Asymmetrie synthesis of unsaturated monocyclic and bicyclic nitrogen heterocycles

Article abstract of DOI:10.1021/ol900880w

Hydrolysis of scalemic trichloroacetamides Cl₃CCONHCH(R) CHCH₂ and allylatlon, or acylatlon with but-3-enoic acid, followed by ring-closing metathesis resulted In the formation of unsaturated pyrrolidine and piperidine building blocks. These were employed in the synthesis of (S)-coniine (R = Pr) and a formal synthesis of (+)-anlsomycln (R = p-MeOC ₆H₄). Extension of this methodology with R = CH ₂CHCH₂ employing two ring-closing metatheses resulted In the synthesis of unsaturated quinolizidinone and indolizidinone frameworks.

Full text of DOI:10.1021/ol900880w

ORGANIC
LETTERS
2009
Vol. 11, No. 13
2892-2895
Asymmetric Synthesis of Unsaturated
Monocyclic and Bicyclic Nitrogen
Heterocycles
Hiroshi Nomura and Christopher J. Richards*
School of Chemical Sciences and Pharmacy, UniVersity of East Anglia,
Norwich, NR4 7TJ, U.K.
chris.richards@uea.ac.uk
Received April 22, 2009
ABSTRACT
Hydrolysis of scalemic trichloroacetamides Cl3CCONHCH(R)CHCH2 and allylation, or acylation with but-3-enoic acid, followed by ring-closing
metathesis resulted in the formation of unsaturated pyrrolidine and piperidine building blocks. These were employed in the synthesis of
(S)-coniine (R ) Pr) and a formal synthesis of (+)-anisomycin (R ) p-MeOC6H4). Extension of this methodology with R ) CH2CHCH2 employing
two ring-closing metatheses resulted in the synthesis of unsaturated quinolizidinone and indolizidinone frameworks.
The advent of active and accessible ruthenium-based ring-
closing metathesis (RCM) catalysts has transformed the
synthesis of cyclic organic compounds.1 Not least among
the categories of compounds synthesized in this way are
alkaloids, especially examples where RCM is employed as
a key step in the synthesis of pyrrolidines, piperidine, and
other nitrogen heterocycles.2 Although desymmetrizing RCM
reactions are now well established for the synthesis of
nonracemic compounds,3 the asymmetric syntheses of chiral
five- and six-membered-ring alkaloids generally employ
scalemic amino dienes derived from a variety of chiral pool
and asymmetric catalysis sources.4 Within the latter category,
transition-metal-catalyzed allylic amination reactions have
been extensively investigated.5 An alternative and highly
enantioselective method for the synthesis of chiral allylic
amines is the allylic imidate (or Overman) rearrangement
(4) (a) Liu, S.; Fan, Y.; Peng, X.; Wang, W.; Hua, W.; Akber, H.; Liao,
L. Tetrahedron Lett. 2006, 47, 7681–7684. (b) Angle, S. R.; Bensa, D.;
Belanger, D. S. J. Org. Chem. 2007, 72, 5592–5597. (c) Lebrun, S.; Couture,
A.; Deniau, E.; Grandclaudon, P. Org. Lett. 2007, 9, 2473–2476. (d) Pearson,
M. S. M.; Evain, M.; Mathe´-Allainmat, M.; Lebreton, J. Eur. J. Org. Chem.
2007, 4888–4894. (e) Murruzzu, C.; Riera, A. Tetrahedron: Asymmetry
2007, 18, 149–154.
(5) (a) Welter, C.; Moreno, R. M.; Streiff, S.; Helmchen, G. Org. Biomol.
Chem. 2005, 3266–3268. (b) Helmchen, G.; Dahnz, A.; Du¨bon, P.;
Schelwies, M.; Weihofen, R. Chem. Commun. 2007, 675–691. (c) Singh,
O. V.; Han, H. J. Am. Chem. Soc. 2007, 129, 774–775.
(1) (a) Grubbs, R. H.; Miller, S. J.; Fu, G. C. Acc. Chem. Res. 1995,
28, 446–452. (b) Grubbs, R. H.; Chang, S. Tetrahedron 1998, 54, 4413–
4450.
(2) (a) Felpin, F.-X.; Lebreton, J. Eur. J. Org. Chem. 2003, 3693–3712.
(b) Brenneman, J. B.; Martin, S. F. Curr. Org. Chem. 2005, 9, 1535–1549.
(c) Compain, P. AdV. Synth. Catal. 2007, 349, 1829–1846.
(3) For application to the asymmetric synthesis of nitrogen heterocycles,
see: (a) Dolman, S. J.; Sattely, E. S.; Hoveyda, A. H.; Schrock, R. R. J. Am.
Chem. Soc. 2002, 124, 6991–6997. (b) Dolman, S. J.; Schrock, R. R.;
Hoveyda, A. H. Org. Lett. 2003, 5, 4899–4902.
(6) Overman, L. E.; Owen, C. E.; Pavan, M. M.; Richards, C. J. Org.
Lett. 2003, 5, 1809–1812.
(7) (a) Anderson, C. E.; Overman, L. E. J. Am. Chem. Soc. 2003, 125,
12412–12413. (b) Kirsch, S. F.; Overman, L. E.; Watson, M. P. J. Org.
Chem. 2004, 69, 8101–8104. (c) Watson, M. P.; Overman, L. E.; Bergman,
R. G. J. Am. Chem. Soc. 2007, 129, 5031–5044. (d) Nomura, H.; Richards,
C. J. Chem.–Eur. J. 2007, 13, 10216–10224.
10.1021/ol900880w CCC: $40.75
Published on Web 05/29/2009
 2009 American Chemical Society

