Syntheses of naturally occurring cytotoxic [7.7]paracyclophanes, (-)-cylindrocyclophane A and its enantiomer, and implications for biological activity

Article abstract of DOI:10.1039/b909646a

The total syntheses of (-)-cylindrocyclophane A (1), a naturally occurring, cytotoxic [7.7]paracyclophane, and its enantiomer have been achieved in an enantiodivergent manner starting from a chiral propargyl alcohol building block using Smith's cross metathesis/ring-closing metathesis protocol as the key step. The biological evaluation of both enantiomers of cylindrocyclophane A (1 and ent-1) and its analogues indicated that the chirality of 1 is irrelevant to its cytotoxicity, which is attributed to the resorcinol motifs embedded in the robust [7.7]paracyclophane framework.

Full text of DOI:10.1039/b909646a

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www.rsc.org/obc | Organic & Biomolecular Chemistry
Syntheses of naturally occurring cytotoxic [7.7]paracyclophanes,
(-)-cylindrocyclophane A and its enantiomer, and implications
for biological activity†
Hiroyuki Yamakoshi,a Fumiya Ikarashi,a Masataka Minami,a Masatoshi Shibuya,a Tsutomu Sugahara,a
Naoki Kanoh,a Hisatsugu Ohori,b Hiroyuki Shibatab and Yoshiharu Iwabuchi*a
Received 15th May 2009, Accepted 16th June 2009
First published as an Advance Article on the web 14th July 2009
DOI: 10.1039/b909646a
The total syntheses of (-)-cylindrocyclophane A (1), a naturally occurring, cytotoxic
[7.7]paracyclophane, and its enantiomer have been achieved in an enantiodivergent manner starting
from a chiral propargyl alcohol building block using Smith’s cross metathesis/ring-closing metathesis
protocol as the key step. The biological evaluation of both enantiomers of cylindrocyclophane A (1 and
ent-1) and its analogues indicated that the chirality of 1 is irrelevant to its cytotoxicity, which is
attributed to the resorcinol motifs embedded in the robust [7.7]paracyclophane framework.
cylindrocyclophanes and nostocyclophanes were found to exhibit
cytotoxicity against the KB and LoVo tumor cell lines at IC50
values of 2–10 mg/mL.3,4
Introduction
Since their introduction by Cram and Steinberg in 19511, the
bridged class of aromatic compounds, widely referred to as
Their unique architectures have necessarily attracted consider-
cyclophanes, have been inspiring chemists to imagine advanced
able attention from the synthetic community and spurred intense
molecules with novel functions.2 In the 1990s, the first naturally oc-
studies on the construction of chirally modified, C2-symmetric cy-
curring [m.n]paracyclophanes, namely, cylindrocyclophanes3 and
nostocyclophanes4, were isolated from extracts of terrestrial blue-
green algae, belonging to Cylindrospermum licheniforme Ku¨tzing
and Nostoc linckia Roth (Bornet), respectively (Fig. 1). Their
unprecedented 22-membered, C2-symmetric [7.7]paracyclophane
structures were unambiguously elucidated on the basis of ex-
tensive NMR studies in conjunction with CD spectroscopy and
X-ray crystallography.5 In addition to their novel structures,
clophanes that have culminated in several elegant total syntheses.6
Meanwhile, little is known about the molecular basis of the
cytotoxicity of these naturally occurring [7.7]paracyclophanes.
We took an interest in these natural products in view of
them being structural hybrids of [7.7]paracyclophane and 2,5-
dialkylresorcinol; the latter motif has attracted attention owing
to its wide range of biological activities, including fungicidal,
bacteriocidal, and cytotoxic activities.7,8 To gain insight into the
cytotoxic origin of these chirally modified [7.7]paracyclophanes,
we envisioned a preliminary SAR study of cylindrocyclophane A
based on its enantiocontrolled total synthesis.
We describe herein the expedient, enantiocontrolled total syn-
theses of both enantiomers of cylindrocyclophane A (1 and ent-1)
starting from a tartrate-derived, chiral propargyl alcohol building
block, and the evaluations of cytotoxicity thereof.
Synthesis plan and SAR panel of cylindrocyclophane A
Considering the synthetic reliability and design of the SAR panel,
we decided to follow Smith’s protocol employing a tandem cross
metathesis/ring-closing metathesis (CM/RCM) of the diolefin
4 for the construction of the [7.7]paracyclophane framework
(Scheme 1).6b–d Thus, it was envisioned that biological evaluations
of a set of synthetic samples, including natural and unnatural cylin-
drocyclophane A, the half-sized analogue 2, and tetramethylate 3,
would lead us to identify toxicophore structures.
To acquire both enantiomers of Smith’s diolefin 4, we intended
to use 5 as the common chiral intermediate, which is a logical
product of the Johnson–Claisen rearrangement of 6. The bottom-
arm portions of 4 would be prepared in an enantiodivergent
manner via two conventional sets of manipulations. Thus, the
conversion of the ethoxycarbonylmethyl moiety of 5 to either a
Fig. 1 Naturally occurring [7.7]paracyclophanes.
aGraduate School of Pharmaceutical Sciences, Tohoku University, 6-3
Aobayama, Sendai, Japan. E-mail: iwabuchi@mail.pharm.tohoku.ac.jp;
Fax: +81 22 795 6845
bDepartment of Clinical Oncology, Institute of Development, Aging and
Cancer, Tohoku University, Sendai, Japan
† Electronic supplementary information (ESI) available: Synthetic meth-
ods and compound data; 1H- and 13C-NMR spectra. See DOI:
10.1039/b909646a
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Scheme 1 Retrosynthetic analysis and intended SAR items.
Scheme 2 Synthesis of the common intermediate 5. Reagents and conditions: a) Tf2O, pyridine, CH2Cl2, 92%; b) TBSCl, imidazole, DMF, 96%; c)
PdCl2(PPh3)2, CuI, PPh3, K2CO3, Bu4NI, THP, 70 ◦C, 78%; d) (i) NaBH4, MeOH; (ii) TBAF, AcOH, THF, 96%; e) TBDPSCl, NEt3, DMAP, CH2Cl2,
77%; f) LAH, THF, 86%; g) CH3C(OEt)3, cat. o-NO2PhOH, 140 ◦C, 72%.
butyl or allyl group, and of the allyl ether moiety to either an allyl
or butyl group, will establish enantiodivergent routes to the 4-(oct-
1-enyl) appendant of 4. As for the upper-arm portions of 4, we
assigned the Evans asymmetric aldolization as a pivotal reaction
for the enantiodivergent installation of contiguous hydroxy and
methyl groups. The intermediate 6 could be synthesized from
syringaldehyde (7) and chiral acetylene 8 via the Sonogashira
coupling reaction10 followed by stereoselective reduction of the
alkyne moiety (Scheme 1).
was determined by HPLC (Scheme 2). It is worth commenting that
when pivalic acid was used as a promoter, pivalate was produced as
the by-product, supporting the advantageous use of o-nitrophenol
as the catalyst.
Synthesis of natural (-)-cylindrocyclophane A
Having secured the chiral building block 5, our focus moved
to tailoring the alkyl terminus as in Smith’s intermediate (+)-4
(Scheme 3). To this end, the ester 5 was partially reduced with
DIBAL, and the aldehyde generated was subjected to the Wittig
reaction using ethylidenetriphenylphosphorane to give 11 in 97%
yield.
After considerable experimentation, a stepwise hydrogenation
of the olefins with catalytic Pd/C and hydrogenolysis15 of the
benzyl ether with catalytic Pd(OH)2 was confirmed to be essential
for procuring the alcohol 12: all the attempted one-step reductions
were thwarted by the production of a considerable amount of
unidentifiable compounds.
The dehydration of the alcohol 12 employing the method of
Grieco et al.16 was followed by desilylation and MnO2-mediated
oxidation to afford 13, the projected substrate for the Evans
aldol reaction. The diastereoselective aldol reaction17 between
the enol borinate of the oxazolidinone 14 and 13 afforded the
desired 15 in 97% yield and >99% de. The TES protection of the
secondary hydroxy group, the formation of the Weinreb amide,
and the following treatment with DIBAL liberated the aldehyde
16. Upon successive Horner–Wadsworth–Emmons reaction, the
1,4-reduction of the a,b-unsaturated ester, LAH reduction, and
Grieco dehydration,16 16 furnished the known diolefin 4.6b–d
Results and discussion
Synthesis of common intermediate 7
The synthesis of the common chiral platform 5 began by triflating
commercially available 7 to give the triflate 7a (Scheme 2). The
propargyl alcohol 8, which was prepared from L-diethyl tartrate
in accordance with the literature,11 was equipped with a TBS
group. The resulting 8a was subjected to Sonogashira coupling10
with 7a using cat. PdCl2(PPh3)2 and CuI in the presence of PPh3,
K2CO3, and Bu4NI in boiling tetrahydropyran (THP)12 to give the
aldehyde 9 in 78% yield12,13 with an enantiomeric excess >99% ee.
To set the stage for the projected Johnson–Claisen rearrangement,
9 was sequentially subjected to NaBH4 reduction, desilylation,
and selective TBDPS protection of the primary hydroxy group to
give 10 in 74% yield. 10 was then reduced in a diastereocontrolled
manner using LiAlH4 in THF to furnish E-alkene 6 in 86% yield.
