Formal total synthesis of atropurpuran

Article abstract of DOI:10.1021/acs.joc.0c01462

Atropurpuran, isolated from the roots of Aconitum hemsleyanum, is a non-alkaloidal diterpene which possesses a unique pentacyclic skeleton that contains an unprecedented tetracyclo[5.3.3.04,9.04,12]tridecane unit. We report herein the formal total synthes

Full text of DOI:10.1021/acs.joc.0c01462

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Article
Formal Total Synthesis of Atropurpuran
Takahiro Suzuki, Takeshi Koyama, Kenta Nakanishi, Susumu Kobayashi, and Keiji Tanino
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.0c01462 • Publication Date (Web): 16 Jul 2020
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The Journal of Organic Chemistry
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Formal Total Synthesis of Atropurpuran
Takahiro Suzuki,*,† Takeshi Koyama,‡ Kenta Nakanishi,‡ Susumu Kobayashi,§ Keiji Tanino*,†
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†Department of Chemistry, Faculty of Science, Hokkaido University, Sapporo, 060-0810, Hokkaido, Japan
‡Graduate School of Chemical Sciences and Engineering, Hokkaido University, Sapporo, 060-0810, Hokkaido, Japan
§Faculty of Pharmaceutical Sciences, Tokyo University of Science, 2641 Yamazaki, Noda, Chiba 278-8510, Japan
E-mail: takahiro-suzuki@sci.hokudai.ac.jp (T. Suzuki); ktanino@sci.hokudai.ac.jp (K. Tanino)
ABSTRACT: Atropurpuran, isolated from the roots of Aconitum
hemsleyanum, is a non-alkaloidal diterpene which possesses a
unique pentacyclic skeleton that contains an unprecedented tet-
racyclo[5.3.3.04,9.04,12]tridecane unit. We report herein the for-
mal total synthesis of atropurpuran. The key features of our syn-
thetic route are a high diastereoselective construction of the tri-
and tetrasubstituted carbons (i.e., C4, C5, C10, C20) through an
Yb-catalyzed Mukaiyama aldol reaction in an aqueous medium and a one-pot operation including an intramolecular Diels-
Alder reaction/ring-closing metathesis to construct the unique pentacyclic skeleton of atropurpuran.
hydrocarbons.[11] Thus, we embarked on the synthetic study
of atropurpuran, focusing particularly on the construction
INTRODUCTION
of the dibarrelane skeleton, and we revealed that an intra-
molecular Diels-Alder (IMDA) reaction strategy using
masked o-benzoquinones (MOBs) is particularly effective in
the construction of this skeleton. Following our synthetic
study, many synthetic studies[12] and two total syntheses of
4 were reported. It should be noted that both total synthe-
ses, i.e., by Qin’s group[13] and Xu’s group,[14] adopted the in-
tramolecular Diels-Alder reaction strategy. Very recently
three total syntheses of arcutines have also been
achieved.[9,15,16] Thus, we herein report the total synthesis of
4 via a single-step construction of the pentacyclic skeleton
using the IMDA reaction of MOBs and a subsequent one-pot
operation.
The Aconitum and Delphinium plants, which have been
used as poisons and herbal medicines since ancient times,
are known as a rich source of C18, C19, and C20 diterpene
alkaloids.[1] These alkaloids have been well studied in terms
of their chemical syntheses and medicinal chemistry due to
their range of biological activities. However, the study of
non-alkaloidal diterpenes from the genera Aconitum[2] and
Delphinium has rarely been reported. The isolation of atise-
nol[3] (1) from A. heterophylllum was first reported in 1982,
and recently, after a lapse of many years, three diterpenes,
namely campylopin[4] (2), Guan Fu diterpenoid A[5] (3), and
atropurpuran[6] (4) were isolated (Figure 1). This led to de-
bate regarding the biogenesis of diterpene alkaloids, i.e.,
whether these diterpenes are biosynthetic intermediates or
degradation products of the corresponding diterpene alka-
loids.[7] Notably, atropurpuran possesses a novel pentacy-
clic skeleton, which is only present in three diterpene alka-
loids, namely arcutines[8] (5a–5c), isolated from A. arcua-
tum Maxim. The biosyntheses of 4 and 5a–5c has been pro-
posed to include a 1,2-shift of the C10–C20 bond of the he-
tidane skeleton to form the C5–C20 bond; recently, a bioin-
spired Wargner-Meerwein approach from hetidine to arcu-
tine was achieved by Li et al.[9] The resulting unprecedented
pentacyclic carbon skeleton of 4 and 5a–5c has also at-
tracted significant attention from synthetic chemists due to
its unique chemical structure. More specifically, the B–E
rings constitute the tetracyclo[5.3.3.04,9.04,12]tridecane skel-
eton, which includes two bicyclo[2.2.2]octane units. This
highly symmetrical (C2v) skeleton, the hydrocarbon (6) of
which was named “dibarrelane” by our group, had previ-
ously only been found in nature prior to our reported syn-
thesis.[10] Moreover, we proposed that 6 is an important
Figure 1. Atropurpuran and its related compounds (1-6)
component of
a
novel class of saturated cage-like
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the investigation of the IMDA/C-H functionalization strat-
egy was pretermitted.
RESULTS AND DISCUSSION
1
In our previous study,[10] the construction of atropurpu-
ran skeleton 9 from phenol 7 was demonstrated using two
strategies based on the IMDA reaction of MOBs (Scheme 1).
One was the IMDA reaction of tricyclic MOB 8, prepared by
the ring-closing metathesis (RCM) and an oxidative
dearomatization of phenol 7. The other was the IMDA reac-
tion of triallylated MOB 10 with a successive RCM. Applying
the former method to the total synthesis of 4, functional
groups are required at the C4 and C20 positions. Thus, tri-
cyclic MOB 11, which possesses dimethyl groups at the C4
carbon in addition to a C20-secondary alcohol, is a potent
IMDA precursor generating pentacyclic compound 12. Then,
a remote C-H functionalization directed by the hydroxyl
groups at C10 and/or C20 alcohols the exo-methylenation
at the C16 position converts pentacyclic compound 12 to
atropurpouran.
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Scheme 2. Initial Attempts to a remote C-H Functionali-
zation Strategy
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Scheme 1. Previous Strategies toward the Atropurpu-
ran skeleton
The sequential IMDA/RCM strategy (Scheme 3) was con-
sidered next. MOB 19, which possesses adjacent C4 and C5
quaternary carbons in addition to C20-secondary and C10-
tertiary alcohols, is a potent precursor for the IMDA/RCM
reaction. The key reaction should provide the pentacyclic
compound 20 in a highly regio- and diastereoselective man-
ner. Furthermore, MOB 19 could be prepared via three C-C
bond-forming reactions from tetralone 21, i.e., an aldol re-
action (C5–C20), the addition of a vinyllithium reagent (C1–
C10), and alkylation of the carbanion (C3–C4). These reac-
tions, however, are particularly challenging in terms of con-
trolling the diastereoselectivities and overcoming increas-
ing steric repulsions. Considering its reactivity and steric
advantage, the cyano group was selected as an electron
withdrawing group (EWG) at the C4 position.
Scheme 2 illustrates our initial attempts based on the
IMDA/C-H functionalization strategy. The tricyclic MOB 13
(see the Supporting Information) was successfully con-
verted using the IMDA reaction to afford pentacyclic 14. Re-
moval of the TES group and hydrogenation provided diol 15
as a precursor for the C-H functionalization. The X-ray crys-
tallographic analysis of diol 15 (see the Supporting Infor-
mation) indicated that both hydroxyl groups are located
within 3Å from the C19-carbon atom, enough to participate
in the remote functionalization. However, all attempts using
typical C-H functionalizations[17] (e.g. the Barton nitrite es-
ter reaction, I2/Pb(OAc)4, I2/PIDA, etc.) using diol 15 failed.
Notably, the Barton nitrile ester reaction produced only un-
desired C20 aldehydes as analyzable by-products, which
probably derived from an oxy-radical via a competitive C5–
C20 bond cleavage. The Barton reaction using the alcohols
18a-18d also resulted in the bond cleavage at C5–C20 and
C5–C10 to form the more stable tertiary C5 radicals than the
C19 primary radical. Transition metal-catalyzed C-H func-
tionalizations[18] of diol 15 did not result in any reaction or
failed to install the requisite directing groups. Therefore,
Scheme 3. IMDA/RCM Strategy toward Atropurpuran
Preparation of the MOB began with bromination of the
commercial 6-methoxy-1-tetralone[19] (22) and subsequent
Hartwig hydroxylation to give phenol 23, the synthesis of
which previously required six steps from ortho-eugenol as
reported in our previous study (Scheme 4). Following the
Bn protection of phenol 23 and a Mannich reaction of the
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resulting tetralone 24, treatment of the resulting mixture of
β-aminoketone and enone with MeI/KCN afforded nitrile
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8
Table 1. Mukaiyama Aldol Reaction with β-Substituted
α,β-Unsaturated Aldehydes
25.[20] After thorough investigation into the aldol reaction
between nitrile 25 and acrolein,[21] we found that a lantha-
noid-catalyzed Mukaiyama aldol reaction carried out in
aqueous media originally reported by Kobayashi[22] was op-
timal. According to Baran’s procedure in the total synthesis
of taxol,[23] the treatment of enol silyl ether 26 with 10
equivalents of acrolein and Yb(OTf)3 as a catalyst in tolu-
ene/EtOH/H2O for 3 days provided aldol adducts 27-anti
and 27-syn, although no selectivity was observed (27-
anti:27-syn = 1:1.3). Due to the substantial amount of im-
purities derived from acrolein, the purification of aldol
products 27-anti and 27-syn was not possible. Thus, Jones
oxidation of the mixture was carried out to obtain diketone
28 in 72% yield from 25, and Luche reduction of diketone
28 afforded 27-anti in 57% isolated yield as the major
product (27-anti:27-syn = 5.7:1). Due to not only the unsat-
isfactory diastereoselectivities[24] in the aldol reaction and
the Luche reduction, in addition to a discontinuation of sales
of acrolein as a reagent, we investigated the Mukaiyama al-
dol reaction using other α,β-unsaturated aldehydes that
could be easily transformed to 27-anti via an olefin metath-
esis reaction (Table 1). The Mukaiyama aldol reaction using
crotonaldehyde 29a under the same conditions essentially
reached completion within 1 h to give 30a in an improved
yield and diastereoselectivity (entry 1, 76% yield, dr =
9.9:1). The Mukaiyama aldol reaction was then repeated us-
ing bulkier aldehydes 29b–29e (entries 2–5); however, rel-
atively poor yields and/or selectivities were obtained. In-
deed, we were unable to provide a clear explanation for the
high diastereoselectivity of 30a. However, the fact that pro-
longation of the reaction time resulted in a decrease in the
diastereoselectivity suggested an unfavored retro-aldol/al-
dol process during the Mukaiyama aldol reaction. Notably,
this result could enable an enantioselective total synthesis
of 4 via a catalytic asymmetric Mukaiyama aldol reaction.
