Total synthesis of asperlicin D

Article abstract of DOI:10.1016/j.tetlet.2005.11.123

Cyclodehydration of a linear tripeptide furnished the first total synthesis of asperlicin D in moderate yield. The cyclodehydration process was triggered by an intramolecular nucleophilic acyl substitution and an intramolecular aza-Wittig reaction.

Full text of DOI:10.1016/j.tetlet.2005.11.123

Tetrahedron
Letters
Tetrahedron Letters 47 (2006) 693–694
Total synthesis of asperlicin D
Naim H. Al-Said* and Lina S. Al-Qaisi
Department of Applied Chemical Sciences, Jordan University of Science and Technology, PO Box 3030, Irbid 22110, Jordan
Received 26 September 2005; revised 14 November 2005; accepted 23 November 2005
Abstract—Cyclodehydration of a linear tripeptide furnished the first total synthesis of asperlicin D in moderate yield. The cyclo-
dehydration process was triggered by an intramolecular nucleophilic acyl substitution and an intramolecular aza-Wittig reaction.
Ó 2005 Elsevier Ltd. All rights reserved.
Recently, several families of natural alkaloids, such as
benzomalvins,1 circumdatins,2–4 asperlicins,5,6 and
scleraotigenin7 incorporating two anthranilic acid units
and an amino acid condensed together forming a quin-
azolino[1,4]-benzodiazepine system have been isolated
from different sources. These naturally occurring alkal-
oids display important biological properties. Asperlicin
A has antagonist activity against cholecystokinin. On
the other hand, asperlicin C and asperlicin D (1) display
lower biological activity.5,6 All members of the asperli-
cin family have been synthesized except asperlicin D.8
These alkaloids seem to be biosynthetically derivable
from linear peptides. Retrosynthetically, cyclodehydra-
tion of a linear peptide precursor represents a concise
and biomimetic route to the tetracyclic quinazo-
lino[1,4]-benzodiazepine ring system.
O
a, b, c
N
H
d
H N
NH
O
2
H
N
CO2Me
N
O
O
NH
O
N
N
H
O
2
4
O
O
N
f
N
H
H
asperlicin D (1)
a, e
N3
NH
O
CO2Me
N
H
3
In our continuing efforts to develop simple synthetic
methods to biologically active compounds,9 we report
the first total synthesis of asperlicin D in a single step
from a linear tripeptide. Our approach to asperlicin D
was based on cyclization of the corresponding linear tri-
peptide analogues 2 and 3. Amine 2 was conveniently
prepared by a one-pot reaction in good yield (75–85%)
by condensation of isatoic anhydride (4) with L-trypto-
phan methyl ester in dry acetonitrile followed by acyla-
tion with freshly prepared 2-nitrobenzoyl chloride and
finally reduction of the nitro group to the corresponding
amine employing SnCl2 as described in Scheme 1.
Scheme 1. Reagents and conditions: (a) L-tryptophan methyl ester.
Et3N, CH3CN, 93%; (b) 2-NO2-PhCOCl, Et3N, 78%; (c) SnCl2,
MeOH, 80%; (d) MgCl2, DMF, 130 °C, 35%; (e) 2-N3-PhCOCl, Et3N,
78%; (f) Bu3P, mesitylene, 150 °C, then H2O–THF, PhSO3H, 62%.
With a convenient access to 2, we focused on the
completion of the synthesis of targeted natural product.
Towards this end, the cylcodehydration of 2 to asper-
licin D was investigated.
Implementation of Wipf methodology (Ph3P/I2/R3N)10
to cyclodehydrate 2 afforded an inseparable mixture of
products. After several attempts, the desired natural
product 1 was isolated in low yield (<20%) contami-
nated with some impurities upon heating amine 2 at
180–200 °C for 2 h. Fortunately, when the reaction
was conducted at 130–135 °C in DMF in the presence
of anhydrous MgCl2 or ZnCl2, asperlicin D (1) was
Keywords: Synthesis of asperlicin D; Linear tripeptide; Cyclodehydra-
tion; Intramolecular aza-Wittig.
*
Corresponding author. Fax: +962 2 7095014; e-mail: naim@just.
edu.jo
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.11.123

