Multiple palladium-catalyzed reactions for the synthesis of analogues of the highly potent insecticide spinosyn A

Article abstract of DOI:10.1002/anie.200601003

Resistance is useless? The increasing resistance towards (-)-spinosyns A (1) and D (2) used as plant-protection agents makes new derivatives of these natural products necessary. On the basis of investigations into the structure-activity relationships a convergent approach to the synthesis of novel spinosyn A analogues (3) is developed. A double Heck reaction is the key step in the construction of the basic carbocyclic framework. (Chemical Equation Presented).

Full text of DOI:10.1002/anie.200601003

Angewandte
Chemie
Plant Protection Agents
The total syntheses of spinosyns[7] are, however, not very
flexible, and are moreover very complex. Herein we report a
convergent approach to the synthesis of structurally simpli-
fied analogues, such as 3, which offers numerous variation
possibilities and in whose key step ring B is constructed in a
double Heck reaction.
The decision to exchange the five-membered aliphatic
ring A in 1 and 2 for a benzene ring was made on the basis of
investigations into structure–activity relationships on 2. It was
DOI: 10.1002/anie.200601003
Multiple Palladium-Catalyzed Reactions for the
Synthesis of Analogues of the Highly Potent
Insecticide Spinosyn A**
Lutz F. Tietze,* Gordon Brasche, Christian Stadler,
Alexander Grube, and Niels Böhnke
ꢀ
shown that an additional C C double bond in ring A of 2
hardly affects the biological activity, whereas in contrast, the
cis linkage of rings B and C is important for insecticidal
activity.[2] One strategy for the efficient construction of cis-
annelated ring systems with the arrangement of the double
bonds necessary in 3 comes from the double Heck reaction
developed by us and first used in the total synthesis of
estradiol.[8] As substrates for the synthesis of spinosyn
analogues we used the bromoarene 7 (derived from 3-
methoxybenzaldehyde (6)) with an iodovinyl side chain, and
the enantiomerically pure cyclopentene derivative 5, which
was obtained in six steps starting from the monoacetate 4
(Scheme 1); 4 was accessible from 1,4-dihydroxycyclopentene
with 99% ee by enzymatic acetylation.[9] The intermolecular
Heck reaction of 5 and 7 with Pd(OAc)2 in DMF provided the
desired coupled product 8 diastereomerically pure in 51%
yield.[10] A regioisomer of 5 with a coupling at the 3’-position
and the corresponding compounds with an E-configured
styrene double bond were isolated as further products.
Carrying out the reaction at the unusually low temperature
for Heck reactions of ꢀ258C gave the highest selectivity and
yield. After cleavage of the acetate group, the tricyclic ring
system 11 was constructed stereoselectively in 90% yield in
an intramolecular Heck reaction with the cyclic palladium
system 10.[11,12] The cis connection of the rings in 11 was
established by a NOESY-NMR spectroscopy experiment.
After protection of the phenolic hydroxy group in 11 as
TIPS ether, cleavage of the TBS ether, and oxidation of the
resulting primary alcohol the aldehyde 12 was obtained into
which the C-3 fragment 13 was inserted as boron enolate in an
Evans aldol addition.[13] The reaction took place with high
diastereoselectivity, presumably through a closed six-mem-
bered transition state,[14] with exclusive formation of 14 in a
yield of 89%. By use of a racemic mixture of aldehyde 12 in
the aldol addition with 13, two enantiomerically pure
diastereoisomers were obtained as expected in a ratio of
approximately 1:1 (in a total yield of 82%) and could be
separated by chromatography on silica gel.
