An enantioselective formal synthesis of 4-demethoxydaunomycin using the catalytic asymmetric ring opening reaction of meso-epoxide with p-anisidine

Article abstract of DOI:10.1016/S0040-4020(01)01088-2

A catalytic asymmetric formal synthesis of 4-demethoxydaunomycin (3) was achieved using a catalytic asymmetric ring opening reaction of meso-epoxide 9 as a key step. The epoxide opening reaction was promoted by 10 mol% of Pr-(R)-BINOL-Ph₃P=O co

Full text of DOI:10.1016/S0040-4020(01)01088-2

TETRAHEDRON
Pergamon
Tetrahedron 58 (2002) 75±82
An enantioselective formal synthesis of 4-demethoxydaunomycin
using the catalytic asymmetric ring opening reaction of
meso-epoxide with p-anisidine
Akihiro Sekine, Takashi Ohshima and Masakatsu Shibasakip
Graduate School of Pharmaceutical Sciences, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
Received 5 October 2001; accepted 5 November 2001
AbstractÐA catalytic asymmetric formal synthesis of 4-demethoxydaunomycin (3) was achieved using a catalytic asymmetric ring opening
reaction of meso-epoxide 9 as a key step. The epoxide opening reaction was promoted by 10 mol% of Pr-(R)-BINOL±Ph3PvO complex to
give the b-amino alcohol 11 in 80% yield with 65% enantiomeric excess (ee). Single recrystallization enhanced the enantiomeric purity of
the b-amino alcohol 11 to 95% ee. The b-amino alcohol 11 was then converted to the known key intermediate 6 through severalsteps,
including a methylation, Hofmann elimination, an oxymercuration, and addition of an ethynyl group in a highly diastereoselective manner.
q 2002 Elsevier Science Ltd. All rights reserved.
1. Introduction
and they are active only in their natural absolute con®gura-
tion.5 Therefore, much effort has been devoted to
developing more ef®cient methods for the synthesis of
enantiomerically pure aglycons.6 Although catalytic asym-
metric syntheses are effective methods in terms of `atom-
economy', there are only a few reports of catalytic asym-
metric synthesis of 3.7 Thus, there is a high demand to
develop a more ef®cient enantioselective method for
synthesis. Herein, we report the short formalsynthesis of
(1)-4-demethoxydaunomycin (3) using the catalytic
asymmetric ring opening reaction of meso-epoxide with
p-anisidine as a key step.
Daunomycin (1) and adriamycin (2) are prominent members
of a class of clinically important anthracycline antibiotics1
used most often in antitumor combination chemotherapy
(Fig. 1). Their utility, however, is limited due to a number
of side effects, the most serious being dose-dependent
cardiotoxicity.2 The 4-demethoxy analogs: 4-demethoxy-
daunomycin (idarubicin) (3) and 4-demethoxyadriamycin
(4) were recently developed as arti®cial anthracyclines to
improve the pharmacologic pro®le.3 Because these non-
naturalanaolgs cannot be synthesized using the fermenta-
tion method, there have been a number of reports on the
synthesis of 3 and 4.4 The antitumor activity of these
compounds is strictly dependent on the chirality at C-9,
Our retrosynthetic analysis is outlined in Scheme 1. The
synthetic target is benzeneboronate 6,8 which is known to
Figure 1. Structure of selected anthracycline antibiotics.
Keywords: 4-demethoxydaunomycin; catalytic asymmetric ring opening
reaction; multifunctional catalyst.
p
Corresponding author. Tel.: 181-3-5841-4830; fax: 181-3-5684-5206;
e-mail: mshibasa@mol.f.u-tokyo.ac.jp
Scheme 1. Retrosynthetic analysis of 4-demethoxydaunomycine (3).
0040±4020/02/$ - see front matter q 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(01)01088-2

76
A. Sekine et al. / Tetrahedron 58 (2002) 75±82
be coupled with bis(trimethylsiloxy)benzocyclobutane then
ef®ciently converted to the aglycon: idarubicinone (5) in
65% yield (3 steps).9 Our synthesis of the key intermediate
6 was designed by the use of a catalytic asymmetric
desymmetrization of meso-epoxide 9 to introduce the
chirality at C-9 with functionality at C-7 (9!8). In addition,
our approach involves the transfer of stereochemical infor-
mation around the cyclohexane ring (A-ring) by a series of
1,3-asymmetric induction events (8!7 and 7!6). Dia-
stereoselective oxymercuration might transfer the chirality
at C-9 in the allylic alcohol 8 to the chirality at C-7 in the
b-methoxyalcohol 20 (Scheme 4), which would be oxidized
to the b-methoxyketone 7. Subsequent diastereoselective
ethynylation followed by boronic ester formation would
set all functionality in the A-ring and stereochemistry at
C-7 and C-9, and thereby complete a formal total synthesis
of 4-demethoxydaunomycin (3).
Scheme 3. Catalytic asymmetric ring opening reaction route.
philes, there are only a few reports employing an alkyl-
amine19 or an arylamine20 as a nucleophile with low
substrate generality, perhaps because of their high af®nity
to Lewis acids. Therefore, we planned to develop an
ef®cient catalytic asymmetric ring opening reaction of
meso-epoxide 9 with aniline derivatives, leading to the
trans-b-amino alcohol 11.
