Asymmetric synthesis of the cis- and trans-3,4-dihydro-2,4,8-trihydroxynaphthalen-1(2H)-ones

Article abstract of DOI:10.1002/hlca.200390014

A short and efficient protocol for the asymmetric synthesis of cis- and trans-3,4-dihydro-2,4,8-trihydroxynaphthalen-1(2H)-one (1 and 2, resp.) is described, with a phthalide annulation as the key step. Introduction of a OH substituent at position 2 was performed by Sharpless dihydroxylation of a silyl enol ether or by means of an N-sulfonyloxaziridine. The absolute configuration of each isomer was determined via Mosherester derivatives. By comparison with previously recorded CD spectra of our natural sample, we established that the natural trans- and cis-isomers from Ceratocystis fimbriata sp. platani were the (-)-(2S,4S)-isomer (-)-2 and the (+)-(2S,4R)-isomer (+)-1, respectively.

Full text of DOI:10.1002/hlca.200390014

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Helvetica Chimica Acta Vol. 86 (2003)
Asymmetric Synthesis of the cis- and trans-3,4-Dihydro-2,4,8-
trihydroxynaphthalen-1(2H)-ones
by Emmanuel Couche¬, Abdellatif Fkyerat, and Raffaele Tabacchi*
¬
√
√
Institut de Chimie, Universite de Neuchatel, Avenue de Bellevaux 51, Case postale 2, CH-2007 Neuchatel
(e-mail: Raphael.Tabacchi@unine.ch)
A
short and efficient protocol for the asymmetric synthesis of cis- and trans-3,4-dihydro-2,4,8-
trihydroxynaphthalen-1(2H)-one (1 and 2, resp.) is described, with a phthalide annulation as the key step.
Introduction of a OHsubstituent at position 2 was performed by Sharpless dihydroxylation of a silyl enol ether
or by means of an N-sulfonyloxaziridine. The absolute configuration of each isomer was determined via Mosher-
ester derivatives. By comparison with previously recorded CD spectra of our natural sample, we established that
the natural trans- and cis-isomers from Ceratocystis fimbriata sp. platani were the (À)-(2S,4S)-isomer (À)-2 and
the (‡)-(2S,4R)-isomer (‡)-1, respectively.
Introduction.
In our investigation of phytotoxic substances produced by
Ceratocystis fimbriata sp. platani, the fungus involved in the canker stain of the plane
tree, we have reported the isolation and structural elucidation by spectroscopic
methods of (‡)-cis- and (À)-trans-3,4-dihydro-2,4,8-trihydroxynaphthalen-1(2H)-ones
((‡)-1 and (À)-2) [1].
These natural naphthalenones are already known as metabolites involved in the
branched pathway of fungal DHN-melanin biosynthesis [2]; a high-molecular-mass
black pigment is arranged into a layer structure between the cell wall and the cell
membrane of the appressorium. Apart from its protective role against the natural
environmental stressors (UV radiations, desiccation, extreme temperatures), the
melanization of the appressorium is essential for the pathogenic virulence of the fungus
[3]. Relatively little work has been reported on metabolites 1 and 2. In previous studies,
Fujimoto and Satoh have extracted the (À)-cis-isomer from Penicillium diversum var.
aureum [4], realized the synthesis of naphthalenones 1 and 2 in racemic form from
juglone, and established the cytotoxic activities of these compounds against Yoshida
sarcoma cells [5]. The lack of regioselectivity and stereoselectivity of their synthesis
and the difficult final separation of the diastereoisomer mixture 1/2 performed by
reversed-phase HPLC, followed by normal-phase HPLC, encouraged us to propose a
new short and efficient protocol for the asymmetric synthesis of these products.

Helvetica Chimica Acta Vol. 86 (2003)
211
For the stereoselective synthesis of naphthalenones 1 and 2, we used the key
intermediate 6 developed by Broom and Sammes [6] for the preparation of
polysubstituted naphthols, performing a tandem Michael-Dieckmann reaction between
phthalide anion 5 and a Michael acceptor. This method was used numerous times in the
synthesis of antitumor antibiotics such as olivomycin A, chrysophanol, or dynemicin A
[7]. In 1997, Bˆs and co-workers used this methodology for the synthesis of O-
methylasparvenone, a serotonin-receptor antagonist [8]. From intermediate 6, two
pathways leading to 1 and 2 can be envisaged (Scheme 1), either an a-hydroxylation
followed by decarboxylation (Pathway A), or decarboxylation followed by oxidation
(Pathway B). Here, we report the total synthesis of cis- and trans-2,4,8-trihydroxy-1-
tetralone 1 and 2 respectively, by Pathways A and B.
Scheme 1. Retrosynthetic Analysis of Naphthalenones 1 and 2
Results and Discussion. Although 7-methoxyphthalide could be synthesized in
three steps in a one-pot procedure from commercially available 3-methoxybenzyl
alcohol [9], the presence of the MeO substituent at the aromatic moiety did not allow
us to obtain the final product during the deprotection step. Therefore, we performed
the key step with 7-(benzyloxy)phthalide 5, which was obtained in two steps in good
yield from ethyl 2-(acetyloxy)-6-(bromomethyl)benzoate (3), the latter being synthe-
sized according to Hamada and co-workers [10] (Scheme 2). The tandem Michael-
Dieckmann reaction of the phthalide carbanion with benzyl acrylate afforded the
1
b-keto ester 6 after acidic hydrolysis. A H-NMR experiment with b-keto ester 6 in
CDCl3 established 26 :36 :38 for the cis-ketonic form/enol form/trans-ketonic form.
Following Pathway A (Scheme 2), we then protected the OHgroup at C(4) of 6, as

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Helvetica Chimica Acta Vol. 86 (2003)
tetrahydro-2H-pyranyl (THP) ether ( ! 7b) prior to the introduction of the OHgroup
by treatment of the corresponding potassium enolate with an oxaziridine [11]. Use of
t
the protecting group THP or BuMe2Si for OHÀC(4) in Pathway A was essential to
avoid the formation of lactone 12 [12]. However, with a benzyloxy group at the
aromatic ring, the protection of OHÀC(4) as a (tert-butyl)dimethylsilyl ether by
t
treatment with BuMe2SiCl and 1H-imidazole in DMF resulted in a low yield of 7a
(15%). Therefore, we continued the synthesis with the THP-protected 7b. Treatment of
its potassium enolate with trans-(Æ)-3-phenyl-2-(phenylsulfonyl)oxaziridine (10) [13]
in THF at low temperature afforded a 77:23 trans/cis-mixture of diastereoisomers
trans-8/8' and cis-8/8' (57% overall yield). In contrast, the use of (‡)-(camphorylsul-
fonyl)oxaziridine (11) [14], allowed us to obtain the products trans-8/8' with worse
diastereoselectivity (de 6%) and a poor 20% yield.
During our work on the introduction of the OHgroup at C(2) with the oxaziridines
10 and 11, we studied the different diastereoselectivities produced by these oxidative
reagents as a function of the protective groups present in derivatives of 6. Thus, we
obtained exclusively the cis-isomer by using oxaziridine 11 and the derivative of 6 with
a tBuMe2SiO group at C(4), a COOBn or COOMe group at C(2), and a MeO group at
C(8) [12].
