Asymmetric synthesis of dihydroquinazolinones via directed ortho metalation and addition to tert-butanesulfinyl imines

Article abstract of DOI:10.1016/j.tetlet.2005.10.067

An asymmetric route to dihydroquinazolinones via the addition of ortho metalated substrates to tert-butanesulfinyl imines is reported. The scope of the nucleophile and electrophile components and the absolute stereochemical outcome are presented.

Full text of DOI:10.1016/j.tetlet.2005.10.067

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 8909–8912
Asymmetric synthesis of dihydroquinazolinones via directed ortho
metalation and addition to tert-butanesulfinyl imines
Hemaka A. Rajapakse,a,* Mary Beth Young,a Hong Zhu,a Samantha Charltona, and
Nancy N. Tsoub
aDepartment of Medicinal Chemistry, Merck Research Laboratories, West Point, PA 19486, USA
bDepartment of Medicinal Chemistry, Merck Research Laboratories, Rahway, NJ 07065, USA
Received 30 September 2005; accepted 17 October 2005
Available online 2 November 2005
Abstract—An asymmetric route to dihydroquinazolinones via the addition of ortho metalated substrates to tert-butanesulfinyl imi-
nes is reported. The scope of the nucleophile and electrophile components and the absolute stereochemical outcome are presented.
Ó 2005 Published by Elsevier Ltd.
Dihydroquinazolinones represent an important class of
biologically active molecules with utility in many thera-
peutic areas (Fig. 1).1–3 Recently reported structures of
this class include DPC-961, a potent second generation
non-nucleoside reverse-transcriptase inhibitor for the
treatment of HIV infection and SM-15811, an effective
Ca2+/Na+ ion exchanger inhibitor with potential utility
for the management of ischemic heart disease.2,3
enic nucleophiles to generate the amine bearing stereo-
center.2,4 During our efforts to synthesize compounds
of this structural class, we focused on the 2-(1-amino-
alkyl)aniline retron present in the 3,4-dihydroquinazoli-
none core. We hypothesized that the addition of an
ortho metalated aniline derivative to a tert-butanesulfin-
yl imine could provide this core in a diastereoselective
manner.5,6 Judicious choice of a directing group can
provide the desired intermediate with differentially pro-
tected amine functionality.
To the best of our knowledge, only two asymmetric
approaches to 3,4-dihydroquinazolinones have been
reported to date. Both these reports target the DPC-
961 class of molecules and utilize either a chiral auxiliary
or catalyst to mediate the asymmetric addition of acetyl-
Boc-protected aniline 1 and benzaldehyde sulfinyl imine
2 were chosen as the initial substrates to examine the
feasibility of this reaction (Table 1). Directed ortho
metalation of 1 with sec-BuLi in THF followed by elec-
trophile addition did not afford any desired product 3.7
Fortunately, 3 was obtained in modest yield in the pres-
ence of one equivalent of TMEDA.8,9 Increasing the
stoichiometry of TMEDA resulted in improved yield
but did not affect the diastereoselectivity of the reaction.
Ph
N
Ph
F3C
Cl
NH
N
N
O
N
H
O
We then surveyed the reaction scope with respect to the
nucleophilic component (Table 2). Electron withdraw-
ing substituents at the para position were found to
enhance the yields for this process (adducts 4, 5, and
6). This trend was confirmed by the addition of ortho
metalated N-Boc-4-methoxyaniline, which gave 7 in
poor yield and selectivity.10 N-Boc-2-aminopyridine
was found to add with excellent yield and selectivity to
afford adduct 8. In contrast, the isomeric N-Boc-4-
aminopyridine provided 9 with poor selectivity. The nat-
ure of the directing group is also critical for the success
H
DPC-961
( )SM-15811
Figure 1. Representative dihydroquinazolinones.
Keywords: Dihydroquinazolinones; Asymmetric synthesis; Sulfinyl
imines; Directed ortho metalation.
Corresponding author. Tel.: +1 215 6525629; fax: +1 215 6523971;
e-mail: hemaka_rajapakse@merck.com
Present address: Thomas Jefferson University Medical School,
Philadelphia, PA, USA.
*
0040-4039/$ - see front matter Ó 2005 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2005.10.067

