Rhodium-Catalyzed Asymmetric N?H Functionalization of Quinazolinones with Allenes and Allylic Carbonates: The First Enantioselective Formal Total Synthesis of (?)-Chaetominine

Article abstract of DOI:10.1002/chem.201705059

An unprecedented asymmetric N?H functionalization of quinazolinones with allenes and allylic carbonates was successfully achieved by rhodium catalysis with the assistance of chiral bidentate diphosphine ligands. The high efficiency and practicality of this method was demonstrated by a low catalyst loading of 1 mol % as well as excellent chemo-, regio-, and enantioselectivities with broad functional group compatibility. Furthermore, this newly developed strategy was applied as key step in the first enantioselective formal total synthesis of (?)-chaetominine.

Full text of DOI:10.1002/chem.201705059

A Journal of
Accepted Article
Title: Rhodium Catalyzed Asymmetric N-H Functionalization of
Quinazolinones with Allenes and Allylic Carbonates: The First
Enantioselective Formal Total Synthesis of (-)-Chaetominine
Authors: Bernhard Breit and Yirong Zhou
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To be cited as: Chem. Eur. J. 10.1002/chem.201705059
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10.1002/chem.201705059
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COMMUNICATION
Rhodium Catalyzed Asymmetric N-H Functionalization of
Quinazolinones with Allenes and Allylic Carbonates: The First
Enantioselective Formal Total Synthesis of (–)-Chaetominine
Yirong Zhou[a,b] and Bernhard Breit*[a]
Abstract: An unprecedented asymmetric N-H functionalization of
quinazolinones with allenes and allylic carbonates was successfully
achieved by rhodium catalysis with the assistance of chiral bidentate
diphosphine ligands. The high efficiency and practicality of this
method was demonstrated by a low catalyst loading of 1 mol% as
well as excellent chemo-, regio-, and enantioselectivities with broad
functional group compatibility. Furthermore, this newly developed
strategy was applied as key step in the first enantioselective formal
total synthesis of (–)-chaetominine.
amines
other
than
asymmetrically
catalyzed
direct
functionalization of the quinazolinone core unit.[5] Very recently,
three examples emerged using palladium catalyzed coupling
reactions of quinazolinones with allylic alcohols, terminal olefins
and internal alkynes, respectively, giving access to achiral linear
products (Scheme 1).[6] The chemoselectivity for this ambident
nucleophile is an essential issue due to the tautomeric
equilibrium between quinazolinone and 4-hydroxyquinazoline,
which might lead to mixtures of O- and N-substituted products.[6]
Moreover, regioselective generation of the enantioenriched
branched N-substituted quinazolinones remains an unsolved
challenge.
The Quinazolinones scaffold, as an important member of the
class of heterocyclic alkaloids, has abundant existence in
various natural products.[1] Optically pure N-alkylated
quinazolinones bearing a stereocenter adjacent to its amide
nitrogen atom, represent a privileged core structure for a vast
array of drug molecules, and they exhibit a broad spectrum of
biological and pharmacological activities.[2,3] For instance, (–)-
chaetominine is an intriguing modified tripeptide alkaloid
displaying stronger cytotoxicity than 5-fluorouracil against
human leukemia K562 and colon cancer SW1116 cell lines
(Figure 1).[4] Accordingly, soon after the first isolation,
tremendous synthetic efforts were devoted towards its total
synthesis.[5] Nevertheless, all previous reports are ex chiral pool
syntheses employing D-tryptophan as starting material. Up to
now, no direct enantioselective catalytic method has been
established. Thus, it is in high demand to develop a general and
straightforward synthetic route to access this type of valuable
chiral N-heterocyclic compounds.
Recently, our group developed
catalyzed atom-economic couplings
a
range of rhodium-
between diverse
pronucleophiles with allenes and alkynes in a highly regio- and
stereoselective manner to access branched allylic products.[7, 8]
In light of these previous results, we envisioned that
quinazolinones might be a suitable pronucleophiles to couple
with allenes and allylic carbonates under appropriate catalytic
system. Herein, we report an unprecedented rhodium catalyzed
asymmetric N-H functionalization of quinazolinones with readily
available unactivated terminal allenes and racemic allylic
carbonates to afford chiral N-allylated quinazolinones, and its
application in the first enantioselective formal total synthesis of
(–)-chaetominine.
a) Previous work: only linear achiral product
OH
N
R
OH
N
N
O
N
or
or
N
O
[Pd]
O
N
N
HO
N
R
N
H
+
O
N
OH
R
O
O
N
N
Ref. [6]
OH
F
N
N
N
Cl
NH
O
HN
R
Me
O
N
F
(-)-Chaetominine
natural product
anticancer activity
(+)-Febrifugine
natural product
antimalarial activity
Albaconazole
antifungal agent
b) This work: only branched product
O
N
Figure 1. Selected examples of chial N-functionalized quinazolinones.
