Enantioselective rhodium-catalyzed [2 + 2 + 2] cycloadditions of terminal alkynes and alkenyl isocyanates: Mechanistic insights lead to a unified model that rationalizes product selectivity

Article abstract of DOI:10.1021/ja905065j

This manuscript describes the development and scope of the asymmetric rhodium-catalyzed [2 + 2 + 2] cycloaddition of terminal alkynes and alkenyl isocyanates leading to the formation of indolizidine and quinolizidine scaffolds. The use of phosphoramidite ligands proved crucial for avoiding competitive terminal alkyne dimerization. Both aliphatic and aromatic terminal alkynes participate well, with product selectivity a function of both the steric and electronic character of the alkyne. Manipulation of the phosphoramidite ligand leads to tuning of enantio- and product selectivity, with a complete turnover in product selectivity seen with aliphatic alkynes when moving from Taddol-based to biphenol-based phosphoramidites. Terminal and 1,1-disubstituted olefins are tolerated with nearly equal efficacy. Examination of a series of competition experiments in combination with analysis of reaction outcome shed considerable light on the operative catalytic cycle. Through a detailed study of a series of X-ray structures of rhodium(cod)chloride/phosphoramidite complexes, we have formulated a mechanistic hypothesis that rationalizes the observed product selectivity.

Full text of DOI:10.1021/ja905065j

Published on Web 10/09/2009
Enantioselective Rhodium-Catalyzed [2 + 2 + 2]
Cycloadditions of Terminal Alkynes and Alkenyl Isocyanates:
Mechanistic Insights Lead to a Unified Model that Rationalizes
Product Selectivity
Derek M. Dalton, Kevin M. Oberg, Robert T. Yu, Ernest E. Lee, Ste´phane Perreault,
Mark Emil Oinen, Melissa L. Pease, Guillaume Malik, and Tomislav Rovis*
Department of Chemistry, Colorado State UniVersity, Fort Collins, Colorado 80523
Received June 19, 2009; E-mail: rovis@lamar.colostate.edu
Abstract: This manuscript describes the development and scope of the asymmetric rhodium-catalyzed [2
+ 2 + 2] cycloaddition of terminal alkynes and alkenyl isocyanates leading to the formation of indolizidine
and quinolizidine scaffolds. The use of phosphoramidite ligands proved crucial for avoiding competitive
terminal alkyne dimerization. Both aliphatic and aromatic terminal alkynes participate well, with product
selectivity a function of both the steric and electronic character of the alkyne. Manipulation of the
phosphoramidite ligand leads to tuning of enantio- and product selectivity, with a complete turnover in
product selectivity seen with aliphatic alkynes when moving from Taddol-based to biphenol-based
phosphoramidites. Terminal and 1,1-disubstituted olefins are tolerated with nearly equal efficacy. Examination
of a series of competition experiments in combination with analysis of reaction outcome shed considerable
light on the operative catalytic cycle. Through a detailed study of a series of X-ray structures of
rhodium(cod)chloride/phosphoramidite complexes, we have formulated a mechanistic hypothesis that
rationalizes the observed product selectivity.
Introduction
Indolizidines and quinolizidines are common motifs found
in many biologically active natural products isolated from
arthropod, amphibian, plant, and marine sources (Figure 1).1
Interest in the synthesis of these compounds is 3-fold: scarcity
of natural sources, pharmacological activity, and unique struc-
tural features. The assembly of these nitrogen heterobicycles is
a proving ground for synthetic methodology.2 Classic syntheses
rely on SN2 cyclization of amines, lactamization, and ring
closing metathesis.3 New methodology showcased in the
construction of these natural products depend on chiral pool
substrates or require lengthy starting material syntheses.4-9
Therefore, the development of new, rapid, and enantioselective
methods to generate nitrogen-containing bicycles would be a
useful contribution to the synthetic community.
(1) (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.
(2) For reviews of recent syntheses, see: (a) Michael, J. P. Nat. Prod.
Rep. 2000, 17, 579–602. (b) Michael, J. P. Nat. Prod. Rep. 2002, 20,
458–475. (c) Michael, J. P. Nat. Prod. Rep. 2005, 22, 603–626. (d)
Michael, J. P. Nat. Prod. Rep. 2007, 24, 191–222. (e) Michael, J. P.
Nat. Prod. Rep. 2008, 25, 139–165.
(3) For selected syntheses: (a) Kim, G.; Jung, S.-d.; Kim, W.-j. Org. Lett.
2001, 3, 2985–2987. (b) Toyooka, N.; Fukutome, A.; Nemoto, H.;
Daly, J. W.; Spande, T. F.; Garraffo, H. M.; Kaneko, T. Org. Lett.
2002, 4, 1715–1717. (c) Hermet, J.-P. R.; McGrath, M. J.; O’Brien,
P.; Porter, D. W.; Gilday, J. Chem. Commun. 2004, 1830–1831. (d)
Zaja, M.; Blechert, S. Tetrahedron 2004, 60, 9629–9634. (e) Toyooka,
N.; Kawasaki, M.; Nemoto, H.; Awale, S.; Tezuka, Y.; Kadota, S.
Synlett 2005, 3109–3110. (f) Toyooka, N.; Dejun, Z.; Nemoto, H.;
Garraffo, H. M.; Spande, T. F.; Daly, J. W. Tetrahedron Lett. 2006,
47, 577–580.
Figure 1. Indolizidine and quinolizidine natural products.
We envisioned the coupling of three separate π-components:
CdN, CdC, and CtC in a metal-catalyzed, [2 + 2 + 2]
cycloaddition10 to construct these bicycles (Scheme 1). Due to
their modest basicity, isocyanates11 have been shown to be
competent partners in transition metal-catalyzed reactions.12
Yamazaki and Hoberg demonstrated that cobalt and nickel
9
10.1021/ja905065j CCC: $40.75  2009 American Chemical Society
J. AM. CHEM. SOC. 2009, 131, 15717–15728 15717

