Total synthesis of (+)-grandiamide D, dasyclamide and gigantamide A from a Baylis-Hillman adduct: A unified biomimetic approach

Article abstract of DOI:10.3762/bjoc.10.9

A unified strategy was followed for the synthesis of three putrescine bisamides, (+)-grandiamide D, dasyclamide and gigantamide A, isolated from leaves of Aglaia gigantea, by making use of a common synthetic intermediate prepared by the Baylis-Hillman rea

Full text of DOI:10.3762/bjoc.10.9

Total synthesis of (+)-grandiamide D, dasyclamide
and gigantamide A from a Baylis–Hillman adduct:
A unified biomimetic approach
Andivelu Ilangovan*1 and Shanmugasundar Saravanakumar1,2
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2014, 10, 127–133.
1School of Chemistry, Bharathidasan University, Tiruchirappalli,
620024, India and 2Syngene International Ltd., Bangalore, 560 099,
India
doi:10.3762/bjoc.10.9
Received: 05 September 2013
Accepted: 26 November 2013
Published: 10 January 2014
Email:
Andivelu Ilangovan* - ilangovanbdu@yahoo.com
This article is part of the Thematic Series "Natural products in synthesis
and biosynthesis".
* Corresponding author
Keywords:
Guest Editor: J. S. Dickschat
Baylis–Hillman reaction; dasyclamide; gigantamide A;
(+)-grandiamide D; natural products; putrescine bisamides
© 2014 Ilangovan and Saravanakumar; licensee Beilstein-Institut.
License and terms: see end of document.
Abstract
A unified strategy was followed for the synthesis of three putrescine bisamides, (+)-grandiamide D, dasyclamide and gigantamide
A, isolated from leaves of Aglaia gigantea, by making use of a common synthetic intermediate prepared by the Baylis–Hillman
reaction. Asymmetric synthesis of the natural (+)-grandiamide D was accomplished from camphor sultam.
Introduction
Putrescine bisamides are one of the important naturally occur- various cancer cell lines [4]. Apart from acting as precursors for
ring polyamine alkaloids found in open chain and cyclic forms. flavaglins, some of the cyclic bisamides such as odorine, dehy-
The genera Aglaia are the richest source of putrescine droodorine and odorinol exhibited cytotoxic and antiviral
bisamides. The cyclic 2-aminopyrrolidine compounds are activity [5].
synthesised in plants from open-chained bisamides by enzy-
matic cyclization. It is assumed that both forms of bisamides There is only a limited number of putrescine bisamides isolated
undergo a cycloaddition reaction with a co-occurring flavanol to from natural sources and the amount of synthetic approaches
form highly bioactive flavaglines [1,2]. For example, odorine known for these structurally interesting and biologically impor-
(2) acted as a building block for aglaforbesin A (1) and pyrami- tant molecules is quite low. Except for the elaborate synthetic
datin (4) for pyramidaglain (3) as shown in Figure 1 [3]. The work carried out by Hesse and Detterbeck [6], who described
benzopyran and benzoxepine containing flavaglins showed the synthesis of nine putrescine bisamides isolated from
insecticidal, antifungal and antiproliferative activity against different Aglaia species along with the structural revision for
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Beilstein J. Org. Chem. 2014, 10, 127–133.
Figure 1: Bisamides as building blocks for flavaglins.
one of the compounds and determination of absolute configur- Baylis–Hillman adducts are densely functionalized synthons,
ation for another compound, no other literature precedence is which mainly consist of three different functional groups such
available till now.
as the ester, olefin and hydroxy group [8]. Recent develop-
ments made it possible to introduce additional functional groups
Duong et al. have isolated three cinnamoyl bisamide deriva- on them by replacing the starting materials by activated alkenes
tives, two new compounds grandiamide D, gigantamide A and and aldehydes. Various multifunctional molecules including
the known compound dasyclamide (Figure 2) from the leaves of natural products have already been successfully synthesized
Aglaia gigantea [7]. Even though the structures were deter- using the Baylis–Hillman adducts [9].
mined by spectroscopic means, the total synthesis of these
molecules has not been explored so far. As a result of their Structural features of grandiamide D, gigantamide A, dasy-
co-existence, we assumed that these compounds might have clamide reveal that the N-(4-aminobutyl)cinnamamide segment
been formed from a single precursor with the help of elements is common and a remaining part of these molecules could be
present in the plant. Hence we decided to adopt a unified syn- constructed from this common intermediate. The synthetic
thetic strategy for the synthesis of all the three compounds 5–7 versatility of the Baylis–Hillman adducts is a perfect platform
by mimicking the biosynthetic pathway.
for the retrosynthetic plan (Scheme 1). Accordingly, 2-(4-
Figure 2: (+)-Grandiamide D, gigantamide A and dasyclamide.
