A Radical-Based Synthesis of Lingzhiol

Article abstract of DOI:10.1021/acs.joc.7b01416

The polycyclic natural product lingzhiol [(±)-1] was synthesized from dimethoxytetralone 8 via cyclization of an intermediate benzylic radical, generated from spiroepoxide 14, onto an alkynyl substituent generating tetracyclic compound 13 with an exocyclic double bond. After oxidative cleavage of the double bond of 13 and reduction of the keto function of 23, the correct diastereomer, 12-syn, was converted to lingzhiol (1) via known steps. In a similar manner, lingzhiol analogue 39 was synthesized from 5-methoxy-1-tetralone (27).

Full text of DOI:10.1021/acs.joc.7b01416

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Note
A Radical Based Synthesis of Lingzhiol
Lea-Marina Mehl, and Martin E. Maier
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b01416 • Publication Date (Web): 18 Aug 2017
Downloaded from http://pubs.acs.org on August 18, 2017
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A Radical Based Synthesis of Lingzhiol
Lea-Marina Mehl and Martin E. Maier*
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Institut für Organische Chemie, Eberhard Karls Universität Tübingen, Auf der Morgenstelle 18, 72076
Tübingen, Germany
martin.e.maier@uni-tuebingen.de
TOC graphic
R
O
R
O
R
4
steps
Cp2TiCl2, Zn
THF
CO Et
2
MeO
O
O
MeO 8, 27
R = OMe, H
MeO 14, 31
13, 32
6
steps
R
OH
HO
O
O
1, 39
O
ABSTRACT: The polycyclic natural product lingzhiol [(±)-1] was synthesized from dimethoxytetralone 8 via
cyclization of an intermediate benzylic radical, generated from spiroepoxide 14, onto an alkynyl
substituent generating the tetracyclic compound 13 with an exocyclic double bond. After oxidative
cleavage of the double bond of 13 and reduction of the keto function of 23, the correct diastereomer 12-
syn was converted to lingzhiol (1) via known steps. In a similar manner, lingzhiol analog 39 was
synthesized from 5-methoxy-tetralone (27).
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Due to the extensive medicinal use of mushrooms belonging to the genus Ganoderma, these species are
promising sources of novel natural products. For example, quite recently the polycyclic compounds
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lingzhiol (1) and sinensilactam (2) were isolated from Ganoderma lucidum and Ganoderma sinensis,
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respectively (Figure 1). Interestingly, both compounds appear as racemates in these mushrooms.
Figure 1. Structures of the polycyclic natural products (–)-lingzhiol (1) and (–)-sinensilactam (2).
It was suggested that these compounds are biosynthesized in plants from 4-hydroxybenzoic acid (3), a
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product of the shikimic acid pathway, and geranyl diphosphate (Scheme 1). In a second proposal,
geranylhydroquinone would be cyclized and oxidized to polycycle 6. A subsequent semipinacol
rearrangement of the epoxyalcohol function would lead to advanced intermediate 7. Regarding the
biosynthesis of these compounds it is not sure whether a cyclase phase precedes the oxidation phase or
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vice versa. Both 1 and 2 were found to be inhibitors of Smad3 phosphorylation in TGF-β1 induced
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cellular assays. Smad3 is a transcription protein implicated in renal fibrosis. Common structural features
for 1 and 2 are an acylated hydroquinone and a central cyclopentane ring featuring two vicinal
quaternary centers.
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Scheme 1. Possible key intermediates and key steps in the biosynthesis of lingzhiol (1).
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Due to the interesting structure lingzhiol (1) has attracted significant interest from synthetic groups. Up
to now five total syntheses from other groups were reported. Three of them start from 5,8-dimethoxy-
6
7
tetralone (8) and two use 2-oxo-cyclopentanecarboxylate 9 as starting material. Our own group
contributed with a synthesis of lingzhiol and some analogs where an alkylation and Wittig reaction on
ethyl 2–oxocyclopentancarboxylate (9) to exo-alkene 10 allowed for a short route to epoxide 11 which
7a
underwent a Lewis acid promoted intramolecular Friedel-Crafts alkylation to key tetracyclic
8
intermediate 12 (Scheme 2).
Scheme 2. Published routes to lingzhiol either start from tetralone 8 or oxocyclopentane carboxylate 9.
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In our retrosynthetic plan tetracyclic intermediate 12 would originate from exocyclic alkene 13 (Scheme
3
). After this key FGI, a radical cyclization of benzylic radical A to its alkyne function becomes obvious.
The benzylic radical A would be generated from spiroepoxide 14, which in turn can be traced back to
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tetralone 8. In this paper we detail the implementation of this plan, the associated difficulties and
how this strategy led to lingzhiol (±-1) and the deoxy analog 39.
Scheme 3. Retrosynthesis for lingzhiol featuring a radical cyclization to form the cyclopentane ring.
Dimethoxytetralone 8 was prepared from p-dimethoxybenzene (15) by the classical Haworth strategy.
11
Here we could improve the yield for the Friedel-Crafts acylation with succinic anhydride by running the
AlCl induced reaction in a mixture of nitromethane and dichloromethane (Scheme 4). This way ketoacid
3
1
6 was obtained in 80% yield. For the subsequent reductive removal of the keto function we relied on
12
ionic reduction using triethylsilane in presence of trifluoroacetic acid in dichloromethane. The second
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Friedel-Crafts reaction to tetralone was performed as described yielding ketone 8 in 75% yield.
Scheme 4. Synthesis of tetralone 8 via Haworth strategy.
