The first synthesis of the ABC-ring system of 'upenamide

Article abstract of DOI:10.1021/ol701772d

The first synthetic route to the spirooxaquinolizidinone core (ABC core) of the macrocyclic marine alkaloid 'upenamide (1) has been developed. All five stereocenters were introduced with complete stereocontrol. The hydroxyl group at C-11 was introduced by a regio- and stereoselective SeO₂-mediated allylic oxidation. The spirocyclic skeleton was formed by a stannous chloride induced deacetalization-bicyclization procedure. Further stereocenters were introduced by an enzymatic desymmetrization and by incorporation of an (S)-malic acid derived building block.

Full text of DOI:10.1021/ol701772d

ORGANIC
LETTERS
2007
Vol. 9, No. 20
4041-4044
The First Synthesis of the ABC-Ring
System of ‘Upenamide
Jan Peter Schmidt,† Sandra Beltra´n-Rodil,† Rhona J. Cox,‡ Graeme D. McAllister,†
Mark Reid,† and Richard J. K. Taylor*,†
Department of Chemistry, UniVersity of York, York, YO10 5DD, U.K., and
AstraZeneca R&D Charnwood, Medicinal Chemistry, Bakewell Road,
Loughborough, Leics LE11 5RH, U.K.
rjkt1@york.ac.uk
Received July 25, 2007
ABSTRACT
The first synthetic route to the spirooxaquinolizidinone core (ABC core) of the macrocyclic marine alkaloid ‘upenamide (1) has been developed.
All five stereocenters were introduced with complete stereocontrol. The hydroxyl group at C-11 was introduced by a regio- and stereoselective
SeO2-mediated allylic oxidation. The spirocyclic skeleton was formed by a stannous chloride induced deacetalization
−bicyclization procedure.
Further stereocenters were introduced by an enzymatic desymmetrization and by incorporation of an (S)-malic acid derived building block.
The macrocyclic marine alkaloid ‘upenamide (1) was isolated
from the branching sponge Echinochalina sp. found in the
coastal waters of Derawan Island, Indonesia (Figure 1).1
tricyclic spirooxaquinolizidinone system and accounts for
five of the eight stereocenters in ‘upenamide. The DE ring
system comprises an unusual octahydropyrano[2,3-b]pyridine
system and contains the remaining three stereocenters. The
C and D rings are linked by an all-trans triene system. A
fully saturated aliphatic chain then completes the 20-
membered macrocycle joining rings A and E.
To the best of our knowledge, no total synthesis of ‘upen-
amide has been achieved so far. However, in a previous
communication, we described a route for the preparation of
a model ABC spirocyclic core of ‘upenamide,2 which was
adopted by Ong and co-workers for the construction of an
organoiron complex of an ABC model core.3 This methodol-
ogy was utilized for the preparation of novel polycyclic
heterocycles and was published recently.4 Subsequently, we
reported stereoselective syntheses of the DE bicyclic system.5
In addition, Marazano et al. published the synthesis of
a model of the DE core in racemic form,6 and more re-
cently, Sulikowski et al. reported the stereo- and enantio-
controlled synthesis of an advanced intermediate containing
Figure 1. Structure of ‘upenamide (1).
The name is coined from ‘upena, a Hawaiian word
meaning fishing net or trap. ‘Upenamide may be considered
as two distinct core units. The ABC core comprises a novel
† University of York.
(2) Reid, M.; Taylor, R. J. K. Tetrahedron Lett. 2004, 45, 4181.
(3) Han, J. L.; Ong, C. W. Tetrahedron 2007, 63, 609.
(4) Cayley, A. N.; Cox, R. J.; Me´nard-Moyon, C.; Schmidt, J. P.; Taylor,
R. J. K. Tetrahedron Lett. 2007, 48, 6556.
‡ AstraZeneca R&D Charnwood.
(1) Jime´nez, J. I.; Goetz, G.; Mau, C. M. S.; Yoshida, W. Y.; Scheuer,
P. J.; Williamson, R. T.; Kelley, M. J. Org. Chem. 2000, 65, 8465.
10.1021/ol701772d CCC: $37.00
© 2007 American Chemical Society
Published on Web 09/01/2007

