Enantioselective biomimetic cyclization of homo(polyprenyl)arenes. A new entry to (+)-podpcarpa-8,11,13-triene diterpenoids and (-)-tetracyclic polyprenoid of sedimentary origin [4]

Full text of DOI:10.1021/ja003541x

J. Am. Chem. Soc. 2001, 123, 1505-1506
1505
Table 1. Enantioselective Cyclization of Homogeranylbenzene
Derivatives 2a-c
Enantioselective Biomimetic Cyclization of
Homo(polyprenyl)arenes. A New Entry to
(+)-Podpcarpa-8,11,13-triene Diterpenoids and
(-)-Tetracyclic Polyprenoid of Sedimentary Origin
Kazuaki Ishihara,† Hideaki Ishibashi,‡ and
Hisashi Yamamoto*,‡
molar ratioa
Graduate School of Engineering and Research Center for
AdVanced Waste and Emission Management
Nagoya UniVersity, CREST
(R)-1
solvent,
3a-c
entry 2a-c (R2)
(equiv) time (h) [ee (%)]b 4a-c 5a-c 2a-c
Japan Science and Technology Corporation (JST)
Furo-cho, Chikusa, Nagoya 464-8603, Japan
1c 2a (H)
1a (1.1) CH2Cl2, 14 87 [38]
1a (1.1) toluene, 14 28 [49]
1a (2.0) toluene, 19 10 [59]
1b (2.0) toluene, 24 13 [61]
6
40
36
33
35
44
40
7
32
36
32
35
47
41
0
0
18
22
17
0
2c 2a
3
4
2b (Me)
2b
ReceiVed September 29, 2000
5d 2c (t-BuPh2Si) 1a (2.0) toluene, 24 13 [72]
Acid-induced cyclization of polyprenoids is one of the simplest
and most widely used methods for the synthesis of polycyclic
terpenoids.1 We recently reported the first enantioselective
cyclization of 2-polyprenylphenols induced by a Lewis acid-
assisted chiral Brønsted acid (chiral LBA), 1.2 A hydroxy group
in polyprenylphenols assists this polyene cyclization as a good
nucleophilic internal terminator. We describe here the application
of this approach to a more challenging synthetic problem: the
first enantioselective cyclization of homo(polyprenyl)arenes 2
possessing an aryl group that serves as a less-nucleophilic
terminator than a hydroxy group (eq 1).
6d 2c
7d 2c
1c (2.0) toluene, 48
1d (1.1) toluene, 96 19 [80]
9 [81]
0
a Determined by GC and 1H NMR analyses. b Determined by chiral
1
HPLC analysis. c Product ratio was determined by GC and H NMR
analyses after acetylation of products. d Product ratio was determined
by GC and 1H NMR analyses after desilylation and acetylation of
products.
2 (n ) 1), we found that triphenylsilylpropargyl or o-fluorobenzyl
group and tert-butyldiphenylsilyl group were the most suitable
R1 and R2, respectively, with regard to enantioselectivity (entries
6 and 7): the reaction of 2c with (R)-1c gave trans-3c in 9%
yield and 81% ee (entry 6). The relationship between enantio-
selectivity and R1 is not clear. The steric bulkiness of R2 may
impair interaction between tin tetrachloride and the basic oxygen
atom of OR2. The absolute configuration of trans-3 shown in
Table 1 was assigned to be 5S and 10S based on the known optical
rotation.3c Notably, the tricyclic compounds 3a-c obtained in the
cyclization of 2a-c were only trans isomers regardless of the
reaction conditions.3e,f
The diastereoselective cyclization of 4 and 5 with achiral LBA
was explored to increase the chemical yield of 3. After treating
2b with (R)-1b at -78 °C for 3 days to completely consume 2b,
an achiral LBA, tin tetrachloride-trifluoroacetic acid, was added
to the reaction solution at the same temperature and the mixture
was stirred for an additional 1 day. As expected, the desired
product 3b was obtained in 62% ee and 86% yield from 2b in a
one-pot procedure (cf. entry 4 in Table 1). Furthermore, the
desilylation of a crude mixture of 3c, 4c, and 5c, which were
obtained in the enantioselective cyclization of 2c induced by (R)-
1c, with tetrabutylammonium fluoride was highly effective at
increasing the reactivity of the subsequent diastereoselective
cyclization. Thus, the desired product 3a was obtained in 78%
ee and 94% yield from 2c in three steps (Scheme 1; cf. entry 6
in Table 1). Since (()-3 has already been converted into (()-
ferruginol (6) by King6 and Ghatak,3d the present method
represents a formal and the first enantioselective total synthesis
of (+)-6.
Although cyclization via 2-(2-arylethyl)-1,3,3-trimethylcyclo-
hexyl carbocations has been widely used to contruct the B-ring
of podocarpa-8,11,13-triene diterpenoids 3,3 there have been only
a few reports on successive cyclizations of homogeranylbenzene
derivatives 2 (n ) 1) to 3.4 We initially studied the enantio-
selective cyclization of 4-homogeranylphenol (2a) and its ether
derivatives 2b and 2c5 with (R)-1. Representative results are
summarized in Table 1. Reaction of 2a in dichloromethane with
(R)-1a at -78 °C for 14 h gave the desired trans tricyclic product
3a in 87% yield and 38% ee (entry 1). The other products were
monocyclization products, 4a and 5a. The enantioselectivity of
3a was improved to 49% ee with toluene in place of dichloro-
methane, but the yield of 3a was decreased and the yields of 4a
and 5a were increased (entry 2). Furthermore, the enantioselec-
tivity increased to 59% ee when 2b was used in place of 2a (entry
3). In screening several protective groups, R1 in (R)-1 and R2 in
† Graduate School of Engineering.
‡ Research Center for Advanced Waste and Emission Management.
(1) Bartlett, P. A. In Asymmetric Synthesis; Morrison, J. D., Ed.; Academic
Press: New York, 1984; Vol. 3, Part B, pp 341-409.
(2) (a) Ishihara, K.; Nakamura, S.; Yamamoto, H. J. Am. Chem. Soc. 1999,
121, 4906. (b) Nakamura, S.; Ishihara, K.; Yamamoto, H. J. Am. Chem. Soc.
2000, 122, 8131.
The enantioselective cyclization of 1-homogeranyl-3-(tert-
butyldiphenylsiloxy)benzene (2d) was also examined with use
of (R)-1c in toluene at -78 °C (Scheme 2). As expected, tricyclic
product 3d was obtained in 78% ee (trans only), together with
the monocyclization products 4d and 5d. However, the subsequent
cyclization of desilylated compounds 4e and 5e with BF3‚Et2O
in nitromethane4c gave a 37:63 mixture of trans- and cis-3e
together with a small amount of trans-7.7 Fortunately, the
(3) (a) Matsumoto, T.; Usui, S. Bull. Chem. Soc. Jpn. 1979, 52, 212. (b)
Matsumoto, T.; Suetsugu, A. Bull. Chem. Soc. Jpn. 1979, 52, 1450. (c) Axon,
B. W.; Davis, B. R.; Woodgate, P. D. J. Chem. Soc., Perkin Trans. 1 1981,
2956. (d) Banik, B. K.; Chakraborti, A. K.; Ghatak, U. R. J. Chem. Res. (S)
1986, 3391. (e) Banik, B. K.; Ghosh, S.; Ghatak, U. R. Tetrahedron 1988,
44, 6947. (f) Ghosh, S.; Banik, B. K.; Ghatak, U. R. J. Chem. Soc., Perkin
Trans. 1 1991, 3189 and references therein.
(4) For the cationic cyclization of homogeranylbenzene derivatives bearing
regioselectivity- and/or diastereoselectivity-inducing auxiliaries, see the fol-
lowing. Tosyl group: (a) Janssen, C. G. M.; Godefroi, E. F. J. Org. Chem.
1982, 47, 3274. Trimethylsilyl group: (b) Janssen, C. G. M.; Godefroi, E. F.
J. Org. Chem. 1984, 49, 3600. Cyano group: (c) Harring, S. R.; Livinghouse,
T. Tetrahedron 1994, 50, 9229.
(6) King, F. E.; King, T. J.; Topliss, J. G. J. Chem. Soc. 1957, 573.
(7) Although several ethers of 4e and 5e were examined regarding the
second cyclization induced by SnCl4‚CF3CO2H or BF3‚Et2O, cis tricyclic
compounds were produced as major products in all cases.
(5) For preparation of 2, see: Araki, S.; Sato, T.; Butsugan, Y. J. Chem.
Soc., Chem. Commun. 1982, 285.
10.1021/ja003541x CCC: $20.00 © 2001 American Chemical Society
Published on Web 01/27/2001

1506 J. Am. Chem. Soc., Vol. 123, No. 7, 2001
Scheme 1. Enantioselective Synthesis of (5S,10S)-3a
Communications to the Editor
Scheme 3. Possible Reaction Paths for the Acid-Induced
Cyclization of 2 (n ) 1)
Scheme 2. Enantioselective Synthesis of (5S,10S)-8
alizations.3,13 The possible reaction paths are shown in Scheme
3. Initial cyclization of 2 (n ) 1) induced by (R)-1d should take
place through a concerted pathway involving transition states
(TSs) 12 and 13 enantioselectively: TS-12 stereospecifically leads
to trans-3, while TS-13 leads to a mixture of 4 and 5. 4-Ho-
mogeranylphenol 2a was completely consumed in toluene in the
presence of 1.1 equiv of (R)-1b (Table 1, entry 2), while the
corresponding ethers 2b and 2c were obtained in ca. 20% yield
even in the presence of 2 equiv of (R)-1 (Table 1, entries 3-5).
These experimental results indicate that protection of a hydroxy
group in 2a suppresses not only the second cyclization to form
the B-ring but also the initial cyclization to form the A-ring. Thus,
an aryl moiety in 2 (n ) 1) serVes not only as a nucleophilic
internal terminator to form the B-ring but also as a remote
promoter of cyclization to form the A-ring (a secondary effect)
Via TS-12. Furthermore, the stereochemistry in the subsequent
cyclization of 4 and 5 strongly depends on the nucleophilicity of
their terminal benzene ring. Benzene rings without an electron-
donating substituent, para to the site of electrophilic attack, are
not sufficiently nucleophilic to react through the concerted
pathways; rather, they require complete protonation to a carbo-
cation 14 which reacts with high stereoselectivity by a stepwise
pathway due to the minimum steric effects giving trans-3: e.g.
the second cyclization of 4a-c, 5a-c, and acetates of 4e and 5e
leads only to trans-3. With an electron-donating substituent, the
concerted pathways that give a mixture of trans- and cis-3
predominate over the stepwise pathway.
cyclization of acetates of 4e and 5e under the same conditions
gaVe (+)-13-acetoxypodocarpa-8,11,13-triene (8) with high di-
astereoselectiVity (trans only) and high regioselectiVity (no
detectable amount of 7). Thus, the desired product 8 was obtained
in 75% ee and 89% yield from 2d. This compound 8 can be easily
converted into (+)-podocarpa-8(14)-en-13-one (9),3a,8 a versatile
intermediate for synthesis of naturally occurring diterpenes, e.g.
isophyllocladene,9a phyllocladene,9a hibaone,9b manool,9c sclareol,9c
manoyl oxide,9c isoabienol,9d trans-abienol,9d and anticopalic
acid.9e,f Therefore, the present work can be regarded as the
enantioselective total syntheses of the above natural diterpenes.
In 1990, Azevedo’s group found 13-methylpodocarpa-8,11,-
13-triene (3f) in a Tasmanian tasmanite sediment.10 Four years
later, Albrecht’s group reported the isolation of a series of chiral
tetracyclic (10), pentacyclic, hexacyclic (11), heptacyclic, and
octacyclic homologues, from Eocene Messel shale (Germany),
which appear to be the remnants of an ancient family of
cyclopolyprenoids.11 Very recently, Corey’s group achieved the
asymmetric synthesis of 10 and 11 using the diastereoselective
Lewis acid-catalyzed polycyclization of polyunsaturated ox-
iranes.12 To demonstrate the generality of our synthetic strategy,
polycyclic terpenes 3f and 10 were concisely synthesized by using
the LBA 1d-induced enantioselective cyclization of 3-homo-
(polyprenyl)toluenes as a key step (eq 2). An achiral LBA,
Nonenzymatic enantioselective polyene cyclization of 2 is a
very attractive alternative to multistep synthesis from naturally
occurring chiral synthons. We have demonstrated the effectiveness
of chiral LBAs for absolute stereocontrol in the initial cyclization
step of 2 to form an A-ring and the importance of the nucleo-
philicity of the internal terminator in 2 for the relative stereo-
control in the subsequent cyclization step.
Supporting Information Available: Experimental details and char-
acterization data (PDF). This material is available free of charge via the
Internet at http://pubs.acs.org.
JA003541X
(9) (a) Duc, D. K. M.; Fetizon, M.; Lazare, S. J. Chem. Soc., Chem.
Commun. 1975, 282. (b) Duc, D. K. M.; Fetizon, M.; Flament, J. P. J. Chem.
Soc., Chem. Commun. 1972, 886. Duc, D. K. M.; Fetizon, M.; Flament, J. P.
Tetrahedron 1975, 31, 1897. (c) Wenkert, E.; Mahajan, J. R.; Nussim, M.;
Schenker, F. Can. J. Chem. 1966, 44, 2575. (d) Vlad, P. F.; Russo, A. G.;
Kuang-fang, C. Zh. Obsch. Chim. (Engl. Ed.) 1969, 39, 423. (e) Manh, D. D.
K.; Fetizon, M.; Kone, M. Tetrahedron 1975, 31, 1903. (f) Ohloff, G. Justus
Liebigs Ann. Chem. 1958, 615, 134.
SnCl4‚CF3CO2H/CH2Cl2, as well as BF3‚Et2O/MeNO2, was ef-
fective for the second step.
The present investigation on the stereochemistry of the acid-
induced polyene cyclization of 2 provide some important gener-
(10) Azevedo, D. A.; Aquino Neto, F. R.; Simoneit, B. R. T. Org. Mass
Spectrom. 1990, 25, 475 and references therein.
(11) Schaeffer, P.; Poinsot, J.; Hauke, V.; Adam, P.; Wehrung, P.; Trendel,
J.-M.; Albrecht, P.; Dessort, D.; Connan, J. Angew. Chem., Int. Ed. Engl.
1994, 33, 1166.
(12) Corey, E. J.; Luo, G.; Shouzhong, L. Angew. Chem., Int. Ed. 1998,
37, 1126.
(13) Corey, E. J.; Staas, D. D. J. Am. Chem. Soc. 1998, 120, 3526.
(8) (a) Bartltrop, J. A.; Rogers, N. A. J. Chem. Soc. 1958, 2566. (b) Church,
R. F.; Ireland, R. E.; Marshall, J. A. J. Org. Chem. 1966, 31, 2526.