General synthesis of pyrroloquinolizidines: Synthesis of an unnatural homologue of the pyrroloindolizidine myrmicarin alkaloid 215B

Article abstract of DOI:10.1021/jo062262a

A general synthesis approach to pyrroloquinolizidines (3,4,5,5a,6,7,8- heptahydropyrrolo[2,1,5-de]-quinolizines) via a muenchnone 1,3-dipolar cycloaddition is reported. The approach was applied to the synthesis of an unnatural pyrroloquinolizidine homologue of myrmicarin 215B.

Full text of DOI:10.1021/jo062262a

General Synthesis of Pyrroloquinolizidines: Synthesis of an
Unnatural Homologue of the Pyrroloindolizidine Myrmicarin
Alkaloid 215B
Steven R. Angle,* Xuelei Lily Qian, Alexandre A. Pletnev, and Jason Chinn
Department of Chemistry, UniVersity of CaliforniasRiVerside, RiVerside, California 92521-0403
steVen.angle@wright.edu
ReceiVed NoVember 1, 2006
A general synthesis approach to pyrroloquinolizidines (3,4,5,5a,6,7,8-heptahydropyrrolo[2,1,5-de]-
quinolizines) via a m u¨ nchnone 1,3-dipolar cycloaddition is reported. The approach was applied to the
synthesis of an unnatural pyrroloquinolizidine homologue of myrmicarin 215B.
Introduction
The myrmicarin alkaloids are a structurally novel group of
oligocyclic indolizidine-derived alkaloids and are the major
constituent of the poison gland secretion of the African ant
1
species Myrmicaria opaciVentris (Figure 1). These ants are an
ecologically dominant species and a significant anthropoid
1
d
1a
1a
predator. Myrmicarins 217 (1) and 215A/B (2, 3) were
isolated by Schr o¨ der, Francke, and co-workers, and the structures
were assigned on the basis of spectroscopic studies. Myrmicarin
4
30A, 4, is a structurally novel heptacyclic bisenamine that could
1b
not be isolated or purified due to its instability. The structure
of myrmicarin 430A was determined by NMR studies directly
on poison gland secretions.
The combination of the unique structure and promising
biological activity of the myrmicarin alkaloids inspired signifi-
cant interest in the synthesis of these air- and temperature-
2
sensitive compounds. Schr o¨ der and Francke reported the first
synthesis of racemic myrmicarin 217, 1, by the conversion of
an indolizine derivative to myrmicarin 217 via an unsaturated
3
a
derivative of myrmicarin 237A (5). Vallee and co-workers
*
To whom correspondence should be addressed. Current address: Department
of Chemistry, Wright State University, Dayton OH, 45435; Fax: 937-775-2421.
1) (a) Schr o¨ der, F.; Franke, S.; Francke, W.; Baumann, H.; Kaib, M.;
(
Pasteels, J. M.; Daloze, D. Tetrahedron 1996, 52, 13539-13546. (b)
Schr o¨ der, F.; Sinnwell, V.; Baumann, H.; Kaib, M. Chem. Commun. 1996,
FIGURE 1. Structure of natural and unnatural myrmicarins.
2
139-2140. (c) Schr o¨ der, F.; Sinnwell, V.; Baumann, H.; Kaib, M.; Francke,
W. Angew. Chem., Int. Ed. Engl. 1997, 36, 77-80. (d) Francke, W.;
Schr o¨ der, F.; Walter, F.; Sinnwell, V.; Baumann, H.; Kaib, M. Liebigs Ann.
described the total synthesis of (+)-(R)-myrmicarin 217 and its
enantiomer from D-glutamic acid. This same group also reported
the synthesis of a mixture of myrmicarin 215A and 215B via a
regioselective Vilsmeier-Haack acylation of pyrroloindoliz-
1
995, 965-977.
(
2) Francke, W.; Schr o¨ der, F. Tetrahedron 1998, 54, 5259-5264.
(3) (a) Sayah, B.; Pelloux-Leon, N.; Vallee, Y. J. Org. Chem. 2000, 65,
2
824-2826. (b) Sayah, B.; Pelloux-Leon, N.; Milet, A.; Pardillos-Guindet,
3
b
J.; Vallee, Y. J. Org. Chem. 2001, 66, 2522-2525.
idines from the same starting material. Recently, Movassaghi
1
0.1021/jo062262a CCC: $37.00 © 2007 American Chemical Society
Published on Web 02/22/2007
J. Org. Chem. 2007, 72, 2015-2020 2015

Angle et al.
SCHEME 1. Retrosynthesis of M-215 A/B and 6
SCHEME 2. Synthesis of Indolizidine Acid 10
and Ondrus4a reported the enantioselective total synthesis of
tricyclic myrmicarin alkaloids via stereospecific palladium-
catalyzed coupling of a Z-vinyl triflate and a pyrrole followed
by a copper-catalyzed enantioselective conjugate reduction. They
also studied the possible dimerization of (+)-myrmicarin 215B
to myrmicarin 430A.4b Their studies showed that myrmicarin
SCHEME 3. Attempted 1,3-Dipolar Reaction
2
15B does react to afford dimeric compounds upon treatment
with acid; however, they were unable to provide direct evidence
for the formation of myrmicarin 430A. The sensitive nature of
1,4b
myrmicarin 215A/B, and the instability of myrmicarin 430A,
led us to consider the synthesis of related compounds that might
be more stable and have biological activity similar to the natural
products. Accordingly, we examined 6 and 7 which are unnatural
homologues of myrmicarin 215 (2/3) and myrmicarin 430 (4).
