (m, 5H), 7.10 (m, 1H), 5.38 (s, 1H),
4.27 (s, 2H), 3.88 (m, 1H), 3.52 (t, J¼6.0 Hz, 2H), 3.20e3.14 (m, 2H),
2.12 (m, 1H), 2.08 (t, J¼8.4 Hz, 2H), 1.69e1.53 (m, 4H), 1.40e1.23 (m,
2H), 1.15 (s, 9H), 0.91 (d, J¼7.2 Hz, 3H); 13C NMR (150 MHz, C6D6)
change; 13C NMR (125 MHz, CDCl3)
d 188.1, 135.5 (5C), 133.5, 129.7
(2C), 127.7 (4C), 94.9, 81.1, 71.6, 62.0, 49.5, 42.9, 30.5, 28.8, 28.1, 26.8
(3C), 26.4, 26.1, 26.0, 19.1, 15.6; HRMS (ESI) calcd for C30H40O3SiNa
[(MþNa)þ] 499.2639, found 499.2632.
d
195.7, 174.8, 139.2, 135.9 (4C), 135.9 (2C), 134.0 (2C), 130.0 (2C),
According to GP-3, the above
b
-hydroxy ynone (42.1 mg,
128.6,128.3,128.1 (2C),127.9,127.7,127.7,103.4, 81.7, 73.0, 69.7, 63.0,
43.2, 31.0, 29.6, 27.3, 27.0 (3C), 26.1, 19.4, 9.6; HRMS (ESI) calcd for
C35H45O4Si [(MþH)þ] 557.3082, found 557.3101.
0.0883 mmol) was reacted with AgOTf (2.3 mg, 0.00088 mmol) in
CH2Cl2 (1.5 mL) to give the title compound (ꢁ)-41 (41.1 mg, 98%) as
a pale yellow oil: IR (film) 2928, 2855, 1669, 1607, 1109, 822 cmꢀ1
;
Data for (þ)-43b: ½a D28
þ59.1 (c 1.00, CHCl3); IR (film) 2930, 2857,
ꢅ
1H NMR (500 MHz, CDCl3)
d
7.63e7.62 (m, 4H), 7.42e7.35 (m, 6H),
2361,1671,1613,1428,1393,1213,1109, 964 cmꢀ1; 1H NMR (600 MHz,
5.29 (s, 1H), 4.00 (m, 1H), 3.67e3.61 (m, 2H), 2.42e2.26 (m, 4H),
C6D6) d 7.75e7.73 (m, 4H), 7.30e7.23 (m, 5H), 7.20e7.16 (m, 5H), 7.10
1.86e1.58 (m, 9H), 1.28e1.18 (m, 4H), 1.03 (s, 9H); 13C NMR
(m, 1H), 5.40 (s, 1H), 4.30 (s, 2H), 3.61 (m, 1H), 3.56e3.52 (m, 2H),
3.24e3.20(m, 2H), 2.10e2.07 (m, 2H), 2.04 (m,1H),1.73e1.69 (m, 2H),
1.65e1.58 (m, 2H), 1.58e1.46 (m, 2H), 1.17 (s, 9H), 1.00 (d, J¼7.2 Hz,
(125 MHz, CDCl3)
d 193.7, 177.7, 135.5 (2C), 135.4 (2C), 133.6, 129.6
(2C), 127.6 (4C), 104.0 (2C), 83.2, 62.6, 41.4, 38.2, 31.2, 29.2, 28.2,
28.1, 26.8 (3C), 26.2, 25.8, 25.7, 19.2; HRMS (ESI) calcd for
C30H41O3Si [(MþH)þ] 477.2819, found 477.2809.
3H); 13C NMR (150 MHz, C6D6)
d 193.4, 174.5, 139.2, 135.9 (4C), 134.0
(2C), 130.0 (2C), 128.6, 128.5, 128.1 (4C), 127.9, 127.7 (2C), 103.8, 83.6,
73.0, 69.8, 63.0, 43.3, 31.1, 29.6, 29.4, 27.0 (3C), 25.3, 19.4, 10.6; HRMS
(ESI) calcd for C35H45O4Si [(MþH)þ] 557.3082, found 557.3086.
4.4.7. 6-Cyclohexyl-1-phenyl-5,6-dihydro-4H-pyran-4-one
(ꢁ)-42. According to GP-2, treatment of
(86.5 mg, 0.230 mmol) with DDQ (59.1 mg, 0.253 mmol) in CH2Cl2/
pH 7 buffer (10:1, v/v, 2.2 mL) gave a -hydroxy ynone (51.6 mg,
b-alkoxy ynone (ꢁ)-33
4.4.9. 1-Benzyloxycarbonyl-6-(3-benzyloxypropyl)-2-[3-(tert-bu-
tyldiphenylsilyloxy)propyl]-5,6-dihydro-1H-pyridin-4-one
b

5008
H. Fuwa et al. / Tetrahedron 67 (2011) 4995e5010
(ꢁ)-44. According to GP-3, treatment of (ꢁ)-35 (12.9 mg,
0.0191 mmol) with AgOTf (5.4 mg, 0.021 mmol) and 2,6-di-tert-
butylpyridine (1.0 M solution in 1,2-dichloroethane, 0.286 mL,
0.286 mmol) in 1,2-dichloroethane (1.9 mL) at 60 ꢂC gave the title
compound (ꢁ)-44 (6.5 mg, 50%) along with recovered (ꢁ)-35
(2.8 mg, 22%). Data for (ꢁ)-44: IR (film) 2929, 2856,1718,1668,1594,
1455, 1427, 1402, 1320, 1232, 1169 cmꢀ1; 1H NMR (600 MHz, CDCl3)
chromatography on silica gel (8e20% EtOAc/hexanes) gave b-hy-
droxy enone (ꢀ)-48 (399.6 mg, 71% for the two steps) as a yellow
oil.
