Lewis acid mediated highly regioselective intramolecular cyclization for the synthesis of β-lapachone

Article abstract of DOI:10.1016/j.tetlet.2014.01.059

A highly regioselective intramolecular cyclization of lapachol mediated by Lewis acids including NbCl₅, AlCl₃, and FeCl₃ was developed for synthesizing β-lapachone in excellent yields without any formation of the isomer α-lapachone. This procedure was efficient, mild, and easily scalable that avoided using highly hazardous concd H ₂SO₄. In the case of ZrCl₄ the cyclization was found to give α-lapachone as the main product. A possible mechanism for the Lewis acid mediated cyclization was also discussed.

Full text of DOI:10.1016/j.tetlet.2014.01.059

Tetrahedron Letters 55 (2014) 1475–1478
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Lewis acid mediated highly regioselective intramolecular cyclization
for the synthesis of b-lapachone
a,c
a,c
a,d,
⇑
c
c
c
c
Jinlei Bian , Bang Deng , Xiaojin Zhang
, Tianhan Hu , Nan Wang , Wei Wang , Haixiang Pei ,
c
a,c
a
a,c
a,b,c,
⇑
Yu Xu , Hongxi Chu , Xiang Li , Haopeng Sun , Qidong You
a
Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China
State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China
Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China
Department of Organic Chemistry, School of Science, China Pharmaceutical University, Nanjing 210009, China
b
c
d
a r t i c l e i n f o
a b s t r a c t
Article history:
A highly regioselective intramolecular cyclization of lapachol mediated by Lewis acids including NbCl5,
Received 25 November 2013
Revised 30 December 2013
Accepted 14 January 2014
Available online 20 January 2014
AlCl
of the isomer
3
, and FeCl
3
was developed for synthesizing b-lapachone in excellent yields without any formation
-lapachone. This procedure was efficient, mild, and easily scalable that avoided using
a
2 4 4
highly hazardous concd H SO . In the case of ZrCl the cyclization was found to give a-lapachone as
the main product. A possible mechanism for the Lewis acid mediated cyclization was also discussed.
Ó 2014 Elsevier Ltd. All rights reserved.
Keywords:
b-Lapachone
Lewis acid
Intramolecular cyclization
Regioselective
Quinone
b-Lapachone (1) (Fig. 1) is a natural tetrahydropyran-fused
ortho-naphthoquinone isolated from the Bignoniaceae family (Tab-
could be prepared from 1,4-naphthoquinone in two steps with
1
2
only 29% combined yield. The third and the shortest approach to-
ward b-lapachone (1) (route C), involved a protonic acid mediated
intramolecular cyclization of lapachol (2) through a stable tertiary
carbocation intermediate, which was formed by the protonation of
the carbon–carbon double bond of the isopentenyl group.1
Lapachol (2) could be obtained efficiently from 2-hydroxy-1,4-
1
ebuia sp.). It has been shown to exhibit a wide range of significant
2
3
biological activities such as antitumor, trypanocidal, anti-inflam-
matory, antibacterial, and antifungal.5 Unlike conventional che-
motherapeutic agents, b-lapachone (1) has been reported to
selectively kill human cancer cells through rapid reactive oxygen
species (ROS) generation mediated by NAD(P)H:quinone oxidore-
4
3,14
1
5
naphthoquinone in 78% yield. Treatment of lapachol (2) with
excessive concd H SO in water was reported to directly provide
39% yield of b-lapachone (1), but together with 34% yield of the iso-
6
,7
ductase-1 (NQO1). In fact, b-lapachone (1) is currently in multi-
2
4
8
ple phase II clinical trials for the treatment of pancreatic cancer.
1
3
Therefore, it is not surprising that the total synthesis of this
pharmaceutically important natural product has attracted great
interest in recent decades.
Three synthetic approaches toward b-lapachone (1) have been
reported as shown in Figure 1. The first one (route A) involved a
meric
SO
by ArQule Inc. was shown to provide b-lapachone (1) in a multi-
a-lapachone (3). While using large amounts of concd
H
2
4
as both the catalyst and solvent, the cyclization disclosed
1
6
gram scale with over 90% yield. However, the significant excess
of concd H SO used in these methods was highly hazardous and
2
4
relatively tedious multistep sequence starting from
and provided b-lapachone (1) in poor total yields (23–55%).
The second one (route B) involved an epoxide rearrangement pro-
a
-naphthol
hard to handle, making them not suitable for industrial-scale
production.
