Добавил:
Sekretar
kiopkiopkiop18@yandex.ru
t.me/Prokururor I Вовсе не секретарь, но почту проверяю
Опубликованный материал нарушает ваши авторские права? Сообщите нам.
Вуз:
Предмет:
Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5262_Библиотеки_им_академика_М_И_Перельмана.pdf
4 Mechanism Problems from Reactions Give Expected Products128
as eluent. From this chromatography, 3, 4, and 5 were isolated and subsequently
identified.
3: (1-benzyl-4-methyl-3-(1R-phenethyl)-1,3-dihydroimidazol-2-one, C
19
H
20
N
2
O
[292.38 g/mol]):
1
HNMR 1.62 (s, 3H), 1.80 (d, 3H, J = 7.1), 4.63 (s, 2H), 5.49 (q, 1H,
J = 7.1), 5.61 (s, 1H), 7.1–7.5 (m, 10H). MS (CI-methane) 293 (M
+
, 100), 217 (12),
189 (48), 105 (43), 91 (36).
4: (1-benzyl-3-(1R-phenethyl)-1,4-dihydro-3H-thieno-[3,4-d]imidazol-2,6-dione,
C
20
H
18
N
2
O
2
S [350.44 g/mol]):
1
HNMR 1.71 (d, 3H, J = 7.1), 3.12 (d, 1H, J = 17.4),
3.71 (d, 1H, J = 17.4), 4.95 (s, 2H), 5.61 (q, 1H, J = 7.1), 7.27–7.40 (m, 8H), 7.49
(dd, 2H, J = 8, 1.5). MS (CI-methane) 351 (M
+
, 100), 247 (34), 105 (98), 91 (55).
The Mechanism
According to soft-hard acid-base principle, AcSK is classified as a soft base. The thio-
acetate would attack at the soft acid C-6 of 1 rather than at C-4. This reaction can be
regarded as trans-esterification. Thio anion in AcSK is a much stronger nucleophile
than oxygen anion in AcOK.
The formation of compound 3 is postulated as 1,2-hydrogen shift and decarbox-
ylation side product.
Compound 4 likely originates from its own oxidation by the oxygen present in the
reaction system. The percentage of 4 was reduced from 2.0% to 0.4% by diminishing
the oxygen level from air atmosphere to <0.3 ppm via argon protection [92].
O
NBn
O
O
AcS
–
NBn
O
O
NBn
O
O
O
AcSK
AcOK
S
NBn
O
O
1
2
S
O
O
1
2
3
4
5
6
Ph
Ph
Ph
Ph
–
O
–
S
NBn
O
O
O
–
S
Ph
H
O
A
NBn
O
3
Ph
1,2-Hydrogen
shift
NBn
O
O
O
–
Ph
Decarboxylation
AcS
–
CO
2
S
NBn
O
O
2
Ph
H
H
O O
Triplet
oxygen
S
NBn
O
O
Ph
H
HO O
H
2
O
2
S
NBn
O
O
Ph
4
4.5 Formation of Nonaromatic Heterocycles 129
Problem 33: Preparation of D-Erythronolactone from Erythorbic Acid
Nelfinavir 1 is one of the most prescribed therapeutic agents to suppress the AIDS
epidemic. (2S,3R)-3-(N-Benzyloxycarbonyl)amino-1-chloro-4-phenylthiobutan-2-ol
(2) is a central building block of nelfinavir [93]. An enantioselective synthesis of
2 is starting from erythorbic acid (3) and the first step is the oxidation of 3 with
hydrogen peroxide to give D-erythronolactone 4 [94, 95].
Please suggest a mechanism for the reaction from 3 to 4.
