Directed metalation?￡?cross-coupling strategies. Total syntheses of the alleged and the revised phenanthrene natural product gymnopusin

Article abstract of DOI:10.1002/hlca.201200564

The total synthesis of gymnopusin (2) is described. The originally assigned structure for gymnopusin 1a was found to be incorrect by total synthesis using the Directed ortho-Metalation (DoM)?￡?Cross- Coupling?￡?Directed remote Metalation (DreM) sequence, a demonstrable key strategy for the regioselective construction of the 9-phenanthrol core. The revised structure of gymnopusin (2) was confirmed by synthesis by adopting the same strategy but involving a key remote anionic Fries-rearrangement step. Both routes highlight methodologies and concepts which may be of value in the regiocontrolled synthesis of phenanthrenoids specifically and in complex polycyclic aromatics in general. Copyright

Full text of DOI:10.1002/hlca.201200564

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Directed MetalationꢀCross-Coupling Strategies. Total Syntheses of the
Alleged and the Revised Phenanthrene Natural Product Gymnopusin
by Xin Wang1), Jian-min Fu2), and Victor Snieckus*3)
Guelph-Waterloo Centre for Graduate Work in Chemistry, University of Waterloo, Waterloo, ON, N2L
3G1, Canada
Dieter Seebach, in Anerkennung seiner Beitrꢀge zur Carbanion-Chemie, Carbanione natꢁrlich, seiner
hingebungsvollen und begeisternden Lehrtꢀtigkeit und seiner unaufhçrlichen, richtungsweisenden
Forschung, gewidmet von einem Chemiker desselben Jahrgangs
The total synthesis of gymnopusin (2) is described. The originally assigned structure for gymnopusin
1a was found to be incorrect by total synthesis using the Directed ortho-Metalation (DoM)ꢀCross-
CouplingꢀDirected remote Metalation (DreM) sequence, a demonstrable key strategy for the
regioselective construction of the 9-phenanthrol core. The revised structure of gymnopusin (2) was
confirmed by synthesis by adopting the same strategy but involving a key remote anionic Fries-
rearrangement step. Both routes highlight methodologies and concepts which may be of value in the
regiocontrolled synthesis of phenanthrenoids specifically and in complex polycyclic aromatics in general.
Introduction. – The phenanthrene nucleus is representative of a substantial class of
fossil fuel – derived polycyclic aromatic hydrocarbons (PAHs) [1] which is a significant
class of soil, sediment, and aquatic environmental pollutants [2]. The phenanthrene
PAHs show substantial levels of toxicity towards marine diatoms, gastropods, mussels,
crustaceans, and especially fish for which the key biological marker is retene (¼ 7-
isopropyl-1-methylphenanthrene) [3], appear as residues in milk, urine, and faeces [4].
Phenanthrenes are also an expanding group of natural products [5], substructures in
several major classes of alkaloids [6], common moieties in pharmaceutically and
biologically active molecules [7], and, recently, on the wave of interest in material
science [8].
In targeting the synthesis of phenanthrenes [9], the strategy adopted for the
construction of the core ring has generally involved the initial formation of the
C(9)¼C(10) bond (stilbene), followed by biaryl ring closure. Following this approach,
developed classical methods include Pschorr reaction [10], Mallory photocyclization4),
radical cyclization [12], and oxidative coupling [13]. Advances, especially in transition-
metal catalytic chemistry, have provided new methods for phenanthrene construction
1
)
)
)
Current address: Isis Pharmaceuticals, Inc., 2855 Gazelle Court, Carlsbad, CA 92010, USA.
Current address: Pharmaron, 6 Taihe Road, Beijing 100176, P. R. China.
Current address: Department of Chemistry, Queenꢃs University, Kingston, ON, K7L 3N6, Canada
(phone: þ 1-613-533-2239; fax: þ 1-613-533-2837; e-mail: snieckus@chem.queensu.ca).
For reviews, see [11a,b]; for recent work, see [11c – i].
2
3
4
)
ꢂ 2012 Verlag Helvetica Chimica Acta AG, Zꢁrich

Helvetica Chimica Acta – Vol. 95 (2012)
2681
[14]. In a contrasting approach, the biaryl bond is formed first, and the core ring is
constructed by i) the formation of C(9)¼C(10) bond through the McMurry reaction5),
and ring-closing metathesis [16]; ii) CꢀC bond-formation between C(9) and C(2) on
the side phenyl ring [17]. Other methods for the phenanthrenes-ring construction
include benzyne cotrimerization with alkynes6) and allenes [19], and biaryl annulation
with alkynes [20]. The phenanthrene skeleton can also be constructed by the formation
of the side aryl ring, e.g., intramolecular electrophilic cyclization [21], a combined
coupling and C(9)¼C(10) bond-formation reaction [22], and inter- or intra-molecular
cycloaddition [23].
Although an in-depth analysis is required of the above collection of references in
order to achieve critical appraisal, most available methodologies suffer, to various
degrees, in length, labor, overall yields, and, perhaps most definitively, lack of
regiochemical control. As part of recent efforts in carbanionic aromatic chemistry7),
we are developing routes to a variety of polycondensed aromatics and heteroaromatics
which incorporate combined directed ortho-metalation (DoM), transition metal-
catalyzed cross-coupling (mainly SuzukiꢀMiyaura and Negishi)8), and directed remote
metalation (DreM)9) reactions. The overall strategy, initially demonstrated for the
synthesis of 9-phenanthrols [27], which conceptually inverts the CꢀC bond-forming
steps to those involved in most of the general methods summarized above, constitutes a
powerful tool for the regioselective and concise synthesis of polysubstituted aromatics,
heteroaromatics, environmental alkylphenanathrenes [27b], and several classes of
natural products10).
In pursuit of further application of the combined metalationꢀcross-coupling
strategy, we undertook a regioselective synthesis of the phenanthrenoid gymnopusin,
the first and only C(9),C(10)-dioxygenated phenanthrene natural product from
Bulbophyllum gymnopus (Orchidaceae) [29] whose structure 1a (Scheme 1) was
assigned solely based on its 1H- and 13C-NMR spectra, and those of its diacetate 1b. In
the course of these studies, Hughes and Sargent [30], and subsequently we [31]
demonstrated the incorrectness of the originally assigned structure 1a and reported on
the synthesis of authentic gymnopusin (2). At the conclusion of the synthesis of 1a, we
learned of the revised structure 2 [32]. Herein, we report the details of the total
synthesis of the natural product 2 and our previously unreported synthesis of the
purported gymnopusin structure 1a and attempts to convert it to the revised
gymnopusin structure 2. Both syntheses take advantage of the versatile DoMꢀcross-
coupling synthetic link8) but differ in the terminal DreM9) approaches.
5
)
)
)
)
For reviews, see [15a – c]; for selected work, see [15d,e].
For a review, see [18a]; for selected work, see [18b – g].
For reviews, see [24].
For reviews, see [25a,b]; for a historical perspective on the cross-coupling reaction since the 2010
Nobel Prize in Chemistry, see [25c].
Terminology intended to indicate non-ortho-positions. For its conceptual, mechanistic, and synthetic
aspects in the context of the complex induced proximity effect (CIPE), see [26].
Selected recent examples: azaindoles [28a], benzopyranones [28b], benzocarbazoles and indoloin-
danones [28c], acridones [28d], indolocarbazoles [28e], liquid-crystal fluorenones [28f].
6
7
8
9
)
10
)

