Total Synthesis of 3-Oxo- and 3β-Hydroxytauranin via Negishi Coupling of a Bis(ortho-oxy)-Functionalized Benzyl Chloride

Article abstract of DOI:10.1002/ejoc.201500815

The first asymmetric synthesis of the sesquiterpene quinones 3-oxo- and 3β-hydroxytauranin (1, 2) was achieved and the originally proposed structure of 3α-hydroxytauranin was revised. The protected benzyl chloride 5 was obtained in six steps starting from 4-bromo-3,5-dihydroxybenzoic acid (8) via a highly scalable approach. The troublesome Negishi coupling of the benzyl chloride 5 with alkenyldimethylalane 6 was optimized to furnish all-trans-farnesylarene 14 in very good yield. This prenylated arene was transformed in six additional steps to 3β-hydroxytauranin (2). Finally, a new convenient access to propargylated terpenes without using dry cryogenic ammonia and gaseous allene or propyne is described. The first total synthesis of the sesquiterpene quinones 3-oxo- and 3β-hydroxytauranin (2) was achieved and the originally proposed structure of 3α-hydroxytauranin was revised. The key step of the synthesis is the Negishi coupling of the bis(ortho-oxy)-functionalized benzyl chloride 5 with the alkenyldimethylalane 6.

Full text of DOI:10.1002/ejoc.201500815

FULL PAPER
DOI: 10.1002/ejoc.201500815
Total Synthesis of 3-Oxo- and 3β-Hydroxytauranin via Negishi Coupling of a
Bis(ortho-oxy)-Functionalized Benzyl Chloride
Matthias Göhl[a] and Karlheinz Seifert*[a]
Keywords: Total synthesis / Natural products / Terpenoids / Epoxides / Cyclization / Radical reactions
The first asymmetric synthesis of the sesquiterpene quinones
6 was optimized to furnish all-trans-farnesylarene 14 in very
3-oxo- and 3β-hydroxytauranin (1, 2) was achieved and the
good yield. This prenylated arene was transformed in six ad-
originally proposed structure of 3α-hydroxytauranin was re- ditional steps to 3β-hydroxytauranin (2). Finally, a new con-
vised. The protected benzyl chloride 5 was obtained in six
steps starting from 4-bromo-3,5-dihydroxybenzoic acid (8)
via a highly scalable approach. The troublesome Negishi
coupling of the benzyl chloride 5 with alkenyldimethylalane
venient access to propargylated terpenes without using dry
cryogenic ammonia and gaseous allene or propyne is de-
scribed.
Introduction
Sesquiterpene quinones and hydroquinones possess
many of interesting pharmacological activities. Avarol and
avarone inhibit the reverse transcriptase of the HIV-virus
and in this way the replication of the AIDS virus is suppres-
sed.[1a] Ilimaquinone shows an inhibition of the RNase-H-
function of the HIV-1 reverse transcriptase[1b] and the tubu-
lin-polymerization.[1c] Bolinaquinone, 21-dehydrobolina-
quinone, and dysidine possess inhibitory activity against
hPTP1B, a potential drug target for treatment of type-II
diabetes and obesity.[1d] Yahazunol, cyclozonarone, spongi-
aquinone and hyatellaquinone show good cytostatic/cyto-
toxic activity against the tumour cell lines HM02 (gastric
adenocarcinoma), HepG2 (hepatocellular carcinoma), and
MCF7 (breast carcinoma).[1e] Wiedendiol B exhibits a
strong and selective cyclooxygenase-2 (COX2) inhibition.
COX2 inhibitors are drugs with antiphlogistic and anti-
rheumatic activities.[1f]
Gunatilaka’s group claimed to have isolated the sesqui-
terpene quinones tauranin, 3-oxotauranin (1), 3α-hydroxy-
tauranin, and 14-hydroxytauranin (Figure 1) from Phyllo-
stigta spinarum, a fungal strain endophytic in Platycladus
orientalis from the Sonoran Desert. Tauranin shows
apoptotic activity toward several human solid tumor cell
1
lines.[1g] Analyzing the H NMR spectroscopic data of 3α-
hydroxytauranin[1g] it is obvious that the reported coupling
constants of the proton in position 3 (δ = 3.29 ppm, dd,
J2ax,3ax = 11.3 Hz, J2eq,3ax = 4.3 Hz) are in agreement with
the 3β-epimer of 2 (Figure 1). The 3-H signal of 3β-
[a] Lehrstuhl für Organische Chemie, NW II, Universität
Bayreuth,
Universitätsstraße 30, 95447 Bayreuth
E-mail: karlheinz.seifert@uni-bayreuth.de
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201500815.
1
Figure 1. Structures of tauranins and expected H NMR coupling
constants.
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M. Göhl, K. Seifert
FULL PAPER
hydroxyalbicanyl acetate shows very similar coupling con- from 4-bromo-3,5-dihydroxybenzoic acid (8) by benzylation
stants (δ = 3.25 ppm, dd, J2ax,3ax = 11.4 Hz, J2eq,3ax
to yield the ester 9[3a–3c] (Scheme 2). Reduction of 9 with
=
4.3 Hz).[1h] Our goal was to develop a straightforward syn- LiAlH4 gave benzylic alcohol 10[3a] which was protected
thesis of both 3-oxo- and 3β-hydroxytauranin (1, 2). The with TIPSCl to 4.[3c,3d] This procedure is highly scalable as
NMR spectroscopic data and optical rotations of com- no chromatography is needed and all intermediates can be
pounds 1 and 2 should be compared with those of the natu- purified by crystallization on a multigram scale. All conver-
ral products to confirm their correct structures and absolute sions are almost quantitative and the overall yield of 74%
configurations. Furthermore, 3-oxo- and 3β-hydroxy- over three steps is justified by waste of product due to
tauranin (1, 2) should be tested for their pharmacological crystallization.
activities as cytostatic/cytotoxic, antiphlogistic, antirheu-
matic, and anti-inflammatory.
Almost all total syntheses of sesquiterpene quinones use
the direct disconnection between an arene chore and the
bicyclic sesquiterpene moiety.[2] This approach usually de-
mand a protected terpenoid, whose asymmetric de novo
synthesis is often cumbersome. Commonly functional
group interconversions (FGI) or deprotections are neces-
sary to manipulate the sesquiterpene chore in the desired
manner. This is especially difficult in the case of in position
3 functionalized terpenes.
Scheme 2. Synthesis of the aryl bromide 4.
Results and Discussion
We employed a bioinspired and more convenient ap-
proach and retrosynthetically reduced the quinonic chore
Many attempts to lithiate the benzyl-protected arene 4
showed that nBuLi in a very apolar solvent mixture (benz-
ene and Et2O) is crucial for a clean conversion.[3e] Subse-
to the orthogonally protected 3β-hydroxyalbicanylresorcin
quent coupling with farnesyl bromide (3) led mainly to eli-
A (Scheme 1). Double retrosynthetic ring opening between
mination products besides the desired prenylated arene 14
the positions 4,5 and 9,10 of A resulted in (S)-epoxide B.
Our methodology offers two further disconnections as
in 34% to 48% yield (Scheme 3).
shown in Scheme 1. Disconnection a leads to farnesylbrom-
ide (3) and aryl bromide 4 and disconnection b to alkenyldi-
methylalane 6 and benzyl chloride 5.
Scheme 3. Synthesis of the coupling product 14.
For this reason disconnection b was chosen (Scheme 1).
The Pd-catalyzed Negishi coupling of benzyl chlorides has
been explored by Negishi.[4a] Lipshutz studied and im-
proved it by using a Ni0 catalyst and broadened the scope
to highly electron rich benzyl chlorides, which could be
coupled in excellent yields.[4b–4g] For this approach the nec-
essary benzyl chloride 5 could be obtained via an optimized
lithium–halogen exchange of the aryl bromide 4 with nBuLi
and subsequent reaction with DMF to provide the aldehyde
11 (Scheme 4).[5a] The formyl group of 11 was reduced with
NaBH4 to the benzylic alcohol 12[5b] which was trans-
formed with TMSCl to the benzyl chloride 5.[5c] The elabo-
rated approach is also highly scalable since all products
were purified by crystallization on a multigram scale.
The most frequently applied method to obtain proparg-
ylated prenyls is the elongation of the corresponding prenyl
halide with lithiated 1-(trimethylsilyl)propyne and subse-
quent desilylation[4e] or nucleophilic substitution of the lat-
Scheme 1. Retrosynthesis of 3-oxo- and 3β-hydroxytauranin (1, 2).
ter halide with a dilithiated species derived from gaseous
Pursuing disconnection a we examined the lithiation of allene[6a] or propyne.[4g] The former reaction leads to by-
aryl bromide 4. The required aryl bromide 4 was prepared products which are difficult to separate.[4g] Concerning the
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Total Synthesis of 3-Oxo- and 3β-Hydroxytauranin
from 13 (Scheme 5) with lithium in anhydrous ammonia.[6b]
Since the drying of cryogenic liquid ammonia is cumber-
some and the water content is crucial for a clean conversion
of the phenyl thioether 13 to the alkyne 7, we looked for a
more appropriate procedure. We found that the reductive
desulfurization with catalytic amounts of naphthalene and
lithium dust[6c] resulted in a clean conversion and gave the
desired alkyne 7 (Scheme 5) after 1 h at 0 °C with a 87%
yield after distillation on a 100 mmol scale.
