Stereodivergent total syntheses of precoccinelline, hippodamine, coccinelline, and convergine

Article abstract of DOI:10.1021/ol0619359

(Chemical Equation Presented) A stereodivergent approach toward total syntheses of Coccinellidae defensive alkaloids is described. These syntheses feature a highly diastereoselective intramolecular aza-[3 + 3] annulation strategy, which represents a de no

Full text of DOI:10.1021/ol0619359

ORGANIC
LETTERS
2006
Vol. 8, No. 21
4899-4902
Stereodivergent Total Syntheses of
Precoccinelline, Hippodamine,
Coccinelline, and Convergine†
Aleksey I. Gerasyuto and Richard P. Hsung*
DiVision of Pharmaceutical Sciences and Department of Chemistry, Rennebohm Hall,
777 Highland AVenue, UniVersity of Wisconsin, Madison, Wisconsin 53705
rhsung@wisc.edu
Received August 4, 2006
ABSTRACT
A stereodivergent approach toward total syntheses of Coccinellidae defensive alkaloids is described. These syntheses feature a highly
diastereoselective intramolecular aza-[3 3] annulation strategy, which represents a de novo approach to this family of natural products.
+
Ladybird beetles (Coccinellidae) play an important role in
controlling populations of agricultural pests such as aphids,
mealy bugs, and scale insects, and to protect themselves from
their natural predators such as ants and quails, they utilize a
reflex bleeding mechanism.1 When scarred or disturbed, they
release an orange fluid from their joints that contains a
mixture of defensive alkaloids.2 In 1971, Tursch and co-
workers3a first isolated precoccinelline 1 from this fluid along
with a crystalline substance, which was confirmed as the
N-oxide of 1 or as coccinelline 2 by X-ray analysis.3b
Isolations of hippodamine3c,d 3, its N-oxide convergine3c,d
4, and the thermodynamically most stable all syn isomer
myrrhine3e 5 were reported later. Alkaloids 1 and 3 represent
the two other possible stereoisomers of the 2-methyl-
perhydro-9b-azaphenalene system with the methyl group
being equatorial. Interestingly, N-oxide of myrrhine 5 does
not occur naturally.
† Dedicated to Professor Jeffrey D. Winkler on the occasion of his 50th
birthday.
(1) Happ, G. M.; Eisner, T. Science 1961, 134, 329.
(2) For reviews, see: (a) King, A. G.; Meinwald, J. Chem. ReV. 1996,
96, 1105. (b) Stevens, R. V. Acc. Chem. Res. 1984, 17, 289.
(3) (a) Tursch, B.; Daloze, D.; Dupont, M.; Pasteels, J. M.; Tricot, M.-
C. Experientia 1971, 27, 1380. (b) Karlsson, R.; Losman, D. J. Chem. Soc.,
Chem. Commun. 1972, 626. (c) Tursch, B.; Daloze, D.; Pasteels, J. M.;
Cravador, A.; Braekman, J. C.; Hootele, C.; Zimmermann, D. Bull. Soc.
Chim. Belg. 1972, 81, 649. (d) Tursch, B.; Daloze, D.; Braekman, J. C.;
Hootele, C.; Cravador, A.; Losman, D.; Karlsson, R. Tetrahedron Lett. 1974,
409. (e) Tursch, B.; Daloze, D.; Braekman, J. C.; Hootele, C.; Pasteels, J.
M. Tetrahedron 1975, 31, 1541.
Their unique structural feature has attracted a lot of
attention4-6 in the last 30 years, commencing with Ayer’s
first total syntheses of all these alkaloids in 19764a,5a and
some elegant constructions of 1 and 2 by Mueller,5b,c who
also synthesized 3-5,5c and by Stevens in 1979.5d Interest-
ingly, most of these syntheses intercept a key intermediate
10.1021/ol0619359 CCC: $33.50
© 2006 American Chemical Society
Published on Web 09/16/2006

