Studies toward the synthesis of azadirachtin, part 1: Total synthesis of a fully functionalized ABC ring framework and coupling with a norbornene domain

Article abstract of DOI:10.1002/anie.200500216

(Chemical Equation Presented) The advanced decalin intermediate 1 was synthesized and elaborated into the potential azadirachtin precursor 2. The challenging synthesis involved several protecting-group manipulations and coupling of 1 with an appropriate norbornene unit.

Full text of DOI:10.1002/anie.200500216

Angewandte
Chemie
Natural Products Synthesis (1)
decalin intermediate 3 and its coupling with a suitable
norbornene system 4 to afford a C7–C13 linked product,
which was elaborated into the advanced intermediate 2 and
whose structural disposition might allow its eventual con-
version into azadirachtin (1). In the following Communica-
tion in this issue,[6] we describe both the total synthesis and
semisynthesis of a different decalin intermediate and its
elaboration into a close precursor of the target molecule, as
well as some interesting reactions made possible by the
special proximity effects that uniquely characterize the
azadirachtin structural motif.[7]
Studies toward the Synthesis of Azadirachtin,
Part 1: Total Synthesis of a Fully Functionalized
ABC Ring Framework and Coupling with a
Norbornene Domain**
K. C. Nicolaou,* Pradip K. Sasmal, A. J. Roecker,
Xiao-Wen Sun, Sunil Mandal, and Antonella Converso
We recently embarked on a program directed towards the
total synthesis of azadirachtin (1, Scheme 1), the remarkable
According to our previously disclosed strategy,[3–5] azadir-
achtin (1) was to be approached through a path marked by
key intermediates such as 2, 3, and 4 as retrosyntheti-
cally outlined in Scheme 1. Crucial to the success of such
a plan is the availability of fully functionalized advanced
decalin systems such as 3, which have the potential to
yield azadirachtin upon coupling with norbornene
derivatives such as 4 followed by appropriate elabo-
ration.
The fundamental strategy for the synthesis of the
norbornene precursor 4 has already been reported in a
previous Communication.[5] The construction of the
fully functionalized decalin system 3 in its enantiomer-
ically pure form is depicted in Scheme 2. Thus, starting
from enantiopure compound 5,[5] ketone 6 was produced
by dibenzylation (for abbreviations and conditions, see
legends in schemes) followed by desilylation and Swern
oxidation of the resulting secondary alcohol. Ketone 6
was then converted into enone 7 in 81% overall yield
for the three-step sequence with a regioselectivity of
approximately 10:1. Subsequent functionalization of 7
by Mander carboxylation[8] followed by aldol reaction of
the resulting b-ketoester with paraformaldehyde in the
presence of Yb(OTf)3 led to the corresponding hydroxyester,
whose hydroxy group was protected as a TBS ether (69%
yield for three steps). Subsequent epoxidation of the enone
moiety of the so-obtained intermediate by TBHP in the
presence of triton B furnished, stereoselectively, epoxide 8 in
87% yield. The required 1,3-diaxial diol system within the
growing substrate was established first by regioselective
opening of the epoxide moiety of 8 (91% yield) with
PhSeNa (generated in situ from PhSeSePh and NaBH4)[9]
and then stereoselective reduction (NaBH4) of the inter-
mediate hydroxyketone to afford the desired compound 9 in
63% yield. Selective removal of the TBS group, peracetyla-
tion, debenzylation, and finally, regioselective monoprotec-
tion of the primary alcohol of the resulting diol as a TES ether
yielded alcohol 10 in 74% yield over four steps. The hydroxy
compound 10 was then oxidized with DMP, and the resulting
ketone was olefinated with Ph3P = CH2 prior to removal of
the TES group in the presence of catalytic DDQ.[10] The
primary alcohol was then oxidized to the corresponding
aldehyde 11 (once again with DMP) in 65% overall yield over
the four steps. The targeted coupling partner 3 was finally
obtained from the latter intermediate 11 in 48% overall
yield,[11] by the following sequence: 1) oxidation with NaClO2,
2) exposure to ethanolic HCl (0.5m), and 3) allylic oxidation
with SeO2 and TBHP.
