Synthetic studies of a didemnin B analog based on a 2,3-diamino sugar scaffolding

Article abstract of DOI:10.1002/jccs.200100001

Reductive amination, amide formation using BOP [(1H-1,2,3-benzotriazol-1-yloxy)tris(dimethyl-amino)-phosphonium hexafluorophosphate] and esterification via DCC (dicyclohexylcarbodiimide) were the key synthetic steps to generate an advanced intermediate in the preparation of a didemnin B analog based on a sugar scaffolding (2). This analog should provide insight into the bioactive conformation of didemnin B.

Full text of DOI:10.1002/jccs.200100001

JournaloftheChineseChemicalSociety, 2001, 48, 1-4
1
Communication
Syn thetic Studies of a Didemnin B An a log Based on a 2,3-Diamino
SugarScaffolding
Joshi M. Ramanjulua, Mad eleine M. Joulliéa and Wen-Ren Li*b (
)
李文仁
aDepartmentofChemistry,UniversityofPennsylvania,Philadelphia,Pennsylvania19104, U.S.A.
bDepartmentofChemistry,NationalCentralUniversity,Chung-Li,Taiwan32054,R.O.C.
Reductive amination, am ide for ma tion us ing BOP [(1H-1,2,3-benzotriazol-1-yloxy)tris(dimethyl-
amino)- phosphonium hexafluorophosphate] and esterification via DCC (dicyclohexylcarbodiimide) were the
keysyntheticstepstogenerateanadvancedintermediateinthepreparationofadidemnin B an a log based on a
sugarscaffolding(2). This an a log should pro vide in sight into the bioactive con for ma tion of didemnin B.
Didemnin B (1) , a novel cyclodepsipeptide, was
isolated in 1981 from a marine tuni cate of the fam ily
Didemnidae.l This nat u ral prod uct was found to dis play a
widespectrumofbiologicalactivityincludingantitumor,an-
ti vi ral and immunosuppressive ac tiv i ties. The pro posed ac-
tive sites for the bioactivity based on the X-ray anal y sis and
solutionconformationstudiesarethesidechainattachedto
the amino group of threonine, the hydroxyl group of isos-
tatine, and the ty ro sine unit.2,3 However, preliminarystruc-
ture ac tiv ity re la tion ships sug gest that the side chain is the
mostessentialfeatureofthethree.4
Scheme I
Me
N
N
OH
O
O
O
O
OMe
O
O
N
H
AcN
MeO
AcN
Me
O
analog 2
CO2Me
OH
O
OMe
Pro
O
Me
N
O
PMBO
N3
OBn
(NMe)(OMe)Tyr
N
O
N
HO
Leu
N
O
O
O
Me
Me
N
O
Me
O
O
NH
H2N
OBn
O
3
4
OH
O
N
N
H
S
O
OH
O
O
O
R
O
S
NH
HIP
O
S
OH
O
OH
S
H
AcN
MeO
Me
5
6
OMOM
Didemnin B, 1
2,3-dideoxy- -D-glucopyranoside (3) and the three side
chains (4, 5, 6). We en vi sioned the in tro duc tion of the un-
saturationinthesugarringaftertheincorporationoftheside
chains.
The syn the sis of the 2-amino-3-azido sugar (3) and
didemnin B side chain ( 4)wasreportedearlier.6 Theprepara-
tion of the side chain 5 began with pro tected L-tyrosine
(Scheme II). Phase trans fer re ac tion with dimethyl sul fate
gave a permethylated com pound which was im me di ately
deprotected and acylated un der stan dard con di tions. Hy dro-
Amolecularmodelingstudywasinitiatedtofindasuit-
abletemplatewhichwouldmaintainthespacialrelationship
of the three ac tive sites.5 Theminimizedmolecularmodeling
structureofdidemninB( 1)wasoriginallygeneratedfromthe
X-raycoordinatesprovidedbyHossainandcoworkers.2 The
best over lay of the struc tures was ob tained with all three
structuralfeaturesinpresumedbioactiveconformationwhen
2,3-diamino glycal was used as the tem plate (Fig. 1). The
retrosynthetic anal y sis of an a log 2 (Scheme I) pro vided
benzyl 2-amino-3-azido-4-O-p-methoxybenzyl-6-O- benzyl-

