Total Synthesis and Cytotoxic Activity of 5′-Hydroxyzearalenone and 5′β-Hydroxyzearalenone

Article abstract of DOI:10.1002/ejoc.201701272

An efficient and convergent synthesis of 5′-hydroxyzearalenone and 5′β-hydroxyzearalenone, 14-membered β-resorcylic acid lactone (RAL) natural products, has been achieved in a longest linear sequence of 19 steps, and a total of 29 steps, starting from commercially available 5-hexen-1-ol and methyl 2-(3,5-dimethoxyphenyl)acetate. The key features of our synthesis include a Jacobsen hydrolytic kinetic resolution, a Mitsunobu esterification and (an E)-selective ring-closing metathesis (RCM). Our synthesis also highlights the utility of the acetal protecting group for the resorcylate moiety, and its compatibility with RCM reactions for the synthesis of 14-membered RALs. The cytotoxic activity of both synthetic compounds was evaluated against seven human cancer cell lines. 5′-Hydroxyzearalenone shows more potent cytotoxic activity against most of the cancer cell lines tested than its epimer, 5′β-hydroxyzearalenone. Both compounds show significant cytotoxic activity against the C33A cervical cancer cell line, with IC₅₀ values of 21.33 ± 6.43 μm and 16.00 ± 12.17 μm, respectively.

Full text of DOI:10.1002/ejoc.201701272

A Journal of
Accepted Article
Title: Total synthesis and cytotoxic activity of 5′-hydroxyzearalenone
and 5′β-hydroxyzearalenone
Authors: Kwanruthai Tadpetch, Aticha Thiraporn, Vatcharin
Rukachaisirikul, Panata Iawsipo, and Tatiyar Somwang
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201701272
Link to VoR: http://dx.doi.org/10.1002/ejoc.201701272
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10.1002/ejoc.201701272
European Journal of Organic Chemistry
Total synthesis and cytotoxic activity of 5′-hydroxyzearalenone and
5′-hydroxyzearalenone
Aticha Thiraporn,[a] Vatcharin Rukachaisirikul,[a] Panata Iawsipo,[b] Tatiyar Somwang,[b] and
Kwanruthai Tadpetch*[a]
ABSTRACT
An efficient and convergent synthesis of 5′-hydroxyzearalenone and 5′β-hydroxyzearalenone,
14-membered -resorcylic acid lactone (RAL) natural products, has been achieved in 19
longest linear and 29 total steps starting from commercially available 5-hexen-1-ol and
methyl 2-(3,5-dimethoxyphenyl)acetate. The key features of our synthesis include the
Jacobsen hydrolytic kinetic resolution, Mitsunobu esterification and E-selective ring-closing
metathesis (RCM). Our synthesis also highlights the utility of the acetal protecting group of
the resorcylate moiety and its compatibility in RCM for synthesis of 14-membered RALs.
Cytotoxic activity of both synthetic compounds against seven human cancer cell lines was
evaluated. 5′-Hydroxyzearalenone exhibits more potent cytotoxic activity against most of
cancer cell lines tested than its epimer, 5′β-hydroxyzearalenone. Both compounds display
significant cytotoxic activity against the C33A cervical cancer cell line with IC50 values of
21.33  6.43 M and 16.00  12.17 M, respectively.
[a]
Department of Chemistry and Center of Excellence for Innovation in Chemistry,
Faculty of Science, Prince of Songkla University, Hat Yai, Songkhla 90112, Thailand
E-mail: kwanruthai.t@psu.ac.th
Tel.: +66 74 288437; fax: +66 74 558841
[b]
Department of Biochemistry and Center of Excellence for Innovation in Chemistry,
Faculty of Science, Burapha University, Chonburi 20131, Thailand
1
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European Journal of Organic Chemistry
Introduction
Resorcylic macrolides are a group of fungal polyketide metabolites consisting of 14-
membered resorcylic acid lactone (RAL) derivatives that possess diverse pharmacological
profiles.1 Selected examples of these macrolides are zearalenone (1),2 radicicol (2),3
hypothemycin (3),4 and aigialomycin D (4)5 (Figure 1). These RALs have been shown to
exhibit cytotoxic,6 antifungal,7 antiplasmodial,8 antifouling9 and antiviral against Herpes
Simplex Virus 1 (HSV1)10 activities as well as estrogen antagonism11 and inhibitory effects
against ATPases and kinases.12 Owing to their impressive profiles of biological activity, this
class of macrolides has attracted considerable interest as a target for total chemical synthesis
from many synthetic groups worldwide.1
Figure 1. Examples of resorcylic acid lactone natural products.
5′-Hydroxyzearalenone (5) and 5′β-hydroxyzearalenone (6) are new 14-membered -
resorcylic macrolides isolated from the seagrass-derived fungi Fusarium sp. PSU-ES73 by
Arunpanichlert et al. in 2011 and Fusarium sp. PSU-ES123 by Saetang et al. in 2016,
respectively (Figure 2).13,14 Structurally, compounds 5 and 6 are 5′-hydroxy analogues of
zearalenone and consist of two stereogenic centers at the 5′ and 10′-positions. The absolute
configuration of C10′ of 5 and 6 was proposed to be S based on the well-established absolute
configuration at this chiral center of zearalenone natural product analogues and comparison
of the negative Cotton effect at 266 nm with that of 3R,5S-sonnerlactone.15 The absolute
configuration of the alcohol stereogenic center at the 5′-position of 5 and 6 was assigned
based on the Mosher ester analysis. Due to paucity of materials and promising biological
activities of this class of natural products, we became interested in synthesizing 5′-hydroxy-
(5) and 5′β-hydroxyzearalenones (6) in order to confirm the absolute stereochemistry of the
natural products and to provide materials for further biological activity evaluation. Herein, we
describe efficient and convergent syntheses of both natural products and evaluation of their
cytotoxic activity against seven human cancer cell lines.
2
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European Journal of Organic Chemistry
Figure 2. Structures of 5′-hydroxy- (5) and 5′β-hydroxyzearalenones (6).
Results and discussion
A retrosynthetic analysis of 5 and 6 is outlined in Scheme 1. We relied on the well-
precedented ring-closing metathesis (RCM)16,17 as a key macrocyclization and to establish the
(E)-geometry of C1′–C2′ olefin. The RCM diene precursor 7a or 7b would be assembled by
Mitsunobu esterification16a˗e between benzoic acid derivative 8a or 8b and advanced alcohol
intermediate 9. Alcohol 9 would be constructed by addition of the corresponding acetylide of
known alkyne 1118 to chiral aldehyde 10. We envisioned that synthesis of the 5′β-
hydroxyzearalenone (6) would be viable via the same strategy starting from the enantiomer of
10 (epi-10).
Scheme 1. Retrosynthetic analysis of 5′-hydroxy- (5) and 5′β-hydroxyzearalenones (6).
The synthesis of chiral aldehyde 10 is illustrated in Scheme 2. We utilized the
Jacobsen hydrolytic kinetic resolution (HKR) to install the stereogenic center in 10.19 The
synthesis of 10 commenced with protection of commercially available 5-hexen-1-ol (12) with
a benzyl (Bn) group, followed by epoxidation of the corresponding alkene with m-CPBA to
3
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European Journal of Organic Chemistry
yield racemic epoxide 13.20 Hydrolytic kinetic resolution of 13 using (S,S)-
Co(III)(salen)(OAc) catalyst resulted in the formation of (R)-diol 14 in 45% yield (88% ee).
Selective protection of the secondary alcohol moiety of diol 14 was achieved in 3 steps:
benzoylation of the primary alcohol, protection of the secondary alcohol with methoxymethyl
(MOM) group and removal of the benzoate group using K2CO3 in MeOH to give alcohol 15
in 73% over three steps. The absolute configuration of the alcohol chiral center was
confirmed by the Mosher ester analysis of the corresponding benzoate (see Supporting
Information). Subsequent oxidation of 15 with PhI(OAc)2 in the presence of catalytic
TEMPO smoothly gave the desired chiral aldehyde 10 in 87% yield.
Scheme 2. Synthesis of chiral aldehyde 10. Reagents and conditions: (a) NaH, BnBr, THF, 0
°C to rt, 78%; (b) m-CPBA, CH2Cl2, 0 °C to rt, 93%; (c) (S,S)˗Co(III)(salen)(OAc), H2O,
0 °C to rt, 45% (88% ee); (d) BzCl, Et3N, CH2Cl2, 0 °C to rt; (e) MOMCl, EtN(i-Pr)2,
toluene/CH2Cl2, 0 °C to rt; (f) K2CO3, MeOH, 73% over 3 steps; (g) PhI(OAc)2, cat TEMPO,
CH2Cl2, rt, 87%.
We next focused on the key acetylide addition to construct the C6′–C7′ bond of
alcohol intermediate 9 (Scheme 3). Addition of the acetylide generated in situ by
deprotonation of alkyne 11 with n-BuLi to aldehyde 10 afforded propargylic alcohol 16 as a
mixture of diastereomers in 81% yield based on recovered starting aldehyde.18 The
diastereoselectivity of this addition was inconsequential as the C6′ stereogenic center would
eventually be oxidized to the corresponding ketone. The newly generated alcohol 16 was then
protected with Ac2O to give the corresponding acetate ester 17. Reduction of alkyne and
concomitant removal of the benzyl protection group under catalytic hydrogenation in ethanol
provided alcohol 18 in 75% yield. Conversion of the resultant alcohol 18 to the
corresponding alkene was accomplished in 2 steps via iodination using I2, PPh3 and imidazole
and subsequent elimination with KOt-Bu in THF at 0 °C. It should be noted that excess (3.5
equivalents) KOt-Bu was required to ensure complete consumption of the starting iodide,
4
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nevertheless, the acetyl protecting group was simultaneously removed in this step. Thus,
alcohol 19 was reprotected with the Ac group under previously described conditions to give
ester 20 in 98%. Finally, deprotection of the TBDPS group with TBAF in THF smoothly
gave the requisite alcohol intermediate 9 in 83% yield.
Scheme 3. Synthesis of advanced alcohol intermediate 9. Reagents and conditions: (a) n-
BuLi, THF, –78 °C to –30 °C then 10, –78 °C to 0 °C, 81% based on recovered aldehyde
(21%); (b) Ac2O, Et3N, cat DMAP, CH2Cl2, rt, 97% for 17, 98% for 20; (c) H2, Pd/C, EtOH,
rt, 75%; (d) I2, PPh3, imidazole, CH2Cl2, 0 °C to rt, 93%; (e) KOt-Bu, THF, 0 °C to rt, 89%;
(f) TBAF, THF, 0 °C to rt, 83%.
For the synthesis of benzoic acid derivative as a Mitsunobu coupling partner, we
initially chose the methyl protecting groups for the phenol moieties. The known benzoic acid
derivative 8a was prepared according to the procedure reported by Nanda and Jana16c under
slightly modified conditions as illustrated in Scheme 4. Wittig olefination of 3,5-
dimethoxybenzaldehyde (21) using methyltriphenylphosphonium bromide and n-BuLi
provided styrene 22 in 96% yield. Vilsmeier-Haack reaction of 22 using oxalyl chloride as an
activating agent instead of POCl3 introduced the formyl group in the position ortho to the
vinyl substituent to give unstable benzaldehyde 23 in 94% yield. Lastly, Pinnick oxidation of
23 furnished the desired benzoic acid 8a in 76% yield.17c,21
5
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Scheme 4. Preparation of benzoic acid derivative 8a. Reagents and conditions: (a)
Ph3PCH3Br, n-BuLi, THF, 0 °C, 96%; (b) (COCl)2, DMF, CH2Cl2, 0 °C to rt, 94%; (c)
NaClO2, NaH2PO4, 2-methyl-2-butene, t-BuOH, H2O, 76%.
