Diastereoselective control of intramolecular aza-Michael reactions using achiral catalysts

Article abstract of DOI:10.1021/ol202276h

An intramolecular aza-Michael reaction with a Cbz carbamate and an enone is reported to result in 3,5-disubstituted nitrogen-containing heterocycles. Either cis or trans isomers were obtained selectively using chiral substrates and an achiral Pd (II) comp

Full text of DOI:10.1021/ol202276h

ORGANIC
LETTERS
2011
Vol. 13, No. 20
5556–5559
Diastereoselective Control of
Intramolecular Aza-Michael Reactions
Using Achiral Catalysts
Cheng Zhong, Yikai Wang, Alvin W. Hung, Stuart L. Schreiber, and
Damian W. Young*
Chemical Biology Program, Broad Institute of Harvard and MIT, 7 Cambridge Center,
Cambridge, Massachusetts 02142, United States, and Department of Chemistry and
Chemical Biology, Harvard University, 12 Oxford Street, Cambridge, Massachusetts
02138, United States
dyoung@broadinstitute.org
Received August 24, 2011
ABSTRACT
An intramolecular aza-Michael reaction with a Cbz carbamate and an enone is reported to result in 3,5-disubstituted nitrogen-containing
heterocycles. Either cis or trans isomers were obtained selectively using chiral substrates and an achiral Pd (II) complex or strong Brønsted acid
catalysis. A range of substrates undergoes these selective transformations. Functionalization of the resulting products yielding bicyclic
heterocycles is also demonstrated.
Stereochemical diversity is a useful feature of compound
libraries since it can yield stereochemical structureꢀactiv-
ity relationships.1 The introduction of stereogenic elements
within a chiral substrate has been catalyzed selectively to
provide either diastereomer in a number of studies.2 How-
ever, chiral catalyst-based control of diasteroselectivity
is often challenging due to the difficulty of overcom-
ing the intrinsic stereochemical preference of the chiral
substrates. Here, we describe the use of achiral transition-
metal- and Brønsted acid-based catalysts in intramolecular
aza-Michael reactions that yield either cis- or trans-disub-
stituted nitrogen-containing heterocycles.
(1) (a) Spiegel, D. A.; Schroeder, F. C.; Duvall, J. R.; Schreiber, S. L.
J. Am. Chem. Soc. 2006, 128, 14766. (b) Marcaurelle, L. A.; Comer, E.;
Dandapani, S.; Duvall, J. R.; Gerard, B.; Kesavan, S.; Lee, M. D., IV;
Liu, H.; Lowe, J. T.; Marie, J.-C.; Mulrooney, C. A.; Pandya, B. A.;
Rowley, A.; Ryba, T. D.; Suh, B.-C.; Wei, J.; Young, D. W.; Akella,
L. B.; Ross, N. T.; Zhang, Y.-L.; Fass, D. M.; Reis, S. A.; Zhao, W.-N.;
Haggarty, S. J.; Palmer, M.; Foley, M. A. J. Am. Chem. Soc. 2010, 132,
16962. (c) Hung, A. W.; Ramek, A.; Wang, Y.; Kaya, T.; Wilson, J. A.;
Clemons, P. A.; Young, D. W. Proc. Natl. Acad. Sci. U.S.A. 2011, 108,
6799.
Figure 1. Diastereoselective intramolecular aza-Michael addition.
(2) For representative examples, see: (a) Evans, D. A.; Clark, J. S.;
Metternich, R.; Novack, V. J.; Sheppard., G. S. J. Am. Chem. Soc. 1990,
112, 866. (b) Potuzak, J. S.; Moilanen, S. B.; Tan., D. S. J. Am. Chem.
Soc. 2005, 127, 13796. (c) Balskus, E. P.; Jacobsen., E. N. Science. 2007,
317, 1736. (d) Guo, H.; Dong, C.-G.; Kim, D.-S.; Urabe, D.; Wang, J.;
Kim, J. T.; Liu, X.; Sasaki, T.; Kishi., Y. J. Am. Chem. Soc. 2009, 131,
15387.
