Synthesis of HIV-Maturation Inhibitor BMS-955176 from Betulin by an Enabling Oxidation Strategy

Article abstract of DOI:10.1021/acs.joc.7b00438

A concise and scalable second generation synthesis of HIV maturation inhibitor BMS-955176 is described. The synthesis is framed by an oxidation strategy highlighted by a Cu^I mediated aerobic oxidation of betulin, a highly selective PIFA mediated dehydrogenation of an oxime, and a subsequent Lossen rearrangement which occurs through a unique reaction mechanism for the installation of the C17 amino functionality. The synthetic route proceeds in 7 steps with 47% overall yield and begins from the abundant and inexpensive natural product betulin.

Full text of DOI:10.1021/acs.joc.7b00438

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Note
Synthesis of HIV-Maturation Inhibitor BMS-955176
from Betulin by an Enabling Oxidation Strategy
Adrian Ortiz, Maxime Soumeillant, Scott A. Savage, Neil A. Strotman, Matthew Haley, Tamas
Benkovics, Jeffrey Nye, Zhongmin Xu, Yichen Tan, Sloan Ayers, Qi Gao, and Susanne Kiau
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b00438 • Publication Date (Web): 13 Apr 2017
Downloaded from http://pubs.acs.org on April 13, 2017
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Synthesis of HIV-Maturation Inhibitor BMS-955176 from
Betulin by an Enabling Oxidation Strategy
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*Adrian Ortiz, Maxime Soumeillant, Scott A. Savage, Neil A. Strotman, Matthew Haley, Tamas
Benkovics, Jeffrey Nye, Zhongmin Xu, Yichen Tan, Sloan Ayers, Qi Gao, and Susanne Kiau
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BristolꢀMyers Squibb, Chemical and Synthetic Development, 1 Squibb Drive, New Brunswick, NJ, 08903.
Abstract
A concise and scalable 2nd generation synthesis of HIV maturation inhibitor BMSꢀ955176 is described.
The synthesis is framed by an oxidation strategy highlighted by a CuI mediated aerobic oxidation of
betulin, a highly selective PIFA mediated dehydrogenation of an oxime, and a subsequent Lossen
rearrangement which occurs through a unique reaction mechanism for the installation of the C17 amino
functionality. The synthetic route proceeds in 7 steps, 47% overall yield, and begins from the abundant
and inexpensive natural product betulin.
.
Figure 1: Key bond disconnections of the synthesis of BMTꢀ955176 (1).
According to the World Health Organization, there are >35 million people infected with the HIV virus
worldwide,1 a staggering number despite significant advancements in treatments option made available as
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a result of over 3 decades of research and development. While many patients respond well to highly
active antiretroviral therapy (HAART), a standard of care therapy that acts to reduce viral load in the
blood, there are a growing number of patients demonstrating resistance to this treatment. In fact, more
than 25% of newly infected patients contract a therapy resistant strain of the HIV virus.2 Therefore, it is
important to continue to identify and evaluate new therapies including more potent antiꢀretrovirals as well
as those possessing new modes of action. BMSꢀ955176 (1, Figure 1) is a second generation HIVꢀ
maturation inhibitor possessing a recently validated novel mode of action2 and currently under Phase IIb
clinical evaluation. The discovery, design, and 1st generation synthesis of 1 were recently disclosed by
researchers at BristolꢀMyers Squibb3 which utilized a semiꢀsynthetic route starting from the natural
product betulinic acid (2). This synthetic route was successfully implemented to produce initial clinical
supplies, however, when considering the requirements of a potential commercial manufacturing route,
this strategy possessed a single fundamental shortcoming, namely, the use of betulinic acid as starting
material. As summarized in Figure 2, the use of 2 enabled the “purchase” of a fully oxidized C28
synthetic handle suitable for nitrogen introduction at the requisite C17 position, along with the ability for
facile chemoselective differentiation between the C3 and C17 functional groups (i.e. 2o ꢀOH vs ꢀCO2H).
However, when compared to a structurally similar relative, betulin (3), 2 came at the expense of a
relatively high cost (10 X greater than 3), and questionable sustainable availability. And while both
molecules are derived from the Birch tree, only 3 is naturally abundant (30ꢀ40 wt% of 3 vs 1 wt% of 2 in
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the dry extract)4,5. Moreover, many commercial sources actually obtain 2 from 3 via synthetic means6aꢀc
.
Although many incremental improvements are conceivable within the 1st generation approach, the major
driving force for a 2nd generation route was to enable the use of 3 instead of 2 as a raw material. To
accomplish this task, a synthetic strategy was required which enabled both the chemoselective
differentiation between the C3 and C17 positions of betulin and the appropriate oxidation strategy to
enable the eventual introduction of the C17 amino group.
Figure 2: Comparison of natural products betulinic acid (2) and betulin (3) as semisynthetic starting
materials for the preparation of 1.
