One-pot Crabbe homologation-radical cascade cyclisation with memory of chirality

Article abstract of DOI:10.1039/c2cc17830c

The tandem Crabbe homologation-radical rearrangement of terminal enediynes leads, in a one-pot procedure, to the enantioselective synthesis of six- and seven-membered ring α-aminoesters bearing a quaternary stereocenter based on the phenomenon of memory of chirality. The Royal Society of Chemistry 2012.

Full text of DOI:10.1039/c2cc17830c

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COMMUNICATION
´
One-pot Crabbe homologation-radical cascade cyclisation with memory
of chiralitywz
Shovan Mondal,a Malek Nechab,*a Nicolas Vanthuyneb and Michele P. Bertrand*a
Received 14th December 2011, Accepted 11th January 2012
DOI: 10.1039/c2cc17830c
´
The tandem Crabbe homologation-radical rearrangement of terminal
reported by Ma and co-workers where i-Pr2NH was replaced by
dicyclohexylamine (Cy2NH), and copper bromide by copper
iodide (eqn (1)).12
enediynes leads, in a one-pot procedure, to the enantioselective
synthesis of six- and seven-membered ring a-aminoesters bearing
a quaternary stereocenter based on the phenomenon of memory
of chirality.
ð1Þ
Allenes are highly reactive species that have become very
attractive building blocks to achieve numerous regio- and
stereoselective synthetic transformations.1,2 Meanwhile, cascade
processes have gained popularity due to the ever growing interest
for efficient selective syntheses of complex molecules from an
ecologically and economically favorable point of view.3 In this
context, the synthetic potential of enyne-allenes rearrangements
proceeding via highly reactive s–p biradicals has been wide-
spread.4,5 Most of these research studies have been driven by
the interest of chemists and biologists for the discovery of new
anticancer agents.6 The search for new routes to constrained
polyaromatics has stimulated more recent interest.7
The designed substrates (1a–f) were easily available from
1,2-diiodobenzene, according to Scheme 1, through two subsequent
Sonogashira coupling reactions coupled with one-pot TMS
deprotection.
Gratifyingly, when enediyne 1a (Scheme 2 and Table 1,
entry 1) was refluxed in dioxane in the presence of Cy2NH,
CuI and paraformaldehyde, the allene underwent spontaneous
Myers–Saito cycloaromatisation to afford biradical A. The
latter evolved through a 1,5-hydrogen atom shift from the
captodative position, which led to the formation of biradical B
(scheme 2) in a chiral conformation.
We have recently reported the enantioselective cascade
rearrangement of enediynes leading to heterocycles bearing
quaternary stereogenic centers.8 These reactions proceed with
memory of chirality.9 In order to increase the synthetic
efficiency of these reactions regarding the one-pot regio-, and
enantioselective construction of potentially bioactive molecules,10 it
was necessary to overcome the inconvenience of the lack of
diastereoselectivity of our initial strategy, which involves introducing
an electronwithdrawing group on the terminus of the allene moiety.
The copper-catalysed synthesis of terminal allenes from alkynes
The polar-radical crossover cascade was achieved in dioxane, at
reflux in 2 hours. It led to 2a in 81% yield, with total preservation
of the chirality of the starting material. The observed memory of
chirality can be rationalised by the fact that recombination upon
concomitant rotations around bonds a and g is much faster than
rotation around bond b that would racemize the short-lived
intermediate B.13 Retention of configuration was confirmed by
the determination of the absolute configuration from X-rays.14
It is to be emphasized that the homologation procedure is
completely compatible with the radical cascade process and
according to Crabbe
´
homologation11 was well suited to this
purpose. This Mannich-type reaction involving paraformaldehyde,
diisopropylamine, and terminal alkynes was initially catalysed by
copper(I) bromide. An improved methodology has recently been
a Institut de Chimie Radicalaire (ICR), UMR 7273,
´
´
´ ˆ
Aix-Marseille Universite, Faculte de St Jerome,
Avenue Escadrille Normandie-Niemen, 13397 Marseille Cedex 20,
France. E-mail: malek.nechab@univ-provence.fr,
michele.bertrand@univ-cezanne.fr
b
´
´
´ ˆ
ISM2, UMR 6263, Aix-Marseille Universite, Faculte de St Jerome,
Avenue Normandie-Niemen, 13397 Marseille Cedex 20, France
w This article is part of ChemComm ‘Chirality’ web themed issue.
z Electronic supplementary information (ESI) available: Experimental
procedures, characterisation of hybrid materials and new compounds,
and analysis by chiral HPLC. CCDC 858572. For ESI and crystallo-
graphic data in CIF or other electronic format see DOI: 10.1039/
c2cc17830c
Scheme 1
c
This journal is The Royal Society of Chemistry 2012
Chem. Commun., 2012, 48, 2549–2551 2549