4.6.1. (2E,5R)-8-Benzyloxy-1-cyclohexyl-5-hydroxy-1-octen-3-one
(ꢀ)-48. ½a 2D5
ꢅ
ꢀ26.0 (c 1.00, CHCl3); IR (film) 3483, 2925, 2851, 1659,
1098, 735, 697 cmꢀ1
;
1H NMR (600 MHz, C6D6)
d
7.30 (d, J¼7.3 Hz,
d
7.64e7.62 (m, 4H), 7.44e7.26 (m, 16H), 5.45 (s, 1H), 5.17 (d,
2H), 7.19e7.16 (m, 2H), 7.09 (m,1H), 6.57 (dd, J¼16.1, 6.8 Hz,1H), 5.89
(d, J¼16.1 Hz,1H), 4.32 (d, J¼16.2 Hz,1H), 4.29(d, J¼16.2 Hz,1H), 4.10
(m, 1H), 3.36e3.32 (m, 2H), 2.40 (dd, J¼17.2, 8.6 Hz, 1H), 2.31 (dd,
J¼17.2, 3.1 Hz,1H),1.83 (m,1H),1.75e1.68 (m, 2H),1.56e1.47 (m, 7H),
1.08e0.96 (m, 3H), 0.89e0.83 (m, 2H), one proton missing due to H/
J¼2.4 Hz, 2H), 4.76 (m, 1H), 4.40 (d, J¼3.6 Hz, 2H), 3.58e3.51 (m,
2H), 3.38e3.32 (m, 2H), 3.05 (m, 1H), 2.78 (dd, J¼17.4, 6.0 Hz, 1H),
2.51 (m, 1H), 2.32 (d, J¼16.8 Hz, 1H), 1.77 (m, 1H), 1.69e1.48 (m, 5H),
1.04 (s, 9H); 13C NMR (150 MHz, CDCl3)
d 193.6, 158.0, 153.3, 138.3,
135.5 (2C), 135.4 (2C), 135.0, 133.6, 129.7 (2C), 128.7 (2C), 128.4 (2C),
128.3 (4C), 127.68 (2C), 127.67 (2C), 127.57, 127.56 (2C), 113.0, 72.9,
69.5, 68.7, 62.7, 56.1, 41.3, 32.4, 31.0, 27.0, 26.8 (3C), 26.5,19.2; HRMS
(ESI) calcd for C42H50NO5Si [(MþH)þ] 676.3453, found 676.3466.
D exchange; 13C NMR (150 MHz, C6D6)
d 200.5, 152.3, 139.4, 128.6,
128.5 (2C),127.8 (2C),127.6, 72.9, 70.5, 67.7, 46.8, 40.6, 34.0, 31.8 (2C),
26.4, 26.1, 25.9 (2C); HRMS (ESI) calcd for C21H30O3Na [(MþNa)þ]
353.2087, found 353.2084.
4. 6. 2. (2E, 6R)-9-Benzyloxy-6-hydroxy-2-nonen-4-one
(ꢀ)-49. According to GP-4, thioester (ꢀ)-16c (306.6 mg, 0.660 mmol)
was reacted with alkenylboronic acid 46 (62.4 mg, 0.726 mmol) in the
presence of Pd2(dba)3$CHCl3 (34.2 mg, 0.0330 mmol), (2-furyl)3P
(60.4 mg, 0.260 mmol), and CuTC (188.8 mg, 0.990 mmol) in THF
(6.6 mL) to give an enone (166.0 mg). According to GP-5, this material
was treated with DDQ (108.0 mg, 0.461 mmol) in CH2Cl2/pH 7 buffer
(10:1, v/v, 4 mL) to give the title compound (ꢀ)-49 (115.6 mg, 66% for
4.5. Synthesis of optically active dihydropyrone derivative
(D)-39
4.5.1. (5R)-8-Benzyloxy-1-cyclohexyl-5-(4-methoxybenzyloxy)oct-1-
yn-3-one (þ)-30. According to GP-1, thioester (ꢀ)-16c (240.8 mg,
0.518 mmol) was reacted with cyclohexylacetylene (0.140 mL,
1.04 mmol) in the presence of Pd2(dba)3$CHCl3 (26.8 mg,
0.0259 mmol), (2-furyl)3P (48.1 mg, 0.207 mmol), and CuI
(167.8 mg, 0.881 mmol) in DMF/Et3N (5:1, v/v, 6 mL) to give the title
thetwosteps)asayellowoil:½a D25
ꢅ
ꢀ27.4(c1.00, CHCl3); IR (film)3444,
2916, 2856, 1661, 1099, 970 cmꢀ1; 1H NMR (600 MHz, C6D6)
d
7.30 (d,
compound (þ)-30 (145.2 mg, 62%) as a brown oil: ½a D23
þ2.0 (c 1.00,
ꢅ
J¼7.6 Hz, 2H), 7.19e7.16 (m, 2H), 7.09 (m,1H), 6.35 (dq, J¼15.8, 6.9 Hz,
1H), 5.80 (d, J¼15.8 Hz, 1H), 4.30 (s, 2H), 4.07 (m, 1H), 3.35e3.31 (m,
2H), 2.32 (dd, J¼17.2, 8.9 Hz,1H), 2.23 (dd, J¼17.2, 3.1 Hz,1H),1.81 (m,
1H),1.70(m,1H),1.70(m,1H),1.56e1.50(m, 2H),1.29(d, J¼6.9 Hz,3H);
CHCl3). Other data identical to racemic compound.