Upon heating in triethyl orthoacetate in the presence of a catalytic
amount of o-nitrophenol,14 6 furnished the g,d-unsaturated ester
5 in 72% yield with a high enantiomeric excess (>99% ee), which
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◦
Scheme 3 Total synthesis of (-)-cylindrocyclophane A (1). Reagents and conditions: a) DIBAL, toluene, -78 C, 86%; b) Ph3P+EtI-, KHMDS, THF,
97%; c) H2, Pd/C, THP; Pd(OH)2, 94%; d) o-NO2PhSeCN, PBu3, THF; H2O2, THF, 94%; e) TBAF, THF, 99%; f) MnO2, CH2Cl2, 97%; g) NEt3,
Bu2BOTf, CH2Cl2, -78 ◦C, 97%; h) HN(OMe)Me·HCl, Me3Al, THF, -15 ◦C, 91%; i) TESCl, imidazole, DMF, 99%; j) DIBAL, toluene, -78 ◦C, 96%; k)
EtO2P(O)CH2CO2Et, NaH, THF, 0 ◦C, 94%; l) Mg, MeOH, 0 ◦C, 98%; m) LAH, THF, 0 ◦C, 91%; n) o-NO2PhSeCN, PBu3, THF; H2O2, THF (93%);
o) Grubbs 2nd, DCE, 80 ◦C, 40%; p) TBAF, THF, 74%; q) H2, PtO2, EtOH, 99%; r) PhSH, K2CO3, NMP, sealed tube, 215 ◦C, 85%.
Scheme 4 Total synthesis of (+)-cylindrocyclophane A (ent-1). Reagents and conditions: a) H2, Pd/C, Pd(OH)2, THP, 99%; b) 1-Me-AZADO, BAIB,
CH2Cl2, 87%; c) Ph3P+MeBr-, KHMDS, THF, 84%; d) H2, Pd/C, AcOEt, 98%; e) DIBAL, toluene, 99%; f) Ph3P+MeBr-, KHMDS, THF, 84%; g) TBAF,
THF, 99%; h) MnO2, CH2Cl2, 97%; i) NEt3, Bu2BOTf, CH2Cl2, -78 ◦C, 83%.
The crucial CM/RCM reaction constructing the [7.7]paracyclo-
phane framework was experimented on by following Smith et al.’s
procedures.6b–d The dimerization of 5 proceeded best using Grubbs
2nd-generation catalyst in boiling dichloroethane to give 17 in 40%
yield. The deprotection of the TES ether with TBAF, followed by
hydrogenation with PtO2 afforded the tetramethylate 3. Finally,
the treatment of 3 with PhSH and K2CO3 in NMP at 215 ◦C gave
clean demethylation to furnish (-)-cylindrocyclophane A (1). The
1H- and 13C-NMR spectral data of synthetic 1 were identical to
those reported by Smith et al.6b–d and Hoye et al.6e
was cleanly oxidized to give the corresponding aldehyde in 87%
yield. The subjection of 19 to Wittig methylenation followed by
hydrogenation gave the ester 20. Next, the ethoxycarbonylmethyl
appendage was transformed into an allyl group in a conventional
two-step operation entailing the partial reduction of 20 with
DIBAL and the following Wittig reaction. Desilylation and MnO2-
mediated oxidation furnished ent-13, on which the same set
of operations, except the use of the oxazolidinone 21 in the
aldolization, was performed as described for the synthesis of 1,
and furnished (+)-cylindrocyclophane A (ent-1). All the spectral
data of ent-1 were identical to those of 1 and the absolute value of
optical rotation was identical but in an opposite sense to that of
(-)-cylindrocyclophane A (1).
Synthesis of unnatural (+)-cylindrocyclophane A
The synthesis of unnatural (+)-cylindrocyclophane A (ent-1)
began with the transformation of the allyl ether moiety of 5
into a butyl group (Scheme 4). Thus, 5 was subjected to a
sequential hydrogenation/hydrogenolysis to give the alcohol 18.
Upon treatment with a catalytic amount of 1-Me-AZADO18
in the presence of 1.1 equivalent of PhI(OAc)2 in CH2Cl2, 18
Synthesis of a half-sized analogue
The acquisition of the projected half-sized analogue 2 from the
intermediate 16 was unexpectedly hampered by the methyl groups
that had been charged with protecting the resorcinol moiety: all
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Table 1 Cell growth inhibitions against HCT116
attempts, including the use of Smith’s conditions that enabled the
acquisition of 1 from 3, resulted in an intractable decomposition
of 2 (Scheme 5).
compound
Gl50 (mM)
(-) cylindrocyclophane A (1)
(+) cylindrocyclophane A (ent-1)
tetramethylate 3
2
2
> 50
20
half-sized 32
LiBH4 to give the alcohol 30.22 1-Me-AZADO18 catalyzed oxi-
dation, Wittig reaction with ethylidenetriphenylphosphorane, and
hydrogenation of the resulting alkene, followed by global depro-
tection completed the construction of the half-sized analogue 32
(Scheme 6).
Scheme 5 Attempted synthesis of the half-sized analogue 2. Reagents
and conditions: a) Ph3P+MeBr-, KHMDS, THF, 99%; b) H2, PtO2, EtOH,
99%; c) TBAF, THF, 88%.
Revisions, therefore, were made to the synthesis plan: (a) switch-
ing the protective groups; (b) removing the stereogenic center
by adding an extra carbon to 2 to save synthetic steps, thereby
revealing the new target 32 (Scheme 6). To this end, the ester
2419 was converted to 25 via double alkylation using butyllithium
followed by dehydration. A straightforward sequence entailing
hydrogenation, the hydrolytic deprotection of the dimethyl acetal,
LiAlH4 reduction, and BBr3-mediated demethylation allowed us
to transform 25 into 26 in 26% yield.20 The oxidation of the
benzyl alcohol 26 to the corresponding aldehyde failed owing to
damage of the resorcinol portions. However, it was found that
TEMPO+·Cl- allowed the transformation in 69% yield,21 where
MnO2 oxidation resulted in 27% yield. Upon bis-TBS protection,
and Evans aldolization using 14, 28 afforded 29 in 97% yield.
After the protection of the secondary hydroxy group with the
TES group, the chiral auxiliary was detached reductively using
Evaluation of biological activities
Both enantiomers of cylindrocyclophane A, tetramethylate 3, and
the half-sized analogue 32 were evaluated for tumor cell growth
inhibitory activity against the human colon cancer cell line HCT-
116 (Table 1).23 From the cell growth inhibition assay, (i) synthetic
(-)-cylindrocyclophane A (1) exhibited activity (GI50 = 2 mM)
comparable to the reported cytotoxicity of natural 1 against KB
and LoVo tumor cell lines3; (ii) (+)-cylindrocyclophane A (ent-1)
exhibited cell growth inhibition at almost the same level as that
of (-)-cylindrocyclophane A (1); (iii) the half-sized analogue
32 which has the 2,5-dialkylresorcinol motif of 1, showed a
decreased cell growth inhibition level; (iv) the cylindrocyclophane
A tetramethylate 3 showed no cell growth inhibition. Taken
together, these results indicated that: (a) 2,5-dialkylresorcinol
functionality is essential for eliciting the cytotoxicity; (b) the
[7.7]paracyclophane framework enhances the potency of the
resorcinol toxicophore; (c) chirality is irrelevant to the cytotoxicity,
implying that cylindrocyclophane A elicits its toxicity through
actions in biological spaces where chirality plays no dominant
roles.
Conclusions
We have demonstrated an enantiodivergent synthesis of natu-
ral and unnatural cylindrocyclophane A’s, by adopting Smith’s
CM/RCM protocol. Both enantiomers of Smith’s diolefin 4
were accessed from a common intermediate, which was readily
synthesized from the commercially available L-diethyl tartrate and
syringaldehyde.
The cytotoxic activities of both enantiomers of cylindrocyclo-
phane A and its analogues 3 and 32 indicated that the toxicophore
of cylindrocyclophane A is attributed to the resorcinol portion and
that the paracyclophane structure is auxiliary. This information
would be helpful for future development of [m.n]paracyclophane-
based molecular tools in biological systems.
Scheme 6 Synthesis of the half-sized analogue 32. Reagents and condi-
tions: a) BuLi, THF, -78 ◦C, 66%; b) CH(OMe)3, c. HCl, MeOH, -78 ◦C,
E:Z = 2.2:1; c) (i) H2, Pd/C, AcOEt; (ii) AcOH, H2O, reflux; (iii) LAH,
THF, 0 ◦C, 52%; d) BBr3, CH2Cl2, -78 ◦C; 10% aq. NaOH, 51%; e)
TEMPO+Cl-, CH2Cl2, 69%; f) TBSCl, imidazole, CH2Cl2, 80%; g) NEt3,
Bu2BOTf, CH2Cl2, -78 ◦C, 97%; h) TESCl, imidazole, DMF, 99%; i)
LiBH4, THF, 88%; j) 1-Me-AZADO, BAIB, CH2Cl2, 70%; k) Ph3P+EtI-,
n-BuLi, THF, -78 ◦C, 72%; l) H2, Pd/C, AcOEt, 94%; m) TBAF, THF,
84%.
