Enantioselective rhodium-catalyzed [2+2+2] cycloaddition of alkenyl isocyanates and terminal alkynes: Application to the total synthesis of (+)-lasubine II

Article abstract of DOI:10.1021/ja064868m

The use of TADDOL-based phosphoramidite ligands on rhodium allows for the incorporation of terminal alkynes in the [2+2+2] cycloaddition with alkenyl isocyanates. Terminal aliphatic alkynes provide bicyclic lactams, while the use of aryl alkynes provides complementary access to vinylogous amides. Product selectivity seems to be governed by a combination of electronics and sterics, with smaller and/or more electron-deficient substituents favoring lactam formation. The use of homologous alkenyl isocyanates leads to an expedient asymmetric total synthesis of the alkaloid lasubine II. Copyright

Full text of DOI:10.1021/ja064868m

Published on Web 09/01/2006
Enantioselective Rhodium-Catalyzed [2+2+2] Cycloaddition of Alkenyl
Isocyanates and Terminal Alkynes: Application to the Total Synthesis of
(+)-Lasubine II
Robert T. Yu and Tomislav Rovis*
Department of Chemistry, Colorado State UniVersity, Fort Collins, Colorado 80523
Received July 8, 2006; E-mail: rovis@lamar.colostate.edu
Table 2. Scope of the Cycloaddition with Aryl Acetylenesa
Cycloaddition reactions of [m+n+o] type catalyzed by transition
metals are powerful methods to construct polycyclic carbocycles
and heterocycles of structural and functional complexity.1 In light
of potentially providing a general and efficient route to many indo-
and quinolizidine alkaloid natural products,2 our group has focused
on developing a catalyzed [2+2+2] cycloaddition of alkenyl
isocyanates and alkynes.3,4 Previously, we have disclosed a Rh(I)/
P(4-MeO-C5H4)3-catalyzed [2+2+2] cycloaddition between pen-
tenyl isocyanate 2 and a variety of internal alkynes.5 The cycload-
dition reaction includes a CO migration process to afford Vinylogous
amides as the major products in good yields. Herein, we describe
the regio- and enantioselective rhodium-catalyzed [2+2+2] cy-
cloaddition of alkenyl isocyanates with terminal alkynes to afford
the corresponding bicyclic lactams and/or Vinylogous amides using
chiral phosphoramidites6 as ligands (eq 1). The synthetic utility is
demonstrated in an expedient asymmetric total synthesis of (+)-
lasubine II.
a-d See Table 1. e Absoloute configuration assigned by analogy to (S)-
3j and (R)-4j (established by X-ray analysis). f L3 used as the ligand.
Under our previously reported reaction conditions, the use of
discovery of Rh(I)/phosphoramidite complexes as more efficient
phenyl acetylene 1a or other terminal alkynes often results in
catalysts. Treatment of 1a and isocyanate 2 with 5 mol % [Rh-
sluggish reactions and poor isolated yields (entry 1, Table 1), partly
(C2H4)2Cl]2 and 10 mol % BINOL-derived ligand L1 (MONO-
due to the competitive Rh-catalyzed head-to-tail dimerization of
PHOS) furnishes the cycloadducts 3a/4a in 32% combined yield
terminal alkynes.7 Attempts to improve the reaction led to the
with a 1:2.2 product selectivity, favoring the Vinylogous amide 4a
Table 1. Ligand Screena
with a moderate enantioselectivity (entry 2). While the bulkier
ligand L2 increases both the reactivity and lactam-Vinylogous amide
selectivity, the enantioselectivity of 4a decreases significantly (entry
3). Conversely, TADDOL-derived phosphoramidites are found to
be much superior ligands. The cycloaddition generally proceeds
cleanly to furnish the cycloadducts in high yields and enantiose-
lectivity (entries 4-6). The commercially available L3 affords (R)-
4a with very good lactam-Vinylogous amide selectivity (entry 4).
Replacing the dimethylamino group with the more rigid piperidinyl
as in L4 increases the production of the lactam (S)-3a (entry 5).
The pyrrolidinyl-substituted ligand L5 is the current standard,
providing a slightly better product selectivity and reactivity (entry
6).8 It is noteworthy that the cycloaddition proceeds in a highly
regioselective manner, as both (S)-3a and (R)-4a are isolated as
a Conditions: 1 (2 equiv), 2, Rh catalyst (5 mol %), L (10 mol %) in
PhMe at 110 °C for 16 h. b Lactam-vinylogous amide product selectivity
determined by 1H NMR of the unpurified reaction mixture. c Combined
isolated yield. d Determined by HPLC using a chiral stationary phase. e Other
enantiomer.
1
single regioisomers (>20:1 by H NMR).
Table 2 summarizes the scope of the enantioselective [2+2+2]
cycloaddition of isocyanate 2 with a variety of aryl acetylenes.
Electron-rich substituted aryl acetylenes readily participate in the
cycloaddition to afford almost exclusively the Vinylogous amide 4
products in good yields and high enantiomeric excess (entries 1-5).
Heteroaryl acetylenes including both free and protected indoles also
undergo the cycloaddition efficiently (entries 6-8). Electron-
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10.1021/ja064868m CCC: $33.50 © 2006 American Chemical Society