It may be that 7 would be more stable than 4 because of
decreased ring strain realized upon moving from an indolizidine
pyroglutamic acid,1
1-13
was reacted with acrolein in the presence
of tributyltin hydride and AIBN to afford hemiaminal 15 in 37%
1
4
yield (Scheme 2). The corresponding open-chain aldehyde 14
was not observed. The low yield of 15 was likely due to
instability upon silica gel chromatography. To circumvent this
problem, crude 15 was treated with trimethylsilyl cyanide and
5
to a quinolizidine skeleton. Our initial goal was to develop an
efficient route to 6 that would allow sufficient quantities of
compound to be prepared so that the acid-mediated dimerization
of 6 to 7 could be studied. We report here our studies on the
attempted synthesis of myrmicarin 215A/B and the synthesis
of 6, which could be viewed as myrmicarin 229B, an unnatural
homologue of myrmicarin 215B.
1
5
trimethylsilyl triflate to afford nitrile 16 in 61% yield for the
two steps (Scheme 2). Nitrile 16 appeared to be a single
1
diastereomer by H NMR analysis. Hydrolysis of the nitrile
afforded acid 10 in 95% yield. Again, the compound was a
single diastereomer by H NMR analysis. The peak multiplicity
1
and H-H coupling constant corresponding to the hydrogen
adjacent to the carboxylic acid (δ 4.82, doublet, J ) 5.7 Hz)
lead to the conclusion that the carboxylic acid is in a pseudoaxial
orientation and is consistent with the expected conformation
due to A-strain.
We were now in a position to examine the key 1,3-dipolar
Results and Discussion
Retrosynthetic analysis of myrmicarin 215A/B (2/3) and
homologue 6 shows that carboxylic acids 10 and 11 might
provide rapid access to the tricyclic skeleton (8/9; Scheme 1).
16
6-8
Cyclodehydration of 10/11 to a m u¨ nchnone
intermediate
9
followed by 1,3-dipolar cycloaddition and retro-Diels-Alder
reaction would afford tricyclic pyrroles 8/9 which might easily
be transformed to the target compounds.
cycloaddition. Treatment of acid 10 with acetic anhydride to
7
induce cyclodehydration to a m u¨ nchnone intermediate followed
by a 1,3-dipolar cycloaddition reaction with an acetylene should
afford tricyclic pyrrole 8 (Scheme 3). Unfortunately, many
attempts to effect this transformation using a variety of
conditions were unsuccessful.
It appeared the problem was the generation of the m u¨ nchnone
intermediate. This might not be surprising because of the
expected strain in the rigid, tricyclic m u¨ nchnone. In contrast,
molecular models and modeling studies showed the higher
We first set out to prepare indolizidine carboxylic acid 10.
1
0
The known iodide 13, prepared in four steps from (S)-
(
4) (a) Movassaghi, M.; Ondrus, A. E. Org. Lett. 2005, 7, 4423-4426.
b) Ondrus, A. E.; Movassaghi, M. Tetrahedron 2006, 62, 5287-5297.
5) Lowry, T. H.; Richardson, K. S. Mechanism and Theory in Organic
Chemistry, 3rd ed.; Harper & Row: New York, 1987; p 169.
6) (a) Huisgen, R.; Gotthardt, H.; Bayer, H. O. Chem. Ber. 1970, 103,
368-2387. (b) Knorr, R.; Huisgen, R. Chem. Ber. 1970, 103, 2598-2610.
c) Huisgen, R.; Gotthardt, H.; Bayer, H. O.; Schaefer, F. C. Chem. Ber.
(
(
(
2
(
1
1
970, 103, 2611-2624. (d) Gotthardt, H.; Huisgen, R. Chem. Ber. 1970,
(10) (a) Molin-Case, J. A.; Fleischer, E.; Urry, D. W. J. Am. Chem. Soc.
1970, 92, 4728-4730. (b) Karsten, W. F. J.; Moolenaar, M. J.; Rutjes,
F. P. J. T.; Grabowska, U.; Speckamp, W. N.; Hiemstra, H. Tetrahedron
Lett. 1999, 40, 8629-8632. (c) Hjelmgaard, T.; Tanner, D. Org. Biomol.
Chem. 2006, 4, 1796-1805.
03, 2625-2638.
(7) Padwa, A.; Burgess, E. M.; Gingrich, H. L.; Roush, D. M. J. Org.
Chem. 1982, 47, 786-791.
8) (a) Dalla Croce, P.; La Rosa, C. Heterocycles 1988, 27, 2825-2832.
b) Ibata, R.; Hamaguchi, M.; Kiyohara, H. Chem. Lett. 1975, 21-24. (c)
Clerici, F.; Erba, E.; Mornatti, P.; Trimarco, P. Chem. Ber. 1989, 122, 295-
00. (d) Texier, F.; Mazari, M.; Yebdri, O.; Tonnard, F.; Carrie, R. Bull.
Soc. Chim. Fr. 1991, 128, 926-927.
9) (a) Huisgen, R.; Grashey, R.; Sauer, J. In The Chemistry of Alkenes;
(
(
(11) Acevedo, C. M.; Kogut, E. F.; Lipton, M. A. Tetrahedron 2001,
57, 6353-6359.
3
(12) Holmes, A. B.; Smith, A. L.; Williams, S. F.; Hughes, L. R.; Lidert,
Z.; Swithenbank, C. J. Org. Chem. 1991, 56, 1393-1405.
(13) Adcock, J. L.; Luo, H. J. Org. Chem. 1992, 57, 2163-2166.
(14) For a similar intermolecular radical reaction, see: Giese, B. Angew.
Chem., Int. Ed. Engl. 1985, 24, 553-565.
(15) Dhimane, H.; Vanucci-Bacque, C.; Hamon, L.; Lhommet, G. Eur.
