The total synthesis and biological evaluation of nafuredin-γ and its analogues

Article abstract of DOI:10.1016/j.tet.2008.06.066

Nafuredin (1) is converted to nafuredin-γ (2) under mild basic conditions and both compounds exhibit the same inhibitory activity and selectivity against NADH-fumarate reductase (complex I). The total synthesis of 2 was achieved by a convergent approach u

Full text of DOI:10.1016/j.tet.2008.06.066

Tetrahedron 64 (2008) 8117–8127
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
The total synthesis and biological evaluation of nafuredin-g and its analogues
Tohru Nagamitsu a, Daisuke Takano a, Miyuki Seki a, Shiho Arima a, Masaki Ohtawa a, Kazuro Shiomi b,
a
b,
*
ꢀ
Yoshihiro Harigaya , Satoshi Omura
a School of Pharmacy, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641, Japan
b Kitasato Institute for Life Sciences and Graduate School of Infection Control Sciences, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Nafuredin (1) is converted to nafuredin-g (2) under mild basic conditions and both compounds exhibit
Received 27 February 2008
Received in revised form 17 June 2008
Accepted 17 June 2008
the same inhibitory activity and selectivity against NADH-fumarate reductase (complex I). The total
synthesis of 2 was achieved by a convergent approach using Stille coupling. The structural elements
required for inhibitory activity against NADH-fumarate reductase (complex I) were then investigated by
Available online 21 June 2008
evaluation of nafuredin-g (2) and its structural analogues.
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
we previously reported the elucidation of the absolute configura-
tion3 and the total synthesis4 of 1.
Nafuredin (1)1,2 was isolated from the fermentation broth of
a fungal strain, Aspergillus niger FT-0554, in the course of our
screening for NADH-fumarate reductase (NFRD) inhibitors, and is
potentially a selective antiparasitic agent. Nafuredin inhibited
NFRD of Ascaris suum with an IC50 value of 12 nM and showed se-
lective inhibition of the target enzyme complex I in helminth mi-
tochondria. In addition, nafuredin demonstrated anthelmintic
activity against Haemonchus contortus in in vivo trials with sheep.1
These useful biological activities of 1 attracted our attention, and
During the course of our synthetic studies, we discovered that
under mild basic conditions, nafuredin (1) was converted to a novel
g
-lactone derivative (2), which existed as a mixture of keto–enol
tautomers (Scheme 1).5 We named this
-lactone derivative (2)
nafuredin- . Since nafuredin- (2) is not detected at all in the
g
g
g
aforementioned fermentation broth, it must not be produced di-
rectly by the above strain and must be formed from 1 under basic
conditions via
b-elimination of the epoxide followed by trans-
lactonization. Because the conversion of 1 to 2 likely occurs under
–
O
O
O
K2CO3
MeOH, r.t.
O
O
O
HO
HO
HO
H
O
O
O
–Base
Nafuredin (1)
O
OH
O
O
O
O
OH
OH
Nafuredin-γ (2)
Scheme 1. Proposed mechanism of the conversion of nafuredin (1) to nafuredin-
g
(2).
* Corresponding author. Tel.: þ81 3 5791 6101; fax: þ81 3 3444 8360.
ꢀ
E-mail address: omura-s@kitasato.or.jp (S. Omura).
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.06.066

8118
T. Nagamitsu et al. / Tetrahedron 64 (2008) 8117–8127
the NFRD assay conditions, we expected 2 to also have inhibitory
activity against NFRD. Our tests indeed showed that 2 possessed
the same inhibitory activity and selectivity as 1, suggesting it may
be an active form of 1. This finding led us to embark on the total
cyclopentanone in the presence of a catalytic amount of TsOH in
benzene caused serious racemization by transesterification of the
p-methoxybenzoyl ester. However, treatment with cyclopentanone
dimethylacetal in the presence of Sc(OTf)3 catalyst11 gave 9 almost
quantitatively without loss of stereochemical integrity. Cleavage of
the p-methoxybenzoyl ester with sodium methoxide in methanol
produced 10 in 97% yield. Oxidation of 10 with Dess–Martin peri-
odinane12 followed by Wittig reaction with methyl (triphenyl-
phosphoranylidene)acetate furnished 11 in 75% yield over 2 steps.
The resulting ester was reduced with DIBAL to give allyl alcohol 12
in 94% yield. Sharpless asymmetric epoxidation of 12 using
(þ)-diethyl tartrate provided the corresponding epoxide (94% de),
which was then converted to chloride 7 by treatment with NCS and
Ph3P in the presence of an excess amount of 2-methyloxirane as
a chloride ion scavenger in 94% yield over 2 steps. This reaction in
the absence of 2-methyloxirane gave a mixture of undesired
products formed by addition of chloride ion to the epoxide. Base-
induced elimination13 of 7 with n-BuLi furnished 13 in 99% yield.
Silyl ether protection of 13 with TBSOTf and 2,6-lutidine followed
by hydrolysis of the cyclopentylidene acetal with 70% aqueous
AcOH led to diol 14 in 87% yield over 2 steps.
synthesis of nafuredin-g
(2)6 and allowed structural simplification
of the lactone moiety in the structure–activity relationship studies
of 1. We provide herein a detailed account of the total synthesis and
the structure–activity relationship studies of nafuredin-g (2).
2. Results and discussion
2.1. Total synthesis of nafuredin-
g (2)
As outlined in Scheme 2, our retrosynthetic strategy toward
nafuredin-g (2) is convergent and involves the assembly of the C1–
C7 segment 3 and the C8–C18 segment 4,4 which will be joined in
the final step by Stille coupling. This route provides a simple and
efficient method to synthesize various nafuredin-g analogues with
modifications of the side chain moiety and also promises to be
especially effective for the synthesis of C4 and/or C5 stereoisomers
of nafuredin-g (2). The enol lactone 3 will be constructed by
Oxidation of the primary alcohol in 14 with 2,2,6,6-tetrame-
Horner–Wadsworth–Emmons reaction of aldehyde 5 with known
thylpiperidine-1-oxyl (TEMPO) and trichloroisocyanuric acid14
phosphonate 67 followed by hydrostannylation. The aldehyde 5 will
OH
OH
O
1
O
8
18
4
O
O
+
5
SnBu3
I
7
OH
OH
4
2
3
O
HO
OHC
(MeO)2P(O)
CO2Me
OTBS
O
Cl
+
O
OTBS
7
5
6
Scheme 2. Retrosynthesis of nafuredin-g (2).
be derived from the epoxy chloride 7, which will be constructed by
Sharpless asymmetric epoxidation8 and dihydroxylation9 as key
reactions.
gave the desired aldehyde 5 (Scheme 4), while DMSO oxidation
(Swern conditions and Parikh–Doering conditions), Dess–Martin
oxidation, and TEMPO–NaClO–KBr oxidation caused de-
composition of the product. The use of trichloroisocyanuric acid as
a co-oxidant in the TEMPO oxidation of 14 was crucial for high yield
The known diol 8 (97% ee)10 was used as the precursor to al-
dehyde
5
as shown in Scheme 3. Acetalization of
8
with
HO
O
O
O
O
e
a
b
c,d
HO
f,g
OPMBz
O
O
O
h
O
OH
OPMBz
OH
CO2Me
8
9
10
11
12
HO
O
O
i.j
HO
O
O
Cl
O
OTBS
OH
13
7
14
Scheme 3. Reagents and conditions: (a) cat. Sc(OTf)3, 1,1-dimethoxycyclopentane, MeCN, rt, 99%; (b) NaOMe, MeOH, rt, 97%; (c) Dess–Martin periodinane, CH2Cl2, rt; (d)
Ph3P]CHCO2Me, benzene, reflux, 75% (2 steps); (e) DIBAL, CH2Cl2, ꢀ78 ꢁC, 94%; (f) (þ)-DET, Ti(Oi-Pr)4, TBHP, CH2Cl2, ꢀ20 ꢁC; (g) NCS, PPh3, 2-methyloxirane, CH2Cl2, rt, 94% (2
steps); (h) n-BuLi, THF, ꢀ40 ꢁC, 99%; (i) TBSOTf, 2,6-lutidine, CH2Cl2, rt; (j) 70% aq AcOH, rt, 87% (2 steps).

T. Nagamitsu et al. / Tetrahedron 64 (2008) 8117–8127
8119
OH
OH
OH
O
O
O
HO
HO
OHC
a
b
d
SnBu3
HO
+
O
O
O
5
SnBu3
OTBS
OTBS
OR
OR
OR
18 R = TBS (52%)
3 R = H (39%)
19 R = TBS (23%)
17 R = H (30%)
15 R = TBS
16 R = H
14
5
c
f,g
e
OH
O
O
OH
Nafuredin-γ (2)
Scheme 4. Reagents and conditions: (a) cat. TEMPO, trichloroisocyanuric acid, CH2Cl2, 0 ꢁC; (b) 6, DBU, LiCl, MeCN, 0 ꢁC, 75% (2 steps); (c) HF$pyridine, THF, rt, 91%; (d) Bu3SnH, cat.
PdCl2(PPh3)2, THF, 0 ꢁC; (e) 4, cat. PdCl2(MeCN)2, NMP, 50 ꢁC, 72%; (f) 4, cat. PdCl2(MeCN)2, NMP, Ph2P(O)OꢀBu4Nþ, 50 ꢁC, 63%; (g) HF$pyridine, THF, rt, 85%.
and reproducibility. Aldehyde 5 was subjected to the next reaction
without further purification because of its instability. Horner–
Wadsworth–Emmons reaction of 5 with the known phosphonate
Next, we focused on the high regioselectivity of palladium-
´
catalyzed hydrostannylation of alkynyl bromides reported by Guibe
et al.19 Bromination of the terminal alkynes 15 and 16 led to de-
composition of the substrates. Therefore, TBS protected enol ether
20 was constructed by oxidation of 14 followed by Horner–Wads-
worth–Emmons reaction with 6 and LHMDS (75% yield, 2 steps).
Enol ether 20 afforded alkynyl bromide 21 quantitatively upon
67 in the presence of DBU and LiCl15 afforded
g-lactone 15 in 75%
yield over 2 steps.
g-Lactone 15 was treated with HF$pyridine to
give 16 in 91% yield. Subsequent palladium-catalyzed hydro-
stannylation16 of 16 with Bu3SnH and PdCl2(PPh3)2 proceeded
nonregioselectively, yielding the desired E-alkenylstannane 3 (39%)
and its regioisomer 17 (30%). After separation by silica gel chro-
matography, Stille coupling17 between 3 and vinyl iodide 4 in the
20
treatment with NBS and AgNO3 (Scheme 5). Removal of the TBS
ether group with HF$pyridine gave enol 22 quantitatively. Sub-
sequent palladium-catalyzed hydrostannylation of 22 provided the
desired E-alkenylstannane 3 in 71% yield with high regioselectivity
presence of PdCl2(MeCN)2 gave nafuredin-
g
(2) in 72% yield.
