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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 Products278
Experimental Procedure (from WO2014, 165815, A2)
6 -Imidazol-lyl-3,5-cycloandrostan-17-benzimidazole-l-yl-16-ene (5), 3ɑ-(lH-
imidazol-l-yl)-17-(lH-benzimidazol-l-yl)androsta-5,16-diene (4) and 3 -(lH-
imidazol-l-yl)-17-(lH-benzimidazol-l-yl)androsta-5,16-diene (2). A round bot-
tom flask equipped with Dean-Stark apparatus and condenser is charged with 3
(0.6 g, 1.3 mmol), imidazole (0.3 g, 4.4 mmol) and toluene. Reaction mixture is
refluxed for 12 h. Reaction mixture is cooled, solvent is evaporated under vacuum,
and the residue is washed with water to get a crude product. Purification by FCC [1%
ethanol in DCM with traces of TEA] to get product of three components 2, 4, and 5
(0.23 g, 61%): This three-component mixture was subjected to preparative HPLC for
the isolation of individual compounds. HPLC separation: Preparative HPLC separa-
tion was performed on Waters Prep Nova-Pak (7.8 × 300 mm, 60 A, 6 µm) HR C-18
reversed-phase HPLC column (Waters, Milford, MA) coupled with Waters 2489 UV/
visible detector operated at 254 nm. Elution was performed using Waters model 2535
Quartenary Gradient Module pump to deliver a constant flow rate of 6 mL/min.
The solvent system consisted of water/MeOH/CH
3
CN (200:500:300, v/v/v + 500 µ
of TEA per 1000 mL of mobile phase) and maintained isocratically. Sample stock
N
N
HO
1, Galeterone
N
N
N
N
2
N
N
HO
1, Galeterone
MsCl, DCM
TEA, 4 °C
100%
N
N
MsO
3
Imidazole
toluene
reflux, 12 h
N
N
2 (11%)
N
N
4 (3%)
5 (35%)
N
N
1
3
5
16
4.8 Miscellaneous 279
solution was prepared by dissolving 200 mg (three-component mixture obtained
by FCC) in 20 mL of mobile phase. A total of 20 injections, each with a volume of
1 mL and a run time of 13 minutes, was performed. Compound 5 was collected bet-
ween 5.12 and 6.73 min, 4 collected between 7.77 and 8.93 min and 2 was collected
between 10.07 and 12.09 min. Figure shows an example of HPLC chromatogram of
a three-component mixture. The retention times for 5, 4 and 2 were 5.14, 7.87 and
10.07 min, respectively. See Figure 11. 33063
6 -Imidazol-lyl-3,5-cycloandrostan-17-benzimidazole-l-yl-16-ene (5).
Retention time 5.14 min; 0.13 g, 34.6%: mp 104–106 °C;
1
HNMR (400 MHz,
DMSO-d
6
) δ ppm 0.67 (s, 3H), 0.91 (s, 3H), 3.73 (br. s., 1H), 6.09 (s, 1H), 6.93 (br. s.,
1H), 7.21–7.33 (m, 2H), 7.36 (s, 1H), 7.57 (d, J = 7.82 Hz, 1H), 7.70 (d, J = 7.58 Hz,
1 H), 7.85 (br. s., 1 H), 8.25 (s, 1 H);
13
CNMR (400 MHz, CDC1
3
) 5147.35, 143.24,
141.49, 136.41, 134.47, 128.62, 123.52, 123.48, 122.54, 120.21, 1 18.13, 1 1 1.07, 58.61,
55.37, 48.47, 47.42, 43.24, 35.18, 34.90,, 34.34, 33.34, 30.14, 29.19, 24.78, 24.24, 22.01,
19.72, 16.25, 14.31; HRMS calcd 439.2856 (C
29
H
34
N
4
O)H
+
, found 439.2858.
3ɑ-lH-imidazol-l-yl)-17-(lH-benzimidazol-l-yl)androsta-5,16-diene
(4).
Retention time, 8.87 min. 0.012 g, 3.2%. m.p. 199–200 °C.
