Total Synthesis and Biological Evaluation of Irciniastatin A (a.k.a. Psymberin) and Irciniastatin B

Article abstract of DOI:10.1021/acs.joc.5b02256

Irciniastatin A (a.k.a. psymberin) and irciniastatin B are members of the pederin natural product family, which have potent antitumor activity and structural complexity. Herein, we describe a full account of our total synthesis of (+)-irciniastatin A and (-)-irciniastatin B. Our synthesis features the highly regioselective Eu(OTf)₃-catalyzed, DTBMP-assisted epoxide ring opening reaction with MeOH, which enabled a concise synthesis of the C1-C6 fragment, extensive use of AZADO (2-azaadamantane N-oxyl) and its related nitroxyl radical/oxoammonium salt-catalyzed alcohol oxidation throughout the synthesis, and a late-stage assembly of C1-C6, C8-C16, and C17-C25 fragments. In addition, for the synthesis of (-)-irciniastatin B, we achieved the C11-selective control of the oxidation stage via regioselective deprotection and AZADO-catalyzed alcohol oxidation. The synthetic irciniastatins showed high levels of cytotoxic activity against mammalian cells. Furthermore, chemical footprinting experiments using synthetic compounds revealed that the binding site of irciniastatins is the E-site of the ribosome.

Full text of DOI:10.1021/acs.joc.5b02256

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Article
Total Synthesis and Biological Evaluation of
Irciniastatin A (a.k.a. Psymberin) and Irciniastatin B
Shun-ichiro Uesugi, Tsubasa Watanabe, Takamichi Imaizumi, Yu Ota, Keisuke Yoshida, Haruna Ebisu,
Takumi Chinen, Yoko Nagumo, Masatoshi Shibuya, Naoki Kanoh, Takeo Usui, and Yoshiharu Iwabuchi
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.5b02256 • Publication Date (Web): 06 Nov 2015
Downloaded from http://pubs.acs.org on November 15, 2015
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Total Synthesis and Biological Evaluation of Irciniastatin A (a.k.a.
Psymberin) and Irciniastatin B
Shunꢀichiro Uesugi,† Tsubasa Watanabe,† Takamichi Imaizumi,† Yu Ota,‡ Keisuke Yoshida,‡ Haruna
Ebisu,‡ Takumi Chinen,‡ Yoko Nagumo,§‡ Masatoshi Shibuya,† Naoki Kanoh,† Takeo Usui,*§‡ and
Yoshiharu Iwabuchi*†
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†Department of Organic Chemistry, Graduate School of Pharmaceutical Sciences, Tohoku University,
Aobayama, Sendai 980ꢀ8578, Japan
‡Graduate School of Life and Environmental Sciences, University of Tsukuba, Tennodai, Tsukuba,
Ibaraki 305ꢀ8572, Japan
§Faculty of Life and Environmental Sciences, University of Tsukuba, Tennodai, Tsukuba, Ibaraki 305ꢀ
8572, Japan
*usui.takeo.kb@u.tsukuba.ac.jp; yꢀiwabuchi@m.tohoku.ac.jp
OMe O
OH
OMe
O
OMe O
OH
OMe
O
OH
O
N
H
N
H
11
11
HO
HO
O
OH
O
OH
OH
O
OH
O
(+)ꢀirciniastatin A
0.49 ± 0.10 nM
(−)ꢀirciniastatin B
IC50 (HeLa)
0.25 ± 0.02 nM
Abstract: Irciniastatin A (a.k.a. psymberin) and irciniastatin B are members of the pederin natural
product family, which have potent antitumor activity and structural complexity. Herein, we describe a
full account of our total synthesis of (+)ꢀirciniastatin A and (−)ꢀirciniastatin B. Our synthesis features the
highly regioselective Eu(OTf)3ꢀcatalyzed, DTBMPꢀassisted epoxide ring opening reaction with MeOH,
which enabled a concise synthesis of the C1ꢀC6 fragment, extensive use of AZADO (2ꢀazaadamantane
Nꢀoxyl) and its related nitroxyl radical/oxoammonium saltꢀcatalyzed alcohol oxidation throughout the
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synthesis, and a lateꢀstage assembly of C1ꢀC6, C8ꢀC16, and C17ꢀC25 fragments. In addition, for the
synthesis of (−)ꢀirciniastatin B, we achieved the C11ꢀselective control of oxidation stage via
regioselective deprotection and AZADOꢀcatalyzed alcohol oxidation. The synthetic irciniastatins
showed high levels of cytotoxic activity against mammalian cells. Furthermore, chemical footprinting
experiments using synthetic compounds revealed that the binding site of irciniastatins is the Eꢀsite of the
ribosome.
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Introduction
In 2004, (+)ꢀirciniastatin A (1) and (−)ꢀirciniastatin B (2) were isolated by Pettit and coꢀworkers1 from
marine sponge Ircinia ramosa. Independently, psymberin was isolated by Crews and coꢀworkers2 from
marine sponge Psammocinia in the same year (Figure 1). These two reports revealed that these natural
products possessed a complex molecular architecture consisting of an unstable N,Oꢀaminal moiety, a
highly substituted 2,6ꢀtransꢀtetrahydropyran skeleton, and either nine or eight stereogenic centers. At
that time, Crews assumed that irciniastatin A and psymberin are identical; however, the stereochemistry
of both compounds was not determined completely.
In 2005, the first total synthesis of (+)ꢀirciniastatin A (1) was accomplished by De Brabander and coꢀ
workers,3 who established the absolute configuration of (+)ꢀ1 and demonstrated that (+)ꢀirciniastatin A
and psymberin possess identical structures. After this pioneering synthesis, seven total synthesis4
including the synthesis by our laboratory,4d two formal synthesis,5 and ten synthetic studies6 have been
reported.
Besides their fascinating structures, both (+)ꢀirciniastatin A (1) and (−)ꢀirciniastatin B (2) show strong
inhibitory activity against a series of human cancer cell lines at the nanomolar level.1 Interestingly, these
two congeners possess different values of activity against several human cancer cell lines,1 although
these structures were considered to differ only in the oxidation level at C11. Subsequently, some
analogues of 1 were synthesized and tested for their biological activities,4d, 4e, 4g, 7 which gave highly
potent derivatives and biological insights.8
However, compared with those of (+)ꢀirciniastatin A (1), the structural and biological details of (−)ꢀ
irciniastatin B (2) have not been intensively investigated. In 2012, Smith and coꢀworkers achieved the
first total synthesis and determination of the absolute configuration of (−)ꢀirciniastatin B (2),9 which is
the only example of total synthesis.
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To shed light on the impact of C11 oxidation level on their biological activity,10 we explored efficient
synthetic routes to irciniastatins. Herein, we provide a full account of our work including the total
synthesis of (+)ꢀirciniastatin A (1) and (−)ꢀirciniastatin B (2). Subsequently, we describe the binding
mode of irciniastatins on the ribosome, which might induce the inhibition of protein translation.
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OMe O
OMe
OMe O
OMe
OH
O
N
H
N
H
11
11
OH
O
OH
O
HO
HO
O
OH
O
OH
OH
O
OH
O
(+)ꢀirciniastatin A(1)
(−)ꢀirciniastatin B (2)
OMe O
OH
OMe
O
OMe O
OH
O
O
O
O
OH
OMe
N
N
H
H
O
MeO
HO
OMe
OMe
pederin (3)
mycalamide B (4)
Figure 1. Pederinꢀtype natural products
Results and Discussion
Total Synthesis of (+)-irciniastatin A (1). Considering stereochemical complexity and structural
clarity, coupled with our assumption that irciniastatins would be only distinguished by the oxidation
stage at C11, we set (+)ꢀirciniastatin A as the first goal of our synthetic venture. Our firstꢀgeneration
retrosynthetic analysis of (+)ꢀirciniastatin A (1) is depicted in Scheme 1. 1 was disconnected at the
amide bond, leading to the protected hemiaminal 5 and the C1ꢀC6 acyclic side chain 6. For the
installation of the hemiaminal functionality in 5, we relied on the Curtius rearrangement approach
developed by Smith and coꢀworkers.4b, 9 The key intermediate 5 was conceived to be transformed from 9
via a diastereoselective reduction of the aldol moiety and a reductive translactonization. We envisioned
that 9 would be united via a substrateꢀcontrolled aldol reaction of the C16ꢀC25 ketone fragment 10 and
the C8ꢀC15 tetrahydropyran fragment 11. We envisioned synthesizing not only both fragments 6 and 11
but also their enantiomers and diastereomers for future SAR study; we decided to adopt “Sharpless
asymmetric epoxidation ꢀ regioselective epoxide ring opening” sequence as a key maneuver.11 1,2ꢀDiol
7 would be synthesized via a Lewis acidꢀmediated regioselective ring opening from 2,3ꢀepoxy alcohol 8,
which could be easily obtained using the Sharpless asymmetric epoxidation reaction. Independently,
tetrahydropyran unit of 11 would be constructed in the same manner from epoxy alcohol 13. The aldol
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counterpart 10 would be accessed from Eꢀalkene 12 via the Sharpless asymmetric dihydroxylation, γꢀ
5
6
7
8
lactonization, and oxidation of the resultant alcohol.
OMe
O
OMe O
OMe
11
Teoc
OTBS
OH
6
N
H
8
N
H
OH
O
9
17
TIPSO
HO
10
11
12
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OTBS
O
O
OH
TIPSO
O
OH
O
5
(+)ꢀirciniastatin A (1)
OBOM
MeO
OTBS
MeO
OMe O
O
MeO
OH
15
O
OSEM
O
16
OH
6
O
9
O
OBOM
OMe
OMe
MeO
O
OH
O
OH
O
7
O
OMe
10
OTBS 11
OH
TES
MeO
O
OH
O
O
CO2Me
8
OMe
12
OTES
13
Scheme 1. First-Generation Retrosynthetic Analysis of (+)-irciniastatin A (1)
The synthesis of side chain 6 began with the regioselective ring opening of the known 2,3ꢀepoxy
alcohol (+)ꢀ812 with MeOH (Scheme 2). The Ti(OꢀiꢀPr)4ꢀmediated nucleophilic ring opening of 2,3ꢀ
epoxy alcohols was developed by Sharpless and coꢀworkers, which provides 3ꢀsubstitutedꢀ1,2ꢀdiol
derivatives.13 Initially, we tried this condition, but the yield and selectivity were unsatisfactory, giving
the desired 1,2ꢀdiol 7 and undesired 1,3ꢀdiol 16 (54% yield, 7:16 = 3:1) as an inseparable mixture. After
extensive screening the reaction conditions, we found that the combined use of catalytic amounts of
Eu(OTf)3 and 2,6ꢀdiꢀtertꢀbutylꢀ4ꢀmethylpyridine (DTBMP) gave the desired 1,2ꢀdiol 7 in high yield and
regioselectivity. In addition, we also found that this catalytic method can be applied to various epoxy
alcohols and nucleophiles (alcohols, thiols, and amines).14 The 1,2ꢀdiol 7 was converted to primary
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alcohol (+)ꢀ15 via a protectionꢀdeprotection sequence. Oxidation of (+)ꢀ15 using 1ꢀMeꢀ
AZADO/PhI(OAc)215 provided carboxylic acid (−)ꢀ6.