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In the next step a carboxylation reaction on tetralone 8 using diethyl carbonate in presence of sodium
hydride delivered β-ketoester 17 (Scheme 5). The plan was then to alkylate ketoester 17 with 4-bromo-1-
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butyne (18). However, the desired product 19 could not be observed [NaH (1.6 equiv), 18 (1.4 equiv),
THF, 0 to 80 °C, 20 h]. We therefore prepared aldehyde 20 by base induced Michael addition of ketoester
15
17 to acrolein. Subsequently, aldehyde 20 was reacted with the Ohira-Bestmann reagent, the diazo
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compound 21, in ethanol in presence of potassium carbonate, giving rise to alkyne 19 in 58% yield. For
the synthesis of spiroepoxide 14 we first considered an olefination reaction on ketone 19 followed by
epoxidation of the exocyclic double bound. However, neither Wittig (Ph PCH Br, n-BuLi, THF; Ph PCH Br,
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3
3
3
17
KOt-Bu, t-BuOH) nor Lombardo conditions (20% of 22) nor Peterson olefination led to the desired
alkene 22 in satisfactory yields. Therefore, we focused on a formal carbene addition to the keto function
+
–
of 19. While epoxidation with the Corey-Chaykowski reagent ((CH ) S I , NaH, DMSO) was not successful,
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18,19
the intended transformation could be realized with (bromomethyl) lithium,
generated from
dibromomethane (1.5 equiv) and n-BuLi (1.2 equiv) in THF at –78 °C. Epoxide 14 was obtained essentially
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as a single diastereomer (~ 6:1). In the H NMR spectrum epoxide 14 shows a characteristic peak at δ =
3.25 ppm (d, J = 4.3 Hz) which can be assigned to one of the CH epoxide protons. The diastereomeric
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ratio of the epoxides was determined by integration of the OCH CH triplets at δ = 1.04 and 0.99 ppm,
2
3
respectively. A small amount of starting ketone 19 (~ 20%) could be separated by chromatography.
Unfortunately, we were not able to obtain epoxide 14 in very pure form. Alternatively, it was possible to
use the crude mixture from the epoxidation reaction, containing some ketone 19, for the subsequent
radical cyclization reaction. In these cases the yield of 14 was determined by integration of the aromatic
protons. It seems that epoxide formation on ketone 19 is hampered by steric hindrance and electronic
deactivation of the keto function by the 8-OCH substituent. For the radical cyclization epoxide 14 was
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subjected to a preformed mixture of zinc (9 equiv) and Cp TiCl (3 equiv) in THF at 0˚C followed by
2
2
stirring of the mixture for 2 d. This gave tetracyclic lactone 13 in 69% yield as yellow powder. In addition
to tetracycle 13 around 20% of alkene 22 was formed under these conditions.
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Scheme 5. Synthesis of tetracycle 13.
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The subsequent oxidative cleavage of the exocyclic double bond was best performed as a one pot
process. Thus, alkene 13 was stirred in an aqueous solution of THF in presence of catalytic amounts of
2
0
potassium osmate(VI) dihydrate (K OsO ·2H O) and sodium periodate (NaIO , 4 equiv) to give ketone
2
4
2
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23 in 63% yield (Scheme 6). Its spectral data were in accordance with a sample that was prepared by
8
oxidation of the corresponding alcohol. As a final challenge, the diastereoselective reduction of ketone
2
3 remained. Using sodium borohydride in methanol a 1:2 mixture of 12-syn and 12-anti was obtained.
Here syn refers to the isomer where the hydroxyl group points towards the butyrolactone part. Other
conditions (NaBH , EtOH, 0 °C to rt, 1.5 h, syn/anti = 25:75, 75% yield; Et SiH, TiCl , CH Cl , –40 °C, 30
4
3
4
2
2
min, no reaction; L-Selectride, THF, –78 °C to rt, 3 h, syn/anti = 33:67) also preferentially led to 12-anti.
However, in presence of cerium trichloride hydrate (CeCl ·7H O, 1 equiv) a 1:1 mixture of 12-syn and 12-
3
2
21
anti was formed. Both isomers could be separated by chromatography. It was possible to recycle the
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2-anti isomer by oxidation to ketone 23 using the Dess-Martin periodinane reagent. Inversion of the
stereochemistry at C-6' of 12-anti under Mitsunobu conditions remained fruitless. For the conversion of
6,8
alcohol 12-syn to lingzhiol we followed literature precedence. Thus, acetylation of 12-syn to acetate 24
was followed by benzylic oxidation with oxygen in presence of N-hydroxyphthalimide and AIBN which
gave phenone 25 in a decent yield of 42%. An X-ray analysis of acetate 24 (see Supporting Information)
proved the relative stereochemistry of the reduction step. Subsequent hydrolysis of the acetate led to
hydroxyphenone 26. A final cleavage of the aromatic ether functions with aluminium chloride in
presence of tert-butyl mercaptan provided racemic lingzhiol 1. Its spectral data fully matched the
literature values.
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Scheme 6. Conversion of exocyclic alkene 13 to lingzhiol (1).
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In order to elucidate the stereoelectronic influence of the 4-OCH group (lingzhiol numbering) on the
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reactivity of the tetralone carbonyl group and to shed light on the role of the corresponding hydroxyl
function in lingzhiol we designed analog 39 (Scheme 7). The synthesis of 39 was patterned along the
route shown for (±)-1 (Scheme 5 and 6). Even though 5-methoxy-1-tetralone (27) is commercially
available, we prepared it from naphthalene-1,5-diol via catalytic hydrogenation which led to 5-hydroxy-
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-tetralone followed by a Williamson ether synthesis (K CO , MeI, acetone, 56% yield).
2 3
24
Following the route of Schemes 5 and 6, 27 was carboxylated to ketoester 28 and then added to
acrolein under basic conditions (Scheme 7). Aldehyde 29 could be converted to alkyne 30 using the
Ohira-Bestmann reagent. Reaction of ketone 30 with lithiated dibromomethane furnished epoxide 31 in
4
8% yield. The reductive cyclization provided tetracycle 32 in 75% yield. Again, some deoxygenation of
the epoxide to the corresponding alkene 33 (17%) was observed. While the transformations up to 32
proceeded with somewhat higher yields as compared to the sequence for (±)-1, the oxidative cleavage of
the double bond was less efficient providing ketone 34 in 53% yield. Moreover, the reduction of ketone
34 favored the wrong isomer, even in presence of CeCl ·7H O (35-syn/35-anti = 1:2). Four further steps
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converted alcohol 35-syn via acetate 36, phenone 37, and hydroxyketone 38 to lingzhiol analog 39.
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Scheme 7. Synthesis of lingzhiol analog (±)-39.
