Total synthesis of rhazinilam: Axial to point chirality transfer in an enantiospecific Pd-catalyzed transannular cyclization

Article abstract of DOI:10.1021/ol101523z

Figure Presented. A total synthesis of rhazinilam based on a transannular cyclization strategy is described. Using a Heck reaction, the axial chirality of a halogenated 13-membered lactam can be exploited to create the quaternary chiral stereogenic center in the target molecule with high enantiospecificity.

Full text of DOI:10.1021/ol101523z

ORGANIC
LETTERS
2010
Vol. 12, No. 19
4224-4227
Total Synthesis of Rhazinilam: Axial to
Point Chirality Transfer in an
Enantiospecific Pd-Catalyzed Transannular
Cyclization
Zhenhua Gu and Armen Zakarian*
Department of Chemistry and Biochemistry, UniVersity of California at Santa Barbara,
Santa Barbara, California 93106
zakarian@chem.ucsb.edu
Received July 2, 2010
ABSTRACT
A total synthesis of rhazinilam based on a transannular cyclization strategy is described. Using a Heck reaction, the axial chirality of a
halogenated 13-membered lactam can be exploited to create the quaternary chiral stereogenic center in the target molecule with high
enantiospecificity.
The unusual structure of rhazinilam provided an attractive
platform for the development and exploration of new
methods and strategies in synthesis. Rhazinilam is character-
ized by a tetracyclic framework that incorporates a hetero-
biaryl fragment containing a pyrrole and substituted aniline
units, a strained nine-membered lactam, and a quaternary
chiral center linked to the pyrrole at the C2-position (Figure
1). Originally isolated from Rhazya stricta Decaisne,1
rhazinilam belongs to a group of natural products that mirror
the cellular activity of taxol,2 generating an additional
incentive for their synthesis. It showed inhibition of both
microtubule assembly and disassembly in vitro, promoted
the formation of abnormal tubulin spirals, and was found to
lead to microtubule bundles, multiple asters, and stability of
microtubules at low temperatures.3 Rhazinilam showed
Figure 1. Rhazinilam natural products.
cytotoxicity toward various cancer cell lines at low micro-
molar range in vitro and no activity in vivo.3
The first synthesis of rhazinilam by Smith and co-workers
in 1973 relied on an electrophilic aromatic substitution
reaction at the C2 position of the protected pyrrole nucleus
to install the quaternary stereogenic center (pyrrole number-
(1) Banerji, A.; Majumder, P. L.; Chatterjee, A. G. Phytochemistry 1970,
9, 1491–1493.
(3) (a) De´cor, A.; Bellocq, D.; Thoison, O.; Lekieffre, N.; Chiaroni,
A.; Ouazzani, J.; Cresteil, T.; Gue´ritte, F.; Baudoin, O. Bioorg. Med. Chem.
2006, 14, 1558–1564. (b) David, B.; Se´venet, T.; Thoison, O.; Awang, K.;
Pa¨ıs, M.; Wright, M.; Gue´nard, D. Bioorg. Med. Chem. Lett. 1997, 7, 2155–
2158.
(2) David, B.; Se´venet, T.; Morgat, M.; Gue´nard, D.; Moisand, A.;
Tollon, Y.; Thoison, O.; Wright, M. Cell Motil. Cytoskeleton 1994, 28,
317–326.
10.1021/ol101523z  2010 American Chemical Society
Published on Web 08/26/2010

ing).4 Similar ring-formation order was employed in a
number of more recent syntheses, including those highlight-
ing modern C-H-functionalization tactics reported by the
groups of Gaunt (rhazinicine),5 Sames,6 and Trauner.7 The
synthesis developed by Magnus and Rainey in 2001 illustrates
a new method for pyrrole synthesis and avoids the C5-protection
of the heterocycle.8 A gold(I)-catalyzed allene annulation was
utilized by the group of Nelson in 2006 to accomplish an
enantioselective total synthesis of rhazinilam.9 In the same year,
Banwell and co-workers described the synthesis of (-)-
rhazinilam and (-)-rhazinal capitalizing on enantioselective
electrophilic pyrrole alkylation under imminium-ion catalysis
to form the tetrahydroindolizine fragment.10
an initial study of the transannular cyclization, unveiling 13-
membered macrolactam 4 as a key precursor. We anticipated
that a variety of chiral ligands available for palladium would
eventually allow for the development of an enantioselective
version of the palladium-catalyzed transannular reaction.13
In practice, the pursuit of this synthesis plan provided an
unexpected insight into the stereochemistry of advanced
macrocyclic intermediates offering a distinct approach to
enantioselective synthesis of rhazinilam alkaloids in the
future.
