Enzymatic desymmetrization/resolution of epoxydiols derived from 1,4-naphthoquinone, 5-hydroxy-1,4-naphthoquinone and 5,8-dihydroxy-1,4- naphthoquinone

Article abstract of DOI:10.1016/j.tetasy.2004.07.051

The enzymatic desymmetrization/resolution of epoxydiols generated from the basic epoxidation and reduction of 1,4-naphthoquoinone, 5-hydroxy-1,4- naphthoquinone and 5,8-dihydroxy-1,4-naphthoquinone is described. 2,3-Epoxy-1^α,2^α,3^α,4 ^α-tetrahydronaphthalene-1,4-diol and 5,8-diallyloxy-2,3-epoxy- 1^α,2^α,3^α,4 ^α-tetrahydronaphthalene-1,4-diol were desymmetrized in the presence of isopropenyl acetate using Burholderia cepacia lipase and Candida antartica lipase B, respectively. An enzymatic resolution of 8-benzyloxy-2,3-epoxy-1^α,2^α,3 ^α,4^α-tetrahydronaphthalene-1,4-diol using B. cepacia lipase in isopropenyl acetate is also described.

Full text of DOI:10.1016/j.tetasy.2004.07.051

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 15 (2004) 2853–2860
Enzymatic desymmetrization/resolution of epoxydiols derived
from 1,4-naphthoquinone, 5-hydroxy-1,4-naphthoquinone and
5,8-dihydroxy-1,4-naphthoquinone
Russell L. Betts, Sean T. Murphy and Carl R. Johnson*
Department of Chemistry, Wayne State University, Detroit, MI 48202, USA
Received 28 May 2004;accepted 13 July 2004
Available online 11 September 2004
Abstract—The enzymatic desymmetrization/resolution of epoxydiols generated from the basic epoxidation and reduction of 1,
4-naphthoquoinone, 5-hydroxy-1,4-naphthoquinone and 5,8-dihydroxy-1,4-naphthoquinone is described. 2,3-Epoxy-1a,2a,3a,4a-tetra-
hydronaphthalene-1,4-diol and 5,8-diallyloxy-2,3-epoxy-1a,2a,3a,4a-tetrahydronaphthalene-1,4-diol were desymmetrized in the pres-
ence of isopropenyl acetate using Burholderia cepacia lipase and Candida antartica lipase B, respectively. An enzymatic resolution of
8-benzyloxy-2,3-epoxy-1a,2a,3a,4a-tetrahydronaphthalene-1,4-diol using B. cepacia lipase in isopropenyl acetate is also described.
ꢀ 2004 Elsevier Ltd. All rights reserved.
OH
OH
O
O
O
O
O
O
1. Introduction
Our laboratory has been involved in a research program
that utilizes simple, readily available, achiral starting
material such as cyclopentadiene, benzene, p-benzoqui-
none and cycloheptatriene as the starting point in the
synthesis of densely functionalized, enantiopure, bioac-
tive molecules.1 This strategy has led to the synthesis
of numerous biologically interesting compounds such
as: (+)- and (ꢀ)-bromoxone,2 (+)- and (ꢀ)-harveynone,3
(ꢀ)-tricholomen A,3 LL-C10037a,4 (ꢀ)-SS20846A,5 the
core ring system of zaragozic acid6 and a variety of
unnatural amino acids.7 A feature common to each of
these syntheses is an enzymatic resolution8 or desym-
metrization8 to establish the absolute stereochemistry
of a key intermediate.
OH
1
2
3
2. Results and discussion
2.1. 1,4-Naphthoquinone
The first step in the functionalization of 1 was the basic
epoxidation of the quinone type alkene. Initial attempts
towards the epoxidation of 1 (NaOH, H2O2 at 0ꢁC) re-
sulted in the production of epoxide 4 along with the gen-
eration of aromatic impurities due to the decomposition
of the target epoxide in the high pH medium. The
decomposition of the 4 was avoided by substituting
K2CO3 for NaOH. This simple modification of the reac-
tion conditions delivered epoxide 4 in 80% yield. Subse-
quent reduction of 4 with NaBH4 in methanol at ꢀ78ꢁC
delivered meso-syn,syn-epoxydiol 5.10 The excellent dia-
stereoselectivity of this reduction is probably due to the
epoxide oxygen effectively blocking approach of the
reducing species to the a-face, forcing reduction to occur
exclusively from the less hindered b-face (Fig. 1).
Desymmetrization of 5, upon incubation with Burholde-
ria cepacia lipase11 (Amano Lipase PS) using isoprop-
enyl acetate (IPA) as the acetate donor, produced
acetate 6 (1R,2R,3S,4S) in 85% yield with >95% ee as
Our interest in the production of enantiopure com-
pounds using enzymatic transformations has led us to
explore the previously overlooked 1,4-naphthoquinones.
Herein we report the transformation of 1,4-naphthoqui-
none 1, 5-hydroxy-1,4-naphthoquinone (juglone) 29a
and 5,8-dihydroxy-1,4-naphthoquinone (naphthazarin)
3,9b into highly oxygenated enantiopure compounds
poised for further elaboration into bioactive target
molecules.
