Total synthesis of (-)-allosecurinine

Article abstract of DOI:10.1002/anie.200803257

(Chemical Equation Presented) Safe and secure: An efficient methodology which provides access to homochiral 2,5-cis pyrrolidines in excellent yields starting from chiral alkoxyamine cyclopropanes was used in the total synthesis of (-)-allosecurinine (see

Full text of DOI:10.1002/anie.200803257

Angewandte
Chemie
DOI: 10.1002/anie.200803257
Natural Products
Total Synthesis of (ꢀ)-Allosecurinine**
Andrew B. Leduc and Michael A. Kerr*
In memory of Jennifer Robertson (Dresch)
The Securinega alkaloids are a small family of molecules
isolated from plants of the Euphorbiaceae family (Figure 1).[1]
One of the most obvious characteristic features of this family
is an azabicyclo [3.2.1] ring system that is common to most
members. Securinine (1) was first isolated in 1956 from the
been used in traditional folk medicine. Further biological
research has shown some members to have antimalarial,[7]
antibiotic,[8] and antifungal[9] activities to name but a few. Our
interest in the Securinega alkaloids began several years ago
with the total synthesis of (+)-phyllantidine 5,[10] a recently
isolated natural product containing a tetrahydro-1,2-oxazine
ring system.[11] Our focus then fell upon allosecurinine, which,
though isolated in 1962 has not been prepared by chemical
synthesis, although there is a single synthesis reported for its
enantiomer (also naturally occurring), viroallosecurinine.[5c]
Recently, we have reported a methodology that allows easy
access to both 2,5-trans- and 2,5-cis-substituted pyrrolidines
(Scheme 1), and it was decided that its first application would
be the synthesis of allosecurinine.[12]
Figure 1. Representative members of the Securinega alkaloids.
leaves of Securinega suffruticosa.[2] However, its structure was
not determined until 1962 when it was isolated once again and
studied further.[3] Along with securinine, a small amount of
another compound was isolated and was found to be epimeric
at the C2 position.[3a] This new compound was named
allosecurinine. Further work by other research groups has
since led to the discovery of several other securinega alkaloids
including the enantiomeric forms of both 1 and 2, virosecur-
inine (3) and viroallosecurinine (4), respectively.[4] The family
is currently composed of 20 or more members.
There is great interest in this family of alkaloids in the
synthetic chemistry community,[5] both for the synthetic
challenge represented by their complex ring system and
because of the known biological activities of some family
members. Securinine, for instance, has been shown to be a
g-aminobutyric acid (GABA) receptor antagonist,[6] and
many of the plants that produce Securinega alkaloids have
Scheme 1. Afacile approach to 2,5- trans and 2,5-cis pyrrolidines. OTf=
trifluoromethanesulfonate, Boc=tert-butoxycarbonyl.
[*] A. B. Leduc, Dr. M. A. Kerr
Department of Chemistry, The University of Western Ontario
London, ON, N6A5B7 (Canada)
Fax: (+1)519-661-3022
Our initial retrosynthesis (Scheme 2) began with a
disconnection of the piperidine ring and removal of the
butenolide to give pyrrolidine 7. Further disconnections
resulted in bisalkene 8. The formation of compound 8 was
envisioned to occur from a-oxygenation of an ester followed
by oxidation-state manipulation and a Grignard addition to 9.
Ester 9 could then be simplified to diester 10 by a proposed
dehydration and Krapcho decarboxylation. Pyrrolidine 10 is
then a direct product from the unmasking of pyrroloisoxazo-
E-mail: makerr@uwo.ca
[**] We thank the Natural Sciences and Engineering Research Council
(NSERC) and Merck Frosst for funding. We are grateful to Doug
Hairsine for performing MS analyses. A.B.L. is the recipient of an
NSERC CGS-D postgraduate scholarship. We also thank Avedis
Karadeolian for developing the enantiopure cyclopropane synthesis.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200803257.