Scheme 4. Synthesis of the benzyl chloride 5.
latter reaction, the handling and availability of gaseous
allene or propyne is difficult, so we attempted to improve a
protocol developed by Negishi, which exploits dilithiated
phenyl propargyl thioether as a nucleophile.[6b] This pro-
cedure uses a reductive desulfurization of the anion derived Scheme 5. Synthesis of the Negishi coupling product 14.
Table 1. Screening of Negishi coupling conditions.
Entry[a]
MX[b]
Conditions, catalyst [mol-%][c]
Conversion[d]
1
2
3
4
5
6
7
8
none
none
none
Pd(PPh3)4 (5)
2%
Ni(PPh3)2Cl2, 2 BuLi (5)
69% (30%)
11% (10%)
55% (8%)
66%
67%
49%
55%
18%
32%
28%
8%
19%
3%
14% (4%)
72%
40%
54%
83%
Ni(dppp)[e]Cl2, 2 BuLi (5)
[f]
ZnCl2
ZnCl2
ZnCl2
InCl3
ZnCl2
ZnCl2
ZnCl2
ZnCl2
ZnCl2
ZnCl2
InCl3
Ni(PPh3)2Cl2, 2 BuLi (5)
Ni(PPh3)2Cl2, 2 BuLi (5)
Ni(acac)2, 2 PPh3, 2 DIBAL (5)
Ni(acac)2, 2 PPh3, 2 DIBAL (5)
Ni(acac)2, 2 PPh3, 2 DIBAL (2)
Ni(acac)2, 2 P(o-tol)3, 2 DIBAL (2)
C (3)
9
10
11
12
13
14
15
16
17
18
19
Ni(acac)2, 2 IPr·HCl (D), 4 DIBAL (3)
Pd(PPh3)2Cl2, 2 BuLi (5)
Pd(dppf)[g]Cl2, 2 DIBAL (3)
Pd(dppf)Cl2, 2 DIBAL (3)
ZnCl2, LiBr[h]
ZnCl2
ZnCl2
ZnCl2
ZnCl2
PEPPSI-IPr (E) (3) in THF/NMP 2:1
Ni(acac)2, 2 PPh3, 2 DIBAL (25)
Ni(acac)2, 2 PPh3, 2 DIBAL (40)
Ni(acac)2, 2 PPh3, 2 DIBAL (40) in THF/NMP 2:1
Ni(acac)2, 2 PPh3, 2 DIBAL (15) in THF/NMP 2:1 at –45 °C
[a] All reaction were performed with 1 mmol benzyl chloride 5 and 1.4 mmol carboaluminated alkyne 6 in 5 mL of THF at room temp.
(unless otherwise stated). [b] Added metal salt (MX) based on amount of alane 6. Unless stated otherwise 1.05 equiv. ZnCl2 respectively
1
0.34 equiv. InCl3 were used. [c] Amount of catalyst based on amount benzyl chloride 5 is given in parenthesis. [d] Determined by H-
NMR of the crude reaction mixture, yield of ethylbenzene 19 is given in parenthesis. [e] dppp = 1,3-bis(diphenylphosphanyl)propane.
[f] 0.45 equiv. ZnCl2 were used. [g] dppf = 1,1-bis(diphenylphosphanyl)ferrocene. [h] 2.0 equiv. LiBr was added.
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M. Göhl, K. Seifert
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Thus we developed a new convenient method for the
multigram preparation of propargylated terpenes without
using time-consuming manipulations. Compound 7 reacted
with Cp2ZrCl2/AlMe3 to the alkenyldimethylalane 6.[4a]
With the two building blocks 5 and 6 in our hands we
performed the standard Negishi coupling protocol of Lip-
shutz[4d] to obtain the prenylated arene 14 (Scheme 5). We
observed that in our case a large amount of the correspond-
ing ethylbenzene derivative 19 is produced via methyl trans-
fer from the alkenyldimethylalane 6 to the benzyl chloride 5
(Table 1, entry 2). This is the first bis(ortho-oxy)-substituted
benzyl chloride coupled in a Negishi fashion as well as the
first described methyl transfer in such a case. Since the eth-
ylbenzene 19 has the same polarity as the required prenyl-
ated arene 14 and is not separable by standard column
chromatography, it was highly desirable to suppress its for-
mation. Therefore we screened different catalyst systems
and reaction conditions. As Lipshutz already stated
Pd(PPh3)4 catalysis (entry 1) is less efficient.[4b,4c] The use
of Ni0 catalyst obtained by treatment of Ni(dppp)Cl2 with
BuLi led to the formation of the ethylbenzene derivative 19
together with the prenylated arene 14, both of them with
poor yields of 10% and 11% (entry 3). Changes introduced
in the preparation of the Ni0 catalyst either by addition of
PPh3, tri(o-tolyl)phosphane [P(o-tol)3][7a] (entry 9) or and
reducing agents such as DIBAL,[4b–4d] transmetallation of
the carboalumination product either by addition of
ZnCl2[7b] or InCl3,[7c,7d] or the addition of precatalysts C,[7e]
D, E[7f,7g] (entries 10, 11, 15) did not provide any better
results in the first attempts, but suppressed the formation
of the unwanted ethylbenzol 19. However, larger amounts
of Ni0 catalyst derived from Ni(acac)2, PPh3 and DIBAL,
increased the yields to a certain extent (entries 16–17).
Moreover, the change of solvent from THF to THF/NMP,
2:1 at –45 °C[4f] gave the desired product 14 with an accept-
able yield of 83% (entry 19).
Scheme 6. Synthesis of 3β-hydroxyalbicanylarene 18; yields in
parenthesis are based on the recovered starting material.
The debenzylation of 18 under gentle conditions with
lithium naphthalide at –21 °C yielded the desired resorcine
20[10] (Scheme 7) in an almost quantitative yield. Attempts
to oxidize the resorcine moiety to the 2-hydroxyquinone
motif with salcomine [N,NЈ-bis(salicylidene)ethylenedi-
aminocobalt(II)] in DMF,[11a,11b] MeCN or MeOH under
The asymmetric Sharpless dihydroxylation[8a] of 14[8b]
with Noe-Lin-ligand[8c–8e] to 15 was difficult because of sol-
ubility problems and produced 26% of (R)-glycol 15 plus a
huge amount of overoxidized byproducts after 2 d under
standard conditions (Scheme 6). After numerous efforts, we
found that making use of THF as less polar cosolvent,
tetrabutylammonium acetate as a phase-transfer catalyst,[8f]
and the addition of K2CO3 (6 equiv.), K3[Fe(CN)6]
(6 equiv.) and methanesulfonamide (1.5 equiv.) furnished
the desired (R)-glycol 15 with a 56% yield, which repre-
sented 81% yield based on the recovered starting material
(brms) with an enantiomeric ratio of 95:5.[8g] Mesylation of
the secondary alcohol function of 15 and basic cyclization
with K2CO3 in MeOH furnished the desired (S)-10,11-ep-
oxyfarnesylarene 16 in a one pot reaction with 97%
yield.[8d] The resulting (10S,2E,6E)-10,11-epoxyfarnesylar-
ene 16 was subjected to a known bioinspired TiIII-mediated
cyclization cascade[9a–9j] to give 3β-trimethylsilyloxyalbican-
ylarene 17.[9i,9j] Since the TIPS group was partially removed
via the standard deprotection protocol with TBAF,[9a–9j] we
used a selective TMS deprotection method making use of
K2CO3 in MeOH/DCM to afford 18 with 34% yield.
Scheme 7. Synthesis of 3-oxo- and 3β-hydroxytauranin (1, 2); yields
in parenthesis are based on the recovered starting material.
