Design, synthesis, and evaluation of a helicenoidal DMAP lewis base catalyst

Article abstract of DOI:10.1021/ol2001705

The design, synthesis, and study of a helical dialkylaminopyridine Lewis base catalyst is reported. Helical DMAP analogue 4 is based upon a helicenoid structure and displays good to excellent levels of selectivity (S ≤ 116) in the kinetic resolution of chiral secondary alcohols. Catalyst 4 displays excellent reactivity with exceptionally low loadings of 0.05 mol % effecting practical levels of selectivity in kinetic resolutions.(Figure Presented)

Full text of DOI:10.1021/ol2001705

ORGANIC
LETTERS
2011
Vol. 13, No. 5
1250–1253
Design, Synthesis, and Evaluation of a
Helicenoidal DMAP Lewis Base Catalyst
Matthew R. Crittall,† Henry S. Rzepa,‡ and David R. Carbery*,†
Department of Chemistry, University of Bath, Bath, BA2 7AY, United Kingdom, and
Department of Chemistry, Imperial College London, South Kensington, London,
SW7 2AZ, United Kingdom
d.carbery@bath.ac.uk
Received January 19, 2011
w This paper contains enhanced objects available on the Internet at http://pubs.acs.org/OrgLett.
n
ABSTRACT
The design, synthesis, and study of a helical dialkylaminopyridine Lewis base catalyst is reported. Helical DMAP analogue 4 is based upon a
helicenoid structure and displays good to excellent levels of selectivity (S e 116) in the kinetic resolution of chiral secondary alcohols. Catalyst 4
displays excellent reactivity with exceptionally low loadings of 0.05 mol % effecting practical levels of selectivity in kinetic resolutions.
Helical structures attract extensive interest within the
chemistry community by virtue of their chirality. The
importance of helicity in biochemistry with respect to
DNA and peptide tertiary structures is patent.1 Structures
which are chiral exclusively due to their helical shape,
particularly helicenes,2 currently demand attention. For
example, a number of important optical and electronic
materials3 and telomerase inhibitors4 are reliant on the
chiroptical properties of helicenes. In contrast, one specific
area of functional molecules where helicenes have been
underdeveloped is that of asymmetric catalysis and, in
particular, organocatalysts.5 Takenaka has made consid-
erable strides in recent years by demonstrating the value
of helicity with reports of effective helicenyl pyridine
N-oxides6 and 2-aminopyridinium7 catalysts.
The Lewis base catalyst dimethylaminopyridine (DMAP,
1) is the prototypical synthetic nucleophilic catalyst, drama-
tically enhancing the rate of transfer of C-electrophiles to
O-, N-, and C-nucleophiles.8 The area of synthetic chemistry
associated with DMAP has matured to the extent that
developing effective chiral DMAP analogues for asym-
metricsynthesishasbecomenot onlyanimportant exercise
in synthesis but also as a contextual testing ground for
applying new design principles to asymmetric catalysis.9
The difficulties in successfully desymmetrizing two planes
of symmetry present in 1 have led to the application of less
† University of Bath.
‡ Imperial College London.
(1) (a) Saenger, W. Principles of Nucleic Acid Structure; Springer-
Verlag: New York, 1984. (b) Schulz, G. E.; Schirmer, R. H. Principles of
Protein Structure; Springer-Verlag: New York, 1979.
(5) (a) Sato, I.; Yamashima, R.; Kadowaki, K.; Yamamoto, J.;
Shibata, T.; Soai, K. Angew. Chem., Int. Ed. 2001, 40, 1096. (b) Dreher,
S. D.; Katz, T. J.; Lam, K.-C.; Rheingold, A. L. J. Org. Chem. 2000, 65,
815. (c) Reetz, M. T.; Sostmann, S. J. Organomet. Chem. 2000, 603, 105.
(d) Reetz, M. T.; Beuttenmuller, E. W.; Goddard, R. Tetrahedron Lett.
1997, 38, 3211.
