Asymmetric synthesis of homoallylic amines bearing adjacent stereogenic centers by addition of substituted allylic zinc reagents to n-tert- butanesulfinylimines

Article abstract of DOI:10.1021/ol800998u

(Chemical Equation Presented) A highly diastereoselective addition of substituted racemic allylic zinc reagents to chiral N-tert-butanesulfinylimines resulting in the formation of homoallylic amines is reported. This method is quite general and also efficient for the preparation of enantiomerically pure homoallylic amines bearing quaternary centers and also adjacent quaternary centers.

Full text of DOI:10.1021/ol800998u

ORGANIC
LETTERS
2008
Vol. 10, No. 14
3109-3112
Asymmetric Synthesis of Homoallylic
Amines Bearing Adjacent Stereogenic
Centers by Addition of Substituted
Allylic Zinc Reagents to
N-tert-Butanesulfinylimines†
Leleti Rajender Reddy,* Bin Hu, Mahavir Prashad, and Kapa Prasad
Chemical and Analytical DeVelopment, NoVartis Pharmaceuticals Corporation,
One Health Plaza, East HanoVer, New Jersey 07936
rajender.leleti@noVartis.com
Received May 21, 2008
ABSTRACT
A highly diastereoselective addition of substituted racemic allylic zinc reagents to chiral N-tert-butanesulfinylimines resulting in the formation
of homoallylic amines is reported. This method is quite general and also efficient for the preparation of enantiomerically pure homoallylic
amines bearing quaternary centers and also adjacent quaternary centers.
The stereoselective formation of a carbon-carbon bond is
of greatest importance in asymmetric synthesis. Especially
challenging is the generation of adjacent stereogenic centers
including quaternary centers.1 In simple systems, this has
been achieved by the face-selective addition of carbon
nucleophiles to carbon-heteroatom double bonds. Addition
of unsubstituted allylic organometallic reagents to Ellman’s
imine (1)2 leading to the formation of chiral homoallylic
amines bearing a single stereogenic center is an excellent
example in the present context.3 To our knowledge, there is
no report on asymmetric addition of highly substituted
racemic allylic organometallic reagents to 1 since they are
not readily accessible.4,5 During the total synthesis of
salinosporamide A, Corey provided an elegant method for
† This paper is dedicated to Professor E. J. Corey on the occasion of his
80th birthday.
(1) (a) Corey, E. J.; Guzman-Perez, A. Angew. Chem., Int. Ed. 1998,
37, 388. (b) Christoffers, J.; Mann, A. Angew. Chem., Int. Ed. 2001, 40,
4591. (c) Sklute, G.; Amsallem, D.; Shabli, A.; Varghese, J. P.; Marek, I.
J. Am. Chem. Soc. 2003, 125, 11776. (d) d’Augustin, M.; Palais, L.;
Alexakis, A. Angew. Chem., Int. Ed. 2005, 44, 1376. (e) Sklute, G.; Marek,
I. J. Am. Soc. Chem. 2006, 128, 4642. (f) Breit, B.; Demel, P.; Studte, C.
Angew. Chem., Int. Ed. 2004, 43, 3785. (g) Li, H.; Walsh, P. J. J. Am. Soc.
Chem. 2004, 126, 6538. (h) Kennedy, J. W. J.; Hall, D. G. J. Am. Chem.
Soc. 2002, 124, 898. (i) Denmark, S. E.; Fu, J. J. Am. Chem. Soc. 2001,
123, 9488. (j) Denmark, S. E.; Fu, J. Org. Lett. 2002, 4, 1951. (k) Heo,
J.-N.; Micalizio, G. C.; Roush, W. R. Org. Lett. 2003, 5, 1693.
(2) For recent reviews, see: (a) Ellman, J. A.; Owens, T. D.; Tang, T. P.
Acc. Chem. Res. 2002, 35, 984. (b) Ellman, J. A. Pure Appl. Chem. 2003,
75, 39. (c) Zhou, P.; Chen, B. C.; Davis, F. A. Tetrahedron 2004, 60, 8003.
(3) (a) Sun, X.-W.; Xu, M.-H.; Lin, G.-Q. Org. Lett. 2006, 8, 4979. (b)
Hua, D. H.; Miao, S. W.; Chen, J. S.; Iguchi, S. J. Org. Chem. 1991, 56,
4. (c) Cogan, D. A.; Liu, G.-C.; Ellman, J. A. Tetrahedron 1999, 55, 8883.
(d) Maji, M. S.; Fro¨hlich, R.; Studer, A. Org. Lett. 2008, 10, 1847. (e)
Kolodney, G.; Sklute, G.; Perrone, S.; Knochel, P.; Marek, I. Angew. Chem.,
Int. Ed. 2007, 46, 9291. (f) Foubelo, F.; Yus, M. Tetrahedron: Asymmetry
2004, 15, 3823.
10.1021/ol800998u CCC: $40.75
Published on Web 06/11/2008
2008 American Chemical Society

