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Short Lit. - 7-12-2010Jonathan A. Brekan
a Department of Chemistry, Northwestern University, 2145 Sheridan Road, 60208, Evanston, Illinois, United States of America
Citronellal
Me
Me
O
HMe
Monoterpenoid
– distillate of Cymbopogan– antifungal– typically isolated as a non-racemic mixture of R and S isomers
Citronellal
Me
Me
O
HMe
Monoterpenoid
– distillate of Cymbopogan– antifungal– typically isolated as a non-racemic mixture of R and S isomers
Annual production of citronella oil (40-50%citronellal) is ~2300 metric tons.
~2000 tons of (R)-citronellal produced per year.
Me
O
H
HH
Me
Me Me Me Me
Me Me Me Me
HO HO HO HO
(+)-neoiso-isopulugol
5%
(+)-iso-isopulugol15%
(+)-neo-isopulugol19%
(–)-isopulugol61%
H2
Me Me
Me
HO
(–)-menthol
+ + +
Me
O
Me
HH
H
carbonyl-eneMe
OH
Me
H
H
(–)-isopulugol
Synthesis of (–)-menthol
Ohloff, G. Tetrahedron Letters, 1960, 1(32), 10-14
MeMe
n-BuLi (cat.)
Et2NH(telomerization)
MeMe
LiNEt2 Me
MeMe
NEt2
diethyl-geranylaminemyrcene
Me
MeMe
NEt2
[Rh((S)-BINAP)(COD) ClO4 (cat.)
100 oC (ca. 100%)
citronellal(R,E)-diethylenamine
Takasago Corporation in Japan – 1984
MeMe
Me
OH
(R)-menthol
A Classic Synthesis- Chapter 22, Menthol
TelomerizationFrom Wikipedia, the free encyclopedia
Telomerization is a radical polymerization reaction where a chain transfer limits the size of the oligomer molecule product–the telomer.[1][2] Telomerization requires a telogen to react with at least one unsaturated taxogen molecule.[2] Fluorotelomers are an example.
RhP
P H* NR2
R
RhP
P
R2N
*Hsuprafacial transfer
of H from Rh to C3
A Divergent Approach to the Diastereoselective Synthesis of SeveralAnt-Associated Iridoids
Joel S. Beckett, James D. Beckett, and John E. Hofferberth*
Department of Chemistry, Kenyon College, Gambier, Ohio 43022
CHO
CHO
Me
N
Me
Me
O
Me
Me
O
O
Me O
MeNepetalactol
4 steps
Dolichodial5 steps
Actinidine3 steps
Isoirdomyrmecin11 steps
Dihydronepetalactone6 steps
O
Me OH
Me
CHO
Me
CHOMe
Me
Me
CHOMe
citronellal
A Divergent Retrosynthesis
O
Me N
Me
R R1
O
Me OH
Me
N
Me
Me
CHO
CHO
MeO
Me O
Me
O
Me
Me
O
Me
Me
CHOMe
SeO2 (3 mol %)t-BuOOHsalicylic acid
DCM, rt40-50%
Me
CHOMe
O
H +
Me
CHOMe
OH
IBX, DMSO
80-90%
Me
O Se OR H
Me
RSe O
HO
Me
R OSe
OH
H–H2OMe
R O+
SeoH+
Neopetalactol
Me
Me
CHOMe
SeO2 (3 mol %)t-BuOOHsalicylic acid
DCM, rt40-50%
Me
CHOMe
O
H +
Me
CHOMe
OH
IBX, DMSO
80-90%
NHMePh
Et2O, rt, 24 hr84%
O
Me N
Me
Me Ph
TsOH
THF (wet)84%
O
Me OH
Me
α/β 1:10neopetalactol
Neopetalactol
Schreiber, S. L.; Meyers, H. V.; Wiberg, K. B. J. Am. Chem. Soc. 1986, 108, 8277
Me
HPhMeN
H
Me
HO
H
Me
H
NMePh
H
Me
O
H
Actinidine
Me
CHOMe
O
H
NH2OH, TsOHTHF
70% N
Me
Me
Me
MeO
NOH
H
Dolichodial
Me
O
Me N
Me
Me Ph
NBSMeOH
72%ONMePh
Me H
Br
O
Me N
Me
Me Ph
BrOMe
+ O
Me N
Me
Me Ph
OMe
(3:4)
Br
t-BuOK, 50 oC
THF, HCl87%
CHO
CHO
Me
O
Me OH
MeH2, Pd/C
95% O
Me OH
Me H
Ag2CO3/celite88%
O
Me O