Experimental
General
All reactions were carried out under an atmosphere of argon
unless otherwise specified. Anhydrous solvents were transferred
via syringe to flame-dried glassware, which had been cooled under
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a stream of dry nitrogen. Ethereal solvents and dichloromethane
(anhydrous; Kanto Chemical Co., Inc) were used as received. All
other solvents were dried and distilled by standard procedures.
Yields refer to chromatographically and spectroscopically (1H
NMR) homogeneous materials unless otherwise stated. Reagents
were purchased at highest commercial quality and used without
further purification unless otherwise stated.
Reaction were monitored by thin-layer chromatography (TLC)
carried out on 0.25 mm Merck silica gel plates (60F-254)
using UV light as visualizing agent and p-anisaldehyde in
ethanol/aqueous H2SO4/CH3CO2H for staining. Column chro-
matography was performed using silica gel 60 particle size
0.063–0.210 mm. The eluents employed are reported as volume/
volume.
Proton nuclear magnetic resonance (1H NMR) spectra were
recorded using JEOL JMN-AL400 (400 MHz), and JEOL JNM-
ECP-500 (500 MHz) spectrometers. Chemical shift (d) is reported
in parts per million (ppm) downfield relative to tetramethylsilane
(TMS). Coupling constants (J) are reported in Hz. Multiplicities
are reported using the following abbreviations: s, singlet; d,
doublet; t, triplet; q, quartet; br, broad. Carbon-13 nuclear
magnetic resonance (13C NMR) spectra were recorded using JEOL
JMN-AL400 (100 MHz) and JEOL JNM-ECP-500 (125 MHz)
spectrometers. Chemical shift is reported in ppm relative to the
center of CDCl3 or CD3OD.
Melting point were determined using Yazawa BY-2 melting
point apparatus and are reported uncorrected. Infrared spectra
were obtained on a JASCO FT/IR-410 Fourier Transform In-
frared Spectrophotometer at 4.0 cm-1 resolution and are reported
in wavenumbers. Low and high resolution mass spectra were
recorded on a JEOL JMS-DX303 or a JMS-700 using electron
impact (EI). FAB mass spectra were recorded on a JEOL-JMS700
spectrometer using 3-nitrobenzyl alcohol as a matrix. Optical
rotations were measured on a JASCO DIP-370 Digital Polarimeter
using the sodium D line.
[(M-H)+], 91 (100%); HRMS (FAB) m/z calcd for C36H33O5Si
[(M-H)+]: 453.6229, found: 453.2029.
(R)-1-Benzyloxy-4-(4-hydroxymethyl-2,6-dimethoxyphenyl)-
but-3-yn-2-ol. To a solution of 9 (200 mg, 0.44 mmol) in MeOH
(2.2 mL) was added NaBH4 (10 mg, 0.26 mmol) at 0 ◦C and the
mixture was stirred for 1 h. The reaction mixture was quenched
with 1% aqueous HCl (2.2 mL) and MeOH was evaporated
under reduced pressure. The residue was extracted AcOEt and
the combined organic layers were washed with brine, dried over
MgSO4 and concentrated under reduced pressure. The residue
was dissolved in THF (2.2 mL) and then, acetic acid (0.05 mL,
0.88 mol) and TBAF (1M in THF, 0.88 mL, 0.88 mmol) were
added at 0 ◦C. The reaction mixture was stirred for 30 h at room
temperature and extracted with AcOEt. The combined organic
layers were washed with brine, dried over MgSO4 and concentrated
under reduced pressure. The residue was purified by silica gel
column chromatography (AcOEt/Hexane = 4/1) to give the diol
33
(146 mg, 96% yield) as a yellow oil; [a]D +5.7 (c 0.96, CHCl3);
FT-IR (neat) n 3376, 1574, 1459, 1416, 1126 cm-1; 1H-NMR
(400 MHz, CDCl3) d 7.39–7.26 (5H, m), 6.48 (2H, s), 4.87 (1H,
dd, J = 7.0, 3.9 Hz), 4.70 (1H, d, J = 12.1 Hz), 4.65 (1H, d,
J = 12.1 Hz), 4.64 (2H, s), 3.80 (6H, s), 3.79 (1H, ddd, J = 10.0,
3.9, 1.0 Hz), 3.72 (1H, ddd, J = 10.0, 7.0, 0.9 Hz), 3.01 (1H, brs),
2.30 (1H, brs); 13C-NMR (100 MHz, CDCl3) d 161.5, 143.6, 137.9,
128.4, 127.7, 127.6, 101.7, 995, 95.3, 76.7, 73.8, 73.4, 65.2, 62.6,
55.9; MS (EI) m/z 342 (M+), 221 (100%); HRMS (EI) m/z calcd
for C20H22O5 (M+): 342.1467, found: 342.1477.
(R)-1-Benzyloxy-4-(4-tert-butyldiphenylsilyloxymethyl-2,6-
dimethoxyphenyl) but-3-yn-2-ol 10. To a solution of the diol
(108 mg, 0.31 mmol) in CH2Cl2 (1.6 mL) was added TBDPSCl
(0.081 mL, 0.31 mmol), followed by Et3N (0.087 mL, 0.63 mmol)
and DMAP (7 mg, 0.063 mmol) at 0 ◦C. The mixture was stirred for
1 h and extracted with Et2O. The combined organic layers were
washed with brine, dried over MgSO4 and concentrated under
reduced pressure. The residue was purified by silica gel column
chromatography (AcOEt/Hexane = 1/2) to give 10 (140 mg, 77%
yield) as a colorless amorphous solid; [a]D29 +4.9 (c 1.02, CHCl3);
FT-IR (neat) n 3452, 1574, 1461, 1416, 1230, 1128 cm-1; 1H-NMR
(400 MHz, CDCl3) d 7.68–7.66 (4H, m), 7.45–7.27 (11H, m), 6.50
(2H, s), 4.89 (1H, dd, J = 7.3, 3.7 Hz), 4.87 (2H, s), 4.72 (1H, d,
J = 12.1 Hz), 4.66 (1H, d, J = 12.1 Hz), 3.82 (1H, dd, J = 9.9,
3.7 Hz), 3.79 (6H, s), 3.74 (1H, dd, J = 9.9, 7.3 Hz), 2.66 (1H,
brs), 1.10 (9H, s); 13C-NMR (100 MHz, CDCl3) d 161.5, 143.5,
138.0, 135.5, 133.3, 129.8, 128.4, 127.8, 127.7, 127.6, 100.9, 98.9,
94.8, 76.7, 73.9, 73.4, 65.5, 62.7, 55.9, 26.8, 19.3; MS (EI) m/z 580
(M+), 523 (100%); HRMS (EI) m/z calcd for C36H40O5Si (M+):
580.2645, found: 580.2631.
Synthesis of (-)-cylindrocyclophane A
(R)-4-(4-Benzyloxy-3-tert-butyldimethylsilyloxybut-1-ynyl)-3,5-
dimethoxybenzaldehyde 9. The triflate 7a (500 mg, 1.6 mmol),
(PPh3)2PdCl2 (111 mg, 0.16 mmol), PPh3 (125 mg, 0.48 mmol),
Bu4NI (1.2 g, 3.2 mmol), K2CO3 (660 mg, 4.8 mmol) and CuI
(91 mg, 0.48 mmol) were charged in a 2-necked, round-bottomed
50 mL flask equipped with a rubber septum and a condenser. To
the flask was introduced a degassed solution of the propargyl
ether 8a (600 mg, 2.1 mmol) in tetrahydropyran (16 mL). The
mixture was heated at 70 ◦C for 18 h. After cooling to room
temperature, the mixture was filtered through a pad of Celite and
the Celite layer was washed with Et2O. The combined filtrate was
concentrated under reduced pressure. The residue was purified by
silica gel column chromatography (AcOEt/Hexane = 1/4) to give
(R,E)-1-Benzyloxy-4-(4-tert-butyldiphenylsilyloxymethyl-2,6-
dimethoxyphenyl) but-3-en-2-ol 6. To a solution of 10 (130 mg,
0.22 mmol) in THF (1.1 mL) was added LAH (10 mg, 0.27 mmol)
at 0 ◦C. After stirring for 3 h at room temperature, another
portion of LAH (10 mg, 0.27 mmol) was added at 0 ◦C. The
reaction mixture was stirred for 3 h at room temperature and
quenched by addition of H2O. The mixture was filtered through
a pad of Celite and the Celite layer was washed with AcOEt.