A R T I C L E S
Dalton et al.
Scheme 1. [2 + 2 + 2] Cycloadditions with Alkynes and
Isocyanates
alkynyl isocyanate with an exogenous alkyne to form bicyclic
pyridones (Scheme 1, eq 3) and applied this methodology to
the synthesis of camptothecin.14 More recently, rhodium, cobalt,
nickel, and ruthenium have been shown to catalyze [2 + 2 +
2] cycloadditions of alkynes and isocyanates, forming pyri-
dones.15 Although useful for the synthesis of heterocycles, these
methods use two alkynes to form achiral cycloadducts. A notable
exception is Tanaka’s use of a chiral rhodium complex to access
pyridone atropisomers.16 It would be a clear benefit if an alkene
could be incorporated in place of one of the alkynes to form an
sp3 stereocenter in a reaction that could be rendered asymmetric.
Prior to our work, three component [2 + 2 + 2] cycloaddi-
tions between an isocyanate, alkene, and alkyne were un-
known.17 In 2006, we demonstrated that a rhodium(I)/tris(para-
methoxyphenyl)phosphine complex catalyzes the [2 + 2 + 2]
cycloaddition of 4-pentenyl isocyanate with symmetrical internal
alkynes (Scheme 1, eq 4).17a Our initial studies revealed that
dialkyl alkynes provide lactam 3 while diaryl alkynes favor
vinylogous amide 4, which arises from fragmentation of the
isocyanate moiety (Vide infra). To increase the utility of the
reaction, we expanded the substrate scope to readily available
terminal alkynes and rendered the transformation asymmetric
with chiral phosphoramidite ligands.17b A variety of structurally
and electronically different terminal alkynes and isocyanates
are tolerated, enabling the synthesis of a wide range of
indolizidines and quinolizidines. Herein, we disclose a full
description of the development of this reaction, the effects of
steric and electronic changes of the phosphoramidite ligand,
single X-ray crystal analysis of six previously unpublished
rhodium(cod)chloride/phosphoramidite complexes, and mecha-
nistic insight into the rhodium-catalyzed [2 + 2 + 2] cycload-
dition of terminal alkynes and alkenyl isocyanates.
catalyze the [2 + 2 + 2] cycloaddition of an isocyanate and
two equivalents of an alkyne to form 2-pyridone (Scheme 1,
eqs 1 and 2).13 Vollhardt later found that cobalt can couple an
Initial Ligand Screen. Our initial efforts to incorporate
terminal alkynes began with an examination of the conditions
that were effective for internal alkynes.17a We found that the
ligand tris(para-methoxyphenyl)phosphine provides less than
20% of 3a and 4a in a 1:1 ratio (Table 1, entry 1); the low
yield is due to the known dimerization of terminal alkynes (eq
(4) For tandem conjugate additions, see: (a) Back, T. G.; Nakajima, K. J.
Org. Chem. 1998, 63, 6566–6571. (b) Ma, D.; Zhu, W. Org. Lett.
2001, 3, 3927–3929. (c) Back, T. G.; Hamilton, M. D.; Lim, V. J. J.;
Parvez, M. J. Org. Chem. 2005, 70, 967–972. (d) Cai, G.; Zhu, W.;
Ma, D. Tetrahedron 2006, 62, 5697–5708.
(5) For cascade reactions, see: (a) Amorde, S. M.; Judd, A. S.; Martin,
S. F. Org. Lett. 2005, 7, 2031–2033. (b) Padwa, A.; Bur, S. K.
Tetrahedron 2007, 63, 5341–5378.
(6) For the use of dihydro-4-pyridones as synthons, see: (a) Joseph, S.;
Comins, D. L. Curr. Opin. Drug DiscoVery DeV. 2002, 5, 870. (b)
Young, D. W.; Comins, D. L. Org. Lett. 2005, 7, 5661–5664.
(7) For intramolecular Schmidt reaction, see: (a) Aube´, J.; Milligan, G. L.
J. Am. Chem. Soc. 1991, 113, 8965–8966. (b) Gracis, V.; Zeng, Y.;
Desai, P.; Aube´, J. Org. Lett. 2003, 5, 4999–5001.
(14) (a) Earl, R. A.; Vollhardt, K. P. C. J. Am. Chem. Soc. 1983, 105,
6991–6993. (b) Earl, R. A.; Vollhardt, K. P. C. J. Org. Chem. 1984,
49, 4786–4800.
(15) Cobalt: (a) Diversi, P.; Ingrosso, G.; Lucherini, A.; Malquori, S. J.
Mol. Catal. 1987, 40, 267–280. (b) Bonaga, L. V. R.; Zhang, H.-C.;
Moretto, A. F.; Ye, H.; Gauthier, D. A.; Li, J.; Leo, G. C.; Maryanoff,
B. E. J. Am. Chem. Soc. 2005, 127, 3473–3485. Nickel: (c) Takahashi,
T.; Tsai, F.; Li, Y.; Wang, H.; Kondo, Y.; Yamanaka, M.; Nakajima,
K.; Kotora, M. J. Am. Chem. Soc. 2002, 124, 5059–5067. (d) Duong,
H. A.; Cross, M. J.; Louie, J. J. Am. Chem. Soc. 2004, 126, 11438–
11439. (e) Duong, H. A.; Louie, J. J. Organomet. Chem. 2005, 690,
5098–5104. (f) Duong, H. A.; Louie, J. Tetrahedron 2006, 62, 7552–
7559. Ruthenium: (g) Yamamoto, Y.; Takagishi, H.; Itoh, K. Org. Lett.
2001, 3, 2117–2119. (h) Yamamoto, Y.; Kinpara, K.; Saigoku, T.;
Takagishi, H.; Okuda, S.; Nishiyama, H.; Itoh, K. J. Am. Chem. Soc.
2005, 127, 605–613. Rhodium: (i) Flynn, S. T.; Hasso-Henderson,
S. E.; Parkins, A. W. J. Mol. Catal. 1985, 32, 101–105. (k) Kondo,
T.; Nomura, M.; Ura, Y.; Wada, K.; Mitsudo, T. Tetrahedron Lett.
2006, 47, 7107–7111.
(8) For a three component coupling using silyl dithianes, see: (a) Smith,
A. B., III; Kim, D.-S. Org. Lett. 2004, 6, 1493–1495. (b) Smith, A. B.,
III; Kim, D.-S. J. Org. Chem. 2006, 71, 2547–2557.
(9) For a catalytic, asymmetric aza-Diels-Alder reaction, see: (a) Garc´ıa-
Manchen˜o, O.; Go´mez-Arraya´s, R.; Carretero, J. C. J. Am. Chem. Soc.
2004, 126, 456–457. (b) Garc´ıa-Manchen˜o, O.; Go´mez-Arraya´s, R.;
Adrio, J.; Carretero, J. C. J. Org. Chem. 2007, 72, 10294–10297.
(10) For reviews on [2 + 2 + 2] cycloadditions of alkynes see: (a) Saito,
S.; Yamamoto, Y. Chem. ReV. 2000, 100, 2901–2915. (b) Agenet,
N.; Busine, O.; Slowinski, F.; Gandon, V.; Aubert, C.; Malacria, M.
Org. React. 2007, 68, 1–302. (c) Galan, B. R.; Rovis, T. Angew. Chem.,
Int. Ed. 2009, 48, 2830–2834. For reviews on [2 + 2 + 2]
cycloadditions of alkynes and nitrogen moieties see: (d) Varela, J. A.;
Saa´, C. Chem. ReV. 2003, 103, 3787–3801. (e) Heller, B.; Hapke, M.
Chem. Soc. ReV. 2007, 36, 1085–1094. (f) Chopade, P. R.; Louie, J.
AdV. Synth. Catal. 2006, 348, 2307–2327.
(16) (a) Tanaka, K.; Wada, A.; Noguchi, K. Org. Lett. 2005, 7, 4737–
4739. (b) Tanaka, K. Synlett 2007, 1977–1993. (c) Tanaka, K.;
Takahashi, Y.; Suda, T.; Hirano, M. Synlett 2008, 1724–1728.
(17) (a) Yu, R. T.; Rovis, T. J. Am. Chem. Soc. 2006, 128, 2782–2783. (b)
Yu, R. T.; Rovis, T. J. Am. Chem. Soc. 2006, 128, 12370–12371. (c)
Lee, E. E.; Rovis, T. Org. Lett. 2008, 10, 1231–1234. (d) Yu, R. T.;
Rovis, T. J. Am. Chem. Soc. 2008, 130, 3262–3263. (e) Yu, R. T.;
Lee, E. E.; Malik, G.; Rovis, T. Angew. Chem., Int. Ed. 2009, 48,
2379–2382. (f) Keller Friedman, R.; Rovis, T. J. Am. Chem. Soc. 2009,
131, 10775–10782.
(11) Ozaki, S. Chem. ReV. 1972, 72, 457–496.
(12) Braunstein, P.; Nobel, D. Chem. ReV. 1989, 89, 1927–1945.
(13) (a) Hong, P.; Yamazaki, H. Synthesis 1977, 1, 50–52. (b) Hong, H.;
Yamazaki, H. Tetrahedron Lett. 1977, 15, 1333–1336. (c) Hoberg,
H.; Oster, B. W. Synthesis 1982, 324–325. (d) Hoberg, H.; Oster, B. W.
J. Organomet. Chem. 1983, 234, C35–C38. (e) Hoberg, H.; Oster,
B. W. J. Organomet. Chem. 1983, 252, 359–364.
9
15718 J. AM. CHEM. SOC. VOL. 131, NO. 43, 2009