OH
OTBS
O
OTBS
O
O
HO
a,b
c
Br
d
e
Br
HO
O
O
O
OTBS
OH
22
OTBS
OTBS
21
14
20
OH
OH
O
O
f
O
O
SnBu3
OH
OH
3
Nafuredin-γ (2)
[α]25D = + 4.0° (c = 0.1, CHCl3): Synthetic
[α]26D = + 4.6° (c = 1.0, CHCl3): From natural
Scheme 5. Reagents and conditions: (a) cat. TEMPO, trichloroisocyanuric acid, CH2Cl2, 0 ꢁC; (b) 6, LHMDS, THF, 0 ꢁC, 75% (2 steps); (c) cat. AgNO3, NBS, acetone, rt, 100%; (d)
HF$pyridine, THF, rt, 100%; (e) Bu3SnH, cat. PdCl2(PPh3)2, THF, 0 ꢁC, 71%; (f) 4, cat. PdCl2(MeCN)2, NMP, 50 ꢁC, 72%.
Although the total synthesis of 2 was achieved, a more effective
hydrostannylation procedure with higher regioselectivity was re-
quired for large-scale synthesis of 2. We therefore examined
hydrostannylation of the TBS ether 15, which provided 18 in 52%
yield along with its regioisomer 19 (23%). However, subsequent
Stille coupling of 18 with 4 did not proceed well under the same
conditions (20% yield). Addition of Ph2P(O)OꢀBu4Nþ18 improved
(3/17¼15:1). This was converted to nafuredin-
mentioned above. Synthetic nafuredin- (2) was identical to that
derived from natural nafuredin (1) in all respects ([
]D, 1H and 13C
NMR, IR, FABMS, and inhibitory activity against NFRD).
g (2) in good yield as
g
a
2.2. Synthesis of analogues of nafuredin-g (2)
the yield of the coupled product (63%), affording nafuredin-
g
(2) in
Our continued efforts on the structure–activity relationships of
85% yield after removal of the TBS ether group with HF$pyridine.
Unfortunately, these moderate yields in hydrostannylation and
Stille coupling were still far from satisfactory.
2 led to the synthesis of new analogues 23–25 (Fig. 1) using our
strategy for the total synthesis of nafuredin-g 6
.
These new nafur-
edin-
g analogues are the C4-epimer (23), the C5-epimer (24), and

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T. Nagamitsu et al. / Tetrahedron 64 (2008) 8117–8127
OH
O
1
2
3
5
4
O
OH
Nafuredin-γ (2)
OH
OH
O
O
O
O
O
O
OH
OH
OH
23
24
25
Figure 1. Chemical structures of nafuredin-g (2) and new nafuredin-g analogues (23–25).
the 2-dehydroxy-
a
,
b
-unsaturated lactone (25). These analogues
amount of PdCl2(MeCN)2 and subsequent deprotection of the silyl
enol ether gave the desired C4-epimer (23).
were selected in order to elucidate the requirements of the C4 and
C5 stereochemistries and the enol in 2 for inhibitory activity against
NADH-fumarate reductase (complex I).
The synthesis of the C4-epimer (23) started from methallyl al-
cohol, which was readily converted into the chiral diol 2610 (97% ee)
through asymmetric dihydroxylation (Scheme 6). The Sc(OTf)3-
catalyzed acetalization of 26 followed by cleavage of the p-
methoxybenzoyl ester with sodium methoxide furnished alcohol
27. Subsequent Dess–Martin oxidation and Wittig reaction afforded
We next synthesized the C5-epimer (24) as shown in Scheme 7.
Allyl alcohol 12, an advanced intermediate in the total synthesis of
2, was converted into chloride 34 by Sharpless asymmetric epoxi-
dation using (ꢀ)-diethyl tartrate followed by chlorination of the
resulting epoxy alcohol. Further transformations from the chloride
34 to the C5-epimer (24) were achieved in the same manner as the
synthesis of 23.
Finally, we investigated the synthesis of the 2-dehydroxy-a,b-
the corresponding
a
,
b
-unsaturated ester, which was reduced with
unsaturated lactone (25) (Scheme 8). Diol 14 was oxidized with
TEMPO to furnish the corresponding aldehyde, which was sub-
jected to Still–Gennari olefination21 followed by deprotection of the
silyl ether to give a,b-unsaturated lactone 39. Hydrostannylation of
39 led to the desired E-alkenylstannane 40. Stille coupling between
40 and the vinyl iodide 4 in the presence of a catalytic amount of
DIBAL to give allyl alcohol 28. Sharpless asymmetric epoxidation of
28 using (þ)-diethyl tartrate provided the corresponding epoxy
alcohol, which was further converted to chloride 29 by treatment
with NCS and Ph3P in the presence of 2-methyloxirane. Base-in-
duced elimination of 29 with n-BuLi furnished propargyl alcohol
30. A two-step sequence of protecting group manipulations pro-
vided diol 31. Oxidation of the primary alcohol in 31 with TEMPO
gave the corresponding aldehyde, which was subjected to Horner–
Wadsworth–Emmons reaction using 6, followed by deprotection of
PdCl2(MeCN)2 gave the desired 2-dehydroxy-
tone (25). Although the regioselectivities and yields of several re-
actions in the synthesis of nafuredin- analogues were
unsatisfactory, priority was given to their biological evaluation.
a,b-unsaturated lac-
g
the silyl ethers to produce 2-hydroxy-a,b-unsaturated lactone 32.
After the enol of 32 was protected as a TBDPS ether to facilitate
handling and NMR assignment of the substrate, hydrostannylation
afforded the desired E-alkenylstannane 33 as the major product.
Stille coupling with the vinyl iodide 4 in the presence of a catalytic
2.3. Biological evaluation of the new nafuredin-g analogues
With the nafuredin-
g analogues 23–25 in hand, the inhibitory
activity against NFRD of A. suum was evaluated and the results are
O
O
HO
c,d
e-g
h,i
a,b
OH
HO
OPMBz
O
OH
O
OH
27
28
26(97% e.e.)
OH
O
O
O
O
HO
j
k,l
m-o
p,q
O
Cl
HO
O
O
OH
OTBS
31
OH
32
29
30
OTBDPS
OH
O
O
r,s
O
O
SnBu3
OH
OH
33
23
Scheme 6. Reagents and conditions: (a) PMBzCl, Et3N, cat. DMAP, CH2Cl2, rt, quant.; (b) (DHQ)2PHAL, K2OsO4$2H2O, K3Fe(CN)6, K2CO3, t-BuOH/H2O, 0 ꢁC, 95%; (c) cat. Sc(OTf)3, 1,1-
dimethoxycyclopentane, MeCN, rt, 84%; (d) NaOMe, MeOH, rt, 73%; (e) Dess–Martin periodinane, CH2Cl2, rt; (f) Ph3P]CHCO2Et, benzene, 80 ꢁC, 75% (2 steps); (g) DIBAL, CH2Cl2,
ꢀ78 ꢁC, 82%; (h) (þ)-DET, Ti(Oi-Pr)4, TBHP, CH2Cl2, ꢀ20 ꢁC; (i) NCS, PPh3, 2-methyloxirane, CH2Cl2, rt, 86% (2 steps); (j) n-BuLi, THF, ꢀ40 ꢁC, 99%; (k) TBSOTf, 2,6-lutidine, CH2Cl2,
0 ꢁC, 99%; (l) 70% aq AcOH, rt, 78%; (m) cat. TEMPO, trichloroisocyanuric acid, CH2Cl2, 0 ꢁC; (n) LHMDS, 6, THF, ꢀ78 ꢁC; (o) HF$pyridine, THF, rt, 52% (3 steps); (p) TBDPSCl, Et3N, THF,
rt, 56%; (q) cat. PdCl2(PPh3)2, Bu3SnH, THF, 0 ꢁC, 47%; (r) cat. PdCl2(MeCN)2, 4, NMP, 50 ꢁC, 32%; (s) HF$pyridine, THF, rt, 85%.

T. Nagamitsu et al. / Tetrahedron 64 (2008) 8117–8127
8121
OH
HO
O
O
O
HO
a,b
c
d,e
f-h
O
O
12
O
Cl
OTBS
O
OH
OH
37
34
35
OH
36
OTBDPS
O
O
k,l
i.j
O
O
SnBu3
OH
OH
38
24
Scheme 7. Reagents and conditions: (a) (ꢀ)-DET, Ti(Oi-Pr)4, TBHP, CH2Cl2, ꢀ20 ꢁC; (b) NCS, PPh3, 2-methyloxirane, CH2Cl2, rt, 92% (2 steps); (c) n-BuLi, THF, ꢀ40 ꢁC, 97%; (d) TBSOTf,
2,6-lutidine, CH2Cl2, 0 ꢁC, 96%; (e) AcOH, rt, 86%; (f) cat. TEMPO, trichloroisocyanuric acid, CH2Cl2, 0 ꢁC; (g) LHMDS, 6, THF, ꢀ78 ꢁC; (h) HF$pyridine, THF, rt, 49% (3 steps); (i)
TBDPSCl, Et3N, THF, rt, 65%; (j) cat. PdCl2(PPh3)2, Bu3SnH, THF, 0 ꢁC, 73%; (k) cat. PdCl2(MeCN)2, 4, NMP, 50 ꢁC, 28%; (l) HF$pyridine, THF, rt, 84%.
inhibitory activity of 2. These results will allow further structural
simplification of the lactone moiety and lead to the development of
O
O
a-c
d
14
O
O
SnBu3
shorter and more efficient syntheses for new nafuredin-
g ana-
logues. Additional structure–activity relationship studies of 2 are in
progress and will be reported in due course.
OH
39
OH
40
O
4. Experimental
e
O
4.1. General information
OH
25
Commercial reagents were used without further purification
unless otherwise indicated. Organic solvents were distilled and
dried over 3 Å or 4 Å molecular sieves. Reactions were performed in
flame-dried glassware under positive Ar pressure unless otherwise
indicated. Cold baths were generated as follows: 0 ꢁC, wet ice/wa-
ter; ꢀ78 ꢁC, dry ice/acetone. Flash chromatography was performed
Scheme 8. Reagents and conditions: (a) cat. TEMPO, trichloroisocyanuric acid, CH2Cl2,
0 ꢁC; (b) LHMDS, (CF3CH2O)2P(O)CH2CO2Me, THF, 0 ꢁC; (c) HF$pyridine, THF, rt, 55% (3
steps); (d) cat. PdCl2(PPh3)2, Bu3SnH, THF, rt, 68%; (e) cat. PdCl2(MeCN)2, 4, NMP, 50 ꢁC,
70%.
on silica gel 60 N (spherical, neutral, particle size 40–50 mm). TLC
was performed on 0.25 mm E. Merck silica gel 60 F254 plates and
visualized by UV light (254 nm) and cerium ammonium
molybdenate.
