Total synthesis and biological evaluation of (-)-apicularen A and its analogues

Article abstract of DOI:10.1021/jo2019762

The total synthesis of (-)-apicularen A (1), a highly cytostatic 12-membered macrolide, and its analogues is described. The convergent and distinct approach not only provides 1, but also opens the opportunity to synthesizeC10-C11 functional analogues of 1

Full text of DOI:10.1021/jo2019762

Article
pubs.acs.org/joc
Total Synthesis and Biological Evaluation of (−)-Apicularen A and
Its Analogues
Sanjay S. Palimkar, Jun’ichi Uenishi,* and Hiromi Ii
Kyoto Pharmaceutical University, Misasagi, Yamashina, Kyoto 607-8412, Japan
S
* Supporting Information
ABSTRACT: The total synthesis of (−)-apicularen A (1), a
highly cytostatic 12-membered macrolide, and its analogues is
described. The convergent and distinct approach not only
provides 1, but also opens the opportunity to synthesize
C10−C11 functional analogues of 1. The key steps of the total
synthesis include assembling of iodoalkene 12 and aldehyde 13
by Nozaki−Hiyama−Kishi (NHK) coupling, stereospecific
construction of 2,6-trans-disubstituted dihydropyran by Pd(II)-
catalyzed 1,3-chirality transfer reaction, and Yamaguchi macrolactonization. The (17E,20Z,22Z)-heptadienoylenamine moiety in
the side chain is installed by an efficient Cu(I)-mediated coupling to complete the synthesis. Analogues of C11-epi-, C11-deoxy-
C10-α-hydroxy-, and C10−C11 dehydrated apicularen A 3−5 were also prepared. Cytostatic activities of (−)-apicularen A and
the three analogues for three different cancer cell lines are described.
synthetic efforts9 as well as analogue syntheses10 have also been
reported.
Although apicularen A displays potent cytostatic activity
INTRODUCTION
(−)-Apicularen A (1), a highly cytostatic 12-membered macro-
lide, was first isolated by Kunze et al. from a variety of strains of
■
the myxobacterial genus Chondromyces in 1998.1 Subsequently,
with an IC50 value in the low nanomolar range, its O-glycoside
apicularen B with N-acylglucosamine shows markedly less
Jansen et al. determined the gross structure of 1 by X-ray crys-
activity,1 and its C11 O-acetate 2 exhibits 75% less potency.10a
Nicolaou’s group10a and Maier’s group10b have synthesized
several analogues of apicularen A by modifying the side chain,
and in studying their activity against different cancer cell lines,
they found an importance of the N-(2Z,4Z)-heptadienoylen-
amine unit for the biological activity. It is interesting that the
C11 deoxy analogue was less active than 1 against several cancer
cell lines but was 2-fold more potent against a few multidrug-
resistant cell lines.10b These results imply an important role
of the functionality around the C11 position as well as the
(17E,20Z,22Z)-N-dienoylenamine moiety for the cytostatic
activities in 1 and these related compounds. However, no
synthetic and biological studies for the C10 hydroxy and C10−
C11 dehydrated analogues have yet been made. In this paper,
we report a full account of the total synthesis of (−)-apicularen
A involving more details of C10−C11 functionalization and
stereospecific construction of the dienoylenamine unit as well as
the synthesis and cytostatic activity of its C10−C11 functional
analogues 3−5 (Figure 2).
tallographic analysis.2 Compound 1 showed not only the potent
cytostatic activity against a wide range of human cancer cell lines,
such as ovarian, prostate, lung, kidney, cervix, leukemia, and
histiocytic cells, with IC50 values in the range of 0.23−6.79 nM,1
but also antiangiogenesis properties,3a induction of apoptosis,3b,c
production of nitric oxide,3d and inhibition of vacuolar (H+)-
ATPase (V-ATPase).3e−g
The structures of apicularen A and B and salicylhalamides4a
possess a unique N-(2Z,4Z)-heptadienoylenamine unit in the
branch of the benzomacrolactone ring, and other related mem-
bers of this benzomacrolactone having the O-methyloxime
butenamide moiety instead of heptadienoylenamide of
apicularen include lobatamides,4b oximidines,4c CJ-12950, and
CJ-133574d (Figure 1). All the members of this macrolide family
were found to be potent and selective inhibitors of mammalian
V-ATPase.4−6 Indeed, these naturally occurring V-ATPase
inhibitors have received increasing attention5 and are expected
to be promising molecules for the treatment of diseases such as
cancer and osteoporosis.6
The key structural features of (−)-apicularen A include a
2,6-trans-tetrahydropyran (THP) ring and four stereogenic
centers embedded in a 12-membered salicylate macrolactone.
A highly unsaturated N-(2Z,4Z)-heptadienoylenamine side
chain also appears on the macrolactone core. Because of the
unique structural features and potent biological activity, 1 has
attracted interest from a number of synthetic research groups.
To date, five total syntheses7 including ours have been
achieved. In addition, five formal total syntheses8 and several
RESULTS AND DISCUSSION
■
Strategic Consideration. Our interest in the synthesis of
(−)-apicularen A and its analogues stemmed from its unique
molecular architecture with a bridged 2,6-trans-tetrahydropyran
located in a 12-membered macrolactone ring and also because
Received: September 28, 2011
Published: November 25, 2011
© 2011 American Chemical Society
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Figure 1. Structures of benzolactone N-acylenamide natural products.
Scheme 1. Retrosynthetic Analysis of 1
Figure 2. Structure of (−)-apicularen A and its analogues.
of its potent biological activity. Recently in our laboratory, an
efficient protocol has been developed for the stereoselective
construction of 2,6-cis- or 2,6-trans-disubstituted dihydropyran
and tetrahydropyran rings by using Pd(II)-catalyzed 1,3-
chirality transfer reactions.11,12 This synthetic methodology
has been applied for the synthesis of several complex natural
products successfully. In continuation, we sought to apply this
methodology to the synthesis of 1, as outlined in our retro-
synthetic plan (Scheme 1). In the preceding total syntheses of
apicularen A,7a−d three different strategies were taken for the
construction of the highly sensitive (Z,Z)-dienoylenamine side
chain. De Brabander et al. constructed the side chain from the α,β-
unsaturated carboxylic acid via Curtius rearrangement, followed
by addition of an organometallic reagent to the isocyanide
intermediate to afford the dienoylenamine unit as a mixture of
alkenes.7a Maier et al. generated the side chain dienoylenamine
unit from the N-dienoyl hemiaminal by dehydration to provide
the unit as a 3:1 mixture of E- and Z-isomers.7d Nicolaou et al.
introduced the conjugated (Z,Z)-dienoylenamine moiety prior to
the macrolactonization by Cu(I)-catalyzed coupling of iodoalkene
with (2Z,4Z)-hepta-2,4-dienamide 7 under Shen and Porco’s
conditions13 because attempts to construct the side chain
(Z,Z)-dienoylenamine on the macrolactone core gave poor results
due to its instability under harsh coupling reaction conditions.7b
Although Panek et al. successfully attached the (Z,Z)-dienoylen-
amine side chain to the macrolactone core,7c the coupling product
was obtained only in 40% yield.
These reported methods for construction of the side chain
have been limited by harsh reaction conditions, low yields, and
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poor selectivities. The development of an efficient and selective
method for the construction of the highly sensitive side chain
is still required. We have planned an introduction of the
N-(2Z,4Z)-hepta-2,4-dienoylenamide side chain by Cu(I)-
mediated coupling of the iodoalkene 6 with the dienamide 7
under modified conditions originally developed by Shen and
Porco13 or Buchwald et al.14 Introduction of an α-hydroxy
group at the C11 position would be achieved by oxidation of
alkene 9 via epoxidation−reduction, hydroboration−oxidation,
or oxymercuration−reduction reaction sequences. The macro-
lactone 9 could be realized by the Yamaguchi macrolacton-
ization.15 We envisioned that the Pd(II)-catalyzed cyclization
would be useful for regio- and stereospecific construction of
the 2,6-trans-disubstituted 3,6-dihydro-2H-pyran ring system in
10.12 The precursor of the cyclization is envisaged as allylic
alcohol 11, which could be assessed by NHK coupling16 of two
advanced fragments, iodoalkene 12 and aldehyde 13 followed
by deprotection of benzylidene acetal.
was derived from commercially available methyl 2,6-dihydroxy-
benzoate. The Stille coupling of 14 with allyltributyltin in the
presence of Pd-catalyst gave alkene 15 in 90% yield. Ozonolytic
cleavage of the terminal alkene 15 followed by Takai
iodoolefination18 afforded 12 in 72% yield in two steps with
excellent selectivity (E:Z = 9:1).
The synthesis of 13 was performed by the common
procedure in the following six steps: (i) Horner−Wadsworth−
Emmons condensation of 3-benzyloxypropanal19 with triethyl
phosphonobutenoate20 (55%), (ii) Sharpless asymmetric
dihydroxylation of the alkene (85%, 98% ee), (iii) formation
of cyclic carbonate from the resulting diol with carbonyl-
diimidazole (86%), (iv) Pd-catalyzed reductive ring-opening
of the cyclic carbonate (82%), (v) formation of the benzylidene
acetal by the Evans protocol21 (65%), and (vi) DIBAL-H
reduction of the ester (90%).
