Syntheses of anolignans A and B using ruthenium-catalyzed cross-enyne metathesis

Article abstract of DOI:10.1021/jo0107913

Anolignans A and B were synthesized using ruthenium-catalyzed cross-enyne metathesis as the key steps. The 1,3-diene moieties of these natural products were constructed by the introduction of the methylene parts of ethylene into alkyne using Grubbs' catalyst.

Full text of DOI:10.1021/jo0107913

224
J . Org. Chem. 2002, 67, 224-226
Syn th eses of An olign a n s A a n d B Usin g Ru th en iu m -Ca ta lyzed
Cr oss-En yn e Meta th esis
Miwako Mori,* Keisuke Tonogaki, and Nao Nishiguchi
Graduate School of Pharmaceutical Sciences, Hokkaido University, Sapporo 060-0812, J apan
Received August 6, 2001
Anolignans A and B were synthesized using ruthenium-catalyzed cross-enyne metathesis as the
key steps. The 1,3-diene moieties of these natural products were constructed by the introduction of
the methylene parts of ethylene into alkyne using Grubbs’ catalyst.
Ch a r t 1
Anolignan A and anolignan B are new dibenzylbuta-
diene lignans isolated from Anogeissus acuminata. They
were identified as the active HIV-1 reverse transcriptase
inhibitory constituents of this plant.1 A remarkable
feature of these compounds is that they have a 1,3-diene
moiety in the molecules (Chart 1).
A total synthesis of anolignan A was achieved by
Hatakeyama,2and he utilized a Lewis acid-catalyzed
allenylsilene addition to piperonal.
Sch em e 1. Novel Syn th esis of 1,3-Dien e fr om
Alk yn e a n d Eth ylen e An olign a n A a n d An olign a n
We have already reported the novel synthesis of 1,3-
diene from alkyne and ethylene using ruthenium carbene
complex 1a 3e,f reported by Grubss.4a,b When a CH2Cl2
solution of alkyne 2 was stirred in the presence of 1a at
room temperature under an atmosphere of ethylene, 1,3-
diene 3 was obtained in high yield. In this reaction, each
methylene part of ethylene is introduced onto the two-
alkyne carbons, respectively (Scheme 1).
This novel method prompted us to synthesize anolig-
nans. A retrosynthetic analysis of anolignans is shown
in Scheme 2. Alkyne II would be synthesized by conden-
Sch em e 2. Retr osyn th etic An a lysis of An olign a n s
(1) Rimando, A. M.; Pezzuto, J . M.; Farnsworth, N. R. J . Nat. Prod.
1994, 57, 896.
(2) Luo, M.; Matsui, A.; Esumi, T.; Iwabuchi, Y.; Hatakeyama, S.
Tetrahedron Lett. 2000, 41, 4401.
(3) Enyne metathesis: (a) Mori, M. In Topics in Organometallic
Chemistry; Furstner, A., Ed.; Springer-Verlag: Berlin, Heidelberg,
1998; Vol. 1, p 133. (b) Mori, M.; Kitamura, T.; Sakakibara, N.; Sato,
Y. Org. Lett. 2000, 2, 543. (c) Renaud, J .; Graf, C.-D.; Oberer, L. Angew.
Chem., Int. Ed. 2000, 39, 3101. (d) Mori, M.; Kitamura, T.; Sato, Y.
Synthesis 2001, 654, references are therein. Cross-enyne metathesis:
(e) Kinoshita, A.; Sakakibara, N.; Mori, M. J . Am. Chem. Soc. 1997,
119, 12388. (f) Kinoshita, A.; Sakakibara, N.; Mori, M, Tetrahedron
1999, 55, 8155. (g) Schuster, M.; Lucas, N. Blechert, S. Chem. Commun.
1997, 823. (h) Stragies, R.; Schuster, M. Blechert, S. Angew. Chem.,
Int. Ed. Engl. 1997, 36, 2518. (i) Schu¨rer, S. C.; Blechert, S. Synlett
1998, 166. (j) Schuster, M.; Blechert, S. Tetrahedron Lett. 1998, 39,
2295. (k) Stragies, R.; Schuster, M. Blechert, S. Chem. Commun. 1999,
237. (l) Schu¨rer, S. C.; Blechert, S. Synlett 1999, 1879. (m) Schu¨rer, S.
