Enantioselective mannich reactions with the practical proline mimetic N-(p-dodecylphenylsulfonyl)-2-pyrrolidinecarboxamide

Article abstract of DOI:10.1021/jo8027938

A highly enantioselective and diastereoselective protocol for performing Mannich reactions has been developed by using a p-dodecylphenylsulfonamide-based proline catalyst. This catalyst facilitates the use of common, nonpolar solvents and increased concen

Full text of DOI:10.1021/jo8027938

SCHEME 1. Highly Enantioselective Aldol Reactions
Utilizing a p-Dodecylphenylsulfonamide Proline Mimetic
Enantioselective Mannich Reactions with the
Practical Proline Mimetic N-(p-Dodecylphenyl-
sulfonyl)-2-pyrrolidinecarboxamide
Hua Yang and Rich G. Carter*
Department of Chemistry, Oregon State UniVersity, 153
Gilbert Hall, CorVallis, Oregon 97331
rich.carter@oregonstate.edu
ReceiVed December 22, 2008
The vast majority of examples have employed proline as the
viable organocatalyst for these transformations.4,5 These reac-
tions are typically performed in polar organic solvents,6 such
as DMSO and MeCNsin large part to improve the solubility
of the organocatalyst in the solution. Consequently, a series of
pyrrolidine-based alternatives have been developed which offer
improved solubility profiles.7 Unfortunately, many of these
catalysts are derived from expensive starting materials and/or
are nontrivial to prepare in large quantities. Our laboratory has
recently reported the development of a p-dodecylphenylsul-
fonamide proline derivative 3 that has shown a remarkable
solubility and reactivity profile in nonpolar organic solvents
(Scheme 1).8 This catalyst 3 is readily available from inexpen-
sive starting materials (proline and p-dodecylphenylsulfonic
chloride) and we routinely prepare this catalyst on >40 mmol
scale. As both D- and L-proline are commercially available and
inexpensive, this catalyst system allows ready access to both
enantiomeric series of productssan attribute that the catalysts
derived from 4-hydroxyproline do not share. In this Note, we
disclose the application of this catalyst system to enantioselective
and diastereoselective Mannich reactions.
A highly enantioselective and diastereoselective protocol for
performing Mannich reactions has been developed by using
a p-dodecylphenylsulfonamide-based proline catalyst. This
catalyst facilitates the use of common, nonpolar solvents and
increased concentrations as compared to alternative methods.
A series of syn-selective Mannich reactions is reported,
including the rapid access of R- and ꢀ-amino acids sur-
rogates. The use of the industrially attractive nonpolar
solvents,suchas2-methyl-tetrahydrofuran,isalsodemonstrated.
We first screened the reactivity of imine 6 with a series of
carbonyl-containing nucleophiles (Scheme 2). Using our previ-
ously optimized conditions for the aldol reaction, we were
pleased to find that the syn-selective Mannich product 7 could
be produced from cyclohexanone (5) and imine 6 in excellent
enantio- and diastereoselectivity using catalyst 3 (93% yield,
>20:1 dr, 96% ee). As we8 and others9 have observed, the
addition of water had a beneficial effect particularly on the rate
of the reaction. For example, the Mannich reaction of 5 and 6
performed in the absence of water proceeded at approximately
Mannich reactions occupy an important position in the lore
of organic synthesissowing to their critical importance for the
construction of alkaloids and amino acids structures.1 Conse-
quently, considerable energy has been focused on optimizing
this reaction for enantioselective and diastereoselective pro-
cesses.2 Organocatalysis has proven particularly effective at
constructing these enantioselective ꢀ-amino carbonyl motifs.3
(1) Martin, S. F. Acc. Chem. Res. 2002, 35, 895–904.
(2) EnantioselectiVe Synthesis of Beta-Amino Acids; Juaristi, E., Soloshonok,
V. A., Eds.; Wiley-VCH: Hoboken, NJ, 2005.
(5) For a computational investigation in proline-catalyzed Mannich reactions,
see: (a) Parasuk, W.; Parasuk, V. J. Org. Chem. 2008, 73, 9388–9392. (b)
Allemann, C.; Gordillo, R.; Clemente, F. R.; Cheong, P. H.-Y.; Houk, K. N.
Acc. Chem. Res. 2004, 37, 558–569.
