Intramolecular Sakurai Allylation of Geminal Bis(silyl) Enamide with Indolenine. A Diastereoselective Cyclization to Form Functionalized Hexahydropyrido[3,4- b]Indole

Article abstract of DOI:10.1021/acs.orglett.0c03806

A fluoride-promoted intramolecular Sakurai allylation of geminal bis(silyl) enamide with indolenine has been developed. The reaction facilitates an efficient cyclization to give hexahydropyrido[3,4-b]indoles in good yields with high diastereoselectivity. The resulted cis, trans-stereochemistry further enables the ring-closing metathesis (RCM) reaction of two alkene moieties, giving a tetracyclic N-hetereocycle widely found as the core structure in akuammiline alkaloids.

Full text of DOI:10.1021/acs.orglett.0c03806

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Letter
Intramolecular Sakurai Allylation of Geminal Bis(silyl) Enamide with
Indolenine. A Diastereoselective Cyclization To Form Functionalized
Hexahydropyrido[3,4‑b]Indole
Yi Chen, Xuanyi Song, Lu Gao,* and Zhenlei Song*
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ABSTRACT: A fluoride-promoted intramolecular Sakurai allylation of geminal bis(silyl) enamide with indolenine has been
developed. The reaction facilitates an efficient cyclization to give hexahydropyrido[3,4-b]indoles in good yields with high
diastereoselectivity. The resulted cis, trans-stereochemistry further enables the ring-closing metathesis (RCM) reaction of two alkene
moieties, giving a tetracyclic N-hetereocycle widely found as the core structure in akuammiline alkaloids.
also provide a double hyperconjugation effect between the two
C−Si bonds and the enol double bond. These two effects work
together to make the alkene behave as an allyl bis(silane)
rather than as an enol, leading to Sakurai allylation3 in an
intermolecular manner to give 1,2-diols4 or an intramolecular
manner to give γ-lactones.5
The above success to construct the oxygen-containing
structures leads us to examine the feasibility of the geminal
bis(silane)-controlled umpolung in constructing the N-hetero-
cycles. Herein, we report a fluoride-promoted intramolecular
Sakurai allylation of geminal bis(silyl) enamide6 with
indolenine (Scheme 1). The reaction facilitates a regio- and
diastereoselective cyclization of 2 to deliver hexahydropyrido-
[3,4-b]indoles 3 in good yields. The resulted cis, trans-
stereochemistry of 3 further enables the ring-closing metathesis
(RCM) reaction of two alkene moieties, giving tetracyclic 4
widely found as the core structure in akuammiline alkaloids7
such as (+)-strictamine, (−)-2(S)-cathafoline, and (−)-pic-
rinine.
eminal bis(silane) and its variants, in which two silyl
Ggroups are attached to one carbon center, are emerging
as valuable synthons in organic synthesis.1 We have shown that
the steric and electronic effects of silicon are duplicated in
these structures, thereby leading to unusual reactivities and
certain chemo-, regio-, or diastereoselectivity that would be
impossible or difficult to achieve by other methods.2 For
example, geminal bis(silyl) enol derivatives adopt the most
favorable conformation as 1 (Scheme 1), which minimizes
allylic strain and nonbonded interactions. Thus, two silyl
groups not only shield both sides of the β-position of enol but
Scheme 1. Intramolecular Sakurai Allylation of Geminal
Bis(silyl) Enamide with Indolenine To Give Functionalized
Hexahydropyrido[3,4-b]indole
The required geminal bis(silyl) enamide 7a was synthesized
from 5a (Scheme 2), which is prepared from tryptamine by
four steps.8 TFAA-promoted condensation of the secondary p-
Received: November 17, 2020
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© XXXX American Chemical Society
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A

