Concise Enantioselective Synthesis of 3,5-Dialkyl-Substituted Indolizidine Alkaloids via Sequential Cross-Metathesis - Double-Reductive Cyclization

Article abstract of DOI:10.1021/jo0346095

An efficient stereoselective synthesis of two 3,5-dialkyl-substituted indolizidine alkaloids is reported. The convergent syntheses are based on a novel sequence of a cross-metathesis (CM) reaction of an α,β -unsaturated ketone and a chiral homoallylic amine followed by a domino reaction involving hydrogenation, N-deprotection, and two diastereoselective reductive aminations. Our concept presents one of a few examples of a highly selective CM reaction in the synthesis of a natural product.

Full text of DOI:10.1021/jo0346095

Con cise En a n tioselective Syn th esis of 3,5-Dia lk yl-Su bstitu ted
In d olizid in e Alk a loid s via Sequ en tia l
Cr oss-Meta th esis-Dou ble-Red u ctive Cycliza tion
Stefan Randl and Siegfried Blechert*
Technische Universita¨t Berlin, Institut fu¨r Chemie, Strasse des 17. J uni 135, D-10623, Germany
blechert@chem.tu-berlin.de
Received May 9, 2003
An efficient stereoselective synthesis of two 3,5-dialkyl-substituted indolizidine alkaloids is reported.
The convergent syntheses are based on a novel sequence of a cross-metathesis (CM) reaction of an
R,â-unsaturated ketone and a chiral homoallylic amine followed by a domino reaction involving
hydrogenation, N-deprotection, and two diastereoselective reductive aminations. Our concept
presents one of a few examples of a highly selective CM reaction in the synthesis of a natural
product.
In tr od u ction
We and others have studied intensively cross-meta-
thesis (CM) reactions between terminal alkyl-substi-
tuted olefins and electron-deficient olefins.10 In contrast
to the classical Grubbs catalyst Cl2(PCy3)2RudCHPh, Ru
catalysts bearing N-heterocyclic ligands (NHC) such as
the second-generation Grubbs catalysts [R u -1]11 and
[Ru -2]12 (Figure 1) were found to efficiently catalyze CM
reactions of this type. Unlike most CM reactions, these
couplings are generally highly selective affording the
desired cross-products in good to excellent yields and high
E/Z selectivities, which makes them a versatile tool for
the synthesis of acceptor-substituted double bonds and
an alternative to “classical” carbonyl chemistry such as
the Horner-Wadsworth-Emmons reaction.
In the past decade, olefin metathesis has emerged as
a powerful tool for the formation of carbon-carbon
bonds.1 Consequently, over the past few years several
sequential and tandem processes involving a metathesis
step have been developed, which allow for the rapid
construction of complex structures from relatively simple
starting compounds. Combinations of multiple meta-
thesis steps have been described such as the ring-rear-
rangement metathesis (RRM),2 ring-closing enyne meta-
thesis3 and enyne metathesis-ring-closing-ring-opening
metathesis.4 Other sequences combine a metathesis step
with other reactions such as, for example, subsequent
hydrogenation of the newly formed double bond,5 Pd-
catalyzed reactions,6 [3,3]-sigmatropic rearrangements,7
Diels-Alder reactions,8 and allylboration reactions.9
We were interested in utilizing a sequence of a CM
reaction between a terminally unsaturated amine 1 and
an enedione of type 2 and a subsequent double-reductive
* To whom correspondence should be addressed. Tel: +49-30-
31422255. Fax: +49-30-31423619.
(1) For recent reviews, see: (a) Trnka, T. M.; Grubbs, R. H. Acc.
Chem. Res. 2001, 34, 18-29. (b) Fu¨rstner, A. Angew. Chem., Int. Ed.
2000, 39, 3012-3043. (c) Grubbs, R. H.; Chang, S. Tetrahedron 1998,
54, 4413-4450. (d) Armstrong, S. K. J . Chem. Soc., Perkin Trans. 1
1998, 317-388. (e) Fu¨rstner, A. Top. Organomet. Chem. 1998, 1, 37-
72. (f) Schuster, M.; Blechert, S. Angew. Chem., Int. Ed. Engl. 1997,
36, 2036-2056. (g) Connon, S. J .; Blechert, S. Angew. Chem. Int. Ed.
