Enantioselective Synthesis of Nelfinavir via Asymmetric Bromocyclization of Bisallylic Amide

Article abstract of DOI:10.1021/acs.joc.8b00039

We describe a concise enantioselective synthesis of the HIV-protease inhibitor nelfinavir (1) via a new route in which the key step is construction of the central optically active 1,2-amino alcohol framework via asymmetric bromocyclization of bisallylic amide with N-bromosuccinimide in the presence of a catalytic amount of (S)-BINAP or (S)-BINAP monoxide. The remaining alkene and bromo functionalities were used to install the requisite thioether and chiral perhydroisoquinoline units, respectively.

Full text of DOI:10.1021/acs.joc.8b00039

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Note
Enantioselective Synthesis of Nelfinavir via
Asymmetric Bromocyclization of Bisallylic Amide
Yoshihiro Nagao, Tatsunari Hisanaga, Takahiro Utsumi,
Hiromichi Egami, Yuji Kawato, and Yoshitaka Hamashima
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b00039 • Publication Date (Web): 26 Feb 2018
Downloaded from http://pubs.acs.org on February 26, 2018
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The Journal of Organic Chemistry
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Enantioselective Synthesis of Nelfinavir via Asymmetric Bro-
mocyclization of Bisallylic Amide
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Yoshihiro Nagao, Tatsunari Hisanaga, Takahiro Utsumi, Hiromichi Egami, Yuji Kawato, and Yoshitaka
Hamashima*
School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka 422-8526, Japan
Supporting Information Placeholder
ABSTRACT: We describe a concise enantioselective synthesis of the HIVꢀprotease inhibitor nelfinavir (1) via a new route, in
which the key step is construction of the central optically active 1,2ꢀamino alcohol framework via asymmetric bromocyclization of
bisallylic amide with Nꢀbromosuccinimide in the presence of a catalytic amount of (S)ꢀBINAP or (S)ꢀBINAP monoxide. The reꢀ
maining alkene and bromo functionalities were used to install the requisite thioether and chiral perhydroisoquinoline units, respecꢀ
tively.
Infection with human immunodeficiency virus (HIV) is the
cause of acquired immune deficiency syndrome (AIDS),1 and
AIDS patients are at risk of opportunistic infections, cancer,
and dysfunction of various organ systems, if not appropriately
treated. Many antiretroviral drugs have been developed, tarꢀ
geting various stages of the HIV life cycle. At present, nucleoꢀ
side/nonꢀnucleoside reverseꢀtranscriptase inhibitors, HIVꢀ
protease inhibitors, integrase strandꢀtransfer inhibitors, and Cꢀ
C chemokine receptor type 5 (CCR5) inhibitors are in clinical
use for the treatment of HIV infection. Current guidelines recꢀ
ommend the use of combination antiretroviral therapies, and
these enable HIVꢀinfected patients to live essentially normal
lives. However, there are nearly 36.7 million patients in the
world, and their number is still increasing. In 2016, 1 million
people died from AIDSꢀrelated diseases, while about 1.8 milꢀ
lion people were newly infected. Thus, HIV/AIDS is still a
very important issue, and there is a continuing need to reduce
the cost of synthesizing antiꢀHIV agents, especially for the
treatment of patients in less developed countries, where this is
a particular concern.
radiation therapy are underway. In this context, a variety of
synthetic approaches to 1 have been investigated,5,6 including
syntheses through optical resolution, chiral pool methodology,
and asymmetric catalysis. These earlier approaches mainly
focused on the synthesis of the optically active central fourꢀ
carbon framework 2, in which each carbon is connected to
heteroatom functionalities.7 Among them, Inaba and coꢀ
workers have developed a highly efficient synthesis of 1, in
which chiral titanium catalyst was utilized for asymmetric
aminolysis of mesoꢀepoxides with racemic amine.6b,7a
Figure 1. Structure of nelfinavir.
Nelfinavir (1; Figure 1), the active ingredient in Viracept, is
one of the most widely prescribed HIVꢀprotease inhibitors
owing to its efficacy, safety, and favorable pharmacokinetics.2
In addition, recent studies have revealed that 1 inhibits the
growth of a wide variety of tumor cells and triggers apoptoꢀ
sis.3–4 These findings have stimulated research on 1 as a potenꢀ
tial antiꢀcancer agent, and several clinical trials of 1 in combiꢀ
nation with other wellꢀestablished chemotherapeutic agents or
Catalytic asymmetric haloꢀfunctionalization of alkenes has atꢀ
tracted great interest over the last decade.8 The enantioenriched
heterocyclic products are of great utility as key intermediates in
syntheses of natural products and medicinal agents. In our continꢀ
uing research program on asymmetric halogenation reactions,9 we
have recently developed a desymmetrization of bisallylic amides
3 by enantioselective bromocyclization with BINAP monoxide as
a catalyst (Scheme 1).10 In this bromocyclization reaction, the
catalytic bromophosphonium (P+Br) species was first generated
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by the reaction of the catalyst with Nꢀbromosuccinimide (NBS).
