Highly Enantioselective Construction of a Chiral Tertiary Carbon Center by Alkynylation of a Cyclic N-Acyl Ketimine: An Efficient Preparation of HIV Therapeutics

Article abstract of DOI:10.1002/anie.200352301

Second-generation nonnucleoside reverse transcriptase inhibitors can now be efficiently prepared. Alkynylation of the ketimine (see scheme; PMB=p-methoxybenzyl) leads to the synthesis of tertiary amines in excellent yield and with high enantioselectivity. The ligand used in the reaction is a derivative of chloramphenicol base.

Full text of DOI:10.1002/anie.200352301

Communications
Enantioselective Synthesis
the enantiomeric excess is consistently around 92% to 94%,
requires the use of 3–5 equivalents of organometallic acety-
lide and low temperatures (À608C to À758C). In addition, the
strongly basic conditions lead to decomposition of the
product. Therefore, it is highly desirable to search for a
practical asymmetric synthesis of this new class of dihydro-
quinazolinones which can then be scaled up to satisfy clinical
demands.
The method involving a chiral additive appears to be the
most advantageous because it avoids the step involving
auxiliary attachment and removal and holds the potential
for direct recovery and reuse of the unchanged chiral reagent.
We have been developing a practical enantioselective prep-
Highly Enantioselective Construction of a Chiral
Tertiary Carbon Center by Alkynylation of a
Cyclic N-Acyl Ketimine: An Efficient Preparation
of HIV Therapeutics**
Biao Jiang* and Yu-Gui Si
Recently great efforts have been made on developing
methodology for generating secondary carbinols as well as
secondary propargyl alcohol and propargyl amine by enan-
tioselective alkynylation of aldehydes and aldimines.[1] How-
ever, the asymmetric synthesis of tertiary carbinols and
carbinamines by addition of carbon nucleophiles to ketones
and ketimines has experienced considerable frustration.
Human immunodeficiency virus (HIV) is prone to mutation,
which in turn leads to drug resistance. Dihydroquinazolines
DPC 961 and DPC 083 are second-generation HIV non-
nucleoside reverse transcriptase inhibitors (NNRTIs) with
enhanced potency when compared to Efavirenz (Sustiva).[2]
DPC 961 is currently undergoing clinical evaluation owing to
its activity against wild-type HIV-1 and its increased potency
toward the K103N-containing HIV as well as other NNRTI-
resistant mutant viruses.[3]
À
aration of chiral alchohols with C C bond formation by
À
alkynylation of a carbonyl group and activation of the C H
bond in terminal alkynes by a combination of zinc salt,
tertiary amine, and a readily available chiral amino alcohol as
the ligand.[7] We were interested in studying the enantiose-
lective alkynylation of the cyclic N-acyl ketimine 1 (see
Scheme 1) using a chiral amino alcohol as ligand by activation
À
of the C H bond in terminal alkynes.
To examine the possibility of alkynylation of ketimine 1
with a terminal acetylene, the reaction was carried out in the
presence of zinc salts and triethylamine without a chiral
amino alcohol as ligand. Treatment of 1 with one equivalent
of cyclopropyl acetylene (2a), Zn(OTf)2, and triethylamine
gave the racemic adduct 3a in 95% yield at room
temperature after 10 h (Scheme 1). The use of ZnCl2
instead of Zn(OTf)2 could not promote the reaction.
This result stimulated us to investigate the asymmetric
alkynylation of the ketimine using a chiral ligand.
We examined the alkynylation of the ketimine with
derivatives of ephedrine as ligands since N-methyl
ephedrine (4a)[8] and (1S, 2S)-5a[7b] have been success-
fully used in the asymmetric alkynylation of aldehydes
The challenge for synthesizing this class of
NNRTIs is to form a tertiary carbinamine in an
asymmetric manner. The syntheses of these
compounds include diastereoselective 1,4-addi-
tion of a magnesium acetylide to 2(3H)-quina-
zolinone containing a chiral auxiliary substitu-
ent[4] or 1,2-enantioselective addition of a
lithium acetylide to a cyclic N-acyl ketimines
using lithium cinochona alkaloids[5] or lithium
4b-morpholinocaran-3a-ol as a chiral modera-
Scheme 1. The alkynylation of ketimine 1 with cyclopropylacetylene. OTf=trifluorome-
tor.[6] The asymmetric addition step, for which thanesulfonate.
[*] Prof. Dr. B. Jiang, Y.-G. Si
with a terminal acetylene. However, the derivatives of
ephedrine ligands 4a and 4b (Bn = benzyl) gave very poor
enantioselectivity and low yields in the alkynylation reaction,
even when 1.1 equivalents of ligand and zinc triflate were
used (Table 1, entries 1 and 2). In consideration of cost and
availability, we decided to improve the enantioselectivity by
using derivatives of chloramphenicol base. Both enantiomers
of chloramphenicol bases are easily obtained from commer-
cial chloramphenicol synthesis. In the subsequent investiga-
tions, a series of derivatives (5a–5d, 6; TMDMS = tert-
Shanghai Institute of Organic Chemistry
Chinese Academy of Sciences
354 Fenglin Road, Shanghai 200032 (P.R. China)
Fax: (+86)21-6416-6128
E-mail: jiangb@mail.sioc.ac.cn
[**] This work was financially supported by the Science & Technology
Commission of Shanghai Municipality and the National Natural
Science Foundation of China.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
216
ꢀ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
DOI: 10.1002/anie.200352301
Angew. Chem. Int. Ed. 2004, 43, 216 –218

