First synthesis of nonracemic (R)-(+)-myrmicarin 217

Full text of DOI:10.1021/jo9918697

2824
J . Org. Chem. 2000, 65, 2824-2826
Ch a r t 1
F ir st Syn th esis of Non r a cem ic
(R)-(+)-Myr m ica r in 217
Babak Sayah, Nadia Pelloux-Le´on, and Yannick Valle´e*
LEDSS, Universite´ J oseph Fourier - CNRS,
B.P. 53, 38041 Grenoble, France
Received December 6, 1999
Although ants (Formicidae) have been known to pro-
duce various monocyclic and bicyclic alkaloids for a long
time,1 it is only recently that tricyclic and oligocyclic
alkaloids were found in their poison glands. Such com-
pounds were discovered by Schro¨der et al. in the secre-
tions of Myrmicaria ants, a genus of african Myrmicinae
(M. striata, M. eumenoides, and M. opaciventris), and
named myrmicarins (Chart 1). Myrmicarins 217 and
215A-C are simple pyrrolo[2,1,5-cd]indolizidines. In
myrmicarin 217 (M217) the substituents on the pyrrole
ring are an ethyl and a propyl group.2 For M215A,B the
propyl group is replaced by a propenyl substituent ((Z)
for M215A, (E) for M215B). M215C is probably formed
by air oxidation of M217. M430 can be regarded as a
dimer of M215.3 It is composed of a complex four-ring
system and a pyrroloindolizidine subunit. M663 possesses
a trimeric structure, also including a pyrroloindolizidine
moiety.4 Another compound, M645, has been tentatively
assigned a trimeric structure containing two pyrroloin-
dolizidine moieties. All these compounds can be postu-
lated to derive biochemically from two other myrmicarins,
M237A,B, which are epimers at position 5, but in which
position 8a is known to be (R). Thus, even though the
absolute configuration of M215A-C, M217, M430, and
M663 are not known, it is probable that stereogenic
centers of these pyrroloindolizidines also have a (R)
configuration.
NaBH3CN in the presence of ZnI2 to reduce the ketone
function into a methylene group9 and LiAlH4 in THF to
reduce the ester function into an alcohol. Using these
conditions, compound 3 was obtained in 72% yield from
2. At this stage, one further carbon atom was to be
introduced. The alcohol 3 was transformed into a sul-
fonate, which upon treatment with cyanide anions gave
nitrile 4. Interestingly, when this nucleophilic substitu-
tion was carried out with a triflate group, the yield of
this two-step homologation was 55%, while a 90% yield
was obtained when the leaving group was a mesylate.
Chiral GC analysis of compound 4 showed that it was
97% enantiomerically pure. Hydrolysis of the nitrile
group was performed in 90% yield using an aqueous
sodium hydroxide solution in methanol. Cyclization of the
corresponding acid 5 to the tetrahydro-1H-pyrroloindol-
izine 6 was achieved in poor yield (20%) with phosphorus
pentaoxide in toluene.10 A more efficient process (57%
yield) involved the formation of a mixed anhydride
followed by ring closure at 40 °C in CH2Cl2 in the
presence of BF3‚OEt2. Afterward, a Friedel-Crafts acy-
lation was carried out to introduce an acetyl group on
C4 of the pyrrole ring,11 and as expected, due to the
carbonyl group at the C2 position, the reaction was totally
regioselective. Once more, two carbonyl groups had to be
reduced. To our surprise, the substrate 7 underwent
polymerization when the previously used conditions
(NaBH3CN, ZnI2) were employed. Attempts using the
Syntheses of M237A,B have been reported,5,6 as well
as a synthesis of racemic M217.7 Here we present the
first synthesis of nonracemic (R)-(+)-myrmicarin 217 and
of its enantiomer.
We choose L and D glutamic acids to introduce the
stereogenic center of (R)-M217 and of its enantiomer.
According to a procedure described by J efford et al.,8 the
diethyl ester of D-glutamic acid was condensed with
tetrahydro-2,5-dimethoxyfuran to give the pyrrole 1
(Scheme 1) which when treated by BBr3 gave the bicyclic
compound 2. A first attempt to reduce simultaneously
the two carbonyl groups of this ketoester, using LiAlH4,
failed. A two-step strategy was then envisaged using
* To whom correspondence should be addressed. e-mail:
Yannick.Vallee@ujf-grenoble.fr.