O
O
CO Et
NaH, (EtO) CO
2
CHO
2
THF, 80 °C, 2 h
(97%)
EtN, DMF, rt
2 h (91%)
MeO
27
MeO 28
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O
4'
O
O
3'
H
P(OEt)2
2'
1'
O
O
8
2
1
8a
N2
1
4
CO Et
2
CO Et
2
2
K CO , EtOH
2
3
6
4
a
0
(
°C to rt, 20 h
67%)
5
MeO 29
MeO
30
O
CH Br , n-BuLi
Cp TiCl , Zn
2 2
2
2
CO Et
–78 °C to rt, 3 h
48%)
2
THF, rt, 2 d
(
MeO 31
CO Et
2
+
MeO
O
3
3 (17%)
3
2 (75%)
MeO
O
O
K OsO —2H O
NaBH4, CeCl3—7H2O
2
4
2
3
2
NaIO , THF/H O
rt, 2 d (53%)
MeOH, rt, 2 h
(64%, dr = 1:2.2)
4
2
MeO
O
3
4
O
H
HO
OH
H
+
MeO
MeO
O
O
35-syn
35-anti
O
O
H
OAc
Ac O, pyr, DMAP
NHPI, AIBN, O2
2
3
5-syn
CH Cl , rt, 12 h
MeCN, 85 °C, 12 h
(45%)
2
2
MeO
O
(
92%)
O
36
H
H
OAc
OH
HCl (3N), MeOH
MeO
85 °C, 12 h (64%)
MeO
O
O
O
O
O
37
38
O
H
6'
7'
OH
5
4
AlCl , t-BuSH
5'
DMP, CH2Cl2
3
6
3
8'
35-anti
34
4'
CH Cl , 40 °C
12 h (63%)
HO 1
0 °C to rt, 2 h
(86%)
2
2
2
'
O
'
3
'
1'
9
O
O
(±)-39
Starting from tetralone 8 we developed a novel strategy to the polycyclic natural product lingzhiol (1).
The key reaction was a radical cyclization of epoxyalkyne 14 under reductive conditions using in situ
generated Cp TiCl leading to polycycle 13. Oxidative cleavage of the exocyclic double bond furnished
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ketone 23. Reduction of ketone 23 with sodium borohydride in presence of cerium trichloride delivered
a 1:1 mixture of alcohols 12-syn and 12-anti. Using an established sequence of reactions alcohol 12-syn
could be converted to lingzhiol (±)-1. In a similar strategy 5-methoxy-1-tetralone (27) was converted to
lingzhiol analog (±)-39.
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Experimental Section
General. Reactions were generally run under nitrogen atmosphere in oven dried glassware. Progress of
the reactions was followed using TLC plates "POLYGRAM SIL G/UV254", petroleum ether, ethyl acetate
(
EtOAc), dichloromethane, methanol and mixtures of them as an eluent. Dry diethyl ether (Et O) and
2
tetrahydrofuran were distilled from sodium and benzophenone, whereas dry CH Cl , methanol and
2
2
1
EtOAc were distilled from CaH . Distilled petroleum ether with a boiling range of 40–60 °C was used. H
2
13
NMR (400.160 MHz) and C NMR (100.620 MHz) spectra were measured on a "Bruker Avance 400"
spectrometer using CDCl as solvent at room temperature. Peak assignments were done by NMR
3
1
13
spectroscopy ( H, C, DEPT-135, H,H-COSY, HSQC, and HMBC). High-resolution mass spectra (HRMS)
were recorded on a "Bruker maXis 4G" instrument with electron spray ionization (ESI) and TOF mass
detector. Not all the compound names may correspond to IUPAC nomenclature.
4
-(2',5'-Dimethoxyphenyl)-4-oxobutyric acid (16). Succinic anhydride (11.25 g, 11.25 mmol) and p-
dimethoxybenzene (15) (13.88 g,10.04 mmol) were added to a solution of AlCl (30.0 g, 0.23 mol) in a
3
mixture of CH Cl /nitromethane (1:1, each 125 mL) at 0 °C. The mixture was allowed to warm from 0 °C
2
2
to rt and stirred over 3 h, after which the solution was poured into ice-water (about 500 mL). This
mixture was acidified to pH 1 using concentrated HCl while cooling the mixture in an ice bath. The
mixture was extracted with EtOAc (3 × 250 mL). The combined organic extracts were dried over Na SO ,
2
4
filtered, and concentrated under reduced pressure. The crude residue was recrystallized from a mixture
of CHCl (about 15 mL) and petroleum ether (few drops). The resulting very pale yellow solid was filtered
3
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and dried (19.0 g, 80%). R = 0.32 (petroleum ether/EtOAc, 2:1). H NMR data for keto acid 16 matched
f
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those reported in the literature.
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Ethyl 5,8-dimethoxy-1-oxo-1,2,3,4-tetrahydronaphthalene-2-carboxylate (17). A solution of tetralone 8
10
11
12
13
14
15
16
17
18
19
20
21
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23
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56
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59
60
(13.8 g, 66.9 mmol, 1 equiv) in THF (335 mL) was dropped into a suspension of NaH (3.30 g, 83.6 mmol,
1
.25 equiv, 60% in mineral oil) and freshly distilled diethyl carbonate (80.9 g, 83.0 mL, 0.685 mol) in THF
(
220 mL) under a nitrogen atmosphere. The mixture was then heated to 70 °C for additional 2 h. The
color of the reaction mixture turned from yellow to dark red. The mixture was diluted with a saturated
aqueous solution of NH Cl (450 mL) and extracted with Et O (3 × 140 mL). The combined organic extracts
4
2
were dried over Na SO , filtered and concentrated under reduced pressure. The crude product was
2
4
crystallized from a mixture of Et O and petroleum ether (10:1; about 20 mL) to give ketoester 17 (16.7 g,
2
1
90%) as fawn solid. R = 0.48 (petroleum ether/EtOAc, 1:1); H NMR (400 MHz, CDCl ): δ = 7.01 (d, J = 8.8
f
3
Hz, 1H, 6-H), 6.82 (d, J = 9.1 Hz, 1H, 7-H), 4.23 (q, J = 7.1 Hz, 2H, OCH CH ), 3.86 (s, 3H, OCH ), 3.83 (s, 3H,
2
3
3
OCH ), 3.58 (dd, J = 10.9, 4.8 Hz, 1H, 2-H), 3.10 (dt, J = 18.2, 5.3 Hz, 1H, 4-H), 2.83-2.74 (m, 1H, 4-H), 2.47-
3
1
3
2.28 (m, 2H, 3-H), 1.26 (t, J = 7.1 Hz, 3H, OCH CH ); C NMR (100 MHz, CDCl ): δ = 192.7 (C-2), 170.4
2
3
3
(
(
CO Et), 154.3 (C-8), 150.1 (C-5), 134.1 (C-4a), 122.2 (C-8a), 115.7 (C-6), 110.2 (C-7), 61.0 (OCH CH ), 56.4
2
2
3
C-2), 55.9, 55.7 (OCH ), 25.1 (C-3), 22.0 (C-4), 14.2 (OCH CH ).
