Improved and large-scale synthesis of 10-methyl-aplog-1, a potential lead for an anticancer drug

Article abstract of DOI:10.1016/j.tet.2014.11.026

10-Methyl-aplog-1 (1), a simplified analog of tumor-promoting aplysiatoxin, is a potential lead for cancer therapy that exhibits marked and selective growth inhibitory effects against several human cancer cell lines and negligible tumor-promoting activity in vivo. However, more detailed evaluations of its toxicity and anticancer activity in vivo are hampered by supply problems associated with a non-optimal synthetic method. We here addressed this issue through a more practical and reliable synthetic method that afforded several hundred milligrams of 1 with high purity (>98%) in 23 steps from commercially available m-hydroxycinnamic acid with an overall yield of 1.1%. The utilization of two key reactions, substrate-controlled epoxidation and the oxidative cleavage of alkene with a free hydroxyl group, successfully reduced the existing five synthetic steps and markedly improved the handling of large amounts of intermediates. We also demonstrated for the first time that such an analog was synthetically accessible in reliable quantities and also that this large supply could advance in vivo trials for the treatment of cancer.

Full text of DOI:10.1016/j.tet.2014.11.026

Tetrahedron xxx (2014) 1e7
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Improved and large-scale synthesis of 10-methyl-aplog-1,
a potential lead for an anticancer drug
,
Masayuki Kikumori a, Ryo C. Yanagita b, Kazuhiro Irie a
*
a Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University, Kyoto 606-8502, Japan
b Department of Applied Biological Science, Faculty of Agriculture, Kagawa University, Kagawa 761-0795, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
10-Methyl-aplog-1 (1), a simplified analog of tumor-promoting aplysiatoxin, is a potential lead for cancer
therapy that exhibits marked and selective growth inhibitory effects against several human cancer cell
lines and negligible tumor-promoting activity in vivo. However, more detailed evaluations of its toxicity
and anticancer activity in vivo are hampered by supply problems associated with a non-optimal syn-
thetic method. We here addressed this issue through a more practical and reliable synthetic method that
afforded several hundred milligrams of 1 with high purity (>98%) in 23 steps from commercially
available m-hydroxycinnamic acid with an overall yield of 1.1%. The utilization of two key reactions,
substrate-controlled epoxidation and the oxidative cleavage of alkene with a free hydroxyl group, suc-
cessfully reduced the existing five synthetic steps and markedly improved the handling of large amounts
of intermediates. We also demonstrated for the first time that such an analog was synthetically accessible
in reliable quantities and also that this large supply could advance in vivo trials for the treatment of
cancer.
Received 3 October 2014
Received in revised form 6 November 2014
Accepted 7 November 2014
Available online xxx
Keywords:
Anticancer
Aplysiatoxin
Phorbol ester
Protein kinase C
Simplified analog
Ó 2014 Elsevier Ltd. All rights reserved.
1. Introduction
drugs at remarkably low doses (w50 m
g/m2, or w1e1.5 mg per 8-
week treatment cycle). Moreover, bryo-1 improved learning and
memory in animal models,8 and its therapeutic potential for Alz-
heimer’s disease and other neurodegenerative disorders attracted
much attention. Despite the promising biological properties of
bryo-1, further studies on its unique mode of action and the clinical
development have been hampered by its limited availability. Re-
cently, function oriented synthesis of the simplified analogs of
bryo-1 have been carried out to address these problems.9,10
As an alternative approach, we developed 10-methyl-aplog-1 (1,
Scheme 1), a simplified analog of aplysiatoxin that exhibits signif-
icant anti-proliferative activity against several human cancer cell
lines and negligible tumor-promoting activity in mouse skin.11
Extensive growth inhibitory assays against 39 human cancer cell
lines revealed that its anti-proliferative activity was cell line se-
lective and also that its efficacy profile (fingerprint) was completely
different from that of any type of anticancer agent available today,
thereby supporting its unique mode of action and a new aspect of
anticancer drug development (Fig. 2).
The family of enzymes known as protein kinase C (PKC) has been
widely recognized as an attractive target for treating intractable
diseases such as cancer,1 Alzheimer’s disease (AD),2 and acquired
immune deficiency syndrome (AIDS)3 because of its pivotal role in
many cellular events including differentiation, proliferation, and
apoptosis. Thus, natural PKC activators such as phorbol esters,
ingenol esters, teleocidins, and aplysiatoxins may serve as thera-
peutic leads (Fig. 1). Although 12-O-tetradecanoylphorbol 13-
acetate (TPA) and ingenol 3-angelate have already been evaluated
in clinical trials for several cancers,4,5 their therapeutic use has
been impeded by low natural abundance, structural complexity,
difficulties associated with their synthesis and modification, as well
as their undesired side effects such as tumor-promoting and severe
inflammatory activities.
Bryostatin 1 (bryo-1), a lead member of this family, is a fasci-
nating and mysterious PKC activator without tumor-promoting
activity in vivo. Bryo-1 has been investigated for anticancer activ-
ity in at least 43 phase I and phase II clinical trials,6,7 where it
demonstrated an ability to enhance the effects of some anticancer
The analog 1 lacked the chiral methyl groups at positions 4, 12,
and 30, the methoxy group at position 15 as well as the bromine
atom at position 21 to decrease hydrophobicity, and replaced the
labile hemiacetal hydroxyl group at position 3 with a hydrogen
atom to increase chemical stability. This structural simplification
successfully eliminated over 20 synthetic steps and reduced
* Corresponding author. Tel.: þ81 75 753 6281; fax: þ81 75 753 6284; e-mail
address: irie@kais.kyoto-u.ac.jp (K. Irie).
http://dx.doi.org/10.1016/j.tet.2014.11.026
0040-4020/Ó 2014 Elsevier Ltd. All rights reserved.
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M. Kikumori et al. / Tetrahedron xxx (2014) 1e7
Fig. 1. Structures of naturally occurring tumor promoters and simplified analogs of aplysiatoxin.
Scheme 1. Retrosynthetic analysis of 1.
barriers against its practical synthesis without attenuating its
marked anti-proliferative activities and ability to activate PKCs.12
Despite these prospective features as a future therapeutic candi-
date, the inefficiency of our first-generation synthesis of 1 pre-
vented further experiments on animals and structural optimization
for clinical use. To satisfy these needs, we attempted to develop
a more practical synthetic method for 1 for the preparation of
sufficient amounts of the sample in order to examine its toxicity
and anticancer effects in an animal model.
