A route to 1,4-disubstituted aromatics and its application to the synthesis of the antibiotic culpin

Article abstract of DOI:10.1021/jo8015192

(Chemical Equation Presented) A method is described for converting tert-butyl benzoates or tert-butyl 1-naphthoates into derivatives having an alkyl or substituted alkyl group in a 1,4-relationship to an alkyl, aryl, alkenyl, or alkynyl group. Key steps in the sequence are (i) addition of an organometallic species to a cross-conjugated cyclohexadienone obtained by Birch alkylation of a tert-butyl benzoate or a tert-butyl 1-naphthoate, followed by allylic oxidation, and (ii) treatment with BiCl₃·H ₂O, which results in removal of the tert-butyl group and spontaneous decarboxylative aromatization. The method was applied to the synthesis of the antimicrobial fungal metabolite culpin.

Full text of DOI:10.1021/jo8015192

A Route to 1,4-Disubstituted Aromatics and Its Application to the
Synthesis of the Antibiotic Culpin
Rajesh Sunasee and Derrick L. J. Clive*
Chemistry Department, UniVersity of Alberta, Edmonton, Alberta T6G 2G2, Canada
derrick.cliVe@ualberta.ca
ReceiVed July 10, 2008
A method is described for converting tert-butyl benzoates or tert-butyl 1-naphthoates into derivatives
having an alkyl or substituted alkyl group in a 1,4-relationship to an alkyl, aryl, alkenyl, or alkynyl
group. Key steps in the sequence are (i) addition of an organometallic species to a cross-conjugated
cyclohexadienone obtained by Birch alkylation of a tert-butyl benzoate or a tert-butyl 1-naphthoate,
followed by allylic oxidation, and (ii) treatment with BiCl3 · H2O, which results in removal of the tert-
butyl group and spontaneous decarboxylative aromatization. The method was applied to the synthesis of
the antimicrobial fungal metabolite culpin.
SCHEME 1. Principle of the Method
Introduction
Although many approaches are available for the synthesis of
substituted aromatics,1 the general importance of such com-
pounds leaves considerable room for the development of new
synthetic procedures, and we report a method that starts with
tert-butyl benzoates or tert-butyl 1-naphthoates and allows the
introduction of two substituents in a 1,4-relationship.
Results and Discussion
Numerous cross-conjugated dienones of type 3 have been
prepared in this laboratory by alkylative Birch reduction (1 f
2), followed by allylic oxidation (2 f 3) (Scheme 1).2 Some
of these dienones were then elaborated into the alcohols 4, which
underwent aromatization (4 f 5) on heating (70-80 °C) with
BiCl3 ·H2O, a reagent known3 to be useful for deprotection of
tert-butyl carbamates but which we had found to be equally
effective for deprotection of tert-butyl esters.2 This earlier work
was aimed specifically at the preparation of benzo-fused
carbocycles (such as 5), but the facility of the decarboxylative
aromatization step (4 f 5) suggested that monocyclic com-
pounds of type 6, which would be readily available from the
cross-conjugated dienones 3 by Grignard or organolithium
addition, might likewise be aromatized to afford para-disubsti-
(1) (a) Modern Arene Chemistry; Astruc, D., Ed.; Wiley-VCH: Weinheim,
2002. (b) Snieckus, V. Chem. ReV. 1990, 90, 879–933. (c) Donohoe, T. J.; Orr,
A. J.; Bingham, M. Angew. Chem., Int. Ed. 2006, 45, 2–9.
(2) (a) Clive, D. L. J.; Sunasee, R. Org. Lett. 2007, 9, 2677–2680. (b) Clive,
D. L. J.; Sunasee, R.; Chen, Z. Org. Biomol. Chem. 2008, 2434–2441. (c)
Beckwith, A. L. J.; Roberts, D. H. J. Am. Chem. Soc. 1986, 108, 5893–5901.
(d) Schultz, A. G.; Lavieri, F. P.; Macielag, M.; Plummer, M. J. Am. Chem.
Soc. 1987, 109, 3991–4000. (e) Schultz, A. G.; Taveras, A. G.; Harrington, R. E.
Tetrahedron Lett. 1988, 29, 3907–3910.
