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
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
(d) Burckhardt, U.; Baumann, M.; Togni, A. Tetrahedron: Asymmetry 1997,
8, 155-159.
(19) OMP ) o-methoxyphenyl. TMP ) 3,4,5-trimethoxyphenyl.
2664
Org. Lett., Vol. 6, No. 16, 2004