Concise synthesis of alkaloid (-)-205B

Article abstract of DOI:10.1021/jacs.5b00243

Described herein is a short total synthesis of alkaloid (-)-205B (1) by means of an anti-selective S_N2 alkylation of an attractively functionalized cyclopropanol and diastereoselective cyclization of the resulting aminoallene adduct for bicyclic ring formation. The synthesis features a general route to cis- or trans-2,6-disubstituted piperidines by lithium aluminum hydride reduction of the imine intermediate by an appropriate choice of solvent and cis- or trans-2,5-disubstituted pyrrolidines by an exceptional level of chirality transfer from a pendant allene. Particularly noteworthy are the brevity and convergence made possible by a segment-coupling strategy.

Full text of DOI:10.1021/jacs.5b00243

Subscriber access provided by FLORIDA ATLANTIC UNIV
Communication
Concise Synthesis of Alkaloid (–)-205B
Nagavaram Narsimha Rao, and Jin Kun Cha
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.5b00243 • Publication Date (Web): 30 Jan 2015
Downloaded from http://pubs.acs.org on January 31, 2015
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a free service to the research community to expedite the
dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts
appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been
fully peer reviewed, but should not be considered the official version of record. They are accessible to all
readers and citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered
to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published
in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just
Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor
changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers
and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors
or consequences arising from the use of information contained in these “Just Accepted” manuscripts.
Journal of the American Chemical Society is published by the American Chemical
Society. 1155 Sixteenth Street N.W., Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the course
of their duties.

Page 1 of 5
Journal of the American Chemical Society
1
2
3
4
5
6
Concise Synthesis of Alkaloid (–)-205B
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Nagavaram Narsimha Rao and Jin Kun Cha*
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Department of Chemistry, Wayne State University, 5101 Cass Ave, Detroit, Michigan 48202
ABSTRACT: Described herein is a short total synthesis of alkaloid (–)-205B, 1, by utilizing anti-selective SN2’ alkylation of an
attractively functionalized cyclopropanol and diastereoselective cyclization of the resulting aminoallene adduct for bicyclic ring
formation. The synthesis features a general route to cis- or trans-2,6-disubstituted piperidines by LAH reduction of the imine in-
termediate by an appropriate choice of solvent; and cis- or trans-2,5-disubstituted pyrrolidines by an exceptional level of chirality
transfer from a pendant allene. Particularly noteworthy is the brevity and convergency made possible by a segment coupling strat-
egy.
Part of our research program has been directed at the devel-
opment of a general synthetic method for indolizidine, pyrrol-
izidine, and related alkaloids with particular emphasis on se-
lectivity, efficiency, and convergency. Neotropical poisonous
frogs Dendrobates have been a rich source of a structurally
diverse array of alkaloids, including indolizidines, pyrrolizidi-
Structurally, 1 is composed of a 2,6-trans-piperidine adorned
3
with two methyl groups, a 2,6-cis-Δ -piperidine, and a 2,5-
trans-pyrrolidine that are encased within the tricyclic skeleton.
Our principal objective was to devise a convergent strategy
that is flexible enough to allow the stereoselective synthesis of
1
and other possible stereoisomers, as well as cis- or trans-
1
nes, quinolizidines, and piperidines. A subset of amphibian
piperidines and pyrrolidines, common structural motifs in or-
1
1
alkaloids are characterized by the presence of two alkyl sub-
stituents at the C3 and C5 positions, as exemplified by alka-
loid (–)-205B (1), indolizidines (–)-223AB (2), (–)-239AB (3),
ganic synthesis and medicinal chemistry. An attractive solu-
tion was found in anti-selective SN2’ alkylation of attractively
functionalized, yet readily available cyclopropanols, one of the
C–C bond forming reactions of cyclopropanols which were
2
and (–)-239CD (4). As a logical progression of our recently
3
1
2,13
disclosed synthesis of 2–4, the structurally more complex
recently developed in our group.