(6) Takenaka, N.; Sarangthem, R. S.; Captain, B. Angew. Chem., Int.
(2) For a review of recent helicene syntheses, see: Urbano, A. Angew.
Chem., Int. Ed. 2003, 42, 3986.
(3) For reviews discussing helicenes and helicenoidal compounds in
electronic and optical contexts, see: (a) Rajca, A.; Miyasaka, M. In
Functional Organic Materials: Syntheses, Strategies, and Applications;
M€uller, T. J. J., Bunz, U. H. F., Eds.; Wiley-VCH: Weinheim, 2007; p 543. (b)
Rajca, A.; Miyasaka, M. Angew. Chem., Int. Ed. 2003, 42, 2448. (c)
Nuckolls, C.; Shao, R. F.; Jang, W. G.; Clark, N. A.; Walba, D. M.;
Katz, T. J. Chem. Mater. 2002, 14, 773. (d) Osuga, H.; Tanaka, K. J.
Synth. Org. Chem. Jpn. 2002, 60, 593. (e) Katz, T. J. Angew. Chem., Int.
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Ed. 2008, 47, 9708.
(7) Takenaka, N.; Chen, J.; Captain, B.; Sarangthem, R. S.;
Chandrakumar, A. J. Am. Chem. Soc. 2010, 132, 4536.
(8) (a) Litvinenko, L. M.; Kirichenko, A. I. Dokl. Akad. Nauk. SSSR
€
Ed. 2000, 39, 1921. (f) Grimme, S.; Harren, J.; Sobanski, A.; Vogtle, F.
€
Eur. J. Org. Chem. 1998, 1491.
1967, 176, 97. (b) Steglich, W.; Hofle, G. Angew. Chem., Int. Ed. 1969, 8,
981.
(4) Shinohara, K.; Sannohe, Y.; Kaieda, S.; Tanaka, K.; Osuga, H.;
Tahara, H.; Xu, Y.; Kawase, T.; Bando, T.; Sugiyama, H. J. Am. Chem.
Soc. 2010, 132, 3778.
(9) For a review of chiral DMAP catalysts in asymmetric synthesis,
see: Wurz, R. P. Chem. Rev. 2007, 107, 5570.
r
10.1021/ol2001705
Published on Web 02/08/2011
2011 American Chemical Society

Ourdesignconcept iscenteredupon the placementof the
catalytically crucial 4-dialkylaminopyridine moiety within
a helicenoidal20 framework. Importantly, this design con-
sideration promised a highly active catalyst by conforma-
tional fixation through ring-fusion of the DMAP core.21,22
A [2 þ 2 þ 2]-cycloisomerization23 of a suitable triyne
would allow for a convergent synthesis, with suitable lipo-
philic functionality assisting solubility.24 The aminopyri-
dine moiety would be desymmetrised by the placement
of π-electron density from a suitable aromatic moiety,
ultimately controlled by the chirality of the helix.
Figure 1. DMAP, planar chiral, and axially chiral DMAP
analogues.
common chirality elements with Fu’s planar chiral 210
and Spivey’s axially chiral 311 designs arguably offering
the most imaginative solutions to this scientific problem
(Figure 1).12 The efficacy of 2 and 3 in contexts such as
the kinetic resolution of chiral alcohols13 mean chiral
DMAP analogues offer themselves as valuable chiral acyla-
tion catalysts, complementing the phosphine,14 oligo-
peptide,15 amidine,16 amidine-ferrocene hybrids,17 and
N-heterocyclic carbene18 catalyst approaches addition-
ally reported in recent years.
Scheme 1. Synthesis of Helicenoidal DMAP 4a
Figure 2. Design concept of helicenoidal DMAP catalyst 4.
a Catalyst 4 was resolved by preparative-scale chiral HPLC, both
enantiomers >99% ee (Chiralpak IC).
As DMAP acts as a genuine molecular challenge to
assess unusual asymmetry elements in catalysis, we have
chosen to examine the feasibility of a DMAP structure
adapted to a helical environment (Figure 2).19
The synthesis of catalyst 4 is outlined in Scheme 1.
