Catalytic, asymmetric indolizidinone aza-quaternary stereocenter synthesis: Expedient synthesis of the cylindricine alkaloid core

Article abstract of DOI:10.1021/ol400529k

The Rh(I)?CKphos catalyzed [2 + 2 + 2] cycloaddition of 1,1-disubstituted alkenyl isocyanates and alkyl alkynes selectively forms previously inaccessible vinylogous amide indolizidinone cycloadducts, establishing an aza-quaternery stereocenter with excellent enantioselectivities (up to 98% ee). This advance enables a seven step catalytic, asymmetric synthesis of the tricyclic core of the cylindricine alkaloids with excellent control of product selectivity as well as regio- and enantioselectivity.

Full text of DOI:10.1021/ol400529k

ORGANIC
LETTERS
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Vol. XX, No. XX
000–000
Catalytic, Asymmetric Indolizidinone
Aza-Quaternary Stereocenter Synthesis:
Expedient Synthesis of the Cylindricine
Alkaloid Core
Derek M. Dalton and Tomislav Rovis*
Department of Chemistry, Colorado State University, Ft. Collins, Colorado 80523,
United States
rovis@lamar.colostate.edu
Received February 25, 2013
ABSTRACT
The Rh(I)•CKphos catalyzed [2 þ 2 þ 2] cycloaddition of 1,1-disubstituted alkenyl isocyanates and alkyl alkynes selectively forms previously
inaccessible vinylogous amide indolizidinone cycloadducts, establishing an aza-quaternery stereocenter with excellent enantioselectivities
(up to 98% ee). This advance enables a seven step catalytic, asymmetric synthesis of the tricyclic core of the cylindricine alkaloids with excellent
control of product selectivity as well as regio- and enantioselectivity.
Efficient, selective N-heterocycle synthesis is a vital area
of research due to the abundance and biological importance
of molecules that contain such motifs. Transition metal
catalysis offers efficient access to complex N-heterocycles
through [2 þ 2 þ 2] cycloadditions with N-containing
π-components, such as isocyanates.1 We have made a
number of contributions in this area2 and found that alkyl
alkynes give lactam products while aryl alkynes provide
vinylogous amides with 1,1-disubstituted alkenyl isocya-
nates (Scheme 1).3 A limitation of our methodology was
the ability to synthesize vinylogous amide cycloadducts
with alkyl alkynes (Scheme 1).4 Alkyl susbstituted vinylo-
gous amide indolizidinones are valuable synthetic targets
due to the abundance (>200) of indolizidine and quino-
lizidine natural products5 that have 5-alkyl substituents.
A number of tricyclic indolizidine and quinolizidine alka-
loids, including the cylindricines,6 lepadiformines,7 fasi-
cularin,8 and FR901483,9 have 5,9-alkyl substitution with
(1) For reviews of cycloadditions involving isocyanates, see: (a)
Varela, J. A.; Saa, C. Chem. Rev. 2003, 103, 3787–3801. (b) Louie, J.
Curr. Org. Chem. 2005, 9, 605–623. (c) Chopade, P. R.; Louie, J. Adv.
€
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Chem. Soc. Rev. 2007, 36, 1095–1108. (e) Perreault, S.; Rovis, T. Chem.
Soc. Rev. 2009, 38 (11), 3149–3159. (f) Friedman, R. K.; Oberg, K. M.;
Dalton, D. M. Pure Appl. Chem. 2010, 82 (7), 1353–1364. (g)
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Domınguez, G. G.; Perez-Castells, J. J. Chem. Soc. Rev. 2011, 40,
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3430–3444. (h) Broere, D.; Ruijter, E. Synthesis 2012, 44, 2639–2672.
(i) Shibata, Y.; Tanaka, K. Synthesis 2012, 44, 323–350. (j) For a review
of metal catalyzed [2 þ 2 þ 2] cycloadditions, see: Agenet, N.; Busine, O.;
Slowinski, F.; Gandon, V.; Aubert, C.; Malacria, M. Org. React. 2007,
68, 1–302.
(2) For our previous work in this area, see: (a) Yu, R. T.; Rovis, T.
J. Am. Chem. Soc. 2006, 128 (9), 2782–2783. (b) Yu, R. T.; Rovis, T.
J. Am. Chem. Soc. 2006, 128 (38), 12370–12371. (c) Yu, R. T.; Rovis, T.
J. Am. Chem. Soc. 2008, 130 (11), 3262–3263. (d) Oinen, M. E.; Yu,
R. T.; Rovis, T. Org. Lett. 2009, 11 (21), 4934–4937. (e) Friedman, R. K.;
Rovis, T. J. Am. Chem. Soc. 2009, 131 (30), 10775–10782. (f) Oberg,
K. M.; Lee, E. E.; Rovis, T. Tetrahedron 2009, 65 (26), 5056–5061. (g)
Dalton, D. M.; Oberg, K. M.; Yu, R. T.; Lee, E. E.; Perreault, S.; Oinen,
M. E.; Pease, M. L.; Malik, G.; Rovis, T. J. Am. Chem. Soc. 2009, 131
(43), 15717–15728.
(3) Lee, E. E.; Rovis, T. Org. Lett. 2008, 10 (6), 1231–1234.
(4) Yu, R. T.; Lee, E. E.; Malik, G.; Rovis, T. Angew. Chem., Int. Ed.
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(5) (a) Daly, J. W. J. Med. Chem. 2003, 46, 445–452. (b) Daly, J. W.;
Spande, T. F.; Garraffo, H. M. J. Nat. Prod. 2005, 68, 1556–1575.
(6) For a recent review on cylindricines, see: Weinreb, S. M. Chem.
Rev. 2006, 106, 2531–2549.
(7) Biard, J. F.; Guyot, S.; Roussakis, C.; Verbist, J. F.; Vercauteren,
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r
10.1021/ol400529k
XXXX American Chemical Society

