Enantioselective synthesis of highly functionalised amides by copper-catalysed vinylogous Mukaiyama aldol reaction

Article abstract of DOI:10.1039/c0cc00996b

Amides with quaternary stereogenic centers have been synthesised by catalytic asymmetric vinylogous Mukaiyama aldol reactions. The chiral copper-sulfoximine catalyst gives rise to products with moderate to good yields and up to 92% ee. The Royal Society o

Full text of DOI:10.1039/c0cc00996b

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Enantioselective synthesis of highly functionalised amides by
copper-catalysed vinylogous Mukaiyama aldol reactionw
Marcus Frings, Daniel Goedert and Carsten Bolm*
Received 17th April 2010, Accepted 9th June 2010
First published as an Advance Article on the web 24th June 2010
DOI: 10.1039/c0cc00996b
Amides with quaternary stereogenic centers have been synthesised
by catalytic asymmetric vinylogous Mukaiyama aldol reactions.
The chiral copper–sulfoximine catalyst gives rise to products
with moderate to good yields and up to 92% ee.
To the best of our knowledge VMARs between N,O-silyl
ketene aminals 3 and ketonic electrophiles such as pyruvates
and related a-ketoesters have never been described. Because
those transformations would lead to synthetically valuable,
highly functionalised amides with quaternary stereogenic
centers we wondered if our recently introduced copper(II)
complexes of C1-symmetric sulfoximines were effective
catalysts here, too. In previous studies the latter had proven
to be highly selective in additions of both cyclic and acyclic
dienol- or enolsilanes to activated ketones affording products
with excellent regio-, diastereo- and enantioselectivities.7–9
As model reaction the addition of morpholine-derived
dienol silane 3a to methyl pyruvate (5a) was chosen
(Scheme 2). The initial conditions involved Et2O as solvent,
a catalyst stemming from Cu(OTf)2 and sulfoximine (S)-6a
(10 mol% each) and 2,2,2-trifluoroethanol (TFE) as additive
(Table 1, entry 1). A control experiment revealed that in the
absence of the metal–sulfoximine complex and the additive no
reaction took place. Next, the effects of the aminosulfoximine
structure and the solvents on the catalysis were briefly
evaluated. Use of (S)-6b or (S)-6c instead of (S)-6a (entries 2
and 3) showed that steric bulk at the aryl moiety or the alkyl
group adjacent to sulfur did not have the same beneficial
impact as observed in the previous VMAR studies7f and led
to product formations of 7a with comparable yields but
significantly reduced ees. When (S)-6d with the strongly
electron-withdrawing pentafluoro aryl group was utilised,
yield and stereoselectivity were dramatically reduced (entry 4).
The use of toluene and dichloromethane instead of Et2O
decreased both yields and ee (entries 5 and 6). To our surprise,
yields and stereoselectivities showed a large variance within
the family of ethereal solvents (entries 1, 7–10). Cyclic ethers
such as THF and 1,4-dioxane gave product 7a either in very
low yield and enantioselectivity or even not at all.
The vinylogous Mukaiyama aldol reaction (VMAR) is a fast
and straightforward approach to d-hydroxy-a,b-unsaturated
carbonyl compounds which are common scaffolds in various
naturally occurring polyketides.1 Probably due to the additional
challenges in regioselectivity (as illustrated in Scheme 1) the
progress in developing catalytic asymmetric VMARs has been
limited until recently, despite of the immense potential for the
synthesis of such compounds.
Dienol silanes 1 are usually derived from a,b-unsaturated
lactones, lactams, ketones (R1 = alkyl, aryl) or (thio-)esters
(R1 = O-alkyl, S-alkyl), and aldehydes 2 serve as preferred
electrophilic coupling partners.2 In strong contrast, the use of
ketones is comparatively rare,3 and also N,O-silyl ketene
aminals 3 (Fig. 1), which originate from a,b-unsaturated
amides, are only scarcely applied in VMARs.4 This is very
surprising, considering the success of the analogous Evans
reagents 4, which have quite frequently been utilised as chiral
dienolates in auxiliary-driven natural product syntheses5
following Kobayashi’s pioneering work in 2004.6
Scheme 1 a- versus g-addition in VMARs.
Since Et2O was a rather effective solvent, acyclic ethers
appeared beneficial for achieving high enantioselectivities.
Confirming this hypothesis, use of tert-butyl methyl ether
(TBME) afforded amide 7a in high ee (85%). However, the
yield was lower than in Et2O. An excellent enantioselectivity of
94% was reached with diisopropyl ether (DIPE) as solvent,
albeit the yield was rather low. Next, the temperature and
substrate ratio of the reactants 3a and 5a were varied.
Delightfully, the enantioselectivity (92% ee) and the yield
(75%) could be improved when the reaction was carried out
at À78 1C followed by slow warming up to rt (entry 11). The
same trend with respect to the stereoselectivity and yield was
observed when the reaction was conducted at a constant
temperature of À20 1C (entry 12). Although a product with
a very high ee (93%) was obtained, the yield (65%) was lower
Fig. 1 N,O-Silyl ketene aminals 3 and related chiral auxiliaries 4.
Institute of Organic Chemistry RWTH Aachen University,
Landoltweg 1, 52056 Aachen, Germany.
E-mail: carsten.bolm@oc.rwth-aachen.de; Fax: +49 241 8092391
w Electronic supplementary information (ESI) available: Experimental
procedures and full characterisation of all new compounds. See DOI:
10.1039/c0cc00996b
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Scheme 2 Identification of the optimal reaction parameters for the VMAR between dienol silane 3a and methyl pyruvate (5a).
Table 1 Optimisation of reaction conditions for the VMAR to give
7aa
Table 2 Scope of substrates in the VMAR of various N,O-silyl ketene
aminals 3 and b-ketoesters 5a
Entry
Ligand
Solvent
Temperature
Yield (ee) [%]
1
2
3
4
5
6
7
8
(S)-6a
(S)-6b
(S)-6c
(S)-6d
(S)-6a
(S)-6a
(S)-6a
(S)-6a
(S)-6a
(S)-6a
(S)-6a
(S)-6a
(S)-6a
Et2O
Et2O
Et2O
Et2O
Toluene
CH2Cl2
THF
1,4-Dioxane
TBME
DIPE
Et2O
rt
rt
rt
rt
rt
rt
rt
rt
49 (85)
43 (68)
42 (67)
19 (15)
35 (63)
8 (9)
10 (24)
0 (—)
9
rt
rt
42 (85)
18 (94)
75 (92)
65 (93)
59 (89)
10
11
12
13b
À78 1C to rt
À20 1C
rt
Et2O
Et2O
a
Reaction conditions: Cu(OTf)2 (0.03 mmol), (S)-6 (0.03 mmol), 5a
(0.30 mmol), 3a (0.33 mmol), TFE (0.36 mmol), solvent (2 mL),
b
temperature. A ratio of 3a : 5a = 1 : 5 was used.
Entry
Dienol silane
Electrophile
Product
Yield (ee) [%]
1
2
3
4
5
6
7
8
3b
3c
3a
3d
3a
3a
3a
3a
3a
3a
3a
3a
3a
5a
5a
5a
5a
5b
5c
5d
5e
5f
5g
5h
5c
5d
7b
7c
7a
7d
7e
7f
7g
7h
7i
45 (11)
75 (45)
75 (92)
0 (—)
66 (87)
36 (67)
49 (56)
64 (91)
54 (76)
66 (87)
58 (86)
23 (73)
45 (70)
than in the reaction run at À78 1C. Compared to the standard
conditions at rt (entry 1) it was still higher. Furthermore, it
was observed that a fivefold excess of ketoester 5a raised the
yield while the stereoselectivity remained almost the same
(entry 13).
Under the optimised conditions (as described in entry 11 of
Table 1) various ketoesters 5 and dienol silanes 3 were applied
in order to demonstrate the scope of the reaction (Table 2).
First, nucleophiles 3 were varied. The results depicted in
entries 1 to 4 show that both yield and enantioselectivity
significantly relied on the substitution pattern of the nitrogen
in N,O-silyl ketene aminals 3. Denmark and Heemstra
discovered that the enantiomeric excesses of the VMAR
products derived from reactions between 3a–c and benzaldehyde
directly correlated with the nucleophilicity of the terminal CH2
group of dienol silanes 3.4b This nucleophilicity (indicated by
chemical shifts of the g-carbon in the 13C-NMR spectra) is
controlled through the electronic properties of the remote
environment of the amino group and hence an excellent
example for the vinylogy concept. The same trend was
observed here, i.e. the reaction of the comparatively strong
nucleophile 3b with methyl pyruvate (5a) led to product 7b
with a very low ee (11%) in rather moderate yield (45%; entry 1).
As the nucleophilicity decreased (as in piperidyl and morpholinyl
derivatives 3c and 3a, respectively) a rise of stereoselectivity
from 45 to 92% ee was observed (entries 2 and 3). This led to
the hypothesis that use of an even less nucleophilic ketene
aminal should result in a further improved enantiocontrol.
Hence, dienolate 3d with a 3,5-dimethyl pyrazole unit was
tested (entry 4). Unfortunately, however, no product was
9
10
11
12b
13b
7j
7k
7f
7g
a
Reaction conditions: Cu(OTf)2 (0.03 mmol), (S)-6a (0.03 mmol), 5
(0.30 mmol), 3 (0.33 mmol), TFE (0.36 mmol), Et2O (2 mL), À78 1C to
b
rt, 16 h. Reaction conditions: Cu(OTf)2 (0.02 mmol), (S)-6a
(0.02 mmol), 5 (0.50 mmol), 3 (0.20 mmol), TFE (0.24 mmol), Et2O
(2 mL), À20 1C, 24 h.
formed, even when the reaction was performed at room
temperature, and unreacted dienolate 3d was detected by
NMR spectroscopy. Presumably, 3d bound too tightly to the
copper ion rendering the catalytic system inactive. This
assumption was supported by the fact that the green solution
immediately turned blue-black upon addition of the dienolate.
Next, electrophiles 5 were varied, and the influence of the
substituents of the ester group or the ketonic moiety on the
reaction behavior was investigated (entries 5–11). Increasing
the steric demand of the ketonic part of 5 from methyl to ethyl,
isopropyl or phenyl resulted in products 7 with lower ees and
yields (entries 5–7, 9). On the other hand, the catalysis was less
sensitive to a steric enlargement of the ester functionality
(entries 8, 10 and 11) and ethyl, isopropyl and benzyl esters
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Notes and references
1 For selected reviews, see: (a) G. Casiraghi, F. Zanardi,
G. Appendino and G. Rassu, Chem. Rev., 2000, 100, 1929–1972;
(b) S. E. Denmark, J. R. Heemstra, Jr. and G. L. Beutner, Angew.
Chem., Int. Ed., 2005, 44, 4682–4698; (c) M. Kalesse, Top. Curr.
Chem., 2005, 244, 43–76; (d) T. Brodmann, M. Lorenz,
R. Scha
174–192.
2 (a) S. E. Denmark and J. R. Heemstra, Jr., Synlett, 2004,
2411–2416; (b) B. Bazan-Tejeda, G. Bluet, G. Broustal and
J.-M. Campagne, Chem.–Eur. J., 2006, 12, 8358–8366;
(c) S. Simsek, M. Horzella and M. Kalesse, Org. Lett., 2007, 9,
5637–5639; (d) L. V. Heumann and G. E. Keck, Org. Lett., 2007, 9,
4275–4278; (e) T. Ollevier, J.-E. Bouchard and V. Desyroy, J. Org.
Chem., 2008, 73, 331–334; (f) C. Curti, A. Sartori, L. Battistini,
G. Rassu, F. Zanardi and G. Casiraghi, Tetrahedron Lett., 2009,
50, 3428–3431.
¨
ckel, S. Simsek and M. Kalesse, Synlett, 2009,
´
Scheme 3 Determination of absolute configuration of VMAR product
7a. Reaction conditions: (a) Ac2O, pyridine, 3 d, rt, 94% yield. (b)
NaIO4, RuCl3ÁH2O, MeCN/H2O, 14 h, rt. (c) (COCl)2, DMF,
CH2Cl2, 3 h, rt. (d) MeOH, THF, 12 h, rt (30% yield over 3 steps).
7h, 7j and 7k, respectively, were obtained in high ees
(86–91%), albeit slightly lower yields.
3 For a recent review, see: S. Adachi and T. Harada, Eur. J. Org.
Chem., 2009, 3661–3671.
Because the optimisation process had revealed that both a
constant temperature of À20 1C and an excess of a-ketoester 3
led to improved yields and enantioselectivities (Table 1, entries
12 and 13, respectively), a combined approach was finally
tested. Although it was particularly desirable to increase the
ees of products 7b and 7c (Table 2, entries 1 and 2), their
accessibilities were not further investigated due to the instabilities
of N,O-silyl ketene aminals 3b and 3c.10 To our delight, the
positive trend under the optimised conditions was confirmed
and VMAR products 7f and 7g had ees of 73 and 70%,
respectively, when the reactions were performed at À20 1C
with a 2.5-fold excess of methyl benzoylformate (5c) and ethyl
3-methyl-2-oxo-butyrate (5d), respectively (Table 2, entries 12
and 13). It should also be noted that in all cases the unprotected
hydroxy esters were directly obtained although a rather stable
TBDMS group had been utilised. Hence, an additional
desilylation step involving an acidic work-up, for example,
was not necessary.
4 For the use of dienol silanes 3 in asymmetric Mukaiyama aldol
type additions to aldehydes, see: (a) S. E. Denmark and
J. R. Heemstra, Jr., J. Am. Chem. Soc., 2006, 128, 1038–1039;
(b) S. E. Denmark and J. R. Heemstra, Jr., J. Org. Chem., 2007, 72,
5668–5688; for applications of 3 in enantioselective Mannich
reactions, see: (c) D. S. Giera, M. Sickert and C. Schneider, Org.
Lett., 2008, 10, 4259–4262; (d) D. S. Giera, M. Sickert and
C. Schneider, Synthesis, 2009, 3797–3802; for the non-asymmetric
addition of dienol silane 3a to b-nitrostyrene, see:
(e) S. E. Denmark and M. Xie, J. Org. Chem., 2007, 72,
7050–7053; for an early application of an N,O-silylated ketene
aminal, see: (f) J. R. Green, M. Majewski, B. I. Alo and
V. Snieckus, Tetrahedron Lett., 1986, 27, 535–538.
5 For some recent examples, see: (a) X. Jiang, B. Liu, S. Lebreton
and J. K. De Brabander, J. Am. Chem. Soc., 2007, 129, 6386–6387;
(b) K. C. Nicolaou, R. Guduru, Y.-P. Sun, B. Banerji and
D. Y.-K. Chen, Angew. Chem., Int. Ed., 2007, 46, 5896–5900;
(c) K. C. Nicolaou, Y.-P. Sun, R. Guduru, B. Banerji and
D. Y.-K. Chen, J. Am. Chem. Soc., 2008, 130, 3633–3644;
(d) B. H. Lipshutz and B. Amorelli, J. Am. Chem. Soc., 2009,
131, 1396–1397.
6 (a) S.-i. Shirokawa, M. Kamiyama, T. Nakamura, M. Okada,
A. Nakazaki, S. Hosokawa and S. Kobayashi, J. Am. Chem. Soc.,
2004, 126, 13604–13605; (b) M. Shinoyama, S.-i. Shirokawa,
A. Nakazaki and S. Kobayashi, Org. Lett., 2009, 11,
1277–1280.
To establish the absolute configuration of amides 7, the
morpholinyl derivative 7a was chemically degraded (Scheme 3)
to known (R)-dimethyl 2-acetoxy-2-methylsuccinate (9).
Treatment of 7a with acetic anhydride gave ester 8 in high
yield (94%). Oxidative degradation to the crude acid, conversion
into the acid chloride and subsequent esterification with
methanol provided 9 in 30% yield (over the last three steps).
By comparison of the measured value of the optical rotation
for succinate 9 with the one from the literature,11 the absolute
configuration of amide 7a was determined to be R. All other
products were assigned in analogy.
7 (a) M. Langner and C. Bolm, Angew. Chem., Int. Ed., 2004, 43,
´
5984–5987; (b) M. Langner, P. Remy and C. Bolm, Chem.–Eur. J.,
2005, 11, 6254–6265; (c) P. Remy, M. Langner and C. Bolm, Org.
´
Lett., 2006, 8, 1209–1211; (d) J. Sedelmeier, T. Hammerer and
C. Bolm, Org. Lett., 2008, 10, 917–920; (e) M. Frings, I. Atodiresei,
J. Runsink, G. Raabe and C. Bolm, Chem.–Eur. J., 2009, 15,
1566–1569; (f) M. Frings, I. Atodiresei, Y. Wang, J. Runsink,
G. Raabe and C. Bolm, Chem.–Eur. J., 2010, 16, 4577–4587.
8 For the use of C1-symmetric aminosulfoximines in other catalyses,
see: (a) M. Langner, P. Remy and C. Bolm, Synlett, 2005,
´
781–784; (b) M. Frings and C. Bolm, Eur. J. Org. Chem., 2009,
4085–4090.
In conclusion, we developed a procedure for the copper-
catalysed asymmetric synthesis of amides by vinylogous
Mukaiyama aldol reaction starting from a-ketoesters and
achiral N,O-silylated ketene aminals. The highly functionalised
products, bearing a fully substituted stereogenic center, a
double bond and two different carbonyl groups were obtained
in moderate to good yields with good to high enantio-
selectivities. The ease of further transformations of chiral
amides 7 may open synthetically valuable alternatives to the
application of Kobayashi’s dienolates 4. Finally, the new
protocol reported here complements existing methods where
O,O-silyl ketene acetals or related dienol silanes are utilised.
The authors are grateful to the Fonds der Chemischen
Industrie for financial support.
9 For reviews on the use of sulfoximines as ligands in asymmetric
metal catalysis, see: (a) M. Harmata, Chemtracts, 2003, 16,
660–666; (b) H. Okamura and C. Bolm, Chem. Lett., 2004,
482–487; (c) H. Pellissier, Tetrahedron, 2007, 63, 1297–1330;
(d) C. Bolm, in Asymmetric Synthesis with Chemical and
Biological Methods, ed. D. Enders and K.-E. Jaeger, Wiley-VCH,
Weinheim, Germany, 2007, pp. 149–175; (e) C. Worch,
A. C. Mayer and C. Bolm, in Organosulfur Chemistry in Asym-
metric Synthesis, ed. T. Toru and C. Bolm, Wiley-VCH, Weinheim,
Germany, 2008, pp. 209–229.
10 Ketene aminals 3b and 3c decompose rapidly even when stored
under argon at À24 1C. In contrast, 3a and 3d proved stable under
these storage conditions.
11 S. V. Frye and E. L. Eliel, Tetrahedron Lett., 1985, 26,
3907–3910.
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Chem. Commun., 2010, 46, 5497–5499 | 5499