Synthetic studies on actinorhodin and γ-actinorhodin: Synthesis of deoxyactinorhodin and deoxy-γ-actinorhodin/crisamicin a

Article abstract of DOI:10.1002/chem.201406431

A strategy based on bidirectional D?tz benzannulation and the oxa-Pictet-Spengler reaction toward the synthesis of actinorhodin and γ-actinorhodin has been explored. This work has resulted in the synthesis of deoxyactinorhodin and deoxy-γ-actinorhodin. The latter is a regioisomer of crisamicin A (which has 10,10'-dihydroxy groups).

Full text of DOI:10.1002/chem.201406431

DOI: 10.1002/chem.201406431
Full Paper
&
Actinorhodins
Synthetic Studies on Actinorhodin and g-Actinorhodin: Synthesis
of Deoxyactinorhodin and Deoxy-g-actinorhodin/Crisamicin A
Isomer
Sandip V. Mulay and Rodney A. Fernandes*[a]
Abstract: A strategy based on bidirectional Dçtz benzannu-
lation and the oxa-Pictet–Spengler reaction toward the syn-
thesis of actinorhodin and g-actinorhodin has been explored.
This work has resulted in the synthesis of deoxyactinorhodin
and deoxy-g-actinorhodin. The latter is a regioisomer of cri-
samicin A (which has 10,10’-dihydroxy groups).
Introduction
of 1 (1R,1’R,3S,3’S) were confirmed by comparison of the opti-
cal rotary dispersion (ORD) curves of triacid (obtained from the
oxidative degradation of actinorhodin diethyl ester with alka-
line H2O2) with that of (+)-(S)-lactic acid.[4b,c] Actinorhodin
1 shows activity against the Staphylococcus aureus[2] bacteria
found in the human respiratory tract and on the skin. Crisami-
cin A (3) was isolated from Micromonospora purpureochromo-
genes[8] and shows activity against B16 murine melanoma cells,
herpes simplex, and vesicular stomatitis viruses.[9] A closely re-
lated compound GTRI-BB (4)[10] has shown very promising anti-
cancer activities, such as renal (ACHN; IC50 =0.08 mgmLÀ1),
colon (SW 620; IC50 =0.11 mgmLÀ1), and melanoma (UACC 62;
IC50 =0.08 mgmLÀ1). The inhibitory effect is much higher than
adriamycin (a commercial anticancer drug). This indicates that
a structure–activity relationship (SAR) study might enhance the
cytotoxic efficacy of these compounds. Whereas the syntheses
of monomeric pyranonaphtho-
The soil-dwelling bacteria Streptomyces coelicolor[1–3] produces
a red pigment that shows litmuslike properties, bright blue in
alkaline and red in acid media. The red pigment structure was
assigned by means of extensive chemical degradation[4] and
mass spectrometry[5] to be the dimeric pyranonaphthoquinone
known as actinorhodin 1 (Figure 1). The other congeners of
1 have been isolated from the same culture of bacteria[6,7] in-
cluding g-actinorhodin 2. H and 13C NMR spectroscopic stud-
1
ies[5,7] showed that 1 and 2 are dimeric with two similar halves
joined in a symmetrical C8ÀC8’ linkage. The dihydropyran ring
contains a quasi-axial methyl group at C1, which is trans to an
equatorial acetic acid side chain at C3 that is able to partici-
pate in g-lactone formation thorough a quinone–methide in-
termediate. The absolute configuration of stereogenic centers
quinones and hemi-1 and 2 are
well documented,[11] the total
synthesis of 1 and 2 is yet to be
achieved. The first synthetic at-
tempt toward ent-1 was report-
ed by Laatsch[12] from a degrada-
tion product of the antibacterial
metabolite a-naphthocyclinone.
Brimble and co-workers[13] have
reported the synthesis of ana-
logues of 1 and 3. A racemic
synthesis of crisamicin A (3) was
elegantly achieved by Wang and
co-workers[14] by homocoupling
Figure 1. Some dimeric pyranonaphthoquinones.
of monomer units. In our efforts
toward the synthesis of pyrano-
napthoquinones and related
compounds,[11g–m,15] we observed that the sequence of Dçtz
benzannulation[16] and oxa-Pictet–Spengler[17] reaction enables
the rapid construction of the pyranonaphthoquinone frame-
work. Recently we adopted a bidirectional strategy for the syn-
thesis of (+)-demethoxycardinalin 3.[15] Herein we wish to
[a] S. V. Mulay, Prof. Dr. R. A. Fernandes
Department of Chemistry, Indian Institute of Technology Bombay
Powai, Mumbai 400 076, Maharashtra (India)
E-mail: rfernand@chem.iitb.ac.in
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201406431.
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report our bidirectional synthetic studies on the dimeric pyra-
nonaphthoquinones 1 and 2 based on Dçtz benzannulation
and oxa-Pictet–Spengler reactions.
gave dimeric diol 7 in good yields (93%). Further 2-iodoxyben-
zoic acid (IBX) oxidation gave the dialdehyde in moderate yield
(60%). The oxidation conditions by Piancatelli et al.[20] with
a
catalytic amount of 2,2,6,6-tetramethylpiperidin-1-yl)oxyl
(TEMPO) in the presence of [bis(acetoxy)iodo]benzene deliv-
ered the dialdehyde in good yield, and subsequent allylation
gave 5 in 85% yield from 7. The oxa-Pictet–Spengler reaction
has worked well to construct the pyran ring for the monomeric
molecules.[11g,h,k–m,15] However, under similar conditions, com-
pound 5 failed to provide pyran 15. We employed various
Lewis acids such as BF3·OEt2, TiCl4, trimethylsilyl trifluorometha-
nesulfonate (TMSOTf), and ZnCl2, or changed solvents and tem-
perature conditions, but with no success. We believe the
highly oxygenated aryl ring has the Lewis acid coordinated to
the methoxy groups. Carrying out the reaction by bubbling
dry HCl gas[15] through a solution of 5 in ether as well as acet-
aldehyde dimethylacetal also failed to yield the pyran product
15.
We next planned to use a different alkyne 17 (Scheme 3) in
Dçtz benzannulation to deliver 16. The latter through an oxa-
Pictet-Spengler reaction would lead to 1 and then to 2.
The Dçtz benzannulation of 9 with alkyne 17[21] delivered
bisnaphthol 18 in 52% yield (Scheme 4). The protection of
phenolic OH (19, 88%) and subsequent TBS removal gave diol
16 in excellent yield (96%). The oxa-Pictet–Spengler reaction
on 16 delivered the inseparable mixture of syn/anti-pyran
products 20. This mixture was subjected to cerium(IV) ammo-
nium nitrate (CAN) oxidation. However, it gave a complex mix-
ture. We also tried other condi-
Results and Discussion
Our bidirectional retrosynthetic strategy is depicted in
Scheme 1. Both 1 and 2 could be traced to the common inter-
mediate diol 7. Actinorhodin 1 can be traced from 7 through
a sequence of allylation, pyran formation, and terminal double-
bond cleavage. A modified Knoevenagel condensation on the
aldehyde from 7 would lead to ester 8. Subsequent dihydroxy-
lation and pyran formation would give 2. By biomimicking the
viability of 1 to 2 conversion chemically (oxidative cyclization)
and vice versa (reductive lactone opening), we could adopt
either a route to 1 or 2 and their interconversion. The intercon-
version, although unknown for the dimeric compounds, is
quite feasible for the monomeric molecules.[11k,18] Diol 7
seemed easily possible through the Dçtz benzannulation of di-
meric Fischer carbene 9 with alkyne 10.
To synthesize dimeric Fischer carbene 9, we needed the
requisite dibromobiaryl compound 11 a (Scheme 2). Commer-
cially available 4-methoxyphenol was converted to 11 a in two
steps.[19] The biaryl phenol 11 a was methylated to 12 (94%;
Scheme 2). Fischer carbene 9 was prepared from 12 and con-
densed with alkyne 10 in a bidirectional Dçtz benzannulation
reaction to afford 13 (70%). The protection of phenolic OH
(14, 86%) and subsequent tert-butyldimethylsilyl(TBS) removal
tions using Ag2O, phenyliodine
bis(trifluoroacetate) (PIFA), and
CrO3. In all cases either the start-
ing material decomposed or it
delivered regioisomeric and dif-
ferently oxidized inseparable
quinone mixtures, which could
be due to multiple 1,4-dime-
thoxy aryl units present and/or
possible quinone isomerizations.
As illustrated in Scheme 1, we
moved our attention toward g-
actinorhodin 2 synthesis as this
in turn can be converted into
1
through reductive lactone
opening. The reaction of dialde-
hyde from 7 with half ester of
malonic acid under decarboxyla-
tive deconjugative Knoevenagel
condensation[22] delivered the
mixture (63%) of desired b,g-un-
saturated ester
8 along with
a trace amount of a,b-unsaturat-
ed isomer (Scheme 5). Upon di-
hydroxylation[23] the mixture
gave the bis-g-lactones 6 (70%)
as a single diastereomer (ee not
determined). Lactone 6 has the
Scheme 1. Retrosynthesis of actinorhodin 1 and g-actinorhodin 2.
