Synthesis of hexahydroindoles by intramolecular C sp 3-H alkenylation: Application to the synthesis of the core of aeruginosins

Article abstract of DOI:10.1002/anie.201205403

Give me five: Pd-catalyzed intramolecular C sp 3-H arylations have been successfully extended to alkenylations. This method shows remarkable selectivity and gives synthetically useful hexahydroindoles, as illustrated with the synthesis of the octahydroind

Full text of DOI:10.1002/anie.201205403

Angewandte
Chemie
DOI: 10.1002/anie.201205403
ꢀ
C H Activation
ꢀ
Synthesis of Hexahydroindoles by Intramolecular Csp3 H Alkenylation:
Application to the Synthesis of the Core of Aeruginosins**
Julien Sofack-Kreutzer, Nicolas Martin, Alice Renaudat, Rodolphe Jazzar, and Olivier Baudoin*
ꢀ
The functionalization of C H bonds has recently emerged as
an atom- and step-economical alternative to more traditional
synthetic methods based on functional group transformation,
which often require multistep sequences.[1] In particular,
transition metal catalysis has been shown to be a powerful
ꢀ
ꢀ
tool to functionalize otherwise unreactive Csp2 H and Csp3
H
bonds. These advances have enabled the construction of
a variety of carbon–carbon and carbon–heteroatom bonds
with great efficiency and selectivity, even in structurally
complex organic molecules.[2] In this context, our recent
research has focused on the intramolecular arylation of
ꢀ
unactivated Csp3 H bonds with aryl halides under palla-
dium(0) catalysis,[3] to give synthetically useful polycylic
molecules such as benzocyclobutenes (Scheme 1a).[4] Unlike
ꢀ
ꢀ
Csp3 H arylations with aryl halides, Csp3 H alkenylations with
alkenyl halides are very scarce.[5,6] In such reactions, the
replacement of a benzene by a cyclohexene ring is actually
more challenging than it first appears. Indeed, when cyclo-
ꢀ
hexenyl bromide 1a was subjected to Pd-catalyzed C H
activation under similar reaction conditions as the corre-
sponding aryl bromide (Scheme 1c), a complex mixture was
obtained, in which diene 3a (as a mixture of E and Z isomers)
was identified and not the desired fused cyclobutene 2a.
Diene 3a arises from the electrocyclic ring opening of 2a,
a transformation that occurs easily under thermal condi-
tions.[7] The reaction of isomeric cyclohexenyl bromide 1b,
which was designed to avoid cyclobutene ring opening,
resulted in an inseparable mixture of the desired cyclobutane
2b and diene 3b in low yield (Scheme 1d). Diene 3b
presumably arises from opening of the five-membered
ꢀ
palladacycle intermediate leading to 2b, followed by C H
activation on the cyclohexene ring, in a similar way to
1,4-palladium migrations observed with benzocyclobute-
nes.[4c] Therefore, C H activation occurred in both cases,
but it did not give rise to the desired fused four-membered
rings because of the instability of the desired products and
ꢀ
ꢀ
Scheme 1. Palladium(0)-catalyzed Csp3 H arylations and alkenylations
from aryl and alkenyl halides.
ꢀ
because of the high activation energy for the final C C
coupling step. In light of these initial findings, we turned our
attention to the formation of five-membered rings, the
[*] Dr. J. Sofack-Kreutzer, Dr. N. Martin, Dr. A. Renaudat, Dr. R. Jazzar,
Prof. Dr. O. Baudoin
synthesis of which was deemed more facile due to a much
[8]
ꢀ
Universitꢀ Claude Bernard Lyon 1, CNRS UMR 5246—Institut de
Chimie et Biochimie Molꢀculaires et Supramolꢀculaires, CPE Lyon
43 Boulevard du 11 Novembre 1918, 69622 Villeurbanne (France)
E-mail: olivier.baudoin@univ-lyon1.fr
more kinetically favorable C C reductive elimination step.
Inspired by the related
ꢀ
C H arylation of nitrogen-containing substrates to give
indolines (Scheme 1b),[9,4e] we turned our attention toward
the alkenylation of cyclohexenyl bromides 4 that should give
hexahydroindoles 5 (Scheme 1e). The latter are interesting
nitrogen heterocycles that should be easily converted into
bicyclic analogues of proline (R2 = CO2H),[10] which are of
interest for asymmetric organocatalysis[11] and natural prod-
uct synthesis. In particular, octahydroindoles are found as the
Homepage: http://cosmo.univ-lyon1.fr/Index.html
[**] This work was financially supported by Rꢀgion Rhꢁne-Alpes (Cluster
5), ANR (programme blanc “AlCaCHA”), and the Institut Universi-
taire de France. We also thank Johnson Matthey PLC (donation of
palladium acetate).
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201205403.
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hindered bromocyclohexenes 4h and 4i, which have diaste-
reotopic methyl groups on the quaternary Ca center, provided
the corresponding products 5h and 5i with moderate yields
and diastereoselectivities (entries 7 and 8). We next studied
the reactivity of diastereomerically pure substrates 4j–p
