Synthesis and absolute configuration of nocardione A and B, furano-o-naphthoquinone-type metabolites of Nocardia sp. with antifungal, cytotoxic, and enzyme inhibitory activities

Article abstract of DOI:10.1002/1099-0690(200111)2001:22<4313::AID-EJOC4313>3.0.CO;2-J

(±)-Nocardione A (1), (S)-(-)-nocardione A, and (R)-(+)-nocardione B (2) were synthesized by starting from the enantiomers of propylene oxide and 5-benzyloxy (or methoxy)-1-tetralone. The absolute configurations of the naturally occurring (-)-1 and (-)-2 were established as (S).

Full text of DOI:10.1002/1099-0690(200111)2001:22<4313::AID-EJOC4313>3.0.CO;2-J

FULL PAPER
Synthesis and Absolute Configuration of Nocardione A and B,
Furano-o-naphthoquinone-Type Metabolites of Nocardia sp. with Antifungal,
Cytotoxic, and Enzyme Inhibitory Activities[‡]
Yoshihisa Tanada[a][‡‡] and Kenji Mori*[a]
Keywords: Antibiotics / Asymmetric synthesis / Configuration determination / Heterocycles / Quinones
(±)-Nocardione A (1), (S)-(−)-nocardione A, and (R)-(+)-nocar- tetralone. The absolute configurations of the naturally occur-
dione B (2) were synthesized by starting from the enanti- ring (−)-1 and (−)-2 were established as (S).
omers of propylene oxide and 5-benzyloxy (or methoxy)-1-
Introduction
ticed the work of Merlic et al.[2] who oxidized an o-naph-
thoquinone A with ferric chloride to give a calphostin-type
compound, B, and nocardione-type compound C. The lat-
ter compound was obtained only as a minor product, and
therefore this reaction could not be employed in the syn-
thesis of nocardiones.
As shown in Scheme 2, our plan was to build the unstable
o-naphthoquinone system at a later stage in the synthesis,
and envisage D as an intermediate for building up 1 and 2.
For the construction of the dihydrofuran ring a Mitsunobu
reaction was considered the method of choice.
In 2000 Otani et al. isolated two new furano-o-naphtho-
quinones, (Ϫ)-nocardione A (1, Scheme 1) and (Ϫ)-nocar-
dione B (2) as new tyrosine phosphatase inhibitors with
moderate antifungal and cytotoxic activities.[1] Due to the
scarcity of the materials (only 8 mg of 1 and 0.3 mg of 2
were obtained from 4.5 L of the culture broth of Nocardia
sp. TP-A0248), their absolute configuration remained un-
known. In order to solve this problem, we undertook a syn-
thesis of optically active 1 and 2 with known absolute con-
figuration. After the completion of our synthesis, we no-
Scheme 2. Retrosynthetic analysis of 1 and 2
This suggested E as an ideal intermediate, which could be
synthesized from 5-alkoxy-1-tetralone F and (R)-propylene
oxide G.
Results and Discussion
Scheme 1. Structures of (Ϫ)-nocardione A (1), B (2), and related
compounds
Scheme 3 summarizes the synthesis of (Ϯ)-nocardione A
(1) and (R)-(ϩ)-nocardione B (2). Commercially available
5-methoxy-1-tetralone (3) was treated with lithium hexa-
methyldisilazide (LHMDS), followed by (S)-propylene ox-
ide (4) in the presence of scandium triflate in dry toluene[3]
to give hydroxy ketone 5. The hydroxy group of 5 was pro-
tected as 2,2,2-trichloroethoxycarbonate (Troc), which was
known to be readily removable under reducing conditions,
[‡]
Synthetic Microbial Chemistry, XXXVII. Ϫ Part XXXVI:
Y. Tanada, K. Mori, Eur. J. Org. Chem. 2001, 1963Ϫ1966.
[‡‡] Research fellow on leave from Otsuka Pharmaceutical Co.
(2000Ϫ2002).
[a]
Department of Chemistry, Faculty of Science, Science
University of Tokyo,
Kagurazaka 1Ϫ3, Shinjuku-ku, Tokyo 162Ϫ8601, Japan
Fax: (internat.)ϩ81Ϫ3/3235-2214
Eur. J. Org. Chem. 2001, 4313Ϫ4319
WILEY-VCH Verlag GmbH, 69451 Weinheim, 2001
1434Ϫ193X/01/1122Ϫ4313 $ 17.50ϩ.50/0
4313

Y. Tanada, K. Mori
FULL PAPER
thetic material. The natural product was apparently con-
1
taminated with impurities, as evidenced by additional H
and 13C NMR signals observed in its spectra. To ascertain
the homogeneity of our synthetic material, (R)-(ϩ)-2 was
analyzed by HPLC on a chiral stationary phase, and shown
to be enantiomerically pure. Unfortunately, no sample of
the natural 2 was available to allow its HPLC analysis. Since
the naturally occurring nocardione B is levorotatory, its ab-
solute configuration was determined as (S), although there
is a slight possibility that impurities in the natural 2 might
have reversed the sign of its optical rotation. The overall
yield of (R)-nocardione B (2) was 5.1% based on (S)-propy-
lene oxide (6 steps).
Finally, demethylation of (R)-nocardione B (2) was ac-
complished by treatment with aluminum chloride in dichlo-
romethane.[7] This step caused complete racemization of the
product, and (Ϯ)-nocardione A (1) was obtained as dark
red needles, m.p. 156.0Ϫ157.0 °C. HPLC analysis of this
compound on a chiral stationary phase revealed it to be
racemic. All our attempts to effect demethylation without
racemization were unsuccessful. A logical alternative to cir-
cumvent this difficulty was to use a more readily removable
protective group for the phenolic hydroxy group than the
methyl group.
Accordingly, (S)-(؊)-nocardione A (1) was synthesized
as shown in Scheme 4 by employing a benzyl group as the
Scheme 3. Synthesis of (Ϯ)-nocardione A (1) and (R)-(ϩ)-nocar-
dione B (2); reagents and conditions: (a) 1.0  LHMDS in hexane,
toluene, Ϫ4Ϫ0 °C, 1 h then 10 mol % Sc(OTf)3, room temp., 22 h;
(b) Cl3CCH2OC(O)Cl, C5H5N, CH2Cl2, 0 °C, 30 min, then room
temp., 11 h; (c) SeO2, 1,4-dioxane, reflux 15 h (32%, 3 steps);
(d) powdered Zn, AcOH, under Ar, room temp., 2 h (81%); (e)
EtO2CNϭNCO2Et, Ph3P, THF, room temp., 17 h (28%);
(f) (PhSeO)2O, THF, 50 °C, 0.5 h (71%); (g) AlCl3, 0 °C, 0.5 h, then
room temp., 13.5 h, (quant.)
to furnish 6. Conversion of 6 to p-naphthoquinone 7 was
executed with selenium dioxide in 32% overall yield based
on (S)-4 (3 steps). Reduction of the quinone 7 with zinc
and acetic acid to hydroquinone 8 was accompanied with
concomitant removal of the Troc group, giving 8. The hy-
droquinone 8 was so easily oxidized in air that the crude
product had to be completely reduced by catalytic hydro-
genation with palladiumϪcharcoal to give pure hydroquin-
one 8.
