An expedient and short synthesis of a 6-iodo isocoumarin building block for the rubromycin family and its first palladium-catalyzed couplings

Article abstract of DOI:10.1055/s-2004-835658

An efficient six-step synthesis of 6-iodo substituted isocoumarin 6 is presented, which is a suitable building block for the preparation of rubromycin type compounds. Key transformations of the sequence were achieved by directed ortho-lithiation, Horner-W

Full text of DOI:10.1055/s-2004-835658

2736
LETTER
An Expedient and Short Synthesis of a 6-Iodo Isocoumarin Building Block for
the Rubromycin Family and its First Palladium-Catalyzed Couplings
Synthesis of
a
6-Iodo I
a
socoumarin
l
Build
t
e
ck for the
R
ubrom
B
ycin Family rasholz, Hans-Ulrich Reissig*
Institut für Chemie, Freie Universität Berlin, Takustr. 3, 14195 Berlin, Germany
Fax +49(30)83855367; E-mail: hans.reissig@chemie.fu-berlin.de
Received 2 September 2004
rected ortho-lithiation and carboxylation of acetal 1 was
Abstract: An efficient six-step synthesis of 6-iodo substituted iso-
coumarin 6 is presented, which is a suitable building block for the
preparation of rubromycin type compounds. Key transformations of
the sequence were achieved by directed ortho-lithiation, Horner–
optimized and finally performed with n-butyllithium in
cyclohexane.6 After 3 hours of metallation at ambient
temperature, methyl chloroformate was added and direct
Wadsworth–Emmons olefination and condensation processes. The deprotection of the crude carboxylation product provided
ester 27 in satisfactory 58% yield. The iodination of 2
protected isocoumarin 7 was successfully employed in first Heck
and Sonogashira coupling reactions.
proceeded smoothly using tetramethylammonium di-
chloroiodate8 as source of electrophilic iodine. Iodide 3
Key words: rubromycins, isocoumarins, ortho-lithiation, olefin-
was formed regioselectively9 and in excellent 91% yield.
ation, palladium catalysis
Enol ether 5 could be obtained from aldehyde 3 without
previous protection of the free hydroxyl group. Two
Natural products from the known rubromycin family1 dis- equivalents of NaHMDS were used in the Horner–
play various biological activities. g-Rubromycin2 may
serve as a representative example for the remarkable mo-
OMe
OMe
lecular architecture consisting of a 5,6-spiroketal core
fused to hydroxynaphthoquinone and isocoumarin units
(Figure 1).
TBSO
HO
a
b
97%
82%
O
O
O
1
O
O
TBS = tert-butyldimethylsilyl
MeO
OH
HO
O
c
58%
CO2Me
O
O
O
OMe
HO
OMe
HO
I
CO2Me
O
HO
CO2Me
O
γ-rubromycin
d
Figure 1
91%
3
2
To date, only one total synthesis of a rubromycin com-
pound, namely heliquinomycinone, has been reported.3
Versatile building blocks for their syntheses thus remain
desirable targets.4 In this letter, we report a concise pre-
paration of a 6-iodo-substituted isocoumarin fragment de-
signed for insertion into rubromycin syntheses. We also
present first C,C-coupling reactions of our building block
with several substrates, which is planned to be a key step
in a future synthesis of rubromycin type compounds.
O
P
O
e
MeO
MeO
OMe
82%
OMe
4
MeO
O
OMe
RO
I
HO
I
CO2Me
OMe
O
f
Our six-step protocol for the synthesis of the 6-iodo iso-
coumarin derivative 6 is depicted in Scheme 1. Vanillin
was first protected as TBS ether (97% yield), which fur-
nished an intermediate with two differentiated hydroxyl
groups. Its conversion into the 1,3-dioxane derivative 1
was performed under mild conditions using tetra-n-butyl-
ammonium tribromide as catalyst5 (82% yield). The di-
55–68%
CO2Me
CO2Me
6: R = H
5
g
7: R = Bn
81%
Scheme 1 Reagents and conditions: a) TBSCl, Et3N, DMAP,
CH2Cl2, r.t., 24 h; b) 1,3-propanediol, n-Bu4NBr3, HC(OMe)3,
CH2Cl2, r.t., 2.5 h; c) i: 1.2 equiv n-BuLi, cyclohexane, r.t., 3 h; ii:
ClCO2Me, 0 °C → r.t., overnight; iii: 37% HCl (aq), KF, THF, r.t.,
6–24 h; d) Me4NICl2, NaHCO3, CH2Cl2, r.t., 4 h; e) 4, 2 equiv
NaHMDS, THF, –78 °C → r.t.; f) 47% HBr (aq):MeOH = 1:1, reflux,
12 h; g) BnBr, i-Pr2NEt, DMF, 65 °C, 24 h.