(1) Ho¨lldobler, B.; Wilson, E. O. The Ants; The Belknap Press of
Harvard University Press: Cambridge, MA, 1990; pp 227-297.
(2) Schro¨der, F.; Franke, S.; Francke, W.; Baumann, H.; Kaib, M.;
Pasteels, J . M.; Daloze, D. Tetrahedron 1996, 52, 13539.
(3) Schro¨der, F.; Sinnwell, V.; Baumann, H.; Kaib, M. J . Chem. Soc.,
Chem. Commun. 1996, 2139.
(4) Schro¨der, F.; Sinnwell, V.; Baumann, H.; Kaib, M.; Francke, W.
Angew. Chem., Int. Ed. Engl. 1997, 36, 77.
(5) Thanh, G. V.; Ce´le´rier, J . P.; Lhommet, G. Tetrahedron Lett.
1999, 40, 3713.
(6) Francke, W.; Schro¨der, F.; Walter, F.; Sinnwell, V.; Baumann,
H.; Kaib, M. Liebigs Ann. 1995, 965.
(7) Schro¨der, F.; Francke, W. Tetrahedron 1998, 54, 5259.
(8) J efford, C. W.; Sienkiewicz, K.; Thornton, S. R. Helv. Chim. Acta
1995, 78, 1511.
(9) J efford, C. W.; Sienkiewicz, K.; Thornton, S. R. Tetrahedron Lett.
1994, 35, 4759.
(10) Box, S. J .; Corbett, D. F. Tetrahedron Lett. 1981, 22, 3293.
(11) Anderson, H. J .; Loader, C. E.; Foster, A. Can. J . Chem. 1980,
58, 2527.
10.1021/jo9918697 CCC: $19.00 © 2000 American Chemical Society
Published on Web 04/06/2000

Notes
J . Org. Chem., Vol. 65, No. 9, 2000 2825
characterized by 1H and 13C NMR spectroscopy.1H NMR (200
MHz; CDCl3) δ (ppm) 1.26 (t, 3H, J ) 6.8 Hz, Me), 1.78 (m, 2H,
H-6), 2.19 (m, 2H, H-7), 2.79 (m, 2H, H-8), 4.21 (q, 2H, J ) 6.8
Hz, O-CH2), 4.70 (m, 1H, H-5), 5.84 (m, 1H, H-2), 6.13 (m, 1H,
H-1), 6.49 (m, 1H, H-3); 13C NMR (50 MHz; CDCl3) δ 14.1 (Me),
18.8, 23.1, 27.2, 57.2, 61.3, 104.3 (C-2), 108.2 (C-1), 119.2 (C-3),
128.6, 170.8 (CO).
Sch em e 1
The previous crude ester was then dissolved in dry THF (50
mL) and stirred under N2 at 0 °C. A suspension of LiAlH4 (0.608
g) in THF (40 mL) was then added, and the resulting mixture
was allowed to warm to room temperature. After stirring for 2
h at room temperature, the solution was cooled to 0 °C and
quenched with a saturated aqueous solution of Na2SO4. After
filtration, the organic layer was dried over MgSO4 and concen-
trated. Column chromatography on silica gel (CH2Cl2/AcOEt, 9:1)
of the residue yielded 1.09 g (72% from 2) of 3. [R]20 ) -33.7 (c
D
1.00, CH2Cl2); IR (NaCl) 3485 (OH) cm-1
;
1H NMR (200 MHz;
CDCl3) δ (ppm) 1.65-2.06 (m, 4H, H-6 and H-7), 2.71 (m, 2H,
H-8), 3.77 (m, 3H, CH2O and OH), 4.08 (m, 1H, H-5), 5.81 (m,
1H, H-2), 6.10 (m, 1H, H-1), 6.70 (m, 1H, H-3); 13C NMR (50
MHz; CDCl3) δ (ppm) 18.7 (C-7), 23.1 (C-8), 25.3 (C-6), 55.2
(CH2O), 65.1 (C-5), 103.5 (C-2), 107.2 (C-1), 117.1 (C-3), 129.3.
