Total synthesis of (±)-rhazinal using novel palladium-catalyzed cyclizations

Article abstract of DOI:10.1021/jo801791j

A concise synthesis of (±)-rhazinal that hinges on novel oxidative Heck cyclizations and palladium- catalyzed direct couplings is described. An X-ray structure of N-MOM-rhazinal, which provides insight into the conformation of the strained 9-membered lact

Full text of DOI:10.1021/jo801791j

Total Synthesis of (()-Rhazinal Using Novel Palladium-Catalyzed
Cyclizations
Alfred L. Bowie, Jr. and Dirk Trauner*
Department of Chemistry, UniVersity of California, Berkeley, California 94720
trauner@berkeley.edu
ReceiVed August 29, 2008
A concise synthesis of (()-rhazinal that hinges on novel oxidative Heck cyclizations and palladium-
catalyzed direct couplings is described. An X-ray structure of N-MOM-rhazinal, which provides insight
into the conformation of the strained 9-membered lactam ring, is described.
SCHEME 1. Classical and Emerging Cross-Coupling
Reactions
Introduction
Transition-metal-catalyzed cross-coupling reactions have
revolutionized the logic of chemical synthesis and have found
innumerable applications in total synthesis.1 Traditionally, both
coupling partners must be properly functionalized prior to cross-
coupling (Scheme 1). This usually requires installation of an
organometallic moiety on one side to allow for transmetalation
and a halide or triflate functional group on the other side to
permit oxidative addition to a low-valent transition metal
catalyst. The preparation of these precursors can involve several
steps, and their reactions suffer from the formation of waste
products (MX or HX), since neither of the two functional
handles is incorporated into the final product.
Accordingly, there has been an increasing interest in the
development of catalytic methods that allow the coupling of
less functionalized components. Two palladium-catalyzed vari-
ants of these reactions have recently emerged, which gradually
reduce the amount of prefunctionalization required (Scheme 1).
The so-called “direct coupling” can be carried out with a Pd(0)
catalyst due to the inbuilt oxidizing power of one of the reaction
partners.2 In terms of their atom-economy, however, “oxidative
direct couplings”, wherein both partners are unfunctionalized,
are even more advantageous.3 These reactions typically involve
the electrophilic palladation of one reaction partner and require
the addition of an external oxidant, ideally molecular oxygen,
to close the catalytic cycle.4
The Heck coupling has undergone a similar development
toward decreased functionalization.5 Like traditional cross-
couplings, classical Heck reactions suffer from the stoichiometric
production of HX, which needs to be intercepted with stoichio-
metric amounts of a base. To overcome this requirement,
oxidative methodologies have been explored for the direct
coupling of arenes with alkenes, though few reliable catalytic
methods have emerged (Scheme 2).6 Until recently, only a
limited number of these catalytic processes had been applied
(1) For reviews on this topic, see: (a) Metal-catalyzed Cross-coupling
Reactions, 2nd ed.; Diederich, F., Stang, P. J., Eds.; Wiley-VCH: New York,
2004. (b) Hassa, J.; Sevignon, M.; Gozzi, C.; Schulz, E.; Lemaire, M. Chem.
ReV. 2002, 102, 1359.
10.1021/jo801791j CCC: $40.75
Published on Web 01/26/2009
2009 American Chemical Society
J. Org. Chem. 2009, 74, 1581–1586 1581

Bowie and Trauner
SCHEME 2. Variants of the Heck Reaction
FIGURE 1. Antitumor alkaloids rhazinilam and rhazinal.
SCHEME 3. Retrosynthetic Analysis of Rhazinal
to the synthesis of complex products due to the harsh condition
employed and difficulties with controlling the selectivity in these
reactions.
In 2005, we have described the application of a palladium-
catalyzed “direct coupling” in the total synthesis of the antitumor
alkaloid rhazinilam 1 (Figure 1).7 Herein, we demonstrate an
extension of this strategy in the synthesis of the congener
rhazinal (2). In addition, we wish to report on the development
and application of an oxidative Heck coupling to furnish the
tetrahydroindolizidine core of the natural products, which played
a key role in our total synthesis of 2.8
In 1998, Kam and co-workers reported the isolation of the
alkaloid (-)-rhazinal (2) from the stem extracts of a Malayan
Kopsia species.9 Similar to Taxol and vincristine, rhazinal was
found to interfere with tubulin polymerization dynamics, making
it a promising starting point for the development of anticancer
agents. Accordingly, compound 2 and its deformylated congener
rhazinilam (1) have attracted considerable attention both in the
biological and synthetic communities.10
Synthetically, rhazinal poses interesting challenges due to the
presence of a strained nine-membered lactam ring incorporating
a biaryl moiety and a quaternary stereocenter. Rhazinal, which
can be prepared by Vilsmeier-Haack formylation of the closely
related alkaloid (-)-rhazinilam (1),11 has been the subject of
two successful total syntheses to date by Banwell.10h This
elegant work relied on an organocatalytic intramolecular Michael
addition of a pendant pyrrole onto a tethered enal to afford the
tetrahydroindolizine scaffold.10d Another notable feature of this
synthesis was the usage of an intermolecular Suzuki coupling
to afford the key biaryl linkage.
