Stereoregulations of pyrimidinone based chiral auxiliary in aldol and alkylation reactions: A convenient route to oxyneolignans

Article abstract of DOI:10.1021/ol302653g

(S)-4-Isopropyl-1-phenyltetrahydropyrimidin-2(1H)-one was synthesized and evaluated as a chiral auxiliary for asymmetric acetate and propionate aldol reactions, by generation of titanium and lithium enolates, affording excellent yields and stereoselectivities for syn and anti aldol diastereomers, respectively. High stereoselectivities were also obtained in lithium mediated alkylation reactions. The application of the auxiliary was exemplified in the asymmetric synthesis of a natural oxyneolignan, (+)-(7S,8S)-4-hydroxy-3, 3′,5′-trimethoxy-8′,9′-dinor-8,4′-oxyneoligna-7, 9-diol-7′-oic acid.

Full text of DOI:10.1021/ol302653g

ORGANIC
LETTERS
2012
Vol. 14, No. 22
5672–5675
Stereoregulations of Pyrimidinone Based
Chiral Auxiliary in Aldol and Alkylation
Reactions: A Convenient Route to
Oxyneolignans
Mangilal Chouhan, Ratnesh Sharma, and Vipin A. Nair*
Department of Medicinal Chemistry, National Institute of Pharmaceutical Education
and Research, Sector 67, Mohali, Punjab 160062, India
vn74nr@yahoo.com
Received September 27, 2012
ABSTRACT
(S)-4-Isopropyl-1-phenyltetrahydropyrimidin-2(1H)-one was synthesized and evaluated as a chiral auxiliary for asymmetric acetate and propionate
aldol reactions, by generation of titanium and lithium enolates, affording excellent yields and stereoselectivities for syn and anti aldol diastereomers,
respectively. High stereoselectivities were also obtained in lithium mediated alkylation reactions. The application of the auxiliary was exemplified in the
asymmetric synthesis of a natural oxyneolignan, (þ)-(7S,8S)-4-hydroxy-3,30,50-trimethoxy-80,90-dinor-8,40-oxyneoligna-7,9-diol-70-oic acid.
Aldol and alkylation reactions employing a chiral auxiliary
are a widely recognized approach for generating stereogenic
centers during CꢀC bond formation.1 Evans et al. illus-
trated the usefulness of an oxazolidinone based chiral
auxiliary in a dialkylboron triflate mediated propionate
aldol reaction, affording the syn selective β-hydroxy acids
in high enantiomeric purity.2 Later enolates of Li,3 Ti,4 and
Sn5 have also been used extensively in stereoselective aldol
reactions. Despite the high selectivity in the propionate
aldol reaction, the oxazolidinone auxiliary fails in acetate
aldol reactions especially with aliphatic4e and R,β-unsatur-
ated aldehydes.2,4d The auxiliary also suffers from endo-
cyclic cleavage in cases of highly congested aldol adducts.6
Many of these issues have been addressed later with their
solutions in the form of new or improved auxiliaries.4c,g,h
However, several problems including narrow substrate
scope, modest diastereoselectivity with either aliphatic or
aromatic aldehydes, limitations in reactivity, expensive
reagents and metal sources, and difficulty in handling the
reagents restricted the wide synthetic applicability.2,4,5
These limitations demand development of a robust aux-
iliary for CꢀC bond forming reactions.
