Concise and Practical Asymmetric Synthesis of a Challenging Atropisomeric HIV Integrase Inhibitor

Article abstract of DOI:10.1002/anie.201501575

Abstract A practical and efficient synthesis of a complex chiral atropisomeric HIV integrase inhibitor has been accomplished. The combination of a copper-catalyzed acylation along with the implementation of the BI-DIME ligands for a ligand-controlled Suzuki cross-coupling and an unprecedented bis(trifluoromethane)sulfonamide-catalyzed tert-butylation renders the synthesis of this complex molecule robust, safe, and economical. Furthermore, the overall synthesis was conducted in an asymmetric and diastereoselective fashion with respect to the imbedded atropisomer. Atropselective: An efficient asymmetric synthesis of an atropisomeric HIV inhibitor has been accomplished. The combination of a copper-catalyzed acylation with the implementation of BI-DIME ligands for a ligand-controlled Suzuki cross-coupling and an unprecedented bis(trifluoromethane)sulfonamide-catalyzed tert-butylation renders the synthesis of this complex molecule robust, safe, and economical.

Full text of DOI:10.1002/anie.201501575

Angewandte
Chemie
International Edition: DOI: 10.1002/anie.201501575
German Edition: DOI: 10.1002/ange.201501575
Asymmetric Synthesis
Concise and Practical Asymmetric Synthesis of a Challenging
Atropisomeric HIV Integrase Inhibitor
Keith R. Fandrick,* Wenjie Li, Yongda Zhang, Wenjun Tang, Joe Gao, Sonia Rodriguez,
Nitinchandra D. Patel, Diana C. Reeves, Jiang-Ping Wu, Sanjit Sanyal, Nina Gonnella, Bo Qu,
Nizar Haddad, Jon C. Lorenz, Kanwar Sidhu, June Wang, Shengli Ma, Nelu Grinberg,
Heewon Lee, Youla Tsantrizos, Marc-Andrꢀ Poupart, Carl A. Busacca, Nathan K. Yee,
Bruce Z. Lu, and Chris H. Senanayake
Abstract: A practical and efficient synthesis of a complex
chiral atropisomeric HIV integrase inhibitor has been accom-
plished. The combination of a copper-catalyzed acylation
along with the implementation of the BI-DIME ligands for
a ligand-controlled Suzuki cross-coupling and an unprece-
dented bis(trifluoromethane)sulfonamide-catalyzed tert-buty-
lation renders the synthesis of this complex molecule robust,
safe, and economical. Furthermore, the overall synthesis was
conducted in an asymmetric and diastereoselective fashion
with respect to the imbedded atropisomer.
based allosteric integrase inhibitors are being investigated to
target the LEDGF/p75 binding site.[8,9] Compound 1[7,10] is in
development as a quinoline-based allosteric integrase inhib-
itor. To support the advancement of this molecule in
development, a robust and practical synthesis was required.
The search for increased drug safety and specificity[11] has
translated for the most part into increased complexity for
drug candidates. Chirality not only imparts additional com-
plexity, but enantiomers generally differ in their biological
activity, including toxicity.[12] An emerging element of chir-
ality in drug discovery is atropisomerism,[13] whereby a hin-
drance of rotation about a specific axis can generate a new
element of chirality. In contrast to traditional stereogenic
centers, the axially chiral unit can readily interconvert
depending on the degree of steric impair-
ment. If the axially chiral element is
thermally stable, the drug candidate
would then necessitate the synthesis of
a single atropisomer, and this was the
case for the integrase inhibitor
1 (Figure 1). Owing to the similar com-
plexities of the top quinoline boronate 2
and the lower chiral hydroxy ester quin- Figure 1. HIV inte-
T
he acquired immunodeficiency syndrome (AIDS) and the
human immunodeficiency virus (HIV) are considered a sig-
nificant global problem. The advent of multidrug cocktails of
different drug classes (highly active antiretroviral therapy)
has transformed this disease into what is now considered
a treatable chronic infection.[1] Aside from these advances,
drug resistance and in particular multidrug resistance are
emerging as threats to this therapeutic advancement.[2]
Therefore, the advent of new therapeutic approaches is
required to keep this disease under control. In the search for
new targets for HIV treatment, the integrase enzyme, which
catalyzes the insertion of viral DNA into the host genome, is
particularly attractive.[3,4] Merckꢀs raltegravir[5] was the first
FDA-approved integrase inhibitor (2007). However, resist-
ance mutations have reduced the effectiveness of raltegravir
against HIV.[6] An alternate approach is to target the protein–
protein interactions of the integrase dimer to stabilize the
protein–protein interactions and promote the formation of
inactive integrase multimers.[7] In this context, quinoline-
grase inhibitor 1.