2
J. Chin. Chem. Soc., Vol. 48, No. 1, 2001
Ramanjulu et al.
Scheme II
-
1. Bu4N+SO4 , Me2SO4,
KOH, THF, 83%
2. H2, Pd/C, EtOAc /
MeOH (1:1), 96%
O
O
MeO
HO
OH
3. Ac2O, TEA, DMAP
(cat), CH2Cl2, 72%
4. LiOH, THF:H2O
(1:1), 88%
NMeAc
NHZ
7
5
Scheme III
O
O
1. NaNO2, H2SO4
HO
MeO
2. MeOH, H2SO4 (cat),
52% (two steps)
NH2
OH
9
8
O
1. MOMCl, DIPEA, CH2Cl2, 87%
2. LAH, Et2O,93%
H
OMOM
3. Dess-Martin Periodiane,
CH2Cl2
6
ly sis of the methyl es ter gave com pound 5 in 88% yield. 2-
Amino pentenoic acid (8) was used to syn the size the side
chain 6 (Scheme III). Con ver sion to the -hydroxy acid fol-
lowed by methanolysis gave the methyl es ter 9. The hydroxyl
wasprotectedasaMOMether. Reductionofthemethylester
followedbyoxidationgavethealdehyde6, which was used in
thenextstepwithoutpurification.
benzyl group un der ox i da tive con di tions gave com pound
11.9,10
DCCcouplingoftheresultingsecondaryalcoholwith
N-methyl-Boc-D-leucine, fol lowed by dihydroxylation of the
ter mi nal alkene gave the diol 12. Periodate cleav age of com-
pound 12 generatedanaldehydewhichwasfurtheroxidized
to the cor re spond ing carboxylic acid un der Masamune’s con-
ditions.11 The resulting acid was esterified with methyl
(S)-2-hydroxy-3-methylbutanoate12 un der DCC con di tions.
Re moval of Boc and MOM groups was ac com plished in one
step using trifluoroacetic acid. The final coupling with
L-lactyl-L-proline12 was achieved un der BOP con di tions to
providecompound13 in 81% yield. Cur rently, we are look-
ing into ways of in tro duc ing unsaturation in the sugar ring
and in the pro cess of test ing the bi o log i cal ac tiv ity of com-
pound 13.
In cor po ra tion of the first side chain was ef fected by
reductiveaminationofaldehyde6with com pound3 us ing so-
dium triacetoxyborohydride7,8 and the re sult ing amine was
im me di ately pro tected as its ac e tate (Scheme IV). Chemo-
selective re duc tion of the azide with H2S(g) fol lowed by the
cou pling of acid5 us ing BOP and the re moval ofp-methoxy
The solid state struc ture of didemnin B clearly shows
that the dimethyltyrosine res i due and the isostatine hydroxyl
groupprotrudeoutwardfromtheinteriorofthemacrocycle,2
leadingtospeculationthattheymaybeinvolvedinreceptor
bind ing. How ever, our pre lim i nary work on the struc ture-
activity re la tion ships of the didemnins has re sulted in an in-
congruentandcontradictorypicture.Therefore,wehopeto
learn whether the im por tance of the isostatine re gion is re-
lated to stereochemistry or conformational ef fects by check-
ingthebiologicalactivitiesofcompound13and an a log2
sincetheyareonlyalittledifferentinthesugarring. Compar-
isonofthebiologicalactivitiesofcompound13 and an a log2
Fig. 1. Molecular mod el ing over lay of didemnin B
(1) with an a log 2.

