A direct asymmetric synthesis of juglomycin A

Full text of DOI:10.1021/jo952077p

2986
J . Org. Chem. 1996, 61, 2986-2987
A Dir ect Asym m etr ic Syn th esis of J u glom ycin A
Hiroshi Maeda and George A. Kraus*
Department of Chemistry, Iowa State University, Ames, Iowa 50011
Received November 27, 1995X
J uglomycin A has been synthesized in four steps from 5-methoxy-1-naphthol.
In 1971 Ono and co-workers isolated juglomycin A (1)
and juglomycin B (2) from Streptomyces sp. 190-2.1 The
absolute configurations of 1 and 2 were confirmed by
single crystal X-ray determination.2 Syntheses of race-
mic 1 and 2 have been reported by Giles and co-workers.3
A formal total synthesis of 1 has recently been reported.4
No asymmetric synthesis of either 1 or 2 has been
reported. According to the literature,5 juglomycin A is
readily converted into a mixture of juglomycin A and
juglomycin B under acidic and weakly basic conditions.
Both 1 and 2 exhibit modest antitumor activity as well
conducted with 5-acetoxy-1-naphthol (5b). In this case,
the ratio of diastereomers was only 12:1 and the yield
was 57%.
The construction of the naphthoquinone subunit was
achieved by treating 7a with phenyliodine(III) bis(tri-
fluoroacetate). Quinone 8 was produced in only 34%
yield. Alternatively, quinone 8 could be generated using
salcomine and molecular oxygen in 72% yield.8 After
several unsuccessful experiments using aqueous acids
(HCl, HBr), the transformation of 8 into hydroxy lactone
3 was effected using anhydrous trifluoroacetic acid in
methylene chloride. Both lactonization and deprotection
of the BOM group were achieved. Attempts to produce
a lactone from hydroxy ester 7 using either acid or base
catalysis led to extensive epimerization of the benzylic
alcohol, possibly by way of a quinone methide intermedi-
ate. Deprotection of 3 using boron trichloride in meth-
ylene chloride at -20 °C afforded 1 in 49% yield from 8
without significant epimerization at the benzylic position.
Significant epimerization had previously been observed
using aluminum chloride.3 The spectral data (IR, 1H
NMR) for synthetic 1 were identical to those reported for
the natural substance.
as antibacterial activity against both Gram-negative and
Gram-positive bacteria.1 Since juglomycin A is a frag-
ment of the anticoccidial agent frenolicin B (4a ) and the
antifungal agent kalafungin (4b), a synthesis of juglo-
mycin A could in principle be a stepping stone to a
versatile synthesis of pyranonaphthoquinones. We re-
port herein an efficient asymmetric synthesis of juglo-
mycin A.
After a few unsuccessful approaches, our synthetic
efforts focussed on the reaction of a naphthol anion with
a chiral aldehyde. This reaction has been studied with
simple phenols by Casiraghi and co-workers.6 Our
synthesis of 1 began with naphthol 5a which was
deprotonated using methyl magnesium bromide and then
treated with aldehyde 67 derived from D-malic acid.
Diastereomer 7a was produced as the major isomer of a
24:1 mixture (determined by 1H NMR integration of
phenol OH) in 67% isolated yield. This reaction was also
J uglomycin A has been synthesized from naphthol 5a
in four steps. This direct and flexible synthetic route will
permit further evaluation of this novel compound. We
are presently studying the conversion of juglomycin A
into kalafungin.
Exp er im en ta l Section
Optical rotations were measured with a DIP-370 polarim-
eter using a 10 cm cell. H:EA refers to hexanes:ethyl acetate
solvent mixtures for thin layer chromatography and silica gel
flash chromatography (sgc). Infrared spectra (IR) were re-
corded on a FTS-7 spectrophotometer. Proton NMR spectra
were measured at 300 MHz with tetramethylsilane as an
internal standard. 13C NMR spectra were recorded in CDCl3
at 75 MHz. High resolution mass spectra (HRMS) were EI
spectra obtained by a Kratos MS50 magnetic sector mass
spectrometer.