Experimental Procedure (from J. Org. Chem., 1991, 56, 6225)
Dihydro-3(R),4(R)-dihydroxy-2(3H)-furanone (4). According to the procedure
of Cohen, D-isoascorbic acid (704 g) in water (10 L, 4 °C) was sequentially treated
with sodium carbonate (848 g over 30 min; conversion to sodium enolate), hydrogen
peroxide (CAUTION, 30%, 880 mL over 1 h; exotherm from 5 to 35 °C; warmed
to 40 °C for 30 min), and Darco G-60 (160 g in portions, 0–4 °C, then 25 °C). After
observing a negative peroxide test, the mixture was filtered through Celite (2-L
boiling water wash), treated with 6 N hydrochloric acid (2.1 L, pH 1.5), and con-
centrated to dryness under vacuum (45–50 °C). The solid was extracted with boiling
ethyl acetate (5 × 3 L portions). These combined extracts were concentrated in
vacuo, treated with diethyl ether (2 L), filtered, affording D–erythronohctone (436 g,
94%), which was suitable for further use: mp 101–103 °C [ɑ]
25
D
73° (c 1.00, H
2
O).
The Mechanism
One possible mechanism involves the free radical pathway. The initial step likely
involves the oxidation of compound 3 by hydrogen peroxide through a free rad-
ical process, resulting in the formation of diketone A. Subsequently, the addition
of hydrogen peroxide to the C-3 carbonyl group yields hydroperoxyl alcohol B.
A hydroxyl radical then attacks the C-4 carbonyl, generating intermediate C, which
undergoes ring cleavage with the loss of a hydroxyl radical. At this stage, the ester
may be hydrolyzed to produce oxalic salt and the sodium salt D. Following acidifica-
tion, cyclization occurs, leading to the formation of D-erythronolactone 4.
Another plausible mechanism is the oxidation of the di-enol carbons by hydrogen
peroxide and cleavage of the C3-C4 bond (next page).
Problem 34: Synthesis of L-lyxonolactone-2,3-O-isopropylidene
L-lyxonolactone-2,3-O-isopropylidene (1) is a key intermediate for the synthesis
of UT-231B (iminosugar, 2) [96], an analog of deoxynojirimycin. Iminosugar 2 is
currently in clinical trials as an antiviral agent for the treatment of hepatitis C.
O
O
OH
HO
HO
HO
H
2. HCl
O
OH
HO
O
3
4
Steps
PhS
Cl
NHCbz
OH
PhS
N
NH
OH
2
1 (Nelfinavir)
H
H
NHO
O
HO
1. 30% H
2
O
2
Na
2
CO
3
4 Mechanism Problems from Reactions Give Expected Products130
One of the reported synthesis of 1 is starting from D-ribose 3 as shown below [97].
The (R-) stereochemistry at C-4 in compound 5 is converted to (S-) form in 2 via
mesylation and hydrolysis of the C-5 primary alcohol. Please suggest a mechanism
for the reaction from 6 to 1.
H
O
O
H
2 HO
O
O
O
O
HO
OH
H
3
H
H
HO
OH
H
2
O
2
O
O
O
O
HO
OH
H
A
H
O
O
H
O
O
OH
O
HO
OH
H
B
O
O H
HO
HO
O
O
OH
HO
HO
OH
H
C
O
OH
O
HO
O
O
OH
HO
HO
OH
H
D
O
O
Na
2
CO
3
NaO
ONa
O
O
OH
NaO
HO
OH
O
HCl
NaCl
H
2
O
O
OH
HO
O
4
HCl
2 NaCl
2H
2
O
H
2
O
(CO
2
H)
2
H
2
O
2
OH
HO
O
O
OH
HO
HO
HO
H
3
H
2
O
2
O
O
OH
O
HO
HO
H
E
H
ONa
O
O
HCl
2 NaCl
O
HO
H
HO
HO
H
O
O
O
OHO
F
hydrolysis
OH
NaO
HO
HO
O
HCl
O
OH
HO
O
4
+
NaO
ONa
O
O
NaCl
H
2
O
H
2
O
HO
–
H
2
O
2
Na
2
CO
3
(CO
2
H)
2
O
OH
HO
HO
OH
Br
2
, H
2
O
K
2
CO
3
0 °C - rt
3 (D-ribose)
O
OH
HO
HO
O
4
Acetone
H
2
SO
4
65%, 2 steps
200 kg
O
HO
O
5
O O
MsCl, Et
3
N
DCM
O
MsO
O
6
O O
KOH
H
2
O
59%, 2 steps
200 kg
O
HO
O
1
O O
Steps
N
+
H O
HO
OH
OH
HO
2
C
CO
2
–
2 (UT-231B)
4.5 Formation of Nonaromatic Heterocycles 131
Experimental Procedure (from Org. Process Res. Dev., 2006, 10, 484)
L-Lyxonolactone-2,3-O-isopropylidene (1). To D-ribonolactone-2,3-O-
isopropylidene (5) (50 kg, 266 mol, 1.0 equiv) was added DCM (750 L) and triethyl-
amine (29.8 kg, 41.0 L, 294 mol, 1.1 equiv) under nitrogen. This mixture was stirred
at ambient temperature until it became clear, and then it was cooled to 20 °C.
