A metallocene-pyrrolidinopyridine nucleophilic catalyst for asymmetric synthesis

Article abstract of DOI:10.1021/ol053050n

A highly active chiral 4-aminopyridine nucleophilic catalyst, available in three steps from (S,S)-hexane-2,5-diol, was applied to the asymmetric Steglich rearrangement of O-aceylated azlactones (1 mol % loading, up to 76% ee).

Full text of DOI:10.1021/ol053050n

ORGANIC
LETTERS
2006
Vol. 8, No. 4
769-772
A Metallocene-Pyrrolidinopyridine
Nucleophilic Catalyst for Asymmetric
Synthesis
Huy V. Nguyen, David C. D. Butler, and Christopher J. Richards*
School of Biological and Chemical Sciences, Queen Mary, UniVersity of London,
Mile End Road E1 4NS, U.K.
c.j.richards@qmul.ac.uk
Received December 16, 2005
ABSTRACT
A highly active chiral 4-aminopyridine nucleophilic catalyst, available in three steps from (S,S)-hexane-2,5-diol, was applied to the asymmetric
Steglich rearrangement of O-aceylated azlactones (1 mol % loading, up to 76% ee).
Since its introduction by Litvinenko and Steglich in the late
1960s,1 4-(dimethylamino)pyridine (4-DMAP) and the more
active 4-pyrrolidinopyridine (4-PPY) have been extensively
employed as nucleophilic catalysts for acyl transfer reac-
tions.2 The high activity of these systems is exemplified by
the 3.4 × 108 rate enhancement of alcohol acylation (by
benzoyl chloride) in the presence of a stoichiometric quantity
of 4-DMAP.3 As a consequence, the 4-aminopyridine moiety
has been incorporated into a variety of acyl transfer catalysts
for application in asymmetric synthesis (Figure 1). When
considering how to introduce chirality into these catalysts it
is important not to attach a substituent at the pyridine
2-position, as this significantly attenuates nucleophilicity
(e.g., A).4 The challenge is to introduce a substituent at the
3-position (e.g., B)5 or even more remotely (e.g., C)6 and
yet maintain an asymmetric environment about the active
pyridine nitrogen. The only exceptions to this requirement
are planar chiral ferrocene derivatives such as D,7 where the
balance of fair reactivity8 and high selectivity in many
different reactions comes at the cost of a lengthy synthesis
(1) (a) Litvinenko, L. M.; Kirichenko, A. I. Dokl. Chem. 1967, 763; Dokl.
Akad. Nauk SSSR Ser. Chim. 1967, 176, 97. (b) Steglich, W.; Ho¨fle, D.
Angew. Chem. 1969, 81, 1001; Angew. Chem., Int. Ed. Engl. 1969, 8, 981.
(2) (a) Scriven, E. F. V. Chem. Soc. ReV. 1983, 12, 129. (b) Grondal, C.
Synlett 2003, 1568. (c) Murugan, R.; Scriven, E. F. V. Aldrichimica Acta
2003, 36, 21.
(3) Bondarenko, L. I.; Kirichenko, A. I.; Litvinenko, L. M.; Dmitrenko,
I. N.; Koberts, V. D. J. Org. Chem. USSR (Engl. Transl.) 1981, 2310; Zh.
Org. Khim. 1981, 17, 2588.
Figure 1. Known chiral 4-aminopyridine nucleophilic catalysts.
(4) Vedejs, E.; Chen, X. J. Am. Chem. Soc. 1996, 118, 1809.
10.1021/ol053050n CCC: $33.50
© 2006 American Chemical Society
Published on Web 01/26/2006

