Asymmetric synthesis of amines by the knochel-type MgCl2- enhanced addition of benzyl zinc reagents to N -tert -Butanesulfinyl aldimines

Article abstract of DOI:10.1021/ol103002t

The MgCl₂-enhanced addition of benzyl zinc reagents to N-tert-butanesulfinyl imines proceeds readily at room temperature to afford the N-tert-butanesulfinyl-protected amine products in good yields and diastereomeric ratios. This method is functional group tolerant in both the imine substrate and benzyl zinc coupling partner. Moreover, benzyl zinc reagent addition to the N-tert-butanesulfinyl imine 3o prepared from isopropylidene-protected glyceraldehyde proceeds in high yield and with exceptional selectivity to provide rapid entry to hydroxyethylamine-based aspartyl protease inhibitors.(Figure Presented)

Full text of DOI:10.1021/ol103002t

ORGANIC
LETTERS
2011
Vol. 13, No. 5
964–967
Asymmetric Synthesis of Amines
by the Knochel-Type MgCl2-Enhanced
Addition of Benzyl Zinc Reagents to
N-tert-Butanesulfinyl Aldimines
Andrew W. Buesking, Tyler D. Baguley, and Jonathan A. Ellman*
Department of Chemistry, Yale University, New Haven, Connecticut 06520-8107,
United States
jonathan.ellman@yale.edu
Received December 10, 2010
ABSTRACT
The MgCl2-enhanced addition of benzyl zinc reagents to N-tert-butanesulfinyl imines proceeds readily at room temperature to afford the N-tert-
butanesulfinyl-protected amine products in good yields and diastereomeric ratios. This method is functional group tolerant in both the imine
substrate and benzyl zinc coupling partner. Moreover, benzyl zinc reagent addition to the N-tert-butanesulfinyl imine 3o prepared from
isopropylidene-protected glyceraldehyde proceeds in high yield and with exceptional selectivity to provide rapid entry to hydroxyethylamine-
based aspartyl protease inhibitors.
The addition of organometallic reagents to N-tert-butane-
sulfinyl imines is one of the most extensively used approaches
for the asymmetric synthesis of amines.1 The addition of
Grignard and organolithium reagents was developed first
and proceeded with high yields and diastereoselectivities
for a broad range of coupling partners.2 Still, these meth-
ods suffer from poor functional group compatibility and
require low reaction temperatures. Rhodium-catalyzed
additions of boron reagents to N-tert-butanesulfinyl aldi-
mines greatly expanded the breadth of functionality that
may be present during the addition step.3 However, these
methods are currently limited to the coupling of aryl and
vinyl boron reagents, which are sp2 hybridized. Therefore,
additions of sp3 hybridized organometallic reagents that
also proceed with broad functional group compatibility
would represent a significant advance, but to date func-
tional group tolerant additions of allylzinc4 and allylin-
dium reagents5 have primarily been reported.
Recently, Knochel and co-workers reported that while
organozinc halides normally do not react with aldehydes
or ketones, the preparation of alkyl and benzyl reagents
using a mixture of Mg0, LiCl, and ZnCl2 (Scheme 1) results
in a species that adds efficiently in high yields and with
good functional group compatibility.6 Herein we report
(1) (a) Robak, M. T.; Herbage, M. A.; Ellman, J. A. Chem. Rev. 2010,
110, 3600. (b) Ferreira, F.; Botuha, C.; Chemla, F.; Perez-Luna, A.
Chem. Soc. Rev. 2009, 38, 1162. (c) Morton, D.; Stockman, R. A.
Tetrahedron 2006, 62, 8869. (d) Senanayake, C. H.; Krishnamurthy, D.
Lu, Z.-H.; Han, Z.; Gallou, I. Aldrichim. Acta 2005, 38, 93. (e) Zhou, P.;
Chen, B.-C.; Davis, F. A. Tetrahedron 2004, 60, 8003.
(2) For initial reports, see: (a) Cogan, D. A.; Liu, G.; Ellman, J.
Tetrahedron 1999, 55, 8883. (b) Liu, G.; Cogan, D. A.; Ellman, J. A.
J. Am. Chem. Soc. 1997, 119, 9913. (c) Pflum, D. A.; Krishnamurthy, D.;
Han, Z.; Wald, S. A.; Senanayake, C. H. Tetrahedron Lett. 2002, 43, 923.
(d) Plobeck, N.; Powell, D. Tetrahedron: Asymmetry 2002, 13, 303.
(3) For rhodium-catalyzed additions to N-tert-butanesulfinyl imines,
see: (a) Weix, D. J.; Shi, Y.; Ellman, J. A. J. Am. Chem. Soc. 2005, 127,
1092. (b) Bolshan, Y.; Batey, R. A. Org. Lett. 2005, 7, 1481. (c) Beenen,
M. A.; Weix, D. J.; Ellman, J. A. J. Am. Chem. Soc. 2006, 128, 6304.
(d) Truong, V. L.; Pfeiffer, J. Y. Tetrahedron Lett. 2009, 50, 1633. (e)
Brak, K.; Ellman, J. A. J. Am. Chem. Soc. 2009, 131, 3850. (f) Brak, K.;
Ellman, J. A. J. Org. Chem. 2010, 75, 3147.
(4) (a) Sun, X.-W.; Xu, M.-H.; Lin, G.-Q. Org. Lett. 2006, 8, 4979.
(b) Kolodney, G.; Sklute, G.; Perrone, S.; Knochel, P.; Marek, I. Angew.
Chem., Int. Ed. 2007, 46, 9291. (c) Sun, X.-W.; Liu, M.; Xu, M.-H.
Lin, G.-Q. Org. Lett. 2008, 10, 1259. (d) Reddy, L. R.; Hu, B.;Prashad, M.
Org. Lett. 2008, 10, 3109. (e) Shen, A.; Liu, M.; Jia, Z.-S.; Xu, M.-H.;
Lin, G.-Q. Org. Lett. 2010, 12, 5154.
(5) (a) Cooper, I. R.; Grigg, R.; MacLachlan, W. S.; Thornton-
Pett, M.; Sridharan, V. Chem. Commun. 2002, 1372. (b) Foubelo, F.;
Yus, M. Tetrahedron: Asymmetry 2004, 15, 3823. (c) Gonzalez-Gomez,
J. C.; Medjahdi, M.; Foubelo, F.; Yus, M. J. Org. Chem. 2010, 75, 6308.
r
10.1021/ol103002t
Published on Web 02/09/2011
2011 American Chemical Society

time and 2.0 equiv of reagent in the addition were found to
produce the optimal results (entries 1 and 3). Extended
reagent preparation time was found to result in lower
diastereoselectivity (entry 2) and overaddition into the
ester functional group (entry 4). These negative effects
were not observed whenthe reagent was filtered away from
excess magnesium immediately after consumption of the
benzyl chloride starting material. Despite a decrease in
reagent concentration from 0.33 to 0.19 M,9 reagent stored
in a Schlenk flask for 20 days reacted similarly to freshly
preparedreagent (entry 5). Furthermore, overaddition was
not observed with a large excess of benzyl zinc reagent
prepared under the standard conditions (entry 6). To-
gether, these results suggest that the presence of excess
Mg0 after formation of the initial desired benzyl zinc
reagent leads to the formation of a second more reactive
and less selective organometallic reagent.
Scheme 1. Preparation of Benzyl Zinc Reagents
the application of this new methodology for the diaster-
eoselective addition of a variety of benzyl zinc reagents to
N-tert-butanesulfinyl imine substrates with excellent func-
tional group tolerance.7,8
Table 2. Benzyl Zinc Additions to N-tert-Butanesulfinyl
Aldimines
Table 1. Optimization of Benzyl Zinc Additions
entry reagent preparation
R
4
yield,a %
drb
1
30 min
3 h
OMe
OMe
4a
4a
70
76
77
92:8
81:19
93:7
entry
R
1
X
4
yield,a %
drb
2
1
2
4-OMeC6H4
1a
H
H
H
H
H
H
4a
4b
4c
4d
4e
4f
85
86
87
86
79
98
69
42
86
83
77
76
90:10c
92:8
3
30 min
3 h
CO2Me 4b
CO2Me 4b overadditionc ndd
4-CO2MeC6H4 1a
4
5e
6f
30 min
30 min
CO2Me 4b
CO2Me 4b
83
88
90:10
93:7
3
4-ClC6H4
3-ClC6H4
2-ClC6H4
3-Py
1a
1a
1a
1a
92:8
4
92:8
5
>99:1
96:4
94:6d
98:2
a Determined by 1H NMR relative to an external standard. b Deter-
mined by 1H NMR. c 57% triple addition product, 37% double addition
product. d Not determined. e Reagent stored in a Schlenk flask under
static N2 for 20 days. f 4.0 equiv of 1a.
6
7
4-CO2MeC6H4 1b 4-OMe 4g
3-Py 1b 4-OMe 4h
4-CO2MeC6H4 1c 4-F
8
9
4i
94:6
10
11
12
4-CNC6H4
tBu
1c 4-F
1c 4-F
1c 4-F
4j
98:2
We began by investigating the addition of the unsub-
stituted benzyl zinc reagent 1a to the p-methoxy- and p-
methylcarboxy-substituted aromatic imine substrates 3
(Table 1). Appropriate reagent preparation time was
found to vary with the quality of the magnesium used,
and therefore initial reagent preparations were monitored
by following consumption of the benzyl chloride by GC.
For benzyl zinc reagent 1a, a 30 min reagent preparation
4k
41
76:24d,e
77:23f
PhCH2CH2
a Isolated yield of mixture of diastereomers after purification by
chromatography. b Determined by HPLC comparison to authentic
diastereomers. c Absolute configuration determined by comparison of the
optical rotation of the amine obtained upon sulfinyl deprotection to
literature values (see the Supporting Information). d Absolute configuration
was determined by X-ray crystallography. e Determined by mass balance of
separately isolated diastereomers. f Determined by 1H and 19F NMR.
The optimal conditions were next evaluated for a range
of N-tert-butanesulfinyl aldimine substrates and organo-
zinc coupling partners (Table 2). Reactions with both
electron-rich (entry 1) and electron-poor aromatic imines
(entries 2-5) proceeded with excellent yields and good
diastereoselectivity. Para-, meta-, and ortho-substitution
were all well tolerated (entries 3-5). As expected, ortho-
substitution resulted in a slightly diminished yield but
proceeded with very high diastereoselectivity. Additions
(6) (a) Metzger, A.; Bernhardt, S.; Manolikakes, G.; Knochel, P.
Angew. Chem., Int. Ed. 2010, 49, 4665. (b) Piller, F. M.; Metzger, A.;
Schade, M. A.; Haag, B. A.; Gavryushin, A.; Knochel, P. Chem.;Eur.
J. 2009, 15, 7192.
(7) For studies on the addition of organozincates, prepared from
Grignard and dialkylzinc reagents, to N-tert-butanesulfinyl imines, see:
(a) Almansa, R.; Guijarro, D.; Yus, M. Tetrahedron: Asymmetry 2008,
19, 603. (b) Almansa, R.; Guijarro, D.; Yus, M. Tetrahedron:
Asymmetry 2008, 19, 2484. (c) Almansa, R.; Guijarro, D.; Yus, M.
Tetrahedron. Lett. 2009, 50, 3198.
(8) For an important application of substituted benzyl Grignard
reagent addition to N-tert-butanesulfinyl imines for the preparation of
inhibitors of aspartyl proteases such as HIV protease and β-secretase,
see: Harried, S. S.; Croghan, M. D.; Kaller, M. R.; Lopez, P.; Zhong, W.;
Hungate, R.; Reider, P. J. J. Org. Chem. 2009, 74, 5975.
(9) Determined by iodometric titration.
Org. Lett., Vol. 13, No. 5, 2011
965

