Synthetic Progress toward Azadirachtins. 2. Enantio- and Diastereoselective Synthesis of the Right-Wing Fragment of 11-epi-Azadirachtin I

Article abstract of DOI:10.1021/acs.orglett.5b00831

(Chemical Equation Presented). A stereoselective three-component coupling reaction of allylzinc bromide, silyl glyoxylate, and a β-lactone has been developed. This has been successfully applied to the enantio- and diastereoselective synthesis of the fully

Full text of DOI:10.1021/acs.orglett.5b00831

Letter
pubs.acs.org/OrgLett
Synthetic Progress toward Azadirachtins. 2. Enantio- and
Diastereoselective Synthesis of the Right-Wing Fragment of 11-epi-
Azadirachtin I
Ceheng Tan,† Wei Chen,† Xinpeng Mu,† Qi Chen,† Jianxian Gong,*,† Tuoping Luo,*,‡
and Zhen Yang*,†,‡,§
†Laboratory of Chemical Genomics, School of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School,
Shenzhen 518055, China
‡Key Laboratory of Bioorganic Chemistry and Molecular Engineering, Ministry of Education and Beijing National Laboratory for
Molecular Science (BNLMS) and Peking-Tsinghua Center for Life Sciences, Peking University, Beijing 100871, China
§Key Laboratory of Marine Drugs, Chinese Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, 5
Yushan Road, Qingdao 266003, China
S
* Supporting Information
ABSTRACT: A stereoselective three-component coupling reaction of allylzinc bromide, silyl glyoxylate, and a β-lactone has
been developed. This has been successfully applied to the enantio- and diastereoselective synthesis of the fully functionalized
furopyran moiety of azadirachtins.
zadirachtins 1−3 are complex natural products isolated
developing a novel approach for the synthesis of furopyran
moiety 5.
A
from the Indian neem tree (Scheme 1).1 They are potent
Synthetically, there are many methods for the synthesis of
furo[2,3b]furans.2 In contrast, there are relatively few reports
for furo[2,3b]pyrans.3 Our aim was to develop a flexible and
relatively short route to the bioactive portion of the most
potent azadirachtins.
Scheme 1. Azadirachtins and Retrosynthetic Analysis
Our retrosynthetic analysis for the synthesis of furopyran 5 is
illustrated in Scheme 2. This could be generated from lactone 6
Scheme 2. Retrosynthetic Analysis
insect antifeedants and growth inhibitors. Their interesting
biological activity, together with their complex structures, has
generated great interest in their chemical synthesis.
In a previous paper,1 we described the analysis for total
syntheses of azadirachtin I (2) and 11-epi-azadirachtin I (3),
and a novel gold-catalyzed tandem reaction of a 1,7-diyne for
the enantio- and diastereoselective synthesis of fully function-
alized trans-decalin (4) (Scheme 1). We are also interested in
Received: March 20, 2015
© XXXX American Chemical Society
A
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Letter
via the methodology reported by Ley and co-workers,3
featuring a reduction/ozonolysis/methanolysis sequence. Lac-
tone 6 could be made via the chemo- and stereoselective
reduction of ketone 7, followed by intramolecular lactonization.
Key intermediate 7, with a quaternary center, could be
constructed using a modified diastereoselective three-compo-
nent coupling3 of silyl glyoxylate 8, allylzinc bromide 9, and β-
lactone 10. To the best of our knowledge, there are no reports
on the use of allylzinc bromide as a nucleophile to initiate the
silyl glyoxylate-mediated diastereoselective cascade reaction.