Terminal Alkynes and Alkenyl Isocyanates
A R T I C L E S
Table 1. Initial Ligand Screena
Table 2. Terminal Aryl Alkyne Scopea
entry
L
3a:4ab
yield (%)c
ee (%)d 3a
ee (%)d 4a
1
2
3
4
5
6
7
8
9
P(4-MeO-C6H4)3
1:1
-
<20
NR
<5
32
50
26
80
87
76
-
-
BINAP
dppb
B1
B2
B3
T1
T2
T3
-
-
>20:1
1:2.2
1:4.5
1:2.7
1:7.0
1:7.3
1:3.3
-
-
5e
45
5e
83
89
90
55e
8
45e
94
94
81
a Reaction conditions: 1 (2 equiv), 2, [Rh(C2H4)2Cl]2 5 mol %, L 10
mol % in PhMe at 110 °C for 16 h. b Ratio determined by 1H NMR of
crude reaction. c Combined isolated yield. d Determined by HPLC
analysis on a chiral stationary phase. e Opposite enantiomer.
5).18 BINAP gives no desired product while dppb affords only
trace amounts of 3a, suggesting that a monodentate ligand is
required (Table 1, entries 2, 3). MonoPhos (B1) affords a 32%
yield and induces a modest 55% ee (entry 4). In addition to
higher yields, phosphoramidites do not promote dimerization
of terminal alkynes (eq 6). Binol-based phosphoramidite B2
provides a slightly higher yield of vinylogous amide but poor
enantioselectivity, while phosphite B3 shows lower yields than
B1 and B2 (Table 2, entries 5, 6). Finally, we were delighted
to find that Taddol-based phosphoramidite T1 increases the yield
(80%), product selectivity toward vinylogous amide (1:7.0), and
enantioselectivity (94%, entry 7). After modifying the amine,
we found T2 was the optimal ligand for this transformation
(entry 8).
a Reaction conditions: 1 (2 equiv), 2, [Rh(C2H4)2Cl]2 5 mol %, L 10
mol % in PhMe at 110 °C for 16 h. b Ratio determined by 1H NMR of
crude reaction. c Combined isolated yield. d Determined by HPLC
analysis on a chiral stationary phase. e T3 used as ligand.
rich aryl alkynes provide exclusively vinylogous amide 4 in
good yield and high enantioselectivity (entries 1-4).19 In
addition, sterically bulky o-substituted aryl alkynes are tolerated
(entry 3). Alkynes bearing a variety of heterocycles, including
protected and unprotected indoles, readily participate, providing
vinylogous amide with high enantioselectivity (entries 5-7).
As the alkyne is made more electron-deficient, increasing
amounts of lactam 3 are seen (entries 10-14). Vinylogous amide
product formation is not limited to aryl acetylenes; 1-ethynyl-
cyclohexene 1p gives 4p exclusively in a 96% yield and 92% ee
Scope of Terminal Alkynes. We investigated the scope of this
reaction with terminal aryl alkynes (Table 2) and found electron-
(19) In our experience, this chemistry has proven to be very robust. Roughly
25% of all reactions described herein have been conducted multiple
times often by different coworkers. We have found that yields vary
slightly between runs (∼5%) while product selectivities ((0.2, e.g.,
7.0:1 to 7.2:1) and enantioselectivities ((0.5%) change little. Product
selectivity is determined by analysis of 1H NMR spectra of unpurified
reaction mixtures and can be complicated by unreacted starting material
and symmetrical ureas arising from partial hydrolysis of the isocyanate.
(18) (a) Albano, P.; Aresta, M. J. Organomet. Chem. 1980, 190, 243–246.
(b) Scha¨fer, H.; Marcy, R.; Ru¨ping, T.; Singer, H. J. Organomet. Chem.
1982, 240, 17–25. (c) Ohshita, J.; Furumori, K.; Matsuguchi, A.;
Ishikawa, M. J. Org. Chem. 1990, 55, 3277–3280.
9
J. AM. CHEM. SOC. VOL. 131, NO. 43, 2009 15719