With both benzoic acid derivative 8a and alcohol 9 in hand, the stage was then set for
union of the two fragments under Mitsunobu esterification conditions (DIAD, PPh3)17c, which
afforded ester diene 7a in good yield (Scheme 5). This Mitsunobu esterification step should
also provide the correct stereochemistry of the C2′ stereogenic center of the natural product.
Gratifyingly, ring-closing metathesis of 7a in the presence of second-generation Grubbs
catalyst (5 mol %) in toluene (3.5 mM) at 80 °C provided the desired macrocycle 24 in 74%
yield as a separable 1.5:1 mixture of diastereomers.16b,17c The E-geometry of the newly
generated C1′–C2′ olefin was confirmed based on the coupling constant of 15.7 Hz between
H1′ and H2′ of the minor diastereomer. Removal of the acetate protecting group of each
diastereomer with K2CO3 in methanol smoothly produced alcohol 25 in good yield.
Subjection of each diastereomer of 25 to Dess-Martin periodinane (DMP) oxidation in
CH2Cl2 resulted in the formation of the identical ketone 26 in excellent yields (88% for the
major diastereomer and 85% for the minor diastereomer). Unfortunately, attempts to globally
remove both methyl protecting groups on the aromatic ring and the MOM group using
23
various Lewis acids e.g. BCl3,22 BBr3 and AlCl3 were unsuccessful and led to unidentified
complex mixture or decomposition. Previous reports by Maier17a, b, Yadav17c and Minnaard17d
have demonstrated the successful deprotection of both methyl groups on the resorcylate
moieties in the synthesis of some 14-membered RALs. However, in our case when treating
macrocycle 26 with AlI3 in benzene at 0 °C, 4-O-methyl 5′-hydroxyzearalenone (27) was
obtained as a major isolated product in 25% yield.17 Attempt to remove the remaining Me
group on the aromatic ring of 27 by further treatment with AlI3 led to decomposition.
6
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Scheme 5. Attempted synthesis of 5′-hydroxyzearalenone (5). Reagents and conditions: (a)
DIAD, PPh3, toluene, rt, 71%; (b) Grubbs II (5 mol %), toluene, 80 °C, 74% (major:minor =
1.5:1); (c) K2CO3, MeOH, rt, 81% for major isomer, 82% for minor isomer; (d) DMP,
CH2Cl2, rt, 88% for major isomer, 85% for minor isomer; (e) i. BCl3, CH2Cl2, 0 °C; ii. BCl3,
CH2Cl2, –78 °C; iii. BBr3, CH2Cl2, 0 °C; iv. BBr3, CH2Cl2, –78 °C; v. AlCl3, CH2Cl2, 0 °C;
(f) AlI3, benzene, 0 °C, 25%.
To circumvent the methyl deprotection problems, we decided to switch the phenol
protecting groups from methyl to ethoxymethyl (EOM) groups for the purpose of final global
deprotection by simply treating with HCl. The synthesis of benzoic acid derivative 8b was
achieved in 10 steps from commercially available methyl 2-(3,5-dimethoxyphenyl)acetate (28)
(Scheme 6). Phenol 30 was prepared in 2 steps from 28 according to a procedure reported by
Dong et al. under slightly modified conditions.24 EOM ether 31 was achieved by reprotection
of the free phenol moieties of 30 with EOMCl. To convert ester 31 to the desired styrene
derivative, we proceeded with reduction of both carbonyl groups of 31 using excess NaBH4 in
a mixture of MeOH and THF to afford diol 32 in quantitative yield and no chromatographic
purification. Selective tosylation of the presumably less sterically hindered hydroxyl group of
32 with 1 equivalent of tosyl chloride resulted in the formation of the desired monotosylate
albeit in 37% yield. Due to poor stability of the resulting tosylate, it was immediately used in
the next step to protect the remaining hydroxyl group with t-butyldimethylsilyl chloride
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(TBSCl), which delivered silyl ether 33 in 71% yield. Subsequent elimination of tosylate 33
with KOt-Bu in THF at 0 °C furnished styrene 34 in 85% yield. Removal of the TBS group
was accomplished by treating 34 with TBAF to give alcohol 35 in 93% yield. The hydroxyl
group of 35 was then converted to carboxylic acid via benzaldehyde 36 by IBX oxidation,
followed by Pinnick oxidation to afford the desired benzoic acid 8b in 81% yield.17c,21
Scheme 6. Preparation of benzoic acid derivative 8b. Reagents and conditions: (a) (COCl)2,
DMF, CH2Cl2, 0 °C to rt, 70% (and 12% of isomeric formylated product); (b) AlCl3 CH2Cl2,
reflux, 98%; (c) EOMCl, EtN(i-Pr)2, cat DMAP, CH2Cl2, 0 °C to rt, 84%; (d) NaBH4,
MeOH/THF, 0 °C to rt, quant.; (e) TsCl, Et3N, cat DMAP, CH2Cl2, 0 °C to rt, 37%; (f)
TBSCl, imidazole, cat DMAP, CH2Cl2, 0 °C, 71%; (g) KOt-Bu, THF, 0 °C to rt, 85%; (h)
TBAF, THF, 0 °C to rt, 93%; (i) IBX, toluene/DMSO, 96%; (j) NaClO2, NaH2PO4, 2-methyl-
2-butene, t-BuOH, H2O, 0 °C to rt, 81%.
The benzoic acid derivative 8b and alcohol intermediate 9 were subjected to the
Mitsunobu esterification conditions16c,which afforded ester diene 7b in 70% yield (Scheme
7). To our delight, ring-closing metathesis of 7b in the presence of second-generation Grubbs
catalyst (10 mol %) in refluxing CH2Cl2 at high dilution (2 mM) provided the desired
macrocycle 37 in a remarkable 87% yield as separable diastereomers (major:minor =
1.7:1).16c The geometry of the resulting C1′–C2′ olefin of the macrocylic product was
confirmed by the coupling constant of 15.9 Hz between H1′ and H2′ of the minor
8
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diastereomer of 37. However, no attempts were made to assign the absolute configuration of
the C6′ stereogenic center since it would be oxidized to ketone in the penultimate step of the
synthetic sequence. We then proceeded with removal of the acetate protecting group of each
diastereomer with K2CO3 in methanol, which smoothly produced alcohol 38 in good yield.
As anticipated, subjection of each diastereomer of 38 to DMP oxidation in CH2Cl2 at room
temperature led to the identical ketone 39. This step also confirmed that our RCM conditions
gave (E)-olefin exclusively. Finally, global deprotection of both EOM groups on the aromatic
ring and the MOM group using concentrated HCl in MeOH at 0 °C produced 5′-
hydroxyzearalenone in 62% yield. The 1H and 13C NMR spectroscopic data as well as HRMS
data of synthetic 5′-hydroxyzearalenone (5) were in good agreement with those reported for
natural 5 (see Supporting Information). The specific rotation of synthetic 5 was observed as
28
[]D –25.9 (c 0.10, acetone), which was nearly identical to that of the natural product 5
([]D25 –29.5, c 1.00, acetone).13 The circular dichroism (CD) spectrum of synthetic 5 showed
a negative Cotton effect at 266 nm, confirming the S configuration of the C10′ stereogenic
center analogous to that reported by Lin and co-workers.15 Our synthesis thus verified the
absolute configuration of the natural product.
Scheme 7. Completion of the synthesis of 5′-hydroxyzearalenone (5). Reagents and
conditions: (a) DIAD, PPh3, toluene, rt, 70%; (b) Grubbs II (10 mol %), CH2Cl2, 45 °C, 87%
(major:minor = 1.7:1); (c) K2CO3, MeOH, rt, 76% for major isomer, 70% for minor isomer;
(d) DMP, CH2Cl2, rt, 83% for major isomer, 81% for minor isomer; (e) conc HCl, MeOH, 0
°C to rt, 62%.
9
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The natural product 5′β-hydroxyzearalenone (6) was synthesized via the same strategy
starting from chiral aldehyde epi-10. Hydrolytic kinetic resolution of epoxide 13 in the
presence of (R,R)-Co(III)(salen)(OAc) catalyst afforded (S)-diol 40 in 45% yield (94% ee)
(Scheme 8). Chiral aldehyde epi-10 was thus prepared in 4 steps from (S)-diol 40 using the
previously described protocol. Aldehyde epi-10 was further elaborated to the desired alcohol
epi-9 in 7 steps utilizing the same synthetic sequence outlined in Scheme 9.
Scheme 8. Synthesis of chiral aldehyde epi-10. Reagents and conditions: (a) (R,R)˗
Co(III)(salen)(OAc), H2O, 0 °C to rt, 45% (94% ee); (b) BzCl, Et3N, CH2Cl2, 0 °C to rt; (c)
MOMCl, EtN(i-Pr)2, toluene/CH2Cl2, 0 °C to rt; (d) K2CO3, MeOH, 72% over 3 steps; (e)
PhI(OAc)2, cat TEMPO, CH2Cl2, rt, 93%.
Scheme 9. Synthesis of alcohol epi-9. Reagents and conditions: (a) n-BuLi, THF, –78 °C to
–30 °C then epi-10, –78 °C to 0 °C, 83% based on recovered aldehyde (22%); (b) Ac2O,
Et3N, cat DMAP, CH2Cl2, rt, 97% for 43 and 46; (c) H2, Pd/C, EtOH, rt, 66%; (d) I2, PPh3,
imidazole, CH2Cl2, 0 °C to rt, 94%; (e) KOt-Bu, THF, 0 °C to rt, 96%; (f) TBAF, THF, 0 °C
to rt, 76%.
10
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Completion of the synthesis of 5′β-hydroxyzearalenone (6) was achieved via the same
synthetic sequence as that of 5 (Scheme 10). Mitsunobu esterification reaction between
benzoic acid 8b and alcohol epi-9 furnished the desired ester 47 in 70% yield. The ring-
closing metathesis of diene 47 using second-generation Grubbs catalyst (10 mol %) in
refluxing CH2Cl2 (2 mM) produced the macrocyclic product 48 in 65% yield as an
inseparable mixture of diastereomers. It should be noted that the geometry of the resulting
C1′–C2′ olefin could not be determined at this point. We then carried these diastereomeric
mixtures to the next step, which was acetyl group deprotection by treatment with K2CO3 in
MeOH. Gratifyingly, these alcohol products 49 could be separated by silica gel column
chromatography to result in a 1.3:1 ratio of diastereomers and 77% combined yield. We also
confirmed the geometry of C1′–C2′ olefin to be E from the coupling constant (16.2 Hz)
between H1′ and H2′ of each diastereomer. Each diastereomer of 49 was subsequently
oxidized with DMP in CH2Cl2 to furnish the identical ketone 50 (88% for the major
diastereomer and 79% for the minor diastereomer). Similarly, global deprotection of both
EOM and the MOM groups of 50 under the same conditions to those of 39 delivered 5′-
hydroxyzearalenone (6) in 75% yield. The 1H and 13C NMR spectroscopic and HRMS data of
synthetic 6 were in good agreement with those reported for natural product 6 (see Supporting
28
Information). The specific rotation of synthetic 6 ([]D –97.4, c 0.10, acetone) was in
accordance with the reported value for the natural product 6 ([]D25 –65.0, c 1.00, acetone).14
Similarly, the CD spectrum of synthetic 6 displayed a negative Cotton effect at 266 nm,
which confirmed the absolute configuration of the natural product.
