Catalyzed vinylogous Mukaiyama aldol reactions with controlled enantio-and diastereoselectivities

Article abstract of DOI:10.1002/chem.200802359

The applicability of various cyclic dienol silanes in combination with other ketonic substrates was examined by evaluating the substrate scope of the vinylogous Mukaiyama aldol reaction (VMAR). The substrate combinations afforded Mukaiyama aldol products

Full text of DOI:10.1002/chem.200802359

DOI: 10.1002/chem.200802359
Catalyzed Vinylogous Mukaiyama Aldol Reactions with Controlled Enantio-
and Diastereoselectivities
Marcus Frings, Iuliana Atodiresei, Jan Runsink, Gerhard Raabe, and Carsten Bolm*[a]
Dedicated to Professor Dr. Peter Luger on the occasion of his 65th birthday
The Mukaiyama aldol reaction is an important and valua-
ble carbon–carbon bond-forming reaction, and its enantiose-
lective metal-catalyzed version has attracted much atten-
tion.[1] By using chiral Lewis acids, enantiomerically en-
riched alcohols are accessible that frequently occur in natu-
ral or bioactive compounds.[2] By applying the concept of vi-
nylogy,[3] d-hydroxy a,b-unsaturated carbonyl compounds
can be prepared in a highly stereoselective manner.[4] The
vinylogous Mukaiyama aldol reaction (VMAR), which in-
volves the use of O-silylated dienolates, is of particular in-
terest in that respect, and much progress has been made in
controlling its regio- and stereoselectivity.[5,6]
ketonic electrophiles. In contrast to the large number of
studies with aldehydes as carbonylic substrates,[11] reports on
reactions with ketones are relatively rare,[13] and only a few
of those include pyruvates as starting materials.[12b,c,13] Pre-
sumably the additional demand for diastereoselectivity in
the simultaneous formation of two stereogenic centers (in-
cluding one with a fully substituted carbon) in conjunction
with the general requirement of top-level regio- and enan-
tioselectivities have posed additional challenges, which have
not allowed rapid progress in this area.
For the initial adjustment of the reaction conditions, com-
mercially available 2-(trimethylsilyloxy)furan (TMSOF, 3a)
and methyl pyruvate (4a) were chosen as starting materials
(Scheme 1). After a brief optimization, we found that with a
As part of our ongoing studies on the use of sulfoximines
in metal catalysis,[7] we recently reported that C1-symmetric
amino sulfoximines 1 and oxazolinyl sulfoximines 2 were ef-
fective ligands in asymmetric copper catalyses.[8–10]
Scheme 1. Synthesis of g-butenolide 5a by VMAR with TMSOF (3a)
and methyl pyruvate (4a).
catalyst loading of 10 mol%, a CuACHTNUTRGNEUNG(OTf)2 to sulfoximine 1a
ratio of 1:1 and 2,2,2-trifluoroethanol (1.2 equiv) as additive
in dry diethyl ether, g-butenolide 5a could be obtained in
88% yield after only 5 h at room temperature. No a-substi-
tution product was observed, and both the de and ee values
were remarkably high (94 and 95%, respectively). At a tem-
perature of À688C neither the yield (88%) nor the stereose-
lectivities (95% de, 94% ee) were significantly affected, but
the reaction time had to be extended (to 16 h) to achieve a
high conversion.
We now describe the use of sulfoximine 1a in copper-cat-
alyzed VMARs between various cyclic dienol silanes and
[a] M. Frings, Dr. I. Atodiresei, Dr. J. Runsink, Prof. Dr. G. Raabe,
Prof. Dr. C. Bolm
Institut fꢀr Organische Chemie der RWTH Aachen University
Landoltweg 1, 52056 Aachen (Germany)
Fax : (+49)241-8092391
To evaluate the substrate scope of the VMAR, the appli-
AHCTUNGTREGcNNNU ability of various cyclic dienol silanes 3 in combination
E-mail: carsten.bolm@oc.rwth-aachen.de
with other ketonic substrates 4 was examined. All catalyses
were performed under the reaction conditions summarized
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.200802359.
1566
ꢁ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2009, 15, 1566 – 1569

COMMUNICATION
above (unless otherwise noted). The results are presented in
Table 1.
perature to 08C or À308C had no beneficial effect on the
enantioselectivity. Control experiments showed that a rapid
uncatalyzed background reac-
tion (leading to the racemate)
could be responsible for this
Table 1. Effect of the substrates in reactions between 3 and 4 to give 5.[a]
result.
g-Butenolide
5b
(entry 2), formed from phenyl-
pyruvic acid methyl ester (4b)
and TMSOF (3a), was obtained
in low yield (20%) but very
good stereoselectivity (92% de
and 93% ee). A considerable
amount of the corresponding
furan-2ACTHNUGRTENUNG(5H)-one was formed as
Entry
Dienol silane
Electro-
phile
R1
R2
Prod.