C9 being a tetrasubstituted aza-quaternary stereocenter
(Scheme 1).
cyclindricine core; Zhang’s synthesis does not incorporate
the 5-alkyl side chain. We saw asymmetric Rh(I) catalyzed
[2 þ 2 þ 2] cycloadditions asa complementary approach to
the aza-Michael synthesis of the tricyclic cylindricine core
because it easily accesses a variety of analogs.
Scheme 1. Rh(I) Catalyzed Cycloadditions of 1,1-Disubstituted
Alkenyl Isocyanates and Alkynes, and Select Natural Products
Accessible from the Alkyl-Substituted Vinylogous Amide
Scaffold
Crucial to the development of an efficient route to the
cylindricine molecules was the design of a perfluorinated
Taddol phosphoramidite, CKphos,14 that overrides sub-
strate based control of product selectivity in the [2 þ 2 þ 2]
cycloaddition. This discovery allows for the highly selec-
tive formation of vinylogous amide indolizidinones with a
wide range of alkynes, including alkyl alkynes. Herein, we
report that Rh(I)•CKphos catalyzed cycloadditions are a
highly enantioselective method to form tetrasubstituted
N-stereocenters from 1,1-disubstitutedalkenyl isocyanates
and alkyl alkynes. Furthermore, Rh(I)•CKphos was used
to synthesize the tricyclic cylindricine core in 7 steps,
95% ee, and 11% overall yield.
Table 1. Ligand Screen for Rh(I) Catalyzed Cycloadditions of
1,1-Disubstituted Alkenyl Isocyanates and Alkynes
Due to their interesting architecture and biological
activity many methods to synthesize these tricyclic alka-
loids have been developed. Most of these syntheses are
racemic10 or use chiral starting materials11 and take ad-
vantage of an aza-Michael addition (single or double)
to form the functionalized piperidine core. Shibasaki12
(5 steps, 82% ee) and Zhang13 (10 steps, 87% ee) have
reported catalytic asymmetric approaches to the cylindri-
cines. While Shibasaki’s approach is very efficient, it uses
the traditional aza-Michael addition to synthesize the
a Reaction conditions: 1, 2 (1.3 equiv), [Rh(C2H4)2Cl]2 (2.5 mol %),
L (5 mol %) in PhMe at 110 °C for 16 h. b The combined isolated yield is
reported. c The enantiomeric excess shown is of the major product.
(10) (a) Snider, B. B.; Liu, T. J. Org. Chem. 1997, 62, 5630–5633. (b)
Liu, J. F.; Heathcock, C. H. J. Org. Chem. 1999, 64, 8263–8266. (c) Flick,
A. C.; Caballero, M. J. A.; Padwa, A. Org. Lett. 2008, 10, 1871–1874. (d)
Vital, P.; Hosseini, M.; Shanmugham, M. S.; Gotfredsen, C. H.; Harris,
P.; Tanner, D. Chem. Commun. 2009, 1888–1890. (e) Donohoe, T. J.;
Brian, P. M.; Hargaden, G. C.; O’Riordan, T. J. C. Tetrahedron 2010, 66,
6411–6420. (f) Lapointe, G.; Schenk, K.; Renaud, P. Org. Lett. 2011, 13,
4774–4777.
Vinylogous amide formation with 1,1-disubstituted al-
kenes previously required aryl acetylenes because alkyl
alkynes produced a lactam cycloadduct (Table 1).4 A
screen of ligands revealed that this inherent substrate bias
of product selectivity could be altered by the phosphor-
amidite on rhodium. m-Xylyl Taddol phosphoramidite
T2 provides lactam 3 in 6.5:1 selectivity. Guiphos B1 and
t-BuBiaryl B2 modestly favor vinylogous amide, but in the
case of B2 the enantioselectivity is poor (27%). CKPhos
provides vinylogous amide 4 with excellent product
(1:>19) and enantioselectivity (90%) and good yield (61%).
We found that Rh(I)•CKphos provides a selective
means of forming vinylogous amides from alkyl alkynes
and 1,1-disubstituted alkenes (Figure 1). A variety of
€
(11) (a) Molander, G. A.; Ronn, M. J. Org. Chem. 1999, 64, 5183–
5187. (b) Trost, B. M.; Rudd, M. T. Org. Lett. 2003, 5, 4599–4602. (c)
Canesi, S.; Bouchu, D.; Ciufolini, M. A. Angew. Chem., Int. Ed. 2004, 43,
4336–4338. (d) Arai, T.; Abe, H.; Aoyagi, S.; Kibayashi, C. Tetrahedron
Lett. 2004, 45, 5921–5924. (e) Liu, J.; Hsung, R. P.; Peters, S. D. Org.
Lett. 2004, 6, 3989–3992. (f) Abe, H.; Aoyagi, S.; Kibayashi, C. J. Am.
Chem. Soc. 2005, 127, 1473–1480. (g) Liu, J.; Swidorski, J. J.; Peters,
S. D.; Hsung, R. P. J. Org. Chem. 2005, 70, 3898–3902. (h) Swidorski, J.;
Wang, J.; Hsung, R. P. Org. Lett. 2005, 8, 777–780. (i) Zou, J.; Cho,
D. W.; Mariano, P. S. Tetrahedron 2010, 66, 5955–5961. (j) Mei, S.-L.;
Zhao, G. Eur. J. Org. Chem. 2010, 1660–1668. (k) Hardin Narayan,
A. R.; Sarpong, R. Org. Biomol. Chem. 2012, 10, 70–78.
(12) Shibuguchi, T.; Mihara, H.; Kuramochi, A.; Sakuraba, S.;
Ohshima, T.; Shibasaki, M. Angew. Chem., Int. Ed. 2006, 45, 4635–4637.
(13) Zhang, X.-M.; Wang, M.; Tu, Y.-Q.; Fan, C.-A.; Jiang, Y.-J.;
Zhang, S.-Y.; Zhang, F.-M. Synlett 2008, 2831–2835.
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2062–2070. (b) Perreault, S.; Rovis, T. Synthesis 2013, 45, 719–728.
B
Org. Lett., Vol. XX, No. XX, XXXX