J. Org. Chem. 1998, 1955-1963.
(16) Pott, D.; Stevenson, P. J.; Thompson, N. Tetrahedron Lett. 2000,
41, 275-278.
(
Patai, S., Ed.; Interscience: London, 1964; pp 739-848. (b) Huisgen, R.
Angew. Chem., Int. Ed. Engl. 1963, 2, 565-598. (c) Woodward, R. B.;
Hoffmann, R. The ConserVation of Orbital Symmetry; Verlag Chemie:
Weinheim, 1970. (d) Houk, K. N.; Gonzales, J.; Li, Y. Acc. Chem. Res.
1
9
995, 28, 81-90. (e) Gothelf, K. V.; Jorgensen, L. A. Chem. ReV. 1998,
8, 863-909.
2016 J. Org. Chem., Vol. 72, No. 6, 2007

General Synthesis of Pyrroloquinolizidines
SCHEME 4. Synthesis of Quinolizidine 11
TABLE 1. Cycloaddition with Ethyl Propiolate
rxn conditions
base
none
Et3N
DBU
DIEA
PMP
DTBMP
DTBMP
solvent
23 (%)
1
2
3
4
5
6
7
5 h, 130 °C
5 h, 130 °C
5 h, 130 °C
5 h, 130 °C
5 h, 130 °C
5 h, 130 °C
3 h, 100 °C
Ac2O
Ac2O
Ac2O
none
none
none
trace
37
homologue, the 6,6-membered quinolizidine ring, 11, should
provide a much less strained m u¨ nchnone intermediate. Thus,
in spite of the failed approach with acid 10, we elected to prepare
quinolizidine homologue 11 and to examine the m u¨ nchnone 1,3-
dipolar cycloaddition.
Ac O
2
Ac2O
Ac2O
58
80
10% Ac2O in toluene
Quinolizidine carboxylic acid 11 was prepared from the
SCHEME 5. Synthesis of Pyrroloquinolizidines
known17 6-hydroxymethyl-2-piperidinone 17 which was in turn
18
derived from L-lysine methyl ester dihydrochloride. Conversion
of alcohol 17 to the iodide using triphenylphosphine, imidazole,
1
9
and iodine afforded 18 in modest yield, but we were unable
to adequately purify it due to the fact that small amounts of
triphenylphosphine oxide coeluted with the product. Alterna-
tively, treatment of alcohol 17 with methyl triphenoxy phos-
phonium iodide in DMF20 gave iodide 18 in 58% yield. In an
effort to improve the yield of 18, we examined the same reaction
in the less polar solvent THF21 and were pleased to obtain 18
in 76% yield (Scheme 4). Reaction of 18 with acrolein in the
presence of tributyltin hydride14 and AIBN afforded hemiaminal
1
9, which was treated with trimethylsilyl cyanide and trimeth-
1
5
ylsilyl triflate to afford nitrile 20 in 50% overall yield.
Hydrolysis of 20 afforded acid 11 in 72% yield. This radical
reaction appears to be a general method for the annulation of
six-membered rings onto lactam iodides such as 13 and 18.
With quinolizidine carboxylic acid 11 in hand, we turned our
attention to the formation of m u¨ nchnone 22 and the subsequent
1
,3-dipolar cycloaddition (Table 1). To our knowledge, there
is no report of a cycloaddition carried out on a tricyclic
6
-8
m u¨ nchnone.
Ethyl propiolate was selected as our “test”
dipolarophile, and a variety of conditions were explored for the
transformation (Table 1). Carrying out the reaction in acetic
anhydride (solvent) at 130 °C in the absence of a base (entry
1
) or with a relatively strong, unhindered amine base (TEA,
DBU; Table 1, entries 2 and 3) failed to afford any of the desired
pyrrole 23. Using the more hindered tertiary amines, N,N-
diisopropylethylamine (DIEA) and 1,2,2,6,6-pentamethylpip-
eridine (PMP), afforded 23 in low to modest yield (Table 1,
entries 4 and 5). Using 2,6-di-tert-butyl-4-methylpyridine (DT-
BMP) in acetic anhydride provided 23 in 58% yield (entry 6),
and using a solvent of 10% acetic anhydride in toluene and
lowering the temperature to 100 °C afforded 23 in 80% yield
We then studied the generality of the 1,3-dipolar cycloaddition
using the optimized reaction conditions in Table 1, entry 7. To
our delight, the m u¨ nchnone cycloadditions proceeded very well
(Scheme 5). Reaction of quinolizidine 11 and dimethyl acety-
lenedicarboxylate, 24, in acetic anhydride gave pyrroloquino-
lizidine 25 in 95% yield. When 3-butyn-2-one, 26, was used as
the dipolarophile, the corresponding pyrroloquinolizidine 27 was
obtained in 94% yield. Carrying out the reaction with disub-
stituted alkyne 28 resulted in the formation of pyrroloquino-
lizidine 29 in 74% yield. This is a surprisingly good yield for
a disubstituted alkyne in this type of cycloaddition. The related
alkyne, 30, with an ester rather than a ketone afforded 31 in
(entry 7).
(
17) Davies, C. E.; Heightman, T. D.; Hermitage, S. A.; Moloney,
M. G. Syn. Commun. 1996, 26, 687-696. For a detailed procedure and
spectral data for intermediates, see Supporting Information.
(
18) Commercially available.
(19) (a) Detmer, I.; Summerer, D.; Marx, A. Eur. J. Org. Chem. 2003,
1
837-1846. (b) Clive, D. L.; Fletcher, S. P.; Liu, D. J. Org. Chem. 2004,
6
9, 3282-3293.