6
7
8
9
20 mol % Eu(OTf)3
OMe
20 mol % DTBMP
OH
OH
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O
MeOH, reflux, 94%
1,2ꢀdiol 7 : 1,3ꢀdiol 16 = 18:1
OH
8
7
1) SEMCl, iꢀPr2NEt
0 °C to rt, 94%
OMe
OMe
PivCl
OH
OSEM
(+)ꢀ15
OPiv
pyridine
0 °C to rt
89%
2) DIBAL, CH2Cl2
ꢀ78 °C, 66%
OH
14
1ꢀMeꢀAZADO
PhI(OAc)2
OMe O
OH
OH
OH
CH2Cl2/pH 7 buffer (1:1)
0 °C, 76%
OSEM
OMe
16
(−)ꢀ6
Scheme 2. Synthesis of Carboxylic Acid (−)-6
Access to the 2,6ꢀtransꢀtetrahydropyran fragment 11, began with the known epoxy alcohol (+)ꢀ17,16
which was prepared from (−)ꢀpantolactone (Scheme 3). Protection of the primary alcohol (+)ꢀ17 as the
THP ether, followed by regioselective ring opening of epoxide with lithium acetylide and BF3·OEt2,17
furnished the secondary alcohol 18. Removal of the THP group and the subsequent TEMPOꢀcatalyzed
oxidation gave aldehyde (+)ꢀ19 selectively. A diastereoselective allylation of (+)ꢀ19 using
allyltributylstannane in the presence of MgBr218 produced diol (+)ꢀ20 with high selectivity. Protecting
group manipulation, followed by (E)ꢀselective reduction of the alkyne, furnished the corresponding allyl
alcohol, which was then converted to the epoxide (+)ꢀ22 through the Sharpless asymmetric epoxidation
and protection of the primary alcohol.
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OPMB
3
4
5
6
1) DHP, PPTS, CH2Cl2
0 °C to rt, 91%
1) PPTS, EtOH
50 °C, 92%
THPO
HO
2)
2) TEMPO
PhI(OAc)2
CH2Cl2, rt
76%
O
OPMB
(+)ꢀ17
nꢀBuLi, BF3—OEt2
THF, ꢀ78 °C, 87%
OH
18
7
8
9
OPMB
OPMB
allyltributylstannane
MgBr2—OEt2
OH
H
O
10
11
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CH2Cl2, ꢀ78 °C to 0 °C
90% (dr >20:1)
OH (+)ꢀ19
OH (+)ꢀ20
OH
1) RedꢀAl, THF
0 °C to rt, 91%
1) TESCl, imidazole
DMF, 0 °C, 100%
TES
O
2) (−)ꢀDET, Ti(OꢀiꢀPr)4
TBHP, 4A MS
CH2Cl2, ꢀ20 °C
94% (dr >20:1)
2) DDQ
CH2Cl2/pH 7 buffer (20:1)
ꢀ30 °C to ꢀ10 °C, 90 %
OTES (+)ꢀ21
OH
OBOM
TES
TES
BOMCl, iꢀPr2NEt
O
O
O
O
CH2Cl2, 0 °C
87%
OTES (+)ꢀ13
OTES (+)ꢀ22
Scheme 3. Synthesis of Tetrahydropyran Precursor (+)-22
We then focused on the epoxide ring opening ꢀ tetrahydropyran ring formation using (+)ꢀ22 (Scheme
4). Fortunately, we found that the catalytic amount of camphorsulfonic acid (CSA) simultaneously
promoted the removal of TES group and oxyꢀcyclization to furnish the 2,6ꢀtransꢀtetrahydropyran (+)ꢀ
23.19 For regioselective methylation of C8 hydroxyl group, four types of conditions were screened: (1)
KOH/MeI (64% yield), (2) tBuOK/MeI (39% yield), (3) DTBMP/MeOTf (complex mixtures), (4)
NaH/Me2SO4 (78%), indicating that bulkiness of the methylating reagent was important. Protection of
C11 hydroxyl group and the oxidative cleavage of the terminal alkene gave the desired aldehyde 11.
OBOM
OBOM
TES
10 mol % CSA
O
O
OH
O
CH2Cl2/MeOH (10:1)
0 °C to rt, 83%
(+)ꢀ22
(+)ꢀ23
OTES
OH
OBOM
1) NaH, Me2SO4
THF, 0 °C, 78%
1) OsO4, NMO, THF/H2O
0 °C to rt
8
O
OMe
2) TBSOTf
2,6ꢀlutidine
CH2Cl2, 0 °C, 90%
2) NaIO4, MeOH/H2O, rt
(+)ꢀ24
OTBS
OBOM
O
OMe
O
11
OTBS
Scheme 4. Concise ynthesis of 2,6-trans-Tetrahydropyran Fragment 11
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Synthesis of the requisite leftꢀwing fragment (+)ꢀ10 began with the installation of a methyl group onto
26 to give 27 via an electrophilic methoxymethylation of the benzene nuclei and the following
hydrogenolytic cleavage of the methoxy group (Scheme 5). The remaining phenolic group was triflated
to give 28, the SuzukiꢀMiyaura coupling of which with alkenyl boronate 29 in the presence of Pd(PPh3)4
and K3PO4 in dioxane at 100 °C gave 12 in 83% yield. Upon treatment with Sharpless ADꢀmixꢀα, the Eꢀ
alkene 12 furnished γꢀlactone (+)ꢀ30 in 88% (>99% ee after recrystallization) via the enantioselective
dihidroxylation and concomitant lactonization. 1ꢀMeꢀAZADOꢀcatalyzed oxidation15 of (+)ꢀ30 using
PhI(OAc)2 gave ketone (+)ꢀ10 without losing enantiomeric integrity.
10
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Having secured both the coupling partners, we next examined the aldol reaction to construct the C15ꢀ
C16 bond. Disappointingly, our attempt was hampered by the highly acidic nature of the C18ꢀmethine
proton, which caused a facile scrambling of enolates generated from (+)ꢀ10, impairing the enantiomeric
purity. Worse still, a model study using nonanal with lithium enolate, generated in situ from the ketone
(+)ꢀ10 and LDA in THF at −78 °C, gave exclusively C18ꢀaldol 31, indicating the pronounced reactivity
of the C18ꢀenolate in aldol reaction compared with the C16ꢀenolate. These observations led us to alter
our synthetic plan shown in Scheme 6.
1) CH3OCHCl2, TiCl4
CH2Cl2, ꢀ20 °C
1) Me2SO4, K2CO3
acetone, reflux
MeO
OH
HO
OH
MeO
OH
Tf2O, pyridine
CO2Me
CO2H
2) H2, Pd/C
MeOH/CHCl3, rt
88% over 2 steps
CO2Me
2) BCl3, CH2Cl2
ꢀ78 °C to rt
46% over 2 steps
CH2Cl2, 0 °C to rt
90%
OMe
OH
OMe
25
26
27
O
B
O
HO
O
29
MeO
OTf
MeO
MeO
ADꢀmixꢀα, MeSO2NH2
Pd(PPh3)4, K3PO4
CO2Me
CO2Me
t-BuOH/H2O
0 °C, 88%, >99% ee
dioxane, 100 °C
83%
O
OMe
28
OMe
OMe
12
(+)ꢀ30
OBOM
OMe
OBOM
OTBS
O
O
MeO
O
O
MeO
MeO
OTBS
MeO
11
1ꢀMeꢀAZADO, PhI(OAc)2
CH2Cl2, rt, 92%, >99% ee
O
O
18
Diastereoselective
aldol reaction
15
O
O
16
OMe
(+)ꢀ10
OH
O
9
O
18
MeO
nonanal, LDA
C8H17
OH
O
THF, ꢀ78 °C
quant.
O
OMe
31
Scheme 5. Synthesis of Left Fragment (+)-10 and Attempts at Aldol Reaction
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Thus, the projected key intermediate 5 was disconnected in a retroꢀaldol fashion into the C17ꢀC25
5
6
7
8
aldehyde fragment 32 and the C8ꢀC16 tetrahydropyran fragment 33 in light of successful precedents by
De Brabander3, 4g and Smith4b, 9. The requisite ketone 33 would be prepared from the aldehyde 11 via
nucleophilic introduction of an ethyl group.
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10
11
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OMe O
OH
OMe
O
OMe
OH
Teoc
OTBS
N
H
N
H
11
O
17
HO
TIPSO
16
O
OH
OTBS
O
OH
O
TIPSO
O
(+)ꢀirciniastatin A (1)
5
O
CO2Bn
OMe
OMe O
TIPSO
O
OH
O
OSEM
CO2Me
TIPSO
32
33
OTBS
6
OBOM
OMe
OMe
O
OH
OH
OH
O
O
8
7
11
OTBS
Scheme 6. Alternative Synthetic Strategy
To install the ethyl ketone moiety, 11 was treated with ethylmagnesium bromide followed by 1ꢀMeꢀ
AZADO oxidation15 to give ketone (+)ꢀ34 in good yield (Scheme 7). To complete the synthesis of the
tetrahydropyran fragment, oneꢀpot oxidation conditions developed in our laboratory20 were utilized for
the construction of the carboxylic acid moiety. Thus, deprotection of the BOM ether gave the
corresponding primary alcohol, which was oxidized using 1ꢀMeꢀAZADO+BF4 /NaClO2, followed by
ꢀ
treatment with benzyl bromide to provide the desired central fragment (+)ꢀ33.
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OBOM
OMe
OBOM
1) EtMgBr, THF, 0 °C
O
O
OMe
2) 1ꢀMeꢀAZADO, PhI(OAc)2
CH2Cl2, rt
O
O
11
88% over 4 steps
(+)ꢀ34
OTBS
OTBS
7
8
9
CO2Bn
OMe
1) H2, Pd(OH)2, MeOH
rt, 99%
O
10
11
12
13
14
15
16
17
18
ꢀ
+
2) 1ꢀMeꢀAZADO BF4, NaClO2
CH3CN/pH 7 buffer (1:1), rt
3) BnBr, Cs2CO3, DMF, 0 °C
97% over 2 steps
O
(+)ꢀ33
OTBS
Scheme 7. Concise Synthesis of Tetrahydropyran Fragment (+)-33
With the fragment (+)ꢀ33 in hand, we examined the coupling reaction of (+)ꢀ33 with the aldehyde 32.3
Treatment of (+)ꢀ33 with dichlorophenylborane21 provided the Zꢀenolate, and the addition of 32
provided the aldol product (+)ꢀ35 with high diastereoselectivity (Scheme 8). Subsequent
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diastereoselective reduction of the C15 ketone (+)ꢀ35 with NaBH4 in the presence of Et3B followed by
lactonization provided dihydroisocoumarin (+)ꢀ36. The benzyl ester moiety in (+)ꢀ36 was then
converted to a carboxylic acid via hydrogenation, which was subjected to a Curtius sequence using 2ꢀ
(trimethylsilyl)ethanol as a nucleophile to give Teocꢀprotected hemiaminal (+)ꢀ5 in high yield.
For the synthesis of 1, the stage was set to examine the coupling of (+)ꢀ5 with the acylic chain (−)ꢀ6.
Initially, we tried the coupling using the acyl chloride derivative from (−)ꢀ6, but we only observed
decomposition of acid chloride. We assumed that these results were due to instability of acid chloride
compounds in this condition. After intensive effort, we found that the choice of the protecting group of
alcohol in (−)ꢀ6 was important,23 and Smith’s protocol4b, 9 was the only successful method of this
coupling reaction. Finally, the deprotection of all of the protecting groups using TASF provided (+)ꢀ
irciniastatin A [(+)ꢀ1] in 53% yield. We used this synthetic route for the synthesis of unnatural (−)ꢀ
irciniastatin A [(−)ꢀ1] and (+)ꢀalkymberin [(+)ꢀ39] for our biological studies.4d
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Scheme 8. Total Synthesis of (+)-Irciniastatin A [(+)-1]
Total Synthesis of (−)-irciniastatin B (2). Toward the total synthesis of (−)ꢀirciniastatin B (2), we
initially ambitioned the direct conversion strategy from (+)ꢀirciniastatin A [(+)ꢀ1] (Scheme 9). Thus, we
anticipated that the C11 hydroxyl group would be the most sterically hindered among the hydroxyl
groups of irciniastatin A (1), thereby resisting protection by a hindered silyl group. Indeed, the treatment
of (+)ꢀ1 with 7 eq. of TBSOTf gave tetrakisꢀTBS ether together with pentakisꢀTBS ether. After
chromatographic separation, the tetrakisꢀTBS ether was oxidized by AZADO15 to furnish the ketone.
