Access to Chiral Hydropyrimidines through Palladium-Catalyzed Asymmetric Allylic C?H Amination

Article abstract of DOI:10.1002/anie.201709681

A palladium-catalyzed asymmetric intramolecular allylic C?H amination controlled by a chiral phosphoramidite ligand was established for the preparation of various substituted chiral hydropyrimidinones, the precursors of hydropyrimidines, in high yields with high enantioselectivities. In particular, dienyl sodium N-sulfonyl amides bearing an arylethene-1-sulfonyl group underwent a sequential allylic C?H amination and intramolecular Diels–Alder (IMDA) reaction to produce chiral fused tricyclic tetrahydropyrimidinone frameworks in high yields and with high levels of stereoselectivity. Significantly, this method was used as the key step in an asymmetric synthesis of letermovir.

Full text of DOI:10.1002/anie.201709681

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Accepted Article
Title: An Unprecedented Access to Chiral Tetrahydropyrimidines via
Palladium-Catalyzed Asymmetric Allylic C-H Amination
Authors: Liuzhu Gong, Pu-Sheng Wang, Meng-Lan Shen, Tian-Ci
Wang, and Hua-Chen Lin
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201709681
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10.1002/anie.201709681
Angewandte Chemie International Edition
COMMUNICATION
An Unprecedented Access to Chiral Tetrahydropyrimidines via
Palladium-Catalyzed Asymmetric Allylic C-H Amination
Pu-Sheng Wang, Meng-Lan Shen, Tian-Ci Wang, Hua-Chen Lin, Liu-Zhu Gong*
Abstract: A chiral phosphoramidite ligand-controlled palladium-
catalyzed asymmetric intramolecular allylic C-H amination has been
established to prepare various substituted chiral tetrahydropyrim-
idines in high levels of yields and enantioselectivities. Particularly,
dienyl sodium N-sulfonyl amides bearing an arylethene-1-sulfonyl
group underwent sequential allylic C-H amination and intramolecular
Diels-Alder (IMDA) reaction to produce chiral fused tricyclic tetrahy-
dropyrimidine frameworks in high yields and stereoselectivities.
Significantly, an asymmetric synthesis of letermovir has been ac-
complished by using this method as the key step.
the most popular and widely applicable chemical reactions for
assembling chemical bonds.[3] Since pioneering reports by Tsuji
and Trost,[4] this reaction has been intensively studied to ad-
dress issues concerning chemo-, regio-, and stereoselectivity
with excellent tolerance of various nucleophiles.[5] Basically, the
Tsuji−Trost type reactions require pre-oxidized allylic substrates,
such as allylic halides, esters, and carbonates to complicate the
whole synthetic process during installation of these functional
groups.
Chiral tetrahydropyrimidine has frequently been encountered in
numerous complex bioactive molecules as a core skeleton,[1]
which possess a diverse spectrum of remarkable biological
properties and thereby prompt the invention of innovative phar-
maceuticals (Figure 1). For instance, DPC-083 is a potent re-
verse transcriptase inhibitor for the treatment of HIV infection,[1a]
and KCP10043F is a selective T-type Ca2+ channel blocker,[1f]
which can inhibit the growth of the human lung cancer cells.
Among them, letermovir shows great potential in the next-
generation human cytomegalovirus (HCMV) infection treatment
without observation of dose-dependent toxicity,[1c] and has al-
ready been approved for the phase III clinical trials. Therefore,
the development of unprecedented synthetic methods, which are
not only able to efficiently access chiral tetrahydropyrimidines
frameworks,[2] but enable a divergent and flexible modulation of
these structures and thereby allow building up a chemical library
holding a structurally diverse range of molecules for high-
throughput screening, turns out to be essential for drug discov-
ery.
