Method for Highly Enantioselective Ligation of Two Chiral C(sp3) Stereocenters

Article abstract of DOI:10.1021/jacs.7b07366

A method is described for the joining of two α-lithiated C(sp³) stereocenters efficiently and with retention of configuration. The key step involves the effective removal of two electrons from a chiral organocuprate R₂CuLi, by i-propyl 2,4-dinitrobenzoate to form a Cu(III) complex that undergoes at -90 °C accelerated reductive elimination enantioselectively and exclusively without the formation of free radicals.

Full text of DOI:10.1021/jacs.7b07366

Subscriber access provided by UNIVERSITY OF THE SUNSHINE COAST
Communication
A Method for Highly Enantioselective
3
Ligation of Two Chiral C(sp) Stereocenters
Eswar Bhimireddy, and E. J. Corey
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.7b07366 • Publication Date (Web): 31 Jul 2017
Downloaded from http://pubs.acs.org on July 31, 2017
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a free service to the research community to expedite the
dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts
appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been
fully peer reviewed, but should not be considered the official version of record. They are accessible to all
readers and citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered
to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published
in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just
Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor
changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers
and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors
or consequences arising from the use of information contained in these “Just Accepted” manuscripts.
Journal of the American Chemical Society is published by the American Chemical
Society. 1155 Sixteenth Street N.W., Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the course
of their duties.

Page 1 of 5
Journal of the American Chemical Society
1
2
3
4
5
6
7
8
9
A Method for Highly Enantioselective Ligation of Two Chiral
C(sp3) Stereocenters
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Eswar Bhimireddy and E. J. Corey*
Department of Chemistry and Chemical Biology, Harvard University, Cambridge, Massachusetts 02138, United States
Supporting Information Placeholder
required reductive elimination of (RCuR)could be
ABSTRACT: A method is described for the joining of two
lithiated C(sp3)-stereocenters efficiently and with retention
of configuration. The key step involves the effective removal
of two electrons from a chiral organocuprate R2CuLi, by i-
propyl 2,4-dinitrobenzoate to form a Cu(III) complex which
undergoes at –90 °C accelerated reductive elimination
enantioselectively and exclusively without the formation of
free radicals.
enormously accelerated by the effective removal of two
electrons. In the extreme ease, RR coupling from the Cu(III)
species RCuR (or its equivalent) can be expected to be very
fast, since it is a close analog of R+ RCu → RR + Cu+. Some
years ago, we reported the isolation of an adduct of Me2CuLi
and 2-cyclohexenone (at 20 oC or below), 1a/1 which was
instantly transformed either into 2 or 3 as shown in equation
(1).11,12 The TMS–Cl accelerated and extremely rapid
The enantioselective joining of two chiral C(sp3) stereocenters
to form an enantiomerically pure product with retention of
configuration at each chiral center has been a formidable
challenge for synthetic chemists, and has remained beyond
reach.1 It also seems not to occur in the biosynthetic domain.
Reported herein is a simple solution of this classical unsolved
problem using an approach based on the convergence of three
aspects of synthetic chemistry: (1) the use of transition metal
mediated CC coupling, (2) methodology for the formation of
Cchiral organolithium reagents, and (3) the idea of
accelerating reductive elimination by electron removal. The
rational application of transition metal chemistry has
transformed the ways in which organic molecules are
constructed over the past 56 decades, especially using as
metals Ni, Ru, Rh and Pd to generate a CC bond by reductive
olefin forming elimination.
reductive elimination leading to
2 accords with the
expectation that removal of electron density by any means
Scheme 1. Conjugate Addition of Me2CuLi to 2-
Cyclohexenone
should accelerate reductive elimination. In the extreme case of
RCuR the formation of RR can be energetically similar to an
attack of R on R–Cu– which surely would be extremely
rapid.12
This mode of coupling requires that competing pathways
such as olefin-forming β-hydrogen elimination, free radical
Scheme 2. Enantioselective Lithiation of
C(sp3)C(sp3) Coupling
4
and
formation
by
homolysis
of
R–M
and
stereo-
mutation/rearrangement do not intervene. For this reason,
acceleration of reductive elimination is important.
The methodology for accessing C-chiral organolithium
reagents which now exists is largely due to the cumulative
studies of several groups using complexes of R–Li with chiral
diamines, especially sparteine, as controllers for the
enantioselective CH → CLi metalation.2-8 We selected the
readily available (S)-2-lithio derivative of N-tert-
butyloxycarbonyl (Boc) pyrrolidine5 as the substrate for the
initial C(sp3)C(sp3) coupling studies which are described in
detail herein. We also chose copper as the transition metal to
effect CC bond formation, partly because the use of this metal
has a long and impressive history for achiral (sp3)(sp2) and
(sp3)(sp3) coupling.9 In addition copper is considerably less
prone to β-hydrogen elimination to form CuH and CC, e.g. as
indicated by the relative stability of intermediates such as t-
BuCu and the mixed cuprate (t-Bu)(n-Bu)CuLi, the second of
which can be made and used in conjugate addition to α,β-
enones.10 The choice of copper was further indicated by the
general availability of Gilman cuprate reagents of the type
(RCuR)MWe were also guided by the concept that the
The above considerations led to
a highly successful
enantioselective coupling reaction of 5, (from N-Boc
pyrrolidine, 4) to form the (R,R)-coupling product 7 using ()-
sparteine as ligand for the lithiation 4 → 5, as summarized in
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 2 of 5
Scheme 2. The chiral lithiated substrate 5 was generated in
ether by the method of Beak et al.5 at78 oC and then
converted to the soluble homocuprate 6 at 90 C by
treatment with a concentrated solution of CuI and isopropyl
sulfide (1:3) in THF.14 Slow addition of a cold solution of i-
propyl 2,4-dinitrobenzoate (2,4-PDB) in THF to the 90 oC
solution of the cuprate 6 led to an extremely rapid and highly
exothermic reaction to produce 7. The very fast rate of
reaction was evident by an instantaneous color change (to
dark red brown) and heat evolution as 2,4-PDB was added.
Two experimental variables are especially important for the
successful enantioselective formation of the coupling product
7, including: (1) limiting the time for formation of the cuprate
Quenching of 10 with an aqueous solution of NaI containing

