An Olefin Cross-Metathesis Approach to Depudecin and Stereoisomeric Analogues

Article abstract of DOI:10.1021/acs.joc.7b00424

A new total synthesis of the natural product (?)-depudecin, a unique and unexplored histone deacetylase (HDAC) inhibitor, is reported. A key feature of the synthesis is the utilization of an olefin cross-metathesis strategy, which provides for an efficient and improved access to natural depudecin, compared with our previous linear synthesis. Featured by its brevity and convergency, our developed synthetic strategy was applied to the preparation of the 10-epi derivative and the enantiomer of depudecin, which represent interesting stereoisomeric analogues for structure-activity relationship studies.

Full text of DOI:10.1021/acs.joc.7b00424

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Article
An Olefin Cross-Metathesis Approach to
Depudecin and Stereoisomeric Analogues
Iván Cheng-Sánchez, Cristina García-Ruiz, Guillermo A. Guerrero-Vásquez, and Francisco Sarabia
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b00424 • Publication Date (Web): 11 Apr 2017
Downloaded from http://pubs.acs.org on April 11, 2017
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An Olefin Cross-Metathesis Approach to Depudecin and
Stereoisomeric Analogues

Iván Cheng-Sánchez, Cristina García-Ruiz, Guillermo A. Guerrero-Vásquez
and Francisco Sarabia
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Department of Organic Chemistry
Faculty of Sciences. University of Malaga.
Campus de Teatinos s/n. 29071. Malaga (SPAIN)
Telephone: 34-952 134258. Fax: 34-952 131941
Email: frsarabia@uma.es
#
Current address: School of Chemistry, University of Bristol
Cantock´s Close, Bristol BS8 1TS, UK
Abstract: A new total synthesis of the natural product (-)-depudecin, a unique and unexplored
histone deacetylase (HDAC) inhibitor, is reported. A key feature of the synthesis is the
utilization of an olefin cross-metathesis strategy, which provides for an efficient and improved
access to natural depudecin, compared with our previous linear synthesis. Featured by its
brevity and convergency, our developed synthetic strategy was applied to the preparation of
the 10-epi derivative and the enantiomer of depudecin, which represent interesting
stereoisomeric analogues for structure-activity relationship studies.
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INTRODUCTION
The disclosure and recognition of the crucial role of histone deacetylases (HDAC) and histone
acetyl transferases (HAT) in the regulation of gene expression, which occurs through a tight
control of the acetylation state of histones, has generated significant interest in their utility as
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new promising targets for cancer therapies. Thus, whereas the acetylated histones lead to a
local expansion of chromatin, increasing the accessibility of regulatory proteins to DNA, the
action of HDACs produces positively-charged histones that increase their affinities with DNA
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and, thereby, block the transcription of anti-tumor genes. HDACs are the enzymes
responsible for the removal of the acetyl group from lysine residues of histones and other
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proteins; and are comprised of 18 isoforms grouped into four different classes (I-IV). The
inhibition of these enzymes in the context of a neoplastic epigenome, in which they are
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overexpressed and play important roles in promoting cancer progression, leads to the
restoration of a normal epigenetic state and induces the expression of tumor-suppresive
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genes. Consequently, inhibitors of HDAC (HDACi) have attracted considerable attention
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from the scientific community as novel potential anticancer agents. An indication of this
interest is the flurry of activity directed towards the design and synthesis of inhibitors, which
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have been classified into five categories according to their modes of action. As a
consequence of this intense activity, three of them (vorinostat, belinostat and romidespin)
have been recently approved by the FDA for clinical anticancer therapies, whereas a
remarkable number of other HDACi have undergone clinical trials for the treatment of a
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variety of hematological malignancies and solid tumors. The fact that other proteins,
including transcription factors, DNA repair enzymes, signal transduction and inflammation
mediators, among others, are also substrates of HDACs, further demonstrates their
involvement in a wide variety of biological processes, including cell cycle and mitosis, DNA
damage repair, cellular stress responses, protein degradation, cytokine signalling, immunity,
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inflammation, angiogenesis, apoptosis and cell invasion. In fact, HDACs are involved not
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only in cancer, but also in other pathologies such as neurological diseases, immune disorders10
and infections.11 On the other hand, the general lack of isoform selectivity exhibited by
current inhibitors towards the HDAC family,12,13 which are involved in a plethora of
biological functions, explains the diverse biological effects that they may produce,14 thus
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reducing their therapeutic window by promoting undesirable side effects and toxicity.
In this context, (-)-depudecin (1), isolated from the culture broths of the fungus Alternaria
brassicicola in 199215 and later, from the weed pathogen Nimbya scirpicola,16 has been
identified as a selective inhibitor of histone deacetylases I and II with an IC50 in the low M
range, according to biological studies carried out by Schreiber et al.17 In contrast to
representative HDACi, such as 2-6 (Figure 1), depudecin represents a unique inhibitor of
these enzymes by virtue of its molecular structure, featuring the presence of two oxirane rings
separated by a trans double bond.15 Originally discovered as part of a biological screen
directed towards the identification of antitumour agents with detransforming activity,18
depudecin was identified as a bioactive metabolite capable of reverting the transformed
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morphology of tumor cells NIH3T3, doubly transfected with v-ras and v-src oncogenes. The
ability of depudecin to regulate the cytoskeletal architecture of tumoral cells is due to the
restoration of the actin stress fiber. This biological activity elicited a great biomedical and
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biological interest by virtue of its potential as an antitumor agent and as a molecular probe
for the investigation of signalling pathways that regulate the actin stress fiber, as well as for
further understanding the biological roles of HDACs. Depudecin induced not only
morphological changes but also cell cycle arrest and cellular differentiation, which could be
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attributed to its inhibition against HDAC as mentioned above. It is likely that its inhibitory
action against HDCA is a result of the presence of biologically reactive oxirane rings that
could block the active site of the enzymes through the irreversible formation of a covalent
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bond between the nucleophlic residues within the active site and the oxirane rings. In fact,
Schreiber demonstrated that the epoxy and hydroxyl groups of depudecin were essential for
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the biological activity, as the synthetic analogue 9 showed very weak activity, and 7 and 8
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were completely inactive against transformed NIH3T3 cells. Furthermore, depudecin also
exhibited remarkable anti-angiogenesis activity that endowed it with potent anti-proliferative
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activity against HUVEC. Finally, in addition to its antitumor properties, depudecin was also
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identified as a potent anti-protozoal agent against Neospora caninum, without any side effects
for the host cell.26
Figure 1. Molecular Structures of (-)-Depudecin (1) and Other HDAC Inhibitors
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Despite the intriguing biological activities of depudecin and its unique molecular structure, it
is rather surprising that only one total synthesis has been reported so far, by the group of
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Schreiber in 1995. This synthesis was based on an asymmetric methodology that used a one-
pot procedure for the stereoselective conversion of syn-vicinal diols into trans-epoxides,
proceeding in 23 steps with an overall yield of 0.7%. Although the synthesis was a long linear
synthesis, it was able to provide sufficient amounts of synthetic (-)-depudecin, together with
related intermediates (7-9) for further biological studies.
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Prompted by its striking biological properties and enticing structure, we decided to initiate a
research program directed towards the synthesis of natural depudecin and analogues. Our
synthetic plan has recently culminated with a total synthesis based on the retrosynthetic
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analysis depicted in Scheme 1. Accordingly, we envisioned triepoxy alcohol 10 as a direct
precursor of depudecin via an epoxide reductive elimination process. For the preparation of
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0, we devised the use of a new class of chiral sulfonium salts (12 and ent-12), developed in
our laboratories,28,29 for the stereoselective construction of the oxirane rings contained in the
natural product. Thus, we prepared triepoxy amide 13 in a remarkable 51% overall yield over
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steps and with complete stereoselectivity from ,-unsaturated aldehyde 11, involving a
sequential formation of a diepoxide system mediated by sulfonium salt 12. From this highly
valuable tri-epoxide amide, the completion of the synthesis of depudecin was achieved
without problems through triepoxy alcohol 10 (Scheme 1).
