Stereoselective synthesis of (-)-lepadins A-C

Article abstract of DOI:10.1039/c3cc46801a

A concise synthesis of the marine alkaloids (-)-lepadins A-C from a phenylglycinol-derived tricyclic lactam is reported. Key steps from the stereochemical standpoint involve stereoselective cyclocondensation, double bond hydrogenation, oxazolidine opening

Full text of DOI:10.1039/c3cc46801a

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Stereoselective synthesis of (À)-lepadins A–C†
Mercedes Amat,* Alexandre Pinto, Rosa Griera and Joan Bosch
Cite this: Chem. Commun., 2013,
4
9, 11032
Received 5th September 2013,
Accepted 5th October 2013
DOI: 10.1039/c3cc46801a
www.rsc.org/chemcomm
A concise synthesis of the marine alkaloids (À)-lepadins A–C from a
phenylglycinol-derived tricyclic lactam is reported. Key steps from the
stereochemical standpoint involve stereoselective cyclocondensation,
double bond hydrogenation, oxazolidine opening, hydroboration–
oxidation, and Horner–Wadsworth–Emmons reactions.
The lepadin alkaloids are a small group of cis-decahydroquinoline
alkaloids isolated during the period 1991–2002 from different
1
marine sources such as the tunicate Clavelina lepadiformis and its
1b
predator the flatworm Prostheceraeus vittatus, as well as the
2
Australian Great Barrier Reef tunicate Didemnum sp. and ascidian
3
Aplidium tabascum. Structurally, all of them incorporate a methyl
substituent at the C-2 position of the decahydroquinoline nucleus,
a functionalized eight-carbon chain at C-5, and a free or acylated
hydroxy group at C-3. However, they display a diversified array of
relative stereochemical relationships (Fig. 1). Lepadins A and B
have been shown to exhibit significant in vitro cytotoxicity against
Fig. 1 Lepadin alkaloids.
1b
several human cancer cell lines. In addition, lepadin B is a
4
potent blocker for neuronal nicotinic acetylcholine receptors.
Lepadins D–F exhibit low cytotoxicity but significant and selective
2
antiplasmodial and antitrypanosomal activity. Further pharma-
cological research on these alkaloids has been hampered by
the low quantities of samples available from natural sources.
5
This has stimulated considerable synthetic effort in this area,
although the development of facile enantioselective routes to
lepadins or synthetic analogs is still required.
Scheme 1 Synthetic strategy.
6
In the context of our studies on the use of phenylglycinol-
derived chiral tricyclic lactams for the enantioselective synthesis
of alkaloids, we present herein a straightforward synthesis of and an appropriate cyclohexenone-derived d-keto ester A.
À)-lepadins A–C. As outlined in Scheme 1, the synthesis of lepadins A–C from
Our approach takes advantage of unsaturated tricyclic lactams B, lactams B would involve (i) the stereoselective hydrogenation of
(
functionalized platforms that are assembled in a straightforward the C–C double bond to obtain the required configuration
manner by a cyclocondensation reaction between (R)-phenylglycinol at C-5, (ii) the stereoselective opening of the oxazolidine ring
to give the natural cis-decahydroquinoline stereochemistry,
Laboratory of Organic Chemistry, Faculty of Pharmacy, and Institute of Biomedicine
(iii) the stereoselective introduction of the C-2 methyl and C-3
(
IBUB), University of Barcelona, 08028-Barcelona, Spain. E-mail: amat@ub.edu;
Fax: +34 93 402 45 39; Tel: +34 93 402 45 40
Electronic supplementary information (ESI) available: Detailed experimental
hydroxy substituents, taking advantage of the lactam carbonyl,
and (iv) the elongation of the C-5 side chain.
†
1
13
As a model system for evaluating the viability of our strategy,
procedures and copies of H and C NMR spectra of all compounds. See DOI:
0.1039/c3cc46801a
6
1
we selected the known lactam 1, which lacks the functionalized
1
1032 Chem. Commun., 2013, 49, 11032--11034
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Scheme 2 Model studies. Reagents and conditions: (a) LiAlH
4
, AlCl
, (Boc) O, MeOH, rt,
O, 0 1C, 5 min, then rt 1 h, 73%;
-Pyr, THF, then rt, 1.5 h, 95%; (e) CuI,
MeLi, THF, À20 1C, 30 min, À78 1C, then rt, 16 h; (f) BH ÁSMe , THF, À78 1C,
then rt, 16 h, then Me O, THF, reflux, 45 min, 78% (steps e and f).
