Iron-Catalyzed Prins-Peterson Reaction for the Direct Synthesis of δ4-2,7-Disubstituted Oxepenes

Article abstract of DOI:10.1021/acs.joc.8b01978

A direct iron(III)-catalyzed Prins-Peterson reaction involving α-substituted γ-triphenylsilyl bis-homoallylic alcohols and aldehydes is described. Thus, cis-⁴-2,7-disubstituted oxepenes were synthesized in a diastereoselective reaction using su

Full text of DOI:10.1021/acs.joc.8b01978

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Article
Iron-Catalyzed Prins-Peterson Reaction for the
Direct Synthesis of #4-2,7-disubstituted oxepenes.
Daniel A Cruz, Victoria Sinka, Victor S. Martin, and Juan Ignacio Padrón
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b01978 • Publication Date (Web): 25 Sep 2018
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IronꢀCatalyzed PrinsꢀPeterson Reaction for the Direct
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Synthesis of ꢁ ꢀ2,7ꢀdisubstituted oxepenes.
b
a
b
a,b
Daniel A. Cruz, Victoria Sinka, Víctor S. Martín, and Juan I. Padrón *
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a) Instituto de Productos Naturales y Agrobiología, Consejo Superior de
Investigaciones Científicas (IPNAꢀCSIC), Avda. Astrofísico Francisco Sánchez 3, 38206
La Laguna, Tenerife, Islas Canarias, Spain.
b)
Instituto Universitario de BioꢀOrgánica “Antonio González” (CIBICAN),
“Síntesis Orgánica Sostenible, Unidad Asociada al CSIC”, Departamento de Química
Orgánica, Universidad de La Laguna C/ Francisco Sánchez 2, 38206 La Laguna,
Tenerife Tenerife, Islas Canarias, Spain.
Eꢀmail: jipadron@ipna.csic.es
TOC
Abstract. A direct iron(III)ꢀcatalyzed PrinsꢀPeterson reaction involving αꢀsubstituted γꢀ
4
triphenylsilyl bisꢀhomoallylic alcohols and aldehydes is described. Thus cisꢀꢀ ꢀ2,7ꢀ
disubstituted oxepenes were synthesized in a diastereoselective reaction using
sustainable catalytic conditions (3ꢀ5 mol%). This highly productive process is the result
of a cascade of three chemical events with the concomitant formation of a CꢀO bond, a
4
CꢀC bond and a ꢀ endocyclic double bond, through a Prins cyclization followed by a
Petersonꢀtype elimination. This tandem reaction is chemoselective vs the classical Prins
cyclization.
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Introduction.
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Figure 1. Some representative examples of ladderꢀether marine toxins and
lauroxepanes.
Oxepenes, unsaturated sevenꢀmembered ring oxacycles, are common structural
units in the field of organic chemistry. Thus, they can be found in a number of natural
products from ladderꢀether marine toxins to lauroxanes, nonterpenoid C15ꢀmetabolites
1
,2
isolated from the Laurencia species of red algae. They can also act as synthetic
intermediates in the preparation of more complex structures such as the isoprelaurefucin
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ꢀ6
family (Figure 1).
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These oxepenes often have useful biological activities, so direct and efficient
new methods are still necessary. Several methodologies have been developed toward the
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synthesis of cyclic ethers based mainly on three different approaches: (a) formation of
a CꢀO bond, usually based on the nucleophilic attack of an oxygen functionality; (b) Cꢀ
C bond formation through a ringꢀclosing metathesis in an acyclic ether, and (c)
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simultaneous CꢀO and CꢀC bond formation around the oxygen of the cyclic ether.
Among these processes, those based on the Prins cyclization (c) have been less explored
in the synthesis of these unsaturated disubstituted oxacycles (Scheme 1).
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Scheme 1. Previous strategies and our method of accessing cisꢀꢁ ꢀ2,7ꢀdisubstituted
oxepenes.
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Several groups have reported the use of this approach. Overman and coꢀworkers
obtained unsaturated oxacycles from mixed acetals, and later Yu and coꢀworkers
developed a twoꢀstep synthesis of oxepenes using palladium catalysis. However, an
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undesired excess of harsh Lewis acid, as well as highly toxic organotin reagents were
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used, giving rise to undesired byproducts (Scheme 1).
In 1989, Miginiac et al. described the reaction of ωꢀsilyloxyallyltrimethylsilanes
.
with aldehydes, using stoichiometric amounts of BF
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OEt
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as Lewis acid, which yielded
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ꢀalkylꢀmonosubstituted oxepenes. This report remained virtually unnoticed until it
was rediscovered by Suginome et al. (2001) and Panek et al. (2009) in order to
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synthesize monosubstituted oxepene derivatives. Despite its potential as a synthetic
tool, to the best of our knowledge, no further attempts towards the synthesis of 2,7ꢀ
disubstituted oxepenes have been made to date. This encouraged us to design and
develop a direct process for the synthesis of disubstituted oxepenes, starting from αꢀ
substituted γꢀtriphenylsilyl bisꢀhomoallylic alcohols and aldehydes, using metal
sustainable catalysis.
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Herein, the first diastereoselective synthesis of cisꢀꢁ ꢀ2,7ꢀdisubstituted oxepenes
catalyzed by just 3ꢀ5 mol% of iron(III) bromide is described. It uses a tandem process
that combines a Prins cyclization alongside a Petersonꢀtype elimination (PrinsꢀPeterson
reaction, PPR). The low amounts of metal used highlight the efficacy of this catalytic
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process. From a formal point of view this reaction could be also considered as an
intramolecular HosomiꢀSakurai reaction or a Nokamiꢀtype transformation.
Results and discussion.
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Over the last decade, our research group has developed new methods for the synthesis
of oxacycles with sixꢀ and seven membered rings, using sustainable metal catalysis
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based on iron(III) salts (Scheme 2).
The reaction of bisꢀhomoallylic alcohols with
aldehydes, catalyzed by iron(III) salts, led directly to 4ꢀchloroꢀcisꢀ2,7ꢀdisubstitutedꢀ
oxepanes with excellent yields. Using this methodology, we performed the shortest total
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synthesis of (+)ꢀisolaurepan (Scheme 2).
Scheme 2. Synthesis of sixꢀ and sevenꢀmembered ring oxacycles catalyzed by iron
(III) salts.
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As a continuation of this previous work, we focused on the synthesis of ꢀ ꢀ2,7ꢀ
disubstituted oxepenes (Figure 1) through elimination of the chlorine at Cꢀ4 to obtain
the specific intramolecular doubleꢀbond (Scheme 3). However, this elimination reaction
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led to an inseparable mixture of ꢀ ꢀ and ꢀ ꢀ2,7ꢀdisubstituted oxepenes in a ratio 70:30
respectively, of limited use for further synthetic progress.
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Scheme 3. Elimination reaction of 4ꢀchloroꢀcisꢀ2,7ꢀdialkylꢀoxepane.
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Aiming to minimize the amount of undesirable ꢀ ꢀoxepene, we next tried
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different conditions, varying the type of base (tꢀBuOK, MeONa, DBN and LiClO ) and
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solvents (pyridine and methanol). These neither obtained the ꢀ ꢀ2,7ꢀdisubstituted
oxepenes exclusively nor improved on the results with DBU and LiCl.
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We still pursued the synthesis of the only desirable isomer ꢀ ꢀoxepene, and
planned a retrosynthetic pathway with dichloride oxepanes as key intermediate
compounds (Figure 2). In this case, the bisꢀhomoallylic alcohol, necessary for Prins
cyclization, should have a chlorine at the allylic position (precursor 3, Figure 2).
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Figure 2. First approach to ꢀ ꢀ2,7ꢀdisubstituted oxepenes through dichloride oxepanes.
Initially, the alcohol 3 was prepared, to achieve the ironꢀcatalyzed synthesis of
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the unsaturated disubstituted sevenꢀmembered ring oxacycle 2 as precursor to ꢀ −2,7ꢀ
disubstituted oxepene 1. However, we obtained a sixꢀmembered oxacycle 5 (2,3,4,6ꢀ
tetrasubstituted tetrahydroꢀ2Hꢀpyrans) with four stereogenic centers, three of them
generated in one single step, instead of the expected sevenꢀmembered ring 2 (Scheme
3
). The reaction involves a tandem process via the S
intermediate 4, and a further Prins cyclization reaction without competitive [3,3]ꢀ
sigmatropic rearrangement. DFT calculations support the in situ S 2’ reaction as a
N
2´ step, generating the
N
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preliminary step of the Prins cyclization. The relative syn/anti stereochemistry at the
chlorine atom in the starting material is irrelevant to the outcome of the subsequent
Prinsꢀcyclization reaction. These activated tetrahydroꢀ2Hꢀpyran units are easily
derivatizable through CuAAC conjugations, in order to generate multiꢀfunctionalized
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complex molecules (Scheme 4).
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Scheme 4. Attempt to obtain ꢀ4ꢀ2,7ꢀdisubstituted oxepenes. Synthesis of 2,3,4,6ꢀ
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tetrasubstituted tetrahydroꢀ2Hꢀpyrans via tandem S 2´ꢀPrins cyclization.
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Despite this unexpected good result, we remained focused on a direct synthesis
of oxepenes 1. The retrosynthetic proposal was then modified, replacing the chlorine at
the allylic position with a silyl group. This change opened the way to isolating 6,
avoiding the isomerization in 7, which led us to the tetrahydropyran ring 5 (Figure 3).
This approach is comparable to the original proposal by Miginiac, who used a similar
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alcohol but primary and silylated, (TMSO(CH
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)
2
CH(TMS)CH=CH
2
). This led us to
synthesize the alcohol 7 and check its reactivity with aldehydes using sustainable metal
catalysis.
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Figure 3. Second approach to ꢀ ꢀ2,7ꢀdisubstituted oxepenes. Silyl version.
The synthesis of silyl alcohol 7 was obtained in oneꢀstep, using the protocol of
Schaumann et al., which consists in opening an epoxide by the carbanion of the
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corresponding allyl silyl compound. In our case, we chose a commercial available
epoxide (2ꢀethyloxirane) as starting material. The desired βꢀsilyl unsaturated alcohol 7a
was obtained, as minor compound, the major being the alcohol 8a, produced by opening
the 2ꢀethyloxirane by means of the rearranged isomer of the trimethylsilyl ylide
(Scheme 5).
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Scheme 5. Synthesis of βꢀsilyl unsaturated alcohol 7.
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Despite the low selectivity of this opening reaction, we next examined the
reactivity of 5ꢀ(trimethylsilyl)ꢀheptꢀ6ꢀenꢀ3ꢀol (7a) with 3ꢀmethyl butanal (9a) in the
presence of iron salts as catalysts. To our delight, the desired oxepene 1a was directly
obtained without any trace of the oxepane 6a (Scheme 6). On the other hand, the major
silyl alcohol 8a was inert under the Prins cyclization conditions, so it was not possible
3
to obtain the ꢀ ꢀ2,7ꢀdisubstituted oxepene isomer (Scheme 6).
Scheme 6. Proof of concept on the synthesis of oxepene 1a.