C.; Blechert, S. Chem. Commun. 1999, 1203. (n) Schu¨rer, S. C.;
Blechert, S. Tetrahedron Lett. 1999, 40, 1877. (o) Stragies, R.; Voigt-
mann, U. Blechert, S. Tetrahedron Lett. 2000, 41, 5465. (p) Kotha S.;
Halder, S.; Brahmachary, E.; Genesh, T. Synlett 2000, 853. ROM-RCM
of enyne: (q) Kitamura, T.; Sato. Y.; Mori, M. Chem. Commun. 2001,
1258. (r) Smulik, J . A.; Diver, S. T. J . Org. Chem. 2000, 65, 1788. (s)
Smulik, J . A.; Diver, S. T. Org. Lett. 2000, 2, 2271.
(4) (a) Fu, G. C.; Nguyen, S. T.; Grubbs, R. H. J . Am. Chem. Soc.
1993, 115, 9856. (b) Schwab, P.; France, M. B.; Ziller, J . W.; Grubbs,
R. H. Angew. Chem., Int. Ed. Engl. 1995, 34, 2039. For recent review
on olefin metathesis see: (c) Grubbs, R. H.; Miller, S. J . Acc. Chem.
Res. 1995, 28, 446. (d) Schuster, M.; Blechert, S. Angew. Chem., Int.
Ed. Engl. 1997, 36, 2036. (e) Schmalz, H.-G. Angew. Chem., Int. Ed.
Engl. 1995, 34, 1833. (f) Fu¨rstner, A. Topics in Organometallic
Chemistry; Springer-Verlag: Berlin, Heidelberg, 1998; Vol. 1. (g)
Grubbs, R. H.; Chang, S. Tetrahedron 1998, 54, 4413. (h) Armstrong,
S. K. J . Chem. Soc., Perkin Trans. 1 1998, 371. (i) Phillips, A. J .; Abell,
A. D. Aldrichim. Acta 1999, 32, 75. (j) Fu¨rstner, A. Angew. Chem., Int.
Ed. 2000, 39, 3013.
Sch em e 3. P r oblem s for En yn e Meta th esis
sation of two aldehydes IIIa and IIIb with acetylene.
Conversion of alkyne II into 1,3-diene I should proceed
using ruthenium carbene complex4 under ethylene gas.
Removal of two acetoxy groups from I using palladium
catalyst would be achieved, since Hatakeyama success-
fully removed an acetoxy group in the synthesis of
anolignan A.2
However, it was previously found that a heteroatom
such as a benzoyloxy group or a tosyl amide group at a
propargylic position accelerates the reaction rate.3f For
10.1021/jo0107913 CCC: $22.00 © 2002 American Chemical Society
Published on Web 12/14/2001

Syntheses of Anolignans A and B
J . Org. Chem., Vol. 67, No. 1, 2002 225
Ta ble 1. Syn th esis of 1,3-Dien e
run
alkyne
R1
R2
X
n
yield of 3 (%)
1
2
3
4
2a
2b
2c
2d
CHdCHCO2Menthyl
CHdCHCO2Me
(CH2)3CH3
H
CH2
CH2
NTs
NTs
1
1
1
2
10
53
81
11
CH2OBz
H
H
(CH2)3CH3
Ta ble 2. Effects of th e P r otectin g Gr ou p on th e P r op or gyl Alcoh ol
run
R
“Ru” (mol %)
yield (%)
5 (%)
1
2
3
4
5
6
7
8
CO2Me
Bz
Ac
TBDPS
TBDMS
TMS
MOM
H
4a
4b
4c
4d
4e
4f
10
10
5
5
5
5
5
5
5a
5b
5c
5d
5e
5f
76
77
80
<5
10
8
12
6
16
87
74
62
64
<58
4g
4h
5g
5h
18
<6
Sch em e 4. P r ep a r a tion of Su bstr a te for
Syn th esis of An olign a n A
example, when alkyne 2a was treated with ruthenium
carbene complex 1a under ethylene gas (Scheme 3 and
Table 1), 1,3-diene 3a was obtained in only 10% yield
(conversion yield, 58%), while 2b gave 3b in 53% yield
(conversion yield, 82%). Furthermore, when alkyne 2c
having the tosyl amide group at the propargylic position
was treated with ruthenium carbene complex 1a under
ethylene gas, the desired 1,3-diene 3c was obtained in
81% yield, while alkyne 2d having the tosyl amide group
at the homopropargylic position gave 1,3-diene 3d in only
11% yield.3f
Thus, at first, what protecting group on the hydroxyl
group at the propargylic position is suitable was exam-
ined. As a model compound, alkyne 4 was chosen (Table
2). Cross-enyne metathesis of alkyne 4 and ethylene was
carried out using ruthenium carbene complex 1a . When
a CH2Cl2 solution of 4a and 10 mol % of 1a was stirred
at room temperature under ethylene gas (1 atm) for 45
h, the desired 1,3-diene 5a was obtained in 76% yield
along with the starting material 4a in 12% yield.
Both alkynes, 4b and 4c, having the benzoyl and the
acetyl groups, also afforded the desired 1,3-dienes, 5b and
5c, in high yields, respectively. However, the silyl and
MOM groups did not give good yields of the desired 1,3-
dienes 5 (runs 4-7). The alkyne 4h having no protecting
group also did not give a good result (run 8). These results
indicated that the MOM group having strong coordina-
tion ability to ruthenium or the bulky silyl group5
decreased the reaction rate. Thus, an acetyl group was
chosen as the protecting group.
6b gave diol, whose hydroxy group was protected by the
acetyl group.
For the construction of 1,3-diene moiety, a CH2Cl2
solution of 8 was stirred in the presence of 10 mol % of
1a under ethylene gas (1 atm) at room temperature. After
36 h, 1,3-diene 9 was obtained in 65% yield along with
the starting material 8 in 15% yield. On the other hand,
when a new generation ruthenium carbene complex 1b6e
containing N-heterocyclic carbene ligand was used for
this reaction, the yield increased to 86%. Hydrogenolysis
of two acetoxy groups in 9 was successfully achieved by
treatment with Pd2(dba)3‚CHCl3 and Bu3P in the pres-
ence of HCO2H and Et3N7 to give 10 (Scheme 5).
Deprotection of 10 with PhLi8,9 in ether at room
temperature proceeded smoothly to give phenolic com-
pound, whose spectral data agree with those of anolignan
A reported in the literature.1 Thus, we succeeded in the
total synthesis of anolignan A via six steps in 30% overall
yield.
The starting alkyne 8 was prepared (Scheme 4). To a
THF solution of lithium trimethylsilylacetylide was
added piperonal 6a and after a spot of piperonal disap-
peared on TLC, Bu4NF was added. After the usual work
up, alkyne 7 was obtained in 95% yield. Treatment of 7
with 2 equiv of BuLi and then dimesyloxybenzaldehyde
(5) The fact that the silyl groups did not give the good results may
be due to the pπ-dπ interaction of the oxygen and the silicon.
(6) (a) Schwab, P.; France, M. B.; Ziller, J . W.; Grubbs, R. H. Angew.
Chem., Int. Ed. Engl. 1995, 34, 2039. (b) Weskamp, T.; Schattenmann,
W. C.; Spiegler, M.; Herrmann, W. A. Angew. Chem., Int. Ed. 1998,
37, 2490. (c) Huang, J .; Stevens, E. D.; Nolan, S. P.; Peterson, J . L. J .
Am. Chem. Soc. 1999, 121, 2674. (d) Scholl, M.; Trnka, T. M.; Morgan,
J . P.; Grubbs, R. H. Tetrahedron Lett. 1999, 40, 2247. (e) Scholl, M.;
Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett. 1999, 1, 953.
(7) Tsuji, J .; Minami, I.; Shimizu, I. Synthesis 1986, 623.
(8) Baldwin, J . E.; Barton, D. H. R.; Dainis, I.; Pereira, J . L. C. J .
Chem. Soc. C 1965, 2283.
(9) Treatment of 8 with aqueous NaOH in EtOH did not afford
anolignan A and two products were formed, but the structures of them
could not be determined.

226 J . Org. Chem., Vol. 67, No. 1, 2002
Mori et al.
Sch em e 6. Syn th esis of An olign a n B
Sch em e 5. Syn th esis of An olign a n A
The synthesis of anolignan B was also achieved from
acetylene and 4-benzenesulfonyloxybenzaldehyde 6c
(Scheme 6). Condensation of 6c with lithium acetylide
gave 11, which was treated with BuLi (2 equiv) and then
6c followed by acetylation to give alkyne 12. Reaction of
alkyne 12 with ethylene smoothly proceeded using 10 mol
% of ruthenium catalyst 1a to give 1,3-diene 13 in 60%
yield along with the starting material 12 in 32% yield.
Treatment of 12 with 7.5 mol % of 1b as a catalyst in
toluene at 80 °C for 14 h under ethylene gas gave 1,3-
diene 13 in 94% yield. Removal of the two acetoxy groups
with a palladium catalyst followed by deprotection of the
benzenesulfonyl group with aqueous NaOH gave anolig-
nan B.10
Thus, we succeeded in the total syntheses of anolignans
A and B using ruthenium-catalyzed cross-enyne meta-
thesis. The remarkable feature of these synthetic proce-
dures is that the 1,3-diene moieties of anolignans are
construced by the carbon-carbon bond formation be-
tween the alkyne carbon and the methylene carbon of
ethylene. This method was very effective for making
symmetrical or asymmetrical 1,3-diene.
Gen er a l P r oced u r e for Cr oss-En yn e Meta th esis. A
CH2Cl2 or toluene solution of alkyne and ruthenium carbene
complex 1 (5-10 mol %) was stirred at room temperature or
80 °C under ethylene gas (1 atm). After the appropriate hours,
the solution was allowed to stir under air, and then the
solution was concentrated. The residue was purified by column
chromatography on silica gel.
Acetic Acid 3-(Acetoxyben zo[1,3]d ioxol-5-ylm eth yl)-1-
(2,4-bism eth a n esu lfon yloxyp h en yl)- 2-m eth ylen ebu t-3-
en yl ester (9). According to the general procedure, a solution
of 8 (184.4 mg, 0.333 mol) and 1b (28 mg, 0.033 mmol) in
toluene (13.0 mL) was stirred at 80 °C for 36 h under an
ethylene. The crude residue was purified by flash column
chromatography on silica gel (CH2Cl2/AcOEt, 20:1) to yield 9
(166.3 mg, 86%) as a colorless sticky oil of a mixture of
diastereomer. IR (neat): 1737, 1605, 1373, 1262, 1183 cm-1
.
1H NMR (270 MHz, CDCl3): δ 2.05 (s, 3 H), 2.05 (s, 3 H), 2.07
(s, 3 H), 2.07 (s, 3 H), 3.15 (s, 3 H), 3.17 (s, 3 H), 3.26 (s, 3 H),
3.28 (s, 3 H), 5.17-5.38 (m, 4 H × 2), 5.94 (s, 2 H), 5.95 (s, 2
H), 6.38 (s, 1 H), 6.40 (s, 1 H), 6.60 (s, 1 H), 6.60 (s, 1 H), 6.68-
6.87 (m, 4 H · 2), 7.06-7.07 (m, 1 H × 2), 7.33-7.43 (m, 1 H
× 2). 13C NMR (100 MHz, CDCl3): δ 20.84, 21.09, 37.50, 37.57,
38.46, 67.77, 68.07, 74.69, 74.75, 101.12, 107.76, 107.79,
114.35, 115.59, 115.86, 116.05, 116.12, 116.59, 120.36, 120.71,
121.60, 121.78, 122.58, 122.90, 129.41, 129.82, 130.31, 130.36,
130.99, 131.19, 141.73, 142.27, 142.86, 143.41, 146.69, 146.77,
147.39, 147.43, 147.48, 147.55, 148.90, 169.25, 169.32, 169.48.
Exp er im en ta l Section
Gen er a l P r oced u r e. CH2Cl2 was distilled under an argon
atmosphere from CaH2 and other solvents, and reagents were
purified when necessary using standard procedures. All the
solvents using the organometallic agents were degassed
through a freeze-pump-thaw cycle. Ethylene gas was purified
by passing through the aqueous CuCl solution, concentrated
H2SO4, and a KOH tube.
-
LRMS m/z: 605 (M+ + Na), 463 (M+ CH3CO2). HRMS m/z.
Calcd for C25H26O12NaS2 (M+ + Na): 605.09. Found: 605.0743.
Su p p or tin g In for m a tion Ava ila ble: Text describing the
experimental procedure and the spectral data of 4c, 5c, 6b,c,
7, 8, 10-14, anolignane A, and anolignane B. This material
is available free of charge via the Internet at http://pubs.acs.org.
(10) The spectral data of anolignan B agreed with those reported
in the literature.1
J O0107913