Reengineered BI-DIME Ligand Core Based on Computer Modeling to Increase Selectivity in Asymmetric Suzuki–Miyaura Coupling for the Challenging Axially Chiral HIV Integrase Inhibitor

Article abstract of DOI:10.1002/adsc.201600889

Through a computer-guided approach, new series of monophosphine ligands were designed and developed for asymmetric Suzuki–Miyaura couplings of challenging heterocyclic substrates. Computer modeling pointed to a tunable, yet unexplored quadrant in BI-DIME, leading to the discovery of the 3′,5′-dimethyl-substituted ligand which improved the atropisomeric selectivity of the Suzuki–Miyaura reaction from the previously reported 5:1 dr to 15:1 dr for the synthesis of a challenging HIV integrase intermediate, and up to 24:1 dr with various other quinoline substrates. (Figure presented.).

Full text of DOI:10.1002/adsc.201600889

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DOI: 10.1002/adsc.201600889
Reengineered BI-DIME Ligand Core Based on Computer
Modeling to Increase Selectivity in Asymmetric Suzuki–Miyaura
Coupling for the Challenging Axially Chiral HIV Integrase
Inhibitor
Nizar Haddad,a,* Hari P. R. Mangunuru,a Keith R. Fandrick,a Bo Qu,a
Joshua D. Sieber,a Sonia Rodriguez,a Jean-Nicolas Desrosiers,a
Nitinchandra D. Patel,a Heewon Lee,a Dmitry Kurouski,a Nelu Grinberg,a
Nathan K. Yee,a Jinhua J. Song,a and Chris H. Senanayakea
a
Chemical Development, Boehringer Ingelheim Pharmaceuticals, Inc., 900 Ridgebury Road/P.O. Box 368, Ridgefield,
Connecticut 06877-0368, USA
Fax : (+1)-203-791-6130; e-mail: nizar.haddad@boehringer-ingelheim.com
Received: August 11, 2016; Published online: && &&, 0000
Supporting information for this article can be found under: http://dx.doi.org/10.1002/adsc.201600889.
Abstract: Through a computer-guided approach,
new series of monophosphine ligands were designed
and developed for asymmetric Suzuki–Miyaura cou-
plings of challenging heterocyclic substrates. Com-
puter modeling pointed to a tunable, yet unex-
plored quadrant in BI-DIME, leading to the discov-
ery of the 3’,5’-dimethyl-substituted ligand which
improved the atropisomeric selectivity of the
Suzuki–Miyaura reaction from the previously re-
ported 5:1 dr to 15:1 dr for the synthesis of a chal-
lenging HIV integrase intermediate, and up to 24:1
dr with various other quinoline substrates.
ments.[3] Recently, we have disclosed a convergent 12-
step process for the synthesis of this challenging mole-
cule with an asymmetric Suzuki–Miyaura cross-cou-
pling as the key step for constructing the bi-heteroaryl
core (Scheme 1).[4] After extensive screening, the
chiral BI-DIME monophosphine ligand 6 which was
discovered in our laboratories,[5] provided a 5:1 diaste-
reomeric ratio for coupling of aryl chloride 2 and bor-
onic acid 3. However, in order to develop a more eco-
Keywords: asymmetric Suzuki reaction; atropisom-
ers; BI-DIME; heterocycles; phosphine ligands;
Suzuki coupling
Axially chiral biaryl compounds continue to attract
the attention of the chemistry community due to their
widespread applications in the synthesis of natural
products[1] as well as chiral ligands such as BINAP,
BINOL and MOP for asymmetric catalysis
(Figure 1).[2]
Biaryl axial chirality has also been increasingly em-
ployed in the design of new therapeutic agents. Com-
pound 1, which contains a unique atropisomeric bi-
heteroaryl element, emerged from our discovery pro-
gram as a potent HIV integrase inhibitor, targeting
the protein-protein interaction of the integrase dimer
Figure 1. Natural products and biologically active com-
in order to overcome drug resistance in HIV treat- pounds containing axially chiral biaryl structures.