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Total Synthesis of 3-Oxo- and 3β-Hydroxytauranin
Figure 2. NOE correlations of 3α-hydroxytauranin and NOESY correlations of 3β-hydroxytauranin (2).
an O2 atmosphere were disappointing and afforded 21 with The NMR spectroscopic data of both compounds 1 and 2
10–40% yields after 36 h in addition to several overoxidized matched those reported by Wijeratne et al.[1g] The optical
byproducts. Several attempts to perform the oxidation with rotation of 3-oxotauranin (1) ([α]2D3 = –160, CHCl3) showed
IBX (2-iodoxybenzoic acid) in DMF,[11c] CAN in MeCN/ reasonable agreement with the value reported in the litera-
H2O,[11d] PCC/H5IO6 in MeCN,[11e,11f] were not satisfying ture ([α]D23 = –130.2, CHCl3). The absolute value for 3β-
and showed a tendency towards oxidative destruction of the hydroxytauranin (2) ([α]2D3 = –149, CHCl3) is similar to that
already formed quinonic moiety. Oxidation with PIFA reported by Wijeratne et al.[1g] ([α]D23 = +139.5, CHCl3) but
[(bis(trifluoroacetoxy)iodo)benzene] in MeCN/H2O, 2:1 at of opposite sign. Since compounds 1 and 2 were derived
0 °C[11g] was more promising, but led to several byproducts. from the same precursor 21, the sign of the optical rotation
Fortunately, changing the solvent system to DMF/H2O fur- of the natural product 2 must be wrong. In summary we
nished the desired quinone 21 with an excellent yield (91%). showed that the natural product isolated from Phyllostigta
Finally, TBAF promoted TIPS[12a] deprotection led to spinarum has indeed a 3β-configuration and is not 3α-hy-
the isolation of 3β-hydroxytauranin (2) with 92% yield. No droxytauranin as proposed by Wijeratne et al.[1g] According
oxidation of an alcohol function besides the oxidation labile to our interpretation of NMR spectroscopic data for 3-ox-
2-hydroxyquinone moiety is reported in literature. The otauranin (1) and 3β-hydroxytauranin (2) the revised NMR
Dess–Martin-periodinan (DMP) oxidation[12b] of the sec- assignments for both natural products can be found in the
ondary alcohol moiety of 21 to ketone 22 was stopped after supplement. The incorrect assignment of both methyl
a reaction time of 1 h at 0 °C due to oxidative destruction groups 13 and 14 in compound
1
and 3α-
of the quinonic motif. In this way, the TIPS protected hydroxytauranin suggests also, that the postulated natural
ketone 22 could be obtained with 61% yield, which repre- product has to be 13- and not 14-hydroxytauranin (Fig-
sented 81% yield brsm (based on the recovered starting ma- ure 1). Furthermore, a new convenient access to proparg-
terial). Treatment of the isolated ketone 22 with TBAF in ylated terpenes on a multigram scale without using dry
THF furnished 3-oxotauranin (1) with an excellent yield cryogenic ammonia and gaseous allene or propyne has been
(93%).
demonstrated.
NOE correlations of 3α-hydroxytauranin were obtained
in the Gunatilaka group by 1D NOE measurements.[1g] Ir-
radiation of the signal at δ = 0.98 ppm (CH3-13) showed
enhancements of the signals at δ = 0.76 ppm (CH3-15) and
3.29 ppm (3-Heq) indicating that the both methyl groups
and 3-H are on the same side of the molecule. Since CH3-
15 is β-oriented, CH3-13 and 3-H must also be β-oriented
(Scheme 2). The chemical shifts for the signals of CH3-15
and CH3-14 are δ = 0.76 ppm and δ = 0.77 ppm. This
means, the assumed NOE CH3-15/CH3-13 is actually the
Experimental Section
General: All moisture or oxygen sensitive reactions were performed
in oven-dried glassware under an argon atmosphere using standard
Schlenk techniques. Unless otherwise stated silica gel (Macherey–
Nagel, particle size 40–63 μm) was used for column chromatog-
raphy. The oxidation labile 2-hydroxyquinones were handled under
an inert gas atmosphere and frozen in a benzene matrix at –21 °C
for longer storage. Optical rotations of these compounds have to
NOE CH3-13/CH3-14. The NOESY correlations CH3-13/5- be measured direct after purification. Melting points were deter-
mined in open capillary tubes with a Büchi M-565 melting point
apparatus. Mass spectra were measured on an Orbitrap Elite
(Thermo Fisher Scientific) mass spectrometer (HRMS, ESI). NMR
spectroscopic data were recorded under conditions as indicated
with a Bruker Avance 300 and a Bruker Avance-III-HD 500 spec-
trometer. Solvent signals were used as internal standard (1H =
H and CH3-13/6-Heq of 3β-hydroxytauranin (2) showed the
α-orientation of CH3-13. Due to the NOESY correlation
CH3-13/3-Hax the hydroxy group of 2 is β-oriented (Fig-
ure 2).
1
7.26 ppm and 13C = 77.0 ppm for CDCl3; H = 2.05 ppm and 13C
Conclusions
= 29.8 ppm for [D6]acetone). Multiplicity mc = centered multiplet.
We developed a bioinspired approach for the straightfor-
Benzyl 3,5-Bis(benzyloxy)-4-bromobenzoate (9): A solution of 8
ward synthesis of 3-oxo- and 3β-hydroxytauranin (1, 2). (69.90 g, 300.0 mmol) in DMF (250 mL) was prepared in a three-
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M. Göhl, K. Seifert
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neck flask equipped with a dropping funnel and a KPG stirrer
under an inert gas atmosphere. Finely divided K2CO3 (165.8 g,
1.200 mol) was added in small portions. Then benzyl bromide
(121.3 mL, 1.020 mol) was added under vigorous stirring in a man-
ner to keep the reaction temperature at about 60 °C (0.5–1 h). After
one further hour of stirring at room temperature a highly viscous
suspension has formed due to crystallization of the product 9. To
induce further crystallization H2O (300 mL) was added within
15 min whilst stirring and the resulting suspension was poured into
H2O (1 L). The white solid was collected by suction filtration and
washed with H2O (3ϫ 500 mL) and pentane (2ϫ 300 mL). After
drying at 40 °C and 7 mbar the crude product was recrystallized
from hexanes/MTBE/CHCl3 to yield the title compound 9 (134.9 g,
266.9 mmol, 89%). RfЈ = 0.24 (10% EtOAc/hexanes), m.p. 134.1 °C
DMF (4.11 mL, 53.4 mmol) was added dropwise during 5 min. The
reaction mixture was allowed to come to room temperature within
25 min and then half saturated NH4Cl solution (250 mL) was
added. After separation of phases the aqueous phase was extracted
with MTBE (250 mL). The combined organic phases were washed
with brine and dried with MgSO4. After evaporation of all volatiles
the crude product was filtered through a plug of silica (h = 5 cm)
eluting with 15% MTBE/hexanes. Removal of solvent and frac-
tional crystallization from hexanes yielded the desired benzalde-
hyde 11 (20.42 g, 40.46 mmol, 89%). RfЈ = 0.27 (15% MTBE/hex-
anes), m.p. 60.7 °C (hexanes). 1H NMR (500 MHz, CDCl3, 298 K):
δ = 1.08 (d, J = 6.7 Hz, 18 H), 1.13–1.20 (m, 3 H), 4.80 (s, 2 H),
5.20 (s, 4 H), 6.69 (s, 2 H), 7.32 (mc, 2 H), 7.40 (mc, 4 H), 7.48 (mc,
4 H), 10.65 (s, 1 H) ppm. 13C NMR (125 MHz, CDCl3, 298 K): δ
(hexanes/MTBE/CHCl3). 1H NMR (500 MHz, CDCl3, 298 K): δ = = 11.8, 17.9, 64.6, 70.3, 102.2, 113.6, 126.8, 127.8, 128.5, 136.3,
5.21 (s, 4 H), 5.36 (s, 2 H), 7.33–7.37 (m, 4 H), 7.38–7.45 (m, 9 H), 150.7, 161.2, 188.8 ppm. ESI-HRMS: calcd. for [C31H40O4Si + H]+:
7.49–7.53 (m, 4 H) ppm. 13C NMR (125 MHz, CDCl3, 298 K): δ m/z = 505.2769; found m/z = 505.2763.
= 67.0, 70.9, 107.3, 108.3, 127.0, 128.0, 128.1, 128.3, 128.5, 128.6,
{2,6-Bis(benzyloxy)-4-[(triisopropylsilyloxy)methyl]phenyl}methanol
(12): To a solution of benzaldehyde 11 (35.38 g, 70.10 mmol) in
THF/MeOH (60 mL, 5:1) NaBH4 (2.686 g, 70.10 mmol) was added
129.9, 135.7, 136.1, 156.1, 165.7 ppm. ESI-HRMS: calcd. for
[C28H23O479Br + H]+: m/z = 503.0852; found m/z = 503.0853.
