Diastereoselective addition of allylzinc bromide to imines derived from (R)-phenylglycine amide

Article abstract of DOI:10.1021/ol016840f

equation presented The highly diastereoselective addition of allylzinc bromide to imines derived from (R)-phenylglycine amide is reported. Homoallylamines with high enantiomeric purity are obtained from the adducts in three steps on removal of the chiral

Full text of DOI:10.1021/ol016840f

ORGANIC
LETTERS
2001
Vol. 3, No. 24
3943-3946
Diastereoselective Addition of Allylzinc
Bromide to Imines Derived from
(R)-Phenylglycine Amide
Marcel van der Sluis,† Jan Dalmolen,‡ Ben de Lange,§ Bernard Kaptein,§
,†
,§
Richard M. Kellogg,* and Quirinus B. Broxterman*
Syncom B.V., Kadijk 3, 9747 AT Groningen, The Netherlands, UniVersity of
Groningen, Department of Organic and Molecular Inorganic Chemistry, Nijenborgh 4,
9747 AG Groningen, The Netherlands, and DSM Fine Chemicals-AdVanced Synthesis
and Catalysis, P.O. Box 18, 6160 MD Geleen, The Netherlands
rinus.broxterman@dsm.com
Received October 1, 2001
ABSTRACT
The highly diastereoselective addition of allylzinc bromide to imines derived from (R)-phenylglycine amide is reported. Homoallylamines with
high enantiomeric purity are obtained from the adducts in three steps on removal of the chiral auxiliary by means of a nonreductive protocol.
Removal of the auxiliary by hydrogenation leads to the saturated amines, also in high enantiomeric purity.
Chiral homoallylamines are valuable synthons for the
preparation of topically interesting compounds such as
â-amino acids, 1,3-amino alcohols, and 1-amino-3,4-
epoxides.1 Recently,2,3 homoallylamines proved to be key
building blocks for the preparation of some pyrrolidines and
piperidines via the ring-closing metathesis approach. The
most frequently employed methodology for the synthesis of
homoallylamines is the allylation of imines by allyl Si, Sn,
Sm, Li, Mg, Zn, Ce, Cr, B, or Cr reagents.4
as R-arylethylamines,5 â-amino alcohols, â-alkoxy amines,
and R-amino acid esters.6 A common feature of the latter
three auxiliaries is the presence of a second heteroatom,
which is capable of rigidifying the transition state of the 1,2-
(4) (a) Enders, D.; Reinhold, U. Tetrahedron: Asymmetry 1997, 8, 1895.
(b) Jones, P.; Knochel, P. J. Org. Chem. 1999, 64, 186. (c) Wang, D.-K.;
Zhou, Y.-G.; Hou, X.-L.; Dai, L.-X. J. Org. Chem. 1999, 64, 4233. (d)
Nakamura, K.; Nakamura, H.; Yamamoto, Y. J. Org. Chem. 1999, 64, 2614.
(e) Nakamura, H.; Nakamura, K.; Yamamoto, Y. J. Am. Chem. Soc. 1998,
120, 4242. (f) Yamamoto, Y.; Asao, N. Chem. ReV. 1993, 93, 2207. (g)
Wang, D.-K.; Dai, L.-X.; Hou, X.-L.; Zhang, Y. Tetrahedron Lett. 1996,
37, 4187. (h) Negoro, N.; Yanada, R.; Okaniwa, M.; Yanada, K.; Fujita, T.
Synlett 1998, 835. (i) Itsuno, S.; Yokoi, A.; Kuroda, S. Synlett 1999, 1987.
(j) El-Shehawy, A. A.; Omara, M. A.; Ito, K.; Itsuno, S. Synlett 1998, 367.
(k) Yanada, R.; Negoro, N.; Okaniwa, M.; Ibuka, T. Tetrahedron 1999,
55, 13947. (l) Fang, X.; Johannsen, M.; Yao, S.; Gatherhood, N.; Hazel, R.
G.; Jørgensen, K. A. J. Org. Chem. 1999, 64, 4844.
(5) Juaristi, E.; Leon-Romo, J. L.; Reyes, A.; Escalante, J. Tetrahedron:
Asymmetry 1999, 10, 2441.
(6) (a) Alvaro, G.; Martelli, G.; Savoia, D. J. Chem. Soc., Perkin Trans.
1998, 1, 777. (b) Bocoum, A.; Savoia, D.; Umani-Ronchi, A. J. Chem.
Soc., Chem. Commun. 1993, 1542 (b) Razavi, H.; Polt, R. J. Org. Chem.
2000, 65, 5693.
High 1,3-asymmetric induction during the addition can be
achieved by using imines derived from chiral auxiliaries such
* E-mail for R.M.K.: r.m.kellogg@syncom.nl.
† Syncom B.V..
‡ University of Groningen.
§ DSM Fine Chemicals-Advanced Synthesis and Catalysis.
(1) Laschat, S.; Kunz, H. J. Org. Chem. 1991, 56, 5883.
(2) Felpin, F.-X.; Girard, S.; Vo-Thanh, G.; Robins, R. J.; Villieras, J.;
Lebreton, J. J. Org. Chem. 2001, 66, 6305.
(3) Wright, D. L.; Schulte, J. P., II; Page, M. A. Org. Lett. 2000, 2,
1847.
10.1021/ol016840f CCC: $20.00 © 2001 American Chemical Society
Published on Web 11/03/2001

