Organic Letters
Letter
dihydroisocoumarin motif. Notably, in this process, free β-
hydroxyl group was tolerated, affording compound 4 in 67%
yield. Then, transformation of the alcohol into azido with
inversion of C-3 configuration gave compound 10 in 74%
yield, which was reduced under Pd/C promoted hydro-
genation to render amino 2 in an overall yield of 45% from 6.
Note that the free amino lactone 2 is not stable for storage,21
so it was used immediately or stored as its hydrochloride salt.
The preparation of acid segment 3 commenced with the
debenzylation of 11, which was readily produced in high yield
(>90%) by enantioselective aldol addition developed by Evans
et al. After obtaining alcohol 5 from 11, various one-pot
oxidation methods were investigated (Scheme 4), and treating
Scheme 2. Retrosynthetic Analysis of Amicoumacin-Type
Skeletons
Scheme 4. Preparation of the Acid Segment 3
should be obtainable via decoration of compound 1, which is
proposed to be assembled via peptide coupling of the amine
part 2 with the acid part 3. The amine part 2 could be traced
back to corresponding alcohol 4 with inversion of C3
configuration. For the preparation of 4, our previously
employed method in the total synthesis of (−)-berkelic
acid,16 namely, Pd(II)-catalyzed C−H alkylation of N-
methoxybenzamide with epoxides should be appropriate to
construct the 3,4-dihydroisocoumarin motif in 4. On the other
hand, the acid part 3 would be derived from chemoselective
oxidation of 1,2-diol 5, which is considered to be readily
accessible by enantioselective aldol addition developed by
Evans in 1998.17
a
b
c
Isolated yields. Yield of the oxidative cleavage product. Reaction
temperature: 25 °C.
1,2-diol 5 under Baskaran’s22 (1 equiv TEMPO/2 equiv
NaClO), Massanet’s,23 and Shibuya’s condition24 (cat.
TEMPO/cat. NaClO/NaClO2) all gave only trace amounts
of the desired acid 3. In view of the fact that the key for the
successful oxidation of 1,2-diols to corresponding α-hydroxy
acids is the use of a two-phase condition, which is consisted of
hydrophobic solvent and water to suppress the concomitant
oxidative cleavage; however, water-soluble 1,2-diols did not
produce the desired product under these conditions.24 In order
to make the water-soluble substrate 5 enter to the organic
phase to participate in the oxidate reaction, higher water
solubility solvent ethyl acetate was added in toluene; to our
delight, the yield of α-hydroxy acids 3 increased to 48%,
accompanied by 34% yield of the oxidative cleavage product
acetate alone gave only trace amounts of acid 3, which
indicated that the solvent played a crucial role in this type of
reaction (entry 5). Finally, when pH was adjusted from 6.8 to
6.5, the desired acid 3 was obtained in 65% yield with the yield
of oxidative cleavage byproduct decreased to 21% (entry 6).
Having successfully prepared the amine part 2 and acid part
3, we proceeded to the final stage of the syntheses of
compounds 12−21 (Scheme 5). Condensation of the acid with
the amine in the presence of EDCI gave the key intermediate 1
in 74% yield. Treatment of 1 with BBr3 in the presence of
anisole afforded AI-77-F (12), hydrogenolysis of which
resulted in the quantitative formation of bacillcoumacin D
(13). On the other hand, the key intermediate 1 reacted with
sodium azide in aqueous acetic acid gave the conjugate adduct
product 14 as a 6:1 mixture of its epimer at the azidebearing
stereogenic center in 40% yield (86% brsm). Compound 14
was then reduced to 15 by catalytic hydrogenation and
followed by direct acylation with the corresponding acyl
chlorides in the presence of Et3N at −10 °C to give
With the above retrosynthetic analysis in mind, our
syntheses of these amicoumacin-type natural products began
with the synthesis of the 3,4-dihydroisocoumarin motif in the
amine part 2 (see Scheme 3). Since the sequential reports of
Scheme 3. Preparation of the 3,4-Dihydroisocoumarin
Moiety 2
Pd-catalyzed C−H alkylation reactions of arylpyridines and
benzoic acids with epoxides in 2015,18 these types of reactions
have been fully developed19 and used as a labor-saving
alternative to construct isochroman-based natural prod-
ucts.16,20 Recently, we found that N-methoxyamide as a
stronger coordinating directing group, compared to carbonyl,
gave higher yields of 3,4-dihydroisocoumarins under slightly
basic conditions, especially for the substrates incorporating
multiple oxygen-containing functional groups.19d Thus, we
applied this optimized reaction condition to N,2-dimethox-
ybenzamide 6 and epoxy alcohol 7 to render the 3,4-
B
Org. Lett. XXXX, XXX, XXX−XXX
Wang, Hui-Hong