4.5.2. (6R)-6-(3-Benzyloxypropyl)-2-cyclohexyl-5,6-dihydro-4H-py-
ran-4-one (þ)-39. According to GP-2, ynone (þ)-30 (100.9 mg,
0.220 mmol) was treated with DDQ (57.9 mg, 0.250 mmol) in
13C NMR (150 MHz, C6D6)
d 200.0,142.6,139.3,132.4,128.5 (2C),127.8
(2C), 127.6, 73.0, 70.4, 67.7, 46.5, 34.0, 26.4, 17.7; HRMS (ESI) calcd for
CH2Cl2/pH 7 buffer (10:1, v/v, 2.2 mL) to give a
b-hydroxy ynone
C16H22O3Na [(MþNa)þ] 285.1461, found 285.1457.
(68.1 mg, 94%). According to GP-3, the -hydroxy ynone thus
b
obtained (24.8 mg, 0.0755 mmol) was reacted with AgOTf (21.4 mg,
4. 6 . 3. (7E)-1 -B en zylox y-4-hydroxy-7-undecen-6-one
(ꢁ)-50. According to GP-4, thioester (ꢁ)-16c (485.6 mg, 1.05 mmol)
was reacted with alkenylboronic acid 47 (131.0 mg, 1.15 mmol) in the
presence of Pd2(dba)3$CHCl3 (54.1 mg, 0.0523 mmol), (2-furyl)3P
(97.1 mg, 0.418 mmol), and CuTC (299.0 mg,1.57 mmol) inTHF (8.0 mL)
gave an enone (298.2 mg). According to GP-5, this material was treated
with DDQ (187.0 mg, 0.80 mmol) in CH2Cl2/pH 7 buffer (10:1, v/v,
7.7 mL) to give the title compound (ꢁ)-50 (168.4 mg, 55% for the two
steps) as a pale yellow oil: IR (film) 3446, 3029, 2930, 2868,1660,1624,
0.0831 mmol) in CH2Cl2 (1.5 mL) to give the title compound (þ)-39
(24.8 mg, 100%). ½a D23
þ86.8 (c 1.00, CHCl3). Other data identical to
ꢅ
racemic compound.
4.6. General procedure for the palladium-catalyzed coupling
of thioesters and alkenylboronic acids and subsequent
deprotection
Step 1: Palladium-catalyzed coupling of thioesters with alke-
nylboronic acids. General procedure (GP-4): A mixture of thioester
(ꢀ)-16c (790.1 mg, 1.701 mmol), alkenylboronic acid 45 (290.2 mg,
1.884 mmol), Pd2(dba)3$CHCl3 (88.8 mg, 0.0858 mmol), (2-furyl)3P
(158.9 mg, 0.6844 mmol), and CuTC (509.6 mg, 2.672 mmol) in THF
(10 mL) was stirred at 50 ꢂC for 4 h. After being cooled to room
temperature, the reaction mixture was diluted with diethyl ether
(10 mL), washed with saturated aqueous NaHCO3 solution (10 mL)
and brine (10 mLꢄ2), dried (MgSO4), filtered, and concentrated
under reduced pressure. Purification of the residue by flash chro-
1454, 1361, 1181, 1098, 977 cmꢀ1; 1H NMR (600 MHz, C6D6)
d 7.30 (d,
J¼7.6 Hz, 2H), 7.21e7.17 (m, 2H), 7.09 (t, J¼7.3 Hz,1H), 6.50 (m,1H), 5.87
(d, J¼15.8 Hz,1H), 4.31 (s, 2H), 4.09 (m, 1H), 3.77 (s, 3H), 3.49 (br s,1H),
3.37e3.30 (m, 2H), 2.40 (dd, J¼17.2, 8.9 Hz,1H), 2.28 (dd, J¼17.2, 3.1 Hz,
1H),1.82 (m,1H),1.59e1.48 (m, 2H),1.16e1.10 (m, 2H), 0.69 (t, J¼7.2 Hz,
3H); 13C NMR (150 MHz, C6D6)
d 200.1, 147.3, 139.4, 131.1, 128.5 (2C),
128.3, 127.7 (2C), 72.9, 70.5, 67.7, 46.7, 34.4, 34.0, 26.4, 21.4, 13.7; HRMS
(ESI) calcd for C18H26O3Na [(MþNa)þ] 313.1774, found 313.1762.
4.6.4. (4E)-1-Cyclohexyl-1-hydroxy-4-octen-3-one (ꢁ)-51. According
to GP-4, thioester (ꢁ)-19 (188.1 mg, 0.454 mmol) was reacted with
alkenylboronic acid 47 (56.9 mg, 0.499 mmol) in the presence of
Pd2(dba)3$CHCl3 (23.5 mg, 0.0227 mmol), (2-furyl)3P (42.1 mg,
0.181 mmol), and CuTC (129.8 mg, 0.68 mmol) in THF (2.5 mL) gave
an enone (115.2 mg). According to GP-5, this material was treated
with DDQ (86.1 mg, 0.368 mmol) in CH2Cl2/pH 7 buffer (10:1, v/v,
3.3 mL) to give the title compound (ꢁ)-51 (58.5 mg, 64% for the two
steps) as a pale yellow oil: IR (film) 3475, 2926, 2852, 1660, 1625,
matography on silica gel (5 to 11% EtOAc/hexanes) gave a b-alkoxy
enone (544.9 mg), which was contaminated with some impurities
and used in the next reaction without further purification.
