Communication
the diphenylphosphine oxide, which produced 9 in 83% yield.
Removal of the benzyl protecting group and formation of ben-
zopyran 11 proceeded smoothly. Notably, a modification of our
previously published method,[15] adding an equivalent of
LiHMDS before adding LDA significantly improved yields from
35% up to 75%. A high yielding three step sequence of depro-
tection, triflate formation, and aldehyde reduction produced
the key benzyne precursor 12. Exposure to NaH in DMF
smoothly exchanged three functional groups on 12 yielding
aminophenol 13, which was then converted to PMP acetal 14
after reduction of the aldehyde. Conversion to the unstable
benzyl chloride 15 proceeds smoothly using well-established
conditions with methyl chloroformate and potassium carbon-
ate.[16]
formation. Singlet oxygen oxidation with rose bengal as a sensi-
tizer, followed by peroxide reduction with SMe2 produced the
corresponding lactol, which was oxidized to the target cou-
marin 20 with manganese dioxide. Conversion to the requisite
aldehyde 21 for dimerization was completed by acidic removal
of the acetal, oxidation of the benzylic alcohol to the aldehyde,
and finally allyl protection of the phenol. We were pleased to
see that dimerization occurred upon addition of 1,1,3,3-tetra-
methyldisiloxane and catalytic TMSOTf.[18] Final deprotection
then produced the reported structure of 6.[14]
Unfortunately, comparison of our synthetic compound 6 did
not match the reported literature values for gigasol.[14] Inspec-
tion of the data suggested that the aliphatic side chain
matched the decursinol skeleton better than the peucedanol
framework found in 6 (Scheme 6). To test our proposal, we
The benzylic chloride 15 was found to be very prone to de-
composition in solution, particularly upon heating. To circum-
vent this challenge and activate the benzylic chloride for nu-
cleophilic attack on the TBS-protected Weinreib amide of (S)-
lactic acid, we selected a tellurium-mediated process,[17] which
yielded 16 in 84% yield (Scheme 5). Reduction of the ketone
Scheme 5. (a) Te/nBuLi, THF, 08C, 30 min; nBuLi, À788C, 25 min; Weinreb
amide, À788C, 15 min, À788C to rt, 30 min, 84%; (b) LiAlH(OtBu)3, diglyme,
08C, 12 h, rt, 1 h, 75%; (c) K2CO3 (cat.), MeOH, rt, 20 h, 89%; (d) Swern oxida-
tion; (e) TBAF, THF, 08C, 2 h; (f) MeLi, THF, À788C, 2 h, 75% over 3 steps;
(g) Ac2O, Et3N, DMAP (cat.), DCM, rt, 44 h; (h) O2 (air), rose bengal (cat.),
EtOAc, irr, rt, 4 h; EtOAc, Me2S, rt, 20 h; MnO2, DCM, rt, 8 h, 72% over 2
steps; (i) 80% AcOH, rt, 24 h; (j) MnO2, DCM, rt, 2 h; (k) AllylBr, NaHCO3, DMF,
rt, 72 h, 66% over 3 steps; (l) TMDS, TMSOTf (cat.), toluene, À308C, 3 h;
(m) K2CO3, MeOH, rt, 12 h; (n) Et3SiH, [Pd(Ph3P)4] (cat.), AcOH, DCM, rt, 2 h,
64% over 2 steps.
Scheme 6. (a) CH3C(OCH3)2CH3, PPTS (cat.), DCM, rt, 30 min; (b) O2 (air), rose
bengal (cat.), EtOAc, irr, rt, 5 h; Me2S, rt, 20 h; MnO2, DCM, rt, 20 h; 72% over
2 steps; (c) 70% AcOH, rt, 3 h, 81%; (d) MnO2, DCM, rt, 20 h; (e) BnBr, K2CO3,
DMF, rt, 44 h, 77% over 2 steps; (f) PTSA (cat.), MeOH, 508C, 44 h, 88%;
(g) MsCl, Et3N, DCM, 08C, 1 h; (h) DBU, DCM, rt, 3 h, 67% over 2 steps; (i) 1,4-
CHD, Pd/C, MeOH, rt, 2 h; (j) PTSA (cat.), DCM, 08C, 30 min; (k) Ac2O, Py,
DMAP (cat.), DCM, rt, 1 h; (l) 80% AcOH, rt, 30 min, 61% over 4 steps;
(m) TMDS, TMSOTf (cat.), toluene, À308C, 1 h, 91%; (n) Et3N, H2O, MeOH, rt,
44 h, 89%.
with LiAlH(tBuO)3 (85:15 crude d.r., separable) was then carried
out, followed by a base-induced migration of the TBS group to
the internal hydroxyl. Given the modest steric differences be-
tween the two hydroxyls, only a slight excess of the desired
TBS-protected alcohol could be acquired in a single reaction.
As 17 and 18 are easily separable on silica gel, recovered start-
ing material could be recycled through the process to push
material to the desired 18 (89% yield, 3 cycles). This was fol-
lowed by Swern oxidation, TBS ether cleavage, and addition of
MeLi to produce diol 19. After protection to the corresponding
diacetate (20), we investigated the chromene/coumarin trans-
synthesized the revised target 30 to incorporate the peuceda-
nol aliphatic portion. From intermediate 19, protection of the
diol as an acetonide was followed by chromene/coumarin oxi-
dation as previously described to produce 23. Exposure of 23
to 70% acetic acid selectively cleaved the p-methoxyphenyl
moiety while leaving the acetonide intact. Oxidation of the
benzylic alcohol and benzyl protection of the phenolic position
occurred under standard conditions to yield 25. Treatment
with PTSA in MeOH then cleaved the acetonide protection of
the diol with concomitant dimethylacetal protection of the al-
dehyde forming 26. Formation of epoxide 27 occurred with
Chem. Eur. J. 2016, 22, 8479 – 8482
8481
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