On the basis of our previous results, we investigated the
catalytic asymmetric ring opening reaction of cyclohexene
oxide (12) as a modelsubstrate using multifunctionalasym-
metric catalysts.21 In screening of catalysts, including the
Ga±Li±BINOL complex (GaLB), the alkali-metal free
Ga±BINOL complex, and several alkali-metal free lantha-
noid±BINOL complexes, the best result was obtained using
the alkali-metal free Pr±BINOL complex as a catalyst and
p-anisidine as a nucleophile, although the ee of 13 was still
unsatisfactory. We also performed investigations on the
ratio of Pr(O-i-Pr)3 and BINOL (Table 1). In the absence
of (R)-BINOL, the reaction did not proceed at all (entry 1),
indicating ligand acceleration of the reaction.22 Increasing
the amount of (R)-BINOL relative to Pr increased both
yields and ees (entries 2±7). The complex generated from
Pr(O-i-Pr)3 and (R)-BINOL in a ratio of 1:2 was the most
effective asymmetric catalyst for the ring opening reaction
of meso-epoxide 12. The catalyst was easily prepared from
Pr(O-i-Pr)3 and (R)-BINOL, which were mixed in tetra-
hydrofuran followed by removal of tetrahydrofuran and
resulting i-PrOH under reduced pressure. The residual
pale green powder was used directly in the reaction. The
absolute con®guration of trans-b-amino alcohol 13 was
determined to be (1R,2R) by comparing the measured
2. Results and discussion
The synthesis of the benzeneboronate 6 began with the
readily available meso-epoxide 910 subjected to a catalytic
asymmetric desymmetrization. Desymmetrization of an
achiral meso molecule to yield enantiomerically enriched
products is proving to be a powerfulsynthetic too.l
catalytic asymmetric epoxide rearrangement using a chiral
lithium amide is one of the most widely used methods for
preparing chiral allylic alcohols.12 In our preliminary study
of catalytic asymmetric epoxide rearrangements of meso-
epoxide 9 using the chiralilthium amide, however, the
epoxide rearrangement strategy for the synthesis of the
11
The
allylic alcohol
8
produced unsatisfactory results
(Scheme 2). Because of the high acidity of the benzylic
proton of 9, not only chiral lithium amide (20 mol%) but
also non-chiral lithium amide (LDA, 200 mol%) reacted
with the substrate to give the allylic alcohol 8 in low
enantiomeric excess (,1% ee). Even using a stoichiometric
amount of chiralilthium amide produced an unsatisfactory
result (25% ee).
20b
opticalrotations with the ilterature.
Thus, we chose a strategy based on the catalytic asymmetric
ring opening reaction of meso-epoxide with amine
(Scheme 3). The resulting chiral trans-b-amino alcohol 11
would be converted to the desired chiral allylic alcohol 8 by
quaternary amine formation followed by Hofmann elimina-
tion. Recently, we and others achieved an ef®cient catalytic
asymmetric ring opening reaction of meso-epoxide with
various nucleophiles, such as trialkylsilyl azide,13 trimethyl-
silyl cyanide,14 thiol,15 aryllithium,16 halides,17 and
phenol.18 In contrast to the great success of such nucleo-
In the asymmetric epoxidation of enones promoted by
alkali-metal free lanthanoid±BINOL complexes, addition
of triphenylphosphine oxide (Ph3PvO) and triphenylarsine
Table 1. Catalytic asymmetric ring opening reaction with p-anisidine.
Effect of the ratio of (R)-BINOL to Pr
Entry
(R)-BINOL (xmolequiv. to Pr)
Yield (%)
ee (%)
1
2
3
4
5
6
7
±
No reaction
0.33
0.5
1.0
1.5
2.0
3.0
30
53
68
72
73
70
9
13
22
28
30
23
Scheme 2. Asymmetric epoxide rearrangement route.

A. Sekine et al. / Tetrahedron 58 (2002) 75±82
77
Table 2. Catalytic asymmetric opening reaction with p-anisidine. Effect of
additives
reaction of several meso-epoxides using the asymmetric
catalyst generated from Pr(O-i-Pr)3, (R)-BINOL, and
Ph3PvO in ratios of 1:1.5:3 and 1:2:3 (Table 3). As
shown, these asymmetric catalysts were also effective for
cyclohexadiene mono oxide (14) and cyclopentene oxide
(16) to afford desired trans-b-amino alcohols 15 and 17
with higher enantioselectivities (50±53% ee, entries 3±6).
In the case of epoxide 18, which is the 5,8-didemethoxy
analog of epoxide 9, trans-b-amino alcohols 19 was
obtained with moderate enantioselectivities (36±38% ee,
entries 7, 8). Not only electronic effect but also conforma-
tionaleffect might in¯uence on enantiomeric selection. The
absolute con®guration of 15 was determined by transforma-
tion to 13 and that of 19 was determined on the basis of 1H
NMR analysis of the corresponding Mosher's ester.23 The
absolute con®guration of 17 was tentatively determined on
the basis of the result using aniline as a nucleophile.20b
Entry
Additives (xmol%)
Yield (%)
ee (%)
1
2
3
±
73
87
40
30
35
34
Ph3PvO (30)
Ph3AsvO (30)
oxide (Ph3AsvO) was effective for enhancing the reaction
rate while maintaining high ee.22 Thus, we next examined
the in¯uence of these additives (Table 2). The addition of
Ph3PvO induced higher solubility of the catalyst to the
solvent to afford 13 with slightly higher ee (entry 2),
whereas the addition of Ph3AsvO resulted in a decreased
yield (entry 3).
