Synthesis of azadirachtin: A long but successful journey

Article abstract of DOI:10.1002/anie.200703027

(Chemical Equation Presented) 22 Years in the making: Azadirachtin (1) was synthesized for the first time by a highly convergent approach, utilizing a Claisen rearrangement and a radical cyclization as key steps. End-game strategies relied on intermediate

Full text of DOI:10.1002/anie.200703027

Angewandte
Chemie
DOI: 10.1002/anie.200703027
Total Synthesis
Synthesis of Azadirachtin: A Long but Successful Journey**
Gemma E. Veitch, Edith Beckmann, Brenda J. Burke, Alistair Boyer, Sarah L. Maslen, and
Steven V. Ley*
Azadirachtin (1)[1] is a complex natural product that has been
at the center of structural,[2–5] biological,[6] and synthetic
studies[7,8] ever since its isolation from the Indian neem tree
Azadirachta indica in 1968.[9]
Despite enormous efforts within the synthetic community
its synthesis has, until now, resisted all attempts. This is
undoubtedlydue to its complex molecular architecture, which
comprises sixteen contiguous stereogenic centers, seven of
which are tetrasubstituted carbon atoms. Azadirachtin pos-
sesses a diverse arrayof oxgyenated functionalities in
addition to a rigid conformation imposed byintramolecular
hydrogen-bonding.[5] Furthermore its sensitivityto acid and
base together with its photoinstabilitymake it particularly
prone to rearrangement[10] therebyfrustrating manysynthesis
plans. Nevertheless we are pleased to report a successful
outcome to our ambitions making use of both relaystudies
and prior work from our group.[11,12]
A degradative approach towards azadirachtin has been
adopted in order to facilitate the investigation of end-game
strategies, therebyrendering intermediate 2 the current target
for total synthesis (Scheme 1).[11,12] The critical consideration
in anyapproach towards azadirachtin is the construction of
[13]
À
the stericallycongested C8 C14 bond.
We originally
envisioned a highlyconvergent strategyin which this central
bond could be forged bythe coupling of two fragments, which
together contain all the requisite functionalityfor conversion
Scheme 1. Retrosynthetic analysis. Bn=benzyl, Ms=methanesulfonyl,
TBS=tert-butyldimethylsilyl, TES=triethylsilyl.
[*] G. E. Veitch, Dr. E. Beckmann, Dr. B. J. Burke, A. Boyer, S. L. Maslen,
Prof. Dr. S. V. Ley
to the natural product. However, all attempts to directly
[8,14]
À
install the C8 C14 linkage met with failure,
and an
Department ofChemistry
University ofCambridge
Lensfield Road, Cambridge, CB2 1EW (UK)
Fax: (+44)1223-336-442
E-mail: svl1000@cam.ac.uk
alternative was therefore sought. Our current approach was
devised to maintain a high level of convergencywhilst
minimizing steric crowding in the fragment coupling process
byselective O-alkylation of 6 with 7.
Homepage: http://leygroup.ch.cam.ac.uk
Our new synthetic route relies on a late-stage, facially
selective epoxidation to provide intermediate 2 from tetra-
substituted alkene 3, which in turn is accessible from 5-exo
cyclization of the C17 radical species 4. In order to circumvent
[**] We gratefully acknowledge the many co-workers who have worked
on this project and the EPSRC (G.E.V. and A.B.), Alexander von
Humboldt Foundation (E.B.), and Novartis (S.V.L.) for generous
funding.
À
problems associated with intermolecular C8 C14 bond for-
mation, it was envisaged that this central linkage be con-
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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Communications
[19]
structed byClaisen rearrangement of propargylic enol ether
ring was constructed bydeglycosidation
and ozonolysis of
5. Intermediate 5 could then derive from O-alkylation of
decalin 6 with propargylic mesylate 7. Decalin fragment 6 was
available both bytotal synthesis, published previouslywithin
our group,[15] and also bydegradation of the natural prod-
uct.[16]
The synthesis of pyran coupling partner 7 commenced
from known diol 8, available in three steps from b-d-galactose
pentaacetate (Scheme 2).[17] Standard protecting-group
manipulation and an oxidation/Grignard-addition sequence
allyl tetrahydropyran 9 followed byoxidation of the resulting
lactol to lactone 10.[20] Transformation of 10 to xanthate 11
was followed byBarton–McCombie deoxygenation [21] and an
oxidation/Wittig protocol to yield dibromoolefin 12. At this
stage it was necessaryto use an alternative protecting group at
C17 as preliminarystudies had shown that the MOM ether
could not be removed selectivelyat a more advanced stage of
the synthesis.[8,22]
The MOM ether of 12 was therefore cleaved and replaced
with a PMB ether, and a reduction/acetalization sequence was
then performed to yield a 1:1 mixture of the two diastereo-
mers a-13 and b-13, which could be separated bycolumn
chromatography. The two epimers of 13 were then independ-
ently subjected to Corey–Fuchs alkynylation conditions and
further homologated with para-formaldehyde, and the result-
ing propargylic alcohols were treated with methanesulfonic
anhydride to furnish the desired propargylic mesylates a-7
and b-7 readyfor coupling with decalin fragment 6. At this
stage we had made no firm decisions as to whether one or
both of these diastereomers would be brought forward to the
natural product. In the end both served as viable precur-
sors.[23]
led to differentiallyprotected carbohdyrate
9 as the only
observed diastereoisomer.[18] The requisite tetrahydrofuran
With the fullyfunctionalized fragments a-7/b-7 and 6 in
hand, it was finallypossible to effect the crucial coupling
reaction (Scheme 3). Preliminarystudies indicated that a
tenfold excess of decalin 6 was required for complete
conversion to propargylic enol ether 14,[24,25] which subse-
quentlyunderwent TBAF-mediated desillyation to afford
diol 15. Claisen rearrangement[26] of propargylic enol ether 15
under thermal or gold(I)-catalyzed conditions was then
À
employed both to construct the key C8 C14 bond whilst
simultaneouslyinstalling the requisite allene for the ensuing
radical cyclization leading to 16. Following protecting-group
manipulations, the desired C17 radical precursor 17 was
formed in anticipation of the pivotal cyclization event. As
expected from model studies,[25] treatment of 17 with tribu-
tyltin hydride and AIBN in refluxing toluene initiated 5-exo
cyclization to smoothly furnish alkene 18.
Selective epoxidation of tetrasubstituted alkene 18, the
onlyremaining step in the synthesis, presented the greatest
synthetic challenge. Following extensive optimization, we
were finallyrewarded when prolonged heating of 18 with
magnesium monoperoxyphthalate[27] in the presence of a
radical inhibitor resulted in the formation of relayintermedi-
ate 2 for the first time (Scheme 3). Interestingly, epoxidation
of both a- and b-18 yielded the b diastereomer of our relay
target (b-2), implying an epimerization of alkene a-18 to its b
form prior to epoxidation. This assumption is also supported
bythe lower yield from the transformation of a-18. Epoxide
b-2 was identical in all respects to material derived from our
relaystudies [11] and therefore constitutes the final step in the
synthesis of azadirachtin (1).
The work reported herein represents the conclusion of a
22-year synthesis journey leading to the first successful
preparation of the insect antifeedant azadirachtin. While
onlya fragment of the total synthesis effort is reported here,
the challenge has, over the years, generated new chemistry
and elucidated a wealth of information concerning the
Scheme 2. Synthesis ofpropargylic mesylates 7. Reagents and condi-
tions: a) Bu2SnO, MeOH, reflux, then MOMCl, 1,4-dioxane, RT, 82%;
b) 1. SO3·py, DMSO, iPr2NEt,CH2Cl2, 08C; 2. AllylMgCl, THF, À788C,
85%; c) BnBr, NaH, DMF, RT, 87%; d) NBS, MeCN/H2O (9:1), pH 7,
RT, 60%; e) Zn, EtOH, NH4Cl, 808C, 99%; f) 1. O3, CH2Cl2, À788C,
then PS-PPh3, RT; 2. TPAP, NMO, CH3CN, RT, 95%; g) CH2Cl2/TFA/
H2O (20:1:1), RT, 99%; h) TBSCl, DMAP, DMF, NEt3, RT, 90%; i) CS2,
NaHMDS, À788C, then MeI, À788C, 99%; j) AIBN, nBu3SnH, toluene,
1108C, 70%; k) CH2Cl2/TFA/H2O (20:1:1), RT, 80%; l) 1. SO3·py,
DMSO, iPr2NEt, CH2Cl2, 08C; 2. tBuOK, Ph3PCHBr2·Br, THF, RT, 80%;
m) TMSBr, CH2Cl2, 08C, 82%; n) PMBTCA, La(OTf)3, THF, RT, 90%;
o) 1. DIBAL-H, CH2Cl2, hexane, À788C; 2. Amberlyst15, MeOH, RT,
70%; p) MeLi·LiBr, THF, À788C–08C, 80%; q) iPrMgCl, (CH2O)n, THF,
458C, 80%; r) Ms2O, iPr2NEt, CH2Cl2, 08C, 90%. AIBN=azobisisobu-
tyronitrile, DIBAL-H=diisobutylaluminium hydride, DMAP=4-dime-
thylaminopyridine, DMF=N,N-dimethyl formamide, DMSO=dimethyl
sulfoxide, HMDS=hexamethyldisilazanide, MOMCl=chloromethyl
methyl ether, NBS=N-bromosuccinimide, NMO=N-methyl morpho-
line-N-oxide, PMBTCA=p-methoxybenzyl trichloroacetimidate,
PS=polymer support, py=pyridine, TBS=tert-butyldimethylsilyl,
Tf =trifluoromethane sulfonyl, TFA=trifluoroacetic acid, TPAP=tetra-
propylammonium perruthenate.
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Keywords: azadirachtin · Claisen rearrangement · epoxidation ·
.
radical cyclization · total synthesis
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Scheme 3. Fragment coupling and completion ofthe synthesis.
Reagents and conditions: a) NaH, [15]crown-5, THF, 08C, a: 81%, b:
76%; b) TBAF, THF, 08C, a: 90%, b: 95%; c) Microwave, 1,2-
dichlorobenzene, 1858C, 80% or [(Ph3PAu)3O]BF4, CH2Cl2, RT, 80%;
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anticipate that this will be the start of other research
programs, which one daymaylead to alternative compounds
for insect pest control.
Received: July7, 2007
Published online: July30, 2007
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