This P+Br substructure is considered to function as a Lewis acid,
which interacts with the pendant amide nucleophile to define its
position, thus affording enantiomerically enriched oxazolines 4
with vicinal chiral carbon stereocenters. Since hydroxyethylamine
substructures are well known as bioisosteres of amide bonds in
the development of inhibitors against aspartyl protease such as
HIV protease and γꢀsecretase, the compound 4 would be a useful
platform in synthesizing this class of peptidemimetics and other
bioactive compounds. Considering the cisꢀorientation of the oxaꢀ
zoline ring and facile derivatization to the advanced intermediate
5 with suitable functional groups for further manipulation, we
anticipated that the oxazoline 4 would be an appropriate intermeꢀ
diate for an efficient synthesis of 1. As a suitable demonstration of
the utility of our asymmetric bromocyclization, we embarked on
the synthesis of 1 according to the retrosynthesis in Scheme 1.
Herein, we report a concise enantioselective synthesis of 1 using
our catalytic asymmetric bromocyclization of bisallylic amides as
a key step.
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Scheme 1. Retrosynthesis of 1.
Table 1. Optimization of desymmetrization of bisallylic amides.a
X
conc.
(M)
yieldb
(%)
eed
(%)
entry
(S)ꢀcat.
3
Ar
4
cis/transc
(mol%)
1
2
BINAP monoxide
BINAP monoxide
BINAP monoxide
BINAP monoxide
BINAP
10
10
10
10
10
5
3a 3ꢀMeOꢀ2ꢀMeC6H3
3b Ph
4a
4b
4c
0.05
0.05
0.05
0.05
0.05
0.05
0.1
79e
91e
87e
88e
89
82:18
93:7
93:7
94:6
93:7
93:7
93:7
93:7
93:7
93:7
37
92
93
95
94
91
92
95
94
91
3
3c
4ꢀBrC6H4
4
3d 4ꢀMeOC6H4
3d 4ꢀMeOC6H4
3d 4ꢀMeOC6H4
3d 4ꢀMeOC6H4
3d 4ꢀMeOC6H4
3d 4ꢀMeOC6H4
3d 4ꢀMeOC6H4
4d
4d
4d
4d
4d
4d
4d
5
92
6
BINAP
99
7
BINAP
5
95
8
BINAP
5
0.2
9
BINAP
5
0.5
91
10
BINAP
3
0.5
91
aCH2Cl2: fixed at 2.0 mL, 3: varied from 0.10 mmol to 1.0 mmol as appropriate. bNMR yield of the cisꢀproduct. cDetermined by 1H NMR
d
e
spectroscopic analysis of the crude mixture. Enantiomeric excess (ee) of cisꢀ4 was determined by HPLC analysis. Isolated yield of the
cisꢀproduct.
Initially, we set out to identify suitable reaction conditions
for the key asymmetric bromocyclization of 3. Considering the
chemical structure of the benzamide unit, the use of 3ꢀ
methoxyꢀ2ꢀmethylbenzamide 3a would streamline the syntheꢀ
sis of 1 by eliminating an additional amidation process. Unforꢀ
tunately, however, the reaction with 10 mol% of (S)ꢀBINAP
monoxide (P/P=O cat.) in CH2Cl2 gave the oxazoline product
4a with unsatisfactory enantioselectivity (Table 1, entry 1).11
Therefore, we needed to install the requisite amide moiety at a
later stage. Among the other bisallylic amides screened (enꢀ
tries 2–4), 4ꢀmethoxybenzamide 3d afforded 4d with the highꢀ
est enantioselectivity (95% ee) (entry 4). Commercially availꢀ
able simple BINAP (P/P cat.) serves as a catalyst precursor to
afford 4d in comparable yield and stereoselectivity, which
would be advantageous for practical application (entry 5). The
enantioselectivity of 4d was slightly reduced when the catalyst
amount was decreased to 5 mol% (entry 6). Interestingly,
however, this reaction exhibited improved enantioselectivity at
higher concentration. Thus, 4d was obtained with comparable
stereoselectivity (94% ee, 93:7 diastereomeric ratio) in tenfold
0.5 M CH2Cl2 solution (entry 9). At this higher concentration,
high yield and acceptable stereoselectivity were achieved even
with 3 mol% of the BINAP catalyst (entry 10). However, the
reaction mixture tended to coagulate during the reaction proꢀ
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cess when the reaction was carried out at 0.3–0.5 M, probably
duced by oxidation of the tertiary amine structure. Therefore,
the reaction was carried out in the presence of a slight excess
of acid additive to protect the amine.15 The ozonolysis proꢀ
ceeded cleanly, and reductive workꢀup with sodium borohyꢀ
dride directly delivered alcohol 9 in 58% yield. The stage was
set for the incorporation of the thiolate group. As shown in
Scheme 4, a straightforward, threeꢀstep approach to nelfinavir
