rcm strategy for the enantiosynthesis of new polyhydroxylated quinolizidines, indolizidines and...
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NOBn
OO
H
NOBn
OO
H
NOBn
O
H
O
HO
HO
HO
HO
HO
HO
NOBn
NH
OBn
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HN
OHH
HO
HO
NOBn
NH
OBn
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HO
NH
OBn
ON
OBn
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NOH
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8a
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6
8a
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6
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7
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3
NOMe
OBocN
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NOMe
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NOHHO
NOAcHO
Cbz CbzN
OH
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NOH
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NOH
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NOH
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NOH
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1R 1S
1S
2S
2S 2R
2R
5S5S
6S 6S
8aR 8aR
9aR 9aR
.
RCM strategy for the enantiosynthesis of new polyhydroxylated RCM strategy for the enantiosynthesis of new polyhydroxylated quinolizidines, indolizidines and pyrrolizidinesquinolizidines, indolizidines and pyrrolizidines
Alessia Colombo, Nicola Landoni, Giordano Lesma, Alessandro Sacchetti and Alessandra Silvani
Dipartimento di Chimica Organica e Industriale,Università degli Studi di Milano, via Venezian 21 – 20133 Milano, Italy E-mail: [email protected] , [email protected]
Glycosidases are enzymes that catalyse the hydrolysis of glycosidic bonds in complex carbohydrates and glycoconjugates. They have been identified as an important class of therapeutic targets with applications in the treatment of influenza infection, cancer, AIDS, and diabetes. Since the beginning of the 1960s, a number of polyhydroxylated alkaloids that are potent glycosidase inhibitors have been found in plants and microorganisms. The first natural polyhydroxylated alkaloid to be detected was the piperidine alkaloid nojirimycin, isolated from a Streptomyces filtrate in 1966 by Inouye et al. The high therapeutic potential of these alkaloids, also called azasugars, has prompted considerable efforts towards their structural modifications and towards the design of new stereocontrolled synthetic routes also for unnatural isomers, which might be of interest for SAR studies. In fact, the specificity of natural alkaloids toward their molecular target remains to be optimized and novel synthetic strategies to expand the repertoire of available analogues are needed.
We are pursuing a noncarbohydrate based approach to various azabicyclic ring skeletons, starting from chemoenzimatically derived or commercially available chiral synthons and relying on RCM reactions in the key steps.
Nojirimycin isolated from Streptomices
THE KEY REACTION: DIHYDROXYLATION WITH OSO4
THE KEY REACTION: ENZIMATIC DESYMMETRIZATION WITH IONIC LIQUIDS
The ionic liquid 1-butyl-3-methylimidazolium hexafluorophosphate.
(1) With Candida Antarctica lipase and Vinyl acetate as solvent:
(2) With Candida Cylindracea lipase using stoichiometric vinyl acetate and 1-butyl-3-methylimidazolium hexafluorophosphate as solvent:
NHO OH
CbzOAc N
HO OAc
Cbz
1-butyl-3-methylimidazoliumhexafluorophosphate
, Lipase from CandidaCylindracea, 30°C
NHO OH
CbzOAc
NHO OAc
Cbz
C.A.L
, 30°C
Enzyme Solvent Yield ee Time
CAL Vinyl acetate 62% 90% 48 h
CCLVinyl acetate +
Ionic liquid80% 96% 7h
Heating Catalyst Solvent Temperature Yield Time
Oil bath
Microwave
Grubbs catalyst 2nd generation
5% mol
Toluene
Toluene
120°C
180°C
65%
72%
20h
60min.
T (°C)
10 60
180
40
THE KEY REACTION: RING CLOSING METATHESIS TS relative energies for
Quinolizidine derivatives dr calcd. dr exp.
α-Attack
0.0 Kcal/mol
76 75
β-Attack
0.7 Kcal/mol
24 25
a b
d
c
f
e
h
g
j
i
Reagents and conditions: (a) Vinyl acetate, C.C.L., 1-butyl-3-methylimidazolium hexafluorophosphate, 30°C, (62%), (b) (1) Swern oxidation, (2) t-BuOK, Ph3P(Me)Br, (3) KOH, MeOH, (54%), (c) Na2CO3, Acetone/Water, 2:1, Acryloyl chloride, (73%), (d) EDC, DMAP, 3-butenoic acid, (69%), (e) Grubbs catalyst 2nd generation 5% mol, Toluene, reflux, 20h, (65%), (f) Grubbs catalyst 2nd generation 5% mol, Toluene, reflux, 20h, (87%), (g) (1) OsO4, TMAO, (2) 2,2-dimethoxypropane, H+, (3) Chromatographic separation, (47%), (h) (1) OsO4, TMAO, (2) Chromatographic separation, (64%), (i) (1) BH3
.SMe2, EtOH (2) Acid resin (H+ form), (67%), (j) BH3·SMe2, EtOH, (85%).