The synthesis of 1 commenced (Scheme 1) with the oxidation of betulin (3) to the corresponding ketoꢀ
aldehyde (4) using a Cu(I) / ABNO / TEMPO catalyzed aerobic oxidation transformation [CH2Cl2 /
CH3CN (10:1), 220 psi of 10% O2 / 90% N2, 40 °C, 2 h, 84% yield] that was inspired by the work of the
Stahl group.7,8 The use of this unusual combination of nitroxyl radical catalyst precursors (2% ABNO /
10% TEMPO) was critical to the success of the reaction ꢀ ABNO enabling the oxidation of the uniquely
hindered hydroxy groups of the betulin core and TEMPO, utilized not as a typical oxidant for hydroxyl
groups, but as a highly effective stabilizing reagent capable of inhibiting undesired oxidation of the
tertiary aldehyde and alkene moieties.9 Traditional stoichiometric oxidations such as CrIV (PCC) and Ru
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(TPAP) based reagents and activated DMSO type oxidations (Moffatt / ParikhꢀDoering) all performed
satisfactorily, but a catalytic oxidation using dioxygen was preferred for process “greenness”
considerations. Next, Ketoꢀaldehdye 4 was subjected to triflation conditions (PhNTf2, NaHMDS, MTBE,
ꢀ10 to 0 °C) generating enol triflate 5 in 84% yield. Triflation of the ketone served to accomplish two
goals: (1) facile preparation of the required electrophile for subsequent Suzuki coupling, and (2) a
strategically necessary and simple chemoselective solution needed to differentiate the C3 and C17
positions of the betulin core. 5 was then united with commercially available (4ꢀ(methoxycarbonyl)phenyl)
boronic acid under standard Suzuki coupling conditions (1.5 mol% XantphosPdCl2, aq. K3PO4, THF, 60
°C, 5 h) to give the corresponding Suzuki product (6a).
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Scheme 1: Preparation of Oxime (6b) from betulin (3).
Figure 3. Initial (A) and alternative (B) strategies to install the Cꢀ17 amino group.
Having now successfully differentiated the two halves of the molecule and completed the
functionalization of the Aꢀring, we turned our attention to address the transformation of the Cꢀ17
aldehyde into the corresponding amino group. The obvious approach (Figure 3, A) of an oxidation
(6a→6c) followed by a Curtius rearrangement (6c→7) to install the Cꢀ17 amino group was initially
explored. However, this standard protocol was unsuccessful primarily with the oxidation step rather than
the subsequent Curtius rearrangement. A failure due to a combination of functional group instability with
electrophilic oxidants (i.e. NaOCl) and/or the unfavorable physical properties inherent in these
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pentacyclic triterpenoid intermediates resulting in triphasic mixtures, for example when Pinnick oxidation
conditions10 were explored. And while this strategy worked in principle, it was not amenable to multiꢀ
gram or Kg scale synthesis. Consequently, an alternative approach (Figure 3, B) was envisioned in which
the corresponding oxime (6b) could be potentially rearranged to the desired amine (7), but the exact
method to do so was not immediately clear. We were initially inspired by the work by the Rawal group in
their synthesis of Nꢀmethylwelwitindolinone11 in which a tertiary oxime was converted / rearranged to the
isothiocyanate via the intermediacy of a chloroꢀoxime (RꢀCH=NOH→ RꢀCCl=NOH→ RꢀN=C=S) and
hoped that a similar strategy could be employed to grant access to the requisite amine (7). To this end,
oxime 6b, which was generated most efficiently by exposure of the crude Suzuki reaction stream to aq.
NH2OH (IPA, pH = 6.5, 40 °C, 96% overall yield from 5), was treated with various chloronium based
reagents (e.g., NCS, dichlorohydantoin, NaOCl, and ChloramineꢀT) in an attempt to produce the
corresponding chloroꢀoxime. However, this approach proved unsuccessful, consistent with our previous
attempts at chloronium based oxidations of 6a.
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6b
d) PIFA
TFAA
H
H
Me Me
O
Me Me
H
O
H
N
O
N
CF3
H
Me
O
H
Me
O
Ar
X-ray
Ar
H
CF3
H
8b
8a confirmation
H2O
95%
d) DBU
H
H
CH3CN / THF
O
NH2
Me Me
H
Me Me
H
H2O, 65oC
HN
H
Me
OH
H
Me
96%
Ar
X-ray
confirmation
Ar
H
7
H
8c
Scheme 2: Preparation of hydroxamic acid 8c and Lossen rearrangement to amine 7.
Figure 4: ORTEP representations of nitrile oxide 8a (top) and hydroxamic acid 8c (bottom), with 50%
probability level.
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We next considered the possibility of a dehydrogenation / hydration sequence of 6b to access hydroxamic
acid 8c, a functional group that would enable exploration of the desired C to N migration by a Lossen
rearrangement. Fortunately, it was discovered that treatment 6b with PIFA (acetone / CH3CN, 0 °C to rt,
30 min, Scheme 2) very cleanly resulted in dehydrogenation and formation of the corresponding and
surprisingly stable nitrile oxide (8a), an outcome confirmed by Xꢀray crystallographic analysis (Figure 4,
top).12 Next, the mild hydration of the nitrile oxide to hydroxamic acid 8c was carried out by a 2ꢀstep
sequence beginning with the addition of TFAA (3.5 eq, 10 °C, 30 min) to give the resultant N,Oꢀ
bis(trifluoroacetyl)hydroxamic ester 8b13 followed by the addition of H2O. The role of H2O was twoꢀfold:
acting to facilitate the hydrolysis of the two trifluoroacetyl groups of 8b and then functioning as an antiꢀ
solvent to enable the isolation of 8c (Figure 4, bottom)12 in an impressive 95% overall yield from 6b and
as a single flask operation. At this point in the synthesis, it should be noted that the oxidation state of the
C28 position of 8c, which began oxidatively deficient due to the required use of 3, had now been
effectively raised to that of the carboxylic acid present in 2, via a CuII mediated aerobic oxidation
followed by the PIFA mediated dehydrogenation / hydration sequence (6b→8c). The combined sequence
culminated in a highly selective, safe, and scalable alternative to more traditional oxidation strategies.