However, extensive structural analysis revealed that the product was not 41 but (+)ꢀ40 having the
unexpected C15ꢀcarbonyl moiety instead of C11.24 This result could be due to the decrease in the
nucleophilicity of the C15ꢀhydroxy group via the intramolecular hydrogen bonding effect. Because the
direct conversion from irciniastatin A to B was difficult, we decided to develop an alternative strategy
toward the synthesis of 2.
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Scheme 9. Attempted Direct Conversion of Irciniastatin A (1) to B (2)
For the synthesis of (−)ꢀirciniastatin B (2), we considered that the oxidation of C11 should be
conducted at the lateꢀstage of the synthesis of 2. In fact, Smith and coꢀworkers reported that the 2,6ꢀ
transꢀtetrahydropyranꢀ4ꢀone core was very unstable under basic conditions.9 The synthesis of new
tetrahydropyran fragment (+)ꢀ44 for (−)ꢀirciniastatin B (2) commenced from the functional group
manipulation of diol (+)ꢀ23 (Scheme 10). Upon the selective methylation of the C8 hydroxy group, and
the deprotection of benzyloxymethyl group using LiBF4,25 (+)ꢀ23 was converted to diol (+)ꢀ42, the
remaining two hydroxyl groups of which were protected by benzyl ether to give (−)ꢀ43 in 80% yield.
Next, the ketone (+)ꢀ44 was synthesized via a fourꢀstep sequence, as in the synthesis of (+)ꢀ33.
OBOM
OH
OH
1) NaH, Me2SO4
THF, 0 °C
78%
8
O
O
OMe
2) LiBF4
CH3CN/H2O
reflux, 90%
(+)ꢀ23
OH
(+)ꢀ42
OH
OBn
1) OsO4, NMO, THF/H2O
0 °C to rt
BnBr, NaH
TBAI
O
2) NaIO4, MeOH/H2O, rt
OMe
THF, reflux
80%
3) EtMgBr, THF, 0 °C
4) 1ꢀMeꢀAZADO, PhI(OAc)2
CH2Cl2, rt
OBn
(−)ꢀ43
81% over 4 steps
OBn
OMe
O
O
OBn
(+)ꢀ44
Scheme 10. Synthesis of Fragment (+)-44
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With (+)ꢀ44 in hand, we examined the aldol coupling with the aldehyde 32 (Scheme 11). Also in this
case, dichlorophenylborane21 was the best Lewis acid for the coupling, which gave (+)ꢀ45 with good
7
8
9
diastereoselectivity. Reduction of (+)ꢀ45 with NaBH4 in the presence of Et2BOMe provided the 1,3ꢀsyn
diol product, which was converted to lactone (+)ꢀ46 in 78% over 2 steps. We then focused on the
selective oxidation of the primary alcohol to the corresponding carboxylic acid. After screening, we
found that the selective oneꢀpot oxidation proceeded smoothly using the salt of DMNꢀAZADO26 (1,5ꢀ
dimethylꢀ9ꢀazanoradamantane Nꢀoxyl), which gave (+)ꢀ48 in 81% yield. Note that the same oxidative
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ꢀ
conversion using TEMPO+BF4 catalyst resulted in a modest yield of (+)ꢀ48 (12 h, 56% yield).
Subsequent Curtius rearrangement followed by the protection of the C11 alcohol as a TES ether
furnished Teocꢀprotected hemiaminal (+)ꢀ50. The final fragment union of (+)ꢀ50 with the acyclic side
chain 37 was achieved using the same conditions as those for the synthesis of (+)ꢀ38. The selective
deprotection of the TES ether of (+)ꢀ51 using 1M HCl followed by AZADO oxidation15 gave protectedꢀ
irciniastatin B (+)ꢀ52. Finally, global deprotection using TASF provided (−)ꢀirciniastatin B (2). However,
there were some slight differences in 1H and 13C NMR spectra and the optical rotation value between the
(−)ꢀ2 isolated by Pettit and coꢀworkers1 and our synthetic (−)ꢀ2.
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OMe
OBn
OMe
BnO
OBn
CHO
PhBCl2
iꢀPr2NEt
1) NaBH4, Et2BOMe, MeOH/THF (1:2)
ꢀ78 to 0 °C, 78%
O
TIPSO
O
O
+
O
TIPSO
CH2Cl2, ꢀ78 °C
82% (dr >20:1)
2) CSA, CH2Cl2, rt
3) TBSOTf, 2,6ꢀlutidine, CH2Cl2, 0 °C
78% over 2 steps
CO2Me
OBn
OTIPS
OH
CO2Me
OTIPS
(+)ꢀ44
32
(+)ꢀ45
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OMe
O
OMe
BnO
OBn
HO
OH
O
DMNꢀAZADO+BF4ꢀ, NaClO2
H2, Pd/C
TIPSO
TIPSO
MeOH, rt, 95%
CH3CN/pH 7 buffer (2:1)
rt, 81%
O
OTBS
O
OTBS
TIPSO
HO
O
TIPSO
O
(+)ꢀ46
(+)ꢀ47
OMe
OMe
OH
Teoc
OH
N
H
1) EtOCOCl, NMM, THF;
NaN3, H2O, ꢀ20 °C
O
O
O
TESOTf, 2,6ꢀlutidine
CH2Cl2, 0 °C
TIPSO
TIPSO
2) TMS(CH2)2OH, toluene, 100 °C
86% over 2 steps
O
OTBS
OTBS
O
TIPSO
O
TIPSO
O
(+)ꢀ48
(+)ꢀ49
OMe O
OPiv
OMe
OMe O
OMe
Teoc
OTES
OTES
N
H
N
37
OSEM
LHMDS
Teoc
O
SEMO
O
1) 1M HCl, THF, rt
TIPSO
TIPSO
4A MS, THF
ꢀ78 °C to ꢀ60 °C
47% over 2 steps
(91% BRSM)
2) AZADO, PhI(OAc)2, CH2Cl2, rt
95% over 2 steps
OTBS
O
O
OTBS
TIPSO
O
TIPSO
O
(+)ꢀ51
50
OMe O
OMe
OMe O
OH
OMe
H
O
O
N
N
H
8
O
11
Teoc
SEMO
O
O
13
O
13
11
R
TASF
N
8
TIPSO
HO
OMe
O
DMF, 50 °C
55%
HN
O
OTBS
O
OH
H
H
DMNꢀAZADO
R
TIPSO
O
OH
O
NOE
(−)ꢀirciniastatin B [(−)ꢀ2]
(+)ꢀ52
Scheme 11. Total Synthesis of (−)-Irciniastatin B [(−)-2]
Nevertheless, all of the spectral data for our synthetic (−)ꢀ2 were in full agreement with the data
reported by Smith and coꢀworkers.9 Thus, so we concluded that the structure and absolute configuration
of our synthetic (−)ꢀ2 are correct. In addition, we confirmed that our synthetic (−)ꢀ2 possessed the
desired 2,6ꢀtransꢀtetrahydropyranꢀ4ꢀone core by 2DꢀNOE correlations.27
Biological studies of Irciniastatin A and B. Synthetic irciniastatins A and B were evaluated for their
cytotoxicity against mammalian cell lines (Table 1). As we previously reported,28 (+)ꢀirciniastatin A
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[(+)ꢀ1] showed potent cytotoxicity, but (−)ꢀirciniastatin B [(−)ꢀ2] showed more potent cytotoxicity. We
previously reported that (+)ꢀirciniastatin A [(+)ꢀ1] inhibited protein translation and cell cycle
progression in the G1 phase in Jurkat cells. As expected, both irciniastatins A and B also potently
inhibited protein translation in HeLa and 3Y1 cells and cell cycle progression in G1 phase in 3Y1 cells
(Table 2 and Table 3). These results strongly suggest that (−)ꢀirciniastatin B [(−)ꢀ2] as well as (+)ꢀ
irciniastain A [(+)ꢀ1] is a potent protein translation inhibitor.
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IC50 (nM)
HeLa
Irciniastatin A 0.49 ± 0.10
Irciniastatin B 0.25 ± 0.02
3Y1
MCAS
SKOV3
1.24 ± 0.40
0.41 ± 0.04
1.36 ± 0.37
0.61 ± 0.08
0.34 ± 0.03
0.16 ± 0.00
Table 1. IC50 value for cytotoxicity against mammalian cells: Exponentially growing cells were
treated with various concentrations of irciniastatins A and B for 48 h (HeLa and 3Y1) or 72 h (MCAS
and SKOV3). Cell viability was determined by WSTꢀ8. Values are expressed as mean ± deviation of
two independent experiments (MCAS and SKOV3), or mean ± SD of three independent experiments
(HeLa and 3Y1).
IC50 (nM)
HeLa
3Y1
Irciniastatin A
Irciniastatin B
3.84 ± 0.13
0.98 ± 0.06
3.05 ± 0.33
0.71 ± 0.04
Table 2. IC50 value for protein synthesis of 3Y1 and HeLa cells: Exponentially growing 3Y1 and
HeLa cells were treated with various concentrations of irciniastatins A and B for 2 h followed by
[methylꢀ3H] methionine treatment for 2 h. Radioactivity in acidꢀinsoluble fractions was determined.
Values are expressed as mean ± deviation of two independent experiments.
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Concentration
(nM)
DNA content (%)
4
5
6
7
8
9
10
11
12
13
14
15
16
2C
2ꢀ4C
25.6
15.5
16.9
4C
10.7
6.0
Control
0.0
1.0
0.3
63.7
78.5
77.0
Irciniastatin A
Irciniastatin B
6.1
Table 3. Distribution of DNA content in 3Y1: Exponentially growing 3Y1 cells were treated with
various concentrations of irciniastatins A and B for 18 h, and the distribution of DNA content and
relative cell number were determined.
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Chemical footprinting has been used to map the binding site of translation inhibitors, and mycalamide
B (4), another pederinꢀtype translation inhibitor, has given rise to a footprint at the Eꢀsite of the 60S
ribosomal subunit.29 Therefore, we next investigated whether (+)ꢀirciniastatin A [(+)ꢀ1] and (−)ꢀ
irciniastatin B [(−)ꢀ2] also bind in the same site to the mycalamide Bꢀbinding site.
Purified yeast ribosomes were incubated with each compound, followed by treatment with dimethyl
sulfate (DMS). Footprints were obtained with extracted ribosome RNA by primer extension using avian
myeloblastosis virus (AMV) reverse transcriptase. As shown in Figure 2, a specific methylation of
C2765 on the 25S rRNA (corresponding to C3993 on 28S rRNA in mammalian cells) of the large
subunit by DMS treatment was seen in DMSO samples, and this methylation was inhibited by
pretreatment with 100 nM (+)ꢀirciniastatin A [(+)ꢀ1], (−)ꢀirciniastatin B [(−)ꢀ2] and cycloheximide
(CHX). These results strongly suggested that (+)ꢀirciniastatin A [(+)ꢀ1] and (−)ꢀirciniastatin B [(−)ꢀ2]
bind in the same site to the mycalamide Bꢀbinding site, the Eꢀsite of ribosome.
Taken together, the results strongly suggest that (+)ꢀirciniastatin A [(+)ꢀ1] and (−)ꢀirciniastatin B [(−)ꢀ
2] bind in the Eꢀsite of the 60S ribosomal subunit and inhibit protein translation.
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Figure 2. Inhibition of protein synthesis by binding to the E site of the 60S subunit: The chemical
footprinting of irciniastatin A and B. Ribosomes were incubated with 100 nM solutions of the
compounds as indicated and methylated with DMS. Extracted rRNAs were subjected to reverse
transcription. (a) rRNA not treated with DMS was the control. The [32P]ꢀlabeled DNA was resolved on a
denaturing polyacrylamide gel. (b) Secondary structure of the 25S LSU domain V (nucleotides 2365ꢀ
2423 and 2607ꢀ2994). The primer hybridized with extracted rRNA is underlined. The binding site
(C2765) in domain V of the 28S rRNA is indicated.