(20) Verheyden, H. P. H.; Moffatt, J. G. J. Org. Chem. 1970, 35, 2319-
2
8% yield using 2,6-di-tert-butyl-4-methylpyridine (DTBMP)
2
326.
21) Dimitrijevich, S. D.; Verheyden, J. P. H.; Moffatt, J. G. J. Org.
Chem. 1979, 44, 400-406.
as the base and in 33% yield using pentamethylpiperidine (PMP)
as the base.
(
J. Org. Chem, Vol. 72, No. 6, 2007 2017

Angle et al.
SCHEME 6. Synthesis of 6, M-229B
synthesis of 6, myrmicarin 229B. Studies on the dimerization
of 6 (myrmicarin 229B) to 7 (myrmicarin 430A homologue)
are currently under investigation.
Experimental Section
General Information. HPLC was carried out on a Chiralcel
OD00CE-GL072 column (4.6 × 250 mm). Flow rate ) 0.5 mL/
min. The appropriate mixture of hexanes/methanol was used.
(
-)-(4R,8aR)-6-Oxo-4-indolizidinecarboxylic Acid (10). A
suspension of AIBN (0.10 g, 0.60 mmol) in toluene (3 mL) was
stirred for 10 min at room temperature, and then tributyltin hydride
Traditionally, m u¨ nchnone cycloadditions exhibit modest to
very good regioselectivity.22 In the case of symmetrical pyr-
roloquinolizidine 25, which is achiral, the regioselectivity is
irrelevant. However, the other pyrroloquinolizidines in Scheme
(
1.3 mL, 4.8 mmol) was added. The mixture was added to a solution
of (-)-(S)-5-iodomethyl-2-pyrrolidinone 13 (0.90 g, 4.0 mmol) and
acrolein (1.34 mL, 20.0 mmol) in toluene (25 mL) at 110 °C via a
syringe pump at the rate of 0.07 mL/min. The resulting solution
was refluxed for 15 min. The mixture was cooled, concentrated,
dissolved in CH
removed in vacuo to afford a yellow oil. To a solution of the above
yellow residue in CH Cl (25 mL) at -78 °C were added dropwise
trimethylsilyl cyanide (2.7 mL, 20 mmol) and trimethylsilyl
trifluoromethanesulfonate (2.17 mL, 12.0 mmol). The resulting
mixture was allowed to warm to room temperature and stirred
overnight. The reaction was then poured into a stirring saturated
5
were derived from unsymmetrical alkynes, and thus the
regioselectivity of the cycloaddition determines the optical purity
of these products. If the cycloaddition is highly regioselective,
products with high optical purity would be obtained, whereas
low or no regioselectivity would afford pyrrole products of low
or zero optical purity. Compounds 27 and 29 are optically active,
indicative of some degree of regioselectivity in the cycloaddition
reaction. Determination of the optical purity of these two
compounds required the synthesis of racemic 27 and 29 from
racemic 11. Chiral HPLC showed the ratio of the two enanti-
omers of 27 to be 1.65:1 (24% ee), whereas the ratio of the
two enantiomers of 29 was 3.20:1 (52% ee). Thus, the
m u¨ nchnone cycloaddition exhibits only modest regioselectivity.
The absolute stereochemistry of the major enantiomer of 27
and 29 could not be determined. Because of the low yield, the
optical purity of 31 was not determined.
3
CN, and washed with hexanes. The solvent was
2
2
aqueous solution of NaHCO (100 mL). After 15 min, the aqueous
3
layer was extracted with CH Cl (3 × 100 mL) and the combined
2
2
4
organic extracts were dried (MgSO ). Concentration afforded crude
product as a yellow oil. Flash chromatography (ethyl acetate) gave
4R,8aR)-(+)-4-cyano-6-oxoindolizine 16 (0.401 g, 61%) as a light
(
1
20
yellow oil (single diastereomer by H NMR analysis): [R]
D
)
1
+
126.8 (c 1.5, CH
2 2 3
Cl ); H NMR (300 MHz, CDCl ) δ 5.17 (d,
J ) 4.6 Hz, 1H), 3.68 (m, 1H), 2.40 (m, 2H), 2.31 (m, 1H), 2.01-
1
3
1
.75 (m, 4H), 1.71-1.59 (m, 2H), 1.25-1.13 (m, 1H); C NMR
The factors governing the regiochemistry of m u¨ nchnone
cycloadditions are not fully understood. Whereas some 1,3-
dipolar cycloadditions are rationalized in terms of simple FMO
(
2
75 MHz, CDCl ) δ 174.0, 117.4, 54.6, 40.7, 33.0, 30.2, 28.3, 25.8,
3
-1
3
0.8; IR (CDCl ) 2945, 2865, 2232, 1699, 1456, 1409 cm . To a
solution of nitrile 16 (0.80 g, 4.87 mmol) in methanol (100 mL)
was added 25% aqueous NaOH (20 mL). The resulting mixture
was refluxed for 6 h and then concentrated. The remaining solution
was cooled to 0 °C, acidified to pH 5 (pH paper) by the addition
of concentrated HCl, and then extracted with EtOAc. The combined
organic extracts were dried (MgSO ) and concentrated to give acid
4
1
-
1
22
theory, this does not correctly predict the results in other cases.
A combination of steric, electronic, dipole, and other ground-
state and transition-state interactions play a role in determining
the regiochemistry; no single criterion successfully predicts the
2
3
regioselectivity of m u¨ nchnone cycloaddition reactions.
