Syntheses of Combretastatins D-1, D-2, and D-4 via Ring Contraction by Flash Vacuum Pyrolysis

Article abstract of DOI:10.1021/acs.joc.6b02586

We report the syntheses of combretastatins D-2 and D-4 as well as a formal synthesis of combretastatin D-1 by a conceptually new route harnessing a ring-contracting flash vacuum pyrolytic extrusion of sulfur dioxide from the respective 16-membered sulfone precursors. Via flash vacuum pyrolysis, even metaparacyclophanes as small and strained as the hitherto unknown oxa[1.5]metaparacyclophane could be prepared as a side product en route to combretastatin D-2 by synchronous extrusion of SO₂ and CO₂.

Full text of DOI:10.1021/acs.joc.6b02586

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Article
Syntheses of Combretastatins D-1, D-2, and D-4
via Ring Contraction by Flash Vacuum Pyrolysis
Marina Harras, Wolfgang Milius, R. Alan Aitken, and Rainer Schobert
J. Org. Chem., Just Accepted Manuscript • Publication Date (Web): 07 Dec 2016
Downloaded from http://pubs.acs.org on December 7, 2016
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The Journal of Organic Chemistry
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Syntheses of Combretastatins D-1, D-2, and D-4
via Ring Contraction by Flash Vacuum Pyrolysis
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†
‡
§,
†,
Marina Harras, Wolfgang Milius, R. Alan Aitken * and Rainer Schobert *
†
Organic Chemistry Laboratory, University Bayreuth, 95440 Bayreuth, Germany
‡
Lehrstuhl fuer Anorganische Chemie I, University Bayreuth, 95440 Bayreuth, Germany
§
EaStCHEM School of Chemistry, University of St Andrews, North Haugh, St Andrews, Fife, KY16 9ST,
U. K.
raa@st-and.ac.uk and Rainer.Schobert@uni-bayreuth.de
RECEIVED
We report the syntheses of combretastatins D-2 and D-4, as well as a formal synthesis of combretastatin
D-1 by a conceptually new route harnessing a ring-contracting flash vacuum pyrolytic extrusion of
sulfur dioxide from the respective 16-membered sulfone precursors. Via flash vacuum pyrolysis even
metaparacyclophanes as small and strained as the hitherto unknown oxa[1.5]metaparacyclophane could
be prepared as a side product en route to combretastatin D-2 by synchronous extrusion of SO and CO .
2
2
Keywords: Combretastatin D, diaryl ether heptanoid, oxa[1.5]metaparacyclophane, flash vacuum
pyrolysis.
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Introduction
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Naturally occurring cyclic diaryl ether heptanoids (DAEH) share an oxa[1.7]metaparacyclophane
scaffold while differing in the nature and position of additional functional groups on the n-heptyl spacer
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and the phenyl rings. The high incidence of biological activity among these plant metabolites, their
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challenging structures, and their potential chirality originating from a restricted conformational
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flexibility attracted the interest of organic chemists. Figure 1 shows typical examples of natural DAEH:
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the longest known optically active acerogenin A 1 and the optically inactive diene tedarene A 2. The
combretastatins D constitute a particulary interesting subclass of DAEH, both chemically and with
6
respect to their biological activity. They are metabolites of various Combretaceae species which feature
a lactone group as part of the 7-atom tether. The epoxy macrolide (–)-combretastatin D-1 3 and its
deoxygenated congener combretastatin D-2 4 were isolated from the South-African bushwillow
7
Combretum caffrum and were structurally elucidated in the late 1980s by Pettit et al. They were found
to interfere with the dynamics of the polymerization of tubulin in cells by stabilizing the microtubules,
in contrast to the stilbene-like combretastatins A which stabilize the tubulin heterodimers and inhibit
8
their polymerization. Pettit et al. also reported antiproliferative activities of combretastatin D-2 with
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single-digit micromolar IC50 values against various cancer cell lines. The saturated analogue
combretastatin D-4 5 was isolated from the stem of Getonia floribunda (Combretaceae), characterized,
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and found inactive in all biological tests by Vongvanich et al. The same compound was later isolated
by Ponnapalli et al. from the Mangrove shrub Aegeceras corniculatum (Aegecerataceae) and termed
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corniculatolide A. No specific optical rotations were reported of combretastatins D-2 and D-4. The
known synthetic approaches to the combretastatins D differ by the ring closure reaction and by the
method and timing of the introduction of the alkene or epoxide, respectively. The first synthesis of
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combretastatin D-2 4 by Boger et al. employed an Ullmann coupling for the cyclization and a Still-
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Gennari olefination to introduce the (Z)-alkene. The groups of Deshpande and Couladouros closed
the macrocycle by means of a Mitsunobu lactonization under high-dilution conditions which gave high
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yields only when preceding the introduction of the alkene. Mann et al. used a (Z)-selective Wittig
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olefination to close the ring of 4. Combretastatin D-1 3 was synthesized by Rychnovsky et al. and
Couladouros et al. by a Mitsunobu macrolactonization followed by introduction of the epoxide, either
16
via epoxidation of an alkene with mCPBA or enantioselectively with a Jacobsen catalyst, or via
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dehydration of a vicinal diol. The macrocycle of combretastatin D-4 5 was closed in previous
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syntheses by the groups of Imoto , Reddy, and Pettit either via Mitsunobu lactonization or Ullmann
coupling.
Because of our interest in antimitotic agents and the combretastatins in particular, we now developed a
conceptually new approach to the combretastatins D that generates the 15-membered ring via
contraction of a macrocyclic sulfone precursor by flash vacuum pyrolysis (FVP).
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Figure 1. Structures of diaryl ether heptanoids.
Results and Discussion
Initially, we intended to contract 16-membered sulfone derivatives of the respective combretastatins D
20
by extrusion of sulfur dioxide according to the Ramberg-Baecklund protocol. Although all attempts to
initiate this reaction failed, the sulfone precursors turned out to undergo the desired ring contraction
when submitted to a flash vacuum pyrolysis under carefully adjusted conditions. Scheme 1 shows the
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synthesis of sulfone 14, the precursor leading up to combretastatin D-2 4. 4-Bromobenzaldehyde 6 was
converted to the (Z)-bromocinnamate 7 by a HWE reaction with the anion of an Ando ester phosphonate
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in near quantitative yield. Reduction of this ester with DIBAL-H afforded the (Z)-bromocinnamyl
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alcohol 8 which was submitted to a copper-mediated Ullmann coupling to give the corresponding
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diphenyl ether 9 in 57% yield. Steglich-Hassner esterification of the alcohol 9 with S-acetylthioacetic
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acid furnished aldehyde 10 which was reduced to the benzyl alcohol 11 with sodium borohydride.
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Deacetylation of 11 with hydrazine liberated the thiol 12 which underwent an intramolecular
thioetherification to give macrolide 13 when treated with sulfuric acid in acetonitrile. Quantitative
26
oxidation with mCPBA eventually afforded sulfone 14.
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SCHEME 1. Synthesis of Sulfone 14, a Precursor to Combretastatin D-2.
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Reagents and conditions: (i) (PhO) P(O)CH CO Me, KOtBu, THF, !78 °C, 2 h; (ii) DIBAL-H,
2
2
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CH Cl , –78 °C, 1 h; (iii) isovanillin, CuI, Cs CO , N,N-dimethylglycine, 1,4-dioxane, reflux, 24 h; (iv)
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S-acetylthioacetic acid, EDC, DMAP, CH Cl , rt, 3 h; (v) NaBH , 20% MeOH/THF (1:1), rt, 5 min; (vi)
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4
H NNH , MeCN, rt, 2 h; (vii) H SO , MeCN, 0 °C, 30 min; (viii) mCPBA, CH Cl , 0 °C ! rt, 2 h.
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2
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The Journal of Organic Chemistry
Sulfone 20, the saturated congener of 14 and precursor to combretastatin D-4 5, was obtained
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analogously starting with the PtO -catalyzed hydrogenation of the more readily available (E)-isomer of
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9 (cf the Supporting Information) (Scheme 2).
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SCHEME 2. Synthesis of Sulfone 20, a Precursor to Combretastatin D-4.
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Reagents and conditions: (i) PtO , MeOH, H (1 bar), rt, 15 min; (ii) S-acetylthioacetic acid, EDC,
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DMAP, CH Cl , rt, 3 h; (iii) NaBH , 20% MeOH/THF (1:1), rt, 5 min; (iv) H NNH , MeCN, rt, 2 h; (v)
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H SO , MeCN, 0 °C, 30 min; (vi) mCPBA, CH Cl , 0 °C ! rt, 2 h, 98%.
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A formal synthesis of combretastatin D-1 3 was achieved by first establishing the macrolide by
extrusion of SO from a cyclic sulfone precursor containing a protected, appropriately configured syn-
2
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diol (Scheme 3). The diol was obtained by first protecting the alcohol (E)-9 as the pivalate 21 which
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was dihydroxylated according to Sharpless with ADmix-ß to afford pure syn-diol 22 in almost 60%
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yield and > 99% ee as to chiral HPLC. The hydroxy groups were protected as TIPS ethers to give ester
3
0
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3 which was reduced to the diol 24 with DIBAL-H. Selective oxidation with MnO2 afforded the
hydroxyaldehyde 25 which was esterified with S-acetylthioacetic acid to give aldehyde 26. The latter
was reduced quantitatively to the benzylalcohol 27 which was deacetylated with hydrazine to leave the
31
thiol 28 in 94% yield. Finally, a new mild macrocyclization protocol employing SO • pyridine instead
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of sulfuric acid afforded the thioether 29 which was oxidized to the cyclic sulfone 30 with mCPBA.
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SCHEME 3. Synthesis of Sulfone 30, a Precursor to Combretastatin D-1.
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Reagents and conditions: (i) PivCl, CH Cl , 40 °C, 20 h; (ii) ADmix-ß, MeSO NH , tBuOH/H O (1:1),
2
2
2
2
2
3
°C, 28 h; (iii) TIPSOTf, 2,6-lutidine, DMF, 60 °C, 27 h; (iv) DIBAL-H, CH Cl ,
2 2
–78 °C, 1 h; (v) MnO , CHCl , rt, 22 h; (vi) S-acetylthioacetic acid, EDC, DMAP, CH Cl , rt, 18 h; (vii)
2
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2
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NaBH , 20% MeOH/THF (1:1), rt, 10 min; (viii) H NNH , MeCN, rt, 2 h; (ix) SO •py, toluene, 111 °C,
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h; (x) mCPBA, CH Cl , 0 °C ! rt, 2 h, 83%.
