Stereocontrolled synthesis of 2-substituted-1,3-azasilaheterocycles

Article abstract of DOI:10.1021/ol101379t

(Equation Presented). Chiral α-silylsulfinamides, prepared by the treatment of an alkyldiphenylsilane with lithium followed by its addition to a sulfinimine, can be applied to the synthesis of 1,3-azasilaheterocycles as derivatives of cyclic alkaloids. Th

Full text of DOI:10.1021/ol101379t

ORGANIC
LETTERS
2010
Vol. 12, No. 15
3528-3531
Stereocontrolled Synthesis of
2-Substituted-1,3-Azasilaheterocycles
´
Da´cil Herna´ndez, Lone Nielsen, Karl B. Lindsay, M. Angeles Lo´pez-Garc´ıa,
Klaus Bjerglund, and Troels Skrydstrup*
Center for Protein Structures, Department of Chemistry and Interdisciplinary Nanoscience
Center, Aarhus UniVersuty, Langelandsgade 140, 8000 Aarhus C, Denmark
ts@chem.au.dk
Received June 15, 2010
ABSTRACT
Chiral r-silylsulfinamides, prepared by the treatment of an alkyldiphenylsilane with lithium followed by its addition to a sulfinimine, can be
applied to the synthesis of 1,3-azasilaheterocycles as derivatives of cyclic alkaloids. This synthetic route, which involves intramolecular
substitution of an amino alcohol or cyclization of an amino acid promoted by 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC), represents
a convenient means for accessing these silicon-containing heterocycles.
Nitrogen-containing heterocycles constitute structural frame-
works in a plethora of pharmaceuticals and alkaloids and
are essential components of the pharmacophore.1 In recent
years, there has been an interest in the preparation of
heterocycles in which one of the ring carbons has been
replaced by silicon. A few bioactive silicon-nitrogen
heterocycles have already been synthesized. The dopamine
receptor antagonist silahaloperidol 1 (Figure 1) displays
improved selectivity compared to haloperidol. Furthermore,
its metabolic fate in human liver microsomas does not
produce a silicon analogue of the neurotoxic metabolite
HPP+, which is responsible for the severe side effects of
haloperidol.2 Several other heterocyclic sila analogues have
been prepared, including a class of spirocyclic σ receptor
ligands, such as 2,3 the neurotropic tetrahydroisoquinoline
sila analogue 3,4 and the silicon analogue 45 of the antide-
pressive agent dimetracrine (Figure 1). Another important
compound in the biorganosilicon area is a sila analogue of
proline prepared enantioselectively by Vivet et al.6
Figure 1. Examples of bioactive silicon-nitrogen heterocycles.
(1) (a) Reynolds, T. Phytochemistry 2005, 66, 1399. (b) Tallent, W. H.;
Stromberg, V. L.; Horning, E. C. J. Am. Chem. Soc. 1955, 77, 6361. (c)
Cooper, J. C.; Gutbrod, O.; Witzemann, V.; Methfessel, C. Eur. J. Phar-
macol. 1996, 309, 287. (d) El Nemr, A. Tetrahedron 2000, 56, 8579. (e)
Iminosugars as Glycosidase Inhibitors. Nojirimycin and Beyond; Stu¨tz,
A. E., Ed.; Wiley-VCH Verlag: Weinheim, 1999.
Different approaches have been developed to prepare such
heterocyclic systems containing silicon and nitrogen;6,7
(4) E. Lukevics, I. S.; Germane, S.; Zablotskaya, A. Chem. Heterocycl.
Compd. 1997, 33, 234.
(2) Johansson, T.; Weidolf, L.; Popp, F.; Tacke, R.; Jurva, U. Drug
Metab. Dispos. 2010, 38, 73.
(5) Wannagat, U.; Wiese, D.; Struckmeier, G.; Thewalt, U.; Debaerde-
maeker, T. Liebigs Ann. Chem. 1988, 241.
(3) Tacke, R.; Handmann, V. I.; Bertermann, R.; Burschka, C.; Penka,
M.; Seyfried, C. Organometallics 2003, 22, 916.
(6) Vivet, B.; Cavelier, F.; Martinez, J. Eur. J. Org. Chem. 2000, 807.
10.1021/ol101379t  2010 American Chemical Society
Published on Web 07/12/2010