Conclusion
We have accomplished the divergent total synthesis of (+)ꢀirciniastatin A [(+)ꢀ1] and (−)ꢀirciniastatin B
[(−)ꢀ2] using “Sharpless asymmetric epoxidation ꢀ regioselective epoxide ring opening” chemistry as a
key maneuver. In the synthesis of the side chain, we have demonstrated an effective protocol for
regioselective epoxide ring opening reaction using Eu(OTf)3/DTBMP, which realized the shortest (eight
steps from commercially available propargyl alcohol) synthesis of this fragment reported to date. The
convergent synthetic routes were developed via a lateꢀstage assembly of C1ꢀC6, C8ꢀC16, and C17ꢀC25
fragments. In the total synthesis of (−)ꢀirciniastatin B, we achieved the C11ꢀselective control of the
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oxidation stage via expedient functional group transformations and AZADOꢀcatalyzed alcohol oxidation.
Eight of nine stereocenters (for irciniastatin A) / seven of eight stereocenters (for irciniastatin B), except
one derived from (−)ꢀpantolactone, were constructed employing Sharpless asymmetric epoxidation or
substrate control transformations. Although our synthetic routes rely on frequent use of protecting
groups (for irciniastatin A, 11 steps out of total 31 steps were allocated for protection/deprotection
reaction; for irciniastatin B, 12 steps out of total 33 steps), the robust sequence allowed to give sufficient
amount of irciniastatins for biological evaluation.
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The biological studies using synthetic compounds showed a high level of cytotoxic activity against
mammalian cells. Furthermore, chemical footprinting experiments revealed that the binding site of
irciniastatins is the Eꢀsite of the ribosome.
Experimental Section
General Procedure. All reactions were carried out under an argon atmosphere with dehydrated solvents
under anhydrous conditions, unless otherwise noted. Dehydrated THF and CH2Cl2 were purchased and
other solvents were dehydrated and distilled according to standard protocols. Reagents were obtained
from commercial suppliers and used without further purification, unless otherwise noted. Reactions were
monitored by thinꢀlayer chromatography (TLC) carried out on silica gel plates (60F254). Column
chromatography was performed on Silica gel 60N (spherical, neutral, 63ꢀ210 ꢁm) and flash column
chromatography was performed on Silica gel 60N (spherical, neutral, 40ꢀ50 ꢁm). Optical rotations were
measured at rt, using the sodium D line. Infrared spectra were obtained at 4.0 cmꢀ1 resolution and are
reported in wavenumbers. Proton nuclear magnetic resonance (1H NMR) spectra were recorded using
400 or 600 MHz spectrometers. The chemical shifts (δ) are given from TMS (0.00 ppm) in CDCl3 and
from residual nonꢀdeuterated solvent peak in methanolꢀd4 (methanolꢀd4: 3.30 ppm) as internal
standards. Coupling constants (J) are reported in hertz. The following abbreviations were used to explain
the multiplicities: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, sept = septet, br = broad.
Carbonꢀ13 nuclear magnetic resonance (13C NMR) spectra were recorded using a 100 or 150 MHz
spectrometer. The chemical shifts are given from CDCl3 (77.0 ppm) and methanolꢀd4 (49.0 ppm) as
internal standards. Lowꢀresolution mass spectra (MS) and highꢀresolution mass spectra (HRMS) were
recorded using electron impact (EI) with a magnetic sector or timeꢀofꢀ flight mass analyzer, or by fast
atom bombardment (FAB) with a magnetic sector or timeꢀofꢀ flight mass analyzer, or by electrospray
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ionization (ESI) with an ionꢀtrap mass analyzer. HPLC was performed using a UV/vistbl1 detector at
254 nm.
7
8
9
(2R,3S)-3-Methoxy-5-methylhex-5-ene-1,2-diol 7: To a solution of epoxy alcohol 812 (708 mg, 5.53
mmol) in MeOH (28 mL) was added 2,6ꢀdiꢀtertꢀbutylꢀ4ꢀmethylpyridine (227 mg, 1.11 mmol) followed
by Eu(OTf)3 (780 mg, 1.11 mmol) and the reaction was stirred for 19 h at 70 °C. After cooling of the
reaction, sat. NaHCO3 (15 mL) was added and the layers were separated. The aqueous layer was
extracted with EtOAc and the combined organic layers were washed with brine, dried over MgSO4, and
concentrated. Purification by column chromatography (EtOAc/Hexane 2/1) gave diol 7 (835 mg, 5.22
mmol, 94%) as a pair of regioisomers (1,2ꢀdiol 7 : 1,3ꢀdiol 16 = 18:1 determined by 1HꢀNMR spectrum).
7 : IR (neat) : 3390, 2936, 1648, 1446, 1214, 1100 cmꢀ1 ; 1HꢀNMR (400 MHz, CDCl3) δ : 4.84 (brs, 1H),
4.80 (brs, 1H), 3.84ꢀ3.77 (m, 1H), 3.73ꢀ3.67 (m, 2H), 3.54 (dt, J = 6.6, 4.1 Hz, 1H), 3.47 (s, 3 × 1/19H),
3.43 (s, 3 × 18/19H), 2.70 (d, J = 6.3 Hz, 1H), 2.44ꢀ2.41 (m, 1H), 2.38 (dd, J = 14.1, 6.8 Hz, 1H), 2.18
(dd, J = 14.3, 6.5 Hz, 1H), 1.79 (s, 3H) ; MS (EI) calculated for C7H13O2 [MꢀCH3O]+ : 129.0916, found
129.0894.
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(2R,3S)-2-Hydroxy-3-methoxy-5-methylhex-5-en-1-yl pivalate 14: To a solution of diol 7 (205 mg,
1.28 mmol) in pyridine (2.6 mL) was added PivCl (0.173 mL, 1.41 mmol) at 0 °C. The reaction was
allowed to warm to rt and after 2 h the reaction was cooled to 0 °C and Et2O (3 mL) was added. Sat.
NaHCO3 (3 mL) was then added and the mixture was extracted with Et2O. The combined organic layers
were washed with brine, dried over MgSO4, and concentrated. Purification by column chromatography
(EtOAc/Hexane 1/8) gave pivalate ester 14 (276 mg, 1.13 mmol, 89%) as a pair of regioisomers.
14 : IR (neat) : 3479, 2973, 2828, 1730, 1460, 1285, 1164, 1104 cmꢀ1 ; 1HꢀNMR (400 MHz, CDCl3) δ :
4.78 (s, 1H), 4.76 (s, 1H), 4.18 (dd, J = 11.2, 3.6 Hz, 1H), 4.11 (dd, J = 11.2, 6.4 Hz, 1H), 3.85ꢀ3.82 (m,
2H), 3.40ꢀ3.36 (m, 1H), 3.35 (s, 3H), 2.27 (dd, J = 14.4, 7.6 Hz, 1H), 2.21 (dd, J = 14.8, 5.2 Hz, 1H),
1.74 (s, 3H), 1.17 (s, 9H) ; MS (EI) calculated for C13H24O4 [M]+ : 244.1675, found 244.1703.
(2R,3S)-3-Methoxy-5-methyl-2-((2-(trimethylsilyl)ethoxy)methoxy)hex-5-en-1-yl pivalate 53: To a
solution of pivalate ester 14 (276 mg, 1.13 mmol) in CH2Cl2 (3.8 mL) was added iꢀPr2NEt (0.494 mL,
2.83 mmol) followed by SEMCl (0.400 mL, 2.26 mmol) at 0 °C and the reaction was allowed to warm
to rt. After stirring for 4 h, the reaction was cooled to 0 °C and sat. NH4Cl (3 mL) was added. The
mixture was extracted with EtOAc and the combined organic layers were washed with brine, dried over
MgSO4, and concentrated. Purification by column chromatography (EtOAc/Hexane 1/20) gave SEMꢀ
ether 53 (399 mg, 1.07 mmol, 94%) as a pair of regioisomers.
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53 : IR (neat) : 2955, 1733, 1249, 1159, 1106, 1059, 1031 cmꢀ1 ; HꢀNMR (400 MHz, CDCl3) δ : 4.82
(brs, 1H), 4.79 (brs, 1H), 4.77 (d, J = 7.2 Hz, 1H), 4.74 (d, J = 7.2 Hz, 1H), 4.30 (dd, J = 11.6, 4.0 Hz,
1H), 4.12 (dd, J = 11.6, 6.4 Hz, 1H), 3.83 (dt, J = 6.4, 4.0 Hz, 1H), 3.69 (dt, J = 10.0, 6.4 Hz, 1H), 3.60
(dt, J = 10.0, 6.8 Hz, 1H), 3.50 (ddd, J = 7.2, 5.2, 4.0 Hz, 1H), 3.40 (s, 3H), 2.28ꢀ2.26 (m, 2H), 1.78 (s,
3H), 1.20 (s, 9H), 0.95ꢀ0.90 (m, 2H), 0.00 (s, 9H) ; MS (FAB) calculated for C19H39O5Si [M+H]+ :
375.2548, found 375.2567.
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(2R,3S)-3-Methoxy-5-methyl-2-((2-(trimethylsilyl)ethoxy)methoxy)hex-5-en-1-ol (+)-15: To
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solution of SEM ether 53 (399 mg, 1.07 mmol) in CH2Cl2 (5.3 mL) was added DIBAL (1.0 M in
toluene, 2.35 mL, 2.35 mmol) at −78 °C. After 10 min, the reaction was quenched with MeOH (0.6 mL).
The reaction was allowed to warm to rt and EtOAc (6 mL) and sat. Rochelle’s salt (6 mL) were added.
After 1 h, the layers were separated and the aqueous layer was extracted with EtOAc. The combined
organic layers were washed with brine, dried over MgSO4, and concentrated. Purification by column
chromatography (EtOAc/Hexane 1/6) gave alcohol (+)-15 (204 mg, 0.704 mmol, 66%) as a colorless oil.
(+)-15 : [α]D +34.3 (c 1.98, CHCl3) ; IR (neat) : 3454, 2952, 1649, 1445, 1376, 1250, 1107 cmꢀ1 ; 1Hꢀ
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NMR (400 MHz, CDCl3) δ : 4.80 (s, 1H), 4.80 (d, J = 7.2 Hz, 1H), 4.76 (s, 1H), 4.68 (d, J = 6.8 Hz,
1H), 3.77ꢀ3.68 (m, 3H), 3.68ꢀ3.55 (m, 2H), 3.48 (dt, J = 9.6, 4.4 Hz, 1H), 3.39 (s, 3H), 3.24 (dd, J = 7.2,
4.4 Hz, 1H), 2.30 (dd, J = 14.4, 7.6 Hz, 1H), 2.20 (dd, J = 14.8, 5.2 Hz, 1H), 1.76 (s, 3H), 0.94 (t, J = 8.4
Hz, 2H), 0.00 (s, 9H) ; 13CꢀNMR (100 MHz, CDCl3) δ : 142.3, 112.9, 95.3, 82.2, 80.7, 65.7, 62.3, 58.3,
39.2, 22.7, 18.0, −1.6 ; MS (FAB) calculated for C14H31O4Si [M+H]+ : 291.1992, found 291.1979.
(2S,3S)-3-Methoxy-5-methyl-2-((2-(trimethylsilyl)ethoxy)methoxy)hex-5-enoic acid (−)-6: To a
solution of alcohol (+)-15 (90.1 mg, 0.311 mmol) in CH2Cl2/pH7 buffer (1.0 mL/1.0 mL) was added 1ꢀ
MeꢀAZADO (10.3 mg, 0.0621 mmol) and PhI(OAc)2 (300 mg, 0.932 mmol) at 0 °C. After 2 h, the
reaction was quenched with sat. Na2S2O3 and allowed to warm to rt. After 1 h, the mixture was extracted
with EtOAc and the combined organic layers were washed with brine, dried over MgSO4, and
concentrated. Purification by column chromatography (EtOAc/Hexane 1/1) gave carboxylic acid (−)-6
(71.5 mg, 0.235 mmol, 76%) as a colorless oil.