2003, 42, 1900-1923.
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3308.
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Braddock, D. C.; Procopiou, P. A.; White, A. J . P.; Williams, D. J . J .
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1784-1786. (c) Bentz, D.; Laschat, S. Synthesis 2000, 1766-1773. (d)
Heerding, D. A.; Takata, D. T.; Kwon, C.; Huffman, W. F.; Samanen,
J . Tetrahedron Lett. 1998, 39, 6815-6818.
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41, 807-810. (b) Barrett, A. G. M.; Beall, J . C.; Gibson, V. C.; Giles,
M. R.; Walker, G. L. P. Chem. Commun. 1996, 2229-2230.
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Am. Chem. Soc. 2001, 123, 10417-10418. (b) Choi, T.-L.; Chatterjee,
A. K.; Grubbs, R. H. Angew. Chem., Int. Ed. 2001, 40, 1277-1279. (c)
Randl, S.; Gessler, S.; Wakamatsu, H.; Blechert, S. Synlett 2001, 430-
432. (d) BouzBouz, S.; Cossy, J . Org. Lett. 2001, 3, 1451-1454. (e)
Imhof, S.; Randl, S.; Blechert, S. Chem. Commun. 2001, 1692-1693.
(f) Cossy, J .; BouzBouz, S.; Hoveyda, A. H. J . Organomet. Chem. 2001,
634, 216-221. (g) Chatterjee, A. K.; Morgan, J . P.; Scholl, M.; Grubbs,
R. H. J . Am. Chem. Soc. 2000, 122, 3783-3784.
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2648-2649. (c) Stragies, R.; Blechert, S. J . Am. Chem. Soc. 2000, 122,
9584-9591. (d) Ovaa, H.; Stragies, R.; van der Marel, G. A.; van Boom,
J . H.; Blechert, S. Chem. Commun. 2000, 1501-1502, (e) Zuercher,
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6634-6640.
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Mulder, J . A.; Grebe, T. P. Org. Lett. 2002, 4, 2417-2420. (b) Boyer,
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10.1021/jo0346095 CCC: $25.00 © 2003 American Chemical Society
Published on Web 10/23/2003
J . Org. Chem. 2003, 68, 8879-8882
8879

Randl and Blechert
SCHEME 2. Syn th esis of In d olizid in e Alk a loid s
15a ,ba
F IGURE 1. Ruthenium metathesis catalysts.
SCHEME 1. Sequ en ce of CM a n d
Dou ble-Red u ctive Am in a tion a
a
Reagents and conditions: (a) (i) C2H3MgBr, Cu(COD)Cl (10
mol %), THF, -78 °C f rt, 12 h, (ii) Ts-Cl, DMAP (10 mol %),
CH2Cl2, 36 h (65%); (b) NaN3, DMF, 40 °C, 12 h (92%); (c) (i) LAH,
Et2O, 0 °C f rt, 2 h, (ii) Cbz-Cl, K2CO3, THF, 12 h (89%); (d)
3-benzyl-5-(2-hydroxyethyl)-4-methylthiazolium chloride (5 mol %),
NEt3 (0.5 equiv), 65 °C, 18 h (85% for 12a , 87% for 12b); (e) flash
pyrolysis: 500 °C, 10 mbar (81% for 13a , 76% for 13b); (f) 13a ,b
(1 equiv), [Ru -2] (5 mol %), CH2Cl2, reflux, 4 h (89% for 14a , 87%
for 14b); (g) H2, Pd/C, MeOH, rt, 48 h (75% for 15a , 62% for 15b).
a
PG ) protecting group labile to hydrogenation.
be formed with high diastereoselectivity. This tandem
sequence of CM followed by double-reductive cyclization
would offer rapid entry into bicyclic alkaloid structures
containing nitrogen as a bridging atom such as the
pyrrolizidines, indolizidines, and the quinolizidines. Due
to their exotic provenance, scarcity, and pharmacological
activity, indolizidine alkaloids have been a focus of
synthetic organic chemists for some time.15
We decided to apply our strategy in the enantioselec-
tive synthesis of the indolizidine alkaloids (+)-monomo-
rine I, a trail pheromone of the tropical pharao ant
Monomorium pharaonis L.16 (Scheme 2, 15a ), and
(3R,5S,9S)-3-ethyl-5-methylindolizidine (15b), which was
isolated from the venom of the ant Solenopsis (Diplor-
hoptrum) conjurata.17 Having been synthesized earlier
by several groups, (+)-monomorine I seemed as a suitable
target to test the reaction and compare the efficiency of
the concept.18,19
cyclization for the construction of bicyclic N-heterocycles
5 (Scheme 1).