Scheme 1. Pd-catalyzed asymmetric allylic C-H functionalization
In sharp contrast, the direct oxidative allylic C-H functionaliza-
tion of simple alkenes[6] appears to be a more straightforward
approach to provide unprecedented retrosynthetic disconnec-
tions for chemical synthesis. As such, the establishment of en-
antioselective variants for the allylic C-H functionalization con-
tinues to receive a broad range of research interest.[7-10] In re-
cent years, the enantioselective formation of C−O7 and
C−C[8f,9,10] bonds via allylic C−H activation-based substitution
has been successfully established (Scheme 1a and 1b). White
and co-workers found that a chiral Lewis acid reversibly coordi-
nated ligand[7a] was able to offer modest enantioinduction to the
allylic C-H oxidation. Subsequently, chiral phosphoramidite
ligands[7c] and chiral aryl sulfoxide-oxazoline ligands[7d,11] were
respectively found capable of inducing high enantioselectivity in
intramolecular asymmetric allylic C-H oxidation reactions. In
particular, Trost[9,12] and our group[10] indicated that both tri-
phenylphosphine and chiral phosphoramidite ligands were not
only suitable for the regeneration of Pd(II) from Pd(0) under
suitable oxidation conditions, but also able to accelerate the
asymmetric allylic C−H alkylation with acidic carbon nucleophiles,
therefore providing unusual opportunities to create enantioselec-
tive allylic C-H alkylation reactions. However, a palladium-
catalyzed direct asymmetric allylic C-H amination to generate
highly synthetically useful chiral amine derivatives has not been
reported, yet. Herein, we will present an approach to access
pharmaceutically interesting chiral tetrahydropyrimidine deriva-
Figure 1. Representative biologically active molecules containing tetrahydro-
pyrimidine scaffold.
Palladium-catalyzed asymmetric allylic substitution is one of
[*]
P.-S. Wang, M.-L. Shen, T.-C. Wang, H.-C. Lin, L.-Z. Gong
Hefei National Laboratory for Physical Sciences at the Microscale
and Department of Chemistry, University of Science and
Technology of China, Hefei, China, 230026
Prof. Dr. L.-Z. Gong
E-mail: gonglz@ustc.edu.cn
Collaborative innovation Center of Chemical Science and
Engineering (Tianjin), China
Supporting information for this article is given via a link at the end of
the document.((Please delete this text if not appropriate))
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10.1002/anie.201709681
Angewandte Chemie International Edition
COMMUNICATION
tives via palladium-catalyzed asymmetric intramolecular allylic
C−H amination (Scheme 1c), and its application in a concise
enantioselective synthesis of an optically pure drug candidate,
letermovir.
on the benzene ring led to a diminished enantioselectivity (2l),
but the results could be slightly improved by using ligand L7 in
lieu of L5. Particularly, the absence of the benzyl group could
also result in the formation of the allylic C-H amination product
2m in a high yield and modest enantioselectivity, which strongly
demonstrated that the phosphoramidite ligands could regulate
the property of Pd(II) species to activate the allylic C-H bond,
rather than to promote a Wacker process reported previously
furnishing the oxidative alkene diamination product.[13]
Table 1. Optimization of the reaction conditions [a]
entry
L
T / oC
yield (%)[b]
e.r. [c]
1
2
3
4
L1
L2
L3
L4
L5
L5
L5
L5
L6
--
25
25
25
25
25
25
15
15
15
15
99
97
92
93
92
96
98
97
86:14
90.5:9.5
91:9
91.5:8.5
92.5:7.5
93.5:6.5
94:6
94.5:5.5
--
--
Figure 2. Chiral ligands used in this study
5
6[d]
7[d]
8[d,e]
9[d,e]
10[d,e]
As shown in our previous reports,[7c,10c] chiral phosphoramidite
ligands (Figure 2) were beneficial for both the palladium-
catalyzed allylic C−H activation and the subsequent substitution
process. Therefore, chiral phosphoramidite ligand L1 was initial-
ly used in our preliminary optimization of conditions for the in-
tramolecular asymmetric allylic C−H amination reaction of 1a
(Table 1). Encouragingly, the desired product tetrahydropyrimi-
dine 2a was furnished in nearly quantitative yield, albeit with a
modest enantioselectivity (entry 1). Particularly, the use of H8-
BINOL-derived phosphoramidite ligand L2 could offer a higher
enantioselectivity (entry 2). Fine-tuning of the amine moiety in
the phosphoramidite ligands found that α-substitution of the
cyclic piperidine moiety would slightly improve the enantioselec-
tivity (entries 3-5). Further optimization of the reaction conditions
revealed that a higher concentration, lower reaction temperature
and the absence of OFBA turned out to be beneficial to the
stereochemcial control (entries 6-8), and thereby enabled the
reaction to give 97% yield and 94.5:5.5 er (entry 8). Notably,
either chiral aryl sulfoxide-oxazoline ligand L6 or the absence of
the phosphoramidite ligand under otherwise identical conditions
resulted in a trace amount of 2a and nearly quantitative recovery
of the starting material 1a (entries 9-10), implying that a pivotal
role of the phosphoramidite ligand was played in this asymmetric
allylic C−H amination.