1
HNMR (400 MHz,
DMSO-d
6
) δ 0.97 (s, 3H, 18-CH
3
), 1.10 (s, 3H, 19-CH
3
), 4.42 (br. s., 1H, 3β-Η), 5.53
(br. s., 1H, 6-H), 6.06 (br. s., 1H, 16-H), 6.86 (s, 1H), 7.19–7.33 (m, 3H), 7.56 (d, J =
7.83 Hz, 1H), 7.69 (d, J = 7.34 Hz, 2H), 8.24 (s, 1H);
13
CNMR (400 MHz, CDC1
3
) δ
147.11, 143.29, 141.64, 139.13, 134.58, 128.56, 124.18, 123.41, 123.36, 122.48, 120.22,
118.70, 1 11.13, 55.74, 53.00, 50.19, 47.23, 37.27, 35.97, 34.74, 32.29, 31.12, 30.23,
30.20, 29.71, 28.39, 20.27, 19.32, 16.01; HRMS calcd 439.2856 found 439.2857.
3 -(lH-imidazol-l-yl)-17-(lH-benzimidazol-l-yl)androsta-5,16-diene (2).
Retention time 10.074 min; 0.04 g, 10.6%: mp 198–200 °C;
1
HNMR (400 MHz,
DMSO-d
6
) δ ppm 0.99 (s, 3H), 1.12 (s, 3H), 3.93–4.03 (m, 1H), 5.47 (d, J = 4.65 Hz,
1H), 6.07 (s, 1H), 6.88 (s, 1H), 7.23–7.32 (m, 2H), 7.33 (s, 1H), 7.57 (d, J = 7.58 Hz,
1H), 7.71 (d, J = 7.58 Hz, 1H), 7.74 (s, 1H), 8.27 (s, 1H).
13
CNMR (400 MHz, CDC1
3
)
δ 147.25, 143.40, 141.72, 140.20, 134.68, 129.27, 124.21, 123.55, 122.63, 122.39,
120.34, 116.97, 111.26, 57.54, 55.92, 50.62, 47.35, 40.67, 38.00, 37.03, 34.94, 31.17,
30.41, 30.02, 29.83, 20.73, 19.47, 16.15, 0.14; HRMS calcd 439.2856 (C
29
H34N
4
O)H
+
,
found 439.2858.
The Mechanism
Direct substitution of the mesylate by imidazole (SN2 mechanism) provides 4.
Due to the participation of C5═C6 double bond, ionization of mesylate produces
homoallylic hybrid carbonium ion intermediate A. The nucleophile (imidazole)
attacks the C3 position to generate products 2 and 4, while attack at the C6 position
leads to product 5. However, since the reaction is highly stereoselective, favoring the
formation of the 6β-isomer, a synergistic process is also reasonable.
4 Mechanism Problems from Reactions Give Expected Products280
Nucleophilic substitution of this type of homoallylic hybrid carbonium ion has
been previously reported [327–329].
Problem 116: Preparation of 21-Hydroxypregna-4,9(11), 16-triene-3,20-dione-
21-acetate
Dexamethasone (3) is a steroid drug first approved in 1958 and has shown mortality
reduction in severe COVID-19 patients [330]. In a synthesis of compound 3,
21-hydroxypregna-4,9(11),16-triene-3,20-dione-21-acetate (2) was a key intermediate
[331]. This intermediate (2) was also prepared from 1 in 3 steps via precursor 4 [332].
Please propose a mechanism for the reaction from 4 to 2.
Experimental Procedure (from US 4,216,159, August 5, 1980)
21-Hydroxypregna-4,9(11),16-triene-3,20-dione-21-acetate (2). Anhydrous
sodium acetate (5.8 g.) and DMF are stirred and heated at 120 °C under nitrogen.
