Synthesis of acridinedione derived mono spiro-pyrrolidine/pyrrolizidine derivatives - A facile approach via intermolecular [3+2] cycloaddition reaction

Article abstract of DOI:10.1016/j.tetlet.2014.05.133

A facile synthesis of acridinedione derived mono spiro-pyrrolidine and pyrrolizidine derivatives has been accomplished by 1,3-dipolar cycloaddition reaction. The O-acryloylacridinediones, as dipolarophiles reacted with azomethine ylide derived from di-/tr

Full text of DOI:10.1016/j.tetlet.2014.05.133

Accepted Manuscript
Synthesis of acridinedione derived mono spiro-pyrrolidine/pyrrolizidine deriv-
atives-A facile approach via intermolecular [3+2] cycloaddition reaction
R. Rajesh, M. Suresh, R. Selvam, R. Raghunathan
PII:
S0040-4039(14)00966-6
DOI:
http://dx.doi.org/10.1016/j.tetlet.2014.05.133
TETL 44724
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
13 February 2014
30 May 2014
31 May 2014
Please cite this article as: Rajesh, R., Suresh, M., Selvam, R., Raghunathan, R., Synthesis of acridinedione derived
mono spiro-pyrrolidine/pyrrolizidine derivatives-A facile approach via intermolecular [3+2] cycloaddition reaction,
Tetrahedron Letters (2014), doi: http://dx.doi.org/10.1016/j.tetlet.2014.05.133
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers
we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and
review of the resulting proof before it is published in its final form. Please note that during the production process
errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

1
Graphical Abstract
Synthesis of acridinedione derived mono
Leave this area blank for abstract info.
spiro-pyrrolidine/pyrrolizidine derivatives-A facile
approach via intermolecular [3+2]-cycloaddition reaction
R. Rajesh, M. Suresh, R. Selvam , R. Raghunathan*

1
Tetrahedron Letters
jo u rn al h ome p ag e : w ww .e lse vie r .c om
Synthesis of acridinedione derived mono spiro-pyrrolidine/pyrrolizidine derivatives-A
facile approach via intermolecular [3+2] cycloaddition reaction
R. Rajesh, M. Suresh, R. Selvam and R. Raghunathan∗
Department of Organic Chemistry, University of Madras, Guindy Campus, Chennai 600025, India
ARTICLE INFO
ABSTRACT
Article history:
Received
A facile synthesis of acridinedione derived mono spiro-pyrrolidine and pyrrolizidine derivatives
has been accomplished by 1,3–dipolar cycloaddition reaction. The O- acryloylacridinediones,
as dipolarophiles reacted with azomethine ylide derived from di-/tri-ketones and sec-amino
acids to give acridinedione derived mono spiropyrrolidine/pyrrolizidine derivatives in good
yield.
Received in revised form
Accepted
Available online
Keywords:
2009 Elsevier Ltd. All rights reserved.
Dipolar cycloaddition
acridindione
azomethine ylide
spiro-heterocycle
Acridine and its derivatives are class of compounds, which
were first used as pigments and dyes1 and as probes for nucleic
acid structure and conformation determination. Their importance
is due to their chemotherapeutics and foot-printing applications
and gene manipulation in biotechnology and medicines.2-4 These
scaffolds possess a broad range of biological activities such as
antibacterial, antimalarial, anticancer, antimicrobial activity,
DNA-binding and DNA photo-damaging ability.5-7 Moreover,
there are a number of fused ring alkaloids having acridine
skeleton with good biological activity.8
available on the synthesis of acridinedione substituted pyrrolidine
and pyrrolizidine derivatives.
