Diastereoselective Intramolecular Cyanoamidation with Alkenes

Article abstract of DOI:10.1002/ejoc.201601283

Reported herein is a diastereoselective intramolecular alkene cyanoamidation, wherein high d.r. values are imparted by chiral directing groups. Lactams with an α-all-carbon quaternary stereocenter are readily synthesized, which may enable access to structures frequently found in biologically active molecules and natural products.

Full text of DOI:10.1002/ejoc.201601283

DOI: 10.1002/ejoc.201601283
Communication
Diastereoselective Cyanoamidation
Diastereoselective Intramolecular Cyanoamidation with Alkenes
Ashley M. Dreis,[a][‡] Sadie C. Otte,[a] Matthew S. Eastwood,[a] Elizabeth R. Alonzi,[a]
Jason T. Brethorst,[a] and Christopher J. Douglas*[a]
Abstract: Reported herein is a diastereoselective intramolec- quaternary stereocenter are readily synthesized, which may en-
ular alkene cyanoamidation, wherein high d.r. values are im- able access to structures frequently found in biologically active
parted by chiral directing groups. Lactams with an α-all-carbon molecules and natural products.
Introduction
In particular, cyanoamidation with 1,1-disubstituted alkenes en-
ables efficient formation of all-carbon quaternary stereocenters
The stereoselective formation of all-carbon quaternary centers while forming two new C–C bonds.
is a significant synthetic challenge that is particularly important
Asymmetric construction of ring systems is one achievement
for the synthesis of complex molecules. Cyanoamidation, one of C–CN bond activation methods. Since various therapeutic
of several emerging C–CN bond activation methods, involves alkaloids and/or synthetic drug targets often contain highly-
the activation of a C–CN bond and subsequent addition of the functionalized cyclic amines, C–CN bond activation (e.g., cyano-
cyanoformamide carbonyl and nitrile groups to a double bond. amidation) may be employed to easily streamline the synthesis
Scheme 1. Intramolecular cyanoamidation with alkenes.
of such scaffolds. For example, C–CN bond activation has
[a] Department of Chemistry, University of Minnesota–Twin Cities
proven to be a rapid complexity-building tool, as showcased in
207 Pleasant St. SE, Minneapolis, MN 55155, USA
E-mail: cdouglas@umn.edu
http://www1.chem.umn.edu/groups/douglas/
the total syntheses of esermethole[1,2] and vincorine.[3]
A decade ago, Takemoto[4,5] disclosed the formation of 3,3-
disubstituted oxindoles through intramolecular cyanoamidation
and later developed an asymmetric version of this reaction
(Scheme 1a).[6,7] An aliphatic-tethered alkene derivative
[‡] Current address: Benesch, Friedlander, Coplan, & Aronoff LLP,
41 South High Street, Suite 2600, Columbus, OH 43215, USA
Supporting information and ORCID(s) from the author(s) for this article are
available on the WWW under http://dx.doi.org/10.1002/ejoc.201601283.
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Communication
(Scheme 1b) did not cyclize with the same efficiency as the ratory.[12] Therefore, we began our studies on diastereoselective
aromatic-tethered substrates.[7] High levels of stereocontrol cyanoamidations with chiral N-benzyl and N-naphthyl deriva-
have been limited to cyanoamidation reactions that form ox-
indoles. However, intramolecular cyanoamidation with ali-
phatic-tethered alkynes to give α-alkylidene lactams was suc-
cessful.[1]
tives.
Cyanoformamide 1a was heated to 130 °C in the presence
of Pd2dba3, triphenylphosphine, and triphenylborane for 48 h,
which resulted in full consumption of the starting material 1 to
the desired piperidinone product 2a. The d.r. of the reaction
was determined to be 3.8:1 (Table 1, entry 1). We were encour-
aged because this selectivity was achieved in the absence of a
chiral catalyst; the chiral directing group alone was sufficient to
impart diastereoselectivity. Other achiral phosphine ligands
were examined in order to probe their stereoelectronic effects.
Ligand parameters such as cone angle and electron-donating
ability did not appear to significantly influence the reaction and
we were unable to make correlations between the ligand struc-
ture and the stereoselectivity (entries 2–4). Decreasing the tem-
perature resulted in only 67 % consumption of 1 (as deter-
mined by the ratio of 1:2 in the 1H NMR) and did not affect the
diastereoselectivity (entry 5).