Furthermore, the use of NH2OH alleviated the safety concerns over the potential presence of hydrazoic
acid intrinsic with any azide based reagent protocol. With the hydroxamic acid in place we were now
poised to explore its rearrangement to 7 via a Lossen rearrangement. Traditional Lossen rearrangements
occur most commonly through the activation of the hydroxamic acid with dehydrating reagents14 leading
to isocyanate products. However, recent reports have demonstrated baseꢀmediated Lossen
rearrangements, and are believed to proceed through a selfꢀpropagating mechanism that directly lead to
primary amines15ꢀ17. Over the course of our work, we identified exceptionally mild baseꢀcatalyzed
conditions (25 mol% DBU, CH3CN /THF, 65oC, 4h) that could efficiently and fully convert hydroxamic
acid 8c directly to amine 7 without the observation of isocyanate and in excellent yield (96% yield,
crystallized by addition of H2O). The mechanism of this transformation was found to employ a novel
mode of activation, and the complete details of this study is disclosed in an accompanying article in this
same issue.18
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Scheme 3: Methods evaluated for the Installation of thiomorpholine side chain 9 to prepare 10 and final
conversion to 1.
The next key step (Scheme 3) required a formal monoꢀalkylation of the recently generated Cꢀ17 amino
group using an activated version of commercially available thiomorpholine 9 (7 → 10). In order to avoid
the seemingly inevitable issue of over alkylation, we first investigated the possibility of reductive
amination approaches. In our initial route (A, see ref. 3), a stepꢀwise reductive amination sequence
installed the desired side chain (3 steps, 38% overall yield) but required the use of divinyl sulfone, a skin
sensitizer which proved difficult to source, thus prohibiting its use. Similarly, the use of Ir or Ru based
“borrowing hydrogen” protocols19 (B) were unsuccessful resulting in either decomposed or unreacted 7,
presumably due to the instability of the aldehyde derived from 9 which could not be prepared by standard
oxidation protocols (swern, SO3ꢀpyr, TPAP, etc). Fortunately, after screening various activation modes of
9 (ꢀOTs, Cl, I, Br, OTf) we found that conversion to its mesylate (C, Ms2O, DIPEA, 0 °C, CH2Cl2)
resulted in a relatively stable alkylating reagent that readily reacted with 7 to produce 10 in 84% yield
after crystallization of its oxalate salt from THF. Furthermore, the use of the mesylate resulted in very
high selectivity for the desired monoꢀalkylation of 7, demonstrating typically <2% of the bisꢀalkylation
side product, a result that can be attributed to both the relatively low reactivity of the mesylate with the
uniquely hindered environment of the Cꢀ17 amino group of the betulin core. Finally subjection of 10 to
hydrolytic conditions (nꢀBu4NOH, aq. in THF, 20 °C) gave BMSꢀ955176 (1) in 91% yield (isolated as an
HCl salt) and completed the synthesis of this experimental HIV maturation inhibitor.
Conclusion:
In summary, we have demonstrated a novel, economical, and highly efficient synthesis of BMSꢀ955176
(1) starting from Betulin (3) in 7 steps and 47% overall yield. Critical to the success of this program was
identifying a safe, effective, and scalable “oxidation strategy” to enable the use of betulin (3) as a starting
material instead of the more expensive, less abundant, but more highly oxidized derivative, betulinic acid
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(2). This case study also serves to demonstrate the effective and scalable use of the copper/nitroxyl radical
mediated aerobic oxidations of hydroxyl groups as well as the implementation of the Lossen
rearrangement instead of the more common Curtius reaction when C to N bond migration is tactically
required.
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Experimental Section:
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General Remarks: All starting materials and reagents were corrected for potency and used as is.
HPLC was carried out on a Shimadzu Prominence LC to determine reaction converison. The term “vol”
refers to ml solvent / g substrate of limiting reagent. Melting points were determined with a Thomas
Hoover capillary melting point apparatus and are uncorrected. Proton nuclear magnetic resonance (1H
NMR) spectra were recorded with a Bruker Ultrashield 400 spectrophotometer and are recorded in parts
per million from internal tetramethylsilane on the δ scale and are referenced from the residual protium in
the NMR solvent (CHCl3: δ 7.27, C2D5HSO: δ 2.50). Data is reported as follows: chemical shift
[multiplicity (app = apparent, s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet), coupling
constants(s) in Hertz, integration]. Carbon nuclear magnetic resonance (13C NMR) spectra were recorded
with a Bruker Ultrashield 400 spectrophotometer and are recorded in parts per million from internal
tetramethylsilane on the δ scale and are referenced from the carbon resonances in the NMR solvent
(CHCl3: δ 77.0, C2D5HSO: δ 39.5). Data is reported as follows: chemical shift. High resolution mass
spectrometry was performed on a ThermoFisher Scientific LTQ OrbitrapTM mass spectrometer.
Keto-Aldehyde 4: To a 3ꢀL buchi reactor was added CH2Cl2 (1.2 L) and MeCN (120 mL), followed by
the addition of 4,4'ꢀdimethoxybipyridine (3.11 g, 0.1 eq.), tetrakisacetonitrile copper (I) triflate (5.27 g,
0.1 eq.), NMI (2.20 g, 0.2 eq.), TEMPO (2.10 g, 0.1 eq.), ABNO (0.39 g, 0.02 eq.) and then betulin (3)
(60g, 1.0 eq.). The reaction mixture was pressurized to 15 bar with 10% O2 in N2, and heated at 40 °C
with overhead stirring (1500 rpm) for 18 h. After the completion of the reaction as indicated by HPLC,
the pressure was slowly released and the reactor was purged with nitrogen (3 bar). The reaction stream
was transferred to a 5ꢀL reactor, and the reaction mixture was washed with of 5% EDTA and 10% aq.