O
N
R
·
[Rh]
N
R
NH
or
+
*
chiral ligand
OCO2Me
Chiral N-substituted quinazolinones are generally prepared
by construction of the quinazolinone ring starting form chiral
R
high chemo-, regio-, and enantioselectivities
Scheme 1. Transition metal catalyzed N-H functionalization of quinazolinone
[a]
[b]
Dr. Y. Zhou and Prof. Dr. B. Breit
Institut für Organische Chemie and Freiburg Institute of Advanced
Studies (FRIAS)
Initial reactivity assays for the optimization process utilized
quinazolinone 1a and unactivated aliphatic terminal allene 2a as
model substrates for the coupling reaction.[9] To our delight, only
branched N-allylated quinazolinone product 3a was generated
with exclusive regioselectivity and no trace for any other
possible either O-substituted or linear isomers could be detected
Albert-Ludwigs-Universität, Alberstr. 21, 79104 Freiburg (Germany)
E-mail: bernhard.breit@chemie.uni-freiburg.de
Dr. Y. Zhou
Key Laboratory of Functional Small Organic Molecules, Ministry of
Education, College of Chemistry and Chemical Engineering
Jiangxi Normal University, Nanchang, 330022, China
Supporting information for this article is given via a link at the end of
the document.
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10.1002/chem.201705059
Chemistry - A European Journal
COMMUNICATION
(Table 1). After a comprehensive screening of various chiral
bidentate diphosphine ligands, (R,R)-QuinoxP L1 was identified
to be the superior ligand to deliver a high ee of 86% (Table 1,
entry 1). It was further found that the acid additives play a pivotal
role in the catalytic process. Both yield and enantiomeric excess
of the product could be significantly enhanced in the presence of
diverse acids (Table 1, entries 2-5). Subsequently, a survey of
various chiral and achiral acids was performed and (R)-
camphorsulfonic acid (CSA) improved the enantioselectivity to
91%. Further solvent investigation revealed that the best result
(96% ee) was obtained in a 4:1 mixture of 1,2-dichloroethane
(DCE) and acetonitrile. More importantly, the catalyst loading
could be decreased to 1 mol% along with 2 mol% chiral ligand
L1 and (R)-CSA without any erosion in either the high efficiency
or enantioselectivity (Table 1, entry 6).
The chain length of linear allenes did not have any influence on
the reaction (3a vs. 3b). Compared to linear alkylated allenes,
cycloalkyl substituted allenes with steric hindrance maintained
the same high enantioselectivities although with slightly lower
yields (3f and 3g). However, in the case of phenylallene, the
yield of 5a significantly dropped to 33% along with a moderate
ee of 73%. It is noteworthy that an indole moiety could also be
tolerated to give good yield and selectivity (3k).
Next the scope of quinazolinone reaction partners was
explored. For this an increased catalyst loading of 2 mol% and
acid as well as a prolonged reaction time were required to
smoothly
lead
to
complete
conversion.
Excellent
enantioselectivities along with slightly diminished yields were
achieved for diverse quinazolinones. A variety of substituents on
different positions of the aromatic ring were compatible.
Quinazolinones bearing a different halogen atoms, including
fluorine, chlorine and bromine behaved well (3l−3n, 3r−3t, 3w).
Functional motifs such as ether and ester groups did not
influence the reaction evidently (3o and 3p). Both electron rich
and deficient substrates could react well to deliver the expected
branched products (3q and 3v). Steric hindrance exerted
negligible effect for the process (3w and 3x). Additionally,
extension of the quinazolinone core by an additional benzo
condensation was well tolerated (3y).
