Total synthesis of (±)-rocaglamide and some aryl analogues

Article abstract of DOI:10.1016/S0040-4039(01)01807-X

The insecticidal activity found for rocaglamide and its congeners, prompted us to establish a short and efficient synthesis of the natural product and some synthetic 'halo-aryl' analogues. Pd-catalysed cross-coupling reactions of the bromo analogue were then explored in order to gain a suitable access to a broad range of unnatural analogues. The key step of our approach is a keto-aldehyde acyloin ring-closure followed by a Stiles carboxylation.

Full text of DOI:10.1016/S0040-4039(01)01807-X

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 8281–8284
Total synthesis of ( )-rocaglamide and some aryl analogues
Markus R. Dobler,a,* Ian Bruce,b Fredrik Cederbaum,a Nigel G. Cooke,b Louis J. Diorazio,b
Roger G. Halla and Ed Irvingb
aNovartis Crop Protection AG, 4002 Basel, Switzerland
bNovartis Pharmaceuticals, Central Research, Hulley Road, Macclesfield SK10 2NX, UK
Received 8 November 2000; accepted 22 May 2001
Abstract—The insecticidal activity found for rocaglamide and its congeners, prompted us to establish a short and efficient
synthesis of the natural product and some synthetic ‘halo-aryl’ analogues. Pd-catalysed cross-coupling reactions of the bromo
analogue were then explored in order to gain a suitable access to a broad range of unnatural analogues. The key step of our
approach is a keto-aldehyde acyloin ring-closure followed by a Stiles carboxylation. © 2001 Elsevier Science Ltd. All rights
reserved.
Recently, members of the plant genus Aglaia (A. ellip-
tica, A. odorata and A. roxburghiana) were shown to
contain more than 20 novel insecticidal constituents of
the rocaglamide type featuring its unique cyclopentatet-
rahydrobenzofuran skeleton.1–4 These compounds
inhibit larval growth and are insecticidal to both varie-
gated cutworms and Asian armyworms. This interesting
biological activity prompted us to investigate a reliable
synthetic approach to the natural products and a broad
range of unnatural analogues. In order to evaluate the
contribution of the various functional groups to the
biological activity of 1, we focused on the derivatisation
of both aryl groups and the amide function (Fig. 1).
The starting point of our synthesis was the Michael
addition of benzofuranone 2 to cinnamaldehyde (3) as
reported by Tayler et al.8,9 yielding the desired syn-
arranged product 4 in 57% yield (Scheme 1).
The intramolecular pinacol coupling reaction of 4 using
reductive cyclisation procedures had been extensively
studied in the past8–10 and indeed following the litera-
ture, a multigram quantity of 7 was synthesised by
treatment of 4 with SmI2 followed by Parikh–Doering
oxidation (Scheme 2). However, the method was rather
elaborate and incompatible with substituents sensitive
to reduction, which were of high interest for our SAR
study.
Despite the existence of several synthetic approaches to
the carbon framework of 1,5–10 a shorter, more conver-
gent synthesis that allows an agrochemical application
was needed. We were able to realise this idea by apply-
ing a keto-aldehyde acyloin ring-closure step and a
Stiles11,12 carboxylation.
Therefore we planned to achieve the final annelation
step through an Umpolungs sequence. In fact Taylor et
al. reported a successful ring-closure of the dithiane
derivative of 4,7–9 but failed to hydrolyse it after-
wards.13 In light of these results, we favoured a
O
O
MeO
O
HO
HO
MeO
MeO
O
H
NMe2
2
3
OMe
3a
O
MeO
sites of interest
for SAR study
O
O
MeO
MeO
2
O
+
Lit.8,9
keto-aldehyde acyloin
condensation and Stiles
carboxylation
H
OMe
OMe
1
4
3
Figure 1.
* Corresponding author. Present address: Syngenta Crop Protection AG, WRO-1060.3.10, 4002 Basel, Switzerland; e-mail: markus.dobler@
syngenta.com
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)01807-X

