C-H/C-C Functionalization Approach to N-Fused Heterocycles from Saturated Azacycles

Article abstract of DOI:10.1021/jacs.0c04278

Herein we report the synthesis of substituted indolizidines and related N-fused bicycles from simple saturated cyclic amines through sequential C-H and C-C bond functionalizations. Inspired by the Norrish-Yang Type II reaction, C-H functionalization of azacycles is achieved by forming α-hydroxy-β-lactams from precursor α-ketoamide derivatives under mild, visible light conditions. Selective cleavage of the distal C(sp2)-C(sp3) bond in α-hydroxy-β-lactams using a Rh-complex leads to α-acyl intermediates which undergo sequential Rh-catalyzed decarbonylation, 1,4-addition to an electrophile, and aldol cyclization, to afford N-fused bicycles including indolizidines. Computational studies provide mechanistic insight into the observed positional selectivity of C-C cleavage, which depends strongly on the groups bound to Rh trans to the phosphine ligand.

Full text of DOI:10.1021/jacs.0c04278

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Article
C–H/C–C Functionalization Approach to N-
Fused Heterocycles from Saturated Azacycles
jin su ham, Bohyun Park, Mina Son, Jose B. Roque, Justin
Jurczyk, Charles S. Yeung, Mu-Hyun Baik, and Richmond Sarpong
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.0c04278 • Publication Date (Web): 05 Jul 2020
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C‒H/C‒C Functionalization Approach to N-Fused Heterocycles from
Saturated Azacycles
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Jin Su Ham||, Bohyun Park,‡, † Mina Son,‡, † Jose B. Roque,|| Justin Jurczyk,|| Charles S. Yeung,*# Mu-
Hyun Baik,* †,‡ Richmond Sarpong*||
|| Department of Chemistry, University of California, Berkeley, CA 94720, United States
‡ Department of Chemistry, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 34141,
Republic of Korea
†
Center for Catalytic Hydrocarbon Functionalizations, Institute for Basic Science (IBS), Daejeon 34141, Re-
public of Korea
# Disruptive Chemistry Fellow, Department of Discovery Chemistry, Merck & Co., Inc., 33 Avenue Louis Pasteur,
Boston, MA 02115, United States
ABSTRACT: Herein, we report the synthesis of substituted indolizidines and related N-fused bicycles from simple saturated
cyclic amines through sequential C–H and C–C bond functionalizations. Inspired by the Norrish-Yang Type II reaction, C–H
functionalization of azacycles is achieved by forming α-hydroxy-β-lactams from precursor α-ketoamide derivatives under
mild, visible light conditions. Selective cleavage of the distal C(sp2)–C(sp3) bond in α-hydroxy-β-lactams using a Rh-complex
leads to α-acyl intermediates which undergo sequential Rh-catalyzed decarbonylation, 1,4 addition to an electrophile, and
aldol cyclization, to afford N-fused bicycles including indolizidines. Computational studies provide mechanistic insight into
the observed positional selectivity of C–C cleavage, which depends strongly on the groups bound to Rh trans to the phosphine
ligand.
Introduction
reaction of the resulting enolate with the ketone moiety (see
proposed intermediate 3). Indeed, subjecting a mixture of
the HCl salt of 1 (1•HCl) and t-butyl acrylate (3 equiv) in
methylene chloride to triethylamine (2 equiv) over 6 h
smoothly led to the formation of 4a (70% yield, 72:28 d.r).
As shown in Table 1, this transformation works well for the
small subset of acrylates (see 4b, 4c) and only moderately
for methacrylate derivatives (4d) that were investigated in
a preliminary study. However, despite the seemingly
straightforward nature of this transformation, we quickly
came to recognize several challenges that needed to be
overcome in order to make this process more practical and
widely useful.
Indolizidine-type alkaloids, three examples of which are
shown in Figure 1 (castanospermine, gephyrotoxin and
rhazinilam), display a wide array of biological activity1 in-
cluding, but not limited to, antiviral,2 CNS modulation,3 and
anticancer4 properties. In addition, other N-fused saturated
bicycles, featuring for example an azepane ring, occur in
other bioactive natural products such as the stemona alka-
loid family (see stemoamide) which display antitussive
properties.5
Table 1. Preliminary study of indolizidine bicycle formation
from α-acyl piperidine salt 1.a
Figure 1. Indolizidine and N-fused bicycle-containing nat-
ural products.