This highly productive process is the result of a cascade of three chemical events
4
with the concomitant formation of a CꢀO bond, a CꢀC bond and a ꢀ endocyclic doubleꢀ
1
5
bond, through a Prins cyclization followed by a Petersonꢀtype elimination. Therefore,
this opened up the route to studying the reactivity of this reaction, using different
conditions and iron salts (Table 1). As shown in Scheme 6, the iron catalytic system
formed from FeX
3
3
or Fe(acac) and trimethylsilyl halides was applied, based on
11,16
previous work.
The cyclization works well, with a 51% yield, leading to a cis:trans
mixture (6:1) of 2,7ꢀdisubstituted oxepenes (1a and 10a), but with a 22% yield of the
tetrasubstituted tetrahydropyran 11a as side product (Table 1, entry 2). A similar result
was obtained using a stoichiometric amount of FeCl (Table 1, entry 1). The
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3 3
replacement of FeCl with Fe(acac) , a less hygroscopic species, slightly lowered the
overall yield and the amount of side product (Table 1, entry 3).
Next, the reaction was run using only catalytic amounts of FeCl
3
(10 mol%,
Table 1, entry 4), and surprisingly it was completed quickly with a 72% yield. Iron salts
thus effectively catalyzed the reaction, without adding TMSCl as coꢀcatalyst. It also
worked with aldehydes bearing other functionalities, although the catalyst load had to
be raised to 15 mol% (Table 1, entry 11).
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In all cases, the ꢀ ꢀoxepenes were produced with tetrasubstituted desilylated
tetrahydropyrans 11 as side product, resulting from a tandem reaction that combines
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protodesilylation with allylic rearrangment, and a final Prins cyclization (Scheme 7).
Scheme 7. Protodesilylation reaction with allylic rearrangement and Prins
cyclization in the synthesis of tetrasubstituted desilylated tetrahydropyran 11a.
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Table 1. First optimization of the PrinsꢀPeterson reaction in the synthesis of ꢁ ꢀ
a
2,7ꢀdisubstituted oxepenes. Trimethylsilyl option.
Fe (III)
TMSCl
1
10
11
1
2
Entry 7 ( R )
9 ( R )
t (h)
0.25
b
(mol %) (equiv.)
yield (%)
7
Et
a
9a
FeCl
(100)
3
1a 10a 11a
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1
2
3
4
ꢀ
iꢀBu
15
19
FeCl
10)
3
Et
iꢀBu
iꢀBu
iꢀBu
1.1
1.1
ꢀ
0.5
44
7
22
(
Fe(acac)
10)
3
Et
Et
0.25
0.25
43
44
55
13
14
11
14
(
FeCl
10)
3
(
Fe(acac)
(10)
3
5
6
Et
Et
iꢀBu
iꢀBu
0.1
ꢀ
110
NR
13 traces
NR
NR NR
Fe(acac)
3
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(10)
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Et
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3ꢀbutenyl
Fe(acac)
(10)
3
1b 10b 11b
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1.1
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ꢀ
0.15
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12
15
Fe(acac)
(10)
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Et
3ꢀbutenyl
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10 traces
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iꢀBu
FeCl
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1c 10c
11c
0.17
0.42
0.33
nꢀdecyl
(15)
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16
6
Fe(acac)
3
10
nꢀdecyl
iꢀBu
1.1
ꢀ
46
15
15
(10)
7b
9b
3ꢀbutenyl
FeCl
(15)
3
1d 10d 11d
45 13
11
nꢀdecyl
8
a
Reaction conditions: 7aꢀb (0.5 mmol), 9aꢀb (1.0 mmol), Lewis Acid, dry solvent (0.1M), rt, without
inert atmosphere. The stereochemistry of the oxepenes and THP 11 was assigned by GOESY
b
experiments (see the Supporting Information). Yields of isolated products after purification by silicaꢀ
gel column chromatography.
The amount of these tetrahydropyrans 11 depends directly on the amount of acid
generated in the reaction medium (Table 1). Reducing the amount of TMSCl also
lowered the amount of THPs 11 to trace levels (Table 1, entries 5 and 8). The
combination of 10 mol% Fe(acac) and 0.1 equiv. of trimethylsilyl halides slowly
3
3
generates FeCl in situ. This fact avoids the protodesilylation of the alcohol 7, however
the reaction time increased up to 18h or 110h, with moderate yields.
At this point, it was clear that a change in the silyl group was necessary, to
improve the synthesis of the correct isomer type 7a and avoid protodesilylation and thus
the formation of THP 11.For this reason, our next focus was the triphenylsilyl (TPS)
group, which is more stable and less electrofugal than the TMS group. The desired
precursor 12a was therefore easily prepared from the corresponding epoxide and the
lithiated allyltriphenylsilane, using the methodology developed by Schaumann et al.
14
(
Scheme 8).
Scheme 8. Synthesis of 3ꢀ(triphenylsilyl)pentadecꢀ1ꢀenꢀ5ꢀol (12a).
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5
5
5
5
5
6
In this case, we used an epoxide with a long sideꢀchain to generate 12a, a less
volatile alcohol than 7a. This epoxide opening worked really well with excellent yield
(95%), leading to the desired 12a as a major compound in a ratio 12a:13a, 87:13.
According to the results described above (Table 1), we checked the reactivity of 12a
using only substoichiometric amounts of Lewis acids to avoid the formation of THPs
11, thus favouring the exclusive formation of 2,7ꢀdisubstituted oxepenes.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
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1
2
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1
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3
4
5
6
7
8
9
0
The reactivity of 3ꢀ(triphenylsilyl)pentadecꢀ1ꢀenꢀ5ꢀol (12a) was first examined
with 3ꢀmethyl butanal (9a) in the presence of iron salts as catalysts (Table 2). First,
different amounts of iron(III) chloride were evaluated using dry methylene chloride
(DCM) as solvent (entries 1ꢀ4). The cyclization proceeded satisfactorily, affording
4
exclusively the desired ꢀ ꢀ2,7ꢀdisubstituted oxepene in good yield, without the presence
of the THPs 11. In all cases, the major compound was the cis isomer, the cis:trans ratio
being practically constant around 4:1. Replacing iron(III) chloride with iron(III)
bromide under otherwise identical reaction conditions improved the yield (entries 5ꢀ6),
whereas the cis:trans ratio remained the same. Although different catalysts were used
(
entries 1, 6, 13ꢀ15), the best result was obtained with 5 mol% of FeBr , and dry DCM
3
as solvent at room temperature (entry 6). The results of InBr
of FeBr , but with longer reaction time than with iron (entry 14). The use of other
solvents led to worse results (entries 7ꢀ10). Decreasing the amount of FeBr below 5
3
are comparable with those
3
3
mol% increased the reaction time, while inducing a decrease in the reaction yields,
which was more evident when 1 mol% was used (entries 11 and 12). Applying lower
temperature (0 ºC) did not affect the diastereomeric ratio.
4
Table 2. Optimization of PrinsꢀPeterson reaction in the synthesis of ꢁ ꢀ2,7ꢀ
a
disubstituted oxepenes. Triphenylsilyl option.
b
Entry
cat. (mol %)
solvent
DCM
DCM
DCM
t (h)
0.25
0.25
23
yield (%)
1c:10c
83:17
82:18
82:18
1
2
3
FeCl
FeCl
3
3
(15)
(10)
86
75
80
FeCl (7)
3
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7
8
9
c
4
FeCl
3
(5)
DCM
DCM
DCM
DCE
23
0.5
0.5
0.5
1.5
1.5
1.5
2
63
88
95
90
76
NR
74
76
58
69
90
72
NR
80:20
82:18
82:18
82:18
83:17
NR
5
FeBr (7)
3
6
7
8
9
FeBr
FeBr
FeBr
3
3
3
(5)
(5)
(5)
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
CHCl
THF
3
FeBr (5)
3
1
0
FeBr
FeBr
FeBr
3
3
3
(5)
(3)
(1)
6
C H
77:23
83:17
81:19
72:28
82:18
67:33
NR
6
11
DCM
DCM
DCM
DCM
DCM
DCM
1
2
d
22
e
1
3
InCl (5)
17
3
1
4
InBr
Fe(OTf)
Fe(acac)
3
(5)
1.5
1.5
1.5
15
3
(5)
(5)
1
6
3
a
Reaction conditions: 12a (0.5 mmol), 9a (1.0 mmol), LA, dry solvent (0.1 M), rt, without inert
atmosphere. Yield of isolated product. 75% conversion. 69% conversion. 77% conversion. NR = no
reaction.
b
c
d
e
Related to our methodology, Panek and coꢀworkers have studied the reactivity of
vinyl and crotyl silanes in the synthesis of dihydropyrans through [4+2] annulation.
They concluded that the stereochemical course of the annulation was determined by
relative stereochemical arrangement (syn or anti) of the silicon with the silyl ether and
18
the adjacent α groups to this silyl ether. However, we synthesized a seven membered
ring oxacycle and the relative stereochemistry of the silicon with the hydroxy group
(
syn or anti), with one carbon more between them, has no influence in the cis:trans
1
9
diastereoselectivity of the corresponding oxepene. In fact, the treatment of two
different syn/anti mixtures of 12a (50:50 and 71:29) led to the same oxepenes cis:trans
2
0
ratio 4:1.
Encouraged by our initial results, we decided to study a series of alkenols 12 and
aldehydes 9 to determine the scope of our direct Prins Peterson type reaction (PPR). We
examinated the PPR starting with alkenols bearing a nonꢀfunctionalized side chain and
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5
5
5
5
5
6
finishing with more functionalized chain (bearing double bond or an aromatic group).
As shown in Table 3, a range of aldehydes could be efficiently used to generate the
corresponding oxepenes 1aꢀ1t. First, we used alkenols with a large side chain. The
21
reaction worked well with aliphatic and aromatic aldehydes. Interestingly, good
results with aldehydes bearing double bonds such as 1d and 1e were observed leading to
oxepenes with endocyclic and exocyclic olefins. The case of 1e is particularly notorious
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
due to the difficulty of incorporating acrolein under iron(III) catalyst. In the case of
aromatic aldehydes, we observed a decrease on the reaction yields when oxygenated
2 2
substituents were present (NO , OMe). In the case of NO substituent, we only observed
cis oxepene, problably due to steric factors in the oxocarbenium ion C (Scheme 13).
Furthermore, to show the synthetic applicability of this cyclization, the reaction of 12a
and 9a was carried out in a 3 mmol scale, and oxepene 1c was isolated in 87% yield.
Next, we moved to alkenols with a functionality at the side chain (entries 11ꢀ14).
The reactions worked really well both with isovaleraldehyde (entry 11) and with
functionalized aldehydes (entries 12 and 14). Although with moderate yield, the PPR
also worked with a heteroaromatic aldehyde such as furanꢀ3ꢀcarbaldehyde (entry 13).
Moreover, the relative cis configuration of the two stereocenters in the final oxepene
4
ring as well as ꢀ ꢀdouble bond were confirmed by Xꢀray diffraction analysis of 1s
22
(
Table 3, entry 17) (Figure 4). This method permitted the access to oxepenes with both
side chains functionalized.