The last step of Pathway A, the hydrogenolysis with H2 over Pd/C in AcOEt, gave
exclusively the cis-isomer 1 (25%) and a large amount (16%) of by-product 9 starting
from cis-8/8'. Hydrogenolysis of trans-8/8' under the same conditions produced
epimerization at C(2) resulting in a similar mixture of 1 and 9 (7% yield for each).
The key intermediate of Pathway B (Scheme 3) was isosclerone (ˆ 3,4-dihydro-4,8-
dihydroxynaphthalen-1(2H)-one; 13). This product can be obtained by reduction of
juglone with LiAlH4 in THF [5]. However, this method provides a 4 :1 mixture of the
regioisomeric reduction products isosclerone and sclerone (ˆ 3,4-dihydro-4,5-dihy-
droxynaphthalen-1(2H)-one). In 1964, Volkov and co-workers showed that isosclerone
could be obtained exclusively in four steps from juglone [15]. In our case, we obtained
directly 8-(benzyloxy)isosclerone by hydrolysis of the tandem Michael-Dieckmann
reaction mixture containing 6 with distilled water. However, the lack of reproducibility
of yield (25 41%), encouraged us to first hydrogenolyze purified 6 over Pd/C in THF.
After removal of the catalyst, 1% H2O was added to the THF solution, and the mixture
was heated for 5 h at 508 to provide isosclerone (13). Hydrogenolysis in AcOEt as
solvent yielded large amounts of the 4-dehydroxylated product 20.
Silyl enol ether 14 was then obtained from isosclerone (13) on treatment with Et3N,
and (tert-butyl)dimethylsilyl triflate at room temperature in 1,2-dichloroethane. After
purification by column chromatography, 14 was subjected to epoxidation with 3-
chloroperbenzoic acid (m-CPBA) at À158 [16] to give in 67% yield the cis/trans-
isomers 15/16 (56 :44). The latter were treated with Amberlyst 15 in MeOHfor 5 days
at room temperature, whereupon the target racemic cis/trans-mixture 1/2 (59 :41) was
isolated in 55% yield.
We also submitted pure silyl enol ether 14 to asymmetric Sharpless dihydroxylation
[17] at 08 in the presence of (DHQD)2PHAL (ˆ hydroquinine 1,4-phthalazinediyl
ether) or (DHQ)2PHAL (ˆ hydroquinidine 1,4-phthalazinediyl ether), as chiral ligand
and obtained mainly the trans-isomer 18 (de 30 56%). After separation of the
diastereoisomer mixture 17/18, the enantiomer excess and absolute configuration of

Helvetica Chimica Acta Vol. 86 (2003)
213
Scheme 2. Synthesis of 1 by Pathway A (for racemates, only one enantiomer is shown)
a) H2O/dioxane 1:1, D, overnight; >90%. b) BnBr (2 equiv.), K2CO3 (3 equiv.), DMF, r.t., overnight; 65%.
t
c) Lithium diisopropylamide (LDA; 2 equiv.), THF. d) BuMe2SiCl, 1H-imidazole, DMF; 15% of 7a; or 3,4-
dihydro-2H-pyran (3 equiv.), cat. camphorsulfonic acid (CSA), CH2Cl2; 73% of 7b. e) Hexamethyldisilazane
potassium salt (KHMDS; 1 equiv.), (‡)-(camphorsulfonyl)oxaziridine (11) or trans-(Æ)-3-phenyl-2-(phenyl-
sulfonyl)oxaziridine (10; 1.5 equiv.), THF, À78 to À108, 1.5 h; 20 57%. f) H2 (1 atm), 10% Pd/C AcOEt,
overnight, r.t.; 7 25% of 1 and 7 16% of 9
each isomer were determined by formation of their Mosher esters with (À)-(R)MTPCl
((À)-(R)-a-methoxy-a-(trifluoromethyl)benzeneacetyl chloride). The Mosher esters
allowed us to establish that the configuration of the main enantiomer was in accordance
with the Sharpless prediction of the configuration generated upon dihydroxylation of a
trisubstituted olefin [17]. Thus, use of (DHQD)2PHAL gave mainly the (2R,4R)-
isomer (À)-18, and use of (DHQ)2PHAL afforded mainly the (2S,4S)-isomer (‡)-18
(Fig. 1). In 1994, Curran and Ko achieved a 74% ee in the dihydroxylation of the olefin
precursor for the six-membered a-hydroxylactone E-ring of camptothecin [18]. In our
case, the presence of the aromatic moiety outside of the attractive area (SW) combined
t
with the presence of the BuMe2SiO group at C(4) of the substrate seem to be

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Helvetica Chimica Acta Vol. 86 (2003)
Scheme 3. Synthesis of 1 and 2 by Pathway B (for racemates, only one enantiomer is shown)
a) 1. H2 (1 atm), 10% Pd/C, THF, overnight, then removal of Pd/C; 2. additionof 1% H2O, 508, 5 h; 41%. b)
tBuMe2SiOTf (3 equiv.), Et3N (4.5 equiv.), 1,2-dichloroethane; 90%. c) m-CPBA, CH2Cl2, 158; 67% (de 12%);
or K2CO3 (3 equiv.), 2% OSO4, 5% (DHQD)2PHAL or (DHQ)2PHAL, K3[Fe(CN)6], (3 equiv.),
t
methanesulfonamide (1 equiv.), BuOH/H2O 1:1, 08, overnight; 33 39%. d) Amberlyst 15, MeOH, r.t., 5
6
days.
responsible for the low ee (12 30%). However, much to our surprise, the isomer (‡)-
17 obtained with (DHQ)2PHAL exhibited an ee of 94%. These differences of ee could
be attributed to the instability of the Mosher esters in CDCl3 in the presence of
pyridine. However, the nondestructive circular-dichroism measurements confirmed the
above observations. The optical rotations at 546 nm of compounds 17 and in MeOH 18
are given in Table 1 and their CD spectra in Fig. 2.
The products 17 and 18 were deprotected in MeOHwith Amberlyst 15 during 5
days, providing the final compounds 1 and 2, respectively. The rotations of 1 and 2 (see
Table 2) indicate that an inversion of sign occurred between the protected form and the
final product, in the case of the trans-isomers 2, e.g., (‡)-18 was transformed to (À)-2
Table 1. Asymmetric Dihydroxylation of Silyl Enol Ether 14
a
20
Equiv.
OsO4
Ligand
Equiv.
ligand
Products
de [%]
ee [%]
Yield [%]
[a]
)
546
0.02
0.02
AD-mix a
AD-mix b
0.05
0.05
(‡)-17
(‡)-18
(À)-17
(À)-18
30
56
> 94
30
22
33
39
‡ 38.6 Æ 0.7 (c ˆ 0.40)
ca. 0 (c ˆ 0.67)
À 15.7 Æ 1.0 (c ˆ 0.30)
12
À 0.5 Æ 0.3 (c ˆ 1.02)
a) In MeOH; c in g/100 ml.