(6) One impressive exception is a series of glycolate imine-derived Mannich
reactions performed in dioxane: Co´rdova, A.; Watanabe, S.; Tanaka, F.; Notz,
W.; Barbas, C. F., III. J. Am. Chem. Soc. 2002, 124, 1866–1867.
(7) (a) Cobb, A. J. A.; Shaw, D. M.; Longbottom, D. A.; Gold, J. B.; Ley,
S. V. Org. Biomol. Chem. 2005, 3, 84–96. (b) Franze´n, J.; Marigo, M.;
Fielenbach, D.; Wabnitz, T. C.; Kjaersgaard, A.; Jørgensen, K. A. J. Am. Chem.
Soc. 2005, 127, 18296–18304. (c) Enders, D.; Grondal, C.; Vrettou, M. Synthesis
2006, 3597–3604. (d) Ibrahem, I.; Co´rdova, A. Chem. Commun. 2006, 1760–
1762. (e) Hayashi, Y.; Urshima, T.; Aratake, S.; Okano, T.; Obi, K. Org. Lett.
2008, 10, 21–24. (f) Kano, T.; Hato, Y.; Yamamoto, A.; Maruoka, K. Tetrahedron
2008, 64, 1197–1203. (g) Pouliquen, M.; Blanchet, J.; Lasne, M. C.; Rouden, J.
Org. Lett. 2008, 10, 1029–1032. (h) Hayashi, Y.; Okano, T.; Itoh, T.; Urushima,
T.; Ishikawa, H.; Uchimaru, T. Angew. Chem., Int. Ed. 2008, 47, 9053–9058.
(8) Yang, H.; Carter, R. G. Org. Lett. 2008, 10, 4649–4652.
(3) For recent reviews, see: (a) Melchiorre, P.; Marigo, M.; Carlone, A.;
Bartolim, G. Angew. Chem., Int. Ed. 2008, 47, 6138–6171. (b) Dondoni, A.;
Massi, A. Angew. Chem., Int. Ed. 2008, 47, 4338–4360. (c) Longbottom, D. A.;
Franckevicius, V.; Kumarn, S.; Oelke, A. J.; Wascholowski, V.; Ley, S. V.
Aldrichim. Acta 2008, 41, 3–11. (d) Verkade, J. M. M.; van Hemert, L. J. C.;
Quaedflieg, P. J. L. M.; Rutjes, F. P. J. T. Chem. Soc. ReV. 2008, 37, 29–41. (e)
Mukherjee, S.; Yang, J. W.; Hoffmann, S.; List, B. Chem. ReV. 2007, 107, 5471–
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(4) For select examples, see: (a) List, B.; Pojarliev, P.; Biller, W. T.; Martin,
H. J. J. Am. Chem. Soc. 2002, 124, 827–833. (b) Notz, W.; Tanaka, F.; Watanabe,
S.-i.; Chowdari, N. S.; Turner, J. M.; Thayumanavan, R.; Barbas, C. F., III. J.
Org. Chem. 2003, 68, 9624–9634. (c) Notz, W.; Watanabe, S.; Chowdari, N. S.;
Zhong, G.; Betancort, J. M.; Tanaka, F.; Barbas, C. F., III. AdV. Synth. Catal.
2004, 346, 1131–1140. (d) Westermann, B.; Neuhaus, C. Angew. Chem., Int.
Ed. 2005, 44, 4077–4079. (e) Hayashi, Y.; Urushima, T.; Tsuboi, W.; Shoji, M.
Nat. Protocols 2007, 2, 113–117. (f) Yang, J. W.; Chandler, C.; Stadler, M.;
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2246 J. Org. Chem. 2009, 74, 2246–2249
10.1021/jo8027938 CCC: $40.75 2009 American Chemical Society
Published on Web 02/04/2009

SCHEME 2. Enantioselective Mannich Reactions with
Imine 6a
SCHEME 3. Three-Component Enantioselective Mannich
Reactionsa
a All reactions were performed at 1 M. Five equivalents of 5 or 19
was used. Dr was determined by 1H NMR of crude reaction mixture. Ee
was determined by chiral HPLC. b Absolute configuration for this product
was not determined.
led to a noticeable decrease in enantioselectivity (92% ee in
DCE vs 75% ee in acetone). Interestingly, with thiopyran-4-
one (10), pyran-4-one (12), and 4-methylcyclohexanone (14),
we found that the use of DMF led to an improvement in
diastereoselectivity for these reactions (e.g., compound 11). We
noticed no impact on enantioselectivity by changing the solvent
choice between DMF and DCE.
Three-component couplings could also be accomplished by
using this protocol (Scheme 3). By using aldehyde 16 and
anilines 17 and 20, the cyclohexanone-derived product 18 and
the ꢀ-amino alcohol 21 could be prepared in excellent enanti-
oselectivity and good syn diastereoselectivity. No water was
added to these experiments as 1 equiv is released during imine
formation. Interestingly, this coupling was highly dependent on
the structure of the imine-forming component. Using R,R-
dimethoxyaldehyde 227e and amine 20 led to a complete reversal
in diastereoselectivitysnow favoring the anti diastereomer in
modest enantioselectivity. Access to anti-selective Mannich
reactions has recently been of considerable interest to the
synthetic community.7b,d,f,g,10
a All reactions were performed at 1 M. Five equivalents of ketone was
1
used. Dr was determined by H NMR of crude reaction mixture. Ee was
determined by chiral HPLC. b Absolute configuration established by
comparison of optical rotation to literature value.
We were also interested in exploring the synthesis of N-Boc-
protected ꢀ-amino aldehydes using an asymmetric Mannich
half the rate (36 h without H2O vs 16 h with H2O). Additionally,
alternate nonpolar solvents such as industrially attractive 2-me-
thyltetrahydrofuran (2-Me-THF) could be substituted with only
slightly reduced yield (93% in DCE vs 85% in 2-Me-THF).
Acetone (8) proved to be a viable substrate in these transforma-
tions. Use of a nonpolar solvent was important to this
transformation as performing the reaction in straight acetone
(10) Secondary amine catalysts: (a) Co´rdova, A.; Barbas, C. F. Tetrahedron
Lett. 2002, 43, 7749–7752. (b) Kano, T.; Yamaguchi, Y.; Tokuda, O.; Maruoka,
K. J. Am. Chem. Soc. 2005, 127, 16408–16409. (c) Mitsumori, S.; Zhang, H.;
Cheong, P. H.-Y.; Houk, K. N.; Tanaka, F.; Barbas, C. F., III. J. Am. Chem.
Soc. 2006, 128, 1040–1041. (d) Zhang, H.; Mifsud, M.; Tanaka, F.; Barbas,
C. F., III. J. Am. Chem. Soc. 2006, 128, 9630–9631. (e) Kano, T.; Hato, Y.;
Maruoka, K. Tetrahedron Lett. 2006, 47, 8467–8469. (f) Ramasastry, S. S. V.;
Zhang, H.; Tanaka, F.; Barbas, C. F., III. J. Am. Chem. Soc. 2007, 129, 288–
289. (g) Dziedzic, P.; Co´rdova, A. Tetrahedron: Asymmetry 2007, 18, 1033–
1037. (h) Zhang, H.; Mitsumori, S.; Utsumi, N.; Imai, M.; Garcia-Delgado, N.;
Mifsud, M.; Albertshofer, K.; Cheong, P. H.-Y.; Houk, K. N.; Tanaka, F.; Barbas,
C. F., III J. Am. Chem. Soc. 2008, 130, 875–886. (i) Zhang, H.; Ramasastry,
S. S. V.; Tanaka, F.; Barbas, C. F., III. AdV. Synth. Catal. 2008, 350, 791–796.
(j) Gianelli, C.; Sambri, L.; Carlone, A.; Bartoli, G.; Melchiorre, P. Angew. Chem.,
Int. Ed. 2008, 47, 8700–8702. For a review of primary amine organocatalysts,
see: (k) Xu, L.-W.; Lu, Y. Org. Biomol. Chem. 2008, 6, 2047–2053.
(9) Water effects in organocatalyzed aldol reactions: (a) Nyberg, A. I.; Usano,
A.; Pihko, P. M. Synlett 2004, 1891–1896. (b) Pihko, P. M.; Laurikainen, K. M.;
Usano, A.; Nyberg, A. I.; Kaavi, J. A. Tetrahedron 2006, 62, 317–328. (c)
Hayashi, Y.; Sumiya, T.; Takahashi, J.; Gotoh, H.; Urushima, T.; Shoji, M.
Angew. Chem., Int. Ed. 2006, 45, 958–961. (d) Aratake, S.; Itoh, T.; Okano, T.;
Nagae, N.; Sumiya, T.; Shoji, M.; Hayashi, Y. Chem. Eur. J. 2007, 13, 10246–
10256. Effects of water on organocatalyzed Mannich reactions: (e) Itoh, T.;
Yokoya, M.; Miyauchi, K.; Nagata, K.; Ohsawa, A. Org. Lett. 2003, 5, 4301–
4304. (f) See also ref 4c.
J. Org. Chem. Vol. 74, No. 5, 2009 2247

SCHEME 4. Synthesis of N-Boc-Protected ꢀ-Amino
SCHEME 5. Synthesis of N-Boc-Protected ꢀ-Amino
Aldehydesa
Ketonesa
a All reactions were performed at 1 M with the ketone as solvent. Dr
was determined by 1H NMR of crude reaction mixture. Ee was determined
by chiral HPLC
SCHEME 6. Large-Scale Example of the Enantioselective
Mannich Reaction
to improve reaction turnover. Both the acetone and cyclohex-
anone-derived products 34-36 could be obtained with this
method.
We have also demonstrated the scalability of this protocol
by performing the Mannich reaction of cyclohexanone (5) and
imine 6 on 100 mmol scale (Scheme 6) in a single 250 mL
round-bottomed flask. In this example, the catalyst loading was
reduced to 15 mol % and the experiment was conducted in
2-Me-THF. We were pleased to observe excellent conversion
to the desired product (81% yield, 97% ee, >20:1 dr). The
catalyst 3 could be easily recovered in 92% yield.
In conclusion, we have developed an enantio- and diaster-
oselective Mannich protocol using the practical and readily
available proline derivative 3. The use of industrially attractive
solvents such as 2-Me-THF has also been shown to be viable.
Further applications of this catalyst 3 will be reported in due
course.
a All reactions were performed at 1 M. Two equivalents of 19 was used.
Dr was determined by 1H NMR of crude reaction mixture. Ee was
determined by chiral HPLC
reaction (Scheme 4). Recent reports of proline-catalyzed
methods for accomplishing these types of transformations have
been published with use of primarily polar aprotic solvents
MeCN and DMF.7c,11 We were pleased to find that we can
perform Mannich reactions in nonpolar solvents on N-Boc
imines using catalyst 3 in excellent enantioselectivity and
diastereoselectivity. Interestingly, CH2Cl2 proved to be a slightly
better solvent for these transformations than DCE in more
challenging examples (e.g., 28). The exact rationale for this
difference is not apparent at this juncture. Additionally, the
inclusion of water in these reactions proved detrimental. We
attribute this behavior to the increased susceptibility of N-Boc-
protected imines to hydrolysis. This transformation appears to
work on a range of substrates. The pyridyl example 32 is
particularly noteworthy as proline gave inferior diastereoselec-
tivity (15:1 dr using catalyst 3 vs 1.2:1 dr using proline) in a
side-by-side comparison. It should be noted that these N-Boc
imines are in general challenging substrates as decomposition
is slowly observed in CH2Cl2 at rt.
Experimental Section
General Procedure for Mannich Reaction with Iminoester
6 in Solvent (20 mol % Catalyst). To a solution of iminoester 67a
(0.125 mmol) and the corresponding ketone (0.625 mmol, 5 equiv)
in the appropriate solvent (DCE, 2-Me-THF or DMF) was added
sulfonamide 3 (10.6 mg, 0.025 mmol) and water (0.125 mmol, 2.3
mg, 1 equiv) at 4 °C or room temperature. After being stirred at
same temperature for the denoted time, the reaction was loaded
directly onto silica gel and was purified by chromatography, eluting
with 10-30% EtOAc/hexanes, to give the corresponding Mannich
product (62-93%).
(2S,1′S)-Ethyl 2-(p-Methoxyphenylamino)-2-(2′-oxocyclohex-1′-
yl)acetate, 7:7a purified by chromatography over silica gel, eluting
with 10-30% EtOAc/hexanes, to give the known amine 7 (in DCE:
35.4 mg, 0.116 mmol, 93%, >20:1 dr; in 2-Me-THF: 32.5 mg,
0.106 mmol, 85%, >20:1 dr). Enantiomeric excess was determined
by chiral HPLC [4.6 × 250 mm Daicel OD column, 92:8 hexanes/
i-PrOH, 1.0 mL min-1, retention times 23.5 (minor) and 25.2
(major)] to be 96% ee: [R]23D -41.3 (c 1.4, CHCl3); 1H NMR (400
This technology could be extended to the synthesis of N-Boc-
protected ꢀ-amino ketones as well (Scheme 5). These reactions
were typically run in a neat solution of the ketone component
(11) (a) Yang, J. W.; Stadler, M.; List, B. Angew. Chem., Int. Ed. 2007, 46,
609–611. (b) Vesley, J.; Rios, R.; Ibrahem, I.; Co´rdova, A. Tetrahedron Lett.