oline 3, the most convergent approach
would entail a late-stage Suzuki cou-
pling[14] between these two fragments
(Scheme 1).[10] Studies determined that the desired atropiso-
mer is the thermodynamically less stable diastereomer,[15] and
thus the development of an asymmetric and diastereoselec-
tive synthesis was required.
[*] Dr. K. R. Fandrick, Dr. W. Li, Dr. Y. Zhang, Dr. W. Tang, J. Gao,
Dr. S. Rodriguez, N. D. Patel, Dr. D. C. Reeves, Dr. J.-P. Wu, S. Sanyal,
Dr. N. Gonnella, Dr. B. Qu, Dr. N. Haddad, Dr. J. C. Lorenz, K. Sidhu,
J. Wang, Dr. S. Ma, Dr. N. Grinberg, Dr. H. Lee, Dr. C. A. Busacca,
Dr. N. K. Yee, Dr. B. Z. Lu, Dr. C. H. Senanayake
Chemical Development
Boehringer-Ingelheim Pharmaceuticals Inc.
900 Ridgebury Road, P.O. Box 368, Ridgefield, CT 06877-0368 (USA)
E-mail: keith.fandrick@boehringer-ingelheim.com
Dr. Y. Tsantrizos, Dr. M.-A. Poupart
Research and Development
Boehringer Ingelheim (Canada) Ltd.
2100 Cunard Street, Laval, Quꢀbec H7S 2G5 (Canada)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201501575.
Scheme 1. Retrosynthetic strategy.
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Table 1: Acylation studies of iodo-quinoline 14.[a]
Entry Reagent
Additive
(equiv)
T [8C]
Yield
Yield
4[b]
15[b]
1
2
3
4
5
6
7
iPrMgCl
iPrMgCl
iPrMgCl·LiCl
iPrMgCl
iPrMgCl
iPrMgCl
iPrMgCl
–
–
–
À208C to RT 48%
À788C to RT 50%
À208C to RT 53%
À788C to RT 28%
À208C to RT 29%
40%
50%
47%
72%
71%
n.d.
[Fe(acac)2] (0.1)
16 (1.2)
ZnCl2 (1.1)
À208C to RT
0%
CuBr·SMe2 (1.1), À208C to RT 79%
n.d.
LiBr (2)
À208C to RT 75%[c]
n.d.
n.d.
Figure 2. Synthesis of quinoline boronic acid 2 and chloro/iodo-
substituted quinoline 13.
8
9
iPrMgCl
iPrMgCl
CuBr (1.1),
LiBr (2)
CuBr (0.05)
À208C to RT 78%
[a] Reactions conducted in THF (5–8 mL of THF/gram of 13) with methyl
chlorooxoacetate (1.2 equiv). [b] Determined by HPLC analysis. [c] Yield
of isolated product after crystallization: 68%. acac=acetylacetonate.
The synthesis of the northern quinoline segment was
initiated by the acylation of aniline 6 with unsaturated
anhydride 7 (Figure 2). The subsequent intermediate was
cyclized by treatment with concentrated sulfuric acid to form
2-oxo-dihydroquinoline 8. The corresponding ester was
reduced with Red-Al to afford diol 9 in 91% yield. After
chlorination with POCl3 and in situ cyclization (80% yield),
the resulting quinoline chloride was dechlorinated with Zn
(90%). A short solvent survey indicated that the lithiation
required for the borylation could be efficiently conducted at
À408C in toluene.[16] Hydrolysis with aqueous HCl formed the
desired boronic acid 2, which was isolated as the HCl salt in
75–80% yield.
the desired product, the use of copper salts[21] was found to
completely suppress the formation of the deiodinated side
product 15 and provided the desired ketoester 4 in good yield
(75–78%). The effects of the copper salt were found to be
preserved even when only catalytic quantities were used
(5 mol%, 78% yield).