Helvetica Chimica Acta Vol. 86 (2003)
215
Fig. 1. Asymmetric dihydroxylation of silyl enol ether 14
Fig. 2. CDSpectra a) of (‡)-17 (red) and (À)-17 (blue) and b) of (‡)-18 (blue) and (À)-18 (red)

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Helvetica Chimica Acta Vol. 86 (2003)
([a] determined under the same conditions). However, this sign inversion could be
caused by epimerization of trans compound 18 to cis-isomer 1, which has a higher [a]
than the trans-isomer 2. Thus, if the trans-isomer has a specific rotation [a] ˆ ‡1, the
presence of a few percent of the epimer with higher [a] can reverse the sign of the
sample. The CD spectra of isomers 1 and 2 are similar to those of derivatives 17 and 18,
respectively (see Fig. 2). Finally, comparison with previously recorded CD spectra of
our natural sample established that our natural trans- and cis-isomers were the (À)-
(2S,4S)-isomer (À)-2 and the (‡)-(2S,4R)-isomer (‡)-1.
Table 2. Rotatory Power of Final Product 1 and 2
a
20
Substrat
Products
Yield [%]
de [%]
[a]
)
546
(À)-17
(À)-18
(‡)-17
(‡)-18
(À)-1
(‡)-2
(‡)-1
(À)-2
80
46
92
51
100
52
100
64
À 4.9 Æ 3.7
‡ 3.4 Æ 1.3
‡ 6.2 Æ 1.3
À 11.4 Æ 0.5
(c ˆ 0.082)
(c ˆ 0.090)
(c ˆ 0.240)
(c ˆ 0.630)
a) In MeOH, c in g/100 ml.
Conclusions. An asymmetric synthesis of cis- and trans-2,4,8-trihydroxynaphtha-
len-1(2H)-ones 1 and 2 was achieved, in which Sharpless dihydroxylation of the silyl
enol ether 14 and a tandem Michael-Dieckmann reaction producing 6 were the most
efficient steps. Although the natural anthracycline antibiotics comprising the structure
1 or 2 do not exist, they could be used as building blocks for the synthesis of artificial
anthracyclines of clinical use for the treatment of various human solid tumors and
leukemias.
Financial support from the Swiss National Science Foundation (20-61879.00) is gratefully acknowledged.
Experimental Part
General. Benzyl acrylate was prepared from acryloyl chloride and benzyl alcohol with Et3N in CH2Cl2 and
purified by distillation over hydroquinone monomethyl ether. CC ˆ column chromatography. M.p.: B¸chi 510
melting-point apparatus; corrected. Optical rotations: Perkin-Elmer 241 polarimeter. Circular dichroism:
Jasco 710; [f] (l). IR Spectra: Perkin-Elmer FT-IR 1720; in cmÀ1. NMR Spectra: Bruker AMX-400; d in ppm
rel. to SiMe4, J in Hz. ESI-MS: Finnigan LCQ; in m/z (rel. %). Microanalyses were performed in the
Mikroelementaranalytisches Laboratorium, ETH-Z¸rich.
7-Hydroxyisobenzofuran-1-(3H)-one (ˆ 7-Hydroxyphthalide; 4). To a stirred (stirring bar) soln. of ethyl 2-
(acetyloxy)-6-(bromomethyl)benzoate (25 g, 0.113 mol) [9] in CCl4 (500 ml), N-bromosuccinimide (28 g,
0.124 mol) and benzoyl peroxide (2.6 g, 0.011 mol) were added in small portions. The mixture was heated under
reflux for 4 h, then cooled to r.t., and evaporated to give ethyl 2-(acetyloxy)-6-(bromomethyl)benzoate (3) as a
pale yellow oil. The latter was suspended crude without further purification in H2O/dioxane 1:1 (200 ml) and
then heated under reflux overnight. The solvent was evaporated and the resulting beige solid recrystallized from
petroleum ether (70 908): 13.7 g (81%) of 4. White crystals. M.p. 135 1368. 1H-NMR (200 MHz, CDCl3): 5.35
(s, 2 HÀC(3)); 6.98 (t, J ˆ 8, HÀC(4), HÀC(6)); 7.59 (t, J ˆ 8, HÀC(5)).
7-(Benzyloxy)isobenzofuran-1(3H)-one (ˆ 7-(Benzyloxy)phthalide; 5). To 4 (6 g, 0.04 mol) and K2CO3
(16.6 g, 0.12 mol) in dry DMF under Ar (100 ml), benzyl bromide (9.5 ml, 0.08 mol) was added dropwise at r.t.
The mixture was stirred at r.t. until consumption of the starting material (TLC monitoring) and then poured an
ice (100 g). The pale yellow solid obtained was dissolved in AcOEt, the aq. layer extracted with AcOEt, the
combined org. phase washed with brine (100 ml), dried (MgSO4), and evaporated, and the crude product

Helvetica Chimica Acta Vol. 86 (2003)
217
purified by CC (silica gel, AcOEt/hexane 2 :8): 6.2 g (65%) of 5. Recrystallization from AcOEt/hexane gave
white crystals. M.p. 1098. IR (KBr): 1764s, 1746m, 1616m, 1604m, 1498s, 1489s, 1454s. 1H-NMR (400 MHz,
CDCl3): 5.25 (s, 2 HÀC(3)); 5.35 (s, 2 HÀC(8)); 6.93 (d, J ˆ 8.3, HÀC(6)); 7.01 (dd, J ˆ 0.6, 7.5, HÀC(4)); 7.32
(m, 1 H); 7.39 (m, 2 H); 7.53 (m, 3 H ). 13C-NMR (100 MHz, CDCl3; HETCOR): 69.07 (C(3)); 70.80 (C(8));
112.93 (C(6)); 114.35; 114.39 (C(4)); 127.13; 128.37; 129.10; 136.44; 136.53; 149.82; 158.12 (C(7)); 169.23 (C(1)).
‡
‡
‡
ESI-MS (pos.): 263 ([M ‡ Na] ), 258 ([M ‡ H2O] ); MS-MS of 258: 241 ([M ‡ H] ). Anal. calc. for C15H12O3
(240.26): C 74.99, H5.03; found: C 74.92, H4.96.