Sonogashira reaction of 1-iodo-2-naphthol 5 and TMS-
acetylene with subsequent O-propargylation and in situ
desilylation accessed 6 in an excellent 94% yield. A second
Sonogashira reaction between 6 and iodopyridine 7
formed diyne 8. Triyne 9 was synthesized after sequen-
tial N-propargylation of 8 and Boc deprotection with
telescoped N-methylation. The synthesis of helicenoidal
(10) Ruble, J. C.; Latham, H. A.; Fu, G. C. J. Am. Chem. Soc. 1997,
119, 1492.
(11) Spivey, A. C.; Fekner, T.; Spey, S. E. J. Org. Chem. 2000, 65,
3154.
(12) For selected references detailing chiral DMAP analogues
founded on point chirality, see: (a) Kawabata, T.; Nagato, M.; Takasu,
K.; Fuji, K. J. Am. Chem. Soc. 1997, 119, 3169. (b) Shaw, S. A.; Aleman,
(20) We use the word helicenoidal to differentiate 4 from bona fide
helicenyl pyridine nucleophilic catalysts with the “oid” suffix used to
clarify the helicene-like nature of 4 as conferred by the break in
aromaticity.
(21) Heinrich, M. R.; Klisa, H. S.; Mayr, H.; Steglich, W.; Zipse, H.
Angew. Chem., Int. Ed. 2003, 42, 4826.
(22) The use of a [6]azahelicene as a nucleophilic catalyst has been
ꢀ
ꢀ
P.; Vedejs, E. J. Am. Chem. Soc. 2003, 125, 13368. (c) O Dalaigh, C.;
Connon, S. J. J. Org. Chem. 2007, 72, 7066. (d) Yamada, S.; Misono, T.;
Iwai, Y.; Masumizu, A.; Akiyama, Y. J. Org. Chem. 2006, 71, 6872.
(13) (a) Denmark, S. E.; Beutner, G. L. Angew. Chem., Int. Ed. 2008,
47, 1560. (b) Vedejs, E.; Jure, M. Angew. Chem., Int. Ed. 2005, 44, 3974.
(c) Dalko, P. I.; Moisan, L. Angew. Chem., Int. Ed. 2004, 43, 5138. (d)
Jarvo, E. R.; Miller, S. J. In Comprehensive Asymmetric Catalysis,
Supplement 1; Jacobsen, E. N., Pfaltz, A., Yamamoto, H., Eds.; Springer-
Verlag: Berlin, 2004.
reported. This system was reported to offer moderate selectivity (S = 8
ꢁ
ꢀ
ꢁ
sek, J.;
for 10a) and reactivity (5-25 mol % loading); see: Samal, M.; Mı
´
ꢀ
ꢀ
Stara, I. G.; Stary, I. Collect. Czech. Chem. Commun. 2009, 74, 1151.
(23) For transition-metal-catalyzed [2 þ 2 þ 2]-cycloisomerization
(14) Vedejs, E.; Daugulis, O.; Diver, S. T. J. Org. Chem. 1996, 61, 430.
(15) Copeland, G. T.; Miller, S. J. J. Am. Chem. Soc. 2001, 123, 6469.
(16) Birman, V. B.; Uffman, E. W.; Hui, J.; Li, X. M.; Kilbane, C. J.
J. Am. Chem. Soc. 2004, 126, 12226.
(17) Hu, B.; Meng, M.; Wang, Z.; Du, W.; Fossey, J. S.; Hu, X.;
Deng, W.-P. J. Am. Chem. Soc. 2010, 132, 17041.
(18) Kano, T.; Sasaki, K.; Maruoka, K. Org. Lett. 2005, 7, 606.
(19) For our work concerning the synthesis of helicenyl carboxylic
acids, see: Pearson, M. S. M.; Carbery, D. R. J. Org. Chem. 2009, 74,
5320.