8016 J. Org. Chem. 2008, 73, 8016–8020
10.1021/jo8015192 CCC: $40.75 2008 American Chemical Society
Published on Web 09/25/2008

Synthesis of the Antibiotic Culpin
TABLE 1. Formation of 1,4-Disubstituted Aromatics
TABLE 2. Formation of Acetylenic Compounds
consequence, however, because treatment with 1 equiv of
BiCl3 ·H2O2,3 in MeCN-water at 70-80 °C converts the
alcohols smoothly into the desired aromatized products. The
overall yield for the two stepsscarbanion addition and
aromatizationsis generally above 75%. We did not establish if
the bismuth salt plays a role in the decarboxylation or is involved
only in removal of the tert-butyl group.
tuted benzenes 7. We have now established that the short
sequence 3 f 6 f 7 is general, and we describe several
examples of this route as well as its application to the synthesis
of the antibiotic culpin (19).4
Most of the cross-conjugated ketones we have examined are
listed in Tables 1 and 2; several were available from our earlier
study2 (hence the presence of a bromine or iodine atom at the
end of the first alkyl chain), but we have also prepared some
new examples. All were made by a Birch reduction/alkylation
sequence, followed by oxidation with CrO3-AcOH or PDC-t-
BuOOH, using procedures described earlier.2 The cross-
conjugated ketones react efficiently with Grignard reagents and
organolithiums to produce the expected alcohols as a mixture
of diastereoisomers. The formation of a mixture is of no
Entry 5 of Table 1 and entry 3 of Table 2 show that a tert-
butyldimethylsilyl group is removed by the bismuth reagent,
which we use in stoichiometric amounts; other bismuth salts,
such as Bi(OTf)3 (in MeOH) and BiBr3 (in wet MeCN), are
known to cleave tert-butyldimethylsilyl ethers, but BiCl3 (in
catalytic amounts) in MeOH is reported5 to have no effect on
this protecting group.
The overall sequence is applicable to naphthalenes (Table 1,
entries 6 and 7; Table 2, entry 1) and can be used to introduce
an alkyl, alkenyl, aryl, or alkynyl group. As the examples show,
the presence of halogens is tolerated (Table 2, entry 2) as well
as those substituents on the starting tert-butyl benzoate that are
5
6
(3) Cf. (a) Navath, R. S.; Pabbisetty, K. B.; Hu, L. Tetrahedron Lett. 2006,
47, 389–393. (b) Review on applications of Bi(III) compounds: Leonard, N. M.;
Wieland, L. C.; Mohan, R. S. Tetrahedron 2002, 58, 8373–8397.
(4) (a) Johnson, J. H.; Meyers, E.; O’Sullivan, J.; Phillipson, D. W.; Robinson,
G.; Trejo, W. H.; Wells, J. S. J. Antibiot. 1989, 42, 1515–1517. (b) Robinson,
G. W.; O’Sulivan, J.; Meyers, E.; Wells, J. S.; Del Mar, J. H. US 4,914,245,
1990.
(5) Firouzabadi, H.; Mohammadpoor-Baltork, I.; Kolagar, S. Synth. Commun.
2001, 31, 905–909.
(6) Bajwa, J. S.; Vivelo, J.; Slade, J.; Repic, O.; Blacklock, T. Tetrahedron
Lett. 2000, 41, 6021–6024.
J. Org. Chem. Vol. 73, No. 20, 2008 8017

Sunasee and Clive
SCHEME 2. Initial Approach to Culpin
SCHEME 4. Synthesis of Culpin
SCHEME 3. Additional Example of Loss of a Prenyl
Substituent
compatible with conditions of the Birch reduction (Table 1, entry
5, Table 2, entry 2).
as a bis-MOM ether (27). Birch alkylation with BrCH2CO2Me,
followed by allylic oxidation, gave the cross-conjugated ketone
28. Reaction with the lithium salt of acetylene 23 and treatment
with BiCl3 ·H2O under our standard conditions resulted not only
in aromatization but also in loss of the MOM groups. Accord-
ingly, the resulting bis-phenol 29 was silylated, and the ester
side chain was elaborated to the required prenyl unit by standard
reactions (DIBAL reduction and Wittig olefination). Finally,
desilylation produced culpin (19). While we expect that culpin
should be more easily accessible by transition-metal-catalyzed
coupling reactions, using a suitably protected 2,5-dihalo-1,4-
benzenediol, our study shows that the present method is not
limited to simple alkyl substituents, and a potentially useful
characteristic is that it is applicable to cases where the
substructure that is incorporated does itself bear a metal-sensitive
substituent such as a halogen (Table 2, entry 2). The work on
culpin also served to identify a limitation in the nature of the
groups that survive the decarboxylative aromatization in the
presence of BiCl3 ·H2O.