(1) from 9 was unsuccessful, being accompanied by formation
of the regioisomer 1’, the amine and sulfur functionalities of
which were transposed from their original positions. This unꢀ
desired production of 1’ could be explained by assuming the
following reaction process. During the course of mesylation of
9, the transient mesylate 10 might undergo an intramolecular
SN2 reaction with the tertiary amine to form quaternary ammoꢀ
nium salt 11. Ringꢀopening of the pyrrolidinium intermediate
11 with PhSH seemed poorly regioselective, and thus the subꢀ
sequent methanolysis of the two ester groups afforded 1 in
only 31% yield along with 1’ in 41% yield. Inaba and coꢀ
workers observed a similar transposition reaction in the conꢀ
version of the oxazoline 14 to 1, which was considered to ocꢀ
cur through the formation of the corresponding quaternary
ammonium salt (Scheme 5).6b After extensive investigations,
they found that the formation of the positional isomer 1’ could
be minimized by using the combination of KHCO3 as a base
and methyl isobutyl ketone (MIBK) as a solvent. Since all of
our attempts at the ring opening of 11 under various reaction
conditions were unsuccessful, we planned to lead 9 to Inaba’s
precursor 14. To our delight, upon treatment with NaH in
DMF at 50 ºC, 11 was transformed smoothly to the more staꢀ
ble oxazoline 12. The transformation from 9 proceeded in one
pot. After removal of DMF under reduced pressure, treatment
with MeOH under basic conditions afforded the desired interꢀ
mediate 14 in 81% yield over three steps. This methanolysis
first gave the benzoylꢀprotected intermediary 13. We also atꢀ
tempted oxazoline opening of the isolated 13 with thiolate ion
under various conditions, but the reaction did not proceed well.
Finally, 14 was reacted with PhSH under Inaba’s conditions,6b
furnishing nelfinavir (1) in 78% yield.
1
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7
8
due to the poor solubility of the oxazoline product. Considerꢀ
ing that homogeneous reaction is generally desirable from the
viewpoint of reproducibility, we selected the conditions shown
in entry 8 for a gramꢀscale reaction. Thus, the asymmetric
bromocyclization with 10.0 g of bisallylic amide 3d proceeded
without difficulty, affording 4d in 92% yield with 95% ee (dr
= 93:7) (Scheme 2). After aqueous workꢀup, the catalyst was
fully oxidized to BINAP dioxide (P=O/P=O cat.), which was
readily isolated in 90% yield during the purification of 4d.
This recovered dioxide was subsequently reduced to BINAP in
92% yield according to the reported procedure,12 allowing for
efficient recycling of the costly BINAP catalyst.
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Scheme 2. Gram-scale reaction of 3d.
Synthesis of 1 from the oxazoline product 4d is illustrated in
Scheme 3. Compound 4d was treated with Lꢀphenylalanineꢀ
derived chiral amine 6 in DMF to give enantiomerically pure 7
in 75% yield.13 The oxazoline ring was efficiently hydrolyzed
by treatment with 1 N HCl to give the corresponding benzoate
intermediate, and the resulting primary amino group was couꢀ
pled with 3ꢀacetoxyꢀ2ꢀmethylbenzoyl chloride to afford amide
8 as the sole product.14 In contrast, when 4c was subjected to
hydrolysis, the pꢀbromobenzoyl group migrated partially to the
resulting primary amine during the purification, affording a
mixture of the corresponding ester and amide. Ozonolysis of
the terminal alkene of 8 under typical conditions gave a comꢀ
plex mixture, probably due to undesired decomposition inꢀ
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Scheme 3. Synthesis of nelfinavir 1.
1
(TOF(+)) were measured on Bruker Deltonics micrOTOF. Optical
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rotation was measured using a 1 mL cell with a 1.0 dm path length on
a JASCO polarimeter Pꢀ2200. HPLC analysis was conducted on a
Shimadzu HPLC system with chiralꢀstationaryꢀphase columns (ϕ 0.46
cm × 25 cm). Compounds 4b, 4c, 4d, 14, and 1 are known compounds
(CAS registry numbers 2149042ꢀ27ꢀ1, 2149042ꢀ29ꢀ3, 2149042ꢀ31ꢀ7,
188936ꢀ07ꢀ4 and 159989ꢀ64ꢀ7, respectively).