*
Corresponding author. Tel.: +1 313 577 2579;fax: +1 313 577
2554;e-mail: crj@chem.wayne.edu
0957-4166/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2004.07.051

2854
R. L. Betts et al. / Tetrahedron: Asymmetry 15 (2004) 2853–2860
-
O
O
O
H
β-face
leasthindered
approach
a
c
b
2
O
O
OBn
OBn
10
( )-11
OH
OAc
d
O
O
+
(+)-12
-
H
α-Face
hindered
approach
OH OBn
OH OBn
( )-12
(+)-13
OAc
OH
Figure 1. The b-face approach of the reducing species is favored due to
the steric bulk of the epoxide on the a-face.
e
f
(+)-13
O
O
determined by F19 NMR of
derivative.12
a
MosherÕs ester
TBSO
14
OBn
TBSO
15
OBn
Protection of the (R)-alcohol of 6 with TBSCl/imidazole
delivered silyl ether 7. The latter upon subsequent
hydrolysis with K2CO3 in methanol produced 8 with
the (S)-alcohol unprotected (Scheme 1). This simple pro-
tection/deprotection strategy enables the liberation of
each prochiral alcohol independent of the other and
could be used to generate either enantiomer of a target
compound from the same biocatalytic transformation.
Scheme 2. Reagents and conditions: (a) BnBr, AgO, CH2Cl2, 65%;(b)
H2O2, K2CO3, H2O/acetone, 0ꢁC, 87%;(c) K-Selectride, ꢀ78ꢁC, 60%;
(d) 200wt% Amano Lipase PS, isopropenyl acetate, 50ꢁC, 16h, (+)-13
30%, P95% ee, (+)-12 31%, P95% ee;(e) TBSOTf, imidazole,
CH2Cl2, 75%;(f) K 2CO3, MeOH, 93%.
sulted in the complete decomposition of starting mate-
rial. The decomposition of the starting material was
minimized by simply protecting the phenol moiety of 2
as a benzyl ether. Incubating 2 with benzyl bromide/
AgO produced benzyl ether 10, which, upon exposure
to K2CO3 and H2O2 delivered the desired epoxide 11
(Scheme 2).
The relative stereochemistry of acetate 6 was confirmed
by X-ray crystal structure analysis. The predicted abso-
lute stereochemistry of 6 (1R,2R,3S,4S) was confirmed
indirectly by X-ray crystal structure analysis of
(1S,2S,3S,4S)-chloride 9, generated upon incubation of
6 with mesyl chloride and triethylamine for 18h (Scheme
1).
The reduction of diketone ( )-11 was expected to pro-
duce the racemic syn,syn-epoxydiol ( )-12. However,
NaBH4 reduction of ( )-11 produced a mixture of diol
diastereomers. Fortunately, when ( )-11 was exposed
to the sterically demanding reducing agent K-Selectride,
( )-12 was produced as the sole product. The selectivity
of the reduction was examined in detail in the napht-
hazarin 3 case (vide infra). Incubation of ( )-12 with
Amano Lipase PS in the presence of IPA at 50ꢁC re-
sulted in the generation of enantiopure acetate (+)-13
(30% yield, >95% ee) and the recovery of enantiopure
diol (+)-12 (31% yield, >95% ee). The enantiomeric ex-
cess was determined using chiral shift analysis
[300MHz, (+)-Eu(hfc)3].13 The absolute stereochemistry
for compounds 12 and 13 were established using the
simple model for predicting the enantiomer (or prochiral
alcohol) that will be acetylated preferentially in the reac-
tion between a lipase and the secondary alcohol of a
substrate (Fig. 2).14 Using this simple model and the
stereochemical data obtained for the structurally similar
acetate 6 the absolute stereochemistry was determined to
be (1R,2R,3S,4S) for (+)-13 and (1S,2S,3R,4R) for (+)-
2.2. 5-Hydroxy-1,4-naphthoquinone
The elaboration and resolution of 2 followed the general
protocol established for 1 with some minor variations.
Initial attempts towards the basic epoxidation of 2 re-
OH
O
a
c
b
1
O
O
OH
O
4
5
OTBS
OTBS
e
O
O
d
OH
OAc
OH
O
7
8
f
Cl
OAc
6
O
(Ac)
HO
H
OAc
O
small
group
9
large
OBn OH
group
Scheme 1. Reagents and conditions: (a) H2O2, K2CO3, H2O/acetone,
0ꢁC, 80%;(b) NaBH 4, MeOH, ꢀ78ꢁC, 93%;(c) 200wt% Amano
Lipase PS, isopropenyl acetate, 50ꢁC, 24h, 85%;(d) TBSCl, imidazole,
85%;(e) Na 2CO3, methanol, 100%;(f) MsCl, TEA, 18h, 97%.
Figure 2. Simple model used to predict the enantioselective acylation
of a secondary alcohol substrate.

R. L. Betts et al. / Tetrahedron: Asymmetry 15 (2004) 2853–2860
2855
12. Treatment of 13 with TBSOTf and imidazole deliv-
ered silyl ether 14, which, upon hydrolysis with
K2CO3, revealed alcohol 15.
of all possible diastereomers (Table 1). The reduction
selectivity problem was solved by utilizing L-Selectride
at ꢀ78ꢁC, which delivered meso-syn,syn-epoxydiol 18
as the only diastereomer, which could be detected by
NMR. It was presumed that the diastereomer formed
was meso-syn,syn-epoxydiol 18, which was later con-
firmed by X-ray analysis after enzymatic acetylation
(vide infra). The issue of stereochemical control in the
double reduction is addressed below.