Table 1. Reaction conditions optimization.[a]
O
O
N
2.5 mol% [Rh(COD)Cl]2
5.0 mol% ligand/acid
DCE (0.2 M), 80 o
C
Ph
3
Ph
NH
N
+
·
3
N
3a
1a
2a
SO3H
Me
t-Bu
Me
MeO
MeO
PAr2
PAr2
Table 2: Substrate scope for the reaction of quinazolinones with allenes.[a,b]
N
P
P
SO3H
O
N
t-Bu
Me
O
(R)-CSA
O
1 or 2 mol% [Rh(COD)Cl]2
Ar=3,5-dit-BuC6H3
PTSA
2 or 4 mol% L1/(R)-CSA
DCE:MeCN(4:1, 0.2 M), 80 o
NH
R2
(R,R)-QuinoxP, L1
R1
N
R2
+
·
R1
(R)-DTB-MeO-Biphep, L2
C
N
N
1
2
3
Entry
Ligand
Acid
Yield [%][b]
ee [%][c]
86
O
O
O
N
1
L1
L1
L2
L1
L1
L1
none
57
76
69
64
78
82
Ph
n
R
N
N
O
N
2
PTSA
PTSA
TFA
88
N
N
n
R = Bn, 3c, 75% yield, 93% ee
R = Bz, 3d, 79% yield, 90% ee
R = TBS, 3e, 76% yield, 94% ee
n = 3, 3a, 82% yield, 96% ee
n = 2, 3b, 81% yield, 94% ee
n = 0, 5a, 33% yield, 73% ee
3
56
n = 1, 3f, 61% yield, 95% ee
n = 2, 3g, 69% yield, 95% ee
4
90
O
N
N
O
O
O
R
5
(R)-CSA
(R)-CSA
91
N
N
N
3
3
O
N
N
6[d]
96
N
Boc
R = Et, 3h, 52% yield, 90% ee
R = CO2Me, 3i, 92% yield, 93% ee
3j, 95% yield, 94% ee
3k, 59% yield, 94% ee
[a] The reactions were carried out on a 0.2 mmol scale of 1a with 1.5
equivalents of 2a in the presence of 2.5 mol% of [Rh(COD)Cl]2 and 5.0 mol%
of chiral ligand in DCE (1.0 mL) at 80 °C for 24 h. [b] Isolated yield. [c] The ee
was determined by chiral HPLC analysis. [d] The reaction was carried out in a
mixture of DCE:MeCN = 4:1 (1.0 mL) using 1.0 mol% of [Rh(COD)Cl]2, 2.0
mol% of L1, 2.0 mol% of (R)-CSA and 2.0 equivalents of 2a.
O
N
O
Ph
R
Ph
N
N
3
3
R
N
R = F, 3l, 60% yield, 96% ee
R = Cl, 3m, 56% yield, 96% ee
R = Br, 3n, 51% yield, 97% ee
R = CF3O, 3o, 73% yield, 96% ee
R = AcO, 3p, 71% yield, 95% ee
R = NO2, 3q 47% yield, 98% ee
R = F, 3r, 70% yield, 96% ee
R = Cl, 3s, 64% yield, 96% ee
R = Br, 3t, 45% yield, 95% ee
R = CF3, 3u, 54% yield, 96% ee
R = MeO, 3v, 43% yield, 95% ee
O
N
With the optimized reaction conditions in hand, the substrate
scope and generality was investigated. The results are
summarized in Table 2. In general, the reaction proceeded well
to afford moderate to good yields along with high atom economy
and excellent enantioselectivities for a broad substrate scope.
Firstly, a variety of readily available terminal allenes were
examined and several functional groups such as amide (3j),
ester (3d and 3i) and ether (3c) were well tolerated, granting
selective access to the branched N-allylated quinazolinones.
O
Ph
F
O
N
Ph
3
Ph
N
N
3
3
N
Me
N
3w, 48% yield, 96% ee
3x, 63% yield, 95% ee
3y, 83% yield, 92% ee
[a] For products 3a to 3k, the reactions were carried out on a 0.3 mmol scale
of 1a with 2.0 equivalents of 2 in the presence of 1.0 mol% of [Rh(COD)Cl]2,
2.0 mol% of L1 and 2 mol% of (R)-CSA in a mixture of DCE:MeCN = 4:1 (1.5
mL) at 80 °C for 24 h. For products 3l to 3y, the reactions were carried out on
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10.1002/chem.201705059
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COMMUNICATION
a 0.2 mmol scale of 1 with 2.0 equivalents of 2a in the presence of 2.0 mol%
of [Rh(COD)Cl]2, 4.0 mol% of L1 and 4 mol% of (R)-CSA in a mixture solvent
of DCE:MeCN = 4:1 (1.0 mL) at 80 °C for 48 h. [b] Isolated yield and the ee
was determined by chiral HPLC analysis.