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The cyclic sulfones 14, 20, and 30 were then subjected to various modifications of the Ramberg-
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Baecklund reaction, however, to no avail. In contrast, their flash vacuum pyrolysis
under carefully
adjusted conditions led to the extrusion of SO with formation of the 15-membered combretastatin D
2
skeleton. Extrusion of SO using flash vacuum pyrolysis has been widely used in classic synthetic
2
3
4
approaches to cyclophanes but the targets in these studies were typically hydrocarbons with no
sensitive functional groups present. For all three compounds 14, 20, and 30, 600 °C was found to be the
optimum temperature, with 550 °C and lower temperatures giving partly unchanged starting material,
and values of 625 °C and higher leading to increased decomposition and in the case of 14 to increased
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formation of 35 at the expense of the desired product 34. The sterically least hindered sulfone 20
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afforded the ring-contracted macrolide 31 in 53% yield when submitted to a FVP at 600 °C and 5 " 10
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Torr. It was demethylated with AlCl /EtSH to give combretastatin D-4 5 in 96% yield (Scheme 4). The
3
FVP of sulfone 30 bearing two bulky OTIPS groups also furnished the corresponding macrolide 32
albeit in only 30% yield. Deprotection of 32 with aqueous HF afforded the diol 33 in 53% yield. To
complete the synthesis of combretastatin D-1 the diol 33 would have to be demethylated with
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AlCl /EtSH and converted to the target epoxide by dehydration according to Couladouros et al. For
3
sulfone 14, void of bulky groups and featuring a Z-alkene that might confer some rigidity and pre-
orientation for the SO extrusion, we expected a smoothly proceeding FVP. What we actually found
2
upon FVP of sulfone 14 was a separable mixture of the expected macrolide 34 (20%), which was
demethylated with AlCl /EtSH to give combretastatin D-2 4, and of the first ever
3
oxa[1.5]metaparacyclophane 35 (6%), originating from a concomitant extrusion of SO and CO . A
2
2
single crystal X-ray diffraction analysis of 35 showed that the two phenyl rings were oriented almost
perpendicular to each other, with the isolated H-atom of the trisubstituted phenyl ring located
perpendicular to the center of the disubstituted phenyl ring at a remarkably short distance of 2.28 Å
(Fig. 2). The structure of 35 in solution probably does not deviate much from its crystal structure since
1
in the H NMR spectrum of 35 this H-atom resonates at a conspicuous high-field shift of 4.08 ppm.
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a
SCHEME 4. Flash Vacuum Pyrolysis of Sulfones 14, 20, and 30.
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&$%&%'%*
!#'
!,-#
,:-
a
–2
Reagents and conditions: (i) Flash vacuum pyrolysis, 600 °C, 5 " 10 Torr; (ii) AlCl , EtSH, CH Cl ,
17 °C, 1 h; (iii) HF , THF, rt, 3 d.
(aq)
3
2
2
!
8
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The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Figure 2. Molecular structure of oxa[1.5]metaparacyclophane 35, as thermal ellipsoid representations at
5
0% probability level showing the atomic numbering schemes (H-atoms omitted). CCDC 1505171.
Selected bond lengths [Å] and angles [°]: O2–C11 1.408(6), O2–C13 1.426(6), C1–C2 1.330(9), C1–
C16 1.492(8), C5–C6 1.515(7), O2–C11–C9 117.6(4), O2–C11–C12 123.6(4), C5–C6–C12 121.3(4),
O2–C13–C14 117.9(5), O2–C13–C18 118.3(5), O2–C13–C18–C17 151.6(5), O2–C13–C14–C15
1
51.4(5), C1–C16–C17–C18 –154.2(5), C16–C1–C2–C3 –2.1(9), C1–C2–C3–C4 94.6(7).
Conclusions
The combretastatins D-1, D-2, and D-4 were synthezised by a conceptually new route harnessing a ring-
contracting flash vacuum pyrolytic extrusion of sulfur dioxide from the respective 16-membered sulfone
precursors. The latter were obtained by an intramolecular thiol benzylation followed by an oxidation of
the resulting thioether. Via flash vacuum pyrolysis even the oxa[1.5]metaparacyclophane 35 could be
prepared as a side product en route to combretastatin D-2 by synchronous extrusion of SO and CO .
2
2
The mechanism of this process as well as the chemistry and potential chirality of such diaryl ether
pentanoids (DAEP) remain to be elucidated.
9
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Experimental Section
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
General Remarks. All moisture or air sensitive reactions were performed in oven-dried glassware
under an argon atmosphere using standard Schlenk techniques. IR spectra were recorded with an FT-IR
spectrophotometer equipped with an ATR unit. Melting Points were determined with a Büchi M-565
melting point apparatus and are uncorrected. Chemical shifts of NMR signals are given in parts per
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
13
million (!) downfield from tetramethylsilane for H and C NMR spectra. Mass spectra were obtained
under EI (70 eV) conditions. High resolution mass spectra were obtained with a UPLC/Orbitrap MS
system in ESI mode. For chromatography silica gel 60 (230-400 mesh) was used. Flash vacuum
pyrolysis (FVP) was carried out in a conventional flow system by subliming the starting material
through a horizontal quartz tube (30 " 2.5 cm) externally heated by a tube furnace to 600 °C and
–
2
maintained at a pressure of 5 " 10 torr by a rotary vacuum pump. Products were collected in a liquid
N cooled U-shaped trap and purified as noted.
2
3
5
Methyl (Z)-4-Bromocinnamate 7. A solution of (PhO) P(O)CH CO Me (11.4 g, 37.2 mmol) in dry
2
2
2
THF (315 mL) was treated with KOtBu (5.01 g, 44.7 mmol) at !78 °C for 15 min under an inert gas
atmosphere. p-Bromobenzaldehyde 6 (6.25 g, 33.8 mmol) was added and the mixture was stirred at !78
°
C. After 2 h the reaction mixture was quenched with saturated aqueous NH Cl (20 mL) and diluted
4
with EtOAc (30 mL). After separation of the layers the aqueous phase was extracted three times with
EtOAc (20 mL). The combined organic phases were washed with brine and dried over anhydrous
Na SO . The volatiles were removed under reduced pressure and the crude product was purified by
2
4
column chromatography (cyclohexane/EtOAc 5:1) to yield 7 (7.91 g, 32.8 mmol, 97%) as colorless
36
crystals of mp 41–44 °C [lit. 40–42 °C]; R = 0.66 (cyclohexane/EtOAc 3:1). IR (ATR) # 2950,
f
max
!
1
1
1721, 1632, 1587, 1488, 1439, 1197, 1168, 1072, 1011, 844, 819 cm ; H NMR (CDCl , 500 MHz) !
3
13
3
.71 (s, 3 H), 5.98 (d, J = 12.7 Hz, 1 H), 6.88 (d, J = 12.7 Hz, 1 H), 7.47–7.50 (m, 4 H); C NMR
(
CDCl , 125 MHz) ! 51.5, 119.9, 123.4, 131.2, 131.4, 133.5, 142.3, 166.3; MS (EI) m/z (%) 242 (54),
3
1
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+
2
40 (56) [M] , 211 (87), 209 (88), 183 (35), 181 (37), 102 (100), 75 (26), 51 (31).
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
(
Z)-4-Bromocinnamyl alcohol 8. A solution of ester 7 (9.20 g, 38.3 mmol) in CH Cl (72 mL) was
2 2
cooled to !78 °C and treated dropwise with DIBAL-H (1M in hexane, 84.2 mL, 84.2 mmol). After 1 h
the reaction mixture was quenched with MeOH (20 mL) and the formed Al(OH) precipitate was
3
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
carefully dissolved by addition of 1M aqueous HCl solution (100 mL). The reaction mixture was
allowed to warm to room temperature and the layers were separated. The aqueous phase was extracted
with CH Cl (2 " 100 mL). The combined organic phases were washed with brine (100 mL), dried over
2
2
anhydrous Na SO and concentrated under reduced pressure. The crude product was crystallized from
2
4
9
hexane to afford 6.62 g of 8 (31.1 mmol, 81%) as colorless crystals of mp 69–71 °C [lit. 69.3–70.6 °C];
R 0.38 (cyclohexane/EtOAc 3:1). IR (ATR) # 3239, 3016, 1488, 1388, 1323, 1114, 1077, 1026,
f
max
!
1 1
1
005, 974, 943, 835, 791, 671 cm ; H NMR (CDCl , 500 MHz) ! 1.57 (t, J = 5.5 Hz, OH), 4.36–4.42
3
(
(
(
m, 2 H), 5.90 (dt, J = 11.8, 6.5 Hz, 1 H), 6.50 (d, br, J = 11.8 Hz, 1 H), 7.05–7.11 (m, 2 H), 7.44–7.49
1
3
m, 2 H); C NMR (CDCl , 125 MHz) ! 59.5, 121.3, 130.0, 130.3, 131.4, 131.8, 135.3; MS (EI) m/z
3
+
%) 214 (88), 212 (90) [M ], 171 (80), 169 (78), 158 (28), 156 (30), 133 (100), 115 (51), 104 (38), 91
(63), 77 (43), 66 (25), 55 (31), 51(33).
(
Z)-3-[4-(3-Hydroxyprop-1-en-1-yl)phenoxy]-4-methoxybenzaldehyde (Z)-9. A solution of alcohol 8
(3.74 g, 17.6 mmol) and isovanillin (4.00 g, 26.3 mmol) in 1,4-dioxane (13.4 mL) was treated with
Cs CO (11.4 g, 35.1 mmol), CuI (334 mg, 1.76 mmol), and dimethylglycine hydrochloride (544 mg,
2
3
5
.27 mmol). The resulting suspension was stirred at 101 °C for 24 h, cooled, and treated with ethyl
acetate (50 mL). The organic phase was washed with brine (50 mL), the aqueous phase was extracted
with ethyl acetate (3 " 50 mL), and the combined organic layers were dried over anhydrous Na SO .
2
4
The volatiles were removed under reduced pressure and the remaining crude was purified by column
chromatography (cyclohexane/ethyl acetate 3:1) to yield (Z)-9 (2.84 g, 9.99 mmol, 57%) as a light
yellow oil of R 0.38 (cyclohexane/ethyl acetate 1:1). IR (ATR) # 3349, 2844, 1683, 1598, 1578,
f
max
1
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!
