Enantio- and diastereoselective stepwise cyclization of polyprenoids induced by chiral and achiral LBAs. A new entry to (-)-ambrox, (+)-podocarpa-8,11,13-triene diterpenoids, and (-)-tetracyclic polyprenoid of sedimentary origin

Article abstract of DOI:10.1021/ja0124865

An enantio- and diastereoselective stepwise cyclization of polyprenoids induced by Lewis acid-assisted chiral Bronsted acids (chiral LBAs) and achiral LBAs is described. In particular, the absolute stereocontrol in the initial cyclization of polyprenoids to form an A-ring induced by chiral LBAs and the importance of the nucleophilicity of the internal terminator in polyprenoids for the relative stereocontrol in subsequent cyclization are demonstrated. (-)-Ambrox was synthesized via the enantioselective cyclization of (E,E)-homofarnesyl triethyrsily ether with triethylsilyl ether with tin(IV) chloride-coordinated (R)-2-(o-fluorobenzyloxy)-2′-hydroxy-1,1′-binaphthyl ((R)-BINOL-o-FBn) and subsequent diastereoselective cyclization with CF₃CO₂H·SnCl₄ as key steps. Protection of (E,E)-homofarnesol by a triethylsilyl group increased the enantioselectivity of chiral LBA-induced cyclization and both the chemical yield and diastereoselectivity in the subsequent cyclization. The enantioselective cyclization of homo(polyprenyl)arenes possessing an aryl group was also induced by (R)-BINOL-o-FBn·SnCl₄. Several optically active podocarpa-8,11,13-triene diterpenoids and (-)-tetracyclic polyprenoid of sedimentary origin were synthesized (75-80% ee) by the enantioselective cyclization of homo(polyprenyl)benzene derivatives induced by (R)-BINOL-o-FBn·SnCl₄ and subsequent diastereoselective cyclization induced by BF₃-Et₂O/EtNO₂ or CF₃CO₂H·SnCl₄.

Full text of DOI:10.1021/ja0124865

Published on Web 03/16/2002
Enantio- and Diastereoselective Stepwise Cyclization of
Polyprenoids Induced by Chiral and Achiral LBAs. A New
Entry to (-)-Ambrox, (+)-Podocarpa-8,11,13-triene
Diterpenoids, and (-)-Tetracyclic Polyprenoid of Sedimentary
Origin
Kazuaki Ishihara, Hideaki Ishibashi, and Hisashi Yamamoto*
Contribution from the Graduate School of Engineering, Nagoya UniVersity, SORST, Japan and
Science Technology Corporation (JST), Furo-cho, Chikusa, Nagoya 464-8603, Japan
Received November 6, 2001
Abstract: An enantio- and diastereoselective stepwise cyclization of polyprenoids induced by Lewis acid-
assisted chiral Brønsted acids (chiral LBAs) and achiral LBAs is described. In particular, the absolute
stereocontrol in the initial cyclization of polyprenoids to form an A-ring induced by chiral LBAs and the
importance of the nucleophilicity of the internal terminator in polyprenoids for the relative stereocontrol in
subsequent cyclization are demonstrated. (-)-Ambrox was synthesized via the enantioselective cyclization
of (E,E)-homofarnesyl triethylsilyl ether with tin(IV) chloride-coordinated (R)-2-(o-fluorobenzyloxy)-2′-hydroxy-
1,1′-binaphthyl ((R)-BINOL-o-FBn) and subsequent diastereoselective cyclization with CF3CO2H‚SnCl4 as
key steps. Protection of (E,E)-homofarnesol by a triethylsilyl group increased the enantioselectivity of chiral
LBA-induced cyclization and both the chemical yield and diastereoselectivity in the subsequent cyclization.
The enantioselective cyclization of homo(polyprenyl)arenes possessing an aryl group was also induced by
(R)-BINOL-o-FBn‚SnCl4. Several optically active podocarpa-8,11,13-triene diterpenoids and (-)-tetracyclic
polyprenoid of sedimentary origin were synthesized (75-80% ee) by the enantioselective cyclization of
homo(polyprenyl)benzene derivatives induced by (R)-BINOL-o-FBn‚SnCl4 and subsequent diastereoselective
cyclization induced by BF3‚Et2O/EtNO2 or CF3CO2H‚SnCl4.
mercuric salt.3,6 We recently reported the first example of the
enantioselective cyclization of polyprenyl alcohols induced by
Introduction
A variety of terpenoids are enzymatically synthesized by
cyclization of polyprenoids such as farnesol, geranylgeraniol,
and squalene in biological systems.1 The stereospecific forma-
tion of polycyclic terpenoids may be rationalized by the Stork-
Eshenmoser hypothesis.2 The chemical simulation of this elegant
biosynthetic process has been developed as an important
methodology in organic synthesis.3 van Tamelen’s approach
induced by the acid-catalyzed cyclization of chiral terminal
epoxides of polyprenes4 and Johnson’s approach via the acid-
catalyzed cyclization of polyprenic acetals derived from chiral
diols5 must be the most important contribution to this field.
Alternative approaches to the biomimetic olefin cyclization are
the treatment of polyprenoids with a variety of electrophiles
such as proton, bromonium ion, acyl cation, Lewis acid, or
Lewis acid-assisted chiral Brønsted acids (chiral LBAs) (Scheme
1).7 A hydroxy group in polyprenyl alcohols assists this polyene
cyclization as a good nucleophilic internal terminator. However,
hydroxy groups in a substrate may act as achiral LBAs in the
presence of Lewis acid. Chiral LBAs should be designed so
that the Lewis acid predominantly coordinates with a chiral
Brønsted acid. Alternatively, protection of hydroxy groups in a
substrate should help to avoid the generation of achiral LBA
species. The nucleophilicity of the internal terminator may
decrease due to its protection, and as a result, the reactivity of
cyclization may decrease. To overcome these problems, an
enantio- and diastereoselective stepwise cyclization of poly-
prenoids induced by chiral LBAs and stronger achiral LBAs
was developed.
In the first stage, (-)-ambrox (1A)8 was concisely synthesized
via the enantioselective cyclization of (E,E)-homofarnesyltri-
alkylsilyl ethers (4: P ) SiR3) induced by chiral LBAs and
(1) (a) Abe, I.; Rohmer, M.; Prestwich, G. D. Chem. ReV. 1993, 93, 2189. (b)
Wendt, K. U.; Schulz, G. E.; Corey, E. J.; Liu, D. R. Angew. Chem., Int.
Ed. 2000, 39, 2812.
(2) (a) Stork, G.; Burgstahler, A. W. J. Am. Chem. Soc. 1955, 77, 5068. (b)
Eschenmoser, A.; Ruzicka, L.; Jeger, O.; Arigoni, D. HelV. Chim. Acta
1955, 38, 1890.
(3) Bartlett, P. A. In Asymmetric Synthesis; Morrison, J. D., Ed.; Academic
Press: New York, 1984; Vol. 3, part B, pp 341-409.
(4) (a) van Tamelen, E. E. Acc. Chem. Res. 1968, 1, 111; 1975, 8, 152. (b)
Corey, E. J.; Sttas, D. D. J. Am. Chem. Soc. 1998, 120, 3526 and references
therein.
(5) (a) Johnson, W. S. Acc. Chem. Res. 1968, 1, 1. (b) Johnson, W. S. Angew.
Chem., Int. Ed. Engl. 1976, 15, 9. (c) Johnson, W. S. Bioorg. Chem. 1976,
5, 51.
(6) (a) Nishizawa, M.; Takenaka, H.; Hayashi, Y. J. Am. Chem. Soc. 1984,
106, 4290. (b) Nishizawa, M.; Takenaka, H.; Hayashi, Y. J. Org. Chem.
1986, 51, 806 and references therein.
(7) (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.
(8) Registered trademark of Firmenich S. A. for (-)-8R,12-epoxy-13,14,15,16-
tetranorlabdane.
9
10.1021/ja0124865 CCC: $22.00 © 2002 American Chemical Society
J. AM. CHEM. SOC. 2002, 124, 3647-3655
3647

A R T I C L E S
Ishihara et al.
Scheme 3. Retrosynthesis of Podocarpa-8,11,13-triene
Scheme 1. Enantioselective Cyclization of Polyprenyl Alcohols
Induced by Chiral LBA
Diterpenoids (6) and Their Polycyclic Analogues
1A. Ambergris is a metabolic product that is found in the gut
of some blue sperm whales (Physeter macrocephalus L.).10 After
several years of aging, ambergris is used in perfumery as a
valuable ingredient in many fine fragrances because of its unique
scent and fixative properties. One of the constituents of the
ambergris tincture11 is the labdane-like tricyclic ether 1A that
has a powerful amber-type aroma. As a consequence of the
growing demand for ambergris-type odorants coupled with the
almost complete worldwide ban on whaling, 1A probably has
become the most commercially important synthetic equivalent
of scarce natural ambergris. For this reason, several syntheses
of (-)-1A have been developed since it was initially prepared
in 1950.12 Most of them13 use the terpene-type starting materials
(-)-sclareol,14 (-)-drimenol,15 (+)-manool,16 manoyl oxide,17
(+)-abietic acid,18 (-)-levopimaric acid,19 and (-)-labdanolic
acid.20 In addition, diverse total syntheses of (()-1A use
biogenetic-type cyclizations from (E,E)-farnesic or (E)-mono-
cyclofarnesic acids or their derivatives.21 We describe here the
concise enantioselective synthesis of (-)-1A using the enanti-
oselective cyclization of (E,E)-4 induced by chiral LBA9,22 and
the subsequent diastereoselective cyclization of 2 and 3 induced
by achiral LBA as key steps (Scheme 2).
Scheme 2. Retrosynthesis of (-)-1A
(9) Part of this work has been publiahed as a preliminary communication, see:
Ishihara, K.; Ishibashi, H.; Yamamoto, H. J. Am. Chem. Soc. 2001, 123,
1505.
(10) Ohloff, G. The Fragrance of Ambergris. In Fragrance Chemistry; Theimer,
E. T., Ed.; Academic Press: New York, 1982; pp 535-573.
(11) Mookherjee, B. D.; Patel, R. R. In Proceedings of the 7th International
Congress on Essential Oils; Kyoto, 1977; p 479.
the subsequent diastereoselective cyclization of dicyclic and
monocyclic products, 2 and 3, induced by achiral LBAs as key
steps (Scheme 2).
(12) (a) Stoll, M.; Hinder, M. HelV. Chim. Acta 1950, 33, 1251. (b) Hinder,
M.; Stoll, M. HelV. Chim. Acta 1950, 33, 1308.
(13) For the synthesis of (-)-1A from (+)-carvone, see: Verstegen-Haaksma,
A. A.; Swarts, H. J.; Jansen, B. J. M.; de Groot, A. Tetrahedron 1994, 50,
10095.
In the next stage, we applied this approach to a more
challenging synthetic problem: the enantioselective cyclization
of (all-E)-homo(polyprenyl)arenes (8) possessing an aryl group,
which serves as a less-nucleophilic terminator than a hydroxy
group (Scheme 3). Several optically active podocarpa-8,11,13-
triene diterpenoids (6) and (-)-tetracyclic polyprenoid (7) of
sedimentary origin were synthesized (75-80% ee) by the
enantioselective cyclization of (all-E)-8 induced by chiral LBAs
and subsequent diastereoselective cyclization induced by achiral
LBAs. Thus, the effectiveness of chiral LBAs for providing
absolute stereocontrol in the initial cyclization of polyprenoids
to form an A-ring and the importance of the nucleophilicity of
the internal terminator in polyprenoids for the relative stereo-
control in the subsequent cyclization are demonstrated.9
(14) (a) Ruzicka, L.; Seidel, C. F.; Engel, L. L. HelV. Chim. Acta 1942, 25,
621. (b) Patent JP6133. (c) Patent DE3610063. (d) Patent EP 2996564. (e)
Decorzant, R.; Vial, C.; Na¨f, F.; Whitesides, G. M. Tetrahedron 1987, 43,
1871. (f) Christenson, P. A. Tetrahedron 1988, 44, 1925. (g) Coste-Manie`re,
I. C.; Zahra, J. P.; Waegell, B. Tetrahedron Lett. 1988, 29, 1017 and
references therein. (h) Martres, P.; Perfetti, P.; Zahra, J.-P.; Waegell, B.;
Giraudi, E.; Petrzilka, M. Tetrahedron Lett. 1993, 34, 629. (i) Barrero, A.
F.; Alvarez-Manzaneda, E. J.; Altarejos, J.; Salido, S.; Ramos, J. M.
Tetrahedron 1993, 49, 10405.
(15) Gonzalez-Sierra, M.; Ruvida, E. A.; Lo´pez, J. T.; Corte´s, M. J. Heterocycles
1987, 26, 2801.
(16) Schenk, H. R.; Gutman, H.; Jeger, O.; Ruzicka, L. HelV. Chim. Acta 1954,
37, 543.
(17) Cambie, R. C.; Joblin, K. N.; Preston, A. F. Aust. J. Chem. 1971, 24, 583.
(18) Koyama, H.; Kaku, Y.; Ohno, M. Tetrahedron Lett. 1987, 28, 2863.
(19) Nishi, Y.; Ishihara, H. J. Jpn. Oil Chem. Soc. 1989, 38, 276.
(20) Pascual T. J.; Urones, J. G.; Montan˜a, Pedrero, A.; Basabe, P. Tetrahedron
Lett. 1985, 26, 5717.
(21) (a) Snowden, R. L.; Eichenberger, J.-C.; Linder, S. M.; Sonnay, P.; Vial,
C.; Schulte-Elte, K. H. J. Org. Chem. 1992, 57, 955. (b) Barrero, A. F.;
Altarejos, J.; Alvarez-Manzaneda, E. J.; Ramos, J. M.; Salido, S. J. Org.
Chem. 1996, 61, 2215. (c) Tanimoto, H.; Oritani, T. Tetrahedron:
Asymmetry 1996, 7, 1695.
Discussion
Protective Effect of a Hydroxy Group Terminator on
LBA-Induced Cyclization of (E,E)-4: Total Synthesis of (-)-
9
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Cyclization of Polyprenoids
A R T I C L E S
Table 1. Enantioselective Cyclization of (E,E)-Homofarnesol Derivatives 4 Induced by Chiral LBAs
GC ratio (Ee)
1
entry
P
R of (R)-LBA
solvent, time (h)
yield (%)b 1A−D
1A
1B
1C
1D
1a
2
3
4
5
H
H
SiEt3
SiEt3
Sit-BuMe2
Me
CH2Cl2, 72
toluene, 72
toluene, 72
CH2Cl2, 72
toluene, 72
54
29
18
32
<1
56 (42% ee)
64 (50% ee)
84 (76% ee)
56 (44% ee)
9
17
6
26
18
11
12
9
2
0
0
o-FBn
o-FBn
o-FBn
o-FBn
32
a Data in ref. 7. b Isolated yield of 1 is indicated. Starting material was completely consumed. Other main products were monocyclic compounds 3a-c
and dicyclic compounds 2a-c.
Scheme 4. Preparation of (E,E)-4a from (E,E)-5
Scheme 5. Preparation of (E,E)-4a from (E,E)-8
(E,E)-farnesyl chloride (12) without loss of the double bond
geometry. Treatment of (E,E)-farnesylbarium(II) with excess
carbon dioxide gave (E,E)-4,8,12-trimethyl-3,7,11-tridecatrienoic
acid (13) in 68% yield. The reduction of 13 with lithium
aluminum hydride gave (E,E)-4a in 84% yield.26 Thus, (E,E)-
4a was obtained in 57% overall yield in two steps.
(E,E)-Homofarnesol (4a: P ) H) was prepared in 70% overall
yield in three steps from commercially available (E,E)-farnesol
(5) by a slight modification of the method described by Leopold
(Scheme 4).23 In the first step, (E,E)-5 was oxidized to (E,E)-
farnesal (10) in hexane at 0 °C by using manganese(IV) oxide.24
The stereoisomeric purity of product (E,E)-6 was at least 99%.
Next, the Wittig methylenation of (E,E)-10 to (E,E)-4,8,12-
trimethyl-1,3,7,11-tridecatetraene (11) was carried out with
phenyllithium in THF. Finally, the selective hydroboration of
(E,E)-11 was carried out by adding disiamylborane, which was
prepared from 2-methyl-2-butene and borane‚THF in situ, to
give (E,E)-4a.
A more concise preparation of (E,E)-4a was achieved by
using the regio- and stereoselective carboxylation of allylic
barium reagents as a key reaction (Scheme 5).25 (E,E)-
Farnesylbarium(II) was prepared directly by the reaction of in
situ generated barium metal (Ba*) with commercially available
We have previously reported that the enantioselective cy-
clization of (E,E)-4a with tin(IV) chloride-coordinated (R)-2-
hydroxy-2′-methoxy-1,1′-binaphthyl, (R)-BINOL-Me‚SnCl4, in
dichloromethane gives a diastereomeric mixture (56:9:26:9
molar ratio) of tricyclic ethers, ambrox 1A, epi-ambrox 1B, 1C,
and 1D, in 54% yield (entry 1, Table 1).7 The ee of the resulting
(-)-1A is 42%. To achieve the concise total asymmetric
synthesis of 1a, we reinvestigated the optimal conditions for
the enantioselective cyclization of (E,E)-4a with tin(IV) chloride-
coordinated (R)-2-alkoxy-2′-hydroxy-1,1′-binaphthyl, (R)-BINOL-
R‚SnCl4. Representative results are summarized in Table 1.
While the use of o-fluorobenzyl ether of (R)-BINOL [(R)-
BINOL-o-FBn] instead of (R)-BINOL-Me in toluene gave
higher enantioselectivity and diastereoselectivity, these values
were still low (50% ee, 64% ds) (entry 2). Furthermore, the
enantioselectivity and diastereoselectivity of (-)-1A were
improved to 76% ee and 84% ds by using (E,E)-homofarnesyl
triethylsilyl ether (4b) as a substrate (entry 3), but the yield of
1 was decreased to 18%. Other main products were monocyclic
triethylsilyl ether 3b and dicyclic triethylsilyl ether 2b. In the
(22) The enantioselective cyclization of homofarnesyl triisopropylsilyl ether
induced by chiral iron catalyst was presented in the Poster Session, see:
Allemann, C.; Jenny, T. A. The 11th IUPAC Symposium on Organometallic
Chemistry directed towards Organic Synthesis (OMCOS 11), Taipei
(Taiwan), July 23, 2001, P007.
(23) For preparation of (E)-homogeraniol, see: Leopold, E. J. Organic Syntheses;
Wiley: New York, 1990;, Collect Vol. VII, 258.
(24) Corey, E. J.; Gilman, N. W.; Ganem, B. E. J. Am. Chem. Soc. 1968, 90,
5616.
(25) (a) Yanagisawa, A.; Yasue, K.; Yamamoto, H. Organic Syntheses; Wiley:
New York, 1998; Collect Vol. IX, 317. (b) Yanagisawa, A.; Yasue, K.;
Yamamoto, H. Synlett 1992, 593. (c) Yanagisawa, A.; Habaue, S.; Yasue,
K.; Yamamoto, H. J. Am. Chem. Soc. 1994, 116, 6130.
(26) Cornforth, J. W.; Cornforth, R. H.; Mathew, K. K. J. Chem. Soc. 1959,
2539.
9
J. AM. CHEM. SOC. VOL. 124, NO. 14, 2002 3649

A R T I C L E S
Ishihara et al.
Table 2. Diastereoselective Cyclization of a Mixture of 3b and 2b
Induced by Acids
enantioselective formation of an A-ring is rationalized by the
Stork-Eschenmoser hypothesis,2 which postulates a synchro-
nous internal antiaddition via a chairlike conformation of the
nascent cyclohexane ring, initiated by protonation at the terminal
C(11)dC(12) bond. (R)-BINOL-o-FBn‚SnCl4 was almost inert
in the subsequent cyclization of the resulting (E)-3b and 2b. It
is important to note that 1B was obtained as a minor diastere-
omer. The following three pathways are essentially possible for
the formation of 1B: (1) epimerization from 1A to 1B, (2) the
synchronous or nonsynchronous cyclization process of (3Z,7E)-
4a, which is generated by isomerization of (3E,7E)-4a,21a and
(3) the nonsynchronous cyclization process of (3E,7E)-4a.
However, epimerization from 1A to 1B did not occur under
these cyclization conditions based on control experiments. In
addition, the cyclization of (3Z,7E)-4b was ruled out because
no isomerization of (3E,7E)-4b to (3Z,7E)-4b occurred. There-
fore, the formation of 1B is explained by a synchronous or
nonsynchronous cyclization process to form an AB-ring via a
chair-boat transition state (the A/B-trans and 9,10-syn stereo-
chemistry), conformational inversion of the B-ring cation from
boat form to chair form, and subsequent cyclization of the
C-ring.6,27 For the other three diastereomers 1A, 1C, and 1D,
the reaction pathways can be rationalized by a totally synchro-
nous or nonsynchronous cyclization process (Figure 1).
The stronger LBA CF3CO2H‚SnCl4 was required for the
transformation from (E)-3b and 2b to 1. According to mecha-
nistic studies by Snowden et al.,21a the FSO3H-initiated cycliza-
tion of (E)-3a in 2-nitropropane gives a cis-fused AB-ring
isomer, 1C, as a major product. The diastereoselectivity is
explained by the assumption that the side chain of (E)-3b is
oriented axially in the major conformer (eq 2). In our case, a
trans-fused AB-ring isomer 1A was obtained as the major
product by the cyclization of (E)-3b with CF3CO2H‚SnCl4 in
nitroethane. The latter result with relatively milder acids can
be rationalized by a nonsynchronous process in which the
conformational inversion of the cyclohexyl cation generated by
protonation occurs faster than B-ring closure.
GC ratio (Ee)
yield (%)b
entry
P
achiral LBA (equiv)
1A−D
1A
1B 1C 1D
1
2
3
4
5
6
SiEt3
CF3CO2H (10)‚SnCl4 (2)
CF3CO2H (10)
62c 76 (78% ee) 7 15
0c
2
SiEt3
SiEt3
SiEt3
H
EtNO2 (excess)‚SnCl4 (2)
11d 79
6 14
1
2
EtNO2 (excess)‚SnCl4 (10) 15c 56
11 31
9 23.5 2.5
7 17
CF3CO2H (10)‚SnCl4 (2)
25c 65
28d 74
Sit-BuMe2 CF3CO2H (10)‚SnCl4 (2)
2
a Starting material containing 3b, 2b, and other unknown compounds
was prepared from (E,E)-4b [entry 3 in Table 1; GC ratio, 3b:2b:others )
53(endo:exo ) 55:45):30(endo:exo ) 81:19):17]. b Isolated yield of 1 is
indicated. c 3b and 2b were completely consumed. d 3b and 2b remained.
cyclization of (E,E)-homofarnesyl tert-butyldimethylsilyl ether
(4c) with (R)-BINOL-o-FBn‚SnCl4, 3c and 2c were the main
products but no tricyclic ether 1 was produced (entry 5). In
screening several protective groups, we found that a triethylsilyl
group was the most suitable with respect to the enantioselectivity
of 1A and diastereoselectivity of 1. Although the use of
dichloromethane increased the yield of 1, the enantioselectivity
and diastereoselectivity were reduced (entry 3 vs entry 4). It
seems that the balance between the stability of the Si-O bond
in 4 and the Brønsted acidity of chiral LBA is very important
in this cyclization.
Next, the diastereoselective cyclization of a mixture of 3 and
2 with achiral acids was explored to increase the chemical yield
of (-)-1A. Tricyclic ethers 1 were separated from the crude
mixture obtained in the cyclization (entry 3 in Table 1) by
column chromatography on silica gel, and alcohol products 3a
and 2a, which were partially desilylated, were reprotected with
chlorotriethylsilane before use as a starting material in the
subsequent cyclization. As shown in Table 2, CF3CO2H (10
equiv)‚SnCl4 (2 equiv) in nitroethane gave the best result in
the diastereoselective cyclization (1, 62% yield; 1A, 76% ds;
entry 1). The ee of (-)-1A was identical with that obtained in
the initial enantioselective cyclization (see entry 3 in Table 1).
The use of CF3CO2H or SnCl4 alone did not give 1 in good
yield, although 3b and 2b were completely consumed (entries
2 and 4). The diastereoselectivity of 1A and the chemical yield
of 1 in the subsequent cyclization of triethyl silyl ethers 3b and
2b with CF3CO2H‚SnCl4 were much better than those in the
cyclization of desilylated alcohols (entry 1 vs entry 5). In
screening several protective groups for the starting materials,
the triethylsilyl group was the most suitable for diastereoselec-
tive cyclization (e.g., entry 1 vs entry 6).
Finally, the protective effect of a hydroxy group in (E,E)-4a
was demonstrated in superacid-induced biogenetic polyene
cyclization. According to the pioneering effort by Snowden et
al.21a and Barrero et al.,21b ca. a 1:1 mixture of 1A and 1B is
obtained in ca. 80% GC yield by the cyclization of (E,E)-4a
induced by excess amounts of FSO3H and ClSO3H in 1- or
2-nitropropane. Although the protection of (E,E)-4a with a
trialkylsilyl group was unrelated to the diastereoselectivity, it
was very effective for increasing the chemical yield of 1 (Table
3). In the cyclization of (E,E)-4, formation of the C-ring initiated
by protonation at the C(3)dC(4) bond competes with the
formation of 1.18 Protection of the hydroxy group in (E,E)-4a
prevented this side reaction. Interestingly, the ratios of 1A and
1B in Table 3 are quite different from those in Tables 1 and 2.
Epimerization from 1A to 1B did not occur even under these
Finally, (-)-1A was obtained in 54% yield with 75% ee and
76% ds from (E,E)-4b through enantioselective cyclization,
silylation, and diastereoselective cyclization (eq 1). Separation
of 1 by column chromatography on silica gel was carried out
only after the final step.
The following hypothesis is proposed for the enantioselective
cyclization of (E,E)-4b with (R)-BINOL-o-FBn‚SnCl4. The
(27) Corey, E. J.; Wood, H. B., Jr. J. Am. Chem. Soc. 1996, 118, 11982.
9
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Cyclization of Polyprenoids
A R T I C L E S
Figure 1. The enantioselective cyclization of (E,E)-4b induced by (R)-BINOL-o-FBn‚SnCl4: nonsynchronous pathway (Figure for synchronous pathway is
omitted.).
BINOL-R1‚SnCl4. Representative results are summarized in
Table 3. Diastereoselective Cyclization of (E,E)-4
Table 4. Reaction of (E)-8a in dichloromethane with (R)-
BINOL-Me‚SnCl4 at -78 °C for 14 h gave the desired trans
tricyclic product 6a in 87% yield and 38% ee (entry 1). The
other products were single-cyclization products, 14a and 15a.
yield of
1 (%)a
b
entry
P
acids (equiv)
1A:1B:1C:1D
The enantioselectivity of 6a was improved to 49% ee by using
toluene in place of dichloromethane, but the yield of 6a was
decreased and the yields of 14a and 15a were increased (entry
2). Furthermore, the enantioselectivity increased to 59% ee when
(E)-8b was used in place of (E)-8a (entry 3). In screening several
protective groups, R1 in (R)-BINOL-R1‚SnCl4 and P in (E)-8
(n ) 1), we found that triphenylsilylpropargyl or the o-
fluorobenzyl group and the tert-butyldiphenylsilyl group were
the most suitable R1 and P, respectively, with regard to
enantioselectivity (entries 6 and 7): the reaction of (E)-8c with
(R)-BINOL-o-FBn‚SnCl4 gave trans-6c in 9% yield and 81%
ee (entry 6). The relationship between enantioselectivity and
R1 is not clear. The steric bulkiness of P may impair interaction
between SnCl4 and the basic oxygen atom of OP. The absolute
configuration of trans-6 shown in Table 4 was assigned to be
5S and 10S based on the known optical rotation.30c Notably,
the tricyclic compounds 6a-c obtained in the cyclization of
(E)-8a-c were only trans isomers regardless of the reaction
conditions.30e,f The monobenzoate of (R)-BINOL‚SnCl4, which
was the most effective LBA for the enantioselective cyclization
of 2-polyprenylphenol derivatives,7 was inert in the cyclization
of (E)-8c.
1
2
3
4
5
H
CF3CO2H (10)‚SnCl4 (2)
CF3CO2H (10)‚SnCl4 (2)
ClSO3H (10)
31
69
61
87
91
42:53:3:2
43:50:5:2
58:36:4:1
54:46:0.4:0.4
58:40:1:1
SiEt3
SiEt3
Sit-BuMe2 ClSO3H (10)
Sit-BuPh2 ClSO3H (10)
a Isolated yield. b GC ratio.
conditions based on control experiments. Therefore, the ratio
of 1A and 1B would be controlled by the relative energies of
the chair-chair and chair-boat transition states.
Enantioselective Cyclization of (all-E)-8. (all-E)-Homo-
(polyprenyl)arenes 8 were prepared in good yields by reaction
of arylmethylmagnesium choride with polyprenyl diethyl phos-
phates (9) according to Butsugan’s method (Scheme 3).29
Although cyclization via 2-(2-arylethyl)-1,3,3-trimethyl-
cyclohexyl carbocations has been widely used to construct the
B-ring of podocarpa-8,11,13-triene diterpenoids 6,30 there have
been only a few reports on successive cyclizations of (E)-
homogeranylbenzene derivatives 8 (n ) 1) to 6.31 We initially
studied the enantioselective cyclization of (E)-4-homogera-
nylphenol (8a) and its ether derivatives 8b and 8c32 with (R)-
(28) For preparation of 8, see: Araki, S.; Sato, T.; Butsugan, Y. J. Chem. Soc.,
Chem. Commun. 1982, 285.
Although the enantiomeric purity of 14a-c and 15a-c could
not be determined, we expected that they would be as pure as
trans-6a-c, since no achiral stereoisomer was observed during
the cyclization of (E)-8a-c. Thus, the diastereoselective cy-
clization of 14 and 15 with achiral LBA was explored to increase
the chemical yield of 6. After treating (E)-8b with (R)-BINOL-
Bn‚SnCl4 at -78 °C for 3 days to completely consume (E)-8b,
an achiral LBA, CF3CO2H‚SnCl4, was added to the reaction
solution at the same temperature and the mixture was stirred
for an additional day. As expected, the desired product 6b was
obtained in 62% ee and 86% yield from (E)-8b in a one pot
procedure (cf. entry 4 in Table 4). Furthermore, the desilylation
(29) (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.
(30) For the cationic cyclization of homogeranylbenzene derivatives bearing
regioselectivity- and/or diastereoselectivity-inducing auxiliaries, see: 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.
(31) King, F. E.; King, T. J.; Topliss, J. G. J. Chem. Soc. 1957, 573.
(32) Although several ethers of 14e and 15e were examined regarding the second
cyclization induced by CF3CO2H‚SnCl4 or BF3‚Et2O, cis tricyclic com-
pounds were produced as major products in all cases.
9
J. AM. CHEM. SOC. VOL. 124, NO. 14, 2002 3651

A R T I C L E S
Ishihara et al.
Table 4. Enantioselective Cyclization of (E)-8a-c
molar ratioa
14a−c
1
entry
8a−c(P)
8a (H)
8a
8b (Me)
R , (R)-LBA (equiv)
solvent, time (h)
6a−c [ee (%)]b
15a−c
8a−c
1c
2c
3
Me (1.1)
Me (1.1)
Me (2.0)
Bn (2.0)
Me (2.0)
o-FBn (2.0)
PH3SiCC (1.1)
CH2Cl2, 14
toluene, 14
toluene, 19
toluene, 24
toluene, 24
toluene, 48
toluene, 96
87 [38]
28 [49]
10 [59]
13 [61]
13 [72]
9 [81]
6
40
36
33
35
44
40
7
32
36
32
35
47
41
0
0
18
22
17
0
4
8b
5d
6d
7d
8c (t-BuPh2Si)
8c
8c
19 [80]
0
1
1
a Determined by GC and H NMR analyses. b Determined by chiral 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 H NMR analyses after desilylation and acetylation of products.
1
Scheme 6. Enantioselective Synthesis of (5S,10S)-6a
Scheme 7. Enantioselective Synthesis of (5S,10S)-18
of a crude mixture of 6c, 14c, and 15c, which were obtained in
the enantioselective cyclization of (E)-8c induced by (R)-
BINOL-o-FBn‚SnCl4, with tetrabutylammonium fluoride was
highly effective at increasing the reactivity of the subsequent
diastereoselective cyclization. Thus, the desired product 6a was
obtained in 78% ee and 94% yield from 2c in three steps
(Scheme 6; cf. entry 6 in Table 4). Since (()-6 has already
been converted into (()-ferruginol (16) by King32 and Ghatak,30d
the present method represents a formal and the first enantio-
selective total synthesis of (+)-16.
work can be regarded as the enantioselective total synthesis of
the above natural diterpenes.
The enantioselective cyclization of (E)-1-homogeranyl-3-(tert-
butyldiphenylsiloxy)benzene (8d) was also examined by using
(R)-BINOL-o-FBn‚SnCl4 in toluene at -78 °C (Scheme 7). As
expected, tricyclic product 6d was obtained in 78% ee and in
only the trans configuration, together with the monocyclization
products 14d and 15d. However, the subsequent cyclization of
desilylated compounds 14e and 15e with BF3‚Et2O in nitro-
methane31c gave a 37:63 mixture of trans- and cis-6e together
with a small amount of trans-17.33 Fortunately, we found that
the cyclization of acetates of 14e and 15e under the same
conditions gaVe (+)-13-acetoxypodocarpa-8,11,13-triene (18)
with high diastereoselectiVity (trans only) and regioselectiVity
(no detectable amount of 17). Thus, the desired product 18 was
obtained in 75% ee and 89% yield from 8d. This compound 18
can be easily converted into (+)-podocarpa-8(14)-en-13-one
(19),30a,34 a versatile intermediate for synthesis of naturally
occurring diterpenes, e.g. isophyllocladene,35a phyllocladene,35a
hibaone,35b manool,35c sclareol,35c manoyl oxide,35c isoabienol,35d
trans-abienol,35d and anticopalic acid.35e,f Therefore, the present
In 1990, Azevedo’s group found a ring-C monoaromatic
tricyclic terpene, 13-methylpodocarpa-8,11,13-triene (6f), in a
Tasmanian tasmanite sediment.36 Four years later, Albrecht’s
group reported the isolation of a series of chiral tetracyclic (7),
pentacyclic, hexacyclic (20), heptacyclic, and octacyclic ho-
mologues, from Eocene Messel shale (Germany), which appear
to be the remnants of an ancient family of cyclopolyprenoids.37
Very recently, Corey’s group achieved the asymmetric synthesis
of 7 and 20 using the diastereoselective Lewis acid-catalyzed
polycyclization of polyunsaturated oxiranes.38 To demonstrate
(34) (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; 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.
(35) Azevedo, D. A.; Aquino Neto, F. R.; Simoneit, B. R. T. Org. Mass
Spectrom. 1990, 25, 475 and references therein.
(36) 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.
(37) Corey, E. J.; Luo, G.; Shouzhong, L. Angew. Chem., Int. Ed. Engl. 1998,
37, 1126.
(38) Corey, E. J.; Staas, D. D. J. Am. Chem. Soc. 1998, 120, 3526.
(33) (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.
9
3652 J. AM. CHEM. SOC. VOL. 124, NO. 14, 2002

Cyclization of Polyprenoids
A R T I C L E S
Via TS-21. Furthermore, the stereochemistry in the subsequent
cyclization of 14 and 15 strongly depends on the nucleophilicity
of their terminal benzene ring. Their side chain should be
orientated axially in the major conformer as well as that of (E)-3
(see eq 2).21a Benzene rings without an electron-donating
substituent, para to the site of electrophilic attack, would be
not sufficiently nucleophilic to react through the synchronous
pathways; rather, they may require complete protonation to a
carbocation eq-23 which reacts with high stereoselectivity by a
nonsynchronous pathway due to the minimum steric effects
giving trans-6: e.g. the second cyclization of 14a-c, 15a-c,
and acetates of 14e and 15e leads only to trans-6. With an
electron-donating substituent, the synchronous pathway through
ax-14 and ax-15 or the nonsynchronous pathway through ax-
23 would predominate over the nonsynchronous pathway
through eq-14: e.g. the second cyclization of 14e and 15e gave
a 37:63 mixture of trans- and cis-6e.
Conclusions
Figure 2. Possible reaction paths for the acid-induced cyclization of (E)-8
(n ) 1).
We have demonstrated that chiral LBAs are effective for
absolute stereocontrol in the initial cyclization of polyprenoids
to form an A-ring and that the nucleophilicity of the internal
terminator in polyprenoids is important for relative stereocontrol
in the subsequent cyclization induced by achiral LBAs. Non-
enzymatic enantioselective polyene cyclization of (E,E)-4b and
(all-E)-8 is a very attractive alternative to multistep synthesis
from naturally occurring chiral synthons. (-)-Ambrox 1A was
concisely synthesized by the enantio- and diastereoselective
cyclization of (E,E)-4b, which was prepared by adding a carbon
to commercially available (E,E)-5 or (E,E)-12. Alcohol protec-
tion of (E,E)-4a by a triethylsilyl group increased the enantio-
selectivity of chiral LBA-induced cyclization and both the
chemical yield and diastereoselectivity in the subsequent cy-
clization. The enantioselective and diastereoselective cyclization
of (all-E)-8, which possesses an aryl group, was also induced
by chiral and achiral LBAs. Several optically active podocarpa-
8,11,13-triene diterpenoids 6 and (-)-tetracyclic polyprenoid
7 of sedimentary origin were synthesized (75-80% ee). Further
studies on the rational design of “chiral Brønsted acid catalysts”
based on the concept of LBA may lead to practical artificial
cyclases for the asymmetric synthesis of a wide range of
polycyclic terpenoids.
the generality of our synthetic strategy, polycyclic terpenes 6f
and 7 were concisely synthesized by using the (R)-BINOL-o-
FBn‚SnCl4-induced enantioselective cyclization of 3-homo-
(polyprenyl)toluenes as a key step (eq 3). An achiral LBA,
SnCl4‚CF3CO2H/CH2Cl2, as well as BF3‚Et2O/MeNO2, was
effective for the second step.
Our extensive results in the present investigation on the
stereochemistry of the acid-induced polyene cyclization of (E)-8
(n ) 1) provide some important generalizations.30,39 The possible
reaction paths are shown in Figure 2. Initial cyclization of (E)-8
induced by (R)-BINOL-o-FBn‚SnCl4 should take place through
a synchronous pathway involving transition states (TSs) 21 and
22 enantioselectively: TS-21 stereospecifically leads to trans-
6, while TS-22 leads to a mixture of 14 and 15. (E)-4-
Homogeranylphenol 8a was completely consumed in toluene
in the presence of 1.1 equiv of (R)-BINOL-Me‚SnCl4 (Table 4,
entry 2), while the corresponding ethers (E)-8b and (E)-8c
remained in ca. 20% yield even in the presence of 2 equiv of
(R)-BINOL-R1‚SnCl4 (Table 4, entries 3-5). These experimen-
tal results may indicate that protection of a hydroxy group in
(E)-8a 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 (E)-8 may serVe 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)
Experimental Section
General Methods. High-performance liquid chromatography (HPLC)
was done with Shimadzu 10A instruments using Daicel CHIRALCEL
OD-H (4.6 mm × 25 cm) or OC (4.6 mm × 25 cm). GC analysis was
done with Shimadzu 17A instruments using γ-TA (0.25 mm × 30 m)
or PEG (0.25 mm × 25 m). Low-resolution mass spectra were obtained
by direct insertion for CI (isobutane) on a Shimadzu GC/MS instrument
(GC-17A) and QP-5050A (column: TC-1 (0.25 mm × 30 m)). All
experiments were carried out under an atmosphere of dry argon.
Benzene, hexane, toluene, and dichloromethane were freshly distilled
from calcium hydride. Tin(IV) chloride was distilled under argon. Other
simple chemicals were of commercially available analytical grade
quality.
Enantioselective Synthesis of (-)-Ambrox 1A Using the Enan-
tioselective Cyclization of (E,E)-4b Induced by (R)-BINOL-o-FBn‚
SnCl4 and the Subsequent Diastereoselective Cyclization Induced
by CF3CO2H‚SnCl4 (Eq 1). To a solution of (R)-BINOL-o-FBn (240
mg, 0.6 mmol) in toluene (6 mL) was added a 1.0 M solution of tin-
(IV) chloride (0.6 mL, 0.6 mmol) in toluene at room temperature, and
(39) (a) Mori, K.; Tamura, H. Liebigs Ann. Chem. 1990, 361. (b) Zoretic, P.
A.; Fang, H.; Ribeiro, A. A.; Dubay, G. J. Org. Chem. 1998, 63, 1156.
9
J. AM. CHEM. SOC. VOL. 124, NO. 14, 2002 3653

A R T I C L E S
Ishihara et al.
the solution was stirred for 5 min. After the solution of (R)-BINOL-
o-FBn‚SnCl4 prepared in situ as above was cooled to -78 °C, (E,E)-
4b (105.2 mg, 0.3 mmol) was added dropwise. The reaction mixture
was stirred at -78 °C for 3 days, quenched with saturated aqueous
NaHCO3, and extracted with ether. The combined organic phase was
dried over anhydrous MgSO4 and concentrated. To a solution of the
crude product in DMF (2 mL) were added imidazole (41 mg, 0.6 mmol)
and chlorotriethylsilane (83 µL, 0.5 mmol) at 0 °C, and the reaction
mixture was allowed to warm to ambient temperature. After being
stirred for 5 h, the reaction mixture was quenched with water (2 mL)
twice and extracted with ether. The combined organic phase was washed
with brine (2 mL), dried over MgSO4, and concentrated. To a mixed
solution of trifluoroacetic acid (231 µL, 3 mmol) and tin(IV) chloride
(1.0 M solution in toluene, 0.6 mL, 0.6 mmol) in nitroethane (4 mL)
was added a solution of the crude product in nitroethane (2 mL) at
-78 °C. After being stirred for 1 day, the reaction mixture was
quenched with saturated aqueous NaHCO3, extracted with ether, dried
over MgSO4, and concentrated. The residue was purified as a
diastereomeric mixture of 1A-D (54% yield) by column chromatog-
raphy on silica gel (eluent, hexanes-ether 20:1). Compounds 1A-D
were not isolated, and their identification was effected by comparison
of their 1H and 13C NMR data with those of authentic samples.22b The
product distribution presented in eq 1 was determined by GC (PEG).
The absolute stereochemistry of 1A was ascertained by comparison of
GC (γ-TA) data with that of (-)-ambrox (Aldrich). GC (PEG, 100
Procedure for the Diastereoselective Cyclization of 14a and 15a
Induced by Achiral LBA, CF3CO2H‚SnCl4. To a solution of a mixture
of 6a, 14a, and 15a, which were obtained in the above reaction, in
dichloromethane (2 mL) was successively added a 1 M solution of
tin(IV) chloride in hexane (0.1 mL, 0.1 mmol) and trifluoroacetic acid
(7.7 µL, 0.1 mmol) at -78 °C. The reaction mixture was stirred at
-78 °C for 1 days, quenched with saturated aqueous NaHCO3, and
extracted with ether. The combined organic phases were dried over
anhydrous MgSO4 and concentrated. The crude product was purified
by column chromatography on silica gel (eluent, hexanes-ether) to
give 6a in 94% over yield from (E)-8c in three steps.
General Procedure for the Diastereoselective Cyclization of 14
and 15 Induced by BF3‚Et2O.41 Boron trifluoride‚diethyl etherate (0.84
mmol) was added to a solution of an acetylated mixture of 6e, 14e,
and 15e, which were obtained in the above enantioselective cyclization
of (E)-8d, in nitromethane (3 mL) at room temperature. The reaction
mixture was stirred at room temperature for 5 h, quenched with saturated
aqueous NaHCO3, and extracted with ether. The combined organic
phases were dried over anhydrous MgSO4 and concentrated. The crude
product was purified by column chromatography on silica gel (eluent,
hexanes-ether) to give 18 in 89% over yield from (E)-8d in four steps.
The diastereoselective cyclization of a mixture of products, which
were obtained in the enantioselective cyclization of (E)-8f and (E)-8g,
was also perofrmed in the same manner as above. Polycyclic compound
7 was purified by the oxidatitive treatment of byproducts including
carbon-carbon double bonds with m-chloroperbenzoic acid in dichlo-
romethane and subsequent column chromatography on silica gel
(eluent: hexanes-ether).
kPa, column temperature 120 °C, injection temperature 200 °C) tR
)
14.7 (1B), 15.5 (1D), 17.6 (1A), and 19.5 (1C) min; GC (γ-TA, 75
kPa, column temperature 130 °C, injection temperature 200 °C) tR )
59.1 (major enantiomer of 1B), 60.1 (minor enantiomer of 1B), 61.3
(major enantiomer of 1D), 63.0 (minor enantiomer of 1D), 68.3 ((-
)-1A), 70.2 ((+)-1A), 75.0 (major enantiomer of 1C), and 77.8 (minor
enantiomer of 1C) min.
Although compounds 3 and 2 were not also isolated, 1H and 13NMR
spectroscopic properties of the corresponding alcohols were identical
with those reported.19,21a,39 1H NMR chemical shifts of olefinic protons
in 3b and 2b and their GC/MS data are provided as follows: 1H NMR
(CDCl3) endo-3b: δ 5.27 (brs, 1H); exo-3b: δ 4.53 (s, 1H), 4.75 (s,
1H); endo-2b: δ 5.40 (brs, 1H); exo-2b: δ 4.75 (s, 1H), 4.81 (s, 1H).
GC/MS [CI, 116 kPa, column temperature 70 °C for 5 min and then
warming to 250 °C (+10 °C/min), injection temperature 150 °C] tR )
20.0 (exo-3b), 20.2 (endo-3b), 20.5 (exo-2b), 20.8 (endo-2b) min; m/z
M+ + 1, 351.
Analytical data for these new compounds are provided in the
following paragraphs.
(+)-(5S,10S)-12-Hydroxypodocarpa-8,11,13-triene (6a): GC/MS
(CI, 70 °C for 5 min, warm to 10 °C/min, and then 250 °C for 7 min)
tR ) 18.6 min for acetate of 6a, m/z M+ + 1, 287; HPLC (Daicel OD-H
column, hexane-i-PrOH 20:1, flow rate ) 0.5 mL/min) tR ) 27.7
(acetate of (-)-6a), 31.2 (acetate of (+)-6a) min; IR (film) 3500-
3000 (OH), 2990, 1610, 1584 cm-1; 1H NMR (CDCl3) δ 0.92 (s, 3H),
0.94 (s, 3H), 1.16 (s, 3H), 1.12-1.90 (m, 8H), 2.16 (d, J ) 12.6 Hz,
1H), 2.69-2.92 (m, 2H), 4.9 (br, 1H), 6.57 (dd, J ) 2.4, 8.7 Hz, 1H),
6.73 (d, J ) 2.4 Hz, 1H), 6.89 (d, J ) 8.7 Hz, 1H); 13C NMR (CDCl3)
δ 19.1, 19.3, 21.6, 24.7, 29.6, 33.3, 33.4, 37.8, 41.6, 50.2, 111.0, 112.6,
127.4, 129.9, 151.6, 153.2; [R]26.2 22.3 (c 1.07, CHCl3). Anal. Calcd
D
for C17H24O: C, 83.55; H, 9.90. Found: C, 83.57; H, 9.86.
6-Homo(p-hydroxybenzyl)-1,5,5-trimethylcyclohexene (14a) and
3,3-dimethyl-1-methylene-2-homo(p-hydroxybenzyl)cyclohexane
(15a): Compounds 14a and 15a could not be separated by column
chromatography on silica gel. GC/MS (CI, 70 °C for 5 min, warm to
10 °C/min, and then 250 °C for 7 min) tR ) 17.8 (acetate of 14a), 18.1
General Procedure for the Enantioselective Cyclization of (all-
E)-8 Induced by (R)-BINOL-R1‚SnCl4. To a solution of (R)-BINOL-
R1 (0.4 mmol) in toluene (4 mL) was added a 1.0 M solution of tin(IV)
chloride (0.4 mL, 0.4 mmol) in hexane at room temperature, and the
solution was stirred for 5 min. After the solution of (R)-BINOL-R1‚
SnCl4 prepared in situ as above was cooled to -78 °C, (all-E)-8 (0.2
mmol) was added dropwise over a period of 1 min. The reaction mixture
was stirred at -78 °C for 3 days, quenched with saturated aqueous
NaHCO3, and extracted with ether. The combined organic phases were
dried over anhydrous MgSO4 and concentrated. The crude product was
purified as a mixture of 6, 14, and 15 by column chromatography on
silica gel (eluent, hexanes-ether). These compounds were used for the
subsequent cyclization without further separation to give 6, 14, and 15
as a mixture, which were separable to 6 and a mixture of 14 and 15.
1
(acetate of 15a) min, m/z M+ + 1, 287; H NMR (CDCl3) δ 0.82 (s,
3H (15a)), 0.88 (s, 3H (14a)), 0.90 (s, 3H (15a)), 0.97 (s, 3H (14a)),
1.01-2.62 (m, 9H (14a) and 11H (15a)), 1.67 (s, 3H (14a)), 4.53 (s,
1H), 4.60 (s, 1H (15a)), 4.82 (s, 1H (15a)), 5.30 (brs, 1H (14a)), 6.74
(d, J ) 8.1 Hz, 2H), 7.04 (d, J ) 8.1 Hz, 2H).
(+)-(5S,10S)-12-Methoxypodocarpa-8,11,13-triene (6b):30c,42 GC/
MS (CI, 70 °C for 5 min, warm to 10 °C/min, and then 250 °C for 7
min) tR ) 17.4 min, m/z M+ + 1, 259; HPLC (Daicel OD-H column,
hexane-i-PrOH 100:1, flow rate ) 0.3 mL/min); tR ) 16.5 ((-)-
enantiomer), 22.7 ((+)-enantiomer) min; IR (film) 2900, 1615, 1510,
1250, 1044 cm-1; 1H NMR (300 MHz, CDCl3) δ 0.93 (s, 3H), 0.95 (s,
3H), 1.14-1.91 (m, 8H), 1.19 (s, 3H), 2.19-2.29 (m, 1H), 2.71-2.94
(m, 2H), 3.78 (s, 3H), 6.63-6.69 (m, 1H), 6.81 (s, 1H), 6.96 (d, J )
Representative Procedure for the Desilylation of 14 and 15. To
a solution of a mixture of 6c, 14c, and 15c, which were obtained in
the above reaction, in THF (1 mL) was added dropwise a 1 M solution
of tetrabutylammonium fluoride (TBAF) in THF (0.2 mL, 0.2 mmol)
at room temperature. After being stirred for 1 h, the reaction mixture
was quenched with brine and extracted with ether. The combined
oragnic phases were dried over anhydrous MgSO4 and concentrated.
The crude product was purified as a mixture of 6a, 14a, and 15a by
column chromatography on silica gel (eluent, hexanes-ether).
8.4 Hz, 1H); [R]26.3 21.0 (c 0.36, CHCl3) for 61% ee; lit. [R]D 65,42
D
72.30c
(40) Harring, S. R.; Livinghouse, T. Tetrahedron 1994, 50, 9229.
(41) Bible, R. H. Tetrahedron 1960, 11, 22.
(42) Hodges, R.; Raphael, R. A. J. Chem. Soc. 1960, 50.
9
3654 J. AM. CHEM. SOC. VOL. 124, NO. 14, 2002

Cyclization of Polyprenoids
A R T I C L E S
6-Homo(p-methoxybenzy)-1,5,5-trimethylcyclohexene (14b) and
3,3-dimethyl-1-methylene-2-homo(p-methoxybenzyl)cyclohexane
(15b): Compounds 14b and 15b could not be separated by column
chromatography on silica gel. GC/MS (CI, 70 °C for 5 min, warm to
10 °C/min, and then 250 °C for 7 min) tR ) 17.4 (14b), 17.6 (15b)
tR ) 17.4 min, m/z M+ + 1, 245; HPLC (Daicel OC coulmn, hexane-
i-PrOH 80:1, flow rate ) 0.3 mL/min) tR ) 28.2 ((+)-enantiomer),
30.4 ((-)-enantiomer) min; IR (film) 3700-3000 (OH), 1576, 1456,
1264 cm-1; 1H NMR (300 MHz, CDCl3) δ 0.93 (s, 3H), 0.96 (s, 3H),
1.34 (s, 3H), 1.17-1.86 (m, 8H), 2.84 (t, J ) 4.5 Hz, 2H), 3.11 (dt, J
) 13.5, 3.0 Hz, 1H), 4.69 (s, 1H), 6.42 (d, J ) 8.1 Hz, 1H), 6.60 (d,
J ) 8.1 Hz, 1H), 6.92 (t, J ) 8.1 Hz, 1H); 13C NMR (75 MHz, CDCl3)
δ 18.9, 19.4, 19.9, 22.2, 32.9, 33.74, 33.75, 36.5, 39.4, 41.4, 52.9, 100.0,
1
min, m/z M+ + 1, 259; H NMR (300 MHz, CDCl3) δ 0.82 (s, 3H
(15b)), 0.88 (s, 3H (14b)), 0.90 (s, 3H (15b)), 0.97 (s, 3H (14b)), 1.01-
2.62 (m, 9H (14b) and 11H (15b)), 1.68 (s, 3H (15b)), 3.80 (s, 3H),
4.62 (s, 1H (15b)), 4.82 (s, 1H (15b)), 5.30 (brs, 1H (14b)), 6.82 (d,
J ) 8.7 Hz, 2H), 7.10 (d, J ) 8.7 Hz, 2H).
113.9, 122.3, 125.9, 138.9, 154.1; [R]26.5 12.2 (c 0.27, CHCl3) for
D
73% ee. Anal. Calcd for C17H24O: C, 83.55; H, 9.90. Found: C, 83.51;
H, 9.91.
12-tert-Butyldiphenylsiloxypodocarpa-8,11,13-triene (6c), 6-ho-
mo[p-(tert-butyldiphenylsiloxy)benzyl]-1,5,5-trimethylcyclohexene
(14c), and 3,3-dimethyl-1-methylene-2-homo[p-(butyldiphenyl-
siloxy)benzyl]cyclohexane (15c): Crude compounds of 6c, 14c, and
15c, which were produced in the enantioselective cyclization of 8c
induced by (R)-BINOL-R1‚SnCl4, were transformed into acetates of
6a, 14a, and 15a, respectively, by desilylation with TBAF and
acetylation with acetic anhydride in the presence of triethylamine to
determine the product ratio of 6c, 14c, and 15c and the ee value of 6c.
13-tert-Butyldiphenylsiloxypodocarpa-8,11,13-triene (6d), 6-Ho-
mo[m-(tert-butyldiphenylsiloxy)benzyl]-1,5,5-trimethylcyclohex-
ene (14d), and 3,3-Dimethyl-1-methylene-2-homo[m-(butyldiphen-
ylsiloxy)benzyl]cyclohexane (15d): Crude compounds of 6d, 14d, and
15d, which were produced in the enantioselective cyclization of 8d
induced by (R)-BINOL-o-FBn‚SnCl4, were transformed into 6e, 14e,
and 15e, respectively, by desilylation with TBAF to determine the
product ratio of 6e, 14e, and 15e and the ee value of 6e.
(+)-(5S,10S)-13-Acetoxypodocarpa-8,11,13-triene (18): HPLC
(two linear Daicel OD-H columns, hexane-i-PrOH 80:1, 0.3 mL/min)
tR ) 34.9 ((-)-enantiomer), 45.9 ((+)-enantiomer) min; IR (film) 2900,
1759 (CdO), 1493, 1368, 1210 cm-1; 1H NMR (300 MHz, CDCl3) δ
0.92 (s, 3H), 0.94 (s, 3H), 1.17 (s, 3H), 1.18-1.92 (m, 8H), 2.27 (s,
3H), 2.22-2.30 (m, 1H), 2.82-2.92 (m, 2H), 6.72 (s, 1H), 6.80 (d, J
) 8.4 Hz, 1H), 6.72 (d, J ) 8.4 Hz, 1H); 13C NMR (75 MHz, CDCl3)
δ 18.8, 19.2, 21.2, 21.6, 24.9, 30.3, 33.3, 33.4, 37.6, 38.8, 41.6, 50.1,
118.5, 121.2, 125.5, 136.8, 147.7, 147.9, 169.8; [R]24.0 15.1 (c 0.86,
CHCl3). Anal. Calcd for C19H26FO2: C, 79.68; H, 9.15. Found: C,
79.73; H, 9.12.
D
(+)-13-Methylpodocarpa-8,11,13-triene (6f):44 HPLC (two linear
Daicel OD-H columns, hexane-i-PrOH 400:1, 0.2 mL/min) tR ) 38.9
((-)-enantiomer), 41.4 ((+)-enantiomer) min; IR (film) 2900, 1497,
1474, 1375, 1040, 814 cm-1; 0.92 (s, 3H), 0.94 (s, 3H), 1.02-1.91
(m, 8H), 1.18 (s, 3H), 2.22-2.30 (m, 1H), 2.26 (s, 3H), 2.79-2.95
(m, 2H), 6.86 (s, 1H), 6.93 (d, J ) 8.1 Hz, 1H), 7.15 (d, J ) 8.4 Hz,
1H); 13C NMR (75 MHz, CDCl3) δ 19.0, 19.3, 20.8, 21.6, 24.9, 30.3,
33.3, 33.4, 37.5, 38.9, 41.7, 50.5, 124.3, 126.4, 129.5, 134.5, 135.1,
(+)-(5S,10S)-13-Hydroxypodocarpa-8,11,13-triene (6e):43 GC/MS
(CI, 70 °C for 5 min, warm to 10 °C/min, and then 250 °C for 7 min)
tR ) 17.8 min, m/z M+ + 1, 245; HPLC (Daicel OD-H column, hexane-
i-PrOH 20:1, flow rate ) 0.5 mL/min) tR ) 16.0 ((-)-(5R,10R)), 18.3
((+)-(5S,10S)) min; IR (film) 3400-3050 (OH), 2935, 1607, 1497
147.3; [R]26.9 33.8 (c 1.54, CHCl3).
D
(-)-(4aS,4bR,10bR,12aS)-1,2,3,4,4a,4b,5,6,10b,11,12,12a-Dodecahy-
dro-1,1,4a,8,10b-pentamethylchrysene (7):37,44 IR (film) 2900, 1460
cm-1; 1H NMR (CDCl3, 300 MHz) δ 0.85 (s, 3H), 0.8-1.9 (m, 13H),
0.86 (s, 3H), 0.92 (s, 3H), 1.15 (s, 3H), 1.18 (s, 3H), 2.26 (s, 3H),
2.30-2.40 (m, 1H), 2.70-2.90 (m, 2H), 6.85 (s, 1H), 6.94 (d, J ) 8.4
Hz, 1H), 7.14 (d, J ) 8.1 Hz, 1H); 13C NMR (CDCl3, 75 MHz) δ 16.3
(C16′), 18.0 (C9), 18.6 (C17), 19.1 (C13), 20.8 (C4′), 21.4 (C20′), 26.2
(C12′), 30.8 (C8), 33.3 (C19), 33.3 (C20), 37.6 (C15), 37.8 (C11), 39.8
(C16), 40.7 (C12), 42.0 (C18), 55.3 (C10), 56.3 (C14), 124.5 (C5),
1
cm-1; H NMR (300 MHz, CDCl3) δ 0.92 (s, 3H), 0.94 (s, 3H), 1.15
(s, 3H), 1.16-1.90 (m, 8H), 2.19-2.28 (m, 1H), 2.73-2.94 (m, 2H),
4.54 (brs, 1H), 6.50 (d, J ) 2.7 Hz, 1H), 6.60 (dd, J ) 2.7, 8.7 Hz,
1H), 7.11 (d, J ) 8.7 Hz, 1H); [R]24.0 45.1 (c 0.42, CHCl3) for 78%
D
ee; lit. [R]D 61 (c 1.3).43
6-Homo(m-hydroxybenzyl)-1,5,5-trimethylcyclohexene (14e) and
3,3-dimethyl-1-methylene-2-homo(m-hydroxybenzyl)cyclohexane
(15e): Compounds 14e and 15e could not be separated by column
chromatography on silica gel. GC/MS (CI, 70 °C for 5 min, warm to
10 °C/min, and then 250 °C for 7 min) tR ) 16.7 (14e), 16.9 (15e)
126.5 (C4), 129.3 (C2), 134.4 (C3), 135.0 (C7), 147.6 (C6); [R]26.5
D
-35.6 (c 0.43, CHCl3); the ee value (77%) was measured on the known
1
optical rotation value; lit. [R]23 -46 (c 0.74, CHCl3).37
min, m/z M+ + 1, 245; H NMR (300 MHz, CDCl3) δ 0.83 (s, 3H
D
(15e)), 0.88 (s, 3H (14e)), 0.92 (s, 3H (15e)), 0.98 (s, 3H (14e)), 1.10-
3.00 (m, 9H (14e) and 11H (15e)), 1.70 (s, 3H (14e)), 4.62 (s, 1H
(15e)), 4.82 (s, 1H (15e)), 5.30 (s, 1H (14e)), 6.80-7.20 (m, 4H), the
OH signal was not observed.
(+)-(5S,10S)-11-Hydroxypodocarpa-8,11,13-triene (17): GC/MS
(CI, 70 °C for 5 min, warm to 10 °C/min, and then 250 °C for 7 min)
Supporting Information Available: Experimental procedures
and characterization data for (R)-BINOL-R1, (E,E)-4, and (all-
E)-8 (PDF). This material is available free of charge via the
Internet at http://pubs.acs.org.
JA0124865
(44) Hauke, V.; Trendel, J. M.; Albrecht, P. In Polycyclic Aromatic Compounds;
Garrigues, P., Lamotte, M., Eds.; Gordon and Breach Science Publishers:
Switzerland 1993; p 451.
(43) Tahara, A.; Shimagaki, M.; Ohara, S.; Tanaka, T.; Nakata, T. Chem. Parm.
Bull. 1975, 23, 2329.
9
J. AM. CHEM. SOC. VOL. 124, NO. 14, 2002 3655