The terminal diol of 33 was oxidatively cleaved, and the resulting crude aldehyde
was subjected to an HWE reaction using excess LiCl at room temperature. Under
these conditions, the TES group migrated from the C39 hydroxyl to the C41
hydroxyl, and the newly revealed alcohol underwent 1,4-addition to the enoate.
This one-pot olefination/silyl migration/1,4-addition sequence furnished the
undesired 2,6-trans THP 35 as the major diastereomer (dr ¼ 10:1) in 68 % yield.
Diastereoselectivity was reversed by employing a stepwise procedure involving
HWE olefination, subsequent cleavage of the TES ether, followed by 1,4-addition
under thermodynamic conditions to afford the 2,6-cis THP 34 as the major diastereomer (dr ¼ 25:1) in 65 % yield.
Forsyth and coworkers provided one of the earliest examples of the desilylation/
conjugate addition sequence en route to the total synthesis of phorboxazole A
(Scheme 11) [31, 32]. Subjecting silyl ether 36 to fluoride-mediated deprotection
furnished the alkoxide, which upon conjugate addition to the enoate gave the
THP-containing ester 37 in moderate yield and diastereoselectivity (46 %,
dr ¼ 4:1) after 3 days. The use of shorter reaction times provided a mixture of
mono- and dihydroxy acrylate and THP products. Attempts at improving conversion to the desired THP including increased temperature, longer reaction times, and
stronger bases were unsuccessful.
Me
OH
OH O
OH
Me
O
OTBS
O
O
O
TES
1) NaIO 4 , pH 7 buffer/THF
2) (EtO) 2 P(O)CH 2 CO 2 Me
LiCl, DBU, CH 3 CN
68%
O
OPMB
OTES
Me
F
TBSO
MeO 2 C
Me
O
O
PMB
O
1) NaIO 4 , pH 7 buffer/THF
2) (EtO) 2 P(O)CH 2 CO 2 Me
LiCl, DBU, CH 3 CN
3) PPTS, MeOH, (83%)
4) DBU, DMF, 90 ºC
(65%)
O
OPMB
OH
Me
F
TBSO
MeO 2 C
Me
O
O
O
34 (dr = 25:1)
33
35 (dr = 10:1)
Scheme 10 Selective synthesis of the F ring subunit of spongistatin 1 [30]
O
SEMO
SEMO
Me
O
OBn
O
O
OSEM
OSEM
Me
F
BnO
39
O
OH
AcOH / THF/
H 2 O (9:1:1)
O
OSEM
OSEM
Me
F
BnO
39
O
OH
95%
MeOH/THF, 0 ºC
39
31
cis-32
trans-32
Bn NMe 3 OMe
trans-32/cis-32 = 2.5:1
Å
-
Scheme 9 Conjugate addition approach to the highly substituted F ring of spongistatin 1 [29]
Synthesis of Saturated Tetrahydropyrans
51
was subjected to an HWE reaction using excess LiCl at room temperature. Under
these conditions, the TES group migrated from the C39 hydroxyl to the C41
hydroxyl, and the newly revealed alcohol underwent 1,4-addition to the enoate.
This one-pot olefination/silyl migration/1,4-addition sequence furnished the
undesired 2,6-trans THP 35 as the major diastereomer (dr ¼ 10:1) in 68 % yield.
Diastereoselectivity was reversed by employing a stepwise procedure involving
HWE olefination, subsequent cleavage of the TES ether, followed by 1,4-addition
under thermodynamic conditions to afford the 2,6-cis THP 34 as the major diastereomer (dr ¼ 25:1) in 65 % yield.
Forsyth and coworkers provided one of the earliest examples of the desilylation/
conjugate addition sequence en route to the total synthesis of phorboxazole A
(Scheme 11) [31, 32]. Subjecting silyl ether 36 to fluoride-mediated deprotection
furnished the alkoxide, which upon conjugate addition to the enoate gave the
THP-containing ester 37 in moderate yield and diastereoselectivity (46 %,
dr ¼ 4:1) after 3 days. The use of shorter reaction times provided a mixture of
mono- and dihydroxy acrylate and THP products. Attempts at improving conversion to the desired THP including increased temperature, longer reaction times, and
stronger bases were unsuccessful.
Me
OH
OH O
OH
Me
O
OTBS
O
O
O
TES
1) NaIO 4 , pH 7 buffer/THF
2) (EtO) 2 P(O)CH 2 CO 2 Me
LiCl, DBU, CH 3 CN
68%
O
OPMB
OTES
Me
F
TBSO
MeO 2 C
Me
O
O
PMB
O
1) NaIO 4 , pH 7 buffer/THF
2) (EtO) 2 P(O)CH 2 CO 2 Me
LiCl, DBU, CH 3 CN
3) PPTS, MeOH, (83%)
4) DBU, DMF, 90 ºC
(65%)
O
OPMB
OH
Me
F
TBSO
MeO 2 C
Me
O
O
O
34 (dr = 25:1)
33
35 (dr = 10:1)
Scheme 10 Selective synthesis of the F ring subunit of spongistatin 1 [30]
O
SEMO
SEMO
Me
O
OBn
O
O
OSEM
OSEM
Me
F
BnO
39
O
OH
AcOH / THF/
H 2 O (9:1:1)
O
OSEM
OSEM
Me
F
BnO
39
O
OH
95%
MeOH/THF, 0 ºC
39
31
cis-32
trans-32
Bn NMe 3 OMe
trans-32/cis-32 = 2.5:1
Å
-
Scheme 9 Conjugate addition approach to the highly substituted F ring of spongistatin 1 [29]
Synthesis of Saturated Tetrahydropyrans
51