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tion were apparent on the ligand platform. A guided
approach was required to enable the targeted devel-
opment of a superior ligand which would enable
a truly ideal synthesis of the drug candidate.
Based on the recently proposed model for BI-
DIME-mediated asymmetric Suzuki–Miyaura cou-
plings, we believe that the following two factors were
crucial for achieving stereoselectivities: (i) Pd···O in-
teraction with one of the methoxy groups in BI-
DIME[5c] and (ii) intramolecular hydrogen bonding
between the quinoline nitrogen of the boronic acid 3
and the hydroxy ester functionality in chloroquinoline
2, as depicted in Figure 2. From this hypothesis, com-
putational modeling was performed using a constrain-
ed LowModMD[7] conformer search in Moe2015.09.
A low energy conformer of the resting state Pd-com-
Scheme 1. Diastereoselective Suzuki–Miyaura coupling cata-
lyzed by BI-DIME/Pd.
nomical and greener synthesis for commercial produc- plex before the reductive elimination step was identi-
tion, the diastereoselectivity of this key step must be fied (Figure 2).
further improved.[6] Further optimization of the ligand
A void was observed at the distal C-3’ and C-5’ po-
was at an impasse as no obvious points of derivatiza- sitions of the aryl ring of the ligand (blue spheres) in
the model. It was postulated that suitable substitution
at these positions of the ligand could render the
ligand a better match for the substrate, which would
in effect destabilize potentially destructive lower se-
lectivity isomers in the reductive elimination transi-
tion state. Based on these insights, a new ligand
design was proposed, aiming at improving the diaste-
reoselectivities by installing appropriate substitutions
at the C-3’ and C-5’ positions of the BI-DIME ligand.
Novel monophosphine ligands 7 and 8 were pre-
pared from the corresponding BI-DIME oxide 9
(Scheme 2).[5a,b] Di-bromination of 9 with NBS in
Figure 2. A proposed model of Pd(II)-BI-DIME-derived
catalyst for the synthesis of 4 at the reductive elimination
step.
Scheme 2. Ligand synthesis.
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MeCN[8] at room temperature provided 10 in 79% tivity compared to the reaction with BI-DIME 6, the
isolated yield. Suzuki–Miyaura coupling[9] of aryl- or incorporation of di-CF3- or di-MeO-substituted aryls
cyclopropylboronic acid with 10, furnished the corre- into BI-DIME led to significant improvements of se-
sponding phosphine oxide precursors 11a–d in 71– lectivities to 8.8:1 and 11:1, respectively (7b, c). Re-
90% yield. Negishi coupling[10] of methylzinc chloride placing the aryl substituent with a cyclopropyl group
with 10 gave phosphine oxide 11e in 75% yield. Re- further improved the selectivity to 13:1 (7d). Gratify-
duction of the phosphine oxides with polymethylhy- ingly, the di-methyl substituted ligand 7e (Me2-
drosiloxane (PMHS)[5,11a] or trichlorosilane[5,11b] afford- BIDIME) resulted in the highest diastereomeric ratio
ed 60–95% yields of optically pure ligands[12] 7a– of 15:1 with 98% conversion and 89% isolated yield
e which proved to be air stable solids at room temper- of compound 4 in optically and diastereomerically
ature. The diastereoselectivity of the Suzuki–Miyaura pure form. This represents a significant reduction in
cross-coupling between quinoline chloride 2 and qui- API cost and improvement in synthetic efficiency
nolineboronic acid 3 was examined under our opti- compared to the earlier results where the desired dia-
mized conditions [1 mol% Pd2(dba)3 (Pd/L 1:1.1) in 3- stereomer 4 was obtained in only 71% isolated yield.
pentanol, Na2CO3, 608C, Scheme 3].