In order to develop an improved and expeditious access to natural depudecin, as well as to
access additional analogues for further biological screenings, we explored a synthetic
alternative based on a olefin cross-metathesis strategy as a shorter and more convergent
approach.
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Scheme 1. Synthesis of (-)-Depudecin: The Linear Approach
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RESULTS AND DISCUSSION
For the new synthesis of depudecin, we conceived of a convergent approach wherein an olefin
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cross-metathesis reaction would serve as the key step to join the terminal olefins 15 and 16.
Thus, according to the retrosynthetic analysis depicted in Scheme 2, (-)-depudecin (1) could
be obtained again from a triepoxy alcohol (14 in this case) via an epoxide reductive
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elimination process in the synthetic direction. This triepoxy alcohol 14, in turn, could be
delivered from a key olefin cross-metathesis of compounds 15 and 16. The preparation of
these metathesis precursors was envisioned to be readily feasible from the commercially
available (+)-methyl-D-lactate (17) and cis-2-buten-1,4-diol (18), respectively. The synthesis
of the required precursors proceeded as shown in Scheme 2. Thus, we begun with the
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synthesis of 15 starting from 17, which was transformed into epoxy alcohol 19 via a Sharpless
asymmetric epoxidation (SAE),32 from the corresponding allylic alcohol.33 From epoxy
alcohol 19, the synthesis continued by a two step sequence, involving oxidation and Wittig
reaction, to obtain 15 in a 50% overall yield. For the other key fragment 16, we planned to
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start from the known epoxy alcohol 20, obtained from cis-2-buten-1,4-diol (18) in 4 steps.
From 20, the construction of the second oxirane ring was achieved via the sulfonium salt 12
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by reacting the aldehyde derived from a Parikh-Doering oxidation of 20, to obtain diepoxy
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amide 21 in a remarkable 73% over two steps and complete stereoselectivity. Subsequent
reduction of 21 with Red-Al, followed by a Wittig reaction, afforded alkene 16 in 50% yield
over 2 steps. Alternatively, diepoxy olefin 16 was also obtained via a Sharpless asymmetric
epoxidation (SAE) of allylic alcohol 23, resulting from the reduction of the ,-unsaturated
aldehyde 22, to provide diepoxy alcohol 24, which was transformed into the olefin 16 in 60%
yield over two steps (Scheme 2). Comparatively, the overall yields for both synthetic routes
are similar (36.5 and 31%, respectively), with the advantage of the sulfonium salt route being
shorter than the SAE path.
With both key fragments in hand, we investigated the viability of the cross-metathesis
reaction. For the assembly of both epoxy olefin units, a cross-metathesis of alkenes under the
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influence of the Hoveyda-Grubbs 2 generation catalyst (HG-II) was initially attempted.
The result was the cross-metathesis product 25, however in a very low yield (15%), and with
the homodimerization compound 26, as the major product (60%). Various reaction conditions
and stochiometries of the involved alkenes were evaluated, including second cycles of
metathesis, but these failed to improve the yield of the desired product in all cases. Despite the
yield of this reaction being variable and generally modest, we were able to access 14 by a
selective deprotection step of the primary alcohol, which was accomplished in the presence of
TsOH, resulting in the key triepoxy alcohol 14, in a 50% yield (Scheme 3).
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Scheme 2. The Convergent Approach to (-)-Depudecin via Olefin Cross-Metathesis: Synthesis
of the Precursors
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Despite these discouraging results, we decided to press forward with the synthetic strategy by
exploring the cross-metathesis from different precursors. To this aim, we reasoned that the
placement of a more bulky protected group on the hydroxyl group of the lactate fragment
could reduce the dimerization process thus favoring the cross-metathesis reaction. Therefore,
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we considered a second attempt with the TBDPS derivative 28, prepared in the same way as
for 15 from the known epoxy alcohol 27.27 On the other hand, we decided to use the
unprotected diepoxy olefin 29, as the other metathesis precursor, with the purpose of
obtaining a product more closer to depudecin, and without the requirement of additional
selective deprotection steps. To our delight, the crucial cross-metathesis reaction between
precursors 28 and 29, in the presence of HG-II catalyst in refluxing dichloromethane,
proceeded smoothly to afford the coveted cross-metathesis product 10 in a reasonable and
reproducible 50% yield, exclusively as the E-isomer, with no detection of the corresponding
dimer of 28. With compound 10 in hand, we proceeded to completion of the synthesis of (-)-
depudecin. To this end, we initially attempted a straightforward synthesis of depudecin
derivative 32 from triepoxy alcohol 10 through a titanocene-assisted epoxide reductive
opening.38 In this event, triepoxy alcohol 10 was subjected to the combined action of
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Cp
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TiCl /Zn. Unfortunately, the result of this reaction was a complex mixture of
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decomposition products, with none of the desired protected depudecin 32 detected. Similarly
discouraging was the attempt of preparing iodide 31 directly from 10 by treatment with
iodine/Ph P in the presence of imidazole, which also resulted in a complex mixture of
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degradation products. Given these unsuccessful results in our attempt to shorten the number of
steps for the completion of the synthesis of depudecin, we returned to our synthetic sequence
employed in our first total synthesis. Fortunately, we were able to improve the yields of the
subsequent transformations after optimization of the reaction conditions. Thus, the alcohol 10
was converted into the corresponding alcohol 32, through tosylation and subsequent
displacement of the intermediate tosylate 30 with NaI, to obtain iodide 31, which was then
subjected to treatment with BuLi and no further purification. As a result, the resulting alcohol
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2 was obtained in a 90% overall yield over three steps from 10. The final deprotection step
provided natural depudecin (1), similarly in an improved yield (90% versus 86% in our first
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total synthesis). The physical and spectroscopic properties of synthetic 1 were in accordance
to those reported for the natural compound.15,23
Scheme 3. The Convergent Approach to (-)-Depudecin via Olefin Cross-Metathesis:
Completion
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In light of these encouraging results, we devised the possibility of a direct cross-metathesis
reaction between olefin 28 and diolefin 33 that would furnish the direct precursor 32 in a
single step. It is important to consider that this metathesis reaction is prone to give a mixture
of different products, due to the presence of two terminal olefins in 33. However, a possible
coordination involving the allylic alcohol and the catalyst could arrest the catalytic cycle at
this terminal olefin to favor the metathesis in the desired direction.39 To this end, we
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proceeded with the synthesis of compound 33, whose synthesis was more difficult than
initially expected, despite its small size. Initially, we attempted the direct reductive opening of
diepoxy alcohol 29, again by the action of a titanocene reducing agent. As in the case for
compound 10, the reaction was completely unsuccessful. Thus, we proceeded with the
preparation of iodide 34 by direct iodination of 29 to obtain 34 albeit in a poor yield (25%),
due to the formation of the diiodide 35 in a 47% yield, as the main product. Despite this
disappointing yield, iodide 34 was subjected to the action of BuLi to provide the targeted
diolefin 33, in almost quantitative yield. Given the poor yield of the iodination step, we
attempted the synthesis of this compound via a tosylate derivative. However, the result was
similarly disappointing due to competing ring opening reactions of the oxirane with the
halides present in the reaction mixture, during both the tosylation, as well as during the
nucleophilic iodination step. The low yielding conversion of diepoxy alcohol 29 to the target
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a second attempt, we prepared epoxy alcohol 37 from 20, in order to construct the hydroxy
allylic system via a vinyl magnesium bromide addition to the resulting aldehyde. However,
after oxidation of 37, the reaction with the Grignad reagent failed to deliver the desired
product (Scheme 4, part A). In a third alternative route, we chose to test the approach
involving early stage installation of the allylic alcohol system, in order to construct at a later
time, the terminal olefin adjacent to the epoxide. Thus, starting from 24, which was readily
obtained from diepoxy amide 21, compound 39 was efficiently synthesized and then
elaborated for the introduction of the other terminal olefin. In particular, after protection of 39
as a TBDPS ether, the selective deprotection of the primary alcohol of the resulting bis-silyl
ether 40 afforded, unfortunately, compound 41 as a result of the opening of the resulting
epoxy alcohol by another epoxy alcohol molecule. Finally, in a fourth attempt, from iodide 38,
we decided to prepare olefin 34 prior to the reductive opening process. Thus, desilylation of
iodide 38 was followed by an oxidation step of the resulting alcohol 42, followed by a Wittig
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reaction, to afford 34 in a modest 47% overall yield. From iodide 34, the synthesis of 33
proceeded in a similar manner as described above (Scheme 4, part B).