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Helvetica Chimica Acta – Vol. 95 (2012)
Scheme 1
Results and Discussion. – In the retrosynthetic analysis for the originally assigned
gymnopusin structure 1a (Scheme 1), C(9)ꢀC(10) bond disconnection conceptualizes
the DreM forward step, a vinylogous deprotonationꢀamide cyclization, from the
polyoxygenated biaryl 3, which, in turn, is envisaged to arise from partners 4 and 5
whose combination (X ¼ metal and Y¼ halogen) may be inverted giving flexibility to
attempt both approaches. Experience gained over some time led to focus on the
venerable SuzukiꢀMiyaura protocol (X ¼ B(OH)2, Y¼ halogen or vice versa).
Compound 4 is truly readily available, while 5 would originate from DoM-controlled
regioselective chemistry.
The 2-bromo- and 2-iodo-3,4,5-trimethoxytoluene (7 and 8, resp.) were prepared in
high yields by adopting classical electrophilic halogenation reactions on commercially
available trimethoxytoluene (6; Scheme 2). The required boronic acid 9 was obtained
by a metal/halogen exchange reaction on 7 and quenched with trimethyl borate,
followed by acidic workup, and was used without further purification in the cross-
coupling reaction (vide infra). For reasons which will become apparent, the aqueous
stable boronate 10 was also prepared. The requisite boronic acid 13 and iodo-
benzamide 14 (Scheme 3) were prepared by using the silicon protection tactic [33] for
the more reactive CꢀH metalation site in 11. Thus, metalationꢀsilylation under
standard conditions smoothly afforded 12 which upon application of the same
metalation conditions, followed by B(OMe)3 and I2 quenching, furnished the boronic

Helvetica Chimica Acta – Vol. 95 (2012)
2683
Scheme 2
Scheme 3
acid 13 (undetermined yield) and iodo derivative 14 (quant. yield), respectively. An
effective one-pot procedure for the conversion of 11 into 14 proceeding in 83% overall
yield was also established (see Exper. Part). Desilylation of 14 to 15 was achieved by
refluxing TFA conditions in high yield [34].
Initial attempts to perform cross-coupling of iodo-toluene 8 with arylboronic acid
13 (Table, Entry 1) under our standard conditions [35] were unsuccessful leading to
recovery of starting 8 (74%) and deboronated benzamide 12 (quant.) which suggested
the inhibition of oxidative addition to the Pd catalyst to the sterically congested 8. To
test this tenet, the couplings of the inverted partners, boronic acid 9 and iodo-
benzamides 14 and 15, bearing only one ortho-substituent, were carried out (Entries 2
and 3). However, these reactions failed to give detectable amounts of the desired
biphenyls 16 and 17, respectively and led to the isolation of product 6, undoubtedly the
result of protodeboronation of 9 under the basic aqueous coupling conditions. In
attempts to overcome this problem, the anhydrous conditions described by Suzuki and
co-workers [36] employing dibutyl borate 10 which was stable to aqueous workup (see
Exper. Part) and Tl2CO3 as the non-aqueous base were adapted. In the event, coupling
of 10 with silylated iodo-benzamide 15 using an early Suzuki solvent, benzene, gave the
first encouraging result – the formation of biaryl 17 in 22% yield (Entry 4). Use of the

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Table. Optimization of Conditions for the Synthesis of Biaryls 16 and 17
Entry
Coupling partners
Conditions
Products (Yield [%])
1
2
3
4
5
6
8 þ 13
9 þ 14
DME, aq. Na2CO3, reflux
DME, aq. Na2CO3, reflux
DME, aq. Na2CO3, reflux
Benzene, Tl2CO3, reflux
DME, Tl2CO3, reflux
16 (0)
16 (0)
17 (0)
17 (22)
17 (35)
17 (41)
8 (74)
6 (quant.)
6 (quant.)
12 (quant.)
9 þ 15
10 þ 15
10 þ 15
10 þ 15
DMF, Tl2CO3, 1408
more polar solvents 1,2-dimethoxyethane (DME; Entry 5) and DMF (Entry 6) showed
marked improvement in the formation of 17, undoubtedly reflecting the increased
solubility of the base in these reaction media. The modest optimized yield of 41% of 17
in this cross-coupling reaction is quite remarkable considering the steric factors
involved in the mechanistically uncertain SuzukiꢀMiyaura reaction11).
With sufficient quantities of 17 in hand, the general LiNiPr2 (LDA) protocol used in
the 9-phenanthrol synthesis [27c,e] was applied and gave, not without pleasure, the
phenanthrol 18 (Scheme 4) in 82% yield which, without full characterization, was
subjected to selective deisopropylation with BCl3 [30] to furnish the alleged
gymnopusin 1a in high yield. Dismally, comparison of the melting point and
spectroscopic data of 1a with those reported [29] for the natural product revealed
nonidentity (see Exper. Part) which were confirmed by Majumder and Banerjee who
proposed [32] a revised structure 2 for gymnopusin.
This setback to our synthetic journey to gymnopusin led to contemplation of
potential link compounds between the revised structure 2 and any of the intermediate
synthesized phenanthrenes. Thus, inadvertently, compound 18 was still envisaged as a
key intermediate which, after a sequence of methylation and deisopropylation, would
generate the 7-hydroxyphenanthrene 20, a compound which may be amenable to
oxidation to the extended quinone 21 and hence reduction, steps not without precedent
to 2. In pursuit of translating this suggestion to practice, methylation of 18 under
standard conditions smoothly led to 19, and deprotection with BCl3 led predictably to
20. A survey of a plethora of conditions for the oxidation of simple phenols or para-
methoxyphenols to para-benzoquinones (e.g., cerium(IV) ammonium nitrate (CAN)/
11
)
For studies on sterically hindered coupling partners, see [37].