As a part of a broad program aimed at a general prepara-
tion of N-fused bicycles,6 we questioned whether the seem-
ingly straightforward addition of α-acyl saturated azacycles
(e.g., 1, Table 1) to activated, electron-deficient alkenes (i.e.,
2) could be employed for this purpose. We anticipated that
under the optimal set of conditions, amphoteric molecules7
such as 1 could be preferentially engaged in a conjugate ad-
dition (aza-Michael addition) with 2 followed by an aldol
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aAll yields reported are isolated yields. Reaction was performed with
1•HCl (0.092 mmol), and acrylate 2 (3 equiv). dr was determined by
functionalization reactions, which continue to emerge, pro-
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vide direct access to synthetically complex products from
readily available precursors.15 We theorized that by com-
bining C–H and C–C bond functionalization reactions under
mild conditions, α-acylations of saturated azacycles could
be achieved, concomitant with the generation of a nitrogen
nucleophile, setting the stage for annulations of saturated
azacycles (Figure 2). Specifically, we envisioned that deri-
vatization of saturated azacycles to α-ketoamides such as 5
would set the stage for a Norrish-Yang Type II reaction16 to
form α-hydroxy-β-lactam 6, which we have shown occurs at
room temperature using blue LEDs (400-450 nm) following
the precedent of Aoyama (Figure 2; see the Supporting In-
formation for details on the preparation of 6 and related α-
hydroxy-β-lactams).17 Here, in order to access α-acyl deriv-
atives, we anticipated that a regioselective C‒C bond cleav-
age of the distal bond of the α-hydroxy-β-lactam (see 7)
could be achieved through Rh-catalyzed β-carbon elimina-
tion, in line with the precedent of Murakami.18 Decarbonyl-
ation19 of the acyl rhodium intermediate, 8, would then lead
to rhodated intermediate 9, which would serve as a func-
tional equivalent to amphoteric molecules such as 1. In this
case, we expected that some level of stabilization may be
achieved through a five-membered chelate (see 9), which
would avoid the deleterious decomposition pathways that
1 undergoes upon forming its free base. With 9 in hand,
binding of an alkene (such as acrylate) followed by conju-
gate addition would lead to an enolate that would undergo
a subsequent intramolecular aldol reaction to furnish func-
tionalized indolizidine 10.
comparison of isolated yields.
Notably, as we sought to expand the scope of the annula-
tion reaction to include other α-acylated saturated hetero-
cycles, we found that their reported preparations involved
multiple steps as outlined in Scheme 1 that would not be
compatible with their generation from a saturated azacycle
precursor, especially at a late stage. For example, as shown
in Scheme 1a, the use of a strong base for the α-lithiation in
the Beak preparation of α-acylated azacycles8 severely lim-
its its generality due to the functional group intolerance of
these conditions.9 This limitation also holds for other ele-
gant emerging methods for α-functionalization of saturated
azacycles that also rely on the use of strong bases.10 Another
reported approach to α-acylated saturated azacycles in-
volves hydrogenation of pyridine rings bearing an -acyl
group, followed by oxidation (Scheme 1b).11 This approach
is limited to the preparation of six-membered saturated
azacycles from a pyridine precursor. As a result, the prior
art for the preparation of α-acylated saturated azacycles is
especially limiting if one seeks to prepare them at a late-
stage from an already resident saturated azacycle such as a
piperidine. Piperidines are especially interesting as starting
materials for derivatization given that they are the most
commonly encountered saturated heterocycle in pharma-
ceuticals, and also feature heavily in numerous agrochemi-
cals.12 A vast array of natural products also possess a piper-
idine nucleus, which would serve as an excellent starting
point for diversification.13
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Scheme 1. Previously reported preparations of α-acylated
piperidines
Figure 2. A C–H/C–C Bond Functionalization approach to
synthesis of N-fused heterocycles from saturated azacycles.