Step 2: Deprotection of MPM group. General procedure (GP-5): To
a solution of the above b-alkoxy enone (544.9 mg) in CH2Cl2/pH 7
buffer (10:1, v/v, 11 mL) cooled to 0 ꢂC was added DDQ (314.0 mg,
1.342 mmol), and the resultant mixture was stirred at room tem-
perature for 1 h. The reaction was quenched with saturated aque-
ous NaHCO3 solution (5 mL) at 0 ꢂC. The resultant mixture was
extracted with EtOAc (30 mL), and the organic layer was washed
with brine (20 mLꢄ2), dried (Na2SO4), filtered, and concentrated
under reduced pressure. Purification of the residue by flash
1449, 1309, 1187, 1085, 1041, 977 cmꢀ1 1H NMR (600 MHz, C6D6)
;
d
6.59 (dt, J¼15.8, 6.8 Hz, 1H), 5.92 (d, J¼15.8 Hz, 1H), 3.86 (m, 1H),
3.36 (br s, 1H), 2.45 (dd, J¼16.8, 9.2 Hz, 1H), 2.37 (dd, J¼16.8, 2.8 Hz,
1H), 1.90 (m, 1H), 1.79e1.67 (m, 4H), 1.63e1.57 (m, 2H), 1.29 (m, 1H),

H. Fuwa et al. / Tetrahedron 67 (2011) 4995e5010
5009
1.19e1.04 (m, 7H), 0.71 (t, J¼7.3 Hz, 3H); 13C NMR (150 MHz, C6D6)
4.7.4. (2S0,6S0)-2-Cyclohexyl-6-propyltetrahydro-4H-pyran-4-one
d
200.7, 147.2, 131.1, 71.8, 43.9, 43.6, 34.4, 29.4, 28.4, 26.9, 26.7, 26.6,
(ꢁ)-55. According to GP-6, treatment of -hydroxy enone (ꢁ)-51
b
21.4, 13.7; HRMS (ESI) calcd for C14H24O2Na [(MþNa)þ] 247.1669,
(22.0 mg, 0.0981 mmol) with AgOTf (5.0 mg, 0.020 mmol) in CH2Cl2
(2.0 mL) gave the title compound (ꢁ)-55 (22.0 mg, 100%) as a 3:1
mixture of cis/trans isomers. Data for the major product (2,6-cis
isomer): IR (film) 2926, 2853, 1719, 1450, 1324, 1270, 1159, 1064,
found 247.1667.
4.7. General procedure for 6-endo-trig cyclization of
845 cmꢀ1; 1H NMR (600 MHz, CDCl3)
d
3.47 (m,1H), 3.23 (ddd, J¼6.8,
b-hydroxy enones
2.4, 2.4 Hz,1H), 2.35 (dd, J¼14.0, 2.1 Hz,1H), 2.31 (dd, J¼14.0, 2.1 Hz,
1H), 2.23e2.15 (m, 2H), 1.96 (dd, J¼13.0, 1.7 Hz, 1H), 1.66e1.58 (m,
4H),1.53e1.30 (m, 4H),1.25e1.08 (m, 4H), 0.97 (dt, J¼8.9, 2.1 Hz, 2H),
General procedure (GP-6): To a solution of
b-hydroxy enone
(ꢀ)-48 (26.9 mg, 81.4
m
mol) in CH2Cl2 (1.6 mL) was added AgOTf
0.90 (t, J¼7.2 Hz, 3H); 13C NMR (150 MHz, CDCl3)
d 208.6, 81.2, 75.7,
(23.7 mg, 92.2 mol), and the resultant mixture was stirred at room
m
72.3, 48.3, 45.4, 43.2, 38.5, 28.9, 28.4, 26.4, 26.0, 18.7, 13.9; HRMS
temperature for 13 h under exclusion of light. The reaction mixture
was diluted with EtOAc (10 mL) and washed with brine (10 mLꢄ2).
The organic layer was dried (Na2SO4), filtered, and concentrated
under reduced pressure. Purification of the residue by flash chro-
matography on silica gel (6e10% EtOAc/hexanes) gave tetrahy-
dropyrone (þ)-52 (25.2 mg, 94%) as a yellow oil. The optical purity
of the synthesized material was determined to be 81% ee by chiral
HPLC analysis [column: CHIRALPAK AD-H (4.6ꢄ250 mm); eluent:
0.7% i-PrOH/n-hexane; flow rate: 1.0 mL/min; column temperature:
30.0 ꢂC; major peak: t1¼19.0 min; minor peak: t2¼21.3 min].
(ESI) calcd for C14H24O2Na [(MþNa)þ] 247.1669, found 247.1672.
4.8. General procedure for stereoselective hydrogenation of
dihydropyrones
General procedure (GP-7): To a solution of dihydropyrone (þ)-39
(5.8 mg,17.7 mmol) and Et3N (11.6 mL) in EtOAc (0.708 mL) was added
10% Pd/C (4.7 mg), and the resultant mixture was stirred at room
temperature for 14.5 h under an atmosphere of hydrogen (balloon).
