XXXXXXXXXXSub-Group Questions 1. Fraudulent fatty acids mimic the structures and activities of oleic and linolenic acids, which activate regulatory pathways in the liver and enhance fatty acid...

XXXXXXXXXXSub-Group Questions
1. Fraudulent fatty acids mimic the structures and activities of oleic and linolenic acids, which activate regulatory pathways in the liver and enhance fatty acid catabolism. The resulting increase
in HDL can have positive effects for improved cardiovascular health. The following reaction chemistry derives from an American research team’s synthetic work towards efficacious fraudulent
fatty acids. (a) For the two bold a
ow reactions, write detailed, a
ow-pushing mechanisms to account for each step in the overall transformations indicated. Note: For the upper left bold
a
ow reaction, the yield was very poor when Bu4NI was not used. (b) Complete the reaction scheme by providing the missing structures and reaction conditions. When providing reaction
conditions, specify reagents, reagent stoichiometry (where appropriate), solvents, and temperature (where appropriate), but you may leave necessay work-up conditions unwritten and implied.
All reaction conditions provided explicitly below do likewise and leave necessary work-up conditions implied to the reader.
O
O
B
OB
Br O
O
O
C
O
A
0.5 eq LDA
THF, -78 °C
1 eq
NaOH, H2O, THF
then HClconc, ∆
OH
2. In the course of research on functional peptidomimetics (i.e. synthetic peptides inspired by nature), a Canadian research team developed improved conditions to install an amine protecting
group du
ed PhF = 9-Phenyl-9-Fluorenyl. Our north-of-the-border colleagues invoke entirely CHEM XXXXXXXXXXmechanistic processes and reagents in the synthetic sequence below. (a) Write a
detailed, a
ow-pushing mechanism to account for each step in the installation of the PhF group on the indicated a-amino amide. (b) Provide the structure of the missing intermediate
compound A. (c) Write a detailed, a
ow-pushing mechanism to account for each step in the bold a
ow reaction.
H2N
N
O
O
N N
O
O
CH3
CH3
H
Ph
Cl Ph
NO
O
CH3
AgNO3
CH3CN NO
OH
CH3
NO3 AgClppt
other products
O2N
Li
THF, -78 °C
(then H3O+
work-up)
A
N
OH
Ph
NO2
NO2
EtOK, EtOH, ∆
O2N
O
H
3. Every portion of the synthetic sequence shown below, executed in the pursuit of compounds with potential for dementia and Alzheimer’s treatment, invokes CHEM XXXXXXXXXXmechanistic
processes and reagents. (a) Complete the reaction scheme by providing the missing intermediate structures. All reaction conditions provided explicitly below leave necessary work-up
conditions implied to the reader. (b) Whether in explicitly drawn compounds or in compound structures you provide, use your favorite highlighting color to indicate all bonds formed via an SN2
step. (c) Write detailed, a
ow-pushing mechanisms to account for each step in the bold a
ow reactions.
O O
HO
H3CO
O
1 eq LDA
then add
1 eq CH3I
then add
1 eq LDA
then add
1 eq CH3I
THF, -78 °C
A
cf. RGB
WTF + OMG
example
1. Ms-Cl
Et3N, CH2Cl2
2. DBU, CH3CN
B
LDA, THF
0 °C to 25 °C
OHH3CO
O
(C17H24O3)
N
N
H3CO
O
O
B
NB
O
O THF, 0 °C
NH
O
O
4. The following reactions derive from an Australian team’s work to develop anti-tumor drugs inspired by natural products isolated from fungus. (a) Below left, a ve
atim screen capture from
this Aussie article is shown. Write a detailed, a
ow-pushing mechanism that accounts for each step in the conversion of the t-butyl esters to ca
oxylic acids and explains why the n-butyl ester
survives unscathed. Note: One equivalent of 2-methylpropene is formed for each t-butyl ester converted to acid. (b) Provide the missing product for the reaction shown below right.
