Stereodivergent synthesis of 1,3-syn- and -anti-tetrahydropyrimidinones

Article abstract of DOI:10.1021/ol101755m

An efficient protocol for the stereoselective synthesis of 1,3-syn and -anti-tetrahydropyrimidinones (syn- and anti-11a) is reported. The modular procedure is based on a stereodivergent cyclization of readily available urea-type substrates (10a) by intram

Full text of DOI:10.1021/ol101755m

ORGANIC
LETTERS
2010
Vol. 12, No. 20
4494-4497
Stereodivergent Synthesis of 1,3-syn-
and -anti-Tetrahydropyrimidinones
Michael Morgen, Sebastian Bretzke, Pengfei Li, and Dirk Menche*
UniVersity of Heidelberg, Department of Organic Chemistry,
INF 270, D-69120 Heidelberg, Germany
dirk.menche@oci.uni-heidelberg.de
Received July 29, 2010
ABSTRACT
An efficient protocol for the stereoselective synthesis of 1,3-syn and -anti-tetrahydropyrimidinones (syn- and anti-11a) is reported. The modular
procedure is based on a stereodivergent cyclization of readily available urea-type substrates (10a) by intramolecular allylic substitution. The
cyclization proceeds with excellent yield (up to 99%) and selectivity (up to dr > 20:1), purely based on substrate control. The product pyrimidines
can be readily transformed into the corresponding free syn- and anti-amines.
The chiral 1,3-diamine motif constitutes an important
structural element in various bioactive natural products and
medicinal compounds.1 Prominent examples include the
marine alkaloids batzelladines (1, Figure 1)2 or HIV-1
protease inhibitors, such as A-74704 (2).3 It is also present
in the chiral core of ligands and synthetic reagents.4 Because
of its prevalence, there are a number of strategies for the
construction of such systems.5,6 However, they are primarily
Figure 1. Chiral 1,3-diamine motif: a key element in the natural
product batzelladine D (1) and the HIV-protease inhibitor A-74704
(2).
(1) For examples of bioactive 1,3-amines of natural or synthetic origin,
see: (a) Jahn, T.; Ko¨nig, G. M.; Wright, A. D. Tetrahedron Lett. 1997, 38,
3883. (b) When, P. M.; Du Bois, J. J. Am. Chem. Soc. 2002, 124, 12950.
(c) Kammermeier, T.; Wiegrebe, W. Arch. Pharm. 1995, 328, 409. (d)
Vickery, K.; Bonin, A. M.; Fenton, R. R.; O’Mara, S.; Russell, P. J.;
Webster, L. K.; Hambley, T. W. J. Med. Chem. 1993, 36, 3663.
(2) Franklin, A. S.; Ly, S. K.; Mackin, G. H.; Overman, L. E.; Shaka,
A. J. J. Org. Chem. 1999, 64, 1512.
based on reduction protocols of suitable precursors, including
diimines,6b pyrazolidines,6c,d pyrimidines,6e azides,6f or
(3) Erickson, J.; Neidhart, D. J.; VanDrie, J.; Kempf, D. J.; Wang, X. C.;
Norbeck, D. W.; Plattner, J. J.; Rittenhouse, J. W.; Turon, M.; Wideburg,
N.; Kohlbrenner, W. E.; Simmer, R.; Helfrich, R.; Paul, D. A.; Knigge, M.
Science 1990, 249, 527.
(6) (a) Merla, B.; Risch, N. Synthesis 2002, 1365. (b) Barluenga, J.;
Olano, B.; Fustero, S. J. Org. Chem. 1983, 48, 2255. (c) Alexakis, A.;
Lensen, N.; Tranchier, J.-L.; Mangeney, P. J. Org. Chem. 1992, 57, 4563.
(d) Denmark, S. E.; Kim, J.-H. Synthesis 1992, 229. (e) Barluenga, J.;
Tomas, M.; Kouznetsov, V.; Pardon, J.; Rubio, E. Synlett 1991, 821. (f)
Enders, D.; Jegelka, U.; Du¨cker, B. Angew. Chem., Int. Ed. Engl. 1993,
32, 423. (g) Merla, B.; Arend, M.; Risch, N. Synlett 1997, 177. (h) Trost,
B. M.; Malhotra, S.; Olson, D. E.; Maruniak, A.; Du Bois, J. J. Am. Chem.
(4) For examples, see: (a) Ozaki, S.; Mimura, H.; Yasuhara, N.; Masui,
M.; Yamagata, Y.; Tomita, K. J. Chem. Soc., Perkin Trans. 2 1990, 353.
(b) Pini, D.; Mastantuono, A.; Uccello-Baretta, G.; Iuliano, A.; Salvatori,
P. Tetrahedron Lett. 1993, 49, 9613.
(5) For a recent review on chiral amine synthesis, see: Nugent, T. C.;
El-Shazly, M. AdV. Synth. Catal. 2010, 352, 753
.
Soc. 2009, 131, 4190.
10.1021/ol101755m  2010 American Chemical Society
Published on Web 09/10/2010