Retrosynthetically, as shown in Scheme 1, we envisioned
that both 1 and 3 could be derived from the same aza-tricyclic
intermediate A upon hydrogenation of the double bonds and
removal of the carboxymethyl group. The key tricycle A can
be prepared via an intramolecular aza-[3 + 3] annulation of
vinylogous urethane 6,7,10 which should be accessible in
several steps from cis-1,3-disubstituted lactam 7 with
bromide 9 and glutarimide 8 as the essential starting points.
Scheme 1. Retrosynthetic Analysis
Our synthesis commenced with alkylation of TBDPS-
protected propargyl alcohol 1011,12 employing excess 1,3-
dibromopropane followed by Lindlar hydrogenation that led
to bromide 9 in 59% overall yield (Scheme 2). Lactam 7
Scheme 2. Synthesis of Lactam 7
in Ayer’s syntheses,5a and in all syntheses of these alkaloids
except for one,4a the equatorial methyl group is being intro-
duced in the latter steps of the sequence. Herein, we report
a de noVo approach to precoccinelline 1 and hippodamine 3
and their respective N-oxides 2 and 4, featuring a highly
stereoselective intramolecular aza-[3 + 3] annulation.7-10
(4) For syntheses of hippodamine, convergine, and myrrhine, see: (a)
Ayer, W. A.; Dawe, R.; Eisner, R. A.; Furuichi, K. Can. J. Chem. 1976,
54, 473. (b) Adams, D. R.; Carruthers, W.; Crowley, P. J. J. Chem. Soc.,
Chem. Commun. 1991, 1261. (c) Rejzek, M.; Stockman, R. A.; Hughes, D.
L. Org. Biomol. Chem. 2005, 3, 73.
(5) For syntheses of precoccinelline and coccinelline, see: (a) Ayer, W.
A.; Furuichi, K. Can. J. Chem. 1976, 54, 1494. (b) Mueller, R. H.;
Thompson, M. E. Tetrahedron Lett. 1979, 1991. (c) Mueller, R. H.;
Thompson, M. E.; DiPardo, R. M. J. Org. Chem. 1984, 49, 2271. (d)
Stevens, R. V.; Lee, A. W. M. J. Am. Chem. Soc. 1979, 101, 7032. (e)
Yue, C.; Nicolay, J.-F.; Royer, J.; Husson, H.-P. Tetrahedron 1994, 50,
3139. (f) Takahata, H.; Ouchi, H.; Ichinose, M.; Nemoto, H. Org. Lett.
2002, 4, 3459.
was prepared via reductive alkylation13 of 4-methyl gluta-
rimide 8.14 The Grignard reagent generated from bromide 9
was added to the Mg salt 8a formed in situ from glutarimide
8 and 1.0 equiv of CH3MgCl, and after stirring overnight at
room temperature, NaBH3CN and AcOH were added to
reduce the intermediate hemi-aminal (see 11a). The reduction
proceeded stereoselectively and afforded lactam 7 in 75%
overall yield exclusively as the 1,3-syn isomer. This is likely
a result of an axial approach of hydride to the conformation
shown for N-acyliminium ion 11b.
(6) For an elegant total synthesis of related alkaloid (-)-205B, see:
Smith, A. B., III.; Kim, D. S. Org. Lett. 2005, 7, 3247.
(7) For reviews, see: (a) Harrity, J. P. A.; Provoost, O. Org. Biomol.
Chem. 2005, 3, 1349. (b) Hsung, R. P.; Kurdyumov, A. V.; Sydorenko, N.
Eur. J. Org. Chem. 2005, 23. (c) Coverdale, H. A.; Hsung, R. P. ChemTracts
2003, 16, 238.
(8) For a review on vinylogous amide chemistry, see: Kucklander, U.
Enaminones as Synthons. In The Chemistry of Functional Groups: The
Chemistry of Enamines Part I. Rappoport, Z., Ed. John Wiley & Sons:
New York, 1994; p 523.
(9) For recent studies in this area, see: (a) Pattenden, L. C.; Wybrow,
R. A. J.; Smith, S. A.; Harrity, J. P. A. Org. Lett. 2006, 8, 3089. (b) Shintani,
R.; Hayashi, T. J. Am. Chem. Soc. 2006, 128, 6330. (c) Halliday, J. I.;
Chebib, M.; Turner, P.; McLeod, M. D. Org. Lett. 2006, 8, 3399. (d) Bose,
D. S.; Kumar, R. K. Heterocycles 2006, 68, 549. (e) Goodenough, K. M.;
Raubo, P.; Harrity, J. P. A. Org. Lett. 2005, 7, 2993. (f) Goodenough, K.
M.; Moran, W. J.; Raubo, P.; Harrity, J. P. A. J. Org. Chem. 2005, 70,
207. (g) Agami, C.; Dechoux, L.; Hebbe, S.; Me´nard, C. Tetrahedron 2004,
60, 5433. (h) Ji, S.-J.; Jiang, Z.-Q.; Lu, J.; Loh, T.-P. Synlett 2004, 831. (i)
Hedley, S. J.; Moran, W. J.; Price, D. A.; Harrity, J. P. A. J. Org. Chem.
2003, 68, 4286.
Converting 7 to the corresponding thiolactam using
Lawesson’s reagent15 followed by alkylation with R-bromo
methyl acetate gave thiol ether 12 in 90% yield over two
steps (Scheme 3). Eschenmoser sulfide contraction16 of 12
proceeded smoothly and led to the protected Z-vinylogous
(11) Toshima, K.; Ohta, K.; Ohashi, A.; Nakamura, T.; Nakata, M.;
Tatsuta, K.; Matsumura, S. J. Am. Chem. Soc. 1995, 117, 4822.
(12) See Supporting Information.
(10) For intramolecular aza-[3 + 3] annulation, see: (a) Swidorski, J.
J.; Wang, J.; Hsung, R. P. Org. Lett. 2006, 8, 777. (b) Gerasyuto, A. I.;
Hsung, R. P.; Sydorenko, N.; Slafer, B. W. J. Org. Chem. 2005, 70, 4248.
(c) Sydorenko, N.; Zificsak, C. A.; Gerasyuto, A. I.; Hsung, R. P. Org.
Biomol. Chem. 2005, 3, 2140. (d) Luo, S.; Zificsak, C. Z.; Hsung, R. P.
Org. Lett. 2003, 5, 4709. (e) Wei, L.-L.; Sklenicka, H. M.; Gerasyuto, A.
I.; Hsung, R. P. Angew. Chem., Int. Ed. 2001, 40, 1516. For references on
intermolecular aza-[3 + 3] annulation, see: (f) Sydorenko, N.; Hsung, R.
P.; Vera, E. L. Org. Lett. 2006, 8, 2611. (g) Sydorenko, N.; Hsung, R. P.;
Darwish, O. S.; Hahn, J. M.; Liu, J. J. Org. Chem. 2004, 69, 6732. (h)
Sklenicka, H. M.; Hsung, R. P.; McLaughlin, M. J.; Wei, L.-L.; Gerasyuto,
A. I.; Brennessel, W. W. J. Am. Chem. Soc. 2002, 124, 10435.
(13) (a) Karstens, W. F. J.; Stol, M.; Rutjes, F. P. J. T.; Kooijman, H.;
Spek, A. L.; Hiemstra, H. J. Organomet. Chem. 2002, 624, 244. (b) Esch,
P. M.; Hiemstra, H.; Klaver, W. J.; Speckamp, W. N. Heterocycles 1987,
26, 75. (c) Evans, D. A.; Thomas, E. W.; Cherpeck, R. E. J. Am. Chem.
Soc. 1982, 104, 3695.
(14) Handley, G. J.; Nelson, E. R.; Somers, T. C. Aust. J. Chem. 1960,
13, 129.
(15) For a recent review, see: Jesberger, M.; Davis, T. P.; Barner, L.
Synthesis 2003, 1929.
(16) (a) Roth, M.; Dubs, P.; Go¨tchi, E.; Eschenmoser, A. HelV. Chim.
Acta 1995, 54, 710. (b) Shiosaki, K. In ComprehensiVe Organic Synthesis;
Trost, B. M., Ed.; Pergamon: Oxford, 1991; Vol. 2, p 865.
4900
Org. Lett., Vol. 8, No. 21, 2006