Table 1 Cascade rearrangement of enediynes 1-fa
Entry Substrateb (ee %)
n
Product
Yieldc eeb (%)
1
2
3
1a (96)
1
81
62d
70
95
85
87
1b (99)
1
1
(S)-1c (99)
4
(R)-1c (99.9)
1
70
90
Scheme 2
5
6
1d (99)
1e (83)
1
2
67
97
56
that overall yields are as high as those reported in our previous
studies, despite the increased number of elementary steps.
As shown in Table 1, the reaction is general and high ee’s
and yields were observed with all substrates leading to intermediate
propargylic amines (n = 1). Submitting L-alanine derivative 1b
(99% ee) (Table 1, entry 2) to ‘‘Ma’s conditions’’ afforded the
desired heterocycle 2b, in 62% yield and 85% ee. Alkene 3b (Fig. 1)
which arose from competitive disproportionation was isolated in
less than 5% yield, that is, a much lower yield than that observed
with the sulfone precursor used in our previous work (20%).1 This
result seems to demonstrate that disproportionation is favoured
with respect to the recombination step by the steric bulk of the
substituents at the radical centers in diradical B.
44e
7
(S)-1f (99.9)
(R)-1f (99.9)
2
2
38.5f 80
8
38.5f 80
When oxazolidinone (S)-1c (99% ee) was submitted to the
same experimental conditions, (S)-2c was isolated in 70% yield and
87% ee.15 The reverse enantiomer was obtained from (R)-1c which
led to (R)- 2c in 70% yield and 90% ee (Table 1, entries, 3–4).
Interestingly, when two competitive hydrogen abstractions
were available, which is the case for the proline derived
enediyne 1d, only the captodative stereocenter was subjected
to a 1,5-hydrogen atom shift (Table 1, entry 5).16 Compound
4d (Fig. 1) that would have resulted from hydrogen atom
transfer from the methylene group could be neither detected
nor isolated from the reaction mixture.
a
Reaction conditions: 100 mg of substrate 1 (0.24–36 mmol), para-
formaldehyde (2.5 equiv.), CuI (0.5 equiv.) and Cy2NH (1.8 equiv.) were
refluxed in 1 mL of dioxane for 2 h. b Enantiomeric excess was measured by
chiral HPLC. c Isolated yield. d Olefin 3b was isolated in less than 5% yield.
e Olefin 3e was isolated in 19.5% yield. f Olefin 3f was isolated in 24% yield.
Several authors have demonstrated that 1,6-hydrogen
abstractions could be performed from aryl radicals.17 Based
on these findings, we have applied the above methodology to
substrates leading to homopropargylic intermediates amines
(n = 2). Much to our satisfaction, seven-membered ring
heterocyclic products 2e–f could be prepared in moderate yields,
and average to good ee’s (44% yield and 56% ee for 2e,18 and
38.5% yield but 80% ee for 2f;18 Table 1, entries 6 and 7).
Notwithstanding the increased flexibility of the lateral
functional chain in the rearranged biradical intermediate,
the reaction remained enantioselective and proceeded
with a rather high degree of retention of configuration
Fig. 1 Structures of compounds 3b, 3e, 3f, and 4d.
(Table 1, entries 7 and 8, see Fig. 2 for the biradical inter-
mediate C issued from (R)-1f).
However, the increased flexibility resulted in the availability
of a disproportionation pathway involving the hydrogen atom
of the methylene group in the oxazolidinone ring that was not
c
2550 Chem. Commun., 2012, 48, 2549–2551
This journal is The Royal Society of Chemistry 2012

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The authors thank the ANR-10-JCJC-0710-MOCER2 for
the financial support and the University de Provence for the
post-doctoral grant of S. Mondal.
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18 It is worth noting that in this case the disproportionation side
product 3e and 3f accounted for 19.5% and 24%, isolated yields,
respectively.
c
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Chem. Commun., 2012, 48, 2549–2551 2551