Upon treatment with hydrogen and a Pd-catalyst,
enones of type 3 lacking a second carbonyl group are
converted into saturated monocyclic N-heterocycles in a
sequence of hydrogenation of the double bond, deprotec-
tion of the amine, and reductive amination.13 Cyclizations
affording pyrrolidines (n ) 0) and piperidines (n ) 1)
proceed with high diastereoselectivity, the stereochem-
istry being controlled by the stereogenic center adjacent
to the nitrogen.14 Based on these literature-known pro-
tocols, we expected an extension of the cyclization process
employing enones 3 containing a second carbonyl group.
The product of the reductive amination 4 was expected
to undergo a second reductive amination with the re-
maining carbonyl group to furnish a bicyclic ring system
5 in one step. Five- and six-membered rings should again
Resu lts a n d Discu ssion
(13) (a) Gosselin, F.; Lubell, W. D. J . Org. Chem. 2000, 65, 2163-
2171. (b) Swarbrick, M. E.; Gosselin, F.; Lubell, W. D. J . Org. Chem.
1999, 64, 1993-2002. (c) Gosselin, F.; Lubell, W. D. J . Org. Chem.
1998, 63, 3, 7463-7471.
The first partner (9) for CM was prepared from (R)-
methyloxirane (6, Scheme 2), which is commercially
(14) For pyrrolidines, see, for example: (a) Francke, W.; Schroeder,
F.; Walter, F.; Sinnwell, V.; Baumann, H.; Kaib, M. Liebigs Ann. Org.
Bioorg. Chem. 1995, 965-978. (b) Vavrecka, M.; Hesse, M. Helv. Chim.
Acta 1991, 74, 438-444. (c) Nakagawa, Y.; Stevens, R. V. J . Org. Chem.
1988, 53, 1871-1873. For piperidines, see, for example, ref 13a-c
and: (d) Yamauchi, T.; Fujikura, H.; Higashiyama, K.; Takahashi, H.;
Ohmiya, S. J . Chem. Soc., Perkin Trans. 1 1999, 2791-2794. (e)
Nagasaka, T.; Kato, H.; Hayashi, H.; Shioda, M.; Hikasa, H.; Hamagu-
chi, F. Heterocycles 1990, 30, 561-566. (f) Yamazaki, N.; Kibayashi,
C. J . Am. Chem. Soc. 1989, 111, 1396-1408.
(15) (a) Michael, J . P. In The Alkaloids; Cordell, G. A., Ed.; Academic
Press: New York, 2001; Vol. 55, pp 91-258. (b) Takahata, H.; Momose,
T. In The Alkaloids; Cordell, G. A., Ed.; Academic Press: New York,
1993; Vol. 44, pp 189-256.
(16) (a) Ritter, F. J .; Rotgans, I. E. M.; Talman, E.; Verwiel, P. E.
J .; Stein, F. Experientia 1973, 29, 530-531. (b) Ritter, F. J .; Persoons,
C. J . Neth. J . Zool. 1975, 25, 261-275.
(17) J ones, T. H.; Hight, R. J .; Blum, M. S.; Fales, H. M. J . Chem.
Ecol. 1984, 10, 1233-1249.