Scheme 4. A Direct Cross-Metathesis Approach to (-)-Depudecin: Synthesis of Precursor 33
0
1
2
3
4
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7
8
9
0
1
2
3
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9
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1
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5
6
7
8
9
0
1
2
3
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8
9
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With the diolefin 33 in hand, the cross-metathesis reaction was attempted under the same
conditions as previously described for the synthesis of 10. To our dismay, the reaction was
completely unsuccessful, with the formation of a complex mixture of compounds and no
detection of any cross-metathesis product, such as the desired 32. In a modified attempt to
obtain additional direct precursor of depudecin, we tried the cross-metathesis of olefins 28 and
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
3
4. Unfortunately, the result was similarly disappointing with no detection of the desired
product 31 (Scheme 5).
Scheme 5. Attempts of the Direct Cross-Metathesis Approach
Due to the previous unsatisfactory results, the direct approach to depudecin was abandoned in
favor of the route described in Scheme 3. Having secured a cross-metathesis strategy for this
natural product, we decided to pursue depudecin analogues utilizing this methodology. Since
the oxirane rings appears to be essential and required for the biological activity of depudecin,
we decided to retain these functional groups within the designed analogues, considering
therefore depudecin stereoisomers as the most interesting and promising compounds from a
biological standpoint. In this sense, we considered as prime candidates the 10-epi analogue of
depudecin, compound 53, and the enantiomer, (+)-depudecin (ent-1), which would be
obtained from the readily available (-)-ethyl L-lactate (43) as a common starting material. In
the case of the 10-epi analogue of depudecin, the synthesis of the precursor 48 was carried out
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8
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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
from (-)-ethyl L-lactate (43) in an efficient and stereoselective manners (54% yield over 7
4
1
42
steps) via a tandem Wittig-Martin /SAE, according to the sequence depicted in Scheme 6.
Then, following on our previously developed strategy to depudecin, we subjected 48 to a
cross-metathesis reaction with 29 to afford product 49 in a reasonable 55% yield. From 49, the
completion of the depudecin analogue 53 followed the same synthetic sequence as for (-)-
depudecin (1) through compounds 50-52 and in similar yields (Scheme 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
Scheme 6. Synthesis of 10-epi-depudecin (53)
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Finally, for the synthesis of the enantiomer of depudecin, the compounds ent-28 and ent-29
were prepared without any difficulty via Sharpless asymmetric epoxidation for ent-28, from
4
3
the corresponding allylic alcohol 46, through epoxy alcohol ent-27, and via chiral sulfonium
salt ent-12 for ent-29. Both olefinic precursors were then joined via a cross-metathesis
reaction to afford ent-10 in a 52% yield, which was taken on to (+)-depudecin (ent-1) as
described above for the natural product (Scheme 7).
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Scheme 7. Synthesis of (+)-depudecin (ent-1)
CONCLUSIONS
In conclusion, we have established a new synthesis of (-)-depudecin 1, which greatly improves
upon our previous linear synthesis. Comparatively, whereas the first total synthesis, reported
by Schreiber, required 23 linear steps from (-)-diethyl D-tartrate (54), with an overall yield of
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8
9
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
.7%, our first linear synthesis from 17 was achieved in 17 steps in a 19% overall yield
(Scheme 8). As continuation of our previous work, we have developed a second generation
synthetic route to depudecin utilizing an olefin cross-metathesis reaction as the key step,
which was successfully achieved in a convergent manner to provide (-)-depudecin (1) in only
12 steps and 26% overall yield from 17.
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
Scheme 8. Summary of the Syntheses of Depudecin and Analogues
In addition, the synthetic route was amenable to stereochemical modifications, allowing the
preparation of two stereoisomers of (-)-depudecin, the 10-epi-depudecin and its enantiomer,
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which represent unique analogues that will further assist us to evaluate the influence of the
stereochemistry upon biological activity. The described chemistry, in addition to rendering (-)-
depudecin (1) readily available for further biological investigations, also provides rapid access
to analogues for structure-activity relationship studies. The biological evaluation of the
described compounds, together with other analogues, is currently in progress and will lead us
to define their clinical potential for anticancer therapy through their inhibitory activity and
isoform specificity against HDACs.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
EXPERIMENTAL SECTION
General Information. All reactions were carried out under an argon atmosphere with dry,
freshly distilled solvents under anhydrous conditions, unless using aqueous reagents or
otherwise noted. All solvents used in reactions were dried and distilled using standard
procedures. Tetrahydrofuran (THF) was distilled from sodium benzophenone, and
dichloromethane (CH
2
Cl
2
) and MeOH from calcium hydride. Yields refer to
1
chromatographically and spectroscopically ( H NMR) homogeneous materials, unless
otherwise stated. All reagents were purchased at highest commercial quality and used without
further purification unless otherwise stated. All solutions used in workup procedures were
saturated unless otherwise noted. Flash column chromatography (FCC) was performed using
silica gel 60 Å (particle size 230-400 mesh) under air pressure. All solvents used for
chromatographic purifications were distilled prior to use. All reactions were monitored by
thin-layer chromatography (TLC) using 0.25 mm silica gel plates (60F-254) and visualized by
UV light (254 nm) or potassium permanganate or acidic ceric ammonium
1
13
molybdate/phosphomolybdic acid soluction and heat as developing agents. H and C NMR
spectra were recorded on a Bruker DPX-400 MHz instrument and calibrated using residual
undeuterated solvent as an internal reference. Chemical shifts are reported in ppm with the
resonance resulting from incomplete deuteration of the solvent as the internal standard
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9
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
(13
CDCl
: 7.26 ppm, s and 77.0 ppm, t). Data are reported as follows: chemical shift δ/ppm
3
(multiplicity (s = singlet, d = doublet, t = triplet; q, quartet; b = broad, m, multiplet or
1
13
combinations thereof), coupling constants J (Hz), integration ( H only) and assignment). C
signals are singles, unless otherwise stated. High resolution mass spectrometry (HRMS) was
performed on a H-ESI and APCI mass spectometer in positive mode and using an ion trap
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
(
Orbitrap) as the mass analyzer type. HRMS signals are reported to 4 decimal places and are
within ± 5 ppm of theoretical values. Specific optical rotations were recorded on a Jasco P-
000 polarimeter with a sodium halogen lamp (ƛ= 589 nm) and a cell path length of 100 mm
c givn in g/100 mL). Melting points were collected using a Gallenkamp or a Griffin melting
point system using a gradient of 0.5ºC per min.