After completion of the reaction, the whole mixture was filtered
through a pad of Celite, and the filtrate was concentrated under
reduced pressure. Purification of the residue by flash chromatogra-
phy on silica gel (10% EtOAc/hexanes) gave tetrahydropyrone (þ)-52
(5.3 mg, 91%) as a yellowoil. The optical purity was determined to be
98% ee by chiral HPLC analysis [column: CHIRALPAK AD-H
(4.6ꢄ250 mm); eluent: 0.7% i-PrOH/n-hexane; flow rate: 1.0 mL/
min; column temperature: 30.0 ꢂC; major peak: t1¼19.0 min; minor
4.7.1. (2R,6R)-6-(3-Benzyloxy)-2-cyclohexyltetrahydro-4H-pyran-4-
one (þ)-52. ½a 2D4
ꢅ
þ3.6 (c 1.00, CHCl3); IR (film) 2925, 2851, 1716, 736,
697 cmꢀ1;1HNMR(600 MHz, C6D6)
d
7.29e7.28(m, 2H), 7.20e7.15 (m,
2H), 7.10 (t, J¼7.2 Hz, 1H), 4.33 (d, J¼12.7 Hz, 1H), 4.30 (d, J¼12.7 Hz,
1H), 3.27e3.24 (m, 2H), 3.14 (m,1H), 2.91 (ddd, J¼11.7, 6.2, 2.4 Hz,1H),
2.20e2.13 (m, 2H), 1.91e1.82 (m, 2H), 1.73 (m, 1H), 1.65e1.53 (m, 5H),
1.42e1.22 (m, 4H), 1.11e1.04 (m, 3H), 0.91e0.80 (m, 2H); 13C NMR
peak: t2¼21.3 min]. ½a D23
þ3.7 (c 0.53, CHCl3). Other data identical to
ꢅ
(150 MHz, C6D6)
d
205.6, 139.3, 128.5 (2C), 127.7 (2C), 127.6, 81.0, 76.7,
the compound prepared above (see Section 4.7.1).
73.0, 70.1, 48.2, 45.2, 43.3, 33.4, 28.7, 28.6, 26.8, 26.3 (2C), 26.2; HRMS
(ESI) calcd for C21H30O3Na [(MþNa)þ] 353.2087, found 353.2078.
4.8.1. (2R0,6S0)-2-(3-Benzyloxypropyl)-6-butyltetrahydro-4H-pyran-
4-one (ꢁ)-56. According to GP-7, dihydropyrone (ꢁ)-36 (7.2 mg,
0.024 mmol) was hydrogenated over 10% Pd/C (2.9 mg) in the pres-
ence of Et3N (0.007 mL) in EtOH (0.48 mL) to give the title compound
(ꢁ)-56 (6.9 mg, 95%) as a colorless oil: IR (film) 2930, 2856,1716,1101,
4.7.2. (2R,6S)-2-(3-Benzyloxypropyl)-6-methyltetrahydro-4H-pyran-
4-one (þ)-53. According to GP-6, treatment of
b-hydroxy enone
(ꢀ)-49 (26.5 mg, 0.101 mmol) with AgOTf (28.5 mg, 0.111 mmol) in
CH2Cl2 (2 mL) gave the title compound (þ)-53 (23.7 mg, 89%) as
a 3:1 mixture of cis/trans isomers. Data for the major 2,6-cis isomer:
739, 698 cmꢀ1; 1H NMR (600 MHz, CDCl3)
d 7.39e7.30 (m, 4H), 7.26
(m,1H), 4.50 (d, J¼12.0 Hz,1H), 4.47 (d, J¼12.0 Hz,1H), 3.54e3.45 (m,
4H), 2.35e2.31 (m, 2H), 2.22e2.16 (m, 2H),1.18 (m,1H),1.71e1.59 (m,
4H), 1.50e1.40 (m, 2H), 1.34e1.26 (m, 3H), 0.89 (t, J¼7.2 Hz, 3H); 13C
½
a 2D4
ꢅ
þ0.72 (c 1.00, CHCl3); IR (film) 2931, 2856, 1719, 1094, 736,
698 cmꢀ1; 1H NMR (600 MHz, CDCl3)
d
7.34e7.25 (m, 5H), 4.49 (d,
J¼12.6 Hz, 1H), 4.47 (d, J¼12.6 Hz, 1H), 3.67 (m, 1H), 3.55 (m, 1H),
3.51e3.45 (m, 2H), 2.35e2.31 (m, 2H), 2.21 (dd, J¼12.0, 3.0 Hz, 1H),
2.18 (dd, J¼12.0, 3.0 Hz, 1H), 1.81e1.59 (m, 4H), 1.29 (d, J¼6.0 Hz,
NMR (150 MHz, CDCl3) d 207.8, 138.4, 128.4 (2C), 127.63 (2C), 127.56,
77.0, 76.7, 72.9, 69.9, 48.0 (2C), 36.1, 33.1, 27.5, 25.8, 22.5, 14.0; HRMS
(ESI) calcd for C19H28O3Na [(MþNa)þ] 327.1931, found 327.1931.
3H); 13C NMR (150 MHz, C6D6)
d 207.5, 138.4, 128.3 (2C), 127.6 (2C),
127.5, 76.7, 73.1, 72.9, 69.9, 49.4, 47.5, 33.1, 25.7, 22.0; HRMS (ESI)
calcd for C16H22O3Na [(MþNa)þ] 285.1461, found 285.1462. The
optical purity of this material was determined to be 92% ee by chiral
HPLC analysis [column: CHIRALCEL OD-H (4.6ꢄ250 mm); eluent:
1.0% i-PrOH/n-hexane; flow rate: 1.0 mL/min; column temperature:
30.0 ꢂC; major peak: t1¼41.3 min; minor peak: t2¼50.9 min].