Moreover, subsequent methanolysis of the carbonate moiety re-
quired careful control of the reaction temperature in order to pre-
vent opening of the epoxide ring.11 This inefficient and complicated
process severely disturbed the large-scale preparation of 1; thus, its
improvement was inevitable. We decided to utilize the one-step
hydroxyl-directed epoxidation of 5. Such an approach could facili-
tate the handling of large-scale intermediates.
The synthesis of 1 started with the hydrogenation of m-
hydroxycinnamic acid (2), followed by esterification, protection of
the phenol group as a benzyl ether, reduction, and bromination to
provide a known bromide (3) in 91% yield from 2 (Scheme 2). In
practice, the first four intermediates of this sequence could be car-
ried forward without purification, and the bromide was purified by
column chromatography before the next step. This procedure could
be performed routinely on a 20-g scale. The substitution of the
known bromide with diethyl malonate gave a diester, which was
decarbalkoxylated without purification to produce an ester (4) in
62% yield. Partial reduction of 4 to an aldehyde was accomplished on
a 5-g scale, and the aldehyde was immediately used for asymmetric
Brown crotylation14 to furnish a homoallyl alcohol (5) in 56e84%
2. Results and discussion
From a synthetic perspective, we maintained the triply con-
vergent route applied in our first-generation synthesis, dissecting 1
at two ester linkages to generate subunits A and B. The further
division of fragment A provided two subunits, C and D (Scheme 1).
Our previous attempt to construct an anti, anti-stereotriad in sub-
unit C using Smith’s iodocarbonate cyclization strategy13 required
three steps from a homoallyl alcohol (5) (Scheme 2) and also gave
unsatisfactory results with poor stereoselectivity and a low yield.
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M. Kikumori et al. / Tetrahedron xxx (2014) 1e7
3
Fig. 2. Efficacy profiles of aplog-1, 10-methyl-aplog-1 (1), and several anti-cancer drugs. Data for these anti-cancer drugs were retrieved from the NCI/NIH public database (http://
dtp.nci.nih.gov/). (A) ‘Fingerprints’ against 26 human cancer cell lines. Data for the following cell lines are listed in top-to-bottom order: breast (MDA-MB-231/ATCC, MCF7); prostate
(DU-145, PC-3); renal (ACHN); ovarian (SK-OV-3, OVCAR-8, OVCAR-5, OVCAR-4, OVCAR-3); melanoma (LOX IMVI); central nervous system (U251, SNB-75, SF-539, SF-295, SF-268);
colon (KM12, HT29, HCT-15, HCT-116, HCC-2998); non-small cell lung (NCI-H522, NCI-H460, NCI-H23, NCI-H226, A549/HTCC). MG-MID, log GI50 (log M, 50% cell growth inhibition)
mean-graph midpoint. (B) A correlation matrix plot based on Pearson correlation coefficients between log GI50 values of aplogs and anti-cancer drugs against 26 human cancer cell
lines, followed by hierarchical clustering using the complete linkage method.
yield from 4. The vanadium-catalyzed epoxidation15 of 5 generated
diastereomeric mixture of epoxyalcohols (anti, anti: syn,
sufficient to consume all of 7 without a prolonged reaction time.
The application of this method succeeded in producing the cou-
pling product at an excellent yield (94%).
a
anti¼3:1). Although it was difficult to completely separate them,
a sufficient amount of pure desired epoxyalcohol (6) with an anti,
anti-stereotriad was obtained by careful and repeated normal phase
chromatography. Therefore, 6 was obtained in 57% yield from 5. The
secondary hydroxyl group of 6 was protected as a p-methox-
yphenylmethyl (MPM) ether (71%). A total of 9.6 g of subunit C (7)
was obtained in 11 steps with an overall yield of 17% from 2.
We previously reported that successful coupling of the epoxide
(7) with the known dithiane (8) required strict dry conditions.16
Normal vacuum drying was inappropriate for dehydrating large
amounts of the compound, and the amount was limited to ap-
proximately 70 mg. The azeotropic dehydration of large-scale ma-
terials using toluene also appeared to be inapplicable because the
benzyl site in the resulting toluene could be lithiated by n-butyl
lithium to react with electrophiles. To overcome this problem,
200 mg of 7 and 245 mg of 8 were charged in 10-mL flasks sepa-
rately, spread on the inside walls of the flasks, dried in a vacuum
over 2 h, and the reaction was performed several times. Although
our previous method utilized a 2.0 equiv of 8, a 1.5 equiv was
Oxidation of the coupling product at the benzyl site of the MPM
ether by treating 1 equiv of DDQ formed anisylidene acetal to
protect the secondary hydroxyl group. We found that the addition
ꢀ
of 4 A molecular sieves to maintain the dehydrated condition was
not required for intramolecular acetalization and also simplified
the handling of this reaction. Desilylation followed by the Par-
ikheDoering oxidation17 of the alcohol (9) provided an aldehyde.
Maruoka’s asymmetric allylation18 of the aldehyde on a 3-g scale
and simple purification by normal phase column chromatography
provided a homoallyl alcohol (10) in 50e66% yield, as well as
a mixture of (S)-BINOL and the recovered aldehyde. The mixture
was further purified by reverse phase column chromatography to
give pure aldehyde, which was again used for asymmetric allyla-
tion. Collectively, 60% of the total aldehyde was converted to 10.
Deprotection of the anisylidene acetal was challenging because
of the high stability of the acetal moiety. Our screening for an op-
timal method for the detachment of the anisylidene acetal sug-
gested that acid-catalyzed hydrolysis using the TFA/H2O/THF
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4
M. Kikumori et al. / Tetrahedron xxx (2014) 1e7
Scheme 2. Synthesis of 1. Reagents and conditions: (a) (1) 10% Pd/C, H2, MeOH; (2) SOCl2, MeOH; (3) BnBr, K2CO3, acetone; (b) (1) LiAlH4, THF; (2) CBr4, PPh3, CH2Cl2; 91% from 2 in
five steps. (c) (1) Diethyl malonate, NaH, DMF; (2) LiCl, DMSO, H2O; 62% in two steps. (d) (1) DIBAL, toluene; (2) trans-2-butene, KOt-Bu, n-BuLi, (ꢀ)-Ipc2BOMe, BF3$OEt2, THF; 74% in
two steps. (e) VO(acac)2, t-BuOOH, CH2Cl2, 57%. (f) MPMeCl, NaH, DMF, THF, 71%. (g) 8, n-BuLi, THF, 94%. (h) (1) DDQ, CH2Cl2; (2) TBAF$3H2O, THF; 93% in two steps. (i) (1) SO3$Pyr,
DMSO, Et3N, CH2Cl2; (2) TiCl4, Ti(Oi-Pr)4, Ag2O, (S)-BINOL, allyl-SnBu3, CH2Cl2; 60% in two steps. (j) TFA, H2O, THF, 48%. (k) SelectfluorÒ, MeCN, H2O; 12, 56%; 13, 22%. (l) PPTS, MeCN,
CH2Cl2; 12, 73%; 13, 24%. (m) 14, TCBeCl, Et3N, DMAP, toluene, 93%. (n) DDQ, pH 7 buffer, CH2Cl2, 87%. (o) KMnO4, NaIO4, t-BuOH, pH 7 buffer, 71%. (p) TCBeCl, Et3N, DMAP, toluene,
82%. (q) 10% Pd/C, H2, EtOH, 83%. Improved steps are highlighted in red.