NOÁ2H
3
, THF, 0 1C,
3
2
0 min, then À78 1C, 1.5 h and rt, 3 h, 79%; (b) H
0 h, 72%; (c) RuCl O, NaIO , CCl –CH CN–H
ÁnH
2
, Pd(OH)
2
2
3
2
4
4
3
2
(
d) LiHMDS, THF, À78 1C, 2 h; 5-Cl-2-NTf
2
3
2
3
2
carbon chain at C-5 but bears a methyl substituent instead. Slightly
disappointingly, reductive cleavage of the oxazolidine C–O bond
using Et SiH–TiCl took place with only moderate stereoselectivity,
3
4
leading to decahydroquinolone 2a as a 5 : 1 mixture of cis–trans
epimers. A great improvement was achieved by using LiAlH –AlCl
4
3
as the reductant, cis-decahydroquinoline 2b being stereoselectively
obtained under these conditions. Although alane additionally
caused the reduction of the lactam carbonyl, this functionality
was satisfactorily reinstalled, after N-debenzylation with simul-
7
taneous N-Boc protection, by ruthenium-promoted oxidation
Scheme 3 Enantioselective synthesis of (À)-lepadins A–C. Reagents and condi-
of N-Boc derivative 3 (Scheme 2). From the resulting N-protected tions: (a) AcOH, benzene, reflux, 72 h; (b) H , Pt O, MeOH, 5 h, 67% (steps a and b);
2
2
lactam 4, the introduction of the C-2 methyl substituent was (c) LiAlH
4
, AlCl
O, CH
79% (steps d and e); (f) TIPSCl, imidazole, DMF, 16 h, 93%; (g) RuCl
CCl –CH CN–H
O, 0 1C, 5 min, then rt 1 h, 97%; (h) LiHMDS, THF, À78 1C, 2 h;
-Cl-2-NTf
-Pyr, THF, then rt, 2.5 h, 90%; (i) CuI, MeLi, THF, À20 1C, 30 min,
complex and subsequent oxidation of the intermediate borane À78 1C, then rt, 16 h; (j) BH ÁSMe , THF, À78 1C, then rt, 16 h, then Me NOÁ2H O,
3
, THF, 0 1C, 30 min, then À78 1C, 1.5 h and rt, 3 h, 76%;
Cl , 0 1C, then rt, 2 h; (e) H , Pd(OH) , (Boc) O, MeOH, rt, 20 h,
ÁnH O, NaIO
(
d) BF
3
ÁEt
2
2
2
2
2
2
accomplished via the corresponding vinyl triflate, prepared by
8
3
2
4
,
Comins’ protocol, by reaction with lithium dimethylcuprate. With
4
3
2
enecarbamate 5 in hand, hydroboration with the BH
3
ÁSMe
2
5
2
9
3
2
3
2
1
0
with trimethylamine N-oxide stereoselectively provided alcohol 6 THF, reflux, 45 min, 81% (steps i and j); (k) Dess–Martin, CH
2
Cl
O, DMAP, Et
then rt, 3 h, 91%; (n) TBAF, AcOH, 30–40 1C, 24 h, 83%; (o) Dess–Martin,
CH Cl , rt, 3 h; (p) KHMDS, (E)-C –CHQCH–CH P(O)(OEt)
(15), THF, À78 1C,
6 h, 68% (steps n–p); (q) TFA, CH Cl , 0 1C, then rt, 1 h, 99%; (r) NaHMDS,
–C8a bond is (E)-MeC(O C H )(CH ) –CHQCH–CH P(O)(OEt) (17), DME, À78 1C, 57%.
2
, rt, 2.5 h; (l) NaBH
4
,
MeOH, À40 1C, 16 h, 84% (steps k and l); (m) Ac
2
3
N, CH Cl , 0 1C,
2
2
in excellent overall yield. The facial selectivity, with exclusive
formation of the H-2/H-8a cis isomer, was not unexpected as it
involves the syn addition of borane from the less hindered face of
the double bond, via a transition state in which the C
axially oriented to avoid the A
2
2
4
H
9
2
2
1
2
2
8
2
2
4
2 2
2
2
(
1,3)
strain (Fig. 2).
The application of the above strategy to the synthesis of
carried out in satisfactory overall yield as in the above model series.