K2HPO4 solution (2 x 600 mL). Solvent was removed under vacuum and then the crude mixture was
subjected to carbon treatment (10wt% Cunoꢀ5 / 600 mL acetone). Carbon was removed by filtration and
the filtrate was concentrated to a final volume of 300 mL. The resulting mixture was heated to 50 °C and
H2O (60 mL) was added over 1 h, stirred for an additional 1 h at this temperature and then an additional
60 mL of water added slowly to facilitate the crystallization of the product. After completion of the
addition, the mixture was cooled to ambient temperature. The resulting slurry was filtered and washed
with Acetone/H2O (2:1, 250 mL) to afford 4 (49.83 g, 84% yield) as an offꢀwhite crystalline solid. 4: mp
= 160ꢀ163 °C; 1H NMR (600 MHz, CDCl3): δ 9.66 (d, J = 1.6 Hz, 1H), 4.75 (m, 1H), 4.62 (m, 1H), 2.87
(td, J = 11.2, 5.9, 1H), 2.48 (J = ddd, 17.4, 9.9, 7.6 Hz, 1H), 2.39 (ddd, J = 15.7, 7.6, 4.3 Hz, 1H), 2.09
(m, 1H), 2.05 (m, 1H), 1.89 (m, 1H), 1.87 (m, 1H), 1.77 (m, 1H), 1.76 (m, 1H), 1.73 (m, 1H), 1.69 (s,
1H), 1.48 (m, 1H), 1.46 (m, 1H), 1.44 (m, 1H), 1.44 (m, 1H), 1.44 (m, 1H), 1.43 (m, 1H), 1.41 (m, 2H),
1.37 (m, 1H), 1.33 (m, 1H), 1.30 (m, 1H), 1.28 (m, 1H), 1.19 (m, 1H), 1.06 (s, 1H), 1.05 (m, 1H), 1.01 (s,
13
1H), 0.98 (s, 1H), 0.95 (s, 1H), 0.92 (s, 1H). C NMR (150 MHz, CDCl3): δ 218.3, 206.8, 149.9, 110.4,
59.5, 55.1, 50.0, 48.2, 47.7, 47.5, 42.8, 41.0, 39.8, 39.0, 37.1, 34.3, 33.8, 33.4, 30.0, 29.3, 29.0, 26.8, 25.7,
21.5, 21.2, 19.8, 19.2, 16.2, 15.9, 14.4. HRMS (ESIꢀOrbitrap) m/z: [M + H]+ Calcd for C30H47O2
439.3566; Found 439.3571 (1.0 ppm error).
Enoltriflate 5: To a 20ꢀL reactor was added 4 (556.0 g, 1.0 eq.) and Phenylbistriflimide (549.0g, 1.20
eq.) and MTBE (5.5 L). The resulting mixture was cooled to ꢀ10 °C and NaHMDS (1.0 M in THF, 1600
mL, 1.25 eq.) was added by addition funnel or pump at such a rate that the internal temperature is
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maintained below ꢀ5 °C. Upon completion of the addition, the reaction was stirred an additional 30 min,
and then quenched with 30wt% aq. NH4OAc solution (1600 mL). The layers were split and the organic
stream was concentrated under reduced pressure to a final volume of 2800 mL and heated to 40 °C. IPA
was added (2800 mL), followed by the slow addition of H2O (1600 mL) resulting in a crystalline slurry.
The resulting slurry was cooled to ambient temperature, held at that temperature for 6 h, and then filtered
(solids washed with 2800 mL of 70:30 IPA/H2O) to yield 5 (637 g, 84% yield) as a partial THF solvate. 5:
1
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mp = 130 °C (decomp); H NMR (600 MHz, CDCl3): δ 9.66 (d, J = 1.4 Hz, 1H), 5.55 (dd, J = 6.8, 1.9
Hz, 1H), 4.76 (m, 1H), 4.63 (m, 1H), 2.88 (td, J = 11.2, 5.9 Hz, 1H), 2.15 (dd, J = 17.1, 6.8 Hz, 1H), 2.08
(m, 1H), 2.06 (m, 1H), 1.87 (m, 1H), 1.78 (m, 1H), 1.76 (m, 1H), 1.74 (m, 1H), 1.74 (m, 1H), 1.70 (s,
1H), 1.47 (m, 1H), 1.46 (m, 1H), 1.45 (m, 1H), 1.43 (m, 1H), 1.43 (m, 1H), 1.42 (m, 1H), 1.41 (m, 1H),
1.37 (m, 1H), 1.34 (m, 1H), 1.34 (m, 1H), 1.31 (m, 1H), 1.21 (m, 1H), 1.20 (m, 1H), 1.11 (s, 1H), 1.05
(m, 1H), 1.00 (s, 1H), 0.97 (s, 1H), 0.94 (s, 1H), 0.90 (s, 1H). 13C NMR (150 MHz, CDCl3): δ 206.7,
155.6, 149.9, 118.6 (q, J = 319.5 Hz), 113.9, 110.5, 59.5, 53.4, 49.1, 48.1, 47.7, 42.8, 40.9, 40.5, 38.9,
38.1, 36.5, 33.5, 33.4, 30.0, 29.3, 29.0, 27.6, 25.7, 21.5, 19.6, 19.2, 19.2, 16.4, 15.8, 14.4. HRMS (ESIꢀ
Orbitrap) m/z: [M + H]+ Calcd for C31H46F3O4S 571.3063; Found 571.3069 (0.9 ppm error).
