Following an ISES lead: The first examples of asymmetric Ni(0)-mediated allylic amination

Article abstract of DOI:10.1021/ol049159x

An ISES (in situ enzymatic screening) lead pointed to conditions (PMP N-protecting group, Ni(cod)₂ catalyst precursor) under which chiral, bidentate phosphines could promote Ni(0)-mediated allylic amination. Therefore, bidentate phosphines bear

Full text of DOI:10.1021/ol049159x

ORGANIC
LETTERS
2004
Vol. 6, No. 16
2661-2664
Following an ISES Lead: The First
Examples of Asymmetric Ni(0)-Mediated
Allylic Amination
David B. Berkowitz* and Gourhari Maiti
Department of Chemistry, UniVersity of Nebraska, Lincoln, Nebraska 68588-0304
dbb@unlserVe.unl.edu
Received May 8, 2004
ABSTRACT
An ISES (in situ enzymatic screening) lead pointed to conditions (PMP N-protecting group, Ni(cod)2 catalyst precursor) under which chiral,
bidentate phosphines could promote Ni(0)-mediated allylic amination. Therefore, bidentate phosphines bearing central, axial, and planar chirality
were examined with two model substrates of interest for PLP-enzyme inhibitor synthesis. In the best case, with (R)-MeO-BIPHEP, vinylglycinol
derivative 2 was obtained in 75% ee (97% ee, one recrystallization) from 1. Further manipulation provided a Ni(0)-mediated entry into L-vinylglycine.
R-Vinyl amino acids are potential inactivators of pyridoxal
phosphate (PLP) enzymes.1 “Suicide substrates” bearing this
vinylic trigger include the natural product L-vinylglycine2
and the anti-epileptic drug (S)-vigabatrin (γ-vinyl-GABA),3
which may also have potential to treat substance abuse.4 This
has led to considerable synthetic activity toward these tar-
gets.5-7 Among the most efficient and stereocontrolled ap-
proaches to appear are transition-metal-mediated allylic amin-
ation routes by Hayashi,8 Alper,9 Trost,10 and Overman.11
Heretofore, such ventures have been focused on palladium.
In developing an in situ enzymatic screening (ISES)
method for evaluating catalysts, we chose an intramolecular
allylic amination route to a protected vinylglycinol (1 f 2)
as a model reaction. Our initial findings demonstrated that,
among non-Pd metals screened, Ni(0) showed particular
promise for this transformation.12 Furthermore, the PMP
nitrogen-protecting group and bidentate phosphine ligands
were found to promote this chemistry.
As can be seen in Figure 1, ISES reveals that the com-
bination of Ni(cod)2 with chiral, bidentate phosphines also
gives this chemistry. As before, relative ISES rates track well
with relative rates of product formation under standard reac-
tion conditions, as judged by NMR at short times (Table 1).
In our earlier studies, dppb had shown the fastest initial
rates by ISES, and so it was retained as a standard here.
Similarly, SKEWPHOS, a chiral, acyclic three-carbon bridged
bidentate P,P-ligand, gives relatively rapid formation of 2.
The initial ISES screen also pointed to slower, yet potentially
(5) L-Vinylglycine: (a) Rose, N. G. W.; Blaskovich, M. A.; Wong, A.;
Lajoie, G. A. Tetrahedron 2001, 57, 1497-1507. (b) Campbell, A. D.;
Raynam, T. M.; Taylor, R. J. K. Synthesis 1998, 1707-1709. (c) Badorrey,
R.; Cativiela, C.; Diaz-de-Villegas, M. D.; Galvez, J. A. Synthesis 1997,
747-749 (d) Berkowitz, D. B.; Smith, M. K. Synthesis 1996, 39-41. (e)
Griesbeck, A. G.; Hirt, J. Liebigs Ann. 1995, 1957-1961. (f) Hallinan, K.