3
2
3
Ethyl 5,8-dimethoxy-1-oxo-2-(3-oxopropyl)-1,2,3,4-tetrahydro¬naphthalene-2-carboxylate (20). Acrolein
(5.2 g, 6.2 mL, 93 mmol, 1.5 equiv) and NEt (0.88 g, 1.2 mL, 8.7 mmol, 0.14 equiv) were added to a
3
solution of ester 17 (16.7 g, 60.0 mmol, 1 equiv) in DMF (120 mL) under a nitrogen atmosphere. The
mixture was stirred at rt for 2 h. The reaction was quenched using HCl (1
N, 140 mL) and extracted with
Et O (3 × 120 mL). The combined organic extracts were dried over Na SO , filtered and concentrated
2
2
4
under reduced pressure. The crude aldehyde 20 (17.0 g, 81%), obtained as a light yellow oil, was used in
1
the next step without further purification. R = 0.26 (petroleum ether/EtOAc, 1:1); H NMR (400 MHz,
f
CDCl ): δ = 9.79 (t, J = 1.1 Hz, 1H, CHO), 6.96 (d, J = 9.1 Hz, 1H, 6-H), 6.70 (d, J = 9.1 Hz, 1 H, 7-H), 4.06-
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.16 (m, 2H, OCH CH ), 3.86 (s, 3H, OCH ), 3.81 (s, 3H, OCH ), 2.87-2.97 (m, 2H, 4-H), 2.71-2.76 (m, 1H, 2'-
2
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3
H), 2.51-2.61 (m, 2H, 3-H, 2'-H), 2.23-2.31 (m, 1H, 1'-H), 2.09-2.15 (m, 1H, 1'-H), 1.96-2.04 (m, 1H, 3-H),
13
1.12 (t, J = 7.1 Hz, 3H, OCH CH ); C NMR (100 MHz, CDCl ): δ = 201.4 (CHO), 194.7 (C-1), 171.6 (CO Et),
2
3
3
2
0
1
2
3
4
5
6
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8
9
0
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8
9
0
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0
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53.9 (C-8), 150.1 (C-5), 132.9 (C-4a), 122.9 (C-8a), 114.9 (C-6), 110.2 (C-7), 61.1 (OCH CH ), 57.1 (C-2),
2 3
6.4, 55.7 (OCH ), 39.7 (C-2'), 30.3 (C-3), 26.1 (C-1'), 20.5 (C-4), 13.9 (OCH CH ); HRMS (ESI-TOF) m/z: [M
3
2
3
+
+ Na + MeOH] calcd for C H O Na 389.15707; found 389.15717.
19
26
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Ethyl 2-(but-3-yn-1-yl)-5,8-dimethoxy-1-oxo-1,2,3,4-tetrahydro¬naphthalene-2-carboxylate (19).
Anhydrous K CO (7.10 g, 51.4 mmol, 2 equiv) was added to a solution of aldehyde 20 (8.60 g, 25.7
2
3
16
mmol, 1 equiv) in EtOH (150 mL) under a nitrogen atmosphere at 0 °C. The diazophosphonate 21 (7.36
g, 33.4 mmol, 1.3 equiv) was added dropwise as a solution in EtOH (100 mL). The mixture was allowed to
gradually warm to rt over 20 h. The reaction mixture was diluted using a saturated aqueous solution of
NaHCO (300 mL) followed by extraction with EtOAc (2 × 180 mL). The combined organic extracts were
3
dried over Na SO , filtered and concentrated under reduced pressure. The crude product was purified by
2
4
flash chromatography (petroleum ether/EtOAc, 2:1) to afford alkyne 19 (4.82 g, 58%) as a pale yellow
1
solid. R = 0.55 (petroleum ether/EtOAc, 1:1); mp 78.1 °C (EtOAc); H NMR (400 MHz, CDCl ): δ = 6.95 (d, J
f
3
=
9.1 Hz, 1H, 6-H), 6.79 (d, J = 9.1 Hz, 1H, 7-H), 4.07-4.17 (m, 2H, OCH CH ), 3.85 (s, 3H, OCH ), 3.81 (s,
2 3 3
3H, OCH ), 2.89-2.93 (m, 2H, 4-H), 2.54-2.60 (m, 1H, 3-H), 2.36-2.46 (m, 1H, 2'-H), 2.23-2.34 (m, 2H, 1'-H,
3
13
2
'-H), 2.00-2.08 (m, 2H, 3-H, 1'-H), 1.95 (t, J = 2.5 Hz, 1H, 4'-H), 1.12 (t, J = 7.3 Hz, 3H, OCH CH ); C NMR
2 3
(
100 MHz, CDCl ): δ = 194.5 (C-1), 171.3 (CO Et), 153.9 (C-8), 150.0 (C-5), 132.9 (C-4a), 122.9 (C-8a), 114.8
3
2
(C-6), 110.1 (C-7), 84.0 (C-3'), 68.4 (C-4'), 61.1 (OCH CH ), 57.5 (C-2), 56.4, 55.7 (OCH ), 32.8 (C-1'), 29.6
2
3
3
+
(
C-3), 20.4 (C-4), 14.4 (C-2'), 13.9 (OCH CH ); HRMS (ESI-TOF) m/z: [M + Na] calcd for C H O Na
2 3 19 22 5
3
53.13594; found 353.13618.
Ethyl 2-(but-3-yn-1-yl)-5,8-dimethoxy-1-methylene-1,2,3,4-tetrahydronaphthalene-2-carboxylate (22).
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a) Wittig reaction: To a suspension of methyltriphenylphosphonium iodide (365 mg, 0.903 mmol, 3
equiv) in THF (3 mL) was added n-BuLi (0.13 mL, 0.33 mmol, 2.5 M, 1.01 equiv) at –78 °C slowly. The
reaction mixture turned to deep yellow and was stirred for 30 min at –78 °C. Then ketone 19 (100 mg,
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0
.303 mmol, 1 equiv), dissolved in THF (1 mL) was added dropwise. The reaction mixture was brought to
room temperature and stirred overnight. Then it was quenched with saturated NH Cl solution (20 mL)
4
and extracted with EtOAc (3 × 10 mL). The combined organic layers were dried over Na SO , filtered and
2
4
concentrated under reduced pressure. The crude product was purified by flash chromatography
petroleum ether/EtOAc, 4:1) to give alkene 22 (15 mg, 15%) as colorless oil.