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for the good efficiency, while the processes using bases only led
to recovery of 7. BEt3 is believed to serve as a Lewis acid to
coordinate with Lewis basic indole nitrogen, thus enhancing
the nucleophilicity of the C3 position by abstraction of a
hydrogen atom from the NH bond.10 A wide range of 3-aryl or
-heterocyclic-substituted allylic carbonates were tolerated to
give indolenines 2a−2s. Electron-donating substitution on the
phenyl ring of allylic carbonates generally gave higher yields
than electron-withdrawing substitution. The reaction was also
suitable for 2-unsubsitituted allylic carbonate, or 2-methyl or
-phenyl, or 3-methyl-allylic carbonates to give 2t−2w.
However, 3,3-dimethyl allylic carbonate only gave 2x in 29%
yield probably because the dimethyl groups sterically inhibited
formation of the corresponding π-allylpalladium species.11i
Cyclohexenyl carbonate worked to afford 2y in 79% yield but
with moderate dr of 2:1. Dienyl carbonate, which was barely
used in C3-allylation of indole, gave rise to 2z in 83% yield
with complete regio- and E,E-stereochemical control. It
noteworthy that introducing similar dienyl chain previously
used enynes and led to a mixture of E,E- and Z,E-isomers.12 In
addition, 7 prepared from functionalized tryptamine served as
good substrates, giving 2ab−2ad in generally good yields. The
asymmetric version was also tested with 7a using Trost’s
ligands L113 and L214 (Scheme 3). These two ligands worked
Scheme 2. Synthesis of 7a
toluenesulfonamide moiety with geminal bis(silyl) aldehyde
62a proceeded under the thermodynamic control to give
enamide as a single E-isomer in 81% yield. The selective
removal of 2-nitrobenzenesulfone protecting group9 on the
indole nitrogen in the presence of PhSH and Cs2CO3 afforded
7a in 83% yield.
Various cyclization precursors 2 were then synthesized using
Tamaru’s procedure10 by palladium-catalyzed 3-allylic alkyla-
tion of 7 with allylic carbonates (Figure 1).11 BEt3 was crucial
Scheme 3. Asymmetric Synthesis of (S)-2t
effectively with similar substrates to 7a to give high
enantioselectivity. However, in our case, (S)-2t was unfortu-
nately obtained in moderate yields with low ee.15 It is currently
unclear whether the low enantioselectivity is due to the steric
effect of geminal bis(silane) or electron-rich double bond of
enamide.
Cyclization of indolenine 2t to form tricyclic 3a was initially
tested under typical Sakurai allylation using a variety of Lewis
acids such as TMSOTf, BF3·OEt2, and TiCl4. However, the
imine underwent rapid 1,2-allyl migration followed by
aromatization,16 giving 2,3-disubstituted indole 8 as product.
This failure led us to examine the fluoride-promoted
desilylation/cyclization process. Similar to Lewis acids, HF
only gave rise to 8 in 86% yield (Table 1, entry 1). While no
reaction occurred using KF (entry 2), addition of 1.0 equiv of
18-crown-6 as an additive significantly promoted cyclization at
60 °C, giving the desired 3a in 52% yield with 7.8:1 dr (entry
3). The yield of 3a was further improved to 86% using TABF
in THF at room temperature (entry 4). It is noteworthy that
the reaction should be quenched with sat. aq. NH4Cl within 1
min to avoid decomposition of 3a. TBAT also promoted the
cyclization, providing 3a in 61% yield with a comparable dr of
9:1 (entry 5). The cis, trans-stereochemistry of 3a was
determined by its NOE experiments. The stereochemical
Figure 1. Synthesis of indolenine 2. (a) Reaction conditions: 7 (0.1
mmol), allylic carbonates (0.3 mmol), Pd(PPh3)4 (5 mol %) and BEt3
(0.1 mmol) in 2.0 mL CH2Cl2 at rt for 26 h. (b) Isolated yields. (c)
Determined by 1H NMR analysis of the crude product. (d) The yield
of the reaction on 1 mmol scale.
B
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a
Table 1. Screening of Reaction Conditions of Cyclization
b
c
entry
F−
T (°C)
t
yield
dr
1
2
3
4
5
HF
KF
rt to 60
2 h
2 h
2 h
1 min
2 h
N.D.
N.R.
52
86 (76 )
61
N.D.
N.D.
7.8:1
9:1
60
60
rt
KF (18-crown-6)
TBAF
TBAT
d
60
9:1
a
Reaction conditions: 2t (0.1 mmol), [F−] (0.1 mmol), 1.0 mL THF.
b
c
Isolated yields Determined by 1H NMR analysis of the crude
d
product. The yield of the reaction on 1 mmol scale.
outcome of cyclization is rationalized by the reaction model of
2t (in box). As expected, the addition occurs from the
trajectory antiperiplanar to the C3-allyl group in indole. To
further minimize the steric repulsion between geminal
bis(silane) and the indole ring, the geminal bis(silyl) enamide
moiety is oriented away from the indole, leading to the
observed cis, trans-stereochemistry on the ring. In addition, Hβ
and Hγ lie trans to each other to avoid A1,2 strain, such that
elimination of one of the silyl groups generates the observed E-
vinylsilane.
The scope of the fluoride-promoted cyclization of various
indolenine 2 is shown in Figure 2.17 The reaction of indolenine
2 containing 3-aryl or 3-methyl allyl groups proceeded to give
cis, trans-tricyclic 3b−3q with dr at a synthetically useful level.
3r, containing a 1,3-diene moiety, shows the potential to
undergo intramolecular Diels−Alder reaction with vinylsilane
or its variants, leading to more complex polycyclic N-
heterocycles. While 2-methyl allyl substituted 2u served as a
good substrate to give 3t in 83% yield with 9:1 dr, the reaction
of 2x possessing a 3, 3-dimethyl group only provided a
complex mixture instead generating 3s. Substituents on the
indolenine ring showed great impact on the cyclization
efficiency. While cyclization of methoxy or methyl substituted
2ab and 2ac afforded the desired 3u and 3v, 2ad containing a
chloro group decomposed under the cyclization conditions.
The cis, trans-stereochemistry of 3a allows the two alkene
moieties on the piperidine ring to adopt an 1,3-cis orientation.
We envisioned that this structural feature might facilitate an
RCM reaction to construct the tetracyclic structure shown as
4. To this end, the indole nitrogen was protected as carbamate
in 94% yield. Considering that the steric bulkiness of the SiMe3
group might inhibit cyclization, we used second-generation
Hoveyda−Grubbs-type catalyst 9,18 which was modified by
Stewart and Grubbs and has been used specifically for the
RCM reaction of sterically demanding alkenes. The reaction
worked well even with heating in toluene at 120 °C for 48 h.
The desired 4 was delivered in 52% yield (Scheme 4). The
stereochemistry of 4 was confirmed by its X-ray crystallography
and the NOE experiments. Because 4 exists widely as the core
structure in akuammiline alkaloids, our approach should find
Figure 2. Scope of cyclization of 2 to 3. (a)Reaction conditions: 2
(0.1 mmol) and TBAF (0.1 mmol, 1 mol/L in THF) in 1.0 mL THF
1
at rt for 1 min. (b) Isolated yields. (c) Determined by H NMR
analysis of the crude product.
Scheme 4. RCM Reaction of 3a to Tetracyclic 4
useful applications in the synthesis of (+)-strictamine,
(−)-2(S)-cathafoline, and (−)-picrinine (Scheme 1).
In summary, we have developed a fluoride-promoted
intramolecular Sakurai allylation of geminal bis(silyl) enamide
with indolenine. The steric effect and hyperconjugation effect
of geminal bis(silane) work together, making the carbon−
carbon double bond play as an allyl bis(silane) rather than as
an enamide. The reaction facilitates an regio- and diaster-
eoselective cyclization to give hexahydropyrido[3,4-b]indoles
in good yields. The resulted cis, trans-stereochemistry enables
RCM reaction of two alkene moieties, giving a tetracyclic N-
C
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hetereocycle widely found as the core structure in akuammiline
alkaloids. Applications of this methodology in the synthesis of
alkaloids are underway in our group.
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ASSOCIATED CONTENT
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* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c03806.
Experimental procedures and spectra data for products
(PDF)
Accession Codes
CCDC 2017152 (4) contains the supplementary crystallo-
graphic data for this paper. These data can be obtained free of
charge via www.ccdc.cam.ac.uk/data_request/cif, or by email-
ing data_request@ccdc.cam.ac.uk, or by contacting The
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
■
Corresponding Authors
Lu Gao − Key Laboratory of Drug-Targeting and Drug
Delivery System of the Education Ministry and Sichuan
Province, Sichuan Engineering Laboratory for Plant-Sourced
Drug and Sichuan Research Center for Drug Precision
Industrial Technology, West China School of Pharmacy,
Sichuan University, Chengdu 610041, China;
Email: lugao@scu.edu.cn
Zhenlei Song − Key Laboratory of Drug-Targeting and Drug
Delivery System of the Education Ministry and Sichuan
Province, Sichuan Engineering Laboratory for Plant-Sourced
Drug and Sichuan Research Center for Drug Precision
Industrial Technology, West China School of Pharmacy,
Sichuan University, Chengdu 610041, China; orcid.org/
0000-0002-7228-1572; Email: zhenleisong@scu.edu.cn
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Authors
Yi Chen − Key Laboratory of Drug-Targeting and Drug
Delivery System of the Education Ministry and Sichuan
Province, Sichuan Engineering Laboratory for Plant-Sourced
Drug and Sichuan Research Center for Drug Precision
Industrial Technology, West China School of Pharmacy,
Sichuan University, Chengdu 610041, China
Xuanyi Song − Key Laboratory of Drug-Targeting and Drug
Delivery System of the Education Ministry and Sichuan
Province, Sichuan Engineering Laboratory for Plant-Sourced
Drug and Sichuan Research Center for Drug Precision
Industrial Technology, West China School of Pharmacy,
Sichuan University, Chengdu 610041, China
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Complete contact information is available at:
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Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful for financial support from the NSFC
(21921002), MOST (2018ZX09711001-005-004).
D
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