Angewandte
Chemie
ities (up to 99.5% ee) and high yields (Table 2).
When the reaction was run on a 100-gram scale,
3a was obtained in 96% yield and with
99.1% ee (Table 2, entry 1). Simple recrystalli-
zation from heptane afforded 3a in 95% yield
with over 99% ee. The chiral amino alcohol
ligand 6 could be recovered unchanged (90%
recovery) by basification of the acid aqueous
extracts. The recovered ligand was of suitable
purity to be recycled directly (entry 2). Acety-
lenes containing bulky substituents
gave the adducts with up to
Table 1: Effect of the chiral ligand on the selectivity of the alkynylation of ketimine 1 with cyclo-
propylacetylene (see Scheme 1).[a]
99.5% ee (entries 6–8).
In conclusion,
a
novel and
Entry
Ligand (equiv)
Zn(OTf)2
[equiv]
NEt3
[equiv]
T [8C]
t [h]
Yield of
ee
Config. of
highly enantioselective alkynyla-
tion of cyclic ketimine has been
developed for the synthesis of ter-
tiary amines in excellent yield and
with high enantioselectivity. This
approach has provided an efficient
method for the synthesis of the
important second-generation non-
nucleoside reverse transcriptase
inhibitors. The advantages of the
enantioselective reaction include
the following: 1) only 1.1 equiva-
lents of acetylene is required; 2) the
3a[%][b]
3a[%][c]
3a[d]
1
2
3
4
5
6
7
8
9
4a (1.1)
4b (1.1)
1.1
1.1
1.1
1.1
1.1
1.1
1.1
1.1
1.1
2.5
2.5
2.5
2.5
2.5
2.5
1.5
2.5
2.5
25
25
25
25
25
25
60
25
25
14
10
10
10
10
10
10
6
34
24
95
93
91
90
64
95
95
44.1
23.5
99.1
98.0
99.3
42.1
99.0
99.3
99.2
(À)-S
(+)-R
(+)-R
(+)-R
(+)-R
(À)-S
(+)-R
(+)-R
(À)-S
(S,S)-5a (1.1)
(S,S)-5b (1.1)
(S,S)-5c (1.1)
(S,S)-5d (1.1)
(S,S)-5c (1.1)
(S,S)-5c (1.1)
(R,R)-6 (1.1)
6
[a] All reactions were performed on 0.5-mmol scale. [b] Yield of isolated product. [c] Determined by
HPLC on a chiral stationary phase, Chiralcel OD, iPrOH/hexane 10/90, 0.7 mLminÀ1, 254 nm. [d] The
absolute configuration is based on comparison with the literature.[4a,9]
butyldimethylsilyl, Tr= triphenylmethyl) were evaluated as
ligands in an effort to obtain more efficient enantioselective
alkynylation.
Table 2: Effect of the terminal alkynes on the selectivity in the
alkynylation of ketimine 1.[a]
The substituents on the 2-nitrogen and 3-oxygen atoms
greatly affected the enantioselectivity of the reaction. The
derivatives of chloramphenicol base with an amino group
bearing two methyl groups and a C3-oxygen atom attached to
a tertiary carbon atom gave excellent enantioselectivities and
yields (Table 1, entries 3–5). When one of the amino sub-
stituents was changed to benzyl, the enantioselectivity was
severely decreased (entry 6). The inexpensive yet effective
chiral ligand 5c and its enantiomer (1R, 2R)-6 gave excellent
enantioselectivities in the alkynylation reactions (entries 8
and 9). Thus treatment of the cyclic N-acyl ketimine 1 with
1.1 equivalents of cyclopropylacetylene, 1.1 equivalents of
Zn(OTf)2, 1.1 equivalents of (1R, 2R)-6, and 2.5 equivalents
of Et3N in toluene at room temperature for 6 h provided
adduct 3a (isolated in 95% yield with 99.2% ee). Reducing
the amount of Et3N to 1.5 equiv caused a decrease in the
chemical yield (entry 7). Removal of the p-methoxybenzyl
(PMB) group in (À)-3a[9] with ceric ammonium nitrate gave
(À)-(S)-DPC 961 with a specific rotation of [a]2D0 = À63 (c =
0.275, MeOH), which is identical to the reported value.[4a]
Therefore, the stereochemistry of the adduct (À)-3a obtained
using (1R, 2R)-6 as the ligand was assigned the S config-
uration.
Entry 2 (R=)
T [8C] t [h] Product 3
ee of
(yield [%])[b]
3 [%][c]
1
2
3
4
5
6
7
8
2a (cyclopropyl)
25
25
25
25
30
25
25
25
6
3a (96)
99.1[d]
2a (cyclopropyl)
2b 2-phenylethyl)
2c (phenyl)
2d (tert-butyl)
2e (n-butyl)
2 f (trimethylsilyl)
2g (cyclopentyl-
methyl)
10 3a (95)
12 3b (73)
8
99.1[e]
98.2
98.2
98.5
3c (88)
15 3d (63)
6
8
6
3e (92)
3 f (87)
3g (86)
>99.5
>99.5
>99.5
[a] All reactions were performed on 0.5-mmol scale, unless otherwise
stated. [b] Yield of isolated product. [c] Determined by HPLC on a chiral
stationary phase, Chiralcel OD or AD. [d] The reaction was performed on
a 100-gram scale. [e] The chiral ligand was recycled for three runs.
reaction is carried out under standard conditions, avoiding
low temperatures and harmful reagents for generating
organometallic acetylide; and 3) the chiral ligand based on a
derivative of chloramphenicol is easily prepared from a
pharmaceutical commodity source, and can be recovered and
In a brief exploration of the scope of this novel
asymmetric reaction, other acetylenes were studied by using
(1R, 2R)-6 as the ligand. All of the phenyl-, alkyl-, and silyl-
substituted terminal alkynes gave excellent enantioselectiv-
Angew. Chem. Int. Ed. 2004, 43, 216 –218
www.angewandte.org
ꢀ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
217