We chose to take a very different route to demonstrate the
usefulness of novel palladium-catalyzed couplings. Our retro-
synthetic analysis hinges on a late-stage oxidative coupling
(involving 3a), or direct coupling (involving 3b), to form the
critical biaryl bond and close the strained 9-membered lactam
ring of rhazinal (Scheme 3). The formyl group would serve as
an inbuilt “protecting group” of the sensitive pyrrole nucleus
in this step. Retrosynthetic cleavage of the amide bond and
unsaturation would then afford alkene 4, whose tetrahydro-
indolizine system would be formed through an intramolecular
oxidative Heck reaction using a variant of pyrrole 5 as a
substrate.
(2) For recent examples of direct couplings in synthesis, see: (a) Pivsa-Art,
S.; Satoh, T.; Kawamura, Y.; Miura, M.; Nomura, M. Bull. Chem. Soc. Jpn.
1998, 71, 467. (b) Okazawa, T.; Satoh, T.; Miura, M.; Nomura, M. J. Am. Chem.
Soc. 2002, 124, 5286. (c) Sezen, B.; Sames, D. J. Am. Chem. Soc. 2003, 125,
5274. (d) Glover, B.; Harvey, K. A.; Liu, B.; Sharp, M. J.; Tymoschenko, M. F.
Org. Lett. 2003, 5, 301. (e) Park, C.-H.; Ryabova, V.; Seregin, I. V.; Sromek,
A. W.; Gevorgyan, V. Org. Lett. 2004, 6, 1159. (f) Campeau, L.-C.; Parisien,
M.; Leblanc, M.; Fagnou, K. J. Am. Chem. Soc. 2004, 126, 918.
(3) Stuart, D. R.; Fagnou, K. Science 2007, 316, 1172.
(4) Liegault, B.; Lee, D.; Huestis, M. P.; Stuart, D. R.; Fagnou, K. J. Org.
Chem. 2008, 73, 5022.
(5) For a recent review of the Heck reaction, see: (a) Dounay, A. B.; Overman,
L. E. Chem. ReV. 2003, 103, 2945. (b) Moritani, I.; Fujiwara, Y. Tetrahedron
Lett. 1967, 8, 1119. (c) Fujiwara, Y.; Moritani, I.; Matsuda, M.; Teranish, S
Tetrahedron Lett. 1968, 9, 633.
Results and Discussion
(6) (a) Beck, E. M.; Grimster, N. P.; Hatley, R.; Gaunt, M. J. J. Am. Chem.
Soc. 2006, 128, 2528. (b) Grimster, N. P.; Gauntlett, C.; Godfrey, C. R. A.;
Gaunt, M. J. Angew. Chem., Int. Ed. 2005, 44, 3125.
(7) Bowie, A. L.; Hughes, C. C.; Trauner, D. Org. Lett. 2005, 7, 5207.
(8) For related stoichiometric oxidative Heck cyclizations, see: (a) Garg,
N. K.; Capsi, D. D.; Stoltz, B. M. J. Am. Chem. Soc. 2004, 126, 9552. (b) Garg,
N. K.; Capsi, D. D.; Stoltz, B. M. J. Am. Chem. Soc. 2005, 127, 5970. (c) Baran,
P. S.; Corey, E. J. J. Am. Chem. Soc. 2002, 124, 7904.
Oxidative Coupling Studies. In order to access the congested
quaternary center, we first studied the feasibility of an oxidative
Heck cyclization. Our initial synthetic route began with a Claisen
rearrangement12 of known allylic alcohol 613 to afford the
E-trisubstituted ester 7. The ester was then reduced to the
corresponding alcohol, which was then converted into tosylate
8 (Scheme 4). A nucleophilic substitution of the tosyl group by
the potassium salt of pyrrole gave N-alkylated pyrrole 9.
(9) Kam, T. S.; Tee, Y. M.; Subramaniam, G. Nat. Prod. Lett. 1998, 12,
307.
(10) (a) Ratcliffe, A. H.; Smith, G. F.; Smith, G. N. Tetrahedron Lett. 1973,
14, 5179. (b) Johnson, J. A.; Li, N.; Sames, D. J. Am. Chem. Soc. 2002, 124,
6900. (c) Magnus, P.; Rainey, T. Tetrahedron 2001, 57, 8647. (d) Banwell, M. G.;
Edwards, A. J.; Jolliffe, K. A.; Smith, J. A.; Hamel, E.; Verdier-Pinard, P. Org.
Biomol. Chem. 2003, 1, 296–305. (e) Liu, Z. S.; Wasmuth, A. S.; Nelson, S. G.