2
(
33
Epoxy Alkene 15. A solution of epoxy alcohol 19 (220 mg, 0.95 mmol, 1.0 equiv) in a 1:1
DMSO:CH Cl mixture (20 mL) was treated with Et N (0.4 mL, 14.20 mmol, 3.0 equiv) and
SO ·py (375 mg, 2.37 mmol, 2.5 equiv) at 0 ºC. The mixture was stirred until complete
conversion of the alcohol ( 3 h). After this time, the reaction mixture was quenched by
addition of a buffer solution (pH = 7) and diluted with Et O. The aqueous phase was extracted
with Et O twice and the combined organic layers were washed with brine, dried over
anhydrous MgSO , filtered and the solvent evaporated under reduced pressure to give the
2
2
3
3
2
2
4
crude aldehyde (0.95 mmol) which was used in the next step without further purification. To
a stirred suspension of methyl triphenylphosphonium bromide (693 mg, 1.90 mmol, 2.0
equiv) in THF (10 mL) at 0 ºC was added dropwise NaHMDS (0.95 mL, 2.0 M in THF, 1.87
mmol, 2.0 equiv). The resulting suspension was stirred for 30 min at this temperature, and
after this time, a solution of the crude aldehyde (0.95 mmol) in THF (5 mL) was added
dropwise, and the resulting mixture stirred for 1 h. After this time, the crude mixture was
diluted with Et
2
O and washed with a saturated aqueous NH
4
Cl solution. The aqueous phase
was extracted with Et
2
O and the combined organic extracts were washed with brine, dried
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over MgSO
4
, filtered and the solvent evaporated under reduced pressure. The crude product
was purified by flash column chromatography (silica gel, 10% EtOAc in hexanes) to obtain
epoxy alkene 15 (100 mg, 50% over two steps) as a pale yellow oil: R
f
= 0.74 (silica gel, 10%
) δ 5.63–5.53
EtOAc in hexanes); [α]25
= + 35.2 (c 0.40, CH
Cl
); H NMR (400 MHz, CDCl
1
D
2
2
3
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(m, 1 H), 5.45 (dd, J = 17.2, 1.5 Hz, 1 H), 5.26 (ddd, J = 10.2, 1.5, 0.5 Hz, 1 H), 3.66–3.58
m, 1 H), 3.20 (dd, J = 7.5, 2.2 Hz, 1 H), 2.85 (dd, J = 5.9, 2.2 Hz, 1 H), 1.21 (d, J = 6.4 Hz, 3
(
1
3
H), 0.90 (s, 9 H), 0.10 (s, 3 H), 0.07 (s, 3 H); C NMR (100 MHz, CDCl
3
) δ 135.5, 118.9,
Si [M +
6
7.5, 63.5, 56.5, 25.8, 20.8, 18.1, –4.7, –4.9; HRMS (H-ESI) m/e calcd for C12
H
24
O
2
+
H] 229.1624, found 229.1618.
3
4
Diepoxy Amide 21. Epoxy alcohol 20 (640 mg, 2.96 mmol 1.0 equiv) was dissolved in a
CH Cl /DMSO (1:1) mixture (12 mL) and cooled at 0ºC. At this temperature, Et N (1.2 mL,
.88 mmol, 3.0 equiv) was added followed by SO ·Pyr (840 mg, 5.20 mmol, 1.8 equiv). The
reaction mixture was allowed to reach room temperature and, after 5 h, was quenched by
addition of a buffer solution (pH = 7) and diluted with Et O. The aqueous phase was extracted
with Et O (3 x 20 mL) and the combined organic extracts were washed with water and brine,
then dried over anhydrous MgSO and the solvent removed under reduced pressure. The
2
2
3
8
3
2
2
4
resulting crude aldehyde was used in the next step without further purification. To a
suspension of sulfonium salt 1228,29 (1.0 g, 3.40 mmol, 1.1 equiv) in t-BuOH (40 mL) was
added a 5.0 M aqueous NaOH solution (0.6 mL, 3.0 mmol, 1.0 equiv) at 25 ºC. After 1 h at
this temperature, a solution of crude aldehyde in t-BuOH (10 mL) was added and the resulting
reaction mixture was stirred overnight. The crude mixture was then diluted with CH
O and, after decantation, the aqueous phase was extracted with CH Cl three times. The
combined organic extracts were washed with brine, dried over MgSO , filtered and
2
Cl and
2
H
2
2
2
4
concentrated under reduced pressure. The crude product was purified by flash column
chromatography (silica gel, 20% EtOAc in hexanes) to obtain diepoxy amide 21 (920 mg,
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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
7
3% over 2 steps) as a pale yellow oil and whose spectroscopic and physical properties
matched with those described in the literature:36
R
= 0.20 (Silica gel, 40% EtOAc in
); H NMR (400 MHz, CDCl ) δ (ppm): 4.27 (ddd, J
8.8, 4.7, 3.5 Hz, 1 H), 3.97 (ddd, J = 9.1, 5.2, 1.3 Hz, 1 H), 3.89–3.86 (m, 1 H), 3.85 (d, J =
f
hexanes); [α]25
= –17.1 (c 0.34, CH
Cl
1
D
2
2
3
=
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
2.0 Hz, 1 H), 3.69 (dd, J = 12.3, 3.7 Hz, 1 H), 3.54 (d, J = 2.0 Hz, 1 H), 3.30 (dd, J = 3.4, 2.0
Hz, 1 H), 3.11–3.06 (m, 2 H), 2.59–2.50 (m, 1 H), 2.48–2.39 (m, 1 H), 2.08 (s, 3 H), 2.05–
2
0
5
.00 (m, 1 H), 1.83–1.73 (m, 1 H), 1.59 (s, 3 H), 1.48 (s, 3 H), 0.84 (s, 9 H), 0.02 (s, 3 H),
1
3
.00 (s, 3 H); C NMR (100 MHz, CDCl ) δ (ppm): 162.9, 95.9, 67.0, 61.6, 56.3, 55.9, 55.5,
3
1.7, 51.2, 34.4, 30.6, 26.2, 25.8, 22.9, 18.3, 15.7, –5.4, –5.4; HRMS (H-ESI) m/e calcd for
+
C
20
H37NO
5
SSi [M + H] 432.2240, found 432.2239.
Diepoxy Alkene 16. To a solution of diepoxy amide 21 (95 mg, 0.34 mmol, 1.0 equiv) in
THF (1.5 mL) was added dropwise Red-Al (0.03 mL, 70% w/v in toluene, 0.09 mmol, 0.5
equiv) at 0 ºC. After 30 min at this temperature, the reaction mixture was quenched by
+
+
addition of a saturated aqueous Na /K tartrate solution and diluted with EtOAc. The resulting
mixture was vigorously stirred until a clear separation of both oganic and aqueous phases.
After separation of both layers, the aqueous phase was extracted with EtOAc and the
combined organic extracts washed with H
2
O and brine, dried over anhydrous MgSO , and the
4
solvent evaporated under reduced pressure. The resulting crude aldehyde was used in the next
step without further purification. To a stirred suspension of methyl triphenylphosphonium
bromide (123 mg, 0.35 mmol, 1.75 equiv) in THF (1.0 mL) at 0 ºC was added dropwise
NaHMDS (0.18 mL, 2.0 M in THF, 0.35 mmol, 1.75 equiv). The resulting suspension was
stirred for 15 min at this temperature, and after this time, a solution of the crude aldehyde
(
0.20 mmol) in THF (3.0 mL) was added dropwise, and the resulting mixture was stirred for
0 min. After this time, the crude mixture was diluted with Et O and washed with a saturated
aqueous NH Cl solution. The aqueous phase was extracted with Et O and the combined
3
2
4
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organic extracts were washed with brine, dried over MgSO , filtered and the solvent
4
evaporated under reduced pressure. The crude product was purified by flash column
chromatography (silica gel, 20% EtOAc in hexanes) to obtain the epoxy alkene 16 (33 mg,
2
5
5
0% over two steps) as a colorless oil: R
f
= 0.89 (silica gel, 40% EtOAc in hexanes); []
D
=
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
–20.2 (c 0.39, CH
2
Cl
2
); H NMR (400 MHz, CDCl
3
) δ 5.59–5.49 (m, 2 H), 5.35–5.30 (m, 1
H), 3.88 (dd, J = 12.2, 2.9 Hz, 1 H), 3.75 (dd, J = 12.2, 4.0 Hz, 1 H), 3.36 (dd, J = 7.0, 2.1 Hz,
1 H), 3.11 (ddd, J = 4.0, 2.8, 2.2 Hz, 1 H), 3.00 (dd, J = 4.3, 2.2 Hz, 1 H), 2.92 (dd, J = 4.4,
13
2
1
.1 Hz, 1 H), 0.89 (s, 9 H), 0.07 (s, 3 H), 0.07 (s, 3 H); C NMR (100 MHz, CDCl
3
) δ 134.5,
28.5, 62.1, 57.7, 56.0, 55.9, 53.3, 29.7, 25.8, 18.3, –5.4; HRMS (H-ESI) m/z calcd for
+
C
13
H
24
O
3
Si [M + H] 257.1573, found 257.1567.
