First model reactions towards the synthesis of sarain A core skeleton based upon a biogenetic scenario

Article abstract of DOI:10.1002/ejoc.200400645

Sarain A is a complex macrocyclic marine alkaloid extracted from sponges of the order Haplosclerida. It is likely that this alkaloid shares a common origin with manzamine alkaloids, also extracted from sponges of the same order. In this paper, new concepts concerning this origin are presented and constitute the basis for a synthetic strategy. A preliminary evaluation of this strategy is presented and leads, as a first result, to a five-step access to the bicyclic intermediate 43. Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2005.

Full text of DOI:10.1002/ejoc.200400645

FULL PAPER
First Model Reactions towards the Synthesis of Sarain A Core Skeleton Based
upon a Biogenetic Scenario
Stéphane Hourcade,[a] Antoine Ferdenzi,[a] Pascal Retailleau,[a] Stéphane Mons,[a] and
Christian Marazano*[a]
Keywords: Alkaloids / Biomimetic synthesis / Multicomponent synthesis / Knoevenagel reaction / Pyrrolidines / Sarain A
Sarain A is a complex macrocyclic marine alkaloid extracted
from sponges of the order Haplosclerida. It is likely that this
alkaloid shares a common origin with manzamine alkaloids,
also extracted from sponges of the same order. In this paper,
new concepts concerning this origin are presented and con-
stitute the basis for a synthetic strategy. A preliminary evalu-
ation of this strategy is presented and leads, as a first result,
to a five-step access to the bicyclic intermediate 43.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2005)
Sarain A is a complex alkaloid isolated from the sponge molecular cyclization reactions.[3] This theory was further-
Reniera Sarai.[1] Despite its unique skeleton, it is believed extended to others alkaloids in these series.[2a] With regard
to have the same biogenetic origin as other macrocyclic al- to sarain A, we initially suggested a related route, involving
kaloids extracted from sponges of the same order (Haplos- the same dihydropyridine pathway, in which an additional
clerida) such as, inter alia, manzamine A, halicyclamine A, oxidative cyclization was necessary to form the 1–3Ј car-
keramaphidin B.[2] The basis for an understanding of this bon–nitrogen bond.[4]
origin were initially formulated by Baldwin and Whitehead
From the results of model experiments in our laboratory,
who proposed an original pathway for explaining the origin a modification of the Baldwin and Whitehead hypothesis
of keramaphidin B and manzamine A. This pathway in- was proposed.[5] In this new proposal, two molecules of ma-
volved formation of dihydropyridine intermediates from londialdehyde 1 and two unsaturated long-chain aminoal-
long-chain aminoaldehydes and acrolein, followed by intra- dehydes 2 condense to give key intermediate 3 (Scheme 1).
[a] Institut de Chimie des Substances Naturelles, CNRS,
Avenue de la Terrasse, 91198 Gif-sur-Yvette, France
Fax: +33-169-07-72-47
E-mail: marazano@icsn.cnrs-gif.fr
Scheme 1.
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DOI: 10.1002/ejoc.200400645
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First Model Reactions towards the Synthesis of Sarain A Core Skeleton
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This chemistry does not necessarily involve the formation
of dihydropyridine species, which are prone to undesired
oxido-reduction reactions. Another advantage of this modi-
fication is that, if malondialdehyde has the right degree of
oxidation, the real precursors can be malonate units. In this
case, the biosyntheses of this new family of natural products
could be viewed as closely related to the polyketide path-
way. This last biosynthetic process is, in particular, charac-
teristic of bacterial metabolism, and it is quite remarkable
that manzamine A and its 8-hydroxy congener have recently
been shown to be, in fact, produced by an actinomycete
bacteria associated with the sponge.[6]
In this paper we present a new proposal for the origin of
sarain A, which is closely related to our modified hypothesis
involving manzamine A. The hypothesis involves reductive
condensation of malondialdehyde 1 (malonate?) units with
a long-chain aminoaldehyde 4 but, as a third partner, a
sphingolipid derivative 5. Thus, this proposal would have
the advantage of connecting the origin of sarain A with the
well-known family of sphingolipid secondary metabolites
(compare, for example, the structure of intermediate 5 with
the structure of sphingofungin A).[7] If this proposal is
speculative, considering the lack of biogenic experiments, it
constitutes what we believe to be a useful disconnection for
the synthesis of this complex molecule. In this way, prelimi-
Scheme 2.
nary encouraging model experiments are presented.
of the synthesis, vide infra), there are two different ways
to assemble it with malondialdehyde and the amino acid
derivative 12. A first route (a) could involve a Knoevenagel
addition to give adduct 11, followed by addition of the
amino acid 12 to give sarain A precursor 13 (see postulated
intermediate 9 in Scheme 2). An alternate route (b) begins
with the formation of the α,β-unsaturated aldehyde 14, fol-
lowed by the addition of glutacondialdehyde derivative 10.
In this paper, we report the results of model studies involv-
ing route (a).[9]
The Knoevenagel adducts of glutacondialdehyde, analo-
gous to 11, were recently shown to be unstable due to the
addition of a second molecule of glutacondialdehyde, which
resulted in the formation of substituted aromatic deriva-
tives.[9a] By contrast, the corresponding glutaconate deriva-
tives were found to be more stable and were used in this
study. Thus, diethyl glutaconate 15 was reacted with butyr-
aldehyde by using conditions described earlier[9a]
(Scheme 4) to give isomeric adducts 16. Ethyl acetami-
domalonate 17 was chosen as the amino acid equivalent
since the conjugate addition of this derivative to α,β-unsat-
urated esters is well documented.[10] The reaction between
16 and 17 was expected to give, in alkaline conditions, the
pyrrolidone 18 according to our model. However, no trace
of the desired product 18 could be detected, and the only
product isolated was the cyclohexene 19 which was reco-
vered in 36% yield as a single isomer.