We applied these catalyst systems for the catalytic asym-
metric ring opening reaction of meso-epoxide 9 with
p-anisidine (Table 4). The reaction proceeded using
10 mol% of the asymmetric catalyst generated from
Pr(O-i-Pr)3, (R)-BINOL, and Ph3PvO in a ratio of 1:2:3
Next, we examined the catalytic asymmetric ring opening
Table 3. Catalytic asymmetric ring opening reaction with p-anisidine. Applications to several meso-epoxides
Entry
Epoxide
(R)-BINOL (x molequiv. to Pr)
Product
Yield (%)
ee (%)
Con®guration
1
2
3
4
5
6
7
8
1.5
2.0
1.5
2.0
1.5
2.0
1.5
2.0
13
15
17
19
71
87
72
75
82
71
62
70
31
35
50
53
50
50
36
38
(1R,2R)
(1R,2R)
(1R,2R)
(1R,2R)
to afford the desired trans-b-amino alcohol 11 in 74%
yield with 54% ee (entry 3). We reinvestigated the ratio of
BINOL to Pr(O-i-Pr)3 and the solvent effects. In this
case, the asymmetric catalyst generated from Pr(O-i-Pr)3,
(R)-BINOL, and Ph3PvO in a ratio of 1:1.5:3 gave the
best result (entry 2, 73% yield, 59% ee). The slow addition
of p-anisidine had a slightly positive effect as well (entry 5,
80% yield, 65% ee). However, the use of solvent other
than toluene gave less satisfactory result. The structure of
the Pr±BINOL±Ph3PvO complex is not yet clear. On the
basis of the previous structuralinvestigation on La±
BINOL±Ph3AsvO,22 we propose that the active catalyst
Table 4. Catalytic asymmetric ring opening reaction with p-anisidine.
Effects of the ratio of (R)-BINOL to Pr and solvent
Entry (R)-BINOL (xmol equiv. to Pr) Solvent Yield (%) ee (%)
1
2
3
1.0
1.5
2.0
1.5
1.5
1.5
1.5
1.5
Toluene
Toluene
Toluene
Toluene
Toluene
CH2Cl2
THF
75
73
74
75
80
49
10
26
50
59
54
50
65
64
20
34
is
a 1:2:x complex of Pr±BINOL±Ph3PvO. Laser
desorption/ionization time-of-¯ight mass spectrometry
(LDI TOF MS) of the complexes' solution supports our
hypothesis. The peak observed in the negative mode (MW
709) corresponds to the molecular weight of the monomeric
Pr(binaphthoxide)2 complex. Although the af®nity of
Ph3PvO to lanthanoid metals is lower than that of
Ph3AsvO,22 Ph3PvO might coordinate with lanthanoid
metals and contribute to the stability of the active
4a
5b
6
7
8
DME
a
Without Ph3PvO.
p-Anisidine was added slowly over 17 h.
b

78
A. Sekine et al. / Tetrahedron 58 (2002) 75±82
crucial. The addition of NaBH4 to the reaction mixture gave
no desired b-methoxyalcohol 20 with recovery of the start-
ing material 8 in ca. 70% yield. In these reaction conditions,
the elimination reaction of the radical intermediate might
proceed to give 8 in preference to reduction due to the easy
formation of elimination product 8. This led us to investi-
gate the reverse addition method. When the reaction mixture
of oxymercuration was added slowly to a 5% aqueous
NaOH solution of NaBH4,24 the radicalintermediate was
reduced immediately with an excess amount of NaBH4 to
afford the b-methoxyalcohol 20 in 74% yield (2 steps).
Moreover, oxymercuration proceeded in a completely
diastereo- and regiocontrolled manner. Mercury(II) acetate
reacts with ole®ns from the same side with a hydroxyl
group.25 The relative con®guration of 20 was determined
by NOE experiments and coupling constant analysis of 20
and 9-epi-20, which was prepared by reduction of ketone 7
(Fig. 3). The absolute con®guration of 20 was unequivocally
determined by converting to its Mosher's ester.23 The
hydroxylgroup of 20 was oxidized to a ketone using
Dess±Martin periodinane to afford 7 in 95% yield. The
addition of an ethynylgroup to the ketone 7 with a cerium
reagent prepared from ethynylmagnesium bromide and
cerium(III) chloride gave the propargyl alcohol 21 (76%)
in a highly diastereoselective manner (.10:1).26 The
relative con®guration of 21 was determined by considering
relative and absolute con®gurations of 20 and 6. The ethynyl
group of 21 was hydrated to give the ketone 22 using
mercury(II) sulfate as a catalyst. Under these conditions,
the methoxy group was substituted by water at the same
Figure 2. Possible transition state of ring opening reaction of epoxide 9
with p-anisidine.
monomeric species. The possible transition states leading to
11 are shown in Fig. 2. The Pr±BINOL±Ph3PvO complex
would promote the ring opening reaction of meso-epoxides
with p-anisidine through activation of epoxide. The
enantiomeric induction in the present system can be under-
stood by ®xation of the position of the epoxide coordinating
to the Lewis acidic center metaland the orientation of
p-anisidine through a hydrogen bond between the nitrogen
and phenolic protons.18 The absolute con®guration of 11
was determined by transformation to 20 (vide infra).