Our previous work on asymmetric Suzuki–Miyaura
As predicted based on the computer modeling, the coupling using BI-DIME ligands has shown that
atropisomeric ratios were considerably affected by in- higher selectivities were obtained using oxaphosp-
troducing substituents that occupy the targeted quad- hole-C-2 alkyl substituted variants.[5c] Ligands substi-
rant.
tuted at the C-2 oxaphosphole ring were prepared
For example, although a 3’,5’-diphenyl substitution through lithiation of intermediate 11a–c using LDA
on BI-DIME 7a resulted in a similar diastereoselec- followed by addition of MeI or isopropyl iodide to
Scheme 3. Ligand studies for the Suzuki–Miyaura cross-coupling between quinoline chloride 2 with quinolineboronic
acid·HCl 3. Reaction conditions: Quin-Cl 2 (1.0 equiv.), boronic acid (1.1 equiv.), Pd2(dba)3 (1 mol%), ligand (2.2 mol%),
Na2CO3 (2 equiv.), 3-pentanol, water, 608C, 16 h; conversion and dr determined by HPLC at 220 nm.
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Scheme 4. Synthesis of ligands 8.
afford 12a–c in 30–67% isolated yield (Sche-
me 4).[1a,5c,13] Reduction of the phosphine oxides with
trichlorosilane (HSiCl3) in the presence of triethyla-
mine provided ligands 8a–c in 58–89% yields.
To our surprise, when ligands 8a–d[14] were tested
under the described conditions, diminished selectivi-
ties were observed (Scheme 3, 8a–8d).
The improved selectivity (5:1 to 15:1 dr), obtained
by introducing methyl substituents in the tunable
quadrant of ligand 7e, is consistent with our proposed
model depicted in Figure 3. The key reductive elimi-
nation process was studied by DFT calculations using
the Gaussian 09[15] program at the DFT level of
theory with B3LYP[16] and the LANL2DZ basis set
with ECP for Pd[17] and D95v for the remaining
atoms.[18] DFT calculations (Figure 3) support the fea-
sibility of the proposed stereochemical model.[17] Min-
imization of A(1,3) strain with the appended hydroxy
Figure 3. DFT calculations, calculated transition state for
the intramolecular hydrogen bond directed reductive elimi-
nation: B3LYP/LANL2DZ.
stereocenter with the methyl group positions the hy- amining the Suzuki–Miyaura couplings between vari-
droxy group to guide the boronic acid quinoline frag- ous structural analogs of quinolineboronic acid 3 and
ment during the reductive elimination via an intramo- chloroquinoline 2 using ligand 7e. In the absence of
lecular hydrogen bond to provide the (R)-configura- the hydroxy group in the chloroquinoline, low selec-
tion of the atropisomer. Furthermore, the key methyl tivity was obtained from the coupling reaction
substitution at the C-3’ position of the ligandꢁs aryl (Scheme 6, 16). Similarly, low diastereomeric ratios
ring is positioned to orient the southern quinoline were observed in substrates lacking the possibility for
fragment, derived from 2, reinforcing the configura- hydrogen bonding due to either methylation of the
tion which generates the desired axial diastereoselec- hydroxy group in the chloroquinoline or the absence
tivity.
of the heteroatom in the boronic acid (3:1 dr for 17
The proposed Pd···O coordination to the C-2’-me- and 9:1 dr for 18). On the other hand, excellent dia-
thoxy substituent of the ligands 6–8 and its impact on stereoselectivity was observed with 8-quinolineboron-
atropisomeric selectivity was further probed using ic acid (19:1 dr for 19). As expected, the use of a me-
substrates in which the methoxy group was replaced thoxy-substituted quinolineboronic acid that contains
with methyl or hydrogen (Scheme 5). The diminished a more basic quinoline nitrogen resulted in further
selectivity with ligands 13 (2:1) and 15 (1.5:1) com- improvement of the atropisomeric ratio (24:1 dr for
pared to ligand 6 (5:1) clearly illustrated the impor- 20).
tance of the methoxy group of the ligand on the atro-
pisomeric outcome of the Suzuki–Miyaura coupling.
