Modular and stereoselective synthesis of tetrasubstituted helical alkenes via a palladium-catalyzed domino reaction

Article abstract of DOI:10.1021/ol301495q

A highly modular and stereoselective synthesis of tetrasubstituted helical alkenes is accomplished by a Pd-catalyzed norbornene-mediated domino reaction. This protocol features the rapid assembly of four C-C bonds via sequential C-H activations and carbopalladations along with efficient access to enantiopure bromoalkyl aryl alkyne precursors using homologative alkynylation as the key transformation. Three distinct elements of stereoselectivity were observed in the preparation of the chiral helical alkenes: retention of stereochemistry of the substrates, induced helical diastereoselectivity in the alkene formation, and the exclusive exo-facial selectivity of the norbornene incorporation.

Full text of DOI:10.1021/ol301495q

ORGANIC
LETTERS
2012
Vol. 14, No. 14
3648–3651
Modular and Stereoselective Synthesis of
Tetrasubstituted Helical Alkenes via a
Palladium-Catalyzed Domino Reaction
ꢀ ꢀ
Hongqiang Liu, Mohamed El-Salfiti, David I. Chai, Jeremy Auffret, and Mark Lautens*
Davenport Laboratories, Department of Chemistry, University of Toronto, Toronto,
Ontario, Canada M5S 3H6
mlautens@chem.utoronto.ca
Received May 31, 2012
ABSTRACT
A highly modular and stereoselective synthesis of tetrasubstituted helical alkenes is accomplished by a Pd-catalyzed norbornene-mediated
domino reaction. This protocol features the rapid assembly of four CꢀC bonds via sequential CꢀH activations and carbopalladations along with
efficient access to enantiopure bromoalkyl aryl alkyne precursors using homologative alkynylation as the key transformation. Three distinct
elements of stereoselectivity were observed in the preparation of the chiral helical alkenes: retention of stereochemistry of the substrates,
induced helical diastereoselectivity in the alkene formation, and the exclusive exo-facial selectivity of the norbornene incorporation.
With the rapid development of nanotechnology, the
design and efficient construction of molecular motors that
power future nanomachines are highly desirable.1 Among
various types of motors, the light-driven chiral tetrasub-
stituted helical alkenes developed by Feringa and co-
workers2 have attracted attention (Figure 1). In particular,
alkene (1) can undergo unidirectional 360° rotation
around the olefin axis upon light irradiation. Many versa-
tile designs based on these molecules have been realized,
such as a molecular switch3 (2), showing potential in the
application of binary data storage, and a light-driven
asymmetric catalyst4 (3) with the capacity to form either
enantiomer of the product upon modulating the catalyst
form by irradiation. Interestingly, the direction of rotation
of these molecules upon irradiation with light is dictated by
the absolute configuration of stereogenic center(s) next to
the central double bond.2 In order to understand and
harness the unidirectional rotation, efficient access to these
enantiomerically pure helical alkenes has recently intensi-
fied research activity in this area.2c,3,5 Herein, we report a
highly modular and stereoselective approach to synthesize
sterically crowded tetrasubstituted helical alkenes via a
domino reaction from simple starting materials.
On the basis of our previous synthesis of tetrasubstituted
helical alkenes,6a chiral alkenes (4) should be accessible
from the commercially available ortho-subsubstituted aryl
iodides (5) and enantiomerically pure bromoalkyl aryl
alkynes (6) via a palladium-catalyzed, norbornene-mediated
(1) (a) Balzani, V., Credi, A., Venturi, M. Molecular Devices and
Machines-Concepts and Perspectives for the Nanoworld, 2nd ed.; Wiley-
VCH: Weinheim, 2008. (b) Sauvage, J.-P., Ed. Molecular Machines and
Motors; Springer: New York, 2001.
(2) (a) Feringa, B. L. J. Org. Chem. 2007, 72, 6635–6652 and
references therein. (b) Feringa, B. L.; van Delden, R. A.; Koumura,
N.; Geertsema, E. M. Chem. Rev. 2000, 100, 1789–1816 and references
therein. (c) Ruangsupapichat, N.; Pollard, M. M.; Harutyunyan, S. R.;
Feringa, B. L. Nat. Chem. 2011, 3, 53–60.
€
(5) (a) Tietze, L. F.; Dufert, M. A.; Hungerland, T.; Oum, K.; Lenzer,
T. Chem.;Eur. J. 2011, 17, 8452–8461. (b) Tietze, L. F.; Hungerland,
T.; Dufert, A.; Objartel, I.; Stalke, D. Chem.;Eur. J. 2012, 18, 3286–
3291. (c) Hojo, D.; Noguchi, K.; Tanaka, K. Angew. Chem., Int. Ed.
2009, 48, 8129–8132. (d) Pijper, T. C; Pijper, D.; Pollard, M. M.; Dumur,
F.; Davey, S. G.; Meetsma, A.; Feringa, B. L. J. Org. Chem. 2010, 75,
825–838.
€
(3) Tietze, L. F.; Dufert, M. A.; Lotz, F.; Sc-lter, L.; Oum, K.; Lenzer,
T.; Beck, T.; Herbst-Irmer, R. J. Am. Chem. Soc. 2009, 131, 17879–
17884.
(4) Wang, J.; Feringa, B. L. Science 2011, 331, 1429–1432.
r
10.1021/ol301495q
Published on Web 06/27/2012
2012 American Chemical Society

