Highly enantioselective desymmetrization of anhydrides by carbon nucleophiles: Reactions of Grignard reagents in the presence of (-)-sparteine

Article abstract of DOI:10.1002/1521-3773(20020315)41:6<1057::AID-ANIE1057>3.0.CO;2-H

Where other common chiral ligands failed, (-)-sparteine can be employed to form complexes with Grignard reagents. These chirally modified reagents desymmetrize a range of anhydrides with good enantioselectivity (up to 92% ee; see scheme). Whereas (-)-sparteine is well known to form complexes with organolithium reagents and to induce excellent enantioselection in their reactions with electrophiles, (-)-sparteine-controlled asymmetric processes that involve Grignard reagents are rare.

Full text of DOI:10.1002/1521-3773(20020315)41:6<1057::AID-ANIE1057>3.0.CO;2-H

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[55] P. Camps, B. Cusack, W. D. Mallender, R. El Achab, J. Morral, D.
single substrate, a bicyclic anhydride, with Grignard reagents
bearing chiral oxazolidine auxiliaries.[8] In an attempt to
remedy this methodological deficiency, we have recently
initiated an investigation of the desymmetrization of anhy-
drides by carbon nucleophiles. Rather than covalently attach-
ing a chiral auxiliary to the nucleophile and then releasing it,
we chose to concentrate our efforts on the use of chiral ligands
as the source of asymmetry. Here we report that (À)-
sparteine-bound Grignard reagents effectively desymmetrize
an array of cyclic anhydrides to furnish ketoacids in very good
enantiomeric excess.
ƒ
Munoz-Torrero, T. L. Rosenberry, Mol. Pharmacol. 2000, 57, 409
417.
[56] G. M. Morris, D. S. Goodsell, R. S. Halliday, R. Huey, W. E. Hart,
R. K. Belew, A. J. Olson, J. Comput. Chem. 1998, 19, 1639 1662.
[57] Although the lead inhibitor 1 was assembled by Electrophorus
electricus AChE, it has a similarly high affinity for the Torpedo
californica enzyme. This observation suggests
a high degree of
functional similarity with respect to binding in the active center gorge
¬
for these two enzymes (see: S. Simon, J. Massoulie, J. Biol. Chem. 1997,
272, 33045 33055), and justifies our use of the crystallographically
well-characterized (2.8 ä resolution) Torpedo enzyme for modeling
studies. At the present time Electrophorus AChE has only been
characterized to 4.2ä resolution (Y. Bourne, J. Grassi, P. E. Bourgis,
P. Marchot, J. Biol Chem. 1999, 274, 30370 30376).
In our initial work, we decided to explore the ring-opening
of 3-phenylglutaric anhydride by phenylmagnesium chloride.
We examined a structurally diverse set of chiral ligands
(Scheme 1) that have proved useful in a number of other
Highly Enantioselective Desymmetrization
of Anhydrides by Carbon Nucleophiles:
Reactions of Grignard Reagents in the
Presence of (À)-Sparteine**
Me Me
N
H
Me
Ph
HO
O
O
N
N
Me2N
OH
MeO
Ryo Shintani and Gregory C. Fu*
Ph
Ph
N
The desymmetrization of meso and other prochiral com-
pounds represents a powerful approach to asymmetric syn-
thesis,[1] and a number of enantioselective total syntheses have
been based on this strategy.[2] The desymmetrization of
anhydrides has been a particular focus of interest. Most
investigations of this family of substrates have employed an
alcohol as the nucleophile[3] [for example, a chiral alcohol[4] or
an achiral alcohol in combination with a chiral catalyst;[5]
Eq. (1)]. In addition, success has been reported for reactions
with a stoichiometric quantity of an enantiopure reducing
agent[6] or amine.[7]
(+)-1
(+)-2
(+)-3
H
H
Ph
MeO
Ph
N
H
N
OMe
H
(–)-4
(–)-5
Scheme 1. Ligands used in preliminary experiments.
enantioselective processes, including a simple aminoalcohol
(Table 1, entry 1), a cinchona alkaloid (entry 2), a bisoxazo-
line (entry 3), and a dimethyl ether (entry 4). Disappointingly,
all were rather ineffective at desymmetrizing the anhydride
(<40% ee). Fortunately, however, we discovered that readily
available (À)-sparteine accomplishes the ring opening with
high enantioselectivity (88% ee; entry 5).