Herein, we report the first catalytic diastereoselective cyano-
amidation of cyanoformamides with aliphatic-tethered alkenes
(Scheme 1c). A facile synthesis of lactams bearing an α-all-
carbon quaternary stereocenter is achieved. The high stereo-
selectivity is attributed to the strategic placement of a chiral
directing group, which is an underutilized strategy in metal-
catalyzed transformations. Our approach reduces the depend-
ency on synthetically complex or expensive chiral ligands. Fur-
ther, we expand the scope of lactams that can be prepared by
stereoselective cyanoamidation, which should further broaden
its utility in the synthesis of complex molecules.
Results and Discussion
Chiral phosphoramidite ligands were added to the reactions
in an attempt to enhance the stereoselectivity. Ligands 4–6 had
been reported by Takemoto et al.[7] as being effective in the
enantioselective synthesis of oxindoles through cyanoamid-
ation. Reaction of 1a with ligand 4 provided 2a with a d.r. of
1:1.6, in favor of the minor diastereomer that was obtained
when achiral phosphine ligands were employed (entries 1–5 vs.
We have discovered that N-benzyl protected aliphatic-tethered
alkenylcyanoformamide derivatives successfully undergo
cyanoamidation in the presence of Lewis acids.[8] Previous work
suggests that Lewis acids effectively promote C–CN bond acti-
vation reactions in other contexts;[9–11] mechanistic studies re-
garding this effect in cyanoamidation are ongoing in our labo-
Table 1. Optimization of diastereoselective cyanoamidation to form α,α-disubstituted δ-lactams.
Product
Ligand
Temp
[°C]
Consumption
of 1
Product
ratio 2/3
d.r.[a]
1
2
3
4
5
6
7
8
2a
2a
2a
2a
2a
2a
2a
2b
2b
2c
2c
2c
2c
PPh3
P(o-tol)3
PPh2Me
PCy3
PCy3
4
5
6
7
PPh3
4
5
7
130
130
130
130
110
130
130
130
130
130
130
130
130
100 %
100 %
100 %
100 %
67 %
100 %
100 %
100 %
100 %
100 %
100 %
100 %
100 %
1:0
1:0
1:0
1:0
3.8:1
2.6:1
3.1:1
3.4:1
3.4:1
1:1.6
6.3:1
8.1:1
8.7:1
4.1:1
10.2:1
2.3:1
8.3:1
1:0
1.5:1
7.2:1
14.6:1
1:0
9
10
11
12
13
1:0
1.5:1
2.3:1
1:0
[a] Determined by quantitative 1H NMR spectroscopy.
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Communication
entry 6). In addition, a new byproduct 3a was observed in a reaction without a chiral ligand (entry 1 vs. 6). A diastereomer
ratio of 1.5:1, 2a:3a. The five-membered lactam 3a, being void of ligand 6, ligand 7, did not significantly affect the diastereo-
of a nitrile and including an exocyclic olefin, likely formed selectivity of the reaction (entry 7).
through 1) isomerization of the olefin, 2) migratory insertion of
Table 2. Optimization of diastereoselective cyanoamidation to form 3,3-disub-
stituted γ-lactams.
the C–C bond across the gem-dimethyl olefin, and 3) ꢀ-hydride
elimination to release HCN.[12] We hypothesized that a sub-
strate-ligand stereochemical mismatch between 1a and 4 may
have been responsible for the observed change in diastereo-
selectivity and chemoselectivity. Accordingly, we prepared the
enantiomer of ligand 4. As expected, ligand 5 (ent-4) gave an
increased d.r. of 6.3:1 and formation of byproduct 3a decreased
(7.2:1, 2a:3a; entry 7). Introducing methyl substituents on the
1,1′-bi-2-naphthol (BINOL) backbone (ligand 6) further im-
proved the diastereo- and chemoselectivity. In order to pre-
serve the matched relationship between ligand and substrate,
we investigated the enantiomer of 1a (1b, ent-1a) in the reac-
tion with ligand 6; product 2b was obtained in a d.r. of 8.1:1
along with 3b in a ratio of 14.6:1 (entry 8). A diastereomer of
ligand 6, ligand 7, further raised the d.r. to 8.7:1 and byproduct
3b was not observed (entry 9).
Product Catalyst
Ligand Additive
Consumption of 1 d.r.