To this solution was slowly added methanesulfonyl chloride (33.3 kg, 22.5 L,
291 mol, 1.1 equiv), and the solution was stirred for 1 h at 20 °C. The solution was
allowed to attain ambient temperature, and it was maintained at this temperature
for 8 h. The reaction was quenched with water (400 L), and the organic layer was
separated. The aqueous layer was extracted with DCM (2 × 200 L). The organic
layers were combined, washed with water (2 × 200 L), and concentrated in vacuo
below 30 °C to obtain the semisolid mesylate (6). To this crude mesylate was added
a solution of KOH (36.5 kg, 651 mol, 2.44 equiv) in 245 L of water, maintaining the
temperature below 30 °C. This solution was stirred for 4 h at the same tempera-
ture and then adjusted to pH 2.5–3.0 by adding 3 M hydrochloric acid (33.5 L). The
acidic solution was concentrated in vacuo maintaining the temperature below 45 °C
to afford a solid mass. The solid mass was triturated with acetone (300 L) and heated
to reflux. The acetone was decanted, dried over sodium sulfate (35 kg), and filtered.
The clear filtrate was concentrated in vacuo below 35 °C to yield the crude product.
The product was crystallized from 2-propanol (100 L) to afford white, crystalline
L-lyxonolactone-2,3-O-isopropylidene (1), 17.1 kg (43.1%, on a 200-kg scale the
yield improved to 59%); mp 98–99 °C (lit mp 92–93 °C), [R]
D
25
89° (c = 1.0, acetone),
[lit [R]
D
20
85.6° (c = 1.0, acetone)]. IR (KBr):
3423, 1778 cm
1
.
1
HNMR (300 MHz, CDCl
3
): δ 1.36 (s, 3H, CH
3
), 1.44 (s, 3H,
CH
3
), 2.72 (brs, 1H, OH), 3.75–3.77 (d, 1H, C 5′H), 3.91–4.01 (m, 2H, C-5H and
C-5′H), 4.60–4.64 (m, 1H, C-4H), 4.83–4.89 (m, 2H, C-3H and C-2H). Anal. Calcd
for C
8
H
12
O
5
: C, 51.06; H, 6.38. Found: C, 50.96; H, 6.44.
The Mechanism
The process starts from a basic hydrolysis of the ester to form an intermediary epoxide
B via anion A. The configuration at C-4 is retained at this stage. Subsequently intra-
molecular ring opening of the epoxide by the carboxylate nucleophile in a favorable
5-endo-tet process [98] proceeds with inversion of configuration to afford 1.
Problem 35: Thermal Rearrangement of Ozonides
Ozonides (1,2,4-trioxolanes) are a class of cyclic peroxides that are structurally sim-
ilar to 1,2,4-trioxanes. Arterolane (OZ277) [99], which features an ozonide core
structure, is a recently approved antimalarial drug in several countries.
