A novel, stereoselective silyl-directed stevens [1,2]-shift of ammonium ylides

Article abstract of DOI:10.1021/ol025951r

(figure presented) The silyl group of 2-silylpyrrolidines such as 1 plays several critical roles: a stereochemical control element in a facially selective carbenoid addition to the ring nitrogen, a stereochemical "placeholder" during regioselective 1,2-migration with retention by the resulting spirocyclic ammonium ylide, and a hydroxyl surrogate for an eventual stereoselective Fleming-Tamao oxidation. This chemistry represents a novel use of the Stevens rearrangement and offers a short, enantioselective route to hydroxylated quinolizidines such as 3 from Boc-pyrrolidine.

Full text of DOI:10.1021/ol025951r

ORGANIC
LETTERS
2002
Vol. 4, No. 17
2813-2816
A Novel, Stereoselective Silyl-Directed
Stevens [1,2]-Shift of Ammonium Ylides
,†
John A. Vanecko and F. G. West*
Department of Chemistry, UniVersity of Utah, 315 S. 1400 East, Rm. 2020,
Salt Lake City, Utah 84112-0850
frederick.west@ualberta.ca
Received March 29, 2002
ABSTRACT
The silyl group of 2-silylpyrrolidines such as 1 plays several critical roles: a stereochemical control element in a facially selective carbenoid
addition to the ring nitrogen, a stereochemical “placeholder” during regioselective 1,2-migration with retention by the resulting spirocyclic
ammonium ylide, and a hydroxyl surrogate for an eventual stereoselective Fleming−Tamao oxidation. This chemistry represents a novel use
of the Stevens rearrangement and offers a short, enantioselective route to hydroxylated quinolizidines such as 3 from Boc-pyrrolidine.
The Stevens rearrangement of ammonium ylides offers a
convenient approach for the formation of new carbon-
carbon bonds adjacent to nitrogen through a [1,2]-shift of
one of the ammonium substituents to the neighboring ylide
carbon.1 Despite considerable mechanistic evidence in sup-
port of an intermediate radical pair, the Stevens [1,2]-shift
has been shown to proceed with moderate to high retention
of configuration when a chiral migrating group is employed.2
A related issue concerns a chirality transfer from the
stereogenic ammonium nitrogen to the adjacent carbon,
which we have shown to be possible in the case of cyclic
ammonium ylides.3 A recently described synthesis of the
alkaloid epilupinine in five steps from proline ester illustrated
both of these points.4 In this synthesis, the original proline
stereocenter influences the configuration at the second,
temporary one at nitrogen, which then permits the preserva-
tion of the original center during its [1,2]-shift, an example
of the principle Seebach has labeled “self-regeneration of
stereocenters”.5 One limitation of this methodology though
is the need for a conjugating group on the migrating carbon,
typically aryl or carbonyl,6 presumably to stabilize the
intermediate radical center.
The ease with which fused bicyclic amines of the quino-
lizidine, indolizidine, and pyrrolizidine classes might be
constructed using spirocyclic ammonium ylide intermediates
suggested the possible application of this approach to
biologically important indolizidine or quinolizidine alka-
loids,7 as well as related unnatural analogues (Scheme 1).
However, it was unclear how such polyhydroxylated skel-
etons could be efficiently assembled, given the apparent need
for carbon-containing stabilizing groups in the key [1,2]-
shift. For this reason, we set out to develop a new application
of the Stevens rearrangement where a suitable hydroxyl
surrogate (“X”) could be used in place of a conjugating group
and allow for smooth rearrangement followed by convenient
conversion to the desired hydroxyl functionality. Here we
describe a novel silyl-directed Stevens rearrangement and
† Current address: Department of Chemistry, University of Alberta, W5-
67 Chemistry Centre, Edmonton, AB, T6G 2G2, Canada.
(5) Review: Seebach, D.; Sting, A. R.; Hoffmann, M. Angew. Chem.,
Int. Ed. Engl. 1996, 35, 2709-2748.