In none of the cases did we observe a 1,2-alkyl shift7 during
the aromatization step mediated by BiCl3 · H2O, but one
unexpected limitation was identified when we attempted to apply
the method to the synthesis of the antibiotic culpin (19),4 which
is a member of a small group of phenolic natural products8
having an isopentenyne unit, some of which have weak
antimicrobial and/or phytotoxic activity.
Our initial approach to culpin is summarized in Scheme
2. The first three steps (20 f 24) proceeded normally, but
the attempted decarboxylative aromatization resulted in loss
of the prenyl group rather than the carboxyl. This preference
for loss of a prenyl unit (we did not test other allylic
substituents), rather than decarboxylation, appears to be
general, as compound 22a behaved in a similar way to afford
the acid 22b (Scheme 3).
This unexpected result necessitated a different approach in
which the prenyl unit of culpin was elaborated after the
rearomatization step. However, once this problem had been
solved, we found that the sensitivity of the culpin structure
imposed severe restrictions on the types of protecting group
that could be used for the phenolic oxygens,9 and our optimized
route to culpin is that summarized in Scheme 4. Gentisic acid
(26) was converted into its tert-butyl ester and then protected
Experimental Section
General Procedure for Rearomatization. BiCl3 ·H2O2 (1 equiv)
was added to a solution of the intermediate tertiary alcohol in a
mixture of MeCN (5 mL) and water (0.1 mL), and the mixture
was stirred at 75-80 °C for 1-12 h until reaction was complete
(TLC control). The mixture was filtered through Celite, using
CH2Cl2, and the filtrate was washed with brine, dried (MgSO4),
and evaporated. Flash chromatography of the residue over silica
gel gave the aromatized product.
tert-Butyl 1-(3-Bromopropyl)-4-butyl-4-hydroxy-2-methoxy-
cyclohexa-2,5-dienecarboxylate (9a). BuMgBr (2 M in THF, 0.09
mL, 0.2 mmol) was added at a fast dropwise rate to a stirred and
cooled (-78 °C) solution of 9 (54.3 mg, 0.160 mmol) in Et2O (10
mL). The cold bath was removed, and stirring was continued for
1.5 h. The mixture was cooled to 0 °C, quenched slowly with water,
(7) Cf. (a) Newman, M. S.; Eberwein, J.; Wood, L. L., Jr. J. Am. Chem.
Soc. 1959, 81, 6454–6456. (b) Summermatter, W.; Heimgartner, H. HelV. Chim.
Acta 1984, 67, 1298–1309. (c) Laka´c, J.; Heimgartner, H. HelV. Chim. Acta
1985, 68, 355–370.
(8) (a) Kokubun, T.; Irwin, D.; Legg, M.; Veitch, N. C.; Simmonds, M. S. J.
J. Antibiot. 2007, 60, 285–288, and references cited therein. (b) Dubin, G.-M.;
Fkyerat, A.; Tabacchi, R. Phytochemistry 2000, 53, 571–574.
(9) We tried O-methyl and O-tert-butyldimethylsilyl groups. When the
phenolic oxygens were protected as methyl ethers, attempts to carry out the final
demethylation [BBr3, BCl3, (NH4)2Ce(NO2)6 under various conditions, CeCl3 ·H2O·
7H2O/NaI, Me3SiI, EtSNa] that would have released culpin gave complex
mixtures or recovered starting material. In the case of silicon-protected
intermediates, the bismuth reagent resulted in loss of the protecting groups.
