Total synthesis of somamide A, an Ahp (3-amino-6-hydroxy-2-piperidone)-containing cyclic depsipeptide

Article abstract of DOI:10.1016/S0040-4039(02)02178-0

The first total synthesis of somamide A (1), an Ahp (3-amino-6-hydroxy-2-piperidone)-containing cyclic depsipeptide, from the marine cyanobacterium Lyngbya majuscula is described. The efficient and stereospecific dehydration of the N-acyl threonine ester using Martin's sulfurane provided the (Z)-2-amino-2-butenoic acid residue. The macrolactamization using FDPP(Ph₂P(O)OC₆F₅), the final installation of the Ahp moiety by oxidation with 1-hydroxy-1,2-benziodoxol-3(1H)-one 1-oxide, and cyclization of the norvaline derivative to the cyclic hemiaminal afforded somamide A (1).

Full text of DOI:10.1016/S0040-4039(02)02178-0

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 8673–8677
Total synthesis of somamide A, an Ahp
(3-amino-6-hydroxy-2-piperidone)-containing cyclic depsipeptide
Fumiaki Yokokawa† and Takayuki Shioiri*,‡
Graduate School of Pharmaceutical Sciences, Nagoya City University, Tanabe-dori, Mizuho-ku, Nagoya 467-8603, Japan
Received 26 August 2002; revised 24 September 2002; accepted 27 September 2002
Abstract—The first total synthesis of somamide A (1), an Ahp (3-amino-6-hydroxy-2-piperidone)-containing cyclic depsipeptide,
from the marine cyanobacterium Lyngbya majuscula is described. The efficient and stereospecific dehydration of the N-acyl
threonine ester using Martin’s sulfurane provided the (Z)-2-amino-2-butenoic acid residue. The macrolactamization using
FDPP(Ph2P(O)OC6F5), the final installation of the Ahp moiety by oxidation with 1-hydroxy-1,2-benziodoxol-3(1H)-one 1-oxide,
and cyclization of the norvaline derivative to the cyclic hemiaminal afforded somamide A (1). © 2002 Elsevier Science Ltd. All
rights reserved.
Marine cyanobacteria have proven to be exceptionally
rich sources of structurally unique and biologically
active natural products.1 Somamide A (1) was isolated
from assemblages of the marine cyanobacteria Lyngbya
majuscula and Schizothrix sp. from the Fijian Islands.2
The structure of this 19-membered macrocyclic depsi-
peptide is quite unique because it has a 3-amino-6-
hydroxy-2-piperidone (Ahp) unit,
a
(Z)-2-amino-
2-butenoic acid unit, and a sulfoxide function. The
Ahp unit can be considered as a glutamate in
Figure 1. Somamide A (1), dolastatin 13 (2), micropeptin T-20 (3), and Ahp.
Keywords: total synthesis; cyclic depsipeptide; marine cyanobacteria; cyclic hemiaminal; dehydroamino acid.
* Corresponding author. Tel./fax: +81-52-832-1555; e-mail: shioiri@ccmfs.meijo-u.ac.jp
† Present address: Tsukuba Research Institute, Novartis Pharma K.K., Ohkubo 8, Tsukuba, Ibaraki 300-2611, Japan.
‡ Present address: Graduate School of Environmental and Human Sciences, Meijo University, Shiogamaguchi, Tempaku, Nagoya 468-8502,
Japan.
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)02178-0

