Total synthesis of cyclotheonamides E2 and E3: Application of cyano ylide methodology

Article abstract of DOI:10.1016/S0040-4039(02)00599-3

A total synthesis of cyclotheonamides E₂ and E₃ is reported. A key step in the synthesis involves the formation of the α-keto amide linkage by application of the cyano ylide activation of a carboxyl group as developed in our earlier syntheses of cyclic peptides in the family of protease inhibitors.

Full text of DOI:10.1016/S0040-4039(02)00599-3

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 3743–3746
Total synthesis of cyclotheonamides E2 and E3: application of
cyano ylide methodology
Harry H. Wasserman* and Rui Zhang
Department of Chemistry, Yale University, New Haven, CT 06520-8107, USA
Received 15 March 2002; accepted 18 March 2002
Abstract—A total synthesis of cyclotheonamides E2 and E3 is reported. A key step in the synthesis involves the formation of the
a-keto amide linkage by application of the cyano ylide activation of a carboxyl group as developed in our earlier syntheses of
cyclic peptides in the family of protease inhibitors. © 2002 Elsevier Science Ltd. All rights reserved.
The cyclotheonamides (A, B, C, D, E), recently isolated
from marine sources, are a family of cyclic pentapep-
tides which show notable activity as inhibitors of serine
proteases.1,2 Because of their biological properties and
unusual structural features, considerable attention has
been given to the study of the mode of enzyme inhibi-
tion and synthesis of these macrocyclic a-keto lactams.
Total syntheses of cyclotheonamides A and B have
been reported2 by Schreiber, Maryanoff, Wipf, Otten-
heijm and Shioiri.
the place of D-phenylalanine, and side chains contain-
ing benzoylalanine and isovalerylalanine residues. A
unique functional unit in all cyclotheonamides is associ-
ated with the extra carbonyl a to the amide linkage in
the arginine residue. It has been suggested that this
active carbonyl group is involved in the deactivation of
a protease by serving as an enzyme transition state
analogue.2b It is also noteworthy that the cyclotheon-
amides have structural features similar to those of the
immunosuppressants bearing a-keto amide functions
such as FK-506 and rapamycin.3
We now report the first synthesis of cyclotheonamides
E2 and E3. In this work, the cyano ylide methodology is
employed in activating the arginine carboxyl group for
amide bond formation, with the concomitant introduc-
tion of a carbonyl group a to the amide group.4
A
number of the steps in our synthesis make use of
protecting groups in common with the procedures pub-
lished in the early synthetic work. However, our strat-
egy has unique features which should be of
considerable value in future syntheses of compounds in
this family. In particular, the formation of the relatively
robust a-keto amide at an early stage of the synthesis
avoids problems in earlier syntheses associated with
a-hydroxy precursors generated en route to the a-keto
amide residue. It precludes the necessity for carrying a
mixture of diastereomers through subsequent steps in
the synthesis, as well as the protection of the hydroxyl
group needed to avoid the possibility of competing
intramolecular lactone formation. Overall, the simplic-
ity of forming the a-keto amide residue using the cyano
ylide activation procedure avoids the extra steps needed
to generate, protect, deprotect and oxidize an alcohol
intermediate to the a-keto function.5,6
Adding to the interest in this area has been the recent
isolation of two new members of the family,
cyclotheonamides E2 (1a) and E3 (1b),1b which contain
most of the elements of cyclotheonamides A and B,
except for the presence of a
D-alloisoleucine residue in
* Corresponding author.
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)00599-3

