Communications
Scheme 2. Synthesis of key intermediates 8 and 11. a) 9 (1.0 equiv), 2-
buten-1,4-diol (2.0 equiv), Hoveyda–Grubbs catalyst II (0.01 equiv),
CH2Cl2, 238C, 4 h, 97%; b) l-(+) diethyl tartrate (0.12 equiv), Ti(OiPr)4
(0.1 equiv), tBuOOH (1.52 equiv), CH2Cl2, À408C, 30 min; then, 10
(1.0 equiv), À248C, 12 h, 85%; c) SO3·py (3.47 equiv), CH2Cl2/DMSO,
=
08C, 30 min; d) Ph3P CH2 (1.8 equiv), THF, À108C, 10 min, 70% over
two steps; e) Sc(OTf)3 (0.2 equiv), THF/H2O (10:1), 238C, 2.5 h,
100%; f) dimethoxypropane (10 equiv), TsOH·H2O (0.05 equiv),
CH2Cl2, 238C, 12 h, 70%. Grubbs–Hoveyda catalyst II=1,3-(bis-
(mesityl)-2-imidazolidinylidene)dichloro-(o-isopropoxyphenylmethyl-
ene)ruthenium; DET=diethyl tartrate; Tf=trifluoromethanesulfonyl;
Ts =p-toluenesulfonyl.
Treatment of 14 with second-generation Grubbs catalyst[24,25]
under equilibrating conditions[26] (808C for 12 h) afforded the
macrocycle with E/Z > 10:1. This macrocycle was then treated
with H2O2 to oxidize and eliminate the selenide, thus
affording compound 15 in 77% overall yield. Interestingly,
inversing the sequence of reaction (oxidation/elimination of
the selenide followed by the metathesis on the triene) gave
rise to a significant amount of the undesired six-membered
ring product from the cyclization with the benzylic alkene.
Global deprotection of the acetonide and EOM groups
afforded aigialomycin D (1)[27] in a total of 10 steps and 21%
overall yield. When the diol was masked as an epoxide,
macrocycle 16 was obtained in excellent yield starting from
diene 13 through the same sequence (RCM, selenide oxida-
tion/elimination). Interestingly, in this case, the order of
reaction could be inversed without observing the competing
ring-closure corresponding to the six-membered ring (the
geometry of the trans epoxide favors macrocyclization).
However, Lewis or protic acid (ScOTf3, TsOH, TFA, HFIP)
mediated opening of the epoxide failed to yield the desired
1,2-cis-diol and led in all cases to an SN2’ opening to afford
17a or 18a. Although the epoxide 16 could not be converted
into aigialomycin D, this diverging reaction pathway proved
to be quite general and could be carried out with different
nucleophiles such as NaN3 or KCN to obtain 17b and c,
respectively. Deprotection of the EOM ethers (PS-SO3H,
MeOH) from 17a–c or concomitant epoxide opening/depro-
tection with different alcohols (MeOH, EtOH, iPrOH) in the
presence of sulfonic acid resin from 16 afforded aigialomycin
analogues 18a–f.
Scheme 3. Total synthesis of aigialomycin D (1) and divergent syn-
thetic pathways. a) PS-DEAD (2.5 equiv, 1.3 mmolgÀ1), (R)-(+)-penten-
2-ol (1.0 equiv), m-ClPh3P (2.0 equiv), CH2Cl2, 238C, 0.5 h, 83%;
b) iPr2EtN (4.0 equiv), EOMCl (4.0 equiv), TBAI (cat.), DMF, 808C, 5 h,
95%; c) LDA (2.0 equiv), THF, À788C; then (PhSe)2 (0.9 equiv), 2 h,
75%; d) LDA (2.0 equiv), 8 or 11 (1.0 equiv), THF/HMPA (10:1),
À788C, 20 min, 74% (8) and 75% (11); e) Grubbs II catalyst
(0.05 equiv), toluene, 808C, 12 h, 90% (from 13) and 92% (from 14);
f) H2O2 (2.0 equiv), THF, 238C, 3 h, 82% (15) and 85% (16); g) PS-
SO3H (9.0 equiv, 3.2 mmolgÀ1), MeOH, 508C, 2 h, quant.; h) 1. PS-
SO3H (10.0 equiv, 2.9 mmolgÀ1), THF/H2O (1:1); 458C, 16 h, quant.;
or 2. NaN3 (5 equiv), PS-SO3H (0.1 equiv, 2.9 mmolgÀ1), DMF, 658C,
12 h, 83%; or 3. KCN (5 equiv), PS-SO3H (0.1 equiv, 2.9 mmolgÀ1),
DMF, 658C, 12 h, 89%; i) PS-SO3H (10.0 equiv, 2.9 mmolgÀ1), MeOH,
458C, 3 h, >90%; j) PS-SO3H (10.0 equiv, 2.9 mmolgÀ1), R’OH, 458C,
3 h, quant. PS=polymer-supported; DEAD=diethyl azodicarboxylate;
TBAI=tetrabutylammonium iodide; DMF=N,N-dimethylformamide;
LDA=lithium diisopropylamide; HMPA=hexamethylphosphoramide.
In the interest of streamlining the synthesis, the phenyl
selenide was replaced by a polymer-bound thioether. The
required thiol resin was prepared in a similar fashion as
previously reported[28] from 3-hydroxythiophenol rather than
4-hydroxyphenol to avoid the deactivating effect of a para-
phenol (Scheme 4). The chemistry leading to aigialomycin
was found to be equally efficient on solid phase as in solution.
Scheme 4. Conversion of Merrifield resin into a thiophenol resin (20).
a) TrCl (1.0 equiv), pyridine (1.0 equiv), CH2Cl2, 238C, 12 h, 100%;
b) K2CO3 (2.0 equiv), PS-CH2Cl (1.0 equiv), DMF, 508C, 12 h, 100%; c)
TFA/CH2Cl2/Et3SiH (9:10:1), 238C, 1 h, 100%. Tr=triphenylmethyl;
TFA=trifluoroacetic acid.
3952
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2006, 45, 3951 –3954