Studies towards the synthesis of azadirachtin: Enantioselective entry into the azadirachtin framework through cascade reactions

Article abstract of DOI:10.1002/anie.200351744

The carbon framework of azadirachtin (1) has been prepared enantioselectively: The synthesis of compounds 2a-c follows two novel cascade sequences based on intramolecular radical reactions and acid-mediated redox chemistry. Such advanced intermediates sho

Full text of DOI:10.1002/anie.200351744

Angewandte
Chemie
Azadirachtin Precursors
Studies Towards the Synthesis of Azadirachtin:
Enantioselective Entry into the Azadirachtin
Framework through Cascade Reactions**
K. C. Nicolaou,* A. J. Roecker, Holger Monenschein,
Prasuna Guntupalli, and Markus Follmann
As part of a program directed towards the total synthesis of
azadirachtin (1),[1,2] we have adopted
a
radical-based
ꢀ
approach for the construction of its crowded C8 C14
bond.[3] Herein we report further advances along this path-
[*] Prof. Dr. K. C. Nicolaou, A. J. Roecker, Dr. H. Monenschein,
Dr. P. Guntupalli, Dr. M. Follmann
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 spectro-
scopic and mass spectroscopic assistance, respectively, and Dr. Raj
Chadha for X-ray crystallographic analysis. This work was financially
supported by the National Institutes of Health (USA), The Skaggs
Institute for Chemical Biology, predoctoral fellowships from the
Division of Organic Chemistry of the ACS sponsored by Novartis
and the Division of Medicinal Chemistry of the ACS sponsored by
Pfizer (both to A.J.R.), a Feodor Lynen postdoctoral fellowship from
the Alexander von Humboldt Foundation (to H.M.), and a
postdoctoral fellowship from Bayer AG (to M.F.).
Angew. Chem. Int. Ed. 2003, 42, 3637 –3642
DOI: 10.1002/anie.200351744
ꢀ 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3637

Communications
way, including a number of novel cascade reactions and the
arrival at suitably functionalized advanced systems 2a–c,
which contain both domains of the target molecule
(Scheme 1).
Scheme 1. Retrosynthetic analysis of advanced azadirachtin intermedi-
ate 2.
Scheme 1 outlines the retrosynthetic plan for the enantio-
selective construction of azadirachtin systems such as 2a–c,
which feature both a functionalized decalin and a bicyclic
ꢀ
framework linked together through the C8 C14 bond. It was
rationalized that such a compound could be formed through
an acid-induced opening of the mixed ketal moiety within the
polycyclic compound 3, followed by suitable elaboration.
Lactone 3, which contains, in principle, enough functionality
for a drive towards azadirachtin, was reasoned to arise from a
radical cyclization cascade sequence initiated from bromoke-
tal 4. As originally proposed,[3] bromoketal 4 was to be
assembled from the allylic alcohol 5 and methyl enol ether 6.
Hence, enantiocontrolled sequences for the construction of
both 5 and 6 were sought.
Scheme 2. Enantioselective synthesis of decalin coupling partner 5.
a) SEMCl (1.2 equiv), EtNiPr2 (1.5 equiv), CH2Cl2, 258C, 20 h, 85%;
b) Li (7.0 equiv), liquid NH3, ꢀ788C, 1 h, 80%; c) NaBH4 (1.2 equiv),
THF/EtOH (1:1), ꢀ78!258C, 3 h, 99%; d) TBDPSCl (2.0 equiv), imid.