Of course, we are not the first to document the remarkable
capacity of (À)-sparteine to control enantioselection. Pioneer-
ing observations by Nozaki et al. in the 1960×s[9] have been
followed by fascinating studies by a number of groups,
including those of Hoppe and Beak.[10, 11] The large majority
R'
O
R'
O
ROH/base
(1)
RO
OH
desymmetrization
O
O
O
ROH and/or the base is chiral
On the other hand, very little progress has been described
for the desymmetrization of anhydrides with carbon-based
nucleophiles. In fact, to the best of our knowledge, only one
report has begun to successfully address this challenge, a study
by Real and co-workers that focused on the reaction of a
Table 1. Desymmetrization of 3-phenylglutaric anhydride by PhMgCl: a
survey of chiral ligands.[a]
Ph
[*] Prof. Dr. G. C. Fu, R. Shintani
Department of Chemistry
1.0 equiv
of ligand
O
Ph
O
PhMgCl
Massachusetts Institute of Technology
Cambridge, MA 02139 (USA)
Fax : (‡1)617-258-7500
Ph
OH
toluene
*
O
O
O
1.0 equiv
–78 °C, 9 h
E-mail: gcf@mit.edu
Entry
Ligand
ee [%]
Yield [%]
76
[**] We thank Ivory D. Hills for X-ray crystallographic work. Support has
been provided by Bristol-Myers Squibb, Novartis, Pfizer, and Phar-
macia. Funding for the MIT Department of Chemistry Instrumenta-
tion Facility has been furnished in part by NSF CHE-9808061 and NSF
DBI-9729592.
1[b]
2[b]
3
4
5
(‡)-1
(‡)-2
(‡)-3
(À)-4
(À)-5
1
1276
3266
39
77
63
88
Supporting information for this article is available on the WWW under
http://www.angewandte.com or from the author.
[a] All data are the average of two runs. [b] 2.0 equiv of PhMgCl was used.
Angew. Chem. Int. Ed. 2002, 41, No. 6
¹ WILEY-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002
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Table 3. Desymmetrization of anhydrides: scope.[a]
of these investigations have focused on the use of (À)-
sparteine to achieve asymmetric reactions of organolithium
reagents. The result described in Table 1, entry 5, represents a
rare example in which (À)-sparteine furnishes very good
enantiocontrol for a reaction of a Grignard reagent.[12, 13]
For the desymmetrization of 3-phenylglutaric anhydride by
PhMgCl, we subsequently determined that the use of a slight
excess of Grignard reagent/(À)-sparteine leads to an enhance-
ment in stereoselectivity (88% ee !92% ee) and an improve-
ment in yield (63% !91%; entry 5 of Table 1 vs. entry 1 of
Table 2). Under these conditions, a change in the electronic
nature of the Grignard reagent has a relatively moderate
influence on enantioselection (Table 2, entries 1 3), whereas
an increase in the steric demand has a very substantial impact
(entry 1 vs. entry 4).