a homologative alkynylation sequence.8 Reduction of the
lactones to lactols with diisobutylaluminum hydride
(DIBAL) followed by a homologative rearrangement with
TMSCHN2 and LDA provided the corresponding alkynes
in good yields. Interestingly, the formation of C-silated
alkynes 7a0 was observed during the rearrangement to 7a,
which was readily converted to the desired products
through TBAF desilation.9 The required chiral bromoalk-
yl aryl alkyne 6 was readily obtained in high yield with
excellent enantioselectivity (up to 99% ee) through a
modular two-step sequence, including installation of an
aryl group via a Sonogashira coupling and conversion of
Table 1. Synthesis of Enantiomerically Pure Bromoalkyl Aryl
Alkynes
Figure 1. Representative examples of a light-driven molecular
motor (1), molecular switch (2), and motor-based asymmetric
catalyst (3).
domino reaction6b (Scheme 1). This process forms four
carbonꢀcarbon bonds in one synthetic sequence. We
entry
1
8 (R)
7,a yield (%)
6,a yield (%) (ee,b %)
Scheme 1. Proposed synthesis of Chiral Tetrasubstituted Helical
Alkenes
(3S)-8a
(3S)-7a R0 = H, 30
(3S)-7a0 R0 = TMS,
25
(3S)-6a X = OH, 80
(3S)-6aa X = Br,
89 (>99)
(OBn)
2
3
4
5
(3R)-8b
(3R)-7b R0 = H,
(3R)-6b X = OH, 83
(3R)-6ba X = Br,
86 (>99)
(OBn)
55
(3S)-8c
(3S)-7c R0 = H,
(3S)-6c X = OH, 82
(3S)-6ca X = Br,
93 (98.5)
(NHCbz)
38
(3R)-8d
(NHCbz)
(3R)-7d R0 = H,
(3R)-6d X = OH, 82
(3R)-6da X = Br,
92 (98.5)
41
(3R)-8e
(3R)-7e R0 = H,
(3R)-6e X = OH, 80
(3R)-6ea X = Br,
80 (>99)
(CH3)
51
anticipate that the stereochemistry of the bromide-contain-
ing precursor remains intact during the reaction sequence.
The bromides can be retrosynthetically derived from chiral
alkynes (7), which are made from chiral R-substituted
lactones (8). Notably, the ease of access to chiral R-lactones
offers structural diversity of the helical alkene, as a variety
of substituted groups, based on carbon, oxygen, and nitro-
gen, can be introduced at the stereogenic center.
Our synthesis begins with the preparation of optically
pure alkynes 7. During the course of the investigation, we
compared several synthetic pathways, and the most mod-
ular and high yielding method is shown in Table 1. Alkynes
with various R-substituents (OBn, CH3, NHCbz) were
efficiently synthesized from corresponding lactones 87 via
a Yield of isolated products. b The ee values were determined by
chiral HPLC.
the alcohol to a bromide via an Appel reaction.10 The
corresponding enantiomers of the bromide precursors
were prepared from the enantiomers of the chiral lactones
through an identical synthetic sequence. The formation of
both enantiomers allows for an investigation of the stereo-
chemical outcome of the helical alkene formation, along
with the capacity to study their respective rotational path
upon irradiation with light.
With the enantiopure substrates in hand, we examined
the domino process between bromide (3S)-6aa and
(8) (a) Myers, A. G.; Goldberg, S. D. Angew. Chem., Int. Ed. 2000, 29,
2732. (b) Smith, A. B.; Fox, R. J.; Vanecko, J. A. Org. Lett. 2005, 7, 3099.
(9) The side product formation was also observed by others. See:
(6) (a) Gericke, K. M.; Chai, D. I.; Bieler, N.; Lautens, M. Angew.
Chem. 2009, 121, 1475–1479. Angew. Chem., Int. Ed. 2009, 48, 1447–
1451. (b) Catellani, M.; Frignani, F.; Rangoni, A. Angew. Chem., Int.
Ed. 1997, 36, 119–122. For a review on norbornene mediated ortho CꢀH
functionalization, see:Topics in Current Chemistry: CꢀH Activation; Yu,
J.-Q., Shi, Z., Eds.; Springer: Berlin, 2010; Vol. 292, pp 1ꢀ33.
€
Furstner, A.; Wuchrer, M. Chem.ꢀEur. J. 2006, 12, 76–89.
(10) (a) Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron Lett.
1975, 16, 4467–4470. (b) Appel, R. Angew. Chem., Int. Ed. Engl. 1975, 14,
801–811. (c) Gericke, K. M.; Chai, D. I.; Lautens, M. Tetrahedron 2008,
64, 6002–6014.
(7) The enantiomerically pure R-lactones were prepared according to
literature procedures. See the Supporting Information for details.
Org. Lett., Vol. 14, No. 14, 2012
3649