Initial studies at the direct Friedel–Crafts-type acyla-
tion[17] with hydroxyl-quinoline 5 and methyl oxalyl chloride
failed to deliver the desired ketoester. An alternate three-step
procedure was developed to supply the necessary substrate.
Following the iodination with N-iodosuccinimide, the iodo-
substituted hydroxyquinoline 12 was found to precipitate
directly from the iodination reaction mixture in high yield and
purity. The subsequent chlorination with POCl3 provided the
substrate for the metal-promoted acylation.
Attempts employing Knochelꢀs magnesium–iodine
exchange process[18] with either iPrMgCl or iPrMgCl·LiCl to
generate the Grignard reagent of 13 for the acylation with
methyl oxalyl chloride provided the desired ketoester 4 in
approximately 50% yield (Table 1). The remaining material
was found to be deiodinated quinoline 15. Attempts to
modulate the reactivity of the Grignard reagent with catalytic
amounts of [Fe(acac)2][19] or the use of bis[2-(N,N-dimethyl-
amino)ethyl] ether (16) as a ligand[20] did not offer any
improvements. The metalation of the quinoline was shown to
be complete as 95% conversion (83% yield) was observed for
the corresponding aldehyde in a trapping experiment with
DMF. It was postulated that the deiodinated quinoline
product could be due to the concurrent deprotonation of
the acidic methyl moiety of ketoester product 4. The
corresponding acylated side products arising from the trap-
ping of the deprotonated 2-methyl position were also
observed. Although attempts to modulate the reactivity of
the metalated quinoline substrate with zinc failed to deliver
Whereas attempts at the Corey–Bakshi–Shibata (CBS)
reduction[22] of ketoester 4 with the borane/dimethyl sulfide
complex proceeded with 30% ee, the use of catecholborane[23]
increased the enantioselectivity to 94–98% ee. This process
was initially used to provide material for early development,
but owing to the known carcinogenicity of catechol,[24] an
alternate asymmetric reduction was required. A ligand survey
for the Noyori asymmetric transfer hydrogenation[25] revealed
that both para-tolyl-substituted ligand 19 and para-nitro-
substituted 20[26] were superior in terms of both reaction rates
and asymmetric control, providing the desired secondary
alcohol in > 90% ee (Figure 3). The more reactive para-nitro
ligand 20 was able to reach complete conversion at more
economically viable catalyst levels (600 ppm, Rh dimer).
When this system was used at 800 ppm catalyst loading (Rh
dimer), the chiral secondary alcohol 3 was isolated in 87%
yield and 98% ee.
Strategically, the Suzuki–Miyaura cross-coupling was
planned with the tert-butyl ether on the quinoline halide
(quinoline 21). However, all attempts to deliver the desired
atropisomer as the preferred diastereomer failed.[27] It was
found that a preference for the desired atropisomer could be
realized by employing the unsubstituted hydroxy ester 3
(Figure 4). However, an extensive ligand and condition screen
failed to increase the diastereoselectivity to greater than
approximately 2:1 favoring the desired atropisomer. Owing
to the late-stage coupling of two complex fragments and the
low yield of isolated product resulting from this modest
2
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as with the R enantiomer of ligand 46,
complete reversal in atropisomer
a
selectivity was observed, and the race-
mic ligand 43 provided the atropisomers
in equal amounts. Aside from providing
a measurable increase in diastereose-
lectivity, BI-DIME ligand 47 also dis-
played increased reactivity as compared
to the S-Phos ligand. Optimization of
the solvent system increased the diaste-
reoselectivity to 5:1 and enabled
a reduction of the catalyst loading to
1 mol% (Pd; Figure 6). Notably, the
isopropyl substituted BI-DIME ligand
(38, BI-DIME-iPr)[29] provided a similar
selectivity (4.7:1 d.r.) for this challeng-
ing cross-coupling. The crystallization
of the product 24 increased the atropi-
Figure 3. Asymmetric transfer hydrogenation of ketoester 4 and initial attempts at the diastereo-
selective cross-coupling of 21. Cp=cyclopentadienyl, dba=dibenzylideneacetone, DMAc=di-
methyl acetamide.
someric ratio to > 95:5, providing the desired diastereomer in
73% yield.
