Highly stereocontrolled synthesis of trans -2,6-disubstituted-5-methyl-3,6-dihydropyrans: Stereoselective synthesis of the bicyclic core of penostatin b

Article abstract of DOI:10.1021/jo502101u

An efficient, mild, and highly diastereoselective strategy for the synthesis of trans-2,6-disubstituted-5-methyl-3,6-dihydropyran ring systems has been developed starting from δ-hydroxy α-methyl α,β-unsaturated aldehydes and allyltrimethylsilane in the presence of a catalytic amount of ZnBr₂ in a highly diastereoselective manner with excellent yield. The versatility of the above method was also demonstrated for the construction of the bicyclic core present in penostatin B in a concise and highly stereoselective manner.

Full text of DOI:10.1021/jo502101u

Article
pubs.acs.org/joc
Highly Stereocontrolled Synthesis of trans-2,6-Disubstituted-5-
methyl-3,6-dihydropyrans: Stereoselective Synthesis of the Bicyclic
Core of Penostatin B
†
†
,†
D. Srinivas Reddy, Birakishore Padhi, and Debendra K. Mohapatra*
†Natural Products Chemistry Division, CSIR−Indian Institute of Chemical Technology, Hyderabad 500 007, India
*
S Supporting Information
ABSTRACT: An efficient, mild, and highly diastereoselective
strategy for the synthesis of trans-2,6-disubstituted-5-methyl-
3
,6-dihydropyran ring systems has been developed starting
from δ-hydroxy α-methyl α,β-unsaturated aldehydes and
allyltrimethylsilane in the presence of a catalytic amount of
ZnBr in a highly diastereoselective manner with excellent
2
yield. The versatility of the above method was also
demonstrated for the construction of the bicyclic core present in penostatin B in a concise and highly stereoselective manner.
INTRODUCTION
synthesize trans-2,6-disubstituted-5-methyl-3,6-dihydropyran
ring systems starting from δ-hydroxy-α-methyl-α,β-unsaturated
aldehydes and allyltrimethylsilane. The cis-fused dihydropyran
ring systems could be obtained easily by isomerization with
■
Polysubstituted di- and tetrahydropyrans are important
structural motifs that are found in many natural products and
have diverse and potent biological activities.
1
−11
The double
t
23
BuOK in anhydrous THF. We have demonstrated the
bond present in the dihydropyran ring system provides a
functional handle for further manipulation and organic
transformation in natural product synthesis. Because of their
importance in organic synthesis, substantial efforts have been
made to develop methods for the construction of di- and
application of this protocol for an efficient and concise
stereoselective synthesis of the bicyclic core of penostatin B.
Benzyl-protected glycidol prepared from epichlorohydrin and
benzyl alcohol using NaH in dry THF was used as the starting
material for the preparation of δ-hydroxy-α-methyl-α,β-
unsaturated aldehydes. The hydrolytic kinetic resolution of
12
tetrahydropyrans. However, the stereocontrolled synthesis of
these cyclic ethers and related heterocycles is still a challenging
and interesting task. 2,6-Disubstituted-dihydropyrans are
attractive targets, particularly with regard to controlling the
syn and anti disposition of the substitution. Some of the natural
products bearing a trans-2,6-disubstituted-5-methyl-3,6-dihy-
2
4
the terminal epoxide using Jacobsen’s catalyst (S,S)-
III
Co (Salen)(OAc) for 24 h at room temperature afforded
chiral epoxide 10 in 44% yield (∼98% ee).
The enantiomeric excess was determined by chiral HPLC
analysis. The chiral epoxide 10 was then treated with
vinylmagnesium bromide in the presence of CuI at −20 °C
13
dropyran ring system such as penostatin A, B, C, and D, 4,5-
14
15
deoxyneodolabbeline, and methyl sarcophytoate are shown
in Figure 1. Similarly, some of the natural products containing
the cis-2,6-disubstituted-5-methyl-3,6-dihydropyran ring system
25
to produce homoallyl alcohol 11 in 86% yield (Scheme 1).
The terminal olefin was subjected to Jin’s one-step dihydrox-
16
17
18
26
such as ambruticin S, jerangolid D, and funiculosin show
potent antifungal properties (Figure 1). As part of our research
program on the total synthesis of di- and tetrahydropyran-
ylation followed by oxidation protocol to afford aldehyde 12
in 88% yield. The aldehyde 12 was reacted with 2-
(triphenylphosphoranylidene)propanal to obtain the desired
δ-hydroxy-α-methyl-α,β-unsaturated aldehyde 13 in 82% yield
with the E-isomer as the only product. After developing a
general synthetic strategy for the preparation of δ-hydroxy-α-
methyl-α,β-unsaturated aldehydes, the synthesis of trans-2,6-
disubstituted-5-methyl-3,6-dihydropyran ring system was
undertaken.
1
9
containing natural products, it was deemed important to
study and develop new strategies for their rapid, efficient, and
versatile synthesis. To reach this goal, a general and concise
route toward dihydropyran, which would allow a broad
spectrum of substituents at any position of the heterocyclic
20,21
ring system, was sought after.
Although several methods are
already precedent in the literature for the synthesis of 2,6-
1
9d
disubstituted-dihydropyrans including our recent protocol,
RESULTS AND DISCUSSION
22
■
to the best of our knowledge, there is no general report for
the preparation of the trans-2,6-disubstituted-5-methyl-3,6-
dihydropyrans ring system.
As per our earlier report, we envisaged that the same reaction
conditions could be further applied to the synthesis of the
Herein, we report an efficient, mild, versatile, and highly
stereoselective zinc bromide-catalyzed tandem isomerization
followed by C−O and C−C bond formation reaction to
Received: September 11, 2014
©
XXXX American Chemical Society
A
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Figure 1. Structures of trans- and cis-2,6-disubstituted-5-methyl-3,6-dihydropyran containing natural products.
Scheme 1. Synthesis of δ-Hydroxy-α-methyl-α,β-unsaturated
different solvent systems such as CH Cl , Et O, tert-butyl
2 2 2
Aldehyde
methyl ether (TBME), DME, and THF at room temperature
with 10 mol % of molecular iodine. Among them, THF was
found to be superior to other solvents. Next, the reaction was
carried out at room temperature at reflux conditions. Heating
was found to be detrimental, leading to intractable mixtures of
products. The reaction was then carried out carefully under the
influence of different concentrations of the catalyst at room
temperature with THF as the solvent. The use of 20 mol % of
molecular iodine (based on the δ-hydroxy-α-methyl-α,β-
unsaturated aldehyde) gave the best result with a high yield
of 82% in 1 h time (Scheme 2). Increasing the molecular iodine
concentration did not help much in improving the yield, and
reduction of the reaction time instead led to an intractable
mixture of compounds. However, no reaction was observed in
the absence of iodine after a long time (48 h). As already a
common trans-2,6-disubstituted-5-methyl-3,4-dihydropyran
ring system to provide a practical access to the above natural
products. We began our study by using 10 mol % of iodine for
the conversion of δ-hydroxy-α-methyl-α,β-unsaturated alde-
hyde to trans-2,6-disubstituted-6-methyl-3,4-dihydropyran.
After 24 h at room temperature, the reaction provided the
expected trans-2,6-disubstituted-5-methyl-3,6-dihydropyran 14
27
precedent in the literature, it is noteworthy to mention here
that, with 20 mol % and the previously mentioned
concentration of the catalyst, some of the sensitive functional
groups (tert-butyldimethylsilyl (TBS), PMB, Boc, and
acetonide) were getting deprotected. At this juncture, we
postulated the use of a mild Lewis acid, which will not affect the
sensitive protecting groups even under stoichiometric con-
1
13
in 54% yield (Scheme 2). The H and C NMR of the product
Scheme 2. Synthesis of trans-2,6-Disubstituted-5-methyl-3,6-
dihydropyrans
ditions. During the screening, ZnBr was found to be suitable
2
for the purpose. Accordingly, δ-hydroxy-α-methyl-α,β-unsatu-
rated aldehyde was treated with ZnBr and allyltrimethylsilane
2
in THF at room temperature to obtain the expected trans-2,6-
disubstituted-5-methyl-3,4-dihydropyran 14 in 95% yield in 2 h.
With optimal reaction conditions in hand, the generality and
versatility of tandem isomerization followed by C−O and C−C
bond formation reaction was explored via screening of a variety
of structurally diverse δ-hydroxy-α-methyl-α,β-unsaturated
aldehyde (Table 1) with regard to protecting groups. Use of
revealed a single diastereomer. The stereochemistry of the
product at this stage was confirmed by NOE experiments. In
1
13
H and C NMR of the crude product (flash column
chromatography), no cis diastereomer was detected. To
optimize the reaction conditions, screenings were performed
on different parameters, such as solvents, temperature, and
catalyst concentration. Initially, the reaction was performed in
a stoichiometric amount of the ZnBr did not affect the
2
sensitive protecting groups (TBS, PMB, Boc, and acetonide) at
room temperature and provided the expected products in good
B
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Article
Table 1. Synthesis of trans-2,6-Disubstituted-5-methyl-3,6-dihydropyrans
a
ZnBr , allyITMS, THF, rt.
2
yields with a high level of selectivity. It is noteworthy to
mention here that the reaction could be conducted on a gram
scale without a reduction of isolated yield.
which the stereoelectronic and/or steric factors dictate the
direction of the incoming nucleophile (Figure 2). To test the
viability of the proposed reaction pathways (path A), it was
expected that the reaction of a δ-hydroxy-α-methyl-α,β-
unsaturated aldehyde in the presence of a catalytic amount of
TMSBr should generate the corresponding trans-2,6-disubsti-
tuted-5-methyl-3,6-dihydropyran.
