[85, 86]. Wender et al. implemented a Prins reaction in the context of a late-stage
macrocyclization event. Treatment of allylsilane aldehyde 158 with TMSOTf gave
excellent conversion to 20-membered macrocycle 159 (96 % yield). Keck et al. also
disclosed a related intermolecular strategy incorporating an allylsilane and an enal.
In the presence of TMSOTf, allylsilane 160 and enal 161 led to macrocyclic
precursor 162 in an impressive 84 % yield. The highly functionalized substrates
used in these examples underscore the mildness of the reaction conditions.
A subsequent report by Wender and Schrier implemented a similar late-stage
macrocyclization in the synthesis of bryostatin 9 (Scheme 43) [87]. The Lewis acid,
TMSOTf, was abandoned in favor of pyridinium p-toluenesulfonate (PPTS) in
order to mitigate side reactions due to the ketal functionality in the A ring. As a
result, treatment of allylsilane aldehyde 163 with PPTS in MeOH unveiled the
O
O
O
O
OTBS
O
CO 2 Me
C 3 H 7 CO 2
HO
A
B
C
TBDPSO
OTES O
O
O
OTBS
O
CO 2 Me
C 3 H 7 CO 2
HO
A
C
TBDPSO
TMS
MeOH, rt
65%
O
MeO
OAc
MeO
OAc
163
164
PPTS
H
Scheme 43 Highly functionalized Prins macrocyclization en route to bryostatin 9 [87]
O
O
O
O
OTBS
O
CO 2 Me
C 7 H 15 CO 2
HO
A
B
C
TBDPSO
OH O
O
O
OTBS
O
CO 2 Me
C 7 H 15 CO 2
HO
A
C
TBDPSO
Et 2 O, –78 to 0 °C
96%
O
O
OTBDPS
OBOM
O
O
OMe
A
B
C
OTBS
OPMB
OH O
OTBDPS
OBOM
O
O
OMe
A
C
OTBS
OPMB
O
TMSOTf, Et 2 O, –78 °C
84%
O
Wender et al.
Keck et al.
158
159
160
161
162
TMS
TMS
TMSOTf
(eq 1)
(eq 2)
H
H
Scheme 42 B ring assembly of bryostatin analogs in intra- and intermolecular contexts [85, 86]
Synthesis of Saturated Tetrahydropyrans
69