The combined filtrate was concentrated under reduced pressure,
and the residue was purified by silica gel column chromatography
30
9 (565 mg, 78% yield) as a red oil; [a]D -35.0 (c 1.13, CHCl3);
FT-IR (neat) n 1698, 1574, 1462, 1230, 1130 cm-1; 1H-NMR
(400 MHz, CDCl3) d 9.91 (1H, s), 7.39–7.25 (5H, m), 7.01 (2H, s),
4.91 (1H, dd, J = 7.0, 5.0 Hz), 4.70 (2H, s), 3.89 (6H, s), 3.75 (1H,
dd, J = 10.2, 5.0 Hz), 3.70 (1H, ddd, J = 10.2, 7.0, 2.8 Hz), 0.96
(9H, s), 0.22 (3H, s), 0.19 (3H, s); 13C-NMR (100 MHz, CDCl3) d
191.2, 138.4, 136.6, 128.2, 127.5, 127.4, 107.5, 104.3, 100.7, 76.7,
74.5, 73.4, 63.9, 56.1, 25.9, 18.4, -4.6, -4.9; MS (FAB) m/z 453
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(AcOEt/Hexane = 2/3) to give 6 (112 mg, 86% yield) as a colorless
oil. The chiral HPLC analysis showed the product to have >99%
ee.; [a]D -0.5 (c 1.11, CHCl3); FT-IR (neat) n 3450, 1607, 1577,
m/z 608 (M+), 551 (100%); HRMS (EI) m/z calcd for C38H44O5Si
(M+): 608.2958, found: 608.2973.
31
4{[(S,2E,6Z)-1-Benzyloxyocta-2,6-dien-4-yl]-3,5-dimethoxy-
benzyloxy}-tert-butyldiphenylsilane 11. To a solution of ethyl-
triphenylphosphonium iodide (303 mg, 0.73 mmol) in THF
(4.0 mL) was added KHMDS (0.7 M in toluene, 0.90 mL,
0.68 mmol) at -78 ◦C. After stirring for 20 min, a solution of
the aldehyde (138 mg, 0.23 mmol) in THF (1.5 mL) was added
dropwise via cannula. After stirring for 1 h at -78 ◦C, the reaction
mixture was brought to 0 ◦C and quenched with saturated aqueous
NH4Cl and diluted with Et2O. The organic layer was separated,
and the aqueous layer was extracted with Et2O. The combined
organic layers were washed with brine, dried over MgSO4 and
concentrated under reduced pressure. The residue was purified
by silica gel column chromatography (AcOEt/Hexane = 1/9) to
1455, 1420, 1111 cm-1; 1H-NMR (400 MHz, CDCl3) d 7.70–7.68
(4H, m), 7.45–7.26 (11H, m), 6.98 (1H, d, J = 16.2 Hz), 6.60 (1H,
dd, J = 16.2, 6.7 Hz), 6.54 (2H, s), 4.75 (2H, s), 4.61 (2H, s), 4.51
(1H, m), 3.79 (6H, s), 3.63 (1H, dd, J = 9.6, 3.3 Hz), 3.49 (1H, dd,
J = 9.6, 8.3 Hz), 2.47 (1H, brs), 1.10 (9H, s); 13C-NMR (100 MHz,
CDCl3) d 158.2, 141.5, 137.9, 135.3, 133.1, 130.8, 129.5, 128.1,
127.7, 127.5, 127.4, 122.1, 112.0, 101.2, 74.4, 73.1, 72.9, 65.6, 55.4,
26.7, 19.2; MS (EI) m/z 582 (M+), 461 (100%); HRMS (EI) m/z
calcd for C36H42O5Si (M+): 582.2802, found: 582.2755.
(S,E)-Ethyl 6-benzyloxy-3-(4-tert-butyldiphenylsilyloxy-methyl-
2,6-dimethoxyphenyl)hex-4-enoate 5. A mixture of 6 (130 mg,
0.22 mmol) and o-NO2PhOH (1.2 mg, 0.17 mmol) in triethyl
orthoacetate (1.2 mL) was heated for 2 h at 140 ◦C. The mixture
was cooled to room temperature and quenched with saturated
aqueous NaHCO3. The organic layer was separated, and aqueous
layer extracted with Et2O. The combined organic layers were
washed with brine, dried over MgSO4 and concentrated under
reduced pressure. The residue was purified by silica gel column
chromatography (AcOEt/Hexane = 1/4) to give 5 (86 mg, 72%
yield) as a yellowish oil. The chiral HPLC analysis showed the
25
give 11 (136 mg, 97% yield) as a colorless oil; [a]D +6.6 (c 0.96,
1
CHCl3); FT-IR (neat) n 1608, 1585, 1455, 1426, 1111 cm-1; H-
NMR (400 MHz, CDCl3) d 7.70–7.67 (4H, m), 7.43–7.24 (11H,
m), 6.52 (2H, s), 6.15 (1H, dd, J = 15.4, 8.0 Hz), 5.58 (1H, dt,
J = 15.4, 6.4 Hz), 5.39–5.33 (2H, m), 4.73 (2H, s), 4.49 (1H, d,
J = 11.7 Hz), 4.45 (1H, d, J = 11.7 Hz), 4.06 (1H, m), 3.97 (2H,
m), 3.74 (6H, s), 2.57 (2H, m), 1.55 (3H, d, J = 5.9), 1.10 (9H, s);
13C-NMR (100 MHz, CDCl3) d 158.0, 140.4, 138.5, 137.3, 135.5,
133.4, 129.6, 129.5, 128.2, 127.8, 127.6, 127.3, 125.4, 124.0, 118.4,
101.9, 71.3, 71.0, 65.5, 55.7, 38.3, 30.5, 26.9, 19.4, 13.0; MS (EI)
m/z 620 (M+), 565 (100%); HRMS (EI) m/z calcd for C40H48O4Si
(M+): 620.3322, found: 620.3311.
31
product to have >99% ee; [a]D +1.9 (c 0.99, CHCl3); FT-IR
(neat) n 1731, 1672, 1609, 1585, 1455, 1426, 1367, 1116 cm-1; 1H-
NMR (400 MHz, CDCl3) d 7.70–7.68 (4H, m), 7.42–7.19 (11H,
m), 6.53 (2H, s), 6.08 (1H, dd, J = 15.4, 7.7 Hz), 5.63 (1H, dt,
J = 15.4, 6.4 Hz), 4.74 (2H, s), 4.59 (1H, m), 4.44 (2H, s), 4.04
(2H, q, J = 7.1 Hz), 3.96 (2H, d, J = 6.4 Hz), 3.75 (6H, s), 2.97
(1H, dd, J = 15.0, 8.7 Hz), 2.78 (1H, dd, J = 15.0, 6.8 Hz), 1.15
(3H, t, J = 7.1 Hz), 1.11 (9H, s); 13C-NMR (100 MHz, CDCl3) d
172.6, 157.9, 141.0, 138.4, 135.4, 135.2, 129.6, 128.1, 127.6, 127.5,
127.3, 126.1, 116.9, 101.8, 71.3, 70.7, 65.5, 59.9, 55.6, 38.2, 34.6,
26.8, 19.3, 14.2; MS (EI) m/z 652 (M+), 595 (100%); HRMS (EI)
m/z calcd for C40H48O6Si (M+): 652.3220, found: 652.3200.
(S )-4-(4-tert -Butyldiphenylsilyloxymethyl-2, 6-dimethoxy-
phenyl)octan-1-ol 12. A solution of 11 (297 mg, 0.48 mmol) in
THP (4.8 mL) was hydrogenated in the presence of Pd/C (30 mg)
under atmospheric pressure of H2 for 3 h. To the reaction mixture
was added Pd(OH)2 (45 mg) thrice at 3 h intervals. After stirring for
1 d, the reaction mixture was filtered through a pad of Celite and
the Celite layer was washed with Et2O. The combined filtrate was
concentrated under reduced pressure. The residue was purified by
silica gel column chromatography (AcOEt/Hexane = 1/4) to give
(S,E)-6-Benzyloxy-3-(4-tert-butyldiphenylsilyloxymethyl-2,6-
dimethoxyphenyl) hex-4-enal. To a solution of 5 (172 mg,
0.26 mmol) in toluene (3.6 mL) was added DIBAL (1.01 M in
toluene, 0.21 mL, 0.32 mmol) at -78 ◦C, and stirred for 20 min at
the same temperature. The mixture was quenched by addition of
0.5 N aqueous HCl and allowed to warm up to room temperature.
The mixture was diluted with AcOEt and H2O. The organic
layer was separated, and the aqueous layer was extracted with
AcOEt. The combined organic layers were washed with brine,
dried over MgSO4 and concentrated under reduced pressure.