Scheme 1. Retrosynthetic analysis of azadirachtin (1).
antifeedant agent isolated from the Neem tree[1] and currently
in use as an insecticide.[2] Our radical-based approach towards
this unusually challenging target molecule (see Scheme 1) was
validated by a number of model studies,[3–5] which, however,
left much to be desired in terms of functionalities on the
crowded decalin system of the natural product. Herein we
report the total synthesis of a fully functionalized ABC
[*] Prof. Dr. K. C. Nicolaou, Dr. P. K. Sasmal, A. J. Roecker, Dr. X.-W. Sun,
Dr. S. Mandal, Dr. A. Converso
Department of Chemistry and
The Skaggs Institute for Chemical Biology
The Scripps Research Institute
10550 North Torrey Pines Road, La Jolla, CA 92037 (USA)
Fax: (+1)858-784-2469
E-mail: kcn@scripps.edu
and
Department of Chemistry and Biochemistry
University of California, San Diego
9500 Gilman Drive, La Jolla, CA 92093 (USA)
[**] We thank Dr. D. H. Huang and Dr. G. Siuzdak for NMR
spectroscopic and mass spectrometric assistance, respectively.
Financial support for this work was provided by grants from the
National Institutes of Health (USA) and the Skaggs Institute for
Chemical Biology, and a predoctoral fellowship from the Division of
Organic Chemistry of the American Chemical Society sponsored by
Novartis (to A.J.R.).
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DOI: 10.1002/anie.200500216
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With 3 in hand, we were now poised to test the key
bromoketalization[12] reaction between this substrate and
norbornene enol ether 4, a reaction that had shown rather
capricious behavior during our previous model studies. Upon
considerable experimentation, it was found that the optimum
conditions for this coupling required addition of Br2 to
norbornene derivative 4 in CH2Cl2 at ꢀ788C followed by the
sequential addition of N,N-dimethylaniline and allylic alcohol
3, and warming slowly to 08C. Chromatographic resolution of
the rather complex mixture of products led to the isolation
and characterization of two diastereomeric bromoketals (ca.
1:1 ratio, 80% combined yield), whose NMR spectroscopic
analysis revealed structures 12 and 13 (Scheme 3). The ratio
of the two isomers was found to be dependent on reaction
time, temperature, and, apparently, on the steric environment
around the attacking allylic alcohol moiety, since previous[4,5]
and subsequent[6] experiments with other decalin allylic
alcohol substrates led to different results. Scheme 4 provides
a possible explanation for these results by invoking an
oxonium ion intermediate 4b derived from the rupture of
the initially formed bromonium ion 4a as the temperature is
raised to 08C. Attack on oxonium ion 4b from the exo face is
now possible, and leads to the formation of the epi-C13
bromoketal (azadirachtin numbering) 4d (Scheme 4) or 13
(Scheme 3).
Both bromoketals 12 and 13 were subjected to radical
cyclization conditions[13] to afford the desired hexacyclic
products 17 and 18 (Table 1) in 70 and 76% yield, respectively
(Scheme 3). The structures and stereochemistries of 17 and 18
were unambiguously assigned by NMR spectroscopy (1H,13C-
COSY, ROESY, and HMQC). Interestingly, only compound
13 generated the desired polycycle 18 upon treatment with