4.8.2. (2R0,6S0)-2-(3-Benzyloxypropyl)-6-[3-(tert-butyldiphenylsily-
loxy)propyl]tetrahydro-4H-pyran-4-one (ꢁ)-57. According to GP-7,
dihydropyrone (ꢁ)-37 (3.0 mg, 0.0055 mmol) washydrogenated over
10% Pd/C (2.4 mg) in the presence of Et3N (0.006 mL) in EtOAc
(0.55 mL) to give the title compound (ꢁ)-57 (3.0 mg, 100%) as a color-
less oil: IR (film): 2927, 2856,1717,1111, 701 cmꢀ1; 1H NMR (600 MHz,
CDCl3) d 7.70 (m, 1H), 7.64e7.62 (m, 3H), 7.41e7.25 (m, 11H), 4.48 (d,
4.7.3. (2R0,6S0)-2-(3-Benzyloxypropyl)-6-propyltetrahydro-4H-py-
J¼12.0 Hz, 1H), 4.46 (d, J¼12.0 Hz, 1H), 3.66e3.64 (m, 2H), 3.48e3.43
ran-4-one (ꢁ)-54. According to GP-6, treatment of
b-hydroxyenone
(m, 4H), 2.33e2.29 (m, 2H), 2.20e2.15 (m, 2H),1.78e1.57 (m, 8H),1.02
(ꢁ)-50 (79.6 mg, 0.274 mmol) with AgOTf (14.1 mg, 0.0548 mmol)
in CH2Cl2 (5.5 mL) gave the title compound (ꢁ)-54 (68.7 mg, 87%) as
a 10:1 mixture of cis/trans isomers. Data for the major product (2,6-
cis isomer): IR (film) 3029, 2957, 2931, 2855, 2358, 1718, 1455, 1361,
(s, 9H); 13CNMR (150 MHz,CDCl3)
d207.6,135.5(4C),134.8 (2C),133.9,
129.6 (2C), 128.4 (2C), 127.7, 127.63 (5C), 127.56, 76.7, 76.6, 72.9, 69.9,
63.4, 47.98, 47.95, 33.1, 32.7, 28.4, 26.9 (3C), 26.5, 25.8; HRMS (ESI)
calcd for C34H44O4SiNa [(MþNa)þ] 567.2901, found 567.2918.
1326,1259,1098 cmꢀ1; 1H NMR (600 MHz, C6D6)
d
7.27 (d, J¼7.9 Hz,
2H), 7.18 (t, J¼7.6 Hz, 2H), 7.09 (t, J¼7.2 Hz, 1H), 4.31 (s, 2H),
3.28e3.23 (m, 2H), 3.14e3.07 (m, 2H), 2.13e2.08 (m, 2H), 1.83e1.78
(m, 2H), 1.71 (m, 1H), 1.58e1.47 (m, 2H), 1.41e1.30 (m, 3H), 1.18 (m,
1H), 1.09 (m, 1H), 0.78 (t, J¼7.2 Hz, 3H); 13C NMR (150 MHz, C6D6)
4.8.3. (2R0,6R0)-2-(3-Benzyloxypropyl)-6-phenyltetrahydro-4H-py-
ran-4-one (ꢁ)-58. According to GP-7, dihydropyrone (ꢁ)-38 (4.4 mg,
0.014 mmol) was hydrogenated over 10% Pd/C (3.5 mg) in the presence
of Et3N (0.009 mL) in EtOH (0.55 mL) to give the title compound (ꢁ)-58
(2.3 mg, 52%) as a colorless oil: IR (film) 2923, 1715, 1456, 945, 748,
d
205.2,139.3,128.5 (2C),128.3,127.7 (2C),127.6, 76.7, 76.6, 72.9, 70.1,
48.0, 38.7, 33.4, 26.1, 18.8, 14.1; HRMS (ESI) calcd for C18H26O3Na
548 cmꢀ1;1H NMR (600 MHz, CDCl3)
d
7.70 (m, 1H), 7.40e7.25 (m, 9H),
[(MþNa)þ] 313.1774, found 313.1770.
4.60 (dd, J¼11.4, 3.0 Hz,1H), 4.48 (d, J¼12.0 Hz,1H), 4.47 (d, J¼12.0 Hz,

5010
H. Fuwa et al. / Tetrahedron 67 (2011) 4995e5010
ꢀ
Pattenden, G.; Gonzalez, M. A.; Little, P. B.; Millan, D. S.; Plowright, A. T.; Tornos,
J. A.; Ye, T. Org. Biomol. Chem. 2003, 1, 4173e4208 and references cited therein.
4. For recent selected examples, see: (a) Bates, R. W.; Song, P. Synthesis 2010,
2935e2942; (b) Trost, B. M.; Gutierrez, A. C.; Livingston, R. C. Org. Lett. 2009, 11,
1H), 3.76 (m,1H), 3.51e3.48 (m, 2H), 2.62 (dd, J¼14.4, 3.0 Hz, 1H), 2.52
(dd, J¼14.4, 12.0 Hz, 1H), 2.45 (dd, J¼14.4, 2.4 Hz, 1H), 2.36 (dd, J¼14.4,
11.4 Hz,1H),1.87e1.78 (m, 2H), 1.77e1.70 (m, 2H); 13C NMR (150 MHz,
€
2539e2542; (c) O’Neil, G. W.; Furstner, A. Chem. Commun. 2008, 4294e4296; (d)
Bates, R. W.; Song, P. Tetrahedron 2007, 63, 4497e4499; (e) Jung, H. H.; Floreancig,
P. E. J. Org. Chem. 2007, 72, 7359e7366; (f) Furstner, A.; Fenster, M. D. B.; Fasching,
B.; Godbout, C.; Radkowski, K. Angew. Chem., Int. Ed. 2006, 45, 5506e5510; (g) Liu,
J.; Yang, J. H.; Ko, C.; Hsung, R. P. Tetrahedron Lett. 2006, 47, 6121e6123; (h) Oishi,
T.; Suzuki, M.; Watanabe, K.; Murata, M. TetrahedronLett. 2006, 47, 3975e3978; (i)
Clarke, P. A.; Martin, W. H. C.; Hargreaves, J. M.; Wilson, C.; Blake, A. J. Org. Biomol.