(−)-6 : [α]D –24.4 (c 0.53, CHCl3) ; IR (neat) : 2953, 1725, 1649, 1377, 1250, 1110, 1062 cmꢀ1 ; Hꢀ
NMR (400 MHz, CDCl3) δ : 4.84 (s, 1H), 4.81 (s, 1H), 4.79 (s, 2H), 4.40 (d, J = 2.8 Hz, 1H), 3.75 (ddd,
J = 8.4, 5.6, 3.2 Hz, 1H), 3.68 (dd, J = 9.2, 8.0 Hz, 1H), 3.44 (s, 3H), 2.40 (dd, J = 14.4, 8.0 Hz, 1H),
2.28 (dd, J = 14.4, 4.2 Hz, 1H), 1.77 (s, 3H), 0.92 (m, 2H), 0.02 (s, 9H) ; 13CꢀNMR (100 MHz, CDCl3) δ
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: 174.6, 141.6, 113.3, 94.8, 80.7, 75.9, 66.1, 58.1, 38.5, 22.7, 18.0, −1.4 ; MS (FAB) calculated for
C14H28O5SiNa [M+Na]+ : 327.1604, found 327.1585.
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2-(2-Methyl-2-((S)-oxiran-2-yl)propoxy)tetrahydro-2H-pyran 54: To a solution of the epoxide (+)ꢀ
17 (16.6 g, 143 mmol) in CH2Cl2 (143 mL) was added DHP (16.9 mL, 186 mmol) followed by PPTS
(7.17 g, 28.5 mmol) at 0 ºC. After stirring for 10 h, DHP (3.90 mL, 42.8 mmol) was added and stirred
for 1.5 h. The reaction was quenched with Et3N and water. The mixture was extracted with EtOAc and
the combined organic layers were washed with brine, dried over MgSO4 and concentrated. Purification
by column chromatography (EtOAc/Hexane 1/10) gave THP ether 54 (25.9 g, 130 mmol, 91%) as a pair
of diastereomers.
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54 : IR (neat) : 2942, 1477, 1351, 1201, 1122, 1065, 1035 cmꢀ1 ; HꢀNMR (400 MHz, CDCl3) δ : 4.59
(m, 1H), 3.87ꢀ3.81 (m, 1H), 3.61 (d, J = 9.2 Hz, 0.5H), 3.56 (dd, J = 9.2 Hz, 0.5H), 3.54ꢀ3.49 (m, 1H),
3.18 (d, J = 9.2 Hz, 0.5H), 3.11 (d, J = 9.2 Hz, 0.5H), 2.95ꢀ2.91 (m, 1H), 2.68ꢀ2.64 (m, 2H), 1.87ꢀ1.78
(m, 1H), 1.76ꢀ1.64 (m, 1H), 1.64ꢀ1.50 (m, 4H), 0.93 (s, 1.5H), 0.93 (s, 1.5H), 0.90 (s, 1.5H), 0.90 (s,
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1.5H) ; CꢀNMR (100 MHz, CDCl3) δ : 98.6, 98.2, 73.9, 73.6, 61.4, 61.2, 56.9, 56.7, 43.5, 34.4, 34.4,
30.2, 30.2, 25.2, 20.2, 20.1, 20.0, 19.9, 19.0, 18.9 ; MS (EI) calculated for C11H19O3 [MꢀH]+ : 199.1334,
found 199.1335.
(3R)-7-((4-Methoxybenzyl)oxy)-2,2-dimethyl-1-((tetrahydro-2H-pyran-2-yl)oxy)hept-5-yn-3-ol 18:
To a solution of pꢀmethoxybenzyl propargyl ether (792 mg, 4.50 mmol) in THF (6.5 mL) was added nꢀ
BuLi (1.56 M in Hexane, 2.88 mL, 4.50 mmol) at −78 °C. The reaction was allowed to stir at 0 °C for
1.5 h. The solution was cooled to −78 °C and BF3·OEt2 (0.560 mL, 4.50 mmol) was added dropwise.
After 30 min, epoxide 54 (300 mg, 1.50 mmol) was dissolved in THF (1 mL) and added dropwise to the
reaction mixture. After 1 h, the reaction was quenched with Et3N (1.0 mL) and sat. NaHCO3 (5 mL) and
stirred at rt for 1 h. The mixture was extracted with EtOAc and the combined organic layers were
washed with brine, dried over MgSO4, and concentrated. Purification by column chromatography
(EtOAc/Hexane 1/4) gave alkyne 18 (491 mg, 1.31 mmol, 87%) as a pair of diastereomers.
18 : IR (neat) : 3467, 2942, 2871, 1612, 1514, 1249, 1074, 1034 cmꢀ1 ; 1HꢀNMR (400 MHz, CDCl3) δ :
7.28 (d, J = 8.8 Hz, 2H), 6.87 (d, J = 8.8 Hz, 2H), 4.59 (t, J = 3.4 Hz, 0.5H), 4.55ꢀ4.53 (m, 2.5H), 4.16ꢀ
4.14 (m, 2H), 3.86ꢀ3.79 (m, 4H), 3.72ꢀ3.68 (m, 1.5H), 3.60 (d, J = 9.5 Hz, 0.5H), 3.54ꢀ3.51 (m, 1H),
3.35 (brs, 0.5H), 3.28 (d, J = 9.8 Hz, 0.5H), 3.19 (d, J = 9.5 Hz, 0.5H), 3.13 (brs, 0.5H), 2.56ꢀ2.46 (m,
1H), 2.42ꢀ2.34 (m, 1H), 1.79ꢀ1.68 (m, 2H), 1.62ꢀ1.51 (m, 4H), 0.96 (s, 1.5H), 0.95 (s, 1.5H), 0.94 (s,
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1.5H), 0.93 (s, 1.5H) ; CꢀNMR (100 MHz, CDCl3) δ : 159.3, 129.7, 129.7, 128.6, 113.9, 113.8, 99.4,
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99.0, 85.1, 84.9, 76.2, 75.9, 75.8, 75.7, 71.1, 71.1, 65.0, 62.7, 62.0, 57.4, 57.4, 55.3, 55.2, 38.3, 38.1,
30.6, 30.4, 25.3, 25.3, 22.9, 22.6, 22.4, 22.4, 19.7, 19.6, 19.2, 19.2 ; MS (EI) calculated for C17H23O4
[MꢀC5H9O]+ : 291.1596, found 291.1582.
(R)-7-((4-Methoxybenzyl)oxy)-2,2-dimethylhept-5-yne-1,3-diol (+)-55: To a solution of alkyne 18
(3.18 g, 8.45 mmol) in EtOH (42 mL) was added PPTS (425 mg, 1.69 mmol) and the reaction was
stirred for 19 h at 70 °C. After cooling of the reaction, sat. NaHCO3 (20 mL) was added and the mixture
was extracted with EtOAc. The combined organic layers were washed with brine, dried over MgSO4,
and concentrated. Purification by column chromatography (EtOAc/Hexane 1/2) gave diol (+)-55 (2.27 g,
7.78 mmol, 92%) as a colorless oil.
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(+)-55 : [α]D +24.4 (c 1.18, CHCl3) ; IR (neat) : 3411, 2958, 2225, 1612, 1514, 1250, 1066 cmꢀ1 ; 1Hꢀ
NMR (400 MHz, CDCl3) δ : 7.27 (d, J = 8.5 Hz, 2H), 6.88 (d, J = 8.5 Hz, 2H), 4.51 (s, 2H), 4.14 (t, J =
2.2 Hz, 1H), 3.80 (s, 3H), 3.69 (dd, J = 9.5, 3.2 Hz, 1H), 3.52 (d, J = 11.0 Hz, 1H), 3.44 (d, J = 11.0 Hz,
1H), 3.05 (brs, 1H), 2.92 (brs, 1H), 2.49 (ddt, J = 16.7, 3.2, 2.2 Hz, 1H), 2.38 (ddt, J = 16.7, 9.5, 2.2 Hz,
1H), 0.90 (s, 3H), 0.89 (s, 3H) ; 13CꢀNMR (100 MHz, CDCl3) δ : 159.3, 129.6, 129.4, 113.8, 84.2, 78.3,
76.9, 71.6, 71.3, 57.3, 55.2, 38.3, 23.0, 22.2, 18.5 ; MS (EI) calculated for C17H24O4 [M]+ : 292.1675,
found 292.1659.
(R)-3-Hydroxy-7-((4-methoxybenzyl)oxy)-2,2-dimethylhept-5-ynal (+)-19: To a solution of diol (+)-
55 (20.0 g, 68.5 mmol) in CH2Cl2 (69 mL) was added PhI(OAc)2 (28.7 g, 89.0 mmol) followed by
TEMPO (1.61 g, 10.3 mmol). After stirring for 7 h at rt, PhI(OAc)2 (4.41 g, 13.7 mmol) and TEMPO
(530 mg, 3.42 mmol) were added and the reaction was stirred for 1 h. The reaction was then diluted with
Et2O (70 mL) and quenched with sat. Na2S2O3 (70 mL) at 0 °C. After stirring for 1 h, the mixture was
extracted with Et2O and the combined organic layers were washed with brine, dried over MgSO4, and
concentrated. Purification by column chromatography (EtOAc/Hexane 1/3) gave aldehyde (+)-19 (15.1
g, 51.9 mmol, 76%) as a colorless oil.
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(+)-19 : [α]D +24.3 (c 1.38, CHCl3) ; IR (neat) : 3438, 2937, 2235, 1723, 1612, 1250, 1070 cmꢀ1 ; 1Hꢀ
NMR (400 MHz, CDCl3) δ : 9.57 (s, 1H), 7.27 (d, J = 8.4 Hz, 2H), 6.89ꢀ6.86 (m, 2H), 4.51 (s, 2H), 4.13
(t, J = 2.2 Hz, 1H), 3.92 (dd, J = 9.3, 3.7 Hz, 1H), 3.81 (s, 3H), 2.50 (ddt, J = 16.7, 3.7, 2.2 Hz, 1H),
2.39 (ddt, J = 16.7, 9.3, 2.2 Hz, 1H), 1.11 (s, 3H), 1.09 (s, 3H) ; 13CꢀNMR (100 MHz, CDCl3) δ : 205.3,
159.3, 129.6, 129.4, 113.8, 83.1, 79.0, 73.4, 71.3, 57.2, 55.2, 49.7, 22.9, 18.8, 16.7 ; MS (EI) calculated
for C17H22O4 [M]+ : 290.1518, found 290.1504.
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(4R,6R)-10-((4-Methoxybenzyl)oxy)-5,5-dimethyldec-1-en-8-yne-4,6-diol (+)-20: To a solution of
MgBr·OEt2 (405 mg, 1.57 mmol) in CH2Cl2 (2.0 mL) was added aldehyde (+)-19 (207 mg, 0.713 mmol)
in CH2Cl2 (1.5 mL) at −78 °C. After stirring for 30 min, allyltributylstannane (0.490 mL, 1.57 mmol)
was added and the reaction was allowed to stir at 0 °C. After 12 h, the reaction was quenched with sat.
NaHCO3 (3 mL) and the mixture was extracted with EtOAc. The combined organic layers were washed
with brine, dried over MgSO4, and concentrated. Purification by column chromatography
(EtOAc/Hexane 1/3) gave 4Rꢀalcohol (+)ꢀ20 (214 mg, 0.644 mmol, 90%, dr > 20:1) as a colorless oil.