J. Am. Chem. Soc. 2006, 128, 10352. (f) Baudoin, O.; Guenard, D.; Gueritte, F.
Mini-ReV. Org. Chem. 2004, 1, 333. (g) David, B.; Sevenet, T.; Morgat, M.;
Guenard, D.; Moisand, A.; Tollon, Y.; Thoison, O.; Wright, M. Cell Motility
Cytoskeleton 1994, 28, 317. (h) Banwell, M. G.; Beck, D. A. S.; Willis, A. C.
ARKIVOC 2006, 163.
(11) David, B.; Sevenet, T.; Thoison, O.; Awang, K.; Pais, M.; Wright, M.;
Guenard, D. Bioorg. Med. Chem. Lett. 1997, 7, 2155.
(12) Frauenrath, H. In Methods of Organic Chemistry (Houben-Weyl),
StereoselectiVe Synthesis, Vol. E21d; Helmchen, G., Hoffman, R. W., Mulzer,
J., Schaumann, R., Eds.; Thieme: Stuttgart, 1995; Vol. 330, pp 1-3756 and
references cited therein.
(13) Marvel, M; Saunders, J. J. Am. Chem. Soc. 1948, 70, 1698.
1582 J. Org. Chem. Vol. 74, No. 4, 2009

Total Synthesis of (()-Rhazinal
SCHEME 4. Preparations of Unsaturated Pyrrole 9
SCHEME 5. Synthesis of Tosylate 15
TABLE 1. Oxidative Carbocyclization of 9
yield time
(%) (h)
SCHEME 6. Oxidative Cyclization of 16
entry oxidant
additive
solvent
1
2
3
4
5
6
7
t-BuOOH none
t-BuOOH AgOAc
O2 none
t-BuOOH benzoic acid (0.6 equiv) DCE/DMSO (9:1)
O2 benzoic acid (1.5 equiv) DCE/DMSO (9:1)
t-BuOOH benzoic acid (1.5 equiv) DCE/DMSO (9:1)
DCE/DMSO (9:1)
DCE/DMSO (9:1)
DCE/DMSO (9:1)
25
2
10
33
48
54
15
4
13
23
26
19
3
t-BuOOH none
Diox/AcOH/DMSO 62
(9:3:1)
8
O2 none
Diox/AcOH/DMSO 55
(9:3:1)
10
The stage was now set for the investigation of the key
oxidative Heck cyclization. Table 1 depicts a representative list
of conditions and oxidants that were investigated in effecting
the key cyclization of 9. To our delight, exposure of 9 to
Pd(OAc)2 under a variety of conditions led to the formation of
10. The use of benzoic acid to help promote the oxidative
cyclization of 9 is interesting because it obviates the use of acetic
acid as a cosolvent (entry 6).14 Carefully optimized conditions
afforded the tetrahydroindolizidine 10 as a single regioisomer
in 62% yield (entry 7). In our hands, the optimal oxidant appears
to be tert-butyl hydroperoxide (t-BuOOH), and benzoic acid
was not required as an additive. The use of molecular oxygen
resulted in longer reaction times and slightly decreased yields.
A similar protocol was described by Gaunt and co-workers and
recently featured in a total synthesis of the related natural
product rhazinicine.15
With this robust and concise route to heterocycle 10 in hand,
attempts were made to convert 10 into the carboxylic acid 4
(Scheme 3). Unfortunately, the neopentylic vinyl group could
not be functionalized effectively, presumably due to steric
hindrance. Therefore, an alternative approach was developed.
Synthesis of Tetrahydroindolizine 17. Having worked out
a viable method for the oxidative Heck cyclization, we
proceeded to synthesize a more highly functionalized cyclization
precursor (Scheme 5). Mild organocatalytic R-methylenation of
known aldehyde 1116 provided enal 12 in excellent yield.17
Treatment of 12 with methyllithium yielded allylic alcohol 13,
which smoothly underwent Claisen rearrangement to afford
E-trisubstituted ester 14. Deprotection and subsequent tosylation
yielded tosylate 15 in modest yield.
Nucleophilic substitution of the tosyate group with the
potassium salt of pyrrole gave N-alkylated pyrrole 5. With the
requisite functional handle in place, the stage was now set for
the implementation of the key oxidative cyclization (Scheme
6). Gratifyingly, using 10 mol % of Pd(OAc)2 in the presence
of a mixed solvent system and t-BuOOH resulted in the clean
formation of tetrahydroindolizine 16 with the requisite quater-
nary stereocenter in 69% yield. Tetrahydroindolizine 16 was
subjected to facile Vilsmeier-Haack formylation, affording
aldehyde 17 as a single regioisomer.
In parallel to investigating the oxidative Heck approach to
the tetrahydroindolizinyl core of rhazinal, we also pursued a
classical Heck route involving iodopyrole 19 (Scheme 5). This
would open an opportunity to investigate asymmetric Heck
cyclizations, which were found to be elusive under oxidative
conditions. Although 19 is a known compound,18 the published
procedure for its synthesis gave low yields of the desired product
in our hands (∼30%). Gratifyingly, we found that the known
azafulvene 18 could be C-metalated with tert-butyllithium and
quenched with molecular iodine. The corresponding 5-iodo-2-
pyrrole carbaldehyde 19 was isolated via hydrolysis of the
azafulvene with sodium acetate in refluxing THF. A high-
yielding nucleophilic substitution of the tosylate 15 by the
potassium salt of pyrrole 19 then gave N-alkylated pyrrole 20.
