Carbamoyl anion addition to N -sulfinyl imines: Highly diastereoselective synthesis of α-amino amides

Article abstract of DOI:10.1021/ja402647m

Carbamoyl anions, generated from N,N-disubstituted formamides and lithium diisopropylamide, add with high diastereoselectivity to chiral N-sulfinyl aldimines and ketimines to provide α-amino amides. The methodology enables the direct introduction of a carbonyl group without the requirement of unmasking steps as with other nucleophiles. The products may be converted to α-amino esters or 1,2-diamines. Iterative application of the reaction enabled the stereoselective synthesis of a dipeptide. Spectroscopic and computational studies support an anion structure with η² coordination of lithium by the carbonyl group.

Full text of DOI:10.1021/ja402647m

Communication
pubs.acs.org/JACS
Carbamoyl Anion Addition to N‑Sulfinyl Imines: Highly
Diastereoselective Synthesis of α‑Amino Amides
Jonathan T. Reeves,* Zhulin Tan, Melissa A. Herbage, Zhengxu S. Han, Maurice A. Marsini, Zhibin Li,
Guisheng Li, Yibo Xu, Keith R. Fandrick, Nina C. Gonnella, Scot Campbell, Shengli Ma, Nelu Grinberg,
Heewon Lee, Bruce Z. Lu, and Chris H. Senanayake
Chemical Development and Analytical Development, Boehringer Ingelheim Pharmaceuticals, Inc., 900 Ridgebury Road/P.O. Box
368, Ridgefield, Connecticut 06877-0368, United States
S
* Supporting Information
Scheme 1. Conversion of Imines to α-Amino Amides
ABSTRACT: Carbamoyl anions, generated from N,N-
disubstituted formamides and lithium diisopropylamide,
add with high diastereoselectivity to chiral N-sulfinyl
aldimines and ketimines to provide α-amino amides. The
methodology enables the direct introduction of a carbonyl
group without the requirement of unmasking steps as with
other nucleophiles. The products may be converted to α-
amino esters or 1,2-diamines. Iterative application of the
reaction enabled the stereoselective synthesis of a
dipeptide. Spectroscopic and computational studies
support an anion structure with η2 coordination of lithium
by the carbonyl group.
he introduction of carbonyl functionality by umpolung
reagents has been extensively explored over the past several
T
decades.1 The majority of reagents for this purpose require one
or more steps to “unmask” the carbonyl group after an initial
nucleophilic reaction. Less explored are the true carbonyl anions,
in part because of challenges associated with their preparation
and their low stability.2 These species have the advantage of
direct introduction of a carbonyl group without the need for
subsequent unmasking steps. Carbamoyl anions are among the
most stable of the carbonyl anions.3 The first generation of a
additions to imines offer a convenient avenue for synthesizing
structurally diverse chiral α-amino amides.11 Limitations of the
traditional pool of nucleophiles are the requirements for
additional steps to unmask the carbonyl synthon and for
subsequent amide formation by coupling. In addition, many
common nucleophiles (−CN, −CCl3, −CH2NO2) add rever-
sibly and can give low conversions and/or low stereoselectivities
for hindered imine substrates.12 Ellman’s N-tert-butanesulfinyl
(TBS) imines have been shown to be exceptionally versatile
chiral imines for the preparation of amines by addition of
nucleophiles.13 The N-2,4,6-triisopropylphenylsulfinyl (TIPPS)
imines developed by Han and Senanayake have often
demonstrated complementary utility as chiral imines.14 These
two classes of N-sulfinyl imines therefore seemed to be promising
substrates for investigating an asymmetric carbamoyl anion
addition. We report herein the highly diastereoselective addition
of carbamoyl anions, derived from readily available formamides,
to N-sulfinyl imines to provide structurally diverse α-amino
amides.