The installation of the tert-butyl ether functional group on
the bis(quinoline) scaffold of 24 proved to be particularly
challenging. Intermediate 24 not only contains two basic
quinoline nitrogen atoms, but the tert-butyl ether is buried
within a sterically crowded environment with the adjacent top
quinoline ring system. Attempts to install the tert-butyl ether
through acid-promoted processes[30] were shown to be not
robust as the systems proved to be inherently unstable and
would readily revert at ambient temperatures. Jacksonꢀs
method[31] employing tert-butyl trichloroacetimidate 34 was
particularly attractive as the system is neutral and would
therefore be stable and not prone to reversing. Initial
attempts at employing this reagent required large excesses
of the neat reagent 49 to reach high conversions (Table 2). It
was postulated[32] that the counterion (halides and the triflate
anion) could serve a destructive role in the process by
competitively trapping the liberated tert-butyl cation and
catalytically promoting the formation of the isobutylene side
product (Figure 7). In this context, it was found that by
employing a variety of mild Lewis acidic metals (Mg, Cu, Zn)
with the in situ generated hexafluoroantimonate counterion,
the number of equivalents of the tert-butyl reagent 49 could
be reduced to a viable level (5–8) while the reaction was
driven to high conversion (up to 90%). Furthermore, a control
experiment indicated that silver hexafluoroantimonate itself
is competent in the process. Although the catalyst loading
could be reduced to 5 mol% by using the Zn(SbF6)2 system to
supply material for short-term needs, an antimony- and metal-
free process was required owing to safety and regulatory
requirements.
Figure 4. Ligand screen for the Suzuki cross-coupling. The diastereose-
lectivity (d.r.) is given as the ratio of desired 24/undesired 25.
Cy =cyclohexyl.
stereocontrol, a diastereoselectivity of 2:1 was deemed
economically not viable, and a more selective coupling was
required.
Previously, we have shown that the BI-DIME ligands are
effective in the asymmetric Suzuki–Miyaura coupling reac-
tion.[28] In this context, we envisioned that the additional
chiral control element inherent in the BI-DIME ligands could
provide the increase in stereocontrol that was necessary to
render the synthesis efficient. A survey of BI-DIME ligands
indicated that an electron-rich aromatic ring system was
necessary for the coupling (Figure 5). Most of the ligands
surveyed favored the desired atropisomer by employing the
S enantiomer of the respective ligand. Control experiments
confirmed that the diastereoselectivity was ligand-controlled,
To eliminate the antimony-based counterion, a catalyst
formed from the treatment of diethyl zinc with bis(trifluoro-
methane)sulfonamide was tested in the tert-butyl ether
formation reaction with 49, and the reaction was found to
perform well (Table 2). Although diethyl zinc failed to
promote
the
etherification,
bis(trifluoro-
methane)sulfonamide itself was competent even at 5 mol%
catalyst loading. To render the process cost-effective, tert-
butyl trichloroacetimidate (49) was prepared as a 50 wt%
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with nine equivalents of the 50 wt%
reagent solution, and the process
was shown to be robust and stable at
both elevated temperature and with
prolonged aging. The process was
conducted on
a multi-kilogram
scale, providing tert-butyl ether 22
in 95% yield and > 99% d.r. and
99% ee after crystallization. The
synthesis of the integrase inhibitor
was completed by a hydrolysis of
the methyl ester to form carboxylic
acid 1 (93% yield; Figure 8).
The increasing complexity of
compounds in development within
the pharmaceutical industry will
serve as another avenue of innova-
tion. In this context, the complex
atropisomeric integrase inhibitor
required multiple elements of meth-
odological development to derive
a practical synthesis to supply the
necessary material to advance the
project forward in development in
an economical manner. The combi-
nation of the copper-catalyzed acy-
lation along with the implementa-
Figure 5. BI-DIME ligand screen for the Suzuki cross-coupling. The diastereoselectivity (d.r.) is given
as the ratio of desired 24/undesired 25. [a] With 1-pentanol/water as the solvent system instead of
THF.
Table 2: Catalyst survey for the tert-butylation of 24.
Figure 6. Suzuki cross-coupling between quinoline chloride 3 and
boronic acid 2 using BI-DIME ligand 47.