CO2tBu
OHC
CO2tBu
CO2nBuO
Si
O
PH3CO
H3CO
O
O
Si
LiHMDS, THF
-20 °C to 25 °C
A
5. With pandemic curtailment of real travel, let’s take a vicarious chemistry excursion to the Western Pacific rim, with stops in Korea, Japan, and China, to view snippets of work on anti-
tumor compounds derived from and/or inspired by natural products isolated from a mushroom, a liverwort, and a Medite
anean tunicate. (a) Provide the reaction product A and write a
detailed, a
ow-pushing mechanism to account for the excusive stereochemistry A exhibits. (b) Write a detailed, a
ow-pushing mechanism to account for each step in the overall
transformation of the first reaction. Also, provide the product B of the second reaction. (c) Provide product C of the second reaction and write detailed, a
ow-pushing mechanisms to
account for each step in the overall transformations of the first and third reactions. Note: All reaction conditions provided explicitly below leave necessary work-up conditions implied to the
eader.
CH3O
CH3O
O
O
O
O
H CH3O
CH3O
O
O
O
OO
OH cat.F3C
CH2Cl2
1. LiHMDS, THF
-78 °C
S O
2. (CH3)3Si-Cl
CH2Cl2, EtN(i-Pr)2
B
(C26H32O7SSi)
O
OMs
O K
THF, 0 °C
A
(a)
(b)
N N
C
O1 eq LDAthen add
ClCH2CH2B
then add
1 eq LDA
THF, -78 °C
DIBAL
hexane
LDA, THF
S
CH3
H3C CH3
I
(c)
pyliodide, DMF, 120 °C, and 7 h in a sealed tube) to generate
2,2,2-trifluoro-1-((3aR,9bR)-7-(perfluoropropan-2-yl)-9b-
(phenylsulfonyl)-1,2,3a,4,5,9b-hexahydro-3H-benzo[e] indol-
3-yl) ethan-1-one 6 in 73% yield. Compound 6 was then
subjected to nitration with KNO3 and H2SO4, resulting in a
mixture of two regio-isomers (7/7a) in a ratio of 2.5:1 along
with a minor amount (∼8%) of dinitro byproduct 7b. The crude
mixture thus obtained was subjected to reduction with iron and
acetic acid and the desired amine 8 was isolated in 58% yield.
This amine functionality was used as a precursor to install the
fluoro moiety employing the Balz−Schiemann reaction,9 to
furnish 8-fluoro-7-(perfluoropropan-2-yl) derivative 9 in 65%
yield. Basic hydrolysis of the trifluoroacetamide moiety using
LiOH led to the key intermediate 10 in excellent yield (93%).
Although the above scheme could be ca
ied out reasonably
well on a small scale, generating multigram quantities of
compound 10, employing this route, posed serious challenges.
For example, (i) this synthetic protocol employed 12 linear steps
from 6-iodotetralone 1 with an overall yield of only 9.5%; (ii)
incorporation of a fluoro moiety via aromatic nitration using the
KNO3/H2SO4 mixture resulted in significant safety issues, fo
example, the potential explosive nature of aromatic nitro
derivatives.10 (iii) due to the exothermic nature of the nitration
eaction, control on attenuating overnitration could be
challenging and (iv) the nitration reaction led to a mixture of
egio-isomers, and (v) the potential for uncontrolled thermal
decomposition of aryl diazonium fluoroborate salt, especially
when ca
ied out on a large scale (vide infra).11
To investigate the safety concern of this reaction, the
differential scanning calorimetry (DSC) thermogram was
ecorded on pure dinitro compound 7b, which shows a majo
exotherm at 224 °C with an energy of −1371 J/g (estimated
adiabatic temperature increase,ΔTad = +608 °C) and an onset of
a minor exotherm at 102 °C (Figure 1). These data clearly
indicate that compound 7bmight not be a safe byproduct of the
nitration reaction, when conducted on a larger scale, forcing us
Scheme 2. First-Generation Synthesis of BMT-362265
Scheme 3. Synthesis of (R)-N-(2-Chloroethyl)-2-methylpropane-2-sulfinamide 13
Organic Process Research & Development pubs.acs.org/OPRD Article
https:
dx.doi.org/10.1021/acs.oprd.1c00019
Org. Process Res. Dev. 2021, 25, 1001−1014
1002
NO2S
F
F3C
CF3F
O
CO2CH3
A
H2SO4 at 100 °C gave the desired tetralone 14 with high
egioselectivity (24:1) and in 65% isolated yield. The observed
egioselectivity might be attributed to the steric contribution of
the heptafluoroisopropyl group thereby forcing the cyclization
to the para position. The overall yield of tetralone 14 over the
seven-step sequence depicted in Scheme 5 was 24.6%.