9
,10
Lewis acid catalysis has been of great interest in organic synthe-
1
7
tocol in the presence of 15 equiv of concd H
2
SO
4
that led straightly
sis for efficient carbon–heteroatom bond formation. Recently, in
many cases Lewis acid catalysts were found to be effective for the
intramolecular cyclization of unsaturated alcohols to give the
monocyclic tetrahydropyrans, owing to their ability for the electro-
philic activation of the carbon–carbon double bond toward the
to b-lapachone (1) in 90% yield.11 One disadvantage of this protocol
was the limited availability of the key epoxide intermediate, which
⇑
Corresponding authors. Tel.: +86 25 83271216 (X.Z.); tel./fax: +86 25 83271351
Q.Y.).
E-mail addresses: zhangxiaojin@outlook.com (X. Zhang), youqidong@gmail.com
Q. You).
1
8,19
(
(
subsequent attack of a nucleophile.
Hence, we set out to test
the suitability of various readily accessible Lewis acids for the
0
040-4039/$ - see front matter Ó 2014 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2014.01.059

1
476
J. Bian et al. / Tetrahedron Letters 55 (2014) 1475–1478
NHAc
2-6 steps
2-3 steps
(
Route A)
Oxidation
HNO3
O
O
OH
O
O
α-naphthol
O
O
O
O
Rearragement
H SO
O
(Route B)
2
4
O
O
O
β-lapachone (1)
epoxide intermediate
1
,4-naphthoquinone
O
Cyclizaiton
4
O
O
H SO
OH
2
OH
Route C)
(
O
lapachol (2)
2-hydroxy-1,4-naphthoquinone
Figure 1. Synthetic approaches to the natural product b-lapachone.
intramolecular cyclization of lapachol (2), and to develop a high
yielding, regioselective, and scalable procedure for the synthesis
of b-lapachone (1).
Lewis acids (data not shown). The reaction provided moderate
combined yield when ZnCl or CdCl was employed (Table 1, en-
tries 7 and 8). Moreover, the reaction rate decreased when treated
with CdCl (Table 1, entry 7), since a prolonged reaction time was
needed to complete this conversion. Some other relatively weak
Lewis acids classified by Kobayashi (Table 1, entries 9–14) were
shown to be incapable of catalyzing this reaction. These results
indicated that the activities of the Lewis acids to promote the cycli-
zation were in remarkable agreement with their acid strength. In
addition, it must be emphasized that different regioselectivities
were observed in this cyclization by employing different Lewis
2
2
In an initial study we screened various Lewis acids for their
effects on the cyclization of lapachol (2) to b-lapachone (1). The
reactions were carried out at room temperature using dichloro-
methane (DCM) as solvent, which was reported to be the optimal
reaction system for the Lewis acid mediated cyclization to tetra-
2
2
0
1
8
hydropyrans. The reaction mixtures were analyzed by high per-
formance liquid chromatography (HPLC) to determine the ratios
between the potential products b-lapachone (1) and
3) as well as their combined yields. As shown in Table 1, many
Lewis acids such as AlCl , FeCl , BF , BiCl , NbCl , and ZrCl used
a-lapachone
(
acids. For instance, when AlCl
ployed, the reaction was prone to give b-lapachone (1) with the
b: ratios ranging from 1:0.20 to 1:0.41 (Table 1, entry 1/2/3/8).
While in the presence of NbCl or BiCl , a mixture of the b and
isomers in nearly equal proportions was obtained (Table 1, entry
/5). Furthermore, in the case of ZrCl , interestingly, the reaction
3 3 3 2
, FeCl , BF , and CdCl were em-
3
3
3
3
5
4
in 1.5 equiv (Table 1, entries 1–6), were found to be effective to cat-
alyze the cyclization of lapachol (2) in 4 h with good to excellent
combined yields. But no reaction occurred in the absence of these
a
5
3
a
4
4
Table 1
Intramolecular cyclization of lapachol (3) to b-lapachone (1) mediated by different
Lewis acids in 1.5 equiv21
Table 2
O
O
O
The effects of amounts of Lewis acids on regioselectivity of the intramolecular
cyclization21
OH
O
O
Lewis acid
+
Entrya Lewis acid Loading (Equiv.) Selectivityb (b:
a)
Yieldb (b+
a) (%)
DCM
room temperature
1
2
AlCl
AlCl
3
3
5
1:0.001
1:0
Quant.
