Syntheses and Biological Evaluation of Costunolide, Parthenolide, and Their Fluorinated Analogues

Article abstract of DOI:10.1021/acs.jmedchem.5b00915

Inspired by the biosynthesis of sesquiterpene lactones (SLs), herein we report the asymmetric total synthesis of the germacrane ring (24). The synthetic strategy features a selective aldol reaction between β,-unsaturated chiral sulfonylamide 15a and aldehyde 13, as well as the intramolecular α-alkylation of sulfone 21 to construct a 10-membered carbocylic ring. The key intermediate 24 can be used to prepare the natural products costunolide and parthenolide (PTL), which are the key precursors for transformation into other SLs. Furthermore, the described synthetic sequences are amenable to the total synthesis of SL analogues, such as trifluoromethylated analogues 32 and 45. Analogues 32 and 45 maintained high activities against a series of cancer cell lines compared to their parent PTL and costunolide, respectively. In addition, 32 showed enhanced tolerance to acidic media compared with PTL. To our surprise, PTL and 32 showed comparable half-lives in rat plasma and in the presence of human liver microsomes.

Full text of DOI:10.1021/acs.jmedchem.5b00915

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Syntheses and Biological Evaluation of
Costunolide, Parthenolide and their Fluorinated
Analogs
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ZhongꢀJin Yang , WeiꢀZhi Ge , QiuꢀYing Li , Yaxin Lu , JianꢀMiao Gong , BeiꢀJia Kuang ,
†,‡
†,‡
†,
†,
Xiaonan Xi , Haiting Wu , Quan Zhang * and Yue Chen *
†
The State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, Collaborative
Innovation Center of Chemical Science and Engineering (Tianjin), and Tianjin Key Laboratory
of Molecular Drug Research, Nankai University, Tianjin 300071, People's Republic of China
‡
Tianjin International Joint Academy of Biomedicine, Tianjin 300457
，
People's Republic of
China
§
Accendatech Co., Ltd., Tianjin 300384, People's Republic of China
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ABSTRACT
Inspired by the biosynthesis of sesquiterpene lactones (SLs), herein we report the asymmetric
total synthesis of germacrane ring (24). The synthetic strategy features a selective aldol reaction
between β,γꢀunsaturated chiral sulfonylamide 15a and aldehyde 13, as well as the intramolecular
αꢀalkylation of sulfone 21 to construct 10ꢀmembered carbocylic ring. The key intermediate 24
can be used to prepare the natural products costunolide and parthenolide (PTL), which are the
key precursors for transformation into other SLs. Furthermore, the described synthetic sequences
are amenable to the total synthesis of SL analogs, such as trifluoromethylated analogs (32 and
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45). Analogs 32 and 45 maintained high activities against a series of cancer cell lines comparing
to their parent PTL and costunolide, respectively. In addition, 32 showed enhanced tolerance to
acidic media comparing with PTL. To our surprise, PTL and 32 showed comparable halfꢀlives in
rat plasma and in the presence of human liver microsomes.
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INTRODUCTION
Germacranolides, a type of sesquiterpene lactone (SL) having a 10,5ꢀring structure, are present in
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several plant families (Figure 1). They are the key precursor for transformation into other SLs
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with a variety of polycyclic skeletons, such as guaianolides, eudesmanolides, and so on
(Figure 2). However, only recently have they attracted extraordinary research interest due to their
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anticancer bioactivity. In particular, the SLs costunolide (1) and parthenolide (PTL, 2) are two
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small molecules that can selectively kill cancer stem cells. Cancer stem cells are defined as cells
that are able to both extensively selfꢀrenew and differentiate into progenitor cells; moreover,
increasing evidence supports that cancer stem cells are responsible for the initiation, metastasis,
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and treatment resistance of many types of tumors.
Thus, the germacranolides are a class of
promising scaffolds that can treat cancer from its source.
The total synthesis of germacranolides has attracted intense research efforts for decades, but
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only a few synthetic approaches to racemic germacranolides have been published. The total
synthesis of a diastereoisomer of PTL was achieved via a Pdꢀcatalyzed macrocyclization to form
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the 10ꢀmembered germacrane ring system. Recently, our group reported the first total synthesis
of 2, with the formation of the 10ꢀmembered carbocylic ring by a macrocyclic stereocontrolled
Barbier reaction. However, although various reaction conditions were extensively investigated,
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the desired 6,7ꢀtransꢀ10ꢀmembered ring system was achieved with low selectivity. The
preliminary structure–activity relationship (SAR) of PTL analogs was investigated and showed
the following: (1) the Z or E configuration of the 1,10ꢀdouble bond has little or no effect on the
antiꢀcancer activity; (2) the change from trans to cis at the C6 and C7 site of the lactone ring
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results in a moderate decrease of the activity; (3) introducing a polar hydroxyl group at either
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the C9 or C14 position leads to a complete loss of activity, but the substitution of a large
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aromatic substituent has a beneficial effect on the activity.
Despite these exciting bioactivity features, some germacranolides suffer from serious
pharmacological and pharmacokinetic drawbacks that limit their clinical use, including poor
bioavailability, poor toxicology profiles such as offꢀtarget effects, and low metabolic
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stability.
The dimethylamino Michael adduct dimethylaminoꢀPTL can effectively increase
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the oral bioavailability and have acceptable toxicology profiles, but stability problems such as
epoxidation of the electronꢀrich 1,10ꢀdouble bond, hydroxylation of the two allylic sites (C9,
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2,14
C14) by cytochrome P450 enzymes, and possible transannular cyclization in acidic media
have been described. In addition, the P450ꢀcatalyzed oxidation products exhibit significantly
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decreased activity or a complete loss of activity. These findings directed our attention to study
the substitution of the 14ꢀmethyl group with an electronꢀwithdrawing group to protect against
oxidation by cytochrome P450 oxidases. The introduction of a fluorine group into drug
molecules often has positive effects by enhancing membrane permeability, promoting
electrostatic interactions with target proteins, and increasing metabolic stability towards
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oxidative metabolism.
Yet, the lack of available synthetic routes limits the optimization of germacranolides and
their evaluation in spite of our recent total synthesis of 2 with low 6,7ꢀtrans
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diastereoselectivity. Herein, we report a more general and highly stereocontrolled total
synthetic approach that can rapidly provide SLs with various carbocyclic skeletons. Based on
this route, the natural products 1, 2, and their fluorinated analogs were synthesized, and the
SARs of these analogs were determined.
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RESULTS AND DISCUSSION
Retrosynthetic analysis and total synthesis of 1 and 2
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Inspired by the biosynthetic route of SLs (Figure 2), the 6,7ꢀtransꢀgermacrane ring system
(24) was proposed to be the key common intermediate. We planned to utilize an intramolecular
αꢀalkylation as the key step to build up the 10ꢀmembered carbocycle (Scheme 1). The key
common intermediate 24 would be conceived by intramolecular αꢀalkylation of sulfone 21.
Sulfone 21 could be readily manipulated from 16a, which would be prepared by the aldol
reaction of compound 10 and aldehyde 13.
As shown in Scheme 2, the synthesis started with known compound 7, which was readily
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obtained from hydroxypropanone, according to a reported procedure. A HornerꢀWadsworthꢀ
Emmons (HWE) reaction of ketone 7 and Oppolzer’s chiral phosphonate 8 was proposed to
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generate compound 10. However, when the HWE reaction was performed with various bases
(e.g., NaH, LiHMDS, or NaHMDS), most of the starting materials were recovered, and only a
trace of the desired product was detected. Thus, an alternate strategy was attempted. The HWE
reaction of ketone 7 and triethyl phosphonoacetate, followed by ester hydrolysis, was proposed
to generate acid 9. Unfortunately, the hydrolysis procedure led to cleavage of the TBS protecting
group. The desired acid 9 was finally obtained by the HWE reaction of ketone 7 and
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diethylphosphonoacetic acid. According to a reported procedure, compound 10 was readily
prepared from compound 9 in 58% yield over two steps.
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The aldehyde 13 was obtained by oxidation of the reported alcohol 12 with MnO in
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CH Cl in 88% yield (Scheme 3). With aldehyde 13 in hand, the next step was the aldol reaction
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of compound 10 and aldehyde 13 to yield compound 16a. Unfortunately, the regioselectivity of
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the enolate at the
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and desired compound 16a was obtained as a minor product. Alternatively, compound 10 was
first treated with LiHMDS, followed by the addition of aldehyde 13; however, this reaction
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procedure produced an inseparable mixture of 14 and 15b (3:1), based on HꢀNMR. Finally, 16a
was prepared in two steps as follows: compound 10 was first treated with LiHMDS (prepared by
nꢀBuLi and HMDS) and then quenched with aq. NH Cl to obtain 15 (15a:15b = 10:1),
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presumably through a chelated transition state to selectively remove the proton in γ2 carbon;
next, compound 15 and aldehyde 13 were treated with TiCl and iꢀPr NEt in CH Cl to afford the
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desired 6,7ꢀstereochemistry, generating 16a as the major product in 47% yield and 16b in 12%
yield (Scheme 3).
As shown in Scheme 4, selective cleavage of the TBS protecting group of compound 16a
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was achieved with HCl in ethanol at 0 °C. The resulting crude product was treated with 2ꢀ
methoxypropene to produce acetonide 17. After the reduction of 17, the crude product was
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treated with diphenyl disulfide/nꢀBu P to obtain thioether 18. Using H O /(NH ) Mo O in tꢀ
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BuOH and pyridine, thioether 18 was oxidized to compound 19 in 86% yield. The TBDPS
group of compound 19 was removed with tetrabutylammonium fluoride, affording alcohol 20 in
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5% yield. Next, alcohol 20 was converted into three halides, 21a, 21b, and 21c, via different
reaction conditions (Scheme 4). For the preparation of bromide 21b, it was necessary to use 2,6ꢀ
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lutidine as the base because complex products were observed otherwise. Iodide 21c had to be
freshly prepared for use in the next step, due to its instability at ambient temperature.