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(+)-20 : [α]D +30.0 (c 1.74, CHCl3) ; IR (neat) : 3399, 2965, 2225, 1612, 1513, 1250, 1062 cmꢀ1 ; 1Hꢀ
NMR (600 MHz, CDCl3) δ : 7.27 (d, J = 8.5 Hz, 2H), 6.87 (d, J = 8.5 Hz, 2H), 5.92ꢀ5.82 (m, 1H), 5.18ꢀ
5.14 (m, 2H), 4.51 (s, 2H), 4.14 (t, J = 2.2 Hz, 2H), 3.81 (s, 0.06H), 3.80 (s, 2.94H), 3.76 (dt, J = 9.2, 3.9
Hz, 1H), 3.66 (ddd, J = 10.5, 3.9, 2.2 Hz, 1H), 2.49 (ddt, J = 16.6, 3.9, 2.2 Hz, 1H), 2.43 (ddt, J = 16.6,
9.0, 2.2 Hz, 1H), 2.33 (m, 1H), 2.15 (m, 1H), 0.94 (s, 3H), 0.94 (s, 3H) ; 13CꢀNMR (100 MHz, CDCl3) δ
: 159.1, 135.9, 129.5, 129.4, 117.5, 113.6, 84.4, 77.9, 76.7, 76.6, 71.2, 57.3, 55.2, 40.1, 36.4, 22.9, 20.8,
20.5 ; MS (FAB) calculated for C20H27O4 [MꢀH]+ : 331.1909, found 331.1889.
(4R,6R)-4,6-Bistriethylsilyloxy-5,5-dimethyl-10-(4-methoxybenzyloxy)-1-decen-8-yne (+)-56: To a
solution of diol (+)ꢀ20 (17.2 g, 51.8 mmol) in DMF (52 mL) was added imidazole (17.6 g, 259.1 mmol)
followed by TESCl (21.7 mL, 123 mmol) at 0 °C. After stirring for 1.5 h, the reaction was quenched
with sat. NaHCO3 (25 mL). The mixture was extracted with Et2O and the combined organic layers were
washed with brine, dried over MgSO4, and concentrated. Purification by column chromatography
(EtOAc/Hexane 1/30) gave TESꢀether (+)-56 (28.9 g, 51.6 mmol, 100%) as a colorless oil.
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(+)-56 : [α]D +17.4 (c 1.83, CHCl3) ; IR (neat) : 2954, 1613, 1513, 1463, 1249, 1078, 1007 cmꢀ1 ; 1Hꢀ
NMR (400 MHz, CDCl3) δ : 7.28 (d, J = 8.8 Hz, 2H), 6.90ꢀ6.86 (m, 2H), 5.85 (ddt, J = 18.0, 9.5, 7.2
Hz, 1H), 5.07ꢀ5.00 (m, 2H), 4.51 (s, 2H), 4.13 (t, J = 2.2 Hz, 2H), 3.81 (s, 3H), 3.76 (dd, J = 7.1, 4.8 Hz,
1H), 3.64 (dd, J = 7.6, 3.4 Hz, 1H), 2.50 (ddt, J = 17.3, 4.2, 2.0 Hz, 1H), 2.36ꢀ2.25 (m, 2H), 2.14 (m,
1H), 0.97 (t, J = 7.8 Hz, 9H), 0.95 (t, J = 7.8 Hz, 9H), 0.87 (s, 6H), 0.70 (q, J = 7.8 Hz, 6H), 0.60 (t, J =
7.8 Hz, 6H) ; 13CꢀNMR (100 MHz, CDCl3) δ : 159.3, 137.1, 129.7, 129.5, 126.2, 113.7, 85.8, 77.4, 77.3,
76.4, 71.0, 57.4, 55.1, 44.4, 38.0, 23.7, 19.9, 19.7, 7.0, 5.6, 5.5 ; MS (EI) calculated for C30H51O4Si2 [Mꢀ
C2H5]+ : 531.3326, found 531.3350.
(5R,7R)-5,7-Bistriethylsilyloxy-6,6-dimethyl-9-decen-2-yn-1-ol (+)-21: To a solution of bisꢀTES ether
(+)-56 (16.9 g, 30.1 mmol) in CH2Cl2/pH7 buffer (143 mL/7.2 mL) was added DDQ (10.3 g, 45.2
mmol) at −30 °C and the reaction was allowed to stir at 0 °C. After 13 h, the reaction was quenched with
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sat. Na2S2O3 (100 mL) and stirred for 1 h at rt. The reaction mixture was filtered through a pad of celite
followed by washed with EtOAc. The layers were separated and the aqueous layer was extracted with
EtOAc. The combined organic layers were washed with brine, dried over MgSO4, and concentrated.
Purification by column chromatography (EtOAc/Hexane 1/20) gave alcohol (+)-21 (11.9 g, 27.0 mmol,
90%) as a colorless oil.
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(+)-21 : [α]D25 +21.3 (c 1.06, CHCl3) ; IR (neat) : 3327, 2955, 2227, 1640, 1459, 1415, 1238, 1079, 1009
cmꢀ1 ; 1HꢀNMR (400 MHz, CDCl3) δ : 5.85 (ddt, J = 17.3, 8.9, 6.8 Hz, 1H), 5.08ꢀ5.01 (m, 2H), 4.24 (dt,
J = 6.0, 2.2 Hz, 2H), 3.74 (dt, J = 7.0, 4.1 Hz, 1H), 3.64 (dd, J = 7.5, 3.4 Hz, 1H), 2.48 (ddt, J = 17.1,
4.1, 2.2 Hz, 1H), 2.33 (ddd, J = 14.7, 3.4, 1.7 Hz, 1H), 2.26 (ddt, J = 17.1, 7.0, 2.2 Hz, 1H), 2.15 (m,
1H), 1.43 (t, J = 6.0 Hz, 1H), 0.98 (t, J = 8.0 Hz, 9H), 0.96 (t, J = 7.3 Hz, 9H), 0.83 (s, 3H), 0.83 (s, 3H),
0.68 (q, J = 7.3 Hz, 6H), 0.60 (q, J = 7.8 Hz, 6H) ; 13CꢀNMR (100 MHz, CDCl3) δ : 137.2, 116.2, 85.4,
79.7, 77.4, 76.4, 51.4, 44.4, 38.0, 23.7, 20.0, 19.7, 7.1, 7.0, 7.0, 5.6, 5.4 ; MS (EI) calculated for
C22H43O3Si2 [MꢀC2H5]+ : 411.2751, found 411.2739.
(5R,7R,E)-5,7-Bistriethylsilyloxy-6,6-dimethyl-2,9-decadien-1-ol (+)-57: To a solution of alcohol (+)-
21 (786 mg, 1.79 mmol) in THF (7.9 mL) was added RedꢀAl® (1.8 M in toluene, 1.98 mL, 3.57 mmol)
at 0 °C and the reaction was allowed to stir at rt. After stirring for 3 h, the reaction was quenched with
H2O (1 mL) at 0 °C and stirred for 1 h at rt. The reaction mixture was filtered through a pad of celite
followed by washed with EtOAc. The layers were separated and the aqueous layer was extracted with
EtOAc. The combined organic layers were washed with brine, dried over MgSO4, and concentrated.
Purification by column chromatography (EtOAc/Hexane 1/20) gave allyl alcohol (+)-57 (718 mg, 1.62
mmol, 91%) as a colorless oil.
(+)-57 : [α]D22 +28.4 (c 0.65, CHCl3) ; IR (neat) : 3330, 2955, 2877, 1459, 1415, 1238, 1076, 1006 cmꢀ1 ;
1HꢀNMR (400 MHz, CDCl3) δ : 5.85 (ddt, J = 19.0, 10.7, 7.2 Hz, 1H), 5.78ꢀ5.61 (m, 2H), 5.05ꢀ5.01 (m,
2H), 4.11 (d, J = 5.6 Hz, 2H), 3.62ꢀ3.58 (m, 2H), 2.28ꢀ2.20 (m, 2H), 2.14ꢀ2.07 (m, 2H), 0.98 (t, J = 3.6
Hz, 18H), 0.86 (s, 6H), 0.63 (q, J = 3.6 Hz, 6H), 0.59 (q, J = 3.6 Hz, 6H) ; 13CꢀNMR (100 MHz, CDCl3)
δ : 137.2, 131.4, 130.5, 116.2, 77.4, 77.3, 63.8, 44.5, 37.8, 36.1, 19.8, 19.8, 7.09, 5.63 ; MS (FAB)
calculated for C24H51O3Si2 [M+H]+ : 443.3377, found 443.3394.
(2R,3R,5R,7R)-5,7-Bistriethylsilyloxy-6,6-dimethyl-2,3-epoxy-9-decen-1-ol (+)-13: To freshly
activated 4 Å molecular sieves (1.0 g) in CH2Cl2 (2.4 mL) was added (−)ꢀDET (39.6 mg, 0.192 mmol)
in CH2Cl2 (0.1 mL). The solution was cooled to −20 °C and Ti(OiPr)4 (0.0380 mL, 0.128 mmol) was
added followed by TBHP (3.11 M solution in CH2Cl2, 0.823 mL, 2.56 mmol). The reaction was stirred
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for 1 h and then a solution of allyl alcohol (+)-57 (567 mg, 1.28 mmol) in CH2Cl2 (0.1 mL) was added.
After 2 h, the reaction was quenched with a 6:1 mixture of acetone/water (2.8 mL) and stirred for 1 h at
rt. The reaction mixture was filtered through a pad of celite followed by washed with EtOAc. The layers
were separated and the aqueous layer was extracted with EtOAc. The combined organic layers were
washed with brine, dried over MgSO4, and concentrated. Purification by column chromatography
(EtOAc/Hexane 1/12) gave epoxy alcohol (+)-13 (554 mg, 1.21 mmol, 94%, dr > 20:1) as a colorless
oil.
(+)-13 : [α]D30 +46.4 (c 0.61, CHCl3) ; IR (neat) : 3436, 2955, 1639, 1459, 1415, 1239, 1078, 1006 cmꢀ1 ;
1HꢀNMR (400 MHz, CDCl3) δ : 5.84 (ddt, J = 15.3, 8.1, 6.8 Hz, 1H), 5.05ꢀ4.99 (m, 2H), 3.94 (ddd, J =
12.2, 6.1, 2.4 Hz, 1H), 3.81 (dd, J = 9.0, 2.4 Hz, 1H), 3.63 (ddd, J = 12.2, 6.1, 4.4 Hz, 1H), 3.48 (dd, J =
7.6, 3.4 Hz, 1H), 3.11 (dt, J = 7.6, 2.8 Hz, 1H), 2.94 (dt, J = 4.0, 2.4 Hz, 1H), 2.26ꢀ2.22 (m, 1H), 2.14ꢀ
2.06 (m, 1H), 1.78 (ddd, J = 14.4, 9.0, 3.7 Hz, 1H), 1.62 (t, J = 6.1 Hz, 1H), 1.38 (ddd, J = 14.1, 7.8, 2.4
Hz, 1H), 0.99 (t, J = 7.8 Hz, 9H), 0.95 (t, J = 8.1 Hz, 9H), 0.88 (s, 3H), 0.85 (s, 3H), 0.66 (q, J = 8.1 Hz,
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6H), 0.66 (q, J = 7.8 Hz, 6H) ; CꢀNMR (100 MHz, CDCl3) δ : 136.9, 116.2, 77.6, 75.1, 61.6, 59.7,
54.0, 44.0, 37.6, 35.1, 20.0, 19.9, 7.2, 7.2, 5.7, 5.6 ; MS (FAB) calculated for C24H51O4Si2 [M+H]+ :
459.3326, found 459.3304.
(4R,6R,8R,9R)-10-(Benzyloxymethoxy)-4,6-bistriethylsilyloxy-5,5-dimethyl-8,9-epoxy-1-decene (+)-
22: To a solution of epoxy alcohol (+)-13 (2.35 g, 5.13 mmol) in CH2Cl2 (10 mL) was added iꢀPr2NEt
(3.59 mL, 20.5 mmol) followed by BOMCl (1.41 mL, 10.3 mmol) at 0 °C. After stirring for 5.5 h, the
reaction was quenched with sat. NaHCO3 (10 mL). The mixture was extracted with EtOAc and the
combined organic layers were washed with brine, dried over MgSO4, and concentrated. Purification by
column chromatography (EtOAc/Hexane 1/40ꢀ1/20) gave BOM ether (+)-22 (2.59 g, 4.47 mmol, 87%)
as a colorless oil.