(1) (a) Sato, Y.; Shirai, N. Yakugaku Zasshi 1994, 114, 880-887. (b)
Marko´, I. E. In ComprehensiVe Organic Synthesis; Trost, B. M., Fleming,
I., Eds.; Pergamon: Oxford, 1991; Vol. 3, pp 913-974. Lepley, A. R.;
Guimanini, A. G. In Mechanisms of Molecular Migrations; Thyagarajan,
B. S., Ed.; Interscience: New York, 1971; Vol. 3, pp 297-440.
(2) Ollis, W. D.; Rey, M.; Sutherland, I. O. J. Chem. Soc., Perkin Trans.
1 1983, 1009-27.
(3) Glaeske, K. W.; Arif, A. M.; West, F. G. Org. Lett. 1999, 31-33.
(4) (a) Naidu, B. N.; West, F. G. Tetrahedron 1997, 53, 16565-16574.
(b) West, F. G.; Naidu, B. N. J. Am. Chem. Soc. 1994, 116, 8420.
(6) For a prior discussion of the scope of this chemistry, see: West, F.
G.; Naidu, B. N. J. Am. Chem. Soc. 1993, 115, 1177-1178.
(7) Reviews: (a) El Nemr, A. Tetrahedron 2000, 56, 8579-8629. (b)
Elbein, A. D.; Molyneux, R. J. In Iminosugars as Glycosidase Inhibitors;
Stutz, A. E., Ed.; Wiley-VCH: Weinheim, Germany, 1999; pp 216-251.
(c) Tyler, P. C.; Winchestter, B. G. In Iminosugars as Glycosidase Inhibitors;
Stutz, A. E., Ed.; Wiley-VCH: Weinheim, Germany 1999; pp 125-156.
(d) Goss, P. E.; Baker, M. A.; Carver, J. P.; Dennis, J. W. Clin. Cancer
Res. 1995, 1, 935-44.
10.1021/ol025951r CCC: $22.00 © 2002 American Chemical Society
Published on Web 07/20/2002

Scheme 1
Scheme 2
its application to the stereoselective construction of dihy-
droxyquinolizidines.
Combined with the ready accessibility of optically enriched
2-silylpyrrolidines using Beak’s asymmetric lithiation meth-
odology,8 the proven utility of Fleming-Tamao-type oxida-
tive desilylations9 made the silyl group an obvious choice
for exploring new methodology concerning the Stevens
rearrangement. The success of this approach would depend
on the ability of the silyl group to direct and/or facilitate the
[1,2]-shift. A closer look at the literature revealed that in
contrast to their ionic counterparts,10 relatively little is known
regarding the effect of silyl substitution on the generation
or stability of adjacent radicals.11 Wilt and co-workers
reported an increased reactivity of R-halosilanes toward
halogen abstraction by tin radicals but ascribed this to a
kinetic polar effect rather than any special thermodynamic
stability conferred by the silyl group.12,13 Perhaps the closest
recent experimental evidence in support of silyl R-carbon-
centered radical stabilization is found in the report of Uemura
and co-workers.14 This work focused on the rhodium-
catalyzed cycloaromatization of silylated acyclic enediynes
followed by hydrogen abstraction with preferential formation
of R-silyl vs â-silyl radicals. The uncertainty associated with
the effect of silyl groups on adjacent radical centers provided
an additional incentive for investigating the proposed silyl-
directed [1,2]-shift chemistry.