Among the various synthetic strategies, 1,3-dipolar
azomethine ylide cycloaddition is an expedient route for the
synthesis of pyrrolidine derivatives and spiro heterocycles in a
highly regio- and stereoselective manner.25 In continuation of our
work in the area of 1,3-dipolar cycloaddition,26 herein we report
the synthesis of acridinedione substituted
pyrrolidine/pyrrolizidine
cycloaddition reaction.
mono spiro-
1,3- dipolar
derivatives
via
Substituted acridinedione is known to exhibit wide spectrum
of biological activities such as antimalarial,9 antitumor, and
cytotoxic activity.10 Moreover, they structurally resemble to 1,4-
dihydropyridines which are analogs of the biologically important
coenzymes, β-dihydronicotinamide adenine dinucleotide
(NADH).11 Apart from this, acridinedione possess valuable
physical properties, such as fluorescence quenching by forming
complex with α, β and γ-cyclodextrins in ground and excited
state and acid-base properties,.12-14
The synthetic strategy for the construction of acridinedione
derived monospiro heterocycles is shown in Figure 1.
Highly functionalized pyrrolidines and pyrrolizidines, a core
structural unit found in many alkaloids such as (–)-
codonopsinine15 and broussonetines16 are used as intermediates in
the synthesis of natural products with remarkable medicinal
activities.17 Substituted pyrrolidines and its derivatives are
endowed with significant biological activities18-22 Furthermore,
optically pure pyrrolidines has also been used as a chiral
auxiliary and organocatalyst in asymmetric synthesis.23
Figure 1. Synthetic approaches to acridinedione derived monospiro
heterocycles.
Accordingly, the monospiro cycloadducts were synthesized by
1,3-dipolar cycloaddition of azomethine ylide generated from
1,2-diketone and secondary amino acids with p-O-acryloylphenyl
acridinedione as dipolarophile. (Figure 1)
We were interested in synthesizing acridinedione substituted
pyrrolidine and pyrrolizidine derivatives which are expected to
have better bioactivity than the individual molecules. Literature
survey showed that there is only one report on the synthesis of
Our studies commenced with the synthesis of acridinediones
4a-b which were synthesized by the reaction of dimedone 1 (5,5-
dimethyl cyclohexane-1,3-dione) with 4-hydroxy benzaldehyde
pyrrolidine-acridine heterocyclic hybrids24 and no report was
———
∗ Corresponding author. Tel.: +91-44-22202811; e-mail: ragharaghunathan@yahoo.com

2
Tetrahedron Letters
2 in methanol to give 4-hydroxyphenyltetraketone 3. It was
The regioselectivity of cycloadducts can be explained by
secondary orbital interaction (SOI)28 of the carbonyl group of
dipolarophile 6a/6b and the ylide 7a as shown in Figure 2.
refluxed with methyl amine/n-propyl amine in acetic acid to
yield acridinedione 4a/4b. The acridinediones 4a-b were treated
with freshly distilled acryloyl chloride 5 in DCM in the presence
o
triethylamine, at 0 C to afford O-acryloylacridinediones 6a and
6b in 77 % and 79 % yield respectively (Scheme 1).
Scheme 1. Synthesis of O-acryloyl acridinedione derivatives.
In
a
one-pot
three
component
reaction,
O-
acryloylacridinedione 6a/6b was reacted with non-stabilized
azomethine ylide generated by the decarboxylative condensation
of isatin and sarcosine in refluxing acetonitrile, to give mono
spiro-oxindolopyrrolidines 9a/9b in good yield (Scheme 2).27 The
reaction occurred with good regioselectivity and no trace of the
other regioisomer was isolated even after prolonged reaction
time. The reaction was initially carried out in different solvents
such as methanol, toluene, tetrahydrofuran and 1,4-dioxane. It
was observed that the reaction in methanol failed to give the
expected product, and other solvents gave only poor yield. Best
results were obtained with acetonitrile as efficient solvent,
giving high yield of the product.
Figure 2. Mode of approach of azomethine ylide
Accordingly, the regioisomer 9a via path A is more favorable
because of the secondary orbital interaction which is not possible
in path B (carbonyl group of dipole is far away from the
dipolarophile carbonyl group).Hence, the cycloadduct
corresponding to path B was not observed.
