Ring-closing metathesis and palladium-catalyzed formate reduction to 3-methyleneoxepanes. Formal synthesis of (-)-zoapatanol

Article abstract of DOI:10.1016/j.tet.2011.10.023

A sequence of ring-closing metathesis and palladium-catalyzed formate reduction was developed for preparing O-heterocycles with an exocyclic olefin and applied to the asymmetric synthesis of zoapatanol. The key vicinal stereocenters in zoapatanol were constructed from the l-malic acid-derived lactone by successive chelation-controlled addition of alkyl groups. The O-allylations to prepare the dienes for RCM were achieved with the tertiary alcohols bearing internal olefins. The ring opening of oxepane, a new reaction pathway for the Pd-formate reduction, is also reported.

Full text of DOI:10.1016/j.tet.2011.10.023

Tetrahedron 68 (2012) 747e753
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Ring-closing metathesis and palladium-catalyzed formate reduction
to 3-methyleneoxepanes. Formal synthesis of (ꢀ)-zoapatanol
Hsiu-Yi Cheng, Yu-Shiang Lin, Chong-Si Sun, Ting-Wen Shih, Hui-Hsu Gavin Tsai, Duen-Ren Hou
*
Department of Chemistry, National Central University, 300 Jhong-Da Rd., Jhong-Li, Taoyuan 32001, Taiwan
a r t i c l e i n f o
a b s t r a c t
Article history:
A sequence of ring-closing metathesis and palladium-catalyzed formate reduction was developed for
Received 13 September 2011
Received in revised form 7 October 2011
Accepted 9 October 2011
preparing O-heterocycles with an exocyclic olefin and applied to the asymmetric synthesis of zoapatanol.
The key vicinal stereocenters in zoapatanol were constructed from the L-malic acid-derived lactone by
successive chelation-controlled addition of alkyl groups. The O-allylations to prepare the dienes for RCM
were achieved with the tertiary alcohols bearing internal olefins. The ring opening of oxepane, a new
reaction pathway for the Pd-formate reduction, is also reported.
Available online 3 November 2011
Keywords:
Zoapatanol
Ó 2011 Elsevier Ltd. All rights reserved.
Metathesis
Palladium-formate reduction
Exocyclic olefin
1. Introduction
groups to it and its broad applicability to different ring sizes.7,8
Indeed, RCM has been applied to construct the oxepane core of
Zoapatanol (1), a novel diterpenoid oxepane (Fig. 1) was isolated
from the leaves of the Mexican zoapatle plant Montanoa tomentosa1
and has received attention owing to its potential as an antifertility
agent2 and its challenging structure. Although several groups have
reported total syntheses of zoapatanol,3,4 only two have achieved
an asymmetric synthesis, utilizing Sharpless asymmetric epoxida-
tion and dihydroxylation to construct the vicinal stereocenters.4,5
Other asymmetric approaches that were not pursued to comple-
tion have also been described.6
zopatanol by Boom’s and Cossy’s groups.4c,6d Unfortunately, further
modifications on the endocyclic olefin that resulted in order to
obtain the desired exocyclic olefin were unsuccessful.4c We felt that
this key endocyclic to exocyclic transformation could be solved by
the palladium-catalyzed formate reduction of allylic acetates as
recently developed by our group for affording N-heterocycles.9
Herein we report our studies involving combination of RCM and
palladium-catalyzed formate reduction to generate O-heterocycles
containing an exocyclic olefin function. A new asymmetric ap-
proach to generate the vicinal stereocenters was also developed in
this formal synthesis.
OH
HO
2. Results and discussion
Our retrosynthetic analysis of zoapatanol is shown in Scheme 1.
We planned to form the tetrahydrooxepin by RCM, followed by Pd-
catalyzed formate reduction to afford the exocyclic olefin. Allylation
of a tertiary alcohol would produce the diene required for RCM, and
the key stereochemistry would be constructed by successive
chelation-controlled addition of alkyl groups, starting with the
malic acid-derived lactone.
Dihydropyan 5a and tetrahydrooxepin 5b were prepared as the
model substrates since regioselective Pd-catalyzed formate re-
duction in O-heterocycles to give an exocyclic olefin had not been
studied before. The tertiary alcohols 211 were chosen to mimic the
ether linkage in zoapatanol and were converted to the allylic al-
cohols 4 by Williamson ether synthesis with allyl chloride 312
O
O
(+)-Zoapatanol (1)
Fig. 1. Zoapatanol.
In addition to the stereochemical issue, the formation of an
oxepane bearing an exocyclic olefin is another concern. However,
ring-closing metathesis (RCM) is an ideal protocol for preparing
cyclic compounds, owing to the excellent tolerance of functional
* Corresponding author. E-mail address: drhou@cc.ncu.edu.tw (D.-R. Hou).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.10.023

748
H.-Y. Cheng et al. / Tetrahedron 68 (2012) 747e753
Table 1
OAc
Palladium-catalyzed formate reduction of 5
BnO
BnO
Pd, formate
X
Entry
Substrate
PR3
Conditiona
Conv. (%)
Ratiob (6/7)c
RCM
Zoapatanol
BnO
O
O
R
R
1
2
3
4
5a
5a
5a
5a
P(n-Bu)3
PCy3
P(t-Bu)3
PPh3
A
A
A
A
99
80
12
87/13
58/42
100/0
99.7/0.3
H3C
reduction
H3C
X = O, CH2
>99
Cy2P
Cl
BnO
5a
A
99
99
94/6
allylation
+
5
6
O
R
OH
H3C
H3C
OTHP
OMOM
MOMO
(t-Bu) P
5a
A
84/16
O
HO2C
(CH2)3MgBr
CH3Li
OTHP
OBn
O
7
8
5b
5b
PPh3
P(o-Tol)3
B
B
>99
81
77/23
52/48
+
+
HO2C
OH
Malic acid
Cy2P
9
5b
B
56
50/50
Scheme 1. Retrosynthetic analysis of zoapatanol.