1
2
3
4
5
6
7
8
9
1d
1e
1e
1d
1d
1d
1d
1e
1e
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd2dba3
Pd2dba3
Pd2dba3
Pd2dba3
Pd2dba3
Pd2dba3
none
BPh3
BPh3
none
BPh3
BPh3
BPh3
BPh3
BPh3
BPh3
100 %
100 %
100 %
100 %
100 %
100 %
100 %
100 %
100 %
2:1
none
1.9:1
1.1:1
1.7:1
1.3:1
2:1
1.8:1
1.7:1
1.7:1
none
4
5
6
7
6
7
We next prepared substrate 1c, which contains the bulkier
(S)-naphthyl(ethyl) directing group. In the presence of an achiral
catalyst, product 2c was formed selectively as a 4.1:1 mixture
of diastereomers (entry 10). Therefore, the inherent selectivity
for the naphthyl(ethyl) directing group is comparable to the
phenyl(ethyl) analogue. Reaction of 1c in the presence of the
catalyst produced from Pd2dba3 and ligand 4 gave product 2c
in the highest d.r. observed in this study (10.2:1); however, a
significant amount of byproduct 3c was also formed (1.5:1,
2c:3c; entry 11). Ligand 5, the enantiomer of 4, resulted in a
significant decrease of the d.r. (2.3:1, entry 11 vs. 12). These
results suggest that ligand 5 is mismatched with 1c whereas
ligand 4 is matched with 1c. Unlike the phenyl substrate 1a,
the naphthyl substrate 1c favored the same diastereomer with
both matched and mismatched ligands (entries 6 and 7 vs. en-
tries 11 and 12). Ligands 4 and 5 were not able to override the
stereochemical influence of the naphthyl group in 1c, unlike
the reactions with 1a. While the naphthyl group of 1c induces
lower chemoselectivity than the analogue phenyl group of 1a
in the matched cases (entry 7 vs. 11), it induces higher chemo-
selectivity in the mismatched cases (entry 6 vs. 12). Reaction of
1c in presence the larger ligand 7 resulted in complete suppres-
sion of byproduct formation and an 8.3:1 d.r. (entry 13).
The increased steric bulk of naphthyl analogue 1e did not
improve the selectivity in the presence of chiral ligands, and
diastereomeric BINOL ligands 6 and 7 both gave 2e with a d.r.
of 1.7:1. This suggests that the relative stereochemistry of the
amine moiety of the ligand does not heavily influence the
stereochemical outcome (entries 8 and 9). A preliminary sub-
strate scope was explored (Table 3). Cyanoformamides 1f–1h
were subjected to Pd(dba)2, BPh3, ligand 7, and toluene at
130 °C for 48 h. The reaction tolerated ethyl substitution to
provide δ-lactam 2f in 61 % isolated yield and gave a d.r. of
approximately 6:1. The reaction was less effective with the iso-
propyl-substituted substrate; δ-lactam 2g was prepared in 38 %
isolated yield and a d.r. of approximately 5:1. The d.r. was
Table 3. Substrate scope of diastereoselective cyanoamidation.
With these promising results for synthesizing δ-lactams in
hand, we turned our attention to γ-lactams. Subjection of
cyanoformamide 1d to Pd(PPh3)4 yielded the desired γ-lactam
2d as a 2:1 mixture of diastereomers (Table 2, entry 1). The
corresponding naphthyl substrate 1e reacted under identical
conditions to provide 2e in similar diastereoselectivity (entry 2).
Interestingly, the omission of BPh3 diminished the diastereo-
selectivity (entry 2 vs. 3). Surprisingly, replacing Pd(PPh3)4 with
Pd2dba3 and chiral ligand 4 or its enantiomer 5 resulted in a
lower d.r. for the reaction of 1d (entries 4 and 5). Because the
d.r. was slightly higher with PPh3 than with chiral phosphor-
amidites 4 and 5, we suggest that matched/mismatched effects
are no longer operative. Substitution of the BINOL backbone in
ligand 6 provided a stereoselectivity comparable to that of the
[a] Conditions: Pd(dba)2 (0.08 equiv.), BPh3 (1 equiv.), 7 (0.16 equiv.), toluene
(130 °C), 48 h. [b] Single diastereomer detected by 1H NMR spectroscopy. [c]
Conditions: Pd(PPh3)4 (0.08 equiv.), BPh3 (1 equiv.), toluene (130 °C), 48 h. [d]
Incomplete conversion.