The product 9a showed a multiplet in the range δ 3.35-3.43
and 3.03-3.10. for the protons of methylene group of pyrrolidine
ring (-NCH2). Hc proton showed a multiplet in the range δ 2.37-
2.46 and Hd proton showed a multiplet in the range δ 2.61-2.70.
The broad peak appeared at δ 8.81 is due to the –NH proton. The
gem-dimethyl protons showed two singlets at δ 1.00 and 1.03,
and a sharp singlet appeared at δ 3.23 due to N-CH3protons of
acridinedione. The 13C NMR spectrum of cycloadduct 9a showed
two peaks at δ 168.85 and 177.58 for oxindole and ester carbonyl
carbons. The spiro carbon showed a peak at 72.28 ppm. The
DEPT 135 spectrum showed four peaks in negative region at
24.01, 39.42, 48.84, and 52.33 ppm for four methylene carbons
of cycloadduct (Figure 3).29
Under similar reaction conditions the azomethine ylide
generated in situ from isatin and proline reacted with
dipolarophile 6a/6b to yield spiro-oxindolopyrrolizidine 12a/12b
in good yield (Scheme 3).
8.81
72.28
168.85
177.58
2.09
H
N
O
3.84,t
H
H
CH3
H
O
O
N
3.30-3.31,m & 3.35-3.43,m
2.34-2.46,m & 2.61-2.70,m
H
H
O
O
5.18,s
194.48
2.18,s
N
CH3
1.00 & 1.03,s
Scheme 2. Synthesis of monospirooxindolopyrrolidine/pyrrolizidine
derivatives.
2.28-2.59,set of doublets
3.23
Figure 3. Selected 1H and 13C NMR chemical shifts of 9a.
. The 1H NMR spectrum of compound 9a showed a sharp singlet
at δ 2.09 due to N-methyl proton of pyrrolidine ring. The He
proton in pyrrolidine ring showed a triplet at δ 3.81. If other
regioisomer 10a was formed, one would expect a multiplet
instead of a triplet.: Similarly, the azomethine ylide generated in
situ by decarboxylative condensation of isatin and sarcosine
underwent 1,3-dipolar cycloaddition reaction with O-
acryloylacridinediones regioselectively as shown in figure 2.
The same reaction was extended to other di- and triketones
acenaphthequinone and ninhydrin and the cycloaddition of O-
acryloylacridinedione 6a/6b with the azomethine ylide generated
from acenapthequinone 13 and sarcosine 8/proline 11 under the
same reaction conditions resulted in the formation of
monospiroacenapthenopyrrolidines 14a/14b and

3
monospiroacenapthenopyrrolizidine 15a/15b in good yield. In a
similar way, the reaction of ninhydrin 16 and sarcosine 8/proline
11 with O-acryloylacridinedione 6a/6b afforded mono-spiro-1,3–
Table 1. Synthesis of acridinedione substituted mono
spiropyrrolidine/pyrrolizidine derivatives from di/tri ketones
Time (h)a
Products
Yield (%)b
Dipolorophile
Sec-amino acid
Entry
Di/tri-ketone
indanedionopyrrolidine
indanedionopyrrolizidine 18a/18b in good yield (Scheme 4).
17a/17b
and
mono-spiro-1,3–
H
O
N
N
O
O
O
O
H
N
O
O
O
9a
1
5.5
84
6a
N
H
H3C
OH
8
N
7
CH3
H
N
O
O
O
N
O
O
O
O
H
N
O
6.0
82
9b
2
H3
C
OH
6b
N
H
8
N
7
(CH2)3CH3
H
N
O
O
O
N
O
6.0
O
O
6a
84
CO2
H
3
O
N
H
N
H
12a
11
7
N
CH3
H
N
O
O
O
Scheme 3. Synthesis of mono spiroacenaphtheno/indano-
pyrrolidine/pyrrolizidine derivatives.