8674
F. Yokokawa, T. Shioiri / Tetrahedron Letters 43 (2002) 8673–8677
8. As shown in Table 1, we first attempted the forma-
tion of the cyclic sulfamidite from 8 using thionyl
chloride, followed by stereospecific elimination with
1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) according to
the Wandless’ method.11 However, the elimination of
the cyclic sulfamidite could only be achieved in low
yield (20%) due to the further a-elimination of the other
O-acyl threonine moiety (entry 1). An alternative one-
pot procedure using thionyl chloride in the presence of
which the side chain carboxyl has been reduced to an
aldehyde and the aldehyde cyclized with n+1 amide
forms a cyclic hemiaminal that is arguably its most
interesting structural feature. The Ahp unit was first
described as a constituent of dolastatin 13 (2), a cyto-
static agent from the sea hare Dolabella auricularia,3
and has been found in several metabolites of blue-green
algae, namely the cyanopeptolins,4 micropeptins,5 nos-
topeptins,6 oscillapeptins,7 symplostatin 2,8 etc. Most
Ahp-containing metabolites have been discovered as
protease inhibitors, and their unprecedented common
structure can participate in converting the cyclic peptide
into a bioactive conformation due to the conformation-
ally restricted structure and hydrogen bonding with the
free hydroxyl group in Ahp. Interests on the synthesis
of biologically intriguing and structurally unique
peptides9 have led us to focus on the synthesis of the
Ahp-containing cyclic depsipeptides, and we have
already succeeded in the synthesis of micropeptin T-20
(3) as its putative structure having the Ahp unit.10 In
this paper, we describe the first total synthesis of
somamide A (1), clearly demonstrating that our strat-
egy for the construction of the Ahp moiety10 is appro-
priate and reasonable (Fig. 1).
Table 1. Dehydrative elimination of the N-acyl threonine
ester 8
Our retrosynthetic approach is shown in Scheme 1. As
shown in our previous paper,10 the precursor of the
Ahp can be the 5-hydroxynorvaline derivative 4, which
should be cyclized at the Abu (2-amino-2-butenoic
acid)/norvaline site thus reducing the risk of racemiza-
tion at the a-chiral center of the C-terminus during the
macrolactamization. The macrocycle 4 was discon-
nected into the three fragments 5–7.
For the synthesis of the Abu-containing depsipeptide
fragment 9, we chose the stereospecific dehydrative
elimination of the corresponding N-acyl threonine ester
Scheme 1.

F. Yokokawa, T. Shioiri / Tetrahedron Letters 43 (2002) 8673–8677
8675
excess triethylamine also gave the Abu fragment 9 in
low yield (entry 2). Burgess reagent12 was also ineffec-
tive for this dehydrative elimination (entry 3). We next
applied the Shanzer’s one-pot protocol13 from 8 using
(diethylamino)sulfur trifluoride (DAST, Et2N–SF3)
with triethylamine as the dehydrative agent to afford 9
in 51% yield (entry 4). Interestingly, the efficient and
stereospecific elimination of 8 was achieved by using
Martin’s sulfurane (diphenyl bis(1,1,1,3,3,3-hexafluoro-
2-phenyl-2-propyl)sulfurane)14 to produce 9 in 63%
yield (entry 5).
threonine ester 16 led to the formation of the depsipep-
tide fragment 5 in 94% yield (Scheme 2).16
The dipeptide
6 was prepared from Boc-(S)-N-
MeTyr(TBDPS)-OTce (17) through acidic removal of
the Boc group followed by coupling with Boc-(S)-Phe-
OH (18) using bis(2-oxo-3-oxazolidinyl)phosphinic
chloride (BopCl)17 in 76% yield (Scheme 3).
The 5-hydroxynorvaline derivative 7 was obtained from
Aloc-(S)-Glu-OBzl (19) by reduction of the side chain
carboxyl group via the mixed anhydride, protection of
the resulting primary alcohol with TBSCl, and hydroly-
sis of the benzyl ester (Scheme 4).
Since the deprotection of the Troc group in 9 led to
complex mixtures, the synthesis of the depsipeptide
fragment 5 was started by installation of the side chain.
Treatment of HCl·(S)-Met-OMe (10) with hexanoyl
chloride gave the N-acyl methionine 11, which was
hydrolyzed and then coupled with HCl·(S)-Thr-OAllyl
(12) using diethyl phosphorocyanidate (DEPC,
(EtO)2P(O)CN)15 to afford the side chain-containing
threonine 13 in 77% yield. Esterification of the
threonine hydroxy group with Boc-(S)-Val-OH (14)
using
N-ethyl-N%-(3-(dimethylamino)propyl)carbodi-
imide hydrochloride (EDC·HCl) gave the ester 15 in
80% yield, which was treated with Pd(Ph3P)4 in the
presence of morpholine, followed by coupling with
HCl·(S)-Thr-OAllyl (12) using DEPC to afford the
N-acyl threonine ester 16 in 82% yield. The new Mar-
tin’s sulfurane mediated elimination of the N-acyl
Scheme 4.
Scheme 2.
Scheme 3.

