Point-to-helical chirality transfer for a scalable and resolution-free synthesis of a helicenoidal DMAP organocatalyst

Article abstract of DOI:10.1039/c2cc35583c

The synthesis of a second-generation [6]-helicenoidal DMAP organocatalyst is reported. The synthesis is reliant upon a highly diastereoselective Rh-catalysed [2 + 2 + 2] triyne cycloisomerization, using an existing stereocentre to control the sense of forming helicity. Taken together, a scalable (>1 g), resolution-free entry to a helical DMAP with the capacity for subsequent functionalization, has been achieved.

Full text of DOI:10.1039/c2cc35583c

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Point-to-helical chirality transfer for a scalable and resolution-free
synthesis of a helicenoidal DMAP organocatalyst
Matthew R. Crittall,a Nathan W. G. Fairhursta and David R. Carbery*a
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
5
DOI: 10.1039/b000000x
The synthesis of a second-generation [6]-helicenoidal DMAP
organocatalyst is reported. The synthesis is reliant upon a
highly diastereoselective Rh-catalysed [2+2+2] triyne
cycloisomerization, using an existing stereocentre to control
10 the sense of forming helicity. Taken together, a scalable (>1
g), resolution-free entry to a helical DMAP with the capacity
for subsequent functionalization, has been achieved.
Chirality, according to Kelvin’s original definition, centres upon
the geometrical nonꢀsuperimposability of mirror images.
15 Accordingly, molecules are deemed to be either chiral or nonꢀ
chiral. Synthetic chemists however, have had a tendency to
additionally “classify” chiral molecular topographies into more
familiar subsets. For example, chiral structures are regularly
described as possessing centres, planes and axes of chirality. The
20 drive to synthesise chiral molecules with nonꢀtraditional
stereoelements, such as those which contain planar or axial chiral
elements, has arguably been motivated by the continued
development of novel catalystꢀligand designs and the
advancement of modern asymmetric synthetic methodologies.
25 Regularly, a class of ligand, for example chelating bisphosphine
ligands,1 evolve a certain level of synthetic utility which cannot
be improved upon unless novel chiral stereochemical space away
from the ready availability of the chiral pool is examined.
In the arena of organocatalysis, one example which has seen a
30 pronounced level of creative molecular design is the development
of chiral analogues of the Lewis basic catalyst 4ꢀdimethylamino
pyridine (DMAP, 1, Fig 1).2 The challenge of effectively
desymmetrising the pyridine ring has led to some impressive and
imaginative applications of nonꢀtraditional chirality elements to
35 the synthesis of chiral DMAP analogues. For example, Fu has
synthesised the planar chiral, ferroceneꢀbased catalyst 23 and
Spivey has reported the examination of atropisomerism as a
chirality element in the synthesis of 34 (Fig 1).5,6
40
Fig.1 DMAP and nonꢀtraditional chiral analogues
In addition to their wideꢀranging applications in functional
materials chemistry7, helicenes have recently been examined as
the basis of a number of chiral organocatalysts.8 Inspired by these
studies, we chose DMAP as our context to examine helicity as a
45 viable chiral scaffold in organocatalyst design. Accordingly, we
have recently reported the design, synthesis, resolution and
benchmarking of helical catalyst 4.9,10 This catalyst is based upon
a heliceneꢀlike structure and was found to be an effective catalyst
for the acylative kinetic resolution of chiral secondary alcohols.
50 Selectivity factors of up to S=116, with loadings as low as 0.05
mol% on preparative scale reactions were achieved. Whilst this
report on chiral 2° alcohols was encouraging, the primary reason
for study was to gauge the efficacy of heliceneꢀlike structures as a
design element in asymmetric catalysis. A subsequent reꢀ
55 evaluation of this study pinpointed three key deficiencies. Firstly,
the synthesis of 4 required HPLC resolution of the racemic
material, ultimately restricting synthetic applicability. Secondly, a
number of intermediates en route to 4 were found to be sensitive,
leading to limited scalability. Thirdly, it is reasonable to assume
60 that the incorporation of additional functionality upon the
helicenoid body of 4 may, in a general sense, allow enhanced
selectivities and efficacies to be attained in enantioselective
transformations. Therefore, the introduction of a method by
which lateꢀstage functionalization could be achieved was seen to
65 be advantageous. We were keen to address these shortꢀcomings
and develop an asymmetric synthesis of
a functionalized
helicenoidal DMAP. Inspired by the Starý laboratory11 which has
reported excellent levels of pointꢀtoꢀhelicity chirality transfer
during Coꢀcatalysed [2+2+2]ꢀtriyne cycloisomerizations en route
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to heliceneꢀlike molecules, we have opted to design pyridine 5 30 This diastereoselective cycloisomerization has been performed in