As per our postulation, when 5 mol % of TMSBr was added
instead of ZnBr2 at room temperature, the reaction was
completed in 20 min, which strongly supported our proposed
To predict the formation of the trans-2,6-disubstituted-5-
methyl-3,6-dihydropyran from δ-hydroxy-α-methyl-α,β-unsatu-
rated aldehyde following catalytic pathways, we postulated like
earlier that the product could be generated with the activation
28
of aldehyde and isomerization by in situ formation of a
2
9
catalytic amount of TMSBr followed by subsequent
formation of an oxocarbenium intermediate (path A) in
C
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Article
D exihibits significant cytotoxicity against P388 cells. Snider
31
and Liu reported the synthesis of (±)-5-deoxypenostatin A
using an intramolecular Diels−Alder reaction to construct the
32
dihydropyran ring. Later in 2001, Shishido and co-workers
synthesized (±)-penostatin B by applying a relay ring-closing
metathesis protocol. As only one total synthesis of
(
±)-penostatin B is reported so far, we thought of developing
a general and flexible approach toward a stereoselective total
synthesis applying our earlier developed method. Initially, the
synthetic utility of this strategy was demonstrated for a highly
stereoselective synthesis of the bicyclic core of penostatin B.
According to our retrosynthetic analysis, the bicyclic core of
penostain B could be constructed by cross-metathesis of 21
with 1-nonene. Advance intermediate 21 could be achieved
from trisubstituted aldehyde 22 by ZnBr -catalyzed tandem
2
isomerization followed by C−O and C−C bond formation
reaction (Scheme 4). The trisubstituted aldehyde 22 in turn
could be prepared starting from commercially available 2-
cyclohexenone (24).
Figure 2. Plausible mechanistic cycle.
mechanism. Similarly, the reaction of a δ-hydroxy-α-methyl-
α,β-unsaturated aldehyde in the presence of a catalytic amount
of TMSBr led to formation of TMS-protected lactol in 15 min,
Scheme 4. Retrosynthetic Analysis
28
which strongly holds up for the isomerization. To further
ascertain the mechanistic pathways, TMS-protected lactol 18
30
was synthesized following a standard protocol and treated
with allyltrimethylsilane and a catalytic amount of ZnBr to
2
afford the expected allylated compound 14b in 90% yield in 30
min (Scheme 3). To verify the second mechanistic pathway
Scheme 3. Controlled Experiment
The synthesis was begun from commercially available 2-
cyclohexenone (24), which was treated with LiAlH in THF to
4
obtain the corresponding racemic allyl alcohol 25 in 80% yield.
3
3
Compound 25 was subjected to a Sharpless kinetic resolution
3
0
(
path B), the diol compound 19 was prepared by standard
to furnish the enantiomerically pure epoxy alcohol 26 in 45%
yield. The hydroxyl group was protected as its benzyl ether with
benzyl bromide in the presence of NaH in THF at room
temperature to afford 23 in 95% yield (Scheme 5). Considering
the lengthy reaction sequences, an alternative concise protocol
was sought. In this context, commercially available 2-cyclo-
hexenone (24) was reduced with (R)-CBS catalyst to afford the
Grignard reaction followed by treatment of 19 with either
TMSBr or ZnBr , which gave no expected product.
2
34
allyl alcohol and was protected as its benzyl ether. Homoallyl
alcohol was treated with m-CPBA to obtain compound 23
(
97% de as per HPLC) in good overall yield. The benzyl-
protected epoxy compound 23 was treated with vinyl
magnesium bromide in the presence of a catalytic amount of
CuI in anhydrous THF to get homoallyl alcohol 27 in 85%
yield.
The double bond present in compound 27 was oxidatively
To examine the synthetic utility and generality of this novel
methodology for the synthesis of complex biologically active
natural products, the penostatin B, a natural product possessing
tricyclic fused ring systems, was taken as a representative
example. Penostatin A and B were isolated from Penicillium sp.
separated from green alga Enteromerpha intenstinalis by Numata
35
26
cleaved following Jin’s one-pot reaction with OsO , NaIO ,
4
4
and 2,6-lutidine in 1,4-dioxane at room temperature to afford
the corresponding aldehyde 28 that was immediately treated
with 2-(triphenylphosphoranylidene)propionaldehyde in ben-
13
and co-workers in 1996. All the penostatins except penostatin
D
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Article
Scheme 5. Synthesis of Bicyclic Compound 21
and C−C bond formation reaction for the synthesis of trans-
2
,6-disubstituted-5-methyl-3,6-dihydropyran compounds start-
ing from δ-hydroxy-α-methyl-α,β-unsaturated aldehydes has
been developed in good to excellent yield and with high
diastereoselectivity. In addition, the reaction was conducted in
gram scale, highlighting its possible industrial application. The
potential of employing this methodology toward the total
synthesis of natural products is intriguing as C-glycosides
constitute a major component of many natural products. The
synthetic utility of this strategy was demonstrated by achieving
a short and stereoselective synthesis of the bicyclic core of
tricyclic penostatin B. Further progress toward the total
synthesis of penostatin B and other related natural products
(
syn-fused) such as ambruticin S and jerangolid D is in progress
and will be reported in due course.
EXPERIMENTAL SECTION
General Methods. Experiments that required an inert atmosphere
were carried out under argon in flame-dried glassware. Et O and THF
■
2
were freshly distilled from sodium/benzophenone ketyl and trans-
ferred via syringe. Dichloromethane was freshly distilled from CaH2.
Tertiary amines were freshly distilled over KOH. Commercially
available reagents were used as received. Unless detailed otherwise,
“
workup” means pouring the reaction mixture into brine, followed by
extraction with the solvent indicated in parentheses. If the reaction
medium was acidic (basic), an additional washing with 5% aqueous
zene under reflux conditions to furnish δ-hydroxyl-α-methyl-
α,β-unsaturated aldehyde. With the required compound 22 in
NaHCO3 (aqueous NH Cl) was performed. Washing with brine,
4
hand, the stage was set to perform the key ZnBr -catalyzed
drying over anhydrous Na SO , and evaporation of the solvent under
2
2
4
tandem isomerization followed by C−O and C−C bond
reduced pressure followed by chromatography on a silica gel column
(60−120 mesh) with the indicated eluent furnished the corresponding
products. Where solutions were filtered through a Celite pad, the pad
was additionally washed with the same solvent used, and the washings
were incorporated to the main organic layer. 1H and C NMR
chemical shifts are reported in ppm downfield from tetramethylsilane,
and coupling constants (J) are reported in hertz (Hz). High-resolution
mass spectra were run by the electron impact mode (ESIMS, 70 eV)
or by the FAB mode (m-nitrobenzyl alcohol matrix), using an orbitrap
mass analyzer. IR data were measured with oily films on NaCl plates
(oils) or KBr pellets (solids) and are given only for molecules with
relevant functional groups (OH, CO). Specific optical rotations
formation reaction. Aldehyde 22 was treated with 20 mol %
ZnBr in anhydrous THF at room temperature under inert
2
atmosphere to produce the bicyclic trans-fused 21 in 92% yield.
Our next aim was to attach the appendage to cyclic
compound 21, which was carried out by exposing it to Grubbs’
13
36
second-generation catalyst for the isomerization of allyl to
37
propenyl followed by cross-metathesis (Scheme 6).
Scheme 6. Synthesis of the Bicyclic Core of Penostatin B
−1
2
−1
[
α] are given in 10 deg cm g and were measured at 25 °C. The
D
following abbreviations are used to designate signal multiplicity: s =
singlet, d = doublet, t = triplet, q = quartet, quin = quintet, m =
multiplet, and br = broad.
General Procedure for δ-Hydroxyl-α-methyl-α,β-unsatu-
rated Aldehydes. To a stirred solution of β-hydroxy aldehydes
(
(
1. 0 mmol) in toluene (3. 0 mL) was added 2-
triphenylphosphoranylidene)propionaldehyde (1.5 mmol). The
solution was then heated at 85 °C for 12 h. After cooling, the solvent
was removed under reduced pressure and the remaining oil was
triturated with cold hexane. The insoluble triphenylphosphine oxide
was precipitated out. The reaction mixture was filtered through a
sintered funnel (washing with cold hexane), and the filtrate was
concentrated to obtain the crude product, which on purification was
performed using flash chromatography (hexane/ethyl acetate = 1:1) to
obtain δ-hydroxyl-α-methyl-α,β-unsaturated aldehyde in 75−80% of
isolated yield.
Cyclic compound 21 was treated with 10 mol % Grubbs’
second-generation catalyst in methanol at 60 °C to afford
isomerized compound 29 (E/Z = 9:1) with 80% yield. The
isomerized compound 29 again treated after purification with
General Procedure for Iodocyclization. To a stirred solution of
δ-hydroxyl-α-methyl-α,β-unsaturated aldehyde (1.0 mmol), iodine
(0.2 mmol) and allyltrimethylsilane (1.5 mmol) were added in THF
(6 mL) at 0 °C and allowed to come to room temperature. After
1
0 mol % Grubbs’ second-generation catalyst in dichloro-
methane at 40 °C to furnish the cross-metathesis product 20 in
8% yield.
completion of the reaction (monitored by TLC; 30−60 min), the
reaction mixture was quenched with a saturated solution of Na S O
2
2
3
7
(3 mL) and diluted with ethyl acetate (10 mL). The organic layer was
separated and the aqueous layer was extracted with ethyl acetate (2 ×
10 mL). The combined organic layers were dried over anhydrous
Na SO and concentrated under reduced pressure. The crude product
CONCLUSIONS
In conclusion, an efficient, robust, mild, and versatile ZnBr -
catalyzed method for tandem isomerization followed by C−O
■
2
2
4
was purified by silica gel column chromatography using 2−5% ethyl
E
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acetate/hexane as eluent to obtain the cyclized product in 70−82% of
isolated yield.