The aza-Michael reaction has been used for CꢀN bond
formation in the preparation of a variety of biologically
active small molecules.3 Enantioselective syntheses pro-
moted by organocatalysts and transition-metal complexes
r
10.1021/ol202276h
Published on Web 09/14/2011
2011 American Chemical Society

have been extensively studied.4 The intramolecular aza-
Michael reaction has also been useful, yielding natural
products and pharmaceutically relevant nitrogen-containing
heterocyclic small molecules.5 While the catalytic enantiose-
lective aza-Michael reaction has been demonstrated, the
diastereoselective variant yielding one or the other of two
possible stereoisomers is less common. A common strategy
entails treating chiral substrates with chiral catalysts.6 Anti-
podes of the catalyst can, in principle, yield either diastereoi-
somer via “matched” or “mismatched” pathways7 (Figure1).
An alternative approach is the use of distinct achiral catalysts
to access different diastereoisomers through distinct mechan-
istic pathways.2a,b
L-phenylalinol.9 We initially investigated reported methods
of intramolecular aza-Michael reactions.10 Strong Lewis
acids such as BF3 OEt2 led to decomposition of the
3
starting material (Scheme 1A). Organocatalysts includ-
ing chiral proline derivatives and cinchona alkaloids were
also examined. Although these catalysts were reported to
be effective for enal electrophiles with high enantioselec-
tivity, no product formation was observed for the enone
substrate 1a (Scheme 1B). Under basic conditions using
KO-t-Bu (1.0 equiv), 3,5-disubstituted morpholine 2a was
obtained in 54% yield and a moderate 2:1 dr, favoring
the cis isomer; however, decomposition was also detected
(Scheme 1C).
Studies performed by Spencer,11 Kobayashi,12 and
others13 demonstrate that transition-metal complexes can
catalyze intermolecular aza-Michael reactions. When
(MeCN)2PdCl2 (0.1 equiv) was used in dry DCM, Michael
addition was achieved in 5 h in 89% yield. Moreover, the
diastereoselectivity increased to 93:7, favoring the cis iso-
mer (Scheme 1D). Although we imagined that the trans
isomer might be obtained by applying chiral ligands to
palladium(II), this proved not to be the case. Chiral
phosphine ligands14 (BINAP, “Trost ligand”) significantly
diminished the rate of the reaction (Scheme 2E), and
pyridine ligands15 (BOX, PyBOX) promoted no more than
15% conversion over 48 h at room temperature (Scheme 1F).
The Pd(II) chiral counteranion strategy16 was also examined
without encouraging results (Scheme 1G).
Scheme 1. Intramolecular Aza-Michael Addition of an Amino
Alcohol Derived Carbamate-Tethered Enone8
The mechanism of Pd(II) complex catalyzed aza-Michael
reactions may involve enone activation by either a Pd(II)
species11,13 or a proton resulting from hydrolysis of the
transition-metal complex.17 Indeed, strong Brønsted acids
are known to catalyze aza-Michael reactions and are superior
to Pd(II) complexes in some cases.18 Prior to testing chiral
Brønsted acids (thioureas,19 chiral phosphoric acids,20 and
chiral N-triflylphosphoramides21) (Scheme 2A), we per-
formed a control experiment using triflic acid (TfOH). To
our surprise, a catalytic amount of TfOH (0.1 equiv) in
DCM provided 2a in 93% yield in 15 min with reversed
diastereoselectivity (cis/trans 15:85) (Scheme 2B) in relation
to Pd(II) catalysis (cis/trans 93:7). Lowering the tempera-
ture to ꢀ20 °C resulted in improved diastereoselectivity (cis/
trans 9:91) (Scheme 2C). Thus, different achiral catalysts
Our investigation started from the Cbz carbamate-
tethered enone 1a, which was easily prepared from
(3) For recent reviews on asymmetric aza-Michael reactions, see: (a)
Xu, L.-W.; Xia, C.-G. Eur. J. Org. Chem. 2005, 633. (b) Enders, D.;
Wang, C.; Liebich, J. X. Chem.;Eur. J. 2009, 15, 11058. For β-amino
acid synthesis, see: (a) Enantioselective Synthesis of β-Amino Acids;
Juaristi, E., Ed.; Wiley-VCH: New York, 1997. (b) Liu, M.; Sibi, M. P.
