Direct enantio- and diastereoselective Mannich reactions of malonate and β-keto esters with N-Boc and N-Cbz aldimines catalysed by a bifunctional cinchonine derivative

Article abstract of DOI:10.1039/b515725k

A highly enantioselective Mannich reaction between malonate esters and N-Boc and N-Cbz aldimines, catalysed by a bifunctional cinchonine derivative, has been developed; extension of this methodology to encompass the use of 2-substituted-1,3-dicarbonyl nuc

Full text of DOI:10.1039/b515725k

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Direct enantio- and diastereoselective Mannich reactions of malonate
and b-keto esters with N-Boc and N-Cbz aldimines catalysed by a
bifunctional cinchonine derivative{
A. Louise Tillman,a Jinxing Yeb and Darren J. Dixon*b
Received (in Cambridge, UK) 4th November 2005, Accepted 20th December 2005
First published as an Advance Article on the web 1st February 2006
DOI: 10.1039/b515725k
N-protected b-amino carbonyl compounds. This approach also
provides the potential to generate b-amino acid derivatives bearing
a-quaternary centres in high relative and absolute control.
We recently reported thiourea 1 (Fig. 1) to be a highly selective
catalyst for the enantioselective conjugate addition of malonate
nucleophiles to nitro olefins.11,12 This catalyst emerged from our
search for new organic, asymmetric Brønsted base/Brønsted acid
bifunctional catalysts based around the relatively rigid 9-amino(9-
deoxy) epi-Cinchona alkaloid skeleton.13 It was envisaged that the
bridgehead nitrogen in 1 would activate the nucleophile whilst the
thiourea moiety would simultaneously activate and organize
the N-acyl imine through hydrogen bonding interactions. We
hoped that the three dimensional spatial arrangement of the
components would yield the desired products with high levels of
stereocontrol.
A highly enantioselective Mannich reaction between malonate
esters and N-Boc and N-Cbz aldimines, catalysed by a
bifunctional cinchonine derivative, has been developed; exten-
sion of this methodology to encompass the use of 2-substituted-
1,3-dicarbonyl nucleophiles allows the formation of adjacent
stereocentres, one of which is quaternary, in high relative and
absolute stereocontrol.
The b-amino acid motif is found in a vast array of biologically
active natural products and pharmaceutical compounds, as well as
pseudopeptide materials with unusual structural properties. In
addition these compounds are useful chiral starting materials in the
synthesis of bioactive amine containing natural products such as
those belonging to the alkaloid family.1
For their enantioselective synthesis, the Mannich reaction has
revealed itself as an efficient and powerful method allowing the
generation of up to two stereogenic centres in a single carbon–
carbon bond-forming event.2 Asymmetric, metal catalysed
Mannich reactions have been shown to be highly successful and
are well documented in the literature.3,4 Lately organocatalytic
approaches have been introduced5,6 to circumvent the problems
commonly associated with conventional metal catalysis.7 For
example, Uraguchi and Terada have developed a new BINOL-
derived phosphoric acid to catalyse the addition of acetylacetone
to N-Boc imines in a highly enantioselective fashion.8 More
recently, Jørgensen et al. have reported a highly enantio- and
diastereoselective Mannich reaction using a-substituted a-cyanoa-
cetates, catalysed by cinchonine derived catalyst (DHQD)2PYR.9a
Also Schaus et al. have used cinchonine itself to catalyse the highly
enantioselective addition of b-keto esters to N-methyloxycarbonyl
imines.9b
Initially we evaluated the use of catalyst 1 in the addition of
acetylacetone 2 to N-Boc benzaldimine 3. When the reaction was
performed in toluene at room temperature in the presence of
10 mol% 1, product 6 was isolated in quantitative yield with an
encouraging 37% ee.14 Further tuning of the conditions found the
reaction to be optimal when performed in toluene at 278 uC for
72 h, producing 6 in quantitative yield and 82% ee (Table 1).
Variation of the aldimine N-protecting group revealed that N-Cbz
benzaldimine 4 was also an excellent substrate, affording 7 in 73%
yield and 86% ee. However a significant drop in enantioselectivity
was observed when N-ethyloxycarbonyl imine 5 was used as the
electrophile.15
Having established thiourea 1 as an effective catalyst for this
reaction type, a range of commercially available malonate esters
was investigated as potential nucleophilic substrates. In all cases,
good to excellent yields of the desired products were obtained
(Table 2). However the enantioselectivity dropped when the size of
the alkyl group on the ester was increased. Dimethyl and diethyl
With the goal of creating a technically simple, scalable and
metal free Mannich reaction, we became interested in the
possibility of identifying an effective asymmetric organic catalyst
for the addition of 1,3-dicarbonyls to N-acyl aldimines. The
commercial availability of the nucleophilic components and the
facile synthesis of N-Boc and N-Cbz arylaldimines10 make this an
ideal strategy for the synthesis of enantiomerically enriched
aUniversity of Cambridge, Chemical Laboratory, Lensfield Road,
Cambridge, UK CB2 1EW
bSchool of Chemistry, The University of Manchester, Oxford Road,
Manchester, UK M13 9PL. E-mail: Darren.Dixon@manchester.ac.uk;
Tel: +44 (0) 161 275 1426
{ Electronic supplementary information (ESI) available: Details of the
procedure and spectral data for all products and HPLC traces. See DOI:
10.1039/b515725k
Fig. 1 Bifunctional catalyst 1.