X Abstract published in Advance ACS Abstracts, April 1, 1996.
(1) Ushiyama, K.; Tanaka, N.; Ono, H.; Ogata, H. J pn. J . Antibiot.
1971, 24, 197.
(2) Krupa, J .; Lackner, H.; J ones, P. G.; Schmidt-Base, K.; Sheldrick,
G. M. Z. Naturforsch. 1989, 44b, 345.
(3) Giles, R. G. F.; Mitchel, P. R. K.; Roos, G. H. P.; Stru¨mpfer, J .
M. M. J . Chem. Soc., Perkin Trans. 1 1981, 2091.
(4) Brimble, M. A.; Ireland, E. J . Chem. Soc., Perkin Trans. 1 1994,
3109.
(5) Tanaka, N.; Ogata, H.; Ushiyama, K.; Ono, H. J pn. J . Antibiot.
1971, 24, 222.
(6) Casiraghi, G.; Cornia, M.; Casnati, G.; Fava, G. G.; Belicchi, M.
F.; Zetta, L. J . Chem. Soc., Chem. Commun. 1987, 794.
(7) This was perpared according to the method of Keck: Keck, G.
E.; Andrus, M. B.; Romer, D. R. J . Org. Chem. 1991, 56, 417.
(8) Wakamatsu, T.; Nishi, T.; Ohnuma, T.; Ban, Y. Synth. Commun.
1984, 14, 1167.
S0022-3263(95)02077-9 CCC: $12.00 © 1996 American Chemical Society

Asymmetric Synthesis of J uglomycin A
J . Org. Chem., Vol. 61, No. 9, 1996 2987
Meth yl (R)-4-Oxo-3-((p h en ylm eth oxy)m eth oxy)bu ta n -
oa te (6). To a stirred solution of (R)-malic acid dimethyl ester
(3.69 g, 22.8 mmol) and diisopropylethylamine (4.76 mL, 27.4
mmol) in anhydrous CH2Cl2 (30 mL) at 0 °C was added
dropwise chloromethyl benzyl ether (6.34 mL, 45.6 mmol). The
reaction mixture was stirred at rt for 72 h and then quenched
with H2O. After concentration in vacuo, the aqueous layer was
separated and extracted with CH2Cl2. The combined organic
portions were washed with brine, dried over MgSO4, and
concentrated in vacuo. The residue was purified by sgc (H:
J ) 7.8 and 4.2 Hz, 1H), 4.63 (d, J ) 11.8 Hz, 1H), 4.71 (d, J
) 11.8 Hz, 1H), 4.91 (s, 1H), 4.93 (s, 2H), 5.10 (s, 1H), 7.11 (d,
J ) 8.6 Hz, 1H), 7.23 (d, J ) 7.5 Hz, 1H), 7.26-7.41 (m, 6H),
7.44 (t, J ) 7.5 Hz, 1H), 8.17 (d, J ) 8.7 Hz, 1H), 9.16 (s, 1H);
HRMS exact mass calcd for C25H26O8 454.16277, found
454.16303. Anal. Calcd for C25H26O8: C 66.07, H 5.77.
Found: C 65.78, H 5.96.
Meth yl (3R,4R)-4-Hyd r oxy-4-(5-m eth oxy-1,4-n a p h th o-
qu in on -2-yl)-3-((p h en ylm eth oxy) m eth oxy)bu ta n oa te (8).