O
MsO
O
6
O O
KOH
−
OH
O
MsO
OH
O O
MsOK
KOH
O
O O
O
O
HO
O
1
O O
A
B
O
−
−
O
4 Mechanism Problems from Reactions Give Expected Products132
In 1993, our research group reported the thermal rearrangement of a stable ste-
roidal ozonide (1,2,4-trioxolane) 1 to form lactone 2 [ 100 ]. This reaction was discov-
ered serendipitously during a melting point determination. Ozonide 1 has a melting
point of 98–99 °C. While performing the melting point determination using a hot
plate, I momentarily stepped away to attend to another task. Upon returning, I real-
ized the temperature had already reached 150 °C, and the crystalline sample had
melted. Rather than discarding the molten material, I recovered it and analyzed it
using TLC, comparing it with the original crystalline sample. Surprisingly, the TLC
analysis revealed no trace of the starting ozonide 1; instead, a new, more polar major
spot was observed. The thermal reaction was subsequently repeated and scaled up
to obtain sufficient quantities of the pure product, which was ultimately identified
as lactone aldehyde 2 .
Please suggest a mechanism for the rearrangement from 1 to 2 .
Experimental Procedure (from J. Chem. Res., 1993, 30)
1
H and
13
CNMR spectra were measured on a Bruker AM-400 spectrometer using
CDCl
3
as solvent.
3 -Acetoxy-15-oxo-13,14;14,15-disecocholestano-14,13-lactone (2). Crystal-
line 1 (100 mg) was heated under nitrogen at atmospheric pressure in an oil bath
in which the temperature was controlled at 150 ± 2 °C for 20 min. The crude prod-
uct was purified by chromatography (8 g silica gel, eluent: 20% diethyl ether in
petroleum ether) to yield 2 as a viscous oil (80 mg, 80%) (Found: C, 72.9; H, 10.1.
C29H48O5 requires C, 73.07; H, 10.15%). ν
max
/cm
−1
(film) 1734 br vs, 1245, 1030.
δ
H
0.837 (3H, s, 19-H), 0.856, 0.859 (6H, 2d, J 6.6 Hz, 26, 27-H), 0.958 (3H, d, J
6.9 Hz, 21-H), 1.291 (3H, s, 18-H), 2.024 (3H, s, Ac-H), 2.315 (1H, ddd, J 16.0, 5.7,
and 2.6 Hz, 16-H), 2.474 (1H, td, J 11.6 and 4.3 Hz, 8β-H), 2.718 (1H, ddd, J 16.0,
7.8, and 3.2 Hz, 16-H), 4.683 (1H, m, 3 ɑ-H), 9.813 (1H, dd, J 2.7 and 2.9 Hz, 15-H).
δ
C
37.07 (C-1), 27.35 (C-2), 72.98 (C-3), 33.57 (C-4), 43.72 (C-5), 28.46 (C-6), 32.64
(C-7), 45.57 (C-8), 49.14 (C-9), 36.90 (C-10), 21.55 (C-11), 27.19 (C-12), 85.34 (C-13),
178.85 (C-14), 203.29 (C-15), 36.32 (C-16), 50.29 (C-17), 22.10 (C-18), 11.75 (C-19),
32.64 (C-20), 21.33 (C-21), 39.10 (C-22), 25.97 (C-23), 40.43 (C-24), 27.91 (C-25),
22.49 (C-26), 22.64 (C-27), 21.02 (Ac-CH
3
), 170.48 (Ac-C═O) . [
13
CNMR data for
3β-acetoxyandrostane: 21.3 (Ac-CH
3
), 169.9 (Ac-C═O) ] . m/z 476 (2%, M
+
), 458 (8),
432 (16), 363 (23), 307 (100).
The Mechanism
This thermal rearrangement should be similar to the mechanism of Baeyer–Villiger
oxidation. The most substituted alkyl group migrates to the peroxide oxygen and
thus the 1,2,4-trioxolane ring is cleaved to give the product 2 .
AcO
O O
O
H
H
H
H
150 °C
30 min
AcO
H
O
CHO
O
H
H
1
2
(80%)
O
O
O
NH
O
NH
2
Arterolane (OZ277)
4.5 Formation of Nonaromatic Heterocycles 133
To demonstrate that the migrating group maintains its stereochemistry, we
conducted the following reactions [101]. Heating ozonide 3 (neat) yielded lac-
tone 4. Reduction of 3 using Zn-HOAc produced the 1,5-dicarbonyl compound 5.
Subsequent Baeyer-Villiger oxidation of 5 proceeded with both regio and chemose-
lectivity, yielding lactone 4, which was identical to the product obtained from the
thermal rearrangement of 3.
