yield with an er of 99:1 and dr of 6.4:1 (trans–cis/cis–cis). Fast ligand-controlled
cyclization installs the cis-substituted B ring, inhibits formation of the other enantiomer, and leads to the high levels of enantioselectivity observed. The moderate
diastereoselectivity arises from a competitive ligand-controlled cyclization to the
trans-substituted A ring with the substrate-controlled cyclization to the cissubstituted A ring. Specifically, as a result of a matched interaction between ligand
control and steric bias, the B ring allylic stereogenic center has been set in the
R configuration. However, the second cyclization event represents a mismatched
case of ligand control and inherent steric bias. Cyclization of the A ring under
ligand control provided the desired R,R (cis–trans)-isomer with one equatorial and
one axial vinyl group. Cyclization under substrate control provided the more stable
S,R (cis–cis)-isomer with two equatorial vinyl groups. This example highlights the
utility of ligand-controlled Pd-catalyzed desymmetrization to expeditiously produce useful chiral bis-THP building blocks.
White et al. also reported on the palladium(II)-catalyzed 1,2-alkoxycarbonylation in the synthesis of both the B and D rings of phorboxazole A (Scheme 25)
[41]. The D ring THP 73 was prepared in high yield (86 %) from cyclization of
hydroxy alkene 71. The stereochemistry and efficiency of the reaction is best
described by a minimization of steric interactions between the α-methyl substituent
and the exo Pd substituent (e.g., Cl) of the complexed alkene intermediate 72
preceding cyclization. Unfortunately, an excess of palladium acetate was required
to compensate for the reduction of Pd(II) to inactive Pd(0). For the synthesis of the
B ring, use of a stoichiometric oxidant, p-benzoquinone, with catalytic palladium
circumvented this issue. Under these improved conditions, trisubstituted B ring
THP 75 was isolated as a single diastereomer in a moderate 58 % yield along with
15–20 % recovered starting material 74.
OAc
OAc
OH
OH
OH
OH
O
O
OH
A
B
OH
Pd 2 dba 3 ·CHCl 3 (2 mol %)
(R,R)-DPPBA (6 mol %)
Et 3 N, CH 2 Cl 2 , 0 ºC
75%
69
70 (ee = 98%)
Scheme 24 Pd-catalyzed desymmetrization to the bis-THP fragment of the phorboxazoles [51]
OH OH O
OTBS
OMe
MeO 2 C
A
O
OH O
OTBS
B
OMe
MeO 2 C
TIPPSe
A
O
O
O
O
TIPPSeBr, DTBMP
CH 2 Cl 2 , –78 ºC
65%
67
68 (dr = 88:12)
TIPP = triisopropylphenyl
DTBMP = 2,6-di-t-butyl-4-methylpyridine
Scheme 23 Selenium-mediated alkene cyclization to construct the B ring of leucascandrolide A
[22]
58
M.A. Perry et al.
cyclization installs the cis-substituted B ring, inhibits formation of the other enantiomer, and leads to the high levels of enantioselectivity observed. The moderate
diastereoselectivity arises from a competitive ligand-controlled cyclization to the
trans-substituted A ring with the substrate-controlled cyclization to the cissubstituted A ring. Specifically, as a result of a matched interaction between ligand
control and steric bias, the B ring allylic stereogenic center has been set in the
R configuration. However, the second cyclization event represents a mismatched
case of ligand control and inherent steric bias. Cyclization of the A ring under
ligand control provided the desired R,R (cis–trans)-isomer with one equatorial and
one axial vinyl group. Cyclization under substrate control provided the more stable
S,R (cis–cis)-isomer with two equatorial vinyl groups. This example highlights the
utility of ligand-controlled Pd-catalyzed desymmetrization to expeditiously produce useful chiral bis-THP building blocks.
White et al. also reported on the palladium(II)-catalyzed 1,2-alkoxycarbonylation in the synthesis of both the B and D rings of phorboxazole A (Scheme 25)
[41]. The D ring THP 73 was prepared in high yield (86 %) from cyclization of
hydroxy alkene 71. The stereochemistry and efficiency of the reaction is best
described by a minimization of steric interactions between the α-methyl substituent
and the exo Pd substituent (e.g., Cl) of the complexed alkene intermediate 72
preceding cyclization. Unfortunately, an excess of palladium acetate was required
to compensate for the reduction of Pd(II) to inactive Pd(0). For the synthesis of the
B ring, use of a stoichiometric oxidant, p-benzoquinone, with catalytic palladium
circumvented this issue. Under these improved conditions, trisubstituted B ring
THP 75 was isolated as a single diastereomer in a moderate 58 % yield along with
15–20 % recovered starting material 74.
OAc
OAc
OH
OH
OH
OH
O
O
OH
A
B
OH
Pd 2 dba 3 ·CHCl 3 (2 mol %)
(R,R)-DPPBA (6 mol %)
Et 3 N, CH 2 Cl 2 , 0 ºC
75%
69
70 (ee = 98%)
Scheme 24 Pd-catalyzed desymmetrization to the bis-THP fragment of the phorboxazoles [51]
OH OH O
OTBS
OMe
MeO 2 C
A
O
OH O
OTBS
B
OMe
MeO 2 C
TIPPSe
A
O
O
O
O
TIPPSeBr, DTBMP
CH 2 Cl 2 , –78 ºC
65%
67
68 (dr = 88:12)
TIPP = triisopropylphenyl
DTBMP = 2,6-di-t-butyl-4-methylpyridine
Scheme 23 Selenium-mediated alkene cyclization to construct the B ring of leucascandrolide A
[22]
58
M.A. Perry et al.