preparing highly substituted racemic allylic zinc reagents in
high purity and excellent yields.6 With this method in hand,
we investigated the asymmetric addition of substituted
racemic allylic zinc reagents to 1 (Scheme 1) and results
aromatic N-tert-butanesulfinyl aldimines. Interestingly, a
large number of substituted aromatic N-tert-butanesulfinyl
aldimines, such as p-fluoro, p-fluoro-o-bromo, p-methyl, and
p-methoxy derivatives, reacted cleanly with cyclohexenylzinc
chloride (2a) leading to corresponding anti-homoallylic
amines 3b-e (Table 1, entries 2-5) in excellent yields
(93-96%) and high diastereomeric ratios (dr >98:2). In the
same way, aliphatic N-tert-butanesulfinylaldimines such as
cyclohexyl aldimine 1f and ethyl aldimine 1g smoothly
reacted with 2a affording the corresponding anti-homo allylic
amines 3f and 3g in 92% and 97% yield (dr 97:3 and 98:2),
respectively. The heterocyclic N-tert-butanesulfinyl aldimine
1h also reacted with 2a to form anti-homoallylic amine 3h
in 95% yield with dr g98:2.
Scheme 1
.
Reaction of Substituted Allylic Zinc Reagents with
Various N-tert-Butanesulfinylimines
Similarly, reaction of organometallic reagent 2a with
N-tert-butylsulfinyl methyl ketimines 1i and 1j in THF at
-78 to -30 °C for 8 h afforded 3i and 3j, respectively,
bearing a quaternary center in high yields (92-96%) and
with high diastereomeric ratios (dr g98:2). Likewise,
reaction of 2a with N-tert-butylsulfinyl ethyl ketimine 1k
also proceeded to anti-homoallylic amine 3k containing
a quaternary center in 94% yield with dr >98:2. Addition
of 3-methyl-2-cyclohexenylzinc chloride (1b) to N-tert-
butylsulfinyl methyl ketimine 1l resulted in a regiospecific
and diastereospecific addition yielding 3l. Noticeably, the
new carbon-carbon bond is formed exclusively from the
most substituted end of allylic system, leading to the anti-
homoallylic amine 3l bearing two adjacent quaternary
centers in good yield (90%) with dr >98:2.
Interestingly, the cinnamylzinc chloride (2c) also dis-
played high diastereoselectivity (Table 1, entries 13-19).
Thus, the addition of various substituted aromatic N-tert-
butanesulfinyl aldimines, such as p-bromo, p-fluoro,
p-fluoro-o-bromo, p-methyl, and p- methoxy derivatives,
led to the corresponding syn-homoallylic amines (Table
1, entries 13-17) in excellent yields with dr g98:2.
Similarly, heterocyclic N-tert-butanesulfinyl aldimine 1s
and aliphatic N-tert-butanesulfinyl aldimines 1r also
reacted with 2c giving corresponding syn-homoallylic
amines (Table 1, entries 18 and 19) in good yields
(93-95%) and excellent diastereoselectivity (dr >98:2).
Unfortunately, this method is not suitable for crotylation
as it gives a mixture of diastereomers. The structure and
stereochemistry of the syn-homoallylic amine 3m (mp )
82-83 °C) resulting from addition of cinnamylzinc
leading to the formation of a variety of homoallylic amines
bearing adjacent stereogenic centers in high enantiopurity
are reported herein. Chiral homoallylic amines reported
herein are amenable to further modifications, hence opening
an access for novel compounds of pharmaceutical and
biological interest.7
Treatment of (S)-N-tert-butanesulfinylaldimine2,8 1a (1
equiv) with racemic cyclohexenylzinc chloride5 (2a, 1.2
equiv) in THF at -78 °C for 8 h afforded anti-homoallylic
amine 3a in high yield (98%) and with a high diastereomeric
ratio (dr g 98:2). Anti-homoallylic amine 3a was obtained
as a colorless crystalline solid (mp ) 126-128 °C). The
structure and absolute stereochemistry of 3a were confirmed
by single-crystal X-ray diffraction analysis (Figure 1). The
(5) Recently, Knochel reported the LiCl-mediated preparation of sub-
stituted allylic zinc reagents with a moderate formation of homocoupled
products. (a) Ren, H.; Dunet, G.; Mayer, P.; Knochel, P. J. Am. Chem.
Soc. 2007, 129, 5376.
Figure 1. X-ray crystal structure of 3a.
(6) (a) Reddy, L. R.; Saravanan, P.; Corey, E. J. J. Am. Chem. Soc.
2004, 126, 6230. For a recent application, see: (b) Endo, A.; Danishefsky,
S. J. J. Am. Chem. Soc. 2005, 127, 8298.
diastereoselectivity of the reaction was determined to be
>98:2 by 1H NMR analysis of the crude product. Encouraged
by these results, we turned our attention to other substituted
(7) (a) Huber, J. D.; Leighton, L. J. J. Am. Chem. Soc. 2007, 129, 14552.
(b) Trevillyan, J. M.; et al. J. Med. Chem. 2006, 49, 6439. (c) Ovaa, H.;
Stragies, R.; van der Marcel, G. A.; van Boom, J. H.; Blechert, S. Chem.
Commun. 2000, 1501. (d) Hunt, J. C. A.; Laurent, P.; Moody, C. J. Chem.
Commun. 2000, 1771. (e) Enders, D.; Reinhold, U. Tetrahedron: Asymmetry
1997, 8, 1895. (f) Bloch, R. Chem. ReV. 1998, 98, 1407. (g) Felpin, F. X.;
Girard, S.; -T, V.; Robins, R. J.; Villieras, J.; Lebreton, J. J. Org. Chem.
2001, 66, 531. (h) Neipp, C. E.; Humpherey, S. F.; Martin, S. F. J. Org.
Chem. 2001, 66, 6305. (i) Martin, S. F.; Rueger, H.; Williamson, S. A.;
GrzeJszczak, S. J. Am. Chem. Soc. 1987, 109, 6124. (j) Gao, Y.; Sato, F.
J. Org. Chem. 1995, 60, 8136.
(4) Substituted allylic lithium and magnesium reagents display a high
reactivity, and they are unstable. Their synthesis is rather difficult. Direct
zinc insertion to substituted allyl bromides is less satisfactory and gives
homocoupling products. (a) Schlosser, M.; Desponds, O.; Lehmann, R.;
Moret, E.; Raucheschwalbe, G. Tetrahedron 1993, 49, 10175. (b) Bellas-
soued, M.; Frangin, Y.; Gaudemar, M. Synthesis 1977, 205.
3110
Org. Lett., Vol. 10, No. 14, 2008

Table 1. Asymmetric Addition of Substituted Allylic
Organometallic Reagent to N-tert-Butanesulfinylimines
Figure 2. X-ray crystal structure of 3m.
achieved stereoselectivity is depicted in Figure 3, which
involves a chairlike transition state (TS-1).
Figure 3. Possible transition state (TS-1).
Finally, the sulfinyl group can be cleaved readily under
mild acidic conditions to provide free amine 4 in quantitative
yield.
Scheme 2. Deprotection of Sulfinyl Group
a Isolated yield of analytically pure products. b The diastereoselectivity
was determined by 1H NMR analysis. The “g98:2” denotes that signals
for only one diastereomer were observed. dr relative to sulfur. c Reaction
conditions: -78 to -30 °C, 8 h.
chloride (2c) to N-tert-butanesulfinyl aldimine 1m was
confirmed by the single-crystal X-ray diffraction analysis
(Figure 2). A possible mechanistic model to explain the
In summary, we have described an efficient, highly
diastereoselective addition of substituted racemic allyliczinc
(8) (a) Liu, G.; Cogan, D. A.; Owenst, D.; Tang, T. P.; Ellman, J. A. J.
Org. Chem. 1999, 64, 1278.
Org. Lett., Vol. 10, No. 14, 2008
3111

chloride reagents to various chiral N-tert-butanesulfinyl
aldimines and ketimines affording homoallylic amines. This
method is found to be very efficient for the preparation of
enantiomerically and diastereomerically pure homoallylic
amines bearing quaternary centers and also adjacent quater-
nary centers. Extension of this work is currently underway
in our laboratory.
Supporting Information Available: Complete experi-
mental procedures, characterization data, copies of NMR
spectra, and single X-ray crystallographic data for compounds
3a and 3m. This material is available free of charge via the
Internet at http://pubs.acs.org.
OL800998U
3112
Org. Lett., Vol. 10, No. 14, 2008