Synthesis of o -me ulongamide b and o -me ulongamide c, natural modified cyclodepsipeptides

Article abstract of DOI:10.1080/00397911.2011.618284

Synthesis of O-Me ulongamide B and O-Me ulongamide C, modified natural cyclodepsipeptides, was achieved by a convergent route. The respective dipeptides and tridepsipeptides were coupled, obtaining linear depsipentapeptides, which were then deprotected and cyclized. These compounds were tested against three different types of human carcinoma cells and showed only moderate activity.

Full text of DOI:10.1080/00397911.2011.618284

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Synthesis of O-Me Ulongamide B and
O-Me Ulongamide C, Natural Modified
Cyclodepsipeptides
Dr. Cuauhtémoc Alvarado a , Gerardo Hernández a , Eduardo Díaz
a , José D. Soano b , Miguel A. Vilchis-Reyes a , Miguel A. Martínez-
Urbina a & Angel Guzmán a
a Instituto de Química, Universidad Nacional Autónoma de México,
Circuito Exterior s/n Ciudad Universitaria, Coyoacán, México
b Departamento de Biología, Facultad de Química, Universidad
Nacional Autónoma de México, Ciudad Universitaria, Coyoacán,
México
Accepted author version posted online: 10 May 2012.Version of
record first published: 07 Jan 2013.
To cite this article: Dr. Cuauhtémoc Alvarado , Gerardo Hernández , Eduardo Díaz , José D.
Soano , Miguel A. Vilchis-Reyes , Miguel A. Martínez-Urbina & Angel Guzmán (2013): Synthesis
of O-Me Ulongamide B and O-Me Ulongamide C, Natural Modified Cyclodepsipeptides, Synthetic
Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry,
43:7, 993-1006
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Synthetic Communications1, 43: 993–1006, 2013
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2011.618284
SYNTHESIS OF O-ME ULONGAMIDE B AND O-ME
ULONGAMIDE C, NATURAL MODIFIED
CYCLODEPSIPEPTIDES
1
Cuauhtemoc Alvarado, Gerardo Hernandez, Eduardo Dıaz,
1
1
´
Jose D. Soano, Miguel A. Vilchis-Reyes,
´
´
2
1
´
Miguel A. Martınez-Urbina, and Angel Guzman
1
1
´
´
Instituto de Quımica, Universidad Nacional Autonoma de Mexico, Circuito
1
´
Exterior s=n Ciudad Universitaria, Coyoacan, Mexico
´
´
´
Departamento de Biologıa, Facultad de Quımica, Universidad Nacional
´
2
´
Autonoma de Mexico, Ciudad Universitaria, Coyoacan, Mexico
´
´
´
´
´
GRAPHICAL ABSTRACT
Abstract Synthesis of O-Me ulongamide B and O-Me ulongamide C, modified natural
cyclodepsipeptides, was achieved by a convergent route. The respective dipeptides and tri-
depsipeptides were coupled, obtaining linear depsipentapeptides, which were then depro-
tected and cyclized. These compounds were tested against three different types of human
carcinoma cells and showed only moderate activity.
Keywords Anticancer drugs; asymmetric synthesis; cyclodepsipeptides; marine natural
products
INTRODUCTION
Cyanobacteria or blue-green marine algae produce a large number of metabo-
lites with wide structural diversity. The genus Lyngbya is considered to be the most
prolific producer of natural products, with more than 200 compounds reported so
far.[1] A wide variety of biological activities are found in these metabolites, include
antiviral, antimalarial, and principally anticancer properties.[2] Depsipeptides, one
Received August 7, 2011.
Address correspondence to Dr. Cuauhtemoc Alvarado, Instituto de Quımica, Universidad
´
Nacional Autonoma de Mexico, Circuito Exterior s=n Ciudad Universitaria, Coyoacan D. F. 04510,
´
´
Mexico. E-mail: calvarados09@gmail.com
´
´
´
993

994
C. ALVARADO ET AL.
Figure 1. Structure of depsipeptides FK 228 and thiocoraline.
class of compounds produced by cyanobacteria, show potential for the treatment of
cancer.[3] For instance, kahalalide F[4] and thiocoraline[5] are currently under clinical
trials for treatment of several types of cancer. Compound FK228 has been approved
by the U.S. Food and Drug Administration for the treatment of cutaneous T-cell
lymphoma (Fig. 1).[1b] In 2002, six new depsipeptides, designated as ulongamides
A–F, isolated by Luesch et al. from Palauan collections of the marine cyanobacter-
ium Lyngbya sp., showed activity against some types of cancer.[6]
Currently, there is significant interest regarding the isolation[7] and develop-
ment of cyclic depsipeptides through modification of natural products or de novo
design. This has led to the identification of compounds with improved or novel phar-
macological activities.[8] O-Methylation of the hydroxyl group, on the aromatic moi-
ety of any drug, usually makes the drug more biologically active (bioisosterism).[9]
Our group developed a convergent methodology to perform the total synthesis of
ulongamide A in 2007.[10] Ulongamides B and C possess a similar structure, and thus
we thought that by applying the concept of bioisosterism, the same methodology
could be used for the synthesis of their modified derivatives, O-Me ulongamide B
(1) and O-Me ulongamide C (2).
This article describes the synthesis of O-Me ulongamide B (1) and O-Me ulon-
gamide C (2), which are cyclodepsipeptides produced by modifying the naturally
occurring ulongamides B and C.
RESULTS AND DISCUSSION
O-Me ulongamides B (1) and C (2) are cyclic depsipentapeptides derived from
the structural units listed in Fig. 2, which shows the L-lactic acid 3, the unnatural
aminoacids 4, 5 and N,O-dimethyl tyrosine 8, common compounds for both pep-
tides; plus N-methyl L-valine 6 and N-methyl L-phenylalanine 7, specific compounds
for (1) and (2), respectively.
It has been rationalized (Fig. 3) that starting materials required for this aim
should be the common depsitripeptide 11 and dipeptide 9 for compound 1. Likewise,
compound 2 would be obtained using depsitripeptide 11 and dipeptide 10.
The optically pure benzyl ester 3a of L-lactic acid was prepared by established
literature methodology.[11] The unusual b-amino acid 4 (Scheme 1) was synthesized
using a procedure reported by Kimura et al.[12] The (4R,5S)-oxazolidinone derivative
23 was N-acylated with propionyl chloride, and the produced N-propionyl derivative
12 was subjected to low-temperature aldolization with n-butanal. The essentially
pure (2R,3S)-aldol thus obtained, 13, was converted into the azide 14 of inverted