bearing two different substituents on the Ca atom
(entries 9–15). For compounds 4j, 4k, and 4m–o, which
ꢀ
Scheme 2. Optimized Csp3 H alkenylation conditions.
ꢀ
have the same relative configuration, intramolecular C H
core of the aeruginosin family of marine natural products (see
Scheme 1 for the structure of aeruginosin 298A), which show
interesting biological properties as inhibitors of serine
proteases.[12]
We first examined the reactivity of bromoalkene 4a
(Scheme 2), which was synthesized as a racemic single
diastereoisomer in four steps from cyclopentene.[13] Com-
pound 4a is a particularly challenging substrate because the
nitrogen substituent contains several types of C H bonds that
could potentially be activated: primary Csp3 Ha bonds,
a tertiary Csp3 Hb bond adjacent to a nitrogen atom, two
types of secondary Csp3 Hc,d bonds including more-acidic
alkenylation occurred efficiently and with a high regioselec-
ꢀ
tivity in favor of activation at the primary b C H bond
(entries 9, 10, and 12–14). However, different diastereoiso-
mers of the same substrate showed a markedly different
reactivity, as illustrated with 4k and 4l (entries 10 and 11).
Indeed, 4k gave the expected cis-configured cyclization
product 5k, whereas 4l gave a complex mixture containing
mainly olefin isomers. This diastereodivergent behavior
mirrors the cis diastereoselectivity obtained for compounds
4b and 4c (entries 1 and 2) and shows that the product
selectivity, that is, the formation of a five-membered ring
versus an olefin, is strongly affected by steric or conforma-
tional effects.[18] The reaction of cyclohexenyl bromide 4p,
bearing a phenyl group at Ca, was also examined (entry 15).
Intramolecular alkenylation occurred at the phenyl instead of
the methyl group to give tricyclic product 7p in good yield;
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
benzylic protons (Hd), and arylic Csp2 He bonds.
Different palladium sources, phosphine ligands, bases,
solvents, and acid additives were screened.[14] Optimal
conditions were Pd(OAc)2/PCy3 as the catalyst, rubidium
carbonate as the base,[15] and pivalic acid (PivOH) as the
additive[16] in toluene at 1208C, and gave product 5a in 65%
yield upon isolation. The regioselectivity of the C H activa-
tion step involved in this reaction is remarkable. Indeed,
compound 4a underwent selective C H bond cleavage at the
most favorable primary Csp3 Ha bond, in the presence of
this result is consistent with previous observations that Csp2
H
ꢀ
activation is usually favored over Csp3 H activation for the
formation of small (five to seven-membered) rings.[3] Next,
the reaction of other cycloalkenyl bromides was studied
(entries 16–18). Methyl-substituted cyclohexene 4q under-
ꢀ
ꢀ
ꢀ
ꢀ
went intramolecular C H alkenylation successfully
ꢀ
ꢀ
Csp3 Hb–d bonds as well as Csp2 He bonds; this result is
(entry 16), whereas the reaction of analogous cyclopentene
4r (entry 17) and cycloheptene 4s (entry 18) only led to
degradation products. This finding illustrates the impact of
conformational effects and shows that cyclohexenyl bromides,
which are the closest analogues of aryl halides, are also the
consistent with previous mechanistic studies.[4e]
We next examined the reactivity of other bromoalkene
substrates (Table 1). A first set of bromoalkenes, bearing at
least two methyl substituents at the carbon atom a to the
ꢀ
ꢀ
nitrogen atom (Ca), was subjected to the optimized C H
optimal Csp3 H alkenylation substrates.
ꢀ
alkenylation conditions (entries 1–8). Entries 1–6 highlight
the effect of the nitrogen substituent (R1). A trifluoroacetyl
substituent was found to be optimal for compounds bearing
diastereotopic methyl groups at Ca (4b–e, entries 1–4) to
effect the desired cyclization efficiently (entry 2). The lower
yield in the case of 5b (entry 1) is attributable to the
formation of substantial amounts of olefin 6b, which likely
The above Csp3 H alkenylation reaction seemed to work
well for the synthesis of hexahydroindoles with the cis confi-
guration (entries 9–14). We hypothesized that reduction of
the C C bond should provide a unique route to octahydroin-
doles related to aeruginosins (Scheme 1e), with the correct
relative configuration.[19–20] To demonstrate this, enantiopure
benzyl-protected bromide 4t was synthesized in four steps
=
ꢀ
arises from competitive b-H elimination after the C H
and 31% yield, from dibromocyclopropane
l-alaninol (Scheme 3). 2,3-Dibromocyclohexene
6
7
and
was
activation step.[4b,17] Interestingly, hexahydroindoles 5b–c
were isolated as single cis diastereoisomers. For compound
obtained by thermal rearrangement of 6, which is synthesized
from the cyclopropanation of cyclopentene with dibromocar-
bene.[13] The nucleophilic substitution of allylic bromide 7