(t-Bu) P
(t-Bu) P
10
11
5b
5b
Bc
Bd
67
100/0
95/5
followed by reduction with DIBALH. Ring-closing metathesis and
acylation gave the allyl esters 5 (Scheme 2).
>99
EtO2C
1. KH,
CH2Cl
OH
HO
n
3
R
Ph
O
n
R
2. DIBALH
Ph
P(t-Bu)
i-Pr
12
5b
B
43
37/63
i-Pr
2a, R = Ph, n = 1
2b, R = CH3, n = 2
4a, R = Ph, n = 1, 70%
4b, R = CH3, n = 2, 35%
i-Pr
a
The reactions were performed at 25 ꢁC, 16 h, with Pd (10 mol %), PR3 (20 mol %),
formic acid (5 equiv), and triethylamine (6 equiv) in DMF; A: allylpalladium chloride
dimer was used; B: Pd2(dba)3.
O
n
1. Grubbs cat. 2nd Gen.
2. R'COCl, Et3N
R
b
Ratios were determined by 1H NMR analysis of crude reaction mixtures.
R'
O
O
Ph
c
40 ꢁC, 16 h.
5a, R = R' = Ph, n = 1, 56%
5b, R = R' = CH3, n = 2, 62%
d
40 ꢁC, 24 h.
Scheme 2. Preparation of 5.
After defining the method for generating the exocyclic olefin,
our synthesis of zoapatanol started from the lactone 8, derived from
Selected results from screening phosphine ligands for the Pd-
catalyzed formate reductions of 5 [Eq. 1] are summarized in
Table 1. Here, the general reaction parameters, such as the solvent,
reagent/catalyst equivalents, reaction temperatures, and time, were
modeled after our previous studies with N-heterocycles.9a Mono-
dentate phosphines such as P(n-Bu)3 and PCy3, which have often
been applied to this reaction with linear substrates,13 gave only
moderate regioselectivities (entries 1 and 2). The reaction became
very sluggish when the bulky P(t-Bu)3 was used, in spite of the
exclusive formation of the exo-product (entry 3). We were sur-
prised to find that triphenylphosphine was effective for preparing
6a (entry 4), but gave only modest selectivity with the seven-
membered substrate 5b (entry 7). Biphenyldialkylphosphines14
consistently gave good to excellent selectivities in favor of the
exo-products 6 (entries 5, 6 and 10, 11). Further increase in the
steric demands of the Buchwald-type phosphine ligands did not
give better results (entry 12). Thus, (2-biphenyl)di-tert-butylphos-
phine was the choice of the ligand in our ultimate synthesis of
zoapatanol. In addition to the use of allylpalladium chloride dimer
as the source of palladium, Pd2(dba)3 can also be applied with
convenience in stoichiometric amounts.
inexpensive L
-malic acid according to literature procedures.15 The
stereochemical issue associated with addition of alkyl groups,
starting with 8, to give tertiary alcohols such as 11 and 14
(Scheme 3) had not been previously addressed, although the dia-
stereoselective formation of the corresponding secondary alcohol
by the DIBALH reduction and Grignard alkylation of 8 is known.16
Methyllithium and n-pentylmagnesium bromide rather than the
racemic nucleophiles 18 required for the synthesis of zoapatanol
but complicated NMR analysis of the product (vide infra), were
selected to study the stereochemistry of the acyl substitution and
alkyl addition. Thus, reaction of 8 with methyllithium generated the
equilibrated mixture of g-hydroxyl ketone 9 and hemiacetal 10.17
Subsequent addition of n-pentyl magnesium bromide gave the
diol 11 with excellent diastereoselectivity (>20:1).18 The stereo-
chemical outcome was initially assumed as (3S,4S) according to the
Cram chelation model.19 This rationale was later confirmed by
converting 11 to the known g-butyrolactones 13.20 Alternating the
order of alkylation gave the (3S,4R)-diastereomer 14 (Scheme 3),
thereby establishing the stereochemistry associated with this
synthetic approach. We also observed that the addition reaction
was only effective with methylmagnesium bromide, not
methyllithium.
n
The Grignard reagent 18 required for incorporating the carbonic
side chain was prepared from the corresponding alkylbromide 17,
which was derived from diethyl methylmalonate after a series of
transformations, including alkylation, decarboxylation, reduction,
and protection (Scheme 4). Both diastereomeric diols 19 and 20, the
R'CO2
n
n
(1)
+
R
R
O
R
O
O
Ph
Ph
Ph
5a, R = R' = Ph, n = 1 6a, R = Ph, n = 1 7a, R = Ph, n = 1
5b, R = R' = CH3, n = 2 6b, R = CH3, n = 2 7b, R = CH3, n = 2

H.-Y. Cheng et al. / Tetrahedron 68 (2012) 747e753
749
provided alkenes 23 and 24. However, the ensuing allylation was
difficult, as our initial attempts with 23a did not yield any of the
desired product. Although the previous allylation using the model,
tertiary alcohols 2 went smoothly (Scheme 2), the corresponding
reactions of 23a with various allyl halides were unsuccessful. It
seems clear that the additional benzyloxyl group of 23 hinders the
allylation. We therefore resorted to analyzing the allylation with
the simplified tertiary alcohols 28a and b and 3-chloro-2-methyl-1-
propene [Eq. 2, Table 2].22 Indeed, higher reaction temperatures,
assisted by microwave heating, were necessary to facilitate the
allylation of 28, but two by-products, 30 and 31, derived from the
elimination of the benzyloxyl group and the migration of the olefin,
respectively, were also observed under such harsh conditions. Since
these unwanted pathways were all related with the olefin moiety
and became dominant with the terminal olefin 28a (Table 2, entries
1e4), we were glad to find that having an internal olefin, as with
28b, circumvented these problems, and the corresponding diene
29b could be prepared (entries 6 and 7).
