Asymmetric synthesis of (R)-limonene and (S)-cembrene-A by an intramolecular cyclization reaction using a chiral leaving group

Article abstract of DOI:10.1055/s-2001-15151

A six-membered monocyclic terpene, (R)-limonene, and a 14-membered monocyclic diterpene, (S)-cembrene-A, have been synthesized, respectively, by new enantioselective intramolecular cyclization reactions of neryl ether and (all-E)-geranylgeranyl ether using an (R)- 1,1′-binaphthyl-2-benzoxy-2′-oxy auxiliary as a chiral leaving group in the presence of tin(IV) chloride.

Full text of DOI:10.1055/s-2001-15151

LETTER
1113
Asymmetric Synthesis of (R)-Limonene and (S)-Cembrene-A by an
Intramolecular Cyclization Reaction Using a Chiral Leaving Group
Kazuaki Ishihara, Hiroko Nakamura, Hisashi Yamamoto*
Graduate School of Engineering, Nagoya University, CREST, Japan Science of Technology (JST), Furo-cho, Chikusa, Nagoya 464-8603,
Japan
Fax +81-52-789-3222; E-mail: yamamoto@cc.nagoya-u.ac.jp
Received 19 April 2001
Abstract: A six-membered monocyclic terpene, (R)-limonene, and
a 14-membered monocyclic diterpene, (S)-cembrene-A, have been
synthesized, respectively, by new enantioselective intramolecular
cyclization reactions of neryl ether and (all-E)-geranylgeranyl ether
using an (R)-1,1’-binaphthyl-2-benzoxy-2’-oxy auxiliary as a chiral
leaving group in the presence of tin(IV) chloride.
MXn
δ–
MXn
δ+
O
L*
O
L*
L*: chiral leaving group; MXn: Lewis acid
Key words: limonene, cembrene-A, chiral leaving group, intramo-
lecular cyclization, asymmetric synthesis
δ–
MXn
δ+
H O
L*
*
+
The structural diversity found in terpene metabolism is
mostly due to olefinic cyclization of five basic acyclic
precursors, isoprene units. The biological strategy for the
Scheme 1 Asymmetric induction for intramolecular cyclization
using a chiral leaving group.
1
construction of new C C bonds involves intramolecular
electrophilic alkylation of remote double bonds to a cat-
ionic center generated by the ionization of allylic pyro-
a new entry to Lewis acid-assisted chiral electrophiles, we
envisaged that a high level of asymmetric induction from
an allylic ether of (R)-BINOL to a prochiral nucleophile
could be achieved by bidentate coordination of tin(IV)
chloride with its (R)-BINOL moiety.
2
phosphates, in which the enzyme may require a divalent
3
cation, Mg(II) or Mn(II), for catalytic activity. Assuming
that the cyclization of neryl pyrophosphate to limonene
(
2) is initiated by bidentate coordination of the pyrophos-
phate moiety to a metal, we have been intrigued for sever-
al years in simulating such a cyclization with asymmetric
induction in organic chemistry. This assumption regard-
ing the biosynthesis of 2 is also expected to be a suitable
model for the biosynthesis of related cyclic terpenes. In
Eδ+
O
+
E : electrophile
δ–
SnCl4
(H+, Me SiCH CH OCH +,
3
2
2
2
1
2
+
1
983, Yamamoto and co-workers reported the first biomi-
metic asymmetric synthesis of (R)-(+)-2 (up to 77% ee,
4% yield) from (R)-binaphthol(BINOL) mononeryl
ether (1a) using a bulky aluminum reagent, (2,4,6-tri-tert-
butylphenoxy)isobutylaluminum
sulfonate (3 equiv) in fluorotrichloromethane (CCl F) at
R R C=CHCH2 , etc)
OR
5
Lewis acid-assisted chiral electrophiles
trifluoromethane- Figure 1 Examples of Lewis acid-assisted chiral electrophiles.
3
4
1
30 °C. This is a successful example of diastereodiffer-
Initially, we examined various protecting groups, R, of
R)-BINOL mononeryl ether derivatives 1 to effect the in-
tramolecular cyclization of 1 in the presence of one equiv-
alent of tin(IV) chloride in toluene (entries 1 5, Table).
R)-BINOL mononeryl ether 1a (R = H) was easily pre-
pared in good yield from (R)-BINOL and nerol by Mit-
sunobu reaction, while its derivatives, 1b (R = Me), 1c
R = i-Pr), 1d (R = Ts) and 1e (Bz), were prepared by Mit-
sunobu reaction or esterification of 1a. In most cases, the
cyclization reaction of 1 was completed at 78 °C within
half a day. The reactions of 1a and 1d gave (S)-( )-li-
monene (2) and its isomers with only moderate asymmet-
ric induction (18% ee and 25% ee, respectively). On the
other hand, the reactions of 1b and 1c gave (S)-2 with 52%
ee and 45% ee, respectively. Surprisingly, the optical
entiating asymmetric induction with an addition elimina-
tion reaction using a chiral auxiliary as a leaving group,
and provides a direct and efficient route to an enantiomer
(
5
,6
(
(
Scheme 1). Unfortunately, however, the cyclization of
3
(
R)-1a using commercially available DIBAH (1.2 equiv)
in dichloromethane at 78 ~ 0 °C has given (R)-2 with
8
4
only 12% ee. We describe here a more effective and new
(
diastereodifferentiating intramolecular cyclization using a
chiral leaving group for the asymmetric synthesis of 6-
and 14-membered monocyclic terpenes, 2 and cembrene-
A (8).
Recently, we developed (R)-BINOL derivatives tin(IV)
7
chloride as chiral protonation reagents and trimethylsi-
lylethoxymethyl (SEM) ether of (R)-BINOL tin(IV)
6
chloride as a chiral SEM-addition reagent (Figure 1). As
Synlett 2001, No. 7, 1113–1116 ISSN 0936-5214 © Thieme Stuttgart · New York

1
114
K. Ishihara et al.
LETTER
Table Intramolecular cyclization of 1 promoted by Lewis acida
MLn (1 equiv)
+
*
*
6~10 h
O
Cl
OR
2
3
1
c
d
Temp. (°C),
Time (h)
2
Ratio [Yield(%) ]
Entry
1 (R)
Solvent
MLn
Conc.
Ee (%)b
2:3
1
2
3
4
5
6
7
8
9
1a (H)
1b (Me)
1c (i-Pr)
1d (Ts)
1e (Bz)
1e
toluene
toulene
toluene
toluene
toluene
CH Cl
SnCl4
SnCl4
SnCl4
SnCl4
SnCl4
SnCl4
SnCl4
TiCl4
SnCl4
SnCl4
SnCl4
SnCl4
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.4
0.2
0.1
–78, 12
–78, 12
–78, 7
–78, 12
–78, 6
18 [S]
52 [S]
45 [S]
25 [S]
87 [R]
93 [R]
92 [R]
48 [R]
89 [R]
92 [R]
94 [R]
92 [R]
–
–
–
–
–
e
–97, 4
[40]:[51]
2
2
f
1e
1e
PrCl
–78, 12
–78, 12
–78, 12
–97, 6
–97, 6
–78, 12
[37] :[47]
toluene
toluene
toluene
CH Cl
–
1f (p-CF Bz)
45[24]:55[33]
3
e
1
1
1
0
1
2
1f
1f
1f
–
2
2
[38]:[62]
[40]:[48]
PrCl
a
b
Unless otherwise noted, the reaction proceeded with >99% conversion. The enantiomeric excess was determined by GC analysis [column,
CHIRALDEX B-DM (0.25 mmI.D. 20 m); carrier gas, N (7 kPa)]; column temp., 90 °C; t = 56.3 min for (S)-2, t = 59.7 min for (R)-2).
2
R
R
c
1
The absolute configuration of the major enantiomer is indicated in brackets. The ratio was estimated by GC and H NMR spectral analyses.
Isolated chemical yields are indicated. Some of the starting material 1 remained. -Terpinene was produced in 6% yield.
d
e
f
6
b
yield of 2 was increased to 87% ee by using 1e as a purity (Eq). Therefore, (R)-2 was obtained with 93% ee
substrate. Interestingly, the absolute stereochemistry in 77% overall yield from 1d in two steps (entry 6, Table
observed in the reaction of 1e was opposite to that with
a 1d.
Eq).
1
Next, the effect of the solvent on the reaction of (R)-1e in-
duced by tin(IV) chloride was investigated (entries 5 7).
The reaction proceeded faster in dichloromethane than in
toluene, and also proceeded faster with a higher concen-
tration of 1, without reducing the enantioselectivity. In ad-
dition, p-trifluoromethylbenzoate 1f was slightly more
reactive than 1e. The optical yield of 2 was increased to
2
,4,6-collidine
(
R)-3
(R)-2
+
reflux, 8 h
(
93% ee, 0.26 M)
4
2
+4: 90% yield, 2:4=81:19, 2: 93% ee
9
2 94% ee by performing the reaction at 97 °C in
dichloromethane or toluene (entries 6, 10, and 11), but the
reaction of 1f at 97 °C was not completed in toluene af-
ter 6 h (entry 10). Interestingly, the reaction in 1-chloro-
Equation
propane, even at 78 °C, gave (R)-2 with 92% ee (entry Thus, the fraction of (R)-1e•SnCl which cyclizes to (R)-2
4
7
). Unfortunately, chlorinated compound 3 was obtained must do so from a conformation where the remote double
together with 2 as a single by-product regardless of the re- bond is positioned at the back of C(1). Two limiting ori-
9
action conditions. However, the desired product 2 could entations which accommodate this restriction are shown
be isolated by column chromatography on silica gel [entry in Figure 2. The topologically related linalyl system is
3
0.8
1
2: (R)-2 (purified, 92% ee): [ ]D = 103.5 (c 0.87, pen- known to cyclize preferentially from an anti-endo confor-
1
0
tane)]. Although other Lewis acids were also examined mation, and a similar preference is expected for its allyl-
for the reaction of (R)-1e, tin(IV) chloride was the best ic isomer.11 The high sense of asymmetric induction
promoter. For example, titanium(IV) chloride gave (R)-2 observed here may be envisioned as occurring through
with 48% ee (entry 8).
transition-state assembly 5, where the cyclization of the
neryl cation would arise from a preferential anti-endo
conformation. On the other hand, transition-state assem-
bly 6 (anti-exo conformation) would be disfavored not
The chlorinated compound 3 was transformed to an 81:19
mixture of 2 and 4 in 90% yield by heating in 2,4,6-colli-
dine under reflux conditions without reducing the optical
Synlett 2001, No. 7, 1113–1116 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Asymmetric Synthesis of (R)-Limonene and (S)-Cembrene-A
1115
only due to a topological consideration as in the cycliza- the absolute stereochemistry of 8 was opposite to that of 2
tion of a linalyl cation but also due to steric repulsion be- although the same chiral leaving group derived from (R)-
tween the isoprenyl group and the binaphthyl moiety.
BINOL was used for both reactions. Despite the low opti-
cal yield and low chemical yield of 8, macrocyclization is
a very attractive alternative to a multistep synthesis from
naturally occurring chiral synthons.
H
(R)-2
1
O
Cl
SnCl4
Cl
(1 equiv)
Sn
Cl
Cl
anti-endo conformation
Ar
CH2Cl2
–78 °C, 60 h
O
O
O
8
TS-5 (favored)
OBz
ca. 10% isolated yield
(>95% purity)
32% ee (S)
7
(0.1 M)
H
(S)-2
Scheme 2
1
O
Cl
Cl
The limonene synthesis described above provides a new
body of results that, coupled with certain other consider-
ations, (1) indicate that a six-membered ring is formed
with a high degree of neighboring -bond participation
during C O heterolysis of 1, thus allowing the remote
chiral transfer to proceed efficiently, and (2) suggest that
the overall process may involve conformationally rigid
cationic structures. Further studies on the rational design
of chiral leaving groups are expected to enable the asym-
metric synthesis of cyclic terpenoids with rings of differ-
ent sizes.
Sn
Cl
Cl
Ar
O
anti-exo conformation
O
TS-6 (disfavored)
Figure 2 Proposed transition-state assemblies.
To demonstrate the effectiveness of tin(IV) chloride-in-
duced diastereodifferentiating cyclization, we asymmetri-
cally synthesized a fourteen-membered cyclic diterpene,
cembrene-A (8), by macrocyclization of (all-E)-gera-
nylgeranyl ether 7 derived from monobenzoate of (R)-
BINOL (Scheme 2). A cembranoid 8, which has been iso-
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2
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14
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(
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1
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(
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[
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R
(
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2
6.4
1
3
D
Synlett 2001, No. 7, 1113–1116 ISSN 0936-5214 © Thieme Stuttgart · New York

1
116
K. Ishihara et al.
LETTER
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(
(
(
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Synlett 2001, No. 7, 1113–1116 ISSN 0936-5214 © Thieme Stuttgart · New York