Nature-inspired stereospecific total synthesis of P-(+)-dispegatrine and four other monomeric sarpagine indole alkaloids

Article abstract of DOI:10.1002/anie.201206015

All five: The first total synthesis of the C₂-symmetric indole alkaloid 1 involved a late-stage thallium(III) acetate-mediated intermolecular oxidative coupling to construct the C9-C9' bond with complete regio- and stereocontrol. The formation of a single atropodiastereomer in this critical step arises from internal asymmetric induction. The first total synthesis of four other monomeric sarpagine indole alkaloids is also described. Copyright

Full text of DOI:10.1002/anie.201206015

.
Angewandte
Communications
DOI: 10.1002/anie.201206015
Natural Product Synthesis
Nature-Inspired Stereospecific Total Synthesis of P-(+)-Dispegatrine
and Four Other Monomeric Sarpagine Indole Alkaloids**
Chitra R. Edwankar, Rahul V. Edwankar, Jeffrey R. Deschamps, and James M. Cook*
[
6]
The sarpagine-macroline group of indole alkaloids (biogenet-
ically related to the ajmaline-related alkaloids) consists of
date, the sarpagine alkaloid (+)-dispegatrine (1) (Fig-
[
1]
[7]
ure 1b) and the Coryanthꢀ alkaloid blumeanine are the
more than 150 members and is an important class of natural
only two dimeric indoles belonging to this class. (+)-Dis-
pegatrine (1) and the monomer (+)-spegatrine (2), isolated
from the roots of Rauwolfia verticillata (Lour.) Baill var.
[
2]
products with diverse biological activity. Common to these
three classes of alkaloids is the core cycloocta[b]indole
framework A (Figure 1a), which has recently been a subject
[
6]
hainanensis Tsiang, are known to exhibit anti-hypertensive
activity with the affinity of the dimer 1 to both the a1 and
a2 adrenoreceptors at about an order of magnitude greater
[
3]
of biology-oriented synthesis (BIOS), the analogues of
which are promising targets for developing a novel class of
potent and selective Mycobacterium protein tyrosine phos-
phatase B (MptpB) inhibitors against Mycobacterium tuber-
[
8]
than that of the monomer 2. While the structure of 1 was
assigned during isolation, the apparent axial chirality at the
C9ÀC9’ biaryl axis was not determined. Although the
[
4]
culosis. The S configuration at C6 and C10 and the b-
ketoester moiety were key to the inhibitory activity.
Bisphenolic, bisquaternary indole alkaloids are very
isolation chemists attempted a semisynthesis of 1 through
an oxidative phenolic coupling of 2 (Scheme 1a), the yield of
[5]
rare. Of the 300 or so dimeric indole alkaloids isolated to
[6]
Scheme 1. a) Biomimetic semisynthesis of 1 by Yu and co-workers.
Figure 1. a) The cycloocta[b]indole core structure with promising inhib-
itory activity against MptpB. b) Ring-A oxygenated sarpagine indole
alkaloids 1–6. EWG=electron-withdrawing group.
b) Doubly convergent retrosynthetic analysis of 1. Proposed late-stage
nonphenolic oxidative coupling (this work).
[
4]
[6]
the process was very low (0.25%). A number of syntheti-
cally related monomeric alkaloids such as lochneram (3), 10-
methoxyvellosimine (4), lochnerine (5), and sarpagine (6)
[
*] Dr. C. R. Edwankar, Dr. R. V. Edwankar, Prof. Dr. J. M. Cook
Department of Chemistry and Biochemistry
University of Wisconsin-Milwaukee
[2c]
have also been reported (Figure 1b). The complex archi-
[
8]
[8]
3210, North Cramer Street, Milwaukee, WI-53201 (USA)
tecture combined with the promising bioactivity of 1, 2,
[
9]
E-mail: capncook@uwm.edu
Homepage: http://www.uwm.edu/~capncook
Dr. J. R. Deschamps
Center for Biomolecular Science and Engineering, Naval Research
Laboratory, Code 6930, Washington, D. C. 20375 (USA)
and 5 rendered them very attractive targets. Described
herein is the first total synthesis of the sarpagine alkaloids 1, 2,
and 4–6 in a stereospecific manner.