Ring closure of 8 to give tricyclic naphthol 9 with inver-
sion of configuration at C-2 could be accomplished under
the classical Mitsunobu conditions employing triphenyl-
phosphane and diethyl azodicarboxylate (DEAD)[4] in a ra-
ther poor yield of 28%. The use of new reagents for Mitsu-
nobu reactions, as developed by Tsunoda et al.,[5] did not
improve the yield. Oxidation of 9 to (R)-nocardione B was
first attempted with Fremy’s salt. However, this resulted in
the ring opening of 9 to give back naphthoquinone 10. For-
tunately,
Barton’s
benzeneseleninic
anhydride
[(PhSeO)2O][6] smoothly oxidized 9 to furnish (R)-nocar-
Scheme 4. Synthesis of (S)-(Ϫ)-nocardione A (1); reagents and con-
ditions: (a) 1.0  LHMDS in hexane, toluene, Ϫ4Ϫ0 °C, 1 h; then
10 mol % Sc(OTf)3, room temp., 21 h; (b) Cl3CCH2OC(O)Cl,
C5H5N, CH2Cl2, 0 °C, 20 min then room temp., 1 h; (c) SeO2, 1,4-
dioxane, reflux 15 h (36%, 3 steps); (d) powdered Zn, AcOH, under
Ar, room temp., 2 h (81%); (e) EtO2CNϭNCO2Et, Ph3P, THF,
room temp., 19 h (19%); (f) (PhSeO)2O, THF, 50 °C., 0.5 h (78%);
dione
B (2) as dextrorotatory orange needles, m.p.
156.0Ϫ157.0 °C, [α]2D7 ϭ ϩ72.6 (CHCl3). Although these
m.p. and specific rotation values were somewhat different
from those reported for natural (Ϫ)-nocardione B {m.p.
79Ϫ81 °C; [α]2D7 ϭ Ϫ29.8 (CHCl3)},[1] its major 1H and 13
NMR signals perfectly coincided with those of our syn- (g) H2, 10% Pd/C, DMF, room temp., 10 min (50%)
C
4314 Eur. J. Org. Chem. 2001, 4313Ϫ4319

Synthesis and Absolute Configuration of Nocardione A and B
FULL PAPER
(243 mL) was cooled in an ice bath at Ϫ5Ϫ0 °C. To this solution
was added a solution of 3 (39 g, 216 mmol) in toluene (170 mL)
dropwise via cannula over 1.0 h under Ar. After having been stirred
for 1.5 h at Ϫ5Ϫ0 °C, a solution of (S)-(Ϫ)-propylene oxide (4.10 g,
71 mmol) in toluene (38 mL) was added dropwise via cannula over
10 min, and then Sc(OTf)3 (3.9 g, 8 mmol) was added in one por-
tion. The resulting mixture was stirred at room temperature under
Ar for 22 h. The mixture was diluted with Et2O (200 mL) and fil-
tered through a celite pad. The residue on the pad was washed
thoroughly with EtOAc (300 mL). The combined filtrates were
protective group, which could be removed successfully (vide
infra). Known 5-benzyloxy-1-tetralone (11)[8] and (R)-pro-
pylene oxide (4) were converted into benzyl-protected no-
cardione A (17) in the same manner as described above for
the synthesis of (R)-nocardione B via 12, 13, 14, 15, and
16. In this case, too, the Mitsunobu-type ring closure of 15
to give 16 proceeded with the rather miserable yield of 19%.
The final deprotection step was carefully examined to
achieve an acceptable yield. A large amount (40Ϫ50 wt%
of the substrate 17) of palladiumϪcharcoal was added to washed with sat. aq. NH4Cl, 5% HCl and brine (each 200 mL).
All the aqueous layers were combined and extracted with EtOAc
(500 mL). The second extract was washed with brine (200 mL). All
the organic layers were combined, dried with Na2SO4, filtered, and
concentrated in vacuo to give 43.7 g of the crude product. This was
purified twice by silica gel chromatography (400 g, EtOAc/n-hexane
1:2Ϫ4:1 as eluent, then 600 g, EtOAc/n-hexane 1:3Ϫ1:1 as eluent)
to give an inseparable mixture of the diastereomers of 5 (9.89 g) as
a red oil. Ϫ IR (film): ν˜max ϭ 3450 (s, OH), 1680 (s, CϭO), 1580
(m, CϭC). Ϫ 1H NMR (400 MHz, CDCl3): δ ϭ 1.23 (d, J ϭ
6.4 Hz, 1.1 H, CH3CH), 1.27 (d, J ϭ 6.4 Hz, 1.5 H, CH3CH), 1.42
(d, J ϭ 6.4 Hz, 0.4 H, CH3CH), 1.51 (ddd, J ϭ 15.0, 5.1 Hz,
2.7 Hz, 0.5 H), 1.60 (ddd, J ϭ 14.0, 8.2 Hz, 4.2 Hz, 0.5 H),
1.82Ϫ2.01 (m, 1 H), 2.02Ϫ2.15 (m, 1 H), 2.17Ϫ2.30 (m, 1 H),
2.66Ϫ2.85 (m, 2 H), 3.06 (dt, J ϭ 18.0, 4.9 Hz, 0.5 H), 3.11 (dt,
J ϭ 18.0, 4.2 Hz, 0.5 H), 3.87 (s, 3 H, OCH3), 3.90Ϫ4.05 (m, 1 H),
7.02 (d, J ϭ 8.0 Hz, 1 H, ArϪH), 7.28 (t, J ϭ 8.4 Hz, 1 H, ArϪH),
7.64 (dd, J ϭ 8.0, 1.0 Hz, 0.5 H, ArϪH), 7.65 (d, J ϭ8.0 Hz, 0.5
H, ArϪH). Because the obtained material was an inseparable dia-
stereomeric mixture, it was impossible to assign each NMR peak
correctly at this stage.
17 in DMF, and the mixture was stirred under hydrogen for
5Ϫ10 min. Longer reaction time caused decrease in the
yield of 1. Solvents such as THF or ethyl acetate and acetic
acid did not give reproducible yields. After hydrogenation,
the dark brown-red color of the mixture turned pale blue.
Then hydrogen atmosphere was replaced with air to cause
oxidation of the generated hydroquinone as evidenced by
the color change of the solution to dark red. (S)-nocardione
A (1) was obtained as dark red needles, m.p. 172.5Ϫ173.5
°C, [α]2D1 ϭ Ϫ56.0 (CHCl3).
Again, as in the case of (R)-2, the m.p. and specific rota-
tion values were somewhat different from those reported for
the natural (Ϫ)-nocardione A {m.p. 115Ϫ120 °C; [α]D20
ϭ
Ϫ85.4 (CHCl3)}. However, its major 1H and 13C NMR sig-
nals were in perfect agreement with those of our synthetic
1
material. In the H NMR spectrum of the natural product,
we could recognize some additional signals due to impurit-
ies. HPLC analysis of the synthetic (S)-(؊)-1 proved it to
be enantiomerically pure. Here again, no comparison
sample of the natural 1 was available. The naturally occur-
ring (؊)-1 was thus determined to be with (S) absolute con-
figuration. The overall yield of (S)-(؊)-1 was 2.2% based
on (R)-4 (7 steps).
In conclusion, (Ϯ)-nocardione A (1), (S)-(؊)-nocardione
A (1), and (R)-(؉)-nocardione B (2) were synthesized, and
the absolute configurations of the naturally occurring and
levorotatory 1 and 2 were determined as (S). Further im-
(ii) Protection of the Hydroxy Group of 5: To an ice cooled solution
of 5 (9.83 g) and pyridine (7.45 mL, 92 mmol) in CH2Cl2 (50 mL)
was added a solution of 2,2,2-trichloroethyl chloroformate (10.7 g,
50 mmol) in CH2Cl2 (50 mL) over 30 min. After the resulting mix-
ture was stirred for 30 min, an additional amount of 2,2,2-trichloro-
ethyl chloroformate (2.0 g, 9.4 mmol) in CH2Cl2 (2 mL) was ad-
ded to it. The mixture was stirred at room temperature for 10 h.