DidemninBAnalog
J. Chin. Chem. Soc., Vol. 48, No. 1, 2001
3
Scheme IV
PMBO
N3
OBn
1. H2S(g), pyr.:TEA
(10:3), 84%;
1. aldehyde 6, AcOH,
Na(AcO)3BH, DCE,
73%;
PMBO
N3
OBn
O
O
2. acid 5, BOP, DIPEA,
85%
3. DDQ, CH2Cl2:H2O
(9:1), 92%
AcN
OBn
2. Ac2O, TEA, CH2Cl2,
reflux, 48h, 77%
H2N
OBn
OMOM
3
10
HO
OBn
O
1.N-Me-Boc-D-Leu, DCC,
DMAP(cat), CH2Cl2, 77%
O
N
H
AcN
2.OsO4, NMO, acetone:
H2O (8:2), 91%;
MeO
OMe
OBn
AcN
Me
11
MOMO
Me
Me
N
1. NaIO4, THF, H2O
2. 1M KMnO4, tBuOH,
5%NaH2PO4, 42%
3. Methyl (S)-2-hydroxy-
3-methylbutanoate,
DCC, DMAP(cat),
CH2Cl2, 81%
OMe
AcN
Boc
N
OH
N
O
O
O
O
O
OBn
O
O
OBn
O
O
N
O
N
H
H
AcN
OBn
AcN
OBn
OH
Me
AcN
4.TFA, CH2Cl2, quant.
5.L-Lactyl-L-proline,
BOP, NMM, CH2Cl2,
81%
Me
O
OH
O
MeO
MOMO
O
13
12
OH
may prove valu able in the de sign of a sec ond gen er a tion of
drugs based on these conformational and bi o log i cal stud ies.
Althoughweobtainedadiastereomericmixtureofcompound
13, the diastereomers will be sep a rated at a later stage to
make two new analogs with dif fer ent chirality at the isos-
tatineregionforbiologicaltesting. Afterhavingobtained
sufficient structure-conformation-activity data, different
tem plates could be built on the non-critical part of the mol e-
cule with out af fect ing the af fin ity, trans port, and ac tiv ity
propertiesofthedidemnins.
mation; Molecular modeling; Cyclodepsipeptide.
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ACKNOWLEDGMENTS
4. Mayer, S. C.; Ramanjulu, J.; Vera, M. D.; Pfizenmayer,
A.; Joullié, M. M. J. Org. Chem. 1994, 59, 5192.
5. Cal cu la tions were per formed us ing MacroModel v3.1X
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FNMR with MM2 force field to ob tain an over lay. RMS
of carbonyl functionalities (1.687), amide hydrogens
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The au thors are grate ful to the Na tional Sci ence Coun-
cil, ROC (NSC 86-3113-M-008-001) and Na tional In sti tutes
of Health, USA (AC-40081) for the fi nan cial sup port (NSC
86-2113-M-008-001) of this work.
Received September 28, 2000.
Key Words
7. Ramanjulu, J. M.; Joullié, M. M. Synth. Commun. 1996,
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Didemnin B; Sugar scaffolding; Bioactive confor-

4
J. Chin. Chem. Soc., Vol. 48, No. 1, 2001
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3304 (br), 2930 (br), 1625 (s), 1513 (s), 1454 (w), 1248
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ro ta tional iso mers), 3.20-3.28 (br s, 1H), 3.28 (s, 3H),
3.75 (s, 3H, 3.73, 3.72, ro ta tional iso mers), 3.61-3.95 (m,
4H), 4.11-4.14 (m, 1H), 4.44-4.99 (m, 12H), 5.03-5.04
(m, 1H), 5.43-5.44 (m, 1H), 5.61-5.80 (m, 1H), 6.66-6.76
(m, 1H), 6.80-6.81 and 7.01-7.06 (m, 4H), 7.25-7.38 (m,
10H); 13C NMR (500 MHz, CDCl3) 21.7, 22.9, 37.2,
172.0, 172.6; HRMS calcd for C H55N3O10Na: m/z
42
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providedL-lactyl-L-proline.