Crystalline 20-chloropregna-4,9(11),17(20)-triene-3-one-21-al (4, 12 g) was added in
portions of 2 gm every 20 minutes. The mixture was stirred for 90 minutes at 120 °C,
then cooled, and toluene (100 mL) was added. The mixture was extracted with
sodium chloride (5%, 2 × 100 mL) and backwashed with toluene (2 × 20 mL). The
N
N
4
N
N
2
5
N
N
MsO
3
MsO
–
A
A
Imidazole
(SN2 at C3)
Imidazole
(SN1 at C3)
Imidazole
attacks C3
Imidazole
attacks C6
MsO
Nu
Imidazole
synergistic
MsOH
5
N
N
MsO
–
+
+
TsO
OMe
MeOH, KOAc
LiN
3
MeOH
N
3
4.8 Miscellaneous 281
toluene phase was dried over magnesium sulfate and concentrated under reduced
pressure to give the title compound, m.p. 120–124 °C, PMR (CDCl
3
) 0.89, 1.35, 2.18,
4.95, 5.55, 5.72 and 6.74 δ.
The Mechanism
The first reaction should be a Michael addition of KOAc to the , β-unsaturated
aldehyde 4 to give the enol salt A. Then Ac migrates to the enol via intramolecular
transesterification to provide potassium tert-alkoxide B. Intramolecular addition
of the oxygen anion to the double bond in B, followed by elimination of KCl via
intermediate C, generates methylene oxirane D. Finally, rearrangement of the oxi-
rane, possibly catalyzed by K
2
CO
3
, leads to the product 2.
4.8.2 Macrolide
Problem 117: An Ascomycin Rearrangement
Ascomycin 1, also known as immunomycin, is an ethyl analog of tacrolimus that
exhibits potent immunosuppressive activity. It has been investigated for its potential
in treating autoimmune disorders, skin conditions, and in preventing organ trans-
plant rejection. When compound 1 was reacted with triethylamine (Et
3
N) and a
catalytic amount of KOH in refluxing acetonitrile, a rearranged product, compound 2,
was obtained with a yield of 65% [333].
O
H
HO
F H
OH
HO
O
3, dexamethasone
O
H
H
Cl
CHO
4
AcOK, Ac
2
O
K
2
CO
3
, DMF
106 °C
O
H
H
AcO
O
2
O
H
O
H
1
2 steps
O
H
H
AcO
O
2
Ref. 331
7 steps
steps
Ref. 330 Ref. 330
Ref. 331
O
H
H
Cl
4
AcOK
AcO
–
H
Cl
O
O
O
O
–
K
+
H
Cl
OAc
H
Cl
AcO
O
KCl
H
O
OAc
H
O
H
H
AcO
O
2
A
B
C
D
CO
3
2–
Cat.
K
2
CO
3
O
–
K
+
K
+
–
4 Mechanism Problems from Reactions Give Expected Products282
Please suggest a mechanism for this rearrangement.
Experimental Procedure (from Org. Process Res. Dev., 2001, 5, 211)
Procedure for the Ascomycin Rearrangement Step. Crystallized ascomycin
(1, 31.8 kg (98.1%) and 19.3 kg (97.0%)) was dissolved in 529 L toluene at 70 °C
jacket temperature in a 630 L stainless steel reaction vessel and the solvent was
distilled at 60 °C jacket temperature to effect azeotropic water removal. The residue
was redissolved in 427 L of acetonitrile, and 37.96 kg of triethylamine and 56.5 g
of KOH (90%) were added. The suspension was refluxed at 74 °C internal tempera-
ture (corresponding to a jacket temperature of about 100 °C) for 7 h. Afterward, the
suspension was cooled to an internal temperature of 50 °C, and a second portion of
56.5 g of KOH (90%) was added. The suspension was again refluxed at 74 °C internal
temperature for 5 h, and finally the solvents were removed by distillation at a jacket
temperature of 60 °C/process vacuum. The residue was dissolved in 136 L of ethyl
methyl ketone at 60 °C internal temperature, and 80.0 L heptane was added. On
cooling to room temperature (20–25 °C), the product precipitated within 2.5 h. The
suspension was filtered via a centrifuge (80 cm i.d.) equipped with a Meraklon filter
plate. The product was washed with 34 L of ethyl methyl ketone/heptane) 1/4 (V/V)
and dried at 60 °C/<20 mbar. Yield: 33.6 kg (assay: 78.9%, purity: 82.5%, 21-epimer:
11.8%).