nBu3SnH–Et3B[14] at room temperature, whereas compound
12 gave, exclusively, reduction to 16. This observation
suggests that, while the radical formed from 12 (i.e. 14)
requires higher temperature to access the appropriate tran-
sition state for ring closure, the radical obtained from 13
resides in a more privileged position to attain the required
Scheme 2. Construction of decalin fragment 3. Reagents and conditions: a) NaH
(6.0 equiv), BnBr (4.0 equiv), nBu4NI (0.2 equiv), THF/DMF (3:1), 258C, 24 h;
b) TBAF (2.0 equiv), THF, 258C, 15 h, 91% over two steps; c) (COCl)2 (1.5 equiv),
DMSO (3.0 equiv), Et3N (6.0 equiv), ꢀ78!258C, CH2Cl2, 1 h, 89%; d) KHMDS
(1.5 equiv), TESCl (1.5 equiv), THF, ꢀ788C, 30 min; e) PhSeCl (1.1 equiv), CH2Cl2, transition state for cyclization, which apparently takes place
ꢀ788C, 30 min; f) H2O2 (30% v/v, 3.0 equiv), THF, 0!258C, 1 h, 80% over three
steps; g) LiHMDS (2.0 equiv), NCCO2Me (1.5 equiv), THF, ꢀ788C, 6 h, 93%;
h) (CH2O)n (20 equiv), Yb(OTf)3 (2.0 equiv), THF, 258C, 2 h; i) TBSOTf (1.5 equiv),
2,6-lutidine (2.5 equiv), CH2Cl2, ꢀ788C, 30 min, 74% over two steps; j) tritonB
(2.0 equiv), aqueous TBHP (70%; 10 equiv), THF, 258C, 16 h, 87%; k) (PhSe)2
(3.0 equiv), NaBH4 (6.0 equiv), EtOH, 258C, 0.5 h, 91%; l) NaBH4 (8.0 equiv),
MeOH/CH2Cl2 (1:15), 258C, 24 h, 63%; m) TBAF (1.5 equiv), THF, 0!258C, 1 h;
n) Ac2O (6.0 equiv), Et3N (10 equiv), DMAP (0.4 equiv), CH2Cl2, 258C, 6 h, 92%
over two steps; o) Pd/C (10%; 20 wt%), H2 (1 atm), EtOH, 258C, 16 h, 98%;
p) TESCl (1.0 equiv), Et3N (2.0 equiv), CH2Cl2, 0!258C, 2 h, 82%; q) DMP
even at ambient temperature.
Interestingly, the primary radicals initially formed from 14
and 15 only undergo the 5-exo-trig mode of ring closure. The
alternative 6-endo-trig mode of reaction is also available in
principle and, indeed, is observed with other substrates, as we
shall describe in more detail in the following Communication
in this issue.[6] In the present instance the secondary radical
thus formed through the action of (Me3Si)3SiH–AIBN under-
goes ring closure, leading to a primary radical, which in turn
undergoes an intramolecular 1,5-H shift (see 30-H (azadir-
achtin numbering) in structures 14 and 15) to afford ketone
17, in the case of 14, or undergoes an intermolecular quench
to yield PMB ether 18 in the case of 15.
=
(1.5 equiv), NaHCO3 (1.5 equiv), CH2Cl2, 0!258C, 2 h, 91%; r) Ph3P CH2
(5.0 equiv), diethyl ether, 258C, 2 h, 80%; s) DDQ (0.1 equiv), THF/H2O (9:1),
258C, 2 h, 97%; t) DMP (1.5 equiv), CH2Cl2, 0!258C, 2 h, 92%; u) NaClO2
(4.0 equiv), NaH2PO4 (4.0 equiv), 2-methyl-2-butene (75 equiv), THF/tBuOH/H2O
(2:4:1), 258C, 1 h; v) 0.5m HCl, EtOH/Et2O (1:1), 0!258C, 6 h, solvent evapo-
rated; then, Ac2O (6.0 equiv), Et3N (10 equiv), DMAP (0.4 equiv), CH2Cl2, 258C,
6 h, 94% over two steps; w) SeO2 (5.0 equiv), TBHP (10 equiv), CH2Cl2, 258C, 6 h,
51%. Bn=benzyl, DMF=N,N-dimethylformamide, TBAF=tetra-n-butylammo-
nium fluoride, DMSO=dimethyl sulfoxide, HMDS=hexamethyldisilazane, TES=
triethylsilyl, OTf=trifluoromethanesulfonate, TBS=tert-butyldimethylsilyl, tri-
ton B=benzyltrimethylammonium hydroxide, TBHP=tert-butyl hydroperoxide,
DMAP=4-(dimethylamino)pyridine, DMP=Dess–Martin periodinane, DDQ=2,3-
dichloro-5,6-dicyano-p-benzoquinone.