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Beilstein J. Org. Chem. 2014, 10, 127–133.
methoxybenzyloxy)acetaldehyde was expected to provide a
tetra-functionalized Baylis–Hillman adduct (+)-16 from which
grandiamide D can be obtained. A rearrangement of this
common intermediate should be able to provide dasyclamide,
which on oxidation, should give gigantamide A.
Results and Discussion
The synthetic plan was started with the preparation of N-(4-
aminobutyl)cinnamamide (11), in two steps from tert-butyl
4-aminobutylcarbamate and cinnamic acid by EDCI-mediated
coupling followed by removal of the Boc protecting group by
refluxing in ethanolic HCl as given in Scheme 2.
Synthesis of (±)-grandiamide D (5)
The common and crucial intermediate, β,γ-dihydroxy-α-methyl-
enebutyric acid ((±)-16) required a selective protection of the
hydroxy group at γ position. The PMB (p-methoxybenzyl)
group was chosen as a result of its robustness and stability
towards a wide range of acidic or basic conditions [10]. The
entire pathway leading to the synthesis of (±)-grandiamide D is
portrayed in Scheme 3.
Scheme 1: Retrosynthetic analysis: A unified synthetic approach for
the synthesis of grandiamide D, dasyclamide and gigantamide A.
Scheme 2: Preparation of N-(4-aminobutyl)cinnamamide.
Scheme 3: Synthesis of (±)-grandiamide D.
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Beilstein J. Org. Chem. 2014, 10, 127–133.
The reaction between ethyl bromoacetate (12) and p-methoxy- (+)-16 in 71% yield, after purification (Scheme 4). Chiral
benzyl alcohol in the presence of NaH (Scheme 3) furnished the HPLC analysis of (+)-16 showed that the enantiomeric ratio is
desired ester 13 which on reduction with DIBAL-H provided 99.7:0.3 in favour of the (+)-isomer. Further chemistry was
2-((4-methoxybenzyl)oxy)acetaldehyde (14) [11]. In order to carried out as described earlier in Scheme 3, to get (+)-grandi-
reduce the amount of acrylate and to increase the yield of com- amide D (5) in almost the same yield. The enantiomeric purity
pound (±)-16, the Baylis–Hillman reaction between the alde- of (+)-grandiamide D (5) was found to be 98.6%, as deter-
hyde 14 and ethyl acrylate (15) was tried using different cata- mined from chiral HPLC analysis. (observed [α]D25 = +4.7 (c
lysts such as DBU, quinuclidine [12] and n-Bu3P. DABCO was 0.5, CHCl3); reported [7] [α]D20 = +2.0 (c 0.5, CHCl3).
found to be a better catalyst and the adduct (±)-16 was obtained
in high yield [13] in dioxane/water (1:1), at room temperature Synthesis of dasyclamide
after 40 h [13]. Hydrolysis of the ester (±)-16 with aqueous Since Baylis–Hillman adduct (±)-18 was considered as the
LiOH in THF yielded the acid (±)-17 which on EDCI supported common intermediate, we decided to start with the same for the
reaction with N-(4-aminobutyl)cinnamamide (11) gave the synthesis of dasyclamide (6). As explained in Scheme 5
PMB protected grandiamide D ((±)-18). Among different attempts to get enamide 22 by reductive dehydroxylation of
reagents such as DDQ, CAN, Yb(OTf)3 and CeCl3–NaI used compound (±)-18 using NaBH4/CuCl2·2H2O or Al-NiCl2·2H2O
for deprotection of the PMB group, TFA gave the better result. [16-18] and reductive deacetoxylation of compound (±)-21
Even though POCl3 [14] was able to effect complete removal of using NaBH4/t-BuOH or LiBEt3H, THF [19-21] did not yield
the PMB group in short time, the yield was only moderate. Thus fruitful results.
(±)-grandiamide D ((±)-5) was obtained in 16.6% overall yield.
The spectral data obtained for synthetic compound (±)-5 These failures pushed us to explore the dehydroxylation or de-
matches in all respect with the data reported for the natural acetoxylation reaction using a simpler precursor (±)-16.
product [7].