air generates Cu(I) as Na+CuI2 (100%, quantitative), as
1
2
3
4
5
6
7
8
determined by the weight of Cu2S formed after addition of
aqueous Na2S. In addition, the original oxidant 2,4-PDB is
recovered unchanged after extractive workup and column
chromatography. Quenching of 10 with
a solution of
K3Fe(CN)6 also regenerated 2,4-PDB along with the reduction
product K4Fe(CN)6, identified by conversion to Prussian blue,
KFeIII[FeII(CN)6] when treated with FeCl3 in water. These
results are summarized in Scheme 4.
9
Table 1. C(sp3)C(sp3) Coupling of Achiral Reactants (R–
H) to Form Chiral Products, R–R
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
6
to the minimum necessary and (2) controlling the
temperature during the 2,4-PDB accelerated reductive
elimination to avoid homolytic cleavage or decomposition of
6. It should be noted that in the past others have attempted
the enantioselective conversion 5 to 7 without success under
a variety of conditions.15 The choice of 2,4-PDB a strongly π-
electron deficient benzenoid structure with three electron-
withdrawing groups on the ring was made to ensure rapid
removal of negative charge from the cuprate 6 either by dπ*
donor acceptor coordination to form 8 or Cu–Ar σ-bonding to
form 9.
Scheme 3. Reaction of R2CuLi with 2,4-PDB
There is insufficient information at this time to allow a
decision between their two alternatives. In contrast, however
a
single electron transfer pathway from 6 to 7 i.e.
R2Cu→R2Cu → RR + Cu(0), is inconsistent with the fact
that no metallic copper, Cu (0), is produced in the coupling. In

