Combining cycloisomerization with trienamine catalysis: A regiochemically flexible enantio- and diastereoselective synthesis of hexahydroindoles

Article abstract of DOI:10.1039/c5cc08886k

The synthesis of polysubstituted hexahydroindoles through trienamine-organocatalyzed cycloadditions of pyrrolidinyl dienals, prepared by palladium-catalyzed cycloisomerization, is reported. The cycloadditions of this novel class of dienals proceed with excellent levels of enantio- and diastereoselectivity, with the regioselectivity of cycloaddition with respect to the tethering ring readily tuned through design of the cycloisomerization substrate. This work culminates in the first examples of double-stereodifferentiating trienamine catalysis, where catalyst stereocontrol dominates facial selectivity in the cycloaddition, affording azacyclic products that are specifically functionalized at every position.

Full text of DOI:10.1039/c5cc08886k

ChemComm
View Article Online
View Journal
COMMUNICATION
Combining cycloisomerization with trienamine
catalysis: a regiochemically flexible enantio- and
diastereoselective synthesis of hexahydroindoles†
Cite this:DOI: 10.1039/c5cc08886k
Received 28th October 2015,
Accepted 5th November 2015
V. Chintalapudi, E. A. Galvin, R. L. Greenaway and E. A. Anderson*
DOI: 10.1039/c5cc08886k
www.rsc.org/chemcomm
The synthesis of polysubstituted hexahydroindoles through trienamine-
organocatalyzed cycloadditions of pyrrolidinyl dienals, prepared by
palladium-catalyzed cycloisomerization, is reported. The cycloadditions
of this novel class of dienals proceed with excellent levels of enantio-
and diastereoselectivity, with the regioselectivity of cycloaddition with
respect to the tethering ring readily tuned through design of the
cycloisomerization substrate. This work culminates in the first examples
of double-stereodifferentiating trienamine catalysis, where catalyst
stereocontrol dominates facial selectivity in the cycloaddition, affording
azacyclic products that are specifically functionalized at every position.
Trienamine organocatalysis represents a frontier of asymmetric
1
–6
synthesis, with trienamine-catalyzed cycloadditions of acyclic
7
–16
17,18
dienals
and dienones
enabling efficient syntheses of
enantioenriched monocyclic cyclohexenes. In contrast, the use
of exocyclic dienals in trienamine catalysis is comparatively rare,
being limited mainly to elegant work on dearomatized aromatics
19–23
such as indole-2,3-quinodimethane trienes (1 - 2 Scheme 1).
Furthermore, this chemistry has to date accessed only one of two
possible cycloaddition regioisomers with respect to the tethering
ring, presumably due to synthetic constraints in the positioning of Scheme 1 Trienamine-organocatalyzed cycloadditions of exocyclic dienals.
the aldehyde. The wider extension of trienamine chemistry to cyclic
substrates thus depends on the availability of suitable ring-tethered
dienals, and methods that streamline dienal synthesis whilst give a range of regioisomeric hexahydroindole cycloadducts (6, 7),
simultaneously expanding reaction scope would offer a valuable including spirooxindoles and azlactams which are of significant
27–29
entry to densely functionalized chiral (hetero)cyclic scaffolds.
interest as medicinal chemistry scaffolds.
These investigations
Here we report a flexible and atom-efficient synthesis of a culminate with the first examples of double stereodifferentiation in
new class of azacyclic dienals (3 and 4) from enynamides (5) via trienamine catalysis, which afford fully-functionalized hexahydro-
2
4–26
palladium-catalyzed cycloisomerization,
where the relative indole frameworks with precise control over the stereochemistry
positioning of the aldehyde on the dienal framework is dictated of all ring substituents, and thus expand the field of trienamine
by simple variation of the enynamide starting material. The catalysis to access products of unprecedented complexity.
enantio- and diastereoselective cycloadditions of these dienals
Our work began with the preparation of the regioisomeric
ring-constrained dienals 3a and 4a (Scheme 2) by high-yielding
2
4
Chemistry Research Laboratory, 12 Mansfield Road, Oxford, OX1 3TA, UK.
E-mail: edward.anderson@chem.ox.ac.uk; Fax: +44 1865 285002;
Tel: +44 1865 285000
palladium-catalyzed cycloisomerization of enynamides 5a
30
and 5b, followed by desilylation and oxidation. In the case
of 5b, either the partially- (4a) or fully-conjugated (8a) dienal
†
Electronic supplementary information (ESI) available: Experimental procedures,
could be accessed, depending on the oxidation conditions. As
copies of H and C NMR spectra and HPLC traces. See DOI: 10.1039/c5cc08886k the success of trienamine catalysis can depend crucially on the
characterization for novel compounds, stereochemical assignment of cycloadducts,
1
13
This journal is ©The Royal Society of Chemistry 2015
Chem. Commun.