8018 J. Org. Chem. Vol. 73, No. 20, 2008

Synthesis of the Antibiotic Culpin
and extracted with Et2O. The combined organic extracts were
washed with brine, dried (MgSO4), and evaporated. The crude
product (9a) was used directly in the next step.
from a syringe over ca. 2 min, and the resulting solution was
stirred for 2 h at -78 °C. The cooling bath was removed and
the NH3 was allowed to evaporate under a stream of N2 (2-3
h). Water was added and the mixture was extracted with Et2O
(3 times). The combined organic extracts were washed with
brine, dried (MgSO4), and evaporated. Flash chromatography
of the residue over silica gel (2.5 × 18 cm), using 50%
EtOAc-hexane, gave tert-butyl 1-[(methoxycarbonyl)methyl]-
2,5-bis(methoxymethoxy)cyclohexa-2,5-dienecarboxylate (1.83
g, 83%) as an oil: FTIR (CDCl3, microscope) 2954, 2902, 1731,
1-(3-Bromopropyl)-4-butyl-2-methoxybenzene (9b). The gen-
eral procedure for rearomatization was followed, using
BiCl3 · H2O (52.5 mg, 0.160 mmol) and 9a (total product from
the previous step) in MeCN (5 mL) and water (0.1 mL) and a
reaction time of 6 h. Flash chromatography of the crude product
over silica gel (1 × 12 cm), using 10% EtOAc-hexane, gave
9b (39.4 mg, 88%) as an oil: FTIR (microscope, cast) 2999,
1
2956, 2856, 1612, 1580, 1509, 1260 cm-1; H NMR (CDCl3,
1
1665, 1392, 1368, 1251 cm-1; H NMR (CDCl3, 400 MHz) δ
300 MHz) δ 0.94 (t, J ) 7.3 Hz, 3 H), 1.36-1.41 (m, 2 H),
1.54-1.62 (m, 2 H), 2.11-2.16 (m, 2 H), 2.59 (t, J ) 7.6 Hz,
2 H), 2.72 (t, J ) 7.2 Hz, 2 H), 3.40 (t, J ) 6.8 Hz, 2 H), 3.82
(s, 3 H), 6.67 (s, 1 H), 6.71 (d, J ) 7.5 Hz, 1 H), 7.04 (d, J )
7.5 Hz, 1 H); 13C NMR (CDCl3, 100 MHz) δ 13.9 (q), 22.4 (t),
28.5 (t), 32.7 (t), 33.6 (t), 33.7 (t), 35.6 (t), 55.1 (q), 110.5 (d),
120.1 (d), 125.9 (s), 129.8 (d), 142.4 (s), 157.2 (s); exact mass
m/z calcd for C14H2179Br 284.07758, found 284.07763.
tert-Butyl 4-[(4-Bromophenyl)ethynyl]-1-(3-bromopropyl)-4-
hydroxy-2-methylcyclohexa-2,5-dienecarboxylate (16b). (4-Bro-
mophenyl)acetylene (227.0 mg, 1.250 mmol) was added to a stirred
and cooled (-78 °C) solution of LDA [from n-BuLi (2.5 M in
hexane), 0.55 mL, 1.4 mmol) and i-Pr2NH (0.19 mL, 1.4 mmol) in
THF (3.0 mL)]. The resulting mixture was stirred at -78 °C for
1 h. A solution of 16 (495 mg, 1.51 mmol) in THF (2 mL) was
added dropwise, and stirring was continued for 2 h. The mixture
was quenched by slow addition of saturated aqueous NH4Cl and
extracted with Et2O. The combined organic extracts were washed
with brine, dried (MgSO4), and evaporated. The crude product (16b)
was used directly in the next step.
1.42 (s, 9 H), 2.82-2.87 (m, 3 H), 3.39 (s, 3 H), 3.41 (s, 3 H),
3.60 (s, 3 H), 3.66-3.68 (m, 1 H), 4.93-4.97 (m, 5 H),
5.10-5.18 (m, 1 H); 13C NMR (CDCl3, 100 MHz) δ 27.7 (q),
27.9 (t), 40.4 (t), 51.1 (q), 51.3 (s), 55.7 (q), 55.8 (q), 81.0 (s),
93.4 (t), 94.1 (t), 96.5 (d), 98.9 (d), 150.0 (s), 152.1 (s), 171.2
(s), 171.3 (s); exact mass m/z calcd for C18H28NaO8 (M + Na)
395.16764, found 395.16751.