ꢀ
lidine 11 by reductive N O bond cleavage. This compound
Angew. Chem. Int. Ed. 2008, 47, 7945 –7948
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
7945

Communications
Scheme 3. Synthesis of the required R cyclopropane. a) PPh3, DIAD,
THF, 08C then reflux (95%); b) K3[Fe(CN)6], K2CO3, (DHQD)2PHAL,
K2OsO2(OH)4, 1:1 tBuOH/H2O, 08C (67%); c) MsCl, NEt3, CH2Cl2
(quant.); d) dimethylmalonate, NaH, THF, 08C then bismesylate,
reflux (45%); e) CAN, 4:1 AcCN/H2O (93%); f) TsCl, DABCO, CH2Cl2,
08C to RT; g) N-hydroxyphthalimide, DBU, DMF (69% (2 steps),
ꢁ99% ee). DIAD=diisopropyl azodicarboxylate,
(DHQD)2PHAL=hydroquinidine 1,4-phthalazinediyl diether, Ms=me-
thanesulfonyl, CAN=ceric ammonium nitrate, Ts=p-toluenesulfonyl,
DABCO=1,4-diazabicyclo[2.2.2]octane, DBU=1,8-diazabicyclo-
[5.4.0]undec-7-ene.
Scheme 2. Aretrosynthesis for ( ꢀ)-allosecurinine. RCM=ring-closing
metathesis.
can then lead back to an appropriate alkoxyamine cyclo-
propane and aldehyde as previously described.
With our retrosynthesis complete, the synthesis com-
menced with the production of the required enantiopure
cyclopropane 18 (Scheme 3). Protection of homoallylic alco-
hol 13 as a p-methoxyphenyl ether by Mitsunobu displace-
ment provided a substrate (14), which was previously utilized
by Corey et al. in an asymmetric dihydroxylation reaction,
and yielded the required enantiomer of diol 15 for our
purposes.[13] Diol 15 could then be bismesylated to produce
Scheme 4. Pyrrolidine synthesis and elaboration. a) hydrazine hydrate, 3:1 EtOH/CH2Cl2; b) ytterbium(III) trifluoromethanesulfonate hydrate
(5 mol%), CH2Cl2, 30 min, then aldehyde 28 (88%); c) Pd(OH)2/C (30 wt%), Boc2O, H2, MeOH (85%); d) NaCN, wet DMSO, 1408C, 12 min.;
e) TMSCHN2, 2:1 benzene/MeOH (86% from 21 and re-esterified 23); f) Bu3P, o-nitrophenylselenocyanate (29), THF then H2O2, THF (94%, 2
steps); g) KHMDS, THF, ꢀ788C, 1.5 h then Davis oxaziridine 30, ꢀ788C; h) CaCl2, NaBH4, 1:1 THF/EtOH (73%, 2 steps); i) IBX, DMSO (86%);
j) vinylmagnesium bromide, THF, 08C!RT (76%); k) IBX, DMSO (69%). TMS=trimethylsilyl, PMB=p-methoxybenzyl, KHMDS=potassium
bis(trimethylsilyl)amide, IBX=o-iodoxybenzoic acid.
7946 www.angewandte.org
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2008, 47, 7945 –7948

Angewandte
Chemie
16, which then underwent a double displacement with
dimethyl malonate to produce cyclopropane 17 in low yield;
however, the only other materials present after displacement
were the starting bismesylate and malonate. The starting
material could thus be recycled, which greatly increased the
amount of material obtained after several iterations. It is
worthy of note that, regardless of the amount of malonate and
base, this reaction failed to proceeded in higher than 50%
yield. Deprotection of the PMP ether with CAN afforded a
substrate which could then be tosylated and subjected to
displacement with N-hydroxyphthalimide to yield cyclopro-
pane 18 which was recrystallized to a minimum of 99% ee.
Deprotection of cyclopropane 18 with ethanolic hydrazine
yielded free cyclopropane 19, which underwent cyclization in
the presence of Yb(OTf)3. Treatment with protected aldehyde
28 provided 2,5-cis pyrroloisoxazolidine 20 in excellent yield
(Scheme 4). Unmasking of the pyrrolidine proceeded
smoothly under a hydrogen atmosphere in the presence of
Pearlmanꢀs catalyst and di-tert-butyldicarbonate to provide 21
in 85% yield. At this point HPLC analysis on a chiral
stationary phase showed that the cycloaddition had not
eroded the stereochemical integrity of the cyclopropane as
compound 21 was obtained in greater than 95% ee.
yielding a mixture of diastereomeric allylic alcohols, these
were then oxidized with IBX in DMSO to yield a,b-
unsaturated ketone 27. The synthesis of aldehyde 26 also
provided the first opportunity to perform an nuclear Over-
hauser effect (NOE) experiment which confirmed our
predicted relative stereochemistry.
