Regioselective rhodium-catalyzed allylic alkylation/ring-closing metathesis approach to carbocycles

Article abstract of DOI:10.1016/S0040-4039(01)01467-8

Treatment of the allylic carbonates 1a-c with the sodium anion of the α-substituted malonates (n = 0-2) and Wilkinson's catalyst modified with a triorganophosphite, furnished the allylic alkylation products 2/3a-i in 83-97% yield, favoring 2a-i. The diene

Full text of DOI:10.1016/S0040-4039(01)01467-8

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 7015–7018
Regioselective rhodium-catalyzed allylic alkylation/ring-closing
metathesis approach to carbocycles
P. Andrew Evansa,b,* and Lawrence J. Kennedyb
aDepartment of Chemistry, Indiana University, Bloomington, IN 47405, USA
bDepartment of Chemistry and Biochemistry, University of Delaware, Newark, DE 19716, USA
Received 21 April 2001; revised 7 August 2001; accepted 8 August 2001
Abstract—Treatment of the allylic carbonates 1a–c with the sodium anion of the a-substituted malonates (n=0–2) and
Wilkinson’s catalyst modified with a triorganophosphite, furnished the allylic alkylation products 2/3a–i in 83–97% yield, favoring
2a–i. The dienes 2a–i were then subjected to ring-closing metathesis using either I or II, to afford the carbocycles 4a–i in 79–99%
yield. © 2001 Elsevier Science Ltd. All rights reserved.
The stereocontrolled construction of carbocyclic sys-
tems has stimulated the development of new synthetic
methodology for decades. This may be attributed, at
least in part, to their ubiquity in pharmacologically
relevant molecules. Despite the array of synthetic meth-
ods that have been devised to construct these systems,
few methods are applicable to the diastereoselective
construction of adjacent ternary–quaternary and qua-
ternary–quaternary carbon stereogenic centers.1
fluoroethyl phosphite modified Wilkinson’s catalyst,
provides a regio- and diastereospecific approach to
anti-1,3-stereogenic centers.4–6 Hence, we envisioned
the combination of the allylic alkylation with ring
closing metathesis would provide a versatile strategy for
the construction of various carbocycles, vide infra.7,8
Herein, we now describe the regioselective rhodium-cat-
alyzed allylic alkylation, using alkenyl a-branched mal-
onates, followed by ring-closing metathesis (Scheme 1).
This study also provided an opportunity to further
examine the effect of a-substituted malonates on
regioselectivity, and the influence of vicinal substitution
on the ring-closing metathesis reaction.
The metal-catalyzed allylic substitution provides a use-
ful method for the construction of vicinal ternary and
quaternary carbon stereogenic centers. However, this
approach has been somewhat restricted to symmetrical
substrates to circumvent regiochemical problems, par-
ticularly with a-branched malonate derivatives.2,3 We
recently demonstrated the rhodium-catalyzed allylic
alkylation of unsymmetrical chiral non-racemic carbon-
ates with a-branched malonate derivatives, using a tri-
Table 1 summarizes the results for the sequential
rhodium-catalyzed allylic alkylation followed by ring-
closing metathesis. Treatment of the racemic allylic
carbonates 1a–c with the sodium anion of the a-
cat. RhCl(PPh3)3,
P(OR)3, 30 ˚C
E
E
E
E
E
E
OCO2Me
Grubbs' Cat. I/II
Cl , RT
( )n
( )n
( )n
+
R1
R2
CH2
2
( )n
R1
CNaE2
R1
R2
R2
2
1
3
R2
4
83-97%
R = CH2CF3 or Ph
R1/R2 = H, Alkyl and Aryl
79-99%
E = CO2Me
n = 0, 1 and 2
R1
2/3 ≥14 : 1
Scheme 1.
Keywords: rhodium-catalyzed; allylic alkylation; metathesis; vicinal quaternary and ternary carbon stereogenic carbons.
* Corresponding author. Present address: Department of Chemistry, Indiana University, Bloomington, IN 47405, USA. E-mail: paevans@
indiana.edu
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)01467-8

