Asymmetric [3 + 2] annulations catalyzed by a planar-chiral derivative of DMAP

Article abstract of DOI:10.1039/b603172b

A planar-chiral DMAP derivative catalyzes an intriguing [3 + 2] annulation reaction of silylated indenes to produce diquinanes that bear three contiguous stereocenters (one quaternary and two tertiary). The Royal Society of Chemistry 2006.

Full text of DOI:10.1039/b603172b

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Asymmetric [3 + 2] annulations catalyzed by a planar-chiral derivative
of DMAP{
Erhard Bappert, Peter Mu¨ller{ and Gregory C. Fu*
Received (in Bloomington, IN, USA) 1st March 2006, Accepted 7th April 2006
First published as an Advance Article on the web 17th May 2006
DOI: 10.1039/b603172b
(eqn (1)).7 Three contiguous stereocenters (one quaternary and
A planar-chiral DMAP derivative catalyzes an intriguing [3 + 2]
two tertiary) are created in this intriguing annulation process.
annulation reaction of silylated indenes to produce diquinanes
that bear three contiguous stereocenters (one quaternary and
two tertiary).
During the past several years, we have developed applications of
planar-chiral derivatives of DMAP (DMAP = 4-(dimethyl-
amino)pyridine; e.g., 1–4) as asymmetric nucleophilic catalysts
for a variety of processes. In some of these transformations, the
key intermediate is a chiral enolate (A), which reacts at the a
position with an electrophile to furnish the enantioenriched target
(e.g., arypropionic acid derivatives,1 b-lactams,2 and b-lactones3).
In other processes, the critical species is a chiral acylpyridinium ion
(B), which acylates a nucleophile (e.g., kinetic resolutions of
alcohols/amines4 and C-acylations of enolates5). In this commu-
nication, we describe a third mode of reactivity for these DMAP
derivatives, specifically, transformations wherein the central role is
played by a chiral a,b-unsaturated acylpyridinium ion (C), which
reacts in the b position with a nucleophile.
ð1Þ
A possible mechanism for this transformation is illustrated in
Fig. 1. According to this hypothesis, the nucleophilic catalyst
reacts with the acid fluoride to furnish ion pair 1. The fluoride ion
then binds to the silyl group of the indene8 to provide a new ion
pair (2). Conjugate addition of the indenyl nucleophile to its
a,b-unsaturated acylpyridinium counterion produces a zwitterion
(3) that bears two new stereocenters. Next, fragmentation releases
the catalyst and affords ketene 4, which cyclizes via an ene-type
process to generate the observed product.9
If cinnamic anhydride, rather than cinnamoyl fluoride, is
employed as the substrate, a comparable ee, but a lower yield, is
observed (eqn (2)), perhaps due to less efficient activation of the
indene by acetate,10 as compared to fluoride, anion. The use of
acid fluoride that is generated in situ leads to results that are similar
to acid fluoride that is separately prepared and purified by
chromatography (eqn (2)). Cinnamoyl chloride is not a suitable
In an early study, we determined that complex (2)-2 catalyzes
the diastereo- and enantioselective synthesis of a diquinane
derivative6 from a silylated indene and cinnamoyl fluoride
Department of Chemistry, Massachusetts Institute of Technology,
Cambridge, Massachusetts, 02139, USA. E-mail: gcf@MIT.EDU;
Fax: 617 324 3611; Tel: 617 253 2664
{ Electronic supplementary information (ESI) available: Experimental
procedures and compound characterization data. See DOI: 10.1039/
b603172b
{ Correspondence concerning the crystal structure illustrated in Fig. 2
should be directed to P. Mu¨ller: pmueller@MIT.EDU.
Fig. 1 Possible mechanism for nucleophile-catalyzed asymmetric annu-
lations of indenes with a,b-unsaturated carbonyl compounds.
2604 | Chem. Commun., 2006, 2604–2606
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annulation partner (eqn (2)), presumably due to the ineffectiveness
of chloride anion as an activator of the silylindene.
ð2Þ
Fig. 2 ORTEP illustration, with thermal ellipsoids drawn at the 35%
probability level, of N-cinnamoylated (+)-2 (for the sake of clarity, the PF6
counterion and most of the hydrogens have been omitted).
positioned on the side of the upper cyclopentadienyl ring,
presumably for steric reasons. The a,b-unsaturated carbonyl
system lies in an s-cis conformation. The crystal structure suggests
that nucleophiles might prefer to add to the si face of the b carbon,
which is consistent with the stereochemistry that we observe in the
annulation process (cf. eqn (3)).
We have determined that an array of cinnamoyl fluorides and
related compounds may be used in this catalytic asymmetric
annulation process. Thus, electronically diverse (Table 1, entries
2–4), as well as ortho-substituted (entries 5 and 6; somewhat lower
yields are obtained), aryl substituents can be employed. In
addition, heteroaryl groups are tolerated in the b position
(entries 7 and 8).11
Thus, we have established that planar-chiral DMAP derivatives
catalyze intriguing [3 + 2] annulation reactions of silylated indenes
to produce diquinanes that bear three contiguous stereocenters
(one quaternary and two tertiary). We believe that this process
represents the first example of a mode of reactivity for these
DMAP derivatives wherein a transiently generated a,b-unsatu-
rated acylpyridinium ion (e.g., C) serves as an acceptor in a
stereoselective conjugate addition reaction. In future work, we will
exploit the utility of such intermediates in other catalytic
asymmetric processes.
Interestingly, this enantioselective [3 + 2] reaction can be applied
to annulations of unsymmetrical indenes. Thus, an isopropyl/
methyl-substituted substrate reacts to provide a 6 : 1 ratio of D : E
(eqn (3)).
Support has been provided by the NIH (National Institute of
ð3Þ
General
Medical
Sciences:
R01-GM57034),
Deutsche
Forschungsgemeinschaft (postdoctoral fellowship BA 2875/1-1 to
E.B.), Merck, and Novartis. We thank Luke Firmansjah and Dr
Richard J. Staples (Harvard University) for assistance with X-ray
crystallography. Funding for the MIT Department of Chemistry
Instrumentation Facility has been furnished in part by NSF CHE-
9808061 and NSF DBI-9729592.
We have obtained an X-ray crystal structure of the
N-cinnamoylated pyridinium salt derived from (+)-2§ (Fig. 2).12
The cinnamoyl group is essentially coplanar with the heterocycle,
allowing overlap between the p systems of these subunits. With
regard to the orientation around the N–C (carbonyl carbon) bond,
the carbonyl oxygen, rather than the larger alkenyl group, is
Notes and references
§ Crystallographic data for N-cinnamoylated (+)-2 (Fig. 2):
C31H35F6FeN2OP, formula weight: 652.43, tetragonal, P4(3)2(1)2, a =
3
˚
˚
˚
b = 11.9811(3) A, c = 40.4968(19) A, V = 5813.2(3) A , Z = 8, m =
0.641 mm21, reflections collected: 124357, independent reflections: 7504
[R(int) = 0.0955], final R indices [I > 2s(I)]: R1 = 0.0405, wR2 = 0.0862, R
indices (all data): R1 = 0.0501, wR2 = 0.0904.
Table 1 Catalytic asymmetric [3 + 2] annulations
Crystallographic data for the product of entry 4 of Table 1 (generated by
(+)-2): C20H17BrO, formula weight: 353.25, orthorhombic, P2(1)2(1)2(1),
3
˚
˚
˚
˚
a = 7.2277(14) A, b = 14.583(3) A, c = 15.656(3) A, V = 1650.2(5) A , Z =
4, m = 2.490 mm21, reflections collected: 9518, independent reflections:
3593 [R(int) = 0.0238], final R indices [I > 2s(I)]: R1 = 0.0328, wR2 =
0.0694, R indices (all data): R1 = 0.0437, wR2 = 0.0728. CCDC 294368 and
294369. For crystallographic data in CIF or other electronic format see
DOI: 10.1039/b603172b.
Entry
R
Yielda,b (%)
eea (%)
dra
1 B. L. Hodous, J. C. Ruble and G. C. Fu, J. Am. Chem. Soc., 1999, 121,
2637.
2 B. L. Hodous and G. C. Fu, J. Am. Chem. Soc., 2002, 124, 1578;
E. C. Lee, B. L. Hodous, E. Bergin, C. Shih and G. C. Fu, J. Am. Chem.
Soc., 2005, 127, 11586.
3 J. E. Wilson and G. C. Fu, Angew. Chem., Int. Ed., 2004, 43, 6358.
4 J. C. Ruble, H. A. Latham and G. C. Fu, J. Am. Chem. Soc., 1997, 119,
1492; B. Tao, J. C. Ruble, D. A. Hoic and G. C. Fu, J. Am. Chem. Soc.,
1999, 121, 5091; S. Arai, S. Bellemin-Laponnaz and G. C. Fu, Angew.
Chem., Int. Ed., 2001, 40, 234.
1
2
3
4
5
6
7
8
a
Ph
60
51
61
52
41
42
47
48
b
78
58
70
70
66
70
75
77
12 : 1
7 : 1
8 : 1
9 : 1
7 : 1
9 : 1
6 : 1
9 : 1
3-F–C6H4
3,5-(MeO)2C6H3
4-Br–C6H4
2-Me–C6H4
1-Naphthyl
2-Furyl
3-Furyl
Average of two experiments.
diastereomer.
Isolated yield of the major
5 J. C. Ruble and G. C. Fu, J. Am. Chem. Soc., 1998, 120, 11532;
I. D. Hills and G. C. Fu, Angew. Chem., Int. Ed., 2003, 42, 3921;
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A. H. Mermerian and G. C. Fu, J. Am. Chem. Soc., 2003, 125,
4050; A. H. Mermerian and G. C. Fu, J. Am. Chem. Soc., 2005, 127,
5604.
6 For a review that includes methods for the synthesis of diquinanes, see:
G. Mehta and A. Srikrishna, Chem. Rev., 1997, 97, 671.
7 The use of other potential chiral nucleophilic catalysts, including
quinidine and a variety of tertiary phosphines, does not lead to ring
formation.
10 For examples of and leading references to acetate-induced activation of
silylated nucleophiles, see: Y. Kawano, N. Kaneko and T. Mukaiyama,
Chem. Lett., 2005, 34, 1508; A. H. Mermerian and G. C. Fu, J. Am.
Chem. Soc., 2005, 127, 5604.
11 (a) Highly sterically demanding indenes or acid fluorides are not suitable
annulation partners. (b) Attempted reaction of acid fluorides that bear
an alkyl, rather than an aryl, group in the b position leads to little or
none of the desired product. (c) The absolute configurations of the
annulation products were assigned on the basis of an X-ray crystal-
lographic analysis of the product of the annulation illustrated in entry 4
of Table 1 (catalyzed by (+)-2).
12 This was synthesized by reaction of (+)-2 with cinnamoyl chloride,
followed by exchange of the counterion through treatment with AgPF6
(for details, see the electronic supplementary information, ESI{).
8 For leading references to the role of hypervalent silicon in synthetic
organic chemistry, see: S. Rendler and M. Oestrich, Synthesis, 2005,
1727.
1
9 (a) A H NMR study indicates that, during the catalytic process, the
resting state of the catalyst is as the free catalyst. (b) In the absence of
catalyst 2, no reaction is observed.
2606 | Chem. Commun., 2006, 2604–2606
This journal is ß The Royal Society of Chemistry 2006