(see the Supporting Information)
9
entry
aldehydes
yield of 30a
dr
(anti:syn)
9.9:1
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(%)
76
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29a (R = Me)
29b (R = Ph)
29c (R = TMS)
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3.0:1
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3.1:1
29d (R =
29e (R =
)
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60b
70b
7.9:1
5.1:1
)
a Two-step yields from ketone 25, b NMR yield.
The alternative transformation from 25 to 27-anti on
gram-scale was subsequently achieved via a Mukaiyama al-
dol reaction and cross metathesis under an ethylene atmos-
phere in 72% yield (3 steps) and with a high diastereoselec-
tivity (Scheme 5). Following the TES protection of 27-anti,
an addition reaction of vinyl lithium to ketone 31 provided
tert-alcohol 32 in 63% yield as a single diastereomer via
conformer A. The deprotonation of 32 with LiNEt2 in THF at
−78 °C and allylation of the resulting α-cyanocarbanion af-
forded 33 in 90% yield and with a high diastereoselectivity,
which could be accounted for by the chelation control effect
via intermediate B.[25] Notably, the allylation using a dia-
stereomer of 32 (20-epi-32, prepared from 27-syn) under
the same conditions afforded a diastereomeric mixture (see
the Supporting Information). Iterative alkylation using 33
with iodomethane to construct the quaternary carbon cen-
ter at the C4 position would then be expected to provide the
desired product with the same stereochemistry of atropur-
puran. Although the methylation of 33 under the same con-
ditions as the allylation process gave no reaction, when
AlMe3 was employed to mask the hydroxy group, 33 under-
went alkylation and desilylation to afford diol 35 in a low
yield (~20%), along with a certain amount of cyclopropane
36 (0~72%). Due to the low yield and poor reproducibility,
methylation at the C4 position was postponed to the later
stages of the synthetic protocol. Removal of benzyl group of
33 with LDBB and oxidative dearomatization of the result-
ing phenol 37 with PhI(OAc)2 gave MOB 38.
Scheme 4. Synthesis of Aldol 27-antia
a
Reagents and conditions: a) 47% HBr aq, 30% H2O2 aq.,
H2O/AcOH, 54%; b) Pd2(dba)3, t-BuXPhos, 6M KOH aq., 1,4-di-
oxane, 80 °C, 61%; c) BnBr, K2CO3, DMF, 97%; d) HCHO aq.,
Me2NH2Cl, Ac2O, 95 °C; e) MeI, DMF, then KCN, NH4Cl, H2O,
95 °C, 88% (2 steps); f) TMSOTf, Et3N, CH2Cl2, 0 °C; g) acrolein,
Yb(OTf)3, toluene/EtOH/H2O; h) CrO3, acetone, 0 °C, 72% (3
steps); i) NaBH4, CeCl3•7H2O, MeOH/CH2Cl2, −78 °C, 57% for
27-anti, 10% for 27-syn.
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Scheme 5. Preparation of MOB 38a
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a Reagents and conditions: a) TMSOTf, Et3N, CH2Cl2, 0 °C; b) 29a, Yb(OTf)3, toluene/EtOH/H2O, 0 °C; c) Hoveyda-Grubbs 2nd gen-
eration catalyst, ethylene (balloon), toluene, 72%, dr = 10/1 (3 steps); d) TESCl, imidazole, DMAP, CH2Cl2/DMF, 0 °C to rt, 97%; e)
vinyl-Li, THF, −78 °C, 63%, 13% of recovered 31; f) LiNEt2, allyl iodide, THF, −78 °C, 90%; g) LiNEt2, HMPA, MeI, THF, -78 °C; h)
Me3Al, THF, 0 °C; then LiNEt2, HMPA, MeI, THF, -78 to 0 °C; i) LDBB, t-BuOH, THF, −78 °C, 81%; j) PhI(OAc)2, NaHCO3, CH2Cl2/MeOH,
0 °C, 96%. TES = triethylsilyl, DMAP = 4-dimethylaminopyridine, LDBB = lithium di-tert-butylbiphenyl.
With MOB 38 in hand, we moved on to investigate con-
struction of the atropurpuran skeleton (Scheme 6). Heating
at 180 °C in tert-butylbenzene, MOB 38 underwent a regi-
oselective IMDA reaction to give tetracyclic compound 39
as the sole product. Since this thermal Diels-Alder reaction
required no reagents, and the following two steps are both
catalytic reactions, we attempted to conduct the following
steps as a one-pot process. Thus, the Hoveyda-Grubbs 2nd
generation catalyst was added to the reaction mixture at
50 °C to construct the A-ring of atropurpuran. Following
completion of the RCM reaction, Pd(OH)2/C was added to
the mixture containing 40, and the atmosphere was re-
placed with hydrogen gas. Purification of the resulting mix-
ture provided pentacyclic compound 41 in 62% yield from
MOB 38. X-ray crystallographic structural analysis of com-
pound 41 (see the Supporting Information) confirmed that
all stereocenters were successfully generated in the previ-
ous steps of our synthesis. The subsequent reaction, namely
elimination of the tert-alcohol with SOCl2 and pyridine,
could be also included in this one-pot reaction, and as a re-
Scheme 6. One-pot Construction of Pentacyclic Skeleton
42a
a Reagents and conditions: i. t-BuPh, 180 °C, 1 h; ii. Hoveyda-
Grubbs 2nd generation catalyst, 50 °C, 2 h; iii. H2, Pd(OH)2/C,
THF, 2 h; iv, SOCl2, pyridine, 5.5 h, 56%.
sult
MOB
38
underwent
a
one-pot
IMDA/RCM/hydrogenation/elimination operation to yield
the atropurpuran skeleton 42 in 56% yield (average, 87%
yield). It is noted that this one-pot transformation reformed
all five C-C double bonds of 38 to three 6-membered rings,
with the construction of three C-C bonds and four stereo-
centers.
We then proceeded to the final stage of the formal total
synthesis of 4 (Scheme 7). Initially, the keto acetal moiety at
the C15 and C16 positions of 42 was converted to allyl ace-
tate 44 over 3 steps. Reduction of C15 ketone with NaBH4
proceeded from the α-face to give an alcohol with the unde-
sired stereochemistry (α:β = 8.5:1). One-pot acetal hydroly-
sis[26]/acetylation and
a
subsequent Wittig exo-
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methylenation of ketone 43 provided acetate 44. DIBAL re- The aforementioned conditions for the methylation of 48
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4
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duction of the nitrile group of 44 also took place upon re-
moval of the acetyl group, and so alcohol 45 was protected
with the p-NO2Bz group[27] to afford aldehyde 46. Removal
of the TES group and subsequent Dess-Martin oxidation af-
forded keto aldehyde 48 in 57% yield (2 steps). According
to Qin’s synthesis,[13] α-methylation of the aldehyde was
achieved by treating 48 with t-BuOK and iodomethane in t-
BuOH, and a sequential acidic saponification gave 15-epi-
atropurpuran 49. We found that using t-BuOH/CH2Cl2 (2:1)
as a solvent at 0 °C slightly increased the yield and diastere-
oselectivity of 49 (54%, dr = 8:1). All spectral data of 49
were identical to those reported for Qin’s intermediate.
(in t-BuOH/CH2Cl2 at 0 °C) gave the desired 52 (39%, 43%
based on recovered 51 and 4-epi-51) and 4-epi-52 (10%).
Scheme 8. Formal Total Synthesis of Atropurpuran via
Xu’s intermediatea
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Scheme 7. Formal Total Synthesis of Atropurpuran via
Qin’s intermediatea
a
Reagents and conditions: a) DIBAL, CH2Cl2, −78 °C to rt,
97%; b) HF•pyridine, THF, 0 °C to rt, 94%; c) Dess-Martin peri-
odinane, NaHCO3, CH2Cl2, 0 °C to rt, 50%; d) t-BuOK, MeI, t-
BuOH/CH2Cl2, 0 °C, 39%.
In conclusion, we achieved the formal total synthesis of atro-
purpuran based on an IMDA reaction (overall 0.36% yield, 21-
step longest linear sequence from commercial tetralone 22).
This synthetic route features the successive construction of the
C4, C5, C10, and C20 stereocenters of Diels-Alder precursor 27
in a highly diastereoselective manner, based on the use of an
Yb-catalyzed Mukaiyama aldol reaction (C5 and C20), the addi-
tion of vinyllithium (C10), and allylation of the α-cyanocarban-
ion (C4). In addition, it features a one-pot transformation from
38 to 42, which provided a simple solution to construction of
the atropurpuran skeleton. Moreover, the Mukaiyama aldol re-
action using crotonaldehyde not only avoided the use of acro-
lein, but also paved the way for the enantioselective total syn-
thesis of atropurpuran, of which studies are currently under-
way in our group.
a Reagents and conditions: a) NaBH4, MeOH, −78 to −45 °C,
dr = 8.5:1; b) LiBF4, wet MeCN; then Ac2O, pyridine, DMAP, 0 °C,
62% (2 steps); c) Ph3PCH3Br, t-BuOK, THF, 0 °C to rt, 66%; d)
DIBAL, CH2Cl2, −78 °C to rt, 79%; e) p-NO2BzCl, pyridine, DMAP,
CH2Cl2, 0 °C, 86%; f) HF• pyridine, THF, 0 °C to rt, 78%; g) Dess-
Martin periodinane, H2O, CH2Cl2, 0 °C to rt, 73%; h) t-BuOK, MeI,
t-BuOH/CH2Cl2, 0 °C; then 1M HCl, 54% (dr = 8:1). DIBAL =
diisobutylaluminum hydride.
EXPERIMENTAL SECTION
General Information and Reagents. Infrared spectra were
recorded on a JASCO FT-IR 4100 spectrometer with an ATR
unit. Absorbance frequencies are recorded in reciprocal centi-
meters (cm-1). High-resolution mass spectra (HRMS) were ob-
tained from a Thermo Scientific Exactive for electrospray ioni-
zation (ESI). HRMS data are reported as m/e (relative inten-
sity), with accurate mass reported for the molecular ion
[M+Na]+, [M+H]+. 1H and 13C NMR spectra were recorded on a
JEOL ECA-500 spectrometer operating at either 500 MHz (1H
NMR) or 125 MHz (13C NMR) in CDCl3 as a solvent. Chemical
shifts for NMR were reported in ppm relative to the chemical
sift of the residual solvent (1H NMR, 7.26 ppm for CDCl3, 13C
NMR, 77.0 ppm for CDCl3. Multiplicities are indicated as; br
(broad), s (singlet), d (doublet), t (triplet), q (quartet), or m
(multiplet). Coupling constants (J) are reported in Hertz (Hz).
