Synthetic studies toward lapidilectine-type Kopsia alkaloids

Article abstract of DOI:10.1021/ol203302f

A rapid synthesis of the tetracyclic core of Kopsia indole alkaloids related to lapidilectine B, grandilodine C, and tenuisine A is reported. Key to the success of this route was an efficient and scalable Ugi four-component coupling to install all the necessary carbons found in the natural products.

Full text of DOI:10.1021/ol203302f

ORGANIC
LETTERS
2012
Vol. 14, No. 2
648–651
Synthetic Studies toward
Lapidilectine-Type Kopsia Alkaloids
Erica E. Schultz, Brian G. Pujanauski, and Richmond Sarpong*
Department of Chemistry, University of California, Berkeley, California 94720,
United States
rsarpong@berkeley.edu
Received December 9, 2011
ABSTRACT
A rapid synthesis of the tetracyclic core of Kopsia indole alkaloids related to lapidilectine B, grandilodine C, and tenuisine A is reported. Key to the
success of this route was an efficient and scalable Ugi four-component coupling to install all the necessary carbons found in the natural products.
Alkaloids isolated from the Kopsia genus of flowering
plant, representitive examples of which are shown in
Figure 1, demonstrate a wide range of structural diversity
as well as pharmacological activities.1 Extracts from
Kopsia have been used in traditional treatments for various
ailments including rheumatoid arthritis, edema, tonsillitis,
and hypertension. Lapidilectine B (1), grandilodine C (2),2
and lundurine B (7) show multidrug resistance (MDR)
reversing effects in vincristine-resistant KB cancer cells,3
whereas lundurines A (6) and C (8) show selective cyto-
toxicity toward B16 melanoma cells.
A majority of the synthetic efforts aimed at these
compounds have been focused on the lundurine class of
molecules.4 The most advanced approach, which arrives at
the tetracyclic core of lundurine using creative ring closing
metathesis reactions, was recently reported by Martin and
co-workers.5
Figure 1. Selected Kopsia alkaloids.
In addition, an elegant total synthesis of lapidilectine
B (1) was achieved by Pearson and co-workers in 2001 and
featured an inventive use of a 2-azaallyllithium ion in a
[3 þ 2] cycloaddition.6 To date, no synthetic efforts have
been reported toward the tenuisines7 or grandilodines.
We were drawn to these compounds as synthetic targets
because of their unique structures, which offered opportunities
(1) Awang, K.; Svenet, T.; Pais, M. Nat. Prod. 1993, 56, 1134–1139.
(2) For the isolation of the grandilodines, see: Yap, W.-S.; Gan
C.-Y.; Low, Y.-Y.; Choo, Y.-M.; Etoh, T.; Hayashi, M.; Komiyama,
K.; Kam, T.-S. J. Nat. Prod. 2011, 74, 1309–1312.
(3) Kam, T.-S.; Lim, K. H.; Yoganathan, K. Tetrahedron 2004, 60,
10739–10745.
(4) (a) Ferrer, C.; Amijs, C. H. M.; Echavarren, A. M. Chem.;Eur.
J. 2007, 13, 1358–1373. (b) Donets, P. A.; Van Hecke, K.; Van Meervelt,
L.; Van der Eycken, E. V. Org. Lett. 2009, 11, 3618–3621. (c) Ferrer, C.;
Escribano-Cuesta, A.; Echavarren, A. M. Tetrahedron 2009, 65, 9015–
9020.
(6) (a) Pearson, W. H.; Mi, Y.; Lee, I. Y.; Stoy, P. J. Am. Chem. Soc.
2001, 123, 6724–6725. (b) Pearson, W. H.; Lee, I. Y.; Mi, Y.; Stoy, P.
J. Org. Chem. 2004, 69, 9109–9122.
(5) Orr, S. T.; Tian, J.; Niggemann, M.; Martin, S. F. Org. Lett. 2010,
13, 5104–5107.
(7) For the isolation of the tenuisines and an account of their
structural revision, see ref 3.
r
10.1021/ol203302f
Published on Web 01/03/2012
2012 American Chemical Society