SYNLETT 2004, No. 15, pp 2736–2738
0
7
.1
2
.2
0
0
4
Advanced online publication: 10.11.2004
DOI: 10.1055/s-2004-835658; Art ID: G25604ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
Synthesis of a 6-Iodo Isocoumarin Building Block for the Rubromycin Family
2737
Wadsworth–Emmons reaction of 3 with phosphonate 410 In summary, we reported a robust protocol for the prepa-
resulting in a 35:65 mixture of diastereoisomers (82% ration of a 6-iodo isocoumarin building block very
yield), (Z)-5 being the major product.11
suitable for rubromycin syntheses. The feasibility of
palladium-catalyzed couplings on the base-sensitive lac-
tone 7 was demonstrated, paving the way for our future
projects.
The acid-promoted intramolecular condensation of ortho-
carboxyl benzyl ketones or enol ether derivatives12 is a
key step in many isocoumarin syntheses. In the case of 5,
however, harsh conditions were required to achieve lac-
tone formation. Since the condensation under acidic con-
ditions may result in concomitant cleavage of the methyl
ester at C-3, various mixtures of acids and methanol were
applied. Finally, isocoumarin 6 was readily obtained
when 5 was refluxed in a 1:1 mixture of methanol and
concentrated aqueous HBr. The product 6 precipitated
from the mixture in 55–68% yield. The solid was very
poorly soluble and required no purification except wash-
ing and drying. We are confident that this method of con-
verting aldehyde 3 into isocoumarin 6 is convenient for
large-scale preparation. As subsequent step, isocoumarin
derivative 6 was converted into the benzyl ether 7 (81%
yield) previous to its use in coupling reactions.
Acknowledgment
The authors thank the Fonds der Chemischen Industrie and
Schering AG for financial support of this research. We thank Mr. X.
Luan for preliminary investigations in this area and Dr. R. Zimmer
for his assistance during preparation of this manuscript.
References
(1) (a) Brockmann, H.; Lenk, W.; Schwantje, G.; Zeeck, A.
Tetrahedron Lett. 1966, 3525. (b) Brockmann, H.; Lenk,
W.; Schwantje, G.; Zeeck, A. Chem. Ber. 1969, 102, 126.
(c) Brockmann, H.; Zeeck, A. Chem. Ber. 1970, 103, 1709.
(2) g-Rubromycin was isolated from Streptomyces collinus and
showed antibiotic activity against various bacteria strains.
(3) (a) Qin, D.; Ren, R. X.; Siu, T.; Zheng, C.; Danishefsky, S.
J. Angew. Chem. Int. Ed. 2001, 40, 4709; Angew. Chem.
2001, 113, 4845. (b) Siu, T.; Qin, D.; Danishefsky, S. J.
Angew. Chem. Int. Ed. 2001, 40, 4713; Angew. Chem. 2001,
113, 4849.
(4) Syntheses of isocoumarin fragments: (a) Trash, T. P.;
Welton, T. D.; Behar, V. Tetrahedron Lett. 2000, 41, 29.
(b) Waters, S. P.; Kozlowski, M. C. Tetrahedron Lett. 2001,
42, 3567.
(5) Gopinath, R.; Haque, S. J.; Patel, B. K. J. Org. Chem. 2002,
67, 5842.
(6) For related directed ortho-metallations of aromatic acetals,
see: (a) Plaumann, H. P.; Keay, B. A.; Rodrigo, R.
Tetrahedron Lett. 1979, 4921. (b) Winkle, M. R.; Ronald,
R. C. J. Org. Chem. 1982, 47, 2101. (c) Napolitano, E.;
Giannone, E.; Fiaschi, R.; Marsili, A. J. Org. Chem. 1983,
48, 3653. (d) Li, C.; Lobkovsky, E.; Porco, J. A. Jr. J. Am.
Chem. Soc. 2000, 122, 10484.
According to our strategy, isocoumarin 7 should be in-
serted into rubromycin syntheses by means of palladium-
catalyzed coupling reactions with appropriately function-
alized naphthoquinone moieties. To prove this concept,
base-labile lactone 7 was employed in first Sonogashira13
and Heck14 reactions. The Sonogashira couplings were
carried out under standard conditions15 in DMF
(Scheme 2). Both phenylacetylene derivative 8 and 3-
methoxypropyne derivative 9 were cleanly obtained in
high yields (84% and 91%).