the DE bicyclic system.7 In this article, we report investiga-
tions leading to the first synthesis of the ABC spirocyclic
ring system of ‘upenamide in enantiopure form.
In preliminary studies, we developed a tin(II) chloride-
induced deacetalization-bicyclization process to prepare
novel ABC analogues of ‘upenamide.2 We planned to prepare
cyclization precursor 3a and investigate the deacetalization-
bicyclization to furnish the fully functionalized spirooxa-
quinolizidinone 2a (Figure 2). Unfortunately, all attempts
was scalable to a 0.1 mol scale. Meso-anhydride 6 was
reduced and bisacetylated to furnish compound 7 via the
intermediate diol. Bisacetate 7 was subsequently desymme-
trized using porcine pancreatic lipase (Sigma type II) to give
alcohol (-)-5 in good yield and 94% enantiomeric excess
1
as determined by H NMR analysis of the respective (+)-
and (-)-Mosher ester derivatives.9 The free primary alcohol
was subsequently benzyl protected under neutral conditions
using Dudley’s reagent 810 to give an orthogonally protected
cyclohexene diol in excellent yield. It is noteworthy that no
transesterification was observed under these conditions. The
acetate was saponified, and the resulting free primary alcohol
(+)-9 was oxidized to the carboxylic acid, which was taken
on without further purification and converted into methyl
ester (-)-10 by stirring in methanolic HCl.
The quaternary center adjacent to the ester moiety was
installed by formation of the lithium enolate followed by
trapping with the known iodide 11.11 Cyclohexene (+)-12
was isolated in good yield with only the desired diastereomer,
resulting from alkylation from the less-hindered face of the
lithium enolate, being obtained (Scheme 2). It was found
Scheme 2
Figure 2. Retrosynthetic analysis of 2a, the ABC core system of
‘upenamide.
to prepare 3a were unsuccessful. Attention was therefore
turned to the preparation of analogue 2b with the aim of
investigating allylic hydroxylation at a late stage of the
synthesis. We therefore required compound 3b and antici-
pated that methyl ester 4 would be a suitable precursor. This
retrosynthetic analysis suggested the use of substituted
cyclohexene derivative 5 as starting material, a compound
readily available in enantiomerically pure form from inex-
pensive meso-anhydride 6.8
Alcohol (-)-5 was therefore prepared following a desym-
metrization procedure published by von Langen et al.
(Scheme 1).8 It is noteworthy that in our hands this procedure
that use of the lithium enolate together with the soft alkyl
iodide 11 prevented competing O-alkylation. The methyl
ester was then reduced using DIBAL-H to give primary
alcohol (+)-13. The alcohol was protected as the triisopro-
pylsilyl ether following the Corey procedure.12 Subsequent
PMB deprotection using 2,3-dichloro-5,6-dicyano para-
benzoquinone (DDQ)13 and introduction of the azide moiety
Scheme 1
(5) Me´nard-Moyon, C.; Taylor, R. J. K. Eur. J. Org. Chem. 2007,
3698.
(6) Mons, S.; Malves Maia, A.; Mons, S.; Pereira de Freitas Gil, R.;
Marazano, C. Eur. J. Org. Chem. 2004, 1057.
(7) Kiewel, K.; Luo, Z.; Sulikowski, G. A. Org. Lett. 2005, 7, 5163.
(8) von Langen, D. J.; Tolman, R. L. Tetrahedron: Asymmetry 1997, 8,
677.
(9) Seco, J. M.; Quin˜oa´, E.; Riguera, R. Chem. ReV. 2004, 104, 17.
(10) Poon, K. W. C.; Dudley, G. B. J. Org. Chem. 2006, 71, 3923.
(11) Cordero, F. M.; Pisaneschi, F.; Gensini, M.; Goti, A.; Brandi, A.
Eur. J. Org. Chem. 2002, 1941.
(12) Corey, E. J.; Cho, H.; Ru¨cker, C.; Hua, D. H. Tetrahedron Lett.
1981, 22, 3455.
(13) Solladie, G.; Adamy, M.; Colobert, F. J. Org. Chem. 1996, 61, 4369.
4042
Org. Lett., Vol. 9, No. 20, 2007