1
1
1
503, 1432, 1273, 1220, 1163, 1119, 1012, 813, 637 cm ; H NMR (CDCl , 500 MHz) ! 1.67 (s, br,
3
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
OH), 3.94 (s, 3 H), 4.43 (dd, J = 6.5, 1.3 Hz, 2 H), 5.84 (dt, J = 11.7, 6.5 Hz, 1 H), 6.52 (d, J = 11.7 Hz,
H), 6.91–6.97 (m, 2 H), 7.11 (d, J = 8.4 Hz, 1 H), 7.15–7.20 (m, 2 H), 7.47 (d, J = 2.0 Hz, 1 H), 7.67
1
1
3
(
dd, J = 8.4, 2.0 Hz, 1 H), 9.82 (s, 1 H); C NMR (CDCl , 125 MHz) ! 56.3, 59.6, 112.1, 117.6, 119.8,
3
+
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
28.3, 130.2, 130.25, 130.3, 130.5, 131.9, 146.0, 156.0, 156.3, 190.3; HRMS (ESI) m/z [M!H O+H]
2
+
calcd for C H O 267.1016, found 267.1010.
1
7
15
3
(E)-9. Analogously to the synthesis of (Z)-9, the isomer (E)-9 (5.94 g, 20.9 mmol, 80%) was obtained as
17b
a colorless oil from (E)-4-bromocinnamyl alcohol
(5.61 g, 26.3 mmol), isovanillin (6.00 g,
3
9.4 mmol), Cs CO (17.1 g, 52.6 mmol), CuI (0.50 g, 2.63 mmol) and dimethylglycine hydrochloride
2 3
(
0.82 g, 7.88 mmol). R 0.12 (cyclohexane/ethyl acetate 2:1). IR (ATR) # 3502, 2843, 1671, 1598,
f
m
a
x
!
1
1
1
580, 1506, 1435, 1402, 1264, 1228, 1172, 1123, 1088, 1012, 966, 854, 813, 790, 641, 632 cm ; H
NMR (CDCl , 500 MHz) ! 1.51 (t, J = 5.9 Hz, OH), 3.95 (s, 3 H), 4.32 (td, J = 5.9 Hz, 1.4 Hz, 2 H),
3
6
.29 (dt, J = 15.9 Hz, 5.8 Hz, 1 H), 6.59 (d, J = 15.9 Hz, 1 H), 6.90–6.96 (m, 2 H), 7.11 (d, J = 8.4 Hz, 1
1
3
H), 7.34–7.37 (m, 2 H), 7.45 (d, J = 2.0 Hz, 1 H), 7.67 (dd, J = 8.4 Hz, 2.0 Hz, 1 H), 9.82 (s, 1 H); C
NMR (CDCl , 125 MHz) ! 56.3, 63.8, 112.0, 118.2, 119.5, 127.7, 127.9, 128.2, 130.1, 130.3, 132.2,
3
+
+
1
46.1, 156.2, 156.3, 190.4; HRMS (ESI) m/z [M!H O+H] calcd for C H O 267.1016, found
2 17 15 3
2
67.1013.
(Z)-3-[4-(5-Formyl-2-methoxyphenoxy)phenyl]allyl 2-acetylthioacetate 10. A mixture of alcohol 9
3
7
(2.80 g, 9.84 mmol), CH Cl (90 mL), S-acetylthioacetic acid (1.45 g, 10.8 mmol), EDC (2.08 g,
2
2
1
0.8 mmol), and DMAP (602 mg, 4.94 mmol) was stirred for 3 h at room temperature and then washed
with 0.1M citric acid (50 mL) and brine (100 mL), dried over Na SO and concentrated under reduced
2
4
pressure. The crude product was purified by column chromatography (cyclohexane/ethyl acetate 3:1) to
yield 10 (2.65 g, 6.63 mmol, 67%) as a colorless oil. R 0.35 (cyclohexane/ethyl acetate 2:1). IR (ATR)
f
#max 2957, 2844, 1738, 1686, 1598, 1578, 1504, 1432, 1394, 1273, 1221, 1155, 1119, 1110, 1016, 958,
!1
1
8
40, 815, 623 cm ; H NMR (CDCl , 500 MHz) ! 2.38 (s, 3 H), 3.73 (s, 2 H), 3.94 (s, 3 H), 4.89 (dd,
3
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J = 6.8, 1.5 Hz, 1 H), 5.78 (dt, J = 11.7, 6.7 Hz, 1 H), 6.65 (d, J = 11.7 Hz, 1 H), 6.92–6.97 (m, 2 H),
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
7
9
1
.12 (d, J = 8.4 Hz, 1 H), 7.16–7.21 (m, 2 H), 7.49 (d, J = 2.0 Hz, 1 H), 7.69 (dd, J = 8.4, 2.0 Hz, 1 H),
1
3
.84 (s, 1 H); C NMR (CDCl , 125 MHz) ! 30.1, 31.5, 56.3, 62.7, 112.2, 117.6, 120.4, 124.4, 128.3,
3
+
30.25, 130.3, 131.1, 132.8, 145.7, 156.45, 156.5, 168.6, 190.2, 193.7; HRMS (ESI) m/zs [M+Na]
+
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
calcd for C H NaO S 423.0873, found 423.0866.
2
1
20
6
(Z)-3-[4-(5-Hydroxymethyl-2-methoxyphenoxy)phenyl]allyl 2-acetylthioacetate 11. Aldehyde 10
(1.53 g, 3.82 mmol) was dissolved in a 1:1 mixture of THF and 20% aqueous MeOH (52 mL). After
addition of NaBH (72.0 mg, 1.91 mmol) the reaction mixture was stirred for 5 min at room
4
temperature, quenched with water (30 mL) and diluted with ethyl acetate (30 mL). After separation of
the layers the aqueous one was extracted with ethyl acetate (2 " 50 mL). The combined organic phases
were washed with brine (100 mL), dried over Na SO , and concentrated under reduced pressure. The
2
2
crude product was purified by column chromatography (cyclohexane/ethyl acetate 2:1, R 0.32) to yield
f
1
1 (1.17 g, 2.90 mmol, 76%) as a colorless oil. IR (ATR) #max 3432, 1735, 1695, 1604, 1505, 1425,
!
1 1
1
270, 1223, 1163, 1124, 1025, 962 cm ; H NMR (CDCl , 500 MHz) ! 1.69 (t, br, J = 4.4 Hz, OH),
3
2.38 (s, 3 H), 3.72 (s, 2 H), 3.83 (s, 3 H), 4.59 (d, J = 4.4 Hz, 2 H), 4.88 (dd, J = 6.7, 1.4 Hz, 2 H), 5.74
dt, J = 11.7, 6.7 Hz, 1 H), 6.63 (d, J = 11.7 Hz, 1 H), 6.88–6.94 (m, 2 H), 6.99 (d, J = 8.4 Hz, 1 H), 7.01
(
1
3
(d, J = 2.1 Hz, 1 H), 7.11–7.18 (m, 3 H, 2-H); C NMR (CDCl , 125 MHz) ! 30.1, 31.5, 56.1, 62.8,
3
6
4.6, 112.8, 116.9, 120.2, 123.7, 123.9, 130.3, 130.1, 133.0, 134.1, 144.6, 150.9, 157.4, 168.6, 193.8;
+
+
HRMS (ESI) m/z [M+Na] calcd for C H NaO S 425.1029, found 425.1023.
21 22
6
(Z)-3-[4-(5-Hydroxymethyl-2-methoxyphenoxy)phenyl]allyl 2-mercaptoacetate 12. A solution of
thioester 11 (2.02 g, 5.00 mmol) in MeCN (140 mL) was treated with hydrazine solution (5.40 mL; the
upper layer of a 1:3 mixture of hydrazine monohydrate and MeCN) and the resulting mixture was stirred
at room temperature for 2 h. After dilution with CHCl (20 mL) the layers were separated and the
3
organic phase was washed successively with 1M aqueous HCl (20 mL), saturated aqueous NaHCO3
(20 mL), and brine (20 mL), then dried over Na SO and concentrated under reduced pressure. The
2
4
1
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crude product was purified by column chromatography (cyclohexane/ethyl acetate 3:1) to afford thiol 12
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
(
f
1.75 g, 4.86 mmol, 97%) as a colorless oil. R 0.19 (cyclohexane/ethyl acetate 2:1). IR (ATR) #max
3
420, 2935, 1729, 1603, 1583, 1504, 1441, 1424, 1267, 1219, 1167, 1121, 1022, 944, 839, 811, 750
!
1 1
cm ; H NMR (CDCl , 500 MHz) ! 1.74 (s, br, 1 H, OH), 2.01 (t, J = 8.2 Hz, 1H, SH), 3.28 (d, J = 8.2
3
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Hz, 2 H), 3.83 (s, 3 H), 4.59 (s, br, 2 H), 4.89 (dd, J = 6.7, 1.4 Hz, 2 H), 5.75 (dt, J = 11.7, 6.7 Hz, 1 H),
6
.64 (d, J = 11.7 Hz, 1 H), 6.89–6.93 (m, 2 H), 6.99 (d, J = 8.3 Hz, 1 H), 7.02 (d, J = 2.0 Hz, 1 H), 7.11–
1
3
7.17 (m, 2 H), 7.15 (dd, J = 8.3, 2.0 Hz, 1 H); C NMR (CDCl , 125 MHz) ! 26.4, 56.1, 62.6, 64.6,
3
1
12.8, 116.9, 120.2, 123.8, 123.9, 130.1, 130.2, 133.0, 134.1, 144.5, 150.9, 157.4, 170.7; HRMS (ESI)
+
+
m/z [M+Na] calcd for C H NaO S 383.0924, found 383.0923.
19 20
5
3
,7
(
14Z)-4-Methoxy-2,12-dioxa-9-thiatricyclo[14.2.2.1 ]henicosa-1(18),3(21),4,6,14,16,19-heptaen-11-
one 13. A solution of thiol 12 (31 mg, 0.09 mmol) in MeCN (1 mL) was added slowly with a syringe
pump (15 mL/h) to a vigorously stirred solution of H SO (32.0 µL, 0.60 mmol) in MeCN (30 mL) at
2
4
0
°C. The final concentration of the mixture was ca. 3 mM. The reaction mixture was stirred for a further
0 min at 0 °C until TLC showed full consumption of the starting material and then quenched with
3
saturated aqueous NaHCO solution (15 mL). The mixture was concentrated under reduced pressure and
3
then distributed between CH Cl (20 mL) and H O (20 mL). The aqueous phase was extracted with
2
2
2
CH Cl (2 " 25 mL) and the combined organic phases were washed with brine (50 mL), dried over
2
2
anhydrous Na SO and concentrated under reduced pressure. The remainder was purified by column
2
4
chromatography (cyclohexane/ethyl acetate 7:1 ! 3:1) to yield 13 (6.7 mg, 0.02 mmol, 22%) as a white
solid of mp 164.5–166 °C. R 0.46 (cyclohexane/ethyl acetate 3:1). IR (ATR) # 2927, 2854, 1732,
f
max
!