R
1.3 equiv
O
R
O
(–)-sparteine
PhMgCl
Ph
OH
toluene
O
O
O
1.3 equiv
–78 °C, 24 h
Entry
R
ee [%]
Yield [%]
1
2
9291
Me
88
87
74
3
4
91
S
9287
Table 2. Desymmetrization of 3-phenylglutaric anhydride: a survey of
Grignard reagents.[a]
Ph
Me
Me
5
6
90
91
74
76
1.3 equiv
O
Ph
O
(–)-sparteine
ArMgX
Ar
OH
toluene
–78 °C, 24 h
O
O
O
Me
1.3 equiv
Me
Me
Entry
ArMgX
PhMgCl
p-MeOC6H4MgBr
p-FC6H4MgBr
o-TolMgCl
ee [%]
Yield [%]
7
9270
1[b]
2
3
9291
89
78
88
82
66
Me
Me
Me
8
91
87
84
51
4
37
[a] All data are the average of two runs. Ring openings in toluene provide
higher ee than reactions in Et2O or THF. At temperatures above À788C,
slightly lower enantioselection is observed. [b] PhMgBr and PhMgCl
furnish the same level of enantioselectivity.
9[b]
TBSO
[a] All data are the average of two runs. [b] TBS ˆ tert-butyldimethylsilyl.
We have also investigated the scope with respect to the
anhydride, and we have established that the reaction tolerates
a wide range of substituents and provides uniformly high ee
values (Table 3). Thus, substrates that bear hindered aromatic
(88% ee; entry 2) and heteroaromatic groups (91% ee;
entry 3) undergo desymmetrization with good enantioselec-
tivity. Benzyl-substituted (92% ee; entry 4), as well as a
sterically diverse array of alkyl-substituted (90 92% ee;
entries 5 8), anhydrides react to furnish ketoacids with
excellent enantioselectivity. The enantioselective ring-open-
ing of heteroatom-substituted anhydrides also proceeds with
high stereoselection (87% ee; entry 9).
philes by employing (À)-sparteine as a chiral ligand. These
À
C C bond-forming reactions proceed in good enantioselec-
tivity for a range of anhydrides. To the best of our knowledge,
this is the first general method wherein (À)-sparteine, which
exhibits remarkable versatility in enantioselective reactions of
organolithium compounds, has provided excellent stereocon-
trol in reactions of Grignard reagents. We anticipate that this
discovery will stimulate a wide array of studies of applications
of (À)-sparteine-complexed Grignard reagents in asymmetric
synthesis.
Received: December 13, 2001 [Z18376]
We can effectively desymmetrize not only monocyclic, but
also bicyclic anhydrides. Thus, meso 6 reacts with PhMgCl/
(À)-sparteine to generate the chiral ketoacid in good enan-
tiomeric excess [Eq. (2)].
[1] For overviews, see: a) M. C. Willis, J. Chem. Soc. Perkin Trans. 1 1999,
1765 1784; b) T.-L. Lo, Symmetry: A Basis for Synthesis Design,
Wiley-Interscience, New York, 1995, chap. 1.3; c) S. R. Magnuson,
Tetrahedron 1995, 51, 2167 2213.
[2] For a few recent examples, see: a) P. Magnus, I. K. Sebhat, J. Am.
Chem. Soc. 1998, 120, 5341 5342; b) B. M. Trost, L. S. Chupak, T.
L¸bbers, J. Am. Chem. Soc. 1998, 120, 1732 1740; c) I. M. Fellows,
D. E. Kaelin, Jr., S. F. Martin, J. Am. Chem. Soc. 2000, 122, 10781
10787; d) J. D. White, J. Kim, N. E. Drapela, J. Am. Chem. Soc. 2000,
122, 8665 8671; e) A. C. Spivey, S. J. Woodhead, M. Weston, B. I.
Andrews, Angew. Chem. 2001, 113, 791 793; Angew. Chem. Int. Ed.
2001, 40, 769 771.
1.3 equiv
O
O
O
O
O
(–)-sparteine
PhMgCl
Ph
OH (2)
toluene
–78 °C
24 h
1.3 equiv
6
82% ee
77% yield
[3] For leading references, see: A. C. Spivey, B. I. Andrews, Angew.
Chem. 2001, 113, 3227 3230; Angew. Chem. Int. Ed. 2001, 40, 3131
3134.
