Synthetic studies on azadirachtin: stereoselective construction of the ABCE ring system

Article abstract of DOI:10.1016/j.tetlet.2010.03.077

A new method for constructing the ABCE ring system of azadirachtin in a stereoselective manner was developed. The synthesis of the model compound features (1) stereoselective construction of the highly hindered C8 quaternary center by an intermolecular ad

Full text of DOI:10.1016/j.tetlet.2010.03.077

Tetrahedron Letters 51 (2010) 2771–2773
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Tetrahedron Letters
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Synthetic studies on azadirachtin: stereoselective construction of the ABCE
ring system
Daisuke Nakagawa a, Masaaki Miyashita b, Keiji Tanino a,
*
a Division of Chemistry, Faculty of Science, Hokkaido University, Sapporo 060-0810, Japan
b Department of Applied Chemistry, Faculty of Engineering, Kogakuin University, Hachioji 192-0015, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
A new method for constructing the ABCE ring system of azadirachtin in a stereoselective manner was
developed. The synthesis of the model compound features (1) stereoselective construction of the highly
hindered C8 quaternary center by an intermolecular addition reaction of an allylborane with an aldehyde
and (2) construction of the E ring moiety by the Pd-catalyzed Nazarov cyclization.
Ó 2010 Elsevier Ltd. All rights reserved.
Received 8 March 2010
Revised 18 March 2010
Accepted 19 March 2010
Available online 23 March 2010
Azadirachtin (1), which was isolated from the seeds of the In-
dian neem tree Azadirachta indica A. Juss (Meliaceae) in 1968,1
exhibits strong antifeedant activity and growth inhibitory proper-
ties against insects.2 These distinctive biological properties com-
bined with the complex structures having seven rings and
sixteen stereogenic carbon atoms make azadirachtin an extremely
attractive target for synthetic chemists.3 One of the most synthet-
ically challenging structural features in 1 is the highly hindered C8
quaternary center at which the B ring and the E ring are connected.
Thus, this issue was addressed using an intramolecular reaction by
several groups. Ley exploited the diastereoselective Claisen rear-
rangement of a propargyl enol ether and subsequent radical cycli-
zation protocol for constructing the BE ring system, and this led to
the first total synthesis of 1 in 2007.3b–d Murai used an Ireland–Cla-
isen rearrangement to create the C8–C14 bond, which showed its
practicability with the model compound.3e On the other hand,
Nicolaou adopted a tethering strategy followed by a radical-based
intramolecular coupling and dismantling of the temporary
bridge.3f,g Watanabe presented a conceptually different strategy
that involves the formation of the requisite C8–C14 bond at a
rather early stage, and constructed the fully functionalized B ring
and the simplified E ring using an intramolecular tandem radical
cyclization reaction at once.3h
duce the side chain at the C8 position via an intermolecular addi-
tion reaction, we designed allylborane 5 as the precursor of
propargyl alcohol 4.
According to this strategy, a model study was undertaken to
synthesize compound 6 which possesses the ABCE ring system of
1 (Scheme 2). We planned to obtain allylborane 7 via a hydrobora-
tion reaction of diene 8 through the attack of a borane reagent to
the opposite face of the C ring moiety. Construction of the tricyclic
OR
O
MeO2C
H
O
OH
O
O
C
OH
O
RO
R
E
E
F
G
14
8
A
B
O
O
H
OH
RO
RO2C
O
AcO
H
D
O
H
H
MeO2C
OR
azadirachtin (1)
2
OR
O
OR
Pd-catalyzed
Nazarov
cyclization
O
H
OAc
OH
R
We herein report the construction of the ABCE ring system on
the basis of an intermolecular addition reaction at the C8 position.
We focused on the property of an allylborane that readily reacts
with an aldehyde under mild conditions in a regiospecific manner.4
Our synthetic strategy toward 1 is shown in Scheme 1.
From the retrosynthetic perspective, we envisioned 1 to be ob-
tained from the key intermediate 2 which would arise from 3
exploiting the Pd-catalyzed Nazarov cyclization.5 In order to intro-
H
3
4
OR
O
RO
O
+
H
RO
RO2C
H
BPin
OR
5
* Corresponding author. Tel.: +81 11 706 2705; fax: +81 11 706 4920.
E-mail address: ktanino@sci.hokudai.ac.jp (K. Tanino).
