Highly Selective Entry to the Azadirachtin Skeleton via a Claisen Rearrangement/Radical Cyclization Sequence

Article abstract of DOI:10.1021/ol0201557

(Matrix Presented) A highly diastereoselective, microwave-induced Claisen rearrangement of an appropriately substituted propargylic enol ether allows the formation of the sterically congested C₈-C₁₄ bond of azadirachtin. When combine

Full text of DOI:10.1021/ol0201557

ORGANIC
LETTERS
2002
Vol. 4, No. 22
3847-3850
Highly Selective Entry to the
Azadirachtin Skeleton via a Claisen
Rearrangement/Radical Cyclization
Sequence
Thomas Durand-Reville, Luca B. Gobbi, Brian Lawrence Gray,
Steven V. Ley,* and James S. Scott
Department of Chemistry, Cambridge UniVersity, Lensfield Road,
Cambridge CB2 1EW, United Kingdom
sVl1000@cam.ac.uk
Received August 6, 2002 (Revised Manuscript Received September 16, 2002 )
ABSTRACT
A highly diastereoselective, microwave-induced Claisen rearrangement of an appropriately substituted propargylic enol ether allows the formation
of the sterically congested C −C bond of azadirachtin. When combined with a radical-mediated cyclization of the corresponding allene, this
8
14
sequence offers rapid entry to the framework of azadirachtin.
Azadirachtin 1, one of the most structurally complex and
highly oxygenated triterpenoid isolates from the Indian neem
tree Azadirachta indica (A. Juss) Meliaceae,1 has gained
considerable attention as a potential nontoxic, biodegradable,
and natural pesticide.2 However, the utility of this potent
insect antifeedant3 is limited by its instability in the field as
a result of its propensity to undergo complex, irreversible
rearrangements under mild acidic, basic, and photolytic
conditions.2b,4 Furthermore, the biochemical mode of action
of azadirachtin remains unknown.5 To address these issues,
we have undertaken detailed biological and chemical studies
on 1;2b a flexible route to the total synthesis of this natural
product that allows the development of analogues for
biological screening is part of this program. Azadirachtin is
a particularly challenging synthetic target by virtue of its 16
contiguous stereogenic centers, 7 tetrasubstituted carbons,
and array of differentiated oxygen functionality. Additionally,
three intramolecular hydrogen bonds have been proposed to
hold 1 in a highly rigid conformation,6 and the close
proximity of so much restricted functionality renders the
chemistry of azadirachtin subject not only to the inherent
reactivity of the constituent groups but also to more poorly
understood synergistic effects. The combination of these
(1) Butterworth: J. H.; Morgan, E. D. J. Chem. Soc., Chem. Commun.
1968, 23-24.
(2) For reviews on the biological profile and previous synthetic studies
on azadirachtin, see: (a) Ley, S. V. Pure Appl. Chem. 1994, 66, 2099-
2102. (b) Ley, S. V.; Denholm, A. A.; Wood, A. Nat. Prod. Rep. 1993,
109-157.
(3) Munakata, K. Pure Appl. Chem., 1975, 42, 57. An insect antifeedant
is defined as a substance that inhibits feeding but does not kill the insect
directly, with death occurring consequently by starvation.
(4) (a) Johnson, S.; Morgan, E. D.; Wilson, I. D.; Spraul, M.; Hofmann,
M. J. Chem. Soc., Perkin Trans. 1 1994, 11, 1499-1502. (b) Ley, S. V.;
Anderson, J. C.; Blaney, W. M.; Lidert, Z.; Morgan, E. D.; Robinson, N.
G.; Santafianos, D.; Simmonds, M. S. J.; Toogood, P. L. Tetrahedron 1989,
30, 5175-5192. (c) Bilton, J. N.; Jones, P. S.; Ley, S. V.; Robinson, N.
G.; Sheppard, R. N. Tetrahedron Lett. 1988, 29, 1849-1852.
(5) Several mechanisms, in addition to antifeedancy, include growth
inhibition, malformations, and ecdysis inhibition; see: Schmutterer, H.;
Rembold, H. Z. Angew. Entomol. 1980, 89, 179. For structure-activity
relationship studies, see: (a) de la Puente, M. L.; Grossman, R. B.; Ley, S.