Tetrahedron 2002, 58, 7991. For related natural product related reviews,
see: (a) Cardillo, G.; Tomassini, C. Chem. Soc. Rev. 1996, 117.
(4) For recent organocatalysis examples, see: (a) Chen, Y. K.;
Yoshida, M.; MacMillan, D. W. C. J. Am. Chem. Soc. 2006, 128,
9328. (b) Lu, X.; Deng, L. Angew. Chem., Int. Ed. 2008, 47, 7710. (c)
Cai, Q.; Zheng, C.; You, S.-L. Angew. Chem., Int. Ed. 2010, 49, 8666.
For recent examples of transition-metal catalysis, see: (d) Myers, J. K.;
Jacobsen, E. N. J. Am. Chem. Soc. 1999, 121, 8959. (e) Palomo, C.;
(11) Gaunt, M. J.; Spencer, J. B. Org. Lett. 2001, 3, 25.
(12) Kobayashi, S.; Kakumoto, K.; Sugiura, M. Org. Lett. 2002, 3,
1319.
ꢀ
Oiarbide, M.; Halder, R.; Kelso, M.; Gomez-Bengoa, E.; Garcıa, J. M.
J. Am. Chem. Soc. 2004, 126, 9188.
(13) (a) Reiter, M.; Turner, H.; Gouverneur, V. Chem.;Eur. J. 2006,
12, 7190. (b) Ozawa, F.; Yoshifuji, M. Dalton Trans. 2006, 4987.
(14) (a) Miyashita, A.; Yasuda, A.; Takaya, H.; Toriumi, K.; Ito, T.;
Souchi, T.; Noyori, R. J. Am. Chem. Soc. 1980, 102, 7932. (b) Trost,
B. M.; Fandrick, D. R.; Dinh, D. C. J. Am. Chem. Soc. 2005, 127, 14186.
(15) For a review, see: Ghosh, A. K.; Mathivanan, P.; Cappiello, J.
Tetrahedron: Asymmetry 1998, 9, 1.
(16) For example, see: Mukherjee, S.; List, B. J. Am. Chem. Soc. 2007,
129, 11336.
(17) Wabnitz, T. C.; Yu, J. Q.; Spencer, J. B. Chem.;Eur. J. 2004, 10,
484.
(5) (a) Takasu, K.; Maiti, S.; Ihara, M. Heterocycles 2003, 59, 51. (b)
Bandini, M.; Eichholzer, A.; Tragni, M.; Umani-Ronchi, A. Angew.
Chem., Int. Ed. 2008, 47, 3238. (c) Rolfe, A.; Young, K.; Hanson, P. R.
Eur. J. Org. Chem. 2008, 5254.
(6) For the most recent example, see: Ying, Y.; Kim, H.; Hong, J.
Org. Lett. 2011, 13, 796.
(7) For review, see: Masamune, S.; Choy, W.; Petersen, J. S.; Sita,
L. R. Angew. Chem., Int. Ed. 1985, 24, 1.
(8) See the Supporting Information for more detailed screening.
(9) See the Supporting Information for detailed syntheses of all the
substrates.
(18) Wabnitz, T. C.; Spencer, J. B. Org. Lett. 2003, 5, 2141.
(19) (a) Xu, H.; Zuend, S. J.; Woll, M. G.; Tao, Y.; Jacobsen, E. N.
Science 2010, 327, 986.
(20) Garcia-Garcia, P.; Lay, F.; Rabalakos, C.; List, B. Angew.
Chem., Int. Ed. 2009, 48, 4363.
ꢀ
ꢀ
(10) For BF3 OEt2 catalysis, see: Fustero, S.; Jimenez, D.; Sanchez-
3
ꢀ
Rosello, M.; del Pozo, C. J. Am. Chem. Soc. 2007, 129, 6700. For
ꢀ
ꢀ
prolinol silylether catalysis, see: Fustero, S.; Jimenez, D.; Moscardo, J.;
ꢀ
Catalan, S.; del Pozo, C. Org. Lett. 2007, 9, 5283. For basic conditions,
see:Sudhakar, N.; Srinivasulu, G.; Rao, G. S.; Rao., B. V. Tetrahedron:
Asymmetry 2008, 19, 2153.
(21) Cheon, C. H.; Yamamoto, H. J. Am. Chem. Soc. 2008, 130, 9246.
Org. Lett., Vol. 13, No. 20, 2011
5557

Table 1. Diastereoselective Intramolecular Aza-Michael
Addition To Achieve Both Cis and Trans Isomersa
Scheme 2. Diastereoselective Intramolecular Aza-Michael Ad-
dition Catalyzed by Brønsted Acid
can switch the diastereomeric preference to yield either cis
or trans 3,5-disubstituted morpholines selectively.22
In order to determine the generality of these findings,
additional chiral substrates were prepared and subjected to
both conditions (Table 1). A variety of substituents on the
amino alcohol was tolerated, providing up to over 10:1
selectivity for both C-5 epimers and favoring either cis or
trans isomers. Subtle differences were observed (comparing
1a, 1b, and 1c), when different enone substituents were
present at the C-5 position of morpholines. Bulky groups
at the C-3 position yielded slightly improved diastereos-
electivity (comparing 1a, 1f, 1h, and 1l). The lowest degree
of selectivity was observed with methyl and methyl ketone
substituents on the C-3 and C-5 positions (1j).
The enal substrate 1d also underwent this reaction,
although with moderate yields and diastereoselectivities.
The R,β-unsaturated ester 1e gave only a trace amount of
product under both conditions, which is likely due to its
nature as a weak Michael acceptor. However, removing
the N-Cbz group promoted the aza-Michael reaction in situ
to give the cis product in a 97:3 ratio. When the serine de-
rivative 1m was examined, Pd(II) catalysis gave moderate
selectivity (cis/trans 62:38), while the TfOH catalysis also
provided predominantly the cis isomer (cis/trans 76:24).
The preparation of nitrogen-containing heterocycles
other than morpholines was also investigated. Different
linkers were installed on the six-membered ring and sub-
jected to the reaction conditions. The results are summarized
in Scheme 3.
Both amino ester 3a and amino amide 3b did not convert
to the expected products under either of the two catalysis
conditions. We determined that the dipeptide 3c is an
effective substrate under both reaction conditions, and
excellent yields were obtained. However, the stereochemi-
cal outcome was different than that observed with other
substrates. The Pd(II) catalyst provided the trans isomer
predominantly (cis/trans 26:74), while the Brønsted acid
catalysis slightly favored the cis isomer (cis/trans 57:43).
Taken together with the results of serine derivatives (1l
and 1m), we rationalize that the extra carbonyl group(s)
may influence the stereochemical outcomes under both
a The relative stereochemistry of both cis and trans isomers were
determined by NOE after Cbz removal and X-ray structure determina-
tion after the following transformations. b Conditions: (A)
(MeCN)2PdCl2 (0.1 equiv), dry DCM (0.1 M), rt, 4ꢀ7 h; (B) TfOH
(0.1 equiv), dry DCM (0.1 M), ꢀ20 °C, 3ꢀ5 h. c Yield of combined
isomers. d dr ratio determined by NMR. e Pd/C, H2, MeOH, rt.
conditions. Substrate 3d gave similar reactivity and stereo-
chemical outcomes as the morpholines under both con-
ditions. The orthogonally protected nitrogens contained
within these piperazine products can be differentially
functionalized.
Sulfide and sulfone linkers were also prepared. Excellent
yield (91%) and selectivity (cis/trans 7:93) were obtained
for sulfide 3e using the TfOH conditions. However, the
Pd(II) complex failed to catalyze the reaction, mainly due
to the strong coordination of sulfur to Pd(II) species. The
reaction of sulfone substrate 3f proceeded with excellent
yield and diastereoselectivity under both Pd(II) and
Brønsted acid catalysis conditions,24 but the Brønsted acid
catalysis also provided the cis isomer as the major product.
(23) See the Supporting Information for the preparation of sub-
strates. The relative stereochemistries were determined by NOE studies
of both cis and trans isomers after removal of the Cbz group.
(24) The stereochemistry of 4f0-cis was confirmed by X-ray analysis.
(22) The mechanistic basis of stereoselectivity is under investigation.
See the Supporting Information for preliminary studies.
5558
Org. Lett., Vol. 13, No. 20, 2011

Scheme 3. Substrate Scope in the Diastereoselective Intramole-
cular Aza-Michael Addition23
Scheme 4. Nitrogen-Containing Bicyclic Heterocycles Synth-
eses
2a0-cis was unreactive, even under forcing conditions. This
is likely due to the syn-pentane-type repulsion between the
benzyl and phenyl. However, 2a0-trans gave the product
6a-trans in high yield and diastereoselectivity. The X-ray
structures of 5a-trans and 6a-trans confirmed their relative
stereochemistries.
In summary, complementary outcomes of diastereose-
lective intramolecular aza-Michael reactions are reported.
A variety of 3,5-disubstituted nitrogen-containing hetero-
cycles were prepared with good to excellent yields in three
synthetic transformations. Both cis and trans isomers were
obtained with excellent diastereoselectivities by using
(MeCN)2PdCl2 and TfOH. Further investigation of the
mechanisms accounting for the opposing diastereoselec-
tivity resulting from these catalysts is underway. This
report emphasizes the effectiveness and efficiency of achir-
al catalysts in controlling diastereoselectivity.
The all-carbon chain substrate 3g demonstrated excellent
reactivity and stereochemical control comparable to the
morpholine substrates. The lower homologue substrate
(3h) showed great conversion, but only moderate diaster-
eoselectivity was observed. Finally, the higher homologue
substrates (3i, 3j) did not provide the cyclized products.
Additional nitrogen-containing bicyclic heterocycles
were also synthesized as a step toward sp3-enriched com-
pound libraries.25 The resulting products of the aza-
Michael reaction are excellent substrates in efforts to
synthesize skeletally and stereochemically diverse com-
pounds for small-molecule screening. After Cbz removal,
morpholine derivative 2a0 was treated with polarized ole-
fins, yielding a bicyclic product (Scheme 4).26 Both 2a0-cis
and 2a0-trans reacted with nitroethene to give high yields
and diastereoselectivities. When β-nitro styrene was used,
Acknowledgment. We acknowledge support of the
NIGMS Centers of Excellence for Chemical Methodology
and Library Development (P50 GM069721). Dr. Shao-
Liang Zheng in the Department of Chemistry and Chemi-
cal Biology in Harvard University is especially appreciated
for contributions involving X-ray crystallography.
Supporting Information Available. Detailed experimen-
tal procedures and compound characterizations. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(25) Clemons, P. A.; Bodycombe, N. E.; Carrinski, H. A.; Wilson,
J. A.; Shamji, A. F.; Wagner, B. K.; Koehler, A. N.; Schreiber, S. L.
Proc. Natl. Acad. Sci. U.S.A. 2010, 107, 18787.
(26) Chen, Y.; Zhong, C.; Petersen, J. L.; Akhmedov, N. G.; Shi, X.
Org. Lett. 2009, 11, 2333.
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5559