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Scheme 4
CH2Cl2, CAN/MeCN [38], 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ)/MeOH
[39], PhI(O2CCF3)2/K2CO3/MeCN [40], and AgO/MeCN [41]) were unsuccessful and
led to complex intractable mixtures of products.
As a new ascent to the revised structure of gymnopusin 2, and with tenuous
assurance of its certainty from the work of Hughes and Sargent [30], a new
retrosynthetic analysis was proposed which takes advantage of the remote anionic
Fries rearrangement [42]. Thus (Scheme 5), a terminal stage methylation and a
reasonably assured late stage double deisopropylation [30] leads from target 2 to
phenol 22 which, by the DreM disconnection, proceeds to biaryl amide 23. As the key
retro-step, remote metalationꢀcarbamoyl ring-to-ring transfer to the symmetrical lower
ring of 24 reveals also a perceived benefit of the less sterically hindered
SuzukiꢀMiyaura cross-coupling of the bromophenyl carbamate 25 and the readily
available boronic acid 26 partners. The challenge is reduced to the preparation of the
pentasubstituted benzene 25 bearing five different substituents in which four of the
groups have their roles defined: the Br function is required for cross-coupling; the O-
carbamate, qualitatively the most powerful known directed metalation group (DMG)
[43], serves a dual role, first for regioselective Br function introduction by DoM, and
i
second, for carbamoyl ring-to-ring transfer, and the Pr group is posed to release the
phenol by selective deprotection. Only the MeO in starting 25 is maintained throughout
the synthesis to the target molecule 2.

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Scheme 5
To initiate the synthesis (Scheme 6), commercially available 2,6-dibromo-4-
methylphenol was methylated to give 27 whose symmetrical structure allowed mono
metal/halogen exchange and boronationꢀH2O2 oxidation to afford 28. Standard
isopropylation to 29, followed by a second metal/halogen-exchange-mediated OHþ
synthetic-equivalent introduction, smoothly gave 30 which was acylated to afford, in
very good overall yield, the carbamate 31 in which the three contiguous O-
functionalities are differentiated12). Equipped with this powerful ortho-metalation
director, compound 31 was subjected to regioselective metalationꢀbromination with
BrCF2CF2Br, a modification of a reported [45] and an improvement of our original
procedure [43], to give the bromophenyl carbamate 25. Cross-coupling of 25 with the
aryl boronic acid 26, straightforwardly prepared from 1-bromo-4-isopropoxybenzene
(see Exper. Part), under our more customary conditions led to the biaryl 24 in good
yield. The key remote ring-to-ring carbamoyl transposition proceeded smoothly using
excess LDA in refluxing THF to give compound 32, which was methylated under
standard conditions to furnish the biaryl amide 23. As anticipated, treatment with BuLi
resulted in a vinylogous ortho-tolyl metalationꢀcyclization to give phenanthrol 22. Due
to its somewhat unstable nature, 22 was rapidly methylated to deliver 33 in quantitative
yield. Curiously, dimethoxy derivative 33 was also found to be unstable and, therefore,
was immediately treated with BCl3 to afford 2 in excellent yield. Comparison of
physical and spectral data of synthetic 2 with those of authentic gymnopusin confirmed
identity of the two materials (see Exper. Part).
Conclusions. – The syntheses of phenanthrols 1a (Scheme 4) and 2 (Scheme 6) have
been achieved by application of a combined DoM, SuzukiꢀMiyaura cross-coupling,
For other examples of OHþ equivalent introduction by this tactic, see [44].
12
)

Helvetica Chimica Acta – Vol. 95 (2012)
2687
Scheme 6
and DreM strategy which differ in a remote anionic Fries rearrangement step (Scheme
6; 24 ! 32). In the former case, an unnatural (to date) phenanthrenoid was obtained in
eight steps and 15% overall yield; in the latter, the natural gymnopusin (2) was
prepared in twelve steps and 18% overall yield which is comparable to that of Hughes
and Sargent [30] (14 steps, 20% overall yield), all syntheses based on commercially
available starting materials. Leaving the discussion of the value of total synthesis for
structural confirmation aside, the work may be considered as contributing new features
in synthetic methodologies as follows: a) provision of conditions of value in highly
hindered SuzukiꢀMiyaura couplings (Table 1); b) the use of the DreM-induced
carbamoyl transfer (remote anionic Fries rearrangement) as a piggy back method to
prepare hindered biaryls that may be difficult or impossible to achieve by direct
coupling; c) the value of exploring alternate partner coupling-reaction (i.e., 8, 13 ! 10,
15, or vice versa) concepts to achieve optimum results; d) the advantages DoM
chemistry (silicon protection; Scheme 3; 11 ! 15); and e) construction of oxygenated
aromatics with differential protection (Scheme 6; 25) which may be of further value in
contemporary synthetic aromatic chemistry.