8282
M. R. Dobler et al. / Tetrahedron Letters 42 (2001) 8281–8284
MeO
O
MeO
O
CHO
CHO
OMe
O
(i)
+
O
O
MeO
MeO
OMe
O
MeO
5
2
4
57%
19%
OMe
OMe
Scheme 1. Reagents and conditions: (i) (E)-cinnamaldehyde (3), triton B, THF, rt, 1 h.
boxylation of the ketoacid back to the parent ketone 7
occurred only to a minor extent. Evans-type directed
borane reduction of 9 completed our short synthesis of
the natural product 1 (Scheme 3).
cyanohydrin Umpolungs intermediate. Aldehyde 4 was
subjected to TMSCN to yield the cyanohydrin 8 in
quantitative yield. Formation of the acyloin 7 was
initiated by addition of LDA to 8. Subsequent depro-
tection of the resulting mixture with K2CO3 yielded 7 in
high overall yield as shown in Scheme 2.
Following the outlined protocol several unnatural ana-
logues were synthesised by either varying the Michael
donor or acceptor and through ketoamide formation
with different amines. The bromo analogue 11, synthe-
sised using 1015 as the Michael donor and
HN(MeO)Me to form the ketoamide (Fig. 2), was not
only of special interest for itself to explore its biological
activity, but was also our preferred template for the
following cross-coupling reactions (Scheme 4).
According to the published syntheses of 1 and its
derivatives,8–10 the introduction of the dimethylcarbox-
amido substituent requires at least a four-step sequence.
We aimed for a two-step process not requiring the
protection of the tertiary hydroxyl group by utilising
Stiles reagent11,12 for the direct carboxylation of the
acyloin 7. However we were aware of the fact, that
cyclopentanone derivatives were reported14 to be rather
sluggish substrates for magnesium chelate-mediated
carboxylation reactions. Gratifyingly, treatment of 7
with a 2-fold excess of a 2.5 M solution of magnesium
methylcarbonate in DMF at 100°C followed by acid
hydrolysis, resulted in the quantitative formation of the
desired b-ketoacid. The excess of reagent proved to be
critical in driving the reaction to completion. The crude
product was immediately converted to the ketoamide 9
by Py·BOP-mediated condensation. Competing decar-
The Pd-mediated cross-coupling reactions of the highly
functionalised bromo analogue 11, applying Buch-
wald’s protocol,16–19 worked surprisingly well. The
described reaction conditions, using ligand 15, turned
out to be superior to other ‘standard’ Suzuki and
Buchwald–Hartwig conditions described in the litera-
ture.16 The Suzuki reaction with ligand 15 proceeded at
room temperature, but was heated to 100°C to reach
completion. The desired coupling products 12 and 14
could be obtained in moderate to good yields.
HO
OMe
HO
O
MeO
(ii)
80%
O
(i)
OMe
OMe
HO
O
6
50%
CHO
OMe
O
O
MeO
MeO
(iv), (v)
73%
OMe
O
OTMS
CN
(iii)
4
7
OMe
quant.
OMe
O
MeO
8
OMe
Scheme 2. Reagents and conditions: (i) SmI2, anisole, 70°C, 15 min; (ii) Py·SO3, CH2Cl2, rt, 6 h; (iii) TMSCN, ZnI2, CH3CN,
benzene, rt, 12 h; (iv) LDA, THF, −78°C, 1 h; (v) K2CO3, MeOH, rt, 15 min.