Heck reaction of 20 under modified Jeffery conditions yielded
the annulated pyrrole 17 in good yield, which was identical in
all respects to the 17 made from the formylation of 16 (Scheme
7).19 Unfortunately, all attempts to develop an asymmetric
(14) Dams, M.; De Vos, D.; Celen, S.; Jacobs, P. Angew. Chem., Int. Ed.
2003, 42, 3512.
(15) Beck, E. M.; Hatley, R.; Gaunt, M. J. Angew. Chem., Int. Ed. 2008, 47,
3004.
(16) Kim, D.; Freeman, F. J. Org. Chem. 1992, 57, 1727.
(17) Erkkila, A.; Pihko, P. J. Org. Chem. 2006, 71, 2538.
(18) Denat, F.; Gaspard-Iloughmane, H.; Dubac, J. J. Organomet. Chem.
1992, 423, 173.
(19) Gradl, S.; Kennedy-Smith, J.; Kim, J; Trauner, D. Synlett 2002, 1437.
J. Org. Chem. Vol. 74, No. 4, 2009 1583

Bowie and Trauner
SCHEME 7. Heck Reaction of 20
SCHEME 9. Completion of Rhazinal
SCHEME 8. Preparation of Precursor 22
results in formation of the biaryl bond and the strained
9-membered lactam ring. The electron-rich Buchwald ligand
23 may not only facilitate oxidative addition but also the
formation of a more reactive cationic palladium(II) species by
dissociation of the halide. As noted before in our synthesis of
rhazinilam, the MOM group proved crucial for the success of
this cyclization, as the free amide resulted exclusively in proto-
deiodination and no cyclized product could be observed. This
could be due to formation of a very stable six-membered oxa-
palladacyle or the altered conformational preferences of second-
ary vs tertiary amides. The structure of N-MOM rhazinal 26
was confirmed by X-ray crystallography proving our structural
assignment and providing a detailed view of the 9-membered
ring (for clarity the unnatural series is displayed; see the
Supporting Information). As previously observed in the X-ray
structure of rhazinal, the amide adopts an unusual cisoid
conformation.10
The MOM protecting group could be removed by treatment
of 26 with a large excess of boron trichloride at low tempera-
ture.21 This afforded racemic rhazinal (2), which was identical
in all respects to the natural product with the exception of its
optical activity (Scheme 9).9
Attempted Oxidative Direct Coupling. Having worked out
a viable synthesis of rhazinal that involves both an oxidative
Heck reaction and a direct coupling, we finally turned our
attention toward the direct oxidative coupling involving precur-
sor 3a (Scheme 10). We had some hope that such an ambitious
plan would be met with success since the electrophilic ortho-
palladation of acyl anilines is well-known and the resulting
palladium(II) complexes have been shown to engage in Heck
couplings.22 Unfortunately, despite many attempts under a
version of this reaction using chiral phosphine ligands gave low
yields and disappointing ee’s.
Total Synthesis of Rhazinal via Direct Coupling. With two
viable syntheses of racemic tetrahydroindolizidine 17 in hand,
we proceeded to investigate the formation of the 9-membered
lactam ring in the final stages of the synthesis. Chemoselective
reduction of alkene 17 using Crabtree’s catalyst afforded the
corresponding saturated ester, which was subsequently saponi-
fied with lithium hydroxide to reveal the key acid 21 in excellent
yield. Other more common catalysts such as Wilkinson’s and
Pd/C led to partial reduction of the formyl group. Coupling of
21 with 2-iodoaniline under Mukaiyama’s conditions20 then
afforded amide 3b. Subsequent protection of the amide as a
methoxymethyl (MOM) derivative then gave 22, our key
intermediate for the direct coupling (Scheme 8).
After extensive screening of various ligands and metal
sources, we found that the optimal conditions identified in our
previous synthesis of rhazinilam,7 namely heating 22 with 10
mol % of Buchwald’s “DavePhos” ligand (23) and Pd(OAc)2
in the presence of a potassium carbonate, were also most
effective for the formation of the strained 9-membered ring in
N-MOM rhazinal 26 (43% yield). Under a variety of other
conditions we found little or no intended product and usually
observed simple deiodination of the aryl ring.
Mechanistically, this key cyclization reaction could proceed
through intramolecular nucleophilic attack of the pyrrole moiety
onto the Pd(II) center in 24, followed by deprotonation.
Subsequent reductive elimination of Pd(0) from complex 25 then
(21) Nicolaou, K. C.; Chen, David Y.-K.; Huang, X.; Ling, T.; Bella, M.;
Snyder, S. A J. Am. Chem. Soc. 2004, 126, 12888.