O
HO2C
ref. 15
1. MeLi
2. H2O
CO2H
OBn
O
OH
L-Malic acid
8
OH
OH
OH
Me
Me OH
O
(n-C5H11)MgBr
O
n-C5H11
Me
63%, 2 steps
BnO
OBn
OBn
9
10
11
O
O
H2, Pd/C
99%
PDC
55 %
O
O
n-C5H11
n-C5H11
Me
OH
Me
OBn
12
13
O
1. (n-C5H11)MgBr
Me OH
2. MeMgBr
(CH2)2OH
OBn
O
n-C5H11
14
53%, 2 steps
OH
OH
OBn
O
OH
Cl
8
R
R
Scheme 3. Chelation-controlled alkylations.
KH, µW
2 h
OBn
28a, R = H,
28b, R = n-C5H11
OBn
(2)
BnO
29a, R = H,
29b, R = n-C5H11
30
31
precursors to zoapatanol, were prepared after alternating the se-
quence of the alkylations (Scheme 5).
EtO2C
EtO2C
EtO2C
EtO2C
NaH, Br(CH2)3Br
THF, 80%
HBr
(CH2)3Br
CH3
O
CHCH3
AcOH, 85%
O
1. DIBALH
2. R'CH=PPh3
PDC
Me
15
19, 20
CH2Cl2
OBn
OR
(CH2)3Br
.
1. BH3 THF
HO2C
(CH2)3Br
RO
(3S, 4S)-21a,R = TBDPS, 80%
(3S, 4S)-21b,R = THP, 65%
(3S, 4R)-22,R = THP, 63%
2. protection
17a, R = TBDPS, 60%
17b, R = THP, 80%
16
OH
(CH2)3MgBr
Mg
Cl
OMOM
25
RO
KH,
R'
CH3
OR
OBn
THF
18a, R = TBDPS
18b, R = THP
dioxane, 110 oC,
µW
(S, S)-23a,R = TBDPS, R' = H, 64%
(S, S)-23b,R = THP, R' = CH3, 69%
(S, R)-24,R = THP, R' = CH3, 66%
Scheme 4. Preparation of 18.
OMOM
HO Me
O
1. MeLi
O
R'
2. 18
OH
OBn
OBn
O
O
CH3
BnO
OR
OBn
63%, 2 steps
OR
(3S, 4S)-19a, R = TBDPS
(3S, 4S)-19b, R = THP
8
(S, S)-26a,R = TBDPS, R' = H, 0%
(S, S)-26b,R = THP, R' = CH3, 52%
(S, R)-27,R = THP, R' = CH3, 50%
O
Me OH
OH
1. 18b
2. MeMgBr
Scheme 6. Syntheses of the dienes 26 and 27.
OTHP
OBn
53%, 2 steps
8
(3S, 4R)-20
Consequently, internal olefins 23b and 24 were prepared and
their allylations with 25 went smoothly as expected to give the
dienes 26b and 27. We found that the THP protecting group was
more stable than the TBDPS group for the allylation.
Scheme 5. Synthesis of diols 19 and 20.
Conversion of the diols 19 and 20 to the corresponding dienes
for RCM is outlined in Scheme 6. The terminal alcohols 19 and 20
were oxidized with pyridinium dichromate to give lactones 21
and 22.21 Subsequent DIBALH reduction and Wittig olefination
Ring-closing metatheses between the 1,1- and 1,2-disubstituted
olefins in 26b and 27 were performed at elevated temperatures
(110 ꢁC, 20 min), and the oxepanes 32 and 33 were produced in
good yields. The MOM and THP protecting groups were replaced

750
H.-Y. Cheng et al. / Tetrahedron 68 (2012) 747e753
Table 2
ground state conformers of 36 and 37 were very similar; how-
Allylation of tertiary alcohols 28
ever, 36 was slightly more stable by 0.80 kcal/mol in Gibbs free
energy (25 ꢁC).24
Entry
Reactant
Solvent
Temp (ꢁC)
Producta
1
2
3
4
5
6
7
28a
28a
28a
28a
28b
28b
28b
DMF
120
120
120
120
120
120
110
29a(40%), 31(60%)
30
31
29a (28%), 31 (59%)
29b (20%)
29b (27%)
29b (71%)b
HMPA
Toluene
Dioxane
THF
Dioxane
Dioxane
P(t-Bu)2
BnO
BnO
[(η3-C3H5)PdCl]2
(3)
OH
R
O
R
HCO2H, Et3N
DMF, rt
42, 99 %
37
Ratios were determined by 1H NMR of crude reaction mixtures.