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(TFA) solvent and then addition of 6 (in THF) fol-
lowed by (CH3O)2CHCH3 (6.0 equiv). These conditions
worked well to directly deliver the anti-pyran product
in our arizonin C1 synthesis.[11m] However, compound
6
decomposed under these conditions (Table 1,
entry 7).
We next considered lowering the number of me-
thoxy groups on the biaryl system with the aim of in-
vestigating both the oxa-Pictet–Spengler reaction
and the difficulty associated with quinone formation.
Although this means analogue synthesis, the envi-
sioned targets would have the skeletal structures of
1 and 2 with the quinone, pyran, and lactone instal-
led. The freshly prepared Fischer carbene 23[15] on bi-
directional Dçtz benzannulation reaction with alkyne
10 gave 24 (66%; Scheme 6). The protection of phe-
nolic OH (25, 86%) and subsequent TBS removal af-
forded 26 in good yield (93%). The oxidation of 26
to dialdehyde and modified Knoevenagel condensa-
tion delivered the mixture (63%) of desired b,g-unsa-
turated ester 27 along with trace amounts of a,b-un-
saturated isomer. Upon dihydroxylation the mixture
gave the bis-g-lactone 28 in 70% yield as a single
diastereomer (ee not determined). Unfortunately, all
our attempts to construct the pyran ring on 28 using
various Lewis acids (similar to that used in Table 1 for
bis-lactone 6) failed to deliver pyran 29. It is surpris-
ing that on monomer molecules these reactions
worked well in our laboratory.[11k]
We further considered the bidirectional Dçtz ben-
zannulation of Fischer carbene 23 with alkyne 17.
This reaction gave bisnaphthol 30 in 63% yield
(Scheme 7). The protection of free phenolic OH to 31
(88%) and subsequent TBS removal afforded 32 in
excellent yields (96%). The oxa-Pictet–Spengler reac-
tion of 32 using BF3·OEt2 gave a complex mixture,
whereas the same reaction catalyzed by TMSOTf to
our delight afforded the insepa-
Scheme 2. Attempted synthesis of compound 15.
rable mixture of pyran diastereo-
mers 33 (81%). The mixture was
subjected to CAN oxidation to
provide separable quinones 34
and 35 (one pyran ring with syn-
methyl and the other anti to the
C3 substituent) in 62 and 18%
isolated yields, respectively.[24]
The separated quinone 34 on
treatment with AlCl3 gave com-
Scheme 3. Revised plan for 1 and 2.
pound 36 (79%). The undesired
35 was converted into 36 by
desired skeletal structure for 2, minus the pyran rings. All at-
tempts to construct the pyran ring on compound 6 using vari-
ous Lewis acids similar to that used on compound 5 by means
of oxa-Pictet–Spengler reaction failed to deliver product 22
(Table 1). In most cases, decomposition of 6 was observed. We
also attempted the oxa-Pictet–Spengler reaction in a preheated
(808C) mixture of BF3·OEt2 (10 equiv) in trifluoroacetic acid
treatment with AlCl3 and then H2SO4-mediated epimerization.
Compound 36 represents the diethyl ester of deoxyactinorho-
din with pyran and quinone installed. Various bases were
screened for the hydrolysis of ester 36 to liberate the diacid.
However, the acid isolation failed in our hands. Hence the
crude acid was stirred in an open flask in MeOH to deliver 37
through a quinone–methide intermediate[18] in 34% isolated
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Conclusion
We have efficiently utilized the
bidirectional approach through
Dçtz benzannulation and oxa-
Pictet–Spengler reaction to ach-
ieve the synthesis of deoxyacti-
norhodin and deoxy-g-actinorho-
din. The latter is an isomer of cri-
samicin A. Efforts are still under-
way in our laboratory to achieve
target molecules 1 and 2.
Experimental Section
General information
Flasks were oven- or flame-dried
and cooled in a desiccator. Dry re-
actions were carried out under an
atmosphere of Ar or N2. Solvents
and reagents were purified by
standard methods. Thin-layer chro-
matography was performed using
EM 250 Kieselgel 60 F254 silica gel
plates. The spots were visualized
by staining with KMnO4 or by
using a UV lamp. 1H and 13C NMR
spectra were recorded at 400 or
500 and 100 or 125 MHz, respec-
tively, and chemical shifts are
based on the TMS peak at d=
0.00 ppm for proton NMR spec-
troscopy and the CDCl3 peak at
d=77.00 ppm (t) for carbon NMR
spectroscopy. IR samples were pre-
pared by evaporation from CHCl3
on CsBr plates. High-resolution
mass spectra were obtained using
positive electrospray ionization.
Scheme 4. Attempted synthesis of 21 using alkyne 17.
Synthesis
3,3’-Dibromo-2,2’,5,5’-tetrameth-
oxybiphenyl
(12):
Anhydrous
K2CO3 (2.05 g,
14.85 mmol,
3.0 equiv) was added to a stirred
solution of 11 a (2.0 g, 4.95 mmol)
in dry acetone (40 mL) and stirred
at room temperature for 10 min.
Dimethylsulfate (1.56 g, 12.4 mmol,
Scheme 5. Attempted synthesis of pyranolactone 22.
2.5 equiv) was added, and the re-
action mixture was stirred for 12 h
at the same temperature. It was
then quenched with water (20 mL), and acetone was evaporated
at reduced pressure. EtOAc (40 mL) was added, and the separated
aqueous layer was extracted with EtOAc (2ꢁ40 mL). The combined
organic layers were washed with water and brine, dried (Na2SO4),
and concentrated. The residue was purified by silica gel column
chromatography using petroleum ether/EtOAc (19:1 to 9:1) as
eluent to afford 12 (2.01 g, 94%) as a colorless solid. M.p. 99–
yield. Thus the biomimetic conversion of acid to lactone
through the quinone–methide intermediate known for mono-
meric molecules worked well for the diacid here. This complet-
ed the synthesis of deoxy-g-actinorhodin 37, which is also an
isomer of crisamicin A with differently placed hydroxyl groups
(see crisamicin A; Figure 1).
1
1008C; H NMR (400 MHz, CDCl3/TMS): d=3.53 (s, 6H), 3.79 (s, 6H),
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Fischer carbene (9): nBuLi (3.2 mL, 5.1 mmol, 2.2 equiv,
1.6m solution in hexane) was added to a solution of 12
(1.0 g, 2.31 mmol) in dry Et2O (25 mL) at À788C, and the
reaction mixture was stirred for 20 min. It was then
Table 1. The oxa-Pictet–Spengler reaction of bislactone 6.
transferred to
a
suspension of [Cr(CO)6] (1.12 g,
Entry Reaction conditions
Results
5.1 mmol, 2.2 equiv) in dry Et2O (25 mL) at 08C. The reac-
tion mixture was stirred for 1 h at 08C and then at room
temperature for 2 h. Et2O was evaporated and the resi-
due was dissolved in dry CH2Cl2 (30 mL). Me3OBF4
(1.03 g, 6.93 mmol, 3.0 equiv) was added to this solution
in one portion at 08C, and the reaction mixture was
stirred for 1 h. It was warmed to room temperature and
stirred for 2 h. The red reaction mixture was concentrat-
ed, and the residue was purified by silica gel column
chromatography using petroleum ether/CH2Cl2 (9:1 to
3:1) as eluent to give 9 (1.12 g, 65%) as a red solid. This
was immediately used in the next step.