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H. H. Wasserman, R. Zhang / Tetrahedron Letters 43 (2002) 3743–3746
Our synthesis began with the formation of the tripep-
tide from arginine, proline and diaminopropionic acid
(Scheme 1). The latter acid, formed by a Curtius-type
degradation of Teoc-aspargine (2)7 using bis(trifl-
uoroacetyl) iodobenzene (TIB), was then converted to
the N-Boc derivative 3. The acid 3 was then coupled
(EDCl) with proline benzyl ester to form the protected
dipeptide which, on hydrogenation (Pd–C), yielded 4.
In a separate pathway, the ylide 6 was prepared from
arginine having a Boc-protected amino group, and a
doubly Cbz-protected guanidino residue (5).8 Reaction
alloisoleucine gave the dipeptide 10 containing a vinyl-
ogous tyrosine. Removal of the Boc group yielded 11
for reaction in the next stage with 7.
Tripeptide (7) was now ozonized to generate the
strongly electrophilic a,b-diketonitrile intermediate, not
isolable, which formed an amide bond with 11 to yield
the pentapeptide 12 (75%) (Scheme 3). At this point in
the synthesis, we found it expedient to change the allyl
protecting group to a pentafluoro phenoxy group for
enhanced activation of the ester. This was readily
accomplished, first by the use of Pd0 to regenerate the
carboxyl group (86%)10 and then DCC-promoted cou-
pling with pentafluorophenol (PFPOH) yielding 13
(88%).11 For the ring closure of 13 to 14, we first
selectively cleaved the Boc group with HCl in Et2O–
CH2Cl2 in the presence of the acid-labile Teoc group12
and we then carried out lactam formation with DMAP,
NaHCO3 (61%). The removal of the Teoc protecting
group to yield 17 and 18 took place with TFA, permit-
ting the installation of side chains (EDCl, HOBt) with
N-benzoylalanine (15) to yield 17 and isovaleryalanine
(16), forming 18.
of
5
with (triphenylphosphoranylidine)acetonitrile
yielded the acyl cyano ylide 6 (86%).4a TFA removal of
the Boc group from 6 then yielded the free amine for
coupling with 4 (EDCI, HOBt) to form the tripeptide 7
(78%).
To continue the synthesis, L-Boc-tyrosine methyl ester
was converted to the TIPS derivative,9 and then
reduced with DIBALH to the aldehyde 8. A Wittig
reaction of 8 with allyl (triphenylphosphoranylidine)-
acetate (Scheme 2) yielded the allyl-protected a,b-unsat-
urated ester 9 which, on treatment with TFA and
coupling (EDCl, HOBt, Et3N) with
D-Boc-
BocHN
O
NH2
NHBoc
a
b
O
NHTeoc
HO2C
NHTeoc
N
HO2C
NHTeoc
NHBoc
HO2C
4
3
2
BocHN
O
CN
NHBoc
Ph3P
HO2C
CN
Ph3P
O
NHTeoc
O
H
N
N
d
c
O
NCbz
NCbz
HN
HN
NHCbz
NCbz
NHCbz
HN
NHCbz
7
6
5
Scheme 1. Reagents and conditions: (a) TIB, Py; then Boc2O, NaOH, 77%; (b) EDCI, HOBt, Pro-OBn, 88%; then Pd–C, H2,
100%; (c) EDCI, DMAP, Ph3PꢀCHCN, 86%; (d) TFA; then EDCI, HOBt, 4, 78%.
OTIPS
OTIPS
OTIPS
a
O
b
OAll
N
H
OAll
BocHN
BocHN
CHO
BocHN
O
O
8
9
10
OTIPS
O
c
OAll
N
H
NH2
O
11
Scheme 2. Reagents and conditions: (a) Ph3PꢀCHCO2All, 90%; (b) TFA; then EDCI, HOBt, Et3N, D-Boc-alle, 85%; (c) TFA; then
aq. NaHCO3, 100%.