1 1
1
603, 1505, 1442, 1271, 1224, 1169, 1124, 1027, 967, 841, 755 cm ; H NMR (CDCl , 500 MHz) !
3
2
.82 (s, 2 H), 3.63 (s, 2 H), 3.96 (s, 3 H), 4.62 (dd, J = 5.9, 0.8 Hz, 2 H), 5.93 (d, J = 2.1 Hz, 1 H), 5.97
(dt, J = 11.2, 5.9 Hz, 1 H), 6.83 (dd, J = 8.3, 2.1 Hz, 1 H), 6.92 (d, J = 8.3 Hz, 1 H), 6.99 (d, br, J = 11.2
1
3
Hz, 1 H), 7.04–7.08 (m, 2 H), 7.02 (d, J = 2.0 Hz, 1 H), 7.16–7.22 (m, 2 H); C NMR (CDCl , 125
3
MHz) ! 30.6, 33.7, 56.2, 60.6, 113.1, 118.9, 122.2, 122.5, 125.4, 129.3, 129.9, 134.5, 136.6, 148.3,
1
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+
+
1
49.8, 156.7, 169.6; HRMS (ESI) m/z [M+H] calcd for C H O S 343.0999, found 343.0988.
19 19 4
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
3
,7
(
14Z)-4-Methoxy-2,12-dioxa-9-thiatricyclo[14.2.2.1 ]henicosa-1(18),3(21),4,6,14,16,19-heptaen-11-
one 9,9-dioxide 14. A solution of thioether 13 (10 mg, 0.03 mmol) in CH Cl (1.2 mL) was cooled to
2
2
0
°C, treated with mCPBA (70–77% purity, 16.1 mg, 0.09 mmol) and stirred for 2 h at 0 °C. The
reaction was quenched with saturated aqueous Na SO solution (0.6 mL). The mixture was distributed
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
2
3
between CH Cl (2 mL) and H O (2 mL) and the aqueous phase was extracted with CH Cl (2 " 2 mL).
2
2
2
2
2
The combined organic phases were washed with brine (5 mL), dried over anhydrous Na SO and
2
4
concentrated under reduced pressure. The residue was purified by column chromatography
cyclohexane/ethyl acetate 3:1) to yield 14 (11.0 mg, 0.03 mmol, 98%) as a white solid of mp 190–192
(
°
C. R 0.35 (cyclohexane/ethyl acetate 2:1). IR (ATR) # 2936, 1724, 1506, 1315, 1303, 1267, 1210,
f max
!1
1
1
192, 1113, 1030, 972, 874, 825 cm ; H NMR (CDCl , 500 MHz) ! 3.41 (s, 2 H), 3.97 (s, 3 H), 4.38
3
(
s, 2 H), 4.66 (d, J = 6.4 Hz, 2 H), 6.07 (dt, J = 11.0, 6.4 Hz, 1 H), 6.24 (d, J = 1.8 Hz, 1 H), 6.95–7.00
13
(
m, 2 H, 7-H), 7.03–7.08 (m, 3 H), 7.12–7.16 (m, 2 H); C NMR (CDCl , 125 MHz) ! 51.3, 56.1, 59.1,
3
5
9.9, 113.0, 119.3, 120.6, 122.7, 125.6, 129.3, 134.2, 138.8, 150.1, 150.7, 157.1, 163.5; HRMS (ESI)
+
+
m/z [M+H] calcd for C H O S 375.0897, found 375.0888.
1
9
19
6
3
-[4-(3-Hydroxypropyl)phenoxy]-4-methoxybenzaldehyde 15. A mixture of diaryl ether (E)-9
(2.50 g, 8.79 mmol) and a catalytic amount of PtO (40.0 mg, 0.18 mmol) in MeOH (75 mL) was stirred
2
at room temperature under an atmosphere of hydrogen for 15 min. The reaction mixture was filtered
through celite and the filtrate was concentrated under reduced pressure to give the crude product, which
was purified by column chromatography (cyclohexane/ethyl acetate 1:1, R 0.33) to afford 15 (1.83 g,
f
6
.38 mmol, 73%) as a colorless oil. IR (ATR) #max 3386, 2936, 1685, 1598, 1579, 1504, 1432, 1271,
!
1 1
1222, 1167, 1120, 1111, 1015, 813, 637 cm ; H NMR (CDCl , 500 MHz) ! 1.36 (s, br, 1 H), 1.84–1.94
3
(
m, 2 H), 2.65–2.75 (m, 2 H), 3.65–3.73 (m, 2 H), 3.97 (s, 3 H), 6.87–6.96 (m, 2 H), 7.10 (d, J = 8.4 Hz,
1
3
1
H), 7.13–7.21 (m, 2 H), 7.40 (d, J = 2.0 Hz, 1 H), 7.63 (dd, J = 8.4 Hz, 2.0 Hz, 1 H), 9.80 (s, 1 H); C
NMR (CDCl , 125 MHz) ! 31.2, 34.2, 56.3, 62.2, 111.8, 118.4, 118.5, 127.8, 129.7, 130.1, 137.2, 146.9,
3
1
5
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+
+
1
54.5, 156.0, 190.5; HRMS (ESI) m/z [M+H] calcd for C H O 287.1278, found 287.1277.
17 19 4
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
3
-[4-(5-Formyl-2-methoxyphenoxy)phenyl]propyl 2-acetylthioacetate 16. Analogously to compound
10, compound 16 (832 mg, 2.07 mmol, 79%) was prepared as a colorless oil from 15 (750 mg,
37
2
.62 mmol), S-acetylthioacetic acid (351 mg, 2.62 mmol), EDC (552 mg, 2.88 mmol), DMAP
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(160 mg, 1.31 mmol) and CH Cl (50 mL). R 0.60 (cyclohexane/ethyl acetate 1:1); IR (ATR) # 2933,
2
2
f
max
!1
1
1
733, 1688, 1599, 1579, 1505, 1432, 1271, 1222, 1163, 1120, 1110, 1013, 959, 815, 625 cm ; H NMR
(CDCl , 500 MHz) ! 1.90–2.10 (m, 2 H), 2.38 (s, 3 H), 2.60–2.73 (m, 2 H), 3.69 (s, 2 H), 3.95 (s, 3 H),
3
4
2
3
1
.15 (t, J = 6.6 Hz, 2 H), 6.88–6.95 (m, 2 H), 7.09 (d, J = 8.4 Hz, 1 H), 7.12–7.16 (m, 2 H), 7.39 (d, J =
1
3
.1 Hz, 1 H), 7.63 (dd, J = 8.4 Hz, 2.1 Hz, 1 H), 9.79 (s, 1 H); C NMR (CDCl , 125 MHz) ! 30.0, 30.1,
3
1.2, 31.4, 56.2, 65.0, 111.8, 118.3, 118.8, 127.8, 129.7, 130.0, 136.3, 146.6, 154.7, 156.0, 168.7, 190.4,
+
+
93.8; HRMS (ESI) m/z [M+Na] calcd for C H NaO S 425.1029, found 425.1026.
2
1
22
6
3-[4-(5-Hydroxymethyl-2-methoxyphenoxy)phenyl]propyl 2-acetylthioacetate 17. Analogously to
1
1, compound 17 (654 mg, 1.62 mmol, 92%) was prepared as a colorless oil from 16 (710 mg,
.76 mmol) and NaBH (33.0 mg, 0.88 mmol) in a 1:1 mixture of THF and 20% aqueous MeOH
1
4
(24 mL). R 0.48 (cyclohexane/ethyl acetate 1:1); IR (ATR) #max 3499, 2939, 1733, 1694, 1505, 1425,
f
!
1
1
1
2
266, 1217, 1166, 1122, 1016, 959, 813, 625 cm ; H NMR (CDCl , 500 MHz) ! 1.90–1.98 (m, 2 H),
3
.37 (s, 3 H), 2.64 (t, J = 7.6 Hz, 2 H), 3.68 (s, 2 H), 3.82 (s, 3 H), 4.13 (t, J = 6.4 Hz, 2 H), 4.53 (s, br, 2
1
3
H), 6.83–6.89 (m, 2 H), 6.92 (d, J = 2.0 Hz, 1 H), 6.95 (d, J = 8.4 Hz, 1 H), 7.05–7.12 (m, 3 H); C
NMR (CDCl , 125 MHz) ! 30.0, 30.1, 31.1, 31.4, 56.0, 64.5, 65.0, 112.4, 117.5, 119.3, 123.0, 129.4,
3
+
+
1
33.9, 135.2, 145.3, 150.1, 155.7, 168.7, 193.9; HRMS (ESI) m/z [M+Na] calcd for C H NaO S
21 24 6
427.1186, found 427.1182.
3
-[4-(5-Hydroxymethyl-2-methoxyphenoxy)phenyl]propyl 2-mercaptoacetate 18. Analogously to
2, compound 18 (1.32 g, 3.65 mmol, 92%) was prepared as a colorless oil from 17 (1.60 g, 3.95 mmol)
1
and hydrazine solution (4.30 mL) in MeCN (100 mL). R 0.27 (cyclohexane/ethyl acetate 2:1); IR
f
!
1
1
(ATR) #max 3427, 2936, 1729, 1505, 1442, 1424, 1267, 1217, 1167, 1122, 1022, 812 cm ; H NMR
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The Journal of Organic Chemistry
(
CDCl , 500 MHz) ! 1.77 (t, J = 5.6 Hz, 1 H, OH), 1.92–2.01 (m, 2 H), 2.00 (t, J = 8.3 Hz, 1 H, SH),
3
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
2.64–2.69 (m, 2 H), 3.25 (d, J = 8.3 Hz, 2 H), 3.85 (s, 3 H), 4.15 (t, J = 6.6 Hz, 2 H), 4.56 (d, J = 5.6 Hz,
1
3
2
H), 6.85–6.91 (m, 2 H), 6.94 (d, J = 2.1 Hz, 1 H), 6.97 (d, J = 8.2 Hz, 1 H), 7.08–7.12 (m, 3 H); C
NMR (CDCl , 125 MHz) ! 26.5, 30.1, 31.2, 56.0, 64.7, 64.9, 112.5, 117.6, 119.3, 123.1, 129.4, 133.8,
3
+
+
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
35.2, 145.4, 150.6, 155.8, 170.9; HRMS (ESI) m/z [M+Na] calcd for C H NaO S 385.1080, found
19 22 5
3
85.1079.
3
,7
4-Methoxy-2,12-dioxa-9-thiatricyclo[14.2.2.1 ]henicosa-1(18),3(21),4,6,16,19-hexaen-11-one 19.