Aldehyde 22. To a solution of epoxy alcohol 20 (4.0 g, 18.32 mmol, 1.0 equiv) in a 1:1
DMSO:CH Cl mixture (36 mL) was added Et N (7.7 mL, 54.95 mmol, 3.0 equiv) followed
by SO ·py (7.3 g, 45.79 mmol, 2.5 equiv) at 0 ºC. The reaction mixture was stirred at this
2
2
3
3
temperature until depletion of the starting alcohol as judged by TLC ( 5 h). After this time,
the reaction mixture was quenched by addition of a buffer solution (pH = 7) and diluted with
Et
layers were washed with brine, dried over anhydrous MgSO
evaporated under reduced pressure to give the crude aldehyde (18 mmol) which was used in
the next step without further purification. To a solution of the crude aldehyde in CH Cl (95
2
O. The aqueous phase was extracted with Et
2
O (2 x 30 mL) and the combined organic
4
, filtered and the solvent
2
2
mL) was added (formylmethylene)triphenylphosphorane (7.0 g, 23.08 mmol, 1.2 equiv) and
the mixture was stirred for 12 h. After this time the solvent was removed under reduced
pressure and the residue purified by flash column chromatography (silica gel, 10% EtOAc in
hexanes) to obtain aldehyde 22 (3.3 g, 74% over two steps) as a pale yellow oil: R
f
= 0.51
); H NMR (400 MHz,
) δ 9.57 (d, J = 7.7 Hz, 1 H), 6.57 (dd, J = 15.8, 6.9 Hz, 1 H), 6.40 (ddd, J = 15.8, 7.7,
2
5
1
(
silica gel, 30% EtOAc in hexanes); []
D
= –24.8 (c 0.21, CH
2
Cl
2
CDCl
3
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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
.6 Hz, 1 H), 3.94–3.89 (m, 1 H), 3.81 (dd, J = 12.2, 3.8 Hz, 1 H), 3.55 (dd, J = 6.9, 2.0 Hz, 1
1
3
H), 3.12 (ddd, J = 3.8, 3.0, 2.0 Hz, 1 H), 0.90 (s, 9 H), 0.08 (s, 3 H), 0.07 (s, 3 H); C NMR
(100 MHz, CDCl
m/z calcd for C12
3
) δ 192.4, 152.3, 133.9, 61.9, 61.5, 53.4, 25.8, 18.3, –5.3; HRMS (H-ESI)
+
H
22
O
3
Si [M + H] 243.1416, found 243.1398.
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
Allylic Alcohol 23. A solution of aldehyde 22 (3.3 g, 13.61 mmol, 1.0 equiv) in CH
2
Cl (120
2
mL) was cooled at -78 ºC and treated with DIBAL-H (13.6 mL, 1.0 M in toluene, 13.61
mmol, 1.0 equiv). After 20 min, the reaction was quenched by addition of MeOH at -78 ºC
and the mixture was allowed to reach room temperature, treated with a saturated aqueous
+
+
Na /K tartrate solution and diluted with CH
until a clear separation of both organic and aqueous phases. The organic layer was separated
and the aqueous phase was extracted with CH Cl three times. The combined organic layers
were washed with brine, dried over anhydrous MgSO , filtered and the solvent evaporated
under reduced pressure. The residue was purified by flash column chromatography (silica gel,
15% EtOAc in hexanes) to obtain allylic alcohol 23 (3.0 g, 90%) as a yellow oil: R = 0.35
); H NMR (400 MHz,
) δ 6.09 (dt, J = 15.7, 5.3 Hz, 1 H), 5.51 (ddt, J = 15.6, 7.9, 1.7 Hz, 1 H), 4.19 (td, J =
2
Cl2. The resulting mixture was vigorously stirred
2
2
4
f
25
1
(silica gel, 30% EtOAc in hexanes); []
D
= –31.8 (c 0.64, CH
2
Cl
2
CDCl
3
5
.7, 1.6 Hz, 2 H), 3.86 (dd, J = 12.0, 3.3 Hz, 1 H), 3.73 (dd, J = 12.0, 4.4 Hz, 1 H), 3.32 (dd, J
=
7.9, 2.1 Hz, 1 H), 3.02 (ddd, J = 4.4, 3.2, 2.2 Hz, 1 H), 1.39 (t, J = 5.9 Hz, 1 H), 0.90 (s, 9
1
3
H), 0.09 (s, 3 H), 0.08 (s, 3 H); C NMR (100 MHz, CDCl
5.3, 25.9, 18.4, –5.3; HRMS (H-ESI) m/z calcd for C12
245.1595.
3
) δ 132.5, 128.2, 62.9, 62.8, 60.4,
+
5
H
24
O
3
Si [M + H] 245.1573, found
Diepoxy Alcohol 24. To a suspension of titanium tetraisopropoxide (1.27 mL, 4.29 mmol,
0.35 equiv) and 4Å molecular sieves (8.0 g) in CH Cl (85 mL) was added (+)-L-DET (0.74
mL, 4.29 mmol, 0.35 equiv) at -20 ºC. After 15 min at this temperature, a solution of allylic
2
2
2
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alcohol 23 (3.0 g, 12.27 mmol, 1.0 equiv) in CH
2
Cl (100 mL) was added dropwise, followed
2
by the addition, after additional 30 min, of TBHP (5.0 mL, 5.5 M solution in decane, 24.55
mmol, 2.0 equiv) at the same temperature. After 12 h at this temperature, the reaction mixture
was quenched with Me S (4.2 mL, 56.47 mmol, 4.6 equiv) at 0 ºC, filtered off and the solvent
2
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
was evaporated under reduced pressure. The crude product was purified by flash column
chromatography (silica gel, 20% EtOAc in hexanes) to obtain diepoxy alcohol 24 (2.49 g,
2
5
7
8%) as a colourless oil: R
f
= 0.40 (silica gel, 50% EtOAc in hexanes); []
D
= –22.4 (c 0.51,
1
CH
2
Cl
2
); H NMR (400 MHz, CDCl
3
) δ 3.98 (ddd, J = 12.8, 4.9, 2.3 Hz, 1 H), 3.88 (dd, J =
1
3
1
2.2, 2.9 Hz, 1 H), 3.75 (dd, J = 12.2, 4.0 Hz, 1 H), 3.73–3.68 (m, 1 H), 3.17–3.15 (m, 1 H),
.11 (ddd, J = 4.0, 2.9, 2.2 Hz, 1 H), 3.08 (dd, J = 4.6, 2.2 Hz, 1 H), 2.98 (dd, J = 4.7, 2.2 Hz,
1
3
H), 0.89 (s, 9 H), 0.08 (s, 3 H), 0.07 (s, 3 H); C NMR (100 MHz, CDCl
3
) δ 62.5, 62.0,
Si [M + H]+
56.1, 55.8, 53.5, 53.4, 25.8, 18.3, –5.4; HRMS (H-ESI) m/z calcd for C12
61.1522, found 261.1523.