(m, 2H), 1.97−1.92 (m, 2H), 1.81−1.76 (m, 2H), 1.63 (s, 3H). 13C
NMR (CDCl , 75 MHz): δ 138.3, 135.2, 135.1, 128.1, 127.5, 127.3,
3
General Procedure for ZnBr -Catalyzed Cyclization. To a
stirred solution of δ-hydroxyl-α-methyl-α,β-unsaturated aldehyde (1.0
119.6, 116.1, 75.7, 73.1, 72.3, 66.4, 36.2, 35.6, 31.1, 19.7. ESI-HRMS:
2
+
m/z calcd for C H O [M + Na] : 295.1668. Found: 295.1658.
18
24
2
mmol), ZnBr (0.2 mmol) and allyltrimethyl silane (1.5 mmol) were
added in THF (8 mL) at room temperature. After completion of the
(S,E)-5-Hydroxy-2-methylicos-2-enal (13c). Colorless liquid (80
2
mg, 77%), [α]D25 −3.2 (c 1.5, CHCl ). IR (neat) υ 3419, 2924,
3
max
−1 1
reaction (monitored by TLC; 30−60 min), the reaction mixture was
2853, 2351, 1692, 1515, 1188, 1062, 1029 cm . H NMR (CDCl ,
3
quenched with a saturated solution of NaHCO (5 mL) and diluted
500 MHz): δ 9.43 (s, 1H), 6.60 (td, J = 6.0, 1.5 Hz, 1H), 3.81 (quin, J
3
with ethyl acetate (10 mL). The organic layer was separated and the
= 6.0 Hz, 1H), 2.56−2.45 (m, 2H), 1.76 (s, 3H), 1.57−1.38 (m, 3H),
13
aqueous layer was extracted with ethyl acetate (2 × 10 mL). The
1.37−1.15 (m, 24 H), 0.88 (t, J = 6.7 Hz, 3H). C NMR (CDCl , 75
3
combined organic layers were dried over anhydrous Na SO4 and
MHz): δ 195.1, 150.4., 140.9, 70.9, 37.7, 36.8, 31.9, 29.6, 29.5, 29.3,
2
+
concentrated under reduced pressure. The crude product was purified
by silica gel column chromatography using 2−5% ethyl acetate/hexane
as eluent to obtain the cyclized product in 85−95% of isolated yield.
25.6, 22.6, 14.1. ESI-HRMS: m/z calcd for C H O [M + H] :
21
41
2
325.3101. Found: 325.3088.
(2S,6S)-6-Allyl-5-methyl-2-pentadecyl-3,6-dihydro-2H-pyran
2
5
(
R,E)-6-(Benzyloxy)-5-hydroxy-2-methylhex-2-enal (13). Colorless
(14c). Colorless liquid (55 mg, 90%), [α]
(neat): υmax 2922, 2852, 2359, 2341, 1456, 1058 cm . H NMR
(CDCl
D
−30.4 (c 0.9, CHCl ). IR
3
25
−1
1
liquid (130 mg, 77%), [α]D −9.6 (c 1.0, CHCl ). IR (neat): υ
433, 2966, 2864, 2843, 1680, 1453, 1219, 1055, 1032 cm . H NMR
3
max
−1 1
3
3
, 300 MHz): δ 5.94 (m, 1H), 5.49 (m, 1H), 5.14−5.04 (m,
(
CDCl , 300 MHz): δ 9.41 (s, 1H), 7.41−7.29 (m, 5H), 6.60 (td, J =
2H), 4.02 (d, J = 9.0 Hz, 1H), 3.67−3.58 (m, 1H), 2.47−2.28 (m,
3
6
.0, 1.5 Hz, 1H), 4.57 (s, 2H), 4.01 (m, 1H), 3.58−3.38 (m, 2H), 2.55
2H), 2.02−1.82 (m, 3H), 1.64 (s, 3H), 1.55−1.36 (m, 4H), 1.35−1.21
t, J = 6.7 Hz, 2H), 1.75 (s, 3H). 13C NMR (CDCl , 75 MHz): δ
13
(
(m, 26H), 0.88 (t, J = 6.9 Hz, 3H). C NMR (CDCl
3
, 75 MHz): δ
3
1
95.2, 155.1, 137.5, 128.4, 127.9, 127.1, 73.5, 73.0, 72.4, 36.8, 15.5, 9.4.
135.8, 135.2, 119.8, 116.2, 75.9, 67.0, 36.4, 35.6, 31.9, 31.2, 29.6, 29.3,
+
+
ESI-MS for C H O : m/z [M + Na] 257. ESI-HRMS: m/z calcd for
C H O [M + H] : 235.1328. Found: 235.1316.
25.7, 22.6, 9.8, 14.1. ESI-HRMS: m/z calcd for C24H43O [M − H] :
14
18
3
+
347.3308. Found: 347.3293.
14
19
3
(
2R,6S)-6-Allyl-2-((benzyloxy)methyl)-5-methyl-3,6-dihydro-2H-
(R,E)-5-Hydroxy-2-methyldodec-2-enal (13d). Yellow liquid (60
25
25
pyran (14). Colorless liquid (85 mg, 82%), [α]D +2.6 (c 3.0, CHCl ).
mg, 75%) [α]D −14.2 (c 1.2, CHCl ). IR (neat): υ 2925, 2854,
3
3
max
−
1
−1 1
IR (neat): υ 3417, 2929, 2357, 1719, 1451, 1274, 1219, 1110 cm .
1687, 1401, 1219, 1051 cm . H NMR (CDCl , 300 MHz): δ 9.44 (s,
max
3
1
H NMR (CDCl , 500 MHz): δ 7.36−7.26 (m, 5H), 5.97 (m, 1H),
1H), 6.63 (m, 1H), 3.84 (m, 1H), 2.59−2.46 (m, 2H), 1.77 (s, 3H),
3
1
3
5
4
2
1
6
2
.50 (m, 1H), 5.17−5.04 (m, 2H), 4.54 (AB , J = 12.0, 5.2 Hz, 2H),
1.57−1.41 (m, 4H), 1.38−1.21 (m, 12H), 0.89 (t, J = 6.7 Hz, 3H). C
q
.08 (m, 1H), 3.96 (m, 1H), 3.59−3.45 (m, 2H), 2.50−2.29 (m, 2H),
NMR (CDCl , 75 MHz): δ 195.1, 150.6, 70.9, 37.4, 36.8, 31.7, 29.4,
3
13
.10−1.91 (m, 2H), 1.63 (s, 3H). C NMR (CDCl , 75 MHz): δ
29.2, 25.6, 22.6, 14.1, 9.4. ESI-HRMS: m/z calcd for C13
H] : 213.1849. Found: 213.1840.
H
O
25
2
[M +
3
+
38.3, 135.4, 135.1, 128.1, 127.4, 127.3, 119.0, 116.4, 75.7, 73.1, 72.3,
+
6.4, 36.4, 27.4, 19.7. ESI-HRMS: m/z calcd for C H O [M + Na] :
(2R,6R)-6-Allyl-2-heptyl-5-methyl-3,6-dihydro-2H-pyran (14d).
17
22
2
25
81.1505. Found: 281.1512.
4R,5S,E)-6-(Benzyloxy)-5-hydroxy-2,4-dimethylhex-2-enal (13a).
Colorless liquid (45 mg, 94%), [α]
(neat): υmax 2955, 2925, 2855, 2357,1640, 1455, 1123, 1058 cm . H
NMR (CDCl
D
−6.8 (c 1.0, CHCl ). IR
3
−
1 1
(
25
Colorless liquid (85 mg, 75%) [α]D −13.2 (c 0.8, CHCl ). IR (neat):
υmax 3433, 2966, 2864, 2843, 1680, 1453, 1219, 1055, 1032 cm . H
3
, 500 MHz): δ 5.93 (m, 1H), 5.49 (m, 1H), 5.12−5.03
3
−1 1
(m, 2H), 4.02 (d, J = 9.1 Hz, 1H), 3.67−3.57 (m, 1H), 2.44−2.31 (m,
2H), 1.99−1.86 (m, 3H), 1.64 (s, 3H), 1.60 (m, 1H), 1.55−1.37 (m,
NMR (CDCl , 500 MHz): δ 9.39 (s, 1H), 7.39−7.27 (m, 5H), 6.33
3
13
(
dq, J = 7.7, 1.3 Hz, 1H), 4.53 (s, 2H), 3.71 (td, J = 4.1, 3.0 Hz, 1H),
4H), 1.33−1.22 (m, 10H), 0.88 (t, J = 6.8 Hz, 3H). C NMR (CDCl ,
3
3
1
.52 (dd, J = 6.4, 3.0 Hz, 1H), 3.37 (m, 1H), 2.88 (m, 1H), 1.76 (d, J =
75 MHz): δ 135.8, 135.2, 119.8, 116.2, 75.9, 66.9, 36.4, 35.6, 33.4,
31.8, 31.2, 25.7, 22.6, 19.8, 14.0. ESI-HRMS: m/z calcd for C16H O
28
.3 Hz, 3H), 1.16 (d, J = 6.8 Hz, 3H). 13C NMR (CDCl , 75 MHz): δ
3
+
1
95.2, 155.1, 137.5, 128.4, 127.9, 127.1, 73.5, 73.4, 72.4, 36.8, 15.5,
[M + NH
4
] : 254.2478. Found: 254.2476.