[3,5-Bis(benzyloxy)-4-bromophenyl]methanol (10): A solution of 9 at 0 °C. After stirring for 10 min at 0 °C the reaction mixture was
(121.8 g, 242.3 mmol) in THF (600 mL) was chilled in an ice bath
and LAH (14.47 g, 381.3 mmol) was added in small portions. After
stirring for 1 h Me2CO (50 mL) was added and the reaction was
stirred for further 15 min. Then MTBE (800 mL) was added and
the reaction was quenched by addition of 5 m HCl (400 mL,
2.00 mol). After the precipitate has dissolved H2O (400 mL) was
added and the layers were separated. The aqueous phase was ex-
tracted one further time with MTBE (500 mL), the combined or-
ganic phases were washed with brine and dried with MgSO4. After
removal of the solvent the obtained crude product was purified by
recrystallization from hexanes/MTBE/CHCl3 to furnish the desired
benzyl alcohol 10 (87.14 g, 218.2 mmol, 90%). RfЈ = 0.29 (40%
concentrated and partitioned between MTBE (500 mL) and half
saturated NH4Cl (300 mL). After separation of the phases the
aqueous phase was extracted once more with MTBE (150 mL). The
combined organic phases were washed with brine and dried with
MgSO4. After removal of solvent the crude product was crys-
tallized from hexanes to furnish the title compound 12 (34.86 g,
68.79 mmol, 98%). RfЈ = 0.36 (20% EtOAc/hexanes), m.p. 51.2 °C
(hexanes). 1H NMR (500 MHz, CDCl3, 298 K): δ = 1.13 (d, J =
6.8 Hz, 18 H), 1.17–1.25 (m, 3 H), 2.60 (br. s, 1 H), 4.84 (s, 2 H),
4.93 (s, 2 H), 5.15 (s, 4 H), 6.72 (s, 2 H), 7.36 (mc, 2 H), 7.42 (mc,
4 H), 7.47 (mc, 4 H) ppm. 13C NMR (125 MHz, CDCl3, 298 K): δ
= 11.9, 18.0, 55.0, 64.8, 70.2, 102.4, 116.0, 127.1, 127.8, 128.5,
EtOAc/hexanes), m.p. 123.0 °C (hexanes/MTBE/CHCl3). 1H NMR 136.8, 143.3,157.4 ppm. ESI-HRMS: calcd.for [C31H42O4Si + Na]+:
(500 MHz, CDCl3, 298 K): δ = 1.95 (t, J = 5.7 Hz, 1 H), 4.56 (d, m/z = 529.2745; found m/z = 529.2726.
J = 5.7 Hz, 2 H), 5.14 (s, 4 H), 6.61 (s, 2 H), 7.33 (mc, 2 H), 7.40
[3,5-Bis(benzyloxy)-4-(chloromethyl)benzyloxy]triisopropylsilane (5):
Benzylic alcohol 12 (20.94 g, 41.32 mmol) was dissolved in CHCl3
(30 mL) and chilled in an ice bath. TMSCl (12.09 mL, 95.02 mmol)
was added within 5 min under an inert gas atmosphere and the
(mc, 4 H), 7.49 (mc, 4 H) ppm. 13C NMR (125 MHz, CDCl3,
298 K): δ = 64.9, 70.7, 101.1, 104.6, 126.9, 127.8, 128.5, 136.4,
141.6, 156.2 ppm. ESI-HRMS: calcd. for [C21H19O379Br + H]+: m/z
= 399.0590; found m/z = 399.0592.
reaction mixture was stirred for 1 h. The turbid reaction mixture
[3,5-Bis(benzyloxy)-4-bromobenzyloxy]triisopropylsilane (4): To a was partitioned between hexanes (500 mL) and half saturated
solution of benzyl alcohol 10 (99.82 g, 250.0 mmol) and imidazole
(18.72 g, 275.0 mmol) in DMF (250 mL) TIPSCl (57.33 mL,
270.0 mmol) was added. After stirring for 16 h at room temperature
the reaction mixture was partitioned between hexanes (750 mL)
and H2O (750 mL) and the aqueous phase was extracted with hex-
anes (500 mL). The combined organic phases were washed with
brine (250 mL) and dried with MgSO4. After evaporation of the
solvent the crude product was crystallized from hexanes to furnish
NaHCO3 (300 mL) solution. After separation of the phases the or-
ganic phase was washed with brine and dried with MgSO4. Re-
moval of all volatiles yielded the desired benzyl chloride 5 (21.70 g,
41.32 mmol, 100%) as a highly viscous oil or a white solid in quan-
titative yield. This crude product is pure enough and can be used
directly for the next step. Due to its limited shelf life in the liquid
state it is recommended to crystallize the title compound. Crystalli-
zation from pentane afforded benzyl chloride 5 as colorless crystals
the title compound 4 (129.5 g, 233.1 mmol, 93%). RfЈ = 0.42 (5% (20.36 g, 38.77 mmol, 94%), which were stored in a brown glass
MTBE/hexanes), m.p. 66.6 °C (hexanes). 1H NMR (500 MHz, flask for half a year, without any notable decomposition. RfЈ = 0.55
CDCl3, 298 K): δ = 1.13 (d, J = 6.6 Hz, 18 H), 1.17–1.25 (m, 3 H),
4.80 (s, 2 H), 5.21 (s, 4 H), 6.72 (s, 2 H), 7.35 (mc, 2 H), 7.43 (mc, NMR (500 MHz, CDCl3, 298 K): δ = 1.11 (d, J = 6.8 Hz, 18 H),
(5% MTBE/hexanes, decomposition), m.p. 71.2 °C (pentane). 1H
4 H), 7.54 (mc, 4 H) ppm. 13C NMR (125 MHz, CDCl3, 298 K): δ
= 11.9, 17.9, 64.5, 70.6, 100.2, 103.7, 126.7, 127.6, 128.4, 136.6,
142.4, 156.0 ppm. ESI-HRMS: calcd. for [C30H39O379BrSi + H]+:
m/z = 555.1925; found m/z = 555.1912.
1.15–1.24 (m, 3 H), 4.82 (s, 2 H), 4.93 (s, 2 H), 5.18 (s, 4 H), 6.68
(s, 2 H), 7.35 (mc, 2 H), 7.43 (mc, 4 H), 7.51 (mc, 4 H) ppm. 13C
NMR (125 MHz, CDCl3, 298 K): δ = 11.9, 18.0, 36.1, 64.8, 70.1,
102.2, 113.1, 127.0, 127.8, 128.5, 136.9, 144.6, 157.5 ppm. ESI-
HRMS: calcd. for [C31H41ClO3Si – Cl]+: m/z = 489.2819; found m/z
= 489.2812 CHN-Analysis: calcd. C 70.89%, H 7.87%; found C
70.97%, H 7.875.
2,6-Bis(benzyloxy)-4-[(triisopropylsilyloxy)methyl]benzaldehyde
(11): Aryl bromide 4 (25.25 g, 45.44 mmol) was dissolved in Et2O
(100 mL), C6H6 (35 mL) and pentane (250 mL). nBuLi (19.8 mL,
2.41 m in hexane, 47.7 mmol) was added dropwise within 10 min
under an inert gas atmosphere at 0 °C. After stirring for 15 min
(E)-6,10-Dimethylundeca-5,9-dien-1-yne (7): To a vigorous stirred
mixture of lithium dust (11.10 g, 1.600 mol) and naphthalene
6254
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© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2015, 6249–6258

Total Synthesis of 3-Oxo- and 3β-Hydroxytauranin
(1.025 g, 8.000 mmol) in THF (150 mL) propargyl phenyl thioether
(R,6E,10E)-12-{2,6-Bis(benzyloxy)-4-[(triisopropylsilyloxy)-
13 (28.45 g, 100.0 mmol) in THF (25 mL) was added over 30 min methyl]phenyl}-2,6,10-trimethyldodeca-6,10-diene-2,3-diol (15): A
at 0 °C under an inert gas atmosphere. After stirring for 1 h the
starting material was consumed (TLC or GC judgment) and the
reaction mixture was decanted into a vigorous stirred suspension
of ice cold hexanes (600 mL) and half saturated NH4Cl (350 mL).
mixture of finely divided K2CO3 (9.81 g, 71.0 mmol), finely
grounded K3[Fe(CN)6] (23.4 g, 71.1 mmol), methanesulfonamide
(1.69 g, 17.8 mmol), tetrabutylammonium acetate (1.19 g,
3 . 9 5 m m ol ), No e- Li n- li ga nd (2 10 mg , 1 78 μm ol ) and
The surplus lithium dust was washed twice with MTBE (2 ϫ K2OsO4·2H2O (34.7 mg, 88.8 mmol) was chilled in an ice bath and
50 mL) and the supernatant liquid was added to the hexane suspen-
sion. After separation of the phases the organic phase was washed
twice with 1 m KOH (2 ϫ 250 mL) and then with brine (250 mL).