The NHK coupling of the fragments 12 and 13 provided a
diastereomeric mixture of allyllic alcohols 21 and 21′ (dr =
1.3:1) in 43 and 32% yields, respectively (Scheme 4). The
Total Synthesis of (−)-Apicularen A. Syntheses of the
fragments 12 and 13 are outlined in Schemes 2 and 3,
respectively. The synthesis of 12 began with triflate 14,17 which
Scheme 4. Preparation of C1−C17 Unit
Scheme 2. Preparation of 12
Scheme 3. Preparation of 13
undesired diastereoisomer 21′ was converted into the desired
isomer 21 in two steps. Thus, Dess−Martin oxidation22 of 21′,
followed by diastereoface selective reduction of the resulting
ketone using (R)-CBS reagent,23 gave 21 in 72% yield along
with 21′ in 7% yield. Deprotection of the benzylidene acetal
group of 21 in 70% acetic acid afforded the precursor 11 for
the Pd-catalyzed cyclization in 77% yield. The key cyclization
of 11 was performed in THF at rt in the presence of
PdCl2(CH3CN)2 (20 mol %) for 6 h, which smoothly provided
the desired 2,6-trans-dihydropyran 10 in 72% yield as a single
diastereomer, regio- and stereospecifically.
Although we reported the Pd(II)-catalyzed reaction of 6-exo-
and 6-endo-trigonal cyclizations, the mechanism of endo-trigonal
cyclizations12 has not been discussed well in comparison with
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Scheme 5. Reaction Mechanism of 6-endo-Trigonal Cyclization
the exo-trigonal cyclizations.11 We considered the formation of
10 via 6-endo-trigonal cyclization (Scheme 5). An alkene Pd-π-
complex I in the extended conformation of 11 would be
produced mainly by the hydroxy group directed formation.11a
However, this complex could not proceed further. On the other
hand, the alternative alkene Pd-π-complex II generated from
the minor conformer in equilibrium afforded trans-dihydropy-
ran 10 via the Pd-σ-complex after the ligand exchange and
successive intramolecular oxypalladation. Finally, the elimina-
tion of PdCl(OH) followed by regeneration of PdCl2 by the
reaction with HCl to complete its catalytic cycle.
Scheme 7. Introduction of the C11 Hydroxy Group
The next important tasks of the synthesis were to install the
macrolactone ring and an α-hydroxy group at the C-11 posi-
tion regio- and stereoselectively. Saponification of the methyl
ester 10 with LiOH provided the seco acid 22 in 95% yield
(Scheme 6). Yamaguchi macrolactonization of 22 proceeded
quite efficiently to give core macrolactone 9 in 80% yield.
Scheme 6. Synthesis of Macrolactone 9
These results indicate that electrophilic reaction occurs from
the β-face on the dihydropyran ring of 9. The diastereoface-
selective reaction occurred from the β-side of C10−C11 alkene
face in 9, of which the conformation in Scheme 8 was supported
by the calculation study.24 The regioselective formation of the
C−B bond in the hydroboration reaction may take place at the
C10 position by a coordinative induction of the ring oxygen
atom. If this is correct, electrophilic mercuration might favorably
occur at the C10 position from the β-face and install the desired
C11 hydroxy group from the α-face. In fact, the treatment of 9
with Hg(OCOCF3)2 in a mixture of THF and water, followed
by reductive demercuration with NaBH4, gave the desired C11
α-hydroxy product 8 preferentially as a mixture with the
corresponding β-hydroxy isomer in a 3:1 ratio.
Face- and regioselective installation of the α-hydroxy group
at the C11 position on the C10−C11 double bond is important
for the next step. Thus, we explored three different approaches:
(a) face- and regioselective hydroboration and oxidative cleav-
age of the resulting carbon−boron bond; (b) faceselective
epoxidation and regioselective reductive opening of the result-
ing epoxide ring; (c) face- and regioselective oxymercuration
and reductive demercuration of the resulted carbon−Hg bond
(Scheme 7).
Hydroboration of dihydropyran 9 with BH3·THF complex
and subsequent oxidation with alkaline hydrogen peroxide
yielded a C10 secondary alcohol 23 regioselectively in 84%
yield with a 1:2 α:β ratio along with the desired C11 alcohol in
12% yield (Scheme 8). Alternatively, epoxidation of 9 with
m-CPBA followed by DIBAL-H reduction also gave 23 majorly.
Next, the C11 hydroxy group of 8 was protected with TBSOTf
to give 24 and 24′. At this stage, these C11 diastereomers could
be separated, and major α-isomer 24 was obtained in 69% yield
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Scheme 8. Faceselective Electrophilic Reaction to 9
along with undesired minor β-isomer 24′ in 22% yield. The
stereochemistry of the major diastereomer 24 was confirmed by
the single crystal X-ray crystallographic analysis7e as shown in
Scheme 9.
Scheme 9. Preparation of 24
For completion of the total synthesis, a functionalization of
the side chain is remaining, which is outlined in Schemes 10
and 11. Both phenolic and alcoholic O-benzyl ethers were
removed under the Pd-catalyzed hydrogenolytic conditions to
give 25 in quantitative yield. Selective protection of the phenol
with acetic anhydride gave acetate 26, and subsequent oxidation
of the primary alcohol at C17 by Dess−Martin periodinane
afforded aldehyde 27 in 84% overall yield from 25. Iodoolefina-
tion of 27 by the Takai protocol18 gave (E)-iodoalkene 6 in 65%
yield along with the (Z)-isomer in 21% yield.
Several formal syntheses8 have stopped at the stage of 24 or
6. They probably terminated at this step because of a lack of
an efficient coupling method for introducing the conjugated
N-(Z,Z)-dienoylenamine unit.
Our initial attempts to couple the key intermediate 6 with
725 under the Porco’s conditions13 involved catalytic use of
Liebeskind’s catalyst (Cu thiophene-2-carboxylate) with
Cs2CO3 or Rb2CO3 in NMP, DMA, or THF at 70−90 °C or
those in the presence of 1,10-phenanthroline. Indeed, these
efforts were all fruitless, and only a trace amount of the desired
product 28 was obtained.8a Next, we examined Buchwald’s
conditions,14 using 5 mol % of CuI with Cs2CO3 in THF or
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coupling conditions, the phenol acetate was able to be removed
at the same time.
Scheme 10. Preparation of 6
Finally, desilylation of 28 with TBAF afforded (−)-apicularen
A (1) in 96% yield. The physical and spectroscopic data (1H,
13C, IR, HRMS) as well as specific rotation were fully identical
with those reported for the naturally occurring (−)-1.2
Synthesis and Cytostatic Activity of Analogues of
(−)-Apicularen A. In the previous structure and activity
investigations of 1 and its analogues in several cancer cell lines,
little information was reported regarding the role of the C11
part in cytostatic activity.10b Therefore, we planned to synthesize
11-epi-apicularen A (3), 11-deoxy-10-α-hydroxyapicularen A
(4), and C10−C11 dehydrated apicularen A (5).
The corresponding precursor, iodoalkene 6′ for the synthesis
of 3, was prepared from 24′ in the same four steps described
for the synthesis of 6 (Scheme 12). Hydrogenolysis of 24′ gave
Scheme 12. Preparation of 6′
toluene at 60−110 °C in the presence of N,N′-dimethylethy-
lenediamine (DMEDA), and this protocol led to a small
improvement in the yield of 28. However, one of the alkenyl
bonds was partially isomerized with decomposition of the
starting material under the heating conditions, and therefore
we employed milder reaction conditions. Gratifyingly, when
DMF was used with an excess of CuI (2 equiv), this reaction
proceeded at room temperature, and the chemical yield
increased dramatically up to 90% without isomerization of
the alkenyl bonds (Scheme 11). Fortunately, under the
debenzylated product 25′ in quantitative yield. Selective acetyla-
tion of the phenolic hydroxy group followed by oxidation of the
primary hydroxy group gave 27′ in 85% overall yield. The Takai
iodoalkenylation provided inseparable E- and Z-isomers of 6′ in
79% yield with a 3:1 ratio.
Scheme 11. Completion of the Synthesis of 1
Preparation of iodoalkene 33 was derived from 23 (Scheme 13).
The mixture of C10 epimers were silylated with TBSOTf in the
presence of 2,6-lutidine to afford the major β-isomer 29 in 65%
yield and minor α-isomer 29′ in 32% yield. Hydrogenolysis of
29′ gave 30 in 99% yield. Two steps involving selective acetyla-
tion and oxidation provided aldehyde 32 in 83% overall yield
from 30. Iodoalkenylation of 32 gave E-idoalkene 33 in 68%
yield along with Z-isomer in 25% yield.
