Pattenden and Plowright described the synthesis of the B ring of phorboxazole
by a simple conjugate addition (Scheme 12) [33]. Treatment of alcohol 38 with
NaHMDS under typical kinetic control conditions (À78
C) resulted in a selective
intramolecular oxyanion conjugate addition to produce the thermodynamically
favored 2,6-cis THP 39 in 88 % yield and a dr of 86:14. No attempt at equilibration
under thermodynamic conditions to give a higher cis/trans ratio was reported. This
example demonstrates the dramatic effects that subtle changes in substitution can
have on stereochemical outcomes.
2.2 Nucleophilic Substitution Cyclizations
Cyclizations based on nucleophilic substitution represent the simplest strategy
leading to tetrahydropyrans. The plethora of methods for the stereoselective installation of secondary alcohols allows efficient synthesis of the requisite hydroxy
nucleophile as well as the leaving group (usually derived from a chiral alcohol).
The 6-exo-tet cyclization proceeds with inversion at the electrophilic carbon center
in accord with a Williamson reaction [34]. In this way, both the 2,6-cis and
2,6-trans THP are readily accessible based on the configuration of the reactive
center (Scheme 13). Reactivity toward nucleophilic substitution follows the rate
trend of primary > secondary > tertiary; most examples covered herein utilize
secondary electrophiles with secondary alcohol nucleophiles. In contrast to S N 2like processes, S N 1 processes involve the generation of stabilized allylic or benzylic
carbocations for nucleophilic trapping. In this method, the stereochemical outcome
of the cyclization is dictated by the stereogenic composition of the substrate and the
experimental conditions.
OH
O
N
Boc
OTIPS
O
B
O
N
Boc
OTIPS
NaHMDS
EtO 2 C
EtO 2 C
–78 ºC
88%
38
39 (dr = 86:14)
Scheme 12 Synthesis of B ring fragment of phorboxazole A [33]
O
CO 2 Me
OH
Boc
N
O
D
TBSO
MeO 2 C
OTBS
Boc
N
O
TBAF, THF
46%
36
37 (dr = 4:1)
Scheme 11 Desilylation/conjugate addition approach to the D ring of phorboxazole A [31]
52
M.A. Perry et al.
by a simple conjugate addition (Scheme 12) [33]. Treatment of alcohol 38 with
NaHMDS under typical kinetic control conditions (À78
C) resulted in a selective
intramolecular oxyanion conjugate addition to produce the thermodynamically
favored 2,6-cis THP 39 in 88 % yield and a dr of 86:14. No attempt at equilibration
under thermodynamic conditions to give a higher cis/trans ratio was reported. This
example demonstrates the dramatic effects that subtle changes in substitution can
have on stereochemical outcomes.
2.2 Nucleophilic Substitution Cyclizations
Cyclizations based on nucleophilic substitution represent the simplest strategy
leading to tetrahydropyrans. The plethora of methods for the stereoselective installation of secondary alcohols allows efficient synthesis of the requisite hydroxy
nucleophile as well as the leaving group (usually derived from a chiral alcohol).
The 6-exo-tet cyclization proceeds with inversion at the electrophilic carbon center
in accord with a Williamson reaction [34]. In this way, both the 2,6-cis and
2,6-trans THP are readily accessible based on the configuration of the reactive
center (Scheme 13). Reactivity toward nucleophilic substitution follows the rate
trend of primary > secondary > tertiary; most examples covered herein utilize
secondary electrophiles with secondary alcohol nucleophiles. In contrast to S N 2like processes, S N 1 processes involve the generation of stabilized allylic or benzylic
carbocations for nucleophilic trapping. In this method, the stereochemical outcome
of the cyclization is dictated by the stereogenic composition of the substrate and the
experimental conditions.
OH
O
N
Boc
OTIPS
O
B
O
N
Boc
OTIPS
NaHMDS
EtO 2 C
EtO 2 C
–78 ºC
88%
38
39 (dr = 86:14)
Scheme 12 Synthesis of B ring fragment of phorboxazole A [33]
O
CO 2 Me
OH
Boc
N
O
D
TBSO
MeO 2 C
OTBS
Boc
N
O
TBAF, THF
46%
36
37 (dr = 4:1)
Scheme 11 Desilylation/conjugate addition approach to the D ring of phorboxazole A [31]
52
M.A. Perry et al.