However, the trimethylsilylethyl (TMSE) protecting group had to be
replaced by TIPS to avoid its oxidation to trimethylsilylacetyl during
(
À)-lepadins A–C required starting from a tricyclic lactam
bearing a functionalized carbon chain, for instance a protected
hydroxymethyl substituent, at the 5 position of the quinoline
ring. The overall synthetic sequence is outlined in Scheme 3. Such a
lactam, 8, was prepared in two steps by cyclocondensation of d-keto
13
the ruthenium-mediated oxidation step. Thus, LiAlH –AlCl reduc-
4
3
tion of 8, followed by BF
genolysis of the benzylic C–N bond in the presence of (Boc) O
3
ÁEt
2
O-promoted deprotection and hydro-
11
2
ester 7 with (R)-phenylglycinol followed by catalytic hydrogenation
1
2
gave cis-decahydroquinoline 9. After reprotection of the hydroxyl
group as a TIPS derivative, the ruthenium oxidation step took
place in nearly quantitative yield to give lactam 10, which was
efficiently converted to enecarbamate 11 via a triflate, and then
to alcohol 12 by stereoselective hydroboration–oxidation.
The next step was to install the correct C-3 absolute configu-
ration. As anticipated, complete inversion of the C-3 stereochemistry
was accomplished (83% overall yield) by Dess–Martin oxidation
of the resulting unsaturated tricyclic lactams. The conversion
of 8, which possesses the appropriate configuration at the 4a
and 5 positions of the hydroquinoline ring, to alcohol 12 was
4
of alcohol 12 followed by NaBH reduction, with hydride
delivery from the more accessible face of the ketone carbonyl.
Fig. 2 Stereoselectivity of the hydroboration reaction.
This journal is c The Royal Society of Chemistry 2013
The resulting alcohol 13 has the same absolute configuration as
Chem. Commun., 2013, 49, 11032--11034 11033

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lepadins A–C at the five stereogenic centers of the decahydro-
quinoline ring. After protection of the hydroxy group as an
acetate, removal of the TIPS protecting group and subsequent
Dess–Martin oxidation led to aldehyde 14, which was used in
the next step without purification.
2 A. D Wright, E. Goclik, G. M. K o¨ nig and R. Kaminsky, J. Med. Chem.,
2
002, 45, 3067 (lepadins D–F).
R. A. Davis, A. R. Carroll and R. J. Quinn, J. Nat. Prod., 2002, 65, 454
lepadins F–H).
3
(
4 H. Tsuneki, Y. You, N. Toyooka, T. Sasaoka, H. Nemoto, J. A. Dani
and I. Kimura, Biol. Pharm. Bull., 2005, 28, 611.
5
(a) N. Toyooka, M. Okumura and H. Takahata, J. Org. Chem., 1999,
4, 2182 [(À)-lepadin B]; (b) T. Ozawa, S. Aoyagi and C. Kibayashi,
Finally, for the elongation of the C-5 side chain to install the
octadienyl moiety present in lepadins A–C and ensure the required
E,E stereochemistry, we selected the Horner–Wadsworth–Emmons
methodology using an appropriate E-configurated phosphonate.
Thus, reaction of aldehyde 14 with the anion derived from diethyl
6
J. Org. Chem., 2001, 66, 3338 [(À)-A–C]; (c) C. Kala ¨ı , E. Tate and
S. Z. Zard, Chem. Commun., 2002, 1430 [(Æ)-B; formal]; (d) X. Pu and
D. Ma, J. Org. Chem., 2006, 71, 6562 [(À)-A–C, E; (+)-D,H]; (e) G. Barbe
and A. Charette, J. Am. Chem. Soc., 2008, 130, 13873 [(+)-B];
( f ) A. Niethe, D. Fischer and S. Blechert, J. Org. Chem., 2008,
73, 3088 [(+)-F, (À)-G]; (g) G. Li, R. P. Hsung, B. W. Slafer and
I. K. Sagamanova, Org. Lett., 2008, 10, 4991 [(+)-F]; (h) see also: G. Li,
L. J. Carlson, I. K. Sagamanova, B. W. Slafer, R. P. Hsung, C. Gilardi,
H. M. Sklenicka and N. Sydorenko, Synthesis, 2009, 2905(i) for the
absolute configuration of (+)-lepadins F and G, see: G. Li and
R. P. Hsung, Org. Lett., 2009, 11, 4616( j) for a recent review, see:
A. Pelss and A. M. P. Koskinen, Chem. Heterocycl. Compd., 2013,
49, 226.