however, few syntheses have targeted 2-substituted 1,3-
azasilaheterocycles. These include the reaction of a bis-
haloalkylsilane with a primary amine7c and a nonregiose-
lective aminomercuration, which yielded a 2-substituted
azasilinane as a byproduct.7b To the best of our knowledge,
no syntheses have been reported providing a means of
controlling the formation of the silicon-bearing stereogenic
carbon center.
substitution with pyridine occurred giving the corresponding
pyridinium tosylate salt. On the other hand, the corresponding
mesylate proved to be more rewarding when treated with
sodium hydride (entry 4). Satisfyingly, the expected Cbz-
protected azasilinane 16 could be furnished in an 84%
isolated yield.
Table 1. Synthesis of Different Amino Alcohols from
Sulfinimide 11 and Applied Conditions for Cyclization
Scheme 1. Retrosynthetic Analysis of the Silaheterocycles 5
amino
alcohol
productb
(%)
entry
1
PG
R
conditions B
HCl·H
H
12
PPh3, CBr4, Et3N,
CH2Cl2
2
3
4
Ts
Cbz
Cbz
Ts
Ts
H
13
14
15
NaH, DMF
Py, 80 °C
MsCl, Et3N, CH2Cl2; 16 (84)
trace
NaH, THF
a Conditions A: TsCl, Et3N, DMAP, CH2Cl2 or CbzCl, NaHCO3, H2O,
In this paper, we report a flexible and efficient approach
to the stereocontrolled synthesis of 2-substituted 1,3-azasili-
nanes or azasilepanes and a 2-substituted 1,3-azasilinan-2-
one. The synthetic route is outlined in Scheme 1, whereby
the azasilaheterocycles 5a and 5b can be formed by an
intramolecular cyclization of amino alcohols 7 either via an
intramolecular SN2 substitution from the sulfonate 6a or by
an EDC promoted intramolecular coupling of amino acid
6b, respectively. The substrates 7 would in turn be prepared
from sulfinimides 8 from the lithiation of 10 and addition to
sulfinimines 9, a strategy recently and successfully developed
in our group.8
THF. b Isolated yields after column chromatography on silica gel.
Azasilinane 16 was a precursor for the coniine1a analogue
17 (Scheme 2). Standard hydrogenolysis of the Cbz group
and precipitation with HCl in ether gave a quantitative yield
of 17 as its hydrochloride salt.
Scheme 2. Synthesis of the (+)-Coniine Analogue 17
The first approach involving ring closure by intramolecular
nucleophilic substitution of an amino alcohol was studied
using the sulfinimide 117b (Table 1). Several approaches were
examined for this sequence of events, which all involved
the initial and simultaneous liberation of the amine and
alcohol under acidic methanolysis conditions. Application
of the Appel cyclization conditions,9 via in situ activation
of the alcohol as an oxyphosphonium salt, led to the
formation of a complex mixture (entry 1). On the other hand,
ditosylation affording derivative 13 and treatment with NaH
only led to traces of the expected cyclic compound (entry
2). Heating the Cbz-protected derivative 14 in neat pyridine
was not fruitful either (entry 3). Instead, intermolecular
Syntheses of other 2-substituted 1,3-azasilaheterocycles
were also attempted, the results of which are shown in Table
2. Compounds 20, 23, 26, and 29 were prepared in good
yields from the corresponding sulfinimides 18, 21, 24, and
27. The cyclization gave a slightly lower yield of 70% with
amino alcohol 22, but this was not unexpected for the
formation of a larger seven-membered ring.
Synthesis of the silaheterocycles 26 and 29 required a
modified protocol for ring closure. The use of sodium hydride
was not compatible, probably due to Brook rearrangement
followed by decomposition. For this reason, the Boc group
on the amines was removed by treatment with TFA, and the
cyclization of the corresponding ammonium salts was
produced with Et3N, providing the desired silaheterocycles
in good yield. The silaheterocycle 29 represents a model
system to a potential nojirimycin analogue,1d displaying one
protected hydroxy group in the side chain.
(7) (a) Blaszykowski, C.; Brancour, C.; Dhimane, A.-L.; Fensterbank,
L.; Malacria, M. Eur. J. Org. Chem. 2009, 1674. (b) Rousseau, G.; Blanco,
L. Tetrahedron 2006, 62, 7951. (c) Dedeyne, R.; Anteunis, M. J. O. Bull.
Soc. Chim. Belg. 1976, 85, 319. (d) Kim, J.; Sieburth, S. M. J. Org. Chem.
2004, 69, 3008.
(8) (a) Nielsen, L.; Lindsay, K. B.; Faber, J.; Nielsen, N. C.; Skrydstrup,
T. J. Org. Chem. 2007, 72, 10035. (b) Nielsen, L.; Skrydstrup, T. J. Am.
Chem. Soc. 2008, 130, 13145. (c) Herna´ndez, D.; Lindsay, K. B.; Nielsen,
L.; Mittag, T.; Bjerglund, K.; Friis, S.; Mose, R.; Skrydstrup, T. J. Org.
Chem. 2010, 75, 3283.
(9) Appel, R.; Kleinstu¨ck, R. Chem. Ber. 1974, 107, 5.
Org. Lett., Vol. 12, No. 15, 2010
3529

Table 2. Preparation of 1,3-Azasilaheterocycles
a Conditions A: CbzCl, NaHCO3, H2O, THF or Boc2O, Et3N, CH2Cl2. b Conditions B: (a) MsCl, Et3N, CH2Cl2; (b) NaH, THF. c Conditions C: (a) MsCl,
Et3N, CH2Cl2; (b) TFA, CH2Cl2; (c) Et3N, CH2Cl2. d Isolated yields after column chromatography on silica gel. e Yields after two steps. f Yields after three
steps.
To access additional 2-alkylazasilaheterocycles, we applied
an alternative method of ring closure to the previously
Scheme 4. Synthesis of a Diphenylsilane Indolizidine Derivative
reported addition product 307c (Scheme 3). Global depro-
tection and reprotection of the amine were followed by
oxidation of the free alcohol up to the corresponding acid
32. EDC-promoted intramolecular coupling gave the 2-isobu-
tylazasilanone 33 in 75% yield.
Scheme 3. Preparation of Piperidinone 33
The double-cyclization strategy was achieved starting from
the reaction of a sulfinimine bearing a PMB-protected alcohol
35 and alkyldiphenylsilane 34 generating sulfinimide 36 in
an excellent 96% yield (Scheme 4). The coupling product
36 underwent sequential deprotection under oxidative and
acid conditions, followed by Boc protection of the amine
and mesylation of both hydroxyl groups to give the bis-
This cyclization protocol gave direct acces to chiral
2-substituted piperidinones, representing building blocks for
structures of current interest such as 2,6-dialkylpiperidines
and more complex alkaloids.10
With the cyclization strategy developed, we next turned
our attention to the bicyclic indolizidine structures which
are also characteristic of many bioactive natural products
(Scheme 4).11 Through appropriate functionalization of the
sulfinimine side chain, the deprotected amine could be
cyclized twice, giving a bicyclic, tertiary amine.
(10) (a) Amat, M.; Llor, N.; Hidalgo, J.; Escolano, C.; Bosch, J. J. Org.
Chem. 2003, 68, 1919. (b) Pohmakotr, M.; Prateeptongkum, S.; Chooprayoon,
S.; Tuchinda, P.; Reutrakul, V. Tetrahedron 2008, 64, 2339.
(11) (a) Iminosugars as Glycosidase Inhibitors; Stu¨tz, A. E., Ed.; Wiley-
VCH: Weinheim, 1999. (b) Howard, A. S.; Michael, J. P. Simple
indolizidine and quinolizidine alkaloids. In The Alkaloids; Brossi, A.; Ed.;
Academic press: New York, 1986; 183. (c) Michael, J. P. Nat. Prod. Rep.
2007, 24, 191.
3530
Org. Lett., Vol. 12, No. 15, 2010