Silyl glyoxylates have recently emerged as a reliable class of
reagents for the union of nucleophilic and electrophilic
partners.4,5 The reaction of substituted β-lactone D with
intermediate C derived from the addition of Reformatsky’s
agent A to a silyl glyoxylate B, followed by the [1,2]-Brook
rearrangement6 of the resultant zinc aldolate, was developed by
Johnson and co-workers.7 This reaction is thought to proceed
through transition state C formed by stronger chelation with
the pendant ethyl ester.4h This allows the resultant nucleophile
to access β-lactone D via its less hinder convex side to give E in
a highly diastereoselective manner (1,4-induction) (Scheme 3,
eq 1).
center. It is worth mentioning that this excellent diastereose-
lective result is opposite that of the previous results with other
viable terminal electrophiles.9 The structure of 7a was initially
confirmed by NMR study and later was confirmed by its X-ray
crystallographic analysis10 (Scheme 5). Thus, by application of
allylzinc bromide as a nucleophile, we achieved a concise
synthetic pathway for synthesis of the key intermediate 5 in a
highly diastereoselective manner.
To extend the scope of this three-component coupling
reaction, alternative electrophiles, such as other medium-sized
lactones, aldehydes, and ketones, were employed, and the
results are shown in Table 1. The following observations can be
made: (1) Coupling product 7b was obtained in relatively low
yield but with high diastereoselectivity when benzaldehyde was
Table 1. Substrate Scope of the Allylzinc Bromide Initiated
a
Three-Component Coupling Reaction
Scheme 3. Three-Component Coupling Reactions
In consideration of the fact that cationic zinc can form a
complex with olefins,8 we therefore would like to explore the
feasibility of using allylzinc bromide to initiate our three-
component reaction. We envisioned that nucleophilic addition
of allylzinc bromide F to silyl glyoxylate B might form a
transition state G, which could approach β-lactone D from its
less hindered side; as a result, product H with the desired
stereochemistry at C3 and C4 could be obtained (Scheme 3, eq
2). We envisaged that given the lower basicity of allylzinc
bromide, this chemistry could be used to synthesize structurally
more diverse compounds and provide access to lactone 6
(Scheme 2).
Our research began with the identification of the conditions
for the proposed three-component reaction. In the event, the
easily prepared allylzinc bromide 9 (2.0 equiv) was added to a
solution of tert-butyl dimethylsilylglyoxylate 8 (2.0 equiv) in
THF at −78 °C, and the resultant mixture was then mixed with
a solution of β-lactone 10 (1.0 equiv, see the Supporting
Information) in THF at −78 °C, followed by reaction at room
temperature for 10 min to give the expected coupling product
7a in 83% yield with a diastereomeric ratio up to 20:1. This
indicates an excellent stereochemical induction that transmitted
the β-lactone stereochemistry to the newly formed stereo-
a
Reaction conditions: benzyl 2-(tert-butyldimethylsilyl)-2-oxoacetate
(8) (1.8−2.0 equiv), allyl zinc bromide (9) (1.8−2.0 equiv) THF, −
78 °C, then electrophile (1.0 equiv) at −78 °C then 0 °C to ambient
b
c
temperature. All reactions were run at 0.05 M. Isolated yields. The
1
dr values were determined by H NMR spectroscopy.
B
DOI: 10.1021/acs.orglett.5b00831
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used. Coupling product 7c was formed in 81% yield with a
lower diastereoselectivity of 2:1 when 4-methoxybenzaldehyde
(Table 1, entry 3) was used. In contrast, when 4-nitro-
benzaldehyde (Table 1, entry 4) was used, the coupling product
was formed in 79% yield as a single product. This indicates that
the electron-deficient substrate could favor this zinc coordina-
tion. (2) 2,2,2-Trifluoro-1-phenylethanone and acetophenone
(Table 1, entries 5 and 6) undergo the three-component
reaction to afford products 7e and 7f in 67% and 62% yield,
respectively. However, the electron-deficient substrate 2,2,2-
trifluoro-1-phenylethanone gave 20:1 diastereoselectivity, while
acetophenone gave only 1:1. (3) The five- and six-membered
ring-based lactones gave no coupling products (Table 1, entries
7 and 8), indicating that ring strain is the driving force.
5.3d To confirm the stereochemistry, 5 was first treated with
TBAF, and the resultant diol was protected as its benzylidene
acetal, followed by deacetylation to give alcohol 14. The
structure of 14 was confirmed by X-ray crystallography10
(Scheme 5).