Direct biaryl bond formation can be classified into two
types: a) the reductive metal-catalyzed coupling reaction (e.g
Ullmann, Suzuki, Stille, CÀH activation etc.) and b) the
[
**] We wish to acknowledge the NIMH (in part) and the Lynde and
Harry Bradley Foundation for support of this work. X-ray crystallo-
graphic studies were carried out at the Naval Research Laboratory
and supported by NIDA-NRL Interagency Agreement Number Y1-
DA1101.
[10]
oxidative coupling reaction.
The regioselectivity of the
reductive coupling is predetermined by the use of activated
coupling partners (which may have to be synthesized
separately). The oxidative coupling, in contrast, is a more
direct and economical method for the synthesis of bi-
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201206015.
1
1762
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2012, 51, 11762 –11765

Angewandte
Chemie
[
10a,c,e,11]
[19]
aryls.
The lack of preactivation, however, could affect
much milder conditions of Bonjoch et al., thus furnishing 9
in 73% yield (Scheme 2). Wittig reaction of 9 and a sub-
sequent hydrolysis/epimerization sequence provided the
more stable a aldehyde in (+)-10-methoxyvellosimine (4).
the regioselectivity of the process. For example, the presence
of more than one reactive site in a phenolic substrate could
lead to a mixture of regioisomers (through ortho and para
coupling) and subsequent over oxidation to quinones, either
from the coupled product or the original substrate, could
lower the yield of the process. Atropselectivity in both cases is
most commonly achieved by employing chiral catalysts
or, in a few cases, by taking advantage of either the existing
chiral centers in the substrate
Reduction of the aldehyde 4 with NaBH /EtOH furnished
4
(+)-lochnerine (5) in 90% yield. Demethylation of 5 with
BBr /CH Cl furnished the phenolic monomer (+)-sarpagine
(6) in 80% yield. Subsequent N quaternization of 6 at room
temperature with excess methyl iodide provided the Nb-
methiodide salt, which upon stirring with silver chloride in
ethanol furnished (+)-spegatrine chloride (2). The spectral
3
2
2
[10–12]
b
[
13]
or by double diastereo-
[
14]
[20]
differentiation.
The formation of the biaryl bond in a large number of
bisphenolic natural products is assumed, and in some cases
data of the synthetic 2 and 4–6 were in agreement with that
reported for the natural products, and resulted in the first
[15]
[2c]
proven to be a result of an oxidative phenolic coupling. The
existence of 1 as a single atropodiastereomer both in nature
and during semisynthesis suggests the simultaneous formation
of the biaryl bond with internal asymmetric induction by the
sarpagine framework of the monomer 2. We based the
retrosynthetic strategy on these reports (Scheme 1b). A
potentially biomimetic intermolecular biaryl coupling could
be employed to construct the C9ÀC9’ bond in 1. As opposed
total synthesis of the alkaloids.
Intermolecular oxidative dimerizations of complex non-
[
21]
phenolic aryl substrates are very rare. A majority of the
documented examples constitute simpler aromatic systems or
[
10e,22]
substrates with no competing reactive sites.
To test the
feasibility of such an intermolecular oxidative coupling on the
electron-rich indole alkaloid 5 (with two possible reactive
sites, C9 and C11), it was decided to first carry out a model
[
6]
to the extremely low-yielding phenolic coupling of 2,
reaction on a more robust substrate. The N -methyl b-
a
[
16]
a Scholl-type oxidative coupling of the methoxy analogue
lochnerine (5) could be attempted to this end. We have been
interested in the total synthesis of sarpagine indole alkaloids
and a general route for the synthesis of related alkaloids using
the asymmetric Pictet–Spengler reaction has been developed.
Our strategy toward the synthesis of the monomers 2–6, and
carboline 10 (see Scheme 3 for structure), which was synthe-
[
17]
sized earlier, was employed for this purpose. In the absence
of a chiral catalyst, such a model reaction could also provide
an insight into the possible substrate-dependent atropselec-
tivity of the process.
