much as leucascandrolide A. The B ring of this cytotoxic macrolide has been
assembled using variations of this method no less than seven times. Kopecky and
Rychnovsky were the first to demonstrate the allylation of α-acetoxy ether 277 with
allyltrimethylsilane in the presence of boron trifluoride etherate in high yield and
diastereoselectivity (97 %, dr ! 20:1) [78]. The resulting alkene was cleaved by
ozonolysis to furnish aldehyde 278, which was necessary for coupling the two THP
fragments together (Scheme 73, Eq. 1; for coupling, see Scheme 38). Wipf and
Reeves later utilized this strategy for alkylating the opposite side of the B ring to
provide allyl fragment 280 (80 %, dr ¼ 15.6:1), as shown in Scheme 73, Eq. 2 [79].
Reductive acetylation/alkylation has also provided access to advanced bis-THP
intermediates of the type 284 in several reported pursuits of leucascandrolide A
(Scheme 74) [76, 117, 131]. These complex examples highlight the remarkable
functional group tolerance of this reaction type. The elaborate α-acetoxy ethers 283
demonstrate that a number of protecting groups (benzyl, silyl derivatives, and
esters) survive the reaction conditions. Unsaturated silyl enol ethers (i.e., 281 and
282) are effective nucleophiles and provide advanced intermediates like 284 in
excellent yields and diastereoselectivities (80–90 %, dr ! 25:1 for all cases). A
similar strategy, coupled with ring-closing metathesis, was also used by Cossy and
coworkers for this natural product (Scheme 60) [108].
The rapid and highly convergent assembly of the bis-THP fragment 287 in Evans
and Andrews’ synthesis of leucascandrolide A relied on a reductive acetylation/
alkylation strategy (Scheme 75) [132]. Treatment of α-acetoxy ether 285 with
O
OMe
B
OMe
O
OMe
B
OTMS
TMSOTf, MeCN
43%
O
O
OMe
B
TMSOTf
MeCN
276
273
275
274
Allyl-TMS
Patterson et al. (96%)
Keck et al. (84%)
H
Scheme 72 Allylation of α-methoxy ether to access the B ring of the swinholides [20, 130]
O
O
B
OBn
O
OAc
B
OBn
1) Allyl-TMS, BF 3 ·OEt 2
CH 2 Cl 2 , –78 °C (97%)
2) O 3 , CH 2 Cl 2 , –78 °C,
then PPh 3 (95%)
O
B
OAc
OTBS
O
OTBS
B
Allyl-TMS, BF 3 ·OEt 2
CH 2 Cl 2 , –78 °C
80%
277
278 (dr = 20:1)
279
280 (dr = 15.6:1)
Kopecky and Rychnovsky
Wipf and Reeves
H
Scheme 73 Allylation of α-acetoxy ethers to functionalize either side of the B ring fragment of
leucascandrolide A [78, 79]
Synthesis of Saturated Tetrahydropyrans
89
assembled using variations of this method no less than seven times. Kopecky and
Rychnovsky were the first to demonstrate the allylation of α-acetoxy ether 277 with
allyltrimethylsilane in the presence of boron trifluoride etherate in high yield and
diastereoselectivity (97 %, dr ! 20:1) [78]. The resulting alkene was cleaved by
ozonolysis to furnish aldehyde 278, which was necessary for coupling the two THP
fragments together (Scheme 73, Eq. 1; for coupling, see Scheme 38). Wipf and
Reeves later utilized this strategy for alkylating the opposite side of the B ring to
provide allyl fragment 280 (80 %, dr ¼ 15.6:1), as shown in Scheme 73, Eq. 2 [79].
Reductive acetylation/alkylation has also provided access to advanced bis-THP
intermediates of the type 284 in several reported pursuits of leucascandrolide A
(Scheme 74) [76, 117, 131]. These complex examples highlight the remarkable
functional group tolerance of this reaction type. The elaborate α-acetoxy ethers 283
demonstrate that a number of protecting groups (benzyl, silyl derivatives, and
esters) survive the reaction conditions. Unsaturated silyl enol ethers (i.e., 281 and
282) are effective nucleophiles and provide advanced intermediates like 284 in
excellent yields and diastereoselectivities (80–90 %, dr ! 25:1 for all cases). A
similar strategy, coupled with ring-closing metathesis, was also used by Cossy and
coworkers for this natural product (Scheme 60) [108].
The rapid and highly convergent assembly of the bis-THP fragment 287 in Evans
and Andrews’ synthesis of leucascandrolide A relied on a reductive acetylation/
alkylation strategy (Scheme 75) [132]. Treatment of α-acetoxy ether 285 with
O
OMe
B
OMe
O
OMe
B
OTMS
TMSOTf, MeCN
43%
O
O
OMe
B
TMSOTf
MeCN
276
273
275
274
Allyl-TMS
Patterson et al. (96%)
Keck et al. (84%)
H
Scheme 72 Allylation of α-methoxy ether to access the B ring of the swinholides [20, 130]
O
O
B
OBn
O
OAc
B
OBn
1) Allyl-TMS, BF 3 ·OEt 2
CH 2 Cl 2 , –78 °C (97%)
2) O 3 , CH 2 Cl 2 , –78 °C,
then PPh 3 (95%)
O
B
OAc
OTBS
O
OTBS
B
Allyl-TMS, BF 3 ·OEt 2
CH 2 Cl 2 , –78 °C
80%
277
278 (dr = 20:1)
279
280 (dr = 15.6:1)
Kopecky and Rychnovsky
Wipf and Reeves
H
Scheme 73 Allylation of α-acetoxy ethers to functionalize either side of the B ring fragment of
leucascandrolide A [78, 79]
Synthesis of Saturated Tetrahydropyrans
89