On the basis of these considerations, we envisioned an
approach to N-fused azacycles that would begin with the in-
situ generation of α-acyl saturated azacycles under mild
conditions from saturated azacycles. Additionally, we
sought to couple the formation of these desired α-acyl satu-
rated azacyclic addends with the generation of a N-based
nucleophile that would obviate the need for isolating the
free base of amphoteric molecules such as 1. We hypothe-
sized that these requirements could be met using sequential
C–H and C–C bond functionalization reactions. These trans-
formations could be conducted at a late stage in a synthesis
campaign under mildly basic conditions, broadening the
functional group tolerance of methods to N-fused bicycles.
The direct site-selective functionalization of C–H bonds to
form C–C or C–X bonds represents a powerful approach for
diversification in organic synthesis.14 In addition, C–C
Results and Discussion
Reaction discovery and optimization
Our initial studies to convert α-hydroxy-β-lactams related
to 6 to substituted indolizidine products such as 10 cen-
tered on the hypothesis that by tuning the electronic and
steric properties of the ligand on the Rh metal center, posi-
tional selectivity of the β-carbon elimination could be
achieved by cleaving either the proximal C(sp3)–C(sp3)
bond (highlighted in blue, Figure 2) or the distal C(sp2)–
C(sp3) bond (highlighted in red) to the azacyclic ring. Be-
cause our previous studies have shown that Pd complexes
effect proximal cleavage of α-hydroxy-β-lactams,17 we
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focused on Rh-complexes, which are also known to effect SEGPHOS (Table 3, entry 10) gave mixtures of proximal and
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cyclobutanol openings but could offer opportunities for dif-
ferent binding modes and selectivities.20 The ring opening
of 11a was examined under various reaction conditions as
outlined in Table 2. In the presence of a rhodium complex
such as hydroxy(cyclooctadiene) rhodium(I) dimer (i.e.,
[Rh(COD)OH]2) with potassium carbonate as an exogenous
base at 100 ℃, the desired distal bond cleaved product (12)
was formed, albeit in low yield (Table 2, entry 1). The addi-
tion of phosphine ligands facilitated the ring-opening pro-
cess and led to higher conversions to 12 (Table 2, entry 2).
In the presence of tert-butyl acrylate, the desired indoliz-
idine product (4a) was formed in 73% yield as determined
by NMR (Table 2,entry 3). Triphenyl phosphine proved to
be a ligand that led to higher conversions to 4a (Table 2, en-
try 4). Of note, the addition of water (5 equiv) to the reaction
mixture either prevented cyclization and/or led to a retro-
aldol reaction of the product (4a) and β-elimination, effec-
tively reversing the 1,4-addition reaction and giving a low
yield of 4a (Table 2, entry 5). When the reaction was carried
out at 70 ℃, starting material was recovered (Table 2, entry
6), and on the basis of control experiments, potassium car-
bonate alone did not lead to C–C bond cleavage of 11a (Ta-
ble 2, entry 7).
distal cleavage products (i.e., indolizidine 4a and enamide
13 – the latter resulting from β-hydride elimination of an
alkyl Rh intermediate; Table 3, entry 10). The formation of
4a and 13 using (R)-DTBM-SEGPHOS as a ligand highlights
the importance of not only the nature of the metal, but also
the ligand of the complex in driving the regioselectivity of
the C–C bond cleavage (i.e., proximal versus distal). A com-
prehensive ligand screen carried out using HTE screening
in a collaboration with Merck and Co. confirmed the identi-
fication of Xantphos as the optimal ligand for this process
(see the Supporting Information for more details on the
HTE screen). In order to gain insight into the Rh-catalyzed
regioselective opening of the α-hydroxy-β-lactam, as well as
the overall proposed mechanism, a computational study
was undertaken as described below.
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Table 3. Ligand effects on the ring opening reaction.a
Table 2. Initial screening for ring opening reaction.a
aReaction was performed with lactam 11a (0.092 mmol), ligand (15
mol%). b1H NMR yield using trimethoxybenzene as internal standard.
dr was determined by 1H NMR integration of resonances correspond-
ing to diastereomers in the crude NMR mixture. cDioxane (0.12M) sol-
vent. dK2CO3 was not added.
aReaction was performed with lactam 11a (0.092 mmol) b1H NMR con-
version of 11a using trimethoxybenzene as internal standard. dr was
determined by 1H NMR integration of resonances corresponding to di-
astereomers in the crude NMR mixture. c5 equiv of H2O was added.