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Table 1 Preliminary investigations into the addition of acetylacetone
2 to imines 3–5 in the presence of bifunctional catalyst 1
Table 3 Scope of the asymmetric addition of dimethyl malonate 9 to
N-Boc and N-Cbz arylaldimines 16 and 17 catalysed by 1
Imine R1
R2
Yield (%)a ee (%)b
Product
Imine R1
Solvent Temp/uC Yield (%)a ee (%)b Product
16a
16b
16c
16d
17a
17b
17c
17d
a
t-Bu 2-Furanyl
t-Bu 2-Naphthyl
t-Bu p-ClC6H4
95
85
85
94
96
18a
18b
3
3
3
3
4
5
a
t-Bu Toluene rt
t-Bu Toluene 278
.99
.99
94
87
73
37
82
64
76
86
NDc
6
6
6
6
7
8
87 (97)c 18c
t-Bu DCM
t-Bu Et2O
278
278
t-Bu m-MeOC6H4 89
88
97
83
97
97
18d
19a
19b
19c
19d
Bn
Bn
Bn
Bn
2-Furanyl
3-Pyridyl
1-Naphthyl
o-ClC6H4
96
81
.99
93
Bn
Et
Toluene 278
Toluene 278
.99
b
Isolated yields after column chromatography.
Enantiomeric
c
excess was determined by HPLC analysis. Incomplete separation
was attained for this compound—the ee was estimated to be around
50%.
b
Isolated yields after column chromatography.
Enantiomeric
c
excess was determined by HPLC analysis. Enantiomeric excess
after one recrystallisation from hexane.
Table 2 Addition of malonates 9–11 to imines 3 and 5 in the presence
of bifunctional catalyst 1
Table 4 Enantio- and diastereoselective additions of methylcyclo-
pentanone-2-carboxylate 20 to imines catalysed by 1
Malonate R1
R2
Solvent Yield (%)a ee (%)b Product
R
Yield (%)a
dr
ee (%)b
Product
9
9
10
11
9
Me
Me
Et
t-Bu DCM
t-Bu Toluene .99
t-Bu Toluene 96
76
87
89
78
7
12
12
13
14
15
Ph
70
83
97
16 : 1
20 : 1
18 : 1
85
87
84
21a
21b
21c
2-Naphthyl
2-Furanyl
a
t-Bu t-Bu Toluene 81
Me Bn Toluene 86
b
Isolated yields after column chromatography.
excess was determined by HPLC analysis.
Enantiomeric
92
a
b
Isolated yields after column chromatography.
excess was determined by HPLC analysis.
Enantiomeric
of stereogenic quaternary a-centres. Accordingly, catalyst 1 was
used to promote the reaction between methyl cyclopentanone-2-
carboxylate 20 and a selection of imines using the optimised
reaction conditions. The N-Boc imines were identified as the
substrates of choice and in all cases products 21 were formed in
good yield (70–97%) and with high levels of diastereocontrol (16 : 1
to 20 : 1 dr) (Table 4). Furthermore the enantiomeric excess of the
major diastereomer was uniformly good (84–87%). The relative
stereochemistry of the major diastereomer was unambiguously
determined by single crystal X-ray diffraction of 21b (Fig. 2).{
A simple one step dealkyl, decarboxylation was performed on
Mannich products 12 and 15, to afford the corresponding b-amino
esters 22 and 23 in good yield (Scheme 1) without observable
malonate additions to 3 gave 12 and 13 in 89% and 78% ee
respectively, but little stereoinduction was observed when the same
reaction was performed with di-tert-butyl malonate; 14 was
afforded in only 7% ee. Interestingly, a slightly improved
enantioselectivity was observed for the addition to N-Cbz imine
4 (92% ee, entry 5 of Table 2) when compared to the N-Boc imine
(89% ee, entry 2). The high level of stereoinduction obtained in
both cases highlights the practical utility of the chemistry; useful
and orthogonal N-protecting groups can be installed directly into the
b-amino ester products.16
Investigations into the scope of this reaction showed it to be
general for a wide range of N-Boc and N-Cbz protected ortho-,
meta- and para-substituted aromatic and heteroaromatic aldimines
(Table 3). In general, the products 18 and 19 were formed in high
yields (81–99%) and excellent enantiomeric excess (83–97%). More
specifically, entries 5, 7 and 8 highlight the power of this chemistry;
N-Cbz imines bearing the structurally and electronically varied
2-furanyl, 1-naphthyl and o-chlorophenyl all yielded their
respective products with 97% ee.