(
b) Takai-Lombardo reaction: Zinc powder (86 mg, 1.3 mmol, 4.3 equiv) was submitted in a Schlenk-flask
and dried 30 min with a heat gun (300 °C) under vacuo. After cooling, dry THF (10 mL) and CH Cl (5 mL)
2
2
were added. The suspension was cooled to -40 °C before TiCl (0.3 mL, 0.3 mmol, 1M in THF, 1 equiv) was
4
added dropwise. Afterwards the mixture was brought to 5 °C and kept at this temperature for 3 d under
N -atomosphere. The solution turned from green to brown. The stirred mixture was diluted with dry
2
CH Cl (4 mL) and then ketone 19 (100 mg, 0.303 mmol), dissolved in dry CH Cl (2 mL), was added
2
2
2
2
dropwise. The cooling bath was removed and the mixture was stirred for 1.5 h. The reaction was
quenched with saturated NaHCO solution (15 mL), the organic layer was separated and the aqueous
3
layer was extracted with petroleum ether (3 × 10 mL). The combined organic extracts were washed with
saturated NaCl solution (15 mL), dried over Na SO , filtered and concentrated under reduced pressure.
2
4
The crude product was purified by flash chromatography (petroleum ether/EtOAc, 5:1). The product 22
(
20 mg, 20%) was obtained as colorless oil.
1
R = 0.56 (petroleum ether/EtOAc, 4:1); H NMR (400 MHz, CDCl ): δ = 6.74 (d, J = 8.8 Hz, 1H, 6-H), 6.67
f
3
(d, J = 8.8 Hz, 1H, 7-H), 5.91 (s, 1H, 1-CH ), 5.35 (s, 1H, 1-CH ), 4.06-4.18 (m, 2H, OCH CH ), 3.78 (s, 3H,
2
2
2
3
OCH ), 3.77 (s, 3H, OCH ), 2.69-2.90 (m, 2H, 4-H), 2.35-2.42 (m, 1H, 3-H), 2.17-2.32 (m, 3H, 1'-H, 2'-H),
3
3
1
.96-2.00 (m, 1H, 1'-H), 1.71-178 (m, 1H, 3-H), 1.94 (t, J = 2.3 Hz, 1H, 4'-H), 1.14 (t, J = 7.3 Hz, 3H,
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13
OCH CH ); C NMR (100 MHz, CDCl ): δ = 174.6 (CO Et), 151.5 (C-1), 150.8 (C-8), 141.2 (C-5), 127.2, 126.0
2
3
3
2
(
C-4a, C-8a), 114.7 (C-7), 110.0 (C-6), 108.7 (1-CH ), 84.3 (C-3'), 68.2 (C-4'), 60.6 (OCH CH ), 56.3, 55.7
2 2 3
(OCH ), 51.5 (C-2), 35.0 (C-1'), 30.1 (C-3), 20.7 (C-4), 14.4 (C-2'), 14.0 (OCH CH ); HRMS (ESI-TOF): m/z: [M
3
2
3
+
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
+
Na] calcd for C H O Na 351.15668; found 351.15678.
20
24
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Ethyl 2-(but-3-yn-1-yl)-5,8-dimethoxy-3,4-dihydro-2H-spiro[naphthalene-1,2'-oxirane]-2-carboxylate
14). A solution of n-BuLi (2.5 in hexane, 2.61 mL, 6.54 mmol, 1.2 equiv) was added dropwise to a
(
M
solution of dibromomethane (1.42 g, 8.17 mmol, 1.5 equiv) and alkyne 19 (1.80 g, 5.45 mmol, 1 equiv) in
freshly distilled, dry THF (70 mL) at –78 °C under argon atmosphere. The mixture was stirred for 10 min
at –78 °C, then brought to room temperature and stirred for 1 h. The solvent was removed under
reduced pressure and the residue filtered through a pad of silica gel. The filtrate was concentrated in
vacuo and the residue subjected to flash chromatography (petroleum ether/EtOAc, 2:1) which provided
spiroepoxide 14 (810 mg, 43%) as a light yellow oil. Despite the chromatography it was not possible to
1
obtain pure 14. R = 0.60 (petroleum ether/EtOAc, 1:1); H NMR (400 MHz, CDCl ): δ = 6.70 (d, J = 8.9 Hz,
f
3
1H, ArH), 6.63 (d, J = 9.0 Hz, 1H, ArH), 3.93-4.02 (m, 2H, OCH CH ), 3.74 (s, 3H, OCH ), 3.70 (s, 3H, OCH ),
2
3
3
3
3
.26 (d, J = 4.3 Hz, 1H, CH epoxide), 2.96-3.04 (m, 1H), 2.66-2.74 (m, 1H), 2.36-2.42 (m, 1H), 2.21-2.30
2
(
m, 1H), 2.08-2.15 (m, 1H), 1.99-2.05 (m, 1H), 1.92 (t, J = 2.6 Hz, 1H), 1.87-1.97 (m, 1H), 1.70-1.78 (m,
+
1H), 1.04 (t, J = 7.1 Hz, 3H, OCH CH ); HRMS (ESI-TOF) m/z: [M + Na] calcd for C H O Na 367.15159;
2
3
20 24
5
found 367.15137.