2.3. 5,8-Dihydroxy-1,4-naphthoquinone
The functionalization of naphthazarin followed the gen-
eral scheme for 1,4-naphthoquinone 1 with some nota-
ble exceptions (Scheme 3). Naphthazarin
3 was
conveniently prepared from 1,5-dinitronaphthalene by
the Fierz–David and Stoeker15 modification of FieserÕs
method.16 Protection of the two phenols with allyl
groups was accomplished using Ag2O and allyl iodide
to give 16. The allyl protecting group was chosen for
two reasons: (1) it was anticipated that it would be easily
removed and (2) its relatively small size was not ex-
pected to interfere with the enzymatic desymmetriza-
tion. Epoxidation to give 17 with hydrogen peroxide
and sodium bicarbonate proceeded in good yield as in
the 1,4-naphthoquinone 1 case. However, reduction of
the ketone moieties in 17 with sodium borohydride,
which in the 1,4-naphthoquinone 1 example delivered
the meso-syn,syn-epoxydiol 5 with excellent diastereose-
lectivity, gave in the naphthazarin 3 analogue a mixture
At this point, we attempted to desymmetrize meso-diol
18 by enzymatic acylation. The conditions, which were
efficacious in the 1,4-naphthoquinone 1 series (Amano
Lipase PS, isopropenyl acetate, 50ꢁC led to slow conver-
sion to the monoacetate 19 with concomitant decompo-
sition leading to an unidentified side product. After
screening various enzymes, solvents and acetyl donors,
we found that the reaction proceeded cleanly at room
temperature with Candida antartica lipase B (Novo
SP-435) in 4:1 toluene/vinyl acetate. The absolute stere-
ochemistry of 19 was assigned based on the model as
(1R,2R,3S,4S) using the simple model shown in Figure
2 and the results obtained in the 1,4-naphthoquinone
example. The diacetate was not observed by TLC;the
acetylation appeared to be highly enantioselective and
this was confirmed by Mosher ester derivative analysis
(>98% ee by 19F NMR). The X-ray crystal analysis con-
firmed the relative stereochemistry but could not con-
firm absolute stereochemistry.
AllylO
O
O
AllylO
AllylO
O
c
a
b
O
3
Removal of the allyl protecting groups proved to be dif-
ficult. Various conditions based on p-allyl formation or
alkene isomerization followed by hydrolysis either
showed no reaction or decomposition.17 The decomposi-
tion is likely due to the instability of the hydroquinone
21 in the presence of acid, base or oxygen. Considering
the electron rich nature of the allyl-protected hydroqui-
none 19, we devised a two step deprotection strategy.
First, the quinone 20 was formed by oxidation with ceric
ammonium nitrate,18 thereby removing the allyl groups.
Reduction to hydroquinone 21 was accomplished under
neutral catalytic hydrogenation conditions and required
minimal work-up. Hydroquinone 21 proved to be very
unstable to acid, base and oxygen and was therefore
transformed immediately into the more stable benzyl-
idene acetal 22 with the absolute configuration of
(1S,2S,3R,4R). Fortunately, only one diastereomer was
observed by NMR, which was shown by NOE to have
the hydrogen on the b-face (Fig. 3), in agreement with
calculations performed on the two diastereomers.19,20
AllylO
O
16
17
AllylO
AllylO
OH
OH
AllylO
OAc
O
OAc
OH
d
e
O
O
O
AllylO
OH
O
20
19
18
OH OAc
OH OAc
O
g
f
O
O
O
OH OH
Ph
22
21
Scheme 3. Reagents and conditions: (a) allyl iodide, Ag2O, 81%;(b)
H2O2, Na2CO3, 96%;(c) L-Selectride, ꢀ78ꢁC, 82%;(d) 200wt% Novo
SP-435, isopropenyl acetate, toluene, 4d, 93%, P98% ee;(e) CAN,
98%;(f) H 2, Pd/C;(g) PhCH(OMe) 2, PTSA, 58% for two steps.
Table 1. Diastereomeric ratios obtained in reductions of diketone 17
Conditions
AllylO
OH
AllylO
AllylO
OH
OH
AllylO
AllylO
OH
OH
O
O
O
AllylO
OH
18
23
24
NaBH4, 0ꢁC, MeOH/CH2Cl2
NaBH4, ꢀ40ꢁC, MeOH/CH2Cl2
L-Selectride, ꢀ78ꢁC, THF
12%
8%
63%
57%
<2%
25%
35%
<2%
>96%

2856
R. L. Betts et al. / Tetrahedron: Asymmetry 15 (2004) 2853–2860
attack with the relatively small hydride source sodium
OH OAc
H
borohydride. With the sterically demanding L-Selec-
tride, the reduction from the a-face is prevented by the
steric bulk of the epoxide, and the reduction is forced
to proceed from the b-face. In the case of 4, which has
only minimal torsional strain, the bulk of the epoxide
controls the reduction with sodium borohydride and
gives the desired b-face attack.
2%
O
H
H
O
O
H
7%
12%
Ph
Figure 3. Observed NOE signals confirming the stereochemistry of
benzylidene acetal 22.
2.4. Examination of the reduction of 17
3. Conclusion
The diastereoselectivity of the reduction of diketone 17
was examined in detail. Table 1 shows the diastereo-
meric ratios for the reduction of diketone 17 under three
different conditions: Sodium borohydride at 0 and 40ꢁC,
and L-Selectride reduction at ꢀ78ꢁC. Three diastereo-
mers are possible: syn,syn-18, anti-syn-23 and anti,anti-
24. The reduction with sodium borohydride favours
attack by the hydride from the a-face, which, surprisingly,
is on the same face as the epoxide. Recall that in the 1,4-
naphthoquinone 1 series, reduction of the diketone 4 by
sodium borohydride gave exclusively syn,syn-diol 5. The
reduction of 15 by L-Selectride, in contrast, only shows
attack from the b-face, away from the bulk of the
epoxide.
The elaboration of 1,4-naphthoquinone 1, 5-hydroxy-
1,4-naphthoquinone 2 and 5,8-dihydroxy-1,4-naphtho-
quinones 3 has led to the development of three novel
highly functionalized enantiopure intermediates. The
absolute stereochemistry was established by an enzy-
matic resolution of racemic diol ( )-12 and enzymatic
desymmetrizations of meso-diols 5 and 18. We anticipate
that the highly functionalized, enantiopure intermedi-
ates presented in this work will be valuable for the asym-
metric synthesis of a variety of bioactive natural and
unnatural targets.
