Efficient construction of stereodefined α-alkylidene aza-cycloketones via β-amino-alkenyllithium: Straightforward and protection-free synthesis of allopumiliotoxin 267A

Article abstract of DOI:10.1021/ol900452n

Intramolecular nucleophilic acyl substitution of highly functionalized /-amino-alkenyllithium species provided facile access to α-alkylidene aza-cycloketones with defined olefin geometry and rich structural diversity. A concise total synthesis of allopumi

Full text of DOI:10.1021/ol900452n

ORGANIC
LETTERS
2009
Vol. 11, No. 9
2011-2014
Efficient Construction of Stereodefined
r-Alkylidene Aza-cycloketones via
ꢀ-Amino-alkenyllithium: Straightforward
and Protection-Free Synthesis of
Allopumiliotoxin 267A
Bing Wang,*,† Zheng Zhong,†,‡ and Guo-Qiang Lin†,‡,§
Department of Chemistry, Fudan UniVersity, 220 Handan Road, Shanghai 200433, China,
Institutes of Biomedical Sciences, Fudan UniVersity, 138 Yixueyuan Road,
Shanghai 200032, China, and Shanghai Institute of Organic Chemistry, Chinese Academy
of Sciences, 345 Lingling Road, Shanghai 200032, China
wangbing@fudan.edu.cn
Received March 4, 2009
ABSTRACT
Intramolecular nucleophilic acyl substitution of highly functionalized ꢀ-amino-alkenyllithium species provided facile access to r-alkylidene
aza-cycloketones with defined olefin geometry and rich structural diversity. A concise total synthesis of allopumiliotoxin 267A has been
accomplished in 5 steps from 4 featuring this key transformation.
R-Alkylidene cycloketones are versatile building blocks in
organic synthesis,1 as well as common structural features of
many biologically active compounds.2 Conventional methods
such as Wittig,3 Horner-Wadsworth-Emmons3b,c and Julia4
reactions are not effective ways to construct the exocyclic
olefin due to the difficulty in preparing the corresponding
ylides or sulfones, and the intrinsic low reactivity of these
species. Catalyzed or noncatalyzed aldol-dehydration se-
quences are alternative approaches with varying degrees of
success.5 Unfortunately, the olefin geometry is often
noncontrollable,5a,b,6 or limited to the more stable E- isomers.
Bis-condensation was also a serious side-reaction due to the
† Department of Chemistry, Fudan University.
‡ Institutes of Biomedical Sciences, Fudan University.
§ Shanghai Institute of Organic Chemistry.
(1) (a) Wilson, J. E.; Fu, G. C. Angew. Chem., Int. Ed. 2006, 45, 1426.
(b) Wasa, M.; Yu, J.-Q. J. Am. Chem. Soc. 2008, 130, 14058. (c) Xu, W.-
Z.; Huang, Z.-T.; Zheng, Q.-Y. J. Org. Chem. 2008, 73, 5606. (d) Du, Y.;
Lu, X.; Yu, Y. J. Org. Chem. 2002, 67, 8901. (e) Simpson, A. F.; Bodkin,
C. D.; Butts, C. P.; Armitage, M. A.; Gallagher, T. J. Chem. Soc., Perkin
Trans. 1 2000, 3047. For selected overviews: (f) Jung, M. E. In Compre-
hensiVe Organic Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon Press:
Oxford, 1991; Vol. 4, p 1. (g) Lee, V. J. In ComprehensiVe Organic
Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon Elsevier: Oxford, 1991;
Vol. 4, pp 69. (h) Kozlowski, J. A. In ComprehensiVe Organic Synthesis;
Trost, B. M., Fleming, I., Eds.; Pergamon Press: Oxford, 1991; Vol. 4, p
169. (i) Perlmutter, P. Conjugate Addition Reactions in Organic Synthesis;
Pergamon Press: Oxford, 1992.
(2) (a) Yee, S. W.; Jarno, L.; Gomaa, M. S.; Elford, C.; Ooi, L.-L.;
Coogan, M. P.; McClelland, R.; Nicholson, R. I.; Evans, B. A. J.; Brancale,
A.; Simons, C. J. Med. Chem. 2005, 48, 7123. (b) Anto, R. J.; Sukumaran,
K.; Kuttan, G.; Rao, M. N. A.; Subbaraju, V.; Kutton, R. Cancer Lett. 1995,
97, 33.
(3) (a) House, H. O.; Babad, H. J. Org. Chem. 1963, 28, 90. For selected
reviews, see: (b) Maryanoff, B. E.; Reitz, A. B. Chem. ReV. 1989, 89, 863.
(c) Wadsworth, W. S., Jr. Org. React. 1977, 25, 73. (d) Kolodiazhnyi, O. I.
Phosphorus Ylides; Wiley-VCH: Weinheim, 1999.
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Gleiter, R., Hopf, H. Eds.; Wiley-VCH: Weinheim, 2004. (b) Kelly, S. E.
In ComprehensiVe Organic Synthesis; Trost, B. M., Fleming, I., Eds.;
Pergamon Press: Oxford, 1991; Vol. 1, p 729.
10.1021/ol900452n CCC: $40.75
Published on Web 03/31/2009
 2009 American Chemical Society

