Ether-directed, stereoselective aza-claisen rearrangements: Synthesis of the piperidine alkaloid, α-conhydrine

Article abstract of DOI:10.1021/ol070424z

Equation presented A new approach for the stereoselective synthesis of the piperidine alkaloid (+)-α-conhydrine and its pyrrolidine derivative has been developed using a palladium(II)-catalyzed, MOM-ether-directed aza-Claisen rearrangement and ring-closing metathesis to effect the key steps.

Full text of DOI:10.1021/ol070424z

ORGANIC
LETTERS
2
007
Vol. 9, No. 8
609-1611
Ether-Directed, Stereoselective
Aza-Claisen Rearrangements: Synthesis
1
of the Piperidine Alkaloid,
Andrew G. Jamieson and Andrew Sutherland*
r-Conhydrine
WestCHEM, Department of Chemistry, The Joseph Black Building,
UniVersity of Glasgow, Glasgow G12 8QQ, U.K.
andrews@chem.gla.ac.uk
Received February 20, 2007
ABSTRACT
A new approach for the stereoselective synthesis of the piperidine alkaloid (+)-r-conhydrine and its pyrrolidine derivative has been developed
using a palladium(II)-catalyzed, MOM-ether-directed aza-Claisen rearrangement and ring-closing metathesis to effect the key steps.
Biologically active alkaloids containing a 2-(1-hydroxyalkyl)-
piperidine unit are abundant in nature and have attracted
much attention due to their antiviral and antitumor proper-
ties.1 This class of compound includes (+)-R-conhydrine
and co-workers have prepared (+)-R-conhydrine using an
iodocyclocarbamation of tetrahydropyridines to effect the key
5
d
step, and the research group of Kumar has reported the
synthesis of (+)-R-conhydrine using a diastereoselective
addition of an organomagnesium reagent to an amino
,2
1
which was first isolated from the seeds and leaves of the
3
5j
poisonous plant, Conium maculatum L, in 1856.
aldehyde. A number of these elegant approaches give (+)-
Following elucidation of its structure in 1933,4 the
R-conhydrine 1 in good overall yield and enantiopurity but
are limited by access to structural analogues (Figure 1).
synthesis of (+)-R-conhydrine 1 and its stereoisomers has
5
been the subject of intense study. Different approaches for
the synthesis of this piperidine alkaloid include a racemic
synthesis by Beak and co-workers involving the R-lithiation
and electrophilic substitution of Boc-piperidines.5a Comins
(
1) Casiraghi, G.; Zanardi, F.; Rassu, G.; Spanu, P. Chem. ReV. 1995,
5, 1677-1716.
2) Michael, J. P. Nat. Prod. Rep. 1997, 14, 619-636 and references
therein.
9
(
Figure 1. (+)-R-Conhydrine and its pyrrolidine analogue.
(
(
(
3) Wertheim, T. Liebigs. Ann. Chem. 1856, 100, 328-330.
4) Sp a¨ th, E.; Adler, E. Monatsh. Chem. 1933, 63, 127-140.
5) For recent examples, see: (a) Beak, P.; Lee, W. K. J. Org. Chem.
We recently began a program to study how the aza-Claisen
rearrangement of allylic trichloroacetimidates (the Overman
1
993, 58, 1109-1117. (b) Hoye, T. R.; Renner, M. K.; Vos-DiNardo, T. J.
J. Org. Chem. 1997, 62, 4168-4170. (c) Guerreiro, P.; Ratovelomanana-
Vidal, V.; Genet, J.-P. Chirality 2000, 12, 408-410. (d) Comins, D. L.;
Williams, A. L. Tetrahedron Lett. 2000, 41, 2839-2842. (e) Agami, C.;
Couty, F.; Rabacco, N. Tetrahedron 2001, 57, 5393-5401. (f) Lysenko, I.
L.; Bekish, A. V.; Kulinkovich, O. G. Russ. J. Org. Chem. 2002, 38, 875-
6
reaction) can be influenced by stereogenic centers within
the molecule. This work led to the development of a MOM-
ether-directed, palladium(II)-catalyzed reaction which allows
the formation of erthyro-products in diastereomeric ratios
8
79. (g) Enders, D.; Nolte, B.; Raabe, G.; Runsink, J. Tetrahedron:
Asymmetry 2002, 13, 285-291. (h) Kandula, S. V.; Kumar, P. Tetrahedron
Lett. 2003, 44, 1957-1958. (i) Kandula, S. V.; Kumar, P. Tetrahedron:
Asymmetry 2005, 16, 3268-3274. (j) Pandey, S. K.; Kumar, P. Tetrahedron
Lett. 2005, 46, 4091-4093. (k) Chang, M.-Y.; Kung, Y.-H.; Chen, S.-T.
Tetrahedron 2006, 62, 10843-10848.
7
of up to 15:1. Further investigation of this process using a
number of structural analogues has shown that both oxygen
atoms of the MOM group are utilized in directing the Pd(II)
1
0.1021/ol070424z CCC: $37.00
© 2007 American Chemical Society
Published on Web 03/20/2007

Scheme 1. Stereoselective MOM-ether-Directed Aza-Claisen
Scheme 2. Synthesis of E-Allylic Alcohol 3
Rearrangement
catalyst to one face of the allylic trichloroacetimidate,
8
resulting in a highly diastereoselective reaction (Scheme 1).
This process has subsequently been used for the stereo-
9
selective synthesis of â- and γ-hydroxy-R-amino acids.
With a good understanding of the ether-directed aza-
Claisen rearrangement, we were interested in using this
process for the efficient synthesis of cyclic natural products
containing erthyro-hydroxyl and -amino functional groups.
We now report a new approach for the stereoselective
synthesis of (+)-R-conhydrine 1 as well as its pyrrolidine
analogue 2, a known inhibitor of a proline-specific endo-
peptidase using our ether-directed aza-Claisen rearrangement
and ring-closing metathesis (RCM) reactions to effect the
key steps.
The allylic trichloroacetimidate 9 was prepared using a
catalytic amount of DBU and trichloroacetonitrile (Scheme
14
3
(
). Aza-Claisen rearrangement of 9 in THF using bis-
acetonitrile)palladium(II) chloride (10 mol %) as the catalyst
gave the erthyro- and threo-allylic trichloroamides 10a and
0b in 52% yield over the two steps in a 12:1 ratio. We
1
0
1
recently reported that the stereochemical outcome of this
directed rearrangement can be optimized using noncoordi-
nating solvents, and so, the reaction was repeated using
The first stage of the synthesis of (+)-R-conhydrine 1
involved the preparation of allylic alcohol 3 required for the
first key step (Scheme 2). Thus, (S)-glycidol 4 was protected
as the tert-butyldimethylsilyl ether followed by regioselective
ring opening of the epoxide using a copper-catalyzed
Grignard reaction to give 5 in excellent yield.11 Formation
of the MOM-ether 6 using H u¨ nig’s base and bromomethyl
methyl ether and then removal of the silyl-ether using TBAF
gave alcohol 7. A one-pot Swern oxidation/Horner-
Wadsworth-Emmons (HWE) reaction gave E-R,â-unsat-
7b
toluene. This gave 10a and 10b in 55% yield and in an
excellent 16:1 ratio. The desired major isomer 10a was then
easily separated from 10b using flash column chromatog-
7b
raphy. As previously observed, these results clearly dem-
onstrate that by switching to a noncoordinating solvent the
Scheme 3. MOM-ether-Directed Rearrangement of 9
12
urated ester 8 in excellent overall yield. Although a number
of different reaction conditions can be used to carry out the
HWE step, we have found that the Masamune-Roush
procedure for this one-pot process is the most efficient, giving
exclusively the E-alkene.13 Reduction of the ester using
DIBAL-H gave the required E-allylic alcohol 3 in 95% yield.
(
6) Overman, L. E.; Carpenter, N. E. Org. React. 2005, 66, 1-107 and
references therein.
7) (a) Jamieson, A. G.; Sutherland, A. Org. Biomol. Chem. 2005, 3,
(
7
35-736. (b) Jamieson, A. G.; Sutherland, A. Org. Biomol. Chem. 2006,
4
, 2932-2937.
(8) Jamieson, A. G.; Sutherland, A. Tetrahedron 2007, 63, 2123-2131.
9) (a) Fanning, K. N.; Jamieson, A. G.; Sutherland, A. Org. Biomol.
(
Chem. 2005, 3, 3749-3756. (b) Swift, M. D.; Sutherland, A. Org. Biomol.
Chem. 2006, 4, 3889-3891.
(
10) Tamoto, K.; Ohuchi, R.; Ono, K. Eur. Pat. Appl. 1987, 44.
(11) Cywin, C. L.; Webster, F. X.; Kallmerten, J. J. Org. Chem. 1991,
5
6, 2953-2955.
12) Ireland, R. E.; Norbeck, D. W. J. Org. Chem. 1985, 50, 2198-
200.
(
2
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Org. Lett., Vol. 9, No. 8, 2007