[a] The reactions were carried out on a 0.3 mmol scale of 1 with 1.5
equivalentd of 4 in the presence of 1.0 mol% of [Rh(COD)Cl]2 and 2.0 mol% of
L2 in DCE (1.5 mL) at 80 °C for 24 h. [b] For products 5b, 5c, 5f-5h, 5o and
5p, 2.0 mol% of [Rh(COD)Cl]2 and 4.0 mol% of L2 were used. [c] Isolated
yield and the ee was determined by chiral HPLC analysis.
Since the reaction of phenylallene did not provide satisfying
results in terms of yield and selectivities for the preparation of
allylation product 5a, we anticipated that a rhodium-catalyzed
dynamic kinetic asymmetric allylation of quinazolinones with
racemic aryl allylic carbonates might be a complementary and
alternative solution to overcome this limitation.[10, 11] Toward this
end, further optimizations led to adjusted reaction parameters,
and axially chiral biaryl MeO-Biphep ligand L2 turned out to be
the optimal one for the rhodium catalysis in DCE under neutral
conditions in the absence of any external base.[9]
As illustrated in Table 3, a wide range of substituted
aromatic allylic carbonates were investigated, providing the
desired branched N-allylated quinazolinones in high yields and
enantioselectivities. The reaction proceeded with excellent
chemo- and regioselectivities while no other possible isomers
could be observed. A variety of halogen atoms (5b−5d) and
electron donating (5f) or withdrawing substitutions (5g−5j) on the
para-position of the aryl substituent were well tolerated to give
good to almost quantitative yields along with excellent
enantioselectivities. In case of ortho-substituted substrates 5k
and 5m, remarkable 99% ee’s were obtained. On the other hand,
meta-position did not display evident influence on the
transformation (5l, 5n and 5o). Gratifyingly, substrates
containing cyano and ester groups also behaved well (5h and
5j), although these functional groups may possess coordination
Table 3: Substrate scope for the reaction of quinazolinones with allylic
carbonates. [a,b,c]
O
N
O
N
1 mol% [Rh(COD)Cl]2
OCO2Me
R2
2 mol% L2
N
NH
R1
R1
+
R2
DCE (0.2 M), 80 o
C
ability to
a transition metal center with potential catalyst
4
1
5 or 6
poisoning properties. The absolute configuration of 5m was
determined to be S by X-ray crystallographic analysis.[12] It is
worth noting that naphthyl, perfluorophenyl as well as
heterocyclic substituents, including thiophenyl and furanyl, were
all well tolerated (5p−5s). Additionally, some aliphatic substrates
were examined which also showed excellent yields, regio- and
enantioselectivities (5t, 5u, 3h and 3b).
O
N
O
N
Br
O
N
Br
N
N
N
R
5k, 82% yield, 99% ee
5l, 98% yield, 90% ee
R = H, 5a, 99% yield, 95% ee
R = F, 5b, 97% yield, 90% ee
R = Cl, 5c, 96% yield, 93% ee
R = Br, 5d, 97% yield, 92% ee
R = Me, 5e, 98% yield, 92% ee
R = MeO, 5f, 89% yield, 89% ee
R = NO2, 5g, 79% yield, 89% ee
R = CN, 5h, 85% yield, 91% ee
R = CF3, 5i, 89% yield, 93% ee
R = CO2Me, 5j, 87% yield, 93% ee
O
Cl
N
(S)
N
Cl
Next the quinazolinone scope for the allylic substitution was
probed. All tested substrates gave excellent yields and
enantioselectivities. Neither steric hindrance nor electronic
5m, 77% yield, 99% ee
O
O
N
F
O
R
effects exerted any evident influence.
A diverse set of
F
F
N
N
N
halogenated substrates (6a−6d, 6g-6i and 6m) even iodine
substituted compound (6d) could be employed, which permits
N
F
N
R
F
R = F, 5n, 76% yield, 93% ee
R = MeO, 5o, 94% yield, 89% ee
5q, 98% yield, 91% ee
5p, 72% yield, 88% ee
opportunities
for
further
derivatizations.
Disubstituted
quinazolinones were also compatible to provide similar good
results (6p−6r). 2-Pyrimidone could also be applied as
pronucleophile. However, it led to a diminished yield albeit in
high enantioselectivity (6t).
