Asymmetric synthesis of 4,6-disubstituted 1,2,3,4,5,6-hexahydro-5-hydroxypyrimidin-2-ones as potential HIV-protease-inhibitors

Article abstract of DOI:10.3987/COM-02-S(M)20

The first asymmetric synthesis of potential HIV protease inhibitors of type III and IV is described. Key step of the synthesis is an auxiliary based stereoselective alkylation by means of the RAMP-/SAMP-hydrazone method starting from a readily available key building block. The synthesis is short and highly versatile in the choice of the substitution pattern as well as the absolute configuration of the products.

Full text of DOI:10.3987/COM-02-S(M)20

HETEROCYCLES, Vol. 58, 2002, pp. 293-299, Received, 11th March, 2002
ASYMMETRIC SYNTHESIS OF 4,6-DISUBSTITUTED 1,2,3,4,5,6-HEXAHYDRO-5-
HYDROXYPYRIMIDIN-2-ONES AS POTENTIAL HIV-PROTEASE-INHIBITORS
Dieter Enders* and Lars Wortmann
Institut für Organische Chemie der RWTH Aachen, Professor-Pirlet Straße 1, 52074 Aachen,
Germany; Fax: +49(241)8092127, E-mail: Enders@RWTH-Aachen.de
Abstract - The first asymmetric synthesis of potential HIV protease inhibitors of type III
and IV is described. Key step of the synthesis is an auxiliary based stereoselective alkylation
by means of the RAMP-/SAMP-hydrazone method starting from a readily available key
building block. The synthesis is short and highly versatile in the choice of the substitution
pattern as well as the absolute configuration of the products.
Introduction
An infection with the HI virus (Human Immunodeficiency Virus) is the causal reason for the AIDS
desease.1 The HIV protease belongs to the class of aspartate proteases, which cleaves the gag- and gag-
pol- polyproteins (encoded by the pol- gene of the virus) into structural and functional proteins, which in
turn are required for function of the mature virus.2 Inhibition of the HIV protease results in the production
of non-infectious virions,3 which makes the HIV protease an important drug target for the treatment of
AIDS.2, 4 Due to the fact that the HI virus rapidly develops resistance against new drug molecules there is
an ongoing need for new chemical entities.5
O
R
N
R
N
R1
R1
R2
R1
R1
N
N
2
R2
R2
R
HO
OH
HO
Type I
OH
Acyclic
Inhibitor
Scheme 1
ææææææææ
Dedicated to Professor A. I. Meyers on the occasion of his 70th birthday.

All HIV protease inhibitors of the first generation contained typical peptidomimetic structure elements.
Coworkers of the Merck Dupont company could demonstrate that not only the acyclic molecules depicted
in Scheme 1 were excellent HIV protease inhibitors but also their corresponding cyclic analogues of type
I if all stereogenic centers were inverted at the same time.6
According to the C2-symmetry of the HIV protease active site type I inhibitors retain the same symmetry.
It was shown that the trans diaxial arrangement of both R2 residues was not only the preferred
conformation of the free molecule but also crucial for good enzyme inhibition.
O
O
O
R1
R1
R2
R1
R1
R2
R1
R1
R2
N
N
N
N
N
N
R2
2
R
OH
OH
OH
Type IV
Type II
Type III
Scheme 2
Investigation of the influence of different ring sizes resulted in type III inhibitors with low potency
(Scheme 2). As expected in the six membered ring case the residues R2 cannot be arranged in a trans
diaxial manner and therefore are responsible for the low affinity to the HIV protease. However it was
possible to nearly retain potency by simply introducing an additional methylene group on one of the two
R2 groups (type IV inhibitors). This additional CH2 group functions as a joint to turn R2 into a
pseudoaxial position.
Retrosynthesis: After our efforts to develop a new asymmetric synthesis of an acyclic HIV protease
inhibitor7 we became interested in sythesizing type II-IV inhibitors. It was desired that our synthesis
should be short, efficient, and allow a high versatility in the choice of the substitution pattern as well as
free choice of the absolute configuration. Our retrosynthetic strategy was to utilize one central key
building block to built up inhibitors of type II, III and IV. Based on our results of the double alkylation
of dioxanones leading to C2-symmetrical chiral 1,3-diols8 we wanted to apply this idea in the double
alkylation of corresponding nitrogen containing heterocycles (Scheme 3). Recently we described the first