The residue was purified by silica gel column chromatography
(AcOEt/Hexane = 1/4) to give the aldehyde (138 mg, 86% yield)
as a yellowish oil; [a]D25 +0.6 (c 1.00, CHCl3); FT-IR (neat) n 1724,
1585, 1455, 1426, 1112 cm-1; 1H-NMR (400 MHz, CDCl3) d 9.63
(1H, t, J = 2.4 Hz), 7.69–7.67 (4H, m), 7.43–7.24 (11H, m), 6.53
(2H, s), 6.08 (1H, dd, J = 15.4, 7.6 Hz), 5.64 (1H, dt, J = 15.4,
6.2 Hz), 4.73 (2H, s), 4.64 (1H, m), 4.47 (1H, d, J = 11.8 Hz),
4.43 (1H, d, J = 11.8 Hz), 3.97 (2H, d, J = 6.2 Hz), 3.75 (6H, s),
2.92 (1H, ddd, J = 16.3, 7.3, 2.4 Hz), 2.86 (1H, ddd, J = 16.3, 7.6,
2.4 Hz), 1.11 (9H, s); 13C-NMR (100 MHz, CDCl3) d 203.1, 157.8,
141.4, 138.3, 135.4, 135.0, 133.3, 129.6, 128.2, 127.7, 127.6, 127.4,
126.3, 116.2, 101.8, 71.7, 65.5, 55.6, 47.0, 32.6, 26.9, 19.4; MS (EI)
26
12 (243 mg, 95% yield) as a colorless oil; [a]D -0.5 (c 1.16, CHCl3);
FT-IR (neat) n 3357, 1608, 1584, 1461, 1425, 1370, 1112 cm-1; 1H-
NMR (400 MHz, CDCl3) d 7.70–7.68 (4H, m), 7.43–7.35 (6H, m),
6.51 (2H, s), 4.74 (2H, s), 3.72 (6H, s), 3.57 (2H, t, J = 6.6 Hz),
3.28 (1H, m), 1.89–1.78 (2H, m), 1.66–1.55 (2H, m), 1.47–1.32
(2H, m), 1.27–1.05 (5H, m), 1.11 (9H, s), 0.83 (3H, t, J = 7.1 Hz);
13C-NMR (100 MHz, CDCl3) d 139.9, 135.5, 133.5, 129.6, 127.6,
119.4, 65.8, 65.6, 63.5, 34.8, 33.5, 31.6, 30.5, 29.7, 26.9, 22.9, 19.4,
15.3, 14.3, 14.2; MS (EI) m/z 534 (M+), 379 (100%); HRMS (EI)
m/z calcd for C33H46O4Si (M+): 534.3165, found: 534.3167.
(S)-tert-Butyl[3,5-dimethoxy-4-(oct-1-en-4-yl)benzyloxy]-
diphenylsilane. To a solution of 12 (120 mg, 0.22 mmol) in
THF (1.2 mL) was added o-NO2PhSeCN (153 mg, 0.67 mmol)
and PBu3 (0.17 mL, 0.67 mmol). After stirring for 3 h, to the
mixture was added 30% aqueous H2O2 (0.17 mL, 1.5 mmol)
over 10 min at 0 ◦C. The reaction mixture was stirred for 8 h
and diluted with Et2O. The organic layer was separated, and the
aqueous layer was extracted with Et2O. The combined organic
layers were washed with brine, dried over MgSO4 and concentrated
under reduced pressure. The residue was purified by silica gel
column chromatography (AcOEt/Hexane = 1/9) to give the
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26
alkene (109 mg, 94% yield) as a colorless oil; [a]D +0.8 (c 0.96,
phosphate buffer (1.8 mL) and MeOH (1.0 mL) at 0 ◦C, and then
a mixture of MeOH (0.75 mL) and 30% aqueous H2O2 (1.0 mL)
at 0 ◦C. The resultant mixture was stirred for 1 h and the volatile
material was evaporated under reduced pressure. The residue was
extracted with Et2O and the combined organic layers were washed
with brine, dried over MgSO4 and concentrated under reduced
pressure. The crude mixture was purified by silica gel column
chromatography (AcOEt/Hexane = 1/4) to give 15 (106 mg,
CHCl3); FT-IR (neat) n 1609, 1584, 1461, 1426, 1369, 1213,
1112 cm-1; H-NMR (400 MHz, CDCl3) d 7.70–7.68 (4H, m),
1
7.43–7.33 (6H, m), 6.51 (2H, s), 5.70 (1H, m), 4.92 (1H, dd,
J = 17.1, 2.4 Hz), 4.82 (1H, dt, J = 10.2, 1.2 Hz), 4.75 (2H,
s), 3.72 (6H, s), 3.36 (1H, m), 2.53 (1H, m), 2.43 (1H, m), 1.80
(1H, m), 1.60 (1H, m), 1.30–1.04 (4H, m), 1.11 (9H, s), 0.83 (3H, t,
J = 7.2 Hz); 13C-NMR (100 MHz, CDCl3) d 139.9, 139.0, 135.5,
133.5, 129.6, 127.7, 127.6, 119.5, 114.1, 102.0, 65.9, 65.7, 38.3,
35.1, 32.9, 30.5, 26.9, 22.9, 19.4, 14.2; MS (EI) m/z 516 (M+), 475
(100%); HRMS (EI) m/z calcd for C33H44O3Si (M+): 516.3060,
found: 516.3047.
◦
24
97% yield) as a colorless solid; mp 53–54 C; [a]D -6.2 (c 0.93,
CHCl3); FT-IR (neat) n 3498, 1780, 1696, 1638, 1582, 1455, 1367,
1195 cm-1; 1H-NMR (400 MHz, CDCl3) d 7.40–7.22 (5H, m), 6.58
(2H, s), 5.64 (1H, m), 5.32 (1H, d, J = 7.1 Hz), 4.91–4.85 (2H,
m), 4.73 (1H, dd, J = 11.2, 1.0 Hz), 4.55 (1H, m), 4.21 (1H, m),
3.78 (6H, s), 3.36 (1H, m), 3.20 (1H, brs), 2.50 (1H, m), 2.41 (1H,
m), 1.75 (1H, m), 1.60 (1H, m), 1.28 (3H, d, J = 6.8 Hz), 1.26–
0.94 (4H, m), 0.85 (3H, d, J = 6.6 Hz), 0.77 (3H, t, J = 6.8 Hz);
13C-NMR (100 MHz, CDCl3) d 175.7, 152.4, 140.3, 138.6, 132.8,
128.6, 128.5, 125.3, 120.4, 114.1, 102.2, 78.8, 75.1, 60.3, 55.0, 44.8,
37.9, 35.0, 32.8, 30.3, 22.7, 14.3, 14.1, 14.0, 11.7; MS (EI) m/z 509
(M+), 468 (100%); HRMS (EI) m/z calcd for C30H39NO6 (M+):
509.2777, found: 509.2811.
(S)-3,5-Dimethoxy-4-(oct-1-en-4-yl)methanol. To a solution
of the silane (109 mg, 0.21 mmol) in THF (1.1 mL) was added
TBAF (1.0 M in THF, 0.32 mL, 0.32 mmol) at room temperature.
After stirring for 3 h, H2O and AcOEt were added to the
mixture. The organic layer was separated, and the aqueous layer
was extracted with AcOEt. The combined organic layers were
washed with brine, dried over MgSO4 and concentrated under
reduced pressure. The residue was purified by silica gel column
chromatography (AcOEt/Hexane = 3/7) to give the alcohol
◦
24
(2R,3R)-3-{3,5-Dimethoxy-4-[(S)-oct-1-en-4-yl]phenyl}-3-
hydroxy-N-methoxy-N,2-dimethylpropionamide. To a suspen-
sion of HN(OMe)Me·HCl (41 mg, 0.42 mmol) in THF (0.47 mL)
was added Me3Al (1.03 M in hexane, 0.42 mL, 0.42 mmol) at
0 ◦C, and the mixture was stirred for 30 min. To this mixture was
added 15 (72 mg, 0.14 mmol) in THF (0.47 mL) via cannula at
(58 mg, 99% yield) as a colorless solid; mp 39–41 C; [a]D -0.5
(c 0.98, CHCl3); FT-IR (neat) n 3323, 1583, 1455, 1421, 1213,
1135 cm-1; 1H-NMR (400 MHz, CDCl3) d 6.52 (2H, s), 5.67 (1H,
m), 4.90 (1H, d, J = 17.1 Hz), 4.80 (1H, d, J = 10.1 Hz), 4.61
(2H, s), 3.77 (6H, s), 3.37 (1H, m), 2.53 (1H, m), 2.41 (1H, m),
1.89 (1H, brs), 1.80 (1H, m), 1.59 (1H, m), 1.29–1.01 (4H, m), 0.81
(3H, t, J = 7.2 Hz); 13C-NMR (100 MHz, CDCl3) d 139.6, 138.8,
120.4, 114.2, 102.9, 65.6, 55.7, 55.6, 38.1, 35.0, 32.8, 30.4, 22.9,
14.1; MS (EI) m/z 278 (M+), 181 (100%); HRMS (EI) m/z calcd
for C17H26O3 (M+): 278.1882, found: 278.1878.