The crude extract was dried with MgSO4 and all volatiles were
removed under reduced pressure. Distillation (78 °C at 10–3 mbar)
of the residue yielded the desulfurized alkyne 7 (15.39 g,
87.29 mmol, 87 %). RfЈ = 0.22 (hexanes). 1H NMR (500 MHz,
H2O (59 mL) and tBuOH (47.2 mL) was added. After stirring for
5 min the ligand has dissolved and a solution of farnesyl arene 14
(8.06 g, 11.8 mmol) in THF (11.8 mL) was added. After vigorous
stirring at 0 °C for 17 h saturated solutions of Na2SO3 (150 mL)
and Na2S2O3 (150 mL) were added. The reaction mixture was
warmed to room temperature and stirring was continued for fur-
ther 45 min. The reaction mixture was extracted three times with
CDCl3, 298 K): δ = 1.60 (mc, 3 H), 1.62 (mc, 3 H), 1.68 (mc, 3 H), ethyl acetate (500 mL, 2 ϫ 150 mL) and the combined organic
1.94 (t, J = 2.5 Hz, 1 H), 1.97–2.02 (m, 2 H), 2.04–2.11 (m, 2 H),
2.17–2.26 (m, 4 H), 5.09 (mc, 1 H), 5.18 (tq, J = 6.8, 1.2 Hz, 1 H)
ppm. 13C NMR (125 MHz, CDCl3, 298 K): δ = 16.0, 17.6, 18.9,
25.6, 26.5, 27.1, 39.6, 68.1, 84.4, 122.4, 124.1, 131.3, 136.6 ppm.
phases were washed with brine. Evaporation of all volatiles yielded
a highly viscous crude product, which was put on a plug of silica
(ø = 6 cm, h = 5 cm) and eluted with 40 % Me2CO/hexanes
(500 mL) to obtain a fraction containing residual starting material,
product, and overoxidized byproducts. Elution with (25% MeOH/
NH4OH [9:1]/CHCl3) recovered Noe-Lin-ligand (197 mg,
167 μmol, 93%). Flash chromatography of the product 15 contain-
ing fraction (silica gel, 7.5% Me2CO/hexanes to 15% Me2CO/hex-
anes) yielded the starting material 14 (2.50 g, 3.67 mmol) besides
{3,5-Bis(benzyloxy)-4-[(2E,6E)-3,7,11-trimethyldodeca-2,6,10-
trienyl]benzyloxy}triisopropylsilane (14): Cp2ZrCl2 (1.637 g,
5.600 mmol) was dissolved in 1,2-dichloroethane (20 mL) under an
inert gas atmosphere and cooled to 0 °C. AlMe3 (3.225 mL,
33.60 mmol) was added dropwise followed by addition of H2O
(4.2 μL, 233 μmol). After stirring at room temperature for 15 min
the mixture was cooled to –20 °C and alkyne 7 (3.949 g,
22.40 mmol) was added. After 2–3 h the carboalumination is com-
plete (TLC or GC-judgment) and all volatiles were removed in
vacuo (10–3 mbar, 30 °C). To ensure that all AlMe3 has been re-
moved hexanes (15 mL) were added and the solvents evaporated.
To isolate the obtained alane 6 pentane (15 mL) was added and the
obtained suspension filtered under an inert gas atmosphere to re-
move the zirconium salts. After removal of solvent a freshly pre-
pared ZnCl2 solution (26.0 mL, 1.0 m in THF, 26.0 mmol) was
added at 0 °C. Meanwhile Ni(acac)2 (616.6 mg, 2.400 mmol) and
PPh3 (1.259 g, 4.80 mmol) was dissolved in THF (16 mL) and DI-
BAL (4.00 mL, 1.2 m in PhMe, 4.80 mmol) was added dropwise at
the desired glycol 15 (4.72 g, 6.60 mmol, 56%, 81% brsm). RfЈ
=
0.28 (25% Me2CO/hexanes). [α]2D3 = +6.9 (c = 1.1, CHCl3). 1H
NMR (300 MHz, CDCl3, 298 K): δ = 1.09–1.24 (m, 27 H), 1.42
(mc, 1 H), 1.51–1.67 (m, 7 H), 1.93–2.55 (m, 8 H), 3.34 (dd, J =
10.4, 2.0 Hz, 1 H), 3.50 (d, J = 7.0 Hz, 2 H), 4.81 (s, 2 H), 5.12 (s,
4 H), 5.20 (tq, J = 10.4, 2.0 Hz, 1 H), 5.32 (tq, J = 7.0, 1.3 Hz, 1
H), 6.67 (s, 2 H), 7.29–7.49 (m, 10 H) ppm. 13C NMR (75 MHz,
CDCl3, 298 K): δ = 12.0, 15.9, 16.0, 18.0, 22.4, 23.2, 26.6, 29.6,
36.7, 39.8, 65.0, 70.1, 72.9, 78.2, 102.6, 117.3, 123.1, 125.2, 127.1,
127.6, 128.3, 134.2, 134.6, 137.5, 140.6, 157.1 ppm. ESI-HRMS:
calcd. for [C45H66O5Si + Na]+: m/z = 737.4572; found m/z =
737.4541.
[3,5-Bis(benzyloxy)-4-{(2E,6E)-9-[(2S)-3,3-dimethyloxiran-2-yl]-3,7-
0 °C under an inert gas atmosphere to obtain the active catalyst as dimethylnona-2,6-dienyl}benzyloxy]triisopropylsilane (16): To
a
a deep red-brown solution. A solution of benzyl chloride 5 (8.403 g,
16.00 mmol) in THF (10 mL) was added dropwise and the now
deep green-blue solution was stirred for 5 min. The reaction mix-
ture was cooled to –45 °C and NMP (28 mL) was added. The pre-
viously prepared solution containing the organometallic species 6
was added dropwise and the solution was warmed to room tem-
perature within 30 min. After stirring for 15 min at room tempera-
ture the reaction was carefully aborted by addition of aqueous cit-
ric acid solution (200 mL, 30% m/v). After the precipitate has dis-
solved the mixture was partitioned between hexanes (500 mL) and
H2O (250 mL). The aqueous phase was extracted with hexanes
(250 mL) and the combined organic extracts were washed with
brine and dried with MgSO4. After removal of solvents flash
chromatography (silica gel, 15% to 40% C6H6/hexanes) yielded the
solution of glycol 15 (5.45 g, 7.62 mmol) in CH2Cl2 (36.5 mL) and
pyridine (14.6 mL) methanesulfonyl chloride (1.15 mL, 14.9 mmol)
was added at 0 °C under an inert gas atmosphere. The reaction was
warmed to room temperature and stirred for 16 h. After dilution
with MeOH (170 mL) finely divided K2CO3 (4.74 g, 34.3 mmol)
was added and the suspension was vigorously stirred at room tem-
perature for 4 h. After the bulk of volatiles were removed the mix-
ture was partitioned between MTBE (250 mL) and H2O (200 mL).
The aqueous phase was extracted with MTBE (150 mL) and the
combined organic phases were dried with MgSO4. After evapora-
tion of the solvent the crude product was filtered through a plug
of silica gel (h = 5 cm, ø = 4 cm) eluting with 12.5% MTBE/hex-
anes to obtain the title compound 16 (5.14 g, 7.37 mmol, 97%). RfЈ
1
= 0.45 (12.5% MTBE/hexanes). [α]2D3 = –2.1 (c = 0.35, CHCl3). H
desired title compound 14 (9.062 g, 13.31 mmol, 83%). RfЈ = 0.28 NMR (500 MHz, CDCl3, 298 K): δ = 1.11 (d, J = 6.8 Hz, 18 H),
(25 % C6H6/hexanes). 1H NMR (500 MHz, CDCl3, 298 K): δ =
1.15–1.22 (m, 3 H), 1.26 (s, 3 H), 1.31 (s, 3 H), 1.55–1.62 (m, 4 H),
1.29 (d, J = 6.6 Hz, 18 H), 1.31–1.39 (m, 3 H), 1.75–1.79 (m, 6 H), 1.64–1.69 (m, 4 H), 1.96–2.01 (m, 2 H), 2.03–2.17 (m, 4 H), 2.70
1.85 (mc, 3 H), 1.87 (mc, 3 H), 2.11–2.31 (m, 8 H), 3.71 (d, J = (t, J = 6.3 Hz, 1 H), 3.50 (d, J = 7.0 Hz, 2 H), 4.81 (s, 2 H), 5.12
7.0 Hz, 2 H), 4.98 (s, 2 H), 5.25–5.34 (m, 6 H), 5.53 (tq, J = 7.0, (s, 4 H), 5.17 (tq, J = 7.0, 1.2 Hz, 1 H), 5.32 (tq, J = 7.0, 1.2 Hz,
1.2 Hz, 1 H), 6.84 (s, 2 H), 7.46 (mc, 2 H), 7.53 (mc, 4 H), 7.61 (mc, 1 H), 6.67 (s, 2 H), 7.33 (mc, 2 H), 7.39 (mc, 4 H), 7.46 (mc, 4 H)
4 H) ppm. 13C NMR (125 MHz, CDCl3, 298 K): δ = 12.0, 15.9,
ppm. 13C NMR (125 MHz, CDCl3, 298 K): δ = 12.0, 15.9, 16.1,
16.1, 17.6, 18.0, 22.5, 25.6, 26.7, 39.7, 39.8, 65.0, 70.0, 102.5, 117.3, 18.0, 18.7, 22.4, 24.9, 26.7, 27.4, 36.2, 39.8, 58.2, 64.2, 65.0, 70.1,
123.1, 124.4, 127.0, 127.5, 128.3, 130.9, 134.2, 134.5, 137.5, 140.6,
157.1 ppm. ESI-HRMS: calcd. for [C45H64O3Si + H]+: m/z =
681.4697; found m/z = 681.4670.