quaternary immonium salts, generated in situ by aminoalky-
lation of enamines.6g Recently, also a sequential process has
been reported involving an asymmetric allylic amination and
subsequent formation and opening of an aziridine
intermediate.6g Inspired by the natural products in combina-
tion with certain limitations of existing methods, in particular
with respect to modularity and convergence, herein we report
a more direct and flexible procedure for 1,3-diamine syn-
thesis, based on a stereodivergent intramolecular allylic
substitution reaction.7
Scheme 2. Three-Step Preparation of Urea Substrate 3
Our conceptually novel approach relies on an intramo-
lecular allylic substitution reaction8,9 of acyclic urea deriva-
tives of type 5, as shown in Scheme 1. Depending on suitable
isilazide (HMDS), and allyltrimethylsilane in the presence
of catalytic amounts of iron(II) sulfate to access homoallylic
amines of type 7a in high yields. Subsequent homologation
with allylcarbonate 8 by cross metathesis proceeded smoothly
in the presence of Hoveyda-Grubbs catalyst II. Finally,
attachment of tosylisocyanat proceeded with preparatively
useful yields by use of strong bases.11-13
Scheme 1. Concept for a Stereodivergent Cyclization to syn-
and anti-Tetrahydropyrimidinones and the Respective Free
Diamines
To test our notion for a stereoselective intramolecular
allylic substitution, 10a was submitted to various reaction
conditions. As shown in Table 1 (entry 1), initial attempts
Table 1. Diastereodivergent Cyclization of Urea Derivative 10a
to syn- and anti-Tetrahydropyrimidinones 11a
reaction conditions, it was envisioned that they might enable
access to both 1,3-syn- and -anti-tetrahydropyrimidinones (4a
and 4b) in a diastereodivergent fashion. Subsequently, these
heterocycles may then be cleaved to the corresponding syn-
or anti-amines 3a/3b. Notably, this synthetic concept is
highly flexible and convergent and thus offers the potential
to be readily adopted to natural products and pharmaceuticals.
As shown in Scheme 2, the required urea substrates were
obtained in a straightforward sequence in three steps from
commercial material. As depicted for phenyl analogue 10a,
the synthesis was based on a known four-component reaction
developed by Tian,10 which involves condensation of alde-
hyde 6a with benzyl chloroformate (CbzCl), hexamethyld-
conversion
entry
“PdLn”
conditions syn/anti-11aa
[%]b
Pd2(dba)3·CHCl3/ THF, rt,
1
2
3
4
5
6
7
(iPrO)3P
10 min
1:1
>95%
>95%
>95%
>95%
>95%
>95%
>95%
Pd2(dba)3·CHCl3/ ACN, rt,
EtC(CH2O)3P
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
10 min
THF, rt,
10 min
1:12
20:1
toluene,
rt, 10 min
Et2O, rt,
10 min
4:1
2:1
(7) For previous work from our group on direct stereoselective amine
synthesis, see :(a) Menche, D.; Hassfeld, J.; Li, J.; Menche, G.; Ritter, A.;
Rudolph, S. Org. Lett. 2006, 8, 741. (b) Menche, D.; Arikan, F.; Li, J.;
Rudolph, S. Org. Lett. 2007, 9, 267.
DCM, rt,
10 min
1:20
ACN, rt,
10 min
1:10
a Ratio was determined by 1H NMR of the crude products. b Conversion
determined by NMR spectroscopy.
(8) For reviews on allylic substitution reactions, see: (a) Trost, B. M.;
Van Vranken, D. L. Chem. ReV. 1996, 96, 395. (b) Trost, B. M.; Crawley,
M. L. Chem. ReV. 2003, 103, 2921
.
(9) For examples of syntheses of nitrogen-containing heterocycles by
intramolecular allylic substitutions, see: (a) Lee, K.-Y.; Kim, Y.-H.; Park,
M.-S.; Oh, C.-Y.; Ham, W.-H. J. Org. Chem. 1999, 64, 9450. (b) Butler,
D. C.; Inman, G. A.; Alper, H. J. Org. Chem. 2000, 65, 5887. (c) Amador,
M.; Ariza, X.; Garcia, J.; Sevilla, S. Org. Lett. 2002, 4, 4511. (d) Welter,
C.; Dahnz, A.; Brunner, B.; Streiff, S.; Du¨bon, P.; Helmchen, G. Org. Lett.
2005, 7, 1239. (e) Trost, B. M.; Machacek, M. R.; Faulk, B. D. J. Am.
Chem. Soc. 2006, 128, 6745. (f) Broustal, G.; Ariza, X.; Campagne, J.-M.;
Garcia, J.; Georges, Y.; Marinetti, A.; Robiette, R. Eur. J. Org. Chem. 2007,
4293. (g) Gnamm, C.; Krauter, C.; Bro¨dner, K.; Helmchen, G. Chem.sEur.
J. 2009, 15, 2050. (h) For a related process, see; Mun˜iz, K.; Streuff, J.;
were based on Pd/phosphite catalyst (entry 1) which resulted
in smooth cyclization to the desired product tetrahydropy-
rimidinones 11a, albeit with no stereoselectivity. However,
(11) Weaker bases (NEt3, LHMDS, DBU, proton sponge) and less
electron-deficient isocyanates resulted in lower degrees of conversion.
(12) For recent related amination reactions with urea substrates, see ref
Cha´vez, P.; Ho¨velmann, C. H. Chem. Asian J. 2008, 3, 1248
(10) Song, Q.-Y.; Yang, B.-L.; Tian, S.-K. J. Org. Chem. 2007, 72,
5407.
.
9h and: Rice, G. T.; White, M. C. J. Am. Chem. Soc. 2009, 131, 11707
(13) For an amination reaction using a tosyl amide, see: Yin, G.; Wu,
Y.; Liu, G. J. Am. Chem. Soc. 2010, 132, 11978
.
.
Org. Lett., Vol. 12, No. 20, 2010
4495