Dedicated to Professor Dieter Hoppe
on the occasion of his 60th birthday
The natural product class of spinosyns comprises a group of
more than 20 structurally related compounds that have been
isolated from culture broths of the bacterium Saccharopoly-
spora spinosa.[1,2] These include spinosyn A (1) and D( 2),
which are used world-wide in agriculture as extremely potent
and highly selective insecticides[3] under the name Spinosad.[4]
The spinosyns attack the neuronal activity of insects by a
novel mechanism; interaction with the g-aminobutyric acid-
(GABA) receptor plays a role, but it is the nicotinergic
acetylcholine receptors (n-AchR) that are mainly affec-
ted.[2a,5]
In 2000 the development of the first cases of resistance
towards Spinosad was observed,[6] which has made the
preparation of new, active spinosyn derivatives necessary.
The secondary hydroxy group in 14 was then protected as
a TBS ether and the imide converted into a primary alcohol
with LiBH4/EtOH in Et2O (Scheme 2). Oxidation with Dess–
Martin periodinane gave the aldehyde 15. Reaction of 15 with
the enantiomerically pure organomagnesium species 16 and
subsequent transformation of the secondary alcohol thus
formed into a pivaloyl ester provided the two coupled
products 18 and 19 in a ratio of approximately 4:1 in a total
yield of 78%. The preferred formation of diastereoisomer 18
with S-configuration at C-3’’ required for further synthesis can
be explained by a Felkin–Anh transition state. Compound 16
can be prepared in four steps from the known alcohol 17.[15]
[*] Prof. Dr. L. F. Tietze, Dipl.-Chem. G. Brasche, Dipl.-Chem. C. Stadler,
Dipl.-Chem. A. Grube, Dipl.-Chem. N. Böhnke
Institut für Organische und Biomolekulare Chemie
Georg-August-Universität Göttingen
Tammannstrasse 2, 37077 Göttingen (Germany)
Fax: +49 551-399476
E-mail: ltietze@gwdg.de
[**] The investigations were supported by the Deutsche Forschungsge-
meinschaft (SFB 416) and the Fonds der chemischen Industrie. We
thank the companies BASF, Bayer, and Wacker-Chemie for gifts of
chemicals.
Angew. Chem. Int. Ed. 2006, 45, 5015 –5018
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Scheme 1. Synthesis of 14: a) 5 Mol% Pd(OAc)2, 1.0 equiv. TBACl, 3.0 equiv. NaOAc, DMF, ꢀ258C, 6 days, 51%; b) 2.0 equiv. NaHCO3, MeOH,
room temperature, 7 h, 99%; c) 7 Mol% 10, 2.0 equiv. nBu4NOAc, DMF/MeCN/H2O 5:5:1, 1308C, 3.5 h, 90%; d) 1.5 equiv. TIPSOTf, 3.0 equiv.
DMAP, CH2Cl2, 08C, 30 min, 96%; e) 10 mol% TsOH·H2O, MeOH, 08C, 4 h, 95%; f) 1.75 equiv. DMP, CH2Cl2, 08C, 2.5 h, 91%; g) 1.25 equiv. 13,
1.3 equiv. nBu2BOTf, 1.45 equiv. NEt3, C HCl2, ꢀ75!ꢀ258C, 89%. TBS=tert-butyldimethylsilyl, TBACl=tetrabutylammonium chloride, oTol =or-
2
tho-tolyl, TIPS=triisopropylsilyl, OTf=trifluoromethane sulfonate, DMAP=4-dimethylaminopyridine, TsOH=toluene-4-sulfonic acid,
DMP=Dess-Martin periodinane, Bn=benzyl, EA=Evans’ auxiliary.
Scheme 2. Synthesis of 18: a) 5.0 equiv. TBSOTf, 10 equiv. DMAP, CH2Cl2, room temperature, 20 h, 84%; b) 10 equiv. LiBH4, 20 equiv. EtOH,
Et2O, room temperature, 15 min, 63%; c) 1.75 equiv. DMP, CH2Cl2, 08C, 2 h, 91%; d) 1.25 equiv. 16, THF, ꢀ358C, 1.5 h; e) 10 equiv. PivCl,
1.0 equiv. DMAP, pyridine, 608C, 14 h, 63% (two steps). MEM=(2-methoxyethoxy)methyl, PivCl=pivaloyl chloride.