Yield
[%][b]
de [%][c]
ee [%][d]
a by-product. With 4-nitrophe-
nylglyoxylate (4j) as substrate,
the product had a comparably
moderate de (85%, entry 10),
and noteworthy, the syn prod-
uct, which was formed as a
1
2
3
4
5
6
7
8
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3b
3c
3a
4a
4b
4c
4d
4e
4 f
4g
4h
4i
4j
4k
4l
4m
4c
4a
4n
Me
Me
Me
Me
Me
Et
Et
Et
Et
Et
Me
Bn
Ph
CF3
Et
5a
5b
5c
5d
5e
5 f
5g
5h
5i
5j
5k
5l
5m
5n
5o
5p
88
20
99
75
79
92
95
91
99
96
91
84
84
38
52
87
94 (94)
92 (92)
94 (99)
92 (99)
98 (99)
96 (96)
96 (99)
99 (99)
99 (99)
85 (99)
—
95/n.d.
93/n.d.
97/70
4/3
97/n.d.
96/n.d.
98/n.d.
98/n.d.
99/n.d.
91/95
28
98/n.d.
95/n.d.
92/50
82/80
94
Me
Ph
minor diastereomer, had
a
CH2Bn
iPr
4-NO2-Ph
C(O)OEt
Me
Me
Ph
Me
—
higher ee than the (major) anti
product (95 and 91% ee, re-
spectively). Ketodiester 4k also
reacted well with TMSOF (3a)
affording 5k in high yield
(entry 11), but the ee was low
(28%). Also in this case the un-
catalyzed background reaction
was fast as shown by a reaction
in the absence of the catalyst.
Changing the nucleophile in
the reaction with 4c from 3a to
9
10
11
12
13
14
15
16
Et
iPr
Bn
Me
Me
—
94 (99)
96 (96)
16 (99)[e]
7 (7)
99 (99)
[a] Reaction conditions for entries 1—14 and 16: Cyclic dienol silane 3 (0.22 mmol), electrophile 4 (0.2 mmol),
Cu(OTf)2 (10 mol%), amino sulfoximine 1a (10 mol%), CF3CH2OH (0.24 mmol), Et2O (2 mL), RT, 2–6 h; for
ACHTUNGTRENNUNG
entry 15: as before, but at À158C, overnight. [b] Yield of all stereoisomers after column chromatography.
1
[c] Determined by H NMR analysis of the crude reaction mixture; in parentheses, de (referring to the anti:syn
ratio) of the product after column chromatography. [d] Determined by CSP-HPLC; given for anti and syn iso-
mers. [e] Diastereomers were separated by preparative HPLC.
cyclic
dienol
silane
3b
(entry 14) led to the g-product
5n in moderate yield (38%).
Most substrate combinations afforded Mukaiyama aldol
products 5 with excellent stereoselectivities in high yields.
The best result was achieved in the reaction between a-ke-
toester 3a (TMSOF) and 3-methyl-2-oxobutyrate (4i),
which gave 5i with a de and an ee of 99% in essentially
quantitative yield (99%) (Table 1, entry 9). a-Substitution
products were not observed. In most cases it was possible to
isolate the major diastereomer of 5 by column chromatogra-
phy or preparative HPLC to give a diastereomerically pure
product.[14] Increasing the steric bulk at the ester functionali-
ty of 4 (Table 1, compare entries 1, 6, 12, and 13) had almost
no effect on the stereoselectivity (93–98% ee). Only the
yields were slightly lower in the reactions with the isopropyl
or benzyl esters (84% yield for both compared to 88% and
92% yield for the methyl and the ethyl ester, respectively).
The catalysis was more sensitive with respect to the ke-
tonic substituent of 4. Thus, when activated methyl 3,3,3-tri-
fluoropyruvate (4d) was used in combination with TMSOF
(3a, entry 4), product 5d was isolated in good yield (75%)
but, albeit the diastereoselectivity was high, the ee of the
major isomer was low (4%). Decreasing the reaction tem-
While the diastereoselectivity was low (16% de), the enan-
tioselectivity was respectable (92% ee). Use of 3c having a
sulfur (instead of an oxygen as in 3a) in the heterocyclic
ring system had a strong influence on the reaction as well
(entry 15). While at room temperature the product 5o was
isolated in only trace amounts, performing the catalysis at
À158C led to 5o in moderate yield (52%). Although the de
was rather low (7%), the ee values of 80 and 82% were ac-
ceptable for both diastereomers.
Interestingly, pyruvic aldehyde dimethyl acetal (4n) could
also be applied (Table 1, entry 16), and from its reaction
with TMSOF (3a) the product 5p was obtained in very
good yield (87%) with excellent stereoselectivity (99% de
and 94% ee). This is most noteworthy because of the
masked aldehyde functionality in 5p, which offers possibili-
ties for further transformations.
To determine the relative and absolute stereochemistry of
the products, a representative example, g-butenolide 5i, was
analyzed by various experimental and theoretical tech-
niques. First, the relative stereochemistry of 5i was elucidat-
ed by a combination of NMR spectroscopy and quantum-
Chem. Eur. J. 2009, 15, 1566 – 1569
ꢁ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
1567

C. Bolm et al.
chemical calculations. With both (racemic) diastereomers,
anti-5i and syn-5i, NOE effects were observed between the
olefinic proton (C=OCHCH) and the CH proton of the iso-
propyl group. To compare their intensities, NOE ratios (of
0.8 and 0.4) were calculated by dividing these NOE values
by those observed between the two olefinic protons (C=
OCHCH) of each compound. To assign the experimentally
found NOE values to the corresponding diastereomers,
quantum-chemical geometry optimizations were performed
at various levels of theory.[14,15] A comparison of the energet-
ically lowest conformers of both diastereomers obtained at
the highest theoretical level (for graphics see the Supporting
Information) revealed that in anti-5i the calculated distance
between the olefinic and the isopropylic proton is smaller
(2.386 ꢂ) than in syn-5i (4.815 ꢂ). Consequently, the value
of 0.8 of the NOE ratio (revealing a stronger interaction be-
tween the two protons) was assigned to anti-5i, whereas the
value of 0.4 was ascribed to syn-5i.
The relative stereochemistry of anti-5i was confirmed by
single-crystal X-ray analysis (of a racemic sample).[16] The
molecular structure in the solid state (Figure 1) is visually
indistinguishable from the most stable structure predicted
for this stereoisomer at the MP2/6-31+G** level.
Figure 2. a) Experimental CD-spectrum of anti-5i. b) Averaged calculat-
ed CD spectra for (S,S)-5i. The relative energies of the included con-
formers have been obtained at the PCM/MP2/6-31+G**//MP2/6-31+
G** (solid curve) and PCM/B3LYP/6-31+G**//MP2/6-31+G** (dotted
curve) level.
In summary, we have developed a copper-catalyzed vinyl-
ogous Mukaiyama aldol reaction that provides products
with high diastereo- and enantioselectivities. The relative
and absolute stereochemistry of a representative product
was rigorously assigned by experimental and theoretical
means.
Acknowledgements
We are grateful for the support by the Fonds der Chemischen Industrie,
and we thank Professor Dr. Englert and Dr. Braun (both RWTH Aachen
University) for the collection of the diffraction data.
Figure 1. Structure of anti-5i in the solid state obtained from a racemic
sample; the (S,S)-enantiomer is shown.[16]
The NOE ratio was used to identify the enantiomerically
pure product, which was obtained in the catalysis with a
copper complex bearing (S)-1a as the anti-5i diastereomer.
Its absolute configuration was then assigned by a compari-
son of the experimental and calculated CD spectra (shown
in Figure 2a and b, respectively).[14,18]
Both calculated CD spectra showed a strong negative
Cotton effect with a minimum between 220 and 240 nm fol-
lowed by a weaker positive one with a maximum between
200 and 220 nm. The calculated negative Cotton effect was
assigned to the positive one observed at 213 nm, and the cal-
culated positive one to the observed weakly negative band
with a minimum at about 185 nm. Thus the absolute config-
uration of anti-5i stemming from the catalysis with the
copper complex bearing the (S)-configured sulfoximine [(S)-
1a] is most likely opposite to that initially assumed in the
calculations, and, therefore R,R.
Keywords: asymmetric
diastereoselectivity
Mukaiyama aldol reaction
catalysis
enantioselectivity
·
copper
sulfoximines
·
·
·
·
[1] Modern Aldol Reactions (Ed.: R. Mahrwald), Wiley-VCH, Wein-
heim, 2004, and references therein.
[2] For overviews on applications of aldol reactions in natural product
syntheses, see: a) A. K. Ghosh, M. Shevlin in Modern Aldol Reac-
tions, Vol. 1 (Ed.: R. Mahrwald), Wiley-VCH, Weinheim, pp. 105–
119; b) I. Shiina in Modern Aldol Reactions, Vol. 2 (Ed.: R. Mahr-
wald), Wiley-VCH, Weinheim, pp. 105–166.
[3] a) R. C. Fuson, Chem. Rev. 1935, 16, 1–27; b) S. Krishnamurthy, J.
Chem. Educ. 1982, 59, 543–547; c) P. Bruneau, P. J. Taylor, A. J. Wil-
kinson, J. Chem. Soc. Perkin Trans. 2 1996, 2263–2269.
[4] For reviews on vinylogous aldol reactions, see: a) G. Casiraghi, F.
Zanardi, G. Appendino, G. Rassu, Chem. Rev. 2000, 100, 1929–
1972; b) S. E. Denmark, J. R. Heemstra, Jr., G. L. Beutner, Angew.
Chem. 2005, 117, 4760–4777; Angew. Chem. Int. Ed. 2005, 44, 4682–
1568
www.chemeurj.org
ꢁ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2009, 15, 1566 – 1569

Catalyzed Vinylogous Mukaiyama Aldol Reactions
COMMUNICATION
4698; c) M. Kalesse, Top. Curr. Chem. 2005, 244, 43–76; d) S. Hoso-
kawa, K. Tatsuta, Mini-Rev. Org. Chem. 2008, 5, 1–18.
121, 669–685; b) D. A. Evans, C. S. Burgey, M. C. Kozlowski, S. W.
Tregay, J. Am. Chem. Soc. 1999, 121, 686–699; c) S. Naito, M. Esco-
bar, P. R. Kym, S. Liras, S. F. Martin, J. Org. Chem. 2002, 67, 4200–
4208; d) M. De Rosa, L. Citro, A. Soriente, Tetrahedron Lett. 2006,
47, 8507–8510.
[5] For recent contributions on catalyzed asymmetric VMAR, see: a) B.
Bazꢃn-Tejeda, G. Bluet, G. Broustal, J.-M. Campagne, Chem. Eur. J.
2006, 12, 8358–8366; b) S. E. Denmark, J. R. Heemstra, Jr., J. Am.
Chem. Soc. 2006, 128, 1038–1039; c) S. E. Denmark, J. R. Heem-
stra, Jr., J. Org. Chem. 2007, 72, 5668–5688; d) S. Simsek, M. Hor-
zella, M. Kalesse, Org. Lett. 2007, 9, 5637–5639; e) L. V. Heumann,
G. E. Keck, Org. Lett. 2007, 9, 4275–4278; f) G. Broustal, X. Ariza,
J.-M. Campagne, J. Garcia, Y. Georges, A. Marinetti, R. Robiette,
Eur. J. Org. Chem. 2007, 26, 4293–4297.
[6] For recent applications of enantioselective VMAR in natural prod-
uct syntheses, see: a) I. Paterson, A. D. Findlay, G. J. Florence, Tetra-
hedron 2007, 63, 5806–5819; b) S. Shirokawa, M. Shinoyama, I. Ooi,
S. Hosokawa, A. Nakazaki, S. Kobayashi, Org. Lett. 2007, 9, 849–
852; c) X. Jiang, B. Liu, S. Lebreton, J. K. De Brabander, J. Am.
Chem. Soc. 2007, 129, 6386–6387.
[7] For recent reviews on the use of sulfoximines as chiral ligands in
metal catalysis, see: a) M. Harmata, Chemtracts 2003, 16, 660–666;
b) H. Okamura, C. Bolm, Chem. Lett. 2004, 33, 482–487; c) For a
personal account, see: C. Bolm in Asymmetric Synthesis with Chemi-
cal and Biological Methods (Eds.: D. Enders, K.-E. Jaeger), Wiley-
VCH, Weinheim, 2007, pp. 149–175; d) C. Worch, A. C. Mayer, C.
Bolm in Organosulfur Chemistry in Asymmetric Synthesis (Eds.: T.
Toru, C. Bolm), Wiley-VCH, Weinheim, 2008, pp. 209–229.
[8] For syntheses and applications of amino sulfoximines 1, see: a) M.
Langner, C. Bolm, Angew. Chem. 2004, 116, 6110–6113; Angew.
Chem. Int. Ed. 2004, 43, 5984–5987; b) M. Langner, P. Rꢄmy, C.