H
24
O
4
2
Diepoxy Alkene 16 from Diepoxy alcohol 24. Diepoxy alcohol 24 (1.8 g, 6.91 mmol, 1.0
equiv) was converted to diepoxy alkene 16 (1.0 g, 60% over two steps) according to the
procedure described above for 15 by sequential treatments with Et
3
N (2.9 mL)/SO ·py (2.8 g)
3
and methyl triphenylphosphonium bromide (5.0 g)/NaHMDS (7.0 mL). The spectroscopic
properties of the resulting diepoxy alkene were indetical with those exhibited by 16 obtained
above from 21.
Bis(silyl eher) 25 and Dimer 26. Cross-Metathesis of Olefins 15 and 16. Hoveyda-Grubbs
2nd generation catalyst (16 mg, 0.02 mmol, 0.2 equiv), diepoxy alkene 16 (23 mg, 0.09 mmol,
1
.0 equiv) and epoxy alkene 15 (60 mg, 0.27 mmol, 3.0 equiv) were dissolved in degassed
CH Cl (8 mL) and the reaction mixture was heated at 40 ºC for 12 h. After this time, the
solvent was removed under reduced pressure and the resulting crude product was purified by
2
2
2
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9
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
flash column chromatography (silica gel, 5% EtOAc in hexanes) to obtain dimer 26 (23 mg,
6
0%) and bis(silyl ether) 25 (6 mg, 15%) as a colourless and a pale yellow oils, respectively.
2
5
1
[25]: R
f
= 0.57 (silica gel, 10% EtOAc in hexanes); []
D
= –31.4 (c 0.40, CH
2
Cl ); H NMR
2
(400 MHz, CDCl
3
) δ 5.72 (dd, J = 15.7, 7.0 Hz, 1 H), 5.64 (dd, J = 15.6, 7.0 Hz, 1 H), 3.88
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
(dd, J = 12.2, 2.7 Hz, 1 H), 3.74 (dd, J = 12.2, 4.0 Hz, 1 H), 3.67–3.60 (m, 1 H), 3.37 (dd, J =
.0, 2.1 Hz, 1 H), 3.23 (dd, J = 6.9, 2.1 Hz, 1 H), 3.11–3.07 (m, 1 H), 3.00 (dd, J = 4.2, 2.2
7
Hz, 1 H), 2.93 (dd, J = 4.2, 2.1 Hz, 1 H), 2.86 (dd, J = 5.7, 2.1 Hz, 1 H), 1.20 (d, J = 6.4 Hz, 3
13
H), 0.90 (s, 9 H), 0.89 (s, 9 H), 0.09 (s, 3 H), 0.07 (s, 3 H), 0.07 (s, 3 H), 0.06 (s, 3 H); C
NMR (100 MHz, CDCl
3
) δ 132.7, 130.8, 69.2, 64.7, 61.9, 58.1, 56.1, 54.8, 54.8, 53.0, 25.8,
+
2
0.3, 18.3, 18.2, –4.8, –5.4; HRMS (APCI) m/e calcd for C23
found 479.2621; [26]: R
CDCl
Hz, 2 H), 2.78 (dd, J = 4.2, 2.1 Hz, 2 H), 1.23 (d, J = 6.3 Hz, 6 H), 0.88 (s, 18 H), 0.05 (s, 6
H
44
O
5
Si
2
[M + Na] 479.2625,
1
f
= 0.77 (silica gel, 10% EtOAc in hexanes); H NMR (400 MHz,
3
) δ 5.68 (dd, J = 4.4, 2.4 Hz, 2 H), 3.77 (dd, J = 6.2, 4.3 Hz, 2 H), 3.31 (dt, J = 4.4, 2.2
1
3
H), 0.04 (s, 6 H); C NMR (100 MHz, CDCl
3
) δ 131.7, 67.2, 63.9, 55.1, 25.8, 20.8, 18.1, –
+
4
.7, –4.8; HRMS (APCI) m/e calcd for C22
H
44
O
4
Si
2
[M + H] 429.2856, found 429.2862.
Epoxy Alcohol 14. Silyl derivative 25 (30 mg, 0.07 mmol, 1.0 equiv) was dissolved in a
mixture THF-H O (20:1) (5 mL) and over this solution was added p-TsOH (2 mg, 0.01 mmol,
.1 equiv) at 25 ºC. After stirring for 40 min at the same temperature, the solvent was
removed under vacuum and the crude mixture purified by flash column chromatography
2
0
(silica gel, 40% EtOAc in hexanes) to obtain diepoxy alcohol 14 (11 mg, 50%) as a pale
colourless oil: R
f
= 0.38 (Silica gel, 60% EtOAc in hexanes); [α]25
D
= –35.2 (c 0.40, CH
2
Cl );
2
1H NMR (400 MHz, CDCl
H), 3.72 (dd, J = 13.2, 3.1 Hz, 1 H), 3.67–3.59 (m, 1 H), 3.39 (dd, J = 7.2, 2.1 Hz, 1 H), 3.24
dd, J = 7.1, 2.0 Hz, 1 H), 3.19–3.15 (m, 1 H), 3.10 (dd, J = 4.3, 2.2 Hz, 1 H), 3.05–3.01 (m, 1
H), 2.94 (dd, J = 4.3, 2.1 Hz, 1 H), 2.87 (dd, J = 5.7, 2.1 Hz, 1 H), 1.60 (bs, 1 H), 1.20 (d, J =
) δ 5.73 (dd, J = 15.6, 7.1 Hz, 1 H), 5.64 (dd, J = 15.7, 7.2 Hz, 1
3
(
2
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.4 Hz, 3 H), 0.90 (s, 9 H), 0.09 (s, 3 H), 0.07 (s, 3 H); C NMR (100 MHz, CDCl ) δ 132.8,
3
3
4
5
6
7
8
9
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
1
30.5, 69.1, 64.7, 61.7, 60.4, 57.9, 55.7, 54.8, 53.0, 25.8, 20.3, 18.2, –4.7, –4.8; HRMS
+
(APCI) m/e calcd for C17
H
30
O
5
Si [M + H] 343.1941, found 343.1936.
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
7
Epoxy Alkene 28. Epoxy olefin 28 was prepared from epoxy alcohol 27 (2.7 g, 7.57 mmol,
1.0 equiv) by sequential treatments with SO ·py and Ph P=CH according to the same
procedure described above for the preparation of 15, to obtain epoxy alkene 28 (2.2 g, 85%
3
3
2
2
5
over two steps) as a colourless oil: R
f
= 0.66 (silica gel, 20% EtOAc in hexanes); []
D
= +
1
1
2.7 (c 0.59, CH
2
Cl
2
); H NMR (400 MHz, CDCl
3
) δ 7.72–7.68 (m, 4 H), 7.44–7.36 (m, 6 H),
5.56 (ddd, J = 17.3, 10.2, 7.7 Hz, 1 H), 5.44–5.38 (m, 1 H), 5.25 (ddd, J = 10.3, 1.5, 0.5 Hz, 1
H), 3.76–3.68 (m, 1 H), 3.19 (dd, J = 7.7, 2.2 Hz, 1 H), 2.96 (dd, J = 5.7, 2.2 Hz, 1 H), 1.10
1
3
(d, J = 6.4 Hz, 3 H), 1.08 (s, 9 H); C NMR (100 MHz, CDCl
3
) δ 135.9, 135.8, 135.3, 134.3,
1
33.7, 129.7, 129.6, 127.6, 127.5, 119.3, 69.9, 64.3, 56.1, 26.9, 19.9, 19.3; HRMS (H-ESI)
+
m/z calcd for C22
H
28
O Si [M + H] 353.1937, found 353.1933.