ꢀ
approaches to helicenoidal (helicene-like) molecules, see: (a) Stara, I. G.;
ꢁ
Alexandrova, Z.; Teply, F.; Sehnal, P.; Stary, I.; Saman, D.; Budesı
ꢀ
ꢀ
ꢀ
ꢁꢁ
ꢀ
nsky,
´
M.; Cvaka, J. Org. Lett. 2005, 7, 2547. (b) Tanaka, K.; Kamisawa, A.;
Suda, T.; Noguchi, K.; Hirano, M. J. Am. Chem. Soc. 2007, 129, 12078.
ꢀ
ꢀ
ꢀ
ꢀ
ꢁ
´
(c) Sehnal, P.; Krausovy, Z.; Teply, F.; Stara, I. G.; Stary, I.; Rulısek, L.;
ꢁ
ꢀꢁ
ꢁ ꢀ
Saman, D.; Carsarova, I. J. Org. Chem. 2008, 73, 2074.
(24) For discussion of homogeneous and heterogeneous reaction
profiles in DMAP catalysed reactions, see: Spivey, A. C.; Arseniyadis,
S. Angew. Chem., Int. Ed. 2004, 43, 5436.
Org. Lett., Vol. 13, No. 5, 2011
1251

Scheme 2. Substrate Scopea,b
Figure 3. Circular dichroism spectra of resolved 4: (red line)
(M)-4; (black line) (P)-4 (2.5 ꢀ 10-3 M in CH3CN, 25 °C).
DMAP 4 was completed by a Rh(I)-catalyzed triyne
cycloisomerization, offering a synthesis of 4 in six steps
with 41% overall yield and subsequent resolution
through preparative-scale chiral HPLC. Circular di-
chroism spectra of the resolved enantiomers (M)-4 and
(P)-4 are displayed (Figure 3). The sense of helicity has
been assigned as (P)-4 (black plot [R]D = þ540) and (M)-
4 (red plot [R]D = -560) on the basis of sign of optical
rotation and supported by computational studies (see
the interactive table) which have been calibrated against
a Each substrate run in duplicate; data is averaged. b Data presented
as: selectivity S = ln[(1 - c)(1 - eeA)]/ln[(1 - c)(1 þ eeA)] (A = substrate
alcohol); conversion c = 100 ꢀ eeA/(eeA þ eeE) (E = product ester);
time t. c Catalyst (M)-4 used; S-11f,g and S-11i-l formed. d 1 mol % of
catalyst used.
ꢀ 23a,25
the helicene-like structures studied by Stary.
As catalyst 4 was based upon novel design principles
with an assessment of helicity our key consideration,
benchmarking of 4 was conducted through the kinetic
resolution of chiral secondary alcohols, with 10a initially
examined (Scheme 2). A short process of optimization (see
the Supporting Information) led to the conclusion that
resolutions conducted intert-amyl alcohol using isobutyric
anhydride at 0 °C offered optimal selectivity and practi-
cality, a scenario consistent to that observed by Fu.26
Having optimized conditions on 10a, a range of alkyl
aryl chiral alcohols was selected to probe the generality of
catalyst 4 in this kinetic resolution process (Scheme 2).
Aminopyridine 4offers selective resolutions on all substrates
examined at a low catalyst loading of 0.5 mol %. We believe
4 is noteworthy due to the relative rate of acylation of sec-
ondary alcohols, at a lower loading, than other chiral
DMAP systems or other successful Lewis base catalysts.16
Scheme 2 reveals some interesting structure-selectivity
trends. While improvements to selectivity are observed with
increased size of substrate alkyl group (10a,c,d), we find this
structural effect to be minimal with this catalyst system.