<1[f]
<1[f]
[a] Reaction conditions: 1a (0.05 mmol), Pd(dba)2 (5 mol %), L (6 mol %), and
2,5-DMBQ (1.1 equiv), MTBE (1 mL), 24 h, under N2. [b] Isolated yield. [c]
Determined by HPLC. [d] 0.1 mmol scale of 1a in 1 mL MTBE, 48 h. [e]
without 10 mol % OFBA. [f] >99% 1a was recovered. 2,5-DMBQ = 2,5-
dimethylquinone. OFBA = 2-fluorobenzoic acid. The absolute configuration of
2a was assigned by the X-ray analysis of its single crystal (see the Support-
ing Information).
Table 2. Substrate scope for N-((2-allylphenyl)carbamoyl)sulfonamides 1[a]
entry
R
PG
2
yield (%)[b]
er (%)[c]
1[d]
4-Me
4-iPr
4-MeO
4-CF3
4-F
4-Cl
4-Br
5-Me
5-CF3
5-CF3O
6-F
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
H
2b
2c
2d
2e
2f
2g
2h
2i
98
90
91
95
94
96
88
44
81
91
91
92
95.5:4.5
94.5:5.5
94.5:5.5
94.5:5.5
93:7
94:6
95:5
91:9
93:7
2
3[e]
4
5
6[e]
7[e]
8,
Under the optimized reaction conditions, we next explored the
generality of the asymmetric allylic C−H amination reaction
(Table 2). Significantly, a broad scope of aromatic substitutions
9
2j
2k
2l
was nicely tolerated, with both electron-donating and
-
10
11[f]
12[g]
92.5:7.5
91:9
84:16
withdrawing substituents at either 4- or 5-position of the benzene
ring, affording the desired products in moderate to high yields
and good enantioselectivities (2b-k). Notably, both bromide and
chloride substituents were well tolerated, which could provide
additional reactivity to increase structural complexity by under-
going easily preformed reactions for building up chemical library
(2g-h). Unfortunately, the installation of a fluoride at 6-position
H
2m
[a] Reaction conditions: 1a (0.1 mmol), Pd(dba)2 (5 mol %), L5 (6 mol %),
and 2,5-DMBQ (1.1 equiv), MTBE (1 mL), 15 °C, 48 h, under N2. [b] Isolated
yield. [c] Determined by HPLC. [d] With 10 mol % OFBA, 25 °C, 72 h. [e] With
10 mol % OFBA, 25 °C, 48 h. [f] L7 was used instead of L5, with 10 mol %
OFBA, 25 °C, 48 h. [g] With 10 mol % OFBA, 45 °C, 48 h.