Oxime 6b: To a clean reactor inerted with nitrogen, was added a mixture of compound 5 (145.0 g, 1.0
eq.) in degassed THF (1286 mL) followed by 4ꢀ(methoxycarbonyl)phenylboronic acid (61.5 g, 1.5 eq.),
nitrogen degassed THF (244.4 mL), PdCl2Xantphos (2.58 g, 1.5 mol%) and nitrogen degassed THF
(112.2 mL). After a 15 minutes subsurface nitrogen sparging 30 wt% aq. K3PO4 (483.5g, 3.0 eq.) and the
overall reaction mixture was subjected to three vacuum/nitrogen pressure swings to inert the system
whereupon the mixture was heated to 60 °C for 90 min. Upon complete conversion to intermediate 6a,
the mixture was cooled to 45 °C and diluted with MTBE (633 mL) and treated with a solution of Nꢀacetyl
cysteine (9.29 g, 0.25 eq.) in water (165 mL) for 45 min at 45 °C. The lower aqueous layer was removed
by extraction and 50 wt% aq. hydroxylamine (30.1 g, 2.0 eq.) was added to the organic layer and the pH
was adjusted to 7ꢀ8 by addition of acetic acid (0.2 to 0.25 eq. was typical). The reaction mixture was
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agitated for 2ꢀ3 hours at 45 C until less than 1% of compound 6a remained relative to compound 6b
based on HPLC analysis. Upon cooling to 25 °C the reaction mixture was washed with water (362 mL)
and the lower aqueous layer was discarded. The upper organic layer was concentrated under reduced
pressure to a final volume of 1.5 L, whereupon the residual THF was exchanged with 2ꢀpropanol (IPA)
by constant volume distillation with an IPA feed under reduced pressure. To the resulting mixture at 45
°C was added water (825 mL) resulting in a slurry. The slurry was cooled to 20 °C for 3 hours and the
product was collected by filtration, washed twice with IPA/water 3/2 (v/v) to yield compound 6b as an
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offꢀwhite to pale yellow solid (127.0 g, 96% yield). 6b: mp = 175°C; H NMR (600 MHz, DMSOꢀd6): δ
10.57 (s, 1H), 7.87 (d, J = 8.2 Hz, 2H), 7.40 (s, 1H), 7.23 (d, J = 8.2 Hz, 2H), 5.23 (dd, J = 6.2, 1.4 Hz,
1H), 4.71 (d, J = 2.0 Hz, 1H), 4.58 (m, 1H), 3.84 (s, 1H), 2.57 (td, J = 11.3, 5.1 Hz, 1H), 2.06 (dd, J =
17.3, 6.4 Hz, 1H), 1.89 (m, 1H), 1.88 (m, 1H), 1.85 (m, 1H), 1.73 (m, 1H), 1.70 (m, 1H), 1.68 (m, 1H),
1.67 (m, 1H), 1.67 (s, 1H), 1.62 (t, J = 11.5 Hz, 1H), 1.51 (m, 1H), 1.46 (m, 1H), 1.44 (m, 1H), 1.42 (m,
2H), 1.39 (m, 1H), 1.38 (m, 1H), 1.35 (m, 1H), 1.34 (m, 1H), 1.24 (m, 1H), 1.19 (m, 1H), 1.06 (m, 1H),
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1.05 (m, 1H), 0.98 (s, 2H), 0.93 (s, 1H), 0.88 (s, 2H). C NMR (150 MHz, DMSOꢀd6): δ 166.2, 152.6,
149.8, 148.2, 145.7, 130.0, 128.3, 127.6, 123.7, 109.9, 52.2, 52.0, 49.1, 48.6, 48.6, 47.3, 42.4, 41.0, 40.2,
37.9, 37.0, 36.6, 35.7, 33.1, 32.1, 29.3, 29.2, 27.5, 24.8, 20.9, 20.8, 19.3, 18.9, 16.2, 15.5, 14.4. HRMS
(ESIꢀOrbitrap) m/z: [M + H]+ Calcd for C38H54NO3 572.4098; Found 572.4085 (2.3 ppm error).