to ester- and nitrile-substituted imines (entries 2, 7, 9, and
10) demonstrated the functional group compatibility of
this method. Furthermore, the benzyl reagent added to
the 3-pyridyl imine substrate in high yield and with
good diastereoselectivity, indicating that nitrogen
heterocycles that often interfere with transition metal-
catalyzed additions, such as Rh-catalyzed arylboronic
acid additions,3 do not interfere with these MgCl2-
enhanced benzyl reagent additions. Additions to alkyl
imine substrates (entries 11 and 12) also proceeded in
good yields although with only moderate selectivity.
Finally, electron-neutral (entry 2), electron-rich (entry 7),
and electron-poor (entry 9) organozinc coupling part-
ners reacted smoothly and provided good stereoselectiv-
ity and functional group tolerance.
Scheme 2. Stereochemical Rationale
proteases such as HIV protease and β-secretase (BACE
1).8,11 Benzyl zinc reagent 1a added to imine 3o prepared
from isopropylidene-protected glyceraldehyde in high yield
and with exceptionally high selectivity (eq 1). Importantly,
the stereochemistry obtained is that most commonly found
in hydroxyethylamine-based protease inhibitors. Addition
to imine 3p also proceeded in high yield but with modest
selectivity for the syn diastereomer (eq 2).
Table 3. Ester-Substituted Dibenzyl Zinc Additions
Scheme 3. Addition to Glyceraldehyde-Derived Iminesc
entry
R
4
yield,a %
drb
1
2
H
4m
4n
73
74
80:20
97:3c
CN
a Isolated yield of a mixture of diastereomers after purification by
chromatography. b Determined by HPLC comparison to authentic
diastereomers. c HPLC of the crude material suggested a dr of 87:13.
Further highlighting the functional group compatibility
of this method, ester-substituted organozinc reagents were
added to both unsubstituted and nitrile-substituted aro-
matic imines with good yields and moderate to good
selectivity (Table 3). However, these reactions required
the more reactive dibenzyl zinc reagent, prepared with 0.55
equiv of ZnCl2 (Scheme 1).
a Determined by HPLC comparison to authentic diastereomers.
b Determined by mass balance of separately isolated diastereo-
mers. c 1H NMR of the crude material suggested a dr of 67:33.
The sense of induction for these addition reactions was
determined by rigorously establishing the absolute config-
urations of addition product 4a by chemical correlation
and products 4k and 4g by X-ray structural analysis.10 The
sense of induction is consistent with an open transition
state as proposed for a number of N-tert-butanesulfinyl
imine addition reactions (Scheme 2).1 Presumably, the
excess of coordinating ions in conjunction with the use of
a coordinating solvent favor this transition state over a
chelating transition state.
Diastereomer 4o was readily converted to N-Boc amino
diol 5 by simultaneous deprotection of the sulfinyl and
isopropylidene protecting groups followed by Boc-protec-
tion of the amine functionality (Scheme 4). N-Boc-3-
amino-1,2-diols with the stereochemistry present in 5
provide direct access to hydroxyethylamine inhibitors.12
The utility of the method was demonstrated by the
synthesis of anti-3-amino-4-arylbutane-1,2-diol derivatives
(Scheme 3), which are useful intermediates in the prepara-
tion of hydroxyethylamine-based inhibitors of aspartyl
Scheme 4. Elaboration of Amine 4o
(10) See the Supporting Information for more details.
(11) For reviews of aspartyl protease inhibitors and their synthesis,
see: (a) Ghosh, A. K. J. Med. Chem. 2009, 52, 2163. (b) Izawa, K.;
Onishi, T. Chem. Rev. 2006, 106, 2811. (c) Huang, W.-H.; Sheng, R.; Hu,
Y.-Z. Curr. Med. Chem. 2009, 16, 1806–1820.
966
Org. Lett., Vol. 13, No. 5, 2011