[
10e]
Of the various combinations documented,
valent-iodine(III)-mediated coupling conditions developed
the hyper-
[2a]
in turn 1, relied on this approach.
[22b,23]
Analogous to the previous work of Zhao et al. in the
by Kita et al.
of Taylor et al.
and the thallium(III)-mediated conditions
[
17]
[22c,24]
N ÀMe series, the 5-methoxy-N H-D(+)-tryptophan ethyl
seemed best suited to the substrates
a
a
ester 7 was converted into the key tetracyclic core 8 in six
under study here. As illustrated in Scheme 3, 10, when
subjected to iodine(III)- or thallium(III)-mediated oxidative
coupling afforded a mixture of the atropodiastereomers 11a
and 11b with complete regioselectivity. In general, the
steps by an asymmetric Pictet–Spengler approach
(
Scheme 2). Attempts to effect the key enolate-mediated
palladium-catalyzed cyclization of the vinyl iodide 8 under the
modified
tBuONa)
reaction
conditions
([Pd (dba) ]/DPEphos/
hypervalent-iodine-mediated
oxidations
[phenyliodine-
2
3
[18]
furnished the pentacyclic ketone 9 in lower
(III)bis(trifluoroacetate) (PIFA) or phenyliodine diacetate
(PIDA) performed at À788C to 08C] generated a number of
intensely colored baseline impurities. At best a combined
yields (50%), accompanied by the alkyne by-product (not
shown). This problem was circumvented by subjecting 8 to the
Scheme 2. General approach to the total synthesis of the sarpagine
indole alkaloids 2, 4–6. THF=tetrahydrofuran.
Scheme 3. Oxidative nonphenolic coupling of the b-carboline 10.
Recovered 10=14%. b.r.s.m.=based on recovered starting material.
Angew. Chem. Int. Ed. 2012, 51, 11762 –11765
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org 11763

.
Angewandte
Communications
[
27]
yield of 30% (11a/11b = 4:1) was obtained with a combina-
tion of PIFA (0.8 equiv) and BF ·Et O (3 equiv) at À408C.
analysis, which established the axial configuration as P(S).
As anticipated, the rigid sarpagine framework and the existing
stereogenic centers in 5 exerted complete atropselection in
the key biaryl coupling step, thereby forming the single
atropodiastereomer P-(+)-12. This would be in agreement
with a potential biomimetic coupling in the plant since the
other atropodiastereomer of 1 was not reported there or
observed by us.
3
2
However, with the thallium(III) salt [Tl(OCOCF ) /
3
3
Tl(OCOCH ) ] as the oxidant, the reaction was much cleaner
3
3
with very little baseline material. Upon optimization, the
milder thallium(III) acetate (0.7 equiv) with BF ·Et O
3
2
(
3 equiv) at À408C provided a combined yield of 67%
(
b.r.s.m.), in favor of 11b. After chromatographic separation,
the lower-R atropodiastereomer 11b was recrystallized from
With the axial chirality established in the key intermediate
P-(+)-12, the total synthesis of 1 was completed in two steps
as illustrated in Scheme 4. Demethylation of P-(+)-12 was
achieved with 11 equivalents of BBr /CH Cl at À788C to
f
EtOH and confirmed by X-ray analysis to have an axial
[25]
chirality of P(S). With the successful coupling of 10, albeit
in moderate yields, the oxidative dehydrodimerization of the
indole 5 was next attempted.