(1) Selected references for aldol and alkylation reaction: (a) Ager,
D. J.; Prakash, I.; Schaad, D. R. Chem. Rev. 1996, 96, 835. (b) Evans,
D. A. In Asymmetric Synthesis; Morrison, J. D., Ed.; Academic Press: New
York, 1984; Vol. 3. (c) Arya, P.; Qin, H. Tetrahedron 2000, 56, 917. (d)
Evans, D. A. Aldrichimica Acta 1982, 15, 23. (e) Davies, S. G.; Garner,
A. C.; Roberts, P. M.; Smith, A. D.; Sweet, M. J.; Thomson, J. E. Org.
Biomol. Chem. 2006, 4, 2753. (f) Evans, D. A.; Ennis, M. D.; Mathre,
D. J. J. Am. Chem. Soc. 1982, 104, 1737. (g) Evans, D. A; Bartroli, J.
Tetrahedron Lett. 1982, 23, 807. (h) Evans, D. A.; Chapman, K. T.;
Bisaha, J. J. Am. Chem. Soc. 1988, 110, 1238. (i) Le, T. N.; Nguyen,
Q. P. B.; Kim, J. N.; Kim, T. H. Tetrahedron Lett. 2007, 48, 7834.
(2) Evans, D. A.; Bartroli, J.; Shih, T. L. J. Am. Chem. Soc. 1981,103,2127.
(3) (a) Braun, M.; Devant, R. Tetrahedron Lett. 1984, 25, 5031. (b)
Devant, R.; Mahler, U.; Braun, M. Chem. Ber. 1988, 121, 397 and
references cited therein. (c) Saito, S.; Hatanaka, K.; Kano, T.; Yamamoto,
H. Angew. Chem., Int. Ed. 1998, 37, 3378.
(5) (a) Nagao, Y.; Yamada, S.; Kumagai, T.; Ochiai, M.; Fujita, E.
J. Chem. Soc., Chem. Commun. 1985, 1418. (b) Nagao, Y.; Hagiwara, Y.;
Kumagai, T.; Ochiai, M.; Inoue, T.; Hashimoto, K.; Fujita, E. J. Org.
Chem. 1986, 51, 2391.
(6) (a) Kende, A. S.; Kawamura, K.; Orwat, M. J. Tetrahedron Lett.
1989, 30, 5821. (b) Heathcock, C. H.; Pirrung, M. C.; Young, S. D.;
Hagen, J. P.; Jarui, E. T.; Badertscher, D.; Marki, H.-P.; Montgomery,
S. H. J. Am. Chem. Soc. 1984, 106, 8161.
(4) (a) Yan, T. H.; Hung, A. W.; Lee, H. C.; Chang, C. S.; Liu, W. H.
J. Org. Chem. 1995, 60, 3301. (b) Gonzalez, A.; Aiguade, J.; Urpi, F.;
Vilarrasa, J. Tetrahedron Lett. 1996, 37, 8949. (c) Guz, N. R.; Phillips,
A. J. Org. Lett. 2002, 4, 2253. (d) Crimmins, M. T.; Shamszad, M. Org.
Lett. 2007, 9, 149. (e) Osorio-Lozada, A.; Olivo, H. F. Org. Lett. 2008, 10,
617 and references cited therein. (f) Hodge, M. B.; Olivo, H. F. Tetrahedron
2004, 60, 9397. (g) Zhang, Y.; Phillips, A. J.; Sammakia, T. Org. Lett. 2004,
6, 23. (h) Zhang, Y.; Sammakia, T. Org. Lett. 2004, 6, 3139.
r
10.1021/ol302653g
Published on Web 10/30/2012
2012 American Chemical Society

In continuation of our work7 on metal mediated reac-
tions, we investigated the usefulness of (S)-4-isopropyl-1-
phenyltetrahydropyrimidin-2(1H)-one as a chiral auxil-
iary in asymmetric aldol and alkylation reactions. Apart
from the excellent yields and diastereoselectivity obtained
in both these reactions, the auxiliary has an N-phenyl
group which serves as a chromophoric unit that assists in
reaction monitoring and chromatographic purification.
Another advantage is that the cyclic ureido frame resists
endocyclic cleavage while the cyclic carbamate in oxazoli-
dinones is prone to base hydrolysis. The auxiliary under-
goes rapid enolization with a slight excess of the reagents,
compared to the use of 2 equiv or more of a costly Lewis
acid and chiral base.4e,f,8 The application of the auxiliary is
shown in the concise synthesis of a natural oxyneolignan.