higher reactivity of monocondensation product, even if the
parent ketone was used in a large excess.7 Moreover, the
issue of regioselectivity may arise for nonsymmetric ketones.
Alternatively, Sato developed an alkyne-based intramolecular
nucleophilic acyl substitution (INAS) reaction using a Ti(II)
reagent, which afforded exclusively E- product.8 Falck and
co-workers devised an interesting homologation-condensation
cascade involving tert-trihalomethylcarbinols.9 On the other
hand, only one recent report by Overman provided access
to R-Z-alkylidene cycloketones, using a two-step sequence
(RZ ) alkyl).10 Herein we report a convenient, flexible and
stereospecific approach via highly functionalized alkenyl-
lithium, offering a wider choice of alkene substitutions
(RZ ) alkyl, aryl).
reactivity of organolithium species toward various functional
groups including alkoxycarbonyl, this approach is non-
trivial.12
Optimization of reaction parameters was carried out using
substrates 1a-d to evaluate the effects of solvent, lithiating
reagent, and the ester group (Table 1). The optimal results
Table 1. Optimization of INAS Reaction of
ꢀ-Amino-alkenyllithiuma
We envisaged that R-alkylidene aza-cycloketones were
accessible from sequential I-Li exchange of vinyl iodide A
(Figure 1, X ) NR) and cyclization of the ꢀ-amino-
entry
1, R
1a, Me
1a, Me
1a, Me
1a, Me
1a, Me
1b, Et
R′Li (equiv)
solvent
2a (%)b
1
nBuLi (1.0)
nBuLi (1.2)
nBuLi (1.0)
tBuLi (2.0)
MesLi (2.0)
nBuLi (1.0)
nBuLi (1.0)
nBuLi (1.0)
nBuLi (1.0)
nBuLi (1.0)
nBuLi (1.0)
THF
THF
THF
THF
THF
THF
THF
THF
Et2O
Tol
67
60
59
29
complex
65
29
53
24
2
3c
4
5
6
7
8
1c, tBu
1d, CH2CF3
1a, Me
1a, Me
1a, Me
9
10
20
56
11d
THF
a Conditions: 0.5 mmol 1, 5 mL THF, -78 °C, 10-30 min, unless
noted otherwise. b Isolated yields. c Reaction run and quenched at -110
°C. d With 2 equiv TMEDA as the additive.
Figure 1. Approaches to R-alkylidene cycloketones.
n
were obtained by using 1.0 eq. BuLi in THF for methyl/
ethyl esters at -78 °C. Additional amount of this lithiating
reagent or lower temperature (-110 °C) resulted in inferior
alkenyllithium species onto the ester. Since the alkene
geometry of A could be readily established by known
methods,11 this route is amenable to both E- and Z- products
with firm control of stereochemistry. Moreover, the site of
the cyclization is unambiguous, and double condensation
would not interfere. Nevertheless, in view of the high
n
yields (entries 2, 3). It is noteworthy that BuLi metalated
alkenyl iodide preferentially, instead of attacking the ester.
In addition, ꢀ-elimination was not observed, even though
the tertiary amine moiety of alkenyllithium intermediates
cannot be stabilized by N-deprotonation.13 In contrast to some
14a,b
t
other reports, BuLi
and MesLi14c were both inferior
t
(entries 4, 5). With regard to the ester moiety, bulky Bu
was found to be detrimental (entry 7). The slightly electron-
withdrawing CH2CF3 group produced a moderate yield,
although trifluoroethoxy anion is a better nucleofuge than
ordinary alkoxides (entry 8). THF represented the most
suitable solvent, shifting to ether or toluene lowered the yield
considerably (entries 9, 10). Addition of TMEDA (2 equiv)
offered no advantage (entry 11). The reaction time was also
(5) For selected recent examples, see: (a) Goldstein, S. W.; Overman,
L. E.; Rabinowitz, M. H. J. Org. Chem. 1992, 57, 1179. (b) Fox, D. N. A.;
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A. E.; Raston, C. L.; Scott, J. L.; Strauss, C. R. Org. Lett. 2003, 5, 3107.
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Ishihara, K.; Kurihara, H.; Yamamoto, H. Synlett 1997, 597.
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2012
Org. Lett., Vol. 11, No. 9, 2009

critical, prolonged exposure complicated the reaction, pre-
sumably due to the base-labile nature of the enone product.
With this protocol in hand, we examined its scope and
limitations (Table 2). Substrates with various substitution
tion). Aliphatic and aryl esters were both suitable electro-
philes for the INAS process. Seven- and five-membered ring
systems can be obtained in fair to good yields (entries 6-10).
Substrates derived from R-amino acids formed elusive
products which decomposed during purification, while fused-
cyclopentanone products were relatively more stable and thus
isolable (entries 7-10).
Allopumiliotoxin 267A (3), a representative of amphibian
alkaloids, has been the goal of multiple synthetic studies
which stimulated the development of many elegant and useful
synthetic methodologies.16,8a As our continuing efforts in the
synthesis of polyhydroxylated alkaloids,17 we initiated a
novel total synthesis of 3 based on the present protocol, for
which 1h has served as an excellent model substrate with
promising results.
Table 2. Scope of the INAS Reaction of
ꢀ-Amino-alkenyllithium
Chiral E-2-iodoallylic alcohol 416b was conveniently
prepared by the reported route, using Evans asymmetric
alkylation as the key step to establish the stereogenic center.
Azide displacement under Mitsunobu conditions (DPPA,
DEAD, Ph3P) followed by Staudinger reaction18 yielded
amine 5. One-pot alkylation-epoxide opening with 617c
assembled the pyrrolidine unit bearing a chiral quaternary
side chain regio- and stereospecifically in high yield (87%).
Conforming to Baldwin’s rule,19 only the 5-exo-tet product
was formed with complete inversion of configuration at C-3
of compound 6. Protection of the tertiary carbinol with
SEM20 and subsequent INAS reaction of the densely
functionalized 8 smoothly afforded enone 9 (74%). Removal
of SEM under acidic conditions (2 M HCl-MeOH) gave
10 in a moderate yield, while an attempted deprotection using
TBAF resulted in complex mixtures due to the base-
sensitivity of 9.
Scheme 1. Toward the Synthesis of Allopumiliotoxin 267A
a Conditions: See Table 1. b Isolated yields. c Unstable products.
patterns gave moderate to excellent yields of functionalized
piperidin-4-ones. Oxygenated side chains including those at
the allylic position were tolerated, allowing space for further
modifications.15 Notably, additional R-substitutions to the
ester enhanced the yields, which is a desirable characteristic
for the synthesis of complex molecules. Importantly, R-Z-
alkylidene cycloketones were accessible via this protocol
(entries 11-14). The olefin geometry was unambiguously
established by comparison with authentic samples of E-
isomers and by NOE experiments (see Supporting Informa-
As resorting to protection is both aesthetically and practi-
cally unappealing,21 we further explored direct INAS reaction
of unprotected 7 using 2 equiv of nBuLi (Scheme 2).
Gratifyingly, the extra nBuLi exchanged the acidic hydroxyl
proton first, and the cyclization gave an equally good yield
(15) See, for example, transformations via Negishi coupling: Hirashima,
S.; Aoyagi, S.; Kibayashi, C. J. Am. Chem. Soc. 1999, 121, 9873.
Org. Lett., Vol. 11, No. 9, 2009
2013