The remaining precursor 37 was derived from 9 in four
steps (Scheme 14). Debenzylation of 9 with BCl3 in CH2Cl2 at
−78 °C gave 34 in 96% yield. Selective acetylation and Dess−
Martin oxidation gave aldehyde 36 in 80% overall yield from
34. Finally, iodoalkenylation gave the desired E-isomer 37 in
66% yield along with Z-isomer in 22% yield.
The final couplings were carried out under the same condi-
tions described for the synthesis of 28. The reaction of 6′ with
dienamide 7 gave the desired C17 E-isomer 28′ in 70% yield
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Scheme 13. Preparation of 33
Scheme 15. Synthesis of 3, 4, and 5
Biological Studies. The four synthetic apicularens includ-
ing (−)-apicularen A were tested for their effects on the
proliferation of three tumor cell lines, U-937 (human leukemic
monocyte lymphoma cells), HL-60 (human promyelocytic
leukemia cells), and PC-3 (human prostate cancer cells)
(Table 1). Adriamycin was used as a reference. The C11 epimer
Table 1. Cytostatic Activity (IC50 value) of Compounds 1, 3,
4, and 5
Scheme 14. Preparation of 37
compound
cell line
adriamycin
1
3
4
5
a
U-937
6.1
9.2
27
417
449
115
44
27
14
a
HL-60
4.0
3.6
b
PC-3
9.4
9.5
3.0
1.4
a
b
IC50 values [nM]. IC50 values [μM].
3 was found to be 18- or 112-fold less active than 1 against
U-937 and HL-60. On the other hand, the C10 isomer 4
indicated 5- to 10-fold less potency than 1. Compound 5
showed almost the same potency as 1 against U-937 and
weaker against HL-60. However, it is interesting to note that
compound 4 is a little more effective than 1 against PC-3, and
compound 5 is even more active. Although the C11 deoxy
analogue possesses weak activity,10b our study showed that
either C10 α-hydroxy or C10−C11 unsaturated functional
groups on the trans-THP ring are effective for a very high
potency of the cytostatic activity for these cancer cell lines.
CONCLUSION
and the corresponding Z-isomer in 24% yield. Deprotection of
silyl ether of 28′ by TBAF in THF gave C11-epi-apicularen A,
3, in 95% yield. Similarly, the coupling of 33 with 7 followed by
the deprotection of silyl ether furnished the synthesis of C10
α-hydroxy analogue 4 in 84% yield in two steps. Finally, the
coupling of 37 with 7 gave compound 5 directly in 94% yield
(Scheme 15).
■
A concise total synthesis of (−)-apicularen A and novel C10−
C11 functionalized analogues 3, 4, and 5 has been devised. This
convergent and distinct approach involves number of key
features. In particular, we could demonstrate efficiency of
Pd(II)-catalyzed 1,3-chirality transfer reaction for the stereo-
specific construction of 2,6-trans-disubstituted dihydropyran in
this complex natural product synthesis. Oxymercuration and
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72.9, 71.1, 70.9, 70.5, 66.9, 66.3, 65.3, 65.0, 41.0, 39.2, 39.1, 39.0, 38.2,
35.2; EI-MS m/z 502 (M+), 502, 484, 411, 393, 305, 287, 261, 243,
224, 180, 146, 91, 81, 71, 55, 40; EI-HRMS m/z 502.2361 (Calcd for
C31H34O6 502.2355).
reductive demercuration installed the α-hydroxy group at the
C11 position regio- and stereoselectively. The Cu(I)-mediated
coupling of the iodoalkene with the dienamide has been
improved under the mild conditions in DMF without
isomerization of alkenyl bonds. Structure−activity relationship
studies revealed the importance of C11 α-hydroxy group as well
as C10−C11 unsaturated carbon group for high potency of the
activity.
O-TBS Protected Compounds 24 and 24′. To a mixture of 8
(42 mg, 0.083 mmol) and 2,6-lutidine (28 μL, 0.25 mmol) in CH2Cl2
(3 mL) at 0 °C was dropped TBSOTf (38 μL, 0.17 mmol). The
reaction was stirred at 0 °C for 30 min before being quenched with
water (5 mL). The aqueous layer was extracted with CH2Cl2 (30 mL)
and dried over MgSO4. The solvent was evaporated under reduced
pressure, and the crude product was purified by flash column
chromatography (silica gel, 7−10% EtOAc/hexane) to afford major
isomer 24 (36 mg) in 69% yield and minor isomer 24′(11.5 mg) in
22% yield. Major isomer 24: mp 122−125 °C; Rf (20% EtOAc/
hexane) = 0.45; [α]D24 −4.8 (c 0.4 CHCl3); Rf (20% EtOAc/hexane) =
0.45; IR (CHCl3 film, cm−1) 3019, 1715, 1579, 1455, 1215, 755,
EXPERIMENTAL SECTION
■
Preparation of 23 by Hydroboration and Oxidation. To a
stirred solution of 9 (33 mg, 0.081 mmol) in THF (2 mL) was added
BH3·THF (102 μL of 1 M solution in THF, 0.102 mmol) at 0 °C, and
the mixture was stirred for 1 h at rt. The reaction was quenched with
H2O2 (0.5 mL, 30% solution) and NaOH (0.5 mL, 4 N aqueous
solution) and stirred further for 3 h at rt. Then, it was diluted with
water and extracted with EtOAc (3 × 20 mL). The combined organic
layers were dried over MgSO4. Removal of solvent and purification of
the crude product by flash column chromatography (silica gel, 60%
EtOAc/hexane) afforded 23 (28.7 mg) in 84% yield as a mixture of α
and β isomers (1:2) and its regioisomer 8 (4 mg) in 12% yield as a
mixture of α and β isomers (1:2). 23: Colorless oils, Rf (70% EtOAc/
hexane) = 0.50; IR (CHCl3 film, cm−1) 3441, 2924, 1715, 1578, 1455,
1
668; H NMR (300 MHz, CDCl3) δ 7.29 (m, 11H), 6.82 (d, J = 8.4
Hz, 1H), 6.78 (d, J = 7.8 Hz, 1H), 5.75 (m, 1H), 5.00 (s, 2H), 4.36
(td, J = 9.3, 3.3 Hz, 1H), 4.11 (q, J = 11.4 Hz, 2H), 3.98 (m, 2H), 3.60
(dd, J = 14.4, 10.8, Hz, 1H), 3.34 (m, 2H), 2.39 (dd, J = 14.7, 1.5 Hz,
1H), 1.86 (m, 4H), 1.60 (m, 4H), 0.91 (s, 9H), 0.06 (s, 6H); 13C
NMR (75 MHz, CDCl3) δ 169.5, 154.8, 139.4, 138.5, 136.7, 129.8,
128.4, 128.2, 127.9, 127.8, 127.7, 127.3, 126.0, 122.9, 110.1, 74.2, 73.0,
71.1, 70.4, 66.4, 65.4, 65.3, 39.9, 39.6, 38.7, 37.9, 35.1, 25.8, 17.9, −4.8;
EI-MS m/z 616 (M+), 559, 525, 419, 393, 359, 321, 307, 287, 261,
235, 224, 199, 181, 163, 145, 131, 107, 91, 83, 73, 57; EI-HRMS m/z
616.3225 (Calcd for C37H48O6Si 616.3220). Minor isomer 24′: mp
1
1265, 1074, 734, 698; H NMR (270 MHz, CDCl3) major isomer δ
7.28 (m, 11H), 6.83 (m, 2H), 5.76 (m, 1H), 5.00 (s, 2H), 4.07 (m,
4H), 3.80 (dd, J = 9.45, 3.78 Hz, 1H), 3.60 (m, 1H), 3.30 (m, 3H),
2.71 (dd, J = 15.1, 1.1 Hz, 1/2H), 2.60 (dd, J = 14.5, 1.1 Hz, 1H), 1.74
(m, 8H); 13C NMR (67.5 MHz, CDCl3) major isomer δ 169.6, 154.8,
138.7, 138.4, 136.5, 130.0, 129.8, 128.4, 128.2, 128.0, 127.8, 127.7,
127.6, 125.7, 123.2, 123.0, 110.2, 81.1, 72.9, 71.2, 70.5, 69.8, 69.1, 68.8,
68.1, 66.2, 39.1, 37.6, 35.3, 35.0, 34.2, 32.7, 28.3, 27.8, 27.0, 26.6; FAB-
MS m/z 503 (M + H)+; FAB-HRMS m/z 503.2427 (Calcd for
C31H35O6 503.2434).
Preparation of 23 by Epoxidation and Reduction. To a
stirred solution of 9 (12 mg, 0.029 mmol) in CCl4 (2 mL) was added
mCPBA (10.1 mg, 0.0587 mmol), and the mixture was stirred for 48 h
at 0 °C. The mixture was diluted with CH2Cl2 (30 mL) and washed
with aq NaHCO3 and brine. The organic layer was dried over MgSO4
and condensed under reduced pressure. The crude product was
dissolved in dry CH2Cl2 (2 mL), and DIBAL-H (1 M toluene solution
42 μL, 0.042 mmol) was dropped into the mixture at −78 °C. The
mixture was further stirred at the same temperature for 30 min and
quenched with saturated NH4Cl. The mixture was extracted with
CH2Cl2 (30 mL), and the extract was washed with water and brine and
dried over MgSO4. Solvent was removed, and the residue was purified
by flash column chromatography (silica gel, 60% EtOAc/hexane),
which afforded 23 (6.1 mg) in 49% yield as a mixture of α and β
isomers (1:3) and its regioisomer 8 (0.8 mg) in 5% yield as a mixture
of α and β isomers (1:3).