Various cyclization conditions were explored for the cyclization precursors (21a, 21b, and
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1c) to generate the desired 10ꢀmembered carbocyclic germacrane ring (Table 1). According to
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Whitby’s method, the slow addition of 21a (0.02 M in THF) to NaHMDS (3 equiv.) in THF
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(
0.02 M) did not result in the desired cyclization product 22. No reaction was observed, even
under refluxing conditions with excess base (entries 1 and 2, Table 1). Fortunately, treatment of
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1b or 21c with NaHMDS (3 equiv.) provided compound 22 in yields of 65% and 28%,
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respectively (entries 3 and 5, Table 1). At –70 °C, conversion of 21b to 22 was not complete,
and a complex mixture was formed (entry 4, Table 1). When LiHMDS was used as the base,
compound 22 was obtained in only 10% yield (entry 6, Table 1). However, when the base was
changed to KHMDS, compound 22 was achieved in 82% yield (entry 8, Table 1). When the
amount of KHMDS was decreased from 3 equiv. to 2 equiv., only a trace amount of cyclized
product 22 was detected (entry 7, Table 1). Finally, increasing the amount of KHMDS to 4 equiv.
afforded the best yield (84%) of cyclized product 22 (entry 9, Table 1).
As a mixture of two diastereomers, cyclization product 22 was treated with Mg/MeOH to
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remove the sulfone moiety, providing compound 23 in 74% yield (Scheme 5). The acetonide
group of 23 was removed with pyridinium pꢀtoluenesulfonate in MeOH to generate the key
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intermediate 24 in 78% yield.
With the key intermediate 24 in hand, oxidation with MnO in
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CH Cl produced the desired 1. Alternatively, the key intermediate 24 has been used to yield
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other SLs. For example, diol 24 can undergo Sharpless epoxidation, followed by oxidation with
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TEMPO and PhI(OAc) , to yield 2.
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Semisynthesis of mono- and di-fluorinated analogs of PTL
With 2 in hand, reduction of the α,βꢀunsaturated double bond with NaBH provided
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compound 25, and oxidation of the allylic methyl group with SeO /tꢀBuOOH yielded alcohol 26
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(Scheme 6). In addition, fluorination of 26 employing diethylaminosulfur trifluoride (DAST) in
CH Cl provided a 3:1 mixture of 27 and 28, which was recrystallized in ether to give
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monofluorinated analogs 27 (31% yield) and 28 (12% yield). Treatment of 26 with DessꢀMartin
periodinane in the presence of NaHCO afforded aldehyde 29, which was treated with DAST to
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provide difluorinated analog 30 in 43% yield. Further oxidation of the aldehyde with NaClO2
produced acid 31. Attempted decarboxylative trifluoromethylation of acid 31 by using bis(2ꢀ
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methoxyethyl)aminosulfur trifluoride or CF SO Na failed to yield the desired trifluorinated
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analog 32.
Retrosynthetic analysis and total synthesis of trifluoromethylated costunolide and PTL
Scheme 7 outlines our retrosynthetic analysis of trifluoromethylated analogs 45 and 32.
Similarly, the 6,7ꢀtransꢀgermacrane ring diol (43) was proposed to be the key common
intermediate, which could be built up by utilizing an intramolecular αꢀalkylation of sulfone 41.
Sulfone 41 would be conceived by the addition of aldehyde 40 and 3,3,3ꢀtrifluoropropeneꢀ2ꢀyl
lithium, followed by mesylation and bromination. Aldehyde 40 could be readily transformed
from β,γꢀunsaturated chiral sulfonylamide 15a and aldehyde 34.
Similar to the previous synthetic route from aldehyde 13 to alcohol 20, gramꢀscale
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production of alcohol 39 was obtained from alcohol 33 in eight steps. Next, DessꢀMartin
oxidation produced aldehyde 40 (Scheme 8). Using aldehyde 40 as the substrate, bromide 41 was
prepared as a single Zꢀisomer by the addition of the vinyl anion derived from commercially
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available 2ꢀbromoꢀ3,3,3ꢀtrifluoropropene, mesylation, and bromination with NaBr in DMF.
The use of 2,2ꢀdimethylpropane was necessary for the bromination reaction to avoid concomitant
loss of the acetonide, and the use of LiBr instead of NaBr during bromination not only led to the
removal of the acetonide but also produced a mixture of Zꢀ and Eꢀ41, with a ratio of
approximately 1:1.
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With bromide 41 in hand, we explored its cyclization to construct the 10ꢀmembered
carbocyclic germacrane ring. As shown in Table 2, the previously optimized condition for
cyclization reaction in Table 1, i.e. slow addition of bromide 41 to KHMDS in THF (0.02 M),
only produced a trace amount of the desired cyclization product 42 (Entry 1, Table 2), and most
of the starting material was decomposed. The addition of 4 equiv. of NaHMDS to bromide 41
generated the desired compound 42 in 32% yield (Entry 2, Table 2). Reducing the amount of
NaHMDS to 1.5 equiv. reduced the yield of compound 42 to 9% (Entry 3, Table 2). Finally, the
desired cyclization product 42 was obtained in 51% yield by the simultaneous addition of
bromide 41 (0.02 M in THF) and NaHMDS (0.06 M in THF) (Entry 4, Table 2).
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Diol 43 was obtained via the removal of the sulfone moiety and the acetonide, and
subsequent oxidation with MnO afforded trifluoromethylated analog 45 (Scheme 9). Treatment
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of diol 43 with tꢀbutyl hydroperoxide and VO(acac) in CH Cl produced a complex mixture. In
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contrast, direct epoxidation of compound 45 with mꢀchloroperoxybenzoic acid yielded the
desired 4,5ꢀepoxy product 32 in 91% yield. The structure of compound 32 was further confirmed
by Xꢀray analysis (Scheme 9).
Anti-cancer properties in different cancer cell lines
Compounds 1, 2, and their analogs (27, 28, 30, 32, and 45) were evaluated against human
acute myeloid leukemia cell line KG1a, rat glioma cell line C6, cultured acute myeloid leukemia
cell line HLꢀ60, and doxorubicinꢀresistant cell line HLꢀ60/A. As indicated in Table 3, PTL
analogs 27, 30, and 32 retained high activities against the cancer cell lines KG1a, C6, HLꢀ60,
and HLꢀ60/A, with IC values between 1.5 ꢁM and 3.4 ꢁM. Costunolide analog 45, without the
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4,5ꢀepoxy moiety, showed approximately 2ꢀfold less potency against the cancer cell lines KG1a,
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C6, HLꢀ60, and HLꢀ60/A, compared to its counterpart 32. Interestingly, reduced activities
against the cancer cell lines were observed for 1ꢀmonofluorinated PTL (28), perhaps due to the
conformation change resulting from the rearrangement of the 1,10ꢀdouble bond from being a part
of the ring to being exo to the ring. Based on the above results, the preliminary SARs were as
follows: (1) the 4,5ꢀepoxy moiety of PTL shows a moderate effect on the activity; (2) the 1,10ꢀ
double bond is important for the antiꢀcancer activity.
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Chemical stability
Generally, germacranolides are very sensitive to acidic media, and cyclized or rearranged
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products form under these conditions. Compound 2 was readily converted to micheliolide
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under acid condition, i.e. pꢀtoluenesulfonic acid (pTSA) in dichloromethane. With the
synthesized fluorinatedꢀPTL analogs (27, 28, 30, and 32) in hand, we checked their chemical
stability compared with 2. The synthesized fluorinatedꢀPTL analogs (27, 28, 30, and 32) stayed
nearly intact over 48 h under the same condition. These results indicated that the introduction of
fluorine groups with an electronꢀwithdrawing effect, effectively weakened the nucleophilic
ability of the 1,10ꢀdouble bond to attack the epoxy moiety, thus significantly improved the
stability of these fluorinated compounds in acidic media.
Metabolic stability
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It has been reported that PTL is unstable under both acidic and basic conditions as well
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as in mouse plasma; in addition, it is readily oxidized by cytochrome P450 enzymes. The
metabolic stability of 2 and its trifluoromethylated analog 32 in the presence of human liver
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microsomes was tested. To our surprise, there was no significant difference in the halfꢀlives
between 2 (83.5 min) and analog 32 (85.6 min). Next, the halfꢀlives of 2 and analog 32 were
evaluated in rat plasma. The halfꢀlife of 2 was 16.7 min, and that of analog 32 was 20.3 min
0
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(Table 4). These in vitro studies suggest that the structure optimization from 2 to
trifluoromethylated analog 32 did not improve the metabolic stability of the compound toward
cytochrome P450 enzymes of human liver microsomes or rat plasma. Since 11,13ꢀdihydroꢀPTL
3
8
(
25) is inactive against cancer cells, the stability of 25 in rat plasma was also studied.
Compound 25 was degraded by only 20% over 420 min in rat plasma.
CONCLUSIONS
In conclusion, the asymmetric synthesis of the 10ꢀmembered germacrane ring system (24)
was achieved. The synthetic strategies featured a selective aldol reaction between the β,γꢀ
unsaturated chiral sulfonylamide 15a and aldehyde 13, as well as efficient intramolecular αꢀ
alkylation of sulfone 21b to construct 10ꢀmembered carbocyclic ring. Inspired by the
biosynthesis of SLs, the germacranolides 1 and 2, as key precursors to process into a variety of
polycyclic sesquiterpene frameworks, can be prepared via the key intermediate 24. The described
synthetic sequences are amenable to the synthesis of SL analogs, such as trifluoromethylated
analogs of 2 and 1, i.e. 32 and 45, which maintained high activities against a series of cancer cell
lines.
It was reported that 2 suffered from the stability problem in P450 oxidases for the presence of
1
1
electronꢀrich 1,10ꢀdouble bond, and 2 was liable to transannular cyclization with 1,10ꢀdouble
2
bond nucleophilic attacking the epoxy moiety in acidic media . Therefore, the introduction of
electronꢀwithdrawing fluorine groups (i.e. trifluoromethylated analog 32) showed significantly
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enhanced tolerance to acidic media compared to that of 2. However, to our surprise, 2 and
trifluoromethylated analog 32 showed comparable halfꢀlives in rat plasma and in the presence of
human liver microsomes. In contrast, the biologically inactive 25 was very stable in rat plasma.
Therefore, we presumed that the 1,10ꢀdouble bond of PTL probably is not the principle
metabolic moiety, and the αꢀmethyleneꢀγꢀbutyrolactone moiety might be responsible for their
short halfꢀlives in rat plasma and in the presence of human liver microsomes. The αꢀmethyleneꢀγꢀ
butyrolactone moiety is thought to be responsible for inhibitory action function, since it is a
10
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potent Michael reaction acceptor covalently binding to cysteine residues in proteins.