+
9.41. ESI-HRMS: m/z calcd for C H O [M + NH ] : 266.1756.
(5R,7R,E)-5-Hydroxy-7-((4-methoxybenzyl)oxy)-2-methyloct-2-
15
20
3
4
25
Found: 266.1753.
enal (13e). Colorless liquid (100 mg, 77%), [α]
D
+10.3 (c 2.5,
(
2S,3S,6R)-6-Allyl-2-((benzyloxy)methyl)-3,5-dimethyl-3,6-dihy-
CHCl ). IR (neat): υmax 3409, 2924, 2360, 1687, 1400, 1219, 1034
3
25
−1 1
dro-2H-pyran (14a). Colorless liquid (60 mg, 92%) [α]D −32.9 (c
cm . H NMR (CDCl , 300 MHz): δ 9.42 (s, 1H), 7.26 (d, J = 8.6
3
1
1
6
.5, CHCl ). IR (neat): υ 3428, 2964, 2925, 2361, 1452, 1218,
Hz, 2H), 6.88 (d, J = 8.6 Hz, 2H), 6.61 (td, J = 5.9, 1.2 Hz, 1H), 4.60−
4.35 (m, 2H), 4.13 (m, 1H), 3.88 (m, 1H), 3.80 (s, 3H), 2.55−2.45
(m, 2H), 1.78−1.70 (m, 4H), 1.64 (m, 1H), 1.27 (d, J = 6.2 Hz, 3H).
3
max
−1 1
103, 1022 cm . H NMR (CDCl , 300 MHz): δ 7.40−7.27 (m, 5H),
3
.98 (m, 1H), 5.50 (dt, J = 2.2, 1.5 Hz, 1H), 5.16−5.04 (m, 2H), 4.54
13
(
AB , J = 21.9, 12.0 Hz, 2H), 4.01 (m, 1H), 3.62−3.43 (m, 2H), 2.51−
C NMR (CDCl , 125 MHz): δ 195.1, 159.3, 150.7, 140.5, 130.0,
q
3
2
.28 (m, 2H), 2.13 (m, 1H), 1.63 (s, 3H), 0.88 (d, J = 6.8 Hz, 3H).
129.3, 113.9, 71.9, 70.1, 67.4, 55.2, 42.1, 36.8, 18.9, 9.4. ESI-HRMS:
1
3
+
C NMR (CDCl , 75 MHz): δ 138.3, 135.5, 134.1, 128.2, 127.5,
m/z calcd for C H O [M + Na] : 315.1566. Found: 315.1553.
3
17 24
4
1
27.4, 126.4, 116.5, 76.1, 73.2, 70.6, 69.1, 36.1, 30.9, 19.7, 13.6. ESI-
(2S,6R)-6-Allyl-2-((R)-2-((4-methoxybenzyl)oxy)propyl)-5-methyl-
+
25
HRMS: m/z calcd for C H O [M + H] : 273.1849. Found:
3,6-dihydro-2H-pyran (14e). Colorless liquid (82 mg, 88%), [α]
−5.7 (c 2.0, CHCl ). IR (neat): υmax 2930, 2359, 2341,1513, 1247,
D
18
25
2
273.1829.
3
−1 1
(
R,E)-7-(Benzyloxy)-5-hydroxy-2-methylhept-2-enal (13b). Pale
1219, 1062 cm . H NMR (CDCl
2H), 6.86 (d, J = 8.6 Hz, 2H), 5.95 (m, 1H), 5.49 (m, 1H), 5.12−5.03
, J = 11.8, 7.4 Hz, 2H), 4.03 (m, 1H), 3.93
3
, 500 MHz): δ 7.26 (d, J = 8.6 Hz,
25
yellow oil (150 mg, 80%) [α]D −9.2 (c 1.8, CHCl ). IR (neat):
υmax 3443, 2961, 2921, 2851, 1681, 1612, 1513, 1246, 1140, 1032
cm . H NMR (CDCl , 300 MHz): δ 9.43 (s, 1H) 7.39−7.28 (m,
3
(m, 2H), 4.55−4.33 (AB
q
−1 1
(m, 1H), 3.81 (m, 1H), 3.79 (s, 3H), 2.45−2.31 (m, 2H), 1.94−1.89
3
5
3
1
1
H), 6.63 (td, J = 6.0, 1.3 Hz, 1H), 4.54 (s, 2H), 4.06 (m, 1H), 3.80−
(m, 2H), 1.67 (m, 1H), 1.64 (s, 3H), 1.60−1.54 (m, 2H), 1.21 (d, J =
6.2 Hz, 3H). 13C NMR (CDCl
, 125 MHz): δ 159.0, 136.1, 135.0,
3
.64 (m, 2H), 3.28 (br s, 1H), 2.54 (dd, J = 6.7, 0.9 Hz, 2H), 1.92−
.97 (m, 2H), 1.75 (s, 3H). 13C NMR (CDCl , 75 MHz): δ 195.1,
50.4, 140.7, 137.5, 128.5, 127.9, 127.7, 73.4, 70.6, 69.0, 36.7, 36.0, 9.4.
131.1, 129.1, 119.9, 116.1, 113.7, 76.2, 71.7, 70.2, 63.8, 55.5, 43.8, 36.3,
3
+
31.5, 20.1, 19.9. ESI-HRMS: m/z calcd for C20H O [M + Na] :
28 3
+
ESI-MS for C H O : m/z [M + Na] 271. ESI-HRMS: m/z calcd for
C H O Na [M + Na] : 271.1304. Found: 271.1307.
339.1930. Found: 339.1918.
15
20
3
+
(5R,7R,E)-7-(Benzyloxy)-5-hydroxy-2-methyldocos-2-enal (13f).
15
20
3
25
(
2R,6S)-6-Allyl-2-(2-(benzyloxy)ethyl)-5-methyl-3,6-dihydro-2H-
Pale yellow viscous liquid (55 mg, 75%), [α]
D
−16.2 (c 1.6,
−1 1
25
pyran (14b). Colorless liquid (110 mg, 95%) [α]
CHCl ). IR (neat): υ 2915, 2857, 2359, 2342, 1453, 1219, 1100,
−31.5 (c 0.6,
CHCl ). IR (neat): υ 2923, 1401, 1219, 1033, 772 cm . H NMR
D
3
max
(CDCl , 500 MHz): δ 9.43 (s, 1H), 7.40−7.28 (m, 5H), 6.61 (td, J =
3
max
3
−1 1
1
059 cm . H NMR (CDCl , 500 MHz): δ 7.35−7.25 (m, 5H), 5.92
6.2, 0.9 Hz, 1H), 4.56 (AB , J = 16.2, 11.5 Hz, 2H), 4.13(m, 1H), 3.72
3
q
(
m, 1H), 5.49 (m, 1H), 5.12−5.03 (m, 2H), 4.41 (AB , J = 11.9, 7.4
(m, 1H), 3.14 (br s, 1H), 2.56−2.45 (m, 2H), 1.81 (m, 1H), 1.75 (m,
1H), 1.73−1.49 (m, 5H), 1.36−1.18 (m, 23H), 0.88 (t, J = 6.7 Hz,
q
Hz, 2H), 4.02 (m, 1H), 3.86 (m, 1H), 3.66−3.55 (m, 2H), 2.44−2.30
F
DOI: 10.1021/jo502101u
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
+
3
1
2
4
H). 13C NMR (CDCl , 125 MHz): δ 195.1, 150.5, 140.6, 137.4,
MS for C H O: m/z [M + Na] 251. ESI-HRMS: m/z calcd for
3
16 20
+
30.1, 128.4, 127.8, 76.9, 71.1, 67.5, 39.1, 36.9, 33.0, 31.8, 29.5, 29.6,
C H O [M + Na] : 251.1406. Found: 251.1417.
(R,E)-5-Hydroxy-2-methyl-7-phenylhept-2-enal (13j). Pale yellow
−2.4 (c 0.8, CHCl ). IR (neat): υmax
3426, 2924, 1678, 1641, 1402, 1219, 1051 cm . H NMR (CDCl ,
16
20
+
9.2, 25.4, 22.6, 14.0. ESI-HRMS: m/z calcd for C H O [M + Na] :
30
50
3
25
D
81.3652. Found: 481.3640.
2R,6S)-6-Allyl-2-((R)-2-(benzyloxy)heptadecyl)-5-methyl-3,6-di-
liquid (180 mg, 79%), [α]
3
−
1 1
(
3
25
hydro-2H-pyran (14f). Colorless liquid (40 mg, 92%), [α]D −11.3 (c
500 MHz): δ 9.42 (s, 1H) 7.35−7.17 (m, 5H), 6.60 (td, J = 6.2, 0.9
−1
1
.0, CHCl ). IR (neat): υ 2923, 2853, 2356, 1614, 1459, 1065 cm .
Hz, 1H), 3.86 (quin, J = 6.0 Hz, 1H), 2.90−2.65 (m, 2H), 2.61−2.55
3
max
1
13
H NMR (CDCl , 500 MHz): δ 7.37−7.27 (m, 5H), 5.92 (m, 1H),
(m, 2H), 1.90−1.82 (m, 2H), 1.76 (s, 3H). C NMR (CDCl , 75
3
3
5
.50 (m, 1H), 5.13−5.01 (m, 2H), 4.51 (AB , J = 27.9, 11.3 Hz, 2H),
MHz): δ 195.2, 150.7, 141.2, 140.5, 128.2, 128.1, 125.7, 69.7, 38.6,
q
+
4
1
0
1
3
.03 (m, 1H), 3.93 (m, 1H), 3.70 (m, 1H), 2.43−2.26 (m, 2H), 1.98−
36.7, 31.7, 9.4. ESI-HRMS: m/z calcd for C14
H
18
O
2
[M + Na] :
.86 (m, 2H), 1.64 (s, 3H), 1.63−1.53 (m, 6H), 1.29−1.21 (m, 24H),
241.1212. Found: 241.1249
.88 (t, J = 6.7 Hz, 3H). 13C NMR (CDCl , 125 MHz): δ 139.1, 136.1,
(
2R,6R)-6-Allyl-5-methyl-2-phenethyl-3,6-dihydro-2H-pyran (14j).