11
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Scheme 10. Completion of the synthesis of 5′β-hydroxyzearalenone (6). Reagents and
conditions: (a) DIAD, PPh3, toluene, rt, 70%; (b) Grubbs II (10 mol %), CH2Cl2, 45 °C, 65%;
(c) K2CO3, MeOH, rt, 77% (major:minor = 1.3:1); (d) DMP, CH2Cl2, rt, 88% for major
isomer, 79% for minor isomer; (e) conc HCl, MeOH, 0 °C to rt, 75%.
Synthetic compounds 5 and 6 were subjected to cytotoxic activity evaluation against
seven human cancer cell lines including two breast adenocarcinoma (MDA-MB-231 and
MCF-7), three cervical carcinoma (C33A, HeLa and SiHa), one hepatoma (HepG2) and one
colorectal carcinoma (HCT116) cells by MTT assay (Table 1 and Figure 3). It was observed
that both compounds could inhibit the proliferation of all cancer cell lines with the IC50
ranges of 21.33–53.00 M for compound 5 and 16.00–179.33 M for compound 6, albeit in
lower extent compared to standard drugs cisplatin and doxorubicin (Table 1). It should be
noted that 5′-hydroxyzearalenone (5) showed more potent cytotoxic activity against most of
cancer cell lines than its epimer, 5′-hydroxyzearalenone (6). Among the seven cancer cell
lines tested, the C33A was the most sensitive cell to both compounds 5 and 6 with IC50 values
of 21.33  6.43 M and 16.00  12.17 M, respectively. Interestingly, although compounds 5
and 6 are concomitantly toxic to noncancerous Vero cells even at a lower concentration (50
µM), these two compounds at 200 µM preferentially reduced the viability of C33A (9.46%
and 10.71%, respectively) and HepG2 (12.38% and 9.28%, respectively) cells more than 2-
fold compared to Vero cells (25.05% and 29.23%, respectively) (Figure 3).
Table 1. Cytotoxic activity of 5′-hydroxy- (5) and 5′β-hydroxyzearalenones (6) against seven
human cancer cell lines.
Cytotoxicity, IC50 (M)
cell lines
5
6
cisplatin
doxorubicin
MDA-MB-231
MCF-7
53.00 ± 4.36
44.00 ± 5.29
41.33 ± 5.77
42.67 ± 2.31
21.33 ± 6.43
119.33 ± 18.04
110.00 ± 2.00
60.00 ± 3.46
41.00 ± 1.73
>50
0.045 ± 0.001
0.048 ± 0.000
0.048 ±0.000
0.0046 ± 0.000
0.038 ± 0.000
HCT116
HepG2
45.67 ± 1.15
19.00 ± 1.73
7.00 ± 1.00
112.67 ± 10.26
16.00 ± 12.17
C33A
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HeLa
SiHa
Vero
50.00 ± 4.00
128.00 ± 7.21
179.33 ± 9.02
43.33 ± 3.06
16.67 ± 2.31
15.33 ± 2.52
8.00 ± 0.00
0.042 ± 0.001
0.046 ± 0.001
0.058 ± 0.001
48.00 ± 7.21
41.33 ± 2.31
Figure 3. Viability of cells treated with compounds 5 and 6 at 50 and 200 µM for 72 h as
determined by MTT assay. Results are shown as percentages of cell viability relative to
untreated cell (0.2% (v/v) DMSO). Data are expressed as means  SD. Statistical significance
was accepted at p<0.05 when (*) was compared between treated and untreated cells, and (#)
between cancer and Vero cells under the same treatment.
Conclusions
In summary, we have developed an efficient and convergent synthesis of 5′-
hydroxyzearalenone (5) and 5′-hydroxyzearalenone (6) starting from commercially
available 5-hexen-1-ol and methyl 2-(3,5-dimethoxyphenyl)acetate. The synthesis was
achieved in 19 longest linear and 29 total steps and 2.0% and 1.8% overall yields for 5 and 6,
respectively. The key features of our synthesis include the Jacobsen hydrolytic kinetic
resolution to install the C5′ stereogenic center, Mitsunobu esterification to couple the key
fragments and ring-closing metathesis to construct the macrocycle and establish the (E)-
geometry of the C1′–C2′ olefin. Our synthesis also highlights the utility of acetal protecting
group of the resorcylate moiety and its compatibility in the ring-closing metathesis reaction
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for synthesis of 14-membered RALs, which allows for mild deprotection that is not
detrimental to sensitive functional groups. Synthetic compounds 5 and 6 were evaluated for
cytotoxic activity against seven human cancer cell lines. It was observed that the -epimer 5
showed more potent cytotoxic activity against most of cancer cell lines tested than the -
epimer 6. Both compounds 5 and 6 showed significant cytotoxic activity against the C33A
cervical cancer cell lines with IC50 values of 21.33  6.43 M and 16.00  12.17 M,
respectively.
Experimental Section
General information: Unless otherwise stated, all reactions were conducted under a nitrogen
or argon atmosphere in oven- or flamed-dried glassware. Solvents were used as received from
suppliers or distilled prior to use using standard procedures. All other reagents were obtained
from commercial sources and used without further purification. Column chromatography was
performed on SiliaFlash® G60 Silica (60-200 m, Silicycle) or Silica gel 60 (0.063-0.200
mm, Merck). Thin-layer chromatography (TLC) was performed on SiliaPlateTM R10011B-
1
13
323 (Silicycle) or Silica gel 60 F254 (Merck). H, C and 2D NMR spectroscopic data were
1
recorded on 300 MHz Bruker FTNMR Ultra Shield spectrometers. H NMR spectra are
reported in ppm on the  scale and referenced to the internal tetramethylsilane. The data are
presented as follows: chemical shift, multiplicity (s = singlet, d = doublet, t = triplet, q =
quartet, qn = quintet, sext = sextet, m = multiplet, br = broad), coupling constant(s) in hertz
(Hz), and integration. Infrared (IR) spectra were recorded on a Perkin Elmer 783 FTS165
FT-IR spectrometer. High-resolution mass spectra were obtained on a liquid chromatograph-
mass spectrometer (2690, LCT, Waters, Micromass). The optical rotations were recorded on
a JASCO P-1020 polarimeter. The circular dichroism (CD) spectra were recorded on a
JASCO J-815 polarimeter. Melting points were measured using an Electrothermal IA9300
melting point apparatus and are uncorrected. Enantiopurity was determined using HPLC on
an Agilent series 1200 equipped with a diode array UV detector using either CHIRALCEL®
OD-H column (15 cm).
General procedure for hydrolytic kinetic resolution (HKR): To a flame-dried flask was
added (S,S)- or (R,R)-cobalt(II) salen (0.005 equiv) and toluene (0.02 M). The reaction
mixture was treated with AcOH (0.02 equiv) and stirred at room temperature open to air for
30 min over which time the color changed from orange-red to dark brown. The solution was
14
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concentrated under reduced pressure to give a brown solid before the racemic epoxide 13 was
added in one portion. The reaction was cooled to 0 °C and H2O (0.60 equiv) was added
dropwise and stirred at 0 °C to room temperature overnight. The reaction mixture was
purified by column chromatography to afford (R)- or (S)-diol and (S)- or (R)-epoxide.
General procedure for methanolysis: To a solution of benzoate or acetate derivative (1.0
equiv) in MeOH (0.05 M) was added K2CO3 (3.0 equiv) and the reaction was stirred at rt
until the starting benzoate or acetate derivative was completely consumed. The reaction
mixture was concentrated under reduced pressure, diluted with H2O and EtOAc. The aqueous
phase was separated and further extracted with EtOAc (x3). The combined organic phases
were washed with brine, dried over anhydrous Na2SO4 and concentrated in vacuo. The crude
residue was purified by column chromatography to give the corresponding alcohol derivative.
General procedure for TEMPO/PhI(OAc)2-mediated oxidation: To a solution of alcohol
(1.0 equiv) in CH2Cl2 (0.05 M) was added PhI(OAc)2 (1.1 equiv), followed by TEMPO (33
mol%). The reaction mixture was stirred at rt overnight. The reaction mixture was then
quenched with saturated aqueous NH4Cl and the aqueous phase was extracted with CH2Cl2
(x3). The combined organic phases were washed with brine, dried over anhydrous Na2SO4
and concentrated in vacuo. The crude residue was purified by column chromatography to
give aldehyde derivative.
General procedure for acetylide addition: To a solution of alkyne 1118 (1.3 equiv) in
anhydrous THF (0.3 M) was added n-BuLi (ca. 1.5 M solution in hexane, 1.5 equiv)
dropwise at –78 °C. After stirring for 1 h, a solution of aldehyde (1.0 equiv) in anhydrous
THF (0.5 M) was slowly added. The reaction mixture was stirred from –78 °C to
approximately 0 °C for 3 h. The reaction was quenched with saturated aqueous NH4Cl and
extracted with EtOAc (x3). The combined organic layer were washed with brine, dried over
anhydrous Na2SO4 and concentrated in vacuo. Purification of the crude residue by column
chromatography yielded the propargylic alcohol derivative.
General procedure for acetylation: To a solution of alcohol (1.0 equiv) in CH2Cl2 (0.2 M)
were added triethylamine (3.0 equiv), DMAP (0.3 equiv), followed by acetic anhydride (2.5
equiv). After stirring for 1 h at rt, the reaction was quenched with saturated aqueous NH4Cl,
the organic layer was separated and the aqueous phase was extracted with CH2Cl2 (x3). The
combined organic layers were washed with brine, dried over anhydrous Na2SO4 and
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concentrated in vacuo. Purification of the crude residue by column chromatography yielded
the acetate derivative.
General procedure for hydrogenation/hydrogenolysis: To a solution of benzyl ether
derivative (1.0 equiv) in EtOH (0.03 M) was added Pd/C (5 wt%, 20 mol %). The reaction
mixture was stirred at rt under H2 atmosphere until the starting material was completely
consumed, then filtered through a pad of Celite, washed with EtOAc and concentrated in
vacuo. Purification of the crude residue by column chromatography yielded the alcohol
derivative.
General procedure for elimination: To a solution of iodide derivative (1.0 equiv) in THF
(0.2 M) at 0 °C was added KOt-Bu (3.5 equiv). The reaction mixture was stirred from 0 °C to
rt for 3 h, then quenched with saturated aqueous NH4Cl and extracted with EtOAc (x3). The
combined organic layers were washed with brine, dried over anhydrous Na2SO4 and
concentrated in vacuo. Purification of the crude residue by column chromatography yielded
the terminal alkene derivative.