◦
◦
-15 C. The mixture was stirred for 15 min at -15 C and then
◦
warmed to 0 C. After stirring for 3 h at room temperature, the
mixture was added dropwise via cannula into a stirred mixture of
CH2Cl2 and 0.5 N aqueous HCl at 0 ◦C. The resulting two-phase
mixture was stirred for 1 h at 0 ◦C. The organic layer was separated,
and the aqueous layer was extracted with CH2Cl2. The combined
organic layers were washed with brine, dried over MgSO4 and
concentrated under reduced pressure. The residue was purified by
silica gel column chromatography (AcOEt/Hexane = 3/7) to give
(S)-3,5-Dimethoxy-4-(oct-1-en-4-yl)benzaldehyde 13. A mix-
ture of the alcohol (58 mg, 0.21 mmol) and MnO2 (180 mg,
2.1 mmol) in CH2Cl2 (4.2 mL) was stirred for 2 h at room
temperature. The mixture was diluted with Et2O, and filtered
through a pad of Celite and the Celite layer was washed with
Et2O. The combined filtrate was concentrated under reduced pres-
sure. The residue was purified by silica gel column chromatography
(AcOEt/Hexane = 3/7) to give 13 (55 mg, 97% yield) as a colorless
◦
the amide (51 mg, 91% yield) as a colorless solid; mp 77–80 C;
25
[a]D -7.1 (c 0.84, CHCl3); FT-IR (neat) n 3421, 1638, 1582, 1456,
1421, 1134, 1114 cm-1; 1H-NMR (400 MHz, CDCl3) d 6.54 (2H,
s), 5.65 (1H, m), 4.98 (1H, d, J = 3.6 Hz), 4.89 (1H, ddd, J = 17.1,
2.4, 1.2 Hz), 4.78 (1H, dt, J = 10.0, 1.2 Hz), 4.04 (1H, s), 3.77 (6H,
s), 3.61 (3H, s), 3.35 (1H, m), 3.17 (3H, s), 3.14 (1H, brs), 2.53
(1H, m), 2.44 (1H, m), 1.79 (1H, m), 1.59 (1H, m), 1.29–1.00 (4H,
m), 1.14 (3H, d, J = 7.1 Hz), 0.81 (3H, t, J = 7.2 Hz); 13C-NMR
(100 MHz, CDCl3) d 177.5, 140.6, 138.9, 120.0, 114.1, 102.3, 77.2,
73.8, 61.5, 55.8, 41.5, 38.2, 35.0, 32.8, 31.9, 30.4, 22.8, 14.2, 11.0;
MS (EI) m/z 393 (M+), 352 (100%); HRMS (EI) m/z calcd for
C22H35NO5 (M+): 393.2515, found: 393.2522.
24
oil; [a]D -5.3 (c 0.93, CHCl3); FT-IR (neat) n 1695, 1582, 1455,
1421, 1381, 1308, 1213, 1145 cm-1; 1H-NMR (400 MHz, CDCl3) d
9.88 (1H, s), 7.04 (2H, s), 5.65 (1H, m), 4.89 (1H, d, J = 17.1 Hz),
4.80 (1H, d, J = 10.1 Hz), 3.85 (6H, s), 3.49 (1H, m), 2.57 (1H,
m), 2.43 (1H, m), 1.85 (1H, m), 1.63 (1H, m), 1.29–0.99 (4H, m),
0.81 (3H, t, J = 7.2 Hz); 13C-NMR (100 MHz, CDCl3) d 191.5,
138.1, 135.2, 128.7, 114.6, 105.1, 55.7, 55.5, 37.7, 35.6, 32.4, 30.3,
22.7, 14.0; MS (EI) m/z 276 (M+), 179 (100%); HRMS (EI) m/z
calcd for C17H24O3 (M+): 276.1725, found: 276.1745.
(2R,3R)-3-{3,5-Dimethoxy-4-[(S)-oct-1-en-4-yl]phenyl}-N-
methoxy-N,2-dimethyl-3-triethylsilyloxypropionamide. To a sus-
pension of the amide (62 mg, 0.16 mmol) in CH2Cl2 (3.2 mL)
was added 2,6-lutidine (0.12 mL, 1.00 mmol), followed TESOTf
(0.090 mL, 0.39 mmol) at 0 ◦C After stirring for 1.5 h, the mixture
was quenched with saturated aqueous NaHCO3 and extracted
with CH2Cl2. The combined organic layers were washed with
brine, dried over MgSO4 and concentrated under reduced pressure.
The residue was purified by silica gel column chromatography
(AcOEt/Hexane = 1/4) to give the silane (79 mg, 99% yield) as
(4R,5S)-3-{(2R,3R)-3-[3,5-Dimethoxy-4-((S)-oct-1-en-4-yl)-
phenyl]-3-hydroxy-2-methylpropionyl}-4-methyl-5-phenyl-oxazo-
lidin-2-one 15. To a solution of 14 (59 mg, 0.22 mmol) in CH2Cl2
(1.5 mL) at 0 ◦C was added Et3N (0.09 mL, 0.65 mmol) and
dibutylboron triflate (1.1 M in toluene, 0.51 mL, 0.56 mmol). After
stirring for 1 h at 0 ◦C, the mixture was cooled to -78 ◦C. Then,
a solution of 13 (59 mg, 0.22 mmol) in CH2Cl2 (0.70 mL) was
added and the mixture was stirred for 1 h at -78 ◦C and for
◦
2.5 h at 0 C. The mixture was quenched by addition of pH 7.0
3778 | Org. Biomol. Chem., 2009, 7, 3772–3781
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a colorless oil; [a]D -2.3 (c 1.06, CHCl3); FT-IR (neat) n 1657,
(100%); HRMS (EI) m/z calcd for C30H50O5Si (M+): 518.3428,
26
1607, 1583, 1456, 1421, 1098 cm-1; 1H-NMR (400 MHz, CDCl3)
d 6.53 (2H, s), 5.60 (1H, m), 4.83 (1H, dd, J = 17.1, 2.4 Hz), 4.74
-4.69 (2H, m), 3.73 (6H, s), 3.34 (1H, m), 3.20 (1H, brs), 3.16 (3H,
s), 2.95 (3H, s), 2.51 (1H, m), 2.36 (1H, m), 1.80 (1H, m), 1.55
(1H, m), 1.31–0.92 (4H, m), 1.30 (3H, d, J = 6.6 Hz), 0.88 (9H, t,
J = 7.8 Hz), 0.78 (3H, t, J = 7.3 Hz), 0.54 (6H, q, J = 7.8 Hz);
13C-NMR (100 MHz, CDCl3) d 175.3, 142.8, 138.8, 119.7, 113.9,
102.9, 76.8, 61.0, 55.8, 45.0, 38.2, 34.9, 32.7, 31.5, 30.3, 22.8, 15.2,
14.2, 6.8, 4.8; MS (EI) m/z 507 (M+), 466 (100%); HRMS (EI)
m/z calcd for C28H49NO5Si (M+): 507.3380, found: 507.3396.
found: 518.3409.
(4S,5R)-Methyl 5-{3,5-dimethoxy-4-[(S)-oct-1-en-4-yl]phenyl}-
4-methyl-5-triethylsilyloxypentanoate. A mixture of the enoate
(42 mg, 0.080 mmol) and magnesium turnings (20 mg, 0.8 mmol)
in MeOH (0.40 mL) was stirred at 0 ◦C for 10 h. The mixture was
diluted with hexane and Et2O, and filtered through a pad of Celite.
The filtrate was washed consecutively with 0.5 N aqueous HCl,
saturated aqueous NaHCO3, and brine, and dried over MgSO4
and concentrated under reduced pressure. The residue was purified
by silica gel column chromatography (AcOEt/Hexane = 1/99) to
26
(2R,3R)-3-{3,5-Dimethoxy-4-[(S)-oct-1-en-4-yl]phenyl}-2-
methyl-3-triethylsilyloxypropanal 16. To a stirred solution of the
amide (79 mg, 0.16 mmol) in THF (0.79 mL) was added slowly
DIBAL (1.01 M in toluene, 0.31 mL, 0.32 mmol) at -78 ◦C. After
stirring for 3 h at the same temperature, the mixture was quenched
with 0.5 N aqueous HCl and then warmed to room temperature
and diluted with Et2O. The organic layer was separated and the
aqueous layer was extracted with Et2O. The combined organic
layers were washed with brine, dried over MgSO4 and concentrated
under reduced pressure. The residue was purified by silica gel
column chromatography (AcOEt/Hexane = 1/9) to give 16
give the ester (41 mg, 98% yield) as a colorless oil; [a]D +25.0
(c 1.26, CHCl3); FT-IR (neat) n 1741, 1639, 1607, 1583, 1455,
1420, 1135 cm-1; 1H-NMR (400 MHz, CDCl3) d 6.43 (2H, s), 5.67
(1H, m), 4.88 (1H, d, J = 17.0 Hz), 4.78 (1H, d, J = 10.0 Hz), 4.35
(1H, d, J = 5.6 Hz), 3.58 (6H, s), 3.64 (3H, s), 3.33 (1H, m), 2.52
(1H, m), 2.38 (1H, m), 2.32 (1H, m), 2.23 (1H, m), 1.80 (1H, m),
1.78–1.56 (3H, m), 1.40 (1H, m), 1.38–1.02 (4H, m), 0.93 (3H, d,
J = 6.6 Hz), 0.88 (9H, t, J = 7.9 Hz), 0.82 (3H, t, J = 7.2 Hz), 0.51
(6H, m); 13C-NMR (100 MHz, CDCl3) d 174.2, 142.9, 138.9, 119.7,
114.0, 103.1, 79.2, 51.5, 41.0, 38.3, 35.1, 32.7, 32.3, 30.4, 28.6, 22.9,
14.8, 14.2, 6.9, 4.9; MS (EI) m/z 506 (M+), 391 (100%); HRMS
(EI) m/z calcd for C29H50O5Si (M+): 506.3428, found: 506.3413.