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(+)-22 : [α]D +37.8 (c 0.49, CHCl3) ; IR (neat) : 2954, 1457, 1077, 1006 cmꢀ1 ; HꢀNMR (400 MHz,
CDCl3) δ : 7.35ꢀ7.28 (m, 5H), 5.83 (ddt, J = 17.1, 10.0, 7.1 Hz, 1H), 5.02 (d, J = 15.4 Hz, 1H), 5.00 (d, J
= 9.8 Hz, 1H), 4.78 (s, 2H), 4.62 (s, 2H), 3.84ꢀ3.80 (m, 2H), 3.58 (dd, J = 11.5, 5.6 Hz, 1H), 3.46 (dd, J
= 7.6, 3.4 Hz, 1H), 3.02 (dt, J = 8.1, 2.9 Hz, 1H), 2.95 (ddd, J = 5.4, 2.9 Hz, 1H), 2.23 (m, 1H), 2.09 (m,
1H), 1.79 (ddd, J = 12.7, 9.3, 3.4 Hz, 1H), 1.33 (ddd, J = 14.2, 7.8, 2.2 Hz, 1H), 0.98 (t, J = 8.1 Hz, 9H),
0.95 (t, J = 7.8 Hz, 9H), 0.88 (s, 3H), 0.84 (s, 3H), 0.66 (q, J = 8.1 Hz, 6H), 0.59 (q, J = 7.8 Hz, 3H) ;
13CꢀNMR (100 MHz, CDCl3) δ : 137.7, 137.0, 128.4, 127.9, 127.7, 116.2, 94.7, 77.6, 75.1, 69.4, 68.0,
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58.0, 54.2, 44.0, 37.5, 35.1, 19.9, 19.8, 7.1, 7.1, 5.6, 5.5 ; MS (EI) calculated for C30H53O5Si2 [MꢀC2H5]+
: 549.3432, found 549.3449.
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(2R,4R,6S)-2-Allyl-6-((1R)-2-(benzyloxymethoxy)-1-hydroxyethyl)-3,3-dimethyl-4-
hydroxytetrahydropyran (+)-23: To a solution of BOM ether (+)-22 (476 mg, 0.823 mmol) in
CH2Cl2/MeOH (4.1 mL/0.4 mL) was added CSA (19.0 mg, 0.0823 mmol) at 0 °C. After stirring for 19
h, the reaction was quenched with sat. NaHCO3 (1.0 mL) and the mixture was extracted with EtOAc.
The combined organic layers were washed with brine, dried over MgSO4, and concentrated. Purification
by column chromatography (EtOAc/Hexane 1/1) gave diol (+)ꢀ23 (238 mg, 0.680 mmol, 83%) as a
colorless oil.
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(+)-23 : [α]D +41.7 (c 0.94, CHCl3) ; IR (neat) : 3421, 2942, 1640, 1454, 1090 cmꢀ1 ; HꢀNMR (400
MHz, CDCl3) δ : 7.36ꢀ7.29 (m, 5H), 5.82 (ddt, J = 17.1, 10.3, 6.8 Hz, 1H), 5.05 (ddd, J = 17.1, 3.4, 1.5
Hz, 1H), 4.99 (ddd, J = 10.3, 2.0, 1.0 Hz, 1H), 4.81 (d, J = 6.6 Hz, 1H), 4.79 (d, J = 6.6 Hz, 1H), 4.63 (s,
2H), 3.94 (m, 1H), 3.84 (dd, J = 10.6, 2.9 Hz, 1H), 3.81 (dd, J = 5.4, 4.0 Hz, 1H), 3.63 (dd, J = 9.5, 4.0
Hz, 1H), 3.59 (dd, J = 10.6, 6.6 Hz, 1H), 3.23 (dd, J = 10.7, 2.7 Hz, 1H), 2.64 (brs, 1H), 2.35 (m, 1H),
2.22 (m, 1H), 2.11 (dt, J = 13.4, 4.0 Hz, 1H), 1.74 (ddd, J = 13.4, 9.5, 5.4 Hz, 1H), 0.99 (s, 3H), 0.91 (s,
13
3H) ; CꢀNMR (100 MHz, CDCl3) δ : 137.6, 136.8, 128.6, 128.0, 127.9, 116.4, 95.6, 79.5, 72.3, 70.7,
70.7, 69.9, 69.1, 38.4, 33.7, 29.7, 23.9, 14.8 ; MS (EI) calculated for C20H30O5 [M]+ : 350.2093, found
350.2108.
(2R,4R,6S)-2-Allyl-6-((1R)-2-(benzyloxymethoxy)-1-methoxyethyl)-3,3-dimethyl-4-
hydroxytetrahydropyran (+)-58: To a solution of diol (+)-23 (121 mg, 0.344 mmol) in THF (3.4 mL)
was added NaH (60%, 34.4 mg, 0.861 mmol) at 0 °C. After stirring for 30 min, Me2SO4 (0.0390 mL,
0.413 mmol) was added and the reaction was stirred at 0 °C. After 2 h, the reaction was quenched with
sat. NH4Cl (2 mL) and the mixture was extracted with EtOAc. The combined organic layers were
washed with brine, dried over MgSO4, and concentrated. Purification by column chromatography
(EtOAc/Hexane 1/8ꢀ1/4) gave methyl ether (+)-58 (97.4 mg, 0.267 mmol, 78%) as a colorless oil.
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(+)-58 : [α]D +33.3 (c 0.80, CHCl3) ; IR (neat) : 3467, 2935, 1640, 1454, 1100, 1056 cmꢀ1 ; HꢀNMR
(400 MHz, CDCl3) δ : 7.36ꢀ7.27 (m, 5H), 5.84 (ddt, J = 17.1, 10.1, 7.0 Hz, 1H), 5.04 (dd, J = 17.1, 1.5
Hz, 1H), 4.98 (d, J = 10.1 Hz, 1H), 4.79 (s, 2H), 4.63 (s, 2H), 3.95 (ddd, J = 8.9, 6.1, 3.0 Hz, 1H), 3.90
(dd, J = 11.0, 2.2 Hz, 1H), 3.81 (dd, J = 5.4, 3.9 Hz, 1H), 3.73 (dd, J = 9.5, 4.2 Hz, 1H), 3.64 (dd, J =
11.0, 5.5 Hz, 1H), 3.59 (dd, J = 10.6, 4.8 Hz, 1H), 3.53 (ddd, J = 8.9, 4.8, 2.2 Hz, 1H), 3.47 (s, 3H), 3.20
(dd, J = 9.9, 2.7 Hz, 1H), 2.31ꢀ2.18 (m, 2H), 2.06 (dt, J = 13.4, 3.0 Hz, 1H), 1.75 (dt, J = 13.4, 10.6, 6.1
Hz, 1H), 1.44 (brs, 1H), 0.99 (s, 3H), 0.90 (s, 3H) ; 13CꢀNMR (100 MHz, CDCl3) δ : 137.9, 136.7, 128.4,
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127.9, 127.6, 116.3, 95.1, 79.1, 78.6, 72.5, 69.9, 69.4, 66.6, 58.4, 38.6, 33.8, 29.6, 23.5, 13.8 ; MS (EI)
calculated for C18H27O5 [MꢀC3H5]+ : 323.1859, found 323.1841.
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(2R,4R,6S)-2-Allyl-6-((1R)-2-(benzyloxymethoxy)-1-methoxyethyl)-3,3-dimethyl-4-tert-
butyldimethylsilyloxytetrahydropyran (+)-24: To a solution of methyl ether (+)-58 (177 mg, 0.487
mmol) in CH2Cl2 (2.4 mL) was added 2,6ꢀlutidine (0.170 mL, 1.46 mmol) followed by TBSOTf (0.168
mL, 0.730 mmol) at 0 °C. After stirring for 30 min, the reaction was quenched with sat. NaHCO3 (1
mL). The mixture was extracted with EtOAc and the combined organic layers were washed with brine,
dried over MgSO4, and concentrated. Purification by column chromatography (EtOAc/Hexane 1/40ꢀ
1/20) gave TBS ether (+)-24 (209 mg, 0.438 mmol, 90%) as a colorless oil.
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(+)-24 : [α]D +18.5 (c 1.24, CHCl3) ; IR (neat) : 2954, 1640, 1471, 1102 cmꢀ1 ; HꢀNMR (400 MHz,
CDCl3) δ : 7.36ꢀ7.27 (m, 5H), 5.83 (ddt, J = 16.8, 10.0, 6.8 Hz, 1H), 5.02 (d, J = 16.8 Hz, 1H), 4.96 (dd,
J = 10.0, 1.0 Hz, 1H), 4.79 (s, 2H), 4.63 (s, 2H), 3.92ꢀ3.86 (m, 2H), 3.63 (dd, J = 10.7, 5.4 Hz, 1H),
3.56ꢀ3.50 (m, 2H), 3.49 (s, 3H), 3.23 (dd, J = 10.5, 2.4 Hz, 1H), 2.40 (m, 1H), 2.19 (dd, J = 14.4, 6.8
Hz, 1H), 1.94 (dt, J = 13.9, 4.4 Hz, 1H), 1.70 (ddd, J = 13.9, 9.3, 5.4 Hz, 1H), 1.44 (brs, 1H), 0.94 (s,
13
3H), 0.90 (s, 9H), 0.88 (s, 3H), 0.06 (s, 6H) ; CꢀNMR (100 MHz, CDCl3) δ : 137.8, 137.0, 128.3,
127.8, 127.6, 115.9, 95.1, 79.7, 79.3, 73.0, 69.3, 69.0, 67.2, 58.5, 38.8, 33.8, 30.2, 25.9, 24.5, 18.1, 15.8,
−4.1, −4.9 ; MS (EI) calculated for C27H46O5Si [M]+ : 478.3115, found 478.3118.
2-((2R,4R,6S)-6-((R)-2-((Benzyloxy)methoxy)-1-methoxyethyl)-4-((tert-butyldimethylsilyl)oxy)-3,3-
dimethyltetrahydro-2H-pyran-2-yl)acetaldehyde 11: To a solution of TBS ether (+)-24 (500 mg, 1.05
mmol) in THF/H2O (10 mL/1 mL) was added NMO (184 mg, 1.57 mmol) followed by OsO4 (0.196 M
solution in THF, 0.0530 mL, 0.0105 mmol) at 0 °C and the reaction was allowed to stir at rt. After
stirring for 10.5 h, the reaction was quenched with sat. Na2S2O3 (1 mL) and stirred for 1 h at rt. The
mixture was extracted with EtOAc and the combined organic layers were washed with brine, and dried
over MgSO4. Filtration and concentration afforded a crude diol. To a solution of the diol in MeOH/H2O
(18.8 mL/2.1 mL) was added NaIO4 (335 mg, 1.57 mmol) and stirred at rt. After 30 min, EtOAc (30
mL) and H2O (10 mL) was added. The mixture was extracted with EtOAc and the combined organic
layers were washed with brine, and dried over MgSO4. Filtration and concentration afforded aldehyde 11
as a colorless oil.
11 : IR (neat) : 2954, 1727, 1524, 1234, 1071 cmꢀ1 ; 1HꢀNMR (400 MHz, CDCl3) δ : 9.66 (d, J = 2.4 Hz,
1H) 7.29ꢀ7.19 (m, 5H), 4.71 (d, J = 1.2 Hz, 1H), 4.55 (d, J = 1.2 Hz, 1H), 4.61 (s, 1H), 3.89ꢀ3.84 (m,
1H), 3.72 (dd, J = 10.6, 3.0 Hz, 1H), 3.59ꢀ3.53 (m, 1H), 3.45ꢀ3.39 (m, 4H), 3.21 (d, J = 9.6 Hz, 1H),
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(s, 9H), 0.82 (s, 3H), 0.01 (s, 6H) ; CꢀNMR (100 MHz, CDCl3) δ : 201.7, 137.9, 128.3, 127.8, 127.5,
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calculated for C22H35O6Si [MꢀC4H9]+ : 423.2203, found 423.2227.
