A new structural motif for bifunctional bronsted acid/base organocatalysis

Article abstract of DOI:10.1002/anie.201000637

"Chemical equation presented" Naturally synthetic: Acid/base catalyst (S)-I can be used in highly enantioselective alcoholytic desymmetrizations of meso anhydrides. For example, the methanolysis of cyclobutane anhydride deriva-tive 2 gave hemiester 3 in 99:1 e.r. (see scheme). Ester 3 was used in a short enantioselective synthesis of (+ )-grandisol.

Full text of DOI:10.1002/anie.201000637

Communications
DOI: 10.1002/anie.201000637
Asymmetric Catalysis
A New Structural Motif for Bifunctional Brønsted Acid/Base
Organocatalysis**
Vijay N. Wakchaure and Benjamin List*
In recent years the concept of bifunctionality has enriched the
field of asymmetric catalysis. Impressive progress has been
made particularly in the area of enantioselective transition-
metal catalysis,[1] but bifunctional organocatalysis is also being
appreciated increasingly.[2] Indeed, various acids and bases
have been combined to generate powerful organocatalysts
that effectively orient substrates in an enzymelike manner.
Remarkably though, the vast majority of these structures are
based on natural products, such as proline and the cinchona
alkaloids, whilst fully synthetic catalysts are rare.[3] Herein, we
report the design and successful implementation of a new
Brønsted acid/base motif for the highly enantioselective
desymmetrization of meso anhydrides.
and access to both enatiomeric products with the same high
enantioselectivity is not always ensured. Because of this and
because new motifs for bifunctional organocatalysis are
always needed, we became interested in exploring alternative
fully synthetic structures. Our design is inspired by BINOL-
derived phosphoric acids, recently introduced to asymmetric
catalysis by Akiyama and Terada.[14] We were curious if it
would be possible to incorporate a more basic site into such
structures while retaining an acid functional group. We
reasoned that this concept may be realized with structure A
(Scheme 1), in which the base, which also has a Brønsted
acidic site, is incorporated by means of a phosphoramide
bond.[15]
The alcoholytic catalytic asymmetric desymmetrization of
meso anhydrides is a powerful strategy for the preparation of
enantiomerically pure hemiesters, which are valuable build-
ing blocks for the synthesis of various natural products and
biologically active substances.[4–6] Oda and Aitken pioneered
a
cinchona-alkaloid-catalyzed approach which furnished
moderate enantioselectivities.[7,8] Bolm et al. developed a
variant in which 110 mol% of either quinine or quinidine is
utilized. This method generally provides excellent enantiose-
lectivity (up to 99:1 e.r.) and is used frequently both in
academic and industrial laboratories.[9] Later, Deng et al.
introduced commercially available modified cinchona-alka-
loid-derived Sharpless ligands (DHQD)2AQN and its pseu-
doenantiomer (DHQ)2AQN as catalysts (5–20 mol%), which
also give high enantioselectivity.[10] More recently, Song et al.
and Connon et al. observed highly enantioselective metha-
nolyses of cyclic anhydrides catalyzed by cinchona-derived
amine–thiourea bifunctional organocatalyst (10 mol%) at
room temperature.[11,12] A remarkable breakthrough has been
achieved very recently by Song et al.: they developed a robust
cinchona-derived sulfonamide-based bifunctional organoca-
talyst, which shows unprecedented catalytic activity and
excellent enantioselectivity in the methanolytic desymmetri-
zation of meso cyclic anhydrides.[13]
Scheme 1. Design of a new bifunctional chiral Brønsted acid/base
catalyst.