14
(
E)-hept-2-enylphosphonate (15), which occurred with concomi-
tant hydrolysis of the acetate ester, gave alcohol 16. The
synthesis of (À)-lepadin B was completed by cleaving the Boc
protecting group. The preparation of alcohol 16 also represents
5
b,d
a formal total synthesis of (À)-lepadin A.
-oxoocta-1,3-dienyl side chain of (À)-lepadin C was stereo-
selectively assembled by reaction of aldehyde 14 with diethyl
Similarly, the (E,E)-
7
6
7
(a) M. Amat, R. Griera, R. Fabregat, E. Molins and J. Bosch, Angew.
Chem., Int. Ed., 2008, 47, 3348; (b) M. Amat, R. Fabregat, R. Griera
and J. Bosch, J. Org. Chem., 2009, 74, 1794; (c) M. Amat, R. Fabregat,
R. Griera, P. Florindo, E. Molins and J. Bosch, J. Org. Chem., 2010,
5
d
(
E)-6,6-(ethylenedioxy)hept-2-enylphosphonate (17),
leading
5
d
to alcohol 18, a known synthetic precursor of (À)-lepadin C.
In summary, we have developed a concise route to (À)-lepadins
A–C using a phenylglycinol-derived lactam as the starting
enantiopure scaffold, which allows the stereocontrolled genera-
tion of the five stereogenic centers on the decahydroquinoline
ring. Our synthesis (lepadin B: 17 steps; 11.3% overall yield
from 7) compares advantageously in terms of both overall yield
and number of synthetic steps with previous syntheses of
these alkaloids. Inversion of the configuration at C-5 in the
75, 3797.
K. Moriyama, H. Sakai and T. Kawabata, Org. Lett., 2008, 10, 3883,
and references therein.
8 (a) C. J. Foti and D. L. Comins, J. Org. Chem., 1995, 60, 2656;
b) K. Tsushima, T. Hirade, H. Hasegawa and A. Murai, Chem. Lett.,
995, 801.
(
1
9
L. Le Corre, J.-C. Kizirian, C. Levraud, J.-L. Boucher, V. Bonnet and
H. Dhimane, Org. Biomol. Chem., 2008, 6, 3388.
1
0 (a) G. W. Kabalka and H. C. Hedgecock Jr., J. Org. Chem., 1975,
0, 1776; (b) T. Luker, H. Hiemstra and W. N. Speckamp, J. Org.
Chem., 1997, 62, 3592.
4
intermediate aldehyde 14 could provide access to other members 11 Keto ester 7 was prepared from methyl 2,6-dioxocyclohexanepropio-
2 2 2
nate, by reaction with triflic anhydride (Tf O, EDIPA, CH Cl ,
of this family of natural products.
À78 1C, 65%) followed by Pd-catalyzed coupling of the resulting
Financial support from the Spanish Ministry of Economy
and Competitiveness (Project CTQ2012-35250) and the AGAUR,
Generalitat de Catalunya (Grant 2009-SGR-1111), is gratefully
acknowledged.
triflate with potassium trimethylsilylethoxymethyltrifluoroborate
[Pd(dppf)Cl
2
ÁCH
2 2 2 3 2
Cl , Cs CO , 3 : 1 toluene–H O, 100 1C, 94%]. For
related coupling reactions, see: (a) G. A. Molander, J. Ham and
D. G. Seapy, Tetrahedron, 2007, 63, 768; (b) G. A. Molander and
B. Canturk, Org. Lett., 2008, 10, 2135.
1
1
2 Minor amounts of an epimeric lactam at the 4a, 5, and 8a positions
of the decahydroquinoline ring were also isolated.
3 This oxidation was observed from the TMSE derivative of 9.
Notes and references
1
(a) B. Steffan, Tetrahedron, 1991, 47, 8729 (lepadin A); (b) J. Kubanek, 14 Phosphonate 15 was prepared in 76% overall yield from (E)-2-
D. E. Williams, E. D. de Silva, T. Allen and R. J. Andersen, Tetra-
hedron Lett., 1995, 36, 6189 (lepadins A–C).
hepten-1-ol, by tosylation (BuLi, TsCl, THF, À78 1C) followed by
reaction with diethyl phosphonate (KHMDS, THF, 0 1C to À78 1C).
1
1034 Chem. Commun., 2013, 49, 11032--11034
This journal is c The Royal Society of Chemistry 2013