General procedure for desilylation: To a solution of silyl ether derivative (1.0 equiv) in dry
THF (0.25 M) was added TBAF (1.0 M solution in THF, 3.0 equiv) dropwise at 0 °C. The
reaction mixture was stirred from 0 °C to rt overnight. H2O was then added and the mixture
was extracted with EtOAc (x3). The combined organic layers were washed with brine, dried
over anhydrous Na2SO4 and concentrated in vacuo. Purification of the crude residue by
column chromatography yielded the alcohol derivative.
General procedure for Pinnick oxidation: To a solution of aldehyde derivative (1.0 equiv)
in tert-butyl alcohol (0.10 M) at 0 °C was added 2-methyl-2-butene (10.0 equiv), followed by
a solution of sodium phosphate monobasic (6.0 equiv) and sodium chlorite (2.0 equiv) in H2O
(0.30 M). After being stirred at rt for 1 h, the reaction mixture was quenched with 1 M HCl
and extracted with EtOAc (x3). The combined organic layers were washed with brine, dried
over with anhydrous Na2SO4 and concentrated in vacuo. Purification of the crude residue by
column chromatography yielded the benzoic acid derivative.
General procedure for Mitsunobu esterification: To a solution of benzoic acid (1.0 equiv)
and alcohol (1.0 equiv) in toluene (0.1 M) were added PPh3 (2.0 equiv) and diisopropyl
azodicarboxylate (DIAD) (2.0 equiv). The reaction mixture was stirred at rt for 2 h, then
16
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diluted with EtOAc, quenched with H2O and extracted with EtOAc (x3). The combined
organic layers were washed with brine, dried over anhydrous Na2SO4 and concentrated in
vacuo. Purification of the crude residue by column chromatography yielded the ester
derivative.
General procedure for ring-closing metathesis: To a solution of diene (1.0 equiv) in
CH2Cl2 (2.0 mM) was added 2nd generation Grubbs catalyst (10 mol %) and purged with
argon at room temperature. The reaction mixture was heated at reflux until the diene
precursor was completely consumed. The reaction was cooled to room temperature and
concentrated in vacuo. Purification of the crude residue by column chromatography yielded
the desired macrolactone.
General procedure for Dess-Martin periodinane (DMP) oxidation: To a solution of
alcohol derivative (1.0 equiv) in CH2Cl2 (0.03 M) was added Dess-Martin periodinane
(DMP) (2.5 equiv). The reaction mixture was stirred at rt for 5 h, then quenched with
saturated aqueous NaHCO3 and extracted with EtOAc (x3). The combined organic layers
were washed with brine, dried over anhydrous Na2SO4 and concentrated in vacuo.
Purification of the crude residue by column chromatography yielded the ketone derivative.
General procedure for deprotection of alkoxy ether group: To a solution of 39 or 50 (1.0
equiv) in MeOH (0.02 M) was treated with concentrated HCl (180.0 equiv) at 0 °C. The
reaction was stirred from 0 °C to rt for 4 h, then neutralized with saturated NaHCO3 and
extracted with EtOAc (x3). The combined organic layers were washed with brine, dried over
anhydrous Na2SO4 and concentrated in vacuo. Purification of the crude residue by column
chromatography yielded the final product derivative.
(R)-6-(Benzyloxy)hexane-1,2-diol (14): (R)-Diol 14 was prepared from racemic epoxide 13
(5.21 g, 25.30 mmol) and (S,S)-cobalt(II) salen (76.7 mg, 0.13 mmol, 0.5 mol %) using the
general procedure for hydrolytic kinetic resolution (HKR). The crude product was purified by
column chromatography (20% EtOAc/hexanes–100% EtOAc) to afford diol 14 as a light
yellow oil (2.49 g, 45%, 88% ee): Rf = 0.15 (50% EtOAc/hexanes);
= +4.90 (c 0.20,
CHCl3); 1H NMR (300 MHz, CDCl3) δ 7.34–7.25 (m, 5H), 4.48 (s, 2H), 3.67–3.60 (m, 1H),
3.55 (dd, J = 11.1, 2.4 Hz, 1H), 3.47 (t, J = 6.3 Hz, 2H), 3.36 (dd, J = 11.1, 7.8 Hz, 1H),
13
1.67–1.35 (m, 6H); C NMR (75 MHz, CDCl3) δ 138.36, 128.40, 127.74, 127.62, 72.93,
72.08, 70.24, 66.63, 32.77, 29.58, 22.26; IR (thin film) 3377, 2937, 2863, 1453,1097, 736
17
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cm-1; HRMS (ESI) m/z calcd for C13H20NaO3 (M + Na)+ 247.1310, found 247.1310; The
enantiomeric excess was determined by HPLC analysis using CHIRALCEL® OD-H column
eluting with 95:5 isopropanol/hexane (flow rate = 1.0 mL/min, pressure = 33.45 bar, temp =
26-28 °C): retention time = 16.602 min, retention time of (S)-enantiomer = 20.634 min.
(R)-6-(Benzyloxy)-2-(methoxymethoxy)hexan-1-ol (15): Alcohol 15 was prepared from
benzoate 14b (2.58 g, 6.93 mmol) using the general procedure for methanolysis. The crude
residue was purified by column chromatography (20–40% EtOAc/hexanes) to give alcohol
15 (1.78 g, 98%, 73% over 3 steps from (R)-diol 14) as a colorless oil: Rf = 0.23 (30%
1
EtOAc/hexanes);
= 31.98 (c 1.00, CHCl3); H NMR (300 MHz, CDCl3) δ 7.24–7.14
(m, 5H), 4.62 (d, J = 6.6 Hz, 1H), 4.55 (d, J = 6.6 Hz, 1H), 4.38 (s, 2H), 3.51–41 (m, 3H),
13
3.37 (t, J = 6.6 Hz, 2H), 3.28 (s, 3H), 1.56–1.28 (m, 6H); C NMR (75 MHz, CDCl3) δ
138.56, 128.25, 127.52, 127.41, 96.39, 80.34, 72.71, 70.04, 64.93, 55.33, 31.34, 29.67, 22.09;
IR (thin film) 3444, 2939, 1454, 1362, 1098, 1036 cm-1; HRMS (ESI) m/z calcd for
C15H24NaO4 (M + Na)+ 291.1572, found 291.1571.
(R)-6-(Benzyloxy)-2-(methoxymethoxy)hexanal (10): Aldehyde 10 was prepared from
alcohol 15 (1.53 g, 5.71 mmol) using the general procedure for TEMPO/PhI(OAc)2-mediated
oxidation. Purification of the crude residue by column chromatography (10–40%
EtOAc/hexanes) yielded aldehyde 10 as a light yellow oil (1.35 g, 87%): Rf = 0.39 (30%
EtOAc/hexanes);
= +14.87 (c 1.00, CHCl3); 1H NMR (300 MHz, CDCl3) δ 9.60 (d, J =
1.8 Hz, 1H), 7.34–7.25 (m, 5H), 4.72 (d, J = 6.9 Hz, 1H), 4.68 (d, J = 6.9 Hz, 1H), 4.49 (s,
2H), 3.89 (td, J = 6.9, 1.8 Hz, 1H), 3.47 (t, J = 6.0 Hz, 2H), 3.40 (s, 3H), 1.73–1.49 (m, 6H);
13C NMR (75 MHz, CDCl3) δ 202.82, 138.52, 128.37, 127.63, 127.55, 96.76, 82.31, 72.92,
69.91, 55.97, 29.78, 29.50, 21.67; IR (thin film) 2944, 1731, 1454, 1275, 1102, 918 cm-1;
HRMS (ESI) m/z calcd for C15H22NaO4 (M + Na)+ 289.1416, found. 289.1416.
(5R,10R)-5-(4-(Benzyloxy)butyl)-10,13,13-trimethyl-12,12-diphenyl-2,4,11-trioxa-12-
silatetradec-7-yn-6-ol (16): Propargylic alcohol 16 was prepared from alkyne 11 (2.04 g,
6.33 mmol) and aldehyde 10 (1.26 g, 4.70 mmol) using the general procedure for acetylide
addition. The crude residue was purified by column chromatography (5–30%
EtOAc/hexanes) to give propargylic alcohol 16 (1.77 g, 81% based on 270.3 mg of recovered
aldehyde 10) as a light yellow oil: Rf = 0.27 (20% EtOAc/hexanes);
= +17.89 (c 1.00,
CHCl3); 1H NMR (300 MHz, CDCl3) δ 7.68 (d, J = 7.2 Hz, 4H), 7.42–7.24 (m, 11H), 4.72 (d,
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J = 7.2 Hz, 1H), 4.64 (d, J = 7.2 Hz, 1H), 4.48 (s, 2H), 4.26–4.24 (m, 1H), 4.01–3.91 (m,
1H), 3.51–3.43 (m, 1H), 3.45 (t, J = 6.3 Hz, 2H), 3.39 (s, 3H), 2.45–2.26 (m, 2H), 1.78–1.37
(m, 6H), 1.20 (d, J = 6.0 Hz, 3H), 1.05 (s, 9H); 13C NMR (75 MHz, CDCl3) δ 138.60, 135.83,
134.23, 134.17, 134.12, 129.67, 128.38, 127.61, 97.68, 97.46, 84.77, 83.58, 83.25, 80.35,
79.79, 72.91, 70.23, 70.17, 68.29, 68.19, 65.38, 65.23, 55.91, 55.86, 31.42, 31.21, 29.77,
29.65, 29.44, 26.97, 22.97, 22.92, 22.55, 22.01, 19.22; IR (thin film) 3417, 2931, 2857, 1427,
1109, 1041 cm-1; HRMS (ESI) m/z calcd for C36H48NaO5Si (M + Na)+ 611.3169, found
611.3168.
(5R,10R)-5-(4-(Benzyloxy)butyl)-10,13,13-trimethyl-12,12-diphenyl-2,4,11-trioxa-12-
silatetradec-7-yn-6-yl acetate (17): Acetate 17 was prepared from propargylic alcohol 16
(1.40 g, 1.90 mmol) using the general procedure for acetylation. The crude residue was
purified by column chromatography (20% EtOAc/hexanes) to give 17 (1.46 g, 97%) as a light
yellow oil: Rf = 0.40 (20% EtOAc/hexanes);
= +20.88 (c 1.00, CHCl3); 1H NMR (300
MHz, CDCl3) δ 7.69–7.66 (m, 4H), 7.40–7.23 (m, 11H), 5.55 (dt, J = 2.7, 1.8 Hz, 0.65H),
5.46 (dt, J = 5.7, 1.8 Hz, 0.37H), 4.74 (d, J = 6.9 Hz, 1H), 4.59 (d, J = 6.9 Hz, 1H), 4.48 (s,
2H), 4.02–3.91 (m, 1H), 3.71–3.59 (m, 1H), 3.46 (t, J = 6.3 Hz, 2H), 3.35 (s, 3H), 2.42–2.26
13
(m, 2H), 2.06 (s, 3H), 1.73–1.37 (m, 6H), 1.17 (d, J = 6.0 Hz, 3H), 1.05 (s, 9H); C NMR
(75 MHz, CDCl3) δ 169.91, 169.68, 138.60, 135.79, 134.19, 133.99, 129.67, 129.62, 128.34,
127.59, 127.49, 96.88, 96.17, 84.72, 84.37, 78.33, 78.01, 72.87, 70.19, 67.97, 66.20, 66.01,
55.86, 55.79, 30.80, 30.39, 29.77, 29.67, 29.36, 26.91, 22.89, 22.52, 21.83, 21.01, 19.19; IR
(thin film) 2932, 2857, 1743, 1369, 1231, 1106 cm-1; HRMS (ESI) m/z calcd for
C38H50NaO6Si (M + Na)+ 653.3274, found 653.3276.