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Experimental Part
General. All dry solvents used were purified according to Perrin etal. [46]. Tetrahydrofuran (THF),
1,2-dimethoxyethane (DME), and Et2O were distilled from sodium-benzophenone ketyl under N2
immediately prior to use. Solns. of BuLi (hexane), s-BuLi (cyclohexane) and t-BuLi (pentane) were
purchased from Aldrich Chemical Co., stored in resealable containers, and titrated periodically against
2,5-dimethoxybenzyl alcohol. N,N,N’,N’-Tetramethylethylenediamine (TMEDA) was dried over and
distilled from CaH2 before use. Lithium diisopropylamide (LDA) was always prepared before reactions
i
by stirring a 1:1 mixture of Pr2NH and BuLi at 08 for 10 min [47]. All commercial materials were
purchased from Aldrich Chemical Co. or Lancaster Synthesis Ltd. Tetrakis(triphenylphosphine)palla-
dium(0) was prepared as described in [48]. All reactions were carried out under N2 or Ar, unless
otherwise specified. The temp. of ꢀ 788 designated is approximate as achieved by a dry ice/acetone bath.
The phrase ꢄnormal workupꢃ means the addition of a sat. aq. NH4Cl soln. to the reaction mixture,
followed by CH2Cl2 extraction, drying over Na2SO4, filtration, and evaporation of the filtrate in vacuo to
afford the crude product.
Flash chromatography (FC): Merck silica gel 60 (0.04 – 0.06 mm) purchased from BDH Chem. Co.
Canada with AcOEt/hexane as eluent unless otherwise specified. Anal. TLC: Merck pre-coated silica gel
60F-254 sheets. M.p.: Bꢀchi model SMP-20 instrument; uncorrected. IR Spectra: Perkin-Elmer 983 IR
1
spectrophotometer, neat between NaCl plates, in CHCl3 soln., nujol, or KBr plate form; ˜n in cmꢀ1. H-
and 13C-NMR spectra: Bruker AC-200 or AM-250 spectrometers (at 200 and 250 MHz, resp., for 1H) in
CDCl3; chemical shifts, d, rel. to Me4Si as internal standard unless otherwise specified; J in Hz. MS: and
HR-MS by Dr. R. Smith, McMaster University, Hamilton, ON, Canada, using VG 7070F or Varian
spectrometers in EI mode unless otherwise specified; m/z (rel.). Elemental analysis: by Galbraith
Laboratories, Knoxville, Tennessee.
(2,3,4-Trimethoxy-6-methylphenyl)boronic Acid (9). Prepared by the reaction of 7 with BuLi,
followed by B(OMe)3 quenching and acidic workup.
[2-(Diethylcarbamoyl)-4-isopropoxy-3-(trimethylsilyl)phenyl]boronic Acid (13). Prepared by the
reaction of 12 with s-BuLi, TMEDA, followed by B(OMe)3 quenching and acidic workup.
(4-Isopropoxyphenyl)boronic Acid (26). Prepared by the reaction of 1-bromo-4-isopropoxybenzene
with BuLi, followed by B(OMe)3 quenching and acidic workup.
All these boronic acids were used in cross-coupling reactions without purification.
2-Bromo-3,4,5-trimethoxy-1-methylbenzene (7). To a soln. of 1,2,3-trimethoxy-5-methylbenzene (6;
2.75 g, 15.1 mmol), AcONa (1.24 g, 15.0 mmol), and AcOH (0.86 ml, 0.91 g, 15.0 mmol) in CCl4 (75 ml)
was added Br2 (0.78 ml, 2.41 g, 15.0 mmol) at 108. The resulting mixture was stirred at r.t. for 2.5 h,
subjected to filtration, and the filtrate was washed with dil. Na2SO3 soln. Normal workup, followed by FC
(AcOEt/hexane 1:3), afforded two products: an early fraction gave 2,6-dibromo-3,4,5-trimethoxy-
toluene (0.58 g, 11%). Oil. 1H-NMR: 2.57 (s, 3 H); 3.88 (s, 6 H); 3.91 (s, 3 H). MS: 340 (Mþ, 100), 338
(Mþ, 51), 325 (20), 323 (10). HR-MS: 337.9151 (Mþ, C10H12Br2O3; calc. 337.9153). A later fraction
afforded 7 (3.37 g, 86%). Oil. 1H-NMR: 2.37 (s, 3 H); 3.84 (s, 3 H); 3.86 (s, 3 H); 3.89 (s, 3 H); 6.60 (s,
1 H). MS: 262 (Mþ, 100), 260 (Mþ, 100), 247 (49), 245 (51), 219 (28), 217 (30), 204 (34), 202 (37). HR-
MS: 260.0055 (Mþ, C10H13BrOþ3 ; calc. 260.0048).
2-Iodo-3,4,5-trimethoxy-1-methylbenzene (8). To a suspension of 6 (1.58 g, 8.7 mmol) and
CF3COOAg (1.92 g, 8.7 mmol) in CHCl3 (10 ml) was added a soln. of I2 (2.21 g, 8.7 mmol) in CHCl3
(70 ml). The resulting mixture was stirred at r.t. for 3 h, subjected to filtration, and the filtrate was washed
with dil. Na2SO3 soln. Normal workup, followed by FC (AcOEt/hexane 1:10), afforded 2.61 g (98%) of
8. M.p. 52 – 548 (pentane). 1H-NMR: 2.42 (s, 3 H); 3.84 (s, 6 H); 3.87 (s, 3 H); 6.66 (s, 1 H). Anal. calc. for
C10H13O3: C 38.98, H 4.25; found: C 39.16, H 4.26.
N,N-Diethyl-3-isopropoxy-2-(trimethylsilyl)benzamide (12). To a soln. of TMEDA (4.02 ml, 3.10 g,
26.6 mmol) and s-BuLi (20.5 ml, 1.30m soln., 26.6 mmol) in THF (100 ml) was added a soln. of N,N-
diethyl-3-isopropoxybenzamide (11; 5.70 g, 24.2 mmol) in THF (20 ml) at ꢀ 788. The mixture was stirred
at ꢀ 788 for 1.5 h, neat TMSCl (12.3 ml, 10.52 g, 96.8 mmol) was added at ꢀ 788, and the mixture was
warmed to r.t. Normal workup, followed by FC (AcOEt/hexane 1:3), afforded 5.99 g (81%) of 12: B.p.
1
136 – 1388/0.05 Torr. IR (neat): 1622. H-NMR: 0.27 (s, 9 H); 1.07 (t, J ¼ 7.2, 3 H); 1.25 (t, J ¼ 7.2, 3 H);