alkenyl isocyanates.15 For lactam, oxidative cyclization
results in five-membered rhodacycle IIa and CꢀC bond
formation. Migratory insertion of the alkene into IIa pro-
vides seven-membered rhodacycle IIIa, which is followed by
reductive elimination to form lactam 3 and regenerates the
active catalyst.
For vinylogous amide 4, oxidative cyclization gives
rhodacycle IIb and forms a CꢀN bond. The pendent
alkene cannot insert into rhodacycle IIb due to a strained
geometry in the transition state; thus, a reversible CO
migration16 occurs through a highly reactive, four-membered
rhodacycle IIIb to form enamine IVb. Migratory insertion of
the alkene into IVb provides seven-membered metallacycle
Vb. Reductive elimination forms a vinylogous amide and
regenerates the active catalyst.
Scheme 2. Proposed Mechanistic Cycle for Product Formation
Figure 1. Isocyanate and alkyne substrate scope. Reaction condi-
tions: 1, 2 (1.3 equiv), [Rh(C2H4)2Cl]2 (2.5 mol %), L (5 mol %) in
PhMe at 110 °C for 16 h. The combined isolated yield is
reported. The enantiomeric excess shown is of the major pro-
duct. For T1 and T2, the results were previously reported;4
2 equiv of 2 were used.
To showcase the ability of this methodology to rapidly
and enantioselectively assemble indolizidines from simple
starting materials, we sought to apply the Rh(I)•CKphos
catalyzed cycloaddition of 1,1-disubstituted alkenyl iso-
cyanates (2j) with alkyl alkynes to afford alkyl-substituted
indolizidinone4j(eq 1) thatcould be further functionalized
to the tricyclic core. Early attempts at the cycloaddition
with 2j found that Guiphos B1 gives modest product and
functional groups are tolerated on the alkyne, including
esters, chlorides, sily ethers, aryls, and alkenes. Larger 1,1-
disubstituted alkenes provide the vinylogous amide in
lower yields, and an increase in pyridone byproduct is
seen.3 Presumably, the increase in steric bulk on the alkene
slows alkene coordination and subsequent migratory in-
sertion, allowing a second alkyne moiety to incorporate
prior to alkene insertion.
(15) A competition experiment between a monosubstituted pentenyl
isocyanate and 1,1-disubstituted methyl pentenyl isocyanate with benzyl
acetylene gives a 1:1 ratio of vinylogous amide products. See Supporting
Information for further details. This finding is consistent with previously
reported competition experiments with aryl acetylenes as discussed in ref 2g.
(16) (a) Cavallo, L.; Sola, M. J. Am. Chem. Soc. 2001, 123, 12294–
12302. (b) Gonsalvi, L.; Adams, H.; Sunley, G. J.; Ditzel, E.; Haynes, A.
J. Am. Chem. Soc. 2002, 124, 13597–13612. (c) Gonsalvi, L.; Gaunt,
J. A.; Adams, H.; Castro, A.; Sunley, G. J.; Haynes, A. Organometallics
2003, 22, 1047–1054.
The proposed mechanism for the formation of lactam 3
and vinylogous amide 4 is illustrated in Scheme 2.2g Co-
ordination of the alkyne and isocyanate orthogonal to the
square plane precedes oxidative cyclization, which estab-
lishes both lactam and vinylogous amide pathways. Oxi-
dative cyclization is the first irreversible step based on
competition experimentsbetween mono-and disubstituted
Org. Lett., Vol. XX, No. XX, XXXX
C