under Mitsunobu conditions14 produced compound (+)-16
efficiently in 73% yield over four steps.
The reduction of the azide to the amine was accomplished
under Staudinger conditions (Scheme 3).15 The amine could
in its IR spectrum suggesting the absence of a trans-oxa-
quinolizidine system.19 In addition to that, the stereochemistry
was confirmed by 1H NMR studies (NOE between H-2 and
H-10 as well as δC (C-10) 93.3 ppm) and was later validated
by the synthesis of the crystalline 9-anthracenoyl derivative
(-)-22 (Figure 3).20
Scheme 3
Figure 3. Spirooxaquinolizidinone (-)-22, the 9-anthracenoyl ester
derivative of (-)-21. Note that the benzyl ether and anthracenoyl
ester are not shown for clarity (X-ray depicted using Mercury
1.4).
We were now faced with the challenge of introducing the
required hydroxyl group at C-11 (numbering in accordance
with Figure 1). In the late 1930s, Guillemonat postulated a
set of rules for the selectivity of allylic oxidations using
selenium(IV) oxide. He found that hydroxylation of an allylic
position in a ring normally occurs regioselectively adjacent
to the more substituted end of the double bond.21 We
therefore expected a regio- and stereoselective hydroxylation
in favor of the (S)-epimer at C-11. Indeed it was found that
after triisopropylsilyl ether protection of the free hydroxyl
giving compound (-)-23 selenium(IV) oxide hydroxylation
occurred selectively at C-11 giving selectively the (S)-epimer
(-)-24 (Scheme 5). Inversion of this center was accomp-
not be purified by conventional methods and was used di-
rectly in the subsequent step in which the (S)-malic acid de-
rived acid (S)-1716 was coupled to the unpurified amine using
propane phosphonic acid anhydride17 (T3P) to give amide
(+)-18 in good yield. The triisopropylsilyl ether was cleaved
using tetra-n-butylammonium fluoride (TBAF), and the re-
sulting primary alcohol (+)-19 was oxidized to the aldehyde
using Ley’s catalytic tetra-n-propylammonium perruthenate
(TPAP) and 4-methylmorpholine N-oxide (NMO) proce-
dure18 to furnish aldehyde (+)-20 in near quantitative yield.
At this stage, we were in a position to attempt the crucial
cyclization by subjecting aldehyde (+)-20 to tin(II) chlor-
ide dihydrate conditions to induce deacetalization-bicy-
clization. Gratifyingly, the 11-deoxy ABC core (-)-21 of
‘upenamide was formed in 91% yield and excellent diaste-
reoselectivity, affording only the product with the hemi-
aminal proton (H-10) being syn to H-2 (Scheme 4). This
Scheme 5
Scheme 4
was expected and can be rationalized by the thermodynami-
cally more stable product forming under these equilibrating
conditions.2 Compound (-)-21 showed no Bohlmann bands
lished by a manganese(IV) oxide-mediated oxidation of the
secondary alcohol to the corresponding enone (-)-25 and
(14) Lang, S.; Kennedy, A. R.; Murphy, J. A.; Payne, A. H. Org. Lett.
2003, 5, 3655.
(16) Tavares, F.; Lawson, J. P.; Meyers, A. I. J. Am. Chem. Soc. 1996,
118, 3303.
(15) Mahidhar, Y. V.; Rajesh, M.; Chaudhuri, A. J. Med. Chem. 2004,
47, 3938.
(17) Escher, R.; Bu¨nning, P. Angew. Chem., Int. Ed. Engl. 1986, 25,
277.
Org. Lett., Vol. 9, No. 20, 2007
4043