Communications
[8] a) D. E. Frantz, R. Fässler, E. M. Carreira, J. Am. Chem. Soc.
2000, 122, 1806 – 1807; b) N. E. Anand, E. M. Carreira, J. Am.
Chem. Soc. 2001, 123, 9687 – 9688.
reused without decreasing enantioselectivity and chemical
yield.
[9] The specific rotation of 3a {[a]2D5 = À31.6 (c = 0.6, MeOH)}
reported in reference [4a] was not corrected. The reaction with
(1R, 2R)-6 as ligand gave (À)-(S)-3a with a specific rotation
[a]2D0 = À74.1 (c = 0.6, MeOH), while using (1S, 2S)-5c gave (+)-
(R)-3a with a specific rotation [a]2D0 = + 74.3 (c = 0.6, MeOH).
Experimental Section
In a typical experiment, cyclopropyl acetylene (2a; 73 mg, 1.1 mmol)
was added under an argon atmosphere over 2 h at 258C to a solution
of Zn(OTf)2 (396 mg, 1.1 mmol), (1R, 2R)-6 (326 mg, 1.1 mmol), and
triethylamine (252 mg, 2.5 mmol) in dried toluene (1 mL). Then
ketimine 1 (369 mg, 1 mmol) was added. After 6 h the mixture was
cooled to 08C, and 6n HCl (10 mL) was added. The mixture was
extracted with EtOAc (3 ” 5 mL; Ac = acetyl). The combined organic
layer was washed with 6n HCl (3 ” 5 mL), saturated Na2CO3 aqueous,
and brine and then dried with Na2SO4. After removal of solvent under
vacuum, the residue was purified by flash chromatography on silica
gel (hexane/EtOAc 6/1) to afford 3a (412 mg, 95% yield, 99.3% ee).
[a]2D0 = À74.1 (c = 0.6 in methanol); 1H NMR (300 MHz, [D6]DMSO):
d = 9.00 (s, 1H), 7.46 (brs, 1H), 7.41 (dd, J = 2.8 and 8.9 Hz, 1H), 7.13
(d, J = 8.2 Hz, 2H), 6.96 (d, J = 8.7 Hz, 1H), 6.87 (d, J = 8.6 Hz, 2H),
5.12 (d, J = 16.4 Hz, 1H), 4.93 (d, J = 16.5 Hz, 1H), 3.69 (s, 3H), 1.52
(m, 1H), 0.93–0.87 (m, 2H), 0.77–0.72 ppm (m, 2H); 19F NMR
(282 MHz, [D6]DMSO): d = À81.3 ppm (s, 3F); 13C NMR (75 MHz,
[D6]DMSO): d = 158.3, 151.2, 136.6, 130.8, 128.4, 127.6, 127.5, 125.8,
123.8 (q, J = 289 Hz), 117.1, 116.5, 114.0, 91.8, 68.0, 57.7 (q, J = 32 Hz),
54.9, 43.9, 8.3, 8.2, À1.2 ppm; MS (EI) m/e = 434 (M+, 6.6), 365(13.8),
121(100); HR-EI-MS calcd for C22H18ClF3N2O2: 434.1009, found:
434.0967.
Received: July 4, 2003 [Z52301]
Keywords: alkynes · amino alcohols · drug design · ketimines ·
.
zinc
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Angew. Chem. Int. Ed. 2004, 43, 216 –218