4
Figure 4. ORTEP plot of cisꢀ2ꢀbenzylꢀ7ꢀ(furanꢀ3ꢀyl)ꢀꢀ oxepene 1s.
Last, we used alkenols with aromatic ring at the side chain. The yields of the
reaction were almost identical than those described above, but with a better ratio
cis:trans (entries 15ꢀ18). In these cases the ratio of cis isomer increased untill 90%
approximately or even higher (entries 16 and 18). The participation of the aromatic ring
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9
in the oxocarbenium ion intermediate C (Scheme 13), could be the responsible of this
cis isomer increase.
Our next challenges was to check the reactivity of several ketones in this PPR
cyclization, where we never got positive results in our previous experiences with the
16
Prins cyclization and iron(III) salts as catalyts.
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
4
a
Table 3. Substrate scope for direct synthesis of ꢁ ꢀ2,7ꢀdisubstituted oxepenes.
1
2
b
c
Entry
1
12 (R )
9 (R )
yield (%)
1:10
12a, nꢀdecyl
nꢀdecyl
9a
9b
95
78
71
81
54
42
39
76
72
87
88
86
55
1c:10c
1d:10d
1e:10e
1f:10f
1g:10g
1h:10h
1i:10i
82:18
83:17
80:20
85:15
76:24
90:10
100:0
83:17
83:17
91:9
2
3
4
5
6
7
8
9
nꢀdecyl
9e, ethenyl
9f, Cy
nꢀdecyl
nꢀdecyl
9g, Ph
nꢀdecyl
9h, pꢀMeOꢀPh
nꢀdecyl
9i, pꢀNO ꢀPh
2
nꢀdecyl
9j, pꢀFꢀPh
9k, pꢀMeꢀPh
9l, Bn
1j:10j
1k:10k
1l:10l
nꢀdecyl
1
1
1
1
0
1
2
3
nꢀdecyl
12b, 7ꢀoctenyl
7ꢀoctenyl
7ꢀoctenyl
9a
1m:10m
1n:10n
1o:10o
81:19
82:18
82:18
9e
9o, furanꢀ3ꢀyl
9
p, 3ꢀbenzoateꢀ
14
7ꢀoctenyl
83
1p:10p
84:16
propyl
1
1
5
6
12c, Bn
Bn
9a
9e
9o
9p
88
84
42
80
1q:10q
1r:10r
1s:10s
1t:10t
87:13
92:8
d
17
Bn
90:10
94:6
1
8
Bn
a
3
Reaction conditions: 12aꢀc (0.5 mmol), 9aꢀl (1.0 mmol), FeBr (5 mol%), dry solvent (0.1M), rt,
without inert atmosphere. The stereochemistry of the oxepenes was assigned by GOESY experiments
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1
1
1
1
1
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2
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2
2
2
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3
3
3
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4
4
4
4
4
5
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5
5
5
5
5
5
5
5
6
b
c
(
see the Supporting Information). Yields of isolated products are given. Ratio cis:trans (1:10) are
d
given. 74% conversion.
As Scheme 9 shows, the reaction incorporated the cyclohexanone backbone with
moderate yields (14 and 15, Scheme 9). This is a noteworthy result because, as
commented above, all the other ketones were unreactive in the Prins cyclization
catalyzed by iron(III) salts. We checked acyclic (methyl phenyl ketone, acetone and
ethyl methyl ketone) and cyclic ketones unsuccessfully. We therefore tried other cyclic
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
2
3
ketones varying the size of the ring, but without positive results. Neither was any
incorporation detected using cyclohexane bearing two ketones, such as 5,5ꢀ
dimethylcyclohexaneꢀ1,3ꢀdione. At this stage, we decided to check the reactivity of our
1
1
alkenols 12b (R = 7ꢀoctenyl) and 12c (R = Bn) with cyclopentanone (nonꢀreactive
with iron(III)salts) and another Lewis acid that has favored the reaction of ketones in the
.
3
Prins cyclization, BF
OEt
2
. Used in 30 mol% with DCM (0.1M) as solvent, it did not
even show traces of the corresponding oxepene.
Scheme 9. PrinsꢀPeterson type reaction with cyclohexanone.
After this result, we moved on to improve the cis:trans diastereoselectivity. It is
1
2
clear that the sideꢀchains at R and R influence the ringꢀclosing selectivity (entries 6, 7,
10, 16ꢀ18, Table 3). In most cases, the cis:trans diastereoselectivity was around 4:1,
however this ratio change favored the cis isomer in some types of chain (entries 6, 7, 10,
1
6ꢀ18, Table 3). Inspired by this, we proceeded to explore the influence of a bulky
group in the αꢀ position to the hydroxyl moiety. A suitable group should have (a)
adequate bulkiness to drive the process exclusively towards the cis oxepene, and (b)
versatility to be converted into another functional group. The tertꢀbutyldiphenyl silyl
ether (OTBDPS) protecting group (18, Scheme 10) was an ideal candidate.
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9
We focused our attention on the preparation of a model compound that could
also serve as an intermediate to check our method in the synthesis of (+)ꢀ
isolaurepinnacin. Thus, the desired alcohol 18 was synthesized starting from epoxide
24
1
7, which can be obtained from Dꢀmannitol or in a twoꢀstep sequence from the
commercially available allylic alcohol 16, followed by further protection of the
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
6
j,25,26
hydroxyl group (see Supporting Information).
The regioselective ringꢀopening of
epoxide 17 with allyl triphenyl silane under Schaumann´s conditions afforded the
1
4
desired alcohol 18 in 40% yield. We tested its reactivity toward simple aldehydes such
as isobutyraldehyde and 4ꢀpentenal. In both cases, oxepenes 19 and 20 were obtained
with good yields and complete cis diastereoselectivity (Scheme 10).
Scheme 10. Synthesis of cisꢀ2,7ꢀdisubstituted oxepenes.
It is important to highlight the chemoselectivity of this process. The alcohol 18
bears two doubleꢀbonds in a suitable position to lead to an oxepane ring, however the
reaction only proceeded through the doubleꢀbond attack A, leading to oxepenes 19 and
20. The bromoꢀoxepane, resulting from doubleꢀbond attack B, was not formed or even
detected by NMR (Scheme 11).
Scheme 11. Chemoselectivity in the Prins Petersonꢀtype reaction of alcohol 18.
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1
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2
2
2
2
2
2
3
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3
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3
3
3
3
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4
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5
5
5
5
5
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0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
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8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Our attention next became focused on the potential use of an aldehyde bearing a
αꢀprotected hydroxyl group (24, Scheme 12). This aldehyde 24 was obtained in three
steps from commercially available allylic alcohol 21. KatsukiꢀSharpless asymmetric
epoxidation generated the epoxy alcohol 22, which was regioselectively opened under
acidic conditions to proceed to the desired 1,2ꢀdiol 23 and further periodate cleavage of
27
the diol in 89% yield (Scheme 12). The PrinsꢀPeterson type (PPR) reaction catalyzed
by iron(III) bromide between the alcohol 18 and aldehyde 24 produced the oxepene 25
in 40% yield in one single step. A CꢀO bond, a CꢀC and an endocyclic olefin were
generated in a regioselective manner in the course of the catalytic process. As in the
case of oxepenes 19 and 20, the cyclization occurred with complete cis
diastereoselectivity. This substrate has the two hydroxyl moieties orthogonally
protected, allowing us future transformations onto much more complex structures.
Scheme 12. PPR with aldehydes bearing a αꢀprotected hydroxyl group.
With this type of aldehyde, we will be able to prepare more complex substrates
such as 25, which would allow us to generate a wide variety of structures with
2
8
important implications in Diverted Total Synthesis (DTS) Strategies.
Regarding the reaction mechanism of PPR (Scheme 13), we propose that the
attack of alcohol 12 on aldehyde 9 is previously activated by the iron(III) bromide, to
form the zwitterionic species A.
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9
This intermediate leads to the mixed acetal B and the oxocarbenium ion C,
which is intramolecularly trapped by the olefin moiety to give rise to a carbocation D,
2
9
already stabilized by the presence of the silyl group (βꢀeffect). Further attack by
4
Br
3
FeꢀOH generated under the reaction conditions produces the ꢀ ꢀ2,7ꢀdisubstituted
oxepene and triphenylsilanol. The double bond would be formed via a direct elimination
or an induced Petersonꢀtype elimination, in either case regenerating the catalytic species
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
3 3
FeBr . To more strongly verify the generation of Br FeꢀOH and its involvement in the
final elimination step, an isotopic labeling experiment was performed. As shown in
18
Scheme 14, the Oꢀlabeled aldehyde 9e was used under the standard conditions, and the
18
3
silanol product was analyzed by ESIꢀMS. It was found that Oꢀlabeled Ph SiOH was
18
formed with ca. 33% Oꢀlabeled. This result indicated that the oxygen atom of the
aldehyde is involved in the elimination step. This data supports the last stage of the
proposed mechanism.
Scheme 13. Proposed mechanism.
18
Scheme 14. The Prins Petersonꢀtype reaction with Oꢀlabeled aldehyde.
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1
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1
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2
2
2
2
2
2
2
2
3
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3
3
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3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
In summary, we have developed a highly efficient, stereoselective and direct
4
synthesis of ꢀ ꢀ2,7ꢀdisubstituted oxepenes via a low catalyst loading process (LCL)
with iron(III)ꢀbromide. This highly productive process is the result of a cascade of three
4
chemical events with the concomitant formation of a CꢀO bond, a CꢀC bond and a ꢀ
endocyclic double bond. A bulky substituent at the αꢀposition with respect to the
hydroxyl group of the bisꢀhomoallylic alcohol drives the Prins cyclization toward the
exclusive formation of the cisꢀoxepene. The silyl substrate favored elimination rather
than trapping of the carbocation with a nucleophile such as halide. Approaches to (+)ꢀ
isolaurepinnacin and (+)ꢀneoisoprelaurefucin are under development and the results will
be reported in due course.
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Experimental Section
General remarks. NMR spectra were recorded on a Bruker Avance instrument.
1
13
HꢀNMR spectra were recorded at 400, 500 and 600 MHz, and CꢀNMR were recorded
at 100, 125 and 150 MHz, VTU 298.0 °K. Chemical shifts were reported in parts per
million. The residual solvent peak was used as an internal reference (CDCl : δ 7.26, δ
7.0). Dept 90, Dept 135, Cosy and HSQC were used to confirm the NMR peak
assignments.
3
H
C
7
Optical rotations were measured on a PerkinꢀElmer 343 polarimeter by using a
Na lamp. HRMSꢀTOF was used for HRMS measurements and performed on a
2
Micromass Autospec spectrometer by addition of CHO H (10% in water).
Silica gel readyꢀfoils were used for analytical thinꢀlayer chromatography. They
were developed with 254 nm UV light and spraying with a solution of
phosphomolybdic acid solution (20 wt. % in ethanol) and heating. Column
chromatography was performed using silica gel (0.015ꢀ0.04 mm) and Chromatotron
chromatography with 1, 2 and 4 mm silica gel disks, both using nꢀhexane/EtOAc
solvent systems. All reagents were obtained from commercial sources, without further
purification.
General procedure for the preparation of bisꢀhomoallylsilyl alcohols (12).