Results and Discussion
The Biogenetic Scenario
The first step in the retrosynthetic analysis of sarain A
involves a retro-Mannich process, which leads to iminium
salt 6 (Scheme 2). Earlier results from our laboratory sug-
gest that this carbon–nitrogen bond should arise from a
Mannich reaction.[5b] In addition, most of the syntheses un-
der investigation to date use similar bond formation as a
final step for the construction of the core polycyclic system
of sarain A.[8] Hydrolysis of the iminium intermediate 6 re-
sults in the formation of aldehyde 7. We propose that such
an intermediate can be the result of condensation of an
amino aldehyde 4 and the macrocycle 8 (resulting from re-
ductive amination of the sphingolipide derivative 5) with
two three-carbon units such as malondialdehyde 1. Deriva-
tive 9 can be obtained as a neat result of this condensation.
Reductive amination, reduction of the carboxylic acid func-
tion, and reduction of two double bonds are then required
to give the polycyclic molecule 7. There are evidently a
number of different possibilities for both the initial multi-
component condensation and the reduction steps. We de-
cided to evaluate them experimentally.
Model Experiments
The dimerization product 19 is the result of a cycload-
If we assume that the glutacondialdehyde derivative 10 dition process between two molecules of diene 16. This cy-
(Scheme 3) is formed first (but this can be done at the end cloaddition is most likely to proceed through a tandem
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Scheme 3. Two possible pathways towards model intermediate 13.
Scheme 4.
Michael–Michael reaction, since sodium ethoxide proved to isomeric monoamides 20 and the diamide 21. This diamide
be necessary for the reaction to take place (Scheme 5). The was isolated and subjected to conditions described above
relative stereochemistry of the four asymmetric centers was for the preparation of 16, to prepare the Knoevenagel ad-
determined by NOESY experiments. The complete diaster- duct 22, which could eventually cyclized to 23. Such a ring
eoselectivity of the reaction is quite remarkable and is likely formation process is of the type 5-endo-trig, which is usually
to be the result of thermodynamic control.
unfavorable though still possible (vide infra Scheme 9), but
Because the dimerization process of 16 is too fast to al- it was hoped that the double activation of the new double
low the desired intermolecular Michael addition to take bond in 22 would compensate for this lack of reactivity.
place, the addition was attempted intramolecularly However, the vinylogous Knoevenagel reaction of 21 with
(Scheme 6). For this purpose, diethyl aminomalonate was butyraldehyde did not occur at all and only the pyrrolidin-
coupled with glutaconic acid to give a mixture of the two one 24, arising from a favorable 5-exo-trig cyclization, was
Scheme 5.
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First Model Reactions towards the Synthesis of Sarain A Core Skeleton
FULL PAPER
Scheme 6.
Scheme 7.
isolated. This product can be easily obtained in 88% yield
by using simple alumina catalysis.
Since the use of glutaconates derivatives turned out to be
difficult, we targeted intermediate 25 as a precursor of 13
by using the Knoevenagel chemistry of malondialdehyde
(Scheme 7).
Malonaldehyde is known to form the dimer 26[11]
(Scheme 7) but, even with suitable protection, the presence
of an amine invariably led to 1,4-dihydropyridines through
the Hantzsch reaction.[12] An attempt was then made to
modify the reaction pathway through the use of enaminal
27a or aminoacrylate 27b with the hope that a stepwise ap-
proach would allow the corresponding pyrrolines 29 to be
obtained. Compounds 27a and 27b were obtained in very
good yield from ethyl aminomalonate by reaction with ma-
Scheme 8.
lonaldehyde and ethyl propiolate, respectively, (Scheme 8).
Acid derivative 27a was mixed with propanal or butanal
under various conditions, but either no reaction was ob-
It became obvious that the extremely favored Hantzsch
served (LiBr/DBU, K2CO3, TEA, Na2SO4) or the reagents reactivity prevents other transformations to take place,
degraded (NaH, ZnCl2, AcO–pyH+). Reaction with para- which means that enamines should be avoided. For this
toluenesulfonic acid or camphorsulfonic acid afforded the purpose, β-carboxyamide 32 (Scheme 9) was used as a syn-
1,4-dihydropyridine 31a in 90% yield. The same reactivity thetic equivalent of 27a. It cleanly reacted with butanal on
was observed with aminoacrylate 27b but the dihydropyri- alumina to afford the Knoevenagel adduct 33 as a mixture
dine 31b was obtained in only 52% yield.
of E/Z isomers. Finally, 33 underwent the long-awaited 5-
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Scheme 9.
endo-trig cyclization to form pyrrolidone 34 in excellent which could be satisfactorily transformed back to the un-
yield. Such a sequence was then attempted intermolecularly. stable Knoevenagel compound 41. Reaction of the crude
The Knoevenagel compound 35 was prepared from ethyl product with ethyl acetamidomalonate 17 led to the pyrrol-
malonate and butyraldehyde, and it reacted with ethyl acet- idinone 42 in 28% yield from 37. Deprotection of the amine
amidomalonate under the same conditions as above to give moiety, followed by spontaneous cyclization, finally af-
again pyrrolidone 34 in 76% yield. This closely matches the forded pyrrolidinone 43 in 44% nonoptimized yield. An X-
biogenetic pathway depicted in Scheme 2. However, ray analysis of this compound, depicted in Figure 1, shows
NOESY experiments show that proton H-3 has a nOe with that the ring junction in 43 is cis as in sarain A. However
the propyl group at C-4, so protons H-3 and H-4 are trans, the stereochemistry at C-3 is opposite to that required for
a stereochemistry opposite to that required for sarain A (see the synthesis of the natural alkaloid.
7, Scheme 2).
In order to prepare a more advanced model, the same
methodology was applied to the β-aminoaldehyde 37 ob-
Conclusions
tained in two steps from acetal 36 (Scheme 10).[13] By con-
trast, Knoevenagel reaction of 37 with ethyl malonate was
In conclusion, we have shown, through preliminary ex-
not as easy as for the formation of intermediate 35. Either periments, that the hypothetical multicomponent chemistry,
no reaction was observed or the desired Knoevenagel pro- leading to plausible sarain A precursors depicted in
duct 38 was formed, but it reacted immediately with an- Scheme 2, can be modeled in the laboratory. This chemistry
other molecule of ethyl malonate to give adduct 39. Some leads, in particular, to highly functionalized five-membered
methods are described in order to circumvent that kind of nitrogen heterocycles such as 24, 34 or 43. Intermediate 43
over-reactivity of Knoevenagel adducts.[14] They usually in- can be viewed as a possible synthon for further work that
volve trapping the adduct by a nucleophile (methoxide,[15] involves the synthesis of sarain A, since it possesses the
secondary amines,[16] thiols[17]) and regenerating it after all same ring junction as the natural alkaloid. The main diffi-
the malonate has been consumed. Sodium ethoxide failed culty that is associated with this strategy is the inappropri-
to give the desired adduct and even increased the yield of ate β stereochemistry of the C-3 substituent, a pattern
tetraester 39, whereas reaction with piperidine afforded 40, which is evidently thermodynamically favored. Access to
Scheme 10.