condition was the best because this condition made the purification
of the product simpler than previous method. The application of
this condition on a 2-g scale provided a triol (11) in 41e59% yield
and recovered the acetal (10) in 34e45%. Collectively, 3.18 g
(5.30 mmol) of 11 was obtained in 48% yield from 7.89 g
(11.0 mmol) of initial 10. We found that a careful and accurate
workup to neutralize the reaction mixture was essential because
severe decomposition of the substrate and product occurred during
concentration under acidic condition.
in a low yield (22%), presumably because of its poor solubility in the
solvent (t-BuOH/pH 7 phosphate buffer¼1:1). The utilization of
a more hydrophilic olefin (16) with a free hydroxyl group produced
a carboxylic acid (17) in good yield (71%), and oxidation of the free
secondary hydroxylgroupdid not proceed under this condition. This
OH-free method omitted the protection/deprotection steps, and
markedly improved the efficiency of the oxidative cleavage step.
Yamaguchi’s macrolactonization20 of the seco-acid (17) was
performed at 2 mM to efficiently produce a lactone (18) (82%), and
the production of a dimer was not confirmed. We also showed that
a prolonged time for adding a solution of a mixed anhydride into
a solution of DMAP was not needed for the desired intramolecular
reaction; that is, the total time for the reagent adding could be
shortened to only 15 min from 5 h. Finally, removal of two benzyl
groups, and purification by convenient normal phase column
chromatography provided 287 mg of 10-methyl-aplog-1 (1) in 23
steps from m-hydroxycinnamic acid with an overall yield of 1.1%. An
additional 500 mg of 1 could be obtained by treating the other
1.15 g of 12 in a similar manner. 1H, 13C NMR, specific optical ro-
tation, and FABMS data coincided with previous findings.11 Its pu-
rity was confirmed to be more than 98% by 1H, 13C NMR data, and
HPLC analysis (Supplementary data). 1H NMR data of 3, 4, 7, 10, 12,
and 15 also agreed with previous findings.11
The use of selectflourÒ,19 an electrophilic fluorinating reagent,
more efficiently achieved the simultaneous cleavage of 1,3-dithiane
and spiroketalization than the conventional method using haz-
ardous mercury (II). The desired spiroketal (12) and undesired one
(13) were obtained in 51e60% and 22e25% yields, respectively.
Treatment of 13 with PPTS produced a 3:1 mixture of 12 and 13, and
this equilibrium reaction was repeated again. Collectively, 1.89 g of
12 was obtained in 73% yield from the triol (11). A total of 737 mg of
12 was carried forward to the next steps.
Condensation of the spiroketal (12) with the known carboxylic
acid (14) was achieved using Yamaguchi’s method.20 Detachment of
the MPM group using the DDQ/CH2Cl2/H2O condition on a several
hundred milligram scale resulted in the unexpected isomerization
of at least 30% of the spiroketal, presumably because the prolonged
reaction time led to the decomposition of DDQ to acidify the re-
action mixture. Attempts to maintain neutral conditions by
employing a phosphate buffer (pH 7.2) instead of distilled water
successfully prevented this severe isomerization.
In summary, we developed a reliable method for synthesizing
10-methyl-aplog-1 (1) that could be applied to the production of
several hundred milligrams of this potential medicinal lead. Nota-
ble features of this synthetic method include one-step hydroxyl-
directed epoxidation of the homoallyl alcohol (5) and chemo-
selective oxidation of alkene (16) with a free secondary hydroxyl
group. An in vivo evaluation of the anticancer activity of 1 is cur-
rently in progress and will be reported in due course.
Although our previous experiment suggested that switching of
the protecting group from an MPM group to a triethylsilyl group was
successful for providingthe corresponding carboxylic acid, oxidative
cleavage of the olefin group in the corresponding silyl ether resulted
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M. Kikumori et al. / Tetrahedron xxx (2014) 1e7
5
3. Experimental section
3.1. General remarks
297.7 K, CDCl3, 0.047 M)
d
0.96 (3H, d, J¼7.1 Hz), 1.30 (1H, m),
1.43e1.68 (6H, m), 2.14 (1H, d, J¼3.6 Hz), 2.47 (1H, dd, J¼4.9,
2.8 Hz), 2.61 (2H, t, J¼7.6 Hz), 2.76 (1H, dd, J¼4.9, 4.1 Hz), 2.91 (1H,
ddd, J¼8.1, 4.1, 2.8 Hz), 3.65 (1H, m), 5.05 (2H, s), 6.78e6.82 (3H, m),
7.19 (1H, t, J¼7.8 Hz), 7.32e7.45 (5H, m) ppm. 13C NMR (100 MHz,
The following spectroscopic and analytical instruments were
used: Digital Polarimeter, P-2200 (Jasco, Tokyo, Japan); 1H, 13C
NMR, Avance III 400, and Avance III 500 (Bruker, Germany); HPLC,
Waters Model 600E with a Model 2487 UV detector; FABMS and
HR-FABMS, JMS-600H and JMS-700 (JEOL, Tokyo, Japan); IR, FT/IR-
470 Plus (Jasco, Tokyo, Japan). HR-ESI-TOF-MS, Xevo G2-S QTof
(Waters, MS, USA). HPLC was carried out on YMC packed SIL
SL12S05-1006WT, SIL SL12S05-2510WT, ODS-A AA12S05-1006WT
(Yamamura Chemical Laboratory, Kyoto, Japan), and CHIRAL CEL OJ-
RH (Daicel Corporation, Osaka, Japan). Wakogel C-200 (silica gel,
Wako Pure Chemical Industries, Osaka, Japan) and YMC A60-350/
250 gel (ODS, Yamamura Chemical Laboratory, Kyoto, Japan) were
used for column chromatography. All other chemicals and reagents
were purchased from chemical companies and used without fur-
ther purification. Compounds 8 and 14 were synthesized as re-
ported previously.16
298.0 K, CDCl3, 0.047 M) d 12.9, 25.1, 31.4, 34.3, 36.0, 42.2, 45.3, 54.7,
69.9, 75.1,111.8,115.1,121.2,127.5 (2C),127.9,128.6 (2C),129.2,137.2,
144.4,158.9 ppm. IR (KBr) cmꢀ1: 3461, 3033, 2934, 2862,1582,1487,
1454, 1258, 1155, 1027, 756, 697. HR-FABMS (matrix, m-nitrobenzyl
alcohol) m/z: 340.2039 ([M]þ, calcd for C22H28O3 340.2039). [
þ10.8 (c 0.53, CHCl3).