(22) Daugulis, O.; Zaitsev, V. G. Angew. Chem., Int. Ed. 2005, 44, 4046.
(20) Mukaiyama, T. Angew. Chem., Int. Ed. 1979, 18, 707.
1584 J. Org. Chem. Vol. 74, No. 4, 2009

Total Synthesis of (()-Rhazinal
SCHEME 10. Attempted Oxidative Direct Coupling
extraction with CH2Cl2 (3 × 20 mL). The combined organic extracts
were dried, filtered, and concentrated in vacuo to give a dark brown
solid. The product was purified by column chromatography (25%
EtOAc in hexanes) to afford 1.4 g (65%) of 19 as an off-white
1
solid: IR (film) 1730 cm-1; H NMR δ 10.7 (br s, 1H), 9.32 (s,
1H), 6.84 (d, J ) 4.0 Hz, 1H), 6.50 (d, J ) 4.0 Hz, 1H), 13C NMR
δ 177.7, 136.9, 123.2, 120.9, 78.2; HRMS (EI+) m/z (M+) calcd
for C5H4INO 220.9338, found 220.9332.
4-Eth-(Z)-ylidene-7-(2-formyl-5-iodopyrrol-1-yl)heptanoic
Acid Ethyl Ester 20. To 19 (265 mg, 2.79 mmol) in acetonitrile
(7 mL) was added potassium carbonate (1.15 g, 8.4 mmol). The
tosylate 15 was then added to the mixture, and the reaction was
stirred at 45 °C for 8 h. The reaction was allowed to cool to room
temperature and then poured into water (30 mL) and extracted with
ether (3 × 20 mL). The combined organic extracts were washed
with water (2 × 50 mL) and brine (50 mL), dried, filtered, and
concentrated. The product was purified by column chromatography
(15% EtOAc in hexanes) to afford 1.09 g (97%) of 20 as a colorless
1
oil: IR (film) 1728, 1664, 1265 cm-1; H NMR δ 9.10 (s, 1H),
6.76 (d, J ) 4.0 Hz, 1H), 6.34 (d, J ) 4.0 Hz, 1H), 5.15 (q, J )
6.8 Hz, 1H), 4.22 (t, J ) 8.0 Hz, 2H), 4.00 (t, J ) 6.8 Hz, 2H),
2.29 (m, 4H), 2.00 (t, J ) 8.0 Hz, 2H), 1.66 (m, 2H), 1.47 (d, J )
6.8 Hz, 3H), 1.14 (t, J ) 6.8 Hz, 3H); 13C NMR δ 177.3, 173.2,
137.0, 134.3, 125.9, 120.1, 119.9, 87.5, 60.1, 49.4, 33.0, 31.7, 29.1,
26.6, 14.2, 13.2; HRMS (EI+) m/z (M + Na+) calcd for C16H22INO3
426.0542, found 426.0534.
variety of conditions, the desired transformation could not
achieved and the total synthesis of rhazinal through oxidative
direct coupling remains an elusive goal.
Conclusion. In summary, we have developed a highly
efficient and concise synthesis of rhazinal. Notable features of
this synthesis include the development of several oxidative
protocols for the construction of the tetrahydroindolizinyl moiety
present in both rhazinal and rhazinilam. Future work will focus
on the development of oxidative ortho-palladation/direct-
coupling strategies for the synthesis of these natural products
and related biologically active molecules. We are also working
on asymmetric versions of our aerobic cyclization en route to
tetrahydroindolizines.
3-(3-Formyl-8-vinyl-5,6,7,8-tetrahydroindolizin-8-yl)propi-
onic Acid Ethyl Ester 17. To iodopyrrole 20 (1.90 g, 4.7
mmol) were added H2O (1.99 mL, 2.4 M), MeCN (24.3 mL, 0.2
M), Et3N (1.96 mL, 14.0 mmol), tetrabutylammonium bromide
(4.53 g, 14.0 mmol), and finally Pd(OAc)2 (52.5 mg, 0.23 mmol).
The reaction vessel was sparged with N2 atmosphere three times
prior to heating. The solution was heated to 75 °C for 15 h, cooled
to room temperature, and filtered over a plug of silica gel (10%
EtOAc in hexanes). After removal of solvent in vacuo, the product
was purified by flash chromatography on silica gel (10% EtOAc in
hexanes) to afford 0.944 mg (73%) of annulated pyrrole 17: IR
(film) 1727, 1655 cm-1; 1H NMR δ 9.30 (s, 1H), 6.77 (d, J ) 4.0
Hz, 1H), 5.97 (d, J ) 4.0 Hz, 1H), 5.69 (q, J ) 7.0 Hz, 1H), 4.97
(d, J ) 10.5 Hz, 1H), 4.66 (d, J ) 17.0 Hz, 2H), 3.97 (m, 3H),
2.22-2.09 (m, 2H), 1.95 (m, 2H), 1.88 (m, 2H), 1.65 (m, 2H) 1.15
(t, J ) 6.8 Hz, 3H); 13C NMR δ 178.4, 173.0, 143.7, 143.3, 130.8,
124.1, 114.8, 108.1 60.1, 45.4, 42.1, 35.1, 29.4, 29.1, 18.9, 14.1;
HRMS (EI+) m/z (M + H+) calcd for C16H21NO3 276.1599, found
276.1593.