4. Experimental
The results can be understood by examining the tor-
sional strain involved in the reduction (Fig. 4). The allyl-
oxy substituents, which are peri to the carbonyls, have
considerable bulk and force the carbonyls out of the
plane of the aromatic ring. In the case of diketone 4,
the hydrogens peri to the carbonyls have a much smaller
effect. The calculated angle between the carbonyl and
the plane of the ring is 32ꢁ for 17 and 16ꢁ for 4,19 where
the carbonyl is bent away from the epoxide in both
cases. Thus, in the case of 17, there is considerably more
torsional strain involved in reduction from the b-face
because the carbonyl oxygen must be pushed past the
allyloxy substituent. This leads to preferential a-face
4.1. 2,3-Epoxy-1,2b,3b,4-tetrahydronaphthalene-1,4-dione
4
To a cooled (0ꢁC) solution of 1,4-naphthoquinone 1
(8g, 50.6mmol) in acetone (500mL) was added a solu-
tion of basic peroxide (30% solution in water H2O2,
2.58g, 75.9mmol;K CO3, 10.5g, 75.9mmol). The reac-
2
tion mixture was stirred for 2h until the reaction was
determined to be complete by TLC. The solution was
quenched with aqueous FeSO4 and extracted with ethyl
acetate (4 · 300mL). The combined organic layers were
dried with MgSO4, filtered, concentrated and purified by
flash chromatography to afford 7.04g (80%) of 4:
1
mp = 123–125ꢁC; H NMR (400MHz, CDCl3): d 4.01
(s, 2H), 7.65–8.1 (m, 4H); 13C NMR (75MHz, CDCl3):
d 55.27, 127.20, 131.73, 134.70, 190.70;HRMS (EI) cal-
culated for C10H6O3 (M+) 174.0317, found 174.0318.
O
O
O
4
-
H
4.2. 2,3-Epoxy-1a,2a,3a,4a-tetrahydronaphthalene-1,4-
diol 5
º
16
AllylO
AllylO
O
O
-
H
To a cooled (ꢀ78ꢁC) solution of epoxide 4 (3.17g,
18.2mmol) in methanol (180mL) was added sodium
borohydride (692mg, 18.2mmol). The reaction mixture
was stirred for 3h until the reaction had reached room
temperature and was determined to be complete by
TLC. The reaction was quenched with H2O (50mL)
and extracted with ethyl acetate (4 · 50mL). The com-
bined organic layers were dried with MgSO4, filtered,
concentrated and purified by flash chromatography to
afford 3g (93%) of 5: mp = 173–175ꢁC; 1H NMR
(300MHz, CD3OD): d 3.35, (s, 2H) 4.89 (s, 2H), 7.21
(m, 2H), 7.51 (m, 2H); 13C NMR (75MHz, CD3OD):
d 55.15, 66.78, 125.60, 127.29, 134.79;HRMS (EI) cal-
culated for C10H10O3 (M+) 178.0630, found 178.0634.
O
17
-
large H
32º
-
small H
Figure 4. Torsional strain between the carbonyl oxygen and allyloxy
moiety of 17 is responsible for the favourable approach of a small
hydride source from the a-face.

R. L. Betts et al. / Tetrahedron: Asymmetry 15 (2004) 2853–2860
2857
4.3. (1R,2R,3S,4S)-4-Acetoxy-2,3-epoxy-1,2,3,4-tetra-
hydronaphthalen-1-ol 6
culated for C16H24O3Si (M+ꢀC4H9) 235.0790, found
235.0791.
To a solution of diol 5 (100mg, 0.562mmol) in isoprop-
enyl acetate (6mL) was added Amano Lipase PS
(200mg, 200wt%). This solution was stirred at 50ꢁC
for 24h until the reaction was determined to be complete
by TLC. The solution was concentrated and the solid
residue was recrystallized from methanol. The solid
crystalline material was filtered, rinsed with pet. ether
4.6. (1S,2S,3S,4S)-1-Acetoxy-4-chloro-2,3-epoxy-
1,2,3,4-tetrahydronaphthalene 9
To a solution of alcohol 6 (250mg, 1.14mmol) in CH2Cl2
(10mL) was added triethylamine (288mg, 2.85mmol)
and methanesulfonyl chloride (260mg, 2.27mmol). The
reaction mixture was stirred for 18h until the reaction
was determined to be complete by TLC. The solution
was quenched with water and the aqueous layer was ex-
tracted with CH2Cl2 (3 · 50mL). The combined organic
layers were dried with MgSO4, filtered, concentrated and
(2 · 10mL) and concentrated to reveal 105mg (85%)
21
of 6: ½aŠ ¼ þ4:0 (c 1.0, CH2Cl2);mp = 189–190 ꢁC;
D
1H NMR (300MHz, CDCl3): d 2.28 (S, 3H), 3.74 (dd,
1H, J = 1.8, 1.8Hz), 3.77 (dd, 1H, J = 1.8, 1.8Hz),
4.93 (br s, 1H), 6.17 (br s, 1H), 7.18–7.20 (m, 1H),
7.29–7.40 (m, 2H), 7.62–7.65 (m, 1H); 13C NMR
(75MHz, CDCl3): d 21.1, 52.77, 54.71, 66.84, 68.58,
125.57, 126.59, 128.07, 128.47, 129.343, 134.50, 171.07;
HRMS (EI) calculated for C12H11O4 (M+) 220.0736,
found 220.0733.
purified by flash chromatography to afford 263mg (97%)
21
of 9: mp = 145–145.5ꢁC; ½aŠ ¼ þ109 (c 1.27, CH2Cl2);
D
1H (300MHz, CDCl3): d 2.30 (s, 3H), 3.80 (d, 1H,
J = 1.2Hz), 3.81 (d, 1H, J = 1.2Hz), 5.42 (br s, 1H),
6.39 (br s, m), 7.28–7.43 (m, 4H); 13C NMR (75MHz,
CDCl3): d 21.02, 52.15, 52.79, 55.02, 68.42, 126.02,
128.73, 129.73, 129.81, 130.27, 131.58, 170.79;HRMS
(EI) calculated for C12H11ClO3 (M+) 238.0397, found
238.0395.