Colorless liquid (140 mg, 88%) [α]D −8.7 (c 1.6, CHCl ). IR (neat):
υmax 2922, 2852, 1729, 1456, 1376, 1285, 1092, 1037 cm . H NMR
3
25
35.0, 128.2, 127.6, 127.3, 119.9, 116.1, 76.1, 76.0, 70.9, 64.1, 41.0,
6.3, 34.0, 31.9, 31.6, 29.9, 29.7, 29.6, 29.3, 24.7, 22.6, 19.9, 14.1. ESI-
3
−
1 1
+
(CDCl , 300 MHz): δ 7.33−7.14 (m, 5H), 5.98 (m, 1H), 5.49 (m,
HRMS: m/z calcd for C H O [M + Na] : 505.4016. Found:
3
33
54
2
1
2
H), 5.17−5.03 (m, 2H), 4.07 (d, J = 8.2 Hz, 1H), 3.69 (m, 1H),
505.3999.
.90−2.78 (m, 1H), 2.62 (m, 1H), 2.42−2.36 (m, 2H), 1.98−1.90 (m,
(
S,E)-5-((R)-2,2-Dimethyl-1,3-dioxolan-4-yl)-5-hydroxy-2-methyl-
25
13
pent-2-enal (13g). Colorless liquid (72 mg, 80%), [α]D −2.2 (c 3.0,
CHCl ). IR (neat): υ
2H), 1.85 (m, 1H), 1.75 (m, 1H), 1.65 (s, 3H). C NMR (CDCl
3
, 75
−1
1
MHz): δ 142.1, 135.7, 135.0, 128.1, 125.4, 119.5, 116.1, 75.6, 66.3,
7.2, 36.2, 32.0, 31.0, 19.7. ESI-HRMS: m/z calcd for C H O [M +
2360, 1680, 1219, 772 cm . H NMR
3
max
3
(
CDCl , 500 MHz): δ 9.43 (s, 1H), 6.66 (td, J = 6.0, 1.1 Hz, 1H),
17 23
3
+
H] : 243.1743. Found: 243.1748.
3
3
1
.19−3.24 (m, 2H), 3.56−3.61 (m, 2H), 2.63−2.44 (m, 2H), 1.77 (s,
13
(S,E)-7-(4-((tert-Butyldimethylsilyl)oxy)phenyl)-5-hydroxy-2-
methylhept-2-enal (13k). Colorless liquid (74 mg, 78%), [α]D +6.4
(c 1.4, CHCl ). IR (neat): υ 3432, 2927, 2360, 1684, 1399, 1219
cm . H NMR (CDCl , 500 MHz): δ 9.42 (s, 1H),7.04 (d, J = 8.4 Hz,
2H), 6.76 (d, J = 8.4 Hz, 2H), 6.60 (dt, J = 6.0, 1.13 Hz, 1H), 3.89
quin, J = 6.2 Hz, 1H), 2.81−2.50 (m, 4H), 1.87−1.77 (m, 2H), 1.76
(s, 3H), 0.98 (s, 9H), 0.18 (s, 6H). C NMR (CDCl , 75 MHz): δ
H), 1.66−1.56 (m, 6H). C NMR (CDCl , 75 MHz): δ 195.0, 149.8,
3
2
5
41.0, 109.9, 77.7, 70.6, 64.8, 36.1, 34.5, 25.0, 23.6, 9.3. ESI-HRMS:
+
3
max
m/z calcd for C H O [M + Na] : 237.1105. Found: 237.1128.
11
18
4
−1 1
3
(
2S,6R)-6-Allyl-2-((R)-2,2-dimethyl-1,3-dioxolan-4-yl)-5-methyl-
25
3
,6-dihydro-2H-pyran (14g). Colorless liquid (50 mg, 94%), [α]D
(
−
4.1 (c 1.0, CHCl ). IR (neat): υ 2923, 2852, 2352, 1642, 1452,
3 max
13
−1
1
1
384, 1219, 1065 cm . H NMR (CDCl , 500 MHz): δ 5.89 (m, 1H),
3
3
1
2
95.1, 153.7, 150.2, 133.8, 129.1, 120.0, 70.1, 39.0, 36.9, 31.1, 29.6,
5.6, 9.46, −4.4. ESI-HRMS: m/z calcd for C H O Si [M + Na] :
5
.54 (m, 1H), 5.14−5.05 (m, 2H), 4.09−4.01 (m, 2H), 3.98−3.91 (m,
+
2
3
H), 3.56 (m, 1H), 2.46−2.31 (m, 2H), 2.23−2.01 (m, 2H), 1.65 (s,
20 32
3
H), 1.60 (s, 6H). 13C NMR (CDCl , 75 MHz): δ 135.6, 134.9, 119.2,
371.2012. Found: 371.2023.
(
3
4-(2-((2S,6S)-6-Allyl-5-methyl-3,6-dihydro-2H-pyran-2-yl)ethyl)-
phenoxy)(tert-butyl)dimethylsilane (14k). Colorless liquid (50 mg,
116.5, 109.6, 77.7, 75.9, 68.6, 67.0, 36.5, 36.3, 34.7, 28.0, 25.1, 24.0,
+
23.7, 19.8. ESI-HRMS: m/z calcd for C H O [M +Na] : 261.1468.
14
22
3
25
8
6%), [α]D −8.4 (c 1.0, CHCl ). IR (neat): υ 2922, 2853, 1732,
−1 1
3
max
FoundL 261.1488.
1
609, 1462, 1255, 1168, 1101, 1051 cm . H NMR (CDCl , 500
3
(
S,E)-5-Hydroxy-2-methyl-5-((R)-1,4-dioxaspiro[4.5]decan-2-yl)-
25
MHz): δ 7.05 (d, J = 8.5 Hz, 2H), 6.76 (d, J = 8.5 Hz, 2H), 5.96 (m,
H), 5.48 (m, 1H), 5.14−5.05 (m, 2H), 4.06 (m, 1H), 3.66 (m, 1H),
2.77 (m, 1H), 2.56 (m, 1H), 2.41−2.33 (m, 2H), 1.98−1.90 (m, 2H),
.86−1.66 (m, 2H), 1.64 (s, 3H), 0.97 (s, 9H), 0.17 (s, 6H). C NMR
CDCl , 75 MHz): δ 153.5, 135.9, 135.2, 135.0, 129.1, 119.8, 119.6,
116.3, 75.9, 66.6, 37.5, 36.4, 31.3, 31.1, 25.6, 19.8, 18.1, −4.4. ESI-
HRMS: m/z calcd for C H O Si [M + H] : 373.2557. Found:
73.2535.
S)-tert-Butyl-4-((R,E)-1-hydroxy-4-methyl-5-oxopent-3-en-1-yl)-
,2-dimethyloxazolidine-3-carboxylate (13l). Colorless liquid (90
pent-2-enal (13h). Yellow liquid (130 mg, 76%), [α]D −5.1 (c 2.1,
CHCl ). IR (neat): υ 3447, 2922, 2852, 1720, 1681, 1642, 1407,
1
3
max
−1 1
1
1
2
334, 1251, 1098, 1043 cm . H NMR (CDCl , 300 MHz): δ 9.44 (s,
3
13
1
H), 6.65 (td, J = 6.0, 1.1 Hz, 1H), 4.12−4.00 (m, 2H), 3.99−3.87 (m,
(
3
H), 2.69−2.42 (m, 2H), 1.78 (s, 3H), 1.68−1.55 (m, 8H), 1.48−1.37
m, 2H). 1 C NMR (CDCl , 75 MHz): δ 195.0, 149.6, 141.0, 109.9,
3
(
3
+
23
36
2
7
7.7, 70.6, 64.7, 36.1, 34.5, 32.6, 29.6, 25.0, 23.9, 23.6, 9.3. ESI-HRMS:
3
+
m/z calcd for C H O [M + Na] : 277.1416. Found: 277.1411.
14
22
4
(
(
R)-2-((2S,6R)-6-Allyl-5-methyl-3,6-dihydro-2H-pyran-2-yl)-1,4-
2
25
dioxaspiro[4.5]decane (14h). Colorless liquid (105 mg, 90%), [α]D
25
mg, 75%), [α]D +10.3 (c 2.5, CHCl ). IR (neat): υ 3432, 2927,
3
max
−
4.8 (c 1.0, CHCl ). IR (neat): υ 3422, 2926, 2859,1219, 1049
−1 1
3
max
2
361, 1685, 1508, 1400, 1219 cm . H NMR (CDCl , 500 MHz): δ
−1
1
3
cm . H NMR (CDCl , 300 MHz): δ 5.89 (m, 1H), 5.54 (m, 1H),
3
9
.43 (S, 1H), 6.73 (m, 1H), 4.20 (brs, 1H), 4.10 (m, 1H), 4.05−3.95
5
=
.17−5.03 (m, 2H), 4.09−4.00 (m, 2H), 3.99−3.90 (m, 2H), 3.60 (t, J
(
(
m, 2H), 3.94−3.80 (m, 2H), 2.62−2.39 (m, 2H), 1.76 (s, 3H), 1.61
6.8 Hz, 1H), 2.41−2.33 (m, 2H), 2.15−2.01 (m, 1H), 1.96−1.85 (m,
13
m, 3H), 1.53−1.45 (m, 12H). C NMR (CDCl , 75 MHz): δ 195.0,
13
3
1
H), 1.65 (s, 3H), 1.63−1.53 (m, 9H). C NMR (CDCl , 75 MHz):
3
1
54.5, 151.3, 140.5, 94.5, 81.6, 72.6, 65.0, 62.0, 32.4, 28.2, 26.3, 23.8.