8 h.
a
R = (CH2)3CH(CH3)CH2OAc
b
with acetyl groups to give 34 and 35, the substrates for the endo-
cyclic to exocyclic conversions. Performing Pd-catalyzed formate
reduction of 34 and 35 using (2-biphenyl)di-tert-butylphosphine
gave the desired 3-methyleneoxepanes 36 and 37. Then the key
intermediate 41 in Cossy’s synthesis of zoapatanol4c was produced
upon changing the hydroxyl-protecting group to TBDPS and sub-
sequent ozonolysis. The spectroscopic data of our synthetic 41 were
consistent with the reported values, except for the opposite di-
rection of optical rotation (Scheme 7).4b,c
3. Conclusion
We have demonstrated that the combination of ring-closing
metathesis and palladium-catalyzed formate reduction was useful
for preparing zoapatanol, an O-heterocycle with an exocyclic olefin
moiety. In our synthesis, the vicinal stereocenters of zoapatanol
were derived from malic acid, and both epimers were prepared
with excellent stereocontrol. Since both L- and D-malic acids are
commercially available, this synthesis should allow the preparation
of all the stereoisomers of zoapatanol. The allylation of the steri-
cally hindered tertiary alcohols was achieved by modifying the
olefin from terminal to internal. Thus, the chemically inert methyl
group can be considered as a protecting group for the labile ter-
minal olefin since the ring-closing metathesis of the internal olefin
was successful and removed the additional methyl group. We be-
lieve that this sequence of RCM and Pd-catalyzed formate reduction
can also be applied to prepare other heterocycles, where exocyclic
olefins are in need.
4. Experimental section
4.1. General
4.1.1. Palladium-catalyzed formate reduction. Triethylamine (95
mL,
0.69 mmol) and formic acid (25 L, 0.69 mmol) were added to
m
a solution of Pd2(dba)3 (5.5 mg, 0.006 mmol) and (2-biphenyl)di-
tert-butylphosphine (6.86 mg, 0.023 mmol) in DMF (1.5 mL) under
an atmosphere of nitrogen. The solution was stirred at rt for 5 min.
Acetate 5b (30 mg, 0.12 mmol) in DMF (400 mL) was added to the
solution of the palladium complex. After being stirred at 40 ꢁC for
24 h, the reaction mixture was diluted withCH2Cl2 (10 mL), washed
with water (2 mLꢂ2) and saturated NaCl(aq) (5 mL), dried (Na2SO4),
filtered, and concentrated. The crude product was analyzed by 1H
NMR spectroscopy to determine the ratio of 6b to 7b and further
purified by column chromatography (SiO2; ethyl acetate/hexanes,
1:9; Rf 0.80) to give 6b (20 mg, 0.10 mmol, 87%). 1H NMR (300 MHz,
CDCl3)
d
7.41e7.21 (m, 5H), 4.79 (s, 2H), 4.05e3.83 (dd, J¼13.5 Hz,
Scheme 7. Formal syntheses of zoapatanols.
1H), 2.50e2.44 (m, 1H), 2.42e2.11 (m, 3H), 1.73e1.69 (m, 2H), 1.55
(s, 2H), 1.37 (s, 3H), 1.23e1.09 (m, 3H); 13C NMR (75 MHz, CDCl3)
d
164.9, 148.2, 128.2, 126.4, 125.3, 111.9, 79.9, 68.4, 38.8, 36.1, 30.6,
With respect to the low yield of 37 as compared to that of 36
was found to be the result of the formation of the ring-opened
compound 42 in 54% yield. The origin of 42 by over-reduction
of 37 was later substantiated by quantitatively transforming 37
to 42 under the reaction conditions used for the formate re-
duction [Eq. 3]. It is interesting to note that the reaction of di-
astereomer 34 was free of this over-reduced product, suggesting
that compound 37 is more susceptible to the ring opening of the
cyclic, allylic ether. Although the ring opening of strained, vinyl
epoxides by the Pd-catalyzed reduction is known,23 the ring
opening of other allylic cyclic ethers under such conditions has
not been reported. Theoretical calculations showed that the
29.7, 21.9; HRMS (HR-API) calcd for [MþNa] C14H19O: 203.1437,
found 203.1436.
4.1.2. Compound 20. Grignard reagent 18b (0.28 M in THF, 16 mL,
4.48 mmol) was added to a solution of 8 (760 mg, 3.9 mmol) in THF
(30 mL) at 0 ꢁC. After being stirred at 0 ꢁC for 1 h, the reaction
mixture was added to saturated NH4Cl(aq) (10 mL) and extracted
with diethyl ether (2ꢂ20 mL). The combined organic layers were
washed with NaCl(aq) (20 mL), dried (Na2SO4), and concentrated.
The crude ketone (2.1 g) was redissolved in diethyl ether (35 mL),
and methylmagnesium bromide (3.0 M in diethyl ether, 7 mL,
21.1 mmol) was added to the solution dropwise at 0 ꢁC. The

H.-Y. Cheng et al. / Tetrahedron 68 (2012) 747e753
751
reaction mixture was stirred for 14 h, having warmed to rt during
this period. Saturated NH4Cl(aq) was added, and the mixtures were
extracted with diethyl ether (2ꢂ20 mL). The organic layers were
combined, washed with saturated NaCl(aq), dried (Na2SO4), filtered,
and concentrated. The crude product was purified by column
chromatography (SiO2; ethyl acetate/hexanes, 1:1; Rf 0.42) to give
20 (830 mg, 2.1 mmol, 53%, two steps). 1H NMR (300 MHz, CDCl3)
28.0, 25.4, 23.5, 23.4, 20.6, 19.4, 17.9, 17.1, 17.0, 16.9, 12.9; IR (neat)
3439, 2937, 2874,1644,1457,1380,1121, 1032, 742, 700 cmꢀ1; HRMS
(ESI) [MþNa]þ calcd for C25H40O4Na 427.2824, found 427.2817;
[a]
20 þ6.1 (c 1.04, CHCl3).