Large quantities of the enantiomerically enriched trans-b-
amino alcohol 11 (65% ee) allowed for the completion of
the key intermediate 6 (Scheme 4). A single recrystalliza-
tion of 11 (65% ee) from CH2Cl2±heptane enhanced its
enantiomeric purity to 95% ee in 40% recrystallization
yield. Methylation of the trans-b-amino alcohol 11 gave a
quaternary ammonium salt, which was directly treated with
an excess amount of BuLi to afford the allylic alcohol 8 in
52% yield (2 steps) with slight decrease of ee (90% ee).
Other bases such as KHMDS or KO-t-Bu dehydrated the
resulting allylic alcohol 8 to afford 1,4-dimethoxy-
naphtharene. To synthesize the b-methoxyalcohol 20,
oxymercuration of the allylic alcohol 8 with Hg(OAc)2 in
methanol followed by reduction with NaBH4 was examined.
In the second reaction, the addition order of the reagents is
1
time. H NMR revealed that the diastereomeric ratio of
the hydroxylgroup was ca. 1:1. The carbonylgroup of 22
was protected as cyclic ethyleneketal with excess ethylene
glycol, MgSO4, and 10 mol% of p-toluenesulfonic acid to
afford 23 in which the hydroxylgroup was substituted by
ethylene glycol. Decreasing the amount of ethylene glycol,
for example 3 equiv. of ethylene glycol in benzene, resulted
in a decreased yield due to aromatization. Subsequent treat-
ment of the crude diol 23 with phenylboronic acid gave the
known key intermediate 6 in 70% overall yield from 21 (3
steps). The spectraldata were identicalto those previousyl
Scheme 4. Synthesis of the key intermediate 6: Reagents and conditions: (a) CH3I (10 equiv.), K2CO3 (2.0 equiv.), methanol, re¯ux, 24 h; (b) BuLi
(3.0 equiv.), THF, 2788C, 1 h; (c) (i) Hg(OAc)2 (1.1 equiv.), methanol, rt, (ii) NaBH4 (3.0 equiv.), 5% NaOH aq, 508C; (d) Dess±Martin periodinane
(1.5 equiv.), CH2Cl2 08C, 2 h; (e) ethynylmagnesium bromide (2.0 equiv.), CeCl3 (2.0 equiv.), THF 278 to 2308C, 2 h; (f) HgSO4 (20 mol%), 2% H2SO4
aq, acetone, rt, 40 h; (g) TsOH´H2O (10 mol%), MgSO4 (3.0 equiv.), ethylene glycol, 608C, 24 h; (h) PhB(OH)2 (3.0 equiv.), TsOH´H2O (10 mol%), toluene,
rt, 12 h.

A. Sekine et al. / Tetrahedron 58 (2002) 75±82
79
were carried out in dry solvents under an argon atmosphere.
Tetrahydrofuran (THF) was distilled from sodium benzo-
phenone ketyl. Dichloromethane (CH2Cl2) was distilled
from calcium hydride. Toluene was distilled from sodium.
Praseodymium triisopropoxide (Pr(O-i-Pr)3) was purchased
from Kojundo ChemicalLaboratory, 5-1-28, Chiyoda,
Sakado-shi, Saitama 350-0214, Japan (fax: 181-492-84-
1351). Other reagents were puri®ed by usualmethods.
4.2. General procedure for the catalytic asymetric ring
opening reaction of meso-epoxide with p-anisidine
(R)-1,10-Binaphthol(( R)-BINOL) (428 mg, 1.5 mmol),
which was dried under reduced pressure overnight, was
dissolved in THF (20 mL). To this solution was added a
solution of praseodymium triisopropoxide (Pr(O-i-Pr)3)
(1.0 mmol, 0.2 M in THF) at room temperature and the
resulting mixture was stirred for 30 min. Addition of
Ph3PvO (858 mg, 3.0 mmol) to this solution was followed
by stirring for 1 h at room temparature, then the mixture was
concentrated at the same temperature under reduced pres-
sure for 6 h to give Pr-(R)-BINOL±Ph3PvO complex as a
pale green powder. To a solution of the complex in toluene
(40 mL) was added epoxide 9 (2.06 g, 10 mmol) followed
by slow addition of a solution of p-anisidine (1.44 g,
12 mmol) in toluene (5.0 mL) using a syringe pump tech-
nique for 17 h at 508C. The reaction was quenched by
addition of saturated aqueous citric acid (100 mL) and
diethylether (100 mL). The aqueous alyer was separated
and neutralized by 2N aq. NaOH and the resulting suspen-
sion was extracted with diethylether (200 mL). The organic
layer was washed with sat. NH4Cl(100 mL) and brine
(100 mL). The solvent was evaporated under reduced
pressure and the residue was puri®ed by ¯ash silica gel
column chromatography (hexane/ethyl acetate 10/1) to
afford b-amino alcohol 11 (3.11 g, 80%, 65% ee) (Table 4,
entry 5) as a white powder. Enrichment of enantiomeric
excess was achieved by recrystllization. White powder of
11 (3.11 g) was dissolved in CH2Cl2 (20 mL) and heptane
(200 mL) at 508C. The resulting mixture was allowed to
stand for two days to afford nearly enantiomerically pure
11 (1.20 g, 40%, 95% ee).