M. R. Dobler et al. / Tetrahedron Letters 42 (2001) 8281–8284
8283
O
O
O
O
HO
OMe
HO
OMe
HO
OMe
HO
NMe2
NMe2
(i)-(iii)
70%
(iv)
O
O
95%
MeO
MeO
O
MeO
9
1
7
OMe
OMe
OMe
Scheme 3. Reagents and conditions: (i) Stiles reagent (2 equiv.), DMF, rt, 24 h; (ii) 6N HCl, 0°C, 15 min; (iii) HNMe2, Py·BOP,
CH2Cl2, rt, 16 h; (iv) Me4NBH(OAc)3, MeCN, AcOH, rt, 18 h.
O
HO
MeO
H
O
MeO
HO
N(MeO)Me
O
+
Br
O
MeO
O
steps
MeO
Br
10
3
11
Figure 2. The key intermediate 11.
O
O
HO
HO
HO
MeO
HO
MeO
N(MeO)Me
N(MeO)Me
(i)
41%
O
O
MeO
MeO
PCy2
12
11
N
Br
(iii)
(ii)
68%
HO
quant.
O
Me2N
15
O
O
HO
HO
MeO
MeO
HO
N(MeO)Me
N(MeO)Me
O
O
MeO
MeO
14
13
Scheme 4. Reagents and conditions: (i) morpholine, Pd2(dba)3 (5 mol%), 15, Cs2CO3 (1.5 equiv.), dioxane, 80°C, 16 h; (ii)
PhB(OH)2, Pd(OAc)2 (5 mol%), 15, CsF (1 equiv.), dioxane, 100°C, 24 h; (iii) H2, Pd/C (cat.), ethyl acetate, rt, 24 h.
Accordingly several C-3 and C-3a para-substituted aryl
analogues of 1 were synthesised and tested for their
insecticidal and antifungal activity.20 The detailed
results of this SAR study will be published elsewhere.
2. Nugroho, B. W.; Gussregen, B.; Wray, V.; Sitte, L.;
Bringmann, G.; Proksch, P. Phytochemistry 1997, 45,
1579–1585.
3. Nugroho, B. W.; Edrada, R. A.; Gussregen, B.; Wray,
V.; Witte, L.; Proksch, P. Phytochemistry 1997, 44, 1455–
1461.
4. Gussregen, B.; Fuhr, M.; Nugroho, B. W.; Wray, V.;
Witte, L.; Proksch, P. Z. Naturforsch., C: Biosci. 1997,
52, 339–344.
In summary, the shortest and most efficient route today
to the natural product and its aryl analogues has been
described. Especially the use of Stiles reagent led to a
considerable elegant improvement.
5. Trost, B. M.; Greenspan, P. D.; Yang, B. V.; Saulnier,
M. G. J. Am. Chem. Soc. 1990, 112, 9022–9024.
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2000, 41, 1913–1916.
7. Davey, A. E.; Taylor, R. J. K. J. Chem. Soc., Chem.
Commun. 1987, 1, 25–27.
References
1. Bohnenstengel, F. I.; Nugroho, B. W.; Schneider, C.;
Wray, V.; Witte, L.; Hung, P. D.; Kiet, L. C.; Proksch, P.
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M. R. Dobler et al. / Tetrahedron Letters 42 (2001) 8281–8284
8. Davey, A. E.; Schaeffer, M. J.; Taylor, R. J. K. J. Chem.
gave satisfactory spectral and analytical data. Selected
data: Compound 11 1H NMR l: 7.18–7.22 (m, 2H),
6.97–7.07 (m, 5H), 6.80–6.84 (m, 2H), 6.29 (d, J=1.9 Hz,
1H), 6.09 (d, J=2.1 Hz, 1H), 4.99 (dd, J=6.5, 1.5 Hz,
1H), 4.41 (d, J=14.0 Hz, 1H), 4.19 (dd, J=14.1, 6.5 Hz,
1H), 3.99 (m, 1H), 3.88 (s, 3H), 3.84 (s, 3H), 3.82 (s, 3H),
3.18 (s, 3H), 1.76 (s, 1H); ES-MS m/z 570 (M+), 572
(M+2).
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9. Davey, A. E.; Schaeffer, M. J.; Taylor, R. J. K. J. Chem.
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2598–2599.
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1
Compound 12 H NMR l: 7.05–7.15 (m, 5H), 6.93 (m,
13. Only the 3a-phenyl diastereoisomer was hydrolysed by
applying a wide range of published procedures to a 1:1
mixture of 3a- and 3b-phenyl diastereoisomers.
14. Rathke, M. W.; Tirpak, R. E.; Olson, S. J. Org. Chem.
1985, 50, 4877–4879.
15. Bruce, I.; Cederbaum, F.; Cooke, N. G.; Diorazio, L. J.;
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2000; p. 28.
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2H), 6.72 (d, J=9.1 Hz, 2H), 6.30 (d, J=1.9 Hz, 1H),
6.14 (d, J=2.1 Hz, 1H), 5.06 (dm, J=6.8 Hz, 1H), 4.47
(d, J=13.8 Hz, 1H), 4.26 (dd, J=14.2, 6.9 Hz, 1H), 4.09
(m, 1H), 3.94 (s, 3H), 3.88 (s, 3H), 3.86 (s, 3H), 3.81–3.85
(m, 4H), 3.20 (s, 3H), 3.13–3.07 (m, 4H), 1.71 (s, 1H);
ES-MS m/z 577 (M+1).
1
Compound 13 H NMR l: 7.08–7.26 (m, 5H), 6.97–7.00
(m, 3H), 6.84–6.90 (m, 2H), 6.29 (d, J=1.9 Hz, 1H), 6.13
(d, J=2.01 Hz, 1H), 5.06 (d, J=6.5 Hz, 1H), 4.48 (d,
J=14.0 Hz, 1H), 4.27 (dd, J=14.0, 6.5 Hz, 1H), 4.05 (m,
1H), 3.93 (s, 3H), 3.84 (s, 3H), 3.83 (s, 3H), 3.18 (s, 3H),
1.77 (s, 1H); ES-MS m/z 492 (M+1).
1
Compound 14 H NMR l: 7.24–7.51 (m, 9H), 7.00 (m,
3H), 6.91 (m, 2H), 6.31 (d, J=1.9 Hz, 1H), 6.12 (d,
J=2.0 Hz, 1H), 5.08 (dm, J=6.9 Hz, 1H), 4.49 (d,
J=13.6 Hz, 1H), 4.30 (dd, J=13.6, 6.9 Hz, 1H), 4.12 (m,
1H), 3.92 (s, 3H), 3.86 (s, 3H), 3.83 (s, 3H), 3.18 (s, 3H),
1.74 (s, 1H); ES-MS m/z 568 (M+1).
19. Suzuki, A. In Metal-Catalyzed Cross-Coupling Reactions;
Diederich, F.; Stang, J. P., Eds.; Wiley-VCH: New York,
1998; Chapter 2 and references cited therein.
20. All new compounds were completely characterised and