The synthesis of the chiral auxiliary was achieved as
illustrated inScheme1. (S)-4-Methyl-N-phenylpentan-1,3-
diamine 7, obtained by Michael addition9 of the lithiated
chiral secondary amine 2 on (E)-ethyl 4-methylpent-2-
enoate 1, and subsequent functional group transforma-
tions, was cyclized using triphosgene and K2CO3 to obtain
(S)-4-isopropyl-1-phenyltetrahydropyrimidin-2(1H)-one 8.
Acylation of 8 under basic conditions afforded the acety-
lated and propionylated products 9 and 10, respectively.
The acetylated derivative 9 was treated with TiCl4 (1.05
equiv) and DIPEA (1.1 equiv) in DCM at ꢀ78 °C to
generate the titanium enolate. Reaction of the enolate with
benzaldehyde afforded the acetate aldol product (Scheme 2)
1
in excellent yield. H NMR analysis of the crude product
revealed a diastereoselectivity of 97:03. The major acetate
aldol diastereomer 11a was hydrolyzed with lithium hy-
droperoxide. The optical rotation of the resulting free acid
was compared with literature,10a and a syn relation was
concluded between the hydroxy group and the stereodirect-
ing isopropyl group of the auxiliary for 11a. The reaction
conditions when extended to 10 gave the non-Evans syn
aldol diastereomer 12a as the major product, confirmed by
hydrolysis and comparison of the optical rotation of the
resulting acid with the reported value.10b The reaction
afforded a good yield, and a diastereoselectivity of 99:01
was determined from the 1H NMR spectrum of the reac-
tion mixture. The scope of both these aldol reactions were
examined by employing various aromatic, aliphatic, and
R,β-unsaturated aldehydes to afford the corresponding ace-
tate syn aldols (11aꢀj) and non-Evans propionate syn aldols
(12aꢀj) (Table 1). The effect of metal on the stereochemical
outcome of the aldol reaction was evaluated by generating
the lithium enolates of 9 and 10 using LiHMDS (1.05 equiv)
in anhydrous THF at ꢀ78 °C. The reaction of the enolates
with benzaldehyde yielded the aldol products with reversal of
selectivity. A diastereoselectivity of 04:96 favoring the anti
diastereomer 13a was observed for the acetate aldol reaction
while the propionate aldol reaction afforded the non-Evans
anti diastereomer 14a in a ratio of 01:99. The stereochemistry
of the diastereomers 13a and 14a were confirmed by hydro-
lysis of the aldol adducts to the corresponding carboxylic
acids and comparison of the optical rotation values with the
literature.10 The reaction was generalized using various
aldehydes to afford the products (13aꢀj, 14aꢀj) in excellent
yields and stereoselectivities.