Meanwhile, the αꢀmethyleneꢀγꢀbutyrolactone moiety might be prone to be attacked by cysteine
residue. To circumvent the barrier, it is recommended that it could be converted to a prodrug
6
b,13,39
with masking group, such as Mannichꢀbaseꢀprodrug,
and bioavailability.
to improve their stability, solubility
EXPERIMENTAL SECTION
General Chemistry. Unless otherwise mentioned, all reactions were carried out under a
nitrogen atmosphere with dry solvents under anhydrous conditions. The used solvents were
purified and dried according to common procedures. Yields refer to chromatographically and
1
spectroscopically ( H NMR) homogeneous materials, unless otherwise stated. Reactions were
monitored by thinꢀlayer chromatography carried out on 0.25 mm Tsingdao silica gel plates (60Fꢀ
2
54). Visualization was achieved using UV light, phosphomolybdic acid in ethanol or potassium
permanganate in water, each followed by heating. Tsingdao silica gel (60, particle size 0.040–
.063 mm) was used for flash column chromatography. Reagents were purchased at the highest
commercial quality and used without further purification, unless otherwise stated. FTIR spectra
0
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were obtained with a Bruker Tensor 27 instrument. All IR samples were prepared as thin film
–
1
1
and reported in wave numbers (cm ). NMR spectra were recorded with a 400 MHz ( H: 400
13
MHz, C: 100 MHz) spectrometer and referenced to the solvent peak for CDCl . Data are
3
0
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9
0
reported as follows: chemical shift, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet,
br. = broad, m = multiplet), coupling constants and integration. The purity of the final
compounds was determined to be ≥ 95% by means of analytical high pressure liquid
chromatography (HPLC) on a Shimadzu LDꢀ20A system with an ODSꢀC18 column (4.6 × 150
mm, 5 ꢁm) eluted at 1 mL/min with MilliꢀQ water and CH CN.
3
(E)ꢀ4ꢀ((tertꢀButyldimethylsilyl)oxy)ꢀ3ꢀmethylbutꢀ2ꢀenoic acid (9). To a stirred solution of
diethylphosphonoacetic acid (12.34 g, 62.93 mmol) in dry THF (125 mL) at 0 ºC was added
NaHMDS (2 M in THF, 63.0 mL, 126.0 mmol) under Ar atmosphere. After stirring for 0.5 h, the
mixture became a dark yellow jelly; then dry THF (250 mL) was added. After the jelly was
dissolved, compound 7 (14.23 g, 75.53 mmol) was slowly added. After stirring for 4 h, the
mixture was adjusted to pH = 4 with aqueous KHSO (0.5 M) and extracted with ethyl acetate (3
4
×
500 mL). The combined organic layers were washed with saturated brine, dried over Na SO ,
2 4
and concentrated to give an oily crude product, which was purified by silica gel column
petroleum ether (PE)/EtOAc (EA) = 20:1–8:1] to afford compound 9 (11.67 g, 80%) as a
[
–
1
1
colorless oil. IR (KBr) 3069, 2986, 2930, 2856, 1587, 1470,1308, 1217, 1110, 704 cm ; H
NMR (400 MHz, CDCl ) δ 11.70 (s, 1H), 5.95 (s, 1H), 4.05 (s, 2H), 1.97 (s, 3H), 0.84 (s, 9H),
3
13
0
.00 (s, 6H); C NMR (100 MHz, CDCl ) δ 172.9, 160.4, 113.0, 67.2, 26.00, 18.5, 15.8, –5.4;
3
+
HRMS (ESI) calcd for C H O Si(M+H) 231.1411, found 231.1411.
11 23
3
(E)ꢀ4ꢀ((tertꢀButyldimethylsilyl)oxy)ꢀ1ꢀ((3aR,6S,7aS)ꢀ8,8ꢀdimethylꢀ2,2ꢀdioxidohexahydroꢀ1Hꢀ
3a,6ꢀmethanobenzo[c]isothiazolꢀ1ꢀyl)ꢀ3ꢀmethylbutꢀ2ꢀenꢀ1ꢀone (10). To a stirred solution of
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compound 9 (6.34 g, 27.52 mmol) in dry toluene (75 mL) at 0 ºC was added oxalyl chloride
(2.83 mL, 33.02 mmol), then added N, Nꢀdimethylformamide (0.05 mL). The mixture was stirred
for 1.5 h at room temperature. The solvent was removed under vacuum at 25 ºC to give the acid
chloride. To a suspension of NaH (60% in mineral oil, 1.21 g, 30.27 mmol) in dry toluene (50
mL) at 0 ºC was added (+)ꢀCamphorsultam (6.52 g, 30.27 mmol) under Ar atmosphere and
10
11
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13
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15
16
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25
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59
60
stirred for 3 h at room temperature and followed by addition of the acid chloride in dry toluene
o
(
30 mL) at 0 C. The mixture was stirred for 2 h at room temperature, followed by addition of
saturated aqueous NH Cl, and extracted with ethyl acetate (3 × 150 mL). The combined organic
4
layers were washed with saturated brine, dried over Na SO , and concentrated to give an oily
2
4
crude product, which was purified by silica gel column [PE:EA = 25:1–8:1] to give compound
26
o
10 (6.90 g, 59%) as a colorless oil. [α]D +54.6 (c 1.0, CHCl ); IR (KBr) 2953, 2859, 1679,
3
–1
1
1
4
2
–
461, 1371, 1327, 1274, 1240, 1130, 845, 771 cm ; H NMR (400 MHz, CDCl ) δ 6.58 (s, 1H),
3
.00 (s, 2H), 3.76 (s, 1H), 3.36 (d, J = 13.7 Hz, 1H), 3.28 (d, J = 13.7 Hz, 1H), 2.02–1.92 (m,
H), 1.90 (s, 3H), 1.81–1.66 (m, 3H), 1.32–1.16 (m, 2H), 1.03 (s, 3H), 0.81 (s, 3H), 0.79 (s, 9H),
13
0.04 (s, 3H), –0.06 (s, 3H); C NMR (100 MHz, CDCl ) δ 164.1, 159.1, 112.8, 66.8, 64.6, 52.7,
3
47.9, 47.3, 44.4, 38.5, 32.5, 26.3, 25.6, 20.6, 19.6, 17.9, 16.0, –5.7, –5.9; HRMS (ESI) calcd for
+
C H NNaO SSi (M+Na) 450.2105, found 450.2100.
21
37
4
(2E,6E)ꢀ8ꢀ((tertꢀButyldiphenylsilyl)oxy)ꢀ3,7ꢀdimethyloctaꢀ2,6ꢀdienal (13). To a stirred
solution of compound 12 (16.48 g, 40.32 mmol) in dry CH Cl (400 mL) was added MnO (8.77
2
2
2
g, 100.82 mmol). After the mixture was refluxed for 4 h, another portion of MnO (8.77g, 100.82
2
mmol) was added. After another 2 h, the mixture was filtered through a short pad of Celite with
CH Cl . The filtrate was concentrated under reduced pressure to an oily crude product, which
2
2
was purified by column chromatography [PE:EA = 10:1–8:1] to give compound 13 (15.09 g,
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8%) as a colorless oil. IR (KBr) 2961, 2914, 2848, 1761, 1452, 1257, 1044, 981, 926, 848, 790
–
1 1
cm ; H NMR (400 MHz, CDCl ) δ 10.02 (d, J = 8.0 Hz, 1H), 7.70 (d, J = 7.3 Hz, 4H), 7.47–
3
7.38 (m, 6H), 5.93 (d, J = 8.0 Hz, 1H), 5.45 (s, 1H), 4.07 (s, 2H), 2.28 (s, 4H), 2.19 (s, 3H), 1.62
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
(s, 3H), 1.09 (s, 9H); C NMR (100 MHz, CDCl ) δ 191.3, 163.7, 135.6, 135.4, 133.8, 129.7,
3
127.7, 127.5, 122.2, 68.7, 40.4, 26.9, 25.2, 19.4, 17.7, 13.6; HRMS (ESI) calcd for C H NO Si
2
6
38
2
+
(M+NH ) 424.2666, found 424.2666.
4
3
ꢀ(((tertꢀButyldimethylsilyl)oxy)methyl)ꢀ1ꢀ((3aR,6S,7aS)ꢀ8,8ꢀdimethylꢀ2,2ꢀdioxidohexahydroꢀ
1Hꢀ3a,6ꢀmethanobenzo[c]isothiazolꢀ1ꢀyl)butꢀ3ꢀenꢀ1ꢀone (15a). To a stirred solution of
hexamethyldisilazane (11.9 mL, 56.96 mmol) in dry THF (50 mL) at –78 ºC was added nꢀBuLi
(2.5 M in hexane, 22.8 mL, 57.00 mmol) under Ar atmosphere. After 0.5 h, compound 10 (16.2 g,
37.97 mmol) in dry THF (50 mL) was slowly added and soon the solution became yellow. After
stirred for 1 h at –78 ºC, the reaction solution was quenched with saturated aqueous NH Cl and
4
extracted with ethyl acetate (3 × 150 mL). The combined organic layers were washed with
saturated brine, dried over Na SO , and concentrated to give an oily crude product, which was
2
4
purified by silica gel column [PE:EA = 25:1–8:1] to yield compound 15a (14.4 g, 89 %) as a
–
1 1
colorless oil. IR (KBr) 3092, 2885, 1768, 1412, 1126, 1003, 985, 962, 819 cm ; H NMR (400
MHz, CDCl ) δ 5.21 (s, 1H), 4.98 (s, 1H), 4.18–4.08 (m, 2H), 3.86–3.79 (m, 1H), 3.52–3.35 (m,
3
4H), 2.07–2.01 (m, 2H), 1.89–1.80 (m, 3H), 1.41–1.30 (m, 2H), 1.11 (s, 3H), 0.94 (s, 3H), 0.87
1
3
(s, 9H), 0.02 (s, 6H); C NMR (100 MHz, CDCl ) δ 169.4, 141.1, 113.5, 65.5, 65.3, 52.9, 48.4,
3
4
7.8, 44.7, 39.1, 38.4, 32.9, 26.5, 25.9, 20.9, 19.9, 18.4, –5.3, –5.4; HRMS (ESI) calcd for
+
C H NO SSi(M+H) 428.2285, found 428.2290.