Table 1
Inhibitory activity of the nafuredin-
g
analogues against NFRD of Ascaris suum
IC50 (nM)
Compound
4.2. Conversion of nafuredin (1) to nafuredin-g (2)
Nafuredin-
g
(2)
6
7
120
8
23
24
25
Compound 1 (10.0 mg) was dissolved in MeOH (0.28 mL), and
CaCO3 (2.0 mg) was added to the solution. After the solution was
stirred at room temperature for 30 min, EtOAc (10 mL) and a satu-
rated aqueous NaCl solution (10 mL) were added. The organic layer
was dried over anhydrous Na2SO4 and concentrated to yield 25
(9.3 mg, 93%).
summarized in Table 1. Surprisingly, both the IC50 values of the C4-
epimer (23) and the 2-dehydroxy- -unsaturated lactone (25)
were nearly identical to that of nafuredin- (2). However, NFRD
a,b
4.3. Total synthesis of nafuredin-g (2)
g
inhibitory activity of the C5-epimer (24) decreased more than ten
times. Therefore, it was concluded that the stereochemistry at C4
and the presence of the enol (or 2-ketone) are not important, but
the C5 stereochemistry is valuable for the inhibitory activity against
NADH-fumarate reductase (complex I).
4.3.1. (S)-(2-Methyl-1,4-dioxaspiro[4.4]nonan-2-yl)methyl 4-
methoxybenzoate (9)
To a solution of 8 (1.75 g, 7.29 mmol) in MeCN (70 mL) were
added 1,1-dimethoxycyclopentane (2.00 mL, 14.5 mmol) and
Sc(OTf)3 (31.3 mg, 72.9 mmol) at room temperature. The resulting
solution was stirred for 1 h and diluted with a saturated aqueous
NaHCO3 solution. The aqueous phase was extracted with EtOAc. The
combined organic extracts were dried over anhydrous Na2SO4 and
3. Summary
We have discovered nafuredin-
nafuredin (1), and achieved its first total synthesis. This enabled
construction of the diverse nafuredin- analogues 23–25. The
structure–activity relationship studies of 2 revealed that the C4
stereochemistry and the enol (or 2-ketone) functionality as struc-
tural elements are not required as structural elements, but the
stereochemistry of the C5 hydroxy group is important for the NFRD
g
(2), a proposed active form of
concentrated in vacuo. Flash chromatography (30:1 hexanes/
23
EtOAc) afforded 9 (2.21 g, 99%) as a colorless oil. [
a
]
þ2.8 (c 1.0,
D
g
CHCl3); IR (KBr) 2953, 2733, 1770, 1558, 1157, 1110 cmꢀ1
(270 MHz, CDCl3)
;
1H NMR
d
7.99 (d, 2H, J¼8.9 Hz), 6.91 (d, 2H, J¼8.7 Hz),
4.25 (d, 1H, J¼11.2 Hz), 4.17 (d, 1H, J¼11.2 Hz), 4.02 (d, 1H, J¼8.6 Hz),
3.84 (s, 3H), 3.67 (d, 1H, J¼8.6 Hz), 1.76 (m, 8H), 1.38 (s, 3H); 13C
NMR (67.5 MHz, CDCl3) d 165.9, 163.4, 131.6, 122.3, 119.7, 113.6, 78.9,

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T. Nagamitsu et al. / Tetrahedron 64 (2008) 8117–8127
71.8, 67.8, 55.3, 37.3, 37.1, 23.6, 23.3, 22.2; HRMS (FAB, m-NBA) Mþ
calcd for C17H22O5: 306.1467, found: 306.1465.
treated with Celite (10.0 g) and Na2SO4$10H2O (10.0 g). After stir-
ring for 2 h at room temperature, the resulting mixture was filtered
through a pad of Celite and concentrated in vacuo. The residue was
purified by column chromatography (1:1 hexanes/EtOAc) to give
a mixture of the corresponding epoxy alcohol and a small amount
of (þ)-DET. This mixture was employed in the next reaction without
further purification.
4.3.2. (R)-(2-Methyl-1,4-dioxaspiro[4.4]nonan-2-yl)methanol (10)
To a stirred solution of 9 (1.87 g, 6.11 mmol) in MeOH (20 mL)
was added NaH (60% in oil, 49.8 mg, 1.22 mmol). The resulting so-
lution was stirred for 45 min at room temperature, diluted with
H2O, and extracted with EtOAc. The combined organic extracts
were dried over anhydrous Na2SO4 and concentrated in vacuo.
To a solution of the mixture in CH2Cl2 (70 mL), NCS (1.60 g,
11.9 mmol), triphenylphosphine (3.10 g, 11.9 mmol), and 2-meth-
Flash chromatography (5:1 hexanes/EtOAc) afforded 10 (1.02 g,
yloxirane (980 mL, 14.0 mmol) were added. The reaction mixture
was stirred for 10 min at room temperature and concentrated in
vacuo. Flash chromatography (40:1 hexanes/EtOAc) afforded 7
23
97%) as a colorless oil. [
a
]
þ5.0 (c 1.0, CHCl3); IR (KBr) 3327, 2732,
1234, 1103, 1024 cmꢀ1
;
1DH NMR (270 MHz, CDCl3)
d
3.88 (d, 1H,
25
J¼8.6 Hz), 3.59 (d, 1H, J¼8.6 Hz), 3.45 (m, 2H), 2.26 (br s, 1H), 1.75
(1.54 g, 94% for 2 steps) as a colorless oil. [
IR (KBr) 2969, 2873, 1336, 1105 cmꢀ1
3.92 (d,1H, J¼8.6 Hz), 3.66 (d,1H, J¼8.6 Hz), 3.58 (d, 2H, J¼5.3 Hz),
3.22 (dt, 1H, J¼5.3, 2.0 Hz), 2.99 (d, 1H, J¼2.0 Hz), 1.74 (m, 8H), 1.29
a
]
þ4.0 (c 0.1, CHCl3);
D
(m, 8H), 1.32 (s, 3H); 13C NMR (67.5 MHz, CDCl3)
d
119.3, 80.7, 71.1,
;
1H NMR (270 MHz, CDCl3)
66.9, 37.1, 23.5, 23.1, 21.7; HRMS (FAB, m-NBA) Mþ calcd for
d
C9H16O3: 172.1099, found: 172.1103.
(s, 3H, 4-Me); 13C NMR (67.5 MHz, CDCl3)
d 119.9, 77.9, 71.8, 61.7,
4.3.3. (R,E)-Methyl 3-(2-methyl-1,4-dioxaspiro[4.4]nonan-2-
yl)acrylate (11)
54.3, 44.0, 36.9, 36.7, 23.5, 23.2, 21.4; HRMS (FAB, m-NBA) Mþ calcd
for C11H17O3Cl: 232.0866, found: 232.0868.
To a solution of 10 (762 mg, 4.43 mmol) in CH2Cl2 (45 mL) was
added Dess–Martin periodinane (2.40 g, 5.76 mmol) at room tem-
perature. After 1 h, the reaction was quenched with saturated
aqueous solutions of Na2S2O3 and NaHCO3 and extracted with
CH2Cl2. The combined organic extracts were dried over anhydrous
Na2SO4 and concentrated in vacuo. This residue was employed in
the next reaction without further purification.
To a solution of the resulting aldehyde in benzene (45 mL) was
added (carbomethoxymethylene)triphenylphosphorane (2.2 g,
6.64 mmol). The reaction was refluxed for 1 h and concentrated in
4.3.6. (R)-1-[(S)-2-Methyl-1,4-dioxaspiro[4.4]nonan-2-yl]prop-2-
yn-1-ol (13)
To a solution of 7 (1.53 g, 6.61 mmol) in THF (66 mL) was added
n-BuLi (1.6 M in hexane, 20 mL, 33.0 mmol) at ꢀ78 ꢁC. The reaction
mixture was stirred for 2 h at ꢀ40 ꢁC, quenched with a saturated
aqueous NH4Cl solution, and extracted with EtOAc. The combined
organic extracts were dried over anhydrous Na2SO4 and concen-
trated in vacuo. Flash chromatography (10:1 hexanes/EtOAc)
25
afforded 13 (1.28 g, 99%) as a colorless oil. [
a]
ꢀ12.0 (c 0.1,
D
vacuo. Flash chromatography (20:1 hexanes/EtOAc) afforded 11
CHCl3); IR (KBr) 3444, 3307, 2971, 2875, 1336, 1106, 1051 cmꢀ1; 1H
NMR (270 MHz, CDCl3)
25
(751 mg, 75% for 2 steps) as a yellow oil. [
a]
ꢀ54.0 (c 0.1, CHCl3); IR
d
4.32 (dd, 1H, J¼4.0, 2.0 Hz), 4.19 (d, 1H,
D
(KBr) 2973, 2871, 1726, 1662, 1303, 1170, 1105 cmꢀ1
(270 MHz, CDCl3)
6.95 (d, 1H, J¼15.5 Hz), 6.07 (d, 1H, J¼15.5 Hz),
3.84 (d, 1H, J¼8.2 Hz), 3.76 (d, 1H, J¼8.2 Hz), 3.74 (s, 3H), 1.76 (m,
8H), 1.40 (s, 3H); 13C NMR (67.5 MHz, CDCl3)
166.8, 150.5, 120.1,
;
1H NMR
J¼8.7 Hz), 3.68 (d, 1H, J¼8.7 Hz), 2.46 (d, 1H, J¼2.0 Hz), 2.33 (br d,
d
1H, J¼4.0 Hz), 1.77 (m, 8H), 1.40 (s, 3H); 13C NMR (67.5 MHz, CDCl3)
d
120.1, 82.0, 81.7, 74.0, 70.8, 66.3, 37.0, 36.9, 23.6, 23.1, 20.8; HRMS
d
(FAB, m-NBA) [MþH]þ calcd for C11H17O3: 197.1178, found:
119.6, 79.6, 74.0, 51.6, 37.0, 36.8, 24.4, 23.4, 23.3; HRMS (FAB, m-
NBA) [MþH]þ calcd for C12H19O4: 227.1283, found: 227.1272.
197.1183.
4.3.7. (2S,3R)-3-(tert-Butyldimethylsilyloxy)-2-methylpent-4-yne-
1,2-diol (14)
4.3.4. (R,E)-3-(2-Methyl-1,4-dioxaspiro[4.4]nonan-2-yl)prop-2-en-
1-ol (12)
To a solution of 13 (1.29 g, 6.56 mmol) in CH2Cl2 (65 mL) were
added TBSOTf (3.00 mL, 13.1 mmol) and 2,6-lutidine (2.30 mL,
19.6 mmol) at 0 ꢁC. After 30 min at room temperature, the reaction
was quenched with H2O and extracted with CH2Cl2. The combined
organic extracts were dried over anhydrous Na2SO4 and concen-
trated in vacuo. This residue was employed in the next reaction
without further purification.