24
94−97 °C; Rf (20% EtOAc/hexane) = 0.50; [α]D − 11.7 (c 0.2
CHCl3); IR (CHCl3 film, cm−1) 3015, 1715, 1579, 1458, 1259, 1215,
1
1091, 755, 667; H NMR (300 MHz, CDCl3) δ 7.29 (m, 11H), 6.85
(d, J = 8.4 Hz, 1H), 6.81 (d, J = 7.2 Hz, 1H), 5.74 (m, 1H), 5.00 (s,
2H), 4.12 (m, 1H), 4.11 (dd, J = 15.6, 12.0 Hz, 2H), 3.95 (m, 2H),
3.41 (dd, J = 13.8, 1.7, Hz, 1H), 3.33 (m, 2H), 2.33 (dd, J = 14.1, 1.5
Hz, 1H), 1.82 (m, 7H), 1.35 (m, 1H), 0.88 (s, 9H), 0.6 (s, 6H); 13C
NMR (75 MHz, CDCl3) δ 170.2, 154.7, 139.3, 138.5, 136.6, 130.0,
128.5, 128.2, 128.0, 127.9, 127.6, 127.3, 125.8, 123.0, 110.2, 74.9, 72.9,
71.3, 70.5, 67.7, 66.3, 66.0, 41.2, 40.5, 39.1, 36.6, 34.8, 25.8, 18.0, −4.5,
−4.6; FAB-MS m/z 639 (M + Na)+; FAB-HRMS m/z 639.3112
(Calcd for C37H48O6SiNa 639.3118).
(2Z,4Z)-Hepta-2,4-dienamide 7. Amide fragment 7 was pre-
pared according to literature procedure,25 and H NMR was matched
1
1
with that reported in the literature: H NMR (300 MHz, CDCl3) δ
7.20 (m, 1H), 6.81 (dd, J = 11.7, 10.5 Hz, 1H), 5.85 (m, 1H), 5.65 (d,
J = 11.7 Hz, 1H), 5.44 (br, s, 2H), 2.27 (dtd, J = 15, 7.5, 1.5 Hz, 2H),
1.03 (t, J = 7.5 Hz, 3H).
Coupling of 6 and 7, Preparation of 28. An oven-dried two-
neck 10 mL round-bottom flask was cooled under argon and charged
with CuI (8.8 mg, 0.046 mmol), Cs2CO3 (37 mg, 0.116 mmol), and 6
(14 mg, 0.023 mmol). The flask was evacuated and backfilled with
argon. A mixture of N,N′-dimethylethylenediamine (12 μL, 0.116
mmol) and 7 (14.5 mg, 0.116 mmol) in dry degassed DMF (2 mL)
was added under argon. The resulting dark green mixture was stirred
at rt for 1 h. After completion, the reaction mixture was diluted with
water. The aqueous layer was extracted with EtOAc (3 × 10 mL). The
combined organic layer was dried over MgSO4. Removal of solvent
and purification of the crude product by silica gel flash column
chromatography (30% EtOAc/hexane) provided 28 (11.7 mg) in 90%
yield as a white solid: mp 152−155 °C (chloroform); Rf (50% EtOAc/
hexane) = 0.52; [α]D24 +43.7 (c 0.45 CHCl3); IR (CHCl3 film, cm−1)
Preparation of 8 by Oxymercuration of 9. To a stirred
solution of 9 (48 mg, 0.118 mmol) in THF (3 mL) and water (2.5
mL) was added mercury(II) trifluoroacetate (126 mg, 0.297 mmol),
and the mixture was stirred for 1 h at rt. Aq NaOH (3 N, 0.5 mL)
solution and NaBH4 (7.4 mg, 0.198 mmol) were added to the mixture
for few minutes. The mixture was extracted with EtOAc (3 × 20 mL).
The combined organic extract was dried over MgSO4. Removal of
solvent and purification of the crude product by flash column
chromatography (silica gel, 60% EtOAc/hexane) afforded 8 (40 mg)
in 80% yield as an inseparable mixture of α and β diastereomers (3:1).
Colorless oil: Rf (70% EtOAc/hexane) = 0.39; IR (CHCl3 film, cm−1)
1
3304, 2927, 1760, 1644, 1463, 1251, 1067, 835, 773; H NMR (300
MHz, CDCl3) δ 7.28 (m, 2H), 7.15 (t, J = 7.5 Hz, 1H), 6.93 (dd, J =
14.7, 10.8 Hz, 1H), 6.78 (m, 2H), 6.25 (br, s, 1H), 5.87 (m, 1H), 5.53
(d, J = 11.4 Hz, 1H), 5.46 (m, 1H), 5.18 (dt, J = 14.7, 7.5 Hz, 1H),
4.33 (td, J = 9.9, 4.5 Hz, 1H), 4.03 (m, 1H), 3.85 (m, 1H), 3.57 (dd,
J = 14.7, 11.4 Hz, 1H), 2.39 (m, 3H), 2.26 (dtd, J = 15.3, 9.3, 1.5 Hz,
2H), 1.86 (m, 2H), 1.65 (m, 4H), 1.03 (t, J = 7.5 Hz, 3H), 0.90 (s,
9H), 0.05 (s, 6H); 13C NMR (125 MHz, CDCl3) δ 169.2, 163.5,
152.7, 142.4, 139.0, 137.0, 130.6, 125.5, 123.8, 123.2, 122.3, 119.1,
114.9, 107.4, 77.4, 73.9, 65.9, 65.4, 39.9, 39.3, 38.7, 37.8, 35.1, 25.7,
20.7, 18.0, 13.9, −4.7; EI-MS m/z 555 (M+), 540, 526, 498, 480, 446,
1
3434, 2921, 1717, 1578, 1455, 1265, 1091, 751; H NMR (500 MHz,
CDCl3) for major isomer δ 7.21 (m, 11H), 6.77 (d, J = 8.5 Hz, 1H),
6.70 (d, J = 7.5 Hz, 1H), 5.66 (m, 1H), 4.93 (s, 2H), 4.24 (m, 1H),
3.99 (m, 4H), 3.38 (dd, J = 14.5, 10.0 Hz, 1H), 3.26 (m, 2H), 2.38
(dd, J = 15.5, 1.5 Hz, 3/4 H), 2.27 (dd, J = 14.0, 1.5 Hz, 1/3 H,
minor), 1.91 (dt, J = 9.5, 5.0 Hz, 1H) 1.77 (m, 5H), 1.51 (m, 4H); 13C
NMR (125 MHz, CDCl3) for major isomer δ 169.1, 154.9, 138.7,
138.5, 136.6, 129.8, 128.4, 128.2, 128.1, 128.0, 127.98, 127.95, 127.8,
127.6, 127.6, 127.5, 127.4, 127.3, 125.8, 127.7, 123.0, 122.9 110.3, 74.9,
395
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The Journal of Organic Chemistry
Article
423, 404, 390, 373, 347, 321, 298, 272, 252, 233, 215, 191, 163, 149,
135, 125, 109, 96, 81, 73, 67, 56, 44; EI-HRMS m/z 555.3019 (Calcd
for C31H45NO6Si 555.3016).
6.66 (dd, J = 8.3, 0.8 Hz, 1H), 5.71 (tt, J = 11.1, 3.5 Hz, 1H), 3.98 (m,
5H), 3.40 (dd, J = 13.8, 12.1 Hz, 1H), 2.28 (dd, J = 13.8, 1.3 Hz, 1H),
1.91 (m, 2H), 1.71 (m, 5H), 1.35 (m, 1H), 0.87 (s, 9H), 0.05 (s, 6H);
13C NMR (67.5 MHz, CDCl3) δ 169.9, 152.6, 139.1, 130.5, 123.2,
121.7, 114.0, 74.7, 74.6, 67.3, 65.7, 61.5, 41.3, 41.2, 38.5, 36.6, 36.2,
25.7, 18.0, −4.6; FAB-MS m/z 437 (M + H)+; FAB-HRMS m/z
437.2357 (Calcd for C23H37O6Si 437.2359).