Scheme 1. Retrosynthetic analysis of azadirachtin (1).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.03.077

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D. Nakagawa et al. / Tetrahedron Letters 51 (2010) 2771–2773
BH3•THF
then
pinacol
O
O
OR1
OR1
R3O
H
O
H
O
+
C
23
22
hydroboration
E
5
BPin
BPin
THF, 80%
6
tBuO2C
O
A
B
OBn
24
25
O
2:1
RO2C
H
H
RO2C
BPin
OR2
OR2
6
7
O
BH3•THF
then
pinacol
Pd(PPh3)4
Me2Zn
OR1
O
8
OR1
OR1
OTf
I
O
O
H
7
DMF, 93%
THF, 83%
tBuO2C
H
O
O
H
BPin
OBn
BPin
26
27
H
RO2C
RO2C
RO2C
Scheme 4. Hydroboration reactions of dienes 23 and 22.
OR2
OR2
OR2
8
9
achieved by ring-closing metathesis8 of triene 14 which was pre-
pared by the allylation reaction of 13. Hydrolysis of the enol ether
moiety afforded ketone 15 which in turn was subjected to hydro-
genation in methanol followed by acetal formation. Stereoselective
construction of the C4 quaternary center was accomplished by
alkylation of ester 16 with BnOCH2Cl. Hydrolysis of the acetal moi-
ety afforded hydroxy ketone 17 that was reacted with NIS and iso-
propyl vinyl ether to afford iodoacetal 18 as a 1:1 mixture of
diastereomers. Under the influence of KOtBu, the intramolecular
alkylation reaction took place regardless of the stereochemistry
of the acetal moiety. The resulting ketone 19 was oxidized to enone
20 according to the Mukaiyama’s protocol (LDA, PhS(NtBu)Cl).9
Treatment of 20 with KOtBu at 0 °C effected selective formation
of the thermodynamically favored linear dienolate which reacted
with Comins reagent to afford dienol triflate 21. In order to sim-
plify the C ring moiety, the isopropoxy group was removed by ionic
reduction using triethylsilane. The resulting tetrahydropyran 22
was subjected to the Pd-catalyzed cross-coupling reaction with
Me2Zn.10
Scheme 2. Synthetic plan for model compound 6.
skeleton of these compounds was expected to be achieved via an
intramolecular alkylation reaction of ketone 9.
At first, the ABC ring system was constructed as shown in
Scheme 3. Alkylation of the commercially available enone 10 with
t
BrCH2CO2 Bu afforded keto ester 116 which was converted to en-
one 12 by addition of BnOCH2Li7 followed by acidic workup. The
conjugate addition reaction with a vinylcuprate occurred selec-
tively from the opposite face of the side chain, and the product
was isolated as enol silyl ether 13. Construction of the A ring was
OBn
LDA
BrCH2CO2 Bu
O
OEt
BnOCH2Li
then HCl
O
O
OEt
t
THF, 88%
THF, 68%
t
CO2 Bu
t
10
2CuLi
11
12
CO2 Bu
OBn
OBn
With the hydroboration precursor 23 in hand, the reaction with
borane followed by pinacol was performed in THF (Scheme 4).
Disappointingly, a 2:1 mixture of allylborane 24 and 25 was ob-
tained indicating that the C7–C8 double bond is much more reac-
tive than the sterically hindered C5–C6 double bond. These results
led us to examine the hydroboration reaction of dienol triflate 22
because the electron-withdrawing effect of the OTf group may
inactivate the C7–C8 double bond.11 As was expected, the reaction
of dienol triflate 22 occurred at the C5–C6 double bond stereose-
lectively to give allylborane 26. The methyl group was introduced
by the Pd-catalyzed coupling reaction with Me2Zn to afford the de-
sired allylborane 27 in good yield. Since it is difficult to construct
the highly functionalized C ring of 1 from the simplified C ring moi-
ety of model compound 27, we also explored the transformation of
dienol triflate 21 having a cyclic acetal moiety (Scheme 5). Treat-
ment of 21 with borane followed by pinacol afforded allylborane
28 as a mixture of epimers at the acetal moiety. However, the
Pd-catalyzed coupling reaction of 28 with Me2Zn resulted in the
methylation of only one diastereomer, and the corresponding epi-
mer remained unchanged.12 These results prompted us to trans-
form acetal 28 into enol ether 29, which underwent smooth
methylation giving rise to allylborane 30,13 by heating with pyrid-
inium m-nitrobenzenesulfonate14 in toluene.
LDA, HMPA
allylbromide
OTIPS
then TIPSOTf
HMPA
OTIPS
ether/Me2S
91%
Ht
THF, 94%
H
t
CO2 Bu 13
14
CO2 Bu
OBn
O
H2, Pd/C
then TsOH
1) Grubbs' cat.