isomer 4a15 is analogous to that seen in the related proline
series from our labs.4
As in that example, stereoselectivity apparently results
from the preferred attack of the intermediate metallocarbene
cis to the larger non-hydrogen substituent at C-2, followed
by migration with retention (Scheme 3). Assuming a pseu-
Scheme 3
An initial investigation of the feasibility of the silyl-
directed [1,2]-shift strategy employed the known8 (S)-N-Boc-
2-trimethylsilylpyrrolidine 1a, which was deprotected and
alkylated with bromide 26 (Scheme 2). Much to our delight,
when diazoketone substrate 3a was treated with 10 mol %
Cu(acac)2 in toluene at reflux,4 it furnished quinolizidines
4a and 5a in 58% yield as a 2:1 ratio of separable
diastereomers. The relative stereochemistry of the major
doequatorial disposition of the large silyl group, we find that
rapid pyramidal inversion at nitrogen permits two possible
reactive forms leading to diastereomeric ylides A and B. Path
a is expected to be favored due to a preference for the
invertomer possessing a trans relationship between the silyl
group and the carbene side-chain. This argument is consistent
with results seen in our previous studies,4 as well as those
of Clark and co-workers.16
(8) (a) Beak, P.; Kerrick, S. T.; Wu, S.; Chu, J. J. Am Chem. Soc. 1994,
116, 3231-3239. (b) Beak, P.; Basu, A.; Gallagher, D. J.; Park, Y. S.;
Thayumanavan, S. Acc. Chem. Res. 1996, 29, 552-560.
(9) (a) Jones, G. R.; Landais, Y. Tetrahedron 1996, 52, 7599-7682. (b)
Fleming, I. Chemtracts: Org. Chem. 1996, 1-64.
(10) (a) Siehl, H.-U.; Muller, T. In Chemistry of Organic Silicon
Compounds; Rappoport, Z., Apeloig, Y., Eds.; Wiley: Chichester, UK,
1998; Vol. 2, Parts 1-3, pp 595-701. (b) Brinkman, E. A.; Berger, S.;
Brauman, J. I. J. Am. Chem. Soc. 1994, 116, 8304-8310.
(11) Davidson, I. M. T.; Barton, T. J.; Hughes, K. J.; Ijadi-Maghsoodi,
S.; Revis, A.; Paul, G. C. Organometallics 1987, 6, 4-646. For a recent
report on the short lifetime of R-silyl radicals, see: Le Gall, E.; Hurvois,
J.-P.; Sinbandhit, S. Eur. J. Org. Chem. 1999, 2645, 5-2653.
(12) Wilt, J. W.; Belmonte, F. G.; Zieske, P. A. J. Am. Chem. Soc. 1983,
105, 5665-5675.
A homolysis/recombination mechanism can potentially
furnish racemic products through a pathway in which the
intermediate biradical suffers randomization. However, NMR
(13) Wilt, J. W.; Lusztyk, J.; Peeran, M.; Ingold, K. U. J. Am. Chem.
Soc. 1988, 110, 281-287.
(14) Manabe, T.; Yanagi, S.; Ohe, K.; Uemura, S. Organometallics 1998,
17, 2942-2944 and references therein.
(15) Strong support for this stereochemical assignment comes from the
presence of a large 1,2-diaxial coupling between the adjacent bridgehead
and silyl-substituted methines in the proton NMR spectrum.
2814
Org. Lett., Vol. 4, No. 17, 2002

analysis of 4a and 5a using the chiral shift reagent Eu(hfc)3
showed that both were formed with significant stereochem-
ical retention (84% for 4a and 74% for 5a).17 This suggests
that recombination of the initially formed biradical C is fast
in comparison to bond-rotation to achiral biradical D
(Scheme 4). To our knowledge, this represents the first
after 48% conversion.19 Treatment of 3b under the conditions
used for the rearrangement of 3a to 4a + 5a furnished
quinolizidine 4b as a single diastereomer in 55% yield.20
A
slight reduction in reaction temperature led to a small increase
in yield, but at temperatures lower than 85 °C the reaction
became sluggish. Other soluble copper catalysts also gave
inferior results, as did Rh2(OAc)4.
It is interesting to note that 4b was isolated as a single
diastereomer, given the 2:1 ratio of 4a to 5a seen in the
previous series. A possible explanation for this difference is
a higher conformational rigidity of the pyrrolidine ring prior
to carbenoid addition due to the increased steric bulk of the
phenyldimethylsilyl group, leading to a greater preference
for ylide diastereomer A (Scheme 3).
Scheme 4
Quinolizidine 4b was obtained in 77% ee (1H NMR with
Eu(hfc)3), indicating 91% stereochemical retention17 during
the [1,2]-shift. This case displayed a higher degree of
retention than either the trimethylsilyl example 3a or the
earlier proline-derived substrate.4 It is possible that rate of
randomization of the relatively more stable ester-substituted
biradical in the proline example is faster than it is for the
silyl-substituted biradicals. However, the improved degree
of retention by 3b over that by 3a, although welcome, is
not easily explained.
Finally, the suitability of the silyl-directing group as a
hydroxyl surrogate needed to be investigated. Quinolizidine
4b could be diastereoselectively reduced in high yield with
Dibal-H21 to furnish alcohol 6b (Scheme 6).22 Sodium
borohydride furnished diastereomers 6b and 7b with a
modest selectivity for axial attack product 7b. Fleming-
Tamao oxidation of 6b under Denmark’s conditions23
proceeded smoothly to give quinolizidinediol 8b in 91%
yield.24 Support for the stereochemical assignments of 6b
and 7b was obtained by the conversion of the 1:4 mixture
of 6b/7b to 8b and known symmetrical diol 9b.25
example of a silyl-directed Stevens rearrangement. Though
this novel [1,2]-shift is gratifying, this chemistry was not
applicable to the synthesis of hydroxylated quinolizidines
since the trimethylsilyl group is not suitable for subsequent
Fleming-Tamao oxidation. At this point, we next turned
our attention to the corresponding phenyldimethylsilyl
derivative.
Asymmetric lithiation and silylation under the standard
conditions8 furnished (S)-N-Boc-2-phenyldimethylsilylpyr-
rolidine 1b in 92% yield and 85% ee (Scheme 5).18 The Boc
Scheme 5
(19) Alkylation product 3b was found to decompose slowly under the
conditions of its formation, requiring that the reaction be stopped prior to
complete consumption of starting material. The same problem, though less
severe, was encountered in the alkylation of 3a.
(20) Representative Procedure for Conversion of 3b to 4b. To a
stirring solution of Cu(acac)2 (0.011 g, 0.040 mmol) in a solution of degassed
toluene (36 mL) at 85 °C was added a solution of diazoketone 3b (0.123
g, 0.404 mmol) in degassed toluene (4.0 mL) via syringe pump over 1 h.
Upon complete addition, the syringe was washed with 2 mL of toluene
and the contents were added directly to the reaction. The resulting solution
was allowed to cool to room temperature. The reaction mixture was
concentrated and immediately loaded on a 1.5 × 10 cm column and eluted
with a gradient of 20 mL each of 10, 20, and 40% EtOAc/hexanes collecting
2 mL fractions. Product-containing fractions were concentrated under
reduced pressure to give 4b (0.067 g, 58%) as a colorless oil. The product
was a single isomer as determined by proton and carbon NMR: Rf 0.66
(10% MeOH/CH2Cl2); IR (neat) 2937, 2855, 2799, 2752, 1720 cm-1; [R]20
D
+30.8 (c 0.34, CHCl3); 1H NMR (500 MHz, CDCl13) δ 7.48-7.46 (m,
2H), 7.32-7.31 (m, 3H), 2.95-2.85 (br m, 2H), 2.56 (d, J ) 11.0 Hz,
1H), 2.40 (ddd, J ) 11.0, 11.0, 4.0 Hz, 1H), 2.32 (ddd, J ) 13.0, 3.5, 3.5
Hz, 1H), 2.16 (ddd, J ) 13.5, 2.0, 2.0 Hz, 1H), 2.07 (ddd, J ) 12.0, 12.0,
8.0 Hz, 1H), 1.97-1.88 (m, 2H), 1.75-1.70 (br m, 1H), 1.59-1.44 (m,
2H), 1.39 (ddd, J ) 14.5, 11.0, 3.5 Hz, 1H), 1.14 (dddd, J ) 13.5, 12.8,
12.8, 4.0 Hz, 1H), 0.32 (s, 3H), 0.26 (s, 3H); 13C NMR (125 MHz, CDCl3)
δ 207.9, 139.2, 134.4, 128.8, 127.6, 72.7, 56.4, 55.4, 40.3, 26.8, 26.2, 26.2,
22.6, -2.1, -2.7. Anal. Calcd for C17H25NOSi: C, 71.03; H, 8.77; N, 4.87.
