(+)- And (-)-mutisianthol: First total synthesis, absolute configuration, and antitumor activity

Article abstract of DOI:10.1021/jo9000405

The first synthesis of the natural product (+)-mutisianthol was accomplished in 11 steps and in 21% overall yield from 2-methylanisole. The synthesis of its enantiomer was also performed in a similar overall yield. The absolute configuration of the sesquiterpene (+)-mutisianthol was assigned as (15,37?). Key steps in the route are the asymmetric hydrogenation of a nonfunctionalized olefin using chiral iridium catalysts and the ring contraction of 1,2-dihydronaphthalenes using thallium(III) or iodine(III). The target molecules show moderate activity against the human tumor cell lines SF-295, HCT-8, and MDA-MB-435.

Full text of DOI:10.1021/jo9000405

(+)- and (-)-Mutisianthol: First Total Synthesis, Absolute
Configuration, and Antitumor Activity†
Graziela G. Bianco,‡ Helena M. C. Ferraz,‡,¶ Arinice M. Costa,§ Let´ıcia V. Costa-Lotufo,§
Cla´udia Pessoa,§ Manoel O. de Moraes,§ Marcus G. Schrems, Andreas Pfaltz,*, and
Luiz F. Silva, Jr.*,‡
Department of Chemistry, Institute of Chemistry, UniVersity of Sao Paulo, AV. Prof. Lineu Prestes,
748, CP 26077, CEP 05513-970 Sao Paulo SP, Brazil, Departamento de Fisiologia e Farmacologia,
UniVersidade Federal do Ceara´, P.O. Box 3157, 60430-270, Fortaleza, Ceara´, Brazil, and Department of
Chemistry, UniVersity of Basel, St. Johanns-Ring 19, CH-4056 Basel, Switzerland
luizfsjr@iq.usp.br; andreas.pfaltz@unibas.ch
ReceiVed January 8, 2009
The first synthesis of the natural product (+)-mutisianthol was accomplished in 11 steps and in 21%
overall yield from 2-methylanisole. The synthesis of its enantiomer was also performed in a similar
overall yield. The absolute configuration of the sesquiterpene (+)-mutisianthol was assigned as (1S,3R).
Key steps in the route are the asymmetric hydrogenation of a nonfunctionalized olefin using chiral iridium
catalysts and the ring contraction of 1,2-dihydronaphthalenes using thallium(III) or iodine(III). The target
molecules show moderate activity against the human tumor cell lines SF-295, HCT-8, and MDA-MB-435.
Introduction
The phenolic sesquiterpene mutisianthol was isolated by
Bohlmann and co-workers in 1979, from the roots of Mutisia
homoeantha.1 On the basis of spectroscopic data, the relative
configuration of this natural indane was assigned as 1, which
embodies a cis-1,3-disubstituted cyclopentyl unit. Mutisianthol
has been isolated as the dextrorotatory enantiomer, but its
absolute configuration has not yet been assigned. Nearly two
decades after Bohlmann’s work, Ho and co-workers2 reported
the first total synthesis of (()-mutisianthol. In the first route,
the authors obtained the acetylated cis-indane 2, exhibiting a
structure very similar to that of 1. However, comparing the NMR
spectra of this intermediate with those of the natural compound,
the authors considered that the relative configuration of muti-
sianthol should be trans. Eventually, a new route was elaborated
to give 3, which showed spectroscopic data identical to that of
the natural compound (Figure 1). This synthesis was achieved
in 15 steps and in 3% yield from p-methylacetophenone. Thus,
FIGURE 1. Structure of mutisianthol and related indanes.
mutisianthol is one of several examples of a natural product
whose structure was misassigned and later on corrected by
chemical synthesis.3 In the past decade, several approaches were
investigated for the synthesis of indanes through the ring
contraction4 of readily available 1,2-dihydronaphthalenes medi-
ated by thallium(III)5 or by iodine(III),6 including applications
in total synthesis.5d,g,6 One of the targets was (()-mutisianthol,
which was synthesized in 12 steps and in 8% yield from
2-methylanisole.5d
(3) For a review, see Nicolaou, K. C.; Snyder, S. A. Angew. Chem., Int. Ed.
2005, 44, 1012.
† Dedicated with deep respect to Prof. Nicola Petragnani on the occasion of
his 80th birthday.
(4) For reviews concerning ring contraction reactions, see: (a) Redmore, D.;
Gutsche, C. D. In AdVances in Alicyclic Chemistry; Hart, H., Karabastos, G. J.,
Eds.; Academic Press: New York, London, 1971; Vol. 3, p 1. (b) Silva, L. F.,
Jr. Tetrahedron 2002, 58, 9137. For a review concerning ring contraction
reactions mediated by iodine(III), see: (c) Silva, L. F., Jr. Molecules 2006, 11,
421. For reviews concerning ring contraction reactions mediated by thallium(III),
see: (d) Ferraz, H. M. C.; Silva, L. F., Jr. Quim. NoVa 2000, 23, 216.
‡ University of Sao Paulo.
§ Universidade Federal do Ceara´.
University of Basel.
¶ Deceased.
(1) Bohlmann, F.; Zdero, C.; Le Van, N. Phytochemistry 1979, 18, 99.
(2) Ho, T.-L.; Lee, K.-Y.; Chen, C.-K. J. Org. Chem. 1997, 62, 3365.
10.1021/jo9000405 CCC: $40.75
Published on Web 02/20/2009
2009 American Chemical Society
J. Org. Chem. 2009, 74, 2561–2566 2561

Bianco et al.
SCHEME 1. Retrosynthetic Analysis for the Asymmetric
The chemical synthesis of small-molecule natural products
has an important role in the development of chemistry7 and in
the discovery of new compounds with biological activity.8 This
is particularly evident in the search for new anticancer candi-
dates.9 In this context, we herein describe the first asymmetric
synthesis of (+)-mutisianthol and its enantiomer, unraveling the
previously unknown absolute configuration of the two stereo-
genic centers of this natural sesquiterpenene. In addition, results
regarding the antitumor activity of the target molecules and
related indanes are reported.
Synthesis of Mutisianthol
Results and Discussion
The strategy for the asymmetric synthesis of mutisianthol was
based mainly on our previous synthesis of the racemate5d and
on the asymmetric hydrogenation of olefins using iridium
catalysts.10 Thus, it was planned to obtain target molecule 3
from aldehyde 4 through Wittig reaction and deprotection. The
ring contraction of the optically active olefin 5 using either
Tl(III) or I(III) would give the aldehyde 4, which bears the 1,3-
trans-disubstituted indane unit. Olefin 5 would be prepared from
tetralone 6 by reduction and dehydration. We envisioned that
the 4-methyl-1-tetralone 6 could be obtained in high enantio-
meric excess through the asymmetric hydrogenation of the
4-methyl-1,2-dihydronaphthalene 7, followed by benzylic oxida-
tion. Alkene 7 would be obtained from 2-methylanisole (8)
(Scheme 1). The retrosynthesis shown is for (1S,3R)-mutisian-
thol, which was eventually identified as the natural product.
However, as the absolute configuration was unknown at the
beginning of this work, a flexible synthetic plan was chosen to
allow the stereoselective synthesis of both enantiomers. We
therefore decided to use asymmetric hydrogenation of olefin 7
as a key step, which should deliver either the (+)- or the (-)-
enantiomer by proper choice of the catalyst.11
SCHEME 2. Preparation of Olefin 7 and of Racemic (()-11
With the above plan in mind, the total synthesis of mutisian-
thol was initiated. Olefin 7 was obtained in four steps from
commercially available 2-methyl-anisole (8) in 56% yield.5d,12
Tetrahydronaphthalene (()-11 was obtained by hydrogenation
of the 1,2-dihydronaphthalene 7 over Pd/C, in 93% yield.
Racemic (()-11 was used as reference for establishing separa-
tion conditions for its two enantiomeric forms (Scheme 2).
Because 1,2-dihydronaphthalene 12, which is similar to 7,
had been hydrogenated with high enantiomeric excess using
chiral iridium catalysts (Scheme 3 and Figure 2),13,14 we
envisaged that tetrahydronaphthalene 11 could be also obtained
in high enantiomeric purity.
(5) (a) Ferraz, H. M. C.; Silva, L. F., Jr.; Vieira, T. O. Tetrahedron 2001,
57, 1709. (b) Ferraz, H. M. C.; Silva, L. F., Jr. Tetrahedron 2001, 57, 9939. (c)
Ferraz, H. M. C.; Aguilar, A. M.; Silva, L. F., Jr. Synthesis 2003, 7, 1031. (d)
Ferraz, H. M. C.; Aguilar, A. M.; Silva, L. F., Jr. Tetrahedron 2003, 59, 5817.
(e) Silva, L. F., Jr.; Sousa, R. M. F.; Ferraz, H. M. C.; Aguilar, A. M. J. Braz.
Chem. Soc. 2005, 16, 1160. (f) Silva, L. F., Jr.; Quintiliano, S. A. P.; Craveiro,
M. V.; Vieira, F. Y. M.; Ferraz, H. M. C. Synthesis 2007, 355. (g) Silva, L. F.,
Jr.; Craveiro, M. V. Org. Lett. 2008, 10, 5417. (h) Ferraz, H.; M, C.; Carneiro,
V. M. T.; Silva, L. F., Jr. Synthesis 2009, 385.
(6) Silva, L. F., Jr.; Siqueira, F. A.; Pedrozo, E. C.; Vieira, F. Y. M.;
Doriguetto, A. C. Org. Lett. 2007, 9, 1433.
(7) (a) This theme was discussed in the editorial of the JACS virtual issue
regarding the total synthesis of natural products: Roush, W. R. J. Am. Chem.
Soc. 2008, 130, 6654. (b) See also: Hudlicky, T.; Reed, J. W. The Way of
Synthesis; Wiley-VCH: Germany, 2007.
Initially, we expected that olefins 7 and 12 would give
comparable results in the iridium-catalyzed enantioselective
hydrogenation. However, after an initial screening of catalysts
A-C, we were surprised to see that this was not the case (Table
1). Although dihydronaphthalene 12 was converted to 13 in 95%
ee using complex A without any byproducts,14 11 was obtained
in only 68% ee under the same conditions. Even more surprising
was the formation of 23% of naphthalene 14 (entry 1). We had
observed this side reaction only with some tetrasubstituted
dihydronaphthalenes,15 but never in the enantioselective hy-
drogenation of 12. Other catalysts such as B and C gave
significantly less aromatic side product (entries 2 and 3);
(8) For broad reviews, see: (a) Maimone, T. J.; Baran, P. S. Nat. Chem. Biol.
2007, 3, 396. (b) Wilson, R. M.; Danishefsky, S. J. J. Org. Chem. 2006, 71,
8329. (c) Newman, D. J.; Cragg, G. M. J. Nat. Prod 2007, 70, 461. For selected
articles and reviews concerning the total synthesis and the biological evaluation
of natural products, see: (d) Fennell, K. A.; Mo¨llmann, U.; Miller, M. J. J. Org.
Chem. 2008, 73, 1018. (e) Bonazzi, S.; Guttinger, S.; Zemp, I.; Kutay, U.;
Gademann, K. Angew. Chem., Int. Ed. 2007, 46, 8707. (f) Adrio, J.; Cuevas, C.;
Manzanares, I.; Joullie´, M. M. J. Org. Chem. 2007, 72, 5129. (g) Nicolaou,
K. C.; Wu, T. R.; Sarlah, D.; Shaw, D. M.; Rowcliffe, E.; Burton, D. R. J. Am.
Chem. Soc. 2008, 130, 11114. (h) Bowers, A.; West, N.; Taunton, J.; Schreiber,
S. L.; Bradner, J. E.; Williams, R. M. J. Am. Chem. Soc. 2008, 130, 11219. (i)
Tichenor, M. S.; Boger, D. L. Nat. Prod. Rep. 2008, 25, 220. (j) Behenna, D. C.;
Stockdill, J. L.; Stoltz, B. M. Angew. Chem., Int. Ed. 2008, 47, 2365.
(9) For a review, see: Wilson, R. M.; Danishefsky, S. J. Chem. Soc. ReV.
2007, 36, 1207.
(10) For reviews regarding asymmetric hydrogenation mediated by iridium
catalysts, see: (a) Roseblade, S. J.; Pfaltz, A. Acc. Chem. Res. 2007, 70, 1402.
(b) Ka¨llstro¨m, K.; Munslow, I.; Andersson, P. G. Chem. Eur. J. 2006, 12, 3194.
(c) Pfaltz, A.; Blankenstein, J.; Hilgraf, R.; Hormann, E.; McIntyre, S.; Menges,
F.; Schonleber, M.; Smidt, S. P.; Wu¨stenberg, B.; Zimmermann, N. AdV. Synth.
Catal. 2003, 345, 33. See also ref 13.
(12) Zubaidha, P. K.; Chavan, S. P.; Racherle, U. S.; Ayyangar, N. R.
Tetrahedron 1991, 47, 5759.
(13) For a review regarding asymmetric hydrogenation of non-functionalized
olefins, see: Cui, X.; Burgess, K. Chem. ReV. 2005, 105, 3272.
(14) (a) Lightfoot, A.; Schnider, P.; Pfaltz, A. Angew. Chem., Int. Ed. 1998,
37, 2897. (b) Menges, F.; Pfaltz, A. AdV. Synth. Catal. 2002, 344, 40. (ba) Smidt,
S. P.; Menges, F.; Pfaltz, A. Org. Lett. 2004, 6, 2023. (c) Kaiser, S.; Smidt,
S. P.; Pfaltz, A. Angew. Chem., Int. Ed. 2006, 45, 5194. (d) Schrems, M. G.;
Neumann, E.; Pfaltz, A. Heterocycles 2008, 76, 771.
(11) For recent developments in asymmetric hydrogenation, see: Special Issue
on Hydrogenation and Transfer Hydrogenation, Acc. Chem. Res. 2007, 70 (12).
(15) Schrems, M. G.; Neumann, E.; Pfaltz, A. Angew. Chem., Int. Ed. 2007,
46, 8274.
2562 J. Org. Chem. Vol. 74, No. 6, 2009

Total Synthesis of (+)- and (-)-Mutisianthol
TABLE 3. Second Screening of Catalysts for the Hydrogenation
of 7a
H2
7. (100 bar), cat. (2 mol %)8 11 + 14
2 h, rt, CH2Cl2
entry
catalyst
conversion (%)
productsb 11:14
ee (%) of 11
1
2
3
D
E
F
<99
<99
<99
98:2
94:6
99:1
92 (-)
82 (+)
69 (-)
a CH2Cl2 was stirred over activated aluminum oxide and filtered prior
to use. b Ratio determined by GC analysis.
TABLE 4. Hydrogenation of Olefin 7 with catalyst Da
H2 (100 bar), CH2Cl2
7.
8 (-)-11 + 14
FIGURE 2. Structure of iridium catalysts A-F.
D, 2 h, rt
SCHEME 3. Asymmetric Hydrogenation of Olefin 12
entry catalyst load (mol %) conversion (%) productsb 11:14 ee (%)
1
2
3
4
5
2.0
1.5
1.0
0.5
0.1
<99
<99
<99
<99
16
98:2
98:2
97:3
96:4
8:8
92 (-)
92 (-)
91 (-)
89 (-)
4 (-)
a CH2Cl2 was stirred over activated aluminum oxide and filtered prior
to use. b Ratio determined by GC analysis.
TABLE 1. First Screening of Catalysts for the Hydrogenation of 7
and then filtered prior to use, higher enantiomeric excesses could
be obtained and the formation of aromatic side product was
reduced. With 2 mol % of A, tetrahydronaphthalene (+)-11 was
obtained in 80% ee and 13% of naphthalene 14 was formed
(entry 4). To suppress the undesired aromatization, we assumed
that higher pressure would be beneficial. Indeed, we obtained
significantly better results using 100 bar of hydrogen instead
of 50 bar. Using 1 mmol of 7, 2 mol % of complex A, and 100
bar of hydrogen, we obtained tetrahydronaphthalene (+)-5 in
87% ee and the aromatic side product 14 in only 9% (entry 8).
At 50 bar, product (+)-11 was obtained in 80% ee together
with 15% of 14 (entry 4).
entry
catalyst
conversion (%)
productsa 11:14
ee of 11 (%)
1
2
3
A
B
C
<99
<99
<99
77:23
97:3
99:1
68 (+)
34 (+)
5 (+)
a Ratio determined by GC analysis.
TABLE 2.
Hydrogenation of Olefin 7 with Catalyst A
H2, CH2Cl2
7.
8 (+)-11 + 14
With these optimized conditions (high pressure, high catalyst
loading, and freshly dried solvent), we screened other iridium
catalysts (Table 3) and obtained superior results using complex
D, which gave (-)-11, i.e., the opposite enantiomer previously
obtained with catalyst A. The hydrogenation proceeded with
only 2% of side product formation and gave tetrahydronaph-
thalene (-)-11 with an enantiomeric excess of 92% (entry 1).
Using complex E, 82% ee and 6% of 14 was obtained (entry
2), while complex F gave 69% ee and only 1% of 14 (entry 3).
As observed for complex A, lowering the catalyst loading of
D resulted in a lower enantiomeric excess for (-)-11 and an
increase of 14 (Table 4). Using 1 mol % of D, tetrahydronaph-
thalene (-)-11 was obtained in 91% ee together with 3% of
aromatic side product (entry 3). With 0.5 mol % of catalyst
loading, (-)-11 was obtained with 89% ee and 4% of 14 (entry
4). At even lower catalyst loading (0.1 mol %), only 8% of
(-)-11 was obtained with an ee of 4%. Naphthalene 14 was
obtained in 8% and the remaining was unreacted starting
material.
A, 2h,rt
entry
conditions
conversion (%) productsa 11:14 ee (%)
1
2
3
2.0 mol %, 50 bar
1.0 mol %, 50 bar
0.5 mol %, 50 bar
2.0 mol %, 50 bar
1.5 mol %, 50 bar
1.0 mol %, 50 bar
0.5 mol %, 50 bar
2.0 mol %, 100 bar
<99
<99
<99
<99
<99
<99
<99
<99
82:18
77:23
68:32
87:13
83:17
82:18
73:27
91:9
74 (+)
68 (+)
50 (+)
80 (+)
77 (+)
74 (+)
58 (+)
87 (+)
4b
5b
6b
7b
8b
a Ratio determined by GC analysis. b CH2Cl2 was stirred over
activated aluminum oxide and filtered prior to use.
however, the enantiomeric excesses were very low (34% and
5%, respectively).
With these initial results, we decided to optimize the reaction
conditions using complex A (Table 2). Lowering the catalyst
loading to less than 1 mol % gave lower enantiomeric excess
and significantly higher amounts of aromatic side product. For
example, with a catalyst loading of 0.5 mol % of complex A,
(+)-11 was obtained in only 50% ee, whereas 32% of 14 was
formed (entry 3). Using 2 mol % of A, an enantiomeric excess
of 74% was obtained, along with 18% of 14 (entry 1). When
the solvent CH2Cl2 was stirred over activated aluminum oxide
To obtain the required amount of (+)-11 for the synthesis, 7
was hydrogenated in the presence of A under a pressure of 100
bar. Under these conditions, 9% of naphthalene 14 was formed.
For the preparation of (-)-11, we decided to use a catalyst
loading of 0.75 mol % and a pressure of 100 bar, which gave
the desired product in 98% yield, including 3% of naphthalene
J. Org. Chem. Vol. 74, No. 6, 2009 2563

Bianco et al.
TABLE 5. Ring Contraction Reactions with 1.1 equiv of TTN or
HTIB
SCHEME 4.
Asymmetric Hydrogenations of Olefin 7
SCHEME 5. Preparation of 1,2-Dihydronaphthalenes (+)-
and (-)-5
14. Under these conditions, (-)-11 was obtained in 90% ee.
Thus, we had both (+)- and (-)-11 in hand for further
transformations (Scheme 4).
SCHEME 6.
Completion of the Syntheses of Mutisianthol
After having developed an efficient method to perform the
asymmetric hydrogenation of olefin 7, the benzylic oxidation
of the tetralins (+)- and (-)-11 was required. This transforma-
tion was best performed (see Supporting Information for other
conditions) in AcOH/H2O with careful addition of a slight excess
of chromium oxide, which gave the desired tetralones (-)- and
(+)-6 in 94% and 80% yield, respectively. In these oxidations,
the secondary benzylic position of tetralin 11 was oxidized
selectively without any racemization while the tertiary benzylic
position remained untouched. During the development of this
synthesis, Chavan and co-workers16 reported the asymmetric
synthesis of (-)-heritol from tetralone (+)-(R)-6, which was
prepared from (+)-(R)-citronellal. On the basis of their synthesis,
we assigned the absolute configuration of (+)-(R) and (-)-(S)-6
and, consequently, of all optically active compounds described
in this article. Tetralones (+)- and (-)-6 were then transformed
into the corresponding 1,2-dihydronaphthalenes (+)- and (-)-
5, respectively, through reduction with NaBH4 followed by
dehydration with p-toluene sulfonic acid in toluene (Scheme
5).5d,e A slightly lower yield (72%) was obtained for the
dehydration of (-)-6 in benzene.
Treating (-)-5 with thallium(III) trinitrate (TTN) in trim-
ethylorthoformate (TMOF)5a,c,d led to the ketal (-)-15, in 94%
yield (Table 5, entry 1). To introduce the propenyl moiety of
mutisianthol, the aldehyde moiety of (-)-15 was unmasked by
heating in AcOH,5d which gave (-)-4 in 72% yield. Acetonitrile
is also a suitable solvent for the rearrangement of olefins
mediated by TTN.5h Additionally, under this condition aldehyde
(-)-4 would be isolated directly, avoiding the deprotection. First,
we treated the olefin (()-16 using TTN in CH3CN in the
presence of molecular sieves and under inert atmosphere, which
led to (()-17 (entry 2). Under similar conditions, (-)-5 gave
(-)-4 in 74% yield (entry 3). The inert atmosphere and the
molecular sieves are not crucial for the ring contraction, as
shown in the reactions of (()- and (+)-5 (entries 4 and 5,
respectively). The substitution of the toxic thallium(III) salt by
the iodine(III) reagent [hydroxy(tosyloxy)iodo]benzene (HTIB)
was also evaluated. Oxidation of (-)-5 with HTIB6 gave the
desired ketal (-)-15, in 66% yield, together with 18, which was
isolated in 10% yield, as a mixture of diastereomers (entry 6).
The mechanism for the thallium(III)- or iodine(III)-mediated
ring contraction of 1,2-dihydronaphthalenes has been previously
discussed.5,6
Wittig reaction of aldehydes (+)- and (-)-4 with (CH3)2Cd
5d,17,18
PPh3
gave (+)- and (-)-19 in 86% and 67% yield,
respectively. Finally, (+)- and (-)-mutisianthol (3) were
obtained as white solids in good yield by reaction of (+)- and
(-)-19 with Na/EtSH in DMF.5d,19 The spectroscopic data of
the target molecules were in agreement with those described in
the literature.1,2,5d Moreover, based on the value of [R]24
D
reported (+94, c 0.11, CHCl3),1 the absolute configuration of
natural (+)-mutisianthol was assigned as (1S,3R), whereas (-)-
mutisianthol is (1R,3S) (Scheme 6).
For studies regarding biological activity, we also prepared
the olefin (()-20, which bears the main structural features of
mutisianthol except for the substituents on the aromatic ring.
(17) Fagerlund, U. H. M.; Idler, D. R. J. Am. Chem. Soc. 1957, 79, 6473.
(18) Hauser, F. M.; Prasanna, S. Synthesis 1980, 621.
(19) Schow, S. R.; Bloom, J. D.; Thompson, A. S.; Winzenberg, K. N.; Smith,
A. B., III. J. Am. Chem. Soc. 1986, 108, 2662.
(16) Chavan, S. P.; Thakkar, M.; Kalkote, U. R. Tetrahedron Lett. 2007, 48,
643.
2564 J. Org. Chem. Vol. 74, No. 6, 2009

Total Synthesis of (+)- and (-)-Mutisianthol
SCHEME 7. Synthesis of the Olefin (()-25
the trans-1,3-disubstituted-indane. The absolute configuration
of the natural sesquiterperne (+)-mutisianthol was established
as (1S,3R). Finally, we found that that mutisianthol has a
moderate activity against the tumor cells SF-295, HCT-8, and
MDA-MB-435.
Experimental Section
TABLE 6. Cytotoxic Activity of Mutisianthol and Derivatives on
Tumor Cell Linesa
(-)-(R)-1,2,3,4-Tetrahydro-7-methoxy-1,6-dimethylnaphtha-
lene (-)-11. In a glovebox a glass inlay was charged with olefin 7
(0.38 g, 2.0 mmol), Ir-catalyst D (23 mg, 0.015 mmol) and CH2Cl2
(10 mL). The inlay and a magnetic stirring bar were put into an
autoclave. The autoclave was sealed and then purged with H2. A
pressure of 100 bar of H2 was applied, and the mixture was stirred
for 3 h. The pressure was released, and the solvent was removed
under reduced pressure. The crude mixture was taken up in 2 mL
of hexanes, passed through a plug of silica (1 cm × 0.5 cm), and
rinsed with hexanes until no UV-active compound was further
eluted (spotted on TLC). The solvent was evaporated to leave (-)-
11 (0.38 g, 2.0 mmol, 98%) as colorless oil. GC analysis showed
a mixture of 1420 (3%) and (-)-11 (97%): Rf 0.58 (5% EtOAc/
hexanes); IR (film) 2928, 2854, 1617, 1508, 1250 cm-1; 1H NMR
(300 MHz, CDCl3) δ 1.28 (3H, d, J ) 6.9 Hz), 1.4-1.8 (2H, m),
1.8-2.0 (2H, m), 2.16 (3H, s), 2.6-2.7 (2H, m), 2.8-2.9 (1H, m),
3.80 (3H, s), 6.65 (1H, s), 6.82 (1H, s); 13C NMR (75 MHz, CDCl3)
δ 15.7 (CH3), 20.6 (CH2), 23.0 (CH3), 29.0 (CH2), 31.6 (CH2), 32.6
(CH), 55.4 (CH3), 109.6 (CH), 124.0 (C), 128.3 (C), 131.1 (CH),
140.3 (C), 155.8 (C); LRMS m/z (%) 190 (M+•, 57), 175 (100);
HRMS m/z C13H18O (M + H)+ calcd 191.1430, found 191.1430;
IC50 (CI 95%) µg/mL
entry
compound
doxorubicin
(+)-mutisianthol (+)-3
(-)-mutisianthol (-)-3
(()-20
(+)-19
(-)-19
(()-19
(-)-4
SF295
HCT-8
MDA-MB-435
1
2
3
4
5
6
7
8
0.48
4.39
5.27
<25
0.01
3.84
7.83
<25
19.08
<25
0.24
6.73
2.69
<25
<25
<25
<25
19.42
25.08
<25
<25
<25
<25
20.19
a Data are presented as IC50 values and 95% confidence interval
obtained by nonlinear regression from three independent experiments.
Ring contraction of the 1,2-dihydronaphthalene (()-16 mediated
by TTN gave aldehyde (()-17. Wittig reaction on this aldehyde
led to (()-20 in 54% yield for the two steps (Scheme 7).
Once the total synthesis was successfully concluded, we
decided to investigate the antitumor activity of mutisianthol and
analogous compounds, whose biological properties have not yet
been investigated. We tested the cytotoxicity of these compounds
using three tumor cell lines: MDA-MB-435 (human melanoma),
HCT-8 (human colon), and SF-295 (human brain), using
doxorubicin as positive control. Natural (+)-mutisianthol dis-
plays moderate cytotoxicity against the three cell lines when
compared with doxorubicin (Table 6, entry 1), showing IC50
values of 4.39 µg/mL in SF295, 3.84 µg/mL in HCT-8, and
6.73 µg/mL in MDA-MB-435 cells (entry 2). Similarly, non-
natural mutisianthol (-)-3 also shows moderate activity (5.27
µg/mL in SF295, 7.83 µg/mL in HCT-8, and 2.69 µg/mL in
MDA-MB-435 cells, entry 3). The natural enantiomer is slightly
more active in SF295 and twice as active in HCT-8 but less
active in MDA-MB-435 than the (-)-enantiomer. On the other
hand, the structural analog (()-20 displays low activity in all
tumor cell lines (entry 4), showing that the substituents on the
aromatic ring are important for biological activity. The phenol
group and isopropenyl moiety are also essential for activity,
considering the results with protected mutisianthol 19 (entries
5-7) and with the aldehyde (-)-4 (entry 8).
[R]20 -15.5 (c 1.04, CHCl3), 90% ee.
D
(+)-(R)-3,4-Dihydro-6-methoxy-4,7-dimethylnaphthalen-1(2H)-
one (+)-6. A magnetically stirred solution of (-)-11 (0.34 g, 1.8
mmol) in glacial HOAc (11 mL) was cooled to 0 °C. The ice-bath
was removed, and a solution of CrO3 (0.25 g, 2.5 mmol, 1.3 equiv)
in HOAc/H2O (8:2, 3.6 mL) was slowly dropwise. The temperature
of the reaction mixture was allowed to reach rt. After completion
of reaction (ca. 10 min after addition of oxidant), the reaction
mixture was diluted with water. The solution was transferred to a
separatory funnel and was carefully neutralized by addition of a
saturated solution of NaHCO3. The crude product, a yellow solid
insoluble in water, was extracted with Et2O. The organic phase was
washed with brine and dried over anhydrous MgSO4. The solvent
was removed under reduced pressure. The crude yellow solid was
purified by flash chromatography (gradient elution, hexanes/EtOAc,
9:1-6:4), to give (+)-6 (80%, 0.31 g, 1.5 mmol). Alternatively,
the crude product can be purified by recrystallization with hexanes
(about 2 mL for 0.1 g of (+)-6): mp 115.0-116.0 °C (lit.16 110
°C); Rf 0.37 (20% EtOAc/hexanes); [R]21D +19.7 (c 1.08, CHCl3);
[lit.16 [R]25 +26.87 (c 0.9, CHCl3)].
D
(+)-(R)-1,2-Dihydro-7-methoxy-1,6-dimethylnaphthalene (+)-
5. To a stirred solution of the tetralone (+)-6 (0.24 g, 1.2 mmol) in
THF (4.4 mL) and in anhydrous MeOH (11 mL) was added
dropwise NaBH4 (0.22 g, 5.9 mmol, 5 equiv) at 0 °C. The mixture
was stirred for 105 min at rt. The reaction was quenched with brine
and extracted with EtOAc. The organic phase was dried over
anhydrous MgSO4, and the solvent was removed under reduced
pressure. The resulting yellow oil was immediately diluted in
anhydrous toluene (10 mL), and a few crystals of p-TsOH were
added. The mixture was stirred for 1.5 h at rt. The reaction was
quenched with 5% aqueous solution of NaHCO3 and extracted with
EtOAc. The organic phase was washed with brine and dried over
anhydrous Na2SO4. The solvent was removed under reduced
pressure giving yellow oil. The product was purified by flash
chromatography (hexanes/EtOAc, 9:1, as eluent) to give (+)-5
(92%, 0.21 g, 1.1 mmol) as a colorless oil: Rf 0.56 (10% EtOAc/
Conclusion
The first asymmetric synthesis of the natural product (+)-
mutisianthol was accomplished in 11 steps and in 21% overall
yield from 2-methylanisole. The synthesis of its enantiomer was
also performed in the same number of steps in 17% overall
yield (see Supporting Information for a summary of the
syntheses). Compared with our previous synthesis,5d the route
described herein is not only asymmetric but also one step shorter.
Moreover, the reactions were further optimized, and conse-
quently, the overall yield increased from 8% to 17-21%. The
key steps are (i) the asymmetric hydrogenation of the nonfunc-
tionalized olefin 7 using chiral iridium catalysts and (ii) the ring
contraction of the 1,2-dihydronaphthalenes (+)- and (-)-5 using
thallium(III) or iodine(III), which allowed the construction of
(20) Bell, A. A.; Stipanovic, R. D.; Zhang, J.; Mace, M. E. Phytochemistry
1998, 49, 431.
J. Org. Chem. Vol. 74, No. 6, 2009 2565

Bianco et al.
hexanes); IR (film) 2957, 2834, 1611, 1500, 1256 cm-1; 1H NMR
(300 MHz, CDCl3) δ 1.22 (3H, d, J ) 7.0 Hz), 2.07 (1H, dddd, J
) 16.9, 6.9, 5.0, and 1.7 Hz), 2.16 (3H, s), 2.43 (1H, dddd, J )
16.9, 6.8, 4.2 and 2.4 Hz), 2.88 (1H, sextet, J ) 7.0 Hz), 3.83 (3H,
s), 5.79 (1H, dt, J ) 9.5 and 4.6 Hz), 6.34 (1H, dt, J ) 9.5 and 1.6
Hz), 6.66 (1H, s), 6.82 (1H, s); 13C NMR (75 MHz, CDCl3) δ 15.7
(CH3), 20.3 (CH3), 31.1 (CH2), 32.0 (CH), 55.4 (CH3), 108.5 (CH),
123.9 (C), 124.2 (CH), 125.9 (C), 126.8 (CH), 128.8 (CH), 139.4
(C), 156.8 (C); LRMS m/z (%) 188 (M+•, 68), 173 (100), 158 (80).
HRMS m/z C13H16O (M + H)+ calcd 189.1274, found 189.1271;
(3H, d, J ) 1.5 Hz), 1.90-2.00 (2H, m), 2.18 (3H, s), 3.2-3.3
(1H, m), 3.82 (3H, s), 3.96-4.01 (1H, m), 5.11-5.14 (1H, m),
6.67 (1H, s), 6.83 (1H, s); 13C NMR (75 MHz, CDCl3) δ 16.3 (CH3),
18.1 (CH3), 21.0 (CH3), 25.8 (CH3), 38.5 (CH), 41.6 (CH), 42.5
(CH2), 55.5 (CH3), 105.6 (CH), 124.9 (C), 126.2 (CH), 128.7 (CH),
131.1 (C), 137.9 (C), 147.2 (C), 157.0 (C); LRMS m/z (%) 230
(M+•, 66), 215 (100), 201 (96), 186 (26), 128 (43), 115 (46); HRMS
m/z C16H22O (M + Na)+ calcd 253.1563, found 253.1566; [R]20
D
+117.5 (c 1.01, CHCl3), 90% ee.
(+)-(1S,3R)-Mutisianthol (+)-3. Under N2, 0.48 g of NaH (0.29
g, 12 mmol, 60% in mineral oil) was washed with anhydrous
hexanes (3 times). After a few minutes, anhydrous DMF (6.7 mL)
was added. To this mixture was slowly added a solution of EtSH
(0.58 mL, 7.8 mmol, 30 equiv) in anhydrous DMF (0.5 mL) at 0
°C, and the resulting yellow solution was stirred for 20 min at rt.
A solution of (+)-19 (58 mg, 0.25 mmol) in anhydrous DMF (1.5
mL) was then added dropwise, and the resulting mixture was stirred
for 5 h at 130 °C, becoming slightly brown. The mixture was cooled
to rt, and a saturated solution of NH4Cl was added. The mixture
was extracted with Et2O, and the organic phase was washed with
H2O and brine and dried over anhydrous MgSO4. The solvent was
removed under reduced pressure. The resulting brown oil was
purified by flash chromatography (hexanes/EtOAc, 7:3, as eluent)
to give a yellow oil, which was purified by flash chromatography
(hexanes/EtOAc, 9:1, as eluent), affording the (+)-3 (77%, 43 mg,
0.20 mmol) as a white solid: mp 97.0-98.0 °C; Rf 0.38 (30%
EtOAc/hexanes); IR (KBr) 3368, 2951, 2931, 2897, 2861, 1619,
1447, 1295 cm-1; 1H NMR (500 MHz, CDCl3) δ 1.20 (3H, d, J )
7.0 Hz), 1.74 (3H, d, J ) 1.0 Hz), 1.78 (3H, d, J ) 1.5 Hz),
1.88-1.98 (2H, m), 2.20 (3H, s), 3.16-3.23 (1H, m), 3.95-3.99
(1H, m), 4.58 (1H, br s), 5.10-5.12 (1H, m), 6.61 (1H, s), 6.81
(1H, s); 13C NMR (125 MHz, CDCl3) δ 15.8 (CH3), 18.1 (CH3),
20.9 (CH3), 25.8 (CH3), 38.1 (CH), 41.5 (CH), 42.4 (CH2), 110.1
(CH), 121.7 (C), 126.3 (CH), 128.6 (CH), 131.2 (C), 138.7 (C),
147.9 (C), 152.7 (C); LRMS m/z (%) 216 (M+•, 40), 201 (100),
115 (23); HRMS m/z C15H20O (M + H)+ calcd 217.1587, found
[R]21 +35.1 (c 1.07, CHCl3), 90% ee.
D
(+)-(1R,3R)-5-Methoxy-3,6-dimethyl-indan-1-carbaldehyde (+)-
4. To a stirred solution of (+)-5 (0.28 g, 1.5 mmol) in anhydrous
CH3CN (12 mL) was added TTN (0.73 g, 1.6 mmol, 1.1 equiv),
which promptly dissolved. The mixture was stirred for 1 min at 0
°C when an abundant precipitation was observed. The ice bath was
removed, and the solution was stirred for 15 min. The resulting
suspension was filtered through a silica gel pad (ca. 10 cm), using
CH2Cl2 as eluent. The filtrate was washed with H2O (twice) and
brine and dried over anhydrous MgSO4. The solvent was removed
under reduced pressure giving an orange oil, which was immediately
purified by flash chromatography (hexanes/EtOAc/CH2Cl2, 8:1:1,
as eluent), to give (+)-4 (80%, 0.25 g, 1.2 mmol) as a colorless
oil: Rf 0.37 (10% EtOAc/hexanes); IR (film) 2956, 2926, 2833,
2712, 1721, 1613, 1493 cm-1; 1H NMR (300 MHz, CDCl3) δ 1.29
(3H, d, J ) 6.9 Hz), 1.87 (1H, ddd, J ) 13.2, 8.5 and 7.3 Hz),
2.20 (3H, s), 2.66 (1H, ddd, J ) 13.2, 7.9 and 3.8 Hz), 3.30 (1H,
sextet, J ) 7.1 Hz), 3.81-3.86 (1H, m), 3.83 (3H, s), 6.71 (1H, s),
7.04 (1H, s), 9.58 (1H, d, J ) 2.9 Hz). 13C NMR (75 MHz, CDCl3)
δ 16.3 (CH3), 20.8 (CH3), 35.1 (CH2), 38.8 (CH), 55.4 (CH3), 56.2
(CH), 105.8 (CH), 125.6 (C), 126.8 (CH), 128.9 (C), 148.3 (C),
158.3 (C), 200.7 (CH); LRMS m/z (%) 204 (M+•, 10), 175 (100),
160 (18). HRMS m/z C13H16O2 (M + H)+ calcd 205.1223, found
205.1221; [R]21 +57.3 (c 1.12, CHCl3), 90% ee.
D
(+)-(1S,3R)-5-Methoxy-3,6-dimethyl-1-(2-methylprop-1-enyl)-
1H-indane (+)-19. To a stirred solution of Ph3PCH(CH3)2Br17 (0.17
g, 0.44 mmol, 2.1 equiv) in anhydrous THF (3 mL) and under inert
atmosphere was added dropwise n-BuLi (1.56 M in hexanes, 0.28
mL, 0.44 mmol) at 10 °C. The mixture was stirred for 20 min at
10 °C, resulting in a red solution. A solution of the aldehyde (+)-4
(43 mg, 0.21 mmol) in anhydrous THF (3 mL) was added dropwise.
The resulting yellow solution was stirred for 40 min at 0 °C. The
reaction was quenched with H2O and extracted with Et2O. The
organic phase was washed with brine and dried over anhydrous
MgSO4. The solvent was removed under reduced pressure giving
a yellow solid, which was purified by flash chromatography
(hexanes/CH2Cl2/EtOAc, 8:1:1, as eluent) to give (+)-19 (86%, 41
mg, 0.18 mmol) as a colorless oil: Rf 0.64 (10% EtOAc/hexanes);
IR (film) 2954, 2924, 1613, 1491, 1299 cm-1; 1H NMR (500 MHz,
CDCl3) δ 1.23 (3H, d, J ) 7.0 Hz), 1.74 (3H, d, J ) 1.5 Hz), 1.78
217.1584; [R]20D +95.1 (c 1.05, CHCl3), 90% ee; [lit.1 (+)-3 [R]24
+94,0 (c 0.11, CHCl3)].
D
Acknowledgment. Support by FAPESP, CNPq, the Swiss
National Science Foundation (SNF), and the Federal Commis-
sion for Technology and Innovation (KTI) is gratefully ac-
knowledged. We also thank Prof. N. P. Lopes for fruitful
discussions.
Supporting Information Available: Spectroscopic data and
experimental procedures. This material is available free of
charge via the Internet at http://pubs.acs.org.
JO9000405
2566 J. Org. Chem. Vol. 74, No. 6, 2009