All reactions sensitive to oxygen or moisture were performed
under an atmosphere of dry argon in flame-dried glassware.
Reaction mixtures at elevated temperatures were heated in an
oil bath unless otherwise noted. Et3N, 2,6-lutidine, i-Pr2NEt,
and pyridine were distilled from CaH2 and stored over KOH.
Dry THF, CH2Cl2, DMF, EtOH, and toluene was purchased from
KANTO Chemical Industries Ltd. in anhydrous Grade. Chemical
During the development of our synthetic route, Xu and
colleagues reported the total synthesis of 4[14] via an IMDA
reaction using MOB prepared from 1-tetralone. They re-
vealed that intermediate 52 is a desirable precursor for 4
using a 3-step transformation. We therefore focused on the
transformation of 42 to 52 (Scheme 8). Thus, the DIBAL re-
duction of nitrile and ketone moieties of 42 gave aldehyde
50 in 97% yield. Removal of the TES group and subsequent
Dess-Martin oxidation of the resulting diol afforded ketoal-
dehyde 51. All spectral data of 51 were found to be identical
to those of Xu’s intermediate, originally reported as 4-epi-
51.[28] X-ray crystallographic analysis of our synthetic 51
(see the Supporting Information) confirmed the stereo-
chemistry of C4 to be β-CHO. According to Xu’s report, ke-
toaldehyde 51 was treated with MeI and t-BuOK in t-BuOH
to give Xu’s intermediate 52 and 4-epi-52 (33 and 12%, re-
spectively), along with recovered 51 and 4-epi-51 (28 %).
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Page 6 of 12
reagents were commercial grades and were used without any
with EtOAc and the organic layer dried over MgSO4, filtrated
1
2
3
4
5
6
7
8
purification unless otherwise noted. The aldehydes ((E)-3-(tri-
methylsilyl)propenal[29] (29c), (2E)-4-(2-propen-1-yloxy)-2-
butenal[30] (29d), diethyl 2-allyl-2-[(2E)-4-oxobut-2-enyl]ma-
lonate[31] (29e)) were prepared by the known procedures indi-
vidually. Flash chromatography was performed with Silica Gel
60N (spherical, neutral), purchased from KANTO Chemical In-
dustries Ltd, unless otherwise noted. Analytical thin layer chro-
matography (TLC) was performed using commercial silica gel
plates (E. Merck, Silica Gel 60 F254).
and concentrated under reduced pressure. The resulting resi-
due was purified by silica gel column chromatography (n-hex-
ane: EtOAc = 3:1) to afford 25 (3.37 g 88% yield) as a yellow
solid. Mp: 102-103 °C (recrystallized from EtOAc/n-hexane); Rf
0.26 (n-hexane: EtOAc = 2:1 v/v); 1H-NMR (CDCl3, 500 MHz) δ:
7.86 (1H, d, J = 8.6 Hz), 7.41-7.36 (5H, m), 6.93 (1H, d, J = 8.6
Hz), 5.03 (1H, d, J = 11.5 Hz), 5.00 (1H, d, J = 11.5 Hz), 3.97 (3H,
s), 3.19 (1H, dt, J = 17.2, 2.9 Hz), 3.00 (1H, dd, J = 17.2, 4.6 Hz),
2.73-2.70 (1H, m), 2.64-2.53 (2H, m), 2.38 (1H, ddd, J = 13.2, 7.5,
4.6 Hz), 1.82 (1H, ddd, J = 26.1, 13.2, 4.0 Hz); 13C{1H} NMR
(CDCl3, 125 MHz) δ: 194.6, 157.0, 143.7, 138.1, 137.0, 128.25,
128.19, 128.0, 125.1, 124.7, 118.5, 110.3, 74.3, 55.7, 43.5, 27.9,
22.9, 18.1; IR (ATR) νmax 2945, 2885, 1669, 1588, 1277, 1073,
995, 751, 698 cm-1; HRMS (m/z): calcd. for C20H19O3NNa+
[M+Na]+, 344.1257; found, 344.1258.
9
5-Benzyloxy-6-methoxy-1-tetralone 24. To a suspension of 6-
methoxytetralone 22 (50.0 g, 284 mmol) in AcOH (50 mL) and
H2O (150 mL) was added 47% HBr aqueous solution (36 mL,
312 mmol) and the mixture was stirred vigorously at room
temperature. To the mixture was added 30% H2O2 aqueous so-
lution (57 mL, 568 mmol) dropwise using a dropping funnel
over 1 h, and the reaction was stirred for overnight. After com-
pletion of the reaction, the mixture was poured into an ice-wa-
ter (800 mL) and the resulting precipitation was filtered, rinsed
with water, and dried in vacuo. The crude product (including
2,5-dibromo-6-methoxytetralone) was recrystallized from i-
PrOH/H2O to afford 5-bromo-6-methoxy-1-tetralone (38.8 g,
54%) as a white solid. The spectral data were identical to those
reported.20 To a solution of 5-bromo-6-methoxy-1-tetralone
(26.0 g, 102 mmol) in 1,4-dioxane (260 mL) were added 6M
KOH aqueous solution (78 mL, 510 mmol), Pd2(dba)3•CHCl3
(528 mg, 0.510 mmol), and tBuXPhos (434 mg, 1.02 mmol) at
room temperature. The mixture was stirred at 80 °C for 14 h.
After completion of the reaction, the mixture was acidified with
1M HCl aqueous solution. After removal of 1,4-dioxane by ro-
tary evaporator, the mixture was extracted with CH2Cl2 by
three times. The combined organic layers were dried with
MgSO4, filtered and concentrated in vacuo. The residue was pu-
rified by silica gel column chromatography (n-hexane: EtOAc =
10:1 to 2:1) to afford 23 (11.9 g, 61%) as an off-white solid. To
a solution of 23 (9.01 g, 46.9 mmol) in DMF (47 ml) were added
K2CO3 (12.9 g, 93.3 mmol, 2.0 eq.), and BnBr (8.40 ml, 70.6
mmol, 1.5 eq.), and the mixture was stirred for 3 h at room tem-
perature. The reaction mixture was quenched with a saturated
NH4Cl aqueous solution and extracted with ether. The com-
bined organic layer was washed with brine, dried over Na2SO4,
filtered and concentrated in vacuo. The residue was purified by
flash column chromatography (n-hexane/EtOAc = 4/1) to af-
ford 24 (12.9 g, 97%) as a yellow solid. The spectral data of 23
and 24 were identical to those reported in our previous
study.10
10
11
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13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Diketone 28. To a solution of 25 (10.834 g, 33.7 mmol) in CH2Cl2
(55 mL) were added Et3N (19.7 mL, 142 mmol, 4.2 eq.) and
TMSOTf (12.8 mL, 70.8 mmol, 2.1 eq.) at 0 °C. After stirring for
2 h at 0 °C, the reaction mixture was quenched with saturated
NH4Cl solution and extracted with hexane. The combined or-
ganic layer was dried over Na2SO4, filtered and concentrated
under reduced pressure to afford silyl enol ether 26 including
di-TMS compound. To the crude mixture were added toluene
(52.7 mL), acrolein (22.4 mL, 337 mmol, 10 eq.) and Yb(OTf)3
(2.09 g, 3.37 mmol, 0.1 eq.) in EtOH/H2O (131 mL/13.1 mL) at
room temperature. After stirring for 3 days, the mixture was
diluted with H2O, concentrated under reduced pressure to re-
move EtOH and acrolein, and extracted with ether. The com-
bined organic layer was dried over Na2SO4, filtered and concen-
trated under reduced pressure. The crude mixture of 27-anti
and 27-syn including impurity derived from acrolein was used
for the next step without further purification. To a solution of
the crude mixture of 27-anti and 27-syn in acetone (300 mL)
was added Jones reagent (excess) at 0 °C until the color of mix-
ture turned to red. After stirring 30 min, the reaction mixture
was quenched with i-PrOH, filtered over Celite, extracted with
ether. The combined organic layers were dried over MgSO4, fil-
tered and concentrated under reduced pressure. The resulting
residue was purified by silica gel column chromatography (n-
hexane: EtOAc = 3:1), additionally purified by silica gel column
chromatography (toluene: EtOAc = 9:1) to afford diketone 28
(9.179 g, 72% yield) as colorless oil. Rf 0.48 (n-hexane: EtOAc =
1:1 v/v); 1H-NMR (CDCl3, 500 MHz) δ: 7.92 (1H, d, J = 8.6 Hz),
7.39-7.33 (5H, m ), 6.97 (1H, d, J = 8.6 Hz), 6.51-6.39 (2H, m),
5.70 (1H, dd, J = 9.7, 2.3 Hz), 5.03 (1H, d, J = 11.5 Hz), 4.99 (1H,
d, J = 11.5 Hz), 3.98 (3H, s), 2.92-2.77 (4H, m), 2.59 (1H, ddd, J
= 13.8, 5.2, 5.2 Hz), 2.17-2.12 (1H, ddd, J = 14.9, 9.8, 5.2 Hz);
13C{1H} NMR (CDCl3, 125 MHz) δ: 193.7, 192.9, 157.5, 143.4,
137.4, 136.7, 131.3, 130.1, 128.11, 128.09, 127.9, 125.4, 124.5,
116.4, 110.6, 74.0, 58.8, 55.6, 29.2, 21.8, 19.5; IR (ATR) νmax
2941, 2248, 1697, 1667, 1586, 1281, 1216, 1074, 912, 821, 733,
700 cm-1; HRMS (m/z): calcd. for C23H21O4NNa+ [M+Na]+,
398.1363; found, 398.1372.
Ketonitrile 25. To a solution of HNMe2•HCl (1.53 g, 18.7 mmol,
1.58 eq.) in HCHO aq. (1.41 mL, 19.0 mmol, 1.6 eq.) was added
Ac2O (17 mL) at room temperature. After stirring for 1 h, 24
(3.35 g, 11.9 mmol) was added into the reaction mixture in one
portion. The mixture was heated to 95 °C and stirred for 30 min.
After cooling to room temperature, the mixture was basified
with 2 M NaOH aqueous solution. The resulting mixture was
extracted with EtOAc. The combined organic layers were dried
over MgSO4, filtered and concentrated under reduced pressure.