V.; Simmonds, M. S. J.; Blaney, W. M. J. Chem. Soc., Perkin. Trans. 1
1996, 1517-1521. (b) Ley, S. V.; Anderson, J. C.; Blaney, W. M.; Morgan,
E. D.; Sheppard, R. N.; Simmonds, M. S. J.; Slawin, A. M. Z.; Smith, S.
C.; Williams, D. J.; Wood, A. Tetrahedron 1991, 44, 9231-9246.
10.1021/ol0201557 CCC: $22.00 © 2002 American Chemical Society
Published on Web 10/08/2002

Scheme 1
Scheme 2a
a Reagents and conditions: (a) Na, NH3, Et2O, -78 °C, >98%;
(b) DMSO, (COCl)2, NEt3, CH2Cl2, >98%; (c) PPh3, CBr4, Zn,
CH2Cl2, 22 °C, 63%; (d) HFaq (48%), MeCN, 22 °C, 82%; (e) NaH,
THF, NaI, PMBCl, 0 °C, 94%; (f) BuLi, THF, - 78 to 0 °C, then
(CH2O)n, 80%; (g) Ms2O, DIPEA, CH2Cl2, 0 °C, >98%; (h) NaH,
THF, 16 (0.2 equiv relative to 15), -78 °C, 73%, 65% recovered
15.
Furthermore, elaboration of such simple rearrangement
products as 3 into the final azadirachtin skeleton through a
biomimetic sequence initiated from 4 would be costly in
terms of overall synthetic convergence. Here, we report a
method for generating an advanced intermediate 7 by way
of a microwave-assisted Claisen rearrangement10 of the
corresponding propargylic enol ether 5; appropriate substitu-
tion of this precursor allows subsequent radical cyclization
to form the bicyclo[3.2.1] ring system present in azadirachtin
in a more rapid way (Scheme 1, path b) than is possible
with the allylic enol ether systems (i.e. 2).11
On the basis of the above considerations, we elected to
prepare the substituted pyran 15. The coupling of 15 onto
the known Decalin ketone 1612 would set up the Claisen
rearrangement and then by functional group manipulation
provide access to an appropriate substrate for the radical
cyclization. 15 was prepared in seven steps in 37% overall
yield, starting from trityl protected alcohol 8 (Scheme 2).13
Selective deprotection under reductive conditions, Swern
oxidation, and Corey-Fuchs olefination14 of the unstable
aldehyde provided the dibromoalkene 11. Subsequent silyl
removal with aqueous HF occurred in 82% yield and was
factors is responsible for the lack of a total synthesis of 1 to
date, despite significant attempts by the synthetic com-
munity.7 In an earlier communication, we reported on the
potential of using a Claisen rearrangement of simple allylic
enol ethers such as 2 as a means of generating the C8-C14
bond (Scheme 1, path a)8 that we have found resistant to
more direct, intermolecular coupling methods due to the
extreme steric hindrance at this site.9 Unfortunately, attempts
to increase the complexity of the pendant allyl groups
consistently resulted in inhibition of the critical rearrange-
ment process, thus obviating the use of this route to install
the tetracyclic right-hand portion of 1 in a single operation.
(6) (a) Turner, C. J.; Tempesta, M. S.; Taylor, R. B.; Zagorski, M. G.;
Termini, J. C.; Schroeder, D. R.; Nakanishi, K. Tetrahedron 1987, 43,
2789-2803. (b) Kraus, W.; Bokel, M.; Klenk, A.; Pohnl, H. Tetrahedron
Lett. 1985, 26, 6435-6438. (c) Broughton, H. B.; Ley, S. V.; Lidert, Z.;
Slawin, A. M. Z.; Williams, D. J.; Morgan, E. D. J. Chem. Soc., Chem.
Commun. 1986, 46-47.
(7) (a) Nicolaou, K. C.; Roecker, A. J.; Follmann, M.; Baati, R. Angew.
Chem., Int. Ed. 2002, 41, 2107-2110. (b) Nicolaou, K. C.; Follmann, M.;
Roecker, A. J.; Hunt, K. W. Angew. Chem., Int. Ed. 2002, 41, 2103-2106.