and the need for subsequent chromatographic resolution to
obtain the enantiopure catalyst.9
Scheme 1. Synthesis of an Achiral 3-Substituted PPY
We reasoned that an alternative and potentially much
simpler approach to a chiral acyl transfer catalyst would be
to relay the stereochemistry of a readily synthesized enan-
tiopure C2-symmetric pyrrolidine through to the pyridine
nitrogen by use of a bulky metallocene substituent (Figure
2). Attachment of this to the 3-position should ensure the
Nucleophilic Catalyst
this as a reaction partner in the Negishi cross-coupling
protocol gave the novel chiral nucleophilic catalyst 1.
Figure 2. Design rationale for 1.
Scheme 2. Asymmetric Synthesis of a Chiral 3-Substituted
maintenance of high nucleophilicity, while placing the
pyridine nitrogen in an asymmetric environment by projec-
tion of the tetraphenylcyclobutadiene moiety into one of the
quadrants surrounding the pyridine nitrogen. In this Letter
we report on the synthesis and properties of metallocene
catalyst 1 and on the application of this to the asymmetric
Steglich rearrangement.
PPY Nucleophilic Catalyst
We first established a simple procedure for the synthesis
of achiral 3-substituted 4-PPY derivative 4, utilizing a
Negishi cross-coupling to generate the key metallocene-
pyridine C-C bond. (Scheme 1). As it did not prove possible
to lithiate the parent metallocene directly, the known iodo
derivative 210 was subjected to halogen-lithium exchange
and transmetalation with zinc chloride to give the organozinc
intermediate 3. This was not isolated and was instead cross-
coupled with 3-bromo-4-pyrrolidinopyridine11 to give the
novel metallocene 4 as an air-stable yellow crystalline solid.
Adaptation of this methodology for the synthesis of a chiral
complex began with commercially available (S,S)-hexane-
2,5-diol,12 which was converted via an intermediate dimes-
ylate into (R,R)-pyrrolidinopyridine 7 (Scheme 2).13 Use of
Of the two metallocene-substituted nucleophilic catalysts,
we have so far only been successful in obtaining the X-ray
crystal structure of the achiral derivative 4 (Figure 3).14 This
revealed that the size and proximity of the two pyridine
substituents results in (a) a 29° tilt of the pyridine ring with
respect to the cyclopentadienyl ring, (b) a twist in the
pyrrolidine group moving the methylene C(42) away from
the adjacent cyclopentadienyl ring, and (c) the pyridine
carbon C(38) is bent 25° above the plane (as viewed) defined
by C(42)-N(2)-C(39), indicative of some sp3 character in
the pyrrolidine nitrogen. In addition, this structure illustrates
the projection of the cyclobutadiene phenyl groups under
one face of the pyridine.
(5) (a) Jeong, K.-S.; Kim, S. H.; Park, H.-J.; Chang, K.-J.; Kim, K. S.
Chem. Lett. 2002, 1114. (b) Spivey, A. C.; Zhu, F.; Mitchell, M. B.; Davey,
S. G.; Jarvest, R. L. J. Org. Chem. 2003, 68, 7379. (c) Shaw, S. A.; Aleman,
P.; Vedejs, E. J. Am. Chem. Soc. 2003, 125, 13368. (d) Seitzberg, J. G.;
Dissing, C.; Søtofte, I.; Norrby, P.-O.; Johannsen, M. J. Org. Chem. 2005,
70, 8332.
(6) (a) Kawabata, T.; Nagato, M.; Takasu, K.; Fuji, K. J. Am. Chem.
Soc. 1997, 119, 3169. (b) Priem, G.; Pelotier, B.; Macdonald, S. J. F.; Anson,
M. S.; Campbell, I. B. J. Org. Chem. 2003, 44, 3844. (c) Spivey, A. C.;
Maddaford, A.; Fekner, T.; Redgrave, A. J.; Frampton, C. S. J. Chem. Soc.,
Perkin Trans. 1 2000, 3460. (d) Naraku, G.; Shimomoto, N.; Hanamoto,
T.; Inanaga, J. Enantiomer 2000, 5, 135.
An asymmetric catalyst requires selective differentiation
between the two pyridine faces. To examine if 1 displays
this requirement, we next examined the conformational
(7) Fu, G. C. Acc. Chem. Res. 2004, 37, 542.
(8) As an indicatior of the relative activity of D versus 3-substituted-4-
aminopyridines, the former are generally used at 0 °C to catalyze alcohol
acylation, whereas the latter may be employed at -78 °C.
(9) (a) Ruble, J. C.; Fu, G. C. J. Org. Chem. 1996, 61, 7230. (b) Ruble,
J. C.; Latham, H. A.; Fu, G. C. J. Am. Chem. Soc. 1997, 119, 1492.
(10) Rausch, M. D.; Genetti, R. A. J. Org. Chem. 1970, 35, 3888.
(11) Spivey, A. C.; Fekner, T.; Spey, S. E.; Adams, H. J. Org. Chem.
1999, 64, 9430.
(13) Compound 7 was synthesized using a procedure developed for
related C2-symmetric 2,5-disubstituted pyrrolidines; see ref 6c.
(14) Crystal Data for 4. C42H36CoN2O0.50, M ) 635.66, monoclinic, a
) 18.5614(3), b ) 34.2968(8), c ) 10.4254(2) Å, R ) 90°, â ) 107.7760-
(10)°, γ ) 90°, V ) 6319.9(2) Å3, space group C2/c, Z ) 8, Dc ) 1.336
Mg/m3, µ ) 0.579 mm-1, reflections measured 22082, reflections unique
7187 with Rint ) 0.0438, T ) 120(2) K, final R indices [F2 > 2σ(F2)] R1
) 0.0385, wR2 ) 0.0880 and for all data R1 ) 0.0605, wR2 ) 0.0971.
(12) Lieser, J. K. Synth. Commun. 1983, 765.
770
Org. Lett., Vol. 8, No. 4, 2006