of trifluoroacetimidates6 and trichloroacetimidates 1,7 cata-
lyzed by the chloride-bridged cobalt oxazoline palladacycle
3 (Scheme 1).8 In this paper, we illustrate the use of the
Scheme 3. Synthesis of 3,4-Dehydropyrrolidines and
Application to the Synthesis of Protected Azasugar 7
Scheme 1. Allylic Imidate Rearrangement and Catalyst 3
products of this reaction for the generation of unsaturated
mono- and bicyclic nitrogen heterocycles, scalemic building
blocks with the potential to be applied to the synthesis of a
variety of alkaloids and related structures.9,10
We have previously reported that the rearrangement
of trichloroacetimidate 1a catalyzed by just 0.25 mol % of
(S,pR)-3 in acetonitrile at 70 °C resulted in the isolation of
(S)-2a in 90% yield and 92% ee (Scheme 2).7d Due to the
Scheme 2. COP-Cl-Catalyzed Allylic Imidate Rearrangements
ceeded satisfactorally to give amino diene (S)-5a. Application
of 2 mol % of Grubbs’ second-generation catalyst resulted
in an essentially quantitative conversion into unsaturated
pyrrolidine (S)-6a.
This methodolgy was extended to the formal synthesis of
(+)-anisomysin starting from the (E)-4-(4′-methoxyphenyl)-
but-2-enol12-derived trichloroacetimiate 1b. The use of
(S,pR)-3 at a catalyst loading of 0.75 mol % gave (S)-2b in
high yield with an ee of 91% (Scheme 2). Subsequent
transformations as before resulted in the isolation of (S)-6b
with an overall yield of 58% (Scheme 3). This compound,
previously synthesized by the use of a valine-based chiral
formamidine as a chial auxiliary, was reported as an
intermediate in the synthesis of (+)-anisomysin.13 Dihy-
droxylation of (S)-6b with AD-mix-R gave (2S,3S,4R)-7 as
a single diastereoisomer after purification by chromatogra-
phy.14,15 Enantiomeric (2R,3R,4S)-2-epidesacetylanisomycin
has previously been identified as a nanomolar R-galactosidase
inhibitor.16
stability of the conjugate base of 2a, the direct allylation of
this compound proved to be low yielding.11 Instead, follow-
ing facile hydrolysis of the trichloroacetamide and subsequent
Cbz-protection to give (S)-4a (Scheme 3), allylation pro-
(8) (a) Stevens, A. M.; Richards, C. J. Organometallics 1999, 18, 1346–
1348. (b) Anderson, C. E.; Kirsch, S. F.; Overman, L. E.; Richards, C. J.;
Watson, M. P. Org. Synth. 2007, 84, 148–155.
(9) First reported at the 236th ACS National Meeting, Philadelphia, PA,
ORGN 460.
(10) The application of sequential (S)-COP-Cl-catalyzed allylic imidate
rearrangement and RCM was recently reported for the synthesis of
1-trichloroacetamidocyclohex-2-ene: Swift, M. D.; Sutherland, A. Org. Lett.
(12) Taber, D. F.; Sikkander, M. I.; Berry, J. F.; Frankowski, K. J. J.
Org. Chem. 2008, 73, 1605–1607.
2007, 9, 5239–5242
.
(11) The highest yield obtained was 47% using sodium hydride, allyl
bromide, and 18-crown-6.
(13) (a) Meyers, A. I.; Dupre, B. Heterocycles 1987, 25, 113–116. (b)
Schumacher, D. P.; Hall, S. S. J. Am. Chem. Soc. 1982, 104, 6076–6080.
Org. Lett., Vol. 11, No. 13, 2009
2893

