Cobalt-mediated, enantioselective synthesis of C2 and C 1 dienes

Article abstract of DOI:10.1021/ja107968c

The asymmetric C-H functionalization of norbornene and norbornadiene with five-, six-, and seven-membered cyclic enones mediated by the reactive intermediate [{η⁵-(^tBuMe₂Si)C ₅H₄}Co(NO)₂] i

Full text of DOI:10.1021/ja107968c

Published on Web 10/29/2010
Cobalt-Mediated, Enantioselective Synthesis of C2 and C1 Dienes
W. Christopher Boyd, Mark R. Crimmin, Lauren E. Rosebrugh, Jennifer M. Schomaker,
Robert G. Bergman,* and F. Dean Toste*
Department of Chemistry, UniVersity of California, Berkeley, California 94720, United States
Received September 3, 2010; E-mail: fdtoste@berkeley.edu; rbergman@berkeley.edu
[CpCo(NO)2] (Scheme 2).7-9 Herein we report that N-benzylated
Abstract: The asymmetric C-H functionalization of norbornene
and norbornadiene with five-, six-, and seven-membered cyclic
enones mediated by the reactive intermediate [{η5-
(tBuMe2Si)C5H4}Co(NO)2] is reported. A novel base mixture
derived from enantiopure ammonium salts and NaHMDS was
used as a source of chirality, and this enantioselective desym-
metrization of Cs alkenes has been applied to the asymmetric
synthesis of C2- and C1-symmetric diene ligands in high regiose-
lectivity (3.7-20:1 anti/syn), near perfect diastereoselectivity
(>99:1 dr), and high enantioselectivity (90-96% ee).
ammonium chloride salts (Chart 1, 1-4) combined with sodium
hexamethyldisilazide (NaHMDS) can promote this reaction, while
serving as a source of chirality to desymmetrize norbornene and
norbornadiene. This methodology has been applied to a modular
asymmetric synthesis of C1- and C2-symmetric diene ligands.
Initial experiments demonstrated that addition of a mixture of
NaHMDS and the quininium salt 1 to a mixture of 2-cyclohexen-
1-one and cobalt complex 5 gave adduct 6 in 87% de and high
yield. Subsequent cycloreversion of 6 in the presence of norbornene
yielded 5 and the diastereomerically impure alkene 7 which was
obtained in a low but significant 18% ee (Table 1, entry 1). The
order of reagent addition proved to be critical to the enantioinduc-
tion; in fact, adding NaHMDS to a mixture containing the remaining
reagents gave the product with only 2% ee (entry 2). As NaHMDS
alone can promote a racemic background reaction, we suspect a
chiral base formed upon mixing 1 with NaHMDS is responsible
for the observed enantioinduction.
In recent years, enantiopure C2- and C1-symmetric dienes have
been established as authoritative ligands for asymmetric reactions
mediated by late transition metals.1 Despite their utility, current
synthetic routes to these ligands remain unsatisfying and often rely
upon preparative chiral HPLC, chiral auxiliaries, chiral pool starting
materials, or chemoenzymatic reactions to access enantiopure
material.2-6 Hayashi and co-workers reported an effective enan-
tioselective synthesis of C2-symmetric dienes based upon the
desymmetrization of norbornadiene.2a,b In the first step in the
synthesis of the chiral ligand, a double asymmetric hydrosilylation
of norbornadiene with HSiCl3 catalyzed by [PdCl(η3-C3H5)]2 and
a chiral phosphine ligand was reported to yield an enantiopure
di(silane). However, a multistep reaction sequence was required to
re-establish the diene moiety and build steric bulk into the chiral
scaffold.2a,b,3
Chart 1. N-Benzylated Ammonium Chlorides
If the synthesis of C2-dienes could be achieved Via a direct
desymmetrization of the parent diene by an asymmetric C-H
functionalization of the sp2-carbons, it would represent a concise
approach to this important class of chiral ligands (Scheme 1). In
addition, the use of a prochiral electrophile in the reaction would
allow for the preparation of enantiopure ligands that bear additional
stereocenters, provided these reactions proceed with high stereo-
selectivities.