7016
P. A. E6ans, L. J. Kennedy / Tetrahedron Letters 42 (2001) 7015–7018
Grubbs' Catalyst
N-Heterocyclic Carbene Catalyst
N
N
Ar
Ph
Ar
Cl
PCy
3 Ph
Cl
Cl
Ru
Ru
I
II
Cl
PCy3
PCy3
Cy = Cyclohexyl
Ar = 2,4,6-Trimethylbenzene
branched malonates and Wilkinson’s catalyst modified
with the requisite triorganophosphite, furnished the
allylic alkylation products 2/3a–i in 83–97% yield, with
excellent regioselectivity (]14:1) favoring the more
substituted products 2a–i.
lyzed allylic alkylation conditions, with the sodium salt
of methyl homoallylcyanoacetate, furnished the allylic
alkylation products 5a/b in 92% yield, with 14:1
regioselectivity favoring the secondary adduct 5a (by
GLC analysis).11 Interestingly, the analogous allylic
alkylation with a chiral non-racemic allylic carbonate
(R)-1a (95% ee) furnished the allylic alkylation deriva-
tive ent-5a with modest enantiospecificity (80% cee),5c,12
in sharp contrast to related stabilized carbon nucleo-
philes.5b,f Although the reason for the diminished
selectivity is unclear, it is conceivable that the nitrile
coordinates the metal center and disrupts the smooth
transfer of chirality.13
This study demonstrates that the allylic alkylation of
secondary carbonates 1a/b with a-branched malonates
using the trifluoroethyl phosphite modified Wilkinson’s
catalyst proceeds with excellent selectivity (entries 1–
6).9 Although the trifluoroethyl phosphite catalyst
proved optimum for the secondary carbonates,
triphenyl phosphite proved superior for the tertiary
carbonates, affording the vicinal quaternary–quater-
nary alkylation products 2g–i in excellent yield and
with good regioselectivity (entries 7–9).5a
The diene 5a was then subjected to ring-closing
metathesis using the standard Grubbs catalyst I to
furnish the cyclohexene derivative as a mixture of
diastereoisomers. Reductive alkylation of the nitrile,
using lithium naphthalenide and methyl iodide at −
80°C, furnished the vicinal ternary–quaternary substi-
tuted cyclohexene 6a/b in 81% overall yield, as a ]19:1
mixture of diastereoisomers favoring 6a (by 400 MHz
NMR).5f,14 The relative configuration of the product 6a
was confirmed by NOE experiments. The obvious
advantage of this approach is the ability to utilize a
variety of electrophiles in combination with the allylic
alkylation to provide a relatively versatile three-step
method for the construction of a-quaternary-b-ternary
substituted cyclohexene derivatives.
The dienes 2a–i were then treated with Grubbs’ catalyst
I to facilitate ring-closing metathesis and furnish the
monocyclic carbocycles 4a–i in excellent yield, albeit
with the exception of 2i which afforded only a trace
amount of 4i.7 Subsequent attempts to optimize the
cyclization of 2i, through increased reaction tempera-
ture, catalyst loading and dilution (0.001 M), failed to
improve the formation of 4i. However, treatment of the
diene 2i with the more reactive second-generation
Grubbs’ catalyst II, furnished the carbocycle 4i in 87%
yield.7c
The stereoselective construction of vicinal ternary–qua-
ternary substituted cyclohexene derivatives was also
examined, as outlined in Scheme 2. Treatment of the
allylic carbonate 1a under the standard rhodium-cata-
In conclusion, we have developed a convenient syn-
thetic sequence for the construction of vicinal ternary–
Table 1. Scope of the regioselective Rh-catalyzed allylic alkylation/ring-closing metathesis approach to carbocycles10
Entry
Allylic carbonate 1
Nua Phosphite
M/L ratio
Ratio 2:3b
Yield of 2:3
Grubbs’
Yield of 4 (%)c
(%)c
Catalystd
R1
R2
n=
1
2
3
4
5
6
7
8
9
Me
Me
Me
Ph
Ph
Ph
Me
Me
Me
H
H
H
H
H
H
Me
Me
Me
a
a
a
b
b
b
c
c
c
0
1
2
0
1
2
0
1
2
P(OCH2CF3)3
1:4
1:4
1:4
1:4
1:4
1:4
1:3
1:3
1:3
a
b
c
d
e
f
g
h
i
56:1
55:1
49:1
43:1
36:1
38:1
14:1
14:1
16:1
87
86
90
95
83
84
85
91
97
I
I
I
I
I
I
I
I
II
93
88
89
87
84
94
79
99
87
P(OCH2CF3)3
(OCH2CF3)3
P(OCH2CF3)3
P(OCH2CF3)3
P(OCH2CF3)3
P(OPh)3
P(OPh)3
P(OPh)3
a All alkylation reactions were carried out on a 0.5 mmol reaction scale.
b Ratios of regioisomers were determined by GLC analysis of crude reaction mixtures.
c Isolated yields.
d Reaction carried out on a 0.25 mmol reaction scale, using 5 mol% of I or II (0.05 M).