(−)-Apicularen A (1). To a solution of 28 (14 mg, 0.025 mmol)
in dry THF (1 mL) was added TBAF (75 μL, 1 M solution in THF,
0.075 mmol) at rt, and the reaction was stirred for 5 h. Removal of
solvent under reduced pressure and purification by flash column
chromatography (silica gel, 40% acetone/hexane) afforded 1 (10.7
mg) in 96% yield as a white solid: mp 136−140 °C (methanol); Rf
24
30, 99% yield. White solid: Rf (40% EtOAc/hexane) = 0.15; [α]D
+21.8 (c 0.6 CHCl3); IR (CHCl3 film, cm−1) 3502, 3476, 2928, 1721,
1586, 1466, 1215, 1076, 772, 668; 1H NMR (270 MHz, CDCl3) δ 8.63
(br, s, 1H), 7.13 (t, J = 7.8 Hz, 1H), 6.70 (d, J = 7.5 Hz, 1H), 6.65 (d,
J = 8.1 Hz, 1H), 5.73 (m, 1H), 4.09 (t, J = 9.9 Hz, 1H), 3.91 (m, 4H),
3.74 (m, 1H), 3.37 (dd, J = 13.7, 11.8 Hz, 1H), 2.51 (dd, J = 14.0, 1.3,
Hz, 1H), 1.84 (m, 7H), 1.41 (m, 1H), 0.93 (s, 9H), 0.08 (s, 3H), 0.06
(s, 3H); 13C NMR (67.5 MHz, CDCl3) δ 169.6, 152.6, 139.7, 130.5,
123.7, 121.7, 113.9, 80.4, 74.6, 68.5, 67.5, 61.5, 41.1, 36.3, 29.7, 29.4,
28.4, 25.7, 18.0, −4.6, −4.9; FAB-MS m/z 437 (M + H)+; FAB-HRMS
m/z 437.2364 (Calcd for C23H37O6Si 437.2359).
24
(50% acetone/hexane) = 0.40; [α]D −21.0 (c 0.55, CH3CN); IR
(KBr, cm−1) 3337, 2996, 1717, 1646, 1524, 1462, 1289, 1076, 777; 1H
NMR (500 MHz, acetone-d6) δ 9.08 (d, J = 10.0 Hz, 1H), 8.37 (s,
1H), 7.51 (t, J = 11 Hz, 1H), 7.10 (t, J = 7.5 Hz, 1H), 6.91−6.82 (m,
1H), 6.77 (d, J = 8.5 Hz, 1H), 6.69 (d, J = 7.5 Hz, 1H), 5.82−5.78 (m,
1H), 5.74 (d, J = 11 Hz, 1H), 5.47−5.41 (m, 1H), 5.27−5.20 (m, 1H),
4.25 (m, 1H), 3.98 (m, 1H), 3.86 (m, 1H), 3.77 (d, J = 3.5 Hz, 1H),
3.34 (dd, J = 14.5, 9.5 Hz, 1H), 2.43 (d, J = 14.5 Hz, 1H), 2.35−2.28
(m, 2H), 2.27−2.24 (m, 2H), 1.94−1.90 (m, 1H), 1.86−1.79 (m, 1H),
1.70−1.65 (m, 1H), 1.59−1.56 (m, 1H), 1.00 (t, J = 7 Hz, 3H); 13C
NMR (125 MHz, acetone-d6) δ 169.3, 163.6, 154.2, 141.4, 140.2,
136.7, 130.2, 126.3, 125.4, 122.2, 120.9, 114.4, 108.0, 74.2, 73.7, 68.0,
64.9, 40.3, 39.9, 39.6, 38.9, 36.4, 21.0, 14.3; FAB-MS m/z 464 (M +
Na)+; FAB-HRMS m/z 464.2049 (Calcd for C25H31NO6Na
464.2047).
Deprotection of Benzyl Ether for the Synthesis of 34. To a
stirred solution of macrolactone 9 (25 mg, 0.051 mmol) in CH2Cl2
(2 mL) at −78 °C was added BCl3 (1 M solution in CH2Cl2 0.26 mL,
0.26 mmol). The resulting reaction mixture was stirred at the same
temperature for 1 h. The mixture was quenched with methanol
(0.1 mL) and saturated solution of NaHCO3 (3 mL) and allowed to
warm up to rt. The mixture was extracted with CH2Cl2 (2 × 20 mL),
and the organic layer was dried over MgSO4. Solvent was evaporated
under reduced pressure, and the crude product was purified by flash
column chromatography on silica (60% EtOAc/hexane) to afford 34
(14.5 mg) in 92% yield as a white solid: mp 190−193 °C (CH2Cl2); Rf
Synthesis of Analogues. Preparation O-TBS Protected
Compounds 29 and 29′. To a solution of alcohol 23 (80 mg,
0.158 mmol) and 2,6-lutidine (74 μL, 0.636 mmol) in CH2Cl2 (6 mL)
was added TBSOTf (110 μL, 0.476 mmol) dropwise at 0 °C. The
reaction was stirred at 0 °C for 30 min before being quenched with
water. The aqueous layer was extracted with CH2Cl2 and dried over
MgSO4. The solvent was evaporated under reduced pressure. The
crude product was purified by flash column chromatography (silica gel,
7−10% EtOAc/hexane) to afford the O-TBS protected major isomer
29 (64 mg) in 65% yield and minor isomer 29′ (32 mg) in 32% yield
as white solids. Major isomer 29: mp 112−114 °C (20% EtOAc/
hexane); Rf (20% EtOAc/hexane) = 0.46; [α]D24 −1.1 (c 0.5 CHCl3);
IR (CHCl3 film, cm−1) 2928, 1729, 1579, 1455, 1260, 1106, 836, 755,
24
(40% EtOAc/hexane) = 0.17; [α]D +47.0 (c 0.75 CHCl3); IR
(CHCl3 film, cm−1) 3487, 3019, 1723, 1585, 1465, 1215, 769, 668; 1H
NMR (270 MHz, CDCl3) δ 8.91 (br, s, 1H), 7.15 (t, J = 7.5 Hz, 1H),
6.75 (dd, J = 7.5, 0.8 Hz, 1H), 6.68 (dd, J = 8.1, 0.8 Hz, 1H), 5.81 (m,
3H), 4.17 (dt, J = 12.1, 2.7 Hz, 1H), 4.00 (m, 4H), 3.37 (dd, J = 13.5,
11.9 Hz, 1H), 2.41 (dd, J = 13.7, 2.1 Hz, 1H), 1.89 (m, 6H); 13C NMR
(67.5 MHz, CDCl3) δ 169.5, 152.8, 138.8, 130.6, 128.9, 125.5, 123.4,
121.5, 114.3, 76.0, 74.5, 66.3, 61.5, 41.3, 36.5, 36.2, 31.2; FAB-MS m/z
307 (M + H)+; FAB-HRMS m/z 305.1394 (Calcd for C17H21O5
305.1389).
1
697; H NMR (270 MHz, CDCl3) δ 7.31 (m, 11H), 6.81 (d, J = 8.3
Hz, 1H), 6.74 (d, J = 7.5 Hz, 1H), 5.71 (m, 1H), 4.99 (s, 2H), 4.05 (q,
J = 11.6 Hz, 2H), 4.02 (m, 1H), 3.71 (t, J = 7.2 Hz, 1H), 3.50 (m, 1H),
3.33 (m, 2H), 3.08 (dd, J = 14.5, 9.1 Hz, 1H), 2.73 (d, J = 14.0 Hz,
1H), 2.08 (m, 1H), 1.83 (m, 3H), 1.58 (m, 4H), 0.87 (s, 9H), 0.08 (s,
3H), 0.04 (s, 3H); 13C NMR (67.5 MHz, CDCl3) δ 168.9, 155.0,
138.7, 138.5, 136.6, 129.7, 128.5, 128.2, 127.9, 127.8, 127.7, 127.3,
125.6, 123.1, 110.1, 79.3, 72.9, 71.1, 70.5, 70.2, 69.8, 66.3, 37.6, 35.8,
35.4, 29.1, 27.9, 25.7, 17.9, −4.1, −4.7; FAB-MS m/z 639 (M + Na)+;
FAB-HRMS m/z 639.3115 (Calcd for C37H48O6SiNa 639.3118).
Minor isomer 29′: mp 115−117 °C (20% EtOAc/hexane); Rf (20%
EtOAc/hexane) = 0.53; [α]D24 −4.7 (c 0.25 CHCl3); IR (CHCl3 film,
Preparation of 26′, 31, and 35. To a stirred solution of 25′, 30,
or 34 (0.06 mmol) in isopropanol (3 mL) was added aq NaOH
solution (4 N, 0.5 mL). After the reaction was stirred for 5 min, acetic
anhydride (17 μL, 0.18 mmol) was added. The reaction mixture was
further stirred for 10 min at rt and diluted with water (5 mL). The
mixture was extracted with EtOAc (3 × 20 mL), and the combined
organic layer was dried over MgSO4. Removal of solvent and
purification of the crude product by flash column chromatography
(silica gel, 50% EtOAc/hexane) afforded 26′, 31, or 35 in 89, 87, and
88% yields, respectively.