26
(67 mg, 96% yield) as a colorless oil; [a]D +32.0 (c 0.93,
CHCl3); FT-IR (neat) n 1726, 1639, 1606, 1584, 1455, 1419, 1213,
1100 cm-1; 1H-NMR (400 MHz, CDCl3) d 9.72 (1H, d, J = 1.2 Hz),
6.46 (2H, s), 5.66 (1H, m), 5.03 (1H, d, J = 4.9 Hz), 4.88 (1H, ddd,
J = 17.0, 2.4, 1.2 Hz), 4.79 (1H, ddd, J = 10.0, 2.3, 1.2 Hz),
3.76 (6H, s), 3.36 (1H, m), 2.63 (1H, m), 2.51 (1H, m), 2.41 (1H,
m), 1.81 (1H, m), 1.60 (1H, m), 1.29–1.02 (4H, m), 1.09 (3H, d,
J = 6.8 Hz), 0.86 (9H, t, J = 7.8 Hz), 0.81 (3H, t, J = 7.2 Hz), 0.53
(6H, q, J = 7.8 Hz); 13C-NMR (100 MHz, CDCl3) d 204.5, 141.2,
138.8, 120.2, 114.1, 102.4, 74.6, 54.7, 38.2, 35.1, 32.7, 30.4, 30.3,
22.8, 14.2, 8.6, 6.8, 6.7, 4.8; MS (EI) m/z 448 (M+), 407 (100%);
HRMS (EI) m/z calcd for C26H44O4Si (M+): 448.3009, found:
448.3033.
(1R,2S)-5-{3,5-Dimethoxy-4-[(S)-oct-1-en-4-yl]phenyl}-4-
methyl-5-triethylsilyloxypentan-1-ol. To a solution of the ester
(243 mg, 0.48 mmol) in THF (3.2 mL) was added LAH (22 mg,
0.58 mmol) at 0 ◦C. After stirring for 1.5 h at 0 ◦C, the
mixture was quenched with 28% aqueous NH3 and extracted
with Et2O. The combined organic layers were washed with brine,
dried over MgSO4 and concentrated under reduced pressure.
The residue was purified by silica gel column chromatography
(AcOEt/Hexane = 1/4) to give the alcohol (208 mg, 91% yield)
27
as a colorless oil; [a]D +27.9 (c 1.00, CHCl3); FT-IR (neat) n
1
3335, 1639, 1607, 1583, 1455, 1419, 1135, 1099 cm-1; H-NMR
(400 MHz, CDCl3) d 6.43 (2H, s), 5.66 (1H, m), 4.88 (1H, d,
J = 17.0 Hz), 4.78 (1H, d, J = 10.0 Hz), 4.32 (1H, d, J = 5.9 Hz),
3.75 (6H, s), 3.56 (2H, m), 3.33 (1H, m), 2.52 (1H, m), 2.40 (1H,
m), 1.88–1.55 (4H, m), 1.48–1.01 (8H, m), 0.94 (3H, d, J = 6.6 Hz),
0.86 (9H, t, J = 7.9 Hz), 0.80 (3H, t, J = 7.2 Hz), 0.49 (6H, q,
J = 7.9 Hz); 13C-NMR (100 MHz, CDCl3) d 143.2, 138.9, 119.6,
114.0, 103.1, 79.5, 63.2, 41.2, 38.3, 35.1, 32.7, 30.6, 30.4, 29.2,
22.8, 15.2, 14.2, 6.9, 4.9; MS (EI) m/z 478 (M+), 391 (100%);
HRMS (EI) m/z calcd for C28H50O4Si (M+): 478.3478, found:
478.3480.
(4S,5R,E)-Ethyl 5-{3,5-dimethoxy-4-[(S)-oct-1-en-4-yl]phenyl}-
4-methyl-5-triethylsilyloxypent-2-enoate. To a solution of tri-
ethyl phosphonoacetate (0.12 mL, 0.56 mmol) in THF (1.0 mL)
was added NaH (60% in mineral oil, 21 mg, 0.52 mmol) at
0
◦C. After stirring for 10 min, a solution of the aldehyde
(167 mg, 0.37 mmol) in THF (0.90 mL) was added dropwise
via cannula. After stirring for 30 min, H2O was added to the
mixture and extracted with Et2O. The combined organic layers
were washed with brine, dried over MgSO4 and concentrated
under reduced pressure. The residue was purified by silica gel
column chromatography (AcOEt/Hexane = 1/99) to give the
{(1R,2S)-1-[3,5-Dimethoxy-4-((S)-oct-1-en-4-yl)phenyl]-2-
methylpent-4-enyloxy}triethylsilane 4. To a solution of the al-
cohol (49 mg, 0.10 mmol) in THF (0.52 mL) was added
o-NO2PhSeCN (47 mg, 0.21 mmol) and PBu3 (0.050 mL,
0.21 mmol) at 0 ◦C. After stirring for 3 h, the mixture was
added 30% aqueous H2O2 (0.080 mL, 0.67 mmol) over 10 min
at 0 ◦C. The mixture was stirred for 8 h and diluted with Et2O. The
organic layer was separated, and the aqueous layer was extracted
with Et2O. The combined organic layers were washed with brine,
dried over MgSO4 and concentrated under reduced pressure.
The residue was purified by silica gel column chromatography
(AcOEt/Hexane = 1/24) to give 4 (44 mg, 93% yield) as a colorless
oil; [a]D30 +31.9 (c 1.00, CHCl3); FT-IR (neat) n 1639, 1606, 1583,
25
enoate (181 mg, 94% yield) as a colorless oil; [a]D +3.6 (c
1
1.33, CHCl3); FT-IR (neat) n 1722, 1653, 1606 cm-1; H-NMR
(400 MHz, CDCl3) d 6.93 (1H, dd, J = 15.6, 7.7 Hz), 6.40 (2H, s),
5.69 (1H, d, J = 15.6 Hz), 5.65 (1H, m), 4.86 (1H, dd, J = 17.1,
1.7 Hz), 4.77 (1H, d, J = 10.3 Hz), 4.49 (1H, d, J = 5.6 Hz), 4.15
(2H, qd, J = 7.1, 1.5 Hz), 3.74 (6H, s), 3.33 (1H, m), 2.59 (1H,
m), 2.51 (1H, m), 2.38 (1H, m), 1.80 (1H, m), 1.59 (1H, m), 1.26
(3H, t, J = 7.1 Hz), 1.05 (3H, d, J = 6.6 Hz), 1.31–0.96 (4H, m),
0.87 (9H, t, J = 7.9 Hz), 0.80 (3H, t, J = 7.2 Hz), 0.52 (6H, m);
13C-NMR (100 MHz, CDCl3) d 166.5, 151.4, 141.8, 138.9, 120.8,
120.0, 114.0, 102.9, 78.2, 60.1, 45.1, 38.2, 35.1, 32.7, 30.4, 22.8,
14.4, 14.3, 14.2, 6.9, 6.8, 4.9, 4.8; MS (EI) m/z 518 (M+), 391
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1455, 1419, 1134 cm-1; 1H-NMR (400 MHz, CDCl3) d 6.23 (2H,
s), 5.81–5.60 (2H, m), 4.96 (2H, m), 4.87 (1H, d, J = 17.1 Hz), 4.78
(1H, d, J = 10.3 Hz), 4.35 (1H, d, J = 5.4), 3.75 (6H, s), 3.33 (1H,
m), 2.54 (1H, m), 2.40 (1H, m), 2.12 (1H, m), 1.88–1.71 (3H, m),
1.60 (1H, m), 1.31–0.95 (4H, m), 0.91 (3H, d, J = 6.1 Hz), 0.86 (9H,
t, J = 8.0 Hz), 0.80 (3H, t, J = 7.2 Hz), 0.50 (6H, q, J = 8.0 Hz);
13C-NMR (100 MHz, CDCl3) d 143.2, 139.0, 137.7, 119.6, 115.5,
114.0, 103.2, 79.1, 41.4, 38.3, 37.9, 35.1, 32.8, 30.4, 22.9, 14.8,
14.2, 6.9, 5.0; MS (EI) m/z 460 (M+), 419 (100%); HRMS (EI)
m/z calcd for C28H48O3Si (M+): 460.3373, found: 460.3364.
(MEXT) of Japan. We greatly acknowledge useful discussions and
kind assistance of Profs Yoshiteru Oshima, Shoichiro Kurata and
Masanobu Satake and Drs Natsuko Chiba and Kazunori Ueda
(Tohoku University). We also thank Mr. Hiroshi Yasuda, R & D
Center of Showa Denko, K.K. for generous gift of THP.
Notes and references
1 (a) D. J. Cram and H. Steinberg, J. Am. Chem. Soc., 1951, 73, 5691;
(b) C. J. Brown and A. C. Farthing, Nature, 1949, 164, 915.
2 (a) F. Vo¨gtle and R. Hoss, J. Chem. Soc., Chem. Commun., 1992, 1584;
(b) B. R. Peterson, P. Willimann, D. R. Carcanague and F. Diederich,
Tetrahedron, 1995, 51, 401.
3 (a) B. S. Moore, J.-L. Chen, G. M. L. Patterson and R. E. Moore, J. Am.
Chem. Soc., 1990, 112, 4061; (b) B. S. Moore, J.-L. Chen, G. M. L.
Patterson and R. E. Moore, Tetrahedron, 1992, 48, 3001.
4 J. L. Chen, R. E. Moore and G. M. L. Patterson, J. Org. Chem., 1991,
56, 4360.