Analogously to 13, compound 19 (126 mg, 0.37 mmol, 60%) was prepared from 18 (220 mg,
0
.61 mmol) and H SO (227 µL, 4.25 mmol) in MeCN (200 mL). After column chromatography
2 4
(cyclohexane/ethyl acetate 7:1) and recrystallization from n-hexane/CH Cl 4:1 it was obtained as
2
2
colorless crystals of mp 126.5–127 °C. R 0.56 (cyclohexane/ethyl acetate 2:1); IR (ATR) # 2934,
f
max
2915, 2840, 1733, 1513, 1505, 1439, 1420, 1284, 1254, 1224, 1206, 1170, 1151, 1127, 1106, 1030, 988,
!1
1
9
73, 953, 834, 808, 705, 676, 614, cm ; H NMR (CDCl , 500 MHz) ! 2.10–2.16 (m, 2 H), 2.80 (s, 2
3
H), 2.84 (t, J = 6.4 Hz, 2 H), 3.55 (s, 2 H), 3.97 (s, 3 H), 4.12–4.16 (m, 2 H), 5.86 (d, J = 2.1 Hz, 1 H),
.81 (dd, J = 8.2 Hz, 2.1 Hz, 1 H), 6.93 (d, J = 8.2 Hz, 1 H), 6.99–7.06 (m, 2 H), 7.24–7.29 (m, 2 H);
6
1
3
C NMR (CDCl , 125 MHz) ! 28.4, 31.1, 33.9, 34.0, 56.2, 65.8, 113.1, 117.5, 121.6, 122.6, 129.5,
3
+
+
1
31.0, 137.6, 147.8, 149.8, 154.7, 169.4; HRMS (ESI) m/z [M+H] calcd for C H O S 345.1155,
19 21 4
found 345.1161.
3
,7
4-Methoxy-2,12-dioxa-9-thiatricyclo[14.2.2.1 ]henicosa-1(18),3(21),4,6,16,19-hexaen-11-one 9,9-
dioxide 20. Analogously to 14, compound 20 was prepared from 19 (130 mg, 0.38 mmol) and mCPBA
(70–77% purity, 287 mg, 1.66 mmol) in CH Cl (30 mL). After column chromatography
2 2
(cyclohexane/ethyl acetate 3:1) and recrystallization from n-hexane/CH Cl 4:1, 20 (140 mg,
2
2
0
.37 mmol, 98%) was obtained as colorless crystals of mp 207–209 °C; R 0.28 (cyclohexane/ethyl
f
acetate 2:1). IR (ATR) #max 2971, 2931, 1724, 1506, 1460, 1312, 1304, 1265, 1250, 1214, 1196, 1161,
!1
1
1
114, 1032, 972, 880, 871, 825, 818, 621 cm ; H NMR (CDCl , 500 MHz) ! 2.16–2.23 (m, 2 H), 2.85
3
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(
t, J = 6.6 Hz, 2 H), 3.44 (s, 2 H), 3.98 (s, 3 H), 4.21–4.27 (m, 2 H), 4.32 (s, 2 H), 6.06 (t, J = 1.1 Hz, 1
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
1
3
H), 6.96–6.98 (m, 2 H), 6.98–7.02 (m, 2 H), 7.24–7.28 (m, 2 H); C NMR (CDCl , 125 MHz) ! 27.4,
3
3
3.2, 51.5, 56.1, 59.1, 65.6, 112.8, 117.6, 120.5, 122.5, 125.1, 131.3, 136.9, 149.6, 150.7, 154.9, 163.1;
+
+
HRMS (ESI) m/z [M+Na] calcd for C H O NaS 399.0873, found: 399.0878.
1
9
20
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(E)-3-[4-(5-Formyl-2-methoxyphenoxy)phenyl]allyl pivalate 21. A solution of alcohol (E)-9 (1.00 g,
3
.52 mmol) in CH
.28 mmol) and stirred at 40 °C for 20 h. After cooling to room temperature the organic phase was
(50 mL) and brine (50 ml), dried
over anhydrous Na SO and concentrated under reduced pressure. The crude product was purified by
2 2
Cl (15 mL) was treated with pyridine (0.5 mL) and pivaloyl chloride (0.65 mL,
5
washed with 1M aqueous HCl (50 mL), saturated aqueous NaHCO
3
2
4
column chromatography (cyclohexane/ethyl acetate 9:1) to yield 21 (0.97 g, 75% ) as a yellowish oil; Rf
.29 (cyclohexane/ethyl acetate 3:1). IR (ATR) #max 2969, 1722, 1688, 1599, 1579, 1505, 1433, 1274,
0
!
1 1
1224, 1147, 1119, 1019, 960, 812, 769, 636 cm ; H NMR (CDCl , 500 MHz) ! 1.23 (s, 9 H), 3.94 (s, 3
3
H), 4.71 (dd, J = 6.4, 1.1 Hz, 2 H), 6.20 (dt, J = 15.9, 6.3 Hz, 1 H), 6.61 (d, br, J = 15.9 Hz, 1 H), 6.89–
6
1
1
.95 (m, 2 H), 7.11 (d, J = 8.4 Hz, 1 H), 7.33–7.38 (m, 2 H), 7.46 (d, J = 1.9 Hz, 1 H), 7.67 (dd, J = 8.4,
1
3
.9 Hz, 1 H), 9.82 (s, 1 H); C NMR (CDCl , 125 MHz) ! 27.2, 38.8, 56.3, 65.0, 112.1, 118.1, 119.7,
3
+
22.8, 128.1, 128.2, 130.2, 131.8, 132.9, 146.1, 156.3, 156.7, 178.3, 190.3; HRMS (ESI) m/z [M+Na]
+
calcd for C H O Na 391.1516, found 391.1509.
2
2
24
5
(2R,3R)-3-[4-(5-Formyl-2-methoxyphenoxy)phenyl]-2,3-dihydroxypropyl pivalate 22. A mixture of
AD-mix-# (3.43 g, 1.4 g/mmol) and methanesulfonamide (233 mg, 95.0 mg/mmol) were suspended at
room temperature in a H O/tBuOH mixture (1:1, 30.6 mL). After cooling to 0 °C the olefin 21 (902 mg,
2
2
.45 mmol) was added and the mixture was stirred vigorously for 2 d at 3 °C. The reaction was cooled
again to 0 °C, Na SO (3.7 g, 1.5 g/mmol) was added, and stirring was continued for 30 min. The phases
2
3
were separated, and the aqueous one was acidified with saturated NH Cl solution (50 mL) and extracted
4
with ethyl acetate (3 " 50 mL). The combined organic layers were washed with brine (100 mL), dried
over Na SO and concentrated under reduced pressure. The crude product was purified by column
2
4
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The Journal of Organic Chemistry
chromatography (cyclohexane/ethyl acetate 1:1, R 0.20) to yield 22 (575 mg, 1.44 mmol, 59%) as a
f
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
2
3
yellowish oil; [$] –9.4 (c 1.00, acetone), ee > 99%; IR (ATR) #max 3481, 2970, 1727, 1690, 1600,
D
!1
1
1
507, 1435, 1397, 1277, 1225, 1161, 1121, 1023, 816 cm ; H NMR (CDCl , 500 MHz) ! 1.19 (s, 9 H),
3
3
.14 (s, br, 2 " OH), 3.85–3.95 (m, 2 H), 3.90 (s, 3 H), 4.14 (dd, J = 11.6, 3.5 Hz, 1 H), 4.60 (d, J = 6.4
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Hz, 1 H), 6.90–6.94 (m, 2 H), 7.09 (d, J = 8.4 Hz, 1 H), 7.27–7.31 (m, 2 H), 7.44 (d, J = 2.0 Hz, 1 H),
1
3
7
.65 (dd, J = 8.4, 2.0 Hz, 1 H), 9.77 (s, 1 H); C NMR (CDCl , 125 MHz) ! 27.1, 38.8, 56.2, 65.0, 73.8,
3
7
4.1, 112.1, 117.7, 120.0, 128.1, 128.3, 130.0, 135.1, 145.7, 156.4, 156.8, 178.8, 190.5; HRMS (ESI)
+
+
m/z [M+Na] calcd for C H O Na 425.1571, found 425.1568.
2
2
26
7
(2R,3R)-3-[4-(5-Formyl-2-methoxyphenoxy)phenyl]-2,3-bis(triisopropylsilyloxy)propyl pivalate 23.
A solution of diol 22 (4.00 g, 9.94 mmol) and 2,6-lutidine (5.05 mL, 34.8 mmol) in DMF (100 mL) was
slowly treated with TIPS-OTf (8.00 mL, 29.8 mmol) at 0 °C and then stirred at 60 °C for 27 h. The
reaction was quenched with saturated aqueous NH Cl solution (50 mL), the aqueous layer was extracted
4
twice with diethyl ether (50 mL), and the combined organic phases were washed with H O (100 mL)
2
and brine (100 mL), dried over anhydrous Na SO and concentrated under reduced pressure. The residue
2
4
was purified by column chromatography (cyclohexane/ethyl acetate 9:1) to obtain 23 (6.96 g,
23
9
.73 mmol, 98%) as a colorless oil; R 0.43 (cyclohexane/ethyl acetate 3:1); [$] +3.7 (c 0.50, CHCl );
f D 3
IR (ATR) #max 2945, 2867, 1729, 1696, 1600, 1581, 1505, 1463, 1433, 1276, 1224, 1153, 1120, 1091,
!1
1
1
067, 1014, 996, 882, 844, 680 cm ; H NMR (CDCl , 500 MHz) ! 0.99–1.09 (m, 42 H), 1.16 (s, 9 H),
3
3.70 (dd, J = 11.6, 5.6 Hz, 1 H), 3.94 (s, 3 H), 4.20–4.25 (m, 1 H), 4.38 (dd, J = 11.6, 3.4 Hz, 1 H), 4.94
d, J = 4.2 Hz, 1 H), 6.88–6.92 (m, 2 H), 7.10 (d, J = 8.4 Hz, 1 H), 7.35–7.39 (m, 2 H), 7.43 (d, J = 2.0
(
1
3
Hz, 1 H), 7.66 (dd, J = 8.4, 2.0 Hz, 1 H); C NMR (CDCl , 125 MHz) ! 12.4, 12.8, 17.95, 18.0, 18.1,
3
1
1
8.2, 27.2, 38.7, 56.2, 66.4, 74.9, 75.1, 112.1, 117.1, 120.0, 127.3, 128.7, 130.2, 136.1, 146.5, 156.0,
+
+
56.2, 178.5, 190.3; HRMS (ESI) m/z [M+Na] calcd for C H O NaSi 737.4239, found 737.4231.