2
0
0 (0.86 g, 95%) as a white solid: mp ) 148-150 °C; [R]
D
)
With an efficient route to pyrroloquinolizidines, we returned
to the synthesis of nonnatural myrmicarin 229B, 6. Pyrrolo-
quinolizidine 29 contains all the carbons found in 6 and is the
ideal intermediate to complete the synthesis. Using a modifica-
tion of conditions employed by Ondrus and Movassaghi in the
synthesis of myrmicarin 215B,4 we treated 29 with LiAlH4 at
1
2 2 3
48.5 (c 2.56, CH Cl ); H NMR (300 MHz, CDCl ) δ 7.48 (bs,
H), 4.82 (d, J ) 5.7 Hz, 1H), 3.77 (m, 1H), 2.44 (m, 2H), 2.25
(
m, 2H), 1.92 (dd, J ) 2.6, 12.8 Hz, 1H), 1.80 (dt, J ) 3.6, 13.1
13
Hz, 1H), 1.61 (m, 2H), 1.44 (m, 1H), 1.14 (m, 1H); C NMR (75
MHz, CDCl ) δ 176.1, 174.0, 55.5, 51.5, 32.9, 30.5, 26.4, 26.2,
20.7; IR (CDCl ) 2945, 1718, 1676, 1421, 1314 cm ; MS (EI)
m/z 182 (M - H , 100), 113 (25); HRMS (EI) m/z calcd for C
NO
3
a
-1
3
+
-
78 °C followed by workup with acid (HCl/NH4Cl) to afford
9
H
12
-
+
trans-alkene 6 (M-229B) in quantitative yield (Scheme 6). The
synthesis of nonnatural M-229B, 6, was accomplished in seven
steps and in 20% overall yield from the known alcohol 17 (11
steps, 17% yield from commercially available L-lysine methyl
ester dihydrochloride).
3
(M - H ) 182.0822, found 182.0821.
(
-)-(S)-6-Iodomethyl-2-piperidinone (18). Using Triphe-
1
7
nylphosphine and Iodine. To a solution of alcohol 17 (33.0 mg,
.255 mmol) in benzene/acetonitrile (2:1, 3 mL/1.5 mL) at 0 °C
were added triphenylphosphine (167 mg, 0.638 mmol), imidazole
52.1 mg, 0.765 mmol), and iodine (129.4 mg, 0.510 mmol). The
0
(
resulting solution was stirred at room temperature overnight. The
solvent was removed in vacuo, and the mixture was dissolved in
Conclusion
CH
Na
aqueous layer was extracted with CH
combined organic extracts were dried (MgSO
afforded crude product (200 mg) as a yellow oil. Flash chroma-
tography (10% ethanol/ethyl acetate) gave iodide 18 (34.2 mg, 56%)
2
Cl
2
(3 mL). The mixture was washed with 10% aqueous
(3 mL) and saturated aqueous NaHCO (3 mL). The
Cl
(3 × 3 mL), and the
). Concentration
We developed an efficient synthesis of pyrroloquinolizidines
via a 1,3-dipolar cycloaddition reaction and also achieved the
2
2
S O
3
3
2
2
4
(
22) (a) Huisgen, R. In AdVances in Cycloaddition; Curran, D. P., Ed.;
JAI Press: Greenwich, 1988; Vol. 1, pp 1-32. (b) Sustmann, R.; Sicking,
W. Chem. Ber. 1987, 120, 1653-1658. (c) Coppola, B. P.; Noe, M. C.;
Schwartz, D. J.; Abdon, R. L.; Trost, B. M. Tetrahedron 1994, 50, 93-
as a white solid.
1
16. (d) Coppola, B. P.; Noe, M. C.; Hong, S. S.-K. Tetrahedron Lett. 1997,
Using Triphenoxy Phosphonium Iodide. To a solution of 1717
3
8, 7159-7162.
(0.991 g, 7.68 mmol) in tetrahydrofuran (THF, 76.8 mL) at 0 °C
(
23) Gribble, G. W. Mesoionic Ring Systems. In Synthetic Applications
was added methyl triphenoxy phosphonium iodide (6.94 g, 15.3
mmol) in one portion. The solution was stirred for 2 h at room
temperature. Methanol was added, and the solution was stirred
of 1,3-Dipolar Cycloaddition Chemistry Toward Heterocycles and Natural
Products; Padwa, A., Pearson, W. H., Eds.; John Wiley & Sons: New York,
2
002; pp 681-753.
2018 J. Org. Chem., Vol. 72, No. 6, 2007

General Synthesis of Pyrroloquinolizidines
another 20 min at room temperature. The solvent was removed in
and the appropriate alkyne (16.0 equiv). The reaction mixture was
stirred 3 h at 100 °C and concentrated to dryness, and the residue
was purified by flash column chromatography to give tricyclic
pyrroloquinolizidine.