Scheme 5. Synthesis of Furo[2,3b]pyrans 16
Synthesis of the right-wing fragment began with the
preparation of enantioenriched β-lactone 10 (82% ee) using
an organocatalytic reaction (see the Supporting Information for
details).11 Thus, silyl glyoxylate 8, allylzinc bromide, and 10
were then assembled using the optimized conditions to afford
7a in 83% yield as a single diastereomer (Scheme 4).
Scheme 4. Synthesis of Right-Wing Fragment 5
The core structure of 5 with different protecting groups
might be required for the total syntheses of azadirachtins 1−3.
Thus, substrate 16 (Scheme 5) with more stable protecting
groups (PMB/Bn vs TBS/TBS) was selected as an alternative
because this compound had been successfully used as a key
intermediate in the total synthesis of azadirachtin A (1) by Ley
and co-workers.3h
To this end, the primary hydroxyl group in 15 was protected
as its tert-butyldiphenylsilyl ether (TBDPS) by reaction with
TBDPSCl in the presence of imidazole to give 15 in 84% yield.
Regioselective ring opening of the benzylidene acetal protecting
group by DIBAL-H and protection of the resultant C20
hydroxyl group as the corresponding benzyl ether gave rise to
16 in 79% yield in two steps. The spectroscopic data of 16 (1H
and 13C NMR spectra, HRMS analysis) are in good agreement
with those reported by Ley’s group.3f
In summary, we have synthesized the right-wing fragments of
azadirachtin-type limonoids. The synthesis of 5 from chiral β-
lactone 10 constitutes a novel and efficient approach to access
this highly substituted framework, and the highly diastereose-
lective tandem allylation/quaternary Claisen condensation of
the silyl glyoxylate and β-lactone can be applied to a structurally
diverse range of substrates. The work reported herein serves as
a milestone in our program toward understanding and
synthesizing azadirachtin-type limonoids as environmentally
friendly insecticides. Further studies will be reported in due
course.
Stereoselective reduction of the ketone in 7a, followed by
lactonization12 and alcohol protection, afforded lactone 11 in
47% yield over three steps. The stereochemistry of 11 was
assigned using extensive 2D-NMR experiments (see the
Supporting Information).
Removal of the MEM protecting group and DIBAL-H
reduction provided hemiacetal 12 as a pair of inseparable
epimers (1:5). Acetylation of the primary alcohol and
ozonolysis of the olefin furnished bicyclic hemiacetal 13 in
69% yield over two steps, again as a pair of inseparable epimers
(1.8:1). Intriguingly, reaction of 13 with iodomethane in the
presence of silver(I) oxide resulted in only one stereoisomer
ASSOCIATED CONTENT
■
S
* Supporting Information
Experimental procedures, spectral data, and other character-
ization data. The Supporting Information is available free of
charge on the ACS Publications website at DOI: 10.1021/
acs.orglett.5b00831.
C
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Letter
C. C.; Scheidt, K. A. Angew. Chem., Int. Ed. 2008, 47, 2294. (b) Lettan,
R. B.; Galliford, C. V.; Woodward, C. C.; Scheidt, K. A. J. Am. Chem.
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(d) Jiang, J.-L.; Yao, M.; Lu, C.-D. Org. Lett. 2014, 16, 318.
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AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: gongjx@pku.edu.cn.
*E-mail: tuopingluo@pku.edu.cn.
*E-mail: zyang@pku.edu.cn.
Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
■
This work was supported by the NSF of China (Grant Nos.
21372016 and 21402002), 863 Program (Grant No.
2013AA092903), 973 Program (Grant No. 2012CB722602),
NSFC-Shandong Joint Fund for Marine Science Research
Centers (U1406402), and Shenzhen Basic Research Program
( G r a n t N o s . J C Y J 2 0 1 3 0 3 2 9 1 8 0 2 1 7 0 5 9 a n d
ZDSYS20140509094114168).
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