Figure 3. NOE observation and coupling constants of 20. The aromatic part
of 20 is simpli®ed for clarity.
reported. The opticalrotation of the synthetic product
25
([a]D ˆ128, c 0.5, CHCl3, 90% ee) was well within the
limits of polarimetric error for the reported value
([a]D ˆ135, c 0.5, CHCl3, .99% ee).27
20
3. Conclusions
In summary, we succeeded in a catalytic asymmetric formal
synthesis of 4-demethoxydaunomycin (3) using the catalytic
asymmetric ring opening reaction of meso-epoxide 9 with
p-anisidene as a key step. The catalytic asymmetric ring
opening reaction of 9 was promoted by a new multi-
functionalasymmetric cataylst system: Pr(O- i-Pr)3-(R)-
BINOL±Ph3PvO complex to afford the desired b-amino
alcohol 11 (80% yield, 65% ee), which was successfully
converted to the known key intermediate 6. Further optimi-
zation of the reaction, determination of the structure of the
catalyst, and application for other meso-epoxides are
currently in progress.
4. Experimental
4.1. General method and material
4.2.1.
(2R,3R)-5,8-Dimethoxy-3-(4-methoxyphenyl-
amino)-1,2,3,4-tetrahydronaphthalene-2-ol (11). 1H
NMR (CDCl3) d 6.77 (d, Jˆ9.0 Hz, 2H), 6.73 (d,
Jˆ9.0 Hz, 2H), 6.64 (d, Jˆ8.5 Hz, 1H), 6.61 (d,
Jˆ8.5 Hz), 3.82 (ddd, Jˆ5.5, 6.0, 6.0 Hz, 1H), 3.77 (s,
3H), 3.74 (s, 3H), 3.71 (s, 3H), 3.47 (ddd, Jˆ5.5, 9.5,
9.5 Hz, 1H), 3.36 (dd, Jˆ6.0, 6.0 Hz, 1H), 2.61 (dd,
Jˆ9.5, 17.0 Hz, 1H), 2.30 (dd, Jˆ9.5, 17.0 Hz, 1H); 13C
NMR (CDCl3) d 152.98, 151.26, 141.57, 124.44, 116.24,
114.90, 107.59, 107.28, 70.24, 57.13, 55.52, 31.30, 29.89;
FTIR (KBr) n 3541, 3310, 2956, 2833 cm21; MS (m/z) 121
Infrared (IR) spectra were recorded on a JASCO FT/IR-410
Fourier transform infrared spectrometer. NMR spectra were
recorded on a JEOL JNM-LA500 spectrometer, operating at
1
500 MHz for H NMR and 125.65 MHz for 13C NMR.
Chemicalshifts in CDCl 3 are reported on the d scale relative
1
to CHCl3 (7.26 ppm for H NMR and 77.00 ppm for 13C
NMR) as an internalreference. The folowing abbreviations
are used to multiplicities: `s' (singlet), `d' (doublet), `t'
(triplet), `m' (multiplet), `br' (broad). Optical rotations are
measured on a JASCO P-1010 polarimeter. EIMS were
measured on a JEOL JMS-BU20 GCmate. Column chroma-
tography was carried out with silica gel Merck 60 (230±400
mesh ASTM). The enatiomeric excess (ee) was determined
by HPLC analysis. HPLC was performed on JASCO HPLC
systems consisting of the following: pump, PU-980; detec-
tor, UVIDEC-100-IV, measured at 250 nm; column,
DAICEL CHIRALPAK OD or OD-H; mobile phase,
hexane-2-propanol; ¯ow rate 1.0 mL min21. Reactions
24
(base peak), 143, 173, 292, 329 (M1); [a]D ˆ295 (c 1.1,
CHCl3, 95% ee); HRMS calcd for C19H23NO4 329.1627,
found 329.1614; HPLC: CHIRALCEL OD-H, 2-propanol/
hexane 1/9, ¯ow 0.7 mL min21, tR 44.2 min (S) and
48.7 min (R); mp 153±1568C.
4.2.2. (1R,2R)-2-(4-Methoxyphenylamino)cyclohexane-
1-ol (13).20b [a]D ˆ223 (c 1.1, CH2Cl2, 31% ee)
26
(Table 3, entry 1); HPLC: CHIRALCEL OD, 2-propanol/

80
A. Sekine et al. / Tetrahedron 58 (2002) 75±82
hexane 1/9, ¯ow 1.0 mL min21, tR 12.8 min (S) and
18.8 min (R).
6.72 (d, Jˆ9.0 Hz, 1H), 6.67 (d, Jˆ9.0 Hz, 1H), 6.11
(dd, Jˆ4.0, 9.5 Hz, 1H), 3.79 (s, 6H), 4.41±4.45 (m,
1H), 3.12 (dd, Jˆ6.0, 17.0 Hz, 1H), 2.86 (dd, Jˆ9.5,
17.0 Hz, 1H); 13C NMR d 151.21, 149.72, 128.59,
122.35, 122.26, 110.50, 108.94, 63.75, 56.03, 55.94,
29.83; FTIR (KBr) n 3314, 2958, 2823, 1485 cm21; MS
4.2.3. (1R,2R)-2-(4-Methoxyphenylamino)-4-cyclohex-
ene-1-ol (15). 1H NMR (CDCl3) d 6.77 (d, Jˆ8.5 Hz,
2H), 6.71 (d, Jˆ8.5 Hz, 2H), 5.56±5.63 (m, 2H), 3.75 (s,
3H), 3.70±3.75 (m, 1H), 3.37 (ddd, Jˆ5.5, 9.0, 9.0 Hz, 1H),
2.55±2.61 (m, 2H), 2.15±2.21 (m, 1H), 1.84±1.90 (m, 1H),
13C NMR (CDCl3) d 152.96, 141.48, 124.76, 116.40,
116.22, 114.87, 70.38, 57.36, 55.73, 33.13, 31.95; FTIR
(KBr) n 3372, 3027, 2910, 2832, 1511 cm21; MS (m/z)
(m/z) 145, 173, 188, 206 (M1); [a]D ˆ1161 (c 1.5,
25
CH2Cl2, 90% ee); HPLC: CHIRALCEL OD, 2-propanol/
hexane 2/98, ¯ow 1.0 mL min21, tR 34.8 min (S) and
37.8 min (R).
165, 188, 201, 219 (M1); [a]D ˆ248 (c 0.9, CHCl3,
24
4.3.2.
(2R,4S)-4,5,8-Trimethoxy-1,2,3,4-tetrahydro-
53% ee) (Table 3, entry 4); HRMS calcd for C13H17NO2
219.1259, found 219.1256; HPLC: CHIRALCEL OD,
2-propanol/hexane 1/9, ¯ow 1.0 mL min21, tR 11.5 min (S)
and 15.5 min (R).
naphthalene-2-ol (20). To a solution of allylic alcohol 8
(402 mg, 1.95 mmol) in 40 mL of methanol was added
mercury(II) acetate (750 mg 2.34 mmol) at room tempera-
ture, and the resulting mixture was stirred for 2 h. After the
disappearance of starting allylic alcohol was established by
TLC, the reaction mixture was added dropwise to a mixture
of NaBH4 (72 mg, 6.0 mmol) and 10% aqueous NaOH
solution (40 mL) at 508C. After completion of addition,
methanolwas removed under reduced pressure, and then
diethylether (200 mL) was added to the mixture. The
aqueous layer was separated and extracted with diethyl
ether (100 mL). The combined organic layers were washed
with saturated NH4Cl(200 mL) and brine (200 mL), and
dried over MgSO4. The solvent was removed under reduced
pressure and the residue was puri®ed by ¯ash silica gel
column chromatography (hexane/ethyl acetate 1/1) to afford
b-methoxyalcohol 20 (343 mg, 74%) as a colorless oil. The
absolute con®guration was determined by converting to its
4.2.4. (1R,2R)-2-(4-Methoxyphenylamino)cyclopentane-
1
1-ol (17). H NMR (CDCl3) d 6.76 (d, Jˆ8.8 Hz, 2H),
6.63 (d, Jˆ8.8 Hz, 2H), 4.01±4.04 (m, 1H), 3.72 (s, 3H),
3.51±3.54 (m, 1H), 2.20±2.28 (m, 1H), 1.96±2.01 (m, 1H),
1.58±1.83 (m, 3H), 1.33±1.41 (m, 1H); 13C NMR d 144.31,
134.23, 114.95, 114.82, 78.32, 63.09, 55.81, 32.90, 31.21,
20.97; MS (m/z) 162, 174, 189, 207 (M1); HRMS calcd for
28
C12H17NO2 207.1259, found 207.1259; [a]D ˆ217 (c 1.1,
CHCl3, 50% ee) (Table 3, entry 5); HPLC: CHIRALCEL
OD, 2-propanol/hexane 1/9, ¯ow 0.5 mL min21, tR 41.8 min
(S) and 60.3 min (R).
4.2.5. (2R,3R)-3-(4-Methoxyphenylamino)-1,2,3,4-tetra-
hydronaphthalene-1-ol (19). H NMR (CDCl3) d 7.01±
1
1
MTPA ester; H NMR (CDCl3) d 6.72 (d, Jˆ8.0 Hz, 1H),
7.14 (m, 4H), 6.79 (d, Jˆ8.5 Hz, 1H), 6.75 (d, Jˆ8.5 Hz,
1H), 3.87±3.93 (m, 1H), 3.52±3.58 (m, 1H), 3.26±3.31 (m,
2H), 2.93 (dd, Jˆ8.5, 14.5 Hz, 1H), 2.62 (dd, Jˆ9.0,
14.5 Hz, 1H); FTIR (neat) n 3372, 3027, 2910, 2832,
6.68 (d, Jˆ8.0 Hz, 1H), 4.67 (t, Jˆ3.0 Hz, 1H), 4.25±4.32
(m, 1H), 3.80 (s, 3H), 3.75 (s, 3H), 3.45 (s, 3H), 3.27 (ddd,
Jˆ1.0, 5.0, 16.0 Hz, 1H), 2.40±2.45 (m, 1H), 2.28 (dd,
Jˆ10.0, 16.0 Hz, 1H), 1.60 (br, 1H), 1.52 (ddd, Jˆ3.0
12.0, 12.0 Hz, 1H); 13C NMR d 152.0, 151.2, 125.9,
125.9, 109.9, 108.3, 72.6, 63.9, 57.2, 56.0, 55.8, 33.1,
25.7; FTIR (neat) n 3396, 2937, 2832, 1482 cm21; MS
28
1511 cm21; MS (m/z) 117, 136, 269 (M1); [a]D ˆ266 (c
0.3, CHCl3, 36% ee) (Table 3, entry 7); HRMS calcd for
C13H17NO2 269.1416, found 269.1423; HPLC: CHIRAL-
CEL OD, 2-propanol/hexane 1/9, ¯ow 1.0 mL min21, tR
18.4 min (S) and 25.5 min (R).
(m/z) 189, 207, 238 (M1); [a]D ˆ245 (c 1.1, CHCl3,
26
90% ee); HRMS calcd for C13H18O4 238.1205, found
238.1206.
4.3. Procedure for the synthesis of the key intermediate 6
from b-amino alcohol 11
4.3.3.
(S)-4,5,8-Trimethoxy-3,4-dihydro-1H-naphtha-
lene-2-one (7). To a solution of b-methoxyalcohol 20
(780 mg, 3.3 mmol) in CH2Cl2 (50 mL) was added Dess±
Martin periodinane (2.10 g, 4.95 mmol) at 08C. The result-
ing mixture was stirred at room temperature for 1.5 h. The
mixture was diluted with CH2Cl2 (50 mL) and quenched by
addition of saturated aq. NaHCO3 (200 mL). The mixture
was stirred for 20 min and ®ltered through a pad of Celite.
The ®ltrate was evaporated and the residue was puri®ed by
¯ash silica gel column chromatography (hexane/ethyl
acetate 4/1) to afford ketone 7 (735 mg, 95%) as a yellow
4.3.1. (R)-5,8-Dimethoxy-1,2-dihydronaphthalene-2-ol
(8). To a solution of b-amino alcohol 11 (300 mg,
0.911 mmol, 95% ee) in methanol (5.0 mL) was added
MeI (1.30 g) and K2CO3 (251 mg) at room temperature.
The resulting mixture was re¯uxed for 24 h. The reaction
was concentrated under reduced pressure to give crude
quaternary ammonium salt as a white solid, which was
directly used to the next step. The crude solid was
suspended in THF (5.0 mL) and a solution of BuLi
(3.0 mmol, 1.48 M in hexane) was added to the mixture at
2788C. The resulting mixture was stirred for 1 h at the same
temperature. The reaction was quenched by addition of satu-
rated NH4Cl(50 mL) and diethylether (50 mL). The
organic layer was separated, washed with brine (50 mL),
and dried over Na2SO4. The solvent was evaporated under
reduced pressure and the residue was puri®ed by ¯ash silica
gelcoulmn chromatography (hexane/ethylacetate 4/1) to
afford allylic alcohol 8 (97 mg, 2 steps 52, 90% ee) as a
1
oil; H NMR (CDCl3) d 6.79 (d, Jˆ9.0 Hz, 1H), 6.75 (d,
Jˆ9.0 Hz, 1H), 5.13 (dd, Jˆ3.0, 3.0 Hz, 1H), 3.81 (s, 3H),
3.76 (s, 3H), 3.66 (d, Jˆ21.5 Hz, 1H), 3.39 (d, Jˆ21.5 Hz,
1H), 3.23 (s, 3H), 2.91 (dd, Jˆ3.0, 16.0 Hz, 1H), 2.49 (dd,
Jˆ3.0, 16.0 Hz, 1H); 13C NMR d 208.1, 151.2, 150.8,
124.9, 124.5, 110.7, 108.9, 70.6, 56.1, 56.0,55.8, 44.2,
37.3; FTIR (neat) n 2937, 1720, 1487, 1261, 1082 cm21
;
26
MS (m/z) 176, 204, 236 (M1); [a]D ˆ2133 (c 0.8, CH2Cl2,
90% ee); HRMS calcd for C13H16O4 236.1048, found
236.1046.
1
white solid; H NMR (CDCl3) d 6.93 (d, Jˆ9.5 Hz, 1H),

A. Sekine et al. / Tetrahedron 58 (2002) 75±82
81
4.3.4. (2S,4S)-2-Ethynyl-4,5,8-trimethoxy-1,2,3,4-tetra-
hydronaphthalene-2-ol (21). 0.5 M THF solution of
ethynylmagnesium bromide was freshly prepared from
1.0 M THF solution of ethylmagnesium bromide and
acetylene. Cerium(III) chloride (anhydrous, 600 mg
2.5 mmol) was dried under reduced pressure for 1 h at
1008C and then for 5 h at 1408C. After suspending cerium
chloride in THF (3.0 mL), it was sonicated for 2 h. The
resulting slurry was vigorously stirred for 12 h. The solution
of ethynylmagnesium bromide (5.0 mL, 2.5 mmol 0.5 M in
THF) was added at 2788C and the resulting mixture was
stirred at 2308C for 1 h. A solution of ketone 7 (295 mg
1.25 mmol) in THF (3.0 mL) was added to the mixture at the
same temperature and stirred for 2 h. The reaction was
quenched by addition of saturated NH4Claq. (50 mL),
extracted with diethylether (50 mL), washed with 1N HCl
(50 mL), saturated NaHCO3 aq. (50 mL) and brine (50 mL),
and dried over Na2SO4. The solvent was evaporated under
reduced pressure and the residue was puri®ed by ¯ash silica
gelcoulmn chromatography (hexane/ethylacetate 4/1) to
1H); MS (m/z) 259, 274, 310, 350; HRMS calcd for
C18H26O7 254.1679, found 254.1684. To a solution of the
crude 23 in toluene (2.0 mL) was added phenylboronic acid
(208 mg, 1.71 mmol) and p-toluenesulfonic acid mono-
hydrate (10 mg, 0.057 mmol) at room temperature. The
resulting mixture was stirred for 12 h at the same tempera-
ture. After completion of the reaction, saturated NaHCO3
(2 mL) and ethylacetate (10 mL) were added. The organic
layer was separated, washed with brine (10 mL), and dried
over NaSO4. The solvent was evaporated under reduced
pressure and the residue was puri®ed by ¯ash silica gel
column chromatography (hexane/ethyl acetate 8/1) to afford
benzeneboronate 6 (158 mg, 3 steps 70%) as an oily solid;
1H NMR (CDCl3) d 7.68 (d, Jˆ6.7 Hz, 2H), 7.18±7.27 (m,
2H), 6.65 (s, 2H), 5.58 (dd, Jˆ1.5, 1.5 Hz, 1H), 3.99±4.10
(m, 4H), 3.81 (s, 3H), 3.69 (s, 3H), 3.11 (d, Jˆ18.3 Hz, 1H),
2.86 (d, Jˆ18.3 Hz, 1H), 2.31 (dd, Jˆ1.5, 13.5 Hz, 1H),
1.91 (dd, Jˆ1.5, 13.5 Hz, 1H), 1.48 (s, 3H); 13C NMR d
152.25, 151.53, 134.17, 130.65, 130.64, 127.59, 127.46,
123.98, 127.59, 127.46, 123.98, 111.79, 109.97, 109.42,
76.05, 66.19, 66.06, 61.99, 57.00, 55.80, 33.08, 31.31,
afford propargylaclohol
21 (248 mg, 76%) as a white
1
powder; H NMR (CDCl3) d 6.76 (d, Jˆ8.5 Hz, 1H), 6.72
(d, Jˆ8.5 Hz, 1H), 5.15 (s, 1H), 4.73 (dd, Jˆ1.0, 3.5 Hz,
1H), 3.81 (s, 3H), 3.76 (s, 3H), 3.50 (s, 3H), 3.47 (dd, Jˆ1.0,
17.0 Hz, 1H), 2.81 (d, Jˆ17.0 Hz, 1H), 2.74 (ddd, Jˆ1.0,
1.0, 13.5 Hz, 1H), 2.49 (s, 1H), 1.94 (dd, Jˆ3.5, 13.5 Hz,
1H); 13C NMR d 151.8, 151.4. 123.7, 123.5, 110.3, 108.3,
71.8, 70.4, 67.9, 65.4, 56.0, 55.8, 38.3, 36.1, 17.4; FTIR
(neat) n 3425, 3268, 2926, 1482 cm21; MS (m/z) 179,
22.71, 19.87; FTIR (neat) n 2958, 1601, 1484, 1321 cm21
;
MS (m/z) 177, 259, 310, 396 (M1); [a]D ˆ128.5 (c 0.5,
25
CHCl3, 90% ee) (lit.27 [a]D ˆ135.8 (c 0.5, CHCl3));
20
HRMS calcd for C22H25BO6 396.1744, found 396.1737.
Acknowledgements
199, 230, 262(M1); [a]D ˆ29.1 (c 0.4, CH2Cl2, 90%
25
This research was supported by CREST, The Japan Science
and Technology Corporation (JST), RFTF of Japan Society
for the Promotion of Science, and a Grant-in-Aid for
Scienti®c Research on Priority Areas (A) `Exploitation of
Multi-Element Cyclic Molecules' from the ministry of
Education, Culture, Sports, Science and Technology, Japan.
ee); HRMS calcd for C15H18O4 262.1205, found 262.1205.
4.3.5. (3S)-cis-[1-(1,1-Ethylenedioxy)ethyl]-1,2,3,4-tetra-
hydro-5,8-dimethoxynaphthalene-1,3-diyl benzeneboro-
nate (6). To a solution of propargyl alcohol 21 (150 mg,
0.573 mmol) in acetone (1.5 mL) and 2% aqueous H2SO4
(0.15 mL) was added mercury(II) sulfate (34 mg,
0.107 mmol) at room temperature. The resulting mixture
was stirred for 40 h at the same temperature. The reaction
was quenched by addition of saturated NaHCO3 aq. (2 mL).
Acetone was evaporated under reduced pressure, and then
ethylacetate (10 mL) and water (10 mL) were added to the
residue. The organic layer was separated, washed with
brine, and dried over Na2SO4. The organic solvent was
evaporated under reduced pressure to afford crude 22
(148 mg). The crude 22 was dissolved in ethylene glycol
(3 mL), and then p-toluenesulfonic acid monohydrate
(10 mg, 0.057 mmol) and MgSO4 (192 mg, 1.6 mmol) was
added at room temperature. The resulting mixture was stir-
red for 24 h at 608C. The reaction was quenched by addition
of saturated NaHCO3 aq. (2 mL) and ethylacetate (5 mL).
The aqueous layer was separated and extracted with ethyl
acetate (2£5 mL). The combined organic layers were
washed with brine (5 mL) and dried over Na2SO4. The
solvent was evaporated under reduced pressure and the resi-
due was pumped up for 3 h at 508C to afford crude 23 (ca.
150 mg) as a mixture with small amount of ethylene glycol.
This crude mixture was used for the next step without
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