Scheme 1. Synthesis of the Chiral Auxiliary
Table 1. Titanium and Lithium Mediated Stereoselective Aldol Reactions
TiCl4 mediateda
LiHMDS mediatedb
X = H, acetate X = Me, propionate
X = H, acetate
X = Me, propionate
entry
RCHO
C6H5CHO
syn:antic
yield %d
syn:antic
yield %d
syn:antic
yield %d
syn:antic
yield %d
1
2
97:03
98:02
95:05
97:03
98:02
98:02
98:02
93:07
97:03
96:04
11a (88)
11b (86)
11c (78)
11d (87)
11e (85)
11f (80)
11g (85)
11h (83)
11i (75)
11j (79)
99:01
99:01
99:01
97:03
95:05
98:02
95:05
92:08
98:02
97:03
12a (80)
12b (83)
12c (72)
12d (85)
12e (80)
12f (80)
12g (80)
12h (85)
12i (72)
12j (76)
04:96
03:97
06:94
04:96
05:95
06:94
05:95
08:92
02:98
04:96
13a (94)
13b (96)
13c (72)
13d (95)
13e (88)
13f (93)
13g (85)
13h (92)
13i (92)
13j (88)
01:99
02:98
06:94
03:97
02:98
04:96
05:95
06:94
02:98
03:97
14a (96)
14b (97)
14c (88)
14d (98)
14e (93)
14f (93)
14g (85)
14h (95)
14i (92)
14j (88)
4-MeC6H4CHO
4-MeOC6H4CHO
4-ClC6H4CHO
4-BrC6H4CHO
C6H5CH2CHO
C6H5CHdCHCHO
(Me)2CdCHCHO
(Me)3CCHO
3
4
5
6
7
8
9
10
(Me)2CHCHO
a The reactions were carried out at ꢀ78 °C with 1.0 equiv of 9 or 10, 1.05 equiv of TiCl4, 1.1 equiv of DIPEA, and 1.1 equiv of aldehyde in DCM
(5 mL). b The reactions were carried out at ꢀ78 °C with 1.0 equiv of 9 or 10, 1.05 equiv of both LiHMDS and aldehyde in anhydrous THF (5 mL).
c Diastereoselectivity ratios are based on 1H NMR spectra of the crude products. d Isolated yield of the major diastereomer.
Org. Lett., Vol. 14, No. 22, 2012
5673

Scheme 2. Stereoselective Aldol Reactions
Scheme 3. Stereoselectivity in Aldol Reactions
To account for the stereoselectivity, chelated six-
membered chair and nonchelated boat transition state mod-
els were considered respectively, for Ti- and Li-mediated
aldol reactions (Scheme 3).11 TiCl4 is expected to form a Z
enolate with the N-propionyl derivative of the auxiliary,
10. Due to the high coordination ability of titanium, it
complexes with the O-atom of aldehyde and also with any
suitably positioned group on the auxiliary to form a
chelated structure, as shown in TS-A and TS-B. The tight
hexacoordinate species thus adopts an almost perpendicu-
lar conformation between the enolate CdC and aldehyde
CdO groups. In TS-A, the aldehyde substituent R occu-
pies an equatorial position to avoid a 1,3-diaxial interac-
tion, affording the syn aldol diastereomer as the major
product while TS-B leading to the anti aldol would have
the R group positioned axially and, hence, disfavored. It
may also be assumed that in TS-A the enolate substituent
X would be forced into an eclipsed conformation with the
aldehyde CdO group, to avoid a gauche interaction with
the aldehyde substituent R, depending upon the steric
hindrance imparted. Yet, to account for the non-Evans
anti aldol selectivity observed with the lithium enolate,
transition state models TS-C and TS-D can be envisaged.
The gauche interaction between the enolate substituent X
and the aldehyde group R and the freedom experienced
from nonchelation promotes the formation of a boat
transition state over the chair for the Z enolate of lithum.
Table 2. Lithium Mediated Stereoselective Alkylation Reactionsa
entry
conditionb
RCH2Br
drc
yield %d
1
2
3
4
5
6
7
A
B
B
B
B
B
B
C6H5CH2Br
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
15a (30)
15a (98)
15b (95)
15c (98)
15d (96)
15e (94)
15f (98)
C6H5CH2Br
(7) (a) Kumar, V.; Nair, V. A. Tetrahedron Lett. 2010, 51, 966. (b)
Kumar, V.; Raghavaiah, P.; Mobin, S. M.; Nair, V. A. Org. Biomol.
Chem. 2010, 8, 4960. (c) Khatik, G. L.; Pal, A.; Mobin, S. M.; Nair, V. A.
Tetrahedron Lett. 2010, 51, 3654. (d) Khatik, G. L.; Khurana, R.;
Kumar, V.; Nair, V. A. Synthesis 2011, 3123. (e) Kumar, V.; Khatik,
G. L.; Nair, V. A. Synlett 2011, 2997. (f) Kumar, V.; Pal, A.; Khatik,
G. L.; Bhattacharya, S.; Nair, V. A. Tetrahedron: Asymmetry 2012, 23,
434. (g) Khatik, G. L.; Kumar, V.; Nair, V. A. Org. Lett. 2012, 14, 2442.