8880 J . Org. Chem., Vol. 68, No. 23, 2003

Synthesis of 3,5-Dialkyl-Substituted Indolizidine Alkaloids
available or can be conveniently synthesized on large
scale by hydrolytic kinetic resolution of racemic methyl-
oxirane.20 Regioselective copper-catalyzed ring-opening
with vinylmagnesium bromide21 furnished the crude
alcohol,22 which was directly converted into its tosylate
7 due to its high volatility. Efficient tosylation was only
achieved by employing the crude alcohol at high concen-
trations. Catalytic amounts of DMAP proved to be crucial,
as without its addition no product formation could be
observed. Substitution of the tosyloxy group with sodium
azide, which occurred with complete inversion of the
configuration at C-2,23 furnished azide 8. Since azides are
easily reduced to the corresponding amines under hy-
drogenation conditions it was originally envisaged to
couple 8 with enones 13a ,b via CM and convert the
products into the target structures via subsequent reduc-
tive amination in analogy to the reaction sequence
outlined in Scheme 1. Initial experiments, however,
revealed that CM of 8 with enones as, e.g., methyl vinyl
ketone using either catalyst [Ru -1] or [Ru -2] furnished
the desired cross-products in less than 20% yield, which
is probably due to the incompatibility of the azide group
with the Ru-metathesis catalysts (Figure 1).24 Subse-
quent reduction of the azide using LAH and protection
of the resulting amine with carbobenzyloxy chloride
yielded 9 with an overall yield of 53% starting from (R)-
methyloxirane (6).
The desired enones 13a ,b for CM were synthesized by
the Stetter procedure25 starting from 5-norbornen-2-
carbaldehyde (10), which served as a masked equivalent
of acrolein (Scheme 2). With both endo/exo-stereoisomers
furnishing the same olefin after cleavage of the cyclo-
pentadiene protecting group, a mixture of isomers (endo/
exo 1:1) was employed. The synthesis of the 1,4-diketo
functionality was accomplished by umpolung of the
aldehyde 10 and subsequent Michael addition to butyl26
and ethyl vinyl ketone, respectively (11a ,b). The thiazo-
lium salt-catalyzed reaction furnished both diketones
12a ,b in yields of higher than 80%. Subsequent retro-
Diels-Alder-reaction effected by flash-pyrolysis (500 °C,
10 mbar) afforded enones 13a ,b. Slow addition of nor-
bornenes 12a ,b (ca. 1 drop/5 s) into the pyrolysis zone
resulted in substantially higher yields of the products
The CM reaction between olefins 9 and 13a was
investigated. For CM involving acceptor substituted
alkenes, [Ru -1] is known to be a versatile catalyst.10a,b,g
Our group and others have shown that in certain reac-
tions involving electron-deficient olefins phosphane-free
complex [R u -2] exhibits significantly superior activity
compared to [Ru -1].27 Using an 1:1 mixture of the olefin
and 5 mol % of [Ru -2], CM product 14a was obtained in
a gratifying yield of 89%.28 Subsequent treatment of 14a
with Pd/C in a hydrogen atmosphere in MeOH afforded
(+)-monomorine I (15a ) in 75% isolated yield after
column chromatography on neutral alumina. The 3-epi
isomer of 15a , (-)-indolizidin 195B,29 was isolated as a
side product in ca. 15% yield indicating that the anne-
lation of the five-membered ring by the second reductive
amination proceeded with a diastereoselectivity of ca. 5:1.
Since there were no further isomers detected, the first
cyclization to the six-membered ring must have proceeded
with complete stereoselectivity.
Analogously, 15b was prepared from olefins 13b and
9. The lower yield of 15b in the final reduction step (62%)
is due to the loss of product during workup as a
consequence of its higher volatility.
Con clu sion
In summary, we have described a sequence of a CM
reaction and a subsequent domino double reductive
cyclization and applied it successfully in convergent
syntheses of the indolizidine alkaloids 15a ,b. The excep-
tionally concise syntheses comprise of a total of seven
steps each with five steps as the longest linear sequence.
The overall yields starting from (R)-methyl oxirane are
35% (15a ) and 29% (15b), respectively. Compared to
known syntheses, this is the most efficient synthesis of
(+)-monomorine I concerning both number of steps and
total yield. We would like to emphasize that in our
syntheses there is no need for the protection of the
carbonyls, which would have been difficult to achieve
using carbonyl coupling reactions for the syntheses of the
cyclization precursors 14a ,b. This is one of a few exam-
ples of a highly selective CM reaction in natural product
synthesis. Given the high functional group tolerance of
Ru-metathesis catalysts, our concept, in general, opens
up a general highly efficient and stereoselective entry into
2,5-substituted pyrrolidines and 2,6-substituted pip-
eridines, structural motifs commonly found in alkaloids,
and naturally occurring bicyclic alkaloids of different ring
sizes and substitution patterns. Further investigations
and syntheses based on this concept are currently under
study in our laboratories and the results will be reported
in due course.