To a stirred solution of 7a (0.40 g, 0.94 mmol) in dry DMF (20
mL) was added bis(salicylidene)ethylenediiminocobalt (II) (30
mg, 0.092 mmol). The dark suspension was stirred under an
oxygen atmosphere for 15 min. To the reaction mixture were
added H2O and AcOEt. The organic layer was washed with
H2O five times followed by brine and dried over MgSO4, and
concentrated in vacuo. The residue was purified by sgc (H:
EA ) 6:1) to afford 5.40 g (84%) as a colorless oil: [R]25
+
D
40.9° (c ) 1.83, CHCl3); Rf ) 0.24 (H:EA ) 6:1); IR (neat) 1743
cm-1; 1H NMR (CDCl3) δ 2.81 (d, J ) 6.3 Hz, 2H), 3.70 (s, 3H),
3.73 (s, 3H), 4.55-4.75 (m, 3H), 4.85 (d, J ) 7.2 Hz, 1H), 4.88
(d, J ) 7.2 Hz, 1H), 7.20-7.40 (m, 5H); HRMS exact mass calcd
for C13H15O5 (M - OCH3) 251.09195, found 251.09176.
EA ) 1:1) to afford 1.11 g (72%) of 8 as a yellow syrup: [R]25
A solution of dimethyl (R)-2-((phenylmethoxy)methoxy)-
butanedioate (4.70 g, 16.7 mmol) and magnesium bromide
etherate (4.74 g, 18.4 mmol) in anhydrous CH2Cl2 (50 mL) was
stirred at rt for 30 min and then cooled to -90 °C. Diisobu-
tylaluminum hydride (18.4 mL of a 1.0 M solution in hexane,
18.4 mmol) was then added dropwise via syringe pump (one
drop every 5 s). After addition was complete, anhydrous
MeOH (18 mL) was added via syringe pump, and the reaction
was allowed to warm to rt. Saturated Rochelle salts (200 mL)
was added, the solution was stirred for 2 h, and the layers
were separated. The aqueous layer was extracted with CH2-
Cl2, and the combined organic layers were dried over MgSO4.
The residue was purified by sgc using (H:EA ) 4:1) to afford
D
-36.1° (c ) 0.91, CHCl3); Rf ) 0.26 (H:EA ) 1:1); IR (neat)
1
3470 (br), 1734, 1652 cm-1; H NMR (CDCl3) δ 2.71 (dd, J )
15.9 and 5.5 Hz, 1H), 2.79 (dd, J ) 15.9 and 7.2 Hz, 1H), 3.49
(d, J ) 6.9 Hz, 1H), 3.67 (s, 3H), 3.98 (s, 3H), 4.35-4.43 (m,
1H), 4.47 (s, 2H), 4.70 (d, J ) 7.0 Hz, 1H), 4.77 (d, J ) 7.0 Hz,
1H), 4.86-4.94 (m, 1H), 7.00 (d, J ) 1.5 Hz, 1H), 7.15-7.30
(m, 6 H), 7.60-7.73 (m, 2H); 13C NMR (CDCl3) δ 37.4, 51.8,
56.3, 69.6, 69.9, 77.2, 95.0, 117.8, 119.1, 119.3, 127.2, 127.4,
128.2, 134.2, 134.8, 136.9, 137.4, 146.9, 159.3, 171.4, 184.1,
184.8; HRMS exact mass calcd for C24H2408 440.14712, found
440.14724.
5-O-Meth ylju glom ycin A (3). To a stirring solution of 8
(200 mg, 0.46 mmol) in anhydrous CH2Cl2 (4 mL) at 0 °C was
added dropwise trifluoroacetic acid (3.2 mL). The reaction
mixture was stirred at rt for 5 h, and the solvents were
evaporated in vacuo. To the residue were added H2O and
AcOEt. The black precipitate generated was filtered by
suction. The organic layer separated in the filtrate was
washed with brine, dried over MgSO4, and concentrated in
vacuo. The residue was purified by silica gel column chroma-
tography (H:EA ) 2:3) to afford 83 mg (63%) of 3 as a yellow
2.77 g (66%) of 6 as a colorless oil: [R]25 +16.8° (c ) 2.50,
D
CHCl3); Rf ) 0.26 (H:EA ) 3:1); IR (neat) 1738 cm-1; 1H NMR
(CDCl3) δ 2.75 (dd, J ) 16.5 and 6.7 Hz, 1H), 2.83 (dd, J )
16.5 and 4.8 Hz, 1H), 3.70 (s, 3H), 4.37 (dd, J ) 6.7 and 4.8
Hz, 1H), 4.65 (d, J ) 11.7 Hz, 1H), 4.69 (d, J ) 11.7 Hz, 1H),
4.91 (s, 2H), 7.20-7.40 (m, 5H), 9.76 (s, 1H). HRMS exact
mass calcd for C11H13O3 (M - CO2Me) 193.08647, found
193.08640.