4.5.2 Hydrofuran
Problem 36: Preparation of 2,2-Dimethyl-5-phenylfuran-3(2H)-one by a
Rearrangement
In 1958, Parker, Raphael, and Wilkinson reported an unusual rearrangement of
4-hydroxy-4-methyl-1-phenylpent-2-yn-1-one (1) to 2,2-dimethyl-5-phenylfuran-
3(2H)-one (2) in the presence of diethylamine [102]. Recently, that reaction was
applied to the synthesis of polmacoxib [103], which was approved in South Korea
for the treatment of colorectal cancer. The mechanism of the reaction was discussed
in the literature [102].
Please suggest your own mechanism for the reaction.
AcO
O O
O
H
H
H
H
AcO
H
O
CHO
O
H
H
1
2
H H
H
3
O
O O
150 °C
20 min
75%
H H
H
4
O
O
O
H H
H
5
O
O
Zn-HOAc
90%
mCPBA
CHCl
3
94%
O
OH
1
Et
2
NH, EtOH
O
O
2
4 Mechanism Problems from Reactions Give Expected Products134
Experimental Procedure (from J. Med. Chem., 2004, 47, 792)
Preparation of 2,2-Dimethyl-5-{4-(methylthio)-phenyl}-3(2H)-furanone (4).
To a stirred solution of 3 (120 mg) in 20 mL of ethanol was added dropwise dieth-
ylamine (0.08 mL) diluted in 7 mL of ethanol over 5 min at room temperature. The
reaction solution was stirred for another 1 h and then the solvent was removed
in vacuo. The resulting residue was diluted with 50 mL of water and then extracted
with DCM (30 mL × 3). The organic layer was concentrated in vacuo and subjected
to column chromatographic separation (hexane/ethyl acetate) 4:1) to give 90 mg
of 4 as a solid. mp: 107–109 °C. NMR: δ 1.48 (s, 6H), 2.54 (s, 3H), 5.91 (s, 1H), 7.30
(d, J = 8.4 Hz, 2H), 7.72 (d, J = 8.4 Hz, 2H). IR (cm
1
): 1676, 1579, 1485, 1376, 1174,
1095, 1050, 809.
Answer
Parker et al [102]. explained that the mechanism was initially a Michael addition of
diethylamine to the ynone (1) to form adduct A. Cyclization of A provided hemik-
etal B. Subsequently, an oxotropic rearrangement led to dihydrofuran C. Finally,
extrusion of diethylamine generated the product 2.
However, at the Michael addition stage, two geometric isomers, E-isomer A and
Z-isomer A′ could be produced. The Z-isomer A′ could not cyclize to form such
kind of B′. Although A′ could be converted to A through tautomerization, another
mechanism via the epoxide D or E is also possible.
Interconversion of the (Z)- and (E)-isomers (next page).
Problem 37: Decarboxylative Elimination of -Hydroxycarboxylic Acid
Rovafovir etalafenamide (GS-9131, 1) is a phosphonamidate prodrug of the nucle-
otide reverse transcriptase inhibitor (NtRTI). GS-9148 (2) is under investigation for
the treatment of HIV-1 infection by Gilead. The process chemistry of 1 involves a
key decarboxylative elimination of β-hydroxycarboxylic acid 3 along with protection
of the adenine as an iminophosphorane to yield the 2,3-dihydrofuran 4 [104, 105].
Please suggest a mechanism for the reaction from 3 to 4.