The synthesis of macrolactam 4 began with the preparation
of 2-(1H-pyrrol-3-yl)aniline (8) following a literature pre-
cedent.14 Borylation of 3-bromo-N-triisopropylsilylpyrrole
(5) with pinacolborane (1.2 equiv) in the presence of
bis(acetonitrile)palladium dichloride (3 mol %) and S-Phos
(9 mol %) provided boronate 6 (Scheme 2). Cross-coupling
Strategically, all of these syntheses share a sequential ring-
formation approach starting with the assembly of the
tetrahydroindolizine ring system and concluding with the
formation of the nine-membered lactam.
Considering various options in the synthesis design, we
became intrigued by the potential of a transannular cycliza-
tion outlined in Scheme 1 to achieve the installation of the
Scheme 2. Synthesis of 2-(1H-Pyrrol-3-yl)aniline (8)
Scheme 1
.
Transannular Disconnection in the Synthesis of
Rhazinilama
of 6 with 2-iodoaniline was achieved with the same ligand
(S-Phos, 8 mol %), palladium acetate (4 mol %), and
potassium phosphate in aqueous 1-butanol in 91% yield.
Removal of the triisopropylsilyl group was carried out under
basic conditions (MeONa, methanol, reflux) to complete the
synthesis of 8 in 92% yield.15
a M ) transition metal.
quaternary stereogenic center, the nine-membered lactam,
and the tetrahydroindolizine ring system in a single bond-
forming event. Transannular cyclizations have been recog-
nized as a powerful approach in the synthesis of polycyclic
ring systems.11 A transition-metal-catalyzed process such as
a Heck reaction12 was identified as a preferred method for
The preparation of iodoolefin 13 was initiated by the
Michael addition of 2,4-pentanedione to tert-butyl acrylate
upon treatment with potassium carbonate at 70 °C (Scheme
3). The resulting 1,3-diketone was exposed to aqueous
formaldehyde under basic conditions producing enone 10 in
77% yield after a cascade condensation-fragmentation
process.16 Luche reduction (NaBH4, CeCl3·7H2O, MeOH)17
followed by acetylation gave 11, which served as a substrate
for subsequent Ireland-Claisen rearrangement forming acid
12 in 71% yield.18 Selective reduction of 12 followed by
iododehydroxylation provided iodide 13 in 79% overall yield.
Preceding the macrolactam formation, a regioselective
halogenation at the C2 position of 2-(1H-pyrrol-3-yl)aniline
(8) was required. This type of selective functionalization is
useful for the synthesis of a variety of bioactive compounds
(4) Ratcliffe, A. H.; Smith, G. F.; Smith, G. N. Tetrahedron Lett. 1973,
14, 5179–5184.
(5) Beck, E. M.; Hatley, R.; Gaunt, M. J. Angew. Chem., Int. Ed. 2008,
47, 3004–3007.
(6) (a) Johnson, J. A.; Sames, D. J. Am. Chem. Soc. 2000, 122, 6321–
6322. (b) Johnson, J. A.; Li, N.; Sames, D. J. Am. Chem. Soc. 2002, 124,
6900–6903.
(7) (a) Bowie, A. L.; Hughes, C. C.; Trauner, D. Org. Lett. 2005, 7,
5207–5209. (b) Bowie, A. L.; Trauner, D. J. Org. Chem. 2009, 74, 1581–
1586.
(8) Magnus, P.; Rainey, T. Tetrahedron 2001, 57, 8647–8651.