D
4.1.5. Compound (S,R)-27. Potassium hydride (30 wt % in mineral
oil, 842 mg, 6.28 mmol) contained in a reaction tube for the mi-
crowave oven was washed with hexanes (2ꢂ2 mL) and dried with
under a flow of dry nitrogen. 1,4-Dioxane (12 mL), 24 (277 mg,
0.68 mmol), and 25 (204 mg, 1.36 mmol) were added. The reaction
mixture was heated to 110 ꢁC in the microwave oven for 2 h,
cooled in an ice-water bath, quenched with water (10 mL), and
extracted with ethyl acetate (2ꢂ20 mL). The combined organic
layers were washed with saturated NaCl(aq) (10 mL), dried
(Na2SO4), and concentrated. The crude product was purified by
column chromatography (SiO2, EtOAc/hexanes, 1:9; Rf 0.50) to give
27 (176 mg, 0.34 mmol, 50%) as a colorless oil. 1H NMR (300 MHz,
d
7.33e7.24 (m, 5H), 4.64 (d, J¼11.2 Hz, 1H), 4.54e4.51 (m, 1H), 4.53
(d, J¼11.2 Hz, 1H), 3.87e3.73 (m, 2H), 3.69e3.52 (m, 1.5H),
3.52e3.36 (m, 2.5H), 3.24e3.06 (m, 1H), 2.70 (br, 2H), 1.92e1.73
(m, 3H), 1.73e1.60 (m, 2H), 1.60e1.42 (m, 6H), 1.42e1.25 (m, 3H),
1.18 (s, 3H), 1.14e1.02 (m,1H), 0.89 (2d, J¼5.3 Hz, 2ꢂ1.5H); 13C NMR
(75 MHz, CDCl3)
d 138.3, 128.4, 127.8, 99.1, 99.0, 98.9, 98.8, 83.2,
74.9, 73.7, 73.1, 73.0, 72.9, 62.2, 62.1, 59.3, 38.1, 34.3, 33.4, 33.3,
32.2, 30.7, 25.5, 23.7, 20.7, 20.6, 19.5, 17.2, 17.1. IR (neat) 3413, 2941,
2874, 1640, 1453, 1375, 1027, 737 cmꢀ1; HRMS (ESI) [MþNa]þ calcd
20
for C23H38O6Na: 417.2617, found: 417.2623; [
CHCl3).
a
]
þ1.92 (c 1.3,
D
CDCl3)
d 7.35e7.15 (m, 5H), 5.66e5.40 (m, 2H), 5.19 (s, 1H), 5.12 (s,
1H), 4.66 (d, J¼11.3 Hz, 1H), 4.60 (s, 2H), 4.55e4.51 (m, 1H), 4.47 (d,
J¼11.3 Hz, 1H), 4.05 (s, 1H), 4.00e3.90 (m, 1H), 3.90e3.77 (m, 2H),
3.56 (dd, J¼9.3 Hz, 6.2 Hz, 0.5H), 3.52e3.39 (m, 2.5H), 3.34 (s, 3H),
3.19 (dd, J¼9.3 Hz, 5.8 Hz, 0.5H), 3.11 (dd, J¼9.4 Hz, 6.5 Hz, 0.5H),
2.55e2.38 (m, 1H), 2.38e2.07 (m, 1H), 1.89e1.61 (m, 7H),
1.60e1.43 (m, 5H), 1.43e1.21 (m, 3H), 1.15 (s, 3H), 1.12e1.01 (m,
4.1.3. Compound (3S,4R)-22. A suspension of diol 20 (1.1 g,
2.7 mmol), molecular sieves (4 A, 10 g) and pyridinium dichromate
ꢀ
(4.3 g, 11.4 mmol) in dichloromethane (50 mL) was stirred at rt for
14 h. The reaction mixture was diluted with ethyl acetate (50 mL),
filtered through a pad of Celite 545, and concentrated. The crude
product was purified by column chromatography (SiO2; ethyl ace-
tate/hexanes, 1:3; Rf 0.42) to give 22 (0.68 g, 1.7 mmol, 63%) as
1H), 0.91e0.87 (m, 3H); 13C NMR (75 MHz, CDCl3)
d 143.4, 139.1,
129.6, 128.8, 128.2, 127.5, 127.4, 127.3, 126.5, 124.8, 113.0, 99.0, 98.8,
95.6, 83.0, 79.4, 73.7, 73.1, 73.0, 68.2, 62.2, 62.1, 55.2, 35.7, 34.2,
33.9, 33.4, 30.7, 28.1, 25.5, 20.4, 19.5, 18.8, 18.0, 17.1; IR (neat) 2941,
a light yellow oil. 1H NMR (500 MHz, CDCl3)
d 7.34e7.23 (m, 5H),
4.55 (d, J¼11.9 Hz, 1H), 4.55e4.50 (m, 1H), 4.44 (d, J¼11.9 Hz, 1H),
3.94e3.91 (m, 1H), 3.85e3.78 (m, 1H), 3.55e3.44 (m, 2H), 3.18e3.10
(m, 1H), 2.76 (dd, J¼17.7 Hz, 7.0 Hz, 1H), 2.58 (dd, J¼17.7 Hz, 5.5 Hz,
1H), 1.82e1.63 (m, 4H), 1.60e1.45 (m, 7H), 1.43e1.27 (m, 1H), 1.38 (s,
3H), 1.12e1.04 (m, 1H), 0.88 (2d, J¼6.9 Hz, 2ꢂ1.5H); 13C NMR
2874, 1723, 1453, 1380, 1271, 1115, 1002, 975, 711 cmꢀ1; HRMS (ESI)
20
[MþNa]þ calcd for C31H50O6Na 541.3505, found 541.3503. [
þ0.52 (c 1.2, CHCl3).