A R T I C L E S
Dalton et al.
Table 3. Scope of Alkyl Alkynesa
Figure 2. Linear free energy relationship of aryl acetylenes.
(entry 15). The reaction clearly shows that substrate electronics
can be used to tune product selectivity. A plot of electron-rich and
deficient aryl alkynes versus Hammett σm/p values20 indicates a
clear linear free energy relationship, demonstrating that the
electronics of the alkyne can be used to tune product selectivity
(Figure 2). In general, the electronics of the aryl alkyne bias product
selectivity such that electron-rich favor vinylogous amide while
strongly electron-deficient generate lactam.
a Reaction conditions: 1 (2 equiv), 2, [Rh(C2H4)2Cl]2 5 mol %, L 10
mol % in PhMe at 110 °C for 16 h. b Ratio determined by 1H NMR of
crude reaction. c Combined isolated yield. d Determined by HPLC
analysis on a chiral stationary phase. e Opposite enantiomer. f Reaction
conditions: 1 (2 equiv), 2a, [Rh(C2H4)2Cl]2 2.5 mol %, L 5 mol % in
PhMe at 110 °C for 16 h. g T1 used as ligand.
Alkyl alkynes shift product selectivity toward the lactam
adduct with moderate to good yields (Table 3). An initial ligand
screen using Taddols T1-T3 revealed piperidine-substituted T3
to be optimal (for a complete comparison, see Table 4).
Enantioselectivities with alkyl alkynes and T3 are moderate
(76-87%, entries 1-5, 7, 8). Biphenol based phosphoramidite
A1 leads to an inversion in product selectivity with aliphatic
alkynes, preferentially forming vinylogous amide adducts 4 with
excellent enantioselectivities (88-94% ee, entries 1-4, 6,
8-13). Esters, amides, and silyl ethers are tolerated with
moderate yields and enantioselectivities (entries 2, 5, 6 and 13).
Interestingly, bulky cyclohexylacetylene 1w leads to an in-
creased amount of vinylogous amide with T1 relative to other
aliphatic alkynes (1.2:1), while ligand A1 generates the viny-
logous amide with high product selectivity and excellent ee (14:
1, 91% ee, entry 8). Noteworthy is the successful incorporation
of 1,7-octadiyne and 1,8-nonadiyne, with ligand A1 affording
vinylogous amides 4y and 4z in good yields and high ee’s
(entries 10-11). On the other hand, 1,6-heptadiyne exclusively
furnishes the substituted benzene arising from intramolecular
cyclization of the diyne followed by incorporation of a second
equivalent of alkyne. These results suggest that, except for the
case of a 3-carbon tether linking the diyne, an isocyanate is
incorporated in the initial oxidative cycloaddition in preference
to an intramolecular coordination and activation of a second
terminal alkyne.21
sensitive to both (Table 4).22 In general, Taddol-based phosphora-
midites (T1-T9) give more lactam product with aliphatic alkynes,
while Binol and biaryl phosphoramidites (B1-B6, A1) favor
vinylogous amide. Interestingly when the amine of Taddol ligands
is changed from pyrrolidine T2 to piperidine T3, product selectivity
shifts in favor of lactam 3 from 1:7.3 to 1:3.3 with phenyl acetylene
and 2.4:1 to 5:1 with 1-octyne (entries 2, 3), and this trend can be
extended to all of the Taddol ligands (entries 1-9). We suspect
that it is the size of the amine that is affecting product selectivity,
as the basicities of pyrrolidine (11.27 pKa) and piperidine (11.22
pKa) are very similar.23 Furthermore, very large amines, such as
dicyclohexyl amine, completely favor the lactam product, albeit
in low yield (entry 4). Interestingly, the size of the amine has less
effect on product selectivity with Binol/biaryl phosphoramidites
(entries 12-14). These results show that the sterics of the
phosphoramidite play a major role in determining product selectivity.
To investigate the effect of ligand electronics, we synthesized a
ligand (T7) that differs from T6 only in the aryl substituents:
p-MeC6H4 vs p-CF3C6H4 (entry 7). This more electron-deficient
ligand increases product selectivity for vinylogous amide with both
aryl (1:>20 from 1:2.8) and alkyl alkynes (1:1 from 8.3:1),
demonstrating that the ligand electronics can enhance product
selectivity. Also, electron-rich m-xylyl Taddol T9 gives a relative
increase in the amount of lactam product formed with aryl (1:1.6)
and alkyl acetylenes (12.5:1, entry 9).
Ligand Exploration. An examination of the structure and
electronics of the phosphoramidite revealed that the reaction is
(22) During this study, we found that catalyst loading could be reduced
from 10 to 5 mol % without sacrificing yield or enantioselectivity.
(23) Hall, H. K. J. Am. Chem. Soc. 1957, 79, 5441.
(20) Hansch, C.; Leo, A.; Taft, R. W. Chem. ReV. 1991, 91, 165.
(21) TMS-acetylene does not participate under these reaction conditions.
9
15720 J. AM. CHEM. SOC. VOL. 131, NO. 43, 2009

Terminal Alkynes and Alkenyl Isocyanates
A R T I C L E S
Table 4. Electronic and Steric Investigation of Phosphoramidites with Alkyl and Aryl Acetylenesa
b
a Reaction conditions: 1 (2 equiv), 2a, [Rh(C2H4)2Cl]2 2.5 mol %, L 5 mol % in PhMe at 110 °C for 16 h. Ratio determined by H NMR of crude
reaction. c Combined isolated yield. d Determined by HPLC analysis on a chiral stationary phase. e Opposite enantiomer. f Reaction conditions: 1 (2
equiv), 2a, [Rh(C2H4)2Cl]2 5 mol %, L 10 mol % in PhMe at 110 °C for 16 h.
1
Taddol ligands provide the best enantioselectivities for aryl
alkynes (81-97%, entries 1-9) with T8 being optimal, while
Binol and biaryl ligands give higher enantioselectivity for alkyl
alkynes (59-95%, entries 10-14) with B4 and B5 being the
highest. Substitution at the 3,3′-positions of the Binol/biaryl
proves to be essential to improving the enantioselectivity with
alkyl acetylenes. Biaryl A1 provides the highest product ratio
(1:6.2) and excellent enantioselectivity (91%) for vinylogous
amide with alkyl acetylenes (entry 15). Finally, A1 made
possible the construction of indolizidine (-)-209D24 in a 5-step
synthesis from commercially available starting materials, using
4q as the key intermediate.17e
does not provide the desired 1-azabicyclo[5.4.0]undecane,
forming only 2-pyridone 7 (eq 8). The synthetic utility of this
approach to quinolizidine motifs was demonstrated in the 4-step
synthesis of (+)-lasubine II.17b
Alkenyl Isocyanate Scope. The successful incorporation of
homologous alkenyl isocyanates in this transformation would
allow access to quinolizidine natural products. Indeed a longer
tether length is tolerated, but in lengthening the tether, we
observe a significant amount of 2-pyridone 6 side product (eq
7). A further increase in tether length to heptenyl isocyanate
9
J. AM. CHEM. SOC. VOL. 131, NO. 43, 2009 15721