Time (min.)
Second generation Grubbs’s ruthenium catalyst was very suitable for RCM, when the reaction was performed in toluene at reflux. The use of microwave irradiation in this step allowed to complete the reaction in 1 h compared with the 20 h required under conventional oil bath heating.
Second generation Grubbs’s ruthenium catalyst.
TS relative energies for Indolizidine derivatives
dr calcd. dr exp.
α-Attack
0.0 Kcal/mol
96 85
β-Attack
1.98 Kcal/mol
4 15
PM
3 C
alc
. (S
pa
rta
n ’0
6,
Wa
vefu
ctio
n).
5 : 1
3 : 1
NH
HO
OH
HO
Nojirimycin
OH
OH
Glycosidase catalyze the hydrolysis of the glycosidic linkage to generate two smaller
sugars.
(1R,2S,5S,8aR) (1S,2R,5S,8aR)
(1R,2S,6S,9aR) (1S,2R,6S,9aR)
N
OHn1
n2
HOOH
N
OHn1
n2
On3
n1 = 1,2n2 = 1,2
n1 = 1,2n2 = 0,1n3 = 0,1
NH
HO OAc
NHO
COOH
RETROSYNTHETIC STRATEGYFrom enzymatic
desymmetrization
Commercially available
Swainsonine isolated from Swainsona Canescens
N
Swainsonine
HOH
OH
OH
N
Lupinine
H
OH
Lupinine isolated from Maackia Hupehensis
NBnO
O
H
BocCu
RCu
FUTURE DEVELOPMENTS……
Cross Metathesis (CM)Cross Metathesis (CM)
NH
OHO
O
(S)-Pyroglutammic acid
NOBn
O
MeO
Boc
Reagents and conditions: (a) BnBr, iPr2EtN, CH2Cl2, 55°, 4h, (97%), (b) BOC2O, DMAP, CH3CN, r.t, 4h, (98%), (c) LiEt3BH, THF,-78°C, 3h, (98%), (d) pTSA, MeOH, r.t, 3h, (97%), (e) A: allylltrimethylsilane, BF3 etherate, Et2O, -78°C, r.t, 12h, (75%), 4:1 cis:trans, B: allylMgBr, CuBr·Me2S, BF3 etherate, Et2O, -78°C ,5h, r.t, 12h (55%), 96:4 trans:cis: C: vinylllithium, CuBr·Me2S, BF3 etherate, Et2O, -78°C, 6h, r.t, 12h, (42%), 4:1 trans:cis, (f) TFA, CH2Cl2, r.t, 12h, (A:76% cis, B:86% trans, C:57% trans), (g) acryloilchloride, Na2CO3, acetone, 4h, (A:84%, B:80%, C:81%), (h) Grubbs Catalyst 2nd Generation 5% mol, toluene, 120°C, 20h, (A:60%, B:67%, C:45%), (i) OsO4, TMAO, Acetone/Water, 3:1, 40°C, 3h, (A: 87% only (6S,7S), B:72% (6S,7S) 1,5%(6R,7R), C:60% only (6S,7S), (l) LiAlH4,THF, 1.5h, reflux, (A:90%, B:30%, C:40%).
Method
A
Method
B
Method
C
e, f
a, b, c, d
g, h
g, h
g, h
MONOMORINE I
Indolizidine 195B isolated from skin of Dendrobates Auratus
b
Reagents and conditions: (a) allyltrimethylsilane, BF3eterate, ET2O, -78°, r.t, 12h, (80%), (4:1cis/trans), (i) TFA, CH2Cl2, r.t, 3h, (30% cis), (ii) BOC2O, DMAP, TEA , CH3CN, r.t, 12h, (98%), (b) MVK, Grubbs-Hoveyda catalyst 5%mol, CH2Cl2, r.t, 12h, (55%).
a
Castanospermine from seeds of Castanospermum Australe
only (6S,7S)
only (6R,7R)
Nucleophilyc attack on N-acylimminium ion-copper complex
Trans Selectivity
Highly diastereoselective addition of alkylcopper reagents to the optically active N-acylimminium ions derived from proline; the mechanism involving nucleophilic attack on the less hindered face of the ion.
J. Org.Chem., 1995, 60, 5011-5015
N
OHHO
HOH
HO
Castanospermine
N
H
Indolizidine 195B
N
OHH
HO
HO
HO Australine
Australine isolated from Castanospermum Australe
i
i
i
l
l
l
36 : 1 (6S,7S) (6R,7R)
(commercially available)
(3S,6S,7R,8aR)
(3S,6R,7S,8aS)
(3S,6R,7S,7aS)
N
H
Monomorine I
Monomerine I isolated from Monomorium pharaonis