In summary, we have described the first enantioselective
desymmetrizations of anhydrides with carbon-based nucleo-
1058
¹ WILEY-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002
1433-7851/02/4106-1058 $ 17.50+.50/0
Angew. Chem. Int. Ed. 2002, 41, No. 6

COMMUNICATIONS
[4] a) For an early study, see: T. Rosen, C. H. Heathcock, J. Am. Chem.
Soc. 1985, 107, 3731 3733; b) for an overview and leading references,
see Ref. [1a].
[5] a) For an early study, see: J. Hiratake, Y. Yamamoto, J. Oda, J. Chem.
Soc. Chem. Commun. 1985, 1717 1719; b) for an overview and
leading references, see Ref. [3].
[6] a) K. Matsuki, H. Inoue, M. Takeda, Tetrahedron Lett. 1993, 34, 1167
1170; b) K. Matsuki, H. Inoue, A. Ishida, M. Takeda, M. Nakagawa, T.
Hino, Chem. Pharm. Bull. 1994, 42, 9 18.
[7] a) For an early study, see: M. North, G. Zagotto, Synlett 1995, 639
640; b) D. E. Hibbs, M. B. Hursthourse, I. G. Jones, W. Jones, K. M. A.
Malik, M. North, J. Org. Chem. 1999, 64, 5413 5421.
[8] S. D. Real, D. R. Kronenthal, H. Y. Wu, Tetrahedron Lett. 1993, 34,
8063 8066. After the submission of our manuscript, Rovis described
one example of a catalytic asymmetric desymmetrization of an
anhydride by ZnEt2 (79% ee): E. A. Bercot, T. Rovis, J. Am. Chem.
Soc. 2002, 124, 174 175.
[9] a) H. Nozaki, T. Aratani, R. Noyori, Tetrahedron Lett. 1968, 2087
2090; b) H. Nozaki, T. Aratani, R. Noyori, Tetrahedron Lett. 1968,
4097 4098; c) T. Aratani, T. Gonda, H. Nozaki, Tetrahedron Lett.
1969, 2265 2268.
[10] For a general review that includes the work of the Hoppe laboratory,
see: D. Hoppe, T. Hense, Angew. Chem. 1997, 109, 2376 2410; Angew.
Chem. Int. Ed. Engl. 1997, 36, 2282 2316.
[11] a) P. A. Beak, D. R. Anderson, M. D. Curtis, J. M. Laumer, D. J.
Pippel, G. A. Weisenburger, Acc. Chem. Res. 2000, 33, 715 727; b) P.
Beak, A. Basu, D. J. Gallagher, Y. S. Park, S. Thayumanavan, Acc.
Chem. Res. 1996, 29, 552 560.
alkylations normally favor nucleophilic addition to the less
substituted allyl terminus although ligands can influence this
selectivity.[1] Early results demonstrate the effectiveness of
Mo[3] and W[4] catalysts and, more recently, their ability to
induce enantioselectivity.[5] Such catalysts normally do not
work with heteroatom nucleophiles. Iridium catalysts have
been reported to favor attack on the more substituted carbon
with a carbon–and most recently nitrogen–nucleophile, but
the use of an oxygen nucleophile like phenol has not been
reported.[6] Rhodium catalysis has proven to be very interest-
ing in that the regioselectivity of the substitution is deter-
mined by the position of the leaving group.[7] Herein, we
report our preliminary observations that the ruthenium-
catalyzed reaction favors attack at the more substituted
carbon atom regardless of the regioisomeric nature of the
substrate and does so with complete retention of enantiomeric
purity when a chiral scalemic substrate is employed. This
study has led to a facile synthetic strategy to antidepressants
like fluoxetine,[8] the active ingredient of prozac, from
ephedrine.