View Article Online
Communication
ChemComm
Table 1 Enantioselective cycloaddition reactions of dienals 3a and 4a–d.
Reaction conditions: dienophile (1.0 equiv.), aldehyde (1.4 equiv. for
oxindoles, 1.5 equiv. for azlactones and nitrostyrenes), 10 (20 mol%), BzOH
(
20 mol%), toluene, rt, 2–6 h. The products from reaction of 3a with 13a–f
and 15a–c were derivatized via Wittig reaction to aid analysis by chiral
1
HPLC. Yields are isolated yields; dr determined by H NMR spectroscopic
analysis of the crude reaction mixture; ee determined by chiral HPLC
Scheme 2 Palladium-catalyzed synthesis of regioisomeric dienals 3a, 4a
and 8a, and initial study of trienamine-organocatalyzed cycloadditions.
Reagents and conditions: (a) Pd(OAc)
2
(5 mol%), bis-benzylidene ethyl-
enediamine (bbeda) (5 mol%), toluene, 60 1C, 30 min; (b) TBAF, THF, rt, 2 h;
(
(
c) Dess–Martin periodinane, CH
20 mol%), 9a (1.0 equiv.), 3a (1.5 equiv.), toluene, rt, 2 h; (e) SO
Cl , 0 1C, 2 h; (f) 10 (20 mol%), BzOH (20 mol%), 9a (1.0 equiv.),
a (1.5 equiv.), toluene, rt, 6 h.
2
Cl
2
, rt, 1.5 h; (d) 10 (20 mol%), BzOH
3
Ápy, Et N,
3
DMSO, CH
2
2
4
1
6–18
degree of conjugation of the carbonyl substrate,
it is notable
that this cycloisomerization/oxidation approach permits such
regiocontrol in dienal synthesis; in the event this indeed proved
important. We were pleased to find that 3a underwent smooth
cycloaddition with oxindole 9a, promoted by the Jørgensen–
Hayashi catalyst 10, giving cycloadduct 11a in high yield and
enantioselectivity after just 2 h at room temperature (84%,
98% ee, 3.8 : 1 dr). Reaction of 4a was similarly successful, giving
the regioisomeric product 12a (78%, 94% ee, 6 : 1 dr). In contrast,
no reaction was observed between 8a and 9a, even under heating,
emphasizing the importance of the deconjugated nature of dienal
16–18
4a.
With conditions to effect organocatalyzed Diels–Alder reactions
established, we next evaluated the scope of the enantioselective
cycloadditions (Table 1). The reactions of 3a with various oxindoles
were first examined, which afforded spirooxindoles 11b–d with
high enantioselectivity. A selection of electron-deficient and
electron-rich nitroalkenes were next tested, which pleasingly
also underwent high yielding cycloadditions, giving cycloadducts
31
1
4a–f with excellent enantio- and diastereoselectivities. Azlactone
cycloadditions provide a useful route to masked quaternary amino
3
2
acids; for dienal 3a, these reactions were again found to be
exceptionally diastereoselective and enantioselective (16a–d,
499% ee, 420 : 1 dr), albeit moderate yielding. Collectively,
these reactions show a marked increase in rate compared to
1
,2,16
19
related acyclic
or aromatic substrates, which may be due
to the intrinsic s-cis constraint of the reacting diene in the
trienamine intermediate, an effect that appears to override any
electron-withdrawing effects from the sulfonamide group. It is
also notable that formation of the presumed trienamine inter-
mediate from 3a is regioselective for the formation of an
exocyclic, rather than endocyclic double bond.
A similar exploration of reactivity was now conducted with
the regioisomeric aldehyde system (4), which provided an
Chem. Commun.
This journal is ©The Royal Society of Chemistry 2015

View Article Online
ChemComm
Communication
1
opportunity to vary the enamide substituent (R in 4a–d, Table 1);
these cycloadditions afford products that are substituted at all
positions of the cyclohexene ring. We first tested oxindole dienophile
cycloadditions, where variation of the enamide sidechain (12b–d)
and oxindole (12e–g) led to high yields and excellent enantio-
selectivities. Notably, the diastereoselectivities of these ‘regio-
complementary’ cycloadditions were enhanced compared to those
of dienal 3a, and showed some influence from the enamide
1
substituent R . Although cycloadditions with nitrostyrenes and
azlactones proved ineffective, use of the more reactive lactone
1
7 successfully delivered cycloadducts 18a/b in high enantio-
3
3
selectivity, but without endo/exo preference.