The MEM protecting group in 18 was removed with
trimethylsilyl iodide (TMSI) prepared in situ, subsequently
the tert-butyl ester group was cleaved with TMSOTf
(Scheme 3). The hydroxy acid obtained was converted into
the mixed anhydride with trichlorobenzoyl chloride
(TCBzCl) by the method of Yamaguchi et al.,[16] from which
the macrolactone 20a was formed by slow addition to a
solution of DMAP.
To conclude the synthesis of the analogues of Spinosyn-A
aglycone the silyl protecting groups were cleaved and the
enone unit constructed. The two silyl groups in 20a were
removed with HF·pyridine in pyridine at 608C. The subse-
quent oxidation of the secondary allylic alcohol by the
method of Parikh and Doering[17] with SO3·pyridine in DMSO
afforded the desired enone 21a which, after protection of the
phenolic hydroxy group as acetate 21b, could be isolated over
two steps in 34% yield. The low yield is attributed to the
sensitivity of the phenolic hydroxy group towards oxidation.
In contrast, by use of the methyl ether 20b and DMP as the
oxidizing agent the spinosyn analogue 21c was obtained in
86% yield.
The synthesis described, with a double Heck reaction as
the key step, allows rapid access to a structurally new spinosyn
analogue. Future investigations will involve variation of
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Angewandte
Chemie
Moulton, D. A. Pepper, T. J. Dennehy, Pest Manage. Sci. 2000,
56, 842 – 848.
[7] a) D. J. Mergott, S. A. Frank, W. R. Roush,Proc. Natl. Acad. Sci.
USA 2004, 101, 11955 – 11959; b) L. A. Paquette, Z. Gao, Z. Ni,
G. F. Smith, J. Am. Chem. Soc. 1998, 120, 2543 – 2552; c) L. A.
Paquette, I. Collado, M. Purdie, J. Am. Chem. Soc. 1998, 120,
2553 – 2562; d) D. A. Evans, C. Black, J. Am. Chem. Soc. 1993,
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[8] a) L. F. Tietze, M. Spescha, T. Nöbel, J. Am. Chem. Soc. 1998,
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Tietze, W.-R. Krahnert, Chem. Eur. J. 2002, 8, 2116 – 2125;
e) L. F. Tietze, S. Petersen, Eur. J. Org. Chem. 2001, 1619 – 1624.
[9] F. Theil, H. Schick, G. Winter, G. Reck, Tetrahedron Lett. 1991,
32, 7565 – 7582.
[10] 8: A degassed, light-protected solution of 7 (37 mg, 100 mmol)
and 5 (82 mg, 250 mmol, 2.5 equiv.) in absolute DMF (1 mL) at
ꢀ258C under an argon atmosphere was treated with Pd(OAc)2
(1.1 mg, 5 mmol, 5 mol%), NaOAc (25 mg, 300 mmol, 3.0 equiv.),
and TBACl (28 mg, 100 mmol, 1.0 equiv.) and the mixture was
stirred for 6 days at ꢀ258C. The reaction mixture was taken up in
Et2O (10 mL), washed with H2O (1 ” 10 mL), and the aqueous
phase then extracted with Et2O (2 ” 10 mL). The combined