Benzyl 8-(Benzyloxy)-1,2,3,4-tetrahydro-4-hydroxy-1-oxonaphthalene-2-carboxylate (6). To a soln. of 5
(2 g, 8.33 ¥ 10À3 mol) in freshly distilled THF (375 ml) at À408 under Ar, 2m lithium diisopropylamide (8.33 ml,
1.67 ¥ 10À2 mol) was added dropwise by syringe ( ! light-orange soln.). After 5 min, a soln. of benzyl acrylate
(1.735 g, 1.07 ¥ 10À2 mol) in dry THF (35 ml) was slowly added by syringe while maintaining the temp. at À408
( ! cloudy and bleached mixture). Then the mixture was allowed to warm to À108 within 1.5 h and quenched by
addition of 1m HCl (100 ml) followed by dist. H2O (100 ml). The aq. layer was extracted with AcOEt (3 Â
150 ml), the combined org. extract washed with brine (100 ml), dried (MgSO4), and evaporated, and the crude
product purified by CC (silica gel, AcOEt/hexane 1:1): 1.13 g (41%) of 6. Pale yellow oil. Rf (AcOEt/hexane
1:1; UV) 0.39. IR (KBr): 3426s, 1739s, 1680m, 1600s, 1271s. 1H-NMR (400 MHz, CDCl3; COSY): cis: 2.44 2.71
(m, 2 HÀC(3)); 3.73 (dd, J ˆ 5.5, 9.4, HÀC(2)); 4.90 5.48 (m, 5 H ); 6.79 7.66 (m, 13 H); enol: 2.80
(m, 2 HÀC(3)); 4.73 (t, J ˆ 6.6, HÀC(4)); 4.90 5.48 (m, 5 H); 6.79 7.66 (m, 13 H); 13.03 (s, OH ); trans:
2.30 2.71 (m, HÀC(3)); 4.15 (dd, J ˆ 5.1, 10.5, HÀC(2)); 4.90 5.48 (m, 5 H); 6.79 7.66 (m, 13 H). ESI-MS
‡
(pos.): 425 ([M ‡ Na] ).
Benzyl 8-(Benzyloxy)-4-{[(tert-butyl)dimethylsilyl]oxy}-1,2,3,4-tetrahydro-1-oxonaphthalene-2-carbox-
ylate (7a). To a mixture of 6 (640 mg, 1.59 ¥ 10À3 mol) and 1H-imidazole (216 mg, 3.18 ¥ 10À3 mol) in dry DMF
(20 ml) at r.t. under Ar, tBuMe2SiCl (478 mg, 3.18 ¥ 10À3 mol) was added with a spatula. The mixture was stirred
at r.t. overnight and poured into ice/2m HCl (15 ml). The aq. layer was extracted with Et2O (3 Â 20 ml), the
combined org. extract washed with brine (2 Â 20 ml) dried (MgSO4), mixed with silica gel, and evaporated, and
the resulting powder purified by CC (silica gel, AcOEt/hexane 1 :4): 120 mg (15%) 7a. Pale yellow oil. 1H-NMR
(400 MHz, CDCl3; COSY): cis: 2.54 (m, 2 HÀC(3)); 3.73 (dd, J ˆ 6.1, 6.9, HÀC(2)); 4.95 (dd, J ˆ 6.9, 7.5,
HÀC(4)); 5.17 5.37 (m, 4 H); 6.96 7.59 (m, 13 H); enol: 0.16 (s, 3 H); 0.19 (s, 3 H); 1.00 (s, 9 H); 2.53 (dd, J ˆ
11.9, 14.7, HÀC(3)); 2.84 (dd, J ˆ 5.5, 14.7, HÀC(3)); 4.80 (dd, J ˆ 5.5, 11.9, HÀC(4)); 5.17 5.37 (m, 4 H );
6.96 7.59 (m, 13 H); 12.98 (s, OH ); trans: 2.41 (dt, J ˆ 6.2, 13.5, HÀC(3)); 2.56 (ddd, J ˆ 3.1, 4.2, 13.5,
HÀC(3)); 4.10 (dd, J ˆ 5.6, 9.0, HÀC(2)); 5.01 (dd, J ˆ 3.1, 6.2, HÀC(4)); 5.17 5.37 (m, 4 J ˆ 6.96 7.59
(m, 13 H );cis/trans: 0.05 (s, 3 H); 0.22 (s, 6 H); 0.24 (s, 3 H); 0.91 (s, 9 H); 1.02 (s, 9 H ).13C-NMR (100 MHz,
CDCl3; HETCOR): cis: 36.30 (C(3)); 55.11 (C(2)); 68.64 (C(4)); enol: À4.44; À4.12; 18.70; 26.32, 30.73 (C(3));
67.71 (C(4)); 95.13 (C(2)); 167.12 (C(1)); trans: 35.23 (C(3)); 52.13 (C(2)); 69.71 (C(4)); cis/trans: 191.29 (C(1));
191.75 (C(1)); cis/enol/trans: À4.38; À4.22; À4.17; À3.77; 18.48; 18.62; 26.16; 26.28; 66.40; 66.75; 67.35; 67.42;
70.98; 71.63; 113.44; 114.12; 114.23; 117.94; 118.40; 118.51; 120.07; 120.60; 120.86; 126.21 137.38 (m); 146.02
(C(4a)); 147.68 (C(4a)); 149.49 (C(4a)); 157.63 (C(8)); 159.45 (C(8)); 159.48 (C(8)); 170.11 (C(9)); 171.01
(C(9)); 172.93 (C(9)).
Benzyl 8-(Benzyloxy)-1,2,3,4-tetrahydro-1-oxo-4-[(tetrahydro-2H-pyran-2-yl)oxy]naphthalene-2-carboxy-
late (7b). To a mixture of 6 (371 mg, 9.23 ¥ 10À4 mol) and CSA (15 mg) in dry CH2Cl2 (30 ml) at r.t. under
Ar, 3,4-dihydro-2H-pyran (250 ml, 2.77 ¥ 10À3 mol) was added by syringe. The mixture was stirred at r.t. for 2.5 h
and quenched by addition of dist. H2O (20 ml). The aq. layer was extracted with AcOEt (2 Â 20 ml), the
combined org. extract washed with brine (2 Â 20 ml), dried (MgSO4), and evaporated, and the crude product
purified by CC (silica gel, AcOEt/hexane 3 :7): 327 mg (73%) of 7b. Colorless oil. Rf (AcOEt/hexane 3 :7; UV)
0.30. 1H-NMR (400 MHz, CDCl3; COSY): 1.46 1.90 (m, 36 H); 2.43 2.76 (m, 10 H); 2.78 (m, 2 H); 3.52
(m, 6 H); 3.86 (m, 6 H); 4.52 (t, J ˆ 3.3, 2 H); 4.72 (m, 2 H); 4.96 (t, J ˆ 2.5, 2 H); 5.20 5.35 (m, 24 H); 6.95
‡
7.14 (m, 6 H); 7.29 7.54 (m, 18 H); 12.96 (s, OH); 12.98 (s, OH). ESI-MS (pos.): 510 ([M ‡ H ‡ Na] ), 509
‡
‡
‡
([M ‡ Na] ); MS-MS of 509: 401 ([M ‡ Na À THP] ); MS-MS of 401: 310 ([M ‡ Na À THP À Bn] ).