SYNTHESIS OF ULONGAMIDE B AND C
995
Figure 2. O-Me ulongamides B (1) and C (2) and their structural units.
configuration by a Mitsunobu[13] reaction using hydrogen azide (HN3). Cleavage of
the chiral auxiliary from 14 with alkaline hydrogen peroxide, followed by catalytic
reduction of the azide 15, provided the b-amino acid 4, which was transformed into
its N-tert-butoxycarbonyl (N-Boc) derivative 4a.
The (S)-thiazole carboxylic acid 5 was prepared following the procedure
described by Xia and Smith[14] for the (R)-enantiomer (Scheme 2).
The L-alanine 16 was protected as the N-Boc derivative and converted into a
primary amide 17 by amination of the mixed anhydride derived from ethyl chloro-
formate. Thionation of 17 with Lawesson’s reagent produced the thioamide 18,
Figure 3. Convergent frameworks.

996
C. ALVARADO ET AL.
Scheme 1. (i) (1) n-BuLi, THF,ꢀ78 ꢁC, (2). propionyl chloride, 93%. (ii) (1) Dibutyl boron triflate
(DBBT), ethyl diisopropylamine, CH2Cl2, 0 ꢁC: (2). n-butanal, ꢀ78 ꢁC, 84%. (iii) Diethyl azodicarboxylate
(DEAD), PPh3, HN3, toluene, 43%. (iv) H2O2, LiOH, H2O. (v) H2=Pd–C, MeOH, 88%. (vi) (Boc)2O,
Et3N, H2O=p-dioxane, 85%.
which by subsequent reaction with ethyl bromopyruvate generated an intermediate
hydroxythiazoline that was dehydrated and aromatized into thiazole 19 by treatment
with trifluoroacetic anhydride (TFAA) in the presence of 2,6-lutidine. Saponification
of thiazole 19 with aqueous sodium hydroxide (3 equiv) at room temperature gener-
ated the protected amino acid 5a.
With the required starting materials in hand, the synthesis of depsitripeptide 11
was completed by the following sequence of reactions (Scheme 3). Coupling of ben-
zyl lactate 3a with the b-amino acid 4a, mediated by dicyclohexylcarbodiimide
(DCC), provided the bis-protected depsipeptide 20 (70% yield). The t-Boc group
was removed with trifluoroacetic acid (TFA), yielding the aminoester 20a. Coupling
of 20a with the thiazole carboxylic acid derivative 5a, by means of DCC-containing
Scheme 2. (i) (Boc)2O, Et3N, p-dioxane=H2O (3:1), rt, 16–18 h, 87%. (ii) (1) Ethyl chloroformate, CH2Cl2,
ꢀ10 ꢁC: (2) NH3=CH2Cl2, 90%. (iii) Lawesson’s reagent, dimethoxyethane (DME), 16–18 h, 85%. (iv)
Ethyl bromopyruvate, KHCO3, DME, ꢀ15 ꢁC. (v) TFAA, lutidine, ꢀ15 ꢁC, 77%. (vi) NaOH=H2O, 83%.

SYNTHESIS OF ULONGAMIDE B AND C
997
Scheme 3. (i) DCC, 4-dimethylaminopyridine (DMAP), CH2Cl2, 16–18 h, 70%. (ii) TFA, CH2Cl2, 88%.
(iii) DCC=HOBt, CH2Cl2, 16–18 h, 67%. (iv) H2=Pd–C, 87%.
hydroxybenzotriazole (HOBt), produced 11a. Subsequent hydrogenolysis generated
depsitripeptide 11 (58% yield over two steps).
Carbobenzyloxy (Cbz) L-Valine 6a and Cbz-L-phenylalanine 7a were selec-
tively N-methylated with methyl iodide (sodium hydride), then converted into their
respective t-butyl esters 6b and 7b with 2-methylpropene under acidic conditions,
and finally hydrogenolyzed to N-methyl-L-valine t-butyl ester 6c and N-methyl-L-
phenylalanine t-butyl ester 7c (Scheme 4).[15]
L-Tyrosine methyl ester hydrochloride 8a was N-protected with Cbz chloride
in a two-phase system (chloroform–water) using Na2CO3 (Scheme 5),[16] then
N,O-methylated and esterified with dimethyl sulfate under a heterogeneous phase
system using KOH and tetrabutylammonium hydrogen sulfate (as a phase-transfer
catalyst,)[17] and finally saponified in methanol with aqueous NaOH, obtaining
N,O-dimethyl-Cbz-L-tyrosine 8b (74% yield from three steps).[18]
Compounds 6c and 8b were coupled using bis-(2-oxo-3-oxazolidinyl)
phosphonic chloride (BOP-Cl) to produce a bis-protected dipeptide 9a, which after
Scheme 4. (i) CH3I, NaH, THF, 0 ꢁC. (ii) 2-methylpropene, H2SO4, CH2Cl2, 7 days (6b ¼ 70% from steps i
and ii, 7b ¼ 79% from steps i and ii). (iii) Pd-C= H2, AcOEt (6c ¼ 72%, 7c ¼ 92%).