A point of departure
tricylic alkaloid (–)-205B (1) was next chosen as the target for
from previous syntheses was easy pre-installation of the two
methyl groups onto the cyclopropanol partner to obviate the
need for subsequent introduction of the methyl group(s).
Thus, (–)-1 was viewed as an excellent testing ground to high-
light the utility of cyclopropanols as a versatile platform in
natural product synthesis. Additionally, it should be empha-
sized that the use (e.g., alkylation) of cyclopropanols as a
homoenolate equivalent offers greater advantage than ester
homoenolates in rapid assembly of two large segments.
adaptation of a unified approach. Isolation and structure elu-
4
cidation of 1 was reported by Daly and co-workers. The first
synthesis of the unnatural (+)-antipode of 1 by the Toyooka
and Nemoto group in 2003 established its absolute configura-
5
tion. Interestingly, the unnatural (+)-1 was reported to selec-
6
7
tively inhibit α -nicotinic acetylcholine receptors (nAChR).
There have been no complete pharmacological studies of (–)-
1, probably due to its scarcity. The intricate structure of 1,
coupled with interest in biological evaluation, prompted three
recent syntheses by the Smith, Comins, and Micalizio
In our synthetic planning, the only double bond of 1 was the
obvious site for ring closing metathesis (RCM) to unveil 5, an
7
-9
indolizidine having two side chains at the C3 and C5 positions
groups.
These syntheses utilized conceptually different
3
(
Scheme 1). As was the case in our recent syntheses of 2–4,
approaches to streamline the overall synthetic operations.
Given heightened interest in the design and development of
anti-SN2’ alkylation of cyclopropanol 9 with propargylic tosy-
late 8 and subsequent electrophilic allene cyclization of 6
could offer a short route to 1. Exceptional chirality transfer
from the tethered allene in the stereoselective cyclization of
each aminoallene antipode was demonstrated in total synthesis
1
0
selective nAChR modulators, especially α
7
receptors,
a
practical, gram-scale synthesis of 1 is highly desirable. We
herein describe a concise synthesis of (–)-1 by an efficient
coupling of an attractively functionalized cyclopropanol and a
3
(
R)-propargylic tosylate.
of 2 and its 3-epimer. An enantiopure allene was a prerequi-
site for stereoselective formation of a 2,5-trans-disubstituted
(
or, when desired, cis-) pyrrolidine and, in turn, prompted us
1
4
to prepare 5b (over 5a) to set the stage for a relay RCM.
Impressive recent advances in gold- or silver-catalyzed elabo-
1
5
ration of allenes notwithstanding, there are surprisingly only
a handful of applications in alkaloid synthesis, and known
examples are limited primarily to monocyclic ring forma-
1
6,17
tion.
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 2 of 5
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
A key intermediate 5b contains a highly decorated 2,6-trans-
piperidine subunit, which contrasts with the 2,6-cis-
counterpart present in 2–4. The latter stereochemical ar-
rangement is known to be readily accessible by stereoelec-
tronically controlled addition of a hydride nucleophile to the
six-membered cyclic imine (see A) or iminium ion (Scheme
Our segment coupling approach to (–)-1 entailed the prepara-
tion of two segments 8 and 9. The synthesis of cyclopropanol
20
9
commenced with Myers’ asymmetric alkylation of com-
mercially available 12 with iodide 13 (readily available from
21
the corresponding diol) to afford 14 in 91% yield (with
1
8,19
2
).
In contrast, stereoselective formation of 2,6-trans-
>
20:1 ds) (Scheme 3). The latter compound was then con-
piperidines presents a challenge, but might be possible by ad-
aptation of Yamamoto’s method, which exploits the minimiza-
verted to the corresponding methyl ester 10 in 95% yield by
standard methods. The Kulinkovich cyclopropanation of ester
1
,2
19
tion of A steric interaction. A careful analysis of plausible
transition states related to imine 11 under Yamamoto’s condi-
tions raised serious concerns: there may be only a small differ-
ence in energy between two limiting half-chair conformers B
10 proceeded cleanly to deliver cyclopropanol 15 in 92%
22
yield.
