Asymmetric formal synthesis of azadirachtin

Article abstract of DOI:10.1002/anie.201507935

An asymmetric formal synthesis of azadirachtin, a potent insect antifeedant, was accomplished in 30 steps to Ley's synthetic intermediate (longest linear sequence). The synthesis features: 1) rapid access to the optically active right-hand segment starting from the known 5-hydroxymethyl-2-cyclopentenone scaffold; 2) construction of the B and E rings by a key intramolecular tandem radical cyclization; 3) formation of the hemiacetal moiety in the C ring through the α-oxidation of the six-membered lactone followed by methanolysis. The asymmetric formal synthesis of azadirachtin (1) was accomplished by utilizing the tandem radical cyclization reaction as a key step. The route to the key intermediate 2 requires the longest linear sequence of 30 steps.

Full text of DOI:10.1002/anie.201507935

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Angewandte
Communications
International Edition: DOI: 10.1002/anie.201507935
German Edition: DOI: 10.1002/ange.201507935
Natural Product Synthesis
Asymmetric Formal Synthesis of Azadirachtin
Naoki Mori, Takeshi Kitahara, Kenji Mori, and Hidenori Watanabe*
Abstract: An asymmetric formal synthesis of azadirachtin,
a potent insect antifeedant, was accomplished in 30 steps to
Leyꢀs synthetic intermediate (longest linear sequence). The
synthesis features: 1) rapid access to the optically active right-
hand segment starting from the known 5-hydroxymethyl-2-
cyclopentenone scaffold; 2) construction of the B and E rings
by a key intramolecular tandem radical cyclization; 3) for-
mation of the hemiacetal moiety in the C ring through the a-
oxidation of the six-membered lactone followed by methanol-
ysis.
found to be effective to construct the B ring with the C8ÀC14
bond in place. Subsequently, our continuous efforts led us to
achieve a stereoselective synthesis of the fully functionalized
left-hand segment, and an advanced tandem mode enabled
the cyclization of the B and E rings at once. Herein, we
describe an asymmetric formal synthesis of 1 along with
a concise preparation of the optically active right-hand
segment.
[6b]
As depicted in Scheme 1, azadirachtin (1) could be
[5]
accessed from Leyꢀs intermediate 2 in nine steps, and was
A
zadirachtin (1), which was isolated from the neem tree
Azadirachta indica A. Juss (Meliaceae) in 1968, exhibits
[
1]
potent antifeedant and growth inhibitory activities against
[
2]
insects (Figure 1). Since the precise structure of 1 was
Figure 1. Azadirachtin (1).
[3]
elucidated in 1987, this complex molecule, possessing
sixteen contiguous stereogenic centers, as well as various
oxygen-containing functional groups, has reigned as a chal-
lenging target for synthetic chemists. The most difficult issue
for the synthesis of 1 is considered to be the construction of
the extremely hindered C8ÀC14 bond. Although some novel
strategies to form the C8ÀC14 bond have been developed by
Scheme 1. Retrosynthetic analysis.
[4a,b]
[4c]
[4d–g]
the research groups of Ley,
Murai, Nicolaou,
and
[
4h,i]
Tanino,
completion of its synthesis.
Our group embarked on studies toward the synthesis of
to date, only the Ley group arrived at the
[5]
chosen as our synthetic goal. It was envisioned that a benzyl-
protected hemiacetal moiety in 2 would be formed through
the a-oxidation of the six-membered lactone in 3 and
subsequent methanolysis. The complete carbon framework
of 1 would be constructed by the key tandem radical
cyclization of the allene 4, which in turn arises through
a coupling of both segments 5
substitution with a methyl group.
Our synthesis of the optically active right-hand segment 6
commenced with the known (R)-7 (98% ee), which was
[6a]
1
in 1989, during which a radical cyclization approach was
[
*] Dr. N. Mori, Prof. Dr. H. Watanabe
Department of Applied Biological Chemistry, Graduate School of
Agricultural and Life Sciences, The University of Tokyo
[6b, 7]
and 6, followed by S 2’
N
1
-1-1 Yayoi, Bunkyo-ku, Tokyo 113-8657 (Japan)
E-mail: ashuten@mail.ecc.u-tokyo.ac.jp
Prof. Dr. T. Kitahara
Current address: Kitasato University
[8]
reported by Nanda and co-workers (Scheme 2). Firstly, an
aldol reaction of 7 with ethyl acetate gave 8 in 85% yield as
a single diastereomer. Having faced the difficulties in
introducing a benzyl group to the resulting tertiary alcohol,
the TBDPS group was removed with TBAF/AcOH, and the
diol 9 was treated with benzaldehyde dimethyl acetal, and
PPTS to give the cyclic acetal 10 (1:2 inseparable mixture of a/
5
-9-1 Shirokane, Minato-ku, Tokyo 108-0193 (Japan)
Prof. Dr. K. Mori
Present address: Photosensitive Materials Research Center, Toyo
Gosei Co., Ltd
4
-2-1 Wakahagi, Inzai-shi, Chiba 270-1609 (Japan)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201507935.