Again, an additional portion of 2,2,2-trichloroethyl chloroformate
provements are awaited to achieve a better yield in the ring (3.0 g, 14 mmol) in CH2Cl2 (3 mL) was added. After having been
stirred for an additional 30 min, the mixture was diluted with Et2O
(750 mL), washed with sat. aq. CuSO4 (150 mL), water (2 ϫ
150 mL), and brine (150 mL). It was then dried with Na2SO4, fil-
tered, and concentrated in vacuo to give 22.0 g of the crude product
as a red oil. This oil was purified twice by silica gel chromatography
{400 g, EtOAc/n-hexane 1:4 as eluent, then Kanto Chemical silica
gel 60N (spherical, neutral) 210 g EtOAc/n-hexane 1:10Ϫ1:1 as
eluent} to give an inseparable mixture of the diastereomers of 6
(16.1 g) as a red oil. Ϫ IR (film): ν˜max ϭ 1760 (s, OϪCϭO), 1680
closure step (8 Ǟ 9 and 14 Ǟ 15).
Experimental Section
Boiling and melting points: Uncorrected values. Ϫ Melting points:
Yanaco MP-S3. Ϫ [α]D: Jasco DIP-1000, Jasco P-1010. Ϫ IR: Jasco
IRA-102, Jasco FT/IR460. Ϫ 1H NMR: Jeol JNM-EX 90A
(90 MHz), Jeol JNM-LA 400, (TMS at δH ϭ 0.00 or CHCl3 at
δH ϭ 7.26 or CH3OH at δH ϭ 3.30 as internal standard). Ϫ 13C
NMR: Jeol JNM-LA 400 (100 MHz), (CDCl3 at δC ϭ 77.0 or
CD3OD at δC ϭ 49.0 as an internal standard). Ϫ MS: Jeol JMS-
AX 505HA. Ϫ CC: Merck Kieselgel 60 Art. no. 1.07734 or Kanto
Chemical silica gel 60N (spherical, neutral). Ϫ TLC: 0.25 mm
Merck silica gel plates (60F-254). Ϫ HPLC: Column: Daicel
Chiralpak AD Ϫ RH (4.6 mm ϫ150 mm). UV detector: SSC Ϫ
5200. Pump unit: SSC Ϫ Flow system 3100. Recorder: SIC Ϫ
chromatocoder 12. Ϫ UV-Vis: Hitachi U-2010.
1
(s, CϭO), 1600 (s, CϭC), 1580 (s, CϭC). Ϫ H NMR (400 MHz,
CDCl3): δ ϭ 1.40 (d, J ϭ 6.3 Hz, 1.5 H, CH3CH), 1.41 (d, J ϭ
6.3 Hz, 1.5 H, CH3CH), 1.58Ϫ1.94 (m, 3 H), 2.20Ϫ2.36 (m, 1.5
H), 2.48Ϫ2.55 (m, 0.5 H), 2.58Ϫ2.81 (m, 2 H), 3.09 (ddd, J ϭ 18.0,
9.0 Hz, 4.4 Hz, 0.5 H), 3.86 (s, 3 H, OCH3), 4.73 (d, J ϭ 12.0 Hz,
0.5 H, Cl3CCH2), 4.74 (d, J ϭ 12.0 Hz, 0.5 H, Cl3CCH2), 4.77 (d,
J ϭ 12.0 Hz, 0.5 H, Cl3CCH2), 4.80 (d, J ϭ 12.0 Hz, 0.5 H,
Cl3CCH2), 5.06Ϫ5.19 (m, 1 H, CH2CHOCϭO), 7.01 (d, J ϭ
8.3 Hz, 1 H, ArϪH), 7.27 (t, J ϭ 8.0 Hz, 1 H, ArϪH), 7.61 (dd,
J ϭ 8.0, 1.0 Hz, 0.5 H, ArϪH), 7.63 (d, J ϭ8.0 Hz, 0.5 H, ArϪH).
(S)-(؉)-5-Methoxy-2-{2Ј-(2ЈЈ,2ЈЈ,2ЈЈ-trichloroethoxycarbonyl)- Because the obtained material was an inseparable diastereomeric
oxy}propyl-1,4-naphthalenedione (7). ؊ (i) Alkylation with (S)-(؊)- mixture, it was impossible to assign each NMR peak correctly at
Propylene Oxide: A 1.0  solution of LHMDS in n-hexane this stage.
Eur. J. Org. Chem. 2001, 4313Ϫ4319
4315

Y. Tanada, K. Mori
FULL PAPER
(iii) Oxidation with SeO2: A mixture of 6 (16.0 g) and SeO2 (8.7 g,
tion of DEAD (3.00 g, 17.2 mmol) in THF (32 mL) over 2 h under
78 mmol) in 1,4-dioxane (170 mL) was heated under reflux for 11 h Ar at room temperature. The resulting mixture was stirred for 17 h
under Ar. The resulting solution was diluted with EtOAc (500 mL) at room temperature. It was then concentrated in vacuo to give a
and washed with water and brine (each 350 mL). The aqueous
black tar, which was purified twice by chromatography on silica gel
layers were combined and extracted with EtOAc (2 ϫ 500 mL).
{600 g, EtOAc/n-hexane 1:3 as eluent, then 200 g, EtOAc/n-hexane
The organic layers were combined, washed with brine (350 mL), 1:6 as eluent) to give 1.07 g (28%) of 9 as pale yellow powder. This
dried with Na2SO4, filtered, and concentrated in vacuo to give
19.3 g of the crude product as a red oil. This was purified by silica
gel chromatography (1 kg, EtOAc/n-hexane 1:2Ϫ2:3 as an eluent)
was recrystallized from n-hexane to give an analytical sample as
pale yellow plates; m.p. 98.0Ϫ99.0 °C (n-hexane). Ϫ [α]2D6 ϭ Ϫ14.0
(c ϭ 1.00 in MeOH). Ϫ IR (KBr): νmax ϭ 3450 cmϪ1 (s, OϪH),
˜
to give 9.58 g [32% from (S)-propylene oxide in 3 steps] of 7 as an 1640 (m, CϭC), 1600 (s, CϭC), 1515 (m, CϭC). Ϫ 1H NMR
amorphous and sticky solid; [α]2D6 ϭ ϩ17.4 (c ϭ 0.57 in CHCl3). Ϫ
(400 MHz, CDCl3): δ ϭ 1.52 (d, J ϭ 6.3 Hz, 3 H, CH3CH), 2.93
IR (KBr): νmax ϭ 1755 (s, OϪCϭO), 1660 (s, CϭO), 1630 (s, Cϭ (dd, J ϭ 15.0, 7.8 Hz, 1 H, CH2CH), 3.42 (dd, J ϭ 15.0, 9.0 Hz, 1
˜
1
C), 1590 (s, CϭC). Ϫ H NMR (400 MHz, CDCl3): δ ϭ 1.43 (d, H, CH2CH), 4.04 (s,
3 H, CH3O), 5.00Ϫ5.10 (m, 1 H,
J ϭ 6.4 Hz, 3 H, CH3CH), 2.72 (ddd, J ϭ 14.0, 8.8 Hz, 0.8 Hz, 1 CH2CHOAr), 6.72 (d, J ϭ 7.6 Hz 1 H, ArϪH), 6.75 (s, 1 H,
H, CH2CH), 2.96 (ddd, J ϭ 14.0, 4.4 Hz, 0.8 Hz, 1 H, CH2CH), ArϪH), 7.27 (dd, J ϭ 8.5, 7.6 Hz, 1 H, ArϪH), 7.48 (dd, J ϭ 8.5,
4.00 (s, 3 H, CH3O), 4.69 (s, 2 H, Cl3CCH2O), 5.09Ϫ5.19 (m, 1 H, 1.0 Hz, 1 H, ArϪH), 8.93 (s, 1 H, ArϪOH). Ϫ 13C NMR
CH3CHOCϭO), 6.76 (s, 1 H, COϪCHϭC), 7.30 (dd, J ϭ 8.4 Hz, (100 MHz, CDCl3): δ ϭ 21.9, 38.4, 55.9, 79.6, 103.6, 107.1, 113.9,
0.8 Hz, 1 H, ArϪH), 7.68 (dd, J ϭ 8.4, 7.6 Hz, 1 H, ArϪH), 7.76 115.4, 121.7, 121.8, 125.2, 147.5, 148.2, 156.2. Ϫ C14H14O3 (230.3)
(dd, J ϭ 7.6, 0.8 Hz, 1 H, ArϪH). Ϫ 13C NMR (100 MHz, CDCl3): calcd. C 73.03, H 6.13; found C 73.36, H 6.22.