8910
H. A. Rajapakse et al. / Tetrahedron Letters 46(2005) 8909–8912
Table 1. Effect of TMEDA additive
Table 3. Electrophile scope
O
S
O
NHBoc
O
S
Ph
H
S
s-BuLi
N
t-Bu
N
t-Bu
t-Bu
N
O
S
+
R2 R3
TMEDA
H
Cl
–78 o
C
0 o
C
t-Bu
H
Ph
R2
R3
s-BuLi
TMEDA
C
NHBoc
N
H
+
1
2
3
–78 o
0 o
C
NHBoc
Cl
TMEDA (equiv)a
Yield (%)b
drc
0
1
2
3
0
42
61
55
N/A
NHBoc
R2
Ph
R3
H
Adduct
Yield (%)a
79
drb
80:20
80:20
80:20
O
S
Ph
H
Cl
a With respect to the nucleophile.
t-Bu
80:20
N
H
b Combined isolated yield of diastereomeric mixture.
NHBoc
4
c Ratio determined by 400 MHz 1H NMR analysis of the unpurified
reaction mixture.
O
H
i-Bu
S
Cl
i-Bu
H
80
66:34
t-Bu
N
H
Table 2. Nucleophile scope
11
NHBoc
O
S
c-Hex
t-Bu
H
O
O
H
Cl
Cl
S
Ph
Nuc
c-Hex
t-Bu
H
H
75
42
80:20
66:34
t-Bu
N
s-BuLi
N
t-Bu
Nuc +
S
H
t-Bu
TMEDA
N
12
NHBoc
H
H
Ph
–78 o
C
0 o
C
O
S
H
Nuc
Adduct
Yield drb
(%)a
t-Bu
N
H
O
S
13
Ph
H
NHBoc
O
t-Bu
61
79
74
81
30
70
90
80:20
N
NHBoc
Ph Me
H
S
Cl
NHBoc
3
Ph
Me
<5c
N/A
t-Bu
N
H
O
S
Ph
H
14
NHBoc
Cl
Cl
F
t-Bu
80:20
85:15
75:25
70:30
95:05
60:40
N
O
S
Ph Et
H
NHBoc
NHBoc
Cl
Cl
NHBoc
4
Ph
Et
37
91:09
N/A
t-Bu
N
H
O
S
Ph
H
15
NHBoc
F
t-Bu
N
O
i-Pr Me
H
S
i-Pr
Me
t-Bu
<10c
NHBoc
N
5
H
16
NHBoc
O
H
Ph
F3C
H3CO
S
F3C
a Combined isolated yield of diastereomeric mixture.
t-Bu
N
b Ratio determined by 400 MHz 1H NMR analysis of the unpurified
reaction mixture.
H
NHBoc
NHBoc
6
c Based on conversion observed by LC/MS.
O
Ph
H
S
H3CO
t-Bu
N
H
of this reaction. Boc proved to be optimal, and varia-
tions such as pivalate gave the corresponding addition
adduct 10 with severely diminished yield and selectivity.
NHBoc
NHBoc
7
O
S
Ph
H
t-Bu
N
Using N-Boc-4-chloroaniline as the nucleophile precur-
sor, we surveyed the scope of the electrophilic compo-
nent (Table 3). Sulfinyl imine derivatives of enolizable
aldehydes underwent addition in high yield (adducts
11 and 12). However, the selectivity of the addition
was highly dependent on the steric nature of the aldim-
ine. Both a-monosubstituted and a,a,a-trisubstituted
aldimines gave the desired product with poor selectivity
(adducts 11 and 13), whereas a,a-disubstituted cyclo-
hexylcarboxaldehyde sulfinyl imine proved to be compar-
able to 2 for this reaction.
H
NHBoc
N
N
NHBoc
8
O
H
Ph
N
S
t-Bu
N
N
H
NHBoc
NHBoc
9
O
S
Ph
H
t-Bu
N
31
66:34
H
NHPiv
NHPiv
10
a Combined isolated yield of diastereomeric mixture.
b Ratio determined by 400 MHz 1H NMR analysis of the unpurified
reaction mixture.
The feasibility of utilizing ketimines in this reaction
sequence was also examined (Table 3). The sulfinyl imine

