Total synthesis of aspergillide A and B based on the transannular oxy-Michael reaction

Article abstract of DOI:10.1002/anie.201007327

Keys to the kingdom: A highly efficient and diastereoselective transannular oxy-Michael reaction for the construction of the syn- and anti-tetrahydropyran units from a common 14-membered macrolactone is the key step for the total synthesis of aspergillide

Full text of DOI:10.1002/anie.201007327

Communications
DOI: 10.1002/anie.201007327
Natural Product Synthesis
Total Synthesis of Aspergillide A and B Based on the Transannular
Oxy-Michael Reaction**
Makoto Kanematsu, Masahiro Yoshida, and Kozo Shishido*
The aspergillides A, B, and C (1, 2, and 3) comprise a novel
class of 14-membered macrolides that were isolated by
Scheme 1. Retrosynthetic analysis. Bn=benzyl, HWE=Horner–Wads-
worth–Emmons, TBS=tert-butyldimethylsilyl.
Kusumi and co-workers from the marine-derived fungus
Aspergillus ostianus strain 01F313 that was cultured in a
medium composed of bromine-modified artificial sea water.[1]
Their structures were determined by extensive spectroscopic
studies, and their absolute configurations were established by
X-ray crystallography (for 1 and 2) and the modified Mosher
method (for 3).[2] These compounds contain tri-substituted
tetrahydro and dihydropyran units and exhibit cytotoxicity
against mouse lymphocytic leukemia cells (L1210) with
LD50 values of 2.1, 71.0, and 2.0 mgmLÀ1, respectively.
Because of their intriguing structural features and biological
profile, these polyketides have attracted much attention in the
synthetic community as targets for total synthesis. To date,
four total syntheses of 1,[3] six of 2,[3c,4] and two of 3[5] have
been reported. Herein, we describe our total synthesis of the
aspergillides A (1) and B (2) from a common macrolide
intermediate by employing an interesting transannular oxy-
Michael reaction[6] as the key step.
and intramolecular Horner–Wadsworth–Emmons reaction of
the acyclic precursors 5, which could be accessed from the
chiral building block 7[7] and compound 6, which was known in
the literature.[8] Two stereogenic centers at the future C4 and
C7 positions in 5 would be created by taking advantage of the
convex nature of 7.
The optically pure enone 7 with a bicyclo[3.2.1]octane
framework, prepared from 2-furfural by a six-step sequence,
served as the starting material for the synthesis of the alkenyl
alcohol 14 (Scheme 2). Attempted transformation of 7 into 10
using the Wharton transposition[7,9] gave unsatisfactory
results ( ꢀ 20% yield), prompting us to find another route.
Reduction with NaBH4 followed by the Hata reaction[10] of
Our strategy for the synthesis of the aspergillides A and B,
illustrated in Scheme 1, proposes the formation of the
trisubstituted pyran moiety through a base-mediated trans-
annular oxy-Michael reaction from the 14-membered macro-
lactone 4. It was thought that stereochemical control at the
newly generated stereogenic center at C3 could be achieved
by the choice of reaction conditions. The macrolactone 4
could be assembled by using a sequential cross-metathesis
[*] M. Kanematsu, Dr. M. Yoshida, Prof. Dr. K. Shishido
Graduate School of Pharmaceutical Sciences
The University of Tokushima
Scheme 2. Synthesis of the alkenyl alcohol 14. Reagents and condi-
tions: a) NaBH4, CeCl3·7H2O, MeOH, RT, 1 h, 98%; b) PhSSPh, nBu3P,
pyridine, 608C, 16 h, 86%; c) mCPBA, CH2Cl2, À788C, 1.5 h; then
(MeO)3P, EtOH, reflux, 6 h, 71%; d) TBSCl, imidazole, DMAP, CH2Cl2,
RT, 1 h, 94%; e) H2, Pd(OH)2-C, THF, 608C, 8 h, 99%; f) MsCl, Et3N,
CH2Cl2, RT, 1 h; g) LiI, THF, reflux, 8 h, 94% (over 2 steps); h) Zn,
EtOH, reflux, 3 h, 94%; i) LiBH4, THF, 08C, 2 h, quant.; j) PivCl, Et3N;
then TESCl, DMAP, CH2Cl2, RT, 1 h; k) LiBH4, THF, 08C, 3 h, 96%
(over 2 steps, based on recovered diol 13). DMAP=4-dimethylamino-
pyridine, mCPBA=m-chloroperoxybenzoic acid, Ms=methanesulfonyl,
Piv=pivaloyl, TES=triethylsilyl, THF=tetrahydrofuran.
1-78-1 Sho-machi, Tokushima 770-8505 (Japan)
Fax: (+81)88-633-9575
E-mail: shishido@ph.tokushima-u.ac.jp
[**] This work was supported financially by a Grant-in-Aid for the
Program for Promotion of Basic and Applied Research for
Innovations in the Bio-oriented Technology Research Advancement
Institution (BRAIN).
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201007327.
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Angew. Chem. Int. Ed. 2011, 50, 2618 –2620