Having tetralone 14 with a preinstalled 7-fluoro functionality
in hand, it was subjected to TiCl4-mediated vinylthioethe
synthesis using thiophenol and triethylamine, which led to a
mixture of vinylthioether 22a and thioketal 22b as described in
Scheme 6. Without further purification, the mixture of 22a and
22bwas oxidized with potassium peroxymonosulfate to produce
vinylsulfone 23 in 45% isolated yield (after two steps) and 15%
of unreacted tetralone 14 was recovered. Finally, tricyclic core
24 was synthesized in a stereoselective manner using (R)-N-(2-
chloroethyl)-2-methylpropane-2-sulfinamide 13 under basic
conditions (tBuOK) to yield 24 in 60% yield. Deprotection of
Ellman’s chiral auxiliary was achieved in excellent yield (95%)
using HCl in 1,4-dioxane to produce (3aR,9bR)-8-fluoro-7-
(perfluoropropan-2-yl)-9b-(phenylsulfonyl)-2,3,3a,4,5, 9b-hex-
ahydro-1H-benzo[e]indole 10 as a white solid.
Scheme 5. Synthesis of 7-Fluoro-6-(heptafluoroisopropyl)tetralone 14 from 4-Fluorobenzaldehyde 16
Scheme 6. Synthesis of 10 from 7-Fluoro-6-(heptafluoroisopropyl)tetralone 14
Scheme 7. Synthesis of 7-Fluoro-6-iodo-1-tetralone 15 from 4-Fluorobenzaldehyde 16
Organic Process Research & Development pubs.acs.org/OPRD Article
https:
dx.doi.org/10.1021/acs.oprd.1c00019
Org. Process Res. Dev. 2021, 25, 1001−1014
1004
(Ph3P)3RhCl
cf. Special Topic J
from T. M. coverage
Please help…
Cannot recall
what I look like.
6. A process chemistry group in Bangalore, India recently reported efforts to scale-up the production of a drug candidate for treatment of inflammation associated with autoimmune
diseases like lupus and psoriasis. With very few exceptions, the steps featured in their synthetic schemes invoke CHEM XXXXXXXXXXmechanistic processes and reagents. (a) Write a detailed,
a
ow-pushing mechanism to account for each step in the conversion of 3 to 4 (i.e. green a
ow). (b) Provide the missing reaction conditions A to efficiently convert 2° amine 10 to the
indicated 3° amide product. When providing reaction conditions, specify reagents, reagent stoichiometry (where appropriate), solvents, and temperature (where appropriate), but you may
leave necessay work-up conditions unwritten and implied. (c) Provide the reaction product 25 obtained from the indicated reaction of 17. (d) As did all of you, our Indian colleagues
thoroughly enjoyed their undergraduate study of aromatic chemistry. Thus, share your mutual enthusiasm by identifying all reactions below that illustrate an EAS transformation. Also,
identify the Sandmeyer substitution reaction transformation. Note: All reaction conditions provided explicitly below leave necessary work-up conditions implied to the reader.