Letter
a
Scheme 1. Synthesis of Spirocyclic Butenolides 9a and 9b
a
Reagents and conditions: (a) 30% H O , NaOH, MeOH, 0 °C, 95%;
Figure 1. (A) Structure of dihydro-β-agarofuran (1), (−)-isocelorbicol
2
2
(
−
b) vinyllithium, THF, − 78 to −15 °C, 77%; (c) BF ·OEt , CH Cl ,
(
2), and naturally occurring ester derivatives of the latter (3−6). (B)
3
2
2
2
78 to −30 °C, 83%; (d) DIAD, PNBOH, PPh , 1,4-dioxane, 0−90
Rretrosynthetic analysis of 2−6.
3
°
C, 51% (59% based on recovered 14); (e) TMS-acetylene, n-BuLi,
THF, −78 °C, quant; (f) KF, aq DMF, rt, 94%; (g) methyl malonyl
stereocontrolled manner (Scheme 1). Known epoxy ketone 12,
prepared by epoxidation of (R)-11, was subjected to the
addition of vinyllithium to give epoxy alcohol 13 as a single
diastereomer, whose relative configuration was determined on
chloride, pyridine, CH Cl , 0 °C, 71%; (h) Cs CO , DMSO, 40 °C,
8
2
2
2
3
3
4%; (i) methyl propiolate, n-BuLi, THF, − 78 °C, quant; (j) methyl
malonyl chloride, pyridine, CH Cl , 0 °C, 67%; (k) Cs CO , DMSO,
2
2
2
3
40 °C, 76%; [10 → 20 (one pot)] methyl propiolate, n-BuLi, THF,
−78 °C, then methyl malonyl chloride, −78 to +40 °C, then Cs CO
DMSO, 40 °C, 93%; (l) LiCl (1.0 equiv), aq DMSO, 150 °C, 96%;
m) Me SnOH, Cl(CH ) Cl, reflux, 70%.
the basis of some diagnostic NOE correlations depicted in
2
,
3
9
Scheme 1. BF -induced semipinacol rearrangement of 13
3
(
proceeded smoothly below −30 °C to deliver hydroxy ketone 14
with the chiral centers at C10 correctly installed. It is worth
noting that the highly stereoselective transformation of 12 to 14
gave a better yield (64%) than that (30%) obtained previously
3
2 2
selective decarboxylation of 20 was realized by the Krapcho
conditions (LiCl in DMSO at 150 °C) to give 9a almost
quantitatively. On the other hand, treatment of 20 with
10
by a single-step protocol, although ours required a two-step
transformation. The stereochemistry at the hydroxy-bearing C9
chiral center was then inverted by the Mitsunobu reaction to
give p-nitrobenzoyl (PNB) ester 10, albeit in a moderate yield of
Me SnOH in refluxing 1,2-dichloroethane effected decarbox-
3
12
ylation at both the α and γ positions, affording 9b in 70% yield.
The concise six-step preparation of 9a and 9b from (R)-11 in
overall yields of 32% and 23%, respectively, set the stage for the
stereoselective installation of the C4 chiral center of
(−)-isocelorbicol (2).
5
1% (59% based on recovered 14). Nucleophilic addition of
lithium (trimethylsilyl)acetylide to 10 gave tertiary alcohol 15
with complete stereoselection. The axially oriented vinyl group
at C10 would have promoted the axial attack of the acetylide to
the carbonyl group of 10; the configuration of 15 was later
confirmed by NOE results for 21 and ORTEP drawing of 2 in
Scheme 2. The subsequent removal of its TMS group followed
by acylation of the resulting alcohol 16 with methyl malonyl
chloride afforded 17. Conversion of the acetylenic malonate 17
to 9a via 5-exo-dig cyclization was conducted by treating 17 with
various bases including NaH and Cs CO in DMSO, but the
Toward the completion of the total synthesis of 2, we first
undertook the conjugate reduction of the butenolide 9b to
directly obtain the key intermediate 8 in a diastereoselective
manner (Scheme 2). All attempts (e.g., [(Ph P)CuH] /toluene,
3
6
DIBAL/CuI/THF−HMPA, L-Selectride/THF, NaBH /Et N/
4
3
13
THF) were, however, unsuccessful. The conjugate reduction
of 9a bearing an electron-withdrawing methoxycarbonyl group
13c
with NaBH and Et N in THF, on the other hand, proceeded
2
3
4
3
11
yields were modest (up to 34%). The low efficiency in the
butenolide ring formation was significantly improved by using
acetylenic ester 19 as the substrate for the cyclization, which was
prepared in 67% yield from 10 via 18 by the addition of methyl
lithiopropiolate and subsequent acylation. Upon exposure of 19
to Cs CO in DMSO, the butenolide formation proceeded
smoothly at −78 °C with complete stereoselection, providing 21
in 87% yield. The bulky hydride complex (NaBH /Et N) would
4
3
have approached from the less hindered β-face, avoiding the
steric hindrance due to the equatorially oriented C10 methyl
group. The NOE results for 21 depicted in Scheme 2 means that
the addition of methyl lithiopropiolate and lithium
(trimethylsilyl)acetylide to 10 to form 15 and 18, respectively,
occurred by axial attack. Krapcho decarboxylation of 21 gave 8,
which was then reduced with DIBAL in diethyl ether to furnish
2
3
11
smoothly, providing 20 in 76% yield. To our delight, the three-
step sequence from 10 was found to be amenable to one-pot
operation, delivering 20 in an excellent 93% yield. Finally, γ-
B
Org. Lett. XXXX, XXX, XXX−XXX