a]
16.8
D
3.6. Synthesis of (R)-2-((2R,3R)-7-(3-(benzyloxy)phenyl)-3-
((4-methoxybenzyl)oxy)heptan-2-yl)oxirane (7)
The hydroxyl group of 6 (10.0 g, 29.4 mmol) was protected as the
MPM ether, as reported previously,11 in two trials to afford the MPM
ether as a clear oil (7) (9.6 g, 20.9 mmol) in 71% yield.
3.7. Synthesis of 4-(2-(((2R,4S,5R,6R)-6-(4-(3-(benzyloxy)phe-
nyl)butyl)-2-(4-methoxyphenyl)-5-methyl-1,3-dioxan-4-yl)
methyl)-1,3-dithian-2-yl)-4-methylpentan-1-ol (9)
3.2. Synthesis of 1-(benzyloxy)-3-(3-bromopropyl)benzene
(3)
Coupling of the epoxide (7) (9.6 g, 20.9 mmol) with the dithiane
(8) (11.8 g, 31.4 mmol) was performed on a several hundred milli-
gram scale by a previously reported method to afford a coupling
product (16.4 g, 19.6 mmol) in 94% yield. DDQ-mediated oxidative
acetalization, followed by desilylation using a previously reported
method,11,21 gave the alcohol as a clear oil (9) (12.3 g, 18.2 mmol) in
m-Hydroxycinnamic acid (2) (20.0 g, 122 mmol) was treated in
a manner similar to the method reported previously16 to afford the
bromide (3) (33.8 g, 111 mmol, 91%) as a clear oil.
3.3. Synthesis of ethyl 5-(3-(benzyloxy)phenyl)pentanoate (4)
93% yield. 1H NMR: (500 MHz, 295.3 K, CDCl3, 0.017 M)
d 0.93 (3H,
The bromide (3) (33.8 g, 111 mmol) was treated in a manner
similar to the method reported previously16 to afford the ester (4)
(21.5 g, 68.8 mmol, 62%) as a clear oil.
d, J¼6.7 Hz), 1.18 (3H, s), 1.19 (3H, s), 1.44e1.78 (11H, m), 1.85 (1H,
m), 1.94 (1H, m), 2.38 (1H, dd, J¼16.2, 7.2 Hz), 2.46 (1H, d,
J¼16.1 Hz), 2.60 (2H, m), 2.67e2.79 (2H, m), 2.83e2.93 (2H, m), 3.46
(1H, m), 3.55 (2H, br s), 3.79 (3H, s), 3.93 (1H, dd, J¼9.9, 7.1 Hz), 5.04
(2H, s), 5.45 (1H, s), 6.75e6.82 (3H, m), 6.86 (2H, m), 7.19 (1H, t,
J¼7.8 Hz), 7.32 (1H, m), 7.36e7.47 (6H, m) ppm. 13C NMR (125 MHz,
3.4. Synthesis of (3S,4R)-8-(3-(benzyloxy)phenyl)-3-
methyloct-1-en-4-ol (5)
296.2 K, CDCl3, 0.017 M)
d 13.2, 22.5 (br), 23.0 (br), 24.4, 24.9, 26.7,
The ester (4) (21.5 g, 68.8 mmol) was subjected to partial re-
duction16 followed by Brown’s asymmetric crotylation11,14 as re-
ported previously. Four installments afforded homoallyl alcohol as
a clear oil (5) (16.6 g, 51.2 mmol) in 74% yield.
27.6, 28.3, 31.4, 32.6, 32.9, 36.0, 38.9, 41.5, 44.5, 55.3, 63.7, 63.8, 70.0,
80.3, 82.0, 99.5, 111.9, 113.4 (2C), 115.2, 121.2, 127.3 (2C), 127.5 (2C),
127.9, 128.6 (2C),129.2,131.6,137.3,144.5, 158.9,159.7 ppm. IR (KBr)
cmꢀ1: 3421, 3032, 2936, 2860, 1614, 1583, 1518, 1250, 1030, 755,
696. HR-FABMS (matrix, m-nitrobenzyl alcohol): m/z: 701.3335
18.8
3.5. Synthesis of (2R,3R)-7-(3-(benzyloxy)phenyl)-2-((R)-ox-
iran-2-yl)heptan-3-ol (6)
([MþNa]þ, calcd for C40H54O5S2Na 701.3310). [
a
]
ꢀ3.4 (c 0.58,
D
CHCl3).