The residue was dissolved in 70% aqueous AcOH solution
(31 mL). The reaction mixture was stirred for 10 h at room tem-
perature, quenched with a saturated aqueous NaHCO3 solution, and
extracted with EtOAc. The combined organic extracts were dried
over anhydrous Na2SO4 and concentrated in vacuo. Flash chroma-
To a solution of 11 (1.66 g, 7.35 mmol) in CH2Cl2 (70 mL) was
added dropwise DIBAL (1.0 M solution in hexane, 22 mL,
22.0 mmol) at ꢀ78 ꢁC. After stirring for 0.5 h, the reaction mixture
was quenched with MeOH, diluted with CH2Cl2, and treated with
Celite (20 g) and Na2SO4$10H2O (20 g). The resulting mixture was
stirred for 2 h at room temperature and then filtered through a pad
of Celite. The filtrates were concentrated in vacuo. The residue was
purified by column chromatography (3:1 hexanes/EtOAc) to give 12
25
(1.37 g, 94%) as a colorless oil. [
a
]
ꢀ6.0 (c 1.0, CHCl3); IR (KBr) 3428,
2973, 2871, 1334, 1106, 975 cmꢀ1D; 1H NMR (270 MHz, CDCl3)
d 5.91
(dt, 1H, J¼15.5, 4.9 Hz), 5.79 (d, 1H, J¼15.5 Hz), 4.17 (t, 2H, J¼4.9 Hz),
3.77 (d, 1H, J¼8.2 Hz), 3.72 (d, 1H, J¼8.2 Hz), 1.75 (m, 8H), 1.37 (s,
tography (4:1 hexanes/EtOAc) afforded 14 (1.40 g, 87% for 2 steps)
23
3H); 13C NMR (67.5 MHz, CDCl3)
d
143.3, 128.5, 119.5, 79.6, 74.6,
as a colorless oil. [
a
]
ꢀ45.2 (c 1.0, CHCl3); IR (KBr) 3300, 2929,
D
62.7, 37.2, 37.0, 24.4, 23.3; HRMS (FAB, m-NBA) Mþ calcd for
11H18O3: 198.1256, found: 198.1254.
2863, 1239, 1185, 1130, 1025 cmꢀ1; 1H NMR (270 MHz, CDCl3)
d 4.35
C
(d,1H, J¼2.0 Hz), 3.86 (d,1H, J¼11.2 Hz), 3.43 (d,1H, J¼11.2 Hz), 2.64
(br s, 2H), 2.47 (d,1H, J¼2.0 Hz),1.19 (s, 3H), 0.89 (s, 9H), 0.16 (s, 3H),
4.3.5. (S)-2-[(2R,3R)-3-(Chloromethyl)oxiran-2-yl]-2-methyl-1,4-
dioxaspiro[4.4]nonane (7)
0.12 (s, 3H); 13C NMR (67.5 MHz, CDCl3)
d 82.3, 74.8, 73.9, 69.2, 66.8,
25.6, 19.8, 18.0, ꢀ4.8, ꢀ5.4; HRMS (FAB, m-NBA) [MþH]þ calcd for
To
a
mixture of MS 4 Å (3.00 g) and (þ)-DET (1.70 mL,
C12H25O3Si: 245.1573, found: 245.1569.
9.83 mmol) in CH2Cl2 (15 mL) was added dropwise titanium tet-
raisopropoxide (2.30 mL, 7.86 mmol) at ꢀ5 ꢁC. After 20 min, TBHP
(5.0 M in decane, 3.20 mL, 16.3 mmol) was added dropwise to the
mixture at ꢀ20 ꢁC. After stirring for 20 min at ꢀ20 ꢁC, the resulting
mixture was treated with a solution of 12 (1.40 g, 7.07 mmol) in
CH2Cl2 (7 mL) and then stirred at ꢀ20 ꢁC for 15 h. The reaction was
diluted with Et2O (11 mL), warmed to room temperature, and
4.3.8. (S)-5-[(R)-1-(tert-Butyldimethylsilyloxy)prop-2-ynyl]-3-
hydroxy-5-methylfuran-2(5H)-one (15)
To a solution of 14 (161 mg, 657
added TEMPO (20.5 mg, 131 mol) and trichloroisocyanuric acid
(153 mg, 657 mol) at room temperature. The resulting solution
was stirred for 30 min and diluted with a saturated aqueous
mmol) in CH2Cl2 (6.6 mL) were
m
m

T. Nagamitsu et al. / Tetrahedron 64 (2008) 8117–8127
8123
NaHCO3 solution. The aqueous phase was extracted with CH2Cl2.
4.3.11. (S)-5-[(R,E)-1-(tert-Butyldimethylsilyloxy)-3-(tributyl-
The combined organic extracts were dried over anhydrous Na2SO4
and concentrated in vacuo. The crude aldehyde 5 was subjected to
the next reaction without further purification.
stannyl)allyl]-3-hydroxy-5-methylfuran-2(5H)-one (18) and (S)-5-
[(S)-1-(tert-butyldimethylsilyloxy)-2-(tributylstannyl)allyl]-
3-hydroxy-5-methylfuran-2(5H)-one (19)
To a solution of 6 (511 mg, 1.64 mmol) in CH3CN (4.0 mL) were
To a stirred solution of 15 (18.0 mg, 63.8
were added tributyltin hydride (50 L, 19.1
(1.3 mg, 3.19 mol). The resulting mixture was stirred for 30 min at
room temperature and then concentrated in vacuo. The residue was
purified by column chromatography (7:1 hexanes/EtOAc) to give 18
m
mol) in THF (640
mL)
added LiCl (63.8 mg, 1.51 mmol) and DBU (210
mL, 1.51 mmol) at
m
mmol) and PdCl2(PPh3)2
0 ꢁC. After stirring for 30 min, a solution of the crude aldehyde 5 in
THF (1.3 mL) was slowly added dropwise over 60 min to the re-
action mixture at 0 ꢁC. After 5 min, the resulting solution was
quenched with a saturated aqueous NaHCO3 solution and extracted
with EtOAc. The combined organic extracts were dried over anhy-
drous Na2SO4 and concentrated in vacuo. Flash chromatography
m
(19.1 mg, 52%) and 19 (8.4 mg, 23%) as colorless oils.
24
Compound 18: [
a
]
D
ꢀ32.5 (c 0.5, CHCl3); IR (KBr) 2952, 2927,
2858, 1786, 1462, 1385, 1306, 1254, 1184, 1086, 1001, 849, 781,
(7:1 hexanes/EtOAc) afforded 15 (140 mg, 75% for 2 steps) as a col-
681 cmꢀ1 1H NMR (400 MHz, CDCl3) enol
;
d
9.63 (s, 1H), 6.32 (dd,
24
orless oil. [
a
]
D
ꢀ69.3 (c 0.5, CHCl3); IR (KBr) 3369, 3284, 2947, 2868,
1H, J¼19.1, 1.3 Hz), 5.91 (dd, 1H, J¼19.1, 5.9 Hz), 4.09 (dd, 1H, J¼5.9,
1.3 Hz), 1.57–1.42 (m, 6H), 1.39 (s, 3H), 1.36–1.24 (m, 6H), 0.93–0.79
(m, 6H), 0.88 (t, 9H, J¼7.3 Hz), 0.81 (s, 9H), ꢀ0.02 (s, 3H); ketone
1786, 1664, 1462, 1392, 1317, 1252, 1184, 1093, 989, 935, 849, 783,
677 cmꢀ1; 1H NMR (400 MHz, CDCl3) enol
9.80 (s,1H), 6.21 (s,1H),
4.37 (d, 1H, J¼2.2 Hz), 2.50 (d, 1H, J¼2.2 Hz), 1.57 (s, 3H), 0.86 (s,
9H), 0.13 (s, 3H), 0.1 (s, 3H); ketone
d
d
6.43 (dd, 1H, J¼19.1, 1.3 Hz), 6.08 (s, 1H), 5.85 (dd, 1H, J¼19.1,
d
4.39 (d, 1H, J¼2.2 Hz), 3.26 (d,
5.9 Hz), 4.18 (dd, 1H, J¼5.9, 1.3 Hz), 2.99 (d, 1H, J¼18.6 Hz), 2.23 (d,
1H, J¼18.6 Hz), 1.57–1.42 (m, 6H), 1.52 (s, 3H), 1.36–1.24 (m, 6H),
0.93–0.79 (m, 6H), 0.88 (t, 9H, J¼7.3 Hz), 0.81 (s, 9H), ꢀ0.02 (s, 3H);
1H, J¼18.8 Hz), 2.55 (d,1H, J¼2.2 Hz), 2.41 (d,1H, J¼18.8 Hz),1.69 (s,
3H), 0.83 (s, 9H), 0.14 (s, 3H), 0.1 (s, 3H); 13C NMR (100 MHz, CDCl3)
as a keto–enol mixture,
d
191.5,169.4,160.2,142.8,128.3,119.2, 86.3,
13C NMR (100 MHz, CDCl3) as a keto–enol mixture,
d 192.2, 169.7,
83.7, 81.2, 80.5, 76.1, 74.9, 68.5, 67.0, 41.1, 25.5, 25.4, 22.7, 20.7, 18.2,
18.0, ꢀ5.1, ꢀ5.4; HRMS (FAB, m-NBA) [MþH]þ calcd for C14H23O4Si:
283.1366, found: 283.1371.
160.6, 145.5, 144.1, 142.3, 136.0, 133.3, 120.3, 87.1, 84.3, 80.4, 79.5,
40.3, 29.1, 27.2, 25.7, 23.5, 20.8,18.0,13.7, 9.6, ꢀ4.5, ꢀ4.6, ꢀ5.2, ꢀ5.4;
HRMS (FAB, m-NBAþNaI) [MþNa]þ calcd for C26H50O4SiSnNa:
597.2398, found: 597.2404.
24
4.3.9. (S)-3-Hydroxy-5-[(R)-1-hydroxyprop-2-ynyl]-5-
methylfuran-2(5H)-one (16)
Compound 19: [
a
]
ꢀ18.8 (c 0.5, CHCl3); IR (KBr) 3477, 3346,
D
2957, 2927, 2858, 1753, 1687, 1658, 1462, 1384, 1255, 1219, 1153,
A solution of 15 (17.1 mg, 0.06 mmol) in THF (1.2 mL) was
1070, 937, 866, 839, 781, 675 cmꢀ1; 1H NMR (400 MHz, CDCl3) enol
treated with HF$pyridine (600
temperature. The resulting mixture was filtered through a pad of
silica gel and concentrated in vacuo. Flash chromatography (1:1
hexanes/EtOAc) afforded 16 (9.30 mg, 91%) as a colorless oil. [
m
L) and stirred for 24 h at room
d
6.19 (s, 1H), 6.08 (m, 1H), 5.43 (dd, 1H, J¼2.5, 1.0 Hz), 4.20 (s, 1H),
1.51–1.41 (m, 6H), 1.38–1.25 (m, 6H), 1.31 (s, 3H), 1.04–0.81 (m,
6.16 (m, 1H), 5.50 (dd, 1H,
24H), 0.03 (s, 6H), ꢀ0.04 (s, 6H); ketone
d
22
a
]
J¼2.5, 1.0 Hz), 4.41 (s, 1H), 3.14 (d, 1H, J¼18.8 Hz), 2.19 (d, 1H,
J¼18.8 Hz), 1.51–1.41 (m, 6H), 1.49 (s, 3H), 1.38–1.25 (m, 6H), 1.04–
0.81 (m, 24H), 0.03 (s, 6H), ꢀ0.03 (s, 6H); 13C NMR (100 MHz, CDCl3)
D
ꢀ55.1 (c 0.5, CH3OH); IR (KBr) 3288, 2997, 2941, 2902, 2123, 1743,
1658, 1566, 1446, 1385, 1233, 1203, 1134, 1051, 978, 918, 868, 825,
781, 721, 642 cmꢀ1; 1H NMR (400 MHz, CDCl3)
d
6.08 (s,1H), 4.31 (d,
as a keto–enol mixture, d 192.3, 169.4, 160.4, 153.1, 152.2, 141.8,
1H, J¼2.3 Hz), 2.49 (d, 1H, J¼2.3 Hz), 1.48 (s, 3H); 13C NMR
131.1, 128.8, 122.5, 87.1, 84.9, 81.9, 40.0, 29.0, 28.9, 27.4, 27.3, 25.8,
(100 MHz, CDCl3)
d
169.6, 143.9, 119.1, 85.6, 80.5, 74.8, 66.0, 20.9;
25.7, 24.5, 20.0, 18.1, 18.0, 13.6, 13.5, 12.4, 12.3, ꢀ4.3, ꢀ4.0, ꢀ5.2,
HRMS (FAB, m-NBAþNaI) [MþNa]þ calcd for C8H8O4Na: 191.0320,
ꢀ5.5; HRMS (FAB, m-NBAþNaI) [MþNa]þ
calcd for
found: 191.0325.