998
C. ALVARADO ET AL.
Scheme 5. (i) CbzCl, Na2CO3, CHCl3, H2O, 92%. (ii) (CH3)2SO4, KOH, n-Bu4NHSO4, 91%. (iii) NaOH,
MeOH, H2O, 89%.
hydrogenolysis generated the convergent fragment, dipeptide 9 (Scheme 6). The
dipeptide 10 was likewise synthesized using compounds 7c and 8b.
The optimum conditions for the coupling of the convergent frameworks 9, 11 and
10, 11 were found by using BOP-Cl in dichloromethane solution. Depsipentapeptides
21 and 22 (Scheme 7) obtained were deprotected with TFA, and the crude products,
after removal of volatiles under vacuum, were diluted with DMF and cyclized using
benzotriazole-1-yl-oxy-tris-(dimethylamino)-phosphonium
hexafluorophosphate
(BOP) to O-Me ulongamide B (1, 55% yield) and O-Me ulongamide C (2, 53% yield).
Spectral properties of compounds 1 and 2 were identical to those reported[6] for the
natural products ulongamides B and C, except for the methyl ether.
Biological Tests
O-Me ulongamide B (1) and O-Me ulongamide C (2) were tested for cytotoxic
activity against two cell lines derived from human colon adenocarcinoma (SW480
and SW620) and one derived from human cervical carcinoma (HeLa). They dis-
played modest cytotoxic activity, showing IC50 values in the micromolar range
(Table 1).
In summary, two cyclodepsipeptides O-Me-ulongamide B (1) and O-Me ulon-
gamide C (2) were successfully obtained by the convergent methodology here shown,
which was previously described for the synthesis of ulongamide A.[10] The good
yields obtained by this methodology and the moderate cytotoxicity shown for com-
pounds 1 and 2 makes justifiable further structure–activity relationship studies that
might give derivatives with an increased biological activity.
Scheme 6. (i) BOP-Cl, CH2Cl2, 16–18 h (9a ¼ 58%, 10a ¼ 65%). (ii) H2=Pd–C (9 ¼ 89.6%, 10 ¼ 92%).

SYNTHESIS OF ULONGAMIDE B AND C
999
Scheme 7. (i) BOP-Cl, Et3N, CH2Cl2 (21 ¼ 65%, 22 ¼ 67%). (ii) TFA, CH2Cl2. (iii) BOP, DMF, 80–90 ꢁC
(1 ¼ 55%, 2 ¼ 53%).
Table 1. IC50 values of O-Me UB and O-Me UC (2) on human cell lines
Compound
HeLa
SW480
SW620
O-Me UB (1)
O-Me UC (2)
M-amsab
40.9 ꢂ 5.6
66.8 ꢂ 7.0
9.5 ꢂ 0.6
68.3 ꢂ 8.8
36.5 ꢂ 6.2
27.7 ꢂ 2.0
47.1 ꢂ 7.3
21.7 ꢂ 6.0
16.7 ꢂ 2.8
aIC50 value is expressed as meanꢂSD of three independent experiments.
bM-amsa (amsacrine) was used as a positive control.
EXPERIMENTAL
1H NMR spectra were acquired on Varian Gemini spectrometers running at
200 MHz and 300 MHz and on a Varian-Unity spectrometer running at 500 MHz.
13C spectra were acquired in a broad band decoupled mode, on a Varian-Inova spec-
trometer running at 127.5 MHz. Chemical shifts (d) are reported in parts per million
(ppm) relative to tetramethylsilane (TMS, 0 ppm for 1H NMR and [13]C). Mass spec-
trometry of low resolution was performed by electronic impact at 70 eV using a Jeol