mesylate 37 in 57% yield. Boc deprotection with TFA and
cyclization using triethylamine furnished the silicon-contain-
ing indolizidine 38.
the monofluoro compounds 43-45 were obtained in excellent
yields and as a mixture (1:1) of diastereomers by treatment
of the disilanes with trifluoroborane bis(acetic acid) adduct
(Scheme 6). The difluoro derivatives were not detected in
any case.
Scheme 5
.
Synthesis of the Sila Analogue of (+)-Lentiginosine
42
Scheme 6.
Synthesis of Monofluoro Silaheterocyclesa
a
1
Detected by H and 19F NMR but not isolated (labile compound).
For a practical application of this work, the synthesis of
the sila analogue of the glycosidase inhibitor lentiginosine1d
42 was suggested (Scheme 5). Extension of the developed
methodology to this goal required two hydroxy groups with
the correct stereochemistry to be installed in the sulfinimine.
The necessary aldehyde was prepared in four steps from an
L-tartaric acid derivative12 and condensed with (S)-tert-
butanesulfinamide. Then the resulting sulfinimine was applied
in the synthetic sequence showed previously (Scheme 5).
The addition of the silyllithium reagent to 39 took place
without incident providing 40 in a 62% yield.13 Sequential
deprotection with DDQ and hydrogen chloride followed by
Boc protection of the amine gave the diol 41. This interme-
diate was transformed into the bis-mesylate and cyclized to
produce 42, in a good overall yield for the last three steps,
and its stereochemical configuration corresponded to that of
epi-lentiginose.
In summary, we have reported an approach for the
synthesis of 1,3-azasilaheterocycles with a substituent in the
2-position as analogs of cyclic alkaloids. It involves hydri-
dosilane lithiation and sulfinimine addition with good dias-
tereocontrol at the silicon bearing a stereogenic center,
producing the desired compounds in good yield. We have
successfully demonstrated the application of this method for
the synthesis of a sila analogue of a protected version of
(+)-lentiginosine. Ongoing work in this area is directed at
the development of a more general approach, which should
allow the synthesis of more functionalized alkaloids and
hydrolysis of the diphenylsilanes to prepare the silanediol
derivatives and investigate their biological activities. These
results will be reported in due course.
The silaheterocycles 26, 33, and 38 (Scheme 6) were used
as model compounds to study the acid promoted cleavage
of the diphenylsilane moiety. Application of the Sieburth
conditions,14 known for synthesis of the silanediol peptide
mimics, led to the formation of a complex mixture. On the
other hand, hydrogen tetrafluorborate in diethyl ether pro-
duced no transformation of the starting material. However,
Acknowledgment. We acknowlege generous financial
support from the Danish National Research Foundation, the
Lundbeck Foundation, the Carlsberg Foundation, and Aarhus
University. D.H. and M.A.L.-G. thank the Gobierno de
Espan˜a (MICINN) for a posdoctoral contract (Programa
Nacional de Movilidad de Recursos Humanos del Plan
nacional de I+D+I 2008-2011) and a FPU fellowship,
respectively.
(12) The synthesis of 39 is included in the Supporting Information.
(13) The stereochemical assignment at the new stereogenic center was
assigned based on a similar experiment involving the addition of the same
silylithium reagent with the R diastereomer of the sulfinimine 39. This
produced a diastereomer to 41 after the hydrolysis step suggesting that the
adjacent benzyloxy group in 39 is not influencing the stereochcmical
outcome of the silyllithium additions step.
(14) (a) Sieburth, S. M.; Nittoli, T.; Mutahi, A. M.; Guo, L. Angew.
Chem., Int. Ed. 1998, 37, 812. (b) Mutahi, M. W.; Nittoli, T.; Guo, L.;
Sieburth, S. M. J. Am. Chem. Soc. 2002, 124, 7363. (h) Sieburth, S. M.;
Chen, C.-A. Eur. J. Org. Chem. 2006, 311.
Supporting Information Available: Experimental meth-
ods for the preparation of compounds 15-29, 33, and 36-44
and their characterization. Copies of 1H NMR and 13C NMR
spectra of the new compounds (15-29, 33, and 36-44). This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL101379T
Org. Lett., Vol. 12, No. 15, 2010
3531