(4S,5S)-5-(Bromomethyl)-2-(3-methoxy-2-methylphenyl)-4-vinyl-
4,5-dihydrooxazole (4a). 4a was synthesized according to the proceꢀ
dure reported in Ref 10. IR (CHCl3) ν 1647, 1584, 1464, 1261 cm−1;
1H NMR (CDCl3) δ 7.39 (dd, J = 8.0, 1.2 Hz, 1H), 7.19 (t, J = 8.0 Hz,
1H), 6.95 (d, J = 8.0 Hz, 1H), 6.00–5.91 (m, 1H), 5.47 (d, J = 17.2 Hz,
1H), 5.36 (dd, J = 10.4, 1.1 Hz, 1H), 4.98–4.92 (m, 2H), 3.84 (s, 3H),
3.50–3.45 (m, 2H), 2.46 (s, 3H); 13C NMR (CDCl3) δ 164.2, 158.0,
132.5, 128.0, 127.9, 126.1, 122.0, 119.4, 112.6, 81.0, 70.7, 55.8, 30.3,
13.2; HRMS (ESI) calcd. for C14H17BrNO2 m/z 310.0437 [M+H]+,
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Scheme 4. Unsuccessful attempt at the introduction of
PhSH.
22
found 310.0451; [α]D −9.2 (c 1.2 CHCl3, 37% ee); CHIRALPAK
ADꢀH (φ 0.46 cm x 25 cm), 2ꢀpropanol/nꢀhexane = 5/95, flow rate 1.0
mL/min, column temp. 40 ºC, detection at 254 nm, tR = 6.4 min (maꢀ
jor), 9.5 min (minor).
(4S,5S)-5-(Bromomethyl)-2-phenyl-4-vinyl-4,5-dihydrooxazole
(4b). 4b was synthesized according to the procedure reported in Ref
10. Colorless oil; IR (CHCl3): ν 1653, 1608, 1583, 1435, 1298 cm–1;
1H NMR (CDCl3): δ 8.02ꢀ7.98 (m, 2H), 7.50 (t, J = 7.5 Hz, 1H), 7.44ꢀ
7.41 (m, 2H), 5.93 (ddd, J = 17.2, 10.3, 6.9 Hz, 1H), 5.46 (d, J = 17.2
Hz, 1H), 5.36 (d, J = 10.3 Hz, 1H), 5.00 (dt, J = 9.8, 6.9 Hz, 1H), 4.91
(dd, J = 9.8, 6.9 Hz, 1H), 3.49 (d, J = 6.9 Hz, 2H); 13C NMR (CDCl3):
δ 163.5, 132.5, 131.7, 128.4, 128.4, 127.1, 119.7, 81.6, 70.4, 30.3;
CHIRALPAK ADꢀH (ϕ 0.46 cm x 25 cm), 2ꢀpropanol/nꢀhexane =
5/95, flow rate 0.8 mL/min, column temp. 40 ºC, detection at 254 nm,
tR = 6.1 min (major), 7.1 min (minor). These spectral data for 4b were
consistent with those reported in Ref 10.
Scheme 5. An epoxide intermediary through a transient
cyclic quaternary ammonium salt to 1’.
In summary, we have developed a concise synthetic route to
the HIVꢀprotease inhibitor nelfinavir. Asymmetric bromocyꢀ
clization of bisallylic amide with a catalytic amount of BINAP
was performed on a 10ꢀgram scale without difficulty, and the
requisite chiral 1,2ꢀamino alcohol framework was obtained
efficiently. Further application of our bromocyclization to
asymmetric synthesis of other bioactive compounds is underꢀ
way in our laboratory.
(4S,5S)-5-(Bromomethyl)-2-(4-bromophenyl)-4-vinyl-4,5-
dihydrooxazole (4c). 4c was synthesized according to the procedure
reported in Ref 10. Colorless oil; IR (CHCl3): ν 1724, 1651, 1593,
1485, 1265 cm–1; 1H NMR (CDCl3): δ 7.86 (d, J = 8.5 Hz, 2H), 7.57
(d, J = 8.5 Hz, 2H), 5.91 (ddd, J = 17.0, 10.5, 7.5 Hz, 1H), 5.45 (d, J =
17.0 Hz, 1H), 5.36 (d, J = 10.5 Hz, 1H), 4.99 (dt, J = 9.5, 6.5 Hz, 1H),
4.91 (dd, J = 9.5, 7.5 Hz, 1H), 3.48 (d, J = 6.5 Hz, 2H); 13C NMR
(CDCl3): δ 162.7, 132.2, 131.7 129.9, 126.5, 126.1, 119.8, 81.9, 70.5,
30.1; CHIRALPAK ADꢀH (ϕ 0.46 cm x 25 cm), 2ꢀpropanol/nꢀhexane
= 5/95, flow rate 1.0 mL/min, column temp. 40 ºC, detection at 254
nm, tR = 7.4 min (major), 11.0 min (minor). These spectral data for 4c
were consistent with those reported in Ref 10.