(18) For recent enantioselective syntheses of (+)-monomorine I, see,
for example: (a) Riesinger, S. W.; Lo¨fstedt, J .; Petersson-Fasth, H.;
Ba¨ckvall, J .-E. Eur. J . Org. Chem. 1999, 3277-3280. (b) Momose, T.;
Toshima, M.; Seki, S.; Koike, Y.; Toyooka, N.; Hirai, Y. J . Chem. Soc.,
Perkin Trans. 1 1997, 1315-1321. (c) Higashiyama, K.; Nakahata, K.;
Takahashi, H. J . Chem. Soc., Perkin Trans. 1 1994, 351. (d) Munchhof,
M. J .; Meyers, A. I. J . Am. Chem. Soc. 1995, 117, 5399-5400 and
references cited therein.
(19) For a synthesis of (3R,5S,9S)-3-ethyl-5-methylindolizidine (15b),
see: Takahata, H.; Bandoh, H.; Momose, T. Tetrahedron 1993, 49,
11205-11212.
(20) (a)Tokunaga, M.; Larrow, J . F.; Kakiuchi, F.; J acobsen, E. N.
Science 1997, 277, 936. (b) Furrow, M. E.; Schaus, S. E.; J acobsen, E.
N. J . Org. Chem. 1998, 63, 6776-6779.
(21) Fu¨rstner, A.; Thiel, O. R.; Kindler, N.; Bartkowska, B. J . Org.
Chem. 2000, 65, 7990-7995.
Exp er im en ta l Section
(22) The enantiomeric excess of the intermediate (R)-4-penten-2-ol
was determined to 98% ee after conversion into the Mosher ester (GC,
1H and 19F NMR spectroscopy): (a) Dale, J . A.; Mosher, H. S. J . Am.
Chem. Soc. 1973, 95, 512-519. (b) Dale, J . A.; Dull, D. L.; Mosher, H.
S. J . Org. Chem. 1969, 34, 2543-2549.
(S)-((E)-1-Meth yl-5,8-d ioxod od ec-3-en yl)ca r ba m ic Acid
Ben zyl Ester (14a ). To a solution of 0.65 g (3.0 mmol) of
(26) Butyl vinyl ketone 11a was prepared according to Stetter et
al., see ref 25.
(27) See ref 10c, e and: Randl, S.; Connon, S. J .; Blechert, S. Chem.
Commun. 2001, 1796-1797.
(28) Slightly lower yields of 14a were obtained by reducing the
catalyst loading (3 mol % [Ru -2], 72% yield) or using [Ru -1] (5mol %,
82% yield).
(23) The enantiomeric excess of the intermediate (S)-2-amino-4-
pentene was determined by conversion into the Mosher amide (1H
NMR, 19F NMR, GC-MS), see ref 22.
(24) To our knowledge, this is the first example of a Ru-catalyzed
metathesis reaction of an azide. For RCM of an azide using Schrock’s
molybdenum catalyst, see: Fu¨rstner, A.; Thiel, O. J . Org. Chem. 2000,
65, 1738-1742.
(29) Tokuyama, T.; Nishimori, N.; Karle, I. L.; Edwards, M. W.; Daly,
J . W. Tetrahedron 1986, 42, 3453-3460.
(25) Stetter, H.; Landscheidt, A. Chem. Ber. 1979, 112, 1410-1419.