MeO
O
MeO
O
BnO
I
BnO
a
O
O
CO2Me
CO2Me
R
7
(7) Procedure for the Carboxylation 1 → 2: n-BuLi (1.86 mL,
2.50 M in hexanes, 4.65 mmol) was added at 0 °C to a
solution of 1.26 g (3.88 mmol) of 1 in 25 mL of dry
cyclohexane. The mixture was stirred at r.t. for 3 h, recooled
to 0 °C and 1.00 mL (12.9 mmol) of methyl chloroformate
were added. Stirring was continued overnight and the
reaction was allowed to warm up to r.t. After quenching with
10 mL of sat. aq Na2CO3, the layers were separated and the
aqueous layer was extracted with 3 × 10 mL of Et2O. The
combined organic layers were concentrated in vacuo and the
residue was dissolved in 25 mL of THF. Then, 37% HCl (aq,
4 mL), 0.70 g (12.0 mmol) KF and 5 mL of H2O were added
and the mixture was stirred at r.t. until TLC indicated
complete conversion (6–24 h). The mixture was washed with
20 mL of brine. The layers were separated and the aqueous
layer was extracted with 3 × 20 mL of CH2Cl2. The
combined organic layers were dried over MgSO4, filtered
and evaporated. Column chromatography (silica gel,
EtOAc–hexane = 1:1) provided 0.47 g (58%) 2 as reddish
solid. Analytical data for methyl 6-formyl-3-hydroxy-2-
methoxybenzoate (2): mp 102–104 °C. 1H NMR (500 MHz,
CDCl3): d = 3.90 (s, 3 H, OMe), 3.98 (s, 3 H, CO2Me), 6.45
(br s, 1 H, OH), 7.11, 7.55 (2 d, J = 8.4 Hz, 2 × 1 H, 4-H, 5-
H), 9.79 (s, 1 H, CHO) ppm. 13C NMR (126 MHz, CDCl3):
d = 53.0 (q, CO2Me), 62.5 (q, OMe), 116.6, 129.9 (2 d, Ar),
127.0, 127.6, 144.4, 154.4 (4 s, Ar), 166.9 (s, CO), 189.0 (d,
84%
91%
8: R = Ph
9: R = CH2OMe
Scheme 2 Reagents and conditions: a) R-C≡CH, Pd(OAc)2, PPh3,
CuI, Et3N, DMF, r.t., 8 h.
Heck reactions of 7 with tert-butyl acrylate and 3-buten-
2-one proceeded smoothly, the latter being performed
under Jeffery’s mild conditions.16 The a,b-unsaturated
carbonyl compounds 10 and 1117 were isolated in 71%
and 91% yield, respectively (Scheme 3).
MeO
O
MeO
O
BnO
I
BnO
a,b
O
O
R
CO2Me
CO2Me
O
7
71%
91%
10: R = OtBu
11: R = CH3
Scheme
3
Reagents and conditions: a) tert-Butyl acrylate,
Pd(OAc)2, PPh3, LiCl, Et3N, DMF, 85 °C, 8 h; b) 3-buten-2-one,
Pd(OAc)2, n-Bu4NCl, NaHCO3, DMF, r.t., 72 h.
Synlett 2004, No. 15, 2736–2738 © Thieme Stuttgart · New York

2738
M. Brasholz, H.-U. Reissig
LETTER
CHO) ppm. IR (KBr): n = 3150 (O-H), 3005 (=C-H), 2950–
2840 (–C-H), 1740, 1660 (C=O), 1600, 1560, 1505 (C=C)
cm–1. MS (EI, 80 eV, 170 °C): m/z (%) = 210 (99) [M]+, 195
(57) [M – CH3]+, 182 (46), 179 (71) [M – OCH3]+, 151 (100)
[M – CO2CH3]+, 136 (62), 121 (91), 107 (49), 92 (36), 80
(50), 65 (44), 51 (55), 39 (32). Anal. Calcd for C10H10O5
(210.2): C, 57.14; H, 4.80. Found: C, 56.86; H, 4.54.
(16) (a) Jeffery, T. J. Chem. Soc., Chem. Commun. 1984, 1287.
(b) Jeffery, T. Tetrahedron Lett. 1985, 26, 2667.