Bolm, Chem. Eur. J. 2005, 11, 6254–6265; c) P. Rꢄmy, M. Langner,
C. Bolm, Org. Lett. 2006, 8, 1209–1211; d) M. Langner, P. Rꢄmy, C.
Bolm, Synlett 2005, 781–784.
[14] For details, see the Supporting Information.
[15] As starting point, the (S,S)-configured enantiomer of anti-5i was ar-
bitrarily chosen.
[16] Suitable crystals were obtained from hexane/EtOAc. The compound
(C11H16O5) crystallizes in the (centrosymmetric) monoclinic space
group P21/c (no. 14) with cell constants a=9.913(2), b=9.594(2), c=
12.557(3) ꢂ, and b=94.060(3)8. At a molecular weight of 228.24,
Z=4, and a cell volume of 1191.1(5) ꢂ3 the density and the linear
absorption coefficients are 1.273 gcmÀ3 and 0.1 mmÀ1, respectively.
Absorption correction was achieved by using SADABS. Diffraction
data were collected at 298 K on a Bruker SMART diffractometer by
employing MoKa radiation (l=0.71073 ꢂ). A total of 26780 reflec-
tions were collected in the range À13ꢀhꢀ13, À12ꢀkꢀ12, and
À16ꢀlꢀ16 (qmax =28.58), merged to give 2751 independent reflec-
tions (Rint =0.02(2)). The structure was solved by direct methods as
implemented in the XTAL3.7 package of crystallographic routines[17]
employing GENSIN[17] to generate structure-invariant relationships
and GENTAN[17] for the general tangent phasing procedure. A total
of 2751 observed reflections (I>2s(I)) were included in a full-
matrix least squares refinement of 209 parameters converging at
R(Rw)=0.04(0.04; w=1/s2 (F)), and a residual electron density of
À0.38/+0.35 eꢂÀ3. Hydrogen atoms were located and refined iso-
tropically. CCDC-697979 contains the supplementary crystallograph-
ic data for this paper. These data can be obtained free of charge
from The Cambridge Crystallographic Data Centre via www.ccdc.ca-
m.ac.uk/data_request/cif
[9] Both enantiomers of 1a are commercially available (Sigma–Aldrich:
CAS numbers 825612-43-9 and 948831-14-9). In this study, only (S)-
configured 1a was applied.
[10] For syntheses and applications of oxazolinyl sulfoximines, see: J. Se-
delmeier, T. Hammerer, C. Bolm, Org. Lett. 2008, 10, 917–920.
[11] For a recent review on vinylogous aldol reactions with heterocyclic
silyloxy dienes, see: G. Rassu, F. Zanardi, L. Battistini, G. Casiraghi,
Chem. Soc. Rev. 2000, 29, 109–118.
[12] a) C. W. Jefford, D. Jaggi, G. Bernardinelli, J. Boukouvalas, Tetrahe-
dron Lett. 1987, 28, 4041–4044; b) K. Kong, D. Romo, Org. Lett.
2006, 8, 2909–2912; c) F. Zanardi, C. Curti, A. Sartori, G. Rassu, A.
Roggio, L. Battistini, P. Burreddu, L. Pinna, G. Pelosi, G. Casiraghi,
Eur. J. Org. Chem. 2008, 2273–2287.
[17] a) XTAL3.7 System (Eds.: S. R. Hall, D. J. du Boulay, R. Olthof-Ha-
zekamp),University of Western Australia, Perth, 2000; b) V. Subra-
manian, S. R. Hall, GENSIN, XTAL3.7 System (Eds.: S. R. Hall,
D. J. du Boulay, R. Olthof-Hazekamp), University of Western Aus-
tralia, Perth, 2000; c) S. R. Hall, GENTAN, XTAL3.7 System (Eds.:
S. R. Hall, D. J. du Boulay, R. Olthof-Hazekamp), University of
Western Australia, Perth, 2000.
[18] Experimental CD spectra were recorded in acetonitrile at room
temperature using an AVIV 62DS circular dichroism spectrometer.
The concentration was 1.011ꢅ10À3 molLÀ1 and the path length
0.1 cm.
[13] a) D. A. Evans, M. C. Kozlowski, J. A. Murry, C. S. Burgey, K. R.
Campos, B. T. Connell, Richard J. Staples, J. Am. Chem. Soc. 1999,
Received: November 13, 2008
Published online: January 2, 2009
Chem. Eur. J. 2009, 15, 1566 – 1569
ꢁ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
1569