B. Yu et al./Chinese Chemical Letters xxx (2020) xxx-xxx
AA005 (1, Fig. 1) retains the terminal γ-methylated butenolide, a common functionality of most natural ACGs, and replaces the
middle bis-THF core with a simpler triglycol ether moiety. Such a modification greatly simplifies the structural complexity, as well as
its chemical synthesis. Two strategies have been developed and extensively applied into the preparation of the γ-methylated butenolide
of either natural ACGs or unnatural mimics [5], including the one disclosed by our laboratory [5b,5c]. Different chiral pools have been
utilized for the α-alkylation of corresponding carbonyl compounds in the two approaches, resulting in diverse protocols to generate the
requisite conjugate C=C bond. Of note, racemic phenomena of different degrees often happens under basic conditions at the
stereogenic allylic C34 [6], which is usually introduced from proper chiral materials. Avoiding or minimizing use of basic treatments is
preferred after generating this unsaturated-lactone moiety in the synthesis. The other characteristic feature of AA005 (1) is its middle
2
subunit of C -symmetrical triglycol flanking with two chiral secondary alcohols. Since the first report in 2000 [4a], a number of
optimizations have been made for the synthesis of this triglycol unit of AA005 (1) [4b,4d,4f]. In a recent work, both the two chiral
hydroxyls of AA005 (1) were introduced by a chiron approach from commercially available (R)-epichlorohydrins with a 7-step
procedure [4f]. The synthesis enables us to obtain sub-gram of AA005 (1) to support a variety of cell-based studies, while, it seems to
be tedious, of high labor cost and unsatisfying for scale-up preparation. In this study, we explored a shortcut for rapid assembly of the
unique fragments, re-organized and optimized the order of reactions, and eventually completed a multi-gram synthesis of AA005 (1) in
ten overall steps from the simple starting materials.
It was envisioned that AA005 (1) might arise from the internal alkyne 2 through a series of functional groups manipulations
(Scheme 1). Devising a hydroxyl group at C10 of 2 not only helps the further disconnection of C11-C12 bond through epoxide-opening
protocol with a terminal alkyne intermediate 3, but also leaves us an anchor to link labeling functionalities with AA005 (1) in further
biological studies [4e]. It is noteworthy that the absolute stereochemistry of the C10 hydroxyl group of 2 could be neglected in the
synthesis of AA005 (1) [4c]. The resulting epoxide 4 could be readily traced to abundant materials undecenoic acid (10) and ethyl L-
lactate (11) through a key 3-step procedure [4d]. Utilizing partial C
2
symmetry at the middle region, disconnection converts the
polyether segment 3 into building blocks 5, 6a and 7. The C symmetrical bis-epoxide 6a, in principle, would be accessible from the
2
commercially available glycol (8) and (R)-epichlorohydrin (9, abbrev. as (R)-ECH in the following text) [7,8]. Such an expeditious
access could create the requisite polyether unit bearing two stereogenic cabinols in a more direct fashion, and thus shortens the overall
steps of the synthesis. However, such a direct transformation has to check the associated regioselectivity with the two possible
1
3
nucleophilic attacks on epoxide 9 with glycol 8. If random attacks happens upon either carbons of C -Cl bond and epoxide C -O bond
of (R)-ECH (9) by glycol 8, the reaction would deliver bis-epoxide 6a with poor enantiomeric purity finally.
As mentioned above, the newly designed synthesis of AA005 (1) is highly depended on the preparation of enantiopure bis-epoxide
6
a, as well as its scalability. To clarify these concerns, three mechanism-different approaches were examined at the first stage (Scheme
2
). One is the hydrolytic kinetic resolution (HKR), which has emerged as a widely adopted powerful method to produce various
terminal epoxides with high enantiopurities [9]. A mixture of 6 (containing 6a/6b/6c) was applied as the substrate and chiral
III
(
Salen)Co complex was used as the catalyst in the assessment (Scheme 2a). The chiral HPLC analysis of the starting glycol
diglycidyl ether 6 (industrial grade) showed that it comprises (S,S)-6a, meso-(R,S)-6b and (R,R)-6c with a ratio of 28:48:24. Under the
III
standard conditions with 1 mol% (R,R)-salen-Co ·OAc prepared in situ [9b], the percentage of 6a in the mixture increased up to 83%
(30% yield based on 52% content of 6a/6c in the mixture; 17% isolated yield based on all the material). Such a product purity was
insufficiently qualified for the further synthesis. Phase transfer catalyst (PTC) approach was next examined by nucleophilic attack of
1
glycol (8) on (R)-ECH (9) under basic conditions [7]. Nevertheless, it was difficult to predict, a priori, which carbon (C -Cl in green,
3
or C -O in red) of 9 would be predominately attacked by the alkoxy anion of 8. HPLC measurement showed that this approach could
not deliver a good result either (Scheme 2b), and all the 6a, 6b (the diastereomer of 6a) and 6c (the enantiomer of 6a) existed in the
mixture with a ratio of 71:26:3 after the reaction. Several commonly available PTCs, including TBAB, TBAI and TEBAC, were tested
to improve the regioselectivity, as well as varying base concentrations. Unfortunately, all these attempts delivered similar results.
Obviously, both C1 and C3 of epoxide 9 were attacked by glycol 8 under the PTC conditions. The Lewis acid-promoted conditions
were finally explored (Scheme 2c) [8]. To facilitate future scale-up, the neat reaction (without solvent) was tried [8b]. To our delight, a
bis-chlorohydrin intermediate was detected when a mixture of diol 8 and BF
3
·Et
that nucleophilic attack of diol 8 on 9 takes place only at C -O of epoxide 9 in the presence of BF
above resulting bis-chlorohydrin intermediate (after removal of excess (R)-ECH (9) in vacuum) was immediately treated with NaOH
2.1 equiv.) to rebuild the two epoxides, affording enantiopure (S,S)-6a (for details of condition screening see Supporting information).
2
O (0.7 wt%) was exposed to epoxide 9. It indicated
3
3
·Et O. To simplify the procedure, the
2
(
In a scale-up experiment (using 100 g of ethylene glycol 8 as raw material), approximately 111 g of 6a could be harvested in one batch
after final purification by vacuum distillation. Obviously, this reaction shows great scalability and advantages of using economically
available materials, ease of operation, convenient purification and mild reaction conditions.
With large quantity of the C
2
-symmetric bis-epoxide 6a in hand, subsequent C23- and C14-functionalizations of 6a were executed
successively (Scheme 3). Grignard addition of 6a (10 grams, 57 mmol) with 1.2 equiv. of nonylmaganesium bromide 5 in the presence
o
of CuBr·Me
2
S (20 mol%) at -78 C followed by treatment with NaOH (0.5 equiv.) afforded the mono-epoxide 12 (6 g, 34% yield after
recrystallization) [11], while the optimized reaction could proceed in 60% yield in a smaller scale of 2.8 mmol of 6a (Supporting
Yu, Baobao