40 66
7
2
(2R,3R)-3-[4-(5-Hydroxymethyl-2-methoxyphenoxy)phenyl]-2,3-bis(triisopropylsilyl)oxypropan-1-
ol 24. Analogously to 8, alcohol 24 (5.42 g, 8.56 mmol, 94%) was prepared as a colorless oil from 23
1
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(
6.50 g, 9.09 mmol) and DIBAL-H (1M in hexane, 29.1 mL, 29.1 mmol) in CH Cl (120 mL). R 0.44
2 2 f
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
2
3
(
cyclohexane/ethyl acetate 2:1); [$] +19.0 (c 1.0, CHCl ); IR (ATR) # 3410, 2944, 2865, 1608,
D 3 max
!
1
1
1
505, 1463, 1426, 1270, 1222, 1121, 1058, 1031, 1013, 945, 881, 845, 773, 679, 655 cm ; H NMR
(CDCl , 500 MHz) ! 0.96–1.10 (m, 42 H), 1.94 (s, br, 1 H, OH), 2.89 (dd, J = 8.3, 1.7 Hz, 1H, OH),
3
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
3
.45 (ddd, J = 11.0, 8.3, 4.2, 1 H), 3.57 (ddd, J = 11.0, 8.0, 1.7, 1 H), 3.80 (s, 3 H), 4.23 (dt, J = 8.0, 4.2
Hz, 1 H), 4.54 (d, br, J = 2.4 Hz, 1 H), 5.04 (d, J = 4.2 Hz, 1 H), 6.88–6.92 (m, 2 H), 6.94 (d, J = 2.1 Hz,
1
3
1 H), 6.95 (d, J = 8.3 Hz, 1 H), 7.09 (dd, J = 8.3, 2.0 Hz, 1 H), 7.31–7.36 (m, 2 H); C NMR (CDCl ,
3
1
25 MHz) ! 12.1, 12.5, 17.8, 17.9, 18.0, 18.1, 55.9, 63.5, 64.6, 73.3, 77.8, 112.6, 116.6, 119.2, 122.9,
+
+
128.7, 133.85, 133.9, 145.5, 150.5, 156.9; HRMS (ESI) m/z [M+Na] calcd for C H O NaSi
2
3
5
60
6
6
55.3821, found 655.3819.
2R,3R)-3-[4-(5-Formyl-2-methoxyphenoxy)phenyl]-2,3-bis(triisopropylsilyloxy)propan-1-ol 25. A
mixture of diol 24 (5.39 g, 8.51 mmol), activated MnO (22.2 g, 0.26 mol), and CHCl (110 mL) was
stirred at room temperature for 17 h, and then filtered through celite. The combined filtrate and
washings with CH Cl were concentrated under reduced pressure to give the crude product which was
(
2
3
2
2
purified by column chromatography (cyclohexane/ethyl acetate 4:1) to afford 25 (5.33 g, 8.45 mmol,
2
3
9
9%) as a colorless oil; R 0.64 (cyclohexane/ethyl acetate 3:1); [$] –21.4 (c 1.0, CHCl ); IR (ATR)
f D 3
#max 2944, 2863, 1694, 1600, 1581, 1505, 1463, 1433, 1274, 1224, 1111, 1059, 1014, 997, 881, 847,
!
1 1
6
79, 654 cm ; H NMR (CDCl , 500 MHz) ! 0.95–1.14 (m, 42 H), 2.86 (s, br, 1 H, OH), 3.46 (dd, J =
3
10.9, 4.0 Hz, 1 H), 3.58 (dd, J = 10.9, 7.9 Hz, 1 H), 3.92 (s, 3 H), 4.24 (dt, J = 7.9, 4.3 Hz, 1 H), 5.06 (d,
J = 4.3 Hz, 1 H), 6.90–6.96 (m, 2 H), 7.09 (d, J = 8.4 Hz, 1 H), 7.34–7.39 (m, 2 H), 7.42 (d, J = 2.0 Hz,
1
3
1 H), 7.65 (dd, J = 8.4, 2.0 Hz, 1 H), 9.80 (s, 1 H); C NMR (CDCl , 125 MHz) ! 12.1, 12.5, 17.85,
3
1
1
7.9, 18.0, 18.1, 56.1, 63.6, 73.3, 77.7, 112.0, 117.2, 119.5, 127.5, 129.0, 130.1, 134.8, 146.5, 156.0,
+
+
56.1, 190.2; HRMS (ESI) m/z [M+Na] calcd for C H O NaSi 653.3664, found 653.3661.
35 58
6
2
(2R,3R)-3-[4-(5-Formyl-2-methoxyphenoxy)phenyl]-2,3-bis(triisopropylsilyloxy)propyl
2-
acetylthioacetate 26. Analogously to 10, compound 26 was prepared from 25 (0.40 g, 3.25 mmol), S-
2
0
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The Journal of Organic Chemistry
3
7
acethylthioacetic acid (0.96 g, 7.15 mmol), EDC (1.37 g, 7.15 mmol) and DMAP (160 mg,
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
1
.31 mmol) in CH Cl (130 mL). After column chromatography (cyclohexane/ethyl acetate 6:1) 26
2
2
2
3
(3.79 g, 5.08 mmol, 78%) was obtained as a colorless oil; R 0.41 (cyclohexane/ethyl acetate 3:1); [$]
f
D
+
2.9 (c 0.5, CHCl ); IR (ATR) #max 2944, 2865, 1743, 1694, 1600, 1581, 1505, 1463, 1433, 1275, 1224,
3
!
1
1
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
120, 1067, 1013, 960, 881, 844, 680, 624 cm ; H NMR (CDCl , 500 MHz) ! 0.96–1.12 (m, 42 H),
3
2
.36 (s, 3 H), 3.59–3.69 (m, 2 H), 3.71 (dd, J = 11.3, 7.1 Hz, 1 H), 3.92 (s, 3 H), 4.27 (ddd, J = 7.1, 4.2,
3.0 Hz, 1 H), 4.44 (dd, J = 11.3, 3.0 Hz, 1 H), 4.94 (d, J = 4.3 Hz, 1 H), 6.86–6.92 (m, 2 H), 7.09 (d, J =
.4 Hz, 1 H), 7.33–7.37 (m, 2 H), 7.43 (d, J = 2.0 Hz, 1 H), 7.65 (dd, J = 8.4, 2.0 Hz, 1 H), 9.80 (s, 1 H);
8
1
3
C NMR (CDCl , 125 MHz) ! 12.2, 12.7, 17.9, 17.95, 18.0, 18.1, 30.0, 31.3, 56.1, 67.4, 74.2, 75.2,
3
1
12.0, 117.0, 120.0, 127.4, 128.6, 130.1, 135.3, 146.3, 156.1, 156.2, 168.5, 190.2, 193.4; HRMS (ESI)
+
+
m/z [M+Na] calcd for C H O NaSSi 769.3596, found 769.3592.
3
9
62
8
2
(2R,3R)-3-[4-(5-Hydroxymethyl-2-methoxyphenoxy)phenyl]-2,3-bis(triisopropylsilyloxy)propyl 2-
acetylthioacetate 27. Analogously to 11, compound 27 was prepared from 26 (3.59 g, 4.80 mmol) and
NaBH (91.0 mg, 2.40 mmol) in a 1:1 mixture of THF and 20% aqueous MeOH (66 mL). After column
4
chromatography (cyclohexane/ethyl acetate 5:1) 27 (3.57 g, 4.77 mmol, 99%) was obtained as a
2
3
colorless oil; R 0.27 (cyclohexane/ethyl acetate 3:1); [$] +0.5 (c 1.0, CHCl ); IR (ATR) # 3413,
f
D
3
max
2943, 2865, 1743, 1702, 1608, 1505, 1463, 1426, 1270, 1222, 1123, 1092, 1067, 1012, 881, 844, 680,
!1
1
6
24 cm ; H NMR (CDCl , 500 MHz) ! 0.97–1.11 (m, 42 H), 1.62 (t, J = 5.8 Hz, 1 H, OH), 2.37 (s, 3
3
H), 3.59–3.69 (m, 2 H), 3.71 (dd, J = 11.3, 7.1 Hz, 1 H), 3.83 (s, 3 H), 4.26 (ddd, J = 7.1, 4.2, 2.9 Hz, 1
H), 4.42 (dd, J = 11.3, 2.9 Hz, 1 H), 4.57 (d, J = 5.8 Hz, 2 H), 4.93 (d, J = 4.3 Hz, 1 H), 6.85–6.90 (m, 2
H), 6.95 (d, J = 2.1 Hz, 1 H), 6.97 (d, J = 8.3 Hz, 1 H), 7.11 (dd, J = 8.3, 2.1 Hz, 1 H), 7.30–7.34 (m, 2
1
3
H); C NMR (CDCl , 125 MHz) ! 12.3, 12.7, 17.95, 18.0, 18.1, 18.2, 30.1, 31.4, 56.0, 64.8, 67.5, 74.3,
3
7
5.3, 112.7, 116.7, 119.4, 123.0, 128.4, 133.9, 134.6, 145.6, 150.7, 156.8, 168.6, 193.5; HRMS (ESI)
+
+
m/z [M+Na] calcd for C H O NaSSi 771.3753, found 771.3749.
3
9
64
8
2
(2R,3R)-3-[4-(5-Hydroxymethyl-2-methoxyphenoxy)phenyl]-2,3-bis(triisopropylsilyloxy)propyl 2-
2
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mercaptoacetate 28. Analogously to 12, compound 28 was prepared from 27 (4.22 g, 5.63 mmol) and
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
hydrazine solution (6.10 mL) in MeCN (158 mL). After column chromatography (cyclohexane/ethyl
acetate 3:1), 28 (3.73 g, 5.27 mmol, 94%) was obtained as a colorless oil; R 0.27 (cyclohexane/ethyl
f
2
3
acetate 3:1); [$] +2.6 (c 1.0, CHCl ); IR (ATR) # 2944, 2866, 1740, 1505, 1463, 1425, 1270, 1221,
D
3
max
!