The Mechanism
At the basic conditions, the semi-acetal or tetrahydropyran is cleaved to release the
carbonyl compound A, which is epimerized to C via enol B. At this stage, there are
two possible pathways to go further. The path A is the C-14 hydroxyl cyclized with
C-9 carbonyl to form a seven-membered semi-acetal D followed by C-8 acyl shifts
to C-10 to give lactone E. Intramolecular ester condensation between C-2 and C-9
leads to product 2.
O
O OH
N
O
O
O
OMe
OMe
HO
O
HO
MeO
1
2
4
7
8
14
21
24
9
10
Et
3
N (6 eq.)
KOH (0.016 eq.)
CH
3
CN
reflux, 16 h
65%
O
O OH
N
O
OH
OMe
OMe
O
HO
MeO
O
OH
1 (Ascomycin)
2
4.8 Miscellaneous 283
From intermediate C, another possible pathway (path B) is the aldol condensation
between C-2 and C-10. This would generate intermediate F. Then alkyl shifts from
C-10 to C-9 provides product 2.
4.8.3 Gibberellin
Problem 118: An Acyloin Rearrangement in Gibberellin
Gibberellins (GAs) are plant hormones that regulate various developmental
processes, including stem elongation, germination, dormancy, flowering, flower
development, and leaf and fruit senescence. In a synthesis of gibberellin natural
product, compound 2 was obtained in high yield from compound 1 by isomerization
in the presence of MeONa [334].
Please propose a mechanism for this transformation.
N
O
O
O
OMe
O
O
1
2
4
7
8
14
9
10
O
O OH
N
O
OH
OMe
OMe
O
HO
MeO
O
OH
1 (Ascomycin)
2
H
HO
–
KOH
N
O
O
OH
OMe
O
O
1
N
O
O
OH
OMe
HO
O
1
9
11
A
B
N
O
O
OH
OMe
O
O
1
C
9
11 14
Path A
N
O
O
O
OMe
O
O
1
D
11
14
H
N
O
O
OMe
HO
O
E
11
14
Acyl
shift
O
H
Base
N
O
H
O
O
O
Base
OMe
OH
Path B
C
N
O
O
O
O
H
OMe
OH
F
Alkyl
shift
2
2
10
O
HO O
H
O
MeONa
MeOH, DCM
H
MeO
2
C
MOMO
OC
O
OH
O
H
H
MOMO
OC
O
OH
1
2
84%
MeO
2
C
4 Mechanism Problems from Reactions Give Expected Products284
Experimental Procedure (from Tetrahedron, 1998, 54, 11637)
ent- 10 ,13,14ɑ-Trihydroxy-3ɑ-methoxymethoxy-16-oxo-
17,20-dinorgibberellane-7,19-dioic acid 7-methylester 19,10-lactone (2). 5 mg
of NaH (60% in mineral oil) was added to a solution of ketol 1 (10 mg) in CH
2
Cl
2
(1 mL) under a N
2
atmosphere at 25 °C followed by one drop of MeOH. The reac-
tion was quenched with saturated KH
2
PO
4
and the organic layer washed with brine,
dried, reduced to dryness, and chromatographed on silica gel (EtOAc/hexane, 1 : 1)
to afford 2 as a white solid (8.4 mg, 84% yield), m.p. 235–236 °C. Calcd. For C
21
H
28
O
9
C, 59.43; H, 6.65; found C, 59.14; H, 6.36%.
1
HNMR (300 MHz, CDCl
3
) δ 1.22 (3H, s,
4-Me), 2.23 (1H, d, J = 18.7 Hz, H15), 2.41 (1H, d, J = 18.7 Hz, H15), 3.15 (1H, d, J =
9.4 Hz, H6), 3.27 (1H, d, J = 9.4 Hz, H5), 3.38 (3H, s, OMe), 3.68 (1H, br s, H3), 3.73
(3H, s, CO
2
Me), 4.28 (1H, s, H14), 4.63 (1H, d, J = 7.1 Hz, OCH
2
O), 4.74 (1H, d, J =
7.1 Hz, OCH
2
O).