Lingzhiol precursor 13. Zinc (584 mg, 8.94 mmol, 9.0 equiv) and Cp TiCl (742 mg, 2.98 mmol, 3.0 equiv)
2
2
were suspended in freshly distilled THF (100 mL) in a flame dried round bottom flask, followed by stirring
of the slurry for 1 h at rt (the color changed from deep red to green). Meanwhile epoxide 14 (342 mg,
0
.993 mmol, 1 equiv) was dissolved in THF (50 mL) under argon atmosphere and cooled to 0 °C. Then the
titanocene dichloride/zinc solution was added dropwise. The reaction mixture was brought to room
temperature and stirred for 72 h. The mixture was diluted with HCl (1 , 45 mL), stirred for 2 h at rt and
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extracted with EtOAc (3 × 20 mL). The combined organic extracts were dried over Na SO , filtered and
2
4
concentrated under reduced pressure to provide polycycle 13 (240 mg, 69%) as light yellow crystals. R =
f
1
0.40 (petroleum ether/EtOAc, 4:1); H NMR (400 MHz, CDCl ): δ = 6.70 (s, 2H, 5-H, 6-H), 5.12 (t, J = 1.8
3
10
11
12
13
14
15
16
17
18
19
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Hz, 1H, 6'-CH ), 4.97 (t, J = 1.9 Hz, 1H, 6'-CH ), 4.90 (d, J = 10.0 Hz, 1H, 8'-H), 4.43 (d, J = 10.0 Hz, 1H, 8'-H),
2
2
3
.77 (s, 3H, OCH ), 3.75 (s, 3H, OCH ), 2.99 (dt, J = 17.5, 4.9 Hz, 1H, 1'-H), 2.55-2.46 (m, 1H, 1'-H), 2.35-
3 3
2.17 (m, 2H, 5'-H), 2.13-2.05 (m, 1H, 4'-H), 2.01 (dt, J = 13.3, 4.4 Hz, 1H, 2'-H), 1.92-1.85 (m, 1H, 4'-H),
1
3
1
1
5
.67-1.60 (m, 1H, 2'-H); C NMR (100 MHz, CDCl ): δ = 182.2 (C-9'), 152.8 (C-6'), 151.9 (C-4), 150.9 (C-1),
3
27.2, 127.0 (C-2, C-3), 108.7, 108.6 (C-5, C-6), 108.6 (6-CH ), 75.3 (C-8'), 55.8 (OCH ), 55.2 (OCH ), 53.7,
2
3
3
+
3.3 (C-3', C-7'), 32.9 (C-5'), 32.2 (C-4'), 26.9 (C-2'), 18.8 (C-1'); HRMS (ESI-TOF) m/z: [M + Na] calcd for
C H O Na 323.12538; found 323.12537.
18
20
4
Ketone 23. K OsO ·2H O (5.9 mg, 0.016 mmol, 5.5 mol%) was added in one portion to a mixture of olefin
2
4
2
1
3 (96 mg, 0.32 mmol, 1 equiv) and NaIO (2745 mg, 1.28 mmol, 4 equiv) in THF (5.5 mL) and water (5.5
4
mL). The reaction mixture was stirred for 2 d at rt. The mixture was diluted using a saturated aqueous
solution of NaOH (1 , 30 mL). The aqueous layer was extracted with EtOAc (4 × 20 mL). The combined
organic extracts were dried over Na SO , filtered and concentrated under reduced pressure. The crude
N
2
4
product was purified by flash chromatography to give ketone 23 (60 mg, 63%) as fawn-colored solid. Its
8
spectral data were identical to a sample prepared by oxidation of the corresponding alcohol. R = 0.35
f
1
(
petroleum ether/EtOAc, 2:1); H NMR (400 MHz, CDCl ): δ = 6.74 (s, 2H, 5-H, 6-H), 5.09 (d, J = 10.1 Hz,
3
1
H, 8'-H), 4.38 (d, J = 10.1 Hz, 1H, 8'-H), 3,78 (s, 6H, OCH ), 3.02 (dt, J = 17.7, 4.5 Hz, 1H, 1'-H), 2.54-2.63
3
13
(m, 1H, 1'-H), 2.28-2.42 (m, 3H, 4'-H, 5'-H), 2.09-2.15 (m, 2H, 2'-H, 4'-H), 1.75-1.82 (m, 1H, 2'-H); C NMR
(
400 MHz, CDCl ): δ = 210.3 (C-6'), 180.6 (C-9'), 152.8, 150.9 (C-1, C-4), 126.5 (C-2), 121.4 (C-3), 109.8,
3
1
09.6 (C-5, C-6), 72.8 (C-8'), 56.6 (C-7'), 56.2 (OCH ), 55.8 (OCH ), 49.7 (C-3') 36.0 (C-5'), 26.0 (C-2'), 25.9
3 3
+
(
C-4'), 18.7 (C-1'); HRMS (ESI-TOF) m/z: [M + Na] calcd for C H O Na 325.10464; found 325.10460.
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Alcohols 12-syn and 12-anti. A solution of ketone 23 (45 mg, 0.15 mmol, 1 equiv) in MeOH (7 mL) was
treated with CeCl ·7H O (55.5 mg, 0.149 mmol, 1 equiv) and NaBH (8.5 mg, 0.22 mmol, 1.5 equiv) at rt.
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2
4
After 2 h stirring at rt, the reaction mixture was diluted with EtOAc (9 mL) and washed with saturated
NaCl solution (6 mL). The organic layer was dried over Na SO , filtered and concentrated in vacuo to give
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
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0
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9
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5
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a mixture of diastereomeric alcohols 12. The isomers were separated by flash chromatography
CH Cl /EtOAc, 12:1) to give 19 mg (43%) of 12-syn and 19 mg (43%) of 12-anti, both as colorless solid.
(
2
2
6b,6c,7a,8
1
12-syn:
R = 0.29 (CH Cl /EtOAc, 12:1); mp 205.3 °C (CDCl ); H NMR (400 MHz, CDCl ): δ = 6.73 (d, J
f
2
2
3
3
=
4
2
9.0 Hz, 1H, ArH), 6.68 (d, J = 8.9 Hz, 1H, ArH), 5.19 (d, J = 9.9 Hz, 1H, 8'-H), 4.14 (t, J = 6.2 Hz, 1H, 6'-H),
.08 (d, J = 9.8 Hz, 1H, 8'-H), 3.81 (s, 3H, OCH ), 3.78 (s, 3H, OCH ), 3.04 (dt, J = 17.4, 4.0 Hz, 1H, 1'-H),
3
3
.83 (s, 1H, OH), 2.42 (ddd, J = 17.2, 12.6, 4.4 Hz, 1H, 1'-H), 2.18-2.25 (m, 1H, 4'-H), 2.11 (dt, J = 13.6, 3.9
13
Hz, 1H, 2'-H), 1.82-1.94 (m, 2H, 4'-H, 5'-H), 1.66 (dd, J = 13.2, 4.8 Hz, 1H, 2'-H), 1.52-1.58 (m, 1H, 5'-H); C
NMR (400 MHz, CDCl ): δ = 182.2 (C-9'), 151.3, 151.2 (C-1, C-4), 129.4 (C-2), 126.2 (C-3), 108.7, 108.2 (C-
3
5
, C-6), 81.8 (C-6’), 71.0 (C-8'), 55.9, 55.8 (OCH ), 53.6 (C-7'), 52.7 (C-3'), 32.4 (C-5'), 30.1 (C-4'), 26.7 (C-
3
2'), 18.5 (C-1').