N
O
O
O
CO2
H
N
H
4
6b
6.5
85
O
N
H
7
12b
The structure and regiochemistry of all cycloadducts were
unambiguously established by their spectroscopic analysis. The
1H NMR spectrum of the cycloadduct 15b exhibited a multiplet
in the range δ 1.84-2.61 for the pyrrolizidine ring methylene
protons. The gem-dimethyl protons showed two singlets at δ 0.91
and 1.10 and a triplet appeared at δ 0.90-0.95 for N-butyl methyl
protons (–CH2-CH2-CH2-CH3); two multiplets appeared at δ 1.30
and 1.42 for two methylene protons in N-butyl group (–CH2-CH2-
CH2-CH3). The 13C NMR spectrum of the cycloadduct 15b,
showed two peaks at 169.24 and 206.27 ppm for ester and
acenapthenenone carbonyl carbons. The spiro carbon showed
peak at 76.42 ppm. In addition, the DEPT 135 spectrum showed
nine peaks in negative region at 19.81, 28.64, 32.77, 33.42,
34.11, 40.34, 44.57, 47.45 and 49.84 ppm confirmed the presence
of nine methylene carbons present in cycloadduct 15b.29
11
N
(CH2
)
3CH3
O
O
O
N
O
O
O
O
O
H
N
6a
5
83
4.5
H3
C
OH
14a
8
N
13
CH3
O
O
O
N
O
O
O
O
O
H
N
6
4.5
79
6b
14b
H3C
OH
8
N
13
(CH2)3CH3
O
O
O
N
O
O
O
O
CO2H
N
H
5.5
81
7
6a
15a
11
N
The formations of all cycloadducts are summarized in Table
13
CH3
1.
O
O
O
N
O
O
In conclusion, we have accomplishedthe synthesis of novel
acridinedione
O
O
CO2
H
N
H
6b
5.0
79
8
derived
mono
15b
11
N
spiropyrrolidineandmonospiropyrrolizidine derivatives from
simple precursors in a one-pot reaction. The azomethine ylide
generated by decarboxylation condensation of di-/triketones
yield. All cycloadducts are obtained in highly stereo- and
regioselective manner and confirmed by spectral analysisTable 1.
13
(CH2
)
3CH3
O
O
O
O
N
O
O
O
O
H
N
17a
80
6a
4.0
9
O
H3C
OH
8
Synthesis
of
acridinedione
substituted
mono
N
O
16
CH3
spiropyrrolidine/pyrrolizidine derivatives from di/tri ketones
isatin/acenaphthenequinone/ninhydrin and secondary amino acids
sarcosine/proline underwent [3+2]-cycloaddition with O-
acryloylacridinediones afforded monospiro heterocycles in good
yield. All cycloadducts are obtained in highly stereo- and
regioselective manner and confirmed by spectral analysis
O
O
O
O
N
O
O
O
O
O
H
N
10
81
6b
O
17b
4.5
H3C
OH
8
16
N
(CH2
)
3CH3
O
O
O
O
N
O
O
O
O
11
6a
O
83
5.0
CO2
H
18a
N
H
16
11
N
CH3
O
O
O
O
N
O
O
O
6b
5.5
O
O
12
84
CO2
H
N
H
18b
11
16
N
(CH2)3CH3
a.Completion of the reaction based on TLC analysis
b Yield of isolated product after column chromatography

4
Tetrahedron
1995, 123: 296610t; (e) Carroll, W. A.; Grieco, P. A. J. Am.
Chem. Soc. 1993, 115, 1164; (f) Earley, W. G.; Oh, T.; Overman,
L. E. Tetrahedron Lett. 1988, 29, 3785; (g) Ban, Y.; Taga, N.;
Oishi, T. Chem. Pharm. Bull. 1976, 24, 736; (h) Ban, Y.; Seto, M.;
Oishi, T. Chem. Pharm. Bull. 1975, 23, 2605; (i) Ban, Y.; Taga,
N.; Oishi, T. Tetrahedron Lett. 1974, 15, 187; (j) Van Tamelen, E.
E.; Yardley, J. P.; Miyano, M.; Hinshaw, W. B. Jr. J. Am. Chem.