Experimental Section
3-(3-Formyl-8-vinyl-5,6,7,8-tetrahydroindolizin-8-yl)propi-
onic Acid Ethyl Ester 17. To a cooled solution (0 °C) of the
pyrrole 16 (144 mg, 0.60 mmol) and DMF (0.58 mL) in Et2O (6.5
mL) was added phosphorus oxychloride (98.6 mg, 0.64 mmol).
After 0.5 h, the ice bath was removed and the mixture was stirred
at room temperature for 3 h before the addition of Et2O (26 mL)
and Na2CO3 (26 mL of a 2 M aqueous solution). Stirring was
continued for 10 min before the phases were separated, and the
aqueous phase was extracted with Et2O (2 × 30 mL). The combined
organic extracts were dried, filtered, and concentrated in vacuo to
give a dark yellow oil. The product was subsequently purified by
column chromatography (10% EtOAc in hexanes) to afford 146
3-(8-Ethyl-3-formyl-5,6,7,8-tetrahydroindolizin-8-yl)propi-
onic Acid Ethyl Ester. The alkene 17 (958 mg, 3.48 mmol)
was dissolved in CH2Cl2 (25 mL), and then Crabtree’s catalyst (208
mg, 0.35 mmol) was added. The vessel was sparged with an H2
atmosphere three times prior to being charged with an H2 balloon.
The reaction was allowed to stir at room temperature for 18 h. After
removal of solvent in vacuo, the product was purified by flash
chromatography on silica gel (10% EtOAc in hexanes) to afford
0.83 mg (86%) of 3-(8-ethyl-3-formyl-5,6,7,8-tetrahydroindolizin-
8-yl)propionic acid ethyl ester: IR (film) 2982, 1729, 1653, 1265
1
mg (88%) of 17 as a foamy solid: IR (film) 1727, 1655 cm-1; H
NMR δ 9.30 (s, 1H), 6.77 (d, J ) 4.0 Hz, 1H), 5.97 (d, J ) 4.0
Hz, 1H), 5.69 (q, J ) 7.0 Hz, 1H), 4.97 (d, J ) 10.5 Hz, 1H), 4.66
(d, J ) 17.0 Hz, 2H), 3.97 (m, 3H), 2.22-2.09 (m, 2H), 1.95 (m,
2H), 1.88 (m, 2H), 1.65 (m, 2H) 1.15 (t, J ) 6.8 Hz, 3H); 13C
NMR δ 178.4, 173.0, 143.7, 143.3, 130.8, 124.1, 114.8, 108.1 60.1,
45.4, 42.1, 35.1, 29.4, 29.1, 18.9, 14.1; HRMS (EI+) m/z (M +
H+) calcd for C16H21NO3 276.1599, found 276.1598.
1
cm-1; H NMR δ 9.23 (s, 1H), 6.72 (d, J ) 4.0 Hz, 1H), 5.88 (d,
J ) 4.0 Hz, 1H), 4.17 (t, J ) 6.0 Hz, 2H), 3.93 (q, J ) 6.0 Hz,
2H), 2.15-2.00 (m, 2H), 1.83-1.80 (m, 4H), 1.07 (t, J ) 6.0 Hz,
3H), 0.69 (t, J ) 6.0 Hz, 3H); 13C NMR δ 178.1, 173.1, 145.7,
143.3, 130.6, 124.1, 107.2, 60.1, 45.1, 37.8, 34.5, 33.0, 29.5, 28.6,
19.3, 14.0, 8.3; HRMS (EI+) m/z (M + H+) calcd for C16H23NO3
278.1756, found 278.1764.