The cycloisomerization approach to these dienals provides
the opportunity to functionalize the tethering pyrrolidine scaffold.
This raised a question in trienamine catalysis that has not been
addressed in previous studies: what levels of catalyst stereocontrol
could be achieved in a double stereo-differentiating setting, where a
chiral, single enantiomer substrate is reacted under the influence
3
4–41
of enantiomeric catalysts?
To investigate this, we prepared
30
ynamides 5c and 5d (Scheme 3) as single enantiomers. These
were subjected to palladium-catalyzed cycloisomerization, followed
by desilylation and oxidation, to give dienals 3b and 4e respectively.
Scheme 3 Double stereodifferentiating cycloadditions of dienals 3b and
4
e. Diastereomer ratios reflect endo/exo selectivity; in all cases only a
Reaction of monosubstituted dienal 3b with nitrostyrene, under the single face of the diene reacts. Cycloadditions were conducted using
the dienophile (3.0 equiv.), aldehyde (1.0 equiv.), catalyst (10 or ent-10,
influence of catalyst 10, afforded cycloadduct 19a in short reaction
2
0 mol%) and BzOH (20 mol%) in toluene at rt under Ar (18 h). Other
time (2 h at rt) with high diastereoselectivity (58%, 8 : 1 dr). This
matched combination of substrate and catalyst reflects a preference
of both components for approach of the dienophile to the top face
reagents and conditions: (a) Pd(OAc)
0 1C, 30 min, 85% from 5c, 95% from 5d; (b) TBAF, THF, rt, 2 h, 97% from
c, 93% from 5d; (c) SO N, DMSO, CH Cl , 0 1C, 2 h, 40%; (d) Dess–
Ápy, Et
Cl , rt, 1.5 h, 66%; (e) reaction with 13a; (f) reaction
2
(5 mol%), bbeda (5 mol%), toluene,
6
5
3
3
2
2
of the molecule (as drawn). The corresponding mismatched reac- Martin periodinane, CH
2
2
with 9a. See the ESI† for structural assignment.
tion of 3b with nitrostyrene and catalyst ent-10 proceeded at a
reduced reaction rate (7 h at rt), but pleasingly with a complete
reversal of facial selectivity. To our surprise, an increased level of
diastereoselectivity was observed (19b, 53%, 20:1 dr), interestingly
illustrate strong substrate conformational effects that enhance
30
diastereoselectivity.
30
in favour of the endo isomer with respect to the nitro group – an
In conclusion, palladium-catalyzed cycloisomerization provides
a powerful and efficient entry to regioisomeric azacycle-tethered
exocyclic dienals, which undergo enantio- and diastereoselective
trienamine-organocatalyzed cycloadditions. These represent the
first examples of exocyclic dienes to engage in such chemistry that
arise from non-aromatic precursors. In addition to exploring the
relative reactivity of these regioisomeric substrates across a
range of dienophiles, we show that double stereodifferentiating
cycloadditions proceed under high levels of catalyst stereo-
control for both regioisomers, thus permitting the tuneable
synthesis of fully-functionalized hexahydroindole frameworks,
including complex spirooxindoles.
unprecedented observation in trienamine-organocatalyzed nitros-
42
tyrene Diels–Alder reactions. This suggests that although the
catalyst completely controls the facial selectivity of cycloaddition,
the substrate has a significant, and in this case dominant influence
over endo/exo selectivity, such that steric interactions between the
2,19
phenyl groups are minimized, irrespective of electronic
stereocontrolling effects (see TS in Scheme 3).
or other
43
We next examined the reactions of 3b with oxindole 9a,
which generated spirooxindoles 11e and 11f. In the matched
case (giving 11e), we were delighted to find that previously
observed levels of diastereoselectivity for oxindole cycloaddi-
tions (see Scheme 2) were increased (63%, 7 : 1 dr), illustrating a
reinforcing influence of the conformation of the substrate on
reaction diastereoselectivity. The mismatched combination
gave a moderate yield of the cycloadducts 11f, arising from
exclusive addition to the opposite face, but with poor selectivity.
We thank the EPSRC (EP/K005391/1) for financial support.
VC thanks the European Union for an EU-Namaste Fellowship.
RLG thanks Syngenta for an Industrial CASE studentship.
Finally, we addressed the challenge of the stereochemical Notes and references
influence of the doubly-substituted backbone in dienal 4e. To
1
For seminal work, see: Z.-J. Jia, H. Jiang, J.-L. Li, B. Gschwend, Q.-Z.