a more elaborate phosphite ligand in combination with
Pd2(dba)3 or Pd(PPh3)4 resulted in a distinct preference of
either the syn- or anti-diastereomer (entries 2 and 3), again
with very high degrees of conversion. Due to the ready
commercial availability of the latter catalyst, further opti-
mizations were carried out with Pd(PPh3)4. As shown in
entries 3-7, the solvent had a critical influence on the
stereochemical outcome of the reaction. Best results to access
the syn-isomer were obtained in THF (entry 3), while the
anti-diastereomer was effectively generated in DCM (entry
6).14,15
Scheme 3. Diastereodivergent Tetrahydropyrimidinone Synthesis
To assess the generality of this procedure for stereoselec-
tive synthesis of syn- and anti-tetrahydropyrimidinones,
various substrates with different electronic and steric proper-
ties were evaluated.16 As shown in Scheme 3, cyclization
proceeded in all cases with good yields and selectivities,
without the necessity of further adopting the procedure to
specific substrates. This demonstrates the general usefulness
of our protocol for the modular and stereoselective synthesis
of 1,3-syn- and -anti-tetrahydropyrimidinones. It should be
noted that, in contrast to previous work,9 our procedure
enables a much more concise and direct entry into hetero-
cycles. Also, both the syn- and anti-diastereomer can be
obtained with excellent yields and asymmetric induction,
purely based on substrate control in a divergent manner from
the same substrate.
Finally, the applicability of this procedure also for
preparation of the respective free amines was demonstrated.
As depicted in Scheme 4 for substrates syn- and anti-11a,
the tetrahydropyrimidinones may be readily converted to the
respective syn- and anti-amines 14. Notably, selective
deprotection of the two amine moieties is possible. This
involves first deprotecting the “left” nitrogen by removal of
the Cbz group with TMSI giving 12 in high yields for both
the syn- and anti-diastereomer.17 Subsequent treatment with
(14) In all cases, stereochemical assignment was based on NMR
methods, e.g.:
(15) Potentially, this pronounced solvent effect may be rationalized by
a reversal of the enantiofacial bias of the allylic substitution reaction.
Presumably, in THF a conventional attack of the nucleophile on the side
opposite to the π-allyl complex is expected, leading to an inversion at
the configuration of the respective carbon center. In contrast to THF, the
nucleophilic amide should be much less solvated in DCM. Possibly, the
nucleophile may then directly attack the π-allyl intermediate on the same
side as the cationic π-allyl complex, based on attractive charge-charge
interactions. This would then lead to retention of the configuration . For a
recent mechanistic study with “hard” and “soft” nucleophiles in allylic
substitution reactions, see: Shintani, R.; Tsuji, T.; Park, S.; Hayashi, T.
magnesium/MeOH then removes the tosyl substituent lib-
erating the remaining amide moiety, giving syn- and anti-
13 in essentially quantitative yields. Finally, cleavage of the
urea can be effected under acidic conditions to give the free
diamines 14.18 These conversions likewise proceeded with
good yields,19 which demonstrates the ready adaptability of
our procedure for stereoselective amine synthesis.
In summary, we have devised a novel method for the
stereoselective synthesis of 1,3-syn- and -anti-tetrahydro-
pyrimidinones and their conversion to the corresponding
J. Am. Chem. Soc. 2010, 132, 7508
.
(16) All required urea substrates (10a-f) were readily prepared by four-
component coupling, in analogy to Scheme 2, by using either the method
of Tian (ref 10) or: Phukan, P. J. Org. Chem. 2004, 69, 4005. For full
details: see Supporting Information.
4496
Org. Lett., Vol. 12, No. 20, 2010

free amines. The procedure is based on an intramolecular
allylic substitution reaction of readily available urea-type
substrates (5). Depending on reaction conditions, either
the syn- or anti-diastereomer can be obtained with good
to excellent yields and asymmetric induction, purely based
on substrate control. These results may find useful
applications in natural product synthesis or medicinal
chemistry and stimulate further studies for direct asym-
metric amine synthesis.
Scheme 4
. Selective Stepwise Cleavage of
Tetrahydropyrimidinones to 1,3-syn- and -anti-Amines
Acknowledgment. Generous financial support by the
Deutsche Forschungsgemeinschaft (SFB 623 ‘Molekulare
Katalysatoren: Struktur und Funktionsdesign’) and the
Wild-Stiftung is gratefully acknowledged. We thank Prof.
G. Helmchen (University of Heidelberg) for fruitful
discussions.
Supporting Information Available: Experimental details,
spectral data, and copies of NMR spectra for all new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
OL101755M
´
(17) Bolo´s, J.; Pe´rez-Beroy, A.; Gubert, S.; Anglada, L. Tetrahedron
1992, 48, 9567.
(18) (a) Kumar, V.; Ramesh, N. G. Tetrahedron 2006, 62, 1877. (b)
Dunn, P. J.; Ha¨ner, R.; Rapoport, H. J. Org. Chem. 1990, 55, 5017.
(19) In contrast, efforts to remove the urea under similar conditions at
the stage of 11 or 12 resulted in only low degrees of conversion.
Org. Lett., Vol. 12, No. 20, 2010
4497