5 S. C. Bobzin and R. E. Moore, Tetrahedron, 1993, 49, 7615.
6 (a) A. B. Smith, III, S. A. Kozmin and D. V. Paone, J. Am. Chem. Soc.,
1999, 121, 7423; (b) A. B. Smith, III, S. A. Kozmin, C. M. Adams and
D. V. Paone, J. Am. Chem. Soc., 2000, 122, 4984; (c) A. B. Smith, III,
C. M. Adams and S. A. Kozmin, J. Am. Chem. Soc., 2001, 123, 990;
(d) A. B. Smith, III, C. M. Adams, S. A. Kozmin and D. V. Paone,
J. Am. Chem. Soc., 2001, 123, 5925; (e) T. R. Hoye, P. E. Humpal and
B. Moon, J. Am. Chem. Soc., 2000, 122, 4982.
7 (a) M. Arisawa, K. Ohmura, A. Kobayashi and N. Morita, Chem.
Pharm. Bull., 1989, 37, 2431; (b) T.-H. Chuang and P.-L. Wu, J. Nat.
Prod., 2007, 70, 319; (c) A. Pohanka, J. Levenfors and A. Broberg,
J. Nat. Prod., 2006, 69, 654; (d) W. Jin and J. K. Zjawiony, J. Nat.
Prod., 2006, 69, 704; (e) V. S. P. Chaturvedula, J. K. Schilling, J. S.
Miller, R. Andriantsiferana, V. E. Rasamison and D. G. I. Kingston,
J. Nat. Prod., 2002, 65, 1627.
8 (a) R. T. Scannell, J. R. Barr, V. S. Murty, K. S. Reddy and S. M. Hecht,
J. Am. Chem. Soc., 1988, 110, 3650; (b) U. S. Singh, R. T. Scannell,
H. An, B. J. Carter and S. M. Hecht, J. Am. Chem. Soc., 1995, 117,
12691; (c) W. Lytollis, R. T. Scannell, H. An, V. S. Murty, K. S. Reddy,
J. R. Barr and S. M. Hecht, J. Am. Chem. Soc., 1995, 117, 12683; (d) A.
Fu¨rstner, F. Stelzer, A. Rumbo and H. Krause, Chem.–Eur. J., 2002, 8,
1856.
9 Carbamidocyclophanes have recently been isolated. H. T. N. Bui, R.
Jansen, H. T. L. Pham and S. Mundt, J. Nat. Prod., 2007, 70, 499.
10 K. Nakamura, H. Okudo and M. Yamaguchi, Synlett, 1990, 453, and
references therein.
(+)-Cyclophane 17, (-)-Diol, (-)-Tetra-O-methylcylindro-
cyclophane A 3. See ESI.†
(-)-Cylindrocyclophane A 1. To a solution of 3 (15 mg,
0.024 mmol) in 1-methyl-2-pyrrolidinone (3.0 mL) was added
K2CO3 (20 mg, 0.14 mmol) followed by thiophenol (0.73 mL,
◦
7.1 mmol). The reaction vessel was sealed and heated to 215 C
for 6 h, at which time it was diluted with AcOEt (30 mL) and
pH 4 buffer (15 mL). The layers were separated and the aqueous
layer was saturated with NaCl and extracted with AcOEt followed
by 5% MeOH in CH2Cl2. The combined organic layers were
dried over MgSO4 and concentrated under reduced pressure. The
crude mixture was purified by silica gel column chromatography
(AcOEt/Hexane = 1/4) to give 4 (12 mg, 85% yield) as a white
◦
◦
solid; mp 276–278 C {lit.6d mp 276–278 C}; [a]D -24.7 (c 0.61,
30
MeOH) {lit.6d [a]D -20.7 (c 0.14, MeOH); FT-IR (neat) n 3398,
20
1654, 1260, 1024 cm-1; 1H-NMR (500 MHz, CD3OD) d 6.23 (2H,
s), 6.05 (2H, s), 3.73 (2H, d, J = 9.4 Hz), 3.14 (2H, m), 2.03
(2H, m), 1.94 (2H, m), 1.53 (2H, m), 1.40–1.10 (12H, m), 1.07
(6H, d, J = 6.4 Hz), 1.15–0.79 (4H, m), 0.78 (6H, t, J = 7.1 Hz),
0.79–0.60 (8H, m); 13C-NMR (125 MHz, CD3OD) d 158.9, 157.0,
143.9, 117.8, 109.0, 105.1, 81.6, 42.1, 36.9, 35.5, 35.3, 34.9, 31.7,
30.7, 29.9, 23.9, 17.0, 14.5; MS (FAB) m/z 607 [(M + Na)+], 419
(100%); HRMS (FAB) m/z calcd for C36H56O6Na [(M + Na)+]:
607.3935, found: 607.4001.
Synthesis of (+)-Cylindrocyclophane A (ent-1) and the half-sized
analogue 32. See ESI.†
11 (a) S. Takano, T. Sugihara and K. Ogasawara, Synlett, 1991, 279;
(b) S. Takano, K. Samizu, T. Sugihara and K. Ogasawara, J. Chem.
Soc., Chem. Commun, 1989, 1344; (c) O. Yamada and K. Ogasawara,
Synthesis, 1995, 1291.
Cell growth suppression analysis
12 Heating was essential for the efficient Sonogashira coupling in this
particular case. Although 1,4-dioxane (bp. 101 ◦C) showed approxi-
mately 80% yield, we sought for a safer solvent in light of the fact
that 1,4-dioxane is classified by the IARC as a carcinogen in humans
owing to the fact that it is a carcinogen in animals: http://ntp-
server.niehs.nih.gov/ntp/roc/eleventh/profiles/s080diox. pdf. THP
(bp. 88 ◦C) was found as a result.
13 Note that the presence of an electron-withdrawing formyl group at the
p-position of the TfO group is essential for efficient coupling: when 4-
(TBDPSoxymethyl)-2,6-dimethoxyphenyl trifluoromethane sulfonate
was employed as the substrate, only 11 dimerization was observed.
14 (a) H. Tanimoto, R. Saito and N. Chida, Tetrahedron Lett., 2008, 49,
358; (b) M. Bohno, K. Sugie, H. Imase, Y. B. Yusof, T. Oishi and
N. Chida, Tetrahedron, 2007, 63, 6977; (c) H. Tanimoto, T. Kato
and N. Chida, Tetrahedron Lett., 2007, 48, 6267; (d) T. Fukazawa,
Y. Shimoji and T. Hashimoto, Tetrahedron: Asymmetry, 1996, 7,
1649.
HCT116 was obtained from the Cell Resource Center for
Biomedical Research (Institute of Development, Aging and
Cancer, Tohoku University, Sendai, Japan). Growth suppressive
effects of the compounds were measured for 48 hours. Cell
viability was assayed by quantitation of the uptake and di-
gestion of 2-(2-methoxy-4-nitrophenyl)-3-(4-nitrophenyl)-5-(2,4-
disulfophenyl)-2H-tetrazolium monosodium salt according to the
manufacturer’s instructions (Dojindo Laboratories, Kumamoto,
Japan) by 96-well plate reader, MPR-4Ai (Tosoh Corp., Tokyo,
Japan). The percentage cell growth of the control, which was
treated with 1% DMSO alone, was calculated and plotted, and
then the mean growth inhibitory concentration (GI50) value was
determined.
15 The two-step reduction was essential for suppressing the competing
hydrogenolysis, which occurs at the allylic position prior to the
hydrogenolysis of the benzyl group.
Acknowledgements
16 P. A. Grieco, S. Gilman and M. Nishizawa, J. Org. Chem., 1976, 41,
1485.
This work was financially supported in part by a Grant-in-Aid
for Scientific Research on Priority Areas 180320110 from the
Ministry of Education, Culture, Sports, Science and Technology
17 (a) D. A. Evans, J. Bartroli and T. L. Shih, J. Am. Chem. Soc., 1981,
103, 2127; (b) D. A. Evans, S. W. Kaldor, T. K. Jones, J. Clardy and T. J.
Stout, J. Am. Chem. Soc., 1990, 112, 7001.
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18 M. Shibuya, M. Tomizawa, I. Suzuki and Y. Iwabuchi, J. Am. Chem.
Soc., 2006, 128, 8412.
19 (a) U. Azzena, T. Denurra, G. Melloni and A. M. Piroddi, J. Org.
Chem., 1990, 55, 5386; (b) U. Azzena, M. V. Idini and L. Pilo, Synth.
Commun., 2003, 33, 1309.
21 (a) T. Miyazawa and T. Endo, J. Org. Chem., 1985, 50, 3930; (b) T.
Miyazawa and T. Endo, Tetrahedron Lett., 1988, 29, 5671.
22 32 could not be converted to Weinreb amide, although 16 was readily
converted to Weinreb amide. The reaction of 32 may be disrupted by
bulky TBS groups.
20 BBr3-mediated demethylation afforded benzylbromide and then bro-
mide was substituted by NaOH aq. When precursor aldehyde was
treated with BBr3, dibromoacetal was obtained and it was very unstable.
23 H. Ohori, H. Yamakoshi, M. Tomizawa, M. Shibuya, Y. Kakudo, A.
Takahashi, S. Kato, T. Suzuki, C. Ishioka, Y. Iwabuchi and H. Shibata,
Mol. Cancer Ther., 2006, 5, 2563.
This journal is
The Royal Society of Chemistry 2009
Org. Biomol. Chem., 2009, 7, 3772–3781 | 3781
©