8676
F. Yokokawa, T. Shioiri / Tetrahedron Letters 43 (2002) 8673–8677

F. Yokokawa, T. Shioiri / Tetrahedron Letters 43 (2002) 8673–8677
8677
With the required building blocks in hand, the fragment
condensation was initiated by deprotection of the Tce
ester18 in 6 and the Boc group in 5, followed by coupling
of the two deprotected fragments using DEPC to give 22
in 69% yield. After acidic removal of the Boc group in
22, condensation with the norvaline derivative 7 and
reprotection of the partially deprotected OH group with
TBSCl produced the linear depsipeptide 23 in 59% yield.
Treatment of 23 with Pd(Ph3P)4 in the presence of
morpholine caused simultaneous removal of the C-termi-
nus allyl ester and the N-terminus Aloc group, and then
the macrolactamization using pentafluorophenyl
diphenylphosphinate (FDPP, Ph2P(O)OC6F5)19 afforded
the macrocyclic depsipeptide 24 in 64% yield. Finally, the
construction of the Ahp moiety was performed by the
strategy described in our previous paper.10 After removal
of the TBS group in 24, treatment of the resulting primary
alcohol 4 using 1-hydroxy-1,2-benziodoxol-3(1H)-one
1-oxide (IBX)20 in DMSO gave a mixture of the aldehyde
and further oxidized methionine sulfoxide, which were
immediately exposed in TBAF to produce the Ahp moiety
through the deprotection of the TBDPS group in Tyr and
cyclization to the hemiaminal. After separation, the major
product (50% yield) was somamide A (1), which was
completely identical in all respects with spectra provided
for the natural product.21 The minor component 25 (39%
yield) was slowly oxidized at the methionine residue under
exposure to ambient atmosphere and characterized by
conversion to somamide A (1) using aq. hydrogen
peroxide in 57% yield. Therefore, our results indicate that
the minor component 25 might be a true natural product
and somamide A (1) is an artifact (Scheme 5).
2. Nogle, L. M.; Williamson, R. T.; Gerwick, W. H. J. Nat.
Prod. 2001, 64, 716–719.
3. Pettit, G. R.; Kamano, Y.; Herald, C. L.; Dufresne, C.;
Cerny, R. L.; Herald, D. L.; Schmidt, J. M.; Kizu, H. J.
Am. Chem. Soc. 1989, 111, 5015–5017.
4. Martin, C.; Oberer, L.; Ino, T.; Kunig, W. A.; Busch, M.;
Weckesser, J. J. Antibiot. 1993, 46, 1550–1556.
5. Okino, T.; Murakami, M.; Haraguchi, R.; Munekata, H.;
Matsuda, H.; Yamaguchi, K. Tetrahedron Lett. 1993, 34,
8131–8134.
6. Okino, T.; Sun, Q.; Matsuda, H.; Murakami, M.;
Yamaguchi, K. J. Nat. Prod. 1997, 60, 158–161.
7. Sano, T.; Kaya, K. J. Nat. Prod. 1996, 59, 90–92.
8. Harrigan, G. G.; Luesch, H.; Yoshida, W. Y.; Moore, R.
E.; Nagle, D. G.; Paul, V. J. J. Nat. Prod. 1999, 62,
655–658.
9. For a review, see Shioiri, T.; Hamada, Y. Synlett 2001,
184–201.