addition, one-electron oxidants such as NOBF4 or
ferrocenium tetrafluoroborate do not convert 6 to 7.16 When
the chiral coupling product 7 is formed from the Cu(III)
intermediate 8 or 9, a complex is formed which we surmise to
be the π-donor-acceptor complex 10 (Scheme 4). The
intermediate 10 can also be thought of as a Cuπ-coordinated
2,4-PDB dianion.
The highly enantioselective transformation of N-Boc
pyrrolidine (4) to the chiral coupling product 7 provides
ready access to this useful diamine derivative. We have used
the following simple procedure for work up: (1) treatment of
the reaction mixture with aqueous acid and separation of the
ether phase; (2) basification of the aqueous phase and
extraction to recover ()-sparteine (>95%); (3) concentration
of the ether extract and treatment with aqueous base to
saponify 2,4-PDB; (4) extraction with ether to give a mixture
of unreacted 4 and coupling product 7 which may be
separated easily by flash column chromatography on silica
gel; and (5) acidification of the aqueous phase to generate 2,4-
dinitro benzoic acid. By extending the reaction time for the
deprotonation 4 → 5 it is possible to reduce the amount of
unreacted 4 that remains after the coupling reaction.
Scheme 4. Putative Intermediate After RR Coupling of 8
The enantioselective C(sp3)C(sp3) coupling process that
is described above and outlined in Scheme 2 has been applied
successfully to a variety of other substrates that can be
lithiated enantioselectiviely using the ()-sparteine/sec-
2
ACS Paragon Plus Environment