1000
C. ALVARADO ET AL.
AX505HA spectrometer, while high-resolution experiments were undertaken by
fast-atom bombardment (FABþ) using a Jeol JMS-S ꢃ 102A spectrometer. The
value of the molecular ion is denoted as Mþ (m=z) by electronic impact and as
HRFABMS, m=z [M þ H]þ, by FABþ. Infrared (IR) spectrums (film, KBr) were car-
ried out on a Nicolet Magna 750 spectrophotometer and polystyrene was used as the
standard of calibration. Thin-layer chromatography (TLC) was performed using
precoated aluminium-backed plates (Merck Kieselgel 60 F254) and monitored by
ultraviolet radiation. Purification of reaction products was carried out by three tech-
niques: (a) crystallization,(b) flash chromatography (FC) using silica gel Merck-60,
and (c) preparative chromatography using silica gel Merck or Macherey-Nagel
60 F254 20 ꢃ 20 ꢃ 0.2 plates. Optical rotations were measured on a Perkin-Elmer
241 polarimeter. Melting points were determined on a Buchi 510 apparatus and
¨
are uncorrected.
Reagent-grade solvents, Cbz-L-Val 6a, Cbz-L-Phe 7a, L-Ala 16, L-lactic acid
3, and L-Tyr methyl ester hydrochloride 8a, were purchased from Aldrich and used
as received.
Benzyl (2R, 3R)-3-(Boc-amino)-2-methylhexanoil-L-lactic Acid (20)
Dichloromethane (50 mL), benzyl lactate 3a (2 g, 11 mmol), b-aminoacid 4a
(2.45 g, 10 mmol), 4-DMAP (0.12 g, 1 mmol), and DCC (2.24 g, 11 mmol) were intro-
duced into a 100-mL round-bottomed flask. The mixture was stirred for 18 h, and
the solvent was evaporated. Residual oil was redissolved in ethyl acetate (100 mL),
washed with HCl 10% (2 ꢃ 20 mL), washed with saturated solution of sodium bicar-
bonate (2 ꢃ 20 mL), washed with brine (50 mL), and dried with anhydrous sodium sul-
fate. The solvent was evaporated and the crude product was purified by flash
chromatography (hexane–ethyl acetate 90:10). Compound 20 (2.85 g, 70%) was
20
obtained as a white solid, mp 54–56 ꢁC. [a]D þ4.2 (c 0.5, CHCl3). IR (KBr): 3377,
1
2979, 2957, 1744, 1683, 1524, 1458, 1187, 1133, 1100 cmꢀ1. H NMR (200 MHz,
CDCl3): d 0.89 (t, 3H, J ¼ 7.2 Hz), 1.21 (d, 3H, J ¼ 7.0 Hz), 1.30–1.44 (m, 4H), 1.44
(s, 9H), 1.51 (d, 3H, J ¼ 7.2 Hz), 2.72 (m, 1H), 3.72 (m, 1H), 5.15 (q, 1H, J ¼ 7.4 Hz),
5.16 (s, 2H), 5.26 (bs, 1H), 7.25–7.35 (m, 5H). MS (EI): m=z 407 [M]þ.
Benzyl (2R, 3R)-3-Amino-2-methylhexanoil-L-lactic Acid (20a)
Compound 20 (4.07 g, 10 mmol) and dichloromethane (30 mL) were introduced
into a 50-mL round-bottomed flask. Trifluoroacetic acid (6 mL, 80 mmol) was
added, the mixture was stirred for 1 h, and the solvent was evaporated. The resulting
oil was redissolved in ethyl acetate (100 mL), washed with saturated solution of
sodium bicarbonate (2 ꢃ 20 mL), washed with brine (50 mL) and dried with anhy-
drous sodium sulfate. The solvent was evaporated, and the crude product was pur-
ified by flash chromatography (hexane–ethyl acetate–triethylamine 49.5: 50.0: 0.5).
20
Compound 20a (2.76 g, 88%) was obtained as a white amorphous solid. [a]D
26.7 (c 0.3, CHCl3). IR (KBr): 3380, 2960, 2937, 1738, 1684, 1457, 1202, 1132,
ꢀ
1
1099 cmꢀ1. H NMR (200 MHz, CDCl3): d 0.94 (t, 3H, J ¼ 6.7 Hz), 1.39 (d, 3H,
J ¼ 7.2 Hz), 1.40–1.90 (m, 4H), 1.52 (d, 3H, J ¼ 7.2 Hz), 3.10 (m, 1H), 3.60 (m,
1H), 5.10–5.30 (m, 3H), 7.20–7.50 (m, 5H), 8.52 (bs, 2H). MS (EI): m=z 307 [M]þ.

SYNTHESIS OF ULONGAMIDE B AND C
1001
Benzyl (S)-2-[1-(Boc-amino)ethyl]thiazol-4-carboxi-(2R,
3R)-3-amino-2-methylhexyl-L-lactic Acid (11a)
Dichloromethane (30 mL), thiazolic amino acid 5a (2.99 g, 11 mmol), dipeptide
20a (3.07 g, 10 mmol), 4-DMAP (0.12 g, 1 mmol), and DCC (2.24 g, 11 mmol) were
introduced into a 100-mL round-bottomed flask. The mixture was stirred for
16–18 h and then filtered. The solvent was evaporated, and the residual oil was redis-
solved in ethyl acetate (100 mL), washed with HCl 1 N (2 ꢃ 20 mL), and then washed
with brine (50 mL). The organic fraction was dried with anhydrous sodium sulfate.
The solvent was evaporated, and the crude product was purified by flash chromato-
graphy (hexane–ethyl acetate 70:30). Compound 11a (3.93 g, 70%) was obtained as a
20
white amorphous solid. [a]D ꢀ7.0 (c 0.5, AcOEt). IR (KBr): 3307, 2977, 2936,
1738, 1715, 1660, 1542, 1496, 1455, 1368, 1249, 1175, 1132, 1098, 1056, 755 cmꢀ1
.
1H NMR (200 MHz, CDCl3): d 0.90 (t, 3H, J ¼ 7.1 Hz), 1.23 (d, 3H, J ¼ 7.2 Hz),
1.30–1.70 (m, 4H), 1.45 (m, 9H), 1.53 (d, 3H, J ¼ 7.0 Hz), 1.57 (d, 3H, J ¼ 6.6 Hz),
2.84 (dq, 1H, J ¼ 3.8, 7.4 Hz), 4.31 (m, 1H), 5.05 (m, 1H), 5.10–5.30 (m, 4H), 7.33
(m, 5H), 7.90 (bs, 1H), 8.01 (s, 1H). MS (EI): m=z 561 [M]þ.
(S)-2-[1-(Boc-amino)ethyl]thiazol-4-carboxi-(2R, 3R)-3-amino-2-
methylhexyl-L-lactic Acid (11)
Depsitripeptide 11a (5.60 g, 1 mmol), ethyl acetate (50 mL) and Pd-C 10%
(0.84 g) were introduced into a hydrogenation flask and subjected to hydrogenolysis
for 18 h. The reaction was filtered over celite, and the solvent was evaporated. The
20
crude product 11 (4.09 g, 87%) was obtained as a white amorphous solid. [a]D
þ3.3 (c 0.3, CHCl3). IR (KBr): 3315, 3119, 2978, 2937, 1727, 1655, 1549, 1498,
1249, 1215, 1175, 1099, 757 cmꢀ1 1H NMR (200 MHz, CDCl3): d 0.91 (t, 3H,
.
J ¼ 7.2 Hz), 1.29 (d, 3H, J ¼ 7.2 Hz), 1.30–1.80 (m, 4H), 1.51 (s, 9H), 1.57 (d, 3H,
J ¼ 7.2 Hz), 1.61 (d, 3H, J ¼ 6.8 Hz), 2.86 (dq, 1H, J ¼ 3.8, 7.2 Hz), 4.32 (m, 1H),
4.93 (quint, 1H, J ¼ 6.0 Hz), 5.34 (q, 1H, J ¼ 7.0 Hz), 7.90 (bs, 1H), 8.10 (s, 1H),
8.38 (bs, 1H). MS (EI): m=z 471 [M]þ.
N,O-Dimethyl-N-Cbz-L-tyrosyl-N-methyl-L-valine, t-Butyl Ester (9a)
Compound 8b (0.34 g, 1 mmol), dichloromethane (5 mL), triethylamine (0.12 g,
1.20 mmol), and BOP-Cl (0.28 g, 1.10 mmol) were introduced into a 10-mL
round-bottomed flask. Temperature was reduced to 0 ꢁC and then a solution of com-
pound 6c (0.20 g, 1.10 mmol) in dichloromethane (2 mL) and triethylamine (0.10 g,
1 mmol) was added. The mixture was stirred for 20 min and then for 2 h at room tem-
perature. The solvent was evaporated, and the residual oil was redissolved in ethyl
acetate (12 mL), washed with HCl 1 N (2 ꢃ 6 mL), and brine (8 mL), and dried with
anhydrous sodium sulfate. The solvent was evaporated, and the crude product was
purified by preparative chromatography (hexane–ethyl acetate 80:20). Compound 9a
20
(0.19 g, 58%) was obtained as a yellow oil. [a]D ꢀ126.5ꢁ (c 1, CHCl3). IR (film):
3032, 2967, 2935, 1730, 1704, 1654, 1512, 1453, 1397, 1368, 1248, 1156, 1036 cmꢀ1
.
1H NMR (500 MHz, CDCl3): d 4 Rotamers19 N-methyl-L-tyrosine scaffold: CH3O
3.76 (s, 3H); CH aromatic 6.77, 7.03, 7.17 (m, 4H); CH2CH 2.86, 2.88, 2.90, 2.90