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10.1002/anie.201709681
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COMMUNICATION
Dienyl sodium N-sulfonyl amides bearing an arylethene-1-
sulfonyl group 3, after undergoing the allylic C-H amination
reaction, will generate products 4, which can provide additional
1,3-diene functionality and are capable of participating in a sub-
sequent diastereoselective intramolecular Diels-Alder (IMDA)
reaction,[14] allowing for a feasible synthesis of chiral polycyclic
heterocycles 5 (Table 3). Since the simple extension of the
standard conditions failed to give good results, the reaction
conditions were re-optimized and identified that the phospho-
ramidite L8 was the best ligand (See Table S1 in Supporting
Information for detail). The expansion of the re-optimized reac-
tion conditions to different substrates found that the presence of
A Vilsmeier-type condensation[19] of the urea 10 and 1-(3-
methoxyphenyl)piperazine in TFE[20] was able to provide the
highly enantioenriched dihydroquinazoline 11, which was finally
hydrolyzed in the presence of aqueous NaOH at 60 °C to give
letermovir 12 as a white solid.
an aryl group bearing either an electron-donating or
-
withdrawing substituent at either ortho- or para-position was
allowed to undergo the sequential asymmetric allylic C−H ami-
nation and IMDA to give chiral fused tricyclic products 5 in mod-
erate to good yields and with good diastereo- and enantioselec-
tivities (entries 1−9).
Table 3. Substrate scope for dienyl sodium N-sulfonyl amides 3[a]
Scheme 2. Total synthesis of letermovir.
entry
R
5
yield (%)[b]
er (%)[c]
exo/endo[d]
1
2
3
4
phenyl
5a
5b
5c
5d
5e
5f
5g
5h
5i
75
75
71
54
62
50
74
70
77
91:9
88:12
91.5:8.5
89.5:10.5
90.5:9.5
91:9
88:12
89.5:10.5
90.5:9.5
7:1
8:1
8:1
7:1
6:1
8:1
6:1
7:1
7:1
In summary, we have established an unprecedented palladi-
um-catalyzed asymmetric intramolecular allylic C-H amination
reaction, leading to a variety of substituted chiral tetrahydropy-
rimidines in high yields and stereoselectivity. More interestingly,
a sequential protocol consisting of asymmetric allylic C-H amina-
tion and intramolecular Diels-Alder (IMDA) reaction has been
created to allow for stereoselective construction of chiral fused
tricyclic frameworks. Moreover, capitalizing on the current reac-
tion, a concise and enantioselective synthesis of letermovir has
been accomplished to further demonstrate the great potential of
this method in the pharmaceutical chemistry.
2-MeC6H4
2-MeOC6H4
2-FC6H4
2-ClC6H4
2-BrC6H4
4-MeC6H4
4-MeOC6H4
4-BrC6H4
5
6[e]
7
8,
9
[a] Reaction conditions: 1a (0.1 mmol), Pd(dba)2 (5 mol %), L8 (6 mol %),
OFBA (10 mol%) and 2,5-DMBQ (1.1 equiv), DCM (1 mL), 25 °C, 48 h,
under N2; 4 was purified by flash chromatography and then heated in p-
xylene at 140 °C for 24 h. [b] Overall isolated yield. [c] Determined by
HPLC. [d] Measured by 1H NMR. [e] For 96 h in the first step. The absolute
configuration of 5i was assigned by the X-ray analysis of its single crystal
(see the Supporting Information).
Acknowledgements
To showcase the utility of this reaction in the enantioselective
preparation of pharmaceutical compounds, a concise enantiose-
lective synthesis of letermovir was conducted (Scheme 3). A
scale-up reaction of 1l under the optimized reaction conditions
gave 2l in synthetically useful yield and enantioselectivity, which
could be obtained in optically pure form by selective racemate
crystallization (>99:1 er) from Et2O. The arenesulfonamide group
of 2l was readily removed by magnesium reduction under ultra-
sonic conditions[15] to afford 6 in a high yield. A subsequent
regioselective hydroboration-oxidation of 6 furnished an alcohol
7 in 95% yield. A regioselective Ullmann-type N-arylation reac-
tion[16] of 7 and 2-iodo-1-methoxy-4-(trifluoromethyl)benzene
underwent smoothly to provide 8 in a 71% yield. The Sharpless
oxidation[17] of the primary alcohol 8 with RuCl3/NaIO4 followed
by methylation with trimethylsilyl–diazomethane gave rise to the
corresponding ester 9 in 85% yield. The benzyl group of the
intermediate 9 could be cleanly cleaved by the Pd(OH)2/C cata-
lyzed hydrogenolysis in the presence of TFA[18] to give a urea 10.