102.6, 117.3, 123.1, 125.1, 127.1, 127.6, 128.4, 133.8, 134.2, 137.6,
140.7, 157.1 ppm. ESI-HRMS: calcd. for [C45H64O4Si + Na]+: m/z
= 719.4466; found m/z = 719.4445.
Eur. J. Org. Chem. 2015, 6249–6258
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
6255

M. Göhl, K. Seifert
FULL PAPER
(2S,4aR,5S,8aR)-5-{2,6-Bis(benzyloxy)-4-[(triisopropylsilyloxy)- CHCl3). 1H NMR (500 MHz, CDCl3, 298 K): δ = 0.80 (s, 3 H),
methyl]benzyl}-1,1,4a-trimethyl-6-methylenedecahydronaphthalen-2- 0.81 (s, 3 H), 0.99 (s, 3 H), 1.07 (d, J = 6.6 Hz, 18 H), 1.11–1.19
ol (18): A mixture of Mn-dust (3.141 g, 57.17 mmol) and Cp2TiCl2 (m, 4 H), 1.31 (td, J = 13.5, 3.8 Hz, 1 H), 1.41 (dddd, J = 12.9,
(355.8 mg, 1.429 mmol) in carefully degassed THF (90 mL) was 12.9, 12.9, 4.2 Hz, 1 H), 1.54–1.79 (m, 4 H), 2.00 (dd, J = 12.9,
prepared under an inert gas atmosphere at room temperature. The
resulting deep red suspension was stirred for about 20 min until the
color faded to greyish green. TMSCl (3.62 mL, 28.6 mmol) and
2,4,6-collidine (6.62 mL, 50.0 mmol) were added simultaneously
and the resulting greyish brown suspension was stirred for 5 min.
A solution of epoxide 16 (4.981 g, 7.146 mmol) in degassed THF
(5 mL) was prepared at room temperature and added to the reac-
tion mixture. The flask was rinsed twice with THF (2ϫ 2 mL) to
ensure complete transfer and the suspension was stirred for further
16 h. After chilling the reaction mixture in an ice bath 1 m HCl
(125 mL, 125 mmol) was added slowly to dissolve the surplus Mn
and the reaction mixture was partitioned between MTBE (500 mL)
and H2O (350 mL). After extraction with MTBE (3ϫ 250 mL) the
combined organic extracts were washed with brine and dried with
MgSO4. All volatiles were removed under reduced pressure and the
obtained highly viscous oil was redissolved in MeOH/DCM (2:1,
30 mL) and finely divided K2CO3 (9.876 g, 71.46 mmol) was added.
After vigorous stirring at room temperature for 24 h TLC analysis
showed disappearance of the nonpolar TMS protected intermedi-
ate and the reaction mixture was partitioned between MTBE
(300 mL) and H2O (150 mL). The aqueous phase was extracted
with MTBE (2 ϫ 250 mL), the combined organic extracts were
washed with brine and dried with MgSO4. After evaporation of all
volatiles the crude product was purified by flash chromatography
(Merck LiChroprep® Si 60 [15–25 μm], 12.5% to 20% MTBE/hex-
anes) to furnish the title compound 18 (1.712 g, 2.456 mmol, 34%).
RfЈ = 0.17 (20% MTBE/hexanes). [α]2D3 = –21.3 (c = 1.4, CHCl3).
1H NMR (500 MHz, CDCl3, 298 K): δ = 0.73 (s, 3 H), 0.74 (s, 3
H), 0.88–0.97 (m, 2 H), 0.95 (s, 3 H), 1.11 (d, J = 6.7 Hz, 18 H),
1.14–1.23 (m, 3 H), 1.35 (dddd, J = 12.9, 12.9, 12.9, 4.1 Hz, 1 H),
1.40–1.50 (m, 2 H), 1.63–1.71 (m, 2 H), 1.89 (ddd, J = 12.9, 12.9,
4.7 Hz, 1 H), 2.29 (ddd, J = 12.9, 3.9, 2.3 Hz, 1 H), 2.62 (dd, J =
9.8, 3.4 Hz, 1 H), 2.69 (dd, J = 13.8, 3.4 Hz, 1 H), 2.92 (dd, J =
10.5, 5.6 Hz, 1 H), 2.97 (dd, J = 13.8, 9.8 Hz, 1 H), 4.69 (d, J =
1.1 Hz, 1 H), 4.81 (s, 2 H), 5.07 (s, 5 H), 6.66 (s, 2 H), 7.36 (mc, 2
H), 7.41 (mc, 4 H), 7.47 (mc, 4 H) ppm. 13C NMR (125 MHz,
CDCl3, 298 K): δ = 11.9, 14.1, 15.3, 18.0, 19.2, 24.0, 27.8, 28.2,
35.8, 38.4, 39.0, 39.7, 53.9, 54.4, 64.9, 70.3, 78.5, 102.4, 106.8,
117.2, 127.7, 128.4, 137.2, 140.4, 149.1, 157.5 ppm. ESI-HRMS:
calcd. for [C45H64O4Si + H]+: m/z = 697.4647; found m/z =
697.4635.
5.0 Hz, 1 H), 2.04 (dt, J = 13.5, 3.8 Hz, 1 H), 2.27 (dd, J = 7.4,
3.6 Hz, 1 H), 2.40 (ddd, J = 12.5, 4.2, 2.4 Hz, 1 H), 2.64 (dd, J =
14.9, 7.4 Hz, 1 H), 2.88 (dd, J = 14.9, 3.6 Hz, 1 H), 3.28 (dd, J =
11.7, 4.5 Hz, 1 H), 4.66 (s, 2 H), 4.88 (mc, 1 H), 5.10 (mc, 1 H),
5.55 (br. s, 2 H), 6.32 (s, 2 H) ppm. 13C NMR (125 MHz, CDCl3,
298 K): δ = 11.9, 14.1, 15.3, 18.1, 18.8, 24.1, 27.6, 28.2, 36.2, 38.3,
39.1, 40.4, 54.6, 55.6, 64.3, 79.2, 105.1, 107.0, 114.0, 140.8, 150.6,
154.8 ppm. ESI-HRMS: calcd. for [C31H52O4Si + H]+: m/z =
517.3708; found m/z = 517.3708.
3-Hydroxy-2-{[(1S,4aR,6S,8aR)-6-hydroxy-5,5,8a-trimethyl-2-
methylenedecahydronaphthalen-1-yl]methyl}-5-[(triisopropylsilyl-
oxy)methyl]cyclohexa-2,5-diene-1,4-dione (21): A solution of resor-
cine 20 (254 mg, 491 μmol) in DMF (20 mL) and H2O (5 mL) was
chilled in an ice bath and a solution of bis(trifluoroacetoxy)iodo-
benzene (429 mg, 998 μmol) in DMF (8.5 mL) and H2O (2.5 mL)
was added dropwise during 30 min under an inert gas atmosphere.
The reaction mixture was partitioned between hexanes/MTBE (3:1,
200 mL) and half saturated NH4Cl (100 mL) and the aqueous
phase was extracted with hexanes/MTBE (3:1, 100 mL). After the
combined organic phases were washed with brine and dried with
MgSO4 the solvent was evaporated. The crude product was purified
by column chromatography (silica gel, 3% iPrOH/CHCl3) to obtain
the quinone 21 (238 mg, 448 μmol, 91%). RfЈ = 0.31 (3% iPrOH/
CHCl3). [α]2D3 = –101 (c = 0.18, CHCl3). 1H NMR (500 MHz,
CDCl3, 298 K): δ = 0.77 (s, 3 H), 0.78 (s, 3 H), 0.99 (s, 3 H), 1.06
(d, J = 6.9 Hz, 18 H), 1.11–1.19 (m, 4 H), 1.38 (dddd, J = 12.9,
12.9, 12.9, 4.2 Hz, 1 H), 1.44 (br. s, 1 H), 1.51–1.66 (m, 2 H), 1.68–
1.78 (m, 2 H), 1.83 (mc, 1 H), 1.92 (ddd, J = 12.9, 12.9, 5.0 Hz, 1
H), 2.31 (ddd, J = 12.9, 4.0, 2.5 Hz, 1 H), 2.35 (br. d, J = 10.9 Hz,
1 H), 2.50 (dd, J = 13.9, 2.8 Hz, 1 H), 2.67 (dd, J = 13.9, 10.9 Hz,
1 H), 3.31 (dd, J = 11.2, 4.2 Hz, 1 H), 4.61 (d, J = 2.4 Hz, 2 H),
4.69 (mc, 1 H), 4.73 (mc, 1 H), 6.73 (t, J = 2.4 Hz, 1 H), 7.09 (s, 1
H) ppm. 13C NMR (125 MHz, CDCl3, 298 K): δ = 11.8, 14.0, 15.4,
17.9, 19.0, 23.9, 27.9, 28.2, 36.6, 38.0, 39.1, 39.8, 54.1, 54.5, 58.8,
78.7, 107.1, 121.5, 133.2, 143.9, 148.2, 151.0, 182.9, 187.9 ppm.