(4S,5S)-5-(Bromomethyl)-2-(4-methoxyphenyl)-4-vinyl-4,5-
dihydrooxazole (4d, large-scale) To a 500 mL flask equipped with a
magnetic stirring bar and a threeꢀway glass stopcock were added (S)ꢀ
BINAP (1.43 g, 2.30 mmol), 3d (10.0 g, 46.0 mmol) and dry CH2Cl2
(230 mL). The flask was immersed in a cooling bath at −78 °C. To the
solution was added NBS (9.83 g, 55.2 mmol), and the mixture was
stirred at −78 °C for 24 h at the same temperature. The reaction was
quenched by the addition of saturated Na2S2O3 aq. in one portion. The
mixture was allowed to warm gradually to room temperature. The
separated aqueous layer was extracted with CH2Cl2 three times and
the combined organic layers were washed with brine, and dried over
Na2SO4. The filtrate was concentrated under reduced pressure and a
small aliquot of the resulting residue was submitted to 1H NMR analyꢀ
sis to determine the diastereomeric ratio (93:7). The crude product
was purified by flash column chromatography (nꢀhexane/EtOAc =
3/1–1/1) to give 4d (12.6 g, 92%) as a yellowish amorphous solid and
BINAP dioxide (1.36 g, 90%). as a colorless solid. 4d is a known
compound (Ref 10). Colorless oil; IR (CHCl3): ν 1649, 1637, 1610,
1512, 1257 cm–1; 1H NMR (CDCl3): δ 7.92 (d, J = 9.2 Hz, 2H), 6.91
(d, J = 9.2 Hz, 2H), 5.90 (ddd, J = 17.2, 10.3, 6.9 Hz, 1H), 5.43 (d, J =
17.2 Hz, 1H), 5.33 (d, J = 10.3 Hz, 1H), 4.96 (dt, J = 9.8, 6.3 Hz, 1H),
4.86 (dd, J = 9.8, 6.9 Hz, 1H), 3.84 (s, 3H), 3.47 (d, J = 6.3 Hz, 2H);
13C NMR (CDCl3): δ 163.3, 162.4, 132.7, 130.2, 119.5, 119.5 113.7,
81.5, 70.3, 55.4, 30.4; HRMS (ESI) Anal. calcd. for C13H15BrNO2 m/z
EXPERIMENTAL SECTION
General Experimental Methods. Unless otherwise noted, materials
were purchased from commercial suppliers and were used without
purification. THF, toluene and CH2Cl2 were purified by passing
through a solvent purification system (Glass Contour). (S)ꢀBINAP
was purchased from Kanto Chemical Co. Ltd and used as received.
NBS was purified by recrystallization from water according to a genꢀ
eral method. Bisallylic amides were recrystallized from nꢀhexane and
CH2Cl2. Airꢀ and moistureꢀsensitive liquids were transferred via a
gastight syringe and a stainless steel needle. All workup and purificaꢀ
tion procedures were carried out with reagentꢀgrade solvents under
ambient air. Flash column chromatography was performed with silica
gel 60 N (spherical, neutral, 40–50 ꢁm) purchased from Kanto Chemꢀ
ical Co. Ltd.
Infrared (IR) spectra were recorded on a S.T. Japan Inc. DuraSamplIR
Ⅱinfrared spectrophotometer. NMR spectra were recorded on JEOL
ECA500 NMR spectrometers. Proton chemical shifts are reported as δ
in units of parts per million downfield from tetramethylsilane and are
referenced to residual protium in the NMR solvent (CDCl3: δ 7.26
ppm, DMSOꢀd6: δ 2.50 ppm). For 13C NMR, chemical shifts are reꢀ
ported in the scale relative to the NMR solvent (CDCl3: 77.0 ppm,
DMSOꢀd6: 39.5 ppm) as an internal reference. NMR data are reported
as follows: chemical shifts, multiplicity (s: singlet, d: doublet, dd:
doublet of doublets, t: triplet, q: quartet, m: multiplet, br: broad signal),
coupling constant (Hz), and integration. Highꢀresolution mass spectra
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26
296.0286 [M+H]+, found 296.0287; [α]D –16.1 (c 1.1, CHCl3, 95%
ee); CHIRALPAK ADꢀH (ϕ 0.46 cm x 25 cm), 2ꢀpropanol/nꢀhexane =
5/95, flow rate 1.0 mL/min, column temp. 40 ºC, detection at 254 nm,
tR = 11.4 min (major), 17.1 min (minor). These spectral data for 4d
were consistent with those reported in Ref 10.
