A Concise Asymmetric Route to Nuphar Alkaloids. A Formal Synthesis of (-)-Deoxynupharidine

Article abstract of DOI:10.1021/ol035156t

(Equation presented) A stereocontrolled route to Nuphar alkaloids is described that employs a formal [3 + 3] cycloaddition strategy to assemble the piperidine nucleus. The addition of Pd-TMM complexes to aziridine 10 was found to be sluggish; however, the addition of a functionalized allyl Grignard reagent followed by a Mitsunobu condensation reaction provided 11 in high yield. The employment of this route in the formal synthesis of (-)-deoxynupharidine 1 is described.

Full text of DOI:10.1021/ol035156t

ORGANIC
LETTERS
2
003
Vol. 5, No. 19
427-3429
A Concise Asymmetric Route to Nuphar
Alkaloids. A Formal Synthesis of
3
(−)-Deoxynupharidine
†
†
‡
Wesley J. Moran, Katharine M. Goodenough, Piotr Raubo, and
,†
Joseph P. A. Harrity*
Department of Chemistry, UniVersity of Sheffield, Brook Hill, Sheffield S3 7HF, U.K.,
and The Neuroscience Research Centre, Merck, Sharp and Dohme, Terlings Park,
Harlow, Essex CM20 2QR, U.K.
j.harrity@sheffield.ac.uk
Received June 23, 2003
ABSTRACT
A stereocontrolled route to Nuphar alkaloids is described that employs a formal [3 + 3] cycloaddition strategy to assemble the piperidine
nucleus. The addition of Pd−TMM complexes to aziridine 10 was found to be sluggish; however, the addition of a functionalized allyl Grignard
reagent followed by a Mitsunobu condensation reaction provided 11 in high yield. The employment of this route in the formal synthesis of
(−)-deoxynupharidine 1 is described.
(
-)-Deoxynupharidine 1 is a member of a large class of
would represent a late-stage intermediate which could be
transformed into a variety of Nuphar alkaloids after only a
few steps. We wish to disclose herein a short stereoselective
synthesis of 4 and its employment in a formal total synthesis
of (-)-1.
1
terpenoid alkaloids isolated from plants of the genus Nuphar.
All Nuphar alkaloids are characterized by the presence of
one or more furan rings and almost all display a quinolizidine
core. We have been investigating a short and convergent
strategy for the stereocontrolled synthesis of 1 and related
compounds (-)-castoramine 2 and (-)-nupharolutine 3.
Specifically and as outlined in Figure 1, we envisaged that
compounds 1-3 could all be prepared from intermediate 4
after appropriate stereoselective oxidative or reductive alkene
functionalization reactions. Therefore, quinolizidinone 4
2
We have recently reported a stereoselective technique for
the preparation of functionalized piperidines through a formal
3
4
†
University of Sheffield.
Merck, Sharp and Dohme.
‡
(
1) For leading references on isolation studies and bioactivities see: (a)
Miyazawa, M.; Yoshio, K.; Ishikawa, Y.; Kameoka, H. J. Agric. Food Chem.
998, 46, 1059. (b) Matsuda, M.; Shimoda, H.; Yoshikawa, M. Bioorg.
Med. Chem. Lett. 2001, 9, 1031.
2) (a) Hwang, Y. C.; Fowler, F. W. J. Org. Chem. 1985, 50, 2719. (b)
Hwang, Y. C.; Chu, M.; Fowler, F. W. J. Org. Chem. 1985, 50, 3885.
3) Bohlmann, F.; Winterfeldt, E.; Laurent, H.; Ude, W. Tetrahedron
963, 19, 195.
4) (a) Natsume, M.; Ogawa, M. Heterocycles 1981, 15, 237. (b)
LaLonde, R. T.; Muhammad, N.; Wong, C. F.; Sturiale, E. R. J. Org. Chem.
980, 45, 3664.
1
(
(
1
(
Figure 1. Retrosynthesis of alkaloids 1-3 to key lactam 4.
1
1
0.1021/ol035156t CCC: $25.00 © 2003 American Chemical Society
Published on Web 08/28/2003

[
3 + 3] cycloaddition reaction of N-tosylaziridines with Pd-
step,5a,b we opted to examine the diastereoselectivity of a
p-toluenesulfonamide derived aspartate 7. As outlined in
Scheme 2, esterification of (R)-aspartic acid followed by
5,6
trimethylenemethane (Pd-TMM) complexes.
This reaction proved to be an effective and expeditious
method for the synthesis of 2-substituted piperidines in
enantiomerically pure form (Scheme 1, see box). A notable
Scheme 2a
Scheme 1
a
2 3
Key: (a) MeOH, SOCl , 25 °C, 48 h, 98%; (b) TsCl, Et N, 25
°
8
C, 16 h, 79%; (c) LiHMDS, -78 °C; MeI, -78 to +25 °C 16 h,
9%; (d) LiAlH , 25 °C, 16 h, 98%; (e) PBu , ADDP, Tol, 16 h;
(f) TBSCl, imidazole, THF 5 h, 90% over two steps; (g)
AcOCH C(dCH )CH SiMe , 10 mol % Pd(OAc) , 25 mol %
DPPP, THF, 65 °C, 11 (41%), 12 (30%).
characteristic of this process is that the products are armed
with a readily functionalizable exocyclic alkene moiety. This
latter feature made the cycloaddition reaction particularly
suitable for the synthesis of 4 since it offered a potentially
facile route for piperidine assembly with installment of
stereochemistry at C-1 and C-10, as well as introducing the
pivotal alkene moiety at C-7. The retrosynthetic analysis for
our approach to 4 is described in Scheme 1. We anticipated
that the lactam unit could be prepared by suitable elaboration
of alcohol 5, which would in turn be assembled through the
key cycloaddition reaction of aziridine 6. Enantiomerically
pure 2-substituted aziridines are readily derived from the
4
3
2
2
2
3
2
amine protection with tosyl chloride furnished 7 in high yield.
Subsequent deprotonation with LiHMDS at -78 °C followed
by quenching of the ester enolate with methyl iodide provided
the desired product 8 which was isolated as a single
diastereomer in excellent yield. Literature precedent sug-
gested that the requisite (2R,3S)-stereochemistry would be
generated in this process, and this was confirmed by X-ray
7
corresponding amino acids; therefore, we anticipated that
9
crystallographic analysis.
6
would derive from (R)-aspartic acid.
The first goal in our synthetic sequence was to elaborate
At this stage, we were unable to find conditions for the
selective reduction of either ester moiety of 8 and therefore
undertook exhaustive reduction to furnish diol 9. Our final
steps required the selective functionalization of the R-amino
alcohol motif for ring closure to the aziridine; however, we
were unable to carry out selective functionalization reactions
on either alcohol moiety. We therefore decided to exploit
the well-established preference for three-membered ring
closure over four-membered ring cyclization to perform the
necessary differentiation of the alcohol units. Indeed, we were
pleased to find that subjecting 9 to a Mitsunobu condensation
reaction resulted in smooth and selective formation of
aziridine 6. We encountered some difficulties in removing
residual hydrazide in the purification of 6 and therefore
carried out TBS-protection of the crude alcohol to furnish
aziridine 10 in excellent yield over the two steps. Unfortu-
aspartic acid to a â-methylaspartic acid derivative that would
install the Me-group present at the C-1 position of the natural
product with correct stereochemistry. A survey of the
literature revealed that similar alkylation reactions of â-amino
esters proceeded with high levels of stereoselectivity,
particularly when N-tosyl protecting groups were employed.
In view of this fact, coupled with the need for sulfonamide
protection of the aziridine nitrogen in the key cycloaddition
8
(5) (a) Hedley, S. J.; Moran, W. J.; Prenzel, A. H. G. P.; Price, D. A.;
Harrity, J. P. A. Synlett 2001, 1596. (b) Hedley, S. J.; Moran, W. J.; Price,
D. A.; Harrity, J. P. A. J. Org. Chem. 2003, 68, 4286. (c) Recently, a
complementary [3 + 3] cycloaddition approach to piperidines has been
reported: Slkenicka, H. M.; Hsung, R. P.; McLaughlin, M. J.; Wei, L.-I.;
Gerasyuto, A. I.; Brennessel, W. B. J. Am. Chem. Soc. 2002, 124, 10435.
(
6) Trost and co-workers have pioneered the use of Pd-TMM complexes
in cycloaddition reactions: Trost, B. M. Angew. Chem., Int. Ed. Engl. 1986,
5, 1 and references therein.
2
(
7) Berry, M. B.; Craig, D. Synlett 1992, 41.
(9) Crystallographic data for 8 has been deposited with the Cambridge
Crystallographic Data Centre as supplementary publication number CCDC
210220. Copies of these data can be obtained, free of charge, on application
to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK (Fax: +44(0)-1223-
336033 or e-mail: deposit@ccdc.cam.ac.uk).
(8) (a) Hanessian, S.; Vanasse, B. Can. J. Chem. 1993, 71, 1401. (b)
Humphrey, J. M.; Bridges, R. J.; Hart, J. A.; Chamberlin, A. R. J. Org.
Chem. 1994, 59, 2467. (c) Wang, J.; Hou, Y.; Wu, P.; Qu, Z.; Chan, A. S.
C. Tetrahedron: Asymmetry 1999, 10, 4553.
3428
Org. Lett., Vol. 5, No. 19, 2003

nately, 10 proved to be remarkably sluggish toward Pd-
catalyzed [3 + 3] cycloaddition in the presence of phosphite
ligands. In the event, recourse to more electron-rich DPPP
ligand was found to be essential to achieve reasonable levels
of aziridine conversion, albeit furnishing piperidine 11 in a
modest 41% yield. The remainder of the mass balance from
this reaction largely consisted of starting aziridine and
acetate-opened product 12.1
Scheme 4a
0,11
The low yields afforded by the Pd-catalyzed [3 + 3]
cycloaddition process prompted us to investigate alternative,
and more nucleophilic, conjunctive reagents for the prepara-
tion of 11. Indeed, we were pleased to find that subjection
of aziridine 10 to the allyl Grignard reagent derived from
inexpensive 13 furnished 11 in a much improved yield after
a Mitsunobu ring-closure reaction of 14 (Scheme 3). Notably,
a
Key: (a) TBAF, THF, 25 °C, 86%; (b) Swern; (c) Ph P)C(H)-
3
2
CO Et, THF, 25 °C, 16 h, 76% over two steps; (d) Mg, MeOH, 25
°C, 56%; (e) H , 10% Pd/C, 100% (6.5:1).
2
Scheme 3a
in Scheme 4. Desilylation of 11 proceeded without incident
and the resulting alcohol was subjected to Swern oxidation
followed by Wittig olefination to provide ester 15. The final
steps in the reaction sequence to lactam 4 required chemose-
lective reduction of the electron deficient alkene and cleavage
of the sulfonamide group, both of which could potentially
be achieved in a single pot under reductive conditions. We
therefore subjected piperidine 15 to excess Mg metal in
MeOH and were pleased to find that both alkene reduction
and sulfonamide cleavage proceeded smoothly, moreover,
the intermediate amine cyclized spontaneously under the
reaction conditions to furnish key lactam 4 in 56% yield.
Subsequent hydrogenation of 4 over Pd/C provided quino-
lizidinone 16 as an inseparable 6.5:1 mixture of diastereo-
isomers favoring the 7-(S) isomer. Installment of the furan
moiety using Fowler’s procedure allowed a pure sample of
a
Key: (a) (i) n-BuLi (2.6 equiv), TMEDA (3.0 equiv), Et
, 0 °C, 4 h; (b) 10, 25 °C, 48 h, 80%; (c)
P, ADDP, Tol, 25 °C, 87%.
2
O, 0
°
C, 16 h, (ii) MgBr
n-Bu
2
3
the requisite conjunctive reagent for the Pd-catalyzed process
2-[(trimethylsilyl)methyl]-2-propen-1-yl acetate) is prepared
(
12
from 13 by a two-step procedure. Therefore, this stepwise
process represents a complementary technique to the [3 +
] cycloaddition chemistry and promises to furnish pip-
eridines which are currently inaccessible by the Pd-catalyzed
methods.
The final steps toward quinolizidine 4 through homolo-
gation of the protected alcohol unit were carried out as shown
3
(
-)-1 to be obtained that gave spectral data in accord with
2
that reported. The employment of this strategy in the
preparation of other members of the Nuphar family of
alkaloids is underway and will be reported in due course.
(
10) We have investigated a number of phosphine and phosphite ligands
Acknowledgment. We thank the EPSRC and The Uni-
versity of Sheffield for financial support and MSD for a
studentship award (K.M.G.).
in an attempt to promote this transformation and DPPP has been optimum
thus far. For example the use of triisopropyl phosphite resulted in very low
conversion (furnishing 11 in 10-15% yield) whereas tributylphosphine
generated 12 in >70% yield. A full account of our efforts to promote the
Pd-catalysed [3 + 3] cycloaddition reaction will be presented elsewhere.
(
11) Related alkylation products have been observed in [3 + 2]
Supporting Information Available: Full experimental
details for the syntheses reported are provided. This material
is available free of charge via the Internet at http://pubs.acs.org
cycloaddition reactions: (a) Trost, B. M.; Chan, D. M. T. J. Am. Chem.
Soc. 1983, 105, 2315. (b) Naz, N.; Al-Tel, T. H.; Al-Abed, Y.; Voelter,
W.; Ficker, R.; Hiller, W. J. Org. Chem. 1996, 61, 3250.
(12) Trost, B. M.; Chan, D. M. T.; Nanninga, T. N. Org. Synth. 1984,
6
2, 58.
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