Massachusetts Institute of Technology
Organic Chemistry 5.512
May 4, 2005
Prof. Rick L. Danheiser
Problem Set 7
Stereocontrolled Synthesis of Acyclic Molecules
Review Problems for Second Exam
Design a highly stereoselective synthesis of the following target molecules beginning with commercially
available materials. Be sure to explicitly identify all reagents necessary for each transformation.
Enantiomerically enriched reagents may be used if they are commercially available; however, with the
exception of the two compounds shown below, each stereogenic center in the target molecule must be
generated in your synthetic route. In other words, the stereogenic carbons in the chiral reagents you
employ cannot be directly incorporated in the final product. The exceptions are (S) and (R) methyl 3hydroxy-2-methylpropionate, which are commercially available and have been widely employed in total
synthesis.
HO
HO
CO2Me
CO2Me
A stereoselective synthesis of each of these target molecules has been reported in the literature and a
reference for each synthesis is provided at the end as an appendix. In addition, an outline of these
literature syntheses will be posted on the MIT server for your reference. Note, however, that the
original route to each molecule may not be the optimal approach, especially in view of new methods
that have been reported since the literature route was developed!
To derive maximum benefit from these problems, I recommend that for each target you consider all
possible synthetic routes that can be envisioned based on the methods and strategies studied in 5.512,
and then critically compare your viable approaches and decide which would be most practical and
efficient.
(1)
O
O
OHC
OH
(2)
t-BuMe2SiO
O
OH
(3)
Br
Br
O
O
(4)
OH
O
O
OH
(5)
CO2Et
Ph3CO
(6)
t-BuMe2SiO
OBn
(7)
EtO2C
OBn
OBn
(8)
Br
O
OEt
t-BuMe2SiO
(9)
OH
OH
(10)
OH
CO2H
i-Pr3SiO
(11)
OH
BnO
OH
OBn
OMe
(12)
OMe
OSit-BuMe2
OH S S
OHC
(13)
t-BuMe2SiO
OH
CO2Me
(14)
MeO
MeO
(15)
MeO2C
CO2Me
OH
SiMe3
Br
(16)
OH
CO2Me
(17)
BnO
t-BuMe2SiO
OSit-BuMe2
OSit-BuMe2
t-BuMe2SiO
OH
O
(18)
N
OMe
(19)
O
t-BuPh2SiO
OMe
Me
O
OH
O
(20)
O
BnO
OSiMe3
OH
(21)
O
OMe
OH
O
OH
OMe
The following problems are taken from the second exam in previous years. The
instructions were identical to those on page 1.
(22)
CO2Me
BnO t-BuMe2SiO
OH
(23)
OSiMe3
See total synthesis of roflamycoin,
S. Rychnovsky !J. Am. Chem. Soc.
1994, 116, 175
OH
See synthesis of C(1)-C(14) fragment
of callipeltoside A, T. R. Hoye
!Org. Lett. 1999, 1, 169
O
OMe
BnO
(24)
OSit-BuMe2
EtO2C
OBn
(25)
Intermediate for synthesis of epothilone A; see,
for example J. S. Panek !Org. Lett. 2000, 2, 2575
CO2Et
O
H
N
Ph
Ph
O
O
t-BuMe2SiO
OH
O
(26)
Et3Si
OCOt-Bu
O
See total synthesis of sanglifehrin A,
K. C. Nicolaou et al.!
J. Am. Chem. Soc. 2000, 122, 3830
OSit-BuMe2
O
(27)
O
See synthetic studies on miyakolide,
S. Masamune et al.
J. Org. Chem. 1997, 62, 8978
OBn
CH3
O
HN
(28)
O
H
OH
AnCH2O2C
An = p-OMeC6H4
OH
See J. E. Baldwin et al.
Tetrahedron Lett. 1987, 28, 3605
O
OH
O
(29)
H
OSit-BuMe2
OBn
See total synthesis of resiniferatoxin,
P. A. Wender et al.!
J. Am. Chem. Soc. 1997, 119, 12976
(30)
O
O
t-BuMe2SiO
OH
OH
(31)
OBn
See synthetic studies on spongistatin 1,
M. T. Crimmins et al.
Org. Lett. 2001, 3, 949
OPMB
OAc
See total synthesis of (+)-13-deoxytedanolide,
A. B. Smith et al.
J. Am. Chem. Soc. 2003, 125, 350
(32)
t-BuMe2SiO
(33)
OH
H2N
OBn