Table 1. Screening of Reaction Conditions for Addition of
Norbornene to 2-Cyclohexen-1-one
Scheme 1. Synthesis of C2-Dienes by Desymmetrization of
Norbornadiene
Temp
(°C)
Yield de
ee
Entry
Solvent
Cp′
(R*)4NCl
time
of 6 of 6 of 7a
c
c
1
2
3
4
25
25
25
Me4Cp
Me4Cp
Me4Cp
Me4Cp
1
1
1
1
3 h
4 h
17.5 h
87% 87% 18%
81% 72% 2%
75% 94% 36%
THF/HMPA
THF/HMPA
THF
b
-60 THF
6 days (14 h 74% >99% 58%
to 0
at 0 °C)
5
6
7
0
THF
tBuCp
tBuCp
TBDMSCp
1
2
3
22 h
17 h
15 h
35% >99% 72%
53% >99% 74%
73% >99% 83%
Scheme 2. C-H Functionalization Mediated by [CpCo(NO)2]
-45 THF
-58 THF
a NaHMDS and (R*)4NCl premixed and filtered, ee of major
diastereomer only. b NaHMDS added to mixture of substrates and
c
(R*)4NCl. 5.3:1 THF to HMPA. Abbreviations: Me4Cp ) η5-Me4C5H,
tBuCp ) η5-tBuC5H4, TBDMSCp ) η5-tBuMe2SiC5H4.
Recently, we reported a stepwise C-H functionalization of the
sp2 carbon of simple alkenes mediated by the reactive intermediate
Several alternative solvents gave comparable or inferior results
compared to those observed with THF/hexamethylphosphoramide
9
10.1021/ja107968c  2010 American Chemical Society
J. AM. CHEM. SOC. 2010, 132, 16365–16367 16365

C O M M U N I C A T I O N S
Table 2. Asymmetric Synthesis of C2- and C1-Dienes
(HMPA). Performing reactions in THF, however, gave significantly
higher ee at room temperature (entry 3), while lowering the reaction
temperature to -60 °C increased the ee to 58% (entry 4). It is
noteworthy that at lower temperatures, commensurate with the
improvement of enantioselectivity, there was an improvement in
the diastereoselectivity of the reaction. Employing the bulkier and
more directional ligand [η5-(tBu)C5H4] on cobalt allowed optimiza-
tion to 72% ee (entry 5). Comparable results were obtained with
[η5-(tBuMe2Si)C5H4] in place of the [η5-(tBu)C5H4] ligand, and using
quininium salts bearing trifluoromethyl groups on their N-benzyl
moieties allowed further optimization, with the bis(trifluoromethyl)
substituted salt 3 yielding the Michael adduct 6 in 73% yield and
>99% de and the corresponding alkene in 83% ee (entry 7).
Using these conditions, we examined the asymmetric C-H
functionalization of both norbornene and norbornadiene with five-,
six-, and seven-membered cyclic enones. The details of these
experiments are provided in the Supporting Information (Table S3).
Michael addition reactions proceeded in good yields (66-90%) to
give enantioenriched cobalt complexes with high diastereoselectivity
(>99% de) with subsequent retrocycloaddition yielding alkene
products with moderate enantioselectivity (43-85% ee). The
enantioselective functionalization of norbornadiene prompted the
application of this methodology to asymmetric ligand synthesis
(Scheme 3). If two sequential C-H activation/Michael addition
steps could be carried out efficiently and benefit from double
stereodifferentiation, it not only could result in overall higher
enantioselectivities but also would obviate the requirement for
enantiopure precursors in the synthesis of chiral diene ligands.
yield
of 11a
ee of
anti-12
n
m
complex
diene
anti/syn
1
2
2
3
2
1
2
2
3
3
11a
11b
11b
11c
11d
42%
67%
73%b
87%
84%b
12a
12b
12b
12c
12d
3.7:1
20:1
10:1
11:1
11:1
90% (R,R,R,R)
96% (R,R,R,R)
94% (S,S,S,S)c
91% (R,R,R,R)
96% (R,R,R,R)
a Chiral conditions; 3/NaHMDS premixed, filtered, and then added to
reaction mixture at -58 °C. b Reaction conducted at -75 °C. c Salt 4
used in place of 3.
tions only one diastereomer of each regioisomeric product was
observed, and following retrocycloaddition, dienes anti-12a-d were
isolated in good yield and 90-96% ee.