In summary, through a computer-guided approach,
new series of monophosphine ligands 7a–e and 8a–
The validity of the proposed hydrogen bonding be- c were designed and developed for asymmetric
tween the coupling substrates was confirmed by ex- Suzuki–Miyaura couplings of challenging heterocyclic
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substrates. Computer modeling pointed to a tunable,
yet unexplored quadrant in BI-DIME, leading to the
discovery of 3’,5’-dimethyl-substituted ligand 7e which
improved the atropisomeric selectivity of Suzuki–
Miyaura reaction from the previously reported 5:1 dr
to 15:1 dr for the synthesis of challenging HIV Inte-
grase intermediate 4, and up to 24:1 dr with various
other quinoline substrates. Most importantly, the sig-
nificant enhancement in diastereoselectivity of the
key Suzuki–Miyaura step has enabled a truly ideal
synthesis of the drug candidate and led to major cost
reductions on commercial scale.
Experimental Section
Typical Procedure for the Suzuki–Miyaura Couplings
Chloroquinoline 2 (200 mg, 0.75 mmol, 1 equiv.), boronic
acid·HCl (230 mg, 0.83 mmol, 1.1 equiv.), Pd2dba3 (7.0 mg,
0.008 mmol), monophosphine ligand (0.018 mmol), sodium
carbonate (160 mg, 1.51 mmol), degassed 3-pentanol
(1.6 mL), and degassed water (0.8 mL) were added to a 10-
mL sealed vial. The mixture was de-gassed by sparging with
argon for 10–15 min and then the reaction mixture was
heated to 60–638C, agitated at this temperature for 16–20 h
then sampled for HPLC analysis. The reaction mixture was
cooled to 18–238C. Water (2 mL) and EtOAc (10 mL) were
added, the organic phase was separated, washed with water,
dried over MgSO4, and then purified on silica column to
provide the products in isolated yields as indicated in
Scheme 3 and Scheme 5.
Scheme 5. The effect of the methoxy group in the ligand on
the atropisomeric ratio (dr) of 4 and 5. Reaction conditions:
halide (1.0 equiv.), boronic acid (1.2 equiv.), Pd2(dba)3
(1 mol%), ligand (2.2 mol%), Na2CO3 (2 equiv.), 3-pentanol,
water, 608C, 16 h; conversion and dr determined by HPLC
at 220 nm.
Scheme 6. Ligand studies for the Suzuki–Miyaura cross-coupling between quinoline chlorides with quinolineboronic acids.
Reaction conditions: halide (1.0 equiv.), boronic acid (1.2 equiv.), Pd2(dba)3 (1 mol%), Me2-BIDIME (7e) (2.2 mol%),
Na2CO3 (2 equiv.), 3-pentanol, water, 608C, 16 h; unless otherwise noted, yields are isolated yields; conversion and dr/er de-
termined by HPLC at 220 nm.
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COMMUNICATIONS
Reengineered BI-DIME Ligand Core Based on Computer
Modeling to Increase Selectivity in Asymmetric Suzuki–
Miyaura Coupling for the Challenging Axially Chiral HIV
Integrase Inhibitor
7
Adv. Synth. Catal. 2016, 358, 1 – 7
Nizar Haddad,* Hari P. R. Mangunuru, Keith R. Fandrick,
Bo Qu, Joshua D. Sieber, Sonia Rodriguez,
Jean-Nicolas Desrosiers, Nitinchandra D. Patel,
Heewon Lee, Dmitry Kurouski, Nelu Grinberg,
Nathan K. Yee, Jinhua J. Song, Chris H. Senanayake
Adv. Synth. Catal. 0000, 000, 0 – 0
7
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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These are not the final page numbers!