1002
C. ALVARADO ET AL.
(dd, 1H, J ¼ ꢀ14.0, 5.0 Hz), 3.08, 3.18, 3.21 (dd, 1H, J ¼ 7.5, 14.0 Hz); CH2CH 5.30,
5.34 (t, J ¼ 7.5 Hz), 4.99, 5.05 (dd, J ¼ 5.5 Hz); N-Me 2.85, 2.86, 2.90, 2.91 (s, 3H).
Benzyloxycarbonyl moiety: CH aromatic 7.24 (m, 5H); HCH 4.72, 4.78, 4.94, 5.10
(d, 1H, J ¼ 12.5 Hz); HCH 4.99, 5.02, 5.06, 5.19 (d, 1H, J ¼ 12.5 Hz).
N-Methyl-L-valine moiety: CH3CHCH3 0.79, 0.98, 0.99 (d, 3H, J ¼ 6.5 Hz);
CH3CHCH3 0.59, 0.65, 0.76 (d, 3H, J ¼ 6.5 Hz); CH3CHCH3 2.04 (m, 1H);
N-CH-CO 3.88, 4.17, 4.69, 4.70 (d, 1H, J ¼ 10 Hz). Terbutoxy moiety: 1.36, 1.37,
1.38, 1.43 (s, 9H). 13C NMR (125.7 MHz, CDCl3): d 4 rotamers N,O-dimethyl-L-
tyrosine scaffold: MeO 55.10, 55.16, 55.20; MeOC 158.20, 158.26; CH aromatic
113.67, 113.75, 113.81, 113.83; CH aromatic 130.24, 130.27, 130.33, 130.49; C-
CH2 129.20, 129.30, 129.52, 129.80; CH2 34.60, 34.80, 34.82; CH 56.47, 56.80,
57.70, 57.80; N-CH3 29.30, 29.52, 29.68, 30.84. Benzyloxycarbonyl moiety: CH2
67.28, 67.33, 67.60, 67.70; CH aromatic 127.50, 127.59, 128.20, 128.22; C (ipso)
136.07, 136.53, 136.66; CO 154.63, 155.58, 155.90, 156.34. N-Methyl-L-valine moi-
ety: CH3CHCH3 0.79, 0.98. 0.99; CH3CHCH3 0.59, 0.65, 0.76; CH3CHCH3 27.24,
27.59, 28.32; N-CH-CO 62.75, 65.38; CO 169.13, 169.86, 170.20; N-Me 19.53,
29.50, 30.75, 30.76. Terbutoxy moiety: CH3 27.94, 27.96; C 81.27, 81.46, 81.50,
82.27. MS (FABþ): m=z 513 [M þ H]þ.
N,O-Dimethyl-L-tyrosyl-N-methyl-L-valine, t-Butyl Ester (9)
Compound 9a (0.32 g, 0.62 mmol), methanol (5 mL), and Pd-C 10% (48 mg)
were introduced into a hydrogenolysis flask. The heterogeneous mixture was hydro-
genolyzed for 30 min and filtered over celite. The solvent was evaporated, and the
obtained white foam (0.20 g, 89.6%) was immediately used for the next reaction.
N,O-Dimethyl-N-Cbz-L-tyrosyl-N-methyl-L-phenylalanine, t-Butyl
Ester (10a)
The same methodology used for the synthesis of compound 9a was followed,
starting from compound 7c (0.26 g, 1.10 mmol). Compound 10a (0.36 g, 65%) was
20
obtained as a yellow oil. [a]D ꢀ120ꢁ (c 1, CHCl3). IR (film): 3030, 2976, 1731,
1
1701, 1654, 1513, 1451, 1368, 1248, 1152 cmꢀ1. H NMR (500 MHz, CDCl3): d 4
rotamers N-methyl-L-tyrosine moiety: MeO 3.74, 3.75, 3.76, 3.79 (s, 3H); CH aro-
matic 6.69, 6.72, 6.75, 6.77, 6.81, 7.00, 7.14 (m, 4H); CH2CH 2.17, 2.26, 3.05, 3.14
(dd, 1 H, J ¼ ꢀ14.0, 8.0 Hz) 2.73, 2.75, 2.79 (dd, 1 H, J ¼ ꢀ14.0, 8.0 Hz); CH2CH
4.18, 4.63, 4.92, 5.18 (dd, 1 H, J ¼ 5.5, 10.5 Hz); N-Me 2.30, 2.37, 2.74, 2.77 (s,
3H). Benzyloxycarbonyl moiety: CH aromatic 7.24, 7.32, (m, 5H); CH2 4.48, 4.61,
4.81, 5.03 (dd, 1H, J ¼ 12.5 Hz), 4.93, 4.94, 5.04, 5.14 (dd, 1H, J ¼ 12.5 Hz). N-
Methyl-L-phenylalanine moiety: CH aromatic 6.53, 7.06, 7.18, 7.31, 7.34 (m, 5H);
CH2-CH 2.78, 2.88, 2.90 (dd, 1H, J ¼ 4.5, 11.5 Hz), 2.93, 3.27, 3.29, 3.32 (dd, 1H,
J ¼ 3.5, 14.5 Hz); N-CH-CO 4.58, 5.02, 5.08, 5.26 (dd, 1H, J ¼ 4.5, 11.5 Hz); N-Me
2.68, 2.73, 2.84, 2.90 (s, 3H). Terbutoxy moiety: 1.39, 1.40, 1.42, 1.49 (s, 9H). 13C
NMR (125.7 MHz, CDCl3): d 4 rotamers N,O-dimethyl-L-tyrosine scaffold: MeO
55.13, 55.15, 55.17, 55.24; MeOC 158.14, 158.20, 158.26; CH aromatic 113.53,
113.57, 113.72, 113.76; CH aromatic 128.40, 128.72, 128.75, 128.85; CH2 33.77,
33.80, 34.40, 34.46; CH 55.13, 56.75, 58.00, 58.28; N-CH3 28.80, 28.90, 29.00,