Pd(II) catalyst can now bind more effectively to the MOM
group, leading to a significant enhancement in diastereo-
selectivity.
In an effort to produce a substrate which on RCM would
give the piperidine analogue, an acylation strategy was
proposed. Thus, hydrolysis of 10a followed by acylation with
3-butenoyl chloride gave 15 in good yield over the two steps
(Scheme 5). Ring-closing metathesis again proceeded smoothly
Having achieved the first key step, the next stage of our
synthesis of (+)-R-conhydrine 1 was reprotection of the
amine with a more suitable protecting group followed by
alkylation to form a diene which could undergo RCM to
give the piperidine ring. A change of protecting group was
necessary at this stage as early attempts to alkylate 10a gave
only starting material. Amide hydrolysis of 10a and repro-
tection of the resulting amine with the Boc group were easily
achieved giving 11 in good overall yield (Scheme 4).
Scheme 5. Synthesis of (+)-R-Conhydrine 1
Scheme 4. Synthesis of Pyrrolidone 2
using Grubbs’ first-generation catalyst to give the unsaturated
δ-lactam 16 in quantitative yield. Finally, hydrogenation of
the alkene, reduction of the lactam with borane-THF, and
deprotection of the hydroxyl group under acidic conditions
gave (+)-R-conhydrine 1 in 42% yield over the three steps.
In conclusion, we have developed a simple and direct route
for the synthesis of (+)-R-conhydrine 1 and its pyrrolidine
analogue 2 using a MOM-ether-directed, palladium-catalyzed
aza-Claisen rearrangement to establish the second stereogenic
center followed by RCM to form the piperidine and pyrro-
lidine rings, respectively. Although only two compounds
have been made during this study, we believe that a range
of analogues with varying ring sizes can be easily accessed
using this approach. Work is currently underway to achieve
this goal as well as the stereoselective functionalization of
alkenes such as 13 and 16 for the preparation of poly-
hydroxylated derivatives.
Attempted alkylation of 11 using sodium hydride and either
4-bromobutene or the triflate derivative of 3-buten-1-ol
returned only starting material. However, using a procedure
developed by Hartley and co-workers and the more reactive
allyl bromide as an alkylating agent gave diene 12 in good
1
5
yield. Ring-closing metathesis of 12 using Grubbs’ first-
generation catalyst, Cl Ru(dCHPh)(PCy (5 mol %), in
2
3 2
)
refluxing dichloromethane proceeded smoothly to give the
dihydropyrrole 13 in 92% yield.16 Hydrogenation of the
resulting alkene and acid-mediated removal of the protecting
groups gave the endopeptidase inhibitor10 (2S,1′R)-2-(1′-
hydroxypropyl)pyrrolidine 2 in nearly quantitative yield over
the two steps.
Acknowledgment. Financial support from EPSRC (DTA
award) and the University of Glasgow is gratefully acknowl-
edged.
Supporting Information Available: Full experimental
procedures, spectroscopic data, and NMR spectra for com-
pounds 1-3, 6, 8, and 10a-17. This material is available
free of charge via the Internet at http://pubs.acs.org.
(13) Blanchette, M. A.; Choy, W.; Davis, J. T.; Essenfeld, A. P.;
Masamune, S.; Roush, W. R.; Sakai, T. Tetrahedron Lett. 1984, 25, 2183-
2
186.
OL070424Z
(14) Anderson, C. E.; Overman, L. E.; Watson, M. P. Org. Synth. 2005,
8
2, 134-139.
(
15) Macleod, C.; McKiernan, G. J.; Guthrie, E. J.; Farrugia, L. J.;
(16) (a) Grubbs, R. H.; Miller, S. J.; Fu, G. C. Acc. Chem. Res. 1995,
28, 446-452. (b) Trnka, T. M.; Grubbs, R. H. Acc. Chem. Res. 2001, 34,
18-29.
Hamprecht, D. W.; Macritchie, J.; Hartley, R. C. J. Org. Chem. 2003, 68,
87-401.
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