Table 1. Determination of Catalyst Activity
time
(h)
conversion
to 9a (%)
catalyst δ(1H)
â-Hb (ppm)
catalyst
4-PPY
4-DMAP
4
1
5
5
5
68
53
6.38
6.48
6.44
6.61
71
18
38c,d
1
a Determined by H NMR spectroscopy. b Determined in CDCl3. c Re-
covered (S)-8 ) 17% ee (s ) 2.1). d Use of i-Pr2O gave a 50% conversion
with recovered (S)-8 ) 32% ee (s ) 2.6).
Figure 3. Representation of the X-ray crystal structure of 4 (water
of crystallization removed for clarity). Key bond angles and
torsions: C(39)-N(2)-C(42) ) 110.11(15)°, C(39)-N(2)-C(38)
) 119.58(15)°, C(38)-N(2)-C(42) ) 122.33(15)°, C(32)-C(33)-
C(34)-C(38) ) 29.0°, C(34)-C(38)-N(2)-C(39) ) -164.5°,
C(34)-C(38)-N(2)-C(42) ) 49.7°
4-DMAP, with the chiral species 1 being slightly less active.
This was verified by application of these catalysts to the
acetylation of 1-(1-naphthyl)ethanol 8. The conversion
obtained with 4 was similar to that obtained with 4-PPY and
4-DMAP, whereas 1 required a longer reaction time to
achieve a lower conversion. Subsequent analysis of the
recovered alcohol from this last reaction indicated that this
catalyst is not suitable for application in secondary alcohol
kinetic resolution.
properties of this complex by NMR spectroscopy (Figure
4). A gradient-enhanced nuclear Overhauser enhanced spec-
Instead we chose to examine the Steglich rearrangement18
of enol carbonates 10, precursors to azlactones 11 containing
a quaternary stereogenic center.19 Addition of 1 mol % of 1
to 10a resulted in clean rearrangent at 0 °C (Table 2, entry
Table 2. Asymmetric Steglich Rearrangement with Catalyst 1a
Figure 4. GOSEY connectivity and percentage enhancements for
1.
troscopy experiment (GOSEY) revealed connectivity between
the pyridine H-2 singlet and only one of the two diaste-
reotopic R-hydrogens of the cyclopentadienyl group.15,16 That
this is drawn as the pro-pS hydrogen is based on the
assumption that the pyrrolidine methyl substituent adjacent
to the Cp-ring is orientated away from the metallocene.
All of the points (a-c) made in the discussion of the X-ray
structure of 4 could potentially reduce the effectiveness of
this as a nucleophilic catalyst. One method to estimate
activity is by comparison of the chemical shift of the pyridine
temp time conv to
ee
entry
R
solvent
PhCH3
CH2Cl2
t-amyl alcohol
PhCH3
(°C) (h) 11 (%)b
(%)c
1
2
3
Bn
Bn
Bn
0
0
0
48
72
72
100 72 (12a)
100 45 (12a)
70
0 (12a)
4d Bn
-20 156
48
85 75 (12a)
100 76 (11b)
5
C(CCl3)Me2 PhCH3
0
1
â-hydrogen(s) in the H NMR spectra (Table 1).17 This
a 1 mol % unless otherwise stated. b Determined by 1H NMR after
removal of the catalyst by filtration through a SiO2 plug. c Determined by
HPLC (Chiralcel OD). d 3 mol % 1.
indicated that 4 should have an activity similar to that of
(15) Irradiation of pyridine H-2 (7.76 ppm) at 298 K resulted in a pro-
pS (4.92 ppm) to pro-pR (5.14 ppm) enhancement ratio of >23:1 (the latter
was not observed).
(16) An alternative way to consider the stereochemical environment of
the pyridine moiety is to regard it as being in an environment of virtual
planar chirality. See: Jones, G.; Richards, C. J. Organometallics 2001, 20,
1251.
1). Because of the instability of 11a toward chiral HPLC
analysis, we found it more convenient to determine the
(18) (a) Steglich, W.; Ho¨fle, G. Chem. Ber. 1969, 102, 883. (b) Steglich,
W.; Ho¨fle, G. Chem. Ber. 1971, 104, 3644. (c) Ho¨fle, G.; Prox, A.; Steglich,
W. Chem. Ber. 1972, 105, 1718.
(17) Hassner, A.; Krepski, L. R.; Alexanian, V. Tetrahedron 1978, 34,
2069.
Org. Lett., Vol. 8, No. 4, 2006
771

