Bifunctional homoallylic carbamates from chiral silane additions to in situ generated N-acyl iminium ions

Article abstract of DOI:10.1021/ol301428y

Homoallylic carbamates bearing an α,β-unsaturated ester or an allylic carbonate were generated respectively utilizing novel chiral silanes through Lewis acid promoted asymmetric aminocrotylation. Those bifunctional building blocks could further undergo Michael addition or cyclization to selectively form functionalized lactams, azetidines, and tetrahydropyrimidinones.

Full text of DOI:10.1021/ol301428y

ORGANIC
LETTERS
2012
Vol. 14, No. 14
3624–3627
Bifunctional Homoallylic Carbamates
from Chiral Silane Additions to in Situ
Generated N-Acyl Iminium Ions
Jie Wu, Kai-Cheng Zhu, Ping-Wei Yuan, and James S. Panek*
Department of Chemistry and Center for Chemical Methodology and Library
Development, Metcalf Center for Science and Engineering, 590 Commonwealth Avenue,
Boston University, Boston, Massachusetts 02215, United States
Panek@bu.edu
Received May 23, 2012
ABSTRACT
Homoallylic carbamates bearing an R,β-unsaturated ester or an allylic carbonate were generated respectively utilizing novel chiral silanes
through Lewis acid promoted asymmetric aminocrotylation. Those bifunctional building blocks could further undergo Michael addition or
cyclization to selectively form functionalized lactams, azetidines, and tetrahydropyrimidinones.
Highly functionalized vinylogous Mannich products
are valuable synthetic intermediates in organic synthesis
and have been frequently employed in natural product
synthesis.1 In this regard, δ-amino-γ-methyl-R,β-unsatu-
rated carbonyl compounds, behaving as bifunctional
synthons, have been utilized to prepare iminosugar
derivatives2 and Tyr-Gly CH3-ADI (an alkene dipeptide
isostere),3 as well as key intermediates in the synthesis
of the natural product nupharamine.4 These materials
promise to give access to molecules of pharmacological
and biological interest. Established approaches to such
subunits include the Mannich reaction2 and SN20 aziridine
opening5 followed by Wittig homologation and further
functional group manipulation. Direct access of homo-
allylic amines bearing an unsaturated carbonyl group can
be realized by the vinylogous MukaiyamaꢀMannich reac-
tion using ketene acetals.6 However, the corresponding
asymmetric versions7 are rare and remain underdeveloped.
Due to the prevalence of medicinally important com-
pounds bearing stereodefined CꢀN bonds, the asymmetric
addition of allyl metal and related reagents to CdN Pi-bonds
has attracted the attention of the synthetic community.8
Well-documented studies from our laboratory have es-
tablished chiral crotylsilanes of type-2 as carbon nucleo-
philes in highly diastereo- and enantioselective reactions
with in situ generated N-acyl iminium ions to construct
(1) (a) Martin, S. F. Acc. Chem. Res. 2002, 35, 895. (b) Bur, S. K.;
Martin, S. F. Tetrahedron 2011, 57, 3221.
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A. L.; Koten, G. J. Org. Chem. 1994, 59, 7839–7848.
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10, 4259.
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Ishitani, H. Chem. Rev. 1999, 99, 1069–1094. (c) Friestad, G. K. Eur. J.
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Dory, Y. L. Tetrahedron Lett. 2011, 52, 6603–6605.
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Trans. 1 1995, 1359–1371.
r
10.1021/ol301428y
Published on Web 06/27/2012
2012 American Chemical Society

asymmetric Rh(II) and Cu(I) carbenoid SiꢀH
insertion.10 In line with this work, we expected that
extension of these silane reagents to asymmetric amino-
crotylation processes could directly access homoallylic
carbamates containing an R,β-unsaturated ester, thereby
extending our silane-based bond construction methods
(Scheme 1). Herein, we describe an efficient procedure for
the aminocrotylation and [3 þ 2] annulation of novel
crotylsilanes using in situ generated N-acyl iminium ions
as reaction intermediates.11 The generated vinylogous
Mannich products can undergo further diversification
by taking advantage of their rich functionality.
Scheme 1. Extension of Chiral Silane 1 to Homoallylic
Carbamates
Scheme 2. Aminocrotylation Using Silane (S)-1
Table 1. Optimization of the Three-Component Aminocroty-
lation
a Yield based on the purified product. bDr based on the crude 1H
NMR spectra. cEe based on chiral HPLC analysis. dReactions were
conducted at ꢀ10 °C.
Initial experiments were focused on the three-component
crotylation of 2-bromobenzaldehyde, organosilane (S)-1,
and methylcarbamate by evaluating selected Lewis acids
and solvents. Optimization studies (Table 1, entries 1ꢀ5)
indicated that BF3 OEt2 was the optimal promoter.
3
a Isolated yield. b Dr based on analysis of crude 1H NMR spectra.
c Less than 50% conversion after 48 h. d Only observed silane decom-
position. e NR = no reaction. NA = not available.
Further evaluation (entries 5ꢀ9) identified MeCN as the
most efficient solvent in terms of reactivity and selectivity.
Under the optimal conditions, crotylation product 3b was
obtained with 75% yield and 7:1 diastereoselectivity.
A range of aldehydes were evaluated under the opti-
mized conditions to test the reaction scope (Scheme 2).
Similar to the crotylation with aldehydes, the three-
component aminocrotylation between silane (S)-1and aryl
imines afforded homoallylic carbamates in good yield,
but only moderate diastereoselectivity, with the best level
of selectivity being achieved with 2-bromobenzylaldehyde
(3b and 3c). The allylcarbamate (3c) also functioned as
homoallylic carbamates with an isolated olefin.9 We have
recently demonstrated that vinylogous aldol products
can be effectively generated with high levels of diastereo-
and enantioselectivity utilizing crotylsilanes obtained by
(9) (a) Panek, J. S.; Jain, N. F. J. Org. Chem. 1994, 59, 2674–2675. (b)
Schaus, J. V.; Jain, N. J.; Panek, J. S. Tetrahedron 2000, 56, 10263–
10274. (c) Lipomi, D. J.; Panek, J. S. Org. Lett. 2005, 7, 4701–4704. (d)
Ong., W. W.; Beeler, A. B.; Kesavan, S.; Panek, J. S.; Porco, J. A., Jr.
Angew. Chem., Int. Ed. 2007, 46, 7470–7472.
(10) (a) Wu, J.; Chen, Y.; Panek, J. S. Org. Lett. 2010, 12, 2112–2115.
(b) Wu, J.; Becerril, J.; Lian, Y.; Davies, H. M. L.; Porco, J. A., Jr.;
Panek, J. S. Angew. Chem., Int. Ed. 2011, 50, 5938–5942. (c) Wu, J.;
Panek, J. S. J. Org. Chem. 2011, 76, 9900–9918. (d) Lian, Y.; Davies,
H. M. L. J. Am. Chem. Soc. 2011, 133, 11940–11943.
(11) For recent reviews on vinylogous Mannich reactions, see: (a)
Schneider, C.; Sickert, M. Chiral Amine Synth. 2010, 157–177. (b) Burns,
N. Z.; Jacobsen, E. N. Science of Synthesis, Stereoselective Synthesis
2011, 2, 785–834.
Org. Lett., Vol. 14, No. 14, 2012
3625

efficiently as the methylcarbamate. On the other hand, the
reaction generally delivered products in excellent selectivity
with aliphatic imines. Notably, for the cases examined, the
straight chain aliphatic substrate afforded very high syn/
anti selectivity with only one diastereomer (3f) being
observed. Syn products were formed which was consistent
with the well-established anti-SE0 mechanism. Select exam-
ples were carried through ee analysis using chiral HPLC
and showed that the enantioenrichment of the silane
reagent was completely transferred into the homoallylic
carbamate products (3b and 3g).
Scheme 3. [3 þ 2] Annulations Using Silane (R)-4
In anticipation of achieving enhanced selectivity for
aminocrotylation with aromatic substrates, the parent
unsaturated ester (R)-1 was converted to allylic carbonate
(R)-4 by reduction and subsequent acylation of the pri-
mary alcohol. In contrast to silane 1, homoallylic carba-
mates 6 and pyrrolidine products 5 were isolated in certain
instances using reagent (R)-4. At reaction temperatures
lower than ꢀ50 °C, the N-carbamoyl pyrrolidines 5 were
produced in good yield and excellent selectivity with three
in situ generated arylimines (Scheme 3). On the other hand,
acyclic homoallylic carbamates 5 were solely detected
and isolated when the reactions were warmed to ꢀ15 °C
(Scheme 4). For the cases studied, only the arylimines were
effective in the formation of pyrrolidine products. Alkyl
or branched aldehydes required higher temperatures in the
initial condensation and did not produce the kinetically
favored [3 þ 2] annulation product. Interestingly, the imine
derived from 2-bromobenzaldehyde afforded the homo-
allylic carbamate 6b without the annulated pyrrolidine
detected even when the reaction was carried out at low
temperature (ꢀ50 °C), behaving differently than the ar-
ylimines illustrated in Scheme 3. Homoallylic carbamates
of type 5 were generally obtained in high yield and with
good to excellent diastereoselectivity employing silane
(R)-4. Chiral HPLC traces of selected examples (6b and
6h) showed that the chirality of the crotylsilane was
transferred into the homoallylic carbamate productswhich
were obtained in >92% ee.
The resulting homoallylic carbamates 3 and 6 are
potentially useful chiral building blocks that possess both
electrophilic and nucleophilic sites available for further
manipulation. Nitrogen-containing heterocycles, such as
lactams, azetidines, and tetrahydropyrimidinones, are
found in a large number of natural products and com-
pounds of biological significance. We envisioned that the
carbamate-unsaturated ester and carbamate-allylic carbo-
nate subunits could be applied as synthetic platforms that
were capable of delivering lactams, azetidines, and tetra-
hydropyrimidinones with different substitution patterns.
Treatment of allylcarbamate 3c with the polymer-bound
Pd(0) reagent (PS-Ph3-Pd) afforded homoallylic amine 7,12
which cyclized effectively when mediated by microwave
irradiation to give the unsaturated lactam 8 with conco-
mitant E/Z olefin isomerization (Scheme 5). Cyclization of
amine 7 usingZr(OtBu)2-2-hydroxypyridineasthe catalyst
a Yield based on the purified material after chromatography over
silica gel. bDr based on the crude 1H NMR analysis.
Scheme 4. Aminocrotylation Using Silane (R)-4
a Yield based on purified materials. bDr based on crude 1H NMR
analysis. cEe based on chiral HPLC analysis.
afforded the unexpected lactam 9 accompanied by an
olefin migration to the trisubstituted system. On the other
hand, conjugate addition of in situ generated lithium
dimethylcuprate13 to unsaturated ester 3c led to the acyclic
carbamate 10 with moderate diastereoselectivity, which
cyclized during Alloc deprotection to deliver the saturated
lactam 11. The structure of the major diastereomer 11 was
secured by X-ray crystal structural analysis and indicated
that the conjugate addition followed the “modified”
FelkinꢀAnh model for chiral Michael acceptors.14
Palladium- and iridium-catalyzed intramolecular ami-
dation of allylic carbonates represents an effective method
for preparing pyrrolidine and piperidine heterocycles.15
(13) Hanessian, S.; Chahal, N.; Ciroux, S. J. Org. Chem. 2006, 71,
7403–7411.
(14) Yamamoto, Y.; Chounan, Y.; Nishii, S.; Ibuka, T.; Kitahara, H.
J. Am. Chem. Soc. 1992, 114, 7652–7660. For detailed analysis, see
Supporting Information.
€
(15) (a) Welter, C.; Dahnz, A.; Brunner, B.; Streiff, S.; Dubon, P.;
Helmchen, G. Org. Lett. 2005, 7, 1239–1242. (b) Riva, R.; Banfi, L.;
Basso, A.; Cerulli, V.; Guanti, G.; Pani, M. J. Org. Chem. 2010, 75,
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608–611.
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3626
Org. Lett., Vol. 14, No. 14, 2012

Scheme 5. Lactam Formation Using Homoallylic Carbamates 3
Scheme 6. Diversification of Homoallylic Carbamates 6
conducted in CH2Cl2, it afforded the syn-tetrahydropyri-
midinone product 16 as the major product, in contrast to
the anti-selective reaction described by Menche. In this way,
both the syn and anti diastereomers can be accessed by a
simple change in solvents.
In that context, we anticipated that we could extend this
transformation to the synthesis of functionalized azeti-
dines. Indeed, our initial experiments indicated that the
palladium-catalyzed allylic amidation of homoallylic car-
bamate 6b produced the azetidine product 12 in 41% yield
as a mixture of 1:1 ratio diastereomers alone with a linear
diene 13 as a byproduct (Scheme 6). However, with other
homoallylic carbamates 6, only the diene byproduct was
observed, thus indicating that the elimination of a π-allyl
intermediate predominated over our desired azetidine for-
mation. Even though we were not quite clear with the
reason why the ortho bromo substituent helped the forma-
tion of the azetidine product at this stage, we did show that
those homoallyliccarbamates of type 6 hadthe potential as
platforms for the generation of functionalized azetidines.
Further investigations following this line of experiments
are presently underway in our laboratory.
The aminocrotylation products 6 are well suited to the
use of Menche’s method for the conversion into 1,3-syn-
and 1,3-anti-tetrahydropyrimidinones, which can be further
converted to the free diamines.16 When the allylic substitu-
tion of urea 14 derived from carbamate 6a was carried out in
MeCN, the anti-tetrahydropyrimidinone 15 was obtained
with good selectivity. Conversely, when the reaction was
In summary, novel silanes of type 1 and 4, generated
from asymmetric metal catalyzed carbenoid SiꢀH inser-
tion,10a have been applied in three-component aminocro-
tylation to give direct access to homoallylic carbamates
bearing an unsaturated ester or allylic carbonate, in good
yield and selectivity. In some cases, the [3 þ 2] annulation
product through a [1,2]-silyl shift pathway was observed.
The chirality is transferred completely from the enantioen-
riched silane reagents to the products according to chiral
HPLC analysis. Application of this methodology in the
preparation of complex, biologically active molecules is
currently underway in our laboratory.
Acknowledgment. Financial support was obtained
from NIH CA 53604 and NIGMS CMLD initiative
(P50-GM067041). The authors are grateful to Prof. John
A. Porco, Jr. and Prof. AaronB. Beeler(Boston University)
for helpful discussions and Dr. Paul Ralifo, Dr. Norman
Lee, and Dr. Jeffrey Bacon (Boston University) for assis-
tance with NMR, HRMS, and X-ray measurements.
Supporting Information Available. Experimental de-
tails and selected spectra for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(16) Morgen, M.; Bretzke, S.; Li, P.-F.; Menche, D. Org. Lett. 2010,
12, 4494–4497.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 14, 2012
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