Helvetica Chimica Acta – Vol. 95 (2012)
2689
1.31 – 1.39 (m, 6 H); 3.11 – 3.31 (m, 2 H); 3.35 – 3.43 (m, 1 H); 3.58 – 3.69 (m, 1 H); 4.63 (sept., J ¼ 6.1,
1 H); 6.66 – 6.70 (m, 1 H); 6.76 (d, J ¼ 8.2, 1 H); 7.27 (dd, J ¼ 8.2, 8.3, 1 H). EI-MS: 307 (Mþ, 1), 293 (23),
292 (100), 250 (34). CI-MS (NH3): 309 ([M þ 2]þ, 25), 308 ([M þ 1]þ, 100), 292 (15). HR-CI-MS (CH4):
308.2039 ([M þ H]þ, C17H30NO2Siþ; calc. 308.2047).
N,N-Diethyl-6-iodo-3-isopropoxy-2-(trimethylsilyl)benzamide (14). To a soln. of TMEDA (0.83 ml,
0.64 g, 5.5 mmol) and s-BuLi (4.23 ml, 1.3m soln., 5.5 mmol) in THF (45 ml) was added a soln. of 12
(1.54 g, 5.0 mmol) in THF (10 ml) at ꢀ 788. The mixture was stirred at ꢀ 788 for 1 h, solid I2 (5.08 g,
20.0 mmol) was added, and the resulting mixture was stirred at r.t. for 10 h and concentrated in vacuo.
The residue was taken up in CH2Cl2 (50 ml), and the resulting soln. was washed with dil. Na2SO3 soln.
Normal workup, followed by FC (AcOEt/petroleum ether 2 :3), afforded 2.16 g (99%) of 14. M.p. 101 –
1028 (hexane/CH2Cl2). IR (KBr): 1620. 1H-NMR: 0.26 (s, 9 H); 1.12 (t, J ¼ 7.2, 3 H); 1.28 – 1.38 (m, 9 H);
3.02 – 3.27 (m, 3 H); 3.87 – 3.98 (m, 1 H); 4.54 – 4.64 (m, 1 H); 6.51 (d, J ¼ 8.8, 1 H); 7.70 (d, J ¼ 8.8, 1 H).
MS: 433 (Mþ, 9), 419 (22), 418 (100), 376 (12), 319 (9), 177 (14), 149 (29), 137 (15), 129 (11). Anal. calc.
for C17H28INO2Si: C 47.11, H 6.51, N 3.23; found: C 47.36, H 6.56, N 3.21.
One-Pot Procedure. To a soln. of TMEDA (0.6 ml, 0.45 g, 3.9 mmol) and s-BuLi (3.02 ml, 1.29m soln.,
3.9 mmol) in THF (10 ml) was added a soln. of 11 (0.83 g, 3.5 mmol) in THF (5.0 ml) at ꢀ 788. The
mixture was stirred at ꢀ 788 for 1.5 h, neat TMSCl (0.50 ml, 0.42 g, 3.9 mmol) was added, and the
resulting mixture was stirred at r.t. for 10 h. This soln. was added to a soln. of TMEDA (0.59 ml, 0.453 g,
3.9 mmol), and s-BuLi (3.0 ml, 1.29m soln., 3.9 mmol) in THF (20 ml) was added at ꢀ 788 via a double-
tipped syringe. After stirring at ꢀ 788 for 1 h, solid I2 (3.60 g, 14.2 mmol) was added and, the whole was
stirred at r.t. for 10 h and concentrated in vacuo. The residue was taken up in CH2Cl2 (50 ml), and the
soln. was washed with dil. Na2SO3 soln. Normal workup, followed by FC (AcOEt/hexane 1:2), afforded
1.36 g (83%) of 14 whose physical and spectral properties were identical to those of 14 obtained by the
two-step procedure described above.
N,N-Diethyl-2-iodo-5-isopropoxybenzamide (15). A soln. of 14 (1.52 g, 3.5 mmol) in CF3COOH
(40 ml) was heated at reflux for 10 h, cooled to r.t., and neutralized with 2m Na2CO3 until pH 7. Normal
workup, followed by FC (AcOEt/hexane 1:3), afforded 1.05 g (83%) of 15. B.p. 135 – 1408/0.01 Torr. IR
(neat): 1632. 1H-NMR (CH2Cl2 as internal standard): 1.11 (t, J ¼ 7.1, 3 H); 1.28 – 1.44 (m, 9 H); 3.13 – 3.34
(m, 3 H); 3.80 – 4.00 (br., 1 H); 4.52 (sept., J ¼ 6.1, 1 H); 6.64 (dd, J ¼ 8.7, 2.9, 1 H); 6.76 (d, J ¼ 2.9, 1 H);
7.65 (d, J ¼ 8.7, 1 H). MS: 361 (Mþ, 75), 319 (21), 318 (96), 289 (29), 247 (100), 219 (22), 192 (37). HR-
MS: 361.0539 (Mþ, C14H20INOþ2 ; calc. 361.0540).
Dibutyl (2,3,4-Trimethoxy-6-methylphenyl)boronate (10). To a soln. of 7 (5.23 g, 20 mmol) in THF
(100 ml) was added a soln. of t-BuLi (26.67 ml of 1.65m, 44.0 mmol) at ꢀ 788. After 5 min, B(OMe)3
(21.6 ml, 18.4 g, 80 mmol) was added, and the whole was stirred at r.t. for 4 h, concentrated in vacuo, and
the residue was taken up in CH2Cl2 (200 ml). The resulting soln. was subjected to filtration, and the
filtrate was concentrated to dryness in vacuo. Short-path distillation afforded 5.65 g (84%) of 10. B.p.
122 – 1288/0.01 Torr. 1H-NMR: 0.87 – 0.94 (t, J ¼ 7.2, 6 H); 1.29 – 1.64 (m, 8 H); 3.79 – 3.87 (m, 13 H); 6.48
(s, 1 H). MS: 338 (Mþ, 91), 337 (22), 282 (42), 182 (100), 167 (26), 165 (60), 151 (25). HR-MS: 338.2267
(Mþ, C18H31BOþ5 ; calc. 338.2265).
N,N-Diethyl-4-isopropoxy-2’,3’,4’-trimethoxy-6’-methyl-1,1’-biphenyl-2-carboxamide (17). A mixture
of Pd(PPh3)4 (0.03 g, 0.05 mmol), 15 (0.179 g, 0.5 mmol), 10 (0.186 g, 0.57 mmol), and Tl2CO3 (0.27 g,
0.57 mmol) in DMF (5 ml) was heated at 1408 for 36 h. The resulting mixture was cooled to r.t. and
poured onto crushed ice (ca. 20 ml). The aq. soln. was extracted with AcOEt (3 ꢁ 20 ml), and the AcOEt
layer was dried (Na2SO4), subjected to filtration, and the filtrate was concentrated in vacuo to dryness.
FC (AcOEt/hexane 1:3) afforded 0.085 g (41%) of 17. M.p. 106 – 1078 (hexane/CH2Cl2). IR (KBr): 1610.
1H-NMR: 0.80 (t, J ¼ 7.1, 3 H); 1.06 (t, J ¼ 7.1, 3 H); 1.37 (d, J ¼ 6.0, 3 H); 1.39 (d, J ¼ 6.1, 3 H); 2.10 (s,
3 H); 2.80 – 3.00 (br., 2 H); 3.30 – 3.90 (br., 2 H); 3.64 (s, 3 H); 3.81 (s, 3 H); 3.85 (s, 3 H); 4.57 (sept., J ¼
6.1, 1 H); 6.54 (s, 1 H); 6.84 (d, J ¼ 2.6, 1 H); 6.92 (dd, J ¼ 8.4, 2.6, 1 H); 7.08 (d, J ¼ 8.4, 1 H). MS: 415
(Mþ, 71), 372 (20), 343 (51), 342 (64), 312 (24), 301 (30), 300 (84), 286 (24), 271 (23), 270 (37), 248
(100). HR-MS: 415.2355 (Mþ, C24H33NO5þ ; calc. 415.2360).
7-Isopropoxy-2,3,4-trimethoxyphenanthren-9-ol (18). To a soln. of LDA (0.52 mmol) in THF (5 ml)
was added a soln. of 17 (0.073 g, 0.17 mmol) in THF (2 ml) at 08. The mixture was stirred at r.t. for 10 h

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Helvetica Chimica Acta – Vol. 95 (2012)
and acidified with 1n HCl. Normal workup and FC (AcOEt/hexane 1:1) afforded 0.049 g (82%) of 18,
which was used directly for the following reaction.
5,6,7-Trimethoxyphenanthrene-2,10-diol (1a). To a soln. of 18 (0.049 g, 0.14 mmol) in CH2Cl2 (10 ml)
was added BCl3 (0.57 ml, 1.0m soln. in CH2Cl2, 0.07 g, 0.57 mmol) at 08, and the mixture was stirred at 08
for 20 min and warmed to r.t. Normal workup, followed by FC (AcOEt/hexane), afforded 0.040 g (93%)
of 1a. M.p. 171 – 1738 (hexane/AcOEt). IR (KBr): 3329. 1H-NMR: 3.98 (s, 3 H); 3.996 (s, 3 H); 4.002 (s,
3 H); 6.89 (s, 1 H); 6.90 (s, 1 H); 7.22 (dd, J ¼ 9.3, 2.9, 1 H); 7.64 (d, J ¼ 2.9, 1 H); 9.42 (d, J ¼ 9.3, 1 H).
MS: 300 (Mþ, 100), 285 (50), 242 (39). HR-MS: 300.1004 (Mþ, C17H16O5þ ; calc. 300.0998). These physical
and spectral data were found to be different from those reported for gymnopusin [29][30].
7-Isopropoxy-2,3,4,9-tetramethoxyphenanthrene (19). To a soln. of NaH (0.017 g, 50% suspension in
oil, 0.01 g, 0.36 mmol, washed with benzene) in DMF (3 ml) was added a soln. of 18 (0.061 g, 0.18 mmol)
in DMF (2 ml) at r.t. After 30 min, MeI (0.044 ml, 0.10 g, 0.71 mmol) was added, and the mixture was
stirred at r.t. for 10 h and poured onto crushed ice (ca. 10 ml). The aq. soln. was extracted with AcOEt
(3 ꢁ 20 ml), and the AcOEt layer was dried (Na2SO4), subjected to filtration, and the filtrate was
concentrated in vacuo to dryness. Prep. TLC (AcOEt/hexane) afforded 0.045 g (71%) of 19. Oil.
1H-NMR: 1.42 (d, J ¼ 6.0, 6 H); 3.99 (s, 3 H); 4.00 (s, 3 H); 4.05 (s, 3 H); 4.71 (sept., J ¼ 6.0, 1 H); 6.86 (s,
1 H); 6.98 (s, 1 H); 7.24 (dd, J ¼ 9.4, 2.9, 1 H); 7.73 (d, J ¼ 2.9, 1 H); 9.37 (d, J ¼ 9.4, 1 H). MS: 357 (23),
356 (Mþ, 100), 341 (20), 314 (24), 299 (50), 256 (28), 149 (35). HR-MS: 356.1631 (Mþ, C21H24Oþ5 ; calc.
356.1624).
5,6,7,10-Tetramethoxyphenanthren-2-ol (20). To a soln. of 19 (0.05 g, 0.13 mmol) in CH2Cl2 (10 ml)
was added BCl3 (0.25 ml, 1.0m soln. in CH2Cl2, 0.03 g, 0.25 mmol) at 08, and the mixture was stirred for
20 min at 08 and then treated with sat. aq. NH4Cl soln. at 08. Normal workup, followed by prep. TLC
1
(AcOEt/hexane 1:2), afforded 0.032 g (81%) of 20. M.p. 164 – 1668. H-NMR: 3.99 (s, 9 H); 4.03 (s,
3 H); 5.24 (s, 1 H); 6.86 (s, 1 H); 6.98 (s, 1 H); 7.20 (dd, J ¼ 9.2, 2.9, 1 H); 7.69 (d, J ¼ 2.8, 1 H); 9.38 (d, J ¼
9.3, 1 H). MS: 314 (Mþ, 100), 300 (25), 299 (61), 256 (38). HR-MS: 314.1157 (Mþ, C18H18Oþ5 ; calc.
314.1154).
3-Bromo-2-methoxy-5-methylphenol (28). To a soln. of 1,3-dibromo-2-methoxy-5-methylbenzene
(27; 0.278 g, 1.0 mmol) in THF (10 ml) at ꢀ 788 was added a soln. of BuLi (1.1 mmol). After stirring for
15 min at ꢀ 788, B(OMe)3 (1.7 ml, 1.50 mmol) was added, and the mixture was allowed to warm to r.t.
over 4 h. AcOH (1.0 ml) and H2O2 (30% soln., 2.0 ml) were added, and the soln. was stirred at r.t. for 8 h
and treated with a sat. aq. Fe(NH4)2(SO4)2 soln. to destroy the excess H2O2. Normal workup afforded
0.194 g (90%) of 28. B.p. 85 – 898/1 Torr. IR (neat): 3360, 1478. 1H-NMR: 2.22 (s, 3 H); 3.87 (s, 3 H); 5.65
(s, 1 H, exchangeable with D2O); 6.75 (d, J ¼ 2, 1 H); 6.89 (d, J ¼ 2, 1 H). MS: 218 (Mþ, 6), 216 (Mþ, 6),
137 (100). HR-MS: 215.9787 (Mþ, C8H9BrO2þ ; calc. 215.9786).
i
1-Bromo-3-isopropoxy-2-methoxy-5-methylbenzene (29). A soln. of 28 (0.216 g, 1.0 mmol), PrI
(0.253 g, 1.5 mmol), and K2CO3 (0.21 g, 1.5 mmol) in acetone (10 ml) was refluxed for 12 h. Normal
workup afforded 0.206 g (80%) of 29. B.p. 80 – 858/1 Torr. IR (neat): 1408. 1H-NMR: 1.35 (d, J ¼ 6, 6 H);
2.37 (s, 3 H); 3.84 (s, 3 H); 4.55 (sept., J ¼ 6, 1 H); 6.69 (d, J ¼ 2, 1 H); 6.96 (d, J ¼ 2, 1 H). MS: 260 (Mþ,
3), 258 (Mþ, 3), 179 (100). HR-MS: 258.0259 (Mþ, C11H15BrO2þ ; calc. 258.0256).
3-Isopropoxy-2-methoxy-5-methylphenol (30). To a soln. of 29 (0.258 g, 1.0 mmol) in THF (10 ml) at
ꢀ 788 was added a soln. of BuLi (1.05 mmol). After stirring the soln. at ꢀ 788 for 15 min, B(OMe)3
(1.7 ml, 1.5 mmol) was added. The mixture was warmed to r.t. over 4 h, after which AcOH (1.0 ml) and
H2O2 (30% soln., 2.0 ml) were sequentially added, and the resulting soln. was stirred for 8 h. Excess H2O2
was destroyed with a sat. aq. Fe(NH4)2(SO4)2 soln. Normal workup afforded 0.167 g (85%) of 30. B.p.
1
120 – 1308/1 Torr. IR (neat): 3366, 1570. H-NMR: 1.34 (d, J ¼ 6, 6 H); 2.25 (s, 3 H); 3.86 (s, 3 H); 4.55
(sept., J ¼ 6, 1 H); 5.70 (s, 1 H, exchangeable with D2O); 6.30 (d, J ¼ 1.5, 1 H); 6.42 (d, J ¼ 1.5, 1 H). MS:
196 (Mþ, 10), 181 (100). HR-MS: 196.1200 (Mþ, C11H16Oþ3 ; calc. 196.1099).
3-Isopropoxy-2-methoxy-5-methylphenyl N,N-Diethylcarbamate (31). A soln. of 30 (0.196 g,
1.0 mmol), ClCONEt2 (0.204 g, 1.5 mmol), and K2CO3 (0.207 g, 1.5 mmol) in MeCN (10 ml) was
refluxed for 12 h. Normal workup afforded 0.268 g (91%) of 31. Oil. IR (neat): 1720. 1H-NMR: 1.25 (t,
J ¼ 7, 6 H); 1.35 (d, J ¼ 6, 6 H); 2.38 (s, 3 H); 3.41 (q, J ¼ 7, 4 H); 3.82 (s, 3 H); 4.52 (sept., J ¼ 6, 1 H); 6.57
(s, 2 H). MS: 295 (Mþ, 11), 100 (100). HR-MS: 295.1785 (Mþ, C16H25NOþ4 ; calc. 295.1783).