(9) Liu, Z.; Wasmuth, A. S.; Nelson, S. G. J. Am. Chem. Soc. 2006,
128, 10352–10353.
(10) (a) Banwell, M. G.; Beck, D. A. S.; Willis, A. C. ARKIVOC 2006,
163–174. (b) Banwell, M. G.; Edwards, A. J.; Jolliffe, K. A.; Smith, J. A.;
Hamel, E.; Verdier-Pinard, P. Org. Biomol. Chem. 2003, 1, 296–305.
(11) For recent examples, see: (a) Balskus, E. P.; Jacobsen, E. N. Science
2007, 317, 1736. (b) Bodwell, G. J.; Li, J. Angew. Chem., Int. Ed. 2002,
41, 3261–3262. (c) Chandler, C. L.; List, B. J. Am. Chem. Soc. 2008, 130,
6737–6739. (d) Dalgard, J. E.; Rychnovsky, S. D. Org. Lett. 2004, 6, 2713–
2716. (e) Basak, A.; Roy, S. K.; Mandal, S. Angew. Chem., Int. Ed. 2005,
44, 132–135.
(13) Dounay, A. B.; Overman, L. E. Chem. ReV. 2003, 103, 2945–2963.
(14) Morrison, M. D.; Hanthorn, J. J.; Pratt, D. A. Org. Lett. 2009, 11,
1051–1054.
(15) Chan, H.-W.; Chan, P.-C.; Liu, J.-H.; Wong, H. N. C. Chem.
Commun. 1997, 1515–1516.
(16) Kalaus, G.; Juha´sz, I.; Greiner, I.; Kajtar-Peredy, M.; Brlik, J.;
Szabo´, L.; Sza´ntay, C. J. Org. Chem. 1997, 62, 9188–9191.
(17) Gemal, A. L.; Luche, J.-L. J. Org. Chem. 1979, 44, 4187–4189.
(18) (a) Ireland, R. E.; Mueller, R. H. J. Am. Chem. Soc. 1972, 94, 5897–
5898. (b) Ireland, R. E.; Mueller, R. H.; Willard, A. K. J. Am. Chem. Soc.
1976, 98, 2868–2877.
(12) (a) Mizoroki, T.; Mori, K.; Ozaki, A. Bull. Chem. Soc. Jpn. 1971,
44, 581. (b) Heck, R. F.; Nolley, J. P. J. Org. Chem. 1972, 37, 2320–2322.
Org. Lett., Vol. 12, No. 19, 2010
4225

The yields increased with increasing amount of acid, reaching
87% when 3 equiv of trifluoroacetic acid (TFA) was used.
These results suggest that acid additives prevent competitive
halogenation of the aniline that lead to eventual decomposi-
tion. Iodination was explored next, with N-iodosuccinimide
(NIS) as the source of iodine. While reactions in dichlo-
romethane and THF at 0 °C were not productive, application
of 1,1,1,3,3,3-hexafluoroisopropanol (HFIP),21 which acti-
vates NIS and likely stabilizes the product by hydrogen
bonding, resulted in a 30% yield of the 2-iodo derivative 15
along with the recovery of the starting material (37%).
Addition of TFA, on the other hand, led to decomposition.
Iodination with I2 in the presence of TFA (3 equiv) gave
33% of 15 along with recovery of 55% of the starting
material. No complete conversion was achieved even at
higher temperatures. Under the optimal conditions, treatment
of 8 with NIS in the presence of TFA (3 equiv) in THF at
-40 °C smoothly delivered 15 in 88% yield. The only minor
byproduct (e5%) observed in these halogenation reactions
was arising from the 2,5-dihalogenation.