Pioneering work in ruthenium-catalyzed allylic alkylation
by Watanabe et al. with the [Ru(cod)(cot)] (cod ˆ 1,5-cyclo-
octadiene; cot ˆ 1,3,5-cyclooctatriene) complex has indicated
a bias for attack at the more substituted terminus with some
nucleophiles, although only a 50:50 regioisomeric mixture was
obtained by using a cinnamyl carbonate and malonate
anion.[9] [CpRu(cod)Cl][10] (1) and [CpRu(PPh3)2Cl][11] (2)
have been employed together with heteroatom nucleophiles,
but the regioselectivity has not been satisfactorily addressed.
Our recent work on cyclocondensations of allenes and vinyl
ketones using [CpRu(NCCH3)3]PF6 (3) induced us to examine
this complex as a catalyst for regioselective allylic alkylation.
We chose the reaction shown in Equation (1) as a standard.
In contrast to the earlier reports in which 1 or 2 were used and
which required elevated temperatures, complex 3 effected the
[12] a) Kise and Yoshida have provided a single example of the addition of
an RLi/(À)-sparteine/MgBr2 mixture to an aldehyde: N. Kise, T. Urai,
J.-i. Yoshida, Tetrahedron: Asymmetry 1998, 9, 3125 3128; b) Oka-
moto and Yuki have applied RMgBr/(À)-sparteine to asymmetric
polymerization reactions: Y. Okamoto, K. Suzuki, T. Kitayama, H.
Yuki, H. Kageyama, K. Miki, N. Tanaka, N. Kasai, J. Am. Chem. Soc.
1982, 104, 4618 4624.
[13] For an NMR study of dineopentylmagnesium/(À)-sparteine, see: G.
Fraenkel, B. Appleman, J. G. Ray, J. Am. Chem. Soc. 1974, 96, 5113
5119.
A Stereospecific Ruthenium-Catalyzed Allylic
Alkylation**
Ph
LG
4
CH3O2C
Ph
CO2CH3
Barry M. Trost,* Pierre L. Fraisse, and Zachary T. Ball
CO2CH3
CO2CH3
Ph
(1)
NaCH(CO2CH3)2
Metal-catalyzed allylic alkylations provide a powerful tool
for the construction of complex molecules. One of the benefits
of such substitutions is the prospect that the regioselectivity
with unsymmetrical allyl substrates can be controlled by the
catalyst rather than the position of the allylic substituent
serving as the leaving group. Palladium-catalyzed allylic
6
5
a: LG = OCO2tBu
b: LG = OCO2CH3
c: LG = Cl
reaction of carbonate 4a at ambient temperature in DMF to
give a 1:2ratio of 5:6 in nearly quantitative yield. Attempts to
increase this selectivity by varying the reaction conditions
failed and thus we examined changes in the ligand. We
reasoned that a more sterically demanding catalyst might
favor the monosubstituted olefin adduct initially formed from
™branched∫ attack to afford 5. Under identical conditions with
carbonate 4a, [Cp*Ru(NCCH3)3]PF6 (7) (Cp* ˆ h5-C5Me5)
gave a 9:1 ratio of 5:6 (96% yield) in 2h. In acetone, the
selectivity increased to 19:1 (quantitative yield). Reactions of
the methyl carbonate 4b are generally faster. Indeed, in DMF
within 30 min, a quantitative yield of alkylation products was
obtained in a 14:1 ratio of 5:6 with only 1 mol% of catalyst 7.
[*] Prof. B. M. Trost, P. L. Fraisse, Z. T. Ball
Department of Chemistry
Stanford University
Stanford, CA 94305-5080 (USA)
Fax : (‡1)650-725-0002
E-mail: bmtrost@stanford.edu
[**] We thank the National Science Foundation and the National Institutes
of Health, and General Medical Sciences, for their generous support
of our programs. Mass spectra were provided by the Mass Spectrom-
etry Facility of the University of California San Francisco, supported
by the NIH Division of Research Resources.
Supporting information for this article is available on the WWW under
http://www.angewandte.com or from the author.
Angew. Chem. Int. Ed. 2002, 41, No. 6
¹ WILEY-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002
1433-7851/02/4106-1059 $ 17.50+.50/0
1059