J . Org. Chem, Vol. 68, No. 23, 2003 8881

Randl and Blechert
amine 9 and 0.50 g (3.0 mmol) of enone 13a in 60 mL of
CH2Cl2 was added 94 mg ruthenium catalyst [Ru -2], and the
solution was stirred under reflux for 4 h. After removal of the
solvent under vacuum, the residual brown oil was purified
twice by column chromatography on silica gel (hexane/ethyl
acetate 5:2) to yield 0.95 g (2.6 mmol, 89%) of 14a as a colorless
yield 147 mg (0.75 mmol, 75%) of 15a (first fraction) as a
colorless liquid. Spectral data were in accordance with those
previously reported.18b 1H NMR (500 MHz, CDCl3): δ 2.46 (t
br, J ) 9 Hz, 1H), 2.20 (m, 1H), 2.06 (m, 1H), 1.82 (m, 1H),
1.76-1.60 (m, 4H), 1.52 (d br, J ) 8 Hz, 1H), 1.47-1.36 (m,
2H), 1.35-1.17 (m, 8H), 1.12 (d, J ) 7 Hz, 3H), 0.87 (t, J ) 7
Hz, 3H). 13C NMR (125.8 MHz, CDCl3): δ 67.1 (CH), 62.8 (CH),
60.2 (CH), 39.7 (CH2), 35.8 (CH2), 30.8 (CH2), 30.3 (CH2), 29.7
(CH2), 29.3 (CH2), 24.8 (CH2), 22.8 (CH2), 22.8 (CH3), 14.1
(CH3). MS: m/z 194 (1), 180 (15), 138 (100), 124 (8), 95 (11),
55 (9). HR-MS: calcd for C13H24N ([M+] - H) 194.1909, obsd
194.1910. IR (neat, cm-1): 2957, 2928, 2859, 1734, 1454, 1379,
1
solid. H NMR (400 MHz, CDCl3): δ 7.38-7.28 (m, 5H), 6.80
(dt, J ) 16, 7 Hz, 1H), 6.13 (d, J ) 16 Hz, 1H), 5.12-5.05 (m,
2H), 4.66 (d br, J ) 6 Hz, 1H), 3.91 (septett, J ) 6 Hz, 1H),
2.84-2.78 (m, 2H), 2.70 (t, J ) 6 Hz, 2H), 2.46 (t, J ) 7 Hz,
2H), 2.39 (t br, J ) 6 Hz, 2H), 1.56 (tt, J ) 7, 7 Hz, 2H), 1.32
(tq, J ) 7, 7 Hz, 2H), 1.18 (d, J ) 6 Hz, 3H), 0.90 (t, J ) 7 Hz,
3H). 13C NMR (125.8 MHz, CDCl3): δ 209.6 (Cq), 198.3 (Cq),
155.5 (Cq), 142.5 (CH), 136.4 (Cq), 132.5 (CH), 128.5 (CH), 128.1
(CH), 128.0 (CH), 66.6 (CH2), 46.2 (CH), 42.5 (CH2), 39.7 (CH2),
35.9 (CH2), 33.5 (CH2), 25.9 (CH2), 22.2 (CH2), 20.6 (CH3), 13.8
(CH3). MS: m/z 252 (4), 235 (5), 182 (50), 178 (21), 134 (49),
91 (100). HR-MS: calcd for C14H22NO3 252.1600, obsd 252.1607.
IR (neat, cm-1): 3335, 2958, 2933, 1712, 1673, 1527, 1244.
1124. [R]20 ) +34.0 (c 1.09, hexane).
D
Ack n ow led gm en t . Financial support from the
“Fonds der Chemischen Industrie” is gratefully acknowl-
edged. S.R. thanks the Graduiertenkolleg “Synthetische,
mechanistische und reaktionstechnische Aspekte von
Metallkatalysatoren” for a stipend.
[R]20 ) -21.5 (c 0.94, CHCl3). Anal. Calcd for C21H29NO4: C,
D
70.17; H, 8.13; N, 3.90. Found: C, 70.35; H, 8.28; N, 3.72.
(3R,5S,9S)-3-Bu tyl-5-m eth ylin d olizid in e ((+)-Mon om o-
r in e I, 15a ). A suspension of 0.36 g (1.00 mmol) of enedione
14a and 60 mg of Pd/C (10% Pd) in 20 mL of methanol was
stirred under a hydrogen atmosphere for 48 h. After filtration
through a pad of Celite and evaporation of the solvent under
reduced pressure, the residue was purified by column chro-
matography on neutral alumina using CHCl3/hexane (2:1) to
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
cedures and full product characterization for compounds 7-9,
13a ,b, 14a ,b, and 15a ,b. This material is available free of
charge via the Internet at http://pubs.acs.org.
J O0346095
8882 J . Org. Chem., Vol. 68, No. 23, 2003