δ ϭ 20.1, 35.7, 56.3, 74.3, 76.3, 94.2, 117.7, 119.3, 119.5, 134.0,
(R)-(؉)-2,3-Dihydro-6-methoxy-2-methylnaphtho[1,2-b]furan-4,5-
dione [(؉)-Nocardione B (2)]: To a solution of (PhSeO)2O (865 mg,
3.8 mmol) in THF (10 mL), heated at 49 °C, was added a solution
of 9 (2.00 g, 5.0 mmol) in THF (8.5 mL) dropwise through a drop-
ping funnel under Ar. The resulting mixture was stirred for 0.5 h
at 50Ϯ1 °C, then cooled to room temperature and diluted with
EtOAc (150 mL). The EtOAc solution was washed with water
(100 mL), sat. aq NaHCO3, (100 mL), and brine (100 mL). The
aqueous layers were combined and extracted with EtOAc (2 ϫ
150 mL). The organic solutions were combined, washed with brine
(100 mL), dried with Na2SO4, filtered, and concentrated in vacuo
to give 2.38 g of an orange powder. This was purified twice by
chromatography on silica gel {Kanto Chemical silica gel 60N
(spherical, neutral) 270 g, EtOAc/n-hexane 1:1Ϫ3:1 as eluent, then
Kanto Chemical silica gel 60N (spherical, neutral) 350 g, EtOAc/
n-hexane 3:1 as eluent} to give 649 mg (71%) of 2 as an orange
powder. This was recrystallized from EtOAc/n-hexane to give an
analytical sample of 2 as orange needles; m.p. 156.0Ϫ157.0 °C
(EtOAc/n-hexane). {ref.[1] m.p. 79Ϫ81 °C}. Ϫ [α]2D7 ϭ ϩ72.6 (c ϭ
0.32 in CHCl3). {ref.[1] [α]2D7 ϭ Ϫ29.8 (c ϭ 0.32 in CHCl3)}. Ϫ IR
134.7, 138.9, 143.6, 153.3, 159.3, 183.8, 184.8. Ϫ C17H15Cl3O6
(421.7) calcd. C 48.42, H 3.59; found C 48.52, H 3.64.
(S)-(؉)-2-(2Ј-Hydroxypropyl)-5-methoxy-1,4-naphthalenediol (8):
To a degassed solution of 7 (9.28 g, 22 mmol) in AcOH (45 mL),
which was well cooled in an ice bath, was added powdered zinc
(9.0 g, 138 mmol) in one portion. The ice bath was removed and
the resulting suspension was stirred vigorously at room temperature
for 1 h under Ar. The mixture was diluted with EtOAc (700 mL)
and washed with sat. aq. NaHCO3 (2 ϫ 200 mL), water (1 ϫ
200 mL), and brine (1 ϫ 200 mL). The aqueous layers were com-
bined and extracted with EtOAc (400 mL). The second extract was
washed with brine (1 ϫ 200 mL). All the organic layers were com-
bined, dried with Na2SO4 under Ar, filtered, and concentrated in
vacuo to give 8.26 g of the crude product as a black oil. This was
purified by chromatography on silica gel (830 g, EtOAc/n-hexane
1:3Ϫ1:0 as eluent) to give 6.10 g of a dark red oil. (At this point,
TLC analysis showed that the obtained product had been partially
oxidized to quinone in the course of the purification operations.
The crude product was therefore reduced to obtain a single hydro-
quinone product employing the following conditions). The ob-
tained oil and 10% Pd/C (600 mg) in EtOAc (30 mL) were vigor-
ously stirred at room temperature under H2. The mixture was fil-
tered and the filtrate was concentrated in vacuo to give 5.58 g of a
gummy product. This was crystallized from EtOAc/n-hexane to
give 4.99 g of a solid, which was well washed with Et2O/n-pentane
(1:3) to give 4.42 g (81%) of pale brown powder. This was recrystal-
lized from benzene/n-hexane to give an analytical sample of 8 as
pale brown powder; m.p. 109.0Ϫ110.0 °C (benzene/n-hexane). Ϫ
[α]2D7 ϭ ϩ14.9 (c ϭ 0.545 in MeOH). Ϫ IR (KBr): ν˜max ϭ 3400
cmϪ1 (s, OϪH), 3300Ϫ2200 (br, OϪH), 1640 (m, CϭC), 1610(s,
CϭC), 1515 (m, CϭC). Ϫ 1H NMR (400 MHz, CD3OD): δ ϭ 1.18
(d, J ϭ 6.1 Hz, 3 H, CH3CH), 2.80 (dd, J ϭ 14.0, 6.6 Hz, 1 H,
CH2CH), 2.85 (dd, J ϭ 14.0, 4.6 Hz, 1 H, CH2CH), 3.97 (s, 3 H,
CH3O), 4.05Ϫ4.17 (m, 1 H, CHOH), 6.55 (s, 1 H, ArϪH), 6.79 (d,
J ϭ 8.0 Hz, 1 H, ArϪH), 7.24 (t, J ϭ 8.0 Hz, 1 H, ArϪH), 7.75
(d, J ϭ 8.0 Hz, 1 H, ArϪH). Ϫ 13C NMR (100 MHz, CD3OD):
δ ϭ 23.1, 41.7, 56.5, 70.1, 105.0, 113.9, 115.5, 116.9, 123.2, 126.0,
129.6, 144.1, 148.2, 157.3. Ϫ C14H16O4 (248.3) calcd. C 67.73, H
6.50; found C 67.72, H 6.47.
˜
(KBr): νmax ϭ 1690 (m, CϭO), 1660 (s, CϭO), 1620 (s, CϭC),
1580 (s, CϭC), 1465 (s, CϭC), 1405 (m), 1300 (s), 1275 (w), 1250
(w, CϪ OϪC), 1035 (s, CϪ OϪC), 900 (m), 800 (m). {ref.[1] IR
(KBr): νmax ϭ 1650, 1620, 1580, 1300, 1270, 1030.} Ϫ 1H NMR
˜
(400 MHz, CDCl3): δ ϭ 1.56 (d, J ϭ 6.4 Hz, 3 H, CH3CH), 2.72
(dd, J ϭ 15.0, 7.3 Hz, 1 H, CH2CH), 3.26 (dd, J ϭ 15.0, 9.8 Hz, 1
H, CH2CH), 3.99 (s,
3 H, CH3O), 5.17Ϫ5.27 (m, 1 H,
CH2CHOAr), 7.17 (d, J ϭ 8.8 Hz 1 H, ArϪH), 7.28 (d, J ϭ 7.3 Hz
1 H, ArϪH), 7.59 (dd, J ϭ 8.8, 7.3 Hz, 1 H, ArϪH). {ref.[1] 1H
NMR (400 MHz, CDCl3): δ ϭ 1.56 (d, J ϭ 6.3 Hz, 3 H, CH3CH),
2.71 (dd, J ϭ 15.2, 7.3 Hz, 1 H, CH2CH), 3.25 (dd, J ϭ 15.2,
9.6 Hz, 1 H, CH2CH), 3.98 (s, 3 H, CH3O), 5.22 (m, 1 H,
CH2CHOAr), 7.17 (d, J ϭ 8.5 Hz, 1 H, ArϪH), 7.27 (d, J ϭ
8.3 Hz, 1 H, ArϪH), 7.58 (t, J ϭ 8.3 Hz, 1 H, ArϪH).}Ϫ 13C
NMR (100 MHz, CDCl3): δ ϭ 22.0 (10-C), 33.6 (3-C), 56.4 (6-
OCH3), 84.1 (2-C), 114.6 (3a-C), 116.6 (9-C), 117.3 (7-C), 118.1
(5a-C), 129.7 (9a-C), 135.8 (8-C), 161.8 (6-C), 169.2 (9b-C), 175.6
(4-C), 180.4 (5-C). {ref.[1] 13C NMR: (100 MHz, CDCl3): δ ϭ 21.9
(10-C), 33.5 (3-C), 56.2 (6-OCH3), 84.1 (2-C), 114.3 (3a-C), 116.7
(9-C), 117.3 (7-C), 118.1 (5a-C), 129.5 (9a-C), 135.8 (8-C), 161.8
(6-C), 169.3 (9b-C), 175.5 (4-C), 180.2 (5-C)}. The signals due to
(R)-(؊)-2,3-Dihydro-6-methoxy-2-methylnaphtho[1,2-b]furan-5-ol 3a-C and 5a-C were assigned on the basis of HMBC experiments.
1
(9): To a degassed solution of Ph3P (4.52 g, 17.2 mmol) and 8
(4.07 g, 16.4 mmol) in THF (400 mL) was added, dropwise, a solu- tional peaks due to unknown impurities. Ϫ C14H12O4 (244.2) calcd.
The H and 13C NMR spectra of the natural (Ϫ)-2 contain addi-
4316
Eur. J. Org. Chem. 2001, 4313Ϫ4319

Synthesis and Absolute Configuration of Nocardione A and B
FULL PAPER
C 68.85, H 4.95; found C 68.92, H 5.12. Ϫ UV-Vis (MeOH) λmax
15 min, and then Sc(OTf)3 (5.0 g, 10.3 mmol) was added in one
(ε): 230 (22000), 259 (20000), 397 (6000). {ref.[1] 201 (20300), 230 portion. The resulting mixture was stirred at room temperature un-
(15900), 258 (13200), 395 (3700)}. Ϫ UV-Vis (0.01  HCl: MeOH der Ar for 21 h. The mixture was cooled in an ice bath, quenched
1:9) λmax (ε): 231 (20000), 259 (19000), 400 (5800). {ref.[1] 233 with sat. aq. NH4Cl (300 mL), and filtered through a celite pad.
(13600), 258 (13500), 396 (4000)}. Ϫ UV-Vis (0.01  NaOH/MeOH The residue on the pad was washed with EtOAc (300 mL). The
1:9) λmax (ε): 230 (19000), 259 (18000), 400 (5300). {ref.[1] 207 biphasic filtrate was separated. The upper organic phase was
(8300), 231 (11900), 259 (11300), 396 (3000)}. Ϫ The HPLC condi- washed with 5% HCl and brine (each 300 mL). All the aqueous
tions were as follows: Column, Daicel Chiralpak AD Ϫ RH
layers were combined and extracted with EtOAc (300 mL). All the
(4.6 mm ϫ150 mm); eluent, H2O/MeCN (2:1); flow rate, 0.6 mL/ organic layers were combined, dried with Na2SO4, filtered, and
min; Detection at λ ϭ 230 nm; sample concentration and injection
volume, 0.1 mg/mL in MeCN solution ϫ 0.5 µL. Under these con-
ditions, (S)-2 was detected at tR ϭ 15.4 min, and (R)-2 was detected
at tR ϭ 18.9 min, ca.100% ee.
concentrated in vacuo to give 83.7 g of the crude product. This
was purified by silica gel chromatography (1 kg, EtOAc/n-hexane,
1:4Ϫ1:2) to give 20.2 g of an inseparable diastereomeric mixture of
12 as a pale orange solid. Ϫ IR (KBr): ν˜max ϭ 3300 (s, OH), 1680
1
(s, CϭO), 1595 (s, CϭC), 1580 (s, CϭC). Ϫ H NMR (400 MHz,
(؎)-2,3-Dihydro-6-hydroxy-2-methylnaphtho[1,2-b]furan-4,5-dione
[(؎)-Nocardione A (1)]: To a solution of (ϩ)-2 (250 mg, 1.02 mmol)
in CH2Cl2 (7.5 mL) in an ice bath was added finely powdered AlCl3
(2.05 g, 15.4 mmol) in one portion. The resulting mixture was vig-
orously stirred at room temperature for 13.5 h, and then poured
into crashed-ice/water (100 mL). To this mixture was added conc.
HCl (100 mL). After having been stirred vigorously for several mi-
nutes, the mixture was extracted with EtOAc (2 ϫ 150 mL). The
extracts were combined, washed with brine (250 mL), dried with
Na2SO4, filtered, and concentrated in vacuo to give 249 mg of
crude (Ϯ)-1. This was purified by chromatography on silica gel
(30 g, CHCl3/EtOAc 10:1 as an eluent) to give 236 mg of (Ϯ)-1 as
a dark red powder {quant., 5.1% in 7 steps from (S)-4.}. This was
recrystallized from EtOAc/n-hexane to give an analytical sample of
(Ϯ)-1 as dark red needles: m.p. 156.0Ϫ157.0 °C (EtOAc/n-hexane).
CDCl3): δ ϭ 1.23 (d, J ϭ 6.3 Hz, 1.2 H, CH3CH), 1.27 (d, J ϭ
6.1 Hz, 1.5 H, CH3CH), 1.43 (d, J ϭ 6.3 Hz, 0.3 H, CH3CH), 1.52
(ddd, J ϭ 15.0, 5.1 Hz, 2.7 Hz, 0.5 H), 1.56Ϫ1.65 (m, 0.5 H),
1.83Ϫ2.01 (m, 0.5 H), 2.01Ϫ2.16 (m, 1 H), 2.17Ϫ2.40 (m, 1.5 H),
2.66Ϫ3.03 (m, 2 H), 3.15 (dt, J ϭ 18.0, 5.1 Hz, 0.5 H), 3.20 (dt,
J ϭ 18.0, 4.2 Hz, 0.5 H), 3.90Ϫ4.06 (m, 1 H), 5.09 (d, J ϭ 12.0 Hz,
1 H, ArCH2O), 5.13 (d, J ϭ 12.0 Hz, 1 H, ArCH2O), 7.09 (d, J ϭ
8.3 Hz, 1 H, ArϪH), 7.26 (t, J ϭ 8.0 Hz, 1 H, BnOArϪH),
7.35Ϫ7.47 (m, 5 H, ArϪH), 7.65 (dd, J ϭ 8.3, 1.0 Hz, 0.5 H,
BnOArϪH), 7.67 (dd, J ϭ8.3, 1.0 Hz, 0.5 H, BnOArϪH). Since
the obtained material was a diastereomeric mixture, it was imposs-
ible to assign each NMR peak correctly at this stage. Ϫ HRMS
(EI) [Mϩ] (C20H22O3): calcd. 310.1569; found 310.1569.
(ii) Protection of the Hydroxy Group of 12: To an ice-cooled solu-
tion of 12 (20.0 g) and pyridine (11.4 g, 142 mmol) in CH2Cl2
˜
Ϫ IR (KBr): νmax ϭ 1660 (sh., CϭO), 1640 (s, CϭO), 1615 (s, Cϭ
C), 1580 (s, CϭC), 1480 (m), 1450 (s), 1410 (m), 1305 (s), 1240 (m, (125 mL) was added a solution of 2,2,2-trichloroethyl chloro-
CϪ OϪC), 1030 (s, CϪ OϪC). Ϫ 1H NMR (400 MHz, CDCl3): formate (16.4 g, 25 mmol) in CH2Cl2 (25 mL) over 20 min. The re-
δ ϭ 1.57 (d, J ϭ 6.4 Hz, 3 H, CH3CH), 2.72 (dd, J ϭ 15.6, 7.2 Hz, sulting mixture was stirred for 1 h, and then concentrated in vacuo
1 H, CH2CH), 3.26 (dd, J ϭ 15.6, 10 Hz, 1 H, CH2CH), 5.20Ϫ5.27 to1/4 volume. This was diluted with EtOAc (300 mL). The EtOAc
(m, 1 H, CH2CHOAr), 7.11 (dd, J ϭ 8.8, 0.8 Hz, 1 H, ArϪH), solution was washed with water (2 ϫ 200 mL) and brine (200 mL),
7.19 (dd, J ϭ 7.2, 0.8 Hz, 1 H, ArϪH), 7.53 (dd, J ϭ 8.8, 7.2 Hz,
dried with Na2SO4, filtered, and concentrated to give 47.0 g of a
1 H, ArϪH), 11.9 (s, 1 H, OϪH). {ref.[1] 1H NMR (400 MHz, crude product as an oil. This was purified by silica gel chromato-
CDCl3): δ ϭ 1.57 (d, J ϭ 6.4 Hz, 3 H, CH3CH), 2.73 (dd, J ϭ graphy (400 g, EtOAc/n-hexane 1:3 as eluent) to give 19.1 g of pure
15.6, 7.3 Hz, 1 H, CH2CH), 3.27 (dd, J ϭ 15.6, 9.8 Hz, 1 H, fractions as a solid and 13.8 g of impure fractions as an oil. The
CH2CH), 5.25 (m, 1 H, CH2CHOAr), 7.13 (d, J ϭ 8.8 Hz, 1 H, latter was further purified by silica gel chromatography (300 g,
ArϪH), 7.2 (d, J ϭ 7.3 Hz, 1 H, ArϪH), 7.54 (dd, J ϭ 8.8, 7.3 Hz,
EtOAc/n-hexane 1:7 as eluent) to give 8.08 g of pure fractions as
1 H, ArϪH), 11.95 (s, 1 H, OϪH).} Ϫ 13C NMR (100 MHz, an oil. All of the pure fractions were combined, which solidified to
CDCl3): δ ϭ 22.0 (10-C), 33.5 (3-C), 84.6 (2-C), 113.4 (5a-C), 115.2 give 27.0 g of an inseparable and sticky diastereomeric mixture of
(3a-C), 117.6 (9-C), 123.3 (7-C), 127.4 (9a-C), 137.6 (8-C), 164.4 13. Ϫ IR (KBr): ν˜max ϭ 1745 (s, OϪCϭO), 1680 (s, CϭO), 1600
(6-C), 169.2 (9b-C), 175.0 (4-C), 185.4 (5-C). {ref.[1] 13C NMR
(m, CϭC), 1585 (s, CϭC). Ϫ 1H NMR (400 MHz, CDCl3): δ ϭ
(100 MHz, CDCl3): δ ϭ 22.45 (10-C), 34.04 (3-C), 85.04 (2-C), 1.406 (d, J ϭ 6.3 Hz, 1.5 H, CH3CH), 1.413 (d, J ϭ 6.3 Hz, 1.5 H,
113.99 (5a-C), 115.67 (3a-C), 117.98 (9-C), 123.77 (7-C), 128.0 (9a- CH3CH), 1.64 (ddd, J ϭ 15.0, 8.6 Hz, 3.9 Hz, 0.34 H), 1.73 (ddd,
C), 138.03 (8-C), 164.96 (6-C), 169.58 (9b-C), 175.53 (4-C), 185.93 J ϭ 15.0, 9.0 Hz, 4.9 Hz, 0.31 H), 1.79Ϫ1.95 (m, 0.72 H),
1
(5-C)}. The H and 13C NMR spectra were identical with those of 2.20Ϫ2.29 (m, 0.75 H), 2.35 (ddd, J ϭ 13.0, 8.8 Hz, 4.4 Hz, 0.54
the natural (Ϫ)-1, although in the 1H NMR spectrum of (Ϫ)-1,
some signals due to impurities were observable. Ϫ C13H10O4 (230.2)
calcd. C 67.82, H 4.38; found C 67.85, H 4.47. Ϫ The product was
nearly racemic, as revealed by its HPLC analysis on Chiralpak AD-
H), 2.52 (ddd, J ϭ 15.0, 9.5 Hz, 4.6 Hz, 0.56 H), 2.59Ϫ2.69 (m, 1
H), 2.74Ϫ2.89 (m, 1 H), 3.13Ϫ3.23 (m, 1 H), 4.72 (d, J ϭ 12.0 Hz,
0.5 H, Cl3CCH2), 4.75 (d, J ϭ 12.0 Hz, 0.5 H, Cl3CCH2), 4.78 (d,
J ϭ 12.0 Hz, 0.5 H, Cl3CCH2), 4.79 (d, J ϭ 12.0 Hz, 0.5 H,
RH
(vide infra). Experimental [α]D value of the product was Cl3CCH2), 5.06Ϫ5.19 (m, 1 H, CH2CHOCϭO), 5.09 (d, J ϭ
[α]2D6ϭ ϩ0.7 (c ϭ 0.36, CHCl3).
12.0 Hz, 1 H, ArOCH2), 5.12 (d, J ϭ 12.0 Hz, 1 H, ArOCH2), 7.08
(dd, J ϭ 8.3, 1.0 Hz, 1 H, BnOArϪH), 7.26 (t, J ϭ 7.9 Hz, 1 H,
BnOArϪH), 7.35Ϫ7.47 (m, 5 H, ArϪH), 7.63 (dd, J ϭ 7.8, 1.0 Hz,
0.5 H, BnOArϪH), 7.65 (dd, J ϭ7.8, 1.0 Hz, 0.5 H, BnOArϪH).
Since the product was an inseparable diastereomeric mixture, it was
impossible to assign each NMR peak correctly at this stage. Ϫ
HRMS (EI) [Mϩ] (C23H23Cl3O5): calcd. 484.0611; found 484.0618.