21 38
4
Aldol reaction of 10 and aldehyde 13. Compound 10 (214 mg, 0.5 mmol) was dissolved in
anhydrous CH Cl (6 mL) under argon atmosphere and the solution was cooled to –78 °C. TiCl
2
2
4
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(
1.0 M, 0.55 mL, 0.55 mmol) was added and the yellow solution was stirred 5 min. N,Nꢀ
Diisopropylethylamine (0.17 mL, 1 mmol) was added dropwise and the deep purple solution was
stirred at –78 °C for 1 h. Freshly prepared aldehyde 13 (325 g, 0.8 mmol) in 1 mL of CH Cl was
2
2
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
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30
31
32
33
34
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40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
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59
60
added dropwise. The solution was stirred at –78 °C for 2 h, quenched with saturated aqueous
NH Cl, and extracted with CH Cl (3 × 40 mL). The combined organic layers were concentrated
4
2
2
to give a crude residue, which was purified by silica gel column [PE:EA = 25:1–12:1] to obtain
compound 16a (105 mg, 25%) and 16b (165 mg, 40%).
26
o
Compound 16a: Colorless oil; [α]D +21.6 (c 1.0, CHCl ); IR (KBr) 2953, 2857, 1691, 1464,
3
–1
1
1
336, 1258, 1109, 839, 778, 704 cm ; H NMR (400 MHz, CDCl ) δ 7.71–7.64 (m, 4H), 7.39
3
(m, J = 13.8, 4.7 Hz, 6H), 5.44–5.38 (m, 2H), 5.35 (s, 1H), 5.26 (d, J = 8.6 Hz, 1H), 4.84 (t, J =
8
.4 Hz, 1H), 4.31 (d, J = 13.4 Hz, 1H), 4.22 (d, J = 13.4 Hz, 1H), 4.04 (s, 2H), 3.81 (dd, J = 7.3,
.8 Hz, 1H), 3.76 (d, J = 8.1 Hz, 1H), 3.44 (d, J = 13.8 Hz, 1H), 3.35 (d, J = 13.8 Hz, 1H), 3.21
4
(s, 1H), 2.18–2.09 (m, 2H), 2.04–1.95 (m, 3H), 1.93–1.80 (m, 4H), 1.75 (s, 3H), 1.61 (s, 3H),
13
1
.32–1.23 (m, 2H), 1.06 (s, 9H), 1.02 (s, 3H), 0.93 (s, 12H), 0.11 (s, 3H), 0.11 (s, 3H); C NMR
(
100 MHz, CDCl ) δ 170.3, 142.4, 140.4, 135.7, 134.1, 134.0, 129.6, 127.7, 124.8, 124.5, 115.8,
3
69.2, 69.2, 65.8, 64.8, 55.7, 53.2, 48.3, 47.8, 44.6, 39.5, 38.0, 32.8, 27.0, 26.6, 26.2, 26.0, 20.8,
+
20.0, 19.4, 18.4, 17.1, 13.6, –5.3, –5.4; HRMS (ESI) calcd for C H N O SSi (M+NH )
47 75 2 6 2 4
851.4879, found 851.4852.
25
o
1
Compound 16b: Colorless oil; [α]D –27.6 (c 1.0, CHCl ); H NMR (400 MHz, CDCl ) δ
3
3
7.70–7.67 (m, 4H), 7.42–7.35 (m, 6H), 6.38 (s, 1H), 5.41 (t, J = 7.1Hz, 1H), 5.32 (d, J = 8.7 Hz,
1H), 4.86–4.78 (dd, J = 8.4, 7.2 Hz, 1H), 4.36 (s, 1H), 4.04 (s, 2H), 3.89–3.81 (m, J = 6.9, 5.3 Hz,
1H), 3.42 (d, J = 13.7 Hz, 1H), 3.34 (d, J = 13.7 Hz, 1H), 2.61 (s, 1H), 2.18–2.06 (m, 4H), 2.01
(m, 2H), 1.87 (m, 3H), 1.74 (s, 3H), 1.62 (s, 3H), 1.60 (s, 3H), 1.33 (m, 2H), 1.13 (s, 3H), 1.06 (s,
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2
2
2
2
2
2
2
2
2
2
3
3
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5
5
5
6
13
9
1
4
H), 0.94 (s, 12H), 0.16 (s, 3H), 0.15 (s, 3H); C NMR (100 MHz, CDCl ) δ 171.9, 140.3, 139.1,
3
35.6, 134.0, 133.9, 129.5, 127.6, 124.6, 124.4, 108.4, 69.1, 67.6, 64.6, 52.9, 50.8, 48.4, 47.7,
5.0, 39.6, 39.1, 33.0, 26.9, 26.4, 26.3, 25.7, 21.0, 19.9, 19.3, 18.2, 17.0, 15.5, 13.5, ꢀ5.0, ꢀ5.3;
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
+
HRMS (ESI) calcd for C H NNaO SSi (M+Na) 856.4433 , found 856.4425.
4
7
71
6
2
Syntheses of compounds 16a and 16b from 15a. Compound 15a (1.2 g, 2.81 mmol) was
dissolved in anhydrous CH Cl (15 mL) under argon atmosphere and the solution was cooled to
2
2
–
78 °C. TiCl (3.0 mL, 3.0 mmol) was added and the yellow solution was stirred 5 min. N,Nꢀ
4
Diisopropylethylamine (1.3 mL, 7 mmol) was added dropwise and the deep purple solution was
stirred at –78 °C for 1 h. Freshly prepared aldehyde 13 (1.7 g, 4.2 mmol) in 5 mL of CH Cl was
2
2
added dropwise. The solution was stirred at –78 °C for 2 h, quenched with saturated aqueous
NH Cl, and extracted with CH Cl (3 × 40 mL). The combined organic layers were concentrated
4
2
2
to give a crude residue, which was purified by silica gel column [PE:EA = 25:1–15:1] to obtain
compound 16a (1.1 g, 47%) and 16b (280.8 mg, 12%).
(
(4R,5S)ꢀ4ꢀ((1E,5E)ꢀ7ꢀ((tertꢀButyldiphenylsilyl)oxy)ꢀ2,6ꢀdimethylheptaꢀ1,5ꢀdienꢀ1ꢀyl)ꢀ2,2ꢀ
dimethylꢀ6ꢀmethyleneꢀ1,3ꢀdioxepanꢀ5ꢀyl)((3aR,6S,7aS)ꢀ8,8ꢀdimethylꢀ2,2ꢀdioxidohexahydroꢀ1Hꢀ
3a,6ꢀmethanobenzo[c]isothiazolꢀ1ꢀyl)methanone (17). To a solution of compound 16a (3.7 g,
4
.44 mmol) in CH Cl (10 mL) and EtOH (75 mL) at 0 ºC was added a solution of conc. HCl (1
2 2
mL) in EtOH (20 mL). After stirring for 0.5 h, the mixture was concentrated at 30 ºC under
reduced pressure and the remaining water was removed by azeotropy with toluene to give the
crude diol. To a stirred solution of diol and pyridinium pꢀtoluenesulfonate (56 mg, 0.22 mmol) in
dry DMF (30 mL) at 0 ºC was added 2ꢀmethoxypropene (0.54 mL, 5.77 mmol). The mixture was
warmed to room temperature and stirred for 4 h, added 50 mL ethyl acetate (50 mL) and
saturated aqueous NaHCO (20 mL), and extracted with tertꢀbutyl methyl ether (3 × 100 mL).
3
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The combined organic layers were washed with saturated brine, dried over Na SO , and
2
4
concentrated to give an oily crude product, which was purified by silica gel column [PE:EA =
25
o
1
0:1–4:1] to provide compound 17 (2.3 g, 74% for two steps) as an oil. [α]D +27.6 (c 0.5,
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
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43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
–1 1
CHCl ); IR (KBr) 2938, 1765, 1251, 1129, 1033 cm ; H NMR (400 MHz, CDCl ) δ 7.69 (d, J
3
3
= 6.7 Hz, 4H), 7.39 (m, J = 13.8, 6.9 Hz, 6H), 5.42 (t, J = 6.5 Hz, 1H), 5.37 (d, J = 9.6 Hz, 1H),
.11 (s, 1H), 4.98 (t, J = 9.4 Hz, 1H), 4.90 (s, 1H), 4.37 (d, J = 13.0 Hz, 1H), 4.05 (s, 2H), 4.02
d, J = 13.4 Hz, 1H), 3.96 (d, J = 7.1 Hz, 1H), 3.80 (t, J = 6.1 Hz, 1H), 3.46 (d, J = 13.8 Hz, 1H),
5
(
3.37 (d, J = 13.8 Hz, 1H), 2.21–2.06 (m, 4H), 2.03 (m, 2H), 1.86 (m, 3H), 1.72 (s, 3H), 1.62 (s,
13
3
H), 1.39 (s, 3H), 1.38 (s, 3H), 1.33 (m, 2H), 1.11 (s, 3H), 1.06 (s, 9H), 0.95 (s, 3H); C NMR
(
100 MHz, CDCl ) δ 170.3, 144.4, 139.3, 135.7, 134.1, 134.0, 129.6, 127.7, 124.6, 123.7, 115.4,
3
101.5, 69.2, 69.0, 66.9, 65.3, 57.5, 53.2, 48.1, 47.8, 44.6, 39.6, 38.7, 33.0, 26.9, 26.5, 26.4, 25.4,
+
2
5.0, 20.8, 20.0, 19.4, 17.2, 13.6; HRMS (ESI) calcd for C H N O SSi (M+NH ) 777.4327,
4
4
65
2
6
4
found 777.4306.
tertꢀButyl(((2E,6E)ꢀ7ꢀ((4R,5S)ꢀ2,2ꢀdimethylꢀ6ꢀmethyleneꢀ5ꢀ((phenylthio)methyl)ꢀ1,3ꢀ
dioxepanꢀ4ꢀyl)ꢀ2,6ꢀdimethylheptaꢀ2,6ꢀdienꢀ1ꢀyl)oxy)diphenylsilane (18). To a suspension of
LiAlH (47 mg, 1.24 mmol) in dry THF (1 mL) at 0 °C was added a solution of compound 17
4
(
630 mg, 0.83 mmol) in THF (4 mL). After stirring at 0 °C for 1 h, saturated aqueous NH Cl (0.2
4
mL) were added slowly. The mixture was dried over Na SO , filtered through Celite pad and
2
4
silica gel pad, and washed with a mixture of CH Cl and EtOH (10:1). The solvent was removed
2
2
under reduced pressure to afford an oily crude product. To a solution of the above crude and
diphenyl disulfide (362 mg, 1.66 mmol) in toluene (8 mL) was added nꢀBu P (0.42 mL, 1.66
3
mmol) and the mixture was stirred at ambient temperature for 18 h. It was then directly purified
by a column of silica gel (PE:EtOAc = 20:1) to provide compound 18 (490 mg, 92%) as an oil.