with l-alaninol gave a 1:1 mixture of diastereoisomers, which
were separated after the benzylation step. Protected com-
ꢀ
4d, having an N-acetyl substituent, C H activation occurred
at the most acidic position to give the corresponding fused
g-lactam in good yield (entry 3). In addition, the presence of
a nonacidic electron-withdrawing R1 group (CO2Me or
COCF3) was essential, as shown by the complete lack of
reactivity of N-methyl-substituted 4e (entry 4). Interestingly,
compounds 4 f and 4g bearing a quaternary Ca center
(entries 5 and 6) showed a reversal of reactivity as compared
to 4b and 4c (entries 1 and 2), and the reaction of the
compound having an N-CO2Me substituent (4 f) had a slightly
higher yield (entry 5). This result shows that subtle electronic
effects affect the reaction selectivity (entries 1 and 2) and
efficiency (entries 5 and 6). The use of more sterically
ꢀ
pound 4t was then subjected to the above optimized C H
alkenylation conditions, to give cis-hexahydroindole 5t in
75% yield. Next, concomitant diastereoselective alkene
hydrogenation and debenzylation were achieved by using
Pearlmanꢀs catalyst, to afford octahydroindole 8 with the
desired cis, cis configuration.
Derivatization of the latter as p-nitrobenzoyl ester 9 gave
single crystals suitable for X-ray analysis (Scheme 3),[21]
thereby confirming that the structure and absolute config-
2
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[a]
ꢀ
Table 1: Scope of the intramolecular Csp3 H alkenylation.
Entry
1
Bromoalkene
Product(s)
Yield [%][b]
40
Entry
10
Bromoalkene
Product(s)
Yield [%][b]
71
4b
5b
6b
4k
5k
(d.r.>95:5)
2
3
73
83
11
12
–
4c
5c
4l
(d.r.>95:5)
68
4d
4e
4 f
5d
4m
4n
4o
5m
5n
5o
4
5
–
0
13
14
71
84
86
5 f
6
7
78
67
15
16
78
77
4g
4h
5g
4p
4q
7p
5h
5q
(d.r.=2:1)[c]
8
9
53
73
17
18
–
–
–
4i
4j
5i
4r
(d.r.=3:1)[c]
–
5j
4s
[a] Reaction conditions: see Scheme 2. All compounds in this Table are racemic mixtures. [b] Yield of the isolated product or of the isolated mixture of
diastereoisomers (d.r. determined by 1H NMR analysis). Relative configurations of products were assigned by NOESYexperiments. [c] Only the major
diastereoisomer is shown. Cy=cyclohexyl, PMB=p-methoxybenzyl.
ꢀ
uration was the same as that of the octahydroindole core of
the aeruginosins.
trivial extension of the previously developed Csp3 H arylation
reaction which shows impressive regioselectivity and inter-
esting diastereodivergent behavior. This method provides
a unique route to hexahydroindoles that are relevant to
In conclusion, we have shown that the intramolecular
ꢀ
Csp3 H alkenylation from a cycloalkenyl bromide is a non-
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ꢀ
[8] The free energy of activation for the C C reductive elimination
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Scheme 3. Synthesis of the octahydroindole core of the aeruginosins.
The X-ray structure of compound 9 is shown with the thermal
ellipsoids set at 30% probability. Reagents and conditions: a) neat,
1308C; b) l-alaninol, K2CO3, DMF, 508C (1:1 mixture of diastereoiso-
mers); c) NaH, benzyl bromide, DMF, 208C; d) trifluoroacetic anhy-
dride, pyridine, CH2Cl2, 0!208C (31% for 4 steps); e) Pd(OAc)2
(10 mol%), PCy3·HBF4 (20 mol%), Rb2CO3, PivOH (30 mol%), tolu-
ene, 1208C (75%); f) H2, Pd(OH)2/C (10 mol%), THF, 208C (83%);
g) p-NO2C6H4COCl, Et3N, CH2Cl2, 0!208C (69%). Bn=benzyl,
DMF=N,N-dimethylformamide, Piv=trimethylacetyl.
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natural product synthesis, as demonstrated with the synthesis
of the octahydroindole core of aeruginosins.
Received: July 9, 2012
Published online: && &&, &&&&
ꢀ
ꢀ
Keywords: C C coupling · C H activation · natural products ·
nitrogen heterocycles · palladium
.
[14] See the Supporting Information for details.
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ꢀ
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4
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Angew. Chem. Int. Ed. 2012, 51, 1 – 5
These are not the final page numbers!

Angewandte
Chemie
Communications
ꢀ
C H Activation
J. Sofack-Kreutzer, N. Martin,
A. Renaudat, R. Jazzar,
O. Baudoin*
&&&& — &&&&
Synthesis of Hexahydroindoles by
Give me five: Pd-catalyzed intramolecular
synthetically useful hexahydroindoles, as
ꢀ
ꢀ
Intramolecular Csp3 H Alkenylation:
Application to the Synthesis of the Core of
Aeruginosins
Csp3 H arylations have been successfully
extended to alkenylations. This method
shows remarkable selectivity and gives
illustrated with the synthesis of the
octahydroindole core of the aeruginosin
family of natural products (see picture).
Angew. Chem. Int. Ed. 2012, 51, 1 – 5
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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5
These are not the final page numbers!