O.; Crout, D. H. G.; Errington, W. J. Chem. Soc., Perkin Trans. 1 1994,
3537-3543. (g) Carrasco, M.; Jones, R. J.; Kamel, S.; Rapoport, H.; Truong,
T. Org. Synth. 1991, 70, 29-34. (h) Pellicciari, R.; Natalini, B.; Marinozzi,
M. Synth. Commun. 1988, 18, 1715-1721. (i) Duhamel, L.; Duhamel, P.;
Fouquay, S.; Eddine, J. J.; Peschard, O.; Plaquevent, J. C.; Ravard, A.;
Solliard, R.; Valnot, J. Y.; Vincens, H. Tetrahedron 1988, 44, 5495-5506.
(j) Barton, D. H. R.; Crich, D.; Herve, Y.; Potier, P.; Thierry, J. Tetrahedron
1985, 41, 4347-4357. (g) Hanessian, S.; Sahoo, S. P. Tetrahedron Lett.
1984, 25, 1425-1428. (h) Scho¨llkopf, U.; Nozulak, J.; Groth, U. Tetra-
hedron, 1984 40, 1409-1417.
(1) Berkowitz, D. B.; Jahng, W.-J.; Pedersen, M. L. Bioorg. Med. Chem.
Lett. 1996, 6, 2151-2156 and references therein.
(2) Inhibition studies: (a) Liang, F.; Kirsch, J. F. Biochemistry 2000,
39, 2436-2444. (b) Zheng, L.; White, R. H.; Cash, V. L.; Dean, D. R.
Biochemistry 1994, 33, 4714-20. (c) Asada, Y.; Tanizawa, K.; Yonaha,
K.; Soda, K. Agric. Biol. Chem. 1988, 52, 2873-2878. (d) Gehring, H.;
Rando, R. R.; Christen, P. Biochemistry 1977, 16, 4832-4836. (e) Soper,
T. S.; Manning, J. M.; Marcotte, P. A.; Walsh, C. T. J. Biol. Chem. 1977,
252, 1571-1575.
(3) (a) Jung, M. J.; Palfreyman, M. G. Vigabatrin in Antiepileptic Drugs,
4th ed.; Levy, R. H., Mattson, R. H., Eds.; Raven: New York, 1995.
(4) (a) Brodie, J. D.; Figueroa, E.; Dewey, S. L. Synapse 2003, 50, 261-
265. (b) Gerasimov, M. R.; Dewey, S. L. Drug DeV. Res. 2003, 59, 240-
248.
10.1021/ol049159x CCC: $27.50 © 2004 American Chemical Society
Published on Web 07/10/2004

Table 2. Cyclizations of Allylic Amination Substrate 1a
no.
1
ligand
yieldb (%) eec (%) configd
(R,R)-NORPHOS (4)
80
75
94
87
79
37
nr
89
86
78
60
65
17
31
38
79
nr
28
0
13
6
0
4
R
2e (S,S)-CHIRAPHOS (5a )
3f (2S,4S)-SKEWPHOS (5b)
4g (2S,4S)-BPPM (7)
S
R
5
6
(S,S)-DIOP (8)
Trost ligand (9)
S
7h Trost ligand (9)
8g (R,R)-Me-DUPHOS (10a )
48
24
46
7
56
82
22
0
S
S
R
R
S
S
S
9
(S,S)-i-Pr-DUPHOS (10b)
10g (S,S)-Me-en -DUP HOS (10c)
11
12
13
14
15
16
17
18
19
20
21
(S,S)-Et-FerroTANE (11)
J OSIP HOS-typ e (12a )
J OSIP HOS-typ e (12b)
J OSIPHOS-type (12c)
J OSIPHOS-type (12d )
J OSIPHOS-type (12f)
WALPHOS-type (13a )
(Sp)-PHANEPHOS-type (14)
(R)-BINAP (15a)
43
S
nr
90
94
86
88
32
74
nr
46
59
72
75
38
44
S
S
S
S
S
S
(R)-Tol-BINAP (15b)
(R)-MeO-BIP HEP (16a )
22h (R)-MeO-BIP HEP (16a )
23
24
25
(R)- Me2-OMe-BIPHEP (16b)
(R)-iPr2-OMe-BIPHEP (16c)
(R)-tBu2-OMe-BIPHEP (16d )
Figure 1. UV/vis traces for the ISES data in Table 1.