694
N. H. Al-Said, L. S. Al-Qaisi / Tetrahedron Letters 47 (2006) 693–694
isolated in moderate yield (30–40%).11 The isolated
product showed spectral properties identical to those
previously described for the natural product.6 However,
in the absence of salts (MgCl2 or ZnCl2) the starting
material remained intact in DMF under reflux. On the
other hand, attempts to promote cyclodehydration of
2 using CaCl2 and AlCl3 failed, even at reflux after long
periods of time.
2. Rahbek, L.; Breinholt, J.; Frisvad, J. C.; Christophersen,
C. J. Org. Chem. 1994, 74, 1789–1792.
3. Rahbek, L.; Breinholt, J. J. Nat. Prod. 1999, 72, 904–905.
4. Dia, J. R.; Carte, B. K.; Sidebottom, P. J.; Yew, A. L. S.;
Huang, Y.; Butler, M. S. J. Nat. Prod. 2001, 74, 125–126.
5. Chang, R. S. L.; Lotti, V. J.; Monaghan, R. L.; Birnbaum,
J.; Stapley, E. O.; Goetz, M. A.; Albers-Schorberg, J. P.
Science 1985, 230, 177–179.
6. Liesch, J. M.; Hensen, O. D.; Goetz, M. A. J. Antibiot.
1988, 41, 878–881.
Since the yield of the targeted natural product was only
moderate, an alternative route to its synthesis was inves-
tigated. Thus, a tandem aza-Wittig mediated annulation
was studied.12 The azido derivative 3 was the starting
point for the second route. It was prepared in a one-
pot reaction in good yield (>70%) by condensation of
isatoic anhydride (4) with L-tryptophan methyl ester fol-
lowed by acylation with freshly prepared 2-azidobenzoyl
chloride. The Staudinger iminophosphorane intermedi-
ate12 was generated in situ by stirring 3 with Ph3P at
room temperature until the evolution of nitrogen gas
ceased (2 h).13 Initial attempts to promote cyclization
of the iminophosphorane in refluxing benzene or xylene
were unsuccessful even after an extended reaction time.
However, TLC indicated consumption of the starting
material when the reaction was conducted in boiling
mesitylene for 40 h. This reaction afforded two products
(by TLC). Fortunately, after hydrolysis (H2O, THF,
and PhSO3H) the crude reaction mixture furnished the
natural product 1 in 40–50% yield and amine 2. These
two products were formed in variable proportions
depending on the reaction time and temperature. The
yield of 1 was improved to 62% by switching to Bu3P
in mesitylene at reflux.
7. Joshi, B. K.; Gloer, J. B.; Wicjlow, D. T. J. Nat. Prod.
1999, 72, 650–652.
8. (a) He, F.; Foxman, B. M.; Snider, B. B. J. Am. Chem.
Soc. 1998, 120, 6417–6418; (b) Sugimori, T.; Okawa, T.;
Eguchi, S.; Kakehi, A.; Yashima, E.; Okamoto, Y.
Tetrahedron 1998, 54, 7997–8008.
9. Al-Said, N. H.; Ishtaiwi, Z. N. Acta. Chim. Slov. 2005, 52,
328–331.
10. Wipf, P.; Miller, C. P. J. Org. Chem. 1993, 58, 3604–3606.
11. (a) Typical experimental procedure for the cyclization of 2:
A mixture of MgCl2 (0.43 g, 4.5 mmol) and 2 (1.37 g,
3 mmol) in DMF (20 mL) was heated at 135 °C for 36 h,
then the solvent was evaporated. The residue was dis-
solved in ethyl acetate (60 mL) and the organic layer was
washed with water (60 mL) and brine (20 mL). The
organic layer was dried over MgSO4, filtered and concen-
trated. Purification of the residue by column chromato-
graphy on silica gel (60% ethyl acetate in hexane) furnished
1 (0.24 g, 30%); mp 120–121 °C; IR (KBr disk, cmꢀ1) 3340
and 3237, 3045, 2975, 2904, 1681; 1H NMR (250 MHz,
CDCl3) d 9.61 (s, 1H), 8.27 (br d, J = 7.9 Hz, 1H), 8.21
(dd, J = 7.9, J0 = 1.5 Hz, 1H), 8.00 (br s, 1H), 7.73 (m,
2H), 7.51 (dt, J = 8, J0 = 1.5 Hz, 1H), 7.50–7.38 (m, 2H),
7.34 (br d, J = 8.2 Hz, 1H) 7.23 (d, J = 7.3, 1H), 7.15 (dt,
J = 6.9, J0 = 1.3 Hz, 1H), 7.05 (dt, J = 8.52, J0 = 1.2 Hz,
1H), 6.92 (bt, J = 8.7 Hz, 1H), 6.88 (m, 2H), 3.15 (dd,
J = 9.85, J0 = 14.8 Hz, 1H), 3.10 (dd, J = 8.28, J0 =
14.8 Hz, 1H); 13C-NMR (62.9 MHz, CDCl3) d 170.5,
161.5, 151.1, 147.4, 135.9, 135.3, 134.7, 132.6, 132.1, 127.7,
127.4, 127.2, 127.0, 126.8, 125.6, 123.0, 122.2, 120.8, 119.6,
119.6, 118.2, 111.3, 109.0, 56.1, 24.2; CIMS [M+K]+ 445
(calcd C25H18N4O2 406). (b) Typical procedure for the
cyclization of 3: A mixture of 3 (0.468 g, 1 mmol) and
Bu3P (0.202 g, 1 mmol) in mesitylene (10 mL) was heated
at 150 °C for 16 h, then the solvent was evaporated. The
residue was stirred in H2O–THF–PhSO3H(cat) for 3 h. The
reaction mixture was concentrated and purified as in part
a to afford 1 (0.251 g, 62%).
In summary, we have found that linear tripeptide ana-
logues 3 can be converted to the tetracyclic natural
product asperlicin D (1) in a one-pot process. Further-
more, we have demonstrated that iminophosphorane
intermediates having secondary amide protons can be
employed in an intramolecular aza-Wittig reaction to
provide a one step entry to the quinazolino[1,4]-benzodi-
azepine ring system found in asperlicin D.
12. For reviews on aza-Wittig reactions see: (a) Eguchi, S.
ARKIVOC 2005, 98–119; (b) Gololobov, Y. G. Tetra-
hedron 1992, 48, 1353–1407, and references cited therein.
13. See for example: (a) Snider, B. B.; Busuyek, M. V.
Tetrahedron 2001, 5, 3301–3307; (b) Molina, P.; Fresneda,
P. M.; Delgado, S. Synthesis 1999, 327–329; (c) Molina,
P.; Aljarin, M.; Vidal, A. Tetrahedron 1989, 45, 4273–
4287; (d) Sugimori, T.; Okawa, T.; Eguchi, S.; Kakehi, A.;
Yashima, E.; Okamoto, Y. Tetrahedron 1998, 54, 7997–
8008; (e) Eguchi, S.; Ymashita, K.; Matsushita, Y.;
Kakehi, A. J. Org. Chem. 1995, 70, 4007–4012; (f) Molina,
P.; Diaz, I.; Tarraga, A. Tetrahedron 1995, 51, 5717–5730.
Acknowledgements
We thank the Deanship of Research at Jordan Univer-
sity of Science and Technology for financial support,
Grant no. 78/2003.
References and notes
1. Sum, H. H.; Barrow, C. J.; Sedlock, D. M.; Gillum, A. M.;
Cooper, R. J. Antibiot. 1994, 47, 515–522.