δ 135.6, 134.9, 119.2, 116.5, 109.6, 77.7, 75.9, 68.6, 67.1, 61.3, 36.5,
6.3, 34.8, 28.0, 25.1, 24.0, 23.7, 19.8. ESI-HRMS: m/z calcd for
+
ESI-HRMS: m/z calcd for C H O N [M + Na] : 336.1781. Found:
16
27
5
3
3
36.1767.
+
C H O [M + H] : 279.1954. Found: 279.1951.
17
27
3
(S)-tert-Butyl-4-((2R,6S)-6-allyl-5-methyl-3,6-dihydro-2H-pyran-2-
yl)-2,2-dimethyloxazolidine-3-carboxylate (14l). Colorless liquid (70
mg, 85%), [α]D +36.7 (c 1.5, CHCl ). IR (neat): υ 2922, 2853,
730, 1700, 1460, 1379, 1209, 1044 cm . H NMR (CDCl , 500
(
S,E)-5-Hydroxy-2-methyl-6-phenylhex-2-enal (13i). Pale yellow
25
liquid (220 mg, 77%), [α]D +3.6 (c 1.1, CHCl ). IR (neat): υ
3
25
3
max
3
max
−1
1
−1 1
417, 2923, 2360, 1682, 1402, 1219, 1055, 1079 cm . H NMR
1
3
(
CDCl , 500 MHz): δ 9.43 (s, 1H), 7.38−7.18 (m, 5H), 6.65 (t, J =
3
MHz): δ 5.89 (m, 1H), 5.52 (d, J = 12.2, 1H), 5 0.18−5.04 (m, 2H),
7
1
1
.1 Hz, 1H), 4.06 (m, 1H), 2.92−2.72 (m, 2H), 2.64−2.52 (m, 2H),
4
.18 (d, J = 7.9 Hz, 1H), 4.09 (d, J = 7.9 Hz,1H), 3.92 (m, 1H), 3.86−
.76 (s, 3H). 13C NMR (CDCl , 75 MHz): δ 195.0, 150.1, 140.9,
3
3.68 (m, 2H), 2.46−2.30 (m, 2H), 2.11 (m, 1H), 1.91 (m, 1H), 1.64
13
37.5, 129.3, 128.7, 126.8, 71.6, 43.0, 36.4, 9.4. ESI-HRMS: m/z calcd
(s, 3H), 1.57 (s, 3H), 1.51−1.43 (m, 12H). C NMR (CDCl , 75
3
+
for C H O [M + Na] : 227.1042. Found: 227.1041.
MHz): δ 152.7, 135.9, 135.0, 119.7, 116.8, 93.6, 79.9, 76.5, 66.6, 63.9,
60.2, 36.3, 29.6, 28.4, 27.2, 24.6, 19.8. ESI-HRMS: m/z calcd for
13
16
2
(
2S,6R)-6-Allyl-2-benzyl-5-methyl-3,6-dihydro-2H-pyran (14i).
25
+
Colorless liquid (170 mg, 92%), [α]D −2.2 (c 1.5, CHCl ). IR
C H NO [M + Na] : 360.2145. Found: 360.2135.
(R)-6-(Benzyloxymethyl)-5,6-dihydro-2H-pyran-2-ol (17). Lactone
(1.0 g, 4.0 mmol) was dissolved in CH Cl (15 mL) and cooled to
−78 °C under nitrogen atmosphere. DIBAL-H (3.5 mL, 4.8 mmol, 1.4
M in toluene) was slowly added to it over a period of 10 min at −78
°C. After 30 min of stirring at the same temperature, TLC was checked
and showed complete consumption of the starting material. The
3
19 31
4
−
1 1
(
neat): υmax 3417, 2929, 2357, 1719, 1451, 1274, 1219, 1110 cm . H
NMR (CDCl , 500 MHz): δ 7.30−7.18 (m, 5H), 5.70 (m, 1H), 5.48
3
2
2
(
m, 1H), 4.96−4.91 (m, 2H), 4.04 (d, J = 8.1 Hz, 1H), 3.89 (m, 1H),
2
1
1
.87 (m, 1H), 2.70 (m, 1H), 1.36−2.25 (m, 2H), 2.90−1.90 (m, 2H),
.63 (s, 3H). 13C NMR (CDCl , 75 MHz): δ 138.8, 135.5, 135.3,
3
29.3, 128.1, 126.0, 119.5, 116.1, 76.1, 68.5, 42.0, 36.4, 30.7, 19.7. ESI-
G
DOI: 10.1021/jo502101u
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
−
1 1
reaction was quenched by slow addition of a saturated solution of
sodium potassium tartrate (40 mL), diluted with CH Cl (50 mL),
1032 cm . H NMR (CDCl , 300 MHz): δ 4.02 (br s, 1H), 3.38−
3
3.30 (m, 2H), 2.07 (m, 1H), 1.93−1.63 (m, 3H), 1.63−1.29 (m, 2H),
2
2
13
and allowed to stir at room temperature for an additional 2 h to get
two separated layers. The organic layer was separated and the aqueous
layer was extracted with CH Cl (3 × 40 mL). The combined organic
1.28−1.16 (m, 2H). C NMR (CDCl , 75 MHz): δ 67.0, 55.4, 55.3,
3
+
28.5, 22.9, 18.4. ESI-HRMS: m/z calcd for C H O [M + H] :
6
11
2
115.0753. Found: 115.0754.
2
2
layer was washed with brine (2 × 75 mL), dried over anhydrous
(1S,2S,6S)-2-(Benzyloxy)-7-oxabicyclo[4.1.0]heptanes (23). Alco-
hol 26 (5.0 g, 43.8 mmol) in THF (30 mL) was added slowly to a
suspension of NaH (2.6 g, 65.7 mmol) in anhydrous THF (30 mL) at
0 °C. After 20 min, benzyl bromide (5.25 mL, 44.2 mmol) was added
dropwise at 0 °C. The reaction mixture was stirred for 6 h at room
temperature. After completion (monitored by TLC), the reaction
mixture was quenched with ice-cooled water (40 mL) and diluted with
ethyl acetate (50 mL). The organic layer was separated and the
aqueous layer was extracted with ethyl acetate (3 × 50 mL). The
combined organic layers were dried with Na SO , concentrated under
Na SO , and evaporated to dryness under vacuum, which on silica gel
2
4
column chromatography (ethyl acetate/hexane = 1:4) produced the
desired lactol 17 (0.83 g, 83%) as a colorless liquid. [α]D25 −36.2 (c
1
.0, CHCl ). IR (neat): υ 3444, 2926, 1683, 1384, 1251, 1098, 1026
3 max
−1
1
cm . H NMR (CDCl , 300 MHz): δ 7.37−7.25 (m, 5H), 5.63
3
(
(
m,1H), 5.17 (m, 1H), 4.55−4.44 (m, 2H), 4.07 (m, 1H), 3.66−3.56
13
m, 2H), 2.02−1.92 (m, 2H), 1.92−1.80 (m, 2H), 1.68 (s, 3H).
C
NMR (CDCl , 75 MHz): δ 138.3, 132.1, 128.3, 127.7, 127.5, 127.4,
3
1
22.9, 93.4, 72.9, 67.0, 64.2, 35.6, 30.8, 18.9. ESI-HRMS: m/z calcd for
2
4
+
C H O [M + Na] : 271.1304. Found: 271.1295.
reduced pressure, and purified by silica gel column chromatography
(ethyl acetate/hexane = 1:6) to afford compound 23 (7.7 g, 87%) as a
colorless liquid. [α]D27 −13.6 (c 1.0, CHCl ). IR (neat): υ 2952,
15
20
3
(
R)-(6-(Benzyloxymethyl)-5,6-dihydro-2H-pyran-2-yloxy)-
trimethylsilane (18). To a stirring solution of lactol 17 (0.5 g, 2.0
3
max
−1 1
mmol) in dry CH Cl (15 mL) was added imidazole (0.27 g, 4.0
2357, 1454, 1219, 1074 cm . H NMR (CDCl , 300 MHz): δ 7.43−
2
2
3
mmol) at 0 °C under nitrogen atmosphere. After 20 min, a solution of
TMSCl (0.4 mL, 3.0 mmol) was added dropwise. After completion of
the reaction (monitored by TLC), water (20 mL) was added to the
reaction mixture and two layers were separated. The aqueous layer was
extracted with CH Cl (2 × 25 mL), and the combined organic layer
7.26 (m, 5H), 4.70 (m, 2H), 3.80 (m, 1H), 3.31 (dd, J = 2.2 1.5
Hz,1H), 3.27 (dt, J = 3.7, 1.5 Hz, 1H), 1.86−1.77 (m, 2H), 1.80−1.49
(m, 2H), 1.23 (m, 1H). 13C NMR (CDCl , 75 MHz): δ 138.3, 128.1,
3
127.4, 127.3, 74.2, 69.8, 53.8, 53.1, 24.6, 22.7, 19.4. ESI-HRMS: m/z
+
2
2
calcd for C H O [M + Na] : 227.1042. Found: 227.1041.