The typical procedure used for the substrate-controlled epoxi-
dation of the homoallyl alcohol (5) was as follows. To a solution of 5
(3.63 g, 11.2 mmol) in CH2Cl2 (110 mL) were added vanadyl acety-
lacetonate (60 mg, 0.224 mmol) and 5.5 M t-BuOOH in decane
(3.1 mL, 16.8 mmol) at rt. While stirring for 7 h, additional VO
(acac)2 (90 mg, 0.37 mmol) and 5.5 M t-BuOOH in decane (1.0 mL,
5.50 mmol) were added in two portions. The reaction was
quenched with 10% aq Na2S2O3 (100 mL) and the mixture were
extracted three times with EtOAc (200 mLꢁ1, 100 mLꢁ2). The
combined organic layers were washed with brine, dried over
Na2SO4, filtered, and concentrated in vacuo. The residue was puri-
fied by column chromatography (silica gel, 10%/20% EtOAc/hex-
ane) to afford an epoxyalcohol as a clear oil (6) (2.18 g, 6.41 mmol)
and mixture (1.14 g) of the epoxyalcohol (6) and byproduct. This
procedure was repeated four times to afford 8.78 g of the epox-
yalcohol (6) and 4.74 g of the mixture of epoxyalcohol (6) and
byproduct. The combined latter mixture was once again purified by
column chromatography (silica gel, 10%/20% EtOAc/hexane) to
afford the epoxyalcohol (6) (1.21 g). Finally, 10.0 g (29.4 mmol) of
the epoxyalcohol (6) was obtained in 57% yield from 16.6 g
(51.2 mmol) of the homoallyl alcohol (5). 1H NMR (400 MHz,
3.8. Synthesis of (R)-7-(2-(((2R,4S,5R,6R)-6-(4-(3-(benzyloxy)
phenyl)butyl)-2-(4-methoxyphenyl)-5-methyl-1,3-dioxan-4-
yl)methyl)-1,3-dithian-2-yl)-7-methyloct-1-en-4-ol (10)
The alcohol (9) (12.3 g, 18.2 mmol) was subjected to Par-
ikheDoering oxidation, followed by Maruoka’s asymmetric allyla-
tion on a 3-g scale, as reported previously,11,16 to afford the
homoallyl alcohol as a clear oil (10) (7.89 g, 11.0 mmol) in 60% yield.
3.9. Synthesis of (2S,3R,4R)-8-(3-(benzyloxy)phenyl)-1-
(2-((R)-5-hydroxy-2-methyloct-7-en-2-yl)-1,3-dithian-2-yl)-
3-methyloctane-2,4-diol (11)
The typical procedure used for acid hydrolysis of the anisylidene
acetal (10) was as follows. To a solution of the acetal (10) (2.20 g,
3.06 mmol) in THF (120 mL) and H2O (12 mL) was added TFA (6 mL)
at 4 ꢂC. The mixture was heated at 50 ꢂC for 23 h and then cooled to
4
ꢂC. The reaction was quenched with saturated aq NaHCO3
(100 mL). The mixture was extracted with EtOAc (100 mLꢁ3). The
combined organic layers were washed with brine, dried over
Na2SO4, filtered, and concentrated in vacuo. The residue was
Please cite this article in press as: Kikumori, M.; et al., Tetrahedron (2014), http://dx.doi.org/10.1016/j.tet.2014.11.026

6
M. Kikumori et al. / Tetrahedron xxx (2014) 1e7
purified by column chromatography (silica gel, 5%/20%/50%
EtOAc/hexane) to afford the triol as a clear oil (11) (760 mg,
1.27 mmol, 41%) and recovered acetal (10) (990 mg, 1.38 mmol,
45%). An additional 5.69 g of 10 was treated similarly in two por-
tions. Finally, 3.18 g (5.30 mmol) of the triol (11) was obtained from
7.89 g (11.0 mmol) of the acetal (10) in 48% yield. 1H NMR (500 MHz,
0.854 mmol, 73%) and undesired spiroketal (13) (137 mg,
0.278 mmol, 24%).
3.11. Synthesis of (2R,3R,4S,6R,8R)-8-allyl-2-(4-(3-(benzyloxy)
phenyl)butyl)-3,11,11-trimethyl-1,7-dioxaspiro[5.5]undecan-
4-yl (R)-4-(benzyloxy)-3-((4-methoxybenzyl)oxy)butanoate
(15)
296.3 K, CDCl3, 0.012 M)
d
0.84 (3H, d, J¼6.9 Hz), 1.14 (6H, s),
1.38e1.50 (4H, m),1.52e1.68 (6H, m),1.67 (1H, d, J¼3.9 Hz, OH),1.80
(1H, m), 1.90e2.01 (2H, m), 2.13e2.20 (3H, m), 2.32 (1H, m), 2.60
(2H, m), 2.82e2.89 (2H, m), 2.93e3.01 (2H, m), 3.59e3.61 (2H, m),
3.75 (1H, d, J¼2.5 Hz, OH), 4.30 (1H, m), 4.52 (1H, s, OH), 5.05 (2H,
s), 5.13e5.17 (2H, m), 5.82 (1H, m), 6.78e6.83 (3H, m), 7.18 (1H, t,
J¼7.8 Hz), 7.31e7.47 (5H, m) ppm. 13C NMR (125 MHz, 296.9 K,
Condensation of the spiroketal (12) (737 mg, 1.50 mmol) with
the acid (14) (544 mg, 1.65 mmol) was performed in three portions
by a previously reported method6 to afford the ester as a clear oil
(15) (1.13 g, 1.40 mmol) in 93% yield.
CDCl3, 0.012 M)
d
12.9, 22.4, 22.9 (br), 23.0, 25.0, 27.4, 27.5, 31.6,
3.12. Synthesis of (2R,3R,4S,6R,8R)-8-allyl-2-(4-(3-(benzyloxy)
phenyl)butyl)-3,11,11-trimethyl-1,7-dioxaspiro[5.5]undecan-
4-yl (R)-4-(benzyloxy)-3-hydroxybutanoate (16)
32.0, 32.7, 34.5, 36.1, 42.1, 42.3, 44.8, 45.6, 63.3, 70.0, 71.3, 73.9, 74.3,
111.9, 115.2, 118.3, 121.2, 127.5 (2C), 127.9, 128.6 (2C), 129.2, 134.7,
137.3, 144.6, 158.9 ppm. IR (KBr) cmꢀ1: 3409, 3065, 3032, 2933,
2859, 1541, 1507, 1457, 1260, 1154, 1038, 695. HR-FABMS (matrix, m-
The typical procedure used was as follows. To a vigorously
stirred solution of the MPM ether (15) (514 mg, 0.639 mmol) in
CH2Cl2 (30 mL) and 50 mM sodium phosphate buffer (pH 7.2, 10 mL,
Fluka) was added DDQ (290 mg, 1.28 mmol) at rt. After 1 h of
stirring at rt, the mixture was poured into saturated aq NaHCO3
(50 mL) and EtOAc (100 mL). The organic layer was separated, and
the aqueous layer was extracted with EtOAc (50 mLꢁ2). The com-
bined organic layers were washed with brine, dried over Na2SO4,
filtered, and concentrated in vacuo. The residue was purified by
column chromatography (silica gel, 10%/20% EtOAc/hexane) to
afford an alcohol (16) (401 mg, 0.586 mmol, 92%) as a clear oil. An
additional 616 mg (0.766 mmol) of 15 was treated in a manner
similar to that described above. Finally, 832 mg (1.22 mmol) of the
alcohol (16) was obtained from 1.13 g (1.40 mmol) of the MPM ether
nitrobenzyl alcohol): m/z: 601.3356 ([MH]þ, calcd for C35H53O4S2
19.3
601.3385). [
a]
þ2.0 (c 0.38, CHCl3).
D
3.10. Synthesis of (2R,3S,4S,6R,8R)-8-allyl-2-(4-(3-(benzyloxy)
phenyl)butyl)-3,11,11-trimethyl-1,7-dioxaspiro[5.5]undecan-
4-ol (12)
The typical procedure used for spiroketalization was as follows.
To a solution of a dithiane (11) (712 mg, 1.19 mmol) in MeCN
(36 mL) and H2O (1.8 mL) was added SelectfluorÒ (1.05 g,
2.97 mmol) at 4 ꢂC. After stirring for 30 min at the same tem-
perature, the reaction was quenched with saturated aq NaHCO3
(40 mL). The mixture was extracted with EtOAc (50 mLꢁ3), and
the combined organic layers were washed with brine, dried over
Na2SO4, filtered, and concentrated in vacuo. The residue was pu-
rified by column chromatography (silica gel, 5%/15% EtOAc/
hexane) to afford the desired spiroketal as a clear oil (12) (317 mg,
0.644 mmol, 54%) and undesired spiroketal as a clear oil (13)
(131 mg, 0.266 mmol, 22%). An additional 2.47 g of 11 was treated
on a several hundred milligram scale in a similar manner to that
described above. A total of 1.47 g (2.99 mmol, 56%) of 12 and
577 mg (1.17 mmol, 22%) of 13 were obtained from 3.18 g
(5.30 mmol) of 11. Compound 13: 1H NMR (500 MHz, 295.0 K,
(15) in 87% yield. 1H NMR (500 MHz, 295.8 K, CDCl3, 0.017 M)
d 0.80
(3H, d, J¼6.90 Hz), 0.89 (3H, s), 0.93 (3H, s), 1.25 (1H, m), 1.35e1.70
(10H, m), 1.70 (1H, dd, J¼15.2, 3.9 Hz), 2.12 (1H, dd, J¼15.2, 2.7 Hz),
2.42 (2H, m), 2.54 (1H, dd, J¼16.3, 9.3 Hz), 2.59 (1H, t, J¼7.5 Hz),
2.62 (1H, dd, J¼16.3, 3.6 Hz), 3.46 (1H, dd, J¼9.6, 5.2 Hz), 3.51 (1H,
dd, J¼9.6, 5.8 Hz), 3.62 (1H, m), 3.88 (1H, d, J¼3.70 Hz, OH), 3.95
(1H, m), 4.25 (1H, m), 4.56 (2H, s), 4.97e5.01 (2H, m), 5.05 (2H, s),
5.09 (1H, m), 5.75 (1H, m), 6.78e6.84 (3H, m), 7.19 (1H, t, J¼7.9 Hz),
7.27e7.47 (10H, m) ppm. 13C NMR (125 MHz, 296.2 K, CDCl3,
0.017 M) d 13.2, 23.6, 23.8, 24.5, 24.6, 29.9, 31.4, 31.8, 32.4, 36.1, 36.2,
CDCl3, 0.012 M)
d
0.90 (3H, s), 0.95 (3H, s), 0.95 (3H, d, J¼7.0 Hz),
36.8, 39.4, 40.4, 67.0, 68.8, 70.0, 71.8, 72.0, 73.2, 73.5, 100.2, 111.8,
115.2,116.8,121.2,127.5 (2C),127.7 (3C),127.9,128.4 (2C),128.6 (2C),
1.14 (1H, dt, J¼13.0 Hz, 3.1 Hz), 1.31 (1H, d, J¼4.9 Hz, OH),
1.34e1.46 (4H, m), 1.58e1.74 (4H, m), 1.69 (1H, dd, J¼13.0, 10.1 Hz),
1.80 (1H, dd, J¼13.2, 5.7 Hz), 1.88 (1H, td, J¼13.0, 5.2 Hz), 1.96 (1H,
m), 2.11 (1H, m), 2.16 (1H, m), 2.59 (2H, t, J¼7.4 Hz), 3.62 (1H, m),
3.78 (1H, m), 4.22 (1H, m), 4.98e5.04 (2H, m), 5.05 (2H, s), 5.79
(1H, m), 6.78e6.81 (3H, m), 7.19 (1H, t, J¼7.8 Hz), 7.30e7.45 (5H,
129.2, 135.6, 137.3, 138.1, 144.6, 158.9, 171.8 ppm. IR (KBr) cmꢀ1
:
3473, 3065, 3032, 2935, 2859, 1732, 1717, 1583, 1456, 1258, 1155,
915, 875, 739, 696. HR-FABMS (matrix, m-nitrobenzyl alcohol): m/z:
684.4001 ([M]þ, calcd for C43H56O7 684.4026). [
CHCl3).
a
]
29.1 þ47.2 (c 0.57,
D
m) ppm. 13C NMR (125 MHz, 296.0 K, CDCl3, 0.012 M)
d 11.6, 22.9,
25.8, 26.7, 27.3, 31.3, 33.6, 33.9, 34.1, 36.0, 36.2, 36.8, 40.8, 64.4,
68.8, 70.0, 79.0, 102.6, 111.8, 115.3, 116.4, 121.2, 127.5 (2C), 127.9,
3.13. Synthesis of 2-((2R,6R,8R,9R,10S)-10-(((R)-4-(benzyloxy)-
3-hydroxybutanoyl)oxy)-8-(4-(3-(benzyloxy)phenyl)butyl)-
5,5,9-trimethyl-1,7-dioxaspiro[5.5]undecan-2-yl)acetic acid
(17)
128.6 (2C), 129.2, 135.4, 137.2, 144.3, 158.9 ppm. IR (KBr) cmꢀ1
:
3384, 3067, 3033, 2934, 2858, 1584, 1456, 1259, 1155, 985, 917,
758, 740, 695. HR-ESI-TOF-MS (matrix, 50% MeOH/H2O containing
0.1% formic acid): m/z: 515.3124 ([MþNa]þ, calcd for C32H45O4Na
The typical procedure used was as follows. To a suspension of
NaIO4 (1.0 g, 4.69 mmol) in pH 7.2 phosphate buffer (40 mL) was
added KMnO4 (92.6 mg, 0.586 mmol) in one portion. After 15 min
of stirring at rt under an Ar atmosphere, the mixture was added to
a solution of the alkene (16) (401 mg, 0.586 mmol) in t-BuOH
(40 mL). The reaction mixture was stirred at rt for 45 min, and the
reaction was quenched with Na2S2O3 (278 mg, 1.76 mmol). The
resulting mixture was poured into EtOAc (100 mL) and H2O
(100 mL). The organic layer was separated, and the aqueous
layer was extracted with EtOAc (80 mLꢁ2). The combined organic
layers were washed with brine, dried over Na2SO4, filtered, and
concentrated in vacuo. The residue was purified by column
26.2
515.3137). [
a
]
ꢀ9.6 (c 0.36, CHCl3).