Attempted metathesis of 27 proceeded in low and variable
yields; however, metathesis of allylic alcohol 31, followed by
oxidation with IBX yielded a,b-unsaturated ketone 32 albeit
in a low yield of 45% (Scheme 5).
Krapcho decarboxylation[14] of the geminal diesters was
carried out under microwave irradiation and produced the
required monoester 22 in reasonable yield, along with a
significant amount of monoacid 23. This acid was easily
isolated by acidification and extraction, and was transformed
into the required ester 22 by treatment with TMSCHN2.
Dehydration of the primary alcohol in 22 by mesylation and
elimination was attempted with a number of bases, but the
alcohol proved extremely resistant to elimination. Thankfully,
the Grieco procedure that utilizes o-nitrophenylselenocya-
nate and Bu3P followed by oxidation furnished the required
alkene 24 in excellent yield.[15] With pyrrolidine 24 in hand,
the next step was a-hydroxylation of the ester. Deprotonation
with KHMDS at ꢀ788C followed by treatment with the Davis
oxaziridine produced the required a-hydroxy ester,[16] which
was immediately reduced with NaBH4 in the presence of
CaCl2 to provide diol 25. Oxidation of 25 with IBX provided
aldehyde 26, which underwent smooth Grignard addition
Scheme 5. First attempts at completing the synthesis of allosecurinine.
a) Hoveyda–Grubbs 2nd generation catalyst (39), THF, reflux; b) IBX,
DMSO (45%, 2 steps); c) DCC, diethylphosphonoacetic acid, CH2Cl2;
d) LiBr, NEt3, THF. DCC=dicyclohexyl carbodiimide.
Compound 32 could then be further derivatized utilizing
large excesses of DCC and diethylphosphonoacetic acid to
provide Horner–Emmons substrate 33. Compound 33 was
treated with several bases in an attempt to form the
butenolide, but many of these conditions led solely to
decomposition. The use of NEt3 in the presence of LiBr
produced the butenolide 35, but in an unacceptable yield of
approximately 20%, and once again the product was con-
taminated with large amounts of urea. An attempt was then
Scheme 6. Completion of the synthesis of allosecurinine. a) DCC, diethylphosphonoacetic acid, CH2Cl2 (90%); b) LiBr, NEt3, THF; c) Hoveyda–
Grubbs 2nd generation catalyst (39), THF, reflux (40%, 2 steps); d) DDQ, 9:1 CH2Cl2/H2O; e) MsCl, NEt3, THF (83%, 2 steps); f) TFA/CH2Cl2
then silica gel/acetone (65%). DDQ=2,3-dichloro-5,6-dicyano-1,4-benzoquinone. TFA=trifluoroacetic acid.
Angew. Chem. Int. Ed. 2008, 47, 7945 –7948
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org 7947

Communications
e) R. Alibꢁs, M. Ballbꢁ, F. Busquꢁ, P. de March, L. Elias, M.
Figueredo, J. Font, Org. Lett. 2004, 6, 1813– 1816; f) R.
Kammler, K. Polborn, K. T. Wanner, Tetrahedron 2003, 59,
3359 – 3368; g) T. Honda, H. Namiki, M. Kudoh, H. Nagase, H.
Mizutani, Heterocycles 2003, 59, 169 – 187; h) S. Liras, J. E.
Davoren, J. Bordner, Org. Lett. 2001, 3, 703– 706; i) G. Han,
M. G. LaPorte, J. J. Folmer, K. M. Werner, S. M. Weinreb,
Angew. Chem. 2000, 112, 243– 246; Angew. Chem. Int. Ed.
2000, 39, 237 – 240; j) G. Han, M. G. LaPorte, J. J. Folmer, K. M.
Werner, S. M. Weinreb, J. Org. Chem. 2000, 65, 6293– 6306; k) T.