We are grateful for financial support from MOST (973 project
2015CB856600), Chinese Academy of Science (Grant No.
XDB20020000), NSFC (21232007, 21602214), and the China
Postdoctoral Science Foundation (No. 2015M580534 and
2017T100449).
Keywords: Palladium catalysis • C-H activation • Asymmetric
allylic amination • Diels-Alder reaction • Letermovir
[1] a) J. W. Corbett, S. S. Ko, J. D. Rodgers, L. A. Gearhart, N. A.
Magnus, L. T. Bacheler, S. Diamond, S. Jeffrey, R. M. Klabe,
B. C. Cordova, S. Garber, K. Logue, G. L. Trainor, P. S.
Anderson, S. K. Erickson-Viitanen, J. Med. Chem. 2000, 43,
2019–2030; b) C. Tarby, Curr. Top. Med. Chem. 2004, 4,
1045–1057; c) T. Goldner, G. Hewlett, N. Ettischer, H.
Ruebsamen-Schaeff, H. Zimmermann, P. Lischka, J. Virol.
2011, 85, 10884–10893; d) S. Patterson, M. S. Alphey, D. C.
Jones, E. J. Shanks, I. P. Street, J. A. Frearson, P. G. Wyatt, I.
This article is protected by copyright. All rights reserved.

10.1002/anie.201709681
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COMMUNICATION
H. Gilbert, A. H. Fairlamb, J. Med. Chem. 2011, 54, 6514–
6530; e) W. J. Li, Q. Li, D. L. Liu, M. W. Ding, J. Agric. Food
Chem. 2013, 61, 1419–1426; f) J. S. Byun, J. M. Sohn, D. G.
Leem, B. Park, J. H. Nam, D. H. Shin, J. S. Shin, H. J. Kim, K.
T. Lee, J. Y. Lee, Bioorg. Med. Chem. Lett. 2016, 26, 1073–
1079.
a) Y. Kita, K. Higashida, K. Yamaji, A. Iimuro, K. Mashima,
Chem. Commun. 2015, 51, 4380–4382; b) S. Li, J. A. Ma,
Chem. Soc. Rev. 2015, 44, 7439–7448; c) G. R. Humphrey, S.
M. Dalby, T. Andreani, B. Xiang, M. R. Luzung, Z. J. Song, M.
Shevlin, M. Christensen, K. M. Belyk, D. M. Tschaen, Org.
Process Res. Dev. 2016, 20, 1097–1103; d) K. Hemalatha, G.
Madhumitha, Eur. J. Med. Chem. 2016, 123, 596–630.
a) T. Hayashi, J. Organomet. Chem. 1999, 576, 195–202; b)
G. Helmchen, J. Organomet. Chem. 1999, 576, 203–214; c) B.
M. Trost, Chem. Pharm. Bull. 2002, 50, 1–14; d) B. M. Trost,
J. Org. Chem. 2004, 69, 5813–5837; e) B. M. Trost, M. R.
Machacek, A. Aponick, Acc. Chem. Res. 2006, 39, 747–760.
a) J. Tsuji, H. Takahashi, M. Morikawa, Tetrahedron Lett.
1965, 6, 4387–4388; b) B. M. Trost, T. J. Fullerton, J. Am.
Chem. Soc. 1973, 95, 292–294.
52, 1523–1526; b) B. M. Trost, E. J. Donckele, D. A.
Thaisrivongs, M. Osipov, J. T. Masters, J. Am. Chem. Soc.
2015, 137, 2776–2784.
[10] a) P.-S. Wang, H.-C. Lin, Y.-J. Zhai, Z.-Y. Han, L.-Z. Gong,
Angew. Chem. 2014, 126, 12414–12417; Angew. Chem. Int.