carbamoyl anion occurred in 1967 when Schollkopf and Gerhart
̈
treated bis(diethylcarbamoyl)mercury with n-BuLi and trapped
the purported diethylcarbamoyllithium with carbonyl electro-
philes as well as MeI and Bu3SnCl.4 In 1973, Banhidai and
Schollkopf demonstrated that carbamoyllithiums can be
̈
generated directly from formamides by deprotonation with
lithium diisopropylamide (LDA), and the resultant anions can be
added to aldehydes and ketones.5 In the same year, Enders and
Seebach reported the analogous reaction of thioformamides to
form thiocarbamoyllithiums.6
Surprisingly, there have been no reports on the use of
carbamoyllithiums in asymmetric reactions, and the addition of
carbamoyllithiums to imines has not been reported either.7
Addition of carbamoyllithiums to chiral imines would provide an
attractive asymmetric route to α-amino amides (Scheme 1). As
the basic subunit of peptides, α-amino amides are of fundamental
importance in biology and chemistry.8 They are also a common
structural feature in many pharmaceutical agents.9 Their
stereocontrolled synthesis has been researched extensively by
numerous methods.10 Protocols based on stereoselective
Exploratory experiments utilized pivaldehyde-derived TBS
imine 1a and TIPPS imine 1b as electrophiles and N,N-
Received: March 14, 2013
© XXXX American Chemical Society
A
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Communication
a
diisopropylformamide as the pronucleophile (Scheme 2). Under
optimal conditions, a solution of 1a and N,N-diisopropylforma-
Table 1. Formamide Addition to N-Sulfinyl Aldimines
Scheme 2. Synthesis of tert-Leucine Amides 2a and 2b
mide (3.1 equiv) in toluene cooled to −78 °C was treated with
LDA (3 equiv).15 After 10 min, HPLC analysis indicated the
consumption of 1a and the formation of the α-amino amide
product 2a as a 98:2 mixture of diastereomers. Following workup
and chromatographic purification, diastereopure 2a was isolated
in 77% yield. When TIPPS imine 1b was employed under the
same reaction conditions, adduct 2b was formed in >99.5:<0.5
diastereomeric ratio and isolated in 82% yield. Single-crystal X-
ray structure analysis of 2b confirmed the relative stereo-
chemistry. Sulfinyl deprotection with HCl in MeOH afforded α-
amino amide hydrochloride salt 3 in high yield without loss of
optical purity. Both 2a and 2b gave the same S enantiomer of 3,
confirming that the (R)-TBS group directed the addition with
the same stereochemistry as the (R)-TIPPS group. The
stereochemistry is consistent with that observed for other
organolithium additions to N-sulfinyl aldimines and can be
explained by an open transition state model.13,16
The scope of the carbamoyl anion addition was first explored
with sulfinyl aldimines (Table 1). The addition of N,N-
dimethylformamide (DMF) anion to TBS imine 1a gave
amide 4a with 93:7 diastereoselectivity (entry 1), while the
addition to TIPPS imine 1b proceeded with 98:2 diastereose-
lectivity (entry 2). The reaction proceeded equally well using
dimethylthioformamide (entry 3), furnishing thioamide 5b in
84% yield with 99:1 diastereoselectivity. Addition of N-
formylmorpholine was effective (entries 4 and 5), which should
prove useful since morpholine amides may undergo controlled
organometallic additions to give ketones.17 The use of enolizable
imines with one (entry 6) or two (entry 7) α-protons was
possible. In the case of sulfinimine 10, optimal conversion was
obtained when the carbamoyllithium was generated first and the
solution of 10 was subsequently added. Reactions of aryl (entries
8−10) and heteroaryl sulfinimines (entries 11 and 12) gave
access to aryl glycinamides. In general, the bulky TIPPS auxiliary
gave slightly higher diastereoselectivities than the TBS auxiliary.
Organometallic additions to sulfinyl ketimines often proceed
with lower selectivity relative to aldimines.13 Nonetheless, the
present reaction worked well for a variety of ketimine substrates
(Table 2). The reaction of ketimine 20 (entry 1) with DMF gave
21 in 78% yield with 98:2 diastereoselectivity. The relative
stereochemistry of 21 determined by X-ray crystal structure
a
Typical reaction conditions: 1 equiv of sulfinimine, 3.1 equiv of
b
formamide, 3 equiv of LDA, PhMe, −78 °C. Isolated yields.
c
Determined by HPLC comparison to authentic diastereomers.
analysis is consistent with the observed stereochemistry for
organolithium additions to N-sulfinyl ketimines.13,18 Other
sterically demanding α-quaternary ketimines reacted to give α-
quaternary β-quaternary amino amides with uniformly high
diastereoselectivities (entries 2−4, 7, and 8). Importantly, these
highly hindered compounds are not readily accessible by other
methods, particularly with high chiral purity. The reaction was
amenable to cyclopropyl- (entry 4), alkenyl- (entry 6), and
alkynyl-substituted (entry 7) ketimines. Enolizable ketimine 28
(entry 5) was reacted with preformed carbamoyl anion to give
adduct 29 in good yield with high diastereoselectivity (97:3).
The reaction of trifluoromethyl TIPPS imine 34 gave CF3-
substituted adduct 35 in 76% yield with >97:3 diastereoselec-
tivity (entry 8).