Straightforward functional group manipulation gave
alcohol 16 in 76% yield. Stereoselective displacement of the
secondary alcohol of 16 with diphenylphosphoryl azide, fol-
lowed by desilylation, furnished azide 9 in 73% yield. The
coupling partner 8 was easily prepared in two steps from a
1
,2
and C due to competing A strain; and the presence of a
Lewis acid could promote formation of the corresponding
metalloenamine leading to epimerization of the adjacent stere-
ocenter. Unfortunately, there is a dearth of literature prece-
dents on the applicability of Yamamoto’s protocol to substi-
tuted piperidinium ions. If successful, however, the imine
reduction strategy would provide a divergent route to both 2,6-
cis- and trans-piperidines from common imine intermediates.
Because of the potential impact, we decided to forge ahead
with the identification of suitable conditions for stereoselec-
tive reduction of cyclic imine 11.
23
known compound.
ACS Paragon Plus Environment

Page 3 of 5
Journal of the American Chemical Society
tigation of this extraordinary solvent effect in imine reduction
1
2
3
4
5
6
7
8
9
is warranted to shed light on its origin and assess the scope
and limitations.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
The key cross-coupling reaction of 8 and 9 at rt under previ-
3
,12
ously reported conditions
). With 7 in hand, the remaining tasks called for the sequen-
tial construction of the three heterocycles by stereoselective
afforded 7 in 79% yield (Scheme
4
2
3
elaboration of two sp carbons to the respective sp stereocen-
ters. Aza-olefination of 7 by the action of Ph3P gave imine 11
cleanly to set the stage of in situ reduction for the preparation
of piperidine 6 in preference to 17. According to a screening
of common reducing agents, our initial concern that the imine
intermediate could be prone to tautomerization and the ac-
companying epimerization at the methyl stereocenter appeared
to be well-founded (Table 1). Tautomerization/epimerization,
not surprisingly, was more pronounced in a protic solvent (en-
try 1). Similarly, the use of a sterically hindered Lewis acid
(
e.g., Me3Al and Et3Al), the salient feature of Yamamoto’s
elegant tactic, also appeared to promote tautomerization (en-
tries 2–6). Despite a recent renaissance in asymmetric reduc-
2
4
tion of imines and derivatives, there were very few examples
25
involving imines having α-stereocenters in the literature.
Instead of searching for different hydride reagents and Lewis
acids, we were intrigued by the uncommon solvent effects in
LAH reduction of the penultimate imine intermediate reported
in the synthesis of solenopsin A, a prototype 2,6-trans-
piperidine. The degree of selectivity was modest, but the re-
Once reliable access to 6 was secured, the remaining two steps
were uneventful (Scheme 4). Silver nitrate-mediated cycliza-
tion of aminoallene 6 proceeded cleanly to deliver 5b in 83%
1
9a,b
versal (in Et2O vs THF or CH2Cl2) was striking.
If dr
27
yield as a single isomer.
Finally, a short synthesis of alka-
could be improved, this simple tactic based on a judicious
choice of solvent would provide an attractive route to either
loid (–)-205B, 1, was completed by a relay RCM by use of the
2
8
second-generation Grubbs catalyst.
Spectroscopic data and
2
,6-cis- or trans- piperidines. Ultimately, LAH reduction of
optical rotation of (–)-1 were in excellent accord with litera-
1
1 in Et2O gave a satisfactory solution to afford 6 in 67–70%
5
,7-9
ture values.
yield in a 15–19:1 ratio (entry 8 vs 9). The combined use of n-
BuLi and DIBAL-H (entry 7) gave exclusive formation of 17.
Piperidine 6 is easily distinguishable from 17 by TLC, with a
In conclusion, we report a concise synthesis of alkaloid (–)-
205B, 1, that punctuates the simplicity and brevity of the syn-
thetic sequence. The expedient synthesis of (–)-1 is made
large difference in Rf values (0.2 and 0.5, respectively, on neu-
tral alumina TLC plates using 5% EtOAc/hexanes as eluent).