organic extracts were then washed with saturated NaCl solution
(1 ” 20 mL), dried over Na2SO4, filtered, and the filtrate
evaporated under reduced pressure. After preparative thin-
layer chromatography (TLC; 1 plate, n-pentane(P)/ethyl aceta-
te(EE) 10:1) 8 (29 mg, 51 mmol, 51%) was obtained as yellow
oil. The regioisomer of 8 (14 mg, 25 mmol, 25%, Rf = 0.53 (P/EE
10:1)) and a fraction (11 mg, Rf = 0.46 (P/EE 10:1)) which
consisted to a large extent of the corresponding E-configured
coupled products were isolated as further products. 8: Rf = 0.57
(P/EE 10:1); [a]2D0 = ꢀ113.88 (c = 1.0 in CHCl3); UV (MeCN):
lmax(lge) = 194.5 (4.397), 213.0 nm (4.352); IR (Film): n˜ = 2929,
1728, 1462, 1200 cmꢀ1; 1H NMR (300 MHz, CDCl3, 258C TMS):
d = ꢀ0.06 (s, 3H) and ꢀ0.04 (s, 3H) (both Si(CH3)2), 0.77 (s, 9H;
Si(C(CH3)3)), 1.42 (s, 9H; CO2(C(CH3)3)), 2.28 (s, 3H;
OC(O)CH3), 2.30–2.50 (m, 3H; 2-H, 1’-H), 2.81–2.90 (m, 1H;
5’-H), 3.25–3.37 (m, 1H; 2’-H), 3.54 (d, J = 4.5 Hz, 2H; 5’-CH2-
OTBS), 5.51 (t, J = 11.0 Hz, 1H; 1’’-H), 5.62–5.68 (m, 1H) and
5.74–5.81 (m, 1H) (3’-H, 4’-H), 6.45 (d, J = 11.4 Hz, 1H; 2’’-H),
6.88 (dd, J = 8.6, 2.6 Hz, 1H; 4’’’-H), 6.97 (d, J = 2.7 Hz, 1H; 6’’’-
H), 7.54 ppm (d, J = 8.4 Hz, 1H; 3’’’-H); 13C NMR (50 MHz,
CDCl3, 258C): d = ꢀ5.7, ꢀ5.6 (Si(CH3)2), 18.0 (Si(C(CH3)3)),
21.1 (OC(O)CH3), 25.7 (Si(C(CH3)3)), 28.0 (CO2(C(CH3)3)),
34.6 (C-2), 44.7 (C-1’), 48.7 (C-5’), 49.4 (C-2’), 62.5 (C-5’-CH2-
OTBS), 80.1 (CO2(C(CH3)3)), 120.4 (C-2’’’), 121.6 (C-4’’’), 123.5
(C-6’’’), 129.2 (C-2’’), 133.2 (C-3’’’), 134.0, 134.1 (C-3’, C-4’), 137.0
(C-1’’), 138.7 (C-1’’’), 149.4 (C-5’’’), 169.0, 172.9 ppm (C-1,
OC(O)CH3); MS (DCI): m/z (%): 584.3 (42) [M+NH4]+, 567.3
(100) [M+H]+; HRMS (ESI): calcd for [M+Na]+: 587.17988;
found: 587.17989; Elemental analysis (%) calcd for
C28H41BrO5Si (565.61): C 59.46, H 7.31; found: C 59.60, H 7.23.
[11] W. A. Herrmann, C. Broßmer, K. ꢀfele, C.-P. Reisinger, T.
Priermeier, M. Beller, H. Fischer, Angew. Chem. 1995, 107,
1989 – 1992; Angew. Chem. Int. Ed. Engl. 1995, 34, 1844 – 1848.
[12] 11: A degassed mixture of 9 (4.55 g, 8.69 mmol), 10 (572 mg,
610 mmol, 7 mol%), and nBu4NOAc (3.31 g, 17.4 mmol,
2.0 equiv.) in DMF/MeCN/H2O (220 mL, 5:5:1) was heated for
3.5 h in an oil bath pre-heated to 1308C under an argon
atmosphere and with the exclusion of light. After cooling to
room temperature Et2O (150 mL) and H2O (250 mL) were
added after which the organic phase was separated and the
aqueous phase extracted with Et2O (2 ” 150 mL). The combined
organic phases were dried over MgSO4, filtered, and the filtrate
Scheme 3. Synthesis of the spinosyn analogues 21: a) 4.0 equiv.