a Reaction conditions: 10 mol % of Ni(cod)2, 20 mol % of ligand,
LiHMDS (1 equiv), THF, rt, overnight (unless otherwise indicated). b All
yields are isolated yields of pure products. nr ) no reaction observed. c ee’s
were determined by chiral HPLC (Chiralcel OD, hexane/i-PrOH 80/20).
d Configuration assigned by correlation with L-vinylglycine (Scheme 2).e t
) 8 h. f t ) 4 h. g t ) 6 h. h Reaction carried out without exogenous base
(i.e., no LiHMDS); t ) 6 h.
useful conversions with chiral P,P-ligands of the DUPHOS
and BINAP variety (Figure 1). On the contrary, neither
QUINAP (P,N-BINAP analog) nor a prototypical bis-
(oxazoline) (N,N-ligand) gave significant ISES rates. Next,
it was noted that although unconstrained ligands such as
SKEWPHOS gave both very good rates and conversions,
better ee’s could be obtained with BINAP or DUPHOS.
Clearly, we were not seeing a direct correlation between rate
and ee here. On the basis of these observations, it was
decided to explore broadly relatively electron-rich chiral
bidentate phosphines. The ligand array chosen includes
elements of central, planar and axial chirality (Figure 2).
The results for the transformation 1 f 2 are collected in
Table 2. A few patterns emerge. Indeed, all bis(diphe-
Table 1. ISES Evaluation of Bidentate Ligands for
Ni(0)-Mediated Allylic Substitution
(6) S)-Vigabatrin: (a) Anderson, C. E.; Overman, L. E. J. Am. Chem.
Soc. 2003, 125, 12412-12413. (b) Masson, G.; Zeghida, W.; Cividino, P.;
Py, S.; Vallee, Y. Synlett 2003, 1527-1529. (c) Chandrasekhar, S.;
Mohapatra, S. Tetrahedron Lett. 1998, 39, 6415-6418. (d) Alco´n, M.; Poch,
M.; Moyano, A.; Perica`s, M. A.; Riera, A. Tetrahedron: Asymmetry 1997,
8, 2967-2974. (e) Wei, Z.-Y.; Knaus, E. E. Tetrahedron 1994, 50, 5569-
78. (f) Wei, Z. Y.; Knaus, E. E. J. Org. Chem. 1993, 58, 1586-8.
(7) Enantioenriched quaternary, R-vinylic AA’s: (a) Ma, D.; Zhu, W.
J. Org. Chem. 2001, 66, 348-350. (b) Berkowitz, D. B.; McFadden, J. M.;
Chisowa, E.; Semerad, C. L. J. Am. Chem. Soc. 2000, 122, 11031-11032.
(c) Berkowitz, D. B.; McFadden, J. M.; Sloss, M. K. J. Org. Chem. 2000,
65, 2907-2918. (d) Avenoza, A.; Cativiela, C.; Corzana, F.; Peregrina, J.
M.; Zurbano, M. M. J. Org. Chem. 1999, 64, 8220-8225. (e) Berkowitz,
D. B.; Pumphrey, J. A.; Shen, Q. Tetrahedron Lett. 1994, 35, 8743-8747
(f) Colson, P.-J.; Hegedus, L. S. J. Org. Chem. 1993, 58, 5918-5924. (g)
Seebach, D.; Bu¨rger, H. M.; Schickli, C. P. Liebigs Ann. Chim. 1991, 669-
684. (h) Weber, T.; Aeschimann, R.; Maetzke, T.; Seebach, D. HelV. Chim.
Acta 1986, 69, 1365-1377. (i) Groth, U.; Scho¨llkopf, U.; Chiang, Y.-C.
Synthesis 1982, 864-866.
∆O.D.340/time
no.a
bidentate ligand
DPPB (6)
(S,S)-SKEWPHOS (5b)
(R)-BINAP (15a )
(mAbs/min)b
% convc
1
2
3
4
5
6
132 ( 16
64 ( 12
45 ( 10
30 ( 1
18
71
39
28
22
f
(R,R)-Me-DUPHOS (10a )
(S)-QUINAPd
(S,S)-Di-t-Bu-boxe
15 ( 2
f
a Conditions for the biphasic ISES screen (YADH ) yeast alcohol
dehydrogenase and YAlDH ) yeast aldehyde dehydrogenase) as described
in the Supporting Information. b Observed rates (10 min) of NADH
formation in units of ∆O.D.340 min-1. Unless otherwise indicated, ISES
slopes are reported as mean ( SD (duplicate runs). c Reaction conditions:
200 mM 1, 10 mol % of Ni(cod)2, 20 mol % of ligand, LiHMDS (1 equiv),
THF, rt, 15 min. Product/educt ratio estimated by NMR following workup.
d Ligand is (S)-1-(2-diphenylphosphino-1-naphthyl)isoquinoline. e Ligand
is 2,2′-methylenebis[(4S)-4-tert-butyl-2-oxazoline]. f Trace product (crude
NMR).
(8) Hayashi, T.; Yamamoto, A.; Ito, Y. Tetrahedron Lett. 1988, 29, 99-
102.
(9) Larksarp, C.; Alper, H. J. Am. Chem. Soc. 1997, 119, 3709-3715.
(10) Trost, B. M.; Bunt, R. C.; Lemoine, R. C.; Calkins, T. L. J. Am.
Chem. Soc. 2000, 122, 5968-5976.
(11) Overman uses a Pd(II) catalyst and invokes an intramolecular,
aminopalladation mechanism that preserves the Pd(II) oxidation state
throughout the catalytic cycle: Overman, L. O.; Remarchuk, T. P. J. Am.
Chem. Soc. 2002, 124, 12-13.
(12) Berkowitz, D. B.; Bose, M.; Choi, S. Angew. Chem., Int. Ed. 2002,
41, 1603-1607.
2662
Org. Lett., Vol. 6, No. 16, 2004

Figure 2. Array of chiral bidentate phosphine ligands examined.
nylphosphino) L’s with two to four sp3-carbon spacers (4,
5a,b, 7, 8) give excellent conversions, but low ee’s. The
phospholane-based DUPHOS ligands all give excellent
conversion, but only the methyl-substituted ones (10a,c) lead
to ee’s of some note, approaching 50%. The JOSIPHOS
ligand family incorporates both central chirality and planar
chirality. Best results, in terms of both catalysis and
enantioselection, are seen with ligands bearing a (diarylphos-
phino)ferrocene in tandem with a (dialkylphosphino)ethyl
moiety (i.e., 12a,b,f). A similar structure/activity observation
has been made with JOSIPHOS ligands in a model Pd-
mediated allylic alkylation reaction.13 Interestingly, in com-
paring 12a and 12b, one sees that subtle changes in sterics
can have significant consequences in ee and rate (Tables 2
and 3). Thus, 12a (R′ ) cy), gives higher yields (55-65%
vs 17-23%) with both substrates 1 and 19 (vide infra), but
12b (R′ ) tBu) gives higher ee’s (74-82%), indeed among
the highest seen here.
hindered BIPHEP ligands (16b-d) provided less satisfactory
results.
Given the importance of vigabatrin,4,6 we next set out to
examine the Ni(0)-mediated transformation 19 f 20, which
would serve as a formal synthesis of the drug. Note that
substitution of a CH2 for the bridging O means that an
N-PMP amidate replaces the N-PMP carbamate as the formal
nitrogen nucleophile.
Pleasingly, it was found that the requisite substrate 19
could be efficiently assembled via C-alkylation of the dianion
derived from N-PMP-acetamide (Scheme 1). The ligand
Scheme 1. Synthesis of the Vigabatrin Precursor
The most practical results were obtained with ligands
possessing axial chirality. Enantioselection steadily increases
from BINAP (15a, 46% ee) to tol-BINAP (15b, 59% ee) to
MeO-BIPHEP (16a, 72-75% ee),14-16 while yields are
outstanding (86-94%) across the series. More sterically
survey (Table 3) revealed decreased enantioselection for the
(13) Togni, A.; Breutel, C.; Schnyder, A.; Spindler, F.; Landert, H.;
Tijani, A. J. Am. Chem. Soc. 1994, 116, 4062-4066.