To the crude mixture (including β-aminoketone and enone)
were added DMF (17 mL) and MeI (2.22 mL, 35.7 mmol, 3.0 eq.)
at room temperature, the mixture was stirred for 17 h. After
removal of remained MeI under reduced pressure, H2O (8.5
mL), NH4Cl (0.763 g, 14.3 mmol, 1.2 eq.), and KCN (1.16 g, 17.9
mmol, 1.5 eq.) were added to the mixture. After stirring for 1 h
at 95 °C, additional KCN (1.16 g, 17.9 mmol, 1.5 eq.) was added
and the mixture was stirred for 1 h. After cooling to room tem-
perature, the reaction mixture was diluted with H2O, extracted
Aldol 27-anti and 27-syn. To a solution of 28 (0.7639 g, 2.03
mmol) and CeCl3•7H2O (1.13 g, 3.05 mmol, 1.5 eq.) in MeOH
(10.1 mL) and THF (10.1 mL) was added NaBH4 (19.2 mg, 0.508
mmol, 0.25 eq.) at –78 °C, and the reaction mixture was stirred
for 30 min at the same temperature. Another NaBH4 (20.0 mg,
0.529 mmol, 0.25 eq.) was added to the mixture and the mix-
ture was stirred for 60 min. Again, another NaBH4 (20.0 mg,
0.529 mmol, 0.25 eq.) was added to the mixture and the mix-
ture was stirred for 90 min. The reaction mixture was
quenched with acetone and saturated NH4Cl aqueous solution,
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The Journal of Organic Chemistry
and MeOH was removed by rotary evaporator. The residue was
HRMS (m/z): calcd. for C24H25O4NNa+ [M+Na]+, 414.1676;
found, 414.1676.
1
2
3
4
5
6
7
8
diluted with H2O, extracted with ether. The combined organic
layer was dried over Na2SO4, filtered and concentrated under
reduced pressure. The resulting residue was purified by silica
gel column chromatography (n-hexane: EtOAc = 3:1), to afford
27-anti (437 mg, 57% yield) as colorless oil and 27-syn (76.6
mg, 10% yield) as colorless oil.
30a-syn: Rf 0.33 (n-hexane:EtOAc = 2:1 v/v); 1HNMR (CDCl3,
500 MHz) δ: 8.37 (1H, d, J = 8.6 Hz), 7.38-7.36 (5H, m), 6.95 (1H,
d, J = 8.6 Hz), 5.70 (1H, dq, J = 14.9, 6.3 Hz), 5.40 (1H, dd, J = 15.5,
7.5 Hz), 5.04 (1H, d, J = 10.9 Hz), 5.02 (1H, d, J = 10.9 Hz), 4.18
(1H, dd, J = 7.4, 7.4 Hz), 3.98 (3H, s), 2.96 (1H, dt, J = 18.3, 5.8
Hz), 2.79 (2H, m), 2.66 (1H, dq, J = 9.4, 8.6, 5.2 Hz), 2.41 (1H, d,
J = 16.6 Hz), 2.01 (1H, m), 2.00 (1H, m), 1.68 (3H, d, J = 6.3 Hz);
13C{1H} NMR (CDCl3, 125 MHz) δ: 198.1, 157.6, 143.7, 137.9,
137.1, 131.0, 128.6, 128.5, 128.3, 128.2, 125.6, 125.0, 117.3,
110.7, 74.8, 74.5, 56.0, 49.7, 28.0, 20.3, 19.5, 17.8; IR (ATR) νmax
3475, 2979, 2946, 2360, 1672, 1589, 1490, 1455, 1283, 1216,
1075, 1008, 968, 919, 824, 752, 700 cm-1; HRMS (m/z): calcd.
for C24H25O4NNa+ [M+Na]+, 414.1676; found, 414.1673.
1
27-anti: Rf 0.44 (n-hexane: EtOAc = 1:1 v/v); H-NMR (CDCl3,
500 MHz) δ: 7.89 (1H, d, J = 8.6 Hz), 7.37-7.35 (5H, m), 6.97 (1H,
d, J = 9.2 Hz), 5.88 (1H, ddd, J = 16.6, 10.3, 6.3 Hz), 5.40 (1H, d, J
= 16.6 Hz), 5.37 (1H, d, J = 10.3 Hz), 5.07 (1H, d, J = 10.9 Hz),
5.01 (1H, d, J = 11.5 Hz), 4.41 (1H, d, J = 6.3 Hz), 3.99 (3H, s),
2.89 (1H, d, J = 17.2 Hz), 2.85-2.70 (2H, m), 2.60 (1H, s), 2.54
(1H, d, J = 17.2 Hz), 2.22-2.18 (1H, m), 2.07-2.02 (1H, m);
13C{1H} NMR (CDCl3, 125 MHz) δ: 197.5, 157.4, 143.5, 137.5,
137.0, 134.1, 128.5, 128.4, 128.3, 126.0, 124.3, 119.1, 118.0,
110.8, 74.4, 73.3, 55.9, 49.6, 28.6, 19.2, 19.1; IR (ATR) νmax 3466,
2940, 2251, 1673, 1588, 1490, 1455, 1442, 1281, 1216, 1074,
999, 821, 750, 700 cm-1; HRMS (m/z): calcd. for C23H23O4NNa+
[M+Na]+, 400.1519; found, 400.1520.
9
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12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Alternative route to 27-anti via 30a. To a solution of 25 (3.03 g,
9.34 mmol) in CH2Cl2 (18.9 mL) were added Et3N (5.18 mL,
37.4 mmol, 4.0 eq.) and TMSOTf (3.38 mL, 18.7 mmol, 2.0 eq.)
at 0 °C. After stirring for 2 h at 0 °C, the reaction mixture was
quenched with saturated NH4Cl solution and extracted with
hexane. The combined organic layer was dried over Na2SO4, fil-
tered and concentrated under reduced pressure. To crude mix-
ture of 26 and di-TMS compound were added toluene (15.1
mL), Yb(OTf)3 (0.58 g, 0.93 mmol, 0.1 eq.) in EtOH/H2O (37.4
mL/3.74 mL) at room temperature. After stirring for 2 h, 1H-
NMR confirmed that the mixture of 26 and di-TMS compound
was converged on 26. Crotonaldehyde 29a (2.31 mL, 28.0
mmol, 3.0 eq.) was added to the reaction mixture at 0 °C. After
stirring for 4 h at 0 °C, another Yb(OTf)3 (0.58 g, 0.93 mmol, 0.1
eq.) was added. After stirring for 5 h at 0 °C, another Yb(OTf)3
(0.58 g, 0.93 mmol, 0.1 eq.) was added. After stirring for 12 h at
0 °C, the mixture was diluted with H2O, concentrated under re-
duced pressure to remove EtOH, extracted with ether. The
combined organic layers were dried over Na2SO4, filtered and
concentrated under reduced pressure. The crude 30a was used
for the next step without further purification. To a solution of
crude 30a in toluene (93 mL) was added Hoveyda-Grubbs 2nd
generation catalyst (293 mg, 0.467 mmol, 0.1 eq.) under an ar-
gon atmosphere. The argon gas was purged with ethylene gas,
and the mixture was stirred under an ethylene atmosphere. Af-
ter stirring for 1.5 h, the ethylene was purged with argon and
the crude mixture was directly purified by silica gel column
chromatography (n-hexane: EtOAc = 1:0 to 3:1) to afford 27-
anti (2.55 g, 72% yield (3 steps from 25)).
27-syn: Rf 0.39 (n-hexane: EtOAc = 1:1 v/v); 1H-NMR (CDCl3,
500 MHz) δ: 7.84 (1H, d, J = 8.6 Hz), 7.38-7.36 (5H, m), 6.95 (1H,
d, J = 8.6 Hz), 5.76 (1H, ddd, J = 17.2, 10.9, 6.9 Hz), 5.29 (1H, d, J
= 17.2 Hz), 5.26 (1H, d, J = 10.9 Hz), 5.05 (1H, d, J = 10.9 Hz),
5.18 (1H, d, J = 11.5 Hz), 4.23 (1H, t, J = 6.9 Hz), 3.98 (3H, s), 2.94
(1H, dt, J = 18.3, 7.5 Hz), 2.81 (1H, d, J = 7.5 Hz), 2.80 (1H, d, J =
16.6 Hz), 2.70 (1H, ddd, J = 17.0, 8.0, 5.2 Hz), 2.59 (1H, d, J = 16.6
Hz), 2.25 (1H, ddd, J = 13.2, 8.0, 5.2 Hz), 2.06-2.01 (1H, m);
13C{1H} NMR (CDCl3, 125 MHz) δ: 196.9, 157.2, 143.4, 137.5,
136.8, 135.0, 128.2, 128.1, 128.0, 125.3, 124.8, 117.9, 117.6,
110.5, 74.1, 72.3, 55.7, 50.2, 27.7, 19.6, 19.2; IR (ATR) νmax 2944,
2360, 1671, 1588, 1489, 1281, 1075, 909, 728 cm-1; HRMS
(m/z): calcd. for C23H23O4NNa+ [M+Na]+, 400.1519; found,
400.1522.
General procedure for Table 1. The same procedure for enol
etherification of 25 (64.2 mg, 0.20 mmol) provided a mixture
of 26 and di-TMS compound. To a solution of the mixture in tol-
uene (0.32 mL), were added Yb(OTf)3 (12.4 mg, 0.020 mmol,
0.1 eq.) in EtOH/H2O (0.8 mL/0.08 mL) at room temperature.
After stirring for 2 h, 1H-NMR confirmed that the mixture of 26
and di-TMS compound was converged on 26. Then, the corre-
sponding aldehyde 29a-29e (3.0 eq.) was added to the reaction
mixture. After stirring for 1 h at room temperature, the mixture
was diluted with H2O, extracted with ether. The combined or-
ganic layer was dried over Na2SO4, filtered, and concentrated
under reduced pressure. The resulting residue was purified by
silica gel column chromatography to afford a diastereomeric
mixture of aldol 30b-30e. The analytic sample of 30a and its
diastereomer 30a-syn was obtained by a silica gel column
chromatography (n-hexane: EtOAc = 5:1).