Indeed, several bifunctional chiral Brønsted acid/base
catalysts (3c–i, Table 1, also see the Supporting Information)
were synthesized from the corresponding optically active
BINOL derivatives by phosphorylation or thiophosphoryla-
tion followed by amidation with aminopyridines or pyrimi-
dines. Their catalytic activity and enantioselectivity were
examined in the asymmetric methanolysis of cis-1,2-cyclo-
hexanedicarboxylic anhydride (1a) in toluene in the presence
of 10 equivalents of methanol. Remarkably, in comparison
with phosphoric acid 3a and phosphoramide 3b (both of
which are often considered bifunctional catalysts), the novel
Brønsted acid/base catalyst 3c was far more active and gave
the corresponding hemiester product 2a with a high enantio-
selectivity of 90:10 e.r. (Table 1, entries 1–3). We next studied
the position of nitrogen in the pyridine ring; catalyst 3d,
which was prepared from 3-aminopyridine, was found to be
less reactive and poorly enantioselective (Table 1, entry 4).
Similarly, catalyst 3e derived from 4-aminopyridine gave very
low enantioselectivity and the opposite enantiomer of prod-
uct 2a (Table 1, entry 5). Also,when an additional basic site
was introduced with the incorporation of 2-aminopyrimidine
into catalyst 3 f, no improvement was observed (Table 1,
entry 6). Furthermore, we investigated electronic effects with
the electron-rich, DMAP-like catalyst 3g and its electron-
poor variant 3h, which gave inferior results (Table 1, entries 7
Despite these important advances in bifunctional organo-
catalysis, modification of the cinchona alkaloids is limited,
[*] Dr. V. N. Wakchaure, Prof. Dr. B. List
Max-Planck-Institut fꢀr Kohlenforschung
Kaiser Wilhelm-Platz 1, 45470 Mꢀlheim an der Ruhr (Germany)
Fax: (+49)208-306-2982
E-mail: list@mpi-muelheim.mpg.de
[**] The authors acknowledge generous funding from the Max Planck
Society, the DFG (SPP 1179, Organocatalysis), the Fonds der
Chemischen Industrie, and Wacker Chemie AG.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201000637.
4136
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2010, 49, 4136 –4139

Angewandte
Chemie
Table 1: Catalyst screening.
the desired product 2a even at À358C. Moreover, at this
temperature, the enantioselectivity increased to 96:4 e.r.
(Table 1, entry 13).
With the promising bifunctional organocatalyst 3i in
hand, we next examined its scope and limitation in the
desymmetrization of various meso cyclic anhydrides under
optimized reaction conditions. As shown in Table 2, bicyclic
(entries 1–5) and tricyclic anhydrides (entries 6 and 7) were
readily converted into the corresponding hemiester products
in high yields and enantioselectivities. Only in the case of
cyclopropane derivative 1e (entry 5 Table 2,) and the mono-
Entry
Cat.
X
Y
t
Conv. [%][a]
e.r.[b]
[h]
Table 2: Substrate scope.[a]
1
2
3a
3b
O
O
OH
NHTf
24
24
80
80
61:39
0
3
4
5
3c
3d
3e
O
O
O
5
8
8
quant.
quant.
quant.
90:10
60:40
46:54
6
7
3 f
O
O
8
5
quant.
quant.
74:26
77:23
3g
Entry
Anhydride
Product
t
[d]
T
[8C]
Yield
[%][b]
e.r.[c]
8
3h
O
23
95
77:23
1
2
3
1
5
5
À35
À30
À20
97
92
95
96:4
95:5
96:4
9
3i
3i
3i
3i
3i
S
S
S
S
S
3
quant.
quant.
quant.
quant.
quant.
90:10
90:10
90:10
91:9
10[c]
11[d]
12[e]
13[f]
3
3
4[d]
1.5
4
À35
À20
À20
À10
À35
97
94
81
88
95
99:1
91:9
95:5
95:5
91:9
5
24
96:4
5[d,e]
[a] From NMR analysis. [b] Determined by HPLC analysis on a chiral
stationary phase (see the Supporting Information); quant.=quantita-
tive. [c] The reaction was carried out in toluene (1.0m). [d] The reaction
was carried out in toluene (0.1m). [e] The reaction was carried out at
08C. [f] The reaction was carried out at À358C.