Table 1. Formation of (R)-phenylglycine Amide Imines 2-11 and the Formation of Homoallylamines 12-21 by Addition of
Allylzinc Bromide
entry
imine
R1
yielda (%)
homoallylamine
yielda (%)
er (R,R)/(S,S)-12-21b
dr (R,R)/(R,S)-12-21c
1
2
3
4
5
6
7
8
9
2
3d
4
5
6
7
8
9
10
11
phenyl
84
85
90
87
90
89
80
95
95
86
12
13
14
15
16
17
18
19
20
21
93
81
90
93
43
88
90
89
77
94
>99/1
>99/1
nd
nd
nd
nd
nd
>99/1
nd
nd
>99/1
>99/1
>99/1
>99/1
>99/1
96/4
>99/1
>99/1
99/1
3-piperonyl
p-HOphenyl
2,5-(MeO)2phenyl
3-pyridyl
2-furyl
2-thiophene
tert-butyl
i-propyl
i-butyl
10
>99/1
a Isolated yield. b Determined with HPLC. c dr values were determined with NMR spectroscopy. d In CHCl3 with catalytic p-TolSO3H for 2 h at reflux.
addition through chelation.5 This is also referred to as
“chelation control”.7 Drawbacks are the limited availability
and/or the need of removal of these auxiliaries by procedures
unsuitable for large-scale preparations, i.e., oxidation with
Pb(OAc)4 or treatment with HIO4/eNH2.5
Recently, the use of optically pure (R)-phenylglycine
amide (1) as highly efficient chiral auxiliary in the synthesis
of R-amino acids was reported.8 Its application in the
synthesis of chiral amines and homoallylamines based on
diastereoselective allylation as the key step will be described
here. Both reductive and nonreductive protocols for removal
of the chiral auxiliary have been developed.
Aldimines (R)-2-11 are obtained in 84-95% yield by
stirring a mixture of 1 with the corresponding aldehyde (R1-
CHO) in CH2Cl2 overnight at room temperature. The
formation of aldimine (R)-3 required elevated temperatures
and acid catalysis (Table 1). The addition of allylzinc
bromide (1.5 equiv) to the imines in THF at 0 °C furnishes
the homoallylamines (R,R)-12-21 in yields up to 94% with
diastereomeric ratios of >99/1 in most cases (Table 1).
Allylzinc bromide proved to be the organometallic reagent
of choice. It is easily prepared and is compatible with most
organic groups.9
The phenylglycine amide chiral auxiliary in imines 2-11
contains a chiral center that could racemize under basic
conditions. To determine if any racemization of this chiral
center had occurred during the allylation reaction, we
determined the (R,R)/(S,S) ratio of several adducts by HPLC
(Table 1). The selected compounds contained only the (R,R)
isomers, thereby establishing that the chiral auxiliary does
not racemize under the reaction conditions employed.
The addition of allylzinc reagents to imines is reported to
be limited to those that are nonenolizable or contain branched
R-alkyl substituents.4f This is not true for (R)-phenylglycine
amide derived imines as shown by the allylation of 10 and
11 (entries 9 and 10).
The compatibility of allylzinc bromide with relatively
acidic functionalities such as an amide or hydroxyl group is
remarkable. In view of the approximate relative pKa of 17
for amides,10 the basic allylzinc reagent could well be
protonated by this group. The lack of reaction with an even
more acidic functionality such as a phenolic hydroxyl group
(pKa 8-11) is even more striking (entry 3). The addition of
1.5 equiv of allylzinc bromide to (R)-4 furnished the
homoallylamine (R,R)-14 as the only product in 90% isolated
yield.
Reactions of 2 with, respectively, propylzinc bromide,
n-butyllithium, benzylzinc bromide, or p-anisylmagnesium
bromide failed to produce addition products. In all cases the
starting material was recovered.
We postulate that the two heteroatoms of the (R)-
phenylglycine amide-imine chelate the zinc atom of the
allylzinc reagent to form a five-membered ring.5,7 Simulta-
neously, a six-membered chairlike transition state is formed
(7) Neuman, W. L.; Rogic, M. M.; Dunn, T. J. Tetrahedron Lett. 1991,
32, 5865.
(8) (a) Boesten, W. H. J.; Seerden, J.-P. G.; de Lange, B.; Dielemans,
H. J. A.; Elsenberg, H. L. M.; Kaptein, B.; Moody, H. M.; Kellogg, R. M.;
Broxterman, Q. B. Org. Lett. 2001, 3, 1121. (b) Boesten, W. H. J.; Seerden,
J.-P. G.; de Lange, B.; van der Sluis, M.; Kaptein, B.; Moody, H. M.;
Kellogg, R. M.; Broxterman, Q. B. PCT Int. Appl. WO 01 42,173.
(9) Knochel, P.; Singer, R. D. Chem. ReV. 1993, 93, 2117.
Figure 1. Chelation-controlled addition of allylzinc bromide to
(R)-PGA imines.
3944
Org. Lett., Vol. 3, No. 24, 2001

from the allylic system and the CdN double bond of the
imine. The re-face 1,2-addition proceeds in a concerted
fashion by an allylic rearrangement (Figure 1).
The allylic rearrangement was confirmed by the addition
of crotylzinc bromide11 to imine 2 (Scheme 1). Product 22
Table 2. Synthesis of Chiral Amines by Catalytic
Hydrogenation of Homoallylamines
Scheme 1
a Isolated yield. b Analysis by HPLC (Crownpak analytical column, 150
× 4.6 mm; eluent aqueous HClO4, pH ) 2.0, 1.0 mL/min for 110 min) by
integration of absorption at 216 nm. c Analysis by HPLC after tosylation
with TosCl/Et3N in dichloromethane (Chiralpak AS, 250 × 4.6 mm; eluent
heptane/EtOH/Et2NH, 90/10/0.2, 1.0 mL/min for 20 min) by integration at
258 nm.
was isolated in 98% yield (dr 99/1) as a mixture of two
isomers in a ratio of 1:1.3. As a demonstration of the scope,
the addition of methallyl bromide to 2 furnished (R,R)-23 in
98% isolated yield (dr 99/1).
The R-substituted 1-aminobutanes (R)-24,12 (R)-25,13 and
(R)-2614 were obtained in 49-88% yield with enantiomeric
ratios of 97/3 to >99/1 by catalytic hydrogenation of 12,
20, and 13, respectively, under acidic conditions (Table 2).
The high enantiomeric ratios of these chiral amines are in
accord with the diastereoselectivity of the allylation reaction
and lack of racemization of the phenylglycine amide moiety.
The observed signs of the optical rotations are in accord
with the (R)-configuration (see Supporting Information). In
accord with the model proposed in Figure 1, the absolute
configuration of the adducts 12-21 should be (R,R). This
was unambiguously established by X-ray crystallographic
analysis of 1415 (Figure 2).
human leukocyte elastase inhibitor L-694,458, which was
prepared earlier with an enantiomeric ratio of 97/3 via a
three-step reaction sequence.16
Chiral homoallylamines are valuable synthons for the
preparation of biologically active components including
â-amino carboxylic acids or esters, obtained by oxidation
of the allylic functionality.1,17 As removal of the chiral
auxiliary by hydrogenation leads to the loss of the allylic
functionality, we sought alternative routes for the conversion
of the adduct into the “free” homoallylamines. Using adduct
(R,R)-12 and (R,R)-20 as models, we developed the “retro-
A demonstration of the synthetic value of this methodology
is the preparation of (R)-R-propylpiperonylamine ((R)-26).
This chiral butylamine is an important building block of the
(10) March. J. AdVanced Organic Chemistry; John Wiley: New York,
1992; p 250.
(11) Crotylbromide was used consisting of a cis/trans (1:13) mixture
(85%) and 3-bromo-1-butene (15%).
(12) (a) Bataille, P.; Paterne, M.; Brown, E. Tetrahedron: Asymmetry,
1998, 9, 2181. (b) Nakamura, H.; Nakamura, K.; Yamamoto, Y. J. Am.
Chem. Soc. 1998, 120, 4242. (c) Yamamoto, Y.; Shimota, H.; Oda, J.;
Inouye, Y. Bull. Chem. Soc. Jpn. 1976, 49, 3247.
(13) Yamamoto, Y.; Nishii, S.; Maruyama, K.; Komatsu, T.; Ito, W. J.
Am. Chem. Soc. 1986, 108, 8, 4608.
(14) Cvetovich, R. J.; Chartrain, M.; Hartner, F. W.; Roberge, C.; Amato,
J. S.; Grabowski, E. J. J. J. Org. Chem. 1996, 61, 6575.
(15) X-ray data for 14 is available from the Cambridge Crystallographic
Data Center, 12 Union Road, Cambridge CB2 1EZ, U.K. and was allocated
the deposition number CCDC 154389.
(16) Cvetovich, R. J.; Chartrain, M.; Hartner, F. W., Jr.; Roberge, C.;
Amato, J. S.; Grabowski, E. J. J. J. Org. Chem. 1996, 61, 6575.
(17) (a) Moody, C. J.; Hunt, J. C. A. Synlett 1998, 733. (b) Polniaszek,
R. P.; Belmont, S. E.; Alvarez, R. J. Org. Chem. 1990, 55, 215. (c) Laschat,
S.; Kunz, H. Synlett 1990, 51. (d) Hua, D. H.; Miao, S. W. M.; Chen, J. S.;
Iguchi, S. J. Org. Chem. 1991, 56, 4.
Figure 2. X-ray structure of (R,R)-14.
Org. Lett., Vol. 3, No. 24, 2001
3945