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Communication
slightly lower in both cases in comparison to the d.r. obtained cases the selectivity could be further enhanced by using chiral
for the methyl analogue. Unfortunately, cyanoformamide 1h ligands, which revealed matched/mismatched relationships
bearing an allylic benzyloxy group provided δ-lactam 2h in only with the different directing groups on the cyanoformamide
5 % isolated yield, albeit in a d.r. of > 20:1. The mass balance substrates. This strategy was effective for the stereocontrolled
was a complex mixture of other products.[13] Although ε-lactam synthesis of lactams bearing α-all-carbon quaternary stereocen-
2i was not observed when cyanoformamide 1i was subjected ters.
to the reaction conditions, cyanoformamide 1j was successfully
transformed to ꢀ-lactam 2j with modest conversion and 43 %
Acknowledgments
isolated yield. However, the cyclization to form ꢀ-lactam 2j was
not stereoselective. It is interesting to note that even with our
limited sample size, it was observed that the d.r. increased with
ring size, as our best results were obtained with the six-mem-
bered ring products.
This work was funded by the National Institute of Health (R01
GM095559). NMR spectra were recorded on an instrument pur-
chased with support from the National Institute of Health (S10
OD011952). E. R. A. thanks the University of Minnesota for sup-
port through the Undergraduate Research Opportunities Pro-
gram (UROP) award. We also thank Dr. Letitia Yao (UMN) for
NMR assistance and Zhongda Pan (UMN) for constructive con-
versations and purification of chemical reagents.
Products 2a–2g and 2j were obtained in isolated yields be-
tween 28 and 61 %. The major diastereomer of piperidinone
2a was obtained by medium pressure liquid chromatography
(MPLC). Although we were able to obtain the major diastereo-
mer of piperidinone 2b by MPLC, we succeeded to isolate the
minor diastereomer by semi-preparative HPLC. Isolation and
separation of the five-membered ring products 2d and 2e was
achieved with simple flash chromatography. Semi-preparative
HPLC was required to separate the diastereomers of lactam 2f,
2g, and 2j after initial purification by flash column. Successful
reactions on a 100 mg scale were accomplished for three differ-
ent ring sizes; yields and diastereomeric ratios were similar to
those reported for the smaller scale reactions [compare δ-
lactam 2a (entry 9, Table 1); γ-lactam 2e (entry 2, Table 2); ꢀ-
lactam 2j (Table 3)].
Keywords: Cyanoamidation · Diastereoselectivity · Bond
Activation · Palladium · Homogeneous catalysis
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Optimization for removal of the directing group is ongoing
in our laboratory. Preliminary results with 2a suggest that oxid-
ation with ceric ammonium nitrate may selectively cleave the
directing group from the nitrogen atom.[14] Along these lines,
we may pursue the use of other directing groups and Lewis
acids in the future.
[10] B. D. Swartz, N. M. Reinartz, W. W. Brennessel, J. J. García, W. D. Jones, J.
Am. Chem. Soc. 2008, 130, 8548–8554.
[11] Y. Nakao in C–C Bond Activation, Topics in Current Chemistry (Ed. G. Dong),
Springer, Berlin, 2014, vol. 346, pp. 33–58.
Conclusions
[12] J. M. Ogilvie, N. A. Serratore, G. B. Frost, C. J. Douglas, Manuscript in
Preparation.
[13] One side-product was isolated (3h; see Supporting Information). The
side product 3h resulted from the substitution of the benzyloxy group
for a phenyl group. Upon increasing the BPh3 loading to 2.0 equiv., 3h
became the major product over 2h.
Diastereoselective cyanoamidation with aliphatic-tethered alk-
enes to provide δ-, γ-, and ꢀ-lactams bearing α-all-carbon qua-
ternary stereocenters was accomplished by using a chiral direct-
ing group with both chiral and achiral catalysts. By using an
achiral catalyst, we determined that the directing group alone
imparted diastereoselectivity. Our results indicate that the tri-
phenylborane affects the diastereoselectivity in some reactions,
but we do not have a mechanistic explanation yet as to how
Lewis acids impact the diastereo-determining step. In some
[14] L. N. Gautam, Y. Su, N. G. Akhmedov, J. L. Petersen, X. Shi, Org. Biomol.
Chem. 2014, 12, 6384–6388.
Received: October 13, 2016
Published Online: ■
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Communication
Diastereoselective Cyanoamid-
ation
A. M. Dreis, S. C. Otte,
M. S. Eastwood, E. R. Alonzi,
J. T. Brethorst, C. J. Douglas* ......... 1–5
Diastereoselective
Cyanoamidation with Alkenes
Intramolecular
Lactams with an α-all-carbon quater- molecular alkene cyanoamidation,
nary stereocenter are synthesized wherein high d.r. values are imparted
through
a diastereoselective intra- by chiral directing groups.
DOI: 10.1002/ejoc.201601283
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