for new synthetic tactics, as well as their potential as starting
points for new pharmaceuticals. Furthermore, our analysis of
the subset of Kopsia alkaloids illustrated in Figure 1 indicated a
close structural relationship, which could inform a unified
strategy for their syntheses.
Scheme 1. Retrosynthetic Analysis of Cyclobutanone Precursor
In our analysis of the subset of Kopsia alkaloids depicted
in Figure 1, it seemed plausible that the fused cyclopropane
in the lundurines (see 6ꢀ9) could arise, synthetically (or
even biosynthetically), from a decarboxylation of a related
tenuisine type precursor (e.g., 5).8 Alternatively, the micro-
scopic reverse, i.e., carboxylation of the cyclopropane
moiety of a lundurine precursor (e.g., 7), could provide
an entry to tenuisines such as 5. A similar relationship can
be envisioned between fused γ-lactone compounds 1 or 2
and their respective cyclopropane-containing congeners,
which are yet to be isolated. Furthermore, a selective
carbanion opening of the γ-lactone moiety in 1 or 2 could
lead to 3 and 4, respectively.
In order to test aspects of this unified synthetic plan, we
sought a versatile synthetic precursorthatcould giveaccess
to either the fused γ-lactone or cyclopropane framework.
Fused cyclobutanone 10 (Scheme 1) engendered exciting
possibilities for its conversion to a γ-lactone (as in 1 or 2
with R = H; or 5 with R = OMe) using a BaeyerꢀVilliger
type oxidation9 or to a fused cyclopropane (as in 6ꢀ9;
R = OMe) using a CꢀC bond activation/decarbonylation
sequence.10 As such, 10 was selected as the penultimate
target.
We envisioned cyclobutanone 10 arising from ester
12 (if R = H) via ketene intermediate 11 by a [2 þ 2]
cycloaddition.11 Tetracycle 12 could in turn arise from
spiro-fused R,β-unsaturated lactam derivative 13 by clea-
vage of the cyclohexanone ring and functionalization of
the indole C-2 position. The cleavage step could, in prin-
ciple, be rendered enantioselective by a desymmetrization
of ketone 13. Tryptamine-derived lactam 13 could in turn
arise from a four-component Ugi coupling12 of 14, 15, 16,
and 17.
Our synthetic studies commenced with the Ugi four-
component coupling (Scheme 2), which led to adduct 18 in
95% yield. The virtues of this coupling reaction are many
fold. First, in this single step, we install all the carbons of
the lapidilectine-type Kopsia alkaloid framework. Second,
the product precipitates out of the reaction mixture and
only requires filtration to be obtained free of impurities.
Third, the reaction can be conducted on a large scale
(>200 g) without compromising yield.13 The Armstrong
isocyanide (16)14 was selected for the Ugi coupling on the
basis of the elegant synthetic studies of Sorensen and Seike
on FR901483, which showed (as we found) that the Ugi
product (18) could easily be converted to the correspond-
ing methyl ester (see 19).15 Thus, treatment of 18 with
methanolic HCl provided methyl ester 19, whereby the
esterification was attended by a transketalization to the
dimethylketal.
Following the Sorensen protocol, subjection of aceta-
mide ester 19 to KOt-Bu in THF effected a Dieckmann
condensation. Selective reduction of the ketone group
(NaBH4) and elimination of the resulting hydroxy group
(activated as the carbonate) provided spiro-fused lactam
13 in excellent yield over three steps (Scheme 2). The
accompanying protection of the indole nitrogen made
the handling of this compound straightforward. Of note,
the conversionof19to 13can be consistently performedon
a >5 g scale without appreciable depression in yield.
Scheme 2. Synthesis of Spiro-lactam 13
(8) Kam and co-workers (see ref 3) isolated the lundurine and
tenuisine compounds from the same plant source, lending credence to
a biogenentic connection between these natural products.
(9) Krow, G. R. Org. React. 1993, 43, 251–798.
(10) For a review on this type of CꢀC bond activation: Seiser, T;
Saget, T.; Tran, D. N.; Cramer, N. Angew. Chem., Int. Ed. 2011, 50,
7740–7752.
(11) Snider, B. B. Chem. Rev. 1988, 88, 793–811.
(12) Domling, A.; Ugi, I. Angew. Chem., Int. Ed. 2000, 39, 3168–3210.
(13) Performed by B.G.P. in the Process Group at Eli Lilly,
Indianapolis.
(14) Keating, T. A.; Armstrong, R. W. J. Am. Chem. Soc. 1996, 118,
2574–2583.
(15) Seike, H.; Sorensen, E. J. Synlett 2008, 695–701.
Org. Lett., Vol. 14, No. 2, 2012
649

