Intramolecular 2-propylidene-13-bis(silane) imine cyclizations. An efficient new procedure for the stereocontrolled synthesis of pyrrolidines, isotropanes, and bridged pyrrolizidines

Full text of DOI:10.1021/ja954136m

4200
J. Am. Chem. Soc. 1996, 118, 4200-4201
Scheme 1
Intramolecular 2-Propylidene-1,3-bis(silane) Imine
Cyclizations. An Efficient New Procedure for the
Stereocontrolled Synthesis of Pyrrolidines,
Isotropanes, and Bridged Pyrrolizidines†
Timothy Kercher and Tom Livinghouse*
Department of Chemistry and Biochemistry
Montana State UniVersity, Bozeman, Montana 59717
ReceiVed December 8, 1995
The stereocontrolled addition of silicon-bearing π-nucleo-
philes to carbon-centered electrophiles has come to be regarded
as a particularly versatile means for the construction of strategic
bonds.1 Despite the ongoing activity in this area, there have
been relatively few instances of highly diastereoselective
cyclizations involving the intramolecular addition of allylsilanes2
or related π-systems3 to CdN linkages. In principle, the
stepwise closure of a 2-propylidene-1,3-bis(silane) moiety4 onto
a 2-azaallyl cation equivalent would constitute an exceptionally
efficient means for the topologically defined assembly of bridged
azacyclic ring systems (Scheme 1). In this communication we
report the first examples of diastereoselective cyclizations
terminated by 2-propylidene-1,3-bis(silane)s and provide an
application to the synthesis of a bridged pyrrolizidine model
for the tricyclic core of (()-stemofoline (4).5
At the commencement of this investigation, no preparatively
general methods for the synthesis of molecules containing the
2-propylidene-1,3-bis(silane) subunit were available.4 After
some experimentation, the following procedure was developed
for the large scale synthesis of amine 6 and was later shown to
be extendable to a wide range of intermediates. Treatment of
imide 5a6 with CBr4 and Ph3P (CH2Cl2, 0 °C) provided imide
5b in 86% isolated yield. Exposure of 5b to (Me3SiCH2)2Zn
(1.5 equiv, prepared from Me3SiCH2MgCl + ZnCl2 in situ) in
the presence of 7 mol % PdCl2(PPh3)2 (THF, room temperature
(rt)) furnished 5c in 96% yield after purification which, upon
PHT cleavage with N2H4‚H2O (EtOH, reflux), afforded 6 (78%
oVerall from 5a).7 Condensation of amine 6 with a variety of
aldehydes was readily achieved in the presence of 4 Å molecular
sieves (THF, rt) to provide the corresponding imines 7a-g as
pure E-isomers8 in quantitative yield.
Scheme 2a
a (a) CBr4, Ph3P, CH2Cl2, 0 °C. (b) (TMSCH2)2Zn, (1.5 equiv),
(Ph3P)2PdCl2 (7 mol %), THF, rt. (c) N2H4‚H2O, EtOH, reflux. (d)
RCHO, 4 Å molecular sieves, THF, rt.
Scheme 3a
a (a) TiCl4 (1.0 equiv), CH2Cl2, -78 °C f rt. (b) KHCO3 aqueous,
inverse addition. (c) TsCl, Py, CH2Cl2, 0 °C f rt.