C26H50O4SiSnNa: 597.2398, found: 597.2404.
4.3.10. (S)-3-Hydroxy-5-[(R,E)-1-hydroxy-3-(tributylstannyl)allyl]-
5-methylfuran-2(5H)-one (3) and (S)-3-hydroxy-5-[(S)-1-hydroxy-
2-(tributylstannyl)allyl]-5-methylfuran-2(5H)-one (17)
4.3.12. (S)-3-(tert-Butyldimethylsilyloxy)-5-[(R)-1-(tert-butyl-
dimethylsilyloxy)prop-2-ynyl]-5-methylfuran-2(5H)-one (20)
To a solution of 14 (63.0 mg, 257
added TEMPO (8.03 mg, 51.4 mol) and trichloroisocyanuric acid
(59.7 mg, 257 mol) at room temperature. The resulting solution
mmol) in CH2Cl2 (2.6 mL) were
To a stirred solution of 16 (36.4 mg, 217
mmol) in THF (4.3 mL)
m
were added tributyltin hydride (120
mL, 0.43 mmol) and
m
PdCl2(PPh3)2 (4.4 mg, 10.8
m
mol). The resulting mixture was stirred
was stirred for 30 min and diluted with a saturated aqueous
NaHCO3 solution. The aqueous phase was extracted with CH2Cl2.
The combined organic extracts were dried over anhydrous Na2SO4
and concentrated in vacuo. The crude aldehyde 5 was subjected to
the next reaction without further purification.
for 30 min at room temperature and then concentrated in vacuo.
The residue was purified by column chromatography (7:1 hexanes/
EtOAc) to give 3 (38.9 mg, 39%) and 17 (30.0 mg, 30%) as white
solids.
Compound 3: see Section 4.3.15.
To a solution of 6 (201 mg, 646
LHMDS (1.0 M solution in THF, 590
m
mol) in THF (1.3 mL) was added
22
Compound 17: mp 69–72 ꢁC; [
a
]
ꢀ10.1 (c 0.5, CHCl3); IR
mL, 590
m
mol) at 0 ꢁC. After
D
(KBr) 3469, 3194, 3086, 2951, 2920, 2856, 1739, 1687, 1645, 1415,
1336, 1273, 1219, 1124, 1068, 1034, 985, 937, 785, 690 cmꢀ1 1H
NMR (400 MHz, CDCl3) enol
stirring for 30 min, a solution of the crude aldehyde 5 in THF
(1.3 mL) was slowly added dropwise over 30 min to the reaction
mixture at 0 ꢁC. After 5 min, the resulting solution was quenched
with a saturated aqueous NH4Cl solution and extracted with EtOAc.
The combined organic extracts were dried over anhydrous Na2SO4
and concentrated in vacuo. Flash chromatography (50:1 hexanes/
EtOAc) afforded 20 (76.4 mg, 75% for 2 steps) as a colorless oil.
;
d
9.75 (s, 1H), 6.38 (dd, 1H, J¼19.2,
1.3 Hz), 5.97 (dd, 1H, J¼19.2, 5.5 Hz), 4.20 (br d, 1H, J¼4.9 Hz),
1.55–1.42 (m, 6H), 1.45 (s, 3H), 1.39–1.25 (m, 6H), 0.94–0.83 (m,
6H), 0.89 (t, 9H, J¼7.2 Hz); ketone
d
6.50 (dd, 1H, J¼19.2, 1.5 Hz),
6.14 (s, 1H), 5.94 (dd, 1H, J¼19.2, 5.3 Hz), 4.31 (br d, 1H, J¼4.7 Hz),
3.00 (d, 1H, J¼18.8 Hz), 2.29 (d, 1H, J¼18.8 Hz), 1.57 (s, 3H), 1.55–
1.42 (m, 6H), 1.39–1.25 (m, 6H), 0.94–0.83 (m, 6H), 0.89 (t, 9H,
J¼7.2 Hz); 13C NMR (100 MHz, CDCl3) as a keto–enol mixture,
[
a23
1079, 842 cmꢀ1
]
D ꢀ65.2 (c 3.1, CHCl3); IR (KBr) 2933, 2858,1760, 1656, 1257, 1130,
;
1H NMR (270 MHz, CDCl3)
d
6.20 (s, 1H), 4.34 (d,
1H, J¼2.0 Hz), 2.48 (d, 1H, J¼2.0 Hz), 1.53 (s, 3H), 0.96 (s, 9H), 0.87
d
192.2, 169.4, 160.6, 143.6, 142.7, 142.5, 135.5, 133.5, 120.3, 86.8,
(s, 9H), 0.25 (s, 6H), 0.13 (s, 3H), 0.09 (s, 3H); 13C NMR (67.5 MHz,
84.3, 78.5, 78.3, 40.0, 29.0, 27.2, 23.5, 21.1, 13.7, 9.6; HRMS (FAB, m-
NBAþNaI) [MþNa]þ calcd for C20H36O4SnNa: 483.1533, found:
483.1534.
CDCl3) d 168.5, 143.4, 124.6, 84.3, 81.5, 74.7, 67.2, 25.5, 25.4, 20.9,
18.2, 18.0, ꢀ4.8, ꢀ4.9, ꢀ5.0, ꢀ5.3; HRMS (FAB, m-NBA) [MþH]þ
calcd for C20H37O4Si2: 397.2230, found: 397.2227.

8124
T. Nagamitsu et al. / Tetrahedron 64 (2008) 8117–8127
4.3.13. (S)-5-[(R)-3-Bromo-1-(tert-butyldimethylsilyloxy)prop-2-
ynyl]-3-(tert-butyldimethylsilyloxy)-5-methylfuran-2(5H)-one (21)
4.25 (d, 1H, J¼7.3 Hz), 2.43–2.36 (m, 1H), 2.12–1.91 (m, 3H), 1.70 (s,
3H), 1.46 (s, 3H), 1.32 (m, 2H), 0.99 (d, 3H, J¼6.6 Hz), 0.97 (s, 3H,
To a stirred solution of 20 (227 mg, 573
(5.7 mL) were added NBS (111 mg, 631 mol) and silver(I) nitrate
(11.0 mg, 57.3 mol). The resulting solution was stirred for 1 h at
mmol) in acetone
J¼6.7 Hz), 0.86 (t, 3H, J¼7.6 Hz); ketone
d
6.30 (dd, 1H, J¼15.5,
m
10.2 Hz), 6.18 (dd, 1H, J¼14.8, 10.9 Hz), 6.00 (dd, 1H, J¼15.5,
10.2 Hz), 5.76 (d, 1H, J¼10.9 Hz), 5.70 (dd, 1H, J¼15.5, 7.3 Hz), 5.50
(dd, 1H, J¼15.5, 7.3 Hz), 5.46 (dd, 1H, J¼14.8, 7.6 Hz), 4.21 (m, 1H),
3.03 (d, 1H, J¼18.8 Hz), 2.43–2.36 (m, 1H), 2.32 (d, 1H, J¼18.8 Hz),
2.12–1.91 (m, 3H), 1.70 (s, 3H), 1.54 (s, 3H), 1.32 (m, 2H), 0.99 (d, 3H,
J¼6.6 Hz), 0.97 (s, 3H, J¼6.7 Hz), 0.86 (t, 3H, J¼7.6 Hz); HRMS (FAB,
m-NBA) [MþH]þ calcd for C22H33O4: 361.2379, found: 361.2372.
m
room temperature, filtered through a pad of silica gel, and con-
centrated in vacuo. The residue was purified by column chroma-
tography (50:1 hexanes/EtOAc) to give 21 (272 mg, 100%) as
23
a colorless oil. [
a
]
ꢀ52.8 (c 2.7, CHCl3); IR (KBr) 2931, 2859, 1753,
D
1652, 1259, 1078 cmꢀ1
4.34 (s, 1H), 1.51 (s, 3H), 0.96 (s, 9H), 0.86 (s, 9H), 0.24 (s, 6H), 0.11 (s,
3H), 0.07 (s, 3H); 13C NMR (67.5 MHz, CDCl3)
168.4, 143.4, 124.8,
; d 6.16 (s, 1H),
1H NMR (270 MHz, CDCl3)
d
4.4. Synthesis of nafuredin analogues 23, 24, and 25
84.2, 77.8, 68.4, 46.9, 25.5, 25.4, 20.9, 18.2, 18.0, ꢀ4.8, ꢀ4.9, ꢀ5.0,
ꢀ5.3; HRMS (FAB, m-NBAþNaI) [MþNa]þ calcd for C20H35O4Br-
Si2Na: 497.1154, found: 497.1173.
4.4.1. Synthesis of 26, 27, and 28
These compounds were prepared according to the syntheses of
8, 10, and 12.
4.3.14. (S)-5-[(R)-3-Bromo-1-hydroxyprop-2-ynyl]-3-hydroxy-5-
methylfuran-2(5H)-one (22)
4.4.2. (R)-2-[(2R,3R)-3-(Chloromethyl)oxiran-2-yl]-2-methyl-1,4-
dioxaspiro[4.4]nonane (29)
To a stirred solution of 21 (273 mg, 576 mmol) in THF (6 mL) was
added HF$pyridine (2 mL). The resulting solution was stirred for
24 h at room temperature, filtered through a pad of silica gel, and
concentrated in vacuo. The residue was purified by column chro-
According to the conversion of 12 into 7, 28 (537 mg, 2.71 mmol)
gave 29 (541 mg, 86% for 2 steps) as a colorless oil. 1H NMR
(270 MHz, CDCl3)
d
3.90 (d, 1H, J¼8.9 Hz), 3.63 (dd, 1H, J¼11.5,
matography (2:1 hexanes/EtOAc) to give 22 (142 mg, 100%) as
6.4 Hz), 3.61 (d, 1H, J¼8.9 Hz), 3.52 (dd, 1H, J¼11.5, 6.4 Hz), 3.28 (dt,
1H, J¼6.4, 2.0 Hz), 2.90 (d, 1H, J¼2.0 Hz), 1.78–1.56 (m, 8H), 1.33 (s,
3H).