H. A. Rajapakse et al. / Tetrahedron Letters 46(2005) 8909–8912
8911
derivative of acetophenone proved to be a poor sub-
strate, but we were pleasantly surprised to find that
the tert-butylsulfinyl imine of propiophenone gave
adduct 15 with high selectivity albeit in modest yield.
The ketimine derivative of 3-methyl-2-butanone did
not afford 16 under these conditions. Enolization is the
primary non-productive reaction pathway of ketimines,
as has been previously documented in the literature.11
This was confirmed by quenching ketimine reactions
with MeOH-d4, and observing significant deuteration
of the ketimine component by LC/MS analysis of the
unpurified reaction mixture.12
Back face
addition
Me2N
NMe2
Cl
Li
N
O
H
N
S
O
12
Ot-Bu
t-Bu
Li
Me2N
NMe2
Figure 3. Rationalization of stereochemical outcome.
N
Ph
Ph
i,ii
N
3
X-ray quality single crystals of enantiomerically pure 12
could not be obtained from any of the crystallization
conditions tested. However, rac-12 proved to be more
amenable to crystallization, and the relative stereochem-
istry was determined by single crystal X-ray analysis of
this racemic material.13 These results, shown as a per-
spective drawing of rac-12 in Figure 2, establish the rel-
ative configuration of the two chiral centers to be either
S, R or R, S for S1 and C19, respectively.
H
NHBoc
17
N
Ph
Ph
iii-v
N
• HCl
N
H
O
(+)-SM-15811• HCl
Scheme 1. Reagents and conditions: (i) HCl, Et2O, 95%; (ii)
NaBH(OAc)3, N-benzylpiperidin-4-one, 81%; (iii) TFA, CH2Cl2,
92%; (iv) CDI, CH2Cl2, 83%; (v) HCl, CH2Cl2, 100%.
The relative stereochemical outcome for the addition of
ortho metalated nucleophiles is opposite to that generally
documented in the literature.6 We speculate that due to
the bidentate chelating nature of the nucleophile or the
presence of TMEDA, a Zimmerman–Traxler-like transi-
tion state with ÔinternalÕ activation of the sulfinyl imine
is not feasible. The reversal of facial selectivity could
result from external activation of the sulfinyl imine, pre-
sumably from the lithium counterion that is not
strongly associated with the nucleophile. Addition
occurs at the less hindered back face of the electrophile
through an acyclic transition state (Fig. 3).14
of the chiral auxiliary was effected in high yield with
2 equiv HCl in the presence of the acid labile Boc protec-
tive group. The resulting hydrochloride salt underwent a
reductive amination with N-benzyl-4-piperidinone under
standard conditions to afford 17.
Acid mediated Boc deprotection and isolation of the free
base using SCX ion exchange chromatography16 gave
the requisite diamine, which underwent cyclization in
the presence of carbonyl diimidazole to complete the
synthesis of SM-15811, which was characterized as its
hydrochloride salt.17,18 This asymmetric synthesis was
completed in five steps from commercially available
materials.
We chose the Na+/Ca2+ ion exchanger inhibitor SM-
15811 as a target to illustrate the utility of this method-
ology towards the synthesis of a biologically active 3,4-
dihydroquinazolinone (Scheme 1).3 Adduct 3 was used
as the starting building block.15 Selective deprotection
In conclusion, the addition of ortho metalated substrates
to tert-butane sulfinyl imines provides a useful interme-
diate for the enantioselective synthesis of 3,4-dihydro-
quinazolinones. The modular approach presented by
this work facilitates the synthesis of diverse members
of this class of molecules from readily available materi-
als utilizing a short reaction sequence.
Acknowledgments
We thank Philippe G. Nantermet and James C. Barrow
for helpful discussions, and Joan Murphy for mass spec-
tral data.
Supplementary data
1H NMR spectral data and high resolution mass spec-
tral data for all compounds, 13C NMR and specific rota-
tion data for major products that were isolated as single
Figure 2. X-ray structure of rac-12.

