Synthesis of (±)-7-episordidin

Article abstract of DOI:10.1016/S0040-4039(01)02261-4

The stereoselective synthesis of (±)-7-episordidin, an aggregation pheromone from the male banana weevil, Cosmopolites sordidus Germar, is reported. The key step of this work is a regioselective rhodium(II)-catalyzed diazocarbonyl C-H insertion reaction that simultaneously generates three of the natural product's four stereocenters. The work reported herein also represents a formal synthesis of sordidin.

Full text of DOI:10.1016/S0040-4039(01)02261-4

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 737–739
Synthesis of (±)-7-episordidin
Duncan J. Wardrop* and Raymond E. Forslund
Department of Chemistry, University of Illinois at Chicago, 845 West Taylor Street, Chicago, IL 60607-7061, USA
Received 19 November 2001; accepted 27 November 2001
Abstract—The stereoselective synthesis of (±)-7-episordidin, an aggregation pheromone from the male banana weevil, Cosmopo-
lites sordidus Germar, is reported. The key step of this work is a regioselective rhodium(II)-catalyzed diazocarbonyl CꢀH insertion
reaction that simultaneously generates three of the natural product’s four stereocenters. The work reported herein also represents
a formal synthesis of sordidin. © 2002 Elsevier Science Ltd. All rights reserved.
5
d
3
The exploitation of symmetry as a means to simplify
the synthesis of natural products has found consider-
able success. In this regard, we recently reported an
approach to the bicyclic acetal core of the zaragozic
acids which hinged upon the desymmetrization of a
collected in Kenya. Field trials in Costa Rica have
shown that traps baited with mixtures of 1 have a high
capture rate and offer a viable method for controlling
the population of this pest. Since the natural abundance
of these pheromones is very low (1500 weevils yield ca.
1
5a
2
-diazoacetyl-1,3-dioxane precursor through dirhodium-
1
00 mg), synthesis provides the only practical method
2
(
II)–carbenoid mediated CꢀH insertion. Herein we
for securing quantities of 1. All reported syntheses of
the sordidin family involve formation of the acetal
moiety through acid-catalyzed cyclization of the corre-
report the extension of this strategy to the synthesis of
the insect pheromones (±)-sordidin (1a) and (±)-7-
episordidin (1b).
5
sponding acyclic keto-1,3-diols. Under these condi-
tions, however, the C-7 stereocenter readily epimerizes
and mixtures of diastereomers are obtained. To date,
no stereoselective syntheses of 1 have been reported.
As outlined in Scheme 1, we envisioned 1b arising from
ketone 8 which could, in turn, be accessed through the
metal-catalyzed intramolecular CꢀH insertion of sym-
metric diazoketone 7. This strategy would enable us to
generate three of the four stereocenters centers present
in the target molecule in a single transformation. With
regards to the regioselectivity of this process, we
expected insertion into the axial Cꢀ4/6 CꢀH bonds of 7
The banana weevil, Cosmopolites sordidus Germar, is a3
widespread and highly destructive pest of banana trees.
The impact on crop production is particularly acute
since current methods for controlling this insect are
hampered by its longevity, propensity to reproduce,
and resistance to most classes of insecticides. In 1993,
Budenberg first reported evidence that the male of this
4
species releases a volatile aggregation pheromone. The
major component of this mixture, 1-ethyl-3,5,7-
trimethyl-2,8-dioxabicyclo[3.2.1]octane (1a), was subse-
quently isolated, identified, and synthesized by Ducrot
5a
and co-workers who gave it the trivial name sordidin.
More recently, Kitching has shown that, in addition to
1
a, 7-episordidin (1b) is also released by C. sordidus
5d
from Australia, while Oehlschlager reported that all
four isomers of sordidin (1a–d) are produced by weevils
*
Corresponding author. Tel.: 1-312-355-1035; fax: 1-312-996-0431;
e-mail: wardropd@uic.edu
Scheme 1.