Soc. 1969, 91, 7333.
Acknowledgments
We thank the Department of Science and Technology (DST),
New Delhi for financial support. R.R thanks CSIR, New Delhi
for SRF Fellowship. R.R.N thanks UGC New Delhi for BSR
Faculty Fellowship.
19. Ding, K.; Lu, Y.; Nikolovska-Coleska, Z.; Wang, G.; Qiu, S.;
Shangary, S.; Gao, W.; Qin, D.; Stuckey, J.; Krajeswski, K.;
Roler, P. P.; Wang, S. J. Med. Chem. 2006, 49, 3432.
20. (a) Cui, C. B.; Kakeya, H.; Okada, G.; Onose, R.; Osada, H. J.
Antibiot. 1996, 49, 527; (b) Cui, C.B.; Kakeya, H.; Osada, H.
Tetrahedron 1996, 52, 12651.
21. (a) Khafagy, M. M.; El-Wahas, A. H. F. A.; Eid, F. A.; El-Agrody,
A. M. Farmaco 2002, 57, 715; (b) Sebahar, P. R.; Williams, R. M.
J. Am. Chem. Soc. 2000, 122, 5666.
22. Hilton, S. T.; Ho, T. C. T.; Pljevalijcic, G.; Jones, K. Org. Lett.
2000, 2, 2639.
References and notes
1. (a) Albert, A., 1996. The Acridines, second ed. Edward Arnold
Ltd, London; (b) Ramamurthy, S. P. N.; Shanmugasundaram, P.;
Ramakrishana, V. T.; J. Org. Chem. 1996, 61, 5083; (c)
Ramamurthy, S. P. N.; Shanmugasundaram, P.; Ramakrishana, V.
T.; Acta Specttrochemica 1998, 54, 245.
2. Burkoff, A. M.; Tullius, T. D. Nature 1988, 331, 455.
3. Gupta, N.; Grover, N.; Neyhart, G. A.; Liang, W.; Singh, P.;
Thorp, H. H. Angew. Chem., Int. Ed. 1992, 31, 1048.
23. (a) Paquette, L. A. (Ed.), Chiral Reagents for Asymmetric
Synthesis, Wiley, Chichester, 2003; (b) Hoang, L.; Bahmanyar, S.;
Houk, K. N.; List, B. J. Am. Chem. Soc. 2003, 125, 16; (c) White,
J. D.; J. D.; Xu, Q.; Lee, C. S.; Valeriote, F. A. Org. Biomol.
Chem. 2004, 2, 2092; (d) Rogers, C. J.; Dickerson, T. J.; Brogan,
A. P.; Janda, K. D. J. Org. Chem. 2005, 70, 3705; (e) M.
Gruttadauria, M.; Giacalone, R. F.; Noto, R. Chem. Soc. Rev.
2008, 37, 1666.
4. Tullius, T. D.; Dombroski, B. A. Science, 1985, 230, 679.
5. (a) Girault, S.; Grellier, P.; Berecibar, A.; Maes, L.; Mouray, E.;
Lemiere, P.; Debreu, M.; Davioud-Charvet, E.; Sergheraet, C. J.
Med. Chem 2000, 43, 2646; (b) Gay, F.; Traoré, B.; Zanoni, J.;
Danis, M.; Fribourg-Blanc, A. Trans. Roy. Soc. Trop. Med.
Hyg.1996, 90, 516.
24. Maheswari, S. U.; Perumal, S.; Almansour, A. I. Tetrahedron Lett.
2012, 53, 349.
25. (a) Huisgen, R. Angew. Chem., Int. Ed. Engl. 1963, 2, 565; (b)
Woodward, R. B.; Hoffmann, R. Angew. Chem., Int. Ed. Engl.
1969, 8, 781; (c) Synthetic Applications of Dipolar Cycloaddition
Chemistry Towards Heterocyclic and Natural Product Chemistry;
Padwa, A., Pearson, W., Eds.; WileyVCH: Weinheim, 2002; (d)
Wade, P. A. In Comprehensive Organic Synthesis; Trost, B. M.,
Fleming, I., Semmelhack, M. F., Eds.; Pergmon Press: Oxford,
1991; Vol. 4, p 1111.