Triethylsilyl ether 31. To a solution of 27-anti (2.55 g, 6.75
mmol), imidazole (1.10 g, 16.2 mmol, 2.4 eq.) and DMAP (0.105
g, 0.675 mmol, 0.1 eq.) in CH2Cl2 (61 mL) and DMF (6.1 mL) was
added TESCl (1.36 mL, 8.10 mmol, 1.2eq.) at 0 °C. After stirring
1 h at room temperature, the reaction mixture was quenched
with MeOH (7.6 mL) and saturated NH4Cl solution, extracted
with n-hexane. The combined organic layers were dried over
MgSO4, filtered and concentrated under reduced pressure. The
resulting residue was purified by silica gel column chromatog-
raphy (n-hexane: EtOAc = 8:1), to afford 31 (3.22 g, 97% yield)
1
30a: Rf 0.26 (n-hexane: EtOAc = 3:2 v/v); HNMR (CDCl3, 500
MHz) δ: 7.89 (1H, d, J = 8.6 Hz), 7.38-7.36 (5H, m), 6.96 (1H, d,
J = 8.6 Hz), 5.80 (1H, dq, J = 14.9, 6.9 Hz), 5.52 (1H, dd, J = 16.0,
6.9 Hz), 5.07 (1H, d, J = 10.9 Hz), 5.00 (1H, d, J = 10.9 Hz), 4.33
(1H, dd, J = 7.5 Hz), 3.98 (3H, s), 2.89 (1H, d, J = 17.2 Hz), 2.84-
2.70 (2H, m), 2.55 (1H, d, J = 17.2 Hz), 2.50 (1H, d, J = 2.3 Hz),
2.19-2.15 (1H, m), 2.05-2.00 (1H, m), 1.75 (3H, d, J = 6.3 Hz);
13C{1H} NMR (CDCl3, 125 MHz) δ: 197.9, 157.5, 143.6, 137.7,
137.1, 131.3, 128.6, 128.5, 128.3, 127.0, 126.0, 124.4, 118.1,
110.8, 74.5, 73.5, 55.9, 49.7, 29.1, 19.3, 19.1, 17.9; IR (ATR) νmax
3475, 2940, 1676, 1589, 1490, 1455, 1283, 1075, 970 cm-1;
1
as colorless oil. Rf 0.54 (n-hexane: EtOAc = 2:1 v/v); H-NMR
(CDCl3, 500 MHz) δ: 7.83 (1H, d, J = 8.6 Hz), 7.40-7.34 (5H, m),
6.95 (1H, d, J = 8.6 Hz), 5.81-5.74 (1H, m), 5.24 (2H, m), 5.12
(1H, d, J = 10.9 Hz), 4.98 (1H, d, J = 10.9 Hz), 4.37 (1H, d, J = 6.9
Hz), 3.97 (3H, s), 3.05 (1H, d, J = 16.6 Hz), 2.86 (1H, ddd, J = 9.2,
5.8, 3.5 Hz), 2.63 (1H, ddd, J = 17.8, 11.5, 5.7 Hz), 2.41 (1H, d, J
= 17.2 Hz), 2.14 (1H, ddd, J = 14.3, 12.0, 5.7 Hz), 2.06 (1H, ddd,
J = 14.3, 5.2, 3.5 Hz), 0.79 (9H, t, J = 8.0 Hz), 0.37 (6H, dq, J = 7.5,
2.3 Hz); 13C{1H} NMR (CDCl3, 125 MHz) δ: 195.4, 156.8, 143.4,
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The Journal of Organic Chemistry
Page 8 of 12
137.2, 136.9, 135.7, 128.7, 128.4, 128.3, 125.6, 125.1, 118.7,
organic layer was dried over MgSO4, filtered and concentrated
1
2
3
4
5
6
7
8
118.4, 110.6, 74.3, 73.9, 55.9, 51.2, 28.4, 19.7, 19.6, 6.6, 4.6; IR
(ATR) νmax 2952, 2911, 2875, 1681, 1590, 1489, 1281, 1076 cm-
1; HRMS (m/z): calcd. for C29H37O4NNaSi+ [M+Na]+, 514.2380
found, 514.2384.
under reduced pressure. The resulting residue was purified by
silica gel column chromatography (n-hexane: EtOAc = 6:1), to
afford 37 (1.23 g, 81% yield) as colorless oil. Rf 0.45 (n-hexane:
EtOAc = 2:1 v/v); 1H-NMR (CDCl3, 500 MHz) δ: 7.18 (1H, d, J =
8.6 Hz), 6.80 (1H, d, J = 8.6 Hz), 6.12 (1H, dd, J = 16.6, 10.3 Hz),
5.99 (1H, ddd, J = 17.8, 8.6, 8.6 Hz), 5.93-5.85 (1H, m), 5.71 (1H,
s), 5.53 (1H, s), 5.34-5.14 (6H, m), 4.55 (1H, d, J = 8.6 Hz), 3.87
(3H, s), 2.97 (1H, dd, J = 10.3, 5.7 Hz), 2.89-2.70 (4H, m), 2.20
(1H, ddd, J = 14.4, 9.7, 9.2 Hz), 1.73 (1H, dd, J = 14.4, 8.1 Hz),
0.76 (9H, t, J = 8.0 Hz), 0.45-0.36 (6H, m); 13C{1H} NMR (CDCl3,
125 MHz) δ: 144.6, 141.8, 141.5, 136.5, 135.5, 135.0, 121.4,
119.9, 119.2, 117.7, 116.8, 114.9, 109.1, 80.0, 78.9, 56.0, 45.5,
35.7, 33.7, 26.3, 19.2, 6.2, 4.6; IR (ATR) νmax 3427, 2954, 2911,
2877, 2235, 1490, 1460, 1441, 1414, 1335, 1280, 1239, 1173,
1083, 1048, 1001, 927, 857, 806, 729 cm-1; HRMS (m/z): calcd.
for C27H39O4NNaSi+ [M+Na]+, 492.2541; found, 492.2544.
Tert-alcohol 32. To a solution of n-BuLi in hexane (3.0 mL, 8.2
mmol, 2.5 eq.) was added tetravinyltin (595 μL, 3.28 mmol, 1.0
eq.) at room temperature. A white solid precipitated immedi-
ately. The suspension was stirred for 30 min at room tempera-
ture. After cooling to –78 °C, a solution of ketone 31 (1.62 g,
3.28 mmol) in THF (36 mL) was added to the reaction mixture.
The reaction mixture was stirred for 25 min at the same tem-
perature. The reaction mixture was quenched with AcOH in
THF, neutralized with saturated NaHCO3 solution, and ex-
tracted with EtOAc. The combined organic layers were dried
over MgSO4, filtered and concentrated under reduced pressure.
The resulting residue was purified by silica gel column chroma-
tography (n-hexane: EtOAc = 1:0 to 8:1), to afford 32 (1.08 g,
63% yield) as colorless oil and recovered 31 (0.213 g, 13%). Rf
0.23 (n-hexane: EtOAc = 4:1 v/v); 1H-NMR (CDCl3, 500 MHz) δ:
7.45-7.30 (6H, m), 6.86 (1H, d, J = 8.6 Hz), 6.02 (1H, ddd, J = 16.9,
9.8, 9.8 Hz), 5.86 (1H, dd, J = 16.6, 10.3 Hz), 5.30-5.24 (3H, m),
5.15 (1H, dd, J = 10.3, 1.7 Hz), 5.12-5.07 (2H, m), 4.98 (1H, d, J =
11.5 Hz), 4.31 (1H, d, J = 9.2 Hz), 3.90 (3H, s), 2.86 (1H, d, J =
17.8 Hz), 2.75-2.61 (3H, m), 1.97-1.83 (2H, m), 0.79 (9H, t, J =
8.0 Hz), 0.52-0.38 (6H, m); 13C{1H} NMR (CDCl3, 125 MHz) δ:
151.2, 144.2, 141.1, 137.7, 136.0, 134.2, 128.6, 128.4, 128.3,
128.0, 121.6, 119.6, 119.3, 115.4, 110.7, 79.2, 79.0, 73.9, 55.7,
43.3, 26.2, 19.3, 17.7, 6.4, 4.9; IR (ATR) νmax 3434, 2956, 2912,
2876, 1487, 1455, 1415, 1278, 1083, 1003 cm-1; HRMS (m/z):
calcd. for C31H41O4NNaSi+ [M+Na]+, 542.2697; found, 542.2694.
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MOB 38. To a solution of 37 (0.648 g, 1.38 mmol) and NaHCO3
(0.353 g, 4.20 mmol, 3.0 eq.) in CH2Cl2 (7.0 mL) and MeOH (7.0
mL) was added PhI(OAc)2 (0.496 g, 1.54 mmol, 1.1 eq.) at 0 °C.
After stirring 15 min at room temperature, the reaction mix-
ture was quenched with saturated NaHCO3 solution and ex-
tracted with ether. The combined organic layers were dried
over MgSO4, filtered and concentrated under reduced pressure.
The residue was purified by silica gel column chromatography
(n-hexane: EtOAc = 1:0 to 6:1) to afford 38 (0.660 g, 96% yield)
as yellow oil. Rf 0.45 (n-hexane: EtOAc = 2:1 v/v); 1H-NMR
(CDCl3,500 MHz) δ: 6.61 (1H, d, J = 10.3 Hz), 6.26 (1H, d, J = 10.3
Hz), 5.95-5.75 (4H, m), 5.63 (1H, d, J = 16.0 Hz), 5.38-5.33 (2H,
m), 5.28 (1H, d, J = 17.2 Hz), 5.16-5.10 (2H, m), 4.56 (1H, d, J =
8.6 Hz), 3.34 (3H, s), 3.33 (3H, s), 2.82-2.72 (3H, m), 2.45 (1H,
dd, J = 20.1, 7.5 Hz), 2.33-2.25 (1H, m), 2.06 (1H, ddd, J = 14.4,
10.3, 4.1 Hz), 1.61 (1H, dd, J = 12.6, 4.6 Hz), 0.88 (9H, t, J = 8.0
Hz), 0.56 (6H, q, J = 8.0 Hz); 13C{1H} NMR (CDCl3, 125 MHz) δ:
195.0, 149.3, 137.2, 135.5, 134.6, 132.3, 126.5, 124.9, 120.6,
120.3, 118.7, 118.0, 90.4, 78.9, 78.8, 50.0, 49.9, 44.7, 36.6, 33.4,
25.9, 18.6, 6.4, 4.8; IR (ATR) νmax 3383, 2840, 2877, 2235, 1675,
1457, 1415, 1186, 1143, 1038, 1003, 951, 931, 832, 801, 746
cm-1; HRMS (m/z): calcd. for C28H41O5NNaSi+ [M+Na]+,
522.2646; found, 522.2650.
Triene 33. To a solution of 32 (1.307 g, 2.52 mmol) in THF (63
mL) was added freshly prepared LiNEt2 (12.6 mmol, 5.0 eq.) in
THF (2.5 mL) at –78 °C. After stirring 1 h at the same tempera-
ture, allyl iodide (1.61 mL, 17.6 mmol, 7.0 eq.) was added to the
mixture. The reaction mixture was stirred for additional 1 h at
the same temperature and quenched with a solution of AcOH in
THF. Saturated NaHCO3 solution was added to the mixture and
extracted with EtOAc. The combined organic layers were dried
over MgSO4, filtered and concentrated under reduced pressure.