Benzyl (2RS,4SR)-8-(Benzyloxy)-1,2,3,4-tetrahydro-2-hydroxy-1-oxo-4-{[(2SR)-tetrahydro-2H-pyran-2-
yl]oxy}naphthalene-2-carboxylate (cis-8), Benzyl (2RS,4SR)-8-(Benzyloxy)-1,2,3,4-tetrahydro-2-hydroxy-1-
oxo-4-{[(2RS)-tetrahydro-2H-pyran-2-yl]oxy}naphthalene-2-carboxylate (cis-8'), Benzyl (2RS,4RS)-8-(Benzy-
loxy)-1,2,3,4-tetrahydro-2-hydroxy-1-oxo-4-{[(2RS)-tetrahydro-2H-pyran-2-yl]oxy}naphthalene-2-carboxylate
(trans-8), and Benzyl (2RS,4RS)-8-(Benzyloxy)-1,2,3,4-tetrahydro-2-hydroxy-1-oxo-4-{[(2SR)-tetrahydro-2H-
pyran-2-yl]oxy}naphthalene-2-carboxylate (trans-8'). To a soln. of 7b (296 mg, 6.09 ¥ 10À4 mol) in dry THF
(15 ml) under Ar at À 788, 0.5m KHMDS in toluene (1.18 ml, 6.09 ¥ 10À4 mol) was added by syringe. A soln. of
trans-(Æ)-3-phenyl-2-(phenylsulfonyl)oxaziridine (10; 239 mg, 9.14 ¥ 10À4 mol) in dry THF (5 ml) was added

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Helvetica Chimica Acta Vol. 86 (2003)
dropwise, and the temp. of the mixture was allowed to rise to À108 within 1.5 h. The mixture was quenched at
À108 by addition of sat. aq. Na2SO4 soln. (10 ml), the aq. layer extracted with AcOEt (3 Â 15 ml), the combined
org. extract washed with brine (2 Â 20 ml), dried (MgSO4), and evaporated, and the crude product purified by
CC (silica gel, AcOEt/hexane 3 :7): 41 mg (13%) of cis-8/cis-8' 1:1 as colorless oil and 134 mg (44%) of trans-8/
trans-8' 1:1 as colorless oil.
The procedure was repeated with 7b (163 mg, 3.54 ¥ 10À4 mol) in dry THF (25 ml), 0.5m KHMDS in toluene
(708 ml, 3.54 ¥ 10À4 mol), and (‡)-(camphorsulfonyl)oxaziridine (11; 115 mg, 5.31 ¥ 10À4 mol) in dry THF (5 ml).
Purification by CC (silica gel, AcOEt/hexane 3 :7) gave 14.1 mg (9%) of cis-8/cis-8' 1:1 as colorless oil and
17.2 mg (11%) of trans-8/trans-8' 2 :1 as colorless oil.
Data of cis-8/cis-8': Rf (AcOEt/hexane 3 :7; UV) 0.23. 1H-NMR (400 MHz, CDCl3; COSY): cis-8: 1.55
1.91 (m, 6 H); 2.43 (dd, J ˆ 8.3, 13.6, HÀC(3)); 3.21 (dd, J ˆ 5.0, 13.6, HÀC(3)); 3.55 (m, HÀC(6')); 3.93
(m, HÀC(6')); 5.06 5.30 (m, 5 H); 6.94 7.58 (m, 13 H ); cis-8': 1.55 1.91 (m, 6 H); 2.23 (dd, J ˆ 9.4, 13.1,
HÀC(3)); 3.14 (dd, J ˆ 5.1, 13.1, HÀC(3)); 3.55 (m, HÀC(6')); 3.93 (m, HÀC(6')); 5.06 5.30 (m, 5 H); 6.94
‡
7.58 (m, 13 H );cis-8/cis-8': 4.74 (m, HÀC(2')); 4.88 (m, HÀC(2')). ESI-MS (pos.): 525 ([M ‡ Na] ).
1
Data of trans-8/trans-8': Rf (AcOEt/hexane 3 :7; UV) 0.16. H-NMR (400 MHz, CDCl3; COSY): trans-8:
1.55 1.88 (m, 6 H); 2.66 (dd, J ˆ 4.4, 13.4, HÀC(3)); 2.93 (dd, J ˆ 7.7, 13.4, HÀC(3)); 3.60 (m, HÀC(6')); 3.97
(m, HÀC(6')); 4.84 (t, J ˆ 2.9, HÀC(2')); 5.07 5.25 (m, 5 H); 6.98 7.58 (m, 13 H ); trans-8': 1.55 1.88
(m, 6 H); 2.43 (dd, J ˆ 4.1, 13.7, HÀC(3)); 2.90 (dd, J ˆ 6.2, 13.7, HÀC(3)); 3.60 (m, HÀC(6')); 3.97
(m, HÀC(6')); 4.91 (t, J ˆ 2.1, HÀC(2')); 5.07 5.25 (m, 5 H); 6.98 7.58 (m, 13 H). ESI-MS (pos.): 525
‡
([M ‡ Na] ).
Benzyl (2RS,4SR)-8-(Benzyloxy)-1,2,3,4-tetrahydro-2,4-dihydroxy-1-oxonaphthalene-2-carboxylate. Color-
less oil. 1H-NMR (400 MHz, CDCl3; COSY): 2.31 (dd, J ˆ 7.6, 13.6, HÀC(3)); 3.08 (dd, J ˆ 5.2, 13.6, HÀC(3));
5.06 5.30 (m, 5 H); 6.94 7.58 (m, 13 H ).
(1RS,9RS)-6-(Benzyloxy)-9-hydroxy-11-oxatricyclo [7.2.1.02,7]dodeca-2,4,6-triene-8,10-dione (12). Color-
less oil. 1H-NMR (400 MHz, CDCl3; COSY): 2.82 (d, J ˆ 11.4, HÀC(3)); 3.22 (dd, J ˆ 5.5, 11.4, HÀC(3));
5.02 5.24 (m, 2 H); 5.57 (d, J ˆ 5.5, HÀC(4)); 7.10 7.58 (m, 8 H ).
cis-3,4-Dihydro-2,4,8-trihydroxynaphthalen-1(2H)-one (1) and 3,4-dihydro-2,8-dihydroxynaphthalen-1-
(2H)-one (9). To a soln. of trans-8/trans-8' (130 mg, 2.59 ¥ 10À4 mol) in AcOEt (10 ml), 10% Pd/C (15 mg)
was added. The mixture was stirred overnight under H2 (1 atm). After filtration over Celite, the org. layer was
washed with 1m HCl the aq. layer extracted with AcOEt (3 Â 15 ml), the combined org. extract washed with
brine (2 Â 20 ml), dried (MgSO4), and evaporated, and the crude product purified by CC (silica gel, AcOEt/
hexane 1 :4 and 1:1): 3.3 mg (7%) of 9 as colorless oil and 3.7 mg (7%) of 1 as pale yellow oil that turned red on
contact with air.
The same procedure was repeated with cis-8/cis-8' (40 mg, 7.96 ¥ 10À5 mol) in AcOEt (5 ml). CC (silica gel,
AcOEt/hexane 1:4 and 1:1) gave 2.3 mg (16%) of 9 and 3.8 mg (25%) of 1.