(1.5 equiv), DMAP (0.2 equiv), DMF, 258C, 24 h, 80%; e) PPTS
(0.05 equiv), acetone, 658C, 24 h; f) KHMDS (3.5 equiv), Comin
reagent (1.2 equiv), THF, ꢀ788C, 0.5 h, 72% over two steps;
g) Pd(OAc)2 (0.3 equiv), PPh3 (0.6 equiv), CO (1 atm), EtNiPr2
(3.0 equiv), MeOH (50 equiv), DMF, 608C, 12 h, 89%; h) DIBAL-H
(4.0 equiv), CH2Cl2, ꢀ78!08C, 2 h, 95%; i) BH3·THF(5.0 equiv), THF,
08C, 12 h, 65%; j) TEMPO (0.1 equiv), resin (3.0 equiv), CH2Cl2, 258C,
2 h; k) Ac2O (5.0 equiv), py/CH2Cl2 (1:4), 258C, 0.1 h; l) NaClO2
(5.0 equiv), 2-methyl-2-butene (40 equiv), NaH2PO4 (3.5 equiv),
tBuOH/H2O (10:1), 258C, 2 h; m) HCl (1n)/dioxane (1:1), 758C, 16 h,
83% over four steps; n) TBSOTf (1.1 equiv), 2,6-lut. (1.3 equiv),
CH2Cl2, 258C, 1 h, 72%; o) DMP (1.5 equiv), NaHCO3 (5.0 equiv),
The synthesis of allylic alcohol 5 is depicted in Scheme 2.
Known decalin alcohol 7 (prepared from 1,3-cyclohexane-
dione with approximately 70% ee)[4] was protected as a SEM
ether (SEMCl, EtNiPr2, 85% yield), and the resulting enone
was subjected to a Birch reduction (Li, liquid NH3, 80%
yield) to afford trans-decalin system 9. The ketone function-
ality of compound 9 was then reduced stereoselectively with
NaBH4 (99% yield), and the obtained b-hydroxy compound
was silylated (TBDPSCl, imidazole, DMAP, 80% yield),
leading to protected compound 11. The dioxolane system of
compound 11 was removed upon treatment with mild acid
(PPTS), and the crude ketone was transformed into the
corresponding enol triflate (KHMDS, Comin reagent, 72%
¼
CH2Cl2, 258C, 3 h, 97%; p) Ph3P CH2 (8.0 equiv), THF, 258C, 12 h,
78%; q) SeO2 (3.0 equiv), tBuOOH (5.0 equiv), CH2Cl2, 258C, 6 h,
50%. SEM=2-(trimethylsilyl)ethoxymethyl, TBDPS=tert-butyldiphenyl-
silyl, imid=imidazole, DMAP=4-dimethylaminopyridine, DMF=N,N-
dimethylformamide, PPTS=pyridinium p-toluenesulfonate,
KHMDS=potassium bis(trimethylsilyl)amide, Comin reagent=2-[N,N-
bis(trifluoromethylsulfonyl)amino]-5-chloropyridine, TEMPO=4-oxo-
2,2,6,6-tetramethyl-1-piperidinyloxy (free radical), py=pyridine,
TBS=tert-butyldimethylsilyl, Tf=trifluoromethanesulfonyl,
DMP=Dess–Martin periodinane.
3638
ꢀ 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
Angew. Chem. Int. Ed. 2003, 42, 3637 –3642

Angewandte
Chemie
over two steps). The resulting triflate was then engaged in a
palladium-catalyzed carbonylation reaction to afford a,b-
unsaturated methyl ester 13 in 89% yield.[5] Reduction of 13
with DIBAL-H (95% yield), followed by regio- and stereo-
selective hydroboration led to diol 14 in 65% yield after basic
workup. This diol was then selectively oxidized to the
corresponding hydroxyaldehyde through a polymer-assisted
TEMPO-catalyzed oxidation procedure[6] and subsequently
acetylated (Ac2O, Et3N) to produce aldehyde acetate 15.
Further oxidation to the carboxylic acid, followed by treat-
ment of the resulting compound with aqueous HCl in dioxane,
gave rise to dihydroxy lactone 16 (83% yield over four steps).
Diol 16 was then selectively protected as a TBS ether (72%
yield), which was oxidized to the dicarbonyl system 17 with
DMP (97% yield). Finally, selective olefination of the ketone
functionality of 17 (Ph3P = CH2, 78% yield) followed by
regio- and stereoselective allylic oxidation of the resulting 18
as effected by SeO2 and tBuOOH afforded the desired allylic
alcohol 5 in 50% yield.[7]
used to prepare the desired endo acetate 21 from racemic
acetate 19 in 38% yield with high enantioselectivity
(96% ee).[8] Hydroboration (BH3·THF) of the C Cbond in
¼
21 followed by basic workup with hydrogen peroxide resulted
in an inseparable mixture of regioisomeric alcohols (22/23 ꢁ
1:1.3) in 78% combined yield. This mixture was protected
with a PMB group to provide 24 and 25, the acetate was
removed (K2CO3, MeOH, 84% yield over two steps), and the
resulting alcohols were oxidized to the corresponding ketones
26 and 27 upon treatment with PCC (88% combined yield).