14
This procedure is based on the work published by Schaumann et al. The reagent secꢀ
butyllithium (1.2ꢀ2.5 eq.) was added to a wellꢀstirred solution of allyltriphenylsilane
(
1.2ꢀ2.5 eq.) in dry tetrahydrofuran (THF) (0.08ꢀ0.2 M), previously cooled to ꢀ78 ºC
under inert atmosphere. Then the system was allowed to reach ꢀ50 ºC and this
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temperature was maintained for 2 hours. After that, the system was cooled again to ꢀ78
ºC and the corresponding epoxide (1.0 eq.) was added dropwise, dissolved in a small
amount of dry THF. The reaction was stirred at ꢀ78 ºC until analysis via TLC showed
complete formation of product. Quenched by addition of a mixture of nꢀhexane/ethyl
4
ether/saturated aqueous NH Cl (2:2:1), the volume of this mixture being 25 times the
1
1
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0
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9
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7
8
9
0
equivalents of allyltriphenylsilane used and extracted with ethyl ether. The combined
organic layers were dried over anhydrous magnesium sulfate, filtered and the solvent
was removed under reduced pressure. This crude reaction mixture was purified by flash
silica gel column chromatography (nꢀhexane/EtOAc: 95/5 solvent system).
4
General procedure for the synthesis of ꢁ ꢀ2,7ꢀdisubstituted oxepenes (1 and
10). To a wellꢀstirred and openꢀair solution of bisꢀhomoallylsilyl alcohol 12 (1.0 eq.) in
dry dichloromethane (DCM) (0.1 M) at room temperature, were added the
3
corresponding aldehyde (2.0 eq.) and the FeBr (3 – 5mol%). The reaction is monitored
by TLC and, once complete, the process is quenched by addition of the same amount of
water as DCM. The aqueous phases were separated and washed with DCM. The
combined organic layers were dried over anhydrous magnesium sulfate, filtered and the
solvent was removed under reduced pressure. This crude reaction mixture was purified
by flash silica gel column chromatography (nꢀhexane/EtOAc: 95/5 solvent systems) in
order to obtain the cis:trans mixture of the oxepenes. The final separation of the two
isomers was made using the chromatotron (nꢀhexane/EtOAc: 98/2 solvent system).
General procedure for alcohol tosylation. To a wellꢀstirred solution of the
alcohol (1.0 eq.) in dry dichloromethane (DCM) (0.1 M) at 0 ºC, trimethylamine (Et
3
N)
(3.5 eq.) was added dropwise, and pꢀtoluensulfonyl chloride (TsCl) (2.5 eq.)
portionwise. The system reached room temperature slowly under stirring overnight.
Once the reaction was completed, it was quenched by addition of aqueous saturated
CuSO with vigorous stirring. The solution was extracted with 3 x DCM and the
4
combined organic layer was dried over MgSO4. Organic solvent was removed under
reduced pressure. The crude reaction mixture was purified by flash silica gel column
chromatography (nꢀhexane/EtOAc solvent systems).
General procedure for Sharpless epoxidation of an allylic alcohol. Following
26
the procedure developed by Sharpless et al., MS (4Å) was added into a round bottom
flask equipped with an addition funnel with pressureꢀequalization arm. To activate MS,
the system was flamed under vacuum and cooled under nitrogen. Next, DCM and Ti(iꢀ
OPr)
4
were added and the mixture was cooled to ꢀ20 ºC (this temperature was
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6
maintained through the whole process). After 5 minutes, (+)ꢀ or (ꢀ)ꢀdiethyltartrate
(
DET) was added and the mixture stirred another 5 minutes. Then the allylic alcohol
was added, and the mixture was stirred 20 minutes. Finally, the tertꢀbutylhydroperoxide
TBHP) was added dropwise and the flask placed in the freezer overnight at ꢀ20 ºC.
(
Once the reaction was complete (checked by TLC), the suspension was filtered through
a pad of celite® and then, 15% aqueous tartaric acid was added and stirred 30 min.
Next, the mixture was separated and the organic phase concentrated under reduced
0
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8
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2
3
4
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7
8
9
0
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2
3
4
5
6
7
8
9
0
pressure. The crude was dissolved in Et
added and stirred only 1 minute. The organic phase was separated and extracted with 2
x Et O and 2 x EtOAc, dried over MgSO and concentrated under reduced pressure. The
2
O and cooled to 0 ºC. Aqueous 15% NaCl was
2
4
crude reaction mixture was purified by flash silica gel column chromatography (nꢀ
hexane/EtOAc solvent systems).
5ꢀ(trimethylsilyl)heptꢀ6ꢀenꢀ3ꢀol (7a). Following the general procedure for bisꢀ
homoallylsilyl alcohol formation, 1,2ꢀepoxybutane (11.0 mmol, 1.0 eq.) was added to a
solution of allyltrimethylsilane (10.0 mmol, 1.1 eq.), TMEDA (10.0 mmol, 1.0 eq.) and
secꢀbutyllithium (11.0 mmol, 1.1 eq.) in dry THF (0.2 M) to obtain 0.655 g of the
1
product (32% yield). Colorless oil. HꢀNMR (CDCl
3
, 400 MHz) δ 5.63 (dt, J = 10.1 &
16.9 Hz, 1H), 4.94ꢀ4.90 (dd, J = 1.8 and 10.3 Hz, 1H), 4.89ꢀ4.85 (ddd, J = 0.9, 1.9 and
17.0 Hz, 1H), 3.56 (m, 1H), 1.84 (ddd, J = 2.8, 9.8 and 12.5 Hz, 1H), 1.61ꢀ1.37 (m, 5H),
1
3
1
0
.94 (t, J = 7.5 Hz, 3H), ꢀ0.02 (s, 9H) ppm; C{ H}ꢀNMR (CDCl
3
, 150 MHz) δ 139.8
), 10.2 (CH ), ꢀ3.5
(
CH), 112.5 (CH ), 71.4 (CH), 35.3 (CH ), 30.7 (CH), 30.5 (CH
2
2
2
3
+
+
(3xCH ). HRMS (ESI ): m/z [M+Na] Calcd for C H OSiNa: 209.1338; Found:
3
10 22
209.1334.
3ꢀ(triphenylsilyl)pentadecꢀ1ꢀenꢀ5ꢀol (12a). Following the general procedure for bisꢀ
homoallylsilyl alcohol formation, 1,2ꢀepoxydodecane (8.14 mmol, 1.0 eq.) was added to
a solution of allyltriphenylsilane (9.77 mmol, 1.2 eq.) and secꢀbutyllithium (9.77 mmol,
1.2 eq.) in dry THF (0.2 M) to obtain 2.82 g of the product (72% yield). Colorless oil.
1
HꢀNMR (CDCl , 400 MHz) (mixture syn/anti (41:59)) δ 7.60ꢀ7.55 (dt, J = 1.5 & 8.0
3
Hz, 12H), 7.44ꢀ7.38 (m, 6H), 7.38ꢀ7.32 (m, 12H), 5.94ꢀ5.83 (m, 1H), 5.80ꢀ5.68 (m,
1H), 5.04ꢀ4.93 (m, 4H), 3.76ꢀ3.61 (m, 2H), 2.96 (m, 1H), 2.61 (m, 1H), 1.87 (ddd, J =
2
1
.5 & 6.1 & 14.0 Hz, 1H), 1.79ꢀ1.69 (m, 2H), 1.67ꢀ1.63 (m, 1H), 1.63ꢀ1.58 (m, 1H),
13
1
3
.41ꢀ1.18 (m, 36H), 0.90ꢀ0.85 (m, 6H). C{ H}ꢀNMR (CDCl , 150 MHz) (mixture
syn/anti (41:59)) δ 139.6 (CH), 138.6 (CH), 136.2 (6 x CH), 136.1 (6 x CH), 133.8 (3 x
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C), 133.6 (3xC), 129.5 (3 x CH), 129.4 (3 x CH), 127.8 (6 x CH), 127.x7 (6 x CH),
1
15.2 (CH
36.2 (CH ), 31.9 (2xCH
), 25.3 (CH ), 22.7 (2xCH
44OSiNa: 507.3059; Found: 507.3050.
2
), 114.9 (CH2), 73.2 (CH), 69.7 (CH), 38.0 (CH
), 30.9 (CH), 29.6 (8 x CH ), 29.3 (2xCH
), 14.1 (2xCH
2 2 2
), 37.1 (CH ), 36.7 (CH ),
2
2
2
2
), 27.9 (CH), 25.9
+
(CH
2
2
2
3
). HRMS (ESI+): m/z [M+Na] Calcd for
C
33
H
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
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0
3ꢀ(triphenylsilyl)tridecaꢀ1,12ꢀdienꢀ5ꢀol (12b). Following the general procedure for
bisꢀhomoallylsilyl alcohol formation, 1,2ꢀepoxyꢀ9ꢀdecene (6.5 mmol, 1.0 eq.) was
added to a solution of allyltriphenylsilane (7.8 mmol, 1.2 eq.) and secꢀbutyllithium (7.8
mmol, 1.2 eq.) in dry THF (0.2 M) to obtain 1.72 g of the product (70% yield, 83%
1
conversion). Colorless oil. HꢀNMR (CDCl , 400 MHz) (mixture syn/anti (41:59)) δ
3
7.57 (brddd, J = 1.5, 8.0 & 8.0 Hz, 12H), 7.44ꢀ7.32 (m, 18H), 5.95ꢀ5.64 (m, 4H), 5.03ꢀ
4.90 (m, 8H), 3.68 (m, 2H), 2.95 (m, 1H), 2.61 (m, 1H), 2.03 (m, 4H), 1.86 (ddd, J =
2.5, 6.2 & 14.1 Hz, 1H), 1.79ꢀ1.68 (m, 2H), 1.68ꢀ1.57 (m, 2H), 1.47 (m, 1H), 1.43ꢀ1.19
1
3
1
(m, 20H). C{ H}ꢀNMR (CDCl
39.2 (CH), 139.1 (CH), 138.5 (CH), 136.2 (6xCH), 136.1 (6xCH), 133.8 (3xC), 133.6
3xC), 129.6 (3xCH), 129.4 (3xCH), 127.8 (6xCH), 127.8 (6xCH), 115.2 (2xCH2),
115.0 (2xCH ), 114.1 (4xCH ), 73.2 (CH), 69.7 (CH), 37.9 (CH ), 37.1 (CH ), 36.7
), 36.2 (CH ), 33.8 (CH ), 33.7 (CH ), 30.9 (CH), 29.4 (2xCH ), 29.1 (CH ), 29.0
), 28.8 (CH ), 27.8 (CH), 25.8 (CH ), 25.2 (CH ). HRMS (ESI+): m/z
38OSiNa: 477.2590; Found: 477.2592.