Me H
O
Me O
Me
O
Me O
MeH
Ag2CO3/celite70%
H2, Pd/C95%, 95:5 dr
Dihydronepetalactones A and B
O
Me N
Me
MePh
1) H2, Pd/C, EtOH2) 1,2-ethandithiol, BF3•OEt2
3) BnBr, NaH, n-Bu4NI (cat.)Me
Me
S
S
OBn
80%
1) CAN, MeCN, NaBH4
2) Ac2O, Py, DMAPMe
Me
OAc
OBn
66%
1) Pd/C, H2, EtOH
2) RuCl3, NaIO4, CCl4
CO2H
Me
Me
OAc
TsOH, EtOH
quant.Me
Me
O
O
Isoiridomyrmecin
CHO
CHO
Me
N
Me
Me
O
Me O
Me
Nepetalactol4 steps
Dolichodial5 steps
Actinidine3 steps
Dihydronepetalactone6 steps
O
Me OH
Me
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/ locate/tetlet
Tetrahedron Letters 51 (2010) 3966–3968
Total synthesis of (+)-aspermytin AAtsushi Inoue, Makoto Kanematsu, Masahiro Yoshido, Kozo Shishido*Gradute School of Pharmaceutical Sciences, The University of Takushima
Me
HMe
OH
Me
O
H
OH
Me
H
H
Me
OHO NMe
HO
O
Me
aspermytin A equisetin
Retrosynthesis
Me
HMe
OH
Me
O
H
OH
Me
HCHO
Me
H
O
Me
HCHO
Me
H
OR
Me
HCHO
Me
OR
MeCHO
Me
Me
(S)-citranellal
MeCHO
Me
Me
Me
Me
Me
O
O
HO(CH2)2OHpTsOH, benzene
MeO
O
OHO3, thenNaBH
MeCHO
OTBS1) 0.5 M HCl2) TBSClimidazole,DMAP
MeCHO
OTBS
Me
OTBS
BO
O
Me
OTBS
OTfMe
OTBS
O
Takai*, K.; Kunisada, Y.; Tachibana, Y.; Yamaji, N.; Nakatani, E. Bull. Chem. Soce. Jpn. 2004, 77, 1581-1586
RCHCl2 CCrX2R
H CrX2
R1
OCrX2
R
CrX2
R1R
(X2Cr)2O
2 CrX3+
2 CrX3
4 CrX2
2 TMSCl(TMS)2O2 Mn
2 MnX2
R1CHO
ClB
Cl
O
O
CrCl2 (0.6 equiv)Mn (6 equiv)LiI (4 equiv)
TMSCl (6 equiv)
MeCHO
OTBS
Me
OTBS
BO
O
Me
OH
OTBDPS
Br OTBDPSPd2(dba)3CHCl3, PPh31N NaOH,then 0.5 N HCl
83% over 3 steps
1) Swern, 86%2) HWE, 99%
Me OTBDPS
CO2Et
Me
Me OTBDPS
MeO1) DIBAH, 99%
2) MnO2, quant.
ClB
Cl
O
O
CrCl2 (0.6 equiv)Mn (6 equiv)LiI (4 equiv)
TMSCl (6 equiv)
Me OTBDPS
MeO
OHCH
Me Me
H
H
CHOMe Me
H
OR ORConditions
+
Me3Al (1.5)
Et2AlCl (0.5)
Me2AlCl (1.5)
–78 to 0
–78 to 0
–78 to 0
1.5 hrs
2 hrs
8.5 hrs
52%
78%
92%
(13.5:1)
(10:1)
(8:1)
MeMe
O OR
H
H
H
Me
O
ORMe
HH
vs
H
Me
Me
H
OR
OH
1) MOMCl quant.
2) TBAF
H
Me
Me
H
OH
OMOM
1) DMP, 94%
2) NaClO2 NaH2PO4 2-Me-2-Butene3) CH2N2, 98% (2 steps)
CO2MeH
Me
Me
H
OMOM
CO2MeH
Me
Me
H
OMOMKHMDS, O2(EtO)3P
CO2MeH
Me
Me
H
OMOM
CO2MeH
Me
Me
H
OMOM
+OH
OH27% 38%
H
Me
Me
H
OH
OMOM 1) H2, Pd/C, 96%2)nBu3P, o-nitro-phenylselenocyanate, 30% H2O2
H
Me
Me
H
OMOM
OH
Me
Me
H
OMOM
O3
Grieco, P. A.; Gilman, S.; Nishizawa, M. J. Org. Chem. 1976, 41, 1485
Change of Strategy
Se
N
NO2 PBu3H
Me
Me
H
OPBu3
OMOM
H
Me
Me
H
SeAr
OMOM
+HCN
[O]
H
Me
Me
H
OH
OMOM 1) H2, Pd/C, 96%2)nBu3P, o-nitro-phenylselenocyanate, 30% H2O2
H
Me
Me
H
OMOM
OH
Me
Me
H
OMOM
O3
IBX, DMSO OH
Me
Me
H
OMOM
OH
Me
Me
H
O
+1) HCl2) DMP O
H
Me
Me
H
O
MeLi, THF80% H
Me
Me
H
HO
MeOH
TPAP, NMO92% H
Me
Me
H
O
MeOH
H
Me
Me
H
O
MeOH
OH
NN
N
OH
LDA
95%
aspermytin A
Let’s Wrap This Up
Nicolaou, K.C.; Zhong, Y.L.; Baran, P. S. J. Am. Chem. Soc. 2000, 122, 7596
Deguest, G.; Bischoff,* L.; Fruit, C.; Marsais, F. Org. Lett. 2007, 9, 1165[α]28
d = +7.6 ; lit. [α]25d = +1.2
Citronellal
Me
Me
O
HMe