2-iodotoluene using the standard condition used in our
previous work.6a The desired tetrasubstituted alkene 4a-S
was formed in 71% yield (Scheme 2). Its helical structure
and connectivity as well as the absolute stereochemistry
were confirmed by X-ray crystal analysis. No significant
improvement in yield was observed upon reaction optimi-
zation (see the Supporting Information). In the same
manner as 4a-S, the corresponding enantiomer 4b-R was
prepared from bromide (3R)-6ba in good yield. The tetra-
substituted alkenes bearing nitrogen (4c-S and 4d-R) and
carbon 4e-R substituents at the stereogenic center were
also obtained in good yield. It is noteworthy that the
stereoselective process with exclusive exo-facial selectivity
as shown by the two X-ray crystal structures, 4f and 4g.
Scheme 2. Synthesis of Tetrasubstituted Alkenes with Various
d
Substitutents at the Stereogenic Centeraꢀ
Figure 2. X-ray crystal structures of 4f and 4g. (a) 4f was
synthesized in racemic form, and the dr value was determined
by 1H NMR of crude product. (b) 4g was taken from ref 6a.
The origin of the observed diastereoselectivity possibly
results from the induced helical chirality upon carbopalla-
dation onto the tethered alkyne (A to B), as shown in the
proposed reaction mechanism (Scheme 3). Interestingly,
the induced helical chirality isirrelevant tothenatureofthe
substitutent (OBn vs CH3) asshown in the crystal structure
of 4a-S and 4f. We postulate that the helical chirality in the
alkene formation is the result of a conformational pre-
ference of the ring containing the exocyclic double bond (B
to C).11 Presumably, this induction of helical chirality is
driven by the unfavorable 1,3 allylic strain in B between the
pseudoequatorial R group and the phenyl substitutent,12
which leads to the favorable comformation in C with R
being in the pseudoaxial position. Notably, the induced
helical chirality is controlled by the stereogenic center in
the bromide starting materials, given that the (S)-enantio-
mer predominantly affords (P)-helicity and the (R)-enan-
tiomer (M)-helicity.13 It is noteworthy that these tetra-
substituted alkenes are configurationally stable and E/Z
isomerization was not observed.
a Reaction was conducted on a 0.2 mmol scale (4a-S in 0.4 mmol
scale). b Yield of isolated products. c The dr values were determined by
1H NMR of the crude. d The ee values were determined by chiral HPLC.
installation of a nitrogen-substituted group at the stereo-
genic center has not been demonstrated in previous helical
alkene synthesis.2,3,5
The ease of introducing aryl groups on chiral alkynes
through Sonogashira coupling offers a high degree of
modularity for the synthesis of chiral helical alkenes
(Table 2). The bromide precursors bearing an electron-
withdrawing group (NO2, 6ha) and an electron-donating
group (OMe, 6ia) on the aryl moieties afforded 4h and 4i in
The stereochemical outcome of the domino reaction was
analyzed using 1H NMR spectroscopy, HPLC along with
X-ray crystallography. The chiral helical alkenes were
obtained in excellent enantioselectivity (up to 99% ee) in
all cases, suggesting the retention of stereochemistry of the
bromide precursors throughout the various bond forma-
tion process. We observed moderate diastereoselectivity
(5:1ꢀ6.6:1), yet the formation of single diastereomer was
observed in our previous synthesis of tetrasubstituted
alkenes, such as 4g6a (Figure 2). This indicates that the
observed moderate diastereoselectivity is attributed to
the presence of the substituent at the propargyl position
of the bromide precursors. It appears that incorporation of
norbornene in this domino reaction can be a highly
(11) A chelation model between the palladium and hydroxyl sub-
stituent during carbopalladation onto the alkyne was proposed to
explain the complete diastereoselectivity in the tetrasubstituted alkene
formation via a domino reaction. See ref 3 and Machotta, A. B.; Straub,
B. F.; Oestreich, M. J. Am. Chem. Soc. 2007, 129, 13455–13463.
(12) For 1,3 allylic strain as a controlling factor in stereoselective
transformations, see: (a) Johnson, F. Chem. Rev. 1968, 68, 375–411. (b)
Hoffmann, R. W. Chem. Rev. 1989, 89, 1841–1860.
(13) These stereochemical control results are consistent with Tietze’s
work in the synthesis of helical alkenes via an intramolecular domino
reaction; see ref 3 for details.
3650
Org. Lett., Vol. 14, No. 14, 2012