Li, X. Yin, J. Grouleff, Y.-C. Chen and K. A. Jørgensen, J. Am. Chem.
Soc., 2011, 133, 5053–5061.
Z.-J. Jia, Q. Zhou, Q.-Q. Zhou, P.-Q. Chen and Y.-C. Chen, Angew.
Chem., Int. Ed., 2011, 50, 8638–8641.
For reviews, see: I. D. Jurberg, I. Chatterjee, R. Tannert and
P. Melchiorre, Chem. Commun., 2013, 49, 4869–4883.
our delight, the reactions of 4e with 9a, which generate hexa-
hydroindole spirooxindoles featuring a stereogenic centre at
every position on the indole skeleton, proceeded with excellent
yield and stereoselectivity in both the matched (12h, 60%, 20:1 dr)
and mismatched (12i, 45%, 7 : 1 dr) settings; both reactions again
2
3
This journal is ©The Royal Society of Chemistry 2015
Chem. Commun.

View Article Online
Communication
ChemComm
4
I. Kumar, P. Ramaraju and N. A. Mir, Org. Biomol. Chem., 2013, 11, 28 A. P. Antonchick, C. Gerding-Reimers, M. Catarinella, M. Sch u¨ rmann,
7
09–716.
H. Preut, S. Ziegler, D. Rauh and H. Waldmann, Nat. Chem., 2010, 2,
735–740.
5
6
J.-L. Li, T.-Y. Liu and Y.-C. Chen, Acc. Chem. Res., 2012, 45, 1491–1500.
K. L. Jensen, G. Dickmeiss, H. Jiang, Ł. Albrecht and K. A. Jørgensen, 29 M. M. M. Santos, Tetrahedron, 2014, 70, 9735–9757.
Acc. Chem. Res., 2012, 45, 248–264.
30 See the ESI† for details of substrate synthesis and structural
assignment.
31 To facilitate isolation and analysis, the aldehyde product was directly
derivatized via a Wittig olefination to the corresponding (E)-enoate.
32 R. A. Mosey, J. S. Fisk and J. J. Tepe, Tetrahedron: Asymmetry, 2008,
19, 2755–2762.
33 Given the greater diastereoselectivity (typically 44 : 1) observed in
previous cycloadditions between 17 and linear dienals (see ref. 33),
steric effects from the substrate may be responsible for this reduced
selectivity.
34 To the best of our knowledge, no examples of double stereodiffer-
entiating dienamine or trienamine catalysis have been reported. For
examples of double stereodifferentiation in enamine organocataly-
sis, see: J. Marjanovic, V. Divjakovic, R. Matovic, Z. Ferjancic and
R. N. Saicic, Eur. J. Org. Chem., 2013, 5555–5560.
7
8
9
For recent examples, see: H. Jiang, B. Gschwend, Ł. Albrecht, S. G.
Hansen and K. A. Jørgensen, Chem. – Eur. J., 2011, 17, 9032–9036.
Ł. Albrecht, F. Cruz Acosta, A. Fraile, A. Albrecht, J. Christensen and
K. A. Jørgensen, Angew. Chem., Int. Ed., 2012, 51, 9088–9092.
C. Ma, Z.-J. Jia, J.-X. Liu, Q.-Q. Zhou, L. Dong and Y.-C. Chen, Angew.
Chem., Int. Ed., 2013, 52, 948–951.
1
1
1
1
1
1
1
1
1
1
2
2
2
0 K. Zhu, H. Huang, W. Wu, Y. Wei and J. Ye, Chem. Commun., 2013,
4
9, 2157–2159.
1 Z.-J. Jia, K. Jiang, Q.-Q. Zhou, L. Dong and Y.-C. Chen, Chem.
Commun., 2013, 49, 5892–5894.
2 J.-X. Liu, Q.-Q. Zhou, J.-G. Deng and Y.-C. Chen, Org. Biomol. Chem.,
2
013, 11, 8175–8178.
3 C. Ma, J. Gu, B. Teng, Q.-Q. Zhou, R. Li and Y.-C. Chen, Org. Lett.,
013, 15, 6206–6209.
2
4 X. Li, M.-H. Lin, Y. Han, F. Wang and J.-P. Cheng, Org. Lett., 2014, 35 F. Calder ´o n, E. G. Doyag u¨ ez and A. Fern ´a ndez-Mayoralas, J. Org.
6, 114–117, and references therein. Chem., 2006, 71, 6258–6261.