Page 3 of 5
Journal of the American Chemical Society
butyllithium reagent. The results for six different types of
deprotonation by the sec-BuLitetramethylethylenediamine
1
2
3
4
5
6
7
8
substrates (1222) are shown in Table 1. We followed
previously described procedures for the enantioselective
deprotonation of 11,17 13,18 15,19 17,20 19 and 21.21, 22 The
results summarized in Table 1 demonstrate useful and concise
pathways for the synthesis of a variety of C2-symmetric 1,2
diamines 1,2-diols and 1,2-dithiols.
(TMEDA) combination to provide after oxidative coupling the
diastereomer 27 as the major product. The configuration of
27 was established by reduction using LiAlH4 to the known
R,R-amine 28,24 with recovery of phenmenthol.25 The
enantioselective coupling sequence leading to 28 also
demonstrates a novel method for accessing chiral organo-
lithium reagents having the metal attached to an sp3
stereocenter without use of a chiral base.
We have also applied the above C(sp3)C(sp3) coupling
process to a variety of other types of substrates, as illustrated
by the two examples shown in Scheme
5
and 6. The
The formation of CC bonds via higher valent metal
intermediates can also be promoted by the use of electron
donating diamines or solvents which stabilize the higher
valence state sufficiently to allow access to it, but not so much
as to retard reductive elimination. An early example of the
latter is the Ni-mediated cross coupling of π-allylnickel halides
with alkyl, vinyl or aryl halides in strongly coordinating
solvents such as dimethyl formamide.26 Elegant examples of
the former have recently been provided intra alia by the
9
enantioselective deprotonation of 2323 and coupling to 24
demonstrates that primary C(sp3) stereo centers can also be
ligated using the oxidatively accelerated coupling method
described herein. The conversion of 4 to 25 illustrates the
joining of two different groups to form a hetero-coupling
product.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Scheme 5. Primary C(sp3)C(sp3)-Coupling
groups of G.
C M
Fu27 and L. Mirica28 which have
demonstrated useful C–C bond formation reactions via
Ni(III).28 In a similar manner basic ligands facilitate oxidation
of Pd (II) to Pd (IV), as dramatically illustrated by the Yu
group’s discovery that a chiral, strongly electron-supplying
bidentate ligand permits oxidation of Pd (II) to Pd (IV) even
by I2, thus accelerating enantioselective C–H insertion and
functionalization.29
Scheme 6. Hetero C(sp3)C(sp3)-Coupling
In conclusion, the results described herein
a new
methodology that is well suited to the generation in a single
step of compounds with vicinal stereocenters by copper
mediated enantioselective C(sp3)C(sp3) coupling of α-
lithiated sp3 carbons. A critical element in the successful
achievement of these coupling reactions is the use of a 2,4-
dinitrobenzoate ester to effectively remove electron density
from a cuprate, R2CuLi, by dπ* donor-acceptor complexation
to provide a Cu(III) equivalent.
ASSOCIATED CONTENT
Scheme 7. C(sp3)C(sp3)-Coupling using a Chiral
Controller
Supporting Information
Experimental procedures and characterization data for novel
reactions and products including copies of 1H- and 13C-NMR
spectra and chiral HPLC traces. This material is available free
of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*corey@chemistry.harvard.edu
ORCID
Eswar Bhimireddy: 0000-0001-5789-0399
E. J. Corey: 0000-0002-1196-7896
Notes
The authors declare no competing financial interests.
ACKNOWLEDGMENT
We also have discovered that the phenmenthyloxy25
carboxamide of pyrrolidine (26) undergoes diastereoselective
We are indebted to Pfizer, Gilead and Bristol-Myers Squibb for
3
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 4 of 5
financial support of this research.
(14) Corey, E. J.; Carney, R. L. J. Am. Chem. Soc. 1971, 93,
73187322.
1
2
3
4
5
6
7
8
REFERENCES:
(15) Dieter, R. K.; Li, S. J.; Chen, N. J. Org. Chem. 2004, 69,
28672870 references cited therein.
(1) For an example of the synthetic problems that arise using
conventional approaches, see. Overman, L. E.; Pennington, L.
D. Can. J. Chem., 2000, 78, 732–738.
(16) A number of electron accepting aromatic compounds
were ineffective in promoting enantioselective coupling, e.g.
1,3-dinitro benzene (50% yield of racemic 7) and iso-propyl
3,5-dinitro benzoate (30% yield of 7 with 60% ee). For further