23
a colorless oil. [
a
]
ꢀ30.7 (c 1.0, MeOH); IR (KBr) 3322, 3153, 2991,
D
2877, 1743, 1662, 1201, 1132, 1018 cmꢀ1; 1H NMR (270 MHz, CDCl3)
enol 6.21 (s, 1H), 4.46 (s, 1H), 1.07 (s, 3H); ketone 4.53 (s, 1H),
d
d
3.25 (d, 1H, J¼19.1 Hz), 2.49 (d, 1H, J¼19.1 Hz), 1.59 (s, 3H); HRMS
(FAB, m-NBAþNaI) [MþNa]þ calcd for C8H7O4BrNa: 268.9425,
found: 268.9417.
4.4.3. (R)-1-[(R)-2-Methyl-1,4-dioxaspiro[4.4]nonan-2-yl]prop-2-
yn-1-ol (30)
According to the conversion of 7 into 13, 29 (541 mg, 2.33 mmol)
afforded 30 (453 mg, 99%) as a colorless oil. 1H NMR (270 MHz,
4.3.15. (S)-3-Hydroxy-5-[(R,E)-1-hydroxy-3-(tributylstannyl)allyl]-
5-methylfuran-2(5H)-one (3)
CDCl3)
d
4.31 (dd, 1H, J¼4.6, 2.2 Hz), 4.03 (d, 1H, J¼8.9 Hz), 3.68 (d,
1H, J¼8.9 Hz), 2.46 (d, 1H, J¼2.2 Hz), 2.39 (d, 1H, J¼4.6 Hz), 1.84–
To a stirred solution of 22 (48.0 mg, 195
mmol) in THF (2 mL) was
1.59 (m, 8H), 1.42 (s, 3H).
added tributyltin hydride (500 L, 1.85 mmol). The resulting mix-
m
ture was stirred for 30 min at room temperature and then con-
centrated in vacuo. The residue was purified by column
4.4.4. (2R,3R)-3-(tert-Butyldimethylsilyloxy)-2-methylpent-4-yne-
1,2-diol (31)
chromatography (7:1 hexanes/EtOAc) to give 3 (63.8 mg, 71%) as
According to the conversion of 13 into 14, 30 (454 mg,
2.32 mmol) furnished 31 (435 mg, 77% for 2 steps) as a colorless oil.
22
a white solid. Mp 78–80 ꢁC; [
a
]
ꢀ32.9 (c 0.5, CHCl3); IR (KBr) 3539,
D
3454, 3369, 3140, 3074, 2920, 2858, 1732, 1653, 1458, 1377, 1294,
1201, 1144, 1061, 993, 870, 787, 673 cmꢀ1 1H NMR (400 MHz,
CDCl3) enol
1H NMR (270 MHz, CDCl3)
d
4.42 (d, 1H, J¼2.2 Hz), 3.68 (dd, 1H,
;
J¼11.4, 6.3 Hz), 3.56 (dd, 1H, J¼11.4, 5.3 Hz), 2.61 (s, 1H), 2.48 (d, 1H,
J¼2.2 Hz), 2.07 (br s, 1H), 1.21 (s, 3H), 0.92 (s, 9H), 0.20 (s, 3H), 0.16
(s, 3H).
d
9.75 (s, 1H), 6.38 (dd, 1H, J¼19.2, 1.3 Hz), 5.97 (dd, 1H,
J¼19.2, 5.5 Hz), 4.20 (br d, 1H, J¼4.9 Hz), 1.55–1.42 (m, 6H), 1.45 (s,
3H), 1.39–1.25 (m, 6H), 0.94–0.83 (m, 6H), 0.89 (t, 9H, J¼7.2 Hz);
ketone
d
6.50 (dd, 1H, J¼19.2, 1.5 Hz), 6.14 (s, 1H), 5.94 (dd, 1H,
4.4.5. (R)-3-Hydroxy-5-[(R)-1-hydroxyprop-2-ynyl]-5-
methylfuran-2(5H)-one (32)
To a solution of 31 (436 mg,1.79 mmol) in CH2Cl2 (17.8 mL) were
added TEMPO (5.60 mg, 35.7 mmol) and trichloroisocyanuric acid
(415 mg, 1.79 mmol) at 0 ꢁC. After 35 min at 0 ꢁC, the reaction
mixture was filtered through a pad of Celite and concentrated in
vacuo. This crude aldehyde was employed in the next reaction
without further purification.
J¼19.2, 5.3 Hz), 4.31 (br d, 1H, J¼4.7 Hz), 3.00 (d, 1H, J¼18.8 Hz),
2.29 (d, 1H, J¼18.8 Hz), 1.57 (s, 3H), 1.55–1.42 (m, 6H), 1.39–1.25 (m,
6H), 0.94–0.83 (m, 6H), 0.89 (t, 9H, J¼7.2 Hz); 13C NMR (100 MHz,
CDCl3) as a keto–enol mixture,
d
192.2, 169.4, 160.6, 143.6, 142.7,
142.5, 135.5, 133.5, 120.3, 86.8, 84.3, 78.5, 78.3, 40.0, 29.0, 27.2, 23.5,
21.1, 13.7, 9.6; HRMS (FAB, m-NBAþNaI) [MþNa]þ calcd for
C
20H36O4SnNa: 483.1533, found: 483.1528.
To a solution of 6 (1.40 g, 4.46 mmol) in THF (17.8 mL) was added
LHMDS (1.0 M solution in THF, 4.12 mL, 4.12 mmol) at 0 ꢁC. After
stirring for 30 min, a solution of the crude aldehyde in THF
(17.8 mL) was slowly added dropwise over 30 min to the reaction
mixture at 0 ꢁC. After 10 min, the reaction mixture was quenched
with a saturated aqueous NH4Cl solution and extracted with EtOAc.
The combined organic extracts were dried over anhydrous Na2SO4
and concentrated in vacuo. This crude lactone was employed in the
next reaction without further purification.
A solution of the crude lactone in THF (8.8 mL) was treated with
HF$pyridine (200 mL) and stirred for 24 h at room temperature. The
resulting mixture was filtered through a pad of silica gel and con-
centrated in vacuo. Flash chromatography (1:1 hexanes/EtOAc)
afforded 32 (155 mg, 52% for 3 steps) as a colorless oil. 1H NMR
4.3.16. Nafuredin-
To a stirred solution of 3 (16.4 mg, 35.6
46.3 mol) in N-methyl pyrrolidinone (NMP) (500
bisacetonitriledichloropalladium (1.00 mg, 3.85
g (2)
m
mol) and 4 (14.7 mg,
L) was added
mol). The result-
m
m
m
ing mixture was stirred for 30 min at 50 ꢁC, quenched with a satu-
rated aqueous NH4Cl solution, and extracted with EtOAc. The
combined organic extracts were dried over anhydrous Na2SO4 and
concentrated in vacuo. Flash chromatography (4:1 hexanes/EtOAc)
25
afforded 2 (9.24 mg, 72%) as a colorless oil. [
a
]
þ4.0 (c 0.1,
D
CHCl3); IR (KBr) 3374, 2960, 2925, 2858, 1754, 1737, 1660, 1261,
1101 cmꢀ1 1H NMR (270 MHz, CDCl3) enol
;
d
6.30 (dd, 1H, J¼15.5,
10.2 Hz), 6.18 (dd, 1H, J¼14.8, 10.9 Hz), 6.15 (s, 1H), 6.00 (dd, 1H,
J¼15.5, 10.2 Hz), 5.76 (d, 1H, J¼10.9 Hz), 5.70 (dd, 1H, J¼15.5,
7.3 Hz), 5.50 (dd, 1H, J¼15.5, 7.3 Hz), 5.46 (dd, 1H, J¼14.8, 7.6 Hz),
(270 MHz, CDCl3) enol
d 6.25 (s, 1H), 4.36 (s, 1H), 2.56 (d, 1H,

T. Nagamitsu et al. / Tetrahedron 64 (2008) 8117–8127
8125
J¼2.0 Hz),1.62 (s, 3H); ketone
d
4.42 (m, 1H), 3.31 (d, 1H, J¼19.4 Hz),
126.9, 126.8, 125.9, 125.2, 124.7, 120.7, 87.3, 83.2, 78.2, 77.4, 47.4,
47.3, 43.8, 38.6, 34.8, 29.8, 29.7, 23.4, 20.2, 19.8, 19.6, 16.5, 11.8;
HRMS (FAB, m-NBA) [MþNa]þ calcd for C22H32O4Na: 383.2198,
found: 383.2192.
2.63 (d, 1H, J¼2.0 Hz), 2.55 (d, 1H, J¼19.4 Hz), 1.72 (s, 3H).
4.4.6. (R)-3-(tert-Butyldiphenylsilyloxy)-5-[(R,E)-1-hydroxy-3-
(tributylstannyl)allyl]-5-methylfuran-2(5H)-one (33)
To a solution of 32 (155 mg, 0.92 mmol) in THF (9.2 mL) were
added Et3N (193 mL, 1.39 mmol) and TBDPSCl (288 mL, 1.11 mmol) at
4.4.8. (S)-2-[(2S,3S)-3-(Chloromethyl)oxiran-2-yl]-2-methyl-1,4-
dioxaspiro[4.4]nonane (34)
room temperature. The reaction mixture was stirred for 40 min,
quenched with a saturated aqueous NH4Cl solution, and extracted
with EtOAc. The combined organic extracts were dried over anhy-
drous Na2SO4 and concentrated in vacuo. Flash chromatography
(5:1 hexanes/EtOAc) afforded the corresponding TBDPS enol ether
According to the conversion of 12 into 7, 12 (2.17 g, 10.9 mmol)
was subjected to Sharpless epoxidation using (ꢀ)-DET followed by
chlorination to afford 34 (2.34 g, 92% for 2 steps) as a yellow oil. 1H
NMR (270 MHz, CDCl3)
d
3.91 (d, 1H, J¼8.9 Hz), 3.74 (dd, 1H, J¼11.5,
5.3 Hz), 3.62 (d, 1H, J¼8.9 Hz), 3.51 (dd, 1H, J¼11.5, 5.3 Hz), 3.28
(ddd, 1H, J¼10.7, 5.3, 1.7 Hz), 2.89 (d, 1H, J¼1.7 Hz), 1.86–1.56 (m,
8H), 1.33 (s, 3H).
(210 mg, 56%) as a colorless oil. 1H NMR (270 MHz, CDCl3)
d 7.71–
7.40 (m, 10H), 5.62 (s, 1H), 4.04 (d, 1H, J¼2.3 Hz), 2.35 (d, 1H,
J¼2.3 Hz), 1.33 (s, 3H), 1.13 (s, 9H).