enantioselectivity following ring opening to diester 12a. This
revealed an enantiomer ratio of 86:14, and the configuration
of the major isomer was determined by comparison of the
rotation of 11a to the literature value.19 Use of dichlo-
romethane as the reaction solvent significantly reduced the
enantioselectivity (entry 2), and use of tert-amyl alcohol
resulted in no enantioselectivity (entry 3). This latter result
was suprising as this solvent has previously been determined
to maximize enantioselectivity for reactions of this type.5c,19
Returning to toluene and lowering the reaction temperature
resulted in a 75% enantiomeric excess, though at the expense
of a higher catalyst loading and a longer reaction time (entry
4). Essentially the same enantioselectivity was achieved with
1 mol % of 1 and the bulkier 2,2,2-trichloro-1,1-dimethyl-
ethyl group20 of substrate 10b, rearranged azlactone 11b
subsequently being isolated in 65% yield.
highly active 4-aminopyridine nucleophilic catalyst from a
commercially available chiral starting material. Use of a
bulky cobalt metallocene to relay the stereochemistry of the
pyrrolidine results in a defined chiral environment about the
pyridine nitrogen. Preliminary investigations into the use of
this catalyst have resulted in greater than 7:1 enantioselec-
tivity for the rearrangement of an O-acylated azlactone.
Acknowledgment. We thank the EPSRC for financial
support (H.V.N., D.C.D.B.), the EPSRC National Crystal-
lography Service (Southampton University), and the EPSRC
National Mass Spectrometry Service Centre (University of
Wales, Swansea). We also thank Chirotech Technology Ltd
for assistance.
Supporting Information Available: Synthesis, charac-
1
terization, and H NMR spectra of 1, 4, 7, 10b, 11b and
In summary, we have demonstrated a short synthesis of a
12a; methods of ee determination; and details of the X-ray
crystal structure of 4 in CIF format. This material is available
free of charge via the Internet at http://pubs.acs.org.
(19) Ruble, J. C.; Fu, G. C. J. Am. Chem. Soc. 1998, 120, 11532.
(20) This has previously been successfully applied to the related
rearrangement of O-acylated oxindoles, see: Hills, I. D.; Fu, G. C. Angew.
Chem., Int. Ed. 2003, 42, 3921.
OL053050N
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Org. Lett., Vol. 8, No. 4, 2006