Chem. 2005, 3, 3551e3563; (j) Clarke, P. A.; Martin, W. H. C.; Hargreaves, J. M.;
Wilson, C.; Blake, A. J. Chem. Commun. 2005, 1061e1063; (k) Paterson, I.; Coster,
CDCl3)
d 207.0, 134.8, 128.6 (2C), 128.4 (2C), 127.9, 127.7, 127.64 (2C),
127.57,125.6 (2C), 78.5, 77.0, 72.9, 69.9, 49.5, 47.7, 33.1, 25.6; HRMS (ESI)
€
calcd for C21H24O3Na [(MþNa)þ] 347.1618, found 347.1619.
4.8.4. (2R0,6R0)-2-(2-Benzyloxy-1,1-dimethylethyl)-6-(3-benzylox-
ypropyl)tetrahydro-4H-pyran-4-one (ꢁ)-59. According to GP-7,
dihydropyrone (ꢁ)-40 (40.4 mg, 0.099 mmol) was hydrogenated
over 10% Pd/C (8.1 mg) in the presence of Et3N (0.020 mL) in EtOAc
(1.0 mL) to give the title compound (ꢁ)-59 (39.0 mg, 96%) as a col-
orless oil: IR (film) 2960, 2855, 1717, 1099, 737, 698 cmꢀ1; 1H NMR
~
M. J.; Chen, D. Y.-K.; Acena, J. L.; Bach, J.; Keown, L. E.; Trieselmann, T. Org. Biomol.
Chem. 2005, 3, 2420e2430; (l) Trost, B. M.; Yang, H.; Wuitschik, G. Org. Lett. 2005,
7, 4761e4764; (m) Evans, P. A.; Andrews, W. J. Tetrahedron Lett. 2005, 46,
5625e5627 and references cited therein. Hong et al. recently reported tandem
MnO2 oxidation/intramolecular oxa-conjugate cyclization of d-hydroxy allylic
(600 MHz, CDCl3)
d
7.34e7.23 (m, 10H), 4.48 (d, J¼12.0 Hz, 1H), 4.48
alcohols, although the promoter of the cyclization remains elusive, see: (n) Kim,
H.; Hong, J. Org. Lett. 2010, 12, 2880e2883; (o) Kim, H.; Park, Y.; Hong, J. Angew.
Chem., Int. Ed. 2009, 48, 7577e7581.
(d, J¼15.0 Hz, 1H), 4.44 (d, J¼15.0 Hz, 1H), 4.44 (d, J¼12.0 Hz, 1H),
3.53e3.44 (m, 4H), 3.33 (d, J¼9.0 Hz, 1H), 3.19 (d, J¼8.4 Hz, 1H),
2.32e2.30 (m, 3H), 2.16 (dd, J¼13.8, 11.4 Hz, 1H), 1.79 (m, 1H),
1.66e1.57 (m, 3H), 0.95 (s, 3H), 0.88 (s, 3H); 13C NMR (150 MHz,
5. For mechanistic studies on intramolecular oxa-conjugate cyclization, see: (a)
ꢀ
ꢀ
Betancort, J. M.; Martín, V. S.; Padron, J. M.; Palazon, J. M.; Ramírez, M. A.; Soler,
M. A. J. Org. Chem. 1997, 62, 4570e4583; (b) Schneider, C.; Schuffenhauer, A. Eur.
J. Org. Chem. 2000, 73e82.
C6D6)
d 208.8, 138.6, 138.4, 128.4 (2C), 128.3 (2C), 127.63 (2C),
6. Sudek, S.; Lopanik, N. B.; Waggoner, L. E.; Hildebrand, M.; Anderson, C.; Liu, H.;
Patel, A.; Sherman, D. H.; Haygood, M. G. J. Nat. Prod. 2007, 70, 67e74 Similar
proposals have been made for the biosynthesis of tetrahydropyran-containing
natural products, pederin, ambruticin, jerangolid, and sorangicin, see: (a) Piel, J.
Proc. Natl. Acad. Sci. U.S.A. 2002, 99, 14002e14007; (b) Julien, B.; Tian, Z.-Q.;
Reid, R.; Reeves, C. D. Chem. Biol. 2006, 13, 1277e1286; (c) Irschik, H.; Kopp, M.;
Weissman, K. J.; Buntin, K.; Piel, J.; Muller, R. ChemBioChem 2010, 11,
1840e1849.
7. Inspired by the postulated biosynthesis, we have recently found that intra-
molecular oxa-conjugate cyclization of
a,b-unsaturated thioesters could be ef-
127.55, 125.4, 127.3 (2C), 80.1, 76.5, 76.4, 73.2, 72.9, 69.9, 45.0, 42.5,
38.6, 33.0, 25.7, 21.0, 20.2; HRMS (ESI) calcd for C26H34O4Na
[(MþNa)þ] 433.2349, found 433.2348.