D
The undesired spiroketal (13) was subjected to the following
acid catalyzed equilibrium reaction. To a solution of 13 (577 mg,
1.17 mmol) in MeCN (20 mL) and CH2Cl2 (20 mL) was added PPTS
(29.3 mg, 0.117 mmol) at rt. After stirring for 30 min, the reaction
was quenched with saturated aq NaHCO3 (20 mL). After the organic
layer was separated, the aqueous layer was extracted with CH2Cl2
(40 mLꢁ2). The combined organic layers were washed with brine,
dried over Na2SO4, filtered, and concentrated in vacuo. The residue
was purified by column chromatography (silica gel, 5%/10%/20%
EtOAc/hexane) to afford the desired spiroketal (12) (420 mg,
Please cite this article in press as: Kikumori, M.; et al., Tetrahedron (2014), http://dx.doi.org/10.1016/j.tet.2014.11.026

M. Kikumori et al. / Tetrahedron xxx (2014) 1e7
7
chromatography (silica gel, 20%/40% EtOAc/hexane containing
0.1% AcOH) to afford a seco-acid (17) (322 mg, 0.459 mmol, 78%) as
a clear oil. An additional 431 mg (0.630 mmol) of 16 was treated in
a method reported previously11 to afford a crude 1 (357 mg), which
was purified by column chromatography (silica gel, 25%/50%
EtOAc/hexane) to afford 1 (287 mg, 0.596 mmol, 83%) as a clear oil.
The purity of 1 was more than 98%, which was confirmed by two
diverse HPLC systems: YMC packed SIL SL12S05-1006WT using i-
PrOH/CHCl3/hexane¼5:15:80 (flow rate of 1.0 mL/min; retention
time of 11.0 min); YMC packed ODA-A AA12S05-1006WT using
MeOH/H2O¼75:25 (flow rate of 1.0 mL/min; retention time of
13.8 min). IR (KBr) cmꢀ1: 3423, 3021, 2938, 2860, 1717, 1588, 1457,
1297, 1276, 1060, 756, 696. FABMS (matrix, m-nitrobenzyl alcohol):
m/z 505 ([MH]þ). 1H NMR and 13C NMR data coincided with those
reported previously.11 A portion of 1 from above (10 mg) was fur-
ther purified by HPLC (column, YMC-Pack SIL SL12S05-2510WT;
solvent, i-PrOH/CHCl3/hexane¼5:15:80; flow rate, 3.0 mL/min;
a
manner similar to that described above. Finally, 609 mg
(0.867 mmol) of 17 was obtained from 832 mg (1.22 mmol) of 16 in
71% yield. 1H NMR (400 MHz, 297.3 K, CDCl3, 0.032 M)
0.80 (3H, d,
d
J¼8.9 Hz), 0.91 (3H, s), 0.94 (3H, s), 1.30 (1H, m), 1.40e1.70 (9H, m),
1.75 (1H, m), 1.75 (1H, dd, J¼15.2, 3.9 Hz), 2.10 (1H, dd, J¼15.2,
2.7 Hz), 2.47e2.53 (3H, m), 2.57e2.62 (2H, m), 2.72 (1H, dd, J¼15.0,
8.0 Hz), 3.48 (1H, dd, J¼9.6, 4.5 Hz), 3.50 (1H, dd, J¼9.6, 6.4 Hz), 3.95
(1H, m), 4.11 (1H, m), 4.30 (1H, m), 4.57 (2H, s), 5.05 (2H, s), 5.12
(1H, m), 6.78e6.87 (3H, m), 7.19 (1H, t, J¼7.8 Hz), 7.28e7.45 (10H,
m) ppm. 13C NMR (100 MHz, 297.5 K, CDCl3, 0.032 M)
d 13.2, 23.7,
23.8, 24.4, 26.0, 30.1, 31.4, 31.5, 32.4, 36.0, 36.1, 36.9, 39.1, 41.2, 67.0,
69.3, 69.5, 69.9, 71.2, 73.4, 73.6, 101.2, 111.8, 115.2, 121.2, 127.5 (2C),
127.9, 127.9, 128.0 (2C), 128.5 (2C), 128.6 (2C), 129.2, 137.2, 137.5,
144.5, 158.9, 171.5, 173.0 ppm. IR (KBr) cmꢀ1: 3033, 2935, 2861,
1733, 1717, 1685, 1577, 1457, 1258, 1058, 740, 696. HR-FABMS (ma-
trix, m-nitrobenzyl alcohol): m/z: 703.3876 ([MH]þ, calcd for
pressure, 570 j; retention time, 24.3 min) to afford the material for
confirmation of optical purity by measurement of specific optical
rotation and chiral HPLC analysis. [
a
]
25.8 þ67.6 (c 0.505, CHCl3: lit.,11
D
þ76.2ꢂ). Only one peak was detected by two diverse HPLC systems
on CHIRAL CEL OJ-RH using MeOH/H2O¼80:20 (flow rate of 0.5 mL/
min; retention time of 19.2 min) and MeCN/H2O¼40:60 (flow rate
of 0.5 mL/min; retention time of 26.2 min).
C
42H55O9 703.3846). [
a]
30.8 þ38.8 (c 0.37, CHCl3).
D
3.14. Synthesis of (1R,3R,4R,5S,9R,13R)-9-((benzyloxy)
methyl)-3-(4-(3-(benzyloxy)phenyl)butyl)-4,16,16-trimethyl-
2,6,10,17-tetraoxatricyclo[11.3.1.11,5]octadecane-7,11-dione (18)
Acknowledgements
This work was supported by a Grant-in-Aid for Scientific Re-
search on Innovative Areas ‘Chemical Biology of Natural Products’
(No. 23102011 to K.I. and R.C.Y.) and a Grant-in-Aid for the Pro-
motion of Science for Young Scientists (No. 25.2518 to M.K.) from
Ministry of Education, Culture, Sports, Science, and Technology,
Japan. This study was partly carried out with the JEOL JMS-700 MS
spectromer in the Joint Usage/Research Center (JURC) at the In-
stitute for Chemical Research, Kyoto University.
