Enantioselective Synthesis of Lepadins A-D from a Phenylglycinol-Derived Hydroquinolone Lactam

Article abstract of DOI:10.1002/chem.201501909

The marine alkaloids (-)-lepadins A-C and (+)-lepadin D, belonging to two diastereoisomeric series, were synthesized from an (R)-phenylglycinol-derived tricyclic lactam via a common cis-decahydroquinoline intermediate. Crucial aspects of the synthesis are the stereochemical control in the assembly of the cis-decahydroquinoline platform, in the introduction of the C2 methyl and C3 hydroxy substituents, and in the generation of the C5 stereocenter. Using (R)-phenylglycinol as the source of chirality, the marine alkaloids (-)-lepadins A-C and (+)-lepadin D, with opposite absolute configuration at the C3 and C5 ring positions, have been synthesized. The synthesis features the use of a tricyclic oxazoloquinolone lactam as the key enantiomeric scaffold and proceeds via an advanced common decahydroquinoline intermediate.

Full text of DOI:10.1002/chem.201501909

DOI: 10.1002/chem.201501909
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Total Synthesis |Hot Paper|
Enantioselective Synthesis of Lepadins A–D from
a Phenylglycinol-Derived Hydroquinolone Lactam
Mercedes Amat,* Alexandre Pinto, Rosa Griera, and Joan Bosch*[a]
Abstract: The marine alkaloids (À)-lepadins A–C and (+)-lep-
adin D, belonging to two diastereoisomeric series, were syn-
thesized from an (R)-phenylglycinol-derived tricyclic lactam
via a common cis-decahydroquinoline intermediate. Crucial
aspects of the synthesis are the stereochemical control in
the assembly of the cis-decahydroquinoline platform, in the
introduction of the C2 methyl and C3 hydroxy substituents,
and in the generation of the C5 stereocenter.
Introduction
Decahydroquinoline (DHQ) alkaloids constitute an important
group of natural products, which exhibit a wide range of bio-
logical activities. Rather than in plants, they occur mainly in
other terrestrial (amphibians, arthropods) and marine (tuni-
cates, flatworms) organisms.[1] Most of these alkaloids are 2,5-
disubstituted DHQs (for instance, pumiliotoxin C, the most rep-
resentative member of this group), but they also include 5,7-
disubstituted (the phlegmarine-type Lycopodium alkaloids)[2]
and 2,3,5-trisubstituted derivatives (lepadins). The latter are
a relatively small group of cis-DHQ alkaloids isolated from
marine sources, characterized by a C2 methyl substituent, a C3
oxygenated (hydroxy or acyloxy) group, and a C5 functional-
ized eight-carbon chain. From the stereochemical standpoint,
lepadins can be classified into three series, as shown in
Figure 1.
Figure 1. Lepadin alkaloids.
The first isolation of a member of this group, lepadin A, was
reported by Steffan in 1991[3] from the tunicate Clavelina lepa-
diformis. A few years later, Andersen et al. described the isola-
tion of lepadins A–C from the flatworm Prostheceraeus villatus
and its prey C. lepadiformis.[4] Lepadins A and B were found to
exhibit significant in vitro cytotoxicity against several human
cancer cell lines. Then, in 2002, Wright and co-workers report-
ed the isolation of lepadins DÀF from the tunicate Didemnum
sp.[5] and Carroll et al. reported lepadins FÀH from the Austral-
ian ascidian Aplidium tabascum.[6,7] Lepadins DÀF possess sig-
nificant and selective antiplasmodial and antitrypanosomal act-
vivity. Their low cytotoxicity makes them attractive models for
the development of new antimalarial agents.
More recently, lepadin B was found to block neuronal nico-
tinic acetylcholine receptors.[8] However, extensive bioactivity
studies with lepadin alkaloids have been thwarted by the
minute amounts isolated from natural sources.
Several enantioselective total syntheses of lepadins have
been reported so far,[9,10] which have allowed the relative and
absolute configuration of these alkaloids to be unequivocally
established. All these syntheses involve two phases: 1) con-
struction of a protected 3-hydroxy-2-methyl-cis-hydroquinoline
platform, either functionalized at C5 or bearing an oxidized
one-carbon substituent at this position, and 2) installation of
the appropriate C5 eight-carbon chain. A variety of methodolo-
gies have been developed for the first phase: closure of the
carbocyclic ring by aldol cyclization[9a,b] or a ring-closing/ring-
opening metathesis sequence;[9d] closure of the piperidine ring
by intermolecular [3+3]-azacycloaddition,[9f,g,11] xanthate-medi-
ated free radical cyclization,[10] or alkylative cyclization proces-
ses;[9c] and sequential one-pot construction of both rings from
[a] Prof. Dr. M. Amat, A. Pinto, Dr. R. Griera, Prof. Dr. J. Bosch
Laboratory of Organic Chemistry
Faculty of Pharmacy and Institute of Biomedicine (IBUB)
University of Barcelona, 08028 Barcelona (Spain)
Fax: (+34)93-402-45-39
E-mail: amat@ub.edu
joanbosch@ub.edu
Homepage: http://www.ub.edu/sintefarma/
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201501909.