Hydroxamic acid (8c): To a 10ꢀL reactor was added oxime 6b (400.0 g, 1.0 eq.) and acetone (6 L, 15
vol). The resulting thin slurry was stirred at 20 °C and PIFA (359.0 g, 1.2 eq.) was added. The resulting
slurry, which initially became homogenous upon PIFA addition, slowly resulted in a 2nd slurry after
crystallization of the corresponding nitrile oxide 8a (see below for characterization). The reaction mixture
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was aged for 30 min and then cooled to 10 °C. TFAA (337.0 mL, 3.5 eq.) was added slowly over 20 min
by addition funnel and then aged for 1 h. Water (1.2 L, 5 vol) was then added resulting in the
crystallization of the product and the slurry was aged for 12 h at ambient temperature before being
isolated by filtration (cake washed with 3:1 acetone /H2O) to yield hydroxamic acid 8c (390.5 g, 95%
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yield) as an offꢀwhite crystalline solid. 8a: mp = 260 °C (decomp); H NMR (600 MHz, CDCl3): δ 7.93
(d, J = 8.2 Hz, 2H), 7.19 (d, J = 8.2 Hz, 2H), 5.29 (dd, J = 6.3, 1.7 Hz, 1H), 4.77 (br d, 1H), 4.66 (m, 1H),
3.90 (s, 1H), 2.59 (td, J = 11.1, 6.0 Hz, 1H), 2.13 (m, 1H), 2.11 (m, 1H), 2.04 (m, 1H), 2.01 (m, 1H), 1.85
(m, 1H), 1.79 (m, 1H), 1.78 (m, 1H), 1.69 (s, 1H), 1.67 (m, 1H), 1.59 (m, 1H), 1.58 (m, 1H), 1.56 (m,
1H), 1.55 (m, 1H), 1.52 (m, 1H), 1.50 (m, 1H), 1.48 (m, 2H), 1.47 (m, 1H), 1.39 (m, 1H), 1.35 (m, 1H),
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1.22 (m, 1H), 1.13 (s, 1H), 1.10 (m, 1H), 0.99 (s, 1H), 0.98 (s, 1H), 0.93 (s, 1H), 0.92 (s, 1H). C NMR
(150 MHz, CDCl3): δ 167.4, 148.9, 148.3, 146.5, 130.3, 128.7, 128.1, 124.1, 111.2, 53.0, 52.2, 52.0, 50.3,
49.6, 49.1, 42.5, 42.2, 41.9, 41.6 (v br), 40.7, 37.7, 37.0, 36.5, 33.8, 32.3, 29.9, 29.7, 29.6, 25.3, 21.3,
21.2, 19.9, 19.9, 16.7, 16.0, 15.1. HRMS (ESIꢀOrbitrap) m/z: [M + H]+ Calcd for C38H52NO3 570.3942;
Found 570.3946 (0.7 ppm error).
1
8c: mp = 225 °C (decomp); H NMR (600 MHz, 1:1 DMSOꢀd6:CDCl3): δ 10.32 (br s, 1H), 7.83 (d, J =
8.2 Hz, 2H), 7.15 (d, J = 8.2 Hz, 2H), 5.21 (dd, J = 6.3, 1.6 Hz, 1H), 4.63 (d, J = 2.1 Hz, 1H), 4.50 (m,
1H), 3.82 (s, 1H), 3.04 (td, J = 10.8, 4.3 Hz, 1H), 2.57 (m, 1H), 2.05 (m, 1H), 2.04 (m, 1H), 1.80 (m, 1H),
1.78 (m, 1H), 1.65 (m, 1H), 1.63 (m, 1H), 1.61 (s, 1H), 1.47 (m, 1H), 1.46 (m, 1H), 1.42 (m, 1H), 1.40
(m, 1H), 1.38 (m, 2H), 1.36 (m, 1H), 1.36 (m, 1H), 1.34 (m, 1H), 1.31 (m, 1H), 1.25 (m, 1H), 1.22 (m,
1H), 1.16 (m, 1H), 1.08 (m, 1H), 0.94 (s, 1H), 0.93 (m, 1H), 0.92 (s, 1H), 0.92 (s, 1H), 0.86 (s, 1H), 0.86
(s, 1H). 13C NMR (150 MHz, 1:1 DMSOꢀd6:CDCl3): δ 173.1, 166.0, 150.4, 148.0, 145.5, 129.6, 127.9,
127.3, 123.6, 108.9, 53.4, 52.1, 51.5, 50.0, 48.9, 46.0, 41.7, 41.0, 40.0, 37.7, 36.8, 36.8, 35.6, 33.0, 32.0,
30.2, 29.0, 28.8, 25.1, 20.8, 20.6, 19.2, 18.8, 16.0, 15.5, 14.1. HRMS (ESIꢀOrbitrap) m/z: [M + H]+ Calcd
for C38H54NO4 588.4047; Found 588.4031 (2.8 ppm error).
Amine (7): To a 250 mL reactor was added hydroxamic acid 8c (25.0 g, 1.0 eq.), a mixture of THF /
CH3CN (1:1, 100 mL), and water (2.5 g, 3.4 eq.). The resulting mixture was heated to 65 °C and then
DBU (1.61 g, 0.26 eq.) was added and the resulting mixture was aged at that temperature for 2 h. CH3CN
(150 mL) was added 65 °C to facilitate the crystallization and the resulting slurry was cooled to 0 °C aged
for 12 h, and then filtered (cake washed with CH3CN) to produce 7 (21.4 g, 96% yield) as an offꢀwhite
crystalline solid. 7: mp = 240ꢀ243 °C; 1H NMR (600 MHz, 1:0.7 DMSOꢀd6:CDCl3): δ 7.84 (d, J = 8.2 Hz,
2H), 7.16 (d, J = 8.2 Hz, 2H), 5.22 (dd, J = 6.2, 1.3 Hz, 1H), 4.66 (d, J = 2.1 Hz, 1H), 4.52 (br s, 1H),
3.83 (s, 1H), 2.52 (td, J = 11.0, 5.9 Hz, 1H), 2.06 (dd, J = 17.2, 6.4 Hz, 1H), 1.96 (m, 1H), 1.73 (m, 1H),
1.72 (m, 1H), 1.65, (m, 1H), 1.64 (m, 1H), 1.63 (s, 1H), 1.50 (m, 1H), 1.49 (m, 1H), 1.46 (m, 1H), 1.43
(m, 1H), 1.42 (m, 2H), 1.40 (m, 1H), 1.39 (m, 1H), 1.37 (m, 1H), 1.35 (m, 1H), 1.33 (m, 1H), 1.28 (m,
1H), 1.24 (m, 1H), 1.18 (m, 1H), 1.05 (s, 1H), 1.03 (m, 1H), 1.03 (m, 1H), 0.94 (s, 1H), 0.93 (s, 1H), 0.88
13
(s, 1H), 0.87 (s, 1H). C NMR (150 MHz, 1:0.7 DMSOꢀd6:CDCl3): δ 166.0, 149.7, 148.0, 145.5, 129.6,
127.9, 127.3, 123.5, 109.2, 59.2, 52.1, 51.5, 48.7, 47.9, 47.1, 41.6, 41.0, 40.0, 39.3, 37.1, 36.8, 35.6, 34.5,
32.9, 28.9, 28.9, 26.3, 24.6, 20.8, 20.6, 19.1, 18.9, 16.0, 15.3, 13.6. HRMS (ESIꢀOrbitrap) m/z: [M + H]+
Calcd for C37H54NO2 544.4149; Found 544.4133 (2.9 ppm error).