(17) Procedure for Heck Reaction 7 → 11: To a solution of 95
mg (0.20 mmol) of 7 and 0.04 mL (0.50 mmol) freshly
distilled 3-buten-2-one in 3 mL of dry DMF were added 59
mg (0.21 mmol) of tetra-n-butylammonium chloride, 44 mg
(0.52 mmol) of NaHCO3 and 4 mg (0.02 mmol) of
(8) Hajipour, A. R.; Arbabian, M.; Ruoho, A. E. J. Org. Chem.
2002, 67, 8622.
(9) The constitution of 3 was confirmed by a NOESY
experiment.
(10) (a) a-Bromination of methyl methoxyacetate: Gagliardi, S.;
Nadler, G.; Consolandi, E.; Parini, C.; Morvan, M.; Legave,
M.-N.; Belfiore, P.; Zocchetti, A.; Clarke, G. D.; James, I.;
Nambi, P.; Gowen, M.; Farina, C. J. Med. Chem. 1998, 41,
1568. (b) Arbuzov reaction leading to 4: Guay, V.;
Brassard, P. Synthesis 1987, 294.
(11) Assignment of the diastereoisomers was made on the basis
of NOESY experiments.
(12) (a) Adler, E.; Magnusson, R.; Berggren, B. Acta Chem.
Scand. 1960, 14, 539. (b) Sakamoto, T.; Kondo, Y.;
Yamanaka, H. Heterocycles 1988, 27, 453. (c) Also see
refs. 3a,4b.
(13) (a) Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron
Lett. 1975, 4467. (b) Sonogashira, K. J. Organomet. Chem.
2002, 653, 46.
(14) (a) Heck, R. F.; Nolley, J. P. Jr. J. Am. Chem. Soc. 1968, 90,
5518. (b) Heck, R. F. Acc. Chem. Res. 1979, 12, 146. (c)
Review: Beletskaya, I. P.; Cheprakov, A. V. Chem. Rev.
2000, 100, 3009.
palladium(II) acetate. The mixture was stirred at r.t. and the
conversion was monitored by TLC. After 72 h, the mixture
was diluted with 3 mL of EtOAc and washed with 2 × 3 mL
of brine. The layers were separated and the aqueous layer
was reextracted with 1 × 5 mL of EtOAc. The combined
organic layers were dried over MgSO4, filtered and
evaporated. Column chromatography (silica gel, EtOAc–
hexane = 1:1) provided 76 mg (91%) 11 as yellow solid.
Analytical data for methyl 7-benzyloxy-8-methoxy-1-oxo-
6-(3-oxo-but-1-enyl)-1H-isochromene-3-carboxylate (11):
mp 169 °C. 1H NMR (500 MHz, DMSO-d6): d = 2.23 (s, 3
H, 4¢-H), 3.86 (s, 3 H, CO2Me), 3.92 (s, 3 H, OMe), 5.13 (s,
2 H, CH2), 6.77 (d, J = 16.6 Hz, 1 H, 2¢-H), 7.33–7.46 (m, 5
H, Ph), 7.53 (s, 1 H, 4-H), 7.55 (d, J = 16.6 Hz, 1 H, 1¢-H),
8.01 (s, 1 H, 5-H) ppm. 13C NMR (126 MHz, DMSO-d6):
d = 27.3 (q, C-4¢), 52.9 (q, CO2Me), 61.8 (q, OMe), 76.3 (t,
CH2), 112.1 (d, C-4), 117.3, 132.3, 136.37, 136.40, 142.0,
152.2, 155.2 (7 s, Ar, C-3, Ph), 122.2 (d, C-5), 128.70,
128.71, 129.0 (3 d, Ph), 131.5 (d, C-2¢), 135.5 (d, C-1¢),
156.2, 160.3, 198.0 (3 s, CO) ppm. IR (KBr): n = 3090–3005
(=C-H), 2950–2850 (-C-H), 1750, 1730, 1675 (C=O), 1620,
1600, 1550, 1500 (C=C) cm–1. MS (EI, 80 eV, 170 °C): m/z
(%) = 408 (5) [M]+, 366 (12) [M – C2H2O]+, 275 (12), 91
(100) [C7H7]+, 43 (18), 28 (21). HRMS (EI, 80 eV, 170 °C):
m/z calcd for C23H20O7: 408.1209. Found: 408.1224.
(15) For a scope of reaction conditions, see: Sonogashira, K. In
Metal-Catalyzed Cross-Coupling Reactions; Diederich, F.;
Stang, P. J., Eds.; Wiley-VCH: Weinheim, 1998, 213.
Synlett 2004, No. 15, 2736–2738 © Thieme Stuttgart · New York