Arylnaphthalene lignans through Pd-catalyzed [2+2+2] cocyclization of arynes and diyness: Total synthesis of taiwanins C and E

Article abstract of DOI:10.1002/anie.200453809

3 in 1 : A novel method for the synthesis of the arylnaphthalene skeleton by the Pd⁰-catalyzed [2+2+2] cocyclization of diynes and arynes involves three C-C bond-forming reactions in a single step (see scheme; R = CON(OCH₃)CH₃, dba = dibenzylideneacetone). This cocyclization was the key step in the total synthesis of the arylnaphthalene lignans taiwanins C and E.

Full text of DOI:10.1002/anie.200453809

Communications
Scheme 1. Synthesis of biaryl compounds by [2+2+2] cocyclization.
zation of alkyne A and two molecules of acetylene or by that
[
3]
of diyne B and one molecule of acetylene. In this context, we
planned the synthesis of arylnaphthalene derivatives G
through the [2+2+2] cocyclization of diyne F and an aryne
(Scheme 2).
Biaryl Compounds
Arylnaphthalene Lignans through Pd-Catalyzed
Scheme 2. Plan for [2+2+2] cocyclization of diynes and arynes.
[
2+2+2] Cocyclization of Arynes and Diynes:
Total Synthesis of Taiwanins C and E
Arylnaphthalene lignans occur widely in nature and
[
4]
exhibit various biological activities. If this [2+2+2] cocyc-
Yoshihiro Sato,* Takayuki Tamura, and Miwako Mori*
[
5–8]
lization were to proceed between diyne 3 and aryne 2
[
9]
(
derived from precursor 4 ), various arylnaphthalene deriv-
Biaryl compounds are an important class of substances, not
only as structures found in a variety of natural products, but
also as a chiral source for asymmetric synthesis. A biaryl
skeleton such as C is usually constructed through an aryl–aryl
coupling reaction between two aromatic compounds such as
atives 1 would be synthesized in a few steps involving three
CÀC bond-forming reactions (Scheme 3). Those arylnaph-
[
1]
D and E (Scheme 1).
On the other hand, a transition-metal-catalyzed [2+2+2]
cocyclization of alkynes is useful for the construction of an
[
2]
aromatic ring. Recently, we reported a conceptually new
methodology for the synthesis of biaryl molecules through
0
Ni -catalyzed [2+2+2] cocyclization, by which various biaryls
C were obtained in excellent yields by the [2+2+2] cocycli-
[
*] Dr. Y. Sato, T. Tamura, Prof. M. Mori
Graduate School of Pharmaceutical Sciences
Hokkaido University
Sapporo 060-0812 (Japan)
Fax : (+81)11-706-4982
E-mail: biyo@pharm.hokudai.ac.jp
mori@pharm.hokudai.ac.jp
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
Scheme 3. Retrosynthetic analysis for the synthesis of arylnaphthalene
lignans. TMS=trimethylsilyl, Tf=trifluoromethanesulfonyl.
2
436
ꢀ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
DOI: 10.1002/anie.200453809
Angew. Chem. Int. Ed. 2004, 43, 2436 –2440

Angewandte
Chemie
[
a]
thalene derivatives should be key intermediates for the
syntheses of chinensin, justicidin B, diphyllin, and taiwanins C
and E. Herein we report the total synthesis of taiwanins C and
Table 1: [2+2+2] Cocyclization of diynes 3 and aryne precursor 4a
[
10]
E
by using [2+2+2] cocyclization as a key step.