1
12-anti: R = 0.36 (CH Cl /EtOAc, 12:1); H NMR (400 MHz, CDCl ): δ = 6.74 (s, 2H, 5-H, 6-H), 4.66 (t, J =
f
2
2
3
3
3
.1 Hz, 1H, 6'-H), 4.38 (d, J = 10.3 Hz, 1H, 8'-H), 4.29 (d, J = 10.3 Hz, 1H, 8'-H), 3.80 (s, 3H, OCH ), 3.77 (s,
3
H, OCH ), 2.65-2.69 (m, 2H, 1'-H), 2.16-2.20 (m, 2H, 4'-H), 1.94-2.00 (m, 2H, 2'-H), 1.87-1.92 (m, 2H, 5'-
3
1
3
H); C NMR (400 MHz, CDCl ): δ = 182.0 (C-9'), 151.2, 150.7 (C-1, C-4), 129.4 (C-2), 125.7 (C-3), 109.3,
3
1
2
08.3 (C-5, C-6), 80.6 (C-6'), 76.9 (C-8'), 56.6 (C-7'), 55.9, 55.6 (OCH ), 52.7 (C-3'), 34.6 (C-4'), 31.6 (C-5'),
3
+
8.2 (C-2'), 19.4 (C-1'); HRMS (ESI-TOF) m/z: [M + Na] calcd for C H O Na 327.12029; found 327.12070.
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Ketone 23 from alcohol 12-anti. A suspension of DMP (25 mg, 0.059 mmol, 1.3 equiv) in CH Cl (2.1 mL)
2
2
was cooled to 0 °C. Alcohol 12-anti (15 mg, 0.049 mmol, 1 equiv) dissolved in CH Cl (0.9 mL) was added
2
2
slowly. The mixture was stirred for 2 h at room temperature before it was treated with a solution of
NaOH (1 , 4.5 mL) and extracted with diethyl ether (2 × 4.5 mL). The ethereal extracts were dried with
N
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Na SO , filtered and concentrated in vacuo. Ketone 23 (13 mg, 86%) was obtained without purification as
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a light brown solid.
6b,8
Acetate 24. Acetic anhydride (19.1 mg, 0.187 mmol, 3 equiv), pyridine (14.8 mg, 15.1 ꢀL, 0.187 mmol,
3 equiv) and DMAP (1.3 mg, 0.011 mmol, 0.17 equiv) were added successively to a solution of alcohol 12-
syn (19 mg, 0.060 mmol, 1 equiv) in CH Cl (0.8 mL) at 0 °C. The reaction mixture was allowed to warm to
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rt and subsequently stirred overnight. It was then diluted with CH Cl (1.5 mL), washed with HCl solution
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(
1
N, 0.5 mL) and once with a saturated NaCl solution (1.5 mL). The combined organic extracts were dried
over Na SO , filtered and concentrated under reduced pressure. Flash chromatography (petroleum
2
4
ether/EtOAc, 1:1) gave acetate 24 (21 mg, 98%) as colorless solid. R = 0.61 (petroleum ether/EtOAc, 1:1);
f
1
mp 191.5 °C (EtOAc); H NMR (400 MHz, CDCl ): δ = 6.71 (d, J = 8.9 Hz, 1H, 6-H), 6.67 (d, J = 8.9 Hz, 1H, 5-
3
H), 5.42 (s, 1H, 6'-H), 4.90 (d, J = 10.1 Hz, 1H, 8'-H), 4.09 (d, J = 10.2 Hz, 1H, 8'-H), 3.78 (s, 3H, OCH ), 3.76
3
(
s, 3H, OCH ), 3.08 (ddd, J = 17.0, 4.4, 2.4 Hz, 1H, 1'-H), 2.30-2.48 (m, 2H, 1'-H, 5'-H), 2.16-2.21 (m, 1H, 2'-
3
1
3
H), 2.11 (s, 3H, C(=O)CH ), 1.94-2.02 (m, 1H, 5'-H), 1.60-1.76 (m, 3H, 4'-H, 2'-H); C NMR (400 MHz,
3
CDCl ): δ = 182.5 (C-9'), 170.2 (C(=O)CH ), 151.4, 150.7 (C-1, C-4), 127.2, 125.7 (C-2, C-3), 109.0, 108.4 (C-
3
3
5
, C-6), 82.2 (C-6'), 72.2 (C-8'), 55.8, 55.4 (OCH ), 54.9, 51.6 (C-3', C7'), 32.3 (C-4'), 31.3 (C-5'), 27.4 (C-2'),
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+
2
1.4 (C(=O)CH ), 18.3 (C-1’); HRMS (ESI-TOF) m/z: [M + Na] calcd for C H O Na 369.13086; found
3
19 22
6
369.13098.
6b,8
Phenone 25. N-hydroxyphthalimide (24.7 mg, 0.152 mmol, 2.5 equiv) and AIBN (5.0 mg, 0.03 mmol,
0
.5 equiv) were added to a solution of acetate 24 (21 mg, 0.061 mmol, 1 equiv) in acetonitrile (1.8 mL) at
rt. Through a steel needle oxygen was continuously bubbled through the solution. The reaction mixture
was stirred overnight at 85 °C. Afterwards it was cooled to room temperature and the solvent removed
under reduced pressure. The crude product was purified by flash chromatography (petroleum
ether/EtOAc, 1:1) to give phenone 25 (9.2 mg, 42%) as colorless solid. R = 0.22 (petroleum ether/EtOAc,
f
1
1
:1); H NMR (400 MHz, CDCl ): δ = 7.08 (d, J = 9.3 Hz, 1H, 5-H), 6.93 (d, J = 9.3 Hz, 1H, 6-H), 5.48 (broad,
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H, 6'-H), 4.99 (d, J = 10.4 Hz, 1H, 8'-H), 4.29 (d, J = 10.4 Hz, 1H, 8'-H), 3.84 (s, 3H, OCH ), 3.82 (s, 3H,
3
OCH ), 2.87 and 2.79 (AB system, J = 12.8 Hz, 2H, 2'-H), 2.44-2.53 (m, 1H, 4'-H), 2.12 (s, 3H, C(=O)CH ),
3
3
13
1.92-1.99 (m, 1H, 4'-H), 1.63-1.74 (m, 2H, 5'-H); C NMR (400 MHz, CDCl ): δ = 194.1 (C-1'), 179.4 (C-9'),
3
0
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0
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70.0 (C(=O)CH ), 152.3 (C-3), 150.3 (C-2), 130.2 (C-1), 122.9 (C-4), 117.0 (C-5), 112.5 (C-6), 81.6 (C-6'),
3
1.1 (C-8'), 56.6, 56.0 (OCH ), 55.2 (C-3') 52.8 (C-7'), 44.3 (C-2'), 31.8 (C-4'), 31.5 (C-5'), 21.3 (C(=O)CH );
3
3
+
HRMS (ESI-TOF) m/z: [M + Na] calcd for C H O Na 383.11012; found 383.11028.