Recrystallization of a mixture of anti- and syn-12b from
n-pentane removed the minor regioisomer and increased the ee to
99%. The absolute configuration of anti-12b was determined as
(R,R,R,R)-12b by single crystal X-ray diffraction analysis (Figure
1). The enantiomer, (S,S,S,S)-12b, is available in 94% ee Via use
of chiral ammonium salt 4 in the synthetic sequence.
Scheme 3. Synthesis of C-H Functionalized Norbornadiene
Complexes
We propose that the high selectivity in this C-H functionaliza-
tion reaction sequence occurs because desymmetrization of the
nucleophile controls enantioselectivity while the approach of the
electrophile controls diastereoselectivity (Figure 2). The two
stereoselection events are orthogonal, and two pairs of noncon-
tiguous stereocenters are set with near perfect control in the
enantioselective synthesis of the anti-regioisomer of these diene
ligands. The minor regioisomeric products, syn-12a-c, are meso-
symmetric and arise from imperfect regiocontrol in the second
carbon-carbon bond forming step.
Scheme 4. Isomerization of 8a-c to 10a-c
In a further demonstration of utility, the ease of ligand deriva-
tization by functional group manipulation of the ketone moieties
of (R,R,R,R)-12b was demonstrated. Thus, reduction of the carbonyl
groups with NaBH4 followed by xanthate formation and Barton-
The first step of this preparation was the isomerization of
enantioenriched complexes 8a-c to 10a-c (Scheme 4). Despite
the fact that the alkene that accepts the [Cp′Co(NO)2] fragment is
not present in excess, these reactions proceeded cleanly and in high
yield (80-93%) by simply heating samples of 8a-c in toluene or
THF solution. A second asymmetric C-H functionalization of
10a-c yielded a mixture of cobalt complexes anti-11a-d and syn-
11a-d which could be converted, Via alkene exchange with
norbornadiene, to a mixture of the corresponding dienes anti-12a-d
and syn-12a-d respectively (Table 2).
While poor anti/syn selectivity (1.3-2.7:1) was observed using
achiral starting materials and a nonchiral base (see Supporting
Information, Figure S6),10 by using enantioenriched starting materi-
als and the asymmetric base mixture (Vide supra) anti/syn ratios
were 3.7-20:1 across the series of substrates. Under these condi-
Figure 1. ORTEP representation of (R,R,R,R)-12b. H-atoms omitted for
clarity. Selected bond lengths (Å): C(5)-C(6) 1.332(2), C(5)-C(4) 1.502(2),
C(2)-O(2) 1.216(2). Flack parameter ) 0.1451(0.1655).
9
16366 J. AM. CHEM. SOC. VOL. 132, NO. 46, 2010

C O M M U N I C A T I O N S
Figure 2. Proposed origin of stereoselectivity.
McCombie reduction yielded (1R,4R)-2,5-dicyclohexylbicyclo-
[2.2.1]hepta-2,5-diene, an effective ligand for rhodium-catalyzed
asymmetric conjugate addition (see Supporting Information for
experimental details).3
In short, we have demonstrated an asymmetric synthesis of C2-
and C1-symmetric dienes, based upon a C-H functionalization
reaction mediated by cobalt di(nitrosyl) complexes that proceeds
with excellent regio-, diastereo-, and enantiocontrol. We are
continuing to study the nature of the active base derived from
quininium salt/metal amide mixtures and the applications of the
enantiopure products described herein as ligands in asymmetric
catalysis.
References
(1) For review articles, see: (a) Glorius, F. Angew. Chem., Int. Ed. 2004, 43,
3364. (b) Defieber, C.; Grutzmacher, H.; Carreira, E. M. Angew. Chem.,
Int. Ed. 2008, 47, 4482. (c) Shintani, R.; Hayashi, T. Aldrichimica Acta
2009, 42, 31.