P. A. E6ans, L. J. Kennedy / Tetrahedron Letters 42 (2001) 7015–7018
7017
cat. RhCl(PPh3)3
P(OCH2CF3)3
CN
CN
E
E
OCO2Me
+
Me
THF, 30 °C
CNa(CN)E
92%
Me
1a
5a
5b
Me
5a/5b = 14 : 1
(E = CO2Me)
1. I, CH2Cl2, RT
2. LiC10H8, THF
-80 °C, MeI
81%
Me
Me
CO2Me
CO2Me
+
Me
Me
6a
6b
6a/6b 19 : 1
Scheme 2.
quaternary and quaternary–quaternary substituted five-,
six- and seven-membered monocyclic carbocycles using
the regioselective rhodium-catalyzed allylic alkylation
in conjunction with ring-closing metathesis. Further-
more, this study demonstrates that a-substituted
cyanoacetates may be utilized in the allylic alkylation
for the stereoselective construction of a-quaternary-b-
Trost, B. M.; Hachiya, I. J. Am. Chem. Soc. 1998, 120,
1104; (d) Ir: Takeuchi, R.; Tanabe, K. Angew. Chem., Int.
Ed. 2000, 39, 1975 and references cited therein.
4. Evans, P. A.; Kennedy, L. J. J. Am. Chem. Soc. 2001,
123, 1234.
5. (a) Evans, P. A.; Nelson, J. D. Tetrahedron Lett. 1998,
38, 1725; (b) Evans, P. A.; Nelson, J. D. J. Am. Chem.
Soc. 1998, 120, 5581; (c) Evans, P. A.; Robinson, J. E.;
Nelson, J. D. J. Am. Chem. Soc. 1999, 121, 6761; (d)
Evans, P. A.; Robinson, J. E. Org. Lett. 1999, 1, 1929; (e)
Evans, P. A.; Leahy, D. K. J. Am. Chem. Soc. 2000, 122,
5012; (f) Evans, P. A.; Kennedy, L. J. Org. Lett. 2000, 2,
2213; (g) Evans, P. A.; Robinson, J. E. J. Am. Chem. Soc.
2001, 123, 4609.
ternary
cyclohexenes,
albeit
with
diminished
enantiospecificity.
Acknowledgements
6. For other rhodium-catalyzed allylic alkylation reactions,
see: (a) Minami, I.; Shimizu, I.; Tsuji, J. J. Organomet.
Chem. 1985, 296, 269; (b) Takeuchi, R.; Kitamura, N.
New. J. Chem. 1998, 659; (c) Fagnou, K.; Lautens, M.
Org. Lett. 2000, 2, 2319; (d) Muraoka, T.; Matsuda, I.;
Itoh, K. Tetrahedron Lett. 2000, 41, 8807 and references
cited therein.
7. For recent reviews on ring-closing metathesis, see: (a)
Randall, M. L.; Snapper, M. L. J. Mol. Cat. A Chem.
1998, 133, 29; (b) Armstrong, S. K. J. Chem. Soc., Perkin
Trans 1 1998, 371; (c) Grubbs, R. H. Tetrahedron 1998,
54, 4413; (d) Pandit, U. K.; Overleeft, H. S.; Borer, B. C.;
Bieraugel, H. Eur. J. Org. Chem. 1999, 959; (e) Fu¨rstner,
A. Angew. Chem., Int. Ed. 2000, 39, 3013 and references
cited therein.
8. (a) Fu, G. C.; Nguyen, S. T.; Grubbs, R. H. J. Am.
Chem. Soc. 1993, 115, 9856; (b) Scholl, M.; Trnka, T. M.;
Morgan, J. P.; Grubbs, R. H. Tetrahedron Lett. 1999, 40,
2247; (c) Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H.
Org. Lett. 1999, 1, 953; (d) Smulik, J. A.; Diver, S. T.
Tetrahedron Lett. 2001, 42, 167.
We sincerely thank the National Institutes of Health
(GM58877) for generous financial support. We also
thank Zeneca Pharmaceuticals for an Excellence in
Chemistry Award, Eli Lilly for a Young Faculty Grantee
Award, GlaxoWellcome for a Chemistry Scholar Award
and Novartis Pharmaceuticals for an Academic
Achievement Award. The Camille and Henry Dreyfus
Foundation is also thanked for a Camille Dreyfus
Teacher-Scholar Award (P.A.E.).
References
1. For recent reviews on asymmetric quaternary carbon
construction, see: (a) Fuji, K. Chem. Rev. 1993, 93, 2037;
(b) Corey, E. J.; Guzman-Perez, A. Angew. Chem., Int.
Ed. 1998, 37, 388.
2. Tsuji, J. Palladium Reagents and Catalysts; Wiley: New
York, 1996; Chapter 4, pp. 290–404. For a recent review
on the transition metal-catalyzed allylic alkylation, see:
Trost, B. M.; Van Vranken, D. L. Chem. Rev. 1996, 96,
395.
3. For examples of allylic alkylation with branched mal-
onates, see: (a) W: Trost, B. M.; Hung, M.-H. J. Am.
Chem. Soc. 1983, 105, 7757; (b) Rh: Tsuji, J.; Minami, I.;
Shimizu, I. Tetrahedron Lett. 1984, 25, 5157; (c) Mo:
9. The trimethyl phosphite modified Wilkinson’s catalyst
also favors the formation of the secondary product 2a
(2°:1°=32:1) albeit with slightly reduced selectivity.
1
10. All new compounds exhibited spectroscopic (IR, H and
13C NMR) and analytical (HRMS) data in accord with
the assigned structure.