The TBDPS enol ether (210 mg, 0.52 mmol) was dissolved in THF
4.4.9. (S)-1-[(S)-2-Methyl-1,4-dioxaspiro[4.4]nonan-2-yl]prop-2-
yn-1-ol (35)
(4.9 mL) and treated with PdCl2(PPh3)2 (10.1 mg, 24.4
mmol) and
Bu3SnH (262
m
L, 0.974 mmol) at 0 ꢁC. After 1 h, the reaction mixture
According to the conversion of 29 into 30, 34 (2.34 g, 10.1 mmol)
was quenched with H2O and extracted with EtOAc. The combined
organic extracts were dried over anhydrous Na2SO4 and concen-
trated in vacuo. Flash chromatography (50:1 hexanes/EtOAc)
gave 35 (1.92 g, 97%) as a yellow oil. 1H NMR (270 MHz, CDCl3)
d
4.31 (dd, 1H, J¼4.6, 2.0 Hz), 4.03 (d, 1H, J¼8.9 Hz), 3.68 (d, 1H,
J¼8.9 Hz), 2.45 (d, 1H, J¼2.0 Hz), 2.39 (d, 1H, J¼4.6 Hz), 1.84–1.67
24
afforded 33 (303 mg, 47%) as a white solid. Mp 49–50 ꢁC; [
a]
D
þ31.4
(m, 8H), 1.42 (s, 3H).
(c 0.5, CHCl3); IR (KBr) 3427, 2924, 2858, 1749, 1647, 1462, 1433,
1238, 1200, 1109, 1068, 833, 754, 702 cmꢀ1 1H NMR (400 MHz,
CDCl3)
;
4.4.10. (2S,3S)-3-(tert-Butyldimethylsilyloxy)-2-methylpent-4-yne-
1,2-diol (36)
d
7.73–7.67 (m, 4H), 7.50–7.38 (m, 6H), 5.96 (dd, 1H, J¼19.0,
1.0 Hz), 5.60 (dd, 1H, J¼19.0, 6.0 Hz), 5.50 (s, 1H), 3.67 (m, 1H), 2.02
(d, 1H, J¼3.0 Hz), 1.46–1.36 (m, 6H), 1.29–1.19 (m, 6H), 1.16 (s, 3H),
According to the conversion of 30 into 31, 35 (1.92 g, 9.79 mmol)
gave 36 (1.98 g, 83% for 2 steps) as a yellow oil. 1H NMR (270 MHz,
1.12 (s, 9H), 0.88–0.80 (m, 15H); 13C NMR (100 MHz, CDCl3)
d
168.3,
CDCl3)
d
4.42 (d, 1H, J¼2.3 Hz), 3.68 (dd, 1H, J¼11.3, 6.9 Hz), 3.55
143.4, 142.3, 135.5, 135.4, 134.1, 130.5, 130.4, 128.0, 127.6, 85.3, 80.1,
29.0, 27.1, 26.2, 19.4, 18.7, 13.6, 9.4; HRMS (FAB, m-NBAþNaI)
[MþNa]þ calcd for C36H54O4SiSnNa: 721.2711, found: 721.2700.
(dd,1H, J¼11.3, 5.9 Hz), 2.60 (s, 1H), 2.48 (d, 1H, J¼2.3 Hz), 2.11–2.04
(m, 1H), 1.24 (s, 3H), 0.92 (s, 9H), 0.20 (s, 3H), 0.16 (s, 3H).
4.4.11. (S)-3-Hydroxy-5-[(S)-1-hydroxyprop-2-ynyl]-5-
methylfuran-2(5H)-one (37)
4.4.7. C4-epimer (23)
To a solution of 33 (65.2 mg, 93.3 mmol) in NMP (2 mL) were
According to the conversion of 31 into 32, 36 (1.03 g, 4.22 mmol)
added 4 (39.0 mg, 0.123 mmol) and PdCl2(MeCN)2 (2.40 mg,
mol). After stirring for 1.5 h at 50 ꢁC, the reaction mixture was
gave 37 (347 mg, 49% for 3 steps) as a yellow oil. 1H NMR (270 MHz,
9.43
m
CDCl3) d 6.25 (s, 1H, enol), 4.42 (br s, 1H, ketone), 4.36 (br s, 1H,
quenched with H2O and extracted with EtOAc. The combined or-
ganic extracts were dried over anhydrous Na2SO4 and concentrated
in vacuo. Flash chromatography (20:1 hexanes/EtOAc) afforded the
corresponding coupling product (17.9 mg, 32%) as a colorless oil. 1H
enol), 3.13 (d, 1H, J¼19.3 Hz, ketone), 2.56 (d, 1H, J¼2.0 Hz), 2.54 (d,
1H, J¼19.3 Hz, ketone), 1.71 (s, 3H).
4.4.12. (S)-3-(tert-Butyldiphenylsilyloxy)-5-[(S,E)-1-hydroxy-3-
(tributylstannyl)allyl]-5-methylfuran-2(5H)-one (38)
NMR (270 MHz, CDCl3)
d 7.71–7.41(m, 10H), 6.25 (m, 1H), 6.18 (m,
1H), 6.17 (s, 1H), 6.01 (m, 1H), 5.74 (d, 1H, J¼10.7 Hz), 5.59 (m, 1H),
5.58 (m, 1H), 5.39 (m, 1H), 4.10 (m, 1H), 2.40 (m, 1H), 2.31 (m, 1H),
1.93 (m, 2H), 1.67 (s, 3H), 1.32 (s, 3H), 1.25 (m, 2H), 0.93 (d, 3H,
J¼6.6 Hz), 0.90 (d, 3H, J¼6.8 Hz), 0.80 (t, 3H, J¼7.4 Hz), 0.79 (s, 9H).
The coupling product (17.9 mg, 29.9 mmol) was dissolved in THF
According to the conversion of 32 into 33, 37 (199 mg,
1.18 mmol) gave 38 (389 mg, 47% for 2 steps) as a white solid. Mp
23
61–62 ꢁC; [
a]
D
ꢀ37.5 (c 0.5, CHCl3); IR (KBr) 3425, 2954, 2924, 2858,
1749, 1645, 1462, 1431, 1240, 1198, 1109, 1068, 833, 754, 702 cmꢀ1
;
1H NMR (400 MHz, CDCl3)
d
7.73–7.67 (m, 4H), 7.50–7.38 (m, 6H),
(5 mL) and treated with HF$pyridine (200
at room temperature, the resulting mixture was filtered through
a pad of silica gel and concentrated in vacuo. Flash chromatography
m
L). After stirring for 24 h
5.96 (dd, 1H, J¼19.0, 1.0 Hz), 5.60 (dd, 1H, J¼19.0, 6.0 Hz), 5.50 (s,
1H), 3.67 (m, 1H), 2.02 (d, 1H, J¼3.0 Hz), 1.46–1.36 (m, 6H), 1.29–1.19
(m, 6H), 1.16 (s, 3H), 1.12 (s, 9H), 0.88–0.80 (m, 15H); 13C NMR
(4:1 hexanes/EtOAc) afforded the C4-epimer (23) (9.20 mg, 85%) as
(100 MHz, CDCl3) d 168.3, 143.4, 142.3, 135.5, 135.4, 134.1, 130.5,
27
a colorless oil. [
a
]
þ114.3 (c 0.52, CHCl3); IR (KBr) 3446, 2961, 2925,
130.4, 128.0, 127.6, 85.3, 80.1, 29.0, 27.1, 26.2, 19.4, 18.7, 13.6, 9.4;
HRMS (FAB, m-NBAþNaI) [MþNa]þ calcd for C36H54O4SiSnNa:
721.2711, found: 721.2719.
D
2860, 2360, 2300, 1749, 1717, 1698, 1683, 1653, 1636, 1558, 1540,
1521, 1507, 1488, 1456, 1418, 1376, 1203, 1130, 1078, 991, 970 cmꢀ1
1H NMR (600 MHz, CDCl3) enol
;
d
6.27 (dd, 1H, J¼15.5, 10.4 Hz), 6.17
(dd, 1H, J¼15.2, 11.1 Hz), 6.15 (s, 1H), 6.00 (dd, 1H, J¼15.2, 10.4 Hz),
5.76 (d, 1H, J¼11.1 Hz), 5.69 (dd, 1H, J¼15.2, 7.3 Hz), 5.50–5.43 (m,
2H), 4.12 (d, 1H, J¼8.0 Hz), 2.46–2.37 (m, 1H), 2.12–1.94 (m, 3H),
1.70 (s, 3H), 1.47 (s, 3H), 1.32 (m, 2H), 0.99 (d, 3H, J¼6.6 Hz), 0.97 (d,
4.4.13. C5-epimer (24)
To a solution of 38 (35.3 mg, 0.051 mmol) in NMP (1.01 mL)
were added 4 (20.9 mg, 0.066 mmol) and PdCl2(MeCN)2 (1.31 mg,
5.00 m
mol). After stirring for 4 h at 50 ꢁC, the reaction mixture was
quenched with H2O and extracted with EtOAc. The combined or-
ganic extracts were dried over anhydrous Na2SO4 and concentrated
in vacuo. Flash chromatography (20:1 hexanes/EtOAc) afforded the
corresponding coupling product (8.50 mg, 28%) as a colorless oil. 1H
3H, J¼6.8 Hz), 0.86 (t, 3H, J¼7.4 Hz); ketone
d
6.27 (dd, 1H, J¼15.5,
10.4 Hz), 6.17 (dd, 1H, J¼15.2, 11.1 Hz), 6.00 (dd, 1H, J¼15.2, 10.4 Hz),
5.76 (d, 1H, J¼11.1 Hz), 5.69 (dd, 1H, J¼15.2, 7.3 Hz), 5.50–5.43 (m,
2H), 4.06 (d, 1H, J¼8.0 Hz), 3.08 (d, 1H, J¼18.6 Hz), 2.51 (d, 1H,
J¼18.6 Hz), 2.46–2.37 (m,1H), 2.12–1.94 (m, 3H), 1.70 (s, 3H), 1.53 (s,
3H), 1.32 (m, 2H), 0.99 (d, 3H, J¼6.6 Hz), 0.97 (d, 3H, J¼6.8 Hz), 0.86
(t, 3H, J¼7.4 Hz); 13C NMR (150 MHz, CDCl3) as a keto–enol mixture,
NMR (270 MHz, CDCl3)
d 7.70 (m, 4H), 7.48–7.41 (m, 6H), 6.24–6.15
(dd, 1H, J¼15.0, 10.2 Hz), 5.90–5.82 (m, 2H), 5.77 (d, 1H, J¼10.2 Hz),
5.63–5.54 (dd, 1H, J¼14.8, 7.3 Hz), 5.51 (s, 1H), 5.51–5.43 (dd, 1H,
J¼15.3, 7.8 Hz), 5.17–5.09 (dd, 1H, J¼14.2, 6.9 Hz), 3.73 (d, 1H,
d
191.9, 160.6, 144.0, 143.0, 138.8, 138.7, 137.5, 135.4, 134.0, 133.9,

8126
T. Nagamitsu et al. / Tetrahedron 64 (2008) 8117–8127
J¼7.3 Hz), 2.38 (m, 1H), 2.05 (m, 1H), 1.94 (m, 1H), 1.71 (s, 3H), 1.62
(m, 1H), 1.35–1.26 (m, 2H), 1.20 (s, 3H), 1.12 (s, 9H), 0.99 (d, 3H,
J¼6.9 Hz), 0.95 (d, 3H, J¼6.6 Hz), 0.86 (t, 3H, J¼7.1 Hz).