vacuo, and the mixture was dissolved in chloroform (CHCl
mL). The resulting solution was washed with 10% aqueous Na
and H O. The aqueous layer was extracted with CHCl , and the
combined organic extracts were dried (MgSO ). Concentration
3
, 40
2 2 3
S O
2
3
4
(
-)-1-(Carboethoxy)-(3,4,5,5a,6,7,8-heptahydro)pyrrolo[2,1,5-
de]quinolizine (23). Using the general experimental procedure, acid
afforded crude product (7.63 g) as a yellow oil. Flash chromatog-
raphy (10% ethanol/ethyl acetate) gave iodide 18 (1.40 g, 76%) as
1
1 (5.8 mg, 0.029 mmol) and alkyne 21 afforded 23 (5.5 mg, 80%)
2
0
a white needle solid: mp ) 175-177 °C; [R]
D
) -13.7 (c 1.5,
20
1
as a light yellow oil: [R]
D
2 2
) -0.99 (c 0.71, CH Cl ); H NMR
1
CH Cl ); H NMR (300 MHz, CDCl ) δ 6.50 (s, 1H), 3.51 (m,
2
2
3
(
6 6
300 MHz, C D ) δ 6.64 (s, 1H), 4.30 (q, J ) 7.0 Hz, 2H), 3.52
1
1
1
2
1
H), 3.26 (dd, J ) 5.3, 10.1 Hz, 1H), 3.14 (dd, J ) 10.1, 7.0 Hz,
(dd, J ) 6.4, 18.7 Hz, 1H), 2.96-2.84 (m, 2H), 2.57 (dd, J ) 6.3,
H), 2.44-2.26 (m, 2H), 2.03 (m, 1H), 1.89 (m, 1H), 1.72 (m,
1
4
5.8 Hz, 1H), 2.41 (m, 1H), 1.56 (m, 1H), 1.45 (m, 1H), 1.22 (m,
H), 1.50 (m, 1H); 1 C NMR (75 MHz, CDCl
3
) δ 172.5, 53.8, 31.4,
13
3
H), 1.16 (t, J ) 7 Hz, 3H), 1.00-0.95 (m, 2H); C NMR (75
3
9.1, 19.5, 11.4; IR (CDCl ) 3368, 2957, 1663, 1450, 1418, 1346,
6 6
MHz, C D ) δ 165.9, 134.4, 126.6, 111.7, 106.9, 59.3, 55.6, 30.7,
-1
+
300 cm ; MS (EI) m/z 240 (MH , 22), 127 (7), 98 (100); HRMS
-1
30.4, 24.3, 23.1, 21.9, 21.5, 15.2; IR (C
6 6
D
) 2944, 1696, 1521 cm ;
+
(EI) m/z calcd for C
6
H
11NOI (MH ) 239.9885, found 239.9879.
+
MS (EI) m/z 233 (M , 54), 204 (100), 188 (16), 160 (19); HRMS
(
()-6-Iodomethyl-2-piperidinone (()-18: mp ) 153.7-156.2 °C;
+
(
EI) m/z calcd for C14
,2-Bis(carbomethoxy)-(3,4,5,5a,6,7,8-heptahydro)pyrrolo-
2,1,5-de]quinolizine (25). Using the general experimental proce-
2
H19NO (M ) 233.1416, found 233.1415.
24
lit. mp ) 157-158 °C.
+)-(4R,9aR)-Octahydro-6-oxo-4-(cyano)quinolizidine (20). A
1
(
[
suspension of AIBN (56.8 mg, 0.346 mmol) in toluene (1.5 mL)
was stirred for 10 min at room temperature, and then tributyltin
hydride (0.744 mL, 2.77 mmol) was added. The mixture was added
to a solution of (-)-(S)-6-iodomethyl-2-piperidinone 18 (0.413 g,
dure, acid 11 (5.5 mg, 0.028 mmol) and alkyne 24 afforded 25
1
(
(
2
(
7.3 mg, 95%) as a white solid: mp ) 148-150 °C; H NMR
300 MHz, C ) δ 3.69 (s, 6H), 3.16 (dd, J ) 5.9, 18.0 Hz, 2H),
.66 (m, 3H), 1.40 (m, 2H), 1.10 (m, 4H), 0.78 (m, 2H); C NMR
75 MHz, C
6
D
6
1
3
1.73 mmol) and acrolein (0.579 mL, 8.64 mmol) in toluene (11
6 6
D ) δ 166.2, 133.6, 112.1, 55.7, 51.2, 30.0, 23.4, 20.3;
IR (C D ) 2947, 2870, 1700, 1530, 1439, 1402 cm ; MS (FAB)
6 6
m/z 278 (MH , 16), 246 (16); HRMS (FAB) m/z calcd for C15H -
20
mL) at 100 °C via a syringe pump at the rate of 0.07 mL/min. The
resulting solution was stirred at 100 °C for another 2 h. The mixture
-
1
+
was cooled, concentrated, dissolved in CH
hexanes. The solvent was removed in vacuo to afford a yellow oil.
To a solution of the above yellow oil in CH Cl (13 mL) at
78 °C was added trimethylsilyl cyanide (1.84 mL, 13.8 mmol)
3
CN, and washed with
+
NO
4
(MH ) 278.1392, found 278.1402.
(
-)-1-Acetyl-(3,4,5,5a,6,7,8-heptahydro)pyrrolo[2,1,5-de]quin-
2
2
olizine (27). Using the general experimental procedure, acid 11
-
(
45.9 mg, 0.233 mmol) and alkyne 26 gave 27 (44.5 mg, 94%) as
and trimethylsilyl trifluoromethanesulfonate (1.49 mL, 8.64 mmol)
dropwise. The resulting mixture was allowed to warm to room
temperature and stirred overnight. The reaction was then poured
20
a light yellow oil: ee ) 24% (Chiral HPLC); [R]
0
J ) 6.2, 18.5 Hz, 1H), 2.90 (m, 2H), 2.59 (dd, J ) 5.3, 14.9 Hz,
D
) -1.66 (c
1
.36, CH
2
Cl
2
); H NMR (300 MHz, C
6
D
6
) δ 6.12(s, 1H), 3.54 (dd,
into a stirring saturated aqueous solution of NaHCO
5 min, the aqueous layer was extracted with CH Cl
and the combined organic extracts were dried (MgSO
3
(10 mL). After
1
1
1
2
H), 2.44 (dd, J ) 5.3, 11.4 Hz, 1H), 2.35 (s, 3H), 1.51 (m, 2H),
.30-1.15 (m, 4H), 0.92 (m, 2H); 13C NMR (75 MHz, C
) δ
93.3, 133.8, 126.2, 121.0, 106.9, 55.6, 30.7, 30.2, 28.5, 24.9, 23.2,
1
2
2
(3 × 10 mL)
6
D
6
4
). Concentra-
tion afforded crude product (0.707 g) as a yellow oil. Flash
-
1
6 6
1.8, 21.4; IR (C D ) 2945, 2867, 1651, 1511 cm ; MS (EI) m/z
chromatography (3:1 hexanes/ethyl acetate) gave cyanide 20 (0.153
+
1
203 (M , 62), 188 (100), 160 (81); HRMS (EI) m/z calcd for C13
NO (M ) 203.1310, found 203.1316.