Scheme 3. Synthesis of Allyl Alcohol 14
urethane 13. Subsequent deprotection of the TBDPS group
with TBAF furnished allyl alcohol 14. It is noteworthy that
the described sequence was suitable for multigram scale
synthesis of alcohol 14 with an 82% overall yield starting
from lactam 7.
Pyr‚SO3 oxidation17 of allyl alcohol 14 led to the corre-
sponding enal 15 as a 7:1 cis/trans isomeric mixture (Scheme
4). Enal 15 was subjected to the aza-[3 + 3] annulation
Figure 1. X-ray structure of the picrate salt of 18b. (a) Structure
with picrate. (b) Structure with picrate removed for clarity.
after the annulation.10e The one-pot protocol allowed us to
access the more stable aza-tricycle 17 with a consistent 43%
overall yield from 15. It is noteworthy that aza-tricycle 17
contains three of the four stereogenic centers required for
precoccinelline 1 and hippodamine 3.
Scheme 4. Key Intramolecular Aza-[3 + 3] Annulation
With aza-tricycle 17 in hand, we hydrogenated the internal
double bond employing Adam’s catalyst18 (Scheme 5).
Scheme 5. Stereodivergent Hydrogenation of 17
conditions employing piperidinium trifluoro acetate in EtOAc.
The desired cycloadduct 16 was obtained as a single
diastereomer in 51% yield, and its anti relative stereochem-
istry at the ring junction was established using nOe’s (see
the box in Scheme 4) and by X-ray of a later intermediate.
The observed stereoselectivity is in good agreement with our
previous experience.10b
Hydrogenation occurred in a stereodivergent manner, leading
to both isomers 18a and 18b with a ratio of 2:1. Major isomer
18a resembles the aza-tricyclic manifold in precoccinelline
1, whereas 18b has the framework of hippodamine 3.
Because of the precarious nature of 16, we found it more
convenient to hydrogenate the reaction mixture over Pd(OH)2
(18) (a) Akhrem, A. A.; Lakhvich, F. A.; Lis, L. G.; Pshenichnyi, V.
N.; Arsen′ev, A. S. Zh. Org. Khim. 1980, 16, 1290. (b) Akhrem, A. A.;
Lakhvich, F. A.; Lis, L. G.; Kuz′mitskii, B. B.; Mizulo, N. A.; Gorbacheva,
I. A. Zh. Org. Khim. 1985, 21, 1348.
(17) (a) Chen, L.; Lee, S.; Renner, M.; Tian, Q.; Nayyar, N. Org. Proc.
Res. DeV. 2006, 10, 163. (b) Parikh, J. R.; Doering, W. von E. J. Am. Chem.
Soc. 1967, 89, 5505.
Org. Lett., Vol. 8, No. 21, 2006
4901