Table 1: Transannular oxy-Michael reaction of 4.
the resulting 8 produced the inverted sulfide 9, which was
treated with mCPBA and (MeO)3P in ethanol at reflux[11] to
give the alcohol 10 in 60% yield from 7. After protection of
the alcohol moiety as the TBS ether, sequential hydrogena-
tion, debenzylation, mesylation, and iodination gave the
iodide 11, which was reduced with zinc in ethanol at reflux to
afford the hemiacetal 12 in good overall yield as a 1.5:1
mixture of diastereoisomers at the acetal carbon atom.
Reduction with LiBH4 gave the diol 13, the primary and the
secondary alcohols of which were sequentially protected as
the pivalate and the TES ether, respectively. The pivalate was
reduced with LiBH4 to give the alkenyl alcohol 14.
Entry Reaction conditions
Yield 18/19
[%][a]
1
2
DBU (10 equiv), CH3CN, reflux, 10 h
DBU (10 equiv), LiCl (10 equiv) CH3CN, reflux, quant.
2 h
50
1:6
7:1
Cross-metathesis[12] of 14 with the phosphonoacetate 6,[8]
prepared from (R)-2-methyloxirane through a two-step
sequence, in the presence the second-generation Grubbs
catalyst (5 mol%) in methylene chloride at reflux provided
the coupled product as the E alkene (> 20:1) in 98% yield
(Scheme 3). Oxidation of 16 with Dess–Martin periodinane
3
DBU (10 equiv), LiCl (10 equiv), CH3CN, RT,
1.5 h
quant.
1:0
4
5
6
KH (1.1 equiv), THF, 08C, 0.5 h
KH (1.1 equiv), THF, 08C, 2 h
KH (1.1 equiv), [18]crown-6 (5 equiv), THF, 08C, 96
90
91
1.6:1
0:1
0:1
0.5 h
[a] Yield of isolated product.
and
a
subsequent intramolecular Horner–Wadsworth–
Scheme 4. From these results it was thought that the anti-
isomer 19 might be the thermodynamic product. Conse-
quently, for the selective formation of 19, we examined the
Scheme 4. Transition state for the conversion of 4 into 18.
reaction under the conditions described in entry 1. Prolonged
reaction times did not result in increased yields of the desired
anti adduct; rather decomposition was observed. Treatment
of 4 with KH in THFat 08C for 0.5 hours produced the pyrans
in a ratio of 1.6:1 in 90% yield (entry 4). However, prolonged
exposure (2 h) of 4 to the same reaction conditions resulted in
the exclusive formation of 19 in comparable yield (entry 5). It
was also determined that the reaction could be accelerated
(ꢀ0.5 h) by the addition of [18]crown-6 to give the anti-adduct
19 in 96% yield (entry 6). Thus, we have demonstrated that
the diastereoselectivity of the addition could be altered
completely by changing the reaction conditions.
To prove the thermodynamic preference, interconversion
between 18 and 19 was attempted (Scheme 5). Exposure of
the syn-adduct 18 to the conditions shown in entry 6 provided
the anti-isomer 19 in 94% yield;[14] on the other hand,
treatment of 19 under the conditions of entry 2 for 12 hours
Scheme 3. Synthesis of the macrolactone 4. DBU=1,8-diazabicyclo-
[5.4.0]undec-7-ene, DMP=Dess–Martin periodinane, PPTS=pyridi-
nium 4-toluenesulfonate.
Emmons reaction[13] gave the macrolactone 17 in 78% yield
over the two steps. Selective removal of the TES ether was
realized by treatment with PPTS to afford the requisite 4, a
substrate ready for the transannular cyclization.
With the macrolactone in hand, we next investigated the
crucial transannular oxy-Michael reaction (Table 1). Treat-
ment of 4 with DBU in acetonitrile at reflux provided in 50%
yield a 1:6 mixture of the cyclized syn- and anti-pyrans 18 and
19, which were separable by column chromatography
(entry 1). When LiCl was used with DBU, the reaction
proceeded faster, and the cycloadduct was obtained quanti-
tatively and with 7:1 syn selectivity (entry 2). Encouraged by
this result, we next proceeded to examine more closely the
reaction conditions. It turned out that the best result was
obtained by treatment of 4 with DBU and LiCl in acetonitrile
at room temperature for 1.5 hours, and provided a quantita-
tive amount of the syn-adduct 18 as a single product (entry 3).
This result can be explained by invoking the lithium-chelated
transition-state 20, in which the conformation is quite similar
to the crystal structure[2] of aspergillide A, as shown in
Scheme 5. Attempted interconversion.
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2619