H
17
-
g, 50%) as a light yellow oil (single diastereomer by H NMR
+
2
0
1
analysis): [R]
D
) +25.2 (c 2.7, CH
) δ 5.87 (d, J ) 3.1 Hz, 1H), 3.53 (m, 1H), 2.45 (td, J )
.4, 17.2 Hz, 1H), 2.30 (ddd, J ) 5.3, 10.6, 16.3 Hz, 1H), 2.07-
2 2
Cl ); H NMR (300 MHz,
CDCl
3
(-)-1-(2-Ethyl)-(3,4,5,5a,6,7,8-heptahydro)pyrrolo[2,1,5-de]-
quinolizin-1-yl)propanone (29). Using the general experimental
procedure, acid 11 (14.3 mg, 0.0725 mmol) and alkyne 28 afforded
29 (13.2 mg, 74%) as a light yellow oil: ee ) 52% (Chiral HPLC);
4
1
(
1
(
13
.91 (m, 2H), 1.85-1.41 (m, 7H), 1.39-1.22 (m, 1H); C NMR
) δ 170.1, 117.8, 54.4, 40.9, 33.0, 30.5, 28.2, 20.5,
75 MHz, CDCl
3
-
1
20
1
9.1; IR (CDCl
3
) 2953, 2251, 1643, 1445, 1414, 1346 cm ; MS
[R]
D
2 2 6 6
) -6.65 (c 0.14, CH Cl ); H NMR (300 MHz, C D ) δ
+
EI) m/z 178 (MH , 33), 151 (82), 82 (100); HRMS (EI) m/z calcd
3.10 (dd, J ) 6.4, 18.2 Hz, 1H, C8-H), 2.93 (partially obscured tt,
J ) 2.9, 6.7 Hz, 1H) 2.85 (m, 2H), 2.71 (dd, J ) 6.4, 11.7 Hz,
1H), 2.66 (q, J ) 7.6 Hz, 2H), 2.56 (dd, J ) 5.8, 17.5 Hz, 1H),
2.29 (ddd, J ) 6.4, 12.3, 17.3 Hz, 1H), 1.54 (m, 2H), 1.33 (t, J )
7.0 Hz, 3H), 1.32 (t, J ) 7.0 Hz, 3H), 1.25 (m, 4H), 0.98 (m, 2H);
+
for C10
-)-(4R,9aR)-6-Oxo-4-quinolizidinecarboxylic Acid (11). To
a solution of nitrile 20 (43.1 mg, 0.242 mmol) in H O (4.8 mL)
and methanol (1.2 mL) was added potassium hydroxide (0.271 g,
.84 mmol). The mixture was refluxed overnight, then allowed to
14 2
H N O (MH ) 178.1106, found 178.1110.
(
2
1
3
4
C NMR (75 MHz, C
6 6
D ) δ 196.2, 132.7, 123.5, 121.9, 120.4,
cool to room temperature. Methanol was removed under reduced
pressure. The remaining solution was acidified to pH ) 3-4 by
55.6, 36.0, 31.1, 30.2, 25.6, 21.9, 21.7, 21.5, 19.6, 16.5, 9.3; IR
(C
m/z 246 (MH , 100), 216 (21); HRMS (CI, NH ) m/z calcd for
C
-
1
6 6 3
D ) 2939, 2870, 1645, 1494, 1427, 1345 cm ; MS (CI, NH )
+
the addition of concentrated HCl and then extracted with CH
2
Cl
) and concen-
trated to give acid 11 (34.4 mg, 72%) as a white solid: mp ) 209-
2
.
3
+
The combined organic extracts were dried (MgSO
4
16
H
24NO (MH ) 246.1858, found 246.1859.
(-)-1-(Carboethoxy)-2-ethyl-(3,4,5,5a,6,7,8-heptahydro)pyr-
12 °C; [R]20
CDCl ) δ 5.50 (d, J ) 4.8 Hz, 1H), 3.49 (m, 1H), 2.54 (d, J )
7.6 Hz, 1H), 2.43-2.30 (m, 2H), 2.01-1.19 (m, 10H); 13C NMR
75 MHz, CDCl ) δ 175.3, 172.2, 55.0, 51.9, 33.4, 33.0, 31.1, 26.6,
1.1, 19.4; IR (CDCl
) -11.9 (c 0.6, CH
Cl
); H NMR (300 MHz,
1
2
D
2
2
rolo[2,1,5-cd]quinolizine (31). To a solution of acid 11 (5.8 mg,
0.029 mmol) in 10% acetic anhydride in toluene (2.5 mL) was
added pentamethylpiperidine (42.5 µL, 0.235 mmol) and ethyl
2-pentynoate (62.0 µL, 0.471 mmol). The reaction mixture was
stirred for 3 h at 95 °C and concentrated to dryness, and the residue
was purified directly by flash column chromatography (10:1
hexanes/ethyl acetate) to give 31 (2.5 mg, 33%) as a light yellow
3
1
(
2
(
3
-
1
3
) 2948, 1714, 1628, 1414, 1261 cm ; MS
EI) m/z 197 (M , 11), 152 (100); HRMS (EI) m/z calcd for C10H -
(M ) 197.1052, found 197.1053. (()-6-Oxo-4-quinolizidin-
ecarboxylic acid (()-11: mp ) 176-179 °C.