2
Diepoxy Alkene 29. To a solution of silyl ether 16 (700 mg, 2.73 mmol, 1.0 equiv) in THF
70 mL) was added TBAF (5.5 mL, 1.0 M in THF, 5.45 mmol, 2.0 equiv) at 0 ºC. The
reaction mixture was stirred at 25 ºC for 1 h and, after this time, diluted with Et O and washed
with a saturated aqueous NH Cl solution. The aqueous phase was then extracted with Et
twice and the organic extracts were washed with brine, dried over MgSO and filtered. The
(
2
4
2
O
4
solvent was removed under vacuum and the crude product was purified by flash column
chromatography (silica gel, 10% EtOAc in hexanes → 30% EtOAc in hexanes) to obtain
diepoxy alkene 29 (314 mg, 81%) as a colourless oil: R
f
= 0.33 (silica gel, 40% EtOAc in
2
5
1
hexanes); []
D
= –15.8 (c 0.27, CH
2
Cl
2
); H NMR (400 MHz, CDCl ) δ 5.47–5.37 (m, 2 H),
3
5
3
.24–5.18 (m, 1 H), 3.79 (ddd, J = 11.4, 9.0, 2.5 Hz, 1 H), 3.53 (dd, J = 12.9, 4.3 Hz, 1 H),
.29–3.25 (m, 1 H), 3.05 (dd, J = 4.3, 2.3 Hz, 1 H), 2.95–2.90 (m, 1 H), 2.81 (dd, J = 4.8, 2.1
2
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2
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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
1
3
Hz, 1 H); C NMR (100 MHz, CDCl ) δ 134.2, 120.4, 60.7, 57.9, 56.0, 55.9, 53.5; HRMS
3
+
(
H-ESI) m/z calcd for C
7
H
10
O [M + H] 143.0708, found 143.0696.
3
Triepoxy Alcohol 10. Cross-Metathesis of Olefins 28 and 29. Hoveyda-Grubbs 2nd
generation catalyst (35 mg, 0.06 mmol, 0.10 equiv), diepoxy alkene 29 (80 mg, 0.56 mmol,
1.0 equiv) and epoxy alkene 28 (595 mg, 1.69 mmol, 3.0 equiv) were dissolved in degassed
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
2
Cl (6 mL) and the reaction mixture was heated at 40 ºC for 12 h. After this time, the
2
solvent was removed under reduced pressure and the resulting crude product was purified by
flash column chromatography (silica gel, 20% EtOAc in hexanes → 40% EtOAc in hexanes)
to obtain triepoxy alcohol 10 (129 mg, 50%) as a colourless oil: R
f
= 0.51 (silica gel, 60%
); H NMR (400 MHz, CDCl ) δ 7.71–7.66
m, 4 H), 7.44–7.35 (m, 6 H), 5.69 (dd, J = 15.7, 7.3 Hz, 1 H), 5.57 (dd, J = 15.6, 7.3 Hz, 1
H), 3.98 (dd, J = 10.7, 2.2 Hz, 1 H), 3.76–3.68 (m, 2 H), 3.37 (dd, J = 7.3, 2.0 Hz, 1 H), 3.21–
.16 (m, 2 H), 3.11 (dd, J = 4.3, 2.2 Hz, 1 H), 2.94 (ddd, J = 6.4, 4.9, 2.1 Hz, 2 H), 1.34 (t, J =
25
1
EtOAc in hexanes); []
D
= –30.3 (c 0.45, CH
2
Cl
2
3
(
3
1
3
7.1 Hz, 1 H), 1.10 (d, J = 6.4 Hz, 3 H), 1.07 (s, 9 H); C NMR (100 MHz, CDCl
3
) δ 135.8,
1
34.2, 133.6, 132.8, 130.5, 129.7, 127.6, 127.6, 69.7, 64.6, 62.5, 60.4, 57.9, 55.7, 54.7, 52.9,
+
26.9, 19.9, 19.3; HRMS (H-ESI) m/z calcd for C27
H
34
O Si [M + Na] 489.2073, found
5
4
89.2073.
Tosyl Derivative 30. Triepoxy alcohol 10 (57 mg, 0.12 mmol, 1.0 equiv) was dissolved in
CH Cl (7 mL) and cooled at 0 ºC. Over this solution was then added p-TsCl (28 mg, 0.15
mmol, 1.2 equiv), TEA (30 L, 0.18 mmol, 1.5 equiv) and 4-DMAP (0.3 mg, 0.002 mmol,
.02 equiv). After 3 h, the reaction mixture was quenched by addition of water and the
aqueous phase was extracted with CH Cl three times. The organic phase was washed with
brine, dried over MgSO , filtered and the solvent removed under reduced pressure to obtain
tosyl derivative 30 (90 mg, 0.12 mmol), which did not require further purification for the
2
2
0
2
2
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next step. For analytical purposes, a sample of this crude (5.0 mg, 0.007 mmol) was purified
by flash column chromatography (silica gel, 20% EtOAc in hexanes) to provide pure tosyl
derivative 30 (3.8 mg, 87%) as a colourless oil: R
f
= 0.33 (silica gel, 40% EtOAc in hexanes);
) δ 7.81–7.78 (m, 2 H), 7.71–7.65
α]25
= –18.6 (c 0.25, CH
Cl
); H NMR (400 MHz, CDCl
1
[
D
2
2
3
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(m, 4 H), 7.43–7.34 (m, 8 H), 5.67 (dd, J = 15.7, 7.3 Hz, 1 H), 5.54 (dd, J = 15.6, 7.6 Hz, 1
H), 4.20 (dd, J = 11.6, 3.7 Hz, 1 H), 4.08 (dd, J = 11.6, 5.2 Hz, 1 H), 3.76–3.68 (m, 1 H), 3.32
(dd, J = 7.4, 1.9 Hz, 1 H), 3.22–3.17 (m, 2 H), 2.98 (dd, J = 4.0, 2.0 Hz, 1 H), 2.94 (dd, J =
5
.5, 2.2 Hz, 1 H), 2.88 (dd, J = 4.0, 2.0 Hz, 1 H), 2.46 (s, 3 H), 1.10 (d, J = 6.4 Hz, 3 H), 1.07
1
3
(
s, 9 H); C NMR (100 MHz, CDCl
3
) δ 145.3, 135.9, 135.8, 134.2, 134.1, 133.6, 133.1,
1
2
30.2, 130.0, 129.7, 129.6, 127.9, 127.6, 127.5, 69.7, 68.5, 64.6, 57.1, 54.8, 54.6, 53.8, 52.3,
+
6.9, 21.7, 19.9, 19.3; HRMS (H-ESI) m/z calcd for C34
H
40
O SSi [M + Na] 643.2162, found
7
643.2161.