1
2
3
4
5
(CH3O)2CHCH3 (4.0 equiv), BF3·OEt2 (4.0 equiv), CH2Cl2,
08C to RT, 12 h
(CH3O)2CHCH3 (4.0 equiv), BF3·OEt2 (6.0 equiv), THF/Et2O (1:4), decomposed
decomposed
08C to RT, 36 h
(CH3O)2CHCH3 (3.0 equiv), BF3·OEt2 (4.0 equiv), THF/Et2O (1:4), decomposed
08C, 24 h
(CH3O)2CHCH3 (4.0 equiv), TMSOTf (4.0 equiv), CH2Cl2,
08C to RT, 12 h
(CH3O)2CHCH3 (4.0 equiv), TiCl4 (4.0 equiv), CH2Cl2,
08C to RT, 10 h
(CH3O)2CHCH3 (6.0 equiv), HCl gas, Et2O, RT, 12 h
preheated mixture of BF3·OEt2 (10.0 equiv) in TFA,
then addition of 6 and (CH3O)2CHCH3 (6.0 equiv), 1 min
complex mixture
complex mixture
6
7
decomposed
decomposed
6,6’-Bis[2-(tert-butyldimethylsilyloxy)ethyl]-
1,1’,4,4’,8,8’-hexamethoxy-2,2’-binaphthyl-5,5’-diol
(13): Alkyne 10 (1.11 g, 6.04 mmol, 4.0 equiv) in dry and
degassed THF (5 mL) was added to
a
solution of freshly prepared
Fischer carbene (1.12 g,
9
1.51 mmol) in dry and degassed
THF (15 mL). The reaction mixture
was heated at 558C for 15 h and
then allowed to cool to room tem-
perature. It was then exposed to
air and stirred for 1 h. THF was re-
moved, and the residue was puri-
fied by silica gel column chroma-
tography using petroleum ether/
EtOAc (9:1 to 4:1) as eluent to
afford 13 (0.83 g, 70%) as an
orange solid. M.p. 146–1478C;
1H NMR (400 MHz, CDCl3/TMS): d=
0.04 (s, 12H), 0.90 (s, 18H), 3.00 (t,
J=7.1 Hz, 4H), 3.51 (s, 6H), 3.90 (t,
J=7.4 Hz, 4H), 3.94 (s, 6H), 4.02 (s,
6H), 6.86 (s, 2H), 7.03 (s, 2H),
9.60 ppm
(s,
2H);
13C NMR
(100 MHz, CDCl3): d=À5.3, 18.4,
26.0, 34.3, 56.8, 57.1, 61.3, 62.8,
109.0, 112.7, 116.9, 120.3, 121.2,
127.4,
145.9,
148.1,
148.2,
151.2 ppm; IR (KBr): n˜ =3384, 2953,
2929, 2856, 1655, 1615, 1519,
1465, 1450, 1419, 1385, 1253,
1221, 1076, 1007, 927, 837, 777,
667 cmÀ1
; HRMS: m/z calcd for
[C42H62O10Si2+H]+:
783.3960;
found: 783.3959.
[1,1’,4,4’,5,5’,8,8’-Octamethoxy-
(2,2’-binaphthalene)-6,6’-diyl]bis-
Scheme 6. Attempted synthesis of pyranolactone 29.
(ethane-2,1-diyl)bis(oxy)bis(tert-
butyldimethylsilane) (14): NaH
(0.046 g, 1.92 mmol, 3.0 equiv) was
6.84 (d, J=3.0 Hz, 2H), 7.14 ppm (d, J=3.0 Hz, 2H); 13C NMR
(100 MHz, CDCl3): d=55.8, 60.9, 115.9, 117.7, 118.3, 133.0, 148.3,
155.5 ppm; IR (KBr): n˜ =3072, 3001, 2941, 2835, 1600, 1567, 1480,
1443, 1424, 1407, 1333, 1285, 1224, 1179, 1123, 1038, 1002, 949,
869, 855, 846, 807, 780, 770, 733, 720, 677, 625, 607 cmÀ1; HRMS:
m/z calcd for [C16H16O4Br2+H]+: 430.9494; found: 430.9492.
added to a solution of 13 (0.50 g, 0.64 mmol) in dry THF (15 mL) at
08C and was stirred for 30 min. MeI (0.16 mL, 2.56 mmol, 4.0 equiv)
was added, and the reaction mixture was stirred for 4 h at room
temperature. Ice-cooled water was added, and the mixture was ex-
tracted with EtOAc (3ꢁ20 mL). The combined organic layers were
washed with water and brine, dried (Na2SO4), and concentrated.
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and the mixture was stirred for
4 h. It was then quenched with
water (5 mL) and stirred for
30 min. THF was removed under
reduced pressure, and the aqueous
layer was extracted with EtOAc
(3ꢁ15 mL). The combined organic
layers were washed with water
and brine, dried (Na2SO4), and con-
centrated. The residue was purified
by silica gel column chromatogra-
phy using petroleum ether/EtOAc
(3:1 to 1:1) as eluent to give 7
(0.187 g, 93%) as a yellow solid.
M.p.
213–2148C;
1H NMR
(400 MHz, CDCl3/TMS): d=2.09 (s,
2H; OH), 3.08 (t, J=6.4 Hz, 4H),
3.54 (s, 6H), 3.83 (s, 6H), 3.96 (s,
6H), 3.97 (s, 6H), 3.97 (t, J=6.4 Hz,
4H), 6.79 (s, 2H), 7.08 ppm (s, 2H);
13C NMR (100 MHz, CDCl3): d=34.1,
56.8, 56.9, 61.7, 62.4, 63.5, 109.7,
111.1, 122.3, 122.6, 128.7, 128.8,
147.6, 148.0, 151.1, 152.7 ppm; IR
(KBr): n˜ =3512, 2925, 2874, 2831,
1596, 1492, 1452, 1368, 1347,
1243, 1197, 1147, 1079, 1058, 1021,
989, 834, 741, 678 cmÀ1; HRMS:
m/z calcd for [C32H38O10+H]+:
583.2543; found: 583.2540.
1,1’-(1,1’,4,4’,5,5’,8,8’-Octameth-
oxy-2,2’-binaphthyl-6,6’-diyl)di-
pent-4-en-2-ol
(0.139 g, 0.43 mmol, 2.5 equiv) and
TEMPO (5.5 mg, 0.035 mmol,
(5):
PhI(OAc)2
0.2 equiv) were added to a solution
of 7 (0.10 g, 0.172 mmol) in pen-
tane/CH2Cl2 (1:1, 8.0 mL) at room
temperature. The resulting mixture
was stirred for 4 h at the same
temperature. It was then diluted
with CH2Cl2 (10 mL) and washed
with saturated aqueous Na2S2O3
(5 mL). The aqueous layer was ex-
tracted with CH2Cl2 (4ꢁ10 mL),
and the combined organic layers
were washed with saturated aque-
Scheme 7. Synthesis of deoxyactinorhodin and deoxy-g-actinorhodin/crisamicin A isomer.
The residue was purified by silica gel column chromatography
ous NaHCO3 (5 mL) and brine, dried (Na2SO4), and concentrated.
The dialdehyde (99.3 mg) obtained was immediately used in the
next step.
using petroleum ether/EtOAc (9:1 to 3:2) as eluent to give 14
(0.445 g, 86%) as
a
yellow solid. M.p. 116–1178C; 1H NMR
(400 MHz, CDCl3/TMS): d=0.06 (s, 12H), 0.91 (s, 18H), 3.04 (t, J=
7.1 Hz, 4H), 3.53 (s, 6H), 3.81 (s, 6H), 3.94 (t, J=7.2 Hz, 4H), 3.95 (s,
6H), 3.96 (s, 6H), 6.85 (s, 2H), 7.07 ppm (s, 2H); 13C NMR (100 MHz,
CDCl3): d=À5.3, 18.4, 26.0, 34.1, 56.7, 56.8, 61.5, 62.5, 63.9, 110.2,
110.9, 122.1, 122.5, 128.6, 129.0, 147.5, 148.0, 151.0, 152.2 ppm; IR
(KBr): n˜ =2954, 2930, 2857, 1591, 1491, 1462, 1435, 1365, 1344,
1320, 1279, 1240, 1192, 1153, 1084, 1063, 1045, 989, 937, 833, 774,
739, 672 cmÀ1; HRMS: m/z calcd for [C44H66O10Si2+H]+: 811.4273;
found: 811.4281.
Allyl magnesium bromide (0.22 mL, 0.43 mmol, 2.5 equiv, 2m solu-
tion in THF) was added to a stirred solution of the above dialde-
hyde (99.3 mg) in dry THF (5 mL) at 08C. The reaction mixture was
stirred at room temperature for 3 h. After completion of the reac-
tion (monitored by TLC), it was quenched with saturated aqueous
NH4Cl (2 mL). The aqueous layer was extracted with EtOAc (3ꢁ
5 mL), and the combined organic layers were washed with water
and brine, dried (Na2SO4), and concentrated. The residue was puri-
fied by silica gel column chromatography using petroleum ether/
EtOAc (4:1 to 1:1) as eluent to afford 5 (97 mg, 85% from 7) as
2,2’-(1,1’,4,4’,5,5’,8,8’-Octamethoxy-2,2’-binaphthyl-6,6’-diyl)di-
ethanol (7): Tetra-n-butylammonium fluoride (TBAF; 0.87 mL,
0.865 mmol, 2.5 equiv, 1m solution in THF) was added to a solution
of 14 (0.28 g, 0.346 mmol) in dry THF (15 mL) at room temperature,
1
a yellow solid. M.p. 168–1698C; H NMR (400 MHz, CDCl3/TMS): d=
2.30–2.44 (m, 4H), 2.92 (dd, J=13.5, 8.1 Hz, 2H), 3.03 (dd, J=13.5,
4.2 Hz, 2H), 3.55 (s, 6H), 3.82 (s, 6H), 3.96 (s, 6H), 3.97 (s, 6H),
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4.06–4.09 (m, 2H), 5.16–5.22 (m, 4H), 5.88–5.98 (m, 2H), 6.79 (s,
2H), 7.09 ppm (s, 2H); 13C NMR (100 MHz, CDCl3): d=38.1, 41.8,
56.7, 56.8, 61.5, 62.2, 71.6, 110.0, 111.2, 117.8, 122.3, 122.5, 128.5,
128.8, 135.0, 147.5, 147.9, 151.0, 152.5 ppm; IR (KBr): n˜ =3454,
3073, 2930, 2836, 1638, 1602, 1495, 1455, 1385, 1365, 1347, 1243,
7.1 Hz, 6H), 2.49–2.60 (m, 4H), 2.98–3.07 (m, 4H), 3.12 (s, 2H; OH),
3.53 (s, 6H), 3.79 (s, 6H), 3.94 (s, 6H), 3.95 (s, 6H), 4.14 (q, J=
7.4 Hz, 4H), 4.40–4.46 (m, 2H), 6.79 (s, 2H), 7.07 ppm (s, 2H);
13C NMR (100 MHz, CDCl3): d=14.1, 37.4, 40.9, 56.6, 56.8, 60.5, 61.5,
62.1, 68.8, 109.8, 111.1, 122.3, 122.4, 127.6, 128.8, 147.5, 147.9,
150.9, 152.4, 172.7 ppm; IR (CHCl3): n˜ =3445, 2930, 2838, 1729,
1195, 1109, 1080, 1049, 1021, 990, 913, 874, 825, 745, 618 cmÀ1
;
HRMS: m/z calcd for [C38H46O10+H]+: 663.3169; found: 663.3172.
1595, 1465, 1368, 1245, 1193, 1155, 1079, 1057, 993, 842, 669 cmÀ1
HRMS: m/z calcd for [C40H50O14+Na]+: 777.3093; found: 777.3093.
Diethyl 2,2’-(5,5’,6,6’,9,9’,10,10’-octamethoxy-1,1’-dimethyl-
;
Diethyl
4,4’-[5,5’-dihydroxy-1,1’,4,4’,8,8’-hexamethoxy-(2,2’-bi-
naphthalene)-6,6’-diyl]bis(3-tert-butyldimethylsilyloxy)butanoate
(18): Alkyne 17 (0.73 g, 2.7 mmol, 4.0 equiv) in dry and degassed
THF (5 mL) was added to a solution of freshly prepared Fischer car-
bene 9 (0.5 g, 0.673 mmol) in dry and degassed THF (10 mL). The
reaction mixture was heated at 458C for 15 h and then allowed to
cool to room temperature. It was exposed to air and stirred for 1 h.
THF was removed under reduced pressure, and the residue was
purified by silica gel column chromatography using petroleum
ether/EtOAc (9:1 to 4:1) as eluent to afford 18 (0.353 g, 52%) as an
3,3’,4,4’-tetrahydro-1H,1’H-8,8’-dibenzo[g]isochromene-3,3’-diyl)-
diacetate (20): Acetaldehyde diethylacetal (0.06 mL, 0.424 mmol,
4.0 equiv) and TMSOTf (0.06 mL, 0.318 mmol, 3.0 equiv) were
added to a solution of 16 (0.080 g, 0.106 mmol) in CH2Cl2 (10 mL)
at 08C. The reaction mixture was warmed to room temperature
and stirred for 2 h. It was then quenched with saturated aqueous
NaHCO3 (5 mL), and the solution was extracted with CH2Cl2 (3ꢁ
20 mL). The combined organic layers were washed with brine,
dried (Na2SO4), and concentrated. The residue was purified by silica
gel column chromatography using petroleum ether/EtOAc (9:1 to
1:1) as eluent to afford 20 (0.063 g, 74%, colorless oil) as an insepa-
1
orange solid. M.p. 173–1748C; H NMR (400 MHz, CDCl3/TMS): d=
0.03 (s, 6H), 0.07 (s, 6H), 0.88 (s, 18H), 1.24 (t, J=7.1 Hz, 6H), 2.44–
2.52 (m, 4H), 2.86 (dd, J=13.0, 7.4 Hz, 2H), 3.10 (dd, J=13.0,
5.6 Hz, 2H), 3.52 (s, 6H), 3.94 (s, 6H), 4.03 (s, 6H), 4.06–4.13 (m,
4H), 4.57–4.62 (m, 2H), 6.80 (s, 2H), 7.03 (s, 2H), 9.60 ppm (s, 2H;
OH); 13C NMR (100 MHz, CDCl3): d=À5.1, À4.6, 14.2, 17.9, 25.8,
39.0, 42.4, 56.8, 57.2, 60.2, 61.3, 69.2, 109.1, 113.1, 116.9, 119.4,
121.4, 127.6, 146.3, 148.1, 148.2, 151.2, 172.1 ppm; IR (CHCl3): n˜ =
3391, 2954, 2930, 2856, 1732, 1612, 1463, 1449, 1412, 1366, 1311,
1
rable mixture of diastereomers. The H NMR spectra showed a mix-
ture of diastereomers with conclusive and characteristic peaks for
pyran methyl, C1 proton, and ester ethyl groups. The entire struc-
ture was confirmed by HRMS: m/z calcd for [C44H54O14+Na]+:
829.3407; found: 829.3412.
(3E,3’E)-Dimethyl
naphthyl-6,6’-diyl)dibut-3-enoate
4,4’-(1,1’,4,4’,5,5’,8,8’-octamethoxy-2,2’-bi-
(8): PhI(OAc)2 (0.139 g,
1251, 1229, 1197, 1149, 1076, 1045, 1005, 962, 838, 812, 667 cmÀ1
;
HRMS: m/z calcd for [C50H74O14Si2+Na]+: 977.4509; found:
0.43 mmol, 2.5 equiv) and TEMPO (5.5 mg, 0.035 mmol, 0.2 equiv)
were added sequentially to a solution of 7 (0.10 g, 0.172 mmol) in
pentane/CH2Cl2 (1:1, 8 mL) at room temperature. The resulting mix-
ture was stirred for 4 h at room temperature. It was then diluted
with CH2Cl2 (10 mL) and washed with saturated aqueous Na2S2O3
(5 mL). The aqueous phase was extracted with CH2Cl2 (4ꢁ10 mL).
The combined organic layers were washed with saturated aqueous
NaHCO3 (5 mL) and brine, dried (Na2SO4), and concentrated. The
crude dialdehyde (0.099 g) obtained was immediately used in the
next step.
977.4509.
Diethyl 4,4’-[1,1’,4,4’,5,5’,8,8’-octamethoxy-(2,2’-binaphthalene)-
6,6’-diyl]bis(3-tert-butyldimethylsilyloxy)butanoate (19): NaH
(24 mg, 1.0 mmol, 3.0 equiv) was added to a solution of 18 (0.32 g,
0.335 mmol) in dry DMF (10 mL) at 08C and stirred for 30 min.
Then MeI (0.1 mL, 1.6 mmol, 4.8 equiv) was added, and the reac-
tion mixture was stirred for 4 h at room temperature. Ice-cooled
water was added, and the mixture was extracted with EtOAc (3ꢁ
20 mL). The combined organic layers were washed with water and
brine, dried (Na2SO4), and concentrated. The residue was purified
by silica gel column chromatography using petroleum ether/EtOAc
(9:1 to 3:2) as eluent to give 19 (0.29 g, 88%) as a yellow solid.
M.p. 139–1418C; 1H NMR (400 MHz, CDCl3/TMS): d=0.01 (s, 6H),
0.06 (s, 6H), 0.87 (s, 18H), 1.23 (t, J=7.1 Hz, 6H), 2.47 (d, J=6.3 Hz,
4H), 2.92 (dd, J=13.0, 7.3 Hz, 2H), 3.11 (dd, J=13.0, 5.9 Hz, 2H),
3.52 (s, 6H), 3.80 (s, 6H), 3.95 (s, 6H), 3.96 (s, 6H), 4.05–4.13 (m,
4H), 4.53–4.60 (m, 2H), 6.80 (s, 2H), 7.07 ppm (s, 2H); 13C NMR
(100 MHz, CDCl3): d=À5.1, À4.7, 14.1, 17.9, 25.7, 38.9, 42.3, 56.6,
56.8, 60.2, 61.5, 62.2, 69.9, 110.5, 111.0, 122.2, 122.5, 127.9, 128.6,
147.5, 148.2, 151.0, 152.1, 171.8 ppm; IR (CHCl3): n˜ =2955, 2930,
2856, 1734, 1595, 1494, 1464, 1367, 1326, 1248, 1216, 1198, 1148,
1081, 962, 838, 667 cmÀ1; HRMS: m/z calcd for [C52H78O14Si2+Na]+:
1005.4822; found: 1005.4822.
The above crude dialdehyde (0.099 g) in DMF (4 mL) was added to
a solution of piperidinium acetate (1.0 mg, 0.007 mmol, 4.0 mol%)
in DMF (1.4 mL). A solution of monomethyl malonate (0.082 g,
0.69 mmol, 4.0 equiv) in DMF (0.6 mL) was added, and the reaction
mixture was stirred at 1008C for 5 h. It was then allowed to cool to
room temperature and diluted with EtOAc/H2O (1:1, 20 mL). The
layers were separated, and the aqueous layer was saturated with
NaCl and extracted with EtOAc (4ꢁ10 mL). The combined organic
layers were washed with water and brine, dried (Na2SO4), and con-
centrated. The residue was purified by silica gel column chroma-
tography using petroleum ether/EtOAc (4:1 to 1:1) as eluent to
afford 8 and its a,b-unsaturated isomer in minor amount (0.075 g,
63% over two steps) as a yellow solid. M.p. 177–1788C; 1H NMR
(400 MHz, CDCl3/TMS): d=3.39 (dd, J=7.1, 1.4 Hz, 4H), 3.54 (s, 6H),
3.76 (s, 6H), 3.79 (s, 6H), 3.96 (s, 6H), 4.01 (s, 6H), 6.39 (dt, J=16.0,
7.2 Hz, 2H), 7.04 (s, 2H), 7.08 (dt, J=16.1, 1.4 Hz, 2H), 7.09 ppm (s,
2H); 13C NMR (100 MHz, CDCl3): d=38.5, 51.8, 56.5, 56.8, 61.5, 62.6,
103.9, 111.4, 122.3, 122.5, 122.7, 126.4, 127.9, 129.3, 147.46 147.5,
151.6, 152.6, 172.1 ppm; IR (KBr): n˜ =3002, 2922, 2833, 1742, 1624,
1588, 1460, 1432, 1410, 1372, 1344, 1284, 1244, 1199, 1165, 1081,
1060, 989, 969, 840, 818, 765, 753 cmÀ1; HRMS: m/z calcd for
[C38H42O12+H]+: 691.2755; found: 691.2749.
Diethyl 4,4’[1,1’,4,4’,5,5’,8,8’-octamethoxy-(2,2’-binaphthalene)-
6,6’-diyl]bis(3-hydroxybutanoate) (16): TBAF (0.64 mL, 0.64 mmol,
2.5 equiv, 1m solution in THF) was added to a solution of 19
(0.25 g, 0.254 mmol) in dry THF (10 mL) at room temperature, and
the mixture was stirred for 4 h. It was then quenched with water
(5 mL) and stirred for 30 min. THF was removed under reduced
pressure, and the aqueous layer was extracted with EtOAc (3ꢁ
15 mL). The combined organic layers were washed with water and
brine, dried (Na2SO4), and concentrated. The residue was purified
by silica gel column chromatography using petroleum ether/EtOAc
(3:1 to 1:1) as eluent to give 16 (0.184 g, 96%) as a yellow solid.
M.p. 201–2028C; 1H NMR (400 MHz, CDCl3/TMS): d=1.24 (t, J=
(4R,4’R,5R,5’R)-5,5’-(1,1’,4,4’,5,5’,8,8’-Octamethoxy-2,2’-binaphth-
yl-6,6’-diyl)bis(4-hydroxydihydrofuran-2(3H)-one) (6): A mixture
of K3[Fe(CN)6] (0.342 g, 1.04 mmol, 8.0 equiv), K2CO3 (0.144 g,
1.04 mmol, 8.0 equiv), MeSO2NH2 (0.037 g, 0.39 mmol, 3.0 equiv),
Chem. Eur. J. 2015, 21, 4842 – 4852
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NaHCO3 (0.087 g, 1.04 mmol, 8.0 equiv), hydroquinidine 1,4-phtha-
lazinediyl diether ((DHQD)2-PHAL) (10 mg, 0.013 mmol, 10 mol%),
and K2OsO4·2H2O (1.5 mg, 3.9 mmol, 3 mol%) in tBuOH (2 mL) and
water (5 mL) was stirred for 5 min at room temperature and then
cooled to 08C. A solution of the b,g-unsaturated ester 8 (0.09 g,
0.13 mmol) in tBuOH (3 mL) was added to this mixture. The reac-
tion mixture was stirred at 08C for 24 h and at room temperature
for 24 h. It was then quenched with solid Na2SO3 (0.164 g) and
stirred for 30 min. The solution was extracted with EtOAc (5ꢁ
10 mL), and the combined organic layers were washed with 1m
KOH (3 mL), water (5 mL), and brine, dried (Na2SO4), and concen-
trated. The residue was purified by silica gel column chromatogra-
phy using petroleum ether/EtOAc (3:2 to 1:3) as eluent to afford 6
(0.063 g, 70%) as a yellow solid. M.p. 2908C (decomp); [a]2D5 = +
10.5 (c=0.44, CHCl3); 1H NMR (400 MHz, CDCl3/TMS): d=2.78 (d,
J=17.7 Hz, 2H), 3.00 (dd, J=17.8, 5.5 Hz, 2H), 3.53 (s, 6H), 3.84 (s,
6H), 3.94 (s, 6H), 4.01 (s, 6H), 4.95–4.97 (m, 2H), 5.93 (d, J=3.5 Hz,
2H), 7.03 (s, 2H), 7.11 ppm (s, 2H); 13C NMR (100 MHz, CDCl3): d=
38.2, 56.5, 56.7, 61.6, 62.5, 69.7, 82.2, 104.9, 110.8, 121.7, 123.2,
123.7, 129.5, 146.2, 147.6, 150.9, 153.2, 175.6 ppm; IR (CHCl3): n˜ =
3472, 2929, 2850, 1776, 1595, 1506, 1468, 1452, 1371, 1309, 1242,
1196, 1159, 1114, 1079, 1055, 1032, 905, 843, 797, 701 cmÀ1; HRMS:
m/z calcd for [C36H38O14+Na]+: 717.2154; found: 717.2159.
2,2’-(1,1’,5,5’,8,8’-Hexamethoxy-2,2’-binaphthalene-6,6’-diyl)bis-
(ethan-1-ol) (26): TBAF (1.2 mL, 1.2 mmol, 2.5 equiv, 1m solution in
THF) was added to a solution of 25 (0.35 g, 0.47 mmol) in dry THF
(15 mL) at room temperature, and the mixture was stirred for 4 h.
It was then quenched with water (5 mL) and stirred for 30 min.
THF was removed under reduced pressure and the aqueous layer
was extracted with EtOAc (3ꢁ15 mL). The combined organic layers
were washed with water and brine, dried (Na2SO4), and concentrat-
ed. The residue was purified by silica gel column chromatography
using petroleum ether/EtOAc (3:1 to 1:1) as eluent to give 26
(0.227 g, 93%) as
a
yellow solid. M.p. 196–1988C; 1H NMR
(400 MHz, CDCl3/TMS): d=2.11 (s, 2H; OH), 3.08 (t, J=6.4 Hz, 4H),
3.56 (s, 6H), 3.92 (s, 6H), 3.97 (t, J=6.4 Hz, 4H), 3.98 (s, 6H), 6.72 (s,
2H), 7.65 (d, J=8.7 Hz, 2H), 7.85 ppm (d, J=8.7 Hz, 2H); 13C NMR
(100 MHz, CDCl3): d=33.8, 56.4, 61.6, 61.9, 63.2, 107.9, 117.3, 120.5,
127.1, 129.1, 130.7, 131.0, 147.7, 152.8, 154.1 ppm; IR (CHCl3): n˜ =
3431, 2934, 2840, 1619, 1598, 1570, 1453, 1380, 1359, 1341, 1244,
1135, 1099, 1045, 1016, 843 cmÀ1
; HRMS: m/z calcd for
[C30H34O8+Na]+: 545.2146; found: 545.2146.
(3E,3’E)-Dimethyl 4,4’-(1,1’,5,5’,8,8’-hexamethoxy-2,2’-binaphtha-
lene-6,6’-diyl)bis(but-3-enoate) (27): PhI(OAc)2 (0.31 g, 0.96 mmol,
2.5 equiv) and TEMPO (0.012 g, 0.077 mmol, 0.2 equiv) were added
sequentially to a solution of 26 (0.2 g, 0.383 mmol) in pentane/
CH2Cl2 (1:1, 14 mL) at room temperature. The resulting mixture was
stirred for 4 h at room temperature and then diluted with CH2Cl2
(10 mL) and washed with saturated aqueous Na2S2O3 (5 mL). The
aqueous phase was extracted with CH2Cl2 (4ꢁ10 mL). The com-
bined organic layers were washed with saturated aqueous NaHCO3
(5 mL) and brine, dried (Na2SO4), and concentrated. The crude dia-
ldehyde (0.197 g) obtained was immediately used in the next step.