7018
P. A. E6ans, L. J. Kennedy / Tetrahedron Letters 42 (2001) 7015–7018
11. Representative experimental procedure: Wilkinson’s cata-
lyst (233 mg, 0.25 mmol) was suspended in anhydrous
THF (20 mL) and sonicated for ca. 2 min then warmed
to 30°C under an argon atmosphere. Tris(2,2,2-tri-
fluoroethyl) phosphite (221 mL, 1.0 mmol) was added to
the deep red solution, resulting in a yellow–orange homo-
geneous catalyst which was stirred for an additional ca.
30 min. In a separate flask, sodium hydride (289 mg, 7.2
mmol, 60% dispersion in mineral oil) was suspended in
anhydrous THF (30 mL), and the homoallylcyanoacetate
(1.16 g, 7.5 mmol) added dropwise via tared microsyringe
over ca. 10 min at ambient temperature. The resulting
anion was then added to the catalyst using a Teflon®
cannula, followed by the neat allylic carbonate 1a (650
mg, 5.0 mmol) via a tared microsyringe. The reaction
mixture was then stirred at 30°C for ca. 4 h (tlc control)
before being quenched and partitioned between aqueous
saturated NH4Cl solution and diethyl ether. The organic
layers were combined, washed with saturated NaCl solu-
tion, dried (Na2SO4), filtered and concentrated in vacuo
to afford a pale-yellow oil. Purification by flash chro-
matography (SiO2, gradient elution with 5–10% ethyl
acetate/hexane), followed by distillation (Kugelrohr,
125°C, 1 mmHg) afforded the allylic alkylation product
5a/b (949 mg, 92%) as a colorless oil; 2:1=14:1; ds=1:1
by GLC analysis: IR (CHCl3) 3083 (w), 2982 (w), 2956
(w), 2937 (w), 2850 (w), 2244 (w), 1742 (s), 1449 (m), 1436
(m), 1252 (m) cm−1; 1H NMR (400 MHz, CDCl3) l
5.82–5.68 (m, 2H), 5.24–5.18 (m, 1H), 5.14–4.99 (m, 3H),
3.83 (s, 1.5H), 3.77 (s, 1.5H), 2.69–2.61 (m, 1H), 2.38–
2.27 (m, 1H), 2.08–1.85 (m, 3H), 1.23 (d, J=6.7 Hz, 1.5
H), 1.14 (d, J=6.7 Hz, 1.5H); 13C NMR (100 MHz,
CDCl3) l 169.63 (e), 169.07 (e), 137.38 (o), 136.85 (o),
136.15 (o), 136.13 (o), 119.11 (e), 118.18 (e), 118.01 (e),
117.93 (e), 116.47 (e), 116.41 (e), 54.75 (e), 54.23 (e),
53.45 (o), 53.18 (o), 45.48 (o), 45.32 (o), 35.73 (e), 34.53
(e), 30.13 (e), 30.07 (e), 17.48 (o), 15.89 (o); HRMS (ES,
M+Na) calcd for C12H17NO2Na 230.1157, found
230.1158.
12. The analogous allylic alkylation of the enantiomerically
enriched carbonate (R)-1a with the trimethylphosphite
modified Wilkinson’s catalyst, also led to diminished
enantiospecificity. Hence, it appears that the nitrile on the
nucleophile is responsible for the diminished enantiospe-
cificity rather than the change from the trimethyl to
trifluoroethyl phosphite modified rhodium-catalyst.
13. For an example of a rhodium complex coordinating a
nitrile group of an a-substituted cyanoacetate, see: Sawa-
mura, M.; Sudoh, M.; Ito, Y. J. Am. Chem. Soc. 1996,
118, 3309.
14. For a related example of a reductive alkylation from an
a-cyano ketone, see: Liu, H.-J.; Zhu, J.-L.; Shia, K.-S.
Tetrahedron Lett. 1998, 39, 4183 and pertinent references
cited therein.