Enhanced selectivities are observed in this particular catalyst
system when the substrate aryl group bears ortho-substitu-
tion (10e-l) although not to the extent of the Fu10,26 and
Vedejs14 catalysts. Finally, anthracenyl substrate 10l offered
optimal selectivity (S = 116) in this screen. This substrate
has not been examined in an asymmetric organocatalytic
context before but has been resolved via Pd-catalyzed
oxidation with substantially lower selectivity (S = 12).27
These chiral anthracenyl alcohols have found considerable
application in synthesis as effective chiral auxiliaries.28
Wehave endeavoredto rationalize the sense of selectivity
observed in this kinetic resolution. Catalyst (P)-4 results in
a faster acylation of the (R)-10a enantiomer. Simple mod-
eling is suggestive of π-stacking arrangements between sub-
strate aryl group and catalyst aminopyridine unit in com-
bination with the minimization of steric clash between the
methyl group of 10a and electrophile iPr group (Figure 4).
Figure 4. Proposed model of stereoselectivity.
This model largely mirrors that recently discussed by
Birman and Houk.29 Indeed, a trend of improving selectiv-
ity is observed in three ortho-substituted alcohols (10g-i,
S = 23 to S = 43) where increased aryl electron density
would improve electrostatic aromatic π-stacking.
(25) Efforts have been made unsuccessfully to obtain an assignment
of configuration through crystallographic means. These efforts are
ongoing.
(26) Ruble, J. C.; Tweddell, J.; Fu, G. C. J. Org. Chem. 1998, 63, 2794.
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Org. Lett., Vol. 13, No. 5, 2011

In an attempt to demonstrate the synthetic potential
and excellent reactivity of catalyst 4, we have performed a
resolution of10eataminimized loading of0.05mol % on a
5 mmol scale (Scheme 3).
In conclusion, the first helicenoidal asymmetric organo-
catalyst has been designed, synthesized and assessed in the
kinetic resolution of chiral secondary aryl alkyl alcohols.
Catalyst 4 offers good to excellent levels of selectivity and
particularly excellent levels of reactivity when compared
with other chiral nucleophilic catalyst systems. Attempts
are underway in our laboratory to enhance catalyst stereo-
selectivity through further design iterations and further
probe substrate-stereoselectivity trends commented upon
in this Letter.
Scheme 3. Preparative-Scale, Low-Loading Kinetic Resolution
Acknowledgment. We thank The University of Bath
and the EPSRC (EP/E017495/1) for studentship funding
(M.R.C.). We are indebted to Drs. A. Knaggs, S. Peace,
and D. Hulcoop (GlaxoSmithKline, Stevenage) for the
resolution of 4. Dr. N. Thiyagarajan and Prof R. Acharya
(Department Biology & Biochemistry, University of
Bath) are thanked for access and assistance with circular
dichroism spectroscopy. Mr. J. Allen, Miss H. Edwards,
and Dr. C. Frost (Department Chemistry, University of
Bath) are thanked for access and assistance with chiral
HPLC.
A conversion of 60% was attained after 48 h, offering
a selectivity of S = 34. This example is noteworthy for the
exceptionally low loading attainable with catalyst 4, which
we believe is the lowest loading reported for a preparative
scale organocatalytic kinetic resolution of chiral carbinols.30
(27) Ebner, D. C.; Trend, R. M.; Genet, C.; McGrath, M. J.; O’Brien,
P.; Stoltz, B. M. Angew. Chem., Int. Ed. 2008, 47, 6367.
(28) For recent examples, see: (a) Liu, X.; Snyder, J. K. J. Org. Chem.
ꢀ
2008, 73, 2935. (b) Adams, H.; Elsunaki, T. M.; Ojea-Jimenez, I.; Jones,
S.; Meijer, A. J. H. M. J. Org. Chem. 2010, 75, 6252.
(29) Li, X.; Peng, L.; Houk, K. N.; Birman, V. B. J. Am. Chem. Soc.
2008, 130, 13836.
(30) There has been one preceding report of a 0.05 mol % loading
using a chiral DMAP catalyst on an analytical-scale kinetic resolution of
10f with isobutyric anhydride; see ref 12d.
Supporting Information Available. Experimental pro-
cedures, HPLC chromatograms, and NMR spectra. This
material is available free of charge via the Internet at
http://pubs.acs.org.
Org. Lett., Vol. 13, No. 5, 2011
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