The stereochemical determination of 6 and 17 was secured by
possible by anti-S 2’ alkylation of attractively functionalized
N
cyclopropanols. This work also delineates a general strategy
for preparing 2,6-cis- or 2,6-trans-piperidines by stereoselec-
2
6
their eventual conversion to (–)-1 and its epimer. The inves-
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 4 of 5
tive reduction of imines; and 2,5-cis- or 2,5-trans-pyrrolidines
by diastereoselective cyclization of aminoallenes. These new
synthetic methods hold promise in the stereoselective synthe-
ses of pyrrole, pyrrolizidine, and indolizidine alkaloids, along
with other natural products containing aza- and oxygen-
heterocycles.
(14) (a) Hoye, T. R.; Jeffrey, C. S.; Tennakoon, M. A.; Wang, J.;
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Zhao, H. J. Am. Chem. Soc. 2004 126, 10210. (b) Hansen, E. C.; Lee,
D. Org. Lett. 2004, 6, 2035. (c) Wang, X.; Bownman, E. J.; Bowman,
B. J.; Porco, J. A. Jr. Angew. Chem., Int. Ed. 2004, 43, 3601. (d)
Wallace, D. J. Angew. Chem., Int. Ed. 2005, 44, 1912.
(
15) For recent work, (a) Marshall, J. A.; Pinney, K. G. J. Org.
Chem. 1993, 58, 7180. (b) Nishina, N.; Yamamoto, Y. Angew.
Chem., Int. Ed. 2006, 45, 3314. (c) Zhang, Z.; Liu, C.; Kinder, R. E.;
Han, X.; Qian, H.; Widenhoefer, R. A. J. Am. Chem. Soc. 2006 128,
ASSOCIATED CONTENT
9
2
066. (d) Hamilton, G. L.; Kang, E. J.; Mba, M.; Toste, F. D. Science
007, 317, 496 and references therein. For reviews, (e) Weibel, J.-
Supporting Information
Experimental procedures and compound characterization data.
This material is available free of charge via the Internet at
http://pubs.acs.org.
M.; Blanc, A.; Pale, P. Chem. Rev. 2008, 108, 3149. (f) Álvarez-
Corral, M.; Muñoz-Dorado, M.; Rodríguez-García, I. Chem. Rev.
2008, 108, 3174. (g) Muñoz, M. P. Chem. Soc. Rev. 2014, 43, 3164.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(
1
h) Nishina, N.; Yamamoto, Y. Top. Organomet. Chem. 2013, 43,
15. (i) Ma, S. Acc. Chem. Res. 2009, 42, 1679.
16) (a) Arseniyadis, S.; Gore, J. Tetrahedron Lett. 1983, 24, 3997.
b) Arseniyadis, S.; Sartoretti, J. Tetrahedron Lett. 1985, 26, 729. (c)
AUTHOR INFORMATION
(
Corresponding Author
(
jcha@chem.wayne.edu.
Lathbury, D.; Gallagher, T. J. Chem. Soc., Chem. Commun. 1986,
114. (d) Shaw, R. W.; Gallagher, T. J. Chem. Soc., Perkin Trans. 1
1
1
17) Cf. (a) Ha, J. D.; Lee, D.; Cha, J. K. J. Org. Chem. 1997, 62,
4550. (b) Ha, J. D.; Cha, J. K. J. Am. Chem. Soc. 1999, 121, 10012.
18) (a) Deslongchamps, P. Stereoelectronic Effects in Organic
Chemistry; Pergamon Press: Oxford, 1983. (b) Stevens, R. V. Acc.
Chem. Res. 1984, 17, 289. (c) Overman, L. E.; Fukuya, C. J. Am.
Chem. Soc. 1980, 102, 1454. (d) Overman, L. E.; Freerks, R. L. J.
Org. Chem. 1981, 46, 2833.
Notes
994, 3549. (e) Prasad, J. S.; Liebeskind, L. S. Tetrahedron Lett.
988, 29, 4253.
(
The authors declare no competing financial interest.
ACKNOWLEDGMENT
(
We thank NSF (CHE-1265843) for generous financial support.