a]
D
(125 MHz, CDCl3)
d
173.9, 137.2, 128.4, 127.9, 127.6, 127.4, 99.0, 98.9,
4.1.6. Compound (S,R)-33. A solution of 27 (250 mg, 0.48 mmol),
Grubbs catalyst, second generation (41 mg, 0.048 mmol), and
dichloromethane (60 mL) was heated to 110 ꢁC in the microwave
oven for 20 min. The solvent was removed under vacuum and the
crude product was purified by column chromatography (SiO2,
EtOAc/hexanes, 1:4; Rf 0.32) to give 33 (184 mg, 0.39 mmol, 80%) as
98.8, 89.0, 88.9, 78.7, 78.6, 72.9, 72.8, 72.7, 72.0, 62.2, 62.1, 40.1, 40.0,
35.2, 33.8, 33.2, 30.6, 25.4, 20.9, 19.6, 19.5, 19.3, 19.2, 17.0, 16.9, 16.8;
IR (neat) 2941, 2869, 1774, 1727, 1457, 1380, 1271, 1121, 1027, 975,
742, 700 cmꢀ1
413.2304, found 413.2296. [
;
HRMS (ESI) [MþNa]þ calcd for C23H34O5Na
20
a
]
þ29.7 (c 1.15, CHCl3).
D
a light yellow oil. 1H NMR (500 MHz, CDCl3)
d 7.3e7.23 (m, 5H),
4.1.4. Compound (S,R)-24. Diisobutylaluminium hydride (1.0 M in
cyclohexane, 0.4 mL, 0.4 mmol) was added to a solution of 22
(100 mg, 0.26 mmol) in dichloromethane (4 mL) at ꢀ78 ꢁC. The
reaction mixture was stirred for 1 h at ꢀ78 ꢁC, quenched with sat-
urated NH4Cl(aq) (0.5 mL), diluted with diethylether (10 mL),
warmed to rt, and filtered. The filtrate was washed with water
(5 mL), saturated NaCl(aq) (10 mL), dried (Na2SO4), and concentrated
to give the crude lactol (91 mg). A solution of ethylidene(triphenyl)
phosphorane was prepared from ethyltriphenylphosphonium bro-
mide (407 mg, 1.1 mmol) and n-butyllithium (1.6 M, 0.6 mL,
0.96 mmol) in THF (4 mL) at 0 ꢁC. The ylide was added to the so-
lution of the lactol in THF (4 mL) at ꢀ78 ꢁC. After the addition, the
reaction mixture was warmed to rt and heated at reflux for 2 h,
quenched with saturated NH4Cl(aq) (5 mL), and extracted with
diethylether (2ꢂ20 mL). The combined organic layers were washed
with saturated NaCl(aq) (20 mL), dried (Na2SO4), filtered, and con-
centrated. The crude product was purified by column chromatog-
raphy (SiO2, EtOAc/hexanes, 1:4; Rf 0.40) to give 24 (69 mg,
0.17 mmol, 66%) as a colorless oil. 1H NMR (300 MHz, CDCl3)
5.68e5.67 (m, 1H), 4.58e4.53 (m, 4H), 4.33 (d, J¼11.6 Hz, 1H), 4.16
(d, J¼16.7 Hz, 1H), 4.04 (d, J¼16.7 Hz, 1H), 3.91e3.80 (m, 3H),
3.59e3.56 (m, 0.5H), 3.48e3.43 (m, 2.5H), 3.32 (s, 3H), 3.25e3.18
(m, 0.5H), 3.13e3.10 (m, 0.5H), 2.61e2.56 (m, 1H), 2.31 (dd,
J¼16.9 Hz, 7.1 Hz, 1H), 1.85e1.79 (m, 1H), 1.75e1.63 (m, 2H),
1.63e1.45 (m, 6H), 1.45e1.25 (m, 3H), 1.16 (s, 3H), 1.09e1.07 (m, 1H),
0.90 (2d, J¼6.8 Hz, 2ꢂ1.5H); 13C NMR (125 MHz, CDCl3)
d 138.3,
138.3, 128.1, 127.3, 127.2, 125.1, 98.9, 98.6, 95.0, 84.6, 79.5, 77.2, 76.9,
76.7, 71.7, 70.1, 62.6, 62.0, 55.1, 36.5, 34.1, 33.3, 30.6, 27.4, 25.4, 20.3,
19.5, 19.4, 18.1, 18.0, 17.1, 17.0, 16.9; IR (neat) 2937, 2869, 1629, 1457,
1375, 1147, 1100, 1092, 929, 737, 700 cmꢀ1; HRMS (ESI) [MþNa]þ
calcd for C28H44O6Na 499.3036, found 499.3046. [
CHCl3).