5-Iodopyrrole-2-carbaldehyde 19. To a cooled (-15 °C)
solution of azafulvene 18 (1.2 g, 4.92 mmol) in 50 mL of anhydrous
t
THF was added 11.68 mmol of BuLi (1.6 M in pentane). The
3-(8-Ethyl-3-formyl-5,6,7,8-tetrahydroindolizin-8-yl)propi-
onic Acid 21. To 3-(8-ethyl-3-formyl-5,6,7,8-tetrahydroindolizin-
8-yl)propionic acid ethyl ester (963 mg, 3.48 mmol) in THF (17.4
mL) was added a solution of lithium hydroxide (291 mg, 12.2
mmol) in H2O (8.7 mL). The reaction was allowed to stir for 16 h
at room temperature. The mixture was diluted with H2O (20 mL)
and then extracted with EtOAc. The aqueous layer was then
mixture was stirred for 15 min at -15 °C then for 30 min at 0 °C
and 1 h at room temperature. The violet solution thus formed was
cooled to -75 °C, iodine (2.9 g, 11.68 mmol) was added slowly,
and the mixture was stirred for 2 h at room temperature, becoming
dark blue-green to black. Hydrolysis with a 1:1 solution of water
and saturated bicarbonate at reflux for 5 h was followed by
J. Org. Chem. Vol. 74, No. 4, 2009 1585

Bowie and Trauner
acidified to pH 2 with 1 N hydrochloric acid and then extracted
with CH2Cl2 (3 × 25 mL). The combined organic extracts were
dried, filtered, and concentrated in vacuo to give a yellow oil. The
product was subsequently purified by column chromatography (35%
EtOAc in hexanes) to afford 859 mg (99%) of 21 as a foamy solid:
IR (film) 3055, 2987, 1653 cm-1; 1H NMR δ 9.33 (s, 1H), 6.90 (d,
J ) 5.0 Hz, 1H), 6.04 (d, J ) 5.0 Hz, 1H), 4.31 (m, 2H), 2.33-2.21
(m, 2H), 2.04-1.92 (m, 4H), 1.76 (m, 1H), 1.67 (m, 3H), 0.80 (t,
J ) 6.0 Hz, 3H); 13C NMR δ 179.1, 178.7, 146.3, 130.7, 125.1,
107.7, 45.4, 38.1, 34.5, 33.2, 29.6, 28.8, 26.6, 19.5, 8.5; HRMS
(EI+) m/z (M + H+) calcd for C14H19NO3 250.1443, found
250.1443.
Lactam 26. Iodide 22 (53.5 mg, 0.11 mmol), potassium
carbonate (29.9 mg, 0.22 mmol), 2-dicyclohexylphosphino-2′-(N,N-
dimethylamino)biphenyl (4.3 mg, 0.11 mmol), and palladium
acetate (2.5 mg, 0.11 mmol) were placed in a flame-dried vial. The
vial was flushed with nitrogen, N,N-dimethylacetamide (DMA, 1.8
mL) was added, and the solution was heated to 135 °C. After 18 h,
the solution was allowed to cool, and the solvent was removed by
rotary evaporation under high vacuum. The resulting black residue
was diluted with CH2Cl2 and passed through a plug of silica gel.
The product was purified by column chromatography (25% EtOAc
in hexanes) to afford 17.3 mg (43%) of 26 as a white solid: IR
1
(film) 1653 cm -1; H NMR δ 9.37 (s, 1 H), 7.43 (m, 1 H), 7.35
(m, 3 H) 6.57 (s, 1 H), 5.17 (d, J ) 10.0 Hz, 1 H), 4.75 (m, 1 H),
4.30 (d, J ) 10.0 Hz, 1 H), 3.93 (m, 1 H), 3.26 (s, 3 H), 2.50 (m,
2 H), 2.17 (m, 2 H), 1.92 (m, 1 H), 1.73 (m, 1 H), 1.55 (m, 4 H),
0.86 (t, J ) 10.0 Hz, 3H); 13C NMR δ 178.6, 175.3, 142.5, 141.4,
136.9, 131.3, 129.9, 129.1, 127.5, 127.1, 125.6, 120.0, 78.9, 56.8,
46.3, 39.7, 36.8, 31.9, 29.8, 29.4, 18.5, 8.2; HRMS (EI+) m/z (M
+ Na+) calcd for C22H26N2O3 389.1841, found 389.1842.
Rhazinal 2. To a solution of lactam 26 (16 mg, 0.044 mmol) in
CH2Cl2 (2.2 mL) at -78 °C was added boron trichloride (0.44 mL,
1.0 M, 0.44 mmol) dropwise via syringe over 2 min. After 2.5 h at
-78 °C, the reaction was quenched with a saturated NaHCO3
solution (5 mL), and the mixture was extracted with EtOAc (3 ×
15 mL), dried, and concentrated down. The crude solid was
dissolved in MeOH (2.2 mL) and Et3N (0.14 mL) and the solution
was heated at 50 °C for 2 h. The product was purified by column
chromatography (30% EtOAc in hexanes) to give 8.0 mg (45%)
of 1 as a white solid: mp 230-234 °C; IR (film) 3510, 1662 cm
-1; 1H NMR δ 9.39 (s, 1 H), 7.41 (m, 1 H), 7.37 (m, 3 H) 6.74 (br
s, 1 H), 6.55 (s, 1 H), 4.78 (m, 1 H), 3.98 (m, 1 H), 2.50 (m, 2 H),
2.19 (m, 1 H), 2.04 (m 1 H), 1.97 (m, 1 H), 1.79 (m, 1 H), 1.55
(m, 3 H), 1.24 (m, 1 H), 0.71 (t, J ) 7.5 Hz, 3 H); 13C NMR δ
178.6, 176.57, 141.4, 138.2, 137.5, 131.3, 130.1, 129.0, 127.8,
127.1, 125.6, 120.4, 46.3, 39.6, 36.6, 31.9, 29.8, 28.0, 18.5, 8.1;
HRMS (EI+) m/z (M + H+) calcd for C20H22N2O2 323.1759, found
323.1755.