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an acyclic precursor by a tandem ene-yne-ene ring-closing
metathesis.[9e]
On the other hand, different strategies have been used to
assemble the eight-carbon chain at the DHQ C5 position:
1) starting from a C5 unsubstituted DHQ, direct introduction of
an eight-carbon chain (C0 +C8 strategy),[9d] or sequential intro-
duction of either one carbon and a seven-carbon chain (C0 +
C1 +C7)[9a,c] or two and six carbons (C0 +C2 +C6);[9c,f,g] 2) starting
from a DHQ bearing a functionalized one-carbon substituent
at C5, direct elongation of a seven-carbon chain (C1 +C7 strate-
gy)[9e] or sequential elongation of one carbon and a six-carbon
chain (C1 +C1 +C6).[9b]
Results and Discussion
Scheme 2. Synthetic strategy.
In previous work, we have developed straightforward proce-
dures for the enantioselective synthesis of cis-DHQs bearing
substituents at the 2-, 5-, and 6-positions, for instance, the
dendrobatid alkaloid (À)-pumiliotoxin C, using phenylglycinol-
derived oxazoloquinolone lactams A as enantiomeric scaffolds
(Scheme 1).[12] These lactams are easily accessible by a stereose-
Scheme 3. Initial steps of the synthesis.
would afford (+)-lepadin D and their acylated derivatives (À)-
lepadin E and (+)-lepadin H.
Scheme 1. Enantioselective access to substituted cis-decahydroquinolines
from oxazoloquinolone lactams.
Scheme 3 outlines the initial steps of the synthesis. The re-
quired d-keto ester 3, bearing a trimethylsilylethyl (TMSE)-pro-
tected hydroxymethyl substituent, was prepared in two steps
from diketo ester 1, by Pd-catalyzed cross-coupling of either
the corresponding vinyl triflate or, more conveniently, bromo
lective cyclocondensation reaction between (R)-phenylglycinol
and appropriate cyclohexenone-derived d-keto esters.[13]
We envisaged tricyclic lactams A as suitable synthetic pre-
cursors of lepadins AÀC and D, E, H, belonging to two different
stereochemical series. Starting from a lactam B (A; R1 =
CH2OProt, R2 =H), bearing an oxidized one-carbon substituent
at the quinoline C5 position, after stereoselective hydrogena-
tion of the CÀC double bond and reductive removal of the ox-
azolidine ring, the stereoselective introduction of the methyl
and hydroxy substituents, taking advantage of the lactam
functionality, would give rise to a cis-DHQ C, which was visual-
ized as a common intermediate en route to lepadins AÀE and
H (Scheme 2).
enone with potassium alkoxymethyltrifluoroborate
(Scheme 3).[15]
2
A cyclocondensation reaction of d-keto ester 3 with (R)-phe-
nylglycinol, followed by catalytic hydrogenation of the result-
ing mixture of endocyclic and exocyclic unsaturated lactams
led to saturated tricyclic lactam 4 in 67% overall yield.[16]
The reductive opening of the oxazolidine ring was accom-
plished with complete retention of configuration by alane re-
duction, which also caused the reduction of the lactam carbon-
yl. A subsequent hydrogenolysis of the benzylic CÀN bond in
the presence of Boc2O stereoselectively gave cis-DHQ 5 in 75%
overall yield (Boc=tert-butoxycarbonyl). Although the use of
the above sequence requires an additional oxidation step to
recover the lactam functionality, it ensures the cis DHQ ring
The synthesis of (À)-lepadins AÀC from C would involve the
inversion of the configuration of the DHQ C3 position and the
elongation of the C5 side chain.[14] In turn, an inversion of the
configuration at C5 followed by the elongation of the C5 chain
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Scheme 4. Access to the advanced common intermediate 11.
fusion characteristic of lepadins.[17] The lactam carbonyl was ef-
ficiently reinstalled by ruthenium-promoted oxidation,[18] al-
though these conditions unexpectedly caused the concomitant
oxidation of the silylethoxy moiety to give lactam ester 6.
To overcome this inconvenience, the TMSE protecting group
was replaced by TIPS[19] as shown in Scheme 4 and, satisfactori-
ly, the ruthenium-mediated oxidation of the TIPS-substituted
DHQ 7 afforded lactam 8 in nearly quantitative yield.
Following our synthetic plan, the next step of the synthesis
was the stereoselective introduction of the C2 methyl and C3
hydroxy substituents. This was achieved in three steps, via the
enecarbamate 10, which was prepared by treatment of lactam
8 with Comins’ triflating reagent,[20] followed by reaction of the
resulting vinyl triflate 9 with Me2CuLi[21] (Scheme 4).
A
subsequent hydroboration-oxidation sequence using
BH3·SMe2 complex[22] and trimethylamine N-oxide[22,23] stereose-
lectively provided the C2/C3 trans alcohol 11 (C, Prot=TIPS) in
84% overall yield from 9. The formation of a single stereoiso-
mer in the process is a consequence of borane approaching
the most accessible face of the double bond of 10, which
adopts a conformation with an axial C8ÀC8a bond to avoid the
A(1,3) strain caused by the Boc substituent.
Scheme 5. Inversion of the C3 configuration and elongation of the C5 side
chain. Enantioselective synthesis of (À)-lepadins A and B.
Starting from the above aldehyde 14, a similar Horner–
Wadsworth–Emmons reaction, using the functionalized phos-
phonate 17, led to 18, a known precursor[9c] of (À)-lepadin C
(Scheme 6).
The inversion of the C3 configuration, required for the syn-
thesis of lepadins AÀC from intermediate 11, was accom-
plished in 84% yield by Dess–Martin oxidation followed by
NaBH4 reduction of the resulting ketone 12, which occurred
stereoselectively from the less-hindered face of the carbonyl
group (Scheme 5). After protection of the C3 hydroxy group of
13 as an acetate, and conversion of the protected hydroxy-
methyl substituent into a formyl group, the required E,E-con-
figurated eight-carbon chain at C5 was directly assembled, in
a stereoselective manner, from aldehyde 14 by the Horner–
Wadsworth–Emmons methodology using the anion derived
from diethyl (E)-hept-2-enylphosphonate (15) (C1 +C7 strategy).
Diene 16, in which deprotection of the C3 hydroxy group
had occurred, was obtained in 52% overall yield from 13. A
final removal of the Boc protecting group gave (À)-lepadin B.
The synthesis of 16 also constitutes a formal total synthesis of
(À)-lepadin A.[9b,c]
The key step to access lepadin D, and the configurationally
related lepadins E and H, from the common intermediate 11
was the inversion of the C5 configuration. To accomplish this,
we envisaged a synthetic sequence involving the stereoselec-
tive hydrogenation of a substituted DHQ, such as 20a, bearing
an exocyclic double bond at the C5 position. In this way, the
eight-carbon chain would be assembled in two phases (C1 +
C2 +C5 strategy). Following the same three-step sequence used
for the above conversion 13!14, alcohol 11 was converted to
aldehyde 19a in excellent overall yield (Scheme 7).
The NMR data of our synthetic (À)-lepadin B were coinci-
dent with those reported in the literature, while its specific ro-
tation was in good agreement with the value reported for this
compound.[9a] The synthesis of (À)-lepadin B consists of 19 syn-
thetic steps from d-keto ester 3 and takes place in 7.6% overall
yield, which represents a significant improvement with regard
to previous syntheses of this alkaloid.
Scheme 6. Elongation of the C5 side chain. Enantioselective synthesis of (À)-
lepadin C.
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Scheme 7. Inversion of the C5 configuration and two-carbon elongation.
Scheme 8. Completion of the C5 side chain. Enantioselective synthesis of
(+)-lepadin D.
An initial two-carbon elongation by Wittig olefination with
(ethoxycarbonylmethylene)triphenylphosphorane, followed by
base-promoted isomerization of the resulting conjugated
carbon–carbon double bond to an exocyclic position[24] led to
unsaturated ester 20a.[25,26] After removal of the Boc protecting
group,[27] catalytic hydrogenation of the resulting secondary
amine (as hydrochloride)[28] in AcOH stereoselectively installed
the required C5 stereochemistry. A subsequent protection with
Boc2O afforded 21a.[29]
Conclusion
In conclusion, enantioselective synthetic routes to two stereo-
chemical groups of lepadins have been developed from
a common DHQ intermediate. The synthesis relies on the ver-
satility of phenylglycinol-derived lactams as multipurpose scaf-
folds for the enantioselective construction of complex nitro-
gen-containing natural products.