The resulting residue was purified by silica gel column chroma-
tography (n-hexane: EtOAc = 8:1), to afford 33 (1.26 g, 90%
yield) as colorless oil. Rf 0.23 (n-hexane: EtOAc = 4:1 v/v); 1H-
NMR (CDCl3, 500 MHz) δ: 7.45-7.33 (6H, m), 6.89 (1H, d, J = 8.6
Hz), 6.10 (1H, dd, J = 17.8, 11.5 Hz), 5.96-5.82 (2H, m), 5.54 (1H,
s), 5.29-5.20 (2H, m), 5.16-5.06 (4H, m), 5.00 (1H, d, J = 11.5 Hz),
4.43 (1H, d, J = 8.6 Hz), 3.89 (3H, s), 2.93 (1H, dd, J = 10.9, 4.6
Hz), 2.87-2.80 (2H, m), 2.72-2.67 (2H, m), 2.09 (1H, ddd, J = 14.3,
9.8, 9.8 Hz), 1.63-1.57 (1H, m), 0.76 (9H, t, J = 8.0 Hz), 0.44-0.34
(6H, m); 13C{1H} NMR (CDCl3, 125 MHz) δ: 151.1, 144.1, 141.6,
137.8, 136.4, 135.3, 135.1, 128.44, 128.36, 128.07, 128.06,
121.7, 121.4, 119.4, 117.8, 115.3, 111.1, 80.1, 79.0, 74.1, 55.8,
45.3, 35.9, 33.8, 26.5, 20.1, 6.4, 4.7; IR (ATR) νmax 3422, 2955,
2917, 2876, 1732, 1488, 1280, 1084, 1042, 1000, 929, 808, 743,
699 cm-1; HRMS (m/z): calcd. for C34H45O4NNaSi+ [M+Na]+,
582.3010; found, 582.3015.
Pentacyclic 42. A solution of 38 (0.443 g, 0.888 mmol) in t-BuPh
(88.8 mL) in a sealed tube was heated in an aluminium heating
block to 180 °C for 1 h. After the reaction mixture was cooled
to room temperature, Hoveyda-Grubbs 2nd generation catalyst
(56 mg, 0.0888 mmol, 0.1 eq.) was added. After stirring for 2 h
at 50 °C, the reaction mixture was cooled to room temperature.
To the reaction mixture, THF (18 mL) and 10% Pd(OH)2/C
(0.44 g, 100 wt%) were added under an argon atmosphere and
the argon was purged with H2 gas. After stirring under H2 at-
mosphere for 2 h, H2 gas was purged with argon gas; and then
pyridine (18 mL) and SOCl2 (0.64 mL, 8.88 mmol, 10 eq.) were
added to the reaction mixture at 0 °C. After stirring for 5.5 h at
room temperature, the reaction mixture was quenched with i-
PrOH and directly purified by silica gel column chromatog-
raphy (n-hexane: EtOAc = 1:0 to 4:1) to afford 42 (0.227 g, 56%
yield) as white solid. To determine the structure of the inter-
mediates 40 and 41, the reactions were individually termi-
nated by silica gel column chromatography. The overall yield
from 38 (0.198 g, 0.396 mmol) to 40 (0.108 g) was 68%, that
from 38 (0.523 g, 1.05 mmol) to 41 (0.314 g) was 63%, respec-
tively.
Phenol 37. To a solution of 33 (1.81 g, 3.24 mmol) in THF (32
mL) and t-BuOH (0.92 mL, 9.71 mmol, 3.0 eq.) was added
freshly prepared 1M LDBB (excess) in THF at –78 °C until the
color of the reaction mixture turned dark blue. After stirring 15
min at the same temperature, the reaction mixture was
quenched with AcOH in THF. Saturated NaHCO3 solution was
added to the mixture and extracted with EtOAc. The combined
40: white solid; Mp. 189-191 °C (recrystallized from EtOAc/n-
1
hexane); Rf 0.22 (n-hexane: EtOAc = 2:1 v/v); H-NMR (CDCl3,
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The Journal of Organic Chemistry
500 MHz) δ: 6.50 (1H, d, J = 6.3 Hz), 6.14 (1H, dd, J = 9.2, 1.7 Hz),
38.5, 35.9, 32.7, 31.4, 29.9, 24.2, 23.3, 21.9 (2C), 20.4, 6.8, 4.8;
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5.88-5.84 (1H, m), 3.44-3.38 (2H, m), 3.34 (3H, s), 3.26 (3H, s),
3.29-3.24 (1H, m), 2.80-2.72 (1H, m), 2.54-2.48 (1H, m), 2.39
(1H, dd, J = 13.2, 6.9 Hz), 2.16 (1H, dd, J = 10.9, 10.3 Hz), 2.09-
2.02 (2H, m), 1.81 (1H, d, J = 9.2 Hz), 1.67 (1H, ddd, J = 13.2, 10.3,
10.3 Hz), 1.57-1.48 (2H, m), 0.94 (9H, t, J = 8.0 Hz), 0.70-0.57
(6H, m); 13C{1H} NMR (CDCl3, 125 MHz) δ: 203.6, 144.4, 130.1,
129.1 (2C), 122.0, 94.8, 79.7, 73.5, 52.4, 52.2, 50.4, 49.3, 48.9,
42.2, 33.2, 29.5, 26.2, 17.6, 17.5, 6.9, 4.8; IR (ATR) νmax 3478,
2953, 2910, 2874, 1733, 1139, 1109, 1090, 1058, 998, 849 cm-
1; HRMS (m/z): calcd. for C26H37O5NNaSi+ [M+Na]+, 494.2333;
found, 494.2331.
FT-IR (ATR) νmax 2955, 2902, 2874, 2235, 1744, 1733, 1457,
1374, 1241, 1113, 1082, 1072, 1047, 1015, 1000, 834, 723 cm-
1; HRMS (m/z): calcd. for C26H37O4NNaSi+ [M+Na]+, 478.2384;
found, 478.2383.
Allyl acetate 44. To a solution of Ph3PCH3Br (60.6 mg, 0.170
mmol, 3.5 eq.) in THF (1 mL) was added t-BuOK (16.3 mg, 0.146
mmol, 3.0 eq.) at room temperature. After stirring for 30 min, a
solution of 43 (22.2 mg, 0.0485 mmol) in THF (0.3 mL) was
added at 0 °C. The reaction mixture was stirred for 9 h at room
temperature. The reaction was quenched with saturated NH4Cl
solution and extracted with ether. The combined organic layer
was dried over MgSO4, filtered and concentrated under re-
duced pressure. The resulting residue was purified by silica gel
column chromatography (CH2Cl2), to afford 44 (14.4 mg, 66%
yield) as white solid. Mp. 103-104 °C (recrystallized from
CH2Cl2/n-hexane); Rf 0.50 (n-hexane: EtOAc = 4:1 v/v); 1H-
NMR (CDCl3, 500 MHz) δ: 5.61 (1H, br), 5.37 (1H, s), 4.94 (1H,
s), 4.81 (1H, s), 3.40 (1H, s), 2.89 (1H, dd, J = 5.2, 3.4 Hz), 2.31-
2.29 (3H, m), 2.14-1.98 (6H, m), 1.90-1.80 (3H, m), 1.69-1.67
(1H, m), 1.60-1.52 (2H, m), 1.33-1.21 (3H, m), 0.97 (9H, t, J = 8.0
Hz), 0.61 (5H, t, J = 8.0 Hz); 13C NMR (CDCl3, 125MHz) δ 171.1,
150.4, 143.7, 121.6, 121.1, 108,8, 80.0, 74.0, 41.4, 38.3, 37.1,
36.2, 36.0, 35.4, 34.9, 32.0, 24.9, 23.5, 22.5, 22.3, 21.0, 6.8, 4.9;
FT-IR (ATR) νmax 2937, 2874, 1737, 1458, 1370, 1233, 1113,
1070, 1034, 1004, 974, 909, 835, 810, 742, 725 cm-1; HRMS
(m/z): calcd. for C27H39O3NNaSi+ [M+Na]+, 476.2591; found,
476.2593.
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60
41: white solid; Mp. 209-211 °C (recrystallized from CH2Cl2/n-
1
hexane); Rf 0.22 (n-hexane: EtOAc = 2:1 v/v); H-NMR (CDCl3,
500 MHz) δ: 3.91 (1H, s), 3.30 (3H, s), 3.29 (3H, s), 2.91 (1H, dd,
J = 12.6, 4.0 Hz), 2.31-2.24 (2H, m), 2.17-2.11 (1H, m), 1.98 (1H,
dd, J = 12.6, 3.6 Hz), 1.90 (1H, dd, J = 13.8, 4.0 Hz), 1.81-1.55
(11H, m), 1.43 (1H, d, J = 13.7 Hz), 1.10 (1H, s), 0.97 (9H, t, J =
8.0 Hz), 0.74-0.59 (6H, m); 13C{1H} NMR (CDCl3, 125 MHz) δ:
208.7, 122.4, 96.6, 78.6, 72.1, 50.2, 49.2, 44.9, 43.6, 43.1, 41.1,
36.9, 32.7, 32.6, 27.5, 27.2, 21.2, 19.9, 19.7, 15.9, 7.0, 4.8; IR
(ATR) νmax 3456, 2942, 2894, 2874, 1726, 1123, 1068, 1041,
1011, 836, 730 cm-1; HRMS (m/z): calcd. for C26H41O5NNaSi+
[M+Na]+, 498.2646; found, 498.2648.
42: Mp. 69-70 °C (recrystallized from CH2Cl2/n-hexane); Rf
0.53 (n-hexane: EtOAc = 2:1 v/v); 1H-NMR (CDCl3, 500 MHz) δ:
5.67-5.63 (1H, m), 3.48 (1H, s), 3.28 (3H, s), 3.28 (3H, s), 2.89
(1H, dd, J = 4.6, 4.0 Hz), 2.44 (1H, d, J = 9.2 Hz), 2.36-2.22 (4H,
m), 2.10 (1H, d, J = 17.8 Hz), 2.04-1.99 (1H, m), 1.93-1.88 (1H,
m), 1.86-1.75 (3H, m), 1.71-1.51 (3H, m), 1.28-1.22 (1H, m),
0.95 (9H, t, J = 8.0 Hz), 0.60 (6H, q, J = 8.0 Hz); 13C{1H} NMR
(CDCl3, 125 MHz) δ 208.0, 142.6, 121.9, 120.7, 97.1, 79.2, 50.2,
49.3, 45.7, 41.6, 41.8, 36.5, 32.9, 31.8, 30.6, 29.1, 23.0, 22.3, 22.1,
21.1, 6.8, 4.8; HRMS (m/z): calcd. for C26H39O4NNaSi+ [M+Na]+,
480.2541; found, 480.2541.
Alcohol 45. To a solution of 44 (0.120 g, 0.265 mmol) in CH2Cl2
(0.53 mL) was added DIBAL in toluene (1.29 mL, 1.32 mmol,
5.0 eq.) at –78 °C. The reaction mixture was stirred for 1 h at
room temperature, then EtOAc (2 mL) and 10% tartaric acid aq.