The desired ketone 26 was separated from its unwanted
isomer 27 by flash column chromatography (silica gel), and
then transformed into the targeted enol ether 6 by first
constructing its dimethyl ketal ((MeO)3CH, p-TsOH, 98%
yield) and then eliminating one molecule of MeOH under the
conditions reported by Gassman et al. (TMSOTf/EtNiPr2,
57% yield).[9]
With both building blocks 5 and 6 in hand, the next task
was the tethering of the two domains through a ketal bridge.
As depicted in Scheme 4, treatment of enol ether 6 with
bromine in CH2Cl2 in the presence of N,N-dimethylaniline at
The enantioselective synthesis of the required enol ether 6
is shown in Scheme 3. A known resolution procedure was
ꢀ
Scheme 4. Radical cascade-based construction of the C8 C14 bond of
azadirachtin; construction of 3 and 29. a) Br2 (1.0 equiv), N,N-
dimethylaniline (2.0 equiv), CH2Cl2, 6 (1.3 equiv), 5 (1.0 equiv), ꢀ78!
08C, 12 h, 72% combined yield; b) nBu3SnH (1.3 equiv), AIBN
(0.5 equiv) in toluene (0.01m), 1108C, 15 h, 75% (4), 74% (29).
AIBN=2,2’-azobisisobutyronitrile.
Scheme 3. Enantioselective synthesis of bicyclic methyl enol ether 6
(dihydrofuran coupling partner). a) See reference [8]; b) BH3·THF
(1.0 equiv), THF, 08C, 1 h; then NaOH (1m; 5.0 equiv), aqueous H2O2
(30 wt%; 5.0 equiv), 30 min, 78%; c) p-methoxybenzyltrichloroacetimi-
date (2.0 equiv), p-TsOH (0.1 equiv), CH2Cl2, 258C, 10 h; d) K2CO3
(0.5 equiv), MeOH, 258C, 8 h, 84% over two steps; e) PCC (2.5 equiv),
M.S. (4 ꢀ), CH2Cl2, 258C, 1 h, 88%; f) (MeO)3CH (1.5 equiv), p-TsOH
(0.05 equiv), MeOH, 258C, 3 h, 98%; g) TMSOTf (1.1 equiv), EtNiPr2
(1.2 equiv), CH2Cl2, ꢀ20!258C, 16 h, 57%. PMB=p-methoxybenzyl,
p-TsOH=p-toluenesulfonic acid monohydrate, PCC=pyridinium chlor-
ochromate.
ꢀ788C, followed by addition of allylic alcohol 5 at that
temperature, afforded bromoketal 4 as the major product
(57%) together with bromoketal 28 as a minor product
(15%).[10] Individual treatment of these ketals with nBu3SnH
and AIBN (0.01m in toluene, 1108C) led to hexacyclic
products 3 (75%, desired product for azadirachtin; see
Table 1) and 29 (74%), respectively. Interestingly, loss of
Angew. Chem. Int. Ed. 2003, 42, 3637 –3642
www.angewandte.org
ꢀ 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3639

Communications
the PMB ether and concomitant conversion into a ketone
the intermediate radical species 31’.[12] To confirm the
structure of 3, a suitably crystalline derivative for X-ray
crystallographic analysis was sought and found in the 3,5-
dinitrobenzoate 33. The latter compound was obtained by a
stereoselective reduction of 3 with NaBH4 (80% yield)
followed by reaction with 3,5-dinitrobenzoyl chloride and
Et3N in the presence of DMAP (85% yield). Indeed, the X-
ray crystallographic analysis of 33 revealed its structure (see
ORTEP drawing, Scheme 5) and, by extension, that of 3.