(5R,10R)-5-(4-Hydroxybutyl)-10,13,13-trimethyl-12,12-diphenyl-2,4,11-trioxa-12-
silatetradecan-6-yl acetate (18): Alcohol 18 was prepared from compound 17 (1.36 g, 2.15
mmol) using the general procedure for hydrogenation/hydrogenolysis. The crude product was
purified by column chromatography (20–40% EtOAc/hexanes) to afford alcohol 18 (916.9
mg, 75%) as a light yellow oil: Rf = 0.17 (30% EtOAc/hexanes);
= +7.88 (c 1.02,
1
CHCl3); H NMR (300 MHz, CDCl3) δ 7.67 (d, J = 7.5 Hz, 4H), 7.41–7.34 (m, 6H), 5.03–
4.91 (m, 1H), 4.70 (d, J = 7.2 Hz. 1H), 4.57 (d, J = 7.2 Hz, 1H), 3.82 (sext, J = 6.0 Hz, 1H),
13
3.66–3.49 (m, 3H), 3.37 (s, 3H), 2.03 (s, 3H), 1.58–1.20 (m, 12H), 1.04 (s, 12H); C NMR
(75 MHz, CDCl3) δ 170.79, 135.83, 134.76, 134.42, 129.46, 129.39, 127.47, 127.37, 96.55,
95.90, 78.32, 77.94, 74.90, 74.39, 69.43, 69.19, 62.51, 62.39, 55.84, 55.72, 39.39, 39.13,
19
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32.58, 30.23, 30.09, 30.03, 29.23, 26.99, 23.26, 23.17, 21.93, 21.61, 21.53, 21.35, 21.09,
19.23; IR (thin film) 3451, 2933, 1737, 1373, 1243, 1110 cm-1; HRMS (ESI) m/z calcd for
C31H48NaO6Si (M + Na)+ 567.3118, found 567.3120.
(5R,10R)-5-(But-3-enyl)-10,13,13-trimethyl-12,12-diphenyl-2,4,11-trioxa-12-silatetra
decan-6-ol (19): Compound 19 was prepared from iodide 18a (920.0 mg, 1.40 mmol) using
general procedure for elimination. Purification of the crude residue by column
chromatography (20% EtOAc/hexanes) afforded 19 (606.6 mg, 89%) as a light yellow oil: Rf
= 0.56 (30% EtOAc/hexanes);
= +5.26 (c 0.19, CHCl3); 1H NMR (300 MHz, CDCl3) δ
7.70–7.66 (m, 4H), 7.41–7.33 (m, 6H), 5.87–5.75 (m, 1H), 5.03 (dd, J = 17.1, 1.5 Hz, 1H),
4.98 (dd, J = 10.2, 1.5 Hz, 1H), 4.71 (d, J = 6.9 Hz, 1H), 4.62 (d, J = 6.9 Hz, 1H), 3.88–
3.81(m, 1H), 3.52–3.45 (m, 2H), 3.40 (s, 3H), 2.23–1.99 (m, 2H), 1.74–1.26 (m, 8H), 1.08 (s,
3H), 1.05 (s, 9H); 13C NMR (75 MHz, CDCl3) δ 138.24, 135.89, 134.91, 134.64, 129.45,
129.39, 127.47, 127.40, 114.96, 114.90, 97.31, 97.21, 83.23, 82.99, 72.94, 72.72, 69.59,
69.50, 55.81, 39.55, 39.46, 33.23, 31.80, 30.31, 30.08, 29.44, 29.29, 27.06, 23.22, 23.14,
21.94, 21.30, 19.26; IR (thin film) 3461, 2932, 1427, 1105, 1036, 702 cm-1; HRMS (ESI) m/z
calcd for C29H44NaO4Si (M + Na)+ 507.2907, found 507.2907.
(5R,10R)-5-(But-3-enyl)-10,13,13-trimethyl-12,12-diphenyl-2,4,11-trioxa-12-silatetra
decan-6-yl acetate (20): Compound 20 was prepared from 19 (606.6 mg, 1.25 mmol) using
the general procedure for acetylation. Purification of the crude residue by column
chromatography (10% EtOAc/hexanes) afforded 20 (652.6 mg, 98%) as a light yellow oil: Rf
= 0.62 (30% EtOAc/hexanes);
= +10.0 (c 0.20, CHCl3); 1H NMR (300 MHz, CDCl3) δ
7.67 (d, J = 7.8 Hz, 4H), 7.44–7.34 (m, 6H), 5.88–5.73 (m, 1H), 5.08–5.06 (m, 1H), 5.02–
4.93 (m, 2H), 4.71 (d, J = 6.9 Hz, 1H), 4.57 (d, J = 6.9 Hz, 1H), 3.82 (sext, J = 6.0 Hz, 1H),
3.63–3.51 (m, 1H), 3.38 (s, 3H), 2.31–2.07 (m, 2H), 2.03 (s, 3H), 1.72–1.19 (m, 8H), 1.04 (s,
12H); 13C NMR (75 MHz, CDCl3) δ 170.67, 170.43, 138.10, 135.85, 134.94, 134.85, 134.64,
134.50, 129.48, 129.40, 129.35, 127.49, 127.43, 127.35, 115.02, 114.86, 96.77, 96.10, 95.98,
77.88, 77.80, 77.68, 77.44, 77.36, 75.00, 74.87, 74.49, 74.38, 69.49, 69.29, 69.23, 55.77,
55.67, 39.45, 39.24, 29.99, 29.92, 29.82, 29.53, 27.03, 23.28, 23.18, 23.09, 21.56, 21.33,
21.09, 20.94, 19.26, 19.23; IR (thin film) 2932, 2858, 1737, 1374, 1240, 1105 cm-1; HRMS
(ESI) m/z calcd for C31H46NaO5Si (M + Na)+ 549.3012, found 549.3012.
20
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(5R,10R)-10-Hydroxy-5-(methoxymethoxy)undec-1-en-6-yl acetate (9): Alcohol 9 was
prepared from compound 20 (656.2 mg, 1.24 mmol) using the general procedure for
desilylation. The crude residue was purified by column chromatography (10–30%
EtOAc/hexanes) to give alcohol 9 (298.2 mg, 83%) as a colorless oil: Rf = 0.22 (30%
1
EtOAc/hexanes);
= +4.35 (c 0.23, CHCl3); H NMR (300 MHz, CDCl3) δ 5.88–5.73
(m, 1H), 5.08–4.97 (m, 3H), 4.72 (d, J = 7.2 Hz, 1H), 4.59 (d, J = 6.9 Hz, 1H), 3.78–3.74 (m,
1H), 3.67–3.56 (m, 1H), 3.39 (s, 3H), 2.36–2.13 (m, 2H), 2.07 (s, 3H), 1.71–1.32 (m, 8H),
13
1.17 (d, J = 6.0 Hz, 3H); C NMR (75 MHz, CDCl3) δ 170.88, 170.77, 137.97, 137.93,
115.01, 114.97, 96.64, 95.94, 77.72, 77.51, 74.81, 74.25, 67.54, 55.84, 55.72, 38.85, 29.80,
29.76, 29.66, 29.62, 29.49, 29.28, 23.38, 21.86, 21.70, 21.08, 21.03 ;IR (thin film) 3447,
2934, 1736, 1374, 1242, 1097 cm-1; HRMS (ESI) m/z calcd for C15H28NaO5 (M + Na)+
311.1834, found 311.1834.
Methyl 2-(3,5-bis(ethoxymethoxy)-2-formylphenyl)acetate (31): To a solution of phenol
30 (2.20 g, 10.47 mmol) in CH2Cl2 (100 mL) at 0 °C was added DMAP (383.6 mg, 31.40
mmol, 0.3 equiv) and EtN(i-Pr)2 (11 mL, 62.82 mmol, 6.0 equiv), followed by chloromethyl
ethyl ether (EOMCl) (3.1 mL, 33.50 mmol, 3.2 equiv) dropwise. The reaction was stirred
from 0 °C to rt overnight before saturated aqueous NH4Cl (70 mL) was added and extracted
with EtOAc (3x50 mL). The combined organic layers were washed with brine, dried over
with anhydrous Na2SO4 and concentrated in vacuo. Purification of the crude residue by
column chromatography (5–20% EtOAc/hexanes) yielded 31 (2.87 g, 84%) as a yellow solid:
Rf = 0.46 (40% EtOAc/hexanes); mp 81–83 °C; 1H NMR (300 MHz, CDCl3) δ 10.45 (s, 1H),
6.88 (d, J = 2.1 Hz, 1H), 6.53 (d, J = 2.1 Hz, 1H), 5.31 (s, 2H), 5.26 (s, 2H), 3.93 (s, 2H),
3.79–3.69 (m, 4H), 3.71 (s, 3H), 1.27–1.20 (m, 6H); 13C NMR (75 MHz, CDCl3) δ 190.21,
171.53, 163.27, 162.44, 138.70, 118.15, 113.37, 101.86, 93.60, 92.85, 64.88, 64.74, 51.86,
40.43, 15.04; IR (thin film) 2978, 1740, 1677, 1602, 1285, 1149 cm-1; HRMS (ESI) m/z calcd
for C16H22NaO7 (M + Na)+ 349.1263, found 349.1263.
2-(3,5-Bis(ethoxymethoxy)-2-(hydroxymethyl)phenyl)ethanol (32): To a solution of ester
31 (2.79 g, 8.47 mmol) in MeOH (21 mL) and THF (21 mL) at 0 °C were added NaBH4
(966.4 mg, 25.41 mmol, 3.0 equiv). The reaction was stirred from 0 °C to rt overnight before
saturated aqueous NH4Cl (70 mL) was added and extracted with EtOAc (3x20 mL). The
combined organic layers were washed with brine, dried over with anhydrous Na2SO4 and
concentrated in vacuo to give diol 32 (2.66 g, quant.) as a light yellow oil, which was used
21
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for the next step without further purification: Rf = 0.07 (40% EtOAc/hexanes); 1H NMR (300
MHz, CDCl3) δ 6.73 (d, J = 2.4 Hz, 1H), 6.57 (d, J = 2.1 Hz, 1H), 5.22 (s, 2H), 5.18 (s, 2H),
4.64 (s, 2H), 3.79 (t, J = 6.0 Hz, 2H), 3.76–3.67 (m, 4H), 2.88 (t, J = 6.3 Hz, 2H), 1.21 (t, J =
6.9 Hz, 6H); 13C NMR (75 MHz, CDCl3) δ 157.89, 156.86, 141.03, 122.89, 110.70, 102.28,
93.94, 93.10, 64.51, 64.24, 63.27, 55.15, 35.87, 15.05; IR (thin film) 3347, 2975, 2896, 1605,
1281, 1144 cm-1; HRMS (ESI) m/z calcd for C15H24NaO6 (M + Na)+ 323.1471, found
323.1471.
2-((tert-Butyldimethylsilyloxy)methyl)-3,5-bis(ethoxymethoxy)phenethyl
4-methylbenzenesulfonate (33): To a solution of diol 32 (608.2 mg, 2.00 mmol) in CH2Cl2
(20 mL) was added triethylamine (390 µL, 2.80 mmol, 1.4 equiv) and DMAP (73.7 mg, 0.60
mmol, 0.3 equiv). The reaction was cooled to 0 °C, added TsCl (533.9 mg, 2.80 mmol, 1.4
equiv) and stirred from 0 °C to rt for 1.5 h. The reaction mixture was quenched with saturated
NH4Cl (25 mL) and extracted with EtOAc (3x10 mL). The combined organic layers were
washed with brine, dried over with anhydrous Na2SO4 and concentrated in vacuo. The crude
residue was purified by column chromatography (20% EtOAc/hexanes) to give the desired
monotosylate (340.5 mg, 37%) as a light yellow oil, which was immediately used in the next
step: Rf = 0.23 (40% EtOAc/hexanes).
To a solution of the monotosylate (180.6 mg, 0.40 mmol) in CH2Cl2 (3 mL) at 0 °C were
added imidazole (54.2 mg, 0.80 mmol, 2 equiv), DMAP (14.6 mg, 0.12 mmol, 0.3 equiv),
followed by TBSCl (90.4 mg, 0.60 mmol, 1.5 equiv). After stirring at rt for 1 h, it was
quenched with H2O (5 mL) and extracted with EtOAc (3x5 mL). The combined organic
phases were washed with brine, dried over anhydrous Na2SO4 and concentrated under
reduced pressure. The crude residue was purified by column chromatography (5–20%
EtOAc/hexanes) to give 33 (160.9 mg, 71%) as a colorless oil: Rf = 0.58 (40%
EtOAc/hexanes); 1H NMR (300 MHz, CDCl3) δ 7.71 (d, J = 8.1 Hz, 2H), 7.28 (d, J = 8.7 Hz,
2H), 6.73 (d, J = 2.4 Hz, 1H), 6.48 (d, J = 2.4 Hz, 1H), 5.18 (s, 2H), 5.15 (s, 2H), 4.64 (s,
2H), 4.24 (t, J = 7.5 Hz, 2H), 3.71 (q, J = 6.9 Hz, 2H), 3.70 (q, J = 6.9 Hz, 2H), 3.05 (t, J =
7.5 Hz, 2H), 2.42 (s, 3H), 1.22 (t, J = 6.9 Hz, 3H), 1.21 (t, J = 6.9 Hz, 3H), 0.85 (s, 9H), 0.04
(s, 6H); 13C NMR (75 MHz, CDCl3) δ 157.63, 156.54, 144.49, 138.36, 133.24, 129.75,
127.82, 122.02, 111.00, 102.34, 93.66, 93.15, 70.92, 64.32, 64.26, 55.91, 32.69, 25.97, 21.59,
18.36, 15.08, -5.34; IR (thin film) 2956, 2895, 1605, 1360, 1176, 1062 cm-1; HRMS (ESI)
m/z calcd for C28H44NaO8SSi (M + Na)+ 591.2424, found 591.2424.
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(2,4-Bis(ethoxymethoxy)-6-vinylbenzyloxy)(tert-butyl)dimethylsilane (34): Alkene 34
was prepared from tosylate 33 (85.2 mg, 0.15 mmol) using the general procedure for
elimination. The crude residue was purified by column chromatography (10%
EtOAc/hexanes) to give 34 (50.6 mg, 85%) as colorless oil: Rf = 0.65 (40% EtOAc/hexanes);
1H NMR (300 MHz, CDCl3) δ 7.14 (dd, J = 17.4, 10.8 Hz, 1H), 6.90 (d, J = 2.4 Hz, 1H), 6.81
(d, J = 2.4 Hz, 1H), 5.69 (dd, J = 17.4, 1.2 Hz, 1H), 5.34 (dd, J = 10.8, 1.2 Hz, 1H), 5.24 (s,
4H), 4.77 (s, 2H), 3.76 (q, J = 7.2 Hz, 2H), 3.75 (q, J = 7.2 Hz, 2H), 1.25 (t, J = 7.2 Hz, 6H),
13
0.92 (s, 9H), 0.09 (s, 6H); C NMR (75 MHz, CDCl3) δ 157.67, 156.39, 140.34, 134.88,
121.03, 116.24, 106.67, 103.11, 93.73, 93.22, 64.28, 64.19, 55.96, 25.98, 18.45, 15.10, -5.23;
IR (thin film) 2930, 1601, 1579, 1471, 1254, 1148 cm-1; HRMS (ESI) m/z calcd for
C21H36NaO5Si (M + Na)+ 419.2230, found 419.2231.
(2,4-Bis(ethoxymethoxy)-6-vinylphenyl)methanol (35): To a solution of silyl ether 34
(160.6 mg, 0.40 mmol) in THF (4 mL) at 0 °C was added TBAF (1.0 M solution in THF, 1.6
mL, 1.6 equiv). The reaction mixture was stirred from 0 °C to room temperature for 1 h
before it was heated at 60 °C for 1.5 h. The reaction was then cooled to room temperature,
then quenched with H2O (5 mL) and extracted with EtOAc (3x5 mL). The combined organic
phases were washed with brine, dried over anhydrous Na2SO4 and concentrated under
reduced pressure. The crude residue was purified by column chromatography (10–30%
EtOAc/hexanes) to give alcohol 35 (106.5 mg, 93%) as a colorless oil: Rf = 0.38 (40%
EtOAc/hexanes); 1H NMR (300 MHz, CDCl3) δ 7.07 (dd, J = 17.4, 10.8 Hz, 1H), 6.87 (d, J =
2.1 Hz, 1H), 6.79 (d, J = 2.4 Hz, 1H), 5.67 (dd, J = 17.4, 1.2 Hz, 1H), 5.36 (dd, J = 10.8, 1.2
Hz, 1H), 5.23 (d, J = 1.8 Hz, 2H), 5.21 (d, J = 1.8 Hz, 2H), 4.71 (s, 2H), 3.73 (q, J = 7.2 Hz,
2H), 3.72 (q, J = 7.2 Hz, 2H), 1.22 (t, J = 7.2 Hz, 6H); 13C NMR (75 MHz, CDCl3) δ 157.86,
156.92, 139.57, 134.11, 121.29, 117.42, 107.09, 103.37, 93.97, 93.13, 64.64, 64.25, 56.04,
15.07, 15.04; IR (thin film) 3444, 2977, 1601, 1578, 1283, 1146 cm-1; HRMS (ESI) m/z calcd
for C15H22NaO5 (M + Na)+ 305.1365, found 305.1365.
2,4-Bis(ethoxymethoxy)-6-vinylbenzaldehyde (36): To a solution of alcohol 35 (106.5 mg,
0.38 mmol) in DMSO (4.3 mL) and toluene (4.3 mL) were added IBX (376.2 mg, 1.33 mmol,
3.5 equiv). The reaction mixture was stirred at rt for 2 h before being quenched with H2O (4
mL), filtered and extracted with EtOAc (3x5 mL). The combined organic layers were washed
with brine, dried over with anhydrous Na2SO4 and concentrated in vacuo. The crude residue
was purified by column chromatography (5–20% EtOAc/hexanes) to give aldehyde 36 (101.2
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mg, 96%) as a light yellow oil: Rf = 0.57 (40% EtOAc/hexanes); 1H NMR (300 MHz, CDCl3)
δ 10.50 (s, 1H), 7.56 (dd, J = 17.4, 10.8 Hz, 1H), 6.84 (s, 2H), 5.63 (dd, J = 17.4, 1.5 Hz,
1H), 5.37 (dd, J = 10.8, 1.2 Hz, 1H), 5.31 (s, 2H), 5.28 (s, 2H), 3.76 (q, J = 7.2 Hz, 2H), 3.75
(q, J = 7.2 Hz, 2H), 1.24 (t, J = 7.2 Hz, 3H), 1.23 (t, J = 7.2 Hz, 3H); 13C NMR (75 MHz,
CDCl3) δ 190.55, 162.54, 162.29, 143.00, 136.02, 117.44, 108.10, 102.08, 102.03, 93.63,
92.84, 64.88, 64.68, 15.05; IR (thin film) 2977, 1678, 1594, 1277, 1149, 1026 cm-1; HRMS
(ESI) m/z calcd for C15H20NaO5 (M + Na)+ 303.1208, found 303.1209.
2,4-Bis(ethoxymethoxy)-6-vinylbenzoic acid (8b): Benzoic acid 8b was prepared from
aldehyde 36 (101.2 mg, 0.36 mmol) using the general procedure for Pinnick oxidation. The
crude residue was purified by column chromatography (20–40% EtOAc/hexanes) to give
1
benzoic acid 8b (86.6 mg, 81%) as a light yellow oil: Rf = 0.18 (40% EtOAc/hexanes); H
NMR (300 MHz, CDCl3) δ 7.01 (dd, J = 17.4, 11.1 Hz, 1H), 6.93 (d, J = 2.1 Hz, 1H), 6.86 (d,
J = 2.1 Hz, 1H), 5.71 (d, J = 17.4 Hz, 1H), 5.36 (d, J = 11.1 Hz, 1H), 5.28 (s, 2H), 5.26 (s,
13
2H), 3.75 (qn, J = 7.2 Hz, 4H), 1.23 (t, J = 6.9 Hz, 6H); C NMR (75 MHz, CDCl3) δ
171.28, 159.68, 156.25, 139.53, 134.38, 117.23, 115.61, 107.01, 103.31, 94.02, 93.00, 64.80,
64.49, 15.04, 14.98; IR (thin film) 2978, 1709, 1599, 1285, 1153, 1027 cm-1; HRMS (ESI)
m/z calcd for C15H20NaO6 (M + Na)+ 319.1158, found 319.1159.
(2S,7R)-6-Acetoxy-7-(methoxymethoxy)undec-10-en-2-yl
2,4-bis(ethoxymethoxy)-6-
vinylbenzoate (7b): Ester 7b was prepared from alcohol 9 (98.4 mg, 0.34 mmol) and benzoic
acid 8b (108.1 mg, 0.36 mmol) using the general procedure for Mitsunobu esterification. The
crude residue was purified by column chromatography (10–20% EtOAc/hexanes) to give ester
7b (135.6 mg, 70%) as a light yellow oil: Rf = 0.63 (50% EtOAc/hexanes);
= +5.00 (c
1
0.20, CHCl3); H NMR (300 MHz, CDCl3) δ 6.88 (d, J = 2.1 Hz, 1H), 6.81 (d, J = 2.1 Hz,
1H), 6.69 (dd, J = 17.4, 10.8 Hz, 1H), 5.88–5.77 (m, 1H), 5.71 (d, J = 17.4 Hz, 1H), 5.33 (d,
J = 10.8 Hz, 1H), 5.22 (s, 2H), 5.20 (s, 2H), 5.19–5.11 (m, 1H), 5.08–4.97 (m, 3H), 4.71 (d, J
= 6.9 Hz, 1H), 4.59 (d, J = 6.9 Hz, 1H), 3.71 (qd, J = 6.9, 1.8 Hz, 4H), 3.66–3.55 (m, 1H),
3.39 (s, 3H), 2.31–2.10 (m, 2H), 2.06 (s, 3H), 1.71–1.36 (m, 8H), 1.33 (d, J = 6.3 Hz, 3H),
13
1.22 (t, J = 6.9 Hz, 3H), 1.21 (t, J = 6.9 Hz, 3H); C NMR (75 MHz, CDCl3) δ 170.71,
170.55, 167.39, 158.86, 155.27, 137.98, 137.15, 133.38, 118.12, 117.17, 115.10, 115.04,
105.65, 103.09, 96.65, 96.02, 93.35, 93.06, 77.68, 77.50, 74.74, 74.06, 71.65, 64.39, 64.29,
55.90, 55.79, 35.73, 29.91, 29.87, 29.55, 29.05, 21.75, 21.57, 21.13, 21.07, 19.99, 15.07,
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15.03; IR (thin film) 2976, 2934, 1732, 1601, 1265, 1151 cm-1; HRMS (ESI) m/z calcd for
C30H46NaO10 (M + Na)+ 589.2989, found 589.2988.
Macrolactones 37: Macrolactones 37 were prepared from ester 7b (80.2 mg, 0.10 mmol)
using the general procedure for ring-closing metathesis. The crude residue was purified by
column chromatography (10–20% EtOAc/hexanes) to give macrolactones 37 as a mixture of
diastereomers.
Major diastereomer of 37. colorless oil (42.5 mg, 56%); Rf = 0.53 (50% EtOAc/hexanes);
1
= +100.02 (c 0.14, CHCl3); H NMR (300 MHz, CDCl3) δ 6.83 (d, J = 1.8 Hz, 1H),
6.73 (d, J = 1.8 Hz, 1H), 6.38–6.34 (m, 2H), 5.22 (s, 4H), 5.20–5.05 (m, 2H), 4.68 (d, J = 6.9
Hz, 1H), 4.54 (d, J = 6.9 Hz, 1H), 3.76–3.67 (m, 5H), 3.37 (s, 3H), 2.39–2.35 (m, 2H), 2.07
(s, 3H), 2.00–1.46 (m, 8H), 1.34 (d, J = 6.3 Hz, 3H), 1.25–1.19 (m, 6H); 13C NMR (75 MHz,
CDCl3) δ 170.76, 168.23, 158.67, 154.76, 135.86, 132.48, 125.66, 118.36, 105.17, 102.22,
95.77, 93.23, 93.09, 75.39, 75.00, 69.34, 64.41, 64.30, 55.72, 34.92, 29.69, 29.37, 25.89,
25.52, 21.23, 20.60, 20.47, 15.09, 15.01; IR (thin film) 2932, 1730, 1601, 1239, 1149, 1021
cm-1; HRMS (ESI) m/z calcd for C28H42NaO10 (M + Na)+ 561.2676, found 561.2676.
Minor diastereomer of 37. colorless oil (24.0 mg, 31%); Rf = 0.48 (50% EtOAc/hexanes);
1
= +110.02 (c 0.10, CHCl3); H NMR (300 MHz, CDCl3) δ 6.80 (d, J = 1.8 Hz, 1H),
6.76 (d, J = 1.8 Hz, 1H), 6.41 (d, J = 15.9 Hz, 1H), 6.09 (ddd, J = 15.9, 9.3, 5.1 Hz, 1H),
5.47–5.37 (m, 1H), 5.22 (s, 4H), 4.97 (dt, J = 9.6, 2.7 Hz, 1H), 4.66 (d, J = 6.9 Hz, 1H), 4.60
(d, J = 6.9 Hz, 1H), 3.76–3.67 (m, 5H), 3.37 (s, 3H), 2.42–2.13 (m, 2H), 2.09 (s, 3H), 2.00–
13
1.33 (m, 8H), 1.28–1.19 (m, 9H); C NMR (75 MHz, CDCl3) δ 170.52, 167.38, 158.81,
154.82, 136.64, 132.73, 128.03, 118.16, 105.81, 102.51, 96.54, 93.31, 93.09, 74.44, 71.98,
70.14, 64.37, 64.32, 55.77, 34.05, 29.67, 29.15, 28.75, 28.11, 21.19, 18.82, 17.76, 15.07,
15.00; IR (thin film) 2944, 1728, 1601, 1246, 1151, 1104 cm-1; HRMS (ESI) m/z calcd for
C28H42NaO10 (M + Na)+ 561.2676, found 561.2676.
Major diastereomer of alcohol 38: The major diastereomer of alcohol 38 was prepared
from the major diastereomer of macrolactone acetate 37 (42.5 mg, 0.08 mmol) using the
general procedure for methanolysis. The crude residue was purified by column
chromatography (20–40% EtOAc/hexanes) to give the major diastereomer of alcohol 38
(30.2 mg, 76%) as a colorless oil: Rf = 0.23 (50% EtOAc/hexanes);
= +90.02 (c 0.10,
1
CHCl3); H NMR (300 MHz, CDCl3) δ 6.81 (d, J = 1.8 Hz, 1H), 6.73 (d, J = 1.8 Hz, 1H),
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6.33 (s, 2H), 5.22–5.16 (m, 5H), 4.70 (d, J = 6.9 Hz, 1H), 4.59 (d, J = 6.9 Hz, 1H), 3.88–3.84
(m, 1H), 3.71 (qd, J = 6.9, 4.2 Hz, 4H), 3.65–3.61 (m, 1H), 3.40 (s, 3H), 2.44–2.25 (m, 2H),
1.90–1.36 (m, 8H), 1.35 (d, J = 6.3 Hz, 3H), 1.23 (t, J = 6.9 Hz, 3H), 1.21 (t, J = 6.9 Hz,
3H); 13C NMR (75 MHz, CDCl3) δ 168.13, 158.68, 154.82, 136.09, 132.79, 126.03, 118.50,
105.53, 102.34, 96.03, 93.33, 93.16, 78.42, 73.30, 69.91, 64.43, 64.33, 55.76, 35.12, 31.23,
29.70, 26.04, 24.41, 20.50, 20.27, 15.10, 15.02; IR (thin film) 3468, 2933, 1725, 1599, 1262,
1149 cm-1; HRMS (ESI) m/z calcd for C26H40NaO9 (M + Na)+ 519.2570, found 519.2570.
Minor diastereomer of alcohol 38: The minor diastereomer of alcohol 38 was prepared
from the minor diastereomer of macrolactone acetate 37 (24.0 mg, 0.044 mmol) using the
general procedure for methanolysis. The crude residue was purified by column
chromatography (20% EtOAc/hexanes) to give the minor diastereomer of alcohol 38 (15.3
mg, 70%) as a light yellow oil: Rf = 0.32 (50% EtOAc/hexanes);
= + 52.64 (c 0.30,
1
CHCl3); H NMR (300 MHz, CDCl3) δ 6.82 (d, J = 1.5 Hz, 1H), 6.76 (d, J = 1.5 Hz, 1H),
6.39 (d, J = 15.9 Hz, 1H), 6.15 (ddd, J = 15.9, 8.4, 4.8 Hz, 1H), 5.36–5.31 (m, 1H), 5.23 (s,
4H), 4.65 (s, 2H), 3.76–3.67 (m, 4H), 3.61–3.58 (m, 1H), 3.52–3.46 (m, 1H), 3.39 (s, 3H),
13
2.45–2.16 (m, 2H), 1.98–1.53 (m, 8H), 1.30 (d, J = 6.6 Hz, 3H), 1.25–1.19 (m, 6H); C
NMR (75 MHz, CDCl3) δ 167.86, 158.92, 154.93, 136.61, 132.86, 127.80, 118.34, 105.68,
102.55, 97.14, 93.38, 93.20, 78.51, 70.97, 70.50, 64.52, 64.46, 55.97, 35.13, 32.76, 29.33,
28.06, 19.77, 18.92, 15.22, 15.14; IR (thin film) 3483, 2932, 1722, 1601, 1262, 1150 cm-1;
HRMS (ESI) m/z calcd for C26H40NaO9 (M + Na)+ 519.2570, found 519.2570.
(3S,8R,E)-14,16-Bis(ethoxymethoxy)-8-(methoxymethoxy)-3-methyl-3,4,5,6,9,10-hexa
hydro-1H-benzo[c][1]oxacyclotetradecine-1,7(8H)-dione (39): Ketone 39 was prepared
from the major diastereomer of alcohol 38 (30.2 mg, 0.061 mmol) and the minor
diastereomer of alcohol 38 (15.3 mg, 0.031 mmol) using the general procedure for DMP
oxidation. The crude residue was purified by column chromatography (20% EtOAc/hexanes)
to give ketone 39 (26.5 mg, 83% from the major diastereomer of 38 and 12.4 mg, 81% from
the minor diastereomer of 38) as a colorless oil: Rf = 0.48 (50% EtOAc/hexanes);
=
+60.01 (c 0.20, CHCl3); 1H NMR (300 MHz, CDCl3) δ 6.82 (d, J = 1.8 Hz, 1H), 6.76 (d, J =
1.8 Hz, 1H), 6.41 (d, J = 15.9 Hz, 1H), 6.82 (d, J = 2.1 Hz, 1H), 6.17 (ddd, J = 15.9, 7.8, 5.1
Hz, 1H), 5.23–5.16 (m, 5H), 4.63 (d, J = 6.9 Hz, 1H), 4.57 (d, J = 6.9 Hz, 1H), 4.21 (t, J =
6.0 Hz, 1H), 3.76–3.68 (m, 4H), 3.32 (s, 3H), 2.55–1.61 (m, 10H), 1.36 (d, J = 6.0 Hz, 3H),
13
1.23 (t, J = 6.9 Hz, 3H), 1.22 (t, J = 6.9 Hz, 3H); C NMR (75 MHz, CDCl3) δ 210.54,
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167.90, 158.87, 154.91, 136.15, 132.42, 127.79, 118.16, 105.49, 102.52, 96.25, 93.31, 93.08,
78.23, 70.88, 64.43, 64.34, 55.80, 40.88, 34.75, 29.57, 27.33, 20.98, 20.66, 15.07, 14.99; IR
(thin film) 2974, 2930, 1724, 1599, 1262, 1150 cm-1; HRMS (ESI) m/z calcd for C26H38NaO9
(M + Na)+ 517.2414, found 517.2415.
5'-Hydroxyzearalenone (5): 5'-Hydroxyzearalenone (5) was prepared from ketone 39 (31.2
mg, 0.063 mmol) using the general procedure for deprotection of alkoxy ether group. The
crude residue was purified by column chromatography (20–40% EtOAc/hexanes) to give
5'-hydroxyzearalenone (5) (13.1 mg, 62%) as a white solid: Rf = 0.25 (50% EtOAc/hexanes);
mp 173–175 °C;
= −25.98 (c 0.15, acetone); CD (c 1.72x10-3 M, MeOH) max(mdeg):
266 nm (–21.73); 1H NMR (300 MHz, acetone-d6) δ 11.13 (s, 1H), 9.10 (brs, 1H), 6.83 (d, J
= 15.6 Hz, 1H), 6.44 (d, J = 2.4 Hz, 1H), 6.25 (d, J = 2.4 Hz, 1H), 6.02 (ddd, J = 15.6, 6.9,
6.6 Hz, 1H), 5.11–5.01 (m, 1H), 4.24 (q, J = 5.1 Hz, 1H), 4.15 (d, J = 5.1 Hz, 1H), 2.77–2.69
(m, 1H), 2.48–2.36 (m, 1H), 2.33–2.23 (m, 1H), 2.19–2.05 (m, 1H), 1.94–1.72 (m, 6H), 1.34
13
(d, J = 6.0 Hz, 3H); C NMR (75 MHz, acetone-d6) δ 213.03, 171.66, 164.57, 162.67,
143.32, 132.32, 131.31, 108.20, 105.56, 102.35, 76.03, 74.26, 38.77, 35.18, 32.27, 28.79,
21.10, 19.88; IR (thin film) 3279, 2931, 1702, 1648, 1610, 1259 cm-1; HRMS (ESI) m/z calcd
for C18H22NaO6 (M + Na)+ 357.1314, found 357.1314.