O
O
O
Me
N
n
N
N
Ph
X
N
N
N
n = 0, 5t, 95% yield, 94% ee
n = 2, 5u, 96% yield, 97% ee
n = 4, 3h, 93% yield, 97% ee
X = S, 5r, 98% yield, 92% ee
X = O, 5s, 97% yield, 90% ee
3b, 95% yield, 97% ee
O
CO2Me
O
O
N
O
O
O3, DCM, MeOH
NaOH, -78 o
A: Allene addition
N
N
NH
R
F
O
N
N
Ph
N
Ph
C
B: Allylic substitution
N
N
N
Ph
R
N
OTBS
72% yield, 96% ee
N
OTBS
1a
8
7
A: 80% yield, 96% ee
B: 94% yield, 96% ee
R = F, 6a, 98% yield, 92% ee
R = Cl, 6b, 97% yield, 93% ee
R = Br, 6c, 99% yield, 94% ee
R = I, 6d, 92% yield, 94% ee
R = CF3O, 6e, 98% yield, 96% ee
R = NO2, 6f, 93% yield, 93% ee
R = F, 6g, 99% yield, 94% ee
R = Cl, 6h, 96% yield, 94% ee
R = Br, 6i, 98% yield, 94% ee
R = CF3, 6j, 97% yield, 93% ee
R = MeO, 6k, 83% yield, 97% ee
R = NO2, 6l, 95% yield, 92% ee
6m, 98% yield, 92% ee
HOAc, THF, H2O, rt
DMP
O
N
COOMe
HO
O
CO2Me
N
O
H
O
N
N
PhNHNH2·HCl
CAN, MW, 80 o
N
O
O
O
N
N
C
H
Cl
Br
ref [5d, 5h]
O
N
N
Ph
N
Ph
N
Ph
HN
O
10
67% yield, 96% ee
9
N
N
N
(-)-Chaetominine
74% yield for 2 steps
R
Me
Br
R = Me, 6n, 99% yield, 94% ee
R = CF3, 6o, 93% yield, 90% ee
6q, 96% yield, 95% ee
6p, 97% yield, 90% ee
Scheme 2. Enantioselective formal total synthesis of (–)-chaetominine. DMA =
Dess–Martin periodinane. CAN = ceric ammonium nitrate.
O
O
O
MeO
N
Ph
N
Ph
N
Ph
MeO
N
N
N
Finally, the synthetic utility of this newly developed
asymmetric catalytic methodology was demonstrated by its
6t, 49% yield, 96% ee
6r, 92% yield, 95% ee
6s, 87% yield, 95% ee
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10.1002/chem.201705059
Chemistry - A European Journal
COMMUNICATION
[5]
a) B. B. Snider, X. Wu, Org. Lett. 2007, 9, 4913–4915; b) M. Toumi, F.
Couty, J. Marrot, G. Evano, Org. Lett. 2008, 10, 5027–5030; c) A.
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Papeo, Chem. Eur. J. 2009, 15, 7922–792; e) Q. Peng, S. Luo, X. Xia,
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Luo, A. Wang, P. Huang, Org. Biomol. Chem. 2014, 12, 2859–2863; g)
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757–770; h) X. Deng, K. Liang, X. Tong, M. Ding, D. Li, C. Xia,
Tetrahedron 2015, 71, 3699–3704; i) Z. Mao, H. Geng, T. Zhang, Y.
Ruan, J. Ye, P. Huang, Org. Chem. Front. 2016, 3, 24–37.
application to the first enantioselective formal total synthesis of
(–)-chaetominine (Scheme 2). Applying the above mentioned
two newly established rhodium-catalyzed couplings with the
corresponding allene and allylic carbonate, the same high
enantiomeric excess of 96% was obtained for compound 7. The
alkene could be cleaved through ozonolysis and trapped in situ
by a methanolate anion to provide the corresponding optically
active methyl ester 8 in 72% yield without racemization.[13]
Subsequently, the TBS group was removed under mild
conditions,[14] followed by Dess-Martin oxidation to furnish
aldehyde 9 in 74% yield over two steps. A Fischer indole
synthesis was successfully accomplished by treatment of
[6]
[7]
[8]
a) D. Kumar, S. R. Vemula, G. R. Cook, Green Chem. 2015, 17, 4300–
4306; b) S. R. Vemula, D. Kumar, G. R. Cook, ACS Catal. 2016, 6,
5295−5301; c) C. Lu, D. Chen, H. Chen, H. Wang, H. Jin, X. Huang, J.