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First Model Reactions towards the Synthesis of Sarain A Core Skeleton
FULL PAPER
down to room temperature. Acetic acid (60 μL, 1.05 mmol) was
added, followed by DCM (100 mL). The organic layer was washed
with water (3×100 mL), dried with MgSO4, and the solvents were
evaporated under vacuum. The yellow oily residue (403 mg) was
purified by column chromatography on silica gel (pentane/ether,
8:2) to afford the title compound (114 mg, 0.24 mmol, 38% yield).
1H NMR (400 MHz, C6D6): δ = 0.94 (t, 3 H, J = 7.4 Hz), 0.97 (t,
3 H, J = 7.3 Hz), 0.98 (t, 3 H, J = 7.1 Hz), 1.04 (t, 3 H, J = 7.1 Hz),
1.07 (t, 3 H, J = 7.1 Hz), 1.13 (t, 3 H, J = 7.1 Hz), 1.42–1.52 (m,
3 H), 1.61 (m, 1 H), 1.78 (m, 1 H), 2.10 (m, 1 H), 2.46 (m, 2 H),
3.76 (t, 1 H, J = 10.7 Hz), 3.80 (m, 1 H), 3.83 (t, 1 H, J = 11.2 Hz),
3.90–4.21 (m, 8 H), 4.61 (dt, 1 H, J = 10.9, 1.9 Hz), 7.24 (t, 1 H,
J = 7.2 Hz), 7.33 (t, 1 H, J = 1.9 Hz) ppm. 13C NMR (100 MHz,
C6D6): δ = 14.0, 14.2, 14.3, 14.6, 18.9, 22.4, 30.9, 35.4, 38.7, 40.2,
46.1, 48.3, 60.3, 60.4, 60.5, 60.8, 130.7, 135.6, 135.8, 148.2, 166.6,
166.8, 172.6, 177.1 ppm. IR (film): ν = 2964, 1719, 1707,
˜
1632, 1464, 1289, 1183 cm–1. HRMS (ESI+): m/z = 503.26219
[M + Na]+ (C16H40O8Na: calcd. 503.26209).
Derivatives 20 and 21: Ethyl aminomalonate hydrochloride (1.95 g,
9.21 mmol) was dissolved in DCM (100 mL) and washed with a
saturated calcium carbonate solution (100 mL). The organic layer
was dried with MgSO4 and evaporated under reduced pressure. The
colorless oil obtained (1.61 g, 9.20 mmol) was dissolved in MeCN/
water (1:1, 10 mL) and cooled down to –5 °C under argon. Gluta-
conic acid (598 mg, 4.60 mmol) was added. A solution of DCC
(1.89 g, 9.20 mmol) in acetonitrile (5 mL) was then added dropwise.
After 16 h at room temperature, the mixture was filtered, and the
filtrate evaporated under vacuum. The solid residue was taken up
in DCM (50 mL), stirred for 15 min, and the persistent precipitate
filtered off. The filtrate was evaporated, and the operation was re-
peated until no precipitate was formed. The white solid obtained
was purified by column chromatography on silica gel (DCM/
MeOH, 99:1 to 95:5) to afford a mixture of the two regioisomers 20
(564 mg, 1.97 mmol, 42%) in ratio 4:1 and the diamide 21 (897 mg,
2.02 mmol, 44%).
Figure 1. The molecular structure of pyrrolidinone 43; the displace-
ment ellipsoids are plotted at the 50% probability level.
the H-3,H-3a cis derivatives, along with a study of route (b)
(Scheme 3), will be reported in a future paper.
(E)-N-Bis(ethoxycarbonyl)methyl-2H and –4H-Glutaconic Acids
(20):1H NMR (250 MHz, [D6]acetone): δ = 1.25 (7.5 H, t, J =
7.1 Hz), 3.27 (dd, 2 H, J = 7.1, 1.5 Hz), 3.34 (0.5 H, dd, J = 7.1,
1.5 Hz), 4.21 (m, 5 H), 5.14 (d, 1 H, J = 7.3 Hz), 5.25 (0.25 H, d,
J = 7.6 Hz), 5.97 (d, 1 H, J = 15.6 Hz), 6.25 (0.25 H, d, J =
15.4 Hz), 6.92 (dt, 1 H, J = 15.4, 7.1 Hz), 7.00 (0.25 H, dt, J =
15.6, 7.1 Hz), 7.91 (1.25 H, br. s) ppm. 13C NMR (62.5 MHz, [D6]
acetone): δ = 14.3, 37.2, 38.9, 57.3, 62.7, 124.7 126.6, 137.9, 142.9,
165.3, 167.1, 167.3, 171.6 ppm. MS (ESI+): m/z = 288 [M + H]+,
310 [M + Na]+, 326 [M + K]+.