Prospective methods for initiating the cationic monodesi-
lylative cyclization of imine 7a were first examined. After
screening a large number of Lewis and Bro¨nsted acids under a
variety of reaction conditions, it was discovered that precom-
plexation of 7a with 1.0 equiv of TiCl4 (CH2Cl2, -78 °C)
followed by slow warming to rt and final inverse addition to
saturated aqueous KHCO3 provided optimal conversion to the
1,2-disubstituted pyrrolidine 8a, which could be isolated as a
single stereoisomer (Vide infra) in 98% purified yield.9 Alterna-
tive initiators (including Me3SiOTf, BF3‚OEt2, SnCl4, ZnI2,
Me2O‚HBF4, CSA and TFAA) led to incomplete conversion
with the frequent coproduction of undesired biproducts. In this
connection, it is noteworthy that a principle side reaction
appeared to involve protomonodesilylation of the sensitive
2-propylidene-1,3-bis(silane) moiety to give imines of the type
9a, even when rigorously anhydrous reaction conditions were
maintained.10 Monodesilylative cyclization of imines 7b-g
under conditions analogous to those described above9,11 provided
the 1,2-disubstituted pyrrolidines 8b-g in good to outstanding
chemical yield and, with the exception of 8g, with excellent
diastereoselectivity. In the case of 8g, a 1.0:1.7 ratio of isomeric
pyrrolidines was obtained. N-Tosylation of this mixture (TsCl,
Py, CH2Cl2, 0 °C, rt) followed by fractional crystallization
provided the pure isomers 10gcis and 10gtrans. NOE spectro-
scopic analyses of the individual isomers provided compelling
† Dedicated to the memory of Professor William S. Johnson.
(1) The Electrophilic Substitution of Allylsilanes and Vinylsilanes.
Fleming, I.; Dunogue`s, J.; Smithers, R. In Organic Reactions, Kende, A.
S., Ed.; John Wiley and Sons: New York, 1989, Vol. 37, Chapter 2, p 57.
(2) (a) Heerding, D. A.; Hong, C. Y.; Kado, N.; Look, G. C.; Overman,
L. E. J. Org. Chem. 1993, 58, 6947. (b) Hong, C. Y.; Kado, N.; Overman,
L. E. J. Am. Chem. Soc. 1993, 115, 11028. (c) Hiemstra, H.; Forgens, H.
P.; Speckamp, W. N. Tetrahedron Lett. 1985, 26, 3155. (d) Hiemstra, H.;
Sno, M. H. A. M.; Vijn, R. J.; Speckamp, W. N. J. Org. Chem. 1985, 50,
4014. (e) An account addressing stereoselective cyclizations of allylsilanes
with iminium ions generated by a Beckmann rearrangement has appeared,
see: Schinzer, D.; Bo, Y. Angew. Chem., Int. Ed. Engl. 1991, 30, 687.
(3) (a) Jin, J.; Smith, D. T.; Weinreb, S. M. J. Org. Chem. 1995, 60,
5366. (b) Borzilleri, R. M.; Weinreb, S. M. J. Am. Chem. Soc. 1994, 116,
9789.
(4) (a) In contrast to allylsilanes, 2-propylidene-1,3-bis(silane)s have seen
relatively little use in synthesis. For pertinent references concerning the
use of these compounds as well as related methodology, see: Rubiralt, M.;
Diez, A.; Miguel, D. Syn. Commun. 1992, 22, 359. (b) Guyot, B.; Pornet,
J.; Miginiac, L. J. Organomet. Chem. 1990, 386, 19. (c) Guyot, B.; Pornet,
J.; Miginiac, L. Tetrahedron 1991, 47, 3981.
(5) (a) Rie, H.; Masaki, N.; Ohno, K.; Osaki, K.; Taga, T.; Uyeo, S. J.
Chem. Soc., Chem. Commun. 1973, 125. (b) Sakata, K.; Aoki, K.; Chang,
C.; Sakurai, A.; Tamura, S.; Murakoshi, S. Agric. Biol. Chem. 1978, 42,
457.
(6) Danishefsky, C.; McKee, R.; Singh, R. K. J. Am. Chem. Soc. 1977,
99, 7711.
(7) All new compounds have been fully characterized by 1H and 13C
NMR and IR and possess satisfactory combustion analyses or exact mass.
1
(8) Aldimine geometrical constitution was determined by 300 MHz H
NMR.
S0002-7863(95)04136-9 CCC: $12.00 © 1996 American Chemical Society

Communications to the Editor
J. Am. Chem. Soc., Vol. 118, No. 17, 1996 4201
Scheme 4
Figure 1.
Scheme 5a
Table 1. Stereocontrolled Monocyclizations of Representative
2-Propylidene-1,3-bis(silane) Bearing Iminesa
a (a) i: TiCl4 (1 equiv), CH2Cl2, -78 °C f rt. ii: KHCO3 aqueous,
inverse addition. (b) Lawesson’s reagent (0.55 equiv), (i-Pr)2NEt (0.25
equiv). (c) Et3O+BF4-, CH3CN, 0 °C f rt.
a 1Isolated yield from aminoallylbis(silane) (2 steps). 2Obtained from
integration of expanded olefinic region of 300 MHz H NMR spectra
bicyclization of amine 6 could be readily achieved by treatment
with aqueous CH2O (4.0 equiv, CH3CN, 1-2 h, rt) followed
by TFA (1.0 equiv, rt, 8 h) to furnish 3c as its trifluoroacetate
derivative in 88% yield.14
1
of crude pyrrolidines and/or isolated N-tosylates. All N-tosylates were
prepared from crude pyrrolidines. In some cases, the presence of mono-
desilylated imine complicated analysis of crude pyrrolidines, hence N-Ts
derivatives were prepared in all cases for accurate analysis. 3Other
product is monodesilylated imine. 4Imine prepared at -10 °C with
In 1973, the potent natural insecticide stemofoline (4) was
isolated and structurally characterized by Sakata and co-
workers.5 In principle, the essential azatricyclic core of this
structurally unique alkaloid could be elaborated in a highly
convergent manner via tandem intramolecular 2-propylidene-
1,3-bis(silane) imine cyclizations. This possibility was tested
for a model substrate as follows. Condensation of 6 with ethyl
levulinate provided 11 in quantitative yield as a g9:1 E:Z
mixture (NMR). Exposure of 11 to TiCl4 (1.0 equiv, Vide supra)
resulted in sequential stereoselective allylsilane-imine cycliza-
tion-lactam formation to secure pyrrolizidone 12a directly as a
single diastereomer in 80% yield after chromatography.15
Treatment of 12a with Lawesson’s reagent [0.55 equiv, 0.25
equiv (i-Pr)2NEt, PhMe, rt] provided thiolactam 12b in 97%
1
1.1 equiv CH3CHO. 5Single diastereomer detected in 300 MHz H
NMR spectrum. 6Inverse addition of the aldimine to TiCL4 prior to
cyclization.
evidence for the relative stereochemical orientation of the
substituents at positions 2 and 3. Specifically, irradiation of
the C-3 methine (H(3)) of the major isomer (10gcis) gave rise
to a 11.7% NOE enhancement at H(2). Corresponding irradiation
of H(3) of the minor isomer (10gtrans) led to a much smaller
(2.4%) NOE signal at H(2). Conclusive proof of cis relative
stereochemistry within the major isomer was subsequently
provided by single-crystal X-ray structure determination (Figure
1). Stereochemical assignments for pyrrolidines 8a-f were
derived by analogous NOE studies on the corresponding N-tosyl
derivatives (10a-f). A summary of the results obtained for
TiCl4-mediated cyclizations of imines 7a-g is provided in Table
1.
The ability of 2-propylidene-1,3-bis(silane) moieties to
participate as nucleophiles in consecutive cyclizations leading
to 1-aza[3.2.1]bicyclooctanes12 was subsequently demonstrated
by sequential exposure of pyrrolidines 8a and 8b to aqueous
CH2O [2.0 equiv, H2O-THF (3:1)] followed by TFA [1.05
equiv, 0 °C f rt]13 to provide isotropanes 3a and 3b in 73%
and 76% isolated yield, respectively. Significantly, direct
-
yield. Exposure of 12b to Et3O+BF4 (1.0 equiv, CH3CN, 0
°C) followed by warming to rt resulted in consecutive S-alky-
lation-intramolecular desilylative cyclization to deliver the
bridged tricyclic pyrrolizidine 13 in 90% isolated yield.