The stereochemistry of the newly generated stereogenic
1
centers within 18 was confirmed by H NMR NOE studies
(see Scheme 3). As further proof of its structure, compound
17 was also constructed from the previously synthesized[5]
intermediate 19 as shown in Scheme 5. Thus, 19 was converted
into compound 20 by protection as a BOM ether, desilylation,
and oxidation under Swern conditions. Regioselective unsa-
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Scheme 4. Proposed mechanism for bromoketalization of 3 and 4.
Scheme 3. Coupling of decalin system 3 with norbornene derivative 4 and
synthesis of hexacyclic compounds 17 and 18. Reagents and conditions:
a) Br2 (1.5 equiv), N,N-dimethylaniline (2.0 equiv), 4 (2.0 equiv), CH2Cl2,
ꢀ788C, 10 min; then 3, ꢀ78!08C over 2 h, 08C, 1 h, 12 (38%) and 13
(42%); b) (Me3Si)3SiH (2.0 equiv), AIBN (1.0 equiv), toluene (0.007m),
1108C, 30 min, 70%; c) Et3B (5.0 equiv), nBu3SnH (5.0 equiv), CH2Cl2,
258C, 1 h, 80%; d) (Me3Si)3SiH (2.0 equiv), AIBN (1.0 equiv), toluene
(0.007m), 1108C, 30 min, 76%; e) Et3B (5.0 equiv), nBu3SnH (5.0 equiv),
CH2Cl2, 258C, 1 h, 80%. AIBN=2,2’-azobisisobutyronitrile.
turation of ketone 20 with IBX,[15] followed by sequential
treatment with LiHDMS/NCCO2Me and Yb(OTf)3/(CH2O)n,
furnished hydroxyenone 21, whose protection with TBS,
stereoselective epoxidation, and reductive epoxide opening
(PhSeNa, 81% over two steps) led to b-hydroxyketone 22.
Following stereoselective reduction (30%) of 22 with NaBH4,
desilylation and then peracetylation of the resulting triol
afforded triacetate 23. Finally, hydrogenolysis of the BOM
protecting group from intermediate 23 followed by oxidation
with DMP furnished the desired hexacyclic ketone 17, whose
spectroscopic and chromatographic properties matched those
of a sample obtained from the more convergent and
expedient route depicted in Scheme 3.
Scheme 5. Construction of hexacyclic compound 17 from 19. Reagents and
conditions: a) BOMCl (5.0 equiv), iPr2NEt (10 equiv), DMF, 408C, 24 h, 96%;
b) TBAF (2.0 equiv), THF, 258C, 12 h, 94%; c) (COCl)2 (2.0 equiv), DMSO
(3.0 equiv), Et3N (4.0 equiv), ꢀ78!258C, CH2Cl2, 1 h, 74%; d) IBX
(1.5 equiv), DMSO, 658C, 36 h, 75%; e) LiHMDS (1.5 equiv), NCCO2Me
(1.2 equiv), HMPA (1.5 equiv), THF, ꢀ788C, 3 h, 65%; f) (CH2O)n (5.0 equiv),
Yb(OTf)3 (2.0 equiv), THF, 258C, 1 h, 72%; g) TBSOTf (1.1 equiv), 2,6-lutidine
(2.0 equiv), CH2Cl2, ꢀ788C, 1 h, 90%; h) triton B (2.0 equiv), aqueous TBHP
(70%; 10 equiv), THF, 258C, 16 h; i) PhSeNa (3.0 equiv), EtOH, 258C, 4 h,
81% over two steps; j) NaBH4 (8.0 equiv), THF, 258C, 30 min, 30%; k) TBAF
(1.5 equiv), THF, 0!258C, 1 h; l) Ac2O (6.0 equiv), Et3N (10 equiv), DMAP
(0.4 equiv), CH2Cl2, 258C, 6 h, 80% over two steps; m) Pd(OH)2/C (20%;
10 wt%), H2 (1 atm), EtOH, 258C, 1 h; n) DMP (2.0 equiv), CH2Cl2, 0!258C,
2 h, 90% over two steps. BOM=benzyloxymethyl, IBX=o-iodoxybenzoic acid,
HMPA=hexamethylphosphoramide.