6[d]
6
7[d,e]
6
and 8). Gratifyingly, we found that the sulfur analogue 3i was
more reactive than catalyst 3c and just as enantioselective
(Table 1, entry 9), and this catalyst was selected for further
optimization. More interestingly, we found that the stereose-
lectivity of the Brønsted acid/base catalyst 3i does not show
significant concentration dependence (Table 1, entries 9–11).
The bifunctional Brønsted acid/base catalyst 3i proved to
be a highly active catalyst and gave full conversion of 1a to
8[d]
4
[a] Reaction scale: 0.5 mmol. [b] Yield of isolated product. [c] Deter-
mined by HPLC analysis on a chiral stationary phase (see the Supporting
Information). [d] The reaction was carried out in toluene (0.25m). [e] The
reaction was carried out with 3i (15 mol%).
Angew. Chem. Int. Ed. 2010, 49, 4136 –4139
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
4137

Communications
cyclic substrate 1h (entry 8) were enantioselectivities below
95:5 e.r. observed.
The exceptionally high enantioselectivity in the metha-
nolysis of cyclobutane anhydride 1d (99:1 e.r.) to furnish
hemiester product 2d is particularly noteworthy when
compared with the results obtained by employing the best
known alternative methods (94:6/3:97 e.r. with Bolmꢀs
method using stoichiometric amounts of quinine or quinidi-
ne,[9b] 98:2 e.r. with Songꢀs cinchona-derived sulfonamide
catalyst, and 6:94 e.r. with Dengꢀs method using
(DHQD)2AQN as the catalyst (see the Supporting Informa-
tion). In addition, using our methodology, the opposite
enantiomer of 2d can be prepared with the same enantiose-
lectivity by using catalyst (R)-3i (Table 3, entry 2).
Scheme 2. Formal synthesis of (+)-grandisol.
subjecting lactone 6 to potassium tert-butoxide in DMF at
higher temperature resulted in the clean elimination furnish-
ing carboxylic acid 7 in 75% yield. The absolute configuration
of intermediate 7 was determined by comparison of its optical
rotation with the literature value.[17] Olefin 7 has already been
transformed into (+)-grandisol, and our sequence therefore
constitutes a formal synthesis.[17,18] In fact, of the catalytic
asymmetric total syntheses of grandisol reported to date, our
synthesis requires the fewest steps.
Table 3: Asymmetric alcoholysis of cyclic anhydride 1d with different
alcohols.[a]
Entry
ROH
Hemiester
T
Yield
[%][b]
e.r.[c]
[8C]
In conclusion, we have successfully developed a novel
bifunctional chiral Brønsted acid/base organocatalyst 3i,
which shows good catalytic activity and good to excellent
enantioselectivity in the methanolytic desymmetrization of a
variety of meso cyclic anhydrides. Alcohols other than
methanol were effective nucleophiles in the desymmetriza-
tion reaction and also provided excellent enantioselectivities.
In addition, the synthetic utility of this methodology was
demonstrated with the formal synthesis of (+)-grandisol. We
are currently investigating the intriguing mode of action of
our novel organocatalyst motif as well as its application in
other transformations.
1[d]
2[d,e]
3[f]
methanol
methanol
ethanol
1-propanol
2-propanol
propargyl alcohol
2d
ent-2d
2i
2j
2k
À35
À35
À30
À30
10
97
94
98
93
91
91
99:1
99:1
97:3
98:2
97:3
97:3
4[f]
5[f,g]
6[f]
2l
À30
[a] Reaction scale: 0.5 mmol. [b] Yield of isolated product. [c] Deter-
mined by HPLC analysis on a chiral stationary phase (see the Supporting
Information). [d] Reaction time: 36 h. [e] The reaction was carried out
with (R)-3i. [f] Reaction time: 4 d. [g] The reaction was carried out in
toluene (0.4m).