Diamine (10): To a 1ꢀL reactor was added thiomorpholine 9 (21.1 g, 1.6 eq.), DIPEA (15.8 g, 1.65 eq.),
and CH2Cl2 (180 mL, 4.5 vol). The resulting mixture was cooled to ꢀ10 °C and a CH2Cl2 (100 mL, 2.5
vol) solution of Ms2O (21.8 g, 1.65 eq.) was added and the resulting mixture was aged at ꢀ10 °C for 10
min then 7 (40.0 g, 1.0 eq.) and DIPEA (16.3, g, 1.7 eq.) was added and the mixture was refluxed for 22ꢀ
24h. After the reaction was determined complete based on HPLC analysis, the mixture was diluted with
CH2Cl2 (240 mL, 6 vol) and aq. NaOH (1N, 320 mL, 8 vol) was added. The layers are split and the
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organic stream was washed with aq. AcOH (10 wt%, 320 mL, 8 vol), then again with aq. NaOH (1N, 320
mL, 8 vol), and finally washed once with water (320 mL, 8.0 vol). The CH2Cl2 was exchanged for THF
(12 vol) under reduced pressure. The resulting THF stream was heated to 35oC and water was added (4.4
g, 3.3 eq.) followed by the slow addition oxalic acid (7.0 g, 1.1 eq.) as a solution in THF (160 mL, 4 vol)
over 4 h. Upon completion of the addition, the resulting slurry was cooled to ambient temperature, aged
for 6 h, then filtered to yield oxalic acid salt 10 (48.8 g, 84% yield) as a white crystalline solid. 10: mp =
214 °C; 1H NMR (600 MHz, DMSOꢀd6): δ 7.88 (d, J = 8.3 Hz, 2H), 7.24 (d, J = 8.3 Hz, 2H), 5.24 (dd, J
= 6.1, 1.6, 1H), 4.73 (br s, 1H), 4.62 (br s, 1H), 3.84 (s, 1H), 3.15/3.07 (m, 2H), 3.08 (m, 2H), 2.96 (m,
1H), 2.91 (m, 1H), 2.76 (m, 1H), 2.75 (m, 1H), 2.08 (m, 1H), 2.04 (m, 1H), 2.03 (m, 1H), 1.92 (m, 1H),
1.87 (m, 1H), 1.85 (m, 1H), 1.70 (m, 1H), 1.68 (s, 1H), 1.64 (m, 1H), 1.58 (m, 1H), 1.54 (m, 1H), 1.50
(m, 1H), 1.47 (m, 1H), 1.46 (m, 1H), 1.45 (m, 1H), 1.43 (m, 1H), 1.41 (m, 1H), 1.41 (m, 1H), 1.39 (m,
1H), 1.27 (td, J = 13.1, 4.1, 1H), 1.21 (m, 1H), 1.19 (m, 1H), 1.10 (s, 1H), 1.06 (m, 1H), 1.02 (s, 1H), 1.01
(s, 1H), 0.96 (s, 1H), 0.89 (s, 1H), 0.89 (s, 1H). 13C NMR (150 MHz, DMSOꢀd6): δ 166.1, 164.1 (oxalate),
148.9, 148.1, 145.7, 130.0, 128.2, 127.6, 123.6, 110.5, 68.4, 52.1, 52.0, 50.4, 50.0, 49.2, 48.5, 48.2, 45.3,
41.7, 41.0, 40.2, 39.0, 37.0, 36.7, 36.1, 35.7, 33.2, 31.9, 29.2, 28.1, 25.7, 24.6, 20.9, 20.8, 19.2, 18.8, 16.3,
15.8, 14.0. HRMS (ESIꢀOrbitrap) m/z: [M + H]+ Calcd for C43H65N2O4S 705.4660; Found 705.4644 (2.2
ppm error).