MS (EI) 151 (M.+). Anal. Calcd for C9H13NO: C, 71.48; H, 8.66;
N, 9.26. Found: C, 71.50; H, 8.81; N, 9.11.
(5R)-(5,6,7,8-Tetr a h yd r oin d olizin -5-yl)a ceton itr ile (4). A
solution of methanesulfonyl chloride (1.53 mL, 20 mmol) was
gradually added to a stirred solution of 3 (1.51 g, 10 mmol) in
dry dichloromethane (20 mL) and pyridine (5.6 mL) at 0 °C. After
13 h at room temperature, the mixture was poured into ice-
water and stirred for an additional 30 min at room temperature.
The two-phase system was extracted with CH2Cl2. The combined
organic layers were washed subsequently with aqueous HCl (1
N), NaHCO3 (5%), and brine and then dried, filtered, and
evaporated to yield quantitatively the corresponding methane-
1
sulfonate as a colorless oil. H NMR (200 MHz; CDCl3) δ (ppm)
1.76-2.12 (m, 4H, H-6 and H-7), 2.71 (m, 2H, H-8), 2.82 (s, 3H,
CH3), 4.30 (m, 3H, CH2O, and H-5), 5.79 (m, 1H, H-2), 6.09 (m,
1H, H-1), 6.64 (m, 1H, H-3).
Wolff-Kishner reduction also failed. Finally, it was found
that LiAlH4 efficiently reduced simultaneously the two
ketone functions into methylene groups (60% yield).
Introduction of a propionyl substituent in the last free
position of the pyrrole ring was necessary to complete
the synthesis. The best result was obtained with a
Vilsmeier-type reagent (prepared by the reaction of N,N-
dimethylpropionamide with POCl3) which reacted with
compound 8 to provide the ketone 9 in reasonable yield.12
The last step of the synthesis was the reduction of the
ketone function by LiAlH4 (yield: 60%).
As previously noticed by Schro¨der et al., we observed
that M217 is readily oxidized by air into M215C. How-
ever, M217 can be preserved from oxidation by storing
under a nitrogen atmosphere. The overall yield of
(R)-M217 from pyrrole 1 was 7.5%. Its ee, determined
by chiral gas chromatography, was found to be 98% and
its [R]D was +88 (c 1, CH2Cl2). Similarly, (S)-ent-M217
was obtained from L-glutamic acid.
The obtained crude methanesulfonate and sodium cyanide
(1.47 g, 30 mmol) were dissolved in DMF (20 mL). The resulting
mixture was heated for 15 h at 90 °C, cooled, and then poured
into water (20 mL). Extraction with ether followed by washing,
drying (MgSO4), and evaporation of the solvent gave a residue
which was purified by column chromatography on silica gel (CH2-
Cl2). The nitrile (1.44 g, 90% from 3) was obtained. [R]20D ) +54.5
(c 0.20, CH2Cl2); IR (NaCl) 2242 (CN), 2843, 2928, 3105 cm-1
;
1H NMR (200 MHz; CDCl3) δ (ppm) 1.72-2.31 (m, 4H, H-6 and
H-7), 2.28 (m, 4H, CH2CN and H-8), 4.38 (m, 1H, H-5), 5.83 (m,
1H, H-2), 6.16 (m, 1H, H-1), 6.63 (m, 1H, H-3); 13C NMR (50
MHz; CDCl3) δ (ppm) 18.3, 23.1, 24.7, 28.5, 50.6 (C-5), 104.7 (C-
2), 108.8 (C-1), 116.8 (C-3), 116.9 (CN), 129.1. MS (EI) 160 (M.+).
Anal. Calcd for C10H12N2: C, 74.96; H, 7.54; N, 17.48. Found: C,
74.66; H, 7.53; N, 17.11. The ee’s of isolated nitrile 4 (97%) and
of its enantiomer (96%) were determined by gas chromatography
on a chiral capillary column (hydrodex b cyclodextrin Type 3
(neutral) 25 m × 0.25 mm Macherey Nagel A.G.).
(5R)-(5,6,7,8-Tet r a h yd r oin d olizin -5-yl)a cet ic Acid (5).