(Fig. 1).
good yield on a reasonable scale (0.5 mmol). We have looked to
scaleꢀup this cycloisomerization, but when performed on a 3 g
scale 5 was formed in 33% yield. Despite a lower yield, this
largerꢀscale reaction still enables formation of 5 in over 1 g
The synthesis of an appropriate chiral triyne is outlined in
Scheme 1. This sequence mirrors our original route to 4 but now
relies upon the formation of chiral propargyl ether Sꢀ9 via a
5
Mitsunobu reaction using an enantiopure propargylic alcohol and 35 quantities. A recent discussion has pointed out the difficulties and
a functionalised 2ꢀnaphthol (Scheme 1). Conversion of naphthol
6 to 7 was achieved via regioselective Sonogashira coupling with
trimethylsilylacetylene. Mitsunobu reaction of 7 and propargylic
importance of accessing enantiopure helicenes on scale.12 The
level of pointꢀtoꢀhelical transfer employed in this route to
helicenoidal DMAP 5 is excellent and deserves commenting
upon. We believe stereocontrol is founded upon a minimization
10 alcohol Rꢀ8 formed ether Sꢀ9 with no loss of enantiopurity. A
second Sonogashira coupling between Sꢀ9 and 10 proceeded 40 of A1,3ꢀlike strain between the propargylic methyl group and the
without incident before ultimate conversion to 12 using the
sequence of transformations previously utilised in the synthesis of
4 (Scheme 1).
phenyl group during the construction of the central
hexasubstituted aryl ring. This model places the methyl group
(c.f. I and II, Fig. 2) in a pseudoꢀaxial position, ultimately
controlling the configuration of forming helicity i.e. Sꢀ12 → P,Sꢀ
45 5.
Fig.2 Suggested rationale for chirality transfer
Having demonstrated a scalable, resolutionꢀfree synthesis of a
helicenoidal DMAP, we have in turn examined the third of our
50 perceived drawbacks regarding our initial helical catalyst
synthesis. Preliminary studies have demonstrated the feasibility
of lateꢀstage functionalization by performing a Pdꢀcatalysed
Kumada coupling between 5 and an aryl Grignard reagent to form
13 (eq 1, Scheme 3). Though unoptimized, we feel this represents
55 a significant result due to the structural sensitivity of 5 due to the
strongly Lewis basic pyridyl nitrogen and sp3 centres adjacent to
N- and O-centres.‡ Finally, we have demonstrated that the
structural changes made to the periphery of the helicenoidal
scaffold have not resulted in a deleterious effect on catalysis, with
60 14 resolved with identical selectivity as initially reported by
ourselves (eq 2, Scheme 3).
15
Scheme 1 Chiral pyridyl triyne formation
Our previous experience had pointed towards the sensitivity of
the electronꢀrich naphthalene unit, which ultimately restricted
attempted scaleꢀup of 4. However, a beneficial outcome of
20 incorporating the bromide functionality is that the discussed
instability is now controlled and as a result, triyne 12 can be
prepared on a multiꢀgram scale.
Application of the Rh(I)ꢀcatalysed triyne cycloisomerization
reaction to 12 resulted in the smooth formation of helicenoid 5 in
25 88% yield. We were delighted to observe an excellent level of
diastereoselectivity (95:5), with the major isomer cleanly
recovered as a single diastereomer after chromatography.
Scheme 3 Preliminary lateꢀstage functionalization studies and
demonstration of catalysis
65 Conclusions
Scheme 2 Pointꢀtoꢀhelical chirality transfer
In conclusion a secondꢀgeneration synthesis of a helicenoidalꢀ
2
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reaction between a propargylic alcohol and a naphthol, see: J. Žádný,
A. Jančařík, A. Andronova, M. Šámal, J. V. Chocholouová, J. Vacek,
R. Pohl, D. Šaman, I. Císařová, I. G. Stará, and I. Starý, Angew.
Chem. Int. Ed., 2012, 51, 5857.
DMAP organocatalyst has been achieved. By harnessing pointꢀtoꢀ
helical chirality transfer a scalable, resolutionꢀfree synthesis of a
functionalised helical aminopyridine is possible. The potential for
lateꢀstage Pd(0)ꢀcatalysed functionalization has also been
demonstrated. A systematic optimization study is currently
underway in our laboratory to improve this lateꢀstage coupling
strategy to a useful synthetic process. Practical quantities of
active helical Lewis basic organocatalysts are now available from
this study.
12 J. Vávra, L. Severa, P. Švec, I. Císařová, D. Koval, P. Sázelová, V.
Kašička and F. Teplý, Eur. J. Org. Chem. 2012, 489.
5
10 Notes and references
a Department of Chemistry, University of Bath, Claverton Down, United
Kingdom; Tel: +44 1225 386144; E-mail: d.carbery@bath.ac.uk
† Electronic Supplementary Information (ESI) available: Full
experimental details and NMR data for novel compounds. See
15 DOI: 10.1039/b000000x/
‡ Isolation of analytically pure 13 has so far not been possible due to coꢀ
elution with
5 during attempted chromatographic purification and
postulated catalyst ligation. See ESI for reaction conversion data (NMR
and mass spectral).
20
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