A R T I C L E S
Dalton et al.
Table 5. Conjugated Alkynes with 1,1-Disubstituted Alkenyl
Table 7. Scope of 1,1-Disubstituted Alkenyl Isocyanates
Isocyanatesa
entry
R
yield (%)c
ee (%) 10d
1
2
3
4
5
6
7
8
n-Bu, 2e
i-Bu, 2f
Bn, 2g
71
75
80
83
80
50
19
77
74
63
75
90
94
92
91
90
89
86
92
88
90
91
(CH2)2i-Pr, 2h
(CH2)2Ph, 2i
i-Pr, 2j
Cy, 2k
CH2OCH2Ph, 2 L
(CH2)4OTBS, 2m
(CH2)4Cl, 2n
(CH2)2CHdCH2, 2o
9
10
11
a Reaction conditions: 1 (2 equiv), 2a, [Rh(C2H4)2Cl]2 2.5 mol %, L
5 mol % in PhMe at 110 °C for 16 h. b Ratio determined by 1H NMR
of crude reaction. c Isolated yield. d Determined by HPLC analysis on a
chiral stationary phase.
a Reaction conditions: 1 (2 equiv), 2a, [Rh(C2H4)2Cl]2 2.5 mol %, L
5 mol % in PhMe at 110 °C for 16 h. b Ratio determined by 1H NMR
of crude reaction. c Combined isolated yield. d Determined by HPLC
analysis on a chiral stationary phase.
Table 8. Substitution on the Alkyl Tether.a
Table 6. Alkyl Alkynes with 1,1-Disubstituted Alkenyl Isocyanatesa
entry
L
R1
R2
R3
11:12b yield (%)c ee (%) 11/12d
1
2
3
4
T1 4-MeO-C6H4, 1d CO2Et H, 2p 1:15
B4 4-MeO-C6H4, 1d CO2Et H, 2p 1:1
88
69
72
62
65
72
74/91
<5/16e
-/83
T1 4-MeO-C6H4, 1d Me
B4 4-MeO-C6H4, 1d Me
H, 2q 1:>20
H, 2q 1:5.0
Me, 2r 1:2.2
Me, 2r 1:4.0
-/30e
entry
R
8:9b
yield (%)c
ee (%) 8d
ee (%) 9d
5f B4 PMB, 1af
6f A1 PMB, 1af
Me
Me
52/94e
56/82e
1
2
3
4
5
6
7
8
n-hex, 1q
6.5:1
8:1
9.5:1
13:1
11.5:1
9:1
88
83
71
71
77
70
60
45
91
93
95
92
93
95
91
93
56
49
-
-
-
64
-
85
(CH2)4CO2Me, 1r
(CH2)2Ph, 1b
Bn, 1s
(CH2)2OTBS, 1t
(CH2)3OTBS, 1ad
(CH2)4Cl, 1x
a Reaction conditions: 1 (2 equiv), 2, [Rh(C2H4)2Cl]2 5 mol %, L 10
mol % in PhMe at 110 °C for 16 h. b Ratio determined by 1H NMR of
crude reaction. c Combined isolated yield. d Determined by HPLC
analysis on a chiral stationary phase. e Opposite enantiomer. f Reaction
conditions: 1 (2 equiv), 2, [Rh(C2H4)2Cl]2 2.5 mol %, L 5 mol % in
PhMe at 110 °C for 16 h.
8:1
(CH2)3CCTMS, 1ae 6:1
a Reaction conditions: 1 (2 equiv), 2a, [Rh(C2H4)2Cl]2 2.5 mol %, L
5 mol % in PhMe at 110 °C for 16 h. b Ratio determined by 1H NMR
of crude reaction. c Combined isolated yield. d Determined by HPLC
analysis on a chiral stationary phase.
Variations of the 1,1-disubstituted alkene furnish tetrasubstituted
indolizinones with a range of substitution at the 9 position (Table 7).
Substrates bearing primary alkyl groups on the olefin react smoothly
with high enantioselectivity (entries 1-5). However, the reaction is
sluggish with secondary alkyl substituents and increasing amounts of
pyridone are seen (entries 6, 7). Protected alcohols, halogens, and
alkenes are tolerated in the reaction, providing handles for further
chemical manipulation (entries 9-11).
The cycloaddition of 1,1-disubstituted alkenyl isocyanate 2d with
a variety of conjugated aryl and alkenyl alkynes provides indoliz-
inones bearing a tetrasubstituted stereocenter (Table 5). Electron-
rich alkyne 1d gives exclusively vinylogous amide 9d in 80% yield
with 91% ee (entry 1). Heterocyclic and conjugated terminal
alkynes react smoothly to afford 9 in good yields and enantiose-
lectivity (entries 2-6). We see a general trend that as the aryl
alkyne becomes more electron-deficient, increasing amounts of the
lactam 8 are generated (entry 7). This is consistent with the results
seen with 4-pentenyl isocyanate 2a (Vide supra).
Alkyl alkynes and 1,1-disubstituted alkenyl isocyanates provide
mostly lactam 8 with enantioselectivities ranging from 91 to 95%
ee (Table 6). Functional groups including protected alcohols,
halogens, and internal alkynes are tolerated (entries 5-8). Silyl
alkynes fail to participate in this reaction; this finding allowed the
chemoselective incorporation of monoprotected 1,6-diynes (entry
8).
Substitution on the alkenyl isocyanate tether is tolerated in
the cycloaddition (Table 8). Diethyl malonate derived alkenyl
isocyanate 2p provides yields and enantioselectivities compa-
rable to 2a (entries 1, 2). Geminal dimethyl substituents on the
tether react smoothly providing good yields and selectivities
with T1 (entries 3, 4). This backbone substitution is also
9
15722 J. AM. CHEM. SOC. VOL. 131, NO. 43, 2009

Terminal Alkynes and Alkenyl Isocyanates
A R T I C L E S
Scheme 2. Proposed Catalytic Cycle
tolerated with 1,1-disubstituted alkenes, affording optimal
selectivities when ligand A1 is used (entry 6). Oxygen substitu-
tion in the tether provides 13 in moderate yields and excellent
enantioselectivities up to 96% ee (eq 9).
to form IVb.26 At this point, migratory alkene insertion gives
rhodacycle Vb, and reductive elimination provides vinylogous
amide 4. Additionally, formation of 2-pyridone can be generated
from an exogenous alkyne intercepting either IIa or IIb.17c
4-Pyridone can be formed from alkyne interception of rhoda-
cycle IVb, and its isolation from a similar catalytic system is
further evidence for the formation of IVb.27
Another catalytic cycle can be imagined in which the alkene
of the alkenyl isocyanate coordinates to the rhodium (VI) in
lieu of an alkyne (Scheme 3). Such coordination would lead to
oxidative cyclization, C-N bond formation, and set the stere-
ochemistry for both lactam and vinylogous amide products in
the formation of the bicyclic rhodacycle VII. Migratory alkyne
insertion would give IIIa and subsequent reductive elimination
would generate lactam 3. Alternatively, a CO migration via VIII
could take place prior to alkyne insertion making bicycle IX,
which would then undergo alkyne insertion (X) and reductive
elimination to form vinylogous amide 4.
Several observations suggest that this alternative mechanism
is not the operative catalytic cycle. First, two competition
experiments were conducted between mono (2a) and 1,1-
disubstituted (2d) alkenyl isocyanates (eqs 10, 11) in the
presence of either aryl (1d) or alkyl (1s) acetylenes. These yield
a 1:1 ratio of vinylogous amide or lactam products respectively.
We would predict that 2a should react at a different rate than
2d leading to an unequal product mixture.28 Because olefin
substitution has no effect on the ratio of products obtained, we
propose that the olefin is not involved in the turnover-limiting
step. Second, higher reaction concentrations (0.12 M vs 0.04
Mechanistic Investigation. The proposed catalytic cycle for
the [2 + 2 + 2] cycloaddition of alkenyl isocyanates with
exogenous alkynes to form lactam, vinylogous amide, 2-pyri-
done, and 4-pyridone products is described in Scheme 2. All
products may be accessed from a common coordination of the
alkyne and isocyanate to form the Rh(I)/phosphoramidite
complex (I). From this complex, oxidative cyclization and C-C
bond formation provides IIa.25 Migratory alkene insertion into
IIa generates seven-membered rhodacycle IIIa, which reduc-
tively eliminates to generate lactam 3. Alternatively, the
rhodium(I) coordination complex (I) can oxidatively cyclize to
form IIb, where C-N bond formation occurs first. However,
the alkene is unable to insert into the resultant rhodium(III)
species IIb presumably due to a strained, bridged geometry in
the transition state. A CO migration via IIIb then takes place
(24) Indolizidine (–)-209D is a non-natural indolizidine derived from the
misassignment of pyrrolizidine 209-K; see ref 1b.
(25) For selected publications with similar metallacycles involving an
isocyanate and alkyne see: (a) Hoberg, H. J. Organomet. Chem. 1988,
358 (1-3), 507–517. (b) Duong, H. A.; Louie, J. J. Organomet. Chem.
2005, 690 (23), 5098–5104. (c) Louie, J. Curr. Org. Chem. 2005, 9
(7), 605–623. (d) Yamamoto, Y.; Kinpara, K.; Saigoku, T.; Takagishi,
H.; Okuda, S.; Nishiyama, H.; Itoh, K. J. Am. Chem. Soc. 2005, 127,
605–613. (e) Kondo, T.; Nomura, M.; Ura, Y.; Wada, K.; Mitsudo,
T. Tetrahedron Lett. 2006, 47 (39), 7107–7111. (f) Duong, H. A.;
Louie, J. Tetrahedron 2006, 62 (32), 7552–7559. (g) Kondo, T.;
Nomura, M.; Ura, Y.; Wada, K.; Mitsudo, T.-a. J. Am. Chem. Soc.
2006, 128, 14816–14817.
(26) For selected CO migration references on rhodium(III) species see: (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.
Organometallics 2003, 22, 1047–1054, 5.
(27) Oberg, K. M.; Lee, E. E.; Rovis, T. Tetrahedron 2009, 65, 5056–
5061.
(28) For a study of the effect of olefin substitution on the thermodynamics
of alkene-nickel coordination, see: Tolman, C. A. J. Am. Chem. Soc.
1974, 96, 2780–2789.
9
J. AM. CHEM. SOC. VOL. 131, NO. 43, 2009 15723