Received: February 2, 2010
Published online: May 7, 2010
The strength and scope of our methodology is further
demonstrated in the alcoholysis of anhydride 1d with differ-
ent alcohols (Table 3). Rather independent of the steric
demand of the alcohol, high enantioselectivity was also
obtained in all cases including those with ethanol, 1-propanol,
2-propanol, and propargyl alcohol (Table 3, entries 3–6).
To illustrate the synthetic utility of our methodology, a
short formal synthesis of (+)-grandisol, the main component
of the sex pheromone of the cotton boll weevil, Anthonomous
grandis Boheman, and other insects, was developed
(Scheme 2).[16] As shown before (Table 3, entry 1), methanol-
ysis of anhydride 1d gave the corresponding hemiester 2d in
97% yield and in 99:1 e.r. Upon treatment of ester 2d with
MeMgCl, lactone 4 was formed in 90% yield. Surprisingly, we
found that when we tried to obtain the corresponding a-
methylated lactone 6 by sequential addition of lithium
diisopropylamide (LDA) to lactone 4 followed by MeI at
À788C only Claisen condensation product 5 was formed.
Remarkably though, the intended a-alkylation could indeed
be effected by adding LDA to a premixed solution of lactone
4 and MeI at À788C. Under these conditions, lactone 6 was
obtained in gratifying 82% yield. Finally, we found that
Keywords: asymmetric catalysis · bifunctional catalysis ·
.
desymmetrization · organocatalysis
[1] For a review, see: a) M. Shibasaki, M. Kanai, S. Matsunaga, N.
Kumagai, Acc. Chem. Res. 2009, 42, 1117 – 1127; also see:
b) D. H. Paull, C. J. Abraham, M. T. Scerba, E. Alden-Danforth,
T. Lectka, Acc. Chem. Res. 2008, 41, 655 – 663.
[2] a) Asymmetric Organocatalysis: From Biomimetic Concepts to
Applications in Asymmetric Synthesis (Eds.: A. Berkessel, H.
Grꢁger), Wiley-VCH, Weinheim, 2005; b) B. List, J. W. Yang,
Science 2006, 313, 1584 – 1586; c) D. W. C. MacMillan, Nature
2008, 455, 304 – 308; d) Also see: Organocatalysis edition Chem.
Rev. 2007, 107.
[3] For selected bifunctional organocatalysts, see: demethylated
cinchona alkaloids: a) Y. Iwabuchi, M. Nakatani, N. Yokoyama,
S. Hatakeyama, J. Am. Chem. Soc. 1999, 121, 10219 – 10220;
b) H. Li, Y. Wang, L. Deng, J. Am. Chem. Soc. 2004, 126, 9906 –
9907; proline derivatives: c) B. List, Tetrahedron 2002, 58, 5573 –
5590; cinchona–urea derivatives: d) B. Vakulya, S. Varga, A.
Csꢂmpai, T. Soꢃs, Org. Lett. 2005, 7, 1967 – 1969; e) B.-J. Li, L.
4138
www.angewandte.org
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2010, 49, 4136 –4139

Angewandte
Chemie
Jiang, M. Liu, Y.-C. Chen, L.-S. Ding, Y. Wu, Synlett 2005, 603 –
606; f) J. Ye, D. J. Dixon, P. S. Hynes, Chem. Commun. 2005,
4481 – 4483; g) S. H. McCooey, S. J. Connon, Angew. Chem.
2005, 117, 6525 – 6528; Angew. Chem. Int. Ed. 2005, 44, 6367 –
6370; h) J. Song, Y. Wang, L. Deng, J. Am. Chem. Soc. 2006, 128,
6048 – 6049; i) J. Lubkoll, H. Wennemers, Angew. Chem. 2007,
119, 6965 – 6968; Angew. Chem. Int. Ed. 2007, 46, 6841 – 6844;
trans-diaminocyclohexane–urea derivatives: j) T. Okino, Y.