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BMS-955176 (1): To a 1ꢀL jacketed reactor was charged diamine 10 (50.0 g, 62.9 mmol, 1 eq.), THF,
(200 mL), and TBAOH (95 mL, 55 wt% solution in water, 3.1 eq.). The solution was stirred for 1 h at 20
°C. After completion of the reaction, HCl (48.2 mL, 6 mol/L in water, 4.6 eq.) was added followed by
MeCN (200 mL). The solution was heated to 40 °C. Water (165 mL) was added to achieve a solvent ratio
of 4:5:4 (THF:water:MeCN). The crystallization was seeded followed by a subsequent addition of water
(350 mL) over 4 h. The final solvent ratio was 4:12:4 (THF:water:MeCN). After water addition was
complete, the slurry was cooled to 20 °C, filtered, and washed with 3:1 water:MeCN (200 mL). The
solids were then dried in a vacuum oven overnight at 30 °C to yield 1 as a white solid (44.8 g, 60.1 mmol,
91% yield). 1: mp = 95 °C (decomposition); 1H NMR (600 MHz, DMSOꢀd6): δ 7.86 (d, J = 8.2 Hz, 2H),
7.21 (d, J = 8.2 Hz, 2H), 5.24 (dd, J = 6.1, 1.2, 1H), 4.75 (br s, 1H), 4.64 (br s, 1H), 3.17/3.08 (m, 3H),
3.15 (m, 2H), 3.09 (m, 1H), 3.08 (m, 1H), 2.16 (m, 1H), 2.09 (dd, J = 17.1, 6.1, 1H), 2.08 (m, 1H), 1.92
(m, 1H), 1.91 (m, 1H), 1.88 (m, 1H), 1.70 (m, 1H), 1.69 (s, 1H), 1.68 (m, 1H), 1.68 (m, 1H), 1.61 (m,
1H), 1.54 (m, 1H), 1.46 (m, 1H), 1.46 (m, 1H), 1.43 (m, 1H), 1.42 (m, 1H), 1.42 (m, 1H), 1.41 (m, 1H),
1.39 (m, 1H), 1.27 (m, 1H), 1.23 (m, 1H), 1.21 (m, 1H), 1.09 (m, 1H), 1.09 (s, 1H), 1.02 (s, 1H), 0.96 (s,
1H), 0.89 (s, 1H), 0.89 (s, 1H). 13C NMR (150 MHz, DMSOꢀd6): δ 167.2, 148.7, 147.7, 145.9, 129.8,
128.7, 128.4, 123.5, 110.7, 70.3, 52.1, 49.9, 48.8, 48.5, 47.9, 44.9, 41.7, 41.0, 40.2, 39.1, 37.0, 36.3, 35.8,
33.2, 31.6, 29.2, 28.0, 26.3, 25.6, 24.6, 20.9, 20.8, 19.2, 18.9, 16.3, 15.9, 14.0. HRMS (ESIꢀOrbitrap) m/z:
[M + H]+ Calcd for C42H63N2O4S 691.4503; Found 691.4487 (2.4 ppm error).
Associated content:
The supporting information is available free of charge on the ACS Publications website at DOI:
XXXXXXXXX.
Copies of the of 1H and 13C NMR spectra for all new compounds.
Author Information:
*Eꢀmail: Adrian.Ortiz@BMS.com
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Acknowledgements
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We would also like to thank Dr’s Martin D. Eastgate, David A. Kronenthal, and Robert Waltermire for
their support of this work.
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References:
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Beno, B.R., Huang, X.S., Rahematpura, S., Parker, D.D., Haskell, R., Jenkins, S., Santone, K.S.,
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M.; Chemistry Central Journal. 2012, 6, 137.
6. For selected examples of betulin oxidation see: (a) “Method for Preparation of Betulinic acid”:
Tulisalo, J., Wickholm, N., Pirtimaa, M., Alakurtti, S., Kauhauluoma, J.Y.; WO2013038312 A1,
2013; (b) Melnikova, N., Burlova, I., Kiseleva, T., Klabukova, I, Gulenova, M., Tanaseichuk, B.;
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Syn.Comm., 2004, 34, 21, 3925ꢀ3937.
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8. Steves. J.E., Stahl, S.S.; J. Am. Chem. Soc. 2013, 135, 15742ꢀ15745.
9. Ayers, S., Benkovics, T., Marshall, J., Tan, Y., Strotman, N.A., Kiau, S., J. Nat. Prod. 2016, 79,
2758ꢀ2761.
10. Dalcanale, G., Montanari, F.; J. Org. Chem. 1986, 51, 567ꢀ569.
11. Allan, K. M., Kobayashi, K., Rawal, V.H.; J. Am. Chem. Soc. 2012, 134, 1392ꢀ1395.
12. Full crystallographic data for 8a and 8c have been deposited to the Cambridge Crystallographic
Data Center (CCDC reference numbers: 1534529, 1534530). Copies of the data can be obtained
free of charge via the internet at http://www.ccdc.cam.ac.uk
.
13. Proposed structure of 8b is supported both by 19F NMR, see supporting info, and chemical
conversion tests (8c + TFAA → 8b).
14. Dube, P. Nathel, N.F.F., Vetelino, M., Couturier, M., Aboussafy, C.L., Pichette, S., Jorgensen,
M.L., Hardink, M.; Org. Lett. 2009, 11, 24, 5622ꢀ5625.
15. Hoshino, Y., Okuno, M., Kawamura, E., Honda, K., Inoue, S.; Chem. Commun. 2009, 2281ꢀ2283.
16. Hoshino, Y., Shimbo, Y., Ohtsuka, N., Honda, K., Tet. Lett. 2015, 710ꢀ712.
17. Ohtsuka, N., Okuno, M., Hoshino, Y., Honda, K., Org. Biomol. Chem. 2016. 14, 9046ꢀ9054.
18. Strotman, N.A., Ortiz, A., Savage, S., Wilbert, C., Ayers, S., and Kiau. S., submitted manuscript.
DOI: XXXXXXX.
19. For a review of such transformations see: Leonard, J., Blacker, A.J., Marsden, S.P., Jones, M.F.,
Mulholland, K.R., Newton, R.; Org. Process. Res. Dev. 2015, 19, 1400ꢀ1410.
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