3
2
2
furnish the bisphenol (not shown). N quaternization of the
b
As illustrated in Scheme 4, addition of solid 5 to a mixture
of thallium(III) acetate (0.65 equiv) and BF ·Et O (3.0 equiv)
in acetonitrile at À408C to À108C afforded the C9ÀC9’ biaryl
highly polar bisphenol required heating of the reaction
mixture in a sealed tube at 408C with a large excess of MeI
to provide the methiodide salt. Additional treatment with
AgCl/MeOH at room temperature completed the total
3
2
synthesis of P-(+)-dispegatrine (1). Spectral analysis
1
(
H NMR spectroscopy and HRMS) of the synthetic 1 was
[6]
in good agreement with that in the literature, except the
proton chemical shifts for H5,5’. To obtain better spectro-
scopic data, the bismethylether 13 was synthesized by carrying
out the the N quaternization of P-(+)-12 with MeI/MeOH at
b
either room temperature or 408C. Analogous to blumeanine
[
7]
(
isolated as its diacetate), chromatographic purification and
isolation of the bisquaternary salt 13 proved to be much easier
in comparison to 1. The two-dimensional NMR correlation
experiments (see the Supporting Information) on the dimer
1
3 established the position of the H3,3’ and H5,5’ protons. In
[
28]
the absence of an authentic sample [for circular dichroism
CD) analysis or thin layer chromatography (TLC) compar-
ison], it is impossible to unequivocally report that synthetic
(
1
1
is identical to the natural product even though the H NMR
[29]
data is in good agreement.
However the fact that the
[
6]
biomimetic coupling by Yu et al. gave only the natural
isomer and our oxidative coupling gave the P atropodiaster-
eomer from similar scaffolds strongly suggests that they
presumably are the same.
In summary, a general approach to the ring-A oxgenated
N H sarpagine indole alkaloids has led to the first asymmetric
a
total synthesis of the dimeric indole alkaloid P-(+)-dispega-
trine (1) as well as the monomers 2, 4–6. The synthesis is
notable especially for execution of the direct oxidative
dimerization of (+)-lochnerine (5) in the presence of the
free indole N H, the highly basic N atom, and the C17 OH
Scheme 4. Completion of the total synthesis of the P atropodiastereo-
mer of (+)-dispegatrine (1). Recovered 5=14%, B=the arylthallium
adduct C H N O Tl (8%). Thermal ellipsoids shown at 50% proba-
a
b
2
4
29
2
6
group. To the best of our knowledge, this is the first report of
a direct intermolecular oxidative nonphenolic coupling of
highly functionalized and sensitive substrates (5 and 10) and
has expanded the scope of the thallium(III)-mediated oxida-
tive coupling reaction in heteroaromatic biaryl synthesis.
Additionally an indirect alternative to the less predictable
phenolic coupling, especially in complex aryl substrates is
presented.
bility.
1
2 as the sole atropodiastereomer in 60% yield (b.r.s.m) with
complete regioselectivity, which is in agreememt with the
retrosynthetic analysis. Formation of a small amount of the
the arylthallium adduct B (8%) at C9, is in accordance with
[
26]
the mechanistic studies by Kochi et al. The free indole N H,
a
the highly basic N atom, and the free OH group at C17 were
b
unaffected. Attempts to achieve complete conversion of 5, by
increasing the equivalents of the thallium salt, led to increased
formation of B and baseline impurities. Column chromato-
graphic purification of the dimer 12, followed by recrystalli-
zation from methanol provided white crystals for X-ray
Received: July 24, 2012
Published online: October 16, 2012
Keywords: alkaloids · biaryls · CÀC coupling ·
.
natural product synthesis · thallium
1
1764 www.angewandte.org
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2012, 51, 11762 –11765

Angewandte
Chemie
Angew. Chem. Int. Ed. 2011, 50, 3730 – 3733; b) G. Bringmann,
[
1] M. Ruppert, X. Ma, J. Stçckigt, Curr. Org. Chem. 2005, 9, 1431 –
444.
A. Hamm, M. Schraut, Org. Lett. 2003, 5, 2805 – 2808.
[15] G. M. Keserffl, M. Nógrµdi in Studies in Natural Products
Chemistry, Vol. 20 (Ed.: Atta-ur-Rahman), Elsevier, Amster-
dam, 1998, pp. 263 – 322.
[16] a) P. Kovacic, M. B. Jones, Chem. Rev. 1987, 87, 357 – 379; b) R.