With the aim of synthesizing the taiwanins, substrates 3a–
d were synthesized as shown in Scheme 4. Diynes 3a and 3b
3
[
b]
Run
1
3
R
Catalyst
Ligand
PPh3
t [h]
1
Yield [%]
–
3a
H
[Ni(acac) ]/
16 1aa
2
DIBAL-H
2
3b CO CH
[Ni(acac) ]/
DIBAL-H
PPh3
2
4
1ba
–
2
3
2
3
4
5
6
7
8
9
3a
3b
3b
3b
[Pd (dba )]
–
–
1aa 18
2
3
[Pd (dba )]
18 1ba 43
18 1ba
6
2
2
2
2
3
[Pd (dba )]
PPh3
dppb
P(o-tol)3
P(o-tol)
P(o-tol)3
5
6
2
3
[Pd (dba )]
1ba
2
3
3b
3c CHO
3d CON(OCH )CH [Pd (dba )]
[Pd (dba )]
1ba 57
1ca
1da 78
2
2
3
3
[Pd
(dba
)]
3
2
3
3
2
3
[
a] All reactions were carried out in CH CN at room temperature in the
3
0
presence of 4a (3 equiv) and CsF (6 equiv). [b] For entries 1 and 2, Ni catalyst
was prepared by reduction of [Ni(acac) ] (20 mol%) with DIBAL-H (40 mol%)
2
in the presence of PPh (80 mol%). For entries 3–9, [Pd (dba) ] (5 mol%) was
3
2
3
used. For entries 5, 7, 8, and 9, 40 mol% of the ligand was used. For entry 6,
dppb (20 mol%) was used. dba=dibenzylideneacetone, acac=acetylaceto-
nate, DIBAL-H=diisobutylaluminum hydride, dppb=1,1’-bis(diphenylphos-
phanyl)butane.
of CsF in CH CN at room temperature was again investigated
3
with [Pd (dba )] as catalyst, and the desired product 1aa was
2
3
obtained in 18% yield (Table 1, entry 3). The reaction of 3b
under similar conditions afforded the desired product 1ba in
Scheme 4. Synthesis of substrates 3a–d. D CC=dicyclohexylcarbodii-
mide, DMAP=4-dimethylaminopyridine, TBS=tert-butyldimethylsilyl,
PCC=pyridinium chlorochromate, Ts=p-toluenesulfonyl.
4
3% yield (Table 1, entry 4). It is known that an alkyne with
an electron-withdrawing substituent is more reactive than an
one without an electron-withdrawing group or even one with
0
0
an electron-donating substituent in Ni - or Pd -catalyzed
were prepared by DCC-mediated esterification of carboxylic
[2+2+2] cocyclization, which is consistent with the results of
[
11]
[3,17]
acid 5 with the corresponding propargylic alcohols 6a and
entries 3 and 4.
Next, ligand effects in the reaction of 3b
[
12]
6
b,
respectively. Diyne 3c was synthesized by similar
and 4a under similar conditions were investigated (Table 1,
[
13]
esterification of 5 with 6c followed by cleavage of the TBS
protecting group of 7 and oxidation of the corresponding
alcohol to the aldehyde. Diyne 3d, which bears an N-
entries 5–7), and it was found that P(o-tol) is suitable for this
3
reaction and that the yield of 1ba was improved to 57% yield
(Table 1, entry 7). The reaction of aldehyde-terminated 3c
with 4a gave the desired product 1ca in only 2% yield along
with a complex mixture of polymerization products as the
major product (Table 1, entry 8). On the other hand, the yield
of the desired product was greatly improved to 78% in the
reaction of 3d, which has an N-methoxy-N-methylcarbox-
amide moiety, with 4a under similar conditions (Table 1,
entry 9).
methoxy-N-methylcarboxamide
amide),
moiety
was also synthesized by similar esterification of
with 6d, which in turn was prepared by the Pd-catalyzed
(Weinreb
[
14,15]
5
[
16]
coupling reaction of 8 and 9 followed by cleavage of the
THP protecting group of 10.
To examine the feasibility of the above-mentioned plan,
we initially investigated the [2+2+2] cocyclization of diynes
3
a–d and a simple aryne precursor 4a (Table 1). When the
Encouraged by these results, we turned our attention to
the synthesis of taiwanins C and E through the Pd -catalyzed
0
reaction of 3a or 3b and aryne precursor 4a in the presence of
CsF was carried out in CH CN at room temperature with a
[2+2+2] cocyclization of diyne 3d (Scheme 4) and aryne
precursor 4b (Scheme 5). Aryne precursor 4b was synthe-
sized by a procedure similar to that reported by Peæa et al.:
TMS ether 12, which was prepared by the reaction of 11 with
HMDS, was treated with BuLi. The resulting silyl-migration
3
0
Ni catalyst prepared from [Ni(acac) ], PPh , and DIBAL-
2
3
[
3]
[7d]
H, the desired product 1aa or 1ba was not produced, and a
complex mixture containing some polymerization products
was obtained (Table 1, entries 1 and 2). Thus, the catalyst was
[
6–8]
changed from nickel(0) to palladium(0)
(Table 1, entries 3–
product was subsequently treated with Tf O to give 4b in
2
9
). The reaction of 3a and aryne precursor 4a in the presence
83% yield (3 steps) (Scheme 5).
Angew. Chem. Int. Ed. 2004, 43, 2436 –2440
www.angewandte.org
ꢀ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
2437

Communications
Scheme 5. Synthesis of benzyne precursor 4b. HMDS=hexamethyldi-
silazane.
The reaction of 3d and aryne precursor 4b under the
above-mentioned optimized conditions proceeded suc-
cessfully and gave the desired product 1db in 61% yield
(
Scheme 6).
Scheme 7. Attempted chemoselective reduction of 1db.
Finally, transformations of aldehyde–lactone 13 into
taiwanins C and E were investigated (Scheme 9). Baeyer–
Villiger oxidation of 13 with MCPBA followed by hydrolysis
of the corresponding formate gave taiwanin E in 88% yield
(
2 steps). The spectral data of the product were completely
Scheme 6. [2+2+2] Cocyclization of diyne 3d and benzyne precursor
b.
[
10i]
identical with those previously reported.
also obtained in 64% yield from the same intermediate 13 in
Taiwanin C was
4
one step through a decarbonylation reaction by treatment of
[
19]
We next attempted the transformation of arylnaphthalene
13 with the Wilkinson catalyst (Scheme 9).
product 1db into the taiwanins. To convert 1db into aldehyde
In conclusion, we succeeded in developing a novel method
for the construction of arylnaphthalene skeletons through a
Pd -catalyzed [2+2+2] cocyclization of diynes and arynes.
This cocyclization was the key step in the total synthesis of
taiwanins C and E, which required 9 and 10 steps, respec-
[
14]
lactone 13, chemoselective reduction of the amide moiety
in 1db was initially tried with DIBAL-H at À 788C
0
(
Scheme 7). The desired product 13 was not obtained under
these conditions, but lactone aldehyde 15a and lactol
aldehyde 15b were obtained in 17 and
6
7% yield, respectively. These products
would have been produced through
reduction of the lactone moiety in 1db,
indicating that chemoselective reduction
of the lactone moiety in 1db is relatively
[
18]
difficult at this stage.
On the other
hand, when 1db was treated with
NaOMe in CH Cl at room temperature,
2
2
ring opening followed by rearrangement
of the lactone ring occurred to produce
lactone ester 16 in 78% yield
(
Scheme 8).
Chemoselective reduction of the lac-
tone moiety in 16 successfully gave lactol
7 in good yield. Treatment of 17 with
1
NaBH followed by acidic workup gave
4
the desired alcohol lactone 19 in excel-
lent yield in a one-pot operation via diol
1
8. Oxidation of 19 with PCC afforded
the desired aldehyde lactone 13 in 89%
yield.
Scheme 8. Conversion of 1db into the key intermediate 13. M.S.=molecular sieves.
2
438
ꢀ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
Angew. Chem. Int. Ed. 2004, 43, 2436 –2440

Angewandte
Chemie
Chem. Rev. 1988, 88, 1081; c) D. B. Grotjahn in Comprehensive
Organometallic Chemistry II, Vol. 12 (Eds.: E. W. Abel, F. G. A.
Stone, G. Wilkinson), Pergamon, Oxford, 1995, p. 741 – 770;
d) M. Lautens, W. Klute, W. Tam, Chem. Rev. 1996, 96, 49; e) S.
Saito, Y. Yamamoto, Chem. Rev. 2000, 100, 2901.
[
3] For our recent papers on Ni-catalyzed [2 + 2 + 2] cocyclization,
see: a) Y. Sato, T. Nishimata, M. Mori, J. Org. Chem. 1994, 59,
6
4
5
133; b) Y. Sato, T. Nishimata, M. Mori, Heterocycles 1997, 44,
43; c) Y. Sato, K. Ohashi, M. Mori, Tetrahedron Lett. 1999, 40,
231.
[
[
4] For recent leading reviews on arylnaphthalene lignans, see:
a) R. S. Ward, Nat. Prod. Rep. 1995, 12, 183; b) R. S. Ward, Nat.
Prod. Rep. 1997, 14, 43; c) R. S. Ward, Nat. Prod. Rep. 1999, 16,
75.
0
5] For the [2 + 2 + 2] cycloaddition of an Ni –aryne complex and
alkynes, see: a) M. A. Bennett, E. Wenger, Organometallics
1
1
1
995, 14, 1267; b) M. A. Bennett, E. Wenger, Organometallics
996, 15, 5536; c) M. A. Bennett, E. Wenger, Chem. Ber. 1997,
30, 1029.
0
[
6] For the Pd -catalyzed [2+2+2] homocyclotrimerization of three
aryne molecules, see: a) D. Peæa, S. Escudero, D. PØrez, E.
Guitiꢀn, L. Castedo, Angew. Chem. 1998, 110, 2804; Angew.
Chem. Int. Ed. 1998, 37, 2659; b) D. Peæa, D. PØrez, E. Guitiꢀn,
L. Castedo, Org. Lett. 1999, 1, 1555; c) D. Peæa, A. Cobas, D.
PØrez, E. Guitiꢀn, L. Castedo, Org. Lett. 2000, 2, 1629; d) D.
Peæa, A. Cobas, D. PØrez, E. Guitiꢀn, L. Castedo, Org. Lett.
Scheme 9. Synthesis of taiwanins C and E from 13.
tively, from reported or commercially available compounds.
The present convergent strategy paves the way for the
synthesis of various arylnaphthalene lignans from the combi-
nation of various diynes 3 and aryne precursors 4. Further
studies along this line are in progress in our laboratories.
2
003, 5, 1863.
0
[
7] For the Pd -catalyzed [2+2+2] cocyclotrimerization of an aryne–
aryne–alkyne or and aryne–alkyne–alkyne system to produce
phenanthrene or naphthalene derivatives, see: a) D. Peæa, D.
PØrez, E. Guitiꢀn, L. Castedo, J. Am. Chem. Soc. 1999, 121, 5827;
b) K. V. Radhakrishnan, E. Yoshikawa, Y. Yamamoto, Tetrahe-
dron Lett. 1999, 40, 7533; c) D. Peæa, D. PØrez, E. Guitiꢀn, L.
Castedo, Synlett 2000, 1061; d) D. Peæa, D. PØrez, E. Guitiꢀn, L.
Experimental Section
1
db: [ Pd(dba) ]·CHCl (26 mg, 0.025 mmol) and P(o-tol)3 (61 mg,
2 3 3
0
.20 mmol) were dissolved in CH CN (1.2 mL), and the mixture was
Castedo, J. Org. Chem. 2000, 65, 6944.
3
0
stirred at room temperature for 15 min. The catalyst solution was
[8] For the Pd -catalyzed [2+2+2] cocyclotrimerization of an aryne–
aryne–alkene or an aryne–alkyne–alkene system, see: a) E.
Yoshikawa, Y. Yamamoto, Angew. Chem. 2000, 112, 185; Angew.
Chem. Int. Ed. 2000, 39, 173; b) E. Yoshikawa, K. V. Radhak-
rishnan, Y. Yamamoto, J. Am. Chem. Soc. 2000, 122, 7280.
[9] Y. Himeshima, T. Sonoda, H. Kobayashi, Chem. Lett. 1983, 1211.
10] For references on the previous synthesis of taiwanins C and/or E,
see: a) T. L. Holmes, R. Stevenson, J. Org. Chem. 1971, 36, 3450;
b) B. J. Arnold, S. M. Mellows, P. G. Sammes, J. Chem. Soc.
Perkin Trans. 1 1973, 1266; c) Z. Horii, M. Tsujiuchi, K. Kanai, T.
Momose, Chem. Pharm. Bull. 1977, 25, 1803; T. Momose, K.
Kanai, K. Hayashi, Chem. Pharm. Bull. 1978, 26, 3195; d) H. P.
Plaumann, J. G. Smith, R. Rodrigo, J. Chem. Soc. Chem.
Commun. 1980, 354; S. O. De Silva, C. St. Denis, R. Rodrigo,
J. Chem. Soc. Chem. Commun. 1980, 995; e) J. Mann, S. E. Piper,
L. K. P. Yeung, J. Chem. Soc. Perkin Trans. 1 1984, 2081; f) S.
Takano, S. Otaki, K. Ogasawara, Tetrahedron Lett. 1985, 26,
added through a cannula to a solution of 3d (160 mg, 0.51 mmol), 4b
(
530 mg, 1.6 mmol), and CsF (472 mg, 3.1 mmol) in CH CN (1.8 mL)
3
at 08C. (More CH CN (1.0 mL) was used to wash the catalyst
3
through.) The mixture was stirred at room temperature for 4 h and
then quenched with a saturated solution of NH Cl. The mixture was
4
extracted with EtOAc, and the organic layer was washed with brine
and dried over Na SO . After removal of the solvent, the residue was
[
2
4
purified by column chromatography on silica gel (hexane/EtOAc 3:2)
to give 1db (134 mg, 61%) as a yellowish solid. Unconverted 4b
À1
(
257 mg, 48%) was recovered. IR (neat): n˜ = 1762, 1653 cm
;
1
H NMR (270 MHz, CDCl ): d = 7.26 (s, 1H), 7.25 (s, 1H), 6.97 (d,
3
J = 7.9 Hz, 1H), 6.83–6.74 (m, 2H), 6.10–6.06 (m, 4H), 5.35 (s, 2H),
+
3
.51 (s, 3H), 3.43 (s, 3H); EILRMS: m/z (%): 435 [M ] (375);
EIHRMS: calcd for C H NO : 435.0954; found: 435.0942.
2
3
17
8
Received: January 20, 2004 [Z53809]
1659; g) Y. Ishii, T. Ikariya, M. Saburi, S. Yoshikawa, Tetrahe-
Keywords: arynes · cycloaddition · lignans · palladium ·
synthetic methods · total synthesis
dron Lett. 1986, 27, 365; h) R. Stevenson, J. V. Weber, J. Nat.
Prod. 1989, 52, 367; i) T. Ogiku, M. Seki, M. Takahashi, H.
Ohmizu, T. Iwasaki, Tetrahedron Lett. 1990, 31, 5487; T. Ogiku,
S. Yoshida, H. Ohmizu, T. Iwasaki, J. Org. Chem. 1995, 60, 4585,
and references therein; j) S. Seko, Y. Tanabe, G. Suzukamo,
Tetrahedron Lett. 1990, 31, 6883; Y. Tanabe, S. Seko, Y. Nishii, T.
Yoshida, N. Utsumi, G. Suzukamo, J. Chem. Soc. Perkin Trans. 1
1996, 2157; k) D. C. Harrowven, Tetrahedron Lett. 1991, 32,
3735; S. R. Flanagan, D. C. Harrowven, M. Bradley, Tetrahedron
2002, 58, 5989, and references therein; l) K. Kobayashi, Y.
Kanno, S. Seko, H. Suginome, J. Chem. Soc. Perkin Trans. 1 1992,
3111; m) T. Hattori, H. Tanaka, Y. Okaishi, S. Miyano, J. Chem.
Soc. Perkin Trans. 1 1995, 235; n) J. E. Cochran, A. Padwa, J.
Org. Chem. 1995, 60, 3938; A. Padwa, J. E. Cochran, C. O.
.
[
1] For reviews, see: a) M. Sainsbury, Tetrahedron 1980, 36, 3327;
b) G. Bringmann, R. Walter, R. Weirich, Angew. Chem. 1990,
102, 1006; Angew. Chem. Int. Ed. Engl. 1990, 29, 977; c) D. W.
Knight in Comprehensive Organic Synthesis, Vol. 3 (Eds.: B. M.
Trost, I. Fleming), Pergamon, Oxford, 1991, p. 481 – 520; d) S. P.
Stanforth, Tetrahedron 1998, 54, 263; e) J. Hassan, M. SØvignon,
C. Gozzi, E. Schultz, M. Lemaire, Chem. Rev. 2002, 102, 1359.
2] For reviews, see: a) K. P. C. Vollhardt, Angew. Chem. 1984, 96,
[
525; Angew. Chem. Int. Ed. Engl. 1984, 23, 539; b) N. E. Shore,
Angew. Chem. Int. Ed. 2004, 43, 2436 –2440
www.angewandte.org
ꢀ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
2439

Communications
Kappe, J. Org. Chem. 1996, 61, 3706; o) C. Cow, C. Leung, J. L.
Charlton, Can. J. Chem. 2000, 78, 553.
[16] M. Murakami, Y. Hoshino, H. Ito, Y. Ito, Chem. Lett. 1998, 163.
[17] a) L. D. Brown, K. Itoh, H. Suzuki, K. Hirai, J. A. Ibers, J. Am.
Chem. Soc. 1978, 100, 8232; b) C. Stephan, C. Munz, H. Dieck, J.
Organomet. Chem. 1993, 452, 223. See also references [3] and
[7a].
[
11] Carboxylic acid 5 [CAS Registry No. 10231-46-6] was prepared
in 91% yield by hydrolysis of the corresponding methyl ester,
which was obtained from piperonal in 90% yield (two steps) by
dibromoolefination with CBr –PPh followed by treatment with
[18] Attempts at the chemoselective reduction of 1db with other
4
3
[
18a]
BuLi–methyl chloroformate.
reducing reagents such as LiAl(OtBu) H
with MeOTf
and L-Selectride
3
[
18b]
[
[
12] R. C. Larock, C.-L. Liu, J. Org. Chem. 1983, 48, 2151.
13] R. Livingston, L. R. Cox, S. Odermatt, F. Diederich, Helv. Chim.
Acta 2002, 85, 3052.
14] S. Nahm, S. M. Weinreb, Tetrahedron Lett. 1981, 22, 3815.
15] For reviews, see: a) M. P. Sibi, Org. Prep. Proced. Org. Prep.
Proced. Int. 1993, 25, 15; b) M. Mentzel, H. M. R. Hoffmann, J.
Prakt. Chem./Chem.-Ztg. 1997, 339, 517; c) J. Singh, N. Satya-
murthi, I. S. Aidhen, J. Prakt. Chem. 2000, 342, 340.
were unsuccessful: a) M. Paris, C. Pothion, A.
Heitz, J. Martinez, J.-A. Fehrentz, Tetrahedron Lett. 1998, 39,
1341; b) S.-C. Tsay, J. A. Robl, J. R. Hwu, J. Chem. Soc. Perkin
Trans. 1 1990, 757.
[
[
[19] All spectral data of synthetic taiwanin C are completely identical
[
10n]
to those previously reported.
2
440
ꢀ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
Angew. Chem. Int. Ed. 2004, 43, 2436 –2440