0
040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)02261-4

7
38
D. J. Wardrop, R. E. Forslund / Tetrahedron Letters 43 (2002) 737–739
a
to be highly favored since these bonds are activated by
the adjoining ether oxygens. While our initial synthetic
Table 1. Intramolecular CꢀH Insertion of diazoketone 7
6
efforts focused on the preparation of 6 through acetal-
ization of methyl 2-oxopropylbutyrate and cis-2,4-pen-
7
tanediol (2), all attempts to achieve this goal using a
8
variety of conditions led to the decomposition of 2.
Entry
Catalystb
Isolated yield (%)c,d
ee (%)e,f
8
9
8
9
g
1
2
3
4
5
6
7
8
Rh (OAc)
58
36
31
17
11
15
19
7
28
10
0
5
8
30
20
17
–
20
7
B5
B5
–
–
10
–
B5
7
–
–
–
2
4
1
1a,b
Rh (PTPA)
2
4
Accordingly, we opted to follow a stepwise approach to
11c
Rh (DOSP)
2
4
2
6
(Scheme 2). Thus, 2 was treated with trimethyl
11c
Rh (TBSP)
2
4
1
1d
orthopropionate in the presence of a catalytic amount
of p-TsOH to generate the ortho ester 3, which was
immediately treated in situ with trimethylsilyl cyanide
and BF ·Et O. Upon stirring at room temperature for
Rh (MEPY)
2
4
h
Cu(acac)2
h
Cu(tfacac)
–
–
2
h
Cu(hfacac)2
3
2
1
6 h, cyanation proceeded with retention of configura-
a
Unless otherwise noted, reactions were carried as follows: a solution
of 7 (50 mg, 0.24 mmol) in CH Cl was added via syringe pump to
a solution of catalyst (2 mol%) in CH Cl (0.015 M) at reflux, over
tion to furnish 2-cyano-1,3-dioxane 4 as a single
diastereomer. Hydrolysis of this nitrile with alkaline
hydrogen peroxide then gave 5 in excellent overall yield
from 2. The relative configuration of 5 was confirmed
by a NOESY experiment, which revealed correlations
between the axial protons at Cꢀ4 and Cꢀ6 and the
amide protons.
9
2
2
2
2
2
0 h.
b
Rh (PTPA) was prepared according to the method of Taber (see
2
4
Ref. 11b). The other catalysts are available commercially.
Yields after purification by flash chromatography.
The mass balance was due to polar, intractable material.
Enantiomeric excesses were determined by capillary GC analysis
prior to purification using a J&W cyclodex-B column.
Absolute configuration was not determined.
c
d
e
Although the prospect of now converting 5 to the
corresponding methyl ester 6 was somewhat daunting,
Brocchetta and co-workers recently described the use of
dimethylformamide dimethyl acetal (DMF–DMA) as a
mild reagent for this traditionally difficult transforma-
tion. Gratifyingly, upon heating 5 and DMF–DMA
in anhydrous methanol at 110°C in a sealed tube for 48
h, ester 6 was formed in 97% yield. Diazoketone 7 was
prepared in 94% overall yield by a sequence of saponifi-
cation, mixed-anhydride formation and in-situ treat-
ment with diazomethane. We now proceeded to
evaluate a range of catalysts for the cyclization of 7; the
results of this study are summarized in Table 1. In all
cases diazo decomposition of 7 led to the formation of
f
g
h
Reaction carried out on 8.5 mmol scale.
4
mol% catalyst used.
1
0
anomalous product has recently been reported by a
number of groups
2,12
and is believed to arise from
intramolecular hydride transfer to the initially formed
metallocarbenoid followed by cyclization of the result-
ing zwitterionic species. As expected, products arising
from insertion into the CꢀH bonds of the ethyl chain
were not observed under any conditions. It is clear
from Table 1 that Rh (OAc) (entry 1) was the most
efficient catalyst for effecting cyclization while chiral
dirhodium(II) tetracarboxylates (entries 2–4) and tetra-
carboxyamides (entry 5) failed to provide improvement
in efficiency or useful levels of asymmetric induction.
Copper salts (entries 6–8) were also investigated but
gave only modest yields of CꢀH insertion. The more
electrophilic copper carbenoids appear to favor the
formation of 9 through the hydride abstraction
pathway.