Nitrile 4 (1.6 g, 10 mmol) was added to a mixture of aqueous
sodium hydroxide (25%, 70 mL) and methanol (200 mL). The
solution was stirred under reflux for 6 h, cooled to 0 °C, and
then washed twice with CH2Cl2. The aqueous layer was acidified
to pH 5 with 2 N aqueous hydrochloric acid. Ethyl acetate and
brine were then added. The organic layer was separated, dried
over MgSO4, and evaporated to give the desired acid as a yellow
Exp er im en ta l Section
All commercial solvents were distilled before use. Tetrahy-
drofuran (THF) was distilled from sodium benzophenone ketyl
under nitrogen atmosphere. Column chromatography purifica-
tions were carried out using silica gel (70-230 mesh).1H NMR
and 13C NMR were recorded at 200 and 50 MHz, respectively.
Peak assignments were determined using DEPT and two-
dimensional experiments.
(5R)-(5,6,7,8-Tetr a h yd r oin d olizin -5-yl)m eth a n ol (3). A
solution of 2 (2.03 g, 10 mmol) in dry CH2Cl2 (30 mL) was added
to a suspension of NaBH3CN (0.628 g, 15 mmol) and ZnI2 (10
mmol) in dry CH2Cl2 (30 mL). The resulting mixture was
refluxed for 150 min and then poured onto crushed ice. After
decantation the organic layer was dried over MgSO4 and
concentrated to give the corresponding indolizine which was
oil (1.61 g, 90% yield). [R]20 ) +12.5 (c 0.2, CH2Cl2); IR (NaCl)
D
3420 (OH) cm-1; 1H NMR (200 MHz; CDCl3) δ (ppm) 1.71-2.20
(m, 4H, H-6 and H-7), 2.68-3.09 (m, 4H, CH2CO and H-8), 4.52
(m, 1H, H-5), 5.80 (m, 1H, H-2), 6.12 (m, 1H, H-1), 6.59 (m, 1H,
H-3), 10.05 (bs, 1H, OH); 13C NMR (50 MHz; CDCl3) δ (ppm)
18.5, 23.2, 28.9, 41.1, 50.6 (C-5), 104.7 (C-2), 108.1 (C-1), 117.1
(C-3), 129.2, 176.7 (CO2H). MS (EI) 179 (M˘+).
(7a R)-5,6,7,7a -Tetr a h yd r o-1H-p yr r olo[2,1,5-cd ]in d olizin -
2-on e (6). Triethylamine (6.95 mL, 50 mmol) was added to a
solution of compound 5 (1.79 g, 10 mmol) in dry THF (20 mL).
The solution was cooled to 0 °C, and ethyl chloroformate (1.92
mL, 20 mmol) was added dropwise. The reaction mixture was
stirred at 0 °C for 40 min. The solvent was removed, and the
(12) Lehr, M. J . Med. Chem. 1997, 40, 3381.

2826 J . Org. Chem., Vol. 65, No. 9, 2000
Notes
crude solid was dissolved in dry ether. Triethylamine hydro-
chloride was removed by filtration. The filtrate was then
evaporated to give the crude mixed anhydride which was
characterized by 1H NMR spectroscopy. 1H NMR (200 MHz;
CDCl3) δ (ppm) 1.37 (t, 3H, J ) 7.2 Hz, CH3), 1.79-2.17 (m,
4H, H-6 and H-7), 2.73-3.12 (m, 4H, H-8 and CH2CO), 4.29 (q,
2H, J ) 7.2 Hz, CH2O), 4.38 (m, 1H, H-5), 5.82 (m, 1H, H-2),
6.13 (m, 1H), 6.58 (m, 1H, H-3).
dried and evaporated. Column chromatography on silica gel
(pentane/CH2Cl2, 9:1) of the residue gave 8 (259 mg, yield: 60%).
[R]20 ) +82.2 (c 0.50, CH2Cl2). 1H NMR (200 MHz; CDCl3) δ
D
(ppm) 1.17 (t, 3H, J ) 7.5 Hz, CH3), 1.21-1.44 (m, 1H, H-7),
1.68-1.86 (m, 1H, H-6), 1.89-2.17 (m, 3H, H-1, H-6 and H-7),
2.36-2.67 (m, 4H, CH2Me, H-5 and H-1), 2.70-2.83 (m, 3H, H-5
and 2 H-2), 3.85 (m, 1H, H-7a), 5.68 (s, 1H, H-3). 13C NMR (50
MHz; CDCl3) δ (ppm) 15.6 (CH3), 19.6 (CH2), 20.1 (C-5), 22.3
(C-6), 25.2 (C-2), 29.7 (C-7), 37.2 (C-1), 55.2 (C-7a), 98.7 (C-3),
118.6 (C-2a), 122.7 (C-4), 130.8 (C-4a). MS (EI) 175 (M˘+). Anal.