(b) tert-Butyl 1-[(Methoxycarbonyl)methyl]-2,5-bis(methoxy-
methoxy)-4-oxocyclohexa-2,5-dienecarboxylate (28). Celite (1.0
g) and then PDC (2.18 g, 5.81 mmol) were added to a stirred
solution of tert-butyl 1-[(methoxycarbonyl)methyl]-2,5-bis-
(methoxymethoxy)cyclohexa-2,5-dienecarboxylate (540 mg, 1.45
mmol) in PhH (15 mL). t-BuOOH (7.76 M in decane, 0.75 mL,
5.8 mmol) was added, and stirring at room temperature was
continued for 4 h. The mixture was filtered through Celite, and
the solid was washed CH2Cl2 (2 × 30 mL) and evaporated. Flash
chromatography of the residue over silica gel (1.5 × 18 cm),
using first hexane and then EtOAc-hexane mixtures up to 1:1
EtOAc-hexane, gave 28 (403 mg, 72%) as an oil: FTIR (CDCl3,
microscope) 2978, 2832, 1737, 1665, 1615, 1370, 1250 cm-1
;
4-[(4-Bromophenyl)ethynyl]-1-(3-bromopropyl)-2-methylben-
zene (16d). The general procedure for rearomatization was fol-
lowed, using BiCl3 ·H2O (418.1 mg, 1.250 mmol) and 16b (total
product from the previous step) in MeCN (5 mL) and water (0.1
mL) and a reaction time of 2 h. Flash chromatography of the crude
product over silica gel (1.5 × 11 cm), using 90% EtOAc-hexane,
gave 16d (438.5 mg, 77% over two steps) as an oil: FTIR (CDCl3,
microscope) 2925, 2868, 2211, 1502, 1484 cm-1; 1H NMR (CDCl3,
300 MHz) δ 2.05-2.18 (m, 2 H), 2.33 (s, 3 H), 2.79 (t, J ) 7.3
Hz, 2 H), 3.45 (t, J ) 6.5 Hz, 2 H), 7.15 (d, J ) 7.8 Hz, 1 H),
7.28-7.39 (m, 4 H), 7.46-7.49 (m, 2 H); 13C NMR (CDCl3, 100
MHz) δ 19.5 (q), 31.8 (t), 33.1 (t), 33.5 (t), 88.0 (s), 90.8 (s), 120.9
(s), 122.4 (s), 122.6 (s), 129.3 (d), 129.4 (d), 131.8 (d), 133.1 (d),
133.6 (d), 136.4 (s), 139.9 (s); exact mass m/z calcd for C18H1679Br2
389.96188, found 389.96176.
tert-Butyl 1-[(Methoxycarbonyl)methyl]-2,5-bis(methoxymeth-
oxy)-4-oxocyclohexa-2,5-dienecarboxylate (28). (a) tert-Butyl
1-[(Methoxycarbonyl)methyl]-2,5-bis(methoxymethoxy)cyclohexa-
2,5-dienecarboxylate. The apparatus consists of a three-necked
round-bottomed flask containing a magnetic stirring bar and fitted
with a coldfinger condenser fused onto one of the necks. The
exit of the condenser carried a drying tube filled CaSO4. An
external mark on the flask indicated the level corresponding to
the desired volume of liquid NH3. The central neck was closed
by a septum carrying a nitrogen inlet. The flask was cooled in
a dry ice-acetone bath and the coldfinger condenser was charged
with dry ice-acetone. Another round-bottomed flask was half-
filled with liquid NH3 and several small pieces of Na were added,
so as to form a permanently blue solution. This flask was
connected via bent adaptors and dry Tygon tubing to the third
neck of the other flask. A solution of 27 (1.77 g, 5.94 mmol) in
dry THF (20 mL) and t-BuOH (0.60 mL, 5.9 mmol) was injected
into the three-necked flask, and liquid NH3 (40 mL) was allowed
to condense into the flask. Lithium wire (0.17 g, 24 mmol), cut
into small pieces, was added rapidly to the vigorously stirred
solution. Stirring at -78 °C was continued for 1 h, by which
time a dark blue color persisted. A solution of BrCH2CO2CH3
(1.70 mL, 17.8 mmol) in THF (5 mL) was then added dropwise
1H NMR (CDCl3, 300 MHz) δ 1.40 (s, 9 H), 3.06-3.10 (m, 2
H), 3.42 (s, 3 H), 3.43 (s, 3 H), 3.60 (s, 3 H), 5.10-5.12 (m, 4
H), 5.95 (s, 1 H), 6.10 (s, 1 H); 13C NMR (CDCl3, 100 MHz) δ
27.7 (q), 39.8 (t), 51.7 (q), 53.6 (s), 56.0 (q), 56.9 (q), 83.3 (s),
94.4 (t), 94.9 (t), 106.7 (d), 115.2 (d), 149.2 (s), 167.2 (s), 169.3
(s), 169.7 (s), 182.0 (s); exact mass m/z calcd for C18H26NaO9
(M + Na) 409.14690, found 409.14688.