SYNTHESIS OF ULONGAMIDE B AND C
1003
29.14; CO 169.66, 169.80, 169.86, 170.40. Benzyloxycarbonyl moiety: CH2 67.00,
67.13, 67.50, 67.90; CO 154.48, 155.24, 155.90, 156.00. N-Methyl-L-phenylalanine
moiety: CH2 34.46, 34.66, 34.85, 34.94; N-CH-CO 59.24, 59.88, 61.42; CO 169.15,
169.33, 169.55, 169.75; N-Me 29.77, 31.90, 32.73. CH aromatic (N-Methyl-L-pheny-
lalanine and benzyloxycarbonyl) 126.50, 126.64, 126.80, 126.90, 127.15, 127.53,
127.81, 127.93, 128.04, 128.12, 128.58, 128.64, 128.69, 128.80, 128.90, 129.23,
130.05, 130.15, 130.30, 130.40. C-CH2 (N-methyl-L-phenylalanine, N,O-dimethyl-L-
tyrosine, benzyloxycarbonyl) 136.10, 136.40, 136.73, 137.00, 137.30. Terbutoxy moi-
ety: CH3 27.90, 28.00; C 81.70, 81.95, 82.00, 82.65. MS (FABþ): m=z 561 [M þ H]þ.
N,O-Dimethyl-L-tyrosyl-N-methyl-L-phenylalanine, t-Butyl Ester (10)
The methodology used for the synthesis of compound 9 was followed, starting
from compound 10a (0.35 g, 0.62 mmol). The solvent was evaporated,s and the
obtained white foam (0.24 g, 92%) was immediately used for the next reaction.
bis-Protected Depsipentapeptide (21)
Depsitripeptide 11 (0.47 g, 1 mmol), dichloromethane (5 mL), triethylamine
(0.12 g, 1.2 mmol), and BOP-Cl (0.30 g, 1.2 mmol) were introduced into a 10-mL
round-bottomed flask. Temperature was diminished at 0 ꢁC, and then dipeptide 9
(0.45 g, 1.2 mmol) in dichloromethane (2 mL) and triethylamine (0.12 g, 1.2 mmol)
were added. The mixture was stirred for 30 min and then for 30 min at room tempera-
ture. The solvent was evaporated, and the residual oil was redissolved in ethyl acetate
(20 mL), washed with HCl 1 N (2 ꢃ 10 mL) and brine (10 mL), and dried with anhy-
drous sodium sulfate. The solvent was evaporated, and the crude product was purified
by preparative chromatography (hexane–ethyl acetate 80:20). Compound 21 (0.53 g,
20
65%) was obtained as a white amorphous solid. [a]D ꢀ 69.37 (c 0.32, MeOH). IR
1
(film): 3317, 2971, 2934, 1728, 1650, 1541, 1513, 1248, 1174, 736 cmꢀ1. H NMR
(500 MHz, CDCl3): d 0.74 (d, 3H, J ¼ 6.5 Hz); 0.92 (t, 3H, J ¼ 7 Hz); 0.98 (d, 3H,
J ¼ 6.5 Hz); 1.24 (d, 3H, J ¼ 7.0 Hz); 1.32 (s, 9H); 1.42 (d, 3H, J ¼ 7.0 Hz); 1.43 (m,
2H, J ¼ 6.5 Hz); 1.45 (s, 9H); 1.55 (d, 3H, J ¼ 7.0 Hz); 2.11 (m, 2H, J ¼ 7.0 Hz); 2.75
(dd, 1H, J ¼ 5.5, 13.5 Hz); 2.80 (s, 3H); 2.70–2.90 (m, 1H, J ¼ 3.5 Hz); 3.08 (s, 3H);
3.31 (dd, 1H, J ¼ 9.5, 13.5 Hz); 3.71 (s, 3H); 4.32 (m, 1H, J ¼ 5.0 Hz); 4.67 (d, 1H,
J ¼ 10.5 Hz); 5.34 (q, 1H, J ¼ 7.0 Hz); 5.67 (dd, 1H, J ¼ 5.5, 9.5 Hz); 6.76 (m, 2H);
7.16 (m, 2H); 8.01 (s, 1H). 13C NMR (125.7 MHz, CDCl3): d 13.9, 14.6, 16.5, 18.7,
19.5, 19.8, 21.4, 43.2, 48.8, 50.8, 54.5, 55.1, 62.7, 67.1, 80.3, 81.3, 113.6, 123.0, 129.1,
130.3, 150.2, 154.9, 158.2, 161.2, 169.9, 170.3, 170.6, 173.9, 174.1. HRFABMS: m=z
[M þ H]þ calcd. for C42H66O10N5S: 832.4530; found: 832.4527.
bis-Protected Depsipentapeptide (22)
The same methodology used for the synthesis of compound 21 was followed,
starting from dipeptide 10 (0.51 g, 1.20 mmol). Compound 22 (0.59 g, 67%) was
20
obtained as a white amorphous solid. [a]D ꢀ 78.48 (c 0.33, MeOH). IR (film):
1
3318, 2978, 2934, 1728, 1651, 1495, 1248, 1159, 755 cmꢀ1. H NMR (500 MHz,
CDCl3): d 0.91 (t, 3H, J ¼ 7.5 Hz); 1.36 (s, 9H); 1.45 (s, 9H); 1.21 (d, 3H, J ¼ 7.0 Hz);

1004
C. ALVARADO ET AL.
1.29 (d, 3H, J ¼ 6.5 Hz); 1.43 (m, 2H); 1.46 (m, 2H); 1.52 (d, 3H, J ¼ 7.0 Hz); 2.44 (s,
3H); 2.58 (dd, 1H, J ¼ 5.5, 13.5 Hz); 2.64 (s, 3H); 2.76 (m, 1H); 2.93 (dd, 1H, J ¼ 6.0,
12.5 Hz); 3.25 (dd, 1H, J ¼ 9.0, 13.5 Hz); 3.31 (dd, 1H, J ¼ 5.0, 14.5 Hz); 3.70 (s, 3H);
4.31 (m, 1H); 5.15 (dd, 1H, J ¼ 6.5, 13.0 Hz); 5.18 (q, 1H, J ¼ 6.5 Hz); 5.33 (q, 1H,
J ¼ 6.5 Hz); 5.47 (dd, 1H, J ¼ 5.9 Hz); 6.75 (m, 2H); 7.05 (m, 2H); 7.16 (m, 2H);
7.20 (m, 3H); 8.00 (s, 1H); 8.01 (s, 1H); 8.03 (s, 1H). [13]C NMR (125.7 MHz,
CDCl3): d 13.8, 16.3, 18.9, 19.5, 21.4, 27.8, 28.3, 29.9, 30.1, 32.1, 34.3, 35.3, 35.7,
42.6, 48.7, 50.8, 53.4, 55.3, 59.3, 66.8, 80.0, 81.8, 113.7, 123.0, 129.4, 129.5, 130.1,
130.6, 137.4, 150.2, 154.9, 158.2, 161.2, 169.4, 169.5, 170.2, 173.8, 174.0.
HRFABMS: m=z [M þ H]þ calculated for C46H66O10N5S: 880.4530; found:
880.4519.
O-Methyl Ulongamide B (1)
Bis-protected depsipentapeptide 21 (0.25 g, 0.30 mmol), dichloromethane
(5 mL), and trifluoroacetic acid (1 mL) were introduced into
a
10-mL
round-bottomed flask. The reaction was stirred for 30 min, and the solvent was eva-
porated to dryness. The residual solid was redissolved in DMF (250 mL), and then
BOP (0.53 g, 1.20 mmol) and triethylamine (0.15 g, 1.50 mmol) were added. Tem-
perature was adjusted at 85ꢀ90 ꢁC, and stirring was continued for 16ꢀ18 h. DMF
was evaporated, and the residual solid was redissolved in ethyl acetate (20 mL),
washed with HCl 1 N (2 ꢃ 5 mL) and brine (5 mL), and the organic layer was dried
with anhydrous sodium sulfate. The solvent was evaporated, and the crude product
was purified by flash chromatography (hexane–ethyl acetate 60:40). O-Me ulonga-
mide B (1, 0.11 g, 55%) was obtained as a white amorphous solid, mp 90–92 ꢁC.
25
[a]D þ 26.7 (c 0.15, MeOH). IR (film): 3321, 3109, 2962, 1734, 1674, 1634, 1551,
1516, 1250, 1082, 1041 cmꢀ1 1H NMR (500 MHz, CDCl3): d 0.59 (d, 3H,
.
J ¼ 7.0 Hz); 0.84 (d, 3H, J ¼ 6.5 Hz); 0.96 (t, 3H, J ¼ 7.0 Hz); 1.24 (d, 3H, J ¼ 7.0 Hz);
1.34 (d, 3H, J ¼ 7.0 Hz); 1.45 (m, 4H); 1.46 (d, 3H, J ¼ 7.0 Hz); 2.32 (dq, 1H, J ¼ 2.5,
6.5 Hz); 2.70 (q, 3H, J ¼ 6.5 Hz); 2.99 (s, 3H); 3.11 (dd, 1H, J ¼ 10.5, 15.0 Hz); 3.19
(dd, 1H, J ¼ 9.0, 15.0 Hz); 3.21 (s, 3H); 3.79 (s, 3H); 4.32 (m, 1H); 4.48 (d, 1H,
J ¼ 11.0 Hz); 5.19 (q, 1H, J ¼ 7.0 Hz); 5.33 (q, 1H, J ¼ 7.0 Hz); 6.00 (dd, 1H,
J ¼ 6.0, 9.0 Hz); 6.83 (m, 2H); 7.07 (m, 2H); 8.04 (s, 1H); 8.16 (d, 1H, J ¼ 6.5 Hz);
8.96 (d, 1H, J ¼ 11.0 Hz). [13]C NMR (125.7 MHz, CDCl3): d 14.0, 14.7, 16.1, 18.2,
19.3, 19.6, 24.5, 27.3, 29.0, 30.0, 34.5, 35.8, 45.3, 47.6, 51.0, 51.1, 55.2, 66.3, 67.0,
114.3, 122.9, 129.5, 130.4, 149.0, 158.6, 160.8, 168.0, 169.6, 170.4, 171.9,
172.8. HRFABMS: m=z [M þ H]þ calculated for C33H48O7N5S: 658.3274: found:
658.3289.
O-Methyl Ulongamide C (2)
The same methodology used for the synthesis of compound 1 was followed,
starting from bis-protected depsipentapeptide 22 (0.26 g, 0.30 mmol). O-Me ulonga-
mide C (2, 0.11 g, 53%) was obtained as a white amorphous solid, mp 98–102 ꢁC.
25
[a]D þ 21.2 (c 1.0, CHCl3). IR (film): 3320, 2957, 1936, 1735, 1673, 1633, 1551,
1
1517, 1251, 1215, 1084, 1040 cmꢀ1. H NMR (500 MHz, CDCl3): d 1.06 (t, 3H,
J ¼ 7.0 Hz); 1.21 (d, 3H, J ¼ 7.0 Hz); 1.30 (d, 3H, J ¼ 6.5 Hz); 1.45 (d, 3H,

SYNTHESIS OF ULONGAMIDE B AND C
1005
J ¼ 7.0 Hz); 1.54 (m, 5H); 2.68 (dq, 1H, J ¼ 2.5, 6.5 Hz); 2.80 (dd, 1H, J ¼ 2.5,
11.0 Hz); 2.89 (dd, 1H, J ¼ 4.0, 14.0 Hz); 2.92 (d, 1H, J ¼ 10.5 Hz); 2.98 (d, 1H,
J ¼ 5.0 Hz); 3.01 (s, 3H); 3.07 (s, 3H); 3.77 (s, 3H); 4.34 (m, 1H); 5.11 (q, 1H,
J ¼ 7.0 Hz); 5.30 (dd, 1H, J ¼ 5.0, 10.0 Hz); 5.40 (quintet, 1H, J ¼ 7.0 Hz); 5.59
(dd, 1H, J ¼ 5.5, 11.0 Hz); 6.77 (m, 2H); 6.83 (m, 2H); 7.06 (m, 2H); 7.13 (m, 2H);
7.15 (m, 2H); 8.04 (s, 1H); 8.08 (d, 1H, J ¼ 7.5 Hz); 8.84 (d, 1H, J ¼ 10.5 Hz). 13C
NMR (125.7 MHz, CDCl3): d 14.1, 14.5, 16.1, 19.8, 24.5, 28.8, 29.8, 32.8, 35.3,
36.1, 45.1, 47.2, 50.2, 51.0, 55.2, 61.6, 66.6, 114.0, 122.9, 127.0, 127.9, 129.0, 129.1,
137.0, 149.8, 158.3, 160.9, 167.7, 169.7, 170.6, 171.7, 173.0. HRFABMS: m=z
[M þ H]þ calculated for C37H48O7N5S: 706.3274; found: 706.3265.
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