(14) Schmid, R.; Foricher, J.; Cereghetti, M.; Schoenholzer, P. HelV.
Chim. Acta 1991, 74, 370-389.
(15) BIPHEP ligands have been utilized mostly for asymmetric Ru-
mediated ketone reductions. For a leading reference, see: Jeulin, S.; Duprat
de Paule, S.; Ratovelomanana-Vidal V.; Geneˆt, J.-P.; Champion, N.; Dellis,
P. Angew. Chem., Int. Ed. 2004, 43, 320-325.
Org. Lett., Vol. 6, No. 16, 2004
2663

Table 3. Allylic Aminations to Vigabatrin Derivative 20a
Scheme 2. Ni(0)-Mediated Synthesis of L-Vinylglycine
no.
ligand
yieldb (%) eec (%) configd
1
2
3
4
5
6
7
8
9
(R,R)-Me-DUP HOS (10a )
(S,S)-iPr-DUPHOS (10b)
(S,S)-Et-FerroTANE (11)
J OSIPHOS-type (12a )
J OSIP HOS-typ e (12b)
J OSIPHOS-type (12c)
J OSIPHOS-type (12d )
J OSIPHOS-type (12e)
J OSIPHOS-type (12f)
93
90
28
55
28
23
73
nr
46
8
60
70
84
97
65
60
66
47
8
31
74
22
5
R
R
S
R
R
S
S
36
32
53
43
44
53
54
23
R
S
S
R
R
S
R
R
10 WALPHOS-type (13a )
11 WALP HOS-typ e (13b)
12 (R)-BINAP (15a )
to OMP19 (46%, 64% ee) or TMP19 (83%, 67% ee) was not
beneficial. The (E)-isomer of 1 gave the same sense of
induction, though at lower ee (65%) and yield (69%). This
result is reminiscent of Hayashi’s observations with Pd8 and
may be evidence of rapidly equilibrating π-allylmetal
intermediates.
However, whereas all of the initial screens had employed
10 mol % Ni(cod)2, 20 mol % L, and a full equivalent of
base (LiHMDS), it was found that, at least in this case, base
could be completely eliminated and MeO-BIPHEP reduced
to 10 mol % with essentially no consequence (83%, 75%
ee). Gratifyingly, we also found that with a single recrys-
tallization, the ee of the product could be increased from
75% to 97% with 64% oVerall yield. This refinement then
allowed for a practical entry into L-vinylglycine, centered
around this new asymmetric Ni(0)-mediated intramolecular
allylic amination (Scheme 2). Studies to further delineate
the scope and limitations of this asymmetric Ni(0)-chemistry
are in progress and will be described in due course.
13 (R)-Tol-BINAP (15b)
14e (S)-MeO-BIP HEP (16a )
15 (R)-Me2-OMe-BIP HEP (16b)
16 (R)-tBu2-OMe-BIPHEP (16d )
a Reaction conditions: 67 mM 19, 10 mol % of Ni(cod)2, 20 mol % of
ligand, LiHMDS (1 equiv), THF, rt, overnight. b Isolated yields of pure
products. nr ) no reaction observed. c ee’s determined by chiral HPLC
(Chiralcel OD, hexane/i-PrOH 73/27). d Configuration assigned by correla-
tion with the known γ-lactam, following PMP deprotection (CAN, MeCN,
H2O): [R]23D (66% ee-chiral HPLC; see the Supporting Information) -23.7
(EtOH, c 2.0) [lit.6e [R]23D (S)-isomer) +50.4 (EtOH, c 2.2)]. e No exogenous
base used (i.e., no LiHMDS).
axially chiral ligands, with the exception of 16b. But, these
ligands were eclipsed by DUPHOS ligand 10a (66% ee) and
the PtBu2-bearing JOSIPHOS ligand 12b (74% ee), again,
albeit with low conversion for 12b. Interestingly, one of the
WALPHOS ligands (13b, 60%, 53% ee) also appears to
show promise.