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o
–1 1
[
α]D –10.2 (c 0.5, CHCl ); IR (KBr) 2973, 2934, 2856, 1763, 1439, 1247, 1136, 967 cm ; H
3
NMR (400 MHz, CDCl ) δ 7.72–7.65 (m, 4H), 7.44–7.34 (m, 6H), 7.28–7.20 (m, 4H), 7.16–7.09
3
(
m, 1H), 5.40 (t, J = 6.4 Hz, 1H), 5.22 (d, J = 9.3 Hz, 1H), 5.05 (s, 1H), 4.92 (s, 1H), 4.54 (dd, J
9.3, 7.8 Hz, 1H), 4.32 (d, J = 14.2 Hz, 1H), 4.26 (d, J = 14.2 Hz, 1H), 4.04 (s, 2H), 3.15–3.04
(m, 2H), 2.58 (q, J = 7.7 Hz, 1H), 2.11 (m, 2H), 2.03 (m, 2H), 1.75 (s, 3H), 1.59 (s, 3H), 1.40 (s,
0
1
2
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7
8
9
0
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2
3
4
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9
0
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9
0
1
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3
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8
9
0
1
2
3
4
5
6
7
8
9
0
=
1
3
3
H), 1.36 (s, 3H), 1.06 (s, 9H); C NMR (100 MHz, CDCl ) δ 146.3, 138.7, 137.1, 135.7, 134.4,
3
1
34.0, 129.7, 128.9, 128.8, 127.7, 125.8, 125.2, 124.0, 114.2, 101.8, 70.2, 69.1, 66.5, 52.4, 39.6,
4
+
34.1, 27.0, 26.2, 26.0, 24.5, 19.4, 17.3, 13.6; HRMS (ESI) calcd for C H NO SSi (M+NH )
4
0
56
3
6
58.3745, found 658.3732.
tertꢀButyl(((2E,6E)ꢀ7ꢀ((4R,5S)ꢀ2,2ꢀdimethylꢀ6ꢀmethyleneꢀ5ꢀ((phenylsulfonyl)methyl)ꢀ1,3ꢀ
dioxepanꢀ4ꢀyl)ꢀ2,6ꢀdimethylheptaꢀ2,6ꢀdienꢀ1ꢀyl)oxy)diphenylsilane (19). Compound 18 (470 mg,
0
.73 mmol) was dissolved in tꢀBuOH (3 mL) and pyridine (1 mL). The mixiture was cooled to 0
o
.
C, and a mixture of (NH ) Mo O 4H O (544 mg, 0.44 mmol) in 30% H O (0.9 mL) was
4 6
7
24
2
2
2
added dropwise. The cooling bath was removed and the reaction mixture was stirred at room
temperature for 4 h. Sat. aq. Na S O (0.1 mL), NaHCO (5 mL), H O (5 mL) and EtOAc (15
2
2
3
3
2
mL) were added. The organic layers were separated, and the aqueous phase was extracted with
EtOAc (2 × 15 mL). The combined organic phase was washed with saturated brine, dried over
Na SO , and concentrated to give an oily crude product, which was purified by silica gel column
2
4
2
6
o
(PE:EA = 8:1–4:1) to afford sulfone 19 (422 mg, 86%) as a colorless oil. [α]D –26.5 (c 0.5,
–1
1
CHCl ); IR (KBr) 2952, 2930, 2858, 1696, 1652, 1253, 1117, 839, 777 cm ; H NMR (400
3
MHz, CDCl ) δ 7.91–7.85 (m, 2H), 7.70 (dd, J = 7.8, 1.5 Hz, 4H), 7.61 (d, J = 7.4 Hz, 1H), 7.52
3
(
t, J = 7.6 Hz, 2H), 7.47–7.36 (m, 6H), 5.41 (dd, J = 7.0, 6.0 Hz, 1H), 5.10 (d, J = 9.0 Hz, 1H),
5
.02 (s, 1H), 4.99 (s, 1H), 4.37 (dd, J = 9.3, 6.9 Hz, 1H), 4.25 (d, J = 14.5 Hz, 1H), 4.11 (d, J =
19
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Journal of Medicinal Chemistry
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4.5 Hz, 1H), 4.07 (s, 2H), 3.56 (dd, J = 14.6, 9.8 Hz, 1H), 3.21 (dd, J = 14.6, 3.6 Hz, 1H), 2.84
(m, 1H), 2.16 –2.07 (m, 2H), 2.00 (m, 2H), 1.68 (d, J = 0.6 Hz, 3H), 1.62 (s, 3H), 1.37 (s, 3H),
1
3
1
1
.32 (s, 3H), 1.08 (s, 9H); C NMR (100 MHz, CDCl ) δ 144.7, 139.8, 139.7, 135.7, 134.5,
3
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
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30
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33.9, 133.7, 129.7, 129.2, 128.2, 127.7, 124.3, 123.8, 115.2, 102.0, 69.9, 69.0, 65.9, 56.7, 47.5,
+
39.5, 27.0, 26.2, 25.6, 24.4, 19.4, 17.2, 13.7; HRMS (ESI) calcd for C H NO SSi (M+NH )
4
0
56
5
4
690.3643, found 690.3645.
(
2E,6E)ꢀ7ꢀ((4R,5S)ꢀ2,2ꢀDimethylꢀ6ꢀmethyleneꢀ5ꢀ((phenylsulfonyl)methyl)ꢀ1,3ꢀdioxepanꢀ4ꢀyl)ꢀ
2,6ꢀdimethylheptaꢀ2,6ꢀdienꢀ1ꢀol (20). A mixture of compound 19 (422 mg, 0.63 mmol) in THF
1 mL) and TBAF in THF (0.2 M, 3.9 mL, 0.78 mmol) was stirred overnight at room
(
temperature. The solution was quenched with aqueous ammonium chloride solution and then
extracted with ethyl acetate. The organic layer was dried over Na SO , and concentrated to give
2
4
an oily crude product, which was purified by silica gel column (PE:EA = 2:1–1:1) to afford 20
27
o
(
235 mg, 86%) as a colorless oil. [α]D –34.0 (c 1.0, CHCl ); IR (KBr) 3528, 3066, 2987, 2926,
3
–
1 1
2
863, 1447, 1306,1152, 1072, 793, 690 cm ; H NMR (400 MHz, CDCl ) δ 7.83 (d, J = 7.4 Hz,
3
2
H), 7.61 (t, J = 7.4 Hz, 1H), 7.50 (t, J = 7.4 Hz, 2H), 5.32 (br t, J = 6.8 Hz, 1H), 5.08 (d, J = 9.0
Hz, 1H), 4.93 (s, 1H), 4.90 (s, 1H), 4.33 (dd, J = 9.4, 6.8 Hz, 1H), 4.17 (d, J = 14.5 Hz, 1H), 3.99
d, J = 14.5 Hz, 1H), 3.95 (s, 2H), 3.48 (dd, J = 14.5, 9.5 Hz, 1H), 3.17 (dd, J = 14.5, 3.8 Hz, 1H),
.87–2.78 (m, 1H), 2.23 (br s, 1H), 2.11 (m, 2H), 2.07–1.98 (m, 2H), 1.63 (d, J = 0.8 Hz, 3H),
(
2
1
3
1.62 (s, 3H), 1.32 (s, 3H), 1.28 (s, 3H); C NMR (100 MHz, CDCl ) δ 144.5, 139.7, 139.0,
3
1
35.6, 133.8, 129.2, 128.1, 124.9, 124.6, 115.1, 102.0, 69.8, 68.5, 65.7, 56.6, 47.5, 39.1, 25.6,
+
2
5.3, 24.2, 16.8, 13.8; HRMS (ESI) calcd for C H NO S(M+NH ) 452.2465, found 452.2457.
24 38
5
4
(4R,5S)ꢀ4ꢀ((1E,5E)ꢀ7ꢀBromoꢀ2,6ꢀdimethylheptaꢀ1,5ꢀdienꢀ1ꢀyl)ꢀ2,2ꢀdimethylꢀ6ꢀmethyleneꢀ5ꢀ
(
(phenylsulfonyl)methyl)ꢀ1,3ꢀdioxepane (21b). To a solution of 20 (100 mg, 0.232 mmol) , CBr4
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(
137.3 mg, 0.414 mmol, 1.8 eq) and 2,6ꢀlutidine (0.08 mL,0.69 mmol) in CH Cl (2 mL) was
2
2
added a solution of triphenylphosphine (108.6 mg, 0.414 mmol) in CH Cl (1 mL) at 0 °C under
2
2
Ar atmosphere. The reaction mixture was stirred at that temperature for 30 min, and then directly
0
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0
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8
9
0
purified by a silica gel column (CH Cl :EA = 10:1) to provide 21b (104 mg, 91%) as an oil.
2
2
2
7
o
[α]D –54.2 (c 1.0, CHCl ); IR (KBr) 3064, 2986, 2922, 2856, 1446, 1306, 1216, 1153, 1072,
3
–
1 1
7
96, 747 cm ; H NMR (400 MHz, CDCl ) δ 7.87 (d, J = 7.7 Hz, 2H), 7.64 (t, J = 7.3 Hz, 1H),
3
7
.53 (t, J = 7.6 Hz, 2H), 5.56 (t, J = 6.8 Hz, 1H), 5.13 (d, J = 9.3 Hz, 1H), 4.97 (s, 1H), 4.95 (s,
1H), 4.36 (dd, J = 9.1, 6.9 Hz, 1H), 4.22 (d, J = 14.5 Hz, 1H), 4.06 (d, J = 14.5 Hz, 1H), 3.97 (s,
2
H), 3.53 (dd, J = 14.5, 9.6 Hz, 1H), 3.18 (dd, J = 14.5, 3.7 Hz, 1H), 2.95–2.79 (m, 1H), 2.19–
1
3
2
.09 (m, 2H), 2.07–1.98 (m, 2H), 1.75 (s, 3H), 1.66 (s, 3H), 1.36 (s, 3H), 1.31 (s, 3H); C NMR
(100 MHz, CDCl ) δ 144.8, 140.0, 138.8, 133.8, 132.6, 130.5, 129.3, 128.2, 125.1, 115.1, 102.1,
3
6
9.9, 65.8, 56.8, 47.6, 41.8, 38.8, 26.5, 25.7, 24.4, 17.0, 14.9; HRMS (ESI) calcd for
+
C H NBrO S(M+NH ) 514.1621, found 514.1611.