fied by flash column chromatography (nꢀhexane/EtOAc = 2/1–1/2) to
give 9 (581 mg, 58%) as a colorless solid: Mp: 205–208 ºC (decomp.);
IR (ATR) ν 3380, 1759, 1709, 1643, 1605, 1549, 1250 cm−1; 1H NMR
(CDCl3) δ 8.02 (d, J = 9.0 Hz, 2H), 7.52 (d, J = 9.5 Hz, 1H), 7.44 (d, J
= 7.5 Hz, 1H), 7.23 (t, J = 7.5 Hz, 1H), 7.05 (d, J = 7.5 Hz, 1H), 6.91
(d, J = 9.0 Hz, 2H), 5.54 (brs, 1H), 5.42–5.38 (m, 1H), 4.89–4.77 (m,
1H), 3.88–3.83 (m, 2H), 3.85 (s, 3H), 3.16 (d, J = 10.5 Hz, 1H), 2.80
(dd, J = 12.5, 10.0 Hz, 1H), 2.52–2.49 (m, 1H), 2.33–2.27 (m, 2H),
2.32 (s, 3H), 2.29 (s, 3H), 2.05–1.98 (m, 1H), 1.90–1.83 (m, 1H),
1.79–1.66 (m, 3H), 1.57–1.51 (m, 3H), 1.45–1.20 (m, 5H), 1.16 (s,
9H); 13C NMR (CDCl3) δ 172.6, 169.1, 168.9, 165.8, 163.6, 149.7,
138.7, 132.0, 128.5, 126.5, 125.0, 123.4, 122.2, 113.7, 73.0, 70.7, 62.1,
59.8, 55.4, 55.2, 52.5, 51.4, 35.7, 33.9, 30.9, 30.9, 28.5, 26.3, 25.3,
20.8, 20.5, 12.9; HRMS (ESI) calcd. for C36H50N3O8 m/z 652.3592
[M+H]+, found 652.3602; [α]D22 +29.1 (c 0.39, CHCl3).
1
2
3
4
5
6
7
8
(3S,4aS,8aS)-N-(tert-Butyl)-2-(((4S,5R)-2-(4-methoxyphenyl)-4-
vinyl-4,5-dihydrooxazol-5-yl)methyl)decahydroisoquinoline-3-
carboxamide (7) A mixture of 4d (12.6 g, 42.7 mmol), LꢀPheꢀderived
amine 6 (12.2 g, 51.3 mmol) and Na2CO3 (6.8 g, 64.1 mmol) in DMF
(150 mL) was stirred for 30 h at 120 ºC. The reaction mixture was
diluted with water and extracted with EtOAc. The combined organic
layers were dried over Na2SO4. The filtrate was concentrated under
reduced pressure and the resulting crude product was purified by flash
column chromatography (nꢀhexane/EtOAc = 1/1–1/3) to give 7 (14.6
g, 75%) as a colorless solid: Mp: 153ꢀ154 ºC; IR (ATR) ν 1670, 1645,
1611, 1510, 1452, 1256 cm−1; 1H NMR (CDCl3) δ 7.90 (d, J = 9.0 Hz,
2H), 6.92 (d, J = 9.0 Hz, 2H), 6.40 (brs, 1H), 5.70 (ddd, J = 17.5, 10.0,
8.0 Hz, 1H), 5.32 (d, J = 17.5 Hz, 1H), 5.21 (dd, J = 10.0, 2.0 Hz, 1H),
4.79–4.71 (m, 2H), 3.84 (s, 3H), 3.21 (d, J = 11.5, 3.0 Hz, 1H), 2.78
(dd, J = 14.5, 2.0 Hz, 1H), 2.66 (dd, J = 10.5, 3.0 Hz, 1H), 2.38–2.29
(m, 2H), 1.86–1.73 (m, 4H), 1.70–1.67 (m, 1H), 1.61–1.57 (m, 1H),
1.55–1.20 (m, 6H), 1.34 (s, 9H); 13C NMR (CDCl3) δ 173.7, 163.8,
162.2, 134.0, 130.0, 120.0, 118.8, 113.7, 83.5, 71.3, 69.7, 58.7, 57.1,
55.4, 50.3, 35.7, 32.9, 30.7, 30.4, 28.8, 26.2, 26.0, 20.6; HRMS (ESI)
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
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55
56
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58
59
60
(3S,4aS,8aS)-N-(tert-Butyl)-2-((R)-2-hydroxy-2-((S)-2-(3-hydroxy-
2-methylphenyl)-4,5-dihydrooxazol-4-
yl)ethyl)decahydroisoquinoline-3-carboxamide (14) To a solution
of 9 (1.20 g, 1.84 mmol) and Et3N (380 ꢀL, 2.73 mmol) in DMF (8.0
mL) was added dropwise MsCl (160 ꢀL, 2.02 mmol), and the reaction
mixture was stirred for 20 min at room temperature. NaH (60% disꢀ
persion in mineral oil, 184 mg, 4.60 mmol) was added and the resultꢀ
ing mixture was further stirred at 50 ºC for 3 h. After removal of DMF
under reduced pressure, the resultant residue and K2CO3 (254 mg,
14.7 mol) were suspended in MeOH (10.0 mL) in a PYREX® screw
cap culture tube. The reaction vessel was sealed with a PTFEꢀlined
cap and heated at 100 °C in an oil bath for 2 h. Volatiles were reꢀ
moved, water (80 mL) was added, and the resultant precipitate was
collected by filtration. The crude 14 was suspended in ether to remove
the mineral oil derived from NaH and the coꢀproduct, methyl pꢀanisate.