Met h yl (3R,4R)-4-H yd r oxy-4-(1-h yd r oxy-5-m et h oxy-
n a p h th yl)-3-((p h en ylm eth oxy)m eth oxy)bu ta n oa te (7a ).
To a solution of 5-methoxy-1-naphthol (1.50 g, 8.62 mmol) in
anhydrous Et2O (40 mL) was added a solution of MeMgBr (3.14
mL of a 3.0 M solution in Et2O, 9.41 mmol) at 0 °C, and the
reaction mixture was allowed to warm to rt. The ether was
removed in vacuo, and anhydrous CH2Cl2 (40 mL) was added.
This solution was cooled to -78 °C. To a stirred solution of 6
(2.07 g, 8.21 mmol) in CH2Cl2 (40 mL) was added magnesium
bromide etherate (2.54 g, 9.80 mmol). The suspension was
stirred for 1 h and cooled to -78 °C. This suspension was
added to the above solution at -78 °C, and the reaction
mixture was stirred at rt for 4 h in sonication bath. The
reaction was quenched with saturated aqueous NH4Cl. The
aqueous layer was separated and extracted with CH2Cl2. The
combined organic portions were washed with brine, dried over
MgSO4, and concentrated in vacuo. The residue was purified
by sgc (H:EA ) 3:1) to afford 2.36 g (67%) of 7a as a syrup:
solid: mp 170-173 °C (decomp) (from CH2Cl2-hexane); [R]25
D
-57.5° (c ) 0.20, MeOH); Rf ) 0.16 (H:EA ) 1:2); IR (KBr)
3450 (br), 1791, 1656, 1587 cm-1; 1H NMR (acetone-d6) δ 2.50
(d, J ) 17.4 Hz, 1H), 3.15 (dd, J ) 17.4 and 5.1 Hz, 1H), 3.97
(s, 3H), 4.73 (br, 1H), 4.87-4.94 (m, 1H), 5.66 (dd, J ) 3.6
and 1.5 Hz, 1H), 6.77 (d, J ) 1.5 Hz, 1H), 7.55 (dd, J ) 8.4
and 1.0 Hz, 1H), 7.68 (dd, J ) 7.6 and 1.0 Hz, 1H), 7.80 (dd,
J ) 8.4 and 7.6 Hz, 1H); HRMS exact mass calcd for C15H12O6
288.06339, found 288.06416.