Table 2. Scope of Tetrasubstituted Alkenes with Various Aro-
matic Substitutentsa
Scheme 3. Proposed Reaction Mechanism Explaining the
Stereoselectivity in the Domino Reactiona,b
a Ligand and solvent molecules omitted for clarity. Only key
intermediates are shown; for the detailed mechansim, see ref 6a.
b Modeling on the substrate (3R)-6ea bearing a methyl substituent
was performed.
good yield, respectively. Heterocyles can also be intro-
duced onto the alkyne to give the corresponding bromide
precursors (6ja and 6ka), which delivered the tetrasubsti-
tuted alkene products (4j and 4k) in good to excellent yield.
Interestingly, a single isomer 4k was observed for the
3-thiophene-yl-substituted precursor 6ka. This protocol
also allows for the synthesis of alkene product 4l bearing
a carboxylate group on one aryl ring and nitro group on
the other, which can be used as handles for further
manipulation and incorporation into a larger system.14
In conclusion, we have developed a rapid and highly
modular approach to accessing chiral tetra-substituted
helical alkenes by employing a palladium-catalyzed nor-
bornene-mediated domino reaction as the key step. The
high structural diversity and excellent stereoselectivity is
owed to a very efficient synthesis of a diverse class of
enantiopure bromide precursors stemming from chiral
lactones. Three characteristic elements of stereoselectivity
duringthe multiplebondformationwereobserved, and the
capacity to form both isomers gives rise to further studies
on their photochemical properties as light-driven rotary
molecular motors.
a The domino reaction was conducted in 0.2 mmol scale using the same
reaction conditions as in Scheme 2. b Yield of isolated products. c The dr values
were determined by 1H NMR of the crude. d Performed on 1.0 mmol scale.
Acknowledgment. We thank the Merck Frosst Center
for Therapeutic Research, the Natural Science and En-
gineering Research Council (NSERC), and the University
of Toronto for financial support. H.L. thanks the Ontario
Postdoctoral Fellowship for financial support. M.E.
thanks NSERC for financial support (CGS-M). We also
thank Dr. Alan Lough (Department of Chemistry, Uni-
versity of Toronto) for X-ray analysis.
Supporting Information Available. Experimental pro-
cedures and full spectroscopic data for all new com-
pounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
(14) (a) van Delden, R. A.; ter Wiel, M. K. J.; Pollard, M. M.;
Vicario, J.; Koumura, N.; Feringa, B. L. Nature 2005, 437, 1337. (b)
Eelkema, R.; Pollard, M. M.; Vicario, J.; Katsonis, N.; Ramon, B. S.;
Bastiaansen, C. W. M.; Broer, D. J.; Feringa, B. L. Nature 2006, 440,
163.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 14, 2012
3651