3
, 150 MHz) (mixture syn/anti (41:59)) δ 139.6 (CH),
1
(
2
2
2
2
(CH
2
2
2
2
2
2
2
(CH
), 28.8 (CH
2
2
2
2
+
[
M+Na] Calcd for C31
H
1ꢀphenylꢀ4ꢀ(triphenylsilyl)hexꢀ5ꢀenꢀ2ꢀol (12c). Following the general procedure for
bisꢀhomoallylsilyl alcohol formation, (2,3ꢀepoxypropyl)benzene, (8.5 mmol, 1.0 eq.),
synthesized by epoxidation of allylbenzene with mꢀCPBA, was added to a solution of
allyltriphenylsilane (8.5 mmol, 1.0 eq.) and secꢀbutyllithium (8.5 mmol, 1.0 eq.) in dry
THF (0.2 M) to obtain 1.35 g of the product (two steps: 44% yield, 82% conversion).
1
Colorless oil. HꢀNMR (CDCl
3
, 600 MHz) (mixture syn/anti (41:59)) δ 7.60ꢀ7.53 (m,
12H), 7.41 (m, 6H), 7.36 (m, 12H), 7.28 (m, 4H), 7.21 (m, 2H), 7.15 (m, 4H), 5.89 (m,
H), 5.71 (m, 1H), 5.06ꢀ4.88 (m, 4H), 3.91 (m, 2H), 2.99 (brt, J = 10.3 Hz, 1H), 2.89
dd, J = 4.0 & 13.7 Hz, 1H), 2.72ꢀ2.64 (m, 2H), 2.64ꢀ2.58 (dd, J = 8.9 & 13.7 Hz, 1H),
2.54 (dd, J = 8.5 & 13.6 Hz, 1H), 1.95 (ddd, J = 2.6, 6.8 & 14.0 Hz, 1H), 1.91ꢀ1.82 (m,
1
(
13
1
2
3
H), 1.74 (m, 1H), 1.69 (m, 1H), 1.53 (m, 1H). C{ H}ꢀNMR (CDCl , 150 MHz)
(mixture syn/anti (41:59)) δ 139.3 (CH), 138.8 (C), 138.6 (C), 138.3 (CH), 136.2
(6xCH), 136.1 (6xCH), 133.8 (3xC), 133.4 (3xC), 129.5 (3xCH), 129.4 (3xCH), 129.3
(2xCH), 129.3 (2xCH), 128.5 (2xCH), 128.5 (2xCH), 127.8 (6xCH), 127.8 (6xCH),
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1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
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4
4
4
4
4
4
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5
5
5
5
5
5
5
5
6
1
4
26.4 (CH), 126.3 (CH), 115.3 (CH
2
), 115.1 (CH
), 30.5 (CH), 237.8 (CH). HRMS (ESI+): m/z
30OSiNa: 457.1964; Found: 457.1959.
2 2
), 73.6 (CH), 70.4 (CH), 44.5 (CH ),
2.6 (CH
2
), 36.3 (CH
2
), 36.2 (CH
2
+
[M+Na] Calcd for C30
H
4ꢀbenzoyloxybutanal (9p): A solution of 4ꢀ(benzoyloxy)ꢀ1ꢀbutanol (synthesized
following procedure reported in literature) (10.3 mmol, 1.0 equiv) in dry DCM (2.06 M)
was added in one portion at r.t to a stirred suspension of pyridinium chlorochromate
0
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2
3
4
5
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8
9
0
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2
3
4
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7
8
9
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2
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5
6
7
8
9
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9
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3
4
5
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7
8
9
0
(PCC) (15.5 mmol, 1.5 equiv) and Celite (3.30 g), in the same solvent (27 mL). The
resulting reaction mixture was kept at r.t for 1.5 h then diluted with anhydrous Et O and
2
filtered. The solvents were evaporated under reduced pressure and the crude residue was
purified by column chromatography on silica gel to give the aldehyde 9p as a colorless
30
oil (1.64 g, 83% yield). Spectral data was consistent with the known aldehyde.
)ꢀ1ꢀ(( )ꢀoxiranꢀ2ꢀyl)butꢀ3ꢀenꢀ1ꢀol: this compound was synthesized following the
procedure used by Sharpless et al. Spectral data was consistent with the known
(
S
R
26
25
25
D
product. [α]
tertꢀbutyl(((
= +26.5 (c = 1.0, DCM).
S
)ꢀ1ꢀ(( )ꢀoxiranꢀ2ꢀyl)butꢀ3ꢀenꢀ1ꢀyl)oxy)diphenylsilane (17): to a solution
R
of the previous epoxyalcohol (0.45 g, 4.0 mmol) in dry DCM (0.1 M), was added
imidazole (0.69 g, 10.0 mmol, 2.5 eq.) and the mixture was stirred until totally
dissolved. Then, the mixture was cooled to 0 ºC and TBDPSCl (2.65 mL, 10.0 mmol,
2.5 eq.) was added dropwise (solved in 3 mL of DCM). The mixture was allowed to
reach r.t. slowly and stirred overnight. The quenching was performed by addition of
4
water. Then the mixture was extracted with 3 x DCM, dried over MgSO and
concentrated under reduced pressure. The reaction mixture was purified by flash silica
gel column chromatography (nꢀhexane/EtOAc: 95/5 solvent system) to obtain 1.24 g of
1
the product (88% yield). Colorless oil. HꢀNMR (CDCl
3
, 400 MHz) δ 7.69 (bdd, J = 6.7
&
9.1 Hz, 4H), 7.47ꢀ7.34 (m, 6H), 5.88 (m, 1H), 5.05 (m, 2H), 3.48 (q, J = 5.6 Hz, 1H),
2
2
.91 (ddd, J = 2.9, 3.6 & 6.1 Hz, 1H), 2.46 (dd, J = 4.0 & 5.1 Hz, 1H), 2.35 (m, 2H),
13
1
.15 (dd, J = 2.6 & 5.2 Hz, 1H), 1.06 (s, 9H). C{ H}ꢀNMR (CDCl , 100 MHz) δ 135.9
3
(4 x CH), 133.8 (C), 133.75 (CH), 133.7 (C), 129.8 (CH), 129.7 (CH), 127.6 (2 x CH),
127.5 (2 x CH), 117.6 (CH ), 72.8 (CH), 53.9 (CH), 46.2 (CH ), 39.8 (CH ), 26.9 (3 x
2
2
2
+
+
CH ), 19.4 (C). HRMS (ESI ): m/z [M+Na] Calcd for C H O SiNa: 375.1756;
3
22 28
2
26
D
Found: 375.1743. [α]
3
= +32.2 (c = 1.33, CHCl ).
18
18
Benzaldehydeꢀ O (9gꢀ O): this compound was synthesized following the procedure
3
1
31
by Carlsen and Ystenes. Spectral data was consistent with the known product. The
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crude reaction mixture was used without further purification. HRMS (ESI ): m/z
16 18
5
+
18
[
C
7
H
O O] : Calcd for 123.0330; Found:123.0332. MS analysis revealed an 50% O
isotope incorporation.
,6 )ꢀ6ꢀ((tertꢀbutyldiphenylsilyl)oxy)ꢀ3ꢀ(triphenylsilyl)nonaꢀ1,8ꢀdienꢀ5ꢀol (18).
(5R S
Following the general procedure above for the preparation of bisꢀhomoallylsilyl alcohol,
0.6 g (1.7 mmol, 1.0 eq.) of the epoxide 17 was added to a solution of
allyltriphenylsilane (1.3 g, 4.25 mmol, 2.5 eq.) and secꢀbutyllithium 1.4 M in
cyclohexane (3.04 mL, 4.25 mmol) in 21 mL of dry THF (0.08 M). The crude of the
reaction mixture was purified by flash silica gel column chromatography (nꢀ
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
hexane/EtOAc: 95/5 solvent system) to give 0.27 g of the product (40% yield, 61%
1
conversion). Colorless oil. HꢀNMR (CDCl , 400 MHz) δ 7.68ꢀ7.46 (m, 10H), 7.45ꢀ
3
7
.23 (m, 15H), 5.56 (m, 2H), 4.94ꢀ4.82 (m, 4H), 3.75 (m, 1H), 3.64 (bd, J = 10.2 Hz,
1
H), 2.89 (t, J = 10.7 Hz, 1H), 2.19ꢀ1.98 (m, 2H), 1.89ꢀ1.79 (m, 1H), 1.61ꢀ1.49 (m, 2H),
13
1
0.99 (m, 9H). C{ H}ꢀNMR (CDCl
3
, 100 MHz) δ 137.9 (CH), 136.2 (6 x CH), 136.0
(
CH), 135.9 (CH), 135.8 (CH), 134.5 (CH), 134.0 (2 x C), 129.8 (CH), 129.7 (CH),
1
29.5 (CH), 129.4 (3 x CH), 127.9 (CH), 127.8 (CH), 127.7 (6 x CH), 127.6 (CH),
127.5 (CH), 117.0 (CH
7.2 (CH), 27.0 (3 x CH
Si
2
), 115.2 (CH
2
), 76.4 (CH), 71.6 (CH), 37.3 (CH
2
2
), 30.7 (CH ),
+
+
2
3
), 19.4 (C). HRMS (ESI ): m/z [M+Na] Calcd for
25
D
C
43
H
48
O
2
2
Na: 675.3091; Found: 675.3091. [α]
3
= +1.27 (c = 2.0, CHCl ).
((2
S,3S)ꢀ3ꢀethyloxiranꢀ2ꢀyl)methanol (22). Following the general procedure for
Sharpless epoxidation, (+)ꢀDET (2.1 g, 1.75 mL, 10.1 mmol, 0.35 eq.), 2ꢀpentenꢀ1ꢀol,
9
5 % (21) (2.5 g, 3.1 mL, 29.0 mmol, 1.0 eq.) and TBHP 5.06 M in isooctane (10.3 mL,
.8 eq.), were added to a suspension of MS (4Å) and Ti(iꢀOPr) (2.5 g, 2.6 mL, 0.3 eq.)
1
4
in 145 mL of dry DCM (0.2 M). The crude reaction mixture was purified by flash silica
gel column chromatography (nꢀhexane/EtOAc: 40/60 solvent system) to obtain 2.73 g
of the product 22 (92 % yield). Colorless oil. Spectral data was consistent with the
6
+
+
known product. HRMS (ESI ): m/z [M+Na] Calcd for C
5
H
10
O
2
Na: 125.0578; Found:
= ꢀ31.1 (c = 0.56, EtOH)).
)ꢀ1,2ꢀdihydroxypentanꢀ3ꢀyl benzoate (23). To a solution of Ti(iꢀOPr ) (3.04
25
D
32
22
125.0582. [α]
,3
= ꢀ27.5 (c = 1.0, EtOH, Reference. [α]
D
(
2
S
R
4
mL, 10.3 mmol, 1.5 eq.) and the epoxyalcohol 22 (0.7 g, 6.85 mmol, 1.0 eq.) in 137 mL
of dry DCM (0.05 M), was added benzoic acid (1.51 g, 12.3 mmol, 1.85 eq.). Once the
reaction was completed (monitored by TLC), aqueous 15% tartaric acid was added.
