Angewandte
Communications
Chemie
the preferential formation of the kinetically favorable 5-
ꢀ
membered palladacycle intermediate in the C H activation
step. The reaction also occurred when the b position was
disubstituted (2b), albeit with markedly reduced efficiency.
3
ꢀ
Nevertheless, this is a rare case of C(sp ) H functionalization
of such an unfunctionalized substrate, which does not benefit
from favorable conformational effects. Surprisingly, b-tetra-
ꢀ
substituted substrates 1c,d failed to undergo C H carbamoy-
lation, likely due to excessive repulsion with the adjacent
TMB group. Fortunately, less-hindered
N substituents
restored reactivity for this interesting class of substrates
(Scheme 3c). Indeed the nature of the N substituent had
a marked effect on the reaction efficiency (Scheme 3b). For
instance a phenyl substituent was tolerated, but only when it
Scheme 4. Proof-of-concept enantioselective synthesis of b-lactams
through the desymmetrization of methyl groups.
was separated from the N atom by a sufficiently long carbon
2
ꢀ
chain (2o,p), presumably because competitive C(sp ) H
ꢀ
activation occurs when the chain is too short (2m,n). Other
functional groups such as an ester (2q) and a protected amine
(2r) could be employed, although the reaction occurred with
moderate yield. A range of carbamoyl chlorides bearing
a tetrasubstituted Cb also reacted successfully (Scheme 3c),
including those derived from more elaborate acyclic and
cyclic monoterpene precursors (1u–x). The reaction selectiv-
ity is especially noteworthy for 2v and 2w, wherein the alkene
Finally, this C H carbamoylation method was applied to
the synthesis of the enantiopure free b-lactam 4ac and b-
aminoacid 5ac. The latter, which was previously obtained by
enzymatic resolution, is of high interest for the synthesis of b-
peptides (Scheme 5).[23] Commercially available enantiopure
group did not undergo competitive carbopalladation or
2
ꢀ
C(sp ) H activation. The example of fused b-lactam 2x,
which is reminiscent of bicyclic antibiotics, is also worth
ꢀ
highlighting. In addition to primary C H bonds, activated
ꢀ
tertiary cyclopropyl C H bonds (2y–z) and benzylic secon-
ꢀ
dary C H bonds (2aa–ab) were found to be reactive, thus
affording original spirocyclic and fused b-lactams in high
yields (Scheme 3d). Moreover, we were pleased to find that
less-activated methylenes of both cyclic (2ac–ae) and acyclic
(2af) substrates also underwent carbamoylation (Scheme 3e),
albeit with variable efficiency. The latter was maximal for
product 2ac, which was obtained in quantitative yield using
the two-chamber system, whereas the CO-balloon conditions
were much less efficient (40%).
Scheme 5. Synthesis of an enantiopure b-amino acid. Reagents and
conditions: a) 2,4,6-trimethoxybenzaldehyde (1 equiv), NaBH(OAc)3
(2 equiv), AcOH (2 equiv), 1,2-dichloroethane, 208C, 100%; b) triphos-
gene (0.34 equiv), benzene, 608C, 86%; c) see Scheme 3, condi-
tions A; d) K2S2O8 (2 equiv), Na2HPO4·7H2O (2 equiv), MeCN/H2O
2:1, 808C, 91%; e) 6m HCl, reflux, quant.
0
3
ꢀ
Another attractive feature of Pd -catalyzed C(sp ) H
activation is the possibility to induce enantioselectivity by
using either a chiral ancillary ligand[19] or a chiral base.[20] We
pursued this possibility by examining the effect of various
chiral catalysts in the enantioselective desymmetrization of
carbamoyl chloride 1a (Scheme 4). Extensive screening,
followed by optimization of the best ligand lead structure,
converged towards the new TADDOL-derived phosphonite
L, which enabled the formation of b-lactam 2a in 76% yield
and good e.r. (92:8) under excess CO.[14] Using the COgen
conditions positively affected the yield (86%), but the
enantioselectivity slightly decreased (e.r. 86:14). Although
levels of enantioselectivity higher than 92:8 could not be
reached, this result constitutes a proof-of-concept enantiose-
lective synthesis of b-lactams through the desymmetrization
of unactivated methyl groups, which is to date unprece-
dented.[10] The cleavage of the TMB group was best per-
formed by employing potassium persulfate[21] to give the
known free lactam (R)-4a, which was previously synthesized
through the separation of diastereoisomeric precursors.[22]
tetrahydronaphthylamine 3ac was converted into carbamoyl
ꢀ
chloride 1ac, which underwent C H carbamoylation under
the optimal COgen conditions to give TMB-protected b-
lactam 2ac in 82% yield. Persulfate-mediated oxidative
cleavage provided b-lactam 4ac, which underwent acidic
hydrolysis to give (+)-5ac in very good overall yield (64% for
5 steps).
In conclusion, we report a new method to synthesize
0
3
ꢀ
valuable b-lactams through Pd -catalyzed C(sp ) H carba-
moylation from readily accessible carbamoyl chlorides. This
reaction is compatible with a range of primary, secondary and
ꢀ
activated tertiary C H bonds, in contrast to previous methods
3
ꢀ
based on C(sp ) H activation, and is adaptable to an
enantioselective version using a chiral ligand. Finally, its
applicability to the synthesis of valuable enantiopure free b-
lactams and b-aminoacids was demonstrated.
4
ꢀ 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2017, 56, 1 – 6
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