O
OH
3
Et
2
NH
EtOH, rt
O
O
4
75%
S
S
Steps
O
O
Polmacoxib
S
H
2
N
O
O
F
Ph
O
OH
1
Ph
O
O
2
HNEt
2
Ph
O
HO
O
Ph
O
A
B
H
O
Ph
C
O
H
NEt
2
NEt
2
NEt
2
Et
2
NH
4.5 Formation of Nonaromatic Heterocycles 135
O
Ph
O
B
H
Ph
O
OH
1
HNEt
2
Ph
O
HO
(E)-A
Ph
O
(Z)-Aʹ
OH
Ph
Bʹ
HO
O
+
NEt
2
Et
2
N
Et
2
N
NEt
2
Ph
O
Et
2
N
(Z)-Aʹ
OH
Ph
HO
Ph
O
HO
(E)-A
Ph
OH
Turn 180°
Et
2
+
N
O
–
O
–
N
+
Et
2
NEt
2
Ph
O
OH
Ph
OH
D
O
Ph
O
O
H
2
O
Ph
O
Ph
O
D
O
H
O
Ph
O
E
Et
2
N
Et
2
N
NEt
2
Et
2
NH
Et
2
NH
Et
2
N
Aʹ
O
F
N
OP
PhO
O
H
N
EtO
O
N
N
N
NH
2
1, Rovafovir etalafenamide
(GS-9131)
O
F
N
OP
O
N
N
N
HO
HO
2, GS-9148
NH
2
O
N
N
N
N
F
HO
HO
O
3
DIAD (3 eq.)
Ph
3
P (3 eq.)
THF or acetonitrile
O
N
N
N
N
N
F
4
PPh
3
77%; 72%
Steps
1
NH
2
4 Mechanism Problems from Reactions Give Expected Products136
Experimental Procedure (from Org. Process Res. Dev., 2021, 25, 1215)
Synthesis of N-(9-((2R,3S)-3-Fluoro-2,3-dihydrofuran-2-yl)-9H-purin-6-yl)-
1,1,1-triphenyl-
5
-phosphanimine (4). A reactor was charged with β-hydroxy-
acid 3 (70.0 kg, 97.4 wt % purity, 240.7 mol, scaling factor), triphenylphosphine
(2.7 kg/kg, 189.0 kg, 720.6 mol, 3.0 equiv), and acetonitrile (3.2 kg/kg, 224 kg,
285 L). To this mixture was slowly charged diisopropyl azodicarboxylate (2.1 kg/
kg, 147.0 kg, 727.0 mol, 3.0 equiv) while maintaining the internal temperature
of the reaction mixture below 30 °C. The mixture was agitated at 22 °C for 1 h,
after which seed crystals of 4 (0.001 kg/kg, 0.07 kg) were charged and agitation
was continued until the reaction was complete. After aging an additional 4 h,
isopropyl acetate (10 kg/kg, 700 kg, 805 L) was charged and the slurry was con-
centrated under reduced pressure (45 °C jacket temperature) to ca. 560 L (8 L/kg).
The temperature was adjusted to 37 °C, after which n-heptane (4.2 kg/kg, 294 kg,
430 L) was slowly charged to the slurry. The temperature was adjusted to 15 °C
over 2 h, the contents aged for an additional 5 h at 15 °C, and then filtered into
an agitated filter dryer. After deliquoring the filter cake, it was washed with pre-
heated MTBE (3.0 kg/kg, 210 kg, 284 L) at 40 °C and deliquored. The wet filter
cake was transferred back to the reactor and reslurried with MTBE (22 kg/kg,
1540 kg, 2081 L) at 40 °C for 3 h. The slurry was again filtered and after deliquor-
ing the filter cake, it was washed with preheated MTBE (3.0 kg/kg, 210 kg, 284 L)
at 40 °C and deliquored. The filter cake was again transferred back to the reactor
and reslurried with MTBE (22 kg/kg, 1540 kg, 2081 L) at 40 °C for 3 h. The slurry
was filtered a final time in an agitated filter dryer, rinsed with MTBE (1.1 kg/kg,
77 kg, 104 L), and thoroughly deliquored. The wet cake was dried under vacuum
at 40 °C to yield 90.8 kg of 4 as a tan, crystalline solid. The potency-adjusted yield
was 72.1%; 92.0 wt % purity.
1
H NMR (400 MHz, DMSO-d
6
) δ 8.09 (d, J = 3.5 Hz,
1H), 8.02 (s, 1H), 7.907.83 (m, 6H), 7.667.60 (m, 3H), 7.597.52 (m, 6H), 7.26
(dd, 1H), 6.75 (dd, J = 28.6 and 5.9 Hz, 1H), 5.82 (ddd, J = 60.1, 5.9, and 2.6 Hz,
1H), 5.64 (dd, J = 2.2 and 2.2 Hz, 1H).