10. Yokokawa, F.; Inaizumi, A.; Shioiri, T. Tetrahedron Lett.
2001, 42, 5903–5908.
11. Stohlmeyer, M. M.; Tanaka, H.; Wandless, T. J. J. Am.
Chem. Soc. 1999, 121, 6100–6101.
12. Burgess, E. M.; Penton, H. R., Jr.; Taylor, E. A. J. Org.
Chem. 1973, 38, 26–31.
13. Somekh, L.; Shanzer, A. J. Org. Chem. 1983, 48, 907–
908.
14. Arhart, R. J.; Martin, J. C. J. Am. Chem. Soc. 1972, 94,
5003–5010.
15. Takuma, S.; Hamada, Y.; Shioiri, T. Chem. Pharm. Bull.
1982, 30, 3147–3153 and references cited therein.
16. Deoxo-fluor/Et3N gave 5 in 48% yield. Deoxo-fluor
(bis(2-methoxyethyl)aminosulfur trifluoride) see: Lal, G.
S.; Pez, G. P.; Pesaresi, R. J.; Prozonic, F. M.; Cheng, H.
J. Org. Chem. 1999, 64, 7048–7054.
Insummary, wehaveaccomplishedthefirsttotalsynthesis
of somamide A (1), and demonstrated that our strategy
for the construction of the Ahp moiety is suitable to the
synthesis of the Ahp-containing natural products. Fur-
thermore, we have found that Martin’s sulfurane is a
powerful agent for the dehydrative elimination of the
N-acyl b-hydroxy-a-amino acid esters to the a,b-dehy-
droamino acid esters.22
17. Tung, R. D.; Rich, D. H. J. Am. Chem. Soc. 1985, 107,
4342–4343.
18. Dong, Q.; Anderson, C. E.; Ciufolini, M. A. Tetrahedron
Lett. 1995, 32, 5681–5682.
19. (a) Chen, S.; Xu, J. Tetrahedron Lett. 1991, 32, 6711–
6714; (b) Dudash, J., Jr.; Jiang, J.; Mayer, S. C.; Joullie,
M. M. Synth. Commun. 1993, 23, 349–356; (c) Deng, J.;
Hamada, Y.; Shioiri, T.; Matsunaga, S.; Fusetani, N.
Angew. Chem. Int. Ed. Engl. 1994, 33, 1729–1731; (d)
Deng, J.; Hamada, Y.; Shioiri, T. Synthesis 1998, 627–
638; (e) Yokokawa, F.; Sameshima, H.; Shioiri, T. Syn-
lett 2001, 986–988.
Acknowledgements
20. Frigerio, M.; Santagostino, M.; Sputore, S.; Palmisano,
This work was financially supported in part by Grant-in-
Aids from the Uehara Memorial Foundation (to F.Y.),
the Fujisawa Foundation (to F.Y.), and the Ministry of
Education, Science, Sports and Culture, Japan. We thank
G. J. Org. Chem. 1995, 60, 7272–7276.
21. The relative stereochemistry for the Ahp residue has been
confirmed from the ROESY correlations shown below
(Ref. 8).
1
Professor William H. Gerwick for providing us the H
and13CNMRspectraofsomamideA. Thehighresolution
FAB mass spectra were measured by Dr. Hideo Naoki
andMr. TsuyoshiFujita(SuntoryInstituteforBioorganic
Research), to whom the authors’ thanks are due.
References
1. (a) Barja, A. M.; Banaigs, B.; Abou-Mansor, E.; Burgess,
J. G.; Wright, P. C. Tetrahedron 2001, 57, 9347–9377; (b)
Gerwick, W. H.; Tan, L. T.; Sitachitta, N. In The Alka-
loids; Cordell, G. A., Ed.; Academic Press, 2001; pp.
75–184.
22. The details will be reported in the following paper:
Yokokawa, F.; Shioiri, T. Tetrahedron Lett. 2002, 43,
8679–8682.