1
cm−1) 2926, 1722, 1579, 1456, 1259, 1080, 755, 698; H NMR (270
26′, white solid: Rf (40% EtOAc/hexane) = 0.28; [α]D24 +14.5 (c 0.7
CHCl3); IR (CHCl3 film, cm−1) 3501, 2927, 1771, 1718, 1459, 1366,
1256, 1199, 1085, 836, 755; 1H NMR (270 MHz, CDCl3) δ 7.32 (dd,
J = 8.3, 7.8 Hz, 1H), 7.06 (d, J = 7.8 Hz, 2H), 5.69 (m, 1H), 4.19 (m,
1H), 3.98 (m, 2H), 3.78 (m, 2H), 3.35 (dd, J = 14.5, 11.0 Hz, 1H),
2.41 (dd, J = 14.5, 1.3 Hz, 1H), 2.28 (s, 3H), 2.15 (m, 1H), 1.87 (m,
2H), 1.74 (m, 3H), 1.61 (m, 1H), 1.37 (m, 1H), 0.87 (s, 9H), 0.05 (s,
6H); 13C NMR (67.5 MHz, CDCl3) δ 168. 8, 168.7, 146.5, 139.3,
129.8, 128.6, 128.0, 120.6, 72.6, 68.5, 65.6, 58.9, 39.9, 39.8, 38.9, 37.8,
37.2, 25.7, 20.8, 18.0, −4.6, −4.7; FAB-MS m/z 479 (M + H)+; FAB-
HRMS m/z 479.2460 (Calcd for C25H39O7Si 479.2465).
MHz, CDCl3) δ 7.31 (m, 11H), 6.83 (d, J = 7.8 Hz, 1H), 6.81 (d, J =
8.1 Hz, 1H), 5.76 (m, 1H), 4.99 (s, 2H), 4.09 (dd, J = 16.2, 11.1 Hz,
2H), 3.90 (m, 3H), 3.29 (m, 3H), 2.68 (d, J = 14.5 Hz, 1H), 1.72 (m,
8H), 0.93 (s, 9H), 0.09 (s, 3H), 0.07 (s, 3H); 13C NMR (75 MHz,
CDCl3) δ 170.3, 154.7, 139.9, 138.5, 136.6, 130.0, 128.4, 128.2, 128.0
127.9, 127.6, 127.3, 126.4, 123.0, 109.9, 80.5, 72.9, 71.3, 70.4,
68.6, 67.8, 66.3, 40.1, 34.9, 30.1, 29.2, 28.7, 25.8, 18.0, −4.6, −4.8;
FAB-MS m/z 639 (M + Na)+; FAB-HRMS m/z 639.3115 (Calcd for
C37H48O6SiNa 639.3118).
Preparation of 25′ and 30. A mixture of dibenzyl ether 24′ or
29′ (0.05 mmol) and Pd/C (10 mg, 10% on charcoal) in ethanol
(3 mL) was stirred under H2 at rt for 12 h. The Pd charcoal was
removed by filtration through a pad of Celite, and the filtrate was
condensed. The crude product was purified by flash column
chromatography (silica gel, 60% EtOAc/hexane) to afford diol 25′
or 30 in quantitative yield.
24
31, colorless oil, Rf (50% EtOAc/hexane) = 0.22; [α]D +15.8
(c 0.50 CHCl3); IR (CHCl3 film, cm−1) 3442, 2929, 1771, 1721, 1608,
1
1459, 1369, 1269, 1200, 1079, 733; H NMR (270 MHz, CDCl3) δ
7.32 (dd, J = 8.3, 7.5 Hz, 1H), 7.05 (d, J = 8.3 Hz, 2H), 5.74 (m, 1H),
4.00 (t, J = 10.2 Hz, 1H), 3.82 (m, 4H), 3.29 (dd, J = 14.5, 11.3 Hz,
1H), 2.65 (dd, J = 14.5, 1.3 Hz, 1H), 2.28 (s, 3H), 1.90 (m, 2H), 1.69
(m, 6H), 1.40 (m, 1H), 0.93 (s, 9H), 0.09 (s, 3H), 0.07 (s, 3H); 13C
NMR (67.5 MHz, CDCl3) δ 168.8, 168.7, 146.3, 140.1, 129.9, 129.2,
127.9, 120.4, 79.7, 72.7, 68.4, 68.0, 59.0, 39.8, 37.1, 30.2, 29.0, 28.5,
25′, 99% yield. White solid: Rf (40% EtOAc/hexane) = 0.15;
[α]D24 +22.3 (c 0.7 CHCl3); IR (CHCl3 film, cm−1) 3501, 3019, 1717,
1586, 1466, 1215, 1085, 767, 669; 1H NMR (270 MHz, CDCl3) δ 8.80
(br, s, 1H), 7.14 (t, J = 7.8 Hz, 1H), 6.70 (dd, J = 7.5, 0.8 Hz, 1H),
396
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Article
25.7, 20.9, 18.0, −4.5, −4.9; FAB-MS m/z 479 (M + H)+; FAB-HRMS
m/z 479.2469 (Calcd for C25H39O7Si 479.2465),
EtOAc/hexane) afforded the (E)-iodoalkene 6′, 33, or 37 in 79, 68,
and 66% yields, respectively.
24
6′ (E/Z = 3:1). White solid: Rf (20% EtOAc/hexane) = 0.40; IR
(film, cm−1) 2927, 1772, 1720, 1459, 1365, 1257, 1199, 1085, 756; 1H
NMR (270 MHz, CDCl3) δ 7.32 (t, J = 8.6 Hz, 1H), 7.06 (m, 2H),
6.55 (m, 3/4H), 6.40 (dt, J = 7.5, 1.3 Hz, 1/3H), 6.32 (m, 1/3H), 6.21
(dt, J = 14.5, 1.6 Hz, 3/4H), 5.62 (m, 1H), 4.10 (m, 1H), 3.97 (m,
2H), 3.37 (dd, J = 14.3, 11.6 Hz, 1H), 2.42 (m, 3H), 2.31 (s, 3/4H),
2.24 (s, 1/3H), 1.95 (m, 1H), 1.76 (m, 3H), 1.58 (m, 2H), 1.35 (m,
1H), 0.87 (s, 9H), 0.05 (s, 6H); 13C NMR (67.5 MHz, CDCl3) δ
168.7, 168.5, 146.5, 140.9, 139.5, 136.3, 129.9, 128.6, 127.9, 120.7,
85.4, 77.9, 73.4, 72.7, 67.9, 67.6, 65.6, 40.9, 40.6, 39.9, 39.8, 38.7, 37.2,
25.8, 21.4, 20.9, 18.0, −4.6; FAB-MS m/z 601 (M + H)+; FAB-HRMS
m/z 601.1489 (Calcd for C26H38O6SiI 601.1482).
35, colorless oil, Rf (50% EtOAc/hexane) = 0.22; [α]D +44.5
(c 0.85 CHCl3); IR (CHCl3 film, cm−1) 3435, 2927, 1768, 1715, 1608,
1
1459, 1366, 1204, 1086, 729; H NMR (270 MHz, CDCl3) δ 7.35 (t,
J = 7.8 Hz, 1H), 7.13 (dd, J = 7.8, 1.0 Hz, 1H), 7.06 (dd, J = 8.1,
1.0 Hz, 1H), 5.81 (m, 3H), 4.20 (dt, J = 12.1, 2.4 Hz, 1H), 3.97 (td,
J = 9.7, 3.2 Hz, 1H), 3.80 (m, 2H), 3.33 (dd, J = 14.0, 12.1 Hz, 1H),
2.50 (dd, J = 14.0, 1.3 Hz, 1H), 2.29 (s, 3H), 1.92 (m, 5H), 1.73 (m,
2H); 13C NMR (67.5 MHz, CDCl3) δ 168.8, 146.3, 139.2, 130.1,
129.2, 128.8, 127.6, 125.8, 120.7, 75.9, 72.5, 66.4, 59.0, 40.7, 37.0, 36.6,
31.2, 21.0; FAB-MS m/z 347 (M + H)+; FAB-HRMS m/z 347.1501
(Calcd for C19H23O6 347.1495).
Preparation of 27′, 32, and 36. To a solution of 26′, 31, or 35
(0.05 mmol) in CH2Cl2 (3 mL) was added Dess−Martin periodinane
(32 mg, 0.75 mmol). The resulting mixture was stirred at rt for 1 h.
The reaction was quenched with saturated NaHCO3, extracted with
CH2Cl2 (3 × 10 mL), and dried over MgSO4. Removal of solvent and
purification of the crude product by flash column chromatography
(silica gel, 30% EtOAc/hexane) afforded aldehyde, 27′, 32, or 36 in 96,
95, and 91% yields, respectively.