1
4920
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Scheme 2. Reagents and conditions: a) EtOAc, LiHMDS, THF, À788C,
5%; b) TBAF, AcOH, THF, RT, 98%; c) PhCH(OMe) , PPTS, CH Cl ,
8
2
2
2
RT, 95%; d) LiOH, MeOH/H O (3:1), RT; e) O , CH Cl ; then Me S,
2
3
2
2
2
À788C to RT; then PPTS, 54% (2 steps); f) TBSOTf, 2,6-di-tert-
butylpyridine, CH Cl , RT, 30% (12), 27% (13) and 19% (14).
2
2
LiHMDS=lithium hexamethyldisilazide, PPTS=pyridinium toluene-p-
sulfonate, TBAF=tetra-n-butylammonium fluoride, TBDPS=tert-butyl-
diphenylsilyl, TBS=tert-butyldimethylsilyl, Tf =trifluoromethanesul-
fonyl, THF=tetrahydrofuran.
Scheme 3. Reagents and conditions: a) DIBALH, CH Cl , À788C;
2
2
b) MeI, Ag O, CH CN, RT. DIBALH=diisobutylaluminum hydride,
2
3
MMPP=magnesium monoperoxyphthalate hexahydrate.
b-isomers). The compound 10 was then converted into the
tricyclic hemiacetal 11, which comprises four inseparable
diastereomers, through hydrolysis of ethyl ester followed by
ozonolysis of the double bond and successive treatment with
acid. TBS protection of 11 by using TBSOTf and 2,6-di-tert-
[
9]
butylpyridine gave the three products, 12, 13, and 14, which
could be separated by silica gel column chromatography. The
use of 2,6-di-tert-butylpyridine, a bulkier base, instead of Et N
3
or 2,6-lutidine was crucial to providing the products in higher
[
10]
yield.
With the tricyclic lactones 12–14 in hand, we next
investigated the transformation of the lactone moiety into
[5c]
the methyl acetal (Scheme 3). According to Leyꢀs report,
MMPP epoxidation of a-2 as well as b-2 afforded b-18 with
epimerization at C23, but the yield from the former was much
lower (22%) than that from the latter (65%). This result
suggested that the use of a b-acetal at C23 would be
advantageous for the synthesis of the target molecule.
Pleasingly, a reduction/methylation sequence of 12 afforded
the desired 15 as a single b-isomer, which was selected as
a substrate for the next reaction. In contrast, the compounds
Scheme 4. Reagents and conditions: a) H , Pd(OH) /C, MeOH, RT,
2
2
9
6
9
0
1%; b) BnBr, NaH, DMF, 08C to RT, 86%; c) H , Pd/C, MeOH, RT,
2
7% (76% brsm); d) (COCl) , DMSO, Et N, CH Cl , À78 to 08C,
2
3
2
2
3%; e) MeLi, THF, À788C; f) (COCl) , DMSO, Et N, CH Cl , À78 to
2
3
2
2
8C, 85% (2 steps); g) TMSCꢀCH, nBuLi, THF, À788C, 45% of 23
and 30% of the diastereomer; h) Ac O, DMAP, toluene, reflux, 89%;
2
i) TBAF, AcOH, THF, 308C, 96%; j) MsCl, Et N, CH Cl , 08C; then
3
2
2
1
3 and 14 afforded 16 and 17, respectively, as diastereomeric
mixtures.
The transformation of 15 into the primary alcohol 21 was
then examined (Scheme 4). Since the direct conversion of 15
(PhSe) , NaBH , EtOH, 08C, 89%. DMF=N,N-dimethylformamide,
2 4
DMSO=dimethyl sulfoxide, DMAP=4-dimethylaminopyridine,
Ms=methanesulfonyl, TMS=trimethylsilyl.
[11]
into 21 with DIBALH
was unsuccessful, 15 was trans-
formed into 21 through a three-step sequence. Standard
manipulations of 21 led to the methyl ketone 22 over three
steps. The compound 22 was then treated with lithium
trimethylsilylacetylide, and the major tertiary alcohol 23 was
obtained in 45% yield, together with 30% of a diastereo-
mer, after separation by silica gel column chromatography.