Scholl, C. Seer, Justus Liebigs Ann. Chem. 1912, 394, 111 – 177;
c) R. Scholl, J. Mansfeld, Ber. Dtsch. Chem. Ges. 1910, 43, 1734 –
1746.
[17] S. Zhao, X. Liao, T. Wang, J. Flippen-Anderson, J. M. Cook, J.
Org. Chem. 2003, 68, 6279 – 6295.
[18] X. Liao, H. Zhou, J. Yu, J. M. Cook, J. Org. Chem. 2006, 71,
8884 – 8890.
1
[
2] For reviews on sarpagine-macroline indole alkaloids, see:
a) C. R. Edwankar, R. V. Edwankar, S. K. Rallapalli, J. M.
Cook, Nat. Prod. Commun. 2008, 3, 1839 – 1870; b) S. E. Lewis,
Tetrahedron 2006, 62, 8655 – 8681; c) M. Lounasmaa, P. Hanhi-
nen, M. Westersund in The Alkaloids, Vol. 52 (Ed.: G. A.
Cordell), Academic Press, San Diego, 1999, pp. 103 – 195, and
references therein.
[
3] S. Wetzel, R. S. Bon, K. Kumar, H. Waldmann, Angew. Chem.
2011, 123, 10990 – 11018; Angew. Chem. Int. Ed. 2011, 50, 10800 –
10826.
[
4] a) A. Nçren-Mꢀller, J. I. Reis-CorrÞa, H. Prinz, C. Rosenbaum,
K. Saxena, H. Schwalbe, D. Vestweber, S. Schunk, O. Schwarz,
H. Schiewe, H. Waldmann, Proc. Natl. Acad. Sci. USA 2006, 103,
[19] D. Solꢁ, D. X. Urbaneja, J. Bonjoch, Adv. Synth. Catal. 2004, 346,
1646 – 1650.
[20] N. Yamazaki, W. Dokoshi, C. Kibayashi, Org. Lett. 2001, 3, 193 –
196.
[21] G. Bringmann, S. Tasler, Tetrahedron 2001, 57, 331 – 343.
[22] a) P. A. Keller, N. R. Yepuri, M. J. Kelso, M. Mariani, B. W.
Skelton, A. H. White, Tetrahedron 2008, 64, 7787 – 7795; b) H.
Tohma, H. Morioka, S. Takizawa, M. Arisawa, Y. Kita,
Tetrahedron 2001, 57, 345 – 352; c) A. McKillop, A. G. Turell,
D. W. Young, E. C. Taylor, J. Am. Chem. Soc. 1980, 102, 6504 –
6512.
1
0606 – 10611; b) A. Nçren-Mꢀller, W. Wilk, K. Saxena, H.
Schwalbe, M. Kaiser, H. Waldmann, Angew. Chem. 2008, 120,
061 – 6066; Angew. Chem. Int. Ed. 2008, 47, 5973 – 5977.
6
[
5] a) T.-S. Kam, Y.-M. Choo in The Alkaloids, Vol. 63 (Ed.: G. A.
Cordell), Academic Press, San Diego, 2006, pp. 182 – 345;
b) G. A. Cordell, J. E. Saxton in The Alkaloids, Vol. 20 (Eds.:
R. H. F. Manske, R. G. A. Rodrigo), Academic Press, New York,
1981, pp. 3 – 295.
[
[
6] M. Lin, B. Yang, D.-Q. Yu, Acta Pharm. Sin. 1986, 21, 114 – 118.
7] D. Arbain, D. Firmansyah, D. M. V. Sargent, B. W. Skelton,
A. H. White, J. Chem. Soc. Perkin Trans. 1 1998, 2537 – 2540.
[23] a) T. Dohi, M. Ito, N. Yamaoka, K. Morimoto, H. Fujioka, Y.
Kita, Tetrahedron 2009, 65, 10797 – 10815; b) T. Takada, M.
Arisawa, M. Gyoten, R. Hamada, H. Tohma, Y. Kita, J. Org.
Chem. 1998, 63, 7698 – 7706.