Data of 1: Rf (AcOEt/hexane 1:1; UV) 0.09. 1H-NMR (400 MHz, CD3OD; COSY): 2.04 (dt, J ˆ 11.6, 13.3,
HÀC(3)); 2.66 (dt, J ˆ 4.6, 11.6, HÀC(3)); 4.44 (dd, J ˆ 4.6, 13.3, HÀC(2)); 4.95 (dd, J ˆ 4.6, 11.6, HÀC(4));
6.88 (d, J ˆ 8.2, HÀC(7)); 7.23 (dd, J ˆ 1.0, 7.8, HÀC(5)); 7.57 (dd, J ˆ 7.8, 8.2, HÀC(6)). 13C-NMR (100 MHz,
CD3OD; HETCOR): 41.88 (C(3)); 66.26 (C(4)); 71.17 (C(2)); 113.97 (C(8a)); 116.22 (C(7)); 116.73 (C(5));
‡
136.99 (C(6)); 149.31 (C(4a)); 162.62 (C(8)); 204.98 (C(1)). APCI-MS (pos.): 195 ([M ‡ H] ).
Data of 9: Rf (AcOEt/hexane 1:1; UV) 0.40. 1H-NMR (400 MHz, CDCl3; COSY): 1.59 (s, OH); 2.06
(m, HÀC(3)); 2.52 (m, HÀC(3)); 3.06 (m, 2 HÀC(4)); 4.40 (dd, J ˆ 5.4, 13.2, HÀC(2)); 6.76 (dd, J ˆ 0.9, 7.5,
HÀC(7)); 6.85 (d, J ˆ 8.4, HÀC(5)); 7.44 (t, J ˆ 8.0, HÀC(6)); 11.60 (s, OH ). 13C-NMR (100 MHz, CDCl3;
HETCOR): 28.06 (C(4)); 31.55 (C(3)); 73.60 (C(2)); 115.50 (C(8a)); 115.95 (C(7)); 119.71 (C(5)); 137.58
(C(6)); 145.66 (C(4a)); 163.06 (C(8)); 204.73 (C(1)). ESI-MS (neg.): 177 ([M À H]À).
3,4-Dihydro-4,8-dihydroxynaphthalen-1-(2H)-one (ˆ Isosclerone; 13). To a soln. of 6 (1.1 g, 2.74 ¥ 10À3 mol)
in dry THF (120 ml) 10% Pd/C (75 mg) was added. The mixture was stirred overnight under H2 (1 atm). After
filtration over Celite, dist. H2O (1 ml) was added and the mixture stirred at 508 for 5 h. The solvent was
evaporated and the crude product purified by CC (silica gel, AcOEt/hexane 1:1): 194 mg (40%) of 13. Pale
yellow crystals, which were recrystallized from hexane. White crystals. M.p. 98 998. Rf (AcOEt/hexane 1 :1;
UV) 0.26. IR (KBr): 3264m, 1637s, 1616s, 1454s. 1H-NMR (400 MHz, CDCl3; COSY): 1.82 (s, OH); 2.19
(m, HÀC(3)); 2.34 (m, HÀC(3)); 2.64 (ddd, J ˆ 4.8, 8.3, 17.9, HÀC(2)); 3.00 (ddd, J ˆ 4.7, 8.3, 17.9, HÀC(2));
4.91 (dd, J ˆ 3.7, 7.4, HÀC(4)); 6.92 (d, J ˆ 8.4, HÀC(7)); 7.01 (dd, J ˆ 0.8, 7.5, HÀC(5)); 7.49 (dd, J ˆ 7.5, 8.4,
HÀC(6)); 12.41 (s, OH ). 13C-NMR (100 MHz, CDCl3; HETCOR): 31.48 (C(3)); 34.52 (C(2)); 67.64 (C(4));
115.22 (C(8a)); 117.36 (C(7)); 117.70 (C(5)); 136.95 (C(6)); 145.86 (C(4a)); 162.66 (C(8)); 204.26 (C(1)). EI-

Helvetica Chimica Acta Vol. 86 (2003)
219
.
.
‡
‡
MS: 178 (17, M ), 160 (6.5, [M À H2O] ), 132 (25), 121 (100), 77 (25), 65 (44.5). DCI-MS (NH3): 179 ([M ‡
‡
H] ).
3,4-Dihydro-8-hydroxynaphthalen-1(2H)-one (20). If the transformation 6 ! 13 was performed in AcOEt
or MeOHas solvent, also 20 was formed. White solid. Rf (AcOEt/hexane 1:1; UV) 0.55. 1H-NMR (400 MHz,
CDCl3; COSY): 2.09 (quint., J ˆ 6.1, 2 HÀC(3)); 2.67 (t, J ˆ 6.1, 2 HÀC(4)); 2.91 (t, J ˆ 6.1, 2 HÀC(2)); 6.70
(dd, J ˆ 0.9, 8.4, HÀC(5)); 6.78 (dd, J ˆ 0.9, 7.5, HÀC(7)); 7.33 (dd, J ˆ 7.5, 8.4, HÀC(6)); 12.43 (s, OH ).
13C-NMR (100 MHz, CDCl3; HETCOR): 22.87 (C(3)); 29.75 (C(2)); 38.92 (C(3)); 115.49 (C(7)); 117.03
(C(8a)); 118.82 (C(5)); 136.28 (C(6)); 145.51 (C(4a)); 162.87 (C(8)); 205.21 (C(1)). DCI-MS (NH3): 163 ([M ‡
‡
H] ).
1,4,5-Tris{[(tert-butyl)dimethylsilyl]oxy}-1,2-dihydronaphthalene (14). To a soln. of 13 (190 mg, 1.07 ¥
10À3 mol) in 1,2-dichloroethane (20 ml) under Ar, Et3N (670 ml, 4.82 ¥ 10À3 mol; freshly distilled over KOH)
was added by syringe at r.t. Then tBuMe2SiOTf (740 ml, 3.21 10À3 mol) was added dropwise by syringe, and the
mixture was stirred for 25 min. Then silica gel (2 g) was directly added to the soln., and the mixture was purified
by CC (silica gel, AcOEt/hexane 2 :98): 500.5 mg (90%) of 14. Colorless oil. Rf (AcOEt/hexane 2 :98; UV) 0.63.
1
IR (film): 1635m, 1472s, 1256s. H-NMR (400 MHz, CDCl3; COSY): 0.07 0.16 (m, 18 H); 0.93 (s, 9 H); 0.96
(s, 9 H); 0.99 (s, 9 H); 2.23 (m, 2 HÀC(2)); 4.63 (dd, J ˆ 6.3, 11.0, HÀC(1)); 5.16 (dd, J ˆ 4.0, 6.6, HÀC(3));
6.74 (d, J ˆ 8.0, HÀC(6)); 7.05 (dt, J ˆ 1.1, 7.5, HÀC(8)); 7.13 (t, J ˆ 7.7, H ÀC(7)). 13C-NMR (100 MHz, CDCl3;
HETCOR): À4.46; À4.31; À4.10; À4.00; À3.82; À3.37; 26.36; 26.45; 26.49; 32.56 (C(2)); 70.71 (C(1)); 104.91
(C(3)); 117.60 (C(6)); 121.70 (C(8)); 124.83 (C(4a)); 128.32 (C(7)); 143.45 (C(8a)); 149.19 (C(5)); 152.19
‡
(C(4)). ESI-MS (pos.): 538 ([M ‡ H2O] ).
cis-2,4,8-Tris{[(tert-butyl)dimethylsilyl]oxy}-3,4-dihydronaphthalen-1(2H)-one (15) and trans-2,4,8-
Tris{[(tert-butyl)dimethylsilyl]oxy}-3,4-dihydronaphthalen-1(2H)-one (16). To a soln. of 14 (95 mg, 1.82 ¥
10À4 mol) in 1,2-dichloroethane (10 ml) under Ar at À158 (ice/acetone bath), 70% m-CPBA (45 mg, 1.82 ¥
10À4 mol) in 1,2-dichloroethane (2 ml) was added dropwise by syringe. The mixture was stirred at r.t. for 1.5 h.