Then the mixture was extracted with 3 x DCM and 2 x EtOAc, dried over MgSO and
4
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2
2
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2
2
2
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5
6
concentrated under reduced pressure. The reaction mixture was purified by flash silica
gel column chromatography (nꢀhexane/EtOAc: 40/60 solvent system) to obtain 1.0 g of
1
the diol 23 (65% yield). Colorless oil. HꢀNMR (CDCl
3
, 400 MHz) δ 8.05 (d, J = 1.3
Hz, 2H), 7.59 (tt, J = 1.3 & 7.4 Hz, 1H), 7.46 (t, J = 7.7 Hz, 2H), 5.03 (ddd, J = 3.5, 6.8
8.7 Hz, 1H), 3.74 (ddd, J = 3.1, 4.7 & 7.7 Hz, 1H), 3.71 (dd, J = 3.0 & 14.5 Hz, 1H),
3.62(dd, J = 4.6 & 11.8 Hz, 1H), 3.01ꢀ2.28 (bs, 2H), 2.03ꢀ1.91 (dtd, J = 3.5, 7.5 & 21.9
&
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
13
1
Hz, 1H), 1.90ꢀ1.76 (sex, J = 7.3 & 8.7 Hz, 1H), 1.01 (t, J = 7.4 Hz, 3H). C{ H}ꢀNMR
CDCl , 100 MHz) δ 167.4 (C), 133.4 (CH), 129.8 (2 x CH), 128.5 (2 x CH), 76.1
(CH), 72.8 (CH), 62.5 (CH
Na: 247.0946; Found: 247.0947. [α]
(
3
+
+
2
), 23.9 (CH
2
), 9.8 (CH
3
). HRMS (ESI ): m/z [M+Na] Calcd
2
D
5
for C12
H
16
O
4
= +3.1 (c = 1.07, EtOH).
(
R)ꢀ1ꢀoxobutanꢀ2ꢀyl benzoate (24). To a solution of diol 23 (0.22 g, 1.0 mmol) in
diethyl ether (0.27 M) was added a solution of NaIO (0.27 g, 1.26 mmol) and Bu NF
4
4
(
26 µL, 0.026 mmol) in H
reaction mixture was quenched by diluting with diethyl ether and water. Next, it was
extracted with 3 x Et O and dried over MgSO , followed by concentration under
2
O (0.45 M). Stirred at RT and monitored by TLC. The
2
4
reduced pressure, giving 0.172 g of the crude product (89% yield). Spectral data were
33
consistent with the known compound, so our product was later used without further
purification.
4
cisꢀꢁ ꢀ2ꢀethylꢀ7ꢀisobutyloxepene (1a). Following the general procedure above,
3
isovaleraldehyde (1.08 mmol, 2.0 eq.) and FeCl (0.054 mmol, 0.10 eq.) were added to
a solution of the bisꢀhomoallylsilyl alcohol 7a (0.54 mmol, 1.0 eq.) in dry DCM (0.1 M)
1
to obtain 43.0 mg of the product (44% yield). Colorless oil. HꢀNMR (CDCl
3
, 400
MHz) δ 5.74 (d, J = 3.8 Hz, 1H), 5.73 (d, J = 3.3 Hz, 1H), 3.39 (ddt, J = 1.6 Hz, 3.6 &
.8 Hz, 1H), 3.20 (m, 1H), 2.18 (m, 4H), 1.89 (m, 1H), 1.56 (m, 2H), 1.44 (m, 1H), 1.10
m, 1H), 0.96 (t, J = 7.4 Hz, 3H), 0.90 (d, J = 6.8 Hz, 3H), 0.88 (d, J = 6.7 Hz, 3H).
9
(
1
3
1
C{ H}ꢀNMR (CDCl , 100 MHz) δ 129.7 (CH), 129.6 (CH), 81.9 (CH), 78.0 (CH),
3
2 2 2 2 3 3
46.4 (CH ), 38.5 (CH ), 37.9 (CH ), 30.2 (CH ), 24.4 (CH), 23.5 (CH ), 21.7 (CH ),
+
+
1
0.9 (CH ). HRMS (EI ): m/z [M] Calcd for C H O: 182.1671; Found: 182.1682. IR
3
12 22
ꢀ1
(
CHCl
3
): 2959, 2928, 2855, 1717, 1467, 1368, 1219 cm .
4
1
transꢀꢁ ꢀ2ꢀethylꢀ7ꢀisobutyloxepene (10a). 14.0 mg (14% yield). Colorless oil. Hꢀ
NMR (CDCl , 400 MHz) δ 5.66 (m, 2H), 4.06 (m, 1H), 3.88 (m, 1H), 2.34 (m, 2H),
3
2
.17 (m, 2H), 1.76 (m, 1H), 1.53 (m, 2H), 1.48ꢀ1.37 (m, 1H), 1.10 (ddd, J = 4.5, 8.6 &
3.5 Hz, 1H), 0.91 (t, J = 7.4 Hz, 3H), 0.90 (d, J = 2.8 Hz, 3H), 0.89 (d, J = 2.9 Hz, 3H).
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3
1
C{ H}ꢀNMR (CDCl
5.2 (CH ), 35.7 (CH
10.4 (CH). HRMS (EI ): m/z [M] Calcd for C12
3
, 100 MHz) δ 128.6 (CH), 128.5 (CH), 74.8 (CH), 71.5 (CH),
4
2
2
), 35.0 (CH
2
), 29.1 (CH
2
), 24.5 (CH
3 3 3
), 23.4 (CH ), 22.1 (CH ),
+
+
H
22O: 182.1671; Found: 182.1682. IR
ꢀ1
(
CHCl
3
): 2959, 2928, 2855, 1717, 1467, 1368, 1219 cm .
(2
R
,3
R
,4 ,6 )ꢀ4ꢀchloroꢀ6ꢀethylꢀ2ꢀisobutylꢀ3ꢀmethyltetrahydroꢀ2
R
S
H
ꢀpyran
(11a).
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Following the previous general procedure, 16 mg of the product was obtained (14%
1
yield). Colorless oil. HꢀNMR (CDCl
3
, 400 MHz) δ 3.69 (ddd, J = 4.7, 10.6 & 11.8 Hz,
1
1
3
H), 3.15 (m, 1H), 2.99 (td, J = 2.8 & 9.8 Hz, 1H), 2.17 (dd, J = 4.7 & 12.8 Hz, 1H),
.90 (m, 1H), 1.65 (dd, J = 11.6 & 24.1 Hz, 1H), 1.54ꢀ1.31 (m, 5H), 1.02 (d, J = 6.4 Hz,
13
1
H), 0.96ꢀ0.91 (m, 6H), 0.86 (d, J = 6.5 Hz, 3H). C{ H}ꢀNMR (CDCl
3
, 100 MHz) δ
80.0 (CH), 78.0 (CH), 64.6 (CH), 45.4 (CH), 43.0 (CH
2
), 42.5 (CH
2
), 28.8 (CH ), 24.3
2
+
+
(CH), 23.9 (CH ), 21.2 (CH ), 14.6 (CH ), 10.1 (CH ). HRMS (EI ): m/z [M+H] Calcd
3
3
3
3
for C12H24ClO: 219.1486; Found: 219.1465.
4
cisꢀꢁ ꢀ2ꢀ(butꢀ3ꢀenꢀ1ꢀyl)ꢀ7ꢀethyloxepene (1b). Following the general procedure above,
4
ꢀpentenal (1.48 mmol, 1.1 eq.), TMSCl (1.48 mmol, 1.1 eq.) and Fe(acac) (0.13
3
mmol, 0.10 eq.) were added to a solution of the bisꢀhomoallylsilyl alcohol 7a (1.34
mmol, 1.0 eq.) in dry DCM (0.1 M) to obtain 99.0 mg of the product (41% yield).
1
Colorless oil. HꢀNMR (CDCl
3
, 400 MHz) δ 5.83 (m, 1H), 5.74 (m, 2H), 5.02 (ddd, J =
1.6, 3.3 & 17.2 Hz, 1H), 4.95 (da, J = 10.2 Hz, 1H), 3.33 (ddt, J = 1.7, 3.7 & 9.5 Hz,
1
H), 3.20 (m, 1H), 2.21 (m, 6H), 1.66 (m, 1H), 1.56 (m, 1H), 1.46 (m, 2H), 0.98 (t, J =
1
3
1
7
3
.4 Hz, 3H). C{ H}ꢀNMR (CDCl , 100 MHz) δ 138.8 (CH), 129.6 (CH), 129.4 (CH),
114.4 (CH
2
), 81.8 (CH), 79.3 (CH), 38.1 (CH
2
), 37.7 (CH
2
), 36.4 (CH
2 2
), 30.5 (CH ),
+
+
3
1
0.1 (CH
2
), 11.0 (CH
3
). HRMS (EI ): m/z [M] Calcd for C12
H20O: 180.1514; Found:
ꢀ1
3
80.1520. IR (CHCl ): 2960, 2926, 2856, 1717, 1468, 1219 cm .
4
transꢀꢁ ꢀ2ꢀ(butꢀ3ꢀenꢀ1ꢀyl)ꢀ7ꢀethyloxepene (10b). 29.0 mg (12% yield). Colorless oil.
1
HꢀNMR (CDCl , 400 MHz) δ 5.83 (m, 1H), 5.68 (m, 2H), 5.04 (m, 1H), 4.97 (da, J =
3
10.1 Hz, 1H), 4.00 (m, 1H), 3.91 (m, 1H), 2.23 (m, 1H), 2.21 (m, 5H), 1.66 (m, 1H),
13
1
1
3
.56 (m, 1H), 1.46 (m, 2H), 0.95 (t, J = 7.4 Hz, 3H). C{ H}ꢀNMR (CDCl , 100 MHz)
δ 138.7 (CH), 128.5 (CH), 128.4 (CH), 114.4 (CH ), 75.0 (CH), 72.8 (CH), 35.4 (CH ),
2
2
+
+
3
5.2 (CH
2
), 34.9 (CH
2
), 30.2 (CH
2
), 29.0 (CH
2
), 10.4 (CH
3
). HRMS (EI ): m/z [M]
Calcd for C12
H
20O: 180.1514; Found: 180.1520. IR (CHCl ): 2960, 2926, 2856, 1717,
3
ꢀ1
1468, 1219 cm .
(2
R
,3
R,4R
,6
S)ꢀ2ꢀ(butꢀ3ꢀenꢀ1ꢀyl)ꢀ4ꢀchloroꢀ6ꢀethylꢀ3ꢀmethyltetrahydroꢀ2Hꢀpyran
1
(11b). 44.0 mg (15% yield). Colorless oil. HꢀNMR (CDCl
3
, 400 MHz) δ 5.82 (ddt, J =
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2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
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6
6
.7, 10.5 & 16.9 Hz, 1H), 4.99 (m, 2H), 3.68 (ddd, J = 5.6, 10.7 & 11.6 Hz, 1H), 3.17
(m, 1H), 2.96 (td, J = 2.5 & 9.5 Hz, 1H), 2.28 (m, 1H), 2.19ꢀ2.07 (m, 2H), 1.79ꢀ1.71 (m,
1H), 1.69ꢀ1.60 (dd, J = 11.7 & 24.1 Hz, 1H), 1.60ꢀ1.42 (m, 4H), 1.04 (d, J = 6.7 Hz,
1
3
1
3
H), 0.95 (t, J = 7.4 Hz, 3H). C{ H}ꢀNMR (CDCl
3
, 100 MHz) δ 138.6 (CH), 114.7
(CH ), 80.9 (CH), 77.8 (CH), 64.5 (CH), 44.9 (CH), 42.9 (CH
2
2
2
), 32.6 (CH ), 29.6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
+
ꢀ
(CH ), 28.8 (CH ), 14.5 (CH ), 10.1 (CH ). HRMS (ESI ): m/z [MꢀH] Calcd for
2
2
3
3
C
12
H
20ClO: 215.1203; Found: 215.1206.