(S)-6-(Benzyloxy)hexane-1,2-diol (40): (S)-diol 40 was prepared from racemic epoxide 13
(8.10 g, 39.3 mmol) and (R,R)-cobalt(II) salen (126.4 mg, 0.21 mmol) using general
procedure for hydrolytic kinetic resolution (HKR). Purification of the crude residue by
column chromatography (20% EtOAc/hexanes–100% EtOAc) gave diol 40 as a light yellow
oil (3.95 g, 45%, 94% ee): Rf = 0.17 (50% EtOAc/hexanes);
= −4.76 (c 0.21, CHCl3);
1H NMR (300 MHz, CDCl3) δ 7.34–7.26 (m, 5H), 4.48 (s, 2H), 3.6–3.64 (m, 1H), 3.57 (dd, J
= 11.1, 2.4 Hz, 1H), 3.47 (t, J = 6.0 Hz, 2H), 3.38 (dd, J = 11.1, 7.5 Hz, 1H), 1.71–1.37 (m,
13
6H); C NMR (75 MHz, CDCl3) δ 138.35, 128.41, 127.75, 127.63, 72.93, 72.08, 70.25,
66.61, 32.77, 29.59, 22.27; IR (thin film) 3378, 2937, 2863, 1453, 1098, 736 cm-1; HRMS
(ESI) m/z calcd for C13H20NaO3 (M + Na)+ 247.1310, found 247.1310. The enantiomeric
excess was determined by HPLC analysis using CHIRALCEL® OD-H column eluting with
95:5 isopropanol/hexane (flow rate = 1.0 mL/min, pressure = 32.48 bar, temp = 27-29 °C):
retention time = 20.859 min, retention time of (R)-enantiomer = 17.617 min.
27
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10.1002/ejoc.201701272
European Journal of Organic Chemistry
(S)-6-(Benzyloxy)-2-(methoxymethoxy)hexan-1-ol (41): Alcohol 41 was prepared from
compound 40b (4.28 g, 11.5 mmol) using the general procedure for methanolysis. The crude
residue was purified by column chromatography (20–40% EtOAc/hexanes) to give alcohol
41 (2.96 g, 96%, 72% over 3 steps from (S)-diol 40) as a colorless oil: Rf = 0.20 (30%
1
EtOAc/hexanes);
= +33.67 (c 1.00, CHCl3); H NMR (300 MHz, CDCl3) δ 7.32–7.25
(m, 5H), 4.71 (d, J = 6.9 Hz, 1H), 4.65 (d, J = 6.9 Hz, 1H), 4.47 (s, 2H), 3.53–3.49 (m, 2H),
13
3.45 (t, J = 6.3 Hz, 2H), 3.39 (s, 3H), 1.63–1.42 (m, 6H); C NMR (75 MHz, CDCl3) δ
138.58, 128.34, 127.61, 127.51, 96.85, 81.68, 72.88, 70.11, 65.48, 55.57, 31.45, 29.73, 22.23;
IR (thin film) 3448, 2940, 1454, 1110, 1037, 917 cm-1; HRMS (ESI) m/z calcd for
C15H24NaO4 (M + Na)+ 291.1572, found 291.1572.
(S)-6-(Benzyloxy)-2-(methoxymethoxy)hexanal (epi-10): Aldehyde epi-10 was prepared
from alcohol 41 (1.32 g, 4.92 mmol) using the general procedure for TEMPO/PhI(OAc)2-
mediated oxidation. Purification of the crude residue by column chromatography (10–40%
EtOAc/hexanes) yielded aldehyde epi-10 (1.22 g, 93%) as a light yellow oil: Rf = 0.41 (30%
EtOAc/hexanes);
= 14.74 (c 1.00, CHCl3); 1H NMR (300 MHz, CDCl3) δ 9.60 (d, J =
1.8 Hz, 1H), 7.34–7.24 (m, 5H), 4.72 (d, J = 6.9 Hz, 2H), 4.68 (d, J = 6.9 Hz, 2H), 4.49 (s,
2H), 3.89 (td, J = 7.2, 1.8 Hz, 1H), 3.47 (t, J = 6.0 Hz, 2H), 3.40 (s, 3H), 1.73–1.46 (m, 6H);
13C NMR (75 MHz, CDCl3) δ 202.83, 138.52, 128.37, 127.63, 127.55, 96.76, 82.31, 72.92,
69.91, 55.97, 29.78, 29.50, 21.68; IR (thin film) 2942, 1733, 1454, 1101, 1041, 918 cm-1;
HRMS (ESI) m/z calcd for C15H22NaO4 (M + Na)+ 289.1416, found 289.1416.
(5S,10R)-5-(4-(Benzyloxy)butyl)-10,13,13-trimethyl-12,12-diphenyl-2,4,11-trioxa-12-
silatetradec-7-yn-6-ol (42): Propargylic alcohol 42 was prepared from alkyne 11 (1.79 g,
5.56 mmol) and aldehyde epi-10 (1.13 g, 4.28 mmol) using the general procedure for
acetylide addition. The crude residue was purified by column chromatography (5–30%
EtOAc/hexanes) to give propargylic alcohol 42 (1.62 g, 83% based on 250.1 mg of recovered
aldehyde epi-10) as a light yellow oil: Rf = 0.27 (20% EtOAc/hexanes);
= +16.86 (c
1
1.00, CHCl3); H NMR (300 MHz, CDCl3) δ 7.69–7.65 (m, 4H), 7.41–7.23 (m, 11H), 4.72
(d, J = 6.9 Hz, 1H), 4.64 (d, J = 6.9 Hz, 1H), 4.48 (s, 2H), 4.25–4.22 (m, 1H), 4.01–3.89 (m,
1H), 3.51–3.43 (m, 3H), 3.40 (s, 3H), 2.45–2.26 (m, 2H), 1.80–1.34 (m, 6H), 1.20 (d, J = 6.0
Hz, 3H), 1.05 (s, 9H); 13C NMR (75 MHz, CDCl3) δ 138.62, 135.82, 134.22, 134.16, 129.64,
128.36, 127.60, 97.65, 97.46, 84.63, 83.56, 83.22, 80.38, 79.77, 72.89, 70.22, 70.17, 68.29,
28
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10.1002/ejoc.201701272
European Journal of Organic Chemistry
68.20, 65.37, 65.23, 55.90, 55.84, 31.38, 31.21, 29.76, 29.65, 29.43, 26.96, 22.97, 22.90,
22.52, 21.99, 19.20; IR (thin film) 3410, 2931, 2858, 1427, 1110, 1042 cm-1; HRMS (ESI)
m/z calcd for C36H48NaO5Si (M + Na)+ 611.3169, found 611.3169.
(5S,10R)-5-(4-(Benzyloxy)butyl)-10,13,13-trimethyl-12,12-diphenyl-2,4,11-trioxa-12-
silatetradec-7-yn-6-yl acetate (43): Acetate 43 was prepared from propargylic alcohol 42
(965.8 mg, 1.64 mmol) using the general procedure for acetylation. The crude residue was
purified by column chromatography (20% EtOAc/hexanes) to give 43 (1.01 g, 97%) as a light
1
yellow oil: Rf = 0.41 (20% EtOAc/hexanes);
= 3.84 (c 1.00, CHCl3); H NMR (300
MHz, CDCl3) δ 7.68–7.65 (m, 4H), 7.44–7.23 (m, 11H), 5.55 (d, J = 1.8 Hz, 0.66H), 5.44 (dt,
J = 6.0, 1.8 Hz, 0.34H), 4.74 (d, J = 6.9 Hz, 1H), 4.60 (d, J = 6.9 Hz, 1H), 4.48 (s, 2H), 3.95
(sext, J = 6.0 Hz, 1H), 3.71–3.60 (m, 1H), 3.46 (t, J = 6.3 Hz, 2H), 3.36 (s, 3H), 2.42–2.26
13
(m, 2H), 2.07 (s, 3H), 1.73–1.38 (m, 6H), 1.16 (d, J = 6.0 Hz, 3H), 1.04 (s, 9H); C NMR
(75 MHz, CDCl3) δ 169.97, 169.70, 138.62, 135.81, 134.22, 134.02, 129.69, 129.64, 128.37,
127.62, 127.58, 127.52, 96.91, 96.18, 84.70, 84.43, 78.33, 78.02, 72.90, 70.21, 67.96, 66.22,
66.03, 55.90, 55.83, 30.81, 30.40, 29.78, 29.69, 29.36, 26.92, 22.90, 22.53, 21.85, 21.04,
19.20; IR (thin film) 2932, 2857, 1743, 1599, 1427, 1232 cm-1; HRMS (ESI) m/z calcd for
C38H50NaO6Si (M + Na)+ 653.3274, found 653.3276.
(5S,10R)-5-(4-Hydroxybutyl)-10,13,13-trimethyl-12,12-diphenyl-2,4,11-trioxa-12-
silatetradecan-6-yl acetate (44): Alcohol 44 was prepared from compound 43 (980 mg, 1.55
mmol) using the general procedure for hydrogenation/hydrogenolysis. The crude product was
purified by column chromatography (20–40% EtOAc/hexanes) to afford alcohol 44 (560.1
mg, 66%) as a light yellow oil: Rf = 0.17 (30% EtOAc/hexanes);
= +4.97 (c 1.01,
1
CHCl3); H NMR (300 MHz, CDCl3) δ 7.67 (d, J = 6.6 Hz, 4H), 7.44–7.33 (m, 6H), 5.02–
4.91 (m, 1H), 4.70 (d, J = 6.9 Hz, 1H), 4.58 (d, J = 6.9 Hz, 1H), 3.88–3.76 (m, 1H), 3.66–
13
3.50 (m, 3H), 3.37 (s, 3H), 2.02 (s, 3H), 1.59–1.19 (m, 12H), 1.05 (s, 9H), 1.04 (s, 3H); C
NMR (75 MHz, CDCl3) δ 170.82, 170.77, 135.87, 134.81, 134.44, 129.49, 129.42, 127.51,
127.41, 96.59, 95.95, 78.25, 77.95, 74.97, 74.40, 69.42, 69.20, 62.65, 62.51, 55.89, 55.77,
39.37, 39.19, 32.63, 30.29, 30.09, 29.96, 29.28, 27.03, 23.32, 23.13, 21.96, 21.77, 21.55,
21.13, 19.28; IR (thin film) 3446, 2932, 1736, 1379, 1242, 1109 cm-1; HRMS (ESI) m/z calcd
for C31H48NaO6Si (M + Na)+ 567.3118, found 567.3118.
29
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