Helvetica Chimica Acta – Vol. 95 (2012)
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2-Bromo-5-isopropoxy-6-methoxy-3-methylphenyl N,N-Diethylcarbamate (25). To a soln. of 31
(0.295 g, 1.0 mmol) in THF (10 ml) at ꢀ 788 was added a soln. of s-BuLi (2.2 mmol). The mixture was
stirred at ꢀ 788 for 1 h, after which BrCF2CF2Br (3.0 ml, 2.5 mmol) was added, and the soln. was allowed
to warm to r.t. over 12 h. Normal workup afforded 0.283 g (76%) of 25. Oil: IR (neat): 1718. 1H-NMR:
1.30 (m, 6 H); 1.35 (d, J ¼ 6, 6 H); 2.35 (s, 3 H); 3.45 (m, 4 H); 3.85 (s, 3 H); 4.45 (sept., J ¼ 6, 1 H); 6.70 (s,
1 H). MS: 375 (Mþ, 11), 373 (Mþ, 10), 100 (100). HR-MS: 373.0895 (Mþ, C16H24BrNOþ4 ; calc. 373.0889).
4,4’-Bis(isopropoxy)-3-methoxy-6-methylbiphenyl-2-yl N,N-Diethylcarbamate (24). A soln. of 25
(0.37 g, 1.0 mmol), 26 (0.33 g, 1.5 mmol), Pd(PPh3)4 (0.06 g, 0.05 mmol), and 2m Na2CO3 (5 ml) in DME
(20 ml) was refluxed for 24 h. Normal workup afforded 0.386 g (90%) of 24. Oil: IR (neat): 1713.
1H-NMR: 0.95 (m, 6 H); 1.35 (d, J ¼ 6.0, 6 H); 1.38 (d, J ¼ 6.0, 6 H); 2.05 (s, 3 H); 2.20 (m, 4 H); 3.85 (s,
3 H); 4.55 (sept., J ¼ 6.0, 2 H); 6.70 (s, 1 H); 6.90 (d, J ¼ 8.5, 2 H); 7.10 (d, J ¼ 8.5, 2 H). 13C-NMR
(CDCl3): 13.5, 20.4, 22.2, 22.4, 42.0, 60.6, 69.9, 71.5, 114.9, 115.5, 128.9, 129.2, 131.1, 131.6, 141.1, 143.1,
150.2, 154.0, 156.8. MS: 249 (Mþ, 3), 100 (100). HR-MS: 429.2521 (Mþ, C25H35NOþ5 ; calc. 429.2515).
N,N-Diethyl-2’-hydroxy-4,4’-bis(isopropoxy)-3’-methoxy-6ꢁ-methyl-1,1’-biphenyl-2-carboxamide
(32). To a soln. of LDA (5 mmol) in THF (10 ml) at 08 was added 24 (0.429 g, 1.00 mmol) in THF
(10.0 ml), and the mixture was refluxed for 3 h. Normal workup afforded 0.330 g (77%) of 32. M.p. 167 –
1688 (AcOEt/hexane). IR (nujol): 3370, 1638. 1H-NMR: 0.80 (m, 3 H); 1.00 (t, J ¼ 7.0, 3 H); 1.34 (d, J ¼
6.0, 6 H); 1.47 (d, J ¼ 6.0, 6 H); 2.05 (s, 3 H); 2.8 – 2.9 (m, 4 H); 3.87 (s, 3 H); 4.57 (sept., J ¼ 6, 2 H); 5.70
(s, 1 H, exchangeable with D2O); 6.35 (s, 1 H); 6.54 (dd, J ¼ 2.6, 8.4, 1 H); 6.84 (s, 1 H); 7.12 (d, J ¼ 8.4,
1 H). MS: 429 (Mþ, 21), 329 (100). HR-MS: 429.2516 (Mþ, C25H35NOþ5 ; calc. 429.2515).
N,N-Diethyl-4,4’-bis(isopropoxy)-2’,3’-dimethoxy-6’-methyl-1,1’-biphenyl-2-carboxamide (23). A
soln. of 32 (0.22 g, 0.5 mmol), MeI (0.14 g, 1.0 mmol), and K2CO3 (0.14 g, 1.0 mmol) in acetone
(10 ml) was refluxed for 18 h. Normal workup afforded 0.212 g (96%) of 23. M.p. 125 – 1268 (AcOEt/
hexane). IR (nujol): 1640. 1H-NMR: 0.77 (t, J ¼ 7.0, 3 H); 1.03 (t, J ¼ 7.0, 3 H); 1.33 (d, J ¼ 6.0, 6 H); 1.38