26. (a) Rajesh, R.; Suresh, M.; Raghunathan, R. Tetrahedron Lett.
2014, 55, 699; (b) Rajesh, R.; Raghunathan, R. Synlett 2013, 24,
2107; (c) Rajesh, R.; Raghunathan, R. Eur. J. Org. Chem. 2013,
13, 2597; (d) Rajesh, R.; Raghunathan, R. Tetrahedron Lett. 2010,
51, 5845; (e) Rajesh, R.; Periyasami, G.; Raghunathan, R.
Tetrahedron Lett. 2010, 51, 1896; (f) Rajesh, R.; Raghunathan, R.
Syn Comn. 2012, 42, 1.
6. (a) Sánchez, I.; Reches, R.; Henry, D.; Pierre, C.; Maria, R.; Pujol,
D. Eur. J. Med. Chem. 2006, 41, 340; (b) Crémieux, A.;
Chevalier, J.; Sharples, D.; Berny, H.; Galy, A. M.; Brouant, P.;
Galy, J. P. J. Res. Microbiol. 1995, 146, 73; (c) Shaikh, B. M.;
Konda, S. G.; Mehare, A. V.; Mandawad, G. G.; Chobe, S. S.;
Dawan, B. S. Der. Pharma. Chemica. 2010, 2, 25.
7. (a) Yang, P.; Yang, Q.; Qian, X.; Tong, L.; Li, X. J. Photochem.
Photobiol. 2006, B 84, 221; (b) Gunduz, M. G.; Dogan, A. E.;
Simsek, R.; Erol, K.; Safak, C. Med. Chem. Res.2009, 18, 317.
8. Gallermann, G.; Rudi, A.; Kashman, Y. Tetrahedron Lett. 1992,
33, 5577.
9. Palani, K.; Ambalavanan, P.; Ponnuswamy, M. N.; Murugan, P.;
Ramakrishnan, V. T. Cryst. Res. 2005, 40, 277.
10. (a) Pandi, S. A.; Velmurugan, D.; Govind, M. M.; Kim, M. J.;
Josephrajan, T. Cryst. Res. Technol. 2002, 37, 293; (b) Palani, K.;
Thirumalai, D.; Ambalavanan, P.; Ponnuswamy, M. N.;
Ramakrishnan, V. T. J. Chem. Cryst. 2005, 35, 751; (c) Murugan,
P.; Hwang, K. C.; Ramakrishnan, V. T.; Balasubramanian, S. J.
Materials online 2005, 1,1; (d) Gao, H.; Denny, W. A.; Grag, R.;
Hansch, C. Chemico. Biol. Interact. 1998, 116, 157; (e)
Rajendran, A.; Nair, B. U. Biochimica et Biophysica Acta 2006,
1760, 1794.
11. (a) Srividya, N.; Ramamurthy, P.; Shanmugasundaram, P.;
Ramakrishnan, V. T. J. Org. Chem. 1996, 61, 5083; (b) Selvaraju,
C.; Thiagarajan, V.; Ramamurthy, P. Chem. Phys. Lett. 2003, 379,
437; (c) Geubicki, J.; Marcinek, A.; Adamus, J.; Paneth, P.;
Rogowski, J. J. Am. Chem. Soc. 1996, 118, 691.
27. General procedure for the synthesis of acridinedione derived
mono spiropyrrolidine/pyrrolizidine derivatives.
To a solution of O-acryloylacridinedione dipolarophile 6a (1.0
mmol) in acetonitrile (20 ml), was added sarcosine 8 (1.1 mmol)
and isatin 7 (1.0 mmol). The resulting solution was refluxed for 8
h. After the completion of reaction as indicated by TLC,
acetonitrile was evaporated under reduced pressure and extracted
with dichloromethane (50 ml). The organic layer was washed with
water and brine solution, dried with anhydrous sodium sulfate and
concentrated in vacuo. The residue was purified by column
chromatography using silica gel column with chloroform-
methanol (8:2) as an eluent.
28. (a) Rao, J. N. S.; Raghunathan, R. Tetrahedron Lett. 2012, 53,
854; (b) Vidhya Lakshmi, N.; Thirumurugan, P.; Perumal, P. T.
Tetrahedron Lett. 2010, 51, 1064.
12. Shanmugasundaram, P.; Prabahar, K. J.; Ramakrishnan, V. T. J.
Heterocyclic Chem., 1993, 30, 1003.
29. Representative spectral data of the products.
13. (a) Shanmugasundaram, P.; Murugan, P.; Ramakrishnan, V. T.
Heteroatom Chem., 1996, 7, 17; (b) Murugan, P.; Ramakrishnan,
V. T. Indian. J. Heterocyclic Chem., 1997, 7, 153; (c) Murugan,
P.; Ramakrishnan, V. T. Indian. J. Chem., 2001, 40B, 78.
14. Selvaraju, C.; Sivakumar, A.; Ramamurthy, P. J. Photochem.
Photobiol A., Chemistry, 1997, 110, 79.
15. (a) Yoda, H.; Nakajima, T.; Takabe, K. Tetrahedron Lett. 1996,
37, 5531–5534; (b) Severino, E. A.; Correia, C. R. G. Org. Lett.
2000, 2, 3039.
Compound 9a: Brown solid, (84 %), Mp: 210-212 ˚C; IR (KBr):
3141, 1744, 1712, 1686 cm-1, 1H NMR (300 MHz, CDCl3): δ 1.00
(s, 6H), 1.03 (s, 6H), 2.09 (s, 3H), 2.18 (s, 4H), 2.28-2.34 (d, 2H, J
= 16.8 Hz), 2.52-2.59 (d, 2H, J = 16.8 Hz), 2.37-2.46 (m, 1H),
2.61-2.70 (m, 1H), 3.03-3.10 (m,1H), 3.23(s, 3H), 3.35-3.43
(m,1H), 3.81-3.88 (t, 1H, J = 9.3, 9.6 Hz), 5.186 (s, 1H), 5.987-
6.01 (d, 2H, J=8.4 Hz), 6.84-6.87 (d, 1H, J = 7.8 Hz), 6.95-6.98
(d, 2H, J = 8.4 Hz), 7.02-7.04 (d, 1H, J = 7.2 Hz), 7.14-7.16 (d,
1H, J = 7.5Hz), 7.22 -7.24 (d, 1H, J = 7.5 Hz), 8.81 (s, 1H). 13C
NMR (75 MHz, CDCl3): δ 24.0, 27.3, 27.9, 29.8, 31.7, 32.4, 34.3,
39.4, 48.8, 51.2, 52.3, 72.2, 109.4, 113.5, 113.6, 119.5, 121.6,
124.6, 125.5, 127.1, 128.5, 140.5, 141.9, 147.1, 150.5, 168.8,
177.5, 194.4 ppm. Mass: m/z 607.78 (M+). Anal. Calcd. For
C37H41N3O5: C, 73.12; H, 6.80; N, 6.91 %; Found: C, 73.19; H,
6.84; N, 6.88 %.
16. O’Hagan, D. Nat. Prod. Rep. 2000, 17, 435.
17. (a) Pandey, G.; Banerjee, B.; Gadre, S. R. Chem. Rev. 2006, 106,
4484; (b) Monlineux, R. J.; Pelletier, S. W., Eds.; Wiley: New
York, 1987, Chap. 1.
18. (a) Kozikowski, A. P. Acc. Chem. Res. 1984, 17, 410; (b) Howe,
R. K.; Shelton, B. R. J. Org. Chem. 1990, 55, 4603; (c) De Amici,
M.; De Michelli, C.; Misani, V. Tetrahedron 1990, 46, 1975; (d)
Cohen, V. L.; Kleinmann, E. E. WO 24192, 1995; Chem. Abstr.