1 1
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
122, 1091, 1066, 1012, 881, 844, 754, 680 cm ; H NMR (CDCl , 500 MHz) ! 0.97–1.10 (m, 42 H),
3
1
.57 (s, br, 1 H, OH), 1.94 (t, J = 8.2 Hz, 1 H, SH), 3.17 (dd, J = 8.2, 4.6 Hz, 2 H), 3.71 (dd, J = 11.3,
7.1 Hz, 1 H), 3.83 (s, 3 H), 4.27 (ddd, J = 7.1, 4.3, 2.8 Hz, 1 H), 4.43 (dd, J = 11.3, 2.8 Hz, 1 H), 4.58 (s,
2
H), 4.93 (d, J = 4.3 Hz, 1 H), 6.86–6.90 (m, 2 H), 6.95 (d, J = 2.1 Hz, 1 H), 6.98 (d, J = 8.3 Hz, 1 H),
1
3
7
.11 (dd, J = 8.3, 2.1 Hz, 1 H), 7.30–7.34 (m, 2 H); C NMR (CDCl , 125 MHz) ! 12.2, 12.7, 17.95,
3
1
8.0, 18.1, 18.2, 26.4, 56.0, 64.8, 67.3, 74.3, 75.3, 112.6, 116.6, 119.4, 123.0, 128.4, 133.9, 134.5,
+
+
1
45.5, 150.7, 156.8, 170.8; HRMS (ESI) m/z [M+Na] calcd for C H O NaSSi 729.3647, found
37 62 7 2
729.3635.
(14R,15R)-4-Methoxy-14,15-bis[(triisopropylsilyl)oxy]-2,12-dioxa-9-thiatricyclo-
3
,7
[
14.2.2.1 ]henicosa-1(18),3(21),4,6,16,19-hexaen-11-one 29. A solution of thiol 28 (1.88 g,
2
.66 mmol) in toluene (887 mL) was treated with SO • pyridine (423 mg, 2.66 mmol) and stirred for
3
2
h at 110 °C under reflux. The mixture was allowed to cool to room temperature and then concentrated
under reduced pressure. The residue was purified by column chromatography (cyclohexane/ethyl acetate
0:1, R 0.27) followed by crystallization from hexane/CH Cl to yield 29 (780 mg, 1.13 mmol, 43%) as
3
f
2
2
2
3
a colorless waxy solid; [$] +19.3 (c 1.0, CHCl ); IR (ATR) # 2947, 2865, 1736, 1504, 1265, 1215,
D
3
max
!1
1
1
124, 1087, 1066, 1013, 881, 681 cm ; H NMR (CDCl , 500 MHz) ! 1.01–1.12 (m, 42 H), 2.78 (d, J =
3
2.3 Hz, 2 H), 3.49 (d, J = 4.0 Hz, 2 H), 3.97 (s, 3 H), 4.15–4.26 (m, 3 H), 5.00 (d, J = 4.2 Hz, 1 H), 6.03
(d, J = 2.1 Hz, 1 H), 6.80 (dd, J = 8.3, 2.1 Hz, 1 H), 6.93 (d, J = 8.3 Hz, 1 H), 7.01 (dd, J = 8.2, 2.4 Hz,
1
3
1
H), 7.04 (dd, J = 8.4, 2.4 Hz, 1 H), 7.45 (dd, J = 8.2, 2.2 Hz, 1 H), 7.64 (dd, J = 8.4, 2.2 Hz, 1 H); C
NMR (CDCl , 125 MHz) ! 12.4, 12.5, 18.05, 18.1, 18.2, 31.8, 34.1, 56.2, 63.3, 74.3, 75.7, 113.1, 117.4,
3
+
1
20.9, 121.5, 122.4, 127.8, 129.4, 129.5, 137.9, 147.9, 149.6, 155.7, 169.5; HRMS (ESI) m/z [M+Na]
2
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The Journal of Organic Chemistry
+
calcd for C H O NaSSi 711.3541, found 711.3526.
3
7
60
6
2
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
(14R,15R)-4-Methoxy-14,15-bis(triisopropylsilyloxy)-2,12-dioxa-9-thiatricyclo-
3
,7
[14.2.2.1 ]henicosa-1(18),3(21),4,6,16,19-hexaen-11-one 9,9-dioxide 30. Analogously to 14,
compound 30 was prepared from 29 (440 mg, 0.64 mmol) and mCPBA (353 mg, 2.04 mmol) in CH Cl2
2
(25 mL). After column chromatography (cyclohexane/ethyl acetate 5:1) and recrystallization from
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
hexane/CH Cl 4:1, 30 (384 mg, 0.53 mmol, 83%) was obtained as colorless crystals of mp 176–178 °C;
2
2
2
3
R 0.18 (cyclohexane/ethyl acetate 8:1); [$] –23.3 (c 1.0, CHCl ); IR (ATR) # 2942, 2865, 1738,
f
D
3
max
!
1
1
1
519, 1462, 1318, 1268, 1214, 1126, 1110, 1089, 1066, 1014, 882, 858, 680, 654 cm ; H NMR
(
CDCl , 500 MHz) ! 0.99–1.14 (m, 42 H), 3.34 (dd, J = 17.5, 1.5 Hz, 1 H), 3.47 (d, J = 17.5 Hz, 1 H),
3
3.98 (s, 3 H), 4.05 (dd, J = 11.9, 6.4 Hz, 1 H), 4.17 (dd, J = 14.3, 1.5 Hz, 1 H), 4.27 (dd, J = 6.4, 4.5 Hz,
1
6
H), 4.29 (d, J = 11.9 Hz, 1 H), 4.37 (d, J = 14.3 Hz, 1 H), 4.96 (d, J = 4.5 Hz, 1 H), 6.16 (s, br, 1 H),
.95–6.99 (m, 2 H), 6.97 (dd, J = 8.3, 2.6 Hz, 1 H), 7.09 (dd, J = 8.4, 2.6 Hz, 1 H), 7.49 (dd, J = 8.3, 2.1
13
Hz, 1 H), 7.65 (dd, J = 8.4, 2.1 Hz, 1 H); C NMR (CDCl , 125 MHz) ! 12.6, 12.65, 18.0, 18.05, 18.1,
3
1
8.2, 51.4, 56.1, 59.2, 64.1, 74.8, 76.7, 112.9, 117.3, 120.4, 121.1, 122.8, 125.1, 128.3, 129.7, 137.8,
+
+
149.6, 150.3, 155.7, 162.6; HRMS (ESI) m/z [M+Na] calcd for C H O NaSSi 743.3440, found
3
7
60
8
2
7
43.3420.
11-O-Methylcorniculatolide A 31. Sulfone 20 (200 mg, 0.53 mmol) was subjected to flash vacuum
–2
pyrolysis at 600 °C and 5 " 10 Torr. The crude product was purified by column chromatography
(cyclohexane/ethyl acetate 6:1) to yield 31 (88 mg, 0.26 mmol, 53%) as a white solid of mp 141–143 °C
1
1
[
lit. 142–145 °C]; R 0.44 (cyclohexane/ethyl acetate 3:1); IR (ATR) # 2925, 1727, 1586, 1516,
f
m
a
x
1
7
505, 1465, 1435, 1414, 1358, 1263, 1212, 1149, 1127, 1029, 1008, 978, 906, 891, 867, 830, 799, 727,
!
1 1
01 cm ; H NMR (CDCl , 500 MHz) ! 2.06–2.13 (m, 2 H), 2.23–2.28 (m, 2 H), 2.81 (t, J = 6.6 Hz, 2
3
H), 2.83–2.87 (m, 2 H), 3.95 (s, 3 H), 4.05–4.10 (m, 2 H), 5.34 (d, J = 2.1 Hz, 1 H), 6.63–6.67 (m, 1 H),
1
3
6
.81 (d, J = 8.2 Hz, 1 H), 7.01–7.06 (m, 2 H), 7.27–7.32 (m, 2 H); C NMR (CDCl , 125 MHz) ! 26.9,
3
2
8.6, 32.7, 34.0, 56.2, 64.0, 111.8, 113.3, 120.8, 123.6, 131.0, 133.2, 137.4, 146.1, 151.2, 154.5, 173.8;
2
3
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+
+
HRMS (ESI) m/z [M+H] calcd for C H O 313.1434, found 313.1433.
1
9
21
4
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Combretastatin D-4 5. A mixture of anhydrous AlCl (75.0 mg, 0.56 mmol) and ethanethiol
3
(0.52 mL, 7.04 mmol) in CH Cl (3.5 mL) was cooled to !17 °C and treated with 11-O-
2
2
methylcorniculatolide A 31 (22.0 mg, 0.07 mmol). The mixture was stirred at !17 °C for ca 1 h until
TLC indicated consumption of the starting material. Water (5 mL) was added, the layers were separated,
and the aqueous one was extracted with CH Cl (2 " 5 mL). The combined organic phases were washed
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
2
2
with brine (15 mL), dried over Na SO , and concentrated under reduced pressure. The remainder was
2
2
purified by column chromatography (cyclohexane/ethyl acetate 3:1, R 0.32) followed by crystallization
f
from hexane/acetone 4:1 to yield 5 (20.0 mg, 0.07 mmol, 96%) as colorless crystals of mp 153–156 °C
1
0
[
lit. 155.4–156.3 °C]; IR (ATR) # 3416, 2938, 1701, 1595, 1518, 1504, 1448, 1359, 1243, 1219,
max
!1
1
1
190, 1160, 1115, 942, 912, 870, 884, 805, 602 cm ; H NMR (CDCl , 500 MHz) ! 2.07–2.12 (m, 2
3
H), 2.24–2.27 (m, 2 H), 2.79–2.85 (m, 4 H), 4.04–4.08 (m, 2 H), 5.29 (d, J = 2.1 Hz, 1 H), 5.50 (s, br, 1
H, OH), 6.60 (dd, J = 8.1, 2.1, Hz, 1 H), 6.83 (d, J = 8.1 Hz, 1 H), 6.99–7.04 (m, 2 H), 7.29–7.32 (m, 2
1
3
H); C NMR (CDCl , 125 MHz) ! 27.0, 28.7, 32.7, 34.0, 63.9, 112.6, 114.9, 121.5, 123.5, 131.1, 132.6,
3
+
+
137.9, 142.5, 149.0, 154.2, 173.9; HRMS (ESI) m/z [M!H+Na] calcd for C H NaO 320.1019, found
1
8
17
4
3
20.1017.
3
,7
(13R,14R)-4-Methoxy-13,14-bis(triisopropylsilyl)oxy-2,11-dioxatricyclo-[13.2.2.1 ]icosa-
1
(17),3(20),4,6,15,18-hexaen-10-one 32. Analogously to 31, compound 32 was prepared by FVP of
sulfone 30 (700 mg, 0.97 mmol). The crude product was purified by column chromatography
(cyclohexane/ethyl acetate 40:1) to yield 32 (158 mg, 0.24 mmol, 25%) as a colorless waxy solid; Rf
23
0
.44 (cyclohexane/ethyl acetate 3:1). [$] D –5.0 (c 0.2, CHCl ); IR (ATR) # 2944, 2867, 1737, 1519,
3 max
!
1 1
1504, 1463, 1264, 1216, 1127, 1089, 1067, 1014, 993, 882, 799, 755, 733, 680 cm ; H NMR (CDCl ,
3
5
00 MHz) ! 1.02–1.14 (m, 42 H), 2.18–2.34 (m, 2 H), 2.72 (dd, J = 17.0, 8.2 Hz, 1 H), 2.97 (dd, J =
7.0, 10.3 Hz, 1 H), 3.85 (dd, J = 12.1, 6.6 Hz, 1 H), 3.94 (s, 3 H), 4.22–4.27 (m, 2 H), 4.96 (d, J = 4.3
1
Hz, 1 H), 5.41 (d, J = 2.0 Hz, 1 H), 6.65 (dd, J = 8.2, 2.0 Hz, 1 H), 6.81 (d, J = 8.2 Hz, 1 H), 7.01–7.04
2
4
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The Journal of Organic Chemistry
1
3
(
m, 2 H), 7.42–7.45 (m, 1 H), 7.66–7.70 (m, 1 H); C NMR (CDCl , 125 MHz) ! 12.5, 12.55, 18.1,
3
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
18.15, 26.9, 32.7, 56.3, 63.1, 74.5, 76.5, 111.9, 113.6, 120.7, 122.0, 123.5, 127.8, 128.9, 133.0, 137.6,
+
+
1
6
46.1, 151.2, 155.8, 173.9; HRMS (ESI) m/z [M+Na] calcd for C H NaO Si 679.3821, found
37 60 6 2
79.3811.
3
,7
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(13R,14R)-13,14-Dihydroxy-4-methoxy-2,11-dioxatricyclo[13.2.2.1 ]icosa-1(17),3(20),4,6,15,18-
hexaen-10-one 33. A solution of silyl ether 32 (73.0 mg, 0.11 mmol) in THF (5 mL) was treated with
4
8% aqueous HF (23.0 µL, 1.33 mmol). The mixture was stirred at room temperature for 24 h, then
further HF (23.0 µL, 1.33 mmol) was added and the mixture was stirred for another 3 d at room
temperature. The reaction was terminated by addition of saturated aqueous NaHCO solution (3 mL).
3
The layers were separated and the aqueous phase was extracted with ethyl acetate (3 " 10 mL). The
combined organic phases were dried over Na SO and concentrated under reduced pressure. The crude
2
4
product was taken up in THF (1 mL) and treated once more with HF (50 µL, 2.87 mmol) for 7 d at
room temperature. The identical workup gave a crude product which was purified by column
chromatography (cyclohexane/ethyl acetate 1:2, R 0.36) to afford 33 (20.0 mg, 0.06 mmol, 53%) as a
f
2
3
white solid of mp 222–225 °C. [$] –35 (c 1.0, CHCl ); IR (ATR) # 3522, 3401, 2956, 2919, 1720,
D
3
max
1
9
589, 1517, 1504, 1460, 1435, 1413, 1343, 1270, 1215, 1163, 1147, 1126, 1109, 1098, 1037, 1016, 995,
!
1
1
76, 954, 910, 878, 848, 803 cm ; H NMR (MeOD, 500 MHz) ! 2.11 (ddd, J = 17.0, 11.8, 1.2 Hz, 1
H), 2.45 (ddd, J = 17.0, 7.2, 1.2 Hz, 1 H), 2.59 (dd, J = 16.6, 7.2 Hz, 1 H), 2.98 (ddd, J = 16.6, 11.8, 0.8
Hz, 1 H), 3.59 (d, J = 11.8 Hz, 1 H), 3.82 (t, J = 7.6 Hz, 1 H), 3.89 (s, 3 H), 4.26 (dd, J = 11.8, 7.6 Hz, 1
H), 4.50 (d, J = 8.0 Hz, 1 H), 5.30 (d, J = 2.1 Hz, 1 H), 6.67 (dd, J = 8.2, 2.1 Hz, 1 H), 6.89 (d, J = 8.2
Hz, 1 H), 6.94 (dd, J = 8.2, 2.4 Hz, 1 H), 7.12 (dd, J = 8.5, 2.4 Hz, 1 H), 7.29 (dd, J = 8.2, 2.2 Hz, 1 H),
1
3
7.65 (dd, J = 8.5, 2.2 Hz, 1 H); C NMR (MeOD, 125 MHz) ! 27.9, 33.5, 57.0, 68.8, 76.6, 79.5, 114.0,
1
14.7, 122.4, 124.1, 125.2, 130.1, 131.4, 134.7, 139.1, 147.8, 152.7, 157.9, 175.0; HRMS (ESI) m/z
+
+
[
M!H O+H] calcd for C H O 327.1227, found 327.1224.
2 19 19 5
3
,7
Methylcombretastatin D-2 34
and
(11Z)-4-methoxy-2-oxatricyclo[11.2.2.1 ]octadeca-1(15),
2
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3
(18),4,6,11,13,16-heptaene 35. Analogously to the synthesis of 31, sulfone 14 (150 mg, 0.40 mmol)
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
was submitted to a FVP. The crude product was purified and separated by column chromatography
(cyclohexane/ethyl acetate 40:1) to yield 34 (25 mg, 0.08 mmol, 20%) as white solid of mp 131–133 °C
12
[lit. 130–132 °C] and 35 (6 mg, 0.03 mmol, 6%), which was obtained as colorless crystals of mp 122–
1
24 °C after crystallization from pentane/hexane 3:1.
Compound 34: R 0.30 (cyclohexane/ethyl acetate 5:1); IR (ATR) # 2961, 2908, 1729, 1583, 1519,
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
f
max
-
1
1
1
502, 1464, 1433, 1376, 1345, 1264, 1217, 1149, 1127, 1029, 978, 904, 869, 837, 803, 737 cm ; H
NMR (CDCl , 500 MHz) ! 2.27–2.31 (m, 2 H), 2.87–2.91 (m, 2 H), 3.95 (s, 3 H), 4.66 (d, J = 6.8 Hz, 2
3
H), 5.11 (d, J = 2.1 Hz, 1 H), 6.05 (dt, J = 11.0, 6.8 Hz, 1 H), 6.66–6.70 (m, 1 H), 6.83 (d, J = 8.3 Hz, 1
1
3
H), 7.08–7.13 (m, 3 H), 7.29–7.33 (m, 2 H); C NMR (CDCl , 125 MHz) ! 26.6, 31.2, 59.0, 59.2,
3
1
12.1, 113.2, 121.2, 123.9, 125.4, 128.9, 132.3, 135.0, 137.8, 146.0, 151.3, 155.9, 173.2; HRMS (ESI)
+
+
m/z [M+H] calcd for C H O 311.1278, found 311.1275.
1
9
19
4
Compound 35: R 0.66 (cyclohexane/ethyl acetate 5:1); IR (ATR) # 2928, 1578, 1517, 1491, 1461,
f
max
!
1
1
1408, 1258, 1212, 1191, 1149, 1123, 1091, 1029, 962, 918, 869, 831, 791, 730, 717 cm ; H NMR
(CDCl , 500 MHz) ! 1.22–1.29 (m, 2 H), 1.71–1.82 (m, 2 H), 2.37–2.45 (m, 2 H), 3.93 (s, 3 H), 4.08 (d,
3
J = 2.1 Hz, 1 H), 5.87 (dt, J = 10.9, 8.2 Hz, 1 H), 6.53–6.57 (m, 1 H), 6.74 (d, J = 8.2 Hz, 1 H), 6.93 (d,
13
J = 10.9 Hz, 1 H), 7.21–7.26 (m, 4 H); C NMR (CDCl , 125 MHz) ! 26.1, 26.3, 30.3, 56.3, 112.0,
3
+
1
15.6, 121.5, 126.0, 130.6, 131.4, 133.1, 134.8, 136.4, 145.2, 153.8, 160.4; HRMS (ESI) m/z [M+H]
+
calcd for C H O 267.1380, found 267.1372.
1
8
19
2
Crystal data: C H O , M=1052.36, monoclinic, space group P2 /c, a=8.4129(17), b=18.533(4),
1
8
18
2
1
3
–1
c=9.925(2) Å, $=%=90°, &=112.62(3)°, V=1428.4(5) Å , Z=4, '=0.71073 Å, µ=0.079 mm , T=293(2)
2
K; 10498 reflections measured, 2652 unique; final refinement to convergence on F gave R=0.0540 and
Rw=0.0990, GOF=0.608. CCDC 1505171.
Combretastatin D-2 4. Analogously to 5, compound 4 was prepared from 34 (11.0 mg, 35.4 µmol),
anhydrous AlCl (37.0 mg, 0.28 mmol) and ethanethiol (0.26 mL, 3.54 mmol) in CH Cl (1.48 mL).
3
2
2
2
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The Journal of Organic Chemistry
After column chromatography (cyclohexane/ethyl acetate 5:1, R 0.27) followed by crystallization from
f
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
hexane/acetone 4:1, 4 (7.0 mg, 23.6 µmol, 67%) was obtained as colorless crystals of mp 152–154 °C
7
b
[
lit. 148-151 °C]. IR (ATR) # 3426, 2923, 2854, 1730, 1594, 1519, 1503, 1439, 1376, 1283, 1215,
max
!
1 1
1
2
159, 1111, 978, 869, 807, 729 cm ; H NMR (CDCl , 500 MHz) ! 2.27–2.31 (m, 2 H), 2.85–2.89 (m,
3
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
H), 4.64 (d, J = 6.8 Hz, 2 H), 5.06 (d, J = 2.0 Hz, 1 H), 5,46 (s, br, 1 H, OH), 6.06 (dt, J = 11.1, 6.8
Hz, 1 H), 6.63 (dd, J = 8.2, 2.0 Hz, 1 H), 6.85 (d, J = 8.2 Hz, 1 H), 7.08–7.13 (m, 3 H), 7.31–7.34 (m, 2
1
3
H); C NMR (CDCl , 125 MHz) ! 26.8, 31.3, 59.0, 112.4, 115.3, 121.8, 123.9, 125.6, 129.0, 131.9,
3
+
+
1
2
35.5, 137.7, 142.5, 148.6, 155.5, 173.3; HRMS (ESI) m/z [M+H] calcd for C H O 297.1121, found
18 17 4
97.1113.
ACKNOWLEDGMENT. We thank Dr. Ursula Bilitewski (HZI, Braunschweig, Germany) and Dr.
Katharina Mahal (University Bayreuth) for biological tests, as well as Dr. Anders Kroscky and Dr.
Matthias Göhl (both University Bayreuth) for valuable suggestions of reagents and synthetic protocols.
1
13
Supporting Information Available: H and C NMR spectra of 4, 5, 7–35; HPLC chromatograms of
the ee determination of 22; crystal data for 35. This material is available free of charge via the Internet
at http://pubs.acs.org.
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