Honda, H. Namiki, M. Kudoh, N. Watanabe, H. Nagase, H.
Mizutani, Tetrahedron Lett. 2000, 41, 5927 – 5930; l) P. Magnus, J.
Rꢂdriguez-Lꢂpez, K. Mulholland, I. Matthews, Tetrahedron
1993, 49, 8059 – 8072; m) P. Magnus, J. Rꢂdriguez-Lꢂpez, K.
Mulholland, I. Matthews, J. Am. Chem. Soc. 1992, 114, 382 – 383;
n) P. A. Jacobi, C. A. Blum, R. W. DeSimone, U. E. S. Udodong,
J. Am. Chem. Soc. 1991, 113, 5384 – 5392; o) P. A. Jacobi, C. A.
Blum, R. W. DeSimone, U. E. S. Udodong, Tetrahedron Lett.
1989, 30, 7173– 7176; p) C. H. Heathcock, T. W. Von Geldem,
Heterocycles 1987, 25, 75 – 78; q) Z. Horii, M. Hanaoka, Y.
Yamawaki, Y. Tamura, S. Saito, N. Shigematsu, K. Kotera, H.
Yoshikawa, Y. Sato, H. Nakai, N. Sugimoto, Tetrahedron 1967,
23, 1165 – 1174; r) S. Saito, H. Yoshikawa, Y. Sato, H. Nakai, N.
Sugimoto, Z. Horii, N. Hanaoka, Y. Tamura, Chem. Pharm. Bull.
1966, 14, 313 – 314.
made to prepare acetate 34, however no conditions were
found to successfully produce this ester and only starting
material was recovered in most cases. Our plan was thus
subsequently altered to allow formation of the butenolide
prior to metathesis.
Treatment of 27 with diethylphosphonoacetic acid and
DCC led to the phosphonate 36 required for an intra-
molecular Horner–Emmons reaction (Scheme 6). Treatment
of 36 with LiBr and NEt3 provided butenolide 37, which was
found to decompose upon column chromatography. To
obviate this difficulty, crude 37 was immediately taken up in
THF and treated with the Hoveyda–Grubbs 2nd generation
catalyst (39) at reflux. The resulting a,b,g,d-unsaturated ester
35 was obtained in a reasonable yield of 40%. This compound
could then be deprotected with DDQ and mesylated in 83%
yield to produce the penultimate compound 38. Compound 38
was then treated with TFA in DCM to deprotect the
pyrrolidine nitrogen. Upon neutralization and stirring with
silica gel in acetone, allosecurinine (2) was obtained in 65%
yield.
In summary, we have successfully completed the total
synthesis of (ꢀ)-allosecurinine in 15 steps from homochiral
cyclopropane 18 in an overall yield of 5%. Chiral shift
analysis gave no indication of the enantiomeric viroallosecur-
inine in the sample. The possibility of adapting this method-
ology to the synthesis of other Securinega alkaloids is
currently under investigation.
[6] I. A. Beutler, E. W. Karbon, A. N. Brubaker, R. Malik, D. R.
Curtis, S. J. Enna, Brain Res. 1985, 330, 135 – 140.
[7] H. Weenen, M. H. H. Nkunya, D. H. Bray, L. B. Mwasumbi, L. S.
Kinabo, V. A. E. B. Kilimali, J. B. P. A. Wijnberg, Planta Med.
1990, 56, 371 – 373.
[8] J. L. Mensah, I. Lagarde, C. Ceschin, G. Michelb, J. Gleye, I.
Fouraste, J. Ethnopharmacol. 1990, 28, 129 – 133.
[9] For antifungal activity of allosecurinine, see: a) A. K. Singh,
M. B. Pandey, U. P. Singh, Mycobiology 2007, 35, 62 – 64; For
antifungal activity of norsecurinine, see: b) S. Sangita, S.
Maurya, U. P. Singh, A. K. Singh, V. P. Singh, V. B. Pandey,
Mycobiology 2005, 33, 97 – 103.
Received: July 4, 2008
Published online: September 3, 2008
Keywords: alkaloids · asymmetric synthesis · heterocycles ·
.
natural products · total synthesis
[10] C. Carson, M. A. Kerr, Angew. Chem. 2006, 118, 6710 – 6713;
Angew. Chem. Int. Ed. 2006, 45, 6560 – 6563.