13 16
2
was washed with brine (2 × 30 mL), dried over anhydrous Na SO ,
(1S,2S,6S)-2-(Benzyloxy)-6-vinylcyclohexanol (27). To a solution
of 23 (5.0 g, 24.4 mmol) in anhydrous THF (60 mL) under nitrogen
atmosphere, CuI (0.41 g, 2.44 mmol) was added and the resulting
mixture was stirred at 25 °C for 30 min. It was cooled to −20 °C,
C H MgBr (85.4 mL, 1.0 M in THF) was slowly added, and the
2
4
and concentrated under reduced pressure to get the crude product,
which was purified by flash column chromatography over silica gel
(
ethyl acetate/hexane = 1:20) to furnish the desired TMS-protected
25
lactol 18 (0.56 g, 88%) as a colorless liquid. [α]D −12.2 (c 1.0,
CHCl ). IR (neat): υ 2942, 1723, 1454, 1098, 1064 cm . H NMR
2
3
−1 1
3
max
reaction mixture was stirred at the same temperature for 30 min. It was
(
(
CDCl , 500 MHz): δ 7.37−7.26 (m, 5H), 5.65−5.56 (m, 1H), 5.08
then slowly warmed to room temperature. After 1 h (monitored by
3
m, 1H), 4.51 (dd, J = 11.7, 26.4 Hz, 2H), 4.07 (m, 1H), 3.55 (m,
TLC), it was quenched with saturated NH Cl solution (50 mL) and
4
2
3
1
H), 2.00−1.89 (m, 2H), 1.89−1.79 (m, 2H), 0.18 (s, 6H), 0.16 (s,
diluted with ethyl acetate (75 mL). The organic layer was separated
and the aqueous layer was extracted with ethyl acetate (3 × 60 mL).
The combined organic layers were washed with brine (2 × 150 mL),
dried over anhydrous Na SO , and concentrated under reduced
H). 13C NMR (CDCl , 125 MHz): δ 138.3, 132.2, 128.3, 127.5,
3
27.4, 123.0, 93.4, 72.9, 67.0, 64.2, 35.7, 30.8, 18.9, 1.3. ESI-HRMS:
+
m/z calcd for C H O Si [M + Na] : 343.1699. Found: 343.1693.
18
28
3
2
4
(
2R,6S)-6-Allyl-2-(benzyloxymethyl)-3,6-dihydro-2H-pyran (19).
pressure to afford the crude product, which on purification by column
chromatography over silica gel using (ethyl acetate/hexane = 1:5)
furnished the desired product 27 (4.8 g, 86%) as a colorless liquid.
[α]D27 −9.1 (c 1.6, CHCl ). IR (neat): υ 3434, 3064, 2933, 2357,
To a stirred solution of TMS-protected lactol (0.3 g, 0.93 mmol)
and allyltrimethylsilane (0.3 mL, 1.87 mmol) in THF (8 mL) was
added zinc bromide (41 mg, 0.18 mmol) at 0 °C under nitrogen
atmosphere, and the solution was allowed to come to room
temperature. After completion of the reaction (as indicated by
TLC) (30 min), the reaction mixture was quenched with a saturated
3
max
−1 1
1639, 1454, 1219, 1094 cm . H NMR (CDCl , 300 MHz): δ 7.42−
3
7.26 (m, 5H), 6.82 (m, 1H), 5.15−5.05 (m, 2H), 4.50 (AB , J = 47.5
q
Hz, 12.1 Hz, 2H), 3.80 (m, 1H), 3.32 (m, 1H), 2.39 (m, 1H), 2.08 (m,
solution of NaHCO (5 mL) and diluted with ethyl acetate (10 mL).
The organic layer was separated and the aqueous layer was extracted
1H), 1.75 (m, 1H), 1.58 (m, 1H), 1.55 (m, 1H), 1.32−1.14 (m, 2H).
3
13
C NMR (CDCl , 75 MHz): δ 140.9, 138.6, 128.4, 128.3, 127.6,
3
with ethyl acetate (2 × 10 mL). The combined organic layers were
127.5, 115.2, 76.9, 74.3, 70.8, 44.4, 29.9, 27.6, 19.1. ESI-MS for
+
dried over anhydrous Na SO4 and concentrated under reduced
C H O : m/z [M + Na] 255. ESI-HRMS: m/z calcd for C H O
[M + H] : 233.1536. Found: 233.1523.
2
15 20
2
15 21
2
+
pressure. The crude product was purified by silica gel column
chromatography (ethyl acetate/hexane = 1:20) to obtain the C-
allylated product 14b (0.23 g, 90%).
(2S,3S)-3-(Benzyloxy)-2-hydroxycyclohexanecarbaldehyde (28).
To a stirred solution of 27 (4.0 g, 17.2 mmol) in 1,4-dioxane and
(
1R,2S,6S)-7-Oxabicyclo[4.1.0]heptan-2-ol (26). Molecular sieves
water (3:1) (40 mL), 2,6-lutidine (4.0 mL, 34.4 mmol) and OsO (84
4
i
(
4 Å, 12.0 g) were added to a stirred solution of Ti(O Pr) (3.1 mL,
mg, 0.33 mmol) followed by NaIO4 (14.6 g, 68.8 mmol) were
sequentially added at room temperature and stirred for 4 h at room
temperature. After completion of the reaction (monitored by TLC),
1,4-dioxane was removed under reduced pressure and the residue was
was diluted with CH Cl (50 mL). The organic layer was separated
4
1
1.2 mmol) and D-(−)-diisopropyl tartrate (3.34 mL, 14.2 mmol) in
CH Cl (60 mL) at −20 °C, and the reaction mixture was stirred
vigorously for 30 min. Allyl alcohol 25 (10.0 g, 102.0 mmol) dissolved
2
2
in CH Cl (40 mL) was added to the reaction mixture at the same
2
2
2
2
temperature and stirred again for 30 min followed by addition of tert-
butyl hydroperoxide (6M, 10.1 mL, 61.1 mmol). The stirring was
continued at the same temperature for 24 h. After completion of the
reaction (monitored by TLC), the reaction mixture was filtered
through Celite and washed with CH Cl (3 × 50 mL). The filtrate was
and the aqueous layer was extracted with CH Cl (2 × 50 mL). The
2 2
combined organic layer was quickly washed with 1 N HCl (2 × 75
mL) to remove excess 2,6-lutidine followed by brine (2 × 75 mL). The
organic layer was dried over anhydrous Na SO and concentrated
2
4
2
2
under reduced pressure to get the crude aldehyde, which on
purification through a short silica gel column (ethyl acetate/hexane
= 1:1) afforded aldehyde 28 (3.4 g, 85%) as a colorless liquid.
(E)-3-((1S,2S,3S)-3-(Benzyloxy)-2-hydroxycyclohexyl)-2-methyl-
acryl aldehyde (22). To a stirred solution of 28 (3.0 g, 12.8 mmol) in
toluene (64 mL, 0.2M) was added 2-(triphenylphosphoranylidene)-
propionaldehyde (6.1 g, 19.2 mmol), and the solution was heated at 85
°C for 12 h. After completion of the reaction (monitored by TLC), the
reaction mixture was cooled and the solvent was removed under
reduced pressure. The remaining oil was triturated with cold hexane
quenched with water (23.0 mL) followed by addition of 20% NaOH
solution (60 mL). The mixture was saturated with NaCl and stirred at
room temperature for 3 h. The layers were separated and the aqueous
layer was extracted with CH Cl (2 × 100 mL). The combined organic
2
2
layer was washed with brine (2 × 150 mL), dried over anhydrous
Na SO , and concentrated under reduced pressure. The residue was
2
4
purified on silica gel column chromatography (ethyl acetate/hexane =
:4) to afford epoxy alcohol 26 (5.1 g, 44%) as a colorless liquid.
α]D27 −4.8 (c 2.5, CHCl ). IR (neat): υ 3388, 2933, 1219, 1059,
1
[
3
max
H
DOI: 10.1021/jo502101u
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
(
40 mL), and the insoluble triphenylphosphine oxide was precipitated
1H), 4.62 (d, J = 12.3 Hz, 1H), 4.44 (d, J = 6.4 Hz,1H), 3.83 (m, 1H),
3.26 (dd, J = 7.7, 2.2 Hz, 1H), 2.58 (m, 1H), 2.14−1.95 (m, 3H),
1.79−1.61 (m, 3H), 1.59 (s, 3H), 1.47−1.21 (m, 14H), 1.02−0.83 (m,
out. The precipitate was filtered, and the solid mass was rinsed with
hexane (2 × 40 mL). The filtrate was concentrated to give an oil,
which underwent purification by flash chromatography over silica gel
5H). 13C NMR (CDCl , 75 MHz): δ 139.6, 134.5, 133.3, 132.1, 128.0,
3
(
ethyl acetate/hexane = 1:6) to obtain 22 (2.59 g, 74%) as a colorless
127.5, 127.3, 127.2, 126.9, 126.2, 77.8, 75.7, 75.4, 71.2, 35.5, 33.6, 32.3,
27
liquid. [α]D −20.4 (c 4.5, CHCl ). IR (neat): υ 3434, 2928, 1685,
31.6, 30.7, 29.5, 29.1, 28.8, 22.6, 20.3, 19.8, 14.0. ESI-HRMS: m/z
3
max
−1
1
+
1
7
1
1
1
1
2
2
453, 1219, 1091 cm . H NMR (CDCl , 500 MHz): δ 9.41 (m, 1H),
calcd for C26
H
38
O
2
[M + NH
4
] : 400.3217. Found: 400.3205.