2nd generation
O
OMe
2) 3N HCl
95% (2 steps)
MeOH, 90%
H
H
t
t
CO2 Bu
15
16
CO2 Bu
OiPr
1) Et2NLi
HMPA
BOMCl
OH
iPrO
NIS
O
I
O
O
4
CH2Cl2, 79%
2) 3 M HCl
89%
(2 steps)
tBuO2C
H
18
H
OBn
17
OiPr
OiPr
O
LDA
KOtBu
NtBu
NTf2
O
S
N
KOtBu
O
O
Ph
Cl
THF
Cl
THF
87%
THF
67% (2 steps)
H
H
X
19
20
With the key intermediate 30 in hand, the next stage was set for
the construction of the E ring. The reaction of allylborane 30 with
3-(t-butyldimethylsilyl)-2-propynal in toluene proceeded quanti-
tatively at room temperature, and the adduct was converted to ke-
tone 31 by Dess–Martin oxidation. Successive treatment of ketone
31 with alkenyllithium 3215 and isobutyryl chloride afforded the
adduct as a 1:1 mixture of diastereomers which was subjected to
desilylation with tetrabutylammonium fluoride (TBAF). The Pd-
OiPr
O
O
8
BF3•OEt2
Et3SiH
OTf
Pd(PPh3)4
Me2Zn
DMF, 90%
7
22: X=OTf
23: X=Me
5
CH2Cl2
80%
6
21
Scheme 3. Stereoselective construction of the ABC ring system.

D. Nakagawa et al. / Tetrahedron Letters 51 (2010) 2771–2773
2773
OiPr
gration) from the Ministry of Education, Culture, Sports, Science,
and Technology, Japan.
SO3H•Py
NO2
BH3•THF
then
pinacol
O
O
OTf
OTf
References and notes
21
toluene, 110 °C
64% (2 steps)
THF
1. Buterworth, J. H.; Morgan, E. D. Chem. Commun. 1968, 23.
2. (a) Ley, S. V.; Denholm, A. A.; Wood, A. Nat. Prod. Rep. 1993, 10, 109; (b) Mordue,
A. J.; Blachwell, A. Insect Physiol. 1993, 39, 903.
tBuO2C
H
H
BPin
BPin
O
28
29
OBn
3. For review, see: (a) Veitch, G. E.; Boyer, A.; Ley, S. V. Angew. Chem., Int. Ed. 2008,
47, 9402; for total synthesis, see: (b) Veitch, G. E.; Beckmann, E.; Burke, B. J.;
Boyer, A.; Maslen, S. L.; Ley, S. V. Angew. Chem., Int. Ed. 2007, 46, 7629; (c)
Veitch, G. E.; Beckmann, E.; Burke, B. J.; Boyer, A.; Ayats, C.; Ley, S. V. Angew.
Chem., Int. Ed. 2007, 46, 7633; (d) Ley, S. V.; Somovilla, A. A.; Anderson, J. C.;
Ayats, C.; Bänteli, R.; Beckmann, E.; Boyer, A.; Brasca, M. G.; Brice, A.;
Broughton, H. B.; Burke, B. J.; Cleator, E.; Craig, D.; Denholm, A. A.; Denton, R.
M.; Reville, T. D.; Gobbi, L. B.; Göbel, M.; Gray, B. L.; Grossmann, R. B.;
Gutteridge, C. E.; Hahn, N.; Harding, S. L.; Jennens, D. C.; Jennens, L.; Lovell, P. J.;
Lovell, H. J.; Puente, M. L.; Kolb, H. C.; Koot, W. J.; Maslen, S. L.; McCusker, C. F.;
Mattes, A.; Pape, A. R.; Pinto, A.; Santafianos, D.; Scott, J. S.; Smith, S. C.; Somers,
A. Q.; Spilling, C. D.; Stelzer, F.; Toogood, P. L.; Turner, R. M.; Veitch, G. E.; Wood,
A.; Zumbrunn, C. Chem. Eur. J. 2008, 14, 10683; for recent synthetic studies, see:
(e) Fukuzaki, T.; Kobayashi, S.; Hibi, T.; Ikuma, Y.; Ishihara, J.; Kanoh, N.; Murai,
A. Org. Lett. 2002, 4, 2877; (f) Nicolaou, K. C.; Sasmal, P. K.; Koftis, T. V.;
Converso, E. L.; Kaiser, F.; Roecker, A. J.; Dellios, C. C.; Sun, X.-W.; Petrovic, G.