Communications
resulted in 90% recovery of the starting material. From these
results, the anti-isomer 19 was found to be thermodynamically
favored.
Both macrocyclic pyrans 18 and 19 were independently
treated with acidic conditions (3m aqueous HCl in THF at
room temperature for 3 h) to give quantitatively the asper-
gillides A (1) and B (2), which were spectroscopically
identical to the natural products (Scheme 6 and the Support-
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Pachon, M. N. Kneeteman, J. Murga, M. Carda, J. A. Marco,
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Scheme 6. Completion of the total syntheses and attempted conver-
sions.
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ing Information). Furthermore, the attempted conversion of
natural aspergillide A into aspergillide B under the same
conditions as for 18 was also successful. In addition, exposure
of 1 to the isolation conditions (SiO2 in MeOH/CHCl3 (1:3) at
room temperature) did not produce 2 at all, which indicated
that aspergillide B is not an artifact.
[8] Y. Wang, D. Romo, Org. Lett. 2002, 4, 3231 – 3234.
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In summary, the total synthesis of the aspergillides A and
B has been accomplished in a longest linear sequence of
17 steps in 30% and 28% yield, respectively, from readily
accessible bicyclic chiral building blocks. The unique features
of this work include the first application of a highly efficient
and diastereoselective transannular oxy-Michael reaction for
the construction of the syn and anti tetrahydropyrans, which
are the penultimate intermediates for the natural products.
From a common 14-membered macrolactone, this synthesis is
the first demonstration of the successful conversion of the
syn pyran into the anti isomer, including the conversion of the
natural aspergillide A into aspergillide B by employing basic
conditions for a short period of time. The transannular oxy-
Michael strategy developed here would be applicable to the
synthesis of other related natural products.
[14] It has been mentioned in reference [3a] that an isomerizaton of
the syn pyran into the anti isomer was observed in trace amounts
during the macrolactonization.
Received: November 22, 2010
Revised: January 4, 2010
Published online: February 15, 2011
Keywords: diastereoselectivity · macrocycles · Michael addition ·
.
polyketides · total synthesis
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Angew. Chem. Int. Ed. 2011, 50, 2618 –2620