The resultant precipitate was collected by filtration and dried under
reduced pressure to give pure 14 (685 mg, 81%) as a colorless solid:
Mp: 233ꢀ235 ºC (decomp.); IR (ATR) ν 3250, 1643, 1605, 1557, 1362,
1279; 1H NMR (DMSOꢀd6) δ 9.58 (brs, 1H), 7.40 (s, 1H), 7.07 (d, J =
7.5 Hz, 1H), 7.01 (t, J = 7.5 Hz, 1H), 6.88 (d, J = 7.5 Hz, 1H), 4.77
(brs, 1H), 4.47–4.45 (m, 1H), 4.28–4.25 (m, 1H), 4.14–4.12 (m, 1H),
3.75 (brs, 1H), 2.90 (d, J = 11.5 Hz, 1H), 2.57 (d, J = 11.5 Hz, 1H),
2.35 (dd, J = 11.0, 9.5 Hz, 1H), 2.28 (s, 3H), 2.11 (d, J = 11.0 Hz, 1H),
2.05 (d, J = 12.0 Hz, 1H), 1.91–1.81 (m, 2H), 1.73–1.65 (m, 2H),
1.58–1.46 (m, 3H), 1.36–1.14 (m, 5H), 1.24 (s, 9H); 13C NMR
(DMSOꢀd6) δ 172.6, 163.4, 155.6, 129.2, 125.7, 124.3, 120.1, 116.4,
69.5, 69.2, 69.0, 66.8, 64.9, 59.3, 58.5, 49.9, 35.7, 33.1, 30.6, 30.0,
calcd. for C27H40N3O3 m/z 454.3070 [M+H]+, found 454.3078; [α]D
22
−110.8 (c 0.29, CHCl3).
(2R,3S)-3-(3-Acetoxy-2-methylbenzamido)-1-((3S,4aS,8aS)-3-
(tert-butylcarbamoyl)octahydroisoquinolin-2(1H)-yl)pent-4-en-2-
yl 4-methoxybenzoate (8) To a solution of 7 (14.6 g, 32.2 mmol) in
THF (320 mL) was added 1 N HCl aq. solution (150 mL) at room
temperature. The mixture was stirred for 3.5 h at the same temperature,
and then saturated NaHCO3 aq. solution and water were added to
neutralize it. The separated organic layer was dried over Na2SO4. The
filtrate was concentrated under reduced pressure and the residue was
diluted with CH2Cl2 (300 mL), and then 3ꢀacetoxyꢀ2ꢀmethylꢀbenzoyl
chloride (8.2 mL, 48.3 mmol) and Et3N (9.0 mL, 64.7 mmol) were
added at 0 ºC. Stirring was continued for 30 min at room temperature,
then the reaction mixture was quenched with saturated aq. NH4Cl
solution. The separated aqueous layer was extracted with CH2Cl2 and
the organic layer was washed with brine, and dried over Na2SO4. The
filtrate was concentrated under reduced pressure and the residue was
purified by flash column chromatography (nꢀhexane/EtOAc = 3/1–
1/1) to give 8 (17.2 g, 83%) as a pale yellowish solid: Mp: 193–195
22
28.4, 25.9, 25.3, 20.1, 15.2, 13.3; [α]D −58.4 (c 0.49, DMF). These
ºC; IR (ATR) ν 1767, 1709, 1659, 1643, 1605, 1510, 1248 cm−1; H
1
spectral data for 14 were consistent with those reported in Ref 6b.
Nelfinavir (1) Compound 14 (125 mg, 0.27 mmol), PhSH (55 ꢀL,
0.54 mmol) and dried KHCO3 (54 mg, 0.54 mmol) were suspended in
methylisobutylketone (1.2 mL) in a PYREX® screw cap culture tube.