C O M M U N I C A T I O N S
Scheme 1. Total Synthesis of (+)-Lasubine II
Scheme 2. Proposed Mechanism
formation (pathway B). Subsequent olefin insertion and reductive
elimination provides the lactams.
In summary, we have developed a highly regio- and enantiose-
lective rhodium-catalyzed [2+2+2] cycloaddition involving alkenyl
isocyanates and terminal alkynes, providing efficient access to indo-
and quinolizinone cores.
withdrawing substituted aryl acetylenes also participate readily in
the cycloaddition (up to 94% ee), with the product selectivity
gradually shifting toward increased amount of lactam 3 with
increasing electron-withdrawing ability (entries 10-14).9 The
reaction is not restricted to aryl acetylenes, as the cyclic enyne 1o
also participates to generate exclusively the corresponding Vinylo-
gous amide 4 in high efficiency (entry 15).
Asymmetric syntheses of quinolizinones 6 can also be achieved
in moderate to good yields with excellent enantiocontrol (Scheme
1). The reactions are accompanied by varying amounts of pyridones
7 as side products,10 suggesting that the alkene moiety is the last
2π component incorporated. To demonstrate the synthetic utility
of this methodology, enantioenriched 6b undergoes a diastereose-
lective hydrogenation followed by a Mitsunobu to complete the
total synthesis of (+)-lasubine II11 in only three steps from
isocyanate 5.
In contrast to the Vinylogous amide selectivity observed for most
aryl acetylenes, reactions with alkyl acetylenes provide primarily
lactam products, presumably due to the electronic differences
between the alkyl and aryl groups (Table 3). By employing L4,
cycloadditions with primary alkyl acetylenes proceed smoothly to
afford lactams 3 with excellent product selectivity (up to >20:1),
good enantioselectivity (up to 87% ee), and good isolated yields
(entries 1-6). The more sterically hindered cyclohexyl acetylene
(entry 7) furnishes both types of products in an approximately 1:1
ratio with excellent enantioselectivity for 4v (95% ee), suggesting
that both sterics and electronics play a role in governing product
selectivity.
A proposed mechanism is outlined in Scheme 2. An initial
oxidative cyclization between the isocyanate and alkyne in an
orientation where a C-N bond is formed provides metalacycle A.
A CO migration12,13 to B followed by olefin insertion and reductive
elimination furnishes the Vinylogous amides (pathway A). In a
different orientation, metallacycle D is formed with a C-C bond
Acknowledgment. We thank Susie Miller for X-ray analyses.
We thank Merck, Eli Lilly, Amgen, Johnson and Johnson, and
Boehringer Ingelheim for unrestricted support. T.R. is a fellow of
the Alfred P. Sloan Foundation and thanks the Monfort Family
Foundation for a Monfort Professorship.
Supporting Information Available: Detailed experimental pro-
cedures and compound characterization (PDF, CIF). This material is
available free of charge via the Internet at http://pubs.acs.org.
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Table 3. Scope of the Cycloaddition with Alkyl Acetylenesa
(8) These reaction conditions provide inferior results with internal alkynes.
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