Although esters 18a,b could be separated by a tedious
alumina gel column, it was found that they could be readily
resolved Via a selective alkaline hydrolysis of the equatorial
ester 18a (Scheme 5). Upon treatment of the crude hydro-
genation mixture with 1.7 M aq KOH, unreacted axial ester
18b was recovered by simple extraction in 36% overall yield
from 17. Upon acidification of the aqueous phase, acid 19a
was isolated in 49% yield with its assigned relative stereo-
chemistry being supported by nOe’s.12 The structure of 18b
was unambiguously assigned by X-ray analysis of its
corresponding picrate salt (Figure 1).
reaction mixture with MeOH at 0 °C led to the desired
equatorial ester 18c with 86% yield (Scheme 7). Hydrolysis
Scheme 7. Completion of Total Syntheses of 3 and 4
To complete the total synthesis of precoccinelline 1, acid
19a was subjected to Barton’s decarboxylation conditions19
(Scheme 6). The desired alkaloid was isolated in 43% overall
Scheme 6. Completion of Total Syntheses of 1 and 2
of 18c was successful using 1.7 M aq KOH at 50 °C, leading
to carboxylic acid 19b in 44% yield. Subsequently, hippo-
damine 3 was obtained in 43% overall yield after decar-
boxylation of 19b under Barton’s conditions.19 Successive
oxidation of 3 with m-CPBA afforded convergine 4 in 88%
yield. Both natural products matched the literature spectro-
scopic data.4c,21
We have described here total syntheses of precoccinelline
and hippodamine (overall yields from glutarimide are 4.8%
and 1.3%, respectively) and their respective N-oxides coc-
cinelline and convergine (overall yields from glutarimide are
4.6% and 1.2%, respectively), featuring a stereoselective
intramolecular aza-[3 + 3] annulation strategy, an interesting
Eschenmoser sulfide contraction, and a stereodivergent
hydrogenation. This work provides a novel approach toward
the 2-methyl-perhydro-9b-azaphenalene family of alkaloids.
yield with all physical data matching the reported literature
data.5c,21 Subsequent oxidation of precoccinelline employing
m-CPBA provided coccinelline 2 in excellent yield.
The synthesis of hippodamine 3 turned out to be more
challenging, as all attempts to directly hydrolyze ester 18a
failed. This can be attributed to the inaccessibility of the
hindered axial ester group in 18b. We attempted to epimerize
the axial ester to the more stable equatorial one using
K2CO3/MeOH and DBU/toluene protocols, but neither
condition was suitable with complete recovery of the starting
material.
Acknowledgment. The authors thank the NIH [NS38049]
for funding and Mr. Benjiman E. Kucera and Dr. Vic Young
from the University of Minnesota for providing X-ray
structural analysis. A.I.G. thanks Dr. Lev Lis for valuable
discussions. This work was carried out in part at UMN.
Ultimately, we found that treatment of ester 18b with
KHMDS20 at -78 °C with subsequent quenching of the
Supporting Information Available: Experimental and
1H NMR spectral data and characterizations for all new
compounds as well as X-ray structural data. This material is
available free of charge via the Internet at http://pubs.acs.org.
(19) (a) Barton, D. H. R.; Bridon, D.; Fernandez-Picot, I.; Zard, S. Z.
Tetrahedron 1987, 43, 2733. (b) Barton, D. H. R.; Herve´, Y.; Potier, P.;
Thierry, J. Tetrahedron 1987, 44, 5479.
(20) Klotz, P.; Mann, A. Tetrahedron Lett. 2003, 44, 1927.
(21) Lebrun, B.; Braekman, J. C.; Daloze, D. Magn. Reson. Chem. 1999,
37, 60.
OL0619359
4902
Org. Lett., Vol. 8, No. 21, 2006