4.4. (1S,2S,3S,4R)-1-Acetoxy-4-(tert-butyldimethylsilyl-
oxy)-2,3-epoxy-1,2,3,4-tetrahydronaphthalene 7
4.7. 8-Benzyloxy-2,3-epoxy-1,2a,3a,4-tetrahydronaphtha-
len-1,4-dione 11
To a solution of acetate 6 (95mg, 0.432mmol) in
CH2Cl2 (4mL) was added imidazole (88mg, 1.30mmol)
and TBSCl (71mg, 0.475mmol). This solution was stir-
red for 24h until the reaction was determined to be com-
plete by TLC. The reaction mixture was quenched with
1M HCl (1 · 30mL) and extracted CH2Cl2 (4 · 30mL).
The combined organic layers were dried with MgSO4, fil-
To a cooled (0ꢁC) solution of 10 (792mg, 3.0mmol) in
acetone (30mL) was added a basic peroxide solution
(H2O2, 459mg, 13.5mmol;K CO3, 1.66g, 12.0mmol).
2
The reaction mixture was stirred for 2h at which time
the solution was quenched with aqueous FeSO4 and
extracted with ethyl acetate (4 · 150mL). The combined
organic layers were dried with MgSO4, filtered, concen-
trated and purified by flash chromatography to afford
731mg (87%) of 11. 1H NMR (300MHz, CDCl3): d
3.99 (s, 2H), 5.20 (d, 1H, J = 12.3Hz), 5.27 (d, 1H,
J = 12.3Hz), 7.26–7.65 (m, 8H); 13C (125MHz,
CDCl3): d 55.21, 55.44, 70.91, 119.49, 119.60, 126.74,
128.06, 128.69, 135.00, 135.75, 189.95, 191.66;HRMS
(EI) calculated for C17H12O4 (M+) 280.0736, found
280.0736.
tered, concentrated and purified by flash chromatography
21
to afford 121mg (85%) of 7: mp = 86–87ꢁC; ½aŠ ¼ ꢀ22:0
D
(c 1.50, CH2Cl2); 1H (300MHz, CDCl3): d 3.06 (dd, 1H,
J = 1.2, 5.1Hz), 3.70 (dd, 1H, J = 1.2, 4.8Hz), 5.03 (br s,
1H), 6.15 (br s, 1H), 7.18–7.53 (m, 4H); 13C NMR
(75MHz, CDCl3): d ꢀ4.81, ꢀ4.33, 18.20, 21.05, 25.81,
51.81, 54.40, 67.94, 68.88, 124.76, 125.83, 127.42,
128.03, 129.12, 134.34, 171.00;HRMS (EI) calcu-
lated for C18H26O4Si (M+ꢀC4H9) 277.0896, found
277.0894.
4.5. (1S,2S,3S,4R)-2,3-Epoxy-4-(tert-butyldimethylsilyl-
oxy)-1,2,3,4-tetrahydronaphthalen-1-ol 8
4.8. 8-Benzyloxy-2,3-epoxy-1a,2a,3a,4a-tetrahydronaph-
thalene-1,4-diol 12
To a solution of acetate 7 (956mg, 2.90mmol) in meth-
anol (30mL) was added sodium carbonate (100mg).
This solution was stirred for 1h until the reaction was
determined to be complete by TLC. The solution was
concentrated and partitioned between H2O and ethyl
acetate. The aqueous layer was extracted with ethyl
acetate (4 · 100mL) and the combined organic layers
were dried with MgSO4, filtered, concentrated and puri-
To a cooled (ꢀ78ꢁC) solution of epoxide 11 (296mg,
1.06mmol) in THF (10mL) was added K-selectride
(705mg, 3.17mmol). This solution was stirred for 3h
until the reaction had reached room temperature and
was determined to be complete by TLC. The solution
was quenched with H2O and extracted with ethyl acetate
(4 · 75mL). The combined organic layers were dried
with MgSO4, filtered, concentrated and purified by flash
1
fied by flash chromatography to afford 835mg (100%)
chromatography to afford 161mg (54%) of ( )-12: H
21
of 8 as a clear oil: ½aŠ ¼ ꢀ18 (c 1.0, CH2Cl2);
NMR (300MHz, CDCl3): d 3.74 (dd, 1H, J = 2.4,
4.2Hz), 3.80 (dd, 1H, J = 3.0, 4.8Hz), 4.60 (br s, 1H),
4.86 (d, 1H, J = 2.4Hz), 5.13 (s, 2H), 5.23 (d, 1H,
J = 2.4Hz), 6.89–6.95 (m, 1H), 7.26–7.42 (m, 7H); 13C
NMR (75MHz, CDCl3): d 54.67, 55.56, 64.45, 66.67,
70.86, 111.24, 120.76, 122.44, 127.65, 128.55, 128.91,
129.10, 135.74, 136.24, 156.71;HRMS (EI) calculated
for C17H16O4 (M+) 284.1047, found 284.1047.