Angew. Chem., Int. Ed. 2005, 44, 3443; (g) Nicolaou, K. C.; Sasmal, P. K.; Roecker,
A. J.; Sun, X.-W.; Mandal, S.; Converso, A. Angew. Chem., Int. Ed. 2005, 44, 3447;
(h) Watanabe, H.; Mori, N.; Itoh, D.; Kitahara, T.; Mori, K. Angew. Chem., Int. Ed.
2007, 46, 1512.
O
O
1)
TBS
CHO
Pd(PPh3)4
Me2Zn
toluene, 99%
8
DMF, 99%
2) Dess-Martin
periodinane
CH2Cl2, 95%
H
H
TBS
BPin
30
31
1)
O
iPr
Li
OMe
O
O
32
then
iPrCOCl, 90%
PdCl2(MeCN)2
AcOH
OMe
MeCN, 67%
2) TBAF, 90%
H
33
O
C
OMe
4. (a) Hoffmann, R. W. In Stereocontrolled Organic Synthesis; Trost, B. M., Ed.;
Blackwell Scientific Publications: Oxford, 1994; pp 259–274; (b) Matteson, D. S.
Stereodirected Synthesis with Organoboranes; Springer: Berlin, 1995; (c) Roush,
W. R. Allylboron Reagents. In Stereoselective Synthesis; Ahlbecht, H., Helmchean,
G., Arend, M., Herrmann, R., Eds.; Methods in Organic Chemistry E21b; Georg
Thieme: Stuttgart, 1995; pp 1410–1485.
E
A
B
O
tBuO2C
H
OBn
34
5. Rautenstrauch, V. J. Org. Chem. 1984, 49, 950.
Scheme 5. Synthesis of model compound 6.
6. Horiguchi, Y.; Nakamura, E.; Kuwajima, I. J. Am. Chem. Soc. 1989, 111, 6257.
7. Hara, R.; Furukawa, T.; Horiguchi, Y.; Kuwajima, I. J. Am. Chem. Soc. 1996, 118,
9186.
8. For a review on ring-closing metathesis, see: Grubbs, R. H.; Miller, S. J.; Fu, G. C.
catalyzed Nazarov cyclization was performed by heating alkyne 33
with PdCl2(CH3CN)2, and cyclopentenone 34 was obtained as a 1:1
mixture of diastereomers in 67% yield.5
Acc. Chem. Res. 1995, 28, 446.
9. Mukaiyama, T.; Matsuo, J.; Yanagisawa, M. Chem. Lett. 2000, 1072.
10. Marshall, J. A.; Van Devender, E. A. J. Org. Chem. 2001, 66, 8037.
11. Low reactivity of enol triflates in epoxidation is reported: Evarts, J. B.; Fuchs, P.
L. Tetrahedron Lett. 1999, 40, 2703.
In summary, we have achieved stereoselective synthesis of tet-
racyclic compound 34 which possesses the ABCE ring system of
azadirachtin (1). The synthesis of the model compound features
(1) stereoselective construction of the highly hindered C8 quater-
nary center by an intermolecular addition reaction of allylborane
30 with an aldehyde and (2) construction of the E ring moiety by
the Pd-catalyzed Nazarov cyclization. It is noteworthy that forma-
tion of the C8–C14 bond without using an intramolecular reaction
is generally difficult. Studies toward constructing the EFG ring moi-
ety on the basis of the Nazarov cyclization are in progress in our
laboratory.
12. Epimer 28a in which the isopropoxy group is oriented over the B ring exhibited
poor reactivity probably because of the steric hindrance around the enol
triflate moiety.
OiPr
O
OTf
tBuO2C
H
BPin
28a
OBn
13. The stereochemistry of allylborane 30 was determined by the NOE
measurements.
Acknowledgments
14. Miyashita, M.; Sasaki, M.; Hattori, I.; Sakai, M.; Tanino, K. Science 2004, 305,
495.
15. Alkenyl lithium 32 was prepared by treating (E)-1-methoxy-3-
(tributylstannyl)-2-butene with butyllithium. For the synthesis of (E)-3-
(tributylstannyl)-2-buten-1-ol, see: Yoshimura, F.; Sasaki, M.; Hattori, I.;
Komatsu, K.; Sakai, M.; Tanino, K.; Miyashita, M. Chem. Eur. J. 2009, 15, 6626.
This work was partially supported by the Global COE Program
(Project No. B01: Catalysis as the Basis for Innovation in Materials
Science) and Grant-in-Aid for Scientific Research on Innovative
Areas (Project No. 2105: Organic Synthesis Based on Reaction Inte-