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6a,6b,6c,7a,8
Hydroxyphenone 26.
methanol (1.3 mL) was added HCl (3
rt before the solvent was removed under reduced pressure. The residue was dissolved in water (4 mL)
and extracted with CH Cl (3 × 3 mL). The combined organic extracts were dried with Na SO , filtered and
To a stirred solution of acetate 25 (8.5 mg, 0.024 mmol, 1 equiv) in
N, 1.3 mL). The mixture was heated to 85 °C overnight then cooled to
2
2
2
4
concentrated in vacuo. The crude product was purified by flash chromatography (petroleum
ether/EtOAc, 1:1) to give hydroxyphenone 26 (5 mg, 66%) as colorless solid. R = 0.12 (petroleum
f
1
ether/EtOAc, 1:1); H NMR (400 MHz, CDCl ): δ = 7.09 (d, J = 9.2 Hz, 1H, 5-H), 6.88 (d, J = 9.2 Hz, 1H, 6-H),
3
5.30 (d, J = 10.0 Hz, 1H, 8'-H), 4.27 (t, J = 6.2, 1H, 6'-H), 4.26 (d, J = 10.0 Hz, 1H, 8'-H), 3.87 (s, 3H, OCH3),
3
1
.85 (s, 3H, OCH ), 2.79 and 2.86 (AB system, J = 13.1 Hz, 1H, 2'-H), 2.35-2.38 (m, 1H, 4'-H), 1.90-1.94 (m,
3
1
3
H, 5'-H), 1.75-1.79 (m, 1H, 4'-H), 1.51-1.56 (m, 1H, 5'-H); C NMR (400 MHz, CDCl ): δ = 194.8 (C-1'),
3
179.6 (C-9'), 152.5 (C-1), 150.1 (C-4), 134.0 (C-3), 122.3 (C-2), 117.0 (C-5), 111.4 (C-6), 81.6 (C-6'), 70.1 (C-
8
'), 56.5, 56.4 (OCH ), 53.4 (C-7' or C-3'), 53.4 (C-7' or C-3'), 44.1 (C-2'), 32.2 (C-5'), 31.4 (C-4'); HRMS (ESI-
3
+
TOF) m/z: [M + Na] calcd for C H O Na 341.09956; found 341.09977.
17
18
6
6,7,8
Lingzhiol (±-1). To a solution of AlCl (4.2 mg, 0.031 mmol, 2 equiv) in abs. CH Cl (1.25 mL) was added
3
2
2
t-BuSH (0.6 mL, 0.471 g, 5.22 mmol) at 0 °C. The reaction mixture was stirred for 15 min at 0 °C. A
solution of aryl methyl ether 26 (5.0 mg, 0.016 mmol, 1 equiv) in dry CH Cl (1 mL) was then added
2
2
dropwise at 0 °C. The resulting mixture was refluxed overnight. Thereafter, it was treated with a
saturated solution of NaH PO (1.1 mL). The organic layer was separated and the aqueous layer was
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extracted with EtOAc (3 × 1.5 mL). The combined organic layers were dried over Na SO , filtered and
2
4
concentrated under reduced pressure. The crude product was purified by flash chromatography
(petroleum ether/EtOAc, 1:1) to yield lingzhiol (±-1) (2.3 mg, 50%) as light yellow solid. R = 0.2
f
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(
petroleum ether/EtOAc, 1:1); H NMR (400 MHz, CDCl ): δ = 11.6 (s, 1H, 1-OH), 7.27 (d, J = 9.0 Hz, 1H, 5-
3
H), 6.82 (d, J = 8.9 Hz, 1H, 6-H), 5.26 (d, J = 9.7 Hz, 1H, 8'-H), 4.94 (s, 1H, 6'-OH), 4.67 (t, J = 4.1 Hz, 1H, 6'-
H), 4.49 (d, J = 9.7 Hz, 1H, 8'-H), 3.14 (d, J = 16.1 Hz, 1H, 2'-H), 2.83 (d, J = 15.9 Hz, 1H, 2'-H), 2.47-2.51 (m,
1
3
1
1
7
H, 4'-H or 5'-H), 1.72-1.84 (m, 3H, 4'-H, 5'-H); C NMR (400 MHz, CDCl ): δ = 202.4 (C-1'), 180.1 (C-9'),
3
56.3 (C-3), 148.0 (C-2), 129.0 (C-1), 127.6 (C-5), 117.9 (C-6), 116.5 (C-4), 80.6 (C-6'), 71.0 (C-8'), 56.2 (C-
–
'), 52.5 (C-3'), 42.3 (C-2'), 33.8 (C-4' or C-5'), 33.3 (C-4' or C-5'); HRMS (ESI-TOF) m/z: [M – H] calcd for
C H O 289.07176; found 289.07203.
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ASSOCIATED CONTENT
Supporting Information
Experimental details for the synthesis of analog 39 (compounds 27 – 39). Copies of NMR spectra. X-ray
crystallography data, CIF file, and thermal ellipsoid plot for acetate 24. The Supporting Information is
available free of charge on the ACS Publications website.
AUTHOR INFORMATION
Corresponding Author
*
E-mail: martin.e.maier@uni-tuebingen.de
Present Addresses
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Author Contributions
The manuscript was written through contributions of all authors. All authors have given approval to the
final version of the manuscript.
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Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
This work was supported by the Deutsche Forschungsgemeinschaft (Grant No. Ma 1012/33-1) and the
state of Baden-Württemberg. The authors would like to acknowledge networking contribution by the
COST Action CM1407 "Challenging organic syntheses inspired by nature - from natural products
chemistry to drug discovery". We also thank the students Fabio Mazzotta, Felix Preusch, and Philipp
Weiß for contributions to this project.
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0
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Tetrahedron 2016, 72, 1897.
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