In the final phase of this study, it was important to
demonstrate the cleavage of the temporary bridge that was so
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Table 1: Selected physical properties for compounds 2, 17, and 18.
instrumental in forming the challenging C8–C14 bond as a
2: Rf =0.29 (silica gel, EtOAc/hexanes 1:1); [a]3D2 =ꢀ28.0 (c=0.6,
CH2Cl2); IR (film): n˜max =2923, 2851, 1780, 1745, 1717, 1451, 1376, 1231,
1112, 1048, 963 cmꢀ1; 1H NMR (500 MHz, C6D6): d=8.02 (d, J=7.7 Hz,
2H), 7.58 (t, J=7.7 Hz, 1H), 7.46 (t, J=7.7 Hz, 2H), 5.52 (t, J=2.9 Hz,
1H), 5.16 (d, J=7.0 Hz, 1H), 4.83 (t, J=2.9 Hz, 1H), 4.41 (A of ABq,
J=10.6 Hz, 1H), 4.35 (B of ABq, J=10.6 Hz, 1H), 4.29 (A of ABq,
J=10.5 Hz, 1H), 4.00 (B of ABq, J=10.5 Hz, 1H), 3.82 (s, 3H), 3.22–
3.09 (m, 2H), 2.97 (br s, 1H), 2.93 (d, J=2.2 Hz, 1H), 2.67 (dd, J=15.7,
2.9 Hz, 1H), 2.65 (s, 1H), 2.58 (d, J=4.0 Hz, 1H), 2.44 (dt, J=17.0,
3.5 Hz, 1H), 2.38–2.30 (m, 2H), 2.13–1.95 (m, 3H), 2.07 (s, 3H), 2.06
(s, 3H), 1.99 (s, 3H), 1.29 ppm (s, 3H); 13C NMR (125 MHz, C6D6):
d=214.3, 207.3, 174.0, 172.4, 170.2, 169.9, 169.5, 166.1, 133.4, 130.0,
129.7, 128.6, 77.0, 69.5, 67.3, 66.3, 65.8, 53.9, 53.3, 51.0, 49.2, 48.0, 47.6,
41.6, 34.8, 33.0, 32.9, 32.8, 29.9, 27.6, 23.2, 21.2, 21.0, 20.6 ppm; HRMS
(MALDI): calcd for C36H40O14Na: 719.2310 [M+Na+], found 719.2311
prelude to further advances toward azadirachtin. Towards this
end, the hexacyclic compound 18 was first converted into the
benzoate 24 (by protecting-group exchange through hydro-
genolysis and benzoylation) and followed by hydrolysis to
hemiketal 25 in 75% overall yield (Scheme 6). Finally,
hemiketal 25 was oxidized with PCC to afford diketone 2
(Table 1) in 80% yield. Diastereomer 17 has not, as yet, been
advanced further.
17: Rf =0.11 (silica gel, EtOAc/hexane 1:1); [a]3D2 =ꢀ44.5 (CH2Cl2,
c=0.14); IR (film): n˜max =2954, 2922, 2851, 1778, 1743, 1730, 1439,
1375, 1320, 1234, 1050, 938, 736, 604 cmꢀ1; 1H NMR (600 MHz, C6D6):
d=5.63 (br s, 1H), 4.89 (br s, 1H), 4.39 (d, J=10.5 Hz, 1H), 4.23 (d,
J=10.5 Hz, 1H), 3.76 (d, J=9.6 Hz, 1H), 3.63 (s, 1H), 3.42 (d,
J=9.6 Hz, 1H), 3.14 (s, 3H), 3.10 (s, 3H), 3.05 (s, 1H), 2.98 (dd,
J=13.8, 3.6 Hz, 1H), 2.85 (d, J=4.8 Hz, 1H), 2.46 (br s, 1H), 2.28 (br s,
1H), 2.21–2.17 (m, 2H), 2.05 (dt, J=13.8, 3.6, 1H), 1.69 (s, 3H), 1.68 (s,
3H), 1.67–1.66 (m, 1H), 1.62 (s, 3H), 1.59–1.51 (m, 3H), 1.14 (s, 3H),