(8) (a) Crimmins, M. T.; Chaudhary, K. Org. Lett. 2000, 2, 775. (b)
Cosp, A.; Romea, P.; Urpi, F.; Vilarrasa, J. Tetrahedron Lett. 2001, 42,
4629. (c) Crimmins, M. T.; King, B. W.; Tabet, E. A.; Chaudhary, K.
J. Org. Chem. 2001, 66, 894. (d) Zhang, Y.; Sammakia, T. J. Org. Chem.
2006, 71, 6262.
4-BrC6H4CH2Br
4-MeC6H4CH2Br
EtO2CCH2Br
CH2dCHCH2Br
MeCH2Br
a The reactions were carried out with 1.0 equiv of 10, 1.05 equiv of
both LiHMDS and organic halide in anhydrous THF (5 mL). b Condi-
tion A = 1.05 equiv of LiHMDS, ꢀ78 °C to rt. Condition B = 1.05
equiv of both LiHMDS and TMEDA, ꢀ60 °C to rt. c Diastereoselec-
tivity ratios are based on 1H NMR spectra of the crude products.
d Isolated yield of the major diastereomer.
(9) Davies, S. G.; Ichihara, O. Tetrahedron: Asymmetry 1991, 2, 183.
(10) (a) Ankati, H.; Zhu, D.; Yan, Y.; Biehl, E. R.; Hua, L. J. Org.
Chem. 2009, 74, 1658. (b) Draanen, N. A. V.; Arseniyadis, S.; Crimmins,
M. T.; Heathcock, C. H. J. Org. Chem. 1991, 56, 2499.
Thus in TS-C, the R group is accommodated in such a
position that it encounters less steric repulsions from the
enolate substituent X and the auxiliary, favoring the anti
aldol as the major product. But in the case of TS-D, gauche
(11) (a) Li, Y.; Paddon-Row, M. N.; Houk, K. N. J. Org. Chem. 1990,
55, 481. (b) Shinisha, C. B.; Sunoj, R. B. J. Am. Chem. Soc. 2010, 132,
12319. (c) Evans, D. A.; Nelson, J. V.; Taber, T. R. Topics in Stereo-
chemistry; Wiley-Interscience: New York, 1982; Vol. 13, p 1. (d) Evans,
D. A.; McGee, L. R. Tetrahedron Lett. 1980, 21, 3975.
5674
Org. Lett., Vol. 14, No. 22, 2012

Scheme 4. Synthesis of (þ)-(7S,8S)-4-Hydroxy-3,30,50-trimethoxy-80,90-dinor-8,40-oxyneoligna-7,9-diol-70-oic Acid 25
interaction between the X and R groups arising from the
eclipsed conformation disfavors the syn aldol formation.
The usefulness of the auxiliary was then examined in the
alkylation reaction.1eꢀi Deprotonation of 10 with LiHMDS
at ꢀ78 °C, followed by addition of benzyl bromide either at
the same temperature or 0 °C, witnessed very sluggish
reactions (Table 2, entry 1). Further attempts were made
to enhance the deprotonation by chelating the cation using
tetramethylethylenediamine (TMEDA) so that the hexa-
methyldisilylamide anion is sufficiently basic for proton
abstraction. Addition of equimolar amounts of LiHMDS
and TMEDA to a solution of 10 in THF at ꢀ60 °C followed
by benzyl bromide resulted in a dramatic improvement in the
reaction (Table 2, entry 2). The benzylated product 15a was
obtained in excellent yield (98%) and diastereoselectivity
(>99% de). The alkylated product 15a was hydrolyzed with
lithium hydroperoxide. The optical rotation of the free acid
on comparison with the literature1e revealed an anti relation
between the alkyl group and the stereodirecting isopropyl
group of the auxiliary for 15a. The reaction conditions were
then generalized with substituted benzyl bromides bearing
electron-donating/-withdrawing groups and various alipha-
tic bromides (Table 2, entries 2ꢀ7). The observed stereo-
selectivity in the alkylation reaction can be explained by the
proposed transition state model TS-E (Table 2). Kinetic
deprotonation using LiHMDS at low temperature favors
the formation of a Z enolate. The si face of the enolate is
shielded by the bulky isopropyl group of the auxiliary which
disfavors the approach of the electrophile. The re face on the
other hand is less hindered and hence more accessible,
resulting in high stereoselectivity for the alkylation reactions.