While isolated examples of Ni(0)-mediated allylic amina-
tion haVe been reported,17 to our knowledge, these represent
the first asymmetric examples. At this juncture, we chose to
examine the best case more closely, namely the (R)-MeO-
BIPHEP-Ni(0)-promoted synthesis of 2 (Table 2, entry 21).
Unfortunately, additives found to be beneficial in other late
transition metal-mediated allylic substitutions18 such as
NEt3,18a HOAc,18a NBu4OAc,17a LiCl18b (<5% conversion),
Acknowledgment. We thank the NSF (CHE-0317083)
for support. D.B.B. acknowledges the Alfred P. Sloan
Foundation for a fellowship. This research was facilitated
by shared instrumentation grants for NMR (NIH SIG-1-510-
RR-06301, NSF CHE-0091975, NSF MRI-0079750) and
GC/MS (NSF CHE-9300831), respectively. We thank Rudolf
Schmid (Roche AG) and Hans-Ulrich Blaser & Marc
Thommen (Solvias AG) for providing BIPHEP- and Josi-
phos/Walphos-type ligands, respectively, and Kannan R.
Karukurichi for assistance with ISES experiments.
LiF18c (60%, 73% ee), NBu4F18d (60%, 57% ee), NBu4PF6
17b
18d
(83%, 70% ee), and NBu4BH4 (51%, 26% ee-R) were
deleterious here. Changing the N-protecting group from PMP
(16) For examples of Pd-mediated allylic substitutions using BIPHEP,
see: (a) Sinou, D.; Rabeyrin, C.; Nguefack, C. AdV. Synth. Catal. 2003,
345, 357-363. (b) Bolm, C.; Kaufmann, D.; Gessler, S.; Harms, K. J.
Organomet. Chem. 1995, 502, 47-52. (c) Barbara, P. S.; Pregosin, P. S.;
Salzmann, R.; Albinati, A.; Kunz, R. W. Organometallics 1995, 14, 5160-
5170.
Supporting Information Available: Experimental pro-
cedures, representative chiral HPLC traces, and H NMR
spectra for new compounds. This material is available free
of charge via the Internet at http://pubs.acs.org.
1
(17) (a) Bricout, H.; Carpentier, J.-F.; Mortreux, A. Tetrahedron 1998,
54, 1073-1084. (b) Bricout, H.; Carpentier, J.-F.; Mortreux, A. Chem.
Commun. 1995, 1863-1864. For evidence of π-allyl nickel intermediates,
see: (c) Moberg, C. Tetrahedron Lett. 1980, 21, 4539-4542. (d) Yamamoto,
T.; Ishizu, J.; Yamamoto, A. J. Am. Chem. Soc. 1981, 103, 6863-6869.
(e) Tolman, C. A. J. Am. Chem. Soc. 1970, 92, 6785-6790. For examples
of substrate-directed, regio- and stereoselective Ni(0)-mediated substitutions
of allylic ethers with Grignard reagents, see: (f) Didiuk, M. T.; Morken, J.
P.; Hoveyda, A. H. Tetrahedron 1998, 54, 1117-1130. (g) Farthing, C.
N.; Kocovsky, P. J. Am. Chem. Soc. 1998, 120, 6661-6672.
OL049159X
(18) (a) Trost, B. M.; Shen, H. C.; Dong, L.; Surivet, J.-P. J. Am. Chem.
Soc. 2003, 125, 9276-9277. (b) Bartels, B.; Garc´ıa-Yebra, C.; Rominger,
F.; Helmchen, G. Eur. J. Inorg. Chem. 2002, 2569-2586. (c) Welter, C.;
Koch, O.; Lipowsky, G.; Helmchen, G. Chem. Commun. 2004, 896-897
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8, 155-159.
(19) OMP ) o-methoxyphenyl. TMP ) 3,4,5-trimethoxyphenyl.
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Org. Lett., Vol. 6, No. 16, 2004