Catalytic Asymmetric Iodocarbocyclization Reaction of 4-Alkenylmalonates and Its Application to Enantiotopic Group Selective Reaction

Article abstract of DOI:10.1021/jo970970d

The iodocarbocyclization reaction of 4-alkenylmalonate derivatives proceeded with excellent enantioselectivity (≥95% ee) in the presence of 10-40 mol % of Ti(TADDOLate)₂. The Ti-(TADDOLate)₂-mediated catalytic asymmetric reaction was extended to the enantiotopic group selective reaction of bisalkenylated malonates, giving rise to trisubstituted cyclopentanoid compounds with both high diastereoselectivity (86-94% de) and excellent enantioselectivity (≥95% ee). An efficient synthesis of (+)-boschnialactone from the product of the present reaction was also achieved.

Full text of DOI:10.1021/jo970970d

7384
J . Org. Chem. 1997, 62, 7384-7389
Ca ta lytic Asym m etr ic Iod oca r bocycliza tion Rea ction of
4-Alk en ylm a lon a tes a n d Its Ap p lica tion to En a n tiotop ic Gr ou p
Selective Rea ction
Tadashi Inoue, Osamu Kitagawa, Akio Saito, and Takeo Taguchi*
Tokyo University of Pharmacy and Life Science, 1432-1 Horinouchi, Hachioji, Tokyo 192-03, J apan
Received J une 2, 1997X
The iodocarbocyclization reaction of 4-alkenylmalonate derivatives proceeded with excellent
enantioselectivity (g95% ee) in the presence of 10-40 mol % of Ti(TADDOLate)2. The Ti-
(TADDOLate)2-mediated catalytic asymmetric reaction was extended to the enantiotopic group
selective reaction of bisalkenylated malonates, giving rise to trisubstituted cyclopentanoid
compounds with both high diastereoselectivity (86-94% de) and excellent enantioselectivity (g95%
ee). An efficient synthesis of (+)-boschnialactone from the product of the present reaction was
also achieved.
Sch em e 1
In tr od u ction
The development of catalytic asymmetric reactions is
one of the most challenging tasks in modern synthetic
organic chemistry. In many reactions using a chiral cat-
alyst, a high level of enantioselectivity has been achieved,1
but success has not been reported for halocyclization
reactions. Since a halocyclization reaction usually pro-
ceeds in the presence of an electrophilic halogenating re-
agent without any activating catalyst,2 asymmetric ca-
talysis of these reactions should be difficult to achieve.
In 1992, we reported a titanium alkoxide-mediated
“iodocarbocyclization reaction” of 4-pentenyl- or allylma-
lonate derivatives, which proceeds in a highly regio- and
stereospecific manner to give cyclopentane or cyclopro-
pane derivatives in good yields (Scheme 1).3,4 In this
reaction, the titanium alkoxide acts as a base and en-
hances the nucleophilicity of the malonate moiety through
the formation of titanium enolate.
Sch em e 2
Furthermore, it was also found that the iodocarbocy-
clization reaction of allylmalonate using (-)-8-phenyl-
menthol as a chiral auxiliary proceeds with high diaste-
reoselectivity (94% de, Scheme 2).5 In contrast to the
allylmalonate, the reaction of bis[(-)-8-phenylmenthyl]-
4-pentenylmalonate proceeded without any chiral induc-
tion to give a 1:1 diastereomeric mixture of the cyclo-
pentane derivative (Scheme 2). These results are possibly
explained as follows. In the transition state of cyclopro-
panation, the olefinic moiety would be located close to
the chiral ester, while in the 5-membered ring-forming
reaction, it would be situated close to the Ti atom but
not to the ester (Figure 1).
Therefore, we expected that an efficient enantiofacial
selection of the olefinic group could be achieved through
the formation of chiral titanium enolate by using a chiral
titanium alkoxide. In addition, asymmetric catalysis of
this reaction may be also possible because the present
reaction does not proceed in the absence of titanium
alkoxide.
In this paper, we report the result of catalytic asym-
metric iodocarbocyclization which proceeds with excellent
enantioselectivity (g95% ee) in the presence of a catalytic
amount of Ti(TADDOLate)2.6 The present catalytic reac-
tion can be also applied to enantiotopic group selective
reactions; in these cases, trisubstituted cyclopentane
compounds, which are useful synthetic intermediates of
cyclopentanoid natural products, are obtained with excel-
X Abstract published in Advance ACS Abstracts, September 15, 1997.
(1) (a) Morrison, J . D., Ed. Asymmetric Synthesis, Academic Press:
New York, 1985; Vol. 5. (b) Narasaka, K. Synthesis 1990, 1-11. (c)
Noyori, R. Asymmetric Catalysis in Organic Synthesis, J ohn Wiley:
New York, 1994.
(2) (a) Bougalt, M. J . C. R. Hebd. Seances Acad. Sci. 1904, 139, 864-
870. (b) Bartlett, P. A. Asymmetric Synthesis, Morrison, J . D., Ed.;
Academic Press: Orland, 1984; Vol. 4, Chapter 6, p 411-453. (c)
Gardillo, G.; Orena, M. Tetrahedron 1990, 46, 3321-3408.
(3) (a) Kitagawa, O.; Inoue, T.; Taguchi, T. Tetrahedron Lett. 1992,
33, 2167-2170. (b) Kitagawa, O.; Inoue, T.; Hirano, K.; Taguchi, T.
J . Org. Chem. 1993, 58, 3106-3112. (c) Kitagawa, O.; Inoue, T.;
Taguchi, T. Tetrahedron Lett. 1994, 35, 1059-1062. (d) Inoue, T.;
Kitagawa, O.; Oda, Y.; Taguchi, T. J . Org. Chem. 1996, 61, 8256-
8263. (e) Taguchi, T.; Kitagawa, O.; Inoue, T. J . Synth. Org. Chem.
J pn. 1995, 53, 770-779. (f) Kitagawa, O.; Inoue, T.; Taguchi, T. Rev.
Heteroatom Chem. 1996, 15, 243-262.
(4) Examples of NaH-mediated iodocarbocyclization reaction of
active methine or methylene compounds: (a) Cossy, J .; Thellend, A.
Tetrahedron Lett. 1990, 31, 1427-1428. (b) Beckwith, A. L.; Zozer,
M. J . Tetrahedron Lett. 1992, 33, 4975-4978.
(5) Inoue, T.; Kitagawa, O.; Ochiai, O.; Taguchi, T. Tetrahedron:
Asymmetry 1995, 6, 691-692.
S0022-3263(97)00970-5 CCC: $14.00 © 1997 American Chemical Society

Catalytic Asymmetric Iodocarbocyclization
J . Org. Chem., Vol. 62, No. 21, 1997 7385
Ta ble 1. Ad d itive Effect in Ca ta lytic Asym m etr ic
Iod oca r bocycliza tion
4
yield
ee
entry
additive
(mol %) (%)b
(%)c config
1d
2d
3d
4
5
6
CuO
CuO
CuO
pyridine
2,6-lutidine
Et3N
100
50
25
30
30
30
30
96
85
54
trace
trace
70
85
50
47
R,R
R,R
R,R
98
97
R,R
R,R
7
2,6-dimethoxypyridine
97
a
Iodocarbocyclization: 1a (0.5 mmol), 4 (see table), I2 (2 mmol),
b
additive (1 mmol), CH2Cl2 (5 mL), -78 to 0 °C. Isolated yield.
c The ee was determined by HPLC analysis using a Daicel
F igu r e 1. Transition state model in the reaction of allyl- or
pentenylmalonate.
d
CHIRALPACK AD column. I2 (0.6 mmol), CuO (0.6 mmol).
Sch em e 3
lent enantioselectivity (g95% ee) and high diastereose-
lectivity (86-94% de).
F igu r e 2. Possible mechanism of enantioselective iodocar-
bocyclization.
Resu lts a n d Discu ssion
toluene followed by complete azeotropic removal of pro-
pan-2-ol. In the reaction of 1a using Ti(TADDOLate)2
(4), the removal of propan-2-ol from the reaction mixture
is essential to achieve high enantioselectivity; for ex-
ample, the reaction in the presence of propan-2-ol re-
sulted in a remarkable decrease in enantioselectivity
(13% ee).
Asymmetric catalysis of the present reaction was
further investigated (Table 1). Under conditions similar
to our initial studies, the iodocarbocyclization of malonate
1a using 50 mol % of 4 gave the cyclized product 3a in
good yield (85%) but with lower enantiomeric excess (50%
ee) (entry 2). Further reduction to 25 mol % of 4 under
the same conditions resulted in lowering of both the
enantiomeric excess and the chemical yield (47% ee, 54%,
entry 3). These results may be explained by the following
proposed mechanism (Figure 2).
Ca ta lytic Asym m etr ic Iod oca r bocycliza tion Re-
a ction . The iodocarbocyclization reaction of dibenzyl
4-pentenylmalonate (1a ) with various chiral titanium-
(IV) alkoxides under the conditions [titanium(IV) alkox-
ide (1 equiv), I2 (1.2 equiv), CuO (1.2 equiv), CH2Cl2] pre-
viously reported3 was conducted to examine the enan-
tioselectivity. In the presence of titanium(IV) alkoxide
prepared from Ti(Oi-Pr)4 and L-(+)-diisopropyl tartrate,
binaphthol, or (R,R)-1,2-diphenylethylene glycol, the reac-
tion itself was retarded to give only a trace amount of
the cyclized product 2a or no chiral induction was ob-
served. On the other hand, the iodocarbocyclization
using the 1:1 complex of Ti(IV) and (R,R)-TADDOL7 gave
the cyclized product 3a of 32% ee in good yield (86%,
Scheme 3). Furthermore, the use of 1:2 complex [Ti-
(TADDOLate)2] 48 led to an increase in both enantiose-
lectivity and chemical yield to give the product 3a of 85%
ee in 96% yield (Scheme 3). All the chiral titanium(IV)
alkoxides used in these reactions were prepared in situ
by ligand exchange of Ti(Oi-Pr)4 and chiral diols in
Ti(TADDOLate)2 (4) promotes the deprotonation of
malonate 1 to produce the chiral Ti(IV) enolate 5.
Intramolecular attack of 5 on a double bond activated
by I2 may give a cyclized product 2 in a highly enantio-
selective manner together with the reproduction of
catalyst 4. In the presence of CuO, however, 4 can be
converted by HI or H2O9 to generate other Ti(IV) species
(6) Preliminary communication of this work: (a) Inoue, T.; Kita-
gawa, O.; Kurumizawa, S.; Ochiai, O.; Taguchi, T. Tetrahedron Lett.
1995, 36, 1479-1482. (b) Inoue, T.; Kitagawa, O.; Ochiai, O.; Shiro,
M.; Taguchi, T. Tetrahedron Lett. 1995, 36, 9333-1112.
(7) (a) Narasaka, K.; Inoue, M.; Okada, N. Chem. Lett. 1986, 1109-
1112. (b) Seebach, D.; Beck, A. K.; Imwinkelreid, R.; Roggo, S.;
Wonnacott, A. Helv. Chim. Acta 1987, 70, 954-974. (c) Narasaka, K.;
Iwasawa, N. Organic Synthesis Theory and Applications; Hudlicky,
T., Ed.; J AI Press Inc.: London, 1993; p 93-112. (d) Dahinden, R.;
Beck, A.; K. Seebach, D. Encyclopedia of Reagents for Organic
Synthesis; Paquette, L. A., Ed.; Wiley: Chichester, 1994; Vol. 3, pp
2167-2170.
10
such as (TADDOLate)TiX2 or TiX4 (X ) I or X2 ) O),
which results in the decrease in the enantioselectivity
and the chemical yield.
It follows that trapping HI without generation of H2O
would be crucial to achieve the catalytic reaction. Several
attempts were made by using various amine bases as the
(8) (a) Schmidt, B.; Seebach, D. Angew. Chem. Int. Ed. Engl. 1991,
30, 99-100. (b) Seebach, D.; Behrendt, L.; Felix, D. Angew. Chem.
Int. Ed. Engl. 1991, 30, 1008-1009.
(9) 2CuO + 4HI f I2 + 2CuI + 2H2O.
(10) In the presence of TiCl4 having no activity as a base, the
reaction gave only a complex mixture.

7386 J . Org. Chem., Vol. 62, No. 21, 1997
Inoue et al.
Ta ble 2. Tem p er a tu r e Effect in Ca ta lytic Asym m etr ic
Iod oca r bocycliza tion of 1a a
Ta ble 3. Ca ta lytic Asym m etr ic Iod oca r bocycliza tion of
4-P en ten ylm a lon a te Der iva tivesa
entry
temp (°C)
time (h)
yield (%)b
ee (%)c
1
2
3
4
-78 to 0
29
15
0.5
1.5
86
96
72
87
94
77
56
98
-35
rt
-78
(CH2Cl2:THF ) 4:1)
-78
5d
3
98
98
(CH2Cl2:THF ) 4:1)
a
Reaction conditions: 1 (0.5 mmol), 4 (0.1 mmol), I2 (2 mmol),
DMP (1 mmol), CH2Cl2 (5 mL), -78 °C and then, after workup, to
complete lactonization, the reaction mixture of the iodocarbocy-
b
clization was briefly heated at 140 °C. Isolated yield. c See
d
footnote c of Table 1. 10 mol % of 4 was used.
HI trapping agent. The use of pyridine or 2,6-lutidine
was not effective; in these cases, the reaction hardly
proceeded with a catalytic amount of Ti(TADDOLate)2
(4) (Table 1, entries 4 and 5). In contrast, when 2,6-
dimethoxypyridine (DMP) or Et3N11 was employed as an
HI scavenger, the reaction smoothly proceeded in the
presence of 30 mol % of 4 to give the cyclized product 3a
with higher enantiomeric excess than that obtained in
the reaction using a stoichiometric amount of 4 and CuO
(entries 6 and 7). In particular, the efficiency of DMP
as an HI scavenger is noteworthy; that is, the reaction
of 1a with 30 mol % of 4, DMP (2 equiv) and I2 (4 equiv)
gave the product 3a in nearly quantitative yield (97%)
with excellent enantioselectivity (97% ee).
Effects of reaction temperature and solvent in the
catalytic asymmetric iodocarbocyclization of 1a are sum-
marized in Table 2. With 20 mol % of 4, the product 3a
was obtained in slightly lower yield and ee (86%, 94%
ee, Table 2, entry 1), while the reaction with 10 mol % of
4 resulted in considerable decrease in both yield (73%)
and enantioselectivity (74% ee). On decreasing the
catalyst 4, prolonged time and slightly higher tempera-
ture were needed for completion of the reaction. Since
the enantioselectivity of the present reaction was found
to significantly depend on the reaction temperature (77%
ee at -35 °C, 56% ee at rt, entries 2, 3), the decrease in
enantioselectivity in the reaction using less than 20 mol
% of 4 may be due to the requirement of slightly higher
reaction temperature. After a survey of the reaction
conditions, we found that the use of THF as a cosolvent
is beneficial to both the reactivity and enantioselectivity;
that is, the reaction with 20 mol % of 4 in CH2Cl2-THF
(4:1) proceeded in good yield (87%) even at -78 °C to give
3a of 98% ee (entry 4). Although a slightly longer
reaction time was required, the reaction with 10 mol %
of 4 also gave 3a in excellent yield (98%) and ee (98% ee)
by the addition of THF (entry 5).
a
Reaction conditions: 1 (0.5 mmol), 4 (see table 3), I2 (2 mmol),
DMP (1 mmol), CH2Cl2 (4 mL), THF (1 mL), -78 °C and then,
after workup to complete lactonization, the reaction mixture of
b
the iodocarbocyclization was briefly heated at 140 °C. Isolated
yield. c The ee was determined by HPLC analysis using a CHIRAL-
d
PACK AD, AS, or OD column. The reaction was performed at
-95 °C in CH2Cl2.
(-35 °C), which leads to a decrease in enantioselectivity
(70% ee).12 In the case of a reactive vinyl ether derivative
1d , the reaction proceeded at lower temperature (-95 °C)
even in CH2Cl2 without the addition of THF to give an
optically active tetrahydrofuran derivative 3d with high
enantioselectivity (96% ee, entry 3), while the reaction
of 1d at -78 °C resulted in considerable decrease in
enantioselectivity (78% ee). In the reaction of (Z)-4-
hexenylmalonate derivative 1e, although 40 mol % of 4
was required to achieve high diastereo- and enantiose-
lectivity, the optically active form of the cyclopentanoid
3e having three consecutive chiral centers was obtained
in a highly stereospecific and enantioselective manner
(99% de, 97% ee, entry 4). In the cases of 1a -d , (iodo-
alkyl)cyclopentane derivatives 2a -d formed by iodocar-
bocyclization were heated at 140 °C to convert them to
stable lactone derivatives 3a -d .13
The absolute configurations of 3a and 3b were deter-
mined on the basis of the optical rotation value after
conversion to the known lactone 6a ,14 while those of 3c,
3d , and 3e were assigned on the basis of comparison of
the CD spectra with 3a (Scheme 4).
The absolute configurations of the cyclized products
3a -e clearly indicate that the reactions of 1a -c proceed
in the same enantiofacial selective manner; that is, in
all cases with Ti(TADDOLate)2 (4) prepared from (R,R)-
TADDOL, the enolate and I2 attack in a trans-addition
manner from the Re and Si faces of the olefin, respec-
tively (Figure 3).
The catalytic asymmetric iodocarbocyclization of vari-
ous malonates 1b -e was further examined under the
improved conditions (Table 3). The ester moiety of
pentenylmalonate showed no effect on the ee of the
product; that is, similar to dibenzyl ester 1a , the reaction
of dimethyl ester 1b also gave 3b with excellent enan-
tiomeric excess (99% ee, entry 1). The reaction of 1c
possessing a dimethyl group at the allylic position also
gave the product 3c with excellent enantioselectivity
(98% ee) in CH2Cl2-THF. On the other hand, the
reaction of 1c in CH2Cl2 required higher temperature
(12) In the present reaction, the use of THF as a solvent resulted
in the decrease in both enantioselectivity and yield (85% ee, 34%).
(13) In the reaction of 1e, complete lactonization to 3e from 2e was
observed even at -78 °C.
(14) J akovac, I. J .; Goodbrand, H. B.; Lok, K. P.; J ones, J . B. J . Am.
Chem. Soc. 1982, 104, 4659-4665.
(11) As shown in Table 1, the use of Et3N gave the product in lower
yield (70%) than that of DMP (97%). This result may be due to the
decrease in the basicity of amine and the electrophilicity of iodine on
the basis of the formation of a strong charge transfer complex between
iodine and Et3N.

Catalytic Asymmetric Iodocarbocyclization
J . Org. Chem., Vol. 62, No. 21, 1997 7387
Sch em e 5
Sch em e 6
F igu r e 3. Transition state model in iodocarbocyclization with
(R,R)-TADDOL ligand.
Sch em e 4
En a n tiotop ic Gr ou p Selective Iod oca r bocycliza -
tion Usin g Ti(TADDOLa te)2 Ca ta lyst (4). Catalytic
asymmetric syntheses of cyclopentane derivatives have
attracted much attention in the field of natural product
synthesis because of the large number of cyclopentanoid
natural products and their interesting biological activ-
ity.15 In the above enantiofacial selective reaction, cy-
clopentanoid compounds having two chiral centers on the
ring were obtained with excellent enantioselectivity
(g95% ee). For the synthesis of cyclopentanoid natural
products utilizing the present reaction, however, the
construction of more highly substituted cyclopentane
skeletons is required. For this purpose, we attempted
the application of the present catalytic asymmetric
reaction to enantiotopic group selective reaction; that is,
the enantiotopic group selective iodocarbocyclization of
malonate derivatives with two prochiral olefinic groups
should provide the optically active forms of the cyclopen-
tane derivatives having three chiral centers.16
Sch em e 7
As substrates for the enantiotopic group selective
reaction, three malonate derivatives, 1f, 1g, or 1h , with
enantiotopic vinyl, allyl, or homoallyl groups were chosen.
The reaction of bis-vinyl derivative 1f proceeded with
high diastereoselectivity (cis/trans ) 13) and excellent
enantioselectivity under the above conditions [4 (0.2
equiv), DMP (2 equiv), I2 (4 equiv), CH2Cl2:THF (4:1)] to
give cis-3f17 of 99% ee as the major product (Scheme 5).
Similar to 1a -c and 1e, the use of THF as the cosolvent
was essential for achievement of excellent enantioselec-
tivity, since the reaction of 1f in CH2Cl2 required higher
temperature to give cis-3f of lower ee (68% ee). It should
be also noted that the use of Ti(TADDOLate)2 (4) led to
an increase in diastereoselectivity; for example, the
reaction in the presence of Ti(Ot-Bu)4 instead of 4 gave
3f in a ratio of cis/trans ) 2.5.
The reaction of bis-allyl derivative 1g also proceeded
with excellent diastereo- and enantioselectivity to give
cis-3g17 (cis/trans ) 30) of 95% ee as the major product
(Scheme 6). Again, the increase of diastereoselectivity
by the use of 4 compared to Ti(Ot-Bu)4 was observed in
this reaction.
In contrast, opposite diastereoselectivity was observed
in the reaction of bis-homoallyl derivative 1h to afford
trans-3h 17 (cis/trans ) 1/13) as the major stereoisomer
with excellent enantioselectivity (96% ee, Scheme 6). The
good yield of 3h required the use of 30 mol % of 4, as 20
mol % of 4 provided 3h in lower yield (44%) and slightly
lower enantioselectivity (90% ee).
In order to apply the present approach to natural
product synthesis and to aid the determination of the
absolute configurations of 3f-h , the synthesis of boschnia-
lactone from 3f was examined (Scheme 7). (-)-Boschnia-
lactone,18,19 isolated from Boschniakia rossica hult, pos-
sesses interesting biological properties such as cat-
attracting and insecticidal activities. The cyclized product
(15) Examples of the catalytic asymmetric synthesis of cyclopen-
tanoid compounds: (a) Sato, Y.; Honda, T.; Shibasaki, M. Tetrahedron
Lett. 1992, 33, 2593-2596. (b) Wu, X. M.; Funakoshi, K.; Sakai, K.
Tetrahedron Lett. 1993, 34, 5927-5930. (c) Sato, Y.; Mori, M.;
Shibasaki, M. Tetrahedron: Asymmetry 1995, 6, 757-766. (d) Ohs-
hima, T.; Kagechika, K.; Adachi, M.; Sodeoka, M.; Shibasaki, M. J .
Am. Chem. Soc. 1996, 118, 7108-7116.
(16) (a) Ward, R. S. Chem. Soc. Rev. 1990, 19, 1. (b) Mikami, K.;
Narisawa, S.; Shimizu, M.; Terada, M. J . Am. Chem. Soc. 1992, 114,
6566-6568.
(17) The relative configurations of cis-3f, cis-3g, and trans-3h were
determined on the basis of NOE experiments.

7388 J . Org. Chem., Vol. 62, No. 21, 1997
Inoue et al.
F igu r e 5. Transition state model in the reaction of 1g.
F igu r e 4. Transition state model in the reaction of 1f.
cis-3f having three consecutive cis-substituents on the
ring was viewed as a useful synthetic intermediate for
boschnialactone.
F igu r e 6. Transition state model in the reaction of 1h .
The LiAlH4 reduction of the lactone 6f obtained by
demethoxycarbonylation of cis-3f, followed by the ben-
zylation of the hydroxyl groups gave bis-benzyl ether 7
in good yield (96% from cis-3f). Compound 7 was
converted to bicyclic lactone 8 in a yield of 75% through
hydroboration, J ones oxidation, and hydrogenolysis of
benzyl ether. Tosylation of the hydroxyl group of 8 and
subsequent treatment with Zn-NaI led to boschnialac-
tone in 46% overall yield from cis-3f. Boschnialactone
derived from cis-3f was confirmed to be the antipode of
the natural form on the basis of the comparison of [R]D
value with that reported in the literature18 {[R]D +20.3
(c 1.84, CHCl3), lit.18 [R]D -18.2 (c 2.07, CHCl3)}. Thus,
the stereochemistry of cis-3f which was obtained by the
use of Ti(TADDOLate)2 (4) from (R,R)-TADDOL was
determined as 3S,6S,7R. The absolute configurations of
cis-3g and trans-3h were assigned on the basis of
comparison of the CD spectra with that of 3a .
As mentioned in the enantiofacial selective reaction,
the chiral titanium enolate from (R,R)-4 preferentially
attacks from the Re face of the olefinic group. The
enantiotopic group selectivity in the reaction of 1f-h
would possibly be explained by considering this prefer-
ential Re face attack of the chiral titanium enolate. In
the reaction of bis-vinyl derivative 1f, the chair-like
transition state models A* and B*,20 which give the two
diastereoisomers of product 3f, are shown in Figure 4.
B*, with an equatorial vinyl group, is disfavored relative
to A* with an axial one due to destabilization of B* by
overlap between the π-orbital of the double bond acti-
vated by I2 and the lower lying σ*-orbital of the C-vinyl
bond in comparison with that of the C-H bond.3c,d Thus,
the reaction of 1f preferentially proceeds through transi-
tion state A* with an axial vinyl group leading to attack
of the enolate on the Re face of the pro-S vinyl group to
give 3f having the (3S,6S,7R)-configuration as the major
stereoisomer.
Contrary to the case of 1f, in the reactions of 1g and
1h , the transition states with equatorial allyl and ho-
moallyl groups are more favorable than those with axial
ones due to minimization of 1,3-diaxial repulsion (Figures
5 and 6). Thus, the reactions of 1g and 1h may give cis-
3g and trans-3h as major diastereomers, respectively. In
addition, the preferential Re face attack of the enolate
on the olefin directs attack to the pro-S allyl group in 1g
and to the pro-R homoallyl group in 1h . Thus, the
reactions of 1h and 1g give 3g having the (3S,5S,7R)-
configuration and 3h having the (3S,4R,7R)-configuration
through transition states C* (Figure 5) and D* (Figure
6), respectively.
In conclusion, we have succeeded in the development
of a catalytic asymmetric iodocarbocyclization reaction
which proceeds with excellent enantioselectivity (g95%
ee) using a Ti(TADDOLate)2 catalyst. In the application
to enantiotopic group selective reaction, trisubstituted
cyclopentanoid compounds were obtained with high di-
astereoselectivity and excellent enantioselectivity. As
shown in the synthesis of boschnialactone, the present
reaction should be widely applicable to the catalytic
asymmetric synthesis of cyclopentanoid natural products.
Exp er im en ta l Section
Gen er a l. Melting points were determined on a micro
melting point apparatus and are uncorrected. 1H- and 13C-
NMR spectra were recorded on 400 or 300 MHz spectrometer.
1
In H- and 13C-NMR, chemical shifts were expressed in δ (ppm)
downfield from CHCl3 (7.26 ppm) and CDCl3 (77.0 ppm) as an
internal standard, respectively. Medium-pressure liquid chro-
matography (MPLC) was performed on a 30 cm × 4 cm i.d.
prepacked column (silica gel, 50 µm). Mass spectra were
recorded by electron impact.
Gen er a l P r oced u r e for Ca ta lytic Asym m etr ic Iod oca r -
bocycliza tion . Under an argon atmosphere, to a toluene
solution (3 mL) of (R,R)-TADDOL (93 mg, 0.2 mmol) was added
0.61 M toluene solution of Ti(Oi-Pr)4 (0.16 mL, 0.1 mmol) at
room temperature. After the mixture was stirred for 30 min
at this temperature, toluene and 2-propanol were removed
under reduced pressure. To this solid residue was added CH2-
Cl2:THF solution (4 mL:1 mL) of malonate 1a (176 mg, 0.5
mmol) and 2,6-dimethoxypyridine (0.13 mL, 1.0 mmol), and
then the mixture was cooled to -78 °C. After stirring for 30
min at this temperature, I2 (508 mg, 2.0 mmol) was added to
the mixture and the mixture was then stirred for 1.5 h at -78
°C. The mixture was poured into 10% HCl (10 mL) and
(18) Sakan, T.; Murai, Y.; Hayashi, Y.; Honda, Y.; Shono, T.;
Nakajima, M.; Kato, M. Tetrahedron 1967, 23, 4635-4652.
(19) Examples of asymmetric synthesis of boschnialactone; (a) Arai,
Y.; Kawanami, S.; Koizumi, T. Chem. Lett. 1990, 1585-1586. (b) Arai,
Y.; Kawanami, S.; Koizumi, T. J . Chem. Soc., Perkin Trans. 1 1991,
2969-2975. (c) Tanaka, D.; Yoshino, T.; Kouno, I.; Miyashita, M.; Irie,
H. Tetrahedron 1993, 49, 10253-10262. (d) Nangia, A.; Prasuna, G.;
Bheema Rao, P. Tetrahedron Lett. 1994, 35, 3755-3758.
(20) (a) Labelle, M.; Morton, H. E.; Guindon, Y.; Springler, J . P. J .
Am. Chem. Soc. 1988, 110, 4533-4540. (b) Labelle, M.; Guindon, Y.
J . Am. Chem. Soc. 1989, 11, 2204-2210.

Catalytic Asymmetric Iodocarbocyclization
J . Org. Chem., Vol. 62, No. 21, 1997 7389
extracted with Et2O. The ether extracts were washed with
aqueous Na2S2O3 solution, dried over anhydrous MgSO4, and
evaporated to dryness. Purification of the residue by column
chromatography (hexane:Et2O ) 19:1) gave a mixture of 1,1-
bis[(benzyloxy)carbonyl]-2-(iodomethyl)cyclopentane and 2,6-
dimethoxypyridine. The mixture was heated for 10 min at 140
°C and then purified by column chromatography (hexane:
AcOEt ) 6:1) to give lactone 3a (113 mg, 87%, 98% ee). The
ee was determined by HPLC analysis using a Daicel CHIRAL-
PAK AD column [25 cm × 0.46 cm i.d.; solvent, hexane:i-PrOH
gave 6f (132 mg, 96%). 6f: colorless oil; [R]28D +110.9 (c 0.98,
1
CHCl3); IR (neat) 2959, 2878, 1768 cm-1; H-NMR (CDCl3) δ
5.80 (1H, ddd, J ) 6.4, 10.6, 17.1 Hz), 5.15 (1H, td, J ) 1.5,
10.6 Hz), 5.12 (1H, td, J ) 1.6, 17.1 Hz), 4.26 (1H, dd, J ) 8.5,
9.9 Hz), 4.13 (1H, dd, J ) 4.4, 9.9 Hz), 3.01-3.12 (2H, m), 2.75
(1H, m), 2.16 (1H, dd, J ) 7.0, 13.0 Hz), 1.80-2.04 (2H, m),
1.46 (1H, m); 13C-NMR (CDCl3) δ 181.0, 136.3, 117.0, 68.6, 47.5,
44.2, 41.9, 30.2, 29.3; MS m/z 153 (M+ + H+), 124 (M+ - CO).
Anal. Calcd for C9H12O2: C, 71.03; H, 7.95. Found: C, 70.71;
H, 7.79.
) 99:1 v/v; flow rate, 1.0 mL/min; tR ) 35.4 min (minor), tR
)
(1S,2R,3S)-1,2-Bis[(p h en ylm eth oxy)m eth yl]-3-vin yl-cy-
clop en ta n e (7). To a solution of LiAlH4 (98 mg, 2.57 mmol)
in Et2O (5 mL) at 0 °C was added a solution of 6f (391 mg, 2.6
mmol) in Et2O (5 mL). After being stirred for 30 min at this
temperature, 1 N NaOH (5 mL) was added to the mixture and
then the mixture was dried over MgSO4. Insoluble materials
were removed by filtration with a Celite pad, and the filtrate
was evaporated under reduced pressure. To a suspension of
NaH (320 mg, 7.8 mmol) in 1,4-dioxane (3 mL) was added a
solution of the residue in 1,4-dioxane (3 mL) at 0 °C. After
being stirred for 30 min, BnBr (0.8 mL, 17.8 mmol) was added
and then the reaction mixture was refluxed for 1 h. The
mixture was poured into 10% HCl and extracted with ether.
The ether extracts were dried over MgSO4 and evaporated to
dryness. Purification of the residue by column chromatogra-
phy (hexane:AcOEt ) 30:1) gave 7 (853 mg, 98%). 7: colorless
39.7 min (major)].
(3a R,6a R)-Tet r a h yd r o-3-oxo-1H -cyclop en t a [c]fu r a n -
3a (3H)-ca r boxylic Acid P h en ylm eth yl Ester (3a ). 3a :
colorless oil; [R]28D +68.2 (c 1.11, CHCl3); IR (neat) 2966, 2863,
1
1773, 1741 cm-1; H-NMR (CDCl3) δ 7.28-7.42 (5H, m), 5.24
(1H, d, J ) 12.4 Hz), 5.16 (1H, d, J ) 12.4 Hz), 4.52 (1H, dd,
J ) 7.5, 9.2 Hz), 4.06 (1H, dd, J ) 2.4, 9.2 Hz), 3.06 (1H, m),
2.40 (1H, ddd, J ) 7.0, 9.0, 13.4 Hz), 2.29 (1H, m), 2.05 (1H,
m), 1.82 (1H, m), 1.56-1.71 (2H, m); 13C-NMR (CDCl3) δ 176.2,
169.6, 135.1, 128.6, 128.3, 127.8, 72.9, 67.4, 61.6, 45.6, 34.8,
34.0, 25.8; MS m/z 260 (M+), 232, 184. Anal. Calcd for
C15H16O4: C, 69.21; H, 6.20. Found: C, 69.31; H, 6.21.
(3a S,6a R)-Tet r a h yd r o-4-oxo-fu r o[3,4-b]fu r a n -3a (4H )-
ca r boxylic Acid Meth yl Ester (3d ). According to the
general procedure, Ti(TADDOLate)2 was prepared from Ti-
(Oi-Pr)4 (0.15 mmol) and (R,R)-TADDOL (140 mg, 0.3 mmol).
To the solid residue of Ti(TADDOLate)2 was added a CH2Cl2
solution (5 mL) of malonate 1d 21 (101 mg, 0.5 mmol) and 2,6-
dimethoxypyridine (0.13 mL, 1.0 mmol), and then the mixture
was cooled to -95 °C. After stirring for 30 min at this
temperature, I2 (508 mg, 2 mmol) was added to the mixture
and then the mixture was stirred for 3 h at -95 °C. The
mixture was poured into 10% HCl (10 mL) and extracted with
Et2O. The ether extracts were washed with aqueous Na2S2O3
solution, dried over anhydrous MgSO4, and evaporated to
dryness. Purification of the residue by column chromatogra-
phy (hexane:Et2O ) 19:1) gave 3,3-bis(methoxycarbonyl)-2-
(iodomethyl)tetrahydrofuran. This compound was heated for
6 h at 140 °C and then purified by column chromatography
(hexane:AcOEt ) 6:1) to give lactone 3d (56 mg, 60%, 96%
ee). The ee was determined by HPLC analysis using a Daicel
CHIRALPAK AS column [25 × 0.46 cm i.d.; solvent, hexane:
i-PrOH ) 95:5 v/v; flow rate, 1.0 mL/min; tR ) 15.6 min
(major), tR ) 20.1 min (minor)]. 3d : colorless oil; [R]24D + 87.8
oil; [R]28 +22.5 (c 1.03, CHCl3); IR (neat) 3030, 2862 cm-1
;
D
1H-NMR (CDCl3) δ 7.21-7.40 (10H, m), 5.86 (1H, ddd, J )
8.2, 10.2, 17.2 Hz), 4.92-5.06 (2H, m), 4.45 (2H, s), 4.38 (2H,
s), 3.56 (1H, dd, J ) 7.2, 9.1 Hz), 3.39-3.46 (3H, m), 2.72 (1H,
quint, J ) 7.7 Hz), 2.44 (1H, td, J ) 7.4, 15.2 Hz), 2.30 (1H,
ddd, J ) 5.3, 7.1, 12.4 Hz), 1.50-1.91 (4H, m); 13C-NMR
(CDCl3) δ 140.4, 138.7, 128.3, 128.2, 127.7, 127.5, 127.4, 127.3,
114.3, 73.1, 73.0, 71.9, 68.4, 46.9, 45.3, 42.2, 29.5, 27.8; MS
m/z 337 (M+ + H+), 245 (M+ - Bn). Anal. Calcd for
C23H28O2: C, 82.10; H, 8.39. Found: C, 82.09; H, 8.30.
Hyd r oxybosch n ia la cton e (8). To a solution of 7 (168 mg,
0.5 mmol) in THF (1 mL) at 0 °C was added BH3‚THF (0.5 M
THF solution, 2 mL, 1 mmol) under an argon atmosphere.
After being stirred for overnight at this temperature, J ones
reagent (5 mL) was added and then the reaction mixture was
stirred for 1 h. The mixture was poured into 10% HCl and
extracted with AcOEt. The AcOEt extracts were dried over
MgSO4 and evaporated to dryness. MeOH (1 mL) and 10%
Pd-C was added to the residue and then the reaction mixture
was stirred under a H2 atmosphere for 2 h. Pd-C was
removed by filtration and the filtrate was evaporated under
reduced pressure. A solution of the residue in Et2O (10 mL)
was stirred with MgSO4 for 12 h. After removal of MgSO4 by
filtration and evaporation of Et2O, purification of the residue
by column chromatography (hexane:AcOEt ) 1:1) gave 8 (64
(c 0.51, CHCl3); IR (neat) 2961, 2878, 1780, 1747 cm-1 1H-
;
NMR (CDCl3) δ 4.71 (1H, d, J ) 4.3 Hz), 4.53 (1H, dd, J )
4.3, 10.7 Hz), 4.41 (1H, d, J ) 10.7 Hz), 3.91-4.05 (2H, m),
3.81 (3H, s), 2.75 (1H, td, J ) 7.7, 13.0 Hz), 2.50 (1H, ddd, J
) 6.2, 6.6, 12.7 Hz); 13C-NMR (CDCl3) δ 175.0, 168.1, 83.4,
73.5, 69.6, 62.5, 54.1, 34.7; MS m/z 187 (M+ + H), 156 (M+
-
mg, 75%). 8: white solid; mp 34 °C; [R]28 -13.3 (c 1.10,
OMe), 143. Anal. Calcd for C8H10O5: C, 51.61; H, 5.41.
Found: C, 51.78; H, 5.45.
D
CHCl3); IR (neat) 3424, 2942, 2873, 1741 cm-1
;
1H-NMR
(3aS,6aR)-Tetr ah ydr o-1H-cyclopen ta[c]fu r an -3-on e (6a).
A solution of 3a (130 mg, 0.5 mmol) in 1 N NaOH (10 mL)
was stirred for 12 h at room temperature. The mixture was
poured into 10% HCl and extracted with AcOEt. The AcOEt
extracts were dried over MgSO4 and evaporated to dryness.
The residue was dissolved in xylene (15 mL) and refluxed for
12 h. After evaporation of xylene, purification of the residue
(CDCl3) δ 4.33 (1H, dd, J ) 5.2, 11.6 Hz), 4.26 (1H, J ) 7.6,
11.6 Hz), 3.64-3.80 (2H, m), 2.56-2.71 (3H, m), 2.23-2.38
(2H, m), 1.94 (1H, m), 1.72 (1H, dtd, J ) 2.5, 6.5, 12.1 Hz),
1.35-1.61 (3H, m); 13C-NMR (CDCl3) δ 173.6, 67.2, 62.8, 45.5,
38.1, 35.0, 34.7, 32.8, 27.9; MS m/z 170 (M+). Anal. Calcd for
C9H14O3: C, 63.51; H, 8.29. Found: C, 63.52; H, 8.47.
(+)-Bosch n ia la cton e. According to the procedure in the
literature,19b (+)-boschnialactone was prepared from 8 (48
mg, 0.3 mmol). Purification by column chromatography (hexa-
by column chromatography (hexane:AcOEt ) 5) gave 6a (60
1
mg, 95%). 6a : colorless oil; [R]28 +88.9 (c 1.20, CHCl3); H
D
and 13C-NMR data of 6a coincided with those reported in the
ne:AcOEt
) 2:1) gave boschnialactone (30 mg, 65%).
literature.14
(+)-Boschnialactone: [R]28D +20.3 (c 1.84, CHCl3). [lit.18 [R]28
D
-18.2 (c 2.07, CHCl3).] 1H and 13C-NMR data of boschnialac-
(3aS,6S,6aR)-Hexah ydr o-6-vin yl-1H-cyclopen ta[c]fu r an -
3-on e (6f). A solution of cis-3f (191 mg, 0.9 mmol) in 1 N
NaOH (10 mL) was stirred for 12 h at room temperature. The
mixture was poured into 10% HCl and extracted with AcOEt.
The AcOEt extracts were dried over MgSO4 and evaporated
to dryness. The residue was dissolved in xylene (15 mL) and
refluxed for 12 h. After evaporation of xylene, purification of
the residue by column chromatography (hexane:AcOEt ) 5:1)
tone coincided with those reported in the literature.18
Su ppor tin g In for m ation Available: Characterization data
and experimental procedures of 3b, 3c, 3e, cis-3f, trans-3f, cis-
3g, and trans-3h (4 pages). This material is contained in
libraries on microfiche, immediately follows this article in the
microfilm version of the journal, and can be ordered from the
ACS; see any current masthead page for ordering information.
(21) Sato, T.; Ito, D.; Kuki, M.; Tanaka, H.; Ota, T. Macromolecules
1991, 24, 2963-2967.
J O970970D