After evaporation, the crude product was purified by CC (silica gel, AcOEt/hexane 2 :98). 66 mg (67%) of 15/16
56 :44. Colorless oil. Rf (AcOEt/hexane 2 :98; UV) 0.35. IR (film): 2930m, 2858s, 1708s, 1594m, 1463s, 1255s,
927s, 835s, 779s. 1H-NMR (400 MHz, CDCl3; COSY): 15: 2.19 (dt, J ˆ 11.7, 13.1, HÀC(3)); 2.52 (dt, J ˆ 4.8, 13.1,
HÀC(3)); 4.25 (dd, J ˆ 4.8, 13.1, HÀC(2)); 4.96 (dd, J ˆ 4.9, 11.2, HÀC(4)); 6.83 (m, HÀC(7)); 7.19 (dt, J ˆ 1.0,
7.8, HÀC(5)); 7.39 (t, J ˆ 8.0, HÀC(6)); 16: 2.31 (m, 2 HÀC(3)); 4.65 (dd, J ˆ 4.6, 8.6, HÀC(2)); 5.10 (dd, J ˆ
3.9, 5.8, HÀC(4)); 6.83 (m, HÀC(7)); 6.99 (d, J ˆ 7.6, HÀC(5)); 7.39 (t, J ˆ 8.0, HÀC(6)); 15/16: 0.07 0.16
(m, 18 H); 0.93 (s, 9 H); 0.96 (s, 9 H); 0.99 (s, 9 H ).13C-NMR (100 MHz, CDCl3; HETCOR): 15: 43.92 (C(3));
68.69 (C(4)); 74.22 (C(2)); 119.33 (C(5)); 16: 42.04 (C(3)); 68.13 (C(4)); 72.64 (C(2)); 120.87 (C(5)); 15/16:
À4.96 to À3.71 (m); 18.48; 18.59; 18.84; 18.91; 18.94; 19.09; 26.19; 26.28; 26.30; 26.34; 121.33 (C(7)); 121.70
(C(7)); 122.32 (C(8a)); 122.57 (C(8a)); 133.96 (C(6)); 134.02 (C(6)); 147.09 (C(4a)); 148.84 (C(4a)); 156.52
‡
(C(8)); 156.68 (C(8)); 195.35 (C(1)); 195.61 (C(1)). ESI-MS (pos.): 559 ([M ‡ Na] ). Anal. calc. for
C28H52O4Si3 (536.98): C 62.63, H9.76; found: C 62.60, H9.82.
trans-3,4-Dihydro-2,4,8-trihydroxynaphthalen-1(2H)-one (2). To a soln. of 15/16 (de 12%; 66 mg, 1.23 ¥
10À4 mol) in MeOH(10 ml), Amberlyst 15 was added. The mixture was stirred for 5 6 days and then filtered.
After evaporation, the crude product was purified by CC (silica gel, AcOEt/hexane 1:1): 13.5 mg (55%) of 1/2
59 :41 (de 18%) as pale yellow oil.
Data of 2: Pale yellow solid. Rf (AcOEt/hexane 1:1; UV) 0.09. 1H-NMR (400 MHz, CD3OD; COSY): 2.27
(ddd, J ˆ 3.2, 11.7, 13.2, HÀC(3)); 2.51 (ddd, J ˆ 3.9, 5.1, 13.2, HÀC(3)); 4.81 (dd, J ˆ 5.0, 11.7, HÀC(2)); 4.99
(t, J ˆ 3.4, HÀC(4)); 6.92 (dd, J ˆ 1.1, 8.4, HÀC(7)); 6.98 (dq, J ˆ 0.6, 7.5, HÀC(5)); 7.56 (dd, J ˆ 7.5, 8.4,
HÀC(6)). 13C-NMR (100 MHz, CD3OD; HETCOR): 39.18 (C(3)); 66.59 (C(4)); 68.33 (C(2)); 114.25 (C(8a));
117.41 (C(7)); 120.06 (C(5)); 137.34 (C(6)); 145.21 (C(4a)); 162.65 (C(8)); 205.12 (C(1)).
20
The same protocol was applied to (‡)- and (À)-17 or (‡)- and (À)-18. From pure (‡)-18 (111 mg; [a]
ˆ
546
20
‡4.1 Æ 0.3), 31.5 mg (51%) of 1/(À)-2 was obtained: de 64% for (À)-2, [a] ˆ À11.4 Æ 0.5 (c ˆ 0.630, MeOH).
546
20
From pure (‡)-17 (28 mg; [a] ˆ ‡32.1 Æ 0.5), 12 mg (92%) of (‡)-1 was obtained: de 100% for (‡)-1,
546
20
[a] ˆ ‡6.2 Æ 1.3 (c ˆ 0.240, MeOH).
546
20
From pure (À)-18 (40 mg; [a] ˆ À0.5 Æ 0.2), 11.7 mg (64%) of 1/(‡)-2 was obtained: de 52% for (‡)-2,
546
20
[a] ˆ ‡3.4 Æ 1.3 (c ˆ 0.090, MeOH).
546
20
From pure (À)-17 (11 mg; [a] ˆ À10.3 Æ 0.9), 4.1 mg (80%) of (À)-1 was obtained: de 100% for (À)-1,
546
20
[a] ˆ À4.9 Æ 1.3 (c ˆ 0.082, MeOH).
546
Data of (‡)-2: CD (MeOH, c ˆ 9.00 ¥ 10À4 g ¥ cmÀ3, l ˆ 1 mm): 489 (257), 0 (281), À71 (309), 0 (329).
20
[a] ˆ ‡3.4 Æ 1.3 (c ˆ 0.090, MeOH).
546

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Helvetica Chimica Acta Vol. 86 (2003)
Data of (À)-2: CD (MeOH, c ˆ 4.00 ¥ 10À4 g ¥ cmÀ3, l ˆ 1 mm): À2989 (258), 0 (284), 272 (301), 0 (320).
20
[a] ˆ À8.9 Æ 1.9 (c ˆ 0.040, MeOH).
546
Data of (‡)-1: CD (MeOH, c ˆ 9.20 ¥ 10À5 g ¥ cmÀ3, l ˆ 5 mm): 754 (230), 233 (241), 795 (262), 152 (280), 520
20
(304), 0 (326), À285 (341), 0 (365). [a] ˆ ‡2.2 Æ 3.3 (c ˆ 0.092, MeOH).