6,6’-Bis[2-(tert-butyldimethylsilyloxy)ethyl]-1,1’,8,8’-tetrameth-
oxy-2,2’-binaphthyl-5,5’-diol (24): Alkyne 10 (1.30 g, 7.04 mmol,
4.0 equiv) in dry and degassed THF (5 mL) was added to a solution
of freshly prepared Fischer carbene 23[15] (1.2 g, 1.76 mmol) in dry
and degassed THF (15 mL). The reaction mixture was heated at
558C for 15 h and then allowed to cool to room temperature. It
was exposed to air and stirred for 1 h. THF was removed under re-
duced pressure and the residue was purified by silica gel column
chromatography using petroleum ether/EtOAc (9:1 to 4:1) as
eluent to afford 24 (0.84 g, 66%) as an orange solid. M.p. 131–
1338C; 1H NMR (400 MHz, CDCl3/TMS): d=0.11 (s, 12H), 0.95 (s,
18H), 3.02 (t, J=4.8 Hz, 4H), 3.56 (s, 6H), 3.94 (s, 6H), 4.04 (t, J=
4.9 Hz, 4H), 6.60 (s, 2H), 7.61 (d, J=8.7 Hz, 2H), 8.11 (d, J=8.7 Hz,
2H), 8.52 ppm (s, 2H; OH); 13C NMR (100 MHz, CDCl3): d=À5.6,
18.3, 25.8, 35.8, 57.1, 61.5, 65.9, 110.1, 117.9, 119.7, 120.4, 128.6,
129.4, 129.8, 145.5, 149.5, 153.2 ppm; IR (CHCl3): n˜ =3277, 2954,
2931, 2858, 1661, 1626, 1600, 1464, 1353, 1316, 1257, 1218, 1138,
1098, 1063, 1039, 1008, 939, 925, 856, 837, 777, 667 cmÀ1; HRMS:
m/z calcd for [C40H58O8Si2+H]+: 723.3743; found: 723.3744.
The crude dialdehyde (0.197 g) in DMF (7 mL) was added to a solu-
tion of piperidinium acetate (2.2 mg, 0.0153 mmol, 4.0 mol%) in
DMF (2 mL).
A solution of monomethyl malonate (0.180 g,
1.53 mmol, 4.0 equiv) in DMF (0.6 mL) was added, and the reaction
mixture was stirred at 1008C for 5 h. It was then allowed to cool to
room temperature and diluted with EtOAc/H2O (1:1, 20 mL). The
layers were separated and the aqueous layer was saturated with
NaCl and extracted with EtOAc (4ꢁ10 mL). The combined organic
layers were washed with water and brine, dried (Na2SO4), and con-
centrated. The residue was purified by silica gel column chroma-
tography using petroleum ether/EtOAc (4:1 to 1:1) as eluent to
afford 27 and its a,b-unsaturated isomer in a minor amount
(0.152 g, 63% over two steps) as a yellow solid. M.p. 183–1858C;
1H NMR (400 MHz, CDCl3/TMS): d=3.39 (d, J=7.2 Hz, 4H), 3.56 (s,
6H), 3.76 (s, 6H), 3.90 (s, 6H), 4.02 (s, 6H), 6.43 (dt, J=15.8, 7.2 Hz,
2H), 6.97 (s, 2H), 7.00 (d, J=16.0 Hz, 2H), 7.65 (d, J=8.7 Hz, 2H),
7.89 ppm (d, J=8.7 Hz, 2H); 13C NMR (100 MHz, CDCl3): d=38.6,
52.0, 56.4, 61.7, 62.4, 102.6, 117.7, 121.2, 122.7, 124.9, 127.7, 129.7,
130.8, 131.3, 147.2, 152.8, 154.1, 172.1 ppm; IR (CHCl3): n˜ =2933,
2843, 1738, 1589, 1450, 1383, 1347, 1243, 1167, 1099, 1054, 1018,
976, 798 cmÀ1; HRMS: m/z calcd for [C36H38O10+Na]+: 653.2357;
found: 653.2357.
(1,1’,5,5’,8,8’-Hexamethoxy-2,2’-binaphthalene-6,6’-diyl)bis-
(ethane-2,1-diyl)bis(oxy)bis(tert-butyldimethylsilane) (25): NaH
(0.045 g, 1.87 mmol, 3.0 equiv) was added to a solution of 24
(0.45 g, 0.622 mmol) in dry THF (15 mL) at 08C and stirred for
30 min. Then MeI (0.16 mL, 2.5 mmol, 4.0 equiv) was added, and
the reaction mixture was stirred for 4 h at room temperature. Ice-
cooled water was added, and the mixture was extracted with
EtOAc (3ꢁ20 mL). The combined organic layers were washed with
water and brine, dried (Na2SO4), and concentrated. The residue was
purified by silica gel column chromatography using petroleum
ether/EtOAc (9:1 to 3:2) as eluent to give 25 (0.402 g, 86%) as
(4R,4’R,5R,5’R)-5,5’-(1,1’,5,5’,8,8’-Hexamethoxy-2,2’-binaphtha-
lene-6,6’-diyl)bis(4-hydroxydihydrofuran-2(3H)-one) (28): A mix-
ture of K3[Fe(CN)6] (0.543 g, 1.65 mmol, 8.0 equiv), K2CO3 (0.228 g,
1.65 mmol, 8.0 equiv), MeSO2NH2 (0.059 g, 0.62 mmol, 3.0 equiv),
NaHCO3 (0.136 g, 1.62 mmol, 8.0 equiv), (DHQD)2-PHAL (8.0 mg,
0.0103 mmol, 5 mol%), and K2OsO4·2H2O (1.5 mg, 0.0041 mmol,
2 mol%) in tBuOH (2 mL) and water (5 mL) was stirred for 5 min
and cooled to 08C. A solution of the b,g-unsaturated ester 27
(0.130 g, 0.206 mmol) in tBuOH (3 mL) was added to this mixture.
The reaction mixture was stirred at 08C for 24 h and at room tem-
perature for 24 h. It was then quenched with solid Na2SO3 (0.20 g)
1
a yellow solid. M.p. 121–1228C; H NMR (400 MHz, CDCl3/TMS): d=
0.06 (s, 12H), 0.91 (s, 18H), 3.05 (t, J=7.0 Hz, 4H), 3.56 (s, 6H), 3.92
(s, 6H), 3.95 (t, J=7.3 Hz, 4H), 3.98 (s, 6H), 6.78 (s, 2H), 7.65 (d, J=
8.7 Hz, 2H), 7.85 ppm (d, J=8.7 Hz, 2H); 13C NMR (100 MHz, CDCl3):
d=À5.3, 18.4, 26.0, 33.9, 56.4, 61.6, 62.1, 63.7, 108.4, 117.3, 120.4,
127.4, 129.0, 130.6, 131.0, 147.6, 152.4, 154.0 ppm; IR (CHCl3): n˜ =
2954, 2931, 2857, 1619, 1598, 1570, 1463, 1380, 1360, 1342, 1245,
1100, 1045, 1010, 921, 837, 775, 667 cmÀ1; HRMS: m/z calcd for
[C42H62O8Si2+Na]+: 773.3875; found: 773.3876.
Chem. Eur. J. 2015, 21, 4842 – 4852
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Full Paper
and stirred for 30 min. The solution was extracted with EtOAc (5ꢁ
10 mL), and the combined organic layers were washed sequentially
with 1m KOH (4 mL), water (5 mL), and brine, dried (Na2SO4), and
concentrated. The residue was purified by silica gel column chro-
matography using petroleum ether/EtOAc (3:2 to 1:3) as eluent to
1m solution in THF) was added to a solution of 31 (0.71 g,
0.769 mmol) in dry THF (15 mL) at room temperature, and the mix-
ture was stirred for 4 h. It was then quenched with water (5 mL)
and stirred for 30 min. THF was removed under reduced pressure,
and the aqueous layer was extracted with EtOAc (3ꢁ15 mL). The
combined organic layers were washed with water and brine, dried
(Na2SO4), and concentrated. The residue was purified by silica gel
column chromatography using petroleum ether/EtOAc (1:1 to 1:3)
to give 32 (0.512 g, 96%) as a colorless solid. M.p. 198–2008C;
1H NMR (400 MHz, CDCl3/TMS): d=1.27 (t, J=7.1 Hz, 6H), 2.51–2.62
(m, 4H), 2.99–3.10 (m, 4H) 3.36 (d, J=3.8 Hz, 2H; OH), 3.56 (s, 6H),
3.91 (s, 6H), 3.98 (s, 6H), 4.17 (q, J=7.1 Hz, 4H), 4.40–4.46 (m, 2H),
6.73 (s, 2H), 7.65 (d, J=8.7 Hz, 2H), 7.84 ppm (d, J=8.7 Hz, 2H);
13C NMR (100 MHz, CDCl3): d=14.1, 37.2, 40.8, 56.3, 60.6, 61.6, 61.8,
68.8, 108.1, 117.3, 120.7, 126.1, 129.2, 130.7, 130.9, 147.7, 152.7,
154.1, 172.8 ppm; IR (CHCl3): n˜ =3486, 2984, 2935, 2842, 1732,
1622, 1599, 1569, 1455, 1380, 1338, 1246, 1193, 1145, 1099, 1048,
afford 28 (0.092 g, 70%) as a yellow solid. M.p. 247–2488C; [a]D25
=
À16.3 (c=0.6, CHCl3); 1H NMR (400 MHz, CDCl3/TMS): d=2.77 (d,
J=17.6 Hz, 2H), 2.98 (dd, J=17.7, 5.4 Hz, 2H), 3.55 (s, 6H), 3.95 (s,
6H), 4.00 (s, 6H), 4.89 (t, J=4.3 Hz, 2H), 5.91 (d, J=3.5 Hz, 2H),
6.96 (s, 2H), 7.68 (d, J=8.6 Hz, 2H), 7.82 ppm (d, J=8.7 Hz, 2H);
13C NMR (100 MHz, CDCl3): d=38.3, 56.4, 61.7, 62.2, 69.8, 81.8,
103.8, 117.2, 121.6, 122.4, 129.9, 130.4, 131.0, 146.1, 153.2, 154.2,
175.6 ppm; IR (CHCl3): n˜ =3457, 3007, 2935, 2847, 1778, 1621,
1599, 1572, 1454, 1383, 1339, 1231, 1198, 1157, 1099, 1079, 1060,
1029, 982, 906, 868, 800, 701 cmÀ1
[C34H34O12+H]+: 635.2123; found: 635.2122.