1.09 ppm (d, J=10.2 Hz, 1H); 13C NMR (150 MHz, C6D6): d=214.9,
175.3, 172.5, 169.7, 169.1, 168.6, 115.3, 84.4, 69.6, 67.4, 67.4, 66.8, 66.1,
53.9, 51.9, 51.4, 50.3, 50.0, 46.4, 41.4, 40.4, 39.7, 38.7, 27.8, 27.7, 22.3,
20.5, 20.5, 20.1, 16.3 ppm; HRMS (ESI-TOF): calcd for C30H38O13Na+
[M+Na+]: 629.2204; found: 629.2205
18: Rf =0.26 (silica gel, EtOAc/hexane 1:1); [a]3D2 =+1.4 (CH2Cl2,
c=0.14); IR (film): n˜max =2934, 2851, 1777, 1745, 1612, 1513, 1440,
1372, 1318, 1231, 1182, 1047, 823, 736 cmꢀ1; 1H NMR (600 MHz, C6D6):
d=7.27 (d, J=8.4 Hz, 2H), 6.80 (d, J=8.4 Hz, 2H), 5.69 (br s, 1H),
4.82 (br s, 1H), 4.44 (d, J=11.4 Hz, 1H), 4.43 (d, J=10.2 Hz, 1H), 4.41
(d, J=10.2 Hz, 1H), 4.36 (d, J=11.4 Hz, 1H), 3.95 (br s, 1H), 3.87 (d,
J=10.0 Hz, 1H), 3.63 (d, J=6.0 Hz, 1H), 3.56 (d, J=10.0 Hz, 1H), 3.33
(s, 3H), 3.24 (s, 1H), 3.13 (br s, 1H), 3.11 (s, 3H), 3.04 (s, 3H), 3.02
(dd, J=13.8, 3.0 Hz, 1H), 2.40 (d, J=3.6 Hz, 1H), 2.36 (br d,
J=16.8 Hz, 1H), 2.08 (br d, J=16.8 Hz, 1H), 2.03–1.96 (m, 4H), 1.91
(d, J=9.6 Hz, 1H), 1.68 (s, 3H), 1.60 (s, 3H), 1.53 (br s, 1H), 1.48 (dd,
J=9.6, 3.0 Hz, 1H), 1.44 (s, 3H), 1.11 ppm (s, 3H); 13C NMR
(150 MHz, C6D6): d=176.1, 172.6, 169.6, 169.0, 168.9, 159.6, 131.3,
129.7, 117.1, 114.0, 81.3, 81.2, 71.0, 70.8, 67.1, 66.6, 66.5, 63.6, 54.7,
52.0, 50.6, 50.2, 46.4, 43.6, 43.0, 42.0, 37.9, 33.2, 33.0, 28.5, 27.5, 25.8,
22.2, 20.7, 20.3, 20.0 ppm; HRMS (ESI-TOF): calcd for C38H48O14Na+
[M+Na+]: 751.2936; found: 751.2932
Scheme 6. Conversion of hexacyclic compound 18 into advanced pen-
tacyclic intermediate 2. Reagents and conditions: a) Pd(OH)2/C (20%;
10 wt%), H2 (1 atm), EtOH, 258C, 1 h; b) BzCl (3.0 equiv), Et3N
(6.0 equiv), DMAP (0.1 equiv), CH2Cl2, 0!258C, 4 h; c) aqueous TFA
(90%), 658C, 3 h, 75% over three steps; d) PCC (15 equiv), DCE,
658C, 16 h, 80%. Bz=benzoyl, TFA=trifluoroacetic acid, PCC=pyridi-
nium chlorochromate, DCE=1,2-dichloroethane.
The described chemistry provides solutions to a number of
challenges posed by the decalin domain of azadirachtin (1)
and brings the realization of the synthesis of this molecule
within close range. In the following Communication in this
issue,[6] we describe further studies that place this goal even
closer, but from a different angle.
Received: January 19, 2005
Published online: April 21, 2005
Zagorski, J. S. Termini, D. R. Schroeder, K. Nakanishi, Tetrahe-
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