13
CNMR (75 MHz, CDCl
3
) δ 14.4 (C18), 15.8 (C11), 24.6 (C1), 26.8
(C2), 32.5(C12), 44.3 (C15), 49.8 (C6), 51.2 (C8), 52.4 (CO
2
Me), 54.0, 55.6 (C9, C5),
54.3 (C4), 55.8 (OMe), 75.4, 76.7 (C14, C3), 81.5 (C13), 93.0 (C10), 95.8 (OCH
2
O),
173.4 (C7), 177.4 (C19), 216.8 (C16). MS (EI) m/z 424 (M+, 14%), 406 (6), 293 (35),
365 (97), 332 (100), 316 (30), 301 (20), 157 (40), 143 (27), 129 (26), 117 (18), 105 (30),
91 (34), 79 (21). HRMS found 424.1734, C
21
H
28
O
9
requires 424.1733.
The Mechanism
Treatment of acetate 1 with MeONa leads to the hydrolysis of the 13-acetate, fol-
lowed by an acyloin rearrangement to yield product 2.
Another possible pathway, as shown below, is less reasonable since the
four-membered intermediate is less stable than the five-membered intermediate.
4.8.4 Cannabicitran
Problem 119: Formation of Cannabicitran During the Synthesis of
Cannanbichromene
Cannanbichromene (CBC, 1) exhibits anti-inflammatory properties in vitro, which
may contribute to cannabis analgesic effects. Cannabicitran (CBTC, 2) is a phyto-
cannabinoid natural product as a trace component of Cannabis sativa. It was found
O
HO O
H
O
MeO
–
HO O
H
MeONa
MeOAc
HO OH
H
O
O
H
OH
OH
1
2
O
–
O
HO O
H
O
MeO
–
HO O
H
MeONa
MeOAc
HO O
H
O
H
O
H
OH
OH
1
2
O
–
4.8 Miscellaneous 285
to reduce intraocular pressure in tests on rabbits. In a biomimetic-like synthesis of
cannanbichromene (1), the mixture of citral (3) and olivetol (4) in water was heated
at reflux to give cannanbichromene (1, yield 45%) and cannabicitran (2, yield 5%)
[335]. When 0.2 equivalent of NH
4
Cl was added, the reaction time was reduced to
24 hours and the yield of 1 was improved to 75%.
Please propose mechanisms for the formation of 1 and 2.
Experimental Procedure (from J. Org. Chem., 2021, 86, 3344)
Reaction of Citral with Phenolic Compounds in Water: General Procedure.
To a round bottom flask containing citral were added the phenolic compound and
water. The mixture was then heated at refluxing temperature (oil bath) until the dis-
appearance of the starting material. Then, brine was added, and the aqueous phase
was extracted with EtOAc (×3). The organic layer was dried with Na
2
SO
4
and con-
centrated under a vacuum. The residue was purified by column chromatography.
Using Olivetol as a Phenolic Compound. According to the general procedure,
the reaction of citral (150 mg 0.8 mmol) with olivetol (300 mg, 2.4 mmol) in reflux-
ing water (22.5 mL) for 52 h provided after flash chromatography (H/MTBE, 5:1)
45% of 1 as a colorless oil (113 mg, 0.43 mmol) and 5% of compound 2 as a colorless
oil (13 mg, 0. 04 mmol).
Cannabicitran (2):
1
HNMR (600 MHz, CDCl
3
) δ 6.32 (s, 1H,), 6.27 (s, 1H,), 2.85
(bs, 1H), 2.50 (t, J = 7.7 Hz, 2H), 2.21 (dt, J = 13.1, 4.1 Hz, 1H), 2.01 (ddd, J = 11.3,
5.0, 2.7 Hz, 1H), 1.82 (d, J = 13.1 Hz, 1H), 1.76 (bd, J = 15.3 Hz, 1H), 1.591.53
(m, 2H), 1.51 (s, 3H,), 1.41 (dt, J = 14.5, 7.0 Hz, 1H), 1.37 (s, 3H), 1.341.20 (m, 5H),
1.01 (s, 3H), 0.87 (t, J = 7.0 Hz, 3H), 0.65056 (m, 1H);
13
C
{
1
H
}
NMR (151 MHz,
CDCl3) δ 156.9, 156.5, 142.5, 114.0, 109.7, 108.8, 83.5, 74.4, 46.8, 37.3, 36.1, 35.3,
31.4, 30.9, 29.7, 29.0, 28.1, 23.7, 22.5, 22.1, 14.0; HRMS (ESI-TOF) m/z [M + H]
+
calcd for C
21
H
30
O
2
315.2324, found 315.2324.