REFERENCES
(
1) Reviews: (a) Daly, J. W.; Garraffo, H. M.; Spande, T. F. In Al-
kaloids: Chemical and Biological Perspectives; Pelletier, S. W., Ed.;
Pergamon: New York, 1999; Vol 13, 1-161. (b) Michael, J. P. In
Alkaloids; Cordell, G. A., Ed.; Academic Press: London, 2001; Vol.
(
19) (a) Matsumura, Y.; Maruoka, K.; Yamamoto, H. Tetrahedron
Lett. 1982, 23, 1929. (b) Maruoka, K.; Miyazaki, T.; Ando, M.;
Matsumura, Y.; Sakane, S.; Hattori, K.; Yamamoto, H. J. Am. Chem.
Soc. 1983, 105, 2831. (c) Kavala, M.; Mathia, F.; Kozfsek, J.;
Szolcsányi, P. J. Nat. Prod. 2011, 74, 803. (d) Simon, R. C.; Zepeck,
F.; Kroutil, W. Chem. Eur. J. 2013, 99, 2859.
5
5, 91-258. (c) Daly, J. W.; Spande, T. F.; Garraffo, H. M. J. Nat.
Prod. 2005, 68, 1556. (d) Michael, J. P. Nat. Prod. Rep. 2008, 25,
39.
2) In addition to 3,5-disubstituted indolizidines, 5- and 5,8-
1
(
(
20) (a) Myers, A. G.; Yang, B. H.; Chen, H.; McKinstry, L.; Ko-
substitution patterns are also found in this subclass of alkaloids.
(3) Rao, N. N.; Parida, B. B.; Cha, J. K. Org. Lett. 2014, 16, 6208.
pecky, D. J.; Gleason, J. L. J. Am. Chem. Soc. 1997, 119, 6496. (b)
Myers, A. G.; Yang, B. H. Org. Synth. 2000, 77, 22.
(21) (a) Stefan, E.; Taylor, R. E. Org. Lett. 2012, 14, 3490. (b)
Alegret, C.; Santacana, F.; Riera, A. J. Org. Chem. 2007, 72, 7688.
(
4) (a) Tokuyama, T.; Nishimori, N.; Shimada, A.; Edwards, M.
W.; Daly, J. W. Tetrahedron 1987, 43, 643. (b) Tokuyama, T.; Gar-
raffo, H. M.; Spande, T. F.; Daly, J. W. Anal. Asoc. Quim. Argent.
(
22) Reviews: (a) Kulinkovich, O. G.; de Meijere, A. Chem. Rev.
000, 100, 2789. (b) Kulinkovich, O. G. Chem. Rev. 2003, 103, 2597.
c) Cha, J. K.; Kulinkovich, O. G. Org. Reactions, 2012, 77, 1.
23) See the Supporting Information. Cf. Mukai, C.; Sonobe, H.;
Kim, J. S.; Hanaoka, M. J. Org. Chem. 2000, 65, 6654.
24) (a) Olivier, R.; Naouël, M.; James, C. Synthesis 2004, 2943.
b) Iwasaki, F.; Onomura, O.; Mishima, K.; Kanematsu, T.; Maki, T.;
1
998, 86, 291.
2
(
(5) (a) Toyooka, N.; Fukutome, A.; Shinoda, H.; Nemoto, H.
Angew. Chem., Int. Ed. 2003, 42, 3808. (b) Toyooka, N.; Fukutome,
A.; Shinoda, H.; Nemoto, H. Tetrahedron 2004, 60, 6197.
(
(
6) Tsuneki, H.; You, Y.; Toyooka, N.; Kagawa, S.; Kobayashi,
(
S.; Sasaoka, T.; Nemoto, H.; Kimura, I.; Dani, J. A. Mol. Pharmacol.
(
2
004, 66, 1061.