Experimental Section
Knoevenagel Adducts 16: Ethyl glutaconate (2.00 mL, 11.3 mmol)
was added to a suspension of alumina (38.0 g, 373 mmol) in DCM
(75 mL). A solution of butyraldehyde (1.00 mL, 11.3 mmol) in
DCM (10 mL) was added dropwise over 90 min. After 72 h, alu-
mina was filtered off and washed thoroughly with DCM
(6×50 mL). The solvent was evaporated under vacuum, and the
yellow oily residue was purified by column chromatography over
silica gel (heptanes/EtOAc, 95:5) to afford the title compound
(1.63 g, 6.78 mmol, 60% yield) as a mixture of 4-E/Z isomers (E/Z
ratio 10:3 as determined by NMR spectroscopy and GC). 1H NMR
(mixture of E/Z isomers, 250 MHz, CDCl3): δ = 0.96 (0.9 H, t, J
= 7.3 Hz), 0.97 (t, 3 H, J = 7.3 Hz), 1.30 and 1.34 (1.8 H, t, J =
7.2 Hz), 1.31 and 1.33 (t, 6 H, J = 7.2 Hz), 1.52 (0.6 H, m), 1.54
(m, 2 H), 2.37 (0.6 H, m), 2.39 (m, 2 H), 4.19 and 4.29 (q, 4 H, J
= 7.2 Hz), 4.23 and 4.32 (1.2 H, q, J = 7.2 Hz), 6.02 (0.3 H, d, J
= 15.9 Hz), 6.30 (0.3 H, t, J = 7.8 Hz), 6.50 (d, 1 H, J = 15.9 Hz),
7.02 (t, 1 H, J = 7.8 Hz), 7.26 (0.3 H, d, J = 15.9 Hz), 7.53 (d, 1 H,
J = 15.9 Hz) ppm. 13C NMR (mixture of E/Z isomers, 62.5 MHz,
CDCl3): δ = 13.8, 14.2, 22.0, 22.1, 30.8, 32.1, 60.4, 60.9, 119.1,
122.9, 128.4, 135.6, 142.3, 147.9, 150.3, 166.0, 167.3 ppm. IR (film):
(E)-N,NЈ-Bis[bis(ethoxycarbonyl)methyl]glutaconamide (21): 1H
NMR (250 MHz, CDCl3): δ = 1.29 (t, 12 H, J = 7.1 Hz), 3.23 (dd,
2 H, J = 7.1, 1.3 Hz), 4.26 and 4.27 (q, 8 H, J = 7.1 Hz), 5.11 and
5.23 (d, 2 H, J = 7.0 Hz), 6.12 (dt, 1 H, J = 15.4, 1.3 Hz), 6.70 and
6.71 (d, 2 H, J = 7.4 Hz), 6.95 (dt, 1 H, J = 15.4, 7.1 Hz) ppm. 13
NMR (75 MHz, CDCl3): δ = 14.0, 38.8, 56.5, 62.7, 126.2, 137.1,
C
164.4, 166.1, 166.3, 168.7 ppm. IR (film): ν = 3419, 3052, 2987,
˜
1757, 1742, 1686, 1622, 1502, 1422, 1276, 1253, 1019 cm–1. MS
(ESI+): m/z = 445 [M + H]+, 467 [M + Na]+, 483 [M + K]+.
Substituted Pyrrolidinone 24: Diamide 21 (145 mg, 0.33 mmol) was
added to a suspension of alumina (330 mg, 3.23 mmol) in DCM
(3 mL) at room temperature. After 72 h, alumina was filtered off
and washed thoroughly with DCM (5×20 mL). The solvent was
evaporated under reduced pressure, and the solid residue (132 mg)
was purified by column chromatography over silica gel (heptanes/
EtOAc, 9:1) to afford the title pyrrolidinone (127 mg, 0.29 mmol,
88%) as a white powder. 1H NMR (300 MHz, CDCl3): δ = 1.25 (t,
ν = 2963, 1718, 1632, 1464, 1289, 1179 cm–1. MS (EI): m/z = 240
˜
[M]+.
Cycloadduct 19: Sodium ethoxide (38 mg, 0.56 mmol) was added
to a solution of adducts 16 (300 mg, 1.25 mmol) in absolute ethanol
(2 mL), and the mixture was stirred at reflux for 14 h then cooled
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12 H, J = 7.1 Hz), 2.25 (dd, 1 H, J = 17.1, 8.1 Hz), 2.31 (dd, 1 H,
J = 14.7, 11.8 Hz), 2.68 (dd, 1 H, J = 17.1, 8.4 Hz), 2.76 (dd, 1 H,
J = 14.7, 3.4 Hz), 3.42 (dddd, 1 H, J = 11.8, 8.4, 8.1, 3.4 Hz), 4.20–
4.32 (m, 8 H), 5.14 (d, 1 H, J = 7.0 Hz), 6.76 (s, 1 H), 6.99 (d, 1
H, J = 7.3 Hz) ppm. 13C NMR (62.5 MHz, CDCl3): δ = 13.8, 13.9,
14.0, 35.6, 36.3, 37.5, 56.4, 62.5, 62.6, 62.7, 70.6, 166.2, 167.6,
1,4-Dihydropyridine-3,5-dicarboxylate 31b: Aminoacrylate 27b
(240 mg, 87 mmol) and butyraldehyde (0.10 mL, 1.13 mml) were
dissolved in 1,2-dichloroethane (5 mL). p-Toluenesulfonic acid
(50 mg, 0.29 mmol) was added, and the mixture was heated at re-
flux for 4 h. The solvent was evaporated under vacuum, and the
resulting yellow oil (378 mg) was purified by column chromatog-
raphy over silica gel (heptanes/EtOAc, 8:2) to afford the title dihy-
168,0, 169.8, 175.1 ppm. IR (film): ν = 3418, 3055, 2986, 2916,
˜
1741, 1712, 1505, 1371, 1281, 1217, 1095, 1032, 859 cm–1. MS dropyridine (96 mg, 0.23 mmol, 51%) as a pale yellow oil. 1H
(ESI+): m/z = 445 [M + H]+, 467 [M + Na]+, 483 [M + K]+.
NMR (250 MHz, CDCl3): δ = 0.83 (t, 3 H, J = 7.2 Hz), 0.94 (m,
2 H), 1.30 (t, 14 H, J = 7.1 Hz), 1.31 (m, 2 H), 3.87 (t, 1 H, J =
4.8 Hz), 4.10–4.35 (m, 8 H), 4.68 (s, 1 H), 7.20 (s, 2 H) ppm. 13C
NMR (62.5 MHz, CDCl3): δ = 13.9, 14.0, 14.2, 14.3, 17.6, 30.6,
Ethyl 2-(3-Oxypropenyl)aminomalonates 27a (E/Z Isomers): Ethyl
aminomalonate hydrochloride (2.11 g, 10.0 mmol) was added to a
suspension of the sodium salt of malonaldehyde[18] (1.12 g,
10.0 mmol) in DCM (50 mL) under argon. The mixture was stirred
for 4 h at room temperature, then filtered, and the solid washed
with DCM (3×50 mL). The combined filtrates were evaporated un-
der vacuum, and the orange residue (2.82 g) was purified by col-
umn chromatography over silica gel (heptanes/EtOAc, 1:1) to af-
ford the title aminoacroleine (2.06 g, 9.00 mmol, 90%) as a mixture
isomers in a E/Z ratio of 85:15 as determined by NMR spec-
38.0, 60.1, 62.9, 67.5, 109.3, 137.8, 165.1, 166.9 ppm. IR (film): ν
˜
= 2959, 2936, 1748,1741, 1705, 1592, 1369, 1203, 1185, 1094, 1023,
860 cm–1. MS (EI): m/z = 425 [M]+.