TMSCl, 4.0 equiv. NaI, MeCN/CH2Cl2 4:1, ꢀ358C, 1.5 h, 84%;
b) 25 equiv. TMSOTf, 30 equiv. NEt3, THF, room temperature, 1 h;
c) 4.0 equiv. TCBzCl, 6.0 equiv. NEt3, THF, room temperature, 1.5 h,
then slow addition to 10 equiv. DMAP, toluene, 758C, 5 h, 50% (two
steps); 20a: d) HF·pyridine/pyridine 1:3, 608C , 14 h, 88%;
e) 6.0 equiv. SO3·pyridine, 10 equiv. (iPr)2NEt, DMSO, room temper-
ature, 1 h; f) 5.0 equiv. Ac2O, 10 equiv. NEt3, 0.5 equiv. DMAP, CH2Cl2,
08C, 30 min, 34% 21b (two steps); 20b: d) HF·pyridine/pyridine 1:3,
608C, 14 h, 91%; e) 1.5 equiv. DMP, CH2Cl2, room temperature,
20 min, 86% 21c.
ring A, for example by use of five- and six-membered
heteroarenes.
Received: March 14, 2006
Published online: July 3, 2006
Keywords: Heck reactions · macrocycles · palladium ·
.
plant protection agents · spinosyns
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Angew. Chem. Int. Ed. 2006, 45, 5015 –5018
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Communications
evaporated under reduced pressure. After column chromatog-
5’-CH2-OTBS), 80.7 (CO2(C(CH3)3)), 113.5, 114.0 (C-6’, C-8’),
125.4 (C-5’), 126.7 (C-9a’), 128.9 (C-9’), 129.1 (C-1’), 131.9 (C-4’),
133.1 (C-5a’), 144.2 (C-2’), 154.3 (C-7’), 172.4 ppm (C-1); MS
(ESI): m/z (%) = 467.1 (8), 466.2 (30), 465.2 (100) [M+Na]+;
HRMS (ESI): calcd for [M+H]+: 443.26121; found: 443.26129;
C26H38O4Si (442.66).
raphy on SiO2 (60 g, 4.5 ” 8 cm, P/Et2O 5:1) 11 was obtained as a
yellow oil (3.45 g, 7.79 mmol, 90%). Rf = 0.23 (P/EE 10:1);
[a]2D0 = ꢀ126.28 (c = 1.0 in CHCl3); UV (MeCN): lmax(lge) =
227.5 (4.425), 256.5 (3.656), 265.0 (3.735), 275.0 (3.668), 303.0
(3.368), 313.0 nm (3.307); IR (Film): n˜ = 3392, 2929, 1727,
1462 cmꢀ1 1H NMR (300 MHz, CDCl3, 258C TMS): d = 0.03
;
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(s, 6H; Si(CH3)2), 0.88 (s, 9H; Si(C(CH3)3)), 1.47 (s, 9H;
CO2(C(CH3)3)), 2.29 (dd, J = 15.3, 9.9 Hz, 1H; 2-HB), 2.61 (dd,
J = 15.2, 4.4 Hz, 1H; 2-HA), 2.94–3.04 (m, 1H; 3’-H), 3.09 (mc,
1H; 3a’-H), 4.02 (mc, 1H; 9b’-H), 4.20 (s, 2H; 5’-CH2-OTBS),
5.38–5.45 (m, 2H; 1’-H, OH), 5.71 (dd, J = 9.8, 3.2 Hz, 1H; 4’-H),
6.18 (dd, J = 9.8, 2.0 Hz, 1H; 5’-H), 6.46 (d, J = 2.7 Hz, 1H; 6’-
H), 6.62 (dd, J = 8.1, 2.7 Hz, 1H; 8’-H), 6.95 ppm (d, J = 8.1 Hz,
1H; 9’-H); 13C NMR (75 MHz, CDCl3, 258C): d = ꢀ5.4, ꢀ5.4
(Si(CH3)2), 18.3 (Si(C(CH3)3)), 25.9 (Si(C(CH3)3)), 28.1 (CO2(C-
(CH3)3)), 39.3 (C-2), 44.2, 44.6 (C-3a’, C-9b’), 50.5 (C-3’), 61.1 (C-
5018
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