Acetylation of 23 followed by complete desilylation gener-
ated the hemiacetal 25, whose hydroxy group was then
replaced with a phenylseleno group via the mesylate to
furnish the right-hand segment 6 in 18 steps from 7.
Having achieved the asymmetric synthesis of 6, we set out
to undertake the coupling of both segments (Scheme 5). A
lithium acetylide derived from 6 with LiHMDS reacted with
the aldehyde 5 (98% ee) to give 26 in 46% yield without
generation of the a-isomer. An S 2’ reaction of the propargyl
N
[12]
acetate with a methylcopper reagent proceeded smoothly
[13]
under Macdonaldꢀs conditions
to afford the allene 4,
a precursor for the radical cyclization, as a single diastereo-
mer in 77% yield. Although the configuration of the allene
was not determined, it was supposed to be S from the reported
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Scheme 5. Reagents and conditions: a) LiHMDS, THF, À788C, 46%; b) MeMgBr, CuI, LiBr, THF, 0 to 208C, 77%; c) nBu SnH, AIBN, DMF,
3
1
5
308C, 35%, d) TMSCl, imidazole, DMF, 08C, 87%, e) TBSOTf, Et N, CH Cl , 08C; f) 2-benzenesulfonyl-3-phenyloxaziridine, CH Cl , 08C to RT,
3 2 2 2 2
0% (2 steps); g) TBAF, AcOH, THF, 08C, 70%; h) DMP, CH Cl , RT; i) K CO , MeOH, RT; j) BnBr, Ag O, DMF, RT, 39% of 30 and 36% of 31 (3
2
2
2
3
2
steps); k) NaOMe, MeOH, 608C, 94%; l) PPTS, CH CN/H O, RT, 74%; m) TBSOTf, Et N, CH Cl , RT, 91%. AIBN=2,2’-azobisisobutyronitrile,
3
2
3
2
2
DMP=Dess–Martin periodinane, PMP=p-methoxyphenyl.
[
14]
results of the similar anti-S 2’ reaction.
A preliminary
sequence and 9 more steps are required to 1). The key
elements in the synthesis include: 1) rapid access to the
optically active right-hand segment 6 starting from the known
cyclopentenone derivative 7; 2) construction of the B and E
rings by the key intramolecular tandem radical cyclization
(4!3); 3) formation of the hemiacetal moiety in the C ring
through the a-oxidation of the six-membered lactone fol-
lowed by methanolysis (27!30). This concise and efficient
approach provides new aspects for the synthesis of complex
natural products.
N
investigation showed that DMF was superior to other solvents
we tested (benzene, toluene, dimethoxyethane, 1,4-dioxane,
diglyme). Therefore, the key tandem radical cyclization was
performed by heating 4 with reagents (nBu SnH, AIBN) in
3
[
15]
DMF at 1308C, and the product 3, having the full carbon
framework of azadirachtin, was obtained in a moderate yield.
The hydroxy group of 3 was protected as a TMS ether to
give 27 in 87% yield (Scheme 5). Treatment of 27 with
TBSOTf and Et N formed the intermediate silyl ketene
acetal, which was then oxidized with the Davis reagent to
[16]
3
[17]
afford the a-oxylactone 28. It is worth noting that 3, having
a free hydroxy group, decomposed during the above oxidation Acknowledgements
step. The TBS and TMS groups of 28 were removed by TBAF/
AcOH to give 29 in 70% yield. Oxidation of the diol 29 with
This work was financially supported by a Grant-in-Aid for
Young Scientists (B) (No. 21780108) to N.M. from JSPS.
[
18]
Dess–Martin periodinane followed by methanolysis of the
resulting a-ketolactone gave rise to the formation of the five-
membered cyclic hemiacetal present in the natural product.
Subsequent protection of the hydroxy group with benzyl
bromide and silver(I) oxide in DMF yielded the desired
product 30 (39% in 3 steps) along with the unexpected benzyl
ester 31 (36% in 3 steps), which could be converted into 30 by
methanolysis. Finally, removal of the p-methoxybenzylidene
Keywords: acetals · cyclizations · natural products · radicals ·
stereoselectivity
How to cite: Angew. Chem. Int. Ed. 2015, 54, 14920–14923
Angew. Chem. 2015, 127, 15133–15136
[19]
acetal in 30 by treatment with PPTS in aqueous acetonitrile
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1
13
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Received: August 25, 2015
Published online: October 16, 2015
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