H. H. Wasserman, R. Zhang / Tetrahedron Letters 43 (2002) 3743–3746
3745
Scheme 3. Reagents and conditions: (a) O3; then 11, 75%; (b) Pd(PPh3)4, PhSiH3, 86%; then DCC, PFP-OH, 88%; (c) (1) HCl in
Et2O–CH2Cl2; then DMAP, NaHCO3, 61%; (d) TFA; then aq. NaHCO3, (2) EDCI, HOBt, 15 or 16, 83–85%; (e) HF·Py, 70–72%.
References
The Cbz and TIPS protecting groups in 17 and 18 were
then removed smoothly with HF·Py, yielding synthetic
cyclotheonamides E2 (1a) and E3 (1b), which were fully
1. (a) Nakao, Y.; Oku, N.; Matsunaga, S.; Fusetani, N. J.
Nat. Prod. 1998, 61, 667–670; (b) Fusetani, N.; Mat-
sunaga, S.; Matsumoto, H.; Takebayashi, H. J. Am.
Chem. Soc. 1990, 112, 7053–7056.
1
characterized by HRMS, H and 13C NMR. The NMR
spectra of 1a and 1b were identical in all significant
respects with the corresponding spectra of the natural
materials, kindly sent to us by Professors Fusetani and
Nakao.
2. (a) Hagihara, M.; Schreiber, S. L. J. Am. Chem. Soc.
1992, 114, 6570–6571; (b) Maryanoff, B. E.; Greco, M.
N.; Zhang, H.-C.; Andrade-Gordon, P.; Kauffman, J. A.;
Nicolaou, K. C.; Liu, A.; Brungs, P. H. J. Am. Chem.
Soc. 1995, 117, 1225–1239; (c) Wipf, P.; Kim, H. J. Org.
Chem. 1993, 58, 5592–5594; (d) Bastiaans, H. M. M.; Van
der Baan, J.; Ottenheijm, H. C. J. J. Org. Chem. 1997, 62,
3880–3889; (e) Deng, J.; Hamada, Y.; Shioiri, T.; Mat-
sunaga, S.; Fusetani, N. Angew. Chem., Int. Ed. Engl.
1994, 33, 1729–1731.
Supporting information available. Spectroscopic and
analytical data as well as experimental procedures for
compounds 1–18. See any current masthead page for
ordering and Internet access information.
Acknowledgements
3. Schreiber, S. L.; Crabtree, G. R. Immunol. Today 1992,
13, 136–142.
4. (a) Wasserman, H. H.; Ho, W.-B. J. Org. Chem. 1994, 59,
4364–4366; (b) Wasserman, H. H.; Petersen, A. K. Tetra-
hedron Lett. 1997, 38, 953–956; (c) Wasserman, H. H.;
Petersen, A. K. J. Org. Chem. 1997, 62, 8972–8973.
5. Matsuura, S.; Niu, C.-H.; Cohen, J. S. Chem. Commun.
1976, 451–452.
6. An additional difference between our synthesis and ear-
lier work lies in the final macrolactamization site. In
contrast to the other synthetic routes, the ring closure in
This work was supported by grants from the NIH and
NSF. We thank Dr. Walter McMurray of the Yale
Cancer Center Mass Spectrometry Resource for help in
determining HRMS spectra of new compounds pre-
pared in this synthesis. We are grateful to Professors
1
Fustetani and Nakao for sending us H and 13C NMR
spectra of natural cyclotheonamide E2 and E3 for com-
parison with our synthetic products.

3746
H. H. Wasserman, R. Zhang / Tetrahedron Letters 43 (2002) 3743–3746
our sequence took place between the NH terminus of the
Ottenheijm, H. C. J. Tetrahedron Lett. 1991, 32, 6025–
6028.
diaminopropionic acid residue and the carboxyl group of
the a,b-vinylogous tyrosine. Di-Cbz protection of the
guanidine residue provided excellent protection through-
out the sequence and permitted easy removal at the last
stage with HF·Py and anisole (70–72%).5 As outlined, all
steps were accomplished in good to excellent yields.
9. Corey, E. J.; Venkateswarlu, A. J. Am. Chem. Soc. 1972,
94, 6190–6191.
10. Dessolin, M.; Guillerez, M.-G.; Thieriet, N.; Guibe, F.;
Loffet, A. Tetrahedron Lett. 1995, 36, 5741–5744.
11. Schmidt, U.; Lieberknecht, A.; Griesser, H.; Talbiersky,
J. J. Org. Chem. 1982, 47, 3261–3264.
12. Carpino, L. A.; Tsao, J.-H. Chem. Commun. 1978, 358–
359.
7. Waki, M.; Kitajima, Y.; Izumiya, N. Synthesis 1981,
266–268.
8. Jetten, M.; Peters, C. A. M.; van Nispen, J. W. F. M.;