The reaction vessel was sealed with a PTFEꢀlined cap and heated at
140 °C in an oil bath for 5 h. Volatiles were removed, water and
EtOAc were added to the resultant mixture, and the aqueous layer was
extracted with EtOAc. The combined organic layers were dried over
Na2SO4. The filtrate was concentrated under reduced pressure and the
resulting crude product was purified by flash column chromatography
(nꢀhexane/EtOAc = 3/2–1/1) to give 1 (121 mg, 78%) as a white solid:
NMR (CDCl3) δ 7.94 (d, J = 9.0 Hz, 2H), 7.27 (d, J = 7.5 Hz, 1H),
7.18 (dd, J = 8.0, 7.5 Hz, 1H), 7.02 (d, J = 8.0 Hz, 1H), 6.91 (d, J =
9.0 Hz, 2H), 6.67–6.65 (m, 1H), 6.26 (brs, 1H), 6.08 (ddd, J = 17.0,
11.0, 7.0 Hz, 1H), 5.51–5.49 (m, 1H), 5.34 (d, J = 17.0 Hz, 1H), 5.25
(d, J = 11.0 Hz, 1H), 5.06 (dd, J = 7.5, 7.0 Hz, 1H), 3.83 (s, 3H), 2.90
(dd, J = 11.5, 2.5 Hz, 1H), 2.75 (dd, J = 13.0, 6.5 Hz, 1H), 2.57 (dd, J
= 11.0, 3.0 Hz, 1H), 2.38 (dd, J = 13.5, 7.0 Hz, 1H), 2.29 (s, 3H),
2.22–2.18 (m, 1H), 2.21 (s, 3H), 1.84 (q, 13.0 Hz, 1H), 1.70–1.55 (m,
4H), 1.52–1.43 (m, 3H), 1.31–1.21 (m, 2H), 1.27 (s, 9H), 1.11–1.06
(m, 2H); 13C NMR (CDCl3) δ 173.8, 169.1, 168.5, 165.9, 163.6, 149.7,
138.6, 133.5, 131.8, 128.5, 126.6, 124.6, 123.5, 122.2, 118.0, 113.7,
74.5, 70.8, 59.5, 56.7, 55.4, 53.5, 51.0, 35.7, 33.3, 30.8, 30.7, 28.6,
26.1, 25.4, 20.8, 20.5, 12.9; HRMS (ESI) calcd. for C37H50N3O7 m/z
648.3643 [M+H]+, found 648.3659; [α]D22 −59.2 (c 0.64, CHCl3).
(2R,3S)-3-(3-Acetoxy-2-methylbenzamido)-1-((3S,4aS,8aS)-3-
(tert-butylcarbamoyl)octahydroisoquinolin-2(1H)-yl)-4-
hydroxybutan-2-yl 4-methoxybenzoate (9) A solution of 8 (1.0 g,
1.54 mmol) and 4 N HCl (in EtOAc, 540 ꢀL, 2.15 mmol) in CH2Cl2
(15 mL) was cooled to –78 °C. A mixture of O3/O2 was then bubbled
through the solution for 20 min. Stirring was continued for 15 min at
the same temperature, then the solution was purged with Ar, and
NaBH4 (233 mg, 6.16 mmol) in MeOH (10 mL) was added dropwise.
The mixture was stirred for 10 min at –78 ºC and for 3 h at 0 ºC, and
then the reaction was quenched with saturated NaHCO3 aq. solution.
The resulting mixture was diluted with EtOAc, washed with saturated
NaHCO3 aq. and brine, and then dried over Na2SO4. The filtrate was
concentrated under reduced pressure, and the crude product was puriꢀ
1
Mp >300 ºC; IR (ATR) ν 1622, 1527, 1454, 1287; H NMR (DMSOꢀ
d6) δ 9.36 (s, 1H), 7.89 (d, J = 9.2 Hz, 1H), 7.49 (d, J = 7.5 Hz, 2H),
7.48 (s, 1H), 7.27 (t, J = 8.0 Hz, 2H), 7.14 (t, J = 7.5 Hz, 1H), 6.97 (t,
J = 7.5 Hz, 1H), 6.81–6.77 (m, 2H), 4.81 (d, J = 5.2 Hz, 1H), 4.35–
4.30 (m, lH), 3.94–3.91 (m, 1H), 3.56 (dd, J = 13.2, 4.0 Hz, 1H), 3.14
(dd, J = 13.4, 9.7 Hz, 1H), 2.95 (d, J = 9.7 Hz, 1H), 2.53–2.49 (m, 2H),
2.12 (s, 3H), 2.02–1.98 (m, 2H), 1.91 (q, J = 11.5 Hz, 1H), 1.70–1.67
(m, 2H), 1.55–1.50 (m, 2H), 1.49–1.46 (m, 2H), 1.37–1.20 (m, 5H),
1.14 (s, 9H); 13C NMR (DMSOꢀd6) δ 173.0, 169.2, 155.4, 139.4,
136.9, 128.7, 127.7, 125.7, 124.9, 121.5, 117.8, 115.1, 68.9, 68.5, 58.4,
57.9, 50.8, 50.0, 35.6, 33.4, 31.4, 30.6, 30.0, 28.3, 25.9, 25.1, 20.3,
22
12.7; [α]D −141.4 (c 0.38, DMF). These spectral data for 1 were
consistent with those reported in Ref 6b.
ASSOCIATED CONTENT
Supporting Information
5
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The Journal of Organic Chemistry
Page 6 of 6
1H and 13C NMR spectra of synthesized compounds, HPLC chart
for 4a through 4d, and characterization of intermediates en route
to 1. This Supporting Information is available free of charge on
the ACS Publications website.
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AUTHOR INFORMATION
Corresponding Author
*Eꢀmail: hamashima@uꢀshizuokaꢀken.ac.jp
Notes
9
The authors declare no competing financial interest.
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ACKNOWLEDGMENT
This work was supported by JSPS KAKENHI (Grant Number
16H05077 and 16K18848) and partially supported by Basis for
Supporting Innovative Drug Discovering and Life Science Reꢀ
search (BINDS) from AMED.
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6
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