13
C
{
1
H
}
NMR (101 MHz, DMSO-d
6
) δ 160.4
(d, J = 6.3 Hz), 153.5 (d, J = 12.1 Hz), 151.8, 149.9 (d, J = 5.1 Hz), 138.8 (d, J =
6.5 Hz), 132.7 (d, J = 9.9 Hz), 132.3 (d, J = 2.9 Hz), 128.7 (d, J = 12.2 Hz), 128.4 (d,
J = 99.9 Hz), 125.1 (d, J = 24.3 Hz), 101.1 (d, J = 16.6 Hz), 90.4 (d, J = 192.9 Hz),
83.6 (d, J = 14.5 Hz).
19
F NMR (376 MHz, DMSO-d
6
) δ 167.4 (dddd, J = 60.4,
28.7, 4.0, 4.0 Hz).
31
P
{
1
H
}
NMR (162 MHz, DMSO-d
6
) δ 16.3. HRMS (ESI/TOF)
m/z: [M + H]
+
Calcd for C
27
H
22
FN
5
OP 482.1541; Found 482.1554.
The Mechanism
This is a Mitsunobu type reaction. The initial steps follow the mechanism of
Mitsunobu reaction. However, once the intermediate A is generated, decarboxyl-
ation occurs to give B and triphenylphosphine oxide, rather than cyclized to the
unstable four-membered ring compound C. Since N─P bond energy (617 KJ/mol)
is greater than O─P bond energy (597 KJ/mol), further reaction of B with Ph
3
P═O
provides 4.
4.5 Formation of Nonaromatic Heterocycles 137
4.5.3 Tetrahydropyran
Problem 38: Construction of Fosdenopterin Core by Viscontini Reaction
Fosdenopterin is a medication used to reduce the risk of death due to a rare genetic
disease known as molybdenum cofactor deficiency type A. The synthesis of fosde-
nopterin was published [106]. The core unit 3 was prepared from compounds 1 and
2 as shown below.
Please suggest a mechanism for the reaction.
Experimental Procedure (from J. Med. Chem., 2013, 56, 1730)
(5aS,6R,7R,8R,9aR)-2-Amino-6,7-dihydroxy-8-(hydroxymethyl)-3H,4H,
5H,5aH,6H,7H,8H,9aH,10H-pyrano[3,2-g]pteridin-4-one (3). 2,5,6-Triamino-3,
4-dihydropyrimidin-4-one dihydrochloride (1, 10.0 g, 46.72 mmol), D-galactose
phenylhydrazone (2, 15.78 g, 58.38 mmol), and 2-mercaptoethanol (1 mL) were
stirred and heated under reflux (bath temp 110 °C) in a 1:1 mixture of MeOH/H
2
O
(400 mL) for 2 h. After cooling to room temperature, diethyl ether (500 mL) was
N
N O
O
O
O
DIAD
N
N
O
N
N
N
N
F
HO
O
O
H
N
H
N
O
N
N
N
N
F
HO
O
O
N
N
N
N
F
O
O
N
H
H
N
DIHD
O
N
N
N
N
F
O
4
O
N
N
N
N
F
O
O
H
H
A
CO
2
B
C
NH
2
P
+
Ph
3
CO
2
R
RO
2
C
RO
2
C
P
+
Ph
3
CO
2
R
Ph
3
P
RO
2
C
P
+
Ph
3
CO
2
R
H
2
O
NH
2
NH
2
–
O
NH
2
PPh
3
NH
2
−
–
O
HN
N
N
H
H
N
O
O
P
O
O
HO
OH
O
OH
Fosdenopterin
HN
N
H
2
N
O
+
HO
OH
OH
OHHO
N
NH
Ph
1
2
1. MeOH, H
2
O
110 °C, 2 h
2. TEA, rt
36%
HN
N
N
H
H
N
O
O
OH
OH
OH
H
H
Steps
3
NH
2
NH
2
H
2
N
H
2
N