Synthesis of Second-Generation Palmerolide A Analogues
Scheme 2. Synthesis of tetraene 29. Reagents and conditions:
(a) CBr4 (0.1 equiv.), iPrOH, 23 Ǟ 80 °C, 2 h, 62%; (b) TBSCl
(1.3 equiv.), imidazole (2.5 equiv.), 4-DMAP (cat.), DMF, 23 °C,
5 h, 94%; (c) NBS (1.1 equiv.), AgNO3 (0.1 equiv.), acetone, 23 °C,
1 h, 98%; (d) Pd(dba)2 (0.05 equiv.), PPh3 (0.22 equiv.), nBu3SnH
(2.2 equiv.), THF, 23 °C, 1 h, 70%; (e) Pd(PPh3)4 (0.1 equiv.), CuCl
(5.0 equiv.), LiCl (6.0 equiv.), DMSO, 23 °C, 8 h, 79%. 4-DMAP =
N,NЈ-dimethylaminopyridine, NBS = N-bromosuccinimide; dba =
dibenzylideneacetone.
Variation of the C1–C8 segment of palmerolide A also
called for the preparation of carboxylic acids 7a–d, and
their syntheses are shown in Scheme 3. Acid fragment 7a
was prepared through conjugate reduction of enoate 30
(NaBH4, CuCl), followed by saponification of resulting
ethyl ester 31 (KOH, 75% yield over the two steps). Aro-
matic acid 7b was synthesized from phenolic benzaldehyde
32 through intermediate triflate 33 (Tf2O, 46% yield), fol-
lowed by palladium-mediated cross-coupling with allyltri-
butyltin (34, 99% yield), homologation to enoate 35 (35%
yield), and saponification (LiOH, 95% yield). Two-carbon
homologated acid 7c was synthesized through sequential
Scheme 3. Synthesis of carboxylic acids 7a–d. Reagents and condi-
tions: (a) NaBH4 (10.0 equiv.), CuCl (0.75 equiv.), MeOH/THF
(4:7), 0 °C, 6 h, 91%; (b) KOH (5.0 equiv.), dioxane/H2O, (4:1),
23 °C, 12 h, 82%; (c) Tf2O (1.2 equiv.), pyridine (2.0 equiv.),
CH2Cl2, 0 Ǟ 23 °C, 3 h, 46%; (d) Pd(PPh3)4 (0.1 equiv.), LiCl
(3.0 equiv.), allyltributyltin (1.1 equiv.), 1,4-dioxane, 100 °C, 16 h,
99%; (e) trimethyl phosphonoacetate (1.2 equiv.), LiBr (4.0 equiv.),
oxidation of alcohol 36 (PCC; then NaClO2) in 64% yield Et3N (2.0 equiv.), THF, 23 °C, 16 h, 35%; (f) LiOH (3.0 equiv.),
THF/MeOH/H2O (2:1:1), 23 °C, 4 h, 95%; (g) PCC (1.6 equiv.),
CH2Cl2, 23 °C, 16 h, 88%; (h) NaClO2 (3.0 equiv.), 2-methyl-2-but-
ene (10 equiv.), NaH2PO4 (5.0 equiv.), tBuOH/H2O (1:1), 0 °C, 2 h,
73%; (i) 3-butenylmagnesium bromide (2.0 equiv.), CuCl
over the two steps. Finally, preparation of gem-dimethyl
acid 7d began with conjugate addition of 3-butenylmagne-
sium bromide to α,β-unsaturated diester 38 followed by
thermal decarboxylation to give ethyl ester 40 in 92% yield
over the two steps. Two-carbon homologation of ethyl ester
40 involved a reduction/oxidation/Wittig olefination se-
quence (DIBAL-H, DMP, Ph3P=CHCO2Me), through the
intermediacy of alcohol 41, to furnish α,β-unsaturated
(0.05 equiv.), THF, –30 Ǟ 23 °C, 1.5 h, 97%; (j) LiCl (2.0 equiv.),
H2O (1.0 equiv.), DMSO, reflux, 24 h, 95%; (k) DIBAL-H (1.4 m
in CH2Cl2, 2.5 equiv.), CH2Cl2, –78 °C, 1.5 h, 90%; (l) DMP,
(1.1 equiv.), NaHCO3 (5.0 equiv.), CH2Cl2, 23 °C, 0.5 h; (m) tri-
methyl phosphonoacetate, (1.1 equiv.), LiBr (4.0 equiv.), Et3N
(2.0 equiv.), 23 °C, 12 h, 78% over two steps; (n) LiOH (3.0 equiv.),
methyl ester 42 (70% overall yield). Finally, saponification THF/MeOH/H2O (2:1:1), 23 °C, 4 h, 95%. PCC = pyridinium
chlorochromate, Tf = trifluoromethanesulfonyl.
of methyl ester 42 (LiOH) afforded desired acid 7d in 95%
yield.
With building blocks 29 and 7a–d in hand, the next task
became their unification and further elaboration to targeted sponding aldehydes 45a (77%), 45b (68%), 45c (72%), and
analogues 49a–d, as summarized in Scheme 4. Thus, Yama- 45d (50%). Further elaboration of aldehydes 45a–d to
guchi esterification[11] (2,4,6-trichlorobenzoyl chloride, macrocyclic ring-closing metathesis precursors 47a–d in-
Et3N, 4-DMAP) between alcohol 29 and acid fragments volved Takai olefination[12] (CrCl2, CHI3; 46a–d) and TBS
7a–d afforded esters 43a (69%), 43b (70%), 43c (72%), and ether removal (HCl aq.; 47a: 76%, 47b: 40%, 47c: 42%,
43d (60%), respectively. Selective removal of the primary and 47d: 44% yield over the two steps). With allylic
TBS ether in 43a–d under the mild action of TFA, followed alcohols 47a–d in hand, their ring-closing-metatheses[7] un-
by oxidation (DMP) of resulting alcohols 44a–d gave corre- der the action of Grubbs II catalyst (CH2Cl2, 0.005 m,
Eur. J. Org. Chem. 2011, 463–468
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