Entry Catalyst (equiv)[a] Solvent 38 [equiv] T [8C] Conv. 22 [%][b]
1
2
3
4
5
6
7
8
–
DCM
DCM
DCM
DCM
DCM
DCE
3
18
125
18
45
20
5
8
8
6.8
5
RT
RT
RT
RT
RT
43
RT
43
43
43
55
55
55
40
0
5
BF3·OEt2 (0.5)
Sc(OTf)3 (0.5)
Cu(OTf)2 (0.5)
Mg(OTf)2 (0.5)
Mg(OTf)2 (0.5)
Mg(SbF6)2 (0.25) DCM
Cu(SbF6)2 (0.1)
AgSbF6 (0.5)
82
12
88
88
75
88
93
87
73
0
Figure 7. Proposed counterion effect for the tert-butylation.
DCE
DCE
PhF
9
10
11
12
13
14
Zn(SbF6)2 (0.05)
Zn(Tf2N)2 (0.05)[c] PhF
ZnEt2 (0.05)
Tf2NH (0.05)
Tf2NH (0.05)
PhF
PhF
PhF
5
5
75
96
9[d]
[a] The corresponding metal SbF6 catalysts were prepared from MCl2 or
MgBr2 by treatment with AgSbF6 (2 equiv) followed by filtration before
use. [b] Reported as the molar conversion. [c] The Zn(Tf2N)2 catalyst was
prepared by treatment of Et2Zn with Tf2NH (2 equiv) in PhF for 15 min
before use. [d] Reagent 38 was prepared as a 50 wt% solution in PhF and
heptane by treating Cl3CCN and tBuOH in PhF (0.89 mL PhF/mL of
Cl3CCN) with NaOtBu (3 mol%). The solution was diluted with heptane
(2.0 mL heptane/mL of Cl3CCN) and filtered before use. DCE=1,2-
dichloroethane, DCM=dichloromethane, Tf=trifluoromethanesulfonyl.
Figure 8. Completion of the synthesis of HIV integrase inhibitor 1.
solution in fluorobenzene/heptane from relatively inexpen-
sive trichloroacetonitrile and tert-butanol and used directly in
the etherification. High conversions could be achieved (96%)
4
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and economical. Furthermore, the overall synthesis was
conducted in an asymmetric and diastereoselective fashion
with respect to the imbedded atropisomer. The overall
synthesis was shortened to twelve steps, of which the longest
linear sequence entailed eight transformations. More impor-
tantly, the overall yield was increased to 27% as compared to
the unpractical 1.8% from the initial discovery approach.[7]
This complex synthesis was conducted on multi-kilogram
scale using newly developed innovative processes without any
complications.
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Keywords: acylation · asymmetric synthesis ·
phosphine ligands · Suzuki couplings · tert-butylation
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[30] The tert-butyl ether could be installed using a large excess of the
super acid trifluoromethanesulfonic acid (TfOH) at low temper-
atures. The temperature control is critical as the system would
readily reverse above 08C, and significant precaution is required
handling large amounts of the highly corrosive TfOH.
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Received: February 17, 2015
Published online: && &&, &&&&
Angew. Chem. Int. Ed. 2015, 54, 1 – 6
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!

.
Angewandte
Communications
Communications
Asymmetric Synthesis
K. R. Fandrick,* W. Li, Y. Zhang, W. Tang,
J. Gao, S. Rodriguez, N. D. Patel,
D. C. Reeves, J.-P. Wu, S. Sanyal,
N. Gonnella, B. Qu, N. Haddad,
J. C. Lorenz, K. Sidhu, J. Wang, S. Ma,
N. Grinberg, H. Lee, Y. Tsantrizos,
M.-A. Poupart, C. A. Busacca, N. K. Yee,
B. Z. Lu,
Atropselective: An efficient asymmetric
synthesis of an atropisomeric HIV inhib-
itor has been accomplished. The combi-
nation of a copper-catalyzed acylation
with the implementation of BI-DIME
ligands for a ligand-controlled Suzuki
cross-coupling and an unprecedented
bis(trifluoromethane)sulfonamide-cata-
lyzed tert-butylation renders the synthesis
of this complex molecule robust, safe,
and economical.
C. H. Senanayake
&&&& — &&&&
Concise and Practical Asymmetric
Synthesis of a Challenging Atropisomeric
HIV Integrase Inhibitor
6
www.angewandte.org
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2015, 54, 1 – 6
These are not the final page numbers!