Ethyl 2-(2-Methoxycarbonylacetamido)malonate 32: Ethyl amino-
malonate hydrochloride (2.11 g, 9.87 mmol) and sodium methoxy-
carbonylacetate (1.56 g, 9.78 mmol) were dissolved in acetonitrile/
water (3:1, 60 mL) at –5 °C. DCC (2.06 g, 10.0 mmol) was added,
troscopy. 1H NMR (250 MHz, CDCl3): δ = 1.22 (t, 7 H, J = and the mixture was stirred at –5 °C for 2 h and then for additional
7.1 Hz), 4.05–4.35 (4.72 H, m), 4.55 (0.18 H, d, J = 6.9 Hz), 4.57 4 h at room temperature. The white precipitate was filtered off and
(d, 1 H, J = 6.2 Hz), 5.15 (0.18 H, dd, J = 7.7, 2.1 Hz), 5.17 (dd,
1 H, J = 13.2, 8.5 Hz), 6.46 (t, 1 H, J = 6.6 Hz), 6.72 (0.18 H, m),
7.20 (dd, 1 H, J = 13.2, 7.7 Hz), 9.11 (d, 1 H, J = 8.1 Hz), 9.21
washed with DCM (3×50 mL). The filtrate was diluted with DCM
(200 mL) and washed with water (3×150 mL). The organic layer
was dried with MgSO4 and evaporated under reduced pressure. The
(0.18 H, dd, J = 4.8, 2.1 Hz), 10.12 (0.18 H, m) ppm. 13C NMR residue (3.07 g) was purified by column chromatography over silica
(62.5 MHz, CDCl3): δ = 13.8, 59.7, 62.6, 61.8, 61.9, 97.1, 104.0, gel (DCM/EtOAc, 9:1) to afford the title amide (2.59 g, 9.41 mmol,
1
150.6, 154.4, 165.4, 165.7, 189.4, 190.5 ppm. IR (film): ν = 2984,
96%) as a colorless oil. H NMR (250 MHz, CDCl3): δ = 1.26 (t,
6 H, J = 7.2 Hz), 3.38 (s, 2 H), 3.73 (s, 3 H), 4.24 (m, 4 H), 5.13
(d, 1 H, J = 6.8 Hz), 8.02 (d, 1 H, J = 6.6 Hz) ppm. 13C NMR
(62.5 MHz, CDCl3): δ = 13.8, 40.6, 52.4, 56.4, 62.5, 164.8, 165.8,
˜
2916, 1740, 1618, 1371,1166, 1021, 858 cm–1. MS (CI, isobutane):
m/z = 230 [M + H]+.
Ethyl 2-(2-Ethoxycarbonylvinylamino)malonate 27b (E/Z Isomers):
Ethyl aminomalonate (2.07 g, 11.82 mmol) and ethyl propiolate
(1.2 mL, 11.84 mmol) were mixed in absolute ethanol (25 mL), and
the solution was heated at reflux for 4 h. The solvent was removed
under vacuum, and the yellow oily residue (3.20 g) was purified by
column chromatography over silica gel (DCM/EtOAc, 9:1) to af-
ford the title aminoacrylate (2.92 g, 10.7 mmol, 90%) as an equi-
168.9 ppm. IR (film): ν = 3413, 3353, 2956, 1754, 1742, 1682, 1517,
˜
1373, 1344, 1218, 1178, 1019, 858 cm–1. MS (ESI+): m/z = 276 [M
+ H]+, 298 [M + Na]+, 314 [M + K]+.
Ethyl 2-((2E and 2Z)-2-Methoxycarbonylhex-2-enoylamino)malon-
ate 33: Amide 32 (350 mg, 1.27 mmol) and butyraldehyde
(0.168 mL, 1.90 mmol) were added under argon to a suspension of
alumina (872 mg, 8.55 mmol) in DCM (0.50 mL). The mixture was
stirred at room temperature for 96 h, then filtered through Celite,
and the solid was washed with DCM (5×10 mL). The combined
filtrates were evaporated under vacuum, and the resulting oil
(323 mg) was purified by column chromatography over silica gel
(heptanes/DCM/EtOAc 65:25:10) to afford the two isomeric
1
molar mixture of E- and Z isomers. H NMR (300 MHz, CDCl3):
δ = 1.20–1.30 (m, 18 H), 4.13 (m, 4 H), 4.27 (m, 8 H), 4.50 (d, 1
H, J = 8.5 Hz), 4.54 (d, 1 H, J = 7.0 Hz), 4.66 (d, 1 H, J = 8.1 Hz),
4.77 (d, 1 H, J = 13.6 Hz), 5.49 (d, 1 H, J = 6.8 Hz), 6.58 (dd, 1
H, J = 12.5, 8.1 Hz), 7.49 (dd, 1 H, J = 13.6, 7.3 Hz), 8.33 (dd, 1
H, J = 11.8, 8.8 Hz) ppm. 13C NMR (75 MHz, CDCl3): δ = 13.9,
14.4, 59.0, 59.3, 59.9, 62.5, 62.8, 63.3, 86.8, 89.6, 146.0, 148.8,
amides (192 mg, 0.58 mmol, 46%) and (2E) (68 mg, 0.21 mmol,
1
166.0, 166.4, 168.6, 196.9 ppm. IR (film): ν = 3336, 2982, 2936, 16%). (Z)-Isomer: H NMR (250 MHz, CDCl3): δ = 0.94 (t, 3 H,
˜
1748,1740, 1673, 1622, 1477, 1369, 1301, 1200, 1095, 858, 788 cm–1. J = 7.3 Hz), 1.29 (t, 6 H, J = 7.3 Hz), 1.52 (h, 2 H, J = 7.3 Hz),
MS (EI): m/z = 273 [M]+.