The scope of the auxiliary was further illustrated in the
synthesis of a natural oxyneolignan 25, recently isolated
from the stem of Sinocalamus affinis and identified as
(þ)-(7S,8S)-4-hydroxy-3,30,50-trimethoxy-80,90-dinor-8,40-
oxyneoligna-7,9-diol-70-oic acid.13 Synthesis of the oxy-
neolignan was accomplished from commercially available
syringic acid 16 (Scheme 4). The methyl ester of syringic
acid 17 was alkylated using benzyl bromoacetate and sub-
jected to catalytic hydrogenolysis to give 2-(2,6-dimethoxy-
4-(methoxycarbonyl)phenoxy)acetic acid 19. The corre-
sponding acid chloride was then coupled with the auxiliary
8 to obtain the acylated derivative 20. Subsequent reaction
of the enolate generated from 20 using TiCl4 (1.05 equiv)
and DIPEA (2.5 equiv) with 4-(benzyloxy)-3-methoxyben-
zaldehyde 21 gave the Evans syn aldol8c,12 diastereomer 22
(dr = 9:1). Reductive hydrolysis of the diastereomer 22
yielded the desired intermediate 23. Finally, cleavage of the
aryloxy benzyl group by Pd-catalyzed hydrogenolysis fol-
lowed by base hydrolysis of the ester afforded the oxyneo-
lignan, (þ)-(7S,8S)-4-hydroxy-3,30,50-trimethoxy-80,90-di-
nor-8,40-oxyneoligna-7,9-diol-70-oic acid 25. The structure
and stereochemistry of the oxyneolignan 25 were con-
firmed spectroscopically and by comparing the optical
rotation with the literature.13
In conclusion, the stereoregulations imparted by the
(S)-4-isopropyl-1-phenyltetrahydropyrimidin-2(1H)-one
chiral auxiliary in asymmetric aldol and alkylation reactions
were evaluated. The products were obtained in high yields and
excellent stereoselectivity. The synthetic utility of the auxiliary
was illustrated by a concise synthesis of a newly isolated
natural oxyneolignan in nine steps and 24% overall yield.
Acknowledgment. Research fundings from the Depart-
ment of Science and Technology, Government of India
and NIPER are gratefully acknowledged.
Supporting Information Available. Experimental pro-
cedures; 1H NMR, 13C NMR, and HRMS (ESI) data of
the compounds. This material is available free of charge
via the Internet at http://pubs.acs.org.
(12) When 2.5 equiv of DIPEA was used, the Evans syn aldol adduct
was formed with excellent selectivity. The amine probably coordinates to
titanium disfavoring the chelated transition state.
(13) (a) Xiong, L.; Zhu, C.; Li, Y.; Tian, Y.; Lin, S.; Yuan, S.; Hu, J.;
Hou, Q.; Chen, N.; Yang, Y.; Shi, J. J. Nat. Prod. 2011, 74, 1188. (b)
D
Optical rotation: natural oxyneolignan [R]20 þ13.4 (c 0.13, MeOH);
synthetic oxyneolignan 25 [R]20D þ40.8 (c 1.0, MeOH).
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 22, 2012
5675