details on there and other π-electron deficient aromatic
reagents see Supporting Information.
(2) Nozaki, H.; Aratani, T.; Toraya, T., Noyori, R. Tetrahedron
1971, 27, 905913
(3) Hoppe, D.; Zscharge, O. Angew. Chem., Int. Ed. Engl. 1989,
28, 69. (b) Hoppe, D.; Hintze, F.; Tebben, P. Angew. Chem., Int.
Ed. Engl. 1990, 29, 1422. (c) Marsch, M.; Harms, K.; Zcharge,
O.; Hoppe, D.; Boche, G. Angew. Chem., Int. Ed. Engl. 1991, 30,
321. (d) Hoppe, D.; Paetow, M.; Hintze, F. Angew. Chem., Int. Ed.
Engl. 1993, 32, 394.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(17) Gross, K. M. B.; Jun, Y. M.; Beak, P. J. Org. Chem., 1997, 62,
76797689.
(18) Firth, J. D.; O’Brien, P.; Ferris, L. J. Am. Chem. Soc. 2016,
138, 651659.
(4) Quast, H.; Weise Velez, C. A. Angew. Chem., Int. Ed. Engl.
1978, 17, 213.
(19) Wu, S.; Lee, S.; Beak, P. J. Am. Chem. Soc. 1996, 118,
715721.
(5) Kerrick, S. T.; Beak, P. J. Am. Chem. Soc. 1991, 113, 9708.
(b) Beak, P.; Kerrick, S. T.; Wu, S.; Chen, J. J. Am. Chem. Soc.
1994, 116, 32313239. (c). Nicolic, N.; Beak, P. Org. Synth. 74,
23–31 (1996).
(20) Dearden, M. J.; Firkin, C. R.; Hermet, J. P. R.; O’Brien, P. J.
Am. Chem. Soc. 2001, 124, 1187011871.
(21) Lange, H.; Huenerbein, R.; Frçhlich, R.; Grimme, S.; Hoppe,
D. Chem. Asian J. 2008, 3, 7887
(6) For the use of sparteine as chiral ligand see: Kretchmer, R.
A. J. Org. Chem. 1972, 37, 2744. (b) Okamoto, Y.; Suzuki, K.;
Katayama, T.; Yuki, H.; Kageyama, H.; Miki, K.; Tanaka, N.;
Kasai, N. J. Chem. Soc., Chem. Commun. 1985, 469. (d) Harve, S.;
Junk, P. C.; Raston, C. L.; Salem, G. J. Org. Chem. 1988, 53, 3134.
(22) The chiral lithio-derivatives of 19 and 21 lose
configuration at an appreciable rate even at 90 oC in ether or
toluene and for this reason the enantiomeric purity of the
coupling products 20 and 22 is lower than for other examples
in Table 1.
(7) For an early demonstration of the stability of C(sp3)Li
reagents see: Still, W. C.; Mitra, A. J. Am. Chem. Soc. 1978, 100,
1927–1928.
(23) (a) Muci, A. R.; Campos, K. R.; Evans, D. A. J. Am. Chem. Soc.
1995, 117, 90759076; (b) Dutartre, M.; Bayardon, J.; Juge, S.
Chem. Soc. Rev., 2016, 45, 57715794.
(8) For the use of chiral diamine ligands other than sparteine,
see: (a) O’Brian, P. Chem. Comm. 2008, 655667. (b) Rayner,
P. J.; Smith, J. C.; Denneval, C.; O’Brian, P.; Clark, P. A.; Horan, R.
A. J. Chem. Comm. 2016, 52, 13541357. (c) Dixon, A. V.;
McGrath, M. J.; O’Brian, P. Org. Synth. 2006, 83, 141154.
(24) Hirama, M.; Oishi, T.; Itȏ, S. J. Chem. Soc., Chem. Commun,
1989, 10, 665–666.
(25) Corey, E. J.; Ensley, H. E. J. Am. Chem. Soc. 1975, 97, 6908–
6909.
(9) (a) Kharash, M. S.; Tawney, P.O. J. Am. Chem. Soc. 1941, 63,
2308. (b) Gilman, H.; Straley, J. M. Recl. Trav. Chim. Pays-Bas
Belg. 1936, 55, 821824. (c) House, H. O.; Respess, W. L.;
Whitesides, G. M. J. Org. Chem. 1966, 31, 31283141. (d)
Corey, E. J; Posner, G. H. J. Am. Chem. Soc. 1967, 89,
39113912. (e) Corey, E. J.; Gilman, N. W.; Ganem, B. E. J. Am.
Chem. Soc. 1968, 90, 56165617. (f) Corey, E. J.;
Katzenellenbogen, J. A. J. Am. Chem. Soc. 1969, 91, 18511852.
(26) Corey, E. J.; Semmelhack, M. F. J. Am. Chem. Soc. 1967, 89,
2755–2757.
(27) (a) Cordier, C. J.; Lundgren, R. J.; Fu, G. C. J. Am. Chem. Soc.
2013, 135, 10946–10949; (b) Mu, X.; shibata, Y.; Makida, Y.;
Fu, G. C. Angew. Chem., Int. Ed. 2017, 56, 5821–5824.
(28) Zheng, B.; Tang, F.; Luo, J.; Schultz, J. W.; Rath, N. P;
Mirica, L. M. J. Am. Chem. Soc. 2014, 136, 6499–6504.
(10) Corey, E. J.; Beames, D. J. J. Am. Chem. Soc. 1972, 94,
7210–7211.
(29) Plata, R. E.; Hill, D. E.; Haines, B. E.; Musaev, D. G.; Chu, L.;
Hickey, D. P.; Sigman, M. S.; Yu, J. Q.; Blackmond, D. G. J. Am.
Chem. Soc. 2017, 139, 9238–9245.
(11) Corey, E. J.; Boaz, N. W. Tetrahedron Lett. 1985, 26, 6015–
6018 and 6019–6021.
(12) The intermediacy of Cu(III) β-adducts in cuprate to α,β-
enones has also been supported by NMR studies at low
temperature. See, Bertz, S. H.; Cope, S.; Murphy, M.; Ogle, C. A.;
Taylor, B. J. J. Am. Chem. Soc. 2007, 129, 72087209.
(13) The acceleration of the reductive elimination by the use
of electron withdrawing ligands has been reviewed. See,
Hartwig, J. F. Inorg. Chem. 2007, 46, 19361947.
4
ACS Paragon Plus Environment

Page 5 of 5
Journal of the American Chemical Society
1
2
3
4
5
6
7
For Table of Contents Only
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
ACS Paragon Plus Environment