by reducing the enone under Luche conditions22 to give the
desired (R)-epimer (-)-2a. The respective epimers were
assigned by comparing their NMR data with those published
in the isolation paper of ‘upenamide.1 The NOE correlation
and 13C NMR chemical shifts of C-11 were particularly
characteristic (Table 1).
alkaloid ‘upenamide (1) has been developed. The four
stereocenters of the 11-deoxy fragment (-)-21 were intro-
duced by an enzymatic desymmetrization of meso-diace-
tate 7, followed by a diastereoselective alkylation of ester
(+)-10 to give ester (+)-12. This was followed by an amide
coupling with the (S)-malic acid derived acid (S)-17 and a
subsequent syn-selective deacetalization-bicyclization pro-
cedure to furnish the 11-deoxy ABC core (-)-21. The
hydroxyl group at C-11 was introduced by a regioselective
allylic hydroxylation giving the (S)-epimer (-)-24 in a
stereoselective manner. The stereocenter was inverted by a
MnO2-mediated oxidation followed by a stereoselective
Luche reduction to give the fully functionalized ABC core
fragment (-)-2a. It should be noted that the tricycle (-)-2a
is ideally functionalized for further elaboration at C-16 and
C-36 (numbering in accordance with the isolation paper).
With both core systems synthesized by our group, efforts
are now underway to complete the total synthesis of
‘upenamide (1).
Table 1. NMR Data Comparison of ‘Upenamide (1) and the
ABC Cores (-)-24 and (-)-2aa
compound
13C (C-11)
NOE (H-11)
1
70.0
64.9
70.1
12, 15
2, 3, 7, 10, 16
12, 15
(-)-24
(-)-2a
Acknowledgment. We are grateful to Dr. A. C. Whit-
wood (University of York) for carrying out the crystal-
lography study. The financial support by AstraZeneca
(J.P.S.), the University of York (G.D.M., J.P.S., S.B.R.), as
well as the EPSRC (M.R.) is gratefully acknowledged as is
the assistance of Dr. A. Wells (AstraZeneca, Charnwood)
with scaling up the enzymatic desymmetrization process. We
thank Archimica for their kind donation of T3P.
a
The spectrum of ‘upenamide (1) was recorded in CD3OD at 500 MHz
1
for H NMR and at 125 MHz for 13C NMR, and the spectra for the ABC
cores (-)-24 and (-)-2a were recorded in CD3OD at 400 MHz for 1H NMR
and at 100 MHz for 13C NMR spectroscopy.
In summary, the first synthetic route to the spirooxaquino-
lizidinone core (ABC core) of the macrocyclic marine
Note Added after ASAP Publication: The uncorrected
version of this paper was published September 1, 2007; the
corrected version was published September 5, 2007.
(18) Griffith, W. P.; Ley, S. V.; Whitcombe, G. P.; White, A. D. Chem.
Commun. 1987, 1625.
(19) (a) Bohlmann, F. Angew. Chem. 1957, 69, 641. (b) Bohlmann, F.
Chem. Ber. 1958, 91, 2157. (c) Uskokovic´, M.; Bruderer, H.; von Planta,
C.; Williams, T.; Brossi, A. J. Am. Chem. Soc. 1964, 86, 3364. (d) Crabb,
T. A.; Newton, R. F.; Jackson, D. Chem. ReV. 1971, 71, 109.
(20) CCDC 643699 contains the supplementary crystallographic data for
this paper. These data can be obtained free of charge from the Cambridge
Crystallographic data Centre via www.ccdc.cam.ac.uk/data_request/cif.
(21) Guillemonat, A. Ann. Chim. 1939, 11, 143.
Supporting Information Available: Experimental pro-
cedures and full spectroscopic data for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(22) Gemal, A. L.; Luche, J.-L. J. Am. Chem. Soc. 1981, 103, 5454.
OL701772D
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Org. Lett., Vol. 9, No. 20, 2007