S YNTHETIC S UMMARY
Acid-Mediated Cyclization Approaches to the Densely Substituted Carbocyclic Core of Zoanthenol
Scheme S3.1 Revised retrosynthetic analysis
Zoanthenol (21) 164
203 N
OH O
O
O O
OMe O
O OH
O O
OTBS BocHN hemiaminal
formation
alkyne addition
OMe O
O OMe
O BocN O
TBSO
OMe O
O OMe
O O HO
OMe
OH
R
OR OR TBSO
deoxygenation
Gilbert-Seyferth homologation
acid-mediated cyclization
Grignard addition esterification
Br OMe TBSO
O
R
OR OR
+
C A B
D E F
G
217
218 219
168 220
+
8 7 9
H O
R
OR OR 221 reductive
carbonylation
Scheme S3.2 Access to a meso anhydride
222 OTBS
O O
O
mesitylene, collidine methylene blue
165 °C, 2.5 days O O
O
O
O
O OTBS OTBS
223 224, (66% yield) 225, (9% yield)
O O
O OTBS
H2SO4 (0.5 equiv) DCE, reflux, 3 d
(94% yield)
O O
O
224 226
H2SO4 (0.5 equiv) DCE, reflux, 3 d
(83% yield)
OTBS
O O
O 225
+ +
Scheme S3.2 Desymmetrization and elaboration of a meso anhydride
OH O
O O OMe
O
O 226
PhMe, MeOH
242 quinine, DBU
247 248
O O
O I OMe
1. AgOAc, Py, 32 °C 2. K2CO3, MeOH
(76% yield, 2 steps) O O
O OMe OH KI, I2, NaHCO3
ACN/H2O, dark (75% yield, 2 steps)
Scheme S3.3 Synthesis of a lactone-derived C ring synthon
O O
O OMe OH
1. MnO2, acetone 2. H2, PtO2, EtOAc
(71% yield, 2 steps) O O
O OMe O
O O
O OMe OTf
O O
O OMe O
KHMDS, THF, –25 °C then Tf2NPh
(82% yield)
1. Pd(PPh3)4, LiCl, NMP
(94% yield) 2. OsO4, NaIO4 acetone, H2O, 0 °C (70% yield)
Bu3Sn
O O
O OMe O
N 1. Ac2O, N 2. H2, PtO2, EtOAc (62% yield, 2 steps)
248 249 250
251 252
Scheme S3.4 Fragment coupling and cyclization of the A and lactone-derived C rings
O O
O OMe O
252
OMe
TBSO MgBr
Et2O:THF 1:1, 0 °C (70% yield) H
181
OH TBSO
OMe
O O
O OMe
253
DMP, CH2Cl2, 0 °C (91% yield)
O TBSO
OMe
O O
O OMe
255
OMe
HO O
O O
O
256 HCOOH:H3PO4 3:1
117 °C, 22 h
(47% yield) 9
12 22
H
Scheme S3.5 Elaboration of lactone 248
O O
O OMe OH
TBSOTf, Py CH2Cl2, 0 ! 23 °C
O O
O OMe TBSO
LAH, THF 0 ! 23 °C (83% yield 2 steps)
OH
OH OH OTBS
CuSO4 acetone (88% yield)
1:1.5 ratio OH OTBS
OH
O O OTBS
O O
+
248 257 258 259 260
23
Scheme S3.6 Synthesis of a 7-membered acetal-derived C ring synthon
OH OTBS
O O
OH
OTBS O O
O
OTBS O O 1) MnO2, acetone
2) PtO2, H2, EtOAc (93% yield, 2 steps)
LDA, –78 °C, 2h then HMPA, 0 °C, 1h
then MeI, –30 °C (72% yield, 10 % yield 261)
O
OTBS O O
OTf
OTBS O O
OTBS O O O KHMDS, THF
PhNTf2, –25 °C (92% yield)
Pd(OAc)2, CO, DMA, LiCl TEA, TES-H (2 equiv, slow add'n), 35 °C
(65% yield, 35% recovered 263) (c-Hex)2P P(c-Hex)2
(±)-259 (±)-259 261
262 263 264
10
H
Scheme S3.7 Fragment coupling and cyclization of the A and 7-membered acetal- derived C rings
O TBSO
OMe
266
O O
OTBS
TFA, 65 °C, 5.5 h 20
11 10 12
OMe HO
O O
12 21
270 (16% yield) assigned by 2D NMR
analysis OH
TBSO OMe
265 Et2O:DCM 1.2:1
–12 °C (87% yield) OTBS
O O
264
H O
O O
OTBS
DMP, DCM 0 °C (89% yield)
O TBSO
OMe
266
O O
OTBS 20
(10:1 Mixture at C(20)) (Major diastereomer shown) OMe
TBSO MgBr
181
Scheme S3.8 Synthesis of a homologated nitrile-derived C ring synthon
OH
O O OTBS
PtO2, H2 EtOAc (96% yield)
1) MsCl, TEA, CH2Cl2 0 ! 23 °C 2) DMSO, KCN, 85 °C (76% yield, 2 steps) OH
O O OTBS
260 272 273
274 275
276 277 278
CN
O O OTBS
1) TBAF, THF, 40 °C 2) (COCl)2, DMSO CH2Cl2, TEA, –78 °C ! 23 °C (>99% yield, 2 steps)
CN
O O O
CN
O O O LDA, –78 °C, 2h
then HMPA, 0 °C then MeI, –25 °C (78% yield, 10% recovered 274,
5% bis-alkylation)
CN
O O OTf
KHMDS, THF PhNTf2, –25 °C
(98% yield)
CN
O O Pd(PPh3)4
NMP, LiCl SnBu3
CN
O O
O
OsO4, NaIO4 acetone/H2O, 0 °C (71% yield, 2 steps)
Scheme S3.9 Fragment coupling and cyclization of the A and homologated nitrile- derived C rings
TFA, 60 °C, 5 h
OMe HO
O
270 (42% yield)
O
12 O
TBSO OMe
279
O O
CN O
O CN
O
278
OMe
TBSO MgBr
Et2O:THF 4.8:1, –12 °C
(85% yield, 2 steps) 2) DMP, CH2Cl2, 0 °C 1)
181 H
Scheme S3.10 Synthesis, fragment coupling, and cyclization of the A and homologated carboxylic acid-derived C rings
OMe TBSO
O O
OH MgBr
OMe TBSO
Et2O, CH2Cl2, 0 °C (94% yield)
>10:1 dr
O OH 181
281
277 280
CN
O O
1. KOH, EtOH, 90 °C 2. OsO4, NaIO4 acetone/H2O, 0 °C (81% yield, 2 steps)
O O
O O OH
OMe TBSO
O O
O O OH
282 DMP, CH2Cl2
0 ! 22 °C (78% yield)
H
TFA, 60 °C, 5 h
OMe HO
O
270 O
12
TFA, 22 °C, 21 h then TBAF, THF (70% yield of desired
diastereomer from high Rf alcohol 55% from low Rf alcohol)
OMe HO
O OMe
TBSO
O O
OH O OH
281 269
20
12