(R)-(؊)-5-Benzyloxy-2-[2Ј-(2ЈЈ,2ЈЈ,2ЈЈ-trichloroethoxycarbonyl)-
oxy]propyl-1,4-naphthalenedione (14). ؊ (i) Alkylation with (R)-(؉)-
Propylene Oxide: A 1.0  LHMDS in n-hexane solution (308 mL)
was cooled in an ice/MeOH bath at Ϫ5Ϫ0 °C. To this solution
was added a solution of 11 (64.6 g, 256 mmol) in toluene (250 mL)
dropwise via cannula over 1.0 h under Ar. After having been stirred
for 1 h at Ϫ4Ϫ0 °C, a solution of (R)-(ϩ)-propylene oxide (5.97 g, (iii) Oxidation with SeO2: A mixture of 13 (26.8 g) and SeO2
103 mmol) in toluene (50 mL) was added dropwise via cannula over
(12.2 g, 110 mmol) in 1,4-dioxane (240 mL) was heated under re-
Eur. J. Org. Chem. 2001, 4313Ϫ4319
4317

Y. Tanada, K. Mori
FULL PAPER
flux for 15 h. The resulting solution was diluted with EtOAc (9.2 g, 28.4 mmol) in THF (920 mL) was added a solution of
(1000 mL), and washed with water and brine (each 500 mL). The DEAD (5.2 g, 29.8 mmol) in THF (80 mL), dropwise over 2 h un-
aqueous layers were combined, and extracted with EtOAc
der Ar at room temperature. The resulting mixture was stirred for
(750 mL). The organic layers were combined, dried with Na2SO4, 3 h at room temperature. An additional portion of DEAD (0.52 g,
filtered, and concentrated in vacuo to give 34.3 g of the crude prod- 3.0 mmol)/Ph3P (0.78 g, 3.0 mmol) in THF (1 mL) was added to
uct as a red oil. This was purified by silica gel chromatography
the solution. After 16 h stirring under Ar at room temperature, the
(1 kg, EtOAc/n-hexane 1:3 as eluent) to give 15.9 g of pure fractions solution was concentrated in vacuo to give a black tar. This was
and 6.3 g of impure fractions. The latter was further purified by
silica gel chromatography {Kanto Chemical silica gel 60N (spher-
ical, neutral) 560 g, EtOAc/n-hexane 1:3 as eluent} to give pure
fractions. All of the pure fractions were combined and kept in va-
cuo to give 18.0 g of 14 as a red amorphous and sticky solid. [36%
from (R)-propylene oxide in 3 steps]; [α]2D5 ϭ Ϫ17.6 (c ϭ 1.22 in
purified twice by chromatography on silica gel (500 g, EtOAc/n-
hexane 1:1 as eluent, then 250 g, EtOAc/n-hexane 1:8 as eluent) to
give 1.65 g (19%) of 16 as colorless flakes. These were recrystallized
from EtOAc to give an analytical sample of 16 as colorless flakes;
m.p. 143.5Ϫ144.5 °C (EtOAc). Ϫ [α]2D9 ϭ Ϫ2.22 (c ϭ 1.03 in
CHCl3). Ϫ IR (KBr): ν˜max ϭ 3400 (s, OH), 1640 (m, CϭC), 1605
MeOH). Ϫ IR (KBr): νmax ϭ 1755 (s, OϪCϭO), 1660 (s, CϭO), (s, CϭC), 1520 (m, CϭC). Ϫ 1H NMR (400 MHz, CDCl3): δ ϭ
1630 (s, CϭC), 1585 (s, CϭC). Ϫ 1H NMR (400 MHz, CDCl3): 1.52 (d, J ϭ 6.3 Hz, 3 H, CH3CH), 2.93 (dd, J ϭ 15.0, 7.6 Hz, 1
δ ϭ 1.44 (d, J ϭ 6.4 Hz, 3 H, CH3CH), 2.73 (ddd, J ϭ 14.0, 8.6 Hz, H, CH2CH), 3.42 (dd, J ϭ 15.0, 8.8 Hz, 1 H, CH2CH), 5.00Ϫ5.01
˜
0.8 Hz, 1 H, CH2CH), 2.98 (ddd, J ϭ 14.0, 4.2 Hz, 1.2 Hz, 1 H,
(m, 1 H, CH2CHCH3), 5.25 (s, 2 H, ArOCH2ϪAr), 6.72 (s, 1 H,
CH2CH), 4.71 (s, 2 H, Cl3CCH2), 5.10Ϫ5.19 (m, 1 H, CHOCϭO), ArϪH), 6.81 (d, J ϭ 7.6 Hz, 1 H, BnOArϪH), 7.26 (t, J ϭ 7.8 Hz,
5.31 (s, 2 H, ArOCH2ϪAr), 6.78 (s, 1 H, COϪCHϭC), 7.32 (d,
1 H, BnOArϪH), 7.35Ϫ7.55 (m, 6 H, ArϪH, BnOArϪH), 8.99 (s,
J ϭ 8.3 Hz, 1 H, BnOArϪH), 7.34 (t, J ϭ 7.4 Hz, 1 H, ArϪH), 1 H, OH). Ϫ 13C NMR (100 MHz, CDCl3): δ ϭ 22.0, 38.4, 71.5,
7.42 (t, J ϭ 7.4 Hz, 2 H, ArϪH), 7.57 (d, J ϭ 7.4 Hz, 2 H, ArϪH), 79.7, 105.0, 107.2, 114.1, 115.6, 121.7, 121.9, 125.2, 128.0, 128.8,
7.63 (dd, J ϭ 8.3, 7.4 Hz, 1 H, BnOArϪH), 7.66 (dd, J ϭ 8.3, 129.0, 135.3, 147.5, 148.2, 155.4. Ϫ C20H18O3 (306.4) calcd. C
1.0 Hz, 1 H, BnOArϪH). Ϫ 13C NMR (100 MHz, CD3OD): δ ϭ
20.5, 37.2, 71.6, 75.7, 77.5, 96.1, 120.5, 121.1, 121.2, 128.0, 128.5,
128.9, 129.5, 135.6, 136.1, 137.9, 140.0, 145.9, 155.1, 159.7, 185.5,
186.0. Ϫ C23H19Cl3O6 (497.8) calcd. C 55.50, H 3.85; found C
55.60, H 4.10.
78.41, H 5.92; found C 78.41, H 6.14.
(S)-(؊)-6-Benzyloxy-2,3-dihydro--2-methylnaphtho[1,2-b]furan-4,5-
dione (17): To a solution of (PhSeO)2O (2.78 g, 5.4 mmol) in THF
(44 mL), heated at 50 °C, was added a solution of 16 (1.53 g,
5.0 mmol) in THF (44 mL) dropwise through a cannula under Ar.
The resulting mixture was stirred for 0.5 h at 50 °C, then cooled to
room temperature and diluted with EtOAc (350 mL). The EtOAc
(S)-(؊)-5-Benzyloxy-2-(2Ј-hydroxypropyl)-1,4-naphthalenediol (15):
To a well ice-cooled and degassed solution of 14 (17.8 g, 36 mmol)
in AcOH (85 mL) was added powdered zinc (17.8 g, 272 mmol) in solution was washed with water (150 mL), sat. aq NaHCO3
one portion. After removal of the ice bath, the resulting suspension (150 mL), and brine (150 mL). All of the aqueous layers were com-
was stirred at room temperature for 2 h under Ar. An additional
portion of powdered zinc (2 g) was added. After having been stirred
bined and extracted with EtOAc (2 ϫ200 mL). The organic layers
were combined, dried with Na2SO4, filtered, and concentrated in
for an additional 20 min, the mixture was filtered. The solid residue vacuo to give 3.0 g of an orange solid. This was purified by chroma-
was washed well with EtOAc (500 mL). The filtrates were com- tography on silica gel (80 g, EtOAc/n-hexane 1:1Ϫ3:1 as eluent) to
bined and washed with water (2 ϫ 250 mL). All of the aqueous give 1.24 g (78%) of 17 as an orange powder. This was recrystallized
layers were combined and extracted with EtOAc (250 mL). The from CHCl3/n-hexane to give an analytical sample of 17 as an or-
organic layers were combined, washed with sat. aq. NaHCO3 (2 ange powder; m.p. 202.0Ϫ204.0 °C (CHCl3/n-hexane).