33 (E)-isomer. White solid: Rf (20% EtOAc/hexane) = 0.44 (0.48
for Z-isomer); IR (film, cm−1) 2928, 1772, 1721, 1459, 1367, 1267,
1
1199, 1078, 757; H NMR (270 MHz, CDCl3) δ 7.32 (t, J = 7.8 Hz,
1H), 7.05 (d, J = 8.1 Hz, 2H), 6.40 (dt, J = 14.0, 7.02 Hz, 1H), 6.21
(dt, J = 14.3, 1.3 Hz, 1H), 5.62 (m, 1H), 4.02 (m, 1H), 3.89 (m, 1H),
3.76 (m, 1H), 3.32 (dd, J = 14.3, 11.6 Hz, 1H), 2.62 (dd, J = 14.3, 1.3
Hz, 1H), 2.40 (m, 2H), 2.30 (s, 3H), 1.64 (m, 6H), 0.93 (s, 9H), 0.08
(s, 3H), 0.07 (s, 3H); 13C NMR (67.5 MHz, CDCl3) δ 168.7, 168.6,
146.4, 141.0, 140.2, 129.9, 129.2, 127.8, 120.4, 79.9, 72.6, 68.4, 67.4,
40.8, 39.9, 29.8, 29.4, 28.5, 25.7, 21.4, 18.0, −4.6, −4.9; FAB-MS m/z
601 (M + H)+; FAB-HRMS m/z 601.1486 (Calcd for C26H38O6SiI
601.1482).
24
27′, white solid: Rf (30% EtOAc/hexane) = 0.35; [α]D +14.9
(c 0.60 CHCl3); IR (CHCl3 film, cm−1) 3019, 2929, 2857, 1769, 1729,
1460, 1371, 1214, 1086, 756, 667; 1H NMR (270 MHz, CDCl3) δ 9.79
(dd, J = 2.4. 1.1 Hz, 1H), 7.32 (t, J = 8.1 Hz, 1H), 7.07 (dd, J = 4.3, 0.8
Hz, 1H), 7.07 (dd, J = 4.8, 1.3 Hz, 1H), 6.08 (m, 1H), 4.05 (m, 3H),
3.38 (dd, J = 14.5, 11.8 Hz, 1H), 2.82 (dddd, J = 17.5, 11.0, 8.9,
2.4 Hz, 1H), 2.65 (dddd, J = 17.2, 5.1, 4.0, 1.1 Hz, 1H), 2.39 (dd, J =
14.3, 1.3 Hz, 1H), 2.21 (s, 3H), 2.01 (m, 1H), 1.72 (m, 4H), 1.33 (m,
1H), 0.87 (s, 9H), 0.05 (s, 6H); 13C NMR (67.5 MHz, CDCl3) δ
198.7, 168.7, 168.0, 146.5, 139.4, 130.0, 128.4, 127.8, 120.6, 73.3, 68.6,
67.7, 65.6, 48.1, 40.4, 39.9, 38.7, 37.3, 25.7, 20.8, 18.0, −4.7, −4.6;
FAB-MS m/z 499 (M + Na)+; FAB-HRMS m/z 499.2131 (Calcd for
C25H36O7SiNa 499.2128).
37 (E)-isomer. Colorless oil: Rf (30% EtOAc/hexane) = 0.60 (0.65
for Z-isomer); [α]D24 +6.7 (c 0.4 CHCl3); IR (film, cm−1) 2927, 1770,
1
1717, 1457, 1365, 1263, 1198, 1088; H NMR (270 MHz, CDCl3) δ
7.35 (t, J = 8.1 Hz, 1H), 7.12 (dd, J = 8.1, 0.8 Hz, 1H), 7.07 (dd, J =
7.5, 0.8 Hz, 1H), 6.56 (dt, J = 14.3, 7.0 Hz, 1H), 6.22 (dt, J = 14.5, 1.3
Hz, 1H), 5.88 (m, 1H), 5.73 (dtd, J = 12.9, 2.4, 0.8 Hz, 1H), 5.65 (m,
1H), 4.17 (dt, J = 11.6, 2.4 Hz, 1H), 3.97 (m, 1H), 3.35 (dd, J = 14.0,
11.8 Hz, 1H), 2.43 (m, 3H), 2.30 (s, 3H), 2.24 (s, 1H), 1.81 (m, 3H);
13C NMR (67.5 MHz, CDCl3) δ 168.7, 168.6, 146.4, 140.9, 139.3,
130.1, 129.1, 128.8, 127.6, 125.7, 120.7, 78.0, 75.8, 72.4, 66.1, 40.7,
40.4, 36.6, 31.2, 21.4; FAB-MS m/z 469 (M + H)+; FAB-HRMS m/z
469.0515 (Calcd for C20H22O5I 469.0512).
24
32, white solid: Rf (30% EtOAc/hexane) = 0.35; [α]D +22.8
(c 0.35 CHCl3); IR (CHCl3 film, cm−1) 3034, 2914, 1768, 1730, 1460,
1
1371, 1215, 1078, 757; H NMR (270 MHz, CDCl3) δ 9.79 (dd, J =
2.4. 1.1 Hz, 1H), 7.32 (t, J = 7.8 Hz, 1H), 7.06 (d, J = 1.3 Hz, 1H),
7.03 (dd, J = 2.7, 0.8 Hz, 1H), 6.11 (m, 1H), 4.06 (m, 1H), 3.90 (m,
1H), 3.78 (dddd, J = 11.6, 6.7, 5.4, 1.6 Hz, 1H), 3.34 (dd, J = 14.0,
11.6 Hz, 1H), 2.81 (dddd, J = 17.2, 11.3, 8.9, 2.4 Hz, 1H), 2.65 (dddd,
J = 17.2, 5.1, 3.2, 0.8 Hz, 1H), 2.62 (dd, J = 14.3, 1.6 Hz, 1H), 2.21 (s,
3H), 1.67 (m, 6H), 0.93 (s, 9H), 0.08 (s, 3H), 0.07 (s, 3H); 13C NMR
(67.5 MHz, CDCl3) δ 198.7, 168.7, 168.2, 146.4, 140.2, 130.7, 129.0,
127.7, 120.4, 80.0, 68.6, 68.3, 67.4, 48.1, 40.0, 29.8, 29.2, 28.4, 25.7,
20.8, 18.0, −4.6, −4.9; FAB-MS m/z 499 (M + Na)+; FAB-HRMS
m/z 499.2124 (Calcd for C25H36O7SiNa 499.2128).
Coupling of Iodoalkenes 6′ with 7, Synthesis of 28′. The
reaction of 6′ (10 mg, 0.016 mmol) and 7 (10.5 mg, 0.083 mmol) was
performed by the same procedure described for the synthesis of 28.
After the work up, purification of the crude product by flash column
chromatography (silica gel, 30% EtOAc/hexane) provided 28′
(6.5 mg) in 70% yield and the corresponding Z-isomer (2.2 mg) in
24% yield. Data for major E-isomer 28′, white solid: Rf (30% EtOAc/
hexane) = 0.41 (0.50 for Z-isomer); [α]D24 +41.9 (c 0.25 CHCl3); 1H
NMR (270 MHz, CDCl3) δ 7.27 (m, 3H), 7.16 (t, J = 7.5 Hz, 1H),
6.93 (dd, J = 14.3, 10.8 Hz, 1H), 6.77 (m, 3H), 6.37 (br, s, 1H), 5.85
(m, 1H), 5.54 (d, J = 11.6 Hz, 1H), 5.47 (m, 1H), 5.19 (dt, J = 13.5,
7.5 Hz, 1H), 4.03 (m, 3H), 3.39 (dd, J = 13.7, 11.8 Hz, 1H), 2.37 (m,
2H), 2.25 (dtd, J = 15.1, 7.8, 1.8 Hz, 2H), 1.94 (m, 1H), 1.72 (m, 4H),
1.33 (m, 2H), 1.02 (t, J = 7.3 Hz, 3H), 0.86 (s, 9H), 0.05 (s, 6H); 13C
NMR (67.5 MHz, CDCl3) δ 169.4, 163.4, 152.3, 142.6, 139.0, 137.1,
130.6, 125.7, 123.8, 123.4, 122.4, 119.0, 115.1, 107.2, 77.4, 73.7, 67.6,
65.6, 40.8, 40.2, 38.4, 37.1, 34.7, 25.8, 20.7, 18.0, 13.9, −4.7, −4.6;
FAB-MS m/z 556 (M + H)+; FAB-HRMS m/z 556.3097 (Calcd for
C31H46NO6Si 556.3094).
24
36, colorless oil, Rf (40% EtOAc/hexane) = 0.25; [α]D +47.9
(c 0.65 CHCl3); IR (CHCl3 film, cm−1) 3034, 2914, 1768, 1726, 1459,
1370, 1264, 1202, 1087, 733; 1H NMR (270 MHz, CDCl3) δ 9.81 (dd,
J = 2.4. 1.1 Hz, 1H), 7.35 (t, J = 7.5 Hz, 1H), 7.12 (dd, J = 7.5, 0.8 Hz,
1H), 7.06 (dd, J = 8.1, 0.8 Hz, 1H), 6.15 (m, 1H), 5.88 (m, 1H), 5.74
(dtd, J = 10.2, 2.4, 1.1 Hz, 1H), 4.18 (dt, J = 12.4, 2.4 1H), 4.02 (m,
1H), 3.36 (dd, J = 14.0, 11.8 Hz, 1H), 2.83 (dddd, J = 17.5, 11.0, 8.9,
2.7 Hz, 1H), 2.68 (dddd, J = 17.2, 5.6, 4.6, 1.1 Hz, 1H), 2.49 (dd, J =
14.3, 2.4 Hz, 1H), 2.21 (s, 3H), 1.92 (m, 2H), 1.80 (td, J = 6.7, 2.7 Hz,
2H); 13C NMR (67.5 MHz, CDCl3) δ 198.7, 168.7, 168.1, 146.4,
139.3, 130.2, 128.9, 128.8, 127.5, 125.6, 120.7, 75.8, 68.4, 66.1, 48.1,
40.5, 36.6, 31.1, 20.8; FAB-MS m/z 345 (M + H)+; FAB-HRMS m/z
345.1342 (Calcd for C19H20O6 345.1339).