Screening of a variety of protocols for macrocyclization
indicated that the Mukaiyama reagent, 2-chloro-1-methylpyri-
dinium iodide,22 was uniquely effective for this operation. The
macrolactam ring formation could be carried out at room
temperature affording 21 with yields in the range of 55-60%
over two steps. No macrocyclic lactam was formed under a
variety of conditions using the peptide coupling reagents such
as (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexa-
fluorophosphate (BOP), O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-
tetramethyluroniumhexafluorophosphate(HATU), dicyclohexyl-
carbodiimide (DCC), N-(3-dimethylaminopropyl)-N′-ethylcar-
bodiimide (EDC), 2-methyl-6-nitrobenzoic acid anhydride
(MNBA), or 2,4,6-trichlorobenzoyl chloride.23
Scheme 3. Synthesis of Iodoolefin 13
containing a pyrrole subunit; however, only a few examples
have been described in the literature. In 2004, a team at
Wyeth Research reported a direct bromination at the C2-
position of a 3-arylpyrrole with N-bromo-succinimide (NBS),
although no yields or experimental details were provided.19
Muchowski and co-workers observed a selective C2-bromi-
nation of 3-bromo-1-TIPS-pyrrole upon treatment with 1
equiv of NBS at 23 °C, giving 2,3-dibromo-1-TIPS-pyrrole
in a 2.3:1 mixture along with a 3,4-dibromo product.20 Our
experiments began with bromination of 8 with NBS in THF
at -78 °C as reported by Wyeth researchers (Scheme 4 and
Scheme 4. Synthesis of Macrocyclic Precursors 20 and 21
The NMR spectra of lactam 21 indicated that the two protons
at the C3 position (Scheme 4, Aspidosperma alkaloid number-
ing) are chemically nonequivalent and thus diastereotopic,
revealing that an element of chirality must be present in the
structure which can only be attributed to axial chirality. Hence,
the iodolactone exists as a mixture of axial enantiomers (Ra)-
21 and (Sa)-21 (Figure 2). On the other hand, the same protons
in the acyclic amino acids 18 and 19 proved to be chemically
equivalent at room temperature. Therefore, 18 and 19 do not
possess axial chirality (i.e., exist as rapidly interconverting at
the NMR time-scale axially chiral conformers).
A number of reagents for enantioselective acylation,
including chiral dihydroimidazole reagents 22 and 23
introduced by Birman and Li24 and Mukaiyama-type reagent
24, either were not productive in the macrolactamization
process or displayed no enantioselection under various
reaction conditions when macrolactamization did take place.
On the other hand, the enantiomers could be readily separated
by preparative chiral HPLC, confirming the existence of axial
Table 1). These conditions led mostly to unidentified
polymeric products. An exposure of 8 to pyridinium tribro-
mide in the presence of pyridine at low temperature also led
to decomposition; however, we discovered that when acetic
acid was employed as an additive the 2-brominated product
14 was formed selectively and could be isolated in 33% yield.
(21) Ilardi, E. A.; Stivala, C. E.; Zakarian, A. Org. Lett. 2008, 10, 1727–
1730.
(22) Mukaiyama, T.; Usui, M.; Shimada, E.; Saigo, K. Chem. Lett. 1975,
1045–1048.
(19) Collins, M. A.; Hudak, V.; Bender, R.; Fensome, A.; Zhang, P.;
Miller, L.; Winneker, R. C.; Zhang, Z.; Zhu, Y.; Cohen, J.; Unwalla, R. J.;
Wrobel, J. Bioorg. Med. Chem. Lett. 2004, 14, 2185–2189.
(23) Recent reviews: (a) Montalbetti, C. A. G. N.; Falque, V. Tetrahe-
dron 2005, 61, 10827–1852. (b) Katritzky, A. R.; Angrish, P.; Todadze, E.
Synlett 2009, 2392–2411.
(20) Bray, B. L.; Mathies, P.; Naef, R.; Solas, D. R.; Tidwell, T. T.;
Artis, D. R.; Muchowski, J. M. J. Org. Chem. 1990, 55, 6317–6328.
(24) Birman, V. B.; Li, X. Org. Lett. 2006, 8, 1351–1354.