Hoashi, Y. Takemoto, J. Am. Chem. Soc. 2003, 125, 12672 –
12673; k) T. Okino, S. Nakamura, T. Furukawa, Y. Takemoto,
Org. Lett. 2004, 6, 625 – 627; l) A. Berkessel, S. Mukherjee, F.
Cleemann, T. N. Mꢄller, J. Lex, Chem. Commun. 2005, 1898 –
1900; m) A. Berkessel, F. Cleemann, S. Mukherjee, T. N. Mꢄller,
J. Lex, Angew. Chem. 2005, 117, 817 – 821; Angew. Chem. Int. Ed.
2005, 44, 807 – 811; n) Y.-Q. Fang, E. N. Jacobsen, J. Am. Chem.
Soc. 2008, 130, 5660 – 5661.
[10] Y.-G. Chen, S.-K. Tian, L. Deng, J. Am. Chem. Soc. 2000, 122,
9542 – 9543.
[11] a) H. S. Rho, S. H. Oh, J. W. Lee, J. Y. Lee, J. Chin, C. E. Song,
Chem. Commun. 2008, 1208 – 1210; b) A. Peschiulli, Y. Gunꢀko,
S. J. Connon, J. Org. Chem. 2008, 73, 2454 – 2457.
[12] For thiolysis of meso cyclic anhydrides, see: a) T. Honjo, S. Sano,
M. Shiro, Y. Nagao, Angew. Chem. 2005, 117, 5988 – 5991;
Angew. Chem. Int. Ed. 2005, 44, 5838 – 5841; for polymer-
supported cinchona-based bifunctional sulfonamide catalysis,
see: b) S. H. Youk, S. H. Oh, H. S. Rho, J. E. Lee, J. W. Lee, C. E.
Song, Chem. Commun. 2009, 2220 – 2222; for non-alkaloid-
derived catalysis for this reaction, see: c) Y. Uozumi, K.
Yasoshima, T. Miyachi, S.-I. Nagai, Tetrahedron Lett. 2001, 42,
411 – 414; d) T. Okamatsu, R. Irie, T. Katsuki, Synlett 2007,
1569 – 1572; e) S.-X. Wang, F.-E. Chen, Adv. Synth. Catal. 2009,
351, 547 – 552; f) T. Honjo, T. Tsumura, S. Sano, Y. Nagao, K.
Yamaguchi, Y. Seib, Synlett 2009, 3279 – 3282.
[4] For reviews on the asymmetric alcoholysis of cyclic anhydrides,
see: a) A. C. Spivey, B. I. Andrews, Angew. Chem. 2001, 113,
3227 – 3230; Angew. Chem. Int. Ed. 2001, 40, 3131 – 3134; b) Y.-
G. Chen, P. McDaid, L. Deng, Chem. Rev. 2003, 103, 2965 – 2983;
c) I. Atodiresei, I. Schiffers, C. Bolm, Chem. Rev. 2007, 107,
5683 – 5712.
[5] For catalytic anhydride desymmetrizations using organometallic
nucleophiles, see: a) J. B. Johnson, T. Rovis, Acc. Chem. Res.
2008, 41, 327 – 338; b) M. J. Cook, T. Rovis, Synthesis 2009, 335 –
338.
[6] For chiral Lewis acid mediated desymmetrizations of anhy-
drides, see: a) M. Shimizu, K. Matsukawa, T. Fujisawa, Bull.
Chem. Soc. Jpn. 1993, 66, 2128 – 2130; b) D. Seebach, G.
Jaeschke, Y. M. Wang, Angew. Chem. 1995, 107, 2605 – 2606;
Angew. Chem. Int. Ed. Engl. 1995, 34, 2395 – 2396; c) G.
Jaeschke, D. Seebach, J. Org. Chem. 1998, 63, 1190 – 1197.
[7] a) J. Hiratake, Y. Yamamoto, J. Oda, J. Chem. Soc. Chem.