Computational studies
Regioselectivity of C–C bond cleavage
With the crucial components for an effective reaction us-
ing Rh-catalysis on -hydroxy--lactam 11a established, we
focused on ligands that would facilitate better conversion
and lead to a more efficient overall process (Table 3). XPhos,
RuPhos, and t-BuDavePhos in combination with
[Rh(OH)(COD)]2 led to the desired distal bond-selective
cleavage. However, the subsequent Rh-catalyzed 1,4-addi-
tion and aldol cyclization reactions were inefficient under
these conditions, resulting in lower overall yields of 4a (Ta-
ble 3, entries 1–3). From our studies, we observed that po-
sition-selective distal C–C cleavage and the subsequent Rh-
catalyzed cascade 1,4-addition/aldol cyclization reaction
was most efficiently achieved using Xantphos as ligand (Ta-
ble 3, entry 7). The yields did not improve when the reaction
solvent was changed from toluene to dioxane (Table 3, en-
try 5, 6). Notably, the ligands DPPE (entry 9) and (R)-DTBM-
Density functional theory (DFT) calculations were per-
formed with Xantphos as the prototypical ligand using aza-
cycle 11a and methyl acrylate as the substrate and electro-
phile, respectively. Figure 3 shows the reaction energy pro-
file starting from the Rh–OH complex (A1) through to the
formation of the indolizidine complex A8, which we pro-
pose to be the final intermediate prior to product release. In
our proposed mechanism, α-hydroxy-β-lactam 11a first
binds to the three-coordinate (Xantphos)Rh(I)-OH complex
A1 to form the four-coordinate adduct A2, which undergoes
dehydration to yield alkoxide intermediate A3dis. The Rh(I)-
center in A3dis can ring-open the β-lactam through electro-
philic attack at the carbonyl-carbon (C2) to cleave the distal
C–C bond or at C4, leading to ring-opening at the proximal
C–C bond.
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Figure 3. Free energy reaction profile of the proposed mechanism.
Our calculations indicate that cleavage of the distal C–C
bond is associated with a barrier of 12.8 kcal/mol, travers-
ing transition state A3dis-TS. The alternative transition state
(A3prox-TS) at a relative energy of 9.3 kcal/mol above the
starting point, leads to a barrier of 18.6 kcal/mol. Thus, our
calculations suggest a kinetic preference of 5.8 kcal/mol for
the ring-opening of the distal C–C bond, which is in good
agreement with the experimental observation that the dis-
tal C–C bond is preferentially cleaved using Xantphos as a
ligand (Table 3, entry 9).
analogs, A3dis and A4dis. The energy difference between
A3dis and A3prox arises from the difference in coordination
of the Rh complex and the resulting electronic structure
(see Figure 4b). Rh complex A3dis has a stable 16 e– four-
coordinate square planar structure. To engage the proximal
C–C bond, however, the rhodium complex has to rearrange
via dissociation of the coordinated lactam-carbonyl to give
the three-coordinate 14 e– complex A3prox, which we found
to be 2.1 kcal/mol higher in energy than A3dis as shown in
red in Figure 3.
To account for the selectivity during the C–C bond cleav-
age, a preliminary computational study was carried out to
analyze the characteristics of the substrate itself. The ani-
onic form of the -hydroxy--lactam (A9–, Figure 4a) was
re-optimized and analyzed using a natural bond orbital
(NBO) calculation. Calculations show that the distal (C1–Cx)
bond is shorter at 1.61 Å and has a higher bond order of 0.89,
compared to the proximal C1–C8a bond, computed to be
1.71 Å long and with a 0.77 bond order. The proximal C–C
bond was therefore expected to be easier to break. Con-
sistent with this expectation, our previous work showed
that Pd complexes selectively cleave the proximal C–C
bond.17, 20 On the basis of this precedent, the Rh-mediated
distal C–C bond cleavage observed here is not consistent
with the inherent substrate selectivity. The proximal C–C
bond breaking was modeled, and the related reactant and
product, A3prox and A4 prox (see Figure 3), are both com-
puted to be higher in energy than the respective distal
On the other hand, the energy difference between the re-
lated products, A4dis and A4prox, results from the different
trans influence of the ligands. Along the reaction coordinate,
the transition state A3dis-TS ultimately leads to a Rh–amide
acyl bond, which imposes a stronger trans influence than
the Rh-alkyl bond that results from traversing A3prox-TS.