Ϫ
ϫ150 mL), brine (1ϫ200 mL), dried with Na2SO4, filtered, and [α]2D9 ϭ Ϫ52.1 (c ϭ 1.09 in CHCl3). Ϫ IR (KBr): νmax ϭ 1680 (m,
concentrated in vacuo to give 15.7 g of a crude product as a yellow
solid. This was recrystallized from EtOAc/n-hexane to give 5.58 g
˜
CϭO), 1650 (s, CϭO), 1620 (s, CϭC), 1575 (s, CϭC). Ϫ 1H NMR
(400 MHz, CDCl3): δ ϭ 1.57 (d, J ϭ 6.4 Hz, 3 H, CH3CH), 2.73
(48%) from the first crop of 15 and 2.68 g (23%) of the second crop (dd, J ϭ 16.0, 7.2 Hz, 1 H, CH2CH), 3.27 (dd, J ϭ 16.0, 9.6 Hz, 1
of 15 as white powder. The mother liquor (3.58 g) was purified by
chromatography on silica gel (EtOAc/n-hexane 1:3 as eluent) to
H, CH2CH), 5.18Ϫ5.26 (m, 1 H, CH2CHO), 5.28 (s, 2 H, ArO-
CH2Ar), 7.22 (d, J ϭ 8.8 Hz 1 H, BnOArϪH), 7.26Ϫ7.31 (m, 2 H,
give 1.66 g of a pale brown solid. This powder was washed thor- BnOArϪH, ArϪH), 7.40 (t, J ϭ 7.6 Hz, 2 H, ArϪH), 7.57 (dd, J ϭ
oughly with Et2O to give 1.16 g (10%) of 15 as faint yellow powder. 8.8, 7.2 Hz, 1 H, BnOArϪH), 7.64 (d, J ϭ 7.6 Hz, 2 H, ArϪH). Ϫ
The total amount of 15 was 9.36 g (81%); m.p. 138.0Ϫ139.0 °C 13C NMR (100 MHz, CDCl3): δ ϭ 22.0, 33.6, 70.5, 84.2, 114.6,
(EtOAc/n-hexane). Ϫ [α]2D7 ϭ Ϫ24.0 (c ϭ 1.00 in CHCl3). Ϫ IR
(KBr): ν˜max ϭ 3400 (s, OH), 1640 (s, CϭC), 1610 (s, CϭC). Ϫ H 169.3, 175.6, 180.1. Ϫ C20H16O4 (320.3) calcd. C 74.99, H 5.03;
NMR (400 MHz, CDCl3): δ ϭ 1.30 (d, J ϭ 6.4 Hz, 3 H, CH3CH), found C 75.03, H 4.86.
2.84 (dd, J ϭ 15.0, 7.1 Hz, 1 H, CH2CH), 2.95 (dd, J ϭ 15.0,
117.6, 118.0, 118.4, 126.5, 127.9, 128.6, 129.7, 135.7, 135.8, 160.7,
1
(S)-(؊)-2,3-Dihydro-6-hydroxy-2-methylnaphtho[1,2-b]furan-4,5-
dione [(S)-(؊)-Nocardione A (1)]: To a solution of 17 (424 mg,
1.3 mmol) in DMF (12 mL) was added 10% Pd/C (200 mg). The
resulting mixture was vigorously stirred under H2 for 6 min at room
temperature until disappearance of the red color of the solution.
Then, the mixture was vigorously stirred for 15 min under air in
order to re-oxidize the substrate at room temperature. The mixture
was filtered through a celite pad. The residue on the celite pad was
washed with hot CHCl3 (4 ϫ 25 mL). The combined filtrates were
diluted with EtOAc (150 mL) and washed with brine (3 ϫ 50 mL).
2.4 Hz, 1 H, CH2CH), 4.29Ϫ4.38 (m, 1 H, CHOH), 5.27 (s, 2 H,
ArOCH2ϪAr), 6.56 (s, 1 H, COϪCHϭC), 6.87 (d, J ϭ 7.8 Hz, 1
H, BnOArϪH), 7.31 (dd, J ϭ 8.5, 7.8 Hz, 1 H, BnOArϪH),
7.35Ϫ7.47 (m, 3 H, ArϪH), 7.47Ϫ7.52 (m, 2 H, ArϪH), 7.90 (dd,
J ϭ 8.5, 7.8 Hz, 1 H, BnOArϪH), 8.93 (s, 1 H, ArOH). Ϫ 13C
NMR (100 MHz, CDCl3): δ ϭ 23.2, 40.3, 70.8, 71.5, 105.3, 113.1,
114.7, 116.6, 120.6, 124.9, 128.0, 128.1, 128.7, 128.9, 135.4, 143.4,
147.0, 155.0. Ϫ C20H20O4 (324.4) calcd. C 74.06, H 6.21; found C
74.13, H 6.57.
(S)-(؊)-6-Benzyloxy-2,3-dihydro-2-methylnaphtho[1,2-b]furan-5-ol The aqueous layers were combined and extracted with EtOAc (2
(16): To a degassed solution of Ph3P (7.8 g, 29.8 mmol) and 15
ϫ 50 mL) again. All of the extracts were combined, dried with
4318
Eur. J. Org. Chem. 2001, 4313Ϫ4319

Synthesis and Absolute Configuration of Nocardione A and B
FULL PAPER
Na2SO4, filtered, and concentrated in vacuo to give 1.13 g of a
crude oil. This was purified by chromatography on silica gel [Kanto
Chemical silica gel 60N (spherical, neutral) 80 g, EtOAc/n-hexane
1:1 as eluent] to give 152 mg of (S)-1 as red powder. {50%, 2.2% in
7 steps from (R)-4}; properties of (S)-1: dark red needles (EtOAc/n-
Acknowledgments
Our thanks are due to Prof. Y. Igarashi (Toyama Prefectural Uni-
versity) for kindly sending to us copies of UV, IR, 1H, and 13C
NMR spectra of natural nocardiones A and B. This work was fin-
ancially supported by Otsuka Pharmaceutical Co.
hexane): m.p. 172.5Ϫ173.5 °C {ref.[1] m.p. 115Ϫ120 °C}, [α]2D1
ϭ
Ϫ56.0 (c ϭ 0.97 in CHCl3), {ref.[1] [α]2D0 ϭ Ϫ85.4 (c ϭ 1.0 in
CHCl3)}. Ϫ C13H10O4 (230.2) calcd. C 67.82, H 4.38; found C
67.54, H 4.32. Ϫ UV-Vis (MeOH) λmax (ε): 259 (18000), 414
(4400). {ref.[1] 203 (16400), 237 (15100), 259 (18000), 416 (4900)}.
Ϫ UV-Vis (0.01  HCl/MeOH 1:9) λmax (ε): 260 (17000), 291
(5400), 415 (4300). {ref.[1] 237 (16000), 259 (18300), 415 (5000).}.
Ϫ UV-Vis (0.01  NaOH/MeOH 1:9) λmax (ε): 237 (15000), 259
(12000), 473 (3200). {ref.[1] 205 (15500), 238 (16300), 259 (14400),
474 (4900)}. The IR and NMR spectroscopic data for this com-
pound were in good agreement with those of (Ϯ)-1 and also with
the reported data.[1] The 1H NMR spectrum of the natural product
indicates that it contains some impurities. Ϫ HPLC: The HPLC
conditions were as follows: Column, Daicel Chiralpak AD Ϫ RH
(4.6 mm ϫ150 mm); eluent, H2O/ MeCN (2:1); flow rate, 0.6 mL/
min; Detection at λ ϭ 230 nm; Sample concentration and injection
volume, 0.1 mg/mL in MeCN solution ϫ 0.5µL. Under these con-
ditions, (S)-(Ϫ)-1 was detected at tR ϭ 37.6 min, and (R)-(ϩ)-1 was
detected at tR ϭ 41.4 min: Our synthetic (S)-1 was of ca.100% ee.
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Received May 9, 2001
[O01218]
Eur. J. Org. Chem. 2001, 4313Ϫ4319
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