3-(8-Ethyl-3-formyl-5,6,7,8-tetrahydroindolizin-8-yl)-N-(2-
iodophenyl)propionamide 3b. To a solution of acid 21 (301 mg,
1.20 mmol) in CH2Cl2 (6 mL) were added 2-chloro-1-methyl-
pyridinium iodide (371 mg, 1.45 mmol), 2-iodoaniline (317 mg,
1.45 mmol), and Et3N (0.33 mL, 2.4 mmol). The mixture was heated
at reflux for an additional 15 h, allowed to cool, poured into water
(40 mL), and extracted with CH2Cl2 (3 × 20 mL). The combined
organic extracts were dried, filtered, and concentrated. The product
was purified by column chromatography (25% EtOAc in hexanes)
to furnish 299 mg (55%) of 3 as a foamy solid: IR (film) 3300,
1
2946, 1724, 1654 cm-1; H NMR δ 9.42 (m, 1 H), 8.13 (d, J )
10.0 Hz, 1 H), 7.74 (d, J ) 5.0 Hz, 1 H) 7.42 (br s, 1 H), 7.30 (t,
J ) 5 Hz, 1 H), 6.89 (d, J ) 5.0 Hz, 1 H), 6.82 (t, J ) 5 Hz, 1 H),
6.08 (d, J ) 5.0 Hz, 1 H), 4.37 (m, 1H), 4.28 (m, 1H), 2.34 (m, 1
H), 2.23 (m, 1 H), 2.03 (m, 2 H), 1.97 (m, 2 H), 1.70 (m, 4 H),
0.86 (t, J ) 10 Hz, 3H); 13C NMR δ 178.6, 171.0, 146.1, 138.8,
138.1, 130.9, 129.3, 126.1, 124.7, 122.3, 107.5, 90.3, 45.5, 38.3,
35.3, 33.6, 33.2, 28.8, 19.6, 8.6; HRMS (EI+) m/z (M + H+) calcd
for C20H23IN2O2 451.0883, found 451.0891.
3-(8-Ethyl-3-formyl-5,6,7,8-tetrahydroindolizin-8-yl)-N-(2-
iodophenyl)-N-methoxymethylpropionamide 22. To a solution
of the amide 3b (234 mg, 0.520 mmol) in THF (2.66 mL) at -78
°C was added a solution of sodium bis(trimethylsilyl)amide in THF
(0.34 mL, 2.0 M, 0.68 mmol) dropwise via syringe. After 2 h at 0
°C, a solution of chloromethyl methyl ether in THF (1.0 mL, 0.70
M, 0.70 mmol) was added dropwise. After an additional 10 min,
the mixture was allowed to warm to room temperature over 1 h,
diluted with water (15 mL), and extracted with EtOAc (3 × 20
mL). The product was purified by column chromatography (30%
EtOAc in hexanes) to yield 191 mg (75%) of 22 as a yellowish
solid: IR (film) 3055, 2364, 1722, 1653 cm-1; 1H NMR δ 9.37 (s,
1 H), 7.93 (m, 1 H), 7.37 (t, J ) 8.0 Hz, 1 H) 7.22 (d, J ) 8.0 Hz,
0.5 H), 7.15 (d, J ) 8.0 Hz, 0.5 H), 7.07 (t, J ) 8.0 Hz, 1 H), 6.77
(m, 1 H), 5.80 (m, 1 H), 5.55 (m, 1H), 4.32 (m, 1H), 4.22-4.11
(m, 2 H), 3.42 (s, 3 H), 1.98-1.78 (m, 6 H), 1.61 (m, 1 H), 1.45
(m, 3 H), 0.86 (t, J ) 8.0 Hz, 3H); 13C NMR δ 178.4, 173.7, 146.2,
143.2, 140.1, 130.8, 130.6, 130.2, 129.6, 124.5, 107.5, 100.5, 90.3,
78.1, 57.0, 45.3, 38.1, 38.0, 35.1, 34.9, 35.3, 33.1, 32.9, 30.1, 30.0,
28.9, 28.7, 19.5, 8.5; HRMS (EI+) m/z (M + Na+) calcd for
C22H27IN2O3 517.0964, found 517.0960.
Acknowledgment. We acknowledge financial support from
Novartis, Roche, and the National Institutes of Health (Minority
Supplement). We thank Dr. Frederick J. Hollander and Dr. Allen
G. Oliver for the crystal structure determination of compound
26.
Supporting Information Available: Experimental proce-
dures for the preparation of 5, 7-16, and 3a and the X-ray
structure of 26. Copies of NMR spectra for all new compounds
are available (including X-ray structure CCDC 697745). This
material is available free of charge via the Internet at
http://pubs.acs.org.
JO801791J
1586 J. Org. Chem. Vol. 74, No. 4, 2009