97
O
O
O
3
3
4
FeCl
FeCl
3
3
5
1:0.002
1:0
98
98
lapachol (2)
β-lapachone (1)
α-lapachone (3)
3
5
6
7
8
BF
BF
NbCl
NbCl
BiCl
BiCl
ZrCl
ZrCl
BiCl
ZrCl
NbCl
NbCl
NbCl
NbCl
3
3
5
3
5
3
5
3
5
10
10
4
2
0.1
5
1:0.46
1:0.42
1:0.04
1:0
0.52:1
0.40:1
0.13:1
0.14:1
0.33:1
0.12:1
1:0.002
1:0.74
—
Quant.
98
98
Quant.
Quant.
98
Quant.
Quant.
98
Entrya Lewis acid
Reaction time
Selectivityb
Yieldb (b+
a)
(%)
3
(h)
(b:
a
)
5
1
2
3
4
5
6
7
8
9
1
1
1
1
1
AlCl
FeCl
BF
BiCl
NbCl
ZrCl
ZnCl
CdCl
Cu Cl
3
4
4
4
4
4
4
4
12
12
12
12
12
12
12
1:0.41
1:0.20
1:0.36
0.79:1
0.86:1
0.18:1
0.67:1
1:0.24
—
—
—
—
—
97
5
3
Quant.
Quant.
Quant.
93
93
80
9
3
10
11
12
13
14
15
16
17
18
3
3
3
4
5
4
4
3
2
4
Quant.
98
98
2
79
5
5
5
5
2
2
No reaction
No reaction
No reaction
No reaction
No reaction
No reaction
0
1
2
3
4
CuCl
2
No reaction
c
d
MnCl
2
1:0
97
HgCl
2
a
Reaction conditions: lapachol (0.2 mmol), Lewis acid (different equiv), solvent
DCM, 5 mL), at room temperature, for 4 h.
The selectivity and combined yield were obtained by HPLC analysis of the
NiCl
CoCl
2
Á6H
2
O
(
2
Á6H
2
O
—
b
a
Reaction conditions: lapachol (0.2 mmol), Lewis acid (1.5 equiv), solvent (DCM,
reaction mixture.
c
5
mL), at room temperature.
5
Reaction conditions: lapachol (4.13 mmol, 1 g), NbCl (20.66 mmol, 5 equiv),
b
The selectivity and combined yield were obtained by HPLC analysis of the
solvent (DCM, 50 mL), at room temperature, for 4 h.
d
reaction mixture.
Isolated yield.

J. Bian et al. / Tetrahedron Letters 55 (2014) 1475–1478
1477
preferred to produce
b: ratio of 0.18:1 (Table 1, entry 6).
Next, to improve the regioselectivity for b-lapachone (1), the Le-
a
-lapachone (3) as the main product with a
the b:
a
ratio was retained at about 0.1:1 whenever the ZrCl
4
load-
a
ing was changed from 1.5 to 3, 5, and 10 equiv (Table 2, entry 11/
12/14). Among these Lewis acids tested, NbCl showed the best
5
wis acids with high catalytic activities were further tested at differ-
ent loading amounts (Table 2). An increasing amount of Lewis acid
loading from 1.5 to 3 and 5 equiv was initially evaluated (Table 2,
ability to promote the conversion of lapachol (2) to b-lapachone
(1) with high regioselectivity and quantitative yield (Table 2, entry
8). In order to fully understand the effects of the loading of NbCl
on the regioselectivity, we carefully decreased its amount from 5
to 4 equiv and a trace of -lapachone (3) was detected with a
b: ratio of 1:0.002 (Table 2, entry 15). Moreover, according to
5
entries 1–12). Encouragingly, in the cases of AlCl
3 3 5
, FeCl , and NbCl ,
the b: ratios of the products were found to be greatly elevated by
a
a
increasing the amount to 3 and 5 equiv (Table 2, entries 1–4/7–8).
a
Notably, treatment of lapachol (2) with these three Lewis acids in
the data (Table 2, entry 8/15/7/16; Table 1, entry 5), there was
5
equiv led to highly regioselective formation of b-lapachone (1) as
a single isomer in excellent yields (Table 2, entry 2/4/8). None of
the -lapachone (3) was detected by the HPLC analysis of the reac-
tion mixtures. Whereas in the case of BF (Table 2, entries 5 and 6),
the amount of Lewis acid loading showed less effect on the regiose-
lectivity and a considerable proportion of the isomer -lapachone
3) was always accompanied with b-lapachone (1). For BiCl , a
-lapachone (3) was observed
obviously a downward trend in selectivity for b-lapachone (1) as
the amount of NbCl decreased. Besides, no reaction occurred at
5
low Lewis acid loading in 0.1 equiv (Table 2, entry 17).