Iodide Derivative 31. To a solution of crude tosyl derivative 30 (85 mg, 0.11 mmol, 1.0
equiv) in dry acetone (7 mL) was added dry KI (28 mg, 0.17 mmol, 1.5 equiv) at room
temperature, and the resulting crude mixture was refluxed for 5.5 hours. The reaction mixture
was then allowed to cool to room temperature and the solvent was evaporated under reduced
pressure. The resulting crude was diluted with H
2
O and extracted with Et
2
O. After separation
, filtered and
of both phases, the organic extracts were washed with brine, dried over MgSO
4
the solvent removed under reduced pressure to obtain iodide derivative 31 (80 mg, 0.11
mmol), which did not require further purification for the next step. For analytical purposes, a
sample of this crude (4.5 mg, 0.006 mmol) was purified by flash column chromatography
(silica gel, 10% EtOAc in hexanes) to afford the iodide derivative 31 (3.2 mg, 93%) as a
colourless oil: R
f
= 0.56 (silica gel, 30% EtOAc in hexanes); [α]25
D
= –19.4 (c 0.45 CH
2
Cl );
2
1H NMR (400 MHz, CDCl
Hz, 1 H), 5.56 (dd, J = 15.7, 7.4 Hz, 1 H), 3.76–3.69 (m, 1 H), 3.35 (d, J = 7.2 Hz, 1 H), 3.28–
) δ 7.71–7.66 (m, 4 H), 7.44–7.34 (m, 6 H), 5.69 (dd, J = 15.7, 7.3
3
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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
3
3
.21 (m, 2 H), 3.20 (dd, J = 7.2, 2.1 Hz, 1 H), 3.10 (dd, J = 12.4, 8.8 Hz, 1 H), 2.96–2.93 (m,
1
3
H), 1.10 (d, J = 6.4 Hz, 3 H), 1.07 (s, 9 H); C NMR (100 MHz, CDCl ) δ 135.9, 135.8,
3
134.2, 133.6, 132.9, 130.3, 129.7, 129.6, 127.6, 127.5, 69.7, 64.6, 59.4, 57.3, 55.7, 54.8, 54.6,
+
2
6.9, 19.9, 19.3, 3.2; HRMS (H-ESI) m/z calcd for C27
H33IO
4
Si [M + Na] 599.1091, found
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
599.1088.
Allylic Alcohol 32. To a solution of the crude iodide derivative 31 (80 mg, 0.10 mmol, 1.0
equiv) in THF (10 mL) was added n-BuLi (0.13 mL, 1.6 M in hexane, 0.20 mmol, 2.0 equiv)
at -78 ºC, and the reaction mixture was stirred for 5 min. After this time, the reaction mixture
was then quenched at -78 ºC with MeOH followed by addition of a saturated aqueous NH
solution at 0 ºC. The resulting mixture was extracted with EtOAc (3 x 10 mL) and the organic
extracts were washed with brine, dried over MgSO , and filtered. The solvent was then
4
Cl
4
removed under reduced pressure and the resulting crude mixture purified by flash column
chromatogaphy (silica gel, 20% EtOAc in hexanes) to obtain allylic alcohol 32 (41 mg, 90%
over 3 steps from 10) as a colourless oil: R
f
= 0.57 (silica gel, 40% EtOAc in hexanes);
) δ 7.71–7.66 (m, 4 H), 7.43–7.34
α]25
= –20.9 (c 0.28, CH
Cl
); H NMR (400 MHz, CDCl
1
[
D
2
2
3
(m, 6 H), 5.94 (ddd, J = 17.3, 10.6, 5.5 Hz, 1 H), 5.67 (dd, J = 15.7, 7.1 Hz, 1 H), 5.58 (dd, J
15.7, 7.2 Hz, 1 H), 5.40 (dt, J = 17.3, 1.3 Hz , 1 H), 5.28 (dt, J = 10.6, 1.3 Hz, 1 H), 4.15–
.09 (m, 1 H), 3.76–3.70 (m, 1 H), 3.40 (dd, J = 7.1, 2.2 Hz, 1 H), 3.20 (dd, J = 7.0, 2.1 Hz, 1
H), 2.99 (dd, J = 4.3, 2.2 Hz, 1 H), 2.95 (dd, J = 5.5, 2.1 Hz, 1 H), 1.10 (d, J = 6.4 Hz, 3 H),
=
4
1
3
1
.07 (s, 9 H); C NMR (100 MHz, CDCl ) δ 136.2, 135.9, 135.8, 134.2, 133.6, 132.7, 130.9,
3
129.7, 129.6, 127.6, 127.5, 117.0, 71.5, 69.7, 64.5, 62.4, 55.0, 54.8, 26.9, 19.9, 19.3; HRMS
+
(H-ESI) m/z calcd for C27
H
34
O
4
Si [M + H] 451.2305, found 451.2301.
(-)-Depudecin (1). Silyl derivative 32 (11 mg, 0.02 mmol, 1.0 equiv) was dissolved in THF (3
mL) and over this solution was added TBAF (29 µL, 1.0 M in THF, 0.03 mmol, 1.2 equiv) at
2
8
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The Journal of Organic Chemistry
1
2
2
5 ºC. After 90 min, the reaction mixture was diluted with EtOAc and washed with a
3
4
5
6
7
8
9
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
saturated aqueous NH
4
Cl solution. The aqueous phase was then extracted with EtOAc and the
O, brine, dried over MgSO and filtered. The solvent
organic extracts were washed with H
2
4
was removed under vacuum and the crude product was purified by flash column
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
chromatography (silica gel, 20% EtOAc in hexanes → 60% EtOAc in hexanes) to afford (-)-
= 0.52 (silica gel, EtOAc); [α]25
Depudecin (1) (4.5 mg, 90%) as a colourless oil: R
f
D
= –31.1
);
) δ 5.94 (ddd, J = 17.3, 10.6,
1
5
24
24
23
(
c 0.17, CH
2
Cl
2
) (lit. [α]
D
= –35.8 (c 0.52, MeOH); (lit. [α]
D
= –31.0 (c 0.08, CHCl
3
2
7
25
1
(
lit. [α]
D
= –29.6 (c 0.12, CH
2
Cl
2
); H NMR (400 MHz, CDCl
3
5
.5 Hz, 1 H), 5.72–5.69 (m, 2 H), 5.40 (dt, J = 17.3, 1.3 Hz, 1 H), 5.28 (dt, J = 10.6, 1.3 Hz, 1
H), 4.13 (d, J = 4.4 Hz, 1 H), 3.74 (dd, J = 11.3, 6.2 Hz, 1 H), 3.45–3.42 (m, 1 H), 3.40–3.36
m, 1 H), 3.01 (dd, J = 4.3, 2.2 Hz, 1 H), 2.91 (dd, J = 4.5, 2.2 Hz, 1 H), 1.93 (d, J = 6.5 Hz, 1
(
1
3
H), 1.80 (d, J = 6.1 Hz, 1 H), 1.31 (d, J = 6.5 Hz, 3 H); C NMR (100 MHz, CDCl
3
) δ 136.1,
1
32.0, 131.5, 117.1, 71.5, 66.9, 64.1, 62.4, 55.3, 54.9, 20.0; HRMS (H-ESI) m/z calcd for
+
C
11
H
16
O [M + H] 213.1127, found 213.1115.
4
Diepoxy Iodide 34 and Diiodide 35. Iodination of Diepoxy Alcohol 29. To a solution of
diepoxy alcohol 29 (50 mg, 0.35 mmol, 1.0 equiv) in THF (10 mL) at 0 ºC was added
imidazole (72 mg, 1.05 mmol, 3.0 equiv), PPh
3
(138 mg, 0.53 mmol, 1.5 equiv) and iodine
(134 mg, 0.53 mmol, 1.5 equiv) at 25 ºC. The mixture was vigorously stirred at 25 ºC for 20
min. After this time, the solvent was evaporated under reduced pressure and the crude residue
was purified by flash column chromatography (silica gel, 5% EtOAc in hexanes→10% EtOAc
in hexanes) to obtain diepoxy iodide 34 (22 mg, 25%) and diiodide 35 (42 mg, 47%) as
2
5
yellow oils. [34]: R
f
= 0.90 (silica gel, 40% EtOAc in hexanes); []
D
= –35.8 (c 0.87,
1
CH
2
Cl
2
); H NMR (400 MHz, CDCl
3
) δ 5.58–5.53 (m, 2 H), 5.35–5.31 (m, 1 H), 3.37–3.32
1
3
(m, 1 H), 3.28–3.22 (m, 2 H), 3.12–3.05 (m, 1 H), 2.96–2.94 (m, 2 H); C NMR (100 MHz,
CDCl
3
) δ 134.1, 120.5, 60.1, 59.6, 57.1, 55.6, 3.2; HRMS (H-ESI) m/z calcd for C
7
H
9
IO [M
2
2
9
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