Oxidative conversion of 5 to N-Boc-(S)-phenylalanine also
enabled rigorous assignment of the configuration at the
amine stereocenter.13
In conclusion, the MgCl2-enhanced addition of benzyl
zincreagentstoN-tert-butanesulfinyliminesoccursreadily
at room temperature. Good yields, selectivity, and func-
tional group tolerance are observed for a variety of aro-
matic imines. Moreover, ester-substituted dibenzyl zinc
reagents readily add to nitrile-substituted imines without
cross-reactivity, further highlighting the functional-group
compatible nature of the transformation. Although benzyl
additions to aliphatic imines generally showed only mod-
erate selectivity, addition to sulfinyl imine 3o prepared
from isopropylidene-protected glyceraldehyde proceeded
in high yield and with very high selectivity, indicating that
this method should allow the rapid introduction of a
variety of functionalized benzyl substituents into hydro-
xyethylamine-based aspartyl protease inhibitors.
Acknowledgment. ThisworkwassupportedbytheNSF
(CHE-1049571).
(12) For literature procedures for the straightforward conversion of
Boc amino diol 5 to the corresponding anti-N-protected-3-amino-1,2-
epoxide, see: Branalt, J.; Kvarnstrom, I.; Classon, B.; Samuelsson, B.;
Nillroth, U.; Danielson, U. H.; Karlen, A.; Hallberg, A. Tetrahedron
Lett. 1997, 38, 3483.
Supporting Information Available. Experimental pro-
cedures and characterization data. This material is
available free of charge via the Internet at http://pubs.
acs.org.
(13) See the Supporting Information.
Org. Lett., Vol. 13, No. 5, 2011
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