Ed. 2014, 53, 12218–12221; b) Z.-L. Tao, X.-H. Li, Z.-Y. Han,
L.-Z. Gong, J. Am. Chem. Soc. 2015, 137, 4054–4057; c) H.-
C. Lin, P.-S. Wang, Z.-L. Tao, Y.-G. Chen, Z.-Y. Han, L.-Z.
Gong, J. Am. Chem. Soc. 2016, 138, 14354–14361; d) L.-L.
Li, Z.-L. Tao, Z.-Y. Han, L.-Z. Gong, Org. Lett. 2017, 19, 102–
105.
[11] H. Kondo, F. Yu, J. Yamaguchi, G. Liu, K. Itami, Org. Lett.
2014, 16, 4212–4215.
[12] B. M. Trost, M. M. Hansmann, D. A. Thaisrivongs, Angew.
Chem. 2012, 124, 5034–5037; Angew. Chem. Int. Ed. 2012,
51, 4950–4953.
[2]
[3]
[13] K. Muniz, C. H. Hovelmann, J. Streuff, J. Am. Chem. Soc.
2008, 130, 763–773.
[4]
[5]
[14] a) G. Brieger, J. N. Bennett, Chem. Rev. 1980, 80, 63-97; b)
R. L. Funk, K. P. C. Vollhardt, Chem. Soc. Rev. 1980, 9, 41-
61; c) S. M. Weinreb, Acc. Chem. Res. 1985, 18, 16-21; d) K.
Takao, R. Munakata, K. Tadano, Chem. Rev. 2005, 105,
4779-4807; e) M. Juhl, D. Tanner, Chem. Soc. Rev. 2009, 38,
2983-2992; f) M. M. Heravi, V. F. Vavsari, RSC Adv. 2015, 5,
50890-50912.
a) B. M. Trost, D. L. Van Vranken, Chem. Rev. 1996, 96,
395–422; b) B. M. Trost, M. L. Crawley, Chem. Rev. 2003,
103, 2921–2944; c) L. X. Dai, T. Tu, S. L. You, W. P. Deng, X.
L. Hou, Acc. Chem. Res. 2003, 36, 659–667; d) Z. Lu, S. Ma,
Angew. Chem. 2008, 120, 264 – 303; Angew. Chem. Int. Ed.
2008, 47, 258–297.
[15] B. Nyasse, L. Grehn, U. Ragnarsson, Chem. Commun. 1997,
1017–1018.
[6]
a) T. Jensen, P. Fristrup, Chem. Eur. J. 2009, 15, 9632–9636;
b) G. Liu, Y. Wu, Top. Curr. Chem. 2010, 292, 195–209; c) C.
J. Engelin, P. Fristrup, Molecules 2011, 16, 951–969; d) C.
Liu, H. Zhang, W. Shi, A. Lei, Chem. Rev. 2011, 111, 1780–
1824; e) C. S. Yeung, V. M. Dong, Chem. Rev. 2011, 111,
1215–1292; f) B. J. Li, Z. J. Shi, Chem. Soc. Rev. 2012, 41,
5588–5598; g) F. Liron, J. Oble, M. M. Lorion, G. Poli, Eur. J.
Org. Chem. 2014, 5863–5883; h) C. Zheng, S. L. You, RSC
Adv. 2014, 4, 6173–6214.
[16] a) A. Klapars, X. Huang, S. L. Buchwald, J. Am. Chem. Soc.
2002, 124, 7421–7428; b) S. V. Ley, A. W. Thomas, Angew.
Chem. 2003, 115, 5558–5607; Angew. Chem. Int. Ed. 2003,
42, 5400–5449; c) G. Evano, N. Blanchard, M. Toumi, Chem.
Rev. 2008, 108, 3054–3131; d) F. Monnier, M. Taillefer,
Angew. Chem. 2009, 121, 7088–7105; Angew. Chem. Int. Ed.
2009, 48, 6954–6971; e) C. Sambiagio, S. P. Marsden, A. J.
Blacker, P. C. McGowan, Chem. Soc. Rev. 2014, 43, 3525–
3550.
[7] a) D. J. Covell, M. C. White, Angew. Chem. 2008, 120, 6548–
6551; Angew. Chem. Int. Ed. 2008, 47, 6448–6451; b) K.
Takenaka, M. Akita, Y. Tanigaki, S. Takizawa, H. Sasai, Org.
Lett. 2011, 13, 3506–3509; c) P.-S. Wang, P. Liu, Y.-J. Zhai,
H.-C. Lin, Z.-Y. Han, L.-Z. Gong, J. Am. Chem. Soc. 2015,
137, 12732–12735; d) S. E. Ammann, W. Liu, M. C. White,
Angew. Chem. 2016, 128, 9723–9727; Angew. Chem. Int. Ed.
2016, 55, 9571–9575.
[17] a) P. H. J. Carlsen, T. Katsuki, V. S. Martin, K. B. Sharpless, J.
Org. Chem. 1981, 46, 3936–3938; b) M. Prashad, Y. Lu, H.-Y.
Kim, B. Hu, O. Repic, T. J. Blacklock, Synth. Commun. 1999,
29, 2937–2942.
[18] a) J.-N. Denis, S. Tchertchian, Y. Vallée, Synth. Commun.
1997, 27, 2345–2350; b) H. Ji, S. L. Delker, H. Li, P. Martasek,
L. J. Roman, T. L. Poulos, R. B. Silverman, J. Med. Chem.
2010, 53, 7804–7824; c) H. Ji, Q. Jing, J. Huang, R. B.
Silverman, Tetrahedron 2012, 68, 1359–1366.
[19] a) G. Himbert, W. Schwickerath, Liebigs Ann. Chem. 1982,
1982, 2105–2118; b) W. Zieliꢀski, A. Kudelko, J. Heterocycl.
Chem. 2002, 39, 1289–1292; c) I. Yavari, G. Khalili, A.
Mirzaei, Helv. Chim. Acta 2010, 93, 72–76.
[20] Epimerization was observed in the subsequent Vilsmeier-type
condensation with piperazine, which could be alleviated by
the use of TFE as solvent, see ref. 2c.
[8]
a) G. Liu, G. Yin, L. Wu, Angew. Chem. 2008, 120, 4811-
4814; Angew. Chem. Int. Ed. 2008, 47, 4733-4736; b) S. A.
Reed, A. R. Mazzotti, M. C. White, J. Am. Chem. Soc. 2009,
131, 11701-11706; c) G. T. Rice, M. C. White, J. Am. Chem.
Soc. 2009, 131, 11707-11711; d) G. Yin, Y. Wu, G. Liu, J. Am.
Chem. Soc. 2010, 132, 11978-11987. For the asymmetric
versions: e) H. Du, B. Zhao, Y. Shi, J. Am. Chem. Soc. 2008,
130, 8590–8591; f) A. Sharma, J. F. Hartwig, J. Am. Chem.
Soc. 2013, 135, 17983–17989.
[9]
a) B. M. Trost, D. A. Thaisrivongs, E. J. Donckele, Angew.
Chem. 2013, 125, 1563–1566; Angew. Chem. Int. Ed. 2013,
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10.1002/anie.201709681
Angewandte Chemie International Edition
COMMUNICATION
COMMUNICATION
Pu-Sheng Wang, Meng-Lan Shen, Tian-
Ci Wang, Hua-Chen Lin, Liu-Zhu Gong*
Page No. – Page No.
An Unprecedented Access to Chiral
Tetrahydropyrimidines via Palladium-
Catalyzed Asymmetric Allylic C-H
Amination
A chiral phosphoramidite ligand-controlled asymmetric palladium-catalyzed intramo-
lecular allylic C-H amination has been introduced to access various substituted
chiral tetrahydropyrimidines in high yields and enantioselectivities. Moreover, this
methodology was successfully applied to the asymmetric total synthesis of le-
termovir.
This article is protected by copyright. All rights reserved.