a
3
Subsequently, with the optimal reaction conditions in hand (Ta-
ble 2, entry 8), we intended to apply this strategy to the gram-scale
synthesis of b-lapachone (1). It was shown that a 20-fold scale-up
of the reaction still afforded the product in a high 97% isolated
a
(
3
slight increase in the selectivity for
a
yield mediated by 5 equiv of NbCl
5
(Table 2, entry 18).21 This pro-
as the Lewis acid loading raised from 1.5 to 3 and 5 equiv (Table 2,
entries 9 and 10). Further increasing the amount of BiCl to
0 equiv made little improvement in the selectivity for -lapach-
one (3), and the b: ratio was 0.33:1
Table 2, entry 13). In a manner similar to BiCl
cedure benefits the advantages of high regioselectivity, excellent
yield, mild reaction conditions that avoided using highly hazardous
3
2 4
concd H SO
, and a convenient post-treatment just by extraction.22
1
a
a
Therefore, this Lewis acid mediated intramolecular cyclization has
great potential for the industrial-scale production of the important
ortho-quinone natural product b-lapachone (1).
(
3 4
, when ZrCl was
employed, the reaction provided a mixture of b and
a
isomers and
NbCl5
NbCl5
O
1
O
O
OH
NbCl5
NbCl5
O
O
H
NbCl5
H
2
δ
3
4
O
δ
O
4
O
6
NbCl5
lapachol (2)
NbCl5
H
O
path A
O
intramolecular
+
NbCl5
-NbCl5
O
δ
H
migration
NbCl5
O
O
δ
O
5
NbCl5
O
O
12
path B
+
-
H
NbCl5
from 4
generated from 4
after losing theH
intermolecular
+
H
migration
O
7
H
O
H
O
O
NbCl5
O
O
O
O
O
9
9
O
8
-
NbCl5
O
OH
O
O
O
H
O
O
O
O
O
10
11
-H
drived by 12
-H drived by 12
β-lapachone (1)
O
O
O
O
O
α-lapachone (3)
mixture of α- and β-isomers
Scheme 1. The proposed mechanism for the regioselective formation of b-lapachone (1) mediated by Lewis acid NbCl
β-lapachone (1)
5
.

1
478
J. Bian et al. / Tetrahedron Letters 55 (2014) 1475–1478
Combining all the results above, we have proposed a possible
mechanism for the Lewis acid mediated regioselective intramo-
lecular cyclization by taking NbCl as an example (Scheme 1).
Acknowledgments
5
We are thankful for the financial support of the National Natu-
ral Science Foundation of China (No. 81302636), the National
Natural Science Foundation of Jiangsu Province of China (No.
BK20130656), the Project Program of State Key Laboratory of
Natural Medicines, China Pharmaceutical University (No. SKLN
MZZ201202), and the National Found for Fostering Talents of Basic
Science (NFFTBS) of China (No. J0630858).
Firstly, the substrate lapachol (2) was likely to form reversibly
two possible intermediates 4 and 5, as it has been reported that
some strong Lewis acids could bind bidentately to the adjacent
2
3
carbonyl and hydroxyl groups and activate the carbon–carbon
double bond of the isopentenyl moiety.1
presence of excessive NbCl resulted in the formation of the
intermediate 6, which was stabilized by the coordinate interac-
tions with two moles of NbCl . In view of this, when adequate Le-
8,19
Consequently, the
5
5
Supplementary data
wis acid was employed (5 equiv or more), lapachol (2) could be
fully converted into the stable intermediate 6. Then, it underwent
the intramolecular proton migration to form the carbocation 7 as
shown in path A. The two oxygens at C1 and C2 in the structure of
Supplementary data associated with this article can be found, in
theonlineversion, at http://dx.doi.org/10.1016/j.tetlet.2014.01.059.
7
5
were chelated to one molecule of NbCl . As a result, the exposed
References and notes
carbonyl group at C4 of 7 was more nucleophilic than the oxygen
at C2 and was prior to attack the alkyl cation, leading to the selec-
tive formation of the ortho-product b-lapachone (1) as a single
isomer. However, while inadequate Lewis acid was employed
1. De Castro, S. L.; Emery, F. S.; Da Silva junior, E. N. Eur. J. Med. Chem. 2013, 69,
678.
2
3
.
.
Colucci, M. A.; Moddy, C. J.; Couch, G. D. Org. Biomol. Chem. 2008, 6, 637.
Salas, C. H.; Faundez, M.; Morello, A.; Maya, J. D.; Tapia, R. A. Curr. Med. Chem.
2011, 18, 144.
(
from 1.5 to 4 equiv in our experiments), certain amounts of the
4
5
.
.
Tseng, C.-H.; Cheng, C.-M.; Tzeng, C.-C.; Peng, S.-I.; Yang, C.-L. Bioorg. Med.
Chem. 2013, 21, 523.
Medeiros, C. S.; Pontes-Filho, N. T.; Camara, C. A.; Lima-Fiho, J. V.; Oliveira, P. C.;
Lemos, S. A.; Leal, A. F. G.; Brandao, J. O. C.; Neves, R. P. Braz. J. Med. Biol. Res.
intermediates 4 and 5 were probably co-existent with the inter-
mediate 6. In this case, besides the intramolecular path A, the
NbCl
the NbCl
5
-activated proton of the intermediate 4 could migrate to
-activated isopentenyl moiety of the resulting interme-
2010, 43, 345.
5
6.
Bey, E. A.; Bentle, M. S.; Relnlcke, K. E.; Dong, Y.; Yang, C.-R.; Girard, L.; Minna, J.
D.; Bornmann, W. G.; Gao, J.; Boothman, D. A. Proc. Natl. Acad. Sci. U.S.A. 2007,
104, 11832.
diate 5 via an intermolecular pathway as shown in path B. This
path led to the activated carbocation 9 without any chelated
NbCl
reported,
routes involving the intermediates 10 and 11, which led to the
formation of a mixture of b and isomers. The product 12 gener-
ated from intermediate 4 after losing the proton was supposed to
serve as the driving force for the intermediates 10 and 11 to lose
the proton. This could reasonably explain the observed high
selectivity for b-lapachone (1) when 5 equiv of Lewis acids such
5
, being different from the carbocation 7. As previously
7. Huang, X.; Dong, Y.; Bey, E. A.; Kilgore, J. A.; Bair, J. S.; Li, L.-S.; Patel, M.;
Parkinson, E. L.; Wang, Y.; Williams, N. S.; Gao, J.; Hergenrother, P. J.;
Boothman, D. A. Cancer Res. 2012, 72, 3038.
1
1,24
the carbocation 9 could undergo two possible
8.
Cheng, X.; Liu, F.; Yan, T.; Zhou, X.; Wu, L.; Liao, K.; Wang, G.; Hao, H. Mol.
Pharm. 2012, 9, 3476.
a
9.
Amaral, A. C. F.; Barnes, R. A. J. Heterocycl. Chem. 1992, 29, 1457.
1
1
0. Alves, G. B. C.; Lopes, R. S. C.; Lopes, C. C.; Snieckus, V. Synthesis 1999, 11, 1875.
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12. Claessens, S.; Kesteleyn, B.; Van, T. N.; De Kimpe, N. Tetrahedron 2006, 62, 8419.
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1
1
1
3. Sacau, E. P.; Estevez-Braun, A.; Ravelo, A. G.; Ferro, E. A.; Tokuda, H.;
Mukainaka, T.; Nishino, H. Bioorg. Med. Chem. 2003, 11, 483.
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Ferreira, J.; Maya, J. D.; Morello, A. Bioorg. Med. Chem. 2008, 16, 668.
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Synlett 2011, 1551.
as NbCl
observed decreased selectivity while reducing the Lewis acid
loading to 4 equiv or less. Besides, in the case of Lewis acid ZrCl
it mediated the cyclization in an opposite regioselectivity favor-
ing the formation of -lapachone (3). We speculated that ZrCl
5 3 3
, AlCl , and FeCl were employed, and also explain the
4
,
6. Jiang, Z.; Hopkinton, M.; Hogeland, J.; Woburn, M. E. P. Patent 1, 363, 896, 2004.
a
4
17. Vece, V.; Hassen, K. B. H.; Antoniotti, S.; Dunach, E. Tetrahedron Lett. 2012, 53,
102.
5
was not strong enough to break the intramolecular hydrogen
binding between the carbonyl at C1 and hydroxyl at C2 of lapa-
chol (2), but it was capable to interact with the carbonyl at C4,
1
1
8. Diba, A. K.; Begouin, J.-M.; Niggemann, M. Tetrahedron Lett. 2012, 53, 6629.
9. Coulombel, L.; Favier, I.; Dunach, E. Chem. Commun. 2005, 2286.
20. Kobyashi, S.; Busujima, T.; Nagayama, S. Chem. Eur. J. 2000, 6, 3491.
21. General procedure for the intramolecular cyclization mediated by Lewis acids. To a
solution of lapachol (2) (50 mg, 0.2 mmol) in DCM (5 mL) was added the
appropriate amounts of different Lewis acids. The mixture was stirred at room
temperature for 4 h or 12 h and then the reaction solution was directly
assessed by the HPLC analysis using a mixture of solvent methanol/water (1:3)
resulting in the selective formation of
ally, we found that the b-lapachone (1) and
to convert into each other in the presence of excessive Lewis
acids such as NbCl and ZrCl in our reaction conditions. It
a
-lapachone (3). Addition-
a
-lapachone (3) failed
5
4
1
as the mobile phase. b-Lapachone (1): mp 159–160 °C; H NMR (300 MHz,
suggested that the regioselectivity observed in this Lewis acid
mediated cyclization was kinetically controlled, being different
from the thermodynamically controlled process mediated by
3
CDCl ) d: 8.07 (dd, J = 1.8 Hz, 1H), 7.82 (dd, J = 1.8 Hz, 1H), 7.64 (dt, J = 1.8 Hz,
1
H), 7.53 (dt, J = 1.8 Hz, 1H), 2.58 (t, J = 6.6 Hz, 2H), 1.86 (t, J = 6.5 Hz, 2H), 1.47
13
(s, 6H). C NMR (75 MHz, CDCl
129.7, 128.0, 123.5, 112.2, 78.7, 31.1, 26.2, 15.7. HRMS-ESI m/z [M+H]+
calculated for C15 : 243.1016, found: 243.1019. -lapachone (3): mp 116–
18 °C; H NMR (300 MHz, CDCl ) d: 8.06 (m, 2H), 7.68 (m, 2H), 2.62 (t,
J = 6.6 Hz, 2H), 1.82 (t, J = 6.5 Hz, 2H), 1.44 (s, 6H). C NMR (75 MHz, CDCl
3
) d: 179.3, 178.1, 161.5, 134.2, 132.1, 130.1,
2
4
2 4
concd H SO .
H
15
O
3
a
In summary, we have presented a highly regioselective cycliza-
tion of lapachol (2) to b-lapachone (1) mediated by Lewis acids
1
1
3
13
3
) d:
83.9, 179.5, 154.1, 133.3, 132.4, 131.6, 130.7, 125.8, 125.5, 119.6, 77.6, 30.9,
6.0, 16.2. HRMS-ESI m/z [M+H] calcd for
1
2
2
including NbCl
formation of the isomer
cient, mild, and scalable that avoided using highly hazardous concd
SO . Thus it has great potential for the industrial-scale produc-
tion of the important ortho-quinone natural product b-lapachone
1) and related quinones. In addition, we have found that the reg-
ioselectivity was greatly related to the Lewis acid loading. It has
also been observed that the cyclization was prior to give -lapach-
one (3) as the main product when ZrCl was employed. We have
5 3 3
, AlCl , and FeCl in excellent yields without any
+
15 15 3
C H O : 243.1016, found:
a-lapachone (3). This procedure was effi-
43.1013. The spectroscopic data were identical to those reported in the
literature 14.
22. Procedure for the gram-scale synthesis of b-lapachone (1): To a solution of
H
2
4
lapachol (2) (1 g, 4.13 mmol) in DCM (50 mL) was added the Lewis acid NbCl
5.58 g, 20.66 mmol). The mixture was stirred at room temperature for 4 h.
5
(
(
Then the reaction mixture was poured into cooled water (100 mL), extracted
with ethyl acetate (3 Â 100 mL), and washed with brine (100 mL). The organic
layer was combined, dried over sodium sulfate, and concentrated under
reduced pressure to give the pure product b-lapachone (1) (0.973 g, 97%)
without any need for further purification.
a
4
proposed that Lewis acids promoted the cyclization by activating
both the isopentenyl and hydroxyl groups of lapachol (2) and the
regioselectivity arose from a Lewis acid mediated intramolecular
proton migration.
23. Liu, G.-Q.; Li, W.; Wang, Y.-M.; Ding, Z.-Y.; Li, Y.-M. Tetrahedron Lett. 2012, 53,
393.
4
24. Rio-Luci, C.; Bonifazi, E. L.; Leon, L. G.; Montero, J. C.; Burton, G.; Pandiella, A.;
Misico, R. I.; Padron, J. M. Eur. J. Med. Chem. 2012, 53, 264.