The radical cyclization reaction of the minor bromoketal
(28, Scheme 4) was also intriguing in that it apparently
proceeded through a 6-endo-trig cyclization of the initially
formed radical 34 to form hexacycle 29 as shown in
Scheme 6.[13] The structure of 29 was unambiguously assigned
by X-ray crystallographic analysis of the 3,5-dinitrobenzoate
derivative 35, obtained by desilylation of 29 (100% yield) and
ester formation (80% yield; see ORTEP
accompanied the 5-exo-trig cyclization to give 3 from the
major bromoketal 4. Also of interest is the fact that the minor
ketal underwent cyclization in a 6-endo-trig manner to afford
29 as opposed to the expected 5-exo-trig cyclization.[11]
A mechanistic explanation for the intriguing transforma-
tion of 4 into 3 is shown in Scheme 5. Thus, the secondary
radical generated from 4 (i.e. 30) undergoes the expected 5-
ꢀ
exo-trig cyclization to forge the C8 C14 bond, leading to the
highly reactive primary radical 31. The proximity of the
radical center within 31 to the hydrogen atom on the carbon
atom that bears the PMB ether, five bonds away, coupled with
the overall rigidity and reactivity of the system, apparently
allows the indicated 1,5 H shift, with concomitant oxidative
rupture of the benzyl bond, leading to the observed product 3
and p-methoxytoluene (31’’), which presumably arises from
structure in Scheme 6).
Modeling studies (ball and stick) with
28 indicate that a 5-exo-trig cyclization
would be associated with a severe steric
interaction between the methoxy group
and the olefinic site in contrast to a 6-endo-
trig mode of ring closure, which is devoid
of such interactions. Similar modeling with
the major bromoketal 4, on the other hand,
shows that the expected 5-exo-trig cycliza-
tion does not suffer from the methoxy–
olefin steric interaction, explaining the
difference in the behavior of the two
diastereomeric bromoketals.
A significant finding in this study was
the demonstration of the rupture of the
mixed ketal bridge employed to facilitate
ꢀ
C8 C14 bond formation (Scheme 7).
These studies began with an attempt to
hydrolyze the mixed ketal within 3, or
variants thereof, only to realize the intran-
sigence of the resulting lactol towards
opening to the desired hydroxyketone
form. The sequence 3!36!37!38 (desi-
lylation, p-bromobenzoate formation, and
treatment with H2SO4) is illustrative of
these forays. This intransigence is in con-
trast to previous observations with similar
compounds,[3] and underscores the subtle
intricacies of reactivity within the azadir-
achtin scaffold. In an effort to probe
further these structure-based reactivity
patterns, polycycle 3 was modified to its
olefinic counterpart 39 through Wittig
olefination (62% yield), desilylation
(!40, 91% yield), and acetylation (!41,
90% yield). Gratifyingly, 41 was smoothly
converted into diketone 2a (see Table 1) in
80% yield upon exposure to H2SO4 in
Scheme 5. Proposed cascade sequence for the formation of 3 from major ketal 4 and
structural proof of product. a) NaBH4 (4.0 equiv), MeOH, 08C, 1 h, 80%; b) 3,5-dinitro-
benzoyl chloride (2.0 equiv), Et3N (4.0 equiv), DMAP (0.2 equiv), CH2Cl2, 258C, 12 h,
85%.
CH2Cl2 at 08C.[14] To explain this unusual
transformation we invoke an initial proto-
nation of the olefinic bond leading to a
3640
ꢀ 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
Angew. Chem. Int. Ed. 2003, 42, 3637 –3642

Angewandte
Chemie
tertiary carbocation (42, see Scheme 7)
which then triggers an oxidative 1,5 hydride
transfer with concomitant rupture of the
oxygen bridge between the two domains of
the molecule. Subsequent hydrolysis of the
resulting intermediate 43 then leads to the
observed product 2a.