The spectra data of cannanbichromene (CBC, 1) reported in a recent article [336]
(Supporting Information) are listed here. R
f
– 0.20 (20:1 Hexane:EtOAc).
1
HNMR
(500 MHz, CDCl
3
) δ 6.61 (d, J = 10.0 Hz, 1H), 6.25 (s, 1H), 6.12 (s, 1H), 5.49 (d, J =
10.1 Hz, 1H), 5.10 (t, J = 7.2 Hz, 1H), 4.73 (s, 1H), 2.44 (t, J = 7.8 Hz, 2H), 2.14 – 2.07
(m, 2H), 1.75 – 1.68 (m, 1H), 1.66 (s, 3H), 1.64–1.61(m, 1H), 1.58 (s, 3H), 1.57–1.50
(m, 2H), 1.38 (s, 3H), 1.31 (td, J = 8.5, 7.3, 4.9 Hz, 4H), 0.88 (t, J = 6.8 Hz, 3H).
13
CNMR (126 MHz, CDCl
3
) δ 154.19, 151.11, 144.90, 131.77, 127.38, 124.33, 116.91,
109.28, 107.80, 107.11, 78.31, 41.19, 36.04, 31.61, 30.77, 26.39, 25.81, 22.85, 22.68,
O
OH
HO
+
Citral (3)
Olivetol (4)
H
2
O (0.045 M)
reflux, 51 h
OH
n-C
5
H
12
O
Cannanbichromene
(1, 45%)
+
O O
H
Cannabicitran
(2, yield 5%)
n-C
5
H
12
n-C
5
H
12
4 Mechanism Problems from Reactions Give Expected Products286
17.76, 14.16. HRMS – (ES+, m/z) [M + H]
+
calcd. for C
21
H
31
O
2
315.2324; found,
315.2314. IR – (ATR, neat, cm
1
): 3404 (br), 2962 (s), 2928 (m), 2858 (s), 1624 (m),
1576 (m), 1430 (m), 1083 (m), 774 (m).
The Mechanism
Due to its 1,3-dihydroxylbenzene function, olivetol (4) acts as a good nucleophile,
undergoing aldol condensation with citral (3) to form intermediate A. After dehy-
dration of A, intermediate B is produced, which undergoes an oxo-6π electrocycli-
zation to afford cannanbichromeme (CBC, 1). The weak acidic ammonium chloride
plays dual functions as an activator and a catalyst for both the aldol reaction and the
dehydration, thus accelerating the formation of cannanbichromene (1).
The phenol from CBC could be an equilibrium with its quino form of CBC
(CBC-quinone). An intramolecular Diels-Alder reaction of the CBC-quinone will
lead to the tetracyclic compound 2.
O
OH
O
n-C
5
H
12
Citral (3)
Olivetol (4)
OH
O
OH
A
H
OH
O
H
2
O
H
OH
O
1, cannanbichromene
Oxo 6π
electrocyclization
Dehydration
Aldol
reaction
B
H
N
+
H
H
H
H
N
+
H
H
H
Cl
–
n-C
5
H
12
n-C
5
H
12
n-C
5
H
12
Cl
–
O
n-C
5
H
12
O
1 (CBC)
H
O
O
1 (CBC-quinone)
O
O
1 (CBC-quinone)
Intramolecular
D-A reaction
O O
H
2
n-C
5
H
12
n-C
5
H
12
n-C
5
H
12
4.8 Miscellaneous 287
4.8.5 Serratezomine
Problem 120: Transformation of Serratinine into Serratezomine A
Lycopodium alkaloids exhibiting marked anticholinesterase activity [337]. In a
related study, Morita and Kobayashi transformed serratinine (1) into serratezomine
A (2) and a minor product 3 by the following reaction [338]. Serratezomine A (2)
was converted to compound 3 by treatment with p-TsOH. They also proposed the
mechanism for the transformation.