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Methyl 4,6-dimethoxy-2-hydroxybenzoate 26: To a solution of 2,4,6ꢀtrihydroxybenzoic acid (25)
(10.0 g, 53.2 mmol) in acetone (177 mL) was added K2CO3 (44.1 g, 319 mmol) followed by Me2SO4
(30.2 mL, 319 mmol) and heated to reflux. After stirring for 22 h, the reaction mixture was filtered
through a pad of celite followed by washed with EtOAc. Then concentration afforded a crude trimethyl
ether. To a solution of the crude trimethyl ether in CH2Cl2 (106 mL) was added BCl3 (1.0 M solution,
79.8 mL, 79.8 mmol) at −78 ºC and the reaction was allowed to stir at 0 °C. After stirring for 5 h, the
reaction was quenched with 10% HCl aq. and the mixture was extracted with EtOAc. The combined
organic layers were washed with brine, dried over MgSO4, and concentrated. Purification by column
chromatography (EtOAc/Hexane 1/8) gave phenol 26 (5.16 g, 24.3 mmol, 46% over 2 steps) as a white
solid.
26 : mp : 111ꢀ112 ºC ; IR (neat) : 1638 cmꢀ1 ; 1HꢀNMR (400 MHz, CDCl3) δ : 12.03 (s, 1H), 6.11 (d, J =
13
2.5 Hz, 1H), 5.97 (d, J = 2.5 Hz, 1H), 3.92 (s, 1H), 3.83 (s, 3H), 3.81 (s, 3H) ; CꢀNMR (100 MHz,
CDCl3) δ : 171.6, 166.0, 165.3, 162.1, 96.6, 93.4, 91.5, 56.0, 55.4, 52.2 ; MS (EI) calculated for
C10H12O5 [M]+ : 212.0685, found 212.0692.
Methyl 4,6-dimethoxy-2-hydroxy-3-methylbenzoate 27: To a solution of phenol 26 (5.16 g, 24.3
mmol) in CH2Cl2 (81 mL) was added 1,1ꢀdichlorodimethyl ether (4.40 mL, 48.6 mmol) followed by
TiCl4 (8.00 mL, 72.9 mmol) at −20 °C. After stirring for 1 h, the reaction was quenched with 10% HCl
aq. and the mixture was extracted with EtOAc. The combined organic layers were washed with brine,
and dried over MgSO4. Filtration and concentration afforded a crude benzaldehyde. To a solution of the
crude benzaldehyde in MeOH/CHCl3 (54 mL/27 mL) was added 10% PdꢀC (1.17 g) and hydrogenated
(H2, 1 atm). After 38 h, the catalyst was filtered through a pad of celite followed by washed with EtOAc.
The combined organic layers were concentrated. Purification by column chromatography
(EtOAc/Hexane 1/8) gave methylbenzene 27 (4.83 g, 21.4 mmol, 88%) as a white solid.
27 : mp : 153ꢀ154 ºC ; IR (neat) : 2950, 1729, 1605 cmꢀ1 ; 1HꢀNMR (400 MHz, CDCl3) δ : 12.04 (s, 1H),
13
5.99 (s, 1H), 3.92 (s, 1H), 3.87 (s, 3H), 3.86 (s, 3H), 2.03 (s, 3H) ; CꢀNMR (100 MHz, CDCl3) δ :
171.9, 162.7, 162.1, 160.5, 105.7, 96.5, 87.0, 56.1, 55.4, 52.1, 7.4 ; MS (EI) calculated for C11H14O5
[M]+ : 226.0841, found 226.0828.
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Methyl 4,6-dimethoxy-3-methyl-2-trifluoromethanesulfonyloxybenzoate 28: To a solution of
methylbenzene 27 (82.1 mg, 0.363 mmol) in CH2Cl2 (1.8 mL) was added pyridine (70.0 ꢁL, 0.871
mmol) followed by Tf2O (0.0730 mL, 0.436 mmol) at 0 °C. After stirring for 4 h, the reaction was
quenched with sat. NaHCO3 and the mixture was extracted with EtOAc. The combined organic layers
were washed with brine, dried over MgSO4, and concentrated. Purification by column chromatography
(EtOAc/Hexane 1/3) gave triflate 28 (117 mg, 0.327 mmol, 90%) as a white solid.
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28 : mp : 113ꢀ114 ºC ; IR (neat) : 1735, 1621 cmꢀ1 ; HꢀNMR (400 MHz, CDCl3) δ : 6.46 (s, 1H), 3.90
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(s, 3H), 3.88 (s, 3H), 2.15 (s, 3H) ; CꢀNMR (100 MHz, CDCl3) δ : 163.8, 160.5, 157.3, 145.3, 118.3
(q, J = 318 Hz), 113.2, 109.5, 94.8, 56.6, 56.0, 52.5, 9.6 ; MS (EI) calculated for C12H13F3O7S [M]+ :
358.0334, found 358.0336.
Methyl 2-(1-butenyl)-4,6-dimethoxy-3-methylbenzoate 12: A solution of boronic acid ester 29 (1.14
g, 6.54 mmol) in 1,4ꢀdioxane (16 mL) was first sonicated. To triflate 28 (1.17 g, 3.27 mmol), K3PO4
(1.39 g, 6.54 mmol) and Pd(PPh3)4 (378 mg, 0.327 mmol) was added a solution of boronic acid ester in
1,4ꢀdioxane at rt. After stirring at 100 °C for 12 h, the reaction was quenched with 1M NaOH aq. and the
reaction mixture was filtered through a pad of celite followed by washed with EtOAc. The mixute was
extracted with EtOAc and the combined organic layers were washed with brine, dried over MgSO4, and
concentrated. Purification by column chromatography (EtOAc/Hexane 1/8) gave alkene 12 (717 mg,
2.71 mmol, 83%) as a colorless oil.
12 : IR (neat) : 1731, 1588 cmꢀ1 ; 1HꢀNMR (400 MHz, CDCl3) δ : 6.36 (d, J = 15.8 Hz, 1H), 6.36 (s, 1H),
5.76 (dt, J = 15.8, 6.8 Hz, 1H), 3.82 (s, 3H), 3.81 (s, 3H), 3.78 (s, 3H), 2.16 (dq, J = 7.6, 6.8 Hz, 3H),
13
1.04 (t, J = 7.6 Hz, 3H) ; CꢀNMR (100 MHz, CDCl3) δ : 169.1, 158.8, 155.3, 137.7, 137.6, 125.6,
116.8, 115.8, 93.8, 56.1, 55.6, 51.9, 29.3, 13.6, 11.6 ; MS (EI) calculated for C15H20O4 [M]+ : 264.1362,
found 264.1351.
(3S)-5,7-Dimethoxy-3-[(1S)-1-hydroxypropyl]-4-methylphthalide (+)-30: To a solution of phenol
ADꢀmixꢀα (530 mg, 1.4 g/mmol) in t-BuOH/H2O (1.5 mL/1.5 mL) was added MeSO2NH2 (36.0 mg,
0.379 mmol) at 0 °C. After stirring for 30 min, alkene 12 (100 mg, 0.379 mmol) was added and the
reaction was stirred for 108 h. Then the reaction was quenched with sat. Na2S2O3 and the crude was
extracted with EtOAc. The combined organic layers were washed with brine, dried over MgSO4, and
concentrated. Purification by column chromatography (EtOAc/Hexane 1/4) and then recrystallization
gave phthalide (+)-30 (89.0 mg, 0.335 mmol, 88%, 99% ee) as a white solid. The enantiomeric excess
was determined by HPLC analysis.
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The Journal of Organic Chemistry
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(+)-30 : [α]D +77.7 (c 1.45, CHCl3) ; mp : 178ꢀ179 °C ; IR (neat) : 3469, 1739 cmꢀ1 ; HꢀNMR (400
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J = 7.6, 7.3 Hz, 3H), 2.12 (s, 3H), 1.09 (t, J = 7.3 Hz, 3H) ; CꢀNMR (100 MHz, CDCl3) δ : 168.9,
164.0, 158.0, 148.8, 111.9, 106.0, 94.5, 80.9, 72.1, 55.9, 55.8, 27.6, 10.9, 10.3 ; MS (EI) calculated for
C14H18O5 [M]+ : 266.1154, found 266.1136.
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(3S)-5,7-Dimethoxy-4-methyl-3-(1-oxopropyl)-phthalide (+)-10: To a solution of phthalide (+)-30
(54.6 mg, 0.205 mmol, 99% ee) in CH2Cl2 (0.38 mL) was added PhI(OAc)2 (78.7 mg, 0.244 mmol)
followed by 1ꢀMeꢀAZADO (7.80 mg, 0.0470 mmol) at 0 °C. After stirring for 5 h at rt, the reaction was
then diluted with Et2O (1 mL) and quenched with sat. Na2S2O3 (1 mL) at 0 °C. After stirring for 1 h, the
crude was extracted with EtOAc and the combined organic layers were washed with brine, dried over
MgSO4, and concentrated. Purification by column chromatography (EtOAc/Hexane 1/2) and then
recrystallization gave ketone (+)-10 (49.7 mg, 0.188 mmol, 92%, 99% ee) as a white solid. The
enantiomeric excess was determined by HPLC analysis.
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(+)-10 : [α]D +241 (c 0.66, CHCl3) ; mp : 130ꢀ131 °C ; IR (neat) : 1768, 1726 cmꢀ1 ; HꢀNMR (400
MHz, CDCl3) δ : 6.46 (s, 1H), 5.58 (s, 1H), 4.01 (s, 3H), 3.94 (s, 3H), 3.81 (s, 3H), 2.61 (dq, J = 18.8,
7.5 Hz, 1H), 2.19 (dq, J = 18.8, 7.1 Hz, 1H), 2.08 (s, 3H), 0.97 (m, 3H) ; 13CꢀNMR (100 MHz, CDCl3) δ
: 204.8, 168.2, 164.5, 158.4, 145.0, 114.0, 103.9, 95.2, 83.3, 56.1, 56.1, 29.5, 10.7, 7.1 ; MS (EI)
calculated for C14H16O5 [M]+ : 264.0998, found 264.0984.
(3R)-3-(1-Hydroxynonyl)-5,7-dimethoxy-4-methyl-3-propionylphthalide 31: To a solution of LDA
in THF (1.24 mL, 0.390 mmol) was added ketone (+)-10 (87.0 mg, 0.329 mmol) in THF at −78 °C.
After stirring for 30 min, nonanal (95.0 mg, 0.658 mmol) was added. After 2 h at −78 °C, the reaction
was quenched with sat. NH4Cl at 0 °C. The crude was extracted with EtOAc and the combined organic
layers were washed with brine, dried over MgSO4, and concentrated. Purification by column
chromatography (EtOAc/Hexane 1/2) gave aldol 31 (134 mg, 0.329 mmol, quant., mixture of
diastereomer) as a white solid.
31 : IR (neat) : 3464, 1759, 1725, 1614, 1597 cmꢀ1 ; 1HꢀNMR (400 MHz, CDCl3, major diastereomer) δ :
6.48 (s, 1H), 4.81 (dt, J = 9.6, 2.4 Hz, 1H), 4.02 (s, 3H), 3.95 (s, 3H), 2.69 (dq, J = 13.2, 5.6 Hz, 1H),
2.27 (dq, J = 13.2, 5.6 Hz, 1H), 2.16 (s, 3H), 2.04 (d, J = 9.6 Hz), 1.47ꢀ1.45 (m, 1H), 1.32ꢀ1.14 (m,
12H), 0.97 (t, J = 7.2 Hz, 3H), 0.84 (t, J = 6.4 Hz, 4H) ; 13CꢀNMR (100 MHz, CDCl3) δ : 208.7, 166.2,
164.8, 163.4, 160.6, 158.7, 158.1, 130.6, 121.9, 114.4, 100.0, 95.3, 83.1, 71.8, 71.5, 56.6, 56.2, 56.1,
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