24 37
4
4
(5aS,8E,12E,13aR)ꢀ2,2,8,12ꢀTetramethylꢀ5ꢀmethyleneꢀ6ꢀ(phenylsulfonyl)ꢀ
4
,5,5a,6,7,10,11,13aꢀoctahydrocyclodeca[d][1,3]dioxepine (22). A solution of 21b (0.02 M in
THF, 8.5 mL) was slowly added (about one drop per second) to KHMDS (1.0 M in THF, 0.68
o
mL, 0.68 mmol, 4 eq) in dry THF (34 mL) at 0 C. The resulting yellow solution was continued
to stir for 15 min at 0 °C, followed by addition of saturated aqueous NH Cl. The reaction mixture
4
was extracted with ethyl acetate (3 × 30 mL). The combined organic layers were washed with
saturated brine, dried over Na SO , and concentrated to give an oily crude, which was purified
2
4
by silica gel column [PE:EA = 15:1–8:1] to afford compound 22 (59.4 mg, 84%) as a mixture of
+
diastereoisomers. HRMS (ESI) calcd for C H O S (M+H) 417.2094, found 417.2100.
2
4
33
4
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(
5aS,8E,12E,13aR)ꢀ2,2,8,12ꢀTetramethylꢀ5ꢀmethyleneꢀ4,5,5a,6,7,10,11,13aꢀ
octahydrocyclodeca[d][1,3]dioxepine (23). A mixture of 22 (59.4 mg, 0.142 mmol) and
activated magnesium turnings (68 mg, 2.85 mmol) in THF (0.5 mL) and MeOH (2.5 mL) was
stirred at room temperature for 8 h under Ar atmosphere. EtOAc (10 mL) was added to the
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
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42
43
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49
50
51
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53
54
55
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58
59
60
reaction mixture. The reaction was quenched with saturated aqueous NH Cl (5 mL). The
4
resulting mixture was extracted with EtOAc (3 × 10 mL). The combined organic solution was
washed with saturated brine, dried over Na SO , and concentrated to give a crude, which was
2
4
purified on silica gel column [PE:EA = 100:1–40:1] to afford compound 23 (29.0 mg, 74%) as a
27
o
colorless oil. [α]D +46.7 (c 0.3, CHCl ); IR (KBr) 3069, 2982, 2923, 2859, 1444, 1372, 1217,
3
–
1 1
1
074, 1014, 892, 846 cm ; H NMR (400 MHz, CDCl ) δ 4.82 (br d, J = 12.0 Hz, 1H), 4.79 (s,
3
2H), 4.74 (d, J = 9.5 Hz, 1H), 4.45–4.38 (m, 2H), 4.25 (d, J = 14.0 Hz, 1H), 2.38–2.20 (m, 4H),
.17–1.85 (m, 4H), 1.65 (m, 1H), 1.64 (d, J = 1.0 Hz, 3H), 1.49 (s, 3H), 1.41 (s, 3H), 1.36 (s, 3H);
2
1
3
C NMR (100 MHz, CDCl ) δ 152.7, 137.3, 136.3, 132.0, 126.2, 110.4, 102.1, 72.2, 67.2, 58.9,
3
+
4
2.8, 39.3, 32.9, 27.1, 26.1, 24.1, 17.2, 16.7; HRMS (ESI) calcd for C H NaO (M+Na)
18
28
2
299.1982, found 299.1985.
(1R,2E,6E,10S)ꢀ10ꢀ(3ꢀHydroxypropꢀ1ꢀenꢀ2ꢀyl)ꢀ3,7ꢀdimethylcyclodecaꢀ2,6ꢀdienol (24). To a
solution of 23 (10.7 mg, 0.04 mmol) in MeOH (0.3 mL) was added ethylene glycol (0.2 mL) and
PPTS (2.4 mg, 0.01 mmol) at room temperature. After stirring for 20 min, the reaction was
immediately poured into sat. aq. NaHCO and extracted with EtOAc. The organic layers were
3
dried over Na SO and concentrated. Purification by column chromatography (50% EA in
2
4
25
o
hexane) afforded diol 24 (7.1 mg, 78%) as a clear oil. [α]D +77.7 (c 0.6, CHCl ); IR (KBr)
3
–
1 1
3
076, 2924, 2857, 1445, 1262, 899, 802 cm ; H NMR (400 MHz, CDCl ) δ 5.15 (s, 1H), 5.01
3
(s, 1H), 4.79 (d, J = 10.9 Hz, 1H), 4.67 (d, J = 9.5 Hz, 1H), 4.16 (m, 3H), 2.67 (br s, 1H), 2.40–
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2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
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4
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5
5
5
5
5
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6
2
3
4
2
.32 (m, 1H), 2.22 (m, 3H), 2.11 (m, 2H), 1.94 (m, 1H), 1.80–1.67 (m, 3H), 1.66 (s, 3H), 1.40 (s,
1
3
H); C NMR (100 MHz, CDCl ) δ 153.2, 138.1, 135.1, 133.0, 126.9, 112.3, 71.5, 65.5, 55.0,
3
+
1.7, 39.6, 32.3, 26.0, 17.1, 16.5; HRMS (ESI) calcd for C H O (M+H) 237.1849, found
1
5
25
2
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
37.1853.
(+)ꢀCostunolide (1). To a stirred solution of compound 24 (49 mg, 0.2 mmol) in CH Cl (4
2
2
mL) was added MnO (180 mg, 2 mmol). After the mixture was stirred for 24 h at room
2
temperature, another portion of MnO (180 mg, 2 mmol) was added. After another 24 h, the
2
mixture was filtered through a short pad of Celite and washed with CH Cl . The filtrate was
2
2
concentrated under reduced pressure to an oily crude product, which was purified by flash
chromatography [PE/EA = 40:1–10:1] to give compound 1 (40 mg, 82%) as an amorphous white
21
o
1a
solid. [α]D +120 (c 0.1, CHCl ), lit. [α] = +128º (c 0.34, CHCl ) ; IR (KBr) 3070, 2930, 2856,
3
D
3
–1
1
1
669, 1428, 1376, 1216, 1110, 823, 739, 703 cm ; H NMR (400 MHz, CDCl ) δ 6.24 (d, J =
3
3
.6 Hz, 1H), 5.51 (d, J = 3.2 Hz, 1H), 4.84 (d, J = 11.0 Hz, 1H), 4.72 (d, J = 9.9 Hz, 1H), 4.55 (t,
J = 9.3 Hz, 1H), 2.56 (m, 1H), 2.44 (dd, J = 13.2, 5.9 Hz, 1H), 2.34–1.97 (m, 6H), 1.68 (s, 3H),
13
1
.65 (m, 1H), 1.41 (s, 3H); C NMR (100 MHz, CDCl ) δ 170.6, 141.6, 140.2, 137.1, 127.3,
3
127.1, 119.8, 82.0, 50.5, 41.1, 39.5, 28.1, 26.3, 17.4, 16.2; HRMS (ESI) calcd for C H O
2
1
5
21
+
(M+H) 233.1536, found 233.1538.
Melampomagnolide B (26). A solution of 2 (1.0 g, 4.3 mmol) in dichloromethane (20 mL)
was treated with SeO (324 mg, 2.4 mmol) and preꢀdried tꢀBuOOH ( 70% in H O, 1.48 mL, 10.8
2
2
mmol) over Na SO . The mixture was refluxed gently for 10 h, and stirred for 4 days at room
2
4
temperature. The reaction mixture was diluted with dichloromethane (20 mL) and the organic
layer was washed with sat. aqueous Na S O , brine and dried over anhydrous Na SO . The
2
2
3
2
4
solvent was removed under vacuum to get the crude, which was purified by column
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chromatography [PE:EA = 2:1–1:2] to give the alcohol 26 (810 mg, 72%) as a white solid. mp
o
21
o
1
71–173 C; [α] –33.9 (c 1.0, CHCl ); IR (KBr) 3466, 3096, 2957, 2867, 1747, 1309, 1151,
D 3
–
1 1
8
18 cm ; H NMR (400 MHz, CDCl ) δ 6.20 (d, J = 3.4 Hz, 1H), 5.63 (t, J = 8.1 Hz, 1H), 5.54
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
(
d, J = 3.1 Hz, 1H), 4.14 (d, J = 12.7 Hz, 1H), 4.05 (d, J = 12.7 Hz, 1H), 3.84 (t, J = 9.3 Hz, 1H),
2.84 (d, J = 9.4 Hz, 1H), 2.81 (m, 1H), 2.47–2.35 (m, 3H), 2.31–2.24 (m, 1H), 2.20–2.10 (m,
1
3
2
H), 1.98 (br s, 1H), 1.63 (t, J = 11.2 Hz, 1H), 1.53 (s, 3H), 1.07 (t, J = 12.5 Hz, 1H); C NMR
(100 MHz, CDCl ) δ 169.8, 139.6, 138.9, 127.2, 120.4, 81.3, 65.6, 63.4, 60.3, 42.8, 36.8, 25.6,
3
+
24.0, 23.7, 18.0. HRMS (ESI) calcd for C H NaO [M + Na ] 287.1254; found, 287.1259.
1
5
20
4
(
1aR,7aS,10aS,10bS,E)ꢀ5ꢀ(Fluoromethyl)ꢀ1aꢀmethylꢀ8ꢀmethyleneꢀ2,3,6,7,7a,8,10a,10bꢀ
octahydrooxireno[2',3':9,10]cyclodeca[1,2ꢀb]furanꢀ9(1aH)ꢀone (27) and (1aR,7aS,10aS,10bS)ꢀ
ꢀfluoroꢀ1aꢀmethylꢀ5,8ꢀdimethylenedecahydrooxireno[2',3':9,10]cyclodeca[1,2ꢀb]furanꢀ9(1aH)ꢀ
one (28). The solution of the alcohol 26 (94 mg, 0.356 mmol) in dry CH Cl (20 mL) was cooled
4
2
2
o
to –75 C and DAST (0.22 mL, 1.78 mmol) was added under Ar. The cooling bath was removed,
and the reaction mixture was stirred at room temperature for 2 h. Sat. aqueous NaHCO (5 mL)
3
was added, and the organic layer was separated, dried over Na SO and concentrated. The
2
4
residue was purified by column chromatography [PE:EA = 5:1–2:1] to yield a 3:1 mixture of 27
and 28 (68.3 mg, 72%), which was recrystallized in ether to get 27 (29.3 mg, 31%) as an oil and
2
8 ( 11.3 mg, 12%) a white solid.