In an extension of this concept and to
obtain a functional handle at what will
become C21 of azadirachtin,
a second
foray was designed and executed. Hence,
compound 3 (Scheme 7) was transformed
into styrene derivative 44 via its enol triflate
(KHMDS, Comin reagent, 65% yield) and
through a Suzuki reaction ([Pd(PPh3)4],
PhB(OH)2, 78% yield). The TBS group
within 44 was then replaced by an acetate
group to afford 46 via 45 (82% for two
steps). Exposure of 46 to H2SO4 as above
gave 2b, presumably through the same
cascade mechanism that led to 2a. The
phenyl ring of the latter intermediate (2b)
was then oxidatively degraded[15] by the
action of RuCl3 and NaIO4 to reveal carbox-
ylic acid 47, whose methylation afforded
advanced intermediate 2c (80% yield over
two steps) equipped with a synthetically
useful handle at C21.
Scheme 6. Structural proof of polycycle 29. a) TBAF(3.0 equiv), THF, 25 8C, 4 h, 100%;
b) 3,5-dinitrobenzoyl chloride (2.0 equiv), Et3N (5.0 equiv), DMAP (0.2 equiv), CH2Cl2,
258C, 12 h, 80%. TBAF=tetrabutylammonium fluoride.
The described chemistry represents con-
siderable progress toward the azadirachtin
structure and its congeners. Specifically, a
sequence based on intramolecular radical
chemistry followed by a cation-induced
rupture of an initially formed bridge enabled
the construction of the suitably functional-
ized system 2c, setting the stage for further
advances towards this formidable target.
Furthermore, the observed radical- and
ionic-based cascade sequences may prove
Scheme 7. Hydrolysis of mixed ketal polycycles
and synthesis of 2a–c. a) CSA (2.0 equiv), MeOH,
258C, 1 h, 90%; b) 4-bromobenzoyl chloride
(2.0 equiv), Et3N (5.0 equiv), DMAP (0.2 equiv),
CH2Cl2, 258C, 12 h, 81%; c) H2SO4 (5.0 equiv),
¼
CH2Cl2, 08C, 0.5 h, 85%; d) Ph3P CH2
(10.0 equiv), THF, 258C, 15 h, 62%; e) TBAF
(3.0 equiv), THF, 408C, 0.5 h, 91%; f) Ac2O
(10.0 equiv), DMAP (1.0 equiv), py, 258C, 6 min,
90%; g) H2SO4 (5.0 equiv), CH2Cl2, 08C, 10 min,
80% (2a), 81% (2b); h) KHMDS (3.0 equiv),
Comin reagent (2.0 equiv), THF, ꢀ788C, 1 h, 65%;
i) [Pd(PPh3)4] (0.1 equiv), PhB(OH)2 (5.0 equiv),
Cs2CO3 (10.0 equiv), DMF/MeOH (10:1), 808C,
1 h, 78%; j) RuCl3 (0.5 equiv), NaIO4 (20.0 equiv),
CH3CN/CCl4/H2O (1:1:1), 258C, 24 h; k) Cs2CO3
(5.0 equiv), MeI (10.0 equiv), DMF, 258C, 2 h,
80% over two steps. CSA=camphorsulfonic acid.
Angew. Chem. Int. Ed. 2003, 42, 3637 –3642
www.angewandte.org
ꢀ 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3641

Communications
Nicolaou, A. J. Roecker, M. Follmann, R. Baati, Angew. Chem.
2002, 114, 2211 – 2214; Angew. Chem. Int. Ed. 2002, 41, 2107 –
2110.
Table 1: Selected data for 3 and 2a.
3: Colorless oil; [a]D =À148 (c=0.10 in CHCl3); Rf =0.27 (silica, 25%
EtOAc in hexanes); IR (thin film): n˜max =2930, 2861, 1766, 1742, 1508,
[3] K. C. Nicolaou, M. Follmann, A. J. Roecker, K. W. Hunt, Angew.
Chem. 2002, 114, 2207 – 2210; Angew. Chem. Int. Ed. 2002, 41,
2103 – 2106.
[4] R. Hanselmann, M. Benn, Synth. Commun. 1996, 26, 945 – 961.
[5] T. Nagamitsu, T. Sunazuka, R. Obata, H. Tomoda, H. Tanaka, Y.