The Rh–amide acyl bond in A4dis likely tolerates the strong
trans influence of the phosphine ligand, thus stabilizing the
complex without significant structural change. Analysis of
the electronic structures (Figure 4c) clearly supports this
assertion, as atomic charges on the phosphine centers in
A3dis were computed to be –0.91 and –0.72, whereas those
on the phosphine centers in A4dis were computed to be re-
duced to –0.49 and –0.52, respectively. On the contrary, the
alkyl ligand in A4prox has a weaker trans influence and is,
therefore, less capable of supporting the strongly trans di-
recting phosphine ligand, leading to greater distortion of
A4prox from A3prox. As a result, A4prox adopts a trigonal
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pyramidal structure with the alkyl ligand occupying the ax- and –27.5 kcal/mol, respectively) than the lactam adducts.
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ial position. In this conformation, the substrate cannot ef-
fectively distribute the electron density imparted by the
phosphines, resulting in atomic charges of –0.59 and –0.80
on each phosphine. This also leads to average P–Rh bond
lengths that are 0.06 Å longer in A4dis. In summary, the lig-
and strength difference between the amide acyl and alkyl
groups attached to the Rh-center engenders structural dif-
ferences between A4dis and A4prox, making A4prox 6.4
kcal/mol higher in energy as compared to A4dis. On the ba-
sis of the Hammond postulate,21 A3prox-TS should have a
higher associated barrier compared to A3dis-TS. Because
both C–C bond cleaving steps were computed to be essen-
tially irreversible, the distal C–C bond breaking pathway
should be favored as experimentally observed.
Interestingly, our calculations show that the amide carbonyl
binds in an η2-fashion to the rhodium center, instead of
forming a six-membered metallacycle using the carbonyl
oxygen functionality. In the productive direction, interme-
diate A4dis undergoes decarbonylation19b to form interme-
diate A5 (Figure 3), a piperidine-bound Rh(I)-carbonyl
complex. This step is associated with a barrier of 25.3
kcal/mol, which should be accessible under the experi-
mental conditions employed. Our calculations estimate the
barrier for the liberation of carbon monoxide to be rela-
tively high at 34.6 kcal/mol. Given the low solubility of CO
in the solvents employed,22 the CO release to give three-co-
ordinate Rh(I)-piperidine complex A6 is likely irreversible,
as indicated in Figure 3.
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Diastereoselectivity in the aldol-like cyclization
The final sequence envisioned in the overall annulation to
afford the N-fused bicyclic products consists of a conjugate
addition of the Rh-bound acylpiperidine (A7 or A7’, Figure
5) and methyl acrylate followed by an aldol cyclization to
produce the indolidizine. The phenyl group and the hydro-
gen at the ring-fusion carbon are syn-disposed in the exper-
imentally observed major diastereomer product (A8). Our
calculations show that the conjugate addition and aldol cy-
clizations are concerted and not stepwise processes, pass-
ing through a single transition state (A7-TS at 3.1 kcal/mol)
resulting in a barrier of 17.5 kcal/mol from A6. To rational-
ize the stereochemical outcome of this transformation, we
considered the energetics of the two diastereomeric possi-
bilities, as illustrated in Figure 5. The energetically most fa-
vorable binding of the acylpiperidine is to engage the axial
N-lone pair, leading to intermediate A7.
Alternatively, in A7’ (6.8 kcal/mol higher in energy) the
equatorial N-lone pair binds the metal. This energy differ-
ence is propagated and enhanced in the cyclization transi-
tion states, leading to a kinetic preference of 11.7 kcal/mol
for the experimentally observed diastereomer that arises
from A7. A distortion-interaction analysis was carried out
by dividing the intermediates into [Rh+] and [N–] fragments,
as shown in Figure 5b–e. The structures of metal-containing
A7-[Rh+] and A7’-[Rh+] fragments are almost superimpos-
able (Figure 5c) and unlikely to contribute to the energy dif-
ference. The main factor for the energy difference appears
to be the orientation of the benzoyl moiety in [N–], increas-
ing the distortion in A7' to ~5.7 kcal/mol higher than in A7.
The stronger interaction in A7’ of about 2.0 kcal/mol cannot
compensate for the larger distortion energy and gives a final
electronic energy difference of 3.8 kcal/mol between A7’
and A7. Entropy and solvation energy differences contrib-
ute 3 kcal/mol. Thus, the diastereoselectivity is mainly de-
termined by the orientation of the benzoyl group as the
metal binds the piperidine. Despite the low solubility of the
potassium salts employed in this study in the optimal sol-
vents, a formal cycloaddition reaction involving a potassium
amido generated from A5 and the electron-deficient alkene
coupling partner cannot be ruled out. Further mechanistic
studies are on-going (see the Supporting Information for
details).
Figure 4. (a) Optimized structure of free anionic azacycle,
A9 . Bond orders are obtained from the Mayer-Mulliken
–
bond order calculation implemented in the NBO calculation.
(b) Atomic charge and P–Rh bond length in indicated struc-
tures. Atomic charges are obtained from the electrostatic
potential. (c) Optimized structures of A3dis, A3prox, A3dis-TS,
A4dis, A3prox-TS, and A4prox. White, red, blue, orange and purple
balls represent carbon, oxygen, nitrogen, phosphorus, and
rhodium, respectively. Hydrogen atoms are omitted for
clarity.
Unsurprisingly, the products A4dis and A4prox containing
strong Rh–carbon bonds are much lower in energy (at –33.9
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Fused pyrrole 4o and fused tricycle (epi-4p) were obtained
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by using an electrophilic alkyne (phenyl substituted methyl
propiolate) or cyclopentenone as electrophiles, respectively.
However, when cyclopentenone was used, epi-4p was
formed as the major product presumably due to developing
1,3 diaxial interactions between the cyclopentanone ring
and the ring fusion hydrogen and phenyl groups.
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Table 4. Scope of indolizidine formation with respect to
electrophiles.a
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Figure 5. (a) Free energy profile for determining C1 posi-
tion. (b) Distortion-interaction analysis of 7 and 7’. (c) Over-
lapped structures of A7-[Rh+] and A7’-[Rh+]. Structures of
(d) A7-[N–] and (e) A7’-[N–]. Unimportant hydrogen atoms
are omitted for clarity.
Substrate scope for the N-fused heterocycle formation
Following our computational mechanistic interrogation, the
substrate scope for various electrophiles was investigated
(Table 4). A wide range of α,β-unsaturated carbonyl com-
pounds underwent the Rh-catalyzed cascade reaction to
yield the corresponding indolizidine products. Specifically,
t-butyl-, butyl-, and methyl acrylate, as well as methyl meth-
acrylate underwent the cascade sequence with similar effi-
ciencies (4a–4d). Fluorine-substituted indolizidines (4e)
could be accessed using an α-fluoro substituted acrylate.
When β-substituted electrophiles (e.g., methyl crotonate,
methyl cinnamate, and dimethyl fumarate) were used, only
one diastereomer was observed (4f–4h). Likely, developing
1,3-diaxial interactions in the transition state dictate the di-
astereoselectivity and lead to the high observed dr for al-
kenes bearing substituents at the beta position (see the Sup-
porting Information for more details on a computational
model). Interestingly, indolizidine 4f was obtained by using
methyl 3-butenoate as an electrophile. Presumably, the β,γ-
unsaturated ester underwent base-promoted isomerization
to methyl crotonate prior to reaction with Rh-amido inter-
mediate 9.23 In addition, a diverse array of electrophiles
were viable substrates for this process. A variety of elec-
tron-withdrawing groups including cyanide, amide, ketone,
sulfone, and phosphonate on the electrophile were success-
fully engaged to give the corresponding indolizidines (4i–
4n). Due to the instability and separation challenges associ-
ated with the amide products under the purification condi-
tions (SiO2 or neutral Al2O3), 4j and 4k gave relatively low
isolation yields of the corresponding indolizidine products.
aReaction was performed with lactam 11a (0.092 mmol),
[Rh(OH)(COD)]2 (5 mol%), Xantphos (15 mol%), K2CO3 (1.1 equiv),
acrylates (3 equiv) and toluene (0.11M) at 100 ℃ for 20 h. dr was de-
termined by 1H NMR integration of resonances corresponding to dia-
stereomers in the crude NMR mixture. bDavePhos as ligand. c5 equiv of
electrophiles used. d10 equiv of acrylonitrile used. eNMR yield using tri-
methoxybenzene as internal standard.
We have also investigated the substrate scope with re-
spect to the azacyclic ring of the β-lactams, which were
readily accessed through Norrish-Yang II type reactions
analogous to those employed for the formation of 11a (see
the Supporting Information for details). Morpholine led to
the corresponding fused bicycle 14a, and saturated hetero-
cycles of increasing ring size (azepane and azocane) also
proved competent as substrates to form heterocycles 14b
and 14c. Functionalized piperidines bearing gem-dimethyl
(see 14d), cyclohexyl (14e), 1,3-dioxolane (14f), phenyl
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(14g), and nitrile groups (14i) at C4 also led to the desired (i.e., 17b, 17c, 17i, 17j) may be further diversified through
1
products in moderate to good yields.
cross-coupling.
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Table 5. Scope of indolizidine formation with respect to
Table 6. Scope studies: Functionalization of aromatic ring.a
the azacycle ring size.a
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aReaction was performed with β-lactams (0.092 mmol),
[Rh(OH)(COD)]2 (5 mol%), Xantphos (15 mol%), K2CO3 (1.1 equiv), t-
butyl acrylate (3 equiv) and toluene (0.11M) at 100 ℃ for 20 h. dr was
determined by 1H NMR integration of resonances corresponding to di-
astereomers in the crude NMR mixture. b[Rh(OH)(COD)]2 (10 mol%),
Xantphos (30 mol%) used.
aReaction was performed with β-lactam (0.092 mmol),
[Rh(OH)(COD)]2 (5 mol%), Xantphos (15 mol%), K2CO3 (1.1 equiv), t-
butyl acrylate (3 equiv) and toluene (0.11M) at 100 ℃ for 20 h. dr was
determined by 1H NMR integration of resonances corresponding to di-
astereomers in the crude NMR mixture. bDavePhos as ligand.
Some additional studies that we have conducted provide
even more insight into the proposed mechanism for the Rh-
mediated bicyclizations described here. For example, heat-
ing diastereomeric indolizidines 4a/epi-4a at 100 ℃ under
the reaction conditions (in the presence of rhodium com-
plex [Rh(OH)(COD)]2, base, and tert-butyl acrylate), did not
lead to epimerization at C2, supporting a kinetically-driven
diastereomeric outcome, likely arising from the aldol cy-
clization step (Figure 6a).
Monocyclic β-lactam 15, prepared from linear N,N-diben-
zyl-2-oxo-2-phenylacetamide,24 also underwent C–C bond
cleavage followed by Rh-mediated annulation to afford 16
(with methyl vinyl ketone), albeit in lower yield compared
to that obtained using the bicyclic -hydroxy--lactams
(Scheme 2).
Scheme 2. Pyrrolidine 16 from a monocyclic β-lactam.
We have also explored the effect of varying the position
of substitution on the aromatic group or varying the elec-
tronic properties of the arene group by installing electron-
donating or electron-withdrawing groups.25 In most cases,
electron-rich (17d, 17e) or electron-poor (17f, 17g) aryl
groups on the α-hydroxy-β-lactam substrates gave the de-
sired indolizidine products in similar yields and diastere-
oselectivities. α-Hydroxy-β-lactams bearing halide, meth-
oxy, cyanide, methyl, and trifluoromethyl substituents (Ta-
ble 6) were all competent substrates, providing the corre-
sponding indolizidine products in moderate yields (17a–
17k). Notably, the halide-containing indolizidine products
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Innovation for support of his graduate studies and J. B. R. is
Figure 6. Additional insight into the bicyclization reac-
tion.26 (a) Lack of reversibility of observed diastereoselec-
tivity. (b) One pot indolizidine synthesis.
