Total synthesis of (±)-nitidanin and novel procedures for determination of the location of the side chains on 1,4-benzodioxane

Article abstract of DOI:10.1016/j.tetlet.2006.11.170

Regioselective cycloaddition of o-quinone 4 and protected sinapyl alcohol 2 gave 1,4-benzodioxane 5, which was converted to (±)-nitidanin (6), an antimalarial compound. Two novel procedures were developed to determine the location of the side chains of th

Full text of DOI:10.1016/j.tetlet.2006.11.170

Tetrahedron Letters 48 (2007) 771–774
Total synthesis of ( )-nitidanin and novel procedures
for determination of the location of the side chains
on 1,4-benzodioxane
Atsuhito Kuboki,* Toru Yamamoto, Mamie Taira, Tetsuya Arishige and Susumu Ohira*
Department of Biochemistry, Okayama University of Science, 1-1 Ridai-cho, Okayama 700-0005, Japan
Received 26 October 2006; revised 29 November 2006; accepted 30 November 2006
Available online 19 December 2006
Abstract—Regioselective cycloaddition of o-quinone 4 and protected sinapyl alcohol 2 gave 1,4-benzodioxane 5, which was con-
verted to ( )-nitidanin (6), an antimalarial compound. Two novel procedures were developed to determine the location of the side
chains of the adduct (5) based on partial ring cleavage.
Ó 2006 Elsevier Ltd. All rights reserved.
We recently reported that a cycloaddition reaction of a
stable o-quinone 1 and sinapyl alcohol unit 2 gave 1,4-
benzodioxanes 3 and 30 (3/30 = 2:1).1 Although the reg-
iochemistry of each isomer was not clear at this stage,
the major adduct 3 was converted to the known natural
product ( )-aiphanol to establish its structure (see
Scheme 1).
In this Letter, we wish to report the highly regioselective
cycloaddition of o-quinones 4 and 2, and conversion of
the resulting adduct 5 to the antimalarial agent nitidanin
(6), isolated from the wood of Xanthoxylum nitidum
D.C. as a racemate2 and from the heartwood of Indian
Santalum album L. as a 7S,8S enantiomer (see Fig. 1).3
OMe
OMe
O
O
OTBS
OMe
OH
O
O
+
2
OTBS
O
O
O
O
O
O
a
+
OMe
OMe
OH
5
4
O
O
OMe
2
1
O
O
OH
OMe
+
OMe
OH
HO
OMe
OH
OH
O
O
OTBS
O
O
OMe
OMe
OMe
nitidanin (6)
O
O
Figure 1. Regioselective cycloaddition of 4 and 2 to give adduct 5 and
synthesis of ( )-nitidanin (6).
OH
OMe
3
3'
Scheme 1. Reagents and conditions: (a) THF, rt, 3 h [69% (3/30 2:1)].
In addition, we describe two series of novel procedures
for determination of the structure of 5 by chemical
transformation. These transformations could be gener-
ally useful for discrimination of isomers such as 5 and
*
Corresponding authors. Tel.: +81 86 2569489; fax: +81 86
2569489; e-mail: kuboki@dbc.ous.ac.jp
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.11.170

772
A. Kuboki et al. / Tetrahedron Letters 48 (2007) 771–774
50 (regioisomer of 5), which is often difficult, even using
modern 2D NMR techniques.
Since the structure of 5 could not be directly determined
from our NMR experiments, we aimed to develop a sim-
ple method to identify 5 or 50 (regioisomer of 5) that did
not depend on derivatization to a known compound.
Our plan was based on selective cleavage of the 1,4-diox-
ane ring. The orientation of substituents around the
benzene ring of the cleavage product would reflect the
original substitution pattern around the 1,4-benzodiox-
ane, and could easily be determined by NMR experi-
ments (see Scheme 3).10
o-Quinone 4 was prepared from commercially available
syringaldehyde (7) as shown in Scheme 2. Phenol 7 was
protected by a TBS group, which was treated with
methyl lithium followed by TPAP catalyzed oxidation
to provide acetophenone 8 in 82% yield. Protection of
ketone 8 and removal of the TBS ether gave phenol 9
in 83% yield. Oxidation of 9 with IBX1,4,5 in DMSO
afforded o-quinone 46 in 82% yield. The o-quinone 4
was so stable that it could be stored without any decom-
position for 1 year at ꢀ20 °C. Cycloaddition of 4 and 2
proceeded smoothly to give the adduct 57 as a single iso-
mer in 83% yield. The presence of a methoxy group in
the quinone apparently increased the chemical yield
and regioselectivity of the reaction. At this point, we
could not clarify whether the structure of the adduct
was 5 or 50 by HMBC and NOESY experiments. To
confirm the structure, we derivatized the adduct to 6,
the structure of which had been determined using
advanced NMR techniques.
OMe
a,b
c,d
O
O
OMOM
OMe
5
O
OMOM
OMe
10
OMe
g
O
O
OMOM
OMe
OMOM
R
OMe
OMe
OH
OTBS
OMe
a,b,c
d,e
R = CO2Me: 11
R = CHO: 12
OMe
e,f
OHC
OMe
O
OMe
7
8
h,i
O
O
OMOM
OMe
OMOM
6
OMe
OH
f
g
MeO2C
5
4
OMe
13
OMe
O
O
Scheme 3. Reagents and conditions: (a) AcCl, MeOH, 0 °C to rt, 1 h
(80%); (b) MOMCl, i-Pr2NEt, THF, rt, 1 h (quant.); (c) KI, H2O, I2,
NaOH, DME, 0 °C, 30 min; (d) MeI, K2CO3, DMF, 0 °C to rt, 3 h
(75% in two steps); (e) LiAlH4, THF, 0 °C to rt, 30 min (75%); (f)
Dess–Martin periodinane, CH2Cl2, rt, 30 min; (g) (MeO)2P(O)CH2-
CO2Me, t-BuOK, THF, 0 °C to rt, 30 min (73% in two steps); (h)
AcCl, MeOH, 0 °C to rt, overnight; (i) DIBAL-H, CH2Cl2, ꢀ78 °C,
1 h (67% in two steps).
9
Scheme 2. Reagents and conditions: (a) TBSCl, imidazole, DMF, 0 °C
to rt, 30 min (92%); (b) MeLi, THF, ꢀ78 °C, 1 h (94%); (c) TPAP,
NMO, CH2Cl2, 0 °C to rt, 30 min (95%); (d) ethylene glycol, pTsOH,
benzene, reflux, 3 h; (e) TBAF, THF, 0 °C to rt, 30 min (83% in two
steps); (f) IBX, DMSO, rt, 30 min (82%); (g) 2, THF, rt, 3 h (83%,
single isomer).
Removal of the protecting groups from 5 under acidic
conditions in 88% yield, followed by protection of the
hydroxyl group and phenol as MOM ether gave ace-
tophenone 10 in quantitative yield. Acetophenone 10
was converted to methyl ester 11 by the iodoform reac-
tion and subsequent esterification in 75% yield. Methyl
ester 11 was transformed to benzaldehyde 12 by reduc-
tion using a LiAlH4/Dess–Martin oxidation sequence.
Treatment of 12 with trimethyl phosphonoacetate and
potassium t-butoxide gave a,b-unsaturated ester 13 in
55% yield from 11. Deprotection of all the MOM groups
in 13 under acidic conditions and successive reduction
with DIBAL-H provided 6 in 67% yield in two steps.
1H and 13C NMR spectra of the synthetic 6 were identi-
cal to those of the naturally isolated compound.8,9 Thus,
the total synthesis of ( )-nitidanin was accomplished in
10% overall yield from syringaldehyde (4) and the struc-
ture of intermediate 5 was confirmed.
The adduct 5 was subjected to the reactions shown in
Scheme 4. Adduct 5 was converted to iodide 14 by
sequential desilylation, mesylation and iodination in
76% in three steps. A 3-min treatment of 14 with n-BuLi
at ꢀ78 °C induced cleavage of the 1,4-dioxane ring after
halogen–metal exchange to afford the desired phenol 15.
A prolonged reaction time or the use of bromide instead
of iodide decreased the yield substantially. Immediate
methylation of 15 using methyl iodide and sodium
hydride gave the desired methyl ether 1611 in 44% yield
1
from 14. H NMR signals for 16 showed three singlets
(d 3.86, 3.876, 3.879 ppm), which indicated two non-
equivalent methoxy groups on the benzene ring originat-
ing from o-quinone. If the isomer 50 had been subjected
to the same process, the product should be 160, which
contains two equivalent methoxy groups on the benzene
ring. Thus, the orientation of the side chain of the
adduct was unambiguously established as 5.

A. Kuboki et al. / Tetrahedron Letters 48 (2007) 771–774
773
was sometimes unsuccessful owing to decomposition of
the product. After protection of phenol 5 as the mesy-
late, the TBS group was removed to give 17. Primary
alcohol 17 was converted to organoselenium compound
18 in 57% yield and oxidative elimination gave enol 19 in
94% yield, which was hydrolyzed under acidic condi-
tions to hemiketal 20 in quantitative yield. Although
cleavage of the hemiketal was troublesome by reduction
and treatment with methylmagnesium bromide, the tau-
tomeric phenol 20 could be directly methylated by treat-
ment with methyl iodide and potassium carbonate to
OMe
a,b,c
d
O
O
I
5
OMe
OMs
O
O
OMe
14
δ 3.86 ppm
3.876 ppm
OMe
OR
1
provide the desired methyl ether 2112 in 40% yield. H
OMe
OMs
O
R = H: 15
R = Me: 16
NMR spectra of 21 indicated two non-equivalent meth-
oxy groups on the benzene ring and again confirmed the
structure of 5.
O
O
e
OMe
OMe
In conclusion, we developed a highly regioselective
cycloaddition of o-quinone 4 and sinapyl alcohol unit
2 and achieved total synthesis of ( )-nitidanin (6) from
the adduct 5. In addition, we investigated two novel pro-
cedures for determination of the structure of 5 based on
partial cleavage of the 1,4-benzodioxane ring. Applica-
tion of these procedures to other systems and further
studies on effect of substituents of the o-quinone to the
regioselectivities are currently being conducted.
OMs
OMe
OMe
O
OMe
O
O
16'
Scheme 4. Reagents and conditions: (a) TBAF, THF, rt, 2 h; (b)
MsCl, Et3N, CH2Cl2, 0 °C, 30 min (87% in two steps); (c) NaI,
i-Pr2NEt, DMF, 80 °C, 1 h (87%); (d) n-BuLi, THF, ꢀ78 °C, 3 min; (e)
MeI, NaH, DMF, rt, 2 h (44% in two steps).
Acknowledgements
The authors thank Professor T. Ishikawa of Chiba Uni-
versity for his kindness in providing the NMR spectrum
of nitidanin. We are grateful to Assistant Professor K.
Hayashi and Mr. K. Kakumoto of Okayama University
of Science for assistance with NMR measurements.
We turned to the alternative mild method shown in
Scheme 5, since the ring cleavage reaction using n-BuLi
OMe
a,b
O
O
R
References and notes
5
R = OH: 17
R =
c
Ar
1. Kuboki, A.; Yamamoto, T.; Ohira, S. Chem. Lett. 2003,
32, 420–421.
O
O
: 18
Se
2. Ishikawa, T.; Seki, M.; Nishigaya, K.; Miura, Y.; Seki, H.;
Chen, I.-S.; Ishi, H. Chem. Pharm. Bull. 1995, 43, 2014–
2018.
3. Kim, T. H.; Ito, H.; Hayashi, K.; Hasegawa, T.; Mach-
iguchi, T.; Yoshida, T. Chem. Pharm. Bull. 2005, 53, 641–
644.
O2N
OMe
OMe
OH
O
O
O
d
e
O
Ar
Ar
4. Magdziak, D.; Rodriguez, A. A.; Water, R. W. V. D.;
Pettus, T. R. R. Org. Lett. 2002, 4, 285–288.
O
O
O
5. Ozanne, A.; Pouysegu, L.; Depernet, D.; Franc¸ois, B.;
Quideau, S. Org. Lett. 2003, 5, 2903–2906.
19
20
6. Spectral data for 4: 1H NMR (400 MHz, CDCl3): d 1.61 (s,
3H), 3.82 (s, 3H), 3.88 (dd, J = 6.8, 7.3 Hz, 2H), 4.08 (dd,
J = 6.8, 7.3 Hz, 2H), 6.05 (s, 1H), 6.26 (s, 1H); 13C NMR
(100 MHz, CDCl3): d 23.9, 55.9, 64.7, 106.9, 117.1, 152.9,
175.0, 178.8.
δ 3.93 ppm
3.96 ppm
OMe
OMe
OMs
OMe
O
f
OMe
7. Spectral data for 5: 1H NMR (400 MHz, CDCl3): d 0.08 (s,
6H), 0.90 (s, 9H), 1.64 (s, 3H), 3.60 (dd, J = 3.3, 12.6 Hz,
1H), 3.80–3.85 (m, 4H), 3.88 (s, 9H), 3.92–3.98 (m, 2H),
4.00–4.02 (m, 2H), 4.97 (d, J = 7.2 Hz, 1H), 5.61 (s, 1H),
6.66 (d, J = 1.9 Hz, 1H), 6.69 (s, 2H), 6.78 (d, J = 1.9 Hz,
1H); 13C NMR (100 MHz, CDCl3): d ꢀ5.7, ꢀ5.2, 14.2,
18.2, 25.8, 27.5, 56.2, 62.2, 64.4, 76.1, 78.3, 101.9, 104.1,
108.6, 127.7, 132.9, 134.5, 135.4, 135.8, 143.7, 147.0, 148.7.
8. Spectral data for synthetic 6: 1H NMR (400 MHz, CDCl3):
d 3.56 (dd, J = 3.2, 12.7 Hz, 1H), 3.90 (s, 9H), 4.30 (dd,
Ar =
O
Ar
O
21
Scheme 5. Reagents and conditions: (a) MsCl, Et3N, CH2Cl2, 0 °C,
30 min (60%); (b) TBAF, THF, rt, 1 h (quant.); (c) 4-nitrophenylsel-
enyl cyanide, n-Bu3P, THF, rt, overnight (57%); (d) mCPBA, CH2Cl2,
40 °C, overnight (94%); (e) 1 M HCl/THF (1:1), rt, overnight (quant.);
(f) MeI, K2CO3, DMF, rt, 3 h (40%).

774
A. Kuboki et al. / Tetrahedron Letters 48 (2007) 771–774
J = 1.2, 4.6 Hz, 2H), 4.96 (d, J = 8.24 Hz, 1H), 5.62 (s,
nitidanin was obtained using a mixed solvent of CDCl3/
CD3OD, as recommended in a personal communication
with the authors of Ref. 2.
1H), 6.25 (tt, J = 5.6, 16.0 Hz, 1H), 6.49 (dd, J = 16.0 Hz,
1H), 6.60 (d, J = 1.8 Hz, 1H), 6.67 (s, 2H), 6.69 (d,
J = 1.8 Hz, 1H); 1H NMR (500 MHz, CD3OD/CDCl3
1:1): d 3.54 (dd, J = 4.4, 12.7 Hz, 1H), 3.76 (dd, J = 2.4,
12.7 Hz, 1H), 3.89 (s, 3H), 3.93 (s, 6H), 4.06 (ddd, J = 2.4,
4.4, 8.3 Hz, 1H), 4.23 (dd, J = 1.5, 5.8 Hz, 2H), 4.90 (d,
J = 8.3 Hz, 1H), 6.23 (dt, J = 5.8, 5.8, 16.1 Hz, 1H), 6.49
(dt, J = 1.5, 1.5, 16.1 Hz, 1H), 6.66 (d, J = 1.8 Hz, 1H),
6.68 (d, J = 1.8 Hz, 1H), 6.70 (s, 2H); 13C NMR
(100 MHz, CDCl3): d 56.1, 56.4, 61.5, 63.7, 76.8, 78.3,
102.6, 104.1, 108.8, 127.1, 127.3, 129.5, 130.9, 132.8, 135.3,
144.3, 147.3, 147.8; 13C NMR (100 MHz, CD3OD/CDCl3
1:1): d 55.3, 55.4, 60.3, 62.0, 75.9, 78.2, 102.0, 103.9, 107.5,
126.3, 126.8, 129.1, 132.1, 135.2, 143.6, 147.4, 147.9.
10. In more complicated cases, NOE experiments would be
useful for determining the substitution pattern.
11. Spectral data for 16: 1H NMR (400 MHz, CDCl3): d
1.58 (s, 3H), 3.28 (s, 3H), 3.53–3.59 (m, 1H), 3.63–3.66 (m,
1H), 3.86 (s, 3H), 3.876 (s, 3H), 3.879 (s, 6H), 3.90–3.97
(m, 2H), 5.28 (d, J = 6.4 Hz, 1H), 5.41 (d, J = 17.2 Hz,
1H), 5.63 (d, J = 6.1 Hz, 1H), 6.09 (ddd, J = 6.1, 6.4,
17.2 Hz, 1H), 6.67 (d, J = 1.8 Hz, 1H), 6.69 (d, J = 1.8 Hz,
1H), 6.72 (s, 2H); 13C NMR (100 MHz, CDCl3): d 27.4,
39.8, 56.1, 56.3, 60.8, 64.4, 82.0, 103.1, 103.4, 107.3, 108.5,
117.3, 127.3, 137.3, 138.7, 138.9, 140.0, 150.6, 153.2, 153.4.
1
12. Spectral data for 21: H NMR (400 MHz, CDCl3): d 2.25
9. There were some differences between the 1H and 13C
NMR data for synthetic 6 in CDCl3 and those reported in
the literature, and we were thus skeptical about the
structure of 5. This is another reason why we started to
develop a procedure to determine the structure of 5. Good
accordance of the NMR spectra for synthetic and natural
(s, 3H), 2.50 (s, 3H), 3.30 (s, 3H), 3.91 (s, 6H), 3.93 (s, 3H),
3.95 (s, 3H), 5.54 (s, 1H), 6.81 (s, 2H), 7.12 (d, J = 1.8 Hz,
1H), 7.25 (d, J = 1.8 Hz, 1H); 13C NMR (100 MHz,
CDCl3): d 25.1, 26.3, 39.9, 56.3, 56.4, 61.1, 86.6, 103.2,
106.9, 110.3, 128.3, 132.6, 134.5, 143.7, 150.4, 153.6, 153.7,
196.4, 204.6.