4.8.5. (2S0,6S0)-2-[3-(tert-Butyldiphenylsilyloxy)propyl]-6-cyclo-
hexyltetrahydro-4H-pyran-4-one (ꢁ)-60. According to GP-7, dihy-
dropyrone (ꢁ)-41 (8.1 mg, 0.017 mmol) was hydrogenated over 10%
Pd/C (6.5 mg) in the presence of Et3N (0.016 mL) in EtOAc (0.60 mL)
to give the title compound (ꢁ)-60 (7.8 mg, 96%) as a colorless oil: IR
(film) 2929, 2855, 1715, 1111, 706 cmꢀ1; 1H NMR (600 MHz, CDCl3)
€
fected by carbonyl activation under Brønsted catalysis to give 2,6-cis-
substituted tetrahydropyrans in a highly stereoselective manner. See: Fuwa, H.;
Noto, K.; Sasaki, M. Org. Lett. 2011, 13, 1820–1823.
8. Fuwa, H.; Saito, A.; Sasaki, M. Angew. Chem., Int. Ed. 2010, 49, 3041e3044.
9. (a) Fuwa, H.; Yamaguchi, H.; Sasaki, M. Org. Lett. 2010, 12, 1848e1851; (b) Fuwa,
H.; Yamaguchi, H.; Sasaki, M. Tetrahedron 2010, 66, 7492e7503.
10. (a) Fuwa, H.; Sasaki, M. Org. Lett. 2010, 12, 584e587; (b) Fuwa, H.; Suzuki, T.;
Kubo, H.; Yamori, T.; Sasaki, M. Chem.dEur. J. 2011, 17, 2678e2688.
11. Fuwa, H.; Noto, K.; Sasaki, M. Heterocycles 2010, 82, 641e647.
d
7.64e7.63 (m, 4H), 7.42e7.34 (m, 6H), 3.68e3.65 (m, 2H), 3.43 (m,
1H), 3.17 (ddd, J¼11.4, 6.6, 2.4 Hz, 1H), 2.36e2.82 (m, 2H), 2.19 (dd,
J¼11.4, 3.6 Hz, 1H), 2.16 (dd, J¼11.4, 3.6 Hz, 1H), 1.93 (m, 1H),
1.76e1.58 (m, 8H), 1.42 (m, 1H), 1.23e1.08 (m, 3H), 1.03 (s, 9H),
0.99e0.90 (m, 2H); 13C NMR (150 MHz, CDCl3)
d 208.5, 135.5 (4C),
12. For the synthesis of tetrahydropyrone derivatives via 6-endo cyclization of b-
133.9 (2C), 129.6 (2C), 127.6 (4C), 81.1, 76.6, 63.4, 48.2, 45.4, 43.2,
32.7, 28.8, 28.4 (2C), 26.9 (3C), 26.4, 26.0, 25.9, 19.2; HRMS (ESI)
calcd for C30H42O3Na [(MþNa)þ] 501.2795, found 501.2793.
hydroxy enones, see: (a) Yadav, L. D. S.; Singh, S.; Rai, V. K. Synlett 2010, 240e246;
(b) Reiter, M.; Turner, H.; Gouverneur, V. Chem.dEur. J. 2006, 12, 7190e7203; (c)
Hilli, F.; White, J. M.; Rizzacasa, M. A. Org. Lett. 2004, 6, 1289e1292; (d) Hilli, F.;
White, J. M.; Rizzacasa, M. A. Tetrahedron Lett. 2002, 43, 8507e8510.
13. For the synthesis of dihydropyrone derivatives via 6-endo cyclization of b-hy-
droxy ynones, see: (a) Reddy, C. R.; Srikanth, B. Synlett 2010, 1536e1538; (b)
Schuler, M.; Silva, F.; Bobbio, C.; Tessier, A.; Gouverneur, V. Angew. Chem., Int. Ed.
2008, 47, 7927e7930; (c) Nicolaou, K. C.; Frederick, M. O.; Burtoloso, A. C. B.;
Denton, R. M.; Rivas, F.; Cole, K. P.; Aversa, R. J.; Gibe, R.; Umezawa, T.; Suzuki, T.
J. Am. Chem. Soc. 2008, 130, 7466e7476; (d) Wang, C.; Forsyth, C. J. Org. Lett.
2006, 8, 2997e3000.
Acknowledgements
This work was supported in part by a Grant-in-Aid for Young
Scientists (B) from the Ministry of Education, Culture, Sports,
Science and Technology (MEXT), Japan.
14. Paterson, I.; Osborne, S. Tetrahedron Lett. 1990, 31, 2213e2216.
15. Silva, F. A.; Gouverneur, V. Tetrahedron Lett. 2005, 46, 8705e8709.
16. For examples, see: (a) Fuwa, H.; Ishigai, K.; Goto, T.; Suzuki, A.; Sasaki, M. J. Org.
Chem. 2009, 72, 4024e4040; (b) Fuwa, H.; Suzuki, A.; Sato, K.; Sasaki, M. Het-
erocycles 2007, 72, 139e144.
Supplementary data
Supplementary data related to this article can be found online at
doi:10.1016/j.tet.2011.03.114.
17. For a preliminary communication of this work, see: Fuwa, H.; Matsukida, S.;
Sasaki, M. Synlett 2010, 1239e1242.
18. We have recently applied palladium-catalyzed organostannaneethioester
coupling to complex natural product synthesis, see: (a) Saito, T.; Fuwa, H.;
Sasaki, M. Tetrahedron 2011, 67, 429e445; (b) Saito, T.; Fuwa, H.; Sasaki, M. Org.
Lett. 2009, 11, 5274e5277.
References and notes
ꢀ
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€
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