Matsumura, Y. Tetrahedron Lett. 2001, 42, 2525. (c) Lipshutz, B. H.;
Shimizu, H. Angew. Chem., Int. Ed. 2004, 43, 2228. (d) Eisenberger,
P.; Bailey, A. M.; Crudden, C. M. J. Am. Chem. Soc. 2012, 134,
17384. (e) Rueping, M.; Sugiono, E.; Azap, C.; Theissmann, T.;
Bolte, M. Org. Lett. 2005, 7, 3781. (f) Hoffmann, S.; Seayad, A. M.;
List, B. Angew. Chem., Int. Ed. 2005, 44, 7424. (g) Menche, D.;
Hassfeld, J.; Li, J.; Menche, G.; Ritter A.; Rudolph, S. Org. Lett.
(7) (a) Smith, A. B., III; Kim, D.-S. Org. Lett. 2005, 7, 3247. (b)
Smith, A. B., III; Kim, D.-S. J. Org. Chem. 2006, 71, 2547.
8) (a) Tsukanov, S. V.; Comins, D. L. Angew. Chem., Int. Ed.
(
2
2
011, 50, 8626. (b) Tsukanov, S. V.; Comins, D. L. J. Org. Chem.
014, 79, 9074.
(
9) Yang, D.; Micalizio, G. C. J. Am. Chem. Soc. 2012, 134,
15237.
(10) (a) Jensen, A. A.; FrØlund, B.; Liljefors, T.; Krogsgaard-
2
2
006, 8, 741. (h) Li, G.; Liang, Y.; Antilla, J. C. J. Am. Chem. Soc.
007, 129, 5830. (i) Xiao, X.; Wang, H.; Huang, Z.; Yang, J.; Bian,
Larsen, P. J. Med. Chem. 2005, 48, 4705. (b) Mazurov, A.; Hauser,
T.; Miller, C. H. Curr. Med. Chem. 2006, 13, 1567. (c) Mazurov, A.
A.; Speake, J. D.; Yohannes, D. J. Med. Chem. 2011, 54, 7943.
X.; Qin, Y. Org. Lett. 2006, 8, 139.
25) Cf. Maughan, M. A. T.; Davies, I. G.; Claridge, T. D. W.;
Courtney, S.; Hay, P.; Davis, B. G. Angew. Chem., Int. Ed. 2003, 42,
788.
26) There are unmistakable differences in H NMR spectra be-
(
(
11) Reviews: (a) Baliah, V.; Jeyaraman, R.; Chandrasekaran, L.
3
1
Chem. Rev. 1983, 83, 379. (b) Pinder, A. R. Nat. Prod. Rep. 1987, 4,
527. (c) Rubiralta, M.; Giralt, E.; Diez, A. Piperidine: Structure,
Preparation, Reactivity, and Synthetic Applications of Piperidine and
its Derivatives; Elsevier: Amsterdam, 1991. (d) Pichon, M.; Figadère,
B. Tetrahedron: Asymmetry 1996, 7, 927. (e) O’Hagan, D. Nat. Prod.
Rep. 2000, 17, 435. (f) Pandey, G.; Banerjee, P.; Gadre, S. R. Chem.
Rev. 2006, 106, 4484.
(
tween 1 and its epimer. Particularly diagnostic is the (equatorial)
proton at 3.86 ppm in 1, which is absent in the epimer.
(
27) Stereoselective cyclization of aminoallene 6 required an
1
enantiopure allene subunit (i.e., 5b where R ≠ H). Our preliminary
study during total synthesis of 4 guided us to rely on a relay RCM
strategy.
3
(12) Das, P. P.; Belmore, K.; Cha, J. K. Angew. Chem., Int. Ed.
(
28) Reviews: (a) Trnka, T. M.; Grubbs, R. H. Acc. Chem. Res.
2
2
012, 51, 9517.
13) Parida, B. B.; Das, P. P.; Niocel, M.; Cha, J. K. Org. Lett.
013, 15, 1780.
2001, 34, 28. (b) Grubbs, R. H. Chem. Rev. 2010, 110, 1746.
(
ACS Paragon Plus Environment

Page 5 of 5
Journal of the American Chemical Society
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
ACS Paragon Plus Environment