enantioselectivity. CKphos maintains good yield and
excellent selectivities with 1-octyne.
Scheme 3. Synthesis of the Cylindricine Core Framework
Table 2. Optimization of Reaction Conditions at 70 °C
entry
precatalyst
additive
3:4
% conversionb % ee
1
2
3
4
[Rh(C2H4)2CI]2
1: >19
33
28
69
4
90
96
95
[Rh(C2H4)2CI]2 AgOTfa 1:>19
[Rh(C2H4)2CI]2 AgOTsa 1:>19
[Rh(cod)CI]2
1: >19
a 1,2-Dichloroethane (DCE) was used as solvent with 4 A MS. b 1
NMR conversion reported after 16 h based on isocyanate conversion.
H
confirmed by X-ray analysis of the hydrochloride salt
(9•HCl). In summary, the (þ)-cylindricine core was syn-
thesized enantioselectively in 7 steps, 95% ee, and 11%
overall yield from simple commercially available starting
materials.
In conclusion, we have developed an enantioselective
Rh(I)•CKphos catalyzed cycloaddition of 1,1-disubsti-
tuted alkenyl isocyanates and alkynes that overcomes
substrate control of product selectivity to access vinylo-
gous amide cycloadducts. This contribution is significant
because the vinylogous amide cycloadduct was previously
only accessible with aryl acetylenes, and a greater number
of C5 alkyl-substituted indolizidine natural products are
found in biological systems. We applied the method to the
synthesis of the tricyclic core of the cylindricine alkaloids in
7 steps, 11% overall yield, and 95% ee.
For our synthesis of the tricyclic core of these alkaloids,
1-hexyne was chosen since n-butyl is the smallest alkyl
chain found in the cylidricine alkaloids, and we anticipated
it would be more challenging to synthesize. Indeed, the
low boiling point proved problematic under our standard
reaction conditions and low yields were seen in the cy-
cloaddition with 2j (Table 2). To improve the yield a
variety of precatalysts were screened. We determined that
[Rh(C2H4)2Cl]2 is the most effective precatalyst and tosy-
late is the best counterion for the synthesis of 4l, improving
conversion and enantioselectivity at lower temperatures.
With an improved catalyst for the synthesis of 4l, we
investigated conditions for vinylogous amide reduction.
Under acidic conditions, sodium cyanoborohydride re-
duces vinylogous amide 4l to the tertiary amine, which is
N-alkylated to form ammonium chloride 8 (Scheme 3). On
the other hand, Diisobutylaluminum hydride (DIBAL-H)
selectively reduces vinylogous amide 4l in 1,4 fashion to
indolizidine 7 with moderate yields and good diastereo-
selectivity (12:1). Once isolated, 7 slowly decomposes by
N-alkylation. However, if 7 is immediately subjected to
potassium tert-butoxide (KOt-Bu) in polar protic (t-BuOH)
or aprotic (DMSO, DMF) solvents with heat (65 °C) the
cis-decalin system 9 is obtained.17 Alkylation in DMF
provides the highest yield of the cylindricine core (68%).
Both the relative and absolute stereochemistry of 9 were
Acknowledgment. We thank NIGMS (GM80442) for
generous support. T.R. thanks Amgen and Roche for
unrestricted support. D.M.D. thanks the NIH Ruth
Kirschstein predoctoral fellowship for funding. We thank
Johnson Matthey for a generous loan of metal salts.
Supporting Information Available. Detailed experimen-
tal procedures and characterization of compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(17) A related alkylation was carried out by Padwa and co-workers;
see ref 10c.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX