Stereoselective formation of α-quaternary stereocenters in the mannich reaction

Article abstract of DOI:10.1021/ol802643k

Condensation of α,aα-disubstituted lithium enolates derived from bicyclic thioglycolate lactams with benzenesulfonyl imines affords Mannich addition products with excellent diastereoselectivity. Cleavage of the auxiliary under hydrolytic or reducing condi

Full text of DOI:10.1021/ol802643k

ORGANIC
LETTERS
2009
Vol. 11, No. 8
1725-1728
Stereoselective Formation of
r-Quaternary Stereocenters in the
Mannich Reaction
Erica A. Tiong and James L. Gleason*
Department of Chemistry, McGill UniVersity, 801 Sherbrooke St. W.,
Montreal, QC, Canada H3A 2K6
jim.gleason@mcgill.ca
Received February 7, 2009
ABSTRACT
Condensation of r,r-disubstituted lithium enolates derived from bicyclic thioglycolate lactams with benzenesulfonyl imines affords Mannich
addition products with excellent diastereoselectivity. Cleavage of the auxiliary under hydrolytic or reducing conditions affords ꢀ-amino acids
and alcohols, respectively.
The Mannich reaction is a fundamental process for the
synthesis of the ꢀ-amino carbonyl motif found in ꢀ-amino
acids and ꢀ-lactams and used as a precursor to ꢀ-amino
alcohols.1 There is a great deal of precedent for stereose-
lective formation of ꢀ-amino carbonyl compounds that are
either unsubstituted or contain a single alkyl group at the
R-position. This includes methods based on chiral auxilia-
ries,2 Brønsted and Lewis acid activation of the imine,3,4
and organocatalytic activation of a ketone or aldehyde.5 In
contrast, methods for the preparation of R,R-dialkyl-
substituted Mannich products are much less common,
particularly in cases where the two R-substituents are
nonequivalent.5e,6,7 In such instances, limited control over
enolate E/Z stereochemistry often results in variable syn/
anti selectivity. In this paper, we describe a stereoselective
Mannich addition using a bicyclic lactam auxiliary that
affords differentially R,R-disubstituted ꢀ-aminocarbonyl
products in high yields and with excellent stereoselectivity.
We recently described a practical method for stereocon-
trolled formation of R,R-disubstituted enolates based on the
reductive enolization of chiral thioglycolate lactams.8 Pre-
(4) For selected examples of Brønsted acid catalyzed Mannich reactions,
see: (a) Wenzel, A. G.; Jacobsen, E. N. J. Am. Chem. Soc. 2002, 124, 12964.
(b) Yamanaka, M.; Itoh, J.; Fuchibe, K.; Akiyama, T. J. Am. Chem. Soc.
2007, 129, 6756. (c) Uraguchi, D.; Terada, M. J. Am. Chem. Soc. 2004,
126, 5356. (d) Hasegawa, A.; Naganawa, Y.; Fushimi, M.; Ishihara, K.;
Yamamoto, H. Org. Lett. 2006, 8, 3175. (e) Tillman, A. L.; Dixon, D. J.
(1) (a) Cole, D. C. Tetrahedron 1994, 50, 9517. (b) Hart, D. J.; Ha,
D. C. Chem. ReV. 1989, 89, 1447. (c) Abele, S.; Seebach, D. Eur. J. Org.
Chem. 2000, 2000, 1.
Org Biomol. Chem. 2007, 5, 606
.
(5) For selected examples of organocatalytic Mannich reactions, see:
(a) List, B.; Pojarliev, P.; Biller, W. T.; Martin, H. J. J. Am. Chem. Soc.
2002, 124, 827. (b) Chowdari, N. S.; Ahmad, M.; Albertshofer, K.; Tanaka,
F.; Barbas, C. F., III. Org. Lett. 2006, 8, 2839. (c) Ibrahem, I.; Zou, W.;
Engqvist, M.; Xu, Y.; Co´rdova, A. Chem.-Eur. J. 2005, 11, 7024. (d) Cobb,
A. J. A.; Shaw, D. M.; Longbottom, D. A.; Gold, J. B.; Ley, S. V. Org.
Biomol. Chem. 2005, 3, 84. (e) Chowdari, N. S.; Suri, J. T.; Barbas, C. F.,
(2) For selected examples of a chiral auxiliary in Mannich reaction, see:
(a) Tang, T. P.; Ellman, J. A. J. Org. Chem. 2002, 67, 7819. (b) Kawakami,
T.; Ohtake, H.; Arakawa, H.; Okachi, T.; Imada, Y.; Murahashi, S. I. Org.
Lett. 1999, 1, 107. (c) Palomo, C.; Oiarbide, M.; Landa, A.; Gonza´lez-
Rego, M. C.; Garcia, J. M.; Gonza´lez, A.; Odriozola, J. M.; Martin-Pastor,
M.; Linden, A. J. Am. Chem. Soc. 2002, 124, 8637. (d) Muller, R.;
Goesmann, H.; Waldmann, H. Angew. Chem., Int. Ed. 1999, 38, 184.
(3) For selected examples of Lewis acid catalyzed Mannich reactions,
see: (a) Saruhashi, K.; Kobayashi, S. J. Am. Chem. Soc. 2006, 128, 11232.
(b) Juhl, K.; Gathergood, N.; Jørgensen, K. A. Angew. Chem., Int. Ed. 2001,
40, 2995. (c) Trost, B. M.; Jaratjaroonphong, J.; Reutrakul, V. J. Am. Chem.
Soc. 2006, 128, 2778. (d) Yamaguchi, A.; Matsunaga, S.; Shibasaki, M.
III. Org. Lett. 2004, 6, 2507
(6) Lee, E. C.; Hodous, B. L.; Bergin, E.; Shih, C.; Fu, G. C. J. Am.
Chem. Soc. 2005, 127, 11586
.
.
(7) In the formation of cyclic R-quaternary centers, E/Z control is not
an issue. For examples of formation of cyclic R-quaternary centers, see:
(a) Ting, A.; Lou, S.; Schaus, S. E. Org. Lett. 2006, 8, 2003. (b) Tillman,
Tetrahedron Lett. 2006, 47, 3985
.
A. L.; Ye, J.; Dixon, D. J. Chem. Commun. 2006, 1191.
10.1021/ol802643k CCC: $40.75
Published on Web 03/24/2009
2009 American Chemical Society

liminary studies showed that enolates formed from proline-
derived bicyclic lactams underwent highly selective alkyla-
tion and aldol additions, the latter after transmetalation of
the lithium enolate to boron in order to achieve high
diastereoselectivity.9 Subsequently, we developed chiral
auxiliary 1, which may be prepared on large scale in three
short steps from commercially available materials and which
proved to be highly effective in alkylation reactions through
both E- and Z-enolates (Scheme 1).10
Direct analysis of amides of form 16 is difficult due to
the presence of amide rotamers in the H NMR and their
1
instability at high temperatures, which precludes high-
temperature NMR and GC as analysis methods. To facilitate
HPLC analysis of the diastereoselectivity, 16 was partially
hydrolyzed using 1 M HCl in dioxane over a period of 12 h
at room temperature to provide the stable valinol amide 19a
(Table 2). An authentic standard of all four diastereomers
Table 2. Scope of the Mannich Reaction
Scheme 1. R,R-Disubstituted Enolate Formation and Alkylation
yield
lactam R1
R2 imine
R3
product (%)
ds
2a
2b
2c
2d
2e
2f
2g
2h
2b
2b
2b
2b
Me Et
9a
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
19a
19b
19c
19d
19e
19f
19g
19h
19i
83 92:4:3:1
83a 97:1:1:1
100 87:10:2:1
100 95:3:2:0
72 98:1:1:0
76 93:5:2:0
86 94:4:2:0
98 93:5:2:0
93a 99:1:0:0
80 97:2:1:0
76 85:12:2:1
86a 92:5:2:1
Et
Me
9a
9a
9a
9a
9a
9a
9a
9b
9c
9d
9e
Me Pr
Pr
Me
Me Bn
Bn Me
Me allyl
allyl Me
Et
Et
Et
Et
Me
Me
Me
Me
Ph(p-OMe)
Ph(p-Br)
CHdCHPh
2-furyl
19j
19k
19l
a Reaction completed in 6 h.
To examine the application of our bicyclic lactams to
Mannich additions, amide 2a was prepared, as a single
diastereomer, by sequential alkylation of 1. Addition of
E-enolate 3a, formed by reductive enolization of 2a with
lithium di-tert-butylbiphenylide (LiDBB), to a series of
N-protected benzaldimines was examined.11 Although simple
imines such as N-benzyl and N-phenyl were unreactive at
-78 °C, imines bearing either electron-withdrawing or metal-
chelating groups afforded addition products in moderate to
excellent yields (Table 1). The best compromise between
of 19 was prepared via a Mannich reaction of a pyrrolidinyl
amide (Scheme 2). Thus, deprotonation of pyrrolidine amide
Scheme 2. Synthesis of Authentic Standards
Table 1. Imine Protecting Group Optimization
entry
imine
R4
product
yield (%)
1
2
3
4
5
6
7
5
6
7
8
9
Bn
Ph
12
13
14
15
16
17
18
N.R.
N.R.
44
N.R.
83
o-MeO-C6H4
SO2PhMe
SO2Ph
P(O)Ph2
Bz
20 with LDA at 0 °C, followed by addition to benzaldimine
9a, gives the Mannich adduct 21 in 41% yield in a 2:1
diastereomeric ratio, a reflection of the low enolization
stereoselectivity. Reduction of the amide to the primary
alcohol using lithium amidoborohydride followed by reoxi-
dation and treatment with HBTU affords ꢀ-lactam 22, again
10
11
33
100
yield and ease of protecting group removal was the benzene
sulfonyl group (entry 5).
1726
Org. Lett., Vol. 11, No. 8, 2009

as a 2:1 mixture, in 36% yield over four steps. Treatment of
the lactam with valinol in THF at reflux provides an authentic
mixture of all four diastereomers of 19 in 86% yield and in
a 1:2:1:2 ratio. Analysis of the Mannich addition product
from 2a by normal phase HPLC indicated that the addition
had proceeded with high diastereoselectivity (92:4:3:1). This
stereoselectivity was excellent given that no transmetalation
of the lithium enolate was necessary. Moreover, reductive
enolization of lactam 2b to form Z-enolate 3b and subsequent
addition to imine 9a afforded 19b, again with excellent
diastereoselectivity (Table 2).
observed in reactions of 3a/b with alkyl halides.10 A plausible
transition state for reaction of enolate 3a with 9a is shown
in Figure 2. The enolate nitrogen is undoubtedly pyrami-
The stereochemistry of both 19a and 19b could be
determined explicitly by X-ray crystallography (Figure 1).
Figure 2. Proposed transition states.
dalized, and the enolate presumably twists to relieve A-1,3
interactions between the R-substituents and the ring and syn-
pentane interactions between the R-substituents and R/R′
groups; the imine then approaches from the more accessible
face.12,13 By comparison of the HPLC traces of the authentic
standard with the condensation products of 2a and 2b with
9a, it was possible to determine that the minor isomers
formed in 4% and 3% yield from 2a arise from a small
proportion of the Z-enolate and opposite facial approach of
the imine on the E-enolate, respectively.
A survey revealed that the reaction displays high diaste-
reoselectivity and yields with a variety of amide and imine
substrates (Table 2). A variety of R-substituents are well
tolerated (propyl, benzyl, allyl), each affording good to
excellent diastereoselectivity with both E- and Z-enolates.
The reaction also works well with a series of electron-poor,
electron-rich, heteroaromatic, and R,ꢀ-unsaturated imines.14
The chiral auxiliary could be removed cleanly under two
sets of conditions. The Mannich addition product 16a could
be cleaved directly under reductive conditions using lithium
amidoborohydride to afford protected ꢀ-amino alcohols in
75% yield (Scheme 3).15,16 Alternatively, the N-protected
Figure 1. X-ray crystal structures of 19a (top) and 19b (bottom).
In both instances, the products are consistent with a
Zimmerman-Traxler transition state with approach of the
imine from the back face of the enolate (as drawn in Scheme
1). This sense of facial selectivity is consistent with that
Scheme 3. Chiral Auxiliary Removal
(8) (a) Manthorpe, J. M.; Gleason, J. L. J. Am. Chem. Soc. 2001, 123,
2091. For recent non-reductive alternative approaches, see: (b) Qin, Y.-C.;
Stivala, C. E.; Zakarian, A. Angew. Chem., Int. Ed. 2007, 46, 7466. (c)
Kummer, D. A.; Chain, W. J.; Morales, M. R.; Quiroga, O.; Myers, A. G.
J. Am. Chem. Soc. 2008, 130, 13231.
(9) (a) Manthorpe, J. M.; Gleason, J. L. Angew. Chem., Int. Ed. 2002,
41, 2338. (b) Burke, E. D.; Gleason, J. L. Org. Lett. 2004, 6, 405.
(10) Arpin, A.; Manthorpe, J. M.; Gleason, J. L. Org. Lett. 2006, 8,
1359.
(11) In contrast to our alkylation studies, use of Li/NH3 as reducing
medium did not produce any imine addition products.
(12) Pugh, J. K.; Streitwieser, A. J. Org. Chem. 2001, 66, 1334–1338.
(13) Due to the pseudo-C2-symmetric nature of the enolate auxiliary,
rotation about the enolate C-N bond would produce transition states with
a similar energy difference as those shown in Figure 2.
(14) Addition of the disubstituted enolates to aliphatic imines gave no
identifiable Mannich products.
ꢀ-amino acid may be revealed using a three-step hydrolytic
sequence involving acid-catalyzed N f O acyl transfer,
nitrogen acetylation, and saponification of the resultant amido
(15) Myers, A. G.; Yang, B. H.; Kopecky, D. J. Tetrahedron Lett. 1996,
37, 3623.
Org. Lett., Vol. 11, No. 8, 2009
1727

ester.17 Finally, N-deprotection may carried out by titration
with LiDBB to give the free amine quantitatively (Scheme
4).
of groups on both the enolate and imine functional groups,
and the products can be cleaved to afford ꢀ-amino acid and
ꢀ-amino alcohol products in high yield.
Acknowledgment. The authors thank Boehringer Ingel-
heim Canada Inc. and the Natural Science and Engineering
Research Council (NSERC) for funding for this research.
E.T. acknowledges support from NSERC and FQRNT in the
form of postgraduate scholarships. We thank Vincent Jaz-
eron, Christopher P. Godbout, and Prof. D. Scott Bohle
(McGill Univeristy) for X-ray crystallography.
Scheme 4. Removal of the Sulfonamide Protecting Group
Supporting Information Available: Experimental pro-
cedures and characterization data. This material is available
free of charge via the Internet at http://pubs.acs.org.
In conclusion, we have developed a highly diastereose-
lective method for the formation of quaternary carbon centers
via the Mannich reaction. The method is tolerant of a variety
OL802643K
(16) Reduction does not proceed efficiently on the partially hydrolyzed
prolinol amides 19.
(17) Attempted direct hydrolysis to the carboxylic acid resulted only in
decomposition.
1728
Org. Lett., Vol. 11, No. 8, 2009