However, attempts to dehydroxylate the Baylis–Hillman adduct
(±)-16 with NaBH4/CuCl2·2H2O [17] and Al-NiCl2·2H2O
proved unsuccessful hence, we focused on the deacetoxylation
of (±)-16. Treatment of (±)-16 with acetyl chloride in the pres-
Asymmetric synthesis of (+)-grandiamide D
(5)
In continuation, we moved on with an asymmetric approach ence of pyridine afforded the corresponding acetate (±)-23 in
towards the synthesis of natural product (+)-grandiamide D (5). almost quantitative yield, which underwent the desired deacet-
We assumed that the asymmetric Baylis–Hillman reaction [15] oxylation with NaBH4/t-butanol [20] to provide the ester 24 in
would be an ideal way to introduce chirality. Reaction between good yield (Scheme 6). The ester 24 was hydrolyzed with
acryloyl sultam 19, and 2-((4-methoxybenzyl)oxy)acetaldehyde aqueous KOH in methanol at room temperature to get acid 25
(14) in DMF [12], afforded cyclic product 20, which was then which was then treated with N-(4-aminobutyl)cinnamamide
treated as such with TEA in ethanol to afford enantiopure ester (11) in the presence of EDCI to get enamide 26. Further, depro-
Scheme 4: Asymmetric synthesis of natural (+)-grandiamide D.
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Beilstein J. Org. Chem. 2014, 10, 127–133.
Scheme 5: Various approaches for the synthesis of (E)-N-(4-cinnamamidobutyl)-4-((4-methoxybenzyl)oxy)-2-methylbut-2-enamide (22).
Scheme 6: Synthesis of dasyclamide.
tection was carried out with TFA to obtain dasyclamide (6) in have also isolated N-(4-(3-methyl-2,5-dioxo-2,5-dihydro-1H-
an overall yield of 9.2% (Scheme 6).
pyrrol-1-yl)butyl)cinnamamide (28) as one of the products
which might have been formed by the oxidation of gigantamide
The spectral data is in accordance with the published data for A (7) by excess of PCC. Comparison of the NMR data with
natural dasyclamide [7] which further confirms the structure of those reported for the natural gigantamide A (7) [7] confirmed
the natural product.
the identity of the synthetic product. The overall yield for the
synthetic route was found to be 2.3%. Chiral HPLC analysis
revealed that it is a racemic compound which was further
Synthesis of gigantamide A
As given in the retrosynthetic analysis and based on the prefer- confirmed by the optical rotation ([α]D23= 0 (c, 0.5, CHCl3);
ence in literature for the preparation of jatropham by photocy- reported for the enatio-pure compound: [α]D20= −10 (c, 0.3,
clization [22], intramolecular cyclization of the aldehyde 27 CHCl3)). Further attempt to get (−)-gigantamide by lipase
was considered for the preparation of gigantamide A (7). The catalyzed kinetic resolution in line with the reported method for
aldehyde 27 in turn could be prepared from dasyclamide (6). R-jatropham [23] was not successful.
Conditions and results for the oxidation of dasyclamide (6) to
give gigantamide A (7) are outlined in Table 1.
Conclusion
In conclusion, a facile synthesis of (±)-grandiamide D (5), dasy-
The results clearly demonstrated that IBX (Table 1, entry 5) is clamide (6) and gigantamide A (7) and asymmetric synthesis of
the best reagent to get the aldehyde 27 in better yield and natural (+)-grandiamide D (5) was achieved with the aid of a
quality. After analyzing the products obtained from the oxi- Baylis–Hillman adduct. We have also demonstrated a one-step
dation with PCC (Table 1, entry 4), we found that the reaction conversion of dasyclamide (6) to gigantamide A (7) by oxida-
produced gigantamide A (7) along with the aldehyde 27. We tive intramolecular cyclization by using PCC.
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Beilstein J. Org. Chem. 2014, 10, 127–133.
Table 1: Synthesis of gigantamide A (7) by oxidation of dasyclamide (6).
Entry
Conditions
Results
1
2
3
4
5
6
MnO2, dioxane, reflux
no reaction
TPAP, NMO, ACN/DCM, rt
Py·SO3, TEA, DMSO, rt to 80 °C
PCC, CHCl3, rt
incomplete reaction & close impurities
no reaction
incomplete reaction & difficulties in isolation
70% of aldehyde after purification.
30% of aldehyde (27) + 25% of gigantamide A + 30% of 28
IBX, fluorobenzene/DMSO (9:1), 90 °C, 4 h
PCC, CHCl3/DMSO (3:1), rt
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Supporting Information
Supporting Information File 1
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13C NMR spectra for the new compounds and chiral HPLC
reports.
6. Detterbeck, R.; Hesse, M. Tetrahedron 2002, 58, 6887–6893.
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