The typical procedure used was as follows. To a solution of the
seco-acid (17) (322 mg, 0.459 mmol) and Et3N (191
in toluene (23 mL), was added 2,4,6-trichlorobenzoyl chloride
(108 L, 0.689 mmol) at rt. The mixture was stirred at rt for 1 h, and
mL, 1.38 mmol)
m
then diluted with toluene (100 mL). The mixture was added
dropwise to a solution of DMAP (840 mg, 6.89 mmol) in toluene
(100 mL) over 15 min. The anhydride flask was rinsed twice with
toluene (5 mL) (each rinse was added in one portion to the reaction
mixture). After an additional 2 h of stirring at rt, saturated
aq NaHCO3 (30 mL) was added and the organic layer was separated.
The aqueous layer was extracted with EtOAc (50 mLꢁ2), and the
combined organic layers were washed with brine, dried over
Na2SO4, filtered, and concentrated in vacuo. The residue was puri-
fied by column chromatography (silica gel, 5%/10% EtOAc/hexane)
to afford a lactone (18) (243 mg, 0.355 mmol, 77%) as a clear oil. An
additional 287 mg (0.408 mmol) of 17 was treated in a manner
similar to that described above. Finally, 489 mg (0.714 mmol) of 18
was obtained from 609 mg (0.867 mmol) of 17 in 82% yield. 1H NMR
Supplementary data
HPLC analysis and NMR spectra of 1. Supplementary data related
to this article can be found at http://dx.doi.org/10.1016/
j.tet.2014.11.026.
References and notes
1. Bosco, R.; Melloni, E.; Celeghini, C.; Rimondi, E.; Vaccarezza, M.; Zauli, G. Mini-
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2. Pascale, A.; Amadio, M.; Govoni, S.; Battaini, F. Pharmacol. Res. 2007, 55,
(500 MHz, 295.0 K, CDCl3, 0.029 M)
d
0.77 (3H, d, J¼6.9 Hz), 0.85
560e569.
(3H, s), 0.96 (3H, s), 1.26e1.57 (10H, m), 1.68 (1H, m), 1.69 (1H, dd,
J¼15.4, 4.0 Hz), 2.34 (1H, dd, J¼12.7, 10.9 Hz), 2.45e2.51 (2H, m),
2.60 (2H, t, J¼7.7 Hz), 2.78 (1H, dd, J¼17.1, 3.1 Hz), 2.91 (1H, dd,
J¼17.1, 11.5 Hz), 3.58 (1H, dd, J¼10.1, 5.5 Hz), 3.64 (1H, dd, J¼10.1,
3.6 Hz), 3.84 (1H, m), 3.93 (1H, m), 4.49 (1H, d, J¼12.0 Hz), 4.57 (1H,
d, J¼12.0 Hz), 5.03 (1H, br s), 5.05 (2H, s), 5.20 (1H, m), 6.79 (1H, dd,
J¼8.2, 2.4 Hz), 6.82 (1H, d, J¼7.5 Hz), 6.86 (1H, br s), 7.18 (1H, t,
J¼7.9 Hz), 7.27e7.45 (10H, m) ppm. 13C NMR (125 MHz, 295.2 K,
3. McKeeran, L. N.; Momjian, D.; Kulkosky, J. Adv. Virol. 2012, 2012: 805347.
4. Schaar, D.; Goodell, L.; Aisner, J.; Cui, X. X.; Han, Z. T.; Chang, R.; Martin, J.;
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10. Kraft, M. B.; Poudel, Y. B.; Kedei, N.; Lewin, N. E.; Peach, M. L.; Blumberg, P. M.;
Keck, G. E. J. Am. Chem. Soc. 2014, 136, 13202e13208.
11. Kikumori, M.; Yanagita, R. C.; Tokuda, H.; Suzuki, N.; Nagai, H.; Suenaga, K.; Irie,
K. J. Med. Chem. 2012, 55, 5614e5626.
12. Irie, K.; Yanagita, R. C. Chem. Rec. 2014, 14, 251e267.
13. Duan, J. J.-W.; Smith, A. B., III. J. Org. Chem. 1993, 58, 3703e3711.
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15. Mihelich, E. D.; Daniels, K.; Eickhoff, D. J. J. Am. Chem. Soc. 1981, 103, 7690e7692.
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N.; Nagai, H.; Irie, K. J. Am. Chem. Soc. 2009, 131, 7573e7579.
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19. Junjie, L.; Wong, C.-H. Tetrahedron Lett. 2002, 43, 4037e4039.
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CDCl3, 0.029 M)
d 13.1, 21.4, 24.3, 26.0, 26.6, 27.3, 31.1, 32.3, 34.7,
36.1, 36.9, 36.9, 37.2, 42.7, 68.3, 68.9, 69.9, 70.2, 70.6, 72.6, 73.5, 99.8,
111.8, 115.2, 121.3, 127.5 (2C), 127.7 (2C), 127.8 (2C), 128.5 (4C), 129.1,
137.4, 137.8, 144.8, 158.9, 170.2 (2C) ppm. IR (KBr) cmꢀ1: 3032, 2935,
2860, 1748, 1733, 1716, 1577, 1457, 1271, 1060, 753, 697. HR-FABMS
(matrix, m-nitrobenzyl alcohol): m/z: 685.3734 ([MH]þ, calcd for
C
42H53O8 685.3740). [
a]
30.1 þ48.7 (c 1.00, CHCl3).
D
3.15. Synthesis of (1R,3R,4R,5S,9R,13R)-9-(hydroxymethyl)-3-
(4-(3-hydroxyphenyl)butyl)-4,16,16-trimethyl-2,6,10,17-
tetraoxatricyclo[11.3.1.11,5]octadecane-7,11-dione (1)
The removal of the two benzyl groups of the lactone (18)
(489 mg, 0.714 mmol) was performed in three portions by
21. Nakagawa, Y.; Kikumori, M.; Yanagita, R. C.; Murakami, A.; Tokuda, H.; Nagai,
H.; Irie, K. Biosci. Biotechnol. Biochem. 2011, 75, 1167e1173.
Please cite this article in press as: Kikumori, M.; et al., Tetrahedron (2014), http://dx.doi.org/10.1016/j.tet.2014.11.026