(2) (a) Uozumi, Y.; Lee, S.-Y.; Hayashi, T. Tetrahedron Lett. 1992, 33, 7185.
(b) Hayashi, T.; Ueyama, K.; Tokunaga, N.; Yoshida, K. J. Am. Chem.
Soc. 2003, 125, 11508. (c) Berthon-Gelloz, G.; Hayashi, T. J. Org. Chem.
2006, 71, 8957. (d) Tokunaga, N.; Otomaru, Y.; Okamoto, K.; Ueyama,
K.; Shintani, R.; Hayashi, T. J. Am. Chem. Soc. 2004, 126, 13584. (e)
Shintani, R.; Okamoto, K.; Otomaru, Y.; Ueyama, K.; Hayashi, T. J. Am.
Chem. Soc. 2005, 127, 54. (f) Otomaru, Y.; Okamoto, K.; Shintani, R.;
Hayashi, T. J. Org. Chem. 2005, 70, 2503. (g) Okamoto, K.; Hayashi, T.;
Rawal, V. H. Chem. Commun. 2009, 4815.
(3) Noe¨l, T.; Vandyck, K.; Van der Eycken, J. Tetrahedron 2007, 63, 12961.
(4) (a) Paquin, J. F.; Defieber, C.; Stephenson, C. R. J.; Carreira, E. M. J. Am.
Chem. Soc. 2005, 127, 10850. (b) Fischer, C.; Defieber, C.; Suzuki, T.;
Carreira, E. M. J. Am. Chem. Soc. 2004, 126, 1628. (c) Defieber, C.; Paquin,
J. F.; Serna, S.; Carreira, E. M. Org. Lett. 2004, 6, 3873. (d) Paquin, J. F.;
Stephenson, C. R. J.; Defieber, C.; Carreira, E. M. Org. Lett. 2005, 2, 3821.
(5) Luo, Y.; Carnell, A. J. Angew. Chem., Int. Ed. 2010, 49, 2750.
(6) Brown, M. K.; Corey, E. J. Org. Lett. 2010, 12, 172.
Acknowledgment. We are grateful for financial support from
the NSF in the form of a research grant to R.G.B. (CHE-0841786)
and a predoctoral fellowship to W.C.B. M.R.C. acknowledges the
Royal Commission for the Exhibition of 1851 for a postdoctoral
fellowship. J.M.S. acknowledges support from a National Institutes
of Health NRSA Ruth Kirschstein postdoctoral fellowship. We are
also grateful to Melanie Chiu, Jerome Volkman, Yiming Wang,
and Chen Zhao for helpful discussions.
(7) (a) Brunner, H. J. Organomet. Chem. 1968, 12, 517. (b) Brunner, H.; Loskot,
S. Angew. Chem., Int. Ed. Engl. 1971, 10, 515. (c) Brunner, H.; Loskot, S.
J. Organomet. Chem. 1973, 61, 401.
(8) (a) Becker, P. N.; Bergman, R. G. Organometallics 1983, 2, 787. (b) Becker,
P. N.; Bergman, R. G. J. Am. Chem. Soc. 1983, 105, 2985.
(9) (a) Schomaker, J. M.; Boyd, W. C.; Stewart, I. C.; Toste, F. D.; Bergman,
R. G. J. Am. Chem. Soc. 2008, 130, 3777. (b) Schomaker, J. M.; Toste,
F. D.; Bergman, R. G. Org. Lett. 2009, 11, 3698.
Supporting Information Available: Experimental procedures and
spectroscopic data for all new compounds; conditions for chiral GC
and HPLC methods; and CIF file for 12b. This material is available
free of charge via the Internet at http://pubs.acs.org.
(10) Lensink, C.; Xi, S. K.; Daniels, L. M.; Verkade, J. G. J. Am. Chem. Soc.
1989, 111, 3478.
JA107968C
9
J. AM. CHEM. SOC. VOL. 132, NO. 46, 2010 16367