3
.41−7.29 (m, 5H), 6.40 (dd, J = 8.4, 1.0 Hz, 1H), 4.50 (AB , J = 47.6,
(3R,E)-6-Methyl-1-phenyldeca-5,9-diene-3,7-diol (19). To a stirred
solution of unsaturated aldehyde 13j (0.2 g, 0.91 mmol) in THF (10
mL) was added allyl magnesium bromide (2.73 mL, 2.73 mmol, 1.0 M
in diethyl ether) at −78 °C, and the reaction mixture was stirred for 2
h at −20 °C. After completion of the reaction (monitored by TLC),
q
2.1 Hz, 2H), 3.84 (m, 1H), 3.46 (dd, J = 7.0, 2.9 Hz, 1H), 2.99 (m,
H), 2.16 (m, 1H), 1.77 (s, 3H), 1.74−1.59 (m, 2H), 1.51 (m, 1H),
.38(m, 1H), 1.20 (m, 1H). 13C NMR (CDCl , 75 MHz) δ 195.3,
3
56.6, 139.9, 138.1, 128.3, 127.6, 127.5, 76.5, 74.4, 70.7, 40.6, 29.3,
+
7.2, 18.6, 9.5. ESI-HRMS: m/z calcd for C H O [M + Na] :
the reaction mixture was quenched with a saturated solution of NH Cl
4
17
22
3
97.1461. Found: 297.1455.
2R,4aS,8S,8aS)-2-Allyl-8-(benzyloxy)-3-methyl-4a,5,6,7,8,8a-
(15 mL) and diluted with ethyl acetate (20 mL). The organic layer was
separated and the aqueous layer was extracted with ethyl acetate (2 ×
20 mL).The combined organic layer was washed with brine (20 mL),
(
hexahydro-2H-chromene (21). Zinc bromide (0.32 g, 1.44 mmol)
was added to a stirred solution of δ-hydroxyl-α-methyl-α,β-unsaturated
aldehyde 22 (2.0 g 7.2 mmol) and allyltrimethyl silane (1.72 mL, 10.8
mmol) in THF (30 mL) at room temperature. After completion of the
reaction (monitored by TLC), the reaction mixture was quenched
dried over anhydrous Na SO , and evaporated under reduced pressure.
2 4
The crude product was purified by silica gel chromatography (ethyl
acetate/hexane = 1:1) to afford diastereomeric mixture 19 (190 mg,
2
5
83% over two steps) as a colorless oil. [α]
(neat): υmax 3398, 2925, 2856, 1723, 1445, 1047 cm . H NMR
(CDCl
−16.2 (c 1.0, CHCl ). IR
D
3
−1
1
with a saturated solution of NaHCO (20 mL) and diluted with ethyl
3
acetate (40 mL). The organic layer was separated and the aqueous
layer was extracted with ethyl acetate (2 × 40 mL). The combined
organic layers were dried over anhydrous Na SO and concentrated
under reduced pressure to give a pale yellow oil, which on purification
by silica gel column chromatography (ethyl acetate/hexane = 1:19)
afforded the cyclized product 21 (1.95 g, 90%). [α]D27 +3.2 (c 2.0,
CHCl ). IR (neat): υ 3067, 3029, 2930, 2858, 1640, 1495, 1452,
1
7
(
=
3
, 500 MHz): 7.31−7.14 (m, 5H), 5.74 (m, 2H), 5.46 (m, 1H),
5.20−5.04 (m, 2H), 4.09 (m, 1H), 3.65 (m, 1H), 2.87−2.62 (m, 2H),
2.39−2.28 (m, 2H), 2.27−2.18 (m, 2H), 1.83−1.73 (m, 2H), 1.64 (s,
2
4
3H). 13C NMR (CDCl
, 125 MHz): δ 142.0, 139.8, 134.6, 128.4,
3
128.3, 125.8, 121.8, 121.6, 117.8, 76.3, (76.2), 70.8, (70.7), 39.8, 38.5,
38.4, 35.5, 32.1, 12.1, (12.0). ESI-HRMS: m/z calcd for C17 [M
H O
24 2
+
+ NH ] : 278.2114. Found: 278.2108.
3
max
4
−1 1
373, 1102, 1085, 1029 cm . H NMR (CDCl , 500 MHz): δ 7.43−
3
.20 (m, 5H), 5.96 (m, 1H), 5.36 (m, 1H), 5.13−5.02 (m, 2H), 4.70
ASSOCIATED CONTENT
■
AB , J = 21.9, 12.8 Hz, 2H), 4.13 (m, 1H), 3.80 (m, 1H), 3.23 (dd, J
q
*
S
Supporting Information
8.3, 1.5 Hz, 1H), 2.55 (m, 1H), 2.43−2.30 (m, 2H), 1.97 (m, 1H),
13
Copies of H and 13C NMR spectra for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
1
1
.71(m, 1H), 1.63 (s, 3H), 1.60 (m, 1H), 1.50−1.22 (m, 3H).
C
NMR (CDCl , 75 MHz): δ 139.5, 136.0, 134.4, 127.2, 126.9, 126.2,
1
HRMS: m/z calcd for C H O [M + Na] : 321.1825. Found:
3
15.6, 76.7, 75.1, 74.9, 71.0, 36.6, 33.6, 30.6, 29.5, 20.2, 19.4. ESI-
+
20
26
2
3
21.1816.
2R,4aS,8S,8aS)-8-(Benzyloxy)-3-methyl-2-((E)-prop-1-en-1-yl)-
a,5,6,7,8,8a-hexahydro-2H-chromene (29). To a solution of 21
AUTHOR INFORMATION
■
(
4
Corresponding Author
*E-mail: mohapatra@iict.res.in.
(
1.0 g, 3.35 mmol) in MeOH (8 mL) was added second-generation
Grubbs’ catalyst (0.28 g, 0.33 mmol) at room temperature. The
suspension was then heated at 60 °C. After 15 min the insoluble
catalyst was dissolved, and the resulting orange−brown solution was
stirred for 12 h at the same temperature. After completion of the
reaction, MeOH was evaporated. The residue was purified by column
chromatography over silica gel using (ethyl acetate/hexane = 1:19) to
give predominately (E)-alkene 29 (0.8 g, 80%) as a colorless liquid.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the Director, CSIR-IICT and HoD, NPCD, for
constant support and encouragement. The authors thank CSIR,
New Delhi, for financial support as part of XII Five Year plan
programme under title ORIGIN (CSC-0108). D.K.M. thanks
the CSIR for a research grant (INSA Young Scientist Award
Scheme). D.S.R. and B.P. thank the Council of Scientific and
Industrial Research (CSIR), New Delhi, India, for financial
assistance in the form of fellowship.
[
1
(
α]D25 −9.2 (c 2.5, CHCl ). IR (neat): υ 3406, 2925, 2854, 1721,
3
max
−1 1
273, 1219, 1067 cm . H NMR (CDCl , 300 MHz): δ 7.43−7.20
m, 5H), 5.73−5.55(m, 2H), 5.39 (m,1H), 4.69 (AB , J = 34.7, 12.0
3
q
Hz, 2H), 4.44 (d, J = 6.0 Hz, 1H), 3.83 (dt, J = 3.0, 2.2 Hz, 1H), 3.26
(
dd, J = 7.5, 2.2 Hz, 1H), 2.58 (m, 1H), 1.99 (m, 1H), 1.80−1.69 (m,
5
2
1
H), 1.61−1.54 (m, 4H), 1.49−1.25 (m, 3H), 1.01(dt, J = 9.0, 3.7 Hz,
H). 13C NMR (CDCl , 75 MHz): δ 139.6, 133.2, 129.0, 128.8, 128.0,
3
27.2, 126.9, 77.8, 75.7, 75.5, 71.2, 33.6, 30.7, 29.5, 20.2, 19.7, 17.8.
+
ESI-HRMS: m/z calcd for C H O [M + H] : 299.2005. Found:
20
27
2
REFERENCES
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99.1999.
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a,5,6,7,8,8a-hexahydro-2H-chromene (20). Isomerized alkene 29
■
(
(1) (a) Faulkner, D. J. Nat. Prod. Rep. 2002, 19, 1. (b) Norcross, R.
D.; Paterson, I. Chem. Rev. 1995, 95, 2041.
4
(
0.2 g, 0.67 mmol) and 1-nonene (4.37 mL, 3.35 mmol) were
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(5) (a) Ando, K.; Matsuura, I.; Nawata, Y.; Endo, H.; Sasaki, H.;
dissolved in CH Cl (10 mL), and argon gas was purged through it for
1
2
2
0 min. Grubbs’ second-generation catalyst (28 mg, 0.03 mmol) was
added to it at room temperature and again degassed for 10 min. The
reaction mixture was allowed to stir for 8 h. After completion of the
reaction (monitored by TLC), solvent was removed under reduced
pressure and directly purified by column chromatography over silica
gel (ethyl acetate/hexane = 1:49) to afford cross-product 20 (0.19 g,
7
2
7
2
5
8%) as a colorless liquid. [α] −5.3 (c 0.8, CHCl ). IR (neat) υ
D
3
max
−
1 1
925, 1219, 1033, 772 cm . H NMR (CDCl , 500 MHz): δ 7.41−
.21 (m, 5H), 5.68−5.53 (m, 2H), 5.39 (m,1H), 4.77 (d, J = 12.3 Hz,
3
Okytomi, T.; Saehi, T.; Tamura, G. J. Antibiot. 1978, 31, 533.
I
DOI: 10.1021/jo502101u
J. Org. Chem. XXXX, XXX, XXX−XXX

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