A R T I C L E S
Dalton et al.
Scheme 3. Alternative Catalytic Cycle
M) (eq 12) or bulky alkene substituents increase pyridone
formation.29 Higher concentrations favor intermolecular inter-
ception of metallacycle IIa/b by a second equivalent of alkyne
over intramolecular migratory insertion of the tethered alkene.
Furthermore, bulky substituents inhibit migratory insertion of
the alkene favoring intermolecular insertion of a second alkyne
to form pyridone. These results suggest that the alkyne and
isocyanate are the first components to oxidatively cyclize. This
is further supported by the observation that 1,7-octadiyne 1y
and 1,8-nonadiyne 1z furnish vinylogous amides 4y and 4z,
showing an apparent kinetic preference for intermolecular
coordination and activation of the isocyanate in spite of the
entropically favored intramolecular coordination of the second
terminal alkyne (Table 3, entries 10, 11). While individually
the preceding pieces of evidence do not eliminate the alternate
catalytic cycle shown in Scheme 3, their aggregate suggests them
to be unlikely. Finally, the vinylogous amide and lactam
products obtained with the same Taddol phosphoramidite are
opposite major enantiomers. This suggests that both products
are not formed from rhodacycle VII as stereoinduction would
occur prior to CO migration. Considering these observations,
we propose that the alkene is the last π-component to be
incorporated and the operative catalytic cycle is likely that
shown in Scheme 2.30
midite complexes32 were undertaken. In each of these structures,
rhodium is in a square planar geometry and a strong phosphora-
midite trans influence is displayed. Generally, Taddol-based
phosphoramidites have a weaker trans influence than Binol/
biaryl phosphoramidite as seen by the Rhsalkene distance
(Table 9).
After examining the X-ray crystal structures, we hypothesize
that the steric environment created by monodentate, C2-
symmetric phosphoramidite ligands explains the exceptional
regioselectivity in the cycloaddition. As we have depicted in
Figure 3, the phosphoramidite ligands sterically hinder one face
of the square planar rhodium(I) complex. One of the m-xylyl
groups sits above the Rh square plane in the structure of
T8•Rh(cod)Cl, with the opposite side of the complex much more
exposed. A naphthyl ring plays this role in the B4•Rh(cod)Cl
complex, reinforced by the TMS group. These effects are also
evident in the other Rh•phosphoramidite crystal structures.31
We propose that this hindrance biases the coordination of the
alkyne and isocyanate such that the sterically smaller substituents
are in the same hemisphere of the square plane as shown in I
(Figure 3). We suggest that the alkynes displace the ethylene
prior to the association of the isocyanate, and as the phosphora-
midite has the greater trans influence than chloride, we predict
that the isocyanate coordinates trans to the phosphoramidite.
From this single coordination, oxidative cyclization accounts
for the single regioisomer of the lactam and vinylogous amide.
Thus, we propose that regioselectivity is controlled predomi-
nately by the sterics of the phosphoramidite ligand.
We see remarkable regioselectivity in this rhodium-catalyzed
cycloaddition, where the vinyl hydrogen is R to the carbonyl in
all terminal alkyne products. As part of our ongoing efforts to
explain the regio- and product selectivity of the reaction, single
crystal X-ray analyses31 of rhodium(I)(cod)chloride/phosphora-
9
15724 J. AM. CHEM. SOC. VOL. 131, NO. 43, 2009

Terminal Alkynes and Alkenyl Isocyanates
A R T I C L E S
Table 9. Selected Bond Lengths of Rhodium(I)(cod)chloride/phosphoramidite Complexes
ligand
Rh-P
Rh-Cl
trans to P Rh-CdCa
CdC
trans to Cl Rh-CdCa
CdC
T9
T8
T1
T2
A1
B4
2.2703(4)
2.2688(6)
2.2648(6)
2.2547(3)
2.2451(4)
2.2388(9)
2.3654(4)
2.3765(6)
2.3777(6)
2.3842(3)
2.3485(4)
2.3455(8)
2.132
2.131
2.140
2.152
2.162
2.151
1.409(2)
1.377(4)
1.376(4)
1.3781(18)
1.369(3)
1.365(5)
1.994
1.992
1.997
1.995
2.013
2.003
1.413(3)
1.395(4)
1.417(3)
1.4131(16)
1.409(2)
1.396(5)
a Bond length from Rh to centroid of alkene.
Figure 3. X-ray crystal structures of Rh(cod)Cl/phosphoramidite complexes.
It may be argued that the alkyne and isocyanate coordinate
to the metal parallel to the square plane.33 However, Wakatsuki
and Yamazaki’s calculations of cobaltacyclopentadienes34 and
ground state X-ray crystal analysis of other d8 complexes35
suggest that an orthogonal coordination of π-components is
operative because steric repulsion between π-components is
minimized and better back-donative stabilization is possible
when orthogonal. Wakatsuki-Yamazaki’s regioselectivity model
9
J. AM. CHEM. SOC. VOL. 131, NO. 43, 2009 15725