546
Data of (À)-1: CD (MeOH, c ˆ 8.21 ¥ 10À4 g ¥ cmÀ3, l ˆ 1 mm): À346 (231), À159 (240), À526 (262), 102
20
(282), À224 (307), 0 (329), 112 (341), 0 (365). [a] ˆ À4.9 Æ 1.3 (c ˆ 0.082, MeOH).
546
cis-4,8-Bis{[(tert-butyl)dimethylsilyl]oxy}-3,4-dihydro-2-hydroxynaphthalen-1(2H)one (17) and trans-4,8-
Bis{[(tert-butyl)dimethylsilyl]oxy}-3,4-dihydro-2-hydroxynaphthalen-1(2H)-one (18). A mixture of K2CO3
t
(175 mg, 1.27 ¥ 10À3 mol), 2.5% OsO4 soln. (86 ml, 8.4 ¥ 10À6 mol) in BuOH, and (DHQD)2(PHAL) (16 mg,
2.1 ¥ 10À5 mol) in dist. H2O (2.1 ml) was stirred at r.t. for 10 min. Then K3Fe(CN)6 (418 mg, 1.27 ¥ 10À3 mol) was
t
added. When all salts were dissolved, BuOH(500 ml) and methanesulfonamide (40 mg, 4.23 ¥ 10À4 mol) were
t
added. The flask was cooled to 08, and 14 (220 mg, 4.23 ¥ 10À4 mol) diluted in BuOH(1.5 ml) was added. The
mixture was stirred overnight at 08 and quenched with Na2SO3 (300 mg). After 45 min stirring r.t., dist. H2O
(3 ml) was added. The aq. layer was extracted with AcOEt (3 Â 15 ml), the combined org. extract washed with
brine (20 ml), dried (MgSO4), and evaporated, and the crude product purified by CC (silica gel, AcOEt/hexane
2 :98 and 5 :95): 15 mg (9%) of (À)-17 as white solid and 53.9 mg (30%) of (À)-18 as colorless oil.
Replacing the chiral ligand by (DHQ)2PHAL (16 mg, 2.1 ¥ 10À5 mol) in exactly the same protocol gave
20.1 mg (11%) of (‡)-17 as white solid and 37.7 mg (21%) of (‡)-18 as colorless oil.
20
Data of (‡)-17: Rf (AcOEt/hexane 5 :95; UV) 0.22. [a] ˆ ‡38.6 Æ 0.7 (c ˆ 0.402, MeOH). IR (film):
546
3434m, 2930s, 2858s, 1690s, 1592m, 1465s. 1H-NMR (400 MHz, CDCl3; COSY): 0.29 (s, 3 H); 0.31 (s, 3 H); 0.33
(s, 3 H); 0.34 (s, 3 H); 1.08 (s, 9 H); 1.12 (s, 9 H); 2.04 (dt, J ˆ 11.1, 13.2, HÀC(3)); 2.72 (dt, J ˆ 5.0, 11.7,
HÀC(3)); 4.37 (dd, J ˆ 5.0, 13.2, HÀC(2)); 5.21 (dd, J ˆ 5.0, 10.9, HÀC(4)); 6.97 (d, J ˆ 8.1, HÀC(7)); 7.31
(dd, J ˆ 1.0, 7.8, HÀC(5)); 7.57 (t, J ˆ 8.0, HÀC(6)). 13C-NMR (100 MHz, CDCl3; HETCOR): À4.41; À3.88;
À3.81; À3.72; 19.24; 19.65; 26.63; 26.67; 44.28 (C(3)); 69.34 (C(4)); 73.17 (C(2)); 121.02 (C(5)); 122.21 (C(8a));
‡
122.75 (C(7)); 135.61 (C(6)); 150.92 (C(4a)); 157.65 (C(8)); 198.72 (C(1)). ESI-MS (pos.): 445 ([M ‡ Na] ).
CD (MeOH, c ˆ 2.01 ¥ 10À4 g ¥ cmÀ3, l ˆ 5 mm): 6936 (230), 3150 (240), 4380 (255), 499 (275), 4744 (309), 0
(349), À195 (364).
20
Data of (‡)-18: Colorless oil. Rf (AcOEt/hexane 5 :95; UV) 0.17. [a] ˆ À0.5 Æ 0.3 (c ˆ 1.018, MeOH). IR
546
(film): 3471m, 2955s, 1688s, 1594s, 1464s. 1H-NMR (400 MHz, CDCl3; COSY): 0.12 (s, 3 H); 0.22 (s, 3 H); 0.24
(s, 3 H); 0.29 (s, 3 H); 0.89 (s, 9 H); 1.06 (s, 9 H); 2.14 (dt, J ˆ 3.1, 12.6, HÀC(3)); 2.56 (ddd, J ˆ 3.2, 5.3, 12.6,
HÀC(3)); 4.84 (dd, J ˆ 4.8, 13.1, HÀC(2)); 4.99 (t, J ˆ 3.1, HÀC(4)); 6.87 (dd, J ˆ 1.0, 8.2, HÀC(7)); 6.90
(dd, J ˆ 1.0, 8.0, HÀC(5)); 7.42 (t, J ˆ 8.0, HÀC(6)). 13C-NMR (100 MHz, CDCl3; HETCOR): À4.51; À4.47;
À4.31; À4.27; 17.99; 18.40; 25.68; 25.72; 40.21 (C(3)); 68.29 (C(4)); 69.15 (C(2)); 120.98 (C(8a)); 121.32 (C(5));
‡
122.09 (C(7)); 134.72 (C(6)); 146.10 (C(4a)); 156.24 (C(8)); 198.23 (C(1)). ESI-MS (pos.): 445 ([M ‡ Na] ).
CD (MeOH, c ˆ 1.35 ¥ 10À4 g ¥ cmÀ3, l ˆ 5 mm): À5573 (252), 0 (280), 110 (325), 0 (365).
Data of (À)-17: [a] ˆ À15.7 Æ 1.0 (c ˆ 0.300, MeOH). CD (MeOH, c ˆ 2.40 ¥ 10À4 g ¥ cmÀ3, l ˆ 5 mm):
20
546
À3624 (230), À1594 (240), À2275 (256), À486 (275), À2299 (309), 0 (346), 115 (358).
Data of (À)-18: [a] ˆ ca. 0 (c ˆ 0.674, MeOH). CD (MeOH, c ˆ 2.04 ¥ 10À4 g ¥ cmÀ3, l ˆ 5 mm): 1400 (252),
20
546
[f]274 ˆ 0 (274), À305 (322), 0 (362).
Determination of Enantiomer Excesses. In a NMR tube (dried for 24 h at 1308), optically active 17 or 18
(10 mg (2.37 ¥ 10À5 mol) was dissolved in dry CDCl3 (1.5 ml). With a 100-ml graduated capillary dry pyridine
(50 ml, 4.59 ¥ 10À4 mol) and (À)-(R)-MTPCl (20 ml, 1.068 ¥ 10À4 mol) were added. The mixture was left at r.t.
1
overnight, and then the H-NMR was measured.
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Received June 7, 2002