4226
Org. Lett., Vol. 12, No. 19, 2010

Table 1. Regioselective Halogenation of 2-(1H-Pyrrol-3-yl)aniline (8)a
entry
reaction conditions
yield
entry
reaction conditions
yield
1
2
3
4
5
NBS, THF, -78 °C
0%
0%
33%
46%
51%
6
7
8
9
10
PyH+ Br3-, THF, TFA, -78 °C
NIS, THF, 0 °C
NIS, HFIP, 0 °C
I2, TFA, THF, -78 °C
NIS, TFA, THF, -40 °C
87%b
0%
PyH+ Br3-, Py, THF, -78 °C
PyH+ Br3-, THF-AcOH (20:1), -78 °C
PyH+ Br3-, THF-AcOH (10:1), -78 °C
PyH+ Br3-, THF-AcOH (3:1), -78 °C
30%c
33%d
88%e
a Reported yields are of isolated products. b 2,5-Dibromo product was isolated in 4% yield. c 37% of the starting material was recovered. d 55% of the
starting material was recovered. e 2,5-Diiodo product was isolated in 5% yield.
23
chirality in 21 and providing facile access to (Ra)-21 ([R]D
As anticipated, when a solution of (Ra)-21 in acetonitrile was
treated with Pd[PPh3]4 (10 mol %) in the presence of
triethylamine at 100 °C,26 a highly enantiospecific transan-
nular cyclization ensued delivering 25 in 54-64% yield and
>99% ee. Hydrodeiodination byproduct 26 was isolated in
∼30% yield. Other combinations of additive (NaHCO3,
1,2,2,6,6-pentamethylpiperidine, i-Pr2NEt, N,N,N′,N′-tetrameth-
ylethylenediamine, quinidine), solvent (DMF, NMP, toluene,
THF), and palladium source (Pd(OAc)2, Pd(dppf)Cl2, Pd(PPh3)2-
Cl2,Pd2(dba)3,Herrmanncatalyst,Pd(OAc)2+SPhos,Pd(OAc)2+
BINAP) were less effective in this reaction. Under the same
reaction conditions, bromide 20 could also be converted to 25,
albeit with a significantly reduced yield (15%) and predominant
formation of 26 (75%). Notably, lactam 26 lacking a halogen
substituent on the pyrrole ring does not display axial chirality.
23
-82 (c 0.42, CH2Cl2)) and (Sa)-21 ([R]D +81 (c 0.42,
CH2Cl2)) in high enantiomeric purity (Figure 2).25
Hydrogenation of 25 (H2, Pd/C, MeOH) produced the
natural enantiomer of rhazinilam in quantitative yield. The
unnatural (+)-rhazinilam has been prepared in a similar
manner from (Sa)-21.
Figure 2. Restricted rotation leads to axial chirality in 21, but not
in 19 and 26.
In summary, experimental realization of the synthesis
strategy based on transannular cyclization to form the ring
system of rhazinilam led to the discovery of axial chirality
in the macrocyclic cyclization precursors 20 and 21. This
observation allows for the development of enantioselective
approaches to rhazinilam alkaloids highlighting axial-to-point
chirality transfer in natural products synthesis.
Availability of enantioenriched (Ra)-21 and (Sa)-21 allowed
for examination of the axial-to-point chirality transfer in the
penultimate transannular cyclization step (Scheme 5). A re-
Scheme 5. Completion of the Total Synthesis of Rhazinilam
Acknowledgment. This research was supported by the
National Institutes of Health/National Institute of General
Medical Sciences (R01 GM77379) and kind gifts from Eli
Lilly and Amgen.
Supporting Information Available: Experimental pro-
cedures and copies of 1H and 13C NMR spectra. This material
is available free of charge via the Internet at http://pubs.acs.org.
OL101523Z
(25) The absolute configuration was assigned based on correlation to
the final natural product and postulated retention of axial configuration
throughout the subsequent transformations.
(26) Beyersbergen van Henegouwen, W. G.; Fieseler, R. M.; Rutjes,
F. P. J. T.; Hiemstra, H. Angew. Chem., Int. Ed. 1999, 38, 2214–2217.
quirement for an efficient chirality transfer is that all steps in
the projected palladium-catalyzed reaction are enantiospecific.
Org. Lett., Vol. 12, No. 19, 2010
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