; HRMS: m/z calcd for
Diethyl 4,4’-(5,5’-dihydroxy-1,1’,8,8’-tetramethoxy-2,2’-binaph-
thyl-6,6’-diyl)bis(3-tert-butyldimethylsilyloxy)butanoate (30):
1013, 980, 857, 829, 798, 667 cmÀ1
[C38H46O12+Na]+: 717.2881; found: 717.2885.
; HRMS: m/z calcd for
Alkyne 17 (1.19 g, 4.4 mmol, 3.0 equiv) in dry and degassed THF
(5 mL) was added to a solution of freshly prepared Fischer carbene
23 (1.0 g, 1.466 mmol) in dry and degassed THF (15 mL). The reac-
tion mixture was stirred at 458C for 15 h and then allowed to cool
to room temperature. It was then exposed to air and stirred for
1 h. THF was removed under reduced pressure, and the residue
was purified by silica gel column chromatography using petroleum
ether/EtOAc (9:1 to 4:1) to afford 30 (0.826 g, 63%) as a pale
yellow solid. M.p. 163–1658C; 1H NMR (400 MHz, CDCl3/TMS): d=
0.09 (s, 6H), 0.13 (s, 6H), 0.95 (s, 18H), 1.28 (t, J=7.1 Hz, 6H), 2.47–
2.58 (m, 4H), 3.02 (dd, J=14.7, 5.8 Hz, 2H), 3.23 (dd, J=14.7,
3.0 Hz, 2H), 3.55 (s, 6H), 3.92 (s, 6H), 4.18 (q, J=7.1 Hz, 4H), 4.53–
4.59 (m, 2H), 6.53 (s, 2H), 7.63. (d, J=8.7 Hz, 2H), 8.10 (d, J=
8.7 Hz, 2H), 8.21 ppm (s, 2H; OH); 13C NMR (100 MHz, CDCl3): d=
À5.03, À5.01, 14.1, 18.0, 25.7, 39.1, 40.5, 56.9, 60.7, 61.5, 70.9,
110.5, 116.2, 117.8, 120.5, 128.4, 129.4, 129.8, 145.2, 149.4, 153.2,
171.6 ppm; IR (CHCl3): n˜ =3305, 2955, 2932, 2858, 1735, 1662,
1626, 1600, 1578, 1464, 1375, 1349, 1315, 1257, 1194, 1146, 1097,
1041, 1008, 961, 839, 812, 778, 703 cmÀ1; HRMS: m/z calcd for
[C48H70O12Si2+K]+: 933.4043; found: 933.4048.
Diethyl 2,2’-(5,5’,9,9’,10,10’-hexamethoxy-1,1’-dimethyl-3,3’,4,4’-
tetrahydro-1H;1’H-8,8’-dibenzo[g]isochromene-3,3’-diyl)diacetate
(33): Acetaldehyde diethylacetal (0.082 mL, 0.576 mmol, 4.0 equiv)
and TMSOTf (0.078 mL, 0.432 mmol, 3.0 equiv) were added to a so-
lution of 32 (0.10 g, 0.144 mmol) in CH2Cl2 (10 mL) at 08C. The re-
action mixture was warmed to room temperature and stirred for
2 h. It was then quenched with saturated aqueous NaHCO3 (5 mL),
and the solution was extracted with CH2Cl2 (3ꢁ20 mL). The com-
bined organic layers were washed with brine, dried (Na2SO4), and
concentrated. The residue was purified by silica gel column chro-
matography using petroleum ether/EtOAc (9:1 to 1:1) to afford an
inseparable mixture of diastereomers 33 (0.087 g, 81%). The mix-
ture was used for the next reaction immediately.
Diethyl
2,2-(9,’9’-dimethoxy-1,1’-dimethyl-5,5’,10,10’-tetraoxo-
3,3’,4,4’,-5,5’,10,10’-octahydro-1H,1’H-[8,8’-dibenzo[g]isochro-
mene]-3,3’-diyl)diacetate (34) and diethyl 2,2’-(9,9’-dimethoxy-
1,1’-dimethyl-5,5’,10,10’-tetraoxo-3,3’,4,4’,-5,5’,10,10’-octahydro-
1H,1’H-[8,8’-dibenzo[g]isochromene]-3,3’-diyl]diacetate (35):
A
solution of ceric(IV) ammonium nitrate (0.235 g, 0.428 mmol,
4.0 equiv) in water (5 mL) was added to a stirred solution of 33
(0.080 g, 0.107 mmol) in CH3CN (5 mL). The reaction mixture was
stirred at room temperature for 45 min. It was then diluted with
EtOAc (15 mL), and the organic layer was separated. The aqueous
layer was extracted with EtOAc (3ꢁ15 mL), and the combined or-
ganic layers were washed with water and brine, dried (Na2SO4),
and concentrated. The residue was purified by silica gel column
chromatography using petroleum ether/EtOAc (9:1 to 7:3) as
eluent to give 34 (45.6 mg, 62%) and 35 (13.3 mg, 18%) as yellow
Diethyl 4,4’-(1,1’,5,5’,8,8’-hexamethoxy-2,2’-binaphthyl-6,6’-diyl)-
bis(3-tert-butyldimethylsilyloxy)butanoate (31): NaH (0.054 g,
2.23 mmol, 2.5 equiv) was added to a solution of 30 (0.80 g,
0.893 mmol) in dry DMF (15 mL) at 08C and stirred for 30 min.
Then MeI (0.25 mL, 4.02 mmol, 4.5 equiv) was added, and the reac-
tion mixture was stirred for 3 h at room temperature. Ice-cooled
water was added, and the mixture was extracted with EtOAc (3ꢁ
20 mL). The combined organic layers were washed with water and
brine, dried (Na2SO4), and concentrated. The residue was purified
by silica gel column chromatography using petroleum ether/EtOAc
(9:1 to 3:2) as eluent to give 31 (0.726 g, 88%) as a colorless solid.