Gao, Org. Biomol. Chem. 2017, 15, 5756–5763.
aldehyde
9
with phenylhydrazine hydrochloride under
microwave heating to furnish the enantiomerically pure key
Recent reviews: a) P. Koschker, B. Breit, Acc. Chem. Res. 2016, 49,
1524−1536; b) A. M. Haydl, B. Breit, T. Liang, M. J. Krische, Angew.
Chem. 2017, 129, 11466−11480; Angew. Chem. Int. Ed. 2017,
56, 11312−11325.
intermediate 10 for the total synthesis of (–)-chaetominine.[5d, 5h,
15, 16]
In conclusion, the first rhodium catalytic asymmetric N-H
functionalization of quinazolinones has been achieved. Both
unactivated terminal allenes and racemic allylic carbonates
proved to be suitable coupling partners to furnish branched
chiral N-allylated quinazolinone products with high efficiency.
This methodology is distinguished by low catalyst loading of
1 mol% and excellent chemo-, regio-, and enantioselectivities for
Recent examples: a) P. Spreider, A. Haydl, M. Heinrich, B. Breit,
Angew. Chem. 2016, 128, 15798−15802; Angew. Chem. Int. Ed. 2016,
55, 15569−15573; b) T. M. Beck, B. Breit, Eur. J. Org. Chem. 2016,
5839−5844; c) N. Thieme, B. Breit, Angew. Chem. 2017, 129,
1542−1546; Angew. Chem. Int. Ed. 2017, 56, 1520−1524; d) T. M.
Beck, B. Breit, Angew. Chem. 2017, 129, 1929−1933; Angew. Chem.
Int. Ed. 2017, 56, 1903−1907; e) J. Schmidt, C. Li, B. Breit, Chem. Eur.
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Commun. 2017, 53, 4966−4968; g) S. Parveen, C. Li, A. Hassan, B.
Breit, Org. Lett. 2017, 19, 2326−2329; h) J. Kuang, S. Parveen, B. Breit,
Angew. Chem. 2017, 129, 8542−18545; Angew. Chem. Int. Ed. 2017,
56, 8422−8425.
a
broad substrate scope. Additionally, application of this
methodology allowed for the first catalytic enantioselective
formal total synthesis of (–)-chaetominine.
[9]
For detailed optimization process, see supporting information.
[10] Selected recent reviews: a) U. Kazmaier (Eds.), Transition Metal
Catalyzed Enantioselective Allylic Substitution in Organic Synthesis,
Springer-Verlag, Berlin, 2012; b) R. L. Grangea, E. A. Clizbeb, P. A.
Evans, Synthesis 2016, 48, 2911−2968; c) N. A. Butt, W. Zhang, Chem.
Soc. Rev. 2015, 44, 7929−7967; d) J. S. Arnold, Q. Zhang, H. M.
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Acknowledgements
This work was supported by the DFG. Y. Z. thanks the Sino-
German (CSC-DAAD) Postdoc Scholarship and the National
Natural Science Foundation of China (no. 21602089) for support.
We thank Dr. D. Kratzert for the X-ray diffraction analysis; Dr. M.
Keller for NMR analysis; X. Iwanowa for HPLC analysis; Solvias,
Umicore, BASF and Wacker for generous gifts of chemicals.
Keywords: allene • asymmetric allylation • chaetominine •
quinazolinone • rhodium
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COMMUNICATION
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Entry for the Table of Contents (Please choose one layout)
Layout 2:
COMMUNICATION
O
N
O
R2
or
OCO2Me
t-Bu
Me
·
[Rh]
MeO
MeO
N
P
P
Y. Zhou and B. Breit*
N
R2
PAr2
PAr2
NH
+
R1
*
R1
L1 or L2
N
Me
N
t-Bu
Page 1. – Page 6.
single regioisomer
up to 99% ee
up to 99% yield
66 examples
R2
L1
Ar=3,5-dit-BuC6H3
L2
Rhodium Catalyzed Asymmetric N-H
Functionalization of Quinazolinones
with Allenes and Allylic Carbonates:
The First Enantioselective Formal
Total Synthesis of (–)-Chaetominine
Chiral N-allylated quinazolinones were successfully prepared by rhodium catalyzed
couplings with allenes and allylic carbonates. The high efficiency and practicality of
this method was demonstrated by the low catalyst loading of 1 mol% and excellent
chemo-, regio-, and enantioselectivities for a broad substrate scope. Furthermore,
this new strategy was applied as key step in the first enantioselective formal total
synthesis of (–)-chaetominine.
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