A R T I C L E S
Dalton et al.
contributions.36 As a result of their calculations and subsequent
correlation with experimental data, they propose a model based
on stereoelectronic effects to explain regioselectivity. They
hypothesize that polarized π components oxidatively cyclize
so that the greatest LUMO coefficient is ꢀ to the metal, due to
enhanced π* mixing with filled dxy orbitals in the transition state
(Scheme 4). In our system, we observe a propensity for lactam
formation when the sterics of the phosphoramidite and alkyne
substrate decrease. Presumably, this is due to the large LUMO
coefficient of the isocyanate at the ꢀ position, lowering the
activation energy for TSIV en route to metallacycle IIa (Scheme
5). However, it does not explain the regioselectivity of the
isocyanate in TSV for vinylogous amide formation or lactam
products derived from electron-rich aryl acetylenes or alkyl
acetylenes. In each of the cases discussed, the largest LUMO
of one of the π-components is R to the metal in the resultant
metallacycle contrary to Stockis-Hoffman.
Scheme 4. Regioselectivity Models for Metallacycle Formation
As neither the Wakatsuki-Yamazaki steric nor the Stockis-
Hoffman stereoelectronic models adequately explain the product
selectivity seen in the cycloaddition, we hypothesize that the
reaction is controlled primarily by sterics and enhanced or
diminished by electronic factors (Scheme 5). Single regioiso-
meric products are explained by alkyne and isocyanate coor-
dination dictated by phosphoramidite sterics, placing the small
substituent of each π-component in a cis orientation. The two
π-components are coordinated orthogonal to the square plane,
as proposed by Wakatsuki-Yamazaki and corroborated by
crystal structures.37 To generate rhodacycle IIa en route to
lactam from the orthogonal coordination seen in Ia, the CO of
the isocyanate and the terminal C-H of the alkyne must bend
away from the Rh center and toward each other passing through
TSIV forming the C-C bond. Similarly, the NsR2 group of
the isocyanate and the CsR1 bond of the terminal alkyne bend
away from the Rh center, forming the C-N bond via TSV, en
route to rhodacycle IIb in the vinylogous amide pathway.
In terms of product selectivity, the LUMO of the isocyanate
favors formation of lactam but is overridden by sterics of the
substrate and ligand. Smaller alkynes (1-octyne, Table 3, entry
1) generate lactam, while larger alkynes (cyclohexylacetylene,
Table 3, entry 7) produce vinylogous amide due to ligand-alkyne
interactions in the transition state (Scheme 5, TSIV). Alkyne
electronics modify product selectivity as seen in Figure 2.
Electron-deficient aryl alkynes override steric control to favor
lactam, as the alkyne and isocyanate LUMOs are ꢀ to the metal
is based on observations and calculations of cobaltacyclopen-
tadiene formation (Scheme 4). The major product results from
a head to tail orientation of the large alkyne substituents to form
cobaltacyclopentadiene 14. We do not observe either lactam or
vinylogous amide products derived from such an orientation.
Wakatsuki and Yamazaki claim the minor product 15 is
kinetically favored over 16 due to steric interactions between
large alkyne substituents as shown in TSIII (Scheme 4). When
the alkynes are not head to tail, they suggest that the large
substituents prefer to be R to the metal. This model accounts
for the regioselectivity seen with rhodacycle IIa, which gener-
ates lactam (Scheme 2). Using this argument, one would predict
that larger alkyne substituents would favor lactam; however,
more vinylogous amide is seen (Table 3, entry 1 vs 8). Finally,
this model does not account for vinylogous amide formation,
since the larger groups are ꢀ to the metal in rhodacycle IIb
(Scheme 2). As product selectivity could not be completely
explained by substrate steric control alone, we sought another
model to rationalize selectivity based on stereoelectronic effects.
Stockis and Hoffman in their theoretical treatise on metal-
lacyclopentane formation discuss the effects that polarized π
components have on regioselectivity in the absence of steric
(30) A mechanism where the alkyne and alkene oxidatively cyclize to make
a rhodacyclopentene followed by isocyanate insertion can be proposed,
but this is unlikely because there is no plausible pathway to vinylogous
amide and 4-pyridone. For computations proposing alkyne-alkyne
cyclization followed by CdN insertion, see: (a) Schmid, R.; Kirchner,
K. J. Org. Chem. 2003, 68, 8339–8344. (b) Dazinger, G.; Schmid,
R.; Kirchner, K. New J. Chem. 2004, 28, 153–155. (c) Dazinger, G.;
Torres-Rodrigues, M.; Kirchner, K.; Calhorda, M. J.; Costa, P. J. J.
Organomet. Chem. 2006, 691, 4434–4445.
(31) For complete details of the rhodium/phosphoramidite X-ray crystal
analysis, see the Supporting Information.
(32) For publications of rhodium and iridium phosphoramidite crystal
structures see: (a) Bartels, B.; Garc´ıa-Yebra, C.; Rominger, F.;
Helmchen, G. Eur. J. Inorg. Chem. 2002, 2569–2586. (b) Leitner,
A.; Shekhar, S.; Pouy, M. J.; Hartwig, J. F. J. Am. Chem. Soc. 2005,
127, 15506–15514. (c) Faller, J. W.; Milheiro, S. C.; Parr, J. J.
Organomet. Chem. 2006, 691, 4945–4955. (d) Giacomina, F.;
Meetsma, A.; Panella, L.; Lefort, L.; de Vries, A. H. M.; de Vries,
J. G. Angew. Chem., Int. Ed. 2007, 46, 1497–1500. (e) Mikhel, I. S.;
Ruegger, H.; Butti, P.; Camponovo, F.; Huber, D.; Mezzetti, A.
Organometallics 2008, 27, 2937–2948. (f) Filipuzzi, S.; Maennel, E.;
Pregosin, P. S.; Albinati, A.; Rizzato, S.; Veiros, L. F. Organometallics
2008, 27, 4580–4588.
(29) If pyridone were to be formed by oxidative cycloaddition of two
equivalents of alkyne prior to isocyanate incorporation, a different
regioisomer would be predicted. Additionally, different alkynes should
give different regioisomers as seen by multiple authors (see refs 15
and 16). Using Rh(I)•A1, we have noted the formation of pyridones
as single regioisomers when the reaction is conducted using isocyanates
lacking the tethered alkene; see ref 27.
9
15726 J. AM. CHEM. SOC. VOL. 131, NO. 43, 2009