(5 mL) was added to the mixture. The reaction mixture was
stirred for additional 1 h at room temperature, extracted with
ether. The combined organic layer was dried over MgSO4, fil-
tered and concentrated under reduced pressure. The resulting
residue was purified by silica gel column chromatography (n-
hexane: EtOAc = 9:1), to afford 45 (86.6 mg, 79% yield) as col-
orless oil. Rf 0.41 (n-hexane: EtOAc = 4:1 v/v) ; 1H-NMR (CDCl3,
500 MHz) δ: 9.81 (1H, d, J = 4.1 Hz), 5.52 (1H, s), 5.03 (1H, s),
4.97 (1H, s), 3.83 (1H, s), 3.49 (1H, s), 2.32-2.28 (2H, m), 2.17-
1.95 (6H, m), 1.85 (1H, d, J = 10.3 Hz), 1.64 (2H, d, J = 5.7 Hz),
1.51-1.45 (2H, m), 1.39-1.33 (2H, m), 1.29-1.18 (1H, m), 0.95
(9H, t, J = 8.1 Hz), 0.61 (6H, q, J = 8.1 Hz); 13C{1H} NMR (CDCl3,
125 MHz) δ: 205.8, 155.6, 144.9, 121.7, 109.1, 84.6, 73.5, 53.5,
43.8, 37.3, 37.1, 36.8, 36.4, 36.1, 36.0, 26.3, 23.9, 21.4, 21.2, 6.9,
4.9; IR (ATR) νmax 3501, 2931, 2872, 1714, 1457, 1415, 1238,
1068, 1003, 897, 817, 726 cm-1; HRMS (m/z): calcd. for
C25H38O3NaSi+ [M+Na]+, 437.2485; found, 437.2482.
Acetate 43. To a solution of 42 (0.144 g, 0.314 mmol) in MeOH
(3.14 mL) was added NaBH4 (36 mg, 0.943 mmol, 3.0 eq.) at –
78 °C. The reaction mixture was stirred at –45 °C for 2 h. The
reaction mixture was quenched with saturated NH4Cl solution
and MeOH was removed by rotary evaporator. The residue was
diluted with H2O, extracted with ether. The combined organic
layer was dried over MgSO4, filtered and concentrated under
reduced pressure. The crude mixture was used for the next step
without further purification. To the crude mixture in MeCN
(3.14 mL) and H2O (63 μL) was added LiBF4 (88 mg, 0.94 mmol
3.0 eq.) at room temperature. After stirring for 2 h (with moni-
toring the completion of hydrolysis by TLC), Ac2O (0.31 mL),
pyridine (0.63 mL) and DMAP (4.9 mg, 0.031 mmol, 0.1 eq.)
was added at 0 °C. After stirring for 1 h at room temperature,
the reaction mixture was quenched with saturated NaHCO3 so-
lution and extracted with ether. The combined organic layers
were dried over MgSO4, filtered and concentrated under re-
duced pressure. The resulting residue was purified by silica gel
column chromatography (n-hexane: EtOAc = 6:1), to afford 43
(89.3 mg, 62% yield, dr = 8.5:1) as a white solid. Mp. 152-154 °C
(recrystallized from EtOAc/n-hexane); Rf 0.13 (n-hexane:
Nitrobenzoate 46. To a solution of 45 (31.9 mg, 77 μmol) in
CH2Cl2 (0.77 mL) was added p-NO2BzCl (71 mg, 0.38 mmol, 5.0
eq.), pyridine (0.38 mL) and DMAP (1.2 mg, 7.7 μmol, 0.1 eq.)
at room temperature. After stirring for 3 h, the reaction mixture
was quenched with saturated NaHCO3 solution and extracted
with ether. The combined organic layers were dried over
Na2SO4, filtered and concentrated under reduced pressure. The
resulting residue was purified by silica gel column chromatog-
raphy (n-hexane: EtOAc = 20:1), to afford 46 (37.0 mg, 86%
yield) as white solid. Mp. 116-117 °C (recrystallized from
EtOAc/n-hexane); Rf 0.56 (n-hexane: EtOAc = 4:1 v/v); 1H-NMR
(CDCl3, 500 MHz) δ: 9.78 (1H, d, J = 3.4 Hz), 8.28 (2H, d, J = 8.0
Hz), 8.19 (2H, d, J = 8.0 Hz), 5.57 (1H, s), 5.54 (1H, s), 5.08 (1H,
s), 5.03 (1H, s), 3.56 (1H, s), 2.42 (1H, s), 2.32 (1H, dd, J = 7.5,
1
EtOAc = 4:1 v/v); H-NMR (CDCl3, 500 MHz) δ: 5.73-5.73 (1H,
m), 5.23 (1H, s), 3.45 (1H, s), 2.98 (1H, dd, J = 3.4, 1.7 Hz), 2.59-
2.57 (1H, m), 2.40-2.37 (2H, m), 2.30-2.28 (1H, m), 2.19-2.13
(6H, m), 2.02 (1H, dd, J = 6.0, 6.0 Hz), 1.95-1.91 (1H, m), 1.88-
1.71 (3H, m), 1.62-1.58 (7H, m), 1.45-1.41 (2H, m), 0.97 (9H, t,
J = 8.0 Hz), 0.59 (6H, q, J = 8.0 Hz); 13C NMR (CDCl3, 125MHz) δ
210.9, 170.2, 142.1, 122.8, 120.5, 77.9, 75.4, 41.7, 41.2, 39.5,
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10.9 Hz), 2.24-2.00 (7H, m), 1.71-1.60 (4H, m), 1.52-1.43 (2H,
s), 2.56 (1H, d, J = 10.9 Hz), 2.37 (1H, s), 2.24 (1H, dd, J = 9.8, 9.8
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5
6
7
8
m), 1.32 (1H, dt, J = 6.9, 11.5 Hz), 1.00 (9H, t, J = 8.0 Hz), 0.66
(6H, q, J = 7.8 Hz); 13C{1H} NMR (CDCl3, 125 MHz) δ: 205.3,
164.5, 150.6, 149.7, 143.9, 135.9, 130.7, 123.6, 122.3, 112.2,
84.1, 75.9, 53.4, 43.6, 38.5, 37.0, 36.6, 36.2, 36.0, 35.5, 26.5, 23.9,
21.1, 21.1, 7.0, 4.9; IR (ATR) νmax 2934, 2874, 1713, 1608, 1530,
1460, 1334, 1267, 1101, 1073, 1011, 958, 918, 870, 839, 801,
716 cm-1; HRMS (m/z): calcd. for C32H41O6NNaSi+ [M+Na]+,
586.2595; found, 586.2607.
Hz), 2.15-1.80 (8H, m), 1.66-1.53 (4H, m), 1.19 (1H, ddd, J = 13.2,
6.9, 1.8 Hz), 1.03 (3H, s); 13C{1H} NMR (CDCl3, 125 MHz) δ:
217.4, 205.6, 154.0, 142.3, 121.9, 111.3, 73.1, 54.9, 45.2, 41.8,
39.1, 38.7, 35.7, 35.1, 31.1, 30.2, 26.2, 25.2, 21.9, 17.4; IR (ATR)
νmax 3411, 2937, 2866, 2729, 1710, 1668, 1461, 1059, 1017,
900 cm-1; HRMS (m/z): calcd. for C20H25O3+ [M+H]+, 313.1798;
found, 313.1798.
Ketoaldehyde 51. To a solution of 42 (149.7 mg, 0.327 mmol) in
CH2Cl2 (3.3 mL) was added 1.0 M solution of DIBAL in hexane
(1.6 mL, 1.6 mmol, 5.0 eq.) at –78 °C. After stirring for 1.5 h at
room temperature, the reaction mixture was cooled at 0 °C and
quenched with EtOAc and 10% tartaric acid aqueous solution.
After stirring for 1 h, the reaction mixture was extracted with
ether. The combined organic layers were dried over Na2SO4, fil-
tered and concentrated under reduced pressure. The resulting
residue was purified by silica gel column chromatography (n-
hexane: EtOAc = 5:1), to afford 50 (147.0 mg, 97%, dr = 3:2) as
colorless oil. To a solution of 50 (128.1 mg, 0.277 mmol) in THF
(1.4 mL) and pyridine (1.4 mL) was added HF·Py (0.4 mL, 2.8
mmol, 10 eq.) at 0 °C. After stirring for 5 h at room temperature,
the reaction mixture was cooled at 0 °C and quenched with
TMSOMe. After stirring for 1 h, the reaction mixture was con-
centrated under reduced pressure to remove MeOH and Py.
The resulting residue was purified by silica gel column chroma-
tography (n-hexane: EtOAc = 5:1 to 1:1), to afford a diastereo-
meric mixture of the resulting diol (90.9 mg, 94%, dr = 3:2) as
colorless oil. To a solution of the mixture of diol (80.2 mg, 0.23
mmol) and NaHCO3 (190 mg, 2.3 mmol, 10 eq.) in CH2Cl2 (2.3
mL) was added Dess-Martin Periodinane (290 mg, 0.69 mmol,
3.0 eq.) at 0 °C. After stirring for 2 h at room temperature, the
reaction mixture was quenched with saturated NaHCO3 solu-
tion and aqueous Na2S2O3 solution. After stirring for 1 h, the re-
action mixture was extracted with ether. The combined organic
layers were dried over Na2SO4, filtered and concentrated under
reduced pressure. The resulting residue was purified by silica
gel column chromatography (n-hexane: EtOAc = 4:1), to afford
51 (39.5 mg, 50%) as a white solid. Mp. 131 °C (recrystallized
from EtOAc/n-hexane); Rf 0.59 (n-hexane: EtOAc = 1:1 v/v); 1H-
NMR (CDCl3, 500 MHz) δ: 9.73 (1H, s), 5.59 (1H, d, J = 5.7 Hz),
3.33 (3H, s), 3.32 (3H, s), 3.28 (1H, dd, J = 2.9, 13.2 Hz), 2.70-
2.66 (1H, m), 2.49 (1H, ddd, J = 2.9, 2.9, 10.9 Hz), 2.40-2.32 (2H,
m), 2.20-2.09 (4H, m), 2.03-1.99 (2H, m), 1.81 (1H, d, J = 11.5
Hz), 1.75-1.65 (2H, m), 1.53-1.50 (1H, m), 1.22 (1H, ddd, J = 13.8,
6.3, 1.7 Hz); 13C{1H} NMR (CDCl3, 125 MHz) δ: 214.6, 205.6,
202.9, 141.4, 123.6, 97.2, 50.8, 50.2, 49.4, 47.5, 46.8, 45.3, 37.8,
33.6, 30.8, 25.6, 24.3, 23.8, 21.3, 17.6; IR (ATR) νmax 2945, 2930,
2832, 1734, 1716, 1456, 1438, 1148, 1129, 1061, 913, 836 cm-
1; HRMS (m/z): calcd. for C20H24O5NNa+ [M+Na]+, 367.1516;
found, 367.1517.