Commun. 1985, 1717 – 1719; b) J. Hiratake, M. Inagaki, Y.
Yamamoto, J. Oda, J. Chem. Soc. Perkin Trans. 1 1987, 1053 –
1058.
[8] a) R. A. Aitken, J. Gopal, J. A. Hirst, J. Chem. Soc. Chem.
Commun. 1988, 632 – 634; b) R. A. Aitken, J. Gopal, Tetrahe-
dron: Asymmetry 1990, 1, 517 – 520.
[9] a) C. Bolm, A. Gerlach, C. L. Dinter, Synlett 1999, 195 – 196;
b) C. Bolm, I. Schiffers, C. L. Dinter, A. Gerlach, J. Org. Chem.
2000, 65, 6984 – 6991; c) C. Bolm, I. Schiffers, I. Atodiresei,
C. P. R. Hackenberger, Tetrahedron: Asymmetry 2003, 14, 3455 –
3467; d) B. Rodrꢅguez, T. Rantanen, C. Bolm, Angew. Chem.
2006, 118, 7078 – 7080; Angew. Chem. Int. Ed. 2006, 45, 6924 –
6926.
[13] S. H. Oh, H. S. Rho, J. W. Lee, J. E. Lee, S. H. Youk, J. Chin,
C. E. Song, Angew. Chem. 2008, 120, 7990 – 7993; Angew. Chem.
Int. Ed. 2008, 47, 7872 – 7875.
[14] For reviews, see: a) T. Akiyama, Chem. Rev. 2007, 107, 5744 –
5758; b) M. Terada, Chem. Commun. 2008, 4097 – 4112; for
selected recent examples, see: c) S. Hoffmann, A. M. Seayad, B.
List, Angew. Chem. 2005, 117, 7590 – 7593; Angew. Chem. Int.
Ed. 2005, 44, 7424 – 7427; d) X. Cheng, S. Vellalath, R. Goddard,
B. List, J. Am. Chem. Soc. 2008, 130, 15786 – 15787; e) M.
Rueping, A. P. Antonchick, Angew. Chem. 2008, 120, 10244 –
10247; Angew. Chem. Int. Ed. 2008, 47, 10090 – 10093; f) G.
Adair, S. Mukherjee, B. List, Aldrichimica Acta 2008, 41, 31 – 39;
g) S. E. Larson, J. C. Baso, G. Li, J. C. Antilla, Org. Lett. 2009, 11,
5186 – 5189; h) S. Mꢄller, B. List, Angew. Chem. 2009, 121,
10160 – 10163; Angew. Chem. Int. Ed. 2009, 48, 9975 – 9978; i) F.-
L. Sun, M. Zeng, Q. Gu, S.-L. You, Chem. Eur. J. 2009, 15, 8709 –
8712; j) M. E. Muratore, C. A. Holloway, A. W. Pilling, R.
Ian Storer, G. Trevitt, D. J. Dixon, J. Am. Chem. Soc. 2009, 131,
10796 – 10797.
[15] D. Nakashima, H. Yamamoto, J. Am. Chem. Soc. 2006, 128,
9626 – 9627.
[16] a) J. H. Tumlinson, D. D. Hardee, R. C. Gueldner, A. C. Thomp-
son, P. A. Hedin, J. P. Minyard, Science 1969, 166, 1010 – 1012;
b) J. H. Tumlinson, R. C. Gueldner, D. D. Hardee, A. C. Thomp-
son, P. A. Hedin, J. P. Minyard, J. Org. Chem. 1971, 36, 2616 –
2621.
[17] K. Mori, K. Fukamatsu, Liebigs Ann. Chem. 1992, 489 – 493.
[18] For alternative asymmetric total and partial syntheses of
grandisol, see: A. Frongia, C. Girard, J. Ollivier, P. Paolo Piras,
F. Secci, Synlett 2008, 2823 – 2825, and references therein.
Angew. Chem. Int. Ed. 2010, 49, 4136 –4139
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
4139