Could you please draw your own mechanism for the formation of 2 and 3?
Experimental Procedure (from J. Org. Chem., 2002, 67, 5378)
A Modified Polonovski Reaction for Serratinine (1). m-Chloroperbenzoic acid
(8 mg, 0.047 mmol) in 0.1 mL of CH
2
Cl
2
was added at 0 °C to a stirred solution of
serratinine (1, 10 mg, 0.036 mmol) in 0.1 mL of CH
2
Cl
2
. After 1 h, the reaction mix-
ture was concentrated and then trifluoroacetic anhydride (0.02 mL, 0.14 mmol) was
added to a stirred solution of the residue in dry CH
2
Cl
2
(0.2 mL) under N
2
at 20 °C.
After 1 h, excess solvent and TFAA were immediately distilled off in vacuo at 0 °C.
The residue was dissolved in MeOH (0.1 mL), and excess NaBH
3
CN was added at
0 °C. After 15 min, the reaction mixture was poured into H
2
O (10 mL) and extracted
with CHCl
3
. C18 HPLC (15% CH
3
CN/0.1% TFA) of the residue afforded compounds
2 (4.8 mg, 48%) and 3 (2.7 mg, 27%). 2: [ɑ]
D
+12° (c 0.6, MeOH), spectral data
and [ɑ]
D
value were identical with those of serratezomine A (2), [ɑ]
D
+13° (c 0.5,
MeOH) [339]. 3: colorless solid; [ɑ]
D
+15° (c 0.5, MeOH); FABMS m/z 280 (M +
H)
+
; HRFABMS m/z 280.1926 (M + H; calcd for C
16
H
26
NO
3
, 280.1939); IR (neat)
ν
max
3374, 3148, 2928, 1780, 1680, and 1195 cm
1
;
1
HNMR (CD
3
OD) δ 3.16 (1H, m,
H-1a), 3.41 (1H, ddd, 10.1, 10.1, 10.1, H-1b), 2.15 (2H, m, H-2), 2.22 (1H, m, H-3a),
2.38 (1H, m, H-3b), 4.02 (1H, dd, 6.8, 12.3, H-4), 2.53 (1H, m, H-6a), 2.61 (1H, dd,
14.1, 16.5, H-6b), 2.35 (1H, m, H-7), 4.44 (1H, dd, 5.4, 12.4, H-8), 2.96 (1H, dt, 3.6,
13.3, H-9a), 3.14 (1H, m, H-9b), 1.74 (1H, brd, 14.5, H-10a), 2.52 (1H, dd, 7.4, 16.5,
H-10b), 1.65 (1H, brd, 13.7, H-11a), 1.88 (1H, dd, 5.0, 14.1, H-11b), 3.95 (1H, dd,
4.8, 11.5, H-13), 1.82 (1H, ddd, 1.9, 4.8, 14.6, H-14a), 2.03 (1H, ddd, 5.3, 11.6, 16.7,
H-14b), 2.46 (1H, m, H-15), 1.04 (3H, d, 7.2, H-16);
13
CNMR (CD
3
OD) δ 54.0 (C-1),
19.7 (C-2), 24.0 (C-3), 63.9, (C-4), 177.5 (C-5), 36.8 (C-6), 43.6 (C-7), 80.8 (C-8), 47.8
(C-9), 21.4 (C-10), 30.4 (C-11), 42.2 (C-12), 76.0 (C-13), 32.3 (C-14), 31.3 (C-15), 11.6
(C-16).
Chemical Conversion of Serratezomine A (2) into Compound 3. A solution
of 2 (1 mg) and p-toluenesulfonic acid (0.1 mg) in 1:1 CHCl
3
/MeOH (0.1 mL) was
stirred at 50 °C for 3 h and then concentrated under reduced pressure. The residue
N
O
OH
OH
H
1
1, mCPBA, DCM, 0 °C, 1 h
2, TFAA, –20 °C, 1 h
3, NaBH
3
CN, MeOH, 0 °C, 15 min
HO
H
2 (48%)
O
O
H
N
H
+
O
3 (27%)
O
N
H
H
OH
p-TsOH, CHCl
3
MeOH, 50 °C