122.7, 89.7, 79.8, 76.0, 65.9, 20.0; HRMS (FAB, m-NBA) [MþH]þ calcd
for C8H9O3: 153.0552, found: 153.0553.
The coupling product (22.3 mg, 37.0
m
mol) was dissolved in THF
4.4.15. (S)-5-[(R,E)-1-Hydroxy-3-(tributylstannyl)allyl]-5-
methylfuran-2(5H)-one (40)
(373 mL) and treated with HF$pyridine (200 mL). After stirring for
24 h at room temperature, the resulting mixture was filtered
through a pad of silica gel and concentrated in vacuo. Flash chro-
To a solution of 39 (79.0 mg, 0.52 mmol) and PdCl2(PPh3)2
(10.7 mg, 26.0
mmol) in THF (5.2 mL) was added dropwise Bu3SnH
matography (4:1 hexanes/EtOAc) afforded the C5-epimer (24)
(420 L, 1.56 mmol) at room temperature. After 10 min, the
resulting mixture was quenched with H2O and extracted with
EtOAc. The combined organic extracts were dried over anhydrous
m
27
(11.2 mg, 84%) as a colorless oil. [
a
]
þ46.0 (c 1.12, CHCl3); IR (KBr)
D
3566, 2962, 2924, 2860, 2360, 2342, 1771, 1750, 1717, 1699, 1684,
1653, 1636, 1558, 1540, 1521, 1507, 1489, 1457, 1418, 1396, 1203,
Na2SO4 and concentrated in vacuo. Flash chromatography (5:1
24
1130, 1064, 991 cmꢀ1
;
1H NMR (600 MHz, CDCl3) enol
d
6.27 (dd,
hexanes/EtOAc) afforded 40 (157 mg, 68%) as a colorless oil. [a]
D
1H, J¼15.3, 10.5 Hz), 6.18 (dd, 1H, J¼15.0, 10.8 Hz), 6.13 (s, 1H), 6.01
(dd,1H, J¼15.0,10.5 Hz), 5.76 (d,1H, J¼11.0 Hz), 5.65 (dd,1H, J¼15.0,
8.5 Hz), 5.55–5.43 (m, 2H), 4.08 (d,1H, J¼8.0 Hz), 2.45–2.39 (m,1H),
2.15–1.92 (m, 3H), 1.71 (s, 3H), 1.46 (s, 3H), 1.32 (m, 2H), 0.99 (d, 3H,
J¼6.5 Hz), 0.97 (d, 3H, J¼6.5 Hz), 0.86 (t, 3H, J¼7.4 Hz); ketone
ꢀ35.0 (c 0.5, CHCl3); IR (KBr) 3458, 2920, 2858, 1753, 1458, 1377,
1288, 1242, 1176, 1107, 999, 960, 877, 822, 683 cmꢀ1 1H NMR
(400 MHz, CDCl3)
1.5 Hz), 6.08 (d, 1H, J¼5.8 Hz), 6.01 (dd, 1H, J¼19.2, 5.3 Hz), 4.19 (m,
1H), 2.33 (br d, 1H, J¼5.1 Hz), 1.76–1.44 (m, 6H), 1.44 (s, 3H), 1.42–
1.24 (m, 6H), 0.92–0.86 (m, 15H); 13C NMR (100 MHz, CDCl3)
;
d
7.42 (d, 1H, J¼5.8 Hz), 6.38 (dd, 1H, J¼19.2,
d
6.27 (dd, 1H, J¼15.3, 10.5 Hz), 6.18 (dd, 1H, J¼15.0, 10.8 Hz), 6.01
(dd,1H, J¼15.0,10.5 Hz), 5.76 (d,1H, J¼11.0 Hz), 5.65 (dd,1H, J¼15.0,
8.5 Hz), 5.55–5.43 (m, 2H), 4.06 (d, 1H, J¼8.0 Hz), 3.07 (d, 1H,
J¼18.6 Hz), 2.51 (d, 1H, J¼18.6 Hz), 2.45–2.39 (m, 1H), 2.15–1.92 (m,
3H), 1.71 (s, 3H), 1.52 (s, 3H), 1.32 (m, 2H), 0.99 (d, 3H, J¼6.5 Hz),
0.97 (d, 3H, J¼6.5 Hz), 0.86 (t, 3H, J¼7.4 Hz); 13C NMR (150 MHz,
d 172.4, 158.4, 143.6, 133.2, 121.7, 90.3, 77.8, 29.0, 27.2, 19.7, 13.6, 9.5;
HRMS (FAB, m-NBA) [MþH]þ calcd for C20H37O3Sn: 445.1765,
found: 445.1769.
4.4.16. 2-Dehydroxy-a,b-unsaturated lactone (25)
CDCl3) as a keto–enol mixture,
d
191.9, 160.7, 143.9, 142.9, 138.7,
To a solution of 40 (89.7 mg, 0.202 mmol) in NMP (2.00 mL)
were added 4 (83.5 mg, 0.263 mmol) and PdCl2(MeCN)2 (5.20 mg,
20.6 m
mol). After stirring for 1.5 h at 50 ꢁC, the reaction mixture was
quenched with H2O and extracted with EtOAc. The combined or-
ganic extracts were dried over anhydrous Na2SO4 and concentrated
in vacuo. Flash chromatography (3:1 hexanes/EtOAc) afforded the
138.6, 137.4, 135.4, 134.0, 133.8, 126.9, 126.7, 126.6, 125.9, 125.2,
124.7, 120.9, 87.3, 83.3, 78.1, 77.4, 47.4, 47.3, 43.8, 38.6, 34.8, 29.8,
29.7, 23.4, 20.2, 19.7, 19.5, 16.5, 11.8; HRMS (FAB, m-NBA) [MþNa]þ
calcd for C22H32O4Na: 383.2198, found: 383.2195.
4.4.14. (S)-5-[(R)-1-Hydroxyprop-2-ynyl]-5-methylfuran-2(5H)-
one (39)
2-dehydroxy-
a
,
b
-unsaturated lactone (25) (50.9 mg, 70%) as a col-
27
orless oil. [
2360, 1750, 1653, 1558, 1540, 1507, 1488, 1456, 1376, 1237, 1110, 992,
966, 818 cmꢀ1 1H NMR (600 MHz, CDCl3)
7.40 (d, 1H, J¼6.0 Hz),
a]
ꢀ8.5 (c 2.1, CHCl3); IR (KBr) 3446, 2961, 2924, 2872,
D
To a solution of 14 (228 mg, 0.932 mmol) in CH2Cl2 (9.3 mL)
were added TEMPO (2.90 mg, 18.7
mmol) and trichloroisocyanuric
;
d
acid (217 mg, 0.932 mmol) at 0 ꢁC. After stirring for 1 h, the
resulting mixture was filtered through a pad of Celite and the fil-
trate was washed with a saturated aqueous NaHCO3 solution. The
organic layers were dried over anhydrous Na2SO4 and concentrated
in vacuo. This crude aldehyde was employed in the next reaction
without further purification.
6.30 (dd, 1H, J¼15.2, 10.5 Hz), 6.17 (dd, 1H, J¼15.0, 11.08 Hz), 6.09 (d,
1H, J¼6.0 Hz), 6.00 (dd, 1H, J¼15.2, 10.5 Hz), 5.76 (d, 1H, J¼10.9 Hz),
5.69 (dd, 1H, J¼15.2, 7.3 Hz), 5.54 (dd, 1H, J¼15.2, 6.6 Hz), 5.45 (dd,
1H, J¼15.0, 7.7 Hz), 4.25 (d, 1H, J¼6.7 Hz), 2.45–2.37 (m, 1H), 2.11–
2.03 (m, 1H), 1.96 (dd, 2H, J¼13.4, 7.8 Hz), 1.70 (s, 3H), 1.46 (s, 3H),
1.35–1.29 (m, 2H), 0.99 (d, 3H, J¼6.8 Hz), 0.97 (d, 3H, J¼6.7 Hz), 0.86
To a solution of (CF3CH2O)2P(O)CH2CO2Me (400
mL, 1.86 mmol)
(t, 3H, J¼7.4 Hz); 13C NMR (150 MHz, CDCl3)
d 172.3, 158.0, 142.8,
was added LHMDS (1.60 mL, 1.60 mmol) at 0 ꢁC. After 30 min,
a solution of the crude aldehyde was added dropwise to the
resulting mixture at 0 ꢁC. The reaction mixture was stirred for
10 min, quenched with saturated aqueous NH4Cl solution, and
extracted with EtOAc. The combined organic extracts were dried
over anhydrous Na2SO4 and concentrated in vacuo. Flash chroma-
138.7, 134.7, 134.0, 126.9, 126.8, 126.2, 124.7, 121.9, 90.6, 75.7, 47.4,
38.6, 34.8, 29.8, 20.2, 20.1, 19.6, 16.5, 11.8; HRMS (FAB, m-NBA)
[MþNa]þ calcd for C22H32O3Na: 367.2249, found: 367.2250.
Acknowledgements
tography (40:1 hexanes/EtOAc) afforded the corresponding
unsaturated lactone (139 mg, 56% for 2 steps) as a colorless oil. [
a,b-
This study was supported in part by a grant from the 21st
Century COE Program, Ministry of Education, Culture, Sports, Sci-
ence, and Technology, Japan. We thank Ms. N. Sato (Kitasato Uni-
versity) for kindly measuring NMR spectra. T.N. acknowledges
a Kitasato University research grant for young researchers.
23
a
]
D
ꢀ175.9 (c 0.5, CHCl3); IR (KBr) 2945, 2864, 1768, 1254, 1113, 976,
843, 783, 675 cmꢀ1 1H NMR (400 MHz, CDCl3)
;
d
7.46 (d, 1H,
J¼5.7 Hz), 6.12 (d, 1H, J¼5.7 Hz), 4.43 (d, 1H, J¼2.2 Hz), 2.54 (d, 1H,
J¼2.2 Hz),1.57 (s, 3H), 0.87 (s, 9H), 0.14 (s, 3H), 0.09 (s, 3H); 13C NMR
(100 MHz, CDCl3)
d 172.0, 156.9, 122.5, 89.7, 81.1, 75.1, 66.6, 25.5,
References and notes
19.8, 18.0, ꢀ5.1, ꢀ5.4; HRMS (FAB, m-NBA) [MþH]þ calcd for
C
14H23O3Si: 267.1416, found: 267.1418.
ꢀ
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