17
o
Compound 27: [α]D –44.78 (c 0.3, CHCl ); IR (KBr) 3098, 2960, 2856, 1768, 1458, 1261,
3
–1
1
1
093, 1030, 805 cm ; H NMR (400 MHz, CDCl ) δ 6.22 (d, J = 3.5 Hz, 1H), 5.75 (dd, J = 13.0,
3
7
.8 Hz, 1H), 5.54 (d, J = 3.2 Hz, 1H), 4.90 (dd, J = 48.4, 10.6 Hz, 1H), 4.77 (dd, J = 47.3, 10.6
Hz, 1H), 3.85 (t, J = 9.4 Hz, 1H), 2.95–2.86 (m, 1H), 2.84 (d, J = 9.4 Hz, 1H), 2.42 (m, 3H),
13
2
.34–2.13 (m, 3H), 1.72–1.65 (m, 1H), 1.54 (s, 3H), 1.11 (t, J = 12.3 Hz, 1H); C NMR (100
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2
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3
3
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5
5
5
5
5
5
5
5
6
MHz, CDCl ) δ 169.5, 138.8, 136.0 (d, J = 14.2 Hz), 132.3 (d, J = 10.9 Hz), 120.2, 86.7 (d, J =
3
19
1
64.9 Hz), 81.0, 63.3, 60.0, 42.8 (d, J = 2.9 Hz), 36.5 (d, J = 4.3 Hz), 26.0, 24.7, 23.8, 18.0; F
NMR (376 MHz, CDCl ) δ –209.79 (t, J = 47.9 Hz); HRMS (ESI) calcd for C H FNaO [M +
3
15 19
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
+
Na ] 289.1210; found, 289.1215.
o
17
o
Compound 28: mp 220–221 C
;
[α]D –63.97 (c 0.2, CHCl ); IR (KBr) 2960, 2856, 1766,
3
–
1
1
1
456, 1260, 1097, 1022, 862 cm ; H NMR (400 MHz, CDCl ) δ 6.23 (d, J = 3.5 Hz, 1H), 5.54
3
(d, J = 3.2 Hz, 1H), 5.51 (dd, J = 6.0, 2.1 Hz, 1H), 5.21 (s, 1H), 4.91 (ddd, J = 45.1, 10.8, 4.4 Hz,
1H), 3.78 (t, J = 9.5 Hz, 1H), 3.29 (m, 1H), 2.82 (d, J = 9.2 Hz, 1H), 2.56–2.41 (m, 2H), 2.26–
13
2
.13 (m, 3H), 2.09–1.95 (m, 1H), 1.80 (m, 1H), 1.50 (s, 3H), 1.07 (t, J = 12.3 Hz, 1H); C NMR
(
100 MHz, CDCl ) δ 169.3, 143.7 (d, J = 14.9 Hz), 139.2, 119.7 (d, J = 7.9 Hz), 119.7, 98.5 (d, J
3
=
164.6 Hz), 79.8, 63.7, 60.2, 42.7, 32.4 (d, J = 12.9 Hz), 28.0 (d, J = 26.1 Hz), 24.1, 23.3, 18.6;
F NMR (376 MHz, CDCl ) δ –155.23 (d, J = 53.1 Hz); HRMS (ESI) calcd for C H FNaO
3
19
3
15 19
+
[
M + Na ] 289.1210; found, 289.1209.
(
1aR,7aS,10aS,10bS,E)ꢀ1aꢀMethylꢀ8ꢀmethyleneꢀ9ꢀoxoꢀ1a,2,3,6,7,7a,8,9,10a,10bꢀ
decahydrooxireno[2',3':9,10]cyclodeca[1,2ꢀb]furanꢀ5ꢀcarbaldehyde (29). To a solution of the
alcohol 26 (66.0 mg, 0.25 mmol) in dry CH Cl (3 mL) was added NaHCO (210.0 mg, 2.5 mmol)
2
2
3
o
followed by the addition of DessꢀMartin periodinane (156.9 mg, 0.37 mmol) in portions at 0 C.
The mixture was stirred for 2 h at room temperature, and quenched by the addition of sat.
aqueous Na S O (3 mL), H O (3 mL) and CH Cl (5 mL). The mixture was stirred until the
2
2
3
2
2
2
phases became clear. The two phases were separated, and the organic layer was washed with
brine, dried over Na SO4, and concentrated to afford the residue, which was purified by flash
2
chromatography [PE:EA = 4:1–2:1] to give the aldehyde 29 (60.5 mg, 92%) as a white foam.
20
o
–1 1
[
α]D –57.0 (c 0.6, CHCl ); IR (KBr) 3064, 2936, 2852, 1767, 1679, 1456, 1262, 812 cm ; H
3
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NMR (400 MHz, CDCl ) δ 9.46 (d, J = 1.2 Hz, 1H), 6.68 (t, J = 8.3 Hz, 1H), 6.18 (d, J = 3.5 Hz,
3
1H), 5.54 (d, J = 3.1 Hz, 1H), 3.78 (t, J = 9.4 Hz, 1H), 2.93 (m, 1H), 2.70 (d, J = 9.5 Hz, 1H),
13
2
.62–2.43 (m, 4H), 2.41–2.25 (m, 2H), 1.64–1.55 (m, 1H), 1.54 (s, 3H), 1.26–1.20 (m, 1H); C
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
NMR (100 MHz, CDCl ) δ 195.2, 169.4, 153.9, 143.8, 138.2, 120.8, 81.2, 63.0, 59.6, 42.2, 36.0,
3
+
25.0, 24.9, 22.4, 17.9; HRMS (ESI) calcd for C H NaO [M + Na ] 285.1097; found, 285.1100
1
5
18
4
(1aR,7aS,10aS,10bS,E)ꢀ5ꢀ(Difluoromethyl)ꢀ1aꢀmethylꢀ8ꢀmethyleneꢀ2,3,6,7,7a,8,10a,10bꢀ
octahydrooxireno[2',3':9,10]cyclodeca[1,2ꢀb]furanꢀ9(1aH)ꢀone (30). The solution of 29 (39.0
o
mg, 0.18 mmol) in dry CH Cl (0.1 mL) was cooled to 0 C and DAST (0.22 mL, 1.8 mmol) was
2
2
added under Ar. The cooling bath was removed and the mixture was stirred at room temperature
for 3 days. CH Cl (10 mL) and Sat. aqueous NaHCO (5 mL) was added, and the organic layer
2
2
3
was separated, dried over Na SO and concentrated. The residue was purified by column
2
4
chromatography [PE:EA = 5:1–2:1] to yield compound 30 (18.3 mg, 43%) as a white solid. mp
o
21
o
1
8
1
02–103 C; [α] –63.79 (c 0.13, CHCl ); IR (KBr) 2960, 2855, 1769, 1459, 1261, 1093, 1022,
D 3
–
1 1
02 cm ; H NMR (400 MHz, CDCl ) δ 6.22 (d, J = 3.3 Hz, 1H), 6.04 (dd, J = 56.9, 54.4 Hz,
3
H), 5.95 (t, J = 8.0 Hz, 1H), 5.53 (d, J = 3.0 Hz, 1H), 3.85 (t, J = 9.4 Hz, 1H), 3.09–2.98 (m,
1H), 2.82 (d, J = 9.4 Hz, 1H), 2.57–2.19 (m, 6H), 1.73–1.62 (m, 1H), 1.56 (s, 3H), 1.14 (td, J =
13
1
2.6, 3.1 Hz, 1H); C NMR (100 MHz, CDCl ) δ 169.5, 138.7, 135.0 (t, J = 10.8 Hz), 134.8 (t, J
3
=
20.0 Hz), 120.3, 118.9 (t, J = 238.0 Hz), 80.9, 63.3, 59.7, 42.8 (d, J = 5.6 Hz, 1H), 36.1, 26.5,
1
9
23.7, 22.7, 18.0; F NMR (376 MHz, CDCl ) δ –107.39 (dd, J = 301.6, 57.1 Hz, 1F), –116.33
3
+
(
dd, J = 301.5, 54.3 Hz, 1F); HRMS (ESI) calcd for C H F NaO [M + Na ] 307.1116; found,
1
5
18
2
3
307.1118.
(1aR,7aS,10aS,10bS,E)ꢀ1aꢀMethylꢀ8ꢀmethyleneꢀ9ꢀoxoꢀ1a,2,3,6,7,7a,8,9,10a,10bꢀ
decahydrooxireno[2',3':9,10]cyclodeca[1,2ꢀb]furanꢀ5ꢀcarboxylic acid (31). To a mixure of
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2
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6
.
aldehyde 29 (50.0 mg, 0.19 mmol), NaH PO 2H O (118mg, 0.76 mmol) and 2ꢀmethylꢀ2ꢀbutene
2
4
2
(
0.2 mL, 1.9 mmol) in tꢀBuOH (2 mL) and H O (0.5 mL) was added NaClO (68.7 mg, 0.76
2
2
o
mmol) at 0 C. After stirring for 1 h at the temperature, the mixture was extracted with EtOAc (3
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
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0
1
2
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9
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4
5
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8
9
0
1
2
3
4
5
6
7
8
9
0
×
10 mL) and H O (5 mL). The organic layer was separated, dried over Na SO and concentrated
2
2
4
to give the residue, which was purified by column chromatography [PE:EA = 1:1–1:4] to yield
o
20
o
compound 31 (46.7 mg, 88%) as a white solid. mp 213–214 C; [α]D –80.4 (c 0.13, CHCl ); IR
3
–
1 1
(
KBr) 3222, 3090, 2926, 2859, 1746, 1714, 1460, 1229, 807, 734 cm ; H NMR (400 MHz,
CDCl ) δ 6.99 (t, J = 8.7 Hz, 1H), 6.22 (d, J = 3.2 Hz, 1H), 5.55 (d, J = 3.0 Hz, 1H), 3.81 (t, J =
3
9
.4 Hz, 1H), 2.80 (dd, J = 13.8, 7.8 Hz, 2H), 2.72–2.56 (m, 2H), 2.45 (m, 3H), 2.25 (m, 1H),
1
3
1
.67–1.58 (m, 1H), 1.56 (s, 3H), 1.19 (m, 1H); C NMR (100 MHz, CDCl ) δ 172.1, 169.6,
3
144.3, 138.5, 132.6, 120.6, 81.7, 62.9, 59.7, 42.3, 35.9, 25.9, 24.7, 23.5, 18.0; HRMS (ESI) calcd
+
for C H O [M – H ] 277.1081; found, 277.1087.