Aldehyde 47. To a solution of 46 (37.0 mg, 66 μmol) in THF
(0.66 mL) was added HF·Py (0.6 mL, 0.66 mmol, 10 eq.) at 0 °C.
After stirring for 1 h at room temperature, the reaction mixture
was quenched with TMSOMe (1 mL) and concentrated under
reduced pressure, The resulting residue was purified by silica
gel column chromatography (n-hexane: EtOAc = 6:1 to 3:1), to
afford 47 (23.0 mg, 78% yield) as colorless oil. Rf 0.22 (n-hex-
ane: EtOAc = 3:1 v/v); 1HNMR (CDCl3, 500 MHz) δ: 9.79 (1H, d,
J = 4.6 Hz), 8.29 (2H, d, J = 8.6 Hz), 8.19 (2H, d, J = 8.6 Hz), 5.58
(1H, s), 5.52 (1H, s), 5.12 (1H, s), 5.04 (1H, s), 3.64 (1H, s), 2.43-
2.38 (2H, m), 2.29-1.93 (8H, m), 1.72-1.67 (4H, m), 1.40 (1H, d,
J = 12.6 Hz), 1.35-1.25 (2H, m); 13C{1H} NMR (CDCl3, 125 MHz)
δ: 206.9, 164.7, 150.5, 149.6, 143.6, 135.8, 130.8, 123.6, 122.0,
112.9, 84.2, 75.8, 54.1, 43.8, 38.68, 38.67, 37.4, 36.8, 35.9, 34.7,
26.5, 24.0, 20.6, 20.5; IR (ATR) νmax 3422, 2933, 2867, 1718,
1606, 1528, 1459, 1408, 1338, 1269, 1103, 1040, 719 cm-1;
HRMS (m/z): calcd. for C26H27O6NNa+ [M+Na]+, 472.1734;
found, 472.1731.
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Ketoaldehyde 48. To a solution of 47 (23.0 mg, 51 μmol) in
CH2Cl2 (0.51 mL) and H2O (3 μL) was added Dess-Martin Peri-
odinane (65 mg, 0.15 mmol, 3.0 eq.) at 0 °C. After stirring for 1
h at room temperature, the reaction mixture was quenched
with saturated NaHCO3 solution and saturated Na2S2O3 solu-
tion, extracted with ether. The combined organic layer was
dried over MgSO4, filtered and concentrated under reduced
pressure. The resulting residue was purified by silica gel col-
umn chromatography (n-hexane: EtOAc = 6:1) to give 48 (16.8
mg, 73% yield) as white solid. Mp. 205-207 °C (recrystallized
from EtOAc/n-hexane); Rf 0.52 (n-hexane: EtOAc = 2:1 v/v);
1HNMR (CDCl3, 500 MHz) δ: 9.75 (1H, s), 8.30 (2H, d, J = 8.6 Hz),
8.18 (2H, d, J = 8.6 Hz), 5.67 (1H, s), 5.57 (1H, d, J = 4.6 Hz), 5.23
(1H, s), 5.12 (1H, s), 3.29 (1H, dd, J = 12.6, 2.3 Hz), 2.73 (1H, d, J
= 11.5 Hz), 2.45 (1H, s), 2.41-2.39 (1H, m), 2.30 (1H. d, J = 13.2
Hz), 2.22-2.00 (4H, m), 1.83-1.73 (3H, m), 1.62-1.49 (2H, m),
1.25-1.21 (2H, m); 13C{1H} NMR (CDCl3, 125 MHz) δ: 216.4,
203.2, 164.5, 156.6, 148.1, 141.6, 135.5, 130.7, 123.7, 123.1,
114.6, 75.3, 51.3, 47.7, 42.7, 38.3, 38.0, 36.1, 35.7, 30.6, 25.6,
24.7, 23.8, 17.6; IR (ATR) νmax 2923, 2851, 1713, 1605, 1527,
1459, 1339, 1267, 1116, 1104, 722 cm-1; HRMS (m/z): calcd. for
C26H25O6NNa+ [M+Na]+, 470.1574; found, 470.1572.
15-Epi-atropurpuran 49. To a solution of 48 (62.8 mg, 0.140
mmol) in t-BuOH (3.1 mL) and CH2Cl2 (3.1 mL) was added t-
BuOK (157 mg, 1.40 mmol, 10 eq.) in t-BuOH (3.1 mL) at 0 °C.
After stirring for 10 min at 0 °C, MeI (0.44 mL, 7.02 mmol, 50
eq.) was added. After stirring for 24 h at 0 °C, the reaction mix-
ture was quenched with 1M HCl aq., and stirred for 40 min at
room temperature. Then, the mixture was neutralized with sat-
urated NaHCO3 solution, and extracted with EtOAc. The com-
bined organic layers were dried over MgSO4, filtered and con-
centrated under reduced pressure. The resulting residue was
purified by silica gel column chromatography (n-hexane: EtOAc
= 10:1) to afford 49 (23.7 mg, 54% yield, dr = 8:1) as white solid.
Rf 0.16 (n-hexane: EtOAc = 2:1 v/v); 1HNMR (CDCl3, 500 MHz)
δ: 9.65 (1H, s), 5.56 (1H, m), 5.08 (1H, s), 5.04 (1H, s), 4.02 (1H,
Xu’s intermediate 52. To a solution of 51 (28.0 mg, 0.0813
mmol) in t-BuOH (4 mL) and CH2Cl2 (2 mL) in a polypropylene
test tube was added a 1.0 M solution of t-BuOK in THF (0.325
mL, 0.325 mmol, 4.0 eq.) and MeI (50 μL, 0.813 mmol, 10 eq.)
at 0 °C. After stirring for 8 h at 0 °C, another t-BuOK solution
(0.081 mL, 0.0813 mmol, 1.0 eq.) and MeI (13 μL, 0.203 mmol,
2.5 eq.) was added. After stirring for 3 h at 0 °C, again another
t-BuOK solution (0.081 mL, 0.0813 mmol, 1.0 eq.) and MeI (13
μL, 0.203 mmol, 2.5 eq.) was added. After stirring for 1 h at 0 °C,
the reaction mixture was quenched with saturated NaHCO3 so-
lution, extracted with EtOAc. The combined organic layers
were dried over Na2SO4, filtered and concentrated under re-
duced pressure. The residue was purified by PTLC (n-hexane:
EtOAc = 3:1×2), to afford epi-52 (10 %, 2.9 mg) 51 (3%, 0.7 mg),
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The Journal of Organic Chemistry
52 (11.3 mg, 39% (43% based on recovered 51 and epi-51)) as
white solid, and epi-51 (8%, 2.3 mg).
Naoki Egashira (Taiho Pharma) and Dr Atsuhiro Takano
1
2
3
4
5
6
7
8
(KOWA CO. Ltd.) for the preliminary investigation of the total
synthesis. We also thank the Naito Foundation, the Uehara Me-
morial Foundation, the Astellas Foundation for Research on
Metabolic Disorders, the Research Foundation for Pharmaceu-
tical Sciences, and the Akiyama Life Science Foundation for fi-
nancial support.
52: Mp. 167-168 ℃ (recrystallized from EtOAc/n-hexane); Rf
0.25 (n-hexane: EtOAc = 4:1 v/v ×2); 1H-NMR (CDCl3, 500 MHz)
δ: 9.68 (1H, s), 5.65 (1H, s), 3.34 (3H, s), 3.31 (3H, s), 2.80-2.73
(1H, m), 2.44-2.31 (3H, m), 2.20-1.92 (5H, m), 1.90-1.60 (5H,
m), 1.30-1.23 (1H, m), 1.04 (3H, s); 13C{1H} NMR (CDCl3, 125
MHz) δ: 214.2, 205.6, 204.9, 141.0, 122.9, 97.3, 54.4, 50.3, 49.4,
46.9, 45.3, 45.2, 38.4, 33.5, 30.1, 29.8, 26.0, 25.8, 21.9, 21.3,
17.4; IR (ATR) νmax 2937, 2824, 2727, 1729, 1708, 1457, 1149,
1057, 1045, 1028, 1004, 914, 839 cm-1; HRMS (m/z): calcd. for
C21H26O5Na+ [M+Na]+, 381.1673; found, 381.1678.
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Epi-51: Rf 0.21 (n-hexane: EtOAc = 4:1 v/v ×2); 1H-NMR (CDCl3,
500 MHz) δ: 9.84 (1H, s), 5.74 (1H, m), 3.34 (3H, s), 3.31 (3H, s),
2.78-2.72 (1H, m), 2.49-2.38 (2H, m), 2.38 (2H, m), 2.28-2.20
(1H, m), 2.18-2.02 (4H, m), 2.00-1.92 (1H, m), 1.88-1.72 (3H,
m), 1.71-1.62 (1H, m), 1.54 (1H, dt, J = 10.9, 6.9 Hz); 13C{1H}
NMR (CDCl3,125 MHz) δ: 213.3, 206.0, 202.6, 141.8, 124.9, 97.2,
53.6, 50.0, 49.8, 49.7, 47.2, 45.2, 37.4, 33.7, 31.9, 29.3, 25.9, 23.6,
21.8, 20.9; IR (ATR) νmax 2943, 2827, 2837, 1717, 1458, 1148,
1052, 978, 837 cm-1; HRMS (m/z): calcd. for C20H24O5NNa+
[M+Na]+, 367.1516; found, 367.1521.
ASSOCIATED CONTENT
Supporting Information.
This material is available free of charge via the Internet at
http://pubs.acs.org.
Scheme for the preparation of tricyclic MOB 13; details of the
further transformation from 27-syn, the catalytic asymmetric
Mukaiyama aldol reaction, and the methylation of aldehyde 48;
compound characterization data; and 1H and 13C NMR spectral
data for all new compounds (PDF)
FAIR Data is available as Supporting Information for Publica-
tion and includes the primary NMR FID files for all new com-
pounds.
Crystallographic information for 15 (CIF)
Crystallographic information for 40 (CIF)
Crystallographic information for 47 (CIF)
AUTHOR INFORMATION
Corresponding Author
* Takahiro Suzuki
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Kobayashi, S. Synthesis of dibarrelane, a dibicyclo[2.2.2]octane hy-
drocarbon. J. Org. Chem. 2014, 79, 2803–2808.
ORCID: 0000-0002-3842-1025
E-mail: takahiro-suzuki@sci.hokudai.ac.jp
* Keiji Tanino
ORCID: 0000-0002-0580-0125
E-mail: ktanino@sci.hokudai.ac.jp
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Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
This research was supported in part by JSPS KAKENHI Grant
Numbers JP15H05842 in Middle Molecular Strategy,
JP18H01970 in Grant-in-Aid for Scientific Research(B),
JP20K05485 in Grant-in-Aid for Scientific Research(C), and the
Photo-excitonix Project in Hokkaido University. We thank Mr.
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