With the objective of synthesizing a piperidine analogue
of the unsaturated pyrrolidine (S)-6a, it was found that the
homoallylation of (S)-4a with 3-butenyl bromide was unsuc-
cessful. Instead, hydrolysis of trichloroacetamide (S)-2a was
followed by DCC-mediated acylation with but-3-enoic acid
to give (S)-8 (Scheme 4). Combination with 7 mol % of
alkene-containing moiety were introduced using the meth-
odologies already described in Schemes 4 and 3 to give (S)-
15 and (S)-17, respectively (Scheme 5).
Scheme 5
.
Synthesis and Ring-Closing Metathesis of Trienes 17
and 19
Scheme 4
.
Synthesis of the 4,5-Dehydropiperidinone Framework
and (S)-Coniine
Grubbs’ second-generation catalyst resulted in the direct
formation of (S)-11 (70% yield), but reducing the catalyst
loading led to a significant deterioration in yield. This
problem was partly circumvented by NH to NBoc conversion
to give (S)-9, RCM with 2.7 mol % catalyst, and subsequent
TFA-mediated deprotection to give (S)-11 in 52% overall
yield. Alkene hydrogenation gave a known intermediate in
the synthesis of (S)-coniine 12,17 and this alkaloid was
isolated in 80% yield as a hydrochloride salt following
subsequent amide reduction.
The extension of this methodology to the synthesis of
bicyclic indolizidine and quinolizidine frameworks required
the replacement of the propyl group of allylic amide 2a with
a propenyl substituent, which can then be used in a RCM
reaction for the generation of a second five- or six-membered
ring. To this end, we have demonstrated previously the
application of the COP-Cl-catalyzed allylic imidate rear-
rangement to the synthesis of (S)-2c (68% yield, 84% ee).7d
Following hydrolysis to (S)-13, a protecting group and a third
On addition of Grubbs’ second-generation catalyst, (S)-
15 cyclized to give only the six-membered derivative (S)-
18 and none of the four- and seven-membered alternatives.
In contrast, the RCM reaction of (S)-17 resulted in the
generation of both the five- and six-membered products (S)-
19 and (S)-20 in a 3:4 ratio.18 This ratio of products remained
the same during the course of the reaction. However, after
standing at room temperature in the presence of the catalyst
for approximately 2 months, the ratio of (S)-19 and (S)-20
was 1:2. The latter observation points to the initial 3:4
(14) AD-mix-R was used for convenience as this reaction is primarily
under substrate control. AD-mix-ꢀ also resulted in the formation of 7, but
in a lower yield, 45%. AD-mix-R or ꢀ gave the same diastereoisomer and
in higher diastereoselectivity than OsO4/NMO for a related dihyroxylation
yielding a 1,2-dihydroxyindolizidine derivative: Lindsay, K. B.; Pyne, S. G.
J. Org. Chem. 2002, 67, 7774–7780.
product ratio being a consequence of kinetic control;19
a
combination of any difference in the reactivity of the three
monosubstituted alkenes and five- versus six-membered ring
formation for the one alkene where these two options are
available.
(15) Dihydroxylation facial stereoselectivity was assigned by analogy
to related reactions with 2-substituted-2,5-dihydropyrroles. See ref 14 and:
Mart´ın, R.; Alco´n, M.; Perica`s, M. A.; Riera, A. J. Org. Chem. 2002, 67,
6896–6901.
(18) These were identified by the characteristic ddd pattern for
1
(16) Chapman, T. M.; Courtney, S.; Hay, P.; Davis, B. G. Chem.–Eur.
J. 2003, 9, 3397–3414.
CHCHdCH2 in the H NMR spectrum of (S)-20.
(19) Kinetic control with Grubbs’ second-generation catalyst has been
observed in a number of macrocyclisation reactions: (a) Fu¨rstner, A.; Mu¨ller,
C. Chem. Commun 2005, 5583–5585. (b) Matsuya, Y.; Takayanagi, S.;
Nemoto, H. Chem.–Eur. J. 2008, 14, 5275–5281.
(17) Burke, A. J.; Davies, S. G.; Garner, A. C.; McCarthy, T. D.; Roberts,
P. M.; Smith, A. D.; Rodriguez-Solla, H.; Vickers, R. J. Org. Biomol. Chem.
2004, 2, 1387–1394.
2894
Org. Lett., Vol. 11, No. 13, 2009

The synthesis of an unsaturated quinolizidinone framework
was completed as outlined in Scheme 6. Removal of the Boc
Scheme 8
.
Double-RCM Strategy for the Synthesis of Scalemic
Indolizidinones
Scheme 6. Synthesis of the Quiniolizidinone Framework
avoided due to the reduced reactivity of the conjugated
alkene, the initial cyclization mirroring that of (S)-17
(Scheme 5).
Accordingly, exposure to 2.5 mol % of Grubbs’ second-
generation catalyst resulted in a 1.5:1 ratio of (S)-27 and
(S)-28. Following separation and an increase in the catalyst
loading, the new indolzidinone (S)-29 and the known
indolzidinone (S)-3022 were generated without any cross-
contamination, further evidence that the initial cyclization
proceeds under kinetic control.
group from (S)-18 was followed by allylation of (S)-21
employing sodium hydride as the base. This resulted in the
isolation of the conjugated enamide (S)-22, which underwent
RCM to give (S)-23.20 Double-bond isomerization was
avoided by the use of cesium carbonate as the base which
resulted in a low yield of (S)-24, which in turn led to the
isolation of (S)-25 following RCM.21
Although an analogous methodology with intermediates
(S)-19 and (S)-20 could have been used for the synthesis of
the indolizidine framework, we chose instead a related
strategy based on the double cyclization of a tetraene. This
approach has been applied to the synthesis of racemic
quinolizidinones, and a challenge is achieving selectivity
between the desired fused and undesired “dumbell” bicyclic
products (Scheme 7).20 With chiral tetraene (S)-26, generated
In summary, the combination of a catalytic asymmetric
allylic imidate rearrangement with a catalytic ring-closing
metathesis provides rapid access to a range of unsaturated
nitrogen heterocycles, versitile building blocks for the
synthesis of natural products and related compounds.
Acknowledgment. We thank the EPSRC National Mass
Spectrometry Centre (University of Wales, Swansea) and
Prof. Sos´nicki (Technical University of Szczecin, Poland)
for 13C NMR spectral data for 24 and 25.
Scheme 7
.
Double-RCM Strategy for the Synthesis of Racemic
Quinolizidinones20
Supporting Information Available: Synthesis and char-
acterization data for all compounds reported and the method
of ee determination for compound 2b. This material is
available free of charge via the Internet at http://pubs.acs.org.
OL900880W
(20) Compounds 22 and 23 have previously been reported as racemates:
(a) Ma, S.; Ni, B. Org. Lett. 2002, 4, 639–641. (b) Ma, S.; Ni, B. Chem.–Eur.
J. 2004, 10, 3286–3300.
(21) Compounds 24 and 25 have previously been reported as racemates:
Sos´nicki, J. G. Tetrahedron Lett. 2006, 47, 6809–6812.
(22) Sato, Y.; Nukui, S.; Sodeoka, M.; Shibasaki, M. Tetrahedron 1994,
50, 371–382.
from (S)-17 by deprotection and coupling with acrylic acid
(Scheme 8), we reasoned “dumbell” cyclization would be
Org. Lett., Vol. 11, No. 13, 2009
2895