2.52 (q, 2 H, J = 7.3 Hz), 3.86 (s, 3 H), 4.26 (m, 4 H), 5.17 (d, 1
H, J = 6.6 Hz), 7.59 (t, 1 H, J = 7.3 Hz), 8.97 (d, 1 H, J = 6.6 Hz)
ppm. 13C NMR (62.5 MHz, CDCl3): δ = 13.8, 13.9, 21.8, 32.5,
Ethyl
2-(3,5-Diformyl-4-propyl-1,4-dihydropyridin-1-yl)malonate
(31a): A solution of aminoacroleine (216 mg, 0.94 mmol) in 1,2-
dichloroethane (5 mL) was added to a solution of butyraldehyde
(0.20 mL, 2.27 mmol) in 1,2-dichloroethane (10 mL). p-Toluenesul-
fonic acid (100 mg, 0.58 mmol) was added, and the mixture was
heated at reflux for 1 h. After evaporation of the solvent under
vacuum, the red oily residue (600 mg) was purified by column
chromatography over silica gel (heptanes/EtOAc, 1:1) to afford the
title dihydropyridine (143 mg, 0.42 mmol, 90%) as a pale yellow
oil. 1H NMR (250 MHz, CDCl3): δ = 0.83 (t, 3 H, J = 7.2 Hz),
1.13 (m, 2 H), 1.35 (t, 6 H, J = 7.1 Hz), 1.47 (m, 2 H), 3.92 (t, 1
H, J = 4.8 Hz), 4.25–4.45 (m, 4 H), 4.90 (s, 1 H), 6.94 (s, 2 H), 9.29
(s, 2 H) ppm. 13C NMR (62.5 MHz, CDCl3): δ = 13.9, 14.0, 17.9,
52.1, 57.1, 62.4, 125.0, 157.8, 165.0, 166.1, 167.2 ppm. IR (film): ν
˜
= 3352, 2961, 2874, 1759, 1743, 1710, 1665, 1512, 1440, 1372, 1281,
1223, 1151, 1023, 808 cm–1. MS (ESI+): m/z = 330 [M + H]+, 352
[M + Na]+, 368 [M + K]+. (E)-Isomer: 1H NMR (250 MHz,
CDCl3): δ = 0.95 (t, 3 H, J = 7.3 Hz), 1.31 (t, 6 H, J = 7.3 Hz),
1.53 (h, 2 H, J = 7.3 Hz), 2.61 (q, 2 H, J = 7.3 Hz), 3.80 (s, 3 H),
4.26 (m, 4 H), 5.21 (d, 1 H, J = 6.6 Hz), 7.29 (t, 1 H, J = 7.3 Hz),
8.20 (d, 1 H, J = 6.6 Hz) ppm. 13C NMR (62.5 MHz, CDCl3): δ =
13.8, 14.0, 22.0, 31.9, 52.5, 56.7, 62.6, 126.6, 156.5, 163.9, 166.0,
166.1 ppm. IR (film): ν = 3344, 2961, 2874, 1759, 1742, 1711, 1678,
˜
1511, 1438, 1372, 1251, 1157, 1024, 860, 807 cm–1. MS (ESI–):
m/z = 328 [M – H]–.
27.4, 36.1, 63.3, 67.1, 122.6, 146.4, 164.6, 189.0 ppm. IR (film): ν
˜
= 2959, 2935, 2873, 1744, 1667, 1580, 1421, 1393, 1369, 1225, 1156,
Pyrrolidinone 34. From Amide 33: Amide 33 (E- or Z-isomer,
304 mg, 0.92 mmol) was dissolved in absolute ethanol (10 mL). So-
1111, 1028, 917, 707 cm–1. MS (EI): m/z = 337 [M]+.
1308
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2005, 1302–1310

First Model Reactions towards the Synthesis of Sarain A Core Skeleton
FULL PAPER
dium ethoxide (31 mg, 0.46 mmol) was added, and the solution was
heated to reflux for 1 h. After cooling to room temperature, the
mixture was neutralized with glacial acetic acid (0.035 mL,
0.77 mmol), then diluted with DCM (100 mL) and washed with
brine (100 mL). The organic layer was dried with MgSO4 and evap-
orated under reduced pressure. The yellowish solid obtained
(330 mg) was recrystallized from 95% ethanol to afford the title
pyrrolidinone (294 mg, 0.86 mmol, 93%) as a white solid. From
up with ether to give a milky mixture which was washed with water.
The organic layer was dried (Na2SO4), and the solvent evaporated
under vacuum to give a mixture of aldehyde, diethyl malonate, and
the expected Knoevenagel adduct 41 (1.63 g). This mixture was
added to a solution of acetamidomalonate (1.01 g, 0.47 mmol) in
absolute ethanol (25 mL). The mixture was stirred at room tem-
perature for 40 min and then heated to reflux for 19 h. The yellow-
ish mixture was acidified with acetic acid (2.4 mL), and ethanol
Knoevenagel Adduct 35: Ethyl acetamidomalonate (277 mg, was azeotropically removed with toluene under reduced pressure.
1.27 mmol) and diester 35 (300 mg, 1.40 mmol) were dissolved in
absolute ethanol (2 mL). Sodium ethoxide (41 mg, 0.60 mmol) was
added, and the mixture was heated to reflux for 14 h. After cooling
to room temperature, glacial acetic acid (0.040 mL, 0.89 mmol) was
added, and the solvents were evaporated from the mixture under
reduced pressure. The resulting orange oil was taken up in water
(3 mL) and stirred for 30 min. The precipitate was filtered off,
washed with water (3×10 mL) and dried under vacuum.
Recrystallization from 95% ethanol afforded the title pyrrolidinone
(332 mg, 0.97 mmol, 76%) as a white solid. M.p. (MeOH) 74 °C.