J u glom ycin A (1). To a stirring solution of 3 (42 mg, 0.146
mmol) in 12 mL of anhydrous CH2Cl2 at -78 °C was added a
solution of BCl3 (0.44 mL of a 1.0 M solution in CH2Cl2, 1.32
mmol), and the reaction mixture was allowed to warm to -20
°C which was maintained for 15 min. The mixture was poured
into a mixture of ice and AcOEt. The organic layer was
washed with brine, dried over MgSO4, and concentrated in
vacuo. The residue was purified by preparative thin layer
chromatography (CH2Cl2:MeOH) 95:5) to afford 31 mg (78%)
of 1 as a yellow solid: mp 175-177 °C (decomp.) (from CH2-
Cl2); lit.,5 mp 172 °C (decomp); [R]25D -49.0° (c ) 0.10, DMSO);
lit.,5 [R]25D -51.9° (c ) 0.42, DMSO); Rf ) 0.39 (CH2Cl2:MeOH
[R]25 -64.5° (c ) 0.62, CHCl3); Rf ) 0.32 (H:EA ) 3:1); IR
D
(neat) 3325 (br), 1737 cm-1; H NMR (CDCl3) δ 2.37 (dd, J )
1
16.2 and 4.0 Hz, 1H), 2.52 (dd, J ) 16.2 and 8.2 Hz, 1H), 3.58
(s, 3H), 3.98 (s, 3H) 4.32 (dt, J ) 8.2 and 4.0 Hz, 1H), 4.64 (d,
J ) 11.9 Hz, 1H), 4.72 (J ) 11.9 Hz, 1H), 4.90 (s, 1H), 4.94 (s,
2H), 5.09 (s, 1H), 6.82 (d, J ) 7.5 Hz, 1H), 7.06 (d, J ) 8.7 Hz,
1H), 7.28-7.45 (m, 6H), 7.72 (d, J ) 8.7 Hz, 1H), 7.84 (d, J )
7.5 Hz, 1H), 9.03 (s, 1H); 13C NMR (CDCl3) δ 12.4, 37.4, 51.7,
55.4, 70.6, 77.8, 81.6, 96.3, 104.6, 113.3, 114.5, 116.1, 125.3,
126.4, 126.6, 128.0, 128.1, 128.6, 136.5, 151.8, 155.0, 171.3;
HRMS exact mass calcd for C24H26O7 426.16785, found
426.16883. Anal. Calcd for C24H26O7: C 67.59, H 6.15.
Found: C 67.65, H 6.29.
1
) 95:5); IR (KBr) 3400 (br), 1781, 1671, 1646, 1621 cm-1; H
NMR (acetone-d6) δ 2.52 (d, J ) 17.4 Hz, 1 H), 3.17 (dd, J )
17.4 and 5.4 Hz, 1 H), 4.78 (d, J ) 3.9 Hz, 1 H), 4.92 (m, 1 H),
5.71 (dd, J ) 3.6 and 1.5 Hz, 1 H), 6.95 (d, J ) 1.5 Hz, 1 H),
7.35 (dd, J ) 8.4 and 1.2 Hz, 1 H), 7.62 (dd, J ) 7.5 and 1.2
Hz, 1 H), 7.79 (dd, J ) 8.4 and 7.5 Hz, 1 H). Anal. Calcd for
C14H10O6: C 61.32, H 3.68. Found: C 60.96, H 3.78.
Ack n ow led gm en t. We thank Hoffmann-LaRoche
for partial financial support of this research.
Meth yl (3R,4R)-4-(5-Acetoxy-1-h yd r oxyn a p h th yl)-4-h y-
d r oxy-3-((p h en ylm eth oxy)m eth oxy)bu ta n oa te (7b). The
same procedures were used as for 7a starting from 5-acetoxy-
1-naphthol (1.95 g, 9.65 mmol) and 6 (2.36 g, 9.37 mmol). The
crude product was purified by sgc (H:EA ) 5:2) to afford 2.41
g (57%) of 7b as a thick syrup: [R]25D -40.1° (c ) 1.01, CHCl3);
1
Su p p or tin g In for m a tion Ava ila ble: Copies of H NMR
spectra of all title compounds and integrated spectra for ratios
of 7a and 7b (8 pages). This material is contained in libraries
on microfiche, immediately follows this article in the microfilm
version of the J ournal, and can be ordered from the ACS; see
any current masthead page for ordering information.
Rf ) 0.22 (H:EA ) 5:2); IR (neat) 3310 (br), 1767, 1738 cm-1
;
1H NMR (CDCl3) δ 2.38 (dd, J ) 16.2 and 4.2 Hz, 1H), 2.44 (s,
3H), 2.50 (dd, J ) 16.2 and 7.8 Hz, 1H), 3.56 (s, 3 H), 4.31 (dt,
J O952077P