Harigaya, S. Omura, A. B. Smith III, J. Org. Chem. 1995, 60,
8126 – 8127.
[6] G. Sourkouni-Argirusi, A. Kirschning, Org. Lett. 2000, 2, 3781 –
3784.
[7] A. F. Barrero, S. Arseniyadis, J. F. Quilez del Moral, M. Mar
Herrador, M. Valdivia, D. Jimenez, J. Org. Chem. 2002, 67,
3781 – 3784.
1
1461, 1249 cmÀ1; HNMR (600 MHz, C 6D6): d=3.71 (d, J=9.7 Hz,
1H), 3.69–3.67 (m, 1H), 3.58–3.50 (m, 1H), 3.37 (d, J=9.7 Hz, 1H),
3.13 (s, 3H), 2.83 (d, J=4.4 Hz, 1H), 2.56 (s, 1H), 2.40 (br s, 1H), 2.32
(br s, 1H), 2.16 (dd, J=17.9, 4.8 Hz, 1H), 1.88–1.80 (m, 1H), 1.61–1.42
(m, 5H), 1.39–1.22 (m, 3H), 1.14 (s, 3H), 1.03 (d, J=10.5 Hz, 1H), 0.96
(s, 9H), 0.95–0.88 (m, 1H), 0.82–0.74 (m, 1H), À0.02 ppm (s, 6H);
13C NMR (150 MHz, C6D6): d=215.1, 171.3, 115.1, 85.2, 71.1, 68.4, 67.7,
54.8, 54.1, 51.0, 42.5, 41.3, 41.1, 39.9, 38.8, 38.1, 35.6, 32.2, 30.4, 28.2,
26.0, 18.1, 16.5, À4.5, À4.6 ppm; HRMS (MALDI, FTMS), calcd for
C27H42O6Si [M+Na+]: 513.2643, found: 513.2631
2a: Colorless oil; [a]D =À348 (c=0.23 in CHCl3); Rf =0.52 (silica, 50%
EtOAc in hexanes); IR (thin film): n˜max =2958, 2868, 1765, 1730, 1454,
1371, 1243 cmÀ1; 1HNMR (600 MHz, C 6D6): d=4.43–4.38 (m, 1H), 3.66
(d, J=9.6 Hz, 1H), 3.48 (dd, J=9.6, 2.2 Hz, 1H), 2.92 (s, 1H), 2.74 (d,
J=4.0 Hz, 1H), 2.62–2.58 (m, 1H), 2.52 (d, J=4.0 Hz, 1H), 2.21–2.15
(m, 1H), 1.94–1.91 (m, 1H), 1.74–1.70 (m, 1H), 1.67 (s, 3H), 1.65 (d,
J=3.5 Hz, 1H), 1.63 (d, J=3.5 Hz, 1H), 1.56–1.53 (m, 1H), 1.38–1.18
(m, 5H), 1.07–1.03 (m, 1H), 1.02–0.98 (m, 1H), 0.96 (s, 3H), 0.77 (d,
J=7.0 Hz, 3H), 0.58–0.52 ppm (m, 1H); 13C NMR (125 MHz, C6D6):
d=215.5, 207.1, 175.5, 169.0, 70.6, 68.6, 60.2, 58.5, 53.4, 50.4, 46.0, 43.3,
40.2, 38.6, 35.4, 34.7, 34.1, 34.0, 30.2, 27.2, 22.2, 20.7, 20.4 ppm; HRMS
(MALDI, FTMS), calcd for C23H30O6 [M+H+]: 403.2115, found: 403.2118
[8] G. Eichberger, G. Penn, K. Raber, H. Griengl, Tetrahedron Lett.
1986, 27, 2843 – 2844.
[9] P. G. Gassman, S. J. Burns, K. B. Pfister, J. Org. Chem. 1993, 58,
1449 – 1457.
[10] For a bromoketalization precedent, see: J. D. White, P. Ther-
amongkol, C. Kuroda, J. R. Engegrecht, J. Org. Chem. 1988, 53,
5909 – 5921.