It was decided to extend this methodology to encompass the use
of 2-alkyl-1,3-dicarbonyls as nucleophiles, leading to the formation
Fig. 2 Single crystal X-ray structure of 21b.
1192 | Chem. Commun., 2006, 1191–1193
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4 Selected direct Mannich reaction: (a) S. Yamasaki, T. Iida and
M. Shibasaki, Tetrahedron Lett., 1999, 40, 307–310; (b) K. Juhl,
N. Gathergood and K. A. Jørgensen, Angew. Chem., Int. Ed., 2001, 40,
2995–2997; (c) Y. Hamashima, N. Sasamoto, D. Hotta, H. Somei,
N. Umebayashi and M. Sodeoka, Angew. Chem., Int. Ed., 2005, 44,
1525–1529; (d) T. Yoshida, H. Morimoto, N. Kumagai, S. Matsunaga
and M. Shibasaki, Angew. Chem., Int. Ed., 2005, 44, 3470–3474; (e)
S. Harada, S. Handa, S. Matsunaga and M. Shibasaki, Angew. Chem.,
Int. Ed., 2005, 44, 4365–4368.
5 Reviews on asymmetric organocatalysis: (a) P. I. Dalko and L. Moisan,
Angew. Chem., Int. Ed., 2001, 40, 3726–3748; (b) B. List, Tetrahedron,
2002, 58, 5573–5590; (c) P. I. Dalko and L. Moisan, Angew. Chem., Int.
Ed., 2004, 43, 5138–5175; (d) J. Seayad and B. List, Org. Biomol. Chem.,
2005, 3, 719–724; (e) for the pioneering proline-catalysed asymmetric
Mannich reaction see: B. List, J. Am. Chem. Soc., 2000, 122, 9336–9337.
6 Asymmetric organocatalysed Mannich reaction with ketene silyl acetal:
(a) A. G. Wenzel and E. N. Jacobsen, J. Am. Chem. Soc., 2002, 124,
12964–12965; (b) T. Akiyama, J. Itoh, K. Yokota and K. Fuchibe,
Angew. Chem., Int. Ed., 2004, 43, 1566–1568.
7 B. Fubini and L. O. Area´n, Chem. Soc. Rev., 1999, 28, 373–382.
8 D. Uraguchi and M. Terada, J. Am. Chem. Soc., 2004, 126, 5356–5357.
9 (a) T. B. Poulsen, C. Alemparte, S. Saaby, M. Bella and K. A. Jørgensen,
Angew. Chem., Int. Ed., 2005, 44, 2896–2899; (b) S. Lou, B. M. Taoka,
A. Ting and S. E. Schaus, J. Am. Chem. Soc., 2005, 127, 11256–11257.
10 All N-Boc imine substrates were made using the procedure reported by
Wenzel and Jacobsen.6a N-Cbz substrates were synthesized using a
method adapted from the Jacobsen procedure (see supporting
information{).
Scheme 1 Racemisation-free dealkyl, decarboxylation of Mannich
products 12 and 15.
racemisation. As well as demonstrating the synthetic utility of this
methodology, synthesis of 22 and 23 allowed us to confirm the
absolute stereochemistry of the products of these reactions as (S)
by comparison of their specific rotations with literature values.17
In summary, a bifunctional cinchonine derived catalyst 1 has
been found to efficiently promote the highly enantio- and
diastereoselective addition of 1,3-dicarbonyls to N-Boc and
N-Cbz aldimines. This provides an efficient synthesis of b-amino
esters containing up to two adjacent stereocentres, one of which
can be quaternary. Further investigations into the application of 1
in new and powerful enantioselective reactions are currently in
progress and the results will be reported in due course.
We gratefully acknowledge the Sims Fund, University of
Cambridge, for a scholarship (to A. L. T.) and the Royal
Society & FCO Chevening China Fellowship (to J. Y.). We are
also indebted to the EPSRC National Mass Spectrometry Service
Centre, Swansea, UK for analysis, Dr John Davies for X-ray
analysis and Dr Stuart Warren for the use of a chiral stationary
phase HPLC column.
11 (a) J. Ye, D. J. Dixon and P. S. Hynes, Chem. Commun., 2005,
4481–4483. See also; (b) S. H. McCooey and S. J. Connon, Angew.