ESI-HRMS: calcd. for [C31H50O5Si + H]+: m/z = 531.3500; found
m/z = 531.3502.
3β-Hydroxytauranin (2): To a solution of quinone 21 (60.0 mg,
113 μmol) in THF (5 mL) TBAF (120 mg, 429 μmol) was added
and the reaction mixture was stirred under an inert gas atmosphere
at room temperature for 30 min. The reaction mixture was parti-
tioned between MTBE (50 mL) and half saturated NH4Cl (25 mL)
and the aqueous phase was extracted with MTBE (25 mL). After
the combined organic phases were washed with brine and dried
with MgSO4 the solvent was evaporated. The crude product was
purified by column chromatography (silica gel, 6.5 % MeOH/
CHCl3) to obtain 3β-hydroxytauranin (2; 38.8 mg, 104 μmol, 92%)
as deep orange crystals. RfЈ = 0.28 (6.5% MeOH/CHCl3), m.p. 185–
190 °C (CHCl3, decomposition). [α]2D3 = –149 (c = 0.11, CHCl3).
1H NMR (500 MHz, CDCl3, 298 K): see supplement. 13C NMR
(125 MHz, CDCl3, 298 K): see supplement. ESI-HRMS: calcd. for
[C22H30O5 + H]+: m/z = 375.2166; found m/z = 375.2167.
2-{[(1S,4aR,6S,8aR)-6-Hydroxy-5,5,8a-trimethyl-2-methylenedeca-
hydronaphthalen-1-yl]methyl}-5-[(triisopropylsilyloxy)methyl]benz-
ene-1,3-diol (20): To a solution of naphthalene (796 mg, 6.21 mmol)
in THF (12 mL) lithium granules (43.1 mg, 6.21 mmol) were added
and the mixture was sonicated for 5 min under an inert gas atmo-
sphere at room temperature. The mixture was stirred with a SmCo-
stir bar for about 3 h until all lithium disappeared and THF
(13 mL) was added. After cooling to –21 °C a solution of the
benzyl protected resorcine 18 (555 mg, 796 μmol) in THF (10 mL)
was added dropwise under vigorous stirring within 5 min and the
reaction mixture was warmed to room temperature. The reaction
mixture was partitioned between MTBE (250 mL) and half satu-
rated NH4Cl (200 mL) and the aqueous phase was extracted with
MTBE (100 mL). The combined organic extracts were washed with
brine, dried with MgSO4, and all volatiles were removed under re-
duced pressure. Column chromatography (silica gel, 25% Me2CO/
hexanes) provided the desired resorcine 20 (396 mg, 766 μmol,
96%). RfЈ = 0.27 (25% Me2CO/hexanes). [α]2D3 = –7.2 (c = 0.64,
3-Hydroxy-5-[(triisopropylsilyloxy)methyl]-2-{[(1S,4aR,8aR)-5,5,8a-
trimethyl-2-methylene-6-oxodecahydronaphthalen-1-yl]methyl}-
cyclohexa-2,5-diene-1,4-dione (22):
A solution of quinone 21
(74.4 mg, 140 μmol) in DCM (6 mL) was chilled in an ice bath
under an inert gas atmosphere. Dess–Martin-periodinan (DMP,
62.4 mg, 147 μmol) was added and the reaction mixture was stirred
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Total Synthesis of 3-Oxo- and 3β-Hydroxytauranin
1645–1648; c) K. C. Nicolaou, K. Koide, M. E. Bunnage,
Chem. Eur. J. 1995, 1, 454–466; d) R. F. Cunico, L. Bedell, J.
Org. Chem. 1980, 45, 4797–4798; e) S. I. Odejinmi, D. F.
Wiemer, Tetrahedron Lett. 2005, 46, 3871–3874.
at 0 °C for 1 h. Then the mixture was diluted with hexanes (90 mL)
and filtered through a pad of silica (h = 4 cm, ø = 3 cm). The
quinones stayed at the baseline and were separated via Dry Column
Vacuum Chromatography (DCVC, silica gel, 5% to 15% Me2CO/
hexanes) yielding the desired ketone 22 (44.9 mg, 84.9 μmol, 61%,
81% brsm) besides recovered starting material 21 (18.7 mg,
35.2 μmol). RfЈ = 0.34 (15% Me2CO/CHCl3). [α]2D3 = –97 (c = 0.13,
CHCl3). 1H NMR (500 MHz, CDCl3, 298 K): δ = 0.95 (s, 3 H),
1.03 (s, 3 H), 1.06 (d, J = 6.9 Hz, 18 H), 1.10 (s, 3 H), 1.11–1.19
(m, 3 H), 1.49 (dddd, J = 13.2, 13.2, 13.2, 4.2 Hz, 1 H), 1.64–1.72
(m, 2 H), 1.94–2.01 (m, 2 H), 2.10 (ddd, J = 13.2, 6.6, 3.9 Hz, 1
H), 2.36 (ddd, J = 12.7, 3.8, 2.5 Hz, 1 H), 2.41–2.48 (m, 2 H), 2.50
(dd, J = 13.9, 2.7 Hz, 1 H), 2.65 (ddd, J = 15.2, 12.4, 6.6 Hz, 1 H),
2.75 (dd, J = 13.9, 11.0 Hz, 1 H), 4.62 (d, J = 2.4 Hz, 2 H), 4.76
(d, J = 0.7 Hz, 1 H), 4.81 (d, J = 0.7 Hz, 1 H), 6.75 (t, J = 2.4 Hz,
1 H), 6.95 (s, 1 H) ppm. 13C NMR (125 MHz, CDCl3, 298 K): δ =
11.8, 13.7, 17.9, 19.3, 21.7, 25.1, 26.0, 34.8, 37.2, 37.7, 39.7, 47.7,
53.4, 55.0, 58.8, 108.0, 121.0, 133.2, 144.0, 147.4, 151.0, 182.9,
187.8, 217.0 ppm. ESI-HRMS: calcd. for [C31H48O5Si + H]+: m/z
= 529.3344; found m/z = 529.3346.
[4]
a) E. Negishi, H. Matsushita, N. Okukado, Tetrahedron Lett.
1981, 22, 2715–2718; b) B. H. Lipshutz, G. Bulow, R. F. Lowe,
K. L. Stevens, J. Am. Chem. Soc. 1996, 118, 5512–5513; c)
B. H. Lipshutz, G. Bulow, R. F. Lowe, K. L. Stevens, Tetrahe-
dron 1996, 52, 7265–7276; d) B. H. Lipshutz, G. Bulow, F. Fer-
nandez-Lazaro, S.-K. Kim, R. Lowe, P. Mollard, K. L. Stevens,
J. Am. Chem. Soc. 1999, 121, 11664–11673; e) B. H. Lipshutz,
P. Mollard, S. S. Pfeiffer, W. Chrisman, J. Am. Chem. Soc. 2002,
124, 14282–14283; f) B. H. Lipshutz, B. Amorelli, J. Am. Chem.
Soc. 2009, 131, 1396–1397; g) B. H. Lipshutz, A. Lower, V.
Berl, K. Schein, F. Wetterich, Org. Lett. 2005, 7, 4095–4097.
a) A. Bernet, K. Seifert, Helv. Chim. Acta 2006, 89, 784–796;
b) J. Clayden, M. N. Kenworthy, M. Helliwell, Org. Lett. 2003,
5, 831–834; c) G. Blame, G. Fournet, J. Gore, Tetrahedron Lett.
1986, 27, 1907–1908.
a) J. Hooz, J. Cabezas, S. Musmanni, J. Calzada, Org. Synth.
1990, 69, 120; Org. Synth., Coll. Vol. 1993, 8, 226; b) E. Negi-
shi, C. L. Rand, K. P. Jadhav, J. Org. Chem. 1981, 46, 5041–
5044; c) E. Alonso, D. J. Ramón, M. Yus, Tetrahedron 1997,
53, 14355–14368.