The mixture was taken up with DCM, washed with a saturated
NaHCO3 solution and brine, and dried with MgSO4. After removal
of the solvents, the resulting oil was chromatographed on silica gel
(heptanes/EtOAc, 6:4 to 5:5) to afford the title pyrrolidinone
(840 mg, 28% from 37). 1H NMR (600 MHz, C6D6): δ = 0.76 (t, J
= 6.9 Hz, 3 H, CH3), 0.84 (t, J = 6.9 Hz, 3 H, CH3), 1.00 (t, J =
6.9 Hz, 3 H, CH3), 1.39–1.43 (m, 1 H, H6), 1.44 (s, 9 H, tBu),
2.016–2.048 (m, 1 H, H6), 2.98–2.99 (m, 1 H, H7), 3.23–3.25 (m,
1 H, H7), 3.49 (d, J = 11.4 Hz, H4) 4.68 (br. s, 1 H, NHBoc), 6.62
(br. s, 1 H, NH) ppm. 13C NMR (75 MHz, CDCl3): δ = 13.9, 14.1,
1H NMR (250 MHz, CDCl3): δ = 0.88 (t, 3 H, J = 7.1 Hz), 1.26 28.4, 30.7, 38.1, 41.8, 53.2, 62.4, 62.8, 63.0, 69.3, 79.3, 155.7, 167.3,
and 1.28 (t, 9 H, J = 7.1 Hz), 1.12–1.32 (m, 3 H), 1.79 (m, 1 H), 168.2, 169.0, 170.4 ppm. IR (film): ν = 3341, 2980, 2937, 1741,
˜
3.28 (m, 2 H), 4.26 (m, 6 H), 7.06 (br. s, 1 H) ppm. 13C NMR
(62.5 MHz, CDCl3): δ = 13.7, 13.9, 20.5, 32.6, 44.4, 53.8, 61.7, 62.4,
1715, 1510, 1367, 1254, 1217, 1169, 1014, 860 cm–1. HRMS (ESI+):
m/z = 467.1998 [M + Na]+. C20H32N2O9Na (467.2006): calcd. C
62.6, 69.8, 167.3, 168.3, 169.1, 171.5 ppm. IR (CH Cl ): ν = 3413, 54.04, H 7.26, N 6.30; found C 54.11, H 7.36, N 6.35.
˜
2
2
2966, 2935, 1742, 1727, 1466, 1370, 1221, 1042, 860 cm–1. MS (EI):
m/z = 343 [M]+. Calcd. C 55.97, H 7.34, N 4.08; found C 56.04, H
7.62, N 4.17.
Pyrrolidinone 43: Trifluoroacetic acid (0.56 mL, 7.54 mmol) was
added to a solution of carbamate 42 (334 mg, 0.75 mmol) in DCM
(3.2 mL). The mixture was heated to reflux for 4.5 h. The solvent
was removed, and residual TFA was co-evaporated with toluene.
The residue was dissolved in a mixture of pyridine/DCM (1:3) and
washed with water. The organic layer was dried (MgSO4) and evap-
orated under reduced pressure. The residue was stirred in methanol,
and the precipitate filtered off and dried under vacuum to give the
title compound (106 mg, 0.33 mmol, 44%) as a white solid. M.p.
Ethyl 2-Butylidenemalonate 35: Ethyl malonate (1.52 mL,
10.0 mmol), butyraldehyde (0.882 mL, 10.0 mmol), and piperidin-
ium acetate (290 mg, 2.00 mmol) were dissolved in DCM (30 mL).
The mixture was stirred for 15 h at room temperature, then diluted
with DCM (150 mL) and washed successively with 0.1 n hydrochlo-
ric acid (150 mL), saturated NaHCO3 solution (150 mL) followed
by brine (150 mL). The organic layer was dried with MgSO4 and
evaporated under reduced pressure. The residue was purified by
column chromatography over silica gel (heptanes/EtOAc, 9:1) to
afford the title Knoevenagel adduct (1.31 g, 6.10 mmol, 61%) as a
colorless oil. 1H NMR (300 MHz, CDCl3): δ = 0.92 (t, 3 H, J =
7.3 Hz), 1.26 and 1.30 (t, 6 H, J = 7.3 Hz), 1.49 (q, 2 H, J = 7.3 Hz),
2.25 (dd, 2 H, J = 7.7, 7.3 Hz), 4.20 and 4.27 (q, 4 H, J = 7.3 Hz),
6.96 (t, 1 H, J = 7.7 Hz) ppm. 13C NMR (75 MHz, CDCl3): δ =
13.7, 14.1, 21.6, 31.7, 61.1, 128.8, 142.1, 163.9, 165.5 ppm. IR
1
(MeOH) 178 °C. H NMR (300 MHz, [D5]pyridine): δ = 1.24 (t, 3
H, J = 6.9 Hz), 1.26 (t, 3 H, J = 6.9 Hz), 1.86–1.94 (m, 1 H), 2.31–
2.39 (m, 1 H), 3.59–3.64 (m, 2 H), 3.80–3.87 (m, 1 H), 3.91 (d, 1
H, J = 4.8 Hz), 4.31 (q, 2 H, J = 6.9 Hz), 4.33 (dq, 1 H, J = 10.9,
J = 6.9 Hz), 4.44 (dq, 1 H, J = 10.9, J = 6.9 Hz), 9.57 (s, 1 H, NH),
11.56 (1 H, NH) ppm. 13C NMR (75 MHz, [D5]pyridine): δ = 13.8
(CH3), 26.5 (C-4), 39.1 (C-5), 41.9 (C-3a), 53.8 (C-3), 61.5 (OCH2),
62.0 (OCH2), 67.5 (C-7a), 167.5 (C-7), 169.2 (C(O)-C-3), 170.6 (C-
2), 171.4 [C(O)-C-7a] ppm. IR (nujol): ν = 3266, 3201, 2924, 2854,
˜
(film): ν = 2964, 2935, 2874, 1734, 1727, 1646, 1465, 1375, 1251,
˜
1728, 1678, 1637, 1457, 1377, 1260, 1184, 1019, 816 cm–1. HRMS
(ESI+): m/z = 321.1057 [M + Na]+. C13H18N2O6Na (321.1063):
calcd. C 52.34, H 6.08, N 9.39; found C 52.23, H 5.91, N 9.13.