a]
20 þ16.8 (c 0.72,
D
4.1.7. Compound (2S,3R)-35. A solution of 33 (169 mg, 0.35 mmol),
ethanol (17 mL), and hydrochloric acid (3 N, 2 mL, 6 mmol) was
heated at reflux for 16 h and concentrated. The residue was redis-
solved in dichloromethane (5 mL), and triethylamine (336
mL,
2.4 mmol) and acetyl chloride (85 L, 1.2 mmol) were added to the
m
d
7.35e7.25 (m, 5H), 5.62e5.45 (m, 2H), 4.72 (d, J¼11.1 Hz, 1H),
solution at 0 ꢁC. The reaction mixture was stirred at rt for 14 h,
diluted with dichloromethane (10 mL), washed with water
(2ꢂ5 mL), dried (Na2SO4), and concentrated. The crude product was
purified by column chromatography (SiO2, EtOAc/hexanes, 1:4; Rf
0.39) to give 35 (96 mg, 0.22 mmol, 63%) as a colorless oil. 1H NMR
4.56e4.51 (m, 1H), 4.48 (d, J¼11.1 Hz, 1H), 3.88e3.77 (m, 1H),
3.62e3.41 (m, 2H), 3.32e3.26 (m, 1H), 3.26e3.08 (m, 1H), 2.39 (m,
2H), 2.20e2.11 (m,1H),1.88e1.70 (m, 2H), 1.70e1.61 (m,1H),1.64 (d,
J¼5.4 Hz, 3H), 1.60e1.31 (m, 9H), 1.16 (s, 3H), 1.13e1.02 (m, 1H),
0.92e0.88 (2d, J¼6.4 Hz, 2ꢂ1.5H); 13C NMR (75 MHz, CDCl3)
d
138.4,
(500 MHz, CDCl3) d 7.32e7.23 (5H, m), 5.74e5.78 (m, 1H), 4.54 (d,
128.6, 128.2, 127.7, 127.6, 127.5, 127.0, 125.2, 98.9, 98.6, 86.3, 86.2,
74.7, 73.9, 73.0, 72.9, 72.8, 62.0, 61.9, 37.4, 37.3, 34.2, 33.8, 33.3, 30.6,
J¼11.6 Hz, 1H), 4.40 (dd, J¼12.5 Hz, 4.5 Hz, 2H), 4.34 (d, J¼11.6 Hz,
1H), 4.08 (q, J¼16.5 Hz, 2H), 3.94e3.90 (m, 1H), 3.84e3.80 (m, 1H),

752
H.-Y. Cheng et al. / Tetrahedron 68 (2012) 747e753
3.43 (m, 1H), 2.64e2.57 (m, 1H), 2.36e2.30 (m, 1H), 2.03 (s, 3H),
2.02 (s, 3H),1.81e1.69 (m, 1H),1.60e1.52 (m, 2H), 1.47e1.40 (m, 1H),
1.40e1.21 (m, 2H), 1.17 (s, 3H), 1.14e1.07 (m, 1H), 0.90 (d, J¼7.0 Hz,
127.4, 127.3, 109.2, 84.8, 84.7, 80.2, 71.7, 68.9, 67.5, 39.6, 35.7, 33.7,
30.6, 27.7, 26.8, 20.6, 20.5, 19.3, 17.6, 16.8; HRMS (ESI) [MþNa]þ
calcd for C37H50O3NaSi: 593.3427, found 593.3424; [
CHCl3).
a]
20 þ7.4 (c 0.4,
D
3H); 13C NMR (125 MHz, CDCl3)
d 171.2, 170.8, 138.4, 136.9, 128.2,
127.4, 127.3, 126.6, 84.5, 84.4, 79.7, 71.8, 69.4, 66.9, 62.4, 36.6, 33.8,
32.5, 27.5, 20.9, 20.4, 18.0, 16.8, 16.7; IR (neat) 2937, 2879, 1738,
4.1.10. Compound 41. Ozone was bubbled into a solution of 39
(8 mg, 0.014 mmol) in dichloromethane (5 mL) at ꢀ78 ꢁC until the
1644, 1557, 1453, 1375, 1235, 1089, 1027, 737, 695 cmꢀ1; HRMS (ESI)
20
[MþNa]þ calcd for C25H36O6Na 455.2410, found 455.2415. [
þ18.1 (c 0.54, CHCl3).
a
]
solution became light blue. Dimethylsulfide (200 mL, 2.7 mmol) was
D
added to the solution, and the reaction mixture was warmed to rt,
stirred for 14 h, and concentrated. The crude product was purified
by column chromatography (SiO2; ethyl acetate/hexanes, 1:10; Rf
0.30) to give 41 (4 mg, 0.007 mmol, 50%) as a colorless oil. 1H NMR
4.1.8. Compound 37. Triethylamine (158
mL, 0.69 mmol) and for-
mic acid (21 L, 0.69 mmol) were added to a solution of allyl-
m
palladium chloride dimer (3.5 mg, 0.009 mmol) and (2-biphenyl)
di-tert-butylphosphine (11.3 mg, 0.047 mmol) in DMF (0.8 mL)
under an atmosphere of nitrogen. The solution was stirred at rt
for 5 min. Acetate 35 (80 mg, 0.18 mmol) in DMF (1.8 mL) was
added to the solution of the palladium complex. After being
stirred at 25 ꢁC for 16 h, the reaction mixture was diluted with
CH2Cl2 (20 mL), washed with water (10 mLꢂ2) and saturated
NaCl(aq) (10 mL), dried (Na2SO4), filtered, and concentrated. The
crude product was purified by column chromatography (SiO2;
ethyl acetate/hexanes, 1:4) to give 37 (Rf 0.66, 14 mg, 0.037 mmol,
20%) and 42 (Rf 0.47, 37 mg, 0.1 mmol, 54%). Spectroscopic data of
(500 MHz, CDCl3) d 7.64e7.62 (m, 4H), 7.39e7.23 (m, 11H), 4.60 (d,
J¼11.6 Hz, 1H), 4.36 (d, J¼11.6 Hz, 1H), 4.11 (dd, J¼18.6 Hz, 1.4 Hz,
1H), 3.92 (d, J¼18.6 Hz, 1H), 3.49e3.40 (m, 2H), 3.39e3.34 (m, 1H),
2.69e2.63 (m, 1H), 2.54e2.49 (m, 1H), 2.13e2.06 (m, 1H), 1.86e1.77