2
4
8
, the product of transannular CꢀH insertion, as well as
bicyclic enol ether 9. The formation of this type of
6e
Continuing with our synthesis of (±)-1b, we now
attempted to install the remaining stereocenter at Cꢀ7
through a sequence of olefination and reduction. How-
ever, 10, the a,b-unsaturated acetal generated upon
methylenation of 8, proved to be highly unstable and
13
Scheme 2. Reagents and conditions: (a) CH CH C(OCH ) ,
we were unable to isolate this material. Fortunately,
addition of methylmagnesium iodide to 8 proceeded
very efficiently to provide 11 as a single diastereomer
(Scheme 3). After considerable investigation, we found
that this tertiary alcohol could be most effectively
deoxygenated to generate 1b using the method of Dolan
3
2
3 3
p-TsOH (2 mol%), CH Cl , rt, 16 h; (b) Me SiCN, BF ·Et O
2
2
3
3
2
(
10 mol%), CH Cl, rt, 16 h, 99%; (c) NaOH, H O , EtOH,
2
2
2
reflux, 3 h, 91%; (d) DMF–DMA (3 equiv.), MeOH, 110°C
sealed tube), 48 h, 97%; (e) NaOH, H O, THF, reflux, 16 h,
(
2
9
8%; (f) (i) Et N, i-BuOCOCl, CH Cl −20°C, 5 min. (ii)
3 2 2,
14
CH N , Et O, −20°C to rt, 16 h, 96%.
and Macmillan. Thus, sequential treatment of 11 with
2
2
2

D. J. Wardrop, R. E. Forslund / Tetrahedron Letters 43 (2002) 737–739
739
zalez, L. M.; Alpizar, D.; Falles, M.; Budenberg, W. J.;
Ahuya, P. J. Chem. Ecol. 1997, 23, 1145–1161.
. Budenberg, W. J.; Ndiege, I. O.; Karago, F. W. J. Chem.
Ecol. 1993, 19, 1905–1916.
. Syntheses of 1: (a) Beauhaire, J.; Ducrot, P.-H.; Malosse,
C.; Ndiege, I. O.; Otieno, D. O. Tetrahedron Lett. 1995,
4
5
36, 1043–1046; (b) Ndiege, I. O.; Jarayaman, S.;
Oehlschlager, A. C.; Gonzalez, L. M.; Alpizar, D.; Falles,
M. Naturwissenschaften 1996, 83, 280–282; (c) Mori, K.;
Nakayama, T.; Takikawa, H. Tetrahedron Lett. 1996, 37,
3741–3744; (d) Fletcher, M. T.; Moore, C. J.; Kitching,
W. Tetrahedron Lett. 1997, 38, 3475–3476; (e) Nakayama,
T.; Mori, K. Liebigs Ann. 1997, 1075–1080.
6
. For reviews concerning CꢀH insertion, see: (a) Adams, J.;
Spero, D. Tetrahedron 1991, 47, 1765–1808; (b) Padwa,
A.; Austin, D. J. Angew. Chem., Int. Ed. Engl. 1994, 33,
1797–1815; (c) Taber, D. F. Methods of Organic Chem-
istry (Houben-Weyl); Helmchen, G.; Hoffmann, R. W.;
Mulzer, J.; Schaumann, E. Eds.; Georg Thieme: Stutt-
gart, 1995, Vol. E21a, pp. 1127–1148; (d) Ye, T.; McKer-
vey, A. Chem. Rev. 1994, 94, 1091–1160; (e) Sulikowski,
G. A.; Cha, K. L.; Sulikowski, M. M. Tetrahedron:
Asymmetry 1998, 9, 3145–3169.
Scheme 3. Reagents and conditions: (a) Ph PꢁCH , THF, rt,
3
2
1
6 h; (b) MeMgI, Et O, 0°C, 3 h, 98%; (c) n-BuLi, THF,
2
−
78°C, 5 min; (ii) ClCOCO Me, −78 to 0°C, 2 h, 78%; (d)
2
Bu SnH (1.5 equiv.), AIBN (1.5 equiv.), PhH, reflux, 16 h,
3
5
0%; (e) p-TsOH, CH Cl (Ref. 5e).
2 2
n-BuLi and methyl oxalyl chloride gave 12 which, after
purification, was heated with Bu SnH and AIBN in
3
benzene for 16 h. The reaction mixture was then con-
centrated by distillation (1 atm) and the residue purified
7
. Diol 2 was separated from a commericially available
mixture of cis- and trans-2,4-pentanediol: Pritchard, J.
G.; Vollmer, R. L. J. Org. Chem. 1964, 28, 1545–1549.
. Ziegler, T. Top. Curr. Chem. 1997, 186, 203–229.
. Nader, F. W.; Elliel, E. L. J. Am. Chem. Soc. 1970, 92,
by radial chromatography (pentane/Et O, SiO ) to
2
2
provide (±)-7-episordidin (1b) as the sole reduction
8
9
1
5
product. The moderate yield of this final transforma-
tion is primarily a reflection of the volatility of 1b
which leads to significant losses during isolation. A
comparison of the spectral and physical properties of
3050–3055.
1
1
0. Anelli, P. L.; Brocchetta, M.; Palano, D.; Visigalli, M.
Tetrahedron Lett. 1997, 38, 2367–2368.
1. (a) Hashimoto, S.; Watanbe, N.; Sato, T.; Shiro, M.;
Ikegami, S. Tetrahedron Lett. 1993, 34, 5109–5112; (b)
Taber, D. F.; Malcolm, S. C. J. Org. Chem. 2001, 66,
1
13
our material (MS, IR and H and C NMR) with those
5
e
reported by Mori indicated a close match.
In summary, we report the first stereoselective synthesis
of 7-episordidin (1b), which is accomplished in nine
steps starting from cis-2,4-pentanediol (2), with an
overall yield of 18%. Since the conversion of (±)-7-
episordidin (1b) to sordidin (1a) has previously been
9
44–953; (c) Davies, H. M. L.; Bruzinki, P. R.; Lake, D.
H.; Kong, N.; Fall, M. J. J. Am. Chem. Soc. 1996, 118,
897–6907; (d) Doyle, M. P.; Winchester, W. R.; Hoorn,
6
J. A. A.; Lynch, V.; Simonsen, S. H.; Ghosh, R. J. J.
Am.. Chem. Soc. 1993, 115, 9968–9978.
5
e
described by Mori, the work reported here also repre-
1
1
2. (a) Doyle, M. P.; Dyatkin, A. B.; Autry, C. L. J. Chem.
Soc., Perkin Trans. 1 1995, 619–621; (b) Clark, J. S.;
Dossetter, A. G.; Russel, C. A.; Whittingham, W. G. J.
Org. Chem. 1997, 62, 4910–4911; (c) White, J. D.; Hrn-
ciar, P. J. Org. Chem. 1999, 64, 7223–7271.
sents a formal synthesis of sordidin (1a).
Acknowledgements
3. Walker, L. F.; Connolly, S.; Wills, M. Tetrahedron Lett.
1
998, 39, 5273–5276.
We thank the National Institutes of Health (GM59157-
14. Dolan, S. C.; MacMillan, J. J. Chem. Soc., Chem. Com-
0
5
1), the National Science Foundation (NSF-DUE-98-
62167), and the University of Illinois at Chicago for
mun. 1985, 1588–1589.
15. 7-Episordidin (1b): IR wmax (film) 2961, 2931, 2887, 1475,
−
1 1
financial support.
1375, 1195, 1163, 1094, 992 cm ; H NMR (500 MHz,
CDCl ) l 4.10–4.05 (m, 1 H), 2.25–2.22 (m, 1 H), 1.99 (t,
3
J=12.5 Hz, 1 H), 1.75–1.62 (m, 1 H), 1.57–1.49 (m, 1 H),
1.49–1.41 (m, 2 H), 1.40–1.37 (m, 1 H), 1.32 (s, 3 H), 1.79
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11
21
2