[5]
[6]
3-Oxotauranin (1): To
a solution of quinone 22 (43.2 mg,
81.1 μmol) in THF (5 mL) TBAF (80.0 mg, 286 μmol) was added
and the reaction mixture was stirred under an inert gas atmosphere
at room temperature for 30 min. The reaction mixture was parti-
tioned between MTBE (50 mL) and half saturated NH4Cl (25 mL)
and the aqueous phase was extracted with MTBE (25 mL). After
the combined organic phases were washed with brine and dried
with MgSO4 the solvent was evaporated. The crude product was
purified by column chromatography (silica gel, 5% MeOH/CHCl3)
to obtain 3-oxotauranin (1; 28.0 mg, 75.2 μmol, 93%). RfЈ = 0.22
(5% MeOH/CHCl3). [α]2D3 = –160 (c = 0.13, CHCl3). 1H NMR
(500 MHz, CDCl3, 298 K): see supplement. 13C NMR (125 MHz,
CDCl3, 298 K): see supplement. ESI-HRMS: calcd. for
[C22H28O5 + H]+: m/z = 373.2010; found m/z = 373.2009.
[7]
a) C. A. Tolman, Chem. Rev. 1977, 77, 313–348; b) E. Negishi,
N. Okukado, A. O. King, D. E. van Horn, B. I. Spiegel, J. Am.
Chem. Soc. 1978, 100, 2254–2256; c) M. Qian, Z. Huang, E.
Negishi, Org. Lett. 2004, 6, 1531–1534; d) M. A. Pena, J. P.
Sestelo, L. A. Sarandeses, Synthesis 2005, 485–492; e) Y.-C. Xu,
J. Zhang, H.-M. Sun, Q. Shen, Y. Zhang, Dalton Trans. 2013,
42, 8437–8445; f) C. J. O’Brien, E. A. B. Kantchev, C. Valente,
N. Hadei, G. A. Chass, A. Lough, A. C. Hopkinson, M. G.
Organ, Chem. Eur. J. 2006, 12, 4743–4748; g) C. Valente, M. E.
Belowich, N. Hadei, M. G. Organ, Eur. J. Org. Chem. 2010,
4343–4354.
[8]
a) H. C. Kolb, M. S. van Nieuwenhze, K. B. Sharpless, Chem.
Rev. 1994, 94, 2483–2547; b) G. Vidari, A. Dapiaggi, G.
Zanoni, L. Garlaschelli, Tetrahedron 1993, 34, 6485–6488; c)
E. J. Corey, M. C. Noe, S. Lin, Tetrahedron Lett. 1995, 36,
8741–8744; d) H. Lin, S. S. Pochapsky, I. J. Krauss, Org. Lett.
2011, 13, 1222–1225; e) an improved, higher yielding prepara-
tion of the precursor O6Ј-(4-heptyl)dihydrocupreidine can be
found in the supplement; f) J. S. M. Wai, I. Marko, J. S.
Svendsen, M. G. Finn, E. N. Jacobsen, K. B. Sharpless, J. Am.
Supporting Information (see footnote on the first page of this arti-
cle): Revised NMR-assignments of 3β-hydroxytauranin (2) and 3-
1
oxotauranin (1), figures of H and 13C NMR spectra of products,
the determination of the enantiomeric purity of glycol 15, and syn-
thesis of O6Ј-(4-heptyl)dihydrocupreidine.
1
Chem. Soc. 1989, 111, 1123–1125; g) determined by H-NMR
using (2-formylphenyl)boronic acid and (R)- and (S)-α-methyl-
benzylamine according to A. M. Kelly, Y. Pérez-Fuertes, J. S.
Fossey, S. L. Yeste, S. D. Bull, T. D. James, Nat. Protoc. 2008,
3, 215–219.
Acknowledgments
Support of this research by a scholarship of the Dr. Hans M. Fi-
scher Foundation is gratefully acknowledged. The authors would
like to thank Prof. Dr. J. Woodring from the University of Bayreuth
for correcting the English of the manuscript.
[9]
a) J. Justicia, A. Rosales, E. Buñuel, J. L. Oller-Lopez, M. Val-
divia, A. Haïdour, J. E. Oltra, A. F. Barrero, D. J. Cárdenas,
J. M. Cuerva, Chem. Eur. J. 2004, 10, 1778–1788; b) A. F. Bar-
rero, M. M. Herrador, J. F. Qílez del Moral, P. Arteaga, J. F.
Arteaga, M. Piedra, E. M. Sánchez, Org. Lett. 2005, 7, 2301–
2304; c) J. Justicia, J. E. Oltra, A. F. Barrero, A. Guadano, A.
González-Coloma, J. M. Cuerva, Eur. J. Org. Chem. 2005, 712–
718; d) V. Domingo, L. Silva, H. R. Diéguez, J. F. Arteaga, J. F.
Quílez del Moral, A. F. Barrero, J. Org. Chem. 2009, 74, 6151–
6156; e) M. D’Acunto, C. Della Monica, I. Izzo, L. De Petro-
cellis, V. di Marzo, A. Spinella, Tetrahedron 2010, 66, 9785–
9789; f) A. F. Barrero, J. F. Quílez del Moral, E. M. Sánchez,
J. F. Arteaga, Eur. J. Org. Chem. 2006, 1627–1641; g) J. Justicia,
Á. de Cienfuegos, A. G. Campaña, D. Miguel, V. Jaoby, A.
Gansäuer, J. M. Cuerva, Chem. Soc. Rev. 2011, 40, 3525–3537;
h) T. Jiménez, S. P. Morcillo, A. Martín-Lasanta, D. Collado-
Sanz, D. J. Cárdenas, A. Gansäuer, J. Justicia, J. M. Cuerva,
Chem. Eur. J. 2012, 18, 12825–12833; i) A. Gansäuer, J. Jus-
ticia, A. Rosales, D. Worgull, B. Rinker, J. M. Cuerva, J. E.
Oltra, Eur. J. Org. Chem. 2006, 4115–4127; j) A. Rosales, J.
Munoz-Bascon, E. Roldan-Molina, N. Rivas-Bascon, N. M.
[1] a) P. Proksch, Dtsch. Apoth. Ztg. 1994, 134 (51/52), 19–20, 23–
27, 30–34; b) S. Loya, R. Tal, Y. Kashman, A. Hizi, Antimicrob.
Agents Chemother. 1990, 34, 2009–2012; c) M.-L. Bourjouet-
Kondracki, A. Longeor, R. Morel, M. Guyot, Int. Immunphar-
mac. 1991, 13, 393–399; d) Y. Li, Y. Zhang, X. Shen, Y. W.
Guo, Bioorg. Med. Chem. Lett. 2009, 19, 390–392; e) T. Laube,
W. Beil, K. Seifert, Tetrahedron 2005, 61, 1141–1148; f) T.
Laube, A. Bernet, H.-M. Dahse, I. D. Jacobsen, K. Seifert, Bio-
org. Med. Chem. 2009, 17, 1422–1427; g) E. M. K. Wijeratne,
P. A. Paranagama, M. T. Marron, M. K. Gunatilaka, A. E. Ar-
nold, A. A. L. Gunatilaka, J. Nat. Prod. 2008, 71, 218–222; h)
M. Göhl, K. Seifert, Eur. J. Org. Chem. 2014, 6975–6982.
[2] M. Gordaliza, Mar. Drugs 2012, 10, 358–402.
[3] a) H. E. Pelish, N. J. Westwood, Y. Feng, T. Kirchhausen,
M. D. Shair, J. Am. Chem. Soc. 2001, 123, 6740–6741; b) Z.
Bo, A. Schäfer, P. Franke, A. D. Schlüter, Org. Lett. 2000, 2,
Eur. J. Org. Chem. 2015, 6249–6258
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
6257

M. Göhl, K. Seifert
FULL PAPER
Padial, R. Rodríguez-Maecker, I. Rodríguez-García, J. E. Ol-
tra, J. Org. Chem. 2015, 80, 1866–1870.
T. R. R. Pettus, Org. Lett. 2004, 4, 285–288; d) H. L. Holland,
J. Qi, T. S. Manoharan, Can. J. Chem. 1995, 73, 1399–1405; e)
M. Hunsen, Synthesis 2005, 2487–2490; f) S. Yamazaki, Tetra-
hedron Lett. 2001, 42, 3355–3357; g) R. Barret, M. Daudon,
Tetrahedron Lett. 1990, 31, 4871–4872.
[10] H.-J. Liu, J. Yip, K.-S. Shia, Tetrahedron Lett. 1997, 38, 2253–
2256.
[11] a) E. R. Dockal, Q. B. Cass, T. J. Brocksom, U. Brocksom,
A. G. Correˇa, Synth. Commun. 1985, 15, 1033–1036; b) M. P.
Uliana, Y. W. Vieira, M. C. Donatoni, A. G. Corrêa, U. Brock-
som, T. J. Brocksom, J. Braz. Chem. Soc. 2008, 19, 1484–1489;
c) D. Magdziak, A. A. Rodriguez, R. D. Van De Water,
[12] a) C. Rücker, Chem. Rev. 1995, 95, 1009–1064; b) D. B. Dess,
J. C. Martin, J. Org. Chem. 1983, 48, 4155–4156.
Received: June 19, 2015
Published Online: August 14, 2015
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Eur. J. Org. Chem. 2015, 6249–6258