Chem., Int. Ed., 2005, 44, 6367–6370; (c) B. Vakulya, S. Varga,
A. Csampai and T. Soo´s, Org. Lett., 2005, 7, 1967–1969.
12 Selected bifunctional organocatalysis: (a) T. Okino, Y. Hoashi and
Y. Takemoto, J. Am. Chem. Soc., 2003, 125, 12672–12673; (b) T. Okino,
S. Nakamura, T. Furukawa and Y. Takemoto, Org. Lett., 2004, 6,
625–627; (c) Y. Hoashi, T. Okino and Y. Takemoto, Angew. Chem., Int.
Ed., 2005, 44, 4032–4035; (d) T. Okino, Y. Hoashi, T. Furukawa,
X. N. Xu and Y. Takemoto, J. Am. Chem. Soc., 2005, 127, 119–125; (e)
H. M. Li, Y. Wang, L. Tang and L. Deng, J. Am. Chem. Soc., 2004,
126, 9906–9907; (f) H. Li, Y. Wang, L. Tang, F. Wu, X. Liu, C. Guo,
B. M. Foxman and L. Deng, Angew. Chem., Int. Ed., 2005, 44, 105–108;
(g) H. Li, J. Song, X. Liu and L. Deng, J. Am. Chem. Soc., 2005, 127,
8948–8949; (h) K. Matsui, S. Takizawa and H. Sasai, J. Am. Chem.
Soc., 2005, 127, 3680–3681; (i) M. Shi, L. H. Chen and C. Q. Li, J. Am.
Chem. Soc., 2005, 127, 3790–3800; (j) A. Berkessel, F. Cleemann,
S. Mukherjee, T. N. Muller and J. Lex, Angew. Chem., Int. Ed., 2005,
44, 807–811; (k) A. Berkessel, S. Mukherjee, F. Cleemann, T. N. Muller
and J. Lex, Chem. Commun., 2005, 1898–1900; (l) A. Lattanzi, Org.
Lett., 2005, 7, 2579–2582.
13 It has recently been reported that the unnatural 9-epi-Cinchona derived
catalysts are more active than those based on the natural Cinchona
skeleton, see ref. 11b.
14 Major enantiomer was (S). Confirmed by comparison of HPLC traces
for the same compound found in ref. 8.
15 Enantiomeric excess was not determined accurately, as complete
separation of enantiomers was not possible. HPLC traces using a
Daicel CHIRALCEL OJ, 25 cm 6 0.46 cm column indicated an ee ca.
50%.
16 These initial results were first disclosed on 20th July 2005 at the 19th
International Symposium: Synthesis in Organic Chemistry, University
of Oxford.
Notes and references
{ Crystal data for 21b. C23H27N1O5, M = 397.46, orthorhombic, a =
3
10.8665(3), b = 11.1927(3), c = 34.5493(12) A, U = 4202.1(2) A , T =
˚
˚
180(2) K, space group P2(1)2(1)2(1), Z = 8, m(Mo-Ka) = 0.08 8 mm21
,
5309 reflections measured. The final wR(F2) was 0.1389 (all data). The
Flack parameter was 0(2). CCDC 289062. For crystallographic data in CIF
or other electronic format see DOI: 10.1039/b515725k
1 (a) E. F. Kleinmann, in Comprehensive Organic Synthesis, ed. B. M.
Trost and I. Flemming, Pergamon Press, New York, 1991, vol. 2, ch. 4.1;
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VCH, New York, 1997; (c) P. A. Magriotis, Angew. Chem., Int. Ed.,
2001, 40, 4377–4379; (d) M. Liu and M. P. Sibi, Tetrahedron, 2002, 58,
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M. Benaglia, M. Cinquini and F. Cozzi, Eur. J. Org. Chem., 2000,
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3 Selected examples: (a) H. Ishitani, M. Ueno and S. Kobayashi, J. Am.
Chem. Soc., 1997, 119, 7153–7154; (b) E. Hagiwara, A. Fujii and
M. Sodeoka, J. Am. Chem. Soc., 1998, 120, 2474–2475; (c) D. Ferraris,
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N. S. Josephsohn, M. L. Snapper and A. H. Hoveyda, J. Am. Chem.
Soc., 2004, 126, 3734–3735.
17 (a) 22: [a]2D5 223.3 (c 0.40, CHCl3), Literature value for the opposite
enantiomer: [a]2D5 +29.9 (c 1.40, CHCl3), F. A. Davis and J. M. Szewczyk,
Tetrahedron Lett., 1998, 39, 5951–5954; (b) 23: [a]2D5 213.7 (c 0.19,
CHCl3), Literature value for the same enantiomer: [a]2D5 215.8 (c 0.55,
CHCl3), L. Crombie, D. Haigh, R. C. F. Jones and A. R. Mat-Zin,
J. Chem. Soc., Perkin Trans. 1, 1993, 2047–2054.
This journal is ß The Royal Society of Chemistry 2006
Chem. Commun., 2006, 1191–1193 | 1193