[11] For another substrate-directed 6-endo-trig over 5-exo-trig rad-
ical cyclization, see: C. Anies, L. Billot, J.-Y. Lallemand, A.
Pancrazi, Tetrahedron Lett. 1995, 36, 7247 – 7250.
[12] For an example of a 1,5 hydrogen-transfer reaction, see: D. P.
Curran, H. Yu, Synthesis 1992, 123 – 127.
[13] For further mechanistic characterization, the cyclization of the
minor bromoketal was also performed with nBu3SnD. The
product showed incorporation of deuterium by MALDI MS and
by 1H NMR (presumably the deuterium was incorporated at C8;
the signal for the proton at C8 is obscured by other protons in the
same region).
useful in other contexts within the general theme of molecular
complexity and diversity construction.
[14] For another example of an intramolecular redox reaction
through a 1,5 hydride shift, see: H. Berner, G. Schultz, H.
Schneider, Tetrahedron 1980, 36, 1807 – 1811.
[15] P. H. J. Carlsen, T. Katsuki, V. S. Martin, K. B. Sharpless, J. Org.
Chem. 1981, 46, 3936 – 3938.
Received: April 24, 2003 [Z51744]
Keywords: asymmetric synthesis · azadirachtin ·
.
domino reactions · hydride shift · natural products · radicals
[1] For the isolation, see: J. H. Butterworth, E. D. Morgan, Chem.
Commun. 1968, 23 – 24.
[2] For the structure determination, see: a) J. N. Bilton, H. B.
Broughton, P. S. Jones, S. V. Ley, Z. Lidert, E. D. Morgan, H. S.
Rszepa, R. N. Sheppard, A. M. Z. Slawin, D. J. Williams, Tetra-
hedron 1987, 43, 2805 – 2815; b) W. Kraus, M. Bokel, A. Bruhn,
R. Cramer, I. Klaiber, A. Klenk, G. Nagl, H. Pohnl, H. Sadlo, B.
Vogler, Tetrahedron 1987, 43, 2817 – 2830; c) C. J. Turner, M. S.
Tempesta, R. B. Taylor, M. G. Zagorski, J. S. Termini, D. R.
Schroeder, K. Nakanishi, Tetrahedron 1987, 43, 2789 – 2804;
Synthetic studies: d) S. V. Ley, C. E. Gutteridge, A. R. Pape,
C. D. Spilling, C. Zumbrunn, Synlett 1999, 1295 – 1297; e) A. A.
Denholm, L. Jennens, S. V. Ley, Tetrahedron 1995, 51, 6591 –
6604; f) S. V. Ley, A. A. Denholm, A. Wood, Nat. Prod. Rep.
1993, 10, 109 – 157; g) H. Kolb, S. V. Ley, Tetrahedron Lett. 1991,
32, 6187 – 6190; h) M. G. Brasca, H. B. Broughton, D. Craig, S. V.
Ley, A. A. Somovilla, P. L. Toogood, Tetrahedron Lett. 1988, 29,
1853 – 1856; i) Y. Yamamoto, J. Ishihara, N. Kanoh, A. Murai,
Synthesis 2000, 1878 – 1893; j) H. Watanabe, T. Watanabe, K.
Mori, T. Kitahara, Tetrahedron Lett. 1997, 38, 4429 – 4432; k) Y.
Nishikimi, T. Iimori, M. Sodeoka, M. Shibasaki, J. Org. Chem.
1989, 54, 3354 – 3359; l) K. J. Henry, Jr., B. Fraser-Reid, J. Org.
Chem. 1994, 59, 5128 – 5129; m) H. Schlesiger, E. Winterfeld,
Chirality 1997, 9, 454 – 458; n) T. Durand-Reville, L. B. Gobbi,
B. L. Gray, S. V. Ley, J. S. Scott, Org. Lett. 2002, 4, 3847 – 3850;
o) T. Fukuzaki, S. Kobayashi, T. Hibi, T. Ikuma, J. Ishihara, N.
Kanoh, A. Murai, Org. Lett. 2002, 4, 2877 – 2880; p) K. C.
3642
ꢀ 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
Angew. Chem. Int. Ed. 2003, 42, 3637 –3642