(d, J ¼ 6.0, 6 H); 2.05 (s, 3 H); 2.8 – 3.9 (m, 4 H); 3.64 (s, 3 H); 3.80 (s, 3 H); 4.57 (sept., J ¼ 6.0, 2 H); 6.52
(s, 1 H); 6.84 (d, J ¼ 2.6, 1 H); 8.91 (dd, J ¼ 2.6, 8.4, 1 H); 7.07 (d, J ¼ 8.4, 1 H). MS: 443 (Mþ, 11), 343
(100). HR-MS: 443.2674 (Mþ, C26H37NO5þ ; calc. 443.2672).
2,7-Bis(isopropoxy)-3,4-dimethoxyphenanthren-9-ol (22). To a soln. of 23 (0.133 g, 0.30 mmol) in
THF (10 ml) at ꢀ 788 was added BuLi (0.70 mmol), and the mixture was stirred at r.t. for 20 min. Normal
workup afforded 0.105 g (95%) of 22. Oil. IR(neat): 3360. 1H-NMR: 1.41 (d, J ¼ 6.0, 6 H); 1.45 (d, J ¼
6.0, 6H); 3.87 (s, 3 H); 3.92 (s, 3 H); 4.72 (sept., J ¼ 6.0, 1 H); 4.79 (sept., J ¼ 6.0, 1 H); 6.73 (s, 1 H); 6.89
(s, 1 H); 7.14 (dd, J ¼ 2.9, 9.4, 1 H); 7.70 (d, J ¼ 2.9, 1 H); 9.30 (d, J ¼ 9.4, 1 H). MS and anal. data were
precluded due to instability.
2,7-Bis(isopropoxy)-3,4,9-trimethoxyphenanthrene (33). A soln. of 22 (0.074 g, 0.2 mmol), MeI
(0.070 g, 0.5 mmol), and K2CO3 (0.055 g, 0.4 mmol) in acetone (20 ml) was refluxed for 3 h. Normal
workup afforded 0.069 g (90%) of 33. Oil: IR (neat): 1578, 1455. 1H-NMR: 1.42 (d, J ¼ 6.0, 6 H); 1.46 (d,
J ¼ 6.0, 6 H); 3.04 (s, 3 H); 3.40 (s, 3 H); 4.72 (sept., J ¼ 6, 1 H); 4.79 (sept., J ¼ 6, 1 H); 6.83 (s, 1 H); 6.99
(s, 1 H); 7.24 (dd, J ¼ 2.9, 9.4, 1 H); 7.73 (d, J ¼ 2.9, 1 H); 9.37 (d, J ¼ 9.4, 1 H). MS and anal. data
collection were precluded due to instability.
3,4,9-Trimethoxyphenanthrene-2,7-diol (Gymnopusin; 2). To a soln. of 33 (0.038 g, 0.10 mmol) in
CH2Cl2 (10 ml) at 08 was added BCl3 (2.0 ml, 1.0m soln. in CH2Cl2, 0.50 mmol). The mixture was stirred
for 30 min at r.t., and the reaction was quenched at 08 with a few drops of H2O. Normal workup afforded
0.029 g (95%) of 2. M.p. 195 – 1968 (hexane) ([29]: 1928; [30]: 202 – 2048). IR (nujol): 3360, 1613, 1578.
1H-NMR: 3.94 (s, 3 H); 3.95 (s, 3 H); 4.02 (s, 3 H); 6.94 (s, 1 H); 7.06 (s, 1 H); 7.19 (dd, J ¼ 2.8, 9.2, 1 H);
7.67 (d, J ¼ 2.8, 1 H); 8.15 (s, 1 H, exchangeable with D2O); 8.53 (s, 1 H, exchangeable with D2O); 9.31 (d,
J ¼ 9.2, 1 H). MS: 300 (Mþ, 4), 285 (100). Physical and spectral data are in full accord with those reported
[29][30].
We are grateful to NSERC Canada for sustaining support of this work through the Discovery Grant
and Monsanto Industrial Research Chair programs. We thank the Ministry of the Environment (MOE) of
Ontario for partial support. We warmly thank Professor P. L. Majumder for correspondence and
provision of gymnopusin diacetate (1b).

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Received October 10, 2012