B
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Journal of the American Chemical Society
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a
CH2Cl2 at room temperature effected intramolecular cyclization
to give the intermediate oxazolone 38, which was opened with
methanol to give ester 39 (91% yield). The mild conditions for
this conversion for such a sterically demanding substrate are
notable. Reduction of 3 with LiAlH4 and subsequent treatment
with HCl gave diamine 40 as its dihydrochloride salt in 77% yield.
Diamine 40 and related compounds have been used as chiral
ligands for asymmetric reactions.20
Table 2. Formamide Addition to N-Sulfinyl Ketimines
Iterative application of the addition reaction enabled the
synthesis of a dipeptide (Scheme 4). Amino amide 3, prepared as
Scheme 4. Stereocontrolled Dipeptide Synthesis
shown in Scheme 2, was sequentially N-formylated and N-
methylated to give 41. Treatment of formamide 41 with LDA in
the presence of TIPPS imine 14 gave dipeptide 42 in 79% yield
with >97:3 dr. The relative stereochemistry of 42 determined by
X-ray crystal structure analysis is consistent with control of the
addition by the sulfinimine auxiliary. This synthesis demonstrates
the power of the methodology as a versatile and highly
stereocontrolled process for peptide construction.
The structure of the carbamoyl anion has historically been
depicted as a C-lithiated anion (44), although an O-lithiated
dialkylamino carbene resonance form (46) has also been
postulated (Scheme 5).4,5 Furthermore, in their ab initio studies
a
Scheme 5. Characterization of the Anion of 43
Typical reaction conditions: 1 equiv of sulfinimine, 3.1 equiv of
b
formamide, 3 equiv of LDA, PhMe, −78 °C. Isolated yields.
c
d
Determined by HPLC comparison to authentic diastereomers. 10.1
e
equiv of DMF, 10.0 equiv of LDA. Stereochemistry was assigned from
f
the X-ray crystal structure. 6.1 equiv of formamide, 6.0 equiv of LDA.
g
1
Determined by H NMR analysis.
The amide moiety of the products could conveniently be
converted to an ester or amine (Scheme 3). The ester conversion
was accomplished by the oxazolone procedure of Heimgartner.19
Deprotection of the sulfinyl group of 21 and subsequent N-
benzoylation afforded diamide 37. Treatment of 37 with HCl in
of formyllithium, Schleyer and Streitweiser found η2 coordina-
tion of Li to be favored.21 The analogous η2 carbamoyl anion
structure (45) is shown canonically as intermediate between 44
and 46. Interestingly, several stable aminooxy carbenes have been
prepared by Alder and co-workers.22 These species showed
characteristic low-field 13C NMR shifts of 262−278 ppm for the
carbenic carbons. We explored the deprotonation of N,N-
diisopropylformamide by low-temperature 13C NMR spectros-
copy with a broad sweep width to ascertain whether any
diagnostic low-field signal characteristic of a carbene such as 46
was generated. To enhance the signal of the key carbonyl carbon,
>99% 13C-labeled 43 was synthesized. Formamide 43 was
deprotonated with t-BuLi at −90 °C, and the 13C NMR spectrum
Scheme 3. Amino Ester or Diamine Synthesis
C
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Communication
was recorded starting at −68 °C.23 A strong signal was observed
at 259.6 ppm. Computational modeling of structures 44−46 at
the B3LYP level of theory with the 6-311G+(d,2p) basis set was
performed using Gaussian 09.24 To preserve the coordinative
saturation of Li, 44, 45, and 46 were coordinated with three, two,
and three molecules of tetrahydrofuran (THF), respectively.25
The calculations showed that among the optimized structures,
η2-coordinated 45 had the lowest free energy. The η1-C−Li
structure 44 was 16.4 kcal/mol higher in free energy, while the
carbenic η1-O−Li structure 46 was 12.2 kcal/mol higher. The
13C chemical shifts of 44−46 were calculated using the individual
gauges for atoms in molecules (IGAIM) method [B3LYP/6-
311G+(d,2p)] within Gaussian 09.24 The calculated shift for η2-
coordinated anion 45 (261.3 ppm) was closest to the observed
shift of 259.6 ppm. The free energy calculations together with the
observed and calculated 13C NMR shifts suggest that the η2-
coordinated structure 45 is the most favored form of the anion.
In summary, we have described the highly diastereoselective
addition of carbamoyl anions to N-sulfinyl aldimines and
ketimines. The process represents the first use of carbamoyl
anions in an asymmetric reaction and the first addition of
carbamoyl anions to imines. The reaction provides simple, atom-
economical, and direct access to diverse chiral α-amino amides
from readily available formamides and either N-tert-butane- or N-
2,4,6-triisopropylphenylsulfinyl imines. Sterically hindered α-
quaternary-β-quaternary α-amino amides not readily available by
other methods are accessible with high diastereoselectivity.
Importantly, the products may be easily converted to α-amino
esters or 1,2-diamines, which further adds to the utility of the
methodology. By iterative application of the reaction, a dipeptide
was prepared with high diastereoselectivity and control of the
new stereocenter by the sulfinyl auxiliary. Finally, 13C NMR and
computational analysis suggested η2 coordination of lithium by
the carbamoyl anion. Further applications of carbamoyl anions in
asymmetric reactions will be reported in due course.
(3) Metallinos, C. Sci. Synth. 2006, 8a, 795.
(4) Schollkopf, U.; Gerhart, F. Angew. Chem., Int. Ed. Engl. 1967, 6, 805.
̈
(5) (a) Banhidai, B.; Schollkopf, U. Angew. Chem., Int. Ed. Engl. 1973,
̈
12, 836. (b) Fraser, R. R.; Hubert, P. R. Can. J. Chem. 1974, 52, 185.
(c) Smith, K.; Swaminathan, K. J. Chem. Soc., Chem. Commun. 1976, 387.
(d) Fletcher, A. S.; Smith, K.; Swaminathan, K. J. Chem. Soc., Perkin
Trans. 1 1977, 1881.
(6) Enders, D.; Seebach, D. Angew. Chem., Int. Ed. Engl. 1973, 12, 1014.
(7) Cunico has described the BF3·OEt2-mediated addition of
carbamoylsilanes to N-alkyl aldimines. See: (a) Chen, J.; Cunico, R. F.
Tetrahedron Lett. 2003, 44, 8025. (b) Chen, J.; Pandey, R. K.; Cunico, R.
F. Tetrahedron: Asymmetry 2005, 16, 941. (c) Cunico, R. F.; Pandey, R.
K.; Chen, J.; Motta, A. R. Synlett 2005, 3157.
(8) Sewald, N.; Jakubke, H.-D. Peptides: Chemistry and Biology, 2nd ed.;
Wiley-VCH: Weinheim, Germany, 2009.
(9) Chatel-Chaix, L.; Germain, M.-A.; Gotte, M.; Lamarre, D. Curr.
Opin. Virol. 2012, 2, 588.
(10) (a) Najera, C.; Sansano, J. M. Chem. Rev. 2007, 107, 4584.
(b) Maruoka, K.; Ooi, T. Chem. Rev. 2003, 103, 3013. (c) Chi, Y.; Tang,
W.; Zhang, X. Rhodium-Catalyzed Asymmetric Hydrogenation. In
Modern Rhodium-Catalyzed Reactions; Evans, P. A., Ed.; Wiley-VCH:
Weinheim, Germany, 2005; pp 1−31.
(11) (a) Wang, J.; Liu, X.; Feng, X. Chem. Rev. 2011, 111, 6947.
(b) Domling, A.; Ugi, I. Angew. Chem., Int. Ed. 2000, 39, 3168.
̈
(c) Enders, D.; Reinhold, U. Tetrahedron: Asymmetry 1997, 8, 1895.
(d) Marques-Lopez, E.; Merino, P.; Tejero, T.; Herrera, R. P. Eur. J. Org.
Chem. 2009, 2401.
(12) Strecker: (a) Liu, L.-J.; Chen, L.-J.; Li, P.; Li, X.-B.; Liu, J.-T. J. Org.
Chem. 2011, 76, 4675. (b) Davis, F. A.; Lee, S.; Zhang, H.; Fanelli, D. L.
J. Org. Chem. 2000, 65, 8704. (c) Avenoza, A.; Busto, J. H.; Corzana, F.;
Peregrina, J. M.; Sucunza, D.; Zurbano, M. M. Synthesis 2005, 575.
(d) Chen, Y.-J.; Chen, C. Tetrahedron: Asymmetry 2008, 19, 2201.
Trichloromethyl: (e) Li, Y.; Cao, Y.; Gu, J.; Wang, W.; Wang, H.; Zheng,
T.; Sun, Z. Eur. J. Org. Chem. 2011, 676. (f) Li, Y.; Zheng, T.; Wang, W.;
Xu, W.; Ma, Y.; Zhang, S.; Wang, H.; Sun, Z. Adv. Synth. Catal. 2012,
354, 308. Aza-Henry: (g) Ruano, J. L. G.; Topp, M.; Lopez-Cantarero,
J.; Aleman, J.; Remuinan, M. J.; Cid, M. B. Org. Lett. 2005, 7, 4407.
(h) Tan, C.; Liu, X.; Wang, L.; Wang, J.; Feng, X. Org. Lett. 2008, 10,
5305.
(13) (a) Robak, M. T.; Herbage, M. A.; Ellman, J. A. Chem. Rev. 2010,
110, 3600. (b) Morton, D.; Stockman, R. A. Tetrahedron 2006, 62, 8869.
(14) (a) Han, Z.; Krishnamurthy, D.; Grover, P.; Fang, Q. K.; Pflum, D.
A.; Senanayake, C. H. Tetrahedron Lett. 2003, 44, 4195. (b) Senanayake,
C. H.; Han, Z.; Krishnamurthy, D. In Organosulfur Chemistry in
Asymmetric Synthesis; Toru, T., Bolm, C., Eds.; Wiley-VCH: Weinheim,
Germany, 2008.
ASSOCIATED CONTENT
* Supporting Information
Procedures, additional data, and complete ref 24 (as SI ref 4).
This material is available free of charge via the Internet at http://
pubs.acs.org.
■
S
(15) (a) Although 3 equiv of nucelophile was employed, lower
stoichiometries were possible for addition of hindered formamides to
aldimines (e.g. 1.5 equiv of 41 enabled complete conversion of 14 to give
42). (b) THF and MTBE are also suitable solvents for the reaction.
(16) Plobeck, N.; Powell, D. Tetrahedron: Asymmetry 2002, 13, 303.
(17) Martin, R.; Romea, P.; Tey, C.; Urpi, F.; Vilarrasa, J. Synlett 1997,
1414.
AUTHOR INFORMATION
Corresponding Author
jonathan.reeves@boehringer-ingelheim.com
Notes
■
The authors declare no competing financial interest.
(18) Cogan, D. A.; Ellman, J. A. J. Am. Chem. Soc. 1999, 121, 268.
(19) Obrecht, D.; Heimgartner, H. Helv. Chim. Acta 1981, 64, 482.
(20) Yu, F.; Hu, H.; Gu, X.; Ye, J. Org. Lett. 2012, 14, 2038.
(21) Kaufmann, E.; Schleyer, P. v. R.; Gronert, S.; Streitweiser, A.;
Halpern, M. J. Am. Chem. Soc. 1987, 109, 2553.
(22) Alder, R. W.; Butts, C. P.; Orpen, A. G. J. Am. Chem. Soc. 1998,
120, 11526.
(23) t-BuLi was used to generate the anion irreversibly and avoid side
reactions from i-Pr2NH.
REFERENCES
■
(1) (a) Corey, E. J. Pure Appl. Chem. 1967, 14, 19. (b) Seebach, D.
Angew. Chem., Int. Ed. Engl. 1969, 8, 639. (c) Evans, D. A.; Andrews, G.
C. Acc. Chem. Res. 1974, 7, 147. (d) Seebach, D.; Kolb, M. Chem. Ind.
(London) 1974, 687. (e) Lever, O. W., Jr. Tetrahedron 1976, 32, 1943.
(f) Grobel, B. T.; Seebach, D. Synthesis 1977, 357. (g) Seebach, D.
̈
Angew. Chem., Int. Ed. Engl. 1979, 18, 239. (h) Martin, S. F. Synthesis
1979, 633. (i) Johnson, J. S. Angew. Chem., Int. Ed. 2004, 43, 1326.
(j) Bugaut, X.; Glorius, F. Chem. Soc. Rev. 2012, 41, 3511.
(24) Frisch, M. J.; et al. Gaussian 09, revision C.01; Gaussian, Inc.:
Wallingford, CT, 2010.
(25) Although monomeric species were employed in these calculations
(2) (a) Narayana, C.; Periasamy, M. Synthesis 1985, 253. (b) Nudel-
man, N. S. In The Chemistry of Double-Bonded Functional Groups; Patai,
S., Ed.; Wiley: Chichester, U.K., 1989; p 799. (c) Najera, C.; Yus, M. Org.
Prep. Proced. Int. 1995, 27, 383. (d) Murai, S.; Iwamoto, K. In Modern
Carbonyl Chemistry; Otera, J., Ed.; Wiley-VCH: Weinheim, Germany,
2000; p 131. (e) Iwamoto, K.; Chatani, N.; Murai, S. J. Org. Chem. 2000,
65, 7944 and references cited therein.
for simplicity, higher aggregates cannot be excluded.
D
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