[11] For isolation of (+)-phyllantidine, see: a) N. H. Lajis, O. B.
Guan, M. V. Sargent, B. W. Skelton, A. H. White, Aust. J. Chem.
1992, 45, 1893– 1897. For isolation of ( ꢀ)-phyllantidine, see:
b) Z. Horii, T. Imanishi, M. Yamaguchi, M. Hanaoka, J. Parello,
S. Munavalli, Tetrahedron Lett. 1972, 13, 1877 – 1880; c) J.
Parello, S. Munavalli, C. R. Hebd. Seances Acad. Sci. 1965, 260,
337 – 340.
[12] S. K. Jackson, A. Karadeolian, A. B. Driega, M. A. Kerr, J. Am.
Chem. Soc. 2008, 130, 4196 – 4201.
[13] E. J. Corey, A. Guzman-Perez, M. C. Noe, J. Am. Chem. Soc.
1995, 117, 10805 – 10816.
[14] a) A. P. Krapcho, G. A. Glynn, B. J. Grenon, Tetrahedron Lett.
1967, 8, 215 – 217; b) A. P. Krapcho, B. P. Mundy, Tetrahedron
1970, 26, 5437 – 5446.
[15] P. A. Grieco, S. Gilman, M. Nishizawa, J. Org. Chem. 1976, 41,
1485 – 1486.
[1] V. Snieckus in The Alkaloids, Vol. 14 (Eds.: R. H. F. Manske),
Academic Press, New York, 1973, p. 425 – 506.
[2] a) V. I. Muravꢀeva, A. I. Banꢀkovskii, Dokl. Akad. Nauk SSSR
1956, 110, 998 – 1000; b) V. I. Muravꢀeva, A. I. Banꢀkovskii, Med.
Prom-st. SSSR 1956, 10, 27 – 28.
[3] a) I. Satoda, M. Murayama, J. Tsuji, E. Yoshii, Tetrahedron Lett.
1962, 3, 1199 – 1206; b) S. Saito, K. Kodera, N. Sugimoto, Z.
Horii, Y. Tamura, Chem. Ind. 1962, 1652; c) S. Saito, K. Kodera,
N. Shigematsu, A. Ide, N. Sugimoto, Z. Horii, M. Hanaoka, Y.
Yamawaki, Y. Tamura, Tetrahedron 1963, 19, 2085 – 2099.
[4] For the isolation of virosecurinine, see: a) T. Nakano, T. H. Yang,
S. Terao, Tetrahedron 1963, 19, 609 – 619; For the isolation of
viroallosecurinine, see: b) S. Saito, T. Iwamoto, T. Tanaka, C.
Matsumura, N. Sugimoto, Z. Horii, Y. Tamura, Chem. Ind. 1964,
28, 1263– 1264.
[5] a) P. Liu, S. Hong, S. M. Weinreb, J. Am. Chem. Soc. 2008, 130,
7562 – 7563.; b) R. Alibꢁs, P. Bayꢂn, P. de March, M. Figueredo,
J. Font, E. Garcia-Garcia, D. Gonzꢃlez-Gꢃlvez, Org. Lett. 2005,
7, 5107 – 5109; c) T. Honda, H. Namiki, M. Watanabe, H.
Mizutani, Tetrahedron Lett. 2004, 45, 5211 – 5213; d) T. Honda,
H. Namiki, K. Kaneda, H. Mizutani, Org. Lett. 2004, 6, 87 – 89;
[16] a) F. A. Davis, J. Lamendola, U. Nadir, E. W. Lluger, T. C.
Sedergran, T. W. Panunto, R. Billmers, R. Jenkins, Jr., I. J.
Turchi, W. H. Watson, J. S. Chen, M. Kimura, J. Am. Chem. Soc.
1980, 102, 2000 – 2005; b) F. A. Davis, L. C. Vishwakarma, J. M.
Billmers, J. Finn, J. Org. Chem. 1984, 49, 3241 – 3243.
7948 www.angewandte.org
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2008, 47, 7945 –7948