8912
H. A. Rajapakse et al. / Tetrahedron Letters 46(2005) 8909–8912
brine, dried over Na2SO4, filtered, and concentrated. The
residue was typically purified using normal phase silica gel
chromatography.
diastereomers. Supplementary data associated with this
article can be found, in the online version, at
doi:10.1016/j.tetlet.2005.10.067.
10. The presence of an electron withdrawing group on the
nucleophile gives higher isolated yields under our condi-
tions. We speculate that charge delocalization due to an
electron withdrawing group results in diminished aggre-
gation or enhanced nucleophilicity.
11. The addition of organolithium and Grignard reagents to
ketimines generally do not proceed in high yield, and
imine 16 is a particularly poor substrate for nuclephilic
addition. Lewis acid activated addition of organolithium
reagents provide optimal results. See: Cogan, D. A.; Liu,
G.; Ellman, J. A. Tetrahedron 1999, 55, 8883.
References and notes
1. Tucker, T. J.; Lyle, T. A.; Wiscount, C. M.; Britcher, S. F.;
Young, S. D.; Sanders, W. M.; Lumma, W. C.; Goldman,
M. E.; OÕBrien, J. A.; Ball, R. G.; Homnick, C. F.; Schleif,
W. A.; Emini, E. A.; Huff, J. R.; Anderson, P. S. J. Med.
Chem. 1994, 37, 2437.
2. Magnus, N. A.; Confalone, P. N.; Storace, L.; Patel, M.;
Wood, C. C.; Davis, W. P.; Parsons, R. L., Jr. J. Org.
Chem. 2003, 68, 754.
12. Comparing the differences in reactivity between imine
substrates 14 and 15 illustrates the fine balance between
nucleophile addition and enolization for ketimines under
our conditions.
3. Hasegawa, H.; Muraoka, M.; Matsui, K.; Kojima, A.
Bioorg. Med. Chem. Lett. 2003, 13, 3471.
4. Jiang, B.; Si, Y.-G. Angew. Chem., Int. Ed. 2004, 43, 216.
5. Davis, F. A.; Reddy, R. E.; Szewczyk, J. M.; Reddy, G.
V.; Portonovo, P. S.; Zhang, H.; Fanelli, D.; Reddy, R. T.;
Zhou, P.; Carroll, P. J. J. Org. Chem. 1997, 62, 2555.
6. Cogan, D. A.; Liu, G.; Kim, K.; Backes, B. J.; Ellman, J.
A. J. Am. Chem. Soc. 1998, 120, 8011.
13. Crystallographic data (excluding structure factors) for the
structures in this letter have been deposited with the
Cambridge Crystallographic Data Center as supplemen-
tary publication number CCDC 283338. Copies of this
data may be obtained free of charge, on application to
CCDC, 12 Union Road, Cambridge, CB2 1EZ, UK [fax:
+44(0)-1223-336033 or e-mail: deposit@ccdc.cam.ac.uk].
14. This transition state model is in accord with that proposed
by Davis to explain the reversal of stereochemistry
observed in the Lewis acid mediated addition of BnMgCl
to glyoxylate sulfinyl imines. See: Davis, F. A.; McCoull,
W. J. Org. Chem. 1999, 64, 3396.
15. Diastereomerically pure 3 was utilized for the synthesis of
(+)-SM-15811. The 80:20 mixture of 3 obtained under our
reaction conditions was separated using a chiral stationary
phase. See Supplementary data for additional details.
16. A Varian prepacked straight barrel solid phase extraction
cartridge packed with a benzenesulfonic acid sorbent was
utilized for this step. See Supporting information for
additional details.
7. For a comprehensive review on directed ortho metalation
see: Snieckus, V. Chem. Rev. 1990, 90, 879.
8. TMEDA has been documented to break down alkyl-
lithium aggregates, increasing their basicity. We suspect
this results in enhanced nucleophilicity of the ortho
metalated anion under our conditions. See: Wakefield, B. J.
The Chemistry of Organolithium Compounds; Pergamon:
Oxford, UK, 1974, The addition of TMEDA before or after
the orthometalation step gave identical results.
9. Representative procedure: To a solution of tert-butyl
phenyl carbamate (0.346 g, 1.79 mmol) in 10 mL THF at
À78 °C was added sec-BuLi (3.90 mL of a 0.92 M solu-
tion, 3.58 mmol). TMEDA (0.540 mL, 3.58 mmol) was
added, and the solution was warmed to À10 °C over 2 h.
The reaction was cooled to À78 °C, and 2-methyl-N-
(phenylmethylene)propane-2-sulfinamide (0.250 g, 1.194
mmol) in 2 mL THF was added via cannula (0.5 mL
THF rinse). The reaction was allowed to warm to À20 °C
over 15 h. The reaction was quenched by the addition of
saturated aqueous NH4Cl and diluted with EtOAc. The
layers were separated, the organics were washed with
17. The synthesis and biological activity of racemic SM-15811
has been reported in the literature (Ref. 3), hence we are
unable to establish the identity of the active enantiomer.
18. The absolute stereochemistry for (+)-SM-15811 was
assigned in analogy to the relative stereochemistry
obtained for adduct rac-12 by single crystal X-ray.