With efficient access to 13, we have investigated several
strategies for the synthesis of the tetracyclic core of the
lapidilectines and structurally related alkaloids (i.e., 12,
Scheme 1). These studies began with the conversion of
13 to 20 by TBS silyl enol ether formation (Scheme 3),
which proceeded in excellent yield. Oxidative opening of
the six-membered ring was effected using the two-stage
protocol of dihydroxylation (OsO4, TBHP) followed by
Pb(OAc)4-mediated cleavage in the presence of methanol,
which afforded aldehyde ester 21. In preparation for
cyclization studies en route to the tetracyclic core structure
(eqs 1ꢀ3), 21was convertedtoacid 22employing a Pinnick
converted to keto-tetracycle 25 (eq 2) in 46% yield upon
treatment with AIBN and dodecyl thiol (C10H21SH), presum-
ably via an acyl radical intermediate.18 We have found this
particular protocol for the formation of 25 to be effective (as
compared to starting from acid 22) because it generally leads to
less byproduct formation. A FriedelꢀCrafts type transforma-
tion could also be initiated from dimethyl acetal 24 using
Amberlyst-15 as the source of acid (eq 3) to afford 26 in 54%
yield.19 The mass balance of the material was accounted for by
aldehyde 21, which likely arises from a competing hydrolyis of
the acetal group. Attempts to effect the conversion of 24f26
using Lewis acids or other protic acids resulted only in the
hydrolysis of the acetal, which reverts back to aldehyde 21.
Scheme 3. Oxidative Opening of Spirocycle 20
Inpreparation for the explorationofendgamescenarios,
tetracycle 26 was converted to 27 (eq 4) by cleavage of
the carbamate group and selective removal of the alkene
group by ionic reduction using methanesulfonic acid and
triethylsilane.20 Our current efforts are focused on the
selective conversion of the methyl ester group of 27 to an
‘activated ester’ to study our proposed ketene generation/
cycloaddition (see 12f10, Scheme 1).
oxidation;16 to C-2 bromo-indole 23 using NBS; and to
dimethylacetal 24 under standard acetalization conditions.
As shown in eqs 1ꢀ3, the lapidilectine-type tetracyclic
core, varying only in the oxidation level about the eight-
membered ring, can be successfully realized from each of
these precursors (i.e., 22, 23, and 24). Tetracycle 25 was
directly accessible from crude acid 22 in 43% yield using a
polyphosphoric acid mediated FriedelꢀCrafts acylation
(eq 1).17 Despite the modest yield of this transformation,
the usual ‘two-step’ FriedelꢀCrafts protocol, involving treat-
ment of the corresponding acid chloride with a Lewis acid
(e.g., AlCl3), was less efficient and resulted in significant
polymerization. Alternatively, aldehyde 23 was successfully
We have also briefly explored opportunities to render
our strategy enantioselective. In this regard, our initial
efforts have focused on the desymmetrization of spiro-
ketones related to 13 (see 28, Table 1). The control of the
single tertiary amine spiro stereocenter would guide the
installation of the three additional stereocenters in the
target natural products, which would substantially simpli-
fy the diastereoselectivity challenge. As a proof of concept
for stereoselective desymmetrization, the enantioselective
€
(16) (a) For a pertinent discussion on this oxidation, see: Kurti, L.;
Czako, B. Strategic Applications of Named Reactions in Organic Synthe-
sis; Elsevier: 2005; pp 354ꢀ355. For seminal publications, see:
(b) Lindgren, B. O.; Nilsson, T. Acta Chem. Scand. 1973, 27, 888–890. (c)
Kraus, G. A.; Roth, B. J. Org. Chem. 1980, 45, 4825–4830. (d) Bal, B. S.;
Childers, W. E., Jr.; Pinnick, H. W. Tetrahedron 1981, 37, 2091–2096.
(17) (a) Owton, W. M.; Brunavs, M. Synth. Commun. 1991, 21, 981–
987. (b) Wood, J. L.; Pujanauski, B. G.; Sarpong, R. Org. Lett. 2009, 11,
3128–3131.
(18) (a) Yoshikai, K.; Hayama, T.; Nishimura, K.; Yamada, K.;
Tomioka, K. J. Org. Chem. 2005, 70, 681–683. (b) For a recent
application in a complex molecule synthesis, see: Enquist, J. A., Jr.;
Stoltz, B. M. Nature 2008, 453, 1228–1231. (c) Tetracycle 25 was
obtained in approximately 85% purity.
(19) Ballini, R.; Gabrielli, S.; Palmieri, A.; Petrini, M. Adv. Synth.
Catal. 2010, 352, 2459–2462.
(20) Larson, G. L.; Fry, J. L. Org. React. 2008, 1–737.
(21) O’Brien, P. J. Chem. Soc., Perkins Trans. 1 1998, 1439–1457.
(22) (a) Majewski, M.; Lazny, R.; Nowak, P. Tetrahedron Lett. 1995,
36, 5465–5468. (b) Of note, diminished enantioselectivity is generally
observed in the absence of the LiCl additive (compare, for example,
entries 5 and 6).
650
Org. Lett., Vol. 14, No. 2, 2012

In conclusion, we have developed an effective and
scalable synthetic sequence to the tetracyclic core of
Kopsia alkaloids related to lapidilectine. The synthetic
sequence features a highly enabling Ugi four-compo-
nent coupling to install all the carbons found in these
natural products. The reported strategy holds high
potential for providing a unified approach to the subset
of Kopsia alkaloids depicted in Figure 1. In addition,
preliminary results on enantioselective deprotonation
of a spirocyclic ketone provides a proof of concept for
the possible enantioselective syntheses of these natural
products.
Table 1. Enantioselective Desymmetrization of 28
Acknowledgment. The authors are grateful to Prof.
Erik J. Sorensen (Princeton University) for detailed
procedures related to ref 15. The authors also thank
Prof. Armen Zakarian (UC Santa Barbara) for gifts of
diamines A, B, and C and Amgen for a gift of tetra-
amine E. The NIH (NIGMS RO1 084906) is gratefully
acknowledged for financial support of this work. E.E.S.
and B.G.P. are grateful for an NSF graduate research
fellowship and Tobacco Related Disease Research
Program (TRDRP) fellowship, respectively. R.S. and
B.G.P. thank Eli Lilly for hosting B.G.P. for a summer
internship in 2009.
deprotonation of ketone 28 was investigated with a range
of chiral, nonracemic kinetic amine bases (see Table 1).21
Our brief survey has revealed that the amide base gener-
ated from amine D, in the presence of LiCl (1 equiv),22
yields enol carbonate 29 in 39% ee and 60% yield (entry 5).
This preliminary result, albeit in modest ee, could provide
the basis for the development of an enantioselective synthesis
of lapidilectine and related Kopsia alkaloids.
Supporting Information Available. Experimental de-
tails and characterization for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
Org. Lett., Vol. 14, No. 2, 2012
651