[
24] A. McKillop, E. C. Taylor in Advances in Organometallic
Chemistry, Vol. 11 (Eds.: F. G. A. Stone, R. West), Academic
Press, New York, 1973, pp. 147 – 206.
[
25] ORTEP view of the crystal structure of P(S)-11b. Thermal
ellipsoids shown at 50% probability.
[
[
8] Y. Feng, H. Gao, G. Zeng, Acta Pharm. Sin. 1986, 21, 1 – 6.
9] a) K. Zaima, I. Koga, N. Iwasawa, T. Hosoya, Y. Hirasawa, T.
Kaneda, I. S. Ismail, N. H. Lajis, H. Morita, J. Nat. Med. 2012,
DOI: 10.1007/s11418-012-0638-y; b) G. H. Svoboda, D. A. Blake
in The Catharanthus Alkaloids (Eds.: W. I. Taylor, N. R. Farns-
worth), Marcel Dekker, New York, 1974, p. 45, and references
therein.
[
10] For reviews on biaryl synthesis, see: a) G. Bringmann, T. Gulder,
T. A. M. Gulder, M. Breuning, Chem. Rev. 2011, 111, 563 – 639;
b) C. S. Yeung, V. M. Dong, Chem. Rev. 2011, 111, 1215 – 1292;
c) G. Bringmann, A. J. Price Mortimer, P. A. Keller, M. J.
Gresser, J. Garner, M. Breuning, Angew. Chem. 2005, 117,
CCDC 893770 [P(S)-11b] contains the supplementary crystallo-
graphic data for this paper. These data can be obtained free of
charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
5
518 – 5563; Angew. Chem. Int. Ed. 2005, 44, 5384 – 5427;
[
26] W. Lau, J. K. Kochi, J. Am. Chem. Soc. 1984, 106, 7100 – 7112.
d) T. M. Wallace, Org. Biomol. Chem. 2006, 4, 3197 – 3210;
e) I. Cepanec, Synthesis of Biaryls, 1 ed, Elsevier, San Diego,
st
[27] CCDC 893771 [P-(+)-12] contains the supplementary crystallo-
graphic data for this paper. These data can be obtained free of
charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
2004; f) J. Hassan, M. Sꢁvignon, C. Gozzi, E. Schulz, M,
Lemaire, Chem. Rev. 2002, 102, 1359 – 1470.
[
11] a) J. A. Ashenhurst, Chem. Soc. Rev. 2010, 39, 540 – 548; b) M. C.
Kozlowski, B. J. Morgan, E. C. Linton, Chem. Soc. Rev. 2009, 38,
[
[
28] A request was made for an authentic sample of 1.
29] For examples of homo- and hetero-atropodiastereomeric natural
3193 – 3207.
1
13
products that have almost identical H and C NMR spectra,
see: a) Y. Hirasawa, M. Hara, A. E. Nugroho, M. Sugai, K.
Zaima, N. Kawahara, Y. Goda, K. Awang, A. H. A. Hadi, M. H.
Litaudon, J. Org. Chem. 2010, 75, 4218 – 4223; b) K. Tatsuta, T.
Yamazaki, T. Mase, T. Yoshimoto, Tetrahedron Lett. 1998, 39,
[
12] a) A. N. Cammidge, K. V. L. Crꢁpy, Tetrahedron 2004, 60, 4377 –
4
1
386; b) J. Yin, S. L. Buchwald, J. Am. Chem. Soc. 2000, 122,
2051 – 12052.
[
13] S. Huang, T. B. Petersen, B. H. Lipshutz, J. Am. Chem. Soc. 2010,
32, 14021 – 14023.
1
1771 – 1772; c) Y. Fukuyama, Y. Asakawa, J. Chem. Soc. Perkin
[
14] a) Y. S. Park, C. I. Grove, M. Gonzalez-Lopez, S. Urgaonkar,
Trans. 1 1991, 2737 – 2741.
J. C. Fettinger, J. T. Shaw, Angew. Chem. 2011, 123, 3814 – 3817;
Angew. Chem. Int. Ed. 2012, 51, 11762 –11765
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org 11765