Calcd for C12H17N: C, 82.23; H, 9.77; N, 7.99. Found: C, 82.12;
H, 9.44; N, 7.68.
The obtained anhydride was dissolved in dry CH2Cl2 (20 mL)
and added dropwise (40 min) at 40 °C to a solution of BF3‚OEt2
(6.33 mL, 50 mmol) in dry CH2Cl2 (100 mL). The solution was
stirred under reflux for 3 h and then cooled. Water was added,
and after decantation and separation, the aqueous layer was
extracted twice with CH2Cl2. The combined organic layers were
dried (MgSO4) and evaporated. The crude residue was purified
by chromatography on silica gel (CH2Cl2/AcOEt, 9:1) to yield
(4a R)-1-(1-Eth yl-3,4,4a ,5,6,7-h exa h yd r op yr r olo[2,1,5-cd ]-
in d olizin -2-yl)p r op a n on e (9). A solution of 8 (200 mg, 1.14
mmol) in dry toluene (10 mL) was added at 90 °C to a mixture
of N,N-dimethylpropionamide (0.136 mL, 1.254 mmol) and
POCl3 (0.117 mL, 1.254 mmol) in toluene (5 mL). The resulting
mixture was stirred for 3 h. Sodium acetate (3 g) in water (10
mL) was then added at 90 °C, and the reaction was carried on
for 15 min. The solution was cooled to room temperature, diluted
with water, and extracted with CH2Cl2. The organic layer was
dried (MgSO4) and evaporated. The residue was purified by
chromatography on silica gel (CH2Cl2) to give compound 9 (179
compound 6 (0.917 g, 57%). [R]20 ) +83.8 (c 0.50, CH2Cl2); IR
D
(NaCl) 1673 (CO) cm-1
;
1H NMR (200 MHz; CDCl3) δ (ppm)
1.46-1.60 (m, 1H, H-7), 1.76-2.08 (m, 1H, H-6), 2.14-2.25 (m,
2H, H-6 and H-7), 2.69-3.11 (m, 4H, H-1 and H-5), 4.29 (m,
1H, H-7a), 6.17 (d, 1H, J ) 4.1 Hz, H-4), 6.67 (d, 1H, J ) 4.1
Hz, H-3). 13C NMR (50 MHz; CDCl3) δ (ppm) 20.3 (C-6), 20.4
(C-5), 27.8 (C-7), 47.0 (C-1), 51.2 (C-7a), 108.3 (C-4), 111.9 (C-
3), 127.4, 132.3, 186.3 (CO). MS (EI) 161(M˘+). Anal. Calcd for
C10H11NO: C, 74.50; H, 6.87; N, 8.68. Found: C, 74.75; H, 6.81;
N, 8.65.
mg, 68% yield). [R]20 ) +64.8 (c 0.50, CH2Cl2). IR (NaCl) 1648
D
(CO) cm-1
;
1H NMR (200 MHz; CDCl3) δ (ppm) 1.10-1.17 (m,
6H, 2 CH3), 1.25-1.38 (m, 1H, H-5), 1.70-1.77 (m, 1H, H-6),
2.02-2.18 (m, 3H, H-4, H-5 and H-6), 2.45-2.73 (m, 7H, 2 H-7,
H-4 and 2 CH2), 2.90-3.05 (m, 2H, H-3) 3.80-3.90 (m, 1H, H-4a).
13C NMR (50 MHz; CDCl3) δ (ppm) 8.5 (CH3), 15.2 (CH3), 19.1,
19.4 (C-7), 22.1 (C-6), 28.1 (C-2), 29.4 (C-5), 34.0 (CH2), 35.9
(C-4), 55.9 (C-4a), 115.9, 121.0, 124.7, 137.7, 196.3 (CO). MS (EI)
231 (M‚+). Anal. Calcd for C15H21NO: C, 77.88; H, 9.15; N, 6.05.