1
5
17
5
(
E)ꢀ6ꢀ((tertꢀButyldiphenylsilyl)oxy)ꢀ3ꢀmethylhexꢀ2ꢀenal (34). The title compound 34 (23.4 g,
9
2%) was prepared from 33 (25.5 g, 69.2 mmol) according to a procedure similar to that
–1
described for the synthesis of 13. IR (KBr) 3069, 2933, 2858, 1641, 1378, 1109, 823, 704 cm ;
1
H NMR (400 MHz, CDCl ) δ 10.00 (d, J = 8.0 Hz, 1H), 7.68 (d, J = 6.6 Hz, 4H), 7.49–7.34 (m,
3
6
H), 5.91 (d, J = 8.0 Hz, 1H), 3.70 (t, J = 6.0 Hz, 2H), 2.33 (t, J = 6.0 Hz,, 2H), 2.15 (s, 3H),
1
3
1
.75 (m, 2H), 1.08 (s, 9H); C NMR (100 MHz, CDCl ) δ 191.3, 164.0, 135.6, 133.7, 129.7,
3
+
127.7, 127.4, 63.0, 37.0, 30.1, 26.9, 19.2, 17.6; HRMS (ESI) calcd for C H NaO Si [M + Na ]
2
3
30
2
389.1907; found, 389.1908.
(
2S,3R,E)ꢀ2ꢀ(3ꢀ((tertꢀButyldimethylsilyl)oxy)propꢀ1ꢀenꢀ2ꢀyl)ꢀ8ꢀ((tertꢀbutyldiphenylsilyl)oxy)ꢀ1ꢀ
(3aR,6S,7aS)ꢀ8,8ꢀdimethylꢀ2,2ꢀdioxidohexahydroꢀ1Hꢀ3a,6ꢀmethanobenzo[c]isothiazolꢀ1ꢀyl)ꢀ3ꢀ
hydroxyꢀ5ꢀmethyloctꢀ4ꢀenꢀ1ꢀone (35). The title compound 35 (11.0 g, 43%) was prepared from
(
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5 (13.8g, 32.3 mmol) according to a procedure similar to that described for the synthesis of 16a.
2
1
o
–1
[
α]D +10.6 (c 1.0, CHCl ); IR (KBr) 3454, 3069, 2999, 2856, 1692, 1335, 1109, 838, 704 cm ;
3
1
H NMR (400 MHz, CDCl ) δ 7.69–7.66 (m, 4H), 7.42–7.37 (m, 6H), 5.39 (s, 1H), 5.35 (s, 1H),
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
5
.24 (d, J = 8.8 Hz, 1H), 4.83 (t, J = 8.6 Hz, 1H), 4.31 (d, J = 13.4 Hz, 1H), 4.22 (d, J = 13.4 Hz,
1H), 3.82–3.72 (m, 2H), 3.66 (t, J = 6.3 Hz, 2H), 3.44 (d, J = 13.7 Hz, 1H), 3.35 (d, J = 13.8 Hz,
H), 3.22 (br s, 1H), 2.07 (m, 2H), 1.98 (m, 1H), 1.83 (m, 4H), 1.73 (s, 3H), 1.68 (m, 2H), 1.29
1
1
3
(m, 2H), 1.05 (s, 9H), 1.02 (s, 3H), 0.93 (s, 12H), 0.11 (s, 3H), 0.11 (s, 3H); C NMR (100 MHz,
CDCl ) δ 170.2, 142.4, 140.3, 135.6, 134.1, 129.5, 127.6, 124.7, 115.7, 69.1, 65.8, 64.8, 63.9,
3
5
5.6, 53.1, 48.2, 47.7, 44.6, 37.9, 35.9, 32.7, 30.9, 26.9, 26.5, 26.0, 20.7, 19.9, 19.3, 18.4, 17.0, ꢀ
+
5.39, ꢀ5.43; HRMS (ESI) calcd for C H NNaO SSi [M + Na ] 816.4120 ; found, 816.4122.
44 67
6
2
((4R,5S)ꢀ4ꢀ((E)ꢀ5ꢀ((tertꢀButyldiphenylsilyl)oxy)ꢀ2ꢀmethylpentꢀ1ꢀenꢀ1ꢀyl)ꢀ2,2ꢀdimethylꢀ6ꢀ
methyleneꢀ1,3ꢀdioxepanꢀ5ꢀyl)((3aR,6S,7aS)ꢀ8,8ꢀdimethylꢀ2,2ꢀdioxidohexahydroꢀ1Hꢀ3a,6ꢀ
methanobenzo[c]isothiazolꢀ1ꢀyl)methanone (36). The title compound 36 (2.44 g, 75%) was
prepared from 35 (3.54 g, 4.46 mmol) according to a procedure similar to that described for the
21
o
synthesis of compound 17. [α]D +9.4 (c 1.0, CHCl ); IR (KBr) 2937, 2897, 1690, 1336, 1109,
3
–1 1
709 cm ; H NMR (400 MHz, CDCl ) δ 7.66 (d, J = 6.6 Hz, 4H), 7.39 (m, 6H), 5.33 (d, J = 9.6
3
Hz, 1H), 5.10 (s, 1H), 4.95 (t, J = 9.4 Hz, 1H), 4.88 (s, 1H), 4.36 (d, J = 13.0 Hz, 1H), 4.01 (d, J
=
13.0 Hz, 1H), 3.94 (m, 1H), 3.76 (t, J = 6.3 Hz, 1H), 3.65 (t, J = 6.5 Hz, 2H), 3.45 (d, J = 13.8
Hz, 1H), 3.34 (d, J = 13.8 Hz, 1H), 2.13–2.00 (m, 4H), 1.84 (d, J = 5.5 Hz, 3H), 1.68 (s, 3H),
13
1.64 (m, 2H), 1.37 (s, 6H), 1.29 (m, 2H), 1.09 (s, 3H), 1.04 (s, 9H), 0.93 (s, 3H); C NMR (100
MHz, CDCl ) δ 170.2, 144.3, 139.1, 135.6, 134.1, 129.5, 127.6, 123.6, 115.4, 101.4, 68.9, 66.9,
3
6
5.2, 63.9, 57.3, 53.1, 48.0, 47.7, 44.6, 38.6, 35.9, 32.9, 31.1, 26.9, 26.4, 25.3, 24.9, 20.7, 19.9,
+
1
9.3, 17.1; HRMS (ESI) calcd for C H NNaO SSi [M + Na ] 742.3568; found, 742.3570.
4
1
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6
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tertꢀButyl(((E)ꢀ5ꢀ((4R,5S)ꢀ2,2ꢀdimethylꢀ6ꢀmethyleneꢀ5ꢀ((phenylthio)methyl)ꢀ1,3ꢀdioxepanꢀ4ꢀ
yl)ꢀ4ꢀmethylpentꢀ4ꢀenꢀ1ꢀyl)oxy)diphenylsilane (37). Compound 37 (1.87g, 81%) was prepared as
an oil from 36 (2.78g, 3.86 mmol) according to a procedure similar to that described for the
0
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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
21
o
synthesis of 18 from 17. [α]D +3.4 (c 1.0, CHCl ; IR (KBr) 3069, 2932, 2858, 1428, 1378,
3
–
1 1
1109, 822, 704 cm ; H NMR (400 MHz, CDCl ) δ 7.66 (d, J = 6.6 Hz, 4H), 7.39 (m, 6H), 7.24
3
(m, 4H), 7.11 (t, J = 6.6 Hz, 1H), 5.20 (d, J = 9.3 Hz, 1H), 5.05 (s, 1H), 4.92 (s, 1H), 4.52 (dd, J
=
9.0, 8.0 Hz, 1H), 4.32 (d, J = 14.1 Hz, 1H), 4.26 (d, J = 14.1 Hz, 1H), 3.63 (t, J = 6.3 Hz, 2H),
3.14–3.02 (m, 2H), 2.56 (br q, J = 7.6 Hz, 1H), 2.09 (m, 2H), 1.71 (s, 3H), 1.67–1.60 (m, 2H),
13
1
.40 (s, 3H), 1.35 (s, 3H), 1.05 (s, 9H); C NMR (100 MHz, CDCl ) δ 146.3, 138.6, 137.1,
3
135.6, 134.1, 129.6, 128.9, 128.8, 127.7, 125.8, 125.2, 114.1, 101.8, 70.1, 66.5, 63.7, 52.4, 36.1,
+
34.0, 30.9, 26.9, 25.9, 24.4, 19.3, 17.1; HRMS (ESI) calcd for C H NaO SSi [M + Na ]
3
7
48
3
623.2986; found, 623.2988.
tertꢀButyl(((E)ꢀ5ꢀ((4R,5S)ꢀ2,2ꢀdimethylꢀ6ꢀmethyleneꢀ5ꢀ((phenylsulfonyl)methyl)ꢀ1,3ꢀdioxepanꢀ
4ꢀyl)ꢀ4ꢀmethylpentꢀ4ꢀenꢀ1ꢀyl)oxy)diphenylsilane (38). The title compound 38 (1.83 g, 93%) was
prepared from 37 (1.87 g, 3.11 mmol) according to a procedure similar to that described for the
21
o
synthesis of compound 19. [α]D –20.7 (c 1.0, CHCl ); IR (KBr) 3069, 2931, 2857, 1428, 1378,
3
–
1 1
1
080, 800, 743 cm ; H NMR (400 MHz, CDCl ) δ 7.88– 7.84 (m, 2H), 7.67 (m, 4H), 7.62–7.57
3
(
m, 1H), 7.50 (t, J = 7.6 Hz, 2H), 7.46–7.36 (m, 6H), 5.07 (d, J = 9.3 Hz, 1H), 5.01 (s, 1H), 4.98
(s, 1H), 4.34 (dd, J = 9.3, 6.9 Hz, 1H), 4.24 (d, J = 14.5 Hz, 1H), 4.08 (d, J = 14.4 Hz, 1H), 3.65
t, J = 6.3 Hz, 2H), 3.54 (dd, J = 14.6, 9.8 Hz, 1H), 3.19 (dd, J = 14.6, 3.6 Hz, 1H), 2.84–2.76 (m,
(
1H), 2.04 (m, 2H), 1.65 m, 2H), 1.63 (d, J = 0.9 Hz, 3H), 1.36 (s, 3H), 1.30 (s, 3H), 1.06 (s, 9H);
1
3
C NMR (100 MHz, CDCl ) δ 144.7, 139.7, 139.6, 135.6, 134.0, 133.7, 129.6, 129.2, 128.2,
3
29
ACS Paragon Plus Environment