integrated into only two steps, which is a significant
improvement to our previous formal synthesis.17c Finally,
substrate-directed22 reduction using Me4NBH(OAc)3 com-
pleted the total synthesis of 3 {[R]22D +34.6 (c 1.15, MeOH),
Scheme 2. Protection-Free Synthesis of Allopumiliotoxin 267A
lit.5a [R]25 +31 (c 0.22, MeOH)}, in only 5 linear steps
D
from the known compound 4. To our knowledge, this is one
of the most straightforward routes to 3, and the only one
without using protective groups.
In summary, an INAS reaction involving the highly
functionalized ꢀ-amino-alkenyllithium species provided facile
access to R-alkylidene aza-cycloketones with defined olefin
geometry and rich structural diversity. Synthetically chal-
lenging R-Z-alkylidene cycloketones can be prepared ef-
ficiently in this manner. A concise total synthesis of
Allopumiliotoxin 267A has been accomplished featuring this
key transformation. Further synthetic applications of R-alky-
lidene cycloketones are currently under investigation in this
laboratory.
(70%) of the desired intermediate 10 {[R]22 -6.8 (c 1.12,
D
CHCl3), lit.8a [R]25 -6.4 (c 0.96, CHCl3)}. Notably, the
D
formation of the bicyclic indolizidine skeleton and the
stereospecific incorporation of the chiral side chain were
(16) (a) Reference 5a. (b) Aoyagi, S.; Wang, T.-C.; Kibayashi, C. J. Am.
Chem. Soc. 1993, 115, 11393. (c) Caderas, C.; Lett, R.; Overman, L. E.;
Rabinowitz, M. H.; Robinson, L. A.; Sharp, M. J.; Zablocki, J. J. Am. Chem.
Soc. 1996, 118, 9073. For an excellent review, see: (d) Franklin, A. S.;
Overman, L. E. Chem. ReV. 1996, 96, 505, and references cited thereinFor
recent progress, see: (e) Tang, X.-Q.; Montgomery, J. J. Am. Chem. Soc.
1999, 121, 6098. (f) Tan, C.-H.; Holmes, A. B. Chem.-Eur. J. 2001, 7,
1845. (g) Comins, D. L.; Huang, S.; McArdle, C. L.; Ingalls, C. L. Org.
Lett. 2001, 3, 469.
Acknowledgment. Financial support from the NSFC
(20832005, 20602008) is gratefully acknowledged.
Supporting Information Available: Characterization data
and NMR spectra for compounds 2, 5, 7, 10, and 3. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(17) (a) Wang, B.; Liu, R.-H. Eur. J. Org. Chem. 2009, DOI: 10.1002/
ejoc.200900231. (b) Liu, R.-H.; Fang, K.; Wang, B.; Xu, M.-H.; Lin, G.-
Q. J. Org. Chem. 2008, 73, 3307. (c) Wang, B.; Fang, K.; Lin, G.-Q.
Tetrahedron Lett. 2003, 44, 7981. (d) Wang, B.; Yu, X.-M.; Lin, G.-Q.
Synlett 2001, 904. (e) Liu, D.-G.; Wang, B.; Lin, G.-Q. J. Org. Chem. 2000,
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OL900452N
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