Coupling of Iodoalkenes 33 and 37 with 7. The coupling
reaction of 33 and 37 with 7 was performed by the same manner
described for the synthesis of 28 to give 38 and 5, both in 94% yield,
respectively. 38, 94% yield. White solid: Rf (30% EtOAc/hexane) =
24
1
Preparation of Iodoalkenes 6′, 33, and 37. Slurry of CrCl2
(49 mg, 0.40 mmol) in dry THF (2 mL) was stirred at rt for 15 min.
The reaction was cooled to 0 °C. A solution of aldehyde, 27′, 32, or 36
(0.06 mmol) and iodoform (53 mg, 0.13 mmol) in THF (1 mL) was
added. The resulting reddish-brown mixture was stirred for 6 h. The
reaction mixture was diluted with water and extracted with ether.
The organic layer was washed with saturated sodium thiosulfate and
dried over MgSO4. Removal of solvent under reduced pressure
and purification by flash column chromatography (silica gel, 10%
0.40; [α]D +42.9 (c 0.25 CHCl3); H NMR (270 MHz, CDCl3) δ
7.24 (m, 2H), 7.16 (t, J = 8.3 Hz, 1H), 6.93 (m, 2H), 6.74 (m, 2H),
6.33 (br, s, 1H), 5.86 (m, 1H), 5.53 (d, J = 11.1 Hz, 1H), 5.46 (m,
1H), 5.18 (dt, J = 14.5, 7.3 Hz, 1H), 4.08 (m, 1H), 3.91 (m, 1H), 3.73
(m, 1H), 3.42 (dd, J = 14.0, 11.8 Hz, 1H), 2.48 (dd, J = 14.0, 1.3 Hz,
1H), 2.38 (t, J = 7.0 Hz, 2H), 2.25 (dtd, J = 15.1, 7.5, 1.3 Hz, 2H),
1.65 (m, 6H), 1.02 (t, J = 7.3 Hz, 3H), 0.93 (s, 9H), 0.08 (s, 3H), 0.06
(s, 3H); 13C NMR (67.5 MHz, CDCl3) δ 169.3, 163.4, 152.4, 142.5,
139.8, 137.1, 130.7, 125.7, 123.8, 122.4, 119.0, 114.9, 107.2, 80.0, 74.1,
397
dx.doi.org/10.1021/jo2019762 | J. Org. Chem. 2012, 77, 388−399

The Journal of Organic Chemistry
Article
68.4, 67.6, 40.0, 34.9, 30.6, 28.8, 28.1, 25.7, 20.7, 18.0, 13.9, −4.6,
−4.9; FAB-MS m/z 556 (M + H) +; FAB-HRMS m/z 556.3085
(Calcd for C31H46NO6Si 556.3094). 5, white solid: mp 149−151 °C
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: juenishi@mb.kyoto-phu.ac.jp.
24
(methanol); Rf (40% EtOAc/hexane) = 0.25; [α]D +3.5 (c 0.25
CHCl3); 1H NMR (270 MHz, acetone-d6) δ 9.10 (d, J = 10.0 Hz, 1H),
8.43 (s, 1H), 7.51 (t, J = 10.8 Hz, 1H), 7.15 (t, J = 7.5 Hz, 1H), 6.89
(m, 2H), 6.79 (d, J = 7.0 Hz, 1H), 5.81 (m, 3H), 5.51 (m, 1H), 5.26
(dt, J = 14.5, 7.2 Hz, 1H), 4.08 (m, 1H), 3.92 (m, 1H), 3.22 (dd, J =
13.7, 11.8 Hz, 1H), 3.46 (dd, J = 13.5, 1.8 Hz, 1H), 2.35 (m, 1H), 2.27
(dtd, J = 15, 7.5, 1.6 Hz, 2H), 1.89 (m, 2H), 1.69 (m, 2H), 0.99 (t, J =
7.5 Hz, 3H); 13C NMR (67.5 MHz, acetone-d6) δ 171.6, 164.7, 155.0,
142.5, 141.3, 137.9, 131.6, 131.5, 127.6, 127.4, 127.1, 126.4, 123.0,
121.9, 115.7, 109.1, 78.1, 75.5, 68.2, 42.1, 38.0, 37.0, 33.1, 22.1, 15.4;
FAB-MS m/z 556 (M + H)+; FAB-HRMS m/z 424.2129 (Calcd for
C25H30NO5 424.2124).
ACKNOWLEDGMENTS
■
This work was supported by Grant-in-Aid for Scientific
Research from the Ministry of Education, Culture, Sports,
Science, and Technology, Japan. S.S.P. acknowledges the Japan
Society for the Promotion of Science.
REFERENCES
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24
1
EtOAc/hexane) = 0.20; [α]D −10.9 (c 0.20, CH3CN); H NMR
(270 MHz, acetone-d6) δ 9.10 (d, J = 11.3 Hz, 1H), 8.48 (s, 1H), 7.51
(m, 1H), 7.13 (t, J = 8.3 Hz, 1H), 6.89 (m, 2H), 6.77 (m, 2H), 6.69 (d,
J = 7.5 Hz, 1H), 5.76 (m, 2H), 5.45 (m, 1H), 5.24 (dt, J = 14.8, 7.8 Hz,
1H), 3.92 (m, 3H), 3.78 (d, J = 4.6 Hz, 1H), 3.31 (dd, J = 13.2, 10.8
Hz, 1H), 2.30 (m, 5H), 1.70 (m, 6H), 0.99 (t, J = 7.3 Hz, 3H); 13C
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137.7, 137.6, 131.3, 127.2, 126.3, 123.1, 121.8, 115.3, 108.9, 76.6, 75.4,
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(M + H)+; FAB-HRMS m/z 442.2224 (Calcd for C25H31NO6
442.2230).
24
4, 93% yield. White solid: mp 107−110 °C (methanol); [α]D
1
−85.0 (c 0.20, CH3CN); Rf (70% EtOAc/hexane) = 0.31; H NMR
(500 MHz, acetone-d6) δ 9.10 (d, J = 11.0 Hz, 1H), 8.45 (s, 1H), 7.51
(t, J = 11 Hz, 1H), 7.11 (t, J = 7.5 Hz, 1H), 6.89 (m, 2H), 6.77 (d, J =
7.5 Hz, 1H), 6.70 (d, J = 7.5 Hz, 1H), 5.79 (q, J = 7.5 Hz, 1H), 5.74
(d, J = 11 Hz, 1H), 5.45 (m, 1H), 5.24 (dt, J = 14.5, 7.5 Hz, 1H), 3.97
(m, 2H), 3.80 (d, J = 7.5 Hz, 1H), 3.16 (dd, J = 15.0, 11.0 Hz, 1H),
2.63 (t, J = 13.5 Hz, 1H), 2.30 (m, 4H), 1.71 (m, 6H), 1.00 (t, J = 7.0
Hz, 3H); 13C NMR (67.5 MHz, acetone-d6) δ 170.9, 164.4, 154.7,
142.3, 141.7, 137.6, 131.1, 127.2, 126.2, 123.0, 121.7, 115.0, 108.8,
80.6, 75.2, 70.0, 69.0, 36.9, 33.0, 32.0, 24.1, 21.8, 15.1; FAB-MS m/z
442 (M + H)+; FAB-HRMS m/z 442.2227 (Calcd for C25H32NO6
442.2230),
Experiment for the Cytostatic Activity. Cell lines (U-937
(human leukemic monocyte lymphoma cell line) and HL-60 (human
promyelocytic leukemia cells)) were provided by the RIKEN BRC
through the National Bio-Resource Project of the MEXT, Japan.
These cells were cultured in RPMI-1640 supplemented with 10% fetal
bovine serum (FBS). PC-3 cells (human prostate cancer cell line) were
cultured in DMEM supplemented with 10% FBS.
MTT Assay. Growth inhibition of various cell lines was determined
4 days after the addition of compounds by a 3-(4,5-dimethylthiazol-2-
yl)-2,5-diphenyltetrazolium bromide (MTT) assay according to the
manufacturer’s directions (Nacalai Tesque Cat. 23506). Briefly, 5 ×
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cells were treated with various concentrations of compounds for
4 days. Then, the treated cells were incubated with MTT reagents at
37 °C for 4 h. After dissolving the resulting crystals in DMSO, plates
were read in a microplate reader (model 680, Bio lad) at 570 nm.
Control contained the same concentration of DMSO as the compound
treated cells.
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