Terminal Alkynes and Alkenyl Isocyanates
A R T I C L E S
Scheme 5. Model to Rationalize Product Selectivity
in TSIVb. Electron-rich aryl alkynes generate vinylogous amide
due to unfavorable steric interactions between the alkyne and
ligand (TSIV), and this selectivity is reinforced by the alkyne
LUMO because it is ꢀ to the metal in TSVa.
conformation and 1,2-migratory insertion leads to the minor
enantiomer. In the second two scenarios, IIa3 and IIa4, we
propose that the alkene coordinates to the less hindered face
of rhodium. Alkene coordination is disfavored in IIa3 because
the tether would be in a strained twist-boat conformation.
On the other hand, the tether shown in metallacycle IIa4 is
in a favorable chair conformation and migratory insertion
provides the major lactam enantiomer. This model for lactam
enantioselectivity rationalizes the correct absolute stereo-
chemistry observed; however, it assumes no rearrangement
of the unobservable rhodium(III) intermediates.
Rationalizing enantioselectivity for vinylogous amide is more
difficult because enantioinduction presumably occurs after several
ligand rearrangements on rhodium(III) species. CO migration from
IIb probably occurs from amide bond cleavage and amine
migration to the unhindered open coordination site, resulting in
These unfavorable alkyne-phosphoramidite interactions are
augmented by changes in the Rh-P bond length, where a shorter
bond favors vinylogous amide while a longer bond favors lactam
(Table 9). Electron-deficient phosphoramidites have shorter
Rh-P bond lengths, which exacerbate the ligand alkyne
interaction in the transition state leading to more vinylogous
amide. On the other hand, electron-rich phosphoramidites have
longer Rh-P bonds, which alleviate the steric interactions
between the alkyne and ligand to generate more lactam.
Additionally, we have seen that in the Taddol series large amines
favor lactam product presumably by increasing the Rh-P bond
length.
Stereochemical Model. A proposed model that rationalizes
the observed enantioselectivity is depicted in Scheme 6. In
metallacycle IIa leading to lactam, we postulate that there
are two factors controlling enantioinduction: facial selectivity
of the alkene dictated by the geometry of the tether and facial
selectivity at rhodium as influenced by the phosphoramidite
ligand. Each of the rhodium(cod)chloride•phosphoramidite
crystal structures show that the ligand hinders one of the open
faces on rhodium and we suggest this facial hindrance is
present in the rhodium(III) intermediates. For migratory
insertion to occur the alkene must be syn-coplanar with the
Rh-N bond, and as a result, only four alkene coordination
scenarios can be envisioned. In the first two scenarios, IIa1
and IIa2, the alkene has to coordinate to the hindered rhodium
face, which is disfavored. Additionally, IIa1 requires the
alkene tether to be in an undesirable twist-boat conformation
further disfavoring it; in IIa2 the tether can adopt a chair
(33) Imabayashi, T.; Fujiwara, Y.; Nakao, Y.; Sato, H.; Sakaki, S.
Organometallics 2005, 24, 2129–2140.
(34) Wakatsuki, Y.; Nomura, O.; Kitaura, K.; Morokuma, K.; Yamazaki,
H. J. Am. Chem. Soc. 1983, 105, 1907–1912.
(35) For crystal structures, see: (a) Davies, G. R.; Hewerston, W. H.; Maise,
R. H. B.; Owston, P. G.; Patel, C. G. J. Chem. Soc. 1970, 1873. (b)
Beauchamp, A. L.; Rochon, F. R.; Theophanides, T. Can. J. Chem.
1973, 51, 126. For computational analysis of alkyne coordination to
Pd, see: (c) de Vaal, P.; Dedieu, A. J. Organomet. Chem. 1994, 478,
121–129.
(36) Stockis, A.; Hoffmann, R. J. Am. Chem. Soc. 1980, 102, 2952–2962.
(37) Kemmitt and coworkers report the crystal structures of
Rh(acac)(C2H4)(CF3CCCF3) and the cyclooctene analog. Both struc-
tures show coordination of the olefin and alkyne orthogonal to the
square plane. Intriguingly, both complexes show unsymmetrical
coordination of the two π-components, with the R atoms having shorter
RhsC distances than the ꢀ atoms, even with a ligand as sterically
undemanding as acac; see: (a) Barlow, J. H.; Clark, G. R.; Curl, M. G.;
Howden, M. E.; Kemmitt, R. D. W.; Russell, D. R. J. Organomet.
Chem. 1978, 144, C47–C51. (b) Barlow, J. H.; Curl, M. G.; Russell,
D. R.; Clark, G. R. J. Organomet. Chem. 1982, 235, 231–241.
9
J. AM. CHEM. SOC. VOL. 131, NO. 43, 2009 15727

A R T I C L E S
Dalton et al.
Scheme 6. Model to Rationalize Enantioselectivity
metallacycle IIIb1,2. We speculate that the alkenyl carbon migrates
to the CO ligand as seen in IIIb1 leading to metallacycle IVb1.
However, coordination of the alkene and migratory insertion of
this metallacycle leads to the minor enantiomer observed for
vinylogous amide. The major enantiomer could be formed by CO
migration onto the alkenyl carbon (IIIb2), but such a migration is
unprecedented.26 Rapid rearrangement of IVb1 to IVb2 and
subsequent alkene insertion would provide the major observed
enantiomer. This rearrangement is potentially influenced by steric
interactions between the alkenyl tether and ligand disfavoring
IVb1.38 As these models are for an unobservable rhodium(III)
species, we can only speculate as to the actual ligand rearrange-
ments. These models are tentative and we are currently undertaking
computational studies to rationalize enantioinduction.
catalytic cycle that accounts for both the lactam and vinylogous
amide products. We conclude that the regio and product
selectivity are controlled primarily by the sterics of the phos-
phoramidite ligand and substrate, while the electronics of both
either enhance or diminish product selectivity.
Acknowledgment. We thank NIGMS (GM80442) for support.
D.M.D. thanks NSF-LSAMP Bridge to the Doctorate Program for
support. S.P. thanks the FQRNT for a postdoctoral fellowship.
R.T.Y. thanks Lilly for a graduate fellowship. K.M.O. and D.M.D.
thank Oren Anderson and Susie Miller (CSU) for support and
guidance. T.R. thanks the Monfort Family Foundation for a Monfort
Professorship. We thank Johnson Matthey for a loan of rhodium
salts.
Conclusion
Supporting Information Available: Experimental procedures
and spectral data for all new compounds, as well as all new
crystal structures. This material is available free of charge via
the Internet at http://pubs.acs.org.
In conclusion, we have developed a rapid, efficient, and highly
enantioselective cycloaddition of alkenyl isocyanates and ex-
ogenous alkynes to access indolizidine and quinolizidine cores
found in biologically relevant natural products. We have found
that single regioisomeric products are obtained in good yields
and excellent enantioselectivities. X-ray crystal analysis of
rhodium(cod)chloride/phosphoramidite complexes has led us to
a mechanistic hypothesis that accounts for the single regioiso-
meric products obtained. In conjunction with competition
experiments and pyridone formation, we have suggested a
JA905065J
(38) It is also possible that the trans influence of the phosphoramidite and
chloride dictate the relative stability of IVbA and IVbB (or the
corresponding transition states). For a review on computational
approaches to studying olefin insertion into metal hydrides, see: Niu,
S.; Hall, M. B. Chem. ReV. 2000, 100, 363–405, and references therein.
9
15728 J. AM. CHEM. SOC. VOL. 131, NO. 43, 2009