Found: C, 71.0; H, 8.93; N, 4.52.
group was removed with anhydrous HCl, and the free amine
was alkylated as before with 2 to provide 3b in 47% yield
(16) (a) Clark, J. S.; Hodgson, P. B.; Goldsmith, M. D.; Blake, A. J.;
Cooke, P. A.; Street, L. J. J. Chem. Soc., Perkin Trans. 1 2001, 3325-
3337. (b) Clark, J. S.; Hodgson, P. B. Tetrahedron Lett. 1995, 36, 2519-
2522.
(17) Retention was calculated as % ee of quinolizidines 4a (71%), 5a
(63%), or 5b (77%) divided by % ee of 3a or 3b (both 85%).
(18) Optical purity of 1b was determined by HPLC, using a Daicel
(21) Reduction with L-selectride or under Meerwein-Pondorff-Verley
conditions also gave 6b exclusively, but in slightly lower yield.
(22) 2D NOESY NMR data clearly indicated the expected axial alcohol
resulting from equatorial attack of the bulky hydride reagent.
i
CHIRACEL OD-H column with a mobile phase of 0.25% PrOH/hex and
a flow rate of 0.5 mL/min.
(23) Denmark, S. E.; Hurd, A. R. J. Org. Chem. 2000, 65, 2875-2886.
Org. Lett., Vol. 4, No. 17, 2002
2815

This work constitutes the first examples of silyl-directed
Stevens [1,2]-shifts of ammonium ylides. Migration occurs
with high retention in the case of 3b, offering a unique
application of Beak’s asymmetric lithiation methodology.
Subsequent stereoselective ketone reduction and Fleming-
Tamao oxidation affords the corresponding diols. This route
furnishes dihydroxyquinolizidines in six steps from readily
available Boc-pyrrolidine. Additional examples of this
chemistry involving other ring skeletons will be described
elsewhere.
Scheme 6
Acknowledgment. This work was supported by the
donors of the Petroleum Research Fund, administered by the
American Chemical Society.
Supporting Information Available: Experimental pro-
cedures and spectral data for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
Polyhydroxylated quinolizidines have been identified in
recent years as potential glycosidase inhibitors26 in analogy
to the better known indolizidines. The strategy described
above offers a short and flexible route to such compounds.
OL025951R
(24) Approximate ee of diol 8b was found to be 60% ee (NMR chiral
shift analysis with Eu(hfc)3), indicating a small degradation in optical purity
of 4b during the subsequent manipulations.
(25) Marquart, A. L.; Podlogar, B. L.; Huber, E. W.; Demeter, D. A.;
Peet, N. P.; Weintraub, H. J. R.; Angelastro, M. R. J. Org. Chem. 1994,
59, 2092-2100.
(26) (a) Schaller, C.; Vogel, P. HelV. Chim. Acta 2000, 83, 193-232.
(b) Overkleeft, H. S.; Bruggeman, P.; Pandit, U. K. Tetrahedron Lett. 1998,
39, 3896-3872. (c) Carretero, J. C.; Arrrayas, R. G.; De Garcia, I. S.
Tetrahedron Lett. 1997, 38, 8537-8540. (d) Pearson, W. H.; Hembre, E.
J. J. Org. Chem. 1996, 61, 5537-5545.
2816
Org. Lett., Vol. 4, No. 17, 2002