D
1H NMR (300 MHz, CDCl3): d 0.21 (s, 3H), 0.24
(s, 3H), 1.03 (s, 9H), 3.60 (dd, 1H, J = 1.5, 1.5Hz),
3.63 (dd, 1H, J = 1.5, 1.5Hz), 4.81 (br s, 1H) 4.99
(br s, 1H), 7.30–7.33 (m, 2H), 7.45–7.48 (m, 1H),
7.53–7.56 (m, 1H); 13C NMR (75MHz, CDCl3): d
ꢀ4.78, ꢀ4.29, 18.21, 25.83, 54.84, 55.45, 67.07, 67.91,
125.67, 125.75, 127.61, 127.79, 133.82;HRMS (EI) cal-

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R. L. Betts et al. / Tetrahedron: Asymmetry 15 (2004) 2853–2860
4.9. (1R,2R,3S,4S)-4-Acetoxy-8-benzyloxy-2,3-epoxy-
1,2,3,4-tetrahydronaphthalen-1-ol 13
6.76 (m, 1H), 7.16–7.37 (m, 7H); 13C NMR (75MHz,
CDCl3): d ꢀ4.86, ꢀ4.30, 18.43, 25.98, 55.76, 57.06,
63.14, 66.29, 69.67, 111.37, 120.46, 123.51, 127.73,
128.47, 129.01, 136.92, 137.24, 157.20;HRMS (EI) cal-
culated for C23H30O4Si (M+ꢀC4H9) 341.1209, found
341.1211.
To a suspension of diol ( )-12 (161mg, 0.567mmol) in
isopropenyl acetate (6mL) was added Amano Lipase
PS (322mg, 200% wt). The reaction mixture was stirred
at 50ꢁC for 16h until the reaction was determined to be
50% complete by HPLC. At which time the solution was
cooled to room temperature and water (2mL) was
added. The resultant aqueous layer was extracted with
ethyl acetate (4 · 20mL) and the combined organic lay-
ers were dried with MgSO4, filtered, concentrated and
purified by flash chromatography to afford 56mg
4.12. 5,8-Diallyloxy-1,4-naphthoquinone 16
A mixture of 3 (0.82g, 4.3mmol), allyl iodide (4.1mL,
45mmol) and silver(I)oxide (10g, 44mmol) was vigor-
ously stirred under N2 in a flask protected from light
for 28h. The mixture was filtered through a pad of Cel-
ite, concentrated in vacuo and placed under high vac-
uum to remove excess allyl iodide. The reddish brown
solid was purified by flash chromatography (gradient
from 3:1 to 1:1 hexanes/ethyl acetate) to provide 16
(0.95g, 81%) as an orange solid: mp = 96–98ꢁC; 1H
NMR (400MHz, CDCl3): d 7.28 (s, 2H), 6.78 (s, 2H),
6.10 (m, 2H), 5.61 (m, 2H), 5.35 (m, 2H), 4.67 (m,
4H); 13C NMR (100MHz, CDCl3): d 184.7, 152.8,
138.3 (CH), 132.3 (CH), 122.1 (CH), 121.5, 118.0
(CH2), 70.5 (CH2);HRMS (EI) calcd for C 16H14O4
270.0892, found 270.0897.
(30%) of (+)-13 and 50mg (31%) of enantioenriched
21
D
alcohol (+)-12: diol rotation ½aŠ ¼ þ26:5 (c 2.50,
23
D
CH2Cl2);acetate data ½aŠ ¼ þ58:4 (c 0.46, CH2Cl2);
1H NMR (300MHz, CDCl3): d 2.27 (s, 3H), 3.76 (s,
2H), 5.14 (s, 2H), 5.26 (br s, 1H), 6.17 (br s, 1H), 6.90
(d, 1H, J = 7.8Hz), 6.95 (d, 1H, J = 8.4Hz), 7.38–7.42
(m, 6H); 13C NMR (125MHz, CDCl3): d 21.12, 51.62,
54.23, 64.55, 68.63, 70.97, 111.65, 119.72, 127.69,
128.62, 128.95, 131.74, 135.20;HRMS (EI) calculated
for C19H18O5 (M+) 326.1154, found 326.1149.
4.10. (1S,2S,3S,4R)-1-Acetoxy-8-benzyloxy-2,3-epoxy-4-
(tert-butyldimethylsilyoxy)-1,2,3,4-tetrahydronaphthal-
ene 14
4.13. 5,8-Diallyloxy-2,3-epoxy-1,2b,3b,4-tetrahydronaph-
thalene-1,4-dione 17
To a solution of alcohol 13 (71mg, 0.218mmol) in
CH2Cl2 was added imidazole (30mg, 0.436mmol) and
TBSOTf (49mg, 0.327mmol). This mixture was stirred
for 1h until determined complete by TLC, at which time
the solution was washed with dilute HCl (1 · 10mL) and
the aqueous layer was extracted with ethyl acetate
(3 · 50mL). The combined organic layers were dried
with MgSO4, filtered and concentrated. The concentrate
was purified by flash chromatography to deliver 14
To a solution of 16 (0.91g, 3.4mmol) in methanol
(150mL) at 0ꢁC was added 30% aqueous hydrogen per-
oxide solution (1.75mL, 17mmol) and 2M aqueous so-
dium bicarbonate solution (3.3mL, 6.6mmol) and the
solution stirred at 0ꢁC for 0.5h. The solution was neu-
tralized with 1N HCl (8mL), filtered through a pad of
Celite and the filtrate was concentrated in vacuo. The
yellow-orange residue was treated with saturated ammo-
nium chloride solution (100mL) and extracted with
ethyl acetate (3 · 70mL). The combined organics were
washed with brine (200mL), dried with MgSO4 and con-
centrated in vacuo to provide epoxide 17 (0.92g, 96%),
which was used without further purification. An analyt-
ically pure sample was obtained from another batch by
flash chromatography on neutral Alumina (gradient
form 4:1 to 2:1 hexanes/ethylacetate) to provide epoxide
(72mg, 0.164mmol) in
a
75% yield. 1H NMR
(300MHz, CDCl3): d 0.08 (s, 3H), 0.12 (s, 3H), 0.92 (s,
9H), 2.25 (s, 3H), 3.69 (t, 1H, J = 3.6Hz), 3.96 (dd,
1H, J = 1.2, 3.0Hz), 5.19 (br s, 2H), 5.35 (d, 1H,
J = 3.6Hz), 6.12 (d, 1H, J = 3.0Hz), 6.74–6.81 (m,
2H), 7.14–7.39 (m, 6H); 13C NMR (125MHz, CDCl3):
d ꢀ4.75, ꢀ4.20, 18.44, 21.09, 25.97, 52.51, 55.67,
63.49, 68.51, 69.55, 111.68, 119.22, 124.16, 126.90,
127.66, 128.45, 128.78, 132.20, 136.90, 157.60, 171.32;
HRMS (EI) calculated for C25H22O5Si (M+ꢀC4H9)
383.1315, found 383.1315.