In conclusion, this study has demonstrated that 2-propylidene-
1,3-bis(silane) moieties can serve as versatile bis-nucleophiles
in highly efficient and stereoselective annulation sequences
leading to bridged polycyclic molecules. The utilization of this
and related allylsilane-based cyclization methodology for the
stereodefined synthesis of bioactive substances is under current
investigation.
Acknowledgment. Generous financial support for this research by
grants from the National Institutes of Health and the National Science
Foundation is gratefully acknowledged. T.S.L. wishes to thank the
Alexander von Humboldt Foundation for a research fellowship (1993-
1995). The authors wish to thank Mr. Ray Larsen of the MSU X-ray
facility for determining the structure of 10gcis.
Supporting Information Available: Listings of 1H and 13C NMR,
IR, and HRMS or elemental composition data for all new compounds
(10 pages). Ordering information is given on any current masthead
page.
(9) Representative experimental procedure: trans-2-Isopropyl-3-[(3-
trimethylsilyl)isopropenyl]pyrrolidine 8a. To a solution of amine 6 (300
mg, 1.22 mmol) in THF (3.5 mL) was added activated 4 Å molecular sieves
(700 mg) followed by isobutyraldehyde (134 µL, 1.48 mmol), and the
solution was stirred for 12 h at rt. The reaction mixture was diluted with
Et2O (3 mL) and filtered through a celite pad. Evaporation of solvents
and excess aldehyde in Vacuo afforded imine 7a (364 mg, 99%) as a
colorless oil which was used immediately in the next step. A solution of
imine 7a (364 mg, 1.22 mmol) in CH2Cl2 (8 mL) was cooled to -78 °C,
and TiCl4 (1.22 mL, 1.22 mmol of a 1.0 M toluene solution) was added
dropwise with vigorous stirring. The resulting deep orange solution was
allowed to gradually warm to room temperature (2-3 h) after which stirring
was maintained for an additional 2 h. The reaction mixture was transferred
dropwise Via cannula into vigorously stirred, saturated aqueous KHCO3
(16 mL) at 0 °C, and the biphasic mixture was stirred for 30 min at rt. The
organic layer was separated and the aqueous phase was extracted with CH2-
Cl2 (2 × 10 mL). The combined organic phases were dried over Na2SO4,
filtered, and concentrated. The residual oil was dissolved in pentane (10
mL), filtered through a celite pad, and concentrated in vacuo to furnish the
title pyrrolidine 8a (272 mg, 98%) as a colorless oil.
JA954136M
(12) Isotropanes of this substructure type have been shown to possess
activity in combatting dementia resulting from Alzheimer’s disease: Jenkins,
S. M.; Wadsworth, H. J.; Bromidge, S.; Orlek, B. S.; Wyman, P. A.; Riley,
G. J.; Hawkins, J. J. Med. Chem. 1992, 35, 2392.
(13) (a) Larsen, S. D.; Grieco, P. A.; Fobare, W. F. J. Am. Chem. Soc.
1986, 108, 3512. (b) Grieco, P. A.; Fobare, W. F. Tetrahedron Lett. 1986,
27, 5067.
(14) The volatile isotropane was isolated by extraction of the basified
reaction mixture followed by neutralization with 1 equiv of TFA.
(15) NMR analysis of the crude cyclization product provided no evidence
for the formation of the diastereomeric cyclization product.
(10) In all likelihood, tautomerization of the intermediate imine-Lewis
Acid complex serves as the source of [H+] in these instances.
(11) Significantly, the majority of cases involving cyclization onto imines
derived from ketones which have been examined thus far proceed with
comparatively poor efficiency.