Synthesis Challenge # 34
Formal Synthesis of Sarain A: Intramolecular Cycloaddition of an Eight-Membered Cyclic Nitrone to Construct the
2-Azabicyclo-[3.3.1]nonane Framework, T. Higo, T. Ukegawa, S. Yokoshima,T. Fukuyama, Angew. Chem.Int. Ed. 2015,
DOI: 10.1002/anie.201501633
O
MeO
TBSO
H
1) 9-BBN
(1.05 equiv), then aq.
Ph Ts
N
NaHCO
3, aq. H2O2 (30 wt %)
Ru equiv), CH Cl ,
2) DMP (1.2
2 2
N Cl
3) Ph
vinylmagnesium
bromide
Tsimidazole, DMF; V
4) TBSCl,
CO3 (1.0 equiv), MeOH,
2K
O
O
OH
TBSO
H
OBn
B
1-6
H
OTBDPS
OBn
O
BocO
N
Boc
OBn
IV
A
?
OPMP
N
Please design an asymmetric synthesis
of B starting from A.
H
C
PMPO
Cl
VI
1) ClCO2Et, Et 3N, THF, 0 ºC ;
NaBH
4, H2O, 0 ºC to RT
2) TBDPSCl, imidazole, DMF, RT;
TFA, 2HO
3) BocNHOBoc, DEAD, Ph3P,
toluene, RT;
4) CAN, NaHCO3, MeCN-H2O, 0ºC
5) (COCl)2, DMSO, CH2Cl2, –78ºC;
N, 0ºC
3Et
6) H2C=NMe2+I–, iPr 2NEt,
CH
2Cl2, reflux; MeI, RT
a) n BuLi, THF, –78ºC; IV, 0ºC
b) V (2 mol%), HCO 2H-Et 3N (1:1),
CH2Cl2, –78 to 0 ºC
c) Red-Al, toluene, RT
d) VI, pyridine, CH2Cl2, 0 ºC
e) LHMDS, TMSCl, Et2O/THF
Please, provide a detailed mechanism
for step 5 & 6.
Step 5: Swern Oxidation
Step 6: Eschemoser Methylation
7) TFA, CH2Cl2, 40ºC; pyridine, 40ºC
8) 9-BBN, THF, RT;
aq. NaOH, aq. 2HO2, RT
9) (COCl)2, DMSO, CH2Cl2, –78 ºC;
N, 0 ºC
3Et
10) aq. HCHO, K 2CO3, 1,4-dioxane, RT
11) toluene, 100ºC;
PivCl, pyridine, DMAP, 100ºC
7-11
O
OPiv
OTBDPS
N
O
OBn
D
12) I, LHMDS, THF, –78 to 0ºC
13) Zn, AcOH-Et2O (1:2), RT
14) II, aq. NaHCO3, CH2Cl2, 0ºC
15) MsCl, Me2N(CH2)3NMe2, CH2Cl2
16) Grubbs II, CH2Cl2, RT
12-16
N
MsO
O
Ph
S
N
N
N N
O
OTBDPS
Julia Kocienski Olefination
OBn
F
17-21
17) TBAF, THF, RT; t BuOK
18) MsCl, i Pr 2NEt, CH2Cl2, 0ºC;
TESOTf
19) NaN3, DMSO, 90ºC; TBAF, 60ºC
20) PivCl, pyridine, DMAP, toluene,
100 ºC
21) H2 (1 atm), Pd(OH) 2 /C,
AcOH/MeOH (1:19), RT
OPiv
O
N
NH2
OH
I
Please, provide a detailed mechanism
for step 12.
OPiv
O
Please, provide a detailed mechanism
for step 7.
G
O
Cl
II
22) TsCl, aq. NaHCO3, CH2Cl2, RT
23) TIPSOTf, i Pr 2NEt, CH2Cl2, 0ºC
24) III, I2, Cs2CO3, CH2Cl2, RT
22-24
N
OPiv
O
I
NH
N
In
OH H
25) TBAF, THF, RT
26) lithium naphthalenide, THF, –78 ºC
25-26
OPiv
O
NH
N
I
O
27) AcOH, 50 ºC
28) TFAA, pyridine, THF, 0 ºC ;
aq. NaHCO
3, RT
29) PMBOC(=NH)CCl3, TfOH, CH2Cl2
30) LiBH4, MeOH, THF, 50ºC
31) LiAlH4, AlCl3, Et2O/THF (14:1)
27-31
OH
N
PMBO
O
I
N
NH
OH
J
III