1212, 1060, 865 cm–1. MS (EI): m/z = 214 [M]+.
3-tert-Butoxycarbonylaminopropanal 37: The title compound was
obtained in 91% yield from 3-aminopropanal diethylacetal follow-
ing a known procedure[13] and was used without purification. 1H
NMR (300 MHz, CDCl3): δ = 1.43 (s, 9 H), 2.71 (t, 2 H, J =
5.6 Hz), 3.42 (q, 2 H, J = 6.3 Hz), 4.90 (br. s, 1 H), 9.81 (s, 1 H)
ppm. 13C NMR (75 MHz, CDCl3): δ = 28.2, 34.0, 44.1, 85.0, 155.8,
X-ray Crystallographic Study of Pyrrolidinone 43: Suitable crystals
for the X-ray crystallographic studies of 43 were obtained as color-
less prisms by crystallization from methanol. The crystals were
mounted on the tip of a glass fiber with epoxy glue. The X-ray data
were collected at 298 K with a Nonius Kappa-CCD diffractometer
equipped with a graphite monochromator and Mo-Kα radiation (λ
= 0.71073 Å). A total of 321 60-s frames were collected in three
sets with a 1.1° ω-scan. Data reduction was carried out with the
DENZO program from the HKL suite.[19] The structure was solved
201.3 ppm. IR (film): ν = 3356, 2927, 2934, 1697 (large), 1522,
˜
1393, 1367, 1277, 1252, 1170, 1006, 862 cm–1. HRMS (ESI+): m/z
= 228.1216 [M + MeOH + Na]+ (C9H19NNaO4: calcd. 228.1212).
Pyrrolidinone 42: A solution of aldehyde 37 (1.15g, 0.66 mmol) in
DCM (0.5 mL) and ether (2 mL) was added over 2.5 h to a solution by direct methods with SHELXS and refined by least-squares
of piperidine (0.55 mL, 0.56 mmol) and diethyl malonate (0.70 mL,
0.46 mmol) in diethyl ether (10 mL) at –5 °C. The mixture was
stirred for 1.5 h and then dried with Na2SO4. The salt was filtered
and washed with DCM. The filtrate was evaporated and taken up
with DCM (4 mL). p-Toluenesulfonic acid (1 g) and Na2SO4 were
added to the mixture at 0 °C, and the mixture was stirred at this
temperature for 3 h. The salt was filtered, and the filtrate was taken
methods on F2, using SHELXL, both programs from the SHELX-
97 package.[20] All non-hydrogen atoms were refined anisotropi-
cally, and the H atoms were located from difference-Fourier synthe-
ses, but their positional parameters were recalculated geometrically
and treated as riding, with Uiso(H) = 1.15 Ueq(parent atom) or
1.2 Ueq(-CH3). CCDC-249235 contains the supplementary crystal-
lographic data for this paper. These data can be obtained free of
Eur. J. Org. Chem. 2005, 1302–1310
www.eurjoc.org
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1309

S. Hourcade, A. Ferdenzi, P. Retailleau, S. Mons, C. Marazano
FULL PAPER
[6] R. T. Hill, M. T. Hamann, O. Peraud, N. Kasanah “Manzam-
ine-producing actinomycetes”; Worldwide patent WO 2004/
013297 (US, 2003/024238), 12 February 2004, pp. 49.
[7] F. VanMiddlesworth, C. Dufresne, F. E. Wincott, R. T. Mosley,
K. E. Wilson, Tetrahedron Lett. 1992, 33, 297–301.
charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
Crystal Data for 43: C13H18N2O6, Mr= 298.29, space group ortho-
rhombic, Pbca (No. 61). Unit cell parameters: a= 7.823(4) Å, b=
13.586(3) Å, c= 26.095(4) Å, V= 2773.5(16) Å3, Z = 8, ρcalcd.
=
[8] Sarain A synthetic studies; a) M. J. Sung, H. I. Lee, H. B. Lee,
J. K. Cha, J. Org. Chem. 2003, 68; 2205–2208; b) O. Irie, K.
Samizu, J. R. Henry, S. M. Weinreb, J. Org. Chem. 1999, 64,
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[9] For other studies from our laboratory concerning the Knoev-
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J. Org. Chem. 2003, 1859–1867; b) M. Sanchez Salvatori, C.
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[10] For exemples see: a) R. B. Silverman, S. M. Nanavati J. Med.
Chem. 1990, 33, 931–936; b) A. Barco, S. Beneti, G. P. Pollini,
P. G. Baraldi, M. Guarneri, C. Gandolfi, R. Ceserani, D. J.
Longiave J. Med. Chem. 1981, 24, 625–628; c) Y. C. Kim, G. H.
Cocolas J. Med. Chem. 1965, 8, 509–512.
1.429 Mgm–3, F(000) = 1264, μ(Mo-Kα) = 0.114 mm–1. Crystal di-
mensions 0.18×0.13×0.13 mm. A total of 5180 reflections col-
lected, 2809 independent reflections (Rint = 0.0287), final Rint [I Ͼ
2σ(I)]: R1 = 0.0432, wR2 = 0.1116 for 192 variable parameters {w
= 1/[σ2Fo + (0.0718P)2 + 0.3488P], where P= (Fo + 2Fc )/3}. (Δ/
σ)max Ͻ 0.001, Δρmax = 0.28 eÅ3, Δρmin = –0.19 eÅ3, GOF = 1.037.
2
2
2
[1] a) Y. Guo, A. Madaio, E. Trivellone, G. Scognamiglio, G. Cim-
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[14] L. F. Tietze, U. Beifuss, in Comprehensive Organic Synthesis
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[3] a) J. E. Baldwin, R. C. Whitehead, Tetrahedron Lett. 1992, 33,
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[18] A. Gómez-Sánchez, I. Hermosín, J.-M. Lassaletta, I. Maya,
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[19] Z. Otwinovski, W. Minor, “Macromolecular Crystallography,
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[20] G. M. Sheldrick, SHELXL-97 Program for crystal structure re-
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Received September 13, 2004
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© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Eur. J. Org. Chem. 2005, 1302–1310