A new artificial cyclase for polyprenoids: Enantioselective total synthesis of (-)-chromazonarol, (+)-8-epi-puupehedione, and (-)-11′-deoxytaondiol methyl ether

Article abstract of DOI:10.1021/ja0472026

This paper describes a new artificial cyclase, optically pure 3-o-fluorobenzyloxy-2-hydroxy-2′-(p-methoxybemzyl)-1,1′-binaphthyl·SnCl₄, which is effective for the enantioselective cyclization of 2-(polyprenyl)phenol derivatives to afford polycy

Full text of DOI:10.1021/ja0472026

Published on Web 08/18/2004
A New Artificial Cyclase for Polyprenoids: Enantioselective Total Synthesis
of (-)-Chromazonarol, (+)-8-epi-Puupehedione, and (-)-11′-Deoxytaondiol
Methyl Ether
Hideaki Ishibashi,† Kazuaki Ishihara,*,† and Hisashi Yamamoto*,‡
Graduate School of Engineering, Nagoya UniVersity, Furo-cho, Chikusa, Nagoya 464-8603, Japan, and
Department of Chemistry, The UniVersity of Chicago, 5735 South Ellis AVenue, Chicago, Illinois 60637
Received May 13, 2004; E-mail: ishihara@cc.nagoya-u.ac.jp; yamamoto@uchicago.edu
Chart 1. Artificial Cyclases, (R)-1‚SnCl4 and (S)-2e‚SnCl4
Lewis acid-assisted chiral Brønsted acid (chiral LBA) induces
the enantioselective biomimetic cyclization of polyprenoids (Chart
1).1,2 For example, 1‚SnCl4 is an effective artificial cyclase for
(homoprenyl)arenes, and trans-fused polycyclic products are ob-
tained with 75∼80% ee.2d However, 1‚SnCl4 is not suitable as an
LBA in the presence of hydroxypolyprenoids. The identification
of additional chiral Brønsted acids that tightly chelate with SnCl4
is required to broaden the range of their application. This paper
describes a new artificial cyclase, 2e‚SnCl4, which is effective for
the enantioselective cyclization of 2-(polyprenyl)phenol derivatives
7 to give polycyclic terpenoids bearing a chroman skeleton. The
synthetic utility of 2e‚SnCl4 is demonstrated by very efficient routes
to (-)-chromazonarol (9), (+)-8-epi-puupehedione (11), a key
synthetic intermediate 13 of (+)-wiedendiol (14), and (-)-11′-
deoxytaondiol methyl ether (16).
Scheme 1. Synthesis of 2a
a Conditions: (a) R1MgX, NiCl2(dppe), THF, reflux (>95%). (b) BuLi,
TMEDA, THF; B(OMe)3; aq HCl; H2O2, NaOH, THF (87%). (c) R2OH,
PPh3, DEAD, THF (>99%). (d) aq HCl, dioxane, reflux (>95%).
According to our recent studies, (R,R)-2-alkoxy-1,2-diarylethanol‚
3
4
SnCl4 and 2-alkoxyphenol‚SnCl4 are effective as LBAs. These
results suggest that five-membered chelation structures of 2-alkoxy-
alcohols and SnCl4 are suitable for use as LBA. On the basis of
these results, we designed a chiral catechol derivative 2, which was
easily prepared from BINOL derivative 3 in four steps as shown
in Scheme 1.
a
Table 1. Enantioselective Cyclization of 4 Induced by (S)-2‚SnCl4
The effects of R1 and R2 in (S)-2 were estimated by examining
(S)-2‚SnCl4 as an artificial cyclase of 4 (Table 1). Cyclization from
4 to 5 was carried out by a stepwise method:2c,d enantioselective
cyclization of 4 with (S)-2‚SnCl4 to give 5 and 6 and subsequent
diastereoselective cyclization of 6 with ClSO3H to give 5. The
o-FBn group was most appropriate as R2. Although the cyclization
of 4 proceeded catalytically in CH2Cl2 at -78 °C, the ee value of
5 was lower than that in toluene. In contrast, the stoichiometric
use of (S)-2b‚SnCl4 in toluene gave 5 with 70% ee. When R1 was
a benzylic group substituted with electron-donating groups, the
enantioselectivity tended to increase (entries 4-6). Use of excess
(S)-2e for SnCl4 further increased the enantioselectivity (81 f 84%
ee). When R2 was a bulky group such as a mesityl group, the
enantioselectivity also increased up to 87 ee, but the reactivity was
significantly reduced. 2e was superior to 1 with respect to
enantioselectivity. Interestingly, (R)-1 and (S)-2 gave (+)-5 and
(-)-5 as major enantiomers, respectively.
4 f 5 + 6
conversion
(%)b
(−)-5 ee
1
2
entry
(S)-2 (R , R )
solvent
(%)c
1d
2d
3
4
5
6
7
8
2a (Me, Me)
CH2Cl2
CH2Cl2
toluene
toluene
toluene
toluene
toluene
toluene
>99
99
99
>99
99
>99
55
99
48
57
70
69
2b (Me, o-FBn)
2b (Me, o-FBn)
2c (p-FBn, o-FBn)
2d (Bn, o-FBn)
2e (p-(MeO)Bn, o-FBn)
2f (2,4,6-Me3Ph, o-FBn)
(R)-1
77
81 (84)e
87
76f
a Unless otherwise noted, (S)-2 (1 equiv) and SnCl4 (1 equiv) were used.
b GC analysis. c Ee value of 5 after treatment with ClSO3H is given (HPLC
analysis). d 2 (0.2 equiv) and SnCl4 (0.2 equiv) were used. e 2 (1 equiv)
and SnCl4 (0.5 equiv) were used. f (+)-5 was a major enantiomer.
We developed an efficient route to several polycyclic terpenoids
bearing a chroman skeleton using the enantioselective cyclization
of 7 induced by 2e‚SnCl4 as a key step. (-)-92a,b was synthesized
with 83% dr and 91% ee in 39% overall yield from 7a through the
enantio- and diastereoselective cyclization of 7a, the recrystallization
of (-)-8, and the reductive elimination of (-)-85 (Scheme 2). In
contrast, the use of (S)-1 gave (-)-8 in 25% yield with 55% dr
and 40% ee. Expectedly, tight chelation of 2e with SnCl4 led to
the successful result for the cyclization of 7a.
The antitumor activity of (+)-11 is much higher than those of
puupehedione and related compounds.6 (+)-11 was synthesized with
89% dr and 89% ee in 57% overall yield from 7b through the
enantio- and diastereoselective cyclization of 7b and the benzylic
oxidation, hydrosilylative acetal cleavage,5 and oxidation of (+)-
10. The purity of (+)-10 was increased to 90% dr and 95% ee by
recrystallization (Scheme 3). (+)-137 was also synthesized with 88%
† Nagoya University.
‡ The University of Chicago.
9
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J. AM. CHEM. SOC. 2004, 126, 11122-11123
10.1021/ja0472026 CCC: $27.50 © 2004 American Chemical Society

C O M M U N I C A T I O N S
Scheme 2. Total Synthesis of (-)-Chromazonarol 9a
The observed absolute stereopreference can be understood in
terms of two proposed transition-state assemblies, 17 and 18 (Figure
1). The direction of the H-O bond of (R)-2e might be fixed in the
naphthoxy plane by bidentate chelation of SnCl4. As in our previous
report,3 the stereochemical course in the enantioselective cyclization
would be controlled by a linear OH/π interaction with an initial
protonation step. Judging from the absolute stereochemistry of the
cyclic products, the re-face of the terminal isoprenyl group of
polyprenoids would preferentially approach the activated proton
of LBA perpendicular to its H-O bond. While 17 is favored due
to minimum steric repulsion, 18 is disfavored due to severe steric
repulsion between R and R1.
a Conditions: (a) (S)-2e, SnCl4, toluene, -78 °C, 2 days; CF3CO2H,
SnCl4, i-PrNO2, -78 °C, 1 day. (b) Recrystallization from hexane; B(C6F5)3,
Et3SiH, hexane, rt, 1 day; Bu4NF, THF, 0 °C, 0.5 h.
dr and 90% ee in 59% overall yield from 7c8 through the enantio-
and diastereoselective cyclization of 7c and the hydrosilylative
acetal cleavage of (+)-12 (Scheme 3).
Scheme 3. Total Synthesis of (+)-8-epi-Puupehedione 11 and
(+)-13a
Figure 1. Possible explanation for the absolute stereochemistry.
In conclusion, the present findings provide critical information
for a more extensive application of the present methodology to a
range of complex polycyclic terpenoids.
Acknowledgment. Financial support for this project has been
provided by SORST, JST, the Mitsubishi Foundation, the Uehara
Memorial Foundation, and the Kowa Life Science Foundation. H.I.
also acknowledges a JSPS Fellowship for Japanese Junior Scientists.
Supporting Information Available: Experimental details and
spectroscopic data. This material is available free of charge via the
Internet at http://pubs.acs.org.
a Conditions: (a) (R)-2e, SnCl4, toluene, -78 °C, 2 days; CF3CO2H,
SnCl4, i-PrNO2, -78 °C, 1 day. (b) DDQ, 1,4-dioxane, 60 °C, 3 h. (c)
B(C6F5)3, Et3SiH, hexane, rt, 1 day. (d) DDQ, 1,4-dioxane, H2O, rt, 3 h.
References
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with 48% dr and 90% ee in 22% yield from 7d through enantio-
selective cyclization (eq 1).5 This is the first example of the
enantioselective cyclization of geranylgeranyl derivatives induced
by LBA.
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