asymmetric synthesis of type II inhibitors as well as an efficient and practical synthesis of key building
block B.9
O
R1
R1
R2
N
N
O
O
R1
R1
R2
R1
R1
3
R
N
N
N
N
N
3
R
N
OH
O
MeO
Type II or III
A
B
ent-Type II or III
ent-A
Scheme 3
The method of choice for the auxiliary directed double alkylation of central building block B was the
RAMP-/SAMP-hydrazone method.10 This methodology has proven to have an enormous scope to use
even unreactive electrophiles such as organic halides with b-oxygen or a-branching.
LiTMP,
SAMP or
RAMP,
CH2Cl2
O
THF,
-78°C,
R1X
N
N
N
N
N
N
O
OMe
OMe
R1
Ph
Ph
N
N
93%
Ph
Ph
Ph
Ph
N
N
O
3 steps, 40%
O
3a-e
1
2
LiTMP,
THF,
O3,
CH2Cl2,
-78°C
O
N
R2
R1
-78°C,
N
R2X
OMe
R2
R1
Ph
Ph
N
N
39-47 %
(3 steps)
Ph
Ph
N
N
O
de = 80 - > 96%
ee = 76 - > 96%
O
5a-e
4a-e
Scheme 4

Results and Discussion
We started our synthesis from the achiral key building block (1) (Scheme 4), which can be readily
prepared in three steps (40 percent yield) on multigram scale from commodity chemicals.9 Simply stirring
ketone (1) with either hydrazine SAMP or RAMP provides hydrazone (2) in almost quantitative yield.10
The first alkylation is best carried out in THF at –78 °C with LiTMP (lithium tetramethylpiperidide) as
base. The reaction was not allowed to reach ambient temperature but was quenched at –78 °C with
saturated aqueous NH4Cl solution. The diastereomeric excess of the reaction could not be determined on
this step as one obtained a mixture of the (E)- and the (Z)-configured hydrazone (3). The second
alkylation is carried out in the same manner to provide 4. Attemps to alkylate 2 directly with two
equivalents of base and electrophile failed and gave a complex mixture of products. To cleave the
hydrazone auxiliary a number of useful methods are known.11 The method of choice in our case was to
1
ozonize 4 at –78 °C. The diastereomeric excess (de) of 5 has been determined by H-NMR-analysis and
lies in the range of 80 - > 96% (Table 1). The enantiomeric excess (ee) was determined by 1H-NMR-shift
experiments with (-)-Pirkle alcohol.19
Table 1
5
R1
R2
Electrophile Yield over de
ee
3 steps [%] [%] [%]
5a
5b
5c
5d
5e
i-Pr
i-Pr
i-PrI
n-BuI
BnBr
PhEtI
43
39
40
47
34
>96 86
>96 >96
>96 76
>96 86
n-Bu n-Bu
Bn Bn
PhEt PhEt
Bn
PhEt BnBr/PhEtI
80
76
The C2-symmetrical ketones (5a-d) could be transformed into their corresponding alcohols (6a-d) using
standard sodium borohydride reduction13 (Scheme 5). The yields of the reduction are shown in Table 2.
In this manner ,the synthesis of type III HIV protease inhibitors was completed.
OH
O
R
R
NaBH4,
MeOH
R
R
Ph
Ph
N
N
Ph
Ph
N
N
71-91%
O
O
5a-d
6a-d
Scheme 5

Table 2
6
Rest R Yield [%] of
the Reduction
6a
6b
6c
6d
i-Pr
n-Bu
Bn
71
85
82
91
PhEt
The reduction of the unsymmetrical system (5e) (Scheme 6) leads to a new stereogenic center. As the
benzyl and the phenylethyl residue in 5e have similar bulk it was ambitious to find an appropriate
reduction reagent leading to a high diastereoselection.
OH
OH
O
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Table 3
+
Ph
N
N
Ph
N
N
Ph
N
N
O
O
O
5e
7
8
Scheme 6
The reagents which were examined for the diastereoselective reduction of 5e leading to the two
diastereomeric alcohols (7 and 8) are listed in Table 3.
Table 3
Reaction conditions
Diastereomeric
Ratio 7 : 8
1 : 2
LiAlH4, Ether, 0 °C12
NaBH4, MeOH, 0 °C13
1 : 2
(L)-Selectride, THF, -78 °C to rt14
Superhydride, THF, Ether, -78 °C to rt15
Catecholborane, Ether, -78 °C to rt16
BH3-SMe2, THF, Ether, rt17
0 : 100
1 : 8.7
1.5 : 1
1.6 : 1

One can see that the best results were obtained with (L)-Selectride (minor diastereomer could not be
detected by 1H-NMR) in favour of diastereomer (8) (89% yield). The selectivity could be partly reversed
if borane reagents were used, however the diastereomeric ratio (dr 1.6 : 1) was not very high. The relative
stereochemistry could be elaborated by comparison with literature data.18 Thus, the first asymmetric
synthesis of inhibitors of type IV was completed.
Conclusion
With our asymmetric synthesis, we have developed a highly efficient route to HIV-protease inhibitors of
type III and IV starting from one central building block. The synthesis is short and flexible with good to
excellent diastereomeric and enantiomeric excesses.
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