(m, 1H), 1.69e1.42 (m, 3H), 1.41e1.17 (m, 4H), 1.13 (s, 3H), 1.03 (s,
3H), 0.90 (2d, J¼6.5 Hz, 2ꢂ1.5H); 13C NMR (125 MHz, CDCl3)
d 214.8,
137.9, 135.5, 134.0, 129.4, 128.2, 127.6, 127.5, 127.4, 83.0, 82.9, 80.6,
71.8, 70.5, 68.8, 39.5, 36.9, 35.6, 35.5, 33.6, 26.8, 22.3, 20.5, 20.4,
19.2, 16.9, 16.8; IR (neat) 2952, 2858, 1717, 1427, 1385, 1256, 1110,
742, 700 cmꢀ1; HRMS (ESI) [MþNa]þ calcd for C36H48O4NaSi
20
595.3220, found 595.3211. [
a
]
ꢀ1.4 (c 0.14, CHCl3); lit. þ5.6 (en-
D
37: 1H NMR (500 MHz, CDCl3)
d
7.32e7.23 (m, 5H), 4.76 (s, 1H),
antiomer, c 1.0, CHCl3).4c
4.71 (s, 1H), 4.60 (d, J¼11.6 Hz, 1H), 4.38 (d, J¼11.6 Hz, 1H), 4.14
(d, J¼14.5 Hz, 1H), 4.05 (d, J¼14.5, 1H), 3.93e3.90 (m, 1H),
3.83e3.80 (m, 1H), 3.24 (dd, J¼9.9 Hz, 2.9 Hz, 1H), 2.45e2.37 (m,
1H), 2.17 (m, 1H), 2.02 (s, 3H), 1.99e1.90 (m, 1H), 1.79e1.64 (m,
2H), 1.62e1.50 (m, 1H), 1.50e1.40 (m, 1H), 1.37e1.26 (m, 3H),
1.16e1.10 (m, 4H), 0.89 (d, J¼6.7 Hz); 13C NMR (125 MHz, CDCl3)
Acknowledgements
This research was supported by the National Science Council
(NSC 98-2119-M-008-001 and NSC 95-2113-M-008-007), Taiwan.
We thank Prof. John C. Gilbert, Santa Clara University, for helpful
comments. We are grateful to Ms. Ping-Yu Lin at the Institute of
Chemistry, Academia Sinica, and Valuable Instrument Center in
National Central University for obtaining mass analysis.
d
171.2, 150.0, 138.7, 128.2, 127.5, 127.4, 127.3, 109.2, 84.8, 80.1,
71.7, 69.4, 67.5, 39.7, 39.6, 33.9, 32.5, 30.6, 27.8, 20.9, 20.4, 17.3,
16.8, 16.7; HRMS (ESI) [MþNa]þ calcd for C23H34O4Na 397.2355,
20
found 397.2361; [
a
]
þ1.3 (c 0.67, CHCl3). Spectroscopic data of
D
42: 1H NMR (500 MHz, CDCl3)
d 7.33e7.26 (m, 5H), 4.72 (s, 1H),
Supplementary data
4.69 (d, J¼11.2 Hz, 1H), 4.68 (s, 1H), 4.58 (d, J¼11.2 Hz, 1H),
3.93e3.90 (m, 1H), 3.85e3.80 (m, 1H), 3.24 (dd, J¼7.9 Hz,
J¼3.7 Hz, 1H), 2.30e2.19 (m, 1H), 2.12e2.07 (m, 1H), 2.03 (s, 3H),
1.79e1.73 (m, 1H), 1.71 (s, 3H), 1.71e1.65 (m, 2H), 1.59e1.43 (m,
2H), 1.41e1.32 (m, 3H), 1.16 (s, 3H), 1.15e1.07 (m, 1H), 0.90 (d,
Experimental procedures, and NMR spectra of the new com-
pounds can be found in the online version, at doi:10.1016/
j.tet.2011.10.023.
J¼6.5 Hz, 3H). 13C NMR (125 MHz, CDCl3)
d 171.2, 145.6, 138.5,
128.4, 128.2, 127.6, 127.5, 110.1, 86.6, 86.5, 75.0, 74.9, 69.4, 69.3,
37.1, 37.0, 34.9, 34.0, 33.9, 32.5, 28.9, 23.7, 23.6, 22.5, 20.9, 20.5,
16.8, 16.7. HRMS (ESI) [MþNa]þ calcd for C23H36O4Na: 399.2511,
found 399.2502.
References and notes
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(11 mg, 0.019 mmol, 51%). 1H NMR (500 MHz, CDCl3)
d 7.65e7.63
(m, 4H), 7.39e7.23 (m, 11H), 4.76 (s, 1H), 4.70 (s, 1H), 4.59 (d,
J¼11.5 Hz, 1H), 4.37 (d, J¼11.5 Hz, 1H), 4.12 (d, J¼14.5 Hz, 1H), 4.03
(d, J¼14.5 Hz, 1H), 3.50e3.46 (m, 1H), 3.44e3.37 (m, 1H), 3.29e3.26
(m, 1H), 2.46e2.40 (m, 1H), 2.19e2.14 (m, 1H), 1.97e1.90 (m, 1H),
1.77e1.68 (m, 1H), 1.65e1.60 (m, 2H), 1.59e1.21 (m, 4H), 1.13 (s, 3H),
1.05e1.0 (m, 1H), 1.03 (s, 9H), 0.89 (2d, J¼6.7 Hz, 2ꢂ1.5H); 13C NMR
(125 MHz, CDCl3)
d 150.0, 138.7, 135.6, 134.1, 129.4, 128.2, 127.5,

H.-Y. Cheng et al. / Tetrahedron 68 (2012) 747e753
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a
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21. DesseMartin periodinane gave the aldehyde/lactol in poor yield, and Swern
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22. See Supplementary data for the preparation of 28a and b.
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gradient-corrected hybrid density functional theory (DFT) at the B3LYP/6-
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ble structures (Fig. S1, in Supplementary data) were examined in terms of vi-
brational frequency calculations with all positive values.
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.
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