4
cisꢀꢁ ꢀ2ꢀdecylꢀ7ꢀisobutyloxepene (1c). Following the general procedure above,
isovaleraldehyde (0.99 mmol, 2.0 eq.) and FeBr (0.025 mmol, 0.05 eq.) were added to
3
a solution of the bisꢀhomoallylsilyl alcohol 12a (0.495 mmol, 1.0 eq.) in dry DCM (0.1
1
M) to obtain 114.0 mg of the product (78% yield). Colorless oil. HꢀNMR (CDCl
3
, 400
MHz) δ 5.74 (m, 2H), 3.38 (ddt, J = 1.6, 3.6 & 9.8 Hz, 1H), 3.28 (m, 1H), 2.18 (m, 4H),
.86 (m, 1H), 1.53 (m, 3H), 1.26 (bs, 16H), 1.09 (m, 1H), 0.90 (d, J = 6.7 Hz, 3H), 0.88
1
13
1
(t, J = 6.7 Hz, 3H), 0.87 (d, J = 6.6 Hz, 3H). C{ H}ꢀNMR (CDCl
3
, 100 MHz) δ 129.7
(CH), 129.6 (CH), 80.2 (CH), 78.0 (CH), 46.4 (CH ), 38.5 (CH ), 38.2 (CH ), 37.2
2
2
2
(
CH
2
), 31.9 (CH
3.6 (CH ), 22.7 (CH
38ONa: 317.2820; Found: 317.2818. IR (CHCl
2
), 29.63 (3 x CH
2
), 29.6 (CH
2
), 29.3 (CH
2
2
), 26.2 (CH ), 24.4 (CH),
+
+
2
3
2
), 21.7 (CH ), 14.1 (CH
3
3
). HRMS (ESI ): m/z [M+Na] Calcd for
C
20
H
3
): 2957, 2928, 2856, 1717, 1467,
ꢀ1
1368, 1219 cm .
4
1
transꢀꢁ ꢀ2ꢀdecylꢀ7ꢀisobutyloxepene (10c). 25.0 mg (17% yield). Colorless oil. Hꢀ
NMR (CDCl
3
, 400 MHz) δ 5.65 (m, 2H), 4.05 (m, 1H), 3.95 (m, 1H), 2.33 (m, 2H),
2.17 (m, 2H), 1.75 (m, 1H), 1.52 (ddd, J = 5.3, 8.7 & 13.7 Hz, 2H), 1.44ꢀ1.34 (m, 2H),
1
.34ꢀ1.19 (m, 18H), 1.10 (ddd, J = 4.5, 8.6 & 13.7 Hz, 1H), 0.91 (d, J = 1.5 Hz, 3H),
1
3
1
0
.89 (d, J = 1.7 Hz, 3H), 0.88 (t, J = 7.0 Hz, 3H). C{ H}ꢀNMR (CDCl
3
, 100 MHz) δ
128.6 (CH), 128.5 (CH), 73.4 (CH), 71.5 (CH), 45.3 (CH ), 36.2 (CH
2
2
), 35.8 (CH ),
2
35.5 (CH ), 31.9 (CH ), 29.7 (CH ), 29.6 (3 x CH ), 29.3 (CH ), 25.9 (CH ), 24.5 (CH),
2
2
2
2
2
2
+
+
23.4 (CH
3
), 22.7 (CH
2
), 22.2 (CH
3
), 14.1 (CH
3
). HRMS (ESI ): m/z [M+Na] Calcd for
): 2957, 2928, 2856, 1717, 1467,
C
20
H
38ONa: 317.2820; Found: 317.2818. IR (CHCl
3
ꢀ1
1368, 1219 cm .
(2
R,3
R,4R
,6
S)ꢀ4ꢀchloroꢀ6ꢀdecylꢀ2ꢀisobutylꢀ3ꢀmethyltetrahydroꢀ2
H
ꢀpyran
(11c).
1
16.4 mg (15% yield). (Table 1, entry 10). Colorless oil. HꢀNMR (CDCl
3
, 400 MHz) δ
3.68 (ddd, J = 4.7, 10.6 & 15.3 Hz, 1H), 3.23 (m, 1H), 2.98 (td, J = 2.8 & 9.8 Hz, 1H),
2
.15 (ddd, J = 1.7, 4.7 & 12.8 Hz, 1H), 1.89 (m, 1H), 1.66 (dd, J = 11.6 & 24.2 Hz, 1H),
.55ꢀ1.24 (m, 21H), 1.02 (d, J = 6.5 Hz, 3H), 0.91 (d, J = 6.6 Hz, 3H), 0.86 (t, J = 6.6
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3
1
Hz, 6H). C{ H}ꢀNMR (CDCl
CH), 43.4 (CH ), 42.5 (CH ), 35.8 (CH
), 25.6 (CH ), 24.3 (CH), 23.9 (CH
3
, 100 MHz) δ 80.0 (CH), 76.5 (CH), 64.6 (CH), 45.4
), 31.9 (CH ), 29.6 (3xCH ), 29.4 (CH ), 29.3
), 22.7 (CH ), 21.2 (CH ), 14.6 (CH ), 14.1
39ClO: 330.2689; Found: 330.2686.
(
2
2
2
2
2
2
(CH
CH
2
3
2
3
2
3
3
+
(
). HRMS (EI): m/z [M] Calcd for C20H
4
cisꢀꢁ ꢀ2ꢀdecylꢀ7ꢀ(3ꢀbutenyl)ꢀoxepene (1d). Following the general procedure above, 4ꢀ
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
pentenal (0.99 mmol, 2.0 eq.) and FeBr (0.025 mmol, 0.05 eq.) were added to a
3
solution of the bisꢀhomoallylsilyl alcohol 12a (0.495 mmol, 1.0 eq.) in dry DCM (0.1
1
M) to obtain 94.5 mg of the product (65% yield). Pale yellow oil. HꢀNMR (CDCl
3
, 400
MHz) δ 5.82 (m, 1H), 5.73 (m, 2H), 5.02 (ddd, J = 1.6, 3.3 & 17.2 Hz, 1H), 4.95 (d, J =
0.2 Hz, 1H), 3.30 (m, 2H), 2.19 (m, 6H), 1.66 (m, 1H), 1.46 (m, 5H), 1.26 (bs, 14H),
1
1
3
1
3
0.88 (t, J = 6.7 Hz, 3H). C{ H}ꢀNMR (CDCl , 100 MHz) δ 138.8 (CH), 129.6 (CH),
1
3
29.4 (CH), 114.4 (CH ), 80.1 (CH), 79.3 (CH), 38.2 (CH ), 38.1 (CH ), 37.2 (CH ),
2
2
2
2
6.4 (CH
2
), 31.9 (CH
2
), 30.5 (CH
2
), 29.63 (3 x CH
2
), 29.6 (CH
2
), 29.3 (CH
2
), 26.4
+
+
(CH
2
), 22.7 (CH
2
), 14.1 (CH
3
). HRMS (ESI ): m/z [M+Na] Calcd for C20
H
36ONa:
ꢀ
3
15.2664; Found: 315.2666. IR (CHCl ): 3020, 2928, 2856, 1717, 1640, 1458, 1220 cm
3
1
.
4
transꢀꢁ ꢀ2ꢀdecylꢀ7ꢀ(3ꢀbutenyl)ꢀoxepene (10d). 18.2 mg (13% yield). Pale yellow oil.
1
3
HꢀNMR (CDCl , 400 MHz) δ 5.83 (m, 1H), 5.65 (m, 2H), 5.02 (ddd, J = 1.7, 3.5 &
17.1 Hz, 1H), 4.95 (bd, J = 10.1 Hz, 1H), 3.97 (m, 2H), 2.42ꢀ2.26 (m, 2H), 2.25ꢀ2.02
1
3
1
(
m, 4H), 1.42ꢀ1.35 (m, 2H), 1.35ꢀ1.20 (bs, 18H), 0.88 (t, J = 6.8 Hz, 3H). C{ H}ꢀ
NMR (CDCl
3
, 100 MHz) δ 138.7 (CH), 128.6 (CH), 128.4 (CH), 114.4 (CH
2
), 73.6
), 30.2
(CH), 72.8 (CH), 36.1 (CH
2
), 35.4 (CH
2
), 35.3 (CH
2
), 35.2 (CH
2
), 31.9 (CH
2
(CH
2
), 29.7 (CH
2
), 29.6 (3 x CH
2
), 29.3 (CH ), 26.0 (CH
2
2
2 3
), 22.7 (CH ), 14.1 (CH ).
+
+
HRMS (ESI ): m/z [M+Na] Calcd for C20
H
36ONa: 315.2664; Found: 315.2666. IR
ꢀ1
(
CHCl
3
): 3020, 2928, 2856, 1717, 1640, 1458, 1220 cm .
(2
R,3
R,4
R
,6
S
)ꢀ2ꢀ(butꢀ3ꢀenꢀ1ꢀyl)ꢀ4ꢀchloroꢀ6ꢀdecylꢀ3ꢀmethyltetrahydroꢀ2
H
ꢀpyran
, 400
1
(11d). 9.3 mg (8% yield). (Table 1, entry 11). Colorless oil. HꢀNMR (CDCl
3
MHz) δ 5.87ꢀ5.75 (m, 1H), 5.06ꢀ4.98 (dd, J = 1.5 & 17.1 Hz, 1H), 4.98ꢀ4.93 (dd, J = 0.8
10.2 Hz, 1H), (td, J = 4.7 & 11.6 Hz, 1H), 3.24 (m, 1H), 2.95 (td, J = 2.4 & 9.6 Hz,
&
1
H), 2.33ꢀ2.22 m, 1H), 2.18ꢀ2.03 (m, 2H), 1.79ꢀ1.71 (m, 1H), 1.71ꢀ1.59 (dd, J = 12.0 &
2
4.3 Hz, 1H), 1.54ꢀ1.46 (m, 2H), 1.46ꢀ1.21 (m, 18H), 1.03 (d, J = 6.5 Hz, 3H), 0.88 (t, J
1
3
1
= 6.4 Hz, 3H). C{ H}ꢀNMR (CDCl , 125MHz) δ 138.6 (CH), 114.7 (CH ), 80.9 (CH),
3
2
7
6.4 (CH), 64.5 (CH), 44.9 (CH), 43.2 (CH
2
), 35.8 (CH
2
), 32.6 (CH
2
2
), 31.9 (CH ), 29.7
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1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
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(
CH
CH
2
3
), 29.6 (3xCH
2
), 29.5 (CH
2
), 29.3 (CH
2
), 25.6 (CH
2 2 3
), 22.7 (CH ), 14.5 (CH ), 14.1
+
(
). HRMS (EI): m/z [M] Calcd for C20
4
H37ClO:328.2533; Found: 328.2545.