2-[2,5-Dihydroxy-4-(3-methylbut-3-en-1-ynyl)phenyl]acetic Acid
Methyl Ester (29). (a) tert-Butyl 4-Hydroxy-1-[(methoxycarbo-
nyl)methyl]-2,5-bis(methoxymethoxy)-4-(3-methylbut-3-en-1-
ynyl)cyclohexa-2,5-dienecarboxylate. n-BuLi (2.5 M in hexane,
0.35 mL, 0.88 mmol) was added at a fast dropwise rate to a
stirred and cooled (-78 °C) solution of 2-methyl-1-buten-3-
yne (0.08 mL, 0.9 mmol) in Et2O (5 mL). The resulting solution
was stirred at -78 °C for 1 h. A solution of 28 (169 mg, 0.440
mmol) in Et2O (3 mL) was added dropwise, and stirring was
continued for 3 h. The mixture was quenched slowly with
saturated aqueous NH4Cl and extracted with Et2O. The combined
organic extracts were washed with brine, dried (MgSO4), and
evaporated. The crude product [tert-butyl 4-hydroxy1-1-[(meth-
oxycarbonyl)methyl]-2,5-bis(methoxymethoxy)-4-(3-methylbut-
3-en-1-ynyl)cyclohexa-2,5-dienecarboxylate] was used directly
in the next step.
(b) 2-[2,5-Dihydroxy-4-(3-methylbut-3-en-1-ynyl)phenyl]ace-
tic Acid Methyl Ester (29). The general procedure for rearoma-
tization was followed, using BiCl3 ·H2O (131.3 mg, 0.440 mmol)
and tert-butyl 4-hydroxy-1-[(methoxycarbonyl)methyl]-2,5-bis-
(methoxymethoxy)-4-(3-methylbut-3-en-1-ynyl)cyclohexa-2,5-di-
enecarboxylate (total product from the previous step) in MeCN (5
mL) and water (0.1 mL) and a reaction time of 3 h. Flash
chromatography of the crude product over silica gel (1 × 10 cm),
using 30% EtOAc-hexane, gave 29 (82.9 mg, 77%) as an oil: FTIR
(CDCl3, microscope) 3398, 2954, 2924, 2196, 1716, 1431, 1199
1
cm-1; H NMR (CDCl3, 300 MHz) δ 2.01 (s, 3 H), 3.64 (s, 2 H),
3.76 (s, 3 H), 5.35-5.37 (m, 2 H), 5.43 (s, 1 H), 6.71 (s, 1 H),
6.87 (s, 1 H), 6.92 (s, 1 H); 13C NMR (CDCl3, 100 MHz) δ 23.4
(q), 37.7 (t), 52.8 (q), 81.7 (s), 97.6 (s), 109.5 (s), 116.6 (d), 119.9
J. Org. Chem. Vol. 73, No. 20, 2008 8019

Sunasee and Clive
(d), 123.0 (s), 123.7 (s), 126.1 (s), 148.2 (t), 150.6 (s), 173.8 (s);
exact mass m/z calcd for C14H14NaO4 (M + Na) 269.07843, found
269.07862.
Supporting Information Available: Experimental proce-
dures and copies of NMR spectra for new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
Acknowledgment. We thank the Natural Sciences and
Engineering Research Council of Canada for financial
support.
JO8015192
8020 J. Org. Chem. Vol. 73, No. 20, 2008