(c) Yamamoto, Y.; Ishihara, J.; Kanoh, N.; Murai, A. Synthesis 2000, 13,
1894-1906. (d) Watanabe, H.; Watanabe, T.; Mori, K.; Kitahara, T.
Tetrahedron Lett. 1997, 38, 4429-4432. (e) Scheliger, H.; Winterfeldt, E.
Chirality 1997, 9, 454-458. (f) Henry, K. J., Jr.; Fraser-Reid, B. J. Org.
Chem. 1994, 59, 5128-5129. (g) Chen, X. T.; Luo, Y. L.; Zhu, Q. B.;
Wang, Z. Q. Chin. Chem. Lett. 1992, 3, 971-974. (h) Kenji, M.; Watanabe,
H. Chemistry 1989, 44, 68-69. (i) Nisikimi, Y.; Iimori, T.; Sodeoka, M.;
Shibasaki, M. J. Org. Chem. 1989, 54, 3354-3359. Added in proof:
Fukuzaki, T.; Kobayashi, S.; Hibi, T.; Ikuma, Y.; Ishihara, J.; Kanoh, N.;
Murai, A. Org. Lett. 2002, 4, 2877-2880.
(10) (a) Lidstrom, P.; Tierney, J.; Wathey, B.; Westman, J. Tetrahedron
2001, 57, 9225-9283. (b) Caddick, S. Tetrahedron 1995, 51, 10403-10432.
(c) Strauss, C. R.; Trainor, R. W. Aust. J. Chem. 1995, 48, 1665-1695.
(11) Elaboration to the 2,4-dioxatricyclo[6.2.1.0]undecane acetal by
epoxidation and dihydroxyfuran ring formation remains a focus of our
ongoing research. For a similar synthesis on a model system, see: Anderson,
J. C.; Ley, S. V. Tetrahedron Lett. 1990, 31, 431-432.
(12) (a) Ley, S. V.; Lovell, P. J.; Slawin, A. M. Z.; Smith, S. C.; Williams,
D. J.; Wood, A. Tetrahedron 1993, 49, 1675-1700. (b) Kolb, H. C.; Ley,
S. V. Tetrahedron Lett. 1991, 32, 6187-6190.
(8) Ley, S. V.; Gutteridge, C. E.; Pape, A. R.; Spilling, C. D.; Zumbrunn,
C. Synlett 1999, 8, 1295-1297.
(9) Koot, W.-J.; Ley, S. V. Tetrahedron 1995, 51, 2077-2090.
(13) Rosen, T.; Taschner, M. J.; Heathcock, C. H. J. Org. Chem. 1984,
49, 3994-4003.
(14) Corey, E. J.; Fuchs, P. L. Tetrahedron Lett. 1972, 36, 3769-3772.
3848
Org. Lett., Vol. 4, No. 22, 2002

Scheme 3 a
Table 1. Claisen Rearrangement Studies
entry subst temp, °C
conditions
DCB, 48 h
DCB, MWI, 1 h
DCB, MWI, 15 min
prod yield
1
2
3
4
5
5
17
17
180
180
180
180
18
18
6
7
25
71a
88b
DCB, MWI, 15 × 1 min
6
a Reagents and conditions: (a) TESOTf, DIPEA, -78 °C, 90%;
(b) DDQ, CH2Cl2, H2O, 0 °C, 76%; (c) NaH, CS2, MeI, THF, -78
to -10 °C, 87%; (d) Bu3SnH, AIBN, toluene, 110 °C, 81%.
a Transformation was capricious, with decomposition often observed.
b Employed 60-s microwave pulses instead of continuous irradiation (DCB
) 1,2-dichlorobenzene; MWI ) microwave irradiation).
microwave heating22 of a solution of 17 in 1,2-dichloroben-
zene at 180 °C after only 15 min resulted in a 71% yield of
the desired allene, and as a single diastereoisomer (Table
1, entry 3).23 While pleased by this result, we quickly found
this transformation to be capricious on scale-up, with
decomposition of both starting material and allene observed.