+
15
+
NO
3
20
1
oil: [R]
D
) -6.67 (c 0.48, CH
2 2 6 6
Cl ); H NMR (300 MHz, C D )
General Experimental Procedure for Pyrroloquinolizidine
Synthesis. To a solution of (-)-(4R,9aR)-6-oxo-4-quinolizidin-
ecarboxylic acid 11 (1.0 equiv) in 10% acetic anhydride in toluene
δ 4.29 (q, J ) 7.0 Hz, 2H), 3.47 (dd, J ) 6.2, 18.0 Hz, 1H), 2.96
(
2
3
1
m, 4H), 2.60 (dd, J ) 5.7, 16.3 Hz, 1H), 2.33 (m, 1H), 1.55 (m,
H), 1.43 (t, J ) 7.0 Hz, 3H), 1.29 (m, 4H), 1.15 (t, J ) 7.0 Hz,
(0.01 M) were added 2,6-di-tert-butyl-4-methylpyridine (8.0 equiv)
13
H), 1.01 (m, 2H); C NMR (75 MHz, C
6 6
D ) δ 166.3, 134.3, 123.1,
22.8, 109.8, 59.0, 55.5, 31.0, 30.5, 24.8, 21.9, 21.6, 21.5, 19.3,
16.6, 15.1; IR (C
-
1
(24) Knapp, S.; Levorse, A. T. J. Org. Chem. 1988, 53, 4006-4014.
D
6 6
) 2943, 2867, 1692, 1572, 1515, 1457 cm
;
J. Org. Chem, Vol. 72, No. 6, 2007 2019

Angle et al.
+
MS (FAB) m/z 261 (MH , 100), 232 (20); HRMS (FAB) m/z calcd
1H), 5.85 (dq, J ) 15.8, 6.4 Hz, 1H), 3.09 (tt, J ) 2.9, 11.7 Hz,
1H), 2.85 (dd, J ) 5.9, 16.4 Hz, 1H), 2.71-2.63 (partially obscured
m, 1H), 2.65 (dq, J ) 2.92, 7.61 Hz, 2H), 2.61-2.40 (m, 2H),
1.95 (dd, J ) 1.8, 6.4 Hz, 3H), 1.63 (m, 2H), 1.36 (m, 3H), 1.29
+
for C16
H23NO
2
(M ) 261.1729, found 261.1716.
(
+)-E-2-Ethyl-(3,4,5,5a,6,7,8-heptahydro)-1-(1′-propenyl)pyr-
rolo[2,1,5-cd]quinolizine (6). Using a modification of a procedure
by Movassaghi and Ondrus,4 lithium aluminum hydride (7.1 mg,
a
13
(t, J ) 7.6 Hz, 3H), 1.20-0.99 (m, 3H); C NMR (75 MHz, C D )
6
6
0
.19 mmol) was added in one portion to a stirring solution of
δ 125.9, 123.9, 122.1, 120.1, 119.2, 116.0, 55.4, 31.4, 31.0, 23.6,
tricyclic ketone 29 (7.7 mg, 0.031 mmol) and diethyl ether (0.63
mL) at -78 °C. The mixture was stirred for 40 min at 0 °C, and
then the suspension was cooled to -78 °C again for 5 min. The
excess hydride was quenched by careful addition of water (0.7 mL)
via syringe. The mixture was allowed to warm to room temperature.
Argon-purged diethyl ether (6 mL) was added, and the organic layer
was separated. The organic solution was stirred for 2-3 min in a
sealed round-bottom flask under argon, with a pH 2 (pH paper)
solution prepared from 1.0 M aqueous ammonium chloride and
concentrated hydrochloric acid (3 mL). The aqueous layer was
removed by syringe. This was repeated twice at which time TLC
showed no starting material left. The organic solution was washed
2
2.6, 22.5, 21.9, 20.1, 18.7, 16.4; IR (C
6
D
6
) 2960, 1646, 1434, 1347,
-1
+
1260 cm ; MS (EI) m/z 229 (M , 100), 214 (93), 200 (50); HRMS
+
(EI) m/z calcd for C16
H23N (M ) 229.1831, found 229.1835.
Acknowledgment. We thank UC Riverside for partial
support of this research. We would like to thank Dr. Dan
Borchardt and Dr. Yi Meng at the UCR NMR facility for
assistance with NMR and Dr. Richard Kondrat and Mr. Ron
New for mass spectra.
Supporting Information Available: Experimental procedures
for the synthesis of alcohol 17 from (S)-lysine methyl ester
2 4
with brine (3 mL), dried (Na SO ), and concentrated under reduced
pressure to give myrmicarin 229B, 6 (7.2 mg, 100%), as an oily
white solid. Flash chromatography of a similar sample failed to
separate the desired compound from oxidized impurities. The
melting point could not be obtained due to extreme air sensitivity
1
13
dihydrochloride and copies of H and C NMR spectra for these
intermediates and compounds 10, 11, 16-18, 20, 23, 25, 27, 29,
31, and 6. This material is available free of charge via the Internet
at http://pubs.acs.org.
20
and the oily nature of the compound: [R]
D
) +13.1 (c 0.60, CH
2
-
1
Cl ); H NMR (300 MHz, C D ) δ 6.64 (dq, J ) 15.8, 1.8 Hz,
2
6
6
JO062262A
2020 J. Org. Chem., Vol. 72, No. 6, 2007