1
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8
grateful for a BMS graduate fellowship. M.-H. B. acknowledges
support from the Institute for Basic Science (IBS-R10-A1) in
Korea. C.S.Y. is a Merck Disruptive Chemistry Fellow and is
grateful to Shane W. Krska, Daniel DiRocco, Thomas W. Lyons,
Dan Lehnherr, Louis-Charles Campeau, Alan Northrup, Nicho-
las K. Terrett, Emma R. Parmee, and Michael H. Kress (Merck)
for support. We are grateful to Dr. Michaelyn Lux (Merck) for
important insightful discussions. We are grateful to Merck & Co.
for providing advanced building blocks to support the syn-
thetic studies reported herein. We thank A.H. Christian and E.
Miller (Berkeley), and Laura Wilson and Christina Kraml (Lotus
Separations, LLC) for chiral resolution of 11a. We thank Lisa M.
Nogle and Spencer McMinn (Merck) for large-scale chiral reso-
lution of 11a and chiral analysis. We are grateful to Lisa M.
Nogle, David A. Smith, Mark Pietrafitta, and Miroslawa Darlak
(Merck) for help with reversed-phase purifications. We thank
Josep Saurí (Merck) for help with 2D NMR analysis. We thank
Dr. Hasan Celik and UC Berkeley's NMR facility in the College of
Chemistry (CoC-NMR) for spectroscopic assistance. Instru-
ments in the CoC-NMR are supported in part by NIH
S10OD024998.
Finally (Figure 6b), the desired N-fused bicyclic products
can also be obtained through a one-pot process from ke-
toamide S11a without isolation of the intermediate β-lac-
tams. This latter observation enhances the synthetic practi-
cality of this method to prepare N-fused bicycles from satu-
rated azacycles.
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Conclusion
In summary, we report a new method for the synthesis of
indolizidines and related N-fused heterocycles from piperi-
dines and other saturated cyclic amines. This process is ini-
tiated by a Rh-catalyzed C–C functionalization of α-hydroxy-
β-lactams prepared through a Norrish-Yang Type II C–H
functionalization of ketoamides derived from the saturated
cyclic amine starting materials. This overall three-step se-
quence transforms readily available saturated cyclic amines
into value-added N-fused heterocycles. A relatively wide
range of N-fused bicyclic β-lactam precursors were ac-
cessed through the Norrish-Yang reaction. In the subse-
quent Rh-catalyzed C–C cleavage process, optimization of
the ligand allowed for the selective cleavage of the distal C–
C bond, followed by the formation of N-fused bicyclic prod-
ucts through a formal cycloaddition process. Computational
studies were carried out to provide more insight into the
factors that influence selectivity for distal C‒C bond cleav-
age, unveiling the importance of trans influences in the
rhodacycle intermediate.
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ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website.
Experimental procedures, computational details, and com-
pound characterization (PDF)
X-ray data for epi-4a (CIF)
X-ray data for 4a (CIF)
X-ray data for epi-4e (CIF)
X-ray data for 4e (CIF)
X-ray data for 4f (CIF)
X-ray data for 14g (CIF)
X-ray data for 16 (CIF)
AUTHOR INFORMATION
Corresponding Author
*charles.yeung@merck.com (C.S.Y).
*mbaik2805@kaist.ac.kr (M.-H.B)
*rsarpong@berkeley.edu (R.S).
Funding Sources
No competing financial interests have been declared.
ACKNOWLEDGMENT
R.S. is grateful to the NSF under the CCI Center for Selective C–
H functionalization (CHE-1700982) for partial support of the
work reported herein (Berkeley). J.-S. H. is grateful to SK
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25. The α-ketoamide precursors were synthesized by NIS- 26. When enantiopure lactam 11a was used as the starting
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catalyzed oxidative amidation of acetophenone deriva-
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material, erosion in ee of the product was observed (4a
73% ee, epi-4a 66% ee), pointing to racemization of α-
carbonyl piperidine intermediate 9 prior to cyclization.
These observations set the stage for a dynamic kinetic
asymmetric annulative transformation, which is cur-
rently under investigation.
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