After extensive optimization studies, we found that irradiation
carried out with 15 consecutiVe 60-s pulses allowed the
formation of the allene, in 88% yield, in a highly reliable
fashion (Table 1, entry 4).24
With the substituted allene 6 in hand, elaboration to the
bicyclic framework found in azadirachtin was effected
(Scheme 3). This necessitated the appropriate protection of
all pendant hydroxyl groups except at C17 (azadirachtin
numbering), which needed to be transformed into an ap-
propriate masked methylene radical for cyclization onto the
allene. Unfortunately, despite forcing conditions including
large excesses of TESOTf and DIPEA, only one of the two
Decalin alcohols could be protected, providing further
evidence of the peculiar steric environment created by the
azadirachtin scaffold. Nonetheless, we continued, hopeful that
the inability to silylate the C3 alcohol would also translate
to lack of reactivity in generation of the radical precursor.
For this, deprotection of the p-methoxybenzyl group gener-
ated 20. After some experimentation, we decided upon use
of a xanthate as an appropriate radical generator.25 However,
followed with efficient alkyne formation and p-methoxy-
benzyl protection as a two-step, single-vessel transformation.
Finally, condensation of 13 with (CH2O)n and mesylation
of the primary alcohol yielded the target pyran as a clear
oil. O-Alkylation proceeded without incident only in the
presence of sodium hydride and a 5-fold excess of 15;
gratifyingly, it was found that the unreacted mesylate could
be recovered by chromatography and reused through at least
four iterations without decomposition.15
Unfortunately, repeated attempts to induce the Claisen
rearrangement of 5 resulted in near complete recovery of
the starting material (Table 1, entries 1 and 2). We quickly
decided on the basis of molecular models that the bulky silyl
groups attached to the C1 and C3 alcohols may have created
a sterically congested environment proximal to the reacting
constituents. Thus, these groups were removed in 83% yield
by treatment with TBAF and 17 was correspondingly
subjected to thermal rearrangement conditions. Addition of
a variety of Lewis acids known to promote Claisen rear-
rangements,16 including iBu3Al,17 Et2AlSPh,17 TiCl4,18 BF3‚
Et2O,19 NH4Cl,20 and Yb(OTf)3,21 were all unsuccessful.
Notably, the thermal stability of 17 is undermined by Et2-
AlSPh, TiCl4, and BF3‚Et2O, with decomposition occurring
even at ambient temperature in the latter two cases. Faced
with these results, we attempted to induce the desired
rearrangement by use of microwave irradiation, noting the
small increase in yield observed when 5 was reacted under
these conditions (Table 1, entry 2).10 To our delight,
(22) A fully automated Coherent Synthesis System microwave machine
was used. This was supplied by Personal Chemistry: Hamnesplanaden 5,
753 19 Uppsala, Sweden; www.personalchemistry.com.
(23) Stereochemistry was determined by nOe experiments and by
comparison to a crystal structure obtained for an analogous compound
(unpublished). See Supporting Information for full details.
(15) Performance of 15, as defined by yield of 5 and recovered mesylate,
does not depreciate with iterative use, although reaction times tend to
increase when recycled material is employed: (round 1) 73%, 64%
recovered 15, 6 h; (round 2) 65%, 65% recovered 15, 3.5 h; (round 3)
73%, 78% recovered 15, 14 h; (round 4) 86%, 80% recovered 15, 20 h.
(16) Lutz, R. P. Chem. ReV. 1984, 84, 206-243.
(24) Reliability was determined by iterative transformation of 15 different
samples of 17. To date, we have never observed decomposition using these
reaction conditions. Typical procedure: A 5-mL base-washed microwave
vial was charged with 17 (9.50 mg, 0.012 mmol) and sealed. To the solid
was added 1.0 mL of degassed 1,2-dichlorobenzene. The resultant mixture
was subjected to 15 separate, 60-s microwave pulses, punctuated by 90-s
cooling periods. After final cooling of the pale yellow solution, it was loaded
onto a plug of silica gel and chromatographed with petroleum ether to
remove the 1,2-dichlorobenzene, and subsequently EtOAc to remove the
allene 6 (8.36 mg, 88%) as a white foam after solvent removal in vacuo.
Attempts to scale this reaction have proceeded uneventfully.
(17) Takai, K.; Mori, I.; Oshima, K.; Nozaki, H. Tetrahedron Lett. 1981,
22, 3985-3988.
(18) Cook, G. R.; Stille, J. R. Tetrahedron 1994, 50, 4105-4124.
(19) Bartlett, P. A.; Hahne, W. F. J. Org. Chem. 1979, 44, 882-883.
(20) Ralls, J. W.; Lundin, R. E.; Bailey, G. F. J. Org. Chem. 1963, 28,
3521-3526.
(21) Sharma, G. V. M.; Ilangovan, A.; Sreenivas, P.; Mahalingam, A.
K. Synlett 2000, 5, 615-618.
(25) Zard, S. Z. Angew. Chem., Int. Ed. Engl. 1997, 36, 672-685.
Org. Lett., Vol. 4, No. 22, 2002
3849

inaccessibility of tertiary radical 23-Int, which allows
protonation only from 7-Int. Interestingly, no quenching of
the initial methylene radical to produce the corresponding
disubstituted allenyl pyran was observed,28 indicating that
closure onto the allene must be a facile event after radical
generation.
Scheme 4
In summary, the rapid entry to the coupled left- and right-
hand skeletons present in azadirachtin has been achieved
through a diastereoselective, microwave-assisted Claisen
rearrangement and subsequent radical cyclization protocol.
7 bears a number of differentially protected reactive sites
for further manipulation to derivatives not previously ac-
cessible,29 and also to azadirachtin itself. Further studies to
probe the generality of the key Claisen and radical cyclization
steps, as well as further elaboration of this key intermediate,
are ongoing and will be the subject of future correspondence
from these laboratories.
Acknowledgment. This work was supported by the
Novartis Research Fellowship and the BP Endowment
(S.V.L.). B.L.G. is grateful for a British Marshall Scholar-
ship. T.D.R. is the recipient of a Marie Curie grant. J.S.S. is
the recipient of a Ramsay Memorial Trust Fellowship. L.B.G.
thanks the Swiss National Foundation for funding. The
authors acknowledge Dr. Angus J. Morrison and Dr. Cornelia
Zumbraunn for helpful discussions.
after treatment with CS2 and MeI under basic conditions,
the mono-xanthate 21 and bis-xanthate 22 were isolated in
equal quantities. Careful optimization of the reaction condi-
tions followed the observation that 21 could be isolated in
87% yield with <5% of 22 generated if the reaction was
stopped just prior to complete consumption of the starting
diol.26
Although it was appreciated that thermodynamic quench-
ing of the radical cyclization intermediate of 21 would yield
the undesired exo-alkene 23,27 in practice, when 21 was
treated with the radical initiator AIBN in the presence of a
solution of Bu3SnH in toluene at elevated temperature, only
the endo-alkene was formed (Scheme 4). The most plausible
rationale for this intriguing result rests upon the steric
Supporting Information Available: Procedures and
characterization for 5-7, 9-15, 17, and 19-21. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL0201557
(28) (a) Barton, D. H. R.; Jang, D. O.; Jaszberenyi, J. C. Tetrahedron
1993, 49, 7193-7214. (b) Barton, D. H. R.; McCombie, S. W. J. Chem.
Soc., Perkin Trans I 1975, 1574-1585.
(26) 22 was only observed to form after consumption of 20 was complete;
thus, by immediate quenching of the reaction when <5% 20 remained,
formation of the undesired bis-xanthate was circumvented.
(27) Sannigrahi, M.; Mayhew, D. L.; Clive, D. L. J. J. Org. Chem. 1999,
64, 2776-2788.
(29) Neither the LHF nor the RHF alone have significant antifeedant
activity. For previous SAR studies, see: (a) Blaney, W. M.; Simmonds,
M. S. J.; Ley, S. V.; Anderson, J. C.; Toogood, P. L. Entomol. Exp. Appl.
1990, 55, 149. (b) Ley, S. V.; Santafianos, D.; Blaney, W. M.; Simmonds,
M. S. J. Tetrahedron Lett. 1987, 28, 221-224.
3850
Org. Lett., Vol. 4, No. 22, 2002