Compound 15b: Pale yellow solid, (79 %), Mp: 198-200 ˚C; IR
(KBr): 1756, 1743, 1675 cm-1, 1H NMR (300 MHz, CDCl3): δ
0.90-0.95 (t, 3H), 0.92 (s, 6H), 0.96(s, 6H), 1.25-1.33 (m, 2H),

5
1.42-1.52 (m, 2H), 1.84-1.93 (m, 2H), 2.06-2.10 (m, 1H), 2.14 (s,
4H), 2.23-2.29 (m, 1H), 2.32 (d, 2H, J = 16.8 Hz), 2.40-2.41 (d,
2H, J = 17.1 Hz), 2.35-2.38 (m, 1H), 2.46-2.61 (m, 3H), 3.53-3.57
(t, 2H, J=7.5 Hz, 7.2 Hz), 4.17-4.19 (m, 1H), 4.13-4.17 (m, 1H),
5.04 (s, 1H), 5.47-5.50 (d, 2H, J = 8.4 Hz), 6.78-6.81 (d, 2H, J =
8.4 Hz), 7.46-7.49 (d, 1H, J = 6.9 Hz), 7.62-7.67 (t, 1H, J=6.9, 8.4
Hz), 7.69-7.74 (t, 1H, J = 7.5 Hz, 7.8 Hz), 7.90-7.93 (d, 1H, J =
8.1 Hz), 7.96-7.99 (d, 1H, J = 6.9 Hz), 8.11-8.14 (d, 1H, J = 8.1
Hz). 13C NMR (75 MHz, CDCl3): δ 13.7, 19.8, 28.0, 28.6, 29.0,
30.9, 32.5, 32.7, 33.4, 34.1, 40.3, 44.5, 47.4, 49.8, 55.7, 65.2, 76.4,
115.1, 119.8, 121.9, 122.5, 125.5, 127.9, 128.1, 128.4, 130.7,
131.7, 132.1, 136.0, 142.2, 142.7, 147.6, 150.2, 169.2, 195.4,
206.2 ppm. Mass: m/z 710.95 (M+). Anal. Calcd. For C46H50N2O5:
C, 77.72; H, 7.09; N, 3.94 %; Found: C, 77.79; H, 7.05; N, 3.98
%.
Compound 17a: Pale yellow solid, (80 %), Mp: 194-196 ˚C; IR
(KBr): 1765, 1762, 1733, 1689 cm-1, 1H NMR (300 MHz, CDCl3):
δ 1.00 (s, 6H), 1.05 (s, 6H), 2.18 (s, 3H), 2.22 (s, 4H), 2.28-2.34
(d, 2H, J = 16.8 Hz), 2.52-2.57 (d, 2H, J = 16.5 Hz), 2.42-2.50 (m,
1H), 2.64-2.74 (m, 1H), 3.21(s, 3H), 3.25-3.28 (m, 1H), 3.30-3.38
(m, 1H), 3.78-3.84 (t, 1H, J = 9.6 Hz), 5.19 (s, 1H), 6.45-6.48 (d,
2H, J = 8.1 Hz), 7.02-7.05 (d, 2H, J = 8.4 Hz), 7.83-7.88 (m, 2H),
7.92-7.94 (m, 1H), 7.98-8.00 (m, 1H). 13C NMR (75 MHz,
CDCl3): δ 25.6, 28.1, 28.5, 28.4, 30.6, 32.4, 32.4, 33.1, 35.9, 40.2,
49.5, 51.1, 53.9, 73.1, 114.3, 119.9, 122.3, 128.0, 135.8, 136.2,
141.3, 142.8, 147.7, 151.0, 169.1, 195.0, 201.3, 202.4 ppm. Mass:
m/z 620.81 (M+). Anal. Calcd. For C38H40N2O6: C, 73.53; H, 6.50;
N, 4.51 %; Found: C, 73.59; H, 6.53; N, 4.55 %