17 as
a
yellow solid: mp = 92–93ꢁC; 1H NMR
(500MHz, CDCl3): d 7.19 (s, 2H), 6.04 (m, 2H), 5.49
(dd, J = 17.2, 1.5Hz, 2H), 5.32 (dd, J = 10.6, 1.0Hz,
2H), 4.66 (m, 2H), 4.54 (m, 4H), 3.97 (s, 2H); 13C
NMR (125MHz, CDCl3): d 190.7, 151.5, 132.3 (CH),
121.9, 120.9 (CH), 118.1 (CH2), 70.6 (CH2), 55.5 (CH);
HRMS (EI) calcd for C16H14O5 286.0841, found
286.0841.
4.11. (1S,2S,3S,4R)-8-Benzyloxy-4-(tert-butyldimethyl-
silyloxy)-2,3-epoxy-1,2,3,4-tetrahydronaphthalen-1-ol 15
To a solution of acetate 14 (72mg, 0.164mmol) in meth-
anol (2mL) was added K2CO3 (10mg). This reaction
mixture was stirred for 24h until the reaction was deter-
mined to be complete by TLC. The solution was diluted
with H2O (3mL) and the reaction was extracted with
ethyl acetate (4 · 5mL) and the combined organic layers
were dried with MgSO4, filtered, concentrated and puri-
fied by flash chromatography to afford 61mg (93%) of
4.14. 5,8-Diallyloxy-2,3-epoxy-1b,2b,3b,4b-tetrahydro-
naphthalene-1,4-diol 18
To a solution of epoxide 17 (0.92g, 3.2mmol) in THF
(50mL) at ꢀ78ꢁC was added dropwise a solution of
1.0M L-Selectride (13mL, 14mmol) and the solution
stirred at ꢀ78ꢁC for 0.5h. The excess L-Selectride was
quenched with water (10mL) and the solution was al-
lowed to warm to 0ꢁC. Organoborane was oxidized by
adding 30% aqueous hydrogen peroxide solution
1
15. H (300MHz, CDCl3): d 0.07 (s, 3H), 0.13 (s, 3H),
0.91 (s, 9H), 2.61 (br s, 1H), 3.69–3.75 (m, 2H), 4.84
(br s, 1H), 5.18 (s, 2H), 5.36 (d, 1H, J = 3.0Hz), 6.37–

R. L. Betts et al. / Tetrahedron: Asymmetry 15 (2004) 2853–2860
2859
(6.7mL, 65mmol) and stirring for 0.5h at room temper-
4.17. (1S,2S,3R,4R)-1-Acetoxy-4,5-benzylidenedioxy-
2,3-epoxy-1,2,3,4-tetrahydronaphthalen-8-ol 22
ature. The solution was diluted with ethyl acetate
(50mL) and washed with saturated ammonium chloride
solution (1 · 100mL), brine (1 · 100mL), dried with
MgSO4 and concentrated in vacuo. The product was
purified by flash chromatography (1:1 hexanes/ethyl ace-
tate, then 19:1 dichloromethane/acetone, then 9:1
dichloromethane/acetone) to give diol 18 (0.76g, 82%)
A solution of 20 (350mg, 1.4mmol) in methanol
(100mL) was stirred with palladium on carbon (Deg-
ussa, 20wt%) under an atmosphere of hydrogen for
52h. The mixture was filtered through a pad of Celite
and immediately concentrated in vacuo. To a solution
of the resulting hydroquinone 21 (358mg, 1.14mmol)
in THF (30mL) was added p-toluene sulfonic acid
(13mg, 0.07mmol) and benzaldehyde dimethyl acetal
(8.5mL, 57mmol) and the solution stirred under nitro-
gen for 53h. The solution was diluted with ethyl acetate
(50mL), washed with water (2 · 80mL), dried with
MgSO4 and concentrated in vacuo. The product was
purified by flash chromatography (hexanes, then 3:1
hexanes/ethyl acetate, then 2:1 hexanes/ethyl acetate)
as
a
white solid: mp = 145–147ꢁC; 1H NMR
(300MHz, acetone-d6): d 6.94 (s, 2H), 6.07–6.19 (m,
2H), 5.44 (ddd, J = 17.1, 3.1, 1.8Hz, 2H), 5.28 (ddd,
J = 10.4, 3.1, 1.8Hz, 2H), 5.14 (m, 2H), 4.58–4.71 (m,
4H), 4.29 (d, J = 3.7Hz, 2H), 3.61 (dd, J = 6.1, 3.1Hz,
2H); 13C NMR (75MHz, acetone-d6): d 151.3, 132.4
(CH), 124.7, 118.5 (CH), 111.7 (CH2), 69.7 (CH2), 64.2
(CH), 54.4 (CH);HRMS (EI) calcd for C 16H18O5
290.1154, found 290.1154.