5 X. Feng, Z. Zhou, C. Ma, X. Yin, R. Li, L. Dong and Y.-C. Chen, Angew. 36 F. Calder ´o n, E. G. Doyag u¨ ez, P. H.-Y. Cheong, A. Fern ´a ndez-
Chem., Int. Ed., 2013, 52, 14173–14176. Mayoralas and K. N. Houk, J. Org. Chem., 2008, 73, 7916–7920.
6 L. Prieto, G. Talavera, U. Uria, E. Reyes, J. L. Vicario and L. Carrillo, 37 B. Alcaide, P. Almendros, A. Luna and M. R. Torres, J. Org. Chem.,
Chem. – Eur. J., 2014, 20, 2145–2148. 2006, 71, 4818–4822.
7 X.-F. Xiong, Q. Zhou, J. Gu, L. Dong, T.-Y. Liu and Y.-C. Chen, Angew. 38 N. Palyam and M. Majewski, J. Org. Chem., 2009, 74, 4390–4392.
1
Chem., Int. Ed., 2012, 51, 4401–4404.
8 P.-Q. Chen, Y.-C. Xiao, C.-Z. Yue and Y.-C. Chen, Org. Chem. Front.,
39 J. Carpenter, A. B. Northrup, d. Chung, J. J. M. Wiener, S.-G. Kim and
D. W. C. MacMillan, Angew. Chem., Int. Ed., 2008, 47, 3568–3572.
40 D. Enders and C. Grondal, Angew. Chem., Int. Ed., 2005, 44, 1210–1212.
2
014, 1, 490–493.
9 Y. Liu, M. Nappi, E. Arceo, S. Vera and P. Melchiorre, J. Am. Chem. 41 For an example of enhanced diastereoselectivity in enantioselective
Soc., 2011, 133, 15212–15218.
0 Y. Liu, M. Nappi, E. C. Escudero-Ad ´a n and P. Melchiorre, Org. Lett.,
organocatalysis through catalyst design, see: L. Caruana, F. Kniep,
T. K. Johansen, P. H. Poulsen and K. A. Jørgensen, J. Am. Chem. Soc.,
2014, 136, 15929–15932.
2
012, 14, 1310–1313.
1 H. Jiang, C. Rodr ´ı guez-Escrich, T. K. Johansen, R. L. Davis and 42 For these highly challenging mismatched cycloadditions, we found it
K. A. Jørgensen, Angew. Chem., Int. Ed., 2012, 51, 10271–10274.
2 For an elegant example of a cross-conjugated cyclohexadiene-
containing trieneamine which proceeds via a stepwise mechanism,
see: K. S. Halskov, T. K. Johansen, R. L. Davis, M. Steurer, F. Jensen
and K. A. Jørgensen, J. Am. Chem. Soc., 2012, 134, 12943–12946.
3 A. Dieckmann, M. Breugst and K. N. Houk, J. Am. Chem. Soc., 2013,
essential to degas the reaction solution to avoid aldehyde decomposi-
tion, a measure which allowed us to successfully employ an excess of
dienophile and only one equivalent of aldehyde, which contrasts with
previous stoichiometries employed in trienamine catalysis.
43 A question arises as to whether the terms ‘matched’ and ‘mismatched’
should refer to the rate of reaction (where 19a would be the ‘matched’
product), or its selectivity (where 19b would be the ‘matched’ product).
For the purposes of this work, we use the former definition; as the
reactions of 3b to generate 11e or 11f proceed with the same trend in
facial selectivity and rate as those to give 19a and 19b, we feel the superior
(inverse) diastereoselectivity arising in the case of 13c is a result solely of
steric interactions imparted by the substrate. In other words, we propose
that this reaction is ‘mismatched’ with respect to the dienophile, and an
overturn in endo/exo selectivity for 19b is a consequence of the enforced
approach of this dienophile to the more hindered face of the molecule.
2
2
2
2
2
1
35, 3237–3242.
4 P. R. Walker, C. D. Campbell, A. Suleman, G. Carr and E. A. Anderson,
Angew. Chem., Int. Ed., 2013, 52, 9139–9143.
5 For seminal work on enynes, see: B. M. Trost, G. J. Tanoury, M. Lautens,
C. Chan and D. T. Macpherson, J. Am. Chem. Soc., 1994, 116, 4255–4267.
6 V. Michelet, P. Y. Toullec and J. P. Genet, Angew. Chem., Int. Ed.,
008, 47, 4268–4315.
7 C. V. Galliford and K. A. Scheidt, Angew. Chem., Int. Ed., 2007, 46,
748–8758.
2
8
Chem. Commun.
This journal is ©The Royal Society of Chemistry 2015