M.p. 139–1418C; 1H NMR (400 MHz, CDCl3/TMS): d=0.00 (s, 6H),
0.06 (s, 6H), 0.87 (s, 18H), 1.24 (t, J=7.1 Hz, 6H), 2.49 (d, J=6.1 Hz,
4H), 2.93 (dd, J=13.1, 7.1 Hz, 2H), 3.10 (dd, J=13.1, 5.9 Hz, 2H),
3.55 (s, 6H), 3.90 (s, 6H), 3.98 (s, 6H), 4.06–4.15 (m, 4H), 4.52–4.58
(m, 2H), 6.73 (s, 2H), 7.66. (d, J=8.7 Hz, 2H), 7.84 ppm (d, J=
8.7 Hz, 2H); 13C NMR (100 MHz, CDCl3): d=À5.1, À4.7, 14.2, 18.0,
25.7, 38.6, 42.3, 56.4, 60.3, 61.6, 61.7, 69.9, 108.8, 117.3, 120.5,
126.5, 129.0, 130.6, 131.0, 148.0, 152.4, 154.0, 171.8 ppm; IR
(CHCl3): n˜ =2954, 2931, 2856, 1737, 1662, 1619, 1600, 1570, 1464,
1381, 1341, 1312, 1251, 1204, 1147, 1099, 1071, 985, 961, 910, 837,
1
solids. For 34: M.p. 165–1668C; H NMR (400 MHz, CDCl3/TMS): d=
1.31 (t, J=7.2 Hz, 6H), 1.57 (d, J=6.8 Hz, 6H), 2.38 (ddd, J=18.9,
10.5, 2.0 Hz, 2H), 2.61–2.69 (m, 4H), 2.81 (dd, J=18.9, 3.1 Hz, 2H),
3.63 (s, 6H), 4.16–4.27 (m, 4H), 4.32–4.39 (m, 2H), 5.06 (q, J=
6.8 Hz, 2H), 7.69 (d, J=7.9 Hz, 2H), 8.00 ppm (d, J=7.9 Hz, 2H);
13C NMR (100 MHz, CDCl3): d=14.2, 19.3, 27.5, 40.7, 60.8, 61.9, 63.5,
67.5, 122.4, 124.5, 133.9, 136.3, 138.6, 139.6, 147.9, 157.8, 170.6,
182.3, 183.4 ppm; IR (CHCl3): n˜ =2980, 2933, 2854, 1738, 1659,
1635, 1558, 1462, 1402, 1373, 1312, 1268, 1205, 1160, 1127, 1093,
1075, 1032, 990, 952, 855, 825, 666 cmÀ1; HRMS: m/z calcd for
1
[C38H38O12+Na]+: 709.2255; found: 709.2253. For 35: H NMR spec-
troscopy indicated one pyran ring with a syn C1 methyl with a C3
side chain and another pyran ring with anti placement of the
812, 777, 735 cmÀ1
;
HRMS: m/z calcd for [C50H74O12Si2+K]+:
961.4356; found: 961.4354.
1
groups. H NMR (400 MHz, CDCl3/TMS): d=1.25–1.35 (m, 6H), 1.52
Diethyl 4,4’-(1,1’,5,5’,8,8’-hexamethoxy-2,2’-binaphthyl-6,6’-diyl)-
bis(3-hydroxybutanoate) (32): TBAF (2.0 mL, 2.0 mmol, 2.6 equiv,
(d, J=6.6 Hz, 3H), 1.53 (d, J=6.7 Hz, 3H), 2.28–2.41 (m, 2H), 2.60–
2.89 (m, 6H), 3.618 (s, 3H), 3.62 (s, 3H), 3.89–3.99 (m, 1H), 4.15–
Chem. Eur. J. 2015, 21, 4842 – 4852
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4.24 (m, 4H), 4.30–4.38 (m, 1H), 4.85–4.95 (m, 1H), 5.01–5.09 (m,
1H), 7.62–7.71 (m, 2H), 7.95–8.03 ppm (m, 2H); HRMS: m/z calcd
for [C38H38O12+Na]+: 709.2255; found: 709.2259.
2923, 2853, 1789, 1652, 1621, 1454, 1423, 1328, 1271, 1243, 1204,
1162, 1085, 1039, 909, 869, 788, 686 cmÀ1; HRMS: m/z calcd for
[C32H22O12+H]+: 599.1184; found: 599.1172.
Diethyl
2,2’-(9,9’-dihydroxy-1,1’-dimethyl-5,5’,10,10’-tetraoxo-
3,3’,4,4’,-5,5’,10,10’-octahydro-1H;1’H-[8,8’-dibenzo[g]isochro-
mene]-3,3’-diyl)diacetate (36): AlCl3 (29 mg, 0.22 mmol, 5.0 equiv)
was added to a solution of 34 (30 mg, 0.044 mmol) in dry CH2Cl2
(15 mL) in portions at 08C, and the reaction mixture was stirred for
10 min. The ice bath was removed and stirring continued at room
temperature for 45 min. It was then quenched with water (5 mL)
and the solution extracted with CH2Cl2 (5ꢁ15 mL). The combined
organic layers were washed with brine, dried (Na2SO4), and concen-
trated. The residue was purified by silica gel flash column chroma-
tography using petroleum ether/EtOAc (4:1 to 4:3) as eluent to
provide 36 (22.7 mg, 79%) as a yellow solid. M.p. 175–1768C;
1H NMR (400 MHz, CDCl3/TMS): d=1.30 (t, J=7.1 Hz, 6H), 1.58 (d,
J=6.8 Hz, 6H), 2.36 (ddd, J=19.2, 10.5, 1.9 Hz, 2H), 2.61–2.73 (m,
4H), 2.85 (dd, J=19.2, 3.3 Hz, 2H), 4.17–4.25 (m, 4H), 4.32–4.38 (m,
2H), 5.02 (q, J=6.3 Hz, 2H), 7.65–7.78 (m, 4H), 12.53 ppm (s, 2H;
OH); 13C NMR (100 MHz, CDCl3): d=14.2, 19.4, 27.9, 40.7, 60.8, 63.4,
67.2, 114.9, 118.6, 131.7, 137.7, 142.5, 146.5, 159.3, 170.6, 182.7,
188.7 ppm; IR (CHCl3): n˜ =3460, 2976, 2918, 2850, 1738, 1661,
1640, 1607, 1471, 1415, 1341, 1270, 1158, 1116, 1078, 1032, 860,
792 cmÀ1; HRMS: m/z calcd for [C36H34O12+Na]+: 681.1942; found:
681.1942.
Acknowledgements
We thank the Department of Science and Technology New
Delhi for financial support (grant no. SB/S1/OC-42/2013). S.V.M.
thanks the Council of Scientific and Industrial Research, New
Delhi and IIT Bombay for a research fellowship.
Keywords: actinorhodins
synthesis · pyranonaphthoquinones · synthetic methods
·
annulation
·
bidirectional
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Synthesis of 36 from 35 through demethylation with AlCl3- and
H2SO4-mediated epimerization: AlCl3 (11.5 mg, 0.086 mmol,
5.0 equiv) was added to a solution of 35 (11.8 mg, 0.0172 mmol) in
dry CH2Cl2 (15 mL) in one portion at 08C, and the reaction mixture
was stirred for 10 min. The ice bath was removed and stirring con-
tinued at room temperature for 40 min. It was then quenched with
water (5 mL), and the solution was extracted with CH2Cl2 (5ꢁ
15 mL). The combined organic layers were washed with brine,
dried (Na2SO4), and concentrated. The residue was purified by silica
gel column chromatography using petroleum ether/EtOAc (4:1 to
4:3) as eluent to provide the demethylated compound (9 mg).
Concentrated H2SO4 (1 mL) was added to a stirred solution of this
in benzene (3 mL) at 58C. The resulting mixture was stirred at
room temperature for 1 h. Brine solution (5 mL) was added, and
the reaction mixture was extracted with EtOAc (3ꢁ10 mL). The
combined organic layers were washed with saturated aqueous
NaHCO3 and brine, dried (Na2SO4), and concentrated. The residue
was purified by silica gel column chromatography using petroleum
ether/EtOAc (4:1 to 4:3) as eluent to give 36 (4.1 mg, 35%, two
steps) as a yellow solid. The spectroscopic data were the same as
before.
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dibenzo[g]furo[3,2-c]isochromene)-2,2’,6,6’,11,11’-
(5H,5’H,11bH,11’bH)-hexanone (37): A solution of LiOH (2 mg) in
H2O (0.5 mL) was added to a solution of 36 (15 mg, 0.0023 mmol)
in THF (0.5 mL) at 08C and stirred for 12 h. HCl (2n, 0.2 mL) was
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filtrate was concentrated, and the residue was dissolved in MeOH
(0.5 mL) and stirred in an open vial for one day at room tempera-
ture. It was then concentrated, and the residue was purified by
silica gel column chromatography using petroleum ether/EtOAc
(1:1) as eluent to give 37 (4.6 mg, 34% from 36) as a yellow solid.
1H NMR (400 MHz, CDCl3/TMS): d=1.59 (d, J=6.8 Hz, 6H), 2.72 (d,
J=17.7 Hz, 2H), 3.00 (dd, J=17.8, 5.2 Hz, 2H), 4.71 (dd, J=5.1,
3.0 Hz, 2H), 5.12 (q, J=6.8 Hz, 2H), 5.28 (d, J=3.0 Hz, 2H), 7.75–
7.82 (m, 4H), 12.35 ppm (s, 2H; OH); 13C NMR (100 MHz, CDCl3):
d=18.6, 36.9, 66.2, 66.4, 68.5, 115.0, 119.2, 131.4, 135.3, 138.55,
138.6, 149.9, 159.6, 173.9, 181.2, 188.3 ppm; IR (CHCl3): n˜ =3435,
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Supporting Information.
Chem. Eur. J. 2015, 21, 4842 – 4852
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[24] The syn/anti configuration was arrived at based on comparison of
proton NMR spectroscopic data with that of monomeric molecules syn-
thesized in our laboratory.
Received: December 11, 2014
Published online on February 11, 2015
Chem. Eur. J. 2015, 21, 4842 – 4852
www.chemeurj.org
4852
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim