Highly Enantioselective Ring Opening of Cyclic Meso-Anhydrides to Isopropyl Hemiesters with Ti-TADDOLates: An Alternative to Hydrolytic Enzymes?

Article abstract of DOI:10.1021/jo971731t

The Lewis acid mediated transfer of an alkoxide ligand from the chiral ligand sphere of Ti - TADDOLate (1) to cyclic meso anhydrides to afford the corresponding hemiesters is described. By using this method a variety of structurally different anhydrides can be converted to isopropyl hemiesters with high enantioselectivities (enantiomer ratios up to 99:1). We have also investigated Lewis acidic titanium complexes, which differ from 1 in the chiral ligand or the alkoxide ligand that is transferred. Finally, a catalytic version, which allows the substoichiometric use of Ti- TADDOLate in the presence of stoichiometric amounts of Al(O_i-P_r)3, is presented.

Full text of DOI:10.1021/jo971731t

1190
J . Org. Chem. 1998, 63, 1190-1197
High ly En a n tioselective Rin g Op en in g of Cyclic Meso-An h yd r id es
to Isop r op yl Hem iester s w ith Ti-TADDOLa tes: An Alter n a tive to
Hyd r olytic En zym es?
Georg J aeschke and Dieter Seebach*
Laboratorium fu¨r Organische Chemie, Eidgeno¨ssische Technische Hochschule, ETH-Zentrum,
Universita¨tstrasse 16, CH-8092 Zu¨rich, Switzerland
Received September 16, 1997
The Lewis acid mediated transfer of an alkoxide ligand from the chiral ligand sphere of
Ti-TADDOLate (1) to cyclic meso anhydrides to afford the corresponding hemiesters is described.
By using this method a variety of structurally different anhydrides can be converted to isopropyl
hemiesters with high enantioselectivities (enantiomer ratios up to 99:1). We have also investigated
Lewis acidic titanium complexes, which differ from 1 in the chiral ligand or the alkoxide ligand
that is transferred. Finally, a catalytic version, which allows the substoichiometric use of Ti-
TADDOLate in the presence of stoichiometric amounts of Al(Oi-Pr)3, is presented.
Hydrolytic enzymes, such as esterases and peptidases,
the possibility of an alkoxide transfer from the chiral
ligand sphere of 1 to the Lewis acid activated substrate.21
For the preparation of enantiomerically pure carboxylic
acid derivatives by such an alkoxide transfer, two dif-
ferent approaches can be envisaged: on one hand,
“desymmetrization” of a meso compound can be achieved
by differentiating enantiotopic carbonyl groups; on the
other hand, kinetic resolution of racemic compounds can
be carried out. These very same strategies are also used
in reactions that are catalyzed by hydrolytic enzymes.
To make sure that the Ti-TADDOLate mediated alco-
holysis is irreversible, we investigated more reactive
substrates than those usually used in enantioselective
enzymatic reactions. For example, diesters were replaced
by cyclic meso-anhydrides,22 monoesters by dioxol-
anones,23 and hydantoins by azlactones23 (Scheme 1).
We have previously published a preliminary report on
the use of this methodology in the Ti-TADDOLate
mediated ring opening of cyclic meso-anhydrides22 and a
full paper has appeared describing the ring opening of
meso-sulfonylimides24 to the corresponding sulfonylamido
isopropyl esters, with selectivities up to 99:1. Recently,
we also described the Ti-TADDOLate mediated kinetic
resolution of racemic dioxolanones, azlactones, and biaryl
lactones giving highly enantioenriched products.23
In this paper the Ti-TADDOLate mediated enantio-
selective ring opening of cyclic Cs-symmetric anhydrides
is reported in full detail.22 Additionally, we describe a
procedure for carrying out this process, using sub-
stoichiometric amounts of Ti-TADDOLates in the pres-
ence of stoichiometric amounts of Al(Oi-Pr)3.
are exceptionally effective for the enantioselective hy-
drolysis of carboxylic acid derivatives,1 and the amount
of literature published in this area is still growing
rapidly. So far, practical, nonenzymatic versions of these
reactions are rare and often restricted to only a few
examples.2-8 We have therefore initiated a program
directed toward enantioselective ester formation using
as chiral titanium Lewis acids the Ti-TADDOLates 1.
These readily accessible chiral titanates9 have been
successfully used as catalysts in enantioselective addition
reactions of carbon-centered nucleophiles to aldehydes,10-14
in [2 + 2] cycloadditions,15,16 and in Diels-Alder
reactions.17-20 Moreover, the presence of a Lewis acidic
and a nucleophilic moiety within the same molecule offers
* To whom correspondence should be addressed. Tel: +41/1/632
29 90. Fax: +41/1/632 11 44. E-mail: seebach@org.chem.ethz.ch.
(1) Wong, C. H.; Whitesides, G. M. Enzymes in Synthetic Organic
Chemistry; Elsevier Science Ltd: Oxford, 1994; Vol. 12, pp 41-87.
(2) Theisen, P. D.; Heathcock, C. H. J . Org. Chem. 1993, 58, 142-
146.
(3) Rosen, T.; Heathcock, C. H. J . Am. Chem. Soc. 1985, 107, 3731-
3735.
(4) Hirataka, J .; Yamamoto, Y.; Oda, J . J . Chem. Soc., Chem.
Commun. 1985, 1717-1719.
(5) Hirataka, J .; Inagaki, M.; Yamamoto, Y.; Oda, J . J . Chem. Soc.,
Perkin Trans. 1 1987, 1053-1058.
(6) Aitken, R. A.; Gopal, J . Tetrahedron Asymm. 1990, 1, 517-520.
(7) Shimizu, M.; Matsukawa, K.; Fujisawa, T. Bull. Chem. Soc. J pn.
1993, 66, 2128-2130.
(8) Albers, T.; Biagini, C. G.; Hibbs, D. E.; Hursthouse, M. B.; Malik,
K. M. A.; North, M.; Uriarte, E.; Zagotto, G. Synthesis 1996, 393-
398.
(9) Beck, A. K.; Bastani, B.; Plattner, D. A.; Petter, W.; Seebach,
D.; Braunschweiger, H.; Gysi, P.; La Vecchia, L. Chimia 1991, 45, 238-
244.
(10) Seebach, D.; Beck, A. K.; Schmidt, B.; Wang, Y.-M. Tetrahedron
1994, 50, 4363-4384.
(19) Narasaka, K.; Iwasawa, N.; Inoue, M.; Yamada, T.; Nakashima,
M.; Sugimori, J . J . Am. Chem. Soc. 1989, 111, 5340-5345.
(20) Seebach, D.; Beck, A. K.; Imwinkelried, R.; Roggo, S.; Wonna-
cott, A. Helv. Chim. Acta 1987, 70, 954-974.
(11) Weber, B.; Seebach, D. Tetrahedron 1994, 50, 7473-7484.
(12) Schmidt, B.; Seebach, D. Angew. Chem. 1991, 103, 1383-1385;
Angew. Chem., Int. Ed. Engl. 1991, 30, 1321-1323.
(13) Schmidt, B.; Seebach, D. Angew. Chem. 1991, 103, 100-102;
Angew. Chem., Int. Ed. Engl. 1991, 30, 99-101.
(14) Minamikawa, H.; Hayakawa, S.; Yamada, T.; Iwasawa, N.;
Narasaka, K. Bull. Chem. Soc. J pn. 1988, 61, 4379-4383.
(15) Engler, T. A.; Letavic, M. A.; Reddy, J . P. J . Am. Chem. Soc.
1991, 113, 5068-5070.
(21) Narasaka, K.; Kanai, F.; Okudo, M.; Miyoshi, N. Chem. Lett.
1989, 1187-1190.
(22) Preliminary communication on part of the results described
here: Seebach, D.; J aeschke, G.; Wang, Y. M. Angew. Chem. 1995,
107, 2605-2606. Angew. Chem., Int. Ed. Engl. 1995, 34, 2395-2396.
(23) Seebach, D.; J aeschke, G.; Gottwald, K.; Matsuda, K.;
Formisano, R.; Chaplin, D. A.; Breuning, M.; Bringmann, G. Tetrahe-
dron 1997, 53, 7539-7556.
(16) Hayashi, Y.; Narasaka, K. Chem. Lett. 1990, 1295-1298.
(17) Seebach, D.; Dahinden, R.; Marti, R. E.; Beck, A. K.; Plattner,
D. A.; Ku¨hnle, F. N. M. J . Org. Chem. 1995, 60, 1788-1799.
(18) Narasaka, K. Synthesis 1991, 1-11.
(24) Ramon, D. J .; Guillena, G.; Seebach, D. Helv. Chim. Acta 1996,
79, 875-894.
S0022-3263(97)01731-3 CCC: $15.00 © 1998 American Chemical Society
Published on Web 02/03/1998

Enantioselective Ring Opening of Cyclic Meso Anhydrides
J . Org. Chem., Vol. 63, No. 4, 1998 1191
Ta ble 1. Op tim iza tion of th e Rea ction Con d ition s for
th e Ti-TADDOLa te Med ia ted Rin g Op en in g of th e Cyclic
An h yd r id e 2 to th e Hem iester 3a
Sch em e 1
temp
(°C)
time
(d)
yield
(%)
entry
1
solvent
er
1
2
3
4
5
1a
1a
1a
1a
1a
1b
1b
1b
1a
1c
1d
1e
Et2O
CH2Cl2
toluene
pentane
THF
THF
THF
THF
THF
0 f rt
0 f rt
0 f rt
0 f rt
0 f rt
0 f rt
-12
0.66
0.66
0.66
0.66
0.66
0.66
0.5
5
5
3
7
6
91
89
30
62
70
71
40
88
91
25
88
87
44:56
40:60
50:50
60:40
86:14
85:15
93:7
96:4
97:3
69:31
99:1
99:1
6
7
8b
9b
10
11b
12b
-30
-30
THF
THF
THF
-20
-30
-30
a
1.05 equiv of the Ti-TADDOLate were used under standard
conditions. The enantiomer ratios were determined by GC-
analysis of the methylisopropyl ester obtained by reaction of 3 with
b
diazomethane or (CH3)3OBF4. 1.20 equiv of Ti-TADDOLate were
used.
was investigated first: in diethyl ether, methylene
chloride, toluene, or pentane, only low enantioselectivities
were obtained (Table 1, entries 1-4); a dramatic increase
in selectivity was, however, obtained in THF (entry 5),
the solvent which was therefore used in all further
experiments. The effect of temperature was then studied
by using Ti-TADDOLate 1b: reducing the temperature
from room temperature or 0 °C to -30 °C resulted in a
considerable increase in the enantioselectivity (85:15 to
96:4), but was, of course, accompanied by a decrease in
the reaction rate (entries 6, 8). A somewhat higher
temperature (-12 °C instead of -30 °C) led to shorter
reaction times, but also resulted in a significant decrease
in the enantioselectivity (entries 7 and 8). The following
experiments were therefore carried out at -30 °C.
Finally, the reaction was optimized with respect to the
substituents on the TADDOLate, as shown in Scheme 2;
by using the â-naphthyl- or hexaphenyl-substituted
titanium TADDOLates 1d and 1e the hemiester 3 was
obtained, after several days, in almost enantiopure form
(er 99:1) and in high yield (entries 11, 12). With the
original titanium TADDOLate 1a and the C1-symmetrical
Ti-TADDOLate 1b, only slightly lower selectivities were
observed (entries 8 and 9, er 96:4 and 97:3). The reaction
with the R-naphthyl-substituted Ti-TADDOLate 1c,
however, occurred much more slowly, and with poorer
selectivity (entry 10), a feature which has already been
observed in other reactions mediated by 1c.23,26 All
further reactions were carried out under the optimized
conditions by using the â-naphthyl- or hexaphenyl-
substituted Ti-TADDOLates 1d and 1e at low temper-
ature in THF.
Sch em e 2
Resu lts a n d Discu ssion
Rin g-Op en in g Rea ction w ith th e Nor bor n en e-
Der ived An h yd r id e 2. Ti(Oi-Pr)4 is known to catalyze
transesterification and deacylation processes very cleanly
under mild conditions.25 Similarly, the Ti-TADDOLate
mediated ring opening reaction of cyclic anhydrides
afforded the corresponding hemiesters without formation
of any side products (Scheme 2).
To optimize the reaction conditions, the commercially
available endo-Diels-Alder adduct 2 of maleic anhydride
and cyclopentadiene was studied as a model compound.
Isolation of the ring-opened product 3 is quite simple:
the hemiester is separated from the TADDOL-ligand by
extraction into an alkaline aqueous solution. The chiral
ligand was recovered in quantitative yield from the
organic phase. The influence of solvent on the selectivity
In vestiga tion of Oth er Cyclic An h yd r id es. With
this result in hand (Table 1, entries 11 and 12), we next
evaluated the scope of the reaction. For this purpose,
we investigated the opening of tricyclic (4-8), bicyclic (9-
13), and monocyclic (14-16) anhydrides.
Due to their strained structures, the tricyclic anhy-
drides 4-8 reacted at the same temperature (-30 °C) as
the model compound 2: even if they contained additional
heteroatoms (see 7 and 8), the anhydride substrates were
ring opened by the Ti-TADDOLates 1d or 1e in good
(25) Seebach, D.; Weidmann, B.; Widler, L. In Modern Synthetic
Methods; R. Scheffold, Ed.; Sauerla¨nder: Aarau, 1983; Vol. 3; pp 217-
353.
(26) Seebach, D.; Plattner, D. A.; Beck, A. K.; Wang, Y. M.; Hunziker,
D.; Petter, W. Helv. Chim. Acta 1992, 75, 2171-2209.

1192 J . Org. Chem., Vol. 63, No. 4, 1998
J aeschke and Seebach
Ta ble 2. Rea ction Con d ition s, Yield s, a n d
En a n tioselectivities of th e Isop r op yl Hem iester s
Obta in ed fr om th e An h yd r id es 2 a n d 4-16 w ith
Ti-TADDOLa tesa
time
(d)
temp
(°C)
yield
(%)
entry
anhydride
er
1
2
2
4
5
6
7
7
6
5
5
6
6
5
5
5
5
9
5
5
9/4
-30
-30
-30
-30
-30
-30
-15
-15
-15
-15
-20
-18
-15
-20/0
88
91
91
92
63
82
59
76
74
87
80
73
64
99
99:1
99:1
99:1
3b
4
97:3
5
6
7
8
99:1c
98:2c
98:2
8
9
10
11
12
13
14
15
16
97:3
9
94:6c
>95:5
63:37c
98:2
10
11
12
13
14
75:25
50:50c
a
Standard conditions: 1.20 equiv of Ti-TADDOLate 1d were
used. The enantiomer ratios were determined by GC-analysis of
the methylisopropyl ester obtained from the hemiesters and
b
diazomethane or (CH3)3OBF4. The Ti-TADDOLate 1e was used.
c The enantiomer ratios were determined by GC or HPLC analysis
of the corresponding lactones, which were obtained from the
hemiesters by reduction with LiBEt3H and lactonization (see
Experimental Section).
F igu r e 1.
(containing the substituents more or less in the plane of
the anhydride CO-O-CO moiety!).
Th e Absolu te Con figu r a tion of th e P r od u cts. The
absolute configurations of the hemiesters 3, 18, 20, and
22 were determined by selective reduction of the ester
group (with LiBEt3H) and lactonization (in one case (19),
the C-C double bond was also hydrogenated) to give the
known lactones 17,27,28 21,29 and 23 (Scheme 3).30 The
senses of optical rotation for these lactones were then
compared with those reported in the literature. The
hemiester 24 was converted (SOCl2, (S)-phenylethy-
lamine) to the crystalline amide 25. The relative con-
figuration of 25, and thus the absolute configuration of
24, was determined by X-ray analysis.
yields and with enantioselectivities up to 99:1 (Table 2,
entries 2-6). The bicyclic anhydrides 9-13 are less
reactive than the tricyclic compounds, and the reactions
were carried out at temperatures ranging from -15 to
-20 °C. The anhydrides with a carbocyclic backbone
(three- to six-membered rings, 9-12) were transformed
to the corresponding hemiesters in a highly enantiose-
lective fashion (er from 94:6 to 98:2). Only the opening
of anhydride 13, which contains a carbamate group,
proceeded with low selectivity (entry 11, er 63:37). Of
the three monocyclic anhydrides investigated, only 14
was ring opened with high enantioselectivity (entry 12,
er 98:2), while with the glutaric acid derivatives 15 and
16, poor selectivities were observed (entries 13 and 14).
In our investigation of different anhydrides, we tried
to identify the structural features which were a prereq-
uisite for the occurrence of highly enantioselective ring
opening. As a working hypothesis, we can now propose
the following two rules:
In all cases, the stereochemical outcome of the reaction
is uniform: by using the projection shown in Figure 1,
the isopropoxy ligand is transferred to the marked
carbonyl group. For the anhydrides containing a car-
bocyclic backbone, this is the Re-carbonyl group; due to
reversal of the CIP-priorities it is the Si-carbonyl group
of the furan-derived anhydrides 7 and 8.
Use of Differ en t Tita n iu m Lew is Acid s. In the
many different applications of Ti-TADDOLates as chiral
Lewis acids, the diisopropoxy derivatives 1 have been
(i) An additional heteroatom within the anhydride can,
but not necessarily will, lead to a decrease in selectivity
(Table 2, entries 5, 6, and 11).
(ii) The nucleophilic attack must occur from one side
of the plane containing the three oxygen atoms of the
anhydride group, while the other side must be sterically
shielded by substituents.
The last rule is fulfilled for all tricyclic and bicyclic
anhydrides as well as for the monocyclic anhydride 14,
but not for the glutaric acid derivatives 15 and 16
(27) Storme, P.; Quaeghebeur, L.; Vandewalle, M. Bull. Soc. Chim.
Belg. 1984, 93, 999-1003.
(28) Harada, T.; Wada, I.; Oku, A. J . Org. Chem. 1989, 54, 2599-
2605.
(29) Bloch, R.; Guibe-J ampel, E.; Girad, C. Tetrahedron Lett. 1985,
26, 4087-4090.
(30) J akovac, I. J .; Goodbrand, H. B.; Lok, K. B.; J ones, J . B. J . Am.
Chem. Soc. 1982, 104, 4659-4665.

Enantioselective Ring Opening of Cyclic Meso Anhydrides
J . Org. Chem., Vol. 63, No. 4, 1998 1193
Sch em e 3a
Ta ble 3. In vestiga tion of Differ en t Ch ir a l Ti-Lew is
Acid s for th e An h yd r id e Rin g Op en in g of 2a
Ti-Lewis
time
(d)
temp
(°C)
yield
(%)
entry
acid
er
1b
2
28
1d
29
30
31
7
7
10
6
-30
-30
25
-22
-22
91
88
5
95
20
85:15
99:1
59:41
45:55
7:93
3b
4
5
6
a
Standard conditions: 1.20 equiv of Ti-Lewis acid were used.
b
The enantiomer ratios were determined by GC-analysis of the
lactone 17, which was obtained from 26 or 27 by reduction with
LiBEt3H and lactonization.
For a comparison, we investigated these complexes in the
ring opening of anhydride 2. The Ti-CYDISate mediated
reaction led to good conversion, but the hemiester 3 was
obtained in almost racemic form (entry 4). Ti-BINOL-
ate, on the other hand, reacted much slower than Ti-
TADDOLate. Even after 6 days the reaction was still
incomplete, and the hemiester 3 was isolated in low yield,
but with good enantioselectivity (entry 5, er 93:7).
Interestingly, an opposite sense of asymmetric induction
was observed when going from (R,R)-Ti-TADDOLate to
(M)-BINOLate, giving 3 and ent-3, respectively. This is
another demonstration of the fact that the topicities of
reactions mediated by (R,R)-TADDOLates and (P)-
BINOLates are often the same. This observation has
been previously rationalized and discussed in detail by
us.17
a
Reagents and conditions: (a) (1) LiBEt3H; (2) H+, H2O; (b) (1)
SOCl2, (2) (S)-phenylethylamine, (c) Pd/C, H2.
employed most frequently.31 With some titanium Lewis
acids (e.g. 30), replacement of the isopropoxy ligand by
a tert-butoxy ligand results in a dramatic increase in
selectivity for certain Lewis acid-catalyzed reactions.32
In the case of the enantioselective ring opening of cyclic
anhydrides, investigation of different alkoxide ligands
was of particular interest for the possible preparation of
other synthetically useful esters. For this reason, we
studied the Ti-TADDOLates 28 and 29 in this reaction
(eq 1).
Su bstoich iom etr ic Use of 1. Since a dramatic effect
of ligand acceleration34 has been observed in the Ti-
TADDOLate catalyzed addition of dialkylzinc or alkyl
titanium compounds to aldehydes,10,12,13,35 we wondered
if such an effect would also be present in the ring opening
of anhydrides mediated by 1. We therefore carried out
a ring opening of 2 using a substoichiometric amount of
Ti-TADDOLate 1d in the presence of a stoichiometric
amount of Ti(Oi-Pr)4 (Scheme 4). We hoped that, as in
the alkyl addition, the Ti(Oi-Pr)4 would regenerate the
catalyst, but not compete with it in a nonstereoselective
ring opening reaction. Indeed, we found that the Ti-
TADDOLate mediated reaction was slightly faster (2-3
With diethoxy Ti-TADDOLate (28), a fast ring open-
ing of anhydride 2 to the hemiester 26 was observed.
However, the enantioselectivity was considerably lower
than that obtained with 1d (Table 3, entries 1 and 2).
The transfer of the tert-butoxy ligand from 29 wasseven
at room temperaturesvery slow, and the hemiester 27
was isolated in low yield and with low enantioselectivity
(entry 3).
Besides the Ti-TADDOLates, the Ti-CYDISate33 30
and the Ti-BINOLate 31 are among the most successful
chiral Lewis acids used in catalytic asymmetric synthesis.
(31) Dahinden, R.; Beck, A. K.; Seebach, D. In Encyclopedia of
Reagents for Organic Synthesis; Paquette, L. A., Ed.; Wiley:
Chichester, GB, 1995; pp 2167-2170.
(34) Barrisford, D. J .; Bolm, C.; Sharpless, K. B. Angew. Chem. 1995,
107, 1159-1171. Angew. Chem., Int. Ed. Engl. 1995, 34, 1050-1064.
(35) Ito, Y. N.; Ariza, X.; Beck, A. K.; Boha´c, A.; Ganter, C.; Gawley,
R. E.; Ku¨hnle, F. N. M.; Tuleja, J .; Wang, Y. M.; Seebach, D. Helv.
Chim. Acta 1994, 77, 2071-2110.
(32) Nowotny, S.; Vettel, S.; Knochel, P. Tetrahedron Lett. 1994, 35,
4539-4540.
(33) CYDIS stands for N,N′-bis(trifluromethylsulfonyl)-1,2-cyclo-
hexanamide.

1194 J . Org. Chem., Vol. 63, No. 4, 1998
J aeschke and Seebach
Ta ble 4. Su bstoich iom etr ic Use of Ti-TADDOLa te 1d
for th e Rin g Op en in g 2 f 3
different cyclic anhydrides and leads to the corresponding
hemiesters of high enantiopurity (er up to 99:1). Simi-
larly, Ti-BINOLate was found to mediate the ring
opening reaction of the model compound 2 with good
enantioselectivity (er 93:7), albeit at a much slower
reaction rate when compared with the TADDOLate 1.
The higher reaction rate of the Ti-TADDOLate mediated
reaction compared with that induced by other Lewis
acidic complexes was used for developing a catalytic
variant of the reaction. By using substoichiometric
amounts of Ti-TADDOLate 1 and stoichiometric amounts
of Al(Oi-Pr)3, we obtained an enantioselectivity of up to
98:2. We hope that this strategy offers a general route
for esterification reactions mediated by catalytic quanti-
ties of 1.
1d
Al(Oi-Pr)3 time temp yield
(d) (°C) (%)
entry anhydride (mol %) (mol %)
er
1
2
3
4
5
6
2
2
2
7
10
14
15
20
10
20
20
20
80a
80
90
80
80
80
20
24
12
24
24
24
-30
-34
-20
-34
-15
-15
80 67:33
74 98:2
88 94:6
83 76:24
78 89:11
84 86:14
a
Ti(Oi-Pr)4 was used instead of Al(Oi-Pr)3.
Sch em e 4
Exp er im en ta l Section
Gen er a l. Abbreviations used: GP (general procedure), HV
(high vacuum, 0.01-0.001 Torr). Ti(Oi-Pr)4 was distilled
under Ar. Et2O was distilled over Na, THF over K, pentane
over P2O5, and ethyl acetate over sikkon. The TADDOLs 1a -e
(4R,5R) were prepared following reported procedures.9,20,36 The
anhydrides 2, 5, 7, 10, 12, and 15 were commercially available.
4, 6, and 8 were obtained from 2, 5, and 7 by hydrogenation
of the double bond (H2/Pd, ethyl acetate). The anhydrides 9,37
11,38 and 1639 were prepared according to literature proce-
dures. 13 and 14 were obtained from the corresponding
diacids (commercially available) by refluxing in acetic anhy-
dride. The enantiomer ratios of the hemiesters resulting from
the anhydride ring opening were determined as follows: (a)
the isopropyl esters were transformed with diazomethane40 or
41
(CH3)3OBF4 to the methylisopropyl esters, which were ana-
lyzed by GC, or (b) the hemiesters were reduced with LiBEt3H
and cyclized to the corresponding lactones (see GP2), which
were analyzed by GC or HPLC. The reaction temperatures
given correspond to bath temperatures. Analytical thin-layer
chromatography (TLC) was performed on precoated silica gel
60 F254 plates. The compounds were visualized by UV254 nm
light or iodine or by spraying with phosphomolybdic acid
solution [phoshomolybdic acid (25 g), Ce(SO4)2‚4H2O (10 g),
H2SO4 (60 mL), H2O (940 mL)]. Flash chromatography (FC)
was carried out using kieselgel 60 (0.040-0.063 mm). Melting
points were measured in open glass capillaries with a Tottoli
apparatus and are uncorrected. Optical rotations [R]D were
determined at rt (ca. 20 °C) using puriss. solvents. Capillary
gas chromatograms (CGC) were obtained using the following
columns: (a) FS-Lipodex E: 2,6-O-Pentyl-3-O-butyryl-γ-CD
(50 m × 0.25 mm ID); (b) FS-Hydrodex â-PM (50 m × 0.25
mm ID); (c) FS-Hydrodex â-3P (50 m × 0.25 mm ID). Injector
temperature 230 °C, detector temperature 250 °C.
HPLC with two pumps, computer-controlled with the pro-
gram Eurochrom Version 1.57, using a Chiralcel OD column
4,6 × 250 mm, 10 µm, λ ) 254 nm, flow 1.5 mL/min. For the
detection a variable wavelength monitor was used. IR spectra
of CHCl3 solution were measured. 1H and 13C NMR spectra
were measured on 200/300 or 50/75 MHz spectrometers,
respectively. Elemental analyses were performed by the
Microanalytical Service Laboratory of the Laboratorium fu¨r
Organische Chemie (ETH).
times) than the Ti(Oi-Pr)4 mediated one (Table 4, entry
1). Better results were obtained by replacing Ti(Oi-Pr)4
with Al(Oi-Pr)3. By using 20 mol % of the Ti-
TADDOLate and 80 mol % Al(Oi-Pr)3, the hemiester 3
was obtained in good yield with an enantioselectivity of
98:2 (entry 2). Assuming that the Ti-TADDOLate and
the Al(Oi-Pr)3 mediated reactions do not interfere with
each other, the difference in the reaction rates was
estimated to be in the range of 100! A proposed catalytic
cycle is shown in Scheme 4. Reduction of the amount of
Ti-TADDOLate and a higher reaction temperature led
to a slight decrease in selectivity (entry 3).
We next examined the ring opening of anhydrides 7,
10, and 14 using the catalytic reaction conditions de-
scribed above. The ring opening of anhydride 7 pro-
ceeded with low enantioselectivity (er 76:24, Table 4,
entry 4), while hemiester 18 had been obtained with high
enantioselectivity with stoichiometric amounts of Ti-
TADDOLate (Table 2, entry 5). Possibly, the additional
heteroatom in 7 was responsible for the lower enanti-
oselectivity (for example through coordination with
Al(Oi-Pr)3). The bicyclic and monocyclic anhydrides 10
and 14 were ring opened with moderate to good (er 89:
11 and 86:14, respectively), although lower selectivities,
as compared with the corresponding stoichiometric reac-
tions (Table 2, entries 8 and 12).
Gen er a l P r oced u r e for th e Ti-TADDOLa te Med ia ted
R in g Op en in g of Cyclic Meso An h yd r id es (GP 1).
Ti(Oi-Pr)4 (0.707 mL, 2.40 mmol) was added dropwise to a
solution of 1.67 g of â-naphthyl-TADDOL (2.50 mmol) in Et2O
(36) Weber, E.; Do¨rpinghaus, N.; Goldberg, I. J . Chem. Soc., Chem.
Commun. 1988, 1566-1568.
(37) Babler, J . H.; Haack, R. A. J . Chem. Soc., Chem. Commun.
1983, 13, 905-911.
(38) Owen, L. N.; Peto, A. G. J . Chem. Soc. 1955, 77, 2383-2390.
(39) Allinger, N. L. J . Am. Chem. Soc. 1959, 81, 232-236.
(40) Black, T. H. Aldrichimia Acta 1983, 16, 3-10.
(41) Raber, D. J .; Gariano, P.; Brod, A. O.; Gariano, A.; Guida, W.;
Guida, A. R.; Herbst, M. D. J . Org. Chem. 1979, 44, 1149-1154.
Su m m a r y
The Ti-TADDOLate (1) mediated ring opening of
cyclic anhydrides is applicable to a variety of structurally

Enantioselective Ring Opening of Cyclic Meso Anhydrides
J . Org. Chem., Vol. 63, No. 4, 1998 1195
(6-10 mL/mmol TADDOL) under argon, and the mixture was
stirred for 3 h at rt to produce the Ti-TADDOLate 1. The
solvent was removed under HV, and the residue was dried for
30 min. The residue was then dissolved in THF (10 mL), and
the solution was cooled to - 30 °C. A cold solution (ca. - 30
°C) of the anhydride (2.0 mmol) in THF (2.5-5 mL/mmol
anhydride, for 13 30 mL/mmol) was added. The homogeneous
solution was sealed and stored for several days in a freezer or
alternatively was kept in a cooling bath under stirring (as
outlined in Tables 1-3). Subsequently, the reaction mixture
was poured into 0.5 N NaOH (80 mL), Et2O (ca. 100 mL) was
added, and the aqueous phase was separated. The organic
phase was extracted with further 0.5 N NaOH (80 mL), and
the combined aqueous phases were washed with Et2O (ca. 100
mL). Acidification with 1 N HCl to pH 1-2, followed by
extraction with Et2O or ethyl acetate (2 × 100 mL), drying
with MgSO4, and evaporation of the solvent yielded the
corresponding hemiesters. If necessary the hemiesters were
purified by FC (Et2O).
°C (30 min), heating rate 0.4 °C/min, up to 120 °C (30 min), t1
) 117.7 (major enantiomer), t2 ) 118.64]; IR(CDCl3) 3191,
2986, 2952, 1723, 1466, 1375, 1108, 1006, 913 cm-1; 1H NMR
(300 MHz, CDCl3) δ 1.22 (d, J ) 6.2, CH3); 1.23 (d, J ) 6.2,
CH3); 2.10-2.50 (m, 4H); 3.30-3.55 (m, 2H); 5.03 (sept, J )
6.2, CH(CH3)2); 13C NMR (75 MHz, CDCl3) δ 21.5, 21.7, 22.0,
40.4, 40.7, 68.1, 172.6, 179.4; EI-MS m/z 187 (M + 1, 6), 169
(6), 145 (11), 144 (3), 140 (2), 128 (8), 127 (100), 99 (15), 43
(5). Anal. Calcd for C9H14O4 (186.21): C, 58.05; H, 7.58.
Found: C, 57.98; H, 7.45.
(2S,3R)-cis-en do-3-(2-Isopr opoxycar bon yl)bicyclo[2.2.2]-
oct-5-en e-2-ca r boxylic a cid (24) (hemiester from 5): Rf )
0.20 (Et2O); mp 100-102 °C (rac), 84-85 °C (en); [R]rtD ) 15.4
(c ) 0.75, ethyl acetate); er ) 99:1 [GC-analysis of the
methylisopropyl ester: â-3P-CD, 1.0 bar, 155 °C (isotherm),
t1 ) 64.1 (major enantiomer), t2 ) 66.1]; IR(CDCl3) 3518, 3046,
2985, 2946, 2871, 1728, 1467, 1415, 1374, 1313, 1282, 1170,
1169, 1108, 908, 869 cm-1; 1H NMR (300 MHz, CDCl3) δ 1.15
(t, J ) 6.4, 2CH3); 1.22-1.60 (m, 4H); 2.83-3.06 (m, 4H); 4.89
(sept, J ) 6.4, CH(CH3)2); 6.20-6.40 (m, CHdCH); 13C NMR
(75 MHz, CDCl3) δ 21.4, 21.7, 24.4, 24.6, 32.3, 32.5, 47.4, 47.7,
67.9, 131.8, 132.6, 172.1, 179.2; EI-MS m/z 239 (M + 1, 10),
238 (8), 196 (25), 179 (97), 178 (25), 160 (35), 151 (24), 133
(15), 118 (86), 106 (29), 105 (22), 100 (40), 91 (17), 80 (100), 79
(55), 78 (70), 77 (21). Anal. Calcd for C13H18O4 (238.28): C,
65.53; H 7.61. Found: C, 65.77; H, 7.49.
All reactions were carried out on a 1-3 mmol scale. The
following analytical and spectroscopic data refer to racemic
(rac) and enantioenriched (en) hemiesters. The racemic
samples were obtained by reaction of the anhydrides with
Ti(Oi-Pr)4 in THF at rt.
(2S,3R)-cis-en do-3-(2-Isopr opoxycar bon yl)bicyclo[2.2.1]-
h ep t-5-en e-2-ca r boxylic a cid (3) (hemiester from 2): Rf )
0.20 (Et2O); mp 85-87 °C (rac), 89-90 °C (en); [R]rt ) +7.5
cis-en do-3-(2-Isopr opoxycar bon yl)bicyclo[2.2.1]h eptan e-
2-ca r boxylic a cid (hemiester from 4): Rf ) 0.20 (Et2O); mp
D
(c ) 2.5, CHCl3); er ) 99:1 [GC-analysis of the methylisopropyl
ester: â-3P-CD, 1.0 bar, 135 °C (isotherm), t1 ) 65.6 (major
enantiomer), t2 ) 68.6]; IR (CDCl3) 3190, 2985, 2941, 1730,
70-72 °C (rac), colorless oil (en); [R]rt ) +8.7 (c ) 1.50, ethyl
D
acetate); er ) 99:1 [GC-analysis of the methylisopropyl ester:
â-3P-CD, 1.0 bar, 135 °C (isotherm), t1 ) 62.9 (major enanti-
omer), t2 ) 63.7]; IR(CDCl3) 2994, 2953, 2872, 1728, 1467,
1456, 1374, 1339, 1174, 1108, 1005, 908, 862, 641 cm-1 1H
;
NMR (300 MHz, CDCl3) δ 1.14 (t, J ) 6.6, 2CH3); 1.29 (d, J )
8.5, 1H); 1.43 (d, J ) 8.5, 1H); 3.12 (br. s, 2H); 3.15-3.31 (m,
2H); 4.88 (sept, J ) 6.6, CH(CH3)2); 6.21 (ddd, J ) 2.9, 5.3,
15.6, CHdCH); 13C NMR (75 MHz, CDCl3) δ 21.4, 21.7, 46.1,
46.2, 46.4, 48.0, 48.6, 67.8, 134.3, 135.2, 171.7, 178.8; EI-MS
m/z 225 (M + 1, 18), 207 (6), 182 (6), 165 (83), 159 (45), 137
(37), 119 (25), 117 (100), 99 (41), 91 (25), 66 (63). Anal. Calcd
for C12H16O4 (224.26): C, 64.27; H, 7.19. Found: C, 64.05; H,
7.01.
1451, 1369, 1292, 1174, 1108, 908, 641 cm-1 1H NMR (300
;
MHz, CDCl3) δ 1.12 (d, J ) 6.2, CH3); 1.14 (d, J ) 6.2, CH3);
1.37 (br. s, 4H); 1.67-1.83 (m, 2H); 2.49 (br. s, 2H); 2.81-2.99
(m, 2H); 4.91 (sept, J ) 6.2, CH(CH3)2); 13C NMR (50 MHz,
CDCl3) δ 21.4, 21.6, 23.7, 39.7, 40.1, 40.2, 46.6, 46.8, 67.5,
171.6, 179.0; EI-MS m/z 227 (M + 1, 18), 209 (4), 168 (10),
167 (100), 166 (30), 160 (58), 159 (7), 148 (15), 139 (14), 138
(23), 118 (40), 117 (20), 111 (3), 100 (19), 99 (12), 93 (9), 91
(7), 67 (10), 66 (11). Anal. Calcd for C12H18O4 (226.27): C,
63.70; H 8.02. Found: C, 63.43; H, 8.23.
(1R,2S)-exo-3,6-Ep oxy-2-(2-isop r op oxyca r bon yl)h ex-4-
en e-1-ca r boxylic a cid (18) (hemiester from 7): Rf ) 0.15
(Et2O); mp 107-108 °C (rac), 94-95 °C (en); [R]rt ) +22.1 (c
cis-en do-3-(2-Isopr opoxycar bon yl)bicyclo[2.2.2]octan e-
2-ca r boxylic a cid (hemiester from 6): Rf ) 0.20 (Et2O); mp
108-109 °C (rac); 91-92 °C (en); [R]rtD ) +7.7 (c ) 2.52, ethyl
acetate); er ) 97:3 [GC-analysis of the methylisopropyl ester:
â-3P-CD, 1.0 bar, 155 °C (isotherm), t1 ) 76.0 (major enanti-
omer), t2 ) 77.3]; IR(CDCl3) 3513, 3237, 2985, 2943, 2870,
D
) 1.75, ethyl acetate); er ) 99:1 [GC-analysis of 21: γ-CD,
1.0 bar, 100 °C (50 min), heating rate 3.0 °C/min, up to 180
°C, t1 ) 99.1 (major enantiomer), t2 ) 105.5]; IR(CDCl3) 3284,
1
2986, 2940, 1734, 1466, 1375, 1308, 1107, 999, 971 cm-1; H
NMR (300 MHz, CDCl3) δ 1.20 (d, J ) 6.2, CH3); 1.22 (d, J )
6.2, CH3); 2.77 (d, J ) 9.0, 1H); 2.83 (d, J ) 9.0, 1H); 5.04
(sept, J ) 6.2, CH(CH3)2); 5.22 (s, 1H); 5.29 (s, 1H); 6.39-6.50
(m, CHdCH); 13C NMR (75 MHz, CDCl3) δ 21.4, 21.7, 46.7,
47.3, 68.9, 80.3, 80.6, 136.2, 136.9, 170.6, 177.4; EI-MS m/z
227 (M + 1, 1), 183 (62), 181 (4), 166 (2), 159 (62), 139 (30),
121 (17), 117 (68), 100 (20), 99 (100), 68 (77). Anal. Calcd for
C11H14O5 (226.23): C, 58.40; H, 6.24. Found: C, 58.15; H, 6.20.
(1R,2S)-exo-3,6-Epoxy-2-(2-isopr opoxycar bon yl)h exan e-
1-ca r boxylic a cid (20) (hemiester from 8): Rf ) 0.15 (Et2O);
mp 132-133 °C (rac), 110-111 °C (en); [R]rtD) +9.3 (c ) 1.80,
ethyl acetate); er ) 98:2 [GC-analysis of 21: γ-CD, 1.0 bar,
1730, 1457, 1374, 1292, 1106, 1005, 912, 867, 836 cm-1 1H
;
NMR (300 MHz, CDCl3) δ 1.17 (d, J ) 6.2, CH3); 1.18 (d, J )
6.2, CH3); 1.29-1.47 (m, 2H); 1.48-1.68 (m, 4H); 1.73-1.90
(m, 2H); 2.01 (s, 2H); 2.78-2.95 (m, 2H); 4.96 (sept, J ) 6.2,
CH(CH3)2); 13C NMR (75 MHz, CDCl3) δ 21.2, 21.5, 21.7, 25.6,
25.7, 26.5, 43.9, 44.0, 67.7, 172.8, 180.2; EI-MS m/z 241 (M +
1, 4), 222 (26), 194 (5), 181 (83), 180 (100), 162 (35), 160 (38),
152 (29), 135 (22), 118 (20), 117 (20), 108 (40), 107 (20), 80
(49), 79 (27). Anal. Calcd for C13H20O4 (240.30): C, 64.98; H,
8.39. Found: C, 64.72; H, 8.45.
cis-3,3-Dim et h yl-2-(2-isop r op oxyca r b on yl)cyclop r o-
p a n e-1-ca r boxylic a cid (hemiester from 9): Rf ) 0.20 (Et2O);
mp 62-63 °C (rac), 76-77 °C (en); [R]rtD ) +3.3 (c ) 0.64, ethyl
acetate); er ) 98:2 [GC-analysis of the methylisopropyl ester:
â-CD, 1.0 bar, 110 °C (isotherm), t1 ) 49.5 (major enantiomer),
t2 ) 51.5]; IR(CDCl3) 3517, 2984, 2666, 1730, 1654, 1434, 1377,
1102, 906 cm-1; 1H NMR (200 MHz, CDCl3) δ 1.31 (d, J ) 6.2,
CH(CH3)2); 1.35 (s, CH3); 1.39 (s, CH3); 1.92 (d, J ) 8.2, CH);
2.06 (d, J ) 8.2, CH); 5.11 (sept, J ) 6.2, CH(CH3)2); 13C NMR
(50 MHz, CDCl3) δ 15.2, 21.6, 21.7, 27.5, 28.2, 33.2, 33.4, 69.4,
171.2, 173.1; EI-MS m/z 201 (M + 1, 51), 159 (14), 158 (11),
143 (21), 141 (75), 114 (20), 113 (100), 95 (22), 67 (12). Anal.
Calcd for C10H16O4 (200.23): C, 59.98; H, 8.05. Found: C,
60.24; H, 7.78.
100 °C (55 min), heating rate 3.0 °C/min, up to 180 °C, t1
104.6 (major enantiomer), t2 ) 110.2]; IR(CDCl3) 3263, 1733,
1466, 1375, 1296, 1108, 1001, 939, 910, 863 cm-1 1H NMR
)
;
(200 MHz, CDCl3) δ 1.20 (d, J ) 6.2, CH3); 1.22 (d, J ) 6.2,
CH3); 1.46-1.60 (m, 2H); 1.78-1.90 (m, 2H); 2.95 (d, J ) 9.6,
1H); 3.03 (d, J ) 9.6, 1H); 4.83-4.96 (m, 2H); 4.99 (sept, J )
6.2, CH(CH3)2); 13C NMR (50 MHz, CDCl3) δ 21.3, 21.6, 28.9,
52.1, 52.3, 68.7, 78.3, 78.6, 170.3, 176.9; EI-MS m/z 229 (M +
1, 15), 211 (9), 200 (6), 187 (9), 169 (100), 158 (16), 142 (33),
141 (59), 124 (46), 123 (75), 118 (18), 100 (28), 99 (23). Anal.
Calcd for C11H16O5 (228.24): C, 57.89; H, 7.07. Found: C,
57.71; H, 7.07.
(1S,2R)-cis-2-(2-Isop r op oxyca r b on yl)cyclob u t a n e-1-
ca r boxylic a cid (22) (hemiester from 10): Rf ) 0.20 (Et2O);
cis-2-(2-Isop r op oxyca r bon yl)cyclop en ta n e-1-ca r boxy-
lic a cid (hemiester from 11): Rf ) 0.20 (Et2O); colorless oil;
Colorless oil; [R]rt ) 14.0 (c ) 0.47, ethyl acetate); er ) 97:3
D
[GC-analysis of the methylisopropyl ester: â-CD, 1.0 bar, 80
[R]rt ) +5.6 (c ) 0.40, ethyl acetate); er ) 94:6 [GC-analysis
D

1196 J . Org. Chem., Vol. 63, No. 4, 1998
J aeschke and Seebach
of the corresponding lactone30 (prepared according to GP2):
γ-CD, 1.0 bar, 80 °C (0 min), heating rate 1.0 °C/min, up to
180 °C (30 min), t1 ) 64.1 (major enantiomer), t2 ) 66.3]; IR-
[GC-analysis of the corresponding lactone43 (prepared accord-
ing to GP2): γ-CD, 130 °C (isotherm), t1 ) 20.9, t2 ) 21.9];
IR(CDCl3): 3690, 3011, 2984, 1721, 1454, 1376, 1272, 1178,
1107, 1080, 910 cm-1; 1H NMR (300 MHz, CDCl3) δ 1.14-1.26
(m, 4CH3); 1.49 (quin, J ) 7.0, CHCH3); 2.12 (quin, J ) 7.8,
CHCH3); 2.38-2.61 (m, 2H); 5.01 (sept, J ) 6.2, CH(CH3)2);
13C NMR (75 MHz, CDCl3) δ 16.8, 17.1, 21.6, 36.7, 37.0, 37.4,
67.6, 175.7, 182.5; EI-MS m/z 203 (M + 1, 8), 185 (8), 184 (1),
161 (2), 160 (2), 156 (4), 144 (8), 143 (100), 142 (30), 132 (5),
(CDCl3) 3156, 2976, 2256, 1719, 1372, 1106, 908, 642 cm-1
;
1H NMR (200 MHz, CDCl3) δ 1.20 (d, J ) 6.2, CH3); 1.21 (d, J
) 6.2, CH3); 1.55-1.78 (m, 1H); 1.78-2.14 (m, 5H); 2.85-3.17
(m, 2H); 4.99 (sept, J ) 6.2, CH(CH3)2); 13C NMR (50 MHz,
CDCl3) δ 21.5, 21.6, 23.7, 28.7, 28.8, 46.7, 47.0, 67.9, 173.3,
180.2; EI-MS m/z 201 (M + 1, 1), 182 (2), 159 (4), 142 (8), 141
(100), 140 (21), 114 (16), 112 (15), 95 (10). Anal. Calcd for
C10H16O4 (200.23): C, 59.98; H, 8.05. Found: C, 59.70; H, 8.15.
cis-2-(2-Isop r op oxyca r b on yl)cycloh exa n e-1-ca r b oxy-
lic a cid (hemiester from 12): Rf ) 0.20 (Et2O); colorless oil;
[R]rtD ) +2.50 (c ) 0.25, ethyl acetate); er > 95:5 [GC-analysis
of the methylisopropyl ester: γ-CD, 1.0 bar, 80 °C (30 min),
heating rate 0.3 °C/min, up to 120 °C (30 min), t1 ) 127.2, t2
) 127.8 (major enantiomer)]; IR(CDCl3) 3162, 2939, 2860,
116 (6), 115 (41), 114 (25). Anal. Calcd for
C10H18O4
(202.25): C, 59.39; H, 8.97. Found: C, 59.44; H, 8.71.
Gen er a l P r oced u r e for Red u ction of th e Hem iester s
to th e Cor r esp on d in g La cton es (GP 2). The hemiester was
dissolved in THF and at 0 °C 3-7 equiv of a 1 M LiBEt3H
solution in THF was added and the mixture was stirred for
3-16 h at room temperature. H2O (5 mL) and 1 M HCl (10
mL) were added, and the mixture was stirred for 1-3 h. The
aqueous phase was extracted twice with Et2O or ethyl acetate
(50 mL), the combined organic phases were dried over MgSO4,
and the solvent was removed under reduced pressure. The
residue was purified by FC.
1719, 1453, 1375, 1305, 1178, 1109, 962, 911, 600 cm-1 1H
;
NMR (200 MHz, CDCl3) δ 1.23 (d, J ) 6.2, 2CH3); 1.30-1.66
(m, 4H); 1.67-1.89 (m, 2H); 1.90-2.17 (m, 2H); 2.77-2.90 (m,
2H); 5.04 (sept, J ) 6.2, CH(CH3)2); 13C NMR (50 MHz, CDCl3)
δ 21.5, 23.4, 23.8, 25.8, 26.3, 42.4, 42.5, 67.8, 173.0, 180.4; EI-
MS m/z 215 (M + 1, 12), 197 (7), 196 (6), 173 (5), 172 (4), 168
(10), 156 (9), 155 (100), 154 (32), 128 (19), 127 (13), 126 (43),
(+)-(2S,3R)-cis-en d o-3-(Hyd r oxym eth yl)bicyclo[2.2.1]-
h ep t-5-en e-2-ca r boxylic Acid La cton e (17). According to
GP2, 100 mg (0.45 mmol) of 3 was dissolved in THF (3 mL),
and LiBEt3H (1.55 mL, 1 M) was added. After FC (Et2O/
pentane 1/1), 43 mg (0.29 mmol, 64%) of 17 was isolated. Rf
109 (24), 108 (15), 81 (38). Anal. Calcd for
C11H18O4
(214.26): C, 61.66; H, 8.47. Found: C, 61.55; H, 8.66.
1,3-Dib en zyl-2-im id a zolid in on e-cis-5-(2-isop r op oxy-
ca r bon yl)-4-ca r boxylic a cid (hemiester from 13): Rf ) 0.30
(Et2O); colorless oil; er ) 63:37 [HPLC-analysis of the corre-
sponding lactone42 (prepared according to GP2): Chirasphere,
Hexan/i-PrOH (90/10), 1.5 mL/min: t1 ) 26.0 (major enanti-
omer), t2 ) 37.4]; IR(CDCl3) 3674, 3011, 1740, 1713, 1449,
) 0.25 (Et2O/pentane 1/1); [R]rt +147.1 (c ) 0.466, CHCl3),
D
lit. +143.2 (c ) 5.2, CHCl3);44 1H NMR (200 MHz, CDCl3) δ
1.48 (d, J ) 8.6, 1H); 1.67 (d, J ) 8.6, 1H); 3.03-3.19 (m, 2H);
3.21-3.39 (m, 2H); 3.82 (dd, J ) 3.4, 9.6, 1H); 4.31 (dd, J )
8.2, 9.6, 1H); 6.25-6.38 (m, 2H).
For further spectroscopic and analytical data see the
1420, 1360, 1105, 1040, 908, 612 cm-1 1H NMR (200 MHz,
;
literature.44
CDCl3) δ 1.18 (d, J ) 6.2, CH3); 1.19 (d, J ) 6.2, CH3); 3.95-
4.15 (m, 4H); 4.90-5.06 (m, 3H), 7.19-7.33 (m, 10H); 13C NMR
(50 MHz, CDCl3) δ 21.3, 21.5, 46.6, 46.7, 56.7, 57.2, 70.1, 127.9,
128.6, 128.7, 135.6, 135.7, 159.8, 167.5, 171.1; EI-MS m/z 397
(M + 1, 5), 396 (16), 353 (2), 352 (5), 351 (9), 350 (10), 337 (6),
336 (25), 310 (21), 309 (100), 308 (9), 305 (6), 266 (9), 265 (50),
264 (39), 263 (8), 173 (7), 132 (4), 92 (4), 91 (60). Anal. Calcd
for C22H24N2O5 (396.44): C, 66.65; H, 6.10; N, 7.07. Found:
C, 66.55; H, 6.22; N, 6.99.
(+)-(1R,2S)-exo-3,6-Epoxy-2-(h ydr oxym eth yl)h ex-4-en e-
1-ca r boxylic Acid La cton e (19). According to GP2, 70 mg
(0.31 mmol) of 18 was dissolved in THF (7 mL), and LiBEt3H
(1.01 mL, 1 M) was added. A fter FC (Et2O/pentane 1/2), 26
mg (0.17 mmol, 55%) of 19 was isolated. Rf ) 0.1 (Et2O/
pentane 1/2); 1H NMR (200 MHz, CDCl3): 1.65-1.90 (m, 2H);
4.19 (dd, J ) 3.5, 9.6, 1H); 4.50 (dd, J ) 8.6, 9.6, 1H); 4.97 (d,
J ) 4.8, 1H); 5.27 (d, J ) 4.8, 1H); 6.38-6.52 (m, CHdCH).
For further spectroscopic and analytical data see the
literature.29
cis-2,3-Dim eth yl-4-(2-isop r op oxyca r bon yl)bu tyr ic a cid
(hemiester from 14): Rf ) 0.20 (Et2O); colorless oil; [R]rt
)
D
(+)-(1R,2S)-exo-3,6-Ep oxy-2-(h yd r oxym eth yl)h exa n e-1-
ca r boxylic Acid La cton e (21). (a ) According to GP2, 90 mg
(0.39 mmol) of 20 was dissolved in THF (7 mL), and LiBEt3H
(1.55 mL, 1 M) was added. After FC (Et2O/pentane 1/2), 30
mg (0.19 mmol, 49%) of 21 was isolated. Rf ) 0.10 (Et2O/
pentane 1/2); [R]rtD ) +105 (c ) 0.53, CHCl3), lit. [R]rtD ) +110
(c ) 1.0, CHCl3);29 1H NMR (200 MHz, CDCl3) δ 1.48-1.62
(m, 2H); 1.70-1.90 (m, 2H); 2.68-2.84 (m, 2H); 4.11 (dd, J )
5.4, 9.3, 1H); 4.43 (t, J ) 8.5, 1H); 4.54 (d, J ) 5.0, 1H); 4.87
(d, J ) 4.8, 1H).
-1.8 (c ) 1.05, ethyl acetate); er ) 98:2 [GC-analysis of the
methylisopropyl ester: γ-CD, 1.0 bar, 65 °C (50 min), heating
rate 0.4 °C/min, up to 85 °C (20 min), t1 ) 71.2, t2 ) 72.6 (major
enantiomer)]; IR(CDCl3) 3105, 2984, 2941, 1713, 1466, 1376,
1272, 1178, 1107, 1080, 937, 899, 867, 635 cm-1; 1H NMR (300
MHz, CDCl3) δ 1.18-1.28 (m, 4CH3); 2.68-2.87 (m, 2CHCH3);
5.05 (sept, J ) 6.3, CH(CH3)2); 13C NMR (75 MHz, CDCl3) δ
14.3, 14.8, 21.7, 42.3, 68.1, 174.0, 180.7; EI-MS m/z 189 (M +
1, 12), 171 (5), 169 (1), 160 (2), 147 (8), 146 (2), 142 (2), 130
(7), 129 (100), 128 (6), 116 (12), 102 (8), 101 (17), 100 (5), 87
(10). Anal. Calcd for C9H16O4 (188.22): C, 57.43; H, 8.57.
Found: C, 57.30; H, 8.32.
For further spectroscopic and analytical data see the
literature.29
(b) A 26 mg (0.17 mmol) amount of 19 was dissolved in ethyl
acetate (5 mL), 20 mg of Pd/C (10%) was added, and the
mixture was stirred under an atmosphere of hydrogen for 12
h. The reaction mixture was filtered through a short silica
gel column (5 cm), and the column was washed with ethyl
acetate (30 mL). The solvent was removed under reduced
pressure to yield 24 mg (0.16 mmol, 91%) of 21.
3-Meth yl-5-(2-isop r op oxyca r bon yl)glu ta r ic a cid (he-
miester from 15): Rf ) 0.20 (Et2O); colorless oil; [R]rt ) -0.9
D
(c ) 0.90, ethyl acetate); er ) 3:1 [GC-analysis of the meth-
ylisopropyl ester: â-CD, 1.0 bar, 85 °C (90 min), heating rate
0.2 °C/min, up to 105 °C (60 min), t1 ) 140.3, t2 ) 141.3]; IR-
(CDCl3) 2984, 1720, 1456, 1375, 1289, 1146, 1107, 1040, 978,
908 cm-1; 1H NMR (300 MHz, CDCl3): 1.05 (d, J ) 6.3, CH3);
1.23 (d, J ) 6.2, 2CH3); 2.12-2.52 (m, 5H); 5.02 (sept, J ) 6.2,
CH(CH3)2); 13C NMR (75 MHz, CDCl3) 19.7, 21.8, 27.3, 40.5,
41.1, 67.7, 171.8, 178.2; EI-MS m/z 189 (M + 1, 12), 188 (1),
172 (1), 171 (9), 170 (2), 169 (1), 160 (1), 147 (4), 146 (4), 142
(2), 130 (7), 129 (100), 128 (19), 118 (3), 102 (5), 101 (17), 100
(14), 87 (4). Anal. Calcd for C9H16O4 (188.22): C, 57.43; H,
8.57. Found: C, 57.69; H, 8.74.
For further spectroscopic and analytical data see above.
(+)-(1S,2R)-cis-2-(Hyd r oxym et h yl)cyclob u t a n e-1-ca r -
boxylic Acid La cton e (23). According to GP2, 94 mg (0.50
mmol) of 22 was dissolved in THF (3 mL), and LiBEt3H (3
mL, 1 M) was added. After FC (Et2O/pentane 1/1), 25 mg (0.22
mmol, 44%) of 23 was obtained. Rf ) 0.25 (Et2O/pentane 1/1);
[R]rt ) +108.4 (c ) 0.98, CHCl3), lit. [R]rt ) +118.7 (c ) 10,
D
D
CHCl3);30 1H NMR (200 MHz, CDCl3) δ 2.00-2.22 (m, 2H);
cis-2,4-Dim eth yl-5-(2-isopr opoxycar bon yl)glu tar ic acid
(hemiester from 16): Rf ) 0.20 (Et2O); colorless oil; er ) 1:1
(43) Brown, K.; Burton, M.; Robins, D. J .; Sim, G. A. J . Chem. Soc.,
Perkin Trans. 1 1986, 1261-1265.
(44) Lok, K. P.; J akovac, I. J .; J ones, J . B. J . Am. Chem. Soc. 1985,
107, 2521-2526.
(42) Kogure, K.; Yoshimura, I.; Fukawa, H.; Shimizu, T. Agric. Biol.
Chem. 1976, 40, 1657-1658.

Enantioselective Ring Opening of Cyclic Meso Anhydrides
J . Org. Chem., Vol. 63, No. 4, 1998 1197
2.30-2.60 (m, 2H); 3.05-3.25 (m, 2H); 4.22 (d, J ) 6.4, 1H);
4.34 (dd, J ) 4.1, 6.4, 1H).
Ti-BINOLate. The Ti-BINOLate was dissolved in THF (10
mL) and cooled to -68 °C, and a solution of 328 mg (2.00 mmol)
of anhydride 2 in THF (5 mL) was added dropwise. After 6
days at -22 °C (freezer), the solution was quenched with
phosphate buffer (40 mL) and the aqueous phase was extracted
with Et2O (1 × 100 mL, 3 × 50 mL). The combined organic
extracts were dried over Na2SO4, and the solvent was removed
under reduced pressure. The residue was purified by FC to
yield 90 mg (0.40 mmol, 20%) of 3. Er: 7:93 [GC-analysis of
the methylisopropyl ester (see above)].
Gen er a l P r oced u r e for th e Rin g Op en in g of An h y-
d r id e 2 by Usin g Su bstoich iom etr ic Am ou n ts of 1 (GP 3).
Ti(Oi-Pr)4 (0.295 mL, 1.0 mmol) was added dropwise to a
solution of â-naphthyl-TADDOL (667 mg, 1.0 mmol) in Et2O
(10 mL) under argon, and the mixture was stirred for 3 h at
rt to produce the Ti-TADDOLate 1d . The solvent was
removed under vacuum and the residue was dried for 30 min.
The residue was then dissolved in THF (5 mL), and the
solution was cooled to - 30 °C. A cold solution (ca. -30 °C) of
the anhydride (5.0 mmol) in THF (1 mL/mmol anhydride, or
3.6 mL/mmol anhydride for 7) and 4.00 mmol Al(Oi-Pr)3 or
Ti(Oi-Pr)4 were added. The homogeneous solution was sealed
and stored for several days in a freezer as outlined in Table 4.
Subsequently, the reaction mixture was poured into 0.5 N
NaOH (150 mL), ca. 200 mL of Et2O was added, and the
aqueous phase was separated. The organic phase was ex-
tracted with further 0.5 N NaOH (80 mL), and the combined
aqueous phases were washed with Et2O (ca. 100 mL). Acidi-
fication with 1 N HCl to pH 1-2, followed by extraction with
Et2O or ethyl acetate (2 × 100 mL), drying with MgSO4, and
evaporation of the solvent yielded the corresponding he-
miesters. If conversion was incomplete the hemiesters were
purified by FC (Et2O).
For further spectroscopic and analytical data see the
literature.30
(2R,3S)-cis-en do-3-(1-(S)-P h en yleth ylcar bam oyl)bicyclo-
[2.2.2]oct-5-en e-2-ca r boxylic Acid Isop r op yl Ester (25).
A 44 mg (0.18 mmol) amount of 24 was dissolved in THF (2
mL), and SO2Cl2 (0.016 mL, 0.22 mmol) was added at 0 °C.
The mixture was stirred for 15 min, Et3N (0.090 mL, 0.65
mmol) and (R)-R-phenylethylamine (0.027 mL, 0.21 mmol)
were added, and the mixture was stirred for a further 2 h at
0 °C. The reaction mixture was quenched with saturated
NaHCO3 solution (10 mL), and the aqueous phase was
extracted twice with Et2O (50 mL). After recrystallization
from Et2O, 39 mg (0.11 mmol, 57%) 25 was obtained as
colorless crystals. 1H NMR (200 MHz, CDCl3) δ 1.12 (d, J )
6.3, CH3); 1.19 (d, J ) 6.3, CH3); 1.10-1.80 (m, 4H); 1.39 (d, J
) 6.9, CH3); 2.70-3.10 (m, 4H); 4.78-5.05 (m, 2H); 5.82 (br.
d, J ) 7.0, 1H); 6.23 (t, J ) 7.5, 1H); 6.57 (t, J ) 7.8, 1H);
7.16-7.40 (m, 5 H).
cis-en d o-3-(E t h oxyca r b on yl)b icyclo[2.2.1]h ep t -5-en e-
2-ca r boxylic Acid (26). According to GP1, 833 mg (1.25
mmol) of â-naphthyl-TADDOL was treated with Ti(OEt)4
(0.251 mL, 1.21 mmol) to afford 28, and then 164 mg (1.00
mmol) of 2 was added. After 7 days at -30 °C, 191 mg (0.91
mmol, 91%) of 26 was obtained. er ) 85:15 [GC-analysis of
17 (prepared according to GP2): γ-CD, 152 °C (isotherm), t1
) 35.1 (major enantiomer), t2 ) 37.9]; 1H NMR (200 MHz,
CDCl3) δ 1.17 (t, J ) 7.2, CH3); 1.30 (d, J ) 8.4, 1H); 1.45 (d,
J ) 8.6, 1H); 3.15 (br. s, 2H); 3.16-3.37 (m, 2H); 3.90-4.15
(m, 2H); 6.23 (ddd, J ) 2.9, 5.4, 19.4, CHdCH).
cis-en d o-3-(ter t-Bu toxyca r bon yl)bicyclo[2.2.1]h ep t-5-
en e-2-ca r boxylic Acid (27). According to GP1, 833 mg (1.25
mmol) of â-naphthyl-TADDOL was treated with Ti(Ot-Bu)4
(0.460 mL, 1.20 mmol) to afford 29, and then 164 mg (1 mmol)
of 2 was added. After 10 days at rt, 12 mg (0.05 mmol, 5%) of
27 was obtained after FC (Et2O/pentane 2/1). Rf ) 0.25 (Et2O/
pentane 1/1); er ) 59:41 [GC analysis of 17 (prepared according
to GP2): γ-CD, 152 °C (isotherm), t1 ) 35.1 (major enanti-
omer), t2 ) 37.9]; 1H NMR (200 MHz, CDCl3) δ 1.30-1.52 (m,
2H); 1.42 (s, C(CH3)3); 3.17-3.23 (m, 2H); 3.24-3.30 (m, 2H);
6.22-6.36 (m, CHdCH).
The reaction for entry 5 (Table 4) was carried out according
to GP3 with the following change: 10 mol % of Ti-TAD-
DOLate 1d (0.75 mmol) was used, the Ti-TADDOLate was
dissolved in 10 mL of THF and the anhydride 2 in 5 mL, and
except for the first day, the reaction mixture was stirred. In
the reaction for entry 1 (Table 4) 15 mol % of Ti-TADDOLate
1d (0.75 mmol) was used.
Ack n ow led gm en t. The work described is part of the
dissertation (No 12300) of G.J ., ETH Zu¨rich, 1997. We
thank the Stiftung Stipendien-Fonds der Chemischen
Industrie, Germany for a Kekule´-fellowship granted to
G.J . For the generous supply of tetrahydrofuran (BASF
AG, D-Ludwigshafen), dimethyl tartrate (Chemische
Fabrik Uetikon, CH-Uetikon), tetraisopropyltitanate
(Hu¨ls AG, D-Troisdorf), and 1,3-dibenzyl-2-imidazolidi-
none-cis-4,5-dicarboxylic acid (Lonza AG, CH-Visp) we
thank the respective companies. We gratefully acknowl-
edge the help of Dr. Armido Studer and Dr. Paul
Comina during the preparation of this manuscript. We
thank Albert K. Beck, Shahidul Chowdhury, J o¨rg Ha¨t-
tenschwiler, and Pascal Coliagnese for carrying out
some of the experiments.
(1R,2R)-Ti-CYDISa te Med ia ted Rea ction : cis-en d o-3-
(2-isop r op oxyca r b on yl)b icyclo[2.2.1]h ep t -5-en e-2-ca r -
boxylic Acid (3). According to GP1, 946 mg (2.50 mmol) of
CYDIS33 was treated with Ti(Oi-Pr)4 (0.72 mL, 2.44 mmol) to
give the Ti-CYDISate. The Ti-CYDISate was dissolved in
THF (10 mL) and cooled to -68 °C, and a solution of 328 mg
(2.00 mmol) of anhydride 2 in THF (5 mL) was added dropwise.
After 6 days at -22 °C (freezer), the solution was quenched
with phosphate buffer (40 mL) and the aqueous phase was
extracted with Et2O (1 × 100 mL, 3 × 50 mL). The combined
organic extracts were dried over Na2SO4 and the solvent was
removed under reduced pressure. The residue was purified
by FC to yield 426 mg 3 (1.90 mmol, 95%). Er: 45:55 [GC-
analysis of the methylisopropyl ester (see above)].
(M)-Ti-BINOLa te Med ia ted Rea ction : cis-en d o-3-(2-
isop r op oxyca r bon yl)bicyclo[2.2.1]h ep t-5-en e-2-ca r boxy-
lic Acid (3). According to GP1, 716 mg (2.50 mmol) of BINOL
was treated with Ti(Oi-Pr)4 (0.72 mL, 2.44 mmol) to give the
J O971731T