2007, 48, 421–425.
2248 J. Org. Chem. Vol. 74, No. 5, 2009

MHz, CDCl3) δ 6.80 (d, J ) 9.2 Hz, 2H), 6.75 (d, J ) 9.2 Hz,
2H), 4.25 (br s, 1H), 4.21-4.14 (m, 2H), 3.92 (br s, 1H), 3.77(s,
3H), 2.83 (dt, J ) 12.4, 5.2 Hz, 1H), 1.58-2.51 (m, 8H), 1.25 (t,
J ) 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 210.1, 173.5,
153.1, 141.1, 116.1, 114.8, 61.1, 58.1, 55.7, 53.4, 41.9, 29.6, 26.9,
24.8, 14.2.
Large-Scale Preparation of Mannich Product 7. To a solution
of iminoester 6 (20.7 g, 100 mmol) and cyclohexanone 5 (49.0 g,
51.7 mL, 500 mmol, 5 equiv) was added sulfonamide 3 (6.33 g,
15 mmol) and water (1.8 g, 1.8 mL, 100 mmol) at rt. After being
stirred at same temperature for 18 h, the reaction mixture was
filtered, and the solid filtrate 3 (3.24 g, 7.68 mmol) was kept. The
mother liquor was diluted with hexanes (50 mL) and filtered through
a silica gel pad (MTBE-20% MeOH/CH2Cl2) to give Mannich
product 7 (24.7 g, 81 mmol, 81% yield, 97% ee, >20:1 dr) and
recovered catalyst 3 (2.58 g, 6.11 mmol, 92% overall recovery).
General Procedure for Mannich Reaction with N-Boc-Protected
Imine in CH2Cl2 (20 mol % Catalyst). To a solution of N-Boc-
protected imine12 (0.125 mmol) and propionaldehyde 19 (14.5 mg,
0.018 mL, 0.25 mmol, 2 equiv) in CH2Cl2 (0.107 mL) was added
sulfonamide 3 (10.6 mg, 0.025 mmol) at room temperature. After
being stirred at the same temperature, the reaction was loaded
directly onto silica gel and purified by chromatography, eluting with
10-30% EtOAc/hexanes, to give the corresponding Mannich
product (38-71%).
syn-tert-Butyl-(2S)-formyl-(1S)-phenylpropylcarbamate, 25:11a
purified by chromatography over silica gel, eluting with 10-30%
EtOAc/hexanes, to give the known amine 25 (23.4 mg, 0.089 mmol,
71%, 19:1 dr). Enantiomeric excess was determined by chiral HPLC
[4.6 × 250 mm Daicel OD column, 90:10 hexanes/i-PrOH, 1.0
mL min-1, retention times 11.4 (minor) and 14.9 (major)] to be
99% ee: [R]23D -5.5 (c 0.8, CHCl3); 1H NMR (400 MHz, CDCl3)
δ 9.74 (s, 1H), 7.26-7.41 (m, 5H), 5.16-5.21 (m, 2H), 2.89 (br s,
1H), 1.44-1.47 (m, 9H), 1.09 (d, J ) 3.2 Hz, 3H); 13C NMR (100
MHz, CDCl3) δ 203.0, 155.1, 128.8, 127.7, 126.7, 125.8, 80.1, 54.7,
51.6, 28.3, 9.3.
Acknowledgment. Financial support was provided by the
Oregon State University (OSU) Venture Fund. The authors
would like to thank Professor Max Deinzer and Dr. Jeff Morre´
(OSU) for mass spectra data. Finally, the authors are grateful
to Dr. Roger Hanselmann (Rib-X Pharmaceuticals) for his
helpful discussions.
Supporting Information Available: Complete experimental
1
procedures are provided, including H and 13C spectra, of all
new compounds. This material is available free of charge via
the Internet at http://pubs.acs.org.
(12) Wenzel, A. G.; Jacobsen, E. N. J. Am. Chem. Soc. 2002, 124, 12964–
12965.
JO8027938
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