to provide benzylidene acetal 22 (278mg, 58%) as an
21
D
4.15. (1R,2R,3S,4S)-4-Acetoxy-5,8-diallyloxy-2,3-epoxy-
1,2,3,4-tetrahydronaphthalen-1-ol 19
off white solid: mp = 126ꢁC (dec); ½aŠ ¼ ꢀ139 (c 1.0,
1
CHCl3); H NMR (400MHz, CDCl3): d 7.63 (m, 2H),
7.45 (m, 3H), 6.82 (d, J = 9.1Hz, 1H), 6.77 (d,
J = 9.1Hz, 1H), 6.39 (s, 1H), 6.18 (s, 1H), 5.83 (s, 1H),
5.34 (s, 1H), 3.87 (d, J = 5.1Hz, 1H), 3.78 (d,
J = 5.1Hz, 1H), 2.29 (s, 3H); 13C NMR (100MHz,
CDCl3): d 170.1, 148.1, 146.1, 136.5, 129.8 (CH), 128.5
(CH), 126.5 (CH), 118.3 (CH), 117.6 (CH), 115.2,
113.2, 100.2, 72.9 (CH), 69.6 (CH), 51.0 (CH), 50.9
(CH), 21.1 (CH3);HRMS (FAB) calcd for C 19H16O6
340.0947, found 340.0949.
A mixture of diol 18 (2.67g, 9.2mmol) and Novo SP-435
enzyme (5.34g) in toluene (400mL) and isopropenyl ace-
tate (100mL) was gently stirred with an overhead stirrer
for 90h. The mixture was filtered and the enzyme was
washed with benzene and hexanes. The filtrate was con-
centrated in vacuo. The product was purified by flash
chromatography (2:1 hexanes/ethyl acetate) to provide
acetate 19 (2.71g, 93%) as a white solid: mp = 151–
21
D
153ꢁC; ½aŠ ¼ ꢀ28:2 (c 1.0, CHCl3); 1H NMR
(400MHz, CD3OD): d 6.96 (d, J = 9.7Hz, 1H), 6.88
(d, J = 9.7Hz, 1H), 6.29 (d, J = 3.2Hz, 1H), 5.96–6.15
(m, 2H) 5.42 (ddd, J = 17.0, 3.2, 1.6Hz, 1H), 5.36
(ddd, J = 17.0, 3.2, 1.6Hz, 1H), 5.27 (ddd, J = 10.5,
1.6, 1.6Hz, 1H), 5.23 (ddd, J = 10.5, 1.6, 1.6Hz, 1H),
5.21 (d, J = 4.1Hz, 1H), 4.56–4.67 (m, 2H), 4.48 (m,
2H), 3.74 (m, 2H), 2.07 (s, 3H); 13C NMR (100MHz,
CD3OD): d 172.6, 152.7, 152.6, 135.00 (CH), 134.96
(CH), 127.6, 122.2, 118.1 (CH2), 117.6 (CH2), 114.4
(CH), 113.1 (CH), 70.9 (CH2), 70.5 (CH2), 66.5 (CH),
64.0 (CH), 56.4 (CH), 54.2 (CH), 21.1 (CH3);HRMS
(EI) calcd for C16H20O5 332.1260, found 332.1256.
4.18. X-ray crystal structures
Crystallographic data for 6, 9 and 19 have been depos-
ited with the Cambridge Crystallographic Data Centre
as supplementary publication numbers CCDC 246669,
CCDC 246671 and CCDC 246965, respectively. Copies
can be obtained, free of charge, on application to
CCDC, 12 Union Road, Cambridge, CB2 1EZ, UK
[fax: +44(0)-1223-336033 or e-mail: deposit@ccdc.cam.
ac.uk].
Acknowledgements
4.16. (5S,6S,7R,8R)-5-Acetoxy-6,7-epoxy-5,6,7,8-tetra-
hydro-1,4-naphthoquinone-8-ol 20
This work was supported by a grant from the National
Science Foundation. We thank Dr. Mary Jane Heeg for
the X-ray crystal structure determinations.
To a solution of allyl-protected hydroquinone 19 (0.50g,
1.5mmol) in acetonitrile (15mL) at 0ꢁC was added
dropwise a solution of ceric ammonium nitrate (2.0g,
3.6mmol) in water (15mL) and the resulting solution
stirred for 10min. The solution was diluted with water
(10mL) and the product was extracted with chloroform
(5 · 20mL). The combined extracts were dried with
MgSO4 and concentrated in vacuo to produce quinone
20 (369mg, 98%) of a bright orange solid: mp = 135–
138ꢁC; 1H NMR (400MHz, CDCl3): d 6.79 (d,
J = 9.8Hz, 1H), 6.77 (d, J = 9.8Hz, 1H), 6.19 (m, 1H),
5.09 (m, 2H) 3.82 (d, J = 4.0Hz, 1H), 3.75 (m, 1H);
13C NMR (100MHz, CDCl3): d 187.9, 184.5, 170.0,
139.1, 137.5 (CH), 136.4 (CH), 135.4 (CH), 63.38
(CH), 63.33 (CH), 53.5 (CH), 51.8 (CH), 20.7 (CH3);
HRMS (EI) calcd for C12H10O6 250.0477, found
250.0475.
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