cisꢀꢁ ꢀ2ꢀdecylꢀ7ꢀvinyloxepene (1e). Following the general procedure above, acrolein
3
(0.99 mmol, 2.0 eq.) and FeBr (0.025 mmol, 0.05 eq.) were added to a solution of the
bisꢀhomoallylsilyl alcohol 12a (0.495 mmol, 1.0 eq.) in dry DCM (0.1 M) to obtain 74.4
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
mg of the product (57% yield). Pale yellow oil. HꢀNMR (CDCl , 400 MHz) δ 5.88
3
(ddd, J = 4.8, 10.6 & 17.3 Hz, 1H), 5.76 (d, J = 3.5 Hz, 1H), 5.26 (td, J = 1.7 & 17.2 Hz,
1
H), 5.06 (td, J = 1.8 & 10.6 Hz, 1H), 3.87 (m, 1H), 3.37 (m, 1H), 2.38ꢀ2.14 (m, 4H),
1
3
1
1
.51ꢀ1.17 (m, 18H), 0.88 (t, J = 6.6 Hz, 3H). C{ H}ꢀNMR (CDCl , 100 MHz) δ 139.9
3
(CH), 129.9 (CH), 128.9 (CH), 113.8 (CH
2
), 80.2 (CH), 80.1 (CH), 38.0 (CH
2
), 37.5
(CH
2
), 37.0 (CH
2
), 31.9 (CH
2
), 29.6 (3 x CH
2
), 29.5 (CH
2
), 29.3 (CH
2
), 26.2 (CH ),
2
+
+
2
2.7 (CH ), 14.1 (CH ). HRMS (ESI ): m/z [M+Na] Calcd for C H ONa: 287.2351;
2
3
18 32
ꢀ1
3
Found: 287.2359. IR (CHCl ): 3020, 2928, 2856, 1718, 1466, 1458, 1218 cm .
4
1
transꢀꢁ ꢀ2ꢀdecylꢀ7ꢀvinyloxepene (10e). 18.6 mg (14% yield). Pale yellow oil. HꢀNMR
(CDCl , 400 MHz) δ 5.89 (ddd, J = 5.7, 10.5 & 17.2 Hz, 1H), 5.68 (m, 2H), 5.23 (td, J =
3
1
.7 & 17.2 Hz, 1H), 5.08 (td, J = 1.7 & 10.5 Hz, 1H), 4.50 (m, 1H), 4.03 (m, 1H), 2.50
(m, 1H), 2.36 (m, 1H), 2.23 (m, 2H), 1.35ꢀ1.19 (m, 18H), 0.88 (t, J = 6.6 Hz, 3H).
13
1
C{ H}ꢀNMR (CDCl
75.1 (CH), 73.9 (CH), 36.2 (CH
9.3 (CH ), 26.0 (CH ), 22.7 (CH
32ONa: 287.2351; Found: 287.2359. IR (CHCl
3
, 100 MHz) δ 139.9 (CH), 129.2 (CH), 127.9 (CH), 114.5 (CH
2
),
),
2
), 35.7 (CH
2
), 34.7 (CH
2
), 31.9 (CH
2
), 29.6 (4 x CH
2
+
+
2
2
2
2
), 14.1 (CH
3
). HRMS (ESI ): m/z [M+Na] Calcd for
C
18
H
3
): 3020, 2928, 2856, 1718, 1466,
ꢀ1
1458, 1218 cm .
4
cisꢀꢁ ꢀ2ꢀdecylꢀ7ꢀcyclohexyloxepene (1f). Following the general procedure above,
3
cyclohexylcarboxaldehyde (0.99 mmol, 2.0 eq.) and FeBr (0.025 mmol, 0.05 eq.) were
added to a solution of the bisꢀhomoallylsilyl alcohol 12a (0.495 mmol, 1.0 eq.) in dry
1
DCM (0.1 M) to obtain 110.0 mg of the product (69% yield). Colorless oil. HꢀNMR
(CDCl
3
, 400 MHz) δ 5.73 (m, 2H), 3.26 (m, 1H), 3.04 (brdd, J = 6.4 & 11.8 Hz, 1H),
2
1
1
3
.28ꢀ2.10 (m, 4H), 1.97 (bd, J = 12.8 Hz, 1H), 1.77ꢀ1.69 (m, 2H), 1.69ꢀ1.60 (m, 2H),
13
1
.60ꢀ1.41 (m, 2H), 1.39ꢀ1.02 (m, 22H), 0.88 (t, J = 6.8 Hz, 3H). C{ H}ꢀNMR (CDCl ,
3
00 MHz) δ 129.7 (CH), 129.2 (CH), 84.6 (CH), 80.3 (CH), 44.0 (CH), 38.0 (CH
2
),
7.2 (CH ), 35.0 (CH ), 31.9 (CH ), 30.1 (CH ), 29.63 (2 x CH ), 29.60 (CH ), 29.56
2
2
2
2
2
2
(CH ), 29.3 (CH ), 28.9 (CH ), 26.6 (CH ), 26.4 (CH ), 26.3 (2 x CH ), 22.7 (CH ),
2
2
2
2
2
2
2
+
+
1
3
4.1 (CH
3
). HRMS (ESI ): m/z [M+Na] Calcd for C22
H
40ONa: 343.2977; Found:
ꢀ1
43.2981. IR (CHCl
3
): 3019, 2929, 2856, 1716, 1451, 1218 cm .
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transꢀꢁ ꢀ2ꢀdecylꢀ7ꢀcyclohexyloxepene (10f). 19 mg (12% yield). Colorless oil. Hꢀ
NMR (CDCl , 400 MHz) δ 5.66 (m, 2H), 3.95 (m, 1H), 3.70 (m, 1H), 2.35 (m, 2H),
2.16 (m, 2H), 1.87 (d, J = 12.6 Hz, 1H), 1.74 (m, 2H), 1.65 (m, 2H), 1.43ꢀ1.16 (m,
3
13
1
2
2H), 1.06ꢀ0.95 (m, 2H), 0.88 (t, J = 6.7 Hz, 3H). C{ H}ꢀNMR (CDCl
3
, 150 MHz) δ
1
28.8 (CH), 128.5 (CH), 77.9 (CH), 73.8 (CH), 42.8 (CH), 36.3 (CH ), 35.2 (CH
2
2
), 32.2
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(CH ), 31.9 (CH ), 29.7 (CH ), 29.6 (3xCH ), 29.3 (CH ), 29.1 (CH ), 29.0 (CH ), 26.7
2
2
2
2
2
2
2
+
(CH
2
), 26.4 (CH
2
), 26.3 (CH
2
), 26.0 (CH
2
), 22.7 (CH
2
), 14.1 (CH
3
). HRMS (ESI ): m/z
): 3019, 2929,
+
[
M+Na] Calcd for C22
H
40ONa: 343.2977; Found: 343.2981. IR (CHCl
3
ꢀ1
2
856, 1716, 1451, 1218 cm .
4
cisꢀꢁ ꢀ2ꢀdecylꢀ7ꢀphenyloxepene (1g). Following the general procedure above,
benzaldehyde (0.99 mmol, 2.0 eq.) and FeBr (0.025 mmol, 0.05 eq.) were added to a
3
solution of the bisꢀhomoallylsilyl alcohol 12a (0.495 mmol, 1.0 eq.) in dry DCM (0.1
1
M) to obtain 64.5 mg of the product (41% yield). Pale yellow oil. HꢀNMR (CDCl
3
, 400
MHz) δ 7.38 (d, J = 7.2 Hz, 2H), 7.33 (t, J = 7.5 Hz, 2H), 7.24 (t, J = 7.3 Hz, 1H), 5.83
t, J = 3.6 Hz, 2H), 4.45 (dd, J = 1.8 & 10.0 Hz, 1H), 3.51 (m, 1H), 2.62ꢀ2.42 (m, 2H),
.42ꢀ2.20 (m, 2H), 1.61 (m, 1H), 1.50ꢀ1.39 (m, 2H), 1.35ꢀ1.21 (m, 15H), 0.88 (t, J = 6.7
(
2
13
1
Hz, 3H). C{ H}ꢀNMR (CDCl
3
, 100 MHz) δ 144.1 (C), 130.1 (CH), 129.2 (CH), 128.1
), 37.9 (CH ),
), 22.7 (CH ), 14.1
34ONa: 337.2507; Found: 337.2509.
(
2 x CH), 126.8 (CH), 125.7 (2 x CH), 81.7 (CH), 80.6 (CH), 39.8 (CH
2
2
37.1 (CH
CH
2
), 31.9 (CH
2
), 29.6 (4 x CH
2
), 29.3 (CH
2
), 26.2 (CH
2
2
+
+
(
3
). HRMS (ESI ): m/z [M+Na] Calcd for C22
H
ꢀ1
3
IR (CHCl ): 3019, 2928, 2856, 1716, 1452, 1428, 1277, 1218, 1116 cm .
4
1
transꢀꢁ ꢀ2ꢀdecylꢀ7ꢀphenyloxepene (10g). 20.2 mg (13% yield). Pale yellow oil. Hꢀ
NMR (CDCl
3
, 400 MHz) δ 7.38 (d, J = 7.9 Hz, 2H), 7.33 (t, J = 7.4 Hz, 2H), 7.24 (t, J =
.0 Hz, 1H), 5.77 (m, 2H), 5.13 (dd, J = 1.6 & 10.2 Hz, 1H), 4.20 (m, 1H), 2.79 (m,
H), 2.50 (m, 1H) 2.42ꢀ2.21 (m, 2H), 1.66 (ddd, J = 8.9, 8.9 & 16.9 Hz, 1H), 1.50ꢀ1.38
7
1
13
1
(
m, 2H), 1.37ꢀ1.20 (m, 15H), 0.89 (t, J = 6.7 Hz, 3H). C{ H}ꢀNMR (CDCl , 100
3
MHz) δ 144.2 (C), 129.3 (CH), 128.8 (CH), 128.2 (2 x CH), 127.0 (CH), 126.2 (2 x
CH), 76.5 (CH), 75.0 (CH), 37.2 (CH
2
), 36.1 (CH
2
), 35.2 (CH
2
), 31.9 (CH
2
), 29.6 (4 x
+
+
CH ), 29.3 (CH ), 26.1 (CH ), 22.7 (CH ), 14.1 (CH ). HRMS (ESI ): m/z [M+Na]
2
2
2
2
3
Calcd for C22
H
3
34ONa: 337.2507; Found: 337.2509. IR (CHCl ): 3019, 2928, 2856,
ꢀ1
1
716, 1452, 1428, 1277, 1218, 1116 cm .
4
cisꢀꢁ ꢀ2ꢀdecylꢀ7ꢀ
p
ꢀmethoxyphenyloxepene (1h). Following the general procedure
(0.025 mmol, 0.05 eq.)
above, pꢀmethoxybenzaldehyde (0.99 mmol, 2.0 eq.) and FeBr
3
were added to a solution of the bisꢀhomoallylsilyl alcohol 12a (0.495 mmol, 1.0 eq.) in
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