A notable improvement in terms of simplicity and chemical
yield was achieved when the above sequence was directly car-
ried out without protecting the C3 hydroxy group, and the
TEMPO/PhI(OAc)2 system was used in the oxidizing step in
a one-pot oxidation-olefination process.[30] Thus, removal of
the TIPS protecting group of 11, followed by chemoselective
oxidation of the primary alcohol function with TEMPO and in
situ Wittig homologation of the resulting aldehyde 19b, gave
an a,b-unsaturated ester, which was converted to DHQ-5-pro-
pionate 21b via olefinic ester 20b, as in the above a series.
To complete the functionalized eight-carbon chain of
(+)-lepadin D from the advanced intermediate 21b, it was nec-
essary to perform a five-carbon elongation. After protection of
the C3 hydroxy group as a tert-butyldimethylsilyl (TBDMS)
ether, LiAlH4 reduction of the ester group, followed by conver-
sion of the resulting alcohol to an iodide using the I2-PPh3-imi-
dazole protocol and subsequent reaction with sodium benze-
nesulfinate gave sulfone 22 (Scheme 8).
The main features of the synthesis are: 1) the straightfor-
ward construction of a DHQ system bearing a functionalized
one-carbon substituent at the C5 position; 2) the incorporation
of the C2 methyl and C3 hydroxy substituents taking advant-
age of the lactam carbonyl; and 3) the elongation of the C5
chain, either directly with a seven-carbon fragment (lepadins
A–C) or sequentially using two- and five-carbon fragments
(lepadin D).
Key aspects from the stereochemical standpoint are: 1) the
stereoselective generation of the cis-DHQ ring fusion by reduc-
tive opening of the oxazolidine ring; 2) the control of the con-
figuration of the C5 stereocenter by stereoselective hydrogena-
tion of a carbon–carbon double bond, either endocyclic in a tri-
cyclic lactam or exocyclic in an N-unsubstituted DHQ deriva-
tive; 3) the installation of the trans 2-Me/3-OH relationship by
a
stereoselective hydroboration–oxidation sequence from
a methyl-substituted N-Boc enamine, with subsequent inver-
sion of the C3 configuration via a ketone; and, finally, 4) the
stereoselective achievement of the (E,E)-configuration of the
C5 chain via a Horner–Wadsworth–Emmons reaction.
Coupling of the sulfonyl carbanion derived from 22 with the
easily accessible epoxide (R)-propyloxirane[31] gave hydroxy sul-
fone 23 (mixture of epimers) in 60% yield. Finally, reductive
desulfonylation with sodium amalgam, followed by simultane-
ous removal of the Boc and silyl protecting groups, completed
the synthesis of (+)-lepadin D, in a total of 25 steps and 1.4% Acknowledgements
overall yield. Both the specific rotation and NMR data of our
synthetic (+)-lepadin D were consistent with those reported
for the natural product.[5]
Financial support from the Spanish Ministry of Economy and
Competitiveness (Project CTQ2012-35250) and the AGAUR,
Generalitat de Catalunya (Grant 2014SGR155) is gratefully ac-
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[14] For a preliminary account of this part of the work, see: M. Amat, A.
Pinto, R. Griera, J. Bosch, Chem. Commun. 2013, 49, 11032–11034.
[15] a) For the preparation of 2 and its cross-coupling reaction with aryl
chlorides, see: G. A. Molander, B. Canturk, Org. Lett. 2008, 10, 2135–
2138; for related processes with alkenyl bromides and potassium alkyl-
trifluoroborates, see: b) G. A. Molander, J. Ham, D. G. Seapy, Tetrahedron
2007, 63, 768–775.
knowledged. Thanks are also due to the MINECO for a fellow-
ship to A.P.
Keywords: alkaloids
· asymmetric synthesis · lactams ·
nitrogen heterocycles · total synthesis
[16] Minor amounts of the epimer at the C5 position (<5%) and the diaste-
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also isolated.
[17] Operating from a model tricyclic lactam bearing a methyl substituent
instead of CH2OTMSE, the reductive cleavage of the oxazolidine CÀO
bond using Et3SiH-TiCl4 took place with moderate stereoselectivity,
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strategy) by B-alkyl Suzuki–Miyaura coupling was not studied because
the required vinyl triflate derived from 19a was obtained in low yield.
[27] Due to conformational factors, the presence of an N-Boc substituent
decreases the stereoselectivity of the catalytic hydrogenation of the
exocyclic double bond in 5-alkylidene-DHQ derivatives. See ref. [9c].
[28] Somewhat unexpectedly, the catalytic hydrogenation (PtO2 or Pt/C,
MeOH or AcOH) of the free base was extremely slow and led to consid-
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[29] The stereochemical assignment of 21a was confirmed by comparing its
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Received: May 15, 2015
Published online on July 21, 2015
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