Strecker” method for the conversion of phenylacetamide
protected homoallylamines into N-benzylidene protected
homoallylamines (R)-29 and (R)-30, respectively (Scheme
2).
M) at room temperature. At 80 °C in 10% aqueous HCl, the
imine is hydrolyzed although aza-Cope rearrangement is a
competitive reaction. A more effective method was treatment
with hydroxylamine hydrochloride19 in aqueous THF, whereby
(R)-316b and (R)-3220 were obtained, respectively (Scheme
2). The homoallylamines were obtained with an enantiomeric
ratio of 97/3 to 99/1 showing that the deprotection sequence
proceeds with almost full retention of configuration. The
overall yield of the deprotection is 78-84%.
Scheme 2c
The results presented here establish that (R)-phenylglycine
amide is an excellent alternative for other chiral auxiliaries
used for the preparation of chiral homoallylamines. Allylation
is readily accomplished via relatively cheap allylzinc bro-
mide, and the chiral auxiliary is conveniently removed under
either reductive or nonreductive conditions. Obviously, (S)-
phenylglycine amide is also accessible and can be used for
the preparation of the opposite isomer of the described
products. Other applications of phenylglycine amide in
asymmetric synthesis are under investigation.
Acknowledgment. The authors would like to thank Erik
van Echten (Syncom B.V.) and Marc B. van Gelder
(University of Groningen) for the HPLC analysis of the chiral
amines.
a Analysis by HPLC. b Analysis by HPLC after tosylation with
TosCl/Et3N in dichloromethane (Chiralpak AS, 250 × 4.6 mm;
eluent heptane/EtOH/Et2NH, 90/10/0.2, 1.0 mL/min for 20 min)
by integration at 258 nm. c (a) Vilsmeier reagent, CH2Cl2, Et3N (1
equiv), 0 °C to room temperature. (b) K2CO3 (2 equiv)/EtOH,
reflux, 2 h. (c) NH2OH‚HCl, THF/H2O, rt, overnight.
Supporting Information Available: Complete experi-
mental procedures and full characterization data of all
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
The amides were readily converted into the nitrile 27 and
28, respectively, by dehydration of the amide moiety by the
OL016840F
+
Vilsmeier reagent (ClCHdN(CH3)2 Cl-). Loss of HCN from
(18) Greene, T. W.; Wuts, P. G. M. ProtectiVe Groups in Organic
Chemistry; John Wiley: New York, 1999.
(19) Logers, M.; Overman, L. E.; Welmaker, G. S. J. Am. Chem. Soc.
1995, 117, 9139.
(20) (a) Curran, D. P.; Gothe, S. A.; Cahoi, S.-M. Heterocycles 1993,
35, 1371. (b) Murakami, M.; Suginome, M.; Fujimoto, K.; Nakamura, H.;
Andersson, P. G.; Ito, Y. J. Am. Chem. Soc. 1993, 115, 6487.
the crude nitrile occurred on treatment with K2CO3 in ethanol
to furnish (R)-29 and (R)-30, respectively.
Acidic hydrolysis is usually the method of choice for the
deprotection of benzylidene-protected amines.18 However,
29 and 30 are rather stable to exposure to aqueous HCl (6
3946
Org. Lett., Vol. 3, No. 24, 2001