Found: C, 77.62; H, 9.19; N, 6.05.
(7a R)-4-Acetyl-5,6,7,7a -tetr a h yd r o-1H-p yr r olo[2,1,5-cd ]-
in d olizin -2-on e (7). A solution of ketone 6 (500 mg, 3.10 mmol)
in CH2Cl2 (5 mL) was added to a suspension of aluminum
chloride (1.53 g, 11.49 mmol) in dry CH2Cl2 (20 mL) and acetyl
chloride (0.288 mL, 4.037 mmol). The resulting mixture was
refluxed for 2 h, poured onto crushed ice, and stirred until
melted. The layers were separated, and the aqueous one was
extracted three times with CH2Cl2. The combined organic layers
were dried (MgSO4) and evaporated. Column chromatography
on silica gel (CH2Cl2/AcOEt, 9:1) of the residue gave pure
(4a R)-1-E t h yl-3,4,4a ,5,6,7-h exa h yd r o-2-p r op ylp yr r olo-
[2,1,5-cd ]in d olizin e M217. Ketone 9 (100 mg, 0.433 mmol) was
reduced with LiAlH4 in refluxing dioxane for 3 h. The crude
product was purified by column chromatography (silica gel) to
yield 56 mg of M217 (60%). The obtained 1H and 13C NMR
compound 7 (584 mg, yield: 93%). [R]20 ) +38.1 (c 1, CH2Cl2);
D
IR (NaCl) 1665 and 1663 (CO) cm-1; 1H NMR (200 MHz; CDCl3)
δ (ppm) 1.46-1.65 (m, 1H, H-7), 1.88-2.09 (m, 1H, H-6), 2.20-
2.33 (m, 2H, H-6 and H-7), 2.40 (s, 3H, CH3), 2.72-2.84 (m, 1H,
H-1), 2.87-3.07 (m, 1H, H-5), 3.10-3.18 (m, 1H, H-1), 3.20-
3.34 (m, 1H, H-5), 4.25-4.34 (m, 1H, H-7a), 7.00 (s, 1H, H-3).
13C NMR (50 MHz; CDCl3) δ (ppm) 20.5 (C-6), 22.9 (C-5), 27.5
(C-7), 28.1 (CH3), 47.3 (C-1), 52.2 (C-7a), 110.0 (C-3), 127.1 (C-
4), 127.6 (C-3a), 137.1 (C-4a), 188.4 (CO), 194.7 (CH3CO). MS
(EI) 203 (M˘+). Anal. Calcd for C12H13NO2: C, 70.91; H, 6.44; N,
6.89. Found: C, 70.64; H, 6.35; N, 6.80.
spectra were in agreement with ref 2. [R]20 ) +88 (c 1, CH2-
D
Cl2).
(4a S)-1-E t h yl-3,4,4a ,5,6,7-h exa h yd r o-2-p r op ylp yr r olo-
[2,1,5-cd ]in d olizin e. The enantiomer of M217 was obtained by
the same series of reaction starting with L-glutamic acid.
The ee’s of isolated M217 (97.9%) and of its enantiomer
(88.5%) were determined by gas chromatography with a chiral
capillary column (hydrodex b cyclodextrin Type 3 (neutral) 25
m ×0.25 mm Macherey Nagel A.G.)
(7a R)-4-E t h yl-1,2,5,6,7,7a -h exa h yd r o-1H -p yr r olo[2,1,5-
cd ]in d olizin e (8). A suspension of LiAlH4 in dry 1,4-dioxane
was added to a stirred solution of compound 7 (500 mg, 2.46
mmol) in the same solvent (20 mL) under N2 at room temper-
ature. The resulting mixture was heated under reflux for 40 h
and then cooled to 0 °C and quenched slowly with a saturated
aqueous Na2SO4 solution. After filtration the organic layer was